I. Synthetic Studies Toward the Total Synthesis of Polycyclic Natural Products – Communesin F, Perophoramidine and Ineleganolide. II. Nickel Catalyzed Intramolecular C–O Bond Formation Citation Han, Seojung (2016) I. Synthetic Studies Toward the Total Synthesis of Polycyclic Natural Products – Communesin F, Perophoramidine and Ineleganolide. II. Nickel Catalyzed Intramolecular C–O Bond Formation. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9NV9G6M. https://resolver.caltech.edu/CaltechTHESIS:05172016-222905476 Abstract Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Finally, a previously unknown mild and efficient deprotection protocol for the o-nitrobenzyl group is disclosed – this serendipitous discovery permitted a concise endgame for the formal syntheses of both communesin F and perophoramidine. In addition, the atroposelective synthesis of PINAP ligands has been accomplished via a palladium-catalyzed C–P coupling process through dynamic kinetic resolution. These catalytic conditions allow access to a wide variety of alkoxy- and benzyloxy-substituted PINAP ligands in high enantiomeric excess. An efficient and exceptionally mild intramolecular nickel-catalyzed carbon–oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step. Finally, synthetic studies toward polycyclic ineleganolide are described. The entire fragmented carbon framework has been constructed from this work. Highly (Z)-selective olefination was achieved by the method by the Ando group. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Synthesis; Natural Products; Communesin F; Perophoramidine; PINAP; Dynamic kinetic resolution; Cross-coupling; Ineleganolide Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Stoltz, Brian M. Thesis Committee: Reisman, Sarah E. (chair) Stoltz, Brian M. Agapie, Theodor Grubbs, Robert H. Defense Date: 13 May 2016 Funders: Funding Agency Grant Number Fulbright 15111120 ILJU Foundation of Education & Culture UNSPECIFIED Record Number: CaltechTHESIS:05172016-222905476 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:05172016-222905476 DOI: 10.7907/Z9NV9G6M Related URLs: URL URL Type Description http://dx.doi.org/10.1021/ol5013263 DOI Article adapted for ch.1 http://dx.doi.org/10.1021/jo502534g DOI Article adapted for ch.1 http://dx.doi.org/10.1021/ar5004658 DOI Article adapted for ch.1 http://dx.doi.org/10.1016/j.tetlet.2014.10.006 DOI Article adapted for ch.2 http://dx.doi.org/10.1002/anie.201601991 DOI Article adapted for ch.4 http://dx.doi.org/10.1016/j.tet.2014.10.065 DOI Article adapted for appendix 4 http://dx.doi.org/10.1016/j.tetlet.2016.04.022 DOI Article adapted for appendix 11 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 9727 Collection: CaltechTHESIS Deposited By: Seojung Han Deposited On: 19 May 2016 21:22 Last Modified: 08 Nov 2023 00:39 Thesis Files Preview PDF (Thesis_Full) - Final Version See Usage Policy. 37MB Preview PDF (Title/TOC/Abstract) - Final Version See Usage Policy. 645kB Preview PDF (Chapter 1) - Final Version See Usage Policy. 19MB Preview PDF (Chapter 2) - Final Version See Usage Policy. 1MB Preview PDF (Chapter 3) - Final Version See Usage Policy. 2MB Preview PDF (Chapter 4) - Final Version See Usage Policy. 10MB Preview PDF (Chapter 5) - Final Version See Usage Policy. 3MB Preview PDF (Bibliography/About the author) - Final Version See Usage Policy. 2MB Repository Staff Only: item control page

I. SYNTHETIC STUDIES TOWARD THE TOTAL SYNTHESIS OF POLYCYCLIC NATURAL PRODUCTS – COMMUNESIN F, PEROPHORAMIDINE AND INELEGANOLIDE II. NICKEL CATALYZED INTRAMOLECULAR C–O BOND FORMATION Thesis by Seojung Han In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 2016 (Defended May 13, 2016)    ii   © 2016 Seojung Han All Rights Reserved    iii   To my family, for their unwavering support and dedication iv ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor, Professor Brian M. Stoltz, for helping me tremendously during my graduate work. Brian has been very generous and supportive advisor who always encourages me to come up with new ideas. He expects us to be creative, thoughtful and curious in what we do. He has offered a lot of guidance in terms of not only chemistry, but also personal development. Brian is an endless source of knowledge and ideas. Whenever I have discussed my project with Brian, I have always become motivated. It is impossible to thank him enough for his mentorship and kindness. I have been fortunate to have him as an advisor over the last five years. My committee members Prof. Sarah E. Reisman, Prof. Theodor Agapie, and Prof. Robert H. Grubbs have provided me with valuable advice on my research and career. Sarah has served as a role model for a great female scientist. She is a generous and thoughtful committee member who has helped me to develop my scientific interests. Theo provided me with scientific insights on transition metalcatalyzed transformations. Bob, who is the final member of my committee, has encouraged me to think about my proposals and chemistry from a broader perspective. I am grateful for all the guidance from my thesis committee. In addition, I would like to thank Dr. Scott C. Virgil of the Caltech Center for Catalysis and Chemical Synthesis. While I was conducting a DKR project with him, he provided me with lots of unique scientific aspects. He also keeps analytical instruments running for us. I also want to thank my past advisors. I am especially thankful to Prof. DuckHyung Lee who was my former advisor at Sogang University. When I was an v undergraduate student, I enjoyed taking his lectures. He motivated me to pursue graduate work in organic chemistry. I learned a great deal of both theoretical and experimental aspects of organic chemistry and developed a stronger synthetic chemistry foundation while I was doing research in his group. Prof. Duck-Hyung Lee deeply cares about his students. He has been a great mentor to me and I cannot thank him enough for his kindness. Dr. Jin Hee Ahn, who was my advisor at Korea Research Institute of Chemical Technology, expanded my interest to medicinal chemistry. He has been supportive and generous to me. I am thankful for all of the patience and guidance from my past advisors. I have been lucky to work with great individuals in the Stoltz group. When I first joined lab, Dr. Florian Vogt, who was doing a project concerning the synthesis of communesin F and perophoramidine, was preparing to leave for his new job. Although I only spent time with him in the lab for about 10 days, I appreciate his helpful discussion, compounds and chemicals. I also want to thank to Dr. Vikram Bhat, who introduced the DKR project to me. In my 4th year, I took a project concerning the total synthesis of ineleganolide from Dr. Rob Craig. I really appreciate his valuable discussion and all the support. It has also been a pleasure to work with Dr. Ryohei Doi, who was a visiting student from Japan, on Ni-catalyzed etherification reactions. Thanks to the Caltech SURF program, I had opportunities to be a mentor for several undergraduate students. My first undergraduate mentee was Yoobin Koh, who came from GIST, Korea. Yoobin was passionate about learning chemistry. Gabriel Fernando de Melo was another mentee from Brazil in the following year. He helped me to explore a project concerning a new method for the cleavage of nitrobenzyl amides and ethers. I am thankful for his hard work on the vi project. I would also like to thank Katherine Bay, who brought a cheerful attitude to the lab. I need to thank all of the Stoltz group members, past and present, for the help that I have received for last five years. First of all, I would like to thank Kelly Kim and Nicholas O’Connor, who are the members of my class within the Stoltz lab. Kelly and Nick are very kind and always volunteer to help me. When we were the 1st and 2nd years of students, Kelly, Nick, Anton (formal Stoltz group member), and I sometimes hung out, played video games at Kelly’s house, and drunk margaritas or beers. I really enjoyed all the activities with them. I also thank Prof. Wen-Bo (Boger) Liu, who was my hoodmate for the last four years. He is a brilliant organic chemist and I really appreciate his helpful discussion and contribution to my development as a chemist. We also enjoyed talking about the cultural differences between USA, Korea, and China. I am certain that he will have a successful career in academia at Wuhan University in China. When I visited Caltech as a prospective student in March 2011, Prof. Jimin Kim, who is a postdoctoral alumnus in the Stoltz group, introduced the Stoltz group to me during the poster session. Jimin and I used to have a lunch together and I enjoyed conversation with her. I am grateful to her for guidance and mentorship. I believe that she will be successful in academia at Chonnam National University in Korea. I also want to thank Dr. Allen Hong, who was one of my baymates. I think he is one of the most diligent people that I have met. He is very brilliant and I appreciate his helpful discussions on my chemistry. In addition, Dr. Chung Whan Lee is thanked for helping me to settle down in the lab in the early days. To Prof. Hosea Nelson, Dr. Alex Goldberg, Dr. Nathan Bennett, Dr. Jeff Holder, Dr. Christopher Haley, Dr. Yoshitaka Numajiri, Doug Duquette, Dr. Doug Behenna, Dr. Corey Reeves, Dr. Yiyang Liu, Dr. Jared Moore, Dr. Eric Welin, vii Dr. Daisuke Saito, Dr. Max Klatte, Dr. Caleb Hethcox, Dr. Marchello Cavitt, Dr. Hendrik F. T. Klare, Dr. Guillaume Lapointe, Dr. Marc Linger, Dr. Alex N. Marziale, Dr. Noriko Okamoto, Dr. Grant Shibuya, Dr. Kristy Tran, Dr. Kun-Liang (Phil) Wu, Dr. Xiangyou Xing, Dr. Jonny Gordon, thank you all for your mentorship and guidance. To the younger students I have had the pleasure to work with, Sam, Beau, Shoshana, Kelvin, Eric, Elizabeth, Jiaming, Carina, Steven, Fa, Chris, Alex, David, and Austin, thank you for all of the support and I wish you all best throughout the rest of your time at Caltech. I especially thank to the numerous people who have helped look over my research proposals, manuscripts, and thesis chapters over the years. I also want to thank to the members of the Reisman group and the Grubbs group for helpful scientific discussion and the sharing of numerous resources. I especially want to acknowledge Kangway Chuang for insightful discussion. I would like to thank to Hyun Gi Yun, who is a graduate student in the Clemons lab and Dr. Sarah Yunmi Lee, who graduated from the Fu lab. I always enjoyed spending time with them. Hyun Gi and Yunmi have been there since the beginning. I also need to thank one of my best friends, Songi Han, who is a graduate student at Rice University studying bioengineering. Songi has accompanied me during my trips to LA, Houston, and Seattle. Songi and I are on the same wavelength. She has provided me the emotional anchoring during the most difficult moments of graduate school. I am deeply indebted to the Fulbright for providing me fellowship during my first two years of graduate school. I would also like to thank the Ilju Foundation of Education & Culture for the pre-doctoral research fellowship during the last three years of graduate school. viii I also want to thank tremendous support from the Caltech staff. Dr. Dave VanderVelde has helped me to analyze complicated NMR data sets for hours and taught me how to use MestReNova program efficiently. In addition, I must thank Larry Henling for providing lots of crucial X-ray crystal structures for my communesin F and perophoramidine project. Also, thanks Lynne Martinez, who is the administrative assistant for our group and the Reisman group, for keeping things running smoothly on a daily basis. I also want to thank Rick Gerhart for helping repair glassware, Dr. Mona Shahgholi and Naseem for helping to obtain HRMS data, Jeff Groseth for his expertise and service to our group, and Agnes Tong for helping with administrative duties. Finally, I would like to acknowledge my lovely family who has always supported me. Dad, Mom, and Sangjun, who always pray for me, have been the most warm and supporting family I could ever ask for. Without their dedication and support, I would not be where I am today. I would also like to thank my aunt, Yuri and her husband. They live in LA and we have occasionally met and had a dinner. We had a trip to Sedona during my first vacation. Thanks to them, it has been very easy for me to get used to life in USA. Without the continued support of all of these people, I would not have made it here.    ix   ABSTRACT Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Finally, a previously unknown mild and efficient deprotection protocol for the onitrobenzyl group is disclosed – this serendipitous discovery permitted a concise endgame for the formal syntheses of both communesin F and perophoramidine. In addition, the atroposelective synthesis of PINAP ligands has been accomplished via a palladium-catalyzed C–P coupling process through dynamic kinetic resolution. These catalytic conditions allow access to a wide variety of alkoxy- and benzyloxy-substituted PINAP ligands in high enantiomeric excess. An efficient and exceptionally mild intramolecular nickel-catalyzed carbon– oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step. Finally, synthetic studies toward polycyclic ineleganolide are described. The entire fragmented carbon framework has been constructed from this work. Highly (Z)-selective olefination was achieved by the method by the Ando group.    x   PUBLISHED CONTENT AND CONTRIBUTIONS   1. Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. A Diastereodivergent Synthetic Strategy for the Syntheses of Communesin F and Perophoramidine. Org. Lett. 2014, 16, 3316–3319. DOI: 10.1021/ol5013263. Han, S.-J. participated in designing the synthesis, synthesized compounds, prepared the data, crystalized the key compounds and wrote the manuscript. 2. Han, S.-J.; Fernando de Melo, G.; Stoltz, B. M. A New Method for the Cleavage of Nitrobenzyl Amides and Ethers. Tetrahedron Lett. 2014, 55, 6467–6469. DOI: 10.1016/j.tetlet.2014.10.006. Han, S.-J. optimized reaction conditions, prepared substrates, investigated the new methodology, characterized compounds, and wrote the manuscript. 3. Lee, C. W.; Han, S.-J.; Virgil, S. C.; Stoltz, B. M. Stereochemical evaluation of bis(phosphine) copper catalysts for the asymmetric alkylation of 3-bromooxindoles with α-arylated malonate esters. Tetrahedron 2015, 71, 3666–3670. DOI: 10.1016/j.tet.2014.10.065. Han, S.-J. participated in optimizing reaction conditions, prepared substrates, and participated in the writing of the manuscript. 4. Han, S.-J.; Vogt, F.; May, J. A.; Krishnan, S.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Evolution of a Unified, Sterodivergent Approach to the Synthesis of Communesin F and Perophoramidine. J. Org. Chem. 2015, 80, 528–547. DOI: 10.1021/jo502534g. Han, S.-J. participated in designing the synthesis, synthesized compounds, prepared the data, crystalized the key compounds and wrote the manuscript. 5. Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the    xi   Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740–751. DOI: 10.1021/ar5004658. Han, S.-J. participated in the writing of the manuscript. 6. Han, S.-J.; Stoltz, B. M. A mild and efficient approach to enantioenriched αhydroxyethyl α,β-unsaturated δ-lactams. Tetrahedron Lett. 2016, 57, 2233–2235. DOI: 10.1016/j.tetlet.2016.04.022. Han, S.-J. designed the synthesis, synthesized the compounds, prepared the data and wrote the manuscript. 7. Han, S.-J.; Doi, R.; Stoltz, B. M. Nickel-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers. Angew. Chem., Int. Ed. 2016, DOI: 10.1002/anie.201601991; Angew. Chem. 2016, DOI: 10.1002/ange.201601991. Han, S.-J. participated in optimizing the reaction parameters, synthesized substrates, investigated the new reactions, prepared the data, and wrote the manuscript.        xii   TABLE OF CONTENTS   Acknowledgements ..........................................................................................iv Abstract ...........................................................................................................ix Published Content and Contributions ................................................................x Table of Contents ............................................................................................xii List of Figures ................................................................................................ xvii List of Schemes ........................................................................................... xxxii List of Tables ............................................................................................... xxxv List of Abbreviations .................................................................................. xxxix CHAPTER 1                              1 The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine       1.1. Introduction .................................................................................................... 1 1.2. Results and Discussion ..................................................................................... 4 1.2.1. Biosynthesis-Inspired Diels–Alder Cycloaddition Strategy to Communesin F .. 4 1.2.2. An Alkylation Route to Communesin F .......................................................... 12 1.2.3. Formal Synthesis of Communesin F (1f) ......................................................... 18 1.2.4. Formal Synthesis of Perophoramidine (3) ...................................................... 28 1.3. Conclusion ................................................................................................... 32 1.4. Experimental Methods and Analytical Data .................................................... 33 1.4.1. Materials and Methods ................................................................................... 33 1.4.2. Experimental Procedures ................................................................................ 34 1.5. References and Notes .................................................................................. 105   APPENDIX 1 Spectra Relevant to Chapter 1   112 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1     211 A2.1. X-Ray Crystal Structure Analysis of 24 .......................................................... 212 A2.2. X-Ray Crystal Structure Analysis of 37 .......................................................... 220 A2.3. X-Ray Crystal Structure Analysis of 42 .......................................................... 228 A2.4. X-Ray Crystal Structure Analysis of 51 .......................................................... 234    xiii   A2.5. X-Ray Crystal Structure Analysis of 52 .......................................................... 242 A2.6. X-Ray Crystal Structure Analysis of 61 .......................................................... 252 A2.7. X-Ray Crystal Structure Analysis of 62 .......................................................... 260 A2.8. X-Ray Crystal Structure Analysis of 72 .......................................................... 265 A2.9. X-Ray Crystal Structure Analysis of 73 .......................................................... 273 A2.10. X-Ray Crystal Structure Analysis of 72 .......................................................... 284 A2.11. X-Ray Crystal Structure Analysis of 94 .......................................................... 297   APPENDIX 3 Synthetic Studies Toward the Total Synthesis of Communesin F 304 A3.1. Direct Lactam–Forming Strategy ................................................................ 304 A3.2. Diels–Alder Strategy ..................................................................................... 306 A3.3. Intramolecular Alkylation of 3-Bromooxindole Strategy ............................... 309 A3.4. Experimental Methods and Analytical Data .................................................. 310 A3.4.1. Materials and Methods ................................................................................. 310 A3.4.2. Experimental Procedures .............................................................................. 312 A3.5. References and Notes .................................................................................. 317   APPENDIX 4 318   Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters   A4.1. Introduction ................................................................................................. 318 A4.2. Results and Discussion ................................................................................. 320 A4.2.1. Initial Screening Results .............................................................................. 320 A4.2.2. Ligand Screening and Optimization Studies ................................................ 322 A4.3. Conclusion .................................................................................................. 326 A4.4. Selected Experiments ................................................................................... 327 A4.4.1. Synthesis of (±)-136 ..................................................................................... 327 A4.4.2. Ligand Screening Procedure ......................................................................... 328 A4.5. References and Notes .................................................................................. 329   APPENDIX 5 Spectra Relevant to Appendix 4     331 CHAPTER 2                                                                      334 A New Method for the Cleavage of Nitrobenzyl Amides and Ethers     2.1. Introduction ................................................................................................. 334    xiv   2.2. Results and Discussion ................................................................................. 335 2.3. Conclusion .................................................................................................. 339 2.4. Experimental Methods and Analytical Data .................................................. 339 2.4.1. Materials and Methods ................................................................................. 339 2.4.2. Experimental Procedures .............................................................................. 340 2.5. References and Notes .................................................................................. 346   APPENDIX 6 Spectra Relevant to Chapter 2     348 CHAPTER 3                                                                      361 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.1. Introduction ................................................................................................. 361 3.2. Results and Discussion ................................................................................. 362 3.3. Conclusion .................................................................................................. 366 3.4. Experimental Methods and Analytical Data .................................................. 367 3.4.1. Materials and Methods ................................................................................. 367 3.4.2. Experimental Procedures .............................................................................. 369 3.4.3. Spectroscopic Data ...................................................................................... 371 3.5. References and Notes .................................................................................. 382   APPENDIX 7 Spectra Relevant to Chapter 3     CHAPTER 4               Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   386                                                      419 4.1. Introduction ................................................................................................. 419 4.2. Results and Discussion ................................................................................. 420 4.3. Conclusion .................................................................................................. 427 4.4. Experimental Methods and Analytical Data .................................................. 427 4.4.1. Materials and Methods ................................................................................. 427 4.4.2. Experimental Procedures .............................................................................. 429 4.5. References and Notes .................................................................................. 459   APPENDIX 8 Spectra Relevant to Chapter 4     465    xv   APPENDIX 9                                                                  570 Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement A9.1. Claisen Rearrangement ................................................................................ 570 A9.2. Experimental Methods and Analytical Data .................................................. 571 A9.2.1. Materials and Methods ................................................................................. 571 A9.2.2. Experimental Procedures .............................................................................. 573 APPENDIX 10 Spectra Relevant to Appendix 9     576 APPENDIX 11 Synthetic Studies Toward Alistonitrine A   583 A11.1. Introduction ................................................................................................ 583 A11.2. Results and Discussion ................................................................................. 584 A11.3. Experimental Methods and Analytical Data .................................................. 590 A11.3.1. Materials and Methods ................................................................................. 590 A11.3.2. Experimental Procedures .............................................................................. 591 A11.4. References and Notes ..................................................................... 607     APPENDIX 12 Spectra Relevant to Appendix 11     CHAPTER 5               Synthetic Studies Toward Polycyclic Ineleganolide 612                                                      635 5.1. Introduction ................................................................................................. 635 5.2. Results and Discussion ................................................................................. 637 5.3. Conclusion .................................................................................................. 649 5.4. Experimental Methods and Analytical Data .................................................. 649 5.4.1. Materials and Methods ................................................................................. 649 5.4.2. Experimental Procedures .............................................................................. 651 5.5. References and Notes .................................................................................. 674   APPENDIX 13 Spectra Relevant to Chapter 5       APPENDIX 14 Notebook Cross-Reference for New Compounds 679 724    xvi   A14.1. Contents ......................................................................................... 724 A14.2. Notebook Cross-Reference Tables ................................................... 725     Comprehensive Bibliography ....................................................................... 744 Index ........................................................................................................... 761 About the Author ......................................................................................... 764              xvii   LIST OF FIGURES   CHAPTER 1 The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine Figure 1.1.1. Communesins (1), Nomofungin (2), and Perophoramidine (3) .......................... 3 Figure 1.2.1. X-ray Structure of Bridged Polycycle 24 ..................................................... 9 Figure 1.2.2. X-ray Structure of Chloroindoline 29 ....................................................... 12 Figure 1.2.3. X-ray Structure of Lactam 32 ................................................................. 12 Figure 1.2.4. X-ray Structure of Oxindole Adduct 42 .................................................... 15 Figure 1.2.5. X-ray Structure of Pyrrolidinoindoline 72 ................................................. 23 APPENDIX 1 Spectra Relevant to Chapter 1 Figure A1.1. 1H NMR (300 MHz, CDCl3) of compound SI-1-11 ......................................113 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound SI-1-11 ............................114 Figure A1.3. 13C NMR (75 MHz, CDCl3) of compound SI-1-11 .......................................114 Figure A1.4. 1H NMR (300 MHz, CDCl3) of compound 35 ............................................115 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 35 ..................................116 Figure A1.6. 13C NMR (75 MHz, CDCl3) of compound 35 .............................................116 Figure A1.7. 1H NMR (300 MHz, CDCl3) of compound 37 ............................................117 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 37 ..................................118 Figure A1.9. 13C NMR (75 MHz, CDCl3) of compound 37 .............................................118 Figure A1.10. 1H NMR (300 MHz, CDCl3) of compound 39 ..........................................119 Figure A1.11. Infrared spectrum (Thin Film, NaCl) of compound 39 ................................120 Figure A1.12. 13C NMR (75 MHz, CDCl3) of compound 39 ...........................................120 Figure A1.13. 1H NMR (300 MHz, CDCl3) of compound SI-1-13 ....................................121 Figure A1.14. Infrared spectrum (Thin Film, NaCl) of compound SI-1-13 ..........................122 Figure A1.15. 13C NMR (75 MHz, CDCl3) of compound SI-1-13 .....................................122 Figure A1.16. 1H NMR (300 MHz, CDCl3) of compound 40 ..........................................123 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 40 ................................124 Figure A1.18. 13C NMR (75 MHz, CDCl3) of compound 40 ...........................................124 Figure A1.19. 1H NMR (300 MHz, CDCl3) of compound 42 ..........................................125 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 42 ................................126 Figure A1.21. 13C NMR (75 MHz, CDCl3) of compound 42 ...........................................126 Figure A1.22. 1H NMR (500 MHz, CDCl3) of compound 44 ..........................................127 Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 44 ................................128 Figure A1.24. 13C NMR (125 MHz, CDCl3) of compound 44 ..........................................128    xviii   Figure A1.25. H NMR (500 MHz, CDCl3) of compound 45 ..........................................129 1 Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 45 ................................130 Figure A1.27. 13C NMR (125 MHz, CDCl3) of compound 45 ..........................................130 Figure A1.28. 1H NMR (500 MHz, CDCl3) of compound 46 ..........................................131 Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 46 ................................132 Figure A1.30. 13C NMR (125 MHz, CDCl3) of compound 46 ..........................................132 Figure A1.31. 1H NMR (500 MHz, CDCl3) of compound 47 ..........................................133 Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 47 ................................134 Figure A1.33. 13C NMR (125 MHz, CDCl3) of compound 47 ..........................................134 Figure A1.34. 1H NMR (500 MHz, CDCl3) of compound 48 ..........................................135 Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 48 ................................136 Figure A1.36. 13C NMR (125 MHz, CDCl3) of compound 48 ..........................................136 Figure A1.37. 1H NMR (500 MHz, CDCl3) of compound 49 ..........................................137 Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 49 ................................138 Figure A1.39. 13C NMR (125 MHz, CDCl3) of compound 49 ..........................................138 Figure A1.40. 1H NMR (400 MHz, CDCl3) of compound 50 ..........................................139 Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 50 ................................140 Figure A1.42. 13C NMR (100 MHz, CDCl3) of compound 50 ..........................................140 Figure A1.43. 1H NMR (400 MHz, CDCl3) of compound 51 ..........................................141 Figure A1.44. Infrared spectrum (Thin Film, NaCl) of compound 51 ................................142 Figure A1.45. 13C NMR (100 MHz, CDCl3) of compound 51 ..........................................142 Figure A1.46. 1H NMR (500 MHz, CDCl3) of compound 52 ..........................................143 Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 52 ................................144 Figure A1.48. 13C NMR (125 MHz, CDCl3) of compound 52 ..........................................144 Figure A1.49. 1H NMR (500 MHz, CDCl3) of compound SI-1-16 ....................................145 Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound SI-1-16 ..........................146 Figure A1.51. 13C NMR (125 MHz, CDCl3) of compound SI-1-16....................................146 Figure A1.52. 1H NMR (500 MHz, CDCl3) of compound 59 ..........................................147 Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 59 ................................148 Figure A1.54. 13C NMR (125 MHz, CDCl3) of compound 59 ..........................................148 Figure A1.55. 1H NMR (500 MHz, CDCl3) of compound SI-1-17 ....................................149 Figure A1.56. Infrared spectrum (Thin Film, NaCl) of compound SI-1-17 ..........................150 Figure A1.57. 13C NMR (125 MHz, CDCl3) of compound SI-1-17....................................150 Figure A1.58. 1H NMR (500 MHz, CDCl3) of compound 57 ..........................................151 Figure A1.59. Infrared spectrum (Thin Film, NaCl) of compound 57 ................................152 Figure A1.60. 13C NMR (125 MHz, CDCl3) of compound 57 ..........................................152 Figure A1.61. 1H NMR (500 MHz, CDCl3) of compound SI-1-18 ....................................153 Figure A1.62. Infrared spectrum (Thin Film, NaCl) of compound SI-1-18 ..........................154    xix   Figure A1.63. C NMR (125 MHz, CDCl3) of compound SI-1-18....................................154 13 Figure A1.64. 1H NMR (500 MHz, CDCl3) of compound 60 ..........................................155 Figure A1.65. Infrared spectrum (Thin Film, NaCl) of compound 60 ................................156 Figure A1.66. 13C NMR (125 MHz, CDCl3) of compound 60 ..........................................156 Figure A1.67. 1H NMR (500 MHz, CDCl3) of compound 61 ..........................................157 Figure A1.68. Infrared spectrum (Thin Film, NaCl) of compound 61 ................................158 Figure A1.69. 13C NMR (125 MHz, CDCl3) of compound 61 ..........................................158 Figure A1.70. 1H NMR (500 MHz, CDCl3) of compound 62 ..........................................159 Figure A1.71. Infrared spectrum (Thin Film, NaCl) of compound 62 ................................160 Figure A1.72. 13C NMR (125 MHz, CDCl3) of compound 62 ..........................................160 Figure A1.73. 1H NMR (500 MHz, CDCl3) of compound 63 ..........................................161 Figure A1.74. Infrared spectrum (Thin Film, NaCl) of compound 63 ................................162 Figure A1.75. 13C NMR (125 MHz, CDCl3) of compound 63 ..........................................162 Figure A1.76. 1H NMR (500 MHz, CDCl3) of compound 65 ..........................................163 Figure A1.77. Infrared spectrum (Thin Film, NaCl) of compound 65 ................................164 Figure A1.78. 13C NMR (125 MHz, CDCl3) of compound 65 ..........................................164 Figure A1.79. 1H NMR (500 MHz, DMSO) of compound 67..........................................165 Figure A1.80. Infrared spectrum (Thin Film, NaCl) of compound 67 ................................166 Figure A1.81. 13C NMR (125 MHz, DMSO) of compound 67 .........................................166 Figure A1.82. 1H NMR (500 MHz, CDCl3) of compound SI-1-19 ....................................167 Figure A1.83. Infrared spectrum (Thin Film, NaCl) of compound SI-1-19 ..........................168 Figure A1.84. 13C NMR (125 MHz, CDCl3) of compound SI-1-19....................................168 Figure A1.85. 1H NMR (500 MHz, CDCl3) of compound 68 ..........................................169 Figure A1.86. Infrared spectrum (Thin Film, NaCl) of compound 68 ................................170 Figure A1.87. 13C NMR (125 MHz, CDCl3) of compound 68 ..........................................170 Figure A1.88. 1H NMR (500 MHz, CDCl3) of compound 69 ..........................................171 Figure A1.89. Infrared spectrum (Thin Film, NaCl) of compound 69 ................................172 Figure A1.90. 13C NMR (125 MHz, CDCl3) of compound 69 ..........................................172 Figure A1.91. 1H NMR (500 MHz, CDCl3) of compound 54 ..........................................173 Figure A1.92. Infrared spectrum (Thin Film, NaCl) of compound 54 ................................174 Figure A1.93. 13C NMR (125 MHz, CDCl3) of compound 54 ..........................................174 Figure A1.94. 1H NMR (300 MHz, CDCl3) of compound 71 ..........................................175 Figure A1.95. Infrared spectrum (Thin Film, NaCl) of compound 71 ................................176 Figure A1.96. 13C NMR (125 MHz, CDCl3) of compound 71 ..........................................176 Figure A1.97. 1H NMR (600 MHz, CDCl3) of compound 72 ..........................................177 Figure A1.98. Infrared spectrum (Thin Film, NaCl) of compound 72 ................................178 Figure A1.99. 13C NMR (125 MHz, CDCl3) of compound 72 ..........................................178 Figure A1.100. 1H NMR (600 MHz, CDCl3) of compound 73 .........................................179    xx   Figure A1.101. Infrared spectrum (Thin Film, NaCl) of compound 73...............................180 Figure A1.102. 13C NMR (125 MHz, CDCl3) of compound 73 ........................................180 Figure A1.103. 1H NMR (500 MHz, CDCl3) of compound 74 .........................................181 Figure A1.104. Infrared spectrum (Thin Film, NaCl) of compound 74...............................182 Figure A1.105. 13C NMR (125 MHz, CDCl3) of compound 74 ........................................182 Figure A1.106. 1H NMR (300 MHz, CDCl3) of compound 75 .........................................183 Figure A1.107. Infrared spectrum (Thin Film, NaCl) of compound 75...............................184 Figure A1.108. 13C NMR (125 MHz, CDCl3) of compound 75 ........................................184 Figure A1.109. 1H NMR (500 MHz, CDCl3) of compound 76 .........................................185 Figure A1.110. Infrared spectrum (Thin Film, NaCl) of compound 76...............................186 Figure A1.111. 13C NMR (125 MHz, CDCl3) of compound 76 ........................................186 Figure A1.112. 1H NMR (500 MHz, CDCl3) of compound 78 .........................................187 Figure A1.113. Infrared spectrum (Thin Film, NaCl) of compound 78...............................188 Figure A1.114. 13C NMR (125 MHz, CDCl3) of compound 78 ........................................188 Figure A1.115. 1H NMR (500 MHz, CDCl3) of compound SI-1-20...................................189 Figure A1.116. Infrared spectrum (Thin Film, NaCl) of compound SI-1-20 ........................190 Figure A1.117. 13C NMR (125 MHz, CDCl3) of compound SI-1-20 ..................................190 Figure A1.118. 1H NMR (500 MHz, CDCl3) of compound 79 .........................................191 Figure A1.119. Infrared spectrum (Thin Film, NaCl) of compound 79...............................192 Figure A1.120. 13C NMR (125 MHz, CDCl3) of compound 79 ........................................192 Figure A1.121. 1H NMR (500 MHz, CDCl3) of compound 53 .........................................193 Figure A1.122. Infrared spectrum (Thin Film, NaCl) of compound 53...............................194 Figure A1.123. 13C NMR (125 MHz, CDCl3) of compound 53 ........................................194 Figure A1.124. 1H NMR (500 MHz, CDCl3) of compound 82 .........................................195 Figure A1.125. Infrared spectrum (Thin Film, NaCl) of compound 82...............................196 Figure A1.126. 13C NMR (125 MHz, CDCl3) of compound 82 ........................................196 Figure A1.127. 1H NMR (500 MHz, CDCl3) of compound 83 .........................................197 Figure A1.128. Infrared spectrum (Thin Film, NaCl) of compound 83...............................198 Figure A1.129. 13C NMR (125 MHz, CDCl3) of compound 83 ........................................198 Figure A1.130. 1H NMR (500 MHz, CDCl3) of compound 81 .........................................199 Figure A1.131. Infrared spectrum (Thin Film, NaCl) of compound 81...............................200 Figure A1.132. 13C NMR (125 MHz, CDCl3) of compound 81 ........................................200 Figure A1.133. 1H NMR (300 MHz, CDCl3) of compound 84 .........................................201 Figure A1.134. Infrared spectrum (Thin Film, NaCl) of compound 84...............................202 Figure A1.135. 13C NMR (125 MHz, CDCl3) of compound 84 ........................................202 Figure A1.136. 1H NMR (600 MHz, CDCl3) of compound 86 .........................................203 Figure A1.137. Infrared spectrum (Thin Film, NaCl) of compound 86...............................204 Figure A1.138. 13C NMR (125 MHz, CDCl3) of compound 86 ........................................204    xxi   Figure A1.139. H NMR (600 MHz, CDCl3) of compound 87 .........................................205 1 Figure A1.140. Infrared spectrum (Thin Film, NaCl) of compound 87...............................206 Figure A1.141. 13C NMR (125 MHz, CDCl3) of compound 87 ........................................206 Figure A1.142. 1H NMR (500 MHz, CDCl3) of compound 88 .........................................207 Figure A1.143. Infrared spectrum (Thin Film, NaCl) of compound 88...............................208 Figure A1.144. 13C NMR (125 MHz, CDCl3) of compound 88 ........................................208 Figure A1.145. 1H NMR (500 MHz, CDCl3) of compound 80 .........................................209 Figure A1.146. Infrared spectrum (Thin Film, NaCl) of compound 80...............................210 Figure A1.147. 13C NMR (125 MHz, CDCl3) of compound 80 ........................................210 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1 Figure A2.1.1. X-ray Crystal Structure of 24 ..............................................................212 Figure A2.2.1. X-ray Crystal Structure of 37 ..............................................................220 Figure A2.3.1. X-ray Crystal Structure of 42 ..............................................................228 Figure A2.4.1. X-ray Crystal Structure of 51 ..............................................................234 Figure A2.5.1. X-ray Crystal Structure of 52 ..............................................................242 Figure A2.6.1. X-ray Crystal Structure of 61 ..............................................................252 Figure A2.7.1. X-ray Crystal Structure of 62 ..............................................................260 Figure A2.8.1. X-ray Crystal Structure of 72 ..............................................................265 Figure A2.9.1. X-ray Crystal Structure of 73 ..............................................................273 Figure A2.10.1. X-ray Crystal Structure of 77 .............................................................284 Figure A2.11.1. X-ray Crystal Structure of 94 .............................................................297 APPENDIX 4 Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Figure A4.2.1. Results with DiazaPHOS and WALPHOS ................................................................ 322 APPENDIX 5 Spectra Relevant to Appendix 4 Figure A5.1. 1H NMR (500 MHz, CDCl3) of compound 136 ..........................................332 Figure A5.2. Infrared spectrum (Thin Film, NaCl) of compound 136 ................................333 Figure A5.3. 13C NMR (125 MHz, CDCl3) of compound 136. .........................................333    xxii   APPENDIX 6 Spectra Relevant to Chapter 2 Figure A6.1. 1H NMR (500 MHz, CDCl3) of compound 137a. ............................................... 349 Figure A6.2. Infrared spectrum (Thin Film, NaCl) of compound 137a. ................................... 350 Figure A6.3. 13C NMR (125 MHz, CDCl3) of compound 137a................................................ 350 Figure A6.4. 1H NMR (500 MHz, CDCl3) of compound 137b. ............................................... 351 Figure A6.5. Infrared spectrum (Thin Film, NaCl) of compound 137b. ................................... 352 Figure A6.6. 13C NMR (125 MHz, CDCl3) of compound 137b ............................................... 352 Figure A6.7. 1H NMR (500 MHz, CDCl3) of compound 137c. ............................................... 353 Figure A6.8. Infrared spectrum (Thin Film, NaCl) of compound 137c.. .................................. 354 Figure A6.9. 13C NMR (125 MHz, CDCl3) of compound 137c................................................ 354 Figure A6.10. 1H NMR (500 MHz, CDCl3) of compound 139 ................................................ 355 Figure A6.11. Infrared spectrum (Thin Film, NaCl) of compound 139 .................................... 356 Figure A6.12. 13C NMR (125 MHz, CDCl3) of compound 139 ............................................... 356 Figure A6.13. 1H NMR (500 MHz, CDCl3) of compound 141 ................................................ 357 Figure A6.14. Infrared spectrum (Thin Film, NaCl) of compound 141 .................................... 358 Figure A6.15. 13C NMR (125 MHz, CDCl3) of compound 141 ............................................... 358 Figure A6.16. 1H NMR (500 MHz, CDCl3) of compound 143 ................................................ 359 Figure A6.17. Infrared spectrum (Thin Film, NaCl) of compound 143 .................................... 360 Figure A6.18. 13C NMR (125 MHz, CDCl3) of compound 143 ............................................... 360 CHAPTER 3 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution Figure 3.1.1. QUINAP (155) and PINAP (156) ....................................................................... 362 APPENDIX 7 Spectra Relevant to Chapter 3 Figure A7.1. 1H NMR (500 MHz, CDCl3) of compound 157a ............................................... 387 Figure A7.2. Infrared spectrum (Thin Film, NaCl) of compound 157a. ................................... 388 Figure A7.3. 13C NMR (126 MHz, CDCl3) of compound 157a................................................ 388 Figure A7.4. 1H NMR (500 MHz, CDCl3) of compound 157b ................................................ 389 Figure A7.5. Infrared spectrum (Thin Film, NaCl) of compound 157b .................................... 390 Figure A7.6. 13C NMR (126 MHz, CDCl3) of compound 157b ............................................... 390 Figure A7.7. 1H NMR (500 MHz, CDCl3) of compound 157c ............................................... 391 Figure A7.8. Infrared spectrum (Thin Film, NaCl) of compound 157c. ................................... 392 Figure A7.9. 13C NMR (126 MHz, CDCl3) of compound 157c................................................ 392    xxiii   1 Figure A7.10. H NMR (500 MHz, CDCl3) of compound 157d ............................................. 393 Figure A7.11. Infrared spectrum (Thin Film, NaCl) of compound 157d ................................. 394 Figure A7.12. 13C NMR (126 MHz, CDCl3) of compound 157d ............................................. 394 Figure A7.13. 1H NMR (500 MHz, CDCl3) of compound 157e ............................................. 395 Figure A7.14. Infrared spectrum (Thin Film, NaCl) of compound 157e ................................. 396 Figure A7.15. 13C NMR (126 MHz, CDCl3) of compound 157e.............................................. 396 Figure A7.16. 1H NMR (500 MHz, CDCl3) of compound 157f .............................................. 397 Figure A7.17. Infrared spectrum (Thin Film, NaCl) of compound 157f ................................... 398 Figure A7.18. 13C NMR (126 MHz, CDCl3) of compound 157f ............................................. 398 Figure A7.19. 1H NMR (500 MHz, CDCl3) of compound 157g ............................................. 399 Figure A7.20. Infrared spectrum (Thin Film, NaCl) of compound 157g ................................. 400 Figure A7.21. 13C NMR (126 MHz, CDCl3) of compound 157g.............................................. 400 Figure A7.22. 1H NMR (500 MHz, CDCl3) of compound 157h ............................................. 401 Figure A7.23. Infrared spectrum (Thin Film, NaCl) of compound 157h ................................. 402 Figure A7.24. 13C NMR (126 MHz, CDCl3) of compound 157h ............................................ 402 Figure A7.25. 1H NMR (500 MHz, CDCl3) of compound 158a ............................................. 403 Figure A7.26. Infrared spectrum (Thin Film, NaCl) of compound 158a ................................. 404 Figure A7.27. 13C NMR (126 MHz, CDCl3) of compound 158a ............................................. 404 Figure A7.28. 1H NMR (500 MHz, CDCl3) of compound 158b ............................................. 405 Figure A7.29. Infrared spectrum (Thin Film, NaCl) of compound 158b ................................. 406 Figure A7.30. 13C NMR (126 MHz, CDCl3) of compound 158b. ............................................ 406 Figure A7.31. 1H NMR (500 MHz, CDCl3) of compound 158c ............................................. 407 Figure A7.32. Infrared spectrum (Thin Film, NaCl) of compound 158c ................................. 408 Figure A7.33. 13C NMR (126 MHz, CDCl3) of compound 158c ............................................. 408 Figure A7.34. 1H NMR (500 MHz, CDCl3) of compound 158d. ............................................. 409 Figure A7.35. Infrared spectrum (Thin Film, NaCl) of compound 158d ................................. 410 Figure A7.36. 13C NMR (126 MHz, CDCl3) of compound 158d. ............................................ 410 Figure A7.37. 1H NMR (500 MHz, CDCl3) of compound 158e ............................................. 411 Figure A7.38. Infrared spectrum (Thin Film, NaCl) of compound 158e ................................. 412 Figure A7.39. 13C NMR (126 MHz, CDCl3) of compound 158e ............................................. 412 Figure A7.40. 1H NMR (500 MHz, CDCl3) of compound 158f .............................................. 413 Figure A7.41. Infrared spectrum (Thin Film, NaCl) of compound 158f .................................. 414 Figure A7.42. 13C NMR (126 MHz, CDCl3) of compound 158f ............................................. 414 Figure A7.43. 1H NMR (300 MHz, CDCl3) of compound 158g ............................................. 415 Figure A7.44. Infrared spectrum (Thin Film, NaCl) of compound 158g. ................................. 416 Figure A7.45. 13C NMR (75 MHz, CDCl3) of compound 158g ............................................... 416 Figure A7.46. 1H NMR (500 MHz, CDCl3) of compound 158h ............................................. 417 Figure A7.47. Infrared spectrum (Thin Film, NaCl) of compound 158h ................................. 418    xxiv   13 Figure A7.48. C NMR (126 MHz, CDCl3) of compound 158h ............................................ 418 APPENDIX 8 Spectra Relevant to Chapter 4: Figure A8.1. 1H NMR (500 MHz, CDCl3) of compound 167 .................................................. 466 Figure A8.2. Infrared spectrum (Thin Film, NaCl) of compound 167 ...................................... 467 Figure A8.3. 13C NMR (126 MHz, CDCl3) of compound 167 ................................................. 467 Figure A8.4. 1H NMR (400 MHz, CDCl3) of compound 169 .................................................. 468 Figure A8.5. Infrared spectrum (Thin Film, NaCl) of compound 169 ...................................... 469 Figure A8.6. 13C NMR (126 MHz, CDCl3) of compound 169 ................................................. 469 Figure A8.7. 1H NMR (500 MHz, CDCl3) of compound 170a ............................................... 470 Figure A8.8. Infrared spectrum (Thin Film, NaCl) of compound 170a ................................... 471 Figure A8.9. 13C NMR (126 MHz, CDCl3) of compound 170a ............................................... 471 Figure A8.10. 1H NMR (400 MHz, CDCl3) of compound 171a .............................................. 472 Figure A8.11. Infrared spectrum (Thin Film, NaCl) of compound 171a ................................. 473 Figure A8.12. 13C NMR (101 MHz, CDCl3) of compound 171a ............................................. 473 Figure A8.13. 1H NMR (300 MHz, CDCl3) of compound 170b ............................................. 474 Figure A8.14. Infrared spectrum (Thin Film, NaCl) of compound 170b ................................. 475 Figure A8.15. 13C NMR (75 MHz, CDCl3) of compound 170b .............................................. 475 Figure A8.16. 1H NMR (300 MHz, CDCl3) of compound 171b ............................................. 476 Figure A8.17. Infrared spectrum (Thin Film, NaCl) of compound 171b ................................. 477 Figure A8.18. 13C NMR (75 MHz, CDCl3) of compound 171b .............................................. 477 Figure A8.19. 1H NMR (400 MHz, CDCl3) of compound 170c ............................................. 478 Figure A8.20. Infrared spectrum (Thin Film, NaCl) of compound 170c ................................. 479 Figure A8.21. 13C NMR (101 MHz, CDCl3) of compound 170c ............................................. 479 Figure A8.22. 1H NMR (400 MHz, CDCl3) of compound 171c ............................................. 480 Figure A8.23. Infrared spectrum (Thin Film, NaCl) of compound 171c ................................. 481 Figure A8.24. 13C NMR (101 MHz, CDCl3) of compound 171c ............................................. 481 Figure A8.25. 1H NMR (400 MHz, CDCl3) of compound 170d ............................................. 482 Figure A8.26. Infrared spectrum (Thin Film, NaCl) of compound 170d ................................. 483 Figure A8.27. 13C NMR (101 MHz, CDCl3) of compound 170d ............................................ 483 Figure A8.28. 1H NMR (400 MHz, C6D6) of compound 171d ............................................... 484 Figure A8.29. Infrared spectrum (Thin Film, NaCl) of compound 171d ................................. 485 Figure A8.30. 13C NMR (101 MHz, C6D6) of compound 171d ............................................... 485 Figure A8.31. 1H NMR (500 MHz, CDCl3) of compound 170e ............................................. 486 Figure A8.32. Infrared spectrum (Thin Film, NaCl) of compound 170e ................................. 487 Figure A8.33. 13C NMR (126 MHz, CDCl3) of compound 170e ............................................. 487 Figure A8.34. 1H NMR (500 MHz, CDCl3) of compound 171e ............................................. 488    xxv   Figure A8.35. Infrared spectrum (Thin Film, NaCl) of compound 171e ................................. 489 Figure A8.36. 13C NMR (126 MHz, CDCl3) of compound 171e ............................................. 489 Figure A8.37. 1H NMR (500 MHz, CDCl3) of compound 170f .............................................. 490 Figure A8.38. Infrared spectrum (Thin Film, NaCl) of compound 170f .................................. 491 Figure A8.39. 13C NMR (126 MHz, CDCl3) of compound 170f ............................................. 491 Figure A8.40. 1H NMR (400 MHz, CDCl3) of compound 171f .............................................. 492 Figure A8.41. Infrared spectrum (Thin Film, NaCl) of compound 171f .................................. 493 Figure A8.42. 13C NMR (101 MHz, CDCl3) of compound 171f ............................................. 493 Figure A8.43. 1H NMR (400 MHz, CDCl3) of compound 170g ............................................. 494 Figure A8.44. Infrared spectrum (Thin Film, NaCl) of compound 170g ................................. 495 Figure A8.45. 13C NMR (101 MHz, CDCl3) of compound 170g ............................................. 495 Figure A8.46. 1H NMR (400 MHz, CDCl3) of compound 171g ............................................. 496 Figure A8.47. Infrared spectrum (Thin Film, NaCl) of compound 171g ................................. 497 Figure A8.48. 13C NMR (101 MHz, CDCl3) of compound 171g ............................................. 497 Figure A8.49. 1H NMR (400 MHz, CDCl3) of compound 170h ............................................. 498 Figure A8.50. Infrared spectrum (Thin Film, NaCl) of compound 170h ................................. 499 Figure A8.51. 13C NMR (101 MHz, CDCl3) of compound 170h ............................................ 499 Figure A8.52. 1H NMR (500 MHz, CD2Cl2) of compound 171h ............................................ 500 Figure A8.53. Infrared spectrum (Thin Film, NaCl) of compound 171h ................................. 501 Figure A8.54. 13C NMR (126 MHz, CD2Cl2) of compound 171h ........................................... 501 Figure A8.55. 1H NMR (500 MHz, CDCl3) of compound 170i .............................................. 502 Figure A8.56. Infrared spectrum (Thin Film, NaCl) of compound 170i .................................. 503 Figure A8.57. 13C NMR (126 MHz, CDCl3) of compound 170i ............................................. 503 Figure A8.58. 1H NMR (400 MHz, CDCl3) of compound 171i .............................................. 504 Figure A8.59. Infrared spectrum (Thin Film, NaCl) of compound 171i .................................. 505 Figure A8.60. 13C NMR (101 MHz, CDCl3) of compound 171i ............................................. 505 Figure A8.61. 1H NMR (500 MHz, CDCl3) of compound SI-4-6 ............................................. 506 Figure A8.62. Infrared spectrum (Thin Film, NaCl) of compound SI-4-6................................. 507 Figure A8.63. 13C NMR (126 MHz, CDCl3) of compound SI-4-6 ............................................ 507 Figure A8.64. 1H NMR (400 MHz, CDCl3) of compound 170j .............................................. 508 Figure A8.65. Infrared spectrum (Thin Film, NaCl) of compound 170j .................................. 509 Figure A8.66. 13C NMR (101 MHz, CDCl3) of compound 170j ............................................. 509 Figure A8.67. 1H NMR (400 MHz, CD2Cl2) of compound 171j ............................................. 510 Figure A8.68. Infrared spectrum (Thin Film, NaCl) of compound 171j .................................. 511 Figure A8.69. 13C NMR (101 MHz, CD2Cl2) of compound 171j ............................................ 511 Figure A8.70. 1H NMR (300 MHz, CDCl3) of compound 172a ............................................. 512 Figure A8.71. Infrared spectrum (Thin Film, NaCl) of compound 172a ................................. 513 Figure A8.72. 13C NMR (75 MHz, CDCl3) of compound 172a ............................................... 513    xxvi   1 Figure A8.73. H NMR (300 MHz, CDCl3) of compound 173a ............................................. 514 Figure A8.74. Infrared spectrum (Thin Film, NaCl) of compound 173a ................................. 515 Figure A8.75. 13C NMR (75 MHz, CDCl3) of compound 173a ............................................... 515 Figure A8.76. 1H NMR (400 MHz, CDCl3) of compound 172b ............................................. 516 Figure A8.77. Infrared spectrum (Thin Film, NaCl) of compound 172b ................................. 517 Figure A8.78. 13C NMR (101 MHz, CDCl3) of compound 172b ............................................ 517 Figure A8.79. 1H NMR (400 MHz, CDCl3) of compound 173b ............................................. 518 Figure A8.80. Infrared spectrum (Thin Film, NaCl) of compound 173b ................................. 519 Figure A8.81. 13C NMR (101 MHz, CDCl3) of compound 173b ............................................ 519 Figure A8.82. 1H NMR (400 MHz, CDCl3) of compound 172c ............................................. 520 Figure A8.83. Infrared spectrum (Thin Film, NaCl) of compound 172c ................................. 521 Figure A8.84. 13C NMR (101 MHz, CDCl3) of compound 172c ............................................. 521 Figure A8.85. 1H NMR (400 MHz, CDCl3) of compound 173c ............................................. 522 Figure A8.86. Infrared spectrum (Thin Film, NaCl) of compound 173c ................................. 523 Figure A8.87. 13C NMR (101 MHz, CDCl3) of compound 173c ............................................. 523 Figure A8.88. 1H NMR (300 MHz, CDCl3) of compound 172d ............................................. 524 Figure A8.89. Infrared spectrum (Thin Film, NaCl) of compound 172d ................................. 525 Figure A8.90. 13C NMR (75 MHz, CDCl3) of compound 172d .............................................. 525 Figure A8.91. 1H NMR (300 MHz, CDCl3) of compound 173d ............................................. 526 Figure A8.92. Infrared spectrum (Thin Film, NaCl) of compound 173d ................................. 527 Figure A8.93. 13C NMR (75 MHz, CDCl3) of compound 173d .............................................. 527 Figure A8.94. 1H NMR (500 MHz, C6D6) of compound 174a ................................................ 528 Figure A8.95. Infrared spectrum (Thin Film, NaCl) of compound 174a ................................. 529 Figure A8.96. 13C NMR (126 MHz, C6D6) of compound 174a ............................................... 529 Figure A8.97. 1H NMR (500 MHz, C6D6) of compound 175a ................................................ 530 Figure A8.98. Infrared spectrum (Thin Film, NaCl) of compound 175a ................................. 531 Figure A8.99. 13C NMR (126 MHz, C6D6) of compound 175a ............................................... 531 Figure A8.100. 1H NMR (500 MHz, CDCl3) of compound 174b ........................................... 532 Figure A8.101. Infrared spectrum (Thin Film, NaCl) of compound 174b ............................... 533 Figure A8.102. 13C NMR (126 MHz, CDCl3) of compound 174b .......................................... 533 Figure A8.103. 1H NMR (400 MHz, CDCl3) of compound 174c ........................................... 534 Figure A8.104. Infrared spectrum (Thin Film, NaCl) of compound 174c ............................... 535 Figure A8.105. 13C NMR (101 MHz, CDCl3) of compound 174c ........................................... 535 Figure A8.106. 1H NMR (500 MHz, CDCl3) of compound 174d ........................................... 536 Figure A8.107. Infrared spectrum (Thin Film, NaCl) of compound 174d ............................... 537 Figure A8.108. 13C NMR (126 MHz, CDCl3) of compound 174d .......................................... 537 Figure A8.109. 1H NMR (400 MHz, C6D6) of compound 175d ............................................. 538 Figure A8.110. Infrared spectrum (Thin Film, NaCl) of compound 175d ............................... 539    xxvii   13 Figure A8.111. C NMR (101 MHz, C6D6) of compound 175d ............................................. 539 Figure A8.112. 1H NMR (400 MHz, CDCl3) of compound 174e ........................................... 540 Figure A8.113. Infrared spectrum (Thin Film, NaCl) of compound 174e ............................... 541 Figure A8.114. 13C NMR (101 MHz, CDCl3) of compound 174e ........................................... 541 Figure A8.115. 1H NMR (400 MHz, C6D6) of compound 175e .............................................. 542 Figure A8.116. Infrared spectrum (Thin Film, NaCl) of compound 175e ............................... 543 Figure A8.117. 13C NMR (101 MHz, C6D6) of compound 175e ............................................. 543 Figure A8.118. 1H NMR (400 MHz, CDCl3) of compound 174f ............................................ 544 Figure A8.119. Infrared spectrum (Thin Film, NaCl) of compound 174f ................................ 545 Figure A8.120. 13C NMR (101 MHz, CDCl3) of compound 174f ........................................... 545 Figure A8.121. 1H NMR (500 MHz, C6D6) of compound 175f .............................................. 546 Figure A8.122. Infrared spectrum (Thin Film, NaCl) of compound 175f ................................ 547 Figure A8.123. 13C NMR (126 MHz, C6D6) of compound 175f ............................................. 547 Figure A8.124. 1H NMR (500 MHz, CDCl3) of compound 174g ........................................... 548 Figure A8.125. Infrared spectrum (Thin Film, NaCl) of compound 174g ............................... 549 Figure A8.126. 13C NMR (126 MHz, CDCl3) of compound 174g ........................................... 549 Figure A8.127. 1H NMR (500 MHz, C6D6) of compound 175g .............................................. 550 Figure A8.128. Infrared spectrum (Thin Film, NaCl) of compound 175g ............................... 551 Figure A8.129. 13C NMR (126 MHz, C6D6) of compound 175g ............................................. 551 Figure A8.130. 1H NMR (500 MHz, CDCl3) of compound 174h ........................................... 552 Figure A8.131. Infrared spectrum (Thin Film, NaCl) of compound 174h ............................... 553 Figure A8.132. 13C NMR (126 MHz, CDCl3) of compound 174h .......................................... 553 Figure A8.133. 1H NMR (600 MHz, C6D6) of compound 175h ............................................. 554 Figure A8.134. Infrared spectrum (Thin Film, NaCl) of compound 175h ............................... 555 Figure A8.135. 13C NMR (151 MHz, C6D6) of compound 175h ............................................. 555 Figure A8.136. 1H NMR (500 MHz, CDCl3) of compound 174i ............................................ 556 Figure A8.137. Infrared spectrum (Thin Film, NaCl) of compound 174i ................................ 557 Figure A8.138. 13C NMR (126 MHz, CDCl3) of compound 174i ........................................... 557 Figure A8.139. 1H NMR (500 MHz, C6D6) of compound 175i .............................................. 558 Figure A8.140. Infrared spectrum (Thin Film, NaCl) of compound 175i ................................ 559 Figure A8.141. 13C NMR (126 MHz, C6D6) of compound 175i .............................................. 559 Figure A8.142. 1H NMR (400 MHz, CDCl3) of compound 174j ............................................ 560 Figure A8.143. Infrared spectrum (Thin Film, NaCl) of compound 174j ................................ 561 Figure A8.144. 13C NMR (101 MHz, CDCl3) of compound 174j ........................................... 561 Figure A8.145. 1H NMR (500 MHz, C6D6) of compound 175j .............................................. 562 Figure A8.146. Infrared spectrum (Thin Film, NaCl) of compound 175j ................................ 563 Figure A8.147. 13C NMR (101 MHz, C6D6) of compound 175j .............................................. 563 Figure A8.148. 1H NMR (500 MHz, CDCl3) of compound 174k ........................................... 564    xxviii   Figure A8.149. Infrared spectrum (Thin Film, NaCl) of compound 174k ............................... 565 Figure A8.150. 13C NMR (126 MHz, CDCl3) of compound 174k ........................................... 565 Figure A8.151. 1H NMR (500 MHz, CDCl3) of compound 174l ............................................ 566 Figure A8.152. Infrared spectrum (Thin Film, NaCl) of compound 174l ................................ 567 Figure A8.153. 13C NMR (126 MHz, CDCl3) of compound 174l ........................................... 567 Figure A8.154. 1H NMR (500 MHz, CD2Cl2) of compound 175l ........................................... 568 Figure A8.155. Infrared spectrum (Thin Film, NaCl) of compound 175l ................................ 569 Figure A8.156. 13C NMR (126 MHz, CD2Cl2) of compound 175l .......................................... 569 APPENDIX 10 Spectra Relevant to Appendix 9 Figure A10.1. 1H NMR (400 MHz, CDCl3) of compound 192 ................................................ 577 Figure A10.2. Infrared spectrum (Thin Film, NaCl) of compound 192 .................................... 578 Figure A10.3. 13C NMR (101 MHz, CDCl3) of compound 192 ............................................... 578 Figure A10.4. 1H NMR (400 MHz, CD2Cl2) of compound 193 .............................................. 579 Figure A10.5. Infrared spectrum (Thin Film, NaCl) of compound 193 .................................... 580 Figure A10.6. 13C NMR (101 MHz, CD2Cl2) of compound 193 .............................................. 580 Figure A10.7. 1H NMR (500 MHz, CDCl3) of compound 194 ................................................ 581 Figure A10.8. Infrared spectrum (Thin Film, NaCl) of compound 194 .................................... 582 Figure A10.9. 13C NMR (101 MHz, CDCl3) of compound 194 ............................................... 582 APPENDIX 11 Synthetic Studies Toward Alistonitrine A Figure A11.1.1. Structure of Alistonitrine A (195) ................................................................... 583 APPENDIX 12 Spectra Relevant to Appendix 11 Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound 202 ................................................ 613 Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound 202 .................................... 614 Figure A12.3. 13C NMR (126 MHz, CDCl3) of compound 202 ............................................... 614 Figure A12.4. 1H NMR (400 MHz, CD2Cl2) of compound 203 ............................................... 615 Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound 203 .................................... 616 Figure A12.6. 13C NMR (101 MHz, CD2Cl2) of compound 203 .............................................. 616 Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound 204 ................................................ 617 Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound 204. ................................... 618 Figure A12.9. 13C NMR (126 MHz, CDCl3) of compound 204 ............................................... 618    xxix   1 Figure A12.10. H NMR (500 MHz, CD3OD) of compound 205 ............................................ 619 Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound 205 .................................. 620 Figure A12.12. 13C NMR (126 MHz, CD3OD) of compound 205 ........................................... 620 Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound 207 .............................................. 621 Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound 207 .................................. 622 Figure A12.15. 13C NMR (126 MHz, CDCl3) of compound 207 ............................................. 622 Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound 208a ........................................... 623 Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound 208a. ............................... 624 Figure A12.18. 13C NMR (126 MHz, CDCl3) of compound 208a............................................ 624 Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound 208b ........................................... 625 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound 208b ............................... 626 Figure A12.21. 13C NMR (126 MHz, CDCl3) of compound 208b .......................................... 626 Figure A12.22. 1H NMR (400 MHz, CDCl3) of compound 211 .............................................. 627 Figure A12.23. Infrared spectrum (Thin Film, NaCl) of compound 211 .................................. 628 Figure A12.24. 13C NMR (101 MHz, CDCl3) of compound 211 ............................................. 628 Figure A12.25. 1H NMR (400 MHz, CDCl3) of compound 213 .............................................. 629 Figure A12.26. Infrared spectrum (Thin Film, NaCl) of compound 213 .................................. 630 Figure A12.27. 13C NMR (126 MHz, CDCl3) of compound 213 ............................................. 630 Figure A12.28. 1H NMR (500 MHz, CDCl3) of compound 215a ........................................... 631 Figure A12.29. Infrared spectrum (Thin Film, NaCl) of compound 215a ............................... 632 Figure A12.30. 13C NMR (126 MHz, CDCl3) of compound 215a ........................................... 632 Figure A12.31. 1H NMR (500 MHz, CDCl3) of compound 215b ........................................... 633 Figure A12.32. Infrared spectrum (Thin Film, NaCl) of compound 215b ............................... 634 Figure A12.33. 13C NMR (126 MHz, CDCl3) of compound 215b .......................................... 634 CHAPTER 5 Synthetic Studies Toward Polycyclic Ineleganolide Figure 5.1.1. Structure of Ineleganolide (238) ........................................................................ 635 APPENDIX 13 Spectra Relevant to Chapter 5: Figure A13.1. 1H NMR (400 MHz, CDCl3) of compound 248 ................................................ 680 Figure A13.2. Infrared spectrum (Thin Film, NaCl) of compound 248 .................................... 681 Figure A13.3. 13C NMR (101 MHz, CDCl3) of compound 248 .............................................. 681 Figure A13.4. 1H NMR (400 MHz, CDCl3) of compound 251 ................................................ 682 Figure A13.5. Infrared spectrum (Thin Film, NaCl) of compound 251 .................................... 683 Figure A13.6. 13C NMR (101 MHz, CDCl3) of compound 251 ............................................... 683    xxx   1 Figure A13.7. H NMR (400 MHz, CDCl3) of compound 252 ................................................ 684 Figure A13.8. Infrared spectrum (Thin Film, NaCl) of compound 252 .................................... 685 Figure A13.9. 13C NMR (101 MHz, CDCl3) of compound 252 ............................................... 685 Figure A13.10. 1H NMR (400 MHz, CDCl3) of compound 254 .............................................. 686 Figure A13.11. Infrared spectrum (Thin Film, NaCl) of compound 254 .................................. 687 Figure A13.12. 13C NMR (101 MHz, CDCl3) of compound 254 ............................................. 687 Figure A13.13. 1H NMR (400 MHz, CDCl3) of compound 244b ........................................... 688 Figure A13.14. Infrared spectrum (Thin Film, NaCl) of compound 244b ............................... 689 Figure A13.15. 13C NMR (101 MHz, CDCl3) of compound 244b .......................................... 689 Figure A13.16. 1H NMR (400 MHz, CDCl3) of compound 260 .............................................. 690 Figure A13.17. Infrared spectrum (Thin Film, NaCl) of compound 260 .................................. 691 Figure A13.18. 13C NMR (101 MHz, CDCl3) of compound 260 ............................................. 691 Figure A13.19. 1H NMR (400 MHz, CDCl3) of compound 264 .............................................. 692 Figure A13.20. Infrared spectrum (Thin Film, NaCl) of compound 264 .................................. 693 Figure A13.21. 13C NMR (101 MHz, CDCl3) of compound 264 ............................................. 693 Figure A13.22. 1H NMR (400 MHz, CDCl3) of compound 266 .............................................. 694 Figure A13.23. Infrared spectrum (Thin Film, NaCl) of compound 266 .................................. 695 Figure A13.24. 13C NMR (101 MHz, CDCl3) of compound 266 ............................................. 695 Figure A13.25. 1H NMR (400 MHz, CDCl3) of compound 268 .............................................. 696 Figure A13.26. Infrared spectrum (Thin Film, NaCl) of compound 268 .................................. 697 Figure A13.27. 13C NMR (101 MHz, CDCl3) of compound 268 ............................................. 697 Figure A13.28. 1H NMR (400 MHz, CDCl3) of compound 269 .............................................. 698 Figure A13.29. Infrared spectrum (Thin Film, NaCl) of compound 269 .................................. 699 Figure A13.30. 13C NMR (101 MHz, CDCl3) of compound 269 ............................................. 699 Figure A13.31. 1H NMR (400 MHz, CDCl3) of compound 270 .............................................. 700 Figure A13.32. Infrared spectrum (Thin Film, NaCl) of compound 270 .................................. 701 Figure A13.33. 13C NMR (101 MHz, CDCl3) of compound 270 ............................................. 701 Figure A13.34. 1H NMR (400 MHz, CDCl3) of compound 271a ........................................... 702 Figure A13.35. Infrared spectrum (Thin Film, NaCl) of compound 271a ............................... 703 Figure A13.36. 13C NMR (101 MHz, CDCl3) of compound 271a ........................................... 703 Figure A13.37. 1H NMR (400 MHz, CDCl3) of compound 271b ........................................... 704 Figure A13.38. Infrared spectrum (Thin Film, NaCl) of compound 271b ............................... 705 Figure A13.39. 13C NMR (101 MHz, CDCl3) of compound 271b .......................................... 705 Figure A13.40. 1H NMR (500 MHz, CDCl3) of compound 274 .............................................. 706 Figure A13.41. Infrared spectrum (Thin Film, NaCl) of compound 274 .................................. 707 Figure A13.42. 13C NMR (126 MHz, CDCl3) of compound 274 ............................................. 707 Figure A13.43. 1H NMR (400 MHz, CDCl3) of compound 275 .............................................. 708 Figure A13.44. Infrared spectrum (Thin Film, NaCl) of compound 275 .................................. 709    xxxi   13 Figure A13.45. C NMR (101 MHz, CDCl3) of compound 275 ............................................. 709 Figure A13.46. 1H NMR (400 MHz, CDCl3) of compound 276 .............................................. 710 Figure A13.47. Infrared spectrum (Thin Film, NaCl) of compound 276 .................................. 711 Figure A13.48. 13C NMR (101 MHz, CDCl3) of compound 276 ............................................. 711 Figure A13.49. 1H NMR (400 MHz, CDCl3) of compound 285 .............................................. 712 Figure A13.50. Infrared spectrum (Thin Film, NaCl) of compound 285 .................................. 713 Figure A13.51. 13C NMR (101 MHz, CDCl3) of compound 285 ............................................. 713 Figure A13.52. 1H NMR (400 MHz, CDCl3) of compound 281 .............................................. 714 Figure A13.53. Infrared spectrum (Thin Film, NaCl) of compound 281 .................................. 715 Figure A13.54. 13C NMR (101 MHz, CDCl3) of compound 281 ............................................. 715 Figure A13.55. 1H NMR (500 MHz, CDCl3) of compound 286 .............................................. 716 Figure A13.56. Infrared spectrum (Thin Film, NaCl) of compound 286 .................................. 717 Figure A13.57. 13C NMR (126 MHz, CDCl3) of compound 286 ............................................. 717 Figure A13.58. 1H NMR (400 MHz, CDCl3) of compound 287 .............................................. 718 Figure A13.59. Infrared spectrum (Thin Film, NaCl) of compound 287 .................................. 719 Figure A13.60. 13C NMR (101 MHz, CDCl3) of compound 287 ............................................. 719 Figure A13.61. 1H NMR (400 MHz, CDCl3) of compound 288 .............................................. 720 Figure A13.62. Infrared spectrum (Thin Film, NaCl) of compound 288 .................................. 721 Figure A13.63. 13C NMR (101 MHz, CDCl3) of compound 288 ............................................. 721 Figure A13.64. 1H NMR (500 MHz, CDCl3) of compound 294 .............................................. 722 Figure A13.65. Infrared spectrum (Thin Film, NaCl) of compound 294 .................................. 723 Figure A13.66. 13C NMR (126 MHz, CDCl3) of compound 294 ............................................. 723          xxxii   LIST OF SCHEMES   CHAPTER 1 The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine   Scheme 1.2.1. Biosynthesis-Inspired Approach ........................................................................ 5 Scheme 1.2.2. Model Studies for a Diels–Alder Cycloaddtion Strategy To Construct the Pentacyclic Core Structure   ........................................................................................................ 6 Scheme 1.2.3. Attempted Diels–Alder Cycloadditions with Advanced Electrophiles ................ 6 Scheme 1.2.4. Retrosynthetic Analysis of Communesin F by an Intramolecular Diels–Alder Cycloaddition   ........................................................................................................................... 7 Scheme 1.2.5. Intramolecular Diels–Alder Cycloaddition ......................................................... 8 Scheme 1.2.6. Reaction of Aurantioclavine Derivative 25 with Bromooxindole 26 ................. 11 Scheme 1.2.7. Construction of 3,3-Disubstituted Oxindoles .................................................. 13 Scheme 1.2.8. Construction of C(7)–C(8) Linkage by Alkylation Strategy ................................ 14 Scheme 1.2.9. Alkylation of Azepine Bromooxindole 40 with Malonate 41 ............................ 15 Scheme 1.2.10. Alkylation of 3-Bromooxindole 43 ................................................................. 16 Scheme 1.2.11. Model Studies for Construction of the Vicinal Quaternary Centers ................. 17 Scheme 1.2.12. Retrosynthesis of Communesin F (1f) .............................................................. 19 Scheme 1.2.13. Development of the Vicinal Quaternary Center ............................................ 20 Scheme 1.2.14. Ozonolysis and Reductive Amination of Lactone 62 ...................................... 21 Scheme 1.2.15. Synthesis of Lactam 54 .................................................................................. 22 Scheme 1.2.16. Reductive Cyclization of Lactam 54 with AlH3-Me2NEt ................................ 23 Scheme 1.2.17. Attempted Reductive Cyclization of Lactam 54.............................................. 25 Scheme 1.2.18. Synthesis of Aminal 81 .................................................................................. 27 Scheme 1.2.19. Completion of Formal Synthesis of Communesin F ........................................ 28 Scheme 1.2.20. Retrosynthesis of Perophoramidine (3) ............................................................ 29 Scheme 1.2.21. Synthesis of Amide 89 ................................................................................... 30 Scheme 1.2.22. Formation of Azepine 91 using Tf2O .............................................................. 31 Scheme 1.2.23. Completion of Formal Synthesis of Perophoramidine .................................... 32 APPENDIX 3 Synthetic Studies Toward the Total Synthesis of Communesin F      xxxiii   Scheme A3.1.1. Direct Lactam Forming Strategy Toward Communesin F (1f) ...................... 304 Scheme A3.1.2. Attempted Lactam Forming Reactions ........................................................ 305 Scheme A3.2.1. Diels–Alder Strategy Toward Communesin F (1f) ......................................... 306 Scheme A3.2.2. Intramolecular Diels–Alder Reactions.......................................................... 307 Scheme A3.2.3. Intermolecular Diels–Alder Reactions ......................................................... 308 Scheme A3.3.1. Intramolecular Alkylation Strategy .............................................................. 309 Scheme A3.3.2. Intramolecular Alkylation of 3-Bromooxindole ............................................ 310 APPENDIX 4 Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Scheme A4.1.1. Construction of 3,3-Disubstituted Oxindoles by Alkylation of 3-Halooxindoles .............................................................................................................................................. 319 Scheme A4.1.2. Attempts for Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters .............................................................................................................................................. 320 Scheme A4.2.1. Synthesis of the Racemic Product ................................................................. 321 CHAPTER 2 A New Method for the Cleavage of Nitrobenzyl Amides and Ethers Scheme 2.2.1. o-Nitrobenzyl group cleavage on perophoramidine intermediate (88) ............ 335   CHAPTER 3 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution   Scheme 3.2.1. Applications .................................................................................................. 366 CHAPTER 4 Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   Scheme 4.2.1. Ni-Catalyzed C–O Bond Formation ................................................................ 421 APPENDIX 9 Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement    xxxiv   Scheme A9.1.1. Ni-Catalyzed C–O Bond Formation and subsequent Claisen Rearrangement 571 APPENDIX 11 Synthetic Studies Toward Alistonitrine A Scheme A11.2.1. Retrosynthetic Analysis of Alistonitrine A (195) ......................................... 584 Scheme A11.2.2. Synthesis of Chiral Amine 205.................................................................... 585 Scheme A11.2.3. Synthesis of α,β-Unsaturated Lactams 208 ................................................. 586 Scheme A11.2.4. Synthesis of α-Substituted α,β-Unsaturated Lactam 199 ............................. 587 Scheme A11.2.5. Synthesis of oxindole Fragment 217 ........................................................... 587 Scheme A11.2.6. Attempted Coupling of malonate 217 and amide 199 ................................ 588 Scheme A11.2.7. A Revised Retrosynthesis Toward Alistonitrine A ........................................ 588 Scheme A11.2.8. Synthesis of Bicycle 226 ............................................................................. 589 CHAPTER 5 Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.1.1. Proposed Biosynthesis of Ineleganolide (238) ................................................ 636 Scheme 5.2.1. Retrosynthesis of Ineleganolide (238) ............................................................. 637 Scheme 5.2.2. Synthesis of (Z)-Selective Enoate 248 ............................................................. 638 Scheme 5.2.3. Synthesis of α-Bromoketone 244b ................................................................. 639 Scheme 5.2.4. Attempts to Synthesize Bicyclic Fragment via Diazo Compounds .................. 641 Scheme 5.2.5. Attempted Williamson Etherifications ............................................................ 642 Scheme 5.2.6. Synthesis Epoxides 271a and 271b ................................................................ 643 Scheme 5.2.7. Formation of Bicyclic Fragment ..................................................................... 644 Scheme 5.2.8. Coupling of the Fragments ............................................................................. 645 Scheme 5.2.9. Synthetic Plan by Using Metathesis Strategies ................................................ 645 Scheme 5.2.10. Coupling of the Fragments by Esterification ................................................ 647 Scheme 5.2.11. Intermolecular Metathesis ............................................................................ 648 Scheme 5.2.12. Alkyne Addition........................................................................................... 649      xxxv   LIST OF TABLES   APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1   Table A2.1.1. Crystal Data and Structure Analysis Details for 24........................................... 212 4 Table A2.1.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 24..................................................................................................................... 214 Table A2.1.3. Bond lengths [Å] and angles [°] for 24 ........................................................... 215 2 4 Table A2.1.4. Anisotropic displacement parameters (Å x 10 ) for 24 ................................ 218 3 2 3 Table A2.1.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 24 ..................................................................................................................................... 218 Table A2.1.6. Hydrogen bonds for 24 [Å and °] ................................................................... 219 Table A2.2.1. Crystal data and structure refinement for 37 .................................................... 220 Table A2.2.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 37..................................................................................................................... 222 Table A2.2.3. Bond lengths [Å] and angles [°] for 37 ........................................................... 223 Table A2.2.4. Hydrogen bonds for 37 [Å and °] .................................................................... 227 Table A2.3.1. Crystal data and structure refinement for 42 .................................................... 228 Table A2.3.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 42..................................................................................................................... 230 Table A2.3.3. Bond lengths [Å] and angles [°] for 42 ........................................................... 230 Table A2.3.4. Anisotropic displacement parameters (Å2x 104 ) for 42 ................................ 232 Table A2.3.5. Hydrogen bonds for 42 [Å and °] ................................................................... 233 Table A2.4.1. Crystal Data and Structure Analysis Details for 51........................................... 234 4 Table A2.4.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 51..................................................................................................................... 236 Table A2.4.3. Bond lengths [Å] and angles [°] for 51 ........................................................... 237 2 4 Table A2.4.4. Anisotropic displacement parameters (Å x 10 ) for 51 ................................ 239 3 2 3 Table A2.4.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 51 ..................................................................................................................................... 240 Table A2.4.6. Hydrogen bonds for 51 [Å and °] ................................................................... 240 Table A2.5.1. Crystal Data and Structure Analysis Details for 52........................................... 242 4 Table A2.5.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters    xxxvi   2 3 (Å x 10 ) for 52..................................................................................................................... 244 Table A2.5.3. Bond lengths [Å] and angles [°] for 52 ........................................................... 245 2 4 Table A2.5.4. Anisotropic displacement parameters (Å x 10 ) for 52 ................................ 249 3 2 3 Table A2.5.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 52 ..................................................................................................................................... 250 Table A2.5.6. Hydrogen bonds for 52 [Å and °] ................................................................... 251 Table A2.6.1. Crystal Data and Structure Analysis Details for 61........................................... 252 4 Table A2.6.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 61..................................................................................................................... 254 Table A2.6.3. Bond lengths [Å] and angles [°] for 61 ........................................................... 255 2 4 Table A2.6.4. Anisotropic displacement parameters (Å x 10 ) for 61 ................................ 258 3 2 3 Table A2.6.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 61 ..................................................................................................................................... 258 Table A2.6.6. Hydrogen bonds for 61 [Å and °] ................................................................... 259 Table A2.7.1. Crystal data and structure refinement for 62 .................................................... 260 Table A2.7.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 62..................................................................................................................... 262 Table A2.7.3. Bond lengths [Å] and angles [°] for 62 ........................................................... 262 Table A2.7.4. Anisotropic displacement parameters (Å2x 104) for 62 .................................. 264 Table A2.8.1. Crystal Data and Structure Analysis Details for 72........................................... 265 4 Table A2.8.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 72..................................................................................................................... 267 Table A2.8.3. Bond lengths [Å] and angles [°] for 72 ........................................................... 267 2 4 Table A2.8.4. Anisotropic displacement parameters (Å x 10 ) for 72 ................................ 270 3 2 3 Table A2.8.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 72 ..................................................................................................................................... 271 Table A2.9.1. Crystal Data and Structure Analysis Details for 73........................................... 273 4 Table A2.9.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 73..................................................................................................................... 275 Table A2.9.3. Bond lengths [Å] and angles [°] for 73 .......................................................... 276 2 4 Table A2.9.4. Anisotropic displacement parameters (Å x 10 ) for 73 ................................ 281 3 2 3 Table A2.9.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 73 ..................................................................................................................................... 282 Table A2.9.6. Hydrogen bonds for 73 [Å and °] ................................................................... 283    xxxvii   Table A2.10.1. Crystal data and structure analysis details for 77 ........................................... 284 4 Table A2.10.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 77..................................................................................................................... 286 Table A2.10.3. Bond lengths [Å] and angles [°] for 77 ........................................................ 287 2 4 Table A2.10.4. Anisotropic displacement parameters (Å x 10 ) for 77 .............................. 293 3 2 Table A2.10.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 3 10 ) for 77 ............................................................................................................................. 295 Table A2.10.6. Hydrogen bonds for 77 [Å and °] ................................................................. 296 Table A2.11.1. Crystal data and structure refinement for 94 .................................................. 297 Table A2.11.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 94..................................................................................................................... 299 Table A2.11.3. Bond lengths [Å] and angles [°] for 94 ........................................................ 300 Table A2.11.4. Anisotropic displacement parameters (Å2x 104 ) for 94 .............................. 302 APPENDIX 4 Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Table A4.2.1. Further investigations using WALPHOS and DiazaPHOS in the alkylation reaction .............................................................................................................................................. 323 Table A4.2.2. Investigation of reaction solvents and bases with WALPHOS in the alkylation reaction ................................................................................................................................. 324 Table A4.2.3. Examination of the amount of catalyst and ligand loading in the alkylation reaction ................................................................................................................................. 325 Table A4.2.4. Examination of concentration in the malonate addition reaction ...................... 325 Table A4.2.5. The effect of WALPHOS substituents under optimized condition in the alkylation reaction ................................................................................................................................. 326   CHAPTER 2 A New Method for the Cleavage of Nitrobenzyl Amides and Ethers Table 2.2.1. Cleavage of nitrobenzyl groups on 3,3-dimethyloxindole ................................... 336 Table 2.2.2. Scope of the o- and p-nitrobenzyl deprotecion reactions .................................... 338   CHAPTER 3 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution    xxxviii     Table 3.2.1. Scope of dynamic kinetic resolution under initial standard conditions................ 363 Table 3.2.2. Optimization of reaction parameters .................................................................. 364 Table 3.2.3. Scope of dynamic kinetic resolution under optimized conditions ....................... 365   CHAPTER 4 Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   Table 4.2.1. Optimization of reaction parameters .................................................................. 422 Table 4.2.2. Intramolecular cross-coupling of amino-cyclohexanols ...................................... 423 Table 4.2.3. Intramolecular cross-coupling of linear aminoalcohols....................................... 424 Table 4.2.4. Synthesis of substituted tetrahydrofuran and dihydropyran rings ......................... 426   APPENDIX 14 Notebook Cross-Reference for New Compounds Table A14.1. Notebook cross-reference for compounds in Chapter 1.................................... 725 Table A14.2. Notebook cross-reference for compounds in Appendix 3 ................................. 731 Table A14.3. Notebook cross-reference for compounds in Appendix 4 ................................. 732 Table A14.4. Notebook cross-reference for compounds in Chapter 2.................................... 732 Table A14.5. Notebook cross-reference for compounds in Chapter 3.................................... 733 Table A14.6. Notebook cross-reference for compounds in Chapter 4.................................... 735 Table A14.7. Notebook cross-reference for compounds in Appendix 9 ................................. 739 Table A14.8. Notebook cross-reference for compounds in Appendix 11 ............................... 739 Table A14.9. Notebook cross-reference for compounds in Chapter 5.................................... 741                xxxix   LIST OF ABBREVIATIONS   Å   Ångstrom   λ     wavelength   µ   micro   µwaves microwave  irradiation [α]D   specific  rotation  at  wavelength  of  sodium  D  line   [H]   reduction   [O]     oxidation   °C     degrees  Celsius   Ac     acetyl   acac   acetylacetonate   AcOH   acetic  acid   APCI atmospheric  pressure  chemical  ionization app     apparent   aq   aqueous   Ar   aryl   atm     atmosphere   B3LYP   3-­‐parameter  hybrid  Becke  exchange/   Lee–Yang–Parr  correlation  functional   Bn     benzyl   Boc     tert-­‐butyloxycarbonyl   BOP   Bis(2-­‐oxo-­‐3-­‐oxazolidinyl)phospinic   bp   boiling  point   br     broad   Bu     butyl   Bz benzoyl c     concentration  for  specific  rotation  measurements      xl   ca. about  (Latin  circa) calc’d     calculated   CAN   cerium  ammonium  nitrate   cat   catalytic   CCDC     Cambridge  Crystallographic  Data  Centre   CDI     1,1'-­‐carbonyldiimidazole     cf. compare  (Latin  confer) CI     chemical  ionization   cm–1 wavenumber(s) cod   1,5-­‐cyclooctadiene   comp   complex   Cp   cyclopentadienyl   Cy     cyclohexyl   d     doublet   D deuterium DABCO   1,4-­‐diazabicyclo[2,2,2]octane   dba     dibenzylideneacetone   DBU     1,8-­‐diazabicyclo[5.4.0]undec-­‐7-­‐ene   DCC   N,N’-­‐dicyclohexylcarbodiimide   DCE   1,2-­‐dichloroethane   DDQ   2,3-­‐dichloro-­‐5,6-­‐dicyano-­‐p-­‐benzoquinone   DEAD   diethyl  azodicarboxylate   dec   decomposition   DFT   density  functional  theory   DIBAL   diisobutylaluminum  hydride   DIPEA   N,N-­‐diisopropylethylamine   DKR   dynamic  kinetic  resolution   DMA   N,N-­‐dimethylacetamide   DMAD   dimethyl  acetylenedicarboxylate      xli   DMAP     4-­‐dimethylaminopyridine   dmdba bis(3,5-­‐dimethoxybenzylidene)acetone DMDO   dimethyldioxirane   DME   1,2-­‐dimethoxyethane   DMF     N,N-­‐dimethylformamide   DMP   Dess–Martin  periodinane   DMS   dimethyl  sulfide   DMSO     dimethyl  sulfoxide   dr   diastereomeric  ratio   e.g. for  example  (Latin  exempli  gratia) EA   activation  energy   EC50     median  effective  concentration  (50%)   EDC   N-­‐(3-­‐dimethylaminopropyl)-­‐N'-­‐ethylcarbodiimide   ee     enantiomeric  excess   EI+   electron  impact   equiv     equivalent   ESI     electrospray  ionization   Et     ethyl   EtOAc   ethyl  acetate   FAB     fast  atom  bombardment   FID flame  ionization  detector g     gram(s)   GC   gas  chromatography   gCOSY     gradient-­‐selected  correlation  spectroscopy   h     hour(s)   hν   light   HBPin   HFIP   4,4,5,5-­‐tetramethyl-­‐1,3,2-­‐dioxaborolane;   pinacolborane   1,1,1,3,3,3-­‐hexafluoro-­‐2-­‐propanol      xlii   HMDS   1,1,1,3,3,3-­‐hexamethyldisilazane   HMPA hexamethylphosphoramide HOBt   hydroxybenzotriazole   HPLC     high-­‐performance  liquid  chromatography   HRMS   high-­‐resolution  mass  spectroscopy   Hz     hertz   i.e. that  is  (Latin  id  est) IBX   2-­‐iodoxybenzoic  acid   IC50     median  inhibition  concentration  (50%)   IMDA   Intramolecular  Diels–Alder  reaction   IPA   isopropanol,  2-­‐propanol   i-­‐Pr   isopropyl   IR     infrared  (spectroscopy)   IRC   intrinsic  reaction  coordinate   J     coupling  constant   K   Kelvin(s)  (absolute  temperature)   kcal kilocalorie KHMDS potassium  hexamethyldisilazide L     liter;  ligand   LAH   lithium  aluminum  hydride   LDA lithium  diisopropylamide LHMDS   lithium  bis(trimethylsilyl)amide   lit. literature  value m     multiplet;  milli   m     meta   M   metal;  molar;  molecular  ion   m/z     mass  to  charge  ratio   m-­‐CPBA   meta-­‐chloroperoxybenzoic  acid   Me     methyl      xliii   mg   milligram(s)   MHz     megahertz   min     minute(s)   MM mixed  method MMPP   magnesium  monoperoxyphthalate   mol     mole(s)   MOM methoxymethyl mp     melting  point   Ms     methanesulfonyl  (mesyl)   MS     molecular  sieves   MVK   methyl  vinyl  ketone   n   nano   N   normal   nbd     norbornadiene   NBS     N-­‐bromosuccinimide   n-­‐Bu   butyl   NHC   N-­‐heterocyclic  carbene   NMO     N-­‐methylmorpholine  N-­‐oxide   NMR     nuclear  magnetic  resonance   NOE     nuclear  Overhauser  effect   NOESY     nuclear  Overhauser  enhancement  spectroscopy   Nosyl   nitrobenzenesulfonyl   Nu   nucleophile   o     ortho   OKR   oxidative  kinetic  resolution   p     para   PCC pyridinium  chlorochromate Pd/C   palladium  on  carbon   PDC     pyridinium  dichromate      xliv   Ph     phenyl   pH     hydrogen  ion  concentration  in  aqueous  solution   PHOX phosphinooxazoline  ligand Piv pivaloyl pKa pK  for  association  of  an  acid PMB   p-­‐methoxybenzyl   pmdba bis(4-­‐methoxybenzylidene)acetone ppm     parts  per  million   PPTS   pyridinium  p-­‐toluenesulfonate   Pr     propyl   PTU   n-­‐Propylthiouracil   Py     pyridine   q     quartet   R   generic  for  any  atom  or  functional  group   Ref.   reference   Rf     retention  factor   s     singlet  or  strong  or  selectivity  factor   sat.   saturated   Selectfluor   1-­‐chloromethyl-­‐4-­‐fluoro-­‐1,4-­‐ diazoniabicyclo[2.2.2]octane  bis(tetrafluoroborate)   SEM   2-­‐(trimethylsilyl)ethoxymethyl   SFC   supercritical  fluid  chromatography   SN 2 second-­‐order  nucleophilic  substitution SN2'   nucleophilic  substitution  with  allylic   rearrangement   sp   sparteine   sp.   species   t     triplet   TBAF     tetrabutylammonium  fluoride        xlv   TBAI   tetrabutylammonium  iodide   TBAT   tetrabutylammonium  difluorotriphenylsilicate   TBDPS   tert-­‐butyldiphenylsilyl   TBHP   tert-­‐butyl  hydroperoxide   TBME   tert-­‐butyl  methyl  ether   TBS     tert-­‐butyldimethylsilyl   t-­‐Bu   tert-­‐butyl   TES   triethylsilyl   Tf     trifluoromethanesulfonyl  (triflyl)   TFA     trifluoroacetic  acid   TFAA   trifluoroacetic  anhydride   TFE   2,2,2-­‐trifluoroethanol   THF     tetrahydrofuran   TIPS     triisopropylsilyl   TLC     thin-­‐layer  chromatography   TMEDA N,N,N’,N’-­‐tetramethylethylenediamine TMS     trimethylsilyl   TOF time-­‐of-­‐flight Tol tolyl tR   retention  time   Ts     p-­‐toluenesulfonyl  (tosyl)   UV     ultraviolet   v/v   volume  to  volume   VO(acac)2   vanadyl  acetoacetonate   w     weak   w/v   weight  to  volume   X   anionic  ligand  or  halide       Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 1 CHAPTER 1 The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine† 1.1. Introduction In 1993, communesin A (1a) was isolated along with communesin B (1b) from a strain of Penicillium sp. found growing on a marine alga by the Numata group (Figure 1.1.1).1 Communesins A (1a) and B (1b) exhibit antiproliferative activity against P-388 lymphocytic leukemia cells (ED50 = 3.5 µg/mL and 0.45 µg/mL, respectively).1 In addition, communesin B (1b) disrupts actin microfilaments in cultured mammalian cells and shows cytotoxic activity against LoVo and KB cells (MIC values of 2.0 µg/mL and 4.5 µg/mL, respectively). 2 Several other members of the comunesin family, communesins B–H (1b–1h), were disclosed from related marine fungal strains of                                                                                                                 †   This work was performed in collaboration with Dr. Florian Vogt, Dr. Jeremy A. May, Dr. Shyam Krishnan, Dr. Michele Gatti, and Dr. Scott C. Virgil. Additionally, this work has been published and adapted with permission from Han, S.-J.; Vogt, F.; May, J. A.; Krishnan, S.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. J. Org. Chem. 2015, 80, 528–547. Copyright 2015 American Chemical Society. Related work has been published and adapted with permission from Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. Copyright 2014 American Chemical Society. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 2 3 Penicillium sp. in the following years. With the exception of communesins G (1g) and H (1h), the communesins show insecticidal activity and antiproliferative activity against a variety of cancer cells, with communesin B (1b) being the most potent. 1–3 These indole alkaloids contain several interesting structural features including vicinal all-carbon quaternary centers, bis-aminal functionalities, and a complex polycyclic core. The communesins are structurally unique when compared against other known microfilamentdisrupting agents, which are primarily macrolides. Macrolide microfilament-disrupting agents show considerable structural similarity, and their interactions with actin have been crystallographically characterized, leading to hypotheses regarding their mechanism of action.4 The unique structure of communesin B (1b) suggests that it may exhibit a novel mechanism of action on the cytoskeleton relative to other microfilament-disrupting agents.5a The development of a unified synthetic route to the communesins would enable the understanding of their effects on the cellular cytoskeleton, while addressing the scarcity of naturally occurring sources of the compounds. In 2001, an intriguing natural product, nomofungin (2) was isolated from an unidentified fungus found on the bark of Ficus microcarpa by the Hemscheidt group.2 Interestingly, the only structural difference between communesin B (1b) and nomofungin (2) is that communesin B has an aminal moiety instead of the N,O-acetal moiety present in nomofungin. A combination of experimental and theoretical exercises led to the independent discovery by our laboratory and the Funk group that the reported structure of nomofungin was incorrect, and that it is actually that of communesin B.5a,b Although the structure of nomofungin was erroneously assigned, its isolation and structural revision to that of an older structure can be viewed as the inception point for all synthetic efforts to Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 3 the communesin family members over the past decade. Interestingly, there were no reports of synthetic efforts toward the communesins from 1993 up to our initial report in 2003.5i A structurally related compound, perophoramidine (3), was isolated in 2002 from the ascidian Perophora namei. 6 The core is comparable to the one found in the communesins, albeit in a higher oxidation state, with the alternate diastereomeric relationship between the vicinal quaternary carbons and without the azepine ring system. Perophoramidine (3) possesses modest cytotoxicity against the HCT 116 human colon carcinoma cell line (IC50 = 60 µM) and induces apoptosis.7 Figure 1.1.1. Communesins (1), Nomofungin (2), and Perophoramidine (3) O O R' N O 21 H N N H N 9 11 8 12a 6 7 N H N N H H N H R Communesin R R' A (1a) B (1b) C (1c) D (1d) E (1e) G (1g) H (1h) CH3 CH3 CH3 pentadienyl H CHO H CH3 CH3 pentadienyl pentadienyl CH3 CH2CH3 CH2CH2CH3 Communesin F (1f) O 22 N O H N Cl 4 19 N H Nomofungin (2) (Original Structure) 1 6 20 17 O N 24 N 15 Cl N 12 N 8 H Perophoramidine (3) Br Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 4 These complex, polycyclic, bioactive alkaloids have been the subject of intense synthetic efforts over the past decade.5 Numerous approaches have been reported in the literature, including three from our laboratory.5a,5c,5w Herein, we report the evolution of an efficient, unified approach toward the synthesis of these unique alkaloids. 1.2. Results and Discussion 1.2.1. Biosynthesis-Inspired Diels–Alder Cycloaddition Strategy to Communesin F Our early efforts toward the communesin structure centered on the laboratory implementation of our proposed biosynthesis (Scheme 1.2.1).5a,c,8 As the key step in the process, we envisioned a Diels–Alder cycloaddition to unite the two indole-based fragments by coupling of 5, an N-methylated derivative of the ergot alkaloid aurantioclavine (4)9,10 and an o-azaxylylene indolone 6 to generate the bridged lactam 7. We anticipated that lactam 7 would be highly reactive due to the poor alignment of the nitrogen lone pair with the carbonyl.11,12,13 As such, the pendant amino group would be expected to easily open the lactam, thus forming spirocycle 8. Further tailoring would produce communesin A (1a) and B (1b). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 5 Scheme 1.2.1. Biosynthesis-Inspired Approach H 2N H H N H 2N NH + N O N N N R 4, R = H (Aurantioclavine) 5, R = Me Me 6 O 7 O R H HN H N O N O H N NH N Me 8 NH N H Me Communesin A (1a) and B (1b) Toward this end, (±)-aurantioclavine was prepared using known methods5a,14 and an enantioselective synthesis of (–)-aurantioclavine utilizing our oxidative kinetic resolution (OKR) technology was developed.15 We proceeded to develop an efficient cycloaddition between (±)-indole 9 as a model coupling partner and chlorotoluamide 10 using conditions previously developed by Steinhagen and Corey16 that resulted in a mixture of pentacyclic diastereomers (89% yield). Removal of the tosyl group with magnesium in methanol produced a 2:1 mixture of diastereomers 11 and 12 in 80% combined yield, with the desired relative stereochemistry evident in the major diastereomer (cf. 11 and 1a) (Scheme 1.2.2).5a Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 6 Scheme 1.2.2. Model Studies for a Diels–Alder Cycloaddtion Strategy To Construct the Pentacyclic Core Structure Boc H N 8 8 Cl 1. Boc N NH HN 10 Ts Cs2CO3, CH2Cl2, –78 °C (89% yield) N H 11 + N Boc H N 2. Mg, NH 4Cl, MeOH (80% yield) 8 (11 :12 = 2:1) 9 NH N H 12 Despite the success of this model system, more advanced electrophiles (e.g., mesylate 14, cyclopropane 16, or epoxide 17 17 ) did not succumb to cycloaddition conditions (Scheme 1.2.3). Nor have we been successful in the oxidation of 11 and 12 at C(8), which would provide a functional handle for introduction of the second quaternary stereocenter. Scheme 1.2.3. Attempted Diels–Alder Cycloadditions with Advanced Electrophiles OH MOMO OMs 9, MsCl, Cs2CO3 8 MOMO CH2Cl2, –78 °C TsHN TsHN 13 14 OMOM H Boc N MeO 2C 8 N N H Ts 15 (Not Observed) O O O N H N H 16 17 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 7 To obviate the difficulties encountered in our attempts to functionalize C(8), we next considered dienes possessing a functional handle at C(8) that could unite diene and dienophile, such as benzisoxazole 19, thereby enabling an intramolecular Diels–Alder cycloaddition (Scheme 1.2.4). Thus, when coupled to aurantioclavine 4, benzisoxazole 20 would offer a stable o-methide imine that could react with the indole moiety of compound 19 in a controlled and intramolecular manner. Scheme 1.2.4. Retrosynthetic Analysis of Communesin F by an Intramolecular Diels–Alder Cycloaddition O O HeteroDiels-Alder Reaction H N N 8 H N O NH N N H H N 18 Communesin F (1f) N H N O O H N O HO Acylation + O N H N 19 4 N 20 Fischer esterification of commercially available carboxylic acid 21, followed by heating in neat sulfuric acid provided the benzisoxazole acid 20 in 44% yield over 2 steps (Scheme 1.2.5).18 Treatment of benzisoxazole acid 20 with oxalyl chloride provided the corresponding acid chloride, which was smoothly coupled with aurantioclavine 4 to furnish carboxamide 22 (91% yield, 2 steps). Similarly, 1-methylaurantioclavine 5 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 8 reacted with the acid chloride to afford carboxamide 19 (77% yield, 2 steps). Substrates 22 and 19 were subjected to an intramolecular Diels–Alder cycloaddition under acidic conditions.19 Unfortunately, the benzisoxazole reacted with the butenyl side chain of the aurantioclavine core to generate the bridged polycycles 23 and 24. Nuclear Overhauser Effect NMR spectroscopy (NOESY) studies and X-ray analysis (Figure 1.2.1) demonstrated the relative stereochemistry shown for 24 and that of 23 was assigned by analogy. Scheme 1.2.5. Intramolecular Diels–Alder Cycloaddition 1. EtOH, cat. H 2SO4 PhMe, reflux HO 2C 2. H 2SO4, 110 °C (44% yield, 2 steps ) O2N 21 O HO 1. (COCl)2 CH2Cl2, DMF, 23 °C O 2. 4 or 5, Et 3N CH2Cl2, 23 °C N 20 N O O O HCl, MeOH N 0 → 23 °C N O N H H N N R R 22, R = H (91% yield, 2 steps) 19, R = Me (77% yield, 2 steps) 23, R = H (31% yield) 24, R = Me (99% yield) (X-ray) Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 9 Figure 1.2.1. X-ray Structure of Bridged Polycycle 24 O N O N H H ≡ N 24 24 At this point, we turned our attention to synthesizing 3-bromooxindole 26, which would be a precursor to an o-methide imine such as reactive intermediate 6, allowing for the construction of the communesin core according to our original biosynthesis-inspired model (Scheme 1.2.1). Aurantioclavine derivative 25 was reacted with bromooxindole 26 in an effort to produce adduct 27 (Scheme 1.2.6a). Interestingly, different reactivity was observed in coordinating and non-coordinating solvents. In THF or acetonitrile, the reaction afforded indole 28 in 69% yield, wherein the oxindole was introduced to position C(2) of the indole nucleus, presumably via rearrangement of the initially formed adduct 27 at C(3) (Scheme 1.2.6b). Sulfonylation of indole 28 with o-NsCl under basic conditions was accompanied by unexpected chlorination of the indole moiety to afford chloroindoline 29 (73% yield), the structure of which was unambiguously confirmed by X-ray crystallography (Figure 1.2.2). To the best of our knowledge, this constitutes the first use of o-NsCl for chlorination of an indole to provide the 3-chloroindolenine. On the other hand, the same coupling of derivatives 25 and 26 in benzene or dichloromethane furnished indole 28 (24% yield), and two additional undesired products 30 (32% yield) and 31 (24% yield) (Scheme 1.2.6c). Adduct 30 results from nucleophilic Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 10 attack at C(6) of the aurantioclavine indole core, while double adduct 31 is produced from both C(6) and C(2) functionalization. The structure of 30 was unambiguously determined following preparation of lactam 32 (Scheme 1.2.6d). Subjecting 30 to excess sodium hydride and o-NsCl conditions functionalized both the oxindole and indole nitrogens (66% yield) and subsequent reduction of the azide allowed for cyclization to lactam 32 in 66% yield. The structure of 32 was confirmed by single crystal X-ray diffraction (Figure 1.2.3). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 11 Scheme 1.2.6. Reaction of Aurantioclavine Derivative 25 with Bromooxindole 26 (a) O O N3 F 3C N F 3C N Br + Cs2CO3 O N H N H 25 NH solvents O N N3 27 (Not Observed) 26 (b) O O F 3C F 3C 26 N H N Cs2CO3 NH THF 23 °C (69% yield) N H 3 O N N3 25 27 O O F 3C F 3C H N H N N3 o-NsCl, NaH 2 N H N3 Cl THF, 0 °C (73% yield) NH N N O o-Ns O 29 (X-ray) 28 (c) O F 3C N3 N Cs2CO3 Br CH2Cl2 23 °C O + N H N H 25 (28: 24% yield, 30: 32% yield, 31: 24% yield) 26 O O F 3C F 3C H N H N N3 N3 N3 28 + + 6 N N 6 H N N O H 2 N H H O O H 31 30 (d) O O F 3C F 3C H N 1. o-NsCl, NaH THF, 0 °C (66% yield) N3 N H N H N HN 2. PPh 3, 50 °C H 2O/THF (1:4) O (66% yield) NsHN O H 30 32 (X-ray) N o-Ns Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 12 Figure 1.2.2. X-ray Structure of Chloroindoline 29 O F 3C H N N3 Cl ≡ N N o-Ns O 29 29 Figure 1.2.3. X-ray Structure of Lactam 32 O F 3C H N ≡ HN N O NsHN o-Ns 32 1.2.2. 32 An Alkylation Route to Communesin F Discouraged by the unsuccessful Diels–Alder cycloaddition-based approaches to communesin F (1f), we considered an alternative strategy toward the natural product. In 2007, as a direct result of our efforts toward the communesins and perophoramidine, we developed a method to generate 3,3-disubstituted oxindoles via the base-mediated coupling of oxindole electrophiles with malonate derived nuclophiles. (Scheme 1.2.7a).20 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 13 We also developed an asymmetric variant of this reaction utilizing copper bis(oxazoline) complexes (Scheme 1.2.7b).21 With the method shown in Scheme 1.2.7, we devised a new synthetic strategy that cast our coupling fragments in an umpolung manner, invoking an electrophilic aurantioclavine portion and a nucleophilic right hand fragment. We first pursued this notion in the context of the model azepine 35 (Scheme 1.2.8). Treatment of 35 with DBU and a pronucleophile (e.g., 3622 and 38) produced oxindole adducts (i.e., 37 and 39) possessing the key C(7)–C(8) linkage in modest but encouraging yields. Importantly, adduct 37 was crystalline, and we confirmed both the new C–C bond as well as the relative stereochemistry of the sole diastereomeric isolate via X-ray analysis. Scheme 1.2.7. Construction of 3,3-Disubstituted Oxindoles (a) X R 2O2C R1 CO2R 2 CO2R 2 R 2O2C R1 DBU O O THF, –78 → 23 °C N H N H R 2 = Me, Et, Bn 33 (±)-34 (47-87% yield) X = Br, Cl R 1 = alkyl, aryl 2+ (b) O O N X R1 Ph Cu N 2SbF6 Ph - (20 mol%) CO2R 2 R 2O2C R1 O N H 33 X = Br, Cl R 1 = alkyl, aryl R 2O2C CO2R 2 i-Pr2NEt or NEt 3 3Å molecular sieves CH2Cl2 R 2 = Me, Et, Bn O N H 34 (42-84% yield, 74-94% ee) Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 14 Scheme 1.2.8. Construction of C(7)–C(8) Linkage by Alkylation Strategy (a) Ts Ts NC N N O2N Br 8 DBU O 7 O N O2N H THF –78 → 23 °C (64% yield) N H 35 CN 36 37 (X-ray) Ts N CN ≡ O N O2N H 37 37 (b) Ts Ts N N MeO 2C Br O NO 2 + N H 35 CO2Me CO2Me CO2Me 38 DBU 8 7 THF –78 → 23 °C (32% yield) O N O N H 2 39 Having produced the key C(7)–C(8) linkage via an umpolung strategy, we treated aurantioclavine-derived bromooxindole 40 with malonate 41 in the presence of DBU (Scheme 1.2.9). Smooth reactivity under our standard conditions led to the isolation of a single stereoisomeric adduct 42 in 74% yield. To our delight, oxindole adduct 42 was amenable to single crystal X-ray diffraction, however, the X-ray analysis surprisingly revealed that the alkylation occurs with high syn selectivity relative to the existing isobutenyl substituent (Figure 1.2.4). This result was intriguing, given that in the Diels– Alder cycloaddition of the corresponding indole 9 with the o-azaxylylene derived from chlorotoluamide 10, the selectivity at C(7) favored the anti diastereomer 11 (cf. Schemes 1.2.9. and 1.2.2).23 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 15 Scheme 1.2.9. Alkylation of Azepine Bromooxindole 40 with Malonate 41 CO2Me Ts 41 N CO2Me N H 40 CO2Me DBU Br O Ts H N 7 THF –78 → 23 °C (>20:1 dr) (74% yield) CO2Me O N H 42 (X-ray) Figure 1.2.4. X-ray Structure of Oxindole Adduct 42 Ts H N CO2Me CO2Me O ≡ N H 42 42 Since the undesired relative stereochemistry was obtained in adduct 42 from the alkylation of azepine 40 and malonate 41, we explored our strategy in a model system lacking the azepine ring of the oxindole (Scheme 1.2.10). Known silyl ether 4321,22 was converted into malonate adducts 46 and 47 in 85% and 96% yield, respectively, under our previously reported conditions in Scheme 1.2.7. Importantly, in the non-azepine system, the efficiency of those alkylations is increased, even in these cases where vicinal quaternary centers are generated.24 Methylation of oxindoles 46 and 47 produced 48 and 49 in 99% and 92% yield, respectively. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 16 Scheme 1.2.10. Alkylation of 3-Bromooxindole 43 AllylO2C TIPSO Br CO2Allyl Cs2CO3 NO 2 + THF 0 → 23 °C O N H R 44, R = H 45, R = Br 43 R R TIPSO TIPSO NO 2 CO2Allyl CO2Allyl O N H 46, R = H (85% yield) 47, R = Br (96% yield) NO 2 Cs2CO3, MeI THF 0 → 23 °C CO2Allyl CO2Allyl O N 48, R = H (99% yield) 49, R = Br (92% yield) Acid-catalyzed desilylation and cyclization of diester 48 proceeded smoothly to furnish lactone 50 in 85% yield as a single diastereomer (Scheme 1.2.11a).25 To our delight, lactone 50 underwent decarboxylative allylic alkylation when treated with Pd(PPh3)4, yielding 51 in 90% yield as a single diastereomer.26,27 Single crystal X-ray analysis confirmed that lactone 51 possesses the relative stereochemistry at the vicinal quaternary carbon centers C(7) and C(8) that is needed for further elaboration to communesin F (1f). Interestingly, direct decarboxylative allylic alkylation of diester 49 again provided an alkylated product (i.e., 52) as a single diastereomer in 78% yield (Scheme 1.2.11b). Through X-ray analysis, we discovered that the relative stereochemistry at the vicinal quaternary stereocenters C(20) and C(4) of 52 was complementary to that of the lactone 51, and thus ideal for elaboration to perophoramidine (3). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 17 Scheme 1.2.11. Model Studies for Construction of the Vicinal Quaternary Centers (a) TIPSO O NO 2 O AcCl CO2Allyl CO2Allyl O CO2Allyl MeOH 0 → 65 °C (85% yield) N O NO N 2 48 50 O Pd(PPh 3)4 (2.5 mol%) O 8 THF (90% yield) ≡ 7 O NO N 2 51 (X-ray) 51 AcN H N 8 7 NH N H Communesin F (1f) (b) Br TIPSO TIPSO NO 2 CO2Allyl Pd(PPh 3)4 (5.0 mol%) CO2Allyl O THF, –78 °C (78% yield) CO2Allyl 4 20 N O N O2N 49 52 (X-ray) ≡ N Cl 20 Cl N H N 4 N Br Perophoramidine (3) 52 Br Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 18 At this time, the underlying reasons for the stereochemical relationships observed in these two alkylation reactions are unclear. The fact that the reactions proceed stereodivergently with high diastereocontrol is quite remarkable. Work toward building reasonable models for stereoinduction of β-quaternary tetrasubstituted enolates in both cyclic and acyclic settings as well as the development of these interesting processes in more general cases is ongoing. Nevertheless, with the promising model systems 51 and 52 completed, we next applied our findings to expedient formal syntheses of communesin F (1f) and perophoramidine (3). 1.2.3. Formal Synthesis of Communesin F (1f) As depicted in our retrosynthetic strategy (Scheme 1.2.12), communesin F could be completed from advanced intermediate 53 in Qin’s synthesis.5g We anticipated the initial disconnection of the aminal linkage in 53, thereby revealing oxindole and aniline moieties in 54. Then, the lactam ring in 54 would be excised, affording lactone 55. We envisioned that the relative stereochemical relationship at C(7) and C(8) of lactone 55 could be established by employing our decarboxylative allylic alkylation. The quaternary center on oxindole 56 was disassembled into 3-bromooxindole 57 and diallyl malonate 44. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 19 Scheme 1.2.12. Retrosynthesis of Communesin F (1f) O H HO N A H N B G 8 7 E N F N Br O C D NH N N CO2Me Communesin F (1f) 53 (Qin's intermediate) PMB TIPSO O N Br O O Br 8 7 O NO N O N HN 54 2 CO2Me 55 OTIPS TIPSO NO 2 Br CO2Allyl CO2Allyl O N H 56 Br Br O O AllylO O OAllyl NO 2 + N H 57 44 In the forward synthetic sense, our efforts toward communesin F commenced with the elaboration of 4-bromoindole 58 to diallyl malonate 60 (Scheme 1.2.13). Treatment of 4-bromoindole 58 with oxalyl chloride and methanol provided an oxoacetate (78% yield, 2 steps), which was reduced to the corresponding primary alcohol 59 with LiAlH4 in 91% yield.5g Silylation of the primary alcohol with TIPSCl (98% yield) and subsequent oxidation with pyridinium tribromide afforded dibromooxindole 57 in 89% yield.28 Despite the extra steric encumbrance of C(4) substitution, we were delighted to find that smooth coupling of dibromooxindole 57 with malonate 44 produced a 3,3disubstituted oxindole in 95% yield. Protection of the oxindole with MeI delivered adduct 60 in 92% yield. Microwave assisted lactonization of diester 60 with p-TsOH proceeded smoothly to furnish lactone 61 as a single diastereomer (85% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 20 Gratifyingly, decarboxylative allylic alkylation constructed the quaternary center at C(8) of compound 62 as a single diastereomer in 97% yield under Pd(PPh3)4 catalysis. The relative stereochemistry at C(7) and C(8) of 61 and 62 was unambiguously confirmed by X-ray analysis. Scheme 1.2.13. Development of the Vicinal Quaternary Center OH 1. (COCl)2, Et 2O, 23 °C 2. MeOH, Et 2O (78% yield, 2 steps) Br 3. LiAlH 4, THF, reflux (91% yield) N H 1. TIPSCl, imidazole DMF, 23 °C (98% yield) Br 2. pyridinium tribromide t-BuOH, H 2O, THF, 23 °C (89% yield) N H 58 59 OTIPS Br Br TIPSO NO 2 Br CO2Allyl 1. 44, Cs2CO3, 0 °C (95% yield) O N H 2. Cs2CO3, MeI, 23 °C (92% yield) 57 CO2Allyl O p-TsOH benzene 85 °C, microwave (85% yield) N 60 O O O Br 8 CO2Allyl 7 O NO N 2 Br O 8 Pd(PPh 3)4 (2.0 mol%) 7 THF, 23 °C (97% yield) O NO N 2 61 (X-ray) 62 (X-ray) ≡ ≡ 61 62 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 21 Although ozonolysis of alkene 62 delivered aldehyde 63 in 94% yield, attempted reductive amination of aldehyde 63 did not produce the desired γ-lactam 66 (Scheme 1.2.14). Upon treatment of aldehyde 63 with p-methoxybenzylammonium acetate and sodium cyanoborohydride, amine intermediate 64 was likely produced.29 Instead of opening the lactone directly (path a), nucleophilic attack by the newly generated amine at the oxindole moiety (path b), and subsequent ring-shift tautomerization delivered dihydroquinolinone 65 in 67% yield. Scheme 1.2.14. Ozonolysis and Reductive Amination of Lactone 62 O O O Br O Br O O3 O NO N O NO N CH2Cl2, MeOH then DMS –78 °C (94% yield) 2 62 2 63 path a O PMBNH 3OAc NaBH 3CN Br MeOH, THF (67% yield) O a NHPMB path b b O NO N path a 2 64 PMB HO Br O PMB path b N Br b a N 65 HO O NO 2 N a O b O N O2N 66 (Not Observed) Alternatively, we found that lactam 54 (an analogue of 66) could be obtained via the reaction sequence summarized in Scheme 1.2.15. The nitro group on compound 62 was reduced to the aniline, which resulted in concomitant lactone ring opening to furnish a bis-oxindole 67 in 80% yield. Protection of the primary alcohol with TIPSCl (90% Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 22 yield) and protection of the oxindole nitrogen with methyl chloroformate afforded carbamate 68 in 98% yield. Ozonolysis of alkene 68 generated aldehyde 69 (94% yield),30 which underwent subsequent reductive amination and selective lactamization with the electron deficient oxindole to afford γ-lactam 54 in 95% yield. Scheme 1.2.15. Synthesis of Lactam 54 O OH O Br TiCl3, NH 4OAc, MeCN O Br H 2O, MeOH, 23 °C (80% yield) NO N 2 NH OO N 67 62 1.TIPSCl, imidazole, DMF 0 → 23 °C (90% yield) 2. ClCO2Me Et 3N, DMAP, CH2Cl2 0 → 23 °C (98% yield) TIPSO TIPSO Br NCO 2Me OO O 3, then PPh 3, CH2Cl2, –78 °C (94% yield) N 68 PMB O TIPSO Br NCO 2Me PMBNH 3OAc, NaBH 3CN OO N THF, MeOH, 0 → 23 °C (95% yield) N Br O O N HN CO2Me 69 54 With lactam 54 in hand, we envisioned that the piperidine D ring of 70 would be prepared by AlH3-Me2NEt mediated reductive cyclization (Scheme 1.2.16).21,31 To our disappointment, treatment of lactam 54 with AlH3-Me2NEt produced undesired pyrrolidinoindoline derivative 71 as a single diastereomer in 61% yield, resulting from chemoselective reduction of the N-PMB-lactam in the presence of the oxindole. After cleavage of the TIPS group by TBAF (98% yield),32 the PMB group was removed with Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 23 33 DDQ to provide alcohol 72. The structure of the pentacyclic heterocycle 72 was confirmed by X-ray analysis (Figure 1.2.5). Scheme 1.2.16. Reductive Cyclization of Lactam 54 with AlH3-Me2NEt PMB TIPSO Br PMB TIPSO N N Br O A AlH3-Me2NEt F O N HN THF, 0 °C D N E N O C CO2Me CO2Me 54 70 (Not Observed) AlH3-Me2NEt THF, 0 °C (61% yield) PMB H N TIPSO CO2Me N Br O N H N HO 1. TBAF, THF, 23 °C (98% yield) 2. DDQ, CH2Cl2, H 2O 23 °C (85% yield) H CO2Me N Br O N 72 (X-ray) 71 Figure 1.2.5. X-ray Structure of Pyrrolidinoindoline 72 HO O NH Me N H N O ≡ Br O 72 72 Having failed on our initial exploration, alternative conditions for construction of the piperidine D ring were next explored. Treatment of the lactam 54 with LiAlH434 produced debrominated compound 73 in 83% yield (Scheme 1.2.17a). X-ray analysis of Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 24 compound 73 showed a hydrogen bonding interaction between the carbonyl group of the PMB protected amide and the NH group of the carbamate. We reasoned that the undesired pyrrolidine was formed preferentially to the piperidine due to the close proximity of the carbamate NH and the carbonyl group of the PMB-protected amide. Next, a reductive cyclization reaction was attempted by treatment of 54 with Tf2O and NaBH4 to construct the piperidine ring. To our surprise, treatment of lactam 54 with Tf2O provided the PMB-protected hexacyclic oxindole 76 in 95% yield (Scheme 1.2.17b). The PMB-protected amide of 54 was activated by Tf2O to provide 74, and nucleophilic attack by the aniline functionality furnished pyrrolidinoindoline derivative 75. After the TIPS group was removed under the reaction conditions, the resultant hydroxyl group attacked the amidinium to generate the propellane structure of hexacyclic oxindole 76. After cleavage of the PMB group using DDQ, the propellane structure of hexacyclic oxindole 77 was confirmed using X-ray analysis. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 25 Scheme 1.2.17. Attempted Reductive Cyclization of Lactam 54 (a) PMB TIPSO Br PMB TIPSO N O H LiAlH 4 THF, 0 °C (83% yield) O N HN N O HN CO2Me O N CO2Me 54 73 (X-ray) hydrogen bond PMB TIPSO N H O HN CO2Me ≡ O N 73 73 (b) PMB TIPSO PMB TIPSO N Br O Br Tf2O CH2Cl2 0 → 23 °C (95% yield) O N HN CO2Me N OTf O N HN CO2Me 54 74 PMB Br N HO CO2Me N Br N O O N N 75 76 Br DDQ N CH2Cl2, 23 °C (92% yield) O N CO2Me O N H 77 (X-ray) Br N N O N CO2Me O N 77 CO2Me O ≡ H 77 PMB Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 26 Despite this unexpected turn of events, we envisaged that the desired aminal 81 could be accessed from the propellane compound 76 using suitable conditions, since the oxidation state at C(9) of 76 is identical to that of the desired aminal 81 (Scheme 1.2.18). Moreover, the reactive N-PMB-pyrrolidinone in 54 is now protected by the propellane structure of 76, thus leaving the oxindole as the only reducible carbonyl group. Fortunately, after extensive experimentation, we were pleased to find that reductive cyclization of hexacyclic oxindole 76 could be accomplished with DIBAL and Et2AlCl to furnish aminal 81 in 87% yield (Scheme 1.2.18). Presumably, the oxindole of 76 was reduced by DIBAL to provide 78, and rearrangement of the propellane structure generated iminium 79. After the work-up, water attacked the iminium moiety of 79 to afford aniline 80, and the resultant aniline group attacked the iminium of 80 to construct aminal 81. In the last stage of the synthesis, we screened a variety of reaction conditions to remove the PMB group on the lactam 81 (e.g., DDQ, CAN, TFA, etc.) but, surprisingly, removal of the PMB group failed under all conditions attempted. This unexpected turn was particularly insidious since the PMB group was easily removed from hexacyclic oxindole 76 by DDQ (Scheme 1.2.17). The cleavage of allyl or benzyl groups were also examined, but disappointingly, cleavage of these groups on the lactam were similarly unsuccessful under several conditions.35 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 27 Scheme 1.2.18. Synthesis of Aminal 81 Br Br O N O 8 N CO2Me 9 N PMB DIBAL then Et 2AlCl O N PMB HO N N Br O work-up OAlR 2 N N R 2Al CO2Me CO2Me 80 PMB HO Br 9 N Br O 8 81 H HO N H HN N 79 N PMB 78 PMB Br N R 2Al 76 O N CO2Me O CH2Cl2 –78 → 23 °C (87% yield) N CO2Me O DDQ, CAN or TFA N H N CO2Me 53 (Not Observed)     Given the difficulty of removal of PMB, allyl, and benzyl groups, our attention turned to exploring the o-nitrobenzyl group as a protecting group. However, subjecting the hexacyclic oxindole 77 to o-nitrobenzyl bromide under basic conditions to produce the o-nitrobenzyl protected propellane hexacyclic oxindole turned out to be challenging. Thus, we next investigated reductive amination of aldehyde 69 and were pleased to find that treatment of 69 with o-nitrobenzylammonium acetate 82 furnished lactam 83 in 97% yield (Scheme 1.2.19). Formation of the o-nitrobenzyl protected propellane hexacyclic oxindole using Tf2O (75% yield) was followed by reductive cyclization with DIBAL and Et2AlCl to furnish aminal 84 in 60% yield. To our delight, we found that removal of the o-nitrobenzyl group could be achieved by photolysis/irradiation at 350nm in 40% yield.36     Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 28 Surprisingly, we discovered that removal of the o-nitrobenzyl group to produce compound 53 was also accomplished using 20% aq NaOH in methanol at 75 °C in 70% yield – a previously unknown deprotection protocol.37 Aminal 53 has been advanced by the Qin group to communesin F,5g thus completing our formal synthesis of the natural product.   Scheme 1.2.19. Completion of Formal Synthesis of Communesin F O2N TIPSO O NO 2 Br NCO 2Me 82 TIPSO NH 3OAc Br O NaBH 3CN THF, MeOH 0 → 23 °C (97% yield) OO N N O N HN CO2Me 69 83 O2N HO 1. Tf2O, CH2Cl2,, 0 → 23 °C (75% yield) 2. DIBAL; Et 2AlCl, CH2Cl2 –78 → 0 °C (60% yield) N Br N H O hv, MeOH (40% yield) CO2Me or 20% aq NaOH MeOH, 75 °C (70% yield) N 84 H HO Ac N N Br O N H 53 1.2.4. N CO2Me H N 11 steps NH Qin and co-workers (2007) N H Communesin F (1f) Formal Synthesis of Perophoramidine (3) Our retrosynthetic analysis of perophoramidine (3) was based on our previously established expedient synthesis of oxindole derivative 52 (Scheme 1.2.20). We speculated that the aminal and lactam ring functionalities of pentacycle 85, an Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 29 5o intermediate in Funk’s synthesis, could be cleaved, thereby leading to aldehyde 86. The N–C bond of the 6-bromooxindole moiety in 86 was excised to arrive at nitroarene 52. The construction of the contiguous quaternary centers at C(20) and C(4) of allyl ester 52 with the proper relative stereochemistry was accessed by decarboxylative allylic alkylation as previously described (Scheme 1.2.11b). Scheme 1.2.20. Retrosynthesis of Perophoramidine (3) TIPSO 22 Cl 19 17 N 24 N A B4 20 F D E N 12 N H 15 Cl 1 O 6 C 8 Perophoramidine (3) Br N N H H Boc Br 85 (Funk's intermediate) Br Br TIPSO H N O TIPSO NO 2 NBoc OO N 4 20 CO2Allyl O N 86 52 Carbamate 88 was obtained by reduction of nitroarene 52 with titanium chloride and simultaneous oxindole formation38 to furnish the bis-oxindole moiety 87 in 91% yield followed by protection with Boc anhydride in 85% yield (Scheme 1.2.21). Ozonolysis of olefin 88 produced aldehyde 86 in 90% yield. Reductive amination of aldehyde 86 with o-nitrobenzylammonium acetate 82 resulted in an amine that underwent in situ lactam formation to afford oxindole lactam 89 in 91% yield. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 30 Scheme 1.2.21. Synthesis of Amide 89 Br Br TIPSO TIPSO NO 2 TiCl3, NH 4OAc CO2Allyl O N NH i-PrOH, H 2O, 23 °C (91% yield) 52 OO N 87 Br TIPSO Boc 2O, DMAP NBoc MeCN, 23 °C (85% yield) O 3, then PPh 3 CH2Cl2, –78 °C (90% yield) OO N 88 O2N Br TIPSO NO 2 O 82 TIPSO N NH 3OAc NBoc OO N 86 O NaBH 3CN THF, MeOH 0 → 23 °C (91% yield) O N HN Br Boc 89 Initially, we attempted to generate the o-nitrobenzyl protected propellane hexacyclic oxindole 90 under analogous conditions to those used in our formal synthesis of communesin F on the pseudo diastereomeric series (vide supra). However, treatment of lactam 89 with Tf2O yielded an unexpected azepine 91 in 70% yield (Scheme 1.2.22). Both the Boc and the TIPS groups on amide 89 were removed under the reaction conditions, and the resulting primary alcohol was presumably converted to the corresponding triflate. Finally, the aniline likely attacked the newly formed triflate to form azepine 91. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 31 Scheme 1.2.22. Formation of Azepine 91 using Tf2O O2N TIPSO N N O O N O N HN NO 2 N Boc O Br Br Boc 89 90 (Not Observed) O2N Tf2O 0 → 23 °C CH2Cl2 (70% yield) Br O N HN O N 91 After extensive experimentation, we discovered that in contrast to the communesin system, the desired reductive cyclization in the perophoramidine diastereomer occurred directly with AlH3-Me2NEt31 to furnish cyclization product 92 in 42% yield (66% yield based on recovered starting material) (Scheme 1.2.23). The indoline methyl group was converted to a formyl group using PDC oxidation in 62% yield (93% yield based on recovered starting material).39 To our delight, an attempt to remove the formyl group with 20% aq NaOH at 75 °C resulted in removal of both the formyl group and the o-nitrobenzyl group to produce aminal 85 in 50% yield.37,40 This molecule was previously advanced by the Funk group to perophoramidine,5o and constitutes an expedient formal synthesis of the natural product. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 32 Scheme 1.2.23. Completion of Formal Synthesis of Perophoramidine O2N TIPSO O2N TIPSO N N AlH3-Me2NEt O O N HN O THF (42% yield) (66% yield, based on Br recovered 89 ) N N H Br Boc Boc 89 92 H TIPSO N 1. PDC, K 2CO3, CH2Cl2 (62% yield; 93% yield, based on recovered 92 ) O N 2. 20% aq NaOH, MeOH, 75 °C (50% yield) H H N Br Boc 85 N 9 steps N Cl Funk and co-workers (2004) N Cl N Br H Perophoramidine (3) 1.3. Conclusion   In conclusion, we have conducted synthetic studies toward unique polycyclic alkaloids, and completed formal syntheses of communesin F (1f) in 9% overall yield over 17 steps and perophoramidine (3) in 6% overall yield (13% overall yield, based on recovered starting material) over 10 steps using a unified stereodivergent alkylation approach. The all-carbon quaternary center on the oxindole was established via stabilized enolate alkylation of 3-bromooxindoles, a method previously developed by our laboratory and now shown to be quite versatile even in particularly sterically challenging situations. The complementary relative stereochemistry of the two contiguous quaternary stereogenic centers found in communesin F (1f) and perophoramidine (3) respectively, was established by substrate controlled diastereoselective decarboxylative allylic Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 33 alkylation. A reductive amination approach furnished the A ring, and reductive cyclization produced the D ring for both communesin F (1f) and perophoramidine (3). En route to the evolution of our eventual successful strategy, we have discovered a method to convert an indole to a 3-chloroindolenine using a mild reagent such as o-NsCl during the synthesis. In addition, previously unknown, mild and efficient deprotection conditions for the o-nitrobenzyl group on the lactam were discovered. Further studies to rationalize unprecedented complementary selectivity by Pd-catalyzed allylic alkylation reactions are currently in progress. 1.4. Experimental Methods and Analytical Data 1.4.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Triethylamine was distilled over CaH2 prior to use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Microwave-assisted reactions were performed in a Biotage Initiator 2.5 microwave reactor. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 34 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, panisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm), or (CD3)2CO (δ 2.05 ppm). 13C NMR spectra are recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm), or (CD3)2CO (δ 29.84 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). X-ray crystallography reports for compounds 29 and 32 can be found in ref 41.41 1.4.2. Experimental Procedures OH OsO 4 (cat), NMO HN Ts SI-1-1 THF/H2O, 23 °C (80% yield) HO HN Ts SI-1-2 Diol SI-1-2. To a solution of styrene SI-1-1 (6.11 g, 22.4 mmol, 1.0 equiv) in THF (140 mL) and water (70 mL) were added N-methylmorpholine N-oxide (5.96 g, 50.8 mmol, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 35 2.3 equiv) and osmium tetroxide (11.6 mg, 43.9 µmol, 0.002 equiv). After addition, reaction was stirred for three days. The reaction was then concentrated to approximately 50 mL under reduced pressure, then extracted with a mixture of ether and THF (1:1) (3 x 45 mL). The organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure. Impurities were removed by washing solid with dichloromethane to afford diol SI-1-2 (5.43 g, 80% yield) as a white solid. For spectrum, see ref 41. Rf = 0.13 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 7.78–7.65 (m, 2H), 7.39 (dd, J = 8.1, 1.1 Hz, 1H), 7.25–7.16 (m, 2H), 7.15–7.03 (m, 2H), 4.86–4.79 (m, 1H), 3.66–3.57 (m, 2H), 2.97 (s, 1H), 2.39 (s, 3H), 1.98 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 144.1, 137.1, 136.3, 129.9, 129.8, 129.2, 128.5, 127.4, 127.0, 122.2, 74.78, 66.0, 21.8; IR (Neat Film NaCl) 3271, 1318, 1150 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C15H18NO4S [M+H]+: 308.0951; found 308.0967. OH HO OH 1. BuSn(OMe) 2 HN Ts SI-1-2 2. MOMCl, Bu 4NI, 23 °C (90% yield, 2 steps) MOMO HN Ts 13 Alcohol 13. To a solution of diol SI-1-2 (500 mg, 1.63 mmol, 1.0 equiv) in toluene (70 mL) was added dibutyltin dimethoxide (410 µL, 1.79 mmol, 1.1 equiv). The flask was fitted with a short path distillation apparatus, and approximately half of the solvent was removed by distillation. To this solution was added MOMCl (136 µL, 1.79 mmol, 1.1 equiv) and tetrabutylammonium iodide (900 mg, 2.44 mmol, 1.5 equiv). After addition, the reaction was stirred for 12 h. Then, brine was added to this solution. The reaction Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 36 mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford alcohol 13 (513 mg, 90% yield, 2 steps) as a white solid. For spectrum, see ref 41. Rf = 0.27 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.27–7.20 (m, 3H), 7.11–7.02 (m, 2H), 4.83–4.78 (m, 1H), 4.64 (s, 2H), 3.60 (dd, J = 10.5, 3.5 Hz, 1H), 3.48–3.41 (m, 2H), 3.39 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.9, 137.1, 136.3, 129.7, 129.5, 128.9, 128.2, 127.2, 124.7, 122.0, 97.0, 73.3, 72.4, 55.6, 21.6; IR (Neat Film NaCl) 3233, 2932, 1598, 1497, 1335, 1161 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H22NO5S [M+H]+: 352.1213; found 352.1219. O O Me MeO S Me I CO2Me Me NaH O N H SI-1-3 O DMSO 23 → 50 °C (69% yield) (1.6:1 dr) N H 16 Cyclopropane 16. A flame-dried flask (25 mL) equipped with a teflon stirbar was charged with sodium hydride (60% dispersion in mineral oil, 22 mg, 0.55 mmol, 1.1 equiv), which was washed 3 times with dry hexanes. Then, DMSO (5.5 mL) and trimethyl sulfoxonium iodide (119 mg, 0.58 mmol, 1.2 equiv) were added. To this solution was added oxindole SI-1-3 (100 mg, 0.49 mmol, 1.0 equiv) in a solution of DMSO (2.5 mL). After addition, the reaction was stirred for 2 h, and then the temperature was raised to 50 °C. The reaction was complete after another hour. Brine Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 37 was added and then the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford oxindole 16 as two diastereomers. Diastereomer 1: (44.7 mg, 42% yield); Diastereomer 2: (28.6 mg, 27% yield). For spectrum, see ref 41. Diastereomer 1: Rf = 0.52 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 9.40 (s, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.04–6.97 (m, 2H), 3.70 (s, 3H), 2.74 (t, J = 8.0 Hz, 1H), 2.18 (dd, J = 4.5, 7.5 Hz, 1H), 2.05 (dd, J = 4.5, 8.5 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 177.5, 169.3, 141.8, 127.9, 126.4, 123.0, 122.4, 110.3, 52.4, 34.3, 32.9, 21.1; IR (Neat Film NaCl) 3214, 1712, 1622, 1470, 1209 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H12NO3 [M+H]+: 218.0812; found 218.0825. Diastereomer 2: Rf = 0.45 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 7.27–7.20 (m, 1H), 7.04–6.97 (m, 2H), 6.83 (d, J = 7.5 Hz, 1H), 3.75 (s, 3H), 2.68 (t, J = 8.0 Hz, 1H), 2.40 (dd, J = 5.0, 8.0 Hz, 1H), 1.84 (dd, J = 5.0, 8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.0, 167.7, 141.1, 129.5, 188.0, 122.4, 118.9, 110.3, 52.6, 33.5, 32.9, 21.3; IR (Neat Film NaCl) 3256, 1739, 1710 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H12NO3 [M+H]+: 218.0812; found 218.0828. 1. EtOH, H 2SO4 (cat) PhMe, reflux HO 2C 2. H 2SO4, 110 °C (44% yield, 2 steps) O2N 21 O HO O N 20 Acid 20. A flame-dried flask (500 mL) equipped with a teflon stirbar was charged with acid 21 (10.0 g, 55.2 mmol, 1.0 equiv), ethanol (60 mL), sulfuric acid (200 µL), and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 38 toluene (280 mL). The flask was fitted with a condenser, and the solution was refluxed for 14 h. The solvent was removed under reduced pressure and sulfuric acid (280 mL) was added. After addition, the reaction was heated to 110 °C and stirred for 90 min. The solution was then poured onto ice (600 g), the mixture was extracted with ether (3 x 200 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. Purification was performed via crystallization from water to afford acid 20 (3.94 g, 44% yield, 2 steps) as an off-white solid. For spectrum, see ref 41. 1 H NMR (300 MHz, acetone-d6) δ 10.82 (br, s, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 10.0 Hz, 1H), 7.50 (dd, J = 6.5, 9.5 Hz, 1H), 7.34 (dd, J = 7.0, 8.5 Hz, 1H); 13C NMR (75 MHz, acetone-d6) δ 158.5, 158.1, 155.3, 132.4, 128.8, 121.4, 121.0, 116.7; IR (Neat Film NaCl) 2360, 1731, 1301, 1231, 1189, 753 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C8H6NO3 [M+H]+: 164.0342; found 164.0341. OH OH H N NO 2 NO 2 NaH, MeI Zn(Hg), HCl THF, 0 → 23 °C (90% yield) MeOH, reflux (60% yield) N H N SI-1-4 SI-1-5 N 5 1-methylaurantioclavine 5. To a solution of indole SI-1-4 (386 mg, 1.41 mmol, 1.0 equiv) in THF (14 mL) was added methyl iodide (875 µL, 14.1 mmol, 10 equiv) at 0 °C. Sodium hydride (60% dispersion in mineral oil, 562 mg, 14.5 mmol, 10.3 equiv) was then added to the solution, and the mixture was stirred for 25 min at 23 °C. The reaction was quenched with saturated ammonium hydroxide solution and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, and concentrated in Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 39 vacuo. The residue was purified by flash column chromatography (3:1 → 2:1 hexanes:EtOAc) to afford nitro compound SI-1-5 (363.5 mg, 90% yield) as a yellow solid. To a solution of nitro compound SI-1-5 (512 mg, 1.78 mmol, 1.0 equiv) in MeOH (125 mL) and 2N HCl (40 mL) was added amalgamated zinc, which had been formed from zinc dust (6.5 g, 98.3 mmol, 55 equiv) and mercuric chloride (1.10 g, 3.55 mmol, 2.0 equiv) in 2N HCl and subsequently rinsed with MeOH. The mixture was stirred at reflux for 3 h. The reaction was then decanted from the remaining amalgam and then basified to pH >10. The solid was removed by filtration, and the resulting solution was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (18:1 CH2Cl2:MeOH) to afford 1-methylaurantioclavine 5 (258 mg, 60% yield) as a yellow oil. For spectrum, see ref 41. Rf = 0.30 (18:1 CH2Cl2:MeOH); 1H NMR (300 MHz, CDCl3) δ 7.19–7.12 (m, 2H), 6.89–6.83 (m, 2H), 5.48 (d, J = 9.0 Hz, 1H), 4.92 (d, J = 9.0 Hz, 1H), 3.76 (s, 3H), 3.62– 3.54 (m, 1H), 3.13–3.02 (m, 3H), 2.26 (br, s, 1H), 1.86 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 138.5, 137.8, 133.3, 127.7, 125.9, 121.1, 117.4, 114.2, 107.3, 62.6, 48.9, 32.7, 30.8, 25.9, 18.4; IR (Neat Film NaCl) 3332, 2910, 1554, 1455 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C16H21N2 [M+H]+: 241.1699; found 241.1712. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 40 N O O HO 1. (COCl)2, CH2Cl2 DMF, 23 °C O 2. N O N H N 20 N H N H 4 CH2Cl2, Et 3N, 23 °C (91% yield, 2 steps) 22 Amide 22. To a solution of acid 20 (262 mg, 1.60 mmol, 1.25 equiv) in dichloromethane (5 mL) was added oxalyl chloride (420 µL, 4.81 mmol, 3.8 equiv) and then a small amount of DMF (~20 µL). The reaction was stirred for 1 h then the solvent was removed under reduced pressure; the residue was evaporated from benzene (2 mL) to remove excess reagent. Dichloromethane (10 mL) and triethylamine (537 µL, 3.85 mmol, 3.0 equiv) were added, and to this solution was added aurantioclavine 4 (290 mg, 1.28 mmol, 1.0 equiv). After addition, the reaction was stirred for 60 min, and then brine was added. The resulting solution was extracted with EtOAc (3 x 7 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford amide 22 (435 mg, 91% yield, 2 steps) as a white solid. For spectrum, see ref 41. Rf = 0.72 (1:2 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (300 MHz, CDCl3) δ 9.00–8.86 (m, 2H), 7.98 (dq, J = 8.9, 0.9 Hz, 1H), 7.71–7.57 (m, 3H), 7.35–7.27 (m, 2H), 7.25–7.22 (m, 1H), 7.22–7.16 (m, 3H), 7.15–7.07 (m, 2H), 7.07–7.01 (m, 2H), 7.01–6.94 (m, 2H), 6.90–6.83 (m, 2H), 6.70 (d, J = 7.5 Hz, 1H), 5.48 (ddq, J = 7.9, 2.8, 1.6 Hz, 2H), 4.82–4.66 (m, 2H), 4.07 (ddd, J = 15.4, 10.0, 5.8 Hz, 1H), 3.82 (td, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 41 J = 13.0, 2.6 Hz, 1H), 3.60–3.46 (m, 1H), 3.23–3.12 (m, 3H), 1.96 (d, J = 1.3 Hz, 3H), 1.79 (d, J = 1.5 Hz, 3H), 1.73 (d, J = 1.6 Hz, 3H), 1.64 (d, J = 1.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5, 158.4, 157.9, 157.8, 156.9, 156.8, 137.7, 137.4, 137.2, 136.9, 135.2, 135.1, 131.5, 131.4, 126.4, 126.1, 124.7, 124.3, 123.9, 123.8, 122.1, 121.9, 121.8, 121.7, 121.1, 121.0, 119.9, 118.3, 117.5, 114.9, 113.3, 112.6, 110.1, 109.9, 61.0, 57.5, 44.5, 43.1, 29.1, 25.9, 25.8, 25.7, 18.9, 18.2; IR (Neat Film NaCl) 3325, 2914, 2246, 1730, 1616, 1447 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H22N3O2 [M+H]+: 372.1707; found: 372.1637. N O HO 1. (COCl)2, CH2Cl2 DMF, 23 °C O 2. N O O N H N 20 N N 5 19 CH2Cl2, Et 3N, 23 °C (77% yield, 2 steps) Amide 19. To a solution of acid 20 (37.5 mg, 0.229 mmol, 1.1 equiv) in dichloromethane (500 µL) was added oxalyl chloride (59 µL, 0.676 mmol, 3.3 equiv) and then a small amount of DMF (~1 µL). The reaction was stirred for 1 h, and then the solvent was removed under reduced pressure. The residue was evaporated from benzene (1 mL) to remove excess reagent. Dichloromethane (1.1 mL) and triethylamine (30 µL, 0.215 mmol, 1.03 equiv) were added, and to this solution was added 1methylaurantioclavine 5 (50.0 mg, 0.208 mmol, 1.0 equiv). After addition, the reaction was stirred for 60 min, and then brine was added. The resulting solution was extracted with EtOAc (3 x 1.5 mL). The combined organic layers were dried over MgSO4, and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 42 concentrated in vacuo. The residue was purified by flash column chromatography (3:1 → 2:1 hexanes:EtOAc) to afford amide 19 (61.6 mg, 77% yield, 2 steps) as a white solid. Rf = 0.79 (1:2 hexanes:EtOAc); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks. For spectrum, see ref 41), 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.62 (t, J = 10.0 Hz, 1H), 7.37–7.30 (m, 1.5H), 7.22–7.18 (m, 2H), 7.13–7.08 (m, 2H), 7.04–6.99 (m, 1H), 6.95 (s, 1H), 6.86–6.84 (m, 2H), 6.67 (d, J = 7.5 Hz, 1H), 5.46 (d, J = 7.5 Hz, 1H), 4.69 (dd, J = 15.0, 38.0 Hz, 1H), 4.04 (dt, J = 4.5, 15.5 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.48 (t, J = 18.0 Hz, 1H), 3.25 (3.11, m, 2H), 1.92 (s, 3H), 1.78 (s, 3H), 1.72 (s, 3H), 1.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5, 158.5, 157.7, 157.6, 156.9, 156.8, 137.8, 137.7, 137.6, 136.8, 135.7, 135.6, 131.3, 131.2, 126.5, 126.3, 125.9, 124.8, 124.4, 124.3, 124.2, 122.1, 121.6, 121.5, 121.2, 121.1, 120.0, 118.1, 117.3, 115.0, 114.9, 112.3, 111.7, 107.9, 107.7, 60.9, 57.3, 44.5, 43.1, 32.6, 29.0, 25.9, 25.7, 18.9, 18.2; IR (Neat Film NaCl) 2913, 2245, 1615, 1455, 1410 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C24H24N3O2 [M+H]+: 386.1863; found 386.1775. N O O O N HCl, MeOH N O N H H 0 → 23 °C (31% yield) N H N H 22 23 Indole 23. A flame-dried vial (20 mL) equipped with a teflon stirbar was charged with amide 22 (100 mg, 0.269 mmol, 1.0 equiv) and cooled to 0 °C. To this reaction mixture Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 43 was added a 0.5 M solution of HCl in MeOH (2.7 mL, generated from addition of acetyl chloride to methanol at 0 oC) at 0 °C. The mixture was stirred for 1 h and then warmed to 23 oC over 30 min. The solvent was then removed under reduced pressure. Purification was performed by washing the solid with dichloromethane to afford indole 23 (31.1 mg, 31% yield) as a white solid. For spectrum, see ref 41. Rf = 0.22 (1:1 hexane:EtOAc); 1H NMR (300 MHz, acetone-d6) δ 11.05 (s, 1H), 7.34– 7.17 (m, 6H), 7.09 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 5.47 (d, J = 6.5 Hz, 1H), 4.21 (d, J = 13.0 Hz, 1H), 3.44 (t, J = 11.0 Hz, 1H), 3.18–2.98 (m, 2H), 2.37 (d, J = 6.5 Hz, 1H), 1.77 (s, 3H), 1.04 (s, 3H); 13C NMR (75 MHz, DMSO) δ 164.3, 153.0, 139.6, 137.0, 134.6, 127.3, 126.6, 123.7, 122.6, 121.4, 118.6, 118.0, 115.2, 112.7, 110.2, 96.4, 70.1, 63.1, 61.2, 44.4, 26.9, 26.6, 26.0; IR (Neat Film NaCl) 3314, 1681, 753 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H22N3O2 [M+H]+: 372.1707; found 372.1710. N O O O N HCl, MeOH N O N H H 0 → 23 °C (99% yield) N N 19 24 Indole 24. A flame-dried vial (20 mL) equipped with a teflon stirbar was charged with amide 19 (100 mg, 0.259 mmol, 1.0 equiv) and cooled to 0 °C. To this solution was added a 0.5 M solution of HCl in MeOH (2.6 mL, generated from addition of acetyl chloride to methanol at 0 °C) at 0 °C. The mixture was stirred for 1 h and then warmed Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 44 to 23 °C over 30 min. The solvent was then removed under reduced pressure. Purification was performed via flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford indole 24 (101 mg, 99% yield) as a white solid. For spectrum, see ref 41. Rf = 0.29 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.37–7.17 (m, 6H), 7.00 (s, 1H), 6.76–6.73 (m, 1H), 5.51 (d, J = 6.5 Hz, 1H), 4.57–4.50 (m, 1H), 3.80 (s, 3H), 3.50–3.15 (m, 3H), 2.57 (d, J = 6.5 Hz, 1H), 1.95 (s, 3H), 1.18 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.4, 153.5, 139.8, 137.9, 135.6, 127.5, 127.0, 126.9, 124.6, 121.9, 119.1, 118.4, 115.9, 113.4, 108.4, 97.2, 70.9, 64.1, 61.9, 45.2, 33.0, 27.5, 27.2, 26.6; IR (Neat Film NaCl) 3315, 2932, 1699, 1456, 1317, 754 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C24H24N3O2 [M+H]+: 386.1863; found 386.1809. O F 3C H N N CF3CO2COCF3, Et 3N N H 4 THF, 0 °C (82% yield) N H 25 N-trifluoroacetate-aurantioclavine 25. To a solution of aurantioclavine 4 (882 mg, 3.90 mmol, 1.0 equiv) in THF (14 mL) were added triethylamine (820 µL, 5.88 mmol, 1.5 equiv) and trifluoroacetic anhydride (606 µL, 4.29 mmol, 1.1 equiv) at 0 oC. The reaction was complete immediately, so it was quenched with methanol. The solvent was then removed under reduced pressure. Purification was performed via flash column chromatography (9:1 → 3:1 hexanes:EtOAc) to afford the N-trifluoroacetateaurantioclavine 25 (1.03 g, 82% yield) as a yellow foam. For spectrum, see ref 41. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 45 Rf = 0.30 (3:1 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (300 MHz, CDCl3) δ 8.51 (br, s, 1H), 7.29–7.26 (m, 1H), 7.02–6.97 (m, 2H), 6.90 (t, J = 7.0 Hz, 1H), 6.23 (d, J = 8.0 Hz, 1H), 5.40 (dd, J = 7.5, 19.5 Hz, 1H), 4.40 (d, J = 13.0 Hz, 1H), 4.16–4.10 (m, 1H), 4.04–3.94 (m, 2H), 3.83 (t, J = 13.0 Hz, 1H), 3.43 (t, J = 16.5 Hz, 1H), 3.27–3.23 (m, 1H), 3.09 (d, J = 16.5 Hz, 1H), 1.91 (s, 3H), 1.86 (s, 3H), 1.78 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 157.5, 157.0, 156.8, 156.3, 138.5, 137.4, 137.2, 137.2, 135.1, 134.4, 124.3, 123.9, 123.5, 123.3, 122.1, 121.9, 121.8, 119.0, 118.8, 118.5, 117.1, 115.2, 115.0, 113.1, 112.6, 110.3, 110.1, 60.7, 60.6, 58.6, 43.7, 43.7, 28.4, 26.2, 25.7, 25.0, 18.9, 18.2; IR (Neat Film NaCl) 3361, 2917, 1667, 1441, 1205 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H18N2OF3 [M+H]+: 323.1366; found 323.1308. N3 N3 N3 Br NBS THF, t-BuOH, H 2O –40 → 0 °C N H SI-1-6 + O N H SI-1-7 (25% yield) O N H 26 (64% yield) Bromooxindole 26. A flame-dried flask (1000 mL) equipped with a teflon stirbar was charged with azide SI-1-61 (5.03 g, 30.3 mmol, 1.0 equiv), to which was subsequently added THF (150 mL), t-BuOH (150 mL), and water (3.75 mL) and cooled to –40 °C. A 0 °C solution of NBS (8.03 g, 45.1 mmol, 1.5 equiv) in THF (450 mL) was then added via cannula over 30 min, and the resulting solution was allowed to warm to –10 °C over 2 h. Warming continued slowly over 30 min to 0 °C. After 20 min at 0 °C, the solvent was                                                                                                                 1  Suzuki, T.; Ota, Y.; Ri, M.; Bando, M.; Gotoh, A.; Itoh, Y.; Tsumoto, H.; Tatum, P. R.; Mizukami, T.; Nakagawa, H.; Iida, S.; Ueda, R.; Shirahige, K.; Miyata, N. J. Med. Chem. 2012, 55, 9562.   Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 46 removed under reduced pressure. Purification was performed via flash column chromatography (9:1→1:2 pentanes:ether) to afford bromooxindole 26 (5.46 g, 64% yield) as a yellow solid. Oxindole SI-1-7 (1.50 g, 25% yield) was also isolated as a light yellow solid. For spectrum, see ref 41. Bromooxindole 26: Rf = 0.46 (2:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.12 (br, s, 1H), 7.28–7.23 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 3.61– 3.44 (m, 2H), 2.32–2.17 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 180.5, 141.7, 128.4, 128.1, 123.8, 122.3, 110.2, 48.0, 43.3, 29.5; IR (Neat Film NaCl) 3228, 2100, 1693, 1620, 1470 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H10N4OBr [M+H]+: 281.0033; found 281.0040. Oxindole SI-1-7: Rf = 0.37 (2:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.21 (br, s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 3.41–3.20 (m, 3H), 2.84–2.57 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 176.6, 139.8, 130.6, 129.1, 124.6, 123.5, 111.4, 54.5, 47.6, 38.0; IR (Neat Film NaCl) 3252, 2102, 1732, 1619, 1471 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H11N4O[M+H]+: 203.0927; found 203.0933. O O H N H N Br THF 23 °C (69% yield) O N H N3 Cs2CO3 + 25 F 3C N3 F 3C N H 26 N H NH O 28 Adduct 28. A flame-dried vial (20 mL) equipped with a teflon stirbar was charged with indole 25 (120 mg, 0.372 mmol, 1.0 equiv) and bromooxindole 26 (157 mg, 0.559 mmol, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 47 1.5 equiv), which were subsequently dissolved in THF (4 mL). Cesium carbonate (243 mg, 0.746 mmol, 2.0 equiv) was then added. After addition, the reaction was stirred for 12 h, and then water was added. The resulting solution was extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (9:1 → 2:1 hexanes:EtOAc) to afford adduct 28 (134 mg, 69% yield) as a yellow foam. For spectrum, see ref 41. Rf = 0.34 (2:1 hexanes:EtOAc x2 elutions); (Due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1 H NMR (300 MHz, CDCl3) δ 8.74 (br, s, 2H), 8.59 (br, s, 1H), 8.97 (br, s, 1H), 7.34– 6.86 (m, 12H), 6.78 (t, J = 7.0 Hz, 1H), 6.11 (d, J = 8.0 Hz, 1H), 5.33 (dd, J = 7.5, 20.5 Hz, 2H), 4.16 (d, J = 13.5 Hz, 1H), 3.96–3.90 (m, 1H), 3.80 (t, J = 16.0 Hz, 1H), 3.63 (t, J = 13.5 Hz, 1H), 3.25–3.12 (m, 5H), 3.09–2.86 (m, 3H), 2.65–2.53 (m, 3H), 1.84 (s, 3H), 1.80 (s, 3H), 1.71 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 178.8, 178.7, 157.1, 156.7, 156.5, 156.0, 141.4, 141.3, 138.4, 137.0, 136.0, 135.6, 135.1, 134.4, 130.1, 129.9, 129.8, 129.5, 129.5, 125.5, 125.0, 124.9, 124.8, 124.4, 123.7, 123.3, 122.4, 122.2, 119.5, 119.0, 118.7, 118.1, 114.9, 111.8, 111.5, 111.2, 111.2, 110.1, 109.8, 60.5, 58.3, 52.7, 52.6, 47.3, 47.3, 43.5, 43.4, 35.0, 34.8, 28.1, 26.3, 25.8, 24.5, 19.0, 18.3; IR (Neat Film NaCl) 3335, 2102, 1713, 1674 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C27H26N6O2F3 [M+H]+: 523.2064; found 523.1982. O O F 3C F 3C H N H N N3 o-NsCl, NaH N3 Cl THF, 0 °C (73% yield) N H 28 NH N N O O 29 Ns Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 48 Chloride 29. To a solution of adduct 28 (183 mg, 0.350 mmol, 1.0 equiv) in THF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 42 mg, 1.05 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred for 5 min and o-nitrobenzylsulfonyl chloride (116 mg, 0.523 mmol, 1.5 equiv) was added at 0 oC. The reaction was stirred for 10 min, and then a saturated solution of ammonium chloride was added. The resulting solution was extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (15:1 → 2:1 hexanes:EtOAc) to afford alkyl chloride 29 (142 mg, 73% yield) as a white crystalline solid. For spectrum, see ref 41. Rf = 0.26 (2:1 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (300 MHz, CDCl3) δ 8.64–8.59 (m, 2H), 7.95–7.84 (m, 8H), 7.55–7.47 (m, 6H), 7.37–7.26 (m, 5H), 7.15 (d, J = 7.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 7.5 Hz, 2H), 5.76– 5.72 (m, 2H), 5.61 (d, J = 7.5 Hz, 1H), 4.20–4.08 (m, 2H), 3.94–3.67 (m, 3H), 3.31–3.19 (m, 2H), 2.99–2.74 (m, 6H), 2.29 (dd, J = 3.0, 10.5 Hz, 1H), 1.75 (s, 6H), 1.65 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 175.9, 175.8, 173.8, 173.6, 156.3, 155.9, 151.7, 151.6, 148.2, 147.9, 141.6, 140.7, 139.9, 139.7, 139.2, 138.2, 137.4, 136.9, 136.4, 136.0, 135.3, 135.2, 132.6, 130.9, 130.8, 130.4, 130.4, 128.3, 126.8, 126.6, 126.4, 126.3, 125.8, 125.4, 125.3, 125.2, 124.9, 121.7, 121.6, 120.6, 119.8, 118.6, 115.4, 115.3, 114.8, 77.7, 77.4, 77.2, 76.8, 75.7, 75.5, 60.1, 57.6, 55.7, 55.6, 46.5, 46.4, 40.0, 39.1, 37.8, 37.6, 36.1, 32.6, 26.5, 26.0, 18.6, 18.1; IR (Neat Film NaCl) 2102, 1755, 1686, 1544, 1146 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C33H28O7N7F3SCl [M+H]+: 758.1406; found 758.1442. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 49 O O F 3C H N H N 26, Cs2CO3 N H 25 O F 3C F 3C CH2Cl2 23 °C 28 + (24% yield) N H N N3 + NH N 3 H N N3 O N H 30 (32% yield) H O O N H 31 (24% yield) Adducts 28, 30, and 31. A flame-dried flask (100 mL) equipped with a teflon stirbar was charged with indole 25 (1.03 g, 3.21 mmol, 1.0 equiv) and bromooxindole 26 (2.25 mg, 8.02 mmol, 2.5 equiv), which were subsequently dissolved in dichloromethane (32 mL). Cesium carbonate (3.14 g, 9.62 mmol, 3.0 equiv) was then added. After addition, the reaction was stirred for 3 h, and then water was added. The resulting solution was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (18:1 → 1:2 hexanes:EtOAc) to afford adduct 28 (404 mg, 24% yield), adduct 30 (538 mg, 32% yield), and adduct 31 (548 mg, 24% yield). For spectrum, see ref 41. Adduct 30: Rf = 0.18 (2:1 hexanes:EtOAc x2 elutions); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks), 1H NMR (300 MHz, CDCl3) δ 8.91 (d, J = 13.0 Hz, 2H), 8.33 (d, J = 6.0 Hz, 2H), 7.28–6.86 (m, 9H), 6.75 (d, J = 7.5 Hz, 1H), 6.11 (d, J = 7.5 Hz, 1H), 5.31 (dd, J = 7.5, 29.5 Hz, 2H), 4.30 (d, J = 13.5 Hz, 1H), 4.06–4.01 (m, 1H), 3.94–3.84 (m, 1H), 3.71 (t, J = 13.0 Hz, 1H), 3.29 (t, J = 13.0 Hz, 1H), 3.17–3.13 (m, 4H), 2.98 (d, J = 16.5 Hz, 1H), 2.89–2.75 (m, 2H), 2.53–2.44 (m, 2H), 1.76 (s, 3H), 1.72 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 181.1, 180.9, 157.4, 157.0, 156.7, 156.2, 141.1, 138.5, 137.5, 137.3, 137.1, 135.5, 134.8, 133.4, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 50 133.2, 132.2, 132.1, 128.8, 128.7, 125.1, 124.0, 123.6, 123.2, 123.1, 122.8, 122.5, 119.0, 118.7, 117.0, 115.7, 115.1, 114.9, 113.3, 112.6, 110.7, 108.6, 108.5, 60.6, 58.6, 55.5, 55.4, 47.9, 43.8, 43.7, 36.6, 36.3, 28.4, 26.3, 25.8, 25.0, 18.9, 18.3; IR (Neat Film NaCl) 3328, 2100, 1712, 1682 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C27H26N6O2F3 [M+H]+: 523.2064, found 523.2002. Adduct 31: Rf = 0.09 (2:1 hexanes:EtOAc x2 elutions); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks), 1H NMR (300 MHz, acetone-d6) δ 10.43 (d, J = 11.5 Hz, 1H), 9.80 (d, J = 8.0 Hz, 1H), 9.59 (s, 1H), 7.36–7.23 (m, 7H), 7.19–6.97 (m, 8H), 5.36 (dd, J = 7.0, 40.0 Hz, 2H), 4.02–3.50 (m, 6H), 3.25–3.10 (m, 8H), 3.04 (s, 2H), 3.01–2.44 (m, 8H), 1.76 (s, 3H), 1.73 (s, 3H), 1.68 (s, 6H); 13C NMR (75 MHz, acetone-d6) δ 180.2, 180.1, 177.9, 177.8, 143.1, 143.0, 142.9, 138.3, 137.4, 137.2, 136.8, 135.3, 134.8, 134.6, 134.4, 133.6, 133.3, 133.2, 133.0, 131.3, 129.9, 129.3, 129.2, 126.1, 125.3, 125.2, 125.0, 124.8, 123.9, 123.6, 122.9, 118.0, 147.1, 111.0, 110.9, 110.3, 109.9, 109.4, 109.2, 61.2, 59.2, 55.8, 55.7, 52.7, 52.7, 48.6, 47.6, 44.0, 37.0, 36.9, 35.4, 28.2, 26.1, 25.7, 24.8, 18.8, 18.3; IR (Neat Film NaCl) 3305, 2101, 1713, 1472 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C37H34N10F3O3 [M+H]+: 723.2762; found 723.2689. O O F 3C F 3C H N H N o-NsCl N N3 H O N H NaH, THF, 0 °C (66% yield) N N3 Ns O N Ns 30 SI-1-8 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 51 Nosylate SI-1-8. A flame-dried vial (4 mL) equipped with a teflon stirbar was charged with adduct 30 (43.7 mg, 0.0836 mmol), which was subsequently dissolved in THF (800 µL). The solution was cooled to 0 °C, and then sodium hydride (60% dispersion in mineral oil, 17 mg, 0.425 mmol) was added. 5 min after the sodium hydride addition, onitrobenzylsulfonyl chloride (93 mg, 0.420 mmol) was added. The reaction was stirred for 10 min, and then a saturated solution of ammonium chloride was added. The resulting solution was extracted 3 times with ether, the organic layers were combined and dried over magnesium sulfate, and the solvent was removed under reduced pressure. Purification was performed via flash column chromatography (9:1 →1:1 hexanes:EtOAc) to afford the bisnosylate SI-1-8 (49.0 mg, 66% yield) as a yellow solid. For spectrum, see ref 41. Rf = 0.42 (1:1 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1 H NMR and 13C NMR contained extra peaks), 1H NMR (300 MHz, CDCl3) δ 8.54–8.51 (m, 2H), 8.03–8.00 (m, 2H), 7.88–7.56 (m, 10H), 7.50 (s, 1H), 7.42–7.35 (m, 5H), 7.18– 7.12 (m, 3H), 6.95 (s, 1H), 6.61 (d, J = 7.5 Hz, 1H), 5.97 (d, J = 7.5 Hz, 1H), 5.23–5.16 (m, 2H), 4.27 (d, J = 13.5 Hz, 1H), 4.02 (d, J = 15.0 Hz, 1H), 3.89–3.79 (m, 1H), 3.64 (t, J = 11.0 Hz, 1H), 3.32–2.80 (m, 10H), 2.48–2.33 (m, 2H), 1.73 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 176.2, 176.0, 157.3, 156.9, 156.5, 148.0, 148.0, 140.2, 140.1, 140.0, 138.6, 137.2, 136.6, 136.2, 136.0, 135.7, 135.5, 134.8, 134.7, 132.8, 132.8, 132.4, 131.2, 131.2, 131.1, 130.9, 130.6, 129.9, 129.8, 129.5, 129.2, 127.4, 127.0, 125.7, 125.7, 125.4, 125.4, 125.2, 125.1, 124.9, 122.8, 121.9, 121.1, 120.0, 118.8, 118.5, 117.9, 115.5, 114.9, 110.6, 60.2, 58.1, 55.0, 55.0, 47.5, 42.8, 42.7, 36.6, 36.6, 39.9, 28.0, 26.3, 25.8, 25.0, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 52 -1 18.9, 18.3; IR (Neat Film NaCl) 2930, 2101, 1754, 1684, 1544 cm ; HRMS (MM: ESIAPCI+) m/z calc’d for C39H32N8O12F3S2 [M+H]+: 925.1528, found 925.1613. O O F 3C F 3C H N H N PPh 3 N N3 Ns H 2O, THF, 50 °C (66% yield) O HN N O NsHN Ns N Ns SI-1-8 32 Lactam 32. To a solution of nosylate SI-1-8 (43.1 mg, 0.0483 mmol, 1.0 equiv) in THF (1 mL) and water (250 µL) was added triphenylphosphine (25 mg, 0.0953 mmol, 2.0 equiv). The reaction was stirred for 3 h at 50 °C, and then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford the lactam 32 (49.0 mg, 66% yield) as a yellow crystalline solid. For spectrum, see ref 41. Rf = 0.14 (1:1 hexanes:EtOAc); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks), 1H NMR (300 MHz, CDCl3) δ 7.75–7.50 (m, 6H), 7.43 (t, J = 7.5 Hz, 1H), 7.34–7.22 (m, 4H), 7.14 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 7.5 Hz, 2H), 6.55 (d, J = 6.5 Hz, 2H), 6.01 (d, J = 7.5 Hz, 1H), 5.32 (d, J = 8.0 Hz, 1H), 5.20 (d, J = 8.0 Hz, 1H), 4.26 (d, J = 13.5 Hz, 1H), 4.02 (d, J = 15.5 Hz, 1H), 3.81 (t, J = 11.5 Hz, 1H), 3.30–3.00 (m, 3H), 2.35–2.28 (m, 2H), 1.67 (s, 3H), 1.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 180.0, 157.3, 156.8, 156.7, 156.2, 147.9, 147.8, 147.7, 139.5, 139.4, 137.8, 137.5, 137.4, 136.9, 136.5, 136.4, 136.2, 136.1, 135.6, 135.3, 135.1, 133.6, 132.9, 132.5, 132.2, 132.0, 131.0, 130.9, 130.5, 129.0, 127.9, 127.8, 126.3, 126.2, 125.2, 125.1, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 53 125.0, 124.9, 124.8, 124.5, 124.4, 124.3, 123.3, 122.4, 121.4, 120.5, 119.2, 118.9, 118.5, 118.4, 115.1, 110.2, 109.7, 77.7, 77.4, 77.2, 76.8, 60.1, 58.2, 57.7, 43.0, 42.8, 39.8, 38.8, 28.5, 26.1, 25.7, 25.3, 18.9, 18.3; IR (Neat Film NaCl) 3098, 2916, 1682, 1545, 1368, 1170, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C39H34N6O12F3S2 [M+H]+: 899.1623, found 899.1731. Ts H N Ts N N TsCl, Et 3N N H SI-1-9 CH2Cl2 0 → 23 °C (82% yield) pyridinium tribromide N H SI-1-10 THF/t-BuOH/H2O 0 → 23 °C (75% yield) O N H SI-1-11 Oxindole SI-1-11. To a solution of indole SI-1-9 (106 mg, 0.614 mmol, 1.0 equiv) and Et3N (0.17 mL, 1.23 mmol, 2.0 equiv) in CH2Cl2 (4 mL) cooled to 0 oC was added a solution of TsCl (117 mg, 0.614 mmol, 1.0 equiv) in CH2Cl2 (3 mL) dropwise. The ice bath was removed and the reaction mixture was stirred for 5 h, then diluted with EtOAc (160 mL) and washed with 0.5 N HCl (2 x 30 mL) and brine. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) to afford indole SI-1-10 (164 mg, 82% yield). Indole SI-1-10 was dissolved in THF (10 mL), t-BuOH (10 mL) and water (1 mL). The solution was cooled to 0 oC and pyridinium tribromide (504 mg, 1.54 mmol, 1.02 equiv) was added. The reaction mixture was stirred at 0 oC for 45 min and then allowed to warm to ambient temperature. The reaction was quenched by addition of 10 mL of 1:1 v/v 1M Na2S2O3:sat. NaHCO3. The reaction mixture was diluted with brine (50 mL) and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 54 extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried with MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (2:1 hexanes:acetone) to afford oxindole SI-1-11 (397 mg, 75% yield) of as a white solid. Rf = 0.15 (1:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.04 (br, s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.21–7.14 (m, 3H), 6.94 (d, J = 7.7 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 4.80 (d, J = 15.5 Hz, 1H), 4.30 (d, J = 13.6 Hz, 1H), 4.15 (d, J = 15.5 Hz, 1H), 3.52 (dd, J = 12.5, 3.5 Hz, 1H), 3.24 (t, J = 12.6 Hz, 1H), 2.38 (s, 3H), 2.30 (m, 1H), 1.53 (m, 1H); 13C (75 MHz, CDCl3) δ 178.4, 143.3, 140.5, 137.1, 135.9, 129.6, 128.4, 128.3, 127.0, 121.5, 109.1, 53.3, 51.6, 46.2, 28.6, 21.5; IR (Neat Film NaCl) 3276, 2925, 2853, 1698, 1618, 1463, 1326, 1153 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C18H19N2O3S [M+H]+ : 343.1111; found: 343.1025. Ts Ts N N Br LiHMDS, NBS O N H SI-1-11 O THF, –78 → –40 °C (76% yield) N H 35 Bromooxindole 35. LiHMDS (429 mg, 2.57 mmol, 2.5 equiv) was dissolved in THF (5 mL). The solution was cooled to –78 oC and a solution of oxindole SI-1-11 (352 mg, 1.03 mmol, 1.0 equiv) in THF (20 mL) was added dropwise over 20 min. The reaction mixture was stirred at –78 oC for 20 min and transferred to a pre-cooled solution of Nbromosuccinimide (457 mg, 2.57 mmol, 2.5 equiv) in THF (10 mL) that was protected from light. The resulting reaction mixture was placed in a –40 oC bath for 1h, while being protected from light, and then quenched with sat. NH4Cl. The reaction mixture was Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 55 allowed to warm to ambient temperature, diluted with brine (100 mL) and extracted with EtOAc (3 x 70 mL). The combined organic extracts were dried over MgSO4 and concentrated to afford a yellow oil, which was purified by silica gel chromatography (2:1 hexanes:EtOAc) to afford bromooxindole 35 (334 mg, 76% yield) as a yellow solid. Rf = 0.40 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.49 (br, s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.24–7.19 (m, 3H), 6.96 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 4.76 (d, J = 15.4 Hz, 1H), 4.32 (m, 2H), 3.80 (t, J = 13.2 Hz, 1H), 2.39 (s, 3H), 2.33 (m, 1H), 1.90 (m, 13 1H); C NMR (75 MHz, CDCl3) δ 175.1, 143.5, 139.0, 137.7, 136.9, 130.7, 129.7, 128.7, 126.9, 122.6, 110.1, 59.2, 51.6, 48. 3, 35.2, 21.5; IR (Neat Film NaCl) 3313, 2930, 1734, 1615, 1460, 1334, 1155, 1096, 727 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C18H18BrN2O3S [M+H]+: 421.0216; found: 421.0213. Ts Ts N Br O N H 35 N NC O2N CN 36 DBU, THF –78 → 23 °C (64% yield) O N O2N H 37 Nitrile 37. A solution of bromooxindole 35 (44.9 mg, 0.107 mmol, 1.0 equiv) and 2nitrophenylacetonitrile 36 (34.6 mg, 0.213 mmol, 2.0 equiv) in THF (3 mL) was cooled to –78 oC. DBU (64 µL, 0.426 mmol, 4.0 equiv) was added dropwise. The reaction mixture was then allowed to gradually warm to ambient temperature. After 8 h, the reaction mixture was quenched with sat. NH4Cl (10 mL) and the mixture was extracted with EtOAc (4 x 5 mL). The combined organic extracts were dried over MgSO4 and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 56 concentrated under reduced pressure to afford a brown oil, which was purified by preparatory thin layer chromatography on silica gel (1:1 hexane:EtOAc x2 elutions) to afford nitrile 37 (34.8 mg, 64% yield) as an orange-yellow solid. Rf = 0.28 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.92 (m, 1H), 7.63 (m, 2H), 7.55 (m, 2H), 7.43 (m, 2H), 7.29 (d, J = 8.0 H, 2H), 7.18 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.48 (d, J = 7.4 Hz, 1H), 6.07 (s, 1H), 4.80 (d, J = 16.2 Hz, 1H), 4.29 (m, 2H), 3.45 (app. t, J = 13.2 Hz, 1H), 2.74 (app. dd, J = 15.0, 2.6 Hz, 1H), 2.43 (s, 3H), 1.94 (m, 13 1H); C NMR (75 MHz, CDCl3) δ 176.2, 147.9, 143.8, 140.3, 137.9, 136.5, 133.5, 132.5, 131.0, 130.3, 130.0, 127.0, 124.8, 124.5, 124.5, 123.7, 116.2, 109.4, 54.4, 52.6, 46.8, 34.2, 32.1, 21.6; IR (Neat Film NaCl) 3302, 2920, 1724, 1527, 1155, 724 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C26H23N4O5S [M+H]+ : 503.1384; found: 503.1411. Ts Ts N MeO 2C Br + CO2Me O2N THF –78 → 23 °C (32% yield) O N H 35 N DBU 38 CO2Me CO2Me O NO N H 2 39 Aryl malonate 39. To a solution of bromooxindole 35 (50.0 mg, 0.119 mmol, 1.0 equiv) and malonate 38 (90.1 mg, 0.356 mmol, 3.0 equiv) in THF (0.6 mL) was added DBU (54.2 mg, 0.356 mmol, 3.0 equiv) at –78 oC. The reaction solution was slowly warmed to 23 oC. The reaction solution was stirred for 12 h, and quenched with sat. NH4Cl. The mixture was extracted with EtOAc (3 x 1 mL) and brine. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure and then the residue Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 57 was purified by preparatory thin layer chromatography on silica gel (1:1 hexane:EtOAc) to afford nitrile 39 (23 mg, 32% yield). Rf = 0.15 (1:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.85 (br, s, 1H), 8.23 (dd, J = 8.0, 1.5 Hz, 1H), 7.58–7.51 (m, 5H), 7.24 (d, J = 8.0 Hz, 2H), 6.96 (dd, J = 7.5, 1.5 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.66 (d, J = 1.0 Hz, 1H), 4.44 (d, J = 15.4 Hz, 1H), 4.15 (d, J = 15.4 Hz, 1H), 3.95 (d, J = 14.6 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.69 (m, 1H), 2.40 (s, 3H), 1.95 (d, J = 14.6 Hz, 1H), 1.66 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 179.1, 168.8, 148.1, 143.4, 141.2, 138.7, 137.0, 134.7, 133.9, 132.0, 129.7, 129.1, 128.3, 126.8, 125.7, 122.8, 110.7, 74.8, 68.7, 53.7, 53.5, 51.3, 46.0, 33.4, 21.5; IR (Neat Film NaCl) 3313, 1737, 1623, 1530, 1450, 1347, 1241, 1153, 1091, 895, 729 cm-1; HRMS (FAB) m/z calc’d for C29H26N3O9S [M-H]- : 592.1395; found: 592.1382. Ts H N Ts N N TsCl, Et 3N N H 4 CH2Cl2 0 → 23 °C (80% yield) pyridinium tribromide N H SI-1-12 THF/t-BuOH/H2O 0 → 23 °C (80% yield) O N H SI-1-13 Oxindole SI-1-13. To a solution of aurantioclavine 4 (300 mg, 0.00133 mol, 1.0 equiv) and Et3N (0.37 mL, 0.00265 mol, 2.0 equiv) in CH2Cl2 (4 mL) cooled to 0 oC was added a solution of TsCl (254 mg, 0.00133 mmol, 1.0 equiv) in CH2Cl2 (3 mL) dropwise. The ice bath was removed and the reaction mixture was stirred for 5 h, then diluted with EtOAc (200 mL) and washed with 0.5 N HCl (2 x 35 mL) and brine. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) to afford indole SI-1-12 (405 mg, 80% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 58 A solution of indole SI-1-12 (902.2 mg, 2.371 mmol, 1.0 equiv) in THF/t-BuOH/H2O (10:10:1 v/v/v, 52.5 mL) was cooled to 0 oC and pyridinium tribromide (834.2 mg, 2.608 mmol, 1.1 equiv) was added in small portions over 5 min. The reaction mixture was stirred at 0 oC for 15 min, and then allowed to warm to ambient temperature. After 5 min at ambient temperature, the reaction mixture was quenched by addition of 1:1 v/v sat. NaHCO3:1M aq Na2S2O3 (15 mL), poured into brine (150 mL) and extracted with EtOAc (3 x 100 mL). The combined extracts were dried over Na2SO4 and concentrated under reduced pressure to afford a brown solid, which was purified by silica gel chromatography (2:1 → 1:1 hexanes:EtOAc) to afford oxindole SI-1-13 (747.5 mg, 80% yield). Rf = 0.22 (5:1 benzene:MeCN); 1H NMR (300 MHz, CDCl3) δ 8.12 (br, s, 1H), 7.33 (dd, J = 8.5, 2.1 Hz, 2H), 7.03 (m, 1H), 6.96 (d, J = 7.2 Hz, 2H), 6.82 (d, J = 7.7 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.76 (d, J = 8.0 Hz, 1H), 5.31 (m, 1H), 4.00 (dt, J = 15.7, 2.8 Hz, 1H), 3.64–3.50 (m, 2H), 2.22 (s, 3H), 2.00 (m, 1H), 1.67 (s, 3H), 1.65 (s, 3H), 1.25 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.4, 142.9, 140.9, 140.5, 138.2, 129.2, 128.3, 128.3, 127.0, 126.7, 121.3, 119.0, 108.7, 59.0, 46.0, 43.8, 27.8, 26.0, 21.4, 18.5; IR (Neat Film NaCl) 3246, 2925, 1713, 1615, 1460, 1326, 1155, 732 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C22H25N2O3S [M+H]+ : 397.1580; found: 397.1586. Ts Ts H N Ts N N NBS, LiHMDS Br O N H SI-1-13 THF –78 → –15 °C (64% yield) + O N H 40 O N H SI-1-14 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 59 Bromooxindole 40. A solution of oxindole SI-1-13 (172.0 mg, 0.434 mmol, 1.0 equiv) in THF (5 mL) was added dropwise to a freshly prepared solution of LiHMDS (217.8 mg, 1.301 mmol, 3.0 equiv) in THF (5 mL) that had been pre-cooled to –78 oC. After 20 min at –78 oC, the resulting solution was transferred via cannula to a solution of Nbromosuccinimide (231.6 mg, 1.301 mmol, 3.0 equiv) in THF (5 mL) that had been precooled to –78 oC. The resulting yellow reaction mixture was allowed to warm to –15 oC (the reaction flask was transferred to a bath composed of ethylene glycol and dry ice) and maintained at this temperature for 2 h. The reaction mixture was then cooled to –78 oC and quenched by addition of sat. NH4Cl (5 mL). The yellow reaction mixture was allowed to warm to ambient temperature and diluted with H2O (80 mL), then extracted with EtOAc (3 x 70 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4 and concentrated under reduced pressure to afford a yellow oil, which was purified immediately by silica gel chromatography (2:1 hexanes:EtOAc) to afford a 3:1 mixture of bromooxindole 40 (>20:1 dr) and dehydrobromination product SI1-14 (131.1 mg, 64% combined yield, 50% yield of bromooxindole 40). Bromooxindole 40 was stored frozen in benzene and used without further purification. The relative configuration of this bromooxindole was assigned based on the stereochemistry of the malonate adduct obtained (see below). Quenching the reaction prior to completion afforded the bromooxindole 40 as a single diastereomer, which showed greater stability, and could be fully characterized. Rf = 0.50 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.62 (br, s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 8.0, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 7.5 Hz, 1H), 6.79 (dd, J = 8.0, 1.0 Hz, 1H), 5.96 (td, J = 8.5, 1.5 Hz, 1H), 5.88 (d, J = 8.5 Hz, 1H), Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 60 4.18–4.02 (m, 2H), 2.35 (s, 3H), 2.27 (m, 1H), 1.97 (m, 1H), 1.76 (d, J = 1.0 Hz, 3H), 1.75 (d, J = 1.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.8, 143.2, 142.4, 140.2, 139.2, 137.8, 130.8, 129.4, 126.9, 126.1, 122.7, 120.1, 109.7, 66.8, 59.5, 39.8, 34.4, 26.1, 21.4, 18.4; IR (Neat Film NaCl) 3291, 1734, 1617, 1602, 1457, 1326, 1156, 1092, 738 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H23BrN2O3S [M+H]+ : 475.0686; found: 475.0668. Ts H Ts H N N MeO 2C Br CO2Me CO2Me 41 DBU CO2Me O O N H 40 >20:1 dr THF –78 → 23 °C (74% yield) N H 42 >20:1 dr Malonate 42. Bromooxindole 40 (>20:1 dr, 51.3 mg, 0.108 mmol, 1.0 equiv) was dissolved in THF (2 mL). Dimethyl malonate 41 (37 µL, 0.324 mmol, 3.0 equiv) was added and the reaction mixture was cooled to –78 oC. DBU (48 µL, 0.324 mmol, 3.0 equiv) was added dropwise. The reaction mixture was stirred at –78 oC for 15 min and then warmed to 23 oC. After maintaining the reaction mixture at 23 oC for 6 h, sat. NH4Cl (2 mL) was added and the reaction mixture was warmed to ambient temperature. The reaction mixture was diluted with EtOAc (50 mL) and sat. NH4Cl (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford colorless oil. Analysis of the crude oil by 1H NMR indicated >20:1 dr of the malonate adduct 42. The residue was purified by silica gel chromatography (1:1 hexane:EtOAc) to afford malonate 42 (42 mg, 74% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 61 1 Rf = 0.20 (1:1 hexane:EtOAc); H NMR (300 MHz, CDCl3) δ 7.88 (br, s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.91, (d, J = 7.5 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.92 (d, J = 4.5 Hz, 1H), 5.38 (d, J = 4.5 Hz, 1H), 4.62 (s, 1H), 4.06 (m, 1H), 3.89 (m, 1H), 3.78 (s, 3H), 3.46 (s, 3H), 2.40 (m, 1H), 2.30 (s, 3H), 1.82 (s, 3H), 1.79 (s, 3H), 1.07 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.8, 166.8, 166.8, 143.0, 141.9, 141.4, 141.0, 137.9, 129.2, 128.9, 127.6, 127.0, 123.0, 124.0, 109.0, 59.6, 53.9, 52.9, 52.3, 51.3, 39.8, 28.9, 26.4, 21.4, 18.6; IR (Neat Film NaCl) 3338, 2953, 1733, 1618, 1597, 1458, 1327, 1158 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C27H31N2O7S [M+H]+ : 527.1846; found: 527.1848. NO 2 O O F O K 2CO3 O O O SI-1-15 DMF, 90 °C (89% yield) O O NO 2 44 Diallyl 2-(2-nitrophenyl)malonate 44. A 500 mL round-bottom flask with a magnetic stir bar was charged with diallyl malonate SI-1-15 (22.0 g, 118 mmol, 1.0 equiv), 1fluoro-2-nitrobenzene (13.7 mL, 129 mmol, 1.1 equiv), and K2CO3 (48.9 g, 354 mmol, 3.0 equiv). DMF (120 mL) was added and the brown suspension was heated to 90 oC for 16 h. The reaction mixture was cooled to ambient temperature and diluted with ice water (250 mL) and Et2O (300 mL). The aqueous phase was extracted with Et2O (3 x 300 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (9:1 hexanes:EtOAc) on silica gel to give arylated malonate 44 (32.1 g, 89% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 62 1 Rf = 0.51 (1:1 hexane:Et2O); H NMR (500 MHz, CDCl3) δ 8.08 (dd, J = 8.5, 1.4 Hz, 1H), 7.66 (td, J = 7.6, 1.4 Hz, 1H), 7.55–7.51 (m, 2H), 5.90 (ddt, J = 17.3, 10.4, 5.7 Hz, 2H), 5.39-5.23 (m, 5H), 4.70 (dt, J = 5.8, 1.4 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 166.8, 148.7, 133.6, 131.4, 131.1, 129.3, 127.9, 125.3, 119.1, 66.8, 54.3; IR (Neat Film NaCl) 3086, 2950, 1738, 1611, 1530, 1447, 1350, 1154, 991, 937, 852, 787, 722 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C15H16NO6 [M+H]+: 306.0972; found: 306.0930. O F O NO 2 O + O O O NO 2 DMF, 90 °C (80% yield) O SI-1-15 K 2CO3 O Br Br 45 Diallyl 2-(4-bromo-2-nitrophenyl)malonate 45. A 500 mL round-bottom flask with a magnetic stir bar was charged with diallyl malonate SI-1-15 (15.0 g, 81.5 mmol, 1.0 equiv), 4-bromo-1-fluoro-2-nitrobenzene (11.0 mL, 89.7 mmol, 1.1 equiv), and K2CO3 (33.8 g, 245 mmol, 3.0 equiv). DMF (163 mL) was added and the brown suspension was heated to 90 oC for 16 h. The reaction mixture was cooled to ambient temperature and diluted with ice water (250 mL) and Et2O (300 mL). The aqueous phase was extracted with Et2O (3 x 300 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (9:1 hexanes:EtOAc) on silica gel to give arylated malonate 45 (32.1 g, 80% yield). Rf = 0.69 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.4, 2.1 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.94–5.84 (m, 2H), 5.37–5.24 (m, 5H), 4.70 (dt, J = 5.9, 1.3 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 166.4, 149.1, 136.5, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 63 132.8, 131.0, 128.2, 126.8, 122.8, 119.3, 66.9, 53.8; IR (Neat Film NaCl) 3085, 2986, 2951, 1733, 1649, 1538, 1348, 1283, 1218, 1148, 989, 936 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C15H15BrNO6 [M+H]+: 384.0077; found: 384.0072. TIPSO O Br O O AllylO OAllyl + NO 2 N H 43 Oxindole 46. TIPSO NO 2 Cs2CO3 THF, 0 °C (85% yield) 44 CO2Allyl CO2Allyl O N H 46 To a suspension of Cs2CO3 (5.37 g, 16.5 mmol, 3.0 equiv) and bromooxindole 43 (2.27 g, 5.50 mmol, 1.0 equiv) in THF (100 mL) was added malonate 44 (5.04 g, 16.5 mmol, 3.0 equiv) at 0 °C. The reaction mixture was then allowed to slowly warm to 23 oC and stirred for 16 h. Solids were removed via a filtration through a celite plug (rinsed with EtOAc) and the resulting purple solution was concentrated under reduced pressure. The residue was purified by column chromatography using a Teledyne Isco CombiFlash (SiO2, 120 g column, 100:0 → 3:1 hexanes:EtOAc) to provide alkylation product 46 (8.9 g, 85% yield) as a colorless oil. Rf = 0.18 (3:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.73 (dd, J = 7.9, 1.6 Hz, 1H), 7.41 (dt, J = 8.0, 1.6 Hz, 1H), 7.38– 7.33 (m, 2H), 7.13 (dt, J = 7.7, 1.1 Hz, 1H), 6.89 (dt, J = 7.7, 1.0 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 5.88–5.73 (m, 2H), 5.25 (ddd, J = 17.2, 2.8, 1.4 Hz, 1H), 5.19–5.11 (m, 3H), 4.69 (tdd, J = 13.3, 5.7, 1.4 Hz, 1H), 4.64 (tdd, J = 13.3, 5.7, 1.3 Hz, 1H), 4.57 (tdd, J = 13.4, 5.9, 1.4 Hz, 1H), 4.48 (tdd, J = 13.1, 5.9, 1.1 Hz, 1H), 3.35 (ddd, J = 9.5, 8.5, 6.9 Hz, 1H), 3.07 (dt, J = 9.5, 4.5 Hz, 1H), 2.95 (ddd, J = 12.9, 8.7, 7.0 Hz, 1H), 2.63 (ddd, J = Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 64 13 12.9, 8.5, 4.5 Hz, 1H), 0.97–0.77 (m, 21H); C NMR (125 MHz, CDCl3) δ 177.8, 166.7, 166.3, 150.2, 140.7, 132.4, 131.3, 131.0, 130.8, 129.5, 129.2, 128.5, 126.9, 125.3, 122.4, 119.2, 118.4, 109.1, 66.8, 66.7, 59.5, 56.7, 38.3, 17.8, 11.8; IR (Neat Film NaCl) 3332, 2942, 1714, 1649, 1618, 1538, 1471, 1356, 1230, 1114, 995, 933, 885, 850, 752, 683 cm1 ; HRMS (MM: ESI-APCI+) m/z calc’d for C34H45N2O8Si [M+H]+ : 637.2940; found: 637.2945. Br AllylO2C TIPSO Br CO2Allyl NO 2 + O N H 43 Br 45 TIPSO NO 2 Cs2CO3 THF 0 → 23 °C (96% yield) CO2Allyl CO2Allyl O N H 47 Oxindole 47. To a solution of 3-bromooxindole 43 (2.0 g, 4.85 mmol, 1.0 equiv) and malonate 45 (3.7 g, 9.70 mmol, 2.0 equiv) in THF (49 mL) was added Cs2CO3 (3.2 g, 9.70 mmol, 2.0 equiv) at 0 oC. The reaction mixture was warmed to 23 oC and stirred overnight. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (9:1 → 4:1 hexanes:EtOAc) on silica gel to give desired alkylated product 47 (3.3g, 96% yield). Rf = 0.33 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.00 (br, s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.8, 2.3 Hz, 1H), 7.43–7.39 (m, 1H), 7.16 (td, J = 7.7, 1.2 Hz, 1H), 6.92 (td, J = 7.7, 1.1 Hz, 1H), 6.75–6.72 (m, 1H), 5.79 (dddt, J = 33.6, 17.2, 10.4, 5.9 Hz, 2H), 5.26–5.18 (m, 2H), 5.19–5.14 (m, 2H), 4.66 (qdt, J = 13.2, 5.9, 1.4 Hz, 2H), 4.55–4.42 (m, 2H), 3.32 (dt, J = 9.7, 7.5 Hz, 1H), 3.09 (ddd, J Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 65 = 9.8, 8.5, 4.5 Hz, 1H), 2.89–2.82 (m, 1H), 2.63 (ddd, J = 12.7, 8.1, 4.5 Hz, 1H), 0.89 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 178.0, 166.6, 166.2, 150.9, 140.9, 134.3, 134.1, 131.3, 130.8, 129.0, 129.0, 128.6, 128.3, 127.2, 122.7, 122.2, 119.6, 119.0, 109.5, 67.2, 67.1, 66.9, 59.7, 57.0, 38.4, 18.0, 11.9; IR (Neat Film NaCl) 3203, 2943, 2865, 1716, 1619, 1538, 1471, 1357, 1229, 1111, 992, 935, 753, 735 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C34H44BrN2O8Si [M+H]+: 715.2045; found: 715.2090. TIPSO NO 2 CO2Allyl CO2Allyl O N H 46 TIPSO NO 2 Cs2CO3, MeI THF 0 → 23 °C (99% yield) CO2Allyl CO2Allyl O N 48 Methyloxindole 48. To a suspension of oxindole 46 (0.50 g, 0.79 mmol, 1.0 equiv) and Cs2CO3 (0.77 g, 2.37 mmol, 3.0 equiv) in THF (4.0 mL) was added methyl iodide (0.3 mL, 4.7 mmol, 6.0 equiv) at 0 oC. The reaction mixture was stirred for 12 h at 23 oC. After the reaction was done, sat. NH4Cl was added. The aqueous phase was extracted with EtOAc (3 x 3 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3:1 hexanes:EtOAc) to give methylated oxindole 48 (0.51g, 99% yield). Rf = 0.33 (3:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.54 (dd, J = 7.9, 1.5 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.31 (dt, J = 7.7, 1.6 Hz, 1H), 7.25 (dt, J = 7.8, 1.2 Hz, 1H), 7.10 (dt, J = 7.7, 0.9 Hz, 1H), 6.85 (dt, J = 7.8, 0.8 Hz, 1H), 6.57 (d, J = 7.7 Hz, 1H), 5.80 (tdd, J = 16.3, 10.7, 5.8 Hz, 1H), 5.71 (tdd, J = 16.4, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 66 10.5, 5.9 Hz, 1H), 5.22–5.02 (m, 4H), 4.69–4.56 (m, 2H), 4.52 (tdd, J = 13.1, 5.8, 1.3 Hz, 1H), 4.36 (tdd, J = 13.3, 5.9, 1.3 Hz, 1H), 3.15–3.02 (m, 4H), 2.96 (ddd, J = 9.7, 8.3, 4.7 Hz, 1H), 2.85 (td, J = 13.2, 7.4 Hz, 1H), 2.67 (ddd, J = 12.8, 8.0, 4.7 Hz, 1H), 0.86–0.71 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 176.3, 166.5, 166.5, 150.3, 143.6, 132.7, 131.3, 130.9, 130.3, 128.8, 128.5, 128.5, 128.3, 126.9, 125.1, 122.3, 119.1, 118.5, 107.3, 66.7, 66.7, 59.6, 56.8, 37.9, 26.1, 17.8, 11.7; IR (Neat Film NaCl) 3421, 3054, 2944, 2866, 1723, 1613, 1539, 1473, 1356, 1253, 1180, 1104, 1068, 935, 862, 840, 752, 690 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C35H47N2O8Si [M+H]+ : 651.3096; found: 651.3184. Br TIPSO Br NO 2 CO2Allyl CO2Allyl O N H 47 TIPSO NO 2 Cs2CO3, MeI THF 0 → 23 °C (92% yield) CO2Allyl CO2Allyl O N 49 Methyloxindole 49. To a solution of oxindole 47 (14.1 g, 0.0197 mol, 1.0 equiv) in THF (106 mL) was added Cs2CO3 (19.3 g, 0.0591 mol, 3.0 equiv) and MeI (7.40 mL, 0.118 mol, 6.0 equiv) at 0 oC. Then, the reaction mixture was stirred for 12 h at 23 oC. After the reaction was done, sat. NH4Cl was added. The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (7:1 hexanes:EtOAc) on silica gel to give methylated oxindole 49 (13.2 g, 92% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 67 1 Rf = 0.40 (4:1 hexanes:EtOAc); H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.53–7.48 (m, 2H), 7.21 (td, J = 7.7, 1.2 Hz, 1H), 6.95 (td, J = 7.6, 1.1 Hz, 1H), 6.69–6.66 (m, 1H), 5.85 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.74 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.26–5.20 (m, 2H), 5.18 (ddt, J = 10.4, 2.2, 1.2 Hz, 2H), 4.72– 4.63 (m, 2H), 4.54 (ddt, J = 13.1, 6.0, 1.4 Hz, 1H), 4.40 (ddt, J = 13.0, 6.0, 1.3 Hz, 1H), 3.18–3.13 (m, 1H), 3.13 (s, 3H), 3.05 (ddd, J = 9.9, 7.9, 4.7 Hz, 1H), 2.82 (dt, J = 13.0, 7.6 Hz, 1H), 2.71 (ddd, J = 12.8, 7.6, 4.7 Hz, 1H), 0.90–0.84 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 176.3, 166.3, 166.2, 150.8, 143.7, 134.4, 133.4, 131.1, 130.8, 128.8, 128.1, 128.0, 127.0, 122.5, 122.1, 119.4, 119.0, 107.6, 67.0, 66.9, 66.9, 59.6, 56.8, 37.9, 26.3, 17.8, 17.8, 11.8; IR (Neat Film NaCl) 2943, 2865, 1747, 1713, 1611, 1538, 1471, 1357, 1223, 1103, 993, 935, 882, 752 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C35H46BrN2O8Si [M+H]+: 729.2201; found: 729.2253. TIPSO O NO 2 CO2Allyl CO2Allyl O N O AcCl CO2Allyl MeOH 0 → 65 °C (85% yield) O NO N 2 48 50 Lactone 50. Acetyl chloride (46.0 μL, 650 μmol, 10.0 equiv) was added to MeOH (1.0 mL) and cooled to 0 °C. The resulting mixture was stirred for 30 min and then the solution of oxindole 48 (21.0 mg, 32.0 μmol, 1.0 equiv) in MeOH (2.0 mL) was added. The reaction was stirred for 2 h at 23 oC and then heated to 65 °C. The reaction mixture was stirred for 16 h at that temperature. The colorless solution was cooled to ambient temperature, concentrated under reduced pressure and subjected to column Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 68 chromatography (4:1 hexanes:EtOAc) to afford the desired lactone 50 (12 mg, 85% yield) as a colorless solid. Rf = 0.29 (50% EtOAc in hexanes); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.4 Hz, 1H), 7.39–7.31 (m, 3H), 7.23–7.15 (m, 2H), 6.82–6.75 (m, 2H), 5.92 (tdd, J = 17.1, 10.6, 5.8 Hz, 1H), 5.30 (ddd, J = 17.2, 2.7, 1.3 Hz, 1H), 5.21 (ddd, J = 10.4, 2.4, 1.2 Hz, 1H), 4.98–4.90 (m, 2H), 4.74 (tdd, J = 13.1, 5.8, 1.3 Hz, 1H), 4.71–4.64 (m, 2H), 3.32 (s, 3H), 2.84–2.70 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.8, 166.5, 165.7, 149.2, 142.2, 131.7, 131.4, 131.1, 128.8, 129.7, 129.3, 129.0, 128.9, 125.6, 124.8, 122.5, 118.9, 108.5, 67.5, 65.4, 53.7, 30.2, 26.7; IR (Neat Film NaCl) 2096, 1718, 1637, 1533, 1475, 1358, 1232, 1184, 760 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H21N2O7 [M+H]+ : 437.1343; found: 437.1298. O O CO2Allyl O NO N 2 50 Pd(PPh 3)4 (2.5 mol%) THF (90% yield) O O O NO N 2 51 Lactone 51. An oven dried flask was charged with ester 50 (1.3 g, 3.05 mmol, 1.0 equiv), sealed with a rubber stopper and evacuated. The flask was brought in a glove box and Pd(PPh3)4 (84 mg, 75.0 μmol, 0.025 equiv) was added. The flask was brought out of the dry box and THF (60 mL) was added. The reaction mixture was stirred for 5 min and concentrated under reduced pressure. Column chromatography using a Teledyne Isco CombiFlash Rf (SiO2, 80 g column, 25→50% EtOAc in hexanes) afforded the desired protected alkylation product 51 (1.1 g, 90% yield) as a colorless solid. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 69 1 Rf = 0.40 (1:1 hexane:EtOAc); H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 7.9, 1.6 Hz, 1H), 7.18 (dt, J = 7.8, 1.4 Hz, 1H), 7.12 (dt, J = 7.5, 1.7 Hz, 1H), 7.07 (dt, J = 7.7, 1.1 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 6.85 (dd, J = 8.0, 1.3 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 6.64 (dt, J = 7.7, 1.0 Hz, 1H), 5.55 (tdd, J = 17.0, 10.2, 6.7 Hz, 1H), 5.33 (ddd, J = 11.6, 10.0, 3.4 Hz, 1H), 5.01 (ddd, J = 17.1, 3.0, 1.5 Hz, 1H), 4.93 (ddd, J = 10.3, 2.7, 1.2 Hz, 1H), 4.68 (td, J = 11.6, 4.7 Hz, 1H), 3.45 (tdd, J = 15.6, 6.6, 1.3 Hz, 1H), 3.26 (s, 3H), 2.99 (tdd, J = 9.0, 6.9, 1.3 Hz, 1H), 2.87 (ddd, J = 14.6, 10.0, 4.6 Hz, 1H), 2.21 (ddd, J = 14.7, 4.8, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.3, 168.5, 149.8, 142.1, 133.9, 133.1, 131.1, 130.6, 130.4, 128.6, 127.8, 125.7, 124.8, 122.2, 119.0, 107.6, 64.8, 54.2, 54.0, 43.7, 30.7, 26.5; IR (Neat Film NaCl) 1701, 1614, 1531, 1473, 1356, 1300, 1259, 1202, 1105, 929, 739 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H21N2O5 [M+H]+ : 393.1445; found: 393.1458. Br Br TIPSO NO 2 CO2Allyl CO2Allyl O Pd(PPh 3)4 (5.0 mol%) TIPSO NO 2 THF, –78 °C (78% yield) CO2Allyl O N N 49 52 Allyl 52. To a 500 mL round-bottom flask with a magnetic stir bar was added malonate 49 (11.1 g, 15.2 mmol, 1.0 equiv). The flask was brought into a N2-filled glove box and then Pd(PPh3)4 (0.88 g, 0.761 mol, 0.05 equiv) was added. The reaction mixture was brought out from the glove box and treated with THF (152 mL). After 1 h stirring, the solvent was evaporated under reduced pressure. The residue was purified by column Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 70 chromatography (1:1 hexane:EtOAc) on silica gel to afford allylated product 52 (8.1 g, 78% yield). Rf = 0.45 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.6, 2.2 Hz, 1H), 7.22 (td, J = 7.7, 1.1 Hz, 1H), 6.83–6.77 (m, 2H), 6.33 (d, J = 7.5 Hz, 1H), 5.66 (ddt, J = 16.9, 10.3, 6.2 Hz, 1H), 5.56 (ddt, J = 17.0, 10.1, 6.9 Hz, 1H), 5.16–5.09 (m, 2H), 4.91 (dq, J = 17.1, 1.5 Hz, 1H), 4.84 (ddd, J = 10.2, 1.9, 1.1 Hz, 1H), 4.38–4.26 (m, 2H), 3.37 (dd, J = 15.3, 7.0 Hz, 1H), 3.23 (s, 3H), 3.21–3.10 (m, 2H), 2.90 (ddd, J = 9.5, 8.5, 4.2 Hz, 1H), 2.59–2.51 (m, 1H), 2.16 (ddd, J = 12.5, 8.1, 4.3 Hz, 1H), 0.92–0.80 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 177.7, 169.6, 152.1, 144.3, 134.8, 134.5, 133.7, 131.3, 131.1, 128.9, 128.8, 128.70, 125.13, 121.9, 121.8, 119.5, 118.2, 108.1, 65.7, 60.7, 59.5, 55.5, 39.0, 36.6, 26.5, 18.0, 11.9; IR (Neat Film NaCl) 2942, 2865, 1713, 1610, 1538, 1495, 1471, 1353, 1106, 995, 918, 882, 750, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C34H46BrN2O6Si [M+H]+: 685.2303; found: 685.2294. 1. (COCl)2, Et 2O 0 → 23 °C Br N H 58 2. MeOH, Et 2O 0 → 23 °C (78% yield, 2 steps) Br O O OMe N H SI-1-16 Oxoacetate SI-1-16. To a solution of 4-bromoindole 58 (8.0 g, 40.8 mmol, 1.0 equiv) in Et2O (204 mL) was added oxalyl chloride (9.25 mL, 102 mmol, 2.5 equiv) dropwise at 0 o C. The reaction mixture was stirred for 16 h at 23 oC. The resulting suspension was filtered and washed with cold ether. The filter cake was dried in vacuo to afford the oxoacetyl chloride, which was used without further purification. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 71 o To a solution of oxoacetyl chloride in Et2O (204 mL) was added MeOH (10 mL) at 0 C, and stirred for 2 h. The resulting mixture was concentrated in vacuo and purified by flash column chromatography (4:1 hexanes:EtOAc) on silica gel to give oxoacetate SI-1-16 (9.0 g, 78% yield, 2 steps). Rf = 0.23 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.01 (br, s, 1H), 8.27 (d, J = 3.2 Hz, 1H), 7.52 (dd, J = 7.6, 0.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 7.8Hz, 1H), 3.95 (s, 13 3H); C NMR (125 MHz, CDCl3) δ 178.3, 164.0, 137.8, 136.2, 128.3, 125.3, 125.2, 115.3, 115.0, 111.0, 53.0; IR (Neat Film NaCl) 3206, 1656, 1500, 1410, 1306, 1252, 1196, 1139, 1104, 789, 770, 731 cm1 ; HRMS (MM: ESI-APCI+) m/z calc’d for C11H9BrNO3 [M+H]+ : 281.9760; found: 281.9760. Br O O OMe N H OH LAH THF 0 → reflux (91% yield) SI-1-16 Br N H 59 Alcohol 59. To a solution of oxoacetate SI-1-16 (6.8 g, 24.1 mmol, 1.0 equiv) in THF (120 mL) was added LAH (2.8 g, 72.3 mmol, 3.0 equiv) in portions at 0 oC. The reaction mixture was refluxed for 4 h. When the reaction was done, the solution was cooled to 0 o C, and quenched by Fieser work-up2. The suspension was filtered and the filter cake was washed with EtOAc. The combined organic phases were concentrated in vacuo, and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine,                                                                                                                 2 Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis 1967, 581-595. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 72 dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 hexane:EtOAc) on silica gel to give alcohol 59 (5.3 g, 91% yield). Rf = 0.27 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.18 (br, s, 1H), 7.31 (dd, J = 7.6, 0.8 Hz, 1H), 7.28 (dd, J = 7.6, 0.8 Hz, 1H), 7.12 (dd, J = 2.8Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 3.28 (dt, J = 6.4, 0.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 137.8, 125.4, 124.1, 123.0, 114.4, 113.1, 110.6, 63.6, 29.5 ; IR (Neat Film NaCl) 3369, 2929, 1899, 1613, 1478, 1425, 1335, 1185, 1029, 913, 815, 770, 736 cm -1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H11BrNO [M+H]+ : 240.0019; found: 240.0021. OH Br OTIPS TIPSCl, imidazole N H 59 DMF, 23 °C (98% yield) Br N H SI-1-17 TIPS-ether SI-1-17. To a solution of alcohol 59 (8.1 g, 33.7 mmol, 1.0 equiv) in DMF (112 mL) was added imidazole (5.0 g, 74.2 mmol, 2.2 equiv) and TIPSCl (10.7 mL, 50.6 mmol, 1.5 equiv). After stirring for 3 h at 23 oC, water (10 mL) was added. The aqueous phase was extracted with Et2O (3 x 100 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (9:1 hexanes:EtOAc) on silica gel to give TIPS-ether SI-117 (13.1 g, 98% yield). Rf = 0.56 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.06 (br, s, 1H), 7.30–7.25 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 4.00 (t, J = 7.1 Hz, 2H), 3.27 (t, J = 7.1 Hz, 2H), 1.05-1.07 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 137.4, 125.7, 124.4, 123.9, 122.6, 114.3, 114.1, 110.4, 64.9, 29.9, 18.1, 12.0; IR (Neat Film NaCl) Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 73 3425, 3286, 2942, 1614, 1561, 1549, 1463, 1425, 1382, 1336, 1246, 1184, 1102, 1064, 1013, 913, 883, 826, 772, 738 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C19H31BrNOSi [M+H]+ : 396.1353; found: 396.1357. TIPSO OTIPS Br pyridinium tribromide N H Br Br t-BuOH, H 2O, THF 23 °C (89% yield) SI-1-17 O N H 57 3-Bromooxindole 57. To a solution of indole SI-1-17 (5.0 g, 12.6 mmol, 1.0 equiv) in tBuOH (100 mL), THF (25 mL), and water (1.1 mL) was added pyridinium tribromide (7.9 g, 24.6 mmol, 1.95 equiv). The reaction mixture was stirred for 30 min and then diluted with EtOAc (50 mL) and water (80 mL). The aqueous phase was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4:1 hexanes:EtOAc) on silica gel to give 3-bromooxindole 57 (5.5 g, 89% yield). Rf = 0.31 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.64 (br, s, 1H), 7.19 (dd, J = 8.1, 1.0 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.86 (dd, J = 7.6, 1.0 Hz, 1H), 3.66 (ddd, J = 10.4, 5.5, 3.3 Hz, 1H), 3.46 (td, J = 10.5, 3.8 Hz, 1H), 3.08 (dt, J = 13.9, 3.5 Hz, 1H), 2.90 (ddd, J = 13.9, 10.6, 5.4 Hz, 1H), 0.87 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 175.8, 142.3, 131.2, 127.5, 127.0, 120.8, 109.5, 60.6, 56.1, 39.6, 17.8, 11.8; IR (Neat Film NaCl) 2941, 2864, 2109, 1728, 1613, 1583, 1312, 1102, 882, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C19H30Br2NO2Si [M+H]+ : 490.0407; found: 490.0340. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 74 TIPSO O Br Br O O AllylO OAllyl + NO 2 N H 57 44 Cs2CO3 THF, 0 °C (95% yield) TIPSO NO 2 Br CO2Allyl CO2Allyl O N H SI-1-18 Oxindole SI-1-18. To a solution of 3-bromooxindole 57 (5.6 g, 11.4 mmol, 1.0 equiv) and malonate 44 (5.2 g, 17.1 mmol, 1.5 equiv) in THF was added Cs2CO3 (7.4 g, 22.8 mmol, 2.0 equiv) at 0 oC. The reaction mixture was stirred for 1 h at 0 oC. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (9:1 → 4:1 hexanes:EtOAc) on silica gel to give desired alkylated product SI-1-18 (5.4 g, 95% yield). Rf = 0.18 (3:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.01 (dd, J = 8.3, 1.3 Hz, 1H), 7.90 (dd, J = 8.1, 1.5 Hz, 1H), 7.68 (ddd, J = 8.5, 7.4, 1.6 Hz, 1H), 7.55 (d, J = 5.3 Hz, 1H), 7.51 (td, J = 7.7, 1.2 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.93 (dd, J = 8.1, 1.0 Hz, 1H), 6.78 (dd, J = 7.6, 1.0 Hz, 1H), 5.92–5.81 (m, 2H), 5.76–5.68 (m, 1H), 5.26–5.18 (m, 2H), 5.17–5.10 (m, 2H), 4.76-4.69 (m, 1H), 4.68-4.63 (m, 1H), 4.51–4.47 (m, 1H), 4.25– 4.20 (m, 1H), 3.33–3.26 (m, 1H), 3.23–3.13 (m, 2H), 2.97-2.90 (m, 1H), 0.91 (m, 21H); 13 C NMR (125 MHz, CDCl3) δ 177.4, 167.0, 166.0, 144.4, 133.8, 131.8, 131.3, 131.1, 129.8, 129.3, 128.3, 127.5, 126.9, 126.5, 121.82, 119.6, 119.0, 118.9, 108.5, 67.6, 66.6, 66.5, 59.5, 58.3, 32.9, 17.9, 11.9; IR (Neat Film NaCl) 3350, 3086, 2943, 1732, 1612, 1574, 1531, 1446, 1354, 1228, 1169, 1104, 992, 931, 789 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C34H44BrN2O8Si [M+H]+ : 715.2045; found 715.2055. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 75 TIPSO NO 2 Br CO2Allyl CO2Allyl O N H SI-1-18 Cs2CO3, MeI THF, 23 °C (92% yield) TIPSO NO 2 Br CO2Allyl CO2Allyl O N 60 Methyloxindole 60. To a solution of oxindole SI-1-18 (5.6 g, 11.2 mmol, 1.0 equiv) in THF (56 mL) was added Cs2CO3 (10.9 g, 33.6 mmol, 3.0 equiv) and MeI (4.3 mL, 67.2 mmol, 6.0 equiv) at 0 oC. Then, the reaction mixture was stirred for 12 h at 23 oC. After the reaction was done, sat. NH4Cl was added. The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (7:1 hexanes:EtOAc) on silica gel to give methylated oxindole 60 (7.5 g, 92% yield). Rf = 0.38 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.01 (dd, J = 8.3, 1.3 Hz, 1H), 7.91 (dd, J = 8.1, 1.6 Hz, 1H), 7.69 (ddd, J = 8.5, 7.3, 1.6 Hz, 1H), 7.54–7.50 (m, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.95 (dd, J = 8.1, 1.0 Hz, 1H), 6.78 (dd, J = 7.8, 1.0 Hz, 1H), 5.88 (ddt, J = 16.5, 10.4, 5.8 Hz, 1H), 5.71 (ddt, J = 16.7, 10.2, 6.3 Hz, 1H), 5.27– 5.11 (m, 4H), 4.78 (ddt, J = 13.1, 6.0, 1.4 Hz, 1H), 4.68 (ddt, J = 13.1, 5.6, 1.5 Hz, 1H), 4.47 (ddt, J = 12.7, 6.3, 1.2 Hz, 1H), 4.21 (ddt, J = 12.8, 6.4, 1.2 Hz, 1H), 3.24 (s, 3H), 3.20–3.15 (m, 3H), 3.00–2.93 (m, 1H), 0.91 (s, 21H); 13C NMR (125 MHz, CDCl3) δ 176.14, 167.03, 165.81, 152.74, 147.67, 147.67, 133.81, 131.78, 131.42, 131.19, 129.73, 129.21, 128.45, 126.99, 126.85, 126.54, 121.57, 119.44, 106.83, 67.43, 66.37, 65.91, 59.57, 57.96, 32.75, 26.77, 17.90, 11.85; IR (Neat Film NaCl) 2917, 2863, 1721, 1600, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 76 -1 1529, 1450, 1350, 1231, 1088, 923, 883, 852 cm ; HRMS (MM: ESI-APCI+) m/z calc’d for C35H46BrN2O8Si [M+H]+ : 729.2201; found: 729.2240. O TIPSO NO 2 Br CO2Allyl CO2Allyl O N p-TsOH H 2O , benzene 85 °C, microwave (85% yield) 60 O Br CO2Allyl O NO N 2 61 Lactone 61. To a 20 mL microwave vial with a magnetic stir bar were added oxindole 60 (500 mg, 0.69 mmol, 1.0 equiv), p-TsOH (520 mg, 2.7 mmol, 4.0 equiv), and benzene (20 mL). The reaction was sealed with a microwave crimp cap and subjected to microwave irradiation in a Biotage Initiator microwave reactor (temperature: 85 oC, sensitivity: low) with a gradual temperature increase over 10 min (10 oC increments). After 20 min of stirring, the vial was cooled to ambient temperature and uncapped. The reaction was diluted with EtOAc (10 mL) and quenched by addition of sat. NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford lactone 61 (300 mg, 85% yield). Rf = 0.23 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.11 (dd, J = 8.2, 1.5 Hz, 1H), 8.00–7.98 (m, 1H), 7.71 (dd, J = 9.1, 7.6 Hz, 1H), 7.61–7.57 (m, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.1, 1.0 Hz, 1H), 6.87 (dd, J = 7.8, 1.0 Hz, 1H), 5.75–5.66 (m, 1H), 5.18–5.07 (m, 3H), 4.71 (td, J = 11.0, 10.4, 7.4 Hz, 1H), 4.55 (ddt, J = 12.9, 5.9, 1.3 Hz, 1H), 4.26 (ddt, J = 12.9, 6.2, 1.3 Hz, 1H), 3.63 (ddd, J = 15.2, 13.1, 7.3 Hz, 1H), 3.34 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 77 13 (s, 3H), 1.69–1.64 (m, 1H); C NMR (125 MHz, CDCl3) δ 175.2, 165.3, 152.1, 145.9, 136.8, 133.5, 131.9, 130.9, 130.2, 130.2, 127.7, 127.5, 119.3, 107.9, 70.5, 67.1, 64.9, 60.4, 54.5, 27.0, 24.1, 21.1, 14.2; IR (Neat Film NaCl) 2929, 1742, 1713, 1601, 1532, 1456, 1353, 1192, 1112, 1058, 1033, 993, 936, 856, 767 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H20BrN2O7 [M+H]+ : 515.0448; found: 515.0450. O Br O CO2Allyl O NO N 2 Pd(PPh 3)4 (2.0 mol%) THF, 23 °C (97% yield) 61 O Br O O NO N 2 62 Allyl 62. To a 250 mL round-bottom flask with a magnetic stir bar was added lactone 61 (2.5 g, 4.9 mmol, 1.0 equiv). The flask was brought into a N2-filled glove box, and then Pd(PPh3)4 (0.1 g, 0.097 mmol, 0.02 equiv) was added. The reaction mixture was brought out from the glove box and treated with THF (97 mL). After 5 min stirring, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford allylated product 62 (2.0 g, 97% yield). Rf = 0.24 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.20 (dd, J = 9.6, 6.5 Hz, 2H), 7.01 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 5.52 (ddt, J = 16.6, 12.0, 6.4 Hz, 1H), 5.43–5.35 (m, 1H), 4.79–4.72 (m, 3H), 4.32 (td, J = 13.7, 7.2 Hz, 1H), 3.31 (s, 3H), 3.13 (dd, J = 15.6, 5.0 Hz, 1H), 2.43–2.36 (m, 1H), 1.73 (dd, J = 14.7, 5.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 175.5, 169.8, 152.4, 146.0, 134.7, 134.3, 130.9, 130.7, 130.4, 128.5, 128.3, 126.0, 125.2, 124.0, 117.8, 107.6, 64.7, 56.7, 54.2, 42.9, 26.4, 23.8; IR (Neat Film Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 78 NaCl) 3418, 2923, 1709, 1601, 1532, 1455, 1361, 1292, 1201, 1113, 1069, 986, 917, 777, 736 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H20BrN2O5 [M+H]+ : 471.0550; found: 471.0552. O Br O O Br O3 O NO N 2 62 CH2Cl2, MeOH then DMS –78 °C (94% yield) O O O NO N 2 63 Aldehyde 63. A solution of alkene 62 (47.1 mg, 100 μmol, 1.0 equiv) in a mixture of CH2Cl2 (2.5 mL) and MeOH (2.5 mL) in a Schlenk flask hooked up to an ozone generator was purged with oxygen gas at –78 °C (5 min, flow 0.25). Then the ozone generator was turned on (low–medium setting) and an ozone/oxygen gas mixture was bubbled through the reaction. The progress of the reaction was checked via TLC (9:1 hexanes:CH2Cl2) in short time intervals (1-2 min). Upon completion of the reaction, the mixture was purged with oxygen gas for 5 min and DMS (36.0 μg, 500 μmol, 5.00 equiv) was added. The reaction mixture was slowly warmed to ambient temperature, and stirred for 16 h. The residue was purified by column chromatography (9:1 CH2Cl2:EtOAc) on silica gel to afford aldehyde 63 (44 mg, 94% yield). Rf = 0.28 (9:1 CH2Cl2:EtOAc); 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 3.4 Hz, 1H), 7.83–7.79 (m, 1H), 7.65–7.59 (m, 1H), 7.43–7.39 (m, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 5.15 (ddd, J = 12.5, 10.8, 4.7 Hz, 1H), 4.59 (dd, J = 11.1, 6.9 Hz, 1H), 3.94 (ddd, J = 14.5, 12.6, 7.1 Hz, 1H), 3.22 (s, 3H), 3.08 (d, J = 17.0 Hz, 1H), 2.67 (dd, J = 17.0, 3.5 Hz, 1H), 1.96 (dd, J = 14.7, 4.6 Hz, 1H); 13C NMR (125 MHz, DMSO) δ 198.0, 174.8, 171.0, 151.5, 146.3, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 79 133.3, 131.9, 131.3, 129.9, 129.7, 127.6, 125.5, 124.6, 122.4, 109.3, 65.4, 55.6, 52.6, 49.8, 26.4, 22.3; IR (Neat Film NaCl) 1695, 1600, 1528, 1458, 1354, 1294, 1222, 1118, 850, 787 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C21H18BrN2O6 [M+H]+ : 473.0343 found:473.0346. PMB O Br HO O O PMBNH 3OAc NaBH 3CN O NO N 2 63 MeOH, THF (67% yield) Br O N N O NO 2 65 Amide 65. To a suspension of aldehyde 63 (47.3 mg, 100 μmol, 1.0 equiv) and the acetic acid ammonium salt of para-methoxybenzylamine (59.2 mg, 300 μmol, 3.0 equiv) in MeOH (4 mL) was added NaBH3CN (2.60 mg, 300 μmol, 3.0 equiv) in THF (2 mL). The reaction mixture was stirred at ambient temperature for 16 h (conversion of the suspension to a clear, colorless solution usually indicated the completion of the reaction) and then concentrated under reduced pressure. Column chromatography using a Teledyne Isco CombiFlash Rf (SiO2, 12 g column, 1. 1:1 → 1:4 hexanes:EtOAc) yielded lactam 65 (39.7 mg, 67% yield) as a colorless solid. Rf = 0.12 (19:1 CH2Cl2:MeOH); 1H NMR (500 MHz, CDCl3) δ 9.10 (dd, J = 8.3, 1.4 Hz, 1H), 7.59–7.55 (m, 1H), 7.43 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.36 (dd, J = 8.0, 1.6 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 8.2, 1.0 Hz, 1H), 7.06–7.02 (m, 2H), 6.81– 6.76 (m, 3H), 4.71 (d, J = 14.6 Hz, 1H), 3.98 (d, J = 14.6 Hz, 1H), 3.76 (s, 3H), 3.53– 3.49 (m, 1H), 3.18 (s, 3H), 3.16–3.08 (m, 3H), 2.90 (ddd, J = 9.6, 8.5, 3.2 Hz, 1H), 2.78 (dt, J = 9.6, 7.3 Hz, 1H), 2.25 (ddd, J = 14.1, 7.1, 3.1 Hz, 1H), 2.14 (ddd, J = 14.0, 8.6, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 80 13 7.6 Hz, 1H); C NMR (125 MHz, CDCl3) δ 177.7, 171.7, 159.2, 152.6, 147.2, 134.4, 130.9, 130.4, 130.3, 129.9, 129.0, 128.0, 127.9, 126.3, 125.5, 122.4, 114.1, 107.3, 60.1, 58.5, 55.7, 55.4, 47.4, 44.0, 32.1, 27.5, 26.8; IR (Neat Film NaCl) 3459, 2931, 1682, 1601, 1574, 1530, 1457, 1360, 1249, 1176, 1037, 910, 849, 783, 731 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C29H29BrN3O6 [M+H]+ : 594.1234; found: 594.1230. O HO O Br TiCl3, NH 4OAc O NO N 2 MeCN, H 2O, MeOH 23 °C (80% yield) 62 Br NH OO N 67 Bis-oxindole 67. To a solution of lactone 62 (2.4 g, 5.6 mmol, 1.0 equiv) in H2O (282 mL) and MeOH (565 mL) were added NH4OAc (43.5 g, 564 mmol, 100.0 equiv) and TiCl3 (10% w/w, 70.3 mL, 56.4 mmol, 10.0 equiv). Then, the reaction was stirred for 12 h at 23 oC. The reaction mixture was diluted with EtOAc (500 mL) and then the phases were separated and the aqueous phase was extracted with EtOAc (3 x 300 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford bis-oxindole 67 (1.99 g, 80% yield). Rf = 0.10 (1:1 hexane:EtOAc); 1H NMR (500 MHz, DMSO) δ 10.33 (s, 1H), 6.98 (dd, J = 8.1, 1.0 Hz, 1H), 6.96–6.87 (m, 2H), 6.77–6.67 (m, 2H), 6.58 (dd, J = 7.8, 1.0 Hz, 1H), 6.45 (d, J = 7.6 Hz, 1H), 4.96 (ddt, J = 16.7, 9.7, 6.9 Hz, 1H), 4.86 (dd, J = 17.0, 2.5 Hz, 1H), 4.74 (dd, J = 9.9, 2.6 Hz, 1H), 4.39 (t, J = 5.0 Hz, 1H), 3.41–3.32 (m, 2H), 3.22– 3.13 (m, 1H), 3.03 (s, 3H), 2.86 (dtd, J = 10.3, 7.9, 5.5 Hz, 1H), 2.76 (dd, J = 13.5, 6.8 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 81 13 Hz, 1H), 2.24 (dt, J = 13.2, 7.9 Hz, 1H); C NMR (125 MHz, DMSO) δ 177.5, 175.8, 146.5, 142.8, 133.4, 130.2, 128.5, 128.1, 126.9, 126.8, 123.5, 120.4, 119.3, 118.9, 108.9, 107.4, 58.4, 57.2, 56.0, 33.5, 28.9, 26.3; IR (Neat Film NaCl) 2917, 2356, 1697, 1599, 1574, 1455, 1349, 1184, 910, 752 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H22BrN2O3 [M+H]+ : 441.0808; found 441.0812. HO TIPSO Br NH OO N 67 TIPSCl, imidazole DMF 0 → 23 °C (90% yield) Br NH OO N SI-1-19 TIPS-ether SI-1-19. Bis-oxindole 67 (1.66 g, 3.76 mmol, 1.0 equiv) was dissolved in DMF (18.8 mL) to which TIPSCl (1.61 mL, 7.52 mmol, 2.0 equiv) and imidazole (1.02 g, 15.0 mmol, 4.0 equiv) were added at 0 oC. The reaction was slowly warmed to 23 oC, and stirred for 12 h. The reaction mixture was extracted with EtOAc (3 x 40 mL), and washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford TIPS protected compound SI-1-19 (2.02 g, 90% yield). Rf = 0.20 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 6.99–6.92 (m, 2H), 6.87–6.80 (m, 2H), 6.76 (t, J = 7.5 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.10 (ddt, J = 16.9, 9.9, 7.1 Hz, 1H), 4.97 (dd, J = 17.1, 2.1 Hz, 1H), 4.77 (dd, J = 9.9, 2.2 Hz, 1H), 3.73 (ddd, J = 8.7, 5.7, 2.6 Hz, 1H), 3.57 (dd, J = 13.6, 7.1 Hz, 1H), 3.47–3.41 (m, 2H), 3.05 (s, 3H), 2.97 (dd, J = 13.6, 7.1 Hz, 1H), 2.60 (ddd, J = 15.0, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 82 13 11.5, 5.6 Hz, 1H), 0.87–0.82 (m, 21H); C NMR (125 MHz, CDCl3) δ 178.1, 175.8, 146.3, 140.9, 132.6, 129.3, 128.2, 127.0, 126.8, 123.7, 120.6, 119.4, 119.1, 108.5, 106.2, 60.9, 57.7, 56.8, 33.0, 28.8, 25.9, 17.8, 17.8, 11.8; IR (Neat Film NaCl) 3191, 3081, 2942, 2865, 2251, 2699, 1602, 1471, 1337, 1236, 1108, 995, 920, 736 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H42BrN2O3Si [M+H]+ : 597.2143; found 597.2141. TIPSO Br NH OO N SI-1-19 methyl chloroformate Et 3N, DMAP CH2Cl2 0 → 23 °C (98% yield) TIPSO Br N CO Me 2 OO N 68 Carbamate 68. To a stirred solution of bis-oxindole SI-1-19 (350 mg, 0.59 mmol, 1.0 equiv) in CH2Cl2 (5.86 mL) were added DMAP (7 mg, 0.059 mmol, 0.1 equiv), Et3N (0.812 mL, 5.9 mmol, 10.0 equiv), and methyl chloroformate (0.16 mL, 1.76 mmol, 3.0 equiv) at 0 oC. The reaction was slowly warmed to 23 oC, and stirred for 12 h. The solvent was concentrated in vacuo, and then the residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford carbamate 68 (377 mg, 98% yield). Rf = 0.61 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.53 (dt, J = 8.2, 0.8 Hz, 1H), 7.05 (ddd, J = 8.1, 6.1, 2.9 Hz, 1H), 6.96 (dd, J = 8.2, 1.0 Hz, 1H), 6.92–6.91 (m, 2H), 6.82 (t, J = 7.9 Hz, 1H), 6.25 (dd, J = 7.8, 1.0 Hz, 1H), 5.06 (ddt, J = 16.6, 9.6, 6.9 Hz, 1H), 5.00 – 4.95 (m, 1H), 4.81–4.78 (m, 1H), 4.00 (s, 3H), 3.72 (ddd, J = 10.2, 5.7, 3.1 Hz, 1H), 3.61 (ddt, J = 13.8, 6.9, 1.0 Hz, 1H), 3.43 (td, J = 10.4, 3.9 Hz, 1H), 3.33– 3.28 (m, 1H), 3.04–2.99 (m, 1H), 3.02 (s, 3H), 2.62 (ddd, J = 14.0, 10.6, 5.7 Hz, 1H), 0.87–0.81 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 175.3, 174.2, 151.3, 146.1, 139.5, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 83 132.0, 129.6, 128.6, 127.1, 126.5, 126.2, 123.2, 122.7, 119.9, 119.0, 113.9, 106.3, 60.7, 58.4, 57.3, 53.7, 33.4, 28.9, 26.0, 17.7, 11.8; IR (Neat Film NaCl) 2942, 2865, 2089, 1722, 1602, 1463, 1348, 1201, 1243, 1166, 1104, 1026, 920, 883, 736, 772 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C33H44BrN2O5Si [M+H]+ : 655.2197; found 655.2199. TIPSO TIPSO Br N CO Me 2 OO N O 3 then PPh 3 CH2Cl2 –78 °C (94% yield) 68 O Br N CO Me 2 OO N 69 Aldehyde 69. To a 25 mL round bottom flask with magnetic stir bar was added alkene 68 (260 mg, 0.40 mmol, 1.0 equiv) and CH2Cl2 (2.0 mL). The flask was connected to an ozone generator, and purged with oxygen gas (flow: 0.5), for 5 min at –78 oC and then ozone gas (flow: 0.5) was bubbled through into the reaction solution for 10 min at –78 oC. After the reaction was done, oxygen gas was bubbled into the reaction mixture for 20 min and PPh3 (313mg, 1.19 mmol, 3.0 equiv) was added. The reaction mixture was slowly warmed to ambient temperature, stirred for 16 h, and then concentrated under reduced pressure. The residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford aldehyde 69 (245 mg, 94% yield). Rf = 0.13 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.46 (d, J=1.0 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.06–7.01 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.88–6.82 (m, 2H), 6.75 (d, J = 7.6 Hz, 1H), 6.23 (d, J = 7.8 Hz, 1H), 4.33 (d, J = 19.4 Hz, 1H), 4.02 (s, 3H), 3.72 (ddd, J = 9.3, 5.6, 2.7 Hz, 1H), 3.58 (dd, J = 19.3, 1.2 Hz, 1H), 3.42 (td, J = 10.3, 3.4 Hz, 1H), 3.23 (dt, J = 14.0, 3.4 Hz, 1H), 2.99 (s, 3H), 2.56–2.48 (m, 1H), 0.86–0.79 (m, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 84 13 21H); C NMR (125 MHz, CDCl3) δ 197.9, 175.4, 174.4, 151.3, 146.0, 140.0, 129.9, 128.8, 127.2, 126.5, 125.2, 122.6, 121.4, 119.3, 114.1, 106.5, 60.6, 58.2, 53.8, 52.8, 44.6, 28.9, 26.0, 17.7, 11.8; IR (Neat Film NaCl) 2942, 2865, 2255, 1773, 1718, 1603, 1576, 1459, 1351, 1295, 1245, 1163, 1108, 914, 883, 771, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C32H41BrN2O6Si [M+H]+ : 657.1990; found: 657.1991. TIPSO PMB O TIPSO Br NCO 2Me PMBNH 3OAc, NaBH 3CN OO N THF, MeOH, 0 → 23 °C (95% yield) N Br O O N HN CO2Me 69 54 Lactam 54. To a solution of aldehyde 69 (100 mg, 0.15 mmol, 1.0 equiv) and pmethoxybenzylammonium acetate (90 mg, 0.46 mmol, 3.0 equiv) in methanol (7.6 mL) was added NaBH3CN (21 mg, 0.30 mmol, 2.0 equiv) in THF (3.8 mL) at 0 oC. The reaction mixture was slowly warmed to 23 oC and stirred overnight. The reaction mixture was washed with EtOAc (3 x 10 mL), and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford lactam 54 (112 mg, 95% yield). Rf = 0.20 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 12.14 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 7.15–7.10 (m, 2H), 7.05 (q, J = 8.5, 7.9 Hz, 2H), 6.88 (t, J = 7.7 Hz, 1H), 6.85–6.80 (m, 2H), 6.49 (d, J = 7.7 Hz, 1H), 4.80 (d, J = 14.4 Hz, 1H), 4.36 (d, J = 14.4 Hz, 1H), 3.78 (s, 3H), 3.70 (s, 1H), 3.63 (s, 3H), 3.52 (td, J = 6.9, 3.6 Hz, 1H), 3.43–3.36 (m, 1H), 3.27 (td, J = 9.3, 5.7 Hz, 1H), 3.17 (t, J = 9.6 Hz, 1H), Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 85 2.87 (ddd, J = 13.3, 6.1, 3.5 Hz, 1H), 2.66–2.60 (m, 1H), 2.56 (s, 3H), 2.54–2.49 (m, 1H), 0.85 (q, J = 3.8 Hz, 21H); 13C NMR (125 MHz, CDCl3) δ 175.94, 173.92, 159.34, 154.32, 146.89, 139.65, 132.30, 130.98, 130.07, 129.75, 128.88, 128.50, 127.57, 127.42, 126.71, 126.45, 121.74, 120.99, 120.75, 114.18, 107.15, 68.21, 61.31, 60.86, 60.43, 55.34, 51.42, 47.61, 44.98, 31.20, 25.78, 17.86, 11.88; IR (Neat Film NaCl) 2944, 2865, 2073, 1716, 1667, 1604, 1513, 1455, 1247, 1227, 1109, 1069, 1034, 883, 761 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C40H53BrN3O6Si [M+H]+ : 778.2882; found: 778.2879. PMB H OMe TIPSO N Br N TIPSO O AlH3-Me2NEt O N HN CO2Me N Br THF, 0 °C (61% yield) O N CO2Me 54 71 Aminal 71. To a solution of amide 54 (0.32 g, 0.41 mmol, 1.0 equiv) in THF (41.1 mL) was added AlH3-Me2NEt (0.5 M in toluene; 1.64 mL, 0.82 mmol, 2.0 equiv) dropwise at 0 oC. The reaction was stirred for 2 h and quenched with MeOH. The reaction solution was concentrated in vacuo and purified by column chromatography (4:1 hexanes:EtOAc) to afford aminal 71 (0.19 g, 61% yield). 1 H NMR (300 MHz, CDCl3) δ 7.58–7.47 (m, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.04–6.93 (m, 3H), 6.80 (dq, J = 14.8, 7.4 Hz, 4H), 6.39–6.24 (m, 2H), 4.00 (d, J = 13.7 Hz, 1H), 3.92– 3.79 (m, 4H), 3.78 (s, 3H), 3.68 (dd, J = 10.2, 5.0 Hz, 1H), 3.57–3.43 (m, 1H), 3.03 (s, 3H), 2.65 (m, 4H), 2.26 (dt, J = 15.0, 7.2 Hz, 1H), 2.09 (dd, J = 11.9, 4.6 Hz, 1H), 0.87 (d, J = 3.2 Hz, 21H); 13C NMR (125 MHz, CDCl3) δ 176.0, 175.7, 160.6, 146.3, 141.7, 133.9, 132.2, 130.3, 130.1, 126.8, 123.6, 123.2, 123.1, 115.1, 114.6, 113.9, 107.3, 107.1, 106.6, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 86 82.4, 60.7, 60.1, 57.2, 55.3, 52.6, 51.0, 31.9, 31.1, 30.7, 29.7, 26.1, 17.7, 11.8; IR (Neat Film NaCl) 2943, 1722, 1604, 1464, 1386, 1344, 1254, 1107, 1033, 885, 760 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C40H53BrN3O5Si [M+H]+ : 762.2932; found: 762.2936. PMB H N TIPSO CO2Me N Br O N 1. TBAF, THF, 23 °C (98% yield) 2. DDQ, CH2Cl2, H 2O 23 °C (85% yield) 71 H N HO H CO2Me N Br O N 72 Aminal 72. To a solution of silyl ether 71 (98 mg, 0.13 mmol, 1.0 equiv) in THF (1.28 mL) was added TBAF (0.15 mL, 1.0 M solution in THF) at 0 oC. The reaction mixture was stirred for 3 h at 23 oC and quenched with sat. NH4Cl. The reaction mixture was washed with EtOAc (3 x 1.5 mL), and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford PMB-protected aminal compound (78 mg, 98% yield). To a solution of PMB-protected aminal compound (96 mg, 0.16 mmol, 1.0 equiv) in CH2Cl2 (3.1 mL) and H2O (0.8 mL) was added DDQ (53 mg, 0.23 mmol, 1.5 equiv) in portions over 30 min at 0 oC. The reaction mixture was stirred for 2 h at 23 oC. The solution was diluted with CH2Cl2 and quenched with sat. NaHCO3. The reaction mixture was washed with CH2Cl2 (3 x 2.5 mL), and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 87 chromatography (4:1 CH2Cl2:acetone) on silica gel to afford aminal 72 (64 mg, 85% yield). Rf = 0.31 (4:1 CH2Cl2:acetone); 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz, 1H), 7.01–6.96 (m, 2H), 6.84 (p, J = 8.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.73 (t, J = 7.5 Hz, 1H), 6.48 (s, 1H), 6.35 (d, J = 7.8 Hz, 1H), 3.87 (d, J = 17.2 Hz, 3H), 3.66 (ddd, J = 10.8, 6.8, 3.7 Hz, 1H), 3.35 (dt, J = 10.9, 5.3 Hz, 1H), 3.11 (s, 3H), 3.01 (dd, J = 10.0, 6.5 Hz, 1H), 2.8–2.76 (m, 1H), 2.76–2.62 (m, 2H), 2.50 (td, J = 10.3, 4.7 Hz, 1H), 2.24 (br, s, 1H), 2.20 (dd, J = 12.7, 4.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 177.6, 152.8, 146.1, 142.7, 130.4, 129.7, 128.9, 127.4, 127.2, 122.8, 121.6, 118.5, 113.8, 106.8, 80.5, 63.4, 60.0, 57.2, 52.6, 44.6, 35.1, 31.5, 26.3; IR (Neat Film NaCl) 3417, 2925, 1710, 1604, 1487, 1458, 1392, 1362, 1272, 1093, 756 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H25BrN3O4 [M+H]+ : 486.1023; found: 486.1014. PMB TIPSO Br O O N HN PMB TIPSO N LiAlH 4 THF, 0 °C (83% yield) N H O HN CO2Me O N CO2Me 54 73 Oxindole 73. To a solution of lactam 54 (10.6 mg, 0.0136 mmol, 1.0 equiv) in THF (1.36 ml) was added LiAlH4 (5.2 mg, 0.136 mmol, 10.0 equiv) in portions at 0 oC. The reaction was stirred for 1 h and then quenched with sat. NaCl. The reaction mixture was washed with EtOAc (3 x 2 mL) and brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford oxindole 73 (7.9 mg, 83% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 88 1 Rf = 0.25 (4:1 hexanes:EtOAc); H NMR (600 MHz, CDCl3) δ 9.64 (br, s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.60 (s, 1H), 7.13 (d, J = 8.4 Hz, 3H), 7.09 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.97 (s, 1H), 6.83 (d, J = 8.3 Hz, 3H), 6.38 (d, J = 7.7 Hz, 1H), 4.55 (d, J = 14.5 Hz, 1H), 4.44 (d, J = 14.5 Hz, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.31–3.27 (m, 1H), 3.24 (br, s, 2H), 3.14 (br, s, 1H), 3.05–3.00 (m, 1H), 2.85 (s, 3H), 2.72 (s, 1H), 2.52 (t, J = 9.9 Hz, 1H), 2.41 (br, s, 1H), 0.86 (q, J = 7.5, 6.2 Hz, 21H); 13C NMR (125 MHz, CDCl3) δ 177.5, 159.4, 154.7, 143.7, 129.6, 129.4, 129.3, 129.2, 128.6, 128.4, 127.7, 127.5, 127.4, 122.2, 122.0, 121.8, 114.3, 107.3, 60.0, 56.6, 55.4, 52.1, 47.1, 44.0, 34.3, 29.9, 26.0, 18.0, 12.0; IR (Neat Film NaCl) 2941, 1732, 1711, 1610, 1515, 1442, 1375, 1248, 1225, 1105, 1070, 1036, 750 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C40H54N3O6Si [M+H]+ : 700.3776; found: 700.3776. PMB TIPSO Br N Br O O N HN CO2Me 54 Tf2O CH2Cl2 0 → 23 °C (95% yield) N O N CO2Me O N PMB 74 PMB-Propellane hexacycle 74. To a solution of lactam 54 (70 mg, 0.090 mmol, 1.0 equiv) in CH2Cl2 (9 mL) was added Tf2O (45 µL, 0.27 mmol, 3.0 equiv) dropwise at 0 oC. The reaction mixture was slowly warmed to 23 oC and stirred for 2 h. The solution was neutralized by adding sat. NaHCO3. The reaction mixture was washed with CH2Cl2 (3 x 5 mL) and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford propellane hexacycle 74 (52 mg, 95% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 89 1 Rf = 0.25 (3:1 hexanes:EtOAc); H NMR (500 MHz, CDCl3) δ 7.67 (s, 1H), 7.16–7.11 (m, 3H), 6.95–6.93 (m, 2H), 6.78 (d, J = 8.6 Hz, 2H), 6.73 (td, J = 7.6, 1.1 Hz, 1H), 6.60 (t, J = 4.4 Hz, 1H), 6.36 (dd, J = 7.6, 1.5 Hz, 1H), 4.53 (dt, J = 11.5, 5.8 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1H), 4.23–4.18 (m, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 3.72 (d, J = 13.7 Hz, 1H), 3.21 (s, 3H), 3.01 (ddd, J = 14.4, 11.7, 8.4 Hz, 1H), 2.77–2.73 (m, 1H), 2.54 (q, J = 9.3 Hz, 1H), 2.13 (td, J = 8.8, 5.3 Hz, 1H), 1.93 (dd, J = 14.2, 6.3 Hz, 1H), 1.80–1.75 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 178.0, 158.5, 153.7, 145.8, 142.5, 132.0, 130.9, 130.1, 129.5, 129.4, 128.9, 128.1, 124.6, 122.9, 121.5, 116.1, 113.6, 112.1, 106.6, 58.2, 57.0, 55.4, 54.4, 52.7, 50.2, 47.9, 33.7, 26.6, 23.2; IR (Neat Film NaCl) 1718, 1601, 1575, 1513, 1484, 1455, 1365, 1245, 1134, 1099, 1037, 912, 764, 731 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H31BrN3O5 [M+H]+ : 604.1442; found: 604.1433. Br N Br O N CO2Me O N 74 PMB DDQ CH2Cl2, 23 °C (92% yield) N O N CO2Me O NH 75 Propellane hexacycle 75. To a solution of oxindole 74 (46 mg, 0.075 mmol, 1.0 equiv) in CH2Cl2 (3.8 mL) and H2O (0.94 mL) was added DDQ (34 mg, 0.15 mmol, 2.0 equiv) at 0 oC. The reaction mixture was slowly warmed to 23 oC and stirred for 2 h. The solution was quenched with sat. NaHCO3. The reaction mixture was washed with CH2Cl2 (3 x 3.0 mL) and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (4:1 CH2Cl2:acetone) on silica gel to afford propellane hexacycle 75 (33 mg, 92% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 90 1 Rf = 0.1 (1:1 hexane:EtOAc); H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.98 (dd, J = 21.2, 8.0 Hz, 2H), 6.71 (d, J = 7.7 Hz, 2H), 6.25 (d, J = 7.6 Hz, 1H), 4.45 (td, J = 11.1, 6.6 Hz, 1H), 4.10–4.02 (m, 1H), 3.92 (s, 3H), 3.23 (s, 3H), 3.14 (dd, J = 9.4, 6.0 Hz, 1H), 3.08–2.92 (m, 1H), 2.68–2.51 (m, 2H), 1.82 (td, J = 14.2, 12.6, 7.1 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 177.9, 153.6, 145.8, 142.4, 133.3, 130.4, 129.7, 129.2, 128.1, 125.7, 123.2, 122.5, 114.3, 111.6, 106.9, 58.5, 55.7, 53.8, 53.0, 43.3, 36.5, 26.6, 23.5; IR (Neat Film NaCl) 2958, 1713, 1602, 1485, 1446, 1373, 1242, 1095, 754 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H23BrN3O4 [M+H]+ : 484.0866; found: 484.0874. Br N PMB HO O N CO2Me O N 74 PMB DIBAL then Et 2AlCl CH2Cl2 –78 → 23 °C (87% yield) N Br O N N CO2Me 76 Aminal 76. To a solution of propellane hexacycle 74 (13 mg, 0.021 mmol, 1.0 equiv) in CH2Cl2 (2.14 mL) was added DIBAL (1.0 M in THF; 0.11 mL, 0.11 mmol, 5 equiv) dropwise at –78 oC. The reaction mixture was stirred for 1 h and warmed to 0 oC. DIBAL (1.0 M in THF; 21.4 µL, 21.4 µmol, 1 equiv) was added dropwise at 0 oC and stirred for 1 h. Then, DIBAL (1.0 M in THF; 21.4 mL, 21.4 mmol, 1 equiv) was added one more time dropwise at 0 oC and stirred for another 1 h. The reaction mixture was warmed to 23 oC and Et2AlCl (1.0 M in hexane; 42.8 mL, 42.8 mmol, 2 equiv) was added dropwise. The mixture was stirred for 30 min and quenched with sat. NH4Cl and sat. potassium sodium tartrate. The reaction mixture was washed with CH2Cl2 (3 x 2.0 mL) Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 91 and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford propellane aminal 76 (10.5 mg, 87% yield). Rf = 0.25 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 7.7 Hz, 1H), 7.24–7.22 (m, 2H), 7.17 (s, 1H), 7.08–7.03 (m, 1H), 6.87–6.84 (m, 2H), 6.82 (t, J = 7.9 Hz, 1H), 6.71 (dd, J = 8.0, 1.0 Hz, 1H), 6.23 (br, s, 1H), 6.01 (dd, J = 7.9, 1.0 Hz, 1H), 5.15 (d, J = 14.5 Hz, 1H), 3.94 (d, J = 14.5 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.72–3.63 (m, 2H), 3.40 (dd, J = 9.5, 7.7 Hz, 1H), 3.12 (td, J = 9.7, 1.5 Hz, 1H), 3.10–3.04 (m, 1H), 2.89–2.82 (m, 1H), 2.48 (s, 3H), 2.32 (dt, J = 14.2, 7.2 Hz, 1H), 1.65 (dt, J = 14.7, 9.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 170.5, 159.2, 152.7, 139.2, 136.3, 134.0, 130.4, 129.8, 128.8, 126.8, 126.7, 126.1, 125.2, 125.0, 122.9, 122.4, 114.2, 104.7, 83.3, 61.0, 60.5, 55.4, 53.6, 53.4, 47.1, 44.3, 35.3, 33.0, 31.1; IR (Neat Film NaCl) 2922, 1689, 1597, 1512, 1444, 1334, 1249, 1178, 1032, 754 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H33BrN3O5 [M+H]+ : 606.1598; found: 606.1592. O2N TIPSO O NO 2 Br NCO 2Me OO N 69 77 TIPSO NH 3OAc Br NaBH 3CN THF, MeOH 0 → 23 °C (97% yield) N O O N HN CO2Me 78 Amide 78. To a solution of aldehyde 69 (100 mg, 0.13 mmol, 1.0 equiv) and onitrobenzylammonium acetate 77 (97 mg, 0.38 mmol, 3.0 equiv) in MeOH (7.6 mL) was added NaBH3CN (21 mg, 0.26 mmol, 2.0 equiv) in THF (3.8 mL) at 0 oC. The reaction mixture was slowly warmed to ambient temperature and stirred for 12 h. Then, H2O (5 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 92 mL) was added and extracted with EtOAc (3 x 20 mL), and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford o-nitrobenzyl protected amide 78 (116 mg, 97% yield). Rf = 0.35 (2:1 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (500 MHz, CDCl3) δ 11.63 (s, 1H), 8.06–7.97 (m, 2H), 7.51 (td, J = 7.6, 1.5 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.25–7.18 (m, 2H), 7.13 (dd, J = 14.1, 8.2 Hz, 2H), 7.05 (t, J = 7.9 Hz, 1H), 6.97–6.90 (m, 1H), 6.53 (d, J = 7.6 Hz, 1H), 5.32 (d, J = 16.5 Hz, 1H), 4.71 (dd, J = 16.4, 6.5 Hz, 1H), 3.70–3.63 (m, 2H), 3.57 (td, J = 6.3, 2.9 Hz, 1H), 3.55–3.51 (m, 1H), 3.35–3.26 (m, 2H), 2.92 (ddd, J = 13.1, 5.4, 3.3 Hz, 1H), 2.84 (s, 1H), 2.69 (ddd, J = 19.4, 8.7, 5.3 Hz, 2H), 2.63 (s, 3H), 0.85 (t, J = 4.1 Hz, 21H); 13C NMR (125 MHz, CDCl3) δ 176.0, 175.4, 154.4, 148.7, 147.1, 139.7, 134.1, 132.1, 131.2, 130.0, 129.4, 128.8, 128.7, 127.6, 126.6, 126.0, 125.3, 122.1, 121.8, 121.3, 107.3, 60.9, 60.6, 60.4, 51.6, 46.0, 45.1, 31.8, 31.6, 25.9, 17.9, 11.9; IR (Neat Film NaCl) 3418, 2943, 2865, 2251, 1717, 1601, 1527, 1456, 1338, 1313, 1282, 1227, 1113, 1069, 911, 883, 857, 730 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C39H50BrN4O7Si [M+H]+ : 793.2627; found: 793.2658. O2N TIPSO Br N Br O O N HN CO2Me 78 Tf2O 0 → 23 °C CH2Cl2 (75% yield) N O N CO2Me O N NO 2 SI-1-20 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 93 Propellane hexacycle SI-1-20. To a solution of amide 78 (54.1 mg, 0.087 mmol, 1.0 equiv) in CH2Cl2 (6.82 mL), was added Tf2O (34 mL, 0.26 mmol, 3.0 equiv) dropwise at 0 oC. The reaction mixture was slowly warmed to 23 oC, and stirred for 2 h. After the reaction was done, the solution was brought to pH 10.5-11.0 by addition of sat. NaHCO3. The reaction mixture was extracted with EtOAc (3 x 6 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford propellane hexacycle SI-1-20 (39.6 mg, 75% yield). Rf = 0.46 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 7.9, 1.2 Hz, 1H), 7.72–7.58 (m, 1H), 7.46–7.40 (m, 2H), 7.30 (ddd, J = 8.0, 6.7, 2.2 Hz, 1H), 7.21– 7.14 (m, 1H), 6.99–6.93 (m, 2H), 6.81–6.76 (m, 1H), 6.64 (dd, J = 7.4, 1.4 Hz, 1H), 6.36 (dd, J = 7.7, 1.3 Hz, 1H), 4.61 (d, J = 16.6 Hz, 1H), 4.54 (d, J = 18.2 Hz, 1H), 4.45 (td, J = 11.4, 6.5 Hz, 1H), 4.18–4.11 (m, 1H), 3.72 (d, J = 9.4 Hz, 3H), 3.21 (s, 3H), 3.11–3.02 (m, 1H), 2.96–2.87 (m, 1H), 2.51 (dt, J = 14.4, 9.0 Hz, 2H), 1.94–1.81 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 177.6, 153.5, 148.9, 145.8, 144.4, 142.1, 136.2, 132.9, 131.0, 130.0, 129.6, 129.1, 128.1, 127.3, 125.1, 124.3, 123.1, 116.1, 111.9, 106.8, 64.5, 58.4, 56.5, 54.5, 52.6, 50.0, 47.9, 33.9, 26.5, 22.8; IR (Neat Film NaCl) 2953, 2360, 1721, 1599, 1573, 1524, 1483, 1455, 1367, 1242, 1134, 1088, 1134, 1088, 947, 856, 761, 733 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C30H28BrN4O6 [M+H]+ : 619.1187; found: 619.1188. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 94 O2N Br HO N O N CO2Me O N NO 2 SI-1-20 DIBAL;Et 2AlCl CH2Cl2 –78 → 0 °C (60% yield) N Br O N N CO2Me 79 Aminal 79. To a solution of propellane hexacyclic oxindole SI-1-20 (14.6 mg, 0.024 mmol, 1.0 equiv) in CH2Cl2 (2.4 mL) was added DIBAL (1.0 M in THF; 0.12 mL, 0.12 mmol, 5 equiv) dropwise at –78 oC. After the reaction mixture was stirred for 1 h at –78 o C, the solution was warmed to 0 oC and DIBAL (1.0 M in THF; 24 mL, 0.024 mmol, 1.0 equiv) was added dropwise. The mixture was stirred for 1 h at 0 oC, and more DIBAL (1.0 M in THF; 24 mL, 0.024 mmol, 1.0 equiv) was added dropwise. The reaction mixture was stirred for 1 h at 0 oC, and warmed to 23 oC. To the reaction mixture was added Et2AlCl (1.0 M in hexanes; 48 mL, 0.048 mmol, 2.0 equiv) dropwise. The reaction was stirred for 30 min and quenched with aq NH4Cl (1 mL) and aq potassium sodium tartrate (1 mL). The reaction mixture was washed with EtOAc (3 x 3 mL), and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford aminal 79 (8.9 mg, 60% yield). Rf = 0.12 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.01 (dd, J = 8.2, 1.3 Hz, 1H), 7.58 (td, J = 7.6, 1.3 Hz, 1H), 7.50–7.48 (m, 1H), 7.44 (ddd, J = 8.6, 7.4, 1.5 Hz, 1H), 7.37–7.34 (m, 1H), 7.23–7.19 (m, 1H), 7.09–7.05 (m, 1H), 6.81 (t, J = 7.9 Hz, 1H), 6.69 (dd, J = 8.0, 1.0 Hz, 1H), 6.26 (s, 1H), 6.01 (dd, J = 7.9, 0.9 Hz, 1H), 5.41 (d, J = 16.3 Hz, 1H), 4.56 (d, J = 16.2 Hz, 1H), 3.86 (s, 3H), 3.73–3.64 (m, 2H), 3.56 (td, J = 9.5, 7.4 Hz, 1H), 3.24–3.18 (m, 1H), 3.09 (ddd, J = 13.6, 8.6, 5.3 Hz, 1H), 2.95 (ddd, J = Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 95 14.2, 7.4, 1.7 Hz, 1H), 2.48 (s, 3H), 2.35 (ddd, J = 13.2, 8.5, 6.2 Hz, 1H), 1.78 (dt, J = 14.2, 9.4 Hz, 1H), 1.74 (br, s, 1H); 13C NMR (125 MHz, CDCl3) δ 171.5, 171.3 152.6, 148.9, 138.8, 136.3, 133.7, 132.1, 130.4, 129.7, 128.4, 126.9, 126.2, 126.0, 125.0, 124.8, 122.7, 122.2, 104.6, 83.2, 64.4, 60.7, 60.4, 53.3, 53.1, 45.3, 44.5, 35.2, 33.0, 31.0; IR (Neat Film NaCl) 2955, 2357, 1694, 1595, 1524, 1444, 1335, 1281, 1073, 1032, 911, 857, 835, 730 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C30H30BrN4O6 [M+H]+ : 621.1343; found: 621.1286. O2N HO HO N Br O N H NH Br O hv MeOH (40% yield) N N CO2Me H N CO2Me 53 79 Amide 53. A solution of aminal 79 (21.5 mg, 0.035 mmol, 1.0 equiv) in anhydrous MeOH (3.5 mL) in a Pyrex flask was purged with N2 for 5 min. The reaction mixture was irradiated in a cylindrical photoreactor with 254 nm lamps under N2 for 3 h and concentrated. The residue was purified by column chromatography (4:1 CH2Cl2:acetone) on silica gel to afford aminal 53 (6.7 mg, 40% yield). See below for characterization data. O2N HO HO N Br O N H N CO2Me 79 NH Br O 20% aq NaOH MeOH, 75 °C (70% yield) N H 53 N CO2Me Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 96 Amide 53. To a solution of o-nitrobenzyl protected aminal 79 (10.8 mg, 0.017 mmol, 1.0 equiv) in MeOH (0.8 mL) was added 20% aq NaOH (0.2 mL) and the mixture was stirred for 4 h at 75 oC. After the reaction mixture was cooled to 23 oC, it was diluted with water and extracted with EtOAc (3 x 2 mL). The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography (4:1 CH2Cl2:acetone) to afford compound 53 (5.9 mg, 70% yield). Rf = 0.18 (4:1 CH2Cl2:acetone); 1H NMR (500 MHz, CDCl3) δ 7.51–7.45 (m, 1H), 7.19 (td, J = 7.6, 1.4 Hz, 1H), 7.05 (td, J = 7.7, 1.4 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.69 (dt, J = 8.0, 1.0 Hz, 1H), 6.60 (br, s, 1H), 6.25 (br, s, 1H), 5.99 (dd, J = 7.9, 0.9 Hz, 1H), 3.87 (s, 3H), 3.74–3.63 (m, 2H), 3.55 (td, J = 9.4, 7.3 Hz, 1H), 3.33 (ddd, J = 9.8, 8.8, 1.5 Hz, 1H), 3.17 (ddd, J = 13.6, 8.4, 5.6 Hz, 1H), 3.03–2.96 (m, 1H), 2.49 (s, 3H), 2.36 (ddd, J = 13.2, 8.2, 6.3 Hz, 1H), 1.92 (dt, J = 14.0, 9.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 174.8, 155.4, 152.9, 138.6, 136.4, 130.4, 126.9, 126.6, 126.1, 125.0, 123.4, 122.5, 104.6, 83.2, 76.9, 60.9, 60.6, 53.5, 52.3, 40.4, 35.8, 35.2, 31.1; IR (Neat Film NaCl) 3418, 2955, 2357, 1693, 1593, 1446, 1335, 1282, 1032, 836, 754 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H25BrN3O4 [M+H]+ : 486.1023; found: 486.1004. Br Br TIPSO TIPSO NO 2 NH TiCl3, NH 4OAc CO2Allyl O N 52 i-PrOH, H 2O, 23 °C (91% yield) OO N 82 Bis-oxindole 82. To a solution of oxindole 52 (7.65 g, 11.2 mmol, 1.0 equiv) in H2O (187 mL) and i-PrOH (373 mL) were added NH4OAc (43.2 g, 0.560 mol, 50 equiv) and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 97 TiCl3 (20% w/w, 69.2 mL, 0.11 mol, 10 equiv). Then, the reaction was stirred for 12 h at 23 oC. The reaction mixture was diluted with EtOAc (200 mL) and then the phases were separated and the aqueous phase was extracted with EtOAc (3 x 300 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford bisoxindole 82 (6.10 g, 91% yield). Rf = 0.68 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.57 (br, s, 1H), 7.31–7.26 (m, 1H), 6.98–6.90 (m, 2H), 6.88 (dd, J = 2.7, 1.5 Hz, 1H), 6.82 (s, 1H), 6.73–6.69 (m, 1H), 6.21 (br, s, 1H), 5.14 (ddt, J = 17.1, 10.0, 7.1 Hz, 1H), 4.96 (ddd, J = 17.1, 2.0, 0.9 Hz, 1H), 4.86–4.80 (m, 1H), 3.42–3.31 (m, 2H), 3.25 (ddd, J = 9.9, 7.5, 4.7 Hz, 1H), 3.05 (dt, J = 14.5, 7.4 Hz, 1H), 2.90 (s, 3H), 2.79 (dd, J = 13.0, 6.9 Hz, 1H), 2.34 (ddd, J = 13.4, 6.8, 4.7 Hz, 1H), 0.92–0.81 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 177.14, 176.05, 144.65, 142.73, 131.37, 128.80, 127.92, 127.73, 125.58, 124.41, 124.20, 121.97, 121.73, 119.88, 112.70, 108.15, 59.61, 56.86, 54.80, 35.16, 32.66, 25.91, 17.82, 11.77; IR (Neat Film NaCl) 3270, 2942, 2865, 1716, 1611, 1471, 1377, 1241, 1105, 916, 883, 791, 734 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H42BrN2O3Si [M+H]+: 597.2143; found: 597.2187. Br Br TIPSO TIPSO NH OO N Boc 2O, DMAP N Boc MeCN, 23 °C (85% yield) OO N 82 83 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 98 Carbamate 83. To a stirred solution of bis-oxindole 82 (2.63 g, 4.40 mmol, 1.0 equiv) in CH2Cl2 (44 mL) were added DMAP (1.08 g, 8.80 mmol, 2.0 equiv) and Boc2O (1.92 g, 8.80 mmol, 2.0 equiv) at 0 oC. The reaction was slowly warmed to 23 oC, and stirred for 12 h. The solvent was concentrated in vacuo and then the residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford protected compound 83 (2.6 g, 85% yield). Rf = 0.52 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 1.9 Hz, 1H), 7.25 (td, J = 7.7, 1.3 Hz, 1H), 7.14–7.09 (m, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.71–6.67 (m, 1H), 6.62–6.53 (m, 1H), 6.47 (s, 1H), 5.10 (ddt, J = 17.0, 9.9, 7.1 Hz, 1H), 4.99–4.92 (m, 1H), 4.83 (dd, J = 10.0, 2.0 Hz, 1H), 3.43 (dd, J = 13.3, 7.3 Hz, 1H), 3.35 (dt, J = 9.9, 7.2 Hz, 1H), 3.20 (ddd, J = 9.9, 7.7, 4.8 Hz, 1H), 2.94 (s, 3H), 2.90 (dd, J = 13.9, 8.0 Hz, 1H), 2.81–2.75 (m, 1H), 2.30 (ddd, J = 13.2, 7.2, 4.8 Hz, 1H), 1.51 (s, 9H), 0.89–0.84 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 175.60, 173.73, 148.46, 144.52, 141.67, 131.26, 128.95, 127.19, 126.28, 126.06, 125.32, 124.15, 122.43, 121.69, 120.23, 118.24, 108.06, 84.08, 59.56, 57.36, 55.29, 34.77, 32.70, 27.92, 25.97, 17.82, 11.76; IR (Neat Film NaCl) 2941, 2866, 1770, 1716, 1610, 1471, 1420, 1370, 1342, 1287, 1246, 1153, 1105, 1067, 1023, 919, 882, 845, 752, 733 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H42BrN2O3Si [M+H-Boc]+: 597.2143 found: 597.2181. Br Br TIPSO TIPSO O O 3, then PPh 3 NBoc OO N NBoc CH2Cl2, –78 °C (90% yield) OO N 83 81 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 99 Aldehyde 81. To a 100 mL round bottom flask with magnetic stir bar was added alkene 83 (2.61 g, 0.00374 mol, 1.0 equiv). The flask was connected to an ozone generator and purged with oxygen gas (flow: 0.5) for 5 min at –78 oC. Then, ozone gas (flow: 0.5) was bubbled through into the reaction solution for 30 min at –78 oC. After the reaction was done, oxygen gas was bubbled into the reaction mixture for 20 min and PPh3 (2.95 g, 0.0112 mol, 3.0 equiv) was added. The reaction mixture was slowly warmed to ambient temperature, stirred for 16 h, and then concentrated under reduced pressure. The residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford aldehyde 81 (2.4 g, 90% yield). Rf = 0.23 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.45 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.21 (td, J = 7.8, 1.2 Hz, 1H), 6.93 (br, s, 1H), 6.77 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 5.99 (br, s, 1H), 4.43 (d, J = 19.1 Hz, 1H), 3.39 (dd, J = 19.2, 1.1 Hz, 1H), 3.31 (dt, J = 9.9, 7.3 Hz, 1H), 3.15 (ddd, J = 9.9, 8.0, 4.7 Hz, 1H), 3.10 (s, 3H), 2.64 (dt, J = 12.8, 7.6 Hz, 1H), 2.20 (ddd, J = 12.6, 7.5, 4.7 Hz, 1H), 1.43 (s, 9H), 0.91–0.82 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 197.38, 175.36, 173.47, 148.07, 144.01, 142.38, 129.18, 126.57, 126.04, 125.73, 124.51, 123.59, 122.99, 121.72, 118.74, 108.14, 83.83, 59.25, 53.78, 53.64, 44.47, 33.42, 27.83, 26.20, 17.80, 11.74; IR (Neat Film NaCl) 1941, 2865, 1771, 1722, 1609, 1471, 1422, 1370, 1345, 1291, 1245, 1152, 1109, 1070, 1015, 882, 845, 793, 749 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C30H40BrN2O4Si [M+H-Boc]+: 599.1935 found: 597.1971. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 100 Br O2N 77 NH 3OAc O TIPSO NO 2 NaBH 3CN TIPSO N O NBoc OO N THF, MeOH 0 → 23 °C (91% yield) O N HN Br Boc 81 84 Amide 84. To a solution of aldehyde 81 (200 mg, 0.29 mmol, 1.0 equiv) and onitrobenzylammonium acetate 77 (182 mg, 0.86 mmol, 3.0 equiv) in MeOH (14.3 mL) was added NaBH3CN (39 mg, 0.57 mmol, 2.0 equiv) in THF (7.2 mL) at 0 oC. The reaction mixture was slowly warmed to ambient temperature, and stirred for 12 h. Then, H2O (10 mL) was added. The mixture was extracted with EtOAc (3 x 20 mL) and washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford o-nitrobenzyl protected amide 84 (221 mg, 91% yield). Rf = 0.22 (4:1 hexanes:EtOAc); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks. See attached the spectrum behind); 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 8.9 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.09 (s, 1H), 8.06–7.96 (m, 2H), 7.83 (s, 1H), 7.62 (d, J = 7.1 Hz, 2H), 7.46 (t, J = 8.5 Hz, 1H), 7.42– 7.30 (m, 6H), 7.23 (d, J = 8.3 Hz, 3H), 7.09 (t, J = 7.6 Hz, 1H), 6.93–6.86 (m, 2H), 6.81 (d, J = 7.5 Hz, 2H), 6.10 (d, J = 7.6 Hz, 1H), 5.00 (d, J = 16.9 Hz, 1H), 4.91 (d, J = 17.3 Hz, 1H), 4.58 (d, J = 17.3 Hz, 1H), 4.27 (s, 1H), 3.75 (s, 1H), 3.37 (t, J = 7.4 Hz, 1H), 3.28 (s, 3H), 3.23 (d, J = 4.9 Hz, 1H), 3.18 (d, J = 7.2 Hz, 4H), 3.14–3.06 (m, 3H), 2.99 (dt, J = 9.2, 4.7 Hz, 2H), 2.80 (dd, J = 13.3, 9.4 Hz, 3H), 2.43 (t, J = 7.8 Hz, 1H), 2.25– 2.13 (m, 1H), 2.06 (d, J = 8.9 Hz, 2H), 0.87 (d, J = 1.9 Hz, 21H), 0.80 (d, J = 2.7 Hz, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 101 13 21H); C NMR (125 MHz, CDCl3) δ 178.3, 176.9, 174.6, 152.9, 148.3, 148.1, 145.0, 144.7, 141.9, 134.5, 134.1, 131.8, 131.0, 129.1, 128.8, 128.8, 128.5, 128.4, 128.4, 128.2, 127.0, 125.3, 125.2, 125.1, 124.9, 123.2, 122.9, 122.1, 121.7, 108.4, 107.9, 79.9, 59.9, 59.2, 59.1, 52.9, 44.6, 44.2, 44.1, 36.4, 34.6, 31.3, 31.1, 28.6, 28.3, 26.5, 26.3, 18.2, 18.0, 17.9, 12.2, 12.1, 11.9; IR (Neat Film NaCl) 3329, 2941, 2866, 1701, 1612, 1531, 1496, 1473, 1344, 1280, 1159, 1103, 1072, 1024, 914, 885, 753, 731, 688 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C42H56BrN4O7Si [M+H]+: 835.3096; found: 835.3105. O2N TIPSO O2N Br N O O N HN N Tf2O O Br 0 → 23 °C CH2Cl2 (70% yield) Boc 84 HN O N 86 Tetrahydroazepine 86. To a solution of amide 84 (20 mg, 0.0239 mmol, 1.0 equiv) in CH2Cl2 (2.39 mL), was added Tf2O (0.0121 ml, 0.0718 mmol, 3.0 equiv) dropwise at 0 o C. The reaction mixture was slowly warmed to 23 oC, and stirred for 2 h. After the reaction was done, the solution was brought to pH 10.5-11.0 by addition of sat. NaHCO3. The reaction mixture was extracted with EtOAc (3 x 3 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford tetrahydroazepine 86 (9.4 mg, 70% yield). Rf = 0.33 (2:1 hexanes:EtOAc); 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 102 6.73 (t, J = 7.7 Hz, 1H), 6.70 (dd, J = 8.4, 1.3 Hz, 1H), 6.18 (d, J = 7.6 Hz, 1H), 5.08 (d, J = 17.1 Hz, 1H), 4.47 (d, J = 17.1 Hz, 1H), 3.89 (s, br, 1H), 3.81–3.75 (m, 1H), 3.31–3.26 (m, 2H), 3.23 (td, J = 9.3, 8.5, 4.1 Hz, 1H), 3.18 (d, J = 1.5 Hz, 3H), 2.97–2.93 (m, 1H), 2.93–2.89 (m, 1H), 2.70 (dt, J = 13.7, 8.6 Hz, 1H), 1.45–1.39 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 180.4, 175.1, 150.3, 148.3, 143.8, 134.2, 132.5, 131.1, 131.1, 129.4, 129.2, 128.3, 127.7, 126.0, 125.3, 125.0, 124.6, 121.7, 121.3, 108.0, 58.8, 50.3, 44.6, 44.1, 43.4, 36.1, 27.6, 26.4; IR (Neat Film NaCl) 3343, 2942, 1703, 1611, 1588, 1524, 1471, 1357, 1285, 1137, 1106, 1065, 984, 858, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C28H26BrN4O4 [M+H]+: 561.1132; found: 561.1165. O2N TIPSO O2N TIPSO N N AlH3-Me2NEt O O N HN Br THF (42% yield) (66% yield, based on recovered 84 ) O N H N Boc Boc 84 87 Br Aminal 87. Oxindole 84 (20 mg, 0.0239 mmol, 1.0 equiv) was dissolved in THF (2.39 mL) and cooled to 0 oC. AlH3-Me2NEt (0.5 M in toluene; 0.096 mL, 0.0478 mmol, 2.0 equiv) was added dropwise at 0 oC. The solution was stirred for 2 h and quenched with MeOH. The solution was concentrated under reduced pressure and purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford cyclized compound 87 (8.23 mg, 42% yield; 66% yield based on recovered starting material). Rf = 0.33 (4:1 hexanes:EtOAc); 1H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 7.9 Hz, 1H), 7.40 (s, 1H), 7.35 (dt, J = 19.0, 7.4 Hz, 2H), 7.06–7.03 (m, 1H), 6.96 (d, J = 7.6 Hz, 1H), Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 103 6.93–6.91 (m, 2H), 6.90–6.86 (m, 1H), 6.40 (t, J = 7.4 Hz, 1H), 6.20 (s, 1H), 6.12 (d, J = 7.8 Hz, 1H), 4.75 (q, J = 16.8, 16.1 Hz, 2H), 3.78 (td, J = 10.7, 10.3, 6.0 Hz, 1H), 3.53 (q, J = 8.8 Hz, 1H), 3.46 (t, J = 9.3 Hz, 1H), 3.16–3.07 (m, 2H), 2.84(s, 3H), 2.75 (dd, J = 13.4, 6.0 Hz, 1H), 2.50 (td, J = 11.4, 5.6 Hz, 1H), 2.23–2.16 (m, 1H), 1.47 (s, 9H), 0.95 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 172.5, 153.6, 150.9, 148.7, 139.9, 133.5, 132.2, 131.0, 130.6, 128.9, 128.5, 128.2, 127.8, 125.2, 124.8, 123.2, 120.6, 116.2, 104.3, 80.9, 79.6, 59.9, 56.9, 54.12, 44.49, 43.5, 39.5, 31.0, 29.6, 28.2, 26.3, 17.9, 11.9; IR (Neat Film NaCl) 2941, 2865, 1697, 1603, 1528, 1491, 1333, 1302, 1168, 1100, 992, 882, 739 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C42H56BrN4O6Si [M+H]+: 819.3147; found: 819.3153. O2N O2N TIPSO TIPSO PDC, K 2CO3 O N N N H N Boc 87 Br CH2Cl2 (62% yield) (93% yield, based on recovered 87 ) O N O H N Br Boc 88 Formyl 88. To a solution of methyl protected compound 87 (11 mg, 0.0161 mmol, 1.0 equiv) in CH2Cl2 (1.61 mL) was added PDC (9.1 mg, 0.0241 mmol, 1.5 equiv) at 23 oC. After being stirred at 23 oC for 12 h, the reaction mixture was quenched with water. The reaction mixture was washed with CH2Cl2 (3 x 2 mL), and brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford aldehyde 88 (7.0 mg, 62% yield; 93% yield based on recovered starting material). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 104 1 Rf = 0.55 (4:1 hexanes:EtOAc); H NMR (500 MHz, CDCl3) δ 8.90 (s, 1H), 7.96 (dd, J = 7.8, 2.5 Hz, 2H), 7.38 (q, J = 8.5, 8.0 Hz, 2H), 7.33 (s, br, 1H), 7.14–6.99 (m, 4H), 6.96– 6.87 (m, 3H), 4.83 (s, br, 1H), 4.70 (d, 15Hz, 1H), 3.64–3.54 (m, 2H), 3.51 (t, J = 9.4 Hz, 1H), 3.26 (q, J = 10.0, 7.4 Hz, 1H), 3.11 (q, J = 10.9 Hz, 1H), 2.79 (dd, J = 13.2, 5.8 Hz, 1H), 2.58 (dt, J = 13.1, 7.8 Hz, 1H), 2.19 (ddd, J = 12.9, 7.9, 4.7 Hz, 1H), 1.44 (s, br, 9H), 0.98–0.76 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 172.1, 161.4, 153.1, 148.7, 141.3, 138.3, 133.5, 131.8, 131.5, 131.2, 129.3, 128.7, 128.4, 125.1, 124.9, 124.2, 123.5, 121.1, 116.0, 81.9, 75.1, 59.4, 57.2, 54.1, 44.6, 43.6, 39.6, 29.7, 28.1, 26.3, 17.9, 17.9, 11.8; IR (Neat Film NaCl) 2942, 2866, 1683, 1591, 1527, 1489, 1393, 1323, 1280, 1155, 1096, 911, 733 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C42H54BrN4O7Si [M+H]+: 833.2940; found: 833.2960. O2N TIPSO TIPSO O H N Boc 88 O 20% aq NaOH O N NH N Br MeOH, 75 °C (50% yield) N N H H Boc Br 80 Amide 80. To a solution of aldehyde 88 (14.8 mg, 0.0177 mmol, 1.0 equiv) in MeOH (0.4 mL) was added 20% aq NaOH (0.2 mL) and the reaction mixture was stirred for 4 h at 75 oC. The reaction mixture was diluted with EtOAc (1 mL) and the aqueous phase was extracted with EtOAc (3 x 1 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford desired amide 80 (5.9 mg, 50% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 105 1 Rf = 0.21 (4:1 hexanes:EtOAc); H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.14 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (dt, J = 7.7, 3.7 Hz, 3H), 6.70 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.17 (s, 1H), 5.72 (s, 1H), 3.69–3.61 (m, 1H), 3.48 (dt, J = 10.8, 5.6 Hz, 1H), 3.07 (m, 1H), 2.85 (m, 1H), 2.77 (m, 2H), 2.33 (d, J = 7.9 Hz, 1H), 1.59 (s, 9H), 0.91 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 176.2, 153.9, 149.2, 138.2, 130.4, 128.9, 127.1, 126.8, 126.5, 124.4, 120.6, 119.5, 109.4, 82.5, 60.3, 55.6, 53.4, 38.9, 35.7, 31.2, 28.6, 18.4, 11.9; IR (Neat Film NaCl) 3401, 2941, 2865, 1696, 1487, 1465, 1314, 1163, 1094, 882, 740 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C34H49BrN3O4Si [M+H]+: 670.2670; found: 670.2679. 1.5. References and Notes                                                                                                                   (1) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355. (2) (a) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem. 2001, 66, 8717. (b) Retraction of this article was prompted by a revision of structure, see ref. 5a and Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem. 2003, 68, 1640.; however, the biological activity reported in this manuscript was not specifically called into question and is distinct relative to previous reports.1 (3) (a) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K; Proksch, P. J. Nat. Prod. 2004, 67, 78. (b) Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci. Biotechnol. Biochem. 2004, 68, 753. (c) Andersen, B.; Smedsgaard, J.; Frisvad, J. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           C. J. Agric. Food Chem. 2004, 52, 2421. (d) Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad, J. C.; Christophersen, C. J. Nat. Prod. 2005, 68, 258. (e) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26. (f) Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561. (4) (a) Tanaka, J.; Yan, Y.; Choi, J.; Bai, J.; Klenchin, V. A.; Rayment, I.; Marriott, G. Proc. Natl. Acad. Sci. 2003, 100, 13851. (b) Klenchin, V. A.; Allingham, J. S.; King, R.; Tanaka, J.; Marriott, G.; Rayment, I. Nat. Struct. Biol. 2003, 10, 1058. (5) (a) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203. (b) Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169. (c) May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262. (d) Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187. (e) Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995. (f) Seo, J. H.; Artman, G. D., III; Weinreb, S. M. J. Org. Chem. 2006, 71, 8891. (g) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794. (h) George, J. H.; Adlington, R. M. Synlett 2008, 2093. (i) Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 8170. (j) Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem., Int. Ed. 2010, 49, 2000. (k) Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132, 13226. (l) Zuo, Z.; Ma, D. Angew. Chem., Int. Ed. 2011, 50, 12008. (m) Belmar, J.; Funk, R. L. J. Am. Chem. Soc. 2012, 134, 16941. (n) Artman, G. D., III; Weinreb, S. M. Org. Lett. 2003, 5, 1523. (o) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068. (p) Sabahi, A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006, 45, 4317. (q) Evans, M. A.; Sacher, J. R.; Weinreb, S. M. Tetrahedron 2009, 65, 6712. (r) Wu, H.; Xue, F.; Xiao, X.; Qin, Y. J. Am. Chem. Soc. 2010, 132, 14052. (s) Schammel, A. W.; Chiou, G.; Garg, N. 106 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           K. Org. Lett. 2012, 14, 4556. (t) Ishida, T.; Takemoto, Y. Tetrahedron 2013, 69, 4517. (u) Ishida, T.; Ikota, H.; Kurahashi, K.; Tsukano, C.; Takemoto, Y. Angew. Chem., Int. Ed. 2013, 52, 10204. (v) Zhang, H.; Hong, L.; Kang, H.; Wang, R. J. Am. Chem. Soc. 2013, 135, 14098. (w) Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2014, 16, 3316. (x) Trost, B. M.; Osipov, M.; Krüger, S.; Zhang, Y. Chem. Sci. 2015, 6, 349. (6) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124. (7) Denault, J.-B.; Salvesen, G. S. Chem. Rev. 2002, 102, 4489. (8) Wigley, L. J.; Perry, D. A.; Mantle, P. G. Mycol. Res. 2008, 112, 131. (9) (a) Kozlovskii, A. G.; Solov’eva, T. F.; Sahkarovskii, V. G.; Adanin, V. M. Dokl. Akad. Nauk SSSR 1981, 260, 230. (b) Sahkarovskii, V. G.; Aripovskii, A. V.; Baru, M. B.; Kozlovskii, A. G. Khim. Prir. Soedin. 1983, 656. (10) (a) Hegedus, L. S.; Toro, J. L.; Miles, W. H.; Harrington, P. J. J. Org. Chem. 1987, 52, 3319. (b) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486. (c) Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J. Org. Chem. 2004, 1244. (11) Greenberg, A. Mol. Struct. Enegetics 1988, 7, 139. (12) Indeed, it was the recognition that an anti-Bredt, twisted amide might be involved in a potentially biogenetic or laboratory synthesis of alkaloids 1a–1h that inspired our fundamental synthetic study in this area. Tani, K.; Stoltz, B. M. Nature, 2006, 441, 731. 107 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           (13) (a) Szostak, M.; Aubé, J. Org. Biomol. Chem. 2011, 9, 27. (b) Szostak, M.; Aubé, J. Chem. Rev. 2013, 113, 5701. (14) (a) Yamada, F.; Makita, Y.; Suzuki, T.; Somei, M. Chem. Pharm. Bull. 1985, 33, 2162. (b) Somei, M.; Yamada, F. Jpn. Patent JP 85-47044 19850308, 1986. (c) Iwao, M.; Motoi, O. Tetrahedron Lett. 1995, 36, 5929. (15) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C. Ramtohul, Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745. (16) Steinhagen, H.; Corey, E. J. Angew. Chem., Int. Ed. 1999, 38, 1928. (17) Kennewell, P. D.; Miller, D. J.; Scrowston, R. M.; Westwood, R. J. Chem. Res. Miniprint 1995, 10, 2380. (18) (a) Hrib, N. J.; Jurcak, J. G.; Burgher, K. L.; Conway, P. G.; Hartman, H. B.; Kerman, L. L.; Roehr, J. E.; Woods, A. T. J. Med. Chem. 1994, 37, 2308. (b) Spence, T. W. M.; Tennant, G. J. Chem. Soc. C 1971, 3712. (c) Eckroth, D. R.; Cochran, T. G. J. Chem. Soc. C 1970, 2660. (19) He, L.; Bekkaye, M.; Retailleau, P.; Masson, G. Org. Lett. 2012, 14, 3158. (20) Krishnan, S.; Stoltz, B. M. Tetrahedron Lett. 2007, 48, 7571. (21) (a) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037. (b) Dou, X.; Yao, W.; Zhou, B.; Lu, Y. Chem. Commun. 2013, 49, 9224. (22) Liu, B.; Hu, L. Bioorg. Med. Chem. 2003, 11, 3889. (23) We thought that the diastereoselectivity might be related to protecting groups and attempted the Diels–Alder cycloaddition with tosyl protected aurantioclavine derivative 108 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           and o-azaxylylene derivative. However, a change of the protecting groups did not significantly affect the diastereoselectivity of the cycloaddition. (a) Ts Cl N Cs2CO3 Ts H N Ts H N + N Ts 93 + CH2Cl2 –78 °C (92: 93 = 1.5:1 ) HN 7 N N H 10 N 7 Ts 94 N H Ts 95 (b) Ts I N Cs2CO3 Ts H N + CH2Cl2 –78 → 23 °C (33% yield) HN N 93 Ts 96 7 N N H Ts 94 (X-ray) (24) Lee, C. W.; Han, S.-J. Virgil, S. C.; Stoltz, B. M. Tetrahedron 2014, 71, 3666–3670. (25) Horvath, A.; Grassberger, M. A.; Schulz, G.; Haidl, E.; Sperner, H.; Steck, A. Tetrahedron 2000, 56, 7469. (26) (a) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381. (b) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793. (c) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. (d) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343. (27) For reviews on allylic alkylation, see; (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. (b) Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715. (c) Mohr, J. T.; Stoltz, B. M. Chem. Asian J. 2007, 2, 1476. (d) Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846. (28) Marfat, A.; Carta, M. P. Tetrahedron Lett. 1987, 28, 4027. (29) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849. 109 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           (30) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365. (31) (a) Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133, 7328. (b) Li, P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 6396. (32) Kotoku, N.; Sumii, Y.; Kobayashi, M. Org. Lett. 2011, 13, 3514. (33) Fernandes, R. A.; Yamamoto, Y. J. Org. Chem. 2004, 69, 3562. (34) Rege, P. D.; Johnson, F. J. Org. Chem. 2003, 68, 6133. (35) Treatment of hexacyclic oxindole 77 with allyl iodide and benzyl bromide under basic conditions provided 97 and 98 in 85% and 80% yield, respectively. Although smooth reductive cyclization of the propellane hexacyclic oxindole 97 and 98 led to aminal 99 and 100, respectively, removal of both allyl and benzyl groups on lactam 99 and 100 turned out to be challenging. Br Br O N N CO2Me O N Allyl iodide, K 2CO3 MeCN, reflux O N N R DIBAL then Et 2AlCl CH2Cl2 –78 → 23 °C 97, R = allyl (85% yield) 98, R = benzyl (80% yield) 77 R HO H HO N Br N Br O O N CO2Me O or Benzyl bromide, K 2CO3 MeCN, reflux H N H N CO2Me 99, R = allyl (90% yield) 100, R = benzyl (89% yield) N H N CO2Me 53 (Not Observed) (36) (a) Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57, 3301. (b) Gareau, Y.; Zamboni, R.; Wong, A. W. J. Org. Chem. 1993, 58, 1582. (c) Voelker, T.; Ewell, T.; Joo, J.; Edstrom, E. D. Tetrahedron Lett. 1998, 39, 359. (37) Han, S.-J.; Fernando de Melo, G.; Stoltz, B. M. Tetrahedron Lett. 2014, 55, 6467. 110 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           (38) Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426. (39) Wang, Y.; Kong, C.; Du, Y.; Song, H.; Zhang, D.; Qin, Y. Org. Biomol. Chem. 2012, 10, 2793. (40) Yamada, Y.; Arima, S.; Okada, C.; Akiba, A.; Kai, T.; Harigaya, Y. Chem. Pharm. Bull. 2006, 54, 788. (41) May, J. A. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, Jul 2005. 111 Appendix 1 – Spectra Relevant to Chapter 1 112 APPENDIX 1 Spectra Relevant to Chapter 1: The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine N N H SI-1-11 Ts O Figure A1.1. 1H NMR (300 MHz, CDCl3) of compound SI-1-11. Appendix 1 – Spectra Relevant to Chapter 1 113 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound SI-1-11. Figure A1.3. 13C NMR (75 MHz, CDCl3) of compound SI-1-11. 114 Ts 35 N N H O Br Figure A1.4. 1H NMR (300 MHz, CDCl3) of compound 35. Appendix 1 – Spectra Relevant to Chapter 1 115 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 35. Figure A1.6. 13C NMR (75 MHz, CDCl3) of compound 35. 116 Ts N 37 O N O2N H CN Figure A1.7. 1H NMR (300 MHz, CDCl3) of compound 37. Appendix 1 – Spectra Relevant to Chapter 1 117 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 37. Figure A1.9. 13C NMR (75 MHz, CDCl3) of compound 37. 118 Ts N 39 O NO N 2 H CO2Me CO2Me Figure A1.10. 1H NMR (300 MHz, CDCl3) of compound 39. Appendix 1 – Spectra Relevant to Chapter 1 119 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.11. Infrared spectrum (Thin Film, NaCl) of compound 39. Figure A1.12. 13C NMR (75 MHz, CDCl3) of compound 39. 120 N N H SI-1-13 Ts O Figure A1.13. 1H NMR (300 MHz, CDCl3) of compound SI-1-13. Appendix 1 – Spectra Relevant to Chapter 1 121 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.14. Infrared spectrum (Thin Film, NaCl) of compound SI-1-13. Figure A1.15. 13C NMR (75 MHz, CDCl3) of compound SI-1-13. .. 122 H Ts 40 N N H O Br Figure A1.16. 1H NMR (300 MHz, CDCl3) of compound 40. Appendix 1 – Spectra Relevant to Chapter 1 123 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 40. Figure A1.18. 13C NMR (75 MHz, CDCl3) of compound 40. .. 124 42 Ts H N N H CO2Me O CO2Me Figure A1.19. 1H NMR (300 MHz, CDCl3) of compound 42. Appendix 1 – Spectra Relevant to Chapter 1 125 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 42. Figure A1.21. 13C NMR (75 MHz, CDCl3) of compound 42. .. 126 O 44 NO 2 O O O                                                                                                     127   Figure A1.22. 1H NMR (500 MHz, CDCl3) of compound 44. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 44.  Figure A1.24. 13C NMR (125 MHz, CDCl3) of compound 44.   128   45 NO 2 O Br O O O                                                                                                     129   Figure A1.25. 1H NMR (500 MHz, CDCl3) of compound 45. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                         130     Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 45.  Figure A1.27. 13C NMR (125 MHz, CDCl3) of compound 45.   N H 46 CO2Allyl O CO2Allyl NO 2 TIPSO                                                                                                     131   Figure A1.28. 1H NMR (500 MHz, CDCl3) of compound 46. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 46.  Figure A1.30. 13C NMR (125 MHz, CDCl3) of compound 46.   132   TIPSO 47 N H CO2Allyl O CO2Allyl NO 2 Br                                                                                                     133   Figure A1.31. 1H NMR (500 MHz, CDCl3) of compound 47. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 47.  Figure A1.33. 13C NMR (125 MHz, CDCl3) of compound 47.   134   48 N CO2Allyl O CO2Allyl NO 2 TIPSO                                                                                                     135   Figure A1.34. 1H NMR (500 MHz, CDCl3) of compound 48. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 48.  Figure A1.36. 13C NMR (125 MHz, CDCl3) of compound 48.   136   TIPSO 49 N CO2Allyl O CO2Allyl NO 2 Br                                                                                                     137   Figure A1.37. 1H NMR (500 MHz, CDCl3) of compound 49. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 49.  Figure A1.39. 13C NMR (125 MHz, CDCl3) of compound 49.   138   50 2 O NO N CO2Allyl O O                                                                                                     139   Figure A1.40. 1H NMR (400 MHz, CDCl3) of compound 50. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 50.  Figure A1.42. 13C NMR (100 MHz, CDCl3) of compound 50.   140   51 2 O NO N O O                                                                                                     141   Figure A1.43. 1H NMR (400 MHz, CDCl3) of compound 51. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.44. Infrared spectrum (Thin Film, NaCl) of compound 51.  Figure A1.45. 13C NMR (100 MHz, CDCl3) of compound 51.   142   TIPSO 52 N CO2Allyl O NO 2 Br                                                                                                     143   Figure A1.46. 1H NMR (500 MHz, CDCl3) of compound 52. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1     Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 52.  Figure A1.48. 13C NMR (125 MHz, CDCl3) of compound 52.   144   SI-1-16 N H OMe O O Br                                                                                                     145   Figure A1.49. 1H NMR (500 MHz, CDCl3) of compound SI-1-16. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound SI-1-16.  Figure A1.51. 13C NMR (125 MHz, CDCl3) of compound SI-1-16.   146   59 N H OH Br                                                                                                     147   Figure A1.52. 1H NMR (500 MHz, CDCl3) of compound 59. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 59.  Figure A1.54. 13C NMR (125 MHz, CDCl3) of compound 59.   148   SI-1-17 N H OTIPS Br                                                                                                     149   Figure A1.55. 1H NMR (500 MHz, CDCl3) of compound SI-1-17. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.56. Infrared spectrum (Thin Film, NaCl) of compound SI-1-17.  Figure A1.57. 13C NMR (125 MHz, CDCl3) of compound SI-1-17.   150   O 57 N H Br Br TIPSO                                                                                                     151   Figure A1.58. 1H NMR (500 MHz, CDCl3) of compound 57. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.59. Infrared spectrum (Thin Film, NaCl) of compound 57.  Figure A1.60. 13C NMR (125 MHz, CDCl3) of compound 57.   152   SI-1-18 N H CO2Allyl O NO 2 CO2Allyl Br TIPSO                                                                                                     153   Figure A1.61. 1H NMR (500 MHz, CDCl3) of compound SI-1-18. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.62. Infrared spectrum (Thin Film, NaCl) of compound SI-1-18.  Figure A1.63. 13C NMR (125 MHz, CDCl3) of compound SI-1-18.   154   60 N CO2Allyl O NO 2 CO2Allyl Br TIPSO                                                                                                     155   Figure A1.64. 1H NMR (500 MHz, CDCl3) of compound 60. Appendix 1 – Spectra Relevant to Chapter 1 156   Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.65. Infrared spectrum (Thin Film, NaCl) of compound 60.  Figure A1.66. 13C NMR (125 MHz, CDCl3) of compound 60 . 61 2 O NO N O CO2Allyl O Br                                                                                                     157   Figure A1.67. 1H NMR (500 MHz, CDCl3) of compound 61. Appendix 1 – Spectra Relevant to Chapter 1 158   Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.68. Infrared spectrum (Thin Film, NaCl) of compound 61.  Figure A1.69. 13C NMR (125 MHz, CDCl3) of compound 61. . 62 2 O NO N O O Br                                                                                                     159   Figure A1.70. 1H NMR (500 MHz, CDCl3) of compound 62. Appendix 1 – Spectra Relevant to Chapter 1 160   Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.71. Infrared spectrum (Thin Film, NaCl) of compound 62.  Figure A1.72. 13C NMR (125 MHz, CDCl3) of compound 62. . O 63 2 O NO N O O Br                                                                                                     161   Figure A1.73. 1H NMR (500 MHz, CDCl3) of compound 63. Appendix 1 – Spectra Relevant to Chapter 1 162   Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.74. Infrared spectrum (Thin Film, NaCl) of compound 63.  Figure A1.75. 13C NMR (125 MHz, CDCl3) of compound 63. . NO 2 65 O N Br PMB N O HO                                                                                                     163   Figure A1.76. 1H NMR (500 MHz, CDCl3) of compound 65. Appendix 1 – Spectra Relevant to Chapter 1 164   Appendix 1 – Spectra Relevant to Chapter 1     Figure A1.77. Infrared spectrum (Thin Film, NaCl) of compound 65.  Figure A1.78. 13C NMR (125 MHz, CDCl3) of compound 65. . 67 N OO NH HO Br                                                                                                     165   Figure A1.79. 1H NMR (500 MHz, DMSO) of compound 67. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.80. Infrared spectrum (Thin Film, NaCl) of compound 67.  Figure A1.81. 13C NMR (125 MHz, DMSO) of compound 67.   166   N OO SI-1-19 NH Br TIPSO                                                                                                     167   Figure A1.82. 1H NMR (500 MHz, CDCl3) of compound SI-1-19. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.83. Infrared spectrum (Thin Film, NaCl) of compound SI-1-19.  Figure A1.84. 13C NMR (125 MHz, CDCl3) of compound SI-1-19.   168   N 68 OO N CO Me 2 Br TIPSO                                                                                                     169   Figure A1.85. 1H NMR (500 MHz, CDCl3) of compound 68. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.86. Infrared spectrum (Thin Film, NaCl) of compound 68.  Figure A1.87. 13C NMR (125 MHz, CDCl3) of compound 68.   170   N 69 OO N CO Me 2 Br O TIPSO                                                                                                     171   Figure A1.88. 1H NMR (500 MHz, CDCl3) of compound 69. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.89. Infrared spectrum (Thin Film, NaCl) of compound 69.  Figure A1.90. 13C NMR (125 MHz, CDCl3) of compound 69.   172   Br CO2Me 54 O N HN O PMB N TIPSO                                                                                                     173   Figure A1.91. 1H NMR (500 MHz, CDCl3) of compound 54. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.92. Infrared spectrum (Thin Film, NaCl) of compound 54.  Figure A1.93. 13C NMR (125 MHz, CDCl3) of compound 54.   174   CO2Me N 71 O PMB H Br TIPSO N N                                                                                                     175   Figure A1.94. 1H NMR (300 MHz, CDCl3) of compound 71. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.95. Infrared spectrum (Thin Film, NaCl) of compound 71.  Figure A1.96. 13C NMR (125 MHz, CDCl3) of compound 71.   176   CO2Me N 72 O H Br N H N HO                                                                                                     177   Figure A1.97. 1H NMR (600 MHz, CDCl3) of compound 72. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.98. Infrared spectrum (Thin Film, NaCl) of compound 72.  Figure A1.99. 13C NMR (125 MHz, CDCl3) of compound 72.   178   CO2Me O HN PMB H N 73 O N TIPSO                                                                                                     179   Figure A1.100. 1H NMR (600 MHz, CDCl3) of compound 73. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.101. Infrared spectrum (Thin Film, NaCl) of compound 73.  Figure A1.102. 13C NMR (125 MHz, CDCl3) of compound 73.   180   PMB CO2Me N N 74 O O N Br                                                                                                     181   Figure A1.103. 1H NMR (500 MHz, CDCl3) of compound 74. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.104. Infrared spectrum (Thin Film, NaCl) of compound 74.  Figure A1.105. 13C NMR (125 MHz, CDCl3) of compound 74.   182   NH CO2Me N 75 O O N Br                                                                                                     183   Figure A1.106. 1H NMR (300 MHz, CDCl3) of compound 75. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.107. Infrared spectrum (Thin Film, NaCl) of compound 75.  Figure A1.108. 13C NMR (125 MHz, CDCl3) of compound 75.   184   N 76 N CO2Me O PMB N Br HO                                                                                               185   Figure A1.109. 1H NMR (500 MHz, CDCl3) of compound 76. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.110. Infrared spectrum (Thin Film, NaCl) of compound 76.  Figure A1.111. 13C NMR (125 MHz, CDCl3) of compound 76.   186   Br TIPSO O 78 CO2Me O N HN N O2N Figure A1.112. 1H NMR (500 MHz, CDCl3) of compound 78. Appendix 1 – Spectra Relevant to Chapter 1   187   Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.113. Infrared spectrum (Thin Film, NaCl) of compound 78.  Figure A1.114. 13C NMR (125 MHz, CDCl3) of compound 78.   188   N O N N SI-1-20 O Br Figure A1.115. 1H NMR (500 MHz, CDCl3) of compound SI-1-20. NO 2 CO2Me Appendix 1 – Spectra Relevant to Chapter 1   189   Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.116. Infrared spectrum (Thin Film, NaCl) of compound SI-1-20.  Figure A1.117. 13C NMR (125 MHz, CDCl3) of compound SI-1-20.   190   Br HO N O 79 CO2Me N N O2N Figure A1.118. 1H NMR (500 MHz, CDCl3) of compound 79. Appendix 1 – Spectra Relevant to Chapter 1   191   Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.119. Infrared spectrum (Thin Film, NaCl) of compound 79.  Figure A1.120. 13C NMR (125 MHz, CDCl3) of compound 79.   192   Br HO N 53 H O CO2Me N NH Figure A1.121. 1H NMR (500 MHz, CDCl3) of compound 53. Appendix 1 – Spectra Relevant to Chapter 1   193   Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.122. Infrared spectrum (Thin Film, NaCl) of compound 53.  Figure A1.123. 13C NMR (125 MHz, CDCl3) of compound 53.   194   NH TIPSO N 82 OO Br                                                                                                     195   Figure A1.124. 1H NMR (500 MHz, CDCl3) of compound 82. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.125. Infrared spectrum (Thin Film, NaCl) of compound 82.  Figure A1.126. 13C NMR (125 MHz, CDCl3) of compound 82.   196   N Boc TIPSO N 83 OO Br                                                                                                     197   Figure A1.127. 1H NMR (500 MHz, CDCl3) of compound 83. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.128. Infrared spectrum (Thin Film, NaCl) of compound 83.  Figure A1.129. 13C NMR (125 MHz, CDCl3) of compound 83.   198   NBoc TIPSO N O 81 OO Br                                                                                                     199   Figure A1.130. 1H NMR (500 MHz, CDCl3) of compound 81. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.131. Infrared spectrum (Thin Film, NaCl) of compound 81.  Figure A1.132. 13C NMR (125 MHz, CDCl3) of compound 81.   200   Br TIPSO 84 Boc O N HN N O O2N                                                                                                     201   Figure A1.133. 1H NMR (300 MHz, CDCl3) of compound 84. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.134. Infrared spectrum (Thin Film, NaCl) of compound 84.  Figure A1.135. 13C NMR (125 MHz, CDCl3) of compound 84.   202   HN Br O 86 O N N O2N                                                                                                     203   Figure A1.136. 1H NMR (600 MHz, CDCl3) of compound 86. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.137. Infrared spectrum (Thin Film, NaCl) of compound 86.  Figure A1.138. 13C NMR (125 MHz, CDCl3) of compound 86.   204   Br 87 N N TIPSO H Boc N O O2N                                                                                                     205   Figure A1.139. 1H NMR (600 MHz, CDCl3) of compound 87. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.140. Infrared spectrum (Thin Film, NaCl) of compound 87.  Figure A1.141. 13C NMR (125 MHz, CDCl3) of compound 87.   206   Br O 88 N N TIPSO H Boc N O O2N                                                                                                     207   Figure A1.142. 1H NMR (500 MHz, CDCl3) of compound 88. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.143. Infrared spectrum (Thin Film, NaCl) of compound 88.  Figure A1.144. 13C NMR (125 MHz, CDCl3) of compound 88.   208   Br 80 N N H H Boc O NH TIPSO                                                                                                     209   Figure A1.145. 1H NMR (500 MHz, CDCl3) of compound 80. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1     Figure A1.146. Infrared spectrum (Thin Film, NaCl) of compound 80.  Figure A1.147. 13C NMR (125 MHz, CDCl3) of compound 80.   210   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 211   APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1: The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.1. X-Ray Crystal Structure Analysis of 24 O N O N H H N 24     Figure A2.1.1. X-ray Crystal Structure of 24 Table A2.1.1. Crystal Data and Structure Analysis Details for 24 Empirical formula C25 H25 Cl2 N3 O2 Formula weight 470.38 Crystallization solvent ???Solvent??? Crystal shape chunk Crystal color colourless Crystal size 0.09 x 0.14 x 0.14 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK Data collection temperature 100 K 212   213   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Theta range for 6076 reflections used in lattice determination 2.60 to 23.34° a= 90° b= 90° g = 90° Unit cell dimensions a = 8.2203(10) Å b = 26.018(3) Å c = 10.2431(12) Å Volume 2190.8(5) Å3 Z 4 Crystal system orthorhombic Space group P n a 21 (# 33) Density (calculated) 1.426 g/cm3 F(000) 984 Theta range for data collection 1.6 to 32.9° Completeness to theta = 25.000° 100.0% Index ranges -12 £ h £ 12, -39 £ k £ 39, -15 £ l £ 15 Data collection scan type and scans Reflections collected 54235 Independent reflections 7838 [Rint= 0.0905] Reflections > 2s(I) 5779 Average s(I)/(net I) 0.0696 Absorption coefficient 0.33 mm-1 Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.0000 and 0.9032 Structure Solution and Refinement Primary solution method direct Secondary solution method ? Hydrogen placement difmap Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 7838 / 1 / 365 Treatment of hydrogen atoms refxyz Goodness-of-fit on F2 1.13 Final R indices [I>2s(I), 5779 reflections] R1 = 0.0490, wR2 = 0.0781 R indices (all data) R1 = 0.0843, wR2 = 0.0857 Type of weighting scheme used calc Weighting scheme used w=1/[^2^(Fo^2^)+(0.0300P)^2^] where P=(Fo^2^+2Fc^2^)/3 Max shift/error 0.000 Average shift/error 0.000 Absolute structure parameter 0.44(6) Extinction coefficient n/a Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Largest diff. peak and hole 214   0.36 and -0.32 e·Å-3 Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.34A (Bruker-AXS, 2007) APEX2 2013.10-0 (Bruker-AXS, 2007) SAINT V8.34A (Bruker-AXS, 2007) XT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.1.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 24. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ O(1) 4(2) 2120(1) 6508(2) 16(1) O(2) 85(2) 911(1) 6456(2) 16(1) N(1) 1141(2) 1782(1) 4648(2) 12(1) N(2) 1982(3) 2496(1) 117(2) 16(1) N(3) -836(3) 449(1) 6069(2) 20(1) C(1) -798(3) 1282(1) 5638(2) 15(1) C(2) 110(3) 1784(1) 5675(2) 13(1) C(3) 2535(3) 2130(1) 4609(3) 14(1) C(4) 2247(3) 2582(1) 3706(2) 16(1) C(5) 2045(3) 2430(1) 2314(2) 14(1) C(6) 2387(3) 2738(1) 1267(2) 16(1) C(7) 2210(4) 2702(1) -1189(3) 29(1) C(8) 1399(3) 2015(1) 413(2) 14(1) C(9) 862(3) 1636(1) -448(2) 16(1) C(10) 332(3) 1183(1) 92(3) 17(1) C(11) 350(3) 1105(1) 1455(2) 16(1) C(12) 898(3) 1479(1) 2324(2) 12(1) C(13) 1425(3) 1954(1) 1793(2) 13(1) C(14) 997(3) 1336(1) 3766(2) 13(1) C(15) -526(3) 1052(1) 4272(2) 13(1) C(16) -460(3) 459(1) 4594(3) 17(1) C(17) 1216(4) 220(1) 4435(3) 22(1) C(18) -1727(4) 147(1) 3860(3) 20(1) C(19) -2483(3) 644(1) 6275(2) 19(1) C(20) -3860(4) 373(1) 6614(3) 26(1) C(21) -5287(4) 655(1) 6750(3) 27(1) C(22) -5336(4) 1177(1) 6574(3) 25(1) C(23) -3924(3) 1452(1) 6225(2) 20(1) C(24) -2515(3) 1175(1) 6080(2) 16(1) Cl(1) 5159(1) 1123(1) 2694(1) 28(1) Cl(2) 5970(1) 875(1) 1(1) 44(1) C(25) 4688(4) 1234(1) 1034(3) 25(1) ________________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 215   Table A2.1.3. Bond lengths [Å] and angles [°] for 24 __________________________________________________________________________________ _ O(1)-C(2) 1.224(3) O(2)-N(3) 1.475(3) O(2)-C(1) 1.471(3) N(1)-C(2) 1.352(3) N(1)-C(3) 1.460(3) N(1)-C(14) 1.475(3) N(2)-C(6) 1.376(3) N(2)-C(7) 1.453(4) N(2)-C(8) 1.375(3) N(3)-C(16) 1.542(3) N(3)-C(19) 1.461(3) C(1)-C(2) 1.504(3) C(1)-C(15) 1.538(3) C(1)-C(24) 1.508(3) C(3)-H(3A) 0.96(3) C(3)-H(3B) 0.99(3) C(3)-C(4) 1.514(4) C(4)-H(4A) 0.95(3) C(4)-H(4B) 0.97(3) C(4)-C(5) 1.490(3) C(5)-C(6) 1.368(3) C(5)-C(13) 1.440(3) C(6)-H(6) 1.00(3) C(7)-H(7A) 0.95(4) C(7)-H(7B) 0.90(4) C(7)-H(7C) 1.02(4) C(8)-C(9) 1.393(3) C(8)-C(13) 1.422(3) C(9)-H(9) 0.95(3) C(9)-C(10) 1.373(4) C(10)-H(10) 0.95(3) C(10)-C(11) 1.411(4) C(11)-H(11) 1.03(3) C(11)-C(12) 1.393(3) C(12)-C(13) 1.419(3) C(12)-C(14) 1.525(3) C(14)-H(14) 0.96(3) C(14)-C(15) 1.543(3) C(15)-H(15) 0.95(3) C(15)-C(16) 1.579(3) C(16)-C(17) 1.520(4) C(16)-C(18) 1.519(4) C(17)-H(17A) 0.98(3) C(17)-H(17B) 1.00(3) C(17)-H(17C) 1.01(3) C(18)-H(18A) 0.98(3) C(18)-H(18B) 0.91(3) C(18)-H(18C) 0.97(3) C(19)-C(20) 1.378(4) C(19)-C(24) 1.396(4) C(20)-H(20) 0.98(3) C(20)-C(21) 1.390(4) C(21)-H(21) 0.86(3) C(21)-C(22) 1.370(4) C(22)-H(22) 0.95(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(22)-C(23) C(23)-H(23) C(23)-C(24) Cl(1)-C(25) Cl(2)-C(25) C(25)-H(25A) C(25)-H(25B) C(1)-O(2)-N(3) C(2)-N(1)-C(3) C(2)-N(1)-C(14) C(3)-N(1)-C(14) C(6)-N(2)-C(7) C(8)-N(2)-C(6) C(8)-N(2)-C(7) O(2)-N(3)-C(16) C(19)-N(3)-O(2) C(19)-N(3)-C(16) O(2)-C(1)-C(2) O(2)-C(1)-C(15) O(2)-C(1)-C(24) C(2)-C(1)-C(15) C(2)-C(1)-C(24) C(24)-C(1)-C(15) O(1)-C(2)-N(1) O(1)-C(2)-C(1) N(1)-C(2)-C(1) N(1)-C(3)-H(3A) N(1)-C(3)-H(3B) N(1)-C(3)-C(4) H(3A)-C(3)-H(3B) C(4)-C(3)-H(3A) C(4)-C(3)-H(3B) C(3)-C(4)-H(4A) C(3)-C(4)-H(4B) H(4A)-C(4)-H(4B) C(5)-C(4)-C(3) C(5)-C(4)-H(4A) C(5)-C(4)-H(4B) C(6)-C(5)-C(4) C(6)-C(5)-C(13) C(13)-C(5)-C(4) N(2)-C(6)-H(6) C(5)-C(6)-N(2) C(5)-C(6)-H(6) N(2)-C(7)-H(7A) N(2)-C(7)-H(7B) N(2)-C(7)-H(7C) H(7A)-C(7)-H(7B) H(7A)-C(7)-H(7C) H(7B)-C(7)-H(7C) N(2)-C(8)-C(9) N(2)-C(8)-C(13) C(9)-C(8)-C(13) C(8)-C(9)-H(9) C(10)-C(9)-C(8) C(10)-C(9)-H(9) C(9)-C(10)-H(10) 1.410(4) 0.99(3) 1.373(4) 1.768(3) 1.762(3) 1.05(3) 0.91(3) 97.38(16) 120.7(2) 115.4(2) 122.2(2) 126.1(2) 108.2(2) 125.7(2) 98.47(17) 98.84(18) 108.8(2) 108.11(19) 100.99(18) 99.71(19) 106.81(19) 128.1(2) 109.7(2) 126.1(2) 127.1(2) 106.7(2) 105.4(16) 104.5(16) 112.0(2) 111(2) 112.9(17) 110.5(17) 109.4(17) 108.2(17) 105(2) 113.3(2) 109.6(18) 110.7(18) 124.9(2) 106.6(2) 128.5(2) 117.3(16) 110.7(2) 131.9(16) 110(2) 109(2) 101(2) 116(3) 116(3) 103(3) 127.9(2) 108.3(2) 123.7(2) 120.8(17) 116.9(2) 122.3(17) 116.5(18) 216   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(9)-C(10)-C(11) C(11)-C(10)-H(10) C(10)-C(11)-H(11) C(12)-C(11)-C(10) C(12)-C(11)-H(11) C(11)-C(12)-C(13) C(11)-C(12)-C(14) C(13)-C(12)-C(14) C(8)-C(13)-C(5) C(12)-C(13)-C(5) C(12)-C(13)-C(8) N(1)-C(14)-C(12) N(1)-C(14)-H(14) N(1)-C(14)-C(15) C(12)-C(14)-H(14) C(12)-C(14)-C(15) C(15)-C(14)-H(14) C(1)-C(15)-C(14) C(1)-C(15)-H(15) C(1)-C(15)-C(16) C(14)-C(15)-H(15) C(14)-C(15)-C(16) C(16)-C(15)-H(15) N(3)-C(16)-C(15) C(17)-C(16)-N(3) C(17)-C(16)-C(15) C(18)-C(16)-N(3) C(18)-C(16)-C(15) C(18)-C(16)-C(17) C(16)-C(17)-H(17A) C(16)-C(17)-H(17B) C(16)-C(17)-H(17C) H(17A)-C(17)-H(17B) H(17A)-C(17)-H(17C) H(17B)-C(17)-H(17C) C(16)-C(18)-H(18A) C(16)-C(18)-H(18B) C(16)-C(18)-H(18C) H(18A)-C(18)-H(18B) H(18A)-C(18)-H(18C) H(18B)-C(18)-H(18C) C(20)-C(19)-N(3) C(20)-C(19)-C(24) C(24)-C(19)-N(3) C(19)-C(20)-H(20) C(19)-C(20)-C(21) C(21)-C(20)-H(20) C(20)-C(21)-H(21) C(22)-C(21)-C(20) C(22)-C(21)-H(21) C(21)-C(22)-H(22) C(21)-C(22)-C(23) C(23)-C(22)-H(22) C(22)-C(23)-H(23) C(24)-C(23)-C(22) C(24)-C(23)-H(23) C(19)-C(24)-C(1) C(23)-C(24)-C(1) 121.3(2) 122.2(18) 122.5(17) 122.3(2) 115.2(17) 117.6(2) 117.8(2) 124.5(2) 106.2(2) 135.6(2) 118.2(2) 113.95(19) 106.4(16) 103.67(18) 107.2(17) 113.51(19) 111.9(15) 103.71(19) 106.3(17) 101.28(18) 110.2(16) 120.7(2) 112.7(15) 102.36(19) 106.3(2) 114.1(2) 109.8(2) 113.2(2) 110.5(2) 112.8(18) 111.4(19) 110.4(19) 110(3) 103(2) 109(3) 109.3(18) 108(2) 113.1(19) 111(3) 105(3) 111(3) 128.3(2) 121.8(3) 109.9(2) 121.3(19) 116.7(3) 121.3(19) 121(2) 122.3(3) 117(2) 120.7(19) 120.8(3) 118.5(19) 118.4(17) 117.1(3) 124.4(17) 102.0(2) 136.5(2) 217   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(23)-C(24)-C(19) Cl(1)-C(25)-H(25A) Cl(1)-C(25)-H(25B) Cl(2)-C(25)-Cl(1) Cl(2)-C(25)-H(25A) Cl(2)-C(25)-H(25B) H(25A)-C(25)-H(25B) 218   121.3(2) 110.2(17) 107(2) 111.07(16) 106.5(17) 108(2) 113(3) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Table A2.1.4. Anisotropic displacement parameters (Å x 10 ) for 24. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2p [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ O(1) 206(9) 155(8) 131(8) -22(7) -1(7) -14(7) O(2) 207(10) 124(8) 161(8) 51(7) -61(7) -31(7) N(1) 126(10) 118(9) 127(9) -25(8) -2(8) -24(8) N(2) 203(11) 166(10) 125(9) 9(9) -8(9) -46(9) N(3) 212(12) 166(11) 214(11) 57(9) -55(9) -61(9) C(1) 171(12) 142(12) 126(11) 41(9) -26(9) 3(10) C(2) 146(12) 138(12) 117(10) 32(9) -22(9) 3(9) C(3) 126(12) 149(12) 159(11) 7(10) -10(9) -34(10) C(4) 177(13) 139(12) 148(11) -8(10) -12(10) -51(10) C(5) 119(12) 133(12) 160(11) -4(9) -4(9) -5(9) C(6) 153(12) 172(12) 166(12) 1(10) -11(10) -24(9) C(7) 420(20) 280(16) 154(13) 27(12) -28(13) -139(15) C(8) 143(12) 150(12) 139(11) 0(9) -5(9) 8(10) C(9) 169(13) 201(13) 121(10) -4(10) -15(10) 24(10) C(10) 212(13) 137(12) 167(11) -54(10) -42(10) 14(10) C(11) 193(13) 109(11) 173(12) -16(10) -4(10) -1(10) C(12) 116(11) 119(11) 131(10) -7(9) -4(8) 17(9) C(13) 102(12) 136(12) 141(11) -3(9) -3(9) 8(9) C(14) 132(12) 97(11) 153(11) -15(9) -13(10) -8(9) C(15) 148(12) 118(12) 112(11) 17(9) -27(9) -10(9) C(16) 191(13) 99(11) 221(12) 26(10) -30(10) 1(9) C(17) 227(15) 118(12) 329(16) 7(12) -65(12) 5(11) C(18) 215(14) 129(13) 264(14) 3(11) -22(11) -38(11) C(19) 216(13) 199(12) 146(11) 44(10) -28(10) -40(10) C(20) 297(17) 272(15) 199(13) 74(12) -32(12) -122(13) C(21) 214(15) 394(17) 194(13) 80(12) 3(11) -141(13) C(22) 181(14) 404(17) 172(13) 48(12) -9(11) 10(13) C(23) 178(13) 276(14) 133(11) 30(11) -6(10) -30(11) C(24) 169(12) 194(12) 123(11) 32(10) -11(9) -46(10) Cl(1) 219(3) 371(4) 261(3) -11(3) -21(3) 63(3) Cl(2) 350(5) 605(5) 360(4) -126(4) 68(4) 131(4) C(25) 205(14) 276(15) 265(14) -15(12) 8(12) 51(12) ______________________________________________________________________________ 3 2 3 Table A2.1.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 24 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 219   H(3A) 344(4) 192(1) 435(3) 17 H(3B) 266(3) 225(1) 552(3) 17 H(4A) 131(4) 277(1) 399(3) 19 H(4B) 315(3) 282(1) 380(3) 19 H(6) 291(3) 308(1) 120(3) 20 H(7A) 249(4) 305(1) -114(4) 43 H(7B) 133(5) 262(1) -168(3) 43 H(7C) 309(5) 246(1) -155(3) 43 H(9) 86(4) 169(1) -136(3) 20 H(10) -5(3) 93(1) -50(3) 21 H(11) -4(3) 77(1) 188(3) 19 H(14) 197(3) 114(1) 388(3) 15 H(15) -145(3) 114(1) 377(3) 15 H(17A) 204(4) 38(1) 500(3) 34 H(17B) 159(4) 23(1) 350(3) 34 H(17C) 121(4) -15(1) 474(3) 34 H(18A) -185(4) -19(1) 428(3) 30 H(18B) -138(4) 11(1) 302(3) 30 H(18C) -280(4) 30(1) 389(3) 30 H(20) -387(4) 0(1) 662(3) 31 H(21) -620(4) 50(1) 691(3) 32 H(22) -632(4) 136(1) 671(3) 30 H(23) -402(4) 183(1) 605(3) 23 H(25A) 349(4) 112(1) 83(3) 30 H(25B) 486(4) 158(1) 87(3) 30 ________________________________________________________________________________ Table A2.1.6. Hydrogen bonds for 24 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ C(7)-H(7B)...O(1)#1 0.90(4) 2.52(4) 3.338(4) 151(3) C(7)-H(7C)...O(1)#2 1.02(4) 2.76(4) 3.325(4) 115(2) C(9)-H(9)...O(1)#1 0.95(3) 2.55(3) 3.436(3) 156(2) ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 x,y,z-1 #2 x+1/2,-y+1/2,z-1     Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.2. X-Ray Crystal Structure Analysis of 37 Ts N CN O N O2N H 37 Figure A2.2.1. X-ray Crystal Structure of 37 Table A2.2.1. Crystal data and structure refinement for 37 Empirical formula C26 H22 N4 O5 S Formula weight 502.54 Crystal Habit Needle Crystal size 0.30 x 0.07 x 0.07 mm3 Crystal color Colorless Data Collection Preliminary Photos Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoK〈 Data Collection Temperature 100(2) K ⎝ range for 1342 reflections used 220   221   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 in lattice determination 2.17 to 18.91° Unit cell dimensions a = 13.243(2) Å b = 14.115(2) Å c = 25.059(4) Å Volume 4684.2(13) Å3 Z 8 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Density (calculated) 1.425 Mg/m3 F(000) 2096 Data collection program Bruker SMART v5.630 ⎝ range for data collection 1.63 to 22.98° Completeness to ⎝ = 22.98° 83.9 % Index ranges -12<=h<=13, -14<=k<=10, -27<=l<=21 Data collection scan type scans at 2 settings   Data  reduction  program     Bruker  SAINT  v6.45A   Reflections  collected   10767   Independent  reflections   5122  [Rint=  0.1652]   Absorption  coefficient   0.185  mm-­‐1   Absorption  correction   None   Max.  and  min.  transmission   0.9871  and  0.9465   Number  of  standards     Variation  of  standards     ?  reflections  measured  every  ?min.     ?%.     Structure solution and Refinement Structure solution program SHELXS-97 (Sheldrick, 1990) Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program SHELXL-97 (Sheldrick, 1997) Refinement method Full matrix least-squares on F2 Data / restraints / parameters 5122 / 0 / 291 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.294 Final R indices [I>2⌠(I), 2377 reflections] R1 = 0.1085, wR2 = 0.1814 R indices (all data) R1 = 0.2168, wR2 = 0.2078 Type of weighting scheme used Sigma Weighting scheme used w=1/s^2^(Fo^2^) Max shift/error 0.015 Average shift/error 0.000 〈= 90° ®= 90° © = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Absolute structure determination ? Absolute structure parameter 0.5(3) Largest diff. peak and hole 0.868 and -1.060 e.Å-3 222   Special Refinement Details Table A2.2.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 37. U(eq) is defined asthe trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ S(1A) 2444(3) 6752(3) 3762(2) 24(1) O(1A) 1847(8) 6830(7) 4221(4) 35(3) O(2A) 2120(8) 7120(7) 3248(4) 25(3) O(3A) 3062(8) 2592(7) 2393(4) 22(3) O(4A) 4152(8) 3228(8) 4567(4) 26(3) O(5A) 2979(9) 2243(8) 4804(4) 34(3) N(1A) 2662(8) 5605(8) 3672(5) 10(3) N(2A) 2007(9) 2282(9) 3084(5) 19(4) N(3A) 3661(10) 2523(10) 4514(5) 27(4) N(4A) 5462(11) 3745(9) 2693(6) 31(4) C(1A) 3644(12) 7259(11) 3917(6) 19(4) C(2A) 3980(11) 7265(11) 4429(6) 20(5) C(3A) 4958(12) 7621(11) 4550(7) 31(5) C(4A) 5605(14) 8037(13) 4166(7) 40(6) C(5A) 5147(11) 8041(10) 3649(7) 21(5) C(6A) 4202(11) 7655(10) 3519(6) 12(4) C(7A) 6579(12) 8456(12) 4253(7) 36(5) C(8A) 2748(12) 5013(10) 4169(6) 21(4) C(9A) 2094(14) 4095(11) 4086(7) 36(5) C(10A) 1349(11) 3803(11) 4439(6) 13(4) C(11A) 810(12) 3025(11) 4359(6) 24(5) C(12A) 966(12) 2434(12) 3927(6) 26(5) C(13A) 1776(11) 2644(10) 3576(6) 19(4) C(14A) 2313(11) 3475(10) 3645(6) 13(4) C(15A) 3070(11) 3547(10) 3202(6) 17(4) C(16A) 3010(11) 4510(10) 2925(6) 14(4) C(17A) 3383(11) 5395(10) 3235(6) 15(4) C(18A) 2703(12) 2749(11) 2827(6) 21(5) C(19A) 4146(10) 3299(9) 3415(5) 3(4) C(20A) 4911(12) 3517(11) 2992(6) 16(4) C(21A) 4200(12) 2245(11) 3559(6) 23(5) C(22A) 4506(10) 1615(10) 3185(6) 10(4) C(23A) 4374(13) 614(12) 3276(7) 38(5) C(24A) 4002(12) 326(12) 3754(7) 33(5) C(25A) 3778(12) 949(11) 4169(7) 26(5) C(26A) 3877(10) 1874(10) 4071(6) 8(4) S(1B) 7184(3) 1177(3) 3593(2) 24(1) O(1B) 6473(8) 1114(7) 4015(4) 28(3) O(2B) 6953(8) 839(7) 3074(4) 24(3) O(3B) 8347(8) 5377(7) 2346(4) 23(3) O(4B) 9055(8) 4456(8) 4514(4) 28(3) O(5B) 8036(9) 5576(8) 4787(5) 39(3) N(1B) 7443(10) 2316(9) 3495(5) 28(4) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 223   N(2B) 7154(9) 5718(9) 3014(5) 18(3) N(3B) 8648(10) 5277(10) 4471(6) 28(4) N(4B) 10569(10) 4005(9) 2678(5) 20(4) C(1B) 8339(12) 633(11) 3783(7) 21(4) C(2B) 8674(11) 682(11) 4310(6) 17(4) C(3B) 9535(12) 304(11) 4441(7) 28(5) C(4B) 10165(13) -92(12) 4072(7) 26(5) C(5B) 9804(12) -94(11) 3538(7) 29(5) C(6B) 8964(11) 227(10) 3393(7) 19(5) C(7B) 11271(11) -495(12) 4220(7) 34(5) C(8B) 7549(12) 2872(9) 4003(6) 15(4) C(9B) 7020(12) 3849(11) 3944(6) 20(4) C(10B) 6276(11) 4107(10) 4280(6) 19(5) C(11B) 5776(12) 4987(11) 4225(7) 25(5) C(12B) 6092(12) 5574(12) 3800(6) 27(5) C(13B) 6847(10) 5316(10) 3459(6) 7(4) C(14B) 7352(12) 4461(11) 3542(7) 25(5) C(15B) 8118(12) 4327(11) 3101(7) 26(5) C(16B) 7989(12) 3429(10) 2779(6) 20(5) C(17B) 8247(12) 2492(10) 3090(6) 22(5) C(18B) 7896(12) 5207(11) 2769(6) 18(4) C(19B) 9211(10) 4501(10) 3372(6) 7(4) C(20B) 9978(12) 4216(11) 2978(7) 24(5) C(21B) 9361(11) 5538(10) 3556(6) 11(4) C(22B) 9696(13) 6156(11) 3175(7) 34(5) C(23B) 9622(12) 7178(12) 3311(7) 28(5) C(24B) 9228(12) 7468(12) 3774(7) 31(5) C(25B) 8888(12) 6840(11) 4145(7) 26(5) C(26B) 9000(11) 5871(10) 4031(6) 9(4) ________________________________________________________________________________ Table A2.2.3. Bond lengths [Å] and angles [°] for 37 _____________________________________________________ S(1A)-O(1A) 1.399(11) S(1A)-O(2A) 1.455(11) S(1A)-N(1A) 1.659(12) S(1A)-C(1A) 1.786(16) O(3A)-C(18A) 1.206(16) O(4A)-N(3A) 1.196(14) O(5A)-N(3A) 1.225(16) N(1A)-C(17A) 1.484(17) N(1A)-C(8A) 1.504(17) N(2A)-C(18A) 1.305(17) N(2A)-C(13A) 1.369(18) N(3A)-C(26A) 1.469(18) N(4A)-C(20A) 1.094(17) C(1A)-C(2A) 1.357(19) C(1A)-C(6A) 1.361(19) C(2A)-C(3A) 1.42(2) C(3A)-C(4A) 1.42(2) C(4A)-C(5A) 1.43(2) C(4A)-C(7A) 1.44(2) C(5A)-C(6A) 1.403(19) C(8A)-C(9A) 1.57(2) C(9A)-C(10A) 1.39(2) C(9A)-C(14A) 1.44(2) C(10A)-C(11A) 1.32(2) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(11A)-C(12A) C(12A)-C(13A) C(13A)-C(14A) C(14A)-C(15A) C(15A)-C(16A) C(15A)-C(18A) C(15A)-C(19A) C(16A)-C(17A) C(19A)-C(20A) C(19A)-C(21A) C(21A)-C(22A) C(21A)-C(26A) C(22A)-C(23A) C(23A)-C(24A) C(24A)-C(25A) C(25A)-C(26A) S(1B)-O(2B) S(1B)-O(1B) S(1B)-N(1B) S(1B)-C(1B) O(3B)-C(18B) O(4B)-N(3B) O(5B)-N(3B) N(1B)-C(17B) N(1B)-C(8B) N(2B)-C(13B) N(2B)-C(18B) N(3B)-C(26B) N(4B)-C(20B) C(1B)-C(2B) C(1B)-C(6B) C(2B)-C(3B) C(3B)-C(4B) C(4B)-C(5B) C(4B)-C(7B) C(5B)-C(6B) C(8B)-C(9B) C(9B)-C(10B) C(9B)-C(14B) C(10B)-C(11B) C(11B)-C(12B) C(12B)-C(13B) C(13B)-C(14B) C(14B)-C(15B) C(15B)-C(16B) C(15B)-C(18B) C(15B)-C(19B) C(16B)-C(17B) C(19B)-C(20B) C(19B)-C(21B) C(21B)-C(26B) C(21B)-C(22B) C(22B)-C(23B) C(23B)-C(24B) C(24B)-C(25B) C(25B)-C(26B) O(1A)-S(1A)-O(2A) 1.38(2) 1.42(2) 1.382(18) 1.50(2) 1.528(18) 1.55(2) 1.562(19) 1.552(18) 1.50(2) 1.532(19) 1.354(19) 1.45(2) 1.44(2) 1.36(2) 1.39(2) 1.336(19) 1.418(11) 1.418(11) 1.662(13) 1.776(16) 1.241(17) 1.282(14) 1.209(16) 1.493(18) 1.501(17) 1.316(17) 1.365(18) 1.463(18) 1.126(18) 1.40(2) 1.40(2) 1.301(19) 1.36(2) 1.42(2) 1.61(2) 1.254(19) 1.55(2) 1.35(2) 1.40(2) 1.41(2) 1.41(2) 1.36(2) 1.396(19) 1.51(2) 1.51(2) 1.52(2) 1.62(2) 1.572(19) 1.47(2) 1.547(19) 1.365(19) 1.37(2) 1.49(2) 1.34(2) 1.36(2) 1.41(2) 122.2(7) 224   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(1A)-S(1A)-N(1A) O(2A)-S(1A)-N(1A) O(1A)-S(1A)-C(1A) O(2A)-S(1A)-C(1A) N(1A)-S(1A)-C(1A) C(17A)-N(1A)-C(8A) C(17A)-N(1A)-S(1A) C(8A)-N(1A)-S(1A) C(18A)-N(2A)-C(13A) O(4A)-N(3A)-O(5A) O(4A)-N(3A)-C(26A) O(5A)-N(3A)-C(26A) C(2A)-C(1A)-C(6A) C(2A)-C(1A)-S(1A) C(6A)-C(1A)-S(1A) C(1A)-C(2A)-C(3A) C(4A)-C(3A)-C(2A) C(3A)-C(4A)-C(5A) C(3A)-C(4A)-C(7A) C(5A)-C(4A)-C(7A) C(6A)-C(5A)-C(4A) C(1A)-C(6A)-C(5A) N(1A)-C(8A)-C(9A) C(10A)-C(9A)-C(14A) C(10A)-C(9A)-C(8A) C(14A)-C(9A)-C(8A) C(11A)-C(10A)-C(9A) C(10A)-C(11A)-C(12A) C(11A)-C(12A)-C(13A) N(2A)-C(13A)-C(14A) N(2A)-C(13A)-C(12A) C(14A)-C(13A)-C(12A) C(13A)-C(14A)-C(9A) C(13A)-C(14A)-C(15A) C(9A)-C(14A)-C(15A) C(14A)-C(15A)-C(16A) C(14A)-C(15A)-C(18A) C(16A)-C(15A)-C(18A) C(14A)-C(15A)-C(19A) C(16A)-C(15A)-C(19A) C(18A)-C(15A)-C(19A) C(15A)-C(16A)-C(17A) N(1A)-C(17A)-C(16A) O(3A)-C(18A)-N(2A) O(3A)-C(18A)-C(15A) N(2A)-C(18A)-C(15A) C(20A)-C(19A)-C(21A) C(20A)-C(19A)-C(15A) C(21A)-C(19A)-C(15A) N(4A)-C(20A)-C(19A) C(22A)-C(21A)-C(26A) C(22A)-C(21A)-C(19A) C(26A)-C(21A)-C(19A) C(21A)-C(22A)-C(23A) C(24A)-C(23A)-C(22A) C(23A)-C(24A)-C(25A) C(26A)-C(25A)-C(24A) C(25A)-C(26A)-C(21A) 106.7(7) 106.2(6) 107.0(7) 108.2(7) 105.4(7) 116.8(11) 114.1(9) 116.3(9) 114.5(13) 127.2(15) 119.8(14) 113.0(13) 120.8(16) 120.0(12) 119.2(12) 120.1(16) 123.5(17) 111.2(16) 127.6(17) 121.2(17) 125.9(16) 118.3(15) 107.8(12) 116.9(15) 123.5(16) 119.5(15) 122.1(16) 122.6(17) 118.2(16) 108.4(14) 130.5(15) 119.2(15) 120.6(14) 108.0(13) 131.4(13) 111.2(12) 101.0(12) 110.8(12) 110.0(12) 113.8(12) 109.4(11) 118.1(12) 109.0(12) 129.1(15) 123.9(15) 106.8(14) 109.5(13) 109.2(12) 109.9(12) 174.7(18) 117.6(14) 119.3(14) 123.0(14) 119.9(15) 118.5(17) 123.1(17) 117.4(17) 123.0(16) 225   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(25A)-C(26A)-N(3A) C(21A)-C(26A)-N(3A) O(2B)-S(1B)-O(1B) O(2B)-S(1B)-N(1B) O(1B)-S(1B)-N(1B) O(2B)-S(1B)-C(1B) O(1B)-S(1B)-C(1B) N(1B)-S(1B)-C(1B) C(17B)-N(1B)-C(8B) C(17B)-N(1B)-S(1B) C(8B)-N(1B)-S(1B) C(13B)-N(2B)-C(18B) O(5B)-N(3B)-O(4B) O(5B)-N(3B)-C(26B) O(4B)-N(3B)-C(26B) C(2B)-C(1B)-C(6B) C(2B)-C(1B)-S(1B) C(6B)-C(1B)-S(1B) C(3B)-C(2B)-C(1B) C(2B)-C(3B)-C(4B) C(3B)-C(4B)-C(5B) C(3B)-C(4B)-C(7B) C(5B)-C(4B)-C(7B) C(6B)-C(5B)-C(4B) C(5B)-C(6B)-C(1B) N(1B)-C(8B)-C(9B) C(10B)-C(9B)-C(14B) C(10B)-C(9B)-C(8B) C(14B)-C(9B)-C(8B) C(9B)-C(10B)-C(11B) C(12B)-C(11B)-C(10B) C(13B)-C(12B)-C(11B) N(2B)-C(13B)-C(12B) N(2B)-C(13B)-C(14B) C(12B)-C(13B)-C(14B) C(13B)-C(14B)-C(9B) C(13B)-C(14B)-C(15B) C(9B)-C(14B)-C(15B) C(16B)-C(15B)-C(14B) C(16B)-C(15B)-C(18B) C(14B)-C(15B)-C(18B) C(16B)-C(15B)-C(19B) C(14B)-C(15B)-C(19B) C(18B)-C(15B)-C(19B) C(15B)-C(16B)-C(17B) N(1B)-C(17B)-C(16B) O(3B)-C(18B)-N(2B) O(3B)-C(18B)-C(15B) N(2B)-C(18B)-C(15B) C(20B)-C(19B)-C(21B) C(20B)-C(19B)-C(15B) C(21B)-C(19B)-C(15B) N(4B)-C(20B)-C(19B) C(26B)-C(21B)-C(22B) C(26B)-C(21B)-C(19B) C(22B)-C(21B)-C(19B) C(21B)-C(22B)-C(23B) C(24B)-C(23B)-C(22B) 116.9(14) 120.1(13) 121.3(7) 103.6(7) 107.9(7) 106.6(7) 110.2(7) 106.2(7) 115.0(12) 114.1(11) 113.6(10) 112.1(13) 122.8(14) 120.5(13) 116.6(13) 119.5(15) 120.4(13) 119.9(13) 119.8(16) 122.2(17) 115.7(16) 122.9(15) 121.4(15) 124.7(17) 118.0(17) 110.0(12) 120.9(15) 120.8(15) 118.3(14) 121.3(17) 116.8(16) 122.1(15) 130.0(15) 110.6(14) 119.2(15) 119.4(15) 108.7(15) 131.3(15) 114.8(14) 111.7(13) 99.6(13) 116.9(13) 105.9(13) 106.2(12) 114.6(12) 108.8(12) 128.9(14) 122.1(15) 108.9(13) 111.7(13) 107.0(13) 112.6(12) 179(2) 120.2(14) 122.6(14) 116.0(14) 115.9(16) 121.5(18) 226   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(23B)-C(24B)-C(25B) 121.5(17) C(24B)-C(25B)-C(26B) 117.3(16) C(21B)-C(26B)-C(25B) 123.3(15) C(21B)-C(26B)-N(3B) 124.9(13) C(25B)-C(26B)-N(3B) 111.7(13) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.2.4. Hydrogen bonds for 37 [Å and °] ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ N(2A)-H(2A)...O(3B)#1 0.88 2.11 2.933(16) 155.2 N(2B)-H(2B)...O(3A)#2 0.88 2.02 2.849(16) 157.3 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,y-1/2,-z+1/2 #2 -x+1,y+1/2,-z+1/2                                 227   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.3. 228   X-Ray Crystal Structure Analysis of 42 Ts H N CO2Me CO2Me O N H   42 Figure A2.3.1. X-ray Crystal Structure of 42 Table A2.3.1. Crystal data and structure refinement for 42 Empirical formula C27 H30 N2 O7 S Formula weight 526.59 Crystal Habit Blade Crystal size 0.33 x 0.26 x 0.07 mm3 Crystal color Colorless Data Collection Preliminary Photos Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoKa Data Collection Temperature 100(2) K q range for 9727 reflections used in lattice determination 2.40 to 33.11° Unit cell dimensions a = 9.5308(8) Å b = 9.7901(9) Å c = 13.8253(12) Å Volume 1266.67(19) Å3 Z 2 Crystal system Monoclinic a= 90° b= 100.914(2)° g = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Space group Pn Density (calculated) 1.381 Mg/m3 F(000) 556 Data collection program Bruker SMART v5.630 q range for data collection 2.08 to 33.37° Completeness to q = 33.37° 79.2 % Index ranges -12<=h<=12, -12<=k<=14, -20<=l<=18 Data collection scan type scans at 5 settings Data reduction program Bruker SAINT v6.45A Reflections collected 17354 Independent reflections 6630 [Rint= 0.0627] Absorption coefficient 0.178 mm-1 Absorption correction None Max. and min. transmission 0.9876 and 0.9436 Number of standards ? reflections measured every ?min. Variation of standards ?%. Structure solution and Refinement Structure solution program SHELXS-97 (Sheldrick, 1990) Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program SHELXL-97 (Sheldrick, 1997) Refinement method Full matrix least-squares on F2 Data / restraints / parameters 6630 / 2 / 339 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.413 Final R indices [I>2s(I), 5764 reflections] R1 = 0.0412, wR2 = 0.0772 R indices (all data) R1 = 0.0487, wR2 = 0.0785 Type of weighting scheme used Sigma Weighting scheme used w=1/s^2^(Fo^2^) Max shift/error 0.003 Average shift/error 0.000 Absolute structure determination ? Absolute structure parameter -0.06(5) Largest diff. peak and hole 0.698 and -0.437 e.Å-3 Special Refinement Details 229   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 230   Table A2.3.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 42. U(eq) is defined as the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ S(1) 2561(1) 4166(1) 5901(1) 20(1) O(1) 1091(2) 3868(1) 5901(1) 28(1) O(2) 3543(2) 3041(1) 5888(1) 26(1) O(3) 5953(1) 9815(1) 6612(1) 23(1) O(4) 7590(1) 7652(1) 8168(1) 25(1) O(5) 7214(1) 9500(1) 9044(1) 22(1) O(6) 4387(1) 10398(1) 8732(1) 21(1) O(7) 3629(1) 8558(1) 9457(1) 19(1) N(1) 3154(2) 5091(2) 6868(1) 18(1) N(2) 3555(2) 10204(2) 6558(1) 18(1) C(1) 2669(2) 5158(2) 4849(2) 17(1) C(2) 3664(2) 4837(2) 4284(2) 21(1) C(3) 3700(2) 5589(2) 3436(2) 23(1) C(4) 2753(2) 6670(2) 3153(2) 21(1) C(5) 1775(2) 6993(2) 3757(2) 24(1) C(6) 1722(2) 6249(2) 4595(2) 22(1) C(7) 2775(3) 7430(2) 2213(2) 33(1) C(8) 4669(2) 5481(2) 7050(2) 19(1) C(9) 4988(2) 6898(2) 6675(2) 17(1) C(10) 4451(2) 8092(2) 7224(1) 15(1) C(11) 2834(2) 8156(2) 7105(1) 15(1) C(12) 1822(2) 7184(2) 7242(1) 15(1) C(13) 2158(2) 5683(2) 7468(1) 16(1) C(14) 2653(2) 5409(2) 8558(2) 18(1) C(15) 2510(2) 4205(2) 8993(2) 23(1) C(16) 1948(2) 2934(2) 8454(2) 32(1) C(17) 2943(2) 4057(3) 10088(2) 37(1) C(18) 404(2) 7610(2) 7130(1) 17(1) C(19) -10(2) 8938(2) 6853(1) 19(1) C(20) 980(2) 9888(2) 6632(1) 18(1) C(21) 2385(2) 9461(2) 6761(1) 15(1) C(22) 4787(2) 9468(2) 6759(1) 18(1) C(23) 5191(2) 8149(2) 8355(1) 16(1) C(24) 6788(2) 8399(2) 8493(1) 18(1) C(25) 8742(2) 9752(2) 9212(2) 27(1) C(26) 4392(2) 9188(2) 8867(1) 15(1) C(27) 2603(2) 9418(2) 9817(2) 25(1) ________________________________________________________________________________ Table A2.3.3. Bond lengths [Å] and angles [°] for 42 _____________________________________________________ S(1)-O(1) 1.4313(14) S(1)-O(2) 1.4482(14) S(1)-N(1) 1.6255(17) S(1)-C(1) 1.767(2) O(3)-C(22) 1.215(2) O(4)-C(24) 1.204(2) O(5)-C(24) 1.338(2) O(5)-C(25) 1.451(2) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(6)-C(26) O(7)-C(26) O(7)-C(27) N(1)-C(8) N(1)-C(13) N(2)-C(22) N(2)-C(21) C(1)-C(2) C(1)-C(6) C(2)-C(3) C(3)-C(4) C(4)-C(5) C(4)-C(7) C(5)-C(6) C(8)-C(9) C(9)-C(10) C(10)-C(11) C(10)-C(22) C(10)-C(23) C(11)-C(12) C(11)-C(21) C(12)-C(18) C(12)-C(13) C(13)-C(14) C(14)-C(15) C(15)-C(16) C(15)-C(17) C(18)-C(19) C(19)-C(20) C(20)-C(21) C(23)-C(24) C(23)-C(26) O(1)-S(1)-O(2) O(1)-S(1)-N(1) O(2)-S(1)-N(1) O(1)-S(1)-C(1) O(2)-S(1)-C(1) N(1)-S(1)-C(1) C(24)-O(5)-C(25) C(26)-O(7)-C(27) C(8)-N(1)-C(13) C(8)-N(1)-S(1) C(13)-N(1)-S(1) C(22)-N(2)-C(21) C(2)-C(1)-C(6) C(2)-C(1)-S(1) C(6)-C(1)-S(1) C(1)-C(2)-C(3) C(2)-C(3)-C(4) C(3)-C(4)-C(5) C(3)-C(4)-C(7) C(5)-C(4)-C(7) C(6)-C(5)-C(4) C(5)-C(6)-C(1) N(1)-C(8)-C(9) C(8)-C(9)-C(10) C(11)-C(10)-C(9) 1.199(2) 1.341(2) 1.449(2) 1.469(2) 1.491(2) 1.361(2) 1.403(2) 1.374(3) 1.400(3) 1.390(3) 1.398(3) 1.401(3) 1.501(3) 1.377(3) 1.531(2) 1.532(2) 1.519(3) 1.551(2) 1.590(2) 1.393(2) 1.402(2) 1.395(2) 1.524(2) 1.515(3) 1.341(3) 1.496(3) 1.499(3) 1.392(3) 1.398(3) 1.382(3) 1.517(2) 1.524(3) 118.70(9) 107.55(8) 107.99(8) 108.78(9) 105.60(9) 107.79(8) 114.58(15) 114.87(15) 120.84(15) 117.58(12) 121.04(13) 111.90(15) 120.90(18) 119.74(14) 119.35(16) 119.21(17) 121.30(19) 118.11(18) 120.25(18) 121.62(17) 121.13(18) 119.32(19) 115.42(15) 114.69(15) 113.86(15) 231   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(11)-C(10)-C(22) 101.80(14) C(9)-C(10)-C(22) 110.06(14) C(11)-C(10)-C(23) 110.93(14) C(9)-C(10)-C(23) 112.65(14) C(22)-C(10)-C(23) 106.77(14) C(12)-C(11)-C(21) 119.60(16) C(12)-C(11)-C(10) 132.16(16) C(21)-C(11)-C(10) 108.20(15) C(11)-C(12)-C(18) 117.54(16) C(11)-C(12)-C(13) 124.25(16) C(18)-C(12)-C(13) 118.17(15) N(1)-C(13)-C(14) 111.94(14) N(1)-C(13)-C(12) 113.07(14) C(14)-C(13)-C(12) 112.87(15) C(15)-C(14)-C(13) 124.25(18) C(14)-C(15)-C(16) 124.3(2) C(14)-C(15)-C(17) 120.4(2) C(16)-C(15)-C(17) 115.24(18) C(19)-C(18)-C(12) 121.84(17) C(18)-C(19)-C(20) 120.92(17) C(21)-C(20)-C(19) 116.63(16) C(20)-C(21)-C(11) 123.04(17) C(20)-C(21)-N(2) 127.26(16) C(11)-C(21)-N(2) 109.68(16) O(3)-C(22)-N(2) 126.81(16) O(3)-C(22)-C(10) 125.37(16) N(2)-C(22)-C(10) 107.82(15) C(24)-C(23)-C(26) 114.28(15) C(24)-C(23)-C(10) 112.17(14) C(26)-C(23)-C(10) 108.22(14) O(4)-C(24)-O(5) 123.72(18) O(4)-C(24)-C(23) 123.19(17) O(5)-C(24)-C(23) 113.04(15) O(6)-C(26)-O(7) 124.28(17) O(6)-C(26)-C(23) 125.06(17) O(7)-C(26)-C(23) 110.58(15) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.3.4. Anisotropic displacement parameters (Å2x 104 ) for 42. The anisotropic displacement factor exponent takes the form: -2p2 [ h2 a*2U 11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ S(1) 284(3) 91(2) 237(3) -5(2) 94(2) -26(2) O(1) 333(8) 219(7) 297(9) -67(6) 115(7) -105(6) O(2) 421(9) 99(6) 292(8) 25(6) 140(7) 25(6) O(3) 230(7) 208(7) 267(8) 36(6) 97(6) -55(6) O(4) 187(7) 262(7) 301(9) 1(6) 61(6) 54(6) O(5) 167(7) 267(7) 229(8) -24(6) 36(6) -9(5) O(6) 212(7) 155(7) 276(8) -7(6) 63(6) 11(5) O(7) 199(7) 208(7) 180(7) 20(5) 78(5) 10(5) N(1) 208(8) 126(8) 211(9) -7(6) 88(6) 4(6) N(2) 222(9) 96(7) 224(9) 48(6) 46(7) -3(6) C(1) 230(10) 101(8) 185(10) -8(7) 38(8) -49(7) C(2) 201(10) 138(9) 284(12) -18(8) 41(8) 15(7) C(3) 239(11) 185(10) 280(12) -13(8) 109(9) 0(7) 232   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(4) 235(10) 133(9) 252(11) 12(8) 34(8) -12(7) C(5) 241(10) 157(9) 309(12) 12(8) 25(8) 47(8) C(6) 230(11) 164(10) 292(12) -33(8) 84(9) 10(8) C(7) 399(13) 255(11) 324(13) 85(10) 58(10) 33(10) C(8) 196(10) 139(9) 246(11) -4(7) 82(8) 25(7) C(9) 172(10) 165(9) 189(10) 3(7) 60(7) 4(7) C(10) 164(9) 124(8) 167(10) 21(7) 54(7) -9(6) C(11) 192(9) 133(9) 127(9) -19(7) 52(7) 9(7) C(12) 194(9) 132(9) 117(9) 9(7) 42(7) 9(7) C(13) 139(9) 134(9) 213(10) -13(7) 89(8) -22(7) C(14) 151(9) 169(9) 240(11) 33(8) 59(8) 1(7) C(15) 146(9) 252(10) 302(12) 115(9) 93(8) 48(8) C(16) 328(12) 154(10) 524(16) 127(10) 173(11) 49(8) C(17) 283(12) 474(14) 361(14) 223(11) 103(10) -17(10) C(18) 185(10) 177(9) 151(10) -8(7) 42(8) -33(7) C(19) 167(9) 221(10) 172(10) -8(8) 10(8) 59(7) C(20) 229(10) 141(9) 167(10) 25(7) 20(8) 50(7) C(21) 225(10) 128(9) 107(9) -1(7) 38(8) -1(7) C(22) 251(10) 130(9) 152(10) 1(7) 42(8) -25(7) C(23) 177(9) 105(8) 192(10) 30(7) 50(8) 12(7) C(24) 186(10) 179(9) 179(10) 64(8) 37(8) 10(7) C(25) 173(10) 374(12) 244(12) -17(9) 12(8) -73(8) C(26) 97(8) 196(9) 151(10) -6(7) -8(7) -9(7) C(27) 231(10) 306(11) 241(11) -9(9) 104(9) 37(8) ______________________________________________________________________________ Table A2.3.5. Hydrogen bonds for 42 [Å and °] ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ N(2)-H(2)...O(2)#1 0.88 2.05 2.928(2) 174.5 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x,y+1,z 233   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.4. X-Ray Crystal Structure Analysis of 51 O O O NO N 2 51 Figure A2.4.1. X-ray Crystal Structure of 51 Table A2.4.1. Crystal Data and Structure Analysis Details for 51 Empirical formula C22 H20 N2 O5 Formula weight 392.40 Crystal shape plate Crystal color colourless Crystal size 0.08 x 0.39 x 0.40 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK 234   235   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Data collection temperature 100 K Theta range for 9925 reflections used in lattice determination 2.59 to 33.53° Unit cell dimensions a = 7.5798(3) Å b = 30.0522(12) Å c = 8.3663(3) Å 〈= 90° ®= 103.6098(19)° © = 90° Volume 1852.24(12) Å3 Z 4 Crystal system monoclinic Space group P 1 21/c 1 (# 14) Density (calculated) 1.407 g/cm3 F(000) 824 Theta range for data collection 2.6 to 36.7° Completeness to theta = 25.000° 99.9% Index ranges -12 ʺ″ h ʺ″ 12, -48 ʺ″ k ʺ″ 48, -13 ʺ″ l ʺ″ 13 Data collection scan type and  scans   Reflections  collected   90271   Independent  reflections   8678  [Rint=  0.0550]   Reflections  >  2⌠(I)   6686     Average  ⌠(I)/(net  I)   0.0317   Absorption  coefficient   0.10  mm-­‐1   Absorption  correction   Semi-­‐empirical  from  equivalents   Max.  and  min.  transmission   1.0000  and  0.9172     Structure Solution and Refinement Primary solution method ? Secondary solution method ? Hydrogen placement difmap Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 8678 / 0 / 322 Treatment of hydrogen atoms refxyz Goodness-of-fit on F2 1.63 Final R indices [I>2⌠(I), 6686 reflections] R1 = 0.0491, wR2 = 0.1139 R indices (all data) R1 = 0.0700, wR2 = 0.1189 Type of weighting scheme used calc Weighting scheme used w=1/[^2^(Fo^2^)+(0.0400P)^2^] where P=(Fo^2^+2Fc^2^)/3 Max shift/error 0.001 Average shift/error 0.000 Extinction coefficient n/a Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Largest diff. peak and hole 236   0.63 and -0.32 e·Å-3 Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.32B (Bruker-AXS, 2007) APEX2 2013.6-2 (Bruker-AXS, 2007) SAINT V8.32B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.4.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 51. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ O(1) 12316(1) 2035(1) 9127(1) 32(1) O(2) 9477(1) 1887(1) 8963(1) 25(1) O(3) 8678(1) 936(1) 10051(1) 25(1) O(4) 11278(1) 1051(1) 9408(1) 24(1) O(5) 5030(1) 428(1) 6376(1) 19(1) N(1) 10836(1) 1886(1) 8401(1) 21(1) N(2) 4779(1) 893(1) 4161(1) 15(1) C(1) 8719(1) 1022(1) 7103(1) 12(1) C(2) 9732(1) 1325(1) 6146(1) 12(1) C(3) 9631(1) 1230(1) 4488(1) 14(1) C(4) 10336(1) 1512(1) 3480(1) 19(1) C(5) 11238(1) 1898(1) 4107(1) 22(1) C(6) 11443(1) 1996(1) 5750(1) 20(1) C(7) 10675(1) 1717(1) 6726(1) 15(1) C(8) 8953(1) 519(1) 6658(1) 12(1) C(9) 10876(1) 364(1) 6877(1) 17(1) C(10) 11560(1) 15(1) 7771(2) 26(1) C(11) 9646(1) 1021(1) 8938(1) 17(1) C(12) 6715(2) 923(1) 9579(1) 25(1) C(13) 5976(2) 1265(1) 8268(1) 21(1) C(14) 6589(1) 1160(1) 6682(1) 13(1) C(15) 6136(1) 1526(1) 5402(1) 12(1) C(16) 6548(1) 1975(1) 5472(1) 14(1) C(17) 6062(1) 2230(1) 4037(1) 15(1) C(18) 5154(1) 2036(1) 2563(1) 15(1) C(19) 4645(1) 1588(1) 2488(1) 14(1) C(20) 5154(1) 1343(1) 3922(1) 13(1) C(21) 5401(1) 776(1) 5771(1) 14(1) C(22) 3576(1) 613(1) 2963(1) 21(1) ________________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 237   Table A2.4.3. Bond lengths [Å] and angles [°] for 51 __________________________________________________________________________________ _ O(1)-N(1) 1.2271(10) O(2)-N(1) 1.2294(12) O(3)-C(11) 1.3390(12) O(3)-C(12) 1.4477(14) O(4)-C(11) 1.2094(12) O(5)-C(21) 1.2218(10) N(1)-C(7) 1.4689(12) N(2)-C(20) 1.4069(10) N(2)-C(21) 1.3641(11) N(2)-C(22) 1.4538(11) C(1)-C(2) 1.5329(12) C(1)-C(8) 1.5766(11) C(1)-C(11) 1.5307(11) C(1)-C(14) 1.6236(11) C(2)-C(3) 1.4007(12) C(2)-C(7) 1.4025(11) C(3)-H(3) 0.978(12) C(3)-C(4) 1.3876(13) C(4)-H(4) 0.997(12) C(4)-C(5) 1.3847(14) C(5)-H(5) 0.971(13) C(5)-C(6) 1.3777(15) C(6)-H(6) 0.998(13) C(6)-C(7) 1.3900(13) C(8)-H(8A) 0.987(11) C(8)-H(8B) 0.950(11) C(8)-C(9) 1.4994(12) C(9)-H(9) 0.991(12) C(9)-C(10) 1.3224(13) C(10)-H(10A) 0.966(14) C(10)-H(10B) 0.964(14) C(12)-H(12A) 0.995(13) C(12)-H(12B) 0.963(14) C(12)-C(13) 1.5109(14) C(13)-H(13A) 1.014(13) C(13)-H(13B) 1.006(13) C(13)-C(14) 1.5372(12) C(14)-C(15) 1.5167(11) C(14)-C(21) 1.5506(12) C(15)-C(16) 1.3832(11) C(15)-C(20) 1.3979(11) C(16)-H(16) 0.966(12) C(16)-C(17) 1.3987(12) C(17)-H(17) 1.136(12) C(17)-C(18) 1.3904(12) C(18)-H(18) 0.950(12) C(18)-C(19) 1.3995(12) C(19)-H(19) 0.987(12) C(19)-C(20) 1.3821(11) C(22)-H(22A) 0.984(13) C(22)-H(22B) 0.962(13) C(22)-H(22C) 0.999(13) C(11)-O(3)-C(12) O(1)-N(1)-O(2) 120.79(7) 124.15(9) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(1)-N(1)-C(7) O(2)-N(1)-C(7) C(20)-N(2)-C(22) C(21)-N(2)-C(20) C(21)-N(2)-C(22) C(2)-C(1)-C(8) C(2)-C(1)-C(14) C(8)-C(1)-C(14) C(11)-C(1)-C(2) C(11)-C(1)-C(8) C(11)-C(1)-C(14) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(2)-C(3)-H(3) C(4)-C(3)-C(2) C(4)-C(3)-H(3) C(3)-C(4)-H(4) C(5)-C(4)-C(3) C(5)-C(4)-H(4) C(4)-C(5)-H(5) C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(5)-C(6)-H(6) C(5)-C(6)-C(7) C(7)-C(6)-H(6) C(2)-C(7)-N(1) C(6)-C(7)-N(1) C(6)-C(7)-C(2) C(1)-C(8)-H(8A) C(1)-C(8)-H(8B) H(8A)-C(8)-H(8B) C(9)-C(8)-C(1) C(9)-C(8)-H(8A) C(9)-C(8)-H(8B) C(8)-C(9)-H(9) C(10)-C(9)-C(8) C(10)-C(9)-H(9) C(9)-C(10)-H(10A) C(9)-C(10)-H(10B) H(10A)-C(10)-H(10B) O(3)-C(11)-C(1) O(4)-C(11)-O(3) O(4)-C(11)-C(1) O(3)-C(12)-H(12A) O(3)-C(12)-H(12B) O(3)-C(12)-C(13) H(12A)-C(12)-H(12B) C(13)-C(12)-H(12A) C(13)-C(12)-H(12B) C(12)-C(13)-H(13A) C(12)-C(13)-H(13B) C(12)-C(13)-C(14) H(13A)-C(13)-H(13B) C(14)-C(13)-H(13A) C(14)-C(13)-H(13B) C(13)-C(14)-C(1) C(13)-C(14)-C(21) 117.31(9) 118.48(7) 124.99(7) 110.73(7) 123.14(7) 110.41(7) 109.21(6) 110.84(6) 110.91(7) 100.61(6) 114.61(7) 118.59(7) 114.70(8) 126.55(7) 120.3(7) 122.62(8) 117.0(7) 121.5(7) 120.40(9) 118.1(7) 121.2(8) 119.15(9) 119.6(8) 119.9(7) 119.50(8) 120.5(7) 122.81(8) 113.54(8) 123.53(8) 108.4(6) 108.6(7) 105.1(10) 115.38(7) 110.1(6) 108.7(7) 116.9(7) 123.80(9) 119.2(7) 119.8(8) 120.9(8) 119.2(12) 120.03(8) 118.26(8) 121.28(8) 102.7(8) 108.1(8) 111.22(8) 108.5(11) 112.8(8) 112.9(8) 107.2(7) 108.4(7) 110.64(8) 107.4(10) 111.1(7) 111.9(7) 110.64(7) 108.51(7) 238   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(15)-C(14)-C(1) C(15)-C(14)-C(13) C(15)-C(14)-C(21) C(21)-C(14)-C(1) C(16)-C(15)-C(14) C(16)-C(15)-C(20) C(20)-C(15)-C(14) C(15)-C(16)-H(16) C(15)-C(16)-C(17) C(17)-C(16)-H(16) C(16)-C(17)-H(17) C(18)-C(17)-C(16) C(18)-C(17)-H(17) C(17)-C(18)-H(18) C(17)-C(18)-C(19) C(19)-C(18)-H(18) C(18)-C(19)-H(19) C(20)-C(19)-C(18) C(20)-C(19)-H(19) C(15)-C(20)-N(2) C(19)-C(20)-N(2) C(19)-C(20)-C(15) O(5)-C(21)-N(2) O(5)-C(21)-C(14) N(2)-C(21)-C(14) N(2)-C(22)-H(22A) N(2)-C(22)-H(22B) N(2)-C(22)-H(22C) H(22A)-C(22)-H(22B) H(22A)-C(22)-H(22C) H(22B)-C(22)-H(22C) 239   112.77(7) 113.42(7) 100.57(6) 110.42(6) 131.73(8) 119.23(7) 109.02(7) 121.0(7) 119.14(8) 119.8(7) 115.2(6) 120.51(8) 124.2(6) 119.0(7) 121.07(8) 119.9(7) 120.2(7) 117.12(8) 122.7(7) 109.59(7) 127.61(8) 122.79(7) 124.73(8) 126.63(8) 108.62(7) 112.4(8) 110.5(8) 111.4(8) 112.9(11) 106.0(11) 103.2(11) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Table A2.4.4. Anisotropic displacement parameters (Å x 10 ) for 51. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2ð [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ O(1) 343(4) 179(3) 323(4) -43(3) -181(3) -49(3) O(2) 381(4) 184(3) 153(3) -24(2) 26(3) 42(3) O(3) 415(4) 203(3) 116(3) 34(2) 60(3) 40(3) O(4) 282(4) 167(3) 184(3) 7(2) -95(3) 12(3) O(5) 154(3) 142(3) 293(4) 70(2) 79(3) 1(2) N(1) 276(4) 106(3) 178(3) -16(3) -71(3) 6(3) N(2) 131(3) 102(3) 205(3) 17(2) 0(3) -11(2) C(1) 136(3) 101(3) 105(3) 0(2) 10(3) 10(3) C(2) 105(3) 102(3) 128(3) -4(3) -1(3) 1(2) C(3) 137(3) 137(3) 146(3) -12(3) 30(3) -2(3) C(4) 213(4) 182(4) 211(4) 8(3) 106(3) 10(3) C(5) 216(4) 171(4) 321(5) 22(4) 156(4) -11(3) C(6) 144(4) 134(4) 310(5) -10(3) 39(3) -25(3) C(7) 137(3) 114(3) 169(4) -19(3) -18(3) -1(3) C(8) 121(3) 95(3) 153(3) -9(3) 21(3) 7(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 240   C(9) 136(3) 132(3) 222(4) -2(3) 30(3) 14(3) C(10) 192(4) 206(4) 367(6) 75(4) 47(4) 61(3) C(11) 280(4) 98(3) 112(3) 0(3) -5(3) 22(3) C(12) 397(6) 217(5) 195(4) 55(4) 171(4) 69(4) C(13) 310(5) 177(4) 201(4) 38(3) 147(4) 78(4) C(14) 148(3) 108(3) 143(3) 18(3) 51(3) 31(3) C(15) 126(3) 103(3) 136(3) 11(3) 38(3) 24(3) C(16) 154(3) 108(3) 152(4) 1(3) 29(3) 18(3) C(17) 158(4) 111(3) 176(4) 23(3) 28(3) 4(3) C(18) 148(4) 133(3) 168(4) 34(3) 28(3) 9(3) C(19) 126(3) 138(3) 157(4) 5(3) 8(3) 12(3) C(20) 103(3) 98(3) 176(4) 8(3) 25(3) 9(2) C(21) 101(3) 123(3) 210(4) 27(3) 53(3) 23(3) C(22) 166(4) 128(4) 281(5) -6(3) -38(3) -19(3) ______________________________________________________________________________ 3 2 3 Table A2.4.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 51 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(3) 900(2) 96(1) 398(1) 17 H(4) 1022(2) 144(1) 229(2) 23 H(5) 1177(2) 209(1) 342(2) 26 H(6) 1209(2) 227(1) 622(2) 24 H(8A) 832(2) 33(1) 732(1) 15 H(8B) 833(2) 47(1) 555(1) 15 H(9) 1164(2) 53(1) 626(2) 20 H(10A) 1081(2) -15(1) 835(2) 31 H(10B) 1279(2) -8(1) 784(2) 31 H(12A) 637(2) 98(1) 1064(2) 30 H(12B) 635(2) 62(1) 924(2) 30 H(13A) 644(2) 157(1) 873(2) 26 H(13B) 461(2) 127(1) 808(2) 26 H(16) 722(2) 211(1) 648(1) 17 H(17) 651(2) 259(1) 417(1) 18 H(18) 484(2) 222(1) 160(2) 18 H(19) 394(2) 146(1) 145(1) 17 H(22A) 232(2) 73(1) 268(2) 31 H(22B) 365(2) 31(1) 333(2) 31 H(22C) 398(2) 60(1) 191(2) 31 ________________________________________________________________________________ Table A2.4.6. Hydrogen bonds for 51 [Å and °]. ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ C(12)-H(12B)...O(5) 0.963(14) 2.442(13) 3.0678(14) 122.4(10) C(13)-H(13A)...O(2) 1.014(13) 2.460(13) 3.1858(14) 128.0(9) C(19)-H(19)...O(4)#1 0.987(12) 2.622(12) 3.5589(11) 158.7(9) C(22)-H(22B)...O(5)#2 0.962(13) 2.418(13) 3.3085(12) 153.8(10) 241   ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 x-1,y,z-1 #2 -x+1,-y,-z+1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.5. X-Ray Crystal Structure Analysis of 52 TIPSO CO2Allyl O N O2N Br 52 Figure A2.5.1. X-ray Crystal Structure of 52 Table A2.5.1. Crystal Data and Structure Analysis Details for 52 Empirical formula C34 H45 Br N2 O6 Si Formula weight 685.72 Crystal shape block Crystal color colourless Crystal size 0.11 x 0.16 x 0.24 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK Data collection temperature 100 K 242   243   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Theta range for 9950 reflections used in lattice determination 2.54 to 27.86° Unit cell dimensions a = 8.0482(4) Å b = 14.1277(8) Å c = 15.3665(8) Å 〈= 99.073(2)° ®= 94.101(3)° © = 91.448(2)° Volume 1719.75(16) Å3 Z 2 Crystal system triclinic Space group P -1 (# 2) Density (calculated) 1.324 g/cm3 F(000) 720 Theta range for data collection 1.8 to 35.3° Completeness to theta = 25.000° 100.0% Index ranges -13 ʺ″ h ʺ″ 11, -20 ʺ″ k ʺ″ 21, -22 ʺ″ l ʺ″ 23 Data collection scan type and  scans   Reflections  collected   70933   Independent  reflections   11961  [Rint=  0.0565]   Reflections  >  2⌠(I)   8549     Average  ⌠(I)/(net  I)   0.0555   Absorption  coefficient   1.27  mm-­‐1   Absorption  correction   Semi-­‐empirical  from  equivalents   Max.  and  min.  transmission   1.0000  and  0.8989     Structure Solution and Refinement Primary solution method ? Secondary solution method ? Hydrogen placement difmap Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 11961 / 0 / 577 Treatment of hydrogen atoms refall Goodness-of-fit on F2 1.12 Final R indices [I>2⌠(I), 8549 reflections] R1 = 0.0402, wR2 = 0.0805 R indices (all data) R1 = 0.0754, wR2 = 0.0892 Type of weighting scheme used calc Weighting scheme used w=1/[^2^(Fo^2^)+(0.0400P)^2^] where P=(Fo^2^+2Fc^2^)/3 Max shift/error 0.003 Average shift/error 0.000 Extinction coefficient n/a Largest diff. peak and hole 0.55 and -0.51 e·Å-3 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 244   Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.32B (Bruker-AXS, 2007) APEX2 2013.6-2 (Bruker-AXS, 2007) SAINT V8.32B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Refinement Details 4 Table A2.5.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 52. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 3260(1) -6095(1) -8561(1) 25(1) Si(1) 380(1) -12429(1) -8560(1) 14(1) O(1) -2560(1) -5767(1) -7181(1) 28(1) O(2) -3551(1) -7223(1) -7270(1) 22(1) O(3) -3839(1) -8167(1) -5718(1) 20(1) O(4) -2148(1) -6852(1) -5561(1) 17(1) O(5) -2199(1) -10064(1) -5391(1) 17(1) O(6) 666(1) -11489(1) -7758(1) 16(1) N(1) -2394(2) -6634(1) -7234(1) 18(1) N(2) -4168(1) -10184(1) -6562(1) 15(1) C(1) -1041(2) -8300(1) -6228(1) 12(1) C(2) -118(2) -7745(1) -6847(1) 12(1) C(3) -688(2) -6993(1) -7276(1) 14(1) C(4) 290(2) -6508(1) -7788(1) 17(1) C(5) 1901(2) -6790(1) -7907(1) 16(1) C(6) 2528(2) -7532(1) -7516(1) 17(1) C(7) 1541(2) -7977(1) -6986(1) 14(1) C(8) -2544(2) -7788(1) -5839(1) 14(1) C(9) -3446(2) -6292(1) -5130(1) 24(1) C(10) -2758(2) -5286(1) -4906(1) 26(1) C(11) -2702(3) -4786(1) -4109(1) 34(1) C(12) 142(2) -8376(1) -5382(1) 16(1) C(13) 1021(2) -7471(1) -4906(1) 19(1) C(14) 2624(2) -7382(1) -4698(1) 26(1) C(15) -1646(2) -9346(1) -6719(1) 11(1) C(16) -2895(2) -9359(1) -7511(1) 12(1) C(17) -2761(2) -9042(1) -8310(1) 17(1) C(18) -4123(2) -9176(1) -8938(1) 21(1) C(19) -5578(2) -9640(1) -8775(1) 22(1) C(20) -5714(2) -9997(1) -7988(1) 19(1) C(21) -4352(2) -9853(1) -7369(1) 14(1) C(22) -2666(2) -9882(1) -6111(1) 13(1) C(23) -5490(2) -10648(1) -6173(1) 26(1) C(24) -176(2) -9986(1) -7005(1) 13(1) C(25) -693(2) -11038(1) -7320(1) 16(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 245   C(26) -826(2) -13397(1) -8136(1) 18(1) C(27) 28(2) -13713(1) -7308(1) 26(1) C(28) -1340(3) -14267(1) -8838(1) 27(1) C(29) 2572(2) -12703(1) -8851(1) 24(1) C(30) 3670(2) -13040(2) -8115(2) 36(1) C(31) 2672(3) -13392(2) -9724(2) 47(1) C(32) -836(2) -12104(1) -9559(1) 21(1) C(33) -47(3) -11230(2) -9867(2) 40(1) C(34) -2704(2) -11962(1) -9483(1) 28(1) ________________________________________________________________________________ Table A2.5.3. Bond lengths [Å] and angles [°] for 52 __________________________________________________________________________________ _ Br(1)-C(5) 1.8927(14) Si(1)-O(6) 1.6623(10) Si(1)-C(26) 1.8817(15) Si(1)-C(29) 1.8856(16) Si(1)-C(32) 1.8850(17) O(1)-N(1) 1.2263(16) O(2)-N(1) 1.2245(16) O(3)-C(8) 1.1986(17) O(4)-C(8) 1.3462(16) O(4)-C(9) 1.4600(18) O(5)-C(22) 1.2110(17) O(6)-C(25) 1.4361(16) N(1)-C(3) 1.4782(18) N(2)-C(21) 1.3931(19) N(2)-C(22) 1.3727(18) N(2)-C(23) 1.4476(19) C(1)-C(2) 1.5425(19) C(1)-C(8) 1.5348(19) C(1)-C(12) 1.576(2) C(1)-C(15) 1.5971(18) C(2)-C(3) 1.4053(19) C(2)-C(7) 1.4058(19) C(3)-C(4) 1.392(2) C(4)-H(4) 0.929(17) C(4)-C(5) 1.382(2) C(5)-C(6) 1.377(2) C(6)-H(6) 0.921(19) C(6)-C(7) 1.386(2) C(7)-H(7) 0.966(18) C(9)-H(9A) 0.982(19) C(9)-H(9B) 0.986(19) C(9)-C(10) 1.491(2) C(10)-H(10) 0.99(2) C(10)-C(11) 1.311(3) C(11)-H(11A) 0.97(2) C(11)-H(11B) 0.95(2) C(12)-H(12A) 0.889(18) C(12)-H(12B) 0.979(17) C(12)-C(13) 1.502(2) C(13)-H(13) 0.945(19) C(13)-C(14) 1.305(2) C(14)-H(14A) 0.94(2) C(14)-H(14B) 0.951(19) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(15)-C(16) C(15)-C(22) C(15)-C(24) C(16)-C(17) C(16)-C(21) C(17)-H(17) C(17)-C(18) C(18)-H(18) C(18)-C(19) C(19)-H(19) C(19)-C(20) C(20)-H(20) C(20)-C(21) C(23)-H(23A) C(23)-H(23B) C(23)-H(23C) C(24)-H(24A) C(24)-H(24B) C(24)-C(25) C(25)-H(25A) C(25)-H(25B) C(26)-H(26) C(26)-C(27) C(26)-C(28) C(27)-H(27A) C(27)-H(27B) C(27)-H(27C) C(28)-H(28A) C(28)-H(28B) C(28)-H(28C) C(29)-H(29) C(29)-C(30) C(29)-C(31) C(30)-H(30A) C(30)-H(30B) C(30)-H(30C) C(31)-H(31A) C(31)-H(31B) C(31)-H(31C) C(32)-H(32) C(32)-C(33) C(32)-C(34) C(33)-H(33A) C(33)-H(33B) C(33)-H(33C) C(34)-H(34A) C(34)-H(34B) C(34)-H(34C) O(6)-Si(1)-C(26) O(6)-Si(1)-C(29) O(6)-Si(1)-C(32) C(26)-Si(1)-C(29) C(26)-Si(1)-C(32) C(32)-Si(1)-C(29) C(8)-O(4)-C(9) C(25)-O(6)-Si(1) O(1)-N(1)-C(3) 1.5199(19) 1.5552(19) 1.5539(19) 1.382(2) 1.3977(19) 0.954(18) 1.397(2) 0.945(19) 1.385(2) 0.93(2) 1.391(2) 0.946(18) 1.388(2) 1.01(2) 0.93(2) 0.91(2) 0.964(17) 0.946(17) 1.5258(19) 0.962(17) 0.974(17) 0.946(17) 1.536(2) 1.529(2) 1.003(19) 1.03(2) 0.94(2) 0.97(2) 1.02(2) 0.99(2) 0.972(19) 1.527(3) 1.537(3) 1.01(2) 0.98(3) 1.00(2) 0.88(3) 0.96(2) 0.99(3) 0.953(19) 1.529(2) 1.533(2) 1.03(3) 0.96(2) 0.94(2) 0.94(2) 1.01(2) 0.95(2) 108.45(6) 102.78(6) 111.24(6) 116.69(7) 108.76(7) 108.83(8) 115.62(11) 122.38(9) 117.69(12) 246   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(2)-N(1)-O(1) O(2)-N(1)-C(3) C(21)-N(2)-C(23) C(22)-N(2)-C(21) C(22)-N(2)-C(23) C(2)-C(1)-C(12) C(2)-C(1)-C(15) C(8)-C(1)-C(2) C(8)-C(1)-C(12) C(8)-C(1)-C(15) C(12)-C(1)-C(15) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(2)-C(3)-N(1) C(4)-C(3)-N(1) C(4)-C(3)-C(2) C(3)-C(4)-H(4) C(5)-C(4)-C(3) C(5)-C(4)-H(4) C(4)-C(5)-Br(1) C(6)-C(5)-Br(1) C(6)-C(5)-C(4) C(5)-C(6)-H(6) C(5)-C(6)-C(7) C(7)-C(6)-H(6) C(2)-C(7)-H(7) C(6)-C(7)-C(2) C(6)-C(7)-H(7) O(3)-C(8)-O(4) O(3)-C(8)-C(1) O(4)-C(8)-C(1) O(4)-C(9)-H(9A) O(4)-C(9)-H(9B) O(4)-C(9)-C(10) H(9A)-C(9)-H(9B) C(10)-C(9)-H(9A) C(10)-C(9)-H(9B) C(9)-C(10)-H(10) C(11)-C(10)-C(9) C(11)-C(10)-H(10) C(10)-C(11)-H(11A) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(1)-C(12)-H(12A) C(1)-C(12)-H(12B) H(12A)-C(12)-H(12B) C(13)-C(12)-C(1) C(13)-C(12)-H(12A) C(13)-C(12)-H(12B) C(12)-C(13)-H(13) C(14)-C(13)-C(12) C(14)-C(13)-H(13) C(13)-C(14)-H(14A) C(13)-C(14)-H(14B) H(14A)-C(14)-H(14B) C(16)-C(15)-C(1) C(16)-C(15)-C(22) 124.37(12) 117.93(12) 124.40(13) 111.59(11) 123.24(13) 109.54(11) 111.12(11) 114.19(11) 102.89(11) 108.71(11) 110.07(11) 128.63(12) 113.94(12) 117.37(12) 123.50(12) 112.78(12) 123.72(13) 119.1(10) 118.92(14) 121.9(10) 118.87(11) 120.73(11) 120.31(13) 121.7(12) 119.26(13) 118.9(12) 118.4(10) 123.79(13) 117.8(10) 123.79(13) 125.80(12) 110.08(11) 109.4(10) 107.4(10) 106.28(13) 110.0(15) 109.9(11) 113.6(11) 113.0(12) 123.47(19) 123.5(12) 121.9(13) 121.7(14) 116.4(19) 106.2(12) 111.1(10) 105.2(15) 117.48(12) 109.4(12) 106.9(10) 117.6(12) 124.11(15) 118.0(12) 120.7(13) 120.4(11) 118.9(17) 114.67(11) 101.34(11) 247   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(16)-C(15)-C(24) C(22)-C(15)-C(1) C(24)-C(15)-C(1) C(24)-C(15)-C(22) C(17)-C(16)-C(15) C(17)-C(16)-C(21) C(21)-C(16)-C(15) C(16)-C(17)-H(17) C(16)-C(17)-C(18) C(18)-C(17)-H(17) C(17)-C(18)-H(18) C(19)-C(18)-C(17) C(19)-C(18)-H(18) C(18)-C(19)-H(19) C(18)-C(19)-C(20) C(20)-C(19)-H(19) C(19)-C(20)-H(20) C(21)-C(20)-C(19) C(21)-C(20)-H(20) N(2)-C(21)-C(16) C(20)-C(21)-N(2) C(20)-C(21)-C(16) O(5)-C(22)-N(2) O(5)-C(22)-C(15) N(2)-C(22)-C(15) N(2)-C(23)-H(23A) N(2)-C(23)-H(23B) N(2)-C(23)-H(23C) H(23A)-C(23)-H(23B) H(23A)-C(23)-H(23C) H(23B)-C(23)-H(23C) C(15)-C(24)-H(24A) C(15)-C(24)-H(24B) H(24A)-C(24)-H(24B) C(25)-C(24)-C(15) C(25)-C(24)-H(24A) C(25)-C(24)-H(24B) O(6)-C(25)-C(24) O(6)-C(25)-H(25A) O(6)-C(25)-H(25B) C(24)-C(25)-H(25A) C(24)-C(25)-H(25B) H(25A)-C(25)-H(25B) Si(1)-C(26)-H(26) C(27)-C(26)-Si(1) C(27)-C(26)-H(26) C(28)-C(26)-Si(1) C(28)-C(26)-H(26) C(28)-C(26)-C(27) C(26)-C(27)-H(27A) C(26)-C(27)-H(27B) C(26)-C(27)-H(27C) H(27A)-C(27)-H(27B) H(27A)-C(27)-H(27C) H(27B)-C(27)-H(27C) C(26)-C(28)-H(28A) C(26)-C(28)-H(28B) C(26)-C(28)-H(28C) 108.87(11) 110.99(11) 112.86(11) 107.29(11) 131.56(13) 119.36(13) 108.89(12) 119.5(11) 119.06(15) 121.4(11) 120.6(12) 120.73(15) 118.7(12) 120.8(12) 121.03(15) 118.1(12) 121.0(11) 117.51(14) 121.4(11) 110.02(12) 127.73(13) 122.21(14) 124.97(13) 126.91(12) 107.94(12) 109.3(13) 110.9(14) 115.0(15) 103.8(18) 104.9(19) 112(2) 108.7(10) 107.9(10) 112.9(14) 113.74(11) 106.1(10) 107.7(10) 107.63(11) 109.7(10) 111.7(10) 110.4(10) 109.9(10) 107.5(14) 104.7(11) 113.72(11) 104.7(11) 114.04(11) 108.3(11) 110.66(13) 113.3(11) 108.8(11) 111.1(12) 106.3(15) 108.5(16) 108.7(15) 112.5(12) 112.6(12) 112.8(12) 248   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 H(28A)-C(28)-H(28B) H(28A)-C(28)-H(28C) H(28B)-C(28)-H(28C) Si(1)-C(29)-H(29) C(30)-C(29)-Si(1) C(30)-C(29)-H(29) C(30)-C(29)-C(31) C(31)-C(29)-Si(1) C(31)-C(29)-H(29) C(29)-C(30)-H(30A) C(29)-C(30)-H(30B) C(29)-C(30)-H(30C) H(30A)-C(30)-H(30B) H(30A)-C(30)-H(30C) H(30B)-C(30)-H(30C) C(29)-C(31)-H(31A) C(29)-C(31)-H(31B) C(29)-C(31)-H(31C) H(31A)-C(31)-H(31B) H(31A)-C(31)-H(31C) H(31B)-C(31)-H(31C) Si(1)-C(32)-H(32) C(33)-C(32)-Si(1) C(33)-C(32)-H(32) C(33)-C(32)-C(34) C(34)-C(32)-Si(1) C(34)-C(32)-H(32) C(32)-C(33)-H(33A) C(32)-C(33)-H(33B) C(32)-C(33)-H(33C) H(33A)-C(33)-H(33B) H(33A)-C(33)-H(33C) H(33B)-C(33)-H(33C) C(32)-C(34)-H(34A) C(32)-C(34)-H(34B) C(32)-C(34)-H(34C) H(34A)-C(34)-H(34B) H(34A)-C(34)-H(34C) H(34B)-C(34)-H(34C) 249   100.8(16) 110.9(16) 106.5(16) 103.4(10) 114.40(13) 107.0(11) 110.15(17) 114.10(13) 107.0(11) 114.8(13) 110.0(15) 111.3(13) 109.4(19) 106.0(18) 104.8(19) 112.5(17) 110.3(14) 112.4(14) 111(2) 101(2) 109(2) 105.3(11) 111.67(13) 103.1(11) 109.47(16) 116.52(12) 109.8(11) 111.4(16) 111.6(14) 110.4(14) 112(2) 108(2) 102.1(19) 111.1(13) 109.4(12) 114.4(13) 105.6(18) 110.8(18) 104.9(17) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Table A2.5.4. Anisotropic displacement parameters (Å x 10 ) for 52. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2π [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ Br(1) 260(1) 269(1) 233(1) 77(1) 68(1) -97(1) Si(1) 147(2) 92(2) 183(2) -2(2) 37(2) -4(1) O(1) 246(6) 146(5) 478(8) 137(5) 54(5) 60(4) O(2) 126(5) 203(6) 324(6) 62(5) -30(4) -23(4) O(3) 173(5) 134(5) 296(6) 8(4) 99(4) 3(4) O(4) 150(5) 92(5) 260(6) -20(4) 38(4) 19(4) O(5) 189(5) 162(5) 179(5) 61(4) 30(4) -3(4) O(6) 137(5) 103(5) 237(6) -30(4) 52(4) 19(4) 250   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 N(1) 146(6) 161(6) 228(7) 73(5) -6(5) 15(5) N(2) 124(5) 122(6) 189(6) 12(5) 34(5) -27(4) C(1) 119(6) 84(6) 141(6) 13(5) 17(5) 11(5) C(2) 118(6) 90(6) 135(6) 0(5) -8(5) -26(5) C(3) 115(6) 109(6) 184(7) 17(5) -6(5) -10(5) C(4) 193(7) 130(7) 176(7) 44(6) -14(6) -27(5) C(5) 178(7) 149(7) 156(7) 17(5) 29(6) -69(5) C(6) 121(7) 152(7) 211(7) -11(6) 18(6) -26(5) C(7) 131(6) 105(6) 175(7) 7(5) -5(5) -7(5) C(8) 163(7) 100(6) 164(7) 14(5) 17(5) 8(5) C(9) 204(8) 150(7) 354(10) -50(7) 71(7) 54(6) C(10) 249(8) 145(7) 351(10) -36(7) 14(7) 48(6) C(11) 428(11) 201(9) 350(11) -42(8) -88(9) 60(8) C(12) 171(7) 147(7) 154(7) 38(6) -7(6) -14(6) C(13) 211(7) 156(7) 173(7) -21(6) 1(6) 12(6) C(14) 212(8) 230(8) 300(9) -44(7) -8(7) -31(7) C(15) 112(6) 76(6) 135(6) 10(5) 14(5) -10(5) C(16) 131(6) 83(6) 153(7) -2(5) -1(5) 13(5) C(17) 193(7) 142(7) 169(7) 15(5) 8(6) 3(6) C(18) 263(8) 207(8) 163(7) 16(6) -30(6) 36(6) C(19) 199(8) 222(8) 209(8) -60(6) -67(6) 44(6) C(20) 139(7) 160(7) 251(8) -51(6) 6(6) 6(6) C(21) 139(6) 106(6) 170(7) -22(5) 39(5) 17(5) C(22) 133(6) 65(6) 174(7) -8(5) 40(5) 7(5) C(23) 201(8) 344(10) 239(9) 43(8) 41(7) -137(7) C(24) 112(6) 104(6) 175(7) 0(5) 22(5) 6(5) C(25) 140(7) 104(6) 223(8) -4(6) 68(6) 17(5) C(26) 195(7) 115(7) 216(8) 23(6) 28(6) -9(6) C(27) 359(10) 214(8) 209(8) 59(7) -3(7) -47(7) C(28) 409(10) 136(7) 254(9) 45(6) -68(8) -75(7) C(29) 182(7) 175(8) 326(9) -49(7) 84(7) -9(6) C(30) 214(9) 371(11) 519(13) 75(10) 60(8) 67(8) C(31) 297(11) 476(14) 534(15) -272(11) 171(10) -23(10) C(32) 273(8) 168(7) 207(8) 46(6) 35(6) -14(6) C(33) 459(13) 424(12) 378(12) 245(10) 12(10) -117(10) C(34) 300(9) 259(9) 283(9) 88(8) -20(7) 56(7) ______________________________________________________________________________ 3 2 3 Table A2.5.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 52 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(4) H(6) H(7) H(9A) H(9B) H(10) H(11A) H(11B) H(12A) H(12B) H(13) H(14A) H(14B) -15(2) 362(2) 203(2) -369(2) -445(2) -237(2) -313(3) -227(3) -48(2) 100(2) 36(2) 333(2) 309(2) -600(1) -770(1) -847(1) -654(1) -636(1) -503(1) -504(2) -414(2) -862(1) -884(1) -696(1) -788(2) -682(1) -803(1) -756(1) -669(1) -459(1) -555(1) -542(1) -362(2) -399(2) -501(1) -552(1) -469(1) -490(1) -432(1) 15(4) 31(5) 22(4) 24(5) 24(5) 35(5) 41(6) 51(7) 22(5) 16(4) 34(5) 37(6) 28(5) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 251   H(17) -174(2) -874(1) -842(1) 20(4) H(18) -408(2) -893(1) -948(1) 28(5) H(19) -647(2) -976(1) -920(1) 32(5) H(20) -670(2) -1033(1) -788(1) 18(4) H(23A) -633(3) -1016(2) -596(2) 50(6) H(23B) -509(3) -1086(2) -566(2) 45(6) H(23C) -609(3) -1111(2) -655(2) 53(7) H(24A) 29(2) -976(1) -750(1) 17(4) H(24B) 60(2) -996(1) -651(1) 12(4) H(25A) -93(2) -1135(1) -682(1) 16(4) H(25B) -171(2) -1108(1) -771(1) 17(4) H(26) -180(2) -1310(1) -794(1) 21(4) H(27A) 98(2) -1415(1) -744(1) 29(5) H(27B) -83(2) -1410(1) -702(1) 36(5) H(27C) 42(2) -1318(1) -689(1) 28(5) H(28A) -199(2) -1409(1) -934(1) 33(5) H(28B) -216(3) -1472(2) -863(1) 39(6) H(28C) -38(3) -1465(2) -903(1) 37(6) H(29) 304(2) -1208(1) -893(1) 24(5) H(30A) 359(3) -1266(2) -751(2) 47(6) H(30B) 483(3) -1304(2) -826(2) 65(8) H(30C) 338(3) -1372(2) -806(2) 48(6) H(31A) 218(3) -1395(2) -972(2) 57(8) H(31B) 381(3) -1347(2) -986(2) 48(6) H(31C) 203(3) -1317(2) -1023(2) 59(8) H(32) -67(2) -1261(1) -1003(1) 27(5) H(33A) -6(3) -1063(2) -940(2) 81(9) H(33B) -54(3) -1113(2) -1043(2) 48(6) H(33C) 106(3) -1134(2) -999(2) 50(7) H(34A) -322(3) -1249(2) -929(1) 44(6) H(34B) -327(3) -1193(2) -1009(2) 45(6) H(34C) -296(3) -1138(2) -913(1) 41(6) ________________________________________________________________________________ Table A2.5.6. Hydrogen bonds for 52 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ C(6)-H(6)...O(2)#1 0.921(19) 2.353(19) 3.1624(18) 146.6(16) C(23)-H(23A)...O(5)#2 1.01(2) 2.45(2) 3.197(2) 129.9(17) ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 x+1,y,z #2 -x-1,-y-2,-z-1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.6. X-Ray Crystal Structure Analysis of 61 O Br O CO2Allyl O NO N 2 61 Figure A2.6.1. X-ray Crystal Structure of 61 Table A2.6.1. Crystal Data and Structure Analysis Details for 61 Empirical formula C23 H19 Br N2 O7.20 Formula weight 518.54 Crystallization solvent ???Solvent??? Crystal shape plate Crystal color colourless Crystal size 0.17 x 0.24 x 0.25 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK 252   253   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Data collection temperature 100 K Theta range for 9593 reflections used in lattice determination 2.62 to 36.54° Unit cell dimensions a = 10.1321(5) Å b = 14.3644(6) Å c = 14.6551(6) Å 〈= 90° ®= 104.647(3)° © = 90° Volume 2063.61(16) Å3 Z 4 Crystal system monoclinic Space group P 1 21/c 1 (# 14) Density (calculated) 1.669 g/cm3 F(000) 1054 Theta range for data collection 2.0 to 42.9° Completeness to theta = 25.000° 100.0% Index ranges -19 ʺ″ h ʺ″ 19, -27 ʺ″ k ʺ″ 27, -27 ʺ″ l ʺ″ 28 Data collection scan type and  scans   Reflections  collected   166238   Independent  reflections   15005  [Rint=  0.0848]   Reflections  >  2⌠(I)   9726     Average  ⌠(I)/(net  I)   0.0622   Absorption  coefficient   2.05  mm-­‐1   Absorption  correction   Semi-­‐empirical  from  equivalents   Max.  and  min.  transmission   1.0000  and  0.9002     Structure Solution and Refinement Primary solution method ? Secondary solution method ? Hydrogen placement mixed Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 15005 / 0 / 309 Treatment of hydrogen atoms constr Goodness-of-fit on F2 1.03 Final R indices [I>2⌠(I), 9726 reflections] R1 = 0.0534, wR2 = 0.1233 R indices (all data) R1 = 0.1009, wR2 = 0.1398 Type of weighting scheme used calc Weighting scheme used w=1/[^2^(Fo^2^)+(0.0618P)^2^+1.7296P] where P=(Fo^2^+2Fc^2^)/3 Max shift/error 0.000 Average shift/error 0.000 Extinction coefficient n/a Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Largest diff. peak and hole 254   5.40 and -1.57 e·Å-3 Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.32B (Bruker-AXS, 2007) APEX2 2012.10-0 (Bruker-AXS, 2007) SAINT V8.32B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.6.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 61. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 2176(1) 3795(1) 4422(1) 16(1) O(1) 4484(1) 6914(1) 2590(1) 19(1) O(2) 4806(1) 5100(1) 1849(1) 17(1) O(3) 3104(1) 5662(1) 752(1) 18(1) O(4) -1522(1) 4433(1) 2271(1) 22(1) O(5) 142(1) 5360(1) 2886(1) 16(1) O(6) 1437(1) 6845(1) 2016(1) 15(1) O(7) 490(1) 5659(1) 1068(1) 13(1) O(8) 1317(5) 4704(4) 5932(3) 13(1) C(4) 1722(2) 5406(1) 5379(1) 15(1) N(1) 3573(1) 7168(1) 3851(1) 14(1) N(2) -318(1) 4658(1) 2439(1) 13(1) C(1) 3379(1) 5631(1) 3242(1) 11(1) C(2) 2724(1) 5722(1) 4069(1) 12(1) C(3) 2202(2) 5102(1) 4617(1) 12(1) C(5) 1834(2) 6343(1) 5635(1) 17(1) C(6) 2449(2) 6977(1) 5154(1) 16(1) C(7) 2877(2) 6651(1) 4388(1) 12(1) C(8) 3878(2) 6644(1) 3160(1) 14(1) C(9) 3948(2) 8140(1) 4012(1) 20(1) C(10) 4635(2) 4985(1) 3515(1) 15(1) C(11) 5536(2) 5040(1) 2835(1) 19(1) C(12) 3523(2) 5408(1) 1558(1) 14(1) C(13) 2536(1) 5327(1) 2228(1) 10(1) C(14) 1976(1) 4321(1) 2117(1) 10(1) C(15) 2786(2) 3606(1) 1902(1) 14(1) C(16) 2314(2) 2703(1) 1684(1) 16(1) C(17) 985(2) 2474(1) 1652(1) 17(1) C(18) 150(2) 3150(1) 1888(1) 15(1) C(19) 644(2) 4040(1) 2126(1) 12(1) C(20) 1417(2) 6040(1) 1779(1) 11(1) C(21) -565(2) 6275(1) 517(1) 15(1) C(22) -1606(2) 6519(1) 1041(1) 16(1) C(23) -2852(2) 6167(1) 839(1) 24(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 255   ________________________________________________________________________________ Table A2.6.3. Bond lengths [Å] and angles [°] for 61 __________________________________________________________________________________ _ Br(1)-C(3) 1.8983(15) O(1)-C(8) 1.2173(19) O(2)-C(11) 1.450(2) O(2)-C(12) 1.3369(19) O(3)-C(12) 1.2057(19) O(4)-N(2) 1.2258(18) O(5)-N(2) 1.2285(17) O(6)-C(20) 1.2060(18) O(7)-C(20) 1.3313(18) O(7)-C(21) 1.4626(18) O(8)-C(4) 1.419(5) O(8)-H(4) 0.5001 O(8)-H(8) 0.8315 C(4)-H(4) 0.9497 C(4)-C(3) 1.396(2) C(4)-C(5) 1.394(2) N(1)-C(7) 1.3965(19) N(1)-C(8) 1.358(2) N(1)-C(9) 1.451(2) N(2)-C(19) 1.4738(19) C(1)-C(2) 1.528(2) C(1)-C(8) 1.555(2) C(1)-C(10) 1.544(2) C(1)-C(13) 1.5768(19) C(2)-C(3) 1.389(2) C(2)-C(7) 1.410(2) C(5)-H(5) 0.9500 C(5)-C(6) 1.391(2) C(6)-H(6) 0.9500 C(6)-C(7) 1.383(2) C(9)-H(9A) 0.9800 C(9)-H(9B) 0.9800 C(9)-H(9C) 0.9800 C(10)-H(10A) 0.9900 C(10)-H(10B) 0.9900 C(10)-C(11) 1.514(2) C(11)-H(11A) 0.9900 C(11)-H(11B) 0.9900 C(12)-C(13) 1.573(2) C(13)-C(14) 1.5460(19) C(13)-C(20) 1.5455(19) C(14)-C(15) 1.400(2) C(14)-C(19) 1.412(2) C(15)-H(15) 0.9500 C(15)-C(16) 1.391(2) C(16)-H(16) 0.9500 C(16)-C(17) 1.376(2) C(17)-H(17) 0.9500 C(17)-C(18) 1.387(2) C(18)-H(18) 0.9500 C(18)-C(19) 1.385(2) C(21)-H(21A) 0.9900 C(21)-H(21B) 0.9900 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(21)-C(22) C(22)-H(22) C(22)-C(23) C(23)-H(23A) C(23)-H(23B) C(12)-O(2)-C(11) C(20)-O(7)-C(21) C(4)-O(8)-H(4) C(4)-O(8)-H(8) H(4)-O(8)-H(8) O(8)-C(4)-H(4) C(3)-C(4)-O(8) C(3)-C(4)-H(4) C(5)-C(4)-O(8) C(5)-C(4)-H(4) C(5)-C(4)-C(3) C(7)-N(1)-C(9) C(8)-N(1)-C(7) C(8)-N(1)-C(9) O(4)-N(2)-O(5) O(4)-N(2)-C(19) O(5)-N(2)-C(19) C(2)-C(1)-C(8) C(2)-C(1)-C(10) C(2)-C(1)-C(13) C(8)-C(1)-C(13) C(10)-C(1)-C(8) C(10)-C(1)-C(13) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(4)-C(3)-Br(1) C(2)-C(3)-Br(1) C(2)-C(3)-C(4) C(4)-C(5)-H(5) C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(5)-C(6)-H(6) C(7)-C(6)-C(5) C(7)-C(6)-H(6) N(1)-C(7)-C(2) C(6)-C(7)-N(1) C(6)-C(7)-C(2) O(1)-C(8)-N(1) O(1)-C(8)-C(1) N(1)-C(8)-C(1) N(1)-C(9)-H(9A) N(1)-C(9)-H(9B) N(1)-C(9)-H(9C) H(9A)-C(9)-H(9B) H(9A)-C(9)-H(9C) H(9B)-C(9)-H(9C) C(1)-C(10)-H(10A) C(1)-C(10)-H(10B) H(10A)-C(10)-H(10B) C(11)-C(10)-C(1) C(11)-C(10)-H(10A) 1.494(2) 0.9500 1.322(3) 0.9500 0.9500 123.19(13) 117.17(12) 16.4 107.5 113.1 8.5 116.4(3) 120.1 123.3(3) 120.1 119.77(14) 124.62(13) 111.67(12) 123.70(14) 123.20(14) 118.81(13) 117.95(12) 101.37(11) 109.88(12) 122.06(12) 107.22(11) 108.64(12) 106.98(11) 135.18(13) 116.15(13) 108.06(12) 115.80(11) 122.67(11) 121.47(14) 119.6 120.74(14) 119.6 121.2 117.54(14) 121.2 110.18(12) 125.78(13) 123.98(14) 125.78(14) 125.49(14) 108.69(12) 109.5 109.5 109.5 109.5 109.5 109.5 109.0 109.0 107.8 113.13(13) 109.0 256   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(11)-C(10)-H(10B) O(2)-C(11)-C(10) O(2)-C(11)-H(11A) O(2)-C(11)-H(11B) C(10)-C(11)-H(11A) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) O(2)-C(12)-C(13) O(3)-C(12)-O(2) O(3)-C(12)-C(13) C(12)-C(13)-C(1) C(14)-C(13)-C(1) C(14)-C(13)-C(12) C(20)-C(13)-C(1) C(20)-C(13)-C(12) C(20)-C(13)-C(14) C(15)-C(14)-C(13) C(15)-C(14)-C(19) C(19)-C(14)-C(13) C(14)-C(15)-H(15) C(16)-C(15)-C(14) C(16)-C(15)-H(15) C(15)-C(16)-H(16) C(17)-C(16)-C(15) C(17)-C(16)-H(16) C(16)-C(17)-H(17) C(16)-C(17)-C(18) C(18)-C(17)-H(17) C(17)-C(18)-H(18) C(19)-C(18)-C(17) C(19)-C(18)-H(18) C(14)-C(19)-N(2) C(18)-C(19)-N(2) C(18)-C(19)-C(14) O(6)-C(20)-O(7) O(6)-C(20)-C(13) O(7)-C(20)-C(13) O(7)-C(21)-H(21A) O(7)-C(21)-H(21B) O(7)-C(21)-C(22) H(21A)-C(21)-H(21B) C(22)-C(21)-H(21A) C(22)-C(21)-H(21B) C(21)-C(22)-H(22) C(23)-C(22)-C(21) C(23)-C(22)-H(22) C(22)-C(23)-H(23A) C(22)-C(23)-H(23B) H(23A)-C(23)-H(23B) 257   109.0 114.73(13) 108.6 108.6 108.6 108.6 107.6 119.80(13) 119.04(14) 120.80(14) 106.83(11) 117.09(11) 106.13(11) 112.41(11) 101.50(11) 111.34(11) 119.25(13) 114.17(13) 126.32(12) 118.4 123.26(14) 118.4 119.8 120.48(14) 119.8 120.7 118.53(14) 120.7 119.8 120.34(15) 119.8 122.70(12) 114.14(13) 123.08(14) 125.14(13) 123.77(13) 110.96(12) 109.3 109.3 111.77(12) 107.9 109.3 109.3 118.2 123.59(16) 118.2 120.0 120.0 120.0 __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 258   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 2 4 Anisotropic displacement parameters (Å x 10 ) for 61. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2ð [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ Br(1) 228(1) 114(1) 135(1) 15(1) 21(1) -20(1) O(1) 183(5) 191(5) 217(5) -12(4) 88(4) -53(4) O(2) 132(5) 207(5) 178(5) -9(4) 52(4) 16(4) O(3) 210(5) 193(5) 160(5) 40(4) 75(4) 13(4) O(4) 116(5) 227(6) 338(7) -22(5) 88(5) -29(4) O(5) 147(5) 162(5) 144(4) -30(4) 14(4) 16(4) O(6) 165(5) 101(4) 174(5) -5(3) 25(4) 13(3) O(7) 127(4) 124(4) 111(4) 5(3) -16(3) 29(3) O(8) 60(20) 270(30) 63(19) 92(17) 11(14) -36(18) C(4) 168(6) 170(6) 118(5) 11(5) 26(5) -2(5) N(1) 152(5) 112(5) 154(5) -21(4) 37(4) -42(4) N(2) 117(5) 145(5) 130(5) 20(4) 28(4) 5(4) C(1) 98(5) 112(5) 124(5) -8(4) 11(4) -8(4) C(2) 107(5) 118(5) 105(5) -9(4) -2(4) -3(4) C(3) 129(6) 122(5) 107(5) 7(4) -1(4) -6(4) C(5) 199(7) 183(6) 128(5) -12(5) 44(5) 11(5) C(6) 176(6) 140(6) 145(6) -30(5) 29(5) 0(5) C(7) 114(5) 120(5) 124(5) -6(4) 5(4) -7(4) C(8) 116(5) 143(6) 150(5) -13(4) 20(4) -31(4) C(9) 210(7) 129(6) 247(7) -32(5) 39(6) -55(5) C(10) 101(5) 195(6) 149(6) -8(5) 0(4) 22(5) C(11) 107(6) 262(8) 188(6) -20(6) 22(5) 12(5) C(12) 130(6) 125(5) 157(6) -9(4) 50(5) -3(4) C(13) 94(5) 101(5) 109(5) -8(4) 12(4) 3(4) C(14) 98(5) 105(5) 96(5) 4(4) -1(4) 8(4) C(15) 129(6) 121(5) 155(5) -10(4) 19(4) 24(4) C(16) 187(7) 114(5) 180(6) -7(5) 22(5) 29(5) C(17) 218(7) 99(5) 179(6) 7(5) 22(5) -10(5) C(18) 161(6) 115(5) 156(5) 24(4) 21(5) -21(4) C(19) 120(5) 107(5) 117(5) 16(4) 18(4) 5(4) C(20) 111(5) 113(5) 113(5) 14(4) 17(4) 10(4) C(21) 156(6) 164(6) 120(5) 31(4) -3(4) 50(5) C(22) 170(6) 154(6) 146(6) 10(5) 6(5) 39(5) C(23) 183(7) 275(8) 256(8) 14(7) 26(6) 15(6) ______________________________________________________________________________ Table A2.6.4. 3 2 3 Table A2.6.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 61 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(4) H(8) H(5) H(6) H(9A) H(9B) H(9C) H(10A) H(10B) 132 171 149 257 316 425 469 518 432 498 481 655 761 850 838 820 515 434 572 649 614 534 409 347 459 415 354 18 23 20 19 30 30 30 18 18 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 259   H(11A) 614 559 300 23 H(11B) 613 448 292 23 H(15) 370 374 191 17 H(16) 292 224 156 20 H(17) 65 187 147 20 H(18) -76 300 189 18 H(21A) -102 596 -8 18 H(21B) -13 685 36 18 H(22) -136 695 155 20 H(23A) -313 573 34 29 H(23B) -347 635 120 29 ________________________________________________________________________________ Table A2.6.6. Hydrogen bonds for 61 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ O(8)-H(8)...O(4)#1 0.83 2.16 2.870(6) 143.3 O(8)-H(8)...N(2)#1 0.83 2.47 2.964(5) 118.6 C(5)-H(5)...O(6)#2 0.95 2.64 3.382(2) 135.3 C(6)-H(6)...O(3)#2 0.95 2.58 3.524(2) 173.5 C(9)-H(9A)...O(4)#3 0.98 2.62 3.270(2) 124.3 C(10)-H(10B)...Br(1) 0.99 2.90 3.5462(16) 123.5 C(18)-H(18)...O(6)#4 0.95 2.52 3.1613(19) 124.5 ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 -x,-y+1,-z+1 #2 x,-y+3/2,z+1/2 #3 -x,y+1/2,-z+1/2 #4 -x,y-1/2,-z+1/2               260   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.7. X-Ray Crystal Structure Analysis of 62 O O Br O NO N 2 62 Figure A2.7.1. X-ray Crystal Structure of 62     Table A2.7.1. Crystal data and structure refinement for 62 Empirical formula C22 H19 Br N2 O5 Formula weight 471.30 Crystallization Solvent ???Solvent??? Crystal Habit Block Crystal size 0.25 x 0.25 x 0.22 mm3 Crystal color Light yellow Data Collection Preliminary Photos Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoKa Data Collection Temperature 100(2) K 261   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 q range for 9803 reflections used in lattice determination 2.44 to 37.44° a= 90° b= 90° g = 90° Unit cell dimensions a = 9.1581(2) Å b = 12.6857(3) Å c = 16.7030(3) Å Volume 1940.50(7) Å3 Z 4 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Density (calculated) 1.613 Mg/m3 F(000) 960 Data collection program Bruker SMART v5.630 q range for data collection 2.02 to 38.73° Completeness to q = 38.73° 98.0 % Index ranges -15<=h<=15, -22<=k<=22, -29<=l<=29 Data collection scan type scans at 9 settings Data reduction program Bruker SAINT v6.45A Reflections collected 61657 Independent reflections 10781 [Rint= 0.0854] Absorption coefficient 2.157 mm-1 Absorption correction None Max. and min. transmission 0.6482 and 0.6146 Structure solution and Refinement Structure solution program SHELXS-97 (Sheldrick, 2008) Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program SHELXL-97 (Sheldrick, 2008) Refinement method Full matrix least-squares on F2 Data / restraints / parameters 10781 / 0 / 272 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.035 Final R indices [I>2s(I), 9216 reflections] R1 = 0.0252, wR2 = 0.0489 R indices (all data) R1 = 0.0337, wR2 = 0.0500 Type of weighting scheme used Sigma Weighting scheme used w=1/s^2^(Fo^2^) Max shift/error 0.002 Average shift/error 0.000 Absolute structure determination ad Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Absolute structure parameter -0.009(3) Largest diff. peak and hole 0.506 and -0.302 e.Å-3 262   Special Refinement Details Table A2.7.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 62. U(eq) is defined asthe trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 6172(1) 8240(1) 8167(1) 15(1) O(1) 3907(1) 9672(1) 4985(1) 17(1) O(2) 6918(1) 8349(1) 5024(1) 15(1) O(3) 8739(1) 9434(1) 5191(1) 14(1) O(4) 8625(1) 7737(1) 6394(1) 15(1) O(5) 10809(1) 8399(1) 6452(1) 19(1) N(1) 3093(1) 10408(1) 6153(1) 12(1) N(2) 9490(1) 8431(1) 6587(1) 12(1) C(1) 4851(1) 9334(1) 7882(1) 11(1) C(2) 4150(1) 9836(1) 8519(1) 13(1) C(3) 3074(1) 10582(1) 8369(1) 13(1) C(4) 2660(1) 10820(1) 7588(1) 13(1) C(5) 3393(1) 10316(1) 6972(1) 10(1) C(6) 4553(1) 9605(1) 7092(1) 9(1) C(7) 5158(1) 9288(1) 6276(1) 10(1) C(8) 3998(1) 9786(1) 5710(1) 12(1) C(9) 1825(1) 10950(1) 5827(1) 16(1) C(10) 5199(1) 8087(1) 6152(1) 12(1) C(11) 5626(1) 7790(1) 5306(1) 15(1) C(12) 7535(1) 9152(1) 5408(1) 11(1) C(13) 6734(1) 9783(1) 6067(1) 9(1) C(14) 6523(1) 10915(1) 5677(1) 12(1) C(15) 7876(1) 11577(1) 5570(1) 14(1) C(16) 8070(1) 12508(1) 5908(1) 22(1) C(17) 7685(1) 9912(1) 6823(1) 9(1) C(18) 7318(1) 10731(1) 7352(1) 12(1) C(19) 8056(1) 10912(1) 8064(1) 15(1) C(20) 9254(1) 10302(1) 8269(1) 17(1) C(21) 9707(1) 9521(1) 7747(1) 14(1) C(22) 8925(1) 9334(1) 7045(1) 11(1) ________________________________________________________________________________ Table A2.7.3. Bond lengths [Å] and angles [°] for 62 _____________________________________________________ Br(1)-C(1) 1.9017(10) O(1)-C(8) 1.2218(12) O(2)-C(12) 1.3289(12) O(2)-C(11) 1.4580(13) O(3)-C(12) 1.2142(12) O(4)-N(2) 1.2271(11) O(5)-N(2) 1.2300(11) N(1)-C(8) 1.3625(13) N(1)-C(5) 1.3999(12) N(1)-C(9) 1.4553(13) N(2)-C(22) 1.4720(12) C(1)-C(6) 1.3911(14) C(1)-C(2) 1.3962(14) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(2)-C(3) C(3)-C(4) C(4)-C(5) C(5)-C(6) C(6)-C(7) C(7)-C(10) C(7)-C(8) C(7)-C(13) C(10)-C(11) C(12)-C(13) C(13)-C(17) C(13)-C(14) C(14)-C(15) C(15)-C(16) C(17)-C(22) C(17)-C(18) C(18)-C(19) C(19)-C(20) C(20)-C(21) C(21)-C(22) C(12)-O(2)-C(11) C(8)-N(1)-C(5) C(8)-N(1)-C(9) C(5)-N(1)-C(9) O(4)-N(2)-O(5) O(4)-N(2)-C(22) O(5)-N(2)-C(22) C(6)-C(1)-C(2) C(6)-C(1)-Br(1) C(2)-C(1)-Br(1) C(3)-C(2)-C(1) C(2)-C(3)-C(4) C(5)-C(4)-C(3) C(4)-C(5)-N(1) C(4)-C(5)-C(6) N(1)-C(5)-C(6) C(1)-C(6)-C(5) C(1)-C(6)-C(7) C(5)-C(6)-C(7) C(6)-C(7)-C(10) C(6)-C(7)-C(8) C(10)-C(7)-C(8) C(6)-C(7)-C(13) C(10)-C(7)-C(13) C(8)-C(7)-C(13) O(1)-C(8)-N(1) O(1)-C(8)-C(7) N(1)-C(8)-C(7) C(11)-C(10)-C(7) O(2)-C(11)-C(10) O(3)-C(12)-O(2) O(3)-C(12)-C(13) O(2)-C(12)-C(13) C(17)-C(13)-C(12) C(17)-C(13)-C(14) C(12)-C(13)-C(14) C(17)-C(13)-C(7) 1.3888(15) 1.3917(15) 1.3854(14) 1.4079(14) 1.5248(13) 1.5383(13) 1.5561(14) 1.6122(13) 1.5149(14) 1.5460(13) 1.5433(13) 1.5885(13) 1.5070(14) 1.3208(15) 1.4016(14) 1.4049(14) 1.3862(14) 1.3857(16) 1.3836(15) 1.3936(14) 124.26(8) 111.30(8) 123.71(8) 124.18(9) 124.19(9) 117.92(8) 117.81(8) 121.36(9) 122.86(7) 115.75(7) 119.98(9) 120.64(9) 117.69(9) 126.35(9) 123.75(9) 109.89(8) 116.17(9) 135.37(9) 108.42(8) 112.93(8) 100.84(7) 109.74(8) 114.61(8) 109.51(8) 108.78(7) 124.44(9) 126.88(9) 108.66(8) 112.23(8) 112.87(8) 117.89(9) 119.40(8) 122.54(8) 111.72(8) 107.93(7) 103.53(7) 111.69(7) 263   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 264   C(12)-C(13)-C(7) 112.19(7) C(14)-C(13)-C(7) 109.36(7) C(15)-C(14)-C(13) 116.88(8) C(16)-C(15)-C(14) 123.95(11) C(22)-C(17)-C(18) 114.45(9) C(22)-C(17)-C(13) 128.21(8) C(18)-C(17)-C(13) 117.30(8) C(19)-C(18)-C(17) 123.03(10) C(20)-C(19)-C(18) 120.40(10) C(21)-C(20)-C(19) 118.74(10) C(20)-C(21)-C(22) 119.86(10) C(21)-C(22)-C(17) 123.37(9) C(21)-C(22)-N(2) 112.90(9) C(17)-C(22)-N(2) 123.65(8) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.7.4. Anisotropic displacement parameters (Å2x 104) for 62. The anisotropic displacement factorexponent takes the form: -2p2[ h2a*2U11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Br(1) 163(1) 167(1) 105(1) 41(1) 8(1) 33(1) O(1) 154(3) 265(4) 81(3) -9(3) -27(3) -9(3) O(2) 166(3) 173(3) 96(3) -45(3) 20(3) -31(3) O(3) 132(3) 170(3) 115(3) 6(2) 34(3) 1(3) O(4) 182(4) 119(3) 161(3) -8(2) 7(3) -30(3) O(5) 111(3) 226(4) 235(4) -21(3) 9(3) 43(3) N(1) 92(4) 177(4) 92(3) 20(3) -10(3) -1(3) N(2) 135(4) 122(4) 108(3) 24(3) -5(3) 14(3) C(1) 99(4) 128(4) 92(4) 7(3) 0(3) -8(3) C(2) 148(5) 155(4) 88(4) -3(3) 29(3) -19(3) C(3) 145(4) 134(4) 113(4) -20(3) 41(3) -17(3) C(4) 115(4) 120(4) 141(4) -1(3) 28(4) -2(3) C(5) 96(4) 118(4) 85(4) 12(3) 10(3) -20(3) C(6) 94(4) 120(4) 70(3) 1(3) 8(3) -15(3) C(7) 92(4) 138(4) 69(4) -13(3) 2(3) -7(3) C(8) 96(4) 164(4) 102(4) 7(3) -10(3) -31(3) C(9) 113(5) 217(5) 157(5) 36(4) -33(4) 13(4) C(10) 130(4) 137(4) 107(4) -16(3) 13(3) -34(3) C(11) 160(5) 158(4) 120(4) -43(3) 4(4) -41(4) C(12) 137(4) 119(4) 60(4) 2(3) -3(3) 7(3) C(13) 91(4) 105(4) 70(4) -3(3) -2(3) -1(3) C(14) 113(4) 134(4) 122(4) 26(3) -8(3) 5(3) C(15) 130(4) 142(5) 158(4) 45(3) 1(3) 0(3) C(16) 203(6) 169(5) 299(6) 19(4) 21(5) -23(4) C(17) 91(4) 109(3) 75(3) -1(3) 2(3) -17(3) C(18) 116(4) 137(4) 106(4) -16(3) 9(3) -9(3) C(19) 159(4) 181(4) 114(5) -54(3) 6(4) -37(4) C(20) 147(4) 262(5) 103(5) -28(4) -31(3) -48(4) C(21) 114(4) 189(5) 124(4) 21(3) -30(3) -10(4) C(22) 104(4) 119(4) 93(3) 4(3) 2(3) -3(3) ______________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.8. X-Ray Crystal Structure Analysis of 72 H N HO H CO2Me N Br O N 72 Figure A2.8.1. X-ray Crystal Structure of 72 Table A2.8.1. Crystal Data and Structure Analysis Details for 72 Empirical formula C23 H24 Br N3 O4 Formula weight 486.36 Crystal shape plate Crystal color colourless Crystal size 0.07 x 0.31 x 0.38 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK Data collection temperature 100 K Theta range for 9871 reflections used 265   266   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 in lattice determination 2.39 to 31.55° Unit cell dimensions a = 8.9320(3) Å b = 27.1836(10) Å c = 9.0145(3) Å Volume 2085.34(13) Å3 Z 4 Crystal system monoclinic Space group P 1 21/c 1 (# 14) Density (calculated) 1.549 g/cm3 F(000) 1000 Theta range for data collection 2.4 to 37.5° Completeness to theta = 25.000° 99.9% Index ranges -15 £ h £ 14, -46 £ k £ 45, -15 £ l £ 15 Data collection scan type and scans Reflections collected 104508 Independent reflections 10606 [Rint= 0.0574] Reflections > 2s(I) 8291 Average s(I)/(net I) 0.0362 Absorption coefficient 2.01 mm-1 Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.0000 and 0.8324 Structure Solution and Refinement Primary solution method dual Secondary solution method ? Hydrogen placement ? Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 10606 / 0 / 376 Treatment of hydrogen atoms refall Goodness-of-fit on F2 2.53 Final R indices [I>2s(I), 8291 reflections] R1 = 0.0470, wR2 = 0.0646 R indices (all data) R1 = 0.0694, wR2 = 0.0654 Type of weighting scheme used calc Weighting scheme used Max shift/error 0.001 Average shift/error 0.000 Extinction coefficient 0 Largest diff. peak and hole 1.86 and -1.09 e·Å-3 Programs Used a= 90° b= 107.683(2)° g = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics 267   SAINT V8.27B (Bruker-AXS, 2007) APEX2 2012.4-3 (Bruker-AXS, 2007) SAINT V8.27B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2012/6 (Sheldrick, 2012) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.8.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 72. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 5616(1) 9528(1) 3588(1) 20(1) O(1) 3320(1) 7660(1) 145(1) 19(1) O(2) 2094(1) 8263(1) 4223(1) 22(1) O(3) 10340(1) 9430(1) 2851(1) 18(1) O(4) 9696(1) 9118(1) 4907(1) 18(1) N(1) 2670(1) 8410(1) -1033(1) 14(1) N(2) 8487(1) 8844(1) 2459(1) 13(1) N(3) 8419(2) 8060(1) 3813(1) 22(1) C(1) 4542(1) 8418(1) 1464(1) 11(1) C(2) 4040(1) 8938(1) 883(1) 11(1) C(3) 4320(1) 9405(1) 1519(1) 14(1) C(4) 3606(2) 9819(1) 682(2) 17(1) C(5) 2602(2) 9765(1) -815(2) 19(1) C(6) 2257(2) 9306(1) -1492(2) 16(1) C(7) 2966(1) 8906(1) -616(1) 12(1) C(8) 3461(1) 8107(1) 138(1) 13(1) C(9) 1534(2) 8243(1) -2468(2) 21(1) C(10) 4148(2) 8288(1) 2965(2) 14(1) C(11) 2418(2) 8357(1) 2804(2) 19(1) C(12) 6299(1) 8286(1) 1562(1) 12(1) C(13) 6798(1) 8517(1) 248(1) 13(1) C(14) 6207(2) 8430(1) -1338(2) 18(1) C(15) 6884(2) 8664(1) -2346(2) 22(1) C(16) 8156(2) 8973(1) -1769(2) 20(1) C(17) 8787(2) 9058(1) -176(2) 17(1) C(18) 8085(1) 8827(1) 816(1) 13(1) C(19) 7546(1) 8484(1) 3051(1) 13(1) C(20) 8360(2) 7697(1) 2606(2) 23(1) C(21) 6642(2) 7726(1) 1632(2) 17(1) C(22) 9528(1) 9132(1) 3521(2) 14(1) C(23) 11536(2) 9722(1) 3929(2) 27(1) ________________________________________________________________________________ Table A2.8.3. Bond lengths [Å] and angles [°] for 72 __________________________________________________________________________________ _ Br(1)-C(3) 1.9025(13) O(1)-C(8) 1.2203(15) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(2)-H(2) O(2)-C(11) O(3)-C(22) O(3)-C(23) O(4)-C(22) N(1)-C(7) N(1)-C(8) N(1)-C(9) N(2)-C(18) N(2)-C(19) N(2)-C(22) N(3)-H(3) N(3)-C(19) N(3)-C(20) C(1)-C(2) C(1)-C(8) C(1)-C(10) C(1)-C(12) C(2)-C(3) C(2)-C(7) C(3)-C(4) C(4)-H(4) C(4)-C(5) C(5)-H(5) C(5)-C(6) C(6)-H(6) C(6)-C(7) C(9)-H(9A) C(9)-H(9B) C(9)-H(9C) C(10)-H(10A) C(10)-H(10B) C(10)-C(11) C(11)-H(11A) C(11)-H(11B) C(12)-C(13) C(12)-C(19) C(12)-C(21) C(13)-C(14) C(13)-C(18) C(14)-H(14) C(14)-C(15) C(15)-H(15) C(15)-C(16) C(16)-H(16) C(16)-C(17) C(17)-H(17) C(17)-C(18) C(19)-H(19) C(20)-H(20A) C(20)-H(20B) C(20)-C(21) C(21)-H(21A) C(21)-H(21B) C(23)-H(23A) C(23)-H(23B) C(23)-H(23C) 0.856(18) 1.4180(16) 1.3461(15) 1.4446(17) 1.2132(15) 1.4020(16) 1.3567(16) 1.4531(16) 1.4145(15) 1.4905(16) 1.3609(16) 0.760(18) 1.4455(17) 1.457(2) 1.5279(16) 1.5399(17) 1.5387(17) 1.5856(17) 1.3835(17) 1.4026(16) 1.3978(18) 0.939(15) 1.3829(19) 0.921(16) 1.381(2) 0.925(14) 1.3800(18) 0.960(17) 0.961(16) 0.996(17) 0.897(13) 0.984(15) 1.5195(18) 0.946(16) 0.983(15) 1.5211(17) 1.5569(17) 1.5515(17) 1.3857(17) 1.3912(17) 0.954(15) 1.3886(19) 0.888(15) 1.382(2) 0.952(13) 1.3941(19) 0.913(14) 1.3892(17) 0.943(12) 0.974(15) 0.997(14) 1.5206(19) 0.939(13) 0.956(14) 0.931(16) 0.962(15) 1.013(16) 268   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(11)-O(2)-H(2) C(22)-O(3)-C(23) C(7)-N(1)-C(9) C(8)-N(1)-C(7) C(8)-N(1)-C(9) C(18)-N(2)-C(19) C(22)-N(2)-C(18) C(22)-N(2)-C(19) C(19)-N(3)-H(3) C(19)-N(3)-C(20) C(20)-N(3)-H(3) C(2)-C(1)-C(8) C(2)-C(1)-C(10) C(2)-C(1)-C(12) C(8)-C(1)-C(12) C(10)-C(1)-C(8) C(10)-C(1)-C(12) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(2)-C(3)-Br(1) C(2)-C(3)-C(4) C(4)-C(3)-Br(1) C(3)-C(4)-H(4) C(5)-C(4)-C(3) C(5)-C(4)-H(4) C(4)-C(5)-H(5) C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(5)-C(6)-H(6) C(7)-C(6)-C(5) C(7)-C(6)-H(6) N(1)-C(7)-C(2) C(6)-C(7)-N(1) C(6)-C(7)-C(2) O(1)-C(8)-N(1) O(1)-C(8)-C(1) N(1)-C(8)-C(1) N(1)-C(9)-H(9A) N(1)-C(9)-H(9B) N(1)-C(9)-H(9C) H(9A)-C(9)-H(9B) H(9A)-C(9)-H(9C) H(9B)-C(9)-H(9C) C(1)-C(10)-H(10A) C(1)-C(10)-H(10B) H(10A)-C(10)-H(10B) C(11)-C(10)-C(1) C(11)-C(10)-H(10A) C(11)-C(10)-H(10B) O(2)-C(11)-C(10) O(2)-C(11)-H(11A) O(2)-C(11)-H(11B) C(10)-C(11)-H(11A) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(13)-C(12)-C(1) C(13)-C(12)-C(19) 108.4(11) 114.73(11) 124.25(11) 111.34(10) 124.10(11) 111.20(10) 131.13(11) 117.66(10) 110.4(14) 107.07(11) 110.6(14) 101.12(9) 113.01(10) 114.20(10) 107.26(9) 107.47(10) 112.73(10) 135.27(11) 116.19(11) 108.38(10) 123.18(9) 121.36(12) 115.42(9) 117.3(9) 119.63(13) 123.1(9) 117.6(10) 121.31(12) 121.0(10) 123.9(9) 117.20(12) 118.9(9) 109.69(10) 126.00(11) 124.23(12) 125.30(12) 125.66(11) 109.04(10) 105.5(10) 108.1(10) 111.5(10) 108.5(13) 112.9(13) 110.0(13) 110.7(8) 110.0(8) 108.0(12) 112.66(10) 108.2(8) 107.2(8) 111.85(11) 104.6(9) 109.4(8) 110.7(9) 110.9(8) 109.2(12) 112.53(10) 103.10(10) 269   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(13)-C(12)-C(21) C(19)-C(12)-C(1) C(21)-C(12)-C(1) C(21)-C(12)-C(19) C(14)-C(13)-C(12) C(14)-C(13)-C(18) C(18)-C(13)-C(12) C(13)-C(14)-H(14) C(13)-C(14)-C(15) C(15)-C(14)-H(14) C(14)-C(15)-H(15) C(16)-C(15)-C(14) C(16)-C(15)-H(15) C(15)-C(16)-H(16) C(15)-C(16)-C(17) C(17)-C(16)-H(16) C(16)-C(17)-H(17) C(18)-C(17)-C(16) C(18)-C(17)-H(17) C(13)-C(18)-N(2) C(17)-C(18)-N(2) C(17)-C(18)-C(13) N(2)-C(19)-C(12) N(2)-C(19)-H(19) N(3)-C(19)-N(2) N(3)-C(19)-C(12) N(3)-C(19)-H(19) C(12)-C(19)-H(19) N(3)-C(20)-H(20A) N(3)-C(20)-H(20B) N(3)-C(20)-C(21) H(20A)-C(20)-H(20B) C(21)-C(20)-H(20A) C(21)-C(20)-H(20B) C(12)-C(21)-H(21A) C(12)-C(21)-H(21B) C(20)-C(21)-C(12) C(20)-C(21)-H(21A) C(20)-C(21)-H(21B) H(21A)-C(21)-H(21B) O(3)-C(22)-N(2) O(4)-C(22)-O(3) O(4)-C(22)-N(2) O(3)-C(23)-H(23A) O(3)-C(23)-H(23B) O(3)-C(23)-H(23C) H(23A)-C(23)-H(23B) H(23A)-C(23)-H(23C) H(23B)-C(23)-H(23C) 270   109.61(10) 114.00(10) 113.78(10) 102.92(10) 128.56(11) 119.71(11) 111.60(10) 119.7(9) 119.53(13) 120.6(9) 116.8(10) 120.22(13) 122.9(10) 116.3(8) 121.18(13) 122.5(8) 120.7(8) 117.89(12) 121.4(8) 108.90(10) 129.64(11) 121.45(11) 104.58(9) 104.9(8) 114.37(10) 105.97(11) 111.9(8) 115.2(8) 109.9(9) 116.1(8) 101.40(11) 107.2(11) 113.9(9) 108.4(8) 110.3(8) 113.5(9) 103.11(11) 108.7(8) 112.2(8) 108.8(12) 112.08(11) 124.48(12) 123.44(12) 112.0(11) 103.6(9) 107.6(9) 106.2(13) 112.2(13) 115.1(12) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Table A2.8.4. Anisotropic displacement parameters (Å x 10 ) for 72. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2p [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 271   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ Br(1) 189(1) 189(1) 183(1) -71(1) -12(1) -6(1) O(1) 199(5) 132(5) 234(5) -45(4) 54(4) -35(4) O(2) 251(5) 251(6) 230(5) 92(4) 159(4) 86(4) O(3) 150(4) 180(5) 203(5) -31(4) 41(4) -51(3) O(4) 139(4) 245(5) 136(4) -30(4) 9(4) 8(4) N(1) 123(5) 170(5) 100(5) -24(4) 12(4) -24(4) N(2) 114(5) 152(5) 116(5) -3(4) 26(4) -17(4) N(3) 163(6) 211(6) 235(6) 66(5) -25(5) 12(5) C(1) 110(5) 111(5) 115(5) -8(4) 25(4) -6(4) C(2) 88(5) 125(6) 111(5) 6(4) 42(4) 0(4) C(3) 108(5) 153(6) 143(6) -18(5) 37(4) -9(5) C(4) 161(6) 126(6) 236(7) 6(5) 71(5) -2(5) C(5) 161(6) 181(7) 218(7) 86(5) 54(5) 38(5) C(6) 124(6) 231(7) 134(6) 43(5) 30(5) 3(5) C(7) 109(5) 158(6) 111(6) -2(5) 49(4) -19(4) C(8) 114(6) 165(6) 126(6) -23(5) 56(5) -15(4) C(9) 216(7) 265(8) 122(6) -53(6) -6(5) -40(6) C(10) 134(6) 151(6) 119(6) 20(5) 39(5) 9(5) C(11) 160(6) 247(7) 188(7) 78(6) 91(5) 60(6) C(12) 115(6) 135(6) 128(6) -6(4) 45(5) -1(4) C(13) 121(6) 129(6) 142(6) -3(5) 55(5) 11(4) C(14) 144(6) 250(7) 165(6) -53(5) 55(5) -14(5) C(15) 216(7) 320(8) 112(6) -31(6) 57(5) 15(6) C(16) 222(7) 242(7) 177(7) 32(6) 118(6) 20(6) C(17) 153(6) 171(6) 191(7) -5(5) 74(5) -13(5) C(18) 119(6) 128(6) 131(6) -2(4) 40(5) 25(4) C(19) 103(5) 172(6) 119(6) 19(5) 29(5) 4(5) C(20) 158(7) 180(7) 362(9) 62(6) 77(6) 53(5) C(21) 155(6) 137(6) 235(7) -3(5) 78(5) 13(5) C(22) 91(5) 142(6) 188(6) -16(5) 28(5) 31(4) C(23) 209(8) 299(8) 313(9) -133(7) 93(7) -119(6) ______________________________________________________________________________ 3 2 3 Table A2.8.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 72 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(2) H(3) H(4) H(5) H(6) H(9A) H(9B) H(9C) H(10A) H(10B) H(11A) H(11B) H(14) H(15) H(16) H(17) 241(2) 926(2) 383(2) 219(2) 159(2) 172(2) 176(2) 44(2) 441(1) 475(2) 211(2) 176(2) 539(2) 645(2) 856(2) 963(2) 797(1) 813(1) 1013(1) 1005(1) 925(1) 790(1) 840(1) 832(1) 798(1) 850(1) 869(1) 814(1) 819(1) 861(1) 913(1) 926(1) 452(2) 424(2) 119(2) -136(2) -249(2) -252(2) -332(2) -248(2) 324(2) 382(2) 257(2) 198(2) -172(2) -336(2) -252(2) 20(2) 42(5) 37(5) 20(4) 30(4) 18(4) 33(5) 32(5) 36(5) 9(3) 21(4) 26(4) 21(4) 21(4) 23(4) 15(4) 12(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 272   H(19) 714(1) 867(1) 373(1) 7(3) H(20A) 868(2) 738(1) 308(2) 23(4) H(20B) 902(2) 777(1) 192(2) 15(4) H(21A) 603(2) 756(1) 216(2) 10(3) H(21B) 646(2) 758(1) 63(2) 18(4) H(23A) 1111(2) 996(1) 442(2) 35(5) H(23B) 1202(2) 990(1) 327(2) 21(4) H(23C) 1226(2) 949(1) 470(2) 30(4) ________________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.9. X-Ray Crystal Structure Analysis of 73 PMB TIPSO N H O HN CO2Me O N 73 Figure A2.9.1. X-ray Crystal Structure of 73 Table A2.9.1. Crystal Data and Structure Analysis Details for 73 Empirical formula C40 H53 N3 O6 Si Formula weight 699.94 Crystal shape plate Crystal color colourless Crystal size 0.04 x 0.20 x 0.20 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK Data collection temperature 100 K 273   274   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Theta range for 9937 reflections used in lattice determination 2.40 to 30.23° a= 90° b= 94.394(3)° g = 90° Unit cell dimensions a = 23.3177(12) Å b = 8.7021(4) Å c = 37.035(2) Å Volume 7492.8(7) Å3 Z 8 Crystal system monoclinic Space group I 1 2/a 1 (# 15) Density (calculated) 1.241 g/cm3 F(000) 3008 Theta range for data collection 2.4 to 35.0° Completeness to theta = 25.000° 99.9% Index ranges -36 £ h £ 37, -13 £ k £ 13, -59 £ l £ 58 Data collection scan type and scans Reflections collected 146937 Independent reflections 15890 [Rint= 0.1927] Reflections > 2s(I) 8277 Average s(I)/(net I) 0.1381 Absorption coefficient 0.11 mm-1 Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.0000 and 0.9156 Structure Solution and Refinement Primary solution method dual Secondary solution method ? Hydrogen placement geom Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 15890 / 0 / 460 Treatment of hydrogen atoms constr Goodness-of-fit on F2 1.25 Final R indices [I>2s(I), 8277 reflections] R1 = 0.0718, wR2 = 0.1071 R indices (all data) R1 = 0.1715, wR2 = 0.1233 Type of weighting scheme used calc Weighting scheme used Max shift/error 0.000 Average shift/error 0.000 Extinction coefficient n/a Largest diff. peak and hole 0.55 and -0.53 e·Å-3 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 275   Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.27B (Bruker-AXS, 2007) APEX2 2012.4-3 (Bruker-AXS, 2007) SAINT V8.27B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.9.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 73. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Si(1) 3732(1) 673(1) 2268(1) 13(1) O(1) 2790(1) -3775(1) 1228(1) 19(1) O(2) 3562(1) -65(1) 1866(1) 18(1) O(3) 793(1) 2007(1) 470(1) 20(1) O(4) 337(1) -285(1) 450(1) 34(1) O(5) 2274(1) 1556(1) 486(1) 16(1) O(6) 5052(1) 5085(1) 1358(1) 26(1) N(1) 1864(1) -2960(1) 1280(1) 14(1) N(2) 1318(1) -73(1) 418(1) 14(1) N(3) 3199(1) 803(1) 470(1) 13(1) C(1) 2509(1) -1080(2) 1090(1) 12(1) C(2) 1946(1) -370(2) 1189(1) 12(1) C(3) 1770(1) 1145(2) 1210(1) 15(1) C(4) 1220(1) 1458(2) 1310(1) 19(1) C(5) 854(1) 271(2) 1390(1) 20(1) C(6) 1027(1) -1258(2) 1380(1) 18(1) C(7) 1575(1) -1538(2) 1283(1) 14(1) C(8) 2421(1) -2773(2) 1207(1) 13(1) C(9) 1600(1) -4446(2) 1329(1) 21(1) C(10) 3042(1) -416(2) 1301(1) 14(1) C(11) 2999(1) -378(2) 1707(1) 18(1) C(12) 2572(1) -1120(2) 660(1) 11(1) C(13) 2066(1) -2081(2) 478(1) 13(1) C(14) 2184(1) -3655(2) 434(1) 18(1) C(15) 1776(1) -4714(2) 307(1) 23(1) C(16) 1224(1) -4227(2) 207(1) 24(1) C(17) 1084(1) -2692(2) 246(1) 20(1) C(18) 1491(1) -1618(2) 387(1) 14(1) C(19) 2649(1) 553(2) 526(1) 12(1) C(20) 3583(1) -490(2) 547(1) 14(1) C(21) 3161(1) -1825(2) 574(1) 14(1) C(22) 776(1) 440(2) 446(1) 19(1) C(23) 254(1) 2706(2) 538(1) 31(1) C(24) 3582(1) -777(2) 2628(1) 21(1) C(25) 3734(1) -2424(2) 2519(1) 34(1) C(26) 2957(1) -746(2) 2726(1) 29(1) C(27) 3303(1) 2471(2) 2331(1) 19(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 276   C(28) 3433(1) 3174(2) 2709(1) 28(1) C(29) 3380(1) 3672(2) 2034(1) 31(1) C(30) 4519(1) 1125(2) 2262(1) 17(1) C(31) 4674(1) 1762(2) 1896(1) 28(1) C(32) 4920(1) -219(2) 2369(1) 28(1) C(33) 3412(1) 2292(2) 352(1) 14(1) C(34) 3837(1) 3026(2) 627(1) 13(1) C(35) 4426(1) 2770(2) 618(1) 18(1) C(36) 4818(1) 3460(2) 866(1) 21(1) C(37) 4626(1) 4444(2) 1127(1) 18(1) C(38) 4044(1) 4715(2) 1142(1) 19(1) C(39) 3654(1) 3996(2) 894(1) 16(1) C(40) 4878(1) 6187(2) 1612(1) 32(1) ________________________________________________________________________________ Table A2.9.3. Bond lengths [Å] and angles [°] for 73 __________________________________________________________________________________ _ Si(1)-O(2) 1.6433(11) Si(1)-C(24) 1.8858(17) Si(1)-C(27) 1.8806(17) Si(1)-C(30) 1.8786(16) O(1)-C(8) 1.2233(18) O(2)-C(11) 1.4245(18) O(3)-C(22) 1.367(2) O(3)-C(23) 1.437(2) O(4)-C(22) 1.2031(19) O(5)-C(19) 1.2376(17) O(6)-C(37) 1.3796(18) O(6)-C(40) 1.425(2) N(1)-C(7) 1.4092(19) N(1)-C(8) 1.358(2) N(1)-C(9) 1.4496(19) N(2)-H(2) 0.8800 N(2)-C(18) 1.4106(19) N(2)-C(22) 1.353(2) N(3)-C(19) 1.3318(19) N(3)-C(20) 1.4511(19) N(3)-C(33) 1.4668(18) C(1)-C(2) 1.519(2) C(1)-C(8) 1.554(2) C(1)-C(10) 1.530(2) C(1)-C(12) 1.609(2) C(2)-C(3) 1.385(2) C(2)-C(7) 1.397(2) C(3)-H(3) 0.9500 C(3)-C(4) 1.390(2) C(4)-H(4) 0.9500 C(4)-C(5) 1.385(2) C(5)-H(5) 0.9500 C(5)-C(6) 1.392(2) C(6)-H(6) 0.9500 C(6)-C(7) 1.375(2) C(9)-H(9A) 0.9800 C(9)-H(9B) 0.9800 C(9)-H(9C) 0.9800 C(10)-H(10A) 0.9900 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(10)-H(10B) C(10)-C(11) C(11)-H(11A) C(11)-H(11B) C(12)-C(13) C(12)-C(19) C(12)-C(21) C(13)-C(14) C(13)-C(18) C(14)-H(14) C(14)-C(15) C(15)-H(15) C(15)-C(16) C(16)-H(16) C(16)-C(17) C(17)-H(17) C(17)-C(18) C(20)-H(20A) C(20)-H(20B) C(20)-C(21) C(21)-H(21A) C(21)-H(21B) C(23)-H(23A) C(23)-H(23B) C(23)-H(23C) C(24)-H(24) C(24)-C(25) C(24)-C(26) C(25)-H(25A) C(25)-H(25B) C(25)-H(25C) C(26)-H(26A) C(26)-H(26B) C(26)-H(26C) C(27)-H(27) C(27)-C(28) C(27)-C(29) C(28)-H(28A) C(28)-H(28B) C(28)-H(28C) C(29)-H(29A) C(29)-H(29B) C(29)-H(29C) C(30)-H(30) C(30)-C(31) C(30)-C(32) C(31)-H(31A) C(31)-H(31B) C(31)-H(31C) C(32)-H(32A) C(32)-H(32B) C(32)-H(32C) C(33)-H(33A) C(33)-H(33B) C(33)-C(34) C(34)-C(35) C(34)-C(39) C(35)-H(35) 0.9900 1.513(2) 0.9900 0.9900 1.558(2) 1.553(2) 1.560(2) 1.409(2) 1.416(2) 0.9500 1.381(2) 0.9500 1.377(2) 0.9500 1.386(2) 0.9500 1.404(2) 0.9900 0.9900 1.529(2) 0.9900 0.9900 0.9800 0.9800 0.9800 1.0000 1.537(2) 1.529(2) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.0000 1.536(2) 1.538(2) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.0000 1.533(2) 1.531(2) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9900 0.9900 1.507(2) 1.394(2) 1.391(2) 0.9500 277   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(35)-C(36) C(36)-H(36) C(36)-C(37) C(37)-C(38) C(38)-H(38) C(38)-C(39) C(39)-H(39) C(40)-H(40A) C(40)-H(40B) C(40)-H(40C) O(2)-Si(1)-C(24) O(2)-Si(1)-C(27) O(2)-Si(1)-C(30) C(27)-Si(1)-C(24) C(30)-Si(1)-C(24) C(30)-Si(1)-C(27) C(11)-O(2)-Si(1) C(22)-O(3)-C(23) C(37)-O(6)-C(40) C(7)-N(1)-C(9) C(8)-N(1)-C(7) C(8)-N(1)-C(9) C(18)-N(2)-H(2) C(22)-N(2)-H(2) C(22)-N(2)-C(18) C(19)-N(3)-C(20) C(19)-N(3)-C(33) C(20)-N(3)-C(33) C(2)-C(1)-C(8) C(2)-C(1)-C(10) C(2)-C(1)-C(12) C(8)-C(1)-C(12) C(10)-C(1)-C(8) C(10)-C(1)-C(12) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(2)-C(3)-H(3) C(2)-C(3)-C(4) C(4)-C(3)-H(3) C(3)-C(4)-H(4) C(5)-C(4)-C(3) C(5)-C(4)-H(4) C(4)-C(5)-H(5) C(4)-C(5)-C(6) C(6)-C(5)-H(5) C(5)-C(6)-H(6) C(7)-C(6)-C(5) C(7)-C(6)-H(6) C(2)-C(7)-N(1) C(6)-C(7)-N(1) C(6)-C(7)-C(2) O(1)-C(8)-N(1) O(1)-C(8)-C(1) N(1)-C(8)-C(1) N(1)-C(9)-H(9A) N(1)-C(9)-H(9B) 1.383(2) 0.9500 1.389(2) 1.382(2) 0.9500 1.388(2) 0.9500 0.9800 0.9800 0.9800 109.49(7) 110.14(7) 103.79(7) 109.92(8) 112.46(7) 110.87(7) 126.94(10) 114.30(13) 116.98(14) 125.13(13) 111.14(12) 123.66(13) 116.7 116.7 126.52(13) 115.41(12) 122.84(12) 121.72(12) 100.58(12) 113.97(12) 113.17(11) 106.16(11) 109.56(12) 112.38(12) 131.70(14) 119.12(14) 109.13(13) 120.5 119.00(15) 120.5 119.8 120.47(15) 119.8 119.2 121.55(15) 119.2 121.6 116.89(15) 121.6 109.37(13) 127.66(14) 122.89(14) 125.48(14) 125.94(14) 108.58(13) 109.5 109.5 278   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 N(1)-C(9)-H(9C) H(9A)-C(9)-H(9B) H(9A)-C(9)-H(9C) H(9B)-C(9)-H(9C) C(1)-C(10)-H(10A) C(1)-C(10)-H(10B) H(10A)-C(10)-H(10B) C(11)-C(10)-C(1) C(11)-C(10)-H(10A) C(11)-C(10)-H(10B) O(2)-C(11)-C(10) O(2)-C(11)-H(11A) O(2)-C(11)-H(11B) C(10)-C(11)-H(11A) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(13)-C(12)-C(1) C(13)-C(12)-C(21) C(19)-C(12)-C(1) C(19)-C(12)-C(13) C(19)-C(12)-C(21) C(21)-C(12)-C(1) C(14)-C(13)-C(12) C(14)-C(13)-C(18) C(18)-C(13)-C(12) C(13)-C(14)-H(14) C(15)-C(14)-C(13) C(15)-C(14)-H(14) C(14)-C(15)-H(15) C(16)-C(15)-C(14) C(16)-C(15)-H(15) C(15)-C(16)-H(16) C(15)-C(16)-C(17) C(17)-C(16)-H(16) C(16)-C(17)-H(17) C(16)-C(17)-C(18) C(18)-C(17)-H(17) N(2)-C(18)-C(13) C(17)-C(18)-N(2) C(17)-C(18)-C(13) O(5)-C(19)-N(3) O(5)-C(19)-C(12) N(3)-C(19)-C(12) N(3)-C(20)-H(20A) N(3)-C(20)-H(20B) N(3)-C(20)-C(21) H(20A)-C(20)-H(20B) C(21)-C(20)-H(20A) C(21)-C(20)-H(20B) C(12)-C(21)-H(21A) C(12)-C(21)-H(21B) C(20)-C(21)-C(12) C(20)-C(21)-H(21A) C(20)-C(21)-H(21B) H(21A)-C(21)-H(21B) O(4)-C(22)-O(3) O(4)-C(22)-N(2) N(2)-C(22)-O(3) 109.5 109.5 109.5 109.5 108.8 108.8 107.7 113.76(13) 108.8 108.8 106.68(13) 110.4 110.4 110.4 110.4 108.6 108.45(12) 110.47(12) 108.49(11) 117.86(12) 100.20(12) 111.17(11) 115.09(13) 116.05(14) 128.49(13) 118.2 123.52(16) 118.2 120.3 119.42(16) 120.3 120.3 119.44(15) 120.3 119.2 121.51(16) 119.2 121.55(13) 118.41(14) 119.97(14) 123.16(14) 126.97(14) 109.83(12) 111.3 111.3 102.24(12) 109.2 111.3 111.3 110.3 110.3 107.14(12) 110.3 110.3 108.5 122.93(16) 128.98(16) 108.09(13) 279   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(3)-C(23)-H(23A) O(3)-C(23)-H(23B) O(3)-C(23)-H(23C) H(23A)-C(23)-H(23B) H(23A)-C(23)-H(23C) H(23B)-C(23)-H(23C) Si(1)-C(24)-H(24) C(25)-C(24)-Si(1) C(25)-C(24)-H(24) C(26)-C(24)-Si(1) C(26)-C(24)-H(24) C(26)-C(24)-C(25) C(24)-C(25)-H(25A) C(24)-C(25)-H(25B) C(24)-C(25)-H(25C) H(25A)-C(25)-H(25B) H(25A)-C(25)-H(25C) H(25B)-C(25)-H(25C) C(24)-C(26)-H(26A) C(24)-C(26)-H(26B) C(24)-C(26)-H(26C) H(26A)-C(26)-H(26B) H(26A)-C(26)-H(26C) H(26B)-C(26)-H(26C) Si(1)-C(27)-H(27) C(28)-C(27)-Si(1) C(28)-C(27)-H(27) C(28)-C(27)-C(29) C(29)-C(27)-Si(1) C(29)-C(27)-H(27) C(27)-C(28)-H(28A) C(27)-C(28)-H(28B) C(27)-C(28)-H(28C) H(28A)-C(28)-H(28B) H(28A)-C(28)-H(28C) H(28B)-C(28)-H(28C) C(27)-C(29)-H(29A) C(27)-C(29)-H(29B) C(27)-C(29)-H(29C) H(29A)-C(29)-H(29B) H(29A)-C(29)-H(29C) H(29B)-C(29)-H(29C) Si(1)-C(30)-H(30) C(31)-C(30)-Si(1) C(31)-C(30)-H(30) C(32)-C(30)-Si(1) C(32)-C(30)-H(30) C(32)-C(30)-C(31) C(30)-C(31)-H(31A) C(30)-C(31)-H(31B) C(30)-C(31)-H(31C) H(31A)-C(31)-H(31B) H(31A)-C(31)-H(31C) H(31B)-C(31)-H(31C) C(30)-C(32)-H(32A) C(30)-C(32)-H(32B) C(30)-C(32)-H(32C) H(32A)-C(32)-H(32B) 109.5 109.5 109.5 109.5 109.5 109.5 107.6 112.36(12) 107.6 112.77(11) 107.6 108.78(14) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 107.0 111.98(12) 107.0 110.83(14) 112.62(12) 107.0 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 106.8 112.51(11) 106.8 114.51(11) 106.8 108.92(14) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 280   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 H(32A)-C(32)-H(32C) H(32B)-C(32)-H(32C) N(3)-C(33)-H(33A) N(3)-C(33)-H(33B) N(3)-C(33)-C(34) H(33A)-C(33)-H(33B) C(34)-C(33)-H(33A) C(34)-C(33)-H(33B) C(35)-C(34)-C(33) C(39)-C(34)-C(33) C(39)-C(34)-C(35) C(34)-C(35)-H(35) C(36)-C(35)-C(34) C(36)-C(35)-H(35) C(35)-C(36)-H(36) C(35)-C(36)-C(37) C(37)-C(36)-H(36) O(6)-C(37)-C(36) O(6)-C(37)-C(38) C(38)-C(37)-C(36) C(37)-C(38)-H(38) C(37)-C(38)-C(39) C(39)-C(38)-H(38) C(34)-C(39)-H(39) C(38)-C(39)-C(34) C(38)-C(39)-H(39) O(6)-C(40)-H(40A) O(6)-C(40)-H(40B) O(6)-C(40)-H(40C) H(40A)-C(40)-H(40B) H(40A)-C(40)-H(40C) H(40B)-C(40)-H(40C) 281   109.5 109.5 109.0 109.0 113.08(12) 107.8 109.0 109.0 120.88(14) 121.12(14) 117.99(14) 119.4 121.12(15) 119.4 120.1 119.81(15) 120.1 115.14(15) 124.72(15) 120.14(15) 120.3 119.46(15) 120.3 119.3 121.46(15) 119.3 109.5 109.5 109.5 109.5 109.5 109.5 __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Anisotropic displacement parameters (Å x 10 ) for 73. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2p [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ Si(1) 140(2) 116(2) 135(2) -12(2) -3(2) -6(2) O(1) 266(6) 110(6) 194(6) 21(4) 21(5) 56(5) O(2) 148(6) 238(6) 160(6) -47(5) -28(5) 6(5) O(3) 166(6) 153(6) 292(7) 27(5) 31(5) 30(5) O(4) 176(7) 275(7) 581(10) -33(7) 54(6) -87(6) O(5) 154(6) 93(5) 220(6) 19(4) 7(5) 9(4) O(6) 238(7) 285(7) 265(7) -39(5) -34(5) -83(6) N(1) 184(7) 74(6) 169(7) 7(5) 26(5) -15(5) N(2) 131(7) 104(6) 192(7) 9(5) 3(5) -40(5) N(3) 144(7) 68(6) 167(6) 14(5) 13(5) 5(5) C(1) 132(7) 96(7) 117(7) -3(6) 7(6) 0(6) C(2) 142(8) 120(8) 102(7) -10(6) -1(6) -8(6) C(3) 181(8) 120(8) 151(8) -15(6) 22(6) -9(6) C(4) 223(9) 149(8) 192(8) -26(6) 29(7) 46(7) C(5) 163(8) 221(9) 228(9) -17(7) 53(7) 30(7) Table A2.9.4. 282   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(6) 183(9) 184(9) 182(8) 0(6) 30(7) -44(7) C(7) 179(8) 117(8) 110(7) -9(6) -6(6) -6(6) C(8) 222(9) 92(7) 86(7) -9(6) 2(6) 8(6) C(9) 306(10) 103(8) 230(9) 16(7) 47(7) -59(7) C(10) 158(8) 136(8) 139(7) -9(6) 4(6) -4(6) C(11) 164(8) 206(9) 153(8) -24(6) -15(6) -19(7) C(12) 143(8) 75(7) 117(7) -6(5) 4(6) 4(6) C(13) 215(8) 87(7) 94(7) 5(6) 13(6) -23(6) C(14) 279(9) 122(8) 123(8) -3(6) 8(7) -14(7) C(15) 412(11) 106(8) 165(8) -31(6) 36(8) -64(8) C(16) 362(11) 167(9) 189(9) -36(7) 10(8) -149(8) C(17) 221(9) 201(9) 169(8) -19(7) 5(7) -78(7) C(18) 219(8) 115(8) 103(7) -1(6) 28(6) -44(6) C(19) 178(8) 90(7) 85(7) -16(5) 6(6) -11(6) C(20) 151(8) 137(8) 150(7) 9(6) 31(6) 37(6) C(21) 196(8) 84(7) 134(7) -6(6) 18(6) 25(6) C(22) 202(9) 208(9) 162(8) 10(7) -8(7) -47(7) C(23) 218(10) 308(11) 402(12) 41(9) 43(8) 87(8) C(24) 216(9) 186(9) 209(8) 36(7) -21(7) -49(7) C(25) 378(12) 160(9) 488(13) 99(9) -31(10) -54(8) C(26) 284(10) 310(10) 265(10) 55(8) 31(8) -112(8) C(27) 163(8) 170(9) 240(9) -27(7) 47(7) -15(7) C(28) 233(10) 234(10) 378(11) -146(8) 87(8) -49(8) C(29) 299(10) 205(10) 443(12) 72(8) 128(9) 89(8) C(30) 147(8) 146(8) 211(8) -31(6) 7(7) 2(6) C(31) 200(9) 309(11) 341(11) 33(8) 94(8) 23(8) C(32) 189(9) 215(9) 412(12) 4(8) -35(8) 35(7) C(33) 161(8) 92(7) 169(8) 30(6) 32(6) -11(6) C(34) 142(8) 91(7) 164(8) 29(6) 17(6) 0(6) C(35) 170(8) 152(8) 211(8) 2(7) 50(7) 20(7) C(36) 121(8) 237(9) 285(10) 19(7) 18(7) 16(7) C(37) 185(8) 140(8) 206(8) 27(7) -19(7) -44(7) C(38) 241(9) 117(8) 205(8) -13(6) 34(7) -7(7) C(39) 146(8) 119(8) 207(8) 33(6) 43(6) 27(6) C(40) 406(12) 303(11) 260(10) -76(8) -16(9) -120(9) ______________________________________________________________________________ 3 2 3 Table A2.9.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 73 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(2) H(3) H(4) H(5) H(6) H(9A) H(9B) H(9C) H(10A) H(10B) H(11A) H(11B) H(14) H(15) 159 202 109 48 78 135 137 190 338 311 273 286 256 187 63 196 249 51 -207 -470 -441 -523 -104 64 44 -138 -401 -577 42 116 132 145 144 111 154 137 125 122 177 179 50 29 17 18 22 24 22 32 32 32 17 17 21 21 21 27 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 283   H(16) 94 -494 11 29 H(17) 70 -236 18 24 H(20A) 382 -34 78 17 H(20B) 384 -65 35 17 H(21A) 330 -254 77 17 H(21B) 312 -240 34 17 H(23A) -3 250 33 46 H(23B) 31 382 57 46 H(23C) 12 228 76 46 H(24) 383 -51 285 25 H(25A) 367 -313 272 52 H(25B) 414 -246 246 52 H(25C) 349 -273 231 52 H(26A) 270 -96 251 43 H(26B) 287 27 282 43 H(26C) 290 -153 291 43 H(27) 289 217 231 23 H(28A) 384 351 274 42 H(28B) 337 240 289 42 H(28C) 318 406 274 42 H(29A) 311 451 206 47 H(29B) 331 319 180 47 H(29C) 377 408 206 47 H(30) 460 196 244 20 H(31A) 508 203 191 42 H(31B) 444 268 184 42 H(31C) 460 98 171 42 H(32A) 485 -106 220 41 H(32B) 484 -58 261 41 H(32C) 532 12 237 41 H(33A) 308 300 30 17 H(33B) 360 215 12 17 H(35) 456 211 44 21 H(36) 522 326 86 26 H(38) 391 539 132 22 H(39) 326 417 91 19 H(40A) 468 704 148 49 H(40B) 522 658 176 49 H(40C) 462 570 177 49 ________________________________________________________________________________ Table A2.9.6. Hydrogen bonds for 73 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ N(2)-H(2)...O(5) 0.88 1.79 2.6356(16) 161.8 C(17)-H(17)...O(4) 0.95 2.27 2.862(2) 119.8 C(21)-H(21A)...O(1) 0.99 2.41 3.1343(19) 129.8 ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.10. X-Ray Crystal Structure Analysis of 77 Br N O N CO2Me O N H 77 Figure A2.10.1. X-ray Crystal Structure of 77 Table A2.10.1. Crystal data and structure analysis details for 77 Empirical formula C46.40 H47.20 Br2 Cl0.80 N6 O8.20 Formula weight 1008.40 Crystallization solvent isopropanol/hexane  (dichloromethane) Crystal shape plate Crystal color colourless Crystal size 0.05 x 0.20 x 0.46 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK 284   285   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Data collection temperature 100 K Theta range for 9880 reflections used in lattice determination 2.32 to 33.69° Unit cell dimensions a = 17.6618(8) Å b = 17.4368(7) Å c = 13.5068(5) Å Volume 4129.7(3) Å3 Z 4 Crystal system monoclinic Space group P 1 21/c 1 (# 14) Density (calculated) 1.622 g/cm3 F(000) 2067 Theta range for data collection 2.1 to 37.6° Completeness to theta = 25.000° 99.9% Index ranges -29 ʺ″ h ʺ″ 30, -29 ʺ″ k ʺ″ 29, -23 ʺ″ l ʺ″ 22 Data collection scan type and  scans   Reflections  collected   213592   Independent  reflections   21060  [Rint=  0.0668]   Reflections  >  2⌠(I)   14742     Average  ⌠(I)/(net  I)   0.0422   Absorption  coefficient   2.08  mm-­‐1   Absorption  correction   Semi-­‐empirical  from  equivalents   Max.  and  min.  transmission   1.0000  and  0.8480     Structure Solution and Refinement Primary solution method dual Secondary solution method ? Hydrogen placement mixed Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 21060 / 3 / 592 Treatment of hydrogen atoms mixed Goodness-of-fit on F2 3.31 Final R indices [I>2⌠(I), 14742 reflections] R1 = 0.0585, wR2 = 0.0955 R indices (all data) R1 = 0.0953, wR2 = 0.0967 Type of weighting scheme used calc Weighting scheme used Max shift/error 0.002 Average shift/error 0.000 Extinction coefficient 0 Largest diff. peak and hole 3.94 and -2.05 e·Å-3 〈= 90° ®= 96.873(2)° © = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 286   Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.27B (Bruker-AXS, 2007) APEX2 2012.4-3 (Bruker-AXS, 2007) SAINT V8.27B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2012/6 (Sheldrick, 2012) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.10.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 77. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1A) 4275(1) 4155(1) 4546(1) 17(1) O(1A) 4849(1) 1093(1) 2821(1) 18(1) O(2A) 3534(1) 1156(1) 3905(1) 14(1) O(3A) 1677(1) 2261(1) 5024(1) 28(1) O(4A) 2118(1) 1113(1) 4589(1) 24(1) N(1A) 5279(1) 2188(1) 2142(1) 14(1) N(2A) 2640(1) 2178(1) 4034(1) 14(1) N(3A) 2591(1) 1331(1) 2600(1) 17(1) C(1A) 4767(1) 3863(1) 3418(1) 14(1) C(2A) 5155(1) 4451(1) 2990(1) 18(1) C(3A) 5568(1) 4292(1) 2204(1) 20(1) C(4A) 5638(1) 3544(1) 1865(1) 17(1) C(5A) 5246(1) 2978(1) 2315(1) 14(1) C(6A) 4769(1) 3120(1) 3055(1) 12(1) C(7A) 4390(1) 2370(1) 3293(1) 11(1) C(8A) 4859(1) 1789(1) 2758(1) 13(1) C(9A) 5816(1) 1822(1) 1554(1) 19(1) C(10A) 4427(1) 2208(1) 4414(1) 13(1) C(11A) 4123(1) 1422(1) 4643(1) 16(1) C(12A) 3085(1) 1712(1) 3373(1) 13(1) C(13A) 3527(1) 2321(1) 2811(1) 11(1) C(14A) 3397(1) 2045(1) 1702(1) 15(1) C(15A) 3031(1) 1255(1) 1744(1) 20(1) C(16A) 3091(1) 3045(1) 2962(1) 12(1) C(17A) 2609(1) 2950(1) 3695(1) 14(1) C(18A) 2158(1) 3551(1) 3966(1) 18(1) C(19A) 2193(1) 4244(1) 3462(1) 21(1) C(20A) 2647(1) 4337(1) 2706(1) 20(1) C(21A) 3102(1) 3731(1) 2452(1) 16(1) C(22A) 2101(1) 1885(1) 4585(1) 19(1) C(23A) 1594(2) 770(1) 5202(2) 34(1) Br(1B) 7671(1) 4207(1) 1850(1) 25(1) O(1B) 9584(1) 1388(1) 2258(1) 28(1) O(2B) 8160(1) 1198(1) 2987(1) 20(1) O(3B) 6232(1) 1864(1) 4406(1) 29(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 287   O(4B) 6979(1) 869(1) 4083(1) 23(1) N(1B) 10134(1) 2569(1) 2268(1) 19(1) N(2B) 7383(1) 2057(1) 3810(1) 18(1) N(3B) 8495(1) 1439(1) 4657(1) 22(1) C(1B) 8749(1) 4072(1) 2061(1) 21(1) C(2B) 9187(2) 4725(1) 1973(2) 29(1) C(3B) 9977(2) 4672(1) 2042(2) 32(1) C(4B) 10341(1) 3971(1) 2150(2) 25(1) C(5B) 9885(1) 3336(1) 2235(1) 20(1) C(6B) 9091(1) 3365(1) 2251(1) 17(1) C(7B) 8814(1) 2560(1) 2462(1) 16(1) C(8B) 9533(1) 2080(1) 2309(1) 19(1) C(9B) 10900(1) 2317(1) 2149(2) 29(1) C(10B) 8104(1) 2283(1) 1797(1) 18(1) C(11B) 7945(1) 1441(1) 1974(1) 21(1) C(12B) 8160(1) 1753(1) 3723(1) 16(1) C(13B) 8665(1) 2476(1) 3597(1) 16(1) C(14B) 9393(1) 2339(1) 4357(1) 20(1) C(15B) 9317(1) 1506(1) 4664(1) 22(1) C(16B) 8167(1) 3112(1) 3924(1) 17(1) C(17B) 7437(1) 2860(1) 4005(1) 17(1) C(18B) 6878(1) 3355(1) 4264(1) 22(1) C(19B) 7080(1) 4112(1) 4481(1) 24(1) C(20B) 7819(2) 4353(1) 4474(1) 27(1) C(21B) 8373(1) 3854(1) 4203(1) 22(1) C(22B) 6812(1) 1614(1) 4130(1) 20(1) C(23B) 6407(1) 360(1) 4393(2) 26(1) Cl(1) 10468(1) 4314(1) 5067(1) 59(1) C(1) 9892(3) 4837(3) 5573(4) 28(1) O(1) 9448(4) 4184(4) 5213(5) 16(2) ________________________________________________________________________________ Table A2.10.3. Bond lengths [Å] and angles [°] for 77 __________________________________________________________________________________ _ Br(1A)-C(1A) 1.9116(18) O(1A)-C(8A) 1.217(2) O(2A)-C(11A) 1.430(2) O(2A)-C(12A) 1.396(2) O(3A)-C(22A) 1.204(2) O(4A)-C(22A) 1.345(2) O(4A)-C(23A) 1.443(2) N(1A)-C(5A) 1.398(2) N(1A)-C(8A) 1.370(2) N(1A)-C(9A) 1.455(2) N(2A)-C(12A) 1.496(2) N(2A)-C(17A) 1.421(2) N(2A)-C(22A) 1.376(2) N(3A)-H(3AA) 0.9200 N(3A)-H(3AB) 0.9200 N(3A)-C(12A) 1.440(2) N(3A)-C(15A) 1.475(2) C(1A)-C(2A) 1.397(3) C(1A)-C(6A) 1.385(2) C(2A)-H(2A) 0.9500 C(2A)-C(3A) 1.386(3) C(3A)-H(3A) 0.9500 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(3A)-C(4A) C(4A)-H(4A) C(4A)-C(5A) C(5A)-C(6A) C(6A)-C(7A) C(7A)-C(8A) C(7A)-C(10A) C(7A)-C(13A) C(9A)-H(9AA) C(9A)-H(9AB) C(9A)-H(9AC) C(10A)-H(10A) C(10A)-H(10B) C(10A)-C(11A) C(11A)-H(11A) C(11A)-H(11B) C(12A)-C(13A) C(13A)-C(14A) C(13A)-C(16A) C(14A)-H(14A) C(14A)-H(14B) C(14A)-C(15A) C(15A)-H(15A) C(15A)-H(15B) C(16A)-C(17A) C(16A)-C(21A) C(17A)-C(18A) C(18A)-H(18A) C(18A)-C(19A) C(19A)-H(19A) C(19A)-C(20A) C(20A)-H(20A) C(20A)-C(21A) C(21A)-H(21A) C(23A)-H(23A) C(23A)-H(23B) C(23A)-H(23C) Br(1B)-C(1B) O(1B)-C(8B) O(2B)-C(11B) O(2B)-C(12B) O(3B)-C(22B) O(4B)-C(22B) O(4B)-C(23B) N(1B)-C(5B) N(1B)-C(8B) N(1B)-C(9B) N(2B)-C(12B) N(2B)-C(17B) N(2B)-C(22B) N(3B)-H(3BA) N(3B)-H(3BB) N(3B)-C(12B) N(3B)-C(15B) C(1B)-C(2B) C(1B)-C(6B) C(2B)-H(2B) C(2B)-C(3B) 1.392(3) 0.9500 1.387(2) 1.405(2) 1.520(2) 1.543(2) 1.534(2) 1.586(3) 0.9800 0.9800 0.9800 0.9900 0.9900 1.517(2) 0.9900 0.9900 1.567(2) 1.564(2) 1.504(2) 0.9900 0.9900 1.524(3) 0.9900 0.9900 1.392(3) 1.383(2) 1.391(3) 0.9500 1.392(3) 0.9500 1.381(3) 0.9500 1.394(3) 0.9500 0.9800 0.9800 0.9800 1.906(2) 1.212(2) 1.439(2) 1.387(2) 1.212(2) 1.336(2) 1.444(2) 1.407(2) 1.368(3) 1.449(3) 1.489(3) 1.426(2) 1.379(3) 0.9200 0.9200 1.436(2) 1.456(3) 1.389(3) 1.383(3) 0.9500 1.390(3) 288   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(3B)-H(3B) C(3B)-C(4B) C(4B)-H(4B) C(4B)-C(5B) C(5B)-C(6B) C(6B)-C(7B) C(7B)-C(8B) C(7B)-C(10B) C(7B)-C(13B) C(9B)-H(9BA) C(9B)-H(9BB) C(9B)-H(9BC) C(10B)-H(10C) C(10B)-H(10D) C(10B)-C(11B) C(11B)-H(11C) C(11B)-H(11D) C(12B)-C(13B) C(13B)-C(14B) C(13B)-C(16B) C(14B)-H(14C) C(14B)-H(14D) C(14B)-C(15B) C(15B)-H(15C) C(15B)-H(15D) C(16B)-C(17B) C(16B)-C(21B) C(17B)-C(18B) C(18B)-H(18B) C(18B)-C(19B) C(19B)-H(19B) C(19B)-C(20B) C(20B)-H(20B) C(20B)-C(21B) C(21B)-H(21B) C(23B)-H(23D) C(23B)-H(23E) C(23B)-H(23F) Cl(1)-C(1)#1 Cl(1)-C(1) C(1)-Cl(1)#1 C(1)-C(1)#1 C(1)-H(1A) C(1)-H(1B) O(1)-H(1C) O(1)-H(1D) C(12A)-O(2A)-C(11A) C(22A)-O(4A)-C(23A) C(5A)-N(1A)-C(9A) C(8A)-N(1A)-C(5A) C(8A)-N(1A)-C(9A) C(17A)-N(2A)-C(12A) C(22A)-N(2A)-C(12A) C(22A)-N(2A)-C(17A) H(3AA)-N(3A)-H(3AB) C(12A)-N(3A)-H(3AA) C(12A)-N(3A)-H(3AB) 0.9500 1.380(3) 0.9500 1.381(3) 1.407(3) 1.524(3) 1.556(3) 1.532(3) 1.592(3) 0.9800 0.9800 0.9800 0.9900 0.9900 1.519(3) 0.9900 0.9900 1.567(3) 1.565(3) 1.515(3) 0.9900 0.9900 1.521(3) 0.9900 0.9900 1.379(3) 1.384(3) 1.386(3) 0.9500 1.388(3) 0.9500 1.373(3) 0.9500 1.391(3) 0.9500 0.9800 0.9800 0.9800 1.794(6) 1.581(6) 1.794(6) 1.734(10) 0.9900 0.9900 0.848(10) 0.855(10) 116.99(13) 113.72(16) 124.50(16) 111.22(14) 122.96(15) 108.96(13) 124.67(15) 121.53(16) 108.7 110.5 110.5 289   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(12A)-N(3A)-C(15A) C(15A)-N(3A)-H(3AA) C(15A)-N(3A)-H(3AB) C(2A)-C(1A)-Br(1A) C(6A)-C(1A)-Br(1A) C(6A)-C(1A)-C(2A) C(1A)-C(2A)-H(2A) C(3A)-C(2A)-C(1A) C(3A)-C(2A)-H(2A) C(2A)-C(3A)-H(3A) C(2A)-C(3A)-C(4A) C(4A)-C(3A)-H(3A) C(3A)-C(4A)-H(4A) C(5A)-C(4A)-C(3A) C(5A)-C(4A)-H(4A) N(1A)-C(5A)-C(6A) C(4A)-C(5A)-N(1A) C(4A)-C(5A)-C(6A) C(1A)-C(6A)-C(5A) C(1A)-C(6A)-C(7A) C(5A)-C(6A)-C(7A) C(6A)-C(7A)-C(8A) C(6A)-C(7A)-C(10A) C(6A)-C(7A)-C(13A) C(8A)-C(7A)-C(13A) C(10A)-C(7A)-C(8A) C(10A)-C(7A)-C(13A) O(1A)-C(8A)-N(1A) O(1A)-C(8A)-C(7A) N(1A)-C(8A)-C(7A) N(1A)-C(9A)-H(9AA) N(1A)-C(9A)-H(9AB) N(1A)-C(9A)-H(9AC) H(9AA)-C(9A)-H(9AB) H(9AA)-C(9A)-H(9AC) H(9AB)-C(9A)-H(9AC) C(7A)-C(10A)-H(10A) C(7A)-C(10A)-H(10B) H(10A)-C(10A)-H(10B) C(11A)-C(10A)-C(7A) C(11A)-C(10A)-H(10A) C(11A)-C(10A)-H(10B) O(2A)-C(11A)-C(10A) O(2A)-C(11A)-H(11A) O(2A)-C(11A)-H(11B) C(10A)-C(11A)-H(11A) C(10A)-C(11A)-H(11B) H(11A)-C(11A)-H(11B) O(2A)-C(12A)-N(2A) O(2A)-C(12A)-N(3A) O(2A)-C(12A)-C(13A) N(2A)-C(12A)-C(13A) N(3A)-C(12A)-N(2A) N(3A)-C(12A)-C(13A) C(12A)-C(13A)-C(7A) C(14A)-C(13A)-C(7A) C(14A)-C(13A)-C(12A) C(16A)-C(13A)-C(7A) 106.25(15) 110.5 110.5 115.20(13) 123.47(13) 121.29(17) 120.1 119.89(17) 120.1 119.5 120.96(17) 119.5 121.5 117.09(17) 121.5 109.47(15) 126.49(17) 123.99(16) 116.32(16) 135.22(16) 108.41(14) 101.00(14) 113.54(14) 112.66(14) 108.40(14) 112.28(14) 108.74(14) 124.26(16) 127.54(16) 108.13(14) 109.5 109.5 109.5 109.5 109.5 109.5 109.0 109.0 107.8 113.14(14) 109.0 109.0 113.43(14) 108.9 108.9 108.9 108.9 107.7 112.12(14) 108.01(14) 115.79(15) 104.45(13) 111.50(16) 104.77(14) 110.33(14) 115.73(14) 103.34(13) 112.41(14) 290   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(16A)-C(13A)-C(12A) C(16A)-C(13A)-C(14A) C(13A)-C(14A)-H(14A) C(13A)-C(14A)-H(14B) H(14A)-C(14A)-H(14B) C(15A)-C(14A)-C(13A) C(15A)-C(14A)-H(14A) C(15A)-C(14A)-H(14B) N(3A)-C(15A)-C(14A) N(3A)-C(15A)-H(15A) N(3A)-C(15A)-H(15B) C(14A)-C(15A)-H(15A) C(14A)-C(15A)-H(15B) H(15A)-C(15A)-H(15B) C(17A)-C(16A)-C(13A) C(21A)-C(16A)-C(13A) C(21A)-C(16A)-C(17A) C(16A)-C(17A)-N(2A) C(18A)-C(17A)-N(2A) C(18A)-C(17A)-C(16A) C(17A)-C(18A)-H(18A) C(17A)-C(18A)-C(19A) C(19A)-C(18A)-H(18A) C(18A)-C(19A)-H(19A) C(20A)-C(19A)-C(18A) C(20A)-C(19A)-H(19A) C(19A)-C(20A)-H(20A) C(19A)-C(20A)-C(21A) C(21A)-C(20A)-H(20A) C(16A)-C(21A)-C(20A) C(16A)-C(21A)-H(21A) C(20A)-C(21A)-H(21A) O(3A)-C(22A)-O(4A) O(3A)-C(22A)-N(2A) O(4A)-C(22A)-N(2A) O(4A)-C(23A)-H(23A) O(4A)-C(23A)-H(23B) O(4A)-C(23A)-H(23C) H(23A)-C(23A)-H(23B) H(23A)-C(23A)-H(23C) H(23B)-C(23A)-H(23C) C(12B)-O(2B)-C(11B) C(22B)-O(4B)-C(23B) C(5B)-N(1B)-C(9B) C(8B)-N(1B)-C(5B) C(8B)-N(1B)-C(9B) C(17B)-N(2B)-C(12B) C(22B)-N(2B)-C(12B) C(22B)-N(2B)-C(17B) H(3BA)-N(3B)-H(3BB) C(12B)-N(3B)-H(3BA) C(12B)-N(3B)-H(3BB) C(12B)-N(3B)-C(15B) C(15B)-N(3B)-H(3BA) C(15B)-N(3B)-H(3BB) C(2B)-C(1B)-Br(1B) C(6B)-C(1B)-Br(1B) C(6B)-C(1B)-C(2B) 102.11(14) 111.64(14) 110.8 110.8 108.8 104.90(14) 110.8 110.8 102.31(14) 111.3 111.3 111.3 111.3 109.2 111.31(15) 128.41(16) 120.22(17) 109.75(15) 129.11(17) 121.06(17) 121.1 117.73(18) 121.1 119.1 121.80(18) 119.1 120.1 119.74(18) 120.1 119.37(18) 120.3 120.3 123.93(18) 125.17(18) 110.89(17) 109.5 109.5 109.5 109.5 109.5 109.5 116.97(14) 114.79(16) 125.24(17) 110.68(17) 123.67(17) 108.85(16) 122.68(15) 121.78(16) 108.6 110.5 110.5 106.38(15) 110.5 110.5 116.23(17) 122.96(16) 120.8(2) 291   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(1B)-C(2B)-H(2B) C(1B)-C(2B)-C(3B) C(3B)-C(2B)-H(2B) C(2B)-C(3B)-H(3B) C(4B)-C(3B)-C(2B) C(4B)-C(3B)-H(3B) C(3B)-C(4B)-H(4B) C(3B)-C(4B)-C(5B) C(5B)-C(4B)-H(4B) C(4B)-C(5B)-N(1B) C(4B)-C(5B)-C(6B) C(6B)-C(5B)-N(1B) C(1B)-C(6B)-C(5B) C(1B)-C(6B)-C(7B) C(5B)-C(6B)-C(7B) C(6B)-C(7B)-C(8B) C(6B)-C(7B)-C(10B) C(6B)-C(7B)-C(13B) C(8B)-C(7B)-C(13B) C(10B)-C(7B)-C(8B) C(10B)-C(7B)-C(13B) O(1B)-C(8B)-N(1B) O(1B)-C(8B)-C(7B) N(1B)-C(8B)-C(7B) N(1B)-C(9B)-H(9BA) N(1B)-C(9B)-H(9BB) N(1B)-C(9B)-H(9BC) H(9BA)-C(9B)-H(9BB) H(9BA)-C(9B)-H(9BC) H(9BB)-C(9B)-H(9BC) C(7B)-C(10B)-H(10C) C(7B)-C(10B)-H(10D) H(10C)-C(10B)-H(10D) C(11B)-C(10B)-C(7B) C(11B)-C(10B)-H(10C) C(11B)-C(10B)-H(10D) O(2B)-C(11B)-C(10B) O(2B)-C(11B)-H(11C) O(2B)-C(11B)-H(11D) C(10B)-C(11B)-H(11C) C(10B)-C(11B)-H(11D) H(11C)-C(11B)-H(11D) O(2B)-C(12B)-N(2B) O(2B)-C(12B)-N(3B) O(2B)-C(12B)-C(13B) N(2B)-C(12B)-C(13B) N(3B)-C(12B)-N(2B) N(3B)-C(12B)-C(13B) C(12B)-C(13B)-C(7B) C(14B)-C(13B)-C(7B) C(14B)-C(13B)-C(12B) C(16B)-C(13B)-C(7B) C(16B)-C(13B)-C(12B) C(16B)-C(13B)-C(14B) C(13B)-C(14B)-H(14C) C(13B)-C(14B)-H(14D) H(14C)-C(14B)-H(14D) C(15B)-C(14B)-C(13B) 119.9 120.3(2) 119.9 119.5 121.1(2) 119.5 121.6 116.8(2) 121.6 125.6(2) 124.3(2) 110.01(17) 116.31(18) 135.46(19) 108.21(16) 100.70(15) 116.13(16) 110.98(15) 108.03(15) 112.10(15) 108.51(16) 123.69(19) 127.66(19) 108.63(16) 109.5 109.5 109.5 109.5 109.5 109.5 109.3 109.3 108.0 111.50(16) 109.3 109.3 113.68(15) 108.8 108.8 108.8 108.8 107.7 112.64(16) 109.16(15) 115.73(15) 105.33(14) 110.71(15) 102.81(16) 109.92(15) 115.40(16) 103.86(15) 112.48(15) 101.45(16) 112.39(15) 111.1 111.1 109.0 103.47(16) 292   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(15B)-C(14B)-H(14C) C(15B)-C(14B)-H(14D) N(3B)-C(15B)-C(14B) N(3B)-C(15B)-H(15C) N(3B)-C(15B)-H(15D) C(14B)-C(15B)-H(15C) C(14B)-C(15B)-H(15D) H(15C)-C(15B)-H(15D) C(17B)-C(16B)-C(13B) C(17B)-C(16B)-C(21B) C(21B)-C(16B)-C(13B) C(16B)-C(17B)-N(2B) C(16B)-C(17B)-C(18B) C(18B)-C(17B)-N(2B) C(17B)-C(18B)-H(18B) C(17B)-C(18B)-C(19B) C(19B)-C(18B)-H(18B) C(18B)-C(19B)-H(19B) C(20B)-C(19B)-C(18B) C(20B)-C(19B)-H(19B) C(19B)-C(20B)-H(20B) C(19B)-C(20B)-C(21B) C(21B)-C(20B)-H(20B) C(16B)-C(21B)-C(20B) C(16B)-C(21B)-H(21B) C(20B)-C(21B)-H(21B) O(3B)-C(22B)-O(4B) O(3B)-C(22B)-N(2B) O(4B)-C(22B)-N(2B) O(4B)-C(23B)-H(23D) O(4B)-C(23B)-H(23E) O(4B)-C(23B)-H(23F) H(23D)-C(23B)-H(23E) H(23D)-C(23B)-H(23F) H(23E)-C(23B)-H(23F) C(1)-Cl(1)-C(1)#1 Cl(1)-C(1)-Cl(1)#1 Cl(1)-C(1)-C(1)#1 Cl(1)#1-C(1)-H(1A) Cl(1)-C(1)-H(1A) Cl(1)#1-C(1)-H(1B) Cl(1)-C(1)-H(1B) C(1)#1-C(1)-Cl(1)#1 C(1)#1-C(1)-H(1A) C(1)#1-C(1)-H(1B) H(1A)-C(1)-H(1B) H(1C)-O(1)-H(1D) 293   111.1 111.1 101.24(16) 111.5 111.5 111.5 111.5 109.3 111.82(16) 119.68(18) 128.31(19) 109.92(17) 121.42(18) 128.6(2) 120.9 118.2(2) 120.9 119.7 120.7(2) 119.7 119.7 120.6(2) 119.7 119.0(2) 120.5 120.5 124.24(19) 124.87(18) 110.89(17) 109.5 109.5 109.5 109.5 109.5 109.5 61.5(3) 118.5(3) 65.3(3) 92.2 117.2 92.2 117.2 53.2(3) 117.2 117.2 114.2 100(2) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: #1 +2 2 4 Table A2.10.4. Anisotropic displacement parameters (Å x 10 ) for 77. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2π [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 ______________________________________________________________________________ Br(1A) 221(1) 127(1) 183(1) -63(1) 55(1) -12(1) O(1A) 226(8) 99(6) 216(7) -16(5) 81(6) 8(5) O(2A) 139(7) 115(6) 164(6) 11(5) 19(5) -6(5) O(3A) 290(10) 282(8) 321(8) -16(7) 201(7) 27(7) O(4A) 256(9) 212(7) 285(8) 29(6) 150(7) -49(6) N(1A) 159(9) 123(7) 149(7) -7(6) 77(6) 14(6) N(2A) 144(9) 142(7) 154(7) -18(6) 62(6) 2(6) N(3A) 158(9) 142(7) 200(8) -24(6) 14(7) -6(6) C(1A) 142(10) 127(8) 156(9) 4(7) 41(7) 3(7) C(2A) 203(11) 111(8) 217(10) 13(7) 19(8) -21(7) C(3A) 203(11) 161(9) 228(10) 62(7) 36(8) -51(8) C(4A) 171(11) 184(9) 168(9) 36(7) 51(8) -15(8) C(5A) 139(10) 128(8) 145(8) 6(7) 19(7) -5(7) C(6A) 128(10) 105(7) 117(8) 8(6) 28(7) 2(7) C(7A) 130(9) 72(7) 121(8) -10(6) 38(7) -4(6) C(8A) 133(10) 128(8) 123(8) -12(6) 24(7) 2(7) C(9A) 182(11) 221(9) 193(9) -12(8) 97(8) 53(8) C(10A) 157(10) 124(8) 108(8) 1(6) 43(7) -5(7) C(11A) 175(11) 157(8) 138(8) 24(7) 28(7) -15(7) C(12A) 134(10) 115(8) 133(8) -11(6) 34(7) -10(7) C(13A) 148(10) 93(7) 95(8) -7(6) 29(7) 4(7) C(14A) 183(11) 154(8) 111(8) -14(7) 21(7) 2(7) C(15A) 242(12) 181(9) 163(9) -55(7) 21(8) -19(8) C(16A) 133(10) 112(8) 115(8) -30(6) 4(7) 4(7) C(17A) 122(10) 152(8) 145(8) -37(7) -6(7) 2(7) C(18A) 139(10) 209(9) 200(9) -67(8) 29(8) 22(8) C(19A) 212(11) 161(9) 252(10) -74(8) -15(8) 65(8) C(20A) 245(12) 132(9) 218(10) -1(7) -30(8) 31(8) C(21A) 192(11) 156(8) 136(9) -8(7) 5(7) 16(7) C(22A) 184(11) 236(10) 159(9) -2(8) 20(8) -43(8) C(23A) 339(15) 331(12) 380(13) 62(11) 178(11) -93(11) Br(1B) 308(1) 227(1) 224(1) 10(1) 22(1) 96(1) O(1B) 288(10) 184(7) 394(9) 21(6) 144(7) 48(6) O(2B) 263(9) 140(6) 210(7) -28(5) 91(6) 7(6) O(3B) 227(9) 276(8) 397(9) -11(7) 150(7) 15(7) O(4B) 265(9) 159(6) 294(8) 25(6) 131(6) -22(6) N(1B) 177(10) 212(8) 205(8) 5(7) 71(7) 0(7) N(2B) 208(10) 138(7) 212(8) 9(6) 101(7) 7(7) N(3B) 275(11) 186(8) 198(8) 31(7) 82(7) 36(7) C(1B) 251(12) 227(10) 161(9) -3(8) 43(8) 4(9) C(2B) 490(17) 152(9) 240(11) 7(8) 77(10) -23(10) C(3B) 484(17) 207(10) 272(12) -32(9) 97(11) -143(10) C(4B) 272(13) 276(11) 204(10) -27(8) 56(9) -99(9) C(5B) 255(12) 200(9) 141(9) 5(7) 53(8) -31(8) C(6B) 201(11) 162(9) 144(9) 5(7) 36(8) -17(8) C(7B) 174(11) 140(8) 179(9) 0(7) 56(8) 6(7) C(8B) 201(12) 211(10) 174(9) 19(8) 62(8) 7(8) C(9B) 167(12) 343(12) 381(13) 2(10) 67(10) -1(10) C(10B) 209(12) 199(9) 137(9) 7(7) 51(8) 2(8) C(11B) 239(12) 188(9) 199(10) -38(8) 21(8) -20(8) C(12B) 180(11) 136(8) 181(9) 3(7) 51(8) 11(7) C(13B) 181(11) 139(8) 179(9) 0(7) 40(8) -6(7) C(14B) 193(12) 226(10) 192(10) -22(8) 29(8) -2(8) C(15B) 241(12) 227(10) 178(10) 31(8) 17(8) 70(9) C(16B) 208(11) 161(9) 150(9) 4(7) 26(8) 22(8) C(17B) 262(12) 146(8) 111(8) 13(7) 35(8) 46(8) C(18B) 279(13) 227(10) 166(9) 1(8) 78(9) 72(9) 294   295   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(19B) 342(14) 211(10) 178(9) -17(8) 36(9) 85(9) C(20B) 470(16) 174(9) 162(10) -35(8) 25(10) 54(9) C(21B) 305(14) 189(9) 178(10) -7(8) 42(9) 3(9) C(22B) 228(12) 216(10) 176(9) 2(8) 63(8) -3(8) C(23B) 267(13) 225(10) 294(11) 39(9) 105(9) -90(9) Cl(1) 275(5) 605(6) 881(8) 237(5) 39(5) -52(4) C(1) 240(30) 410(30) 190(20) -110(20) 40(20) -110(30) ______________________________________________________________________________ 3 2 Table A2.10.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 3 10 ) for 77 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(3AA) H(3AB) H(2A) H(3A) H(4A) H(9AA) H(9AB) H(9AC) H(10A) H(10B) H(11A) H(11B) H(14A) H(14B) H(15A) H(15B) H(18A) H(19A) H(20A) H(21A) H(23A) H(23B) H(23C) H(3BA) H(3BB) H(2B) H(3B) H(4B) H(9BA) H(9BB) H(9BC) H(10C) H(10D) H(11C) H(11D) H(14C) H(14D) H(15C) H(15D) H(18B) H(19B) H(20B) 216 245 514 581 594 632 565 583 496 413 455 392 306 389 269 342 184 190 265 342 170 166 107 836 834 895 1027 1088 1094 1127 1101 766 818 739 823 986 940 951 959 637 670 795 162 86 496 470 343 204 191 127 225 260 105 144 240 201 114 85 349 466 481 379 97 21 89 93 171 521 513 393 176 258 244 259 236 134 113 242 269 115 141 318 447 487 243 281 324 189 135 173 84 169 472 472 470 530 129 142 112 186 448 364 236 193 588 521 493 471 518 186 202 216 225 264 147 194 109 179 153 404 494 418 534 429 464 466 20 20 21 24 21 29 29 29 15 15 19 19 18 18 23 23 22 25 24 19 51 51 51 26 26 35 38 30 44 44 44 22 22 25 25 24 24 26 26 26 29 32 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 296   H(21B) 889 402 421 27 H(23D) 627 53 504 38 H(23E) 661 -16 446 38 H(23F) 596 37 390 38 H(1A) 1010 513 617 33 H(1B) 937 463 560 33 H(1C) 993(1) 423(6) 536(7) 24 H(1D) 929(5) 441(5) 572(5) 24 ________________________________________________________________________________ Table A2.10.6. Hydrogen bonds for 77 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ N(3A)-H(3AB)...Br(1B)#2 0.92 2.92 3.8165(15) 164.2 N(3B)-H(3BB)...Br(1B)#3 0.92 3.11 3.6325(16) 118.2 C(9B)-H(9BC)...O(3A)#4 0.98 2.46 3.406(3) 163.4 C(15B)-H(15C)...O(1B) 0.99 2.65 3.346(2) 127.8 C(23B)-H(23F)...O(1A) 0.98 2.62 3.510(3) 151.5 ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 +2 #2 +1 #3 #4 +1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.11. X-Ray Crystal Structure Analysis of 94 Ts H N N N H Ts 94 Figure A2.11.1. X-ray Crystal Structure of 94 Table A2.11.1. Crystal data and structure refinement for 94 Empirical formula C37 H39 N3 O4 S2 Formula weight 653.83 Crystallization Solvent ???Solvent??? Crystal Habit Fragment Crystal size 0.25 x 0.24 x 0.17 mm3 Crystal color Colorless Data Collection Preliminary Photos Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoK〈 Data Collection Temperature 100(2) K 297   298   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 ⎝ range for 8943 reflections used in lattice determination 2.22 to 27.43° Unit cell dimensions a = 15.5078(13) Å b = 11.2221(10) Å c = 18.4268(16) Å Volume 3195.9(5) Å3 Z 4 Crystal system Monoclinic Space group P2(1)/n Density (calculated) 1.359 Mg/m3 F(000) 1384 Data collection program Bruker SMART v5.630 ⎝ range for data collection 1.65 to 28.34° Completeness to ⎝ = 28.34° 94.1 % Index ranges -20<=h<=20, -14<=k<=14, -24<=l<=24 Data collection scan type scans at 5 settings   Data  reduction  program     Bruker  SAINT  v6.45A   Reflections  collected   44083   Independent  reflections   7500  [Rint=  0.1020]   Absorption  coefficient   0.213  mm-­‐1   Absorption  correction   None   Max.  and  min.  transmission   0.9647  and  0.9487   Number  of  standards     ?  reflections  measured  every  ?min.     Variation  of  standards     ?%.     Structure solution and Refinement Structure solution program SHELXS-97 (Sheldrick, 1990) Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program SHELXL-97 (Sheldrick, 1997) Refinement method Full matrix least-squares on F2 Data / restraints / parameters 7500 / 0 / 420 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.394 Final R indices [I>2⌠(I), 4434 reflections] R1 = 0.0531, wR2 = 0.0888 R indices (all data) R1 = 0.0982, wR2 = 0.0932 Type of weighting scheme used Sigma Weighting scheme used w=1/s^2^(Fo^2^) Max shift/error 0.001 〈= 90° ®= 94.7250(10)° © = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Average shift/error 0.000 Absolute structure determination ? Largest diff. peak and hole 0.629 and -0.498 e.Å-3 299   Special Refinement Details Table A2.11.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 94. U(eq) is defined as the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ S(1) 7430(1) 6065(1) 847(1) 26(1) S(2) 7110(1) 2404(1) -2197(1) 26(1) O(1) 7087(1) 5440(1) 1441(1) 30(1) O(2) 6897(1) 6283(1) 191(1) 31(1) O(3) 7723(1) 2951(1) -2627(1) 31(1) O(4) 6624(1) 1390(1) -2471(1) 30(1) N(1) 8248(1) 5286(2) 622(1) 21(1) N(2) 7649(1) 1964(2) -1428(1) 20(1) N(3) 9053(1) 1794(2) -836(1) 25(1) C(1) 7803(1) 7460(2) 1173(1) 24(1) C(2) 7883(2) 8387(2) 687(1) 29(1) C(3) 8173(2) 9490(2) 943(1) 33(1) C(4) 8386(2) 9698(2) 1672(1) 31(1) C(5) 8312(2) 8744(2) 2161(1) 29(1) C(6) 8016(1) 7645(2) 1910(1) 27(1) C(7) 8701(2) 10883(2) 1936(2) 46(1) C(8) 8655(1) 5616(2) -41(1) 24(1) C(9) 8357(2) 4792(2) -673(1) 22(1) C(10) 8247(1) 3487(2) -452(1) 20(1) C(11) 8970(1) 3097(2) 114(1) 18(1) C(12) 9226(1) 3566(2) 796(1) 21(1) C(13) 8757(1) 4558(2) 1172(1) 22(1) C(14) 9352(1) 5326(2) 1652(1) 25(1) C(15) 9436(2) 5322(2) 2377(1) 28(1) C(16) 10029(2) 6186(2) 2792(1) 40(1) C(17) 8968(2) 4500(2) 2843(1) 39(1) C(18) 9956(1) 3058(2) 1182(1) 24(1) C(19) 10392(1) 2119(2) 898(1) 23(1) C(20) 10133(1) 1653(2) 218(1) 22(1) C(21) 9429(1) 2138(2) -162(1) 17(1) C(22) 8404(1) 2657(2) -1116(1) 22(1) C(23) 7170(1) 1365(2) -902(1) 22(1) C(24) 6883(2) 213(2) -1018(1) 27(1) C(25) 6385(2) -308(2) -509(1) 35(1) C(26) 6207(2) 313(2) 108(1) 33(1) C(27) 6542(2) 1444(2) 235(1) 26(1) C(28) 7023(1) 1991(2) -273(1) 20(1) C(29) 7332(1) 3253(2) -188(1) 21(1) C(30) 9532(2) 1163(2) -1354(1) 31(1) C(31) 6376(2) 3476(2) -1938(1) 23(1) C(32) 6582(2) 4681(2) -1968(1) 27(1) C(33) 6067(2) 5512(2) -1643(1) 27(1) C(34) 5362(2) 5159(2) -1284(1) 29(1) C(35) 5149(2) 3940(2) -1281(1) 30(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 300   C(36) 5649(2) 3115(2) -1606(1) 29(1) C(37) 4847(2) 6041(2) -885(1) 37(1) ________________________________________________________________________________ Table A2.11.3. Bond lengths [Å] and angles [°] for 94 _____________________________________________________ S(1)-O(2) 1.4297(15) S(1)-O(1) 1.4381(16) S(1)-N(1) 1.6227(18) S(1)-C(1) 1.757(2) S(2)-O(3) 1.4257(16) S(2)-O(4) 1.4330(16) S(2)-N(2) 1.6596(18) S(2)-C(31) 1.750(2) N(1)-C(8) 1.468(3) N(1)-C(13) 1.479(3) N(2)-C(23) 1.437(3) N(2)-C(22) 1.482(3) N(3)-C(21) 1.383(3) N(3)-C(30) 1.443(3) N(3)-C(22) 1.460(3) C(1)-C(2) 1.385(3) C(1)-C(6) 1.387(3) C(2)-C(3) 1.387(3) C(3)-C(4) 1.376(3) C(4)-C(5) 1.409(3) C(4)-C(7) 1.485(3) C(5)-C(6) 1.382(3) C(8)-C(9) 1.527(3) C(9)-C(10) 1.533(3) C(10)-C(11) 1.531(3) C(10)-C(29) 1.559(3) C(10)-C(22) 1.573(3) C(11)-C(12) 1.391(3) C(11)-C(21) 1.407(3) C(12)-C(18) 1.406(3) C(12)-C(13) 1.527(3) C(13)-C(14) 1.497(3) C(14)-C(15) 1.331(3) C(15)-C(17) 1.490(3) C(15)-C(16) 1.501(3) C(18)-C(19) 1.379(3) C(19)-C(20) 1.386(3) C(20)-C(21) 1.362(3) C(23)-C(24) 1.378(3) C(23)-C(28) 1.390(3) C(24)-C(25) 1.391(3) C(25)-C(26) 1.380(3) C(26)-C(27) 1.384(3) C(27)-C(28) 1.387(3) C(28)-C(29) 1.498(3) C(31)-C(36) 1.386(3) C(31)-C(32) 1.391(3) C(32)-C(33) 1.395(3) C(33)-C(34) 1.381(3) C(34)-C(35) 1.408(3) C(34)-C(37) 1.501(3) C(35)-C(36) 1.375(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(2)-S(1)-O(1) O(2)-S(1)-N(1) O(1)-S(1)-N(1) O(2)-S(1)-C(1) O(1)-S(1)-C(1) N(1)-S(1)-C(1) O(3)-S(2)-O(4) O(3)-S(2)-N(2) O(4)-S(2)-N(2) O(3)-S(2)-C(31) O(4)-S(2)-C(31) N(2)-S(2)-C(31) C(8)-N(1)-C(13) C(8)-N(1)-S(1) C(13)-N(1)-S(1) C(23)-N(2)-C(22) C(23)-N(2)-S(2) C(22)-N(2)-S(2) C(21)-N(3)-C(30) C(21)-N(3)-C(22) C(30)-N(3)-C(22) C(2)-C(1)-C(6) C(2)-C(1)-S(1) C(6)-C(1)-S(1) C(1)-C(2)-C(3) C(4)-C(3)-C(2) C(3)-C(4)-C(5) C(3)-C(4)-C(7) C(5)-C(4)-C(7) C(6)-C(5)-C(4) C(5)-C(6)-C(1) N(1)-C(8)-C(9) C(8)-C(9)-C(10) C(11)-C(10)-C(9) C(11)-C(10)-C(29) C(9)-C(10)-C(29) C(11)-C(10)-C(22) C(9)-C(10)-C(22) C(29)-C(10)-C(22) C(12)-C(11)-C(21) C(12)-C(11)-C(10) C(21)-C(11)-C(10) C(11)-C(12)-C(18) C(11)-C(12)-C(13) C(18)-C(12)-C(13) N(1)-C(13)-C(14) N(1)-C(13)-C(12) C(14)-C(13)-C(12) C(15)-C(14)-C(13) C(14)-C(15)-C(17) C(14)-C(15)-C(16) C(17)-C(15)-C(16) C(19)-C(18)-C(12) C(18)-C(19)-C(20) C(21)-C(20)-C(19) C(20)-C(21)-N(3) C(20)-C(21)-C(11) 120.13(10) 106.61(9) 106.12(9) 106.75(10) 107.87(10) 109.02(10) 120.13(10) 106.90(10) 106.10(9) 109.52(11) 107.86(11) 105.34(10) 117.95(18) 118.38(15) 120.44(15) 114.75(17) 117.62(15) 120.12(15) 121.98(19) 111.09(17) 117.99(18) 119.6(2) 119.49(18) 120.90(18) 119.6(2) 121.9(2) 118.0(2) 121.2(2) 120.8(2) 120.5(2) 120.4(2) 110.94(18) 114.14(18) 111.28(17) 112.00(18) 111.58(18) 102.01(17) 109.37(18) 110.18(17) 120.0(2) 130.2(2) 109.72(18) 117.4(2) 125.12(19) 117.4(2) 110.77(18) 109.80(17) 113.23(18) 126.6(2) 124.6(2) 120.9(2) 114.5(2) 121.2(2) 121.1(2) 118.3(2) 127.6(2) 121.9(2) 301   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 N(3)-C(21)-C(11) 110.44(19) N(3)-C(22)-N(2) 106.80(17) N(3)-C(22)-C(10) 105.32(17) N(2)-C(22)-C(10) 116.47(18) C(24)-C(23)-C(28) 122.0(2) C(24)-C(23)-N(2) 120.8(2) C(28)-C(23)-N(2) 117.1(2) C(23)-C(24)-C(25) 118.7(2) C(26)-C(25)-C(24) 120.2(2) C(25)-C(26)-C(27) 120.3(2) C(26)-C(27)-C(28) 120.4(2) C(27)-C(28)-C(23) 118.2(2) C(27)-C(28)-C(29) 122.2(2) C(23)-C(28)-C(29) 119.5(2) C(28)-C(29)-C(10) 114.72(18) C(36)-C(31)-C(32) 120.0(2) C(36)-C(31)-S(2) 119.38(19) C(32)-C(31)-S(2) 120.01(18) C(31)-C(32)-C(33) 119.4(2) C(34)-C(33)-C(32) 121.2(2) C(33)-C(34)-C(35) 118.4(2) C(33)-C(34)-C(37) 121.3(2) C(35)-C(34)-C(37) 120.3(2) C(36)-C(35)-C(34) 120.8(2) C(35)-C(36)-C(31) 120.2(2) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.11.4. Anisotropic displacement parameters (Å2x 104 ) for 94. The anisotropic displacement factor exponent takes the form: -2ð2 [ h2 a*2U 11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ S(1) 189(3) 284(4) 294(4) -20(3) 14(3) 21(3) S(2) 246(3) 321(4) 197(3) 2(3) -38(3) 18(3) O(1) 246(10) 297(10) 350(10) -9(8) 77(8) -2(8) O(2) 229(10) 365(11) 334(10) -4(8) -69(8) 60(8) O(3) 337(11) 387(11) 202(9) 68(8) 65(8) 12(8) O(4) 281(10) 335(10) 266(10) -58(8) -110(8) -5(8) N(1) 193(11) 241(11) 202(11) -2(9) 2(9) 7(9) N(2) 195(11) 252(11) 158(10) 20(8) -18(8) -7(9) N(3) 203(11) 288(12) 255(12) -58(9) -4(9) 60(9) C(1) 175(13) 266(14) 284(14) 12(12) 26(11) 57(11) C(2) 272(15) 297(15) 290(15) -13(12) 22(12) 94(12) C(3) 293(15) 290(16) 409(17) 75(13) 106(13) 77(13) C(4) 218(14) 308(15) 429(17) -103(13) 133(12) -2(12) C(5) 299(15) 327(16) 252(14) -62(12) 57(12) 6(12) C(6) 253(14) 272(15) 285(14) 31(12) 75(11) 67(12) C(7) 497(19) 324(17) 580(20) -79(14) 231(16) -43(14) C(8) 179(13) 249(14) 281(14) 19(11) 8(11) 3(11) C(9) 186(13) 272(14) 211(13) 14(11) -2(10) 3(11) C(10) 177(13) 242(14) 187(13) -22(10) -11(10) -10(11) C(11) 128(12) 221(13) 198(13) 13(10) 4(10) -22(10) C(12) 170(13) 222(13) 224(13) 47(11) 22(10) -17(11) C(13) 214(13) 235(13) 194(13) 6(11) 1(10) 10(11) C(14) 187(13) 269(14) 294(15) -11(12) 14(11) 18(11) C(15) 207(14) 332(15) 300(15) -54(12) -47(12) 101(12) 302   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(16) 389(17) 484(18) 316(15) -121(14) -89(13) 67(14) C(17) 384(17) 587(19) 206(14) -17(13) 4(12) 30(15) C(18) 224(14) 250(14) 223(13) 18(11) -25(11) -24(11) C(19) 197(13) 253(14) 243(14) 30(11) -17(11) 28(11) C(20) 204(13) 175(13) 280(14) -29(11) 41(11) -15(11) C(21) 152(12) 187(13) 181(12) -39(10) 8(10) -62(10) C(22) 182(13) 276(14) 214(13) -28(11) 8(10) -33(11) C(23) 146(13) 270(14) 228(14) 45(11) -52(10) -26(11) C(24) 264(14) 283(15) 250(14) -21(12) -77(11) -23(12) C(25) 365(16) 307(15) 340(16) 57(13) -107(13) -127(13) C(26) 277(15) 454(17) 268(15) 84(13) -10(12) -111(13) C(27) 217(14) 366(16) 204(13) 34(12) -9(11) 16(12) C(28) 128(12) 245(14) 216(13) 33(11) -66(10) -4(10) C(29) 163(13) 255(14) 220(13) -6(11) 0(10) 21(11) C(30) 312(15) 320(15) 287(15) -39(12) 5(12) 88(12) C(31) 189(13) 308(15) 185(13) 30(11) -42(10) 26(11) C(32) 269(15) 350(16) 178(13) 75(12) -11(11) 1(13) C(33) 279(15) 293(15) 213(13) 90(11) -58(11) 28(12) C(34) 198(14) 354(16) 286(14) 25(12) -81(11) 83(12) C(35) 148(13) 412(17) 345(15) 48(13) 11(11) 14(13) C(36) 217(14) 303(15) 324(15) 21(12) -69(12) -12(12) C(37) 281(15) 370(16) 443(17) 52(13) 17(13) 61(13) ______________________________________________________________________________ 303   304   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F APPENDIX 3 Synthetic Studies Toward the Total Synthesis of Communesin F A3.1. Direct Lactam-Forming Strategy Having successfully completed our formal synthesis of communesin F (1f) and perophoramidine (3), our attention turned to a total synthesis of communesin F (1f). We envisioned that direct lactamization of malonate 101 would afford allyl ester 102, which could be a potential precursor toward the efficient synthesis of communesin F (1f) (Scheme A3.1.1). Since lactonization of diester 60 afforded lactone 61 as a single diastereomer (Scheme 1.2.13, 60 → 61), we believed that the diastereomer needed for elaboration to communesin F (1f) could be selectively formed by lactamization of malonate 101. Scheme A3.1.1. Direct Lactam-Forming Strategy Toward Communesin F (1f) O H N H 2N NO 2 CO2Allyl Br CO2Allyl O N 101 O Br CO2Allyl N H N O NO N 2 N 102 Communesin F (1f) N H H 305   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F To examine diastereoselective lactam formation, we chose phthalimide 103 as a model substrate. Interestingly, an attempt to remove the phthalyl protecting group and simultaneously construct lactam 104 from malonate 103 furnished a 9:1 diastereomeric mixture of 105 (Scheme A3.1.2a). The double bonds of the allyl groups were reduced and one of the resultant propyl esters was transferred to the amine. Treatment of phthalimide 103 with methylamine generated the desired amine 106 (Scheme A3.1.2b). Despite extensive screening of Lewis acids, acids, and bases (e.g., AlMe3, KOt-Bu, pTsOH), lactamization of malonate 106 proved to be challenging. Scheme A3.1.2. Attempted Lactam-Forming Reactions (a) Br H N PhthN NO 2 CO2Allyl CO2Allyl O O NH 2NH 2•H 2O CO2Allyl EtOH, H 2O, 80 oC O NO N Br 2 N 103 104 (Not Observed) O O NH 2NH 2•H 2O NH O O N O O2N EtOH, H 2O, 80 oC (92% yield) Br 105 (9:1 mixture of diastereomers) (b) Br Br H N PhthN NO 2 CO2Allyl CO2Allyl O MeNH 2 in EtOH H 2N (98% yield) NO 2 CO2Allyl Lewis acids CO2Allyl O or bases N N 103 106 O CO2Allyl O NO N 2 Br 104 (Not Observed) 306   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F A3.2. Diels–Alder Strategy Next, we investigated a Diels–Alder strategy toward the total synthesis of communesin F (1f). As described in Schemes A3.2.1a and 1.2.5, the benzisoxazole in 19 and 22 reacted with the butenyl side chain by an intramolecular Diels–Alder cycloaddtion to afford the undesired bridged polycycles 24 and 23, respectively. We expected that the desired core structure could be constructed via an intramolecular Diels–Alder reaction with substrates, which possess no butenyl side chain (Scheme A3.2.1b). Scheme A3.2.1. Diels–Alder Strategy Toward Communesin F (1f) (a) O N O O N O HCl, MeOH N N H H 0 → 23 °C N N R R 23, R = H (31% yield) 24, R = Me (99% yield) (X-ray) 22, R = H 19, R = Me O (b) O R R N Br O Diels–Alder N 107 O H N N O N H N H N N Br N 108 N H H Communesin F (1f) Treatment of acid 20 with oxalyl chloride produced acyl chloride 109, which was used directly without further purification (Scheme A3.2.2a). Tryptamine (110) was used as the model substrate to explore a Diels–Alder strategy. Reductive amination of tryptamine (110) with benzaldehyde furnished benzyl amine 111, which was coupled 307   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F with acid chloride 109 to afford amide 112. However, all attempts at intramolecular Diels–Alder reactions using a wide variety of conditions (e.g., HCl, BF3·OEt2, Et2AlCl, SnCl4, KOt-Bu, SiO2, MeMgBr, AgClO4, heating) to provide the communesin F core structure were unsuccessful.1 Indole 112 was protected with methyl iodide to produce 114, but the desired Diels–Alder cycloaddition product was not observed (Scheme A3.2.2b). Scheme A3.2.2. Intramolecular Diels–Alder Reactions O (a) CO2H Cl oxalyl chloride O O CH2Cl2, DMF, 0 → 23 °C N N 20 109 NHBn NH 2 O Bn N benzaldehyde NaBH 4 109 , Et 3N MeOH, 23 → 0 °C (82% yield) N H N CH2Cl2, 23 °C (81% yield) N H 110 O N H 111 112 Bn N O Lewis acids/bases acids/heating O N N H H 113 (Not observed) (b) O Bn O Bn Bn N N O MeI, NaH N N O THF (90% yield) 112 N toluene 120 °C O N N N H 114 O 0.5M HCl H N 115 Having failed to access the communesin F core by intramolecular Diels–Alder reactions, we chose to examine intermolecular Diels–Alder reactions (Scheme A3.2.3). 308   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F Intermolecular Diels–Alder reactions between phthalimide 116–118 and benzisoxazole 119–120 did not proceed below 150 °C and the anthranil fragment decomposed at a higher temperature (Scheme A3.2.3a). Addition of Lewis acids did not improve the reactivities. Alternatively, we envisioned that a Diels–Alder reaction of 1,2,3- benzotriazine with phthalimide 116 would afford 127 by loss of N2 (Scheme A3.2.3b).2 Amination of indazole 122 followed by oxidation with lead tetraacetate furnished 1,2,3benzotriazine 126. Disappointingly, the desired adduct (127) was not observed by intermolecular Diels–Alder reactions under several conditions. Scheme A3.2.3. Intermolecular Diels–Alder Reactions (a) O O N O + N O R2 O O N N N R1 121 119 , R 2 = H 120 , R 2 = CO2Me CO2Me CO2Me N N R1 116 , R1 = H 117 , R1 = Me 118 , R1 = Boc (b) R2 microwave NH 2 O + 122 + N NMP, 20 °C (54% yield; 2:1 124 :125 ) O2N N H N 124 125 CO2Me N CH2Cl2, 23 °C N N 126 NPhth CO2Me N + N H N 116 126 N PhthN MeO 2C 3Å MS CH3CN N NH 2 N NH 2 123 Pb(OAc) 4, CaO CO2Me KOt-Bu N N H H 127 309   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F A3.3. Intramolecular Alkylation of 3-Bromooxindole Strategy A plausible rationale for forming syn-selective adduct 42 from alkylation of 3- bromooxindole 40 and malonate 41 is that the tosyl group would be located far from the isobutenyl group due to steric hindrance and thus, malonate 41 would approach syn to the isobutenyl group to reduce the steric interaction with the tosyl group (Scheme 1.2.9). We believed that intramolecular alkylation of the 3-bromooxindole with a tethered malonate derivative in 128 could deliver the stereochemistry needed for the synthesis of communesin F (1f). Scheme A3.3.1. Intramolecular Alkylation Strategy AllylO2C O2N O CO2Allyl O N N bases Br O NO 2 O N H 128 N H 129 Coupling of aurantioclavine (4) and malonate 44 afforded amide 130, which was oxidized with pyridinium tribromide to furnish a mixture of 131, 128, and 132 (Scheme A3.3.2). Unfortunately, intramolecular alkylation of 3-bromooxindole 128 provided a complex mixture of the unisolable desired product and byproducts even after extensive screening of the reaction parameters. 310   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F Scheme A3.3.2. Intramolecular Alkylation of 3-Bromooxindole AllylO2C H N AllylO2C O CO2Allyl N toluene NO 2 + reflux (52% yield) N H 4 N H 44 130 AllylO2C pyridinium tribromide O2N AllylO2C O O2N AllylO2C O N N + Br O Br Br O N H O N H 131 O2N O2N O N + t-BuOH, THF, H 2O, 23 °C (131 , 29% yield; 128 , 64% yield) AllylO2C O2N N H 128 132 O CO2Allyl O N N bases Br O NO 2 O N H 128 N H 129 Although our synthetic efforts toward the total synthesis of communesin F were unsuccessful, we believe that these routes are one of the most expedient routes to complex communesin F. A3.4. Experimental Methods and Analytical Data A3.4.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F 311   benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Triethylamine was distilled over CaH2 prior to use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Microwave-assisted reactions were performed in a Biotage Initiator 2.5 microwave reactor. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, panisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm), or (CD3)2CO (δ 2.05 ppm). 13C NMR spectra are recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm), or (CD3)2CO (δ 29.84 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A 312   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). A3.4.2. Experimental Procedures Br O PhthN NO 2 CO2Allyl CO2Allyl O NH 2NH 2-H2O O NH O O N O O2N Br EtOH, H 2O, 80 oC (92% yield) N 103 105 (9:1 mixture of diastereomers) To a solution of phthalimide 103 (20.0 mg, 0.0285 mmol, 1.00 equiv) in EtOH (3.00 mL) and H2O (2.40 µL) was added hydrazine monohydrate (28.0 µL, 0.577 mmol, 20.0 equiv). The reaction mixture was heated to 80 °C for 1 h. The reaction mixture was then cooled to 23 °C and the resulting solid was filtered through a plug of celite. The residue was purified by column chromatography using mixtures of EtOAc and hexanes to provide oxindole 105 (15.1 mg, 92% yield). 1 H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 5.07 (s, 1H), 4.35 (s, br, 1H), 3.96 (dt, J = 9.9, 6.7 Hz, 2H), 3.86 (t, J = 6.7 Hz, 2H), 3.02 (s, 3H), 2.81 – 2.70 (m, 2H), 2.29 (s, br, 1H), 2.08 – 2.03 (m, 1H), 1.55 – 1.47 (m, 4H), 0.88 (dd, J = 14.0, 7.0 Hz, 3H), 0.76 (t, J = 7.4 Hz, 3H). 313   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F Br PhthN Br NO 2 CO2Allyl CO2Allyl O MeNH 2 in EtOH H 2N NO 2 CO2Allyl (98% yield) CO2Allyl O N N 103 106 To a solution of MeNH2 (8M in EtOH; 9.5 mL) was added phthalimide 103 (20.0 mg, 0.0285 mmol). The solution was stirred for 12 h at 23 °C. Then, the solution was concentrated to afford amine 106 (16.0 mg, 98% yield). 1 H NMR (600 MHz, CDCl3) δ 7.90 (q, J = 2.2 Hz, 1H), 7.49 (dd, J = 7.5, 2.5 Hz, 1H), 7.41 (dt, J = 8.7, 2.4 Hz, 1H), 7.32 – 7.25 (m, 2H), 7.12 (ddd, J = 9.5, 7.6, 2.5 Hz, 1H), 6.70 (dd, J = 7.8, 2.5 Hz, 1H), 5.79 (ddq, J = 15.1, 9.3, 4.6, 4.2 Hz, 1H), 5.68 (ddtd, J = 16.9, 11.4, 5.7, 2.6 Hz, 1H), 5.19 (d, J = 17.1 Hz, 1H), 5.15 – 5.07 (m, 4H), 4.47 (pd, J = 12.2, 11.3, 4.9 Hz, 3H), 4.39 (d, J = 5.3 Hz, 2H), 2.97 (s, 3H), 2.75 (dp, J = 27.3, 6.8 Hz, 2H), 2.29 (dt, J = 12.6, 6.8 Hz, 1H), 2.09 – 2.01 (m, 1H). NHBn NH 2 benzaldehyde NaBH 4 N H 110 MeOH, 23 → 0 °C (82% yield) N H 111 To a solution of tryptamine (110) (500 mg, 3.12 mmol, 1.00 equiv) in MeOH (15.6 mL) at 23 °C was added benzaldehyde (0.350 mL, 3.43 mmol, 1.10 equiv). After 4 h, the reaction mixture was cooled to 0 °C. Then, NaBH4 (177 mg, 4.68 mmol, 1.50 equiv) was added and the reaction mixture was stirred for an additional 1 h. The reaction was quenched with sat. aq NaHCO3. The aqueous phase was extracted with CH2Cl2 (3 x 7.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F 314   concentrated in vacuo to   afford   amine 111 (640 mg, 82% yield). Data for the compound matches reported data.1 NHBn O Bn N 109 , Et 3N N H O N CH2Cl2, 23 °C (81% yield) 111 N H 112 To a solution of acid chloride 109 (0.613 mmol) and Et3N (0.26 mL, 1.84 mmol, 3.00 equiv) in CH2Cl2 (3.10 mL) was added indole 111 (154 mg, 0.613 mmol, 1.00 equiv) at 23 °C. The reaction mixture was stirred for 6 h at 23 °C. After the reaction was done, water was added. The aqueous phase was extracted with CH2Cl2 (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to  afford  amide 112 (197 mg, 81% yield). (Due to the distinct presence of rotameric isomers, the 1H NMR contained extra peaks.) 1 H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.64 – 7.53 (m, 3H), 7.47 – 7.41 (m, 1H), 7.38 – 7.35 (m, 4H), 7.33 – 7.28 (m, 5H), 7.23 – 7.14 (m, 4H), 7.13 – 7.02 (m, 5H), 6.94 (d, J = 2.4 Hz, 1H), 4.85 (s, 4H), 4.01 (t, J = 7.4 Hz, 2H),  3.82 (t, J = 7.6 Hz, 2H), 3.14 (dt, J = 14.5, 7.6 Hz, 4H).                                                                                                                 1 Martin, D. B. C.; Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131, 3472–3473. 315   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F O Bn O Bn N N O MeI, NaH N O N THF (90% yield) N N H 112 114 To a solution of indole 112 (68.4 mg, 0.173 mmol, 1.00 equiv) in THF (0.900 mL) were added MeI (0.110 mL, 1.73 mmol, 10.0 equiv) and NaH (60%; 14.0 mg, 0.346 mmol, 2.00 equiv) at 0 °C. The reaction mixture was stirred at 23 °C for 4 h. The reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to  afford  amide 114 (64.0 mg, 90% yield). (Due to the distinct presence of rotameric isomers, the 1H NMR contained extra peaks.) 1 H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.9 Hz, 0.5H),  7.69 (dt, J = 8.9, 1.1 Hz, 1H), 7.61 (dd, J = 12.1, 8.5 Hz, 1H), 7.54 (dt, J = 9.1, 1.0 Hz, 1H), 7.44 (dt, J = 7.6, 1.2 Hz, 1H), 7.41 – 7.36 (m, 4H), 7.31 (tdd, J = 7.3, 4.0, 1.8 Hz, 5H), 7.12 – 7.05 (m, 4H), 6.91 (s, br, 0.5H), 6.76 (s, 1H), 4.88 (d, J = 2.3 Hz, 3.5H), 4.04 (t, J = 7.2 Hz, 2H), 3.86 – 3.78 (m, 1H), 3.74 (s, 1.5H), 3.57 (s, 3H), 3.16 (d, J = 8.2 Hz, 1H), 3.09 (t, J = 7.1 Hz, 2H).     AllylO2C H N AllylO2C NO 2 toluene N reflux (52% yield) N H 4 O CO2Allyl + O2N 44 N H 130 To a solution of aurantioclavine (4) (10.0 mg, 0.0442 mmol, 1.00 equiv) in toluene (0.200 316   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F mL) was added malonate 44 (15.0 mg, 0.0486 mmol, 1.10 equiv). The reaction mixture was refluxed for 12 h. Then, the reaction was quenched with water. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   indole 130 (10.8 mg, 52% yield). Due to the distinct presence of rotameric isomers and diastereomeric mixtures, the 1H NMR contained extra peaks. AllylO2C O2N AllylO2C O O2N AllylO2C O pyridinium tribromide N AllylO2C O N + t-BuOH, THF, H 2O, 23 °C (131 , 29% yield; 128 , 64% yield) N + Br Br Br O N H 131 O2N O N O N H 130 O2N O N H 128 N H 132 To a solution of indole 130 (10.9 mg, 0.0230 mmol, 1.00 equiv) in t-BuOH (0.230 mL) and THF (0.06 mL), H2O (2.10 µL) was added. Then, pyridinium tribromide (14.3 mg, 0.0448 mmol, 1.95 equiv) was added at 23 °C. The reaction was stirred at 23 °C for 6 h. Then, the reaction was quenched with water. The aqueous phase was extracted with EtOAc (3 x 0.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   mixtures of 131 (3.30 mg, 29% yield), 128 (8.35 mg, 64% yield), and trace amounts of 132. Due to the distinct presence of rotameric isomers and diastereomeric mixtures, the 1H NMR contained extra peaks. Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F A3.5. 317   References and Notes                                                                                                                 (1) (a) Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc. 1993, 115, 10733– 10741. (b) Suzuki, T.; Kobayashi, S. Org. Lett. 2010, 12, 2920–2923. (c) Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682–3685. (d) Martin, D. B. C.; Nguyen, L. Q.; Vanderwal, C. D. J. Org. Chem. 2012, 77, 17–46. (e) Chen, Y.; Wang, L.; Liu, Y.; Li, Y. Chem. Eur. J. 2011, 17, 12582–12586. (2) Koyama, J.; Toyokuni, I.; Tagahara, K. Chem. Pharm. Bull. 1998, 46, 332–334. Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 318   APPENDIX 4 Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with α-Arylated Malonate Esters† A4.1. Introduction 3,3-Disubstituted oxindole moieties are present in a wide variety of natural products and pharmaceutical agents.1 Accordingly, methods for the asymmetric construction of 3,3-disubstituted oxindoles have attracted considerable attention from the synthetic community, and a number of catalytic stereoselective approaches to provide C3 quaternary stereocenters on oxindoles have been reported.2,3 In 2007, we discovered that 3,3-disubstituted oxidoles 34 were furnished efficiently by basemediated alkylation of reactive electrophilic o-azaxylyxene 133, generated from 3halooxindole 33, with nucleophilic malonate esters (Scheme A4.1.1a).3a Additionally, we developed a method for the enantioselective alkylation of 3-bromooxindoles 33 by using a copper (R)-Ph-BOX ligand complex (Scheme A4.1.1b).3b                                                                                                                 †   This work was performed in collaboration with Dr. Chung Whan Lee and Dr. Scott C. Virgil. Additionally, this work has been published and adapted with permission from Lee, C. W.; Han, S.-J.; Virgil, S. C.; Stoltz, B. M. Tetrahedron 2014, 71, 3666–3670. Copyright 2014 Elsevier.   Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 319   Following our development of these methods, our attention turned to the syntheses of the polycyclic alkaloids communesin F (1f) and perophoramidine (3).4 We envisioned that the stereochemistry at the vicinal quaternary centers on communesin F and perophoramidine could be installed utilizing the conditions described in Scheme A4.1.1b. However, attempts to produce diesters 60 and 49 via copper catalyzed enantioselective alkylation of 3-bromooxindoles 57 and 43 with αarylated malonate esters 44 and 45 were unsuccessful (Scheme A4.1.2). Therefore, we pursued the development of an alternative catalytic system. Scheme A4.1.1. Construction of 3,3-Disubstituted Oxindoles by Alkylation of 3-Halooxindoles (a) R R R'O 2C CO2R' DBU X O N H R X = Br, Cl R = alkyl, aryl CO2R' O THF, –78 → 23 °C 33 O CO2R' N H (±)-34 (47–87% yield) N 133 (b) R X [Cu((R)-Ph-BOX)(SbF6)2] (20 mol%) R CO2R' O N H 33 X = Br, Cl R = alkyl, aryl R'O 2C CO2R' Base, 3 Å MS CH2Cl2 R = alkyl, Base = i-Pr2NEt R = aryl, Base = Et 3N CO2R' O N H 34 (42–84% yield) (74–94% ee) Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric 320   Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Scheme A4.1.2. Attempts for Alkylation of 3-Bromooxindoles with α-Arylated Malonate Esters R2 O TIPSO R1 O AllylO Br O TIPSO + N H NO 2 R1 OAllyl [Cu((R)-Ph-BOX)(SbF 6)2] (20 mol%) NO 2 i-Pr2NEt, 3 Å MS CH2Cl2 CO2Allyl CO2Allyl O N H R2 57, R1 = Br 43, R1 = H 44, R 2 = H 45, R 2 = Br 60, R1 = Br, R 2 = H 49, R1 = H, R 2 = Br O N N H N N Cl NH N communesin F (1f) Cl N H N Br Perophoramidine (3) In our previous studies, we tested a variety of metal catalysts (e.g. CuII, MgII, LaIII, and NiII) and discovered that the combination of CuII and a chiral bisoxazoline ligand effectively promoted the catalytic reaction. Chiral Cu(II) bisphosphine complexes have also found use in stereoselective synthesis.5 Since the catalytic system can be formed with a number of different chiral bisphosphine ligands, quite a few options would be available for developing a stereoselective reaction. Herein, we describe several screening studies designed and undertaken to optimize the reaction conditions for the alkylation of 3-bromooxindoles with α-arylated malonate esters using a copper(II) bisphosphine catalyst. A4.2. Results and Discussion A4.2.1. Initial Screening Results To develop a stereoselective alkylation method, we chose simple substrates for optimization studies; specifically, we used bromooxindole 43 without a substituent on Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 321   the aromatic ring and o-nitrophenyl dimethylmalonate 135 as a coupling partner. Bromooxindole 43 was easily prepared from indole (134) in four steps by a known sequence,4 which was then added to o-nitrophenyl dimethylmalonate 135 and cesium carbonate in THF solvent to afford a racemic product 136 in good yield. (Scheme A4.2.1). Scheme A4.2.1. Synthesis of the Racemic Product TIPSO TIPSO NO 2 CO2Me Cs2CO3 THF, 23 ºC Br CO2Me O O N H 4 steps 134 N H MeO 2C 43 CO2Me N H NO 2 (±)-136 135 (80% yield) Choosing (R)-BINAP as a chiral ligand, we began our research by screening various copper sources, bases, and solvents. For instance we attempted the following variations of copper ions: Copper(II) triflate, copper(II) chloride with silver hexafluoroantimodate, copper(II) isobutyrate, copper(II) tert-butoxide (generated in situ by adding lithium tert-butoxide to copper(II) isobutyrate and ligand mixture), copper(II) ethylhexanoate, and copper(II) trifluoroacetylacetonate. We explored both organic and inorganic tetramethylenediamine bases, (TMEDA), including diisopropylethylamine, triethylamine, pyridine, diisopropylamine, 1,8- diazabicyclo[5,4,0]undec-7-ene (DBU), sodium carbonate, potassium acetate, sodium ethylhexanoate and cesium carbonate. The various reactions combinations were attempted in the following solvents: dichloromethane, tetrahydrofuran, benzene, acetonitrile, and dioxane. Evaluating the 93 reactions that were explored,6 we found Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 322   that copper(II) tert-butoxide and the ligand complex generated in THF, which was similar to Fandrick’s conditions for asymmetric propargylation5, exhibited the best reactivity without generation of side products for the coupling of the arylated malonate 135 and bromooxindole 43 in CH2Cl2 (high conversion, 20% ee). A4.2.2 . Ligand Screening and Optimization Studies Based on previous studies, we selected copper(II) iso-butyrate, lithium tertbutoxide and THF solvent for generation of the catalytic species with chiral ligands, diisopropylamine as the base and CH2Cl2 as solvent. We have screened 69 chiral bisphosphine ligands6 under similar condition, finding WALPHOS and DiazaPHOS to give the best enantioselectivities (Figure A4.2.1). Figure A4.2.1. Results with DiazaPHOS and WALPHOS H N N N O Me O O PR 1 2 PR 22 Fe P O Me N H W1 : (S,S,S)-DiazaPHOS-PPE 40% ee Me WALPHOS N1 : R1 ,R2 = Ph, Ph N2 : = Ph, Xyl 27% ee   Having identified the most effective ligands, we next screened several copper sources under lower temperatures. Although none of these sources exhibited better results than the combination of copper(II) isobutyrate and lithium tert-butoxide for WALPHOS (N1 and N2), we were able to observe better stereoselectivity at low temperature (Table A4.2.1, entries 6 and 16). With DiazaPHOS (W1), copper(II) triflate showed better selectivity at 0 ºC (Table A4.2.1, entries 22 and 23). Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric 323   Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Table A4.2.1. Further investigations using WALPHOS and DiazaPHOS in the alkylation reaction O TIPSO Br O O TIPSO MeO OMe + NO 2 CO2Me O Metal, Ligand, Temp. N H 43 NO 2 CO2Me N H i-Pr 2NEt, THF/CH2Cl2 48 h 136 135   Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Metal Sources CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 Cu(iso-butyrate)2 Cu(iso-butyrate)2 Cu(hfacac)2 Cu(OTf)2 Cu(OTf)2 Cu(EH)2 CuCl2 CuCl2 CuCl2 CuCl2 Cu(iso-butyrate)2 Cu(hfacac)2 Cu(OTf)2 Cu(EH)2 Cu(iso-butyrate)2 Cu(iso-butyrate)2 Cu(OTf)2 Cu(OTf)2 Ligand N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N2 N2 N2 N2 N2 N2 N2 N2 W1 W1b W1 W1b Additive AgBF4 AgNTf2 AgPF6 AgSbF6 LiOt-Bu LiOt-Bu AgSbF6 LiOt-Bu AgBF4 AgNTf2 AgPF6 AgSbF6 LiOt-Bu LiOt-Bu LiOt-Bu Temp. −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC 0 ºC 0 ºC 0 ºC 0 ºC   eea − − − − − 44% − trace trace 23% trace − − − − 54% 30% 45% trace trace trace 40% 50% Conditions: 0.0049 mmol 43, 0.0145 mmol 135, Cu (20 mol %), Ligand (22 mol %), Additive (20 mol %), i-Pr2NEt (3 equiv.), 0.1 mL CH2Cl2 (0.049 M). Metal catalyst, ligand and additives were mixed in THF. THF was removed in vacuo, and the resultant was diluted with the reaction solvent. The reaction was initiated by addition of base. Cu(hfacac)2: Copper(II) hexafluoroacetylacetonate, Cu(EH)2: Copper(II) ethylhexanoate. a enantiomeric excess was measured by chiral SFC. b 44 mol % of ligand was used. With a suitable bisphosphine ligand in hand (N1), we tested multiple solvents and bases. However, amine bases weaker than Hünig’s base (Table A4.2.2, entries 112) could not initiate the reaction, whereas stronger bases (entries 13-18) decreased the stereoselectivity. The copper bisphosphine complex demonstrated similar selectivity in dichloromethane (entry 19), THF (entry 20), and chloroform (entry 22), however it showed worse selectivity in acetonitrile (entry 21) and failed to proceed at all in toluene and 1,2-dimethoxyethane (DME). Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric 324   Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Table A4.2.2. Investigation of reaction solvents and bases with WALPHOS in the alkylation reaction PPh 2 PPh 2 O TIPSO Br O O OMe + NO 2 N H 43 Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Fe MeO 135 Solvent CH2Cl2 THF CH3CN CHCl3 Toluene DME CH2Cl2 THF CH3CN CHCl3 Toluene DME CH2Cl2 THF CH3CN CHCl3 Toluene DME CH2Cl2 THF CH3CN CHCl3 Toluene DME Me TIPSO NO 2 CO2Me CO2Me O Cu(iso-butyrate) 2 N H LiOt-Bu, Base THF/Solvent, −45 ºC 48 h Base DABCO DABCO DABCO DABCO DABCO DABCO DMAP DMAP DMAP DMAP DMAP DMAP Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt 136 ee − − − − − − − − − − − − 35% 15% 20% 20% − 10% 40% 50% 30% 40% − − Conditions: 0.0024 mmol 43, 0.0072 mmol 135, Cu (20 mol %), Ligand (22 mol %), LiOt-Bu (20 mol %), Base (3 equiv), 0.06 mL CH2Cl2 (0.04 M). In addition to these studies, we examined the effect of the catalyst and ligand loading on the stereoselectivity of our alkylation reaction. Unsatisfactory results were produced with low catalyst or ligand loading (Table A4.2.3, entries 1,2 and 4), but 20 mol % of copper(II) isobutyrate and 40 mol % of the ligand gave the product in 56% ee (Table A4.2.3, entry 3). Stoichiometric amounts of the copper presursor and ligand produced only a slight increase in ee (Table A4.2.3, entry 5). Additionally, we investigated the impact of the equivalents of Hünig’s base on the selectivity of the reaction. Results showed the amount of Hünig’s base had little effect on the Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 325   stereoselectivity of the product (Table A4.2.3, entries 6-13). Subsequent examination of concentration effects showed lowering the concentration of the reaction mixture from 0.05 M to 0.02 M resulted in increase stereoselectivity (Table A4.2.4). Table A4.2.3. Examination of the amount of catalyst and ligand loading in the alkylation reaction PPh 2 PPh 2 O TIPSO Br O O Fe MeO OMe + NO 2 N H 43 135 Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 Cu(iso-butyrate)2 10 mol % 10 mol % 20 mol % 20 mol % 1 equiv 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % TIPSO Me NO 2 CO2Me CO2Me O Cu(iso-butyrate) 2 N H LiOt-Bu, i-Pr 2NEt THF/CH2Cl2, −45 ºC 48 h 136 i-Pr2NEt Ligand 10 mol % 20 mol % 40 mol % 10 mol % 1 equiv 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % ee 25% 28% 56% 35% 60% 33% 35% 38% 37% 36% 37% 36% 36% 3.0 equiv 3.0 equiv 3.0 equiv 3.0 equiv 3.0 equiv 1.0 equiv 1.5 equiv 2.0 equiv 2.5 equiv 4.0 equiv 5.0 equiv 6.0 equiv 20 equiv Conditions: 0.0049 mmol 43, 0.0145 mmol 135, LiOt-Bu (10 mol %), 0.1 mL CH2Cl2 (0.049 M). Table A4.2.4. Examination of concentration in the malonate addition reaction PPh 2 PPh 2 O TIPSO Br O O MeO OMe + NO 2 N H 43 Entry 1 2 3 4 5 Fe 135 TIPSO Me NO 2 CO2Me CO2Me O Cu(iso-butyrate) 2 LiOt-Bu, i-Pr 2NEt THF/CH2Cl2, −45 ºC 48 h Concentration 0.005 M 0.01 M 0.02 M 0.05 M 0.25 M N H 136 ee 53% 63% 64% 55% 40% Conditions: 0.0049 mmol 43, 0.0145 mmol 135, Cu (20 mol %), Ligand (40 mol %), LiOt-Bu (20 mol %), i-Pr2NEt (3 equiv). Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 326   Table A4.2.5. The effect of WALPHOS substituents under optimized conditions in the alkylation reaction O TIPSO Br O O TIPSO MeO OMe + NO 2 N H 43 135 N H 136 N1 : R 1,R 2 = Ph, Ph PR 22 Fe Me WALPHOS Entry 1 2 3 4 5 6 7 8 CO2Me O Cu(iso-butyrate) 2 LiOt-Bu, i-Pr 2NEt THF/CH2Cl2, −45 ºC 48 h PR 1 2 NO 2 CO2Me N2 : N3 : N4 : N5 : N6 : N7 : N8 : = Ph, Xyl = Ph, XylF = 3,5-Me2-4-MeOPh, XylF = Ph, Cy = Cy, XylF = Xyl, Xyl = Ph, Norbornyl Ligand N1 N2 N3 N4 N5 N6 N7 N8 ee 60% trace 25% 25% 70% − − − Conditions: 0.0049 mmol 43, 0.0145 mmol 135, Cu (20 mol %), Ligand (40 mol %), LiOt-Bu (20 mol %), i-Pr2NEt (3 equiv), 0.25 mL CH2Cl2 (0.02 M). Finally, we explored a set of WALPHOS ligands (N1 – N8) under our optimized conditions. Gratifyingly, we observed improved ee by using (Ph,Cy)WALPHOS (Table A4.2.5, entry 5), leading to product formation in 70% ee, whereas other ligands showed diminished selectivity. To date, this is the best result we have, which is a great improvement over the starting point. A4.3. Conclusion Asymmetric alkylation of 3-halooxindoles with malonate esters is an effective method to construct 3,3,-disubstituted oxindole moieties. Herein, we have reported that copper(II) chiral bisphosphine complex demonstrated reactivity with an αarylated malonate ester, which was an unreactive substrate in previously developed Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 327   conditions. This method could be applied to the installation of vicinal quaternary centers on communesin F and perophoramidine and could be useful in the synthesis of a variety of other natural products. A4.4. Selected Experiments A4.4.1. Synthesis of (±)-136 To a flame-dried round-bottomed flask, equipped with a stirbar, was added bromooxindole 43 (20 mg, 0.045 mmol), o-nitrophenyl dimethylmalonate 135 (37 mg, 0.135 mmol) and THF (0.5 mL). To the mixture was added cesium carbonate (47.4 mg, 0.045 mmol) at ambient temperature and the reaction mixture was then stirred for 3 h. The reaction mixture was then treated with saturated NH4Cl aqueous solution, extracted with EtOAc, washed with brine and dried over MgSO4. After concentration in vacuo, the crude product was obtained. Chromatography (6:1 hexanes : ethyl acetate) on silica gel afforded the title compound 136 (23 mg, 80% yield) as colorless oil: 1H NMR (500 MHz, CDCl3) δ 8.0 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.74 (dd, J = 7.9, 1.7 Hz, 1H), 7.40 (dtd, J = 26.6, 7.4, 1.5 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.14 (td, J = 7.7, 1.3 Hz, 1H), 6.90 (td, J = 7.7, 1.2 Hz ,1H), 6.75 (dd, J = 7.8, 1.1 Hz, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 3.35 (ddd, J = 9.5, 8.4, 6.9 Hz, 1H), 3.06 (td, J = 9.3, 4.5, 1H), 2.93 (ddd, J = 12.6, 8.8, 6.7 Hz, 1H), 2.54 (ddd, J = 12.8, 8.4, 4.4 Hz, 1H), 0.89 (s, 21H). 13C NMR (126 MHz, CDCl3) δ 177.86, 167.63, 167.27, 150.34, 140.67, 132.46, 131.12, 129.49, 129.23, 128.63, 128.61, 126.73, 125.39, 122.45, 109.98, 109.12, 59.52, 56.71, 52.81, 52.80, 38.34, 29.70, 17.85, 17,84, 11.80. IR (Neat Film, NaCl) 2923, 2852, 1722, 1617, 1532, 1463, 1353, 1259, 1097, 992, Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 328   799, 753 cm-1; HRMS (MM) m/z calc’d for C30H40N2O8Si [M+H]+ : 585.2627, found 585.2636. A4.4.2. Ligand Screening Procedure Every step was performed in a nitrogen-filled glove box. Solutions of Copper(II) isoburtyrate (8 mg, 0.034 mmol) in THF (3.5 mL), lithium tert-butoxide (2.72 mg, 0.034 mmol) in THF (3.5 mL), bromooxindole 43 (70 mg, 0.17 mmol) and malonate 135 (129 mg, 0.51 mmol) in CH2Cl2 (1.75 mL), i-Pr2NEt (0.1 ml, 0.57 mmol) in CH2Cl2 (2 mL) were prepared in 2 dram vials prior to reaction setup. To a ligand (1.1 µmol, 22 mol %) in a 1 dram vial equipped with a stirbar was added copper(II) isobutyrate in THF (0.1 mL, 0.97 µmol, 20 mol %). The heterogeneous solution was agitated at room temperature for 10-20 min until a clear homogeneous solution was generated. The reaction mixtures were charged with lithium tert- butoxide in THF (0.1 mL, 0.97 µmol, 20 mol %). Reaction mixtures were allowed to stir for 5 min and concentrated under reduced pressure. A mixture of bromooxindole 43 and malonate 135 in CH2Cl2 (0.05 mL, 4.85 µmol, 14.55 µmol) was dispensed to each vial and allowed to stir for 10 min. After setting the reaction temperature, iPr2NEt in CH2Cl2 (0.05 mL, 14.55 µmol, 3 equiv) was added to the reaction vials and allowed to stir for 48 h. Upon completion, sat. aq ammonium chloride solution (0.1 mL) was added, and the mixture was filtered through silica gel. Each filtrate was diluted by 1 mL of solvent (ethyl acetate or isopropanol) and analyzed by chiral SFC. The mixture was separated by an AD-H column with 20% isopropanol as eluent. Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters A4.5. 329   References and Notes (1) (a) Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med. Chem. 2001, 44, 4641–4649. (b) Woodward, C.; L.; Li, Z.; Kathcart, A. K.; Terrell, J.; Gerena, L.; Lopez-Sanchez, M.; Kyle, D. E.; Bhattacharjee, A. K.; Nichols, D. A.; Ellis, W.; Prigge, S. T.; Geyer, J. A.; Waters, N. C. J. Med. Chem. 2003, 46, 3877– 3882. (c) Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748– 8758. (d) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2219. (e) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36–51. (f) Trost, B. M.; Brennan, M. K. Synthesis, 2009, 3003–3025. (g) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49, 3432–3435. (2) Reviews: (a) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal., 2010, 352, 1381– 1407. (b) Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 6821–6841. (c) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247–7290. (d) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104–6155. (3) Recent examples: (a) Holmquist, M.; Blay, G.; Pedro, J. R. Chem. Commun., 2014, 50, 9309–9312. (b) Hu, F.-L.; Wei, Y.; Shi, M. Chem. Commun., 2014, 50, 8912–8914. (c) Chen, D.; Xu, M.-H. J. Org. Chem. 2014, 79, 7746–7751. (d) Li, C.; Guo, F.; Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Org. Lett. 2014, 16, 3192– 3195. (e) Zhu, X.-L.; Xu, J.-H.; Cheng, D.-J.; Zhao, L.-J.; Liu, X.-Y. Tan, B. Org. Lett. 2014, 16, 2192–2195. (f) Liu, Z.-M.; Li, N.-K.; Huang, X.-F.; Wu, B.; Li, N.; Kwok, C.-Y.; Wang, Y.; Wang, X.-W. Tetrahedron, 2014, 70, 2406–2415. (g) Cao, Z.-Y.; Wang, Y.-H.; Zeng, X.-P.; Zhou, J. Tetrahedron Lett. 2014, 55, 2571–2584. (h) Zhou, F.; Zeng, X.-P.; Wang, C.; Zhao, X.-L.; Zhou, J. Chem. Commun., 2013, 49, Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 330   2022–2024. (i) Katayev, D.; Jia, Y.-X. Sharma, A. K.; Banerjee, D.; Besnard, C.; Sunoj, R. B.; Kündig, E. P. Chem. Eur. J. 2013, 19 11916–11927. (j) Zhing, F.; Dou, X.; Han, X.; Yao, W.; Zhu, Q.; Meng, Y.; Lu, Y. Angew. Chem. Int. Ed. 2013, 52, 943–947. (k) Shen, K.; Liu, X.; Feng, X. Chem. Sci., 2012, 3, 327–334. (l) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583–3586. (m) Ding, M.; Zhou, F.; Qian, Z.-Q.; Zhou, J. Org. Biomol. Chem., 2010, 8, 2912–2914. (4) (a) Krishnan, S.; Stoltz, B. M. Tetrahedron Lett. 2007, 48, 7571–7573. (b) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037–8041. (5) Han, S.-J. Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C. Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. (6) (a) Fandrick, D. R., Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Tang, W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.; Yee, N. K.; Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600-7601. (b) Fandrick, K. R.; Fandrick, D. R.; Reeves, J. T.; Ma, S.; Li, W.; Lee, H.; Grinberg, N.; Lu, B.; Senanayake, C. H. J. Am. Chem. Soc. 2011, 133, 10332-10335. (c) Fandrick, K. R.; Ogikubo, J.; Fandrick, D. R.; Patel, N. D.; Saha, J.; Lee, H.; Ma, S.; Grinberg, N.; Busacca, C. A.; Senanayake, C. H. Org. Lett. 2013, 15, 1214-1217.   Appendix 5 – Spectra Relevant to Appendix 4 331 APPENDIX 5 Spectra Relevant to Appendix 4: Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with α-Arylated Malonate Esters 136 N H CO2Me O CO2Me NO 2 TIPSO                                                                                                     332   Figure A5.1. 1H NMR (500 MHz, CDCl3) of compound 136. Appendix 5 – Spectra Relevant to Appendix 4 Appendix 5 – Spectra Relevant to Appendix 4     Figure A5.2. Infrared spectrum (Thin Film, NaCl) of compound 136.  Figure A5.3. 13C NMR (125 MHz, CDCl3) of compound 136.   333   Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 334   CHAPTER 2 A New Method for the Cleavage of Nitrobenzyl Amides and Ethers† 2.1. Introduction The selection of protection groups is critical to the synthesis of multifunctional complex molecules. Over the past decades, a wide variety of protecting groups have been developed to mask specific functional groups selectively. 1,2 However, despite considerable effort, relatively few protecting groups have been developed for the amide N–H (e.g., PMB, TBS, Benzyl, SEM, allyl, etc.).3 Consequently, limitations associated with cleavage of amide protecting groups often arise.4 Herein, we report o- and pnitrobenzyl groups as easily introducible and removable protecting groups for both R2N– H (including amides) and RO–H groups.                                                                                                                 †   This work was performed in collaboration with Gabriel Fernando de Melo. Additionally, this work has been published and adapted with permission from Han, S.-J.; Fernando de Melo, G.; Stoltz, B. M. Tetrahedron Lett. 2014, 55, 6467–6469. Copyright 2014 Elsevier. 335   Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 2.2. Results  and  Discussion   In the course of our efforts toward the synthesis of the polycyclic, complex alkaloid perophoramidine, we serendipitously found that the o-nitrobenzyl group was easily removed by using 20% aqueous NaOH in methanol at 75 °C (Scheme 1).5 oNitrobenzyl groups have been used as photocleavable protecting groups for amides and heterocycles such as indoles, benzimidazole, and 6-chlorouracil as well as the more common hydroxyl group.6,7 In addition, a method for removing p-nitrobenzyl groups on hydroxyl groups in two steps by reduction to a p-aminobenzyl group followed by electrochemical oxidation was disclosed by the Kusumoto group.8 To the best of our knowledge, ours was the first example of using simple aqueous NaOH to remove a nitrobenzyl group from a lactam. Scheme 2.2.1. o-Nitrobenzyl group cleavage on perophoramidine intermediate (88) O2N TIPSO TIPSO N NH 20% aq NaOH O O MeOH, 75 °C N O H N Boc 88 Br (50% yield) N N H H Boc Br 80 To explore the general reactivity of nitrobenzyl group cleavage reactions by using simple aqueous NaOH, we initially chose 3,3-dimethyl oxindole as a test substrate (Table 2.2.1). We found that both ortho- and para-nitrobenzyl groups on oxindoles 137a and 137c were smoothly cleaved under our standard conditions (entries 1 and 3). However, a meta-nitrobenzyl group as well as a simple benzyl group on the oxindole 336   Notably, the o- Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers nitrogen (137b and 137d) were both unreactive (entries 2 and 4). nitrobenzyl group was also successfully removed even in the absence of light (entry 5). Interestingly, only trace amounts of product were observed when degassed water and methanol were used (entry 6). Furthermore, we discovered that cleavage of the onitrobenzyl group was successful when the degassed water and methanol were purged with oxygen gas (entry 7). We therefore concluded that oxygen was necessary for the reaction, but light was not. Table 2.2.1. Cleavage of nitrobenzyl groups on 3,3-dimethyloxindole   O N Entry 20% aq NaOH O MeOH, 75 °C R N H 137 138 Substrate R Time (h) Yield (%) 1 137a -o-nitrobenzyl 5 69 2 137b -m-nitrobenzyl 24 0 3 137c -p-nitrobenzyl 1.5 63 4 137d -benzyl 24 0 5a 137a -o-nitrobenzyl 6.5 72 6b 137a -o-nitrobenzyl 12 trace 7b,c 137a -o-nitrobenzyl 6.5 66 a The reaction was performed in the dark. b Degassed water and methanol were used. c Purged with O . 2 With the standard conditions in hand, we explored the scope of the o- and pnitrobenzyl group cleavage reactions with various substrates (Table 2.2.2). o- and pNitrobenzyl protected substrates were easily prepared by a variety of methods, including reductive amination, simple alkylation, EDCI coupling, and acylation. The o-nitrobenzyl group on a highly functionalized communesin F intermediate 79 was smoothly cleaved 337   under our standard conditions in good yield (entry 1). p-Nitrobenzyl groups on amide Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 5 139 and lactam 141 were also cleaved in moderate yields (entries 2 and 3). The pnitrobenzyl group on urea 143 was also successfully cleaved and methyl 4-nitrobenzoate was isolated as a by-product (entry 4). An attempt to remove the p-nitrobenzyl group on secondary carbamate 145 proved unsuccessful (entry 5). Additionally, removal of the pnitrobenzyl group on amine 147 was facile, furnishing aniline 148 in 65% yield (entry 6). Interestingly, 4-nitrobenzaldehyde was isolated as a by-product in this reaction, presumably resulting from the oxidation reaction at the benzylic position by oxygen dissolved in the solution. Furthermore, we successfully removed the p-nitrobenzyl groups from ethers 149 and 151 in moderate yields (entries 7 and 8). This work offers a one-step alternative to previous work by the Kusumoto group.8 In the cases of deprotection reactions from urea 143 and ether 149, the corresponding hemiaminal ether and acetal intermediates were observed (see ref. 9). It is important to note that these deprotection conditions are compatible with free hydroxyl groups, aminals, aryl bromides, methyl carbamates, silyl ethers, and Boc groups present on the substrates. A representative procedure is as follows: To a 20 mL scintillation vial with a magnetic stir bar were added p-nitrobenzyl protected oxindole 137c (30 mg, 0.10 mmol, 1.0 equiv), MeOH (1.0 mL), and 20% aq NaOH (1.0 mL). The reaction mixture was stirred for 1.5 h at 75 °C. The reaction mixture was then cooled to 23 °C, and extracted with EtOAc (3 x 2 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography to afford 3,3-dimethyloxindole 138 (10.3 mg, 63% yield). 338   Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers Table 2.2.2. Scope of the o- and p-nitrobenzyl deprotecion reactions Entry Product Substrate Time (h) Yield (%) 4 70 12 42 1 55 10.5 94a,b 6 0 2 65c 32 59b (74)d 48 48 O2N HO HO 1 N Br NH Br O O N N H N H N CO2Me CO2Me 79 53 O O N 2 NH NO 2 139 140 O O N 3 NH NO 2 142 141 O 4 N O N N NH NO 2 143 144 O O 5 O N H O NH 2 NO 2 146 145 NO 2 6 NH N 147 7 148 O OH 149 8 NO 2 150 O OH NO 2 151 152 a Methyl 4-nitrobenzoate was isolated as a by-product. b See Ref. 9 for detail. c 4-Nitrobenzaldehyde was isolated as a by-product. d Yield based on recovered starting material. Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 2.3. 339   Conclusion   In summary, a mild and efficient deprotection protocol was discovered for the cleavage of o- and p-nitrobenzyl ethers, amides, ureas, and anilines. Since relatively few options for protection of the amide N–H functionality exist, easily introducible and removable o- and p-nitrobenzyl groups could prove useful in the synthesis of alkaloids and biologically active molecules, which possess amide functionalities. In our laboratory, this has already been proven to be the case in our formal syntheses of communesin F and perophoramidine. In addition, p-nitrobenzyl-protected anilines, ureas, and alcohols were also competent substrates for this transformation, which may further its utility as a mild deprotection method in cases where other conditions fail. 2.4. Experimental Methods and Analytical Data 2.4.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Triethylamine was distilled over CaH2 prior to use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Microwave-assisted reactions were 340   performed in a Biotage Initiator 2.5 microwave reactor. Glove box manipulations were Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, panisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and were reported relative to residual CHCl3 (δ 7.26 ppm), or (CD3)2CO (δ 2.05 ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm), or (CD3)2CO (δ 29.84 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). 2.4.2. Experimental Procedures o-nitrobenzyl bromide Cs2CO3 O N H 138 THF, 23 °C (93% yield) O N 137a O2N 341   N–2-nitrobenzyloxindole 137a. To a mixture of 3,3-dimethyloxindole 138 (150 mg, Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 1 0.93 mmol, 1.00 equiv) and Cs2CO3 (606 mg, 1.86 mmol, 2.00 equiv) in THF (4.70 mL) was added o-nitrobenzyl bromide (302 mg, 1.40 mmol, 1.50 equiv). The reaction mixture was stirred overnight. Then, the reaction mixture was extracted with EtOAc (3 x 6 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 → 1:2 EtOAc:hexanes) on silica gel to afford N–2-nitrobenzyl-3,3-dimethyloxindole 137a (258 mg, 93% yield). Rf = 0.35 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.16 (dd, J = 8.1, 1.4 Hz, 1H), 7.51 (td, J = 7.6, 1.4 Hz, 1H), 7.44 (dddt, J = 8.1, 7.4, 1.4, 0.7 Hz, 1H), 7.28 (ddd, J = 7.3, 1.3, 0.6 Hz, 1H), 7.17 (td, J = 7.7, 1.3 Hz, 1H), 7.12 (dq, J = 7.8, 1.0 Hz, 1H), 7.09 (td, J = 7.5, 1.1 Hz, 1H), 6.61 (dt, J = 7.8, 0.8 Hz, 1H), 5.33 (d, J = 0.8 Hz, 2H), 1.48 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 181.8, 148.2, 141.4, 135.8, 134.2, 132.0, 128.5, 128.0, 127.6, 125.7, 123.2, 122.8, 108.8, 77.2, 44.5, 41.2, 24.8; IR (Neat Film NaCl) 2968, 1721, 1615, 1524, 1489, 1385, 1338, 1177, 1008, 858, 761 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H17N2O3 [M+H]+ : 297.1234; found: 297.1236. m-nitrobenzyl bromide Cs2CO3 O N H 138 THF, 23 °C (92% yield) O N 137b NO 2 N–3-nitrobenzyloxindole 137b. To a mixture of 3,3-dimethyloxindole 1381 (100 mg, 0.62 mmol, 1.00 equiv) and Cs2CO3 (403 mg, 1.24 mmol, 2.00 equiv) in THF (3.10 mL)                                                                                                                 1 Vu, A. T.; Cohn, S. T.; Zhang, P.; Kim, C. Y. Mahaney, P. E.; Bray, J. A.; Johnston, G. H.; Koury, E. J.; Cosmi, S. A.; Deecher, D. C.; Smith, V. A.; Harrison, J. E.; Leventhal, L.; Whiteside, G. T.; Kennedy, J. D.; Trybulski, E. J. J. Med. Chem. 2010, 53, 2051–2062. Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers was added m-nitrobenzyl bromide (335 mg, 1.55 mmol, 2.50 equiv). 342   The reaction mixture was stirred overnight. Then, the reaction mixture was extracted with EtOAc (3 x 4 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 → 1:2 EtOAc:hexanes) on silica gel to afford N–3-nitrobenzyl-3,3-dimethyloxindole 137b (170 mg, 92% yield). Rf = 0.35 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.16 – 8.11 (m, 2H), 7.60 (ddt, J = 7.7, 1.8, 0.9 Hz, 1H), 7.53 – 7.48 (m, 1H), 7.26 – 7.24 (m, 1H), 7.17 (td, J = 7.7, 1.3 Hz, 1H), 7.07 (td, J = 7.5, 1.0 Hz, 1H), 5.01 (s, 2H), 1.46 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 181.7, 148.6, 141.1, 138.5, 135.9, 133.3, 130.1, 127.9, 123.2, 122.9, 122.8, 122.2, 108.7, 77.2, 44.4, 43.0, 24.7; IR (Neat Film NaCl) 2969, 1652, 1538, 1348, 1011, 933, 761; HRMS (MM: ESI-APCI+) m/z calc’d for C17H17N2O3 [M+H]+ : 297.1234; found: 297.1241. p-nitrobenzyl bromide Cs2CO3 O N H 138 THF, 23 °C (84% yield) O N 137c NO 2 N–4-nitrobenzyloxindole 137c. To a mixture of 3,3-dimethyloxindole 1381 (50 mg, 0.31 mmol, 1.00 equiv) and Cs2CO3 (202 mg, 0.62 mmol, 2.00 equiv) in THF (1.60 mL) was added p-nitrobenzyl bromide (101 mg, 0.47 mmol, 1.50 equiv). The reaction mixture was stirred overnight. Then, the reaction mixture was extracted with EtOAc (3 x 3 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 → 1:2 343   EtOAc:hexanes) on silica gel to afford N–4-nitrobenzyl-3,3-dimethyloxindole 137c (77.5 Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers mg, 84% yield). Rf = 0.35 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 10.0 Hz, 2H), 7.25 (ddd, J = 7.3, 1.5, 0.7 Hz, 1H), 7.16 (td, J = 7.7, 1.3 Hz, 1H), 7.07 (td, J = 7.5, 1.1 Hz, 1H), 6.65 (dt, J = 7.7, 0.7 Hz, 1H), 5.01 (s, 2H), 1.45 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 181.6, 147.6, 143.7, 141.1, 135.8, 128.0, 127.9, 124.2, 123.2, 122.8, 108.7, 77.2, 44.4, 43.1, 24.7; IR (Neat Film NaCl) 2968, 1707, 1613, 1522, 1343, 1173, 1111, 1009, 760; HRMS (MM: ESI-APCI+) m/z calc’d for C17H17N2O3 [M+H]+ : 297.1234; found: 297.1239. O O OH N H + O2N SI-2-1 SI-2-2 EDCI, HOBt N CH2Cl2, 23 °C (73% yield) NO 2 139 Benzamide 139. To a solution of benzoic acid SI-2-1 (57.0 mg, 0.463 mmol, 1.00 equiv) and propylamine SI-2-22 (90.0 mg, 0.463 mmol, 1.00 equiv) in CH2Cl2 (2.30 mL) were added EDCI (90.0 mg, 0.579 mmol, 1.25 equiv) and HOBt (78.0 mg, 0.579, 1.25 equiv). The reaction mixture was stirred overnight at 23 °C. Then, the reaction mixture was extracted with CH2Cl2 (3 x 3 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 → 1:2 EtOAc:hexanes) on silica gel to afford N–3-nitrobenzyl-3,3dimethyloxindole 139 (101 mg, 73% yield).                                                                                                                 2  Hajipour, A. R.; Fontanilla, D.; Chu, U. B.; Arbabian, M.; Ruoho, A. E. Bioorg. Med. Chem. 2010, 18, 4397–4404.   344   Rf = 0.32 (1:2 EtOAc:hexanes); (due to the distinct presence of rotameric isomers, the 1H Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers NMR and 13C NMR contained extra peaks. See the attached spectrum); 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 10 Hz 2H), 7.53 – 7.35 (m, br, 7H), 4.84 – 4.61 (m, br, 2H), 3.43 – 3.18 (m, br, 2H), 1.68 –1.53 (m, br, 2H), 0.95 – 0.73 (m, br, 3H); 13C NMR (126 MHz, CDCl3) δ 172.47, 147.44, 145.42, 136.17, 129.84, 128.71, 127.49, 126.61, 124.06, 77.16, 52.29, 50.82, 47.59, 46.85, 21.87, 20.34, 11.07; IR (Neat Film NaCl) 3060, 2963, 2874, 1633, 1519, 1461, 1412, 1344, 1258, 1098, 859, 791, 736; HRMS (MM: ESIAPCI+) m/z calc’d for C17H19N2O3 [M+H]+ : 299.1390; found: 299.1396. p-nitrobenzyl bromide LHMDS O NH O N THF, 23 °C (69% yield) 142 NO 2 141 N–4-nitrobenzylpiperidin-2-one 141. To a solution of lactam 142 (34.0 mg, 0.203 mmol, 1.00 equiv) in THF (1.40 mL) was added LHMDS (41.0 mg, 0.244 mmol, 1.20 equiv) at 0 °C. The reaction mixture was stirred for 1 h, and then, p-nitrobenzyl bromide (66.0 mg, 0.305 mmol, 1.50 equiv) was added. The reaction mixture was stirred overnight at 23 °C. Then, the reaction mixture was extracted with EtOAc (3 x 3 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:2 EtOAc:hexanes) on silica gel to afford N–4-nitrobenzylpiperidin-2-one 141 (42.0 mg, 69% yield). Rf = 0.25 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 5.80 – 5.71 (m, 1H), 5.11 – 5.04 (m, 2H), 4.65 (d, J = 3.8 Hz, 2H), 3.22 (td, J = 6.1, 1.3 Hz, 2H), 2.54 (ddt, J = 13.5, 6.9, 1.3 Hz, 1H), 2.21 (ddt, J = 345   13.4, 8.0, 1.1 Hz, 1H), 1.81 (dddd, J = 11.9, 6.8, 2.9, 1.4 Hz, 3H), 1.76 – 1.72 (m, 2H), Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 1.55 (dq, J = 13.5, 7.4 Hz, 1H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 174.9, 147.4, 145.6, 134.7, 128.7, 124.0, 118.3, 77.2, 50.5, 48.6, 45.5, 43.3, 31.6, 28.9, 19.9, 8.9; IR (Neat Film NaCl) 2939, 1633, 1519, 1344, 1196, 1109; HRMS (MM: ESIAPCI+) m/z calc’d for C17H23N2O3 [M+H]+ : 303.1703; found: 303.1707. O N H + O Et 3N N Cl NO 2 SI-2-2 CH2Cl2, 23 °C (56% yield) N SI-2-3 N NO 2 143 Urea 11. To a solution of propylamine SI-2-22 (100 mg, 0.515 mmol, 1.00 equiv) and Et3N (0.18 mL, 1.29 mmol, 2.50 equiv) in CH2Cl2 (2.60 mL) was added diethylcarbamoyl chloride SI-2-3 (72.0 mL, 0.566 mmol, 1.10 equiv) at 0 °C. The solution was warmed to 23 °C and stirred overnight. Then, the reaction mixture was extracted with CH2Cl2 (3 x 3.5 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 → 1:4 EtOAc:hexanes) on silica gel to afford urea 143 ( 85 mg, 56% yield). Rf = 0.32 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 4.42 (s, 2H), 3.22 (q, J = 7.1 Hz, 4H), 3.06 – 3.01 (m, 2H), 1.61 – 1.52 (m, 2H), 1.11 (t, J = 7.1 Hz, 6H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 164.9, 147.2, 146.9, 128.4, 123.8, 51.4, 51.2, 42.5, 21.1, 13.4, 11.4; IR (Neat Film NaCl) 2967, 1644, 1520, 1410, 1344, 1251, 1132, 1108; HRMS (MM: ESI-APCI+) m/z calc’d for C15H24N3O3 [M+H]+ : 294.1812; found: 294.1863. Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 2.5. 346   References and Notes                                                                                                                 (1) (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th ed; John Wiley & Sons: New York, 2007. (b) Kocienski, P. J. Protecting Groups; George Thieme Verlag: Stuttgart and New York, 1994. (2) Recent examples: (a) Evans, V.; Mahon, M. F.; Webster, R. L. Tetrahedron, 2014, DOI: 10.1016/j.tet.2014.07.080. (b) Yang, Q.; Njardarson, J. T. Tetrahedron Lett. 2013, 54, 7080–7082. (c) Sugiura, R.; Kozaki, R.; Kitani, S.; Gosho, Y.; Tanimoto, H.; Nishiyama, Y.; Morimoto, T.; Kakiuchi, K. Tetrahedron, 2013, 69, 3984–3990. (3) (a) Williams, R. M.; Kwast, E. Tetrahedron Lett. 1989, 30, 451–454. (b) Pagano, N.; Wong, E. Y. Breiding, T.; Liu, H.; Wilbuer, A.; Bregman, H.; Shen, Q.; Diamond, S. L.; Meggers, E. J. Org. Chem. 2009, 74, 8997–9009. (c) Rodríguez-Vázquez, N.; Salzinger, S.; Silva, L. F.; Amorín, M.; Granja, J. R. Eur. J. Org. Chem. 2013, 17, 3477–3493. (d) Overman, L. E.; Rosen, M. D. Angew. Chem. Int. Ed. 2000, 39, 4596–4599. (e) Würdemann, M.; Christoffers, J. Org. Biomol. Chem. 2010, 8, 1894–1898. (f) Fukuyama, T.; Frank, R. K.; Jewell, C. F., Jr. J. Am. Chem. Soc. 1980, 102, 2122–2123. (4) (a) Hoffmann, R. W.; Breitfelder, S.; Schlapbach, A. Helv. Chim. Acta 1996, 79, 346– 352. (b) Hennessy, E. J.; Buchwald, S. L. J. Org. Chem. 2005, 70, 7371–7375. (c) Madin, A.; O’Donnell, C. J.; Oh, T. Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054–18065. (d) Fetter, J.; Giang, L. T.; Czuppon, T.; Lempert, K.; KajtárPeredy, M; Czira, G. Tetrahedron, 1994, 50, 4185–4200. (e) Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron, 1989, 45, 2431–2449. (5) Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. 347                                                                                                                                                                                                                                                                                                                                             (6) (a) Piloto, A. M.; Costa, S. P. G.; Goncalves, M. S. T. Tetrahedron, 2014, 70, 650– Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 657. (b) Voelker, T.; Ewell, T.; Joo, J.; Edstrom, E. D. Tetrahedron Lett. 1998, 39, 359– 362. (c) Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57, 3301–3307. (d) Miknis, G. F.; Williams, R. M. J. Am. Chem. Soc. 1993, 115, 536–547. (7) (a) Stutz, A.; Pitxch, S. Synlett, 1999, 930–934. (b) Pitsch, S. Helv. Chim. Acta 1997, 80, 2286–2314. (8) Fukase, K.; Tanaka, H.; Torii, S.; Kusumoto, S. Tetrahedron Lett. 1990, 31, 389–392. (9) From the deprotection reaction of urea 143, hemiaminal ether intermediate 153 was observed in 1 hour under the standard reaction conditions and intermediate 153 was converted to propyl urea 144 after 10.5 hours. In addition, acetal 154 was observed in 2 hours during the deprotection reaction of ether 149, and the desired phenylethyl alcohol 150 was isolated after 32 hours. O N O 20% aq NaOH N NO 2 N OMe N N MeOH, 75 °C (94% yield) 143 MeOH, 75 °C (59% yield; 74% yield based on recovered 149 ) 144 OMe 20% aq NaOH NO 2 NH NO 2 153 O 149 O O 154 OH NO 2 150 Appendix 6 – Spectra Relevant to Chapter 2 348 APPENDIX 6 Spectra Relevant to Chapter 2: A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 137a O2N O N                                                                                                     349   Figure A6.1. 1H NMR (500 MHz, CDCl3) of compound 137a. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.2. Infrared spectrum (Thin Film, NaCl) of compound 137a.  Figure A6.3. 13C NMR (125 MHz, CDCl3) of compound 137a.   350   NO 2 137b O N                                                                                                     351   Figure A6.4. 1H NMR (500 MHz, CDCl3) of compound 137b. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.5. Infrared spectrum (Thin Film, NaCl) of compound 137b.  Figure A6.6. 13C NMR (125 MHz, CDCl3) of compound 137b.   352   NO 2 137c O N                                                                                                     353   Figure A6.7. 1H NMR (500 MHz, CDCl3) of compound 137c. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.8. Infrared spectrum (Thin Film, NaCl) of compound 137c.  Figure A6.9. 13C NMR (125 MHz, CDCl3) of compound 137c.   354   139 NO 2 N O                                                                                                     355   Figure A6.10. 1H NMR (500 MHz, CDCl3) of compound 139. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.11. Infrared spectrum (Thin Film, NaCl) of compound 139.  Figure A6.12. 13C NMR (125 MHz, CDCl3) of compound 139.   356   141 NO 2 N O                                                                                                     357   Figure A6.13. 1H NMR (500 MHz, CDCl3) of compound 141. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.14. Infrared spectrum (Thin Film, NaCl) of compound 141.  Figure A6.15. 13C NMR (125 MHz, CDCl3) of compound 141.   358   NO 2 143 N N O                                                                                                     359   Figure A6.16. 1H NMR (500 MHz, CDCl3) of compound 143. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2     Figure A6.17. Infrared spectrum (Thin Film, NaCl) of compound 143.  Figure A6.18. 13C NMR (125 MHz, CDCl3) of compound 143.   360   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 361   CHAPTER 3 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.1. Introduction The unique properties of the axially chiral P,N ligand QUINAP (155a) have been employed widely for various transition metal catalyzed asymmetric reactions.1 However, approaches to the synthesis of QUINAP ligands in high enantiomeric purity are limited.2 In 2013, our laboratories explored the palladium-catalyzed atroposelective synthesis of QUINAP and its derivatives via kinetic resolution and dynamic kinetic resolution.3 With a robust method for the synthesis of chiral QUINAP in hand, we turned our attention to the architecturally related PINAP ligands (156). PINAP ligands (156a and 156b), which possess analogous ligation reactivity to QUINAP, were first developed by the Carreira group in 2004.4 Carreira and co-workers separated the two atropoisomeric diastereomers through column chromatography by preparing chiral ether- or amine-substituted PINAP scaffolds. Herein, we disclose synthetic methods for accessing enantiomerically enriched PINAP ligands via dynamic kinetic resolution (156a, 156c). 362   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution Figure 3.1.1. QUINAP (155) and PINAP (156) R1 O N 3.2. Ph HN Ph N N N N OR 2 N N PPh 2 PPh 2 PPh 2 PPh 2 R 1 = alkyl R 2 = achiral alkyl, benzyl QUINAP (155a) O-PINAP (156a) N-PINAP (156b) PINAP (156c) Results  and  Discussion   Our initial attempts to apply the standard QUINAP dynamic kinetic resolution conditions,3 3.0 mol % of Pd[(o-tol)3P]2 and 4.5 mol % of (S, RFc)-Josiphos at 80 °C, to aryl triflate 157 afforded various alkyl- or benzyl-substituted PINAP ligands (Table 3.2.1). Asymmetric C–P couplings via dynamic kinetic resolution on substrates incorporating methoxy, ethoxy, and isopropoxy groups furnished the corresponding PINAP ligands in good yields and selectivities (158a,b,c). Cyclohexyl, 3,3-dimethyl-1butyl, and homoallyl ether groups were also well tolerated under the reaction conditions to give the desired products. (158d,e,f). Additionally, 3,5-dimethyl benzyloxy- substituted PINAP was obtained in good yield and moderate selectivity (158g). Although these initial results were exciting, it was clear that additional optimization was needed to improve the enantioselectivities in the synthesis of these PINAP ligands. 363   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution Table 3.2.1. Scope of dynamic kinetic resolution under initial standard conditions OR OR Pd[(o-tol)3P] 2 (3.0 mol %) (S, RFc )-Josiphos (4.5 mol %) Ph 2PH, DMAP N N N N dioxane, 80 °C OTf PPh 2 157 158 OMe OEt O O N N N N N N N N PPh 2 PPh 2 PPh 2 PPh 2 158a 158b 158c 158d 90% yieldb, 82% eec 48% yieldb, 71% eec 71% yieldb, 86% eec 80% yieldb, 75% eec t-Bu O O O N N N N N N PPh 2 PPh 2 Cy2P PPh 2 Fe PCy 2 (S, RFc )-Josiphos 158e 158f 158g 61% yieldb, 88% eec 63% yieldb, 82% eec 70% yieldb, 60% eec a Reactions performed with 1.0 equiv of triflate 157, 4.0 equiv of DMAP, 3.0 mol % of Pd[(o-tol)3P]2, 4.5 mol % of (S, RFc)-Josiphos, 1.05 equiv of Ph2PH (1.0 M in dioxane) at 0.20 M in dioxane at 80 °C in a glovebox. Ph2PH (1.0 M in dioxane) was added over 4 h. In order to allow more time for the isomerization of the presumed arylpalladium complex before its subsequent phosphination, diphenylphosphine (1.0 M solution in dioxane) was added slowly.5 In addition, we used pre-stirred 1.0 mol % of Pd[(o-tol)3P]2 and 1.5 mol % of (S, RFc)-Josiphos solutions in dioxane. Interestingly, improved enantioselectivity was observed with reduced palladium and Josiphos ligand loadings (1.0 mol % and 1.5 mol %, respectively) (Table 3.2.2, entries 1 and 2). We were pleased to find that higher enantioselectivities were obtained at lower temperatures (Table 3.2.2, 364   entries 3 and 4). However, the conversion rate was dramatically diminished at 50 °C Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution (Table 3.2.2, entry 5). Table 3.2.2. Optimization of reaction parametersa OMe OMe Pd[(o-tol)3P] 2 (S, RFc )-Josiphos Ph 2PH, DMAP N N OTf N Cy2P N dioxane Fe PCy 2 PPh 2 (S, RFc )-Josiphos 157a entry 158a Pd[(o-tol)3P] 2 (S, RFc )-Josiphos T (°C) yield (%)b ee (%) 82c 1 3.0 mol % 4.5 mol % 80 90 2 1.0 mol % 1.5 mol % 80 95 88c 3 1.0 mol % 1.5 mol % 70 75 92c 4 1.0 mol % 1.5 mol % 60 80 96c 5 1.0 mol % 1.5 mol % 50 –d 94c a   Reactions performed with 1.0 equiv of 157a, 4.0 equiv of DMAP, 1.0 mol % of Pd[(o-tol)3P]2, 1.5 mol % of (S, RFc)-Josiphos, 1.05 equiv of Ph2PH (1.0 M in dioxane) at 0.20 M in dioxane in a glovebox. Pd[(otol)3P]2 and (S, RFc)-Josiphos in dioxane were pre-stirred before use. Ph2PH (1.0 M in dioxane) was added over 8 h. bAll yields are isolated yields. cDetermined by chiral SFC analysis. d~50% conversion. With the optimized conditions in hand, we investigated the substrate scope of the reaction (Table 3.2.3). Several alkoxy- and benzyloxy-substituted PINAP ligands were furnished in improved enantioselectivities under the optimized conditions (158a–158h, 57–80% yields and 82–96% ee). Applying our optimized conditions to a (R)- phenylethoxy-substituted substrate, which was previously prepared by the Carreira group by chromatographic separation, generated the corresponding PINAP product in 95% de (158i). Interestingly, diastereomeric PINAP 158j was produced by our method with lower selectivity using the (R, SFc)-Josiphos ligand indicating some balance between substitute and catalyst in the progress (e.g., mismatched pair). Thankfully, nearly enantiopure PINAP 158j was obtained after recrystallization. Unfortunately, in the case of (R)-α-phenethylamine-substituted PINAP, only moderate selectivity was observed 365   (158k). Additionally, application of our conditions to the reaction of triflate 157a with Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution diphenylphosphine oxide or (p-CF3-C6H4)2PH proved unsuccessful, and only low yield and selectivities were observed.6,7 Table 3.2.3. Scope of dynamic kinetic resolution under optimized conditionsa OR OR Pd[(o-tol)3P] 2 (1.0 mol %) (S, RFc )-Josiphos (1.5 mol %) Ph 2PH, DMAP N N N N dioxane, 60 °C OTf PPh 2 157 158 OMe OEt N N N N N N N N O O PPh 2 PPh 2 158a 158b 158c 158d 80% yieldb, 96% eec 73% yieldb, 94% eec 70% yieldb, 82% eec 67% yieldb, 95% eec t-Bu O O PPh 2 PPh 2 O O N N N N N N N N PPh 2 158e PPh 2 PPh 2 PPh 2 158f 158g 158h 57% yieldb, 95% eec 67% yieldb, 94% eec 60% yieldb, 94% eec 72% yieldb, 94% eec O O Ph Ph HN Ph N N N N N N PPh 2 PPh 2 Cy2P Fe PCy 2 PPh 2 (S, RFc )-Josiphos a 158i 158j f 158k 65% yieldb, 95% ded 71% yieldb, 88% dee (57% yield, >99% dee after recrystallization) 79% yieldb, 60% deg   Reactions performed with 1.0 equiv of 157a, 4.0 equiv of DMAP, 1.0 mol % of Pd[(o-tol)3P]2, 1.5 mol % of (S, RFc)-Josiphos, 1.05 equiv of Ph2PH (1.0 M in dioxane) at 0.20 M in dioxane at 60 °C in a glovebox. Pd[(o-tol)3P]2 and (S, RFc)-Josiphos in dioxane were pre-stirred before use. Ph2PH (1.0 M in dioxane) was added over 8 h. bAll yields are isolated yields. cDetermined by chiral SFC analysis. dDetermined by chiral 366   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution SFC analysis; SFC conditions: 40% IPA, 2.5 mL/min, Chiralpak OD-H column, tR (min): major = 2.81, minor = 3.18. eDetermined by chiral HPLC. f(R, SFc)-Josiphos was used. gDetermined by 1H NMR. We applied PINAP ligand 158a (96% ee) to two different reactions (Scheme 3.2.1).8 Copper catalyzed asymmetric phenylacetylene addition to isoquinoline iminium 159 with PINAP ligand 158a afforded propargylamine 160 in 98% yield and 96% ee (Scheme 3.2.1a).1k, 9 In addition, rhodium-catalyzed enantioselective diboration and oxidation of trans-b-methylstyrene 161 with PINAP 158a produced diol 162 in 71% yield and 88% ee (Scheme 3.2.1b).1e,i,10 The enantioselectivities and yields with PINAP 158a ligand are parallel to those with QUINAP 155a. Scheme 3.2.1. Applications (a) OMe phenylacetylene (10 equiv) 5.0 mol % CuBr 5.5 mol % (R)-PINAP Et 3N (1.0 equiv) MeO N MeO Br Br OMe MeO N MeO CH2Cl2, –55 °C Br Ph 159 160 (98% yield, 96% ee with PINAP 158a ; 85% yield, 95% ee with QUINAP, Ref.1k) (b) Me Ph 1. 5.0 mol % (nbd)Rh(acac) 5.0 mol % (R)-PINAP 1.1 equiv B 2(cat)2 THF, 23 °C OH Me Ph 2. 3N NaOH, 30% H 2O2 OH 161 162 (71% yield, 88% ee with PINAP 158a ; 71% yield, 93% ee with QUINAP, Ref. 1e,i) 3.3. Conclusion   In conclusion, the atroposelective synthesis of various achiral alkyl- or benzyloxy-substituted PINAP ligands via dynamic kinetic resolution has been developed. The asymmetric PINAP ligands formed in this communication are envisioned to be useful in several important asymmetric transformations.4 Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.4. Experimental Methods and Analytical Data 3.4.1. Materials and Methods 367   Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13 C NMR spectra are recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a 368   Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution reported in frequency of absorption (cm-1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell and are reported as: [a]DT (concentration in g/100 mL, solvent). Analytical HPLC was performed with an Agilent 1100 Series HPLC utilizing Chiralpak (AD-H or AS) or Chiralcel (OD-H, OJ-H, or OB-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing Chiralpak (AD-H, AS-H or IC) or Chiralcel (OD-H, OJ-H, or OB-H) columns (4.5 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode, or Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). Triflate substrates 157i–157k were prepared by known methods.11 All the data from pinap 158i–158k were confirmed by reported data.1                                                                                                                 (1) (a) Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem. Int., Ed. 2004, 43, 5971–5973. (b) Fujimori, S.; Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635–1657. 369   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.4.2. Experimental Procedures General Procedure for Synthesis of Triflate Substrates Cl OR N N ROH, NaH N OH SI-3-1 OR N Tf2O, DMAP N dioxane, 60 °C OH SI-3-2 N CH2Cl2 OTf 157 To a solution of NaH (2.64 mmol, 2.00 equiv) in dioxane (5.60 mL) was added alcohol (1.39 mmol, 1.05 equiv) in dioxane (1.00 mL) dropwise. The reaction mixture was stirred for 15 min at 23 °C and then SI-3-1 (1.32 mmol, 1.00 equiv) was added portionwise. The solution was stirred for 18 h at 60 °C then diluted with EtOAc (5.00 mL) and water (10.0 mL). The aqueous phase was extracted with EtOAc (3 x 5.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was used in the next step without further purification. To a solution of crude mixture of SI-3-2 (1.32 mmol, 1.00 equiv) and DMAP (2.64 mmol, 2.00 equiv) in CH2Cl2 (13.2 mL) was added Tf2O (1.32 mmol, 1.00 equiv) dropwise at 0 °C. The reaction mixture was stirred at 23 °C until SI-3-2 was fully consumed by TLC analysis. The reaction mixture was diluted with CH2Cl2 (5.00 mL) and water (5.00 mL). The aqueous phase was extracted with CH2Cl2 (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:4 EtOAc:hexanes) on silica gel to give the corresponding triflate substrates. General Procedure of PINAP from Triflates via Dynamic Kinetic Resolution 370   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution OR N N OR Pd[(o-tol)3P] 2 (1.0 mol %) (S, RFc )-Josiphos (1.5 mol %) Ph 2PH, DMAP OTf N Cy2P N dioxane, 60 °C Fe PCy 2 PPh 2 (S, RFc )-Josiphos 157 158 This reaction was performed in a nitrogen-filled glovebox. Pd[(o-tol)3P]2 (10.8 mg, 0.0151 mmol) and (S, RFc)-Josiphos (13.7 mg, 0.0226 mmol) in dioxane (0.302 mL) were pre-stirred in a vial until all the solids were dissolved. To a solution of triflates 157 (0.211 mmol, 1.00 equiv) in dioxane (1.06 mL) was added DMAP (0.844 mmol, 4.00 equiv) and pre-stirred Pd[(o-tol)3P]2 and (S, RFc)-Josiphos (0.05 M in dioxane; 0.00211 mmol, 0.01 equiv) at 23 °C. The mixture was placed in a reaction well preheated to 60 °C. A solution of Ph2PH (1.00 M in dioxane; 0.317 mmol, 1.50 equiv) was added to the reaction mixture in 20 uL portions every 30 minutes manually. After completion of the addition (8 hours), the reaction was stirred for further 7 hours at which point complete consumption of the starting material was observed. The reaction was cooled, removed from the glovebox and dilulted with EtOAc (1.50 mL) and water (2.00 mL). The aqueous phase was extracted with EtOAc (3 x 1.50 mL). The combined organic phases were washed with brine, dried with MgSO4 and concentrated. The crude material was purified by flash column chromatography on silica gel to afford the corresponding PINAP 158. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.4.3. 371   Spectroscopic Data OMe N N OTf 157a 52% (2-step yield); Rf = 0.29 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.35 (dd, J = 8.2, 1.0 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.87 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.70 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.58 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.42 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.31 (dt, J = 8.4, 1.0 Hz, 1H), 4.41 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.9, 151.1, 145.6, 133.6, 132.7, 132.6, 132.4, 131.9, 129.2, 128.4, 128.1, 127.4, 126.7, 126.6, 125.7, 123.5, 119.9, 119.6, 117.1, 55.3; IR (Neat Film NaCl) 3063, 2945, 1668, 1581, 1541, 1496, 1457, 1420, 1364, 1247, 1213, 1139, 952, 834 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C20H14F3N2O4S [M+H]+ : 435.0621; found: 435.0625. OEt N N OTf 157b 48% (2-step yield); Rf = 0.33 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, Chloroform-d) δ 8.38 (dd, J = 8.2, 1.2 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.87 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.69 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.57 (ddd, J = 8.2, 6.7, 1.4 Hz, 1H), 7.42 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.3, 1.0 Hz, 1H), 4.88 (qd, J = 7.0, 3.9 Hz, 2H), 1.62 (td, J = 372   7.1, 1.6 Hz, 3H); C NMR (126 MHz, CDCl3) δ 160.6, 150.7, 145.6, 133.6, 132.7, 132.5, Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 13 132.3, 131.8, 129.2, 128.4, 128.1, 127.4, 126.7, 126.6, 125.6, 123.6, 120.0, 119.6, 117.1, 63.9, 14.7; IR (Neat Film NaCl) 3066, 2984, 1582, 1540, 1495, 1422, 1381, 1342, 1214, 1140, 1073, 1024, 956, 941, 834 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C21H16F3N2O4S [M+H]+ : 449.0777; found: 449.0780. O N N OTf 157c 37% (2-step yield); Rf = 0.35 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.37 (dd, J = 8.2, 1.0 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.87 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.69 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.58 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.43 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H), 7.40 – 7.35 (m, 1H), 7.30 (dt, J = 8.3, 0.9 Hz, 1H), 5.94 (hept, J = 6.2 Hz, 1H), 1.60 (d, J = 6.1 Hz, 3H), 1.58 (d, J = 6.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 160.3, 150.2, 145.7, 133.5, 132.7, 132.5, 132.4, 132.0, 129.3, 128.5, 128.2, 127.4, 126.6, 126.4, 125.7, 123.7, 120.4, 119.7, 71.1, 22.3, 22.1; IR (Neat Film NaCl) 2981, 1582, 1493, 1417, 1322, 1212, 1140, 1106, 958, 942, 833, 748 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H17F3N2O4S [M+H]+ : 463.0934; found: 463.0964. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 373   O N N OTf 157d 36% (2-step yield); Rf = 0.43 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.2 Hz, 1H), 8.11 (dd, J = 9.1, 1.6 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.85 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.67 (td, J = 7.7, 7.0, 1.4 Hz, 1H), 7.61 (dd, J = 9.1, 2.0 Hz, 1H), 7.57 (ddd, J = 8.2, 6.2, 1.9 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.27 (d, J = 8.3 Hz, 1H), 5.72 (tt, J = 8.7, 3.7 Hz, 1H), 2.25 (d, J = 12.3 Hz, 2H), 1.90 (ddt, J = 13.9, 8.9, 4.5 Hz, 2H), 1.85 – 1.74 (m, 2H), 1.66 (td, J = 8.5, 7.7, 4.2 Hz, 1H), 1.57 (dtt, J = 13.5, 10.2, 3.4 Hz, 2H), 1.45 (ddt, J = 13.3, 10.1, 3.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 160.2, 150.3, 145.6, 133.6, 132.7, 132.3, 132.1, 131.7, 129.3, 128.4, 128.1, 127.3, 126.9, 126.7, 125.5, 123.7, 120.3, 119.7, 75.4, 32.0, 31.8, 25.9, 24.1; IR (Neat Film NaCl) 2937, 2858, 1582, 1537, 1493, 1418, 1362, 1342, 1214, 1140, 959, 944, 834 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C25H22F3N2O4S [M+H]+ : 503.1247; found: 503.1248. O N N OTf 157e 49% (2-step yield); Rf = 0.33 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.86 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.69 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.57 (ddd, 374   J = 8.2, 6.6, 1.3 Hz, 1H), 7.42 (ddd, J = 8.1, 6.6, 1.2 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.29 Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution (d, J = 8.3 Hz, 1H), 4.88 (t, J = 7.2 Hz, 2H), 1.96 (t, J = 7.2 Hz, 2H), 1.10 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 160.7, 150.7, 145.6, 133.6, 132.7, 132.4, 132.3, 131.8, 129.2, 128.4, 128.1, 127.4, 126.6, 125.6, 123.5, 120.0, 119.6, 117.1, 110.2, 65.8, 42.5, 30.0; IR (Neat Film NaCl) 2958, 1582, 1538, 1495, 1422, 1360, 1214, 1141, 1073, 953, 834, 620 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C25H23F3N2O4S [M+H]+ : 505.1403; found: 505.1436. O N N OTf 157f 52% (2-step yield); Rf = 0.33 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.38 – 8.34 (m, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.87 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.69 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.61 (d, J = 9.1 Hz, 1H), 7.57 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.42 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 7.38 – 7.35 (m, 1H), 7.30 (dd, J = 8.3, 1.1 Hz, 1H), 6.04 (ddt, J = 17.1, 10.3, 6.7 Hz, 1H), 5.28 (dq, J = 17.2, 1.7 Hz, 1H), 5.17 (dq, J = 10.3, 1.4 Hz, 1H), 4.94 – 4.83 (m, 2H), 2.78 (dddd, J = 8.1, 6.6, 5.2, 1.4 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 160.6, 150.9, 145.6, 134.6, 133.6, 132.7, 132.5, 132.3, 131.8, 129.2, 128.4, 128.1, 127.4, 126.7, 126.6, 125.6, 123.5, 119.9, 119.6, 117.3, 117.1, 67.0, 33.6; IR (Neat Film NaCl) 1581, 1538, 1494, 1421, 1349, 1213, 1139, 954, 833 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H18F3N2O4S [M+H]+ : 475.0934; found: 475.0956. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 375   O N N OTf 157g 35% (2-step yield); Rf = 0.38 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.40 (dt, J = 8.2, 1.0 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.00 (dt, J = 8.3, 0.9 Hz, 1H), 7.86 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.70 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.63 (d, J = 9.1 Hz, 1H), 7.58 (ddd, J = 8.2, 6.6, 1.3 Hz, 1H), 7.43 (ddd, J = 7.9, 6.6, 1.3 Hz, 1H), 7.39 (dd, J = 8.6, 1.2 Hz, 1H), 7.31 (dt, J = 8.4, 1.0 Hz, 1H), 7.04 (s, 1H), 5.80 (d, J = 2.3 Hz, 2H), 2.39 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 160.6, 151.1, 145.6, 138.3, 136.7, 133.6, 132.7, 132.6, 132.3, 131.8, 130.1, 129.3, 128.4, 128.1, 127.4, 126.7, 126.6, 126.6, 125.6, 123.7, 119.9, 119.7, 117.1, 69.8, 21.4; IR (Neat Film NaCl) 2917, 1581, 1494, 1418, 1343, 1213, 1140, 956, 835 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C28H22F3N2O4S [M+H]+ : 539.1247; found: 539.1252. O N N OTf 157h 68% (2-step yield); Rf = 0.37 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.38 (dt, J = 8.2, 1.0 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.01 (dt, J = 8.3, 0.9 Hz, 1H), 7.85 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.70 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.62 (dd, J = 9.1, 1.1 Hz, 1H), 7.58 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.57 – 7.52 (m, 2H), 7.43 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.37 (dt, J = 8.6, 1.0 Hz, 1H), 7.31 (dt, J = 8.3, 1.0 Hz, 1H), 7.27 (d, J = 7.2 376   Hz, 2H), 5.81 (d, J = 7.1 Hz, 2H), 2.41 (s, 3H); C NMR (126 MHz, CDCl3) δ 160.5, Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 13 151.1, 145.5, 138.3, 133.7, 133.5, 132.6, 132.3, 131.9, 129.4, 129.2, 128.90, 128.4, 128.1, 127.4, 126.7, 126.6, 125.6, 123.6, 119.8, 119.6, 119.6, 117.0, 69.6, 21.4; IR (Neat Film NaCl) 3058, 1581, 1538, 1494, 1422, 1342, 1248, 1266, 1140, 1072, 953, 834, 776 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C27H19F3N2O4S [M+H]+ : 525.1090; found: 525.1096. OMe N N PPh 2 158a [a]D25 +124.5 (c 0.51, CHCl3); Rf = 0.42 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.27 (dt, J = 8.3, 1.0 Hz, 1H), 7.91 (dd, J = 8.6, 0.8 Hz, 1H), 7.90 – 7.87 (m, 1H), 7.74 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.49 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.29 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.27 – 7.14 (m, 11H), 7.07 (dt, J = 8.2, 0.9 Hz, 1H), 4.36 (s, 3H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.4, 156.8, 156.8, 141.5, 141.3, 137.5, 137.4, 137.3, 137.2, 136.0, 135.9, 134.0, 133.9, 133.7, 133.3, 133.2, 133.1, 131.8, 131.7, 130.3, 130.0, 129.9, 129.3, 128.7, 128.4, 128.4, 128.2, 128.1, 127.1, 126.9, 126.7, 126.7, 126.1, 123.2, 119.6, 55.1; 31P NMR (121 MHz, CDCl3) δ -14.3; IR (Neat Film NaCl) 3053, 1582, 1538, 1495, 1456, 1362, 1112, 1018, 744 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C31H23N2OP [M+H]+ : 471.1621; found: 471.1674; SFC conditions: 35% IPA, 2.5mL/min, Chiralcel OD-H column, tR (min): major = 5.81, minor = 5.16. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 377   OEt N N PPh 2 158b [a]D25 +150.3 (c 0.47, CHCl3); Rf = 0.54 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.30 (dd, J = 8.2, 1.0 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.74 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.49 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.29 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.27 – 7.13 (m, 11H), 7.07 (d, J = 8.2 Hz, 1H), 4.83 (qt, J = 7.1, 2.1 Hz, 2H), 1.60 (t, J = 7.1 Hz, 3H); (due to the C–P coupling, the 13 C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.2, 156.5, 156.5, 141.6, 141.3, 137.6, 137.5, 137.3, 137.2, 136.0, 135.9, 134.0, 133.8, 133.7, 133.3, 133.2, 133.1, 131.8, 131.5, 130.3, 130.0, 129.9, 129.2, 128.6, 128.4, 128.4, 128.2, 128.1, 127.1, 126.8, 126.8, 126.7, 126.1, 123.3, 119.6, 63.5, 14.9; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 3053, 2980, 1583, 1538, 1494, 1418, 1378, 1342, 1165, 1110, 1023, 818, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C32H25N2OP [M+H]+ : 485.1777; found: 485.1800; SFC conditions: 30% MeOH, 2.5mL/min, Chiralpak AD-H column, tR (min): major = 2.60, minor = 3.09. O N N PPh 2 158c 378   +131.7 (c 0.57, CHCl3); Rf = 0.54 (1:2 EtOAc:hexanes); H NMR (500 MHz, Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution [a]D 25 1 CDCl3) δ 8.29 (dt, J = 8.1, 1.0 Hz, 1H), 7.90 (t, J = 9.0 Hz, 2H), 7.73 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.52 – 7.42 (m, 3H), 7.30 (ddd, J = 8.4, 6.6, 1.2 Hz, 1H), 7.28 – 7.15 (m, 11H), 7.08 (dt, J = 8.1, 0.9 Hz, 1H), 5.88 (p, J = 6.2 Hz, 1H), 1.58 (d, J = 5.7 Hz, 3H), 1.56 (d, J = 5.7 Hz, 3H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 159.7, 156.0, 156.0, 141.6, 141.3, 137.6, 137.5, 137.3, 137.2, 136.0, 135.9, 134.0, 133.8, 133.7, 133.4, 133.2, 133.2, 133.1, 131.7, 131.4, 130.2, 130.0, 129.2, 128.6, 128.4, 128.4, 128.4, 128.4, 128.2, 128.1, 127.0, 126.8, 126.0, 123.4, 120.0, 70.1, 22.4, 22.3; 31P NMR (121 MHz, CDCl3) δ -13.9; IR (Neat Film NaCl) 3053, 2978, 1584, 1489, 1413, 1383, 1315, 1106, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C33H27N2OP [M+H]+ : 499.1934; found: 499.1960; SFC conditions: 40% MeOH, 2.5mL/min, Chiralpak AD-H column, tR (min): major = 1.94, minor = 2.22. O N N PPh 2 158d [a]D25 +91.0 (c 0.57, CHCl3); Rf = 0.61 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.29 (dt, J = 8.2, 1.0 Hz, 1H), 7.89 (ddd, J = 9.4, 8.2, 0.8 Hz, 2H), 7.73 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.49 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H), 7.46 – 7.41 (m, 2H), 7.29 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.26 – 7.14 (m, 11H), 7.07 (dt, J = 8.3, 0.9 Hz, 1H), 5.67 (tt, J = 8.9, 3.8 Hz, 1H), 2.30 – 2.18 (m, 2H), 1.88 (ddtd, J = 9.3, 7.9, 5.4, 4.0 Hz, 2H), 1.76 (qdt, 379   J = 9.9, 6.1, 3.7 Hz, 2H), 1.64 (tt, J = 9.1, 4.9 Hz, 1H), 1.54 (qq, J = 10.2, 3.5 Hz, 2H), Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 1.42 (ddt, J = 13.4, 10.2, 3.5 Hz, 1H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 159.6, 156.0, 155.9, 141.6, 141.4, 137.6, 137.5, 137.3, 137.2, 136.0, 135.9, 134.0, 133.9, 133.7, 133.4, 133.2, 131.7, 131.4, 130.3, 130.0, 129.2, 128.6, 128.4, 128.4, 128.4, 128.4, 128.2, 128.1, 127.0, 126.8, 126.8, 126.8, 126.0, 123.4, 120.0, 74.8, 32.0, 31.9, 25.9, 24.1, 24.0; 31P NMR (121 MHz, CDCl3) δ -13.9; IR (Neat Film NaCl) 3051, 2933, 2856, 1582, 1538, 1490, 1432, 1413, 1361, 1341, 1311, 1263, 1215, 1165, 1113, 1068, 1046, 1019, 744 cm1 ; HRMS (MM: ESI-APCI+) m/z calc’d for C36H31N2OP [M+H]+ : 539.2247; found: 539.2268; SFC conditions: 25% MeOH, 2.5mL/min, Chiralcel OD-H column, tR (min): major = 7.58, minor = 8.13. O N N PPh 2 158e [a]D25 +101.2 (c 0.42, CHCl3); Rf = 0.62 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.27 (dt, J = 8.2, 1.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.73 (ddt, J = 8.7, 7.1, 1.4 Hz, 1H), 7.49 (ddt, J = 8.5, 6.9, 1.5 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.29 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.27 – 7.14 (m, 11H), 7.06 (d, J = 8.2 Hz, 1H), 4.87 – 4.77 (m, 2H), 1.94 (td, J = 7.1, 1.9 Hz, 2H), 1.09 (s, 9H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.3, 156.5, 156.4, 141.6, 141.3, 137.6, 137.5, 137.3, 137.2, 136.0, 380   135.9, 134.0, 133.9, 133.7, 133.3, 133.2, 133.1, 131.7, 131.6, 130.3, 129.9, 129.2, 128.7, Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 128.4, 128.4, 128.2, 128.1, 127.1, 126.8, 126.8, 126.7, 126.1, 123.2, 119.7, 77.2, 65.4, 42.5, 30.1; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 3051, 2956, 1418, 1386, 1114, 743 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C36H33N2OP [M+H]+ : 541.2403; found: 541.2409; SFC conditions: 35% IPA, 2.5mL/min, Chiralcel OD-H column, tR (min): major = 4.33, minor = 4.84. O N N PPh 2 158f [a]D25 +117.9 (c 0.52, CHCl3); Rf = 0.62 (1:2 EtOAc:hexanes); 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.75 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.52 – 7.41 (m, 3H), 7.30 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.26 – 7.14 (m, 11H), 7.08 (dt, J = 8.4, 0.9 Hz, 1H), 6.04 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.28 (dq, J = 17.2, 1.7 Hz, 1H), 5.17 (dt, J = 10.5, 1.6 Hz, 1H), 4.88 – 4.77 (m, 2H), 2.75 (qt, J = 6.8, 1.3 Hz, 2H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.1, 156.7, 156.6, 141.5, 141.2, 137.6, 137.5, 137.2, 137.2, 136.0, 135.9, 134.9, 134.0, 133.8, 133.7, 133.3, 133.2, 133.2, 133.1, 131.9, 131.6, 130.3, 130.0, 130.0, 129.3, 128.7, 128.4, 128.4, 128.2, 128.1, 127.1, 126.9, 126.7, 126.7, 126.1, 123.2, 119.6, 117.2, 77.2, 66.7, 33.7; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 2096, 1642, 1417, 1348, 1113, 1020, 818, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C34H27N2OP [M+H]+ : 511.1934; 381   found: 511.1954; SFC conditions: 35% MeOH, 2.5mL/min, Chiralpak AD-H column, tR Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution (min): major = 3.00, minor = 3.66. O N N PPh 2 158g [a]D25 +40.1 (c 0.31, CHCl3); Rf = 0.56 (1:2 EtOAc:hexanes); 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 8.2 Hz, 1H), 7.91 (t, J = 7.8 Hz, 2H), 7.73 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.54 – 7.41 (m, 3H), 7.35 – 7.13 (m, 14H), 7.12 – 7.03 (m, 2H), 5.74 (d, J = 5.4 Hz, 2H), 2.39 (s, 6H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (75 MHz, CDCl3) δ 160.1, 156.9, 156.8, 141.5, 141.1, 138.3, 137.5, 137.4, 137.3, 137.1, 136.9, 136.0, 135.9, 134.1, 133.8, 133.7, 133.4, 133.2, 133.1, 133.1, 131.9, 131.6, 130.3, 130.0, 130.0, 129.3, 128.7, 128.5, 128.4, 128.4, 128.2, 128.1, 127.1, 126.9, 126.7, 126.7, 126.6, 126.6, 126.1, 123.4, 119.6, 69.5, 21.5; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 3052, 2917, 1608, 1582, 1538, 1492, 1480, 1432, 1414, 1386, 1345, 1264, 1165, 1113, 1019, 962, 851, 818, 777, 743 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C39H31N2OP [M+H]+ : 575.2247; found: 575.2293; SFC conditions: 40% MeOH, 2.5mL/min, Chiralcel OD-H column, tR (min): major = 5.77, minor = 6.82. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 382   O N N PPh 2 158h [a]D25 +118.5 (c 0.33, CHCl3); Rf = 0.61 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.29 (dt, J = 8.2, 1.7 Hz, 1H), 7.91 (dd, J = 8.6, 2.5 Hz, 1H), 7.88 (dd, J = 8.2, 1.1 Hz, 1H), 7.71 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.52 (dd, J = 8.2, 2.6 Hz, 2H), 7.48 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.43 (dddd, J = 9.2, 6.0, 3.4, 1.8 Hz, 2H), 7.32 – 7.13 (m, 14H), 7.10 – 7.06 (m, 1H), 5.76 (q, J = 12.1 Hz, 2H), 2.40 (s, 3H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.1, 156.9, 156.8, 141.4, 141.2, 138.1, 137.5, 137.4, 137.2, 137.1, 136.0, 135.9, 134.0, 133.9, 133.7, 133.4, 133.2, 133.1, 131.9, 131.6, 130.3, 130.0, 130.0, 129.4, 129.4, 129.3, 128.9, 128.7, 128.4, 128.4, 128.4, 128.4, 128.3, 128.1, 127.1, 126.9, 126.7, 126.7, 126.1, 123.3, 119.6, 69.3, 21.4; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 3051, 1583, 1492, 1416, 1345, 1163, 1112, 1019, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C38H29N2OP [M+H]+ : 561.2090; found: 561.2090; SFC conditions: 40% MeOH, 2.5mL/min, Chiralpak AD-H column, tR (min): major = 3.43, minor = 5.21. 3.5. References and Notes                                                                                                                 (1)   (a) Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J. M. Chem. Eur. J. 1999, 5, 1320–1330. (b) Faller, J. W.; Grimmond, B. J. Organometallics 2001, 20, 2454–2458. (c) Maeda, K.; Brown, J. M. Chem. Commun. 2002, 310–311. (d) Gommermann, N.; 383                                                                                                                                                                                                                                                                                                                                             Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763–5766. (e) Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003, 125, 8702–8703. (f) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174–10175. (g) DauraOller, E.; Segarra, A. M.; Poblet, J. M.; Claver, C.; Fernández, E.; Bo, C. J. Org. Chem. 2004, 69, 2669–2680. (h) Black, A.; Brown, J. M.; Pichon, C. Chem. Commun. 2005, 5284–5286. (i) Trudeau, S.; Morgan, J. B.; Shrestha, M.; Morken, J. P. J. Org. Chem. 2005, 70, 9538–9544. (j) Gommermann, N.; Knochel, P. Chem.–Eur. J. 2006, 12, 4380– 4392. (k) Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143–146. (l) Li, X.; Kong, L.; Gao, Y.; Wang, X. Tetrahedron Lett. 2007, 48, 3915–3917. (m) Miura, T.; Yamauchi, M.; Kosaka, A.; Murakami, M. Angew. Chem., Int. Ed. 2010, 49, 4955–4957. (n) Lim, A. D.; Codelli, J. A.; Reisman, S. E. Chem. Sci. 2013, 4, 650–654. (o) Fernández, E. Guiry, P. J.; Connole, K. P. T.; Brown, J. M. J. Org. Chem. 2014, 79, 5391–5400. (2) (a) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743–756. (b) Lim, C. W.; Tissot, O.; Mattison, A. Hooper, M. W.; Brown, J. M.; Cowley, A. R.; Hulmes, D. I.; Blacker, A. J. Org. Process Res. Dev. 2003, 7, 379–384. (c) Thaler, T.; Geittner, F.; Knochel, P. Synlett 2007, 2655–2658. (d) Clayden, J.; Fletcher, S. P.; McDouall, J. J. W.; Rowbottom, S. J. M. J. Am. Chem. Soc. 2009, 131, 5331–5343. (3) Bhat, V.; Wang, S.; Stoltz, B. M.; Virgil, S. C. J. Am. Chem. Soc. 2013, 135, 16829– 16832. (4) (a) Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971–5973. (b) Fujimori, S.; Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635–1657. (5)  See Ref. 3 for a plausible mechanism of this dynamic kinetic resolution. 384                                                                                                                                                                                                                                                                                                                                               (6)   Attempts to produce PINAP derivatives with diphenylphosphine oxide and (p-CF3Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution C6H4)2PH in high enantioselectivities under our dynamic kinetic resolution conditions were unsuccessful. OMe OMe Pd[(o-tol)3P] 2 (S, RFc )-Josiphos Ar2PH, DMAP N N N N dioxane OTf Cy2P O PCy 2 Fe PAr 2 (S, RFc )-Josiphos 157a 163 O entry Ar2PH T (°C) ee (%) –b 1 diphenylphosphine oxide 60 2 (p-CF3-C6H 4)2PH 60 –c 3 (p-CF3-C6H 4)2PH 70 38d 4 (p-CF3-C6H 4)2PH 80 50d a Reactions performed with 1.0 equiv of 157a , 4.0 equiv of DMAP, 1.0 mol % of Pd[(o-tol) P] , 3 2 1.5 mol % of (S, RFc )-Josiphos, 1.05 equiv of Ar2PH (1.0 M in dioxane) at 0.20 M in dioxane in a b c glovebox. Ar2PH (1.0 M in dioxane) was added over 8 h. No reaction. ~50% conversion. d Determined by chiral SFC analysis; SFC conditions: 35% IPA, 2.5 mL/min, Chiralpak IC column, tR (min): major = 3.06, minor = 3.98.   (7) To demonstrate the scope of our methodology, the enantioselective synthesis of Quinazolinap from triflate 164 was attempted, but our reaction conditions led to poor conversion. Moreover, treatment of triflate 166 with the optimized conditions for PINAP provided the QUINAP ligand in diminished selectivity compared to that with the original reaction conditions3. (a) Pd[(o-tol)3P] 2 (1.0 mol %) (S, RFc )-Josiphos (1.5 mol %) Ph 2PH (1.05 equiv) DMAP (4.0 equiv) N N OTf N N PPh 2 dioxane, 60 °C 164 165 (Low conversion) Pd[(o-tol)3P] 2 (1.0 mol %) (S, RFc )-Josiphos (1.5 mol %) Ph 2PH (1.05 equiv) DMAP (4.0 equiv) (b) N OTf 166 N PPh 2 dioxane, 60 °C 155a (69% yield, 76% ee) 385                                                                                                                                                                                                                                                                                                                                             (8) 96% ee (R)-PINAP 158a was used for both applications. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution (9) Determined by chiral HPLC analysis: conditions: 10% IPA 45 min, AD column, tR: (min): minor = 10.5 min, major = 18.2 min. All the other spectra data were identical to the reported data. (ref. 1k) (10) Determined by chiral SFC analysis: conditions: 20% MeOH, 2.5 mL/min, AD-H column, tR (min): major = 2.46 min, minor = 2.92 min; [a]D25 +38.6 (c 0.19, CHCl3) Appendix 7 – Spectra Relevant to Chapter 3 386 APPENDIX 7 Spectra Relevant to Chapter 3: Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 157a OTf N N OMe                                                                                                   387   Figure A7.1. 1H NMR (500 MHz, CDCl3) of compound 157a. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.2. Infrared spectrum (Thin Film, NaCl) of compound 157a.  Figure A7.3. 13C NMR (126 MHz, CDCl 3) of compound 157a.   388   157b OTf N N OEt                                                                                                   389   Figure A7.4. 1H NMR (500 MHz, CDCl3) of compound 157b. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.5. Infrared spectrum (Thin Film, NaCl) of compound 157b.  Figure A7.6. 13C NMR (126 MHz, CDCl3) of compound 157b.   390   157c OTf N N O                                                                                                   391   Figure A7.7. 1H NMR (500 MHz, CDCl3) of compound 157c. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.8. Infrared spectrum (Thin Film, NaCl) of compound 157c.  Figure A7.9. 13C NMR (126 MHz, CDCl 3) of compound 157c.   392   157d OTf N N O                                                                                                   393   Figure A7.10. 1H NMR (500 MHz, CDCl3) of compound 157d. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.11. Infrared spectrum (Thin Film, NaCl) of compound 157d.  Figure A7.12. 13C NMR (126 MHz, CDCl3) of compound 157d.   394   157e OTf N N O                                                                                                   395   Figure A7.13. 1H NMR (500 MHz, CDCl3) of compound 157e. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.14. Infrared spectrum (Thin Film, NaCl) of compound 157e.  Figure A7.15. 13C NMR (126 MHz, CDCl3) of compound 157e.   396   157f OTf N N O                                                                                                   397   Figure A7.16. 1H NMR (500 MHz, CDCl3) of compound 157f. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.17. Infrared spectrum (Thin Film, NaCl) of compound 157f.  Figure A7.18. 13C NMR (126 MHz, CDCl3) of compound 157f.   398   157g OTf N N O                                                                                                   399   Figure A7.19. 1H NMR (500 MHz, CDCl3) of compound 157g. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.20. Infrared spectrum (Thin Film, NaCl) of compound 157g.  Figure A7.21. 13C NMR (126 MHz, CDCl3) of compound 157g.   400   157h OTf N N O                                                                                                   401   Figure A7.22. 1H NMR (500 MHz, CDCl3) of compound 157h. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3   Figure A7.23. Infrared spectrum (Thin Film, NaCl) of compound 157h.  Figure A7.24. 13C NMR (126 MHz, CDCl3) of compound 157h.   402   158a PPh 2 N N OMe                                                                                                   403   Figure A7.25. 1H NMR (500 MHz, CDCl3) of compound 158a. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                     Figure A7.26. Infrared spectrum (Thin Film, NaCl) of compound 158a.  Figure A7.27. 13C NMR (126 MHz, CDCl3) of compound 158a.   404   158b PPh 2 N N OEt                                                                                                   405   Figure A7.28. 1H NMR (500 MHz, CDCl3) of compound 158b. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.29. Infrared spectrum (Thin Film, NaCl) of compound 158b.  Figure A7.30. 13C NMR (126 MHz, CDCl3) of compound 158b.   406   158c PPh 2 N N O                                                                                                   407   Figure A7.31. 1H NMR (500 MHz, CDCl3) of compound 158c. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.32. Infrared spectrum (Thin Film, NaCl) of compound 158c.  Figure A7.33. 13C NMR (126 MHz, CDCl3) of compound 158c.   408   158d PPh 2 N N O                                                                                                   409   Figure A7.34. 1H NMR (500 MHz, CDCl3) of compound 158d. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.35. Infrared spectrum (Thin Film, NaCl) of compound 158d.  Figure A7.36. 13C NMR (126 MHz, CDCl3) of compound 158d.   410   158e PPh 2 N N O                                                                                                   411   Figure A7.37. 1H NMR (500 MHz, CDCl3) of compound 158e. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.38. Infrared spectrum (Thin Film, NaCl) of compound 158e.  Figure A7.39. 13C NMR (126 MHz, CDCl3) of compound 158e.   412   158f PPh 2 N N O                                                                                                   413   Figure A7.40. 1H NMR (500 MHz, CDCl3) of compound 158f. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.41. Infrared spectrum (Thin Film, NaCl) of compound 158f.  Figure A7.42. 13C NMR (126 MHz, CDCl3) of compound 158f.   414   158g PPh 2 N N O                                                                                                   415   Figure A7.43. 1H NMR (300 MHz, CDCl3) of compound 158g. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.44. Infrared spectrum (Thin Film, NaCl) of compound 158g.  Figure A7.45. 13C NMR (75 MHz, CDCl 3) of compound 158g.   416   158h PPh 2 N N O                                                                                                   417   Figure A7.46. 1H NMR (500 MHz, CDCl3) of compound 158h. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3     Figure A7.47. Infrared spectrum (Thin Film, NaCl) of compound 158h.  Figure A7.48. 13C NMR (126 MHz, CDCl3) of compound 158h.   418   Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   419   CHAPTER 4 Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers† 4.1. Introduction Transition metal-catalyzed cross-coupling reactions have served a powerful tool for efficient carbon–carbon and carbon–heteroatom bond formations over the past several decades. 1 Recently, nickel catalysis has emerged in the synthetic community as an exceptionally useful strategy for cross-coupling. 2 Although tremendous advances in nickel-catalyzed carbon–carbon bond formation have been achieved (e.g., Negishi, Suzuki, Stille, Kumada, Hiyama couplings),3 nickel-catalyzed carbon–oxygen bond forming processes have proven significantly more challenging. The rationale behind this is that reductive elimination of Ni(II) alkoxide complexes is often cited as being significantly challenging even at elevated temperatures. 4 To circumvent this challenge, stoichiometric oxidation of Ni(II) to the less stable Ni(III) analogs has been required. Additionally, reductive elimination of Ni(II) alkoxides is                                                                                                                 †   This work was performed in collaboration with Dr. Ryohei Doi. Additionally, this work has been published and adapted with permission from Han, S.-J.; Doi, R.; Stoltz, B. M. Angew. Chem., Int. Ed. 2016, DOI: 10.1002/anie.201601991; Han, S.-J.; Doi, R.; Stoltz, B. M. Angew. Chem. 2016, DOI: 10.1002/ange.201601991. Copyright 2016 Elsevier. 420     reported to be endothermic via computational analysis. This is in contrast to that of Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers Pd(II) alkoxides, which are exothermic.5 In 1997, Hartwig and co-workers developed the first nickel-catalyzed cross-coupling between electron-deficient aryl halides and pre-formed sodium alkoxides or sodium siloxides.6 In 2014, the Ranu group reported a copper-assisted nickel-catalyzed coupling of phenol derivatives and vinyl halides.7 However, both of these reactions require high temperatures, and the scope of the nucleophiles is limited to pre-formed alkoxides or phenols. Most recently, MacMillan and co-workers developed the nickel-catalyzed intermolecular cross-coupling of aryl bromides and aliphatic alcohols in the presence of light and a photoredox catalyst.8 Importantly, MacMillan and co-workers could not observe their desired C–O coupling products in the absence of either the photocatalyst or light. Although Pd- or Cucatalyzed C–O bond forming reactions have been significantly developed, most of these reactions require high temperature that can limit their utility in the synthesis of multifunctional complex molecules. Moreover, the vast majority of these examples are for aryl ether synthesis, not enol ether synthesis.9,10,11 To our knowledge, a mild and efficient nickel-catalyzed intramolecular cross-coupling cyclization between aliphatic hydroxyl nucleophiles and tethered vinyl halides is unprecedented. 4.2. Results and Discussion In the course of an alkaloid synthesis effort, we attempted a nickel-catalyzed reductive Heck reaction of vinyl iodide 167 with the aim of producing tricycle 168 (Scheme 4.2.1, red arrows).12 Surprisingly, instead of the desired intramolecular C–C bond-forming reaction, a C–O bond-forming cyclization between the vinyl iodide and the free hydroxyl group furnished morpholine derivative 169 (Scheme 4.2.1, blue arrows). Given the lack of precedent in the literature for such a transformation with 421     nickel catalysis, we set out to explore the generality of this reaction. Herein, we Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers describe the first nickel-catalyzed cycloetherification of aliphatic alcohols with pendant vinyl halides. Scheme 4.2.1. Ni-Catalyzed C–O Bond Formation reductive Heck reaction Ni(COD) 2 (50 mol %) Et 3N (10 equiv) O PMB I N H 167 Me H H N N CH3CN, DMF, 23 °C N OH O PMB H C–O bond formation Me H OH 168 (Not Observed) O Ni(COD) 2 (50 mol %) Et 3N (10 equiv) CH3CN, DMF, 23 °C PMB N H N Me O (53% yield) 169 Given this interesting preliminary data, we chose aminocyclohexanols 170a and 170b as simplified substrates for reaction optimization studies (Table 4.2.1). Our initial reaction conditions afforded the corresponding morpholines 171a and 171b in 53% and 42% yield, respectively (entries 1 and 2). A wide variety of bases and additives were investigated to improve the yield and catalytic efficiency (entries 3– 10). We found triethylamine to be superior to others examined (entries 3–5). The use of a 1:1 mixture of triethylamine and DABCO allowed etherification in 69% yield with reduced catalyst loading (i.e., 20 mol % Ni(COD)2, entry 6). Gratifyingly, the use of 2 equiv of zinc powder as an additive resulted in a significant improvement in yield (84%) with only 5 mol % of Ni(COD)2 (entry 10).13,14 ,15,16,17 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   422   Table 4.2.1. Optimization of reaction parametersa OH O I N N Me R R = Me (170a ) R = H (170b ) entry R Ni(COD) 2 bases, additives substrate conc (M) CH3CN, 23 °C Me R = Me (171a ) R = H (171b ) Ni mol % base additive yield (%)b 1c 170a 0.02 50 Et 3N (10 equiv) – 53 2c 170b 0.02 50 Et 3N (10 equiv) – 42 3c 170a 0.02 35 Et 3N (10 equiv) – 42d 4c 170a 0.02 35 Cs2CO3 (3.0 equiv) – 30d 5c 170a 0.02 35 K 3PO 4 (3.0 equiv) – 34d 6 170b 0.10 20 Et 3N (1.0 equiv) DABCO (1.0 equiv) 69 7 170b 0.10 20 Et 3N (1.0 equiv) CsF (1.0 equiv) 51 8 170a 0.04 20 DABCO (1.0 equiv) – 24 9 170a 0.04 20 DABCO (2.0 equiv) – 50d 10 170b 0.15 5 Et 3N (1.1 equiv) Zn (2.0 equiv) 84 a Reactions were performed in a N2-filled glove box. b Yield of isolated product. c DMF (0.04 M) was used as a co-solvent. d The reaction proceeded with incomplete conversion of starting material. With optimized conditions in hand, we investigated the substrate scope of the transformation (Table 4.2.2). In addition to simple vinyl iodides (e.g., 170b, R1 = Me, R2 = H, R3 = H),18 a (Z)-styrenyl iodide (i.e., 170c, R1 = Me, R2 = H, R3 = Ph)19 furnished vinyl ether 171c in high yield and without loss of olefin stereochemical fidelity. Aminocyclohexanols bearing isopropyl and allyl substituents on nitrogen afforded the corresponding products in reduced yields (171d and 171e). Electronically variable benzyl groups were compatible under the reaction conditions, and even an aryl bromide was well tolerated (171f–171h). Additionally, a silyl ether group remained intact, generating substituted morpholine 171i in good yield. Moreover, we discovered that a cis-aminocyclohexanol derived substrate was competent in the reaction, providing the cis-fused bicyclic product 171j.20,21 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   423   Table 4.2.2. Intramolecular cross-coupling of amino-cyclohexanolsa,b OH I N R1 R3 Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M), 23 °C R2 R2 N R3 R1 170 171 Ph O O O N N N 171b 171c 171d 84% yield 93% yield 32% yield O O N N O N MeO F 171e 171f 171g 51% yieldc 76% yield 74% yield O O N N O N TBSO Br a 171h 171i 171j 71% yield 67% yield 55% yield Reactions were performed in a N2-filled glove box. b Yield of isolated product. c 96 h. To our delight, we found that the nickel-catalyzed intramolecular etherification reactions also proceeded with linear aminoalcohol substrates to generate monocyclic morpholine derivatives in moderate to high yields (Table 4.2.3). The steric environment of the alcohol fragment did not hinder the performance, as substrates containing primary, secondary, or highly congested tertiary hydroxyl nucleophiles furnished the corresponding cyclic vinyl ethers in excellent yields (173a–173c). Finally, a benzyl-substituted linear aminoalcohol substrate was transformed to the desired vinyl ether in modest yield (173d). Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   424   Table 4.2.3. Intramolecular cross-coupling of linear aminoalcoholsa,b R2 R3 OH I N Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M), 23 °C R1 R3 R4 O N R4 R1 172 173 Ph a R2 Ph Ph O O O N N N O N 173a 173b 173c 173d 86% yield 94% yield 95% yield 40% yield Reactions were performed in a N2-filled glove box. b Yield of isolated product. We were pleased to discover that additional acyclic substrates undergo the nickel-catalyzed carbon–oxygen cross-coupling to furnish alkylidene tetrahydrofurans and dihydropyrans (Table 4.2.4). Intramolecular etherification of vinyl iodide 174a furnished the cyclic ether 175a in good yield in only 1 h (entry 1). Although less reactive, a vinyl bromide also fared well in the reaction, affording the corresponding product in 52% yield after 12 h (entry 2). Unfortunately, attempts to employ a vinyl chloride as the coupling partner led predominantly to recovery of starting material (entry 3). Mono-methyl and mono-phenyl substituted vinyl iodides (174d and 174e)22 afforded the desired ethers (175d and 175e) in good yields with retention of olefin stereochemistry (entries 4 and 5). Gratifyingly, tetrasubstituted vinyl bromide 174f23 furnished the corresponding tetrahydrofuran product 175f in excellent yield (entry 6). Di-tert-butyl and dibenzyl malonates (174g and 174h) were tolerated under the standard reaction conditions to afford the desired ethers (175g and 175h) in good yields (entries 7 and 8). Additionally, carbon–oxygen bond formations were achieved with nitrile- and amide-containing substituents in 61% and 70% yield, respectively (entries 9 and 10). Formation of a six-membered cyclic vinyl ether (175k) from substrate 174k was found to be challenging with only low levels of conversion (entry 425     11). Interestingly, cycloetherification of 174l did indeed produce a pyran derivative Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers in good yield, but only isomerized product 175l was isolated (entry 12).24,25,26 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   426   Table 4.2.4. Synthesis of substituted tetrahydrofuran and dihydropyran ringsa EWG EWG HO Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) 1-2 X CH3CN (0.15 M), 23 °C R1 EWG EWG 1-2 O R1 R2 R2 174 entry 175 product substrate MeO 2C CO2Me MeO 2C 174a MeO 2C MeO 2C CO2Me MeO 2C HO Cl 174c MeO 2C 174d MeO 2C MeO 2C MeO 2C CO2Me MeO 2C 98 1 87 1 66 12 61 1 70 72 –c 12 76 CO2Me O 174f tBuO C 2 175f CO2tBu tBuO C 2 CO2tBu HO O I 174g BnO 2C 175g CO2Bn BnO 2C CO2Bn HO O I 174h 175h MeO 2C CN MeO 2C CN HO I O 174i 175i O O CO2Me N CO2Me N O O OH MeO 2C 175j MeO 2C CO2Me HO I 174k tBuO C 2 O I 174j CO2tBu CO2Me O 175k tBuO C 2 CO2tBu 12 I O 174l a 48 175e HO Br HO 91 Ph Ph 174e 11 12 CO2Me O I 10 87 175d CO2Me HO 9 2 CO2Me O I 8 –c 175a CO2Me HO 7 60 CO2Me O MeO 2C 6 52 175a 174b 5 12 CO2Me O MeO 2C 4 87 175a CO2Me HO Br 3 1 O I 2 yield (%)b CO2Me HO 1 time (h) 175l Reactions were performed in a N2-filled glove box. b Yield of isolated product. c Low conversion. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   4.3. 427   Conclusion In conclusion, a highly efficient, mild, and operationally simple nickel- catalyzed intramolecular carbon–oxygen bond-forming reaction between vinyl halides and aliphatic alcohols has been developed. We discovered that zinc powder plays an important role in improving catalyst turnover and isolated yields. The reaction is tolerant of many functional groups, affording various cyclic vinyl ethers in good to excellent yields. This work further expands the capability of nickel catalysis in the context of small molecule chemical synthesis. Additional studies are ongoing to expand the scope of the reaction, to understand the mechanism, and to deploy the cyclization in the context of a complex molecular target.27 These efforts will be reported in due course. 4.4. Experimental Methods and Analytical Data 4.4.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, TCI, Oakwood chemicals, Strem, or Alfa Aesar and used as received unless otherwise stated. Ni(COD)2 and NiI2 were purchased from Strem. NiBr2(dme) was purchased from Aldrich. Zinc dust 428     or powder purchased from Aldrich worked well for the reaction but zinc powder Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers (99.999%) purchased from Strem gave poor conversion. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, KMnO4 or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.0400.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), CHDCl2 (δ 5.32) or C6HD6 (δ 7.16 ppm). 13C NMR spectra are recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers (75 MHz, 126 MHz, and 151 MHz, respectively) and are reported relative to CHCl3 (δ 77.16 ppm), CHDCl2 (δ 53.84) or C6HD5 (δ 128.06 ppm). 19 F NMR spectra are recorded on a Varian Mercury 300 MHz (at 282 MHz). 19F NMR spectra are reported relative to CFCl3(δ 0.0 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron 429     ionization (EI+) mode, or Agilent 6200 Series TOF with an Agilent G1978A Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). 4.4.2. Experimental Procedures 1. p-methoxybenzaldehyde 3Å MS; NaBH 4, 0 → 23 °C MeOH O H 2N SI-4-1 O PMB NaHCO 3 N 2. propiolic acid, DCC –20 → 23 °C, CH2Cl2 (65% yield, 2 steps) 1. m-CPBA 0 → 23 °C, CH2Cl2 N SI-4-3 2. aq MeNH 2 80 °C, MeOH 3. (E)-1-bromo-2-iodobut-2-ene 4Å MS, Cs2CO3, THF, DMF (60% yield, 3 steps) 120 °C, toluene (77% yield) PMB SI-4-2 O PMB I N H N OH Me 167 To a solution of amine SI-4-1 (6.66 g, 68.5 mmol, 1.00 equiv), which was prepared according to the literature procedure 1 , in MeOH (171 mL) were added pmethoxybenzaldehyde (10.0 mL, 82.3 mmol, 1.20 equiv) and 3Å MS (18.8 g). The reaction mixture was stirred at 23 °C for 17 h. Then, NaBH4 (5.20g, 0.137 mol, 2.00 equiv) was added to the solution at 0 °C. The solution was stirred at 23 °C for 12 h. After the reaction was done, water (40 mL) was added at 0 °C. The aqueous phase was extracted with EtOAc (3 x 80.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give the PMB-amine, which was used without further purification. A solution of propiolic acid (4.64 mL, 75.4 mmol, 1.10 equiv) in CH2Cl2 (343 mL) was cooled to 0 °C. DCC (15.6g, 75.4 mmol, 1.10 equiv) and the PMB-amine (68.5                                                                                                                 1  (a) Miller, C. A.; Batey, R. A. Org. Lett. 2004, 6, 699–702. (b) Grieco, P. A.; Galatsis, P.; Spohn, R. F. Tetrahedron 1986, 42, 2847–2853. (c) Nieto-García, O.; Alonso, R. J. Org. Chem. 2013, 78, 2564– 2570. 430     mmol, 1.00 equiv) were added to the reaction mixture sequentially. The mixture was Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers warmed to 23 °C and stirred for 30 min. The solvent was evaporated and the residue was purified by flash column chromatography (1:4 EtOAc:hexanes) on silica gel to give amide SI-4-2 (12.0g, 65% yield, 2 steps). To a stirred solution of amide SI-4-2 (12.0 g, 44.6 mmol, 1.00 equiv) in toluene (558 mL) was added solid NaHCO3 (4.50g, 53.5 mmol, 1.20 equiv). The reaction mixture was heated to 120 °C for 48 h. After the reaction was done, water (200 mL) was added. The aqueous phase was extracted with EtOAc (3 x 120 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:4 EtOAc:hexanes) on silica gel to give lactam SI-4-3 (9.25g, 77% yield). To a stirred solution of lactam SI-4-3 (339 mg, 1.26 mmol, 1.00 equiv) in CH2Cl2 (6.30 mL) at 0 °C was added m-CPBA (≤77%, 1.89 mmol, 424 mg, 1.50 equiv), and the mixture was stirred for 3 h at 23 °C. The reaction mixture was quenched with sat. NaHSO3 and sat. NaHCO3. The aqueous phase was extracted with CH2Cl2 (3 x 6.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to furnish the epoxide, which was used without further purification. To a solution of epoxide (1.26 mmol, 1.00 equiv) in MeOH (6.30 mL) was added aq MeNH2 (40 wt.% in H2O, 12.6 mmol, 10.9 mL, 10.0 equiv). The reaction mixture was stirred at 80 °C for 12 h. After the reaction was done, water (6.00 mL) was added. The aqueous phase was extracted with EtOAc (3 x 8.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the aminoalcohol, which was used without further purification. 431     To a solution of the aminoalcohol (1.26 mmol, 1.00 equiv) in THF (3.15 mL) and Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers DMF (3.15 mL) were added 4Å MS (443 mg), (E)-1-bromo-2-iodobut-2-ene (411 mg, 1.58 mmol, 1.25 equiv) and Cs2CO3 (415 mg, 1.27 mmol, 1.01 equiv) at 23 °C. The reaction mixture was stirred at 23 °C for 24 h. The resulting suspension was filtered and washed with EtOAc (5.00 mL). The combined organic phases were extracted with EtOAc (3 x 6.00 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (2:1 EtOAc:hexane) on silica gel to give vinyl iodide 167 (375 mg, 60% yield, 3 steps). 1 H NMR (500 MHz, CDCl3) δ 7.20 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.75 (dt, J = 6.7, 2.1 Hz, 1H), 6.47 – 6.41 (m, 1H), 4.71 (d, J = 14.4 Hz, 1H), 4.41 (d, J = 14.4 Hz, 1H), 3.96 – 3.89 (m, 2H), 3.80 (s, 3H), 3.35 – 3.27 (m, 2H), 3.20 (d, J = 13.6 Hz, 1H), 3.11 (d, J = 13.6 Hz, 1H), 2.99 – 2.91 (m, 1H), 2.61 (td, J = 10.7, 4.4 Hz, 1H), 2.39 – 2.26 (m, 2H), 2.22 (s, 3H), 2.20 – 2.14 (m, 1H), 1.74 (d, J = 7.1 Hz, 3H), 1.56 – 1.45 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 165.3, 159.1, 139.0, 133.7, 130.3, 129.6, 129.5, 114.1, 103.3, 66.8, 60.1, 57.3, 55.4, 49.7, 46.9, 39.3, 35.6, 23.8, 22.3, 17.1; IR (Neat Film NaCl) 3416, 2927, 1663, 1613, 1512, 1454, 1246, 1175, 1034, 817, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H30IN2O3 [M+H]+ : 497.1296; found: 497.1296. O O PMB PMB N H OH 167 I Ni(COD) 2 (50 mol %) Et 3N N 23 °C, CH3CN, DMF (53% yield) Me N H N O 169 To a solution of vinyl iodide 167 (20.0 mg, 0.0402 mmol, 1.00 equiv) and Et3N (56.0 µL, 0.402 mmol, 10.0 equiv) in CH3CN (2.01 mL) and DMF (1.01 mL) in a 432     scintillation vial at 23 °C was added Ni(COD)2 (6.00 mg, 0.0201 mmol, 0.50 equiv) in Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers a nitrogen-filled glove box. The reaction mixture was stirred at 23 °C for 120 min, and then BHT (18.0 mg, 0.0804 mmol, 2.00 equiv) was added. After being stirred for 20 min, the vial was removed from the glovebox and uncapped. Saturated NaHCO3 aqueous solution was added and the mixture was extracted with Et2O (3 x 2.00 mL), the combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1:20 MeOH:CH2Cl2) to give morpholine derivative 169 (7.85 mg, 53% yield). 1 H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.66 (dt, J = 6.8, 1.9 Hz, 1H), 5.03 (qd, J = 7.1, 1.4 Hz, 1H), 4.63 (d, J = 14.4 Hz, 1H), 4.48 (d, J = 14.4 Hz, 1H), 3.78 (s, 3H), 3.76 (d, J = 7.1 Hz, 1H), 3.54 (d, J = 12.5 Hz, 1H), 3.29 – 3.24 (m, 2H), 2.86 – 2.74 (m, 1H), 2.68 – 2.60 (m, 2H), 2.32 (s, 3H), 2.30 – 2.24 (m, 1H), 2.12 – 1.96 (m, 2H), 1.58 (dd, J = 7.1, 1.3 Hz, 3H), 1.55 – 1.49 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 165.0, 158.9, 148.5, 133.5, 129.5, 129.0, 113.9, 103.5, 77.8, 58.4, 52.2, 49.5, 46.6, 42.4, 37.9, 28.9, 24.3, 11.0; IR (Neat Film NaCl) 3416, 2927, 1663, 1613, 1512, 1454, 1246, 1175, 1034, 817, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H29N2O3 [M+H]+ : 369.2173; found: 369.2212. Typical procedure for aminocyclohexanols 170 R2 R3 Br I R 1NH 2 OH 80 °C MeOH NHR1 O SI-4-4 SI-4-5 OH K 2CO3 23 °C, MeCN (32–64% yield, 2 steps) I N R1 R2 170 R3 To a scintillation vial were added cyclohexene oxide SI-4-4 (5.09 mmol, 1.00 equiv), R1NH2 (5.09 mmol, 1.00 equiv), and MeOH (2.50 mL). The reaction mixture was 433     heated to 80 °C for 12 h. The solvent was evaporated to give the corresponding Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers aminocyclohexanols SI-4-5, which were used without further purification. To a solution of aminocyclohexanols SI-4-5 (5.09 mmol, 1.00 equiv) in MeCN (25.0 mL) were added K2CO3 (25.5 mmol, 5.00 equiv) and allyl bromides (5.60 mmol, 1.10 equiv). The reaction mixture was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography, using mixture of hexanes and ethyl acetate as eluent to furnish the product 170. Representative procedure for cross-coupling of aminocyclohexanols 170 OH N I Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) Ph O N Ph 170c 171c Ni-Catalyzed C–O bond formation experiments were performed in a nitrogen-filled glove box. To a solution of aminocyclohexanol 170c (50.0 mg, 0.135 mmol, 1.00 equiv) in MeCN (0.900 mL) in a scintillation vial were added Et3N (21.0 µL, 0.149 mmol, 1.10 equiv), Zn powder (17.7 mg, 0.270 mmol, 2.00 equiv), and Ni(COD)2 (1.90 mg, 0.00673 mmol, 0.05 equiv). The reaction mixture was stirred at 23 °C for 24 h. After the reaction was done, the vial was removed from the glove box and uncapped. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to give 171c (30.7 mg, 93% yield). Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   434   OH N I 170a 1 H NMR (500 MHz, CDCl3) δ 6.41 (q, J = 7.1 Hz, 1H), 4.03 (s, 1H), 3.40 (td, J = 9.8, 4.5 Hz, 1H), 3.15 (d, J = 13.7 Hz, 1H), 3.08 (d, J = 13.9 Hz, 1H), 2.26 (ddd, J = 14.0, 10.2, 3.6 Hz, 1H), 2.18 (s, 3H), 2.15 – 2.11 (m, 1H), 1.79 (dt, J = 8.9, 2.0 Hz, 2H), 1.73 (d, J = 7.2 Hz, 3H), 1.31 – 1.17 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 138.3, 104.4, 69.3, 68.7, 57.3, 35.7, 33.3, 25.6, 24.2, 22.8, 17.0; IR (Neat Film NaCl) 3467, 2930, 2855, 1449, 1282, 1080, 1037 cm-1; HRMS (MM: FAB+) m/z calc’d for C11H21NOI [M+H]+ : 310.0668; found: 310.0654. O N 171a 1 H NMR (400 MHz, CDCl3) δ 5.02 (qd, J = 7.1, 1.6 Hz, 1H), 3.58 (d, J = 12.6 Hz, 1H), 3.35 – 3.23 (m, 1H), 2.62 (d, J = 12.6 Hz, 1H), 2.29 (s, 3H), 2.09 (dtd, J = 12.9, 3.7, 2.0 Hz, 1H), 1.94 (ddt, J = 11.9, 4.5, 2.6 Hz, 1H), 1.85 (s, br, 1H), 1.77 – 1.71 (m, 2H), 1.56 (dd, J = 7.1, 1.5 Hz, 3H), 1.42 – 1.33 (m, 1H), 1.33 – 1.22 (m, 2H), 1.14 – 1.02 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 148.9, 103.3, 81.1, 67.4, 53.0, 42.0, 31.4, 28.1, 24.8, 24.4, 11.1; IR (Neat Film NaCl) 2934, 2861, 2779, 1682, 1451, 1192, 1108, 841 cm-1; HRMS (MM: FAB+) m/z calc’d for C11H20NO [M+H]+ : 182.1545; found: 182.1538. OH N 170b I Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   1 435   H NMR (300 MHz, CDCl3) δ 6.28 (q, J = 1.4 Hz, 1H), 5.86 (dt, J = 0.8, 1.6 Hz, 1H), 3.97 (s, 1H), 3.40 (m, 1H), 3.17 (d, J = 13.7 Hz, 1H), 2.96 (d, J = 13.7 Hz, 1H), 2.28 (m, 1H), 2.18 (s, 3H), 2.13 (m, 1H), 1.75 (m, 3H), 1.20 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 126.8, 113.7, 69.3, 69.1, 64.8, 35.8, 33.1, 25.4, 24.0, 22.6; IR (neat film NaCl) 3470, 2930, 2855, 2796, 1616, 1448, 1079, 1036 cm–1; HRMS (MM: ESIAPCI+) m/z calc’d for C10H19INO, [M+H]+ : 296.0506; found: 296.0499. O N 171b 1 H NMR (300 MHz, CDCl3) δ 4.40 (s, 1H), 4.16 (s, 1H), 3.36 (ddd, J = 2.5, 5.4, 6.7 Hz, 1H), 3.25 (d, J = 7.5 Hz, 1H), 2.81 (7.5 Hz, 1H), 2.24 (s, 3H), 2.09 (m, 1H), 1.98 (m, 1H), 1.84 – 1.73 (m, 3H), 1.43 – 1.07 (m, m, 4H); 13C NMR (75 MHz, CDCl3) δ 156.1, 91.9, 81.1, 66.8, 57.9, 41.7, 31.3, 28.1, 24.3, 24.3; IR (neat film NaCl) 2929, 2858, 2770, 1747, 1653, 1277, 1229, 1074 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H18NO, [M+H]+ : 168.1383; found: 168.1385. OH N 170c 1 I Ph H NMR (400 MHz, CDCl3) δ 7.57 – 7.50 (m, 2H), 7.40 – 7.29 (m, 3H), 6.97 (s, 1H), 4.04 (s, 1H), 3.52 – 3.41 (m, 2H), 3.27 (dd, J = 13.5, 1.1 Hz, 1H), 2.42 – 2.29 (m, 1H), 2.24 (s, 3H), 2.19 – 2.11 (m, 1H), 1.79 (dd, J = 6.9, 3.9 Hz, 2H), 1.75 – 1.64 (m, 1H), 1.35 – 1.15 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 137.4, 135.7, 128.8, 128.3, 128.2, 109.0, 69.5, 69.3, 66.8, 35.8, 33.3, 25.6, 24.2, 22.9; IR (neat film NaCl) 3467, 436     2930, 2855, 1446, 1079, 1058, 1033, 750, 695 cm–1; HRMS (MM: ESI-APCI+) m/z Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers calc’d for C16H23INO, [M+H]+ : 372.0819; found: 372.0859. Ph O N 171c 1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.53 (m, 2H), 7.32 – 7.25 (m, 2H), 7.17 – 7.11 (m, 1H), 5.44 (d, J = 1.7 Hz, 1H), 3.53 (ddd, J = 11.5, 9.1, 4.3 Hz, 1H), 3.32 (d, J = 12.8 Hz, 1H), 3.00 (dd, J = 12.8, 1.6 Hz, 1H), 2.29 (s, 3H), 2.13 (ddtd, J = 12.5, 6.2, 4.3, 3.8, 2.1 Hz, 2H), 1.93 (td, J = 10.2, 9.1, 3.9 Hz, 1H), 1.79 (ddt, J = 13.0, 10.3, 2.9 Hz, 2H), 1.60 – 1.49 (m, 1H), 1.41 – 1.24 (m, 2H), 1.20 – 1.07 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 150.4, 136.0, 128.5, 128.2, 126.0, 107.5, 80.8, 67.0, 59.2, 41.7, 31.4, 28.3, 24.7, 24.4; IR (neat film NaCl) 2935, 2860, 2774, 1664, 1449, 1342, 1179, 1060, 1032, 694 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H22NO, [M+H]+ : 244.1696; found: 244.1716. OH N I 170d 1 H NMR (400 MHz, CDCl3) δ 6.29 (s, 1H), 5.87 (s, 1H), 3.90 (s, 1H), 3.36 – 3.21 (m, 2H), 3.02 (td, J = 13.7, 6.6 Hz, 2H), 2.39 (d, J = 10.5 Hz, 1H), 2.19 – 2.09 (m, 1H), 1.73 (q, J = 10.1 Hz, 3H), 1.35 – 1.17 (m, 4H), 1.14 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 127.2, 116.0, 69.3, 61.7, 57.4, 48.1, 33.2, 28.0, 26.1, 24.4, 22.9, 18.0; IR (neat film NaCl) 2930, 1614, 1173, 1080, 896 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H23NOI, [M+H]+ : 324.0819; found: 324.0845. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   437   O N 171d 1 H NMR (400 MHz, C6D6) δ 4.64 (d, J = 1.1 Hz, 1H), 4.12 (d, J = 1.5 Hz, 1H), 3.48 (ddd, J = 11.1, 8.9, 4.3 Hz, 1H), 3.23 (d, J = 12.7 Hz, 1H), 3.07 (p, J = 6.6 Hz, 1H), 2.89 (dt, J = 12.7, 1.4 Hz, 1H), 2.14 (ddd, J = 10.8, 8.9, 3.9 Hz, 1H), 2.02 – 1.93 (m, 1H), 1.75 (dq, J = 13.6, 2.9, 2.4 Hz, 1H), 1.48 – 1.33 (m, 4H), 0.99 (s, 3H), 0.96 – 0.79 (m, 2H), 0.65 (s, 3H). 13C NMR (101 MHz, C6D6) δ 158.4, 89.6, 81.0, 62.1, 46.7, 45.8, 31.8, 28.1, 25.0, 24.4, 21.4, 12.4; IR (neat film NaCl) 2933, 1657, 1450, 1280, 1175, 1075, 800 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H22NO, [M+H]+ : 196.1696; found: 196.1697. OH N I 170e 1 H NMR (500 MHz, CDCl3) δ 6.29 (d, J = 1.8 Hz, 1H), 5.92 – 5.81 (m, 2H), 5.23 – 5.10 (m, 2H), 3.83 (s, 1H), 3.41 (td, J = 9.9, 4.5 Hz, 1H), 3.34 (d, J = 14.2 Hz, 1H), 3.31 – 3.23 (m, 1H), 2.94 (dd, J = 14.1, 8.4 Hz, 1H), 2.88 (d, J = 14.2 Hz, 1H), 2.41 (ddd, J = 12.7, 9.9, 3.4 Hz, 1H), 2.13 (ddq, J = 12.2, 4.6, 2.0 Hz, 1H), 1.85 – 1.74 (m, 2H), 1.71 – 1.68 (m, 1H), 1.32 – 1.16 (m, 3H), 1.15 – 1.03 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 136.4, 127.6, 117.9, 113.9, 69.1, 64.9, 60.4, 52.4, 33.2, 25.7, 24.2, 23.5; IR (neat film NaCl) 2930, 2856, 1615, 1450, 1157, 1078, 917 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H21NIO, [M+H]+ : 322.0662; found: 322.0668. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   438   O N 171e 1 H NMR (500 MHz, CDCl3) δ 5.86 (dddd, J = 17.1, 10.2, 8.0, 5.4 Hz, 1H), 5.24 – 5.16 (m, 2H), 4.38 (dt, J = 1.3, 0.7 Hz, 1H), 4.13 (dd, J = 1.6, 0.7 Hz, 1H), 3.48 (ddt, J = 13.6, 5.4, 1.6 Hz, 1H), 3.45 – 3.40 (m, 1H), 3.35 (d, J = 12.9 Hz, 1H), 2.88 – 2.79 (m, 2H), 2.17 – 2.04 (m, 2H), 1.99 (dddd, J = 10.2, 4.8, 3.9, 2.4 Hz, 1H), 1.79 – 1.69 (m, 2H), 1.46 – 1.37 (m, 1H), 1.35 – 1.21 (m, 2H), 1.12 (q, J = 12.3, 11.5 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 156.4, 134.3, 118.8, 91.6, 80.8, 64.6, 56.0, 53.7, 31.5, 28.2, 24.8, 24.3; IR (neat film NaCl) 2935, 2862, 1657, 1280, 1075, 839 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H20NO, [M+H]+ : 194.1539; found: 194.1542. OH N MeO 1 I 170f H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.32 (d, J = 1.7 Hz, 1H), 5.90 (t, J = 1.4 Hz, 1H), 3.80 (s, 3H), 3.81 – 3.74 (m, 2H), 3.44 (td, J = 9.8, 4.6 Hz, 1H), 3.36 (d, J = 13.9 Hz, 1H), 3.28 (d, J = 13.2 Hz, 1H), 2.92 (d, J = 14.0 Hz, 1H), 2.42 – 2.29 (m, 1H), 2.13 – 2.04 (m, 1H), 1.90 – 1.81 (m, 1H), 1.75 (ddd, J = 6.7, 4.4, 2.3 Hz, 1H), 1.70 – 1.63 (m, 1H), 1.25 – 1.04 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 159.0, 130.6, 130.5, 128.1, 113.9, 113.5, 68.9, 63.6, 60.5, 55.4, 52.8, 33.3, 25.6, 24.2, 22.6; IR (neat film NaCl) 3483, 2931, 2855, 1612, 1511, 1247, 1036, 813 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H25INO2, [M+H]+ : 402.0924; found: 402.0934. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   439   O N MeO 1 171f H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.33 (s, 1H), 4.09 – 3.96 (m, 2H), 3.81 (s, 3H), 3.51 (s, br, 1H), 3.19 (d, J = 13.0 Hz, 1H), 3.09 (d, J = 12.9 Hz, 1H), 2.71 (d, J = 13.0 Hz, 1H), 2.21 (d, J = 12.9 Hz, 1H), 2.13 (s, br, 1H), 2.06 – 1.96 (m, 1H), 1.84 – 1.72 (m, 2H), 1.50 – 1.36 (m, 1H), 1.32 (qd, J = 11.1, 9.7, 5.6 Hz, 2H), 1.22 (d, J = 22.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 158.9, 156.5, 130.4, 130.2, 113.8, 91.1, 80.4, 65.2, 56.5, 55.4, 53.4, 31.6, 28.7, 24.8, 24.4; IR (neat film NaCl) 2935, 2861, 1733, 1674, 1611, 1511, 1246, 1036, 843 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H24NO2, [M+H]+ : 274.1802; found: 274.1820. OH N F 1 I 170g H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.4, 5.6 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 6.33 (s, 1H), 5.91 (t, J = 1.4 Hz, 1H), 3.80 (d, J = 13.3 Hz, 1H), 3.73 (s, br, 1H), 3.45 (td, J = 9.7, 4.6 Hz, 1H), 3.35 (t, J = 12.6 Hz, 2H), 2.95 (d, J = 13.9 Hz, 1H), 2.33 (d, J = 10.4 Hz, 1H), 2.14 – 2.04 (m, 1H), 1.92 – 1.83 (m, 1H), 1.81 – 1.72 (m, 1H), 1.67 (dt, J = 7.8, 2.8 Hz, 1H), 1.25 – 1.06 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 162.3 (d, J = 245.2 Hz), 134.2, 131.1 (d, J = 8.0 Hz), 128.4, 115.5 (d, J = 21.3 Hz), 113.1, 68.9, 63.8, 60.6, 52.7, 33.3, 25.5, 24.2, 22.6; 19F NMR (282 MHz, CDCl3) δ -115.5; IR (neat film NaCl) 3485, 2930, 2856, 1602, 1508, 1221, 1152, 1073, 818 cm–1; 440     HRMS (MM: ESI-APCI+) m/z calc’d for C16H22FNOI, [M+H]+ : 390.0725; found: Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 390.0732. O N F 1 171g H NMR (400 MHz, CDCl3) δ 7.37 – 7.25 (m, 2H), 7.08 – 6.93 (m, 2H), 4.34 (s, 1H), 4.04 (d, J = 13.1 Hz, 1H), 3.99 (d, J = 1.5 Hz, 1H), 3.50 (tt, J = 11.8, 10.9, 4.1 Hz, 2H), 3.16 (d, J = 13.0 Hz, 1H), 3.08 (d, J = 13.2 Hz, 1H), 2.72 (d, J = 12.9 Hz, 1H), 2.24 – 2.05 (m, 2H), 2.07 – 1.94 (m, 1H), 1.87 – 1.66 (m, 2H), 1.53 – 1.35 (m, 1H), 1.38 – 1.24 (m, 1H), 1.24 – 1.13 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 162.1 (d, J = 244.7 Hz), 156.3, 134.3, 130.1 (d, J = 6.1 Hz), 115.3 (d, J = 20.9 Hz), 91.2, 80.5, 65.3, 56.4, 53.6, 31.6, 28.8, 24.8, 24.3; 19F NMR (282 MHz, CDCl3) δ -116.0; IR (neat film NaCl) 2936, 2862, 1736, 1673, 1604, 1508, 1222, 1075, 821 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H21FNO, [M+H]+ : 262.1602; found: 262.1629. OH N Br 1 I 170h H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.7 Hz, 2H), 7.27 (d, J = 7.7 Hz, 2H), 6.33 (s, br, 1H), 5.91 (t, J = 1.6 Hz, 1H), 3.78 (d, J = 13.3 Hz, 1H), 3.71 (s, br, 1H), 3.53 – 3.41 (m, 1H), 3.42 – 3.26 (m, 2H), 2.95 (d, J = 14.0 Hz, 1H), 2.33 (s, br, 1H), 2.08 (dd, J = 9.6, 4.3 Hz, 1H), 1.94 – 1.54 (m, 3H), 1.27 – 1.03 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 137.5, 131.7, 131.2, 128.6, 121.4, 112.9, 69.0, 63.9, 60.6, 52.9, 33.3, 25.5, 24.2, 22.6; IR (neat film NaCl) 3486, 2930, 2855, 1615, 1486, 1450, 1403, 1152, 441     1071, 1011, 799 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H22BrNOI, Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers [M+H]+ : 449.9924; found: 449.9937. O N Br 1 171h H NMR (500 MHz, CD2Cl2) δ 7.44 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 4.24 (d, J = 1.1 Hz, 1H), 4.02 (d, J = 13.4 Hz, 1H), 3.93 (d, J = 1.5 Hz, 1H), 3.44 (ddd, J = 11.2, 8.7, 4.2 Hz, 1H), 3.13 (d, J = 12.9 Hz, 1H), 3.02 (d, J = 13.5 Hz, 1H), 2.69 (dt, J = 12.9, 1.5 Hz, 1H), 2.18 – 2.07 (m, 2H), 2.02 – 1.91 (m, 1H), 1.75 (tdd, J = 10.4, 5.5, 2.5 Hz, 2H), 1.47 – 1.34 (m, 1H), 1.36 – 1.22 (m, 2H), 1.19 – 1.06 (m, 1H); 13 C NMR (126 MHz, CD2Cl2) δ 157.1, 138.9, 131.8, 131.2, 121.0, 90.7, 81.0, 65.8, 56.9, 54.2, 31.9, 29.1, 25.2, 24.7; IR (neat film NaCl) 2935, 2861, 1654, 1486, 1280, 1074, 1012, 843, 802 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H21BrNO, [M+H]+ : 322.0801; found: 322.0817. OH N TBSO 1 I 170i H NMR (500 MHz, CDCl3) δ 6.28 (s, 1H), 5.84 (s, 1H), 3.83 (s, 1H), 3.66 (td, J = 6.2, 2.2 Hz, 2H), 3.38 (td, J = 9.9, 4.4 Hz, 1H), 3.29 (d, J = 14.1 Hz, 1H), 2.91 (d, J = 14.2 Hz, 1H), 2.65 (dt, J = 13.0, 8.0 Hz, 1H), 2.43 (ddd, J = 13.1, 7.4, 5.8 Hz, 1H), 2.34 (ddd, J = 12.6, 9.8, 3.3 Hz, 1H), 2.17 – 2.08 (m, 1H), 1.82 – 1.72 (m, 2H), 1.71 (dt, J = 8.4, 6.0 Hz, 3H), 1.32 – 1.14 (m, 3H), 1.10 (tt, J = 12.2, 5.9 Hz, 1H), 0.89 (d, 442     J = 0.9 Hz, 9H), 0.05 (s, 3H), 0.05 (s, 3H); 13C NMR (126 MHz, CDCl 3) δ 127.3, Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 114.2, 69.1, 65.6, 61.6, 61.4, 46.1, 33.3, 31.9, 26.1, 25.7, 24.3, 23.1, 18.4, -5.11, -5.13; IR (neat film NaCl) 3489, 2929, 2856, 1255, 1097, 835, 775 cm–1; HRMS (MM: ESIAPCI+) m/z calc’d for C18H37INO2Si, [M+H]+ : 454.1633; found: 454.1658. O N TBSO 1 171i H NMR (400 MHz, CDCl3) δ 4.38 (s, 1H), 4.13 (s, 1H), 3.63 (td, J = 6.2, 2.2 Hz, 2H), 3.47 – 3.31 (m, 2H), 2.94 – 2.79 (m, 2H), 2.34 (s, br, 1H), 2.15 – 2.04 (m, 2H), 1.98 (ddq, J = 11.8, 4.4, 2.4, 1.9 Hz, 1H), 1.79 – 1.59 (m, 5H), 1.46 – 1.21 (m, 3H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 156.5, 91.4, 80.9, 64.6, 61.4, 53.8, 49.3, 31.5, 28.9, 28.3, 26.1, 24.8, 24.3, 18.4, -5.15, -5.17; IR (neat film NaCl) 2931, 2857, 1739, 1674, 1463, 1256, 1094, 838, 776 cm–1; HRMS (MM: ESIAPCI+) m/z calc’d for C18H36NO2Si, [M+H]+ : 326.2510; found: 326.2544. OH N 170b I benzoic acid PPh 3, DEAD OBz toluene (21% yield, 65% yield based on recovered starting material) N I SI-4-6 A solution of cyclohexanol 170b (500 mg, 1.69 mmol, 1.00 equiv) in toluene (1.20 mL) was added to a cooled solution of PPh3 (532 mg, 2.03 mmol, 1.20 equiv) and benzoic acid (248 mg, 2.03 mmol, 1.20 equiv) in toluene (8.45 mL) at –40 °C. Then, DEAD in toluene (40 wt% in toluene, 0.92 mL, 1.20 equiv) was added dropwise to a solution over 20 min at –40 °C. After stirring for 1.5 h at –40 °C, the solution was warmed to 23 °C. After being stirred for 18 h, saturated NaHCO3 aqueous solution 443     was added and the mixture was extracted with EtOAc (3 x 7.00 mL). The combined Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1:20 EtOAc:hexanes) to give benzoate SI-4-6 (142 mg, 21% yield, 65% yield based on recovered starting material). 1 H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.1 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 6.25 (s, 1H), 5.73 (s, 1H), 5.10 (td, J = 10.4, 4.6 Hz, 1H), 3.29 (d, J = 15.1 Hz, 1H), 3.22 (d, J = 15.1 Hz, 1H), 2.79 – 2.69 (m, 1H), 2.25 (s, 3H), 2.19 – 2.11 (m, 1H), 1.92 (d, J = 13.1 Hz, 1H), 1.83 – 1.72 (m, 2H), 1.40 (dddd, J = 17.5, 10.7, 8.0, 3.7 Hz, 2H), 1.35 – 1.23 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 166.0, 132.9, 131.0, 129.9, 128.4, 125.5, 113.4, 73.5, 67.3, 65.8, 36.2, 32.2, 27.4, 25.3, 24.5; IR (Neat Film NaCl) 2934, 2858, 1714, 1450, 1317, 1273, 1175, 1106, 710 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H23INO2 [M+H]+ : 400.0768; found: 400.0769. OBz N SI-4-6 NaOH I MeOH, H 2O (56% yield) OH N I 170j A solution of benzoate SI-4-6 (140 mg, 0.351 mmol, 1.00 equiv) in MeOH (1.80 mL) and H2O (0.20 mL) was treated with NaOH (28 mg, 0.701 mmol, 2.00 equiv) at 60 °C. After 1 h and 45 min, the solution was poured into H2O and the mixture was extracted with CH2Cl2 (3 x 3.00 mL). The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1:8 EtOAc:hexanes) to give cyclohexanol 170j (58 mg, 56% yield). Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   1 444   H NMR (400 MHz, CDCl3) δ 6.28 (q, J = 1.4 Hz, 1H), 5.86 (dt, J = 1.6, 0.8 Hz, 1H), 3.96 (s, 1H), 3.40 (td, J = 9.9, 4.5 Hz, 1H), 3.17 (d, J = 13.8 Hz, 1H), 2.95 (d, J = 13.8 Hz, 1H), 2.28 (ddd, J = 11.4, 9.7, 3.5 Hz, 1H), 2.18 (s, 3H), 2.18 – 2.09 (m, 1H), 1.83 – 1.65 (m, 3H), 1.35 – 1.07 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 127.0, 113.8, 69.4, 69.3, 65.0, 35.9, 33.3, 25.6, 24.2, 22.8; IR (Neat Film NaCl) 3468, 2930, 2855, 2796, 1615, 1449, 1282, 1080, 1036, 901 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H19INO [M+H]+ : 296.0506; found: 296.0528. O N 171j 1 H NMR (400 MHz, CD2Cl2) δ 4.28 (dd, J = 1.4, 0.7 Hz, 1H), 4.09 (dd, J = 1.7, 0.5 Hz, 1H), 3.31 (ddd, J = 11.2, 9.0, 4.2 Hz, 1H), 3.21 (d, J = 12.7 Hz, 1H), 2.75 (dt, J = 12.7, 1.6 Hz, 1H), 2.18 (s, 3H), 2.12 – 2.01 (m, 1H), 1.90 (dtd, J = 13.3, 4.7, 2.7 Hz, 1H), 1.81 – 1.66 (m, 3H), 1.43 – 1.23 (m, 3H), 1.03 (tdd, J = 13.0, 11.2, 3.7 Hz, 1H); 13 C NMR (101 MHz, CD2Cl2) δ 157.3, 91.0, 81.4, 67.2, 58.2, 41.9, 31.7, 28.5, 25.1, 24.8; IR (Neat Film NaCl) 2937, 2862, 2770, 1654, 1451, 1339, 1278, 1161, 1075, 1042, 900, 836 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H18NO [M+H]+ : 168.1383; found: 168.1396. Typical procedure for linear aminoalcohols 172 R4 Br R2 R3 I OH K 2CO3 NHR1 23 °C, MeCN (48–82% yield) SI-4-7 R2 R3 OH N R1 172 I R4 445     To a solution of aminoalcohols SI-4-7 (1.12 mmol, 1.00 equiv) in MeCN (5.60 mL) Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers were added K2CO3 (11.2 mmol, 10.0 equiv) and allyl bromides (1.23 mmol, 1.10 equiv). The reaction mixture was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography, using mixture of hexanes and ethyl acetate as eluent to give the product 172. Representative procedure for cross-coupling of linear aminoalcohols 172 OH N I Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) Ph O N Ph 172c 173c Ni-Catalyzed C–O bond formation experiments were performed in a nitrogen-filled glove box. To a solution of aminoalcohol 172c (50.0 mg, 0.145 mmol, 1.00 equiv) in MeCN (0.97 mL) in a scintillation vial were added Et3N (22.0 µL, 0.160 mmol, 1.10 equiv), Zn powder (19.0 mg, 0.290 mmol, 2.00 equiv), and Ni(COD)2 (2.00 mg, 0.00724 mmol, 0.05 equiv). The reaction mixture was stirred at 23 °C for 24 h. After the reaction was done, the vial was removed from the glovebox and uncapped. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography, using a mixture of hexanes and ethyl acetate as eluent to furnish the product 173c (30.0 mg, 95% yield). OH I N Ph 172a Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   1 446   H NMR (300 MHz, CDCl3) δ 7.54 (m, 2H), 7.36 (m, 3H), 6.98 (s, 1H), 3.65 (t, J = 5.4 Hz, 2H), 3.36 (s, 2H), 2.95 (br, 1H), 2.66 (t, J = 5.5 Hz, 2H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.2, 136.1, 128.7, 128.1, 128.0, 107.1, 70.4, 58.5, 57.8, 40.7; IR (neat film NaCl) 3442, 2946, 2840, 2792, 1490, 1445, 1083, 1066, 1046, 748, 694 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H17INO, [M+H]+ : 318.0349; found: 318.0344. Ph O N 173a 1 H NMR (300 MHz, CDCl3) δ 7.56 (m, 2H), 7.28 (m, 2H), 7.14 (m, 1H), 5.45 (s, 1H), 4.06 (m, 2H), 3.03 (s, 2H), 2.59 (m, 2H), 2.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 149.6, 135.6, 128.4, 128.1, 125.9, 107.9, 67.4, 58.3, 54.1, 46.1; IR (neat film NaCl) 2939. 2790, 1738, 1668, 1452, 1339, 1170, 1051, 695; HRMS (MM: ESI-APCI+) m/z calc’d for C12H16NO, [M+H]+ : 190.1226; found: 190.1228. OH N I Ph 172b 1 H NMR (400 MHz, CDCl3) δ 7.59 – 7.50 (m, 2H), 7.41 – 7.30 (m, 3H), 6.98 (s, 1H), 3.90 (dqd, J = 9.4, 6.1, 3.0 Hz, 1H), 3.75 – 3.53 (m, 1H), 3.47 (d, J = 13.5 Hz, 1H), 3.29 (d, J = 13.5 Hz, 1H), 2.45 (dd, J = 12.3, 3.1 Hz, 1H), 2.41 – 2.36 (m, 1H), 2.32 (s, 3H), 1.16 (d, J = 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 137.4, 136.4, 128.8, 128.3, 128.3, 128.2, 107.1, 70.8, 64.6, 63.3, 41.3, 19.9; IR (neat film NaCl) 3459, 3054, 3023, 2968, 2930, 2843, 2795, 1598, 1491, 1446, 1408, 1361, 1324, 1291, 447     1209, 1161, 1135, 1065, 1029, 935, 841, 750, 695 cm–1; HRMS (MM: ESI-APCI+) Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers m/z calc’d for C13H19NIO, [M+H]+ : 332.0506; found: 332.0519. Ph O N 173b 1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.56 (m, 2H), 7.33 – 7.26 (m, 2H), 7.19 – 7.10 (m, 1H), 5.46 (d, J = 1.4 Hz, 1H), 4.06 (dqd, J = 9.9, 6.3, 2.6 Hz, 1H), 3.20 (dd, J = 12.5, 1.7 Hz, 1H), 2.85 – 2.72 (m, 2H), 2.31 (s, 3H), 2.06 (dd, J = 11.7, 9.8 Hz, 1H), 1.36 (d, J = 6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 150.2, 136.0, 128.6, 128.2, 126.0, 107.8, 73.4, 60.9, 58.0, 46.1, 19.2; IR (neat film NaCl) 2973, 2936, 2788, 1666, 1448, 1328, 1154, 1070, 975, 755, 694 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C13H18NO, [M+H]+ : 204.1383; found: 204.1386. OH I N Ph 172c 1 H NMR (400 MHz, CDCl3) δ 7.57 – 7.48 (m, 2H), 7.33 (s, 3H), 6.99 (s, 1H), 3.46 (s, 2H), 3.26 (s, br, 1H), 2.51 (s, 2H), 2.37 (s, 3H), 1.23 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 137.5, 135.8, 129.2, 128.9, 128.2, 108.3, 73.0, 70.9, 68.1, 44.0, 28.0; IR (neat film NaCl) 2969, 2786, 2360, 1446, 1356, 1121, 1031, 970, 749, 695 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H21NIO, [M+H]+ : 346.0662; found: 346.0664. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   448   Ph O N 173c 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.59 (m, 2H), 7.29 – 7.25 (m, 2H), 7.17 – 7.09 (m, 1H), 5.47 (s, 1H), 2.94 (s, 2H), 2.38 (s, 2H), 2.28 (s, 3H), 1.39 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 149.2, 136.3, 128.3, 128.2, 125.8, 108.7, 76.8, 64.7, 58.3, 46.4, 26.3; IR (neat film NaCl) 2974, 2766, 1663, 1449, 1368, 1346, 1254, 1207, 1152, 1110, 968, 754, 694 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H20NO, [M+H]+ : 218.1539; found: 218.1577. OH N I Ph 172d 1 H NMR (300 MHz, CDCl3) δ 7.38 – 7.25 (m, 5H), 6.33 (q, J = 1.4 Hz, 1H), 5.92 (m, 1H), 3.63 (s, 2H), 3.56 (q, J = 5.4 Hz, 2H), 3.16 (s, 2H), 2.70 (t, J = 5.7 Hz, 1H), 2.65 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 137.8, 129.3, 128.4, 127.9, 127.4, 111.9, 64.8, 58.5, 57.5, 54.1; IR (neat film NaCl) 3435, 3024, 2808, 1616, 1493, 1452, 1257, 1151, 1027, 904, 739, 698 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H17INO, [M+H]+ : 318.0349; found: 318.0356. O N Ph 173d 1 H NMR (300 MHz, CDCl3) δ 7.33 – 7.24 (m, 5H), 4.39 (s, 1H), 4.11 (s, 1H), 3.90 (m, 2H), 3.50 (s, 2H), 2.98 (s, 2H), 2.52 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 155.9, 137.4, 129.3, 128.5, 127.4, 92.2, 67.9, 63.2, 55.3, 52.1; IR (neat film NaCl) 449     2875, 2807, 1653, 1453, 1313, 1278, 1125, 1079, 1067, 851, 699 cm–1; HRMS (MM: Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers ESI-APCI+) m/z calc’d for C12H16NO, [M+H]+ : 190.1226; found: 190.1229. Typical procedure for malonate substrates 174 EWG R1 EWG EWG + NaH R2 Br X SI-4-8 EWG SI-4-9 50 → 40 °C DMF X 1-2 NaHCO 3 or K 2CO3 37% formaldehyde 23 °C, EtOH, H 2O R1 R2 X = Cl, Br, I SI-4-10 EWG EWG HO 1-2 X R1 R2 174 To a suspension of NaH (60% dispersion in mineral oil, 4.16 mmol, 1.10 equiv) in DMF (19.0 mL) at 0 °C was added malonate SI-4-8 (3.78 mmol, 1.00 equiv) in portions. The reaction mixture was stirred at 50 °C for 1 h. The solution was cooled to 0 °C and allyl bromide (3.78 mmol, 1.00 equiv) in DMF (2 mL) was added in portions over 5 min. Then, the mixture was stirred at 40 °C for 1 h. The reaction was quenched by sat. NH4Cl and the aqueous phase was extracted with Et2O (3 x 10.0 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:20 EtOAc:hexanes) on silica gel to give vinyl halide SI-4-10. To a solution of vinyl halide SI-4-10 (0.74 mmol, 1.00 equiv) in EtOH (0.50 mL) and H2O (0.25 mL) were added solid NaHCO3 or K2CO3 (0.15 mmol, 0.20 equiv) and formaldehyde (37wt.% in H2O, 0.89 mmol, 1.20 equiv). The reaction mixture was stirred at 23 °C for 24 h. Then, water (0.40 mL) was added and the aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography, using a mixture of hexanes and ethyl acetate as eluent to furnish the product 174. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   Representative procedure for cross-coupling of malonates 174 MeO 2C CO2Me HO Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) I 174a MeO 2C 450   CO2Me O 175a Ni-Catalyzed C–O bond formation experiments were performed in a nitrogen-filled glove box. To a solution of vinyl iodide 174a (83.9 mg, 0.256 mmol, 1.00 equiv) in MeCN (1.71 mL) in a scintillation vial were added Et3N (39.0 µL, 0.282 mmol, 1.10 equiv), Zn powder (33.0 mg, 0.512 mmol, 2.00 equiv), and Ni(COD)2 (3.50 mg, 0.013 mmol, 0.05 equiv). The reaction mixture was stirred at 23 °C for 1 h. After the reaction was done, the vial was removed from the glovebox and uncapped. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:4 EtOAc:hexanes) to furnish the product 175a (44.5 mg, 87% yield). MeO 2C CO2Me HO I 174a 1 H NMR (500 MHz, C6D6) δ 5.79 (q, J = 1.2 Hz, 1H), 5.61 (d, J = 1.4 Hz, 1H), 4.09 (d, J = 5.8 Hz, 2H), 3.33 (s, 6H), 3.32 (d, J = 1.1 Hz, 2H); 13C NMR (126 MHz, C6D6) δ 169.9, 131.5, 101.2, 63.3, 59.3, 52.4, 45.4; IR (Neat Film NaCl) 3520, 2952, 1731, 1435, 1210, 1033 cm-1; HRMS (MM: FAB+) m/z calc’d for C9H14IO5 [M+H]+ : 328.9886; found: 328.9891. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   MeO 2C 451   CO2Me O 175a 1 H NMR (500 MHz, C6D6) δ 4.53 (q, J = 1.9 Hz, 1H), 4.44 (s, 2H), 3.91 (q, J = 1.7 Hz, 1H), 3.16 (s, 6H), 3.09 (t, J = 1.7 Hz, 2H); 13C NMR (126 MHz, C6D6) δ 169.2, 160.2, 81.8, 74.3, 59.8, 52.6, 37.0; IR (Neat Film NaCl) 2957, 2358, 2340, 1737, 1436, 1280, 1046 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C9H13O5 [M+H]+ : 201.0757; found: 201.0765.   MeO 2C CO2Me HO Br 174b   1   H NMR (500 MHz, CDCl3) δ 5.74 (dt, J = 1.7, 0.9 Hz, 1H), 5.59 (d, J = 1.7 Hz, 1H), 4.09 (s, 2H), 3.79 (s, 6H), 3.25 (d, J = 0.9 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 170.4, 126.6, 122.4, 63.7, 59.0, 53.1, 42.4; IR (Neat Film NaCl) 2953, 1728, 1626, 1435, 1299, 1208, 1032, 902, 857 cm-1; HRMS (MM: FAB+) m/z calc’d for C9H14BrO5 [M+H]+ : 281.0024; found: 281.0036. MeO 2C CO2Me HO Cl 174c 1 H NMR (400 MHz, CDCl3) δ 5.32 (d, J = 1.3 Hz, 1H), 5.30 – 5.28 (m, 1H), 4.07 (s, 2H), 3.78 (s, 6H), 3.13 (d, J = 0.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 170.4, 136.6, 117.7, 63.8, 58.7, 53.0, 40.6; IR (Neat Film NaCl) 2955, 1735, 1632, 1437, 1212, 1035, 898 cm-1; HRMS (MM: FAB +) m/z calc’d for C9H14O5Cl [M+H]+ : 237.0530; found: 237.0540. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   MeO 2C 452   CO2Me HO I 174d 1 H NMR (500 MHz, CDCl3) δ 6.50 (qt, J = 7.2, 0.8 Hz, 1H), 4.04 (d, J = 6.6 Hz, 2H), 3.80 (s, 6H), 3.30 (s, br, 2H), 2.36 (t, J = 6.7 Hz, 1H), 1.70 (dt, J = 7.2, 0.7 Hz, 3H); 13 C NMR (126 MHz, CDCl3) δ 170.7, 142.1, 91.5, 63.6, 59.2, 53.1, 38.7, 17.2; IR (Neat Film NaCl) 2952, 1733, 1436, 1299, 1223, 1040 cm-1; HRMS (MM: FAB +) m/z calc’d for C10H16O5I [M+H]+ : 343.0043; found: 343.0048. MeO 2C CO2Me O 175d 1 H NMR (400 MHz, C6D6) δ 4.97 (qt, J = 7.0, 2.2 Hz, 1H), 4.44 (s, 2H), 3.18 (s, 6H), 3.11 (dq, J = 2.8, 1.5 Hz, 2H), 1.40 (dt, J = 7.1, 1.4 Hz, 3H); 13C NMR (101 MHz, C6D6) δ 169.6, 153.8, 92.2, 73.6, 59.7, 52.6, 34.2, 12.2; IR (Neat Film NaCl) 2956, 1740, 1437, 1275, 1169, 1070, 803 cm-1; HRMS (MM: FAB +) m/z calc’d for C10H14O5 [M]+Ÿ: 214.0841; found: 214.0836. MeO 2C CO2Me HO I Ph 174e 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.28 (m, 5H), 6.88 (s, 1H), 4.15 (s, 2H), 3.81 (s, 6H), 3.57 (d, J = 0.9 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 170.4, 140.1, 138.2, 128.7, 128.3, 128.3, 96.5, 63.6, 59.9, 53.1, 46.9; IR (Neat Film NaCl) 2951, 1727, 1437, 1215, 1032, 696 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C15H18O5I [M+H]+ : 405.0193; found: 405.0195. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   MeO 2C 453   CO2Me O Ph 175e 1 H NMR (400 MHz, C6D6) δ 7.75 – 7.70 (m, 2H), 7.25 (t, J = 7.8 Hz, 2H), 7.05 (ddt, J = 8.6, 7.2, 1.2 Hz, 1H), 5.21 – 5.18 (m, 1H), 4.54 (s, 2H), 3.20 (d, J = 1.6 Hz, 2H), 3.16 (s, 6H); 13C NMR (101 MHz, C6D6) δ 168.8, 153.7, 136.4, 128.2, 127.8, 125.3, 99.4, 75.2, 58.5, 52.3, 38.3; IR (Neat Film NaCl) 2953, 1738, 1678, 1435, 1279, 1210, 1028, 695 cm-1; HRMS (MM: EI +) m/z calc’d for C15H16O5 [M]+Ÿ: 276.0998; found: 276.1012. MeO 2C CO2Me HO Br 174f 1 H NMR (400 MHz, CDCl3) δ 4.02 (s, 2H), 3.78 (s, 6H), 3.37 (s, 2H), 1.88 (d, J = 0.9 Hz, 3H), 1.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.0, 136.4, 114.1, 63.7, 59.3, 53.0, 38.8, 25.9, 21.2; IR (Neat Film NaCl) 2952, 1734, 1437, 1209, 1043 cm-1; HRMS (MM: FAB +) m/z calc’d for C11H18O5Br [M+H]+ : 309.0338; found: 309.0325. MeO 2C CO2Me O 175f 1 H NMR (500 MHz, C6D6) δ 4.12 (d, J = 6.0 Hz, 2H), 3.57 (s, 2H), 3.38 (s, 6H), 1.66 (s, 3H), 1.45 (s, 3H); 13C NMR (126 MHz, C6D6) δ 170.6, 136.2, 115.0, 63.6, 59.5, 52.3, 39.0, 25.6, 20.8; IR (Neat Film NaCl) 2952, 1731, 1437, 1301, 1209, 1043 cm-1; HRMS (MM: FAB +) m/z calc’d for C11H17O5 [M+H]+ : 229.1076; found: 229.1074. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   tBuO C 2 454   CO2tBu HO I 174g 1 H NMR (500 MHz, CDCl3) δ 6.18 (q, J = 1.3 Hz, 1H), 5.91 (d, J = 1.5 Hz, 1H), 4.06 (d, J = 3.6 Hz, 2H), 3.20 (d, J = 1.1 Hz, 2H), 2.32 (s, 1H), 1.50 (s, 18H); 13C NMR (126 MHz, CDCl3) δ 169.1, 130.9, 101.6, 82.8, 63.9, 60.7, 45.4, 28.1; IR (Neat Film NaCl) 2978, 1728, 1369, 1256, 1148, 1020, 842 cm-1; HRMS (MM: FAB +) m/z calc’d for C15H26O5I [M+H]+ : 413.0825; found: 413.0821. tBuO C 2 CO2tBu O 175g 1 H NMR (500 MHz, C6D6) δ 4.54 (q, J = 1.8 Hz, 1H), 4.51 (s, 2H), 3.94 (q, J = 1.6 Hz, 1H), 3.14 (t, J = 1.7 Hz, 2H), 1.27 (s, 18H); 13C NMR (126 MHz, C6D6) δ 168.3, 160.9, 81.8, 81.3, 74.5, 61.2, 37.0, 27.7; IR (Neat Film NaCl) 2979, 1732, 1370, 1146, 1050, 844 cm-1; HRMS (MM: FAB +) m/z calc’d for C15H25O5 [M+H]+ : 285.1702; found: 285.1693. BnO 2C CO2Bn HO I 174h 1 H NMR (500 MHz, CDCl3) δ 7.34 – 7.29 (m, 6H), 7.29 – 7.26 (m, 4H), 6.12 (q, J = 1.1 Hz, 1H), 5.87 (d, J = 1.6 Hz, 1H), 5.17 (d, J = 3.2 Hz, 4H), 4.13 (s, 2H), 3.29 (d, J = 1.1 Hz, 2H), 2.27 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 169.6, 135.1, 131.8, 128.7, 128.6, 128.4, 100.3, 67.8, 63.6, 59.5, 45.4; IR (Neat Film NaCl) 2952, 1725, 1455, 455     1214, 695 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C21H22O5I [M+H]+ : Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 481.0506; found: 481.0509. BnO 2C CO2Bn O 175h 1 H NMR (600 MHz, C6D6) δ 7.10 – 6.90 (m, 10H), 4.83 (d, J = 8.0 Hz, 4H), 4.50 (q, J = 1.8 Hz, 1H), 4.46 (s, 2H), 3.87 (q, J = 1.7 Hz, 1H), 3.11 (t, J = 1.7 Hz, 2H); 13C NMR (151 MHz, C6D6) δ 168.7, 148.2, 135.6, 128.7, 128.5, 128.3, 81.9, 74.3, 67.7, 55.8, 37.0; IR (Neat Film NaCl) 2915, 1732, 1455, 1243, 1045, 901, 695 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C21H21O5 [M+H]+ : 353.1384; found: 353.1394. MeO 2C CN HO I 174i 1 H NMR (500 MHz, CDCl3) δ 6.35 (dt, J = 2.2, 1.1 Hz, 1H), 6.05 (d, J = 2.1 Hz, 1H), 4.04 (dd, J = 11.1, 7.6 Hz, 1H), 3.98 (dd, J = 11.1, 6.5 Hz, 1H), 3.90 (s, 3H), 3.13 (dd, J = 14.9, 1.1 Hz, 1H), 3.05 (dd, J = 14.9, 1.1 Hz, 1H), 2.45 (dd, J = 7.6, 6.5 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 167.6, 132.6, 117.2, 97.2, 66.0, 54.2, 52.1, 46.9; IR (Neat Film NaCl) 2952, 2359, 1738, 1611, 1434, 1224, 1144, 1060, 910 cm-1; HRMS (MM: FAB +) m/z calc’d for C8H11O3NI [M+H]+ : 295.9784; found: 295.9775. MeO 2C CN O 175i 1 H NMR (500 MHz, C6D6) δ 4.44 (q, J = 2.0 Hz, 1H), 3.84 (d, J = 8.9 Hz, 1H), 3.79 – 3.75 (m, 2H), 3.02 (d, J = 0.7 Hz, 3H), 2.69 (dt, J = 15.9, 1.9 Hz, 1H), 2.42 (dt, J = 456     15.9, 1.6 Hz, 1H); 13C NMR (126 MHz, C6D6) δ 166.1, 158.0, 117.3, 83.6, 75.1, 53.3, Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 46.9, 38.7; IR (Neat Film NaCl) 2959, 2249, 1747, 1682, 1435, 1231, 1046, 819 cm-1; HRMS (MM: FAB +) m/z calc’d for C8H10O3N [M+H]+ : 168.0661; found: 168.0666. O CO2Me N O OH I 174j 1 H NMR (400 MHz, CDCl3) δ 6.22 (q, J = 1.2 Hz, 1H), 5.97 (d, J = 1.6 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.81 (s, 3H), 3.79 – 3.55 (m, 6H), 3.39 (s, br, 2H), 3.30 (dd, J = 15.5, 1.0 Hz, 1H), 3.06 (dd, J = 15.4, 1.1 Hz, 1H), 2.60 (s, br, 1H); 13C NMR (101 MHz, CDCl3) δ 171.9, 167.7, 132.2, 99.9, 66.3, 66.1, 57.4, 53.1, 45.6, 37.2; IR (Neat Film NaCl) 2955, 2859, 1733, 1627, 1436, 1272, 1228, 1115, 1064, 999, 851 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C12H19NO5I [M+H]+ : 384.0302; found: 384.0315. O CO2Me N O O 175j 1 H NMR (500 MHz, C6D6) δ 4.60 (d, J = 9.0 Hz, 1H), 4.55 (q, J = 1.8 Hz, 1H), 4.41 (d, J = 9.0 Hz, 1H), 3.94 (q, J = 1.7 Hz, 1H), 3.22 (s, br, 2H), 3.15 – 2.97 (m, 9H), 2.71 (s, br, 2H); 13C NMR (101 MHz, C6D6) δ 171.6, 165.8, 160.7, 81.4, 75.2, 66.4, 66.0, 58.8, 52.5, 46.0, 43.5, 37.5; IR (Neat Film NaCl) 2857, 1733, 1651, 1435, 1274, 1115, 1018, 804 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C12H18NO5 [M+H]+ : 256.1179; found: 256.1196. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   MeO 2C 457   CO2Me HO I 174k 1 H NMR (500 MHz, CDCl3) δ 6.06 (q, J = 1.4 Hz, 1H), 5.72 (d, J = 1.7 Hz, 1H), 3.96 (s, 2H), 3.79 (d, J = 0.6 Hz, 6H), 2.49 – 2.43 (m, 2H), 2.20 – 2.13 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 171.2, 126.4, 109.9, 64.9, 59.0, 52.9, 40.8, 31.5; IR (Neat Film NaCl) 2952, 1729, 1617, 1436, 1205, 1043, 898 cm-1; HRMS (MM: FAB+) m/z calc’d for C10H16IO5 [M+H]+: 343.0043; found: 343.0031. tBuO C 2 CO2tBu I SI-4-10a 1. NaH 2-bromoethyl acetate, THF tBuO C 2 2. K 2CO3, MeOH (38% yield, 2 steps; 65% yields based on recovered starting material) HO CO2tBu I 174l To a solution of NaH (60% dispersion in mineral oil, 78.0 mg, 1.95 mmol, 2.00 equiv) in THF (3.26 mL) was added vinyl iodide SI-4-10a (374 mg, 0.977 mmol, 1.00 equiv), and the solution was stirred until gas evolution was complete. 2-Bromoethyl acetate (0.27 mL, 2.44 mmol, 2.50 equiv) was added to the reaction mixture at 0 °C and then, the solution was stirred at 23 °C for 24 h. The reaction was quenched with sat. NH4Cl at 0 °C and the mixture was extracted with EtOAc (3 x 3.00 mL), the combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1:20 EtOAc:hexanes) to give dialkylated malonate and recovered SI-4-10a. To a solution of dialkylated malonate intermediate (344 mg, 0.735 mmol, 1.00 equiv) in MeOH (2.50 mL) was added K2CO3 (203 mg, 1.47 mmol, 2.00 equiv) and the solution was stirred at 23 °C for 24 h. The reaction mixture was diluted with CH2Cl2 (3.00 mL) and the mixture was extracted with CH2Cl2 (3 x 2.00 mL), the combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   vacuo. 458   The residue was purified by silica gel flash chromatography (1:20 → 1:8 → 1:4 EtOAc:hexanes) to give malonate 174l (159 mg, 38% yield, 2 steps). 1 H NMR (500 MHz, CDCl3) δ 6.14 (q, J = 1.4 Hz, 1H), 5.91 (d, J = 1.7 Hz, 1H), 3.72 (t, J = 6.7 Hz, 2H), 3.17 (d, J = 1.2 Hz, 2H), 2.28 (t, J = 6.7 Hz, 2H), 1.65 (s, br, 1H), 1.47 (s, 18H); 13C NMR (126 MHz, CDCl3) δ 170.0, 130.5, 102.2, 82.5, 59.2, 57.7, 46.9, 34.7, 28.1; IR (Neat Film NaCl) 3447, 2977, 1726, 1368, 1250, 1145, 843 cm-1; HRMS (MM: FAB +) m/z calc’d for C16H28IO5 [M+H]+ : 427.0982; found: 427.0985. tBuO C 2 CO2tBu O 175l 1 H NMR (500 MHz, CD2Cl2) δ 4.68 (h, J = 0.9 Hz, 1H), 4.02 – 3.96 (m, 2H), 2.10 – 2.04 (m, 2H), 1.76 (d, J = 1.0 Hz, 3H), 1.43 (s, 18H); 13C NMR (126 MHz, CD2Cl2) δ 170.6, 153.8, 94.6, 81.7, 64.1, 52.5, 28.7, 28.1, 20.6; IR (Neat Film NaCl) 2977, 2933, 1728, 1369, 1266, 1146, 1108, 1088, 847 cm-1; HRMS (MM: FAB +) m/z calc’d for C16H27O5 [M+H]+ : 299.1858; found: 299.1835. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   4.5. 459   References and Notes                                                                                                                 (1) Selected recent reviews: (a) Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270–5298. (b) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417–1492. (c) Hartwig, J. F. Nature 2008, 455, 314–322. (d) Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79, 663–672. (2) (a) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299–309. (b) Ananikov, V. P. ACS Catal. 2015, 5, 1964–1971. (3) Selected recent reviews: (a) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525–1532. (b) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346–1416. (c) Hu, X. Chem. Sci. 2011, 2, 1867–1886. (d) Standley, E. A.; Tasker, S. Z.; Jensen, K. L.; Jamison, T. F. Acc. Chem. Res. 2015, 48, 1503–1514. ( 4 ) For fundamental studies involving stoichiometric nickel-alkoxides, see: (a) Matsunaga, P. T.; Hillhouse, G. L.; Rheingold, A. L. J. Am. Chem. Soc. 1993, 115, 2075–2077. (b) Han, R.; Hillhouse, G. L. J. Am. Chem. Soc. 1997, 119, 8135–8136. (5) Macgregor, S. A.; Neave, G. W.; Smith, C. Faraday Discuss. 2003, 124, 111–127. (6) Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413–5418. (7) Kundu, D.; Maity, P.; Ranu, B. C. Org. Lett. 2014, 16, 1040–1043. (8) Terrett, J. A.; Cuthbertson, J. D.; Shurtleff, V. W.; MacMillan, D. W. C. Nature 2015, 524, 330–334. (9) For examples of intramolecular C–O cyclization using non-nickel catalysis, see: (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333– 10334. (b) Torraca, K. E.; Kuwabe, S.-I.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907–12908. (c) Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. 460                                                                                                                                                                                                                                                                                                                                 Soc. 2001, 123, 12202–12206. . (d) Sun, C.; Fang, Y.; Li, S.; Zhang, Y.; Zhao, Q.; Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers Zhu, S.; Li, C. Org Lett. 2009, 11, 4084–4087. (e) Fang, Y.; Li, C. J. Am .Chem. Soc. 2007, 129, 8092–8093. (f) Fang, Y.; Li, C. Chem. Commun. 2005, 3574–3576. (10) For examples of intermolecular C–O cyclization using non-nickel catalysis, see: (a) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224–3225. (b) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369–4378. (c) Burgos, C.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 4321–4326. (d) Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2498–2500. (e) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718–10719. (f) Wu, X.; Fors, B. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9943–9947. (g) Surasani, R.; Kalita, D.; Rao, A. V. D.; Chandrasekhar, K. B. Beilstein J. Org. Chem. 2012, 8, 2004–2018. (h) Maiti, D.; Buchwald, S. L. J. Org. Chem. 2010, 75, 1791–1794. (i) Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2009, 74, 5075–5078. (j) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978–4979. (k) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am. Chem. Soc. 2010, 132, 1202–1203. (11) For an example of a base-mediated intramolecular synthesis of an alkylidene morpholine by C–O bond formation, see: Bottini, A. T.; Mullikin, J. A.; Morris, C. J. J. Org. Chem. 1964, 29, 373–379. (12) Teng, M.; Zi, W.; Ma, D. Angew. Chem., Int. Ed. 2014, 53, 1814–1817. (13) Lebedev, S. A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya, I. P. J. Organomet. Chem. 1988, 344, 253–259. 461                                                                                                                                                                                                                                                                                                                                 (14) Importantly, if the Ni(COD)2 catalyst was omitted, no carbon–oxygen bond Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers formation was observed. Addition of other additives such as Mg and CuI decreased the yields (36% and 0% yield, respectively). (15) Intramolecular etherification of vinyl iodide 170b proceeded with 5 mol % of NiI2 or NiBr2(dme) to furnish vinyl ether 171b (entries 1 and 2). An increased rate of cycloetherification was observed with 10 mol % of NiBr2(dme) (entries 2 and 3). Unfortunately, attempts to convert vinyl iodide 170b to enol ether 171b outside a N2filled glove box were unsuccessful (entries 4 and 5). OH N I NiLn Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M), 23 °C Me N Me 170b NiLn Ni mol % time yield (%)a 1b NiI 2 5 16 h 60 2b NiBr 2(dme) 5 48 h 53 3b NiBr 2(dme) 10 16 h 51 4c NiI 2 5 24 h 0 5c NiBr 2(dme) 5 24 h 0 entry a 171b Yield of isolated product. b Reactions were performed in a N2-filled glove box. c Reactions were performed under argon outside a N2-filled glove box. (16) No significant improvement in yield or catalyst turnover was observed when various ligands (e.g., various NHC, PYBOX, BOX, diamine, BiOX ligands) were employed. ( 17 ) Since intramolecular etherifications of aminocyclohexanols 170a or 170b proceeded even without Zn powder despite low yields and catalyst turnover (Table 1), we envision that Zn powder likely plays an important role as a scavenger of the forming HI. (18) Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 12248–12249. 462                                                                                                                                                                                                                                                                                                                                 (19) Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.; Leach, D. C. J. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers Chem. Soc. Perkin. Trans. 1 2002, 58–68. (20) An intramolecular cross-coupling of 170k afforded the desired product 171k in low yield under our standard reaction conditions. Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) (11% yield) OH I N 4k or Ni(COD) 2 (20 mol %) Et 3N (1.0 equiv) DABCO (1.0 equiv) CH3CN (0.04 M) (25% yield) O N 5k ( 21 ) Surprisingly, the cycloetherification of trans- and cis-aminocyclopentanol derived substrates resulted in very low conversion. Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) OH N I 170l OH N I or Ni(COD) 2 (20 mol %) Et 3N (1.0 equiv) DABCO (1.0 equiv) CH3CN (0.04 M) O N 171l (Low conversion) Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M) N 170m 171m (Low conversion) (22) Cao, H.; Yu, J.; Wearing, X. Z.; Zhang, C.; Liu, X.; Deschamps, J.; Cook, J. M. Tetrahedron Lett. 2003, 44, 8013–8017. (23) Gatti, M.; Drinkel, E.; Wu, L.; Pusterla, I.; Gaggia, F.; Dorta, R. J. Am. Chem. Soc. 2010, 132, 15179–15181. (24) Although we attempted to construct 2,3-dihydrobenzofuran 177 from aryl iodide 176 under our standard reaction conditions, only unreacted starting material was recovered. 463                                                                                                                                                                                                                                                                                                                                 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers OH Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) I O 176 177 (Not Observed) (25) Substrates containing alkyl- or mono-ketone substituents instead of a malonate provided a mixture of isomers upon subjection to carbon–oxygen cross-coupling conditions. TBSO Ni(COD) 2 (20 mol %) Et 3N (5.0 equiv) DABCO (1.2 equiv) OH TBSO TBSO O + O CH3CN (0.04 M) (55% combined yield) I 178 179a O Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) OH 179b O O O O + CH3CN (0.15 M) (77% combined yield) I 180 181b 181a (26) Unfortunately, the cyclization reaction of a malonate substrate bearing a nitrogen nucleophile (182) was unsuccessful. MeO 2C BocHN I CO2Me Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) 182 MeO 2C CO2Me BocN 183 (Not Observed) (27) An intermolecular etherification of MacMillan’s substrate 184 (ref. 8) with 1hexanol under our reaction conditions was not successful. Additionally, attempted intermolecular cross-coupling processes of 186 and 188 with 1-hexanol under our standard reaction conditions resulted in no reaction. 464                                                                                                                                                                                                                                                                                                                                 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 1-hexanol (1.0 equiv) Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) Br hex O MeCN (0.15 M) O O 184 185 1-hexanol (1.0 equiv) Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) I N MeCN (0.15 M) O N 187 186 I 1-hexanol (1.0 equiv) Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) hex O MeCN (0.15 M) 188 189 hex Appendix 8 – Spectra Relevant to Chapter 4 465 APPENDIX 8 Spectra Relevant to Chapter 4: Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 167 N Me H OH I N O PMB                                                                                                     466   Figure A8.1. 1H NMR (500 MHz, CDCl3) of compound 167. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.2. Infrared spectrum (Thin Film, NaCl) of compound 167.  Figure A8.3. 13C NMR (126 MHz, CDCl3) of compound 167.   467   169 N O H N O PMB                                                                                                     468   Figure A8.4. 1H NMR (400 MHz, CDCl3) of compound 169. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.5. Infrared spectrum (Thin Film, NaCl) of compound 169.  Figure A8.6. 13C NMR (126 MHz, CDCl3) of compound 169.   469   170a I N OH                                                                                                     470   Figure A8.7. 1H NMR (500 MHz, CDCl3) of compound 170a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.8. Infrared spectrum (Thin Film, NaCl) of compound 170a.  Figure A8.9. 13C NMR (126 MHz, CDCl 3) of compound 170a.   471   171a N O                                                                                                     472   Figure A8.10. 1H NMR (400 MHz, CDCl3) of compound 171a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.11. Infrared spectrum (Thin Film, NaCl) of compound 171a.  Figure A8.12. 13C NMR (101 MHz, CDCl3) of compound 171a.   473   170b I N OH                                                                                                     474   Figure A8.13. 1H NMR (300 MHz, CDCl3) of compound 170b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.14. Infrared spectrum (Thin Film, NaCl) of compound 170b.  Figure A8.15. 13C NMR (75 MHz, CDCl3) of compound 170b.   475   171b N O                                                                                                     476   Figure A8.16. 1H NMR (300 MHz, CDCl3) of compound 171b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.17. Infrared spectrum (Thin Film, NaCl) of compound 171b.  Figure A8.18. 13C NMR (75 MHz, CDCl3) of compound 171b.   477   Ph 170c I N OH                                                                                                     478   Figure A8.19. 1H NMR (400 MHz, CDCl3) of compound 170c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.20. Infrared spectrum (Thin Film, NaCl) of compound 170c.  Figure A8.21. 13C NMR (101 MHz, CDCl3) of compound 170c.   479   171c N Ph O                                                                                                     480   Figure A8.22. 1H NMR (400 MHz, CDCl3) of compound 171c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.23. Infrared spectrum (Thin Film, NaCl) of compound 171c.  Figure A8.24. 13C NMR (101 MHz, CDCl3) of compound 171c.   481   170d I N OH                                                                                                     482   Figure A8.25. 1H NMR (400 MHz, CDCl3) of compound 170d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.26. Infrared spectrum (Thin Film, NaCl) of compound 170d.  Figure A8.27. 13C NMR (101 MHz, CDCl3) of compound 170d.   483   171d N O                                                                                                     484   Figure A8.28. 1H NMR (400 MHz, C6D6) of compound 171d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.29. Infrared spectrum (Thin Film, NaCl) of compound 171d.  Figure A8.30. 13C NMR (101 MHz, C6D6) of compound 171d.   485   170e I N OH                                                                                                     486   Figure A8.31. 1H NMR (500 MHz, CDCl3) of compound 170e. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.32. Infrared spectrum (Thin Film, NaCl) of compound 170e.  Figure A8.33. 13C NMR (126 MHz, CDCl3) of compound 170e.   487   171e N O                                                                                                     488   Figure A8.34. 1H NMR (500 MHz, CDCl3) of compound 171e. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.35. Infrared spectrum (Thin Film, NaCl) of compound 171e.  Figure A8.36. 13C NMR (126 MHz, CDCl3) of compound 171e.   489   MeO 170f I N OH                                                                                                     490   Figure A8.37. 1H NMR (500 MHz, CDCl3) of compound 170f. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.38. Infrared spectrum (Thin Film, NaCl) of compound 170f.  Figure A8.39. 13C NMR (126 MHz, CDCl3) of compound 170f.   491   171f MeO N O                                                                                                     492   Figure A8.40. 1H NMR (400 MHz, CDCl3) of compound 171f. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.41. Infrared spectrum (Thin Film, NaCl) of compound 171f.  Figure A8.42. 13C NMR (101 MHz, CDCl3) of compound 171f.   493   F 170g I N OH                                                                                                     494   Figure A8.43. 1H NMR (400 MHz, CDCl3) of compound 170g. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.44. Infrared spectrum (Thin Film, NaCl) of compound 170g.  Figure A8.45. 13C NMR (101 MHz, CDCl3) of compound 170g.   495   171g F N O                                                                                                     496   Figure A8.46. 1H NMR (400 MHz, CDCl3) of compound 171g. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.47. Infrared spectrum (Thin Film, NaCl) of compound 171g.  Figure A8.48. 13C NMR (101 MHz, CDCl3) of compound 171g.   497   Br 170h I N OH                                                                                                     498   Figure A8.49. 1H NMR (400 MHz, CDCl3) of compound 170h. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.50. Infrared spectrum (Thin Film, NaCl) of compound 170h.  Figure A8.51. 13C NMR (101 MHz, CDCl3) of compound 170h.   499   171h Br N O                                                                                                     500   Figure A8.52. 1H NMR (500 MHz, CD2Cl2) of compound 171h. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.53. Infrared spectrum (Thin Film, NaCl) of compound 171h.  Figure A8.54. 13C NMR (126 MHz, CD2Cl2) of compound 171h.   501   TBSO 170i I N OH                                                                                                     502   Figure A8.55. 1H NMR (500 MHz, CDCl3) of compound 170i. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.56. Infrared spectrum (Thin Film, NaCl) of compound 170i.  Figure A8.57. 13C NMR (126 MHz, CDCl3) of compound 170i.   503   171i TBSO N O                                                                                                     504   Figure A8.58. 1H NMR (400 MHz, CDCl3) of compound 171i. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.59. Infrared spectrum (Thin Film, NaCl) of compound 171i.  Figure A8.60. 13C NMR (101 MHz, CDCl3) of compound 171i.   505   SI-4-6 I N OBz                                                                                                     506   Figure A8.61. 1H NMR (500 MHz, CDCl3) of compound SI-4-6. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.62. Infrared spectrum (Thin Film, NaCl) of compound SI-4-6.  Figure A8.63. 13C NMR (126 MHz, CDCl3) of compound SI-4-6.   507   170j I N OH                                                                                                     508   Figure A8.64. 1H NMR (400 MHz, CDCl3) of compound 170j. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.65. Infrared spectrum (Thin Film, NaCl) of compound 170j.  Figure A8.66. 13C NMR (101 MHz, CDCl3) of compound 170j.   509   171j N O                                                                                                     510   Figure A8.67. 1H NMR (400 MHz, CD2Cl2) of compound 171j. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.68. Infrared spectrum (Thin Film, NaCl) of compound 171j.  Figure A8.69. 13C NMR (101 MHz, CD2Cl2) of compound 171j.   511   Ph 172a I N OH                                                                                                     512   Figure A8.70. 1H NMR (300 MHz, CDCl3) of compound 172a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.71. Infrared spectrum (Thin Film, NaCl) of compound 172a.  Figure A8.72. 13C NMR (75 MHz, CDCl 3) of compound 172a.   513   173a N Ph O                                                                                                     514   Figure A8.73. 1H NMR (300 MHz, CDCl3) of compound 173a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.74. Infrared spectrum (Thin Film, NaCl) of compound 173a.  Figure A8.75. 13C NMR (75 MHz, CDCl 3) of compound 173a.   515   Ph 172b I N OH                                                                                                     516   Figure A8.76. 1H NMR (400 MHz, CDCl3) of compound 172b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.77. Infrared spectrum (Thin Film, NaCl) of compound 172b.  Figure A8.78. 13C NMR (101 MHz, CDCl3) of compound 172b.   517   173b N Ph O                                                                                                     518   Figure A8.79. 1H NMR (400 MHz, CDCl3) of compound 173b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.80. Infrared spectrum (Thin Film, NaCl) of compound 173b.  Figure A8.81. 13C NMR (101 MHz, CDCl3) of compound 173b.   519   Ph 172c I N OH                                                                                                     520   Figure A8.82. 1H NMR (400 MHz, CDCl3) of compound 172c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.83. Infrared spectrum (Thin Film, NaCl) of compound 172c.  Figure A8.84. 13C NMR (101 MHz, CDCl3) of compound 172c.   521   173c N Ph O                                                                                                     522   Figure A8.85. 1H NMR (400 MHz, CDCl3) of compound 173c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.86. Infrared spectrum (Thin Film, NaCl) of compound 173c.  Figure A8.87. 13C NMR (101 MHz, CDCl3) of compound 173c.   523   172d I Ph N OH                                                                                                     524   Figure A8.88. 1H NMR (300 MHz, CDCl3) of compound 172d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.89. Infrared spectrum (Thin Film, NaCl) of compound 172d.  Figure A8.90. 13C NMR (75 MHz, CDCl3) of compound 172d.   525   173d Ph N O                                                                                                     526   Figure A8.91. 1H NMR (300 MHz, CDCl3) of compound 173d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.92. Infrared spectrum (Thin Film, NaCl) of compound 173d.  Figure A8.93. 13C NMR (75 MHz, CDCl3) of compound 173d.   527   HO I 174a CO2Me MeO 2C                                                                                                     528   Figure A8.94. 1H NMR (500 MHz, C6D6) of compound 174a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.95. Infrared spectrum (Thin Film, NaCl) of compound 174a.  Figure A8.96. 13C NMR (126 MHz, C6D6) of compound 174a.   529   175a O CO2Me MeO 2C                                                                                                     530   Figure A8.97. 1H NMR (500 MHz, C6D6) of compound 175a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.98. Infrared spectrum (Thin Film, NaCl) of compound 175a.  Figure A8.99. 13C NMR (126 MHz, C6D6) of compound 175a.   531   HO Br 174b CO2Me MeO 2C                                                                                                     532   Figure A8.100. 1H NMR (500 MHz, CDCl3) of compound 174b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.101. Infrared spectrum (Thin Film, NaCl) of compound 174b.  Figure A8.102. 13C NMR (126 MHz, CDCl3) of compound 174b.   533   HO Cl 174c CO2Me MeO 2C                                                                                                     534   Figure A8.103. 1H NMR (400 MHz, CDCl3) of compound 174c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.104. Infrared spectrum (Thin Film, NaCl) of compound 174c.  Figure A8.105. 13C NMR (101 MHz, CDCl3) of compound 174c.   535   HO 174d I CO2Me MeO 2C                                                                                                     536   Figure A8.106. 1H NMR (500 MHz, CDCl3) of compound 174d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.107. Infrared spectrum (Thin Film, NaCl) of compound 174d.  Figure A8.108. 13C NMR (126 MHz, CDCl3) of compound 174d.   537   175d O CO2Me MeO 2C                                                                                                     538   Figure A8.109. 1H NMR (400 MHz, C6D6) of compound 175d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.110. Infrared spectrum (Thin Film, NaCl) of compound 175d.  Figure A8.111. 13C NMR (101 MHz, C6D6) of compound 175d.   539   HO I 174e Ph CO2Me MeO 2C                                                                                                     540   Figure A8.112. 1H NMR (400 MHz, CDCl3) of compound 174e. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.113. Infrared spectrum (Thin Film, NaCl) of compound 174e.  Figure A8.114. 13C NMR (101 MHz, CDCl3) of compound 174e.   541   175e O Ph CO2Me MeO 2C                                                                                                     542   Figure A8.115. 1H NMR (400 MHz, C6D6) of compound 175e. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.116. Infrared spectrum (Thin Film, NaCl) of compound 175e.  Figure A8.117. 13C NMR (101 MHz, C6D6) of compound 175e.   543   HO Br 174f CO2Me MeO 2C                                                                                                     544   Figure A8.118. 1H NMR (400 MHz, CDCl3) of compound 174f. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.119. Infrared spectrum (Thin Film, NaCl) of compound 174f.  Figure A8.120. 13C NMR (101 MHz, CDCl3) of compound 174f.   545   175f O CO2Me MeO 2C                                                                                                     546   Figure A8.121. 1H NMR (500 MHz, C6D6) of compound 175f. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.122. Infrared spectrum (Thin Film, NaCl) of compound 175f.  Figure A8.123. 13C NMR (126 MHz, C6D6) of compound 175f.   547   HO 174g I CO2tBu tBuO C 2                                                                                                     548   Figure A8.124. 1H NMR (500 MHz, CDCl3) of compound 174g. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                               Figure A8.125. Infrared spectrum (Thin Film, NaCl) of compound 174g.  Figure A8.126. 13C NMR (126 MHz, CDCl3) of compound 174g.   549   CO2tBu 175g O tBuO C 2 Figure A8.127. 1H NMR (500 MHz, C6D6) of compound 175g. Appendix 8 – Spectra Relevant to Chapter 4   550   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.128. Infrared spectrum (Thin Film, NaCl) of compound 175g.  Figure A8.129. 13C NMR (126 MHz, C6D6) of compound 175g.   551   HO CO2Bn 174h I BnO 2C Figure A8.130. 1H NMR (500 MHz, CDCl3) of compound 174h. Appendix 8 – Spectra Relevant to Chapter 4   552   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.131. Infrared spectrum (Thin Film, NaCl) of compound 174h.  Figure A8.132. 13C NMR (126 MHz, CDCl3) of compound 174h.   553   CO2Bn 175h O BnO 2C Figure A8.133. 1H NMR (600 MHz, C6D6) of compound 175h. Appendix 8 – Spectra Relevant to Chapter 4   554   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.134. Infrared spectrum (Thin Film, NaCl) of compound 175h.  Figure A8.135. 13C NMR (151 MHz, C6D6) of compound 175h.   555   I 174i HO MeO 2C CN Figure A8.136. 1H NMR (500 MHz, CDCl3) of compound 174i. Appendix 8 – Spectra Relevant to Chapter 4   556   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.137. Infrared spectrum (Thin Film, NaCl) of compound 174i.  Figure A8.138. 13C NMR (126 MHz, CDCl3) of compound 174i.   557   175i O MeO 2C CN Figure A8.139. 1H NMR (500 MHz, C6D6) of compound 175i. Appendix 8 – Spectra Relevant to Chapter 4   558   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.140. Infrared spectrum (Thin Film, NaCl) of compound 175i.  Figure A8.141. 13C NMR (126 MHz, C6D6) of compound 175i.   559   O 174j OH I CO2Me N O                                                                                                     560   Figure A8.142. 1H NMR (400 MHz, CDCl3) of compound 174j. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.143. Infrared spectrum (Thin Film, NaCl) of compound 174j  Figure A8.144. 13C NMR (101 MHz, CDCl3) of compound 174j.   561   O 175j O CO2Me N O                                                                                                     562   Figure A8.145. 1H NMR (500 MHz, C6D6) of compound 175j. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.146. Infrared spectrum (Thin Film, NaCl) of compound 175j  Figure A8.147. 13C NMR (101 MHz, C6D6) of compound 175j.   563   I HO 174k CO2Me MeO 2C                                                                                                         564   Figure A8.148. 1H NMR (500 MHz, CDCl3) of compound 174k. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.149. Infrared spectrum (Thin Film, NaCl) of compound 174k.  Figure A8.150. 13C NMR (126 MHz, CDCl3) of compound 174k.   565   HO I 174l CO2tBu tBuO C 2                                                                                                     566   Figure A8.151. 1H NMR (500 MHz, CDCl3) of compound 174l. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.152. Infrared spectrum (Thin Film, NaCl) of compound 174l.  Figure A8.153. 13C NMR (126 MHz, CDCl3) of compound 174l.   567   175l O CO2tBu tBuO C 2                                                                                                     568   Figure A8.154. 1H NMR (500 MHz, CD2Cl2) of compound 175l. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.155. Infrared spectrum (Thin Film, NaCl) of compound 175l.  Figure A8.156. 13C NMR (126 MHz, CD2Cl2) of compound 175l.   569   Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement   570   APPENDIX 9 Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement A9.1. Claisen Rearrangement Having successfully investigated Ni-catalyzed intramolecular C–O bond- forming reactions, we envisaged that allyl vinyl ethers prepared under our conditions could be substrates for subsequent Claisen rearrangement. Treatment of epoxide 190 with methylamine followed by alkylation with allyl bromide 191 afforded aminoalcohol 192 (Scheme A9.1.1a). Intramolecular etherification of aminoalcohol 192 furnished the desired allyl vinyl ether 193 (Scheme A9.1.1b). To our delight, microwave-assisted Claisen rearrangement of vinyl ether 193 in m-xylene at 180 °C produced 194 (Scheme A9.1.1c). Further investigation of the substrate scope for Claisen rearrangement is ongoing in our laboratory. Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement   571   Scheme A9.1.1. Ni-Catalyzed C–O Bond Formation and subsequent Claisen Rearrangement (a) 1. MeNH 2 (2M in MeOH) 23 °C O 2. 190 OH I N I Ph Br Ph 192 191 K 2CO3, MeCN, 23 °C (35% yield, 2 steps) (b) OH I N Ph Ni(COD) 2 (5 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M) (72% yield) N Ph 192 193 (c) Ph Ph O microwave N 180 °C, m-xylene (44% yield) 193 O N 194 A9.2. Experimental Methods and Analytical Data A9.2.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, TCI, Oakwood chemicals, Strem, or Alfa Aesar and used as received unless otherwise stated. Ni(COD)2 and NiI2 were purchased from Strem. NiBr2(dme) was purchased from Aldrich. Zinc dust or powder purchased from Aldrich worked well for the reaction but zinc powder (99.999%) purchased from Strem gave poor conversion. Reaction temperatures were 572     controlled by an IKAmag temperature modulator unless otherwise indicated. Glove Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, KMnO4 or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.0400.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), CHDCl2 (δ 5.32) or C6HD6 (δ 7.16 ppm). 13C NMR spectra are recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers (75 MHz, 126 MHz, and 151 MHz, respectively) and are reported relative to CHCl3 (δ 77.16 ppm), CHDCl2 (δ 53.84) or C6HD5 (δ 128.06 ppm). 19 F NMR spectra are recorded on a Varian Mercury 300 MHz (at 282 MHz). 19F NMR spectra are reported relative to CFCl3(δ 0.0 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode, or Agilent 6200 Series TOF with an Agilent G1978A 573     Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). A9.2.2. Experimental Procedures O 1. MeNH 2 (2M in MeOH) 23 °C 2. 190 I N I Ph OH Br Ph 192 191 K 2CO3, MeCN, 23 °C (35% yield, 2 steps) To epoxide 190 (300 mg, 4.28 mmol, 1.00 equiv) was added MeNH2 (2M solution in MeOH; 3.71 mL, 42.8 mmol, 10.0 equiv). The solution was stirred for 12 h at 23 °C. The volatile was evaporated and the residue was used without further purification. To a solution of the amine (4.28 mmol, 1.00 equiv) in MeCN (11.0 mL) were added K2CO3 (2.96 g, 21.4 mmol, 5.00 equiv) and allyl bromide 191 (691 mg, 2.14 mmol, 0.50 equiv). The solution was stirred for 12 h at 23 °C. After the reaction was done, water was added. The aqueous phase was extracted with EtOAc (3 x 7.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:4 EtOAc:hexanes) on silica gel to give aminoalcohol 192 (257 mg, 35% yield based on equivalent of allyl bromide 191, 2 steps). Rf = 0.65 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.55 (m, 2H), 7.43 – 7.34 (m, 3H), 7.10 – 6.98 (s, br, 1H), 5.84 (ddd, J = 17.2, 10.5, 5.8 Hz, 1H), 5.45 – 5.37 (m, 1H), 5.21 (dt, J = 10.5, 1.5 Hz, 1H), 4.29 (s, br, 1H), 3.54 (s, br, 1H), 3.41 (s, br, 1H), 2.58 (s, br, 2H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 138.0, 137.2, 136.9, 128.8, 128.4, 128.3, 116.3, 70.7, 68.7, 62.8, 61.1, 41.2; IR (Neat Film 574     NaCl) 3435, 2795, 1491, 1446, 1083, 1029, 921, 750, 695 cm-1; HRMS (MM: ESIAppendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement APCI+) m/z calc’d for C14H19NOI [M+H]+ : 344.0506; found: 344.0523. OH I N 192 Ph Ph Ni(COD) 2 (5 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M) (72% yield) N 193 Ni-Catalyzed C–O bond formation experiments were performed in a nitrogen-filled glove box. To a solution of aminoalcohol 192 (100 mg, 0.291 mmol, 1.00 equiv) in MeCN (1.94 mL) in a scintillation vial were added Et3N (45 µL, 0.320 mmol, 1.10 equiv), Zn powder (38.0 mg, 0.582 mmol, 2.00 equiv), and Ni(COD)2 (4.00 mg, 0.0146 mmol, 0.05 equiv). The reaction mixture was stirred at 23 °C for 24 h. After the reaction was done, the vial was removed from the glovebox and uncapped. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to furnish the product 193 (45.3 mg, 72% yield). Rf = 0.23 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CD2Cl2) δ 7.51 (dd, J = 8.3, 1.4 Hz, 2H), 7.18 (dd, J = 8.4, 7.0 Hz, 2H), 7.08 – 7.01 (m, 1H), 5.89 (ddd, J = 17.3, 10.7, 5.6 Hz, 1H), 5.40 – 5.32 (m, 2H), 5.19 – 5.16 (m, 1H), 4.35 (dddt, J = 9.8, 5.7, 2.9, 1.5 Hz, 1H), 3.09 (dd, J = 12.6, 1.6 Hz, 1H), 2.78 – 2.69 (m, 2H), 2.21 (s, 3H), 2.08 (dd, J = 11.7, 9.5 Hz, 1H); 13C NMR (101 MHz, CD2Cl2) δ 150.5, 136.4, 136.2, 128.9, 128.6, 126.4, 117.1, 107.9, 78.0, 59.5, 58.3, 46.2; IR (Neat Film NaCl) 2939, 2784, 2360, 1666, 1448, 1328, 1239, 1176, 1133, 1047, 985, 937, 755, 694 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H18NO [M+H]+ : 216.1383; found: 216.1399. Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement   Ph Ph O microwave N 180 °C, m-xylene (44% yield) 193 575   O N 194 A solution of allyl vinyl ether 193 (11.0 mg, 0.0511 mmol, 1.00 equiv) in m-xylene (1.02 mL) was heated to 180 °C (power: 300 W) by microwave for 6 h. The resultant solution was then allowed to cool to ambient temperature, filtered through a pad of SiO2 using hexanes as the eluent to remove m-xylene, at which time separate fractions were collected, eluting with EtOAc, to isolate reaction products. The filtrate was concentrated in vacuo and the residue was subsequently purified by flash chromatography (1:2 EtOAc:hexanes) to afford the Claisen product, 194 (4.80 mg, 44% yield). Rf = 0.39 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 7.45 – 7.41 (m, 2H), 7.35 (ddd, J = 7.7, 6.8, 1.2 Hz, 2H), 7.30 – 7.27 (m, 1H), 5.94 (m, 1H), 5.61 (dt, J = 10.8, 5.1 Hz, 1H), 3.87 (d, J = 13.9 Hz, 2H), 3.55 (d, J = 15.7 Hz, 1H), 3.42 (d, J = 15.3 Hz, 1H), 3.04 (t, J = 15.5 Hz, 1H), 2.84 (d, J = 15.4 Hz, 1H), 2.47 – 2.42 (m, 1H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 210.7, 138.3, 130.9, 129.0, 128.7, 128.1, 127.6, 66.1, 61.3, 58.1, 45.9, 29.1; IR (Neat Film NaCl) 2928, 2791, 1696, 1493, 1451, 1268, 1126, 699 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H18NO [M+H]+ : 216.1383; found: 216.1398. Appendix 10 – Spectra Relevant to Appendix 9 576 APPENDIX 10 Spectra Relevant to Appendix 9: Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement Ph 192 I N OH                                                                                                     577   Figure A10.1. 1H NMR (400 MHz, CDCl3) of compound 192. Appendix 10 – Spectra Relevant to Appendix 9 Appendix 10 – Spectra Relevant to Appendix 9                                                                                                     Figure A10.2. Infrared spectrum (Thin Film, NaCl) of compound 192.  Figure A10.3. 13C NMR (101 MHz, CDCl3) of compound 192.   578   193 N Ph O                                                                                                     579   Figure A10.4. 1H NMR (400 MHz, CD2Cl2) of compound 193. Appendix 10 – Spectra Relevant to Appendix 9 Appendix 10 – Spectra Relevant to Appendix 9                                                                                                     Figure A10.5. Infrared spectrum (Thin Film, NaCl) of compound 193.  Figure A10.6. 13C NMR (101 MHz, CD2Cl2) of compound 193.   580   194 N O Ph                                                                                                     581   Figure A10.7. 1H NMR (500 MHz, CDCl3) of compound 194. Appendix 10 – Spectra Relevant to Appendix 9 Appendix 10 – Spectra Relevant to Appendix 9     Figure A10.8. Infrared spectrum (Thin Film, NaCl) of compound 194.  Figure A10.9. 13C NMR (101 MHz, CDCl3) of compound 194.   582   583   Appendix 11 – Synthetic Studies Toward Alistonitrine A APPENDIX 11 Synthetic Studies Toward Alistonitrine A† A11.1. Introduction The polycyclic monoterpene alkaloid alistonitrine A (195) was isolated from the leaves of Alstonia scholaris in 2014 by the Bai and Jiang groups (Figure A11.1.1).1 The alkaloids extracted from Alstonia scholaris possess interesting biological properties such as anticancer, antibacterial, anti-inflammatory, antiasthmatic, expectorant, analgesic, and antitussive activities. 2 Alistonitrine A (195) possesses intriguing structural features including an unprecedented caged skeleton, consecutive aminals, an epoxide, and a polycyclic system. Synthetic studies toward alistonitrine A have not been reported to date. Herein, we describe our synthetic efforts toward alistonitrine A (195). Figure A11.1.1. Structure of Alistonitrine A (195) MeO 2C H O H N N H ≡ N N H N CO2Me N O Alistonitrine A (195)                                                                                                                 † Portions of this work have been published. Han, S.-J.; Stoltz, B. M. Tetrahedron Lett. 2016, DOI: 10.1016/j.tetlet.2016.04.022 584   Appendix 11 – Synthetic Studies Toward Alistonitrine A A11.2. Results and Discussion Our initial retrosynthetic analysis of alistonitrine A is outlined in Scheme A11.2.1. Disconnection of the aminal at the C21 and epoxide functions in alistonitrine A (195) would afford amide 196. Further cleavage of the C2–C3 bond and the second aminal functional group would provide intermediate 197, in which the acyl telluride would serve as a handle for a decarbonylative radical cyclization.3 We envisioned that the vicinal quaternary centers of intermediate 197 could be constructed by coupling of oxindole 198 and amide 199. Scheme A11.2.1. Retrosynthetic Analysis of Alistonitrine A (195) H O MeO 2C 9 21 7 5 2 12 amide reduction/ aminal formation 3 N N MeO 2C NH N H Alistonitrine A (195) PhthN 196 CO2Me PhthN N 197 allylic alkylation CO2Me N R PhTe OAc O CO2Me O O radical cyclization/ aminal formation O epoxidation N N H H MeO 2C O + N O N H 198 OTIPS 199 The synthesis commenced with the construction of amine 205, which was adapted from Ellman and Nelson protocols (Scheme A11.2.2). Protection of diol 200 with TBSCl furnished bis-silyl ether 201, which was converted to aldehyde 202 by ozonolysis. Condensation with (R)-tert-butanesulfinamide auxiliary produced tert-butylsulfinyl imine 203.4,5 1,2-addition of allylmagnesium bromide to tert-butylsulfinyl imine 203 generated 585   adduct 204 in high diastereoselectivity. Cleavage of the silyl and tert-butanesulfinyl Appendix 11 – Synthetic Studies Toward Alistonitrine A groups under acidic conditions afforded chiral amine 205. Scheme A11.2.2. Synthesis of Chiral Amine 205 OH OTBS TBSCl, imidazole DMAP O 3 then PPh 3 CH2Cl2 (98% yield) CH2Cl2 (97% yield) OH OTBS 200 201 OTBS O 202 OTBS CuSO4 (R)-tert-butanesulfinamide CH2Cl2 (84% yield) allylmagnesium bromide O S N CH2Cl2 (87% yield; single diastereomer) 203 OTBS OH 4N HCl in dioxane O S NH MeOH (90% yield) 204 NH 3Cl 205 With chiral amine 205 in hand, α,β-unsaturated lactam formation was explored (Scheme A11.2.3). Silylation of amine 205 followed by acylation generated metathesis precursor 206. We were delighted to find that ring-closing metathesis of 206 with Hoveyda-Grubbs 2nd generation catalyst smoothly produced lactam 207.6,7 Protection of the nitrogen of amide 207 with MeI or Boc2O afforded the corresponding intermediates 208a and 208b. Unfortunately, attempted Baylis-Hillman reactions to furnish alcohol 209a or 209b, respectively, were unsuccessful.8,9 586   Appendix 11 – Synthetic Studies Toward Alistonitrine A Scheme A11.2.3. Synthesis of α,β-Unsaturated Lactams 208 OH 1. TIPSCl, imidazole, Et 3N DMAP, CH2Cl2 (60% yield) NH 3Cl 2. acryloyl chloride, Et 3N CH2Cl2 (79% yield) OTIPS O 205 206 Hoveyda-Grubbs 2nd generation (5 mol %) CH2Cl2, 45 °C (70% yield) MeI, LHMDS THF (98% yield) O NH OTIPS 207 O or Boc 2O, Et 3N, DMAP CH2Cl2 (89% yield) OH N NH O Baylis-Hillman reactions R N OTIPS R = Me, 208a R = Boc, 208b R OTIPS R = Me, 209a R = Boc, 209b Alternatively, we decided to employ the Baylis-Hillman reaction at an earlier stage (Scheme A11.2.4). Reaction of methyl acrylate (210) with acetaldehyde and subsequent hydrolysis furnished acid 211. Coupling of acid 211 and amine 212 with EDCI and HOBt proceeded smoothly to provide amide 213. To our delight, ring-closing metathesis of 213 occurred with catalyst 214, delivering the desired 2:3 mixture of two diastereomers of lactam 215.10 Coupling of alcohol 215 and acetic acid with EDCI and HOBt generated acetate 199. 587   Appendix 11 – Synthetic Studies Toward Alistonitrine A Scheme A11.2.4. Synthesis of α-Substituted α,β-Unsaturated Lactam 199 1. acetaldehyde DABCO dioxane, H 2O (80% yield) O OMe OH H 2N 211 OH 214 (8 mol %) OH EDCI, HOBt, DIPEA + OH 2. LiOH THF, H 2O (88% yield) 210 O OTIPS N H 213 Cl OAc O NH EDCI, acetic acid DMAP NH CH2Cl2 (90% yield) (73% yield; 78% yield based on recovered starting material) N THF (72% yield) 212 O benzene, 60 °C O OTIPS 215 OTIPS 199 OTIPS N Ru Cl O 214 Having successfully prepared the amide fragment, we began the synthesis of the oxindole fragment 217 (Scheme A11.2.5). The quaternary center of oxindole 198 was constructed by the base-promoted alkylation of 3-bromooxindole 216 with dimethyl malonate, which proceeded via in situ formation of an o-azaxylylene intermediate.11 Boc protection of the oxindole nitrogen generated oxindole fragment 217. Scheme A11.2.5. Synthesis of Oxindole Fragment 217 PhthN PhthN PhthN CO2Me Cs2CO3 dimethyl malonate Br O N H 216 THF (82% yield) CO2Me O N H 198 CO2Me CO2Me Boc 2O, DMAP CH2Cl2 (92% yield) O N Boc 217 With fragments 199 and 217 in hand, we investigated various alkylation reactions of malonate 217 with acetate 199 (Scheme A11.2.6). Unfortunately, only trace amounts 588   of the desired product and some byproducts were observed with palladium catalysts. Appendix 11 – Synthetic Studies Toward Alistonitrine A Additionally, we attempted to form 218 under basic conditions, but only unreacted oxindole 217 and a byproduct were obtained. Scheme A11.2.6. Attempted Coupling of Malonate 217 and Amide 199 PhthN PhthN MeO 2C OAc O CO2Me CO2Me O CO2Me + NH conditions O O N N OTIPS Boc 217 N Boc TIPSO 199 218 (Not observed) Having failed in coupling of oxindole 217 and amide 199, a revised retrosynthesis was devised (Scheme A11.2.7). We envisioned that a late stage Fischer indole synthesis of intermediate 219 would afford the core structure of alistonitrine A. Disconnection of the C15–C20 bond in intermediate 219 provided Heck reaction precursor 220. Vinyl halide 220 was expected to be formed from ketone 221 by reductive amination and subsequent double bond isomerization. Scheme A11.2.7. A Revised Retrosynthesis Toward Alistonitrine A H O MeO 2C 9 15 7 5 2 N H 12 3 H Fischer indole synthesis 20 MeO 2C N N BocHN H O 219 O reductive amination X N N 220 O 20 N Alistonitrine A (195) PMB 15 O O PMB N double bond isomerization O 221 intramolecular reductive Heck reaction 589   Esterification of acid 222 followed by subsequent reductive amination and Appendix 11 – Synthetic Studies Toward Alistonitrine A acylation produced amide 223 (Scheme A11.2.8). Treatment of 223 with NaOMe afforded lactam 224, and a subsequent Robinson annulation furnished bicycle 225.12 Oxidation of enone 225 was accomplished with SeO2 to deliver dienone 226.13 However, an attempted reductive amination of dienone 226 to provide amine 227 resulted in the removal of the ester group and subsequent aromatization, affording phenol 228. Although our synthetic efforts toward alistonitrine A were unsuccessful, we were able to serendipitously discover a novel nickel-catalyzed C–O bond forming reaction (Chapter 4). Scheme A11.2.8. Synthesis of Bicycle 226 1. SOCl2, MeOH 2. p-anisaldehyde Et 3N; NaBH 4, MeOH CO2H H 2N 3. methyl malonyl chloride i-Pr2NEt, CH2Cl2 (74% yield, 3 steps) 222 O PMB CO2Me N 1. 1N KOH in MeOH methyl vinyl ketone 18-crown-6 MeOH O MeO 223 O PMB CO2Me SeO2, AcOH N O 225 O CO2Me MeNH 3Cl, NaBH 3CN N PMB CO2Me N THF, MeOH O NHMe 226 227 (Not observed) O MeNH 3Cl, NaBH 3CN NaOMe toluene, MeOH (70% yield) PMB 224 O CO2Me N 2. pyrrolidine, benzene; AcOH-H2O-NaOAc (46% yield, 2 steps) O PMB O PMB N THF, MeOH (85% yield) OH 228 t-BuOH (40% yield) 590   Appendix 11 – Synthetic Studies Toward Alistonitrine A A11.3. Experimental Methods and Analytical Data A11.3.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Triethylamine was distilled over CaH2 prior to use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Microwave-assisted reactions were performed in a Biotage Initiator 2.5 microwave reactor. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, panisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm), or (CD3)2CO (δ 2.05 ppm). 13C NMR spectra are recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm), or (CD3)2CO (δ 29.84 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app 591   = apparent. Data for C are reported in terms of chemical shifts (ppm). IR spectra were Appendix 11 – Synthetic Studies Toward Alistonitrine A 13 obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). A11.3.2. Experimental Procedures OH OTBS TBSCl, imidazole DMAP CH2Cl2 (98% yield) OH OTBS 200 201 To a solution of diol 200 (0.930 mL, 11.3 mmol, 1.00 equiv) in CH2Cl2 (28.3 mL) were added imidazole (7.69 g, 113 mmol, 10.0 equiv) and TBSCl (5.11 g, 33.9 mmol, 3.00 equiv) at 23 °C. The reaction mixture was stirred for 12 h and quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:8 EtOAc:hexanes) to  afford  bis-silyl ether 201 (3.51 g, 98% yield). The spectroscopic data were identical to those previously reported.1 OTBS OTBS O 3 then PPh 3 CH2Cl2 (97% yield) O OTBS 201                                                                                                                 1 Tran, V. T.; Woerpel, K. A. J. Org. Chem. 2013, 78, 6609–6621. 202 592   A solution of bis-silyl ether 201 (1.00 g, 3.16 mmol, 1.00 equiv) in CH2Cl2 (21.1 mL) Appendix 11 – Synthetic Studies Toward Alistonitrine A was cooled to –78 °C and ozone was bubbled through until the solution turned blue. N2 gas was then bubbled through the solution until the reaction mixture turned colorless. PPh3 (0.99 g, 3.79 mmol, 1.20 equiv) was then added and the mixture was warmed to 23 °C slowly. The reaction mixture was stirred under N2 for 1.5 h and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (1:8 EtOAc:hexanes) to  afford  aldehyde 202 (1.07 g, 97% yield). Rf = 0.25 (1:8 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 9.70 (t, J = 0.8 Hz, 1H), 4.22 (d, J = 0.8 Hz, 2H), 0.93 (s, 9H), 0.10 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 202.5, 69.8, 25.9, 18.5, -5.3; IR (Neat Film NaCl) 2955, 2931, 2858, 1740, 1473, 1256, 1128, 838, 779 cm-1; HRMS (MM: FAB+) m/z calc’d for C8H19O2Si [M+H]+: 175.1154; found: 175.1067. OTBS OTBS CuSO4 (R)-tert-butanesulfinamide CH2Cl2 (84% yield) O 202 O S N 203 To a solution of aldehyde 202 (100 mg, 0.574 mmol, 1.00 equiv) in CH2Cl2 (1.91 mL) was added CuSO4 (275 mg, 1.72 mmol, 3.00 equiv) followed by the addition of tertbutanesulfinamide (104 mg, 0.861 mmol, 1.50 equiv). The reaction mixture was stirred at 23 °C for 12 h. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:8 EtOAc:hexanes) to furnish the tert-butylsulfinyl imine 203 (133 mg, 84% yield). 593   –127.8 (c 0.19, CHCl3); Rf = 0.20 (1:8 EtOAc:hexanes); H NMR (400 MHz, Appendix 11 – Synthetic Studies Toward Alistonitrine A [a]D 25 1 CD2Cl2) δ 7.99 (t, J = 3.1 Hz, 1H), 4.53 (d, J = 3.1 Hz, 2H), 1.17 (s, 9H), 0.92 (s, 9H), 0.10 (d, J = 0.6 Hz, 6H); 13C NMR (101 MHz, CD2Cl2) δ 169.1, 66.1, 57.1, 26.1, 22.6, 18.8, -5.1; IR (Neat Film NaCl) 2956, 2930, 2858, 1628, 1473, 1364, 1255, 1089, 838, 779 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H28NO2SSi [M+H]+: 278.1605; found: 278.1606. OTBS OTBS allylmagnesium bromide O S N 203 CH2Cl2 (87% yield; single diastereomer) O S NH 204 To a solution of tert-butylsulfinyl imine 203 (800 mg, 2.88 mmol, 1.00 equiv) in CH2Cl2 (14.4 mL) was added allylmagnesium bromide (1M in diethyl ether; 6.05 mL, 6.05 mmol, 2.10 equiv) dropwise at –78 °C. The reaction mixture was stirred for 5 h at –78 °C and slowly warmed to 23 °C. The reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with CH2Cl2 (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:4 EtOAc:hexanes) to   afford   silyl ether 204 (797 mg, 87% yield). [a]D25 –53.7 (c 0.26, CHCl3); Rf = 0.25 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 5.79 (ddt, J = 17.3, 10.2, 7.2 Hz, 1H), 5.18 – 5.11 (m, 2H), 3.66 (dd, J = 9.9, 4.2 Hz, 1H), 3.54 – 3.51 (m, 1H), 3.48 (s, 1H), 3.34 (t, J = 5.8 Hz, 1H), 2.55 – 2.48 (m, 1H), 2.39 (dtt, J = 13.9, 6.7, 1.3 Hz, 1H), 1.19 (s, 9H), 0.89 (s, 9H), 0.05 (d, J = 0.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 134.5, 118.6, 77.2, 65.1, 56.5, 56.0, 37.2, 26.0, 22.7, 18.4, - 594   5.3, -5.3; IR (Neat Film NaCl) 2955, 2929, 2858, 1472, 1253, 1113, 1072, 836, 777 cm-1; Appendix 11 – Synthetic Studies Toward Alistonitrine A HRMS (MM: FAB+) m/z calc’d for C15H34NO2SSi [M+H]+: 320.2001; found: 320.2084. OTBS OH 4N HCl in dioxane O S NH MeOH (90% yield) 204 NH 3Cl 205 To a solution of silyl ether 204 (126 mg, 0.394 mmol, 1.00 equiv) in MeOH (1.97 mL) was added 4N HCl in dioxane (1.97 mL, 1.97 mmol, 5.00 equiv) at 0 °C. The reaction mixture was warmed to 23 °C and stirred for 2 h. The volatile was evaporated under reduced pressure. The resulting oil was washed with ether revealing a yellow solid. The solid was filtered to give amine hydrochloride 205 (49.0 mg, 90% yield). [a]D25 +9.52 (c 0.06, MeOH); Rf = 0.10 (2:1 EtOAc:hexane); 1H NMR (500 MHz, CD3OD) δ 5.81 (ddt, J = 17.3, 10.2, 7.2 Hz, 1H), 5.29 – 5.19 (m, 2H), 3.76 (dd, J = 11.6, 3.7 Hz, 1H), 3.55 (dd, J = 11.6, 6.7 Hz, 1H), 3.29 – 3.20 (m, 1H), 2.47 – 2.32 (m, 2H); 13 C NMR (126 MHz, CD3OD) δ 133.28, 120.24, 61.92, 53.96, 34.90; IR (Neat Film NaCl) 3369, 2929, 1618, 1508, 1053, 928 cm-1. OH 1. TIPSCl, imidazole, Et 3N DMAP, CH2Cl2 (60% yield) NH 3Cl 2. acryloyl chloride, Et 3N CH2Cl2 (79% yield) 205 OTIPS Hoveyda-Grubbs 2nd generation (5 mol %) O NH 206 O NH CH2Cl2, 45 °C (70% yield) OTIPS 207 To a solution of amine hydrochloride 205 (188 mg, 1.37 mmol, 1.00 equiv) in CH2Cl2 (7.00 mL) were added Et3N (0.38 mL, 2.74 mmol, 2.00 equiv), imidazole (930 mg, 13.7 mmol, 10.0 equiv), DMAP (8.40 mg, 0.0685 mmol, 0.05 equiv), and TIPSCl (0.59 mL, 595   2.74 mmol, 2.00 equiv). The reaction mixture was stirred for 12 h at 23 °C and quenched Appendix 11 – Synthetic Studies Toward Alistonitrine A with water. The aqueous phase was extracted with CH2Cl2 (3 x 8.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (2:1 EtOAc:hexane) to   afford   the   silyl ether (212 mg, 60% yield). To a solution of the resultant silyl ether (100 mg, 0.388 mmol, 1.00 equiv) and Et3N (0.160 mL, 1.16 mmol, 3.00 equiv) in CH2Cl2 (1.94 mL) was added acryloyl chloride (35.0 µL, 0.427 mmol, 1.10 equiv) at 23 °C. The reaction was stirred for 12 h at 23 °C and quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:4 EtOAc:hexanes) to  afford  amide 206 (95.0 mg, 79% yield). To a stirred solution of amide 206 (1.08 g, 3.47 mmol, 1.00 equiv) in CH2Cl2 (116 mL) was added Hoveyda-Grubbs 2nd generation catalyst (0.109 g, 0.173 mmol, 0.05 equiv) at 23 °C. Then, the solution was stirred at 45 °C for 12 h. After the reaction was done, the solution was cooled to 23 °C and water was added. The aqueous phase was extracted with CH2Cl2 (3 x 30.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:2 EtOAc:hexanes) to  afford  lactam 207 (688 mg, 70% yield). [a]D25 –15.6 (c 0.22, CHCl3); Rf = 0.20 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.58 (ddd, J = 9.9, 5.4, 3.0 Hz, 1H), 5.92 (dtd, J = 9.9, 2.4, 1.3 Hz, 1H), 5.87 (s, br, 1H), 3.80 – 3.72 (m, 2H), 3.66 – 3.58 (m, 1H), 2.31 (dtt, J = 17.6, 5.4, 1.2 Hz, 1H), 2.16 (ddt, J = 17.7, 10.9, 2.8 Hz, 1H), 1.21 – 1.00 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 596   166.0, 140.0, 124.8, 66.0, 52.6, 26.0, 18.1, 12.0; IR (Neat Film NaCl) 2943, 2866, 1682, Appendix 11 – Synthetic Studies Toward Alistonitrine A 1615, 1463, 1114, 813 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C15H30NO2Si [M+H]+: 284.2040; found: 284.2045. O O MeI, LHMDS NH OTIPS 207 THF (98% yield) N OTIPS 208a To a solution of lactam 207 (100 mg, 0.353 mmol, 1.00 equiv) in THF (1.80 mL) was added LHMDS (89.0 mg, 0.530 mmol, 1.50 equiv) at 0 °C. The reaction was stirred for 1 h and then MeI (66.0 µL, 1.06 mmol, 3.00 equiv) was added. The solution was stirred for 4 h at 23 °C and quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:2 EtOAc:hexanes) to  afford  amide 208a (103 mg, 98% yield). [a]D25 +46.9 (c 0.12, CHCl3); Rf = 0.27 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.42 – 6.35 (m, 1H), 5.91 (ddd, J = 9.8, 2.7, 1.1 Hz, 1H), 3.74 (dd, J = 9.6, 5.2 Hz, 1H), 3.66 (dd, J = 9.6, 8.6 Hz, 1H), 3.55 – 3.48 (m, 1H), 3.05 (s, 3H), 2.58 (ddt, J = 6.8, 5.0, 2.0 Hz, 2H), 1.15 – 1.00 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 164.1, 137.3, 125.0, 61.6, 59.2, 34.3, 25.0, 18.1, 12.0; IR (Neat Film NaCl) 2942, 2866, 1670, 1618, 1464, 1111, 882 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H32NO2Si [M+H]+: 298.2197; found: 298.2199. 597   Appendix 11 – Synthetic Studies Toward Alistonitrine A O O Boc 2O, Et 3N, DMAP NH N Boc CH2Cl2 (89% yield) OTIPS 207 OTIPS 208b To a solution of amide 207 (50.0 mg, 0.176 mmol, 1.00 equiv) and DMAP (32.2 mg, 0.264 mmol, 1.50 equiv) in CH2Cl2 (0.90 mL) at 0 °C were added Et3N (49.1 µL, 0.352 mmol, 2.00 equiv) and Boc anhydride (77.0 mg, 0.353 mmol, 2.00 equiv). The reaction mixture was warmed to 23 °C and stirred for 12 h. The reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with CH2Cl2 (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:8 EtOAc:hexanes) to   afford   carbamate 208b (60.0 mg, 89% yield). [a]D25 +11.5 (c 0.07, CHCl3); Rf = 0.85 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.59 (ddt, J = 9.8, 6.3, 1.9 Hz, 1H), 5.94 (ddd, J = 9.8, 3.1, 0.8 Hz, 1H), 4.45 (ddt, J = 9.6, 4.8, 3.1 Hz, 1H), 3.74 (dd, J = 9.3, 4.8 Hz, 1H), 3.67 (t, J = 9.5 Hz, 1H), 2.76 (dd, J = 18.8, 6.3 Hz, 1H), 2.62 – 2.54 (m, 1H), 1.53 (s, 9H), 1.20 – 0.96 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 163.3, 152.3, 140.9, 126.0, 83.1, 77.2, 61.8, 54.6, 28.2, 24.8, 18.1, 12.0; IR (Neat Film NaCl) 2944, 2867, 1717, 1368, 1297, 1239, 1160, 1114, 810 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C15H30NO2Si [M+H–Boc]+: 284.2040; found: 284.2046. 1. acetaldehyde DABCO dioxane, H 2O (80% yield) O OMe 210 2. LiOH THF, H 2O (88% yield) OH O OH 211 To a solution of acetaldehyde (1.27 mL, 22.7 mmol, 1.00 equiv) in dioxane/water (1.10 mL/1.10 mL) was added methyl acrylate 210 (6.13 mL, 68.1 mmol, 3.00 equiv) and 598   DABCO (2.55 g, 22.7 mmol, 1.00 equiv). The reaction was stirred at 23 °C for 48 h. Appendix 11 – Synthetic Studies Toward Alistonitrine A After the reaction was done, water was added. The aqueous phase was extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:4 EtOAc:hexanes) to   afford   the ester (2.36 g, 80% yield). The spectroscopic data were identical to those previously reported.2 To a solution of the resultant ester (300 mg, 2.31 mmol, 1.00 equiv) in THF (12.0 mL) and H2O (5.00 mL) at 23 °C was added LiOH (88.0 mg, 3.69 mmol, 1.60 equiv). The reaction was stirred at 23 °C for 1 h and then water was added. The aqueous phase was separated and acidified until pH = 1 with 1N HCl. Then, the aqueous phase was extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to   afford   acid 211 (236 mg, 88% yield). Rf = 0.15 (1:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.39 (t, J = 0.8 Hz, 1H), 5.96 (t, J = 1.1 Hz, 1H), 4.65 (q, J = 6.5 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.2, 142.8, 127.0, 67.1, 22.2; IR (Neat Film NaCl) 3390, 1694, 1633, 1416, 1277, 1176, 1093, 962, 928 cm-1; HRMS (MM: FAB+) m/z calc’d for C5H9O3 [M+H]+: 117.0552; found: 117.0521. H 2N OH O OTIPS 212 EDCI, HOBt, DIPEA OH 211 THF (72% yield) OH O N H OTIPS 213                                                                                                                 2 Latorre, A.; Sáez, J. A.; Rodríguez, S.; González, F. V. Tetrahedron 2014, 70, 97–102. 599   To a solution of amine 212 (50.0 mg, 0.194 mmol, 1.00 equiv) in THF (1.00 mL) were Appendix 11 – Synthetic Studies Toward Alistonitrine A added acid 211 (24.0 mg, 0.204 mmol, 1.05 equiv), HOBt (39.3 mg, 0.291 mmol, 1.50 equiv), EDCI (45.2 mg, 0.291 mmol, 1.50 equiv), and DIPEA (41.0 µL. 0.233 mmol, 1.2 equiv). The reaction was stirred for 12 h at 23 °C and then quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:4 → 1:2 EtOAc:hexanes)    to  afford   amide 213 (49.7 mg, 72% yield). [a]D25 –29.5 (c 0.07, CHCl3); Rf = 0.35 (1:2 EtOAc:hexanes); (due to the distinct presence of rotameric isomers, the 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (400 MHz, CDCl3) δ 6.65 (dd, J = 18.7, 8.7 Hz, 1H), 5.81 (ddtd, J = 17.2, 10.2, 7.1, 1.5 Hz, 1H), 5.65 (d, J = 6.5 Hz, 1H), 5.45 (s, br, 1H), 5.19 – 5.00 (m, 2H), 4.57 (qt, J = 6.5, 1.2 Hz, 1H), 4.10 (dddddd, J = 8.2, 6.9, 5.1, 3.9, 2.8, 1.2 Hz, 1H), 3.85 – 3.68 (m, 2H), 2.48 – 2.29 (m, 2H), 1.38 (d, J = 6.5 Hz, 3H), 1.16 – 1.02 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 167.7, 167.6, 147.24, 147.17, 134.80, 134.77, 118.0, 117.9, 117.9, 117.7, 69.2, 69.1, 64.12, 64.11, 50.13, 50.12, 36.09, 36.07, 21.94, 21.86, 18.1, 12.0; IR (Neat Film NaCl) 3305, 2943, 2866, 1655, 1618, 1542, 1534, 1460, 1118, 882, 788, 682 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C19H38NO3Si [M+H]+: 356.2615; found: 356.2624. 600   Appendix 11 – Synthetic Studies Toward Alistonitrine A OH 214 (8 mol %) benzene, 60 °C O N H OTIPS 213 (73% yield; 78% yield based on recovered starting material) N Cl OH O NH 215 OTIPS N Ru Cl O 214 To a solution of amide 213 (740 mg, 2.08 mmol, 1.00 equiv) in benzene (104 mL) was added Ru catalyst 214 (95.0 mg, 0.17 mmol, 0.08 equiv). The solution was stirred at 60 °C for 12 h. The solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to furnish two diastereomers of lactam 215 (499 mg, 73% yield; 2:3 215a:215b; 78% yield based on recovered starting material). Diastereomer 215a: [a]D25 –1.54 (c 0.78, CHCl3); Rf = 0.35 (1:1 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.44 (ddd, J = 5.7, 3.0, 1.2 Hz, 1H), 5.93 (s, br, 1H), 4.62 – 4.55 (m, 1H), 3.75 (dd, J = 9.2, 4.3 Hz, 1H), 3.61 (dd, J = 9.2, 8.5 Hz, 1H), 2.38 – 2.31 (m, 1H), 2.22 – 2.15 (m, 1H), 1.38 (d, J = 6.5 Hz, 3H), 1.13 – 1.03 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 167.1, 137.0, 132.9, 66.7, 66.0, 52.3, 25.8, 21.1, 18.1, 12.0; IR (Neat Film NaCl) 3408, 2943, 2866, 1678, 1627, 1461, 1117, 1070, 882, 789, 683 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H34NO3Si [M+H]+: 328.2302; found: 328.2306. Diastereomer 215b: [a]D25 –1.77 (c 0.43, CHCl3); Rf = 0.30 (1:1 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.40 (dd, J = 5.8, 3.0 Hz, 1H), 5.92 (s, br, 1H), 4.54 (q, J = 6.5 Hz, 1H), 3.78 – 3.74 (m, 1H), 3.74 – 3.69 (m, 1H), 3.60 (t, J = 8.8 Hz, 1H), 2.31 (dt, J = 17.5, 5.5 Hz, 1H), 2.22 – 2.15 (m, 1H), 1.40 (d, J = 6.4 Hz, 3H), 1.13 – 1.04 (m, 21H); 601   C NMR (126 MHz, CDCl3) δ 166.9, 137.1, 133.2, 67.7, 66.0, 52.2, 25.8, 21.7, 18.1, Appendix 11 – Synthetic Studies Toward Alistonitrine A 13 12.0; IR (Neat Film NaCl) 3294, 2943, 2866, 1678, 1627, 1463, 1115, 882 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H34NO3Si [M+H]+: 328.2302; found: 328.2303. OH OAc O O NH EDCI, acetic acid, DMAP NH CH2Cl2 (82% yield) OTIPS OTIPS 199a 215a To a solution of EDCI (960 mg, 6.18 mmol, 10.0 equiv) and DMAP (38.0 mg, 0.309 mmol, 0.50 equiv) in CH2Cl2 (6.18 mL) was added acetic acid (0.354 mL, 6.18 mmol, 10.0 equiv). The solution was stirred for 5 min at 0 °C and then lactam 215a (202 mg, 0.618 mmol, 1.00 equiv) in CH2Cl2 (0.5 mL) was added. The reaction mixture was stirred 12 h at 23 °C and then quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 4.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   acetate 199a (187 mg, 82% yield). 1 H NMR (300 MHz, CDCl3) δ 6.48 (ddd, J = 5.4, 3.3, 1.3 Hz, 1H), 6.06 (s, br, 1H), 5.78 (q, J = 6.6 Hz, 1H), 3.76 – 3.68 (m, 2H), 3.65 – 3.58 (m, 1H), 2.34 (dt, J = 17.5, 5.4 Hz, 1H), 2.26 – 2.15 (m, 1H), 2.07 (s, 3H), 1.40 (d, J = 6.5 Hz, 3H), 1.15 – 0.99 (m, 21H). OH OAc O O NH EDCI, acetic acid, DMAP NH CH2Cl2 (98% yield) OTIPS OTIPS 215b 199b 602   To a solution of EDCI (1.41 g, 9.07 mmol, 10.0 equiv) and DMAP (55.4 mg, 0.454 Appendix 11 – Synthetic Studies Toward Alistonitrine A mmol, 0.50 equiv) in CH2Cl2 (9.07 mL) was added acetic acid (0.520 mL, 9.07 mmol, 10.0 equiv). The solution was stirred for 5 min at 0 °C and then lactam 215b (297 mg, 0.907 mmol, 1.00 equiv) in CH2Cl2 (1.0 mL) was added. The reaction mixture was stirred 12 h at 23 °C and then quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 6.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   acetate 199b (328 mg, 98% yield). 1 H NMR (300 MHz, CDCl3) δ 6.52 (ddd, J = 5.6, 3.2, 1.2 Hz, 1H), 6.07 (s, br, 1H), 5.77 – 5.69 (m, 1H), 3.72 (qd, J = 4.5, 2.0 Hz, 2H), 3.65 – 3.56 (m, 1H), 2.41 – 2.27 (m, 1H), 2.25 – 2.17 (m, 1H), 2.06 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.14 – 1.00 (m, 21H). PhthN PhthN CO2Me Cs2CO3 dimethyl malonate Br O N H 216 THF (82% yield) CO2Me O N H 198 To a solution of bromooxindole 216 (3.60 g, 9.34 mmol, 1.00 equiv) and dimethyl malonate (2.62 mL, 28.0 mmol, 3.00 equiv) in THF (47.0 mL) was added Cs2CO3 (9.13 g, 28.0 mmol, 3.00 equiv). The reaction mixture was stirred for 12 h at 23 °C. After the reaction was done, water was added. The aqueous phase was extracted with EtOAc (3 x 15.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with 603   mixtures of EtOAc and hexanes to   afford   oxindole 198 (3.34 g, 82% yield). Data for the Appendix 11 – Synthetic Studies Toward Alistonitrine A compound matches reported data.3 PhthN PhthN CO2Me CO2Me O N H CO2Me CO2Me Boc 2O, DMAP O CH2Cl2 (92% yield) N Boc 198 217 To a solution of oxindole 198 (4.08 g, 9.34 mmol, 1.00 equiv) in CH2Cl2 (47.0 mL) were added DMAP (0.114 g, 0.934 mmol, 0.10 equiv) and Boc2O (3.06 g, 14.0 mmol, 1.50 equiv). The reaction mixture was stirred for 12 h at 23 °C. Then, the reaction was quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 15.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to  afford  carbamate 217 (4.61 g, 92% yield). 1 H NMR (300 MHz, CDCl3) δ 7.82 – 7.76 (m, 1H), 7.74 – 7.68 (m, 2H), 7.68 – 7.62 (m, 2H), 7.61 – 7.56 (m, 1H), 7.18 – 7.11 (m, 1H), 7.01 (td, J = 7.6, 1.2 Hz, 1H), 4.21 (s, 1H), 3.80 (s, 3H), 3.53 (t, J = 7.1 Hz, 2H), 3.49 (s, 3H), 2.51 (dt, J = 14.8, 7.5 Hz, 1H), 2.40 (dt, J = 13.8, 6.8 Hz, 1H), 1.65 (s, 9H). CO2H H 2N 1. SOCl2, MeOH 2. p-anisaldehyde Et 3N; NaBH 4, MeOH 222 PMB N H CO2Me SI-A11-1 β-Alanine (222) (5.00 g, 56.1 mmol, 1.00 equiv) was added to MeOH (94.0 mL) and cooled to 0 °C before dropwise addition of SOCl2 (8.19 mL, 0.112 mol, 2.00 equiv).                                                                                                                 3 Krishnan, S.; Stoltz, B. M. Tetrahedron 2007, 48, 7571–7573. 604   Then, the reaction was stirred for 2 h at 90 °C. The solution was concentrated under Appendix 11 – Synthetic Studies Toward Alistonitrine A reduced pressure and treated with ether. The resulting crystals were removed by filtration to afford the ester, which was used without further purification. To a solution of the resultant ester-HCl salt (2.00 g, 14.4 mmol, 1.00 equiv) and Et3N (4.02 mL, 28.9 mmol, 2.00 equiv) in MeOH (40.0 mL) was added anisaldehyde (1.83 mL, 15.1 mmol, 1.05 equiv) and the reaction mixture was stirred for 1.5 h. Then, NaBH4 (1.09 g, 28.8 mmol, 2.00 equiv) was added in portions in 1 h at 0 °C. The reaction was stirred at 23 °C for 8 h and then quenched with water. The aqueous phase was extracted with EtOAc (3 x 25.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to  afford  amine SI-A11-1. 1 H NMR (300 MHz, CDCl3) δ 7.26 – 7.20 (m, 2H), 6.89 – 6.82 (m, 2H), 3.79 (s, 3H), 3.74 (s, 2H), 3.68 (s, 3H), 2.89 (t, J = 6.5 Hz, 2H), 2.54 (t, J = 6.5 Hz, 2H), 1.87 (s, br, 1H). PMB N H CO2Me methyl malonyl chloride i-Pr2NEt CH2Cl2 (74% yield, 3 steps) SI-A11-1 O MeO O N CO2Me PMB 223 To a solution of amine SI-A11-1 (2.64 g, 11.8 mmol, 1.00 equiv) and i-Pr2NEt (4.22 mL, 24.2 mmol, 2.05 equiv) in CH2Cl2 (59.0 mL) was added methyl malonyl chloride (2.02 mL, 18.9 mmol, 1.60 equiv) at °C. The solution was warmed to 23 °C and stirred for 1 h. Then, the reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with CH2Cl2 (3 x 25.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel 605   chromatography with mixtures of EtOAc and hexanes to  afford  amide 223 (2.82 g, 74% Appendix 11 – Synthetic Studies Toward Alistonitrine A yield, 3 steps). (Due to the distinct presence of rotameric isomers, the 1H NMR contained extra peaks.) 1 H NMR (300 MHz, CDCl3) δ 7.19 (d, J = 8.6 Hz, 1H), 7.14 – 7.06 (m, 1H), 6.93 – 6.87 (m, 1H), 6.87 – 6.82 (m, 1H), 4.57 (s, 1H), 4.52 (s, 1H), 3.80 (s, 2H), 3.79 (s, 1H), 3.76 (s, 1H), 3.72 (s, 2H), 3.68 – 3.58 (m, 5H), 3.52 (t, J = 7.1 Hz, 1H), 3.47 (s, 1H), 2.63 (t, J = 6.9 Hz, 1H), 2.54 (t, J = 7.1 Hz, 1H). O O O MeO N PMB CO2Me NaOMe PMB CO2Me N toluene, MeOH (70% yield) O 223 224 To a solution of NaOMe (95%; 0.87 g, 15.2 mmol, 1.10 equiv) in toluene (69.0 mL) and MeOH (11.0 mL) was added amide 223 (2.81 g, 8.69 mmol, 1.00 equiv) in toluene (1.00 mL) dropwise. The solution was stirred at 90 °C for 6 h. The solution was cooled to 23 °C and water was added. The aqueous phase was extracted with EtOAc (3 x 25.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to  afford  lactam 224 (1.78 g, 70% yield). 1 H NMR (300 MHz, CDCl3) δ 13.91 (s, 1H), 7.24 – 7.17 (m, 2H), 6.87 – 6.81 (m, 2H), 4.57 (s, 2H), 3.93 (s, 3H), 3.79 (s, 3H), 3.31 (t, J = 6.8 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H). O PMB CO2Me N O 224 1. 1N KOH in MeOH methyl vinyl ketone 18-crown-6 MeOH O PMB CO2Me N 2. pyrrolidine, benzene; AcOH-H2O-NaOAc (46% yield, 2 steps) O 225 606   To a stirred solution of lactam 224 (600 mg, 2.06 mmol, 1.00 equiv) in MeOH (1.60 mL) Appendix 11 – Synthetic Studies Toward Alistonitrine A at 23 °C were added 1N KOH solution in MeOH (0.21 mL, 0.206 mmol, 0.10 equiv) and 18-crown-6 (54.0 mg, 0.206 mmol, 0.10 equiv) under N2. After stirring for 10 min, methyl vinyl ketone (0.55 mL, 6.80 mmol, 3.30 equiv) was added dropwise at 23 °C and stirred for 22 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was treated with sat. aq KCl solution. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the ketone, which was used without further purification. To a stirred solution of the resultant ketone (2.06 mmol, 1.00 equiv) in benzene (20.6 mL) was added pyrrolidine (0.43 mL, 5.15 mmol, 2.50 equiv) and the mixture was stirred at 90 °C for 6 h using Dean-Stark apparatus. The solution was cooled to 23 °C. The reaction mixture was treated with a mixture of AcOH/H2O/NaOAc (2/2/1) (7.92 mL) and stirred at 100 °C for 3 h. The solution was cooled to 23 °C and treated with H2O. The aqueous phase was extracted with EtOAc (3 x 25.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   bicycle 225 (325 mg, 46% yield). 1 H NMR (300 MHz, CDCl3) δ 7.23 – 7.08 (m, 2H), 6.94 – 6.77 (m, 2H), 4.73 (d, J = 14.5 Hz, 1H), 4.41 (d, J = 14.5 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.38 (ddd, J = 12.1, 6.3, 3.9 Hz, 1H), 3.24 (ddd, J = 12.2, 9.9, 4.6 Hz, 1H), 3.04 – 2.96 (m, 1H), 2.90 – 2.77 (m, 1H), 2.59 – 2.43 (m, 2H), 2.18 – 2.10 (m, 1H), 2.08 – 2.04 (m, 1H). 607   Appendix 11 – Synthetic Studies Toward Alistonitrine A O PMB O CO2Me SeO2, AcOH N O PMB CO2Me N t-BuOH (40% yield) 225 O 226 To a solution bicycle 225 (28.0 mg, 0.0815 mmol, 1.00 equiv) in t-BuOH (2.04 mL) were added AcOH (0.2 mL) and SeO2 (18.1 mg, 16.3 mmol, 2.00 equiv). The reaction was stirred for 12 h at 100 °C. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography, using mixture of hexanes and ethyl acetate as eluent to furnish dienone 226 (11.1 mg, 40% yield). 1 H NMR (300 MHz, CDCl3) δ 7.53 (dd, J = 10.1, 0.5 Hz, 1H), 7.24 – 7.19 (m, 2H), 6.90 – 6.85 (m, 2H), 6.45 (ddd, J = 10.1, 1.7, 0.6 Hz, 1H), 6.26 (td, J = 1.7, 0.7 Hz, 1H), 4.89 (d, J = 14.6 Hz, 1H), 4.28 (d, J = 14.6 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.42 (ddd, J = 12.1, 7.0, 3.6 Hz, 1H), 3.26 (ddd, J = 12.2, 9.5, 5.6 Hz, 1H), 2.96 (dddd, J = 14.6, 9.3, 7.0, 1.9 Hz, 1H), 2.63 (ddd, J = 14.5, 5.6, 3.6 Hz, 1H). A11.4. References and Notes                                                                                                                 (1) Zhu, G.-Y.; Yao, X.-J.; Liu, L.; Bai, L.-P.; Jiang, Z.-H. Org. Lett. 2014, 16, 1080– 1083. (2) (a) Shang, J. H.; Cai, X. H.; Feng, T.; Zhao, Y. L.; Wang, J. K.; Zhang, L. Y.; Yan, M.; Luo, X. D. J. Ethnopharmacol. 2010, 129, 174–181. (b) Shang, J.; H.; Cai, X. H.; Zhao, Y. L.; Feng, T.; Luo, X. D. J. Ethnopharmacol. 2010, 129, 293–298. (c) Baliga, M. S. Integr. Cancer Ther. 2010, 9, 261–269. (d) Lee, S. J.; Cho, S. A.; An, S. S.; Na, Y. J.; 608                                                                                                                                                                                                                                                                                                                                             Park, N. H.; Kim, H. S.; Lee, C. W.; Kim, H. K.; Kim, E. K.; Jang, Y. P.; Kim, J. W. Appendix 11 – Synthetic Studies Toward Alistonitrine A Evid. Based Complement Alternat. Med. 2012, 2012, 190370. (3) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442–6445. (4) (a) Rech, J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso, P. V.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 490–491. (b) Maurya, S. K.; Dow, M.; Warriner, S.; Nelson, A. Beilstein J. Org. Chem. 2013, 9, 775–785. (c) Koriyama, Y.; Nozawa, A.; Hayakawa, R.; Shimizu, M. Tetrahedron 2002, 58, 9621–9628. (5) Although the Ellman group reported that allylmagnesium bromide was added from the Si-face of (S)-tert-butylsulfinyl imine 229 to deliver 230 (ref 3a), the opposite configuration was later confirmed by the Nelson group (ref 3b). The Nelson group prepared (R)-benzamide 231 from both the commercially available (R)-2-amino-4pentenoic acid (232) and using Ellman’s method with (S)-tert-butanesulfinamide. Then they discovered that the retention time of both benzamides (231) was identical on chiral HPLC.   609                                                                                                                                                                                                                                                                                                                                             Appendix 11 – Synthetic Studies Toward Alistonitrine A (a) Ellman (ref 3a) O S OTBS N 1. allylmagnesium bromide CH2Cl2, –78 → 23 °C (92% yield) 2. 4N HCl, CH3OH (94% yield) 229 OH ClH3N 230 (the proposed structure by the Ellman group) (b) Nelson (ref 3b) O S OTBS N 1. allylmagnesium bromide CH2Cl2, –78 → 23 °C (70% yield) 2. 4N HCl, CH3OH (96% yield) 3. benzoyl chloride Et 3N, CH2Cl2 (58% yield) 229 OH BzHN 231 1. acetyl chloride MeOH, reflux OH H 2N O 232 (commercially available) 2. LAH, THF, 0 °C (80% yield, 2 steps) 3. benzoyl chloride Et 3N, CH2Cl2 (58% yield) OH BzHN 231       (6) (a) Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Org. Lett. 2008, 10, 285–288. (b) Hoffmann, T.; Lanig, H.; Waibel, R.; Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40, 3361–3364. (c) Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 65–66. (7) Acidic removal of the silyl and tert-butanesulfinyl groups of 204 followed by carbamate formation with CDI afforded 233. Although acylation of 233 generated metathesis precursor 234, attempted ring-closing metathesis with Hoveyda-Grubbs 2nd generation catalyst to form bicycle 235 led only to double bond isomerization, generating 236.   610                                                                                                                                                                                                                                                                                                                                             Appendix 11 – Synthetic Studies Toward Alistonitrine A OTBS O 1. 4N HCl in dioxane MeOH O S O NH n-BuLi, acryloyl chloride O O N O NH THF (60% yield) 2. CDI, DMAP, Et 3N, THF (62% yield, 2 steps) 204 233 O Hoveyda-Grubbs 2nd generation (5 mol %) O O O N Hoveyda-Grubbs 2nd generation (5 mol %) H H 45 °C, CH2Cl2 (73% yield) 235 236 N O 45 °C, CH2Cl2 234 O     (8) (a) Latorre, A.; Sáez, J. A.; Rodríguez, S.; González, F. V. Tetrahedron 2014, 70, 97– (Not observed) 102. (b) Rao, V. R.; Muthenna, P.; Shankaraiah, G.; Akileshwari, C.; Babu, K. H.; Suresh, G.; Babu, K. S.; Kumar, R. S. C.; Prasad, K. R.; Yadav, P. A.; Petrash, J. M.; Reddy, G. B.; Rao, J. M. Eur. J. Med. Chem. 2012, 57, 344–361. (c) Lee, K. C.; Loh, T. P. Chem. Commun. 2006, 40, 4209–4211. (9) Although a-bromination of lactam 208a produced bromide 237, attempts to prepare the desired alcohol 209a from bromide 237 were unsuccessful. O O 1. Br 2, CH2Cl2 N OTIPS Br 2. Et 3N, CH2Cl2 (42% yield, 2 steps) 208a n-BuLi acetaldehyde N OTIPS 237 THF OH O N OTIPS 209a     (10) The same result of the ring-closing metathesis of amide 213 was obtained with (Not observed) Hoveyda-Grubbs 2nd generation catalyst. (11) (a) Krishnan, S.; Stoltz, B. M. Tetrahedron Lett. 2007, 48, 7571–7573. (b) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037– 8041. (12) Schultz, A. G.; Lucci, R. D.; Napier, J. J.; Kinoshita, H.; Ravichandran, R.; Shannon, P.; Yee, Y. K. J. Org. Chem. 1985, 50, 217–231. 611                                                                                                                                                                                                                                                                                                                                             (13) Pereira, J.; Barlier, M.; Guillou, C. Org. Lett. 2007, 9, 3101–3103. Appendix 11 – Synthetic Studies Toward Alistonitrine A Appendix 12 – Spectra Relevant to Appendix 11 612 APPENDIX 12 Spectra Relevant to Appendix 11: Synthetic Studies Toward Alistonitrine A O 202 OTBS                                                                                                     613   Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound 202. Appendix 12 – Spectra Relevant to Appendix 11 Appendix 12 – Spectra Relevant to Appendix 11                                                                                                     Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound 202.  Figure A12.3. 13C NMR (126 MHz, CDCl 3) of compound 202.   614   O S 203 N OTBS                                                                                                     615   Figure A12.4. 1H NMR (400 MHz, CD2Cl2) of compound 203. Appendix 12 – Spectra Relevant to Appendix 11 Appendix 12 – Spectra Relevant to Appendix 11                                                                                                     Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound 203.  Figure A12.6. 13C NMR (101 MHz, CD2Cl2) of compound 203.   616   204 NH S O OTBS                                                                                                   617   Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound 204. Appendix 12 – Spectra Relevant to Appendix 11 Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound 204.  Figure A12.9. 13C NMR (126 MHz, CDCl 3) of compound 204.   618   205 NH 3Cl OH Figure A12.10. 1H NMR (500 MHz, CD3OD) of compound 205. Appendix 12 – Spectra Relevant to Appendix 11   619   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound 205.  Figure A12.12. 13C NMR (126 MHz, CD3OD) of compound 205.   620   O 207 NH OTIPS Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound 207. Appendix 12 – Spectra Relevant to Appendix 11   621   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound 207.  Figure A12.15. 13C NMR (126 MHz, CDCl3) of compound 207.   622   O OTIPS 208a N Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound 208a. Appendix 12 – Spectra Relevant to Appendix 11   623   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound 208a.  Figure A12.18. 13C NMR (126 MHz, CDCl3) of compound 208a.   624   O OTIPS Boc 208b N Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound 208b. Appendix 12 – Spectra Relevant to Appendix 11   625   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound 208b.  Figure A12.21. 13C NMR (126 MHz, CDCl3) of compound 208b.   626   O 211 OH OH Figure A12.22. 1H NMR (400 MHz, CDCl3) of compound 211. Appendix 12 – Spectra Relevant to Appendix 11   627   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.23. Infrared spectrum (Thin Film, NaCl) of compound 211.  Figure A12.24. 13C NMR (101 MHz, CDCl3) of compound 211.   628   OH O 213 N H OTIPS Figure A12.25. 1H NMR (400 MHz, CDCl3) of compound 213. Appendix 12 – Spectra Relevant to Appendix 11   629   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.26. Infrared spectrum (Thin Film, NaCl) of compound 213.  Figure A12.27. 13C NMR (126 MHz, CDCl3) of compound 213.   630   OH OTIPS NH 215a O Figure A12.28. 1H NMR (500 MHz, CDCl3) of compound 215a. Appendix 12 – Spectra Relevant to Appendix 11   631   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.29. Infrared spectrum (Thin Film, NaCl) of compound 215a.  Figure A12.30. 13C NMR (126 MHz, CDCl3) of compound 215a.   632   OH OTIPS NH 215b O Figure A12.31. 1H NMR (500 MHz, CDCl3) of compound 215b. Appendix 12 – Spectra Relevant to Appendix 11   633   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.32. Infrared spectrum (Thin Film, NaCl) of compound 215b.  Figure A12.33. 13C NMR (126 MHz, CDCl3) of compound 215b.   634   635   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide CHAPTER 5 Synthetic Studies Toward Polycyclic Ineleganolide 5.1. Introduction The complex polycyclic norcembranoid ineleganolide (238) was first isolated from the Taiwanese coral Sinularia inelegans in 1999 by the Duh group (Figure 5.1.1).1,2 The relative stereochemistry of ineleganolide (238) was unambiguously confirmed by X-ray analysis and spectroscopic method. This complex polycyclic norditerpenoid possesses intriguing architectural features including an ether bridge, which connects two carbocyclic rings and an angular fusion of five-, seven,- and sixmembered carbocyclic rings linked with a five-membered lactone ring. Ineleganolide exhibits cytotoxic activity against P-388 murine leukemia cells (ED50 = 3.82 µg/mL).1 Figure 5.1.1. Structure of Ineleganolide (238). (Originally depicted structure shown on the lefthand side; the proposed actual structure from biosynthetic studies shown on the right-hand side.)3 O O H O H O H O O H O O Ineleganolide (238) O H O H 636   A biosynthetic pathway of ineleganolide was proposed by Pattenden and co- Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide workers (Scheme 5.1.1a). 4 It is hypothesized that ineleganolide (238) is biosynthetically constructed by successive transannular Michael reactions of macrocyclic 5-episinuleptolide (239). An initial intramolecular Michael reaction of 5episinuleptolide (239) establishes the C4–C13 bond to furnish cyclohexanone 240. Dehydration of 240 at C11 and subsequent bond formation between C7 and C11 by a second Michael reaction affords ineleganolide (238). The Pattenden group proved this biosynthetic route experimentally by a semisynthesis of ineleganolide (238) from 5-episinuleptolide (239), which was isolated from Sinularia scabra species (Scheme 5.1.1b).5 Acetylation of the hydroxyl group at C11 position of 5-episinuleptolide (239) furnished acetate 242. Ineleganolide (238) was obtained in 26% yield by treatment of acetate 242 with LHMDS. Scheme 5.1.1. Proposed Biosynthesis of Ineleganolide (238) (a) O O O O H 5 4 HO H Michael reaction O 4 11 H (6-exo-trig cyclization) 13 11 H O dehydration O HO H -H2O O O O 5-episinuleptolide (239) 240 O O O 7 H Michael reaction O (5-endo-trig cyclization) 11 H O H H O O O 241 H O Ineleganolide (238) O (b) O O H O O H 5 4 HO Ac2O, Et 3N O 11 H O O 5-episinuleptolide (239) CH2Cl2, 23 °C (92% yield) O H AcO LHMDS O O O 242 O H H THF, –78 → 0 °C (26% yield) O H O H O Ineleganolide (238) 637   Although this intriguing polycyclic norditerpenoid ineleganolide (238) has Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide attracted much attention from the synthetic community over the past decade including extensive efforts from my lab at Caltech,6 a total synthesis of ineleganolide has not been reported. Herein, we describe new synthetic strategies toward an enantioselective synthesis of ineleganolide (238). We chose to pursue the synthesis of the enantiomer of ineleganolide (238), which was depicted in the original isolation paper. 5.2. Results and Discussion We envisioned that a total synthesis of ineleganolide (238) could be achieved by successive transannular Michael reactions (Scheme 5.2.1). Disconnections of the C4–C13 and C11–C12 bonds affords domino double-Michael reaction precursor 243. The 1,4-diketone and ester functional groups of macrocycle 243 can be disassembled into α,β-unsaturated ester 244 and bicycle 245. Scheme 5.2.1. Retrosynthesis of Ineleganolide (238) O H O 4 7 13 12 H O O 11 O Domino Double-Michael Reaction O O H O O 238 O 243 O OTBS X Alkylation + Esterification O CO2Me O X = Leaving Group 244 245 Our synthesis began with the known acetal 2467 to prepare the α,β-unsaturated ester fragment 248 (Scheme 5.2.2). Subjection of acetal 246 to Still-Gennari 638   olefination conditions afforded the (Z)- and (E)-isomers of enoate 248 in ratios Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 8,9 ranging from 10:1 to 2:1, respectively. We were delighted to find that highly (Z)selective olefination occurred to furnish enoate 248 in 54% yield using conditions developed by the Ando group.10 Scheme 5.2.2. Synthesis of (Z)-Selective Enoate 248 OMe O OMe + O F 3C O OMe O P OMe O OMe THF, –20 °C (58% yield, 2 steps) CF3 246 18-crown-6 KHMDS 247 CO2Me 248 (~10:1 to 2:1 Z:E) OMe O OMe + O P O O 246 O OMe NaI, NaH –78 °C, THF (54% yield) OMe OMe or NaI, DBU –78 °C, THF (54% yield) 249 CO2Me 248 (only Z) Acid-mediated acetal hydrolysis of 248 furnished aldehyde 250 in quantitative yield (Scheme 5.2.3a). Methyl Grignard addition to aldehyde 250 produced diastereomeric mixtures of alcohol 251, which was converted to ketone 252 by Swern oxidation. After extensive experimentation, it was found that employing LiTMP (TMP = 2,2,6,6-tetramethylpiperidine) and TMSCl afforded kinetically favored silyl enol ether 253 selectively.11 Silyl enol ether 253 was subsequently transformed to αhydroxyketone 254 by Rubottom oxidation. 12 Surprisingly, tosylation and bromination of α-hydroxyketone 254 proved to be challenging. However, we were delighted to find that treatment of silyl enol ether 253 with NBS furnished αbromoketone 244b (Scheme 5.2.3b). 639   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.3. Synthesis of α-Bromoketone 244b (a) OMe O 50% aq TFA OMe CO2Me OH MeMgBr H CHCl3, 0 → 23 °C (99% yield) CO2Me 248 250 THF, –78 °C (64% yield; 95% yield based on recoverd SM) CO2Me 251 O OTMS DMSO, oxalyl chloride Et 3N 2,2,6,6-tetramethylpiperidine n-BuLi, TMSCl CH2Cl2, –78 °C (88% yield; 90% yield based on recovered SM) THF, –78 °C CO2Me CO2Me 252 253 p-TsCl pyridine 0 → 23 °C O m-CPBA, NaHCO 3 H 2O, toluene; AcOH, H 2O, THF 0 → 23 °C (56% yield based on recovered starting material, 2 steps) OH O X or PPh 3, CBr4 CH2Cl2, 0 °C CO2Me CO2Me 254 X = OTs, 244a X = Br, 244b (Not observed) (b) OTMS O O 2,2,6,6-tetramethylpiperidine n-BuLi, TMSCl THF, –78 °C CO2Me CO2Me 252 Br NBS, NaHCO 3 THF, –78 °C (50% yield based on recovered starting material, 2 steps) 253 CO2Me 244b With α,β-unsaturated ester fragment 244b in hand, we turned our attention to preparing bicyclic fragment 245. Oxidation of known diol 2556a, 13 with MnO2 delivered aldehyde 256 (Scheme 5.2.4a). Methyllithium addition to aldehyde 256 provided secondary alcohol 257, which was oxidized with MnO2 to afford ketone 258. Unfortunately, we explored diazo transfer reactions extensively with various diazo sources (e.g., p-ABSA, 4-dodecylbenzenesulfonyl azide) under Danheiser’s conditions,14 but the desired diazo 259 was not observed. Another strategy was devised to obtain diazo ketone 259 by using Pinnick oxidation of aldehyde 256 to furnish acid 260 (Scheme 5.2.4b). Treatment of acid 260 with ethyl chloroformate or oxalyl chloride generated the corresponding intermediates 261 or 262, respectively. However, attempts to obtain the desired diazo ketone 259 from intermediate 261 or Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 262 with TMS-diazomethane were unsuccessful. 15,16,17 640   Alternatively, we envisioned that the diazo functional group could be inserted by addition of ethyl diazoacetate to aldehyde 256 (Scheme 5.2.4c). Deprotonation of ethyl diazoacetate by LDA followed by addition to aldehyde 256 resulted in an alcohol (263) that could be oxidized to diazo compound 264. Disappointingly, intramolecular O–H insertion of the tertiary alcohol to the diazo in 264 was found to be challenging under Lewis acid conditions. Despite screening numerous rhodium catalysts, solvents, and temperature, only undesired lactonization occurred to form 266.18 641   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.4. Attempts to Synthesize Bicyclic Fragment via Diazo Compounds (a) OTBS OH OH OTBS OTBS MnO 2 MeLi MnO 2 CH2Cl2, 23 °C (92% yield) Et 2O, –15 °C (88% yield) CH2Cl2, 23 °C (89% yield) O OH 255 256 OH 257 OTBS OTBS N2 Danheiser's O OH diazo transfer conditions OH O 258 OH 259 (Not observed) (b) OTBS O OH OTBS NaClO 2, NaH 2PO 4 30% H 2O2 MeCN, H 2O, 0 °C (87% yield) HO O 256 OTBS Et 3N, ethyl chloroformate THF, –10 °C X or oxalyl chloride, Et 3N DMF, CH2Cl2, 0 °C OH O 260 OH X = OCO 2Et, 261 X = Cl, 262 OTBS N2 TMS-diazomethane MeCN, THF, 0 °C O OH 259 (Not observed) (c) OTBS O THF, –78 °C (62% yield) OH OTBS OTBS LDA ethyl diazoacetate N2 MnO 2 EtO O 256 OH CH2Cl2, 23°C (93% yield) OH EtO O O OH 264 263 OTBS OTBS N2 N2 Lewis acids EtO O O OH or Rh 2(OAc)4 catalysts O O EtO 2C 264 265 (Not observed) OTBS Rh 2(OAc)4, toluene 110 °C (36% yield) or Rh 2(OAc)4, benzene 80 °C (36% yield) O O N2 O 266 Having failed to access the bicyclic fragment using diazo strategies, a revised approach was put forward (Scheme 5.2.5). Treatment of methyl ketone 258 with 642   LiTMP (TMP = 2,2,6,6,-tetramethylpiperidine) and TESCl provided silyl ether 267, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide which was transformed to α-hydroxyketone 268 by Rubottom oxidation. However, the desired bicycle 245 was not observed under various basic conditions (e.g., NaOH, KOtBu, NaH, LHMDS, LDA) from benzoate 269 and mesylate 270, which were prepared from α-hydroxyketone 268.19,20 Scheme 5.2.5. Attempted Williamson Etherifications OTBS OTBS 2,2,6,6-tetramethylpiperidine n-BuLi, TESCl O OH THF, –78 °C m-CPBA, NaHCO 3, H 2O, toluene; TESO 258 OH 267 Bz 2O, Et 3N, DMAP CH2Cl2, 0 → 23 °C (85% yield) or MsCl, Et 3N CH2Cl2, 0 °C (71% yield) OTBS AcOH, H 2O, THF, 0 → 23 °C (42% yield based on recovered starting material, 2 steps) OH O OH 268 OTBS OTBS X 11 bases O OH 9 O 6 8 O 5 X = OBz, 269 X = OMs, 270 245 (Not observed) The desired bicycle 245 seemed highly angularly strained due to the α,βunsaturated ketone at the junction of the bicycle. We envisaged that the strain would be reduced by converting the sp2-hybridized carbon to the sp3-hybridized carbon at C6. After considerable experimentation, we found that diastereomeric mixtures of epoxides 271a and 271b could be obtained by a Corey-Chaykovsky reaction (Scheme 5.2.6a).21 Surprisingly, diol 255 was furnished as a major byproduct under these reaction conditions. Treatment of aldehyde 256 with dibromomethane (or chloroiodomethane) and n-BuLi also produced diastereomeric mixtures of epoxides 271a and 271b along with diol 255 (Scheme 5.2.6b).22 643   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.6. Synthesis Epoxides 271a and 271b (a) H OTBS OH THF, 0 °C O (35% combined yield, 271a, 271b; 19% yield, 255 ) 256 (b) OTBS dibromomethane (or ClCH2I) n-BuLi OH THF, –78 → 23 °C O (39% combined yield, 271a, 271b; 34% yield 255 ) OH OH OH 255 OTBS + 271a OH 271b 6 256 O OH OTBS + 271a OTBS O OTBS + 6 O H OTBS trimethylsulfonium iodide KHMDS OTBS + O OH 271b OH OH 255 With epoxide 271 in hand, direct epoxide ring opening reactions were conducted to deliver 272 (Scheme 5.2.7a). Unfortunately, 5-membered ring formation to generate 272 was not observed with various Lewis acids (e.g., CeCl3, TMSOTf, In(OTf)3, PPTS) or bases (e.g., KHMDS, NaH).23 Interestingly, treatment of epoxide 271 with MgI2 at 40 °C generated iodohydrin 273 along with methyl ketone 258 (Scheme 5.2.7b).24,25 Protection of secondary alcohol 273 with TESCl and subsequent intramolecular etherification of iodide 274 with NaH afforded bicyclc 275.26 Selective removal of TES group in 275 with PPTS furnished mono-silyl ether 276. An attempt to oxidize secondary alcohol 276 to ketone 245 shows promise by TLC analysis but to date we have not successfully isolated and characterized 245.27 644   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.7. Formation of Bicyclic Fragment (a) OTBS OTBS Lewis acids O HO or bases OH O 271 (b) 272 (Not observed) OTBS OTBS MgI 2 O HO THF, 40 °C (63% yield, 273; 16% yield, 258 ) OH + HO I 271 O 273 OTBS HO OTBS NaH TESO CH2Cl2, 23 °C (89% yield) I 273 THF, 23 °C (60% yield) HO 274 PPTS TESO O 275 OTBS EtOH, 23 °C (45% yield) OH 258 OTBS TESCl, imidazole DMAP HO I OTBS OTBS MnO 2 HO O CH2Cl2, 23°C 276 O O 245 We next investigated coupling reactions of α-bromoketone 244b and methylketone 258, which could be easily prepared (Scheme 5.2.8a). Despite extensive experimentation, alkylation of methylketone 258 with α-bromoketone 244b failed under basic conditions. 28 Treatment of hydroxyketone 268 with ethyl chloroformate afforded the carbonate intermediate, which was subjected to αbromoketone 244b to generate 1,4-diketone 279 under basic conditions. However, αbromoketone 244b appeared to decompose under the basic conditions and only the unreacted cyclopentene fragment was recovered. 645   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.8. Coupling of the Fragments (a) O O OTBS Br O OH bases + O CO2Me 244b OH O 258 OMe OTBS 277 (Not observed) (b) Et 3N, DMAP ethyl chloroformate OH O EtO OTBS OH 244b O bases CH2Cl2 0 → 23 °C (92% yield) OH OCO 2Et O O O OTBS THF, –78 °C O 268 OH O 278 OMe OTBS 279 (Not observed) Since coupling reactions of α-bromoketone 244b and the cyclopentene fragment by alkylation did not proceed, we next chose to focus on metathesis strategies to combine these two fragments (Scheme 5.2.9). We believed that esterification of acid 280 and secondary alcohol 281 would afford metathesis precursor diene 282. Intramolecular metathesis reaction between the vinyl groups of 282 was expected to produce macrocycle 283. 1,4-Addition of tertiary alcohol to the α,β-unsaturated ketone could deliver 5-membered ether 243, which would proceed domino double-Michael reaction to afford ineleganolide (238). Scheme 5.2.9. Synthetic Plan by Using Metathesis Strategies O O OH metathesis OH O CO2H O esterification + 280 OH O 281 O O O OH O 282 O O Domino Double-Michael 1,4-addition O O H O Reaction H O 283 O O 243 O O H O Ineleganolide (238) 646   1,2-Addition of vinylmagnesium bromide to aldehyde 256 furnished allyl Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide alcohol 284, which was oxidized by MnO2 to deliver vinyl ketone 285 (Scheme 5.2.10a). Removal of silyl group on 285 with TBAF afforded diol 281. Vinyl Grignard addition to aldehyde 250 and subsequent oxidation of the resultant alcohol 286 produced ketone 287 (Scheme 5.2.10b). However, an attempted hydrolysis of methyl ester 287 afforded Michael adduct 288 instead of the desired acid 280. Additionally, transesterifications of ester 287 with alcohol 281 were unsuccessful with Otera’s catalyst (Scheme 5.2.10c). 29 Therefore, we decided to explore esterification reactions with silyl ether 289 (Scheme 5.2.10d). Silylation of secondary alcohol 286 with TBSCl and subsequent hydrolysis produced acid intermediate 289. Disappointingly, esterification of acid 289 and alcohol 281 was found to be challenging under several coupling conditions (e.g., EDCI, DCC, BOPCl).30 647   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.10. Coupling of the Fragments by Esterification (a) OTBS OTBS OTBS vinylmagnesium bromide H O MnO 2 THF, –78 °C (84% yield; 99% yield based on recovered starting material) OH OH 256 CH2Cl2, 23 °C (63% yield) OH O 284 OH 285 OH TBAF THF, 23 °C (46% yield) O OH 281 (b) O OH H CO2Me vinylmagnesium bromide DMSO, oxalyl chloride Et 3N, CH2Cl2, –78 °C (97% yield) THF, –78 °C (66% yield; 88% yield based on recovered starting material) or MnO 2, CH2Cl2, 23 °C (85% yield) CO2Me 250 286 O O LiOH THF, MeOH, H 2O or K 2CO3, MeOH, H 2O CO2Me CO2H 287 280 (Not observed) LiOH THF, MeOH, H 2O, 23 °C (65% yield) O OMe or K 2CO3, MeOH, H 2O, 23 °C (53% yield) CO2Me 288 (c) O O OH O Otera's catalyst + OH toluene CO2Me 287 O OH O 281 O 282 OH (d) OTBS OH 1. TBSCl, imidazole DMAP, CH2Cl2, 23 °C (95% yield) OTBS OH OH 281 2. LiOH THF, MeOH, H 2O, 23 °C CO2Me (97% yield) 286 O O CO2H 289 coupling conditions O O 290 (Not observed) At this stage, we began to investigate intermolecular metathesis between allyl alcohol 286 and vinyl ketone 285 with Grubbs’ catalysts (Scheme 5.2.11a). 31 648   However, intermolecular metathesis of 286 and 285 to deliver 291 proved to be Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide difficult. Alternatively, we attempted to connect allyl alcohol 286 and diol 284 via a silyl tether, but the yield was unsatisfactory (Scheme 5.2.11b). Scheme 5.2.11. Intermolecular Metathesis (a) OH OH OTBS O OH metathesis + CO2Me 286 O OH O 285 OMe OTBS 291 (Not observed) (b) OH Si OTBS dichlorodiethylsilane + O O HO pyridine CO2Me OH OTBS OH CO2Me 286 284 292 (Not observed) Since combining the two fragments appeared to be challenging, we devised a new synthetic strategy that utilized an alkyne functionality (Scheme 5.2.12). Addition of ethynylmagnesium bromide to aldehyde 256 provided intermediate 293, which was oxidized by MnO2 to generate ynone 294 (Scheme 5.2.12a). Although n-BuLi was subjected to alkyne 294 to form lithium acetylide, which was added to aldehyde 250, little or no conversion was observed (Scheme 5.2.11b). We also attempted the lithium acetylide addition reaction with alcohol 293 or silyl ether 296,32 but only trace amounts of the respective coupling products 297 or 298 were observed. 649   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.12. Alkyne Addition (a) OTBS H O OH 256 (b) OTBS ethynylmagnesium bromide MnO 2 THF, –78 °C (90% yield, 94% yield based on recovered starting material) CH2Cl2, 23 °C (68% yield) O OH OH O 293 OH 294 HO OTBS H OTBS O HO n-BuLi + THF CO2Me 250 O OH CO2Me 294 OTBS 295 (Not observed) O HO OTBS H OR HO n-BuLi + THF, –78 °C CO2Me 250 OR OH R = H, 293 R = TES, 296 CO2Me OTBS R = H, 297 R = TES, 298 (trace) 5.3. Conclusion We have described our efforts toward the synthesis of ineleganolide. Highly (Z)-selective olefination at C12–C13 was achieved by a method developed by the Ando group. The C–O bond formation at C5, which proved to be challenging in the other strategy investigated in our group,6a was accomplished. Although the entire fragmented carbon framework was constructed from this work, unfortunately, coupling of the two fragments was unsuccessful. We will further investigate a total synthesis of ineleganolide using modified strategies. 5.4. Experimental Methods and Analytical Data 5.4.1. Materials and Methods Unless stated otherwise, reactions were performed at ambient temperature (23 °C) in flame-dried glassware under an argon atmosphere using dry, deoxygentated solvents 650   (distilled or passed over a column of activated alumina) using a Teflon -coated Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide ® magnetic stirring bar. Commercially available reagents were used as received unless otherwise noted. Et3N was distilled from calcium hydride immediately prior to use. MeOH was distilled from magnesium methoxide immediately prior to use. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (250 nm) and visualized by UV fluorescence quenching, potassium permanganate, or p-anisaldehyde staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 40-63 nm) was used for flash chromatography. 1 H NMR spectra were recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), CHDCl2 (δ 5.32) or C6HD6 (δ 7.16 ppm). 13 C NMR spectra are recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers (75 MHz, 126 MHz, and 151 MHz, respectively) and are reported relative to CHCl3 (δ 77.16 ppm), CHDCl2 (δ 53.84) or C6HD5 (δ 128.06 ppm). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 Spectrometer and are reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode or acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in atmospheric pressure 651   chemical ionization (APCI) or mixed (MultiMode ESI/APCI) ionization mode. Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path length cell at 589 nm. 5.4.2. Experimental Procedures OMe O OMe + O P O O 246 249 O OMe NaI, NaH –78 °C, THF (54% yield) OMe OMe or NaI, DBU –78 °C, THF (54% yield) CO2Me 248 (only Z) A solution of phosphate 249 (108 mg, 0.322 mmol, 1.20 equiv) in THF (2.68 mL) was treated with NaI (52.0 mg, 0.349 mmol, 1.30 equiv) and DBU (53.0 mg, 0.348 mmol, 1.30 equiv) at 0 °C and stirred for 10 min. After the mixture was cooled to – 78 °C, aldehyde 246 was added. The reaction was done in 3 min, and quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford α,β-unsaturated ester 248 (35.5 mg, 54% yield). (The same result was obtained by using 1.05 equiv NaH instead of DBU.) Rf = 0.62 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.16 (dt, J = 11.5, 7.2 Hz, 1H), 5.79 (dt, J = 11.5, 1.9 Hz, 1H), 4.79 (ddt, J = 13.6, 2.1, 1.1 Hz, 2H), 4.35 (dd, J = 7.0, 4.7 Hz, 1H), 3.70 (s, 3H), 3.31 (s, 3H), 3.30 (s, 3H), 2.80 – 2.71 (m, 2H), 2.37 (tt, J = 8.5, 6.5 Hz, 1H), 1.76 – 1.64 (m, 2H), 1.65 (dd, J = 1.5, 0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.0, 148.9, 146.3, 120.0, 112.7, 103.0, 53.2, 52.7, 51.2, 43.2, 35.9, 32.6, 18.4; IR (Neat Film NaCl) 2949, 2830, 1723, 1646, 1437, 1408, 1203, 1127, 1053, 892, 819 cm-1; HRMS (MM: FAB+) m/z calc’d for C13H21O4 [M+H]+-H2 : 241.1440; found: 241.1431; [α]D25.0 3.04° (c 0.30, CHCl3). 652   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide OMe O OMe CO2Me 50% aq TFA OH CHCl3, 0 → 23 °C (99% yield) 248 MeMgBr H CO2Me 250 THF, –78 °C (64% yield; 95% yield based on recoverd SM) CO2Me 251 To a solution of acetal 248 (129 mg, 0.494 mmol, 1.00 equiv) in CHCl3 (2.47 mL) was added 50% aq TFA (1.23 mL) at 0 °C. The reaction mixture was stirred for 3 h at 23 °C before it was quenched by the addition of sat. aq NaHCO3. The aqueous phase was extracted with CH2Cl2 (3 x 4.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to afford aldehyde 250 (95.0 mg, 99% yield), which was used without further purification. To a solution of aldehyde 250 (95.0 mg, 0.484 mmol, 1.00 equiv) in THF (5.00 mL) was added MeMgBr (3.0 M solution in diethyl ether; 0.21 mL, 0.629 mmol, 1.30 equiv) at –78 °C. The mixture was stirred for 1 h at –78 °C. Then, the solution was quenched by the addition of sat. aq NaHCO3. The aqueous phase was extracted with EtOAc (3 x 5.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford secondary alcohol 251 (65.5 mg, 64% yield). Rf = 0.22 (1:4 EtOAc:hexanes); (due to the presence of diastereomeric mixtures, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum) 1H NMR (400 MHz, CDCl3) δ 6.18 (ddt, J = 11.5, 9.8, 7.4 Hz, 2H), 5.82 – 5.76 (m, 2H), 4.86 – 4.76 (m, 4H), 3.92 – 3.83 (m, 1H), 3.77 (ddt, J = 9.4, 6.3, 3.1 Hz, 1H), 3.70 (s, 6H), 2.87 (dddd, J = 15.1, 7.3, 5.0, 1.8 Hz, 1H), 2.74 (dddd, J = 8.3, 7.3, 5.1, 1.8 Hz, 2H), 2.64 – 2.55 (m, 1H), 2.49 (dddd, J = 10.0, 8.6, 6.5, 4.9 Hz, 1H), 2.37 (dddd, J = 9.8, 8.1, 6.7, 5.0 Hz, 1H), 1.68 (t, J = 1.2 Hz, 3H), 1.63 (dd, J = 1.5, 0.8 Hz, 3H), 1.55 – 1.42 (m, 4H), 1.19 (s, 3H), 1.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 167.0, 149.2, 653   149.1, 147.7, 146.8, 119.9, 112.9, 112.4, 66.6, 65.9, 51.3, 51.2, 45.1, 44.1, 43.1, 42.4, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 33.0, 32.0, 24.2, 23.5, 18.5, 18.1; IR (Neat Film NaCl) 3421, 2966, 2928, 1724, 1646, 1438, 1408, 1203, 1170, 892, 819 cm-1; HRMS (MM: FAB+) m/z calc’d for C12H21O3 [M+H]+: 213.1491; found 213.1489; [α]D25.0 –9.52° (c 0.11, CHCl3). OH O DMSO, oxalyl chloride Et 3N CO2Me 251 CH2Cl2, –78 °C (88% yield; 90% yield based on recovered SM) CO2Me 252 To a stirred solution of oxalyl chloride (0.21 mL, 2.40 mmol, 1.50 equiv) in CH2Cl2 (8.00 mL) was added DMSO (0.34 mL, 4.79 mmol, 3.00 equiv) dropwise at –78 °C. The reaction mixture was stirred for 15 min, and alcohol 251 (339 mg, 1.60 mmol, 1.00 equiv) in CH2Cl2 (1.00 mL) was added dropwise. The solution was stirred for 2 h and 30 min at –78 °C, then Et3N (1.56 mL, 7.00 equiv) was added. After 90 min at –78 °C, the solution was warmed to 23 °C over 30 min and quenched with H2O. The aqueous phase was extracted with CH2Cl2 (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford ketone 252 (295 mg, 88% yield). Rf = 0.35 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.19 – 6.10 (m, 1H), 5.81 (dt, J = 11.6, 1.7 Hz, 1H), 4.79 (p, J = 1.5 Hz, 1H), 4.74 (dt, J = 1.7, 0.8 Hz, 1H), 3.70 (s, 3H), 2.84 – 2.73 (m, 3H), 2.61 – 2.46 (m, 2H), 2.12 (d, J = 0.5 Hz, 3H), 1.68 (dd, J = 1.5, 0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 207.8, 166.9, 148.3, 146.2, 120.4, 112.3, 51.3, 47.6, 42.1, 32.4, 30.6, 19.5; IR (Neat Film NaCl) 2951, 1718, 1647, 1437, 1204, 1272, 821 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H19O3 [M+H]+: 211.1329; found: 211.1327; [α]D25.0 –9.42° (c 0.15, CHCl3). 654   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide O OTMS m-CPBA, NaHCO 3 H 2O, toluene; THF, –78 °C AcOH, H 2O, THF 0 → 23 °C (56% yield based on recovered starting material, 2 steps) CO2Me 252 O 2,2,6,6-tetramethylpiperidine n-BuLi, TMSCl CO2Me 253 OH CO2Me 254 To a solution of 2,2,6,6-tetramethylpiperidine (50 µL, 0.296 mmol, 1.50 equiv) in THF (2.00 mL) was added n-BuLi (2.5 M in hexane; 0.12 mL, 0.296 mmol, 1.50 equiv) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C, and TMSCl (0.13 mL, 0.990 mmol, 5.00 equiv) was added at –78 °C. Then, methyl ketone 252 (42.0 mg, 0.198 mmol, 1.00 equiv) in THF (1.00 mL) was added dropwise at –78 °C. The solution was stirred for 1 h and quenched with Et3N, followed by sat. aq NaHCO3. The aqueous phase was extracted with EtOAc (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was quickly filtered by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford silyl ether 253, which was used without further purification. To a solution of m-CPBA (75%; 41.0 mg, 0.178 mmol, 0.90 equiv) in toluene (2.74 mL) was added solid NaHCO3 (35.0 mg, 0.411 mmol, 2.08 equiv). The heterogeneous mixture was stirred for 15 min at 23 °C, then H2O (0.40 mL) was added. Silyl ether 253 in toluene (0.50 mL) was added dropwise to the reaction mixture at 0 °C. After the solution was stirred for 30 min at 0 °C, sat. aq NaHCO3 was added and stirred for 10 min at 0 °C. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The combined organic phases were washed with NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. To the residue dissolved in THF (0.30 mL) and H2O (0.17 mL) was added AcOH (0.17 mL). The mixture was stirred for 2 h at 23 °C. Then, the solution was diluted with EtOAc and H2O, and solid NaHCO3 was added until the gas evolution ceased. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, 655   dried over MgSO4 and concentrated in vacuo. The residue was purified by column Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide chromatography (1:4 EtOAc:hexanes) on silica gel to afford α-hydoxyketone 254 (12.0 mg, 56% yield based on recovered starting material, 2 steps). Rf = 0.35 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.13 (dt, J = 11.5, 7.1 Hz, 1H), 5.83 (ddd, J = 11.6, 2.0, 1.3 Hz, 1H), 4.82 (p, J = 1.5 Hz, 1H), 4.75 (dt, J = 1.6, 0.8 Hz, 1H), 4.20 (d, J = 3.0 Hz, 2H), 3.71 (s, 3H), 3.05 (s, br, 1H), 2.91 – 2.71 (m, 3H), 2.62 – 2.43 (m, 2H), 1.69 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 208.6, 166.8, 147.6, 145.5, 120.8, 112.8, 68.8, 51.3, 42.3, 42.1, 32.4, 19.5; IR (Neat Film NaCl) 2917, 1716, 1440, 1205, 1172 cm-1; HRMS (MM: FAB+) m/z calc’d for C12H19O4 [M+H]+: 227.1283; found: 227.1288; [α]D25.0 –4.11° (c 0.09, CHCl3). OTMS O O 2,2,6,6-tetramethylpiperidine n-BuLi, TMSCl THF, –78 °C CO2Me CO2Me 252 Br NBS, NaHCO 3 253 THF, –78 °C (50% yield based on recovered starting material, 2 steps) CO2Me 244b To a solution of 2,2,6,6-tetramethylpiperidine (0.23 mL, 1.39 mmol, 1.60 equiv) in THF (8.70 mL) was added n-BuLi (1.98 M in hexane; 0.70 mL, 1.39 mmol, 1.60 equiv) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C, and TMSCl (0.55 mL, 4.35 mmol, 5.00 equiv) was added at –78 °C. Then, methyl ketone 252 (183 mg, 0.870 mmol, 1.00 equiv) in THF (1.00 mL) was added dropwise at –78 °C. The solution was stirred for 1 h and quenched with Et3N, followed by sat. aq NaHCO3. The aqueous phase was extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was quickly filtered by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford silyl ether 253, which was used without further purification. 656   A solution of silyl ether 253 in THF (8.70 mL) at –78 °C was treated with solid Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide NaHCO3 (132 mg, 1.57 mmol, 1.80 equiv) and stirred for 10 min at –78 °C. NBS (248 mg, 1.39 mmol, 1.60 equiv) was then added portionwise and stirred for 15 min at –78 °C. The solvent was evaporated and the residue was purified by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford α-bromoketone 244b (55.0 mg, 50% yield based on recovered starting material, 2 steps). Rf = 0.65 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.14 (dt, J = 11.5, 7.2 Hz, 1H), 5.83 (dt, J = 11.6, 1.6 Hz, 1H), 4.82 (p, J = 1.5 Hz, 1H), 4.77 (dt, J = 1.5, 0.8 Hz, 1H), 3.87 (d, J = 1.0 Hz, 2H), 3.71 (s, 3H), 2.89 – 2.68 (m, 6H), 1.72 – 1.69 (m, 3H), 1.56 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 200.9, 166.9, 147.8, 145.7, 120.7, 112.7, 51.3, 43.7, 42.1, 34.8, 32.2, 19.7; IR (Neat Film NaCl) 2949, 2360, 1716, 1645, 1439, 1203, 1172 cm-1; HRMS (MM: FAB+) m/z calc’d for C11H14O2Br [M-OMe]•: 257.0177; found: 257.0170; [α]D25.0 –4.06° (c 0.09, CHCl3). OTBS OTBS MnO 2 OH OH CH2Cl2, 23 °C (92% yield) 255 O OH 256 To a stirred solution of diol 255 (20.0 mg, 0.0774 mmol, 1.00 equiv) in CH2Cl2 (0.80 mL) was added MnO2 (85%; 119 mg, 1.16 mmol, 15.0 equiv). The solution was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford aldehyde 256 (18.3 mg, 92% yield). All the spectrum data matched with those reported in ref 6a. 657   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide OTBS OTBS MeLi O OH Et 2O, –15 °C (88% yield) OTBS MnO 2 OH 256 OH CH2Cl2, 23 °C (89% yield) O 257 OH 258 To a solution of aldehyde 256 (100 mg, 0.390 mmol, 1.00 equiv) in Et2O (2.00 mL) was added MeLi (1.6 M in diethyl ether; 1.95 mL, 3.12 mmol, 8.00 equiv) at –10 °C. The solution was stirred for 2 h and quenched with sat. aq NH4Cl. The solution was poured into H2O. The aqueous phase was extracted with EtOAc (3 x 3.00 mL), washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:2 EtOAc:hexanes) on silica gel to afford alcohol 257 (93.4 mg, 88% yield). To a stirred solution of alcohol 257 (162 mg, 0.594 mmol, 1.00 equiv) in CH2Cl2 (6.00 mL) was added MnO2 (85%; 1.20 g, 11.9 mmol, 20.0 equiv). The solution was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford ketone 258 (143 mg, 89% yield). All the spectrum data matched with those reported in ref 6a. OTBS O OH 256 OTBS NaClO 2, NaH 2PO 4 30% H 2O2 MeCN, H 2O, 0 °C (87% yield) HO O OH 260 To a stirred solution of aldehyde 256 (18.3 mg, 0.0714 mmol, 1.00 equiv) in MeCN (0.70 mL) were added NaH2PO4 (30.0 mg, 0.25 mmol, 3.50 equiv) in H2O (0.50 mL) and 30% H2O2 (10 µL) at 0 °C. Then, a solution of NaClO2 (23.0 mg, 0.25 mmol, 3.50 equiv) in H2O (0.70 mL) was added dropwise in 1 h at 0 °C. The reaction 658   mixture was stirred for 10 min and quenched with sat. aq Na2SO3. The aqueous phase Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide was extracted with EtOAc (2.00 mL). The combined aqueous phases were acidified with 2N HCl to make the solution pH 5–6. The aqueous phase was extracted with EtOAc (3 x 4.00 mL) washed with brine, dried over MgSO4 and concentrated in vacuo to afford acid 260 (17.0 mg, 87% yield). Rf = 0.15 (1:1 EtOAc:hexane); 1H NMR (500 MHz, CDCl3) δ 6.77 (d, J = 1.8 Hz, 1H), 4.75 (td, J = 6.7, 1.9 Hz, 1H), 2.50 (dd, J = 12.9, 6.9 Hz, 1H), 2.09 – 2.03 (m, 1H), 1.48 (d, J = 0.7 Hz, 3H), 0.90 (s, 9H), 0.10 (d, J = 3.0 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 168.2, 147.9, 139.6, 79.5, 72.7, 51.3, 27.7, 25.9, 18.2, -4.5, -4.6; IR (Neat Film NaCl) 2929, 2857, 1701, 1362, 1258, 1097, 898, 837, 778 cm-1; HRMS (MM: FAB+) m/z calc’d for C12H19O4 [M+H]+-H2: 271.1366; found: 271.1357; [α]D25.0 185.9° (c 0.31, CHCl3). OTBS H O OH THF, –78 °C (62% yield) OTBS OTBS LDA ethyl diazoacetate N2 MnO 2 EtO 256 O OH 263 OH CH2Cl2, 23°C (93% yield) N2 EtO O O OH 264 To a solution of aldehyde 256 (15.0 mg, 0.0585 mmol, 1.00 equiv) and ethyl diazoacetate (22 µL, 0.205 mmol, 3.50 equiv) in THF (0.60 mL) was added LDA (0.20 M solution in THF; 0.44 mL, 0.088 mmol, 1.50 equiv) at –78 °C. The reaction mixture was stirred for 10 min and quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.00 mL) washed with brine, dried over MgSO4 and concentrated in vacuo to afford alcohol 263, which was used without further purification (13.5 mg, 62% yield). To a solution of alcohol 263 (13.0 mg, 0.0351 mmol, 1.00 equiv) in CH2Cl2 (0.40 mL) was added MnO2 (85%; 72.0 mg, 0.702 mmol, 20.0 equiv) at 23 °C. The reaction 659   mixture was stirred overnight. Solids were removed via a filtration through a celite Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford diazo 264 (12.0 mg, 93% yield). Rf = 0.56 (1:2 EtOAc:hexane); 1H NMR (400 MHz, CDCl3) δ 6.27 (d, J = 2.0 Hz, 1H), 4.79 (ddd, J = 6.9, 5.6, 2.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.45 (dd, J = 13.0, 6.9 Hz, 1H), 2.01 (dd, J = 13.0, 5.7 Hz, 1H), 1.39 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 185.4, 161.4, 145.4, 141.0, 82.3, 73.8, 62.0, 51.7, 27.3, 26.0, 25.8, 18.3, 14.4, -4.5, -4.6; IR (Neat Film NaCl) 3499, 2930, 2857, 2141, 1728, 1471, 1370, 1300, 1259, 1094, 906, 837 cm-1; HRMS (MM: FAB+) m/z calc’d for C17H29O5N2Si [M+H]+: 369.1846; found 369.1845; [α]D25.0 14.2° (c 0.25, CHCl3). OTBS N2 EtO O O OH Rh 2(OAc)4, toluene 110 °C (36% yield) or Rh 2(OAc)4, benzene 80 °C (36% yield) 264 OTBS O O N2 O 266 To a solution of diazo 264 (12.0 mg, 0.0326 mmol, 1.00 equiv) in toluene (0.30 mL), was added dirhodium tetraacetate (0.70 mg, 0.00163 mmol, 0.05 equiv). The solution was refluxed under argon for 10 min. Solids were removed via a filtration through a celite plug (rinsed with EtOAc) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford lactone 266 (4.0 mg, 36% yield). (Similar result was obtained with benzene solvent at 80 °C.) Rf = 0.30 (1:2 EtOAc:hexane); 1H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 1.6 Hz, 1H), 4.85 (ddd, J = 7.1, 6.4, 1.7 Hz, 1H), 2.72 (dd, J = 12.6, 6.4 Hz, 1H), 2.40 – 2.30 660   (m, 1H), 1.58 (s, 3H), 0.90 (s, 9H), 0.11 (d, J = 4.6 Hz, 6H); C NMR (101 MHz, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 13 CDCl3) δ 198.7, 175.1, 142.6, 138.1, 87.6, 73.5, 51.1, 26.9, 25.8, 18.2, 14.3, -4.6, 4.7; IR (Neat Film NaCl) 2953, 2856, 2146, 1713, 1661, 1330, 1302, 1097, 1066, 837 cm-1; HRMS (MM: FAB+) m/z calc’d for C15H23O4N2Si [M+H]+: 323.1427; found 323.1417; [α]D25.0 7.77° (c 0.20, CHCl3). OTBS OTBS 2,2,6,6-tetramethylpiperidine n-BuLi, TESCl O OH 258 THF, –78 °C OTBS m-CPBA, NaHCO 3, H 2O, toluene; TESO OH 267 AcOH, H 2O, THF, 0 → 23 °C (42% yield based on recovered starting material, 2 steps) OH O OH 268 To a solution of 2,2,6,6-tetramethylpiperidine (0.20 mL, 1.19 mmol, 5.00 equiv) in THF (2.40 mL) was added n-BuLi (1.96 M in hexane; 0.61 mL, 1.19 mmol, 5.00 equiv) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C, and TMSCl (0.20 mL, 1.19 mmol, 5.00 equiv) was added at –78 °C. Methyl ketone 258 (50.0 mg, 0.238 mmol, 1.00 equiv) in THF (0.60 mL) was added dropwise at –78 °C. The solution was stirred for 30 min and quenched with Et3N, followed by sat. aq NaHCO3. The aqueous phase was extracted with EtOAc (3 x 3.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was quickly filtered by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford silyl ether 267, which was used without further purification. To a solution of m-CPBA (75%; 50.0 mg, 0.217 mmol, 0.91 equiv) in toluene (3.34 mL) was added NaHCO3 (55.0 mg, 0.651 mmol, 2.74 equiv). The heterogeneous mixture was stirred for 15 min at 23 °C, then H2O (0.56 mL) was added. Silyl ether 267 in toluene (0.50 mL) was added dropwise to the reaction mixture at 0 °C. After the solution was stirred for 45 min at 0 °C, sat. aq NaHCO3 was added and stirred for 10 min at 0 °C. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The 661   combined organic phases were washed with NaHCO3 and brine, dried over MgSO4 Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide and concentrated in vacuo. To the residue dissolved in THF (0.42 mL) and H2O (0.21 mL) was added AcOH (0.21 mL). The mixture was stirred for 2 h at 23 °C. After the solution was diluted with EtOAc and H2O, solid NaHCO3 was added until the gas evolution ceased. The aqueous phase was extracted with EtOAc (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford α-hydoxyketone 268 (12.0 mg, 42% yield based on recovered starting material, 2 steps). Rf = 0.30 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.55 (d, J = 1.9 Hz, 1H), 4.79 (td, J = 6.9, 1.9 Hz, 1H), 4.59 (d, J = 18.6 Hz, 1H), 4.51 (d, J = 18.6 Hz, 1H), 3.12 (s, br, 1H), 2.44 (dd, J = 12.8, 7.0 Hz, 1H), 2.05 – 1.99 (m, 1H), 1.47 (s, 3H), 0.90 (s, 9H), 0.10 (d, J = 4.1 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 198.4, 145.8, 143.8, 80.5, 73.4, 65.8, 50.9, 28.0, 25.9, 18.2, -4.5, -4.6; IR (Neat Film NaCl) 3418, 2929, 2857, 1682, 1361, 1259, 1093, 912, 835 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H27O4Si [M+H]+:287.1679; found: 287.1677; [α]D25.0 78.9° (c 0.10, CHCl3). OTBS OH O OTBS Bz 2O, Et 3N, DMAP OH 268 CH2Cl2 0 → 23 °C (85% yield) BzO O OH 269 To a solution of α-hydroxyketone 268 (9.80 mg, 0.0342 mmol, 1.00 equiv) in CH2Cl2 (0.30 mL) were added DMAP (8.40 mg, 0.0684 mmol, 2.00 equiv) and Et3N (38 µL, 0.274 mmol, 8.00 equiv). The solution was cooled to 0 °C and benzoic anhydride (15.0 mg, 0.0684 mmol, 2.00 equiv) was added in one portion. After 30 min, the 662   solution was warmed to 23 °C and stirred for 2 h. After the reaction was done, water Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide was added. The aqueous phase was extracted with CH2Cl2 (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford benzoate 269 (11.4 mg, 85% yield). Rf = 0.75 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.15 – 8.07 (m, 2H), 7.65 – 7.55 (m, 1H), 7.51 – 7.42 (m, 2H), 6.65 (d, J = 1.9 Hz, 1H), 5.30 (d, J = 16.4 Hz, 1H), 5.18 (d, J = 16.4 Hz, 1H), 4.81 (td, J = 7.1, 1.9 Hz, 1H), 2.44 (dd, J = 12.7, 7.0 Hz, 1H), 2.07 – 1.97 (m, 1H), 1.47 (s, 3H), 0.91 (s, 9H), 0.11 (d, J = 4.4 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 192.6, 166.0, 145.5, 144.2, 133.6, 130.1, 129.3, 128.7, 80.6, 73.4, 66.3, 50.7, 28.1, 25.9, 18.3, -4.5, -4.6; IR (Neat Film NaCl) 2928, 1728, 1691, 1259, 1098, 836 cm-1; HRMS (MM: FAB+) m/z calc’d for C21H29O5Si [M+H]+H2: 389.1784; found: 389.1783; [α]D25.0 40.9° (c 0.16, CHCl3). OTBS OH O OTBS MsCl, Et 3N OH 268 CH2Cl2 23 °C (71% yield) MsO O OH 270 To a stirred solution of α-hydroxyketone 268 (49.0 mg, 0.171 mmol, 1.00 equiv) in CH2Cl2 (1.71 mL) were added Et3N (72 µL, 0.513 mmol, 3.00 equiv) and MsCl (20 µL, 0.257 mmol, 1.50 equiv) at 0 °C. The solution was stirred at 0 °C for 2 h and quenched with H2O. The aqueous phase was extracted with CH2Cl2 (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford mesylate 270 (44.0 mg, 71% yield). 663   Rf = 0.43 (1:4 EtOAc:hexanes); H NMR (400 MHz, CDCl3) δ 6.58 (d, J = 1.9 Hz, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 1 1H), 5.15 (s, 2H), 4.78 (td, J = 7.0, 1.9 Hz, 1H), 3.23 (s, 3H), 2.44 (dd, J = 12.8, 7.0 Hz, 1H), 2.05 – 1.95 (m, 1H), 1.95 (s, br, 1H), 1.46 (s, 3H), 0.90 (s, 9H), 0.11 (d, J = 4.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 191.2, 146.5, 143.8, 80.6, 73.3, 69.8, 50.7, 39.3, 27.9, 25.9, 18.2, -4.5, -4.7; IR (Neat Film NaCl) 2930, 2856, 1693, 1354, 1259, 1173, 1091, 1042, 959, 912, 835, 777 cm-1; HRMS (MM: FAB+) m/z calc’d for C15H27O5SiS [M-OH]•: 347.1348; found: 347.1357; [α]D25.0 36.3° (c 0.12, CHCl3). OTBS OTBS trimethylsulfonium iodide KHMDS + H O OH THF, 0 °C O (35% combined yield, 271a, 271b; 19% yield, 255 ) 256 OTBS + O OH OTBS 271a OH OH 271b OH 255 To a solution of trimethylsulfonium iodide (18.0 mg, 0.0877 mmol, 1.50 equiv) in THF (0.60 mL) was added dry KHMDS (17.0 mg, 0.0877 mmol, 1.50 equiv) in portions over 30 min at 0 °C. The mixture was stirred for 1 h. Then, a solution of aldehyde 256 in THF (0.30 mL) was added to a reaction vessel. The solution was stirred for 30 min and quenched with H2O. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford epoxide 271a and 271b (5.50 mg, 35% yield). See below for characterization data. OTBS OTBS dibromomethane n-BuLi + H O OH 256 THF, –78 → 23 °C O (39% combined yield, 271a, 271b; 34% yield 255 ) OTBS OH 271a OTBS + O OH 271b OH OH 255 664   To a solution of aldehyde 256 (155 mg, 0.604 mmol, 1.00 equiv) and Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide dibromomethane (51.0 µL, 0.725 mmol, 1.20 equiv) in THF (3.02 mL) was added nBuLi (2.4 M solution in hexane; 0.28 mL, 0.665 mmol, 1.10 equiv) dropwise over 30 min at –78 °C. The reaction mixture was slowly warmed to 23 °C and stirred overnight. Then, the reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford epoxide 271a and 271b (64.0 mg, 39% yield). Rf = 0.56 (1:2 EtOAc:hexanes); Diastereomer 1: 1H NMR (400 MHz, CDCl3) δ 5.72 (dd, J = 2.2, 1.0 Hz, 1H), 4.61 (ddd, J = 6.5, 3.8, 2.3 Hz, 1H), 3.55 (ddt, J = 4.3, 2.7, 0.8 Hz, 1H), 2.97 (dd, J = 6.0, 4.2 Hz, 1H), 2.74 (dd, J = 6.0, 2.7 Hz, 1H), 2.36 (dd, J = 13.5, 6.5 Hz, 1H), 2.06 (d, J = 15.5 Hz, 1H), 1.89 (dd, J = 13.5, 3.8 Hz, 1H), 1.37 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 148.4, 131.1, 81.3, 73.3, 52.6, 49.7, 48.2, 26.1, 26.0, 18.3, -4.6; IR (Neat Film NaCl) 3408, 2929, 2856, 1361, 1252, 1085, 835 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H25O3Si [M+H]+H2: 269.1573; found: 269.1568; [α]D25.0 44.7° (c 0.08, CHCl3). Diastereomer 2: 1H NMR (400 MHz, CDCl3) δ 5.71 (dd, J = 2.1, 1.0 Hz, 1H), 4.65 (dddd, J = 6.4, 4.4, 2.1, 1.1 Hz, 1H), 3.50 (ddt, J = 3.7, 2.7, 1.0 Hz, 1H), 3.04 (dd, J = 5.7, 4.2 Hz, 1H), 2.88 (dd, J = 5.7, 2.7 Hz, 1H), 2.44 (dd, J = 13.3, 6.5 Hz, 1H), 2.15 (s, 1H), 1.90 (dd, J = 13.3, 4.4 Hz, 1H), 1.44 (s, 3H), 0.90 (s, 9H), 0.09 (d, J = 1.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 148.2, 131.1, 81.1, 73.2, 52.8, 49.5, 47.5, 26.1, 26.0, 18.3, -4.6; IR (Neat Film NaCl) 2956, 2929, 2856, 1361, 1253, 1086, 836, 776 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H25O3Si [M+H]+-H2: 269.1573; found: 269.1577; [α]D25.0 11.5° (c 0.15, CHCl3). 665   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide OTBS OTBS MgI 2 O OH 271 TESCl, imidazole DMAP HO THF, 40 °C (63% yield) I OTBS HO 273 CH2Cl2, 23 °C (89% yield) TESO I HO 274 To a solution of epoxide 271 (64.0 mg, 0.237 mmol, 1.00 equiv) in THF (1.19 mL) was added MgI2 (69.0 mg, 0.248 mmol, 1.05 equiv). The reaction mixture was stirred overnight at 40 °C and then quenched with H2O. The aqueous phase was extracted with EtOAc (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford iodohydrin 273 (59.0 mg, 63% yield). To a solution of iodohydrin 273 (13.5 mg, 0.0338 mmol, 1.00 equiv) in CH2Cl2 (0.20 mL) were added imidazole (11.5 mg, 0.169 mmol, 5.00 equiv), DMAP (0.20 mg, 0.0016 mmol, 0.05 equiv), and TESCl (6.20 µL, 0.0371 mmol, 1.10 equiv). The reaction mixture was stirred overnight at 23 °C and then H2O was added. The aqueous phase was extracted with CH2Cl2 (3 x 0.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford silyl ether 274 (11.5 mg, 89% yield). Rf = 0.80 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 5.89 (ddd, J = 2.1, 1.3, 0.5 Hz, 1H), 4.57 (dtd, J = 5.4, 3.0, 1.4 Hz, 1H), 4.30 (ddt, J = 6.5, 3.9, 1.3 Hz, 1H), 3.59 (dd, J = 10.2, 3.8 Hz, 1H), 3.35 (dd, J = 10.2, 6.4 Hz, 1H), 2.26 – 2.20 (m, 1H), 1.91 – 1.84 (m, 1H), 1.33 (s, 3H), 0.99 – 0.95 (m, 9H), 0.88 (s, 9H), 0.65 – 0.60 (m, 6H), 0.08 (d, J = 0.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 151.8, 132.3, 80.6, 72.8, 69.2, 52.5, 26.0, 25.4, 18.2, 15.4, 7.1, 5.0, -4.4, -4.6; IR (Neat Film NaCl) 2955, 1256, 666   1088, 836, 740 cm ; HRMS (MM: FAB+) m/z calc’d for C20H40O3Si2I [M+H] -H2: Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide -1 + 511.1561; found: 511.1573; [α]D25.0 4.31° (c 0.20, CHCl3). OTBS TESO I OTBS NaH THF, 23 °C (60% yield) HO TESO O 274 275 To a solution of NaH (60%, 1.00 mg, 0.0246 mmol, 1.10 equiv) in THF (1.12 mL) was added silyl ether 274 (11.5 mg, 0.0224 mmol, 1.00 equiv) in THF (0.50 mL) at 23 °C. The solution was stirred overnight and then H2O was added. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford ether 275 (5.20 mg, 60% yield). Rf = 0.23 (1:8 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 5.56 (dd, J = 2.2, 1.1 Hz, 1H), 4.99 (dddd, J = 7.4, 5.4, 3.2, 1.1 Hz, 1H), 4.84 (tdd, J = 7.5, 3.2, 2.2 Hz, 1H), 4.16 (t, J = 7.9 Hz, 1H), 3.56 (dd, J = 8.2, 7.2 Hz, 1H), 2.40 (dd, J = 11.5, 5.4 Hz, 1H), 2.00 (ddd, J = 11.5, 7.3, 1.0 Hz, 1H), 1.21 (d, J = 0.9 Hz, 3H), 0.97 (t, J = 8.0 Hz, 9H), 0.90 (s, 9H), 0.68 – 0.52 (m, 6H), 0.10 – 0.06 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 153.1, 126.0, 89.1, 79.3, 73.6, 68.2, 54.4, 26.0, 6.9, 4.8, -4.5; IR (Neat Film NaCl) 2955, 2927, 2875, 2360, 1459, 1256, 1089, 835 cm-1; HRMS (MM: FAB+) m/z calc’d for C20H39O3Si2 [M+H]+-H2: 383.2438; found: 383.2409; [α]D25.0 12.7° (c 0.15, CHCl3). OTBS OTBS PPTS TESO O 275 EtOH, 23 °C (45% yield) HO O 276 667   To a solution of ether 275 (5.10 mg, 0.0132 mmol, 1.00 equiv) in EtOH (0.13 mL) Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide was added PPTS (0.30 mg, 0.00132 mmol, 0.10 equiv) and stirred at 23 °C for 30 min. The reaction was quenched with sat. aq NaHCO3 and the aqueous phase was extracted with EtOAc (3 x 0.70 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford alcohol 276 (1.61 mg, 45% yield). Rf = 0.23 (1:8 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 5.66 (dd, J = 2.2, 1.2 Hz, 1H), 5.14 – 5.03 (m, 1H), 4.86 (m, br, 1H), 4.35 (dd, J = 9.4, 7.5 Hz, 1H), 3.69 (dd, J = 9.4, 5.5 Hz, 1H), 2.43 (dd, J = 11.7, 5.5 Hz, 1H), 2.02 (ddd, J = 11.7, 7.3, 1.0 Hz, 1H), 1.22 (s, 3H), 0.90 (s, 9H), 0.09 (d, J = 5.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 154.7, 126.3, 90.2, 79.9, 75.1, 68.6, 54.0, 26.0, 24.1, -4.5, -4.6; IR (Neat Film NaCl) 2929, 2857, 1361, 1256, 1084, 835, 776 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H27O3Si [M+H]+: 271.1730; found: 271.1734; [α]D25.0 33.7° (c 0.06, CHCl3). OTBS OTBS vinylmagnesium bromide H O OH 256 THF, –78 °C (84% yield; 99% yield based on recovered starting material) OTBS MnO 2 OH OH 284 CH2Cl2, 23 °C (63% yield) O OH 285 A flame-dried flask was charged with aldehyde 256 (399 mg, 1.56 mmol, 1.00 equiv) and THF (7.80 mL). Then, vinylmagnesium bromide (1.0 M solution in THF; 20.5 mL, 20.3 mmol, 13.0 equiv) was added to the solution at –78 °C and stirred for 3 h. The reaction was quenched with sat. aq NH4Cl and the aqueous phase was extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column 668   chromatography (1:2 EtOAc:hexanes) on silica gel to afford allyl alcohol 284 (371 Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide mg, 84% yield). To a solution of allyl alcohol 284 (371 mg, 1.30 mmol, 1.00 equiv) in CH2Cl2 (13.0 mL) was added MnO2 (85%; 4.00 g, 39.1 mmol, 30.0 equiv). The mixture was stirred for 12 h. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford vinyl ketone 285 (230 mg, 63% yield). Rf = 0.55 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.88 (dd, J = 17.1, 10.5 Hz, 1H), 6.60 (d, J = 1.9 Hz, 1H), 6.35 (dd, J = 17.1, 1.6 Hz, 1H), 5.80 (dd, J = 10.5, 1.6 Hz, 1H), 4.79 (td, J = 7.1, 1.9 Hz, 1H), 3.67 (s, 1H), 2.44 (dd, J = 12.7, 7.0 Hz, 1H), 2.04 (ddd, J = 12.6, 7.1, 0.9 Hz, 1H), 1.46 (s, 3H), 0.91 (s, 9H), 0.11 (d, J = 4.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 189.7, 147.0, 145.9, 132.3, 129.4, 80.4, 73.2, 51.0, 28.2, 25.9, 18.3, -4.4, -4.6; IR (Neat Film NaCl) 2955, 2929, 2856, 1658, 1605, 1361, 1259, 1091, 911, 837, 777 cm-1; HRMS (MM: FAB+) m/z calc’d for C15H25O3Si [M+H]+-H2: 281.1573; found: 281.1569; [α]D25.0 33.3° (c 0.06, CHCl3). OTBS OH TBAF O OH 285 THF, 23 °C (46% yield) O OH 281 To a solution of ketone 285 (22.1 mg, 0.0782 mmol, 1.00 equiv) in THF (0.80 mL) was added TBAF (1.0 M solution in THF; 0.16 mL, 0.156 mmol, 2.00 equiv) at 23 °C and stirred for 30 min. The reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was 669   purified by column chromatography (1:1 EtOAc:hexanes) on silica gel to afford diol Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 281 (6.00 mg, 46% yield). Rf = 0.15 (1:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.84 (dd, J = 17.1, 10.5 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 6.36 (dd, J = 17.1, 1.5 Hz, 1H), 5.85 (dd, J = 10.5, 1.6 Hz, 1H), 4.82 (ddd, J = 7.4, 5.8, 2.1 Hz, 1H), 3.62 (s, br, 1H), 2.51 (dd, J = 13.4, 7.1 Hz, 1H), 2.01 (dd, J = 13.4, 5.7 Hz, 1H), 1.48 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.3, 148.2, 144.3, 132.6, 130.0, 81.2, 73.5, 50.2, 27.7; IR (Neat Film NaCl) 2922, 1657, 1605, 1407, 1264, 1223, 1148, 1067, 961, 796 cm-1; HRMS (MM: FAB+) m/z calc’d for C9H13O3 [M+H]+: 169.0865; found: 169.0864; [α]D25.0 25.8° (c 0.10, CHCl3). O OH vinylmagnesium bromide H CO2Me THF, –78 °C (66% yield; 88% yield based on recovered starting material) 250 CO2Me 286 To a stirred solution of aldehyde 250 (300 mg, 1.53 mmol, 1.00 equiv) in THF (15.3 mL) was added vinylmagnesium bromide (1.0 M solution in THF; 2.29 mmol, 1.50 equiv) at –78 °C. The reaction was stirred for 1 h at –78 °C and quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 6.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford allyl alcohol 286 (227 mg, 66% yield). Rf = 0.32 (1:4 EtOAc:hexanes); (due to the presence of diastereomeric mixtures, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum) 1H NMR (500 MHz, CDCl3) δ 6.23 – 6.14 (m, 2H), 5.92 – 5.82 (m, 2H), 5.82 – 5.77 (m, 2H), 5.23 (ddt, J = 17.2, 5.0, 1.5 Hz, 2H), 5.10 (ddt, J = 13.4, 10.4, 1.4 Hz, 2H), 4.86 – 670   4.74 (m, 4H), 4.17 (q, J = 6.7 Hz, 1H), 4.13 – 4.07 (m, 1H), 3.71 – 3.68 (m, 6H), 2.91 Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide – 2.81 (m, 1H), 2.76 (ddd, J = 7.3, 6.2, 1.8 Hz, 2H), 2.69 – 2.62 (m, 1H), 2.54 (dtd, J = 9.8, 7.6, 4.6 Hz, 2H), 2.37 (ddd, J = 15.1, 9.2, 5.8 Hz, 1H), 1.65 (dq, J = 1.5, 0.8 Hz, 3H), 1.63 – 1.51 (m, 5H); 13C NMR (126 MHz, CDCl3) δ 167.0, 149.1, 149.0, 147.1, 146.5, 141.5, 140.9, 119.9, 115.2, 114.3, 113.2, 112.6, 71.6, 70.9, 51.3, 51.2, 44.2, 40.7, 40.2, 32.9, 32.1, 18.6, 18.2; IR (Neat Film NaCl) 2929, 1722, 1644, 1439, 1202, 1168, 1124, 993 cm-1; HRMS (MM: FAB+) m/z calc’d for C13H21O3 [M+H]+: 225.1491; found: 225.1491. OH O MnO 2 CO2Me CH2Cl2, 23 °C (85% yield) 286 CO2Me 287 To a solution of allyl alcohol 286 (10.0 mg, 0.0446 mmol, 1.00 equiv) in CH2Cl2 (0.45 mL) was added MnO2 (85%; 182 mg, 1.78 mmol, 40.0 equiv). The mixture was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:6 EtOAc:hexanes) on silica gel to afford ketone 287 (8.41 mg, 85% yield). See below for characterization data. OH O DMSO, oxalyl chloride, Et 3N CH2Cl2, –78 °C (97% yield) CO2Me 286 CO2Me 287 To a stirred solution of oxalyl chloride (29 µL, 0.335 mmol, 1.50 equiv) in CH2Cl2 (1.10 mL) was added DMSO (47 µL, 0.669 mmol, 3.00 equiv) at –78 °C. The 671   solution was stirred for 15 min, then alcohol 286 (50.0 mg, 0.223 mmol, 1.00 equiv) Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide in CH2Cl2 (0.6 mL) was added at –78 °C. The mixture was stirred for 3 h and 30 min at –78 °C, and then Et3N (0.22 mL, 1.56 mmol, 7.00 equiv) was added. After 90 min at –78 °C, the solution was slowly warmed to 23 °C over 30 min and H2O was added. The aqueous phase was extracted with CH2Cl2 (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:6 EtOAc:hexanes) on silica gel to afford ketone 287 (47.9 mg, 97% yield). Rf = 0.55 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.34 (dd, J = 17.7, 10.4 Hz, 1H), 6.23 – 6.12 (m, 2H), 5.84 – 5.78 (m, 2H), 4.78 (p, J = 1.5 Hz, 1H), 4.74 (dt, J = 1.7, 0.8 Hz, 1H), 3.70 (s, 3H), 2.88 – 2.77 (m, 3H), 2.73 – 2.61 (m, 2H), 1.69 (dd, J = 1.5, 0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 199.6, 166.9, 148.4, 146.1, 136.8, 128.4, 120.4, 112.3, 51.2, 43.5, 42.2, 32.4, 19.6; IR (Neat Film NaCl) 2950, 1716, 1645, 1439, 1407, 1204, 1173, 992, 895, 818 cm-1; HRMS (MM: FAB+) m/z calc’d for C13H19O3 [M+H]+: 223.1334; found: 223.1325; [α]D25.0 –0.98° (c 0.28, CHCl3). O O OMe LiOH CO2Me 287 THF, MeOH, H 2O, 23 °C (55% yield) CO2Me 288 To a solution of ester 287 (10.0 mg, 0.0449 mmol, 1.00 equiv) in THF (0.50 mL) was added a solution of LiOH (2.20 mg, 0.0898 mmol, 2.00 equiv) in H2O (0.20 mL). After 2 h at 23 °C, the aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 672   EtOAc:hexanes) on silica gel to afford Michael adduct 288 (6.28 mg, 55% yield). See Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide below for characterization data. O O OMe K 2CO3 CO2Me MeOH, H 2O, 23 °C (53% yield) CO2Me 287 288 To a stirred solution of ester 287 (6.80 mg, 0.00306 mmol, 1.00 equiv) in MeOH (0.10 mL) and H2O (0.10 mL) was added K2CO3 (17.0 mg, 0.122 mmol, 4.00 equiv). After 7 h, the aqueous phase was extracted with EtOAc (3 x 0.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford Michael adduct 288 (4.11 mg, 53% yield). Rf = 0.25 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.14 (dt, J = 11.6, 7.1 Hz, 1H), 5.80 (dt, J = 11.6, 1.7 Hz, 1H), 4.78 (p, J = 1.5 Hz, 1H), 4.77 – 4.70 (m, 1H), 3.70 (s, 3H), 3.61 (t, J = 6.3 Hz, 2H), 3.31 (s, 3H), 2.88 – 2.71 (m, 3H), 2.63 (t, J = 6.3 Hz, 2H), 2.61 – 2.45 (m, 2H), 1.68 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 208.0, 166.9, 148.4, 146.2, 120.3, 112.2, 67.6, 59.0, 51.2, 47.3, 43.3, 41.8, 32.3, 19.6; IR (Neat Film NaCl) 2922, 1719, 1646, 1438, 1203, 1172, 1117, 894, 820 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H23O4 [M+H]+: 255.1596; found: 255.1604; [α]D25.0 – 3.01° (c 0.36, CHCl3). OTBS H O OH 256 OTBS OTBS ethynylmagnesium bromide MnO 2 THF, –78 °C (90% yield, 94% yield based on recovered starting material) CH2Cl2, 23 °C (68% yield) OH OH 293 O OH 294 673   A flame-dried flask was charged with aldehyde 256 (53.4 mg, 0.208 mmol, 1.00 Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide equiv) and THF (1.04 mL). Then, ethynylmagnesium bromide (0.4M solution in THF; 5.20 mL, 2.08 mmol, 10.0 equiv) was added at –78 °C and stirred for 3 h. The reaction mixture was slowly warmed to 23 °C and stirred for 5 h. The reaction was quenched by adding sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:2 EtOAc:hexanes) on silica gel to afford diol 293 (53.0 mg, 90% yield). To a solution of diol 293 (11.1 mg, 0.0392 mmol, 1.00 equiv) in CH2Cl2 (0.40 mL) was added MnO2 (85%; 52.0 mg, 0.510 mmol, 13.0 equiv). The mixture was stirred for 12 h. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford ketone 294 (7.50 mg, 68% yield). Rf = 0.56 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 1.9 Hz, 1H), 4.79 (tdd, J = 7.2, 1.9, 0.7 Hz, 1H), 3.29 (s, 1H), 3.09 (s, 1H), 2.47 (dd, J = 12.8, 7.0 Hz, 1H), 2.07 (ddt, J = 12.8, 7.1, 0.8 Hz, 1H), 1.58 (s, br, 1H), 1.46 (s, 3H), 0.91 (s, 9H), 0.11 (d, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 176.1, 151.9, 147.9, 79.9, 79.5, 79.3, 72.9, 51.5, 27.8, 25.9, 18.2, -4.6; IR (Neat Film NaCl) 2929, 2955, 2857, 2097, 1638, 1361, 1272, 1259, 1209, 1093, 837, 777 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C15H25O3Si [M+H]+: 281.1567; found: 281.1569; [α]D25.0 13.3° (c 0.06, CHCl3). Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 5.5. 674   References and Notes                                                                                                                 (1)  Duh, C.-Y.; Wang, S.-K.; Chia, M.-C.; Chiang, M. Y. Tetrahedron Lett. 1999, 40, 6033–6035.   (2) Ineleganolide was also isolated from different soft coral species: (a) Thao, N. P.; Nam, N. H.; Cuong, N. X.; Quang, T. H.; Tung, P. T.; Dat, L. D.; Chae, D.; Kim, S.; Koh, Y.-S.; Kiem, P. V.; Minh, C. V.; Kim, Y. H. Bioorg. Med. Chem. Lett. 2013, 23, 228–231. (b) Ahmed, A. F.; Shine, R.-T.; Wang, G.-H.; Dai, C.-F.; Kuo, Y.-H.; Sheu, J.-H. Tetrahedron 2003, 59, 7337–7344. (3) The absolute stereochemistry has yet to be confirmed. (4) (a) Li, Y.; Pattenden, G. Nat. Prod. Rep. 2011, 28, 429–440. (b) Li, Y.; Pattenden, G. Nat. Prod. Rep. 2011, 28, 1269–1310. (c) Chen, W.; Li, Y.; Guo, Y. Acta Pharm. Sin. B 2012, 2, 227–237. (5) Li, Y.; Pattenden, G. Tetrahedron 2011, 67, 10045–10052. (6) (a) Craig, R. A., II Ph.D. Thesis, California Institute of Technology, Pasadena, CA, May 2015. (b) Roizen, J. L. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, Nov 2009. (c) Tang, F. Thesis, Washington University, St. Louis, MO, May 2009. (d) Liu, G.; Romo, D. Abstracts of Papers, 237th ACS National Meeting, Salt Lake City, UT, Mar 22–26, 2009; American Chemical Society, 2009; ORGN083. (e) O’Connell, C. E.; Frontier, A. J. Abstracts of Papers, 32nd Northeast Regional Meeting of the American Chemical Society, Rochester, NY, Oct 31–Nov 3, 2004; American Chemical Society, 2004, GEN-088. (f) Horn, E. J.; Silverston, J. S.; Vanderwal, C. D. J. Org. Chem. 2016, DOI: 10.1021/acs.joc.5b02550. (7) (a) González, M. A.; Ghosh, S.; Rivas, F.; Fischer, D.; Theodorakis, E. A. Tetrahedron Lett. 2004, 45, 5039–5041. (b) Weinstabl, H.; Gaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834–2837. 675                                                                                                                                                                                                                                                                                                                               (8) For a synthetic procedure of phosphonates, see: Messik, F.; Oberthür, M. Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Synthesis 2013, 45, 167–170. (9) (a) Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5–8. (b) Danishefsky, S. J.; DeNinno, M. P.; Chen, S.-h. J. Am. Chem. Soc. 1988, 110, 3929–3940. (c) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942–10953. (d) Panek, J. S.; Xu, F.; Rondón, A. C. J. Am. Chem. Soc. 1998, 120, 4113–4122. (10) (a) Ando, K. J. Org. Chem. 1997, 62, 1934–1939. (b) Ando, K. J. Org. Chem. 1999, 64, 8406–8408. (c) Ando, K. J. Org. Chem. 2000, 65, 4745–4749. (11) Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 3995–3998. (12) (a) Frontier, A. J.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151–6159. (b) Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2000, 122, 10482–10483. (13) Craig, R. A., II.; Roizen, J. L.; Smith, R. C.; Jones, A. C.; Stoltz, B. M. Org. Lett. 2012, 14, 5716–5719. (14) (a) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959–1964. (b) Arthuis, M.; Beaud, R.; Gandon, V.; Roulland, E. Angew. Chem., Int. Ed. 2012, 51, 10510–10514. (c) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279–9282. (15) Treatment of TMS-diazomethane to acid chloride 262 afforded only methyl ester 299. OTBS HO oxalyl chloride Et 3N TMS-diazomethane Cl MeCN, THF, 0 °C DMF, CH2Cl2, 0 °C O OH OTBS OTBS O OH MeO O OH 299     (16) Addition of diazomethane to intermediate 261 furnished cyclopropane 300. 260 262 676                                                                                                                                                                                                                                                                                                                               Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide OTBS OTBS OTBS Et 3N, ethyl chloroformate HO THF, –10 °C O N2 diazomethane EtO OH O Et 2O, 0 °C O O 260 O OH OH 259 261 (Not observed) OTBS H diazomethane O Et 2O, 0 °C N2 OH 300 (17) (a) Radosevich, A. T.; Chan, V. S.; Shih, H.-W.; Toste, F. D. Angew. Chem., Int. Ed. 2008, 47, 3755–3758. (b) Lam, S. K.; Chiu, P. Chem. Eur. J. 2007, 13, 9589– 9599. (c) Anderluh, M.; Cesar, J.; Štefanič, P.; Kikelj, D.; Janeš, D.; Murn, J.; Nadrah, K.; Tominc, M.; Addicks, E.; Giannis, A.; Stegnar, M.; Dolenc, M. S. Eur. J. Med. Chem. 2005, 40, 25–49. (d) Cesar, J.; Dolenc, M. S.; Tetrahedron Lett. 2001, 42, 7099–7102. (18) (a) Jones, K.; Toutounji, T. Tetrahedron 2001, 57, 2427–2431. (b) Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetrahedron Lett. 1997, 38, 3837–3840. (c) Ziegler, F. E.; Berlin, M. Y.; Lee, K.; Looker, A. R. Org. Lett. 2000, 2, 3619–3621. (d) Calter, M.; Zhu, C. J. Org. Chem. 1999, 64, 1415–1419. (19) (a) Sakai, T.; Matsushita, S.; Arakawa, S.; Kawai, A.; Mori, Y. Tetrahedron Lett. 2014, 55, 6557–6560. (b) Sakai, T; Asano, H.; Fukukawa, K.; Oshima, R.; Mori, Y. Org. Lett. 2014, 16, 2268–2271. (c) Sakai, T.; Sugimoto, A.; Tatematsu, H.; Mori, Y. J. Org. Chem. 2012, 77, 11177–11191. (20) Attempted etherifications of α-bromoketone 301, which was prepared from αhydroxyketone 268, was also unsuccessful.   OTBS OH O OH 268 OTBS OTBS PPh 3, CBr4 CH2Cl2, 0 °C (98% yield) Br bases O OH 301 O O 245 (Not observed)   677                                                                                                                                                                                                                                                                                                                               (21) (a) Garcia, J. A. O. Thesis, The University of British Columbia, Vancouver, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Canada, Oct 2003. (b) Ebner, C.; Müller, C. A.; Markert, C.; Pfaltz, A. J. Am. Chem. Soc. 2011, 133, 4710–4713. (22) Lautens, M.; Maddess, M. L.; Sauer, E. L. O.; Ouellet, S. G. Org. Lett. 2002, 4, 83–86. (23) (a) Sabitha, G.; Rao, V. R. S.; Sudhakar, K.; Kumar, M. R.; Reddy, E. V.; Yadav, J. S. J. Mol. Catal. A: Chem. 2008, 280, 16–19. (b) Aho, J. E.; Salomäki, E.; Rissanen, K.; Pihko, P. M. Org. Lett. 2008, 10, 4179–4182. (c) Kumaran, R. S.; Mehta, G. Tetrahedron 2015, 71, 1718–1731. (24) Karikomi, M.; Watanabe, S.; Kimura, Y.; Uyehara, T. Tetrahedron Lett. 2002, 43, 1495–1498. (25) Only ketone 258 was observed when the reaction was conducted at 80 °C. (26) Attempts on direct intramolecular etherification of iodohydrin 273 under basic conditions failed to produce 276. In addition, oxidation of iodohydrin 273 with MnO2 produced complex mixtures of byproducts. OTBS OTBS bases HO HO I HO O 273 276 OTBS OTBS MnO 2 HO O CH2Cl2, 23 °C I HO I HO     (27) Because oxidation of secondary alcohol 276 with MnO2 was conducted on small 273 302 scale, the amount of the obtained ketone 245 was too little to be characterized by NMR analysis. (28) Nevar, N. M.; Kel’in, A. V.; Kulinkovich, O. L. Synthesis 2000, 9, 1259–1262. 678                                                                                                                                                                                                                                                                                                                               (29) (a) Trost, B. M.; Stiles, D. T. Org. Lett. 2007, 9, 2763–2766. (b) Trost, B. M.; Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Waser, J.; Meyer, A. J. Am. Chem. Soc. 2008, 130, 16424–16434. (c) Otera, J.; Danoh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307–5311. (30) An attempt to oxidize secondary alcohol 303, which was prepared by hydrolysis of ester 286 using Swern oxidation conditions, caused lactonization to give 305 instead of the desired 304. OH OH O DMSO, oxalyl chloride Et 3N LiOH THF, MeOH, H 2O (98% yield) CH2Cl2, –78 °C CO2Me CO2H 286 CO2H 303 304 DMSO, oxalyl chloride Et 3N O O CH2Cl2, –78 °C (72% yield)     (31) (a) Lin, J.-W.; Kurniawan, Y. D.; Chang, W.-J.; Leu, W.-J.; Chan, S.-H.; Hou, 305 D.-R. Org. Lett. 2014, 16, 5328–5331. (b) Aho, J. E.; Piisola, A.; Krishnan, K. S.; Pihko, P. M. Eur. J. Org. Chem. 2011, 9, 1682–1694. (c) Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513–5516. (32) Silyl ether 296 was prepared from diol 293 with TESCl. OTBS OTBS TESCl, imidazole, DMAP OH OH 293 CH2Cl2 (85% yield) TESO OH 296   Appendix 13 – Spectra Relevant to Chapter 5 679 APPENDIX 13 Spectra Relevant to Chapter 5: Synthetic Studies Toward Polycyclic Ineleganolide 248 CO2Me OMe OMe                                                                                                   680   Figure A13.1. 1H NMR (400 MHz, CDCl3) of compound 248. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.2. Infrared spectrum (Thin Film, NaCl) of compound 248.  Figure A13.3. 13C NMR (101 MHz, CDCl3) of compound 248.   681   CO2Me 251 OH                                                                                                   682   Figure A13.4. 1H NMR (400 MHz, CDCl3) of compound 251. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.5. Infrared spectrum (Thin Film, NaCl) of compound 251.  Figure A13.6. 13C NMR (101 MHz, CDCl3) of compound 251.   683   252 CO2Me O                                                                                                   684   Figure A13.7. 1H NMR (400 MHz, CDCl3) of compound 252. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.8. Infrared spectrum (Thin Film, NaCl) of compound 252.  Figure A13.9. 13C NMR (101 MHz, CDCl3) of compound 252.   685   254 CO2Me OH O                                                                                                   686   Figure A13.10. 1H NMR (400 MHz, CDCl3) of compound 254. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.11. Infrared spectrum (Thin Film, NaCl) of compound 254.  Figure A13.12. 13C NMR (101 MHz, CDCl3) of compound 254.   687   CO2Me 244b Br O                                                                                                   688   Figure A13.13. 1H NMR (400 MHz, CDCl3) of compound 244b. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.14. Infrared spectrum (Thin Film, NaCl) of compound 244b.  Figure A13.15. 13C NMR (101 MHz, CDCl3) of compound 244b.   689   HO O 260 OH OTBS                                                                                                   690   Figure A13.16. 1H NMR (400 MHz, CDCl3) of compound 260. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.17. Infrared spectrum (Thin Film, NaCl) of compound 260.  Figure A13.18. 13C NMR (101 MHz, CDCl3) of compound 260.   691   O EtO 264 O OH OTBS N2                                                                                                   692   Figure A13.19. 1H NMR (400 MHz, CDCl3) of compound 264. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.20. Infrared spectrum (Thin Film, NaCl) of compound 264.  Figure A13.21. 13C NMR (101 MHz, CDCl3) of compound 264.   693   N2 O 266 O O OTBS                                                                                                   694   Figure A13.22. 1H NMR (400 MHz, CDCl3) of compound 266. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.23. Infrared spectrum (Thin Film, NaCl) of compound 266.  Figure A13.24. 13C NMR (101 MHz, CDCl3) of compound 266.   695   O 268 OH OTBS OH                                                                                                   696   Figure A13.25. 1H NMR (400 MHz, CDCl3) of compound 268. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.26. Infrared spectrum (Thin Film, NaCl) of compound 268.  Figure A13.27. 13C NMR (101 MHz, CDCl3) of compound 268.   697   O 269 OH OTBS BzO                                                                                                   698   Figure A13.28. 1H NMR (400 MHz, CDCl3) of compound 269. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.29. Infrared spectrum (Thin Film, NaCl) of compound 269.  Figure A13.30. 13C NMR (101 MHz, CDCl3) of compound 269.   699   O 270 OH OTBS MsO                                                                                                   700   Figure A13.31. 1H NMR (400 MHz, CDCl3) of compound 270. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.32. Infrared spectrum (Thin Film, NaCl) of compound 270.  Figure A13.33. 13C NMR (101 MHz, CDCl3) of compound 270.   701   271a OH O OTBS                                                                                                   702   Figure A13.34. 1H NMR (400 MHz, CDCl3) of compound 271a. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.35. Infrared spectrum (Thin Film, NaCl) of compound 271a.  Figure A13.36. 13C NMR (101 MHz, CDCl3) of compound 271a.   703   271b OH O OTBS                                                                                                   704   Figure A13.37. 1H NMR (400 MHz, CDCl3) of compound 271b. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.38. Infrared spectrum (Thin Film, NaCl) of compound 271b.  Figure A13.39. 13C NMR (101 MHz, CDCl3) of compound 271b.   705   I TESO 274 HO OTBS                                                                                                   706   Figure A13.40. 1H NMR (500 MHz, CDCl3) of compound 274. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.41. Infrared spectrum (Thin Film, NaCl) of compound 274.  Figure A13.42. 13C NMR (126 MHz, CDCl3) of compound 274.   707   TESO 275 O OTBS                                                                                                   708   Figure A13.43. 1H NMR (400 MHz, CDCl3) of compound 275. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.44. Infrared spectrum (Thin Film, NaCl) of compound 275.  Figure A13.45. 13C NMR (101 MHz, CDCl3) of compound 275.   709   HO 276 O OTBS                                                                                                   710   Figure A13.46. 1H NMR (400 MHz, CDCl3) of compound 276. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.47. Infrared spectrum (Thin Film, NaCl) of compound 276.  Figure A13.48. 13C NMR (101 MHz, CDCl3) of compound 276.   711   285 OH O OTBS                                                                                                   712   Figure A13.49. 1H NMR (400 MHz, CDCl3) of compound 285. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.50. Infrared spectrum (Thin Film, NaCl) of compound 285.  Figure A13.51. 13C NMR (101 MHz, CDCl3) of compound 285.   713   OH 281 O OH                                                                                                   714   Figure A13.52. 1H NMR (400 MHz, CDCl3) of compound 281. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.53. Infrared spectrum (Thin Film, NaCl) of compound 281.  Figure A13.54. 13C NMR (101 MHz, CDCl3) of compound 281.   715   CO2Me 286 OH                                                                                                   716   Figure A13.55. 1H NMR (500 MHz, CDCl3) of compound 286. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.56. Infrared spectrum (Thin Film, NaCl) of compound 286.  Figure A13.57. 13C NMR (126 MHz, CDCl3) of compound 286.   717   287 CO2Me O                                                                                                   718   Figure A13.58. 1H NMR (400 MHz, CDCl3) of compound 287. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.59. Infrared spectrum (Thin Film, NaCl) of compound 287.  Figure A13.60. 13C NMR (101 MHz, CDCl3) of compound 287.   719   288 CO2Me OMe O                                                                                                   720   Figure A13.61. 1H NMR (400 MHz, CDCl3) of compound 288. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.62. Infrared spectrum (Thin Film, NaCl) of compound 288.  Figure A13.63. 13C NMR (101 MHz, CDCl3) of compound 288.   721   294 OH O OTBS                                                                                                   722   Figure A13.64. 1H NMR (500 MHz, CDCl3) of compound 294. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5     Figure A13.65. Infrared spectrum (Thin Film, NaCl) of compound 294.  Figure A13.66. 13C NMR (126 MHz, CDCl3) of compound 294.   723   Appendix 14 – Notebook Cross-Reference for New Compounds 724     APPENDIX 14 Notebook Cross-Reference for New Compounds A14.1. Contents The following notebook cross-reference has been included to facilitate access to the original spectroscopic data obtained for the compounds presented within this thesis. The information is organized by chapter and sequentially by compound number, noting the instrument on which the primary NMR data was collected. All 1H NMR, 13C NMR, and any two-dimensional NMR data available as well as 19F NMF and 31P NMR, if applicable, are electronically stored on the NMR laboratory server (mangia.caltech.edu, most typically under the username ‘shan’) and on the Stoltz group server. All IR spectra were taken on the Stoltz group IR and an electronic copy of each spectrum as a postscript file can be found on the Stoltz group server. A hard copy of each spectrum has been provided with this text, as well. All laboratory notebooks are stored in the Stoltz group archive. 725   Appendix 14 – Notebook Cross-Reference for New Compounds   A14.2. Notebook Cross-Reference Tables Table A14.1. Notebook cross-reference for compounds in Chapter 1 compound chemical structure 1 H NMR 13 C NMR IR JAMX-95 JAMX-95 JAMX-95 JAMX-75ii JAMX-75ii JAMX-75ii JAMXII-75ii JAMXII-75ii JAMXII-75ii JAMXII-75iii JAMXII-75iii JAMXII-75iii JAMXVI-201 JAMXVI-201 JAMXVI-201 JAMXIII-45i JAMXIII-45i JAMXIII-45i JAMXVI-157 JAMXVI-157 JAMXVI-157 JAMXVI-155 JAMXVI-155 JAMXVI-155 JAMXVI-161 JAMXVI-161 JAMXVI-161 JAMXVI-159 JAMXVI-159 JAMXVI-159 OH HO SI-1-2 HN Ts OH MOMO 13 HN Ts CO2Me 16a O N H CO2Me 16b O N H O HO 20 O N H N 5 N N O O 22 N N H N O O 19 N N O 23 N O N H H N H O 24 N O N H H N 726   Appendix 14 – Notebook Cross-Reference for New Compounds   O F 3C N 25 JAMXVI-41i JAMXVI-41i JAMXVI-41i JAMXV243iii JAMXV243iii JAMXV243iii N H N3 SI-1-7 O N H N3 Br 26 JAMXV-243i JAMXV-243i O JAMXV-243i N H O F 3C H N N3 28 JAMXVI85iib JAMXVI35iib JAMXVI35iib JAMXV-233 JAMXV-233 JAMXV-233 JAMXVI47iib JAMXVI47iib JAMXVI47iib JAMXVI85iv JAMXVI85iv JAMXVI-85iv JAMXVI-93 JAMXVI-93 JAMXVI-93 SK-IV-27-2B SK-IV-272B-c13 Communesin_ SI_11_sk-3281_SI-11 NH N H O O F 3C H N N3 Cl 29 N N o-Ns O O F 3C H N N3 30 N H N O H O F 3C H N 31 N3 N3 N N H N H O O H O F 3C H N 32 HN N O NsHN o-Ns Ts N SI-1-11 O N H 727   Appendix 14 – Notebook Cross-Reference for New Compounds   Ts SK-5-201-2A SK-5-2012A_C13 Communesin_ 35_SK-5125-35 SK-7-183f6+7 SK-7-183C13 37_SK-183-37 SK-4-219-2 SK-4-2192_C13 39_SK-4-21939 SK-5-93-2B SK-5-932B_C13 SI-13_SK5_93_SI-13 SK-6-99-2A SK-6-99-2AC13 40_SK-6-9940 SK-6-203-31H SK-6-203-313C 42_SK-6-20342 hsj_ch_comm hsj_ch_comm _nas _nas 44_Comm_ NAS 20130328_ pero_ch_ coupling_ precursor 20130328_ pero_ch_ coupling_ precursor 45_pero_ coupling_ precursor FV-I-091 FV-I-091 46_ coupling_MS 20130403_ pero_ch_ coupling 20130403_ pero_ch_ coupling 47_pero_ coupling FV-I-097-1 FV-I-097-1 48_MeI_MS N 35 Br O N H Ts N CN 37 O N O2N H Ts N CO2Me CO2Me 39 O N H O2N Ts N SI-1-13 O N H Ts H N 40 Br O N H Ts H N CO2Me 42 CO2Me O O 44 N H O O O NO 2 O O AllylO OAllyl 45 NO 2 Br TIPSO NO 2 CO2Allyl 46 CO2Allyl O N H Br TIPSO NO 2 47 CO2Allyl CO2Allyl O N H TIPSO NO 2 CO2Allyl 48 CO2Allyl O N 728   Appendix 14 – Notebook Cross-Reference for New Compounds   Br TIPSO NO 2 49 CO2Allyl CO2Allyl O pero_ch_ methylation pero_ch_ methylation 49_pero_ methylation FV-I-179 FV-I-179 50_ lactonization FV-I-189-1 FV-I-189-1 51_Tsuji_ model study 20130404_ pero_ch_ Tsuji 20130404_ pero_ch_ Tsuji 52_pero_tsuji 03272012_ Oxyalyl_ column 03272012_ Oxyalyl_ column SI-16_Com_ oxalyl 03282012_ Comm_ LAH 03282012_ Comm_ LAH_ reduction_C 59_Com_LAH reduc Comm_TIPS _protection Comm_TIPS _protection SI-17_Com _tips_protec HSJ_ch_ HSJ_ch_ communesin_ communesin_ oxidative_ oxidative_ bromination bromination 57_3-bromo oxindole ch_commune _coupling hsj_comm_ coupling SI-18_comm_ coupling hsj_ch_ comm_ methylation hsj_ch_ comm_ methylation 60_com_ Methylation hsj_ch_TIPS _depro_cycle hsj_ch_TIPS _depro_cycle 61_Tips_ depro_cycle N O O CO2Allyl 50 O NO N 2 O O 51 O NO N 2 Br 52 TIPSO NO 2 CO2Allyl O N O O Br OMe SI-1-16 N H OH Br 59 N H OTIPS Br SI-1-17 N H TIPSO Br Br 57 O N H SI-1-18 TIPSO NO 2 Br CO2Allyl CO2Allyl O N H 60 TIPSO NO 2 Br CO2Allyl CO2Allyl O N O O CO2Allyl Br 61 O NO N 2 729   Appendix 14 – Notebook Cross-Reference for New Compounds   O O Br 62 hsj_Tsuji Tsuji_C 62_tsuji 20131003_ aldehyde_fl _ch 20131003_ aldehyde_fl _ch 63_Floh_ aldehyde 20131001_ Floh_RA 20131001_ Floh_RA 65_FL_ reductive_ amination 1_comm_ nitro reduction_ 02_17 1_comm_ nitro reduction_ 02_17 67_nitro recution TIPS_ protection TIPS_ protection SI-19_ TIPS Protection N CO Me 2 20121017_ CO2Me_ Chara 20121017_ CO2Me_ Chara 68_ CO2Me_ protection N CO Me 2 1_comm_ aldehyde_ 500 1_comm_ aldehyde_ 500 69_ aldehyde Comm_ PMB_ cycle Comm_ PMB_ cycle 54_PMB_ cycle 1_53_ final_ cyclization_ comm 1_53_ final_ cyclization_ comm 71_5,5_ fused_ AlH3 Comm_final_ 2nd_last Communesin _final_C 72_5,5_ fused_depro O NO N 2 O O Br 63 O O NO N 2 PMB HO Br O N 65 N O NO 2 HO Br 67 NH OO N TIPSO Br SI-1-19 NH OO N TIPSO 68 Br OO N TIPSO 69 O Br OO N PMB TIPSO N Br O 54 O N HN CO2Me PMB N H TIPSO 71 CO2Me N Br O N H N HO 72 H CO2Me N Br O N 730   Appendix 14 – Notebook Cross-Reference for New Compounds   PMB TIPSO N H 73 O HN CO2Me N CO2Me O 20120621_ LAH_new 20120621_ LAH_C 73_LAH_ Debro 20130920_ Tf2O_PMB _char 20130920_ Tf2O_PMB _char 74_Tf2O_ PMB 20130926_ pmb_depro 20130926_ PMB_ depro_cage_ C 75_PMB_ depro_cage 20130922_ Dibal_ PMB_ch 20130922_ Dibal_ PMB_ch 76_dibal_ PMB 20130507_ comm_ch_ reductive_ amination 20130507_ comm_ch_ reductive_ amination 78_comm_ nitro_ reductive amination 20130507_ Comm_ Tf2O 20130507_ comm_ Tf2O_C SI-20_ch_ caged nitro 20130322_ dibal_nitro_ rearr 20130322_ dibal_nitro_ rearr 79_dibal_ nitro 20130325finalcommunesinCDCl3 20130325finalcommunesinCDCl3 53_comm_ final 20130405_ 20130405_ pero_Ti_NO2 pero_Ti_NO2 _reduction _reduction 82_pero_Ti_ cyclization N Br 74 O N O N PMB Br 75 O N N CO2Me O NH PMB HO N Br O 76 N N CO2Me O2N TIPSO 78 N Br O O N HN CO2Me Br O N N CO2Me O SI-1-20 N NO 2 O2N HO 79 N Br O N N CO2Me HO NH Br O 53 N N CO2Me Br TIPSO 82 NH OO N 731   Appendix 14 – Notebook Cross-Reference for New Compounds   Br TIPSO 83 NBoc OO 20130407_ pero_Boc_ protection 20130407_ pero_Boc_ protection_ch 83_pero_Boc _protection 20130408_ pero_ch_ aldehyde 20130408_ pero_ch_ aldehyde 81_pero_ aldehyde 20130409_ pero_ nitrobenzyl_ reductive_ amin 20130508_ pero_ reductive_ amination 84_pero_ nitro_ reductive_ amination 20130410_ pero_Tf2O 20130409_ pero_cage_C 86_pero_Tf2O 20130415_ pero_AlH3 20130414_ AlH3_C_ pero 87_pero_AlH3 20130502_ pero_PDC 20130503_ pero_PDC_C 88_pero_pdc 20130521_ pero_final_2 20130521_ pero_final_C 80_pero_final N Br O TIPSO 81 NBoc OO N O2N TIPSO N 84 O O N HN Br Boc O2N Br O 86 N HN N O O2N TIPSO N 87 O N H N Br Boc O2N TIPSO N 88 O N H O TIPSO N Br Boc NH O 80 N N H H Boc Br Table A14.2. Notebook cross-reference for compounds in Appendix 3 compound chemical structure 1 H NMR 13 C NMR IR –– –– O O NH O O 105 Br N O O2N 20131031_ hydrazine 732   Appendix 14 – Notebook Cross-Reference for New Compounds   Br H 2N 20131108_MeNH2 -major –– –– N 20131125_ coupling –– –– N 20131202_ methylation –– –– 20131217_ coupling –– –– NO 2 CO2Allyl 106 CO2Allyl O N O Bn N 112 O N H O Bn N O 114 N O2N AllylO2C O N 130 N H Table A14.3. Notebook cross-reference for compounds in Appendix 4 compound chemical structure TIPSO 1 H NMR 13 C NMR IR CWL-VI-141 CWL-VI-141oxindole NO 2 CO2Me 136 CO2Me O CWL-VI-141 N H Table A14.4. Notebook cross-reference for compounds in Chapter 2 compound chemical structure O 137a N 1 H NMR 13 C NMR IR 20130830_ o-nitro_ch 20130830_ o-nitro_ch 3a_depro_ o-nitro 20130830_ m-nitro 20130830_ m-nitro 3b_depro_ m-nitro O2N O 137b N NO 2 733   Appendix 14 – Notebook Cross-Reference for New Compounds   O 137c N 20130830_ p-nitro_ch 20130830_ p-nitro_ch 3c_depro_ p-nitro CH-EDCI CH-EDCI 7_depro_ propylbenzamide _pt 20131024_ Boger_ substrate_ protection_ ch(C/H) GFMICARBA MOYL 20131024_ Boger_ substrate_ protection_ ch(C/H) GFMICARBA MOYL NO 2 O N 139 NO 2 O 141 N NO 2 O 143 N N NO 2 9_depro_ r-lactam_pt 11_deprotection _urea Table A14.5. Notebook cross-reference for compounds in Chapter 3 compound chemical structure 1 H NMR 13 C NMR IR OTf PINAP_ OMe_OTf PINAP_ OMe_OTf PINAP_ sjh_OMe OTf PINAP_Et_OTf _ch_H_C PINAP_Et_OTf _ch_H_C PINAP_ sjh_Et PINAP_iPr_OTf PINAP_iPr_OTf PINAP_ OTf_iPr_2 SJHXII_127_ A_ch_H_C SJHXII_127_ A_ch_H_C PINAP_ sjh_A_ cyclohexyl PINAP_L_ again_tBu PINAP_L_ again_tBu PINAP_ OTf_L_tBu OMe N N 157a OEt N N 157b O N 157c N OTf O N 157d N OTf O 157e N N OTf 734   Appendix 14 – Notebook Cross-Reference for New Compounds   O N 157f N OTf PINAP_H_ OTf PINAP_H_ OTf PINAP_ sjh_H_ homoallyl PINAP_N_ OTf PINAP_N_ OTf PINAP_ sjh_ 3,5-dimethyl phenyl PINAP_ 4-methylbenzyl _OTf_C_H_ PINAP_ 4-methylbenzyl _OTf_C_H_ PINAP_ OTf_ 4-MeBn PINAP_OMe character_P_ cdcl3_ 20140626_ PINAP_OMe character_P_ cdcl3_ 20140626_ PINAP_ P_OMe PINAP_Et_P _cdcl3_ 20140626_ PINAP_Et_P _cdcl3_ 20140626_ PINAP_P _Et PINAP_iPr_P _cdcl3_ 20140626_ PINAP_iPr_P _cdcl3_ 20140626_ PINAP_P_ iPr PINAP_P_ char_H_c PINAP_P_ char_H_c PINAP_P_ A PINAP_L_ P_HC PINAP_L_ P_HC PINAP_P_ L PINAP_H_P Ch(H,C) PINAP_H_P Ch(H,C) PINAP_P_ H O N N 157g OTf O N 157h N OTf OMe N N 158a PPh 2 OEt N N 158b PPh 2 O N 158c N PPh 2 O N 158d N PPh 2 O N 158e N PPh 2 O N 158f N PPh 2 735   Appendix 14 – Notebook Cross-Reference for New Compounds   O N N 158g PPh 2 PINAP_N_ PPh2_Ch(C,H) PINAP_N_ PPh2_Ch(C,H) PINAP_P_ N PINAP_ 4-methylbenzyl _P(H,C) PINAP_ 4-methylbenzyl _P(H,C) PINAP_P_ 4-methylBn O N N 158h PPh 2 Table A14.6. Notebook cross-reference for compounds in Chapter 4 chemical structure compound 1 H NMR 13 C NMR IR O PMB 167 I N SJHXI_Alisto_ SJHXI_Alisto_ Ni_SM Ni_SM Alistonitrine _iodo_NiSM N SJHXI_ Alistonitrine_ Ni SJHXI_195_ Alisto_Ni_C_ 15 Alistonitrine _Ni_SJHXI_ 195 I SJHXIII_ model substrate_ ch_H_C SJHXIII_ model substrate_ ch_H_C SJHXIII_Ni_ C–O_ch_H SJHXIII_Ni_ C–O_ch_C RD176column RD1-76carbon RD1-76 RD1212column RD1212column RD1-212 N H OH Me O PMB 169 N H O OH 170a N O 171a N OH 170b I N O 171b N OH 170c SJHXV_19_Ph SJHXV_19_Ph _ch_2 _ch_2 I N Ph Ph O 171c N SJHXV_Ph_ PDT SJHXV_Ph_ PDT SJHXIV_281_ isopropyl SJHXIV_281_ isopropyl OH 170d N I Ni_C_O_ Ni_catalyzed SJHXIII_ model substrate Ni_C_O_ SJHXIII_Ni_ C_O_ Ni_C_O_ SJHXV_19_Ph _substrate Ni_C_O_ SJHXV_27_ Ph_PDT Ni_C_O_ SJHXIV_281_ iPr 736   Appendix 14 – Notebook Cross-Reference for New Compounds   O 171d N SJHXIV_297_ iPr_PDT SJHXIV_297_ iPr_PDT Ni_C_O_ SJHXIV_297_ iPr_PDT SJHXIV_281_ allyl SJHXIV_281_ allyl Ni_C_O_ SJHXIV_281_ allyl SJHXIV_245 _allyl_PDT SJHXIV_245 _allyl_PDT Ni_C_O_ SJHXIV_297_ allyl SJHXV_15_ PMB_ch_ H_C_2 SJHXV_15_ PMB_ch_ H_C_2 Ni_C_O_ SJHXV_15_ PMB_substrate SJHXV_25_ PMB_PDT SJHXV_25_ PMB_PDT Ni_C_O_ SJHXV_25_ PMB_PDT SJHXV_29_ 4-fluoro_ substrate SJHXV_29_ 4-fluoro_ substrate Ni_C_O_ SJHXV_29_ 4_F_ substrate SJHXV_37_ 4-Fluoro_ PDT SJHXV_37_ 4-Fluoro_ PDT Ni_C_O_ SJHXV_37_ 4_F-PDT SJHXV_61_ p-Br_ substrate SJHXV_61_ p-Br_ substrate Ni_C_O_ SJHXV_61_ pBr_ substrate SJHXV_65_ 4-Br_char_ inDCM SJHXV_65_ 4-Br_char_ inDCM Ni_C_O_ SJHXV_65_ p-Br_PDT SJHXV_31_ TBS_ substrate SJHXV_31_ TBS_ substrate Ni_C_O_ SJHXV_31_ TBS_substrate SJHXV_37_ TBS_ PDT SJHXV_37_ TBS_ PDT Ni_C_O_ SJHXV_37_ TBS_PDT SJHXV_77_ Mitsunobu_ 6membered SJHXV_77_ Mitsunobu_ 6membered Ni_C_O_ SJHXV_79_ Mitsunobu_ 6_membered OH 170e I N O 171e N OH I N 170f MeO O N 171f MeO OH I N 170g F O N 171g F OH I N 170h Br O N 171h Br OH I N 170i TBSO O N 171i TBSO OBz SI-4-6 N I 737   Appendix 14 – Notebook Cross-Reference for New Compounds   OH 170j I N O 171j N Ni_C_O_ SJHXV_87_ hydrolysis_ 6-membered Ni_C_O_ SJHXV_89_cis _6-membered_ cyclization SJHXV_87_ hydrolysis_ 6_membered SJHXV_87_ hydrolysis_ 6_membered SJHXV_89_6_ membered_cis _cyclization SJHXV_89_6_ membered_cis _cyclization RD1140column RD1140column RD1-230 RD1168column RD1168column RD1-168 OH 172a I N Ph Ph O 173a N OH 172b I N Ph Ph O 173b N OH 172c I N Ph SJHXIV_301_ monomethyl_C SJHXV_13_ monomethyl_ PDT SJHXV_13_ monomethyl_ PDT SJHXIV_299_ dimethyl_ch_ H SJHXIV_299_ dimethyl_ch_C SJHXV_11_ dimethyl_PDT SJHXV_11_ dimethyl_PDT RD1194column RD1194column RD1-194 RD1206column RD1206carbon RD1-206 SJHXIII_289_ SM_ch SJHXIII_289_ SM_ch SJHXIII_289_ benzene SJHXIII_289_ benzene SJHXIV_31_ bromide_ substrate SJHXIV_177_ vinyl_chloride _H SJHXIV_31_ bromide_ substrate SJHXIV_177_ vinyl_chloride _C Ph O 173c N Ni_C_O_ SJHXIV_301_ monomethyl_ substrate Ni_C_O_ SJHXV_13_ mono_PDT Ni_C_O_ SJHXIV_299_ dimethyl_ substrate Ni_C_O_ SJHXV_11_ dimethyl_PDT SJHXIV_301_ monomethyl_ H OH 172d I N Ph O 173d N Ph MeO 2C 174a HO I MeO 2C 175a CO2Me HO Br MeO 2C 174c CO2Me O MeO 2C 174b CO2Me HO Cl CO2Me Ni_C_O_ SJHXIII_289_ cyclization_ SM Ni_C-O_ SJHXIII_289_ cyclization Ni_C-O_ SJHXIV_31_ vinylbromide Ni_C_O_ SJHXIV_177_ vinyl_chloride Appendix 14 – Notebook Cross-Reference for New Compounds 738     MeO 2C 174d CO2Me HO I MeO 2C 175d CO2Me O MeO 2C 174e CO2Me HO I Ph MeO 2C 175e CO2Me O Ph MeO 2C 174f CO2Me HO Br MeO 2C 175f CO2Me O tBuO C 2 174g CO2tBu HO I tBuO C 2 175g CO2tBu O BnO 2C 174h CO2Bn HO I BnO 2C 175h CO2Bn O MeO 2C 174i HO I MeO 2C 175i CN O CN _substrate Ni_C_O_ SJHXIV_151_ SJHXIV_151_ SJHXIV_151_ methyl_vinyl_ methyl_vinyl_ methylsub_ iodide_H_C iodide_H_C vinyliodide_ substrate Ni_C_O_ SJHXIV_157_ SJHXIV_157_ SJHXIV_147_ methylsub_ methylsub_ methylsub_ cyclization cyclization vinyliodide_ cyclization Ni_C_O_ SJHXIV_167_ SJHXIV_167_ SJHXIV_167_ Ph_substituted Ph_substituted Ph_substituted _substrate _substrate _substrate Ni_C_O_ SJHXIV_169_ SJHXIV_169_ SJHXIV_169_ ph_sub_ ph_sub_ Ph_sub_ cyclization cyclization cyclization Ni_C_O_ SJHXIV_77_ SJHXIV_77_ SJHXIV_77_ gemdimethyl_ gemdimethyl_ gemdimethyl_ substrate substrate_C substrate Ni_C_O_ SJHXIV_85_ SJHXIV_85_ SJHXIV_83_ gemdimethyl_ gemdimethyl_ gemdimethyl_ PDT PDT PDT SJHXIV_47_ SJHXIV_47_ Ni_C_O_SJHX tbutyl_ tbutyl_ IV_47_tbutyl_ substrate substrate substrate Ni_C_O_ SJHXIV_47_ SJHXIV_47_ SJHXIV_57_ tbu_cyclization tbu_cyclization tbutyl_ cyclization SJHXIV_113_ SJHXIV_113_ Ni_C_O_ Bn_substrate_ Bn_substrate_ SJHXIV_113_ ch ch Bn_substrate Ni_C_O_ SJHXIV_117_ SJHXIV_117_ SJHXIV_117_ Bn_cyclization Bn_cyclization cyclization Ni_C_O_ SJHXIV_67_ SJHXIV_67_ SJHXIV_67_ cyanatesubstrat cyanatesubstrat cyanate_ e_down e_down substrate Ni_C_O_ SJHXIV_71_ SJHXIV_71_ SJHXIV_71_ cyanate_ cha_proton_2 cyanate_ cyclization cyclization 739   Appendix 14 – Notebook Cross-Reference for New Compounds   O 174j CO2Me N O OH I SJHXIV_191_ morpholine_ substrate_H SJHXIV_191_ morpholine_ substrate SJHXIV_195_ cyclization_H SJHXIV_195_ cyclization_C SJHXIV_37_ CH2CH2_ substrate SJHXIV_37_ CH2CH2_ substrate SJHXV_179_h ydrolysis_H_c h SJHXV_183_ cyclization_ch _H_C SJHXV_179_c h_hydrolysis_ H_C SJHXV_183_ cyclization_ch _H_C O 175j CO2Me N O O MeO 2C 174k CO2Me HO I tBuO C 2 174l HO CO2tBu I tBuO C 2 CO2tBu 175l O Ni_C_O_ SJHXIV_191_ morpholine_ substrate Ni_C_O_ SJHXIV_195_ morpholine_ cyclization Ni_C_O_ SJHXIV_37_C H2CH2vinylio dide_substrate Ni_C_O_ SJHXV_179_ hydrolysis Ni_C_O_ SJHXV_183_ cyclization   Table A14.7. Notebook cross-reference for compounds in Appendix 9 compound 192 chemical structure OH 1 I N Ph Ph O 193 N H NMR 13 C NMR Ni_Claisen_ SJHXV_241_ alkylation SJHXV_243_Ni Ni_Claisen_ SJHXV_243_Ni_ _cyclization_ SJHXV_245_ cyclization_C bottom_major Claisen_sub SJHXV_241_ alkylation_ch SJHXV_241_ C_moretime SJHXV_261_ Claisen_H SJHXV_269_ Claisen_C Ph O 194 N IR Ni_Claisen_ SJHXV_261_ Claisen PDT Table A14.8. Notebook cross-reference for compounds in Appendix 11 compound chemical structure 1 H NMR 13 C NMR IR SJHVII_77_ TBS_protection –– –– SJHXVI_19_ ozonolysis SJHXVI_19_ ozonolysis Alistonitrine_ SJHXVI_19_ ozonolysis OTBS 201 OTBS OTBS 202 O 740   Appendix 14 – Notebook Cross-Reference for New Compounds   OTBS 203 O N S SJHXVI_21_ sulfinamide_H SJHXVI_21_ sulfinamide_C SJHXVI_23_ allyladdn_ major SJHXVI_23_ allyladdn_ major SJHXVI_25_ amine_MeOD SJHXVI_25_ amine_MeOD SJHVII_167_ acylation –– OTBS 204 O NH S OH 205 NH 3Cl OTIPS 206 O NH O 207 NH OTIPS O 208a N OTIPS O 208b Boc N OTIPS 213 OH O OTIPS N H OH SJHXVI_ SJHXVI_ Grubbs_ Grubbs_ pdt pdt SJHXVI_15_ SJHXVI_15_ Me_ Me_ characterization characterization NH NH Alistonitrine_ SJHXVI_ Grubbs_PDT Alistonitrine_ SJHXVI_ 15_Me Alistonitrine_ SJHXVI_ 17_Boc Alistonitrine_ SJHXVI_ 29_amide Alistonitrine_ SJHXVI_ 31_Grubbs_up Alistonitrine_ SJHXVI_ 31_Grubbs_ down SJHXVI_29_ amide_2 SJHXVI_29_ amide_2 SJHXVI_31_ Grubbs_up SJHXVI_31_ Grubbs_up SJHXVI_31_ Grubbs_down SJHXVI_31_ Grubbs_down SJHVIII_29_ up_acetate –– –– SJHVIII_29_ down_acetate –– –– SJHVIII_33_ Boc_protection –– –– SJHIX_211_ RA_PMB –– –– O 215b Alistonitrine_ SJHXVI_27_ amine_TIPS SJHXVI_17_ Boc OTIPS OH Alistonitrine_ SJHXVI_23_ allyl_addnmajor Alistonitrine_ SJHXVI_25_ amine2 SJHXVI_17_ Boc O 215a Alistonitrine_ SJHXVI_21_ sulfinamide OTIPS OAc O NH 199a OTIPS OAc O NH 199b OTIPS PhthN CO2Me CO2Me 217 O N Boc SI-A11-1 PMB N H CO2Me 741   Appendix 14 – Notebook Cross-Reference for New Compounds   O 223 O MeO CO2Me N PMB O PMB 224 CO2Me N O O PMB 225 CO2Me N O O PMB 226 CO2Me N O SJHIX-213Acylation_ PMB SJHIX-215Dieckmannpmb –– –– –– –– SJHIX_221_ Robinson –– –– SJHIX_239_ SeO2 –– ––   Table A14.9. Notebook cross-reference for compounds in Chapter 5 chemical structure compound 1 H NMR C NMR IR SJHXI_201_PDT SJHXI_201_ Still_Gennari _C Ineleganolide _SJHXI_201_ Still_Gennari SJHXI_INELE_ MeAddn_ch SJHXI_INELE_ MeAddn_ch Inele_SJHXI _211_Me_ Addn_PDt SJHXI_211_ swern_H SJHXI_211_ swern_C Ineleganolide_ SJHXI_211_ Swern SJHXI_ Ineleganolide_ mcpba_H SJHXI_ Ineleganolide_ mcpba_C Ineleganolide_ SJHXI_Inele_ mcpba SJHXV_217_ 7_bromide SJHXV_217_ 7_bromide_C Ineleganolide_ SJHXV_217_ NBS SJH_ ineleganolide _acid_ characterization SJH_ ineleganolide _acid_ characterization Ineleganolide_ SJH_ acid SJHXII_235_ MnO2 SJHXII_235_ MnO2_C Ineleganolide_ SJHXII_Rh_ SM_diazo SJHXII_201_H SJHXII_201_C Ineleganolide_ SJHXII_Rh_ TLC_prep OMe OMe 248 13 CO2Me OH 251 CO2Me O 252 CO2Me O OH 254 CO2Me O Br 244b CO2Me OTBS 260 HO O OH OTBS 264 N2 EtO O 266 O OH OTBS O O N2 O 742   Appendix 14 – Notebook Cross-Reference for New Compounds   OTBS 268 OH O OH SJHXIII_25_ Rubottom_ characterization _H SJHXIII_25_ Rubottom_ characterization _C SJHXIII_39_ Benzoylation_H SJHXIII_39_ Benzoylation_C SJHXIII_27_ Mesyl_ characterization _H SJHXIII_27_ Mesyl_ characterization _C SJHXIII_215_ 1_H SJHXIII_215_ 1_C SJHXIII_215_ 2_H SJHXIII_215_ 2_C SJHXV_201_ TES SJHXV_201_ TES SJHXV_221_ cyclization_H SJHXV_221_ cyclization_C SJHXV_239_ TES_depro_H SJHXV_239_ TES_depro_C SJHXIII_MnO2 _ch_H SJHXIII_MnO2 _ch_C SJHXIII_107_ TBAF_H SJHXIII_107_ TBAF_C SJH_vinyl_ addn_ characterization SJH_vinyl_ addn_ characterization SJHXIII_41_ swern_H-ch SJHXIII_41_ swern_C-ch SJHXIII_85_ OMe_addn_H SJHXIII_85_ OMe_addn_c OTBS 269 BzO O OH OTBS 270 MsO O OH OTBS 271a O OH OTBS 271b O OH OTBS 274 TESO HO I OTBS 275 TESO O OTBS 276 HO O OTBS 285 O OH OH 281 O OH OH 286 CO2Me O 287 CO2Me O OMe 288 CO2Me Ineleganolide_ SJHXIII_25_ rubottom_ RobFrag Ineleganolide_ SJHXIII_39_ benzoyl Ineleganolide_ SJHXIII_27_ Mesylate Ineleganolide_ SJHXIII_231 _epoxide_1_ cosy Ineleganolide_ SJHXIII_231 _epoxide2_ corey Ineleganolide_ SJHXV_201 _TES Ineleganolide_ SJHXV_221 _cyclization Ineleganolide_ SJHXV_239 _TES_depro Ineleganolide_ SJHXIII_ MnO2_after vinyladdn Ineleganolide_ SJHXIII_105 _TBAF_ desilylation Ineleganolide_ SJH_vinyl_ addn_left part Ineleganolide_ SJHXIII_ 81_Swern Ineleganolide_ SJHXIII_ 89_OMe_addn _unexpected 743   Appendix 14 – Notebook Cross-Reference for New Compounds   OTBS 294 O OH SJHXV_271_ MnO2_ oxidation SJHXV_271_ MnO2_ oxidation Ineleganolide_ SJHXV_271_ MnO2 Comprehensive Bibliography 744   COMPREHENSIVE BIBLIOGRAPHY Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849. Ahmed, A. F.; Shine, R.-T.; Wang, G.-H.; Dai, C.-F.; Kuo, Y.-H.; Sheu, J.-H. Tetrahedron 2003, 59, 7337–7344. Aho, J. E.; Piisola, A.; Krishnan, K. S.; Pihko, P. M. Eur. J. Org. Chem. 2011, 9, 1682–1694. Aho, J. E.; Salomäki, E.; Rissanen, K.; Pihko, P. M. Org. Lett. 2008, 10, 4179–4182. Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743– 756. Ananikov, V. P. ACS Catal. 2015, 5, 1964–1971. Anderluh, M.; Cesar, J.; Štefanič, P.; Kikelj, D.; Janeš, D.; Murn, J.; Nadrah, K.; Tominc, M.; Addicks, E.; Giannis, A.; Stegnar, M.; Dolenc, M. S. Eur. J. Med. Chem. 2005, 40, 25–49. Andersen, B.; Smedsgaard, J.; Frisvad, J. C. J. Agric. Food Chem. 2004, 52, 2421. Ando, K. J. Org. Chem. 1997, 62, 1934–1939. Ando, K. J. Org. Chem. 1999, 64, 8406–8408. Ando, K. J. Org. Chem. 2000, 65, 4745–4749. Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369–4378. Arthuis, M.; Beaud, R.; Gandon, V.; Roulland, E. Angew. Chem., Int. Ed. 2012, 51, 10510–10514. Artman, G. D., III; Weinreb, S. M. Org. Lett. 2003, 5, 1523. 745   Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682– Comprehensive Bibliography 3685. Baliga, M. S. Integr. Cancer Ther. 2010, 9, 261–269. Belmar, J.; Funk, R. L. J. Am. Chem. Soc. 2012, 134, 16941. Bhat, V.; Wang, S.; Stoltz, B. M.; Virgil, S. C. J. Am. Chem. Soc. 2013, 135, 16829– 16832. Black, A.; Brown, J. M.; Pichon, C. Chem. Commun. 2005, 5284–5286. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26. Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc. 1993, 115, 10733– 10741. Bottini, A. T.; Mullikin, J. A.; Morris, C. J. J. Org. Chem. 1964, 29, 373–379. Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.; Leach, D. C. J. Chem. Soc. Perkin. Trans. 1 2002, 58–68. Burgos, C.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 4321–4326. Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetrahedron Lett. 1997, 38, 3837–3840. Ziegler, F. E.; Berlin, M. Y.; Lee, K.; Looker, A. R. Org. Lett. 2000, 2, 3619–3621. Calter, M.; Zhu, C. J. Org. Chem. 1999, 64, 1415–1419. Cao, H.; Yu, J.; Wearing, X. Z.; Zhang, C.; Liu, X.; Deschamps, J.; Cook, J. M. Tetrahedron Lett. 2003, 44, 8013–8017. Cao, Z.-Y.; Wang, Y.-H.; Zeng, X.-P.; Zhou, J. Tetrahedron Lett. 2014, 55, 2571– 2584. Cesar, J.; Dolenc, M. S.; Tetrahedron Lett. 2001, 42, 7099–7102. Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174–10175. Comprehensive Bibliography 746   Chen, D.; Xu, M.-H. J. Org. Chem. 2014, 79, 7746–7751. Chen, W.; Li, Y.; Guo, Y. Acta Pharm. Sin. B 2012, 2, 227–237. Chen, Y.; Wang, L.; Liu, Y.; Li, Y. Chem. Eur. J. 2011, 17, 12582–12586. Clayden, J.; Fletcher, S. P.; McDouall, J. J. W.; Rowbottom, S. J. M. J. Am. Chem. Soc. 2009, 131, 5331–5343. Craig, R. A., II Ph.D. Thesis, California Institute of Technology, Pasadena, CA, May 2015. Craig, R. A., II.; Roizen, J. L.; Smith, R. C.; Jones, A. C.; Stoltz, B. M. Org. Lett. 2012, 14, 5716–5719. Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169. Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995. Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 3995–3998. Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247–7290. Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad, J. C.; Christophersen, C. J. Nat. Prod. 2005, 68, 258. Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959–1964. Danishefsky, S. J.; DeNinno, M. P.; Chen, S.-h. J. Am. Chem. Soc. 1988, 110, 3929– 3940. Daura-Oller, E.; Segarra, A. M.; Poblet, J. M.; Claver, C.; Fernández, E.; Bo, C. J. Org. Chem. 2004, 69, 2669–2680. Denault, J.-B.; Salvesen, G. S. Chem. Rev. 2002, 102, 4489. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49, 3432–3435. 747   Ding, M.; Zhou, F.; Qian, Z.-Q.; Zhou, J. Org. Biomol. Chem., 2010, 8, 2912–2914. Comprehensive Bibliography Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Org. Lett. 2008, 10, 285–288. Dou, X.; Yao, W.; Zhou, B.; Lu, Y. Chem. Commun. 2013, 49, 9224. Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J. M. Chem. Eur. J. 1999, 5, 1320– 1330. Duh, C.-Y.; Wang, S.-K.; Chia, M.-C.; Chiang, M. Y. Tetrahedron Lett. 1999, 40, 6033–6035. Ebner, C.; Müller, C. A.; Markert, C.; Pfaltz, A. J. Am. Chem. Soc. 2011, 133, 4710– 4713. Eckroth, D. R.; Cochran, T. G. J. Chem. Soc. C 1970, 2660. Evans, M. A.; Sacher, J. R.; Weinreb, S. M. Tetrahedron 2009, 65, 6712. Evans, V.; Mahon, M. F.; Webster, R. L. Tetrahedron, 2014, DOI: 10.1016/j.tet.2014.07.080. Faller, J. W.; Grimmond, B. J. Organometallics 2001, 20, 2454–2458. Fandrick, D. R., Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Tang, W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.; Yee, N. K.; Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600-7601. Fandrick, K. R.; Fandrick, D. R.; Reeves, J. T.; Ma, S.; Li, W.; Lee, H.; Grinberg, N.; Lu, B.; Senanayake, C. H. J. Am. Chem. Soc. 2011, 133, 10332-10335. Fandrick, K. R.; Ogikubo, J.; Fandrick, D. R.; Patel, N. D.; Saha, J.; Lee, H.; Ma, S.; Grinberg, N.; Busacca, C. A.; Senanayake, C. H. Org. Lett. 2013, 15, 1214-1217. Fang, Y.; Li, C. Chem. Commun. 2005, 3574–3576. Fang, Y.; Li, C. J. Am .Chem. Soc. 2007, 129, 8092–8093. Fernandes, R. A.; Yamamoto, Y. J. Org. Chem. 2004, 69, 3562. 748   Fernández, E. Guiry, P. J.; Connole, K. P. T.; Brown, J. M. J. Org. Chem. 2014, 79, Comprehensive Bibliography 5391–5400. Fetter, J.; Giang, L. T.; Czuppon, T.; Lempert, K.; Kajtár-Peredy, M; Czira, G. Tetrahedron, 1994, 50, 4185–4200. Frontier, A. J.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151– 6159. Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068. Fujimori, S.; Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635–1657. Fukase, K.; Tanaka, H.; Torii, S.; Kusumoto, S. Tetrahedron Lett. 1990, 31, 389–392. Fukuyama, T.; Frank, R. K.; Jewell, C. F., Jr. J. Am. Chem. Soc. 1980, 102, 2122– 2123. Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426. Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748–8758. Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279–9282. Garcia, J. A. O. Thesis, The University of British Columbia, Vancouver, Canada, Oct 2003. Gareau, Y.; Zamboni, R.; Wong, A. W. J. Org. Chem. 1993, 58, 1582. Gatti, M.; Drinkel, E.; Wu, L.; Pusterla, I.; Gaggia, F.; Dorta, R. J. Am. Chem. Soc. 2010, 132, 15179–15181. George, J. H.; Adlington, R. M. Synlett 2008, 2093. Gommermann, N.; Knochel, P. Chem.–Eur. J. 2006, 12, 4380–4392. Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763–5766. 749   González, M. A.; Ghosh, S.; Rivas, F.; Fischer, D.; Theodorakis, E. A. Tetrahedron Comprehensive Bibliography Lett. 2004, 45, 5039–5041. Greenberg, A. Mol. Struct. Enegetics 1988, 7, 139. Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270–5298. Han, R.; Hillhouse, G. L. J. Am. Chem. Soc. 1997, 119, 8135–8136. Han, S.-J. Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C. Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. Han, S.-J.; Fernando de Melo, G.; Stoltz, B. M. Tetrahedron Lett. 2014, 55, 6467. Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. Hartwig, J. F. Nature 2008, 455, 314–322. Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci. Biotechnol. Biochem. 2004, 68, 753. He, L.; Bekkaye, M.; Retailleau, P.; Masson, G. Org. Lett. 2012, 14, 3158. Hegedus, L. S.; Toro, J. L.; Miles, W. H.; Harrington, P. J. J. Org. Chem. 1987, 52, 3319. Hennessy, E. J.; Buchwald, S. L. J. Org. Chem. 2005, 70, 7371–7375. Hoffmann, R. W.; Breitfelder, S.; Schlapbach, A. Helv. Chim. Acta 1996, 79, 346– 352. Hoffmann, T.; Lanig, H.; Waibel, R.; Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40, 3361–3364. Holmquist, M.; Blay, G.; Pedro, J. R. Chem. Commun., 2014, 50, 9309–9312. Horn, E. J.; Silverston, J. S.; Vanderwal, C. D. J. Org. Chem. 2016, DOI: 10.1021/acs.joc.5b02550. Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442–6445. 750   Horvath, A.; Grassberger, M. A.; Schulz, G.; Haidl, E.; Sperner, H.; Steck, A. Comprehensive Bibliography Tetrahedron 2000, 56, 7469. Hrib, N. J.; Jurcak, J. G.; Burgher, K. L.; Conway, P. G.; Hartman, H. B.; Kerman, L. L.; Roehr, J. E.; Woods, A. T. J. Med. Chem. 1994, 37, 2308. Hu, F.-L.; Wei, Y.; Shi, M. Chem. Commun., 2014, 50, 8912–8914. Hu, X. Chem. Sci. 2011, 2, 1867–1886. Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 65–66. Ishida, T.; Ikota, H.; Kurahashi, K.; Tsukano, C.; Takemoto, Y. Angew. Chem., Int. Ed. 2013, 52, 10204. Ishida, T.; Takemoto, Y. Tetrahedron 2013, 69, 4517. Iwao, M.; Motoi, O. Tetrahedron Lett. 1995, 36, 5929. Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K; Proksch, P. J. Nat. Prod. 2004, 67, 78. Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417–1492. Jones, K.; Toutounji, T. Tetrahedron 2001, 57, 2427–2431. Karikomi, M.; Watanabe, S.; Kimura, Y.; Uyehara, T. Tetrahedron Lett. 2002, 43, 1495–1498. Katayev, D.; Jia, Y.-X. Sharma, A. K.; Banerjee, D.; Besnard, C.; Sunoj, R. B.; Kündig, E. P. Chem. Eur. J. 2013, 19 11916–11927. Kennewell, P. D.; Miller, D. J.; Scrowston, R. M.; Westwood, R. J. Chem. Res. Miniprint 1995, 10, 2380. Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 6821–6841. Klenchin, V. A.; Allingham, J. S.; King, R.; Tanaka, J.; Marriott, G.; Rayment, I. Nat. Struct. Biol. 2003, 10, 1058. 751   Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Comprehensive Bibliography Chem., Int. Ed. 2004, 43, 5971–5973. Kocienski, P. J. Protecting Groups; George Thieme Verlag: Stuttgart and New York, 1994. Koriyama, Y.; Nozawa, A.; Hayakawa, R.; Shimizu, M. Tetrahedron 2002, 58, 9621– 9628. Kotoku, N.; Sumii, Y.; Kobayashi, M. Org. Lett. 2011, 13, 3514. Koyama, J.; Toyokuni, I.; Tagahara, K. Chem. Pharm. Bull. 1998, 46, 332–334. Kozlovskii, A. G.; Solov’eva, T. F.; Sahkarovskii, V. G.; Adanin, V. M. Dokl. Akad. Nauk SSSR 1981, 260, 230. Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C. Ramtohul, Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745. Krishnan, S.; Stoltz, B. M. Tetrahedron Lett. 2007, 48, 7571–7573. Kumaran, R. S.; Mehta, G. Tetrahedron 2015, 71, 1718–1731. Kundu, D.; Maity, P.; Ranu, B. C. Org. Lett. 2014, 16, 1040–1043. Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 12248–12249. Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202– 12206. . Lam, S. K.; Chiu, P. Chem. Eur. J. 2007, 13, 9589–9599. Latorre, A.; Sáez, J. A.; Rodríguez, S.; González, F. V. Tetrahedron 2014, 70, 97–102. Lautens, M.; Maddess, M. L.; Sauer, E. L. O.; Ouellet, S. G. Org. Lett. 2002, 4, 83– 86. Lebedev, S. A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya, I. P. J. Organomet. Chem. 1988, 344, 253–259. Lee, C. W.; Han, S.-J. Virgil, S. C.; Stoltz, B. M. Tetrahedron 2014, 71, 3666–3670. Comprehensive Bibliography 752   Lee, K. C.; Loh, T. P. Chem. Commun. 2006, 40, 4209–4211. Lee, S. J.; Cho, S. A.; An, S. S.; Na, Y. J.; Park, N. H.; Kim, H. S.; Lee, C. W.; Kim, H. K.; Kim, E. K.; Jang, Y. P.; Kim, J. W. Evid. Based Complement Alternat. Med. 2012, 2012, 190370. Li, C.; Guo, F.; Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Org. Lett. 2014, 16, 3192–3195. Li, P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 6396. Li, X.; Kong, L.; Gao, Y.; Wang, X. Tetrahedron Lett. 2007, 48, 3915–3917. Li, Y.; Pattenden, G. Nat. Prod. Rep. 2011, 28, 429–440. Li, Y.; Pattenden, G. Tetrahedron 2011, 67, 10045–10052. Lim, A. D.; Codelli, J. A.; Reisman, S. E. Chem. Sci. 2013, 4, 650–654. Lim, C. W.; Tissot, O.; Mattison, A. Hooper, M. W.; Brown, J. M.; Cowley, A. R.; Hulmes, D. I.; Blacker, A. J. Org. Process Res. Dev. 2003, 7, 379–384. Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36–51. Lin, J.-W.; Kurniawan, Y. D.; Chang, W.-J.; Leu, W.-J.; Chan, S.-H.; Hou, D.-R. Org. Lett. 2014, 16, 5328–5331. Liu, B.; Hu, L. Bioorg. Med. Chem. 2003, 11, 3889. Liu, G.; Romo, D. Abstracts of Papers, 237th ACS National Meeting, Salt Lake City, UT, Mar 22–26, 2009; American Chemical Society, 2009; ORGN-083. Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem., Int. Ed. 2010, 49, 2000. Liu, Z.-M.; Li, N.-K.; Huang, X.-F.; Wu, B.; Li, N.; Kwok, C.-Y.; Wang, Y.; Wang, X.-W. Tetrahedron, 2014, 70, 2406–2415. Lu, H.; Li, C. Org. Lett. 2006, 8, 5365. Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037–8041. 753   Macgregor, S. A.; Neave, G. W.; Smith, C. Faraday Discuss. 2003, 124, 111–127. Comprehensive Bibliography Madin, A.; O’Donnell, C. J.; Oh, T. Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054–18065. Maeda, K.; Brown, J. M. Chem. Commun. 2002, 310–311. Maiti, D.; Buchwald, S. L. J. Org. Chem. 2010, 75, 1791–1794. Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413–5418. Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224–3225. Marfat, A.; Carta, M. P. Tetrahedron Lett. 1987, 28, 4027. Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2219. Martin, D. B. C.; Nguyen, L. Q.; Vanderwal, C. D. J. Org. Chem. 2012, 77, 17–46. Matsunaga, P. T.; Hillhouse, G. L.; Rheingold, A. L. J. Am. Chem. Soc. 1993, 115, 2075–2077. Maurya, S. K.; Dow, M.; Warriner, S.; Nelson, A. Beilstein J. Org. Chem. 2013, 9, 775–785. May, J. A. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, Jul 2005. May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262. May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203. Messik, F.; Oberthür, M. Synthesis 2013, 45, 167–170. Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513–5516. Miknis, G. F.; Williams, R. M. J. Am. Chem. Soc. 1993, 115, 536–547. Miura, T.; Yamauchi, M.; Kosaka, A.; Murakami, M. Angew. Chem., Int. Ed. 2010, 49, 4955–4957. Mohr, J. T.; Stoltz, B. M. Chem. Asian J. 2007, 2, 1476. Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003, 125, 8702–8703. Comprehensive Bibliography 754   Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5–8. Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525–1532. Nevar, N. M.; Kel’in, A. V.; Kulinkovich, O. L. Synthesis 2000, 9, 1259–1262. Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2009, 74, 5075–5078. Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978–4979. Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355. O’Connell, C. E.; Frontier, A. J. Abstracts of Papers, 32nd Northeast Regional Meeting of the American Chemical Society, Rochester, NY, Oct 31–Nov 3, 2004; American Chemical Society, 2004, GEN-088. Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307–5311. Overman, L. E.; Rosen, M. D. Angew. Chem. Int. Ed. 2000, 39, 4596–4599. Pagano, N.; Wong, E. Y. Breiding, T.; Liu, H.; Wilbuer, A.; Bregman, H.; Shen, Q.; Diamond, S. L.; Meggers, E. J. Org. Chem. 2009, 74, 8997–9009. Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333– 10334. Panek, J. S.; Xu, F.; Rondón, A. C. J. Am. Chem. Soc. 1998, 120, 4113–4122. Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2498–2500. Pereira, J.; Barlier, M.; Guillou, C. Org. Lett. 2007, 9, 3101–3103. Piloto, A. M.; Costa, S. P. G.; Goncalves, M. S. T. Tetrahedron, 2014, 70, 650–657. Pitsch, S. Helv. Chim. Acta 1997, 80, 2286–2314. Radosevich, A. T.; Chan, V. S.; Shih, H.-W.; Toste, F. D. Angew. Chem., Int. Ed. 2008, 47, 3755–3758. 755   Rao, V. R.; Muthenna, P.; Shankaraiah, G.; Akileshwari, C.; Babu, K. H.; Suresh, G.; Comprehensive Bibliography Babu, K. S.; Kumar, R. S. C.; Prasad, K. R.; Yadav, P. A.; Petrash, J. M.; Reddy, G. B.; Rao, J. M. Eur. J. Med. Chem. 2012, 57, 344–361. Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem. 2001, 66, 8717. Rech, J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso, P. V.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 490–491. Rege, P. D.; Johnson, F. J. Org. Chem. 2003, 68, 6133. Rodríguez-Vázquez, N.; Salzinger, S.; Silva, L. F.; Amorín, M.; Granja, J. R. Eur. J. Org. Chem. 2013, 17, 3477–3493. Roizen, J. L. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, Nov 2009. Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346–1416. Sabahi, A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006, 45, 4317. Sabitha, G.; Rao, V. R. S.; Sudhakar, K.; Kumar, M. R.; Reddy, E. V.; Yadav, J. S. J. Mol. Catal. A: Chem. 2008, 280, 16–19. Sahkarovskii, V. G.; Aripovskii, A. V.; Baru, M. B.; Kozlovskii, A. G. Khim. Prir. Soedin. 1983, 656. Sakai, T; Asano, H.; Fukukawa, K.; Oshima, R.; Mori, Y. Org. Lett. 2014, 16, 2268– 2271. Sakai, T.; Matsushita, S.; Arakawa, S.; Kawai, A.; Mori, Y. Tetrahedron Lett. 2014, 55, 6557–6560. Sakai, T.; Sugimoto, A.; Tatematsu, H.; Mori, Y. J. Org. Chem. 2012, 77, 11177– 11191. Comprehensive Bibliography 756   Schammel, A. W.; Chiou, G.; Garg, N. K. Org. Lett. 2012, 14, 4556. Schultz, A. G.; Lucci, R. D.; Napier, J. J.; Kinoshita, H.; Ravichandran, R.; Shannon, P.; Yee, Y. K. J. Org. Chem. 1985, 50, 217–231. Seo, J. H.; Artman, G. D., III; Weinreb, S. M. J. Org. Chem. 2006, 71, 8891. Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am. Chem. Soc. 2010, 132, 1202–1203. Shang, J. H.; Cai, X. H.; Feng, T.; Zhao, Y. L.; Wang, J. K.; Zhang, L. Y.; Yan, M.; Luo, X. D. J. Ethnopharmacol. 2010, 129, 174–181. Shang, J.; H.; Cai, X. H.; Zhao, Y. L.; Feng, T.; Luo, X. D. J. Ethnopharmacol. 2010, 129, 293–298. Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718– 10719. Shen, K.; Liu, X.; Feng, X. Chem. Sci., 2012, 3, 327–334. Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 8170. Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104–6155. Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron, 1989, 45, 2431–2449. Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942–10953. Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57, 3301–3307. Somei, M.; Yamada, F. Jpn. Patent JP 85-47044 19850308, 1986. Spence, T. W. M.; Tennant, G. J. Chem. Soc. C 1971, 3712. Standley, E. A.; Tasker, S. Z.; Jensen, K. L.; Jamison, T. F. Acc. Chem. Res. 2015, 48, 1503–1514. Steinhagen, H.; Corey, E. J. Angew. Chem., Int. Ed. 1999, 38, 1928. Stutz, A.; Pitxch, S. Synlett, 1999, 930–934. 757   Sugiura, R.; Kozaki, R.; Kitani, S.; Gosho, Y.; Tanimoto, H.; Nishiyama, Y.; Comprehensive Bibliography Morimoto, T.; Kakiuchi, K. Tetrahedron, 2013, 69, 3984–3990. Sun, C.; Fang, Y.; Li, S.; Zhang, Y.; Zhao, Q.; Zhu, S.; Li, C. Org Lett. 2009, 11, 4084–4087. Surasani, R.; Kalita, D.; Rao, A. V. D.; Chandrasekhar, K. B. Beilstein J. Org. Chem. 2012, 8, 2004–2018. Suzuki, T.; Kobayashi, S. Org. Lett. 2010, 12, 2920–2923. Szostak, M.; Aubé, J. Chem. Rev. 2013, 113, 5701. Szostak, M.; Aubé, J. Org. Biomol. Chem. 2011, 9, 27. Tanaka, J.; Yan, Y.; Choi, J.; Bai, J.; Klenchin, V. A.; Rayment, I.; Marriott, G. Proc. Natl. Acad. Sci. 2003, 100, 13851. Tang, F. Thesis, Washington University, St. Louis, MO, May 2009. Tani, K.; Stoltz, B. M. Nature, 2006, 441, 731. Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299–309. Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143–146. Teng, M.; Zi, W.; Ma, D. Angew. Chem., Int. Ed. 2014, 53, 1814–1817. Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79, 663–672. Terrett, J. A.; Cuthbertson, J. D.; Shurtleff, V. W.; MacMillan, D. W. C. Nature 2015, 524, 330–334. Thaler, T.; Geittner, F.; Knochel, P. Synlett 2007, 2655–2658. Thao, N. P.; Nam, N. H.; Cuong, N. X.; Quang, T. H.; Tung, P. T.; Dat, L. D.; Chae, D.; Kim, S.; Koh, Y.-S.; Kiem, P. V.; Minh, C. V.; Kim, Y. H. Bioorg. Med. Chem. Lett. 2013, 23, 228–231. Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2000, 122, 10482–10483. 758   Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583–3586. Comprehensive Bibliography Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med. Chem. 2001, 44, 4641–4649. Torraca, K. E.; Kuwabe, S.-I.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907– 12908. Trost, B. M.; Brennan, M. K. Synthesis, 2009, 3003–3025. Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133, 7328. Trost, B. M.; Osipov, M.; Krüger, S.; Zhang, Y. Chem. Sci. 2015, 6, 349. Trost, B. M.; Stiles, D. T. Org. Lett. 2007, 9, 2763–2766. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc. 2008, 130, 16424–16434. Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343. Trudeau, S.; Morgan, J. B.; Shrestha, M.; Morken, J. P. J. Org. Chem. 2005, 70, 9538–9544. Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381. Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793. Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715. Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124. Voelker, T.; Ewell, T.; Joo, J.; Edstrom, E. D. Tetrahedron Lett. 1998, 39, 359–362. Wang, Y.; Kong, C.; Du, Y.; Song, H.; Zhang, D.; Qin, Y. Org. Biomol. Chem. 2012, 10, 2793. 759   Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, Comprehensive Bibliography 1846. Weinstabl, H.; Gaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834–2837. Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561. Wigley, L. J.; Perry, D. A.; Mantle, P. G. Mycol. Res. 2008, 112, 131. Williams, R. M.; Kwast, E. Tetrahedron Lett. 1989, 30, 451–454. Woodward, C.; L.; Li, Z.; Kathcart, A. K.; Terrell, J.; Gerena, L.; Lopez-Sanchez, M.; Kyle, D. E.; Bhattacharjee, A. K.; Nichols, D. A.; Ellis, W.; Prigge, S. T.; Geyer, J. A.; Waters, N. C. J. Med. Chem. 2003, 46, 3877–3882. Wu, H.; Xue, F.; Xiao, X.; Qin, Y. J. Am. Chem. Soc. 2010, 132, 14052. Wu, X.; Fors, B. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9943–9947. Würdemann, M.; Christoffers, J. Org. Biomol. Chem. 2010, 8, 1894–1898. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th ed; John Wiley & Sons: New York, 2007. Yamada, F.; Makita, Y.; Suzuki, T.; Somei, M. Chem. Pharm. Bull. 1985, 33, 2162. Yamada, Y.; Arima, S.; Okada, C.; Akiba, A.; Kai, T.; Harigaya, Y. Chem. Pharm. Bull. 2006, 54, 788. Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187. Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794. Yang, Q.; Njardarson, J. T. Tetrahedron Lett. 2013, 54, 7080–7082. Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J. Org. Chem. 2004, 1244. Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486. Zhang, H.; Hong, L.; Kang, H.; Wang, R. J. Am. Chem. Soc. 2013, 135, 14098. 760   Zhing, F.; Dou, X.; Han, X.; Yao, W.; Zhu, Q.; Meng, Y.; Lu, Y. Angew. Chem. Int. Comprehensive Bibliography Ed. 2013, 52, 943–947. Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal., 2010, 352, 1381–1407. Zhou, F.; Zeng, X.-P.; Wang, C.; Zhao, X.-L.; Zhou, J. Chem. Commun., 2013, 49, 2022–2024. Zhu, G.-Y.; Yao, X.-J.; Liu, L.; Bai, L.-P.; Jiang, Z.-H. Org. Lett. 2014, 16, 1080– 1083. Zhu, X.-L.; Xu, J.-H.; Cheng, D.-J.; Zhao, L.-J.; Liu, X.-Y. Tan, B. Org. Lett. 2014, 16, 2192–2195. Zuo, Z.; Ma, D. Angew. Chem., Int. Ed. 2011, 50, 12008. Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132, 13226. 761   Index INDEX 3 3,3-disubstituted oxindole ......................................................................................................... 12, 19, 318 A acetal .............................................................................................................. 337, 586, 597, 637, 638, 652 alistonitrine A ................................................................................................................ 583, 584, 588, 589 alkaloid .............................................................................................................................. 4, 335, 420, 583 aminal .............................................................................. 2, 18, 26, 27, 28, 31, 85, 86, 91, 94, 95, 96, 584 asymmetric .............................................................................................................. 13, 318, 322, 361, 366 atroposelective ............................................................................................................................... 361, 366 aurantioclavine .................................................................................... 4, 5, 7, 10, 13, 40, 44, 57, 309, 315 B Baylis-Hillman .............................................................................................................................. 585, 586 biosynthesis ............................................................................................................................................... 4 bromooxindole ......................................................... 9, 14, 46, 49, 55, 56, 59, 63, 320, 322, 327, 328, 602 C caged ...................................................................................................................................................... 583 Claisen ................................................................................................................................... 570, 571, 575 communesin ........... 1, 2, 4, 9, 12, 16, 18, 19, 28, 30, 31, 32, 304, 306, 307, 309, 310, 319, 327, 336, 339 copper .............................................................................. 13, 318, 319, 320, 321, 322, 323, 324, 326, 328 Corey-Chaykovsky ................................................................................................................................ 642 cross-coupling ........................................................................................................ 419, 424, 433, 445, 450 cycloaddition ............................................................................................................... 4, 5, 6, 7, 8, 14, 307 cycloetherification ......................................................................................................................... 421, 425 D Danheiser ............................................................................................................................................... 639 decarboxylative allylic alkylation .................................................................................... 16, 18, 20, 29, 33 diastereomer .................................................................................................. 5, 14, 16, 19, 22, 31, 59, 304 Diazo ...................................................................................................................................................... 641 dynamic kinetic resolution .................................................................................................... 361, 362, 366 E enantioselective ......................................................................................................... 5, 318, 319, 366, 637 Index 762   enol ether ....................................................................................................................................... 420, 638 F Fischer indole ........................................................................................................................................ 588 G Grubbs ................................................................................................................................................... 647 H Heck ............................................................................................................................................... 420, 588 I indole ........................................... 2, 5, 7, 9, 14, 33, 38, 43, 44, 46, 49, 53, 57, 58, 73, 314, 315, 316, 321 ineleganolide .......................................................................................................... 635, 636, 637, 645, 649 K kinetic resolution ....................................................................................................................... 5, 361, 362 L lactam 4, 10, 18, 21, 22, 23, 26, 27, 28, 29, 30, 33, 52, 79, 84, 87, 88, 305, 335, 337, 344, 430, 585, 586, 589, 595, 596, 600, 601, 602, 605, 606 lactone .................................................................................... 16, 18, 19, 21, 68, 76, 77, 80, 304, 635, 659 ligand ............................................................................. 318, 320, 321, 323, 324, 328, 361, 363, 364, 366 M Metathesis ...................................................................................................................................... 645, 648 Michael reaction ............................................................................................................................ 636, 637 microwave ......................................................................................................... 33, 76, 311, 340, 575, 590 N nickel ..................................................................................................................................... 419, 421, 427 nitrobenzyl ..................................................................................................................................... 335, 336 nomofungin ................................................................................................................................................ 2 O oxindole9, 12, 13, 14, 15, 18, 19, 21, 22, 24, 26, 27, 28, 29, 30, 32, 36, 54, 58, 59, 65, 66, 67, 75, 76, 87, 89, 94, 96, 312, 318, 326, 335, 337, 584, 587, 588, 603 P palladium ....................................................................................................................................... 363, 588 Index 763   perophoramidine ............................................................ 3, 12, 16, 18, 28, 31, 32, 304, 319, 327, 335, 339 PINAP ............................................................................................................ 361, 362, 364, 366, 369, 370 Pinnick oxidation ................................................................................................................................... 639 Q quaternary .............................................................. 2, 3, 6, 15, 16, 18, 20, 29, 32, 318, 319, 327, 584, 587 QUINAP ................................................................................................................................ 361, 362, 366 R reductive amination ....................................................................................... 21, 22, 27, 33, 336, 588, 589 reductive cyclization .................................................................................................. 22, 24, 26, 27, 31, 33 Robinson annulation .............................................................................................................................. 589 Rubottom ....................................................................................................................................... 638, 642 S stereochemistry .................................................... 5, 8, 13, 15, 16, 20, 29, 32, 59, 309, 319, 424, 635, 674 Still-Gennari .......................................................................................................................................... 637 T tert-butanesulfinyl ................................................................................................................................. 585 U umpolung ........................................................................................................................................... 13, 14 764   About the Author About the Author Seojung Han was born on March 2nd, 1985 in Gumi, Gyeongsang buk-do Province, South Korea. She spent her early life in the company of her parents and her younger brother Sangjun in Gumi. Seojung attended Gyeongbuk Foreign Language High School, where she learned foreign languages such as English, Japanese and Chinese and developed interest in science. In 2004, she began her undergraduate studies at Sogang University in Seoul, Korea. Seojung became attracted to organic chemistry because any of the desired new compounds could be prepared by organic synthesis. Eager to apply the knowledge from her studies, Seojung joined Prof. Duck-Hyung Lee’s laboratory as an undergraduate research assistant and practiced multi-step reactions and synthesized heterocycles related to medicinal chemistry. Seojung received bachelor’s degree in chemistry summa cum laude from Sogang University in 2008. Upon graduation, Seojung joined the research group of Prof. Duck-Hyung Lee for an M.S. degree in organic chemistry at Sogang University and completed the enantioselective synthesis of a C9–C17 fragment of (–)-amphidinolide O and P. In addition, she synthesized fragments of ascospiroketal B and arenicolide A. Upon obtaining an M.S. degree in 2010 summa cum laude, she worked at the Korea Research Institute of Chemical Technology in the medicinal chemistry department to contribute to the development of novel drug candidates for treatment of metabolic diseases and new fluorescent small molecule probes for staining blood vessels. In the fall of 2011, Seojung moved to Pasadena, California in USA, where she began her doctoral studies in synthetic organic chemistry at the California Institute of Technology. In December of 2011, she eagerly joined the research group of Prof. Brian M. Stoltz to study total synthesis of natural products and development of new 765   methodologies. Seojung earned her Ph.D. in chemistry in 2016. In September of About the Author 2016, she will continue her postdoctoral research under the guidance of Prof. F. Dean Toste at University of California, Berkeley.  I. SYNTHETIC STUDIES TOWARD THE TOTAL SYNTHESIS OF POLYCYCLIC NATURAL PRODUCTS – COMMUNESIN F, PEROPHORAMIDINE AND INELEGANOLIDE II. NICKEL CATALYZED INTRAMOLECULAR C–O BOND FORMATION Thesis by Seojung Han In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 2016 (Defended May 13, 2016)    ii   © 2016 Seojung Han All Rights Reserved    iii   To my family, for their unwavering support and dedication iv ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor, Professor Brian M. Stoltz, for helping me tremendously during my graduate work. Brian has been very generous and supportive advisor who always encourages me to come up with new ideas. He expects us to be creative, thoughtful and curious in what we do. He has offered a lot of guidance in terms of not only chemistry, but also personal development. Brian is an endless source of knowledge and ideas. Whenever I have discussed my project with Brian, I have always become motivated. It is impossible to thank him enough for his mentorship and kindness. I have been fortunate to have him as an advisor over the last five years. My committee members Prof. Sarah E. Reisman, Prof. Theodor Agapie, and Prof. Robert H. Grubbs have provided me with valuable advice on my research and career. Sarah has served as a role model for a great female scientist. She is a generous and thoughtful committee member who has helped me to develop my scientific interests. Theo provided me with scientific insights on transition metalcatalyzed transformations. Bob, who is the final member of my committee, has encouraged me to think about my proposals and chemistry from a broader perspective. I am grateful for all the guidance from my thesis committee. In addition, I would like to thank Dr. Scott C. Virgil of the Caltech Center for Catalysis and Chemical Synthesis. While I was conducting a DKR project with him, he provided me with lots of unique scientific aspects. He also keeps analytical instruments running for us. I also want to thank my past advisors. I am especially thankful to Prof. DuckHyung Lee who was my former advisor at Sogang University. When I was an v undergraduate student, I enjoyed taking his lectures. He motivated me to pursue graduate work in organic chemistry. I learned a great deal of both theoretical and experimental aspects of organic chemistry and developed a stronger synthetic chemistry foundation while I was doing research in his group. Prof. Duck-Hyung Lee deeply cares about his students. He has been a great mentor to me and I cannot thank him enough for his kindness. Dr. Jin Hee Ahn, who was my advisor at Korea Research Institute of Chemical Technology, expanded my interest to medicinal chemistry. He has been supportive and generous to me. I am thankful for all of the patience and guidance from my past advisors. I have been lucky to work with great individuals in the Stoltz group. When I first joined lab, Dr. Florian Vogt, who was doing a project concerning the synthesis of communesin F and perophoramidine, was preparing to leave for his new job. Although I only spent time with him in the lab for about 10 days, I appreciate his helpful discussion, compounds and chemicals. I also want to thank to Dr. Vikram Bhat, who introduced the DKR project to me. In my 4th year, I took a project concerning the total synthesis of ineleganolide from Dr. Rob Craig. I really appreciate his valuable discussion and all the support. It has also been a pleasure to work with Dr. Ryohei Doi, who was a visiting student from Japan, on Ni-catalyzed etherification reactions. Thanks to the Caltech SURF program, I had opportunities to be a mentor for several undergraduate students. My first undergraduate mentee was Yoobin Koh, who came from GIST, Korea. Yoobin was passionate about learning chemistry. Gabriel Fernando de Melo was another mentee from Brazil in the following year. He helped me to explore a project concerning a new method for the cleavage of nitrobenzyl amides and ethers. I am thankful for his hard work on the vi project. I would also like to thank Katherine Bay, who brought a cheerful attitude to the lab. I need to thank all of the Stoltz group members, past and present, for the help that I have received for last five years. First of all, I would like to thank Kelly Kim and Nicholas O’Connor, who are the members of my class within the Stoltz lab. Kelly and Nick are very kind and always volunteer to help me. When we were the 1st and 2nd years of students, Kelly, Nick, Anton (formal Stoltz group member), and I sometimes hung out, played video games at Kelly’s house, and drunk margaritas or beers. I really enjoyed all the activities with them. I also thank Prof. Wen-Bo (Boger) Liu, who was my hoodmate for the last four years. He is a brilliant organic chemist and I really appreciate his helpful discussion and contribution to my development as a chemist. We also enjoyed talking about the cultural differences between USA, Korea, and China. I am certain that he will have a successful career in academia at Wuhan University in China. When I visited Caltech as a prospective student in March 2011, Prof. Jimin Kim, who is a postdoctoral alumnus in the Stoltz group, introduced the Stoltz group to me during the poster session. Jimin and I used to have a lunch together and I enjoyed conversation with her. I am grateful to her for guidance and mentorship. I believe that she will be successful in academia at Chonnam National University in Korea. I also want to thank Dr. Allen Hong, who was one of my baymates. I think he is one of the most diligent people that I have met. He is very brilliant and I appreciate his helpful discussions on my chemistry. In addition, Dr. Chung Whan Lee is thanked for helping me to settle down in the lab in the early days. To Prof. Hosea Nelson, Dr. Alex Goldberg, Dr. Nathan Bennett, Dr. Jeff Holder, Dr. Christopher Haley, Dr. Yoshitaka Numajiri, Doug Duquette, Dr. Doug Behenna, Dr. Corey Reeves, Dr. Yiyang Liu, Dr. Jared Moore, Dr. Eric Welin, vii Dr. Daisuke Saito, Dr. Max Klatte, Dr. Caleb Hethcox, Dr. Marchello Cavitt, Dr. Hendrik F. T. Klare, Dr. Guillaume Lapointe, Dr. Marc Linger, Dr. Alex N. Marziale, Dr. Noriko Okamoto, Dr. Grant Shibuya, Dr. Kristy Tran, Dr. Kun-Liang (Phil) Wu, Dr. Xiangyou Xing, Dr. Jonny Gordon, thank you all for your mentorship and guidance. To the younger students I have had the pleasure to work with, Sam, Beau, Shoshana, Kelvin, Eric, Elizabeth, Jiaming, Carina, Steven, Fa, Chris, Alex, David, and Austin, thank you for all of the support and I wish you all best throughout the rest of your time at Caltech. I especially thank to the numerous people who have helped look over my research proposals, manuscripts, and thesis chapters over the years. I also want to thank to the members of the Reisman group and the Grubbs group for helpful scientific discussion and the sharing of numerous resources. I especially want to acknowledge Kangway Chuang for insightful discussion. I would like to thank to Hyun Gi Yun, who is a graduate student in the Clemons lab and Dr. Sarah Yunmi Lee, who graduated from the Fu lab. I always enjoyed spending time with them. Hyun Gi and Yunmi have been there since the beginning. I also need to thank one of my best friends, Songi Han, who is a graduate student at Rice University studying bioengineering. Songi has accompanied me during my trips to LA, Houston, and Seattle. Songi and I are on the same wavelength. She has provided me the emotional anchoring during the most difficult moments of graduate school. I am deeply indebted to the Fulbright for providing me fellowship during my first two years of graduate school. I would also like to thank the Ilju Foundation of Education & Culture for the pre-doctoral research fellowship during the last three years of graduate school. viii I also want to thank tremendous support from the Caltech staff. Dr. Dave VanderVelde has helped me to analyze complicated NMR data sets for hours and taught me how to use MestReNova program efficiently. In addition, I must thank Larry Henling for providing lots of crucial X-ray crystal structures for my communesin F and perophoramidine project. Also, thanks Lynne Martinez, who is the administrative assistant for our group and the Reisman group, for keeping things running smoothly on a daily basis. I also want to thank Rick Gerhart for helping repair glassware, Dr. Mona Shahgholi and Naseem for helping to obtain HRMS data, Jeff Groseth for his expertise and service to our group, and Agnes Tong for helping with administrative duties. Finally, I would like to acknowledge my lovely family who has always supported me. Dad, Mom, and Sangjun, who always pray for me, have been the most warm and supporting family I could ever ask for. Without their dedication and support, I would not be where I am today. I would also like to thank my aunt, Yuri and her husband. They live in LA and we have occasionally met and had a dinner. We had a trip to Sedona during my first vacation. Thanks to them, it has been very easy for me to get used to life in USA. Without the continued support of all of these people, I would not have made it here.    ix   ABSTRACT Expedient synthetic approaches to the highly functionalized polycyclic alkaloids communesin F and perophoramidine are described using a unified approach featuring a key decarboxylative allylic alkylation to access a crucial and highly congested 3,3-disubstituted oxindole. Described are two distinct, stereoselective alkylations that produce structures in divergent diastereomeric series possessing the critical vicinal all-carbon quaternary centers needed for each synthesis. Synthetic studies toward these challenging core structures have revealed a number of unanticipated modes of reactivity inherent to these complex alkaloid scaffolds. Finally, a previously unknown mild and efficient deprotection protocol for the onitrobenzyl group is disclosed – this serendipitous discovery permitted a concise endgame for the formal syntheses of both communesin F and perophoramidine. In addition, the atroposelective synthesis of PINAP ligands has been accomplished via a palladium-catalyzed C–P coupling process through dynamic kinetic resolution. These catalytic conditions allow access to a wide variety of alkoxy- and benzyloxy-substituted PINAP ligands in high enantiomeric excess. An efficient and exceptionally mild intramolecular nickel-catalyzed carbon– oxygen bond-forming reaction between vinyl halides and primary, secondary, and tertiary alcohols has been achieved. This operationally simple method allows direct access to cyclic vinyl ethers in high yields in a single step. Finally, synthetic studies toward polycyclic ineleganolide are described. The entire fragmented carbon framework has been constructed from this work. Highly (Z)-selective olefination was achieved by the method by the Ando group.    x   PUBLISHED CONTENT AND CONTRIBUTIONS   1. Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. A Diastereodivergent Synthetic Strategy for the Syntheses of Communesin F and Perophoramidine. Org. Lett. 2014, 16, 3316–3319. DOI: 10.1021/ol5013263. Han, S.-J. participated in designing the synthesis, synthesized compounds, prepared the data, crystalized the key compounds and wrote the manuscript. 2. Han, S.-J.; Fernando de Melo, G.; Stoltz, B. M. A New Method for the Cleavage of Nitrobenzyl Amides and Ethers. Tetrahedron Lett. 2014, 55, 6467–6469. DOI: 10.1016/j.tetlet.2014.10.006. Han, S.-J. optimized reaction conditions, prepared substrates, investigated the new methodology, characterized compounds, and wrote the manuscript. 3. Lee, C. W.; Han, S.-J.; Virgil, S. C.; Stoltz, B. M. Stereochemical evaluation of bis(phosphine) copper catalysts for the asymmetric alkylation of 3-bromooxindoles with α-arylated malonate esters. Tetrahedron 2015, 71, 3666–3670. DOI: 10.1016/j.tet.2014.10.065. Han, S.-J. participated in optimizing reaction conditions, prepared substrates, and participated in the writing of the manuscript. 4. Han, S.-J.; Vogt, F.; May, J. A.; Krishnan, S.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Evolution of a Unified, Sterodivergent Approach to the Synthesis of Communesin F and Perophoramidine. J. Org. Chem. 2015, 80, 528–547. DOI: 10.1021/jo502534g. Han, S.-J. participated in designing the synthesis, synthesized compounds, prepared the data, crystalized the key compounds and wrote the manuscript. 5. Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic Enantioselective Construction of Quaternary Stereocenters: Assembly of Key Building Blocks for the    xi   Synthesis of Biologically Active Molecules. Acc. Chem. Res. 2015, 48, 740–751. DOI: 10.1021/ar5004658. Han, S.-J. participated in the writing of the manuscript. 6. Han, S.-J.; Stoltz, B. M. A mild and efficient approach to enantioenriched αhydroxyethyl α,β-unsaturated δ-lactams. Tetrahedron Lett. 2016, 57, 2233–2235. DOI: 10.1016/j.tetlet.2016.04.022. Han, S.-J. designed the synthesis, synthesized the compounds, prepared the data and wrote the manuscript. 7. Han, S.-J.; Doi, R.; Stoltz, B. M. Nickel-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers. Angew. Chem., Int. Ed. 2016, DOI: 10.1002/anie.201601991; Angew. Chem. 2016, DOI: 10.1002/ange.201601991. Han, S.-J. participated in optimizing the reaction parameters, synthesized substrates, investigated the new reactions, prepared the data, and wrote the manuscript.        xii   TABLE OF CONTENTS   Acknowledgements ..........................................................................................iv Abstract ...........................................................................................................ix Published Content and Contributions ................................................................x Table of Contents ............................................................................................xii List of Figures ................................................................................................ xvii List of Schemes ........................................................................................... xxxii List of Tables ............................................................................................... xxxv List of Abbreviations .................................................................................. xxxix CHAPTER 1                              1 The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine       1.1. Introduction .................................................................................................... 1 1.2. Results and Discussion ..................................................................................... 4 1.2.1. Biosynthesis-Inspired Diels–Alder Cycloaddition Strategy to Communesin F .. 4 1.2.2. An Alkylation Route to Communesin F .......................................................... 12 1.2.3. Formal Synthesis of Communesin F (1f) ......................................................... 18 1.2.4. Formal Synthesis of Perophoramidine (3) ...................................................... 28 1.3. Conclusion ................................................................................................... 32 1.4. Experimental Methods and Analytical Data .................................................... 33 1.4.1. Materials and Methods ................................................................................... 33 1.4.2. Experimental Procedures ................................................................................ 34 1.5. References and Notes .................................................................................. 105   APPENDIX 1 Spectra Relevant to Chapter 1   112 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1     211 A2.1. X-Ray Crystal Structure Analysis of 24 .......................................................... 212 A2.2. X-Ray Crystal Structure Analysis of 37 .......................................................... 220 A2.3. X-Ray Crystal Structure Analysis of 42 .......................................................... 228 A2.4. X-Ray Crystal Structure Analysis of 51 .......................................................... 234    xiii   A2.5. X-Ray Crystal Structure Analysis of 52 .......................................................... 242 A2.6. X-Ray Crystal Structure Analysis of 61 .......................................................... 252 A2.7. X-Ray Crystal Structure Analysis of 62 .......................................................... 260 A2.8. X-Ray Crystal Structure Analysis of 72 .......................................................... 265 A2.9. X-Ray Crystal Structure Analysis of 73 .......................................................... 273 A2.10. X-Ray Crystal Structure Analysis of 72 .......................................................... 284 A2.11. X-Ray Crystal Structure Analysis of 94 .......................................................... 297   APPENDIX 3 Synthetic Studies Toward the Total Synthesis of Communesin F 304 A3.1. Direct Lactam–Forming Strategy ................................................................ 304 A3.2. Diels–Alder Strategy ..................................................................................... 306 A3.3. Intramolecular Alkylation of 3-Bromooxindole Strategy ............................... 309 A3.4. Experimental Methods and Analytical Data .................................................. 310 A3.4.1. Materials and Methods ................................................................................. 310 A3.4.2. Experimental Procedures .............................................................................. 312 A3.5. References and Notes .................................................................................. 317   APPENDIX 4 318   Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters   A4.1. Introduction ................................................................................................. 318 A4.2. Results and Discussion ................................................................................. 320 A4.2.1. Initial Screening Results .............................................................................. 320 A4.2.2. Ligand Screening and Optimization Studies ................................................ 322 A4.3. Conclusion .................................................................................................. 326 A4.4. Selected Experiments ................................................................................... 327 A4.4.1. Synthesis of (±)-136 ..................................................................................... 327 A4.4.2. Ligand Screening Procedure ......................................................................... 328 A4.5. References and Notes .................................................................................. 329   APPENDIX 5 Spectra Relevant to Appendix 4     331 CHAPTER 2                                                                      334 A New Method for the Cleavage of Nitrobenzyl Amides and Ethers     2.1. Introduction ................................................................................................. 334    xiv   2.2. Results and Discussion ................................................................................. 335 2.3. Conclusion .................................................................................................. 339 2.4. Experimental Methods and Analytical Data .................................................. 339 2.4.1. Materials and Methods ................................................................................. 339 2.4.2. Experimental Procedures .............................................................................. 340 2.5. References and Notes .................................................................................. 346   APPENDIX 6 Spectra Relevant to Chapter 2     348 CHAPTER 3                                                                      361 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.1. Introduction ................................................................................................. 361 3.2. Results and Discussion ................................................................................. 362 3.3. Conclusion .................................................................................................. 366 3.4. Experimental Methods and Analytical Data .................................................. 367 3.4.1. Materials and Methods ................................................................................. 367 3.4.2. Experimental Procedures .............................................................................. 369 3.4.3. Spectroscopic Data ...................................................................................... 371 3.5. References and Notes .................................................................................. 382   APPENDIX 7 Spectra Relevant to Chapter 3     CHAPTER 4               Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   386                                                      419 4.1. Introduction ................................................................................................. 419 4.2. Results and Discussion ................................................................................. 420 4.3. Conclusion .................................................................................................. 427 4.4. Experimental Methods and Analytical Data .................................................. 427 4.4.1. Materials and Methods ................................................................................. 427 4.4.2. Experimental Procedures .............................................................................. 429 4.5. References and Notes .................................................................................. 459   APPENDIX 8 Spectra Relevant to Chapter 4     465    xv   APPENDIX 9                                                                  570 Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement A9.1. Claisen Rearrangement ................................................................................ 570 A9.2. Experimental Methods and Analytical Data .................................................. 571 A9.2.1. Materials and Methods ................................................................................. 571 A9.2.2. Experimental Procedures .............................................................................. 573 APPENDIX 10 Spectra Relevant to Appendix 9     576 APPENDIX 11 Synthetic Studies Toward Alistonitrine A   583 A11.1. Introduction ................................................................................................ 583 A11.2. Results and Discussion ................................................................................. 584 A11.3. Experimental Methods and Analytical Data .................................................. 590 A11.3.1. Materials and Methods ................................................................................. 590 A11.3.2. Experimental Procedures .............................................................................. 591 A11.4. References and Notes ..................................................................... 607     APPENDIX 12 Spectra Relevant to Appendix 11     CHAPTER 5               Synthetic Studies Toward Polycyclic Ineleganolide 612                                                      635 5.1. Introduction ................................................................................................. 635 5.2. Results and Discussion ................................................................................. 637 5.3. Conclusion .................................................................................................. 649 5.4. Experimental Methods and Analytical Data .................................................. 649 5.4.1. Materials and Methods ................................................................................. 649 5.4.2. Experimental Procedures .............................................................................. 651 5.5. References and Notes .................................................................................. 674   APPENDIX 13 Spectra Relevant to Chapter 5       APPENDIX 14 Notebook Cross-Reference for New Compounds 679 724    xvi   A14.1. Contents ......................................................................................... 724 A14.2. Notebook Cross-Reference Tables ................................................... 725     Comprehensive Bibliography ....................................................................... 744 Index ........................................................................................................... 761 About the Author ......................................................................................... 764              xvii   LIST OF FIGURES   CHAPTER 1 The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine Figure 1.1.1. Communesins (1), Nomofungin (2), and Perophoramidine (3) .......................... 3 Figure 1.2.1. X-ray Structure of Bridged Polycycle 24 ..................................................... 9 Figure 1.2.2. X-ray Structure of Chloroindoline 29 ....................................................... 12 Figure 1.2.3. X-ray Structure of Lactam 32 ................................................................. 12 Figure 1.2.4. X-ray Structure of Oxindole Adduct 42 .................................................... 15 Figure 1.2.5. X-ray Structure of Pyrrolidinoindoline 72 ................................................. 23 APPENDIX 1 Spectra Relevant to Chapter 1 Figure A1.1. 1H NMR (300 MHz, CDCl3) of compound SI-1-11 ......................................113 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound SI-1-11 ............................114 Figure A1.3. 13C NMR (75 MHz, CDCl3) of compound SI-1-11 .......................................114 Figure A1.4. 1H NMR (300 MHz, CDCl3) of compound 35 ............................................115 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 35 ..................................116 Figure A1.6. 13C NMR (75 MHz, CDCl3) of compound 35 .............................................116 Figure A1.7. 1H NMR (300 MHz, CDCl3) of compound 37 ............................................117 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 37 ..................................118 Figure A1.9. 13C NMR (75 MHz, CDCl3) of compound 37 .............................................118 Figure A1.10. 1H NMR (300 MHz, CDCl3) of compound 39 ..........................................119 Figure A1.11. Infrared spectrum (Thin Film, NaCl) of compound 39 ................................120 Figure A1.12. 13C NMR (75 MHz, CDCl3) of compound 39 ...........................................120 Figure A1.13. 1H NMR (300 MHz, CDCl3) of compound SI-1-13 ....................................121 Figure A1.14. Infrared spectrum (Thin Film, NaCl) of compound SI-1-13 ..........................122 Figure A1.15. 13C NMR (75 MHz, CDCl3) of compound SI-1-13 .....................................122 Figure A1.16. 1H NMR (300 MHz, CDCl3) of compound 40 ..........................................123 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 40 ................................124 Figure A1.18. 13C NMR (75 MHz, CDCl3) of compound 40 ...........................................124 Figure A1.19. 1H NMR (300 MHz, CDCl3) of compound 42 ..........................................125 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 42 ................................126 Figure A1.21. 13C NMR (75 MHz, CDCl3) of compound 42 ...........................................126 Figure A1.22. 1H NMR (500 MHz, CDCl3) of compound 44 ..........................................127 Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 44 ................................128 Figure A1.24. 13C NMR (125 MHz, CDCl3) of compound 44 ..........................................128    xviii   Figure A1.25. H NMR (500 MHz, CDCl3) of compound 45 ..........................................129 1 Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 45 ................................130 Figure A1.27. 13C NMR (125 MHz, CDCl3) of compound 45 ..........................................130 Figure A1.28. 1H NMR (500 MHz, CDCl3) of compound 46 ..........................................131 Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 46 ................................132 Figure A1.30. 13C NMR (125 MHz, CDCl3) of compound 46 ..........................................132 Figure A1.31. 1H NMR (500 MHz, CDCl3) of compound 47 ..........................................133 Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 47 ................................134 Figure A1.33. 13C NMR (125 MHz, CDCl3) of compound 47 ..........................................134 Figure A1.34. 1H NMR (500 MHz, CDCl3) of compound 48 ..........................................135 Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 48 ................................136 Figure A1.36. 13C NMR (125 MHz, CDCl3) of compound 48 ..........................................136 Figure A1.37. 1H NMR (500 MHz, CDCl3) of compound 49 ..........................................137 Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 49 ................................138 Figure A1.39. 13C NMR (125 MHz, CDCl3) of compound 49 ..........................................138 Figure A1.40. 1H NMR (400 MHz, CDCl3) of compound 50 ..........................................139 Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 50 ................................140 Figure A1.42. 13C NMR (100 MHz, CDCl3) of compound 50 ..........................................140 Figure A1.43. 1H NMR (400 MHz, CDCl3) of compound 51 ..........................................141 Figure A1.44. Infrared spectrum (Thin Film, NaCl) of compound 51 ................................142 Figure A1.45. 13C NMR (100 MHz, CDCl3) of compound 51 ..........................................142 Figure A1.46. 1H NMR (500 MHz, CDCl3) of compound 52 ..........................................143 Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 52 ................................144 Figure A1.48. 13C NMR (125 MHz, CDCl3) of compound 52 ..........................................144 Figure A1.49. 1H NMR (500 MHz, CDCl3) of compound SI-1-16 ....................................145 Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound SI-1-16 ..........................146 Figure A1.51. 13C NMR (125 MHz, CDCl3) of compound SI-1-16....................................146 Figure A1.52. 1H NMR (500 MHz, CDCl3) of compound 59 ..........................................147 Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 59 ................................148 Figure A1.54. 13C NMR (125 MHz, CDCl3) of compound 59 ..........................................148 Figure A1.55. 1H NMR (500 MHz, CDCl3) of compound SI-1-17 ....................................149 Figure A1.56. Infrared spectrum (Thin Film, NaCl) of compound SI-1-17 ..........................150 Figure A1.57. 13C NMR (125 MHz, CDCl3) of compound SI-1-17....................................150 Figure A1.58. 1H NMR (500 MHz, CDCl3) of compound 57 ..........................................151 Figure A1.59. Infrared spectrum (Thin Film, NaCl) of compound 57 ................................152 Figure A1.60. 13C NMR (125 MHz, CDCl3) of compound 57 ..........................................152 Figure A1.61. 1H NMR (500 MHz, CDCl3) of compound SI-1-18 ....................................153 Figure A1.62. Infrared spectrum (Thin Film, NaCl) of compound SI-1-18 ..........................154    xix   Figure A1.63. C NMR (125 MHz, CDCl3) of compound SI-1-18....................................154 13 Figure A1.64. 1H NMR (500 MHz, CDCl3) of compound 60 ..........................................155 Figure A1.65. Infrared spectrum (Thin Film, NaCl) of compound 60 ................................156 Figure A1.66. 13C NMR (125 MHz, CDCl3) of compound 60 ..........................................156 Figure A1.67. 1H NMR (500 MHz, CDCl3) of compound 61 ..........................................157 Figure A1.68. Infrared spectrum (Thin Film, NaCl) of compound 61 ................................158 Figure A1.69. 13C NMR (125 MHz, CDCl3) of compound 61 ..........................................158 Figure A1.70. 1H NMR (500 MHz, CDCl3) of compound 62 ..........................................159 Figure A1.71. Infrared spectrum (Thin Film, NaCl) of compound 62 ................................160 Figure A1.72. 13C NMR (125 MHz, CDCl3) of compound 62 ..........................................160 Figure A1.73. 1H NMR (500 MHz, CDCl3) of compound 63 ..........................................161 Figure A1.74. Infrared spectrum (Thin Film, NaCl) of compound 63 ................................162 Figure A1.75. 13C NMR (125 MHz, CDCl3) of compound 63 ..........................................162 Figure A1.76. 1H NMR (500 MHz, CDCl3) of compound 65 ..........................................163 Figure A1.77. Infrared spectrum (Thin Film, NaCl) of compound 65 ................................164 Figure A1.78. 13C NMR (125 MHz, CDCl3) of compound 65 ..........................................164 Figure A1.79. 1H NMR (500 MHz, DMSO) of compound 67..........................................165 Figure A1.80. Infrared spectrum (Thin Film, NaCl) of compound 67 ................................166 Figure A1.81. 13C NMR (125 MHz, DMSO) of compound 67 .........................................166 Figure A1.82. 1H NMR (500 MHz, CDCl3) of compound SI-1-19 ....................................167 Figure A1.83. Infrared spectrum (Thin Film, NaCl) of compound SI-1-19 ..........................168 Figure A1.84. 13C NMR (125 MHz, CDCl3) of compound SI-1-19....................................168 Figure A1.85. 1H NMR (500 MHz, CDCl3) of compound 68 ..........................................169 Figure A1.86. Infrared spectrum (Thin Film, NaCl) of compound 68 ................................170 Figure A1.87. 13C NMR (125 MHz, CDCl3) of compound 68 ..........................................170 Figure A1.88. 1H NMR (500 MHz, CDCl3) of compound 69 ..........................................171 Figure A1.89. Infrared spectrum (Thin Film, NaCl) of compound 69 ................................172 Figure A1.90. 13C NMR (125 MHz, CDCl3) of compound 69 ..........................................172 Figure A1.91. 1H NMR (500 MHz, CDCl3) of compound 54 ..........................................173 Figure A1.92. Infrared spectrum (Thin Film, NaCl) of compound 54 ................................174 Figure A1.93. 13C NMR (125 MHz, CDCl3) of compound 54 ..........................................174 Figure A1.94. 1H NMR (300 MHz, CDCl3) of compound 71 ..........................................175 Figure A1.95. Infrared spectrum (Thin Film, NaCl) of compound 71 ................................176 Figure A1.96. 13C NMR (125 MHz, CDCl3) of compound 71 ..........................................176 Figure A1.97. 1H NMR (600 MHz, CDCl3) of compound 72 ..........................................177 Figure A1.98. Infrared spectrum (Thin Film, NaCl) of compound 72 ................................178 Figure A1.99. 13C NMR (125 MHz, CDCl3) of compound 72 ..........................................178 Figure A1.100. 1H NMR (600 MHz, CDCl3) of compound 73 .........................................179    xx   Figure A1.101. Infrared spectrum (Thin Film, NaCl) of compound 73...............................180 Figure A1.102. 13C NMR (125 MHz, CDCl3) of compound 73 ........................................180 Figure A1.103. 1H NMR (500 MHz, CDCl3) of compound 74 .........................................181 Figure A1.104. Infrared spectrum (Thin Film, NaCl) of compound 74...............................182 Figure A1.105. 13C NMR (125 MHz, CDCl3) of compound 74 ........................................182 Figure A1.106. 1H NMR (300 MHz, CDCl3) of compound 75 .........................................183 Figure A1.107. Infrared spectrum (Thin Film, NaCl) of compound 75...............................184 Figure A1.108. 13C NMR (125 MHz, CDCl3) of compound 75 ........................................184 Figure A1.109. 1H NMR (500 MHz, CDCl3) of compound 76 .........................................185 Figure A1.110. Infrared spectrum (Thin Film, NaCl) of compound 76...............................186 Figure A1.111. 13C NMR (125 MHz, CDCl3) of compound 76 ........................................186 Figure A1.112. 1H NMR (500 MHz, CDCl3) of compound 78 .........................................187 Figure A1.113. Infrared spectrum (Thin Film, NaCl) of compound 78...............................188 Figure A1.114. 13C NMR (125 MHz, CDCl3) of compound 78 ........................................188 Figure A1.115. 1H NMR (500 MHz, CDCl3) of compound SI-1-20...................................189 Figure A1.116. Infrared spectrum (Thin Film, NaCl) of compound SI-1-20 ........................190 Figure A1.117. 13C NMR (125 MHz, CDCl3) of compound SI-1-20 ..................................190 Figure A1.118. 1H NMR (500 MHz, CDCl3) of compound 79 .........................................191 Figure A1.119. Infrared spectrum (Thin Film, NaCl) of compound 79...............................192 Figure A1.120. 13C NMR (125 MHz, CDCl3) of compound 79 ........................................192 Figure A1.121. 1H NMR (500 MHz, CDCl3) of compound 53 .........................................193 Figure A1.122. Infrared spectrum (Thin Film, NaCl) of compound 53...............................194 Figure A1.123. 13C NMR (125 MHz, CDCl3) of compound 53 ........................................194 Figure A1.124. 1H NMR (500 MHz, CDCl3) of compound 82 .........................................195 Figure A1.125. Infrared spectrum (Thin Film, NaCl) of compound 82...............................196 Figure A1.126. 13C NMR (125 MHz, CDCl3) of compound 82 ........................................196 Figure A1.127. 1H NMR (500 MHz, CDCl3) of compound 83 .........................................197 Figure A1.128. Infrared spectrum (Thin Film, NaCl) of compound 83...............................198 Figure A1.129. 13C NMR (125 MHz, CDCl3) of compound 83 ........................................198 Figure A1.130. 1H NMR (500 MHz, CDCl3) of compound 81 .........................................199 Figure A1.131. Infrared spectrum (Thin Film, NaCl) of compound 81...............................200 Figure A1.132. 13C NMR (125 MHz, CDCl3) of compound 81 ........................................200 Figure A1.133. 1H NMR (300 MHz, CDCl3) of compound 84 .........................................201 Figure A1.134. Infrared spectrum (Thin Film, NaCl) of compound 84...............................202 Figure A1.135. 13C NMR (125 MHz, CDCl3) of compound 84 ........................................202 Figure A1.136. 1H NMR (600 MHz, CDCl3) of compound 86 .........................................203 Figure A1.137. Infrared spectrum (Thin Film, NaCl) of compound 86...............................204 Figure A1.138. 13C NMR (125 MHz, CDCl3) of compound 86 ........................................204    xxi   Figure A1.139. H NMR (600 MHz, CDCl3) of compound 87 .........................................205 1 Figure A1.140. Infrared spectrum (Thin Film, NaCl) of compound 87...............................206 Figure A1.141. 13C NMR (125 MHz, CDCl3) of compound 87 ........................................206 Figure A1.142. 1H NMR (500 MHz, CDCl3) of compound 88 .........................................207 Figure A1.143. Infrared spectrum (Thin Film, NaCl) of compound 88...............................208 Figure A1.144. 13C NMR (125 MHz, CDCl3) of compound 88 ........................................208 Figure A1.145. 1H NMR (500 MHz, CDCl3) of compound 80 .........................................209 Figure A1.146. Infrared spectrum (Thin Film, NaCl) of compound 80...............................210 Figure A1.147. 13C NMR (125 MHz, CDCl3) of compound 80 ........................................210 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1 Figure A2.1.1. X-ray Crystal Structure of 24 ..............................................................212 Figure A2.2.1. X-ray Crystal Structure of 37 ..............................................................220 Figure A2.3.1. X-ray Crystal Structure of 42 ..............................................................228 Figure A2.4.1. X-ray Crystal Structure of 51 ..............................................................234 Figure A2.5.1. X-ray Crystal Structure of 52 ..............................................................242 Figure A2.6.1. X-ray Crystal Structure of 61 ..............................................................252 Figure A2.7.1. X-ray Crystal Structure of 62 ..............................................................260 Figure A2.8.1. X-ray Crystal Structure of 72 ..............................................................265 Figure A2.9.1. X-ray Crystal Structure of 73 ..............................................................273 Figure A2.10.1. X-ray Crystal Structure of 77 .............................................................284 Figure A2.11.1. X-ray Crystal Structure of 94 .............................................................297 APPENDIX 4 Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Figure A4.2.1. Results with DiazaPHOS and WALPHOS ................................................................ 322 APPENDIX 5 Spectra Relevant to Appendix 4 Figure A5.1. 1H NMR (500 MHz, CDCl3) of compound 136 ..........................................332 Figure A5.2. Infrared spectrum (Thin Film, NaCl) of compound 136 ................................333 Figure A5.3. 13C NMR (125 MHz, CDCl3) of compound 136. .........................................333    xxii   APPENDIX 6 Spectra Relevant to Chapter 2 Figure A6.1. 1H NMR (500 MHz, CDCl3) of compound 137a. ............................................... 349 Figure A6.2. Infrared spectrum (Thin Film, NaCl) of compound 137a. ................................... 350 Figure A6.3. 13C NMR (125 MHz, CDCl3) of compound 137a................................................ 350 Figure A6.4. 1H NMR (500 MHz, CDCl3) of compound 137b. ............................................... 351 Figure A6.5. Infrared spectrum (Thin Film, NaCl) of compound 137b. ................................... 352 Figure A6.6. 13C NMR (125 MHz, CDCl3) of compound 137b ............................................... 352 Figure A6.7. 1H NMR (500 MHz, CDCl3) of compound 137c. ............................................... 353 Figure A6.8. Infrared spectrum (Thin Film, NaCl) of compound 137c.. .................................. 354 Figure A6.9. 13C NMR (125 MHz, CDCl3) of compound 137c................................................ 354 Figure A6.10. 1H NMR (500 MHz, CDCl3) of compound 139 ................................................ 355 Figure A6.11. Infrared spectrum (Thin Film, NaCl) of compound 139 .................................... 356 Figure A6.12. 13C NMR (125 MHz, CDCl3) of compound 139 ............................................... 356 Figure A6.13. 1H NMR (500 MHz, CDCl3) of compound 141 ................................................ 357 Figure A6.14. Infrared spectrum (Thin Film, NaCl) of compound 141 .................................... 358 Figure A6.15. 13C NMR (125 MHz, CDCl3) of compound 141 ............................................... 358 Figure A6.16. 1H NMR (500 MHz, CDCl3) of compound 143 ................................................ 359 Figure A6.17. Infrared spectrum (Thin Film, NaCl) of compound 143 .................................... 360 Figure A6.18. 13C NMR (125 MHz, CDCl3) of compound 143 ............................................... 360 CHAPTER 3 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution Figure 3.1.1. QUINAP (155) and PINAP (156) ....................................................................... 362 APPENDIX 7 Spectra Relevant to Chapter 3 Figure A7.1. 1H NMR (500 MHz, CDCl3) of compound 157a ............................................... 387 Figure A7.2. Infrared spectrum (Thin Film, NaCl) of compound 157a. ................................... 388 Figure A7.3. 13C NMR (126 MHz, CDCl3) of compound 157a................................................ 388 Figure A7.4. 1H NMR (500 MHz, CDCl3) of compound 157b ................................................ 389 Figure A7.5. Infrared spectrum (Thin Film, NaCl) of compound 157b .................................... 390 Figure A7.6. 13C NMR (126 MHz, CDCl3) of compound 157b ............................................... 390 Figure A7.7. 1H NMR (500 MHz, CDCl3) of compound 157c ............................................... 391 Figure A7.8. Infrared spectrum (Thin Film, NaCl) of compound 157c. ................................... 392 Figure A7.9. 13C NMR (126 MHz, CDCl3) of compound 157c................................................ 392    xxiii   1 Figure A7.10. H NMR (500 MHz, CDCl3) of compound 157d ............................................. 393 Figure A7.11. Infrared spectrum (Thin Film, NaCl) of compound 157d ................................. 394 Figure A7.12. 13C NMR (126 MHz, CDCl3) of compound 157d ............................................. 394 Figure A7.13. 1H NMR (500 MHz, CDCl3) of compound 157e ............................................. 395 Figure A7.14. Infrared spectrum (Thin Film, NaCl) of compound 157e ................................. 396 Figure A7.15. 13C NMR (126 MHz, CDCl3) of compound 157e.............................................. 396 Figure A7.16. 1H NMR (500 MHz, CDCl3) of compound 157f .............................................. 397 Figure A7.17. Infrared spectrum (Thin Film, NaCl) of compound 157f ................................... 398 Figure A7.18. 13C NMR (126 MHz, CDCl3) of compound 157f ............................................. 398 Figure A7.19. 1H NMR (500 MHz, CDCl3) of compound 157g ............................................. 399 Figure A7.20. Infrared spectrum (Thin Film, NaCl) of compound 157g ................................. 400 Figure A7.21. 13C NMR (126 MHz, CDCl3) of compound 157g.............................................. 400 Figure A7.22. 1H NMR (500 MHz, CDCl3) of compound 157h ............................................. 401 Figure A7.23. Infrared spectrum (Thin Film, NaCl) of compound 157h ................................. 402 Figure A7.24. 13C NMR (126 MHz, CDCl3) of compound 157h ............................................ 402 Figure A7.25. 1H NMR (500 MHz, CDCl3) of compound 158a ............................................. 403 Figure A7.26. Infrared spectrum (Thin Film, NaCl) of compound 158a ................................. 404 Figure A7.27. 13C NMR (126 MHz, CDCl3) of compound 158a ............................................. 404 Figure A7.28. 1H NMR (500 MHz, CDCl3) of compound 158b ............................................. 405 Figure A7.29. Infrared spectrum (Thin Film, NaCl) of compound 158b ................................. 406 Figure A7.30. 13C NMR (126 MHz, CDCl3) of compound 158b. ............................................ 406 Figure A7.31. 1H NMR (500 MHz, CDCl3) of compound 158c ............................................. 407 Figure A7.32. Infrared spectrum (Thin Film, NaCl) of compound 158c ................................. 408 Figure A7.33. 13C NMR (126 MHz, CDCl3) of compound 158c ............................................. 408 Figure A7.34. 1H NMR (500 MHz, CDCl3) of compound 158d. ............................................. 409 Figure A7.35. Infrared spectrum (Thin Film, NaCl) of compound 158d ................................. 410 Figure A7.36. 13C NMR (126 MHz, CDCl3) of compound 158d. ............................................ 410 Figure A7.37. 1H NMR (500 MHz, CDCl3) of compound 158e ............................................. 411 Figure A7.38. Infrared spectrum (Thin Film, NaCl) of compound 158e ................................. 412 Figure A7.39. 13C NMR (126 MHz, CDCl3) of compound 158e ............................................. 412 Figure A7.40. 1H NMR (500 MHz, CDCl3) of compound 158f .............................................. 413 Figure A7.41. Infrared spectrum (Thin Film, NaCl) of compound 158f .................................. 414 Figure A7.42. 13C NMR (126 MHz, CDCl3) of compound 158f ............................................. 414 Figure A7.43. 1H NMR (300 MHz, CDCl3) of compound 158g ............................................. 415 Figure A7.44. Infrared spectrum (Thin Film, NaCl) of compound 158g. ................................. 416 Figure A7.45. 13C NMR (75 MHz, CDCl3) of compound 158g ............................................... 416 Figure A7.46. 1H NMR (500 MHz, CDCl3) of compound 158h ............................................. 417 Figure A7.47. Infrared spectrum (Thin Film, NaCl) of compound 158h ................................. 418    xxiv   13 Figure A7.48. C NMR (126 MHz, CDCl3) of compound 158h ............................................ 418 APPENDIX 8 Spectra Relevant to Chapter 4: Figure A8.1. 1H NMR (500 MHz, CDCl3) of compound 167 .................................................. 466 Figure A8.2. Infrared spectrum (Thin Film, NaCl) of compound 167 ...................................... 467 Figure A8.3. 13C NMR (126 MHz, CDCl3) of compound 167 ................................................. 467 Figure A8.4. 1H NMR (400 MHz, CDCl3) of compound 169 .................................................. 468 Figure A8.5. Infrared spectrum (Thin Film, NaCl) of compound 169 ...................................... 469 Figure A8.6. 13C NMR (126 MHz, CDCl3) of compound 169 ................................................. 469 Figure A8.7. 1H NMR (500 MHz, CDCl3) of compound 170a ............................................... 470 Figure A8.8. Infrared spectrum (Thin Film, NaCl) of compound 170a ................................... 471 Figure A8.9. 13C NMR (126 MHz, CDCl3) of compound 170a ............................................... 471 Figure A8.10. 1H NMR (400 MHz, CDCl3) of compound 171a .............................................. 472 Figure A8.11. Infrared spectrum (Thin Film, NaCl) of compound 171a ................................. 473 Figure A8.12. 13C NMR (101 MHz, CDCl3) of compound 171a ............................................. 473 Figure A8.13. 1H NMR (300 MHz, CDCl3) of compound 170b ............................................. 474 Figure A8.14. Infrared spectrum (Thin Film, NaCl) of compound 170b ................................. 475 Figure A8.15. 13C NMR (75 MHz, CDCl3) of compound 170b .............................................. 475 Figure A8.16. 1H NMR (300 MHz, CDCl3) of compound 171b ............................................. 476 Figure A8.17. Infrared spectrum (Thin Film, NaCl) of compound 171b ................................. 477 Figure A8.18. 13C NMR (75 MHz, CDCl3) of compound 171b .............................................. 477 Figure A8.19. 1H NMR (400 MHz, CDCl3) of compound 170c ............................................. 478 Figure A8.20. Infrared spectrum (Thin Film, NaCl) of compound 170c ................................. 479 Figure A8.21. 13C NMR (101 MHz, CDCl3) of compound 170c ............................................. 479 Figure A8.22. 1H NMR (400 MHz, CDCl3) of compound 171c ............................................. 480 Figure A8.23. Infrared spectrum (Thin Film, NaCl) of compound 171c ................................. 481 Figure A8.24. 13C NMR (101 MHz, CDCl3) of compound 171c ............................................. 481 Figure A8.25. 1H NMR (400 MHz, CDCl3) of compound 170d ............................................. 482 Figure A8.26. Infrared spectrum (Thin Film, NaCl) of compound 170d ................................. 483 Figure A8.27. 13C NMR (101 MHz, CDCl3) of compound 170d ............................................ 483 Figure A8.28. 1H NMR (400 MHz, C6D6) of compound 171d ............................................... 484 Figure A8.29. Infrared spectrum (Thin Film, NaCl) of compound 171d ................................. 485 Figure A8.30. 13C NMR (101 MHz, C6D6) of compound 171d ............................................... 485 Figure A8.31. 1H NMR (500 MHz, CDCl3) of compound 170e ............................................. 486 Figure A8.32. Infrared spectrum (Thin Film, NaCl) of compound 170e ................................. 487 Figure A8.33. 13C NMR (126 MHz, CDCl3) of compound 170e ............................................. 487 Figure A8.34. 1H NMR (500 MHz, CDCl3) of compound 171e ............................................. 488    xxv   Figure A8.35. Infrared spectrum (Thin Film, NaCl) of compound 171e ................................. 489 Figure A8.36. 13C NMR (126 MHz, CDCl3) of compound 171e ............................................. 489 Figure A8.37. 1H NMR (500 MHz, CDCl3) of compound 170f .............................................. 490 Figure A8.38. Infrared spectrum (Thin Film, NaCl) of compound 170f .................................. 491 Figure A8.39. 13C NMR (126 MHz, CDCl3) of compound 170f ............................................. 491 Figure A8.40. 1H NMR (400 MHz, CDCl3) of compound 171f .............................................. 492 Figure A8.41. Infrared spectrum (Thin Film, NaCl) of compound 171f .................................. 493 Figure A8.42. 13C NMR (101 MHz, CDCl3) of compound 171f ............................................. 493 Figure A8.43. 1H NMR (400 MHz, CDCl3) of compound 170g ............................................. 494 Figure A8.44. Infrared spectrum (Thin Film, NaCl) of compound 170g ................................. 495 Figure A8.45. 13C NMR (101 MHz, CDCl3) of compound 170g ............................................. 495 Figure A8.46. 1H NMR (400 MHz, CDCl3) of compound 171g ............................................. 496 Figure A8.47. Infrared spectrum (Thin Film, NaCl) of compound 171g ................................. 497 Figure A8.48. 13C NMR (101 MHz, CDCl3) of compound 171g ............................................. 497 Figure A8.49. 1H NMR (400 MHz, CDCl3) of compound 170h ............................................. 498 Figure A8.50. Infrared spectrum (Thin Film, NaCl) of compound 170h ................................. 499 Figure A8.51. 13C NMR (101 MHz, CDCl3) of compound 170h ............................................ 499 Figure A8.52. 1H NMR (500 MHz, CD2Cl2) of compound 171h ............................................ 500 Figure A8.53. Infrared spectrum (Thin Film, NaCl) of compound 171h ................................. 501 Figure A8.54. 13C NMR (126 MHz, CD2Cl2) of compound 171h ........................................... 501 Figure A8.55. 1H NMR (500 MHz, CDCl3) of compound 170i .............................................. 502 Figure A8.56. Infrared spectrum (Thin Film, NaCl) of compound 170i .................................. 503 Figure A8.57. 13C NMR (126 MHz, CDCl3) of compound 170i ............................................. 503 Figure A8.58. 1H NMR (400 MHz, CDCl3) of compound 171i .............................................. 504 Figure A8.59. Infrared spectrum (Thin Film, NaCl) of compound 171i .................................. 505 Figure A8.60. 13C NMR (101 MHz, CDCl3) of compound 171i ............................................. 505 Figure A8.61. 1H NMR (500 MHz, CDCl3) of compound SI-4-6 ............................................. 506 Figure A8.62. Infrared spectrum (Thin Film, NaCl) of compound SI-4-6................................. 507 Figure A8.63. 13C NMR (126 MHz, CDCl3) of compound SI-4-6 ............................................ 507 Figure A8.64. 1H NMR (400 MHz, CDCl3) of compound 170j .............................................. 508 Figure A8.65. Infrared spectrum (Thin Film, NaCl) of compound 170j .................................. 509 Figure A8.66. 13C NMR (101 MHz, CDCl3) of compound 170j ............................................. 509 Figure A8.67. 1H NMR (400 MHz, CD2Cl2) of compound 171j ............................................. 510 Figure A8.68. Infrared spectrum (Thin Film, NaCl) of compound 171j .................................. 511 Figure A8.69. 13C NMR (101 MHz, CD2Cl2) of compound 171j ............................................ 511 Figure A8.70. 1H NMR (300 MHz, CDCl3) of compound 172a ............................................. 512 Figure A8.71. Infrared spectrum (Thin Film, NaCl) of compound 172a ................................. 513 Figure A8.72. 13C NMR (75 MHz, CDCl3) of compound 172a ............................................... 513    xxvi   1 Figure A8.73. H NMR (300 MHz, CDCl3) of compound 173a ............................................. 514 Figure A8.74. Infrared spectrum (Thin Film, NaCl) of compound 173a ................................. 515 Figure A8.75. 13C NMR (75 MHz, CDCl3) of compound 173a ............................................... 515 Figure A8.76. 1H NMR (400 MHz, CDCl3) of compound 172b ............................................. 516 Figure A8.77. Infrared spectrum (Thin Film, NaCl) of compound 172b ................................. 517 Figure A8.78. 13C NMR (101 MHz, CDCl3) of compound 172b ............................................ 517 Figure A8.79. 1H NMR (400 MHz, CDCl3) of compound 173b ............................................. 518 Figure A8.80. Infrared spectrum (Thin Film, NaCl) of compound 173b ................................. 519 Figure A8.81. 13C NMR (101 MHz, CDCl3) of compound 173b ............................................ 519 Figure A8.82. 1H NMR (400 MHz, CDCl3) of compound 172c ............................................. 520 Figure A8.83. Infrared spectrum (Thin Film, NaCl) of compound 172c ................................. 521 Figure A8.84. 13C NMR (101 MHz, CDCl3) of compound 172c ............................................. 521 Figure A8.85. 1H NMR (400 MHz, CDCl3) of compound 173c ............................................. 522 Figure A8.86. Infrared spectrum (Thin Film, NaCl) of compound 173c ................................. 523 Figure A8.87. 13C NMR (101 MHz, CDCl3) of compound 173c ............................................. 523 Figure A8.88. 1H NMR (300 MHz, CDCl3) of compound 172d ............................................. 524 Figure A8.89. Infrared spectrum (Thin Film, NaCl) of compound 172d ................................. 525 Figure A8.90. 13C NMR (75 MHz, CDCl3) of compound 172d .............................................. 525 Figure A8.91. 1H NMR (300 MHz, CDCl3) of compound 173d ............................................. 526 Figure A8.92. Infrared spectrum (Thin Film, NaCl) of compound 173d ................................. 527 Figure A8.93. 13C NMR (75 MHz, CDCl3) of compound 173d .............................................. 527 Figure A8.94. 1H NMR (500 MHz, C6D6) of compound 174a ................................................ 528 Figure A8.95. Infrared spectrum (Thin Film, NaCl) of compound 174a ................................. 529 Figure A8.96. 13C NMR (126 MHz, C6D6) of compound 174a ............................................... 529 Figure A8.97. 1H NMR (500 MHz, C6D6) of compound 175a ................................................ 530 Figure A8.98. Infrared spectrum (Thin Film, NaCl) of compound 175a ................................. 531 Figure A8.99. 13C NMR (126 MHz, C6D6) of compound 175a ............................................... 531 Figure A8.100. 1H NMR (500 MHz, CDCl3) of compound 174b ........................................... 532 Figure A8.101. Infrared spectrum (Thin Film, NaCl) of compound 174b ............................... 533 Figure A8.102. 13C NMR (126 MHz, CDCl3) of compound 174b .......................................... 533 Figure A8.103. 1H NMR (400 MHz, CDCl3) of compound 174c ........................................... 534 Figure A8.104. Infrared spectrum (Thin Film, NaCl) of compound 174c ............................... 535 Figure A8.105. 13C NMR (101 MHz, CDCl3) of compound 174c ........................................... 535 Figure A8.106. 1H NMR (500 MHz, CDCl3) of compound 174d ........................................... 536 Figure A8.107. Infrared spectrum (Thin Film, NaCl) of compound 174d ............................... 537 Figure A8.108. 13C NMR (126 MHz, CDCl3) of compound 174d .......................................... 537 Figure A8.109. 1H NMR (400 MHz, C6D6) of compound 175d ............................................. 538 Figure A8.110. Infrared spectrum (Thin Film, NaCl) of compound 175d ............................... 539    xxvii   13 Figure A8.111. C NMR (101 MHz, C6D6) of compound 175d ............................................. 539 Figure A8.112. 1H NMR (400 MHz, CDCl3) of compound 174e ........................................... 540 Figure A8.113. Infrared spectrum (Thin Film, NaCl) of compound 174e ............................... 541 Figure A8.114. 13C NMR (101 MHz, CDCl3) of compound 174e ........................................... 541 Figure A8.115. 1H NMR (400 MHz, C6D6) of compound 175e .............................................. 542 Figure A8.116. Infrared spectrum (Thin Film, NaCl) of compound 175e ............................... 543 Figure A8.117. 13C NMR (101 MHz, C6D6) of compound 175e ............................................. 543 Figure A8.118. 1H NMR (400 MHz, CDCl3) of compound 174f ............................................ 544 Figure A8.119. Infrared spectrum (Thin Film, NaCl) of compound 174f ................................ 545 Figure A8.120. 13C NMR (101 MHz, CDCl3) of compound 174f ........................................... 545 Figure A8.121. 1H NMR (500 MHz, C6D6) of compound 175f .............................................. 546 Figure A8.122. Infrared spectrum (Thin Film, NaCl) of compound 175f ................................ 547 Figure A8.123. 13C NMR (126 MHz, C6D6) of compound 175f ............................................. 547 Figure A8.124. 1H NMR (500 MHz, CDCl3) of compound 174g ........................................... 548 Figure A8.125. Infrared spectrum (Thin Film, NaCl) of compound 174g ............................... 549 Figure A8.126. 13C NMR (126 MHz, CDCl3) of compound 174g ........................................... 549 Figure A8.127. 1H NMR (500 MHz, C6D6) of compound 175g .............................................. 550 Figure A8.128. Infrared spectrum (Thin Film, NaCl) of compound 175g ............................... 551 Figure A8.129. 13C NMR (126 MHz, C6D6) of compound 175g ............................................. 551 Figure A8.130. 1H NMR (500 MHz, CDCl3) of compound 174h ........................................... 552 Figure A8.131. Infrared spectrum (Thin Film, NaCl) of compound 174h ............................... 553 Figure A8.132. 13C NMR (126 MHz, CDCl3) of compound 174h .......................................... 553 Figure A8.133. 1H NMR (600 MHz, C6D6) of compound 175h ............................................. 554 Figure A8.134. Infrared spectrum (Thin Film, NaCl) of compound 175h ............................... 555 Figure A8.135. 13C NMR (151 MHz, C6D6) of compound 175h ............................................. 555 Figure A8.136. 1H NMR (500 MHz, CDCl3) of compound 174i ............................................ 556 Figure A8.137. Infrared spectrum (Thin Film, NaCl) of compound 174i ................................ 557 Figure A8.138. 13C NMR (126 MHz, CDCl3) of compound 174i ........................................... 557 Figure A8.139. 1H NMR (500 MHz, C6D6) of compound 175i .............................................. 558 Figure A8.140. Infrared spectrum (Thin Film, NaCl) of compound 175i ................................ 559 Figure A8.141. 13C NMR (126 MHz, C6D6) of compound 175i .............................................. 559 Figure A8.142. 1H NMR (400 MHz, CDCl3) of compound 174j ............................................ 560 Figure A8.143. Infrared spectrum (Thin Film, NaCl) of compound 174j ................................ 561 Figure A8.144. 13C NMR (101 MHz, CDCl3) of compound 174j ........................................... 561 Figure A8.145. 1H NMR (500 MHz, C6D6) of compound 175j .............................................. 562 Figure A8.146. Infrared spectrum (Thin Film, NaCl) of compound 175j ................................ 563 Figure A8.147. 13C NMR (101 MHz, C6D6) of compound 175j .............................................. 563 Figure A8.148. 1H NMR (500 MHz, CDCl3) of compound 174k ........................................... 564    xxviii   Figure A8.149. Infrared spectrum (Thin Film, NaCl) of compound 174k ............................... 565 Figure A8.150. 13C NMR (126 MHz, CDCl3) of compound 174k ........................................... 565 Figure A8.151. 1H NMR (500 MHz, CDCl3) of compound 174l ............................................ 566 Figure A8.152. Infrared spectrum (Thin Film, NaCl) of compound 174l ................................ 567 Figure A8.153. 13C NMR (126 MHz, CDCl3) of compound 174l ........................................... 567 Figure A8.154. 1H NMR (500 MHz, CD2Cl2) of compound 175l ........................................... 568 Figure A8.155. Infrared spectrum (Thin Film, NaCl) of compound 175l ................................ 569 Figure A8.156. 13C NMR (126 MHz, CD2Cl2) of compound 175l .......................................... 569 APPENDIX 10 Spectra Relevant to Appendix 9 Figure A10.1. 1H NMR (400 MHz, CDCl3) of compound 192 ................................................ 577 Figure A10.2. Infrared spectrum (Thin Film, NaCl) of compound 192 .................................... 578 Figure A10.3. 13C NMR (101 MHz, CDCl3) of compound 192 ............................................... 578 Figure A10.4. 1H NMR (400 MHz, CD2Cl2) of compound 193 .............................................. 579 Figure A10.5. Infrared spectrum (Thin Film, NaCl) of compound 193 .................................... 580 Figure A10.6. 13C NMR (101 MHz, CD2Cl2) of compound 193 .............................................. 580 Figure A10.7. 1H NMR (500 MHz, CDCl3) of compound 194 ................................................ 581 Figure A10.8. Infrared spectrum (Thin Film, NaCl) of compound 194 .................................... 582 Figure A10.9. 13C NMR (101 MHz, CDCl3) of compound 194 ............................................... 582 APPENDIX 11 Synthetic Studies Toward Alistonitrine A Figure A11.1.1. Structure of Alistonitrine A (195) ................................................................... 583 APPENDIX 12 Spectra Relevant to Appendix 11 Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound 202 ................................................ 613 Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound 202 .................................... 614 Figure A12.3. 13C NMR (126 MHz, CDCl3) of compound 202 ............................................... 614 Figure A12.4. 1H NMR (400 MHz, CD2Cl2) of compound 203 ............................................... 615 Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound 203 .................................... 616 Figure A12.6. 13C NMR (101 MHz, CD2Cl2) of compound 203 .............................................. 616 Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound 204 ................................................ 617 Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound 204. ................................... 618 Figure A12.9. 13C NMR (126 MHz, CDCl3) of compound 204 ............................................... 618    xxix   1 Figure A12.10. H NMR (500 MHz, CD3OD) of compound 205 ............................................ 619 Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound 205 .................................. 620 Figure A12.12. 13C NMR (126 MHz, CD3OD) of compound 205 ........................................... 620 Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound 207 .............................................. 621 Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound 207 .................................. 622 Figure A12.15. 13C NMR (126 MHz, CDCl3) of compound 207 ............................................. 622 Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound 208a ........................................... 623 Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound 208a. ............................... 624 Figure A12.18. 13C NMR (126 MHz, CDCl3) of compound 208a............................................ 624 Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound 208b ........................................... 625 Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound 208b ............................... 626 Figure A12.21. 13C NMR (126 MHz, CDCl3) of compound 208b .......................................... 626 Figure A12.22. 1H NMR (400 MHz, CDCl3) of compound 211 .............................................. 627 Figure A12.23. Infrared spectrum (Thin Film, NaCl) of compound 211 .................................. 628 Figure A12.24. 13C NMR (101 MHz, CDCl3) of compound 211 ............................................. 628 Figure A12.25. 1H NMR (400 MHz, CDCl3) of compound 213 .............................................. 629 Figure A12.26. Infrared spectrum (Thin Film, NaCl) of compound 213 .................................. 630 Figure A12.27. 13C NMR (126 MHz, CDCl3) of compound 213 ............................................. 630 Figure A12.28. 1H NMR (500 MHz, CDCl3) of compound 215a ........................................... 631 Figure A12.29. Infrared spectrum (Thin Film, NaCl) of compound 215a ............................... 632 Figure A12.30. 13C NMR (126 MHz, CDCl3) of compound 215a ........................................... 632 Figure A12.31. 1H NMR (500 MHz, CDCl3) of compound 215b ........................................... 633 Figure A12.32. Infrared spectrum (Thin Film, NaCl) of compound 215b ............................... 634 Figure A12.33. 13C NMR (126 MHz, CDCl3) of compound 215b .......................................... 634 CHAPTER 5 Synthetic Studies Toward Polycyclic Ineleganolide Figure 5.1.1. Structure of Ineleganolide (238) ........................................................................ 635 APPENDIX 13 Spectra Relevant to Chapter 5: Figure A13.1. 1H NMR (400 MHz, CDCl3) of compound 248 ................................................ 680 Figure A13.2. Infrared spectrum (Thin Film, NaCl) of compound 248 .................................... 681 Figure A13.3. 13C NMR (101 MHz, CDCl3) of compound 248 .............................................. 681 Figure A13.4. 1H NMR (400 MHz, CDCl3) of compound 251 ................................................ 682 Figure A13.5. Infrared spectrum (Thin Film, NaCl) of compound 251 .................................... 683 Figure A13.6. 13C NMR (101 MHz, CDCl3) of compound 251 ............................................... 683    xxx   1 Figure A13.7. H NMR (400 MHz, CDCl3) of compound 252 ................................................ 684 Figure A13.8. Infrared spectrum (Thin Film, NaCl) of compound 252 .................................... 685 Figure A13.9. 13C NMR (101 MHz, CDCl3) of compound 252 ............................................... 685 Figure A13.10. 1H NMR (400 MHz, CDCl3) of compound 254 .............................................. 686 Figure A13.11. Infrared spectrum (Thin Film, NaCl) of compound 254 .................................. 687 Figure A13.12. 13C NMR (101 MHz, CDCl3) of compound 254 ............................................. 687 Figure A13.13. 1H NMR (400 MHz, CDCl3) of compound 244b ........................................... 688 Figure A13.14. Infrared spectrum (Thin Film, NaCl) of compound 244b ............................... 689 Figure A13.15. 13C NMR (101 MHz, CDCl3) of compound 244b .......................................... 689 Figure A13.16. 1H NMR (400 MHz, CDCl3) of compound 260 .............................................. 690 Figure A13.17. Infrared spectrum (Thin Film, NaCl) of compound 260 .................................. 691 Figure A13.18. 13C NMR (101 MHz, CDCl3) of compound 260 ............................................. 691 Figure A13.19. 1H NMR (400 MHz, CDCl3) of compound 264 .............................................. 692 Figure A13.20. Infrared spectrum (Thin Film, NaCl) of compound 264 .................................. 693 Figure A13.21. 13C NMR (101 MHz, CDCl3) of compound 264 ............................................. 693 Figure A13.22. 1H NMR (400 MHz, CDCl3) of compound 266 .............................................. 694 Figure A13.23. Infrared spectrum (Thin Film, NaCl) of compound 266 .................................. 695 Figure A13.24. 13C NMR (101 MHz, CDCl3) of compound 266 ............................................. 695 Figure A13.25. 1H NMR (400 MHz, CDCl3) of compound 268 .............................................. 696 Figure A13.26. Infrared spectrum (Thin Film, NaCl) of compound 268 .................................. 697 Figure A13.27. 13C NMR (101 MHz, CDCl3) of compound 268 ............................................. 697 Figure A13.28. 1H NMR (400 MHz, CDCl3) of compound 269 .............................................. 698 Figure A13.29. Infrared spectrum (Thin Film, NaCl) of compound 269 .................................. 699 Figure A13.30. 13C NMR (101 MHz, CDCl3) of compound 269 ............................................. 699 Figure A13.31. 1H NMR (400 MHz, CDCl3) of compound 270 .............................................. 700 Figure A13.32. Infrared spectrum (Thin Film, NaCl) of compound 270 .................................. 701 Figure A13.33. 13C NMR (101 MHz, CDCl3) of compound 270 ............................................. 701 Figure A13.34. 1H NMR (400 MHz, CDCl3) of compound 271a ........................................... 702 Figure A13.35. Infrared spectrum (Thin Film, NaCl) of compound 271a ............................... 703 Figure A13.36. 13C NMR (101 MHz, CDCl3) of compound 271a ........................................... 703 Figure A13.37. 1H NMR (400 MHz, CDCl3) of compound 271b ........................................... 704 Figure A13.38. Infrared spectrum (Thin Film, NaCl) of compound 271b ............................... 705 Figure A13.39. 13C NMR (101 MHz, CDCl3) of compound 271b .......................................... 705 Figure A13.40. 1H NMR (500 MHz, CDCl3) of compound 274 .............................................. 706 Figure A13.41. Infrared spectrum (Thin Film, NaCl) of compound 274 .................................. 707 Figure A13.42. 13C NMR (126 MHz, CDCl3) of compound 274 ............................................. 707 Figure A13.43. 1H NMR (400 MHz, CDCl3) of compound 275 .............................................. 708 Figure A13.44. Infrared spectrum (Thin Film, NaCl) of compound 275 .................................. 709    xxxi   13 Figure A13.45. C NMR (101 MHz, CDCl3) of compound 275 ............................................. 709 Figure A13.46. 1H NMR (400 MHz, CDCl3) of compound 276 .............................................. 710 Figure A13.47. Infrared spectrum (Thin Film, NaCl) of compound 276 .................................. 711 Figure A13.48. 13C NMR (101 MHz, CDCl3) of compound 276 ............................................. 711 Figure A13.49. 1H NMR (400 MHz, CDCl3) of compound 285 .............................................. 712 Figure A13.50. Infrared spectrum (Thin Film, NaCl) of compound 285 .................................. 713 Figure A13.51. 13C NMR (101 MHz, CDCl3) of compound 285 ............................................. 713 Figure A13.52. 1H NMR (400 MHz, CDCl3) of compound 281 .............................................. 714 Figure A13.53. Infrared spectrum (Thin Film, NaCl) of compound 281 .................................. 715 Figure A13.54. 13C NMR (101 MHz, CDCl3) of compound 281 ............................................. 715 Figure A13.55. 1H NMR (500 MHz, CDCl3) of compound 286 .............................................. 716 Figure A13.56. Infrared spectrum (Thin Film, NaCl) of compound 286 .................................. 717 Figure A13.57. 13C NMR (126 MHz, CDCl3) of compound 286 ............................................. 717 Figure A13.58. 1H NMR (400 MHz, CDCl3) of compound 287 .............................................. 718 Figure A13.59. Infrared spectrum (Thin Film, NaCl) of compound 287 .................................. 719 Figure A13.60. 13C NMR (101 MHz, CDCl3) of compound 287 ............................................. 719 Figure A13.61. 1H NMR (400 MHz, CDCl3) of compound 288 .............................................. 720 Figure A13.62. Infrared spectrum (Thin Film, NaCl) of compound 288 .................................. 721 Figure A13.63. 13C NMR (101 MHz, CDCl3) of compound 288 ............................................. 721 Figure A13.64. 1H NMR (500 MHz, CDCl3) of compound 294 .............................................. 722 Figure A13.65. Infrared spectrum (Thin Film, NaCl) of compound 294 .................................. 723 Figure A13.66. 13C NMR (126 MHz, CDCl3) of compound 294 ............................................. 723          xxxii   LIST OF SCHEMES   CHAPTER 1 The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine   Scheme 1.2.1. Biosynthesis-Inspired Approach ........................................................................ 5 Scheme 1.2.2. Model Studies for a Diels–Alder Cycloaddtion Strategy To Construct the Pentacyclic Core Structure   ........................................................................................................ 6 Scheme 1.2.3. Attempted Diels–Alder Cycloadditions with Advanced Electrophiles ................ 6 Scheme 1.2.4. Retrosynthetic Analysis of Communesin F by an Intramolecular Diels–Alder Cycloaddition   ........................................................................................................................... 7 Scheme 1.2.5. Intramolecular Diels–Alder Cycloaddition ......................................................... 8 Scheme 1.2.6. Reaction of Aurantioclavine Derivative 25 with Bromooxindole 26 ................. 11 Scheme 1.2.7. Construction of 3,3-Disubstituted Oxindoles .................................................. 13 Scheme 1.2.8. Construction of C(7)–C(8) Linkage by Alkylation Strategy ................................ 14 Scheme 1.2.9. Alkylation of Azepine Bromooxindole 40 with Malonate 41 ............................ 15 Scheme 1.2.10. Alkylation of 3-Bromooxindole 43 ................................................................. 16 Scheme 1.2.11. Model Studies for Construction of the Vicinal Quaternary Centers ................. 17 Scheme 1.2.12. Retrosynthesis of Communesin F (1f) .............................................................. 19 Scheme 1.2.13. Development of the Vicinal Quaternary Center ............................................ 20 Scheme 1.2.14. Ozonolysis and Reductive Amination of Lactone 62 ...................................... 21 Scheme 1.2.15. Synthesis of Lactam 54 .................................................................................. 22 Scheme 1.2.16. Reductive Cyclization of Lactam 54 with AlH3-Me2NEt ................................ 23 Scheme 1.2.17. Attempted Reductive Cyclization of Lactam 54.............................................. 25 Scheme 1.2.18. Synthesis of Aminal 81 .................................................................................. 27 Scheme 1.2.19. Completion of Formal Synthesis of Communesin F ........................................ 28 Scheme 1.2.20. Retrosynthesis of Perophoramidine (3) ............................................................ 29 Scheme 1.2.21. Synthesis of Amide 89 ................................................................................... 30 Scheme 1.2.22. Formation of Azepine 91 using Tf2O .............................................................. 31 Scheme 1.2.23. Completion of Formal Synthesis of Perophoramidine .................................... 32 APPENDIX 3 Synthetic Studies Toward the Total Synthesis of Communesin F      xxxiii   Scheme A3.1.1. Direct Lactam Forming Strategy Toward Communesin F (1f) ...................... 304 Scheme A3.1.2. Attempted Lactam Forming Reactions ........................................................ 305 Scheme A3.2.1. Diels–Alder Strategy Toward Communesin F (1f) ......................................... 306 Scheme A3.2.2. Intramolecular Diels–Alder Reactions.......................................................... 307 Scheme A3.2.3. Intermolecular Diels–Alder Reactions ......................................................... 308 Scheme A3.3.1. Intramolecular Alkylation Strategy .............................................................. 309 Scheme A3.3.2. Intramolecular Alkylation of 3-Bromooxindole ............................................ 310 APPENDIX 4 Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Scheme A4.1.1. Construction of 3,3-Disubstituted Oxindoles by Alkylation of 3-Halooxindoles .............................................................................................................................................. 319 Scheme A4.1.2. Attempts for Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters .............................................................................................................................................. 320 Scheme A4.2.1. Synthesis of the Racemic Product ................................................................. 321 CHAPTER 2 A New Method for the Cleavage of Nitrobenzyl Amides and Ethers Scheme 2.2.1. o-Nitrobenzyl group cleavage on perophoramidine intermediate (88) ............ 335   CHAPTER 3 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution   Scheme 3.2.1. Applications .................................................................................................. 366 CHAPTER 4 Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   Scheme 4.2.1. Ni-Catalyzed C–O Bond Formation ................................................................ 421 APPENDIX 9 Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement    xxxiv   Scheme A9.1.1. Ni-Catalyzed C–O Bond Formation and subsequent Claisen Rearrangement 571 APPENDIX 11 Synthetic Studies Toward Alistonitrine A Scheme A11.2.1. Retrosynthetic Analysis of Alistonitrine A (195) ......................................... 584 Scheme A11.2.2. Synthesis of Chiral Amine 205.................................................................... 585 Scheme A11.2.3. Synthesis of α,β-Unsaturated Lactams 208 ................................................. 586 Scheme A11.2.4. Synthesis of α-Substituted α,β-Unsaturated Lactam 199 ............................. 587 Scheme A11.2.5. Synthesis of oxindole Fragment 217 ........................................................... 587 Scheme A11.2.6. Attempted Coupling of malonate 217 and amide 199 ................................ 588 Scheme A11.2.7. A Revised Retrosynthesis Toward Alistonitrine A ........................................ 588 Scheme A11.2.8. Synthesis of Bicycle 226 ............................................................................. 589 CHAPTER 5 Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.1.1. Proposed Biosynthesis of Ineleganolide (238) ................................................ 636 Scheme 5.2.1. Retrosynthesis of Ineleganolide (238) ............................................................. 637 Scheme 5.2.2. Synthesis of (Z)-Selective Enoate 248 ............................................................. 638 Scheme 5.2.3. Synthesis of α-Bromoketone 244b ................................................................. 639 Scheme 5.2.4. Attempts to Synthesize Bicyclic Fragment via Diazo Compounds .................. 641 Scheme 5.2.5. Attempted Williamson Etherifications ............................................................ 642 Scheme 5.2.6. Synthesis Epoxides 271a and 271b ................................................................ 643 Scheme 5.2.7. Formation of Bicyclic Fragment ..................................................................... 644 Scheme 5.2.8. Coupling of the Fragments ............................................................................. 645 Scheme 5.2.9. Synthetic Plan by Using Metathesis Strategies ................................................ 645 Scheme 5.2.10. Coupling of the Fragments by Esterification ................................................ 647 Scheme 5.2.11. Intermolecular Metathesis ............................................................................ 648 Scheme 5.2.12. Alkyne Addition........................................................................................... 649      xxxv   LIST OF TABLES   APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1   Table A2.1.1. Crystal Data and Structure Analysis Details for 24........................................... 212 4 Table A2.1.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 24..................................................................................................................... 214 Table A2.1.3. Bond lengths [Å] and angles [°] for 24 ........................................................... 215 2 4 Table A2.1.4. Anisotropic displacement parameters (Å x 10 ) for 24 ................................ 218 3 2 3 Table A2.1.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 24 ..................................................................................................................................... 218 Table A2.1.6. Hydrogen bonds for 24 [Å and °] ................................................................... 219 Table A2.2.1. Crystal data and structure refinement for 37 .................................................... 220 Table A2.2.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 37..................................................................................................................... 222 Table A2.2.3. Bond lengths [Å] and angles [°] for 37 ........................................................... 223 Table A2.2.4. Hydrogen bonds for 37 [Å and °] .................................................................... 227 Table A2.3.1. Crystal data and structure refinement for 42 .................................................... 228 Table A2.3.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 42..................................................................................................................... 230 Table A2.3.3. Bond lengths [Å] and angles [°] for 42 ........................................................... 230 Table A2.3.4. Anisotropic displacement parameters (Å2x 104 ) for 42 ................................ 232 Table A2.3.5. Hydrogen bonds for 42 [Å and °] ................................................................... 233 Table A2.4.1. Crystal Data and Structure Analysis Details for 51........................................... 234 4 Table A2.4.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 51..................................................................................................................... 236 Table A2.4.3. Bond lengths [Å] and angles [°] for 51 ........................................................... 237 2 4 Table A2.4.4. Anisotropic displacement parameters (Å x 10 ) for 51 ................................ 239 3 2 3 Table A2.4.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 51 ..................................................................................................................................... 240 Table A2.4.6. Hydrogen bonds for 51 [Å and °] ................................................................... 240 Table A2.5.1. Crystal Data and Structure Analysis Details for 52........................................... 242 4 Table A2.5.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters    xxxvi   2 3 (Å x 10 ) for 52..................................................................................................................... 244 Table A2.5.3. Bond lengths [Å] and angles [°] for 52 ........................................................... 245 2 4 Table A2.5.4. Anisotropic displacement parameters (Å x 10 ) for 52 ................................ 249 3 2 3 Table A2.5.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 52 ..................................................................................................................................... 250 Table A2.5.6. Hydrogen bonds for 52 [Å and °] ................................................................... 251 Table A2.6.1. Crystal Data and Structure Analysis Details for 61........................................... 252 4 Table A2.6.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 61..................................................................................................................... 254 Table A2.6.3. Bond lengths [Å] and angles [°] for 61 ........................................................... 255 2 4 Table A2.6.4. Anisotropic displacement parameters (Å x 10 ) for 61 ................................ 258 3 2 3 Table A2.6.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 61 ..................................................................................................................................... 258 Table A2.6.6. Hydrogen bonds for 61 [Å and °] ................................................................... 259 Table A2.7.1. Crystal data and structure refinement for 62 .................................................... 260 Table A2.7.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 62..................................................................................................................... 262 Table A2.7.3. Bond lengths [Å] and angles [°] for 62 ........................................................... 262 Table A2.7.4. Anisotropic displacement parameters (Å2x 104) for 62 .................................. 264 Table A2.8.1. Crystal Data and Structure Analysis Details for 72........................................... 265 4 Table A2.8.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 72..................................................................................................................... 267 Table A2.8.3. Bond lengths [Å] and angles [°] for 72 ........................................................... 267 2 4 Table A2.8.4. Anisotropic displacement parameters (Å x 10 ) for 72 ................................ 270 3 2 3 Table A2.8.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 72 ..................................................................................................................................... 271 Table A2.9.1. Crystal Data and Structure Analysis Details for 73........................................... 273 4 Table A2.9.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 73..................................................................................................................... 275 Table A2.9.3. Bond lengths [Å] and angles [°] for 73 .......................................................... 276 2 4 Table A2.9.4. Anisotropic displacement parameters (Å x 10 ) for 73 ................................ 281 3 2 3 Table A2.9.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 73 ..................................................................................................................................... 282 Table A2.9.6. Hydrogen bonds for 73 [Å and °] ................................................................... 283    xxxvii   Table A2.10.1. Crystal data and structure analysis details for 77 ........................................... 284 4 Table A2.10.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 77..................................................................................................................... 286 Table A2.10.3. Bond lengths [Å] and angles [°] for 77 ........................................................ 287 2 4 Table A2.10.4. Anisotropic displacement parameters (Å x 10 ) for 77 .............................. 293 3 2 Table A2.10.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 3 10 ) for 77 ............................................................................................................................. 295 Table A2.10.6. Hydrogen bonds for 77 [Å and °] ................................................................. 296 Table A2.11.1. Crystal data and structure refinement for 94 .................................................. 297 Table A2.11.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 94..................................................................................................................... 299 Table A2.11.3. Bond lengths [Å] and angles [°] for 94 ........................................................ 300 Table A2.11.4. Anisotropic displacement parameters (Å2x 104 ) for 94 .............................. 302 APPENDIX 4 Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Table A4.2.1. Further investigations using WALPHOS and DiazaPHOS in the alkylation reaction .............................................................................................................................................. 323 Table A4.2.2. Investigation of reaction solvents and bases with WALPHOS in the alkylation reaction ................................................................................................................................. 324 Table A4.2.3. Examination of the amount of catalyst and ligand loading in the alkylation reaction ................................................................................................................................. 325 Table A4.2.4. Examination of concentration in the malonate addition reaction ...................... 325 Table A4.2.5. The effect of WALPHOS substituents under optimized condition in the alkylation reaction ................................................................................................................................. 326   CHAPTER 2 A New Method for the Cleavage of Nitrobenzyl Amides and Ethers Table 2.2.1. Cleavage of nitrobenzyl groups on 3,3-dimethyloxindole ................................... 336 Table 2.2.2. Scope of the o- and p-nitrobenzyl deprotecion reactions .................................... 338   CHAPTER 3 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution    xxxviii     Table 3.2.1. Scope of dynamic kinetic resolution under initial standard conditions................ 363 Table 3.2.2. Optimization of reaction parameters .................................................................. 364 Table 3.2.3. Scope of dynamic kinetic resolution under optimized conditions ....................... 365   CHAPTER 4 Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   Table 4.2.1. Optimization of reaction parameters .................................................................. 422 Table 4.2.2. Intramolecular cross-coupling of amino-cyclohexanols ...................................... 423 Table 4.2.3. Intramolecular cross-coupling of linear aminoalcohols....................................... 424 Table 4.2.4. Synthesis of substituted tetrahydrofuran and dihydropyran rings ......................... 426   APPENDIX 14 Notebook Cross-Reference for New Compounds Table A14.1. Notebook cross-reference for compounds in Chapter 1.................................... 725 Table A14.2. Notebook cross-reference for compounds in Appendix 3 ................................. 731 Table A14.3. Notebook cross-reference for compounds in Appendix 4 ................................. 732 Table A14.4. Notebook cross-reference for compounds in Chapter 2.................................... 732 Table A14.5. Notebook cross-reference for compounds in Chapter 3.................................... 733 Table A14.6. Notebook cross-reference for compounds in Chapter 4.................................... 735 Table A14.7. Notebook cross-reference for compounds in Appendix 9 ................................. 739 Table A14.8. Notebook cross-reference for compounds in Appendix 11 ............................... 739 Table A14.9. Notebook cross-reference for compounds in Chapter 5.................................... 741                xxxix   LIST OF ABBREVIATIONS   Å   Ångstrom   λ     wavelength   µ   micro   µwaves microwave  irradiation [α]D   specific  rotation  at  wavelength  of  sodium  D  line   [H]   reduction   [O]     oxidation   °C     degrees  Celsius   Ac     acetyl   acac   acetylacetonate   AcOH   acetic  acid   APCI atmospheric  pressure  chemical  ionization app     apparent   aq   aqueous   Ar   aryl   atm     atmosphere   B3LYP   3-­‐parameter  hybrid  Becke  exchange/   Lee–Yang–Parr  correlation  functional   Bn     benzyl   Boc     tert-­‐butyloxycarbonyl   BOP   Bis(2-­‐oxo-­‐3-­‐oxazolidinyl)phospinic   bp   boiling  point   br     broad   Bu     butyl   Bz benzoyl c     concentration  for  specific  rotation  measurements      xl   ca. about  (Latin  circa) calc’d     calculated   CAN   cerium  ammonium  nitrate   cat   catalytic   CCDC     Cambridge  Crystallographic  Data  Centre   CDI     1,1'-­‐carbonyldiimidazole     cf. compare  (Latin  confer) CI     chemical  ionization   cm–1 wavenumber(s) cod   1,5-­‐cyclooctadiene   comp   complex   Cp   cyclopentadienyl   Cy     cyclohexyl   d     doublet   D deuterium DABCO   1,4-­‐diazabicyclo[2,2,2]octane   dba     dibenzylideneacetone   DBU     1,8-­‐diazabicyclo[5.4.0]undec-­‐7-­‐ene   DCC   N,N’-­‐dicyclohexylcarbodiimide   DCE   1,2-­‐dichloroethane   DDQ   2,3-­‐dichloro-­‐5,6-­‐dicyano-­‐p-­‐benzoquinone   DEAD   diethyl  azodicarboxylate   dec   decomposition   DFT   density  functional  theory   DIBAL   diisobutylaluminum  hydride   DIPEA   N,N-­‐diisopropylethylamine   DKR   dynamic  kinetic  resolution   DMA   N,N-­‐dimethylacetamide   DMAD   dimethyl  acetylenedicarboxylate      xli   DMAP     4-­‐dimethylaminopyridine   dmdba bis(3,5-­‐dimethoxybenzylidene)acetone DMDO   dimethyldioxirane   DME   1,2-­‐dimethoxyethane   DMF     N,N-­‐dimethylformamide   DMP   Dess–Martin  periodinane   DMS   dimethyl  sulfide   DMSO     dimethyl  sulfoxide   dr   diastereomeric  ratio   e.g. for  example  (Latin  exempli  gratia) EA   activation  energy   EC50     median  effective  concentration  (50%)   EDC   N-­‐(3-­‐dimethylaminopropyl)-­‐N'-­‐ethylcarbodiimide   ee     enantiomeric  excess   EI+   electron  impact   equiv     equivalent   ESI     electrospray  ionization   Et     ethyl   EtOAc   ethyl  acetate   FAB     fast  atom  bombardment   FID flame  ionization  detector g     gram(s)   GC   gas  chromatography   gCOSY     gradient-­‐selected  correlation  spectroscopy   h     hour(s)   hν   light   HBPin   HFIP   4,4,5,5-­‐tetramethyl-­‐1,3,2-­‐dioxaborolane;   pinacolborane   1,1,1,3,3,3-­‐hexafluoro-­‐2-­‐propanol      xlii   HMDS   1,1,1,3,3,3-­‐hexamethyldisilazane   HMPA hexamethylphosphoramide HOBt   hydroxybenzotriazole   HPLC     high-­‐performance  liquid  chromatography   HRMS   high-­‐resolution  mass  spectroscopy   Hz     hertz   i.e. that  is  (Latin  id  est) IBX   2-­‐iodoxybenzoic  acid   IC50     median  inhibition  concentration  (50%)   IMDA   Intramolecular  Diels–Alder  reaction   IPA   isopropanol,  2-­‐propanol   i-­‐Pr   isopropyl   IR     infrared  (spectroscopy)   IRC   intrinsic  reaction  coordinate   J     coupling  constant   K   Kelvin(s)  (absolute  temperature)   kcal kilocalorie KHMDS potassium  hexamethyldisilazide L     liter;  ligand   LAH   lithium  aluminum  hydride   LDA lithium  diisopropylamide LHMDS   lithium  bis(trimethylsilyl)amide   lit. literature  value m     multiplet;  milli   m     meta   M   metal;  molar;  molecular  ion   m/z     mass  to  charge  ratio   m-­‐CPBA   meta-­‐chloroperoxybenzoic  acid   Me     methyl      xliii   mg   milligram(s)   MHz     megahertz   min     minute(s)   MM mixed  method MMPP   magnesium  monoperoxyphthalate   mol     mole(s)   MOM methoxymethyl mp     melting  point   Ms     methanesulfonyl  (mesyl)   MS     molecular  sieves   MVK   methyl  vinyl  ketone   n   nano   N   normal   nbd     norbornadiene   NBS     N-­‐bromosuccinimide   n-­‐Bu   butyl   NHC   N-­‐heterocyclic  carbene   NMO     N-­‐methylmorpholine  N-­‐oxide   NMR     nuclear  magnetic  resonance   NOE     nuclear  Overhauser  effect   NOESY     nuclear  Overhauser  enhancement  spectroscopy   Nosyl   nitrobenzenesulfonyl   Nu   nucleophile   o     ortho   OKR   oxidative  kinetic  resolution   p     para   PCC pyridinium  chlorochromate Pd/C   palladium  on  carbon   PDC     pyridinium  dichromate      xliv   Ph     phenyl   pH     hydrogen  ion  concentration  in  aqueous  solution   PHOX phosphinooxazoline  ligand Piv pivaloyl pKa pK  for  association  of  an  acid PMB   p-­‐methoxybenzyl   pmdba bis(4-­‐methoxybenzylidene)acetone ppm     parts  per  million   PPTS   pyridinium  p-­‐toluenesulfonate   Pr     propyl   PTU   n-­‐Propylthiouracil   Py     pyridine   q     quartet   R   generic  for  any  atom  or  functional  group   Ref.   reference   Rf     retention  factor   s     singlet  or  strong  or  selectivity  factor   sat.   saturated   Selectfluor   1-­‐chloromethyl-­‐4-­‐fluoro-­‐1,4-­‐ diazoniabicyclo[2.2.2]octane  bis(tetrafluoroborate)   SEM   2-­‐(trimethylsilyl)ethoxymethyl   SFC   supercritical  fluid  chromatography   SN 2 second-­‐order  nucleophilic  substitution SN2'   nucleophilic  substitution  with  allylic   rearrangement   sp   sparteine   sp.   species   t     triplet   TBAF     tetrabutylammonium  fluoride        xlv   TBAI   tetrabutylammonium  iodide   TBAT   tetrabutylammonium  difluorotriphenylsilicate   TBDPS   tert-­‐butyldiphenylsilyl   TBHP   tert-­‐butyl  hydroperoxide   TBME   tert-­‐butyl  methyl  ether   TBS     tert-­‐butyldimethylsilyl   t-­‐Bu   tert-­‐butyl   TES   triethylsilyl   Tf     trifluoromethanesulfonyl  (triflyl)   TFA     trifluoroacetic  acid   TFAA   trifluoroacetic  anhydride   TFE   2,2,2-­‐trifluoroethanol   THF     tetrahydrofuran   TIPS     triisopropylsilyl   TLC     thin-­‐layer  chromatography   TMEDA N,N,N’,N’-­‐tetramethylethylenediamine TMS     trimethylsilyl   TOF time-­‐of-­‐flight Tol tolyl tR   retention  time   Ts     p-­‐toluenesulfonyl  (tosyl)   UV     ultraviolet   v/v   volume  to  volume   VO(acac)2   vanadyl  acetoacetonate   w     weak   w/v   weight  to  volume   X   anionic  ligand  or  halide        Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 1 CHAPTER 1 The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine† 1.1. Introduction In 1993, communesin A (1a) was isolated along with communesin B (1b) from a strain of Penicillium sp. found growing on a marine alga by the Numata group (Figure 1.1.1).1 Communesins A (1a) and B (1b) exhibit antiproliferative activity against P-388 lymphocytic leukemia cells (ED50 = 3.5 µg/mL and 0.45 µg/mL, respectively).1 In addition, communesin B (1b) disrupts actin microfilaments in cultured mammalian cells and shows cytotoxic activity against LoVo and KB cells (MIC values of 2.0 µg/mL and 4.5 µg/mL, respectively). 2 Several other members of the comunesin family, communesins B–H (1b–1h), were disclosed from related marine fungal strains of                                                                                                                 †   This work was performed in collaboration with Dr. Florian Vogt, Dr. Jeremy A. May, Dr. Shyam Krishnan, Dr. Michele Gatti, and Dr. Scott C. Virgil. Additionally, this work has been published and adapted with permission from Han, S.-J.; Vogt, F.; May, J. A.; Krishnan, S.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. J. Org. Chem. 2015, 80, 528–547. Copyright 2015 American Chemical Society. Related work has been published and adapted with permission from Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. Copyright 2014 American Chemical Society. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 2 3 Penicillium sp. in the following years. With the exception of communesins G (1g) and H (1h), the communesins show insecticidal activity and antiproliferative activity against a variety of cancer cells, with communesin B (1b) being the most potent. 1–3 These indole alkaloids contain several interesting structural features including vicinal all-carbon quaternary centers, bis-aminal functionalities, and a complex polycyclic core. The communesins are structurally unique when compared against other known microfilamentdisrupting agents, which are primarily macrolides. Macrolide microfilament-disrupting agents show considerable structural similarity, and their interactions with actin have been crystallographically characterized, leading to hypotheses regarding their mechanism of action.4 The unique structure of communesin B (1b) suggests that it may exhibit a novel mechanism of action on the cytoskeleton relative to other microfilament-disrupting agents.5a The development of a unified synthetic route to the communesins would enable the understanding of their effects on the cellular cytoskeleton, while addressing the scarcity of naturally occurring sources of the compounds. In 2001, an intriguing natural product, nomofungin (2) was isolated from an unidentified fungus found on the bark of Ficus microcarpa by the Hemscheidt group.2 Interestingly, the only structural difference between communesin B (1b) and nomofungin (2) is that communesin B has an aminal moiety instead of the N,O-acetal moiety present in nomofungin. A combination of experimental and theoretical exercises led to the independent discovery by our laboratory and the Funk group that the reported structure of nomofungin was incorrect, and that it is actually that of communesin B.5a,b Although the structure of nomofungin was erroneously assigned, its isolation and structural revision to that of an older structure can be viewed as the inception point for all synthetic efforts to Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 3 the communesin family members over the past decade. Interestingly, there were no reports of synthetic efforts toward the communesins from 1993 up to our initial report in 2003.5i A structurally related compound, perophoramidine (3), was isolated in 2002 from the ascidian Perophora namei. 6 The core is comparable to the one found in the communesins, albeit in a higher oxidation state, with the alternate diastereomeric relationship between the vicinal quaternary carbons and without the azepine ring system. Perophoramidine (3) possesses modest cytotoxicity against the HCT 116 human colon carcinoma cell line (IC50 = 60 µM) and induces apoptosis.7 Figure 1.1.1. Communesins (1), Nomofungin (2), and Perophoramidine (3) O O R' N O 21 H N N H N 9 11 8 12a 6 7 N H N N H H N H R Communesin R R' A (1a) B (1b) C (1c) D (1d) E (1e) G (1g) H (1h) CH3 CH3 CH3 pentadienyl H CHO H CH3 CH3 pentadienyl pentadienyl CH3 CH2CH3 CH2CH2CH3 Communesin F (1f) O 22 N O H N Cl 4 19 N H Nomofungin (2) (Original Structure) 1 6 20 17 O N 24 N 15 Cl N 12 N 8 H Perophoramidine (3) Br Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 4 These complex, polycyclic, bioactive alkaloids have been the subject of intense synthetic efforts over the past decade.5 Numerous approaches have been reported in the literature, including three from our laboratory.5a,5c,5w Herein, we report the evolution of an efficient, unified approach toward the synthesis of these unique alkaloids. 1.2. Results and Discussion 1.2.1. Biosynthesis-Inspired Diels–Alder Cycloaddition Strategy to Communesin F Our early efforts toward the communesin structure centered on the laboratory implementation of our proposed biosynthesis (Scheme 1.2.1).5a,c,8 As the key step in the process, we envisioned a Diels–Alder cycloaddition to unite the two indole-based fragments by coupling of 5, an N-methylated derivative of the ergot alkaloid aurantioclavine (4)9,10 and an o-azaxylylene indolone 6 to generate the bridged lactam 7. We anticipated that lactam 7 would be highly reactive due to the poor alignment of the nitrogen lone pair with the carbonyl.11,12,13 As such, the pendant amino group would be expected to easily open the lactam, thus forming spirocycle 8. Further tailoring would produce communesin A (1a) and B (1b). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 5 Scheme 1.2.1. Biosynthesis-Inspired Approach H 2N H H N H 2N NH + N O N N N R 4, R = H (Aurantioclavine) 5, R = Me Me 6 O 7 O R H HN H N O N O H N NH N Me 8 NH N H Me Communesin A (1a) and B (1b) Toward this end, (±)-aurantioclavine was prepared using known methods5a,14 and an enantioselective synthesis of (–)-aurantioclavine utilizing our oxidative kinetic resolution (OKR) technology was developed.15 We proceeded to develop an efficient cycloaddition between (±)-indole 9 as a model coupling partner and chlorotoluamide 10 using conditions previously developed by Steinhagen and Corey16 that resulted in a mixture of pentacyclic diastereomers (89% yield). Removal of the tosyl group with magnesium in methanol produced a 2:1 mixture of diastereomers 11 and 12 in 80% combined yield, with the desired relative stereochemistry evident in the major diastereomer (cf. 11 and 1a) (Scheme 1.2.2).5a Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 6 Scheme 1.2.2. Model Studies for a Diels–Alder Cycloaddtion Strategy To Construct the Pentacyclic Core Structure Boc H N 8 8 Cl 1. Boc N NH HN 10 Ts Cs2CO3, CH2Cl2, –78 °C (89% yield) N H 11 + N Boc H N 2. Mg, NH 4Cl, MeOH (80% yield) 8 (11 :12 = 2:1) 9 NH N H 12 Despite the success of this model system, more advanced electrophiles (e.g., mesylate 14, cyclopropane 16, or epoxide 17 17 ) did not succumb to cycloaddition conditions (Scheme 1.2.3). Nor have we been successful in the oxidation of 11 and 12 at C(8), which would provide a functional handle for introduction of the second quaternary stereocenter. Scheme 1.2.3. Attempted Diels–Alder Cycloadditions with Advanced Electrophiles OH MOMO OMs 9, MsCl, Cs2CO3 8 MOMO CH2Cl2, –78 °C TsHN TsHN 13 14 OMOM H Boc N MeO 2C 8 N N H Ts 15 (Not Observed) O O O N H N H 16 17 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 7 To obviate the difficulties encountered in our attempts to functionalize C(8), we next considered dienes possessing a functional handle at C(8) that could unite diene and dienophile, such as benzisoxazole 19, thereby enabling an intramolecular Diels–Alder cycloaddition (Scheme 1.2.4). Thus, when coupled to aurantioclavine 4, benzisoxazole 20 would offer a stable o-methide imine that could react with the indole moiety of compound 19 in a controlled and intramolecular manner. Scheme 1.2.4. Retrosynthetic Analysis of Communesin F by an Intramolecular Diels–Alder Cycloaddition O O HeteroDiels-Alder Reaction H N N 8 H N O NH N N H H N 18 Communesin F (1f) N H N O O H N O HO Acylation + O N H N 19 4 N 20 Fischer esterification of commercially available carboxylic acid 21, followed by heating in neat sulfuric acid provided the benzisoxazole acid 20 in 44% yield over 2 steps (Scheme 1.2.5).18 Treatment of benzisoxazole acid 20 with oxalyl chloride provided the corresponding acid chloride, which was smoothly coupled with aurantioclavine 4 to furnish carboxamide 22 (91% yield, 2 steps). Similarly, 1-methylaurantioclavine 5 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 8 reacted with the acid chloride to afford carboxamide 19 (77% yield, 2 steps). Substrates 22 and 19 were subjected to an intramolecular Diels–Alder cycloaddition under acidic conditions.19 Unfortunately, the benzisoxazole reacted with the butenyl side chain of the aurantioclavine core to generate the bridged polycycles 23 and 24. Nuclear Overhauser Effect NMR spectroscopy (NOESY) studies and X-ray analysis (Figure 1.2.1) demonstrated the relative stereochemistry shown for 24 and that of 23 was assigned by analogy. Scheme 1.2.5. Intramolecular Diels–Alder Cycloaddition 1. EtOH, cat. H 2SO4 PhMe, reflux HO 2C 2. H 2SO4, 110 °C (44% yield, 2 steps ) O2N 21 O HO 1. (COCl)2 CH2Cl2, DMF, 23 °C O 2. 4 or 5, Et 3N CH2Cl2, 23 °C N 20 N O O O HCl, MeOH N 0 → 23 °C N O N H H N N R R 22, R = H (91% yield, 2 steps) 19, R = Me (77% yield, 2 steps) 23, R = H (31% yield) 24, R = Me (99% yield) (X-ray) Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 9 Figure 1.2.1. X-ray Structure of Bridged Polycycle 24 O N O N H H ≡ N 24 24 At this point, we turned our attention to synthesizing 3-bromooxindole 26, which would be a precursor to an o-methide imine such as reactive intermediate 6, allowing for the construction of the communesin core according to our original biosynthesis-inspired model (Scheme 1.2.1). Aurantioclavine derivative 25 was reacted with bromooxindole 26 in an effort to produce adduct 27 (Scheme 1.2.6a). Interestingly, different reactivity was observed in coordinating and non-coordinating solvents. In THF or acetonitrile, the reaction afforded indole 28 in 69% yield, wherein the oxindole was introduced to position C(2) of the indole nucleus, presumably via rearrangement of the initially formed adduct 27 at C(3) (Scheme 1.2.6b). Sulfonylation of indole 28 with o-NsCl under basic conditions was accompanied by unexpected chlorination of the indole moiety to afford chloroindoline 29 (73% yield), the structure of which was unambiguously confirmed by X-ray crystallography (Figure 1.2.2). To the best of our knowledge, this constitutes the first use of o-NsCl for chlorination of an indole to provide the 3-chloroindolenine. On the other hand, the same coupling of derivatives 25 and 26 in benzene or dichloromethane furnished indole 28 (24% yield), and two additional undesired products 30 (32% yield) and 31 (24% yield) (Scheme 1.2.6c). Adduct 30 results from nucleophilic Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 10 attack at C(6) of the aurantioclavine indole core, while double adduct 31 is produced from both C(6) and C(2) functionalization. The structure of 30 was unambiguously determined following preparation of lactam 32 (Scheme 1.2.6d). Subjecting 30 to excess sodium hydride and o-NsCl conditions functionalized both the oxindole and indole nitrogens (66% yield) and subsequent reduction of the azide allowed for cyclization to lactam 32 in 66% yield. The structure of 32 was confirmed by single crystal X-ray diffraction (Figure 1.2.3). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 11 Scheme 1.2.6. Reaction of Aurantioclavine Derivative 25 with Bromooxindole 26 (a) O O N3 F 3C N F 3C N Br + Cs2CO3 O N H N H 25 NH solvents O N N3 27 (Not Observed) 26 (b) O O F 3C F 3C 26 N H N Cs2CO3 NH THF 23 °C (69% yield) N H 3 O N N3 25 27 O O F 3C F 3C H N H N N3 o-NsCl, NaH 2 N H N3 Cl THF, 0 °C (73% yield) NH N N O o-Ns O 29 (X-ray) 28 (c) O F 3C N3 N Cs2CO3 Br CH2Cl2 23 °C O + N H N H 25 (28: 24% yield, 30: 32% yield, 31: 24% yield) 26 O O F 3C F 3C H N H N N3 N3 N3 28 + + 6 N N 6 H N N O H 2 N H H O O H 31 30 (d) O O F 3C F 3C H N 1. o-NsCl, NaH THF, 0 °C (66% yield) N3 N H N H N HN 2. PPh 3, 50 °C H 2O/THF (1:4) O (66% yield) NsHN O H 30 32 (X-ray) N o-Ns Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 12 Figure 1.2.2. X-ray Structure of Chloroindoline 29 O F 3C H N N3 Cl ≡ N N o-Ns O 29 29 Figure 1.2.3. X-ray Structure of Lactam 32 O F 3C H N ≡ HN N O NsHN o-Ns 32 1.2.2. 32 An Alkylation Route to Communesin F Discouraged by the unsuccessful Diels–Alder cycloaddition-based approaches to communesin F (1f), we considered an alternative strategy toward the natural product. In 2007, as a direct result of our efforts toward the communesins and perophoramidine, we developed a method to generate 3,3-disubstituted oxindoles via the base-mediated coupling of oxindole electrophiles with malonate derived nuclophiles. (Scheme 1.2.7a).20 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 13 We also developed an asymmetric variant of this reaction utilizing copper bis(oxazoline) complexes (Scheme 1.2.7b).21 With the method shown in Scheme 1.2.7, we devised a new synthetic strategy that cast our coupling fragments in an umpolung manner, invoking an electrophilic aurantioclavine portion and a nucleophilic right hand fragment. We first pursued this notion in the context of the model azepine 35 (Scheme 1.2.8). Treatment of 35 with DBU and a pronucleophile (e.g., 3622 and 38) produced oxindole adducts (i.e., 37 and 39) possessing the key C(7)–C(8) linkage in modest but encouraging yields. Importantly, adduct 37 was crystalline, and we confirmed both the new C–C bond as well as the relative stereochemistry of the sole diastereomeric isolate via X-ray analysis. Scheme 1.2.7. Construction of 3,3-Disubstituted Oxindoles (a) X R 2O2C R1 CO2R 2 CO2R 2 R 2O2C R1 DBU O O THF, –78 → 23 °C N H N H R 2 = Me, Et, Bn 33 (±)-34 (47-87% yield) X = Br, Cl R 1 = alkyl, aryl 2+ (b) O O N X R1 Ph Cu N 2SbF6 Ph - (20 mol%) CO2R 2 R 2O2C R1 O N H 33 X = Br, Cl R 1 = alkyl, aryl R 2O2C CO2R 2 i-Pr2NEt or NEt 3 3Å molecular sieves CH2Cl2 R 2 = Me, Et, Bn O N H 34 (42-84% yield, 74-94% ee) Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 14 Scheme 1.2.8. Construction of C(7)–C(8) Linkage by Alkylation Strategy (a) Ts Ts NC N N O2N Br 8 DBU O 7 O N O2N H THF –78 → 23 °C (64% yield) N H 35 CN 36 37 (X-ray) Ts N CN ≡ O N O2N H 37 37 (b) Ts Ts N N MeO 2C Br O NO 2 + N H 35 CO2Me CO2Me CO2Me 38 DBU 8 7 THF –78 → 23 °C (32% yield) O N O N H 2 39 Having produced the key C(7)–C(8) linkage via an umpolung strategy, we treated aurantioclavine-derived bromooxindole 40 with malonate 41 in the presence of DBU (Scheme 1.2.9). Smooth reactivity under our standard conditions led to the isolation of a single stereoisomeric adduct 42 in 74% yield. To our delight, oxindole adduct 42 was amenable to single crystal X-ray diffraction, however, the X-ray analysis surprisingly revealed that the alkylation occurs with high syn selectivity relative to the existing isobutenyl substituent (Figure 1.2.4). This result was intriguing, given that in the Diels– Alder cycloaddition of the corresponding indole 9 with the o-azaxylylene derived from chlorotoluamide 10, the selectivity at C(7) favored the anti diastereomer 11 (cf. Schemes 1.2.9. and 1.2.2).23 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 15 Scheme 1.2.9. Alkylation of Azepine Bromooxindole 40 with Malonate 41 CO2Me Ts 41 N CO2Me N H 40 CO2Me DBU Br O Ts H N 7 THF –78 → 23 °C (>20:1 dr) (74% yield) CO2Me O N H 42 (X-ray) Figure 1.2.4. X-ray Structure of Oxindole Adduct 42 Ts H N CO2Me CO2Me O ≡ N H 42 42 Since the undesired relative stereochemistry was obtained in adduct 42 from the alkylation of azepine 40 and malonate 41, we explored our strategy in a model system lacking the azepine ring of the oxindole (Scheme 1.2.10). Known silyl ether 4321,22 was converted into malonate adducts 46 and 47 in 85% and 96% yield, respectively, under our previously reported conditions in Scheme 1.2.7. Importantly, in the non-azepine system, the efficiency of those alkylations is increased, even in these cases where vicinal quaternary centers are generated.24 Methylation of oxindoles 46 and 47 produced 48 and 49 in 99% and 92% yield, respectively. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 16 Scheme 1.2.10. Alkylation of 3-Bromooxindole 43 AllylO2C TIPSO Br CO2Allyl Cs2CO3 NO 2 + THF 0 → 23 °C O N H R 44, R = H 45, R = Br 43 R R TIPSO TIPSO NO 2 CO2Allyl CO2Allyl O N H 46, R = H (85% yield) 47, R = Br (96% yield) NO 2 Cs2CO3, MeI THF 0 → 23 °C CO2Allyl CO2Allyl O N 48, R = H (99% yield) 49, R = Br (92% yield) Acid-catalyzed desilylation and cyclization of diester 48 proceeded smoothly to furnish lactone 50 in 85% yield as a single diastereomer (Scheme 1.2.11a).25 To our delight, lactone 50 underwent decarboxylative allylic alkylation when treated with Pd(PPh3)4, yielding 51 in 90% yield as a single diastereomer.26,27 Single crystal X-ray analysis confirmed that lactone 51 possesses the relative stereochemistry at the vicinal quaternary carbon centers C(7) and C(8) that is needed for further elaboration to communesin F (1f). Interestingly, direct decarboxylative allylic alkylation of diester 49 again provided an alkylated product (i.e., 52) as a single diastereomer in 78% yield (Scheme 1.2.11b). Through X-ray analysis, we discovered that the relative stereochemistry at the vicinal quaternary stereocenters C(20) and C(4) of 52 was complementary to that of the lactone 51, and thus ideal for elaboration to perophoramidine (3). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 17 Scheme 1.2.11. Model Studies for Construction of the Vicinal Quaternary Centers (a) TIPSO O NO 2 O AcCl CO2Allyl CO2Allyl O CO2Allyl MeOH 0 → 65 °C (85% yield) N O NO N 2 48 50 O Pd(PPh 3)4 (2.5 mol%) O 8 THF (90% yield) ≡ 7 O NO N 2 51 (X-ray) 51 AcN H N 8 7 NH N H Communesin F (1f) (b) Br TIPSO TIPSO NO 2 CO2Allyl Pd(PPh 3)4 (5.0 mol%) CO2Allyl O THF, –78 °C (78% yield) CO2Allyl 4 20 N O N O2N 49 52 (X-ray) ≡ N Cl 20 Cl N H N 4 N Br Perophoramidine (3) 52 Br Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 18 At this time, the underlying reasons for the stereochemical relationships observed in these two alkylation reactions are unclear. The fact that the reactions proceed stereodivergently with high diastereocontrol is quite remarkable. Work toward building reasonable models for stereoinduction of β-quaternary tetrasubstituted enolates in both cyclic and acyclic settings as well as the development of these interesting processes in more general cases is ongoing. Nevertheless, with the promising model systems 51 and 52 completed, we next applied our findings to expedient formal syntheses of communesin F (1f) and perophoramidine (3). 1.2.3. Formal Synthesis of Communesin F (1f) As depicted in our retrosynthetic strategy (Scheme 1.2.12), communesin F could be completed from advanced intermediate 53 in Qin’s synthesis.5g We anticipated the initial disconnection of the aminal linkage in 53, thereby revealing oxindole and aniline moieties in 54. Then, the lactam ring in 54 would be excised, affording lactone 55. We envisioned that the relative stereochemical relationship at C(7) and C(8) of lactone 55 could be established by employing our decarboxylative allylic alkylation. The quaternary center on oxindole 56 was disassembled into 3-bromooxindole 57 and diallyl malonate 44. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 19 Scheme 1.2.12. Retrosynthesis of Communesin F (1f) O H HO N A H N B G 8 7 E N F N Br O C D NH N N CO2Me Communesin F (1f) 53 (Qin's intermediate) PMB TIPSO O N Br O O Br 8 7 O NO N O N HN 54 2 CO2Me 55 OTIPS TIPSO NO 2 Br CO2Allyl CO2Allyl O N H 56 Br Br O O AllylO O OAllyl NO 2 + N H 57 44 In the forward synthetic sense, our efforts toward communesin F commenced with the elaboration of 4-bromoindole 58 to diallyl malonate 60 (Scheme 1.2.13). Treatment of 4-bromoindole 58 with oxalyl chloride and methanol provided an oxoacetate (78% yield, 2 steps), which was reduced to the corresponding primary alcohol 59 with LiAlH4 in 91% yield.5g Silylation of the primary alcohol with TIPSCl (98% yield) and subsequent oxidation with pyridinium tribromide afforded dibromooxindole 57 in 89% yield.28 Despite the extra steric encumbrance of C(4) substitution, we were delighted to find that smooth coupling of dibromooxindole 57 with malonate 44 produced a 3,3disubstituted oxindole in 95% yield. Protection of the oxindole with MeI delivered adduct 60 in 92% yield. Microwave assisted lactonization of diester 60 with p-TsOH proceeded smoothly to furnish lactone 61 as a single diastereomer (85% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 20 Gratifyingly, decarboxylative allylic alkylation constructed the quaternary center at C(8) of compound 62 as a single diastereomer in 97% yield under Pd(PPh3)4 catalysis. The relative stereochemistry at C(7) and C(8) of 61 and 62 was unambiguously confirmed by X-ray analysis. Scheme 1.2.13. Development of the Vicinal Quaternary Center OH 1. (COCl)2, Et 2O, 23 °C 2. MeOH, Et 2O (78% yield, 2 steps) Br 3. LiAlH 4, THF, reflux (91% yield) N H 1. TIPSCl, imidazole DMF, 23 °C (98% yield) Br 2. pyridinium tribromide t-BuOH, H 2O, THF, 23 °C (89% yield) N H 58 59 OTIPS Br Br TIPSO NO 2 Br CO2Allyl 1. 44, Cs2CO3, 0 °C (95% yield) O N H 2. Cs2CO3, MeI, 23 °C (92% yield) 57 CO2Allyl O p-TsOH benzene 85 °C, microwave (85% yield) N 60 O O O Br 8 CO2Allyl 7 O NO N 2 Br O 8 Pd(PPh 3)4 (2.0 mol%) 7 THF, 23 °C (97% yield) O NO N 2 61 (X-ray) 62 (X-ray) ≡ ≡ 61 62 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 21 Although ozonolysis of alkene 62 delivered aldehyde 63 in 94% yield, attempted reductive amination of aldehyde 63 did not produce the desired γ-lactam 66 (Scheme 1.2.14). Upon treatment of aldehyde 63 with p-methoxybenzylammonium acetate and sodium cyanoborohydride, amine intermediate 64 was likely produced.29 Instead of opening the lactone directly (path a), nucleophilic attack by the newly generated amine at the oxindole moiety (path b), and subsequent ring-shift tautomerization delivered dihydroquinolinone 65 in 67% yield. Scheme 1.2.14. Ozonolysis and Reductive Amination of Lactone 62 O O O Br O Br O O3 O NO N O NO N CH2Cl2, MeOH then DMS –78 °C (94% yield) 2 62 2 63 path a O PMBNH 3OAc NaBH 3CN Br MeOH, THF (67% yield) O a NHPMB path b b O NO N path a 2 64 PMB HO Br O PMB path b N Br b a N 65 HO O NO 2 N a O b O N O2N 66 (Not Observed) Alternatively, we found that lactam 54 (an analogue of 66) could be obtained via the reaction sequence summarized in Scheme 1.2.15. The nitro group on compound 62 was reduced to the aniline, which resulted in concomitant lactone ring opening to furnish a bis-oxindole 67 in 80% yield. Protection of the primary alcohol with TIPSCl (90% Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 22 yield) and protection of the oxindole nitrogen with methyl chloroformate afforded carbamate 68 in 98% yield. Ozonolysis of alkene 68 generated aldehyde 69 (94% yield),30 which underwent subsequent reductive amination and selective lactamization with the electron deficient oxindole to afford γ-lactam 54 in 95% yield. Scheme 1.2.15. Synthesis of Lactam 54 O OH O Br TiCl3, NH 4OAc, MeCN O Br H 2O, MeOH, 23 °C (80% yield) NO N 2 NH OO N 67 62 1.TIPSCl, imidazole, DMF 0 → 23 °C (90% yield) 2. ClCO2Me Et 3N, DMAP, CH2Cl2 0 → 23 °C (98% yield) TIPSO TIPSO Br NCO 2Me OO O 3, then PPh 3, CH2Cl2, –78 °C (94% yield) N 68 PMB O TIPSO Br NCO 2Me PMBNH 3OAc, NaBH 3CN OO N THF, MeOH, 0 → 23 °C (95% yield) N Br O O N HN CO2Me 69 54 With lactam 54 in hand, we envisioned that the piperidine D ring of 70 would be prepared by AlH3-Me2NEt mediated reductive cyclization (Scheme 1.2.16).21,31 To our disappointment, treatment of lactam 54 with AlH3-Me2NEt produced undesired pyrrolidinoindoline derivative 71 as a single diastereomer in 61% yield, resulting from chemoselective reduction of the N-PMB-lactam in the presence of the oxindole. After cleavage of the TIPS group by TBAF (98% yield),32 the PMB group was removed with Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 23 33 DDQ to provide alcohol 72. The structure of the pentacyclic heterocycle 72 was confirmed by X-ray analysis (Figure 1.2.5). Scheme 1.2.16. Reductive Cyclization of Lactam 54 with AlH3-Me2NEt PMB TIPSO Br PMB TIPSO N N Br O A AlH3-Me2NEt F O N HN THF, 0 °C D N E N O C CO2Me CO2Me 54 70 (Not Observed) AlH3-Me2NEt THF, 0 °C (61% yield) PMB H N TIPSO CO2Me N Br O N H N HO 1. TBAF, THF, 23 °C (98% yield) 2. DDQ, CH2Cl2, H 2O 23 °C (85% yield) H CO2Me N Br O N 72 (X-ray) 71 Figure 1.2.5. X-ray Structure of Pyrrolidinoindoline 72 HO O NH Me N H N O ≡ Br O 72 72 Having failed on our initial exploration, alternative conditions for construction of the piperidine D ring were next explored. Treatment of the lactam 54 with LiAlH434 produced debrominated compound 73 in 83% yield (Scheme 1.2.17a). X-ray analysis of Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 24 compound 73 showed a hydrogen bonding interaction between the carbonyl group of the PMB protected amide and the NH group of the carbamate. We reasoned that the undesired pyrrolidine was formed preferentially to the piperidine due to the close proximity of the carbamate NH and the carbonyl group of the PMB-protected amide. Next, a reductive cyclization reaction was attempted by treatment of 54 with Tf2O and NaBH4 to construct the piperidine ring. To our surprise, treatment of lactam 54 with Tf2O provided the PMB-protected hexacyclic oxindole 76 in 95% yield (Scheme 1.2.17b). The PMB-protected amide of 54 was activated by Tf2O to provide 74, and nucleophilic attack by the aniline functionality furnished pyrrolidinoindoline derivative 75. After the TIPS group was removed under the reaction conditions, the resultant hydroxyl group attacked the amidinium to generate the propellane structure of hexacyclic oxindole 76. After cleavage of the PMB group using DDQ, the propellane structure of hexacyclic oxindole 77 was confirmed using X-ray analysis. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 25 Scheme 1.2.17. Attempted Reductive Cyclization of Lactam 54 (a) PMB TIPSO Br PMB TIPSO N O H LiAlH 4 THF, 0 °C (83% yield) O N HN N O HN CO2Me O N CO2Me 54 73 (X-ray) hydrogen bond PMB TIPSO N H O HN CO2Me ≡ O N 73 73 (b) PMB TIPSO PMB TIPSO N Br O Br Tf2O CH2Cl2 0 → 23 °C (95% yield) O N HN CO2Me N OTf O N HN CO2Me 54 74 PMB Br N HO CO2Me N Br N O O N N 75 76 Br DDQ N CH2Cl2, 23 °C (92% yield) O N CO2Me O N H 77 (X-ray) Br N N O N CO2Me O N 77 CO2Me O ≡ H 77 PMB Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 26 Despite this unexpected turn of events, we envisaged that the desired aminal 81 could be accessed from the propellane compound 76 using suitable conditions, since the oxidation state at C(9) of 76 is identical to that of the desired aminal 81 (Scheme 1.2.18). Moreover, the reactive N-PMB-pyrrolidinone in 54 is now protected by the propellane structure of 76, thus leaving the oxindole as the only reducible carbonyl group. Fortunately, after extensive experimentation, we were pleased to find that reductive cyclization of hexacyclic oxindole 76 could be accomplished with DIBAL and Et2AlCl to furnish aminal 81 in 87% yield (Scheme 1.2.18). Presumably, the oxindole of 76 was reduced by DIBAL to provide 78, and rearrangement of the propellane structure generated iminium 79. After the work-up, water attacked the iminium moiety of 79 to afford aniline 80, and the resultant aniline group attacked the iminium of 80 to construct aminal 81. In the last stage of the synthesis, we screened a variety of reaction conditions to remove the PMB group on the lactam 81 (e.g., DDQ, CAN, TFA, etc.) but, surprisingly, removal of the PMB group failed under all conditions attempted. This unexpected turn was particularly insidious since the PMB group was easily removed from hexacyclic oxindole 76 by DDQ (Scheme 1.2.17). The cleavage of allyl or benzyl groups were also examined, but disappointingly, cleavage of these groups on the lactam were similarly unsuccessful under several conditions.35 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 27 Scheme 1.2.18. Synthesis of Aminal 81 Br Br O N O 8 N CO2Me 9 N PMB DIBAL then Et 2AlCl O N PMB HO N N Br O work-up OAlR 2 N N R 2Al CO2Me CO2Me 80 PMB HO Br 9 N Br O 8 81 H HO N H HN N 79 N PMB 78 PMB Br N R 2Al 76 O N CO2Me O CH2Cl2 –78 → 23 °C (87% yield) N CO2Me O DDQ, CAN or TFA N H N CO2Me 53 (Not Observed)     Given the difficulty of removal of PMB, allyl, and benzyl groups, our attention turned to exploring the o-nitrobenzyl group as a protecting group. However, subjecting the hexacyclic oxindole 77 to o-nitrobenzyl bromide under basic conditions to produce the o-nitrobenzyl protected propellane hexacyclic oxindole turned out to be challenging. Thus, we next investigated reductive amination of aldehyde 69 and were pleased to find that treatment of 69 with o-nitrobenzylammonium acetate 82 furnished lactam 83 in 97% yield (Scheme 1.2.19). Formation of the o-nitrobenzyl protected propellane hexacyclic oxindole using Tf2O (75% yield) was followed by reductive cyclization with DIBAL and Et2AlCl to furnish aminal 84 in 60% yield. To our delight, we found that removal of the o-nitrobenzyl group could be achieved by photolysis/irradiation at 350nm in 40% yield.36     Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 28 Surprisingly, we discovered that removal of the o-nitrobenzyl group to produce compound 53 was also accomplished using 20% aq NaOH in methanol at 75 °C in 70% yield – a previously unknown deprotection protocol.37 Aminal 53 has been advanced by the Qin group to communesin F,5g thus completing our formal synthesis of the natural product.   Scheme 1.2.19. Completion of Formal Synthesis of Communesin F O2N TIPSO O NO 2 Br NCO 2Me 82 TIPSO NH 3OAc Br O NaBH 3CN THF, MeOH 0 → 23 °C (97% yield) OO N N O N HN CO2Me 69 83 O2N HO 1. Tf2O, CH2Cl2,, 0 → 23 °C (75% yield) 2. DIBAL; Et 2AlCl, CH2Cl2 –78 → 0 °C (60% yield) N Br N H O hv, MeOH (40% yield) CO2Me or 20% aq NaOH MeOH, 75 °C (70% yield) N 84 H HO Ac N N Br O N H 53 1.2.4. N CO2Me H N 11 steps NH Qin and co-workers (2007) N H Communesin F (1f) Formal Synthesis of Perophoramidine (3) Our retrosynthetic analysis of perophoramidine (3) was based on our previously established expedient synthesis of oxindole derivative 52 (Scheme 1.2.20). We speculated that the aminal and lactam ring functionalities of pentacycle 85, an Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 29 5o intermediate in Funk’s synthesis, could be cleaved, thereby leading to aldehyde 86. The N–C bond of the 6-bromooxindole moiety in 86 was excised to arrive at nitroarene 52. The construction of the contiguous quaternary centers at C(20) and C(4) of allyl ester 52 with the proper relative stereochemistry was accessed by decarboxylative allylic alkylation as previously described (Scheme 1.2.11b). Scheme 1.2.20. Retrosynthesis of Perophoramidine (3) TIPSO 22 Cl 19 17 N 24 N A B4 20 F D E N 12 N H 15 Cl 1 O 6 C 8 Perophoramidine (3) Br N N H H Boc Br 85 (Funk's intermediate) Br Br TIPSO H N O TIPSO NO 2 NBoc OO N 4 20 CO2Allyl O N 86 52 Carbamate 88 was obtained by reduction of nitroarene 52 with titanium chloride and simultaneous oxindole formation38 to furnish the bis-oxindole moiety 87 in 91% yield followed by protection with Boc anhydride in 85% yield (Scheme 1.2.21). Ozonolysis of olefin 88 produced aldehyde 86 in 90% yield. Reductive amination of aldehyde 86 with o-nitrobenzylammonium acetate 82 resulted in an amine that underwent in situ lactam formation to afford oxindole lactam 89 in 91% yield. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 30 Scheme 1.2.21. Synthesis of Amide 89 Br Br TIPSO TIPSO NO 2 TiCl3, NH 4OAc CO2Allyl O N NH i-PrOH, H 2O, 23 °C (91% yield) 52 OO N 87 Br TIPSO Boc 2O, DMAP NBoc MeCN, 23 °C (85% yield) O 3, then PPh 3 CH2Cl2, –78 °C (90% yield) OO N 88 O2N Br TIPSO NO 2 O 82 TIPSO N NH 3OAc NBoc OO N 86 O NaBH 3CN THF, MeOH 0 → 23 °C (91% yield) O N HN Br Boc 89 Initially, we attempted to generate the o-nitrobenzyl protected propellane hexacyclic oxindole 90 under analogous conditions to those used in our formal synthesis of communesin F on the pseudo diastereomeric series (vide supra). However, treatment of lactam 89 with Tf2O yielded an unexpected azepine 91 in 70% yield (Scheme 1.2.22). Both the Boc and the TIPS groups on amide 89 were removed under the reaction conditions, and the resulting primary alcohol was presumably converted to the corresponding triflate. Finally, the aniline likely attacked the newly formed triflate to form azepine 91. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 31 Scheme 1.2.22. Formation of Azepine 91 using Tf2O O2N TIPSO N N O O N O N HN NO 2 N Boc O Br Br Boc 89 90 (Not Observed) O2N Tf2O 0 → 23 °C CH2Cl2 (70% yield) Br O N HN O N 91 After extensive experimentation, we discovered that in contrast to the communesin system, the desired reductive cyclization in the perophoramidine diastereomer occurred directly with AlH3-Me2NEt31 to furnish cyclization product 92 in 42% yield (66% yield based on recovered starting material) (Scheme 1.2.23). The indoline methyl group was converted to a formyl group using PDC oxidation in 62% yield (93% yield based on recovered starting material).39 To our delight, an attempt to remove the formyl group with 20% aq NaOH at 75 °C resulted in removal of both the formyl group and the o-nitrobenzyl group to produce aminal 85 in 50% yield.37,40 This molecule was previously advanced by the Funk group to perophoramidine,5o and constitutes an expedient formal synthesis of the natural product. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 32 Scheme 1.2.23. Completion of Formal Synthesis of Perophoramidine O2N TIPSO O2N TIPSO N N AlH3-Me2NEt O O N HN O THF (42% yield) (66% yield, based on Br recovered 89 ) N N H Br Boc Boc 89 92 H TIPSO N 1. PDC, K 2CO3, CH2Cl2 (62% yield; 93% yield, based on recovered 92 ) O N 2. 20% aq NaOH, MeOH, 75 °C (50% yield) H H N Br Boc 85 N 9 steps N Cl Funk and co-workers (2004) N Cl N Br H Perophoramidine (3) 1.3. Conclusion   In conclusion, we have conducted synthetic studies toward unique polycyclic alkaloids, and completed formal syntheses of communesin F (1f) in 9% overall yield over 17 steps and perophoramidine (3) in 6% overall yield (13% overall yield, based on recovered starting material) over 10 steps using a unified stereodivergent alkylation approach. The all-carbon quaternary center on the oxindole was established via stabilized enolate alkylation of 3-bromooxindoles, a method previously developed by our laboratory and now shown to be quite versatile even in particularly sterically challenging situations. The complementary relative stereochemistry of the two contiguous quaternary stereogenic centers found in communesin F (1f) and perophoramidine (3) respectively, was established by substrate controlled diastereoselective decarboxylative allylic Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 33 alkylation. A reductive amination approach furnished the A ring, and reductive cyclization produced the D ring for both communesin F (1f) and perophoramidine (3). En route to the evolution of our eventual successful strategy, we have discovered a method to convert an indole to a 3-chloroindolenine using a mild reagent such as o-NsCl during the synthesis. In addition, previously unknown, mild and efficient deprotection conditions for the o-nitrobenzyl group on the lactam were discovered. Further studies to rationalize unprecedented complementary selectivity by Pd-catalyzed allylic alkylation reactions are currently in progress. 1.4. Experimental Methods and Analytical Data 1.4.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Triethylamine was distilled over CaH2 prior to use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Microwave-assisted reactions were performed in a Biotage Initiator 2.5 microwave reactor. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 34 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, panisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm), or (CD3)2CO (δ 2.05 ppm). 13C NMR spectra are recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm), or (CD3)2CO (δ 29.84 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). X-ray crystallography reports for compounds 29 and 32 can be found in ref 41.41 1.4.2. Experimental Procedures OH OsO 4 (cat), NMO HN Ts SI-1-1 THF/H2O, 23 °C (80% yield) HO HN Ts SI-1-2 Diol SI-1-2. To a solution of styrene SI-1-1 (6.11 g, 22.4 mmol, 1.0 equiv) in THF (140 mL) and water (70 mL) were added N-methylmorpholine N-oxide (5.96 g, 50.8 mmol, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 35 2.3 equiv) and osmium tetroxide (11.6 mg, 43.9 µmol, 0.002 equiv). After addition, reaction was stirred for three days. The reaction was then concentrated to approximately 50 mL under reduced pressure, then extracted with a mixture of ether and THF (1:1) (3 x 45 mL). The organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure. Impurities were removed by washing solid with dichloromethane to afford diol SI-1-2 (5.43 g, 80% yield) as a white solid. For spectrum, see ref 41. Rf = 0.13 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.47 (s, 1H), 7.78–7.65 (m, 2H), 7.39 (dd, J = 8.1, 1.1 Hz, 1H), 7.25–7.16 (m, 2H), 7.15–7.03 (m, 2H), 4.86–4.79 (m, 1H), 3.66–3.57 (m, 2H), 2.97 (s, 1H), 2.39 (s, 3H), 1.98 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 144.1, 137.1, 136.3, 129.9, 129.8, 129.2, 128.5, 127.4, 127.0, 122.2, 74.78, 66.0, 21.8; IR (Neat Film NaCl) 3271, 1318, 1150 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C15H18NO4S [M+H]+: 308.0951; found 308.0967. OH HO OH 1. BuSn(OMe) 2 HN Ts SI-1-2 2. MOMCl, Bu 4NI, 23 °C (90% yield, 2 steps) MOMO HN Ts 13 Alcohol 13. To a solution of diol SI-1-2 (500 mg, 1.63 mmol, 1.0 equiv) in toluene (70 mL) was added dibutyltin dimethoxide (410 µL, 1.79 mmol, 1.1 equiv). The flask was fitted with a short path distillation apparatus, and approximately half of the solvent was removed by distillation. To this solution was added MOMCl (136 µL, 1.79 mmol, 1.1 equiv) and tetrabutylammonium iodide (900 mg, 2.44 mmol, 1.5 equiv). After addition, the reaction was stirred for 12 h. Then, brine was added to this solution. The reaction Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 36 mixture was extracted with EtOAc (3 x 50 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford alcohol 13 (513 mg, 90% yield, 2 steps) as a white solid. For spectrum, see ref 41. Rf = 0.27 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.76 (s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.0 Hz, 1H), 7.27–7.20 (m, 3H), 7.11–7.02 (m, 2H), 4.83–4.78 (m, 1H), 4.64 (s, 2H), 3.60 (dd, J = 10.5, 3.5 Hz, 1H), 3.48–3.41 (m, 2H), 3.39 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 143.9, 137.1, 136.3, 129.7, 129.5, 128.9, 128.2, 127.2, 124.7, 122.0, 97.0, 73.3, 72.4, 55.6, 21.6; IR (Neat Film NaCl) 3233, 2932, 1598, 1497, 1335, 1161 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H22NO5S [M+H]+: 352.1213; found 352.1219. O O Me MeO S Me I CO2Me Me NaH O N H SI-1-3 O DMSO 23 → 50 °C (69% yield) (1.6:1 dr) N H 16 Cyclopropane 16. A flame-dried flask (25 mL) equipped with a teflon stirbar was charged with sodium hydride (60% dispersion in mineral oil, 22 mg, 0.55 mmol, 1.1 equiv), which was washed 3 times with dry hexanes. Then, DMSO (5.5 mL) and trimethyl sulfoxonium iodide (119 mg, 0.58 mmol, 1.2 equiv) were added. To this solution was added oxindole SI-1-3 (100 mg, 0.49 mmol, 1.0 equiv) in a solution of DMSO (2.5 mL). After addition, the reaction was stirred for 2 h, and then the temperature was raised to 50 °C. The reaction was complete after another hour. Brine Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 37 was added and then the mixture was extracted with EtOAc (3 x 5 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford oxindole 16 as two diastereomers. Diastereomer 1: (44.7 mg, 42% yield); Diastereomer 2: (28.6 mg, 27% yield). For spectrum, see ref 41. Diastereomer 1: Rf = 0.52 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 9.40 (s, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H), 7.04–6.97 (m, 2H), 3.70 (s, 3H), 2.74 (t, J = 8.0 Hz, 1H), 2.18 (dd, J = 4.5, 7.5 Hz, 1H), 2.05 (dd, J = 4.5, 8.5 Hz, 1H); 13 C NMR (75 MHz, CDCl3) δ 177.5, 169.3, 141.8, 127.9, 126.4, 123.0, 122.4, 110.3, 52.4, 34.3, 32.9, 21.1; IR (Neat Film NaCl) 3214, 1712, 1622, 1470, 1209 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H12NO3 [M+H]+: 218.0812; found 218.0825. Diastereomer 2: Rf = 0.45 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 9.06 (s, 1H), 7.27–7.20 (m, 1H), 7.04–6.97 (m, 2H), 6.83 (d, J = 7.5 Hz, 1H), 3.75 (s, 3H), 2.68 (t, J = 8.0 Hz, 1H), 2.40 (dd, J = 5.0, 8.0 Hz, 1H), 1.84 (dd, J = 5.0, 8.5 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 176.0, 167.7, 141.1, 129.5, 188.0, 122.4, 118.9, 110.3, 52.6, 33.5, 32.9, 21.3; IR (Neat Film NaCl) 3256, 1739, 1710 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H12NO3 [M+H]+: 218.0812; found 218.0828. 1. EtOH, H 2SO4 (cat) PhMe, reflux HO 2C 2. H 2SO4, 110 °C (44% yield, 2 steps) O2N 21 O HO O N 20 Acid 20. A flame-dried flask (500 mL) equipped with a teflon stirbar was charged with acid 21 (10.0 g, 55.2 mmol, 1.0 equiv), ethanol (60 mL), sulfuric acid (200 µL), and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 38 toluene (280 mL). The flask was fitted with a condenser, and the solution was refluxed for 14 h. The solvent was removed under reduced pressure and sulfuric acid (280 mL) was added. After addition, the reaction was heated to 110 °C and stirred for 90 min. The solution was then poured onto ice (600 g), the mixture was extracted with ether (3 x 200 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. Purification was performed via crystallization from water to afford acid 20 (3.94 g, 44% yield, 2 steps) as an off-white solid. For spectrum, see ref 41. 1 H NMR (300 MHz, acetone-d6) δ 10.82 (br, s, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.75 (d, J = 10.0 Hz, 1H), 7.50 (dd, J = 6.5, 9.5 Hz, 1H), 7.34 (dd, J = 7.0, 8.5 Hz, 1H); 13C NMR (75 MHz, acetone-d6) δ 158.5, 158.1, 155.3, 132.4, 128.8, 121.4, 121.0, 116.7; IR (Neat Film NaCl) 2360, 1731, 1301, 1231, 1189, 753 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C8H6NO3 [M+H]+: 164.0342; found 164.0341. OH OH H N NO 2 NO 2 NaH, MeI Zn(Hg), HCl THF, 0 → 23 °C (90% yield) MeOH, reflux (60% yield) N H N SI-1-4 SI-1-5 N 5 1-methylaurantioclavine 5. To a solution of indole SI-1-4 (386 mg, 1.41 mmol, 1.0 equiv) in THF (14 mL) was added methyl iodide (875 µL, 14.1 mmol, 10 equiv) at 0 °C. Sodium hydride (60% dispersion in mineral oil, 562 mg, 14.5 mmol, 10.3 equiv) was then added to the solution, and the mixture was stirred for 25 min at 23 °C. The reaction was quenched with saturated ammonium hydroxide solution and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, and concentrated in Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 39 vacuo. The residue was purified by flash column chromatography (3:1 → 2:1 hexanes:EtOAc) to afford nitro compound SI-1-5 (363.5 mg, 90% yield) as a yellow solid. To a solution of nitro compound SI-1-5 (512 mg, 1.78 mmol, 1.0 equiv) in MeOH (125 mL) and 2N HCl (40 mL) was added amalgamated zinc, which had been formed from zinc dust (6.5 g, 98.3 mmol, 55 equiv) and mercuric chloride (1.10 g, 3.55 mmol, 2.0 equiv) in 2N HCl and subsequently rinsed with MeOH. The mixture was stirred at reflux for 3 h. The reaction was then decanted from the remaining amalgam and then basified to pH >10. The solid was removed by filtration, and the resulting solution was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (18:1 CH2Cl2:MeOH) to afford 1-methylaurantioclavine 5 (258 mg, 60% yield) as a yellow oil. For spectrum, see ref 41. Rf = 0.30 (18:1 CH2Cl2:MeOH); 1H NMR (300 MHz, CDCl3) δ 7.19–7.12 (m, 2H), 6.89–6.83 (m, 2H), 5.48 (d, J = 9.0 Hz, 1H), 4.92 (d, J = 9.0 Hz, 1H), 3.76 (s, 3H), 3.62– 3.54 (m, 1H), 3.13–3.02 (m, 3H), 2.26 (br, s, 1H), 1.86 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 138.5, 137.8, 133.3, 127.7, 125.9, 121.1, 117.4, 114.2, 107.3, 62.6, 48.9, 32.7, 30.8, 25.9, 18.4; IR (Neat Film NaCl) 3332, 2910, 1554, 1455 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C16H21N2 [M+H]+: 241.1699; found 241.1712. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 40 N O O HO 1. (COCl)2, CH2Cl2 DMF, 23 °C O 2. N O N H N 20 N H N H 4 CH2Cl2, Et 3N, 23 °C (91% yield, 2 steps) 22 Amide 22. To a solution of acid 20 (262 mg, 1.60 mmol, 1.25 equiv) in dichloromethane (5 mL) was added oxalyl chloride (420 µL, 4.81 mmol, 3.8 equiv) and then a small amount of DMF (~20 µL). The reaction was stirred for 1 h then the solvent was removed under reduced pressure; the residue was evaporated from benzene (2 mL) to remove excess reagent. Dichloromethane (10 mL) and triethylamine (537 µL, 3.85 mmol, 3.0 equiv) were added, and to this solution was added aurantioclavine 4 (290 mg, 1.28 mmol, 1.0 equiv). After addition, the reaction was stirred for 60 min, and then brine was added. The resulting solution was extracted with EtOAc (3 x 7 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford amide 22 (435 mg, 91% yield, 2 steps) as a white solid. For spectrum, see ref 41. Rf = 0.72 (1:2 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (300 MHz, CDCl3) δ 9.00–8.86 (m, 2H), 7.98 (dq, J = 8.9, 0.9 Hz, 1H), 7.71–7.57 (m, 3H), 7.35–7.27 (m, 2H), 7.25–7.22 (m, 1H), 7.22–7.16 (m, 3H), 7.15–7.07 (m, 2H), 7.07–7.01 (m, 2H), 7.01–6.94 (m, 2H), 6.90–6.83 (m, 2H), 6.70 (d, J = 7.5 Hz, 1H), 5.48 (ddq, J = 7.9, 2.8, 1.6 Hz, 2H), 4.82–4.66 (m, 2H), 4.07 (ddd, J = 15.4, 10.0, 5.8 Hz, 1H), 3.82 (td, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 41 J = 13.0, 2.6 Hz, 1H), 3.60–3.46 (m, 1H), 3.23–3.12 (m, 3H), 1.96 (d, J = 1.3 Hz, 3H), 1.79 (d, J = 1.5 Hz, 3H), 1.73 (d, J = 1.6 Hz, 3H), 1.64 (d, J = 1.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5, 158.4, 157.9, 157.8, 156.9, 156.8, 137.7, 137.4, 137.2, 136.9, 135.2, 135.1, 131.5, 131.4, 126.4, 126.1, 124.7, 124.3, 123.9, 123.8, 122.1, 121.9, 121.8, 121.7, 121.1, 121.0, 119.9, 118.3, 117.5, 114.9, 113.3, 112.6, 110.1, 109.9, 61.0, 57.5, 44.5, 43.1, 29.1, 25.9, 25.8, 25.7, 18.9, 18.2; IR (Neat Film NaCl) 3325, 2914, 2246, 1730, 1616, 1447 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H22N3O2 [M+H]+: 372.1707; found: 372.1637. N O HO 1. (COCl)2, CH2Cl2 DMF, 23 °C O 2. N O O N H N 20 N N 5 19 CH2Cl2, Et 3N, 23 °C (77% yield, 2 steps) Amide 19. To a solution of acid 20 (37.5 mg, 0.229 mmol, 1.1 equiv) in dichloromethane (500 µL) was added oxalyl chloride (59 µL, 0.676 mmol, 3.3 equiv) and then a small amount of DMF (~1 µL). The reaction was stirred for 1 h, and then the solvent was removed under reduced pressure. The residue was evaporated from benzene (1 mL) to remove excess reagent. Dichloromethane (1.1 mL) and triethylamine (30 µL, 0.215 mmol, 1.03 equiv) were added, and to this solution was added 1methylaurantioclavine 5 (50.0 mg, 0.208 mmol, 1.0 equiv). After addition, the reaction was stirred for 60 min, and then brine was added. The resulting solution was extracted with EtOAc (3 x 1.5 mL). The combined organic layers were dried over MgSO4, and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 42 concentrated in vacuo. The residue was purified by flash column chromatography (3:1 → 2:1 hexanes:EtOAc) to afford amide 19 (61.6 mg, 77% yield, 2 steps) as a white solid. Rf = 0.79 (1:2 hexanes:EtOAc); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks. For spectrum, see ref 41), 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.62 (t, J = 10.0 Hz, 1H), 7.37–7.30 (m, 1.5H), 7.22–7.18 (m, 2H), 7.13–7.08 (m, 2H), 7.04–6.99 (m, 1H), 6.95 (s, 1H), 6.86–6.84 (m, 2H), 6.67 (d, J = 7.5 Hz, 1H), 5.46 (d, J = 7.5 Hz, 1H), 4.69 (dd, J = 15.0, 38.0 Hz, 1H), 4.04 (dt, J = 4.5, 15.5 Hz, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.48 (t, J = 18.0 Hz, 1H), 3.25 (3.11, m, 2H), 1.92 (s, 3H), 1.78 (s, 3H), 1.72 (s, 3H), 1.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 158.5, 158.5, 157.7, 157.6, 156.9, 156.8, 137.8, 137.7, 137.6, 136.8, 135.7, 135.6, 131.3, 131.2, 126.5, 126.3, 125.9, 124.8, 124.4, 124.3, 124.2, 122.1, 121.6, 121.5, 121.2, 121.1, 120.0, 118.1, 117.3, 115.0, 114.9, 112.3, 111.7, 107.9, 107.7, 60.9, 57.3, 44.5, 43.1, 32.6, 29.0, 25.9, 25.7, 18.9, 18.2; IR (Neat Film NaCl) 2913, 2245, 1615, 1455, 1410 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C24H24N3O2 [M+H]+: 386.1863; found 386.1775. N O O O N HCl, MeOH N O N H H 0 → 23 °C (31% yield) N H N H 22 23 Indole 23. A flame-dried vial (20 mL) equipped with a teflon stirbar was charged with amide 22 (100 mg, 0.269 mmol, 1.0 equiv) and cooled to 0 °C. To this reaction mixture Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 43 was added a 0.5 M solution of HCl in MeOH (2.7 mL, generated from addition of acetyl chloride to methanol at 0 oC) at 0 °C. The mixture was stirred for 1 h and then warmed to 23 oC over 30 min. The solvent was then removed under reduced pressure. Purification was performed by washing the solid with dichloromethane to afford indole 23 (31.1 mg, 31% yield) as a white solid. For spectrum, see ref 41. Rf = 0.22 (1:1 hexane:EtOAc); 1H NMR (300 MHz, acetone-d6) δ 11.05 (s, 1H), 7.34– 7.17 (m, 6H), 7.09 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 7.5 Hz, 1H), 5.47 (d, J = 6.5 Hz, 1H), 4.21 (d, J = 13.0 Hz, 1H), 3.44 (t, J = 11.0 Hz, 1H), 3.18–2.98 (m, 2H), 2.37 (d, J = 6.5 Hz, 1H), 1.77 (s, 3H), 1.04 (s, 3H); 13C NMR (75 MHz, DMSO) δ 164.3, 153.0, 139.6, 137.0, 134.6, 127.3, 126.6, 123.7, 122.6, 121.4, 118.6, 118.0, 115.2, 112.7, 110.2, 96.4, 70.1, 63.1, 61.2, 44.4, 26.9, 26.6, 26.0; IR (Neat Film NaCl) 3314, 1681, 753 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H22N3O2 [M+H]+: 372.1707; found 372.1710. N O O O N HCl, MeOH N O N H H 0 → 23 °C (99% yield) N N 19 24 Indole 24. A flame-dried vial (20 mL) equipped with a teflon stirbar was charged with amide 19 (100 mg, 0.259 mmol, 1.0 equiv) and cooled to 0 °C. To this solution was added a 0.5 M solution of HCl in MeOH (2.6 mL, generated from addition of acetyl chloride to methanol at 0 °C) at 0 °C. The mixture was stirred for 1 h and then warmed Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 44 to 23 °C over 30 min. The solvent was then removed under reduced pressure. Purification was performed via flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford indole 24 (101 mg, 99% yield) as a white solid. For spectrum, see ref 41. Rf = 0.29 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.37–7.17 (m, 6H), 7.00 (s, 1H), 6.76–6.73 (m, 1H), 5.51 (d, J = 6.5 Hz, 1H), 4.57–4.50 (m, 1H), 3.80 (s, 3H), 3.50–3.15 (m, 3H), 2.57 (d, J = 6.5 Hz, 1H), 1.95 (s, 3H), 1.18 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 165.4, 153.5, 139.8, 137.9, 135.6, 127.5, 127.0, 126.9, 124.6, 121.9, 119.1, 118.4, 115.9, 113.4, 108.4, 97.2, 70.9, 64.1, 61.9, 45.2, 33.0, 27.5, 27.2, 26.6; IR (Neat Film NaCl) 3315, 2932, 1699, 1456, 1317, 754 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C24H24N3O2 [M+H]+: 386.1863; found 386.1809. O F 3C H N N CF3CO2COCF3, Et 3N N H 4 THF, 0 °C (82% yield) N H 25 N-trifluoroacetate-aurantioclavine 25. To a solution of aurantioclavine 4 (882 mg, 3.90 mmol, 1.0 equiv) in THF (14 mL) were added triethylamine (820 µL, 5.88 mmol, 1.5 equiv) and trifluoroacetic anhydride (606 µL, 4.29 mmol, 1.1 equiv) at 0 oC. The reaction was complete immediately, so it was quenched with methanol. The solvent was then removed under reduced pressure. Purification was performed via flash column chromatography (9:1 → 3:1 hexanes:EtOAc) to afford the N-trifluoroacetateaurantioclavine 25 (1.03 g, 82% yield) as a yellow foam. For spectrum, see ref 41. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 45 Rf = 0.30 (3:1 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (300 MHz, CDCl3) δ 8.51 (br, s, 1H), 7.29–7.26 (m, 1H), 7.02–6.97 (m, 2H), 6.90 (t, J = 7.0 Hz, 1H), 6.23 (d, J = 8.0 Hz, 1H), 5.40 (dd, J = 7.5, 19.5 Hz, 1H), 4.40 (d, J = 13.0 Hz, 1H), 4.16–4.10 (m, 1H), 4.04–3.94 (m, 2H), 3.83 (t, J = 13.0 Hz, 1H), 3.43 (t, J = 16.5 Hz, 1H), 3.27–3.23 (m, 1H), 3.09 (d, J = 16.5 Hz, 1H), 1.91 (s, 3H), 1.86 (s, 3H), 1.78 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 157.5, 157.0, 156.8, 156.3, 138.5, 137.4, 137.2, 137.2, 135.1, 134.4, 124.3, 123.9, 123.5, 123.3, 122.1, 121.9, 121.8, 119.0, 118.8, 118.5, 117.1, 115.2, 115.0, 113.1, 112.6, 110.3, 110.1, 60.7, 60.6, 58.6, 43.7, 43.7, 28.4, 26.2, 25.7, 25.0, 18.9, 18.2; IR (Neat Film NaCl) 3361, 2917, 1667, 1441, 1205 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H18N2OF3 [M+H]+: 323.1366; found 323.1308. N3 N3 N3 Br NBS THF, t-BuOH, H 2O –40 → 0 °C N H SI-1-6 + O N H SI-1-7 (25% yield) O N H 26 (64% yield) Bromooxindole 26. A flame-dried flask (1000 mL) equipped with a teflon stirbar was charged with azide SI-1-61 (5.03 g, 30.3 mmol, 1.0 equiv), to which was subsequently added THF (150 mL), t-BuOH (150 mL), and water (3.75 mL) and cooled to –40 °C. A 0 °C solution of NBS (8.03 g, 45.1 mmol, 1.5 equiv) in THF (450 mL) was then added via cannula over 30 min, and the resulting solution was allowed to warm to –10 °C over 2 h. Warming continued slowly over 30 min to 0 °C. After 20 min at 0 °C, the solvent was                                                                                                                 1  Suzuki, T.; Ota, Y.; Ri, M.; Bando, M.; Gotoh, A.; Itoh, Y.; Tsumoto, H.; Tatum, P. R.; Mizukami, T.; Nakagawa, H.; Iida, S.; Ueda, R.; Shirahige, K.; Miyata, N. J. Med. Chem. 2012, 55, 9562.   Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 46 removed under reduced pressure. Purification was performed via flash column chromatography (9:1→1:2 pentanes:ether) to afford bromooxindole 26 (5.46 g, 64% yield) as a yellow solid. Oxindole SI-1-7 (1.50 g, 25% yield) was also isolated as a light yellow solid. For spectrum, see ref 41. Bromooxindole 26: Rf = 0.46 (2:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.12 (br, s, 1H), 7.28–7.23 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 3.61– 3.44 (m, 2H), 2.32–2.17 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 180.5, 141.7, 128.4, 128.1, 123.8, 122.3, 110.2, 48.0, 43.3, 29.5; IR (Neat Film NaCl) 3228, 2100, 1693, 1620, 1470 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H10N4OBr [M+H]+: 281.0033; found 281.0040. Oxindole SI-1-7: Rf = 0.37 (2:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.21 (br, s, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 3.41–3.20 (m, 3H), 2.84–2.57 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 176.6, 139.8, 130.6, 129.1, 124.6, 123.5, 111.4, 54.5, 47.6, 38.0; IR (Neat Film NaCl) 3252, 2102, 1732, 1619, 1471 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H11N4O[M+H]+: 203.0927; found 203.0933. O O H N H N Br THF 23 °C (69% yield) O N H N3 Cs2CO3 + 25 F 3C N3 F 3C N H 26 N H NH O 28 Adduct 28. A flame-dried vial (20 mL) equipped with a teflon stirbar was charged with indole 25 (120 mg, 0.372 mmol, 1.0 equiv) and bromooxindole 26 (157 mg, 0.559 mmol, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 47 1.5 equiv), which were subsequently dissolved in THF (4 mL). Cesium carbonate (243 mg, 0.746 mmol, 2.0 equiv) was then added. After addition, the reaction was stirred for 12 h, and then water was added. The resulting solution was extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (9:1 → 2:1 hexanes:EtOAc) to afford adduct 28 (134 mg, 69% yield) as a yellow foam. For spectrum, see ref 41. Rf = 0.34 (2:1 hexanes:EtOAc x2 elutions); (Due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1 H NMR (300 MHz, CDCl3) δ 8.74 (br, s, 2H), 8.59 (br, s, 1H), 8.97 (br, s, 1H), 7.34– 6.86 (m, 12H), 6.78 (t, J = 7.0 Hz, 1H), 6.11 (d, J = 8.0 Hz, 1H), 5.33 (dd, J = 7.5, 20.5 Hz, 2H), 4.16 (d, J = 13.5 Hz, 1H), 3.96–3.90 (m, 1H), 3.80 (t, J = 16.0 Hz, 1H), 3.63 (t, J = 13.5 Hz, 1H), 3.25–3.12 (m, 5H), 3.09–2.86 (m, 3H), 2.65–2.53 (m, 3H), 1.84 (s, 3H), 1.80 (s, 3H), 1.71 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 178.8, 178.7, 157.1, 156.7, 156.5, 156.0, 141.4, 141.3, 138.4, 137.0, 136.0, 135.6, 135.1, 134.4, 130.1, 129.9, 129.8, 129.5, 129.5, 125.5, 125.0, 124.9, 124.8, 124.4, 123.7, 123.3, 122.4, 122.2, 119.5, 119.0, 118.7, 118.1, 114.9, 111.8, 111.5, 111.2, 111.2, 110.1, 109.8, 60.5, 58.3, 52.7, 52.6, 47.3, 47.3, 43.5, 43.4, 35.0, 34.8, 28.1, 26.3, 25.8, 24.5, 19.0, 18.3; IR (Neat Film NaCl) 3335, 2102, 1713, 1674 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C27H26N6O2F3 [M+H]+: 523.2064; found 523.1982. O O F 3C F 3C H N H N N3 o-NsCl, NaH N3 Cl THF, 0 °C (73% yield) N H 28 NH N N O O 29 Ns Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 48 Chloride 29. To a solution of adduct 28 (183 mg, 0.350 mmol, 1.0 equiv) in THF (4 mL) was added sodium hydride (60% dispersion in mineral oil, 42 mg, 1.05 mmol, 3.0 equiv) at 0 °C. The reaction mixture was stirred for 5 min and o-nitrobenzylsulfonyl chloride (116 mg, 0.523 mmol, 1.5 equiv) was added at 0 oC. The reaction was stirred for 10 min, and then a saturated solution of ammonium chloride was added. The resulting solution was extracted with EtOAc (3 x 3 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (15:1 → 2:1 hexanes:EtOAc) to afford alkyl chloride 29 (142 mg, 73% yield) as a white crystalline solid. For spectrum, see ref 41. Rf = 0.26 (2:1 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (300 MHz, CDCl3) δ 8.64–8.59 (m, 2H), 7.95–7.84 (m, 8H), 7.55–7.47 (m, 6H), 7.37–7.26 (m, 5H), 7.15 (d, J = 7.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 1H), 6.31 (d, J = 7.5 Hz, 2H), 5.76– 5.72 (m, 2H), 5.61 (d, J = 7.5 Hz, 1H), 4.20–4.08 (m, 2H), 3.94–3.67 (m, 3H), 3.31–3.19 (m, 2H), 2.99–2.74 (m, 6H), 2.29 (dd, J = 3.0, 10.5 Hz, 1H), 1.75 (s, 6H), 1.65 (s, 3H); 13 C NMR (75 MHz, CDCl3) δ 175.9, 175.8, 173.8, 173.6, 156.3, 155.9, 151.7, 151.6, 148.2, 147.9, 141.6, 140.7, 139.9, 139.7, 139.2, 138.2, 137.4, 136.9, 136.4, 136.0, 135.3, 135.2, 132.6, 130.9, 130.8, 130.4, 130.4, 128.3, 126.8, 126.6, 126.4, 126.3, 125.8, 125.4, 125.3, 125.2, 124.9, 121.7, 121.6, 120.6, 119.8, 118.6, 115.4, 115.3, 114.8, 77.7, 77.4, 77.2, 76.8, 75.7, 75.5, 60.1, 57.6, 55.7, 55.6, 46.5, 46.4, 40.0, 39.1, 37.8, 37.6, 36.1, 32.6, 26.5, 26.0, 18.6, 18.1; IR (Neat Film NaCl) 2102, 1755, 1686, 1544, 1146 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C33H28O7N7F3SCl [M+H]+: 758.1406; found 758.1442. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 49 O O F 3C H N H N 26, Cs2CO3 N H 25 O F 3C F 3C CH2Cl2 23 °C 28 + (24% yield) N H N N3 + NH N 3 H N N3 O N H 30 (32% yield) H O O N H 31 (24% yield) Adducts 28, 30, and 31. A flame-dried flask (100 mL) equipped with a teflon stirbar was charged with indole 25 (1.03 g, 3.21 mmol, 1.0 equiv) and bromooxindole 26 (2.25 mg, 8.02 mmol, 2.5 equiv), which were subsequently dissolved in dichloromethane (32 mL). Cesium carbonate (3.14 g, 9.62 mmol, 3.0 equiv) was then added. After addition, the reaction was stirred for 3 h, and then water was added. The resulting solution was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography (18:1 → 1:2 hexanes:EtOAc) to afford adduct 28 (404 mg, 24% yield), adduct 30 (538 mg, 32% yield), and adduct 31 (548 mg, 24% yield). For spectrum, see ref 41. Adduct 30: Rf = 0.18 (2:1 hexanes:EtOAc x2 elutions); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks), 1H NMR (300 MHz, CDCl3) δ 8.91 (d, J = 13.0 Hz, 2H), 8.33 (d, J = 6.0 Hz, 2H), 7.28–6.86 (m, 9H), 6.75 (d, J = 7.5 Hz, 1H), 6.11 (d, J = 7.5 Hz, 1H), 5.31 (dd, J = 7.5, 29.5 Hz, 2H), 4.30 (d, J = 13.5 Hz, 1H), 4.06–4.01 (m, 1H), 3.94–3.84 (m, 1H), 3.71 (t, J = 13.0 Hz, 1H), 3.29 (t, J = 13.0 Hz, 1H), 3.17–3.13 (m, 4H), 2.98 (d, J = 16.5 Hz, 1H), 2.89–2.75 (m, 2H), 2.53–2.44 (m, 2H), 1.76 (s, 3H), 1.72 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 181.1, 180.9, 157.4, 157.0, 156.7, 156.2, 141.1, 138.5, 137.5, 137.3, 137.1, 135.5, 134.8, 133.4, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 50 133.2, 132.2, 132.1, 128.8, 128.7, 125.1, 124.0, 123.6, 123.2, 123.1, 122.8, 122.5, 119.0, 118.7, 117.0, 115.7, 115.1, 114.9, 113.3, 112.6, 110.7, 108.6, 108.5, 60.6, 58.6, 55.5, 55.4, 47.9, 43.8, 43.7, 36.6, 36.3, 28.4, 26.3, 25.8, 25.0, 18.9, 18.3; IR (Neat Film NaCl) 3328, 2100, 1712, 1682 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C27H26N6O2F3 [M+H]+: 523.2064, found 523.2002. Adduct 31: Rf = 0.09 (2:1 hexanes:EtOAc x2 elutions); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks), 1H NMR (300 MHz, acetone-d6) δ 10.43 (d, J = 11.5 Hz, 1H), 9.80 (d, J = 8.0 Hz, 1H), 9.59 (s, 1H), 7.36–7.23 (m, 7H), 7.19–6.97 (m, 8H), 5.36 (dd, J = 7.0, 40.0 Hz, 2H), 4.02–3.50 (m, 6H), 3.25–3.10 (m, 8H), 3.04 (s, 2H), 3.01–2.44 (m, 8H), 1.76 (s, 3H), 1.73 (s, 3H), 1.68 (s, 6H); 13C NMR (75 MHz, acetone-d6) δ 180.2, 180.1, 177.9, 177.8, 143.1, 143.0, 142.9, 138.3, 137.4, 137.2, 136.8, 135.3, 134.8, 134.6, 134.4, 133.6, 133.3, 133.2, 133.0, 131.3, 129.9, 129.3, 129.2, 126.1, 125.3, 125.2, 125.0, 124.8, 123.9, 123.6, 122.9, 118.0, 147.1, 111.0, 110.9, 110.3, 109.9, 109.4, 109.2, 61.2, 59.2, 55.8, 55.7, 52.7, 52.7, 48.6, 47.6, 44.0, 37.0, 36.9, 35.4, 28.2, 26.1, 25.7, 24.8, 18.8, 18.3; IR (Neat Film NaCl) 3305, 2101, 1713, 1472 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C37H34N10F3O3 [M+H]+: 723.2762; found 723.2689. O O F 3C F 3C H N H N o-NsCl N N3 H O N H NaH, THF, 0 °C (66% yield) N N3 Ns O N Ns 30 SI-1-8 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 51 Nosylate SI-1-8. A flame-dried vial (4 mL) equipped with a teflon stirbar was charged with adduct 30 (43.7 mg, 0.0836 mmol), which was subsequently dissolved in THF (800 µL). The solution was cooled to 0 °C, and then sodium hydride (60% dispersion in mineral oil, 17 mg, 0.425 mmol) was added. 5 min after the sodium hydride addition, onitrobenzylsulfonyl chloride (93 mg, 0.420 mmol) was added. The reaction was stirred for 10 min, and then a saturated solution of ammonium chloride was added. The resulting solution was extracted 3 times with ether, the organic layers were combined and dried over magnesium sulfate, and the solvent was removed under reduced pressure. Purification was performed via flash column chromatography (9:1 →1:1 hexanes:EtOAc) to afford the bisnosylate SI-1-8 (49.0 mg, 66% yield) as a yellow solid. For spectrum, see ref 41. Rf = 0.42 (1:1 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1 H NMR and 13C NMR contained extra peaks), 1H NMR (300 MHz, CDCl3) δ 8.54–8.51 (m, 2H), 8.03–8.00 (m, 2H), 7.88–7.56 (m, 10H), 7.50 (s, 1H), 7.42–7.35 (m, 5H), 7.18– 7.12 (m, 3H), 6.95 (s, 1H), 6.61 (d, J = 7.5 Hz, 1H), 5.97 (d, J = 7.5 Hz, 1H), 5.23–5.16 (m, 2H), 4.27 (d, J = 13.5 Hz, 1H), 4.02 (d, J = 15.0 Hz, 1H), 3.89–3.79 (m, 1H), 3.64 (t, J = 11.0 Hz, 1H), 3.32–2.80 (m, 10H), 2.48–2.33 (m, 2H), 1.73 (s, 12H); 13C NMR (75 MHz, CDCl3) δ 176.2, 176.0, 157.3, 156.9, 156.5, 148.0, 148.0, 140.2, 140.1, 140.0, 138.6, 137.2, 136.6, 136.2, 136.0, 135.7, 135.5, 134.8, 134.7, 132.8, 132.8, 132.4, 131.2, 131.2, 131.1, 130.9, 130.6, 129.9, 129.8, 129.5, 129.2, 127.4, 127.0, 125.7, 125.7, 125.4, 125.4, 125.2, 125.1, 124.9, 122.8, 121.9, 121.1, 120.0, 118.8, 118.5, 117.9, 115.5, 114.9, 110.6, 60.2, 58.1, 55.0, 55.0, 47.5, 42.8, 42.7, 36.6, 36.6, 39.9, 28.0, 26.3, 25.8, 25.0, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 52 -1 18.9, 18.3; IR (Neat Film NaCl) 2930, 2101, 1754, 1684, 1544 cm ; HRMS (MM: ESIAPCI+) m/z calc’d for C39H32N8O12F3S2 [M+H]+: 925.1528, found 925.1613. O O F 3C F 3C H N H N PPh 3 N N3 Ns H 2O, THF, 50 °C (66% yield) O HN N O NsHN Ns N Ns SI-1-8 32 Lactam 32. To a solution of nosylate SI-1-8 (43.1 mg, 0.0483 mmol, 1.0 equiv) in THF (1 mL) and water (250 µL) was added triphenylphosphine (25 mg, 0.0953 mmol, 2.0 equiv). The reaction was stirred for 3 h at 50 °C, and then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (3:1 → 1:1 hexanes:EtOAc) to afford the lactam 32 (49.0 mg, 66% yield) as a yellow crystalline solid. For spectrum, see ref 41. Rf = 0.14 (1:1 hexanes:EtOAc); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks), 1H NMR (300 MHz, CDCl3) δ 7.75–7.50 (m, 6H), 7.43 (t, J = 7.5 Hz, 1H), 7.34–7.22 (m, 4H), 7.14 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 7.5 Hz, 2H), 6.55 (d, J = 6.5 Hz, 2H), 6.01 (d, J = 7.5 Hz, 1H), 5.32 (d, J = 8.0 Hz, 1H), 5.20 (d, J = 8.0 Hz, 1H), 4.26 (d, J = 13.5 Hz, 1H), 4.02 (d, J = 15.5 Hz, 1H), 3.81 (t, J = 11.5 Hz, 1H), 3.30–3.00 (m, 3H), 2.35–2.28 (m, 2H), 1.67 (s, 3H), 1.62 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 180.0, 157.3, 156.8, 156.7, 156.2, 147.9, 147.8, 147.7, 139.5, 139.4, 137.8, 137.5, 137.4, 136.9, 136.5, 136.4, 136.2, 136.1, 135.6, 135.3, 135.1, 133.6, 132.9, 132.5, 132.2, 132.0, 131.0, 130.9, 130.5, 129.0, 127.9, 127.8, 126.3, 126.2, 125.2, 125.1, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 53 125.0, 124.9, 124.8, 124.5, 124.4, 124.3, 123.3, 122.4, 121.4, 120.5, 119.2, 118.9, 118.5, 118.4, 115.1, 110.2, 109.7, 77.7, 77.4, 77.2, 76.8, 60.1, 58.2, 57.7, 43.0, 42.8, 39.8, 38.8, 28.5, 26.1, 25.7, 25.3, 18.9, 18.3; IR (Neat Film NaCl) 3098, 2916, 1682, 1545, 1368, 1170, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C39H34N6O12F3S2 [M+H]+: 899.1623, found 899.1731. Ts H N Ts N N TsCl, Et 3N N H SI-1-9 CH2Cl2 0 → 23 °C (82% yield) pyridinium tribromide N H SI-1-10 THF/t-BuOH/H2O 0 → 23 °C (75% yield) O N H SI-1-11 Oxindole SI-1-11. To a solution of indole SI-1-9 (106 mg, 0.614 mmol, 1.0 equiv) and Et3N (0.17 mL, 1.23 mmol, 2.0 equiv) in CH2Cl2 (4 mL) cooled to 0 oC was added a solution of TsCl (117 mg, 0.614 mmol, 1.0 equiv) in CH2Cl2 (3 mL) dropwise. The ice bath was removed and the reaction mixture was stirred for 5 h, then diluted with EtOAc (160 mL) and washed with 0.5 N HCl (2 x 30 mL) and brine. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) to afford indole SI-1-10 (164 mg, 82% yield). Indole SI-1-10 was dissolved in THF (10 mL), t-BuOH (10 mL) and water (1 mL). The solution was cooled to 0 oC and pyridinium tribromide (504 mg, 1.54 mmol, 1.02 equiv) was added. The reaction mixture was stirred at 0 oC for 45 min and then allowed to warm to ambient temperature. The reaction was quenched by addition of 10 mL of 1:1 v/v 1M Na2S2O3:sat. NaHCO3. The reaction mixture was diluted with brine (50 mL) and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 54 extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried with MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (2:1 hexanes:acetone) to afford oxindole SI-1-11 (397 mg, 75% yield) of as a white solid. Rf = 0.15 (1:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.04 (br, s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.21–7.14 (m, 3H), 6.94 (d, J = 7.7 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 4.80 (d, J = 15.5 Hz, 1H), 4.30 (d, J = 13.6 Hz, 1H), 4.15 (d, J = 15.5 Hz, 1H), 3.52 (dd, J = 12.5, 3.5 Hz, 1H), 3.24 (t, J = 12.6 Hz, 1H), 2.38 (s, 3H), 2.30 (m, 1H), 1.53 (m, 1H); 13C (75 MHz, CDCl3) δ 178.4, 143.3, 140.5, 137.1, 135.9, 129.6, 128.4, 128.3, 127.0, 121.5, 109.1, 53.3, 51.6, 46.2, 28.6, 21.5; IR (Neat Film NaCl) 3276, 2925, 2853, 1698, 1618, 1463, 1326, 1153 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C18H19N2O3S [M+H]+ : 343.1111; found: 343.1025. Ts Ts N N Br LiHMDS, NBS O N H SI-1-11 O THF, –78 → –40 °C (76% yield) N H 35 Bromooxindole 35. LiHMDS (429 mg, 2.57 mmol, 2.5 equiv) was dissolved in THF (5 mL). The solution was cooled to –78 oC and a solution of oxindole SI-1-11 (352 mg, 1.03 mmol, 1.0 equiv) in THF (20 mL) was added dropwise over 20 min. The reaction mixture was stirred at –78 oC for 20 min and transferred to a pre-cooled solution of Nbromosuccinimide (457 mg, 2.57 mmol, 2.5 equiv) in THF (10 mL) that was protected from light. The resulting reaction mixture was placed in a –40 oC bath for 1h, while being protected from light, and then quenched with sat. NH4Cl. The reaction mixture was Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 55 allowed to warm to ambient temperature, diluted with brine (100 mL) and extracted with EtOAc (3 x 70 mL). The combined organic extracts were dried over MgSO4 and concentrated to afford a yellow oil, which was purified by silica gel chromatography (2:1 hexanes:EtOAc) to afford bromooxindole 35 (334 mg, 76% yield) as a yellow solid. Rf = 0.40 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.49 (br, s, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.24–7.19 (m, 3H), 6.96 (d, J = 7.7 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 4.76 (d, J = 15.4 Hz, 1H), 4.32 (m, 2H), 3.80 (t, J = 13.2 Hz, 1H), 2.39 (s, 3H), 2.33 (m, 1H), 1.90 (m, 13 1H); C NMR (75 MHz, CDCl3) δ 175.1, 143.5, 139.0, 137.7, 136.9, 130.7, 129.7, 128.7, 126.9, 122.6, 110.1, 59.2, 51.6, 48. 3, 35.2, 21.5; IR (Neat Film NaCl) 3313, 2930, 1734, 1615, 1460, 1334, 1155, 1096, 727 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C18H18BrN2O3S [M+H]+: 421.0216; found: 421.0213. Ts Ts N Br O N H 35 N NC O2N CN 36 DBU, THF –78 → 23 °C (64% yield) O N O2N H 37 Nitrile 37. A solution of bromooxindole 35 (44.9 mg, 0.107 mmol, 1.0 equiv) and 2nitrophenylacetonitrile 36 (34.6 mg, 0.213 mmol, 2.0 equiv) in THF (3 mL) was cooled to –78 oC. DBU (64 µL, 0.426 mmol, 4.0 equiv) was added dropwise. The reaction mixture was then allowed to gradually warm to ambient temperature. After 8 h, the reaction mixture was quenched with sat. NH4Cl (10 mL) and the mixture was extracted with EtOAc (4 x 5 mL). The combined organic extracts were dried over MgSO4 and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 56 concentrated under reduced pressure to afford a brown oil, which was purified by preparatory thin layer chromatography on silica gel (1:1 hexane:EtOAc x2 elutions) to afford nitrile 37 (34.8 mg, 64% yield) as an orange-yellow solid. Rf = 0.28 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.92 (m, 1H), 7.63 (m, 2H), 7.55 (m, 2H), 7.43 (m, 2H), 7.29 (d, J = 8.0 H, 2H), 7.18 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.48 (d, J = 7.4 Hz, 1H), 6.07 (s, 1H), 4.80 (d, J = 16.2 Hz, 1H), 4.29 (m, 2H), 3.45 (app. t, J = 13.2 Hz, 1H), 2.74 (app. dd, J = 15.0, 2.6 Hz, 1H), 2.43 (s, 3H), 1.94 (m, 13 1H); C NMR (75 MHz, CDCl3) δ 176.2, 147.9, 143.8, 140.3, 137.9, 136.5, 133.5, 132.5, 131.0, 130.3, 130.0, 127.0, 124.8, 124.5, 124.5, 123.7, 116.2, 109.4, 54.4, 52.6, 46.8, 34.2, 32.1, 21.6; IR (Neat Film NaCl) 3302, 2920, 1724, 1527, 1155, 724 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C26H23N4O5S [M+H]+ : 503.1384; found: 503.1411. Ts Ts N MeO 2C Br + CO2Me O2N THF –78 → 23 °C (32% yield) O N H 35 N DBU 38 CO2Me CO2Me O NO N H 2 39 Aryl malonate 39. To a solution of bromooxindole 35 (50.0 mg, 0.119 mmol, 1.0 equiv) and malonate 38 (90.1 mg, 0.356 mmol, 3.0 equiv) in THF (0.6 mL) was added DBU (54.2 mg, 0.356 mmol, 3.0 equiv) at –78 oC. The reaction solution was slowly warmed to 23 oC. The reaction solution was stirred for 12 h, and quenched with sat. NH4Cl. The mixture was extracted with EtOAc (3 x 1 mL) and brine. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure and then the residue Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 57 was purified by preparatory thin layer chromatography on silica gel (1:1 hexane:EtOAc) to afford nitrile 39 (23 mg, 32% yield). Rf = 0.15 (1:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.85 (br, s, 1H), 8.23 (dd, J = 8.0, 1.5 Hz, 1H), 7.58–7.51 (m, 5H), 7.24 (d, J = 8.0 Hz, 2H), 6.96 (dd, J = 7.5, 1.5 Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.66 (d, J = 1.0 Hz, 1H), 4.44 (d, J = 15.4 Hz, 1H), 4.15 (d, J = 15.4 Hz, 1H), 3.95 (d, J = 14.6 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.69 (m, 1H), 2.40 (s, 3H), 1.95 (d, J = 14.6 Hz, 1H), 1.66 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 179.1, 168.8, 148.1, 143.4, 141.2, 138.7, 137.0, 134.7, 133.9, 132.0, 129.7, 129.1, 128.3, 126.8, 125.7, 122.8, 110.7, 74.8, 68.7, 53.7, 53.5, 51.3, 46.0, 33.4, 21.5; IR (Neat Film NaCl) 3313, 1737, 1623, 1530, 1450, 1347, 1241, 1153, 1091, 895, 729 cm-1; HRMS (FAB) m/z calc’d for C29H26N3O9S [M-H]- : 592.1395; found: 592.1382. Ts H N Ts N N TsCl, Et 3N N H 4 CH2Cl2 0 → 23 °C (80% yield) pyridinium tribromide N H SI-1-12 THF/t-BuOH/H2O 0 → 23 °C (80% yield) O N H SI-1-13 Oxindole SI-1-13. To a solution of aurantioclavine 4 (300 mg, 0.00133 mol, 1.0 equiv) and Et3N (0.37 mL, 0.00265 mol, 2.0 equiv) in CH2Cl2 (4 mL) cooled to 0 oC was added a solution of TsCl (254 mg, 0.00133 mmol, 1.0 equiv) in CH2Cl2 (3 mL) dropwise. The ice bath was removed and the reaction mixture was stirred for 5 h, then diluted with EtOAc (200 mL) and washed with 0.5 N HCl (2 x 35 mL) and brine. The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) to afford indole SI-1-12 (405 mg, 80% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 58 A solution of indole SI-1-12 (902.2 mg, 2.371 mmol, 1.0 equiv) in THF/t-BuOH/H2O (10:10:1 v/v/v, 52.5 mL) was cooled to 0 oC and pyridinium tribromide (834.2 mg, 2.608 mmol, 1.1 equiv) was added in small portions over 5 min. The reaction mixture was stirred at 0 oC for 15 min, and then allowed to warm to ambient temperature. After 5 min at ambient temperature, the reaction mixture was quenched by addition of 1:1 v/v sat. NaHCO3:1M aq Na2S2O3 (15 mL), poured into brine (150 mL) and extracted with EtOAc (3 x 100 mL). The combined extracts were dried over Na2SO4 and concentrated under reduced pressure to afford a brown solid, which was purified by silica gel chromatography (2:1 → 1:1 hexanes:EtOAc) to afford oxindole SI-1-13 (747.5 mg, 80% yield). Rf = 0.22 (5:1 benzene:MeCN); 1H NMR (300 MHz, CDCl3) δ 8.12 (br, s, 1H), 7.33 (dd, J = 8.5, 2.1 Hz, 2H), 7.03 (m, 1H), 6.96 (d, J = 7.2 Hz, 2H), 6.82 (d, J = 7.7 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 5.76 (d, J = 8.0 Hz, 1H), 5.31 (m, 1H), 4.00 (dt, J = 15.7, 2.8 Hz, 1H), 3.64–3.50 (m, 2H), 2.22 (s, 3H), 2.00 (m, 1H), 1.67 (s, 3H), 1.65 (s, 3H), 1.25 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 178.4, 142.9, 140.9, 140.5, 138.2, 129.2, 128.3, 128.3, 127.0, 126.7, 121.3, 119.0, 108.7, 59.0, 46.0, 43.8, 27.8, 26.0, 21.4, 18.5; IR (Neat Film NaCl) 3246, 2925, 1713, 1615, 1460, 1326, 1155, 732 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C22H25N2O3S [M+H]+ : 397.1580; found: 397.1586. Ts Ts H N Ts N N NBS, LiHMDS Br O N H SI-1-13 THF –78 → –15 °C (64% yield) + O N H 40 O N H SI-1-14 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 59 Bromooxindole 40. A solution of oxindole SI-1-13 (172.0 mg, 0.434 mmol, 1.0 equiv) in THF (5 mL) was added dropwise to a freshly prepared solution of LiHMDS (217.8 mg, 1.301 mmol, 3.0 equiv) in THF (5 mL) that had been pre-cooled to –78 oC. After 20 min at –78 oC, the resulting solution was transferred via cannula to a solution of Nbromosuccinimide (231.6 mg, 1.301 mmol, 3.0 equiv) in THF (5 mL) that had been precooled to –78 oC. The resulting yellow reaction mixture was allowed to warm to –15 oC (the reaction flask was transferred to a bath composed of ethylene glycol and dry ice) and maintained at this temperature for 2 h. The reaction mixture was then cooled to –78 oC and quenched by addition of sat. NH4Cl (5 mL). The yellow reaction mixture was allowed to warm to ambient temperature and diluted with H2O (80 mL), then extracted with EtOAc (3 x 70 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4 and concentrated under reduced pressure to afford a yellow oil, which was purified immediately by silica gel chromatography (2:1 hexanes:EtOAc) to afford a 3:1 mixture of bromooxindole 40 (>20:1 dr) and dehydrobromination product SI1-14 (131.1 mg, 64% combined yield, 50% yield of bromooxindole 40). Bromooxindole 40 was stored frozen in benzene and used without further purification. The relative configuration of this bromooxindole was assigned based on the stereochemistry of the malonate adduct obtained (see below). Quenching the reaction prior to completion afforded the bromooxindole 40 as a single diastereomer, which showed greater stability, and could be fully characterized. Rf = 0.50 (1:1 hexane:EtOAc); 1H NMR (300 MHz, CDCl3) δ 8.62 (br, s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.21 (t, J = 8.0, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.90 (d, J = 7.5 Hz, 1H), 6.79 (dd, J = 8.0, 1.0 Hz, 1H), 5.96 (td, J = 8.5, 1.5 Hz, 1H), 5.88 (d, J = 8.5 Hz, 1H), Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 60 4.18–4.02 (m, 2H), 2.35 (s, 3H), 2.27 (m, 1H), 1.97 (m, 1H), 1.76 (d, J = 1.0 Hz, 3H), 1.75 (d, J = 1.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.8, 143.2, 142.4, 140.2, 139.2, 137.8, 130.8, 129.4, 126.9, 126.1, 122.7, 120.1, 109.7, 66.8, 59.5, 39.8, 34.4, 26.1, 21.4, 18.4; IR (Neat Film NaCl) 3291, 1734, 1617, 1602, 1457, 1326, 1156, 1092, 738 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H23BrN2O3S [M+H]+ : 475.0686; found: 475.0668. Ts H Ts H N N MeO 2C Br CO2Me CO2Me 41 DBU CO2Me O O N H 40 >20:1 dr THF –78 → 23 °C (74% yield) N H 42 >20:1 dr Malonate 42. Bromooxindole 40 (>20:1 dr, 51.3 mg, 0.108 mmol, 1.0 equiv) was dissolved in THF (2 mL). Dimethyl malonate 41 (37 µL, 0.324 mmol, 3.0 equiv) was added and the reaction mixture was cooled to –78 oC. DBU (48 µL, 0.324 mmol, 3.0 equiv) was added dropwise. The reaction mixture was stirred at –78 oC for 15 min and then warmed to 23 oC. After maintaining the reaction mixture at 23 oC for 6 h, sat. NH4Cl (2 mL) was added and the reaction mixture was warmed to ambient temperature. The reaction mixture was diluted with EtOAc (50 mL) and sat. NH4Cl (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic extracts were dried over Na2SO4 and concentrated to afford colorless oil. Analysis of the crude oil by 1H NMR indicated >20:1 dr of the malonate adduct 42. The residue was purified by silica gel chromatography (1:1 hexane:EtOAc) to afford malonate 42 (42 mg, 74% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 61 1 Rf = 0.20 (1:1 hexane:EtOAc); H NMR (300 MHz, CDCl3) δ 7.88 (br, s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.91, (d, J = 7.5 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 5.92 (d, J = 4.5 Hz, 1H), 5.38 (d, J = 4.5 Hz, 1H), 4.62 (s, 1H), 4.06 (m, 1H), 3.89 (m, 1H), 3.78 (s, 3H), 3.46 (s, 3H), 2.40 (m, 1H), 2.30 (s, 3H), 1.82 (s, 3H), 1.79 (s, 3H), 1.07 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 177.8, 166.8, 166.8, 143.0, 141.9, 141.4, 141.0, 137.9, 129.2, 128.9, 127.6, 127.0, 123.0, 124.0, 109.0, 59.6, 53.9, 52.9, 52.3, 51.3, 39.8, 28.9, 26.4, 21.4, 18.6; IR (Neat Film NaCl) 3338, 2953, 1733, 1618, 1597, 1458, 1327, 1158 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C27H31N2O7S [M+H]+ : 527.1846; found: 527.1848. NO 2 O O F O K 2CO3 O O O SI-1-15 DMF, 90 °C (89% yield) O O NO 2 44 Diallyl 2-(2-nitrophenyl)malonate 44. A 500 mL round-bottom flask with a magnetic stir bar was charged with diallyl malonate SI-1-15 (22.0 g, 118 mmol, 1.0 equiv), 1fluoro-2-nitrobenzene (13.7 mL, 129 mmol, 1.1 equiv), and K2CO3 (48.9 g, 354 mmol, 3.0 equiv). DMF (120 mL) was added and the brown suspension was heated to 90 oC for 16 h. The reaction mixture was cooled to ambient temperature and diluted with ice water (250 mL) and Et2O (300 mL). The aqueous phase was extracted with Et2O (3 x 300 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (9:1 hexanes:EtOAc) on silica gel to give arylated malonate 44 (32.1 g, 89% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 62 1 Rf = 0.51 (1:1 hexane:Et2O); H NMR (500 MHz, CDCl3) δ 8.08 (dd, J = 8.5, 1.4 Hz, 1H), 7.66 (td, J = 7.6, 1.4 Hz, 1H), 7.55–7.51 (m, 2H), 5.90 (ddt, J = 17.3, 10.4, 5.7 Hz, 2H), 5.39-5.23 (m, 5H), 4.70 (dt, J = 5.8, 1.4 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 166.8, 148.7, 133.6, 131.4, 131.1, 129.3, 127.9, 125.3, 119.1, 66.8, 54.3; IR (Neat Film NaCl) 3086, 2950, 1738, 1611, 1530, 1447, 1350, 1154, 991, 937, 852, 787, 722 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C15H16NO6 [M+H]+: 306.0972; found: 306.0930. O F O NO 2 O + O O O NO 2 DMF, 90 °C (80% yield) O SI-1-15 K 2CO3 O Br Br 45 Diallyl 2-(4-bromo-2-nitrophenyl)malonate 45. A 500 mL round-bottom flask with a magnetic stir bar was charged with diallyl malonate SI-1-15 (15.0 g, 81.5 mmol, 1.0 equiv), 4-bromo-1-fluoro-2-nitrobenzene (11.0 mL, 89.7 mmol, 1.1 equiv), and K2CO3 (33.8 g, 245 mmol, 3.0 equiv). DMF (163 mL) was added and the brown suspension was heated to 90 oC for 16 h. The reaction mixture was cooled to ambient temperature and diluted with ice water (250 mL) and Et2O (300 mL). The aqueous phase was extracted with Et2O (3 x 300 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (9:1 hexanes:EtOAc) on silica gel to give arylated malonate 45 (32.1 g, 80% yield). Rf = 0.69 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.4, 2.1 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.94–5.84 (m, 2H), 5.37–5.24 (m, 5H), 4.70 (dt, J = 5.9, 1.3 Hz, 4H); 13C NMR (125 MHz, CDCl3) δ 166.4, 149.1, 136.5, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 63 132.8, 131.0, 128.2, 126.8, 122.8, 119.3, 66.9, 53.8; IR (Neat Film NaCl) 3085, 2986, 2951, 1733, 1649, 1538, 1348, 1283, 1218, 1148, 989, 936 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C15H15BrNO6 [M+H]+: 384.0077; found: 384.0072. TIPSO O Br O O AllylO OAllyl + NO 2 N H 43 Oxindole 46. TIPSO NO 2 Cs2CO3 THF, 0 °C (85% yield) 44 CO2Allyl CO2Allyl O N H 46 To a suspension of Cs2CO3 (5.37 g, 16.5 mmol, 3.0 equiv) and bromooxindole 43 (2.27 g, 5.50 mmol, 1.0 equiv) in THF (100 mL) was added malonate 44 (5.04 g, 16.5 mmol, 3.0 equiv) at 0 °C. The reaction mixture was then allowed to slowly warm to 23 oC and stirred for 16 h. Solids were removed via a filtration through a celite plug (rinsed with EtOAc) and the resulting purple solution was concentrated under reduced pressure. The residue was purified by column chromatography using a Teledyne Isco CombiFlash (SiO2, 120 g column, 100:0 → 3:1 hexanes:EtOAc) to provide alkylation product 46 (8.9 g, 85% yield) as a colorless oil. Rf = 0.18 (3:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.73 (dd, J = 7.9, 1.6 Hz, 1H), 7.41 (dt, J = 8.0, 1.6 Hz, 1H), 7.38– 7.33 (m, 2H), 7.13 (dt, J = 7.7, 1.1 Hz, 1H), 6.89 (dt, J = 7.7, 1.0 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 5.88–5.73 (m, 2H), 5.25 (ddd, J = 17.2, 2.8, 1.4 Hz, 1H), 5.19–5.11 (m, 3H), 4.69 (tdd, J = 13.3, 5.7, 1.4 Hz, 1H), 4.64 (tdd, J = 13.3, 5.7, 1.3 Hz, 1H), 4.57 (tdd, J = 13.4, 5.9, 1.4 Hz, 1H), 4.48 (tdd, J = 13.1, 5.9, 1.1 Hz, 1H), 3.35 (ddd, J = 9.5, 8.5, 6.9 Hz, 1H), 3.07 (dt, J = 9.5, 4.5 Hz, 1H), 2.95 (ddd, J = 12.9, 8.7, 7.0 Hz, 1H), 2.63 (ddd, J = Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 64 13 12.9, 8.5, 4.5 Hz, 1H), 0.97–0.77 (m, 21H); C NMR (125 MHz, CDCl3) δ 177.8, 166.7, 166.3, 150.2, 140.7, 132.4, 131.3, 131.0, 130.8, 129.5, 129.2, 128.5, 126.9, 125.3, 122.4, 119.2, 118.4, 109.1, 66.8, 66.7, 59.5, 56.7, 38.3, 17.8, 11.8; IR (Neat Film NaCl) 3332, 2942, 1714, 1649, 1618, 1538, 1471, 1356, 1230, 1114, 995, 933, 885, 850, 752, 683 cm1 ; HRMS (MM: ESI-APCI+) m/z calc’d for C34H45N2O8Si [M+H]+ : 637.2940; found: 637.2945. Br AllylO2C TIPSO Br CO2Allyl NO 2 + O N H 43 Br 45 TIPSO NO 2 Cs2CO3 THF 0 → 23 °C (96% yield) CO2Allyl CO2Allyl O N H 47 Oxindole 47. To a solution of 3-bromooxindole 43 (2.0 g, 4.85 mmol, 1.0 equiv) and malonate 45 (3.7 g, 9.70 mmol, 2.0 equiv) in THF (49 mL) was added Cs2CO3 (3.2 g, 9.70 mmol, 2.0 equiv) at 0 oC. The reaction mixture was warmed to 23 oC and stirred overnight. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (9:1 → 4:1 hexanes:EtOAc) on silica gel to give desired alkylated product 47 (3.3g, 96% yield). Rf = 0.33 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.00 (br, s, 1H), 7.95 (d, J = 8.9 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.8, 2.3 Hz, 1H), 7.43–7.39 (m, 1H), 7.16 (td, J = 7.7, 1.2 Hz, 1H), 6.92 (td, J = 7.7, 1.1 Hz, 1H), 6.75–6.72 (m, 1H), 5.79 (dddt, J = 33.6, 17.2, 10.4, 5.9 Hz, 2H), 5.26–5.18 (m, 2H), 5.19–5.14 (m, 2H), 4.66 (qdt, J = 13.2, 5.9, 1.4 Hz, 2H), 4.55–4.42 (m, 2H), 3.32 (dt, J = 9.7, 7.5 Hz, 1H), 3.09 (ddd, J Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 65 = 9.8, 8.5, 4.5 Hz, 1H), 2.89–2.82 (m, 1H), 2.63 (ddd, J = 12.7, 8.1, 4.5 Hz, 1H), 0.89 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 178.0, 166.6, 166.2, 150.9, 140.9, 134.3, 134.1, 131.3, 130.8, 129.0, 129.0, 128.6, 128.3, 127.2, 122.7, 122.2, 119.6, 119.0, 109.5, 67.2, 67.1, 66.9, 59.7, 57.0, 38.4, 18.0, 11.9; IR (Neat Film NaCl) 3203, 2943, 2865, 1716, 1619, 1538, 1471, 1357, 1229, 1111, 992, 935, 753, 735 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C34H44BrN2O8Si [M+H]+: 715.2045; found: 715.2090. TIPSO NO 2 CO2Allyl CO2Allyl O N H 46 TIPSO NO 2 Cs2CO3, MeI THF 0 → 23 °C (99% yield) CO2Allyl CO2Allyl O N 48 Methyloxindole 48. To a suspension of oxindole 46 (0.50 g, 0.79 mmol, 1.0 equiv) and Cs2CO3 (0.77 g, 2.37 mmol, 3.0 equiv) in THF (4.0 mL) was added methyl iodide (0.3 mL, 4.7 mmol, 6.0 equiv) at 0 oC. The reaction mixture was stirred for 12 h at 23 oC. After the reaction was done, sat. NH4Cl was added. The aqueous phase was extracted with EtOAc (3 x 3 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (3:1 hexanes:EtOAc) to give methylated oxindole 48 (0.51g, 99% yield). Rf = 0.33 (3:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.54 (dd, J = 7.9, 1.5 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.31 (dt, J = 7.7, 1.6 Hz, 1H), 7.25 (dt, J = 7.8, 1.2 Hz, 1H), 7.10 (dt, J = 7.7, 0.9 Hz, 1H), 6.85 (dt, J = 7.8, 0.8 Hz, 1H), 6.57 (d, J = 7.7 Hz, 1H), 5.80 (tdd, J = 16.3, 10.7, 5.8 Hz, 1H), 5.71 (tdd, J = 16.4, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 66 10.5, 5.9 Hz, 1H), 5.22–5.02 (m, 4H), 4.69–4.56 (m, 2H), 4.52 (tdd, J = 13.1, 5.8, 1.3 Hz, 1H), 4.36 (tdd, J = 13.3, 5.9, 1.3 Hz, 1H), 3.15–3.02 (m, 4H), 2.96 (ddd, J = 9.7, 8.3, 4.7 Hz, 1H), 2.85 (td, J = 13.2, 7.4 Hz, 1H), 2.67 (ddd, J = 12.8, 8.0, 4.7 Hz, 1H), 0.86–0.71 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 176.3, 166.5, 166.5, 150.3, 143.6, 132.7, 131.3, 130.9, 130.3, 128.8, 128.5, 128.5, 128.3, 126.9, 125.1, 122.3, 119.1, 118.5, 107.3, 66.7, 66.7, 59.6, 56.8, 37.9, 26.1, 17.8, 11.7; IR (Neat Film NaCl) 3421, 3054, 2944, 2866, 1723, 1613, 1539, 1473, 1356, 1253, 1180, 1104, 1068, 935, 862, 840, 752, 690 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C35H47N2O8Si [M+H]+ : 651.3096; found: 651.3184. Br TIPSO Br NO 2 CO2Allyl CO2Allyl O N H 47 TIPSO NO 2 Cs2CO3, MeI THF 0 → 23 °C (92% yield) CO2Allyl CO2Allyl O N 49 Methyloxindole 49. To a solution of oxindole 47 (14.1 g, 0.0197 mol, 1.0 equiv) in THF (106 mL) was added Cs2CO3 (19.3 g, 0.0591 mol, 3.0 equiv) and MeI (7.40 mL, 0.118 mol, 6.0 equiv) at 0 oC. Then, the reaction mixture was stirred for 12 h at 23 oC. After the reaction was done, sat. NH4Cl was added. The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (7:1 hexanes:EtOAc) on silica gel to give methylated oxindole 49 (13.2 g, 92% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 67 1 Rf = 0.40 (4:1 hexanes:EtOAc); H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.9 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.53–7.48 (m, 2H), 7.21 (td, J = 7.7, 1.2 Hz, 1H), 6.95 (td, J = 7.6, 1.1 Hz, 1H), 6.69–6.66 (m, 1H), 5.85 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.74 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.26–5.20 (m, 2H), 5.18 (ddt, J = 10.4, 2.2, 1.2 Hz, 2H), 4.72– 4.63 (m, 2H), 4.54 (ddt, J = 13.1, 6.0, 1.4 Hz, 1H), 4.40 (ddt, J = 13.0, 6.0, 1.3 Hz, 1H), 3.18–3.13 (m, 1H), 3.13 (s, 3H), 3.05 (ddd, J = 9.9, 7.9, 4.7 Hz, 1H), 2.82 (dt, J = 13.0, 7.6 Hz, 1H), 2.71 (ddd, J = 12.8, 7.6, 4.7 Hz, 1H), 0.90–0.84 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 176.3, 166.3, 166.2, 150.8, 143.7, 134.4, 133.4, 131.1, 130.8, 128.8, 128.1, 128.0, 127.0, 122.5, 122.1, 119.4, 119.0, 107.6, 67.0, 66.9, 66.9, 59.6, 56.8, 37.9, 26.3, 17.8, 17.8, 11.8; IR (Neat Film NaCl) 2943, 2865, 1747, 1713, 1611, 1538, 1471, 1357, 1223, 1103, 993, 935, 882, 752 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C35H46BrN2O8Si [M+H]+: 729.2201; found: 729.2253. TIPSO O NO 2 CO2Allyl CO2Allyl O N O AcCl CO2Allyl MeOH 0 → 65 °C (85% yield) O NO N 2 48 50 Lactone 50. Acetyl chloride (46.0 μL, 650 μmol, 10.0 equiv) was added to MeOH (1.0 mL) and cooled to 0 °C. The resulting mixture was stirred for 30 min and then the solution of oxindole 48 (21.0 mg, 32.0 μmol, 1.0 equiv) in MeOH (2.0 mL) was added. The reaction was stirred for 2 h at 23 oC and then heated to 65 °C. The reaction mixture was stirred for 16 h at that temperature. The colorless solution was cooled to ambient temperature, concentrated under reduced pressure and subjected to column Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 68 chromatography (4:1 hexanes:EtOAc) to afford the desired lactone 50 (12 mg, 85% yield) as a colorless solid. Rf = 0.29 (50% EtOAc in hexanes); 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.4 Hz, 1H), 7.39–7.31 (m, 3H), 7.23–7.15 (m, 2H), 6.82–6.75 (m, 2H), 5.92 (tdd, J = 17.1, 10.6, 5.8 Hz, 1H), 5.30 (ddd, J = 17.2, 2.7, 1.3 Hz, 1H), 5.21 (ddd, J = 10.4, 2.4, 1.2 Hz, 1H), 4.98–4.90 (m, 2H), 4.74 (tdd, J = 13.1, 5.8, 1.3 Hz, 1H), 4.71–4.64 (m, 2H), 3.32 (s, 3H), 2.84–2.70 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3) δ 175.8, 166.5, 165.7, 149.2, 142.2, 131.7, 131.4, 131.1, 128.8, 129.7, 129.3, 129.0, 128.9, 125.6, 124.8, 122.5, 118.9, 108.5, 67.5, 65.4, 53.7, 30.2, 26.7; IR (Neat Film NaCl) 2096, 1718, 1637, 1533, 1475, 1358, 1232, 1184, 760 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H21N2O7 [M+H]+ : 437.1343; found: 437.1298. O O CO2Allyl O NO N 2 50 Pd(PPh 3)4 (2.5 mol%) THF (90% yield) O O O NO N 2 51 Lactone 51. An oven dried flask was charged with ester 50 (1.3 g, 3.05 mmol, 1.0 equiv), sealed with a rubber stopper and evacuated. The flask was brought in a glove box and Pd(PPh3)4 (84 mg, 75.0 μmol, 0.025 equiv) was added. The flask was brought out of the dry box and THF (60 mL) was added. The reaction mixture was stirred for 5 min and concentrated under reduced pressure. Column chromatography using a Teledyne Isco CombiFlash Rf (SiO2, 80 g column, 25→50% EtOAc in hexanes) afforded the desired protected alkylation product 51 (1.1 g, 90% yield) as a colorless solid. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 69 1 Rf = 0.40 (1:1 hexane:EtOAc); H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 7.9, 1.6 Hz, 1H), 7.18 (dt, J = 7.8, 1.4 Hz, 1H), 7.12 (dt, J = 7.5, 1.7 Hz, 1H), 7.07 (dt, J = 7.7, 1.1 Hz, 1H), 7.00 (d, J = 7.7 Hz, 1H), 6.85 (dd, J = 8.0, 1.3 Hz, 1H), 6.68 (d, J = 7.7 Hz, 1H), 6.64 (dt, J = 7.7, 1.0 Hz, 1H), 5.55 (tdd, J = 17.0, 10.2, 6.7 Hz, 1H), 5.33 (ddd, J = 11.6, 10.0, 3.4 Hz, 1H), 5.01 (ddd, J = 17.1, 3.0, 1.5 Hz, 1H), 4.93 (ddd, J = 10.3, 2.7, 1.2 Hz, 1H), 4.68 (td, J = 11.6, 4.7 Hz, 1H), 3.45 (tdd, J = 15.6, 6.6, 1.3 Hz, 1H), 3.26 (s, 3H), 2.99 (tdd, J = 9.0, 6.9, 1.3 Hz, 1H), 2.87 (ddd, J = 14.6, 10.0, 4.6 Hz, 1H), 2.21 (ddd, J = 14.7, 4.8, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 177.3, 168.5, 149.8, 142.1, 133.9, 133.1, 131.1, 130.6, 130.4, 128.6, 127.8, 125.7, 124.8, 122.2, 119.0, 107.6, 64.8, 54.2, 54.0, 43.7, 30.7, 26.5; IR (Neat Film NaCl) 1701, 1614, 1531, 1473, 1356, 1300, 1259, 1202, 1105, 929, 739 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H21N2O5 [M+H]+ : 393.1445; found: 393.1458. Br Br TIPSO NO 2 CO2Allyl CO2Allyl O Pd(PPh 3)4 (5.0 mol%) TIPSO NO 2 THF, –78 °C (78% yield) CO2Allyl O N N 49 52 Allyl 52. To a 500 mL round-bottom flask with a magnetic stir bar was added malonate 49 (11.1 g, 15.2 mmol, 1.0 equiv). The flask was brought into a N2-filled glove box and then Pd(PPh3)4 (0.88 g, 0.761 mol, 0.05 equiv) was added. The reaction mixture was brought out from the glove box and treated with THF (152 mL). After 1 h stirring, the solvent was evaporated under reduced pressure. The residue was purified by column Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 70 chromatography (1:1 hexane:EtOAc) on silica gel to afford allylated product 52 (8.1 g, 78% yield). Rf = 0.45 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.80 (dd, J = 8.6, 2.2 Hz, 1H), 7.22 (td, J = 7.7, 1.1 Hz, 1H), 6.83–6.77 (m, 2H), 6.33 (d, J = 7.5 Hz, 1H), 5.66 (ddt, J = 16.9, 10.3, 6.2 Hz, 1H), 5.56 (ddt, J = 17.0, 10.1, 6.9 Hz, 1H), 5.16–5.09 (m, 2H), 4.91 (dq, J = 17.1, 1.5 Hz, 1H), 4.84 (ddd, J = 10.2, 1.9, 1.1 Hz, 1H), 4.38–4.26 (m, 2H), 3.37 (dd, J = 15.3, 7.0 Hz, 1H), 3.23 (s, 3H), 3.21–3.10 (m, 2H), 2.90 (ddd, J = 9.5, 8.5, 4.2 Hz, 1H), 2.59–2.51 (m, 1H), 2.16 (ddd, J = 12.5, 8.1, 4.3 Hz, 1H), 0.92–0.80 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 177.7, 169.6, 152.1, 144.3, 134.8, 134.5, 133.7, 131.3, 131.1, 128.9, 128.8, 128.70, 125.13, 121.9, 121.8, 119.5, 118.2, 108.1, 65.7, 60.7, 59.5, 55.5, 39.0, 36.6, 26.5, 18.0, 11.9; IR (Neat Film NaCl) 2942, 2865, 1713, 1610, 1538, 1495, 1471, 1353, 1106, 995, 918, 882, 750, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C34H46BrN2O6Si [M+H]+: 685.2303; found: 685.2294. 1. (COCl)2, Et 2O 0 → 23 °C Br N H 58 2. MeOH, Et 2O 0 → 23 °C (78% yield, 2 steps) Br O O OMe N H SI-1-16 Oxoacetate SI-1-16. To a solution of 4-bromoindole 58 (8.0 g, 40.8 mmol, 1.0 equiv) in Et2O (204 mL) was added oxalyl chloride (9.25 mL, 102 mmol, 2.5 equiv) dropwise at 0 o C. The reaction mixture was stirred for 16 h at 23 oC. The resulting suspension was filtered and washed with cold ether. The filter cake was dried in vacuo to afford the oxoacetyl chloride, which was used without further purification. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 71 o To a solution of oxoacetyl chloride in Et2O (204 mL) was added MeOH (10 mL) at 0 C, and stirred for 2 h. The resulting mixture was concentrated in vacuo and purified by flash column chromatography (4:1 hexanes:EtOAc) on silica gel to give oxoacetate SI-1-16 (9.0 g, 78% yield, 2 steps). Rf = 0.23 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.01 (br, s, 1H), 8.27 (d, J = 3.2 Hz, 1H), 7.52 (dd, J = 7.6, 0.8 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 7.8Hz, 1H), 3.95 (s, 13 3H); C NMR (125 MHz, CDCl3) δ 178.3, 164.0, 137.8, 136.2, 128.3, 125.3, 125.2, 115.3, 115.0, 111.0, 53.0; IR (Neat Film NaCl) 3206, 1656, 1500, 1410, 1306, 1252, 1196, 1139, 1104, 789, 770, 731 cm1 ; HRMS (MM: ESI-APCI+) m/z calc’d for C11H9BrNO3 [M+H]+ : 281.9760; found: 281.9760. Br O O OMe N H OH LAH THF 0 → reflux (91% yield) SI-1-16 Br N H 59 Alcohol 59. To a solution of oxoacetate SI-1-16 (6.8 g, 24.1 mmol, 1.0 equiv) in THF (120 mL) was added LAH (2.8 g, 72.3 mmol, 3.0 equiv) in portions at 0 oC. The reaction mixture was refluxed for 4 h. When the reaction was done, the solution was cooled to 0 o C, and quenched by Fieser work-up2. The suspension was filtered and the filter cake was washed with EtOAc. The combined organic phases were concentrated in vacuo, and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine,                                                                                                                 2 Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis 1967, 581-595. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 72 dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 hexane:EtOAc) on silica gel to give alcohol 59 (5.3 g, 91% yield). Rf = 0.27 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.18 (br, s, 1H), 7.31 (dd, J = 7.6, 0.8 Hz, 1H), 7.28 (dd, J = 7.6, 0.8 Hz, 1H), 7.12 (dd, J = 2.8Hz, 1H), 7.01 (t, J = 7.8 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 3.28 (dt, J = 6.4, 0.8 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 137.8, 125.4, 124.1, 123.0, 114.4, 113.1, 110.6, 63.6, 29.5 ; IR (Neat Film NaCl) 3369, 2929, 1899, 1613, 1478, 1425, 1335, 1185, 1029, 913, 815, 770, 736 cm -1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H11BrNO [M+H]+ : 240.0019; found: 240.0021. OH Br OTIPS TIPSCl, imidazole N H 59 DMF, 23 °C (98% yield) Br N H SI-1-17 TIPS-ether SI-1-17. To a solution of alcohol 59 (8.1 g, 33.7 mmol, 1.0 equiv) in DMF (112 mL) was added imidazole (5.0 g, 74.2 mmol, 2.2 equiv) and TIPSCl (10.7 mL, 50.6 mmol, 1.5 equiv). After stirring for 3 h at 23 oC, water (10 mL) was added. The aqueous phase was extracted with Et2O (3 x 100 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (9:1 hexanes:EtOAc) on silica gel to give TIPS-ether SI-117 (13.1 g, 98% yield). Rf = 0.56 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.06 (br, s, 1H), 7.30–7.25 (m, 2H), 7.12 (d, J = 2.4 Hz, 1H), 6.99 (t, J = 7.8 Hz, 1H), 4.00 (t, J = 7.1 Hz, 2H), 3.27 (t, J = 7.1 Hz, 2H), 1.05-1.07 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 137.4, 125.7, 124.4, 123.9, 122.6, 114.3, 114.1, 110.4, 64.9, 29.9, 18.1, 12.0; IR (Neat Film NaCl) Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 73 3425, 3286, 2942, 1614, 1561, 1549, 1463, 1425, 1382, 1336, 1246, 1184, 1102, 1064, 1013, 913, 883, 826, 772, 738 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C19H31BrNOSi [M+H]+ : 396.1353; found: 396.1357. TIPSO OTIPS Br pyridinium tribromide N H Br Br t-BuOH, H 2O, THF 23 °C (89% yield) SI-1-17 O N H 57 3-Bromooxindole 57. To a solution of indole SI-1-17 (5.0 g, 12.6 mmol, 1.0 equiv) in tBuOH (100 mL), THF (25 mL), and water (1.1 mL) was added pyridinium tribromide (7.9 g, 24.6 mmol, 1.95 equiv). The reaction mixture was stirred for 30 min and then diluted with EtOAc (50 mL) and water (80 mL). The aqueous phase was extracted with EtOAc (3 x 150 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (4:1 hexanes:EtOAc) on silica gel to give 3-bromooxindole 57 (5.5 g, 89% yield). Rf = 0.31 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.64 (br, s, 1H), 7.19 (dd, J = 8.1, 1.0 Hz, 1H), 7.13 (t, J = 7.9 Hz, 1H), 6.86 (dd, J = 7.6, 1.0 Hz, 1H), 3.66 (ddd, J = 10.4, 5.5, 3.3 Hz, 1H), 3.46 (td, J = 10.5, 3.8 Hz, 1H), 3.08 (dt, J = 13.9, 3.5 Hz, 1H), 2.90 (ddd, J = 13.9, 10.6, 5.4 Hz, 1H), 0.87 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 175.8, 142.3, 131.2, 127.5, 127.0, 120.8, 109.5, 60.6, 56.1, 39.6, 17.8, 11.8; IR (Neat Film NaCl) 2941, 2864, 2109, 1728, 1613, 1583, 1312, 1102, 882, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C19H30Br2NO2Si [M+H]+ : 490.0407; found: 490.0340. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 74 TIPSO O Br Br O O AllylO OAllyl + NO 2 N H 57 44 Cs2CO3 THF, 0 °C (95% yield) TIPSO NO 2 Br CO2Allyl CO2Allyl O N H SI-1-18 Oxindole SI-1-18. To a solution of 3-bromooxindole 57 (5.6 g, 11.4 mmol, 1.0 equiv) and malonate 44 (5.2 g, 17.1 mmol, 1.5 equiv) in THF was added Cs2CO3 (7.4 g, 22.8 mmol, 2.0 equiv) at 0 oC. The reaction mixture was stirred for 1 h at 0 oC. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (9:1 → 4:1 hexanes:EtOAc) on silica gel to give desired alkylated product SI-1-18 (5.4 g, 95% yield). Rf = 0.18 (3:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.01 (dd, J = 8.3, 1.3 Hz, 1H), 7.90 (dd, J = 8.1, 1.5 Hz, 1H), 7.68 (ddd, J = 8.5, 7.4, 1.6 Hz, 1H), 7.55 (d, J = 5.3 Hz, 1H), 7.51 (td, J = 7.7, 1.2 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.93 (dd, J = 8.1, 1.0 Hz, 1H), 6.78 (dd, J = 7.6, 1.0 Hz, 1H), 5.92–5.81 (m, 2H), 5.76–5.68 (m, 1H), 5.26–5.18 (m, 2H), 5.17–5.10 (m, 2H), 4.76-4.69 (m, 1H), 4.68-4.63 (m, 1H), 4.51–4.47 (m, 1H), 4.25– 4.20 (m, 1H), 3.33–3.26 (m, 1H), 3.23–3.13 (m, 2H), 2.97-2.90 (m, 1H), 0.91 (m, 21H); 13 C NMR (125 MHz, CDCl3) δ 177.4, 167.0, 166.0, 144.4, 133.8, 131.8, 131.3, 131.1, 129.8, 129.3, 128.3, 127.5, 126.9, 126.5, 121.82, 119.6, 119.0, 118.9, 108.5, 67.6, 66.6, 66.5, 59.5, 58.3, 32.9, 17.9, 11.9; IR (Neat Film NaCl) 3350, 3086, 2943, 1732, 1612, 1574, 1531, 1446, 1354, 1228, 1169, 1104, 992, 931, 789 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C34H44BrN2O8Si [M+H]+ : 715.2045; found 715.2055. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 75 TIPSO NO 2 Br CO2Allyl CO2Allyl O N H SI-1-18 Cs2CO3, MeI THF, 23 °C (92% yield) TIPSO NO 2 Br CO2Allyl CO2Allyl O N 60 Methyloxindole 60. To a solution of oxindole SI-1-18 (5.6 g, 11.2 mmol, 1.0 equiv) in THF (56 mL) was added Cs2CO3 (10.9 g, 33.6 mmol, 3.0 equiv) and MeI (4.3 mL, 67.2 mmol, 6.0 equiv) at 0 oC. Then, the reaction mixture was stirred for 12 h at 23 oC. After the reaction was done, sat. NH4Cl was added. The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (7:1 hexanes:EtOAc) on silica gel to give methylated oxindole 60 (7.5 g, 92% yield). Rf = 0.38 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.01 (dd, J = 8.3, 1.3 Hz, 1H), 7.91 (dd, J = 8.1, 1.6 Hz, 1H), 7.69 (ddd, J = 8.5, 7.3, 1.6 Hz, 1H), 7.54–7.50 (m, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.95 (dd, J = 8.1, 1.0 Hz, 1H), 6.78 (dd, J = 7.8, 1.0 Hz, 1H), 5.88 (ddt, J = 16.5, 10.4, 5.8 Hz, 1H), 5.71 (ddt, J = 16.7, 10.2, 6.3 Hz, 1H), 5.27– 5.11 (m, 4H), 4.78 (ddt, J = 13.1, 6.0, 1.4 Hz, 1H), 4.68 (ddt, J = 13.1, 5.6, 1.5 Hz, 1H), 4.47 (ddt, J = 12.7, 6.3, 1.2 Hz, 1H), 4.21 (ddt, J = 12.8, 6.4, 1.2 Hz, 1H), 3.24 (s, 3H), 3.20–3.15 (m, 3H), 3.00–2.93 (m, 1H), 0.91 (s, 21H); 13C NMR (125 MHz, CDCl3) δ 176.14, 167.03, 165.81, 152.74, 147.67, 147.67, 133.81, 131.78, 131.42, 131.19, 129.73, 129.21, 128.45, 126.99, 126.85, 126.54, 121.57, 119.44, 106.83, 67.43, 66.37, 65.91, 59.57, 57.96, 32.75, 26.77, 17.90, 11.85; IR (Neat Film NaCl) 2917, 2863, 1721, 1600, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 76 -1 1529, 1450, 1350, 1231, 1088, 923, 883, 852 cm ; HRMS (MM: ESI-APCI+) m/z calc’d for C35H46BrN2O8Si [M+H]+ : 729.2201; found: 729.2240. O TIPSO NO 2 Br CO2Allyl CO2Allyl O N p-TsOH H 2O , benzene 85 °C, microwave (85% yield) 60 O Br CO2Allyl O NO N 2 61 Lactone 61. To a 20 mL microwave vial with a magnetic stir bar were added oxindole 60 (500 mg, 0.69 mmol, 1.0 equiv), p-TsOH (520 mg, 2.7 mmol, 4.0 equiv), and benzene (20 mL). The reaction was sealed with a microwave crimp cap and subjected to microwave irradiation in a Biotage Initiator microwave reactor (temperature: 85 oC, sensitivity: low) with a gradual temperature increase over 10 min (10 oC increments). After 20 min of stirring, the vial was cooled to ambient temperature and uncapped. The reaction was diluted with EtOAc (10 mL) and quenched by addition of sat. NaHCO3. The phases were separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford lactone 61 (300 mg, 85% yield). Rf = 0.23 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.11 (dd, J = 8.2, 1.5 Hz, 1H), 8.00–7.98 (m, 1H), 7.71 (dd, J = 9.1, 7.6 Hz, 1H), 7.61–7.57 (m, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.1, 1.0 Hz, 1H), 6.87 (dd, J = 7.8, 1.0 Hz, 1H), 5.75–5.66 (m, 1H), 5.18–5.07 (m, 3H), 4.71 (td, J = 11.0, 10.4, 7.4 Hz, 1H), 4.55 (ddt, J = 12.9, 5.9, 1.3 Hz, 1H), 4.26 (ddt, J = 12.9, 6.2, 1.3 Hz, 1H), 3.63 (ddd, J = 15.2, 13.1, 7.3 Hz, 1H), 3.34 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 77 13 (s, 3H), 1.69–1.64 (m, 1H); C NMR (125 MHz, CDCl3) δ 175.2, 165.3, 152.1, 145.9, 136.8, 133.5, 131.9, 130.9, 130.2, 130.2, 127.7, 127.5, 119.3, 107.9, 70.5, 67.1, 64.9, 60.4, 54.5, 27.0, 24.1, 21.1, 14.2; IR (Neat Film NaCl) 2929, 1742, 1713, 1601, 1532, 1456, 1353, 1192, 1112, 1058, 1033, 993, 936, 856, 767 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H20BrN2O7 [M+H]+ : 515.0448; found: 515.0450. O Br O CO2Allyl O NO N 2 Pd(PPh 3)4 (2.0 mol%) THF, 23 °C (97% yield) 61 O Br O O NO N 2 62 Allyl 62. To a 250 mL round-bottom flask with a magnetic stir bar was added lactone 61 (2.5 g, 4.9 mmol, 1.0 equiv). The flask was brought into a N2-filled glove box, and then Pd(PPh3)4 (0.1 g, 0.097 mmol, 0.02 equiv) was added. The reaction mixture was brought out from the glove box and treated with THF (97 mL). After 5 min stirring, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford allylated product 62 (2.0 g, 97% yield). Rf = 0.24 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.66 (dd, J = 8.0, 1.6 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.20 (dd, J = 9.6, 6.5 Hz, 2H), 7.01 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.48 (d, J = 8.1 Hz, 1H), 5.52 (ddt, J = 16.6, 12.0, 6.4 Hz, 1H), 5.43–5.35 (m, 1H), 4.79–4.72 (m, 3H), 4.32 (td, J = 13.7, 7.2 Hz, 1H), 3.31 (s, 3H), 3.13 (dd, J = 15.6, 5.0 Hz, 1H), 2.43–2.36 (m, 1H), 1.73 (dd, J = 14.7, 5.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 175.5, 169.8, 152.4, 146.0, 134.7, 134.3, 130.9, 130.7, 130.4, 128.5, 128.3, 126.0, 125.2, 124.0, 117.8, 107.6, 64.7, 56.7, 54.2, 42.9, 26.4, 23.8; IR (Neat Film Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 78 NaCl) 3418, 2923, 1709, 1601, 1532, 1455, 1361, 1292, 1201, 1113, 1069, 986, 917, 777, 736 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H20BrN2O5 [M+H]+ : 471.0550; found: 471.0552. O Br O O Br O3 O NO N 2 62 CH2Cl2, MeOH then DMS –78 °C (94% yield) O O O NO N 2 63 Aldehyde 63. A solution of alkene 62 (47.1 mg, 100 μmol, 1.0 equiv) in a mixture of CH2Cl2 (2.5 mL) and MeOH (2.5 mL) in a Schlenk flask hooked up to an ozone generator was purged with oxygen gas at –78 °C (5 min, flow 0.25). Then the ozone generator was turned on (low–medium setting) and an ozone/oxygen gas mixture was bubbled through the reaction. The progress of the reaction was checked via TLC (9:1 hexanes:CH2Cl2) in short time intervals (1-2 min). Upon completion of the reaction, the mixture was purged with oxygen gas for 5 min and DMS (36.0 μg, 500 μmol, 5.00 equiv) was added. The reaction mixture was slowly warmed to ambient temperature, and stirred for 16 h. The residue was purified by column chromatography (9:1 CH2Cl2:EtOAc) on silica gel to afford aldehyde 63 (44 mg, 94% yield). Rf = 0.28 (9:1 CH2Cl2:EtOAc); 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 3.4 Hz, 1H), 7.83–7.79 (m, 1H), 7.65–7.59 (m, 1H), 7.43–7.39 (m, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 5.15 (ddd, J = 12.5, 10.8, 4.7 Hz, 1H), 4.59 (dd, J = 11.1, 6.9 Hz, 1H), 3.94 (ddd, J = 14.5, 12.6, 7.1 Hz, 1H), 3.22 (s, 3H), 3.08 (d, J = 17.0 Hz, 1H), 2.67 (dd, J = 17.0, 3.5 Hz, 1H), 1.96 (dd, J = 14.7, 4.6 Hz, 1H); 13C NMR (125 MHz, DMSO) δ 198.0, 174.8, 171.0, 151.5, 146.3, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 79 133.3, 131.9, 131.3, 129.9, 129.7, 127.6, 125.5, 124.6, 122.4, 109.3, 65.4, 55.6, 52.6, 49.8, 26.4, 22.3; IR (Neat Film NaCl) 1695, 1600, 1528, 1458, 1354, 1294, 1222, 1118, 850, 787 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C21H18BrN2O6 [M+H]+ : 473.0343 found:473.0346. PMB O Br HO O O PMBNH 3OAc NaBH 3CN O NO N 2 63 MeOH, THF (67% yield) Br O N N O NO 2 65 Amide 65. To a suspension of aldehyde 63 (47.3 mg, 100 μmol, 1.0 equiv) and the acetic acid ammonium salt of para-methoxybenzylamine (59.2 mg, 300 μmol, 3.0 equiv) in MeOH (4 mL) was added NaBH3CN (2.60 mg, 300 μmol, 3.0 equiv) in THF (2 mL). The reaction mixture was stirred at ambient temperature for 16 h (conversion of the suspension to a clear, colorless solution usually indicated the completion of the reaction) and then concentrated under reduced pressure. Column chromatography using a Teledyne Isco CombiFlash Rf (SiO2, 12 g column, 1. 1:1 → 1:4 hexanes:EtOAc) yielded lactam 65 (39.7 mg, 67% yield) as a colorless solid. Rf = 0.12 (19:1 CH2Cl2:MeOH); 1H NMR (500 MHz, CDCl3) δ 9.10 (dd, J = 8.3, 1.4 Hz, 1H), 7.59–7.55 (m, 1H), 7.43 (ddd, J = 8.4, 7.3, 1.3 Hz, 1H), 7.36 (dd, J = 8.0, 1.6 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.10 (dd, J = 8.2, 1.0 Hz, 1H), 7.06–7.02 (m, 2H), 6.81– 6.76 (m, 3H), 4.71 (d, J = 14.6 Hz, 1H), 3.98 (d, J = 14.6 Hz, 1H), 3.76 (s, 3H), 3.53– 3.49 (m, 1H), 3.18 (s, 3H), 3.16–3.08 (m, 3H), 2.90 (ddd, J = 9.6, 8.5, 3.2 Hz, 1H), 2.78 (dt, J = 9.6, 7.3 Hz, 1H), 2.25 (ddd, J = 14.1, 7.1, 3.1 Hz, 1H), 2.14 (ddd, J = 14.0, 8.6, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 80 13 7.6 Hz, 1H); C NMR (125 MHz, CDCl3) δ 177.7, 171.7, 159.2, 152.6, 147.2, 134.4, 130.9, 130.4, 130.3, 129.9, 129.0, 128.0, 127.9, 126.3, 125.5, 122.4, 114.1, 107.3, 60.1, 58.5, 55.7, 55.4, 47.4, 44.0, 32.1, 27.5, 26.8; IR (Neat Film NaCl) 3459, 2931, 1682, 1601, 1574, 1530, 1457, 1360, 1249, 1176, 1037, 910, 849, 783, 731 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C29H29BrN3O6 [M+H]+ : 594.1234; found: 594.1230. O HO O Br TiCl3, NH 4OAc O NO N 2 MeCN, H 2O, MeOH 23 °C (80% yield) 62 Br NH OO N 67 Bis-oxindole 67. To a solution of lactone 62 (2.4 g, 5.6 mmol, 1.0 equiv) in H2O (282 mL) and MeOH (565 mL) were added NH4OAc (43.5 g, 564 mmol, 100.0 equiv) and TiCl3 (10% w/w, 70.3 mL, 56.4 mmol, 10.0 equiv). Then, the reaction was stirred for 12 h at 23 oC. The reaction mixture was diluted with EtOAc (500 mL) and then the phases were separated and the aqueous phase was extracted with EtOAc (3 x 300 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford bis-oxindole 67 (1.99 g, 80% yield). Rf = 0.10 (1:1 hexane:EtOAc); 1H NMR (500 MHz, DMSO) δ 10.33 (s, 1H), 6.98 (dd, J = 8.1, 1.0 Hz, 1H), 6.96–6.87 (m, 2H), 6.77–6.67 (m, 2H), 6.58 (dd, J = 7.8, 1.0 Hz, 1H), 6.45 (d, J = 7.6 Hz, 1H), 4.96 (ddt, J = 16.7, 9.7, 6.9 Hz, 1H), 4.86 (dd, J = 17.0, 2.5 Hz, 1H), 4.74 (dd, J = 9.9, 2.6 Hz, 1H), 4.39 (t, J = 5.0 Hz, 1H), 3.41–3.32 (m, 2H), 3.22– 3.13 (m, 1H), 3.03 (s, 3H), 2.86 (dtd, J = 10.3, 7.9, 5.5 Hz, 1H), 2.76 (dd, J = 13.5, 6.8 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 81 13 Hz, 1H), 2.24 (dt, J = 13.2, 7.9 Hz, 1H); C NMR (125 MHz, DMSO) δ 177.5, 175.8, 146.5, 142.8, 133.4, 130.2, 128.5, 128.1, 126.9, 126.8, 123.5, 120.4, 119.3, 118.9, 108.9, 107.4, 58.4, 57.2, 56.0, 33.5, 28.9, 26.3; IR (Neat Film NaCl) 2917, 2356, 1697, 1599, 1574, 1455, 1349, 1184, 910, 752 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H22BrN2O3 [M+H]+ : 441.0808; found 441.0812. HO TIPSO Br NH OO N 67 TIPSCl, imidazole DMF 0 → 23 °C (90% yield) Br NH OO N SI-1-19 TIPS-ether SI-1-19. Bis-oxindole 67 (1.66 g, 3.76 mmol, 1.0 equiv) was dissolved in DMF (18.8 mL) to which TIPSCl (1.61 mL, 7.52 mmol, 2.0 equiv) and imidazole (1.02 g, 15.0 mmol, 4.0 equiv) were added at 0 oC. The reaction was slowly warmed to 23 oC, and stirred for 12 h. The reaction mixture was extracted with EtOAc (3 x 40 mL), and washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford TIPS protected compound SI-1-19 (2.02 g, 90% yield). Rf = 0.20 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 6.99–6.92 (m, 2H), 6.87–6.80 (m, 2H), 6.76 (t, J = 7.5 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 6.28 (d, J = 7.7 Hz, 1H), 5.10 (ddt, J = 16.9, 9.9, 7.1 Hz, 1H), 4.97 (dd, J = 17.1, 2.1 Hz, 1H), 4.77 (dd, J = 9.9, 2.2 Hz, 1H), 3.73 (ddd, J = 8.7, 5.7, 2.6 Hz, 1H), 3.57 (dd, J = 13.6, 7.1 Hz, 1H), 3.47–3.41 (m, 2H), 3.05 (s, 3H), 2.97 (dd, J = 13.6, 7.1 Hz, 1H), 2.60 (ddd, J = 15.0, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 82 13 11.5, 5.6 Hz, 1H), 0.87–0.82 (m, 21H); C NMR (125 MHz, CDCl3) δ 178.1, 175.8, 146.3, 140.9, 132.6, 129.3, 128.2, 127.0, 126.8, 123.7, 120.6, 119.4, 119.1, 108.5, 106.2, 60.9, 57.7, 56.8, 33.0, 28.8, 25.9, 17.8, 17.8, 11.8; IR (Neat Film NaCl) 3191, 3081, 2942, 2865, 2251, 2699, 1602, 1471, 1337, 1236, 1108, 995, 920, 736 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H42BrN2O3Si [M+H]+ : 597.2143; found 597.2141. TIPSO Br NH OO N SI-1-19 methyl chloroformate Et 3N, DMAP CH2Cl2 0 → 23 °C (98% yield) TIPSO Br N CO Me 2 OO N 68 Carbamate 68. To a stirred solution of bis-oxindole SI-1-19 (350 mg, 0.59 mmol, 1.0 equiv) in CH2Cl2 (5.86 mL) were added DMAP (7 mg, 0.059 mmol, 0.1 equiv), Et3N (0.812 mL, 5.9 mmol, 10.0 equiv), and methyl chloroformate (0.16 mL, 1.76 mmol, 3.0 equiv) at 0 oC. The reaction was slowly warmed to 23 oC, and stirred for 12 h. The solvent was concentrated in vacuo, and then the residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford carbamate 68 (377 mg, 98% yield). Rf = 0.61 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.53 (dt, J = 8.2, 0.8 Hz, 1H), 7.05 (ddd, J = 8.1, 6.1, 2.9 Hz, 1H), 6.96 (dd, J = 8.2, 1.0 Hz, 1H), 6.92–6.91 (m, 2H), 6.82 (t, J = 7.9 Hz, 1H), 6.25 (dd, J = 7.8, 1.0 Hz, 1H), 5.06 (ddt, J = 16.6, 9.6, 6.9 Hz, 1H), 5.00 – 4.95 (m, 1H), 4.81–4.78 (m, 1H), 4.00 (s, 3H), 3.72 (ddd, J = 10.2, 5.7, 3.1 Hz, 1H), 3.61 (ddt, J = 13.8, 6.9, 1.0 Hz, 1H), 3.43 (td, J = 10.4, 3.9 Hz, 1H), 3.33– 3.28 (m, 1H), 3.04–2.99 (m, 1H), 3.02 (s, 3H), 2.62 (ddd, J = 14.0, 10.6, 5.7 Hz, 1H), 0.87–0.81 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 175.3, 174.2, 151.3, 146.1, 139.5, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 83 132.0, 129.6, 128.6, 127.1, 126.5, 126.2, 123.2, 122.7, 119.9, 119.0, 113.9, 106.3, 60.7, 58.4, 57.3, 53.7, 33.4, 28.9, 26.0, 17.7, 11.8; IR (Neat Film NaCl) 2942, 2865, 2089, 1722, 1602, 1463, 1348, 1201, 1243, 1166, 1104, 1026, 920, 883, 736, 772 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C33H44BrN2O5Si [M+H]+ : 655.2197; found 655.2199. TIPSO TIPSO Br N CO Me 2 OO N O 3 then PPh 3 CH2Cl2 –78 °C (94% yield) 68 O Br N CO Me 2 OO N 69 Aldehyde 69. To a 25 mL round bottom flask with magnetic stir bar was added alkene 68 (260 mg, 0.40 mmol, 1.0 equiv) and CH2Cl2 (2.0 mL). The flask was connected to an ozone generator, and purged with oxygen gas (flow: 0.5), for 5 min at –78 oC and then ozone gas (flow: 0.5) was bubbled through into the reaction solution for 10 min at –78 oC. After the reaction was done, oxygen gas was bubbled into the reaction mixture for 20 min and PPh3 (313mg, 1.19 mmol, 3.0 equiv) was added. The reaction mixture was slowly warmed to ambient temperature, stirred for 16 h, and then concentrated under reduced pressure. The residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford aldehyde 69 (245 mg, 94% yield). Rf = 0.13 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.46 (d, J=1.0 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.06–7.01 (m, 1H), 6.99 (d, J = 8.1 Hz, 1H), 6.88–6.82 (m, 2H), 6.75 (d, J = 7.6 Hz, 1H), 6.23 (d, J = 7.8 Hz, 1H), 4.33 (d, J = 19.4 Hz, 1H), 4.02 (s, 3H), 3.72 (ddd, J = 9.3, 5.6, 2.7 Hz, 1H), 3.58 (dd, J = 19.3, 1.2 Hz, 1H), 3.42 (td, J = 10.3, 3.4 Hz, 1H), 3.23 (dt, J = 14.0, 3.4 Hz, 1H), 2.99 (s, 3H), 2.56–2.48 (m, 1H), 0.86–0.79 (m, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 84 13 21H); C NMR (125 MHz, CDCl3) δ 197.9, 175.4, 174.4, 151.3, 146.0, 140.0, 129.9, 128.8, 127.2, 126.5, 125.2, 122.6, 121.4, 119.3, 114.1, 106.5, 60.6, 58.2, 53.8, 52.8, 44.6, 28.9, 26.0, 17.7, 11.8; IR (Neat Film NaCl) 2942, 2865, 2255, 1773, 1718, 1603, 1576, 1459, 1351, 1295, 1245, 1163, 1108, 914, 883, 771, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C32H41BrN2O6Si [M+H]+ : 657.1990; found: 657.1991. TIPSO PMB O TIPSO Br NCO 2Me PMBNH 3OAc, NaBH 3CN OO N THF, MeOH, 0 → 23 °C (95% yield) N Br O O N HN CO2Me 69 54 Lactam 54. To a solution of aldehyde 69 (100 mg, 0.15 mmol, 1.0 equiv) and pmethoxybenzylammonium acetate (90 mg, 0.46 mmol, 3.0 equiv) in methanol (7.6 mL) was added NaBH3CN (21 mg, 0.30 mmol, 2.0 equiv) in THF (3.8 mL) at 0 oC. The reaction mixture was slowly warmed to 23 oC and stirred overnight. The reaction mixture was washed with EtOAc (3 x 10 mL), and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford lactam 54 (112 mg, 95% yield). Rf = 0.20 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 12.14 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 7.15–7.10 (m, 2H), 7.05 (q, J = 8.5, 7.9 Hz, 2H), 6.88 (t, J = 7.7 Hz, 1H), 6.85–6.80 (m, 2H), 6.49 (d, J = 7.7 Hz, 1H), 4.80 (d, J = 14.4 Hz, 1H), 4.36 (d, J = 14.4 Hz, 1H), 3.78 (s, 3H), 3.70 (s, 1H), 3.63 (s, 3H), 3.52 (td, J = 6.9, 3.6 Hz, 1H), 3.43–3.36 (m, 1H), 3.27 (td, J = 9.3, 5.7 Hz, 1H), 3.17 (t, J = 9.6 Hz, 1H), Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 85 2.87 (ddd, J = 13.3, 6.1, 3.5 Hz, 1H), 2.66–2.60 (m, 1H), 2.56 (s, 3H), 2.54–2.49 (m, 1H), 0.85 (q, J = 3.8 Hz, 21H); 13C NMR (125 MHz, CDCl3) δ 175.94, 173.92, 159.34, 154.32, 146.89, 139.65, 132.30, 130.98, 130.07, 129.75, 128.88, 128.50, 127.57, 127.42, 126.71, 126.45, 121.74, 120.99, 120.75, 114.18, 107.15, 68.21, 61.31, 60.86, 60.43, 55.34, 51.42, 47.61, 44.98, 31.20, 25.78, 17.86, 11.88; IR (Neat Film NaCl) 2944, 2865, 2073, 1716, 1667, 1604, 1513, 1455, 1247, 1227, 1109, 1069, 1034, 883, 761 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C40H53BrN3O6Si [M+H]+ : 778.2882; found: 778.2879. PMB H OMe TIPSO N Br N TIPSO O AlH3-Me2NEt O N HN CO2Me N Br THF, 0 °C (61% yield) O N CO2Me 54 71 Aminal 71. To a solution of amide 54 (0.32 g, 0.41 mmol, 1.0 equiv) in THF (41.1 mL) was added AlH3-Me2NEt (0.5 M in toluene; 1.64 mL, 0.82 mmol, 2.0 equiv) dropwise at 0 oC. The reaction was stirred for 2 h and quenched with MeOH. The reaction solution was concentrated in vacuo and purified by column chromatography (4:1 hexanes:EtOAc) to afford aminal 71 (0.19 g, 61% yield). 1 H NMR (300 MHz, CDCl3) δ 7.58–7.47 (m, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.04–6.93 (m, 3H), 6.80 (dq, J = 14.8, 7.4 Hz, 4H), 6.39–6.24 (m, 2H), 4.00 (d, J = 13.7 Hz, 1H), 3.92– 3.79 (m, 4H), 3.78 (s, 3H), 3.68 (dd, J = 10.2, 5.0 Hz, 1H), 3.57–3.43 (m, 1H), 3.03 (s, 3H), 2.65 (m, 4H), 2.26 (dt, J = 15.0, 7.2 Hz, 1H), 2.09 (dd, J = 11.9, 4.6 Hz, 1H), 0.87 (d, J = 3.2 Hz, 21H); 13C NMR (125 MHz, CDCl3) δ 176.0, 175.7, 160.6, 146.3, 141.7, 133.9, 132.2, 130.3, 130.1, 126.8, 123.6, 123.2, 123.1, 115.1, 114.6, 113.9, 107.3, 107.1, 106.6, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 86 82.4, 60.7, 60.1, 57.2, 55.3, 52.6, 51.0, 31.9, 31.1, 30.7, 29.7, 26.1, 17.7, 11.8; IR (Neat Film NaCl) 2943, 1722, 1604, 1464, 1386, 1344, 1254, 1107, 1033, 885, 760 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C40H53BrN3O5Si [M+H]+ : 762.2932; found: 762.2936. PMB H N TIPSO CO2Me N Br O N 1. TBAF, THF, 23 °C (98% yield) 2. DDQ, CH2Cl2, H 2O 23 °C (85% yield) 71 H N HO H CO2Me N Br O N 72 Aminal 72. To a solution of silyl ether 71 (98 mg, 0.13 mmol, 1.0 equiv) in THF (1.28 mL) was added TBAF (0.15 mL, 1.0 M solution in THF) at 0 oC. The reaction mixture was stirred for 3 h at 23 oC and quenched with sat. NH4Cl. The reaction mixture was washed with EtOAc (3 x 1.5 mL), and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford PMB-protected aminal compound (78 mg, 98% yield). To a solution of PMB-protected aminal compound (96 mg, 0.16 mmol, 1.0 equiv) in CH2Cl2 (3.1 mL) and H2O (0.8 mL) was added DDQ (53 mg, 0.23 mmol, 1.5 equiv) in portions over 30 min at 0 oC. The reaction mixture was stirred for 2 h at 23 oC. The solution was diluted with CH2Cl2 and quenched with sat. NaHCO3. The reaction mixture was washed with CH2Cl2 (3 x 2.5 mL), and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 87 chromatography (4:1 CH2Cl2:acetone) on silica gel to afford aminal 72 (64 mg, 85% yield). Rf = 0.31 (4:1 CH2Cl2:acetone); 1H NMR (600 MHz, CDCl3) δ 7.50 (d, J = 8.1 Hz, 1H), 7.01–6.96 (m, 2H), 6.84 (p, J = 8.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.73 (t, J = 7.5 Hz, 1H), 6.48 (s, 1H), 6.35 (d, J = 7.8 Hz, 1H), 3.87 (d, J = 17.2 Hz, 3H), 3.66 (ddd, J = 10.8, 6.8, 3.7 Hz, 1H), 3.35 (dt, J = 10.9, 5.3 Hz, 1H), 3.11 (s, 3H), 3.01 (dd, J = 10.0, 6.5 Hz, 1H), 2.8–2.76 (m, 1H), 2.76–2.62 (m, 2H), 2.50 (td, J = 10.3, 4.7 Hz, 1H), 2.24 (br, s, 1H), 2.20 (dd, J = 12.7, 4.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 177.6, 152.8, 146.1, 142.7, 130.4, 129.7, 128.9, 127.4, 127.2, 122.8, 121.6, 118.5, 113.8, 106.8, 80.5, 63.4, 60.0, 57.2, 52.6, 44.6, 35.1, 31.5, 26.3; IR (Neat Film NaCl) 3417, 2925, 1710, 1604, 1487, 1458, 1392, 1362, 1272, 1093, 756 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H25BrN3O4 [M+H]+ : 486.1023; found: 486.1014. PMB TIPSO Br O O N HN PMB TIPSO N LiAlH 4 THF, 0 °C (83% yield) N H O HN CO2Me O N CO2Me 54 73 Oxindole 73. To a solution of lactam 54 (10.6 mg, 0.0136 mmol, 1.0 equiv) in THF (1.36 ml) was added LiAlH4 (5.2 mg, 0.136 mmol, 10.0 equiv) in portions at 0 oC. The reaction was stirred for 1 h and then quenched with sat. NaCl. The reaction mixture was washed with EtOAc (3 x 2 mL) and brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford oxindole 73 (7.9 mg, 83% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 88 1 Rf = 0.25 (4:1 hexanes:EtOAc); H NMR (600 MHz, CDCl3) δ 9.64 (br, s, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.60 (s, 1H), 7.13 (d, J = 8.4 Hz, 3H), 7.09 (t, J = 7.6 Hz, 1H), 7.04 (t, J = 7.7 Hz, 1H), 6.97 (s, 1H), 6.83 (d, J = 8.3 Hz, 3H), 6.38 (d, J = 7.7 Hz, 1H), 4.55 (d, J = 14.5 Hz, 1H), 4.44 (d, J = 14.5 Hz, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 3.31–3.27 (m, 1H), 3.24 (br, s, 2H), 3.14 (br, s, 1H), 3.05–3.00 (m, 1H), 2.85 (s, 3H), 2.72 (s, 1H), 2.52 (t, J = 9.9 Hz, 1H), 2.41 (br, s, 1H), 0.86 (q, J = 7.5, 6.2 Hz, 21H); 13C NMR (125 MHz, CDCl3) δ 177.5, 159.4, 154.7, 143.7, 129.6, 129.4, 129.3, 129.2, 128.6, 128.4, 127.7, 127.5, 127.4, 122.2, 122.0, 121.8, 114.3, 107.3, 60.0, 56.6, 55.4, 52.1, 47.1, 44.0, 34.3, 29.9, 26.0, 18.0, 12.0; IR (Neat Film NaCl) 2941, 1732, 1711, 1610, 1515, 1442, 1375, 1248, 1225, 1105, 1070, 1036, 750 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C40H54N3O6Si [M+H]+ : 700.3776; found: 700.3776. PMB TIPSO Br N Br O O N HN CO2Me 54 Tf2O CH2Cl2 0 → 23 °C (95% yield) N O N CO2Me O N PMB 74 PMB-Propellane hexacycle 74. To a solution of lactam 54 (70 mg, 0.090 mmol, 1.0 equiv) in CH2Cl2 (9 mL) was added Tf2O (45 µL, 0.27 mmol, 3.0 equiv) dropwise at 0 oC. The reaction mixture was slowly warmed to 23 oC and stirred for 2 h. The solution was neutralized by adding sat. NaHCO3. The reaction mixture was washed with CH2Cl2 (3 x 5 mL) and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford propellane hexacycle 74 (52 mg, 95% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 89 1 Rf = 0.25 (3:1 hexanes:EtOAc); H NMR (500 MHz, CDCl3) δ 7.67 (s, 1H), 7.16–7.11 (m, 3H), 6.95–6.93 (m, 2H), 6.78 (d, J = 8.6 Hz, 2H), 6.73 (td, J = 7.6, 1.1 Hz, 1H), 6.60 (t, J = 4.4 Hz, 1H), 6.36 (dd, J = 7.6, 1.5 Hz, 1H), 4.53 (dt, J = 11.5, 5.8 Hz, 1H), 4.47 (d, J = 14.9 Hz, 1H), 4.23–4.18 (m, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 3.72 (d, J = 13.7 Hz, 1H), 3.21 (s, 3H), 3.01 (ddd, J = 14.4, 11.7, 8.4 Hz, 1H), 2.77–2.73 (m, 1H), 2.54 (q, J = 9.3 Hz, 1H), 2.13 (td, J = 8.8, 5.3 Hz, 1H), 1.93 (dd, J = 14.2, 6.3 Hz, 1H), 1.80–1.75 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 178.0, 158.5, 153.7, 145.8, 142.5, 132.0, 130.9, 130.1, 129.5, 129.4, 128.9, 128.1, 124.6, 122.9, 121.5, 116.1, 113.6, 112.1, 106.6, 58.2, 57.0, 55.4, 54.4, 52.7, 50.2, 47.9, 33.7, 26.6, 23.2; IR (Neat Film NaCl) 1718, 1601, 1575, 1513, 1484, 1455, 1365, 1245, 1134, 1099, 1037, 912, 764, 731 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H31BrN3O5 [M+H]+ : 604.1442; found: 604.1433. Br N Br O N CO2Me O N 74 PMB DDQ CH2Cl2, 23 °C (92% yield) N O N CO2Me O NH 75 Propellane hexacycle 75. To a solution of oxindole 74 (46 mg, 0.075 mmol, 1.0 equiv) in CH2Cl2 (3.8 mL) and H2O (0.94 mL) was added DDQ (34 mg, 0.15 mmol, 2.0 equiv) at 0 oC. The reaction mixture was slowly warmed to 23 oC and stirred for 2 h. The solution was quenched with sat. NaHCO3. The reaction mixture was washed with CH2Cl2 (3 x 3.0 mL) and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (4:1 CH2Cl2:acetone) on silica gel to afford propellane hexacycle 75 (33 mg, 92% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 90 1 Rf = 0.1 (1:1 hexane:EtOAc); H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 8.3 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.98 (dd, J = 21.2, 8.0 Hz, 2H), 6.71 (d, J = 7.7 Hz, 2H), 6.25 (d, J = 7.6 Hz, 1H), 4.45 (td, J = 11.1, 6.6 Hz, 1H), 4.10–4.02 (m, 1H), 3.92 (s, 3H), 3.23 (s, 3H), 3.14 (dd, J = 9.4, 6.0 Hz, 1H), 3.08–2.92 (m, 1H), 2.68–2.51 (m, 2H), 1.82 (td, J = 14.2, 12.6, 7.1 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 177.9, 153.6, 145.8, 142.4, 133.3, 130.4, 129.7, 129.2, 128.1, 125.7, 123.2, 122.5, 114.3, 111.6, 106.9, 58.5, 55.7, 53.8, 53.0, 43.3, 36.5, 26.6, 23.5; IR (Neat Film NaCl) 2958, 1713, 1602, 1485, 1446, 1373, 1242, 1095, 754 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H23BrN3O4 [M+H]+ : 484.0866; found: 484.0874. Br N PMB HO O N CO2Me O N 74 PMB DIBAL then Et 2AlCl CH2Cl2 –78 → 23 °C (87% yield) N Br O N N CO2Me 76 Aminal 76. To a solution of propellane hexacycle 74 (13 mg, 0.021 mmol, 1.0 equiv) in CH2Cl2 (2.14 mL) was added DIBAL (1.0 M in THF; 0.11 mL, 0.11 mmol, 5 equiv) dropwise at –78 oC. The reaction mixture was stirred for 1 h and warmed to 0 oC. DIBAL (1.0 M in THF; 21.4 µL, 21.4 µmol, 1 equiv) was added dropwise at 0 oC and stirred for 1 h. Then, DIBAL (1.0 M in THF; 21.4 mL, 21.4 mmol, 1 equiv) was added one more time dropwise at 0 oC and stirred for another 1 h. The reaction mixture was warmed to 23 oC and Et2AlCl (1.0 M in hexane; 42.8 mL, 42.8 mmol, 2 equiv) was added dropwise. The mixture was stirred for 30 min and quenched with sat. NH4Cl and sat. potassium sodium tartrate. The reaction mixture was washed with CH2Cl2 (3 x 2.0 mL) Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 91 and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford propellane aminal 76 (10.5 mg, 87% yield). Rf = 0.25 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.39 (d, J = 7.7 Hz, 1H), 7.24–7.22 (m, 2H), 7.17 (s, 1H), 7.08–7.03 (m, 1H), 6.87–6.84 (m, 2H), 6.82 (t, J = 7.9 Hz, 1H), 6.71 (dd, J = 8.0, 1.0 Hz, 1H), 6.23 (br, s, 1H), 6.01 (dd, J = 7.9, 1.0 Hz, 1H), 5.15 (d, J = 14.5 Hz, 1H), 3.94 (d, J = 14.5 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.72–3.63 (m, 2H), 3.40 (dd, J = 9.5, 7.7 Hz, 1H), 3.12 (td, J = 9.7, 1.5 Hz, 1H), 3.10–3.04 (m, 1H), 2.89–2.82 (m, 1H), 2.48 (s, 3H), 2.32 (dt, J = 14.2, 7.2 Hz, 1H), 1.65 (dt, J = 14.7, 9.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 170.5, 159.2, 152.7, 139.2, 136.3, 134.0, 130.4, 129.8, 128.8, 126.8, 126.7, 126.1, 125.2, 125.0, 122.9, 122.4, 114.2, 104.7, 83.3, 61.0, 60.5, 55.4, 53.6, 53.4, 47.1, 44.3, 35.3, 33.0, 31.1; IR (Neat Film NaCl) 2922, 1689, 1597, 1512, 1444, 1334, 1249, 1178, 1032, 754 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H33BrN3O5 [M+H]+ : 606.1598; found: 606.1592. O2N TIPSO O NO 2 Br NCO 2Me OO N 69 77 TIPSO NH 3OAc Br NaBH 3CN THF, MeOH 0 → 23 °C (97% yield) N O O N HN CO2Me 78 Amide 78. To a solution of aldehyde 69 (100 mg, 0.13 mmol, 1.0 equiv) and onitrobenzylammonium acetate 77 (97 mg, 0.38 mmol, 3.0 equiv) in MeOH (7.6 mL) was added NaBH3CN (21 mg, 0.26 mmol, 2.0 equiv) in THF (3.8 mL) at 0 oC. The reaction mixture was slowly warmed to ambient temperature and stirred for 12 h. Then, H2O (5 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 92 mL) was added and extracted with EtOAc (3 x 20 mL), and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford o-nitrobenzyl protected amide 78 (116 mg, 97% yield). Rf = 0.35 (2:1 hexanes:EtOAc); (Due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (500 MHz, CDCl3) δ 11.63 (s, 1H), 8.06–7.97 (m, 2H), 7.51 (td, J = 7.6, 1.5 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.25–7.18 (m, 2H), 7.13 (dd, J = 14.1, 8.2 Hz, 2H), 7.05 (t, J = 7.9 Hz, 1H), 6.97–6.90 (m, 1H), 6.53 (d, J = 7.6 Hz, 1H), 5.32 (d, J = 16.5 Hz, 1H), 4.71 (dd, J = 16.4, 6.5 Hz, 1H), 3.70–3.63 (m, 2H), 3.57 (td, J = 6.3, 2.9 Hz, 1H), 3.55–3.51 (m, 1H), 3.35–3.26 (m, 2H), 2.92 (ddd, J = 13.1, 5.4, 3.3 Hz, 1H), 2.84 (s, 1H), 2.69 (ddd, J = 19.4, 8.7, 5.3 Hz, 2H), 2.63 (s, 3H), 0.85 (t, J = 4.1 Hz, 21H); 13C NMR (125 MHz, CDCl3) δ 176.0, 175.4, 154.4, 148.7, 147.1, 139.7, 134.1, 132.1, 131.2, 130.0, 129.4, 128.8, 128.7, 127.6, 126.6, 126.0, 125.3, 122.1, 121.8, 121.3, 107.3, 60.9, 60.6, 60.4, 51.6, 46.0, 45.1, 31.8, 31.6, 25.9, 17.9, 11.9; IR (Neat Film NaCl) 3418, 2943, 2865, 2251, 1717, 1601, 1527, 1456, 1338, 1313, 1282, 1227, 1113, 1069, 911, 883, 857, 730 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C39H50BrN4O7Si [M+H]+ : 793.2627; found: 793.2658. O2N TIPSO Br N Br O O N HN CO2Me 78 Tf2O 0 → 23 °C CH2Cl2 (75% yield) N O N CO2Me O N NO 2 SI-1-20 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 93 Propellane hexacycle SI-1-20. To a solution of amide 78 (54.1 mg, 0.087 mmol, 1.0 equiv) in CH2Cl2 (6.82 mL), was added Tf2O (34 mL, 0.26 mmol, 3.0 equiv) dropwise at 0 oC. The reaction mixture was slowly warmed to 23 oC, and stirred for 2 h. After the reaction was done, the solution was brought to pH 10.5-11.0 by addition of sat. NaHCO3. The reaction mixture was extracted with EtOAc (3 x 6 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford propellane hexacycle SI-1-20 (39.6 mg, 75% yield). Rf = 0.46 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 7.9, 1.2 Hz, 1H), 7.72–7.58 (m, 1H), 7.46–7.40 (m, 2H), 7.30 (ddd, J = 8.0, 6.7, 2.2 Hz, 1H), 7.21– 7.14 (m, 1H), 6.99–6.93 (m, 2H), 6.81–6.76 (m, 1H), 6.64 (dd, J = 7.4, 1.4 Hz, 1H), 6.36 (dd, J = 7.7, 1.3 Hz, 1H), 4.61 (d, J = 16.6 Hz, 1H), 4.54 (d, J = 18.2 Hz, 1H), 4.45 (td, J = 11.4, 6.5 Hz, 1H), 4.18–4.11 (m, 1H), 3.72 (d, J = 9.4 Hz, 3H), 3.21 (s, 3H), 3.11–3.02 (m, 1H), 2.96–2.87 (m, 1H), 2.51 (dt, J = 14.4, 9.0 Hz, 2H), 1.94–1.81 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 177.6, 153.5, 148.9, 145.8, 144.4, 142.1, 136.2, 132.9, 131.0, 130.0, 129.6, 129.1, 128.1, 127.3, 125.1, 124.3, 123.1, 116.1, 111.9, 106.8, 64.5, 58.4, 56.5, 54.5, 52.6, 50.0, 47.9, 33.9, 26.5, 22.8; IR (Neat Film NaCl) 2953, 2360, 1721, 1599, 1573, 1524, 1483, 1455, 1367, 1242, 1134, 1088, 1134, 1088, 947, 856, 761, 733 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C30H28BrN4O6 [M+H]+ : 619.1187; found: 619.1188. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 94 O2N Br HO N O N CO2Me O N NO 2 SI-1-20 DIBAL;Et 2AlCl CH2Cl2 –78 → 0 °C (60% yield) N Br O N N CO2Me 79 Aminal 79. To a solution of propellane hexacyclic oxindole SI-1-20 (14.6 mg, 0.024 mmol, 1.0 equiv) in CH2Cl2 (2.4 mL) was added DIBAL (1.0 M in THF; 0.12 mL, 0.12 mmol, 5 equiv) dropwise at –78 oC. After the reaction mixture was stirred for 1 h at –78 o C, the solution was warmed to 0 oC and DIBAL (1.0 M in THF; 24 mL, 0.024 mmol, 1.0 equiv) was added dropwise. The mixture was stirred for 1 h at 0 oC, and more DIBAL (1.0 M in THF; 24 mL, 0.024 mmol, 1.0 equiv) was added dropwise. The reaction mixture was stirred for 1 h at 0 oC, and warmed to 23 oC. To the reaction mixture was added Et2AlCl (1.0 M in hexanes; 48 mL, 0.048 mmol, 2.0 equiv) dropwise. The reaction was stirred for 30 min and quenched with aq NH4Cl (1 mL) and aq potassium sodium tartrate (1 mL). The reaction mixture was washed with EtOAc (3 x 3 mL), and brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (1:1 hexane:EtOAc) on silica gel to afford aminal 79 (8.9 mg, 60% yield). Rf = 0.12 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.01 (dd, J = 8.2, 1.3 Hz, 1H), 7.58 (td, J = 7.6, 1.3 Hz, 1H), 7.50–7.48 (m, 1H), 7.44 (ddd, J = 8.6, 7.4, 1.5 Hz, 1H), 7.37–7.34 (m, 1H), 7.23–7.19 (m, 1H), 7.09–7.05 (m, 1H), 6.81 (t, J = 7.9 Hz, 1H), 6.69 (dd, J = 8.0, 1.0 Hz, 1H), 6.26 (s, 1H), 6.01 (dd, J = 7.9, 0.9 Hz, 1H), 5.41 (d, J = 16.3 Hz, 1H), 4.56 (d, J = 16.2 Hz, 1H), 3.86 (s, 3H), 3.73–3.64 (m, 2H), 3.56 (td, J = 9.5, 7.4 Hz, 1H), 3.24–3.18 (m, 1H), 3.09 (ddd, J = 13.6, 8.6, 5.3 Hz, 1H), 2.95 (ddd, J = Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 95 14.2, 7.4, 1.7 Hz, 1H), 2.48 (s, 3H), 2.35 (ddd, J = 13.2, 8.5, 6.2 Hz, 1H), 1.78 (dt, J = 14.2, 9.4 Hz, 1H), 1.74 (br, s, 1H); 13C NMR (125 MHz, CDCl3) δ 171.5, 171.3 152.6, 148.9, 138.8, 136.3, 133.7, 132.1, 130.4, 129.7, 128.4, 126.9, 126.2, 126.0, 125.0, 124.8, 122.7, 122.2, 104.6, 83.2, 64.4, 60.7, 60.4, 53.3, 53.1, 45.3, 44.5, 35.2, 33.0, 31.0; IR (Neat Film NaCl) 2955, 2357, 1694, 1595, 1524, 1444, 1335, 1281, 1073, 1032, 911, 857, 835, 730 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C30H30BrN4O6 [M+H]+ : 621.1343; found: 621.1286. O2N HO HO N Br O N H NH Br O hv MeOH (40% yield) N N CO2Me H N CO2Me 53 79 Amide 53. A solution of aminal 79 (21.5 mg, 0.035 mmol, 1.0 equiv) in anhydrous MeOH (3.5 mL) in a Pyrex flask was purged with N2 for 5 min. The reaction mixture was irradiated in a cylindrical photoreactor with 254 nm lamps under N2 for 3 h and concentrated. The residue was purified by column chromatography (4:1 CH2Cl2:acetone) on silica gel to afford aminal 53 (6.7 mg, 40% yield). See below for characterization data. O2N HO HO N Br O N H N CO2Me 79 NH Br O 20% aq NaOH MeOH, 75 °C (70% yield) N H 53 N CO2Me Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 96 Amide 53. To a solution of o-nitrobenzyl protected aminal 79 (10.8 mg, 0.017 mmol, 1.0 equiv) in MeOH (0.8 mL) was added 20% aq NaOH (0.2 mL) and the mixture was stirred for 4 h at 75 oC. After the reaction mixture was cooled to 23 oC, it was diluted with water and extracted with EtOAc (3 x 2 mL). The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo. The residue was purified by column chromatography (4:1 CH2Cl2:acetone) to afford compound 53 (5.9 mg, 70% yield). Rf = 0.18 (4:1 CH2Cl2:acetone); 1H NMR (500 MHz, CDCl3) δ 7.51–7.45 (m, 1H), 7.19 (td, J = 7.6, 1.4 Hz, 1H), 7.05 (td, J = 7.7, 1.4 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.69 (dt, J = 8.0, 1.0 Hz, 1H), 6.60 (br, s, 1H), 6.25 (br, s, 1H), 5.99 (dd, J = 7.9, 0.9 Hz, 1H), 3.87 (s, 3H), 3.74–3.63 (m, 2H), 3.55 (td, J = 9.4, 7.3 Hz, 1H), 3.33 (ddd, J = 9.8, 8.8, 1.5 Hz, 1H), 3.17 (ddd, J = 13.6, 8.4, 5.6 Hz, 1H), 3.03–2.96 (m, 1H), 2.49 (s, 3H), 2.36 (ddd, J = 13.2, 8.2, 6.3 Hz, 1H), 1.92 (dt, J = 14.0, 9.5 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 174.8, 155.4, 152.9, 138.6, 136.4, 130.4, 126.9, 126.6, 126.1, 125.0, 123.4, 122.5, 104.6, 83.2, 76.9, 60.9, 60.6, 53.5, 52.3, 40.4, 35.8, 35.2, 31.1; IR (Neat Film NaCl) 3418, 2955, 2357, 1693, 1593, 1446, 1335, 1282, 1032, 836, 754 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H25BrN3O4 [M+H]+ : 486.1023; found: 486.1004. Br Br TIPSO TIPSO NO 2 NH TiCl3, NH 4OAc CO2Allyl O N 52 i-PrOH, H 2O, 23 °C (91% yield) OO N 82 Bis-oxindole 82. To a solution of oxindole 52 (7.65 g, 11.2 mmol, 1.0 equiv) in H2O (187 mL) and i-PrOH (373 mL) were added NH4OAc (43.2 g, 0.560 mol, 50 equiv) and Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 97 TiCl3 (20% w/w, 69.2 mL, 0.11 mol, 10 equiv). Then, the reaction was stirred for 12 h at 23 oC. The reaction mixture was diluted with EtOAc (200 mL) and then the phases were separated and the aqueous phase was extracted with EtOAc (3 x 300 mL). The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford bisoxindole 82 (6.10 g, 91% yield). Rf = 0.68 (1:1 hexane:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.57 (br, s, 1H), 7.31–7.26 (m, 1H), 6.98–6.90 (m, 2H), 6.88 (dd, J = 2.7, 1.5 Hz, 1H), 6.82 (s, 1H), 6.73–6.69 (m, 1H), 6.21 (br, s, 1H), 5.14 (ddt, J = 17.1, 10.0, 7.1 Hz, 1H), 4.96 (ddd, J = 17.1, 2.0, 0.9 Hz, 1H), 4.86–4.80 (m, 1H), 3.42–3.31 (m, 2H), 3.25 (ddd, J = 9.9, 7.5, 4.7 Hz, 1H), 3.05 (dt, J = 14.5, 7.4 Hz, 1H), 2.90 (s, 3H), 2.79 (dd, J = 13.0, 6.9 Hz, 1H), 2.34 (ddd, J = 13.4, 6.8, 4.7 Hz, 1H), 0.92–0.81 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 177.14, 176.05, 144.65, 142.73, 131.37, 128.80, 127.92, 127.73, 125.58, 124.41, 124.20, 121.97, 121.73, 119.88, 112.70, 108.15, 59.61, 56.86, 54.80, 35.16, 32.66, 25.91, 17.82, 11.77; IR (Neat Film NaCl) 3270, 2942, 2865, 1716, 1611, 1471, 1377, 1241, 1105, 916, 883, 791, 734 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H42BrN2O3Si [M+H]+: 597.2143; found: 597.2187. Br Br TIPSO TIPSO NH OO N Boc 2O, DMAP N Boc MeCN, 23 °C (85% yield) OO N 82 83 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 98 Carbamate 83. To a stirred solution of bis-oxindole 82 (2.63 g, 4.40 mmol, 1.0 equiv) in CH2Cl2 (44 mL) were added DMAP (1.08 g, 8.80 mmol, 2.0 equiv) and Boc2O (1.92 g, 8.80 mmol, 2.0 equiv) at 0 oC. The reaction was slowly warmed to 23 oC, and stirred for 12 h. The solvent was concentrated in vacuo and then the residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford protected compound 83 (2.6 g, 85% yield). Rf = 0.52 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.95 (d, J = 1.9 Hz, 1H), 7.25 (td, J = 7.7, 1.3 Hz, 1H), 7.14–7.09 (m, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.71–6.67 (m, 1H), 6.62–6.53 (m, 1H), 6.47 (s, 1H), 5.10 (ddt, J = 17.0, 9.9, 7.1 Hz, 1H), 4.99–4.92 (m, 1H), 4.83 (dd, J = 10.0, 2.0 Hz, 1H), 3.43 (dd, J = 13.3, 7.3 Hz, 1H), 3.35 (dt, J = 9.9, 7.2 Hz, 1H), 3.20 (ddd, J = 9.9, 7.7, 4.8 Hz, 1H), 2.94 (s, 3H), 2.90 (dd, J = 13.9, 8.0 Hz, 1H), 2.81–2.75 (m, 1H), 2.30 (ddd, J = 13.2, 7.2, 4.8 Hz, 1H), 1.51 (s, 9H), 0.89–0.84 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 175.60, 173.73, 148.46, 144.52, 141.67, 131.26, 128.95, 127.19, 126.28, 126.06, 125.32, 124.15, 122.43, 121.69, 120.23, 118.24, 108.06, 84.08, 59.56, 57.36, 55.29, 34.77, 32.70, 27.92, 25.97, 17.82, 11.76; IR (Neat Film NaCl) 2941, 2866, 1770, 1716, 1610, 1471, 1420, 1370, 1342, 1287, 1246, 1153, 1105, 1067, 1023, 919, 882, 845, 752, 733 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C31H42BrN2O3Si [M+H-Boc]+: 597.2143 found: 597.2181. Br Br TIPSO TIPSO O O 3, then PPh 3 NBoc OO N NBoc CH2Cl2, –78 °C (90% yield) OO N 83 81 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 99 Aldehyde 81. To a 100 mL round bottom flask with magnetic stir bar was added alkene 83 (2.61 g, 0.00374 mol, 1.0 equiv). The flask was connected to an ozone generator and purged with oxygen gas (flow: 0.5) for 5 min at –78 oC. Then, ozone gas (flow: 0.5) was bubbled through into the reaction solution for 30 min at –78 oC. After the reaction was done, oxygen gas was bubbled into the reaction mixture for 20 min and PPh3 (2.95 g, 0.0112 mol, 3.0 equiv) was added. The reaction mixture was slowly warmed to ambient temperature, stirred for 16 h, and then concentrated under reduced pressure. The residue was purified by column chromatography (4:1 hexanes:EtOAc) to afford aldehyde 81 (2.4 g, 90% yield). Rf = 0.23 (4:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 9.45 (s, 1H), 8.00 (d, J = 1.8 Hz, 1H), 7.31 – 7.26 (m, 1H), 7.21 (td, J = 7.8, 1.2 Hz, 1H), 6.93 (br, s, 1H), 6.77 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 5.99 (br, s, 1H), 4.43 (d, J = 19.1 Hz, 1H), 3.39 (dd, J = 19.2, 1.1 Hz, 1H), 3.31 (dt, J = 9.9, 7.3 Hz, 1H), 3.15 (ddd, J = 9.9, 8.0, 4.7 Hz, 1H), 3.10 (s, 3H), 2.64 (dt, J = 12.8, 7.6 Hz, 1H), 2.20 (ddd, J = 12.6, 7.5, 4.7 Hz, 1H), 1.43 (s, 9H), 0.91–0.82 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 197.38, 175.36, 173.47, 148.07, 144.01, 142.38, 129.18, 126.57, 126.04, 125.73, 124.51, 123.59, 122.99, 121.72, 118.74, 108.14, 83.83, 59.25, 53.78, 53.64, 44.47, 33.42, 27.83, 26.20, 17.80, 11.74; IR (Neat Film NaCl) 1941, 2865, 1771, 1722, 1609, 1471, 1422, 1370, 1345, 1291, 1245, 1152, 1109, 1070, 1015, 882, 845, 793, 749 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C30H40BrN2O4Si [M+H-Boc]+: 599.1935 found: 597.1971. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 100 Br O2N 77 NH 3OAc O TIPSO NO 2 NaBH 3CN TIPSO N O NBoc OO N THF, MeOH 0 → 23 °C (91% yield) O N HN Br Boc 81 84 Amide 84. To a solution of aldehyde 81 (200 mg, 0.29 mmol, 1.0 equiv) and onitrobenzylammonium acetate 77 (182 mg, 0.86 mmol, 3.0 equiv) in MeOH (14.3 mL) was added NaBH3CN (39 mg, 0.57 mmol, 2.0 equiv) in THF (7.2 mL) at 0 oC. The reaction mixture was slowly warmed to ambient temperature, and stirred for 12 h. Then, H2O (10 mL) was added. The mixture was extracted with EtOAc (3 x 20 mL) and washed with brine. The combined organic phases were dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford o-nitrobenzyl protected amide 84 (221 mg, 91% yield). Rf = 0.22 (4:1 hexanes:EtOAc); (due to the distinct presence of rotameric isomers, the 1H NMR and 13C NMR contained extra peaks. See attached the spectrum behind); 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 8.9 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H), 8.09 (s, 1H), 8.06–7.96 (m, 2H), 7.83 (s, 1H), 7.62 (d, J = 7.1 Hz, 2H), 7.46 (t, J = 8.5 Hz, 1H), 7.42– 7.30 (m, 6H), 7.23 (d, J = 8.3 Hz, 3H), 7.09 (t, J = 7.6 Hz, 1H), 6.93–6.86 (m, 2H), 6.81 (d, J = 7.5 Hz, 2H), 6.10 (d, J = 7.6 Hz, 1H), 5.00 (d, J = 16.9 Hz, 1H), 4.91 (d, J = 17.3 Hz, 1H), 4.58 (d, J = 17.3 Hz, 1H), 4.27 (s, 1H), 3.75 (s, 1H), 3.37 (t, J = 7.4 Hz, 1H), 3.28 (s, 3H), 3.23 (d, J = 4.9 Hz, 1H), 3.18 (d, J = 7.2 Hz, 4H), 3.14–3.06 (m, 3H), 2.99 (dt, J = 9.2, 4.7 Hz, 2H), 2.80 (dd, J = 13.3, 9.4 Hz, 3H), 2.43 (t, J = 7.8 Hz, 1H), 2.25– 2.13 (m, 1H), 2.06 (d, J = 8.9 Hz, 2H), 0.87 (d, J = 1.9 Hz, 21H), 0.80 (d, J = 2.7 Hz, Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 101 13 21H); C NMR (125 MHz, CDCl3) δ 178.3, 176.9, 174.6, 152.9, 148.3, 148.1, 145.0, 144.7, 141.9, 134.5, 134.1, 131.8, 131.0, 129.1, 128.8, 128.8, 128.5, 128.4, 128.4, 128.2, 127.0, 125.3, 125.2, 125.1, 124.9, 123.2, 122.9, 122.1, 121.7, 108.4, 107.9, 79.9, 59.9, 59.2, 59.1, 52.9, 44.6, 44.2, 44.1, 36.4, 34.6, 31.3, 31.1, 28.6, 28.3, 26.5, 26.3, 18.2, 18.0, 17.9, 12.2, 12.1, 11.9; IR (Neat Film NaCl) 3329, 2941, 2866, 1701, 1612, 1531, 1496, 1473, 1344, 1280, 1159, 1103, 1072, 1024, 914, 885, 753, 731, 688 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C42H56BrN4O7Si [M+H]+: 835.3096; found: 835.3105. O2N TIPSO O2N Br N O O N HN N Tf2O O Br 0 → 23 °C CH2Cl2 (70% yield) Boc 84 HN O N 86 Tetrahydroazepine 86. To a solution of amide 84 (20 mg, 0.0239 mmol, 1.0 equiv) in CH2Cl2 (2.39 mL), was added Tf2O (0.0121 ml, 0.0718 mmol, 3.0 equiv) dropwise at 0 o C. The reaction mixture was slowly warmed to 23 oC, and stirred for 2 h. After the reaction was done, the solution was brought to pH 10.5-11.0 by addition of sat. NaHCO3. The reaction mixture was extracted with EtOAc (3 x 3 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (2:1 hexanes:EtOAc) on silica gel to afford tetrahydroazepine 86 (9.4 mg, 70% yield). Rf = 0.33 (2:1 hexanes:EtOAc); 1H NMR (600 MHz, CDCl3) δ 8.04 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.98 (dd, J = 8.4, 2.0 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 102 6.73 (t, J = 7.7 Hz, 1H), 6.70 (dd, J = 8.4, 1.3 Hz, 1H), 6.18 (d, J = 7.6 Hz, 1H), 5.08 (d, J = 17.1 Hz, 1H), 4.47 (d, J = 17.1 Hz, 1H), 3.89 (s, br, 1H), 3.81–3.75 (m, 1H), 3.31–3.26 (m, 2H), 3.23 (td, J = 9.3, 8.5, 4.1 Hz, 1H), 3.18 (d, J = 1.5 Hz, 3H), 2.97–2.93 (m, 1H), 2.93–2.89 (m, 1H), 2.70 (dt, J = 13.7, 8.6 Hz, 1H), 1.45–1.39 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 180.4, 175.1, 150.3, 148.3, 143.8, 134.2, 132.5, 131.1, 131.1, 129.4, 129.2, 128.3, 127.7, 126.0, 125.3, 125.0, 124.6, 121.7, 121.3, 108.0, 58.8, 50.3, 44.6, 44.1, 43.4, 36.1, 27.6, 26.4; IR (Neat Film NaCl) 3343, 2942, 1703, 1611, 1588, 1524, 1471, 1357, 1285, 1137, 1106, 1065, 984, 858, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C28H26BrN4O4 [M+H]+: 561.1132; found: 561.1165. O2N TIPSO O2N TIPSO N N AlH3-Me2NEt O O N HN Br THF (42% yield) (66% yield, based on recovered 84 ) O N H N Boc Boc 84 87 Br Aminal 87. Oxindole 84 (20 mg, 0.0239 mmol, 1.0 equiv) was dissolved in THF (2.39 mL) and cooled to 0 oC. AlH3-Me2NEt (0.5 M in toluene; 0.096 mL, 0.0478 mmol, 2.0 equiv) was added dropwise at 0 oC. The solution was stirred for 2 h and quenched with MeOH. The solution was concentrated under reduced pressure and purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford cyclized compound 87 (8.23 mg, 42% yield; 66% yield based on recovered starting material). Rf = 0.33 (4:1 hexanes:EtOAc); 1H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 7.9 Hz, 1H), 7.40 (s, 1H), 7.35 (dt, J = 19.0, 7.4 Hz, 2H), 7.06–7.03 (m, 1H), 6.96 (d, J = 7.6 Hz, 1H), Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 103 6.93–6.91 (m, 2H), 6.90–6.86 (m, 1H), 6.40 (t, J = 7.4 Hz, 1H), 6.20 (s, 1H), 6.12 (d, J = 7.8 Hz, 1H), 4.75 (q, J = 16.8, 16.1 Hz, 2H), 3.78 (td, J = 10.7, 10.3, 6.0 Hz, 1H), 3.53 (q, J = 8.8 Hz, 1H), 3.46 (t, J = 9.3 Hz, 1H), 3.16–3.07 (m, 2H), 2.84(s, 3H), 2.75 (dd, J = 13.4, 6.0 Hz, 1H), 2.50 (td, J = 11.4, 5.6 Hz, 1H), 2.23–2.16 (m, 1H), 1.47 (s, 9H), 0.95 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 172.5, 153.6, 150.9, 148.7, 139.9, 133.5, 132.2, 131.0, 130.6, 128.9, 128.5, 128.2, 127.8, 125.2, 124.8, 123.2, 120.6, 116.2, 104.3, 80.9, 79.6, 59.9, 56.9, 54.12, 44.49, 43.5, 39.5, 31.0, 29.6, 28.2, 26.3, 17.9, 11.9; IR (Neat Film NaCl) 2941, 2865, 1697, 1603, 1528, 1491, 1333, 1302, 1168, 1100, 992, 882, 739 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C42H56BrN4O6Si [M+H]+: 819.3147; found: 819.3153. O2N O2N TIPSO TIPSO PDC, K 2CO3 O N N N H N Boc 87 Br CH2Cl2 (62% yield) (93% yield, based on recovered 87 ) O N O H N Br Boc 88 Formyl 88. To a solution of methyl protected compound 87 (11 mg, 0.0161 mmol, 1.0 equiv) in CH2Cl2 (1.61 mL) was added PDC (9.1 mg, 0.0241 mmol, 1.5 equiv) at 23 oC. After being stirred at 23 oC for 12 h, the reaction mixture was quenched with water. The reaction mixture was washed with CH2Cl2 (3 x 2 mL), and brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford aldehyde 88 (7.0 mg, 62% yield; 93% yield based on recovered starting material). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 104 1 Rf = 0.55 (4:1 hexanes:EtOAc); H NMR (500 MHz, CDCl3) δ 8.90 (s, 1H), 7.96 (dd, J = 7.8, 2.5 Hz, 2H), 7.38 (q, J = 8.5, 8.0 Hz, 2H), 7.33 (s, br, 1H), 7.14–6.99 (m, 4H), 6.96– 6.87 (m, 3H), 4.83 (s, br, 1H), 4.70 (d, 15Hz, 1H), 3.64–3.54 (m, 2H), 3.51 (t, J = 9.4 Hz, 1H), 3.26 (q, J = 10.0, 7.4 Hz, 1H), 3.11 (q, J = 10.9 Hz, 1H), 2.79 (dd, J = 13.2, 5.8 Hz, 1H), 2.58 (dt, J = 13.1, 7.8 Hz, 1H), 2.19 (ddd, J = 12.9, 7.9, 4.7 Hz, 1H), 1.44 (s, br, 9H), 0.98–0.76 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 172.1, 161.4, 153.1, 148.7, 141.3, 138.3, 133.5, 131.8, 131.5, 131.2, 129.3, 128.7, 128.4, 125.1, 124.9, 124.2, 123.5, 121.1, 116.0, 81.9, 75.1, 59.4, 57.2, 54.1, 44.6, 43.6, 39.6, 29.7, 28.1, 26.3, 17.9, 17.9, 11.8; IR (Neat Film NaCl) 2942, 2866, 1683, 1591, 1527, 1489, 1393, 1323, 1280, 1155, 1096, 911, 733 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C42H54BrN4O7Si [M+H]+: 833.2940; found: 833.2960. O2N TIPSO TIPSO O H N Boc 88 O 20% aq NaOH O N NH N Br MeOH, 75 °C (50% yield) N N H H Boc Br 80 Amide 80. To a solution of aldehyde 88 (14.8 mg, 0.0177 mmol, 1.0 equiv) in MeOH (0.4 mL) was added 20% aq NaOH (0.2 mL) and the reaction mixture was stirred for 4 h at 75 oC. The reaction mixture was diluted with EtOAc (1 mL) and the aqueous phase was extracted with EtOAc (3 x 1 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (4:1 hexanes:EtOAc) on silica gel to afford desired amide 80 (5.9 mg, 50% yield). Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine 105 1 Rf = 0.21 (4:1 hexanes:EtOAc); H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.14 (dd, J = 8.3, 2.0 Hz, 1H), 7.06 (dt, J = 7.7, 3.7 Hz, 3H), 6.70 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 7.7 Hz, 1H), 6.17 (s, 1H), 5.72 (s, 1H), 3.69–3.61 (m, 1H), 3.48 (dt, J = 10.8, 5.6 Hz, 1H), 3.07 (m, 1H), 2.85 (m, 1H), 2.77 (m, 2H), 2.33 (d, J = 7.9 Hz, 1H), 1.59 (s, 9H), 0.91 (m, 21H); 13C NMR (125 MHz, CDCl3) δ 176.2, 153.9, 149.2, 138.2, 130.4, 128.9, 127.1, 126.8, 126.5, 124.4, 120.6, 119.5, 109.4, 82.5, 60.3, 55.6, 53.4, 38.9, 35.7, 31.2, 28.6, 18.4, 11.9; IR (Neat Film NaCl) 3401, 2941, 2865, 1696, 1487, 1465, 1314, 1163, 1094, 882, 740 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C34H49BrN3O4Si [M+H]+: 670.2670; found: 670.2679. 1.5. References and Notes                                                                                                                   (1) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355. (2) (a) Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem. 2001, 66, 8717. (b) Retraction of this article was prompted by a revision of structure, see ref. 5a and Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem. 2003, 68, 1640.; however, the biological activity reported in this manuscript was not specifically called into question and is distinct relative to previous reports.1 (3) (a) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K; Proksch, P. J. Nat. Prod. 2004, 67, 78. (b) Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci. Biotechnol. Biochem. 2004, 68, 753. (c) Andersen, B.; Smedsgaard, J.; Frisvad, J. Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           C. J. Agric. Food Chem. 2004, 52, 2421. (d) Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad, J. C.; Christophersen, C. J. Nat. Prod. 2005, 68, 258. (e) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26. (f) Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561. (4) (a) Tanaka, J.; Yan, Y.; Choi, J.; Bai, J.; Klenchin, V. A.; Rayment, I.; Marriott, G. Proc. Natl. Acad. Sci. 2003, 100, 13851. (b) Klenchin, V. A.; Allingham, J. S.; King, R.; Tanaka, J.; Marriott, G.; Rayment, I. Nat. Struct. Biol. 2003, 10, 1058. (5) (a) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203. (b) Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169. (c) May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262. (d) Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187. (e) Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995. (f) Seo, J. H.; Artman, G. D., III; Weinreb, S. M. J. Org. Chem. 2006, 71, 8891. (g) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794. (h) George, J. H.; Adlington, R. M. Synlett 2008, 2093. (i) Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 8170. (j) Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem., Int. Ed. 2010, 49, 2000. (k) Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132, 13226. (l) Zuo, Z.; Ma, D. Angew. Chem., Int. Ed. 2011, 50, 12008. (m) Belmar, J.; Funk, R. L. J. Am. Chem. Soc. 2012, 134, 16941. (n) Artman, G. D., III; Weinreb, S. M. Org. Lett. 2003, 5, 1523. (o) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068. (p) Sabahi, A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006, 45, 4317. (q) Evans, M. A.; Sacher, J. R.; Weinreb, S. M. Tetrahedron 2009, 65, 6712. (r) Wu, H.; Xue, F.; Xiao, X.; Qin, Y. J. Am. Chem. Soc. 2010, 132, 14052. (s) Schammel, A. W.; Chiou, G.; Garg, N. 106 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           K. Org. Lett. 2012, 14, 4556. (t) Ishida, T.; Takemoto, Y. Tetrahedron 2013, 69, 4517. (u) Ishida, T.; Ikota, H.; Kurahashi, K.; Tsukano, C.; Takemoto, Y. Angew. Chem., Int. Ed. 2013, 52, 10204. (v) Zhang, H.; Hong, L.; Kang, H.; Wang, R. J. Am. Chem. Soc. 2013, 135, 14098. (w) Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2014, 16, 3316. (x) Trost, B. M.; Osipov, M.; Krüger, S.; Zhang, Y. Chem. Sci. 2015, 6, 349. (6) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124. (7) Denault, J.-B.; Salvesen, G. S. Chem. Rev. 2002, 102, 4489. (8) Wigley, L. J.; Perry, D. A.; Mantle, P. G. Mycol. Res. 2008, 112, 131. (9) (a) Kozlovskii, A. G.; Solov’eva, T. F.; Sahkarovskii, V. G.; Adanin, V. M. Dokl. Akad. Nauk SSSR 1981, 260, 230. (b) Sahkarovskii, V. G.; Aripovskii, A. V.; Baru, M. B.; Kozlovskii, A. G. Khim. Prir. Soedin. 1983, 656. (10) (a) Hegedus, L. S.; Toro, J. L.; Miles, W. H.; Harrington, P. J. J. Org. Chem. 1987, 52, 3319. (b) Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486. (c) Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J. Org. Chem. 2004, 1244. (11) Greenberg, A. Mol. Struct. Enegetics 1988, 7, 139. (12) Indeed, it was the recognition that an anti-Bredt, twisted amide might be involved in a potentially biogenetic or laboratory synthesis of alkaloids 1a–1h that inspired our fundamental synthetic study in this area. Tani, K.; Stoltz, B. M. Nature, 2006, 441, 731. 107 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           (13) (a) Szostak, M.; Aubé, J. Org. Biomol. Chem. 2011, 9, 27. (b) Szostak, M.; Aubé, J. Chem. Rev. 2013, 113, 5701. (14) (a) Yamada, F.; Makita, Y.; Suzuki, T.; Somei, M. Chem. Pharm. Bull. 1985, 33, 2162. (b) Somei, M.; Yamada, F. Jpn. Patent JP 85-47044 19850308, 1986. (c) Iwao, M.; Motoi, O. Tetrahedron Lett. 1995, 36, 5929. (15) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C. Ramtohul, Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745. (16) Steinhagen, H.; Corey, E. J. Angew. Chem., Int. Ed. 1999, 38, 1928. (17) Kennewell, P. D.; Miller, D. J.; Scrowston, R. M.; Westwood, R. J. Chem. Res. Miniprint 1995, 10, 2380. (18) (a) Hrib, N. J.; Jurcak, J. G.; Burgher, K. L.; Conway, P. G.; Hartman, H. B.; Kerman, L. L.; Roehr, J. E.; Woods, A. T. J. Med. Chem. 1994, 37, 2308. (b) Spence, T. W. M.; Tennant, G. J. Chem. Soc. C 1971, 3712. (c) Eckroth, D. R.; Cochran, T. G. J. Chem. Soc. C 1970, 2660. (19) He, L.; Bekkaye, M.; Retailleau, P.; Masson, G. Org. Lett. 2012, 14, 3158. (20) Krishnan, S.; Stoltz, B. M. Tetrahedron Lett. 2007, 48, 7571. (21) (a) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037. (b) Dou, X.; Yao, W.; Zhou, B.; Lu, Y. Chem. Commun. 2013, 49, 9224. (22) Liu, B.; Hu, L. Bioorg. Med. Chem. 2003, 11, 3889. (23) We thought that the diastereoselectivity might be related to protecting groups and attempted the Diels–Alder cycloaddition with tosyl protected aurantioclavine derivative 108 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           and o-azaxylylene derivative. However, a change of the protecting groups did not significantly affect the diastereoselectivity of the cycloaddition. (a) Ts Cl N Cs2CO3 Ts H N Ts H N + N Ts 93 + CH2Cl2 –78 °C (92: 93 = 1.5:1 ) HN 7 N N H 10 N 7 Ts 94 N H Ts 95 (b) Ts I N Cs2CO3 Ts H N + CH2Cl2 –78 → 23 °C (33% yield) HN N 93 Ts 96 7 N N H Ts 94 (X-ray) (24) Lee, C. W.; Han, S.-J. Virgil, S. C.; Stoltz, B. M. Tetrahedron 2014, 71, 3666–3670. (25) Horvath, A.; Grassberger, M. A.; Schulz, G.; Haidl, E.; Sperner, H.; Steck, A. Tetrahedron 2000, 56, 7469. (26) (a) Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381. (b) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793. (c) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. (d) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343. (27) For reviews on allylic alkylation, see; (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. (b) Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715. (c) Mohr, J. T.; Stoltz, B. M. Chem. Asian J. 2007, 2, 1476. (d) Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846. (28) Marfat, A.; Carta, M. P. Tetrahedron Lett. 1987, 28, 4027. (29) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849. 109 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           (30) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365. (31) (a) Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133, 7328. (b) Li, P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 6396. (32) Kotoku, N.; Sumii, Y.; Kobayashi, M. Org. Lett. 2011, 13, 3514. (33) Fernandes, R. A.; Yamamoto, Y. J. Org. Chem. 2004, 69, 3562. (34) Rege, P. D.; Johnson, F. J. Org. Chem. 2003, 68, 6133. (35) Treatment of hexacyclic oxindole 77 with allyl iodide and benzyl bromide under basic conditions provided 97 and 98 in 85% and 80% yield, respectively. Although smooth reductive cyclization of the propellane hexacyclic oxindole 97 and 98 led to aminal 99 and 100, respectively, removal of both allyl and benzyl groups on lactam 99 and 100 turned out to be challenging. Br Br O N N CO2Me O N Allyl iodide, K 2CO3 MeCN, reflux O N N R DIBAL then Et 2AlCl CH2Cl2 –78 → 23 °C 97, R = allyl (85% yield) 98, R = benzyl (80% yield) 77 R HO H HO N Br N Br O O N CO2Me O or Benzyl bromide, K 2CO3 MeCN, reflux H N H N CO2Me 99, R = allyl (90% yield) 100, R = benzyl (89% yield) N H N CO2Me 53 (Not Observed) (36) (a) Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57, 3301. (b) Gareau, Y.; Zamboni, R.; Wong, A. W. J. Org. Chem. 1993, 58, 1582. (c) Voelker, T.; Ewell, T.; Joo, J.; Edstrom, E. D. Tetrahedron Lett. 1998, 39, 359. (37) Han, S.-J.; Fernando de Melo, G.; Stoltz, B. M. Tetrahedron Lett. 2014, 55, 6467. 110 Chapter 1 –The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine                                                                                                                                                                                                                                                                                                                                           (38) Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426. (39) Wang, Y.; Kong, C.; Du, Y.; Song, H.; Zhang, D.; Qin, Y. Org. Biomol. Chem. 2012, 10, 2793. (40) Yamada, Y.; Arima, S.; Okada, C.; Akiba, A.; Kai, T.; Harigaya, Y. Chem. Pharm. Bull. 2006, 54, 788. (41) May, J. A. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, Jul 2005. 111 Appendix 1 – Spectra Relevant to Chapter 1 112 APPENDIX 1 Spectra Relevant to Chapter 1: The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine N N H SI-1-11 Ts O Figure A1.1. 1H NMR (300 MHz, CDCl3) of compound SI-1-11. Appendix 1 – Spectra Relevant to Chapter 1 113 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound SI-1-11. Figure A1.3. 13C NMR (75 MHz, CDCl3) of compound SI-1-11. 114 Ts 35 N N H O Br Figure A1.4. 1H NMR (300 MHz, CDCl3) of compound 35. Appendix 1 – Spectra Relevant to Chapter 1 115 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 35. Figure A1.6. 13C NMR (75 MHz, CDCl3) of compound 35. 116 Ts N 37 O N O2N H CN Figure A1.7. 1H NMR (300 MHz, CDCl3) of compound 37. Appendix 1 – Spectra Relevant to Chapter 1 117 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 37. Figure A1.9. 13C NMR (75 MHz, CDCl3) of compound 37. 118 Ts N 39 O NO N 2 H CO2Me CO2Me Figure A1.10. 1H NMR (300 MHz, CDCl3) of compound 39. Appendix 1 – Spectra Relevant to Chapter 1 119 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.11. Infrared spectrum (Thin Film, NaCl) of compound 39. Figure A1.12. 13C NMR (75 MHz, CDCl3) of compound 39. 120 N N H SI-1-13 Ts O Figure A1.13. 1H NMR (300 MHz, CDCl3) of compound SI-1-13. Appendix 1 – Spectra Relevant to Chapter 1 121 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.14. Infrared spectrum (Thin Film, NaCl) of compound SI-1-13. Figure A1.15. 13C NMR (75 MHz, CDCl3) of compound SI-1-13. .. 122 H Ts 40 N N H O Br Figure A1.16. 1H NMR (300 MHz, CDCl3) of compound 40. Appendix 1 – Spectra Relevant to Chapter 1 123 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 40. Figure A1.18. 13C NMR (75 MHz, CDCl3) of compound 40. .. 124 42 Ts H N N H CO2Me O CO2Me Figure A1.19. 1H NMR (300 MHz, CDCl3) of compound 42. Appendix 1 – Spectra Relevant to Chapter 1 125 Appendix 1 – Spectra Relevant to Chapter 1 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 42. Figure A1.21. 13C NMR (75 MHz, CDCl3) of compound 42. .. 126 O 44 NO 2 O O O                                                                                                     127   Figure A1.22. 1H NMR (500 MHz, CDCl3) of compound 44. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 44.  Figure A1.24. 13C NMR (125 MHz, CDCl3) of compound 44.   128   45 NO 2 O Br O O O                                                                                                     129   Figure A1.25. 1H NMR (500 MHz, CDCl3) of compound 45. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                         130     Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 45.  Figure A1.27. 13C NMR (125 MHz, CDCl3) of compound 45.   N H 46 CO2Allyl O CO2Allyl NO 2 TIPSO                                                                                                     131   Figure A1.28. 1H NMR (500 MHz, CDCl3) of compound 46. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 46.  Figure A1.30. 13C NMR (125 MHz, CDCl3) of compound 46.   132   TIPSO 47 N H CO2Allyl O CO2Allyl NO 2 Br                                                                                                     133   Figure A1.31. 1H NMR (500 MHz, CDCl3) of compound 47. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 47.  Figure A1.33. 13C NMR (125 MHz, CDCl3) of compound 47.   134   48 N CO2Allyl O CO2Allyl NO 2 TIPSO                                                                                                     135   Figure A1.34. 1H NMR (500 MHz, CDCl3) of compound 48. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 48.  Figure A1.36. 13C NMR (125 MHz, CDCl3) of compound 48.   136   TIPSO 49 N CO2Allyl O CO2Allyl NO 2 Br                                                                                                     137   Figure A1.37. 1H NMR (500 MHz, CDCl3) of compound 49. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 49.  Figure A1.39. 13C NMR (125 MHz, CDCl3) of compound 49.   138   50 2 O NO N CO2Allyl O O                                                                                                     139   Figure A1.40. 1H NMR (400 MHz, CDCl3) of compound 50. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 50.  Figure A1.42. 13C NMR (100 MHz, CDCl3) of compound 50.   140   51 2 O NO N O O                                                                                                     141   Figure A1.43. 1H NMR (400 MHz, CDCl3) of compound 51. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.44. Infrared spectrum (Thin Film, NaCl) of compound 51.  Figure A1.45. 13C NMR (100 MHz, CDCl3) of compound 51.   142   TIPSO 52 N CO2Allyl O NO 2 Br                                                                                                     143   Figure A1.46. 1H NMR (500 MHz, CDCl3) of compound 52. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1     Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 52.  Figure A1.48. 13C NMR (125 MHz, CDCl3) of compound 52.   144   SI-1-16 N H OMe O O Br                                                                                                     145   Figure A1.49. 1H NMR (500 MHz, CDCl3) of compound SI-1-16. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound SI-1-16.  Figure A1.51. 13C NMR (125 MHz, CDCl3) of compound SI-1-16.   146   59 N H OH Br                                                                                                     147   Figure A1.52. 1H NMR (500 MHz, CDCl3) of compound 59. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 59.  Figure A1.54. 13C NMR (125 MHz, CDCl3) of compound 59.   148   SI-1-17 N H OTIPS Br                                                                                                     149   Figure A1.55. 1H NMR (500 MHz, CDCl3) of compound SI-1-17. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.56. Infrared spectrum (Thin Film, NaCl) of compound SI-1-17.  Figure A1.57. 13C NMR (125 MHz, CDCl3) of compound SI-1-17.   150   O 57 N H Br Br TIPSO                                                                                                     151   Figure A1.58. 1H NMR (500 MHz, CDCl3) of compound 57. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.59. Infrared spectrum (Thin Film, NaCl) of compound 57.  Figure A1.60. 13C NMR (125 MHz, CDCl3) of compound 57.   152   SI-1-18 N H CO2Allyl O NO 2 CO2Allyl Br TIPSO                                                                                                     153   Figure A1.61. 1H NMR (500 MHz, CDCl3) of compound SI-1-18. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.62. Infrared spectrum (Thin Film, NaCl) of compound SI-1-18.  Figure A1.63. 13C NMR (125 MHz, CDCl3) of compound SI-1-18.   154   60 N CO2Allyl O NO 2 CO2Allyl Br TIPSO                                                                                                     155   Figure A1.64. 1H NMR (500 MHz, CDCl3) of compound 60. Appendix 1 – Spectra Relevant to Chapter 1 156   Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.65. Infrared spectrum (Thin Film, NaCl) of compound 60.  Figure A1.66. 13C NMR (125 MHz, CDCl3) of compound 60 . 61 2 O NO N O CO2Allyl O Br                                                                                                     157   Figure A1.67. 1H NMR (500 MHz, CDCl3) of compound 61. Appendix 1 – Spectra Relevant to Chapter 1 158   Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.68. Infrared spectrum (Thin Film, NaCl) of compound 61.  Figure A1.69. 13C NMR (125 MHz, CDCl3) of compound 61. . 62 2 O NO N O O Br                                                                                                     159   Figure A1.70. 1H NMR (500 MHz, CDCl3) of compound 62. Appendix 1 – Spectra Relevant to Chapter 1 160   Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.71. Infrared spectrum (Thin Film, NaCl) of compound 62.  Figure A1.72. 13C NMR (125 MHz, CDCl3) of compound 62. . O 63 2 O NO N O O Br                                                                                                     161   Figure A1.73. 1H NMR (500 MHz, CDCl3) of compound 63. Appendix 1 – Spectra Relevant to Chapter 1 162   Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.74. Infrared spectrum (Thin Film, NaCl) of compound 63.  Figure A1.75. 13C NMR (125 MHz, CDCl3) of compound 63. . NO 2 65 O N Br PMB N O HO                                                                                                     163   Figure A1.76. 1H NMR (500 MHz, CDCl3) of compound 65. Appendix 1 – Spectra Relevant to Chapter 1 164   Appendix 1 – Spectra Relevant to Chapter 1     Figure A1.77. Infrared spectrum (Thin Film, NaCl) of compound 65.  Figure A1.78. 13C NMR (125 MHz, CDCl3) of compound 65. . 67 N OO NH HO Br                                                                                                     165   Figure A1.79. 1H NMR (500 MHz, DMSO) of compound 67. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.80. Infrared spectrum (Thin Film, NaCl) of compound 67.  Figure A1.81. 13C NMR (125 MHz, DMSO) of compound 67.   166   N OO SI-1-19 NH Br TIPSO                                                                                                     167   Figure A1.82. 1H NMR (500 MHz, CDCl3) of compound SI-1-19. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.83. Infrared spectrum (Thin Film, NaCl) of compound SI-1-19.  Figure A1.84. 13C NMR (125 MHz, CDCl3) of compound SI-1-19.   168   N 68 OO N CO Me 2 Br TIPSO                                                                                                     169   Figure A1.85. 1H NMR (500 MHz, CDCl3) of compound 68. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.86. Infrared spectrum (Thin Film, NaCl) of compound 68.  Figure A1.87. 13C NMR (125 MHz, CDCl3) of compound 68.   170   N 69 OO N CO Me 2 Br O TIPSO                                                                                                     171   Figure A1.88. 1H NMR (500 MHz, CDCl3) of compound 69. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.89. Infrared spectrum (Thin Film, NaCl) of compound 69.  Figure A1.90. 13C NMR (125 MHz, CDCl3) of compound 69.   172   Br CO2Me 54 O N HN O PMB N TIPSO                                                                                                     173   Figure A1.91. 1H NMR (500 MHz, CDCl3) of compound 54. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.92. Infrared spectrum (Thin Film, NaCl) of compound 54.  Figure A1.93. 13C NMR (125 MHz, CDCl3) of compound 54.   174   CO2Me N 71 O PMB H Br TIPSO N N                                                                                                     175   Figure A1.94. 1H NMR (300 MHz, CDCl3) of compound 71. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.95. Infrared spectrum (Thin Film, NaCl) of compound 71.  Figure A1.96. 13C NMR (125 MHz, CDCl3) of compound 71.   176   CO2Me N 72 O H Br N H N HO                                                                                                     177   Figure A1.97. 1H NMR (600 MHz, CDCl3) of compound 72. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.98. Infrared spectrum (Thin Film, NaCl) of compound 72.  Figure A1.99. 13C NMR (125 MHz, CDCl3) of compound 72.   178   CO2Me O HN PMB H N 73 O N TIPSO                                                                                                     179   Figure A1.100. 1H NMR (600 MHz, CDCl3) of compound 73. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.101. Infrared spectrum (Thin Film, NaCl) of compound 73.  Figure A1.102. 13C NMR (125 MHz, CDCl3) of compound 73.   180   PMB CO2Me N N 74 O O N Br                                                                                                     181   Figure A1.103. 1H NMR (500 MHz, CDCl3) of compound 74. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.104. Infrared spectrum (Thin Film, NaCl) of compound 74.  Figure A1.105. 13C NMR (125 MHz, CDCl3) of compound 74.   182   NH CO2Me N 75 O O N Br                                                                                                     183   Figure A1.106. 1H NMR (300 MHz, CDCl3) of compound 75. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.107. Infrared spectrum (Thin Film, NaCl) of compound 75.  Figure A1.108. 13C NMR (125 MHz, CDCl3) of compound 75.   184   N 76 N CO2Me O PMB N Br HO                                                                                               185   Figure A1.109. 1H NMR (500 MHz, CDCl3) of compound 76. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.110. Infrared spectrum (Thin Film, NaCl) of compound 76.  Figure A1.111. 13C NMR (125 MHz, CDCl3) of compound 76.   186   Br TIPSO O 78 CO2Me O N HN N O2N Figure A1.112. 1H NMR (500 MHz, CDCl3) of compound 78. Appendix 1 – Spectra Relevant to Chapter 1   187   Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.113. Infrared spectrum (Thin Film, NaCl) of compound 78.  Figure A1.114. 13C NMR (125 MHz, CDCl3) of compound 78.   188   N O N N SI-1-20 O Br Figure A1.115. 1H NMR (500 MHz, CDCl3) of compound SI-1-20. NO 2 CO2Me Appendix 1 – Spectra Relevant to Chapter 1   189   Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.116. Infrared spectrum (Thin Film, NaCl) of compound SI-1-20.  Figure A1.117. 13C NMR (125 MHz, CDCl3) of compound SI-1-20.   190   Br HO N O 79 CO2Me N N O2N Figure A1.118. 1H NMR (500 MHz, CDCl3) of compound 79. Appendix 1 – Spectra Relevant to Chapter 1   191   Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.119. Infrared spectrum (Thin Film, NaCl) of compound 79.  Figure A1.120. 13C NMR (125 MHz, CDCl3) of compound 79.   192   Br HO N 53 H O CO2Me N NH Figure A1.121. 1H NMR (500 MHz, CDCl3) of compound 53. Appendix 1 – Spectra Relevant to Chapter 1   193   Appendix 1 – Spectra Relevant to Chapter 1   Figure A1.122. Infrared spectrum (Thin Film, NaCl) of compound 53.  Figure A1.123. 13C NMR (125 MHz, CDCl3) of compound 53.   194   NH TIPSO N 82 OO Br                                                                                                     195   Figure A1.124. 1H NMR (500 MHz, CDCl3) of compound 82. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.125. Infrared spectrum (Thin Film, NaCl) of compound 82.  Figure A1.126. 13C NMR (125 MHz, CDCl3) of compound 82.   196   N Boc TIPSO N 83 OO Br                                                                                                     197   Figure A1.127. 1H NMR (500 MHz, CDCl3) of compound 83. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.128. Infrared spectrum (Thin Film, NaCl) of compound 83.  Figure A1.129. 13C NMR (125 MHz, CDCl3) of compound 83.   198   NBoc TIPSO N O 81 OO Br                                                                                                     199   Figure A1.130. 1H NMR (500 MHz, CDCl3) of compound 81. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.131. Infrared spectrum (Thin Film, NaCl) of compound 81.  Figure A1.132. 13C NMR (125 MHz, CDCl3) of compound 81.   200   Br TIPSO 84 Boc O N HN N O O2N                                                                                                     201   Figure A1.133. 1H NMR (300 MHz, CDCl3) of compound 84. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.134. Infrared spectrum (Thin Film, NaCl) of compound 84.  Figure A1.135. 13C NMR (125 MHz, CDCl3) of compound 84.   202   HN Br O 86 O N N O2N                                                                                                     203   Figure A1.136. 1H NMR (600 MHz, CDCl3) of compound 86. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.137. Infrared spectrum (Thin Film, NaCl) of compound 86.  Figure A1.138. 13C NMR (125 MHz, CDCl3) of compound 86.   204   Br 87 N N TIPSO H Boc N O O2N                                                                                                     205   Figure A1.139. 1H NMR (600 MHz, CDCl3) of compound 87. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.140. Infrared spectrum (Thin Film, NaCl) of compound 87.  Figure A1.141. 13C NMR (125 MHz, CDCl3) of compound 87.   206   Br O 88 N N TIPSO H Boc N O O2N                                                                                                     207   Figure A1.142. 1H NMR (500 MHz, CDCl3) of compound 88. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1                                                                                                     Figure A1.143. Infrared spectrum (Thin Film, NaCl) of compound 88.  Figure A1.144. 13C NMR (125 MHz, CDCl3) of compound 88.   208   Br 80 N N H H Boc O NH TIPSO                                                                                                     209   Figure A1.145. 1H NMR (500 MHz, CDCl3) of compound 80. Appendix 1 – Spectra Relevant to Chapter 1 Appendix 1 – Spectra Relevant to Chapter 1     Figure A1.146. Infrared spectrum (Thin Film, NaCl) of compound 80.  Figure A1.147. 13C NMR (125 MHz, CDCl3) of compound 80.   210   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 211   APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1: The Evolution of a Unified, Stereodivergent Approach to the Synthesis of Communesin F and Perophoramidine   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.1. X-Ray Crystal Structure Analysis of 24 O N O N H H N 24     Figure A2.1.1. X-ray Crystal Structure of 24 Table A2.1.1. Crystal Data and Structure Analysis Details for 24 Empirical formula C25 H25 Cl2 N3 O2 Formula weight 470.38 Crystallization solvent ???Solvent??? Crystal shape chunk Crystal color colourless Crystal size 0.09 x 0.14 x 0.14 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK Data collection temperature 100 K 212   213   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Theta range for 6076 reflections used in lattice determination 2.60 to 23.34° a= 90° b= 90° g = 90° Unit cell dimensions a = 8.2203(10) Å b = 26.018(3) Å c = 10.2431(12) Å Volume 2190.8(5) Å3 Z 4 Crystal system orthorhombic Space group P n a 21 (# 33) Density (calculated) 1.426 g/cm3 F(000) 984 Theta range for data collection 1.6 to 32.9° Completeness to theta = 25.000° 100.0% Index ranges -12 £ h £ 12, -39 £ k £ 39, -15 £ l £ 15 Data collection scan type and scans Reflections collected 54235 Independent reflections 7838 [Rint= 0.0905] Reflections > 2s(I) 5779 Average s(I)/(net I) 0.0696 Absorption coefficient 0.33 mm-1 Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.0000 and 0.9032 Structure Solution and Refinement Primary solution method direct Secondary solution method ? Hydrogen placement difmap Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 7838 / 1 / 365 Treatment of hydrogen atoms refxyz Goodness-of-fit on F2 1.13 Final R indices [I>2s(I), 5779 reflections] R1 = 0.0490, wR2 = 0.0781 R indices (all data) R1 = 0.0843, wR2 = 0.0857 Type of weighting scheme used calc Weighting scheme used w=1/[^2^(Fo^2^)+(0.0300P)^2^] where P=(Fo^2^+2Fc^2^)/3 Max shift/error 0.000 Average shift/error 0.000 Absolute structure parameter 0.44(6) Extinction coefficient n/a Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Largest diff. peak and hole 214   0.36 and -0.32 e·Å-3 Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.34A (Bruker-AXS, 2007) APEX2 2013.10-0 (Bruker-AXS, 2007) SAINT V8.34A (Bruker-AXS, 2007) XT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.1.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 24. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ O(1) 4(2) 2120(1) 6508(2) 16(1) O(2) 85(2) 911(1) 6456(2) 16(1) N(1) 1141(2) 1782(1) 4648(2) 12(1) N(2) 1982(3) 2496(1) 117(2) 16(1) N(3) -836(3) 449(1) 6069(2) 20(1) C(1) -798(3) 1282(1) 5638(2) 15(1) C(2) 110(3) 1784(1) 5675(2) 13(1) C(3) 2535(3) 2130(1) 4609(3) 14(1) C(4) 2247(3) 2582(1) 3706(2) 16(1) C(5) 2045(3) 2430(1) 2314(2) 14(1) C(6) 2387(3) 2738(1) 1267(2) 16(1) C(7) 2210(4) 2702(1) -1189(3) 29(1) C(8) 1399(3) 2015(1) 413(2) 14(1) C(9) 862(3) 1636(1) -448(2) 16(1) C(10) 332(3) 1183(1) 92(3) 17(1) C(11) 350(3) 1105(1) 1455(2) 16(1) C(12) 898(3) 1479(1) 2324(2) 12(1) C(13) 1425(3) 1954(1) 1793(2) 13(1) C(14) 997(3) 1336(1) 3766(2) 13(1) C(15) -526(3) 1052(1) 4272(2) 13(1) C(16) -460(3) 459(1) 4594(3) 17(1) C(17) 1216(4) 220(1) 4435(3) 22(1) C(18) -1727(4) 147(1) 3860(3) 20(1) C(19) -2483(3) 644(1) 6275(2) 19(1) C(20) -3860(4) 373(1) 6614(3) 26(1) C(21) -5287(4) 655(1) 6750(3) 27(1) C(22) -5336(4) 1177(1) 6574(3) 25(1) C(23) -3924(3) 1452(1) 6225(2) 20(1) C(24) -2515(3) 1175(1) 6080(2) 16(1) Cl(1) 5159(1) 1123(1) 2694(1) 28(1) Cl(2) 5970(1) 875(1) 1(1) 44(1) C(25) 4688(4) 1234(1) 1034(3) 25(1) ________________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 215   Table A2.1.3. Bond lengths [Å] and angles [°] for 24 __________________________________________________________________________________ _ O(1)-C(2) 1.224(3) O(2)-N(3) 1.475(3) O(2)-C(1) 1.471(3) N(1)-C(2) 1.352(3) N(1)-C(3) 1.460(3) N(1)-C(14) 1.475(3) N(2)-C(6) 1.376(3) N(2)-C(7) 1.453(4) N(2)-C(8) 1.375(3) N(3)-C(16) 1.542(3) N(3)-C(19) 1.461(3) C(1)-C(2) 1.504(3) C(1)-C(15) 1.538(3) C(1)-C(24) 1.508(3) C(3)-H(3A) 0.96(3) C(3)-H(3B) 0.99(3) C(3)-C(4) 1.514(4) C(4)-H(4A) 0.95(3) C(4)-H(4B) 0.97(3) C(4)-C(5) 1.490(3) C(5)-C(6) 1.368(3) C(5)-C(13) 1.440(3) C(6)-H(6) 1.00(3) C(7)-H(7A) 0.95(4) C(7)-H(7B) 0.90(4) C(7)-H(7C) 1.02(4) C(8)-C(9) 1.393(3) C(8)-C(13) 1.422(3) C(9)-H(9) 0.95(3) C(9)-C(10) 1.373(4) C(10)-H(10) 0.95(3) C(10)-C(11) 1.411(4) C(11)-H(11) 1.03(3) C(11)-C(12) 1.393(3) C(12)-C(13) 1.419(3) C(12)-C(14) 1.525(3) C(14)-H(14) 0.96(3) C(14)-C(15) 1.543(3) C(15)-H(15) 0.95(3) C(15)-C(16) 1.579(3) C(16)-C(17) 1.520(4) C(16)-C(18) 1.519(4) C(17)-H(17A) 0.98(3) C(17)-H(17B) 1.00(3) C(17)-H(17C) 1.01(3) C(18)-H(18A) 0.98(3) C(18)-H(18B) 0.91(3) C(18)-H(18C) 0.97(3) C(19)-C(20) 1.378(4) C(19)-C(24) 1.396(4) C(20)-H(20) 0.98(3) C(20)-C(21) 1.390(4) C(21)-H(21) 0.86(3) C(21)-C(22) 1.370(4) C(22)-H(22) 0.95(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(22)-C(23) C(23)-H(23) C(23)-C(24) Cl(1)-C(25) Cl(2)-C(25) C(25)-H(25A) C(25)-H(25B) C(1)-O(2)-N(3) C(2)-N(1)-C(3) C(2)-N(1)-C(14) C(3)-N(1)-C(14) C(6)-N(2)-C(7) C(8)-N(2)-C(6) C(8)-N(2)-C(7) O(2)-N(3)-C(16) C(19)-N(3)-O(2) C(19)-N(3)-C(16) O(2)-C(1)-C(2) O(2)-C(1)-C(15) O(2)-C(1)-C(24) C(2)-C(1)-C(15) C(2)-C(1)-C(24) C(24)-C(1)-C(15) O(1)-C(2)-N(1) O(1)-C(2)-C(1) N(1)-C(2)-C(1) N(1)-C(3)-H(3A) N(1)-C(3)-H(3B) N(1)-C(3)-C(4) H(3A)-C(3)-H(3B) C(4)-C(3)-H(3A) C(4)-C(3)-H(3B) C(3)-C(4)-H(4A) C(3)-C(4)-H(4B) H(4A)-C(4)-H(4B) C(5)-C(4)-C(3) C(5)-C(4)-H(4A) C(5)-C(4)-H(4B) C(6)-C(5)-C(4) C(6)-C(5)-C(13) C(13)-C(5)-C(4) N(2)-C(6)-H(6) C(5)-C(6)-N(2) C(5)-C(6)-H(6) N(2)-C(7)-H(7A) N(2)-C(7)-H(7B) N(2)-C(7)-H(7C) H(7A)-C(7)-H(7B) H(7A)-C(7)-H(7C) H(7B)-C(7)-H(7C) N(2)-C(8)-C(9) N(2)-C(8)-C(13) C(9)-C(8)-C(13) C(8)-C(9)-H(9) C(10)-C(9)-C(8) C(10)-C(9)-H(9) C(9)-C(10)-H(10) 1.410(4) 0.99(3) 1.373(4) 1.768(3) 1.762(3) 1.05(3) 0.91(3) 97.38(16) 120.7(2) 115.4(2) 122.2(2) 126.1(2) 108.2(2) 125.7(2) 98.47(17) 98.84(18) 108.8(2) 108.11(19) 100.99(18) 99.71(19) 106.81(19) 128.1(2) 109.7(2) 126.1(2) 127.1(2) 106.7(2) 105.4(16) 104.5(16) 112.0(2) 111(2) 112.9(17) 110.5(17) 109.4(17) 108.2(17) 105(2) 113.3(2) 109.6(18) 110.7(18) 124.9(2) 106.6(2) 128.5(2) 117.3(16) 110.7(2) 131.9(16) 110(2) 109(2) 101(2) 116(3) 116(3) 103(3) 127.9(2) 108.3(2) 123.7(2) 120.8(17) 116.9(2) 122.3(17) 116.5(18) 216   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(9)-C(10)-C(11) C(11)-C(10)-H(10) C(10)-C(11)-H(11) C(12)-C(11)-C(10) C(12)-C(11)-H(11) C(11)-C(12)-C(13) C(11)-C(12)-C(14) C(13)-C(12)-C(14) C(8)-C(13)-C(5) C(12)-C(13)-C(5) C(12)-C(13)-C(8) N(1)-C(14)-C(12) N(1)-C(14)-H(14) N(1)-C(14)-C(15) C(12)-C(14)-H(14) C(12)-C(14)-C(15) C(15)-C(14)-H(14) C(1)-C(15)-C(14) C(1)-C(15)-H(15) C(1)-C(15)-C(16) C(14)-C(15)-H(15) C(14)-C(15)-C(16) C(16)-C(15)-H(15) N(3)-C(16)-C(15) C(17)-C(16)-N(3) C(17)-C(16)-C(15) C(18)-C(16)-N(3) C(18)-C(16)-C(15) C(18)-C(16)-C(17) C(16)-C(17)-H(17A) C(16)-C(17)-H(17B) C(16)-C(17)-H(17C) H(17A)-C(17)-H(17B) H(17A)-C(17)-H(17C) H(17B)-C(17)-H(17C) C(16)-C(18)-H(18A) C(16)-C(18)-H(18B) C(16)-C(18)-H(18C) H(18A)-C(18)-H(18B) H(18A)-C(18)-H(18C) H(18B)-C(18)-H(18C) C(20)-C(19)-N(3) C(20)-C(19)-C(24) C(24)-C(19)-N(3) C(19)-C(20)-H(20) C(19)-C(20)-C(21) C(21)-C(20)-H(20) C(20)-C(21)-H(21) C(22)-C(21)-C(20) C(22)-C(21)-H(21) C(21)-C(22)-H(22) C(21)-C(22)-C(23) C(23)-C(22)-H(22) C(22)-C(23)-H(23) C(24)-C(23)-C(22) C(24)-C(23)-H(23) C(19)-C(24)-C(1) C(23)-C(24)-C(1) 121.3(2) 122.2(18) 122.5(17) 122.3(2) 115.2(17) 117.6(2) 117.8(2) 124.5(2) 106.2(2) 135.6(2) 118.2(2) 113.95(19) 106.4(16) 103.67(18) 107.2(17) 113.51(19) 111.9(15) 103.71(19) 106.3(17) 101.28(18) 110.2(16) 120.7(2) 112.7(15) 102.36(19) 106.3(2) 114.1(2) 109.8(2) 113.2(2) 110.5(2) 112.8(18) 111.4(19) 110.4(19) 110(3) 103(2) 109(3) 109.3(18) 108(2) 113.1(19) 111(3) 105(3) 111(3) 128.3(2) 121.8(3) 109.9(2) 121.3(19) 116.7(3) 121.3(19) 121(2) 122.3(3) 117(2) 120.7(19) 120.8(3) 118.5(19) 118.4(17) 117.1(3) 124.4(17) 102.0(2) 136.5(2) 217   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(23)-C(24)-C(19) Cl(1)-C(25)-H(25A) Cl(1)-C(25)-H(25B) Cl(2)-C(25)-Cl(1) Cl(2)-C(25)-H(25A) Cl(2)-C(25)-H(25B) H(25A)-C(25)-H(25B) 218   121.3(2) 110.2(17) 107(2) 111.07(16) 106.5(17) 108(2) 113(3) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Table A2.1.4. Anisotropic displacement parameters (Å x 10 ) for 24. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2p [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ O(1) 206(9) 155(8) 131(8) -22(7) -1(7) -14(7) O(2) 207(10) 124(8) 161(8) 51(7) -61(7) -31(7) N(1) 126(10) 118(9) 127(9) -25(8) -2(8) -24(8) N(2) 203(11) 166(10) 125(9) 9(9) -8(9) -46(9) N(3) 212(12) 166(11) 214(11) 57(9) -55(9) -61(9) C(1) 171(12) 142(12) 126(11) 41(9) -26(9) 3(10) C(2) 146(12) 138(12) 117(10) 32(9) -22(9) 3(9) C(3) 126(12) 149(12) 159(11) 7(10) -10(9) -34(10) C(4) 177(13) 139(12) 148(11) -8(10) -12(10) -51(10) C(5) 119(12) 133(12) 160(11) -4(9) -4(9) -5(9) C(6) 153(12) 172(12) 166(12) 1(10) -11(10) -24(9) C(7) 420(20) 280(16) 154(13) 27(12) -28(13) -139(15) C(8) 143(12) 150(12) 139(11) 0(9) -5(9) 8(10) C(9) 169(13) 201(13) 121(10) -4(10) -15(10) 24(10) C(10) 212(13) 137(12) 167(11) -54(10) -42(10) 14(10) C(11) 193(13) 109(11) 173(12) -16(10) -4(10) -1(10) C(12) 116(11) 119(11) 131(10) -7(9) -4(8) 17(9) C(13) 102(12) 136(12) 141(11) -3(9) -3(9) 8(9) C(14) 132(12) 97(11) 153(11) -15(9) -13(10) -8(9) C(15) 148(12) 118(12) 112(11) 17(9) -27(9) -10(9) C(16) 191(13) 99(11) 221(12) 26(10) -30(10) 1(9) C(17) 227(15) 118(12) 329(16) 7(12) -65(12) 5(11) C(18) 215(14) 129(13) 264(14) 3(11) -22(11) -38(11) C(19) 216(13) 199(12) 146(11) 44(10) -28(10) -40(10) C(20) 297(17) 272(15) 199(13) 74(12) -32(12) -122(13) C(21) 214(15) 394(17) 194(13) 80(12) 3(11) -141(13) C(22) 181(14) 404(17) 172(13) 48(12) -9(11) 10(13) C(23) 178(13) 276(14) 133(11) 30(11) -6(10) -30(11) C(24) 169(12) 194(12) 123(11) 32(10) -11(9) -46(10) Cl(1) 219(3) 371(4) 261(3) -11(3) -21(3) 63(3) Cl(2) 350(5) 605(5) 360(4) -126(4) 68(4) 131(4) C(25) 205(14) 276(15) 265(14) -15(12) 8(12) 51(12) ______________________________________________________________________________ 3 2 3 Table A2.1.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 24 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 219   H(3A) 344(4) 192(1) 435(3) 17 H(3B) 266(3) 225(1) 552(3) 17 H(4A) 131(4) 277(1) 399(3) 19 H(4B) 315(3) 282(1) 380(3) 19 H(6) 291(3) 308(1) 120(3) 20 H(7A) 249(4) 305(1) -114(4) 43 H(7B) 133(5) 262(1) -168(3) 43 H(7C) 309(5) 246(1) -155(3) 43 H(9) 86(4) 169(1) -136(3) 20 H(10) -5(3) 93(1) -50(3) 21 H(11) -4(3) 77(1) 188(3) 19 H(14) 197(3) 114(1) 388(3) 15 H(15) -145(3) 114(1) 377(3) 15 H(17A) 204(4) 38(1) 500(3) 34 H(17B) 159(4) 23(1) 350(3) 34 H(17C) 121(4) -15(1) 474(3) 34 H(18A) -185(4) -19(1) 428(3) 30 H(18B) -138(4) 11(1) 302(3) 30 H(18C) -280(4) 30(1) 389(3) 30 H(20) -387(4) 0(1) 662(3) 31 H(21) -620(4) 50(1) 691(3) 32 H(22) -632(4) 136(1) 671(3) 30 H(23) -402(4) 183(1) 605(3) 23 H(25A) 349(4) 112(1) 83(3) 30 H(25B) 486(4) 158(1) 87(3) 30 ________________________________________________________________________________ Table A2.1.6. Hydrogen bonds for 24 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ C(7)-H(7B)...O(1)#1 0.90(4) 2.52(4) 3.338(4) 151(3) C(7)-H(7C)...O(1)#2 1.02(4) 2.76(4) 3.325(4) 115(2) C(9)-H(9)...O(1)#1 0.95(3) 2.55(3) 3.436(3) 156(2) ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 x,y,z-1 #2 x+1/2,-y+1/2,z-1     Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.2. X-Ray Crystal Structure Analysis of 37 Ts N CN O N O2N H 37 Figure A2.2.1. X-ray Crystal Structure of 37 Table A2.2.1. Crystal data and structure refinement for 37 Empirical formula C26 H22 N4 O5 S Formula weight 502.54 Crystal Habit Needle Crystal size 0.30 x 0.07 x 0.07 mm3 Crystal color Colorless Data Collection Preliminary Photos Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoK〈 Data Collection Temperature 100(2) K ⎝ range for 1342 reflections used 220   221   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 in lattice determination 2.17 to 18.91° Unit cell dimensions a = 13.243(2) Å b = 14.115(2) Å c = 25.059(4) Å Volume 4684.2(13) Å3 Z 8 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Density (calculated) 1.425 Mg/m3 F(000) 2096 Data collection program Bruker SMART v5.630 ⎝ range for data collection 1.63 to 22.98° Completeness to ⎝ = 22.98° 83.9 % Index ranges -12<=h<=13, -14<=k<=10, -27<=l<=21 Data collection scan type scans at 2 settings   Data  reduction  program     Bruker  SAINT  v6.45A   Reflections  collected   10767   Independent  reflections   5122  [Rint=  0.1652]   Absorption  coefficient   0.185  mm-­‐1   Absorption  correction   None   Max.  and  min.  transmission   0.9871  and  0.9465   Number  of  standards     Variation  of  standards     ?  reflections  measured  every  ?min.     ?%.     Structure solution and Refinement Structure solution program SHELXS-97 (Sheldrick, 1990) Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program SHELXL-97 (Sheldrick, 1997) Refinement method Full matrix least-squares on F2 Data / restraints / parameters 5122 / 0 / 291 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.294 Final R indices [I>2⌠(I), 2377 reflections] R1 = 0.1085, wR2 = 0.1814 R indices (all data) R1 = 0.2168, wR2 = 0.2078 Type of weighting scheme used Sigma Weighting scheme used w=1/s^2^(Fo^2^) Max shift/error 0.015 Average shift/error 0.000 〈= 90° ®= 90° © = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Absolute structure determination ? Absolute structure parameter 0.5(3) Largest diff. peak and hole 0.868 and -1.060 e.Å-3 222   Special Refinement Details Table A2.2.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 37. U(eq) is defined asthe trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ S(1A) 2444(3) 6752(3) 3762(2) 24(1) O(1A) 1847(8) 6830(7) 4221(4) 35(3) O(2A) 2120(8) 7120(7) 3248(4) 25(3) O(3A) 3062(8) 2592(7) 2393(4) 22(3) O(4A) 4152(8) 3228(8) 4567(4) 26(3) O(5A) 2979(9) 2243(8) 4804(4) 34(3) N(1A) 2662(8) 5605(8) 3672(5) 10(3) N(2A) 2007(9) 2282(9) 3084(5) 19(4) N(3A) 3661(10) 2523(10) 4514(5) 27(4) N(4A) 5462(11) 3745(9) 2693(6) 31(4) C(1A) 3644(12) 7259(11) 3917(6) 19(4) C(2A) 3980(11) 7265(11) 4429(6) 20(5) C(3A) 4958(12) 7621(11) 4550(7) 31(5) C(4A) 5605(14) 8037(13) 4166(7) 40(6) C(5A) 5147(11) 8041(10) 3649(7) 21(5) C(6A) 4202(11) 7655(10) 3519(6) 12(4) C(7A) 6579(12) 8456(12) 4253(7) 36(5) C(8A) 2748(12) 5013(10) 4169(6) 21(4) C(9A) 2094(14) 4095(11) 4086(7) 36(5) C(10A) 1349(11) 3803(11) 4439(6) 13(4) C(11A) 810(12) 3025(11) 4359(6) 24(5) C(12A) 966(12) 2434(12) 3927(6) 26(5) C(13A) 1776(11) 2644(10) 3576(6) 19(4) C(14A) 2313(11) 3475(10) 3645(6) 13(4) C(15A) 3070(11) 3547(10) 3202(6) 17(4) C(16A) 3010(11) 4510(10) 2925(6) 14(4) C(17A) 3383(11) 5395(10) 3235(6) 15(4) C(18A) 2703(12) 2749(11) 2827(6) 21(5) C(19A) 4146(10) 3299(9) 3415(5) 3(4) C(20A) 4911(12) 3517(11) 2992(6) 16(4) C(21A) 4200(12) 2245(11) 3559(6) 23(5) C(22A) 4506(10) 1615(10) 3185(6) 10(4) C(23A) 4374(13) 614(12) 3276(7) 38(5) C(24A) 4002(12) 326(12) 3754(7) 33(5) C(25A) 3778(12) 949(11) 4169(7) 26(5) C(26A) 3877(10) 1874(10) 4071(6) 8(4) S(1B) 7184(3) 1177(3) 3593(2) 24(1) O(1B) 6473(8) 1114(7) 4015(4) 28(3) O(2B) 6953(8) 839(7) 3074(4) 24(3) O(3B) 8347(8) 5377(7) 2346(4) 23(3) O(4B) 9055(8) 4456(8) 4514(4) 28(3) O(5B) 8036(9) 5576(8) 4787(5) 39(3) N(1B) 7443(10) 2316(9) 3495(5) 28(4) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 223   N(2B) 7154(9) 5718(9) 3014(5) 18(3) N(3B) 8648(10) 5277(10) 4471(6) 28(4) N(4B) 10569(10) 4005(9) 2678(5) 20(4) C(1B) 8339(12) 633(11) 3783(7) 21(4) C(2B) 8674(11) 682(11) 4310(6) 17(4) C(3B) 9535(12) 304(11) 4441(7) 28(5) C(4B) 10165(13) -92(12) 4072(7) 26(5) C(5B) 9804(12) -94(11) 3538(7) 29(5) C(6B) 8964(11) 227(10) 3393(7) 19(5) C(7B) 11271(11) -495(12) 4220(7) 34(5) C(8B) 7549(12) 2872(9) 4003(6) 15(4) C(9B) 7020(12) 3849(11) 3944(6) 20(4) C(10B) 6276(11) 4107(10) 4280(6) 19(5) C(11B) 5776(12) 4987(11) 4225(7) 25(5) C(12B) 6092(12) 5574(12) 3800(6) 27(5) C(13B) 6847(10) 5316(10) 3459(6) 7(4) C(14B) 7352(12) 4461(11) 3542(7) 25(5) C(15B) 8118(12) 4327(11) 3101(7) 26(5) C(16B) 7989(12) 3429(10) 2779(6) 20(5) C(17B) 8247(12) 2492(10) 3090(6) 22(5) C(18B) 7896(12) 5207(11) 2769(6) 18(4) C(19B) 9211(10) 4501(10) 3372(6) 7(4) C(20B) 9978(12) 4216(11) 2978(7) 24(5) C(21B) 9361(11) 5538(10) 3556(6) 11(4) C(22B) 9696(13) 6156(11) 3175(7) 34(5) C(23B) 9622(12) 7178(12) 3311(7) 28(5) C(24B) 9228(12) 7468(12) 3774(7) 31(5) C(25B) 8888(12) 6840(11) 4145(7) 26(5) C(26B) 9000(11) 5871(10) 4031(6) 9(4) ________________________________________________________________________________ Table A2.2.3. Bond lengths [Å] and angles [°] for 37 _____________________________________________________ S(1A)-O(1A) 1.399(11) S(1A)-O(2A) 1.455(11) S(1A)-N(1A) 1.659(12) S(1A)-C(1A) 1.786(16) O(3A)-C(18A) 1.206(16) O(4A)-N(3A) 1.196(14) O(5A)-N(3A) 1.225(16) N(1A)-C(17A) 1.484(17) N(1A)-C(8A) 1.504(17) N(2A)-C(18A) 1.305(17) N(2A)-C(13A) 1.369(18) N(3A)-C(26A) 1.469(18) N(4A)-C(20A) 1.094(17) C(1A)-C(2A) 1.357(19) C(1A)-C(6A) 1.361(19) C(2A)-C(3A) 1.42(2) C(3A)-C(4A) 1.42(2) C(4A)-C(5A) 1.43(2) C(4A)-C(7A) 1.44(2) C(5A)-C(6A) 1.403(19) C(8A)-C(9A) 1.57(2) C(9A)-C(10A) 1.39(2) C(9A)-C(14A) 1.44(2) C(10A)-C(11A) 1.32(2) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(11A)-C(12A) C(12A)-C(13A) C(13A)-C(14A) C(14A)-C(15A) C(15A)-C(16A) C(15A)-C(18A) C(15A)-C(19A) C(16A)-C(17A) C(19A)-C(20A) C(19A)-C(21A) C(21A)-C(22A) C(21A)-C(26A) C(22A)-C(23A) C(23A)-C(24A) C(24A)-C(25A) C(25A)-C(26A) S(1B)-O(2B) S(1B)-O(1B) S(1B)-N(1B) S(1B)-C(1B) O(3B)-C(18B) O(4B)-N(3B) O(5B)-N(3B) N(1B)-C(17B) N(1B)-C(8B) N(2B)-C(13B) N(2B)-C(18B) N(3B)-C(26B) N(4B)-C(20B) C(1B)-C(2B) C(1B)-C(6B) C(2B)-C(3B) C(3B)-C(4B) C(4B)-C(5B) C(4B)-C(7B) C(5B)-C(6B) C(8B)-C(9B) C(9B)-C(10B) C(9B)-C(14B) C(10B)-C(11B) C(11B)-C(12B) C(12B)-C(13B) C(13B)-C(14B) C(14B)-C(15B) C(15B)-C(16B) C(15B)-C(18B) C(15B)-C(19B) C(16B)-C(17B) C(19B)-C(20B) C(19B)-C(21B) C(21B)-C(26B) C(21B)-C(22B) C(22B)-C(23B) C(23B)-C(24B) C(24B)-C(25B) C(25B)-C(26B) O(1A)-S(1A)-O(2A) 1.38(2) 1.42(2) 1.382(18) 1.50(2) 1.528(18) 1.55(2) 1.562(19) 1.552(18) 1.50(2) 1.532(19) 1.354(19) 1.45(2) 1.44(2) 1.36(2) 1.39(2) 1.336(19) 1.418(11) 1.418(11) 1.662(13) 1.776(16) 1.241(17) 1.282(14) 1.209(16) 1.493(18) 1.501(17) 1.316(17) 1.365(18) 1.463(18) 1.126(18) 1.40(2) 1.40(2) 1.301(19) 1.36(2) 1.42(2) 1.61(2) 1.254(19) 1.55(2) 1.35(2) 1.40(2) 1.41(2) 1.41(2) 1.36(2) 1.396(19) 1.51(2) 1.51(2) 1.52(2) 1.62(2) 1.572(19) 1.47(2) 1.547(19) 1.365(19) 1.37(2) 1.49(2) 1.34(2) 1.36(2) 1.41(2) 122.2(7) 224   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(1A)-S(1A)-N(1A) O(2A)-S(1A)-N(1A) O(1A)-S(1A)-C(1A) O(2A)-S(1A)-C(1A) N(1A)-S(1A)-C(1A) C(17A)-N(1A)-C(8A) C(17A)-N(1A)-S(1A) C(8A)-N(1A)-S(1A) C(18A)-N(2A)-C(13A) O(4A)-N(3A)-O(5A) O(4A)-N(3A)-C(26A) O(5A)-N(3A)-C(26A) C(2A)-C(1A)-C(6A) C(2A)-C(1A)-S(1A) C(6A)-C(1A)-S(1A) C(1A)-C(2A)-C(3A) C(4A)-C(3A)-C(2A) C(3A)-C(4A)-C(5A) C(3A)-C(4A)-C(7A) C(5A)-C(4A)-C(7A) C(6A)-C(5A)-C(4A) C(1A)-C(6A)-C(5A) N(1A)-C(8A)-C(9A) C(10A)-C(9A)-C(14A) C(10A)-C(9A)-C(8A) C(14A)-C(9A)-C(8A) C(11A)-C(10A)-C(9A) C(10A)-C(11A)-C(12A) C(11A)-C(12A)-C(13A) N(2A)-C(13A)-C(14A) N(2A)-C(13A)-C(12A) C(14A)-C(13A)-C(12A) C(13A)-C(14A)-C(9A) C(13A)-C(14A)-C(15A) C(9A)-C(14A)-C(15A) C(14A)-C(15A)-C(16A) C(14A)-C(15A)-C(18A) C(16A)-C(15A)-C(18A) C(14A)-C(15A)-C(19A) C(16A)-C(15A)-C(19A) C(18A)-C(15A)-C(19A) C(15A)-C(16A)-C(17A) N(1A)-C(17A)-C(16A) O(3A)-C(18A)-N(2A) O(3A)-C(18A)-C(15A) N(2A)-C(18A)-C(15A) C(20A)-C(19A)-C(21A) C(20A)-C(19A)-C(15A) C(21A)-C(19A)-C(15A) N(4A)-C(20A)-C(19A) C(22A)-C(21A)-C(26A) C(22A)-C(21A)-C(19A) C(26A)-C(21A)-C(19A) C(21A)-C(22A)-C(23A) C(24A)-C(23A)-C(22A) C(23A)-C(24A)-C(25A) C(26A)-C(25A)-C(24A) C(25A)-C(26A)-C(21A) 106.7(7) 106.2(6) 107.0(7) 108.2(7) 105.4(7) 116.8(11) 114.1(9) 116.3(9) 114.5(13) 127.2(15) 119.8(14) 113.0(13) 120.8(16) 120.0(12) 119.2(12) 120.1(16) 123.5(17) 111.2(16) 127.6(17) 121.2(17) 125.9(16) 118.3(15) 107.8(12) 116.9(15) 123.5(16) 119.5(15) 122.1(16) 122.6(17) 118.2(16) 108.4(14) 130.5(15) 119.2(15) 120.6(14) 108.0(13) 131.4(13) 111.2(12) 101.0(12) 110.8(12) 110.0(12) 113.8(12) 109.4(11) 118.1(12) 109.0(12) 129.1(15) 123.9(15) 106.8(14) 109.5(13) 109.2(12) 109.9(12) 174.7(18) 117.6(14) 119.3(14) 123.0(14) 119.9(15) 118.5(17) 123.1(17) 117.4(17) 123.0(16) 225   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(25A)-C(26A)-N(3A) C(21A)-C(26A)-N(3A) O(2B)-S(1B)-O(1B) O(2B)-S(1B)-N(1B) O(1B)-S(1B)-N(1B) O(2B)-S(1B)-C(1B) O(1B)-S(1B)-C(1B) N(1B)-S(1B)-C(1B) C(17B)-N(1B)-C(8B) C(17B)-N(1B)-S(1B) C(8B)-N(1B)-S(1B) C(13B)-N(2B)-C(18B) O(5B)-N(3B)-O(4B) O(5B)-N(3B)-C(26B) O(4B)-N(3B)-C(26B) C(2B)-C(1B)-C(6B) C(2B)-C(1B)-S(1B) C(6B)-C(1B)-S(1B) C(3B)-C(2B)-C(1B) C(2B)-C(3B)-C(4B) C(3B)-C(4B)-C(5B) C(3B)-C(4B)-C(7B) C(5B)-C(4B)-C(7B) C(6B)-C(5B)-C(4B) C(5B)-C(6B)-C(1B) N(1B)-C(8B)-C(9B) C(10B)-C(9B)-C(14B) C(10B)-C(9B)-C(8B) C(14B)-C(9B)-C(8B) C(9B)-C(10B)-C(11B) C(12B)-C(11B)-C(10B) C(13B)-C(12B)-C(11B) N(2B)-C(13B)-C(12B) N(2B)-C(13B)-C(14B) C(12B)-C(13B)-C(14B) C(13B)-C(14B)-C(9B) C(13B)-C(14B)-C(15B) C(9B)-C(14B)-C(15B) C(16B)-C(15B)-C(14B) C(16B)-C(15B)-C(18B) C(14B)-C(15B)-C(18B) C(16B)-C(15B)-C(19B) C(14B)-C(15B)-C(19B) C(18B)-C(15B)-C(19B) C(15B)-C(16B)-C(17B) N(1B)-C(17B)-C(16B) O(3B)-C(18B)-N(2B) O(3B)-C(18B)-C(15B) N(2B)-C(18B)-C(15B) C(20B)-C(19B)-C(21B) C(20B)-C(19B)-C(15B) C(21B)-C(19B)-C(15B) N(4B)-C(20B)-C(19B) C(26B)-C(21B)-C(22B) C(26B)-C(21B)-C(19B) C(22B)-C(21B)-C(19B) C(21B)-C(22B)-C(23B) C(24B)-C(23B)-C(22B) 116.9(14) 120.1(13) 121.3(7) 103.6(7) 107.9(7) 106.6(7) 110.2(7) 106.2(7) 115.0(12) 114.1(11) 113.6(10) 112.1(13) 122.8(14) 120.5(13) 116.6(13) 119.5(15) 120.4(13) 119.9(13) 119.8(16) 122.2(17) 115.7(16) 122.9(15) 121.4(15) 124.7(17) 118.0(17) 110.0(12) 120.9(15) 120.8(15) 118.3(14) 121.3(17) 116.8(16) 122.1(15) 130.0(15) 110.6(14) 119.2(15) 119.4(15) 108.7(15) 131.3(15) 114.8(14) 111.7(13) 99.6(13) 116.9(13) 105.9(13) 106.2(12) 114.6(12) 108.8(12) 128.9(14) 122.1(15) 108.9(13) 111.7(13) 107.0(13) 112.6(12) 179(2) 120.2(14) 122.6(14) 116.0(14) 115.9(16) 121.5(18) 226   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(23B)-C(24B)-C(25B) 121.5(17) C(24B)-C(25B)-C(26B) 117.3(16) C(21B)-C(26B)-C(25B) 123.3(15) C(21B)-C(26B)-N(3B) 124.9(13) C(25B)-C(26B)-N(3B) 111.7(13) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.2.4. Hydrogen bonds for 37 [Å and °] ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ N(2A)-H(2A)...O(3B)#1 0.88 2.11 2.933(16) 155.2 N(2B)-H(2B)...O(3A)#2 0.88 2.02 2.849(16) 157.3 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,y-1/2,-z+1/2 #2 -x+1,y+1/2,-z+1/2                                 227   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.3. 228   X-Ray Crystal Structure Analysis of 42 Ts H N CO2Me CO2Me O N H   42 Figure A2.3.1. X-ray Crystal Structure of 42 Table A2.3.1. Crystal data and structure refinement for 42 Empirical formula C27 H30 N2 O7 S Formula weight 526.59 Crystal Habit Blade Crystal size 0.33 x 0.26 x 0.07 mm3 Crystal color Colorless Data Collection Preliminary Photos Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoKa Data Collection Temperature 100(2) K q range for 9727 reflections used in lattice determination 2.40 to 33.11° Unit cell dimensions a = 9.5308(8) Å b = 9.7901(9) Å c = 13.8253(12) Å Volume 1266.67(19) Å3 Z 2 Crystal system Monoclinic a= 90° b= 100.914(2)° g = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Space group Pn Density (calculated) 1.381 Mg/m3 F(000) 556 Data collection program Bruker SMART v5.630 q range for data collection 2.08 to 33.37° Completeness to q = 33.37° 79.2 % Index ranges -12<=h<=12, -12<=k<=14, -20<=l<=18 Data collection scan type scans at 5 settings Data reduction program Bruker SAINT v6.45A Reflections collected 17354 Independent reflections 6630 [Rint= 0.0627] Absorption coefficient 0.178 mm-1 Absorption correction None Max. and min. transmission 0.9876 and 0.9436 Number of standards ? reflections measured every ?min. Variation of standards ?%. Structure solution and Refinement Structure solution program SHELXS-97 (Sheldrick, 1990) Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program SHELXL-97 (Sheldrick, 1997) Refinement method Full matrix least-squares on F2 Data / restraints / parameters 6630 / 2 / 339 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.413 Final R indices [I>2s(I), 5764 reflections] R1 = 0.0412, wR2 = 0.0772 R indices (all data) R1 = 0.0487, wR2 = 0.0785 Type of weighting scheme used Sigma Weighting scheme used w=1/s^2^(Fo^2^) Max shift/error 0.003 Average shift/error 0.000 Absolute structure determination ? Absolute structure parameter -0.06(5) Largest diff. peak and hole 0.698 and -0.437 e.Å-3 Special Refinement Details 229   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 230   Table A2.3.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 42. U(eq) is defined as the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ S(1) 2561(1) 4166(1) 5901(1) 20(1) O(1) 1091(2) 3868(1) 5901(1) 28(1) O(2) 3543(2) 3041(1) 5888(1) 26(1) O(3) 5953(1) 9815(1) 6612(1) 23(1) O(4) 7590(1) 7652(1) 8168(1) 25(1) O(5) 7214(1) 9500(1) 9044(1) 22(1) O(6) 4387(1) 10398(1) 8732(1) 21(1) O(7) 3629(1) 8558(1) 9457(1) 19(1) N(1) 3154(2) 5091(2) 6868(1) 18(1) N(2) 3555(2) 10204(2) 6558(1) 18(1) C(1) 2669(2) 5158(2) 4849(2) 17(1) C(2) 3664(2) 4837(2) 4284(2) 21(1) C(3) 3700(2) 5589(2) 3436(2) 23(1) C(4) 2753(2) 6670(2) 3153(2) 21(1) C(5) 1775(2) 6993(2) 3757(2) 24(1) C(6) 1722(2) 6249(2) 4595(2) 22(1) C(7) 2775(3) 7430(2) 2213(2) 33(1) C(8) 4669(2) 5481(2) 7050(2) 19(1) C(9) 4988(2) 6898(2) 6675(2) 17(1) C(10) 4451(2) 8092(2) 7224(1) 15(1) C(11) 2834(2) 8156(2) 7105(1) 15(1) C(12) 1822(2) 7184(2) 7242(1) 15(1) C(13) 2158(2) 5683(2) 7468(1) 16(1) C(14) 2653(2) 5409(2) 8558(2) 18(1) C(15) 2510(2) 4205(2) 8993(2) 23(1) C(16) 1948(2) 2934(2) 8454(2) 32(1) C(17) 2943(2) 4057(3) 10088(2) 37(1) C(18) 404(2) 7610(2) 7130(1) 17(1) C(19) -10(2) 8938(2) 6853(1) 19(1) C(20) 980(2) 9888(2) 6632(1) 18(1) C(21) 2385(2) 9461(2) 6761(1) 15(1) C(22) 4787(2) 9468(2) 6759(1) 18(1) C(23) 5191(2) 8149(2) 8355(1) 16(1) C(24) 6788(2) 8399(2) 8493(1) 18(1) C(25) 8742(2) 9752(2) 9212(2) 27(1) C(26) 4392(2) 9188(2) 8867(1) 15(1) C(27) 2603(2) 9418(2) 9817(2) 25(1) ________________________________________________________________________________ Table A2.3.3. Bond lengths [Å] and angles [°] for 42 _____________________________________________________ S(1)-O(1) 1.4313(14) S(1)-O(2) 1.4482(14) S(1)-N(1) 1.6255(17) S(1)-C(1) 1.767(2) O(3)-C(22) 1.215(2) O(4)-C(24) 1.204(2) O(5)-C(24) 1.338(2) O(5)-C(25) 1.451(2) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(6)-C(26) O(7)-C(26) O(7)-C(27) N(1)-C(8) N(1)-C(13) N(2)-C(22) N(2)-C(21) C(1)-C(2) C(1)-C(6) C(2)-C(3) C(3)-C(4) C(4)-C(5) C(4)-C(7) C(5)-C(6) C(8)-C(9) C(9)-C(10) C(10)-C(11) C(10)-C(22) C(10)-C(23) C(11)-C(12) C(11)-C(21) C(12)-C(18) C(12)-C(13) C(13)-C(14) C(14)-C(15) C(15)-C(16) C(15)-C(17) C(18)-C(19) C(19)-C(20) C(20)-C(21) C(23)-C(24) C(23)-C(26) O(1)-S(1)-O(2) O(1)-S(1)-N(1) O(2)-S(1)-N(1) O(1)-S(1)-C(1) O(2)-S(1)-C(1) N(1)-S(1)-C(1) C(24)-O(5)-C(25) C(26)-O(7)-C(27) C(8)-N(1)-C(13) C(8)-N(1)-S(1) C(13)-N(1)-S(1) C(22)-N(2)-C(21) C(2)-C(1)-C(6) C(2)-C(1)-S(1) C(6)-C(1)-S(1) C(1)-C(2)-C(3) C(2)-C(3)-C(4) C(3)-C(4)-C(5) C(3)-C(4)-C(7) C(5)-C(4)-C(7) C(6)-C(5)-C(4) C(5)-C(6)-C(1) N(1)-C(8)-C(9) C(8)-C(9)-C(10) C(11)-C(10)-C(9) 1.199(2) 1.341(2) 1.449(2) 1.469(2) 1.491(2) 1.361(2) 1.403(2) 1.374(3) 1.400(3) 1.390(3) 1.398(3) 1.401(3) 1.501(3) 1.377(3) 1.531(2) 1.532(2) 1.519(3) 1.551(2) 1.590(2) 1.393(2) 1.402(2) 1.395(2) 1.524(2) 1.515(3) 1.341(3) 1.496(3) 1.499(3) 1.392(3) 1.398(3) 1.382(3) 1.517(2) 1.524(3) 118.70(9) 107.55(8) 107.99(8) 108.78(9) 105.60(9) 107.79(8) 114.58(15) 114.87(15) 120.84(15) 117.58(12) 121.04(13) 111.90(15) 120.90(18) 119.74(14) 119.35(16) 119.21(17) 121.30(19) 118.11(18) 120.25(18) 121.62(17) 121.13(18) 119.32(19) 115.42(15) 114.69(15) 113.86(15) 231   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(11)-C(10)-C(22) 101.80(14) C(9)-C(10)-C(22) 110.06(14) C(11)-C(10)-C(23) 110.93(14) C(9)-C(10)-C(23) 112.65(14) C(22)-C(10)-C(23) 106.77(14) C(12)-C(11)-C(21) 119.60(16) C(12)-C(11)-C(10) 132.16(16) C(21)-C(11)-C(10) 108.20(15) C(11)-C(12)-C(18) 117.54(16) C(11)-C(12)-C(13) 124.25(16) C(18)-C(12)-C(13) 118.17(15) N(1)-C(13)-C(14) 111.94(14) N(1)-C(13)-C(12) 113.07(14) C(14)-C(13)-C(12) 112.87(15) C(15)-C(14)-C(13) 124.25(18) C(14)-C(15)-C(16) 124.3(2) C(14)-C(15)-C(17) 120.4(2) C(16)-C(15)-C(17) 115.24(18) C(19)-C(18)-C(12) 121.84(17) C(18)-C(19)-C(20) 120.92(17) C(21)-C(20)-C(19) 116.63(16) C(20)-C(21)-C(11) 123.04(17) C(20)-C(21)-N(2) 127.26(16) C(11)-C(21)-N(2) 109.68(16) O(3)-C(22)-N(2) 126.81(16) O(3)-C(22)-C(10) 125.37(16) N(2)-C(22)-C(10) 107.82(15) C(24)-C(23)-C(26) 114.28(15) C(24)-C(23)-C(10) 112.17(14) C(26)-C(23)-C(10) 108.22(14) O(4)-C(24)-O(5) 123.72(18) O(4)-C(24)-C(23) 123.19(17) O(5)-C(24)-C(23) 113.04(15) O(6)-C(26)-O(7) 124.28(17) O(6)-C(26)-C(23) 125.06(17) O(7)-C(26)-C(23) 110.58(15) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.3.4. Anisotropic displacement parameters (Å2x 104 ) for 42. The anisotropic displacement factor exponent takes the form: -2p2 [ h2 a*2U 11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ S(1) 284(3) 91(2) 237(3) -5(2) 94(2) -26(2) O(1) 333(8) 219(7) 297(9) -67(6) 115(7) -105(6) O(2) 421(9) 99(6) 292(8) 25(6) 140(7) 25(6) O(3) 230(7) 208(7) 267(8) 36(6) 97(6) -55(6) O(4) 187(7) 262(7) 301(9) 1(6) 61(6) 54(6) O(5) 167(7) 267(7) 229(8) -24(6) 36(6) -9(5) O(6) 212(7) 155(7) 276(8) -7(6) 63(6) 11(5) O(7) 199(7) 208(7) 180(7) 20(5) 78(5) 10(5) N(1) 208(8) 126(8) 211(9) -7(6) 88(6) 4(6) N(2) 222(9) 96(7) 224(9) 48(6) 46(7) -3(6) C(1) 230(10) 101(8) 185(10) -8(7) 38(8) -49(7) C(2) 201(10) 138(9) 284(12) -18(8) 41(8) 15(7) C(3) 239(11) 185(10) 280(12) -13(8) 109(9) 0(7) 232   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(4) 235(10) 133(9) 252(11) 12(8) 34(8) -12(7) C(5) 241(10) 157(9) 309(12) 12(8) 25(8) 47(8) C(6) 230(11) 164(10) 292(12) -33(8) 84(9) 10(8) C(7) 399(13) 255(11) 324(13) 85(10) 58(10) 33(10) C(8) 196(10) 139(9) 246(11) -4(7) 82(8) 25(7) C(9) 172(10) 165(9) 189(10) 3(7) 60(7) 4(7) C(10) 164(9) 124(8) 167(10) 21(7) 54(7) -9(6) C(11) 192(9) 133(9) 127(9) -19(7) 52(7) 9(7) C(12) 194(9) 132(9) 117(9) 9(7) 42(7) 9(7) C(13) 139(9) 134(9) 213(10) -13(7) 89(8) -22(7) C(14) 151(9) 169(9) 240(11) 33(8) 59(8) 1(7) C(15) 146(9) 252(10) 302(12) 115(9) 93(8) 48(8) C(16) 328(12) 154(10) 524(16) 127(10) 173(11) 49(8) C(17) 283(12) 474(14) 361(14) 223(11) 103(10) -17(10) C(18) 185(10) 177(9) 151(10) -8(7) 42(8) -33(7) C(19) 167(9) 221(10) 172(10) -8(8) 10(8) 59(7) C(20) 229(10) 141(9) 167(10) 25(7) 20(8) 50(7) C(21) 225(10) 128(9) 107(9) -1(7) 38(8) -1(7) C(22) 251(10) 130(9) 152(10) 1(7) 42(8) -25(7) C(23) 177(9) 105(8) 192(10) 30(7) 50(8) 12(7) C(24) 186(10) 179(9) 179(10) 64(8) 37(8) 10(7) C(25) 173(10) 374(12) 244(12) -17(9) 12(8) -73(8) C(26) 97(8) 196(9) 151(10) -6(7) -8(7) -9(7) C(27) 231(10) 306(11) 241(11) -9(9) 104(9) 37(8) ______________________________________________________________________________ Table A2.3.5. Hydrogen bonds for 42 [Å and °] ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ N(2)-H(2)...O(2)#1 0.88 2.05 2.928(2) 174.5 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x,y+1,z 233   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.4. X-Ray Crystal Structure Analysis of 51 O O O NO N 2 51 Figure A2.4.1. X-ray Crystal Structure of 51 Table A2.4.1. Crystal Data and Structure Analysis Details for 51 Empirical formula C22 H20 N2 O5 Formula weight 392.40 Crystal shape plate Crystal color colourless Crystal size 0.08 x 0.39 x 0.40 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK 234   235   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Data collection temperature 100 K Theta range for 9925 reflections used in lattice determination 2.59 to 33.53° Unit cell dimensions a = 7.5798(3) Å b = 30.0522(12) Å c = 8.3663(3) Å 〈= 90° ®= 103.6098(19)° © = 90° Volume 1852.24(12) Å3 Z 4 Crystal system monoclinic Space group P 1 21/c 1 (# 14) Density (calculated) 1.407 g/cm3 F(000) 824 Theta range for data collection 2.6 to 36.7° Completeness to theta = 25.000° 99.9% Index ranges -12 ʺ″ h ʺ″ 12, -48 ʺ″ k ʺ″ 48, -13 ʺ″ l ʺ″ 13 Data collection scan type and  scans   Reflections  collected   90271   Independent  reflections   8678  [Rint=  0.0550]   Reflections  >  2⌠(I)   6686     Average  ⌠(I)/(net  I)   0.0317   Absorption  coefficient   0.10  mm-­‐1   Absorption  correction   Semi-­‐empirical  from  equivalents   Max.  and  min.  transmission   1.0000  and  0.9172     Structure Solution and Refinement Primary solution method ? Secondary solution method ? Hydrogen placement difmap Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 8678 / 0 / 322 Treatment of hydrogen atoms refxyz Goodness-of-fit on F2 1.63 Final R indices [I>2⌠(I), 6686 reflections] R1 = 0.0491, wR2 = 0.1139 R indices (all data) R1 = 0.0700, wR2 = 0.1189 Type of weighting scheme used calc Weighting scheme used w=1/[^2^(Fo^2^)+(0.0400P)^2^] where P=(Fo^2^+2Fc^2^)/3 Max shift/error 0.001 Average shift/error 0.000 Extinction coefficient n/a Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Largest diff. peak and hole 236   0.63 and -0.32 e·Å-3 Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.32B (Bruker-AXS, 2007) APEX2 2013.6-2 (Bruker-AXS, 2007) SAINT V8.32B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.4.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 51. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ O(1) 12316(1) 2035(1) 9127(1) 32(1) O(2) 9477(1) 1887(1) 8963(1) 25(1) O(3) 8678(1) 936(1) 10051(1) 25(1) O(4) 11278(1) 1051(1) 9408(1) 24(1) O(5) 5030(1) 428(1) 6376(1) 19(1) N(1) 10836(1) 1886(1) 8401(1) 21(1) N(2) 4779(1) 893(1) 4161(1) 15(1) C(1) 8719(1) 1022(1) 7103(1) 12(1) C(2) 9732(1) 1325(1) 6146(1) 12(1) C(3) 9631(1) 1230(1) 4488(1) 14(1) C(4) 10336(1) 1512(1) 3480(1) 19(1) C(5) 11238(1) 1898(1) 4107(1) 22(1) C(6) 11443(1) 1996(1) 5750(1) 20(1) C(7) 10675(1) 1717(1) 6726(1) 15(1) C(8) 8953(1) 519(1) 6658(1) 12(1) C(9) 10876(1) 364(1) 6877(1) 17(1) C(10) 11560(1) 15(1) 7771(2) 26(1) C(11) 9646(1) 1021(1) 8938(1) 17(1) C(12) 6715(2) 923(1) 9579(1) 25(1) C(13) 5976(2) 1265(1) 8268(1) 21(1) C(14) 6589(1) 1160(1) 6682(1) 13(1) C(15) 6136(1) 1526(1) 5402(1) 12(1) C(16) 6548(1) 1975(1) 5472(1) 14(1) C(17) 6062(1) 2230(1) 4037(1) 15(1) C(18) 5154(1) 2036(1) 2563(1) 15(1) C(19) 4645(1) 1588(1) 2488(1) 14(1) C(20) 5154(1) 1343(1) 3922(1) 13(1) C(21) 5401(1) 776(1) 5771(1) 14(1) C(22) 3576(1) 613(1) 2963(1) 21(1) ________________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 237   Table A2.4.3. Bond lengths [Å] and angles [°] for 51 __________________________________________________________________________________ _ O(1)-N(1) 1.2271(10) O(2)-N(1) 1.2294(12) O(3)-C(11) 1.3390(12) O(3)-C(12) 1.4477(14) O(4)-C(11) 1.2094(12) O(5)-C(21) 1.2218(10) N(1)-C(7) 1.4689(12) N(2)-C(20) 1.4069(10) N(2)-C(21) 1.3641(11) N(2)-C(22) 1.4538(11) C(1)-C(2) 1.5329(12) C(1)-C(8) 1.5766(11) C(1)-C(11) 1.5307(11) C(1)-C(14) 1.6236(11) C(2)-C(3) 1.4007(12) C(2)-C(7) 1.4025(11) C(3)-H(3) 0.978(12) C(3)-C(4) 1.3876(13) C(4)-H(4) 0.997(12) C(4)-C(5) 1.3847(14) C(5)-H(5) 0.971(13) C(5)-C(6) 1.3777(15) C(6)-H(6) 0.998(13) C(6)-C(7) 1.3900(13) C(8)-H(8A) 0.987(11) C(8)-H(8B) 0.950(11) C(8)-C(9) 1.4994(12) C(9)-H(9) 0.991(12) C(9)-C(10) 1.3224(13) C(10)-H(10A) 0.966(14) C(10)-H(10B) 0.964(14) C(12)-H(12A) 0.995(13) C(12)-H(12B) 0.963(14) C(12)-C(13) 1.5109(14) C(13)-H(13A) 1.014(13) C(13)-H(13B) 1.006(13) C(13)-C(14) 1.5372(12) C(14)-C(15) 1.5167(11) C(14)-C(21) 1.5506(12) C(15)-C(16) 1.3832(11) C(15)-C(20) 1.3979(11) C(16)-H(16) 0.966(12) C(16)-C(17) 1.3987(12) C(17)-H(17) 1.136(12) C(17)-C(18) 1.3904(12) C(18)-H(18) 0.950(12) C(18)-C(19) 1.3995(12) C(19)-H(19) 0.987(12) C(19)-C(20) 1.3821(11) C(22)-H(22A) 0.984(13) C(22)-H(22B) 0.962(13) C(22)-H(22C) 0.999(13) C(11)-O(3)-C(12) O(1)-N(1)-O(2) 120.79(7) 124.15(9) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(1)-N(1)-C(7) O(2)-N(1)-C(7) C(20)-N(2)-C(22) C(21)-N(2)-C(20) C(21)-N(2)-C(22) C(2)-C(1)-C(8) C(2)-C(1)-C(14) C(8)-C(1)-C(14) C(11)-C(1)-C(2) C(11)-C(1)-C(8) C(11)-C(1)-C(14) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(2)-C(3)-H(3) C(4)-C(3)-C(2) C(4)-C(3)-H(3) C(3)-C(4)-H(4) C(5)-C(4)-C(3) C(5)-C(4)-H(4) C(4)-C(5)-H(5) C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(5)-C(6)-H(6) C(5)-C(6)-C(7) C(7)-C(6)-H(6) C(2)-C(7)-N(1) C(6)-C(7)-N(1) C(6)-C(7)-C(2) C(1)-C(8)-H(8A) C(1)-C(8)-H(8B) H(8A)-C(8)-H(8B) C(9)-C(8)-C(1) C(9)-C(8)-H(8A) C(9)-C(8)-H(8B) C(8)-C(9)-H(9) C(10)-C(9)-C(8) C(10)-C(9)-H(9) C(9)-C(10)-H(10A) C(9)-C(10)-H(10B) H(10A)-C(10)-H(10B) O(3)-C(11)-C(1) O(4)-C(11)-O(3) O(4)-C(11)-C(1) O(3)-C(12)-H(12A) O(3)-C(12)-H(12B) O(3)-C(12)-C(13) H(12A)-C(12)-H(12B) C(13)-C(12)-H(12A) C(13)-C(12)-H(12B) C(12)-C(13)-H(13A) C(12)-C(13)-H(13B) C(12)-C(13)-C(14) H(13A)-C(13)-H(13B) C(14)-C(13)-H(13A) C(14)-C(13)-H(13B) C(13)-C(14)-C(1) C(13)-C(14)-C(21) 117.31(9) 118.48(7) 124.99(7) 110.73(7) 123.14(7) 110.41(7) 109.21(6) 110.84(6) 110.91(7) 100.61(6) 114.61(7) 118.59(7) 114.70(8) 126.55(7) 120.3(7) 122.62(8) 117.0(7) 121.5(7) 120.40(9) 118.1(7) 121.2(8) 119.15(9) 119.6(8) 119.9(7) 119.50(8) 120.5(7) 122.81(8) 113.54(8) 123.53(8) 108.4(6) 108.6(7) 105.1(10) 115.38(7) 110.1(6) 108.7(7) 116.9(7) 123.80(9) 119.2(7) 119.8(8) 120.9(8) 119.2(12) 120.03(8) 118.26(8) 121.28(8) 102.7(8) 108.1(8) 111.22(8) 108.5(11) 112.8(8) 112.9(8) 107.2(7) 108.4(7) 110.64(8) 107.4(10) 111.1(7) 111.9(7) 110.64(7) 108.51(7) 238   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(15)-C(14)-C(1) C(15)-C(14)-C(13) C(15)-C(14)-C(21) C(21)-C(14)-C(1) C(16)-C(15)-C(14) C(16)-C(15)-C(20) C(20)-C(15)-C(14) C(15)-C(16)-H(16) C(15)-C(16)-C(17) C(17)-C(16)-H(16) C(16)-C(17)-H(17) C(18)-C(17)-C(16) C(18)-C(17)-H(17) C(17)-C(18)-H(18) C(17)-C(18)-C(19) C(19)-C(18)-H(18) C(18)-C(19)-H(19) C(20)-C(19)-C(18) C(20)-C(19)-H(19) C(15)-C(20)-N(2) C(19)-C(20)-N(2) C(19)-C(20)-C(15) O(5)-C(21)-N(2) O(5)-C(21)-C(14) N(2)-C(21)-C(14) N(2)-C(22)-H(22A) N(2)-C(22)-H(22B) N(2)-C(22)-H(22C) H(22A)-C(22)-H(22B) H(22A)-C(22)-H(22C) H(22B)-C(22)-H(22C) 239   112.77(7) 113.42(7) 100.57(6) 110.42(6) 131.73(8) 119.23(7) 109.02(7) 121.0(7) 119.14(8) 119.8(7) 115.2(6) 120.51(8) 124.2(6) 119.0(7) 121.07(8) 119.9(7) 120.2(7) 117.12(8) 122.7(7) 109.59(7) 127.61(8) 122.79(7) 124.73(8) 126.63(8) 108.62(7) 112.4(8) 110.5(8) 111.4(8) 112.9(11) 106.0(11) 103.2(11) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Table A2.4.4. Anisotropic displacement parameters (Å x 10 ) for 51. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2ð [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ O(1) 343(4) 179(3) 323(4) -43(3) -181(3) -49(3) O(2) 381(4) 184(3) 153(3) -24(2) 26(3) 42(3) O(3) 415(4) 203(3) 116(3) 34(2) 60(3) 40(3) O(4) 282(4) 167(3) 184(3) 7(2) -95(3) 12(3) O(5) 154(3) 142(3) 293(4) 70(2) 79(3) 1(2) N(1) 276(4) 106(3) 178(3) -16(3) -71(3) 6(3) N(2) 131(3) 102(3) 205(3) 17(2) 0(3) -11(2) C(1) 136(3) 101(3) 105(3) 0(2) 10(3) 10(3) C(2) 105(3) 102(3) 128(3) -4(3) -1(3) 1(2) C(3) 137(3) 137(3) 146(3) -12(3) 30(3) -2(3) C(4) 213(4) 182(4) 211(4) 8(3) 106(3) 10(3) C(5) 216(4) 171(4) 321(5) 22(4) 156(4) -11(3) C(6) 144(4) 134(4) 310(5) -10(3) 39(3) -25(3) C(7) 137(3) 114(3) 169(4) -19(3) -18(3) -1(3) C(8) 121(3) 95(3) 153(3) -9(3) 21(3) 7(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 240   C(9) 136(3) 132(3) 222(4) -2(3) 30(3) 14(3) C(10) 192(4) 206(4) 367(6) 75(4) 47(4) 61(3) C(11) 280(4) 98(3) 112(3) 0(3) -5(3) 22(3) C(12) 397(6) 217(5) 195(4) 55(4) 171(4) 69(4) C(13) 310(5) 177(4) 201(4) 38(3) 147(4) 78(4) C(14) 148(3) 108(3) 143(3) 18(3) 51(3) 31(3) C(15) 126(3) 103(3) 136(3) 11(3) 38(3) 24(3) C(16) 154(3) 108(3) 152(4) 1(3) 29(3) 18(3) C(17) 158(4) 111(3) 176(4) 23(3) 28(3) 4(3) C(18) 148(4) 133(3) 168(4) 34(3) 28(3) 9(3) C(19) 126(3) 138(3) 157(4) 5(3) 8(3) 12(3) C(20) 103(3) 98(3) 176(4) 8(3) 25(3) 9(2) C(21) 101(3) 123(3) 210(4) 27(3) 53(3) 23(3) C(22) 166(4) 128(4) 281(5) -6(3) -38(3) -19(3) ______________________________________________________________________________ 3 2 3 Table A2.4.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 51 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(3) 900(2) 96(1) 398(1) 17 H(4) 1022(2) 144(1) 229(2) 23 H(5) 1177(2) 209(1) 342(2) 26 H(6) 1209(2) 227(1) 622(2) 24 H(8A) 832(2) 33(1) 732(1) 15 H(8B) 833(2) 47(1) 555(1) 15 H(9) 1164(2) 53(1) 626(2) 20 H(10A) 1081(2) -15(1) 835(2) 31 H(10B) 1279(2) -8(1) 784(2) 31 H(12A) 637(2) 98(1) 1064(2) 30 H(12B) 635(2) 62(1) 924(2) 30 H(13A) 644(2) 157(1) 873(2) 26 H(13B) 461(2) 127(1) 808(2) 26 H(16) 722(2) 211(1) 648(1) 17 H(17) 651(2) 259(1) 417(1) 18 H(18) 484(2) 222(1) 160(2) 18 H(19) 394(2) 146(1) 145(1) 17 H(22A) 232(2) 73(1) 268(2) 31 H(22B) 365(2) 31(1) 333(2) 31 H(22C) 398(2) 60(1) 191(2) 31 ________________________________________________________________________________ Table A2.4.6. Hydrogen bonds for 51 [Å and °]. ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ C(12)-H(12B)...O(5) 0.963(14) 2.442(13) 3.0678(14) 122.4(10) C(13)-H(13A)...O(2) 1.014(13) 2.460(13) 3.1858(14) 128.0(9) C(19)-H(19)...O(4)#1 0.987(12) 2.622(12) 3.5589(11) 158.7(9) C(22)-H(22B)...O(5)#2 0.962(13) 2.418(13) 3.3085(12) 153.8(10) 241   ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 x-1,y,z-1 #2 -x+1,-y,-z+1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.5. X-Ray Crystal Structure Analysis of 52 TIPSO CO2Allyl O N O2N Br 52 Figure A2.5.1. X-ray Crystal Structure of 52 Table A2.5.1. Crystal Data and Structure Analysis Details for 52 Empirical formula C34 H45 Br N2 O6 Si Formula weight 685.72 Crystal shape block Crystal color colourless Crystal size 0.11 x 0.16 x 0.24 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK Data collection temperature 100 K 242   243   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Theta range for 9950 reflections used in lattice determination 2.54 to 27.86° Unit cell dimensions a = 8.0482(4) Å b = 14.1277(8) Å c = 15.3665(8) Å 〈= 99.073(2)° ®= 94.101(3)° © = 91.448(2)° Volume 1719.75(16) Å3 Z 2 Crystal system triclinic Space group P -1 (# 2) Density (calculated) 1.324 g/cm3 F(000) 720 Theta range for data collection 1.8 to 35.3° Completeness to theta = 25.000° 100.0% Index ranges -13 ʺ″ h ʺ″ 11, -20 ʺ″ k ʺ″ 21, -22 ʺ″ l ʺ″ 23 Data collection scan type and  scans   Reflections  collected   70933   Independent  reflections   11961  [Rint=  0.0565]   Reflections  >  2⌠(I)   8549     Average  ⌠(I)/(net  I)   0.0555   Absorption  coefficient   1.27  mm-­‐1   Absorption  correction   Semi-­‐empirical  from  equivalents   Max.  and  min.  transmission   1.0000  and  0.8989     Structure Solution and Refinement Primary solution method ? Secondary solution method ? Hydrogen placement difmap Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 11961 / 0 / 577 Treatment of hydrogen atoms refall Goodness-of-fit on F2 1.12 Final R indices [I>2⌠(I), 8549 reflections] R1 = 0.0402, wR2 = 0.0805 R indices (all data) R1 = 0.0754, wR2 = 0.0892 Type of weighting scheme used calc Weighting scheme used w=1/[^2^(Fo^2^)+(0.0400P)^2^] where P=(Fo^2^+2Fc^2^)/3 Max shift/error 0.003 Average shift/error 0.000 Extinction coefficient n/a Largest diff. peak and hole 0.55 and -0.51 e·Å-3 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 244   Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.32B (Bruker-AXS, 2007) APEX2 2013.6-2 (Bruker-AXS, 2007) SAINT V8.32B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Refinement Details 4 Table A2.5.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 52. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 3260(1) -6095(1) -8561(1) 25(1) Si(1) 380(1) -12429(1) -8560(1) 14(1) O(1) -2560(1) -5767(1) -7181(1) 28(1) O(2) -3551(1) -7223(1) -7270(1) 22(1) O(3) -3839(1) -8167(1) -5718(1) 20(1) O(4) -2148(1) -6852(1) -5561(1) 17(1) O(5) -2199(1) -10064(1) -5391(1) 17(1) O(6) 666(1) -11489(1) -7758(1) 16(1) N(1) -2394(2) -6634(1) -7234(1) 18(1) N(2) -4168(1) -10184(1) -6562(1) 15(1) C(1) -1041(2) -8300(1) -6228(1) 12(1) C(2) -118(2) -7745(1) -6847(1) 12(1) C(3) -688(2) -6993(1) -7276(1) 14(1) C(4) 290(2) -6508(1) -7788(1) 17(1) C(5) 1901(2) -6790(1) -7907(1) 16(1) C(6) 2528(2) -7532(1) -7516(1) 17(1) C(7) 1541(2) -7977(1) -6986(1) 14(1) C(8) -2544(2) -7788(1) -5839(1) 14(1) C(9) -3446(2) -6292(1) -5130(1) 24(1) C(10) -2758(2) -5286(1) -4906(1) 26(1) C(11) -2702(3) -4786(1) -4109(1) 34(1) C(12) 142(2) -8376(1) -5382(1) 16(1) C(13) 1021(2) -7471(1) -4906(1) 19(1) C(14) 2624(2) -7382(1) -4698(1) 26(1) C(15) -1646(2) -9346(1) -6719(1) 11(1) C(16) -2895(2) -9359(1) -7511(1) 12(1) C(17) -2761(2) -9042(1) -8310(1) 17(1) C(18) -4123(2) -9176(1) -8938(1) 21(1) C(19) -5578(2) -9640(1) -8775(1) 22(1) C(20) -5714(2) -9997(1) -7988(1) 19(1) C(21) -4352(2) -9853(1) -7369(1) 14(1) C(22) -2666(2) -9882(1) -6111(1) 13(1) C(23) -5490(2) -10648(1) -6173(1) 26(1) C(24) -176(2) -9986(1) -7005(1) 13(1) C(25) -693(2) -11038(1) -7320(1) 16(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 245   C(26) -826(2) -13397(1) -8136(1) 18(1) C(27) 28(2) -13713(1) -7308(1) 26(1) C(28) -1340(3) -14267(1) -8838(1) 27(1) C(29) 2572(2) -12703(1) -8851(1) 24(1) C(30) 3670(2) -13040(2) -8115(2) 36(1) C(31) 2672(3) -13392(2) -9724(2) 47(1) C(32) -836(2) -12104(1) -9559(1) 21(1) C(33) -47(3) -11230(2) -9867(2) 40(1) C(34) -2704(2) -11962(1) -9483(1) 28(1) ________________________________________________________________________________ Table A2.5.3. Bond lengths [Å] and angles [°] for 52 __________________________________________________________________________________ _ Br(1)-C(5) 1.8927(14) Si(1)-O(6) 1.6623(10) Si(1)-C(26) 1.8817(15) Si(1)-C(29) 1.8856(16) Si(1)-C(32) 1.8850(17) O(1)-N(1) 1.2263(16) O(2)-N(1) 1.2245(16) O(3)-C(8) 1.1986(17) O(4)-C(8) 1.3462(16) O(4)-C(9) 1.4600(18) O(5)-C(22) 1.2110(17) O(6)-C(25) 1.4361(16) N(1)-C(3) 1.4782(18) N(2)-C(21) 1.3931(19) N(2)-C(22) 1.3727(18) N(2)-C(23) 1.4476(19) C(1)-C(2) 1.5425(19) C(1)-C(8) 1.5348(19) C(1)-C(12) 1.576(2) C(1)-C(15) 1.5971(18) C(2)-C(3) 1.4053(19) C(2)-C(7) 1.4058(19) C(3)-C(4) 1.392(2) C(4)-H(4) 0.929(17) C(4)-C(5) 1.382(2) C(5)-C(6) 1.377(2) C(6)-H(6) 0.921(19) C(6)-C(7) 1.386(2) C(7)-H(7) 0.966(18) C(9)-H(9A) 0.982(19) C(9)-H(9B) 0.986(19) C(9)-C(10) 1.491(2) C(10)-H(10) 0.99(2) C(10)-C(11) 1.311(3) C(11)-H(11A) 0.97(2) C(11)-H(11B) 0.95(2) C(12)-H(12A) 0.889(18) C(12)-H(12B) 0.979(17) C(12)-C(13) 1.502(2) C(13)-H(13) 0.945(19) C(13)-C(14) 1.305(2) C(14)-H(14A) 0.94(2) C(14)-H(14B) 0.951(19) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(15)-C(16) C(15)-C(22) C(15)-C(24) C(16)-C(17) C(16)-C(21) C(17)-H(17) C(17)-C(18) C(18)-H(18) C(18)-C(19) C(19)-H(19) C(19)-C(20) C(20)-H(20) C(20)-C(21) C(23)-H(23A) C(23)-H(23B) C(23)-H(23C) C(24)-H(24A) C(24)-H(24B) C(24)-C(25) C(25)-H(25A) C(25)-H(25B) C(26)-H(26) C(26)-C(27) C(26)-C(28) C(27)-H(27A) C(27)-H(27B) C(27)-H(27C) C(28)-H(28A) C(28)-H(28B) C(28)-H(28C) C(29)-H(29) C(29)-C(30) C(29)-C(31) C(30)-H(30A) C(30)-H(30B) C(30)-H(30C) C(31)-H(31A) C(31)-H(31B) C(31)-H(31C) C(32)-H(32) C(32)-C(33) C(32)-C(34) C(33)-H(33A) C(33)-H(33B) C(33)-H(33C) C(34)-H(34A) C(34)-H(34B) C(34)-H(34C) O(6)-Si(1)-C(26) O(6)-Si(1)-C(29) O(6)-Si(1)-C(32) C(26)-Si(1)-C(29) C(26)-Si(1)-C(32) C(32)-Si(1)-C(29) C(8)-O(4)-C(9) C(25)-O(6)-Si(1) O(1)-N(1)-C(3) 1.5199(19) 1.5552(19) 1.5539(19) 1.382(2) 1.3977(19) 0.954(18) 1.397(2) 0.945(19) 1.385(2) 0.93(2) 1.391(2) 0.946(18) 1.388(2) 1.01(2) 0.93(2) 0.91(2) 0.964(17) 0.946(17) 1.5258(19) 0.962(17) 0.974(17) 0.946(17) 1.536(2) 1.529(2) 1.003(19) 1.03(2) 0.94(2) 0.97(2) 1.02(2) 0.99(2) 0.972(19) 1.527(3) 1.537(3) 1.01(2) 0.98(3) 1.00(2) 0.88(3) 0.96(2) 0.99(3) 0.953(19) 1.529(2) 1.533(2) 1.03(3) 0.96(2) 0.94(2) 0.94(2) 1.01(2) 0.95(2) 108.45(6) 102.78(6) 111.24(6) 116.69(7) 108.76(7) 108.83(8) 115.62(11) 122.38(9) 117.69(12) 246   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(2)-N(1)-O(1) O(2)-N(1)-C(3) C(21)-N(2)-C(23) C(22)-N(2)-C(21) C(22)-N(2)-C(23) C(2)-C(1)-C(12) C(2)-C(1)-C(15) C(8)-C(1)-C(2) C(8)-C(1)-C(12) C(8)-C(1)-C(15) C(12)-C(1)-C(15) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(2)-C(3)-N(1) C(4)-C(3)-N(1) C(4)-C(3)-C(2) C(3)-C(4)-H(4) C(5)-C(4)-C(3) C(5)-C(4)-H(4) C(4)-C(5)-Br(1) C(6)-C(5)-Br(1) C(6)-C(5)-C(4) C(5)-C(6)-H(6) C(5)-C(6)-C(7) C(7)-C(6)-H(6) C(2)-C(7)-H(7) C(6)-C(7)-C(2) C(6)-C(7)-H(7) O(3)-C(8)-O(4) O(3)-C(8)-C(1) O(4)-C(8)-C(1) O(4)-C(9)-H(9A) O(4)-C(9)-H(9B) O(4)-C(9)-C(10) H(9A)-C(9)-H(9B) C(10)-C(9)-H(9A) C(10)-C(9)-H(9B) C(9)-C(10)-H(10) C(11)-C(10)-C(9) C(11)-C(10)-H(10) C(10)-C(11)-H(11A) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(1)-C(12)-H(12A) C(1)-C(12)-H(12B) H(12A)-C(12)-H(12B) C(13)-C(12)-C(1) C(13)-C(12)-H(12A) C(13)-C(12)-H(12B) C(12)-C(13)-H(13) C(14)-C(13)-C(12) C(14)-C(13)-H(13) C(13)-C(14)-H(14A) C(13)-C(14)-H(14B) H(14A)-C(14)-H(14B) C(16)-C(15)-C(1) C(16)-C(15)-C(22) 124.37(12) 117.93(12) 124.40(13) 111.59(11) 123.24(13) 109.54(11) 111.12(11) 114.19(11) 102.89(11) 108.71(11) 110.07(11) 128.63(12) 113.94(12) 117.37(12) 123.50(12) 112.78(12) 123.72(13) 119.1(10) 118.92(14) 121.9(10) 118.87(11) 120.73(11) 120.31(13) 121.7(12) 119.26(13) 118.9(12) 118.4(10) 123.79(13) 117.8(10) 123.79(13) 125.80(12) 110.08(11) 109.4(10) 107.4(10) 106.28(13) 110.0(15) 109.9(11) 113.6(11) 113.0(12) 123.47(19) 123.5(12) 121.9(13) 121.7(14) 116.4(19) 106.2(12) 111.1(10) 105.2(15) 117.48(12) 109.4(12) 106.9(10) 117.6(12) 124.11(15) 118.0(12) 120.7(13) 120.4(11) 118.9(17) 114.67(11) 101.34(11) 247   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(16)-C(15)-C(24) C(22)-C(15)-C(1) C(24)-C(15)-C(1) C(24)-C(15)-C(22) C(17)-C(16)-C(15) C(17)-C(16)-C(21) C(21)-C(16)-C(15) C(16)-C(17)-H(17) C(16)-C(17)-C(18) C(18)-C(17)-H(17) C(17)-C(18)-H(18) C(19)-C(18)-C(17) C(19)-C(18)-H(18) C(18)-C(19)-H(19) C(18)-C(19)-C(20) C(20)-C(19)-H(19) C(19)-C(20)-H(20) C(21)-C(20)-C(19) C(21)-C(20)-H(20) N(2)-C(21)-C(16) C(20)-C(21)-N(2) C(20)-C(21)-C(16) O(5)-C(22)-N(2) O(5)-C(22)-C(15) N(2)-C(22)-C(15) N(2)-C(23)-H(23A) N(2)-C(23)-H(23B) N(2)-C(23)-H(23C) H(23A)-C(23)-H(23B) H(23A)-C(23)-H(23C) H(23B)-C(23)-H(23C) C(15)-C(24)-H(24A) C(15)-C(24)-H(24B) H(24A)-C(24)-H(24B) C(25)-C(24)-C(15) C(25)-C(24)-H(24A) C(25)-C(24)-H(24B) O(6)-C(25)-C(24) O(6)-C(25)-H(25A) O(6)-C(25)-H(25B) C(24)-C(25)-H(25A) C(24)-C(25)-H(25B) H(25A)-C(25)-H(25B) Si(1)-C(26)-H(26) C(27)-C(26)-Si(1) C(27)-C(26)-H(26) C(28)-C(26)-Si(1) C(28)-C(26)-H(26) C(28)-C(26)-C(27) C(26)-C(27)-H(27A) C(26)-C(27)-H(27B) C(26)-C(27)-H(27C) H(27A)-C(27)-H(27B) H(27A)-C(27)-H(27C) H(27B)-C(27)-H(27C) C(26)-C(28)-H(28A) C(26)-C(28)-H(28B) C(26)-C(28)-H(28C) 108.87(11) 110.99(11) 112.86(11) 107.29(11) 131.56(13) 119.36(13) 108.89(12) 119.5(11) 119.06(15) 121.4(11) 120.6(12) 120.73(15) 118.7(12) 120.8(12) 121.03(15) 118.1(12) 121.0(11) 117.51(14) 121.4(11) 110.02(12) 127.73(13) 122.21(14) 124.97(13) 126.91(12) 107.94(12) 109.3(13) 110.9(14) 115.0(15) 103.8(18) 104.9(19) 112(2) 108.7(10) 107.9(10) 112.9(14) 113.74(11) 106.1(10) 107.7(10) 107.63(11) 109.7(10) 111.7(10) 110.4(10) 109.9(10) 107.5(14) 104.7(11) 113.72(11) 104.7(11) 114.04(11) 108.3(11) 110.66(13) 113.3(11) 108.8(11) 111.1(12) 106.3(15) 108.5(16) 108.7(15) 112.5(12) 112.6(12) 112.8(12) 248   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 H(28A)-C(28)-H(28B) H(28A)-C(28)-H(28C) H(28B)-C(28)-H(28C) Si(1)-C(29)-H(29) C(30)-C(29)-Si(1) C(30)-C(29)-H(29) C(30)-C(29)-C(31) C(31)-C(29)-Si(1) C(31)-C(29)-H(29) C(29)-C(30)-H(30A) C(29)-C(30)-H(30B) C(29)-C(30)-H(30C) H(30A)-C(30)-H(30B) H(30A)-C(30)-H(30C) H(30B)-C(30)-H(30C) C(29)-C(31)-H(31A) C(29)-C(31)-H(31B) C(29)-C(31)-H(31C) H(31A)-C(31)-H(31B) H(31A)-C(31)-H(31C) H(31B)-C(31)-H(31C) Si(1)-C(32)-H(32) C(33)-C(32)-Si(1) C(33)-C(32)-H(32) C(33)-C(32)-C(34) C(34)-C(32)-Si(1) C(34)-C(32)-H(32) C(32)-C(33)-H(33A) C(32)-C(33)-H(33B) C(32)-C(33)-H(33C) H(33A)-C(33)-H(33B) H(33A)-C(33)-H(33C) H(33B)-C(33)-H(33C) C(32)-C(34)-H(34A) C(32)-C(34)-H(34B) C(32)-C(34)-H(34C) H(34A)-C(34)-H(34B) H(34A)-C(34)-H(34C) H(34B)-C(34)-H(34C) 249   100.8(16) 110.9(16) 106.5(16) 103.4(10) 114.40(13) 107.0(11) 110.15(17) 114.10(13) 107.0(11) 114.8(13) 110.0(15) 111.3(13) 109.4(19) 106.0(18) 104.8(19) 112.5(17) 110.3(14) 112.4(14) 111(2) 101(2) 109(2) 105.3(11) 111.67(13) 103.1(11) 109.47(16) 116.52(12) 109.8(11) 111.4(16) 111.6(14) 110.4(14) 112(2) 108(2) 102.1(19) 111.1(13) 109.4(12) 114.4(13) 105.6(18) 110.8(18) 104.9(17) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Table A2.5.4. Anisotropic displacement parameters (Å x 10 ) for 52. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2π [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ Br(1) 260(1) 269(1) 233(1) 77(1) 68(1) -97(1) Si(1) 147(2) 92(2) 183(2) -2(2) 37(2) -4(1) O(1) 246(6) 146(5) 478(8) 137(5) 54(5) 60(4) O(2) 126(5) 203(6) 324(6) 62(5) -30(4) -23(4) O(3) 173(5) 134(5) 296(6) 8(4) 99(4) 3(4) O(4) 150(5) 92(5) 260(6) -20(4) 38(4) 19(4) O(5) 189(5) 162(5) 179(5) 61(4) 30(4) -3(4) O(6) 137(5) 103(5) 237(6) -30(4) 52(4) 19(4) 250   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 N(1) 146(6) 161(6) 228(7) 73(5) -6(5) 15(5) N(2) 124(5) 122(6) 189(6) 12(5) 34(5) -27(4) C(1) 119(6) 84(6) 141(6) 13(5) 17(5) 11(5) C(2) 118(6) 90(6) 135(6) 0(5) -8(5) -26(5) C(3) 115(6) 109(6) 184(7) 17(5) -6(5) -10(5) C(4) 193(7) 130(7) 176(7) 44(6) -14(6) -27(5) C(5) 178(7) 149(7) 156(7) 17(5) 29(6) -69(5) C(6) 121(7) 152(7) 211(7) -11(6) 18(6) -26(5) C(7) 131(6) 105(6) 175(7) 7(5) -5(5) -7(5) C(8) 163(7) 100(6) 164(7) 14(5) 17(5) 8(5) C(9) 204(8) 150(7) 354(10) -50(7) 71(7) 54(6) C(10) 249(8) 145(7) 351(10) -36(7) 14(7) 48(6) C(11) 428(11) 201(9) 350(11) -42(8) -88(9) 60(8) C(12) 171(7) 147(7) 154(7) 38(6) -7(6) -14(6) C(13) 211(7) 156(7) 173(7) -21(6) 1(6) 12(6) C(14) 212(8) 230(8) 300(9) -44(7) -8(7) -31(7) C(15) 112(6) 76(6) 135(6) 10(5) 14(5) -10(5) C(16) 131(6) 83(6) 153(7) -2(5) -1(5) 13(5) C(17) 193(7) 142(7) 169(7) 15(5) 8(6) 3(6) C(18) 263(8) 207(8) 163(7) 16(6) -30(6) 36(6) C(19) 199(8) 222(8) 209(8) -60(6) -67(6) 44(6) C(20) 139(7) 160(7) 251(8) -51(6) 6(6) 6(6) C(21) 139(6) 106(6) 170(7) -22(5) 39(5) 17(5) C(22) 133(6) 65(6) 174(7) -8(5) 40(5) 7(5) C(23) 201(8) 344(10) 239(9) 43(8) 41(7) -137(7) C(24) 112(6) 104(6) 175(7) 0(5) 22(5) 6(5) C(25) 140(7) 104(6) 223(8) -4(6) 68(6) 17(5) C(26) 195(7) 115(7) 216(8) 23(6) 28(6) -9(6) C(27) 359(10) 214(8) 209(8) 59(7) -3(7) -47(7) C(28) 409(10) 136(7) 254(9) 45(6) -68(8) -75(7) C(29) 182(7) 175(8) 326(9) -49(7) 84(7) -9(6) C(30) 214(9) 371(11) 519(13) 75(10) 60(8) 67(8) C(31) 297(11) 476(14) 534(15) -272(11) 171(10) -23(10) C(32) 273(8) 168(7) 207(8) 46(6) 35(6) -14(6) C(33) 459(13) 424(12) 378(12) 245(10) 12(10) -117(10) C(34) 300(9) 259(9) 283(9) 88(8) -20(7) 56(7) ______________________________________________________________________________ 3 2 3 Table A2.5.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 52 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(4) H(6) H(7) H(9A) H(9B) H(10) H(11A) H(11B) H(12A) H(12B) H(13) H(14A) H(14B) -15(2) 362(2) 203(2) -369(2) -445(2) -237(2) -313(3) -227(3) -48(2) 100(2) 36(2) 333(2) 309(2) -600(1) -770(1) -847(1) -654(1) -636(1) -503(1) -504(2) -414(2) -862(1) -884(1) -696(1) -788(2) -682(1) -803(1) -756(1) -669(1) -459(1) -555(1) -542(1) -362(2) -399(2) -501(1) -552(1) -469(1) -490(1) -432(1) 15(4) 31(5) 22(4) 24(5) 24(5) 35(5) 41(6) 51(7) 22(5) 16(4) 34(5) 37(6) 28(5) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 251   H(17) -174(2) -874(1) -842(1) 20(4) H(18) -408(2) -893(1) -948(1) 28(5) H(19) -647(2) -976(1) -920(1) 32(5) H(20) -670(2) -1033(1) -788(1) 18(4) H(23A) -633(3) -1016(2) -596(2) 50(6) H(23B) -509(3) -1086(2) -566(2) 45(6) H(23C) -609(3) -1111(2) -655(2) 53(7) H(24A) 29(2) -976(1) -750(1) 17(4) H(24B) 60(2) -996(1) -651(1) 12(4) H(25A) -93(2) -1135(1) -682(1) 16(4) H(25B) -171(2) -1108(1) -771(1) 17(4) H(26) -180(2) -1310(1) -794(1) 21(4) H(27A) 98(2) -1415(1) -744(1) 29(5) H(27B) -83(2) -1410(1) -702(1) 36(5) H(27C) 42(2) -1318(1) -689(1) 28(5) H(28A) -199(2) -1409(1) -934(1) 33(5) H(28B) -216(3) -1472(2) -863(1) 39(6) H(28C) -38(3) -1465(2) -903(1) 37(6) H(29) 304(2) -1208(1) -893(1) 24(5) H(30A) 359(3) -1266(2) -751(2) 47(6) H(30B) 483(3) -1304(2) -826(2) 65(8) H(30C) 338(3) -1372(2) -806(2) 48(6) H(31A) 218(3) -1395(2) -972(2) 57(8) H(31B) 381(3) -1347(2) -986(2) 48(6) H(31C) 203(3) -1317(2) -1023(2) 59(8) H(32) -67(2) -1261(1) -1003(1) 27(5) H(33A) -6(3) -1063(2) -940(2) 81(9) H(33B) -54(3) -1113(2) -1043(2) 48(6) H(33C) 106(3) -1134(2) -999(2) 50(7) H(34A) -322(3) -1249(2) -929(1) 44(6) H(34B) -327(3) -1193(2) -1009(2) 45(6) H(34C) -296(3) -1138(2) -913(1) 41(6) ________________________________________________________________________________ Table A2.5.6. Hydrogen bonds for 52 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ C(6)-H(6)...O(2)#1 0.921(19) 2.353(19) 3.1624(18) 146.6(16) C(23)-H(23A)...O(5)#2 1.01(2) 2.45(2) 3.197(2) 129.9(17) ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 x+1,y,z #2 -x-1,-y-2,-z-1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.6. X-Ray Crystal Structure Analysis of 61 O Br O CO2Allyl O NO N 2 61 Figure A2.6.1. X-ray Crystal Structure of 61 Table A2.6.1. Crystal Data and Structure Analysis Details for 61 Empirical formula C23 H19 Br N2 O7.20 Formula weight 518.54 Crystallization solvent ???Solvent??? Crystal shape plate Crystal color colourless Crystal size 0.17 x 0.24 x 0.25 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK 252   253   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Data collection temperature 100 K Theta range for 9593 reflections used in lattice determination 2.62 to 36.54° Unit cell dimensions a = 10.1321(5) Å b = 14.3644(6) Å c = 14.6551(6) Å 〈= 90° ®= 104.647(3)° © = 90° Volume 2063.61(16) Å3 Z 4 Crystal system monoclinic Space group P 1 21/c 1 (# 14) Density (calculated) 1.669 g/cm3 F(000) 1054 Theta range for data collection 2.0 to 42.9° Completeness to theta = 25.000° 100.0% Index ranges -19 ʺ″ h ʺ″ 19, -27 ʺ″ k ʺ″ 27, -27 ʺ″ l ʺ″ 28 Data collection scan type and  scans   Reflections  collected   166238   Independent  reflections   15005  [Rint=  0.0848]   Reflections  >  2⌠(I)   9726     Average  ⌠(I)/(net  I)   0.0622   Absorption  coefficient   2.05  mm-­‐1   Absorption  correction   Semi-­‐empirical  from  equivalents   Max.  and  min.  transmission   1.0000  and  0.9002     Structure Solution and Refinement Primary solution method ? Secondary solution method ? Hydrogen placement mixed Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 15005 / 0 / 309 Treatment of hydrogen atoms constr Goodness-of-fit on F2 1.03 Final R indices [I>2⌠(I), 9726 reflections] R1 = 0.0534, wR2 = 0.1233 R indices (all data) R1 = 0.1009, wR2 = 0.1398 Type of weighting scheme used calc Weighting scheme used w=1/[^2^(Fo^2^)+(0.0618P)^2^+1.7296P] where P=(Fo^2^+2Fc^2^)/3 Max shift/error 0.000 Average shift/error 0.000 Extinction coefficient n/a Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Largest diff. peak and hole 254   5.40 and -1.57 e·Å-3 Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.32B (Bruker-AXS, 2007) APEX2 2012.10-0 (Bruker-AXS, 2007) SAINT V8.32B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.6.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 61. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 2176(1) 3795(1) 4422(1) 16(1) O(1) 4484(1) 6914(1) 2590(1) 19(1) O(2) 4806(1) 5100(1) 1849(1) 17(1) O(3) 3104(1) 5662(1) 752(1) 18(1) O(4) -1522(1) 4433(1) 2271(1) 22(1) O(5) 142(1) 5360(1) 2886(1) 16(1) O(6) 1437(1) 6845(1) 2016(1) 15(1) O(7) 490(1) 5659(1) 1068(1) 13(1) O(8) 1317(5) 4704(4) 5932(3) 13(1) C(4) 1722(2) 5406(1) 5379(1) 15(1) N(1) 3573(1) 7168(1) 3851(1) 14(1) N(2) -318(1) 4658(1) 2439(1) 13(1) C(1) 3379(1) 5631(1) 3242(1) 11(1) C(2) 2724(1) 5722(1) 4069(1) 12(1) C(3) 2202(2) 5102(1) 4617(1) 12(1) C(5) 1834(2) 6343(1) 5635(1) 17(1) C(6) 2449(2) 6977(1) 5154(1) 16(1) C(7) 2877(2) 6651(1) 4388(1) 12(1) C(8) 3878(2) 6644(1) 3160(1) 14(1) C(9) 3948(2) 8140(1) 4012(1) 20(1) C(10) 4635(2) 4985(1) 3515(1) 15(1) C(11) 5536(2) 5040(1) 2835(1) 19(1) C(12) 3523(2) 5408(1) 1558(1) 14(1) C(13) 2536(1) 5327(1) 2228(1) 10(1) C(14) 1976(1) 4321(1) 2117(1) 10(1) C(15) 2786(2) 3606(1) 1902(1) 14(1) C(16) 2314(2) 2703(1) 1684(1) 16(1) C(17) 985(2) 2474(1) 1652(1) 17(1) C(18) 150(2) 3150(1) 1888(1) 15(1) C(19) 644(2) 4040(1) 2126(1) 12(1) C(20) 1417(2) 6040(1) 1779(1) 11(1) C(21) -565(2) 6275(1) 517(1) 15(1) C(22) -1606(2) 6519(1) 1041(1) 16(1) C(23) -2852(2) 6167(1) 839(1) 24(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 255   ________________________________________________________________________________ Table A2.6.3. Bond lengths [Å] and angles [°] for 61 __________________________________________________________________________________ _ Br(1)-C(3) 1.8983(15) O(1)-C(8) 1.2173(19) O(2)-C(11) 1.450(2) O(2)-C(12) 1.3369(19) O(3)-C(12) 1.2057(19) O(4)-N(2) 1.2258(18) O(5)-N(2) 1.2285(17) O(6)-C(20) 1.2060(18) O(7)-C(20) 1.3313(18) O(7)-C(21) 1.4626(18) O(8)-C(4) 1.419(5) O(8)-H(4) 0.5001 O(8)-H(8) 0.8315 C(4)-H(4) 0.9497 C(4)-C(3) 1.396(2) C(4)-C(5) 1.394(2) N(1)-C(7) 1.3965(19) N(1)-C(8) 1.358(2) N(1)-C(9) 1.451(2) N(2)-C(19) 1.4738(19) C(1)-C(2) 1.528(2) C(1)-C(8) 1.555(2) C(1)-C(10) 1.544(2) C(1)-C(13) 1.5768(19) C(2)-C(3) 1.389(2) C(2)-C(7) 1.410(2) C(5)-H(5) 0.9500 C(5)-C(6) 1.391(2) C(6)-H(6) 0.9500 C(6)-C(7) 1.383(2) C(9)-H(9A) 0.9800 C(9)-H(9B) 0.9800 C(9)-H(9C) 0.9800 C(10)-H(10A) 0.9900 C(10)-H(10B) 0.9900 C(10)-C(11) 1.514(2) C(11)-H(11A) 0.9900 C(11)-H(11B) 0.9900 C(12)-C(13) 1.573(2) C(13)-C(14) 1.5460(19) C(13)-C(20) 1.5455(19) C(14)-C(15) 1.400(2) C(14)-C(19) 1.412(2) C(15)-H(15) 0.9500 C(15)-C(16) 1.391(2) C(16)-H(16) 0.9500 C(16)-C(17) 1.376(2) C(17)-H(17) 0.9500 C(17)-C(18) 1.387(2) C(18)-H(18) 0.9500 C(18)-C(19) 1.385(2) C(21)-H(21A) 0.9900 C(21)-H(21B) 0.9900 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(21)-C(22) C(22)-H(22) C(22)-C(23) C(23)-H(23A) C(23)-H(23B) C(12)-O(2)-C(11) C(20)-O(7)-C(21) C(4)-O(8)-H(4) C(4)-O(8)-H(8) H(4)-O(8)-H(8) O(8)-C(4)-H(4) C(3)-C(4)-O(8) C(3)-C(4)-H(4) C(5)-C(4)-O(8) C(5)-C(4)-H(4) C(5)-C(4)-C(3) C(7)-N(1)-C(9) C(8)-N(1)-C(7) C(8)-N(1)-C(9) O(4)-N(2)-O(5) O(4)-N(2)-C(19) O(5)-N(2)-C(19) C(2)-C(1)-C(8) C(2)-C(1)-C(10) C(2)-C(1)-C(13) C(8)-C(1)-C(13) C(10)-C(1)-C(8) C(10)-C(1)-C(13) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(4)-C(3)-Br(1) C(2)-C(3)-Br(1) C(2)-C(3)-C(4) C(4)-C(5)-H(5) C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(5)-C(6)-H(6) C(7)-C(6)-C(5) C(7)-C(6)-H(6) N(1)-C(7)-C(2) C(6)-C(7)-N(1) C(6)-C(7)-C(2) O(1)-C(8)-N(1) O(1)-C(8)-C(1) N(1)-C(8)-C(1) N(1)-C(9)-H(9A) N(1)-C(9)-H(9B) N(1)-C(9)-H(9C) H(9A)-C(9)-H(9B) H(9A)-C(9)-H(9C) H(9B)-C(9)-H(9C) C(1)-C(10)-H(10A) C(1)-C(10)-H(10B) H(10A)-C(10)-H(10B) C(11)-C(10)-C(1) C(11)-C(10)-H(10A) 1.494(2) 0.9500 1.322(3) 0.9500 0.9500 123.19(13) 117.17(12) 16.4 107.5 113.1 8.5 116.4(3) 120.1 123.3(3) 120.1 119.77(14) 124.62(13) 111.67(12) 123.70(14) 123.20(14) 118.81(13) 117.95(12) 101.37(11) 109.88(12) 122.06(12) 107.22(11) 108.64(12) 106.98(11) 135.18(13) 116.15(13) 108.06(12) 115.80(11) 122.67(11) 121.47(14) 119.6 120.74(14) 119.6 121.2 117.54(14) 121.2 110.18(12) 125.78(13) 123.98(14) 125.78(14) 125.49(14) 108.69(12) 109.5 109.5 109.5 109.5 109.5 109.5 109.0 109.0 107.8 113.13(13) 109.0 256   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(11)-C(10)-H(10B) O(2)-C(11)-C(10) O(2)-C(11)-H(11A) O(2)-C(11)-H(11B) C(10)-C(11)-H(11A) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) O(2)-C(12)-C(13) O(3)-C(12)-O(2) O(3)-C(12)-C(13) C(12)-C(13)-C(1) C(14)-C(13)-C(1) C(14)-C(13)-C(12) C(20)-C(13)-C(1) C(20)-C(13)-C(12) C(20)-C(13)-C(14) C(15)-C(14)-C(13) C(15)-C(14)-C(19) C(19)-C(14)-C(13) C(14)-C(15)-H(15) C(16)-C(15)-C(14) C(16)-C(15)-H(15) C(15)-C(16)-H(16) C(17)-C(16)-C(15) C(17)-C(16)-H(16) C(16)-C(17)-H(17) C(16)-C(17)-C(18) C(18)-C(17)-H(17) C(17)-C(18)-H(18) C(19)-C(18)-C(17) C(19)-C(18)-H(18) C(14)-C(19)-N(2) C(18)-C(19)-N(2) C(18)-C(19)-C(14) O(6)-C(20)-O(7) O(6)-C(20)-C(13) O(7)-C(20)-C(13) O(7)-C(21)-H(21A) O(7)-C(21)-H(21B) O(7)-C(21)-C(22) H(21A)-C(21)-H(21B) C(22)-C(21)-H(21A) C(22)-C(21)-H(21B) C(21)-C(22)-H(22) C(23)-C(22)-C(21) C(23)-C(22)-H(22) C(22)-C(23)-H(23A) C(22)-C(23)-H(23B) H(23A)-C(23)-H(23B) 257   109.0 114.73(13) 108.6 108.6 108.6 108.6 107.6 119.80(13) 119.04(14) 120.80(14) 106.83(11) 117.09(11) 106.13(11) 112.41(11) 101.50(11) 111.34(11) 119.25(13) 114.17(13) 126.32(12) 118.4 123.26(14) 118.4 119.8 120.48(14) 119.8 120.7 118.53(14) 120.7 119.8 120.34(15) 119.8 122.70(12) 114.14(13) 123.08(14) 125.14(13) 123.77(13) 110.96(12) 109.3 109.3 111.77(12) 107.9 109.3 109.3 118.2 123.59(16) 118.2 120.0 120.0 120.0 __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 258   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 2 4 Anisotropic displacement parameters (Å x 10 ) for 61. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2ð [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ Br(1) 228(1) 114(1) 135(1) 15(1) 21(1) -20(1) O(1) 183(5) 191(5) 217(5) -12(4) 88(4) -53(4) O(2) 132(5) 207(5) 178(5) -9(4) 52(4) 16(4) O(3) 210(5) 193(5) 160(5) 40(4) 75(4) 13(4) O(4) 116(5) 227(6) 338(7) -22(5) 88(5) -29(4) O(5) 147(5) 162(5) 144(4) -30(4) 14(4) 16(4) O(6) 165(5) 101(4) 174(5) -5(3) 25(4) 13(3) O(7) 127(4) 124(4) 111(4) 5(3) -16(3) 29(3) O(8) 60(20) 270(30) 63(19) 92(17) 11(14) -36(18) C(4) 168(6) 170(6) 118(5) 11(5) 26(5) -2(5) N(1) 152(5) 112(5) 154(5) -21(4) 37(4) -42(4) N(2) 117(5) 145(5) 130(5) 20(4) 28(4) 5(4) C(1) 98(5) 112(5) 124(5) -8(4) 11(4) -8(4) C(2) 107(5) 118(5) 105(5) -9(4) -2(4) -3(4) C(3) 129(6) 122(5) 107(5) 7(4) -1(4) -6(4) C(5) 199(7) 183(6) 128(5) -12(5) 44(5) 11(5) C(6) 176(6) 140(6) 145(6) -30(5) 29(5) 0(5) C(7) 114(5) 120(5) 124(5) -6(4) 5(4) -7(4) C(8) 116(5) 143(6) 150(5) -13(4) 20(4) -31(4) C(9) 210(7) 129(6) 247(7) -32(5) 39(6) -55(5) C(10) 101(5) 195(6) 149(6) -8(5) 0(4) 22(5) C(11) 107(6) 262(8) 188(6) -20(6) 22(5) 12(5) C(12) 130(6) 125(5) 157(6) -9(4) 50(5) -3(4) C(13) 94(5) 101(5) 109(5) -8(4) 12(4) 3(4) C(14) 98(5) 105(5) 96(5) 4(4) -1(4) 8(4) C(15) 129(6) 121(5) 155(5) -10(4) 19(4) 24(4) C(16) 187(7) 114(5) 180(6) -7(5) 22(5) 29(5) C(17) 218(7) 99(5) 179(6) 7(5) 22(5) -10(5) C(18) 161(6) 115(5) 156(5) 24(4) 21(5) -21(4) C(19) 120(5) 107(5) 117(5) 16(4) 18(4) 5(4) C(20) 111(5) 113(5) 113(5) 14(4) 17(4) 10(4) C(21) 156(6) 164(6) 120(5) 31(4) -3(4) 50(5) C(22) 170(6) 154(6) 146(6) 10(5) 6(5) 39(5) C(23) 183(7) 275(8) 256(8) 14(7) 26(6) 15(6) ______________________________________________________________________________ Table A2.6.4. 3 2 3 Table A2.6.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 61 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(4) H(8) H(5) H(6) H(9A) H(9B) H(9C) H(10A) H(10B) 132 171 149 257 316 425 469 518 432 498 481 655 761 850 838 820 515 434 572 649 614 534 409 347 459 415 354 18 23 20 19 30 30 30 18 18 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 259   H(11A) 614 559 300 23 H(11B) 613 448 292 23 H(15) 370 374 191 17 H(16) 292 224 156 20 H(17) 65 187 147 20 H(18) -76 300 189 18 H(21A) -102 596 -8 18 H(21B) -13 685 36 18 H(22) -136 695 155 20 H(23A) -313 573 34 29 H(23B) -347 635 120 29 ________________________________________________________________________________ Table A2.6.6. Hydrogen bonds for 61 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ O(8)-H(8)...O(4)#1 0.83 2.16 2.870(6) 143.3 O(8)-H(8)...N(2)#1 0.83 2.47 2.964(5) 118.6 C(5)-H(5)...O(6)#2 0.95 2.64 3.382(2) 135.3 C(6)-H(6)...O(3)#2 0.95 2.58 3.524(2) 173.5 C(9)-H(9A)...O(4)#3 0.98 2.62 3.270(2) 124.3 C(10)-H(10B)...Br(1) 0.99 2.90 3.5462(16) 123.5 C(18)-H(18)...O(6)#4 0.95 2.52 3.1613(19) 124.5 ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 -x,-y+1,-z+1 #2 x,-y+3/2,z+1/2 #3 -x,y+1/2,-z+1/2 #4 -x,y-1/2,-z+1/2               260   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.7. X-Ray Crystal Structure Analysis of 62 O O Br O NO N 2 62 Figure A2.7.1. X-ray Crystal Structure of 62     Table A2.7.1. Crystal data and structure refinement for 62 Empirical formula C22 H19 Br N2 O5 Formula weight 471.30 Crystallization Solvent ???Solvent??? Crystal Habit Block Crystal size 0.25 x 0.25 x 0.22 mm3 Crystal color Light yellow Data Collection Preliminary Photos Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoKa Data Collection Temperature 100(2) K 261   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 q range for 9803 reflections used in lattice determination 2.44 to 37.44° a= 90° b= 90° g = 90° Unit cell dimensions a = 9.1581(2) Å b = 12.6857(3) Å c = 16.7030(3) Å Volume 1940.50(7) Å3 Z 4 Crystal system Orthorhombic Space group P2(1)2(1)2(1) Density (calculated) 1.613 Mg/m3 F(000) 960 Data collection program Bruker SMART v5.630 q range for data collection 2.02 to 38.73° Completeness to q = 38.73° 98.0 % Index ranges -15<=h<=15, -22<=k<=22, -29<=l<=29 Data collection scan type scans at 9 settings Data reduction program Bruker SAINT v6.45A Reflections collected 61657 Independent reflections 10781 [Rint= 0.0854] Absorption coefficient 2.157 mm-1 Absorption correction None Max. and min. transmission 0.6482 and 0.6146 Structure solution and Refinement Structure solution program SHELXS-97 (Sheldrick, 2008) Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program SHELXL-97 (Sheldrick, 2008) Refinement method Full matrix least-squares on F2 Data / restraints / parameters 10781 / 0 / 272 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.035 Final R indices [I>2s(I), 9216 reflections] R1 = 0.0252, wR2 = 0.0489 R indices (all data) R1 = 0.0337, wR2 = 0.0500 Type of weighting scheme used Sigma Weighting scheme used w=1/s^2^(Fo^2^) Max shift/error 0.002 Average shift/error 0.000 Absolute structure determination ad Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Absolute structure parameter -0.009(3) Largest diff. peak and hole 0.506 and -0.302 e.Å-3 262   Special Refinement Details Table A2.7.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 62. U(eq) is defined asthe trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 6172(1) 8240(1) 8167(1) 15(1) O(1) 3907(1) 9672(1) 4985(1) 17(1) O(2) 6918(1) 8349(1) 5024(1) 15(1) O(3) 8739(1) 9434(1) 5191(1) 14(1) O(4) 8625(1) 7737(1) 6394(1) 15(1) O(5) 10809(1) 8399(1) 6452(1) 19(1) N(1) 3093(1) 10408(1) 6153(1) 12(1) N(2) 9490(1) 8431(1) 6587(1) 12(1) C(1) 4851(1) 9334(1) 7882(1) 11(1) C(2) 4150(1) 9836(1) 8519(1) 13(1) C(3) 3074(1) 10582(1) 8369(1) 13(1) C(4) 2660(1) 10820(1) 7588(1) 13(1) C(5) 3393(1) 10316(1) 6972(1) 10(1) C(6) 4553(1) 9605(1) 7092(1) 9(1) C(7) 5158(1) 9288(1) 6276(1) 10(1) C(8) 3998(1) 9786(1) 5710(1) 12(1) C(9) 1825(1) 10950(1) 5827(1) 16(1) C(10) 5199(1) 8087(1) 6152(1) 12(1) C(11) 5626(1) 7790(1) 5306(1) 15(1) C(12) 7535(1) 9152(1) 5408(1) 11(1) C(13) 6734(1) 9783(1) 6067(1) 9(1) C(14) 6523(1) 10915(1) 5677(1) 12(1) C(15) 7876(1) 11577(1) 5570(1) 14(1) C(16) 8070(1) 12508(1) 5908(1) 22(1) C(17) 7685(1) 9912(1) 6823(1) 9(1) C(18) 7318(1) 10731(1) 7352(1) 12(1) C(19) 8056(1) 10912(1) 8064(1) 15(1) C(20) 9254(1) 10302(1) 8269(1) 17(1) C(21) 9707(1) 9521(1) 7747(1) 14(1) C(22) 8925(1) 9334(1) 7045(1) 11(1) ________________________________________________________________________________ Table A2.7.3. Bond lengths [Å] and angles [°] for 62 _____________________________________________________ Br(1)-C(1) 1.9017(10) O(1)-C(8) 1.2218(12) O(2)-C(12) 1.3289(12) O(2)-C(11) 1.4580(13) O(3)-C(12) 1.2142(12) O(4)-N(2) 1.2271(11) O(5)-N(2) 1.2300(11) N(1)-C(8) 1.3625(13) N(1)-C(5) 1.3999(12) N(1)-C(9) 1.4553(13) N(2)-C(22) 1.4720(12) C(1)-C(6) 1.3911(14) C(1)-C(2) 1.3962(14) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(2)-C(3) C(3)-C(4) C(4)-C(5) C(5)-C(6) C(6)-C(7) C(7)-C(10) C(7)-C(8) C(7)-C(13) C(10)-C(11) C(12)-C(13) C(13)-C(17) C(13)-C(14) C(14)-C(15) C(15)-C(16) C(17)-C(22) C(17)-C(18) C(18)-C(19) C(19)-C(20) C(20)-C(21) C(21)-C(22) C(12)-O(2)-C(11) C(8)-N(1)-C(5) C(8)-N(1)-C(9) C(5)-N(1)-C(9) O(4)-N(2)-O(5) O(4)-N(2)-C(22) O(5)-N(2)-C(22) C(6)-C(1)-C(2) C(6)-C(1)-Br(1) C(2)-C(1)-Br(1) C(3)-C(2)-C(1) C(2)-C(3)-C(4) C(5)-C(4)-C(3) C(4)-C(5)-N(1) C(4)-C(5)-C(6) N(1)-C(5)-C(6) C(1)-C(6)-C(5) C(1)-C(6)-C(7) C(5)-C(6)-C(7) C(6)-C(7)-C(10) C(6)-C(7)-C(8) C(10)-C(7)-C(8) C(6)-C(7)-C(13) C(10)-C(7)-C(13) C(8)-C(7)-C(13) O(1)-C(8)-N(1) O(1)-C(8)-C(7) N(1)-C(8)-C(7) C(11)-C(10)-C(7) O(2)-C(11)-C(10) O(3)-C(12)-O(2) O(3)-C(12)-C(13) O(2)-C(12)-C(13) C(17)-C(13)-C(12) C(17)-C(13)-C(14) C(12)-C(13)-C(14) C(17)-C(13)-C(7) 1.3888(15) 1.3917(15) 1.3854(14) 1.4079(14) 1.5248(13) 1.5383(13) 1.5561(14) 1.6122(13) 1.5149(14) 1.5460(13) 1.5433(13) 1.5885(13) 1.5070(14) 1.3208(15) 1.4016(14) 1.4049(14) 1.3862(14) 1.3857(16) 1.3836(15) 1.3936(14) 124.26(8) 111.30(8) 123.71(8) 124.18(9) 124.19(9) 117.92(8) 117.81(8) 121.36(9) 122.86(7) 115.75(7) 119.98(9) 120.64(9) 117.69(9) 126.35(9) 123.75(9) 109.89(8) 116.17(9) 135.37(9) 108.42(8) 112.93(8) 100.84(7) 109.74(8) 114.61(8) 109.51(8) 108.78(7) 124.44(9) 126.88(9) 108.66(8) 112.23(8) 112.87(8) 117.89(9) 119.40(8) 122.54(8) 111.72(8) 107.93(7) 103.53(7) 111.69(7) 263   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 264   C(12)-C(13)-C(7) 112.19(7) C(14)-C(13)-C(7) 109.36(7) C(15)-C(14)-C(13) 116.88(8) C(16)-C(15)-C(14) 123.95(11) C(22)-C(17)-C(18) 114.45(9) C(22)-C(17)-C(13) 128.21(8) C(18)-C(17)-C(13) 117.30(8) C(19)-C(18)-C(17) 123.03(10) C(20)-C(19)-C(18) 120.40(10) C(21)-C(20)-C(19) 118.74(10) C(20)-C(21)-C(22) 119.86(10) C(21)-C(22)-C(17) 123.37(9) C(21)-C(22)-N(2) 112.90(9) C(17)-C(22)-N(2) 123.65(8) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.7.4. Anisotropic displacement parameters (Å2x 104) for 62. The anisotropic displacement factorexponent takes the form: -2p2[ h2a*2U11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Br(1) 163(1) 167(1) 105(1) 41(1) 8(1) 33(1) O(1) 154(3) 265(4) 81(3) -9(3) -27(3) -9(3) O(2) 166(3) 173(3) 96(3) -45(3) 20(3) -31(3) O(3) 132(3) 170(3) 115(3) 6(2) 34(3) 1(3) O(4) 182(4) 119(3) 161(3) -8(2) 7(3) -30(3) O(5) 111(3) 226(4) 235(4) -21(3) 9(3) 43(3) N(1) 92(4) 177(4) 92(3) 20(3) -10(3) -1(3) N(2) 135(4) 122(4) 108(3) 24(3) -5(3) 14(3) C(1) 99(4) 128(4) 92(4) 7(3) 0(3) -8(3) C(2) 148(5) 155(4) 88(4) -3(3) 29(3) -19(3) C(3) 145(4) 134(4) 113(4) -20(3) 41(3) -17(3) C(4) 115(4) 120(4) 141(4) -1(3) 28(4) -2(3) C(5) 96(4) 118(4) 85(4) 12(3) 10(3) -20(3) C(6) 94(4) 120(4) 70(3) 1(3) 8(3) -15(3) C(7) 92(4) 138(4) 69(4) -13(3) 2(3) -7(3) C(8) 96(4) 164(4) 102(4) 7(3) -10(3) -31(3) C(9) 113(5) 217(5) 157(5) 36(4) -33(4) 13(4) C(10) 130(4) 137(4) 107(4) -16(3) 13(3) -34(3) C(11) 160(5) 158(4) 120(4) -43(3) 4(4) -41(4) C(12) 137(4) 119(4) 60(4) 2(3) -3(3) 7(3) C(13) 91(4) 105(4) 70(4) -3(3) -2(3) -1(3) C(14) 113(4) 134(4) 122(4) 26(3) -8(3) 5(3) C(15) 130(4) 142(5) 158(4) 45(3) 1(3) 0(3) C(16) 203(6) 169(5) 299(6) 19(4) 21(5) -23(4) C(17) 91(4) 109(3) 75(3) -1(3) 2(3) -17(3) C(18) 116(4) 137(4) 106(4) -16(3) 9(3) -9(3) C(19) 159(4) 181(4) 114(5) -54(3) 6(4) -37(4) C(20) 147(4) 262(5) 103(5) -28(4) -31(3) -48(4) C(21) 114(4) 189(5) 124(4) 21(3) -30(3) -10(4) C(22) 104(4) 119(4) 93(3) 4(3) 2(3) -3(3) ______________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.8. X-Ray Crystal Structure Analysis of 72 H N HO H CO2Me N Br O N 72 Figure A2.8.1. X-ray Crystal Structure of 72 Table A2.8.1. Crystal Data and Structure Analysis Details for 72 Empirical formula C23 H24 Br N3 O4 Formula weight 486.36 Crystal shape plate Crystal color colourless Crystal size 0.07 x 0.31 x 0.38 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK Data collection temperature 100 K Theta range for 9871 reflections used 265   266   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 in lattice determination 2.39 to 31.55° Unit cell dimensions a = 8.9320(3) Å b = 27.1836(10) Å c = 9.0145(3) Å Volume 2085.34(13) Å3 Z 4 Crystal system monoclinic Space group P 1 21/c 1 (# 14) Density (calculated) 1.549 g/cm3 F(000) 1000 Theta range for data collection 2.4 to 37.5° Completeness to theta = 25.000° 99.9% Index ranges -15 £ h £ 14, -46 £ k £ 45, -15 £ l £ 15 Data collection scan type and scans Reflections collected 104508 Independent reflections 10606 [Rint= 0.0574] Reflections > 2s(I) 8291 Average s(I)/(net I) 0.0362 Absorption coefficient 2.01 mm-1 Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.0000 and 0.8324 Structure Solution and Refinement Primary solution method dual Secondary solution method ? Hydrogen placement ? Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 10606 / 0 / 376 Treatment of hydrogen atoms refall Goodness-of-fit on F2 2.53 Final R indices [I>2s(I), 8291 reflections] R1 = 0.0470, wR2 = 0.0646 R indices (all data) R1 = 0.0694, wR2 = 0.0654 Type of weighting scheme used calc Weighting scheme used Max shift/error 0.001 Average shift/error 0.000 Extinction coefficient 0 Largest diff. peak and hole 1.86 and -1.09 e·Å-3 Programs Used a= 90° b= 107.683(2)° g = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics 267   SAINT V8.27B (Bruker-AXS, 2007) APEX2 2012.4-3 (Bruker-AXS, 2007) SAINT V8.27B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2012/6 (Sheldrick, 2012) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.8.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 72. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 5616(1) 9528(1) 3588(1) 20(1) O(1) 3320(1) 7660(1) 145(1) 19(1) O(2) 2094(1) 8263(1) 4223(1) 22(1) O(3) 10340(1) 9430(1) 2851(1) 18(1) O(4) 9696(1) 9118(1) 4907(1) 18(1) N(1) 2670(1) 8410(1) -1033(1) 14(1) N(2) 8487(1) 8844(1) 2459(1) 13(1) N(3) 8419(2) 8060(1) 3813(1) 22(1) C(1) 4542(1) 8418(1) 1464(1) 11(1) C(2) 4040(1) 8938(1) 883(1) 11(1) C(3) 4320(1) 9405(1) 1519(1) 14(1) C(4) 3606(2) 9819(1) 682(2) 17(1) C(5) 2602(2) 9765(1) -815(2) 19(1) C(6) 2257(2) 9306(1) -1492(2) 16(1) C(7) 2966(1) 8906(1) -616(1) 12(1) C(8) 3461(1) 8107(1) 138(1) 13(1) C(9) 1534(2) 8243(1) -2468(2) 21(1) C(10) 4148(2) 8288(1) 2965(2) 14(1) C(11) 2418(2) 8357(1) 2804(2) 19(1) C(12) 6299(1) 8286(1) 1562(1) 12(1) C(13) 6798(1) 8517(1) 248(1) 13(1) C(14) 6207(2) 8430(1) -1338(2) 18(1) C(15) 6884(2) 8664(1) -2346(2) 22(1) C(16) 8156(2) 8973(1) -1769(2) 20(1) C(17) 8787(2) 9058(1) -176(2) 17(1) C(18) 8085(1) 8827(1) 816(1) 13(1) C(19) 7546(1) 8484(1) 3051(1) 13(1) C(20) 8360(2) 7697(1) 2606(2) 23(1) C(21) 6642(2) 7726(1) 1632(2) 17(1) C(22) 9528(1) 9132(1) 3521(2) 14(1) C(23) 11536(2) 9722(1) 3929(2) 27(1) ________________________________________________________________________________ Table A2.8.3. Bond lengths [Å] and angles [°] for 72 __________________________________________________________________________________ _ Br(1)-C(3) 1.9025(13) O(1)-C(8) 1.2203(15) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(2)-H(2) O(2)-C(11) O(3)-C(22) O(3)-C(23) O(4)-C(22) N(1)-C(7) N(1)-C(8) N(1)-C(9) N(2)-C(18) N(2)-C(19) N(2)-C(22) N(3)-H(3) N(3)-C(19) N(3)-C(20) C(1)-C(2) C(1)-C(8) C(1)-C(10) C(1)-C(12) C(2)-C(3) C(2)-C(7) C(3)-C(4) C(4)-H(4) C(4)-C(5) C(5)-H(5) C(5)-C(6) C(6)-H(6) C(6)-C(7) C(9)-H(9A) C(9)-H(9B) C(9)-H(9C) C(10)-H(10A) C(10)-H(10B) C(10)-C(11) C(11)-H(11A) C(11)-H(11B) C(12)-C(13) C(12)-C(19) C(12)-C(21) C(13)-C(14) C(13)-C(18) C(14)-H(14) C(14)-C(15) C(15)-H(15) C(15)-C(16) C(16)-H(16) C(16)-C(17) C(17)-H(17) C(17)-C(18) C(19)-H(19) C(20)-H(20A) C(20)-H(20B) C(20)-C(21) C(21)-H(21A) C(21)-H(21B) C(23)-H(23A) C(23)-H(23B) C(23)-H(23C) 0.856(18) 1.4180(16) 1.3461(15) 1.4446(17) 1.2132(15) 1.4020(16) 1.3567(16) 1.4531(16) 1.4145(15) 1.4905(16) 1.3609(16) 0.760(18) 1.4455(17) 1.457(2) 1.5279(16) 1.5399(17) 1.5387(17) 1.5856(17) 1.3835(17) 1.4026(16) 1.3978(18) 0.939(15) 1.3829(19) 0.921(16) 1.381(2) 0.925(14) 1.3800(18) 0.960(17) 0.961(16) 0.996(17) 0.897(13) 0.984(15) 1.5195(18) 0.946(16) 0.983(15) 1.5211(17) 1.5569(17) 1.5515(17) 1.3857(17) 1.3912(17) 0.954(15) 1.3886(19) 0.888(15) 1.382(2) 0.952(13) 1.3941(19) 0.913(14) 1.3892(17) 0.943(12) 0.974(15) 0.997(14) 1.5206(19) 0.939(13) 0.956(14) 0.931(16) 0.962(15) 1.013(16) 268   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(11)-O(2)-H(2) C(22)-O(3)-C(23) C(7)-N(1)-C(9) C(8)-N(1)-C(7) C(8)-N(1)-C(9) C(18)-N(2)-C(19) C(22)-N(2)-C(18) C(22)-N(2)-C(19) C(19)-N(3)-H(3) C(19)-N(3)-C(20) C(20)-N(3)-H(3) C(2)-C(1)-C(8) C(2)-C(1)-C(10) C(2)-C(1)-C(12) C(8)-C(1)-C(12) C(10)-C(1)-C(8) C(10)-C(1)-C(12) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(2)-C(3)-Br(1) C(2)-C(3)-C(4) C(4)-C(3)-Br(1) C(3)-C(4)-H(4) C(5)-C(4)-C(3) C(5)-C(4)-H(4) C(4)-C(5)-H(5) C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(5)-C(6)-H(6) C(7)-C(6)-C(5) C(7)-C(6)-H(6) N(1)-C(7)-C(2) C(6)-C(7)-N(1) C(6)-C(7)-C(2) O(1)-C(8)-N(1) O(1)-C(8)-C(1) N(1)-C(8)-C(1) N(1)-C(9)-H(9A) N(1)-C(9)-H(9B) N(1)-C(9)-H(9C) H(9A)-C(9)-H(9B) H(9A)-C(9)-H(9C) H(9B)-C(9)-H(9C) C(1)-C(10)-H(10A) C(1)-C(10)-H(10B) H(10A)-C(10)-H(10B) C(11)-C(10)-C(1) C(11)-C(10)-H(10A) C(11)-C(10)-H(10B) O(2)-C(11)-C(10) O(2)-C(11)-H(11A) O(2)-C(11)-H(11B) C(10)-C(11)-H(11A) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(13)-C(12)-C(1) C(13)-C(12)-C(19) 108.4(11) 114.73(11) 124.25(11) 111.34(10) 124.10(11) 111.20(10) 131.13(11) 117.66(10) 110.4(14) 107.07(11) 110.6(14) 101.12(9) 113.01(10) 114.20(10) 107.26(9) 107.47(10) 112.73(10) 135.27(11) 116.19(11) 108.38(10) 123.18(9) 121.36(12) 115.42(9) 117.3(9) 119.63(13) 123.1(9) 117.6(10) 121.31(12) 121.0(10) 123.9(9) 117.20(12) 118.9(9) 109.69(10) 126.00(11) 124.23(12) 125.30(12) 125.66(11) 109.04(10) 105.5(10) 108.1(10) 111.5(10) 108.5(13) 112.9(13) 110.0(13) 110.7(8) 110.0(8) 108.0(12) 112.66(10) 108.2(8) 107.2(8) 111.85(11) 104.6(9) 109.4(8) 110.7(9) 110.9(8) 109.2(12) 112.53(10) 103.10(10) 269   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(13)-C(12)-C(21) C(19)-C(12)-C(1) C(21)-C(12)-C(1) C(21)-C(12)-C(19) C(14)-C(13)-C(12) C(14)-C(13)-C(18) C(18)-C(13)-C(12) C(13)-C(14)-H(14) C(13)-C(14)-C(15) C(15)-C(14)-H(14) C(14)-C(15)-H(15) C(16)-C(15)-C(14) C(16)-C(15)-H(15) C(15)-C(16)-H(16) C(15)-C(16)-C(17) C(17)-C(16)-H(16) C(16)-C(17)-H(17) C(18)-C(17)-C(16) C(18)-C(17)-H(17) C(13)-C(18)-N(2) C(17)-C(18)-N(2) C(17)-C(18)-C(13) N(2)-C(19)-C(12) N(2)-C(19)-H(19) N(3)-C(19)-N(2) N(3)-C(19)-C(12) N(3)-C(19)-H(19) C(12)-C(19)-H(19) N(3)-C(20)-H(20A) N(3)-C(20)-H(20B) N(3)-C(20)-C(21) H(20A)-C(20)-H(20B) C(21)-C(20)-H(20A) C(21)-C(20)-H(20B) C(12)-C(21)-H(21A) C(12)-C(21)-H(21B) C(20)-C(21)-C(12) C(20)-C(21)-H(21A) C(20)-C(21)-H(21B) H(21A)-C(21)-H(21B) O(3)-C(22)-N(2) O(4)-C(22)-O(3) O(4)-C(22)-N(2) O(3)-C(23)-H(23A) O(3)-C(23)-H(23B) O(3)-C(23)-H(23C) H(23A)-C(23)-H(23B) H(23A)-C(23)-H(23C) H(23B)-C(23)-H(23C) 270   109.61(10) 114.00(10) 113.78(10) 102.92(10) 128.56(11) 119.71(11) 111.60(10) 119.7(9) 119.53(13) 120.6(9) 116.8(10) 120.22(13) 122.9(10) 116.3(8) 121.18(13) 122.5(8) 120.7(8) 117.89(12) 121.4(8) 108.90(10) 129.64(11) 121.45(11) 104.58(9) 104.9(8) 114.37(10) 105.97(11) 111.9(8) 115.2(8) 109.9(9) 116.1(8) 101.40(11) 107.2(11) 113.9(9) 108.4(8) 110.3(8) 113.5(9) 103.11(11) 108.7(8) 112.2(8) 108.8(12) 112.08(11) 124.48(12) 123.44(12) 112.0(11) 103.6(9) 107.6(9) 106.2(13) 112.2(13) 115.1(12) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Table A2.8.4. Anisotropic displacement parameters (Å x 10 ) for 72. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2p [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 271   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ Br(1) 189(1) 189(1) 183(1) -71(1) -12(1) -6(1) O(1) 199(5) 132(5) 234(5) -45(4) 54(4) -35(4) O(2) 251(5) 251(6) 230(5) 92(4) 159(4) 86(4) O(3) 150(4) 180(5) 203(5) -31(4) 41(4) -51(3) O(4) 139(4) 245(5) 136(4) -30(4) 9(4) 8(4) N(1) 123(5) 170(5) 100(5) -24(4) 12(4) -24(4) N(2) 114(5) 152(5) 116(5) -3(4) 26(4) -17(4) N(3) 163(6) 211(6) 235(6) 66(5) -25(5) 12(5) C(1) 110(5) 111(5) 115(5) -8(4) 25(4) -6(4) C(2) 88(5) 125(6) 111(5) 6(4) 42(4) 0(4) C(3) 108(5) 153(6) 143(6) -18(5) 37(4) -9(5) C(4) 161(6) 126(6) 236(7) 6(5) 71(5) -2(5) C(5) 161(6) 181(7) 218(7) 86(5) 54(5) 38(5) C(6) 124(6) 231(7) 134(6) 43(5) 30(5) 3(5) C(7) 109(5) 158(6) 111(6) -2(5) 49(4) -19(4) C(8) 114(6) 165(6) 126(6) -23(5) 56(5) -15(4) C(9) 216(7) 265(8) 122(6) -53(6) -6(5) -40(6) C(10) 134(6) 151(6) 119(6) 20(5) 39(5) 9(5) C(11) 160(6) 247(7) 188(7) 78(6) 91(5) 60(6) C(12) 115(6) 135(6) 128(6) -6(4) 45(5) -1(4) C(13) 121(6) 129(6) 142(6) -3(5) 55(5) 11(4) C(14) 144(6) 250(7) 165(6) -53(5) 55(5) -14(5) C(15) 216(7) 320(8) 112(6) -31(6) 57(5) 15(6) C(16) 222(7) 242(7) 177(7) 32(6) 118(6) 20(6) C(17) 153(6) 171(6) 191(7) -5(5) 74(5) -13(5) C(18) 119(6) 128(6) 131(6) -2(4) 40(5) 25(4) C(19) 103(5) 172(6) 119(6) 19(5) 29(5) 4(5) C(20) 158(7) 180(7) 362(9) 62(6) 77(6) 53(5) C(21) 155(6) 137(6) 235(7) -3(5) 78(5) 13(5) C(22) 91(5) 142(6) 188(6) -16(5) 28(5) 31(4) C(23) 209(8) 299(8) 313(9) -133(7) 93(7) -119(6) ______________________________________________________________________________ 3 2 3 Table A2.8.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 72 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(2) H(3) H(4) H(5) H(6) H(9A) H(9B) H(9C) H(10A) H(10B) H(11A) H(11B) H(14) H(15) H(16) H(17) 241(2) 926(2) 383(2) 219(2) 159(2) 172(2) 176(2) 44(2) 441(1) 475(2) 211(2) 176(2) 539(2) 645(2) 856(2) 963(2) 797(1) 813(1) 1013(1) 1005(1) 925(1) 790(1) 840(1) 832(1) 798(1) 850(1) 869(1) 814(1) 819(1) 861(1) 913(1) 926(1) 452(2) 424(2) 119(2) -136(2) -249(2) -252(2) -332(2) -248(2) 324(2) 382(2) 257(2) 198(2) -172(2) -336(2) -252(2) 20(2) 42(5) 37(5) 20(4) 30(4) 18(4) 33(5) 32(5) 36(5) 9(3) 21(4) 26(4) 21(4) 21(4) 23(4) 15(4) 12(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 272   H(19) 714(1) 867(1) 373(1) 7(3) H(20A) 868(2) 738(1) 308(2) 23(4) H(20B) 902(2) 777(1) 192(2) 15(4) H(21A) 603(2) 756(1) 216(2) 10(3) H(21B) 646(2) 758(1) 63(2) 18(4) H(23A) 1111(2) 996(1) 442(2) 35(5) H(23B) 1202(2) 990(1) 327(2) 21(4) H(23C) 1226(2) 949(1) 470(2) 30(4) ________________________________________________________________________________ Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.9. X-Ray Crystal Structure Analysis of 73 PMB TIPSO N H O HN CO2Me O N 73 Figure A2.9.1. X-ray Crystal Structure of 73 Table A2.9.1. Crystal Data and Structure Analysis Details for 73 Empirical formula C40 H53 N3 O6 Si Formula weight 699.94 Crystal shape plate Crystal color colourless Crystal size 0.04 x 0.20 x 0.20 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK Data collection temperature 100 K 273   274   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Theta range for 9937 reflections used in lattice determination 2.40 to 30.23° a= 90° b= 94.394(3)° g = 90° Unit cell dimensions a = 23.3177(12) Å b = 8.7021(4) Å c = 37.035(2) Å Volume 7492.8(7) Å3 Z 8 Crystal system monoclinic Space group I 1 2/a 1 (# 15) Density (calculated) 1.241 g/cm3 F(000) 3008 Theta range for data collection 2.4 to 35.0° Completeness to theta = 25.000° 99.9% Index ranges -36 £ h £ 37, -13 £ k £ 13, -59 £ l £ 58 Data collection scan type and scans Reflections collected 146937 Independent reflections 15890 [Rint= 0.1927] Reflections > 2s(I) 8277 Average s(I)/(net I) 0.1381 Absorption coefficient 0.11 mm-1 Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.0000 and 0.9156 Structure Solution and Refinement Primary solution method dual Secondary solution method ? Hydrogen placement geom Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 15890 / 0 / 460 Treatment of hydrogen atoms constr Goodness-of-fit on F2 1.25 Final R indices [I>2s(I), 8277 reflections] R1 = 0.0718, wR2 = 0.1071 R indices (all data) R1 = 0.1715, wR2 = 0.1233 Type of weighting scheme used calc Weighting scheme used Max shift/error 0.000 Average shift/error 0.000 Extinction coefficient n/a Largest diff. peak and hole 0.55 and -0.53 e·Å-3 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 275   Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.27B (Bruker-AXS, 2007) APEX2 2012.4-3 (Bruker-AXS, 2007) SAINT V8.27B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2013/2 (Sheldrick, 2013) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.9.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 73. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Si(1) 3732(1) 673(1) 2268(1) 13(1) O(1) 2790(1) -3775(1) 1228(1) 19(1) O(2) 3562(1) -65(1) 1866(1) 18(1) O(3) 793(1) 2007(1) 470(1) 20(1) O(4) 337(1) -285(1) 450(1) 34(1) O(5) 2274(1) 1556(1) 486(1) 16(1) O(6) 5052(1) 5085(1) 1358(1) 26(1) N(1) 1864(1) -2960(1) 1280(1) 14(1) N(2) 1318(1) -73(1) 418(1) 14(1) N(3) 3199(1) 803(1) 470(1) 13(1) C(1) 2509(1) -1080(2) 1090(1) 12(1) C(2) 1946(1) -370(2) 1189(1) 12(1) C(3) 1770(1) 1145(2) 1210(1) 15(1) C(4) 1220(1) 1458(2) 1310(1) 19(1) C(5) 854(1) 271(2) 1390(1) 20(1) C(6) 1027(1) -1258(2) 1380(1) 18(1) C(7) 1575(1) -1538(2) 1283(1) 14(1) C(8) 2421(1) -2773(2) 1207(1) 13(1) C(9) 1600(1) -4446(2) 1329(1) 21(1) C(10) 3042(1) -416(2) 1301(1) 14(1) C(11) 2999(1) -378(2) 1707(1) 18(1) C(12) 2572(1) -1120(2) 660(1) 11(1) C(13) 2066(1) -2081(2) 478(1) 13(1) C(14) 2184(1) -3655(2) 434(1) 18(1) C(15) 1776(1) -4714(2) 307(1) 23(1) C(16) 1224(1) -4227(2) 207(1) 24(1) C(17) 1084(1) -2692(2) 246(1) 20(1) C(18) 1491(1) -1618(2) 387(1) 14(1) C(19) 2649(1) 553(2) 526(1) 12(1) C(20) 3583(1) -490(2) 547(1) 14(1) C(21) 3161(1) -1825(2) 574(1) 14(1) C(22) 776(1) 440(2) 446(1) 19(1) C(23) 254(1) 2706(2) 538(1) 31(1) C(24) 3582(1) -777(2) 2628(1) 21(1) C(25) 3734(1) -2424(2) 2519(1) 34(1) C(26) 2957(1) -746(2) 2726(1) 29(1) C(27) 3303(1) 2471(2) 2331(1) 19(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 276   C(28) 3433(1) 3174(2) 2709(1) 28(1) C(29) 3380(1) 3672(2) 2034(1) 31(1) C(30) 4519(1) 1125(2) 2262(1) 17(1) C(31) 4674(1) 1762(2) 1896(1) 28(1) C(32) 4920(1) -219(2) 2369(1) 28(1) C(33) 3412(1) 2292(2) 352(1) 14(1) C(34) 3837(1) 3026(2) 627(1) 13(1) C(35) 4426(1) 2770(2) 618(1) 18(1) C(36) 4818(1) 3460(2) 866(1) 21(1) C(37) 4626(1) 4444(2) 1127(1) 18(1) C(38) 4044(1) 4715(2) 1142(1) 19(1) C(39) 3654(1) 3996(2) 894(1) 16(1) C(40) 4878(1) 6187(2) 1612(1) 32(1) ________________________________________________________________________________ Table A2.9.3. Bond lengths [Å] and angles [°] for 73 __________________________________________________________________________________ _ Si(1)-O(2) 1.6433(11) Si(1)-C(24) 1.8858(17) Si(1)-C(27) 1.8806(17) Si(1)-C(30) 1.8786(16) O(1)-C(8) 1.2233(18) O(2)-C(11) 1.4245(18) O(3)-C(22) 1.367(2) O(3)-C(23) 1.437(2) O(4)-C(22) 1.2031(19) O(5)-C(19) 1.2376(17) O(6)-C(37) 1.3796(18) O(6)-C(40) 1.425(2) N(1)-C(7) 1.4092(19) N(1)-C(8) 1.358(2) N(1)-C(9) 1.4496(19) N(2)-H(2) 0.8800 N(2)-C(18) 1.4106(19) N(2)-C(22) 1.353(2) N(3)-C(19) 1.3318(19) N(3)-C(20) 1.4511(19) N(3)-C(33) 1.4668(18) C(1)-C(2) 1.519(2) C(1)-C(8) 1.554(2) C(1)-C(10) 1.530(2) C(1)-C(12) 1.609(2) C(2)-C(3) 1.385(2) C(2)-C(7) 1.397(2) C(3)-H(3) 0.9500 C(3)-C(4) 1.390(2) C(4)-H(4) 0.9500 C(4)-C(5) 1.385(2) C(5)-H(5) 0.9500 C(5)-C(6) 1.392(2) C(6)-H(6) 0.9500 C(6)-C(7) 1.375(2) C(9)-H(9A) 0.9800 C(9)-H(9B) 0.9800 C(9)-H(9C) 0.9800 C(10)-H(10A) 0.9900 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(10)-H(10B) C(10)-C(11) C(11)-H(11A) C(11)-H(11B) C(12)-C(13) C(12)-C(19) C(12)-C(21) C(13)-C(14) C(13)-C(18) C(14)-H(14) C(14)-C(15) C(15)-H(15) C(15)-C(16) C(16)-H(16) C(16)-C(17) C(17)-H(17) C(17)-C(18) C(20)-H(20A) C(20)-H(20B) C(20)-C(21) C(21)-H(21A) C(21)-H(21B) C(23)-H(23A) C(23)-H(23B) C(23)-H(23C) C(24)-H(24) C(24)-C(25) C(24)-C(26) C(25)-H(25A) C(25)-H(25B) C(25)-H(25C) C(26)-H(26A) C(26)-H(26B) C(26)-H(26C) C(27)-H(27) C(27)-C(28) C(27)-C(29) C(28)-H(28A) C(28)-H(28B) C(28)-H(28C) C(29)-H(29A) C(29)-H(29B) C(29)-H(29C) C(30)-H(30) C(30)-C(31) C(30)-C(32) C(31)-H(31A) C(31)-H(31B) C(31)-H(31C) C(32)-H(32A) C(32)-H(32B) C(32)-H(32C) C(33)-H(33A) C(33)-H(33B) C(33)-C(34) C(34)-C(35) C(34)-C(39) C(35)-H(35) 0.9900 1.513(2) 0.9900 0.9900 1.558(2) 1.553(2) 1.560(2) 1.409(2) 1.416(2) 0.9500 1.381(2) 0.9500 1.377(2) 0.9500 1.386(2) 0.9500 1.404(2) 0.9900 0.9900 1.529(2) 0.9900 0.9900 0.9800 0.9800 0.9800 1.0000 1.537(2) 1.529(2) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.0000 1.536(2) 1.538(2) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.0000 1.533(2) 1.531(2) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 0.9900 0.9900 1.507(2) 1.394(2) 1.391(2) 0.9500 277   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(35)-C(36) C(36)-H(36) C(36)-C(37) C(37)-C(38) C(38)-H(38) C(38)-C(39) C(39)-H(39) C(40)-H(40A) C(40)-H(40B) C(40)-H(40C) O(2)-Si(1)-C(24) O(2)-Si(1)-C(27) O(2)-Si(1)-C(30) C(27)-Si(1)-C(24) C(30)-Si(1)-C(24) C(30)-Si(1)-C(27) C(11)-O(2)-Si(1) C(22)-O(3)-C(23) C(37)-O(6)-C(40) C(7)-N(1)-C(9) C(8)-N(1)-C(7) C(8)-N(1)-C(9) C(18)-N(2)-H(2) C(22)-N(2)-H(2) C(22)-N(2)-C(18) C(19)-N(3)-C(20) C(19)-N(3)-C(33) C(20)-N(3)-C(33) C(2)-C(1)-C(8) C(2)-C(1)-C(10) C(2)-C(1)-C(12) C(8)-C(1)-C(12) C(10)-C(1)-C(8) C(10)-C(1)-C(12) C(3)-C(2)-C(1) C(3)-C(2)-C(7) C(7)-C(2)-C(1) C(2)-C(3)-H(3) C(2)-C(3)-C(4) C(4)-C(3)-H(3) C(3)-C(4)-H(4) C(5)-C(4)-C(3) C(5)-C(4)-H(4) C(4)-C(5)-H(5) C(4)-C(5)-C(6) C(6)-C(5)-H(5) C(5)-C(6)-H(6) C(7)-C(6)-C(5) C(7)-C(6)-H(6) C(2)-C(7)-N(1) C(6)-C(7)-N(1) C(6)-C(7)-C(2) O(1)-C(8)-N(1) O(1)-C(8)-C(1) N(1)-C(8)-C(1) N(1)-C(9)-H(9A) N(1)-C(9)-H(9B) 1.383(2) 0.9500 1.389(2) 1.382(2) 0.9500 1.388(2) 0.9500 0.9800 0.9800 0.9800 109.49(7) 110.14(7) 103.79(7) 109.92(8) 112.46(7) 110.87(7) 126.94(10) 114.30(13) 116.98(14) 125.13(13) 111.14(12) 123.66(13) 116.7 116.7 126.52(13) 115.41(12) 122.84(12) 121.72(12) 100.58(12) 113.97(12) 113.17(11) 106.16(11) 109.56(12) 112.38(12) 131.70(14) 119.12(14) 109.13(13) 120.5 119.00(15) 120.5 119.8 120.47(15) 119.8 119.2 121.55(15) 119.2 121.6 116.89(15) 121.6 109.37(13) 127.66(14) 122.89(14) 125.48(14) 125.94(14) 108.58(13) 109.5 109.5 278   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 N(1)-C(9)-H(9C) H(9A)-C(9)-H(9B) H(9A)-C(9)-H(9C) H(9B)-C(9)-H(9C) C(1)-C(10)-H(10A) C(1)-C(10)-H(10B) H(10A)-C(10)-H(10B) C(11)-C(10)-C(1) C(11)-C(10)-H(10A) C(11)-C(10)-H(10B) O(2)-C(11)-C(10) O(2)-C(11)-H(11A) O(2)-C(11)-H(11B) C(10)-C(11)-H(11A) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(13)-C(12)-C(1) C(13)-C(12)-C(21) C(19)-C(12)-C(1) C(19)-C(12)-C(13) C(19)-C(12)-C(21) C(21)-C(12)-C(1) C(14)-C(13)-C(12) C(14)-C(13)-C(18) C(18)-C(13)-C(12) C(13)-C(14)-H(14) C(15)-C(14)-C(13) C(15)-C(14)-H(14) C(14)-C(15)-H(15) C(16)-C(15)-C(14) C(16)-C(15)-H(15) C(15)-C(16)-H(16) C(15)-C(16)-C(17) C(17)-C(16)-H(16) C(16)-C(17)-H(17) C(16)-C(17)-C(18) C(18)-C(17)-H(17) N(2)-C(18)-C(13) C(17)-C(18)-N(2) C(17)-C(18)-C(13) O(5)-C(19)-N(3) O(5)-C(19)-C(12) N(3)-C(19)-C(12) N(3)-C(20)-H(20A) N(3)-C(20)-H(20B) N(3)-C(20)-C(21) H(20A)-C(20)-H(20B) C(21)-C(20)-H(20A) C(21)-C(20)-H(20B) C(12)-C(21)-H(21A) C(12)-C(21)-H(21B) C(20)-C(21)-C(12) C(20)-C(21)-H(21A) C(20)-C(21)-H(21B) H(21A)-C(21)-H(21B) O(4)-C(22)-O(3) O(4)-C(22)-N(2) N(2)-C(22)-O(3) 109.5 109.5 109.5 109.5 108.8 108.8 107.7 113.76(13) 108.8 108.8 106.68(13) 110.4 110.4 110.4 110.4 108.6 108.45(12) 110.47(12) 108.49(11) 117.86(12) 100.20(12) 111.17(11) 115.09(13) 116.05(14) 128.49(13) 118.2 123.52(16) 118.2 120.3 119.42(16) 120.3 120.3 119.44(15) 120.3 119.2 121.51(16) 119.2 121.55(13) 118.41(14) 119.97(14) 123.16(14) 126.97(14) 109.83(12) 111.3 111.3 102.24(12) 109.2 111.3 111.3 110.3 110.3 107.14(12) 110.3 110.3 108.5 122.93(16) 128.98(16) 108.09(13) 279   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(3)-C(23)-H(23A) O(3)-C(23)-H(23B) O(3)-C(23)-H(23C) H(23A)-C(23)-H(23B) H(23A)-C(23)-H(23C) H(23B)-C(23)-H(23C) Si(1)-C(24)-H(24) C(25)-C(24)-Si(1) C(25)-C(24)-H(24) C(26)-C(24)-Si(1) C(26)-C(24)-H(24) C(26)-C(24)-C(25) C(24)-C(25)-H(25A) C(24)-C(25)-H(25B) C(24)-C(25)-H(25C) H(25A)-C(25)-H(25B) H(25A)-C(25)-H(25C) H(25B)-C(25)-H(25C) C(24)-C(26)-H(26A) C(24)-C(26)-H(26B) C(24)-C(26)-H(26C) H(26A)-C(26)-H(26B) H(26A)-C(26)-H(26C) H(26B)-C(26)-H(26C) Si(1)-C(27)-H(27) C(28)-C(27)-Si(1) C(28)-C(27)-H(27) C(28)-C(27)-C(29) C(29)-C(27)-Si(1) C(29)-C(27)-H(27) C(27)-C(28)-H(28A) C(27)-C(28)-H(28B) C(27)-C(28)-H(28C) H(28A)-C(28)-H(28B) H(28A)-C(28)-H(28C) H(28B)-C(28)-H(28C) C(27)-C(29)-H(29A) C(27)-C(29)-H(29B) C(27)-C(29)-H(29C) H(29A)-C(29)-H(29B) H(29A)-C(29)-H(29C) H(29B)-C(29)-H(29C) Si(1)-C(30)-H(30) C(31)-C(30)-Si(1) C(31)-C(30)-H(30) C(32)-C(30)-Si(1) C(32)-C(30)-H(30) C(32)-C(30)-C(31) C(30)-C(31)-H(31A) C(30)-C(31)-H(31B) C(30)-C(31)-H(31C) H(31A)-C(31)-H(31B) H(31A)-C(31)-H(31C) H(31B)-C(31)-H(31C) C(30)-C(32)-H(32A) C(30)-C(32)-H(32B) C(30)-C(32)-H(32C) H(32A)-C(32)-H(32B) 109.5 109.5 109.5 109.5 109.5 109.5 107.6 112.36(12) 107.6 112.77(11) 107.6 108.78(14) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 107.0 111.98(12) 107.0 110.83(14) 112.62(12) 107.0 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 106.8 112.51(11) 106.8 114.51(11) 106.8 108.92(14) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 280   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 H(32A)-C(32)-H(32C) H(32B)-C(32)-H(32C) N(3)-C(33)-H(33A) N(3)-C(33)-H(33B) N(3)-C(33)-C(34) H(33A)-C(33)-H(33B) C(34)-C(33)-H(33A) C(34)-C(33)-H(33B) C(35)-C(34)-C(33) C(39)-C(34)-C(33) C(39)-C(34)-C(35) C(34)-C(35)-H(35) C(36)-C(35)-C(34) C(36)-C(35)-H(35) C(35)-C(36)-H(36) C(35)-C(36)-C(37) C(37)-C(36)-H(36) O(6)-C(37)-C(36) O(6)-C(37)-C(38) C(38)-C(37)-C(36) C(37)-C(38)-H(38) C(37)-C(38)-C(39) C(39)-C(38)-H(38) C(34)-C(39)-H(39) C(38)-C(39)-C(34) C(38)-C(39)-H(39) O(6)-C(40)-H(40A) O(6)-C(40)-H(40B) O(6)-C(40)-H(40C) H(40A)-C(40)-H(40B) H(40A)-C(40)-H(40C) H(40B)-C(40)-H(40C) 281   109.5 109.5 109.0 109.0 113.08(12) 107.8 109.0 109.0 120.88(14) 121.12(14) 117.99(14) 119.4 121.12(15) 119.4 120.1 119.81(15) 120.1 115.14(15) 124.72(15) 120.14(15) 120.3 119.46(15) 120.3 119.3 121.46(15) 119.3 109.5 109.5 109.5 109.5 109.5 109.5 __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: 2 4 Anisotropic displacement parameters (Å x 10 ) for 73. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2p [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U ______________________________________________________________________________ Si(1) 140(2) 116(2) 135(2) -12(2) -3(2) -6(2) O(1) 266(6) 110(6) 194(6) 21(4) 21(5) 56(5) O(2) 148(6) 238(6) 160(6) -47(5) -28(5) 6(5) O(3) 166(6) 153(6) 292(7) 27(5) 31(5) 30(5) O(4) 176(7) 275(7) 581(10) -33(7) 54(6) -87(6) O(5) 154(6) 93(5) 220(6) 19(4) 7(5) 9(4) O(6) 238(7) 285(7) 265(7) -39(5) -34(5) -83(6) N(1) 184(7) 74(6) 169(7) 7(5) 26(5) -15(5) N(2) 131(7) 104(6) 192(7) 9(5) 3(5) -40(5) N(3) 144(7) 68(6) 167(6) 14(5) 13(5) 5(5) C(1) 132(7) 96(7) 117(7) -3(6) 7(6) 0(6) C(2) 142(8) 120(8) 102(7) -10(6) -1(6) -8(6) C(3) 181(8) 120(8) 151(8) -15(6) 22(6) -9(6) C(4) 223(9) 149(8) 192(8) -26(6) 29(7) 46(7) C(5) 163(8) 221(9) 228(9) -17(7) 53(7) 30(7) Table A2.9.4. 282   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(6) 183(9) 184(9) 182(8) 0(6) 30(7) -44(7) C(7) 179(8) 117(8) 110(7) -9(6) -6(6) -6(6) C(8) 222(9) 92(7) 86(7) -9(6) 2(6) 8(6) C(9) 306(10) 103(8) 230(9) 16(7) 47(7) -59(7) C(10) 158(8) 136(8) 139(7) -9(6) 4(6) -4(6) C(11) 164(8) 206(9) 153(8) -24(6) -15(6) -19(7) C(12) 143(8) 75(7) 117(7) -6(5) 4(6) 4(6) C(13) 215(8) 87(7) 94(7) 5(6) 13(6) -23(6) C(14) 279(9) 122(8) 123(8) -3(6) 8(7) -14(7) C(15) 412(11) 106(8) 165(8) -31(6) 36(8) -64(8) C(16) 362(11) 167(9) 189(9) -36(7) 10(8) -149(8) C(17) 221(9) 201(9) 169(8) -19(7) 5(7) -78(7) C(18) 219(8) 115(8) 103(7) -1(6) 28(6) -44(6) C(19) 178(8) 90(7) 85(7) -16(5) 6(6) -11(6) C(20) 151(8) 137(8) 150(7) 9(6) 31(6) 37(6) C(21) 196(8) 84(7) 134(7) -6(6) 18(6) 25(6) C(22) 202(9) 208(9) 162(8) 10(7) -8(7) -47(7) C(23) 218(10) 308(11) 402(12) 41(9) 43(8) 87(8) C(24) 216(9) 186(9) 209(8) 36(7) -21(7) -49(7) C(25) 378(12) 160(9) 488(13) 99(9) -31(10) -54(8) C(26) 284(10) 310(10) 265(10) 55(8) 31(8) -112(8) C(27) 163(8) 170(9) 240(9) -27(7) 47(7) -15(7) C(28) 233(10) 234(10) 378(11) -146(8) 87(8) -49(8) C(29) 299(10) 205(10) 443(12) 72(8) 128(9) 89(8) C(30) 147(8) 146(8) 211(8) -31(6) 7(7) 2(6) C(31) 200(9) 309(11) 341(11) 33(8) 94(8) 23(8) C(32) 189(9) 215(9) 412(12) 4(8) -35(8) 35(7) C(33) 161(8) 92(7) 169(8) 30(6) 32(6) -11(6) C(34) 142(8) 91(7) 164(8) 29(6) 17(6) 0(6) C(35) 170(8) 152(8) 211(8) 2(7) 50(7) 20(7) C(36) 121(8) 237(9) 285(10) 19(7) 18(7) 16(7) C(37) 185(8) 140(8) 206(8) 27(7) -19(7) -44(7) C(38) 241(9) 117(8) 205(8) -13(6) 34(7) -7(7) C(39) 146(8) 119(8) 207(8) 33(6) 43(6) 27(6) C(40) 406(12) 303(11) 260(10) -76(8) -16(9) -120(9) ______________________________________________________________________________ 3 2 3 Table A2.9.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 10 ) for 73 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(2) H(3) H(4) H(5) H(6) H(9A) H(9B) H(9C) H(10A) H(10B) H(11A) H(11B) H(14) H(15) 159 202 109 48 78 135 137 190 338 311 273 286 256 187 63 196 249 51 -207 -470 -441 -523 -104 64 44 -138 -401 -577 42 116 132 145 144 111 154 137 125 122 177 179 50 29 17 18 22 24 22 32 32 32 17 17 21 21 21 27 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 283   H(16) 94 -494 11 29 H(17) 70 -236 18 24 H(20A) 382 -34 78 17 H(20B) 384 -65 35 17 H(21A) 330 -254 77 17 H(21B) 312 -240 34 17 H(23A) -3 250 33 46 H(23B) 31 382 57 46 H(23C) 12 228 76 46 H(24) 383 -51 285 25 H(25A) 367 -313 272 52 H(25B) 414 -246 246 52 H(25C) 349 -273 231 52 H(26A) 270 -96 251 43 H(26B) 287 27 282 43 H(26C) 290 -153 291 43 H(27) 289 217 231 23 H(28A) 384 351 274 42 H(28B) 337 240 289 42 H(28C) 318 406 274 42 H(29A) 311 451 206 47 H(29B) 331 319 180 47 H(29C) 377 408 206 47 H(30) 460 196 244 20 H(31A) 508 203 191 42 H(31B) 444 268 184 42 H(31C) 460 98 171 42 H(32A) 485 -106 220 41 H(32B) 484 -58 261 41 H(32C) 532 12 237 41 H(33A) 308 300 30 17 H(33B) 360 215 12 17 H(35) 456 211 44 21 H(36) 522 326 86 26 H(38) 391 539 132 22 H(39) 326 417 91 19 H(40A) 468 704 148 49 H(40B) 522 658 176 49 H(40C) 462 570 177 49 ________________________________________________________________________________ Table A2.9.6. Hydrogen bonds for 73 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ N(2)-H(2)...O(5) 0.88 1.79 2.6356(16) 161.8 C(17)-H(17)...O(4) 0.95 2.27 2.862(2) 119.8 C(21)-H(21A)...O(1) 0.99 2.41 3.1343(19) 129.8 ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.10. X-Ray Crystal Structure Analysis of 77 Br N O N CO2Me O N H 77 Figure A2.10.1. X-ray Crystal Structure of 77 Table A2.10.1. Crystal data and structure analysis details for 77 Empirical formula C46.40 H47.20 Br2 Cl0.80 N6 O8.20 Formula weight 1008.40 Crystallization solvent isopropanol/hexane  (dichloromethane) Crystal shape plate Crystal color colourless Crystal size 0.05 x 0.20 x 0.46 mm Data Collection Preliminary photograph(s) rotation Type of diffractometer Bruker APEX-II CCD Wavelength 0.71073 Å MoK 284   285   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Data collection temperature 100 K Theta range for 9880 reflections used in lattice determination 2.32 to 33.69° Unit cell dimensions a = 17.6618(8) Å b = 17.4368(7) Å c = 13.5068(5) Å Volume 4129.7(3) Å3 Z 4 Crystal system monoclinic Space group P 1 21/c 1 (# 14) Density (calculated) 1.622 g/cm3 F(000) 2067 Theta range for data collection 2.1 to 37.6° Completeness to theta = 25.000° 99.9% Index ranges -29 ʺ″ h ʺ″ 30, -29 ʺ″ k ʺ″ 29, -23 ʺ″ l ʺ″ 22 Data collection scan type and  scans   Reflections  collected   213592   Independent  reflections   21060  [Rint=  0.0668]   Reflections  >  2⌠(I)   14742     Average  ⌠(I)/(net  I)   0.0422   Absorption  coefficient   2.08  mm-­‐1   Absorption  correction   Semi-­‐empirical  from  equivalents   Max.  and  min.  transmission   1.0000  and  0.8480     Structure Solution and Refinement Primary solution method dual Secondary solution method ? Hydrogen placement mixed Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 21060 / 3 / 592 Treatment of hydrogen atoms mixed Goodness-of-fit on F2 3.31 Final R indices [I>2⌠(I), 14742 reflections] R1 = 0.0585, wR2 = 0.0955 R indices (all data) R1 = 0.0953, wR2 = 0.0967 Type of weighting scheme used calc Weighting scheme used Max shift/error 0.002 Average shift/error 0.000 Extinction coefficient 0 Largest diff. peak and hole 3.94 and -2.05 e·Å-3 〈= 90° ®= 96.873(2)° © = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 286   Programs Used Cell refinement Data collection Data reduction Structure solution Structure refinement Graphics SAINT V8.27B (Bruker-AXS, 2007) APEX2 2012.4-3 (Bruker-AXS, 2007) SAINT V8.27B (Bruker-AXS, 2007) SHELXT (Sheldrick, 2012) SHELXL-2012/6 (Sheldrick, 2012) DIAMOND 3 (Crystal Impact, 1999) References Special Refinement Details 4 Table A2.10.2. Atomic coordinates ( x 10 ) and equivalent isotropic displacement parameters 2 3 (Å x 10 ) for 77. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1A) 4275(1) 4155(1) 4546(1) 17(1) O(1A) 4849(1) 1093(1) 2821(1) 18(1) O(2A) 3534(1) 1156(1) 3905(1) 14(1) O(3A) 1677(1) 2261(1) 5024(1) 28(1) O(4A) 2118(1) 1113(1) 4589(1) 24(1) N(1A) 5279(1) 2188(1) 2142(1) 14(1) N(2A) 2640(1) 2178(1) 4034(1) 14(1) N(3A) 2591(1) 1331(1) 2600(1) 17(1) C(1A) 4767(1) 3863(1) 3418(1) 14(1) C(2A) 5155(1) 4451(1) 2990(1) 18(1) C(3A) 5568(1) 4292(1) 2204(1) 20(1) C(4A) 5638(1) 3544(1) 1865(1) 17(1) C(5A) 5246(1) 2978(1) 2315(1) 14(1) C(6A) 4769(1) 3120(1) 3055(1) 12(1) C(7A) 4390(1) 2370(1) 3293(1) 11(1) C(8A) 4859(1) 1789(1) 2758(1) 13(1) C(9A) 5816(1) 1822(1) 1554(1) 19(1) C(10A) 4427(1) 2208(1) 4414(1) 13(1) C(11A) 4123(1) 1422(1) 4643(1) 16(1) C(12A) 3085(1) 1712(1) 3373(1) 13(1) C(13A) 3527(1) 2321(1) 2811(1) 11(1) C(14A) 3397(1) 2045(1) 1702(1) 15(1) C(15A) 3031(1) 1255(1) 1744(1) 20(1) C(16A) 3091(1) 3045(1) 2962(1) 12(1) C(17A) 2609(1) 2950(1) 3695(1) 14(1) C(18A) 2158(1) 3551(1) 3966(1) 18(1) C(19A) 2193(1) 4244(1) 3462(1) 21(1) C(20A) 2647(1) 4337(1) 2706(1) 20(1) C(21A) 3102(1) 3731(1) 2452(1) 16(1) C(22A) 2101(1) 1885(1) 4585(1) 19(1) C(23A) 1594(2) 770(1) 5202(2) 34(1) Br(1B) 7671(1) 4207(1) 1850(1) 25(1) O(1B) 9584(1) 1388(1) 2258(1) 28(1) O(2B) 8160(1) 1198(1) 2987(1) 20(1) O(3B) 6232(1) 1864(1) 4406(1) 29(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 287   O(4B) 6979(1) 869(1) 4083(1) 23(1) N(1B) 10134(1) 2569(1) 2268(1) 19(1) N(2B) 7383(1) 2057(1) 3810(1) 18(1) N(3B) 8495(1) 1439(1) 4657(1) 22(1) C(1B) 8749(1) 4072(1) 2061(1) 21(1) C(2B) 9187(2) 4725(1) 1973(2) 29(1) C(3B) 9977(2) 4672(1) 2042(2) 32(1) C(4B) 10341(1) 3971(1) 2150(2) 25(1) C(5B) 9885(1) 3336(1) 2235(1) 20(1) C(6B) 9091(1) 3365(1) 2251(1) 17(1) C(7B) 8814(1) 2560(1) 2462(1) 16(1) C(8B) 9533(1) 2080(1) 2309(1) 19(1) C(9B) 10900(1) 2317(1) 2149(2) 29(1) C(10B) 8104(1) 2283(1) 1797(1) 18(1) C(11B) 7945(1) 1441(1) 1974(1) 21(1) C(12B) 8160(1) 1753(1) 3723(1) 16(1) C(13B) 8665(1) 2476(1) 3597(1) 16(1) C(14B) 9393(1) 2339(1) 4357(1) 20(1) C(15B) 9317(1) 1506(1) 4664(1) 22(1) C(16B) 8167(1) 3112(1) 3924(1) 17(1) C(17B) 7437(1) 2860(1) 4005(1) 17(1) C(18B) 6878(1) 3355(1) 4264(1) 22(1) C(19B) 7080(1) 4112(1) 4481(1) 24(1) C(20B) 7819(2) 4353(1) 4474(1) 27(1) C(21B) 8373(1) 3854(1) 4203(1) 22(1) C(22B) 6812(1) 1614(1) 4130(1) 20(1) C(23B) 6407(1) 360(1) 4393(2) 26(1) Cl(1) 10468(1) 4314(1) 5067(1) 59(1) C(1) 9892(3) 4837(3) 5573(4) 28(1) O(1) 9448(4) 4184(4) 5213(5) 16(2) ________________________________________________________________________________ Table A2.10.3. Bond lengths [Å] and angles [°] for 77 __________________________________________________________________________________ _ Br(1A)-C(1A) 1.9116(18) O(1A)-C(8A) 1.217(2) O(2A)-C(11A) 1.430(2) O(2A)-C(12A) 1.396(2) O(3A)-C(22A) 1.204(2) O(4A)-C(22A) 1.345(2) O(4A)-C(23A) 1.443(2) N(1A)-C(5A) 1.398(2) N(1A)-C(8A) 1.370(2) N(1A)-C(9A) 1.455(2) N(2A)-C(12A) 1.496(2) N(2A)-C(17A) 1.421(2) N(2A)-C(22A) 1.376(2) N(3A)-H(3AA) 0.9200 N(3A)-H(3AB) 0.9200 N(3A)-C(12A) 1.440(2) N(3A)-C(15A) 1.475(2) C(1A)-C(2A) 1.397(3) C(1A)-C(6A) 1.385(2) C(2A)-H(2A) 0.9500 C(2A)-C(3A) 1.386(3) C(3A)-H(3A) 0.9500 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(3A)-C(4A) C(4A)-H(4A) C(4A)-C(5A) C(5A)-C(6A) C(6A)-C(7A) C(7A)-C(8A) C(7A)-C(10A) C(7A)-C(13A) C(9A)-H(9AA) C(9A)-H(9AB) C(9A)-H(9AC) C(10A)-H(10A) C(10A)-H(10B) C(10A)-C(11A) C(11A)-H(11A) C(11A)-H(11B) C(12A)-C(13A) C(13A)-C(14A) C(13A)-C(16A) C(14A)-H(14A) C(14A)-H(14B) C(14A)-C(15A) C(15A)-H(15A) C(15A)-H(15B) C(16A)-C(17A) C(16A)-C(21A) C(17A)-C(18A) C(18A)-H(18A) C(18A)-C(19A) C(19A)-H(19A) C(19A)-C(20A) C(20A)-H(20A) C(20A)-C(21A) C(21A)-H(21A) C(23A)-H(23A) C(23A)-H(23B) C(23A)-H(23C) Br(1B)-C(1B) O(1B)-C(8B) O(2B)-C(11B) O(2B)-C(12B) O(3B)-C(22B) O(4B)-C(22B) O(4B)-C(23B) N(1B)-C(5B) N(1B)-C(8B) N(1B)-C(9B) N(2B)-C(12B) N(2B)-C(17B) N(2B)-C(22B) N(3B)-H(3BA) N(3B)-H(3BB) N(3B)-C(12B) N(3B)-C(15B) C(1B)-C(2B) C(1B)-C(6B) C(2B)-H(2B) C(2B)-C(3B) 1.392(3) 0.9500 1.387(2) 1.405(2) 1.520(2) 1.543(2) 1.534(2) 1.586(3) 0.9800 0.9800 0.9800 0.9900 0.9900 1.517(2) 0.9900 0.9900 1.567(2) 1.564(2) 1.504(2) 0.9900 0.9900 1.524(3) 0.9900 0.9900 1.392(3) 1.383(2) 1.391(3) 0.9500 1.392(3) 0.9500 1.381(3) 0.9500 1.394(3) 0.9500 0.9800 0.9800 0.9800 1.906(2) 1.212(2) 1.439(2) 1.387(2) 1.212(2) 1.336(2) 1.444(2) 1.407(2) 1.368(3) 1.449(3) 1.489(3) 1.426(2) 1.379(3) 0.9200 0.9200 1.436(2) 1.456(3) 1.389(3) 1.383(3) 0.9500 1.390(3) 288   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(3B)-H(3B) C(3B)-C(4B) C(4B)-H(4B) C(4B)-C(5B) C(5B)-C(6B) C(6B)-C(7B) C(7B)-C(8B) C(7B)-C(10B) C(7B)-C(13B) C(9B)-H(9BA) C(9B)-H(9BB) C(9B)-H(9BC) C(10B)-H(10C) C(10B)-H(10D) C(10B)-C(11B) C(11B)-H(11C) C(11B)-H(11D) C(12B)-C(13B) C(13B)-C(14B) C(13B)-C(16B) C(14B)-H(14C) C(14B)-H(14D) C(14B)-C(15B) C(15B)-H(15C) C(15B)-H(15D) C(16B)-C(17B) C(16B)-C(21B) C(17B)-C(18B) C(18B)-H(18B) C(18B)-C(19B) C(19B)-H(19B) C(19B)-C(20B) C(20B)-H(20B) C(20B)-C(21B) C(21B)-H(21B) C(23B)-H(23D) C(23B)-H(23E) C(23B)-H(23F) Cl(1)-C(1)#1 Cl(1)-C(1) C(1)-Cl(1)#1 C(1)-C(1)#1 C(1)-H(1A) C(1)-H(1B) O(1)-H(1C) O(1)-H(1D) C(12A)-O(2A)-C(11A) C(22A)-O(4A)-C(23A) C(5A)-N(1A)-C(9A) C(8A)-N(1A)-C(5A) C(8A)-N(1A)-C(9A) C(17A)-N(2A)-C(12A) C(22A)-N(2A)-C(12A) C(22A)-N(2A)-C(17A) H(3AA)-N(3A)-H(3AB) C(12A)-N(3A)-H(3AA) C(12A)-N(3A)-H(3AB) 0.9500 1.380(3) 0.9500 1.381(3) 1.407(3) 1.524(3) 1.556(3) 1.532(3) 1.592(3) 0.9800 0.9800 0.9800 0.9900 0.9900 1.519(3) 0.9900 0.9900 1.567(3) 1.565(3) 1.515(3) 0.9900 0.9900 1.521(3) 0.9900 0.9900 1.379(3) 1.384(3) 1.386(3) 0.9500 1.388(3) 0.9500 1.373(3) 0.9500 1.391(3) 0.9500 0.9800 0.9800 0.9800 1.794(6) 1.581(6) 1.794(6) 1.734(10) 0.9900 0.9900 0.848(10) 0.855(10) 116.99(13) 113.72(16) 124.50(16) 111.22(14) 122.96(15) 108.96(13) 124.67(15) 121.53(16) 108.7 110.5 110.5 289   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(12A)-N(3A)-C(15A) C(15A)-N(3A)-H(3AA) C(15A)-N(3A)-H(3AB) C(2A)-C(1A)-Br(1A) C(6A)-C(1A)-Br(1A) C(6A)-C(1A)-C(2A) C(1A)-C(2A)-H(2A) C(3A)-C(2A)-C(1A) C(3A)-C(2A)-H(2A) C(2A)-C(3A)-H(3A) C(2A)-C(3A)-C(4A) C(4A)-C(3A)-H(3A) C(3A)-C(4A)-H(4A) C(5A)-C(4A)-C(3A) C(5A)-C(4A)-H(4A) N(1A)-C(5A)-C(6A) C(4A)-C(5A)-N(1A) C(4A)-C(5A)-C(6A) C(1A)-C(6A)-C(5A) C(1A)-C(6A)-C(7A) C(5A)-C(6A)-C(7A) C(6A)-C(7A)-C(8A) C(6A)-C(7A)-C(10A) C(6A)-C(7A)-C(13A) C(8A)-C(7A)-C(13A) C(10A)-C(7A)-C(8A) C(10A)-C(7A)-C(13A) O(1A)-C(8A)-N(1A) O(1A)-C(8A)-C(7A) N(1A)-C(8A)-C(7A) N(1A)-C(9A)-H(9AA) N(1A)-C(9A)-H(9AB) N(1A)-C(9A)-H(9AC) H(9AA)-C(9A)-H(9AB) H(9AA)-C(9A)-H(9AC) H(9AB)-C(9A)-H(9AC) C(7A)-C(10A)-H(10A) C(7A)-C(10A)-H(10B) H(10A)-C(10A)-H(10B) C(11A)-C(10A)-C(7A) C(11A)-C(10A)-H(10A) C(11A)-C(10A)-H(10B) O(2A)-C(11A)-C(10A) O(2A)-C(11A)-H(11A) O(2A)-C(11A)-H(11B) C(10A)-C(11A)-H(11A) C(10A)-C(11A)-H(11B) H(11A)-C(11A)-H(11B) O(2A)-C(12A)-N(2A) O(2A)-C(12A)-N(3A) O(2A)-C(12A)-C(13A) N(2A)-C(12A)-C(13A) N(3A)-C(12A)-N(2A) N(3A)-C(12A)-C(13A) C(12A)-C(13A)-C(7A) C(14A)-C(13A)-C(7A) C(14A)-C(13A)-C(12A) C(16A)-C(13A)-C(7A) 106.25(15) 110.5 110.5 115.20(13) 123.47(13) 121.29(17) 120.1 119.89(17) 120.1 119.5 120.96(17) 119.5 121.5 117.09(17) 121.5 109.47(15) 126.49(17) 123.99(16) 116.32(16) 135.22(16) 108.41(14) 101.00(14) 113.54(14) 112.66(14) 108.40(14) 112.28(14) 108.74(14) 124.26(16) 127.54(16) 108.13(14) 109.5 109.5 109.5 109.5 109.5 109.5 109.0 109.0 107.8 113.14(14) 109.0 109.0 113.43(14) 108.9 108.9 108.9 108.9 107.7 112.12(14) 108.01(14) 115.79(15) 104.45(13) 111.50(16) 104.77(14) 110.33(14) 115.73(14) 103.34(13) 112.41(14) 290   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(16A)-C(13A)-C(12A) C(16A)-C(13A)-C(14A) C(13A)-C(14A)-H(14A) C(13A)-C(14A)-H(14B) H(14A)-C(14A)-H(14B) C(15A)-C(14A)-C(13A) C(15A)-C(14A)-H(14A) C(15A)-C(14A)-H(14B) N(3A)-C(15A)-C(14A) N(3A)-C(15A)-H(15A) N(3A)-C(15A)-H(15B) C(14A)-C(15A)-H(15A) C(14A)-C(15A)-H(15B) H(15A)-C(15A)-H(15B) C(17A)-C(16A)-C(13A) C(21A)-C(16A)-C(13A) C(21A)-C(16A)-C(17A) C(16A)-C(17A)-N(2A) C(18A)-C(17A)-N(2A) C(18A)-C(17A)-C(16A) C(17A)-C(18A)-H(18A) C(17A)-C(18A)-C(19A) C(19A)-C(18A)-H(18A) C(18A)-C(19A)-H(19A) C(20A)-C(19A)-C(18A) C(20A)-C(19A)-H(19A) C(19A)-C(20A)-H(20A) C(19A)-C(20A)-C(21A) C(21A)-C(20A)-H(20A) C(16A)-C(21A)-C(20A) C(16A)-C(21A)-H(21A) C(20A)-C(21A)-H(21A) O(3A)-C(22A)-O(4A) O(3A)-C(22A)-N(2A) O(4A)-C(22A)-N(2A) O(4A)-C(23A)-H(23A) O(4A)-C(23A)-H(23B) O(4A)-C(23A)-H(23C) H(23A)-C(23A)-H(23B) H(23A)-C(23A)-H(23C) H(23B)-C(23A)-H(23C) C(12B)-O(2B)-C(11B) C(22B)-O(4B)-C(23B) C(5B)-N(1B)-C(9B) C(8B)-N(1B)-C(5B) C(8B)-N(1B)-C(9B) C(17B)-N(2B)-C(12B) C(22B)-N(2B)-C(12B) C(22B)-N(2B)-C(17B) H(3BA)-N(3B)-H(3BB) C(12B)-N(3B)-H(3BA) C(12B)-N(3B)-H(3BB) C(12B)-N(3B)-C(15B) C(15B)-N(3B)-H(3BA) C(15B)-N(3B)-H(3BB) C(2B)-C(1B)-Br(1B) C(6B)-C(1B)-Br(1B) C(6B)-C(1B)-C(2B) 102.11(14) 111.64(14) 110.8 110.8 108.8 104.90(14) 110.8 110.8 102.31(14) 111.3 111.3 111.3 111.3 109.2 111.31(15) 128.41(16) 120.22(17) 109.75(15) 129.11(17) 121.06(17) 121.1 117.73(18) 121.1 119.1 121.80(18) 119.1 120.1 119.74(18) 120.1 119.37(18) 120.3 120.3 123.93(18) 125.17(18) 110.89(17) 109.5 109.5 109.5 109.5 109.5 109.5 116.97(14) 114.79(16) 125.24(17) 110.68(17) 123.67(17) 108.85(16) 122.68(15) 121.78(16) 108.6 110.5 110.5 106.38(15) 110.5 110.5 116.23(17) 122.96(16) 120.8(2) 291   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(1B)-C(2B)-H(2B) C(1B)-C(2B)-C(3B) C(3B)-C(2B)-H(2B) C(2B)-C(3B)-H(3B) C(4B)-C(3B)-C(2B) C(4B)-C(3B)-H(3B) C(3B)-C(4B)-H(4B) C(3B)-C(4B)-C(5B) C(5B)-C(4B)-H(4B) C(4B)-C(5B)-N(1B) C(4B)-C(5B)-C(6B) C(6B)-C(5B)-N(1B) C(1B)-C(6B)-C(5B) C(1B)-C(6B)-C(7B) C(5B)-C(6B)-C(7B) C(6B)-C(7B)-C(8B) C(6B)-C(7B)-C(10B) C(6B)-C(7B)-C(13B) C(8B)-C(7B)-C(13B) C(10B)-C(7B)-C(8B) C(10B)-C(7B)-C(13B) O(1B)-C(8B)-N(1B) O(1B)-C(8B)-C(7B) N(1B)-C(8B)-C(7B) N(1B)-C(9B)-H(9BA) N(1B)-C(9B)-H(9BB) N(1B)-C(9B)-H(9BC) H(9BA)-C(9B)-H(9BB) H(9BA)-C(9B)-H(9BC) H(9BB)-C(9B)-H(9BC) C(7B)-C(10B)-H(10C) C(7B)-C(10B)-H(10D) H(10C)-C(10B)-H(10D) C(11B)-C(10B)-C(7B) C(11B)-C(10B)-H(10C) C(11B)-C(10B)-H(10D) O(2B)-C(11B)-C(10B) O(2B)-C(11B)-H(11C) O(2B)-C(11B)-H(11D) C(10B)-C(11B)-H(11C) C(10B)-C(11B)-H(11D) H(11C)-C(11B)-H(11D) O(2B)-C(12B)-N(2B) O(2B)-C(12B)-N(3B) O(2B)-C(12B)-C(13B) N(2B)-C(12B)-C(13B) N(3B)-C(12B)-N(2B) N(3B)-C(12B)-C(13B) C(12B)-C(13B)-C(7B) C(14B)-C(13B)-C(7B) C(14B)-C(13B)-C(12B) C(16B)-C(13B)-C(7B) C(16B)-C(13B)-C(12B) C(16B)-C(13B)-C(14B) C(13B)-C(14B)-H(14C) C(13B)-C(14B)-H(14D) H(14C)-C(14B)-H(14D) C(15B)-C(14B)-C(13B) 119.9 120.3(2) 119.9 119.5 121.1(2) 119.5 121.6 116.8(2) 121.6 125.6(2) 124.3(2) 110.01(17) 116.31(18) 135.46(19) 108.21(16) 100.70(15) 116.13(16) 110.98(15) 108.03(15) 112.10(15) 108.51(16) 123.69(19) 127.66(19) 108.63(16) 109.5 109.5 109.5 109.5 109.5 109.5 109.3 109.3 108.0 111.50(16) 109.3 109.3 113.68(15) 108.8 108.8 108.8 108.8 107.7 112.64(16) 109.16(15) 115.73(15) 105.33(14) 110.71(15) 102.81(16) 109.92(15) 115.40(16) 103.86(15) 112.48(15) 101.45(16) 112.39(15) 111.1 111.1 109.0 103.47(16) 292   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(15B)-C(14B)-H(14C) C(15B)-C(14B)-H(14D) N(3B)-C(15B)-C(14B) N(3B)-C(15B)-H(15C) N(3B)-C(15B)-H(15D) C(14B)-C(15B)-H(15C) C(14B)-C(15B)-H(15D) H(15C)-C(15B)-H(15D) C(17B)-C(16B)-C(13B) C(17B)-C(16B)-C(21B) C(21B)-C(16B)-C(13B) C(16B)-C(17B)-N(2B) C(16B)-C(17B)-C(18B) C(18B)-C(17B)-N(2B) C(17B)-C(18B)-H(18B) C(17B)-C(18B)-C(19B) C(19B)-C(18B)-H(18B) C(18B)-C(19B)-H(19B) C(20B)-C(19B)-C(18B) C(20B)-C(19B)-H(19B) C(19B)-C(20B)-H(20B) C(19B)-C(20B)-C(21B) C(21B)-C(20B)-H(20B) C(16B)-C(21B)-C(20B) C(16B)-C(21B)-H(21B) C(20B)-C(21B)-H(21B) O(3B)-C(22B)-O(4B) O(3B)-C(22B)-N(2B) O(4B)-C(22B)-N(2B) O(4B)-C(23B)-H(23D) O(4B)-C(23B)-H(23E) O(4B)-C(23B)-H(23F) H(23D)-C(23B)-H(23E) H(23D)-C(23B)-H(23F) H(23E)-C(23B)-H(23F) C(1)-Cl(1)-C(1)#1 Cl(1)-C(1)-Cl(1)#1 Cl(1)-C(1)-C(1)#1 Cl(1)#1-C(1)-H(1A) Cl(1)-C(1)-H(1A) Cl(1)#1-C(1)-H(1B) Cl(1)-C(1)-H(1B) C(1)#1-C(1)-Cl(1)#1 C(1)#1-C(1)-H(1A) C(1)#1-C(1)-H(1B) H(1A)-C(1)-H(1B) H(1C)-O(1)-H(1D) 293   111.1 111.1 101.24(16) 111.5 111.5 111.5 111.5 109.3 111.82(16) 119.68(18) 128.31(19) 109.92(17) 121.42(18) 128.6(2) 120.9 118.2(2) 120.9 119.7 120.7(2) 119.7 119.7 120.6(2) 119.7 119.0(2) 120.5 120.5 124.24(19) 124.87(18) 110.89(17) 109.5 109.5 109.5 109.5 109.5 109.5 61.5(3) 118.5(3) 65.3(3) 92.2 117.2 92.2 117.2 53.2(3) 117.2 117.2 114.2 100(2) __________________________________________________________________________________ _ Symmetry transformations used to generate equivalent atoms: #1 +2 2 4 Table A2.10.4. Anisotropic displacement parameters (Å x 10 ) for 77. The anisotropic 2 2 2 11 12 displacement factor exponent takes the form: -2π [ h a* U + ... + 2 h k a* b* U ] ______________________________________________________________________________ 11 22 33 23 13 12 U U U U U U Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 ______________________________________________________________________________ Br(1A) 221(1) 127(1) 183(1) -63(1) 55(1) -12(1) O(1A) 226(8) 99(6) 216(7) -16(5) 81(6) 8(5) O(2A) 139(7) 115(6) 164(6) 11(5) 19(5) -6(5) O(3A) 290(10) 282(8) 321(8) -16(7) 201(7) 27(7) O(4A) 256(9) 212(7) 285(8) 29(6) 150(7) -49(6) N(1A) 159(9) 123(7) 149(7) -7(6) 77(6) 14(6) N(2A) 144(9) 142(7) 154(7) -18(6) 62(6) 2(6) N(3A) 158(9) 142(7) 200(8) -24(6) 14(7) -6(6) C(1A) 142(10) 127(8) 156(9) 4(7) 41(7) 3(7) C(2A) 203(11) 111(8) 217(10) 13(7) 19(8) -21(7) C(3A) 203(11) 161(9) 228(10) 62(7) 36(8) -51(8) C(4A) 171(11) 184(9) 168(9) 36(7) 51(8) -15(8) C(5A) 139(10) 128(8) 145(8) 6(7) 19(7) -5(7) C(6A) 128(10) 105(7) 117(8) 8(6) 28(7) 2(7) C(7A) 130(9) 72(7) 121(8) -10(6) 38(7) -4(6) C(8A) 133(10) 128(8) 123(8) -12(6) 24(7) 2(7) C(9A) 182(11) 221(9) 193(9) -12(8) 97(8) 53(8) C(10A) 157(10) 124(8) 108(8) 1(6) 43(7) -5(7) C(11A) 175(11) 157(8) 138(8) 24(7) 28(7) -15(7) C(12A) 134(10) 115(8) 133(8) -11(6) 34(7) -10(7) C(13A) 148(10) 93(7) 95(8) -7(6) 29(7) 4(7) C(14A) 183(11) 154(8) 111(8) -14(7) 21(7) 2(7) C(15A) 242(12) 181(9) 163(9) -55(7) 21(8) -19(8) C(16A) 133(10) 112(8) 115(8) -30(6) 4(7) 4(7) C(17A) 122(10) 152(8) 145(8) -37(7) -6(7) 2(7) C(18A) 139(10) 209(9) 200(9) -67(8) 29(8) 22(8) C(19A) 212(11) 161(9) 252(10) -74(8) -15(8) 65(8) C(20A) 245(12) 132(9) 218(10) -1(7) -30(8) 31(8) C(21A) 192(11) 156(8) 136(9) -8(7) 5(7) 16(7) C(22A) 184(11) 236(10) 159(9) -2(8) 20(8) -43(8) C(23A) 339(15) 331(12) 380(13) 62(11) 178(11) -93(11) Br(1B) 308(1) 227(1) 224(1) 10(1) 22(1) 96(1) O(1B) 288(10) 184(7) 394(9) 21(6) 144(7) 48(6) O(2B) 263(9) 140(6) 210(7) -28(5) 91(6) 7(6) O(3B) 227(9) 276(8) 397(9) -11(7) 150(7) 15(7) O(4B) 265(9) 159(6) 294(8) 25(6) 131(6) -22(6) N(1B) 177(10) 212(8) 205(8) 5(7) 71(7) 0(7) N(2B) 208(10) 138(7) 212(8) 9(6) 101(7) 7(7) N(3B) 275(11) 186(8) 198(8) 31(7) 82(7) 36(7) C(1B) 251(12) 227(10) 161(9) -3(8) 43(8) 4(9) C(2B) 490(17) 152(9) 240(11) 7(8) 77(10) -23(10) C(3B) 484(17) 207(10) 272(12) -32(9) 97(11) -143(10) C(4B) 272(13) 276(11) 204(10) -27(8) 56(9) -99(9) C(5B) 255(12) 200(9) 141(9) 5(7) 53(8) -31(8) C(6B) 201(11) 162(9) 144(9) 5(7) 36(8) -17(8) C(7B) 174(11) 140(8) 179(9) 0(7) 56(8) 6(7) C(8B) 201(12) 211(10) 174(9) 19(8) 62(8) 7(8) C(9B) 167(12) 343(12) 381(13) 2(10) 67(10) -1(10) C(10B) 209(12) 199(9) 137(9) 7(7) 51(8) 2(8) C(11B) 239(12) 188(9) 199(10) -38(8) 21(8) -20(8) C(12B) 180(11) 136(8) 181(9) 3(7) 51(8) 11(7) C(13B) 181(11) 139(8) 179(9) 0(7) 40(8) -6(7) C(14B) 193(12) 226(10) 192(10) -22(8) 29(8) -2(8) C(15B) 241(12) 227(10) 178(10) 31(8) 17(8) 70(9) C(16B) 208(11) 161(9) 150(9) 4(7) 26(8) 22(8) C(17B) 262(12) 146(8) 111(8) 13(7) 35(8) 46(8) C(18B) 279(13) 227(10) 166(9) 1(8) 78(9) 72(9) 294   295   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(19B) 342(14) 211(10) 178(9) -17(8) 36(9) 85(9) C(20B) 470(16) 174(9) 162(10) -35(8) 25(10) 54(9) C(21B) 305(14) 189(9) 178(10) -7(8) 42(9) 3(9) C(22B) 228(12) 216(10) 176(9) 2(8) 63(8) -3(8) C(23B) 267(13) 225(10) 294(11) 39(9) 105(9) -90(9) Cl(1) 275(5) 605(6) 881(8) 237(5) 39(5) -52(4) C(1) 240(30) 410(30) 190(20) -110(20) 40(20) -110(30) ______________________________________________________________________________ 3 2 Table A2.10.5. Hydrogen coordinates ( x 10 ) and isotropic displacement parameters (Å x 3 10 ) for 77 ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(3AA) H(3AB) H(2A) H(3A) H(4A) H(9AA) H(9AB) H(9AC) H(10A) H(10B) H(11A) H(11B) H(14A) H(14B) H(15A) H(15B) H(18A) H(19A) H(20A) H(21A) H(23A) H(23B) H(23C) H(3BA) H(3BB) H(2B) H(3B) H(4B) H(9BA) H(9BB) H(9BC) H(10C) H(10D) H(11C) H(11D) H(14C) H(14D) H(15C) H(15D) H(18B) H(19B) H(20B) 216 245 514 581 594 632 565 583 496 413 455 392 306 389 269 342 184 190 265 342 170 166 107 836 834 895 1027 1088 1094 1127 1101 766 818 739 823 986 940 951 959 637 670 795 162 86 496 470 343 204 191 127 225 260 105 144 240 201 114 85 349 466 481 379 97 21 89 93 171 521 513 393 176 258 244 259 236 134 113 242 269 115 141 318 447 487 243 281 324 189 135 173 84 169 472 472 470 530 129 142 112 186 448 364 236 193 588 521 493 471 518 186 202 216 225 264 147 194 109 179 153 404 494 418 534 429 464 466 20 20 21 24 21 29 29 29 15 15 19 19 18 18 23 23 22 25 24 19 51 51 51 26 26 35 38 30 44 44 44 22 22 25 25 24 24 26 26 26 29 32 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 296   H(21B) 889 402 421 27 H(23D) 627 53 504 38 H(23E) 661 -16 446 38 H(23F) 596 37 390 38 H(1A) 1010 513 617 33 H(1B) 937 463 560 33 H(1C) 993(1) 423(6) 536(7) 24 H(1D) 929(5) 441(5) 572(5) 24 ________________________________________________________________________________ Table A2.10.6. Hydrogen bonds for 77 [Å and °] ____________________________________________________________________ ________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________ ________ N(3A)-H(3AB)...Br(1B)#2 0.92 2.92 3.8165(15) 164.2 N(3B)-H(3BB)...Br(1B)#3 0.92 3.11 3.6325(16) 118.2 C(9B)-H(9BC)...O(3A)#4 0.98 2.46 3.406(3) 163.4 C(15B)-H(15C)...O(1B) 0.99 2.65 3.346(2) 127.8 C(23B)-H(23F)...O(1A) 0.98 2.62 3.510(3) 151.5 ____________________________________________________________________ ________ Symmetry transformations used to generate equivalent atoms: #1 +2 #2 +1 #3 #4 +1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.11. X-Ray Crystal Structure Analysis of 94 Ts H N N N H Ts 94 Figure A2.11.1. X-ray Crystal Structure of 94 Table A2.11.1. Crystal data and structure refinement for 94 Empirical formula C37 H39 N3 O4 S2 Formula weight 653.83 Crystallization Solvent ???Solvent??? Crystal Habit Fragment Crystal size 0.25 x 0.24 x 0.17 mm3 Crystal color Colorless Data Collection Preliminary Photos Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoK〈 Data Collection Temperature 100(2) K 297   298   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 ⎝ range for 8943 reflections used in lattice determination 2.22 to 27.43° Unit cell dimensions a = 15.5078(13) Å b = 11.2221(10) Å c = 18.4268(16) Å Volume 3195.9(5) Å3 Z 4 Crystal system Monoclinic Space group P2(1)/n Density (calculated) 1.359 Mg/m3 F(000) 1384 Data collection program Bruker SMART v5.630 ⎝ range for data collection 1.65 to 28.34° Completeness to ⎝ = 28.34° 94.1 % Index ranges -20<=h<=20, -14<=k<=14, -24<=l<=24 Data collection scan type scans at 5 settings   Data  reduction  program     Bruker  SAINT  v6.45A   Reflections  collected   44083   Independent  reflections   7500  [Rint=  0.1020]   Absorption  coefficient   0.213  mm-­‐1   Absorption  correction   None   Max.  and  min.  transmission   0.9647  and  0.9487   Number  of  standards     ?  reflections  measured  every  ?min.     Variation  of  standards     ?%.     Structure solution and Refinement Structure solution program SHELXS-97 (Sheldrick, 1990) Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program SHELXL-97 (Sheldrick, 1997) Refinement method Full matrix least-squares on F2 Data / restraints / parameters 7500 / 0 / 420 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.394 Final R indices [I>2⌠(I), 4434 reflections] R1 = 0.0531, wR2 = 0.0888 R indices (all data) R1 = 0.0982, wR2 = 0.0932 Type of weighting scheme used Sigma Weighting scheme used w=1/s^2^(Fo^2^) Max shift/error 0.001 〈= 90° ®= 94.7250(10)° © = 90° Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Average shift/error 0.000 Absolute structure determination ? Largest diff. peak and hole 0.629 and -0.498 e.Å-3 299   Special Refinement Details Table A2.11.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 94. U(eq) is defined as the trace of the orthogonalized Uij tensor ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ S(1) 7430(1) 6065(1) 847(1) 26(1) S(2) 7110(1) 2404(1) -2197(1) 26(1) O(1) 7087(1) 5440(1) 1441(1) 30(1) O(2) 6897(1) 6283(1) 191(1) 31(1) O(3) 7723(1) 2951(1) -2627(1) 31(1) O(4) 6624(1) 1390(1) -2471(1) 30(1) N(1) 8248(1) 5286(2) 622(1) 21(1) N(2) 7649(1) 1964(2) -1428(1) 20(1) N(3) 9053(1) 1794(2) -836(1) 25(1) C(1) 7803(1) 7460(2) 1173(1) 24(1) C(2) 7883(2) 8387(2) 687(1) 29(1) C(3) 8173(2) 9490(2) 943(1) 33(1) C(4) 8386(2) 9698(2) 1672(1) 31(1) C(5) 8312(2) 8744(2) 2161(1) 29(1) C(6) 8016(1) 7645(2) 1910(1) 27(1) C(7) 8701(2) 10883(2) 1936(2) 46(1) C(8) 8655(1) 5616(2) -41(1) 24(1) C(9) 8357(2) 4792(2) -673(1) 22(1) C(10) 8247(1) 3487(2) -452(1) 20(1) C(11) 8970(1) 3097(2) 114(1) 18(1) C(12) 9226(1) 3566(2) 796(1) 21(1) C(13) 8757(1) 4558(2) 1172(1) 22(1) C(14) 9352(1) 5326(2) 1652(1) 25(1) C(15) 9436(2) 5322(2) 2377(1) 28(1) C(16) 10029(2) 6186(2) 2792(1) 40(1) C(17) 8968(2) 4500(2) 2843(1) 39(1) C(18) 9956(1) 3058(2) 1182(1) 24(1) C(19) 10392(1) 2119(2) 898(1) 23(1) C(20) 10133(1) 1653(2) 218(1) 22(1) C(21) 9429(1) 2138(2) -162(1) 17(1) C(22) 8404(1) 2657(2) -1116(1) 22(1) C(23) 7170(1) 1365(2) -902(1) 22(1) C(24) 6883(2) 213(2) -1018(1) 27(1) C(25) 6385(2) -308(2) -509(1) 35(1) C(26) 6207(2) 313(2) 108(1) 33(1) C(27) 6542(2) 1444(2) 235(1) 26(1) C(28) 7023(1) 1991(2) -273(1) 20(1) C(29) 7332(1) 3253(2) -188(1) 21(1) C(30) 9532(2) 1163(2) -1354(1) 31(1) C(31) 6376(2) 3476(2) -1938(1) 23(1) C(32) 6582(2) 4681(2) -1968(1) 27(1) C(33) 6067(2) 5512(2) -1643(1) 27(1) C(34) 5362(2) 5159(2) -1284(1) 29(1) C(35) 5149(2) 3940(2) -1281(1) 30(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 300   C(36) 5649(2) 3115(2) -1606(1) 29(1) C(37) 4847(2) 6041(2) -885(1) 37(1) ________________________________________________________________________________ Table A2.11.3. Bond lengths [Å] and angles [°] for 94 _____________________________________________________ S(1)-O(2) 1.4297(15) S(1)-O(1) 1.4381(16) S(1)-N(1) 1.6227(18) S(1)-C(1) 1.757(2) S(2)-O(3) 1.4257(16) S(2)-O(4) 1.4330(16) S(2)-N(2) 1.6596(18) S(2)-C(31) 1.750(2) N(1)-C(8) 1.468(3) N(1)-C(13) 1.479(3) N(2)-C(23) 1.437(3) N(2)-C(22) 1.482(3) N(3)-C(21) 1.383(3) N(3)-C(30) 1.443(3) N(3)-C(22) 1.460(3) C(1)-C(2) 1.385(3) C(1)-C(6) 1.387(3) C(2)-C(3) 1.387(3) C(3)-C(4) 1.376(3) C(4)-C(5) 1.409(3) C(4)-C(7) 1.485(3) C(5)-C(6) 1.382(3) C(8)-C(9) 1.527(3) C(9)-C(10) 1.533(3) C(10)-C(11) 1.531(3) C(10)-C(29) 1.559(3) C(10)-C(22) 1.573(3) C(11)-C(12) 1.391(3) C(11)-C(21) 1.407(3) C(12)-C(18) 1.406(3) C(12)-C(13) 1.527(3) C(13)-C(14) 1.497(3) C(14)-C(15) 1.331(3) C(15)-C(17) 1.490(3) C(15)-C(16) 1.501(3) C(18)-C(19) 1.379(3) C(19)-C(20) 1.386(3) C(20)-C(21) 1.362(3) C(23)-C(24) 1.378(3) C(23)-C(28) 1.390(3) C(24)-C(25) 1.391(3) C(25)-C(26) 1.380(3) C(26)-C(27) 1.384(3) C(27)-C(28) 1.387(3) C(28)-C(29) 1.498(3) C(31)-C(36) 1.386(3) C(31)-C(32) 1.391(3) C(32)-C(33) 1.395(3) C(33)-C(34) 1.381(3) C(34)-C(35) 1.408(3) C(34)-C(37) 1.501(3) C(35)-C(36) 1.375(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(2)-S(1)-O(1) O(2)-S(1)-N(1) O(1)-S(1)-N(1) O(2)-S(1)-C(1) O(1)-S(1)-C(1) N(1)-S(1)-C(1) O(3)-S(2)-O(4) O(3)-S(2)-N(2) O(4)-S(2)-N(2) O(3)-S(2)-C(31) O(4)-S(2)-C(31) N(2)-S(2)-C(31) C(8)-N(1)-C(13) C(8)-N(1)-S(1) C(13)-N(1)-S(1) C(23)-N(2)-C(22) C(23)-N(2)-S(2) C(22)-N(2)-S(2) C(21)-N(3)-C(30) C(21)-N(3)-C(22) C(30)-N(3)-C(22) C(2)-C(1)-C(6) C(2)-C(1)-S(1) C(6)-C(1)-S(1) C(1)-C(2)-C(3) C(4)-C(3)-C(2) C(3)-C(4)-C(5) C(3)-C(4)-C(7) C(5)-C(4)-C(7) C(6)-C(5)-C(4) C(5)-C(6)-C(1) N(1)-C(8)-C(9) C(8)-C(9)-C(10) C(11)-C(10)-C(9) C(11)-C(10)-C(29) C(9)-C(10)-C(29) C(11)-C(10)-C(22) C(9)-C(10)-C(22) C(29)-C(10)-C(22) C(12)-C(11)-C(21) C(12)-C(11)-C(10) C(21)-C(11)-C(10) C(11)-C(12)-C(18) C(11)-C(12)-C(13) C(18)-C(12)-C(13) N(1)-C(13)-C(14) N(1)-C(13)-C(12) C(14)-C(13)-C(12) C(15)-C(14)-C(13) C(14)-C(15)-C(17) C(14)-C(15)-C(16) C(17)-C(15)-C(16) C(19)-C(18)-C(12) C(18)-C(19)-C(20) C(21)-C(20)-C(19) C(20)-C(21)-N(3) C(20)-C(21)-C(11) 120.13(10) 106.61(9) 106.12(9) 106.75(10) 107.87(10) 109.02(10) 120.13(10) 106.90(10) 106.10(9) 109.52(11) 107.86(11) 105.34(10) 117.95(18) 118.38(15) 120.44(15) 114.75(17) 117.62(15) 120.12(15) 121.98(19) 111.09(17) 117.99(18) 119.6(2) 119.49(18) 120.90(18) 119.6(2) 121.9(2) 118.0(2) 121.2(2) 120.8(2) 120.5(2) 120.4(2) 110.94(18) 114.14(18) 111.28(17) 112.00(18) 111.58(18) 102.01(17) 109.37(18) 110.18(17) 120.0(2) 130.2(2) 109.72(18) 117.4(2) 125.12(19) 117.4(2) 110.77(18) 109.80(17) 113.23(18) 126.6(2) 124.6(2) 120.9(2) 114.5(2) 121.2(2) 121.1(2) 118.3(2) 127.6(2) 121.9(2) 301   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 N(3)-C(21)-C(11) 110.44(19) N(3)-C(22)-N(2) 106.80(17) N(3)-C(22)-C(10) 105.32(17) N(2)-C(22)-C(10) 116.47(18) C(24)-C(23)-C(28) 122.0(2) C(24)-C(23)-N(2) 120.8(2) C(28)-C(23)-N(2) 117.1(2) C(23)-C(24)-C(25) 118.7(2) C(26)-C(25)-C(24) 120.2(2) C(25)-C(26)-C(27) 120.3(2) C(26)-C(27)-C(28) 120.4(2) C(27)-C(28)-C(23) 118.2(2) C(27)-C(28)-C(29) 122.2(2) C(23)-C(28)-C(29) 119.5(2) C(28)-C(29)-C(10) 114.72(18) C(36)-C(31)-C(32) 120.0(2) C(36)-C(31)-S(2) 119.38(19) C(32)-C(31)-S(2) 120.01(18) C(31)-C(32)-C(33) 119.4(2) C(34)-C(33)-C(32) 121.2(2) C(33)-C(34)-C(35) 118.4(2) C(33)-C(34)-C(37) 121.3(2) C(35)-C(34)-C(37) 120.3(2) C(36)-C(35)-C(34) 120.8(2) C(35)-C(36)-C(31) 120.2(2) _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.11.4. Anisotropic displacement parameters (Å2x 104 ) for 94. The anisotropic displacement factor exponent takes the form: -2ð2 [ h2 a*2U 11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ S(1) 189(3) 284(4) 294(4) -20(3) 14(3) 21(3) S(2) 246(3) 321(4) 197(3) 2(3) -38(3) 18(3) O(1) 246(10) 297(10) 350(10) -9(8) 77(8) -2(8) O(2) 229(10) 365(11) 334(10) -4(8) -69(8) 60(8) O(3) 337(11) 387(11) 202(9) 68(8) 65(8) 12(8) O(4) 281(10) 335(10) 266(10) -58(8) -110(8) -5(8) N(1) 193(11) 241(11) 202(11) -2(9) 2(9) 7(9) N(2) 195(11) 252(11) 158(10) 20(8) -18(8) -7(9) N(3) 203(11) 288(12) 255(12) -58(9) -4(9) 60(9) C(1) 175(13) 266(14) 284(14) 12(12) 26(11) 57(11) C(2) 272(15) 297(15) 290(15) -13(12) 22(12) 94(12) C(3) 293(15) 290(16) 409(17) 75(13) 106(13) 77(13) C(4) 218(14) 308(15) 429(17) -103(13) 133(12) -2(12) C(5) 299(15) 327(16) 252(14) -62(12) 57(12) 6(12) C(6) 253(14) 272(15) 285(14) 31(12) 75(11) 67(12) C(7) 497(19) 324(17) 580(20) -79(14) 231(16) -43(14) C(8) 179(13) 249(14) 281(14) 19(11) 8(11) 3(11) C(9) 186(13) 272(14) 211(13) 14(11) -2(10) 3(11) C(10) 177(13) 242(14) 187(13) -22(10) -11(10) -10(11) C(11) 128(12) 221(13) 198(13) 13(10) 4(10) -22(10) C(12) 170(13) 222(13) 224(13) 47(11) 22(10) -17(11) C(13) 214(13) 235(13) 194(13) 6(11) 1(10) 10(11) C(14) 187(13) 269(14) 294(15) -11(12) 14(11) 18(11) C(15) 207(14) 332(15) 300(15) -54(12) -47(12) 101(12) 302   Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(16) 389(17) 484(18) 316(15) -121(14) -89(13) 67(14) C(17) 384(17) 587(19) 206(14) -17(13) 4(12) 30(15) C(18) 224(14) 250(14) 223(13) 18(11) -25(11) -24(11) C(19) 197(13) 253(14) 243(14) 30(11) -17(11) 28(11) C(20) 204(13) 175(13) 280(14) -29(11) 41(11) -15(11) C(21) 152(12) 187(13) 181(12) -39(10) 8(10) -62(10) C(22) 182(13) 276(14) 214(13) -28(11) 8(10) -33(11) C(23) 146(13) 270(14) 228(14) 45(11) -52(10) -26(11) C(24) 264(14) 283(15) 250(14) -21(12) -77(11) -23(12) C(25) 365(16) 307(15) 340(16) 57(13) -107(13) -127(13) C(26) 277(15) 454(17) 268(15) 84(13) -10(12) -111(13) C(27) 217(14) 366(16) 204(13) 34(12) -9(11) 16(12) C(28) 128(12) 245(14) 216(13) 33(11) -66(10) -4(10) C(29) 163(13) 255(14) 220(13) -6(11) 0(10) 21(11) C(30) 312(15) 320(15) 287(15) -39(12) 5(12) 88(12) C(31) 189(13) 308(15) 185(13) 30(11) -42(10) 26(11) C(32) 269(15) 350(16) 178(13) 75(12) -11(11) 1(13) C(33) 279(15) 293(15) 213(13) 90(11) -58(11) 28(12) C(34) 198(14) 354(16) 286(14) 25(12) -81(11) 83(12) C(35) 148(13) 412(17) 345(15) 48(13) 11(11) 14(13) C(36) 217(14) 303(15) 324(15) 21(12) -69(12) -12(12) C(37) 281(15) 370(16) 443(17) 52(13) 17(13) 61(13) ______________________________________________________________________________ 303   304   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F APPENDIX 3 Synthetic Studies Toward the Total Synthesis of Communesin F A3.1. Direct Lactam-Forming Strategy Having successfully completed our formal synthesis of communesin F (1f) and perophoramidine (3), our attention turned to a total synthesis of communesin F (1f). We envisioned that direct lactamization of malonate 101 would afford allyl ester 102, which could be a potential precursor toward the efficient synthesis of communesin F (1f) (Scheme A3.1.1). Since lactonization of diester 60 afforded lactone 61 as a single diastereomer (Scheme 1.2.13, 60 → 61), we believed that the diastereomer needed for elaboration to communesin F (1f) could be selectively formed by lactamization of malonate 101. Scheme A3.1.1. Direct Lactam-Forming Strategy Toward Communesin F (1f) O H N H 2N NO 2 CO2Allyl Br CO2Allyl O N 101 O Br CO2Allyl N H N O NO N 2 N 102 Communesin F (1f) N H H 305   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F To examine diastereoselective lactam formation, we chose phthalimide 103 as a model substrate. Interestingly, an attempt to remove the phthalyl protecting group and simultaneously construct lactam 104 from malonate 103 furnished a 9:1 diastereomeric mixture of 105 (Scheme A3.1.2a). The double bonds of the allyl groups were reduced and one of the resultant propyl esters was transferred to the amine. Treatment of phthalimide 103 with methylamine generated the desired amine 106 (Scheme A3.1.2b). Despite extensive screening of Lewis acids, acids, and bases (e.g., AlMe3, KOt-Bu, pTsOH), lactamization of malonate 106 proved to be challenging. Scheme A3.1.2. Attempted Lactam-Forming Reactions (a) Br H N PhthN NO 2 CO2Allyl CO2Allyl O O NH 2NH 2•H 2O CO2Allyl EtOH, H 2O, 80 oC O NO N Br 2 N 103 104 (Not Observed) O O NH 2NH 2•H 2O NH O O N O O2N EtOH, H 2O, 80 oC (92% yield) Br 105 (9:1 mixture of diastereomers) (b) Br Br H N PhthN NO 2 CO2Allyl CO2Allyl O MeNH 2 in EtOH H 2N (98% yield) NO 2 CO2Allyl Lewis acids CO2Allyl O or bases N N 103 106 O CO2Allyl O NO N 2 Br 104 (Not Observed) 306   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F A3.2. Diels–Alder Strategy Next, we investigated a Diels–Alder strategy toward the total synthesis of communesin F (1f). As described in Schemes A3.2.1a and 1.2.5, the benzisoxazole in 19 and 22 reacted with the butenyl side chain by an intramolecular Diels–Alder cycloaddtion to afford the undesired bridged polycycles 24 and 23, respectively. We expected that the desired core structure could be constructed via an intramolecular Diels–Alder reaction with substrates, which possess no butenyl side chain (Scheme A3.2.1b). Scheme A3.2.1. Diels–Alder Strategy Toward Communesin F (1f) (a) O N O O N O HCl, MeOH N N H H 0 → 23 °C N N R R 23, R = H (31% yield) 24, R = Me (99% yield) (X-ray) 22, R = H 19, R = Me O (b) O R R N Br O Diels–Alder N 107 O H N N O N H N H N N Br N 108 N H H Communesin F (1f) Treatment of acid 20 with oxalyl chloride produced acyl chloride 109, which was used directly without further purification (Scheme A3.2.2a). Tryptamine (110) was used as the model substrate to explore a Diels–Alder strategy. Reductive amination of tryptamine (110) with benzaldehyde furnished benzyl amine 111, which was coupled 307   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F with acid chloride 109 to afford amide 112. However, all attempts at intramolecular Diels–Alder reactions using a wide variety of conditions (e.g., HCl, BF3·OEt2, Et2AlCl, SnCl4, KOt-Bu, SiO2, MeMgBr, AgClO4, heating) to provide the communesin F core structure were unsuccessful.1 Indole 112 was protected with methyl iodide to produce 114, but the desired Diels–Alder cycloaddition product was not observed (Scheme A3.2.2b). Scheme A3.2.2. Intramolecular Diels–Alder Reactions O (a) CO2H Cl oxalyl chloride O O CH2Cl2, DMF, 0 → 23 °C N N 20 109 NHBn NH 2 O Bn N benzaldehyde NaBH 4 109 , Et 3N MeOH, 23 → 0 °C (82% yield) N H N CH2Cl2, 23 °C (81% yield) N H 110 O N H 111 112 Bn N O Lewis acids/bases acids/heating O N N H H 113 (Not observed) (b) O Bn O Bn Bn N N O MeI, NaH N N O THF (90% yield) 112 N toluene 120 °C O N N N H 114 O 0.5M HCl H N 115 Having failed to access the communesin F core by intramolecular Diels–Alder reactions, we chose to examine intermolecular Diels–Alder reactions (Scheme A3.2.3). 308   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F Intermolecular Diels–Alder reactions between phthalimide 116–118 and benzisoxazole 119–120 did not proceed below 150 °C and the anthranil fragment decomposed at a higher temperature (Scheme A3.2.3a). Addition of Lewis acids did not improve the reactivities. Alternatively, we envisioned that a Diels–Alder reaction of 1,2,3- benzotriazine with phthalimide 116 would afford 127 by loss of N2 (Scheme A3.2.3b).2 Amination of indazole 122 followed by oxidation with lead tetraacetate furnished 1,2,3benzotriazine 126. Disappointingly, the desired adduct (127) was not observed by intermolecular Diels–Alder reactions under several conditions. Scheme A3.2.3. Intermolecular Diels–Alder Reactions (a) O O N O + N O R2 O O N N N R1 121 119 , R 2 = H 120 , R 2 = CO2Me CO2Me CO2Me N N R1 116 , R1 = H 117 , R1 = Me 118 , R1 = Boc (b) R2 microwave NH 2 O + 122 + N NMP, 20 °C (54% yield; 2:1 124 :125 ) O2N N H N 124 125 CO2Me N CH2Cl2, 23 °C N N 126 NPhth CO2Me N + N H N 116 126 N PhthN MeO 2C 3Å MS CH3CN N NH 2 N NH 2 123 Pb(OAc) 4, CaO CO2Me KOt-Bu N N H H 127 309   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F A3.3. Intramolecular Alkylation of 3-Bromooxindole Strategy A plausible rationale for forming syn-selective adduct 42 from alkylation of 3- bromooxindole 40 and malonate 41 is that the tosyl group would be located far from the isobutenyl group due to steric hindrance and thus, malonate 41 would approach syn to the isobutenyl group to reduce the steric interaction with the tosyl group (Scheme 1.2.9). We believed that intramolecular alkylation of the 3-bromooxindole with a tethered malonate derivative in 128 could deliver the stereochemistry needed for the synthesis of communesin F (1f). Scheme A3.3.1. Intramolecular Alkylation Strategy AllylO2C O2N O CO2Allyl O N N bases Br O NO 2 O N H 128 N H 129 Coupling of aurantioclavine (4) and malonate 44 afforded amide 130, which was oxidized with pyridinium tribromide to furnish a mixture of 131, 128, and 132 (Scheme A3.3.2). Unfortunately, intramolecular alkylation of 3-bromooxindole 128 provided a complex mixture of the unisolable desired product and byproducts even after extensive screening of the reaction parameters. 310   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F Scheme A3.3.2. Intramolecular Alkylation of 3-Bromooxindole AllylO2C H N AllylO2C O CO2Allyl N toluene NO 2 + reflux (52% yield) N H 4 N H 44 130 AllylO2C pyridinium tribromide O2N AllylO2C O O2N AllylO2C O N N + Br O Br Br O N H O N H 131 O2N O2N O N + t-BuOH, THF, H 2O, 23 °C (131 , 29% yield; 128 , 64% yield) AllylO2C O2N N H 128 132 O CO2Allyl O N N bases Br O NO 2 O N H 128 N H 129 Although our synthetic efforts toward the total synthesis of communesin F were unsuccessful, we believe that these routes are one of the most expedient routes to complex communesin F. A3.4. Experimental Methods and Analytical Data A3.4.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F 311   benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Triethylamine was distilled over CaH2 prior to use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Microwave-assisted reactions were performed in a Biotage Initiator 2.5 microwave reactor. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, panisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm), or (CD3)2CO (δ 2.05 ppm). 13C NMR spectra are recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm), or (CD3)2CO (δ 29.84 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A 312   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). A3.4.2. Experimental Procedures Br O PhthN NO 2 CO2Allyl CO2Allyl O NH 2NH 2-H2O O NH O O N O O2N Br EtOH, H 2O, 80 oC (92% yield) N 103 105 (9:1 mixture of diastereomers) To a solution of phthalimide 103 (20.0 mg, 0.0285 mmol, 1.00 equiv) in EtOH (3.00 mL) and H2O (2.40 µL) was added hydrazine monohydrate (28.0 µL, 0.577 mmol, 20.0 equiv). The reaction mixture was heated to 80 °C for 1 h. The reaction mixture was then cooled to 23 °C and the resulting solid was filtered through a plug of celite. The residue was purified by column chromatography using mixtures of EtOAc and hexanes to provide oxindole 105 (15.1 mg, 92% yield). 1 H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.47 – 7.42 (m, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 5.07 (s, 1H), 4.35 (s, br, 1H), 3.96 (dt, J = 9.9, 6.7 Hz, 2H), 3.86 (t, J = 6.7 Hz, 2H), 3.02 (s, 3H), 2.81 – 2.70 (m, 2H), 2.29 (s, br, 1H), 2.08 – 2.03 (m, 1H), 1.55 – 1.47 (m, 4H), 0.88 (dd, J = 14.0, 7.0 Hz, 3H), 0.76 (t, J = 7.4 Hz, 3H). 313   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F Br PhthN Br NO 2 CO2Allyl CO2Allyl O MeNH 2 in EtOH H 2N NO 2 CO2Allyl (98% yield) CO2Allyl O N N 103 106 To a solution of MeNH2 (8M in EtOH; 9.5 mL) was added phthalimide 103 (20.0 mg, 0.0285 mmol). The solution was stirred for 12 h at 23 °C. Then, the solution was concentrated to afford amine 106 (16.0 mg, 98% yield). 1 H NMR (600 MHz, CDCl3) δ 7.90 (q, J = 2.2 Hz, 1H), 7.49 (dd, J = 7.5, 2.5 Hz, 1H), 7.41 (dt, J = 8.7, 2.4 Hz, 1H), 7.32 – 7.25 (m, 2H), 7.12 (ddd, J = 9.5, 7.6, 2.5 Hz, 1H), 6.70 (dd, J = 7.8, 2.5 Hz, 1H), 5.79 (ddq, J = 15.1, 9.3, 4.6, 4.2 Hz, 1H), 5.68 (ddtd, J = 16.9, 11.4, 5.7, 2.6 Hz, 1H), 5.19 (d, J = 17.1 Hz, 1H), 5.15 – 5.07 (m, 4H), 4.47 (pd, J = 12.2, 11.3, 4.9 Hz, 3H), 4.39 (d, J = 5.3 Hz, 2H), 2.97 (s, 3H), 2.75 (dp, J = 27.3, 6.8 Hz, 2H), 2.29 (dt, J = 12.6, 6.8 Hz, 1H), 2.09 – 2.01 (m, 1H). NHBn NH 2 benzaldehyde NaBH 4 N H 110 MeOH, 23 → 0 °C (82% yield) N H 111 To a solution of tryptamine (110) (500 mg, 3.12 mmol, 1.00 equiv) in MeOH (15.6 mL) at 23 °C was added benzaldehyde (0.350 mL, 3.43 mmol, 1.10 equiv). After 4 h, the reaction mixture was cooled to 0 °C. Then, NaBH4 (177 mg, 4.68 mmol, 1.50 equiv) was added and the reaction mixture was stirred for an additional 1 h. The reaction was quenched with sat. aq NaHCO3. The aqueous phase was extracted with CH2Cl2 (3 x 7.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F 314   concentrated in vacuo to   afford   amine 111 (640 mg, 82% yield). Data for the compound matches reported data.1 NHBn O Bn N 109 , Et 3N N H O N CH2Cl2, 23 °C (81% yield) 111 N H 112 To a solution of acid chloride 109 (0.613 mmol) and Et3N (0.26 mL, 1.84 mmol, 3.00 equiv) in CH2Cl2 (3.10 mL) was added indole 111 (154 mg, 0.613 mmol, 1.00 equiv) at 23 °C. The reaction mixture was stirred for 6 h at 23 °C. After the reaction was done, water was added. The aqueous phase was extracted with CH2Cl2 (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to  afford  amide 112 (197 mg, 81% yield). (Due to the distinct presence of rotameric isomers, the 1H NMR contained extra peaks.) 1 H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.64 – 7.53 (m, 3H), 7.47 – 7.41 (m, 1H), 7.38 – 7.35 (m, 4H), 7.33 – 7.28 (m, 5H), 7.23 – 7.14 (m, 4H), 7.13 – 7.02 (m, 5H), 6.94 (d, J = 2.4 Hz, 1H), 4.85 (s, 4H), 4.01 (t, J = 7.4 Hz, 2H),  3.82 (t, J = 7.6 Hz, 2H), 3.14 (dt, J = 14.5, 7.6 Hz, 4H).                                                                                                                 1 Martin, D. B. C.; Vanderwal, C. D. J. Am. Chem. Soc. 2009, 131, 3472–3473. 315   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F O Bn O Bn N N O MeI, NaH N O N THF (90% yield) N N H 112 114 To a solution of indole 112 (68.4 mg, 0.173 mmol, 1.00 equiv) in THF (0.900 mL) were added MeI (0.110 mL, 1.73 mmol, 10.0 equiv) and NaH (60%; 14.0 mg, 0.346 mmol, 2.00 equiv) at 0 °C. The reaction mixture was stirred at 23 °C for 4 h. The reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to  afford  amide 114 (64.0 mg, 90% yield). (Due to the distinct presence of rotameric isomers, the 1H NMR contained extra peaks.) 1 H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.9 Hz, 0.5H),  7.69 (dt, J = 8.9, 1.1 Hz, 1H), 7.61 (dd, J = 12.1, 8.5 Hz, 1H), 7.54 (dt, J = 9.1, 1.0 Hz, 1H), 7.44 (dt, J = 7.6, 1.2 Hz, 1H), 7.41 – 7.36 (m, 4H), 7.31 (tdd, J = 7.3, 4.0, 1.8 Hz, 5H), 7.12 – 7.05 (m, 4H), 6.91 (s, br, 0.5H), 6.76 (s, 1H), 4.88 (d, J = 2.3 Hz, 3.5H), 4.04 (t, J = 7.2 Hz, 2H), 3.86 – 3.78 (m, 1H), 3.74 (s, 1.5H), 3.57 (s, 3H), 3.16 (d, J = 8.2 Hz, 1H), 3.09 (t, J = 7.1 Hz, 2H).     AllylO2C H N AllylO2C NO 2 toluene N reflux (52% yield) N H 4 O CO2Allyl + O2N 44 N H 130 To a solution of aurantioclavine (4) (10.0 mg, 0.0442 mmol, 1.00 equiv) in toluene (0.200 316   Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F mL) was added malonate 44 (15.0 mg, 0.0486 mmol, 1.10 equiv). The reaction mixture was refluxed for 12 h. Then, the reaction was quenched with water. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   indole 130 (10.8 mg, 52% yield). Due to the distinct presence of rotameric isomers and diastereomeric mixtures, the 1H NMR contained extra peaks. AllylO2C O2N AllylO2C O O2N AllylO2C O pyridinium tribromide N AllylO2C O N + t-BuOH, THF, H 2O, 23 °C (131 , 29% yield; 128 , 64% yield) N + Br Br Br O N H 131 O2N O N O N H 130 O2N O N H 128 N H 132 To a solution of indole 130 (10.9 mg, 0.0230 mmol, 1.00 equiv) in t-BuOH (0.230 mL) and THF (0.06 mL), H2O (2.10 µL) was added. Then, pyridinium tribromide (14.3 mg, 0.0448 mmol, 1.95 equiv) was added at 23 °C. The reaction was stirred at 23 °C for 6 h. Then, the reaction was quenched with water. The aqueous phase was extracted with EtOAc (3 x 0.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   mixtures of 131 (3.30 mg, 29% yield), 128 (8.35 mg, 64% yield), and trace amounts of 132. Due to the distinct presence of rotameric isomers and diastereomeric mixtures, the 1H NMR contained extra peaks. Appendix 3 – Synthetic Studies Toward the Total Synthesis of Communesin F A3.5. 317   References and Notes                                                                                                                 (1) (a) Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc. 1993, 115, 10733– 10741. (b) Suzuki, T.; Kobayashi, S. Org. Lett. 2010, 12, 2920–2923. (c) Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682–3685. (d) Martin, D. B. C.; Nguyen, L. Q.; Vanderwal, C. D. J. Org. Chem. 2012, 77, 17–46. (e) Chen, Y.; Wang, L.; Liu, Y.; Li, Y. Chem. Eur. J. 2011, 17, 12582–12586. (2) Koyama, J.; Toyokuni, I.; Tagahara, K. Chem. Pharm. Bull. 1998, 46, 332–334. Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 318   APPENDIX 4 Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with α-Arylated Malonate Esters† A4.1. Introduction 3,3-Disubstituted oxindole moieties are present in a wide variety of natural products and pharmaceutical agents.1 Accordingly, methods for the asymmetric construction of 3,3-disubstituted oxindoles have attracted considerable attention from the synthetic community, and a number of catalytic stereoselective approaches to provide C3 quaternary stereocenters on oxindoles have been reported.2,3 In 2007, we discovered that 3,3-disubstituted oxidoles 34 were furnished efficiently by basemediated alkylation of reactive electrophilic o-azaxylyxene 133, generated from 3halooxindole 33, with nucleophilic malonate esters (Scheme A4.1.1a).3a Additionally, we developed a method for the enantioselective alkylation of 3-bromooxindoles 33 by using a copper (R)-Ph-BOX ligand complex (Scheme A4.1.1b).3b                                                                                                                 †   This work was performed in collaboration with Dr. Chung Whan Lee and Dr. Scott C. Virgil. Additionally, this work has been published and adapted with permission from Lee, C. W.; Han, S.-J.; Virgil, S. C.; Stoltz, B. M. Tetrahedron 2014, 71, 3666–3670. Copyright 2014 Elsevier.   Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 319   Following our development of these methods, our attention turned to the syntheses of the polycyclic alkaloids communesin F (1f) and perophoramidine (3).4 We envisioned that the stereochemistry at the vicinal quaternary centers on communesin F and perophoramidine could be installed utilizing the conditions described in Scheme A4.1.1b. However, attempts to produce diesters 60 and 49 via copper catalyzed enantioselective alkylation of 3-bromooxindoles 57 and 43 with αarylated malonate esters 44 and 45 were unsuccessful (Scheme A4.1.2). Therefore, we pursued the development of an alternative catalytic system. Scheme A4.1.1. Construction of 3,3-Disubstituted Oxindoles by Alkylation of 3-Halooxindoles (a) R R R'O 2C CO2R' DBU X O N H R X = Br, Cl R = alkyl, aryl CO2R' O THF, –78 → 23 °C 33 O CO2R' N H (±)-34 (47–87% yield) N 133 (b) R X [Cu((R)-Ph-BOX)(SbF6)2] (20 mol%) R CO2R' O N H 33 X = Br, Cl R = alkyl, aryl R'O 2C CO2R' Base, 3 Å MS CH2Cl2 R = alkyl, Base = i-Pr2NEt R = aryl, Base = Et 3N CO2R' O N H 34 (42–84% yield) (74–94% ee) Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric 320   Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Scheme A4.1.2. Attempts for Alkylation of 3-Bromooxindoles with α-Arylated Malonate Esters R2 O TIPSO R1 O AllylO Br O TIPSO + N H NO 2 R1 OAllyl [Cu((R)-Ph-BOX)(SbF 6)2] (20 mol%) NO 2 i-Pr2NEt, 3 Å MS CH2Cl2 CO2Allyl CO2Allyl O N H R2 57, R1 = Br 43, R1 = H 44, R 2 = H 45, R 2 = Br 60, R1 = Br, R 2 = H 49, R1 = H, R 2 = Br O N N H N N Cl NH N communesin F (1f) Cl N H N Br Perophoramidine (3) In our previous studies, we tested a variety of metal catalysts (e.g. CuII, MgII, LaIII, and NiII) and discovered that the combination of CuII and a chiral bisoxazoline ligand effectively promoted the catalytic reaction. Chiral Cu(II) bisphosphine complexes have also found use in stereoselective synthesis.5 Since the catalytic system can be formed with a number of different chiral bisphosphine ligands, quite a few options would be available for developing a stereoselective reaction. Herein, we describe several screening studies designed and undertaken to optimize the reaction conditions for the alkylation of 3-bromooxindoles with α-arylated malonate esters using a copper(II) bisphosphine catalyst. A4.2. Results and Discussion A4.2.1. Initial Screening Results To develop a stereoselective alkylation method, we chose simple substrates for optimization studies; specifically, we used bromooxindole 43 without a substituent on Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 321   the aromatic ring and o-nitrophenyl dimethylmalonate 135 as a coupling partner. Bromooxindole 43 was easily prepared from indole (134) in four steps by a known sequence,4 which was then added to o-nitrophenyl dimethylmalonate 135 and cesium carbonate in THF solvent to afford a racemic product 136 in good yield. (Scheme A4.2.1). Scheme A4.2.1. Synthesis of the Racemic Product TIPSO TIPSO NO 2 CO2Me Cs2CO3 THF, 23 ºC Br CO2Me O O N H 4 steps 134 N H MeO 2C 43 CO2Me N H NO 2 (±)-136 135 (80% yield) Choosing (R)-BINAP as a chiral ligand, we began our research by screening various copper sources, bases, and solvents. For instance we attempted the following variations of copper ions: Copper(II) triflate, copper(II) chloride with silver hexafluoroantimodate, copper(II) isobutyrate, copper(II) tert-butoxide (generated in situ by adding lithium tert-butoxide to copper(II) isobutyrate and ligand mixture), copper(II) ethylhexanoate, and copper(II) trifluoroacetylacetonate. We explored both organic and inorganic tetramethylenediamine bases, (TMEDA), including diisopropylethylamine, triethylamine, pyridine, diisopropylamine, 1,8- diazabicyclo[5,4,0]undec-7-ene (DBU), sodium carbonate, potassium acetate, sodium ethylhexanoate and cesium carbonate. The various reactions combinations were attempted in the following solvents: dichloromethane, tetrahydrofuran, benzene, acetonitrile, and dioxane. Evaluating the 93 reactions that were explored,6 we found Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 322   that copper(II) tert-butoxide and the ligand complex generated in THF, which was similar to Fandrick’s conditions for asymmetric propargylation5, exhibited the best reactivity without generation of side products for the coupling of the arylated malonate 135 and bromooxindole 43 in CH2Cl2 (high conversion, 20% ee). A4.2.2 . Ligand Screening and Optimization Studies Based on previous studies, we selected copper(II) iso-butyrate, lithium tertbutoxide and THF solvent for generation of the catalytic species with chiral ligands, diisopropylamine as the base and CH2Cl2 as solvent. We have screened 69 chiral bisphosphine ligands6 under similar condition, finding WALPHOS and DiazaPHOS to give the best enantioselectivities (Figure A4.2.1). Figure A4.2.1. Results with DiazaPHOS and WALPHOS H N N N O Me O O PR 1 2 PR 22 Fe P O Me N H W1 : (S,S,S)-DiazaPHOS-PPE 40% ee Me WALPHOS N1 : R1 ,R2 = Ph, Ph N2 : = Ph, Xyl 27% ee   Having identified the most effective ligands, we next screened several copper sources under lower temperatures. Although none of these sources exhibited better results than the combination of copper(II) isobutyrate and lithium tert-butoxide for WALPHOS (N1 and N2), we were able to observe better stereoselectivity at low temperature (Table A4.2.1, entries 6 and 16). With DiazaPHOS (W1), copper(II) triflate showed better selectivity at 0 ºC (Table A4.2.1, entries 22 and 23). Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric 323   Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Table A4.2.1. Further investigations using WALPHOS and DiazaPHOS in the alkylation reaction O TIPSO Br O O TIPSO MeO OMe + NO 2 CO2Me O Metal, Ligand, Temp. N H 43 NO 2 CO2Me N H i-Pr 2NEt, THF/CH2Cl2 48 h 136 135   Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Metal Sources CuCl2 CuCl2 CuCl2 CuCl2 CuCl2 Cu(iso-butyrate)2 Cu(iso-butyrate)2 Cu(hfacac)2 Cu(OTf)2 Cu(OTf)2 Cu(EH)2 CuCl2 CuCl2 CuCl2 CuCl2 Cu(iso-butyrate)2 Cu(hfacac)2 Cu(OTf)2 Cu(EH)2 Cu(iso-butyrate)2 Cu(iso-butyrate)2 Cu(OTf)2 Cu(OTf)2 Ligand N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N1 N2 N2 N2 N2 N2 N2 N2 N2 W1 W1b W1 W1b Additive AgBF4 AgNTf2 AgPF6 AgSbF6 LiOt-Bu LiOt-Bu AgSbF6 LiOt-Bu AgBF4 AgNTf2 AgPF6 AgSbF6 LiOt-Bu LiOt-Bu LiOt-Bu Temp. −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC −45 ºC 0 ºC 0 ºC 0 ºC 0 ºC   eea − − − − − 44% − trace trace 23% trace − − − − 54% 30% 45% trace trace trace 40% 50% Conditions: 0.0049 mmol 43, 0.0145 mmol 135, Cu (20 mol %), Ligand (22 mol %), Additive (20 mol %), i-Pr2NEt (3 equiv.), 0.1 mL CH2Cl2 (0.049 M). Metal catalyst, ligand and additives were mixed in THF. THF was removed in vacuo, and the resultant was diluted with the reaction solvent. The reaction was initiated by addition of base. Cu(hfacac)2: Copper(II) hexafluoroacetylacetonate, Cu(EH)2: Copper(II) ethylhexanoate. a enantiomeric excess was measured by chiral SFC. b 44 mol % of ligand was used. With a suitable bisphosphine ligand in hand (N1), we tested multiple solvents and bases. However, amine bases weaker than Hünig’s base (Table A4.2.2, entries 112) could not initiate the reaction, whereas stronger bases (entries 13-18) decreased the stereoselectivity. The copper bisphosphine complex demonstrated similar selectivity in dichloromethane (entry 19), THF (entry 20), and chloroform (entry 22), however it showed worse selectivity in acetonitrile (entry 21) and failed to proceed at all in toluene and 1,2-dimethoxyethane (DME). Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric 324   Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters Table A4.2.2. Investigation of reaction solvents and bases with WALPHOS in the alkylation reaction PPh 2 PPh 2 O TIPSO Br O O OMe + NO 2 N H 43 Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Fe MeO 135 Solvent CH2Cl2 THF CH3CN CHCl3 Toluene DME CH2Cl2 THF CH3CN CHCl3 Toluene DME CH2Cl2 THF CH3CN CHCl3 Toluene DME CH2Cl2 THF CH3CN CHCl3 Toluene DME Me TIPSO NO 2 CO2Me CO2Me O Cu(iso-butyrate) 2 N H LiOt-Bu, Base THF/Solvent, −45 ºC 48 h Base DABCO DABCO DABCO DABCO DABCO DABCO DMAP DMAP DMAP DMAP DMAP DMAP Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt i-Pr2NEt 136 ee − − − − − − − − − − − − 35% 15% 20% 20% − 10% 40% 50% 30% 40% − − Conditions: 0.0024 mmol 43, 0.0072 mmol 135, Cu (20 mol %), Ligand (22 mol %), LiOt-Bu (20 mol %), Base (3 equiv), 0.06 mL CH2Cl2 (0.04 M). In addition to these studies, we examined the effect of the catalyst and ligand loading on the stereoselectivity of our alkylation reaction. Unsatisfactory results were produced with low catalyst or ligand loading (Table A4.2.3, entries 1,2 and 4), but 20 mol % of copper(II) isobutyrate and 40 mol % of the ligand gave the product in 56% ee (Table A4.2.3, entry 3). Stoichiometric amounts of the copper presursor and ligand produced only a slight increase in ee (Table A4.2.3, entry 5). Additionally, we investigated the impact of the equivalents of Hünig’s base on the selectivity of the reaction. Results showed the amount of Hünig’s base had little effect on the Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 325   stereoselectivity of the product (Table A4.2.3, entries 6-13). Subsequent examination of concentration effects showed lowering the concentration of the reaction mixture from 0.05 M to 0.02 M resulted in increase stereoselectivity (Table A4.2.4). Table A4.2.3. Examination of the amount of catalyst and ligand loading in the alkylation reaction PPh 2 PPh 2 O TIPSO Br O O Fe MeO OMe + NO 2 N H 43 135 Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 Cu(iso-butyrate)2 10 mol % 10 mol % 20 mol % 20 mol % 1 equiv 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % TIPSO Me NO 2 CO2Me CO2Me O Cu(iso-butyrate) 2 N H LiOt-Bu, i-Pr 2NEt THF/CH2Cl2, −45 ºC 48 h 136 i-Pr2NEt Ligand 10 mol % 20 mol % 40 mol % 10 mol % 1 equiv 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % 20 mol % ee 25% 28% 56% 35% 60% 33% 35% 38% 37% 36% 37% 36% 36% 3.0 equiv 3.0 equiv 3.0 equiv 3.0 equiv 3.0 equiv 1.0 equiv 1.5 equiv 2.0 equiv 2.5 equiv 4.0 equiv 5.0 equiv 6.0 equiv 20 equiv Conditions: 0.0049 mmol 43, 0.0145 mmol 135, LiOt-Bu (10 mol %), 0.1 mL CH2Cl2 (0.049 M). Table A4.2.4. Examination of concentration in the malonate addition reaction PPh 2 PPh 2 O TIPSO Br O O MeO OMe + NO 2 N H 43 Entry 1 2 3 4 5 Fe 135 TIPSO Me NO 2 CO2Me CO2Me O Cu(iso-butyrate) 2 LiOt-Bu, i-Pr 2NEt THF/CH2Cl2, −45 ºC 48 h Concentration 0.005 M 0.01 M 0.02 M 0.05 M 0.25 M N H 136 ee 53% 63% 64% 55% 40% Conditions: 0.0049 mmol 43, 0.0145 mmol 135, Cu (20 mol %), Ligand (40 mol %), LiOt-Bu (20 mol %), i-Pr2NEt (3 equiv). Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 326   Table A4.2.5. The effect of WALPHOS substituents under optimized conditions in the alkylation reaction O TIPSO Br O O TIPSO MeO OMe + NO 2 N H 43 135 N H 136 N1 : R 1,R 2 = Ph, Ph PR 22 Fe Me WALPHOS Entry 1 2 3 4 5 6 7 8 CO2Me O Cu(iso-butyrate) 2 LiOt-Bu, i-Pr 2NEt THF/CH2Cl2, −45 ºC 48 h PR 1 2 NO 2 CO2Me N2 : N3 : N4 : N5 : N6 : N7 : N8 : = Ph, Xyl = Ph, XylF = 3,5-Me2-4-MeOPh, XylF = Ph, Cy = Cy, XylF = Xyl, Xyl = Ph, Norbornyl Ligand N1 N2 N3 N4 N5 N6 N7 N8 ee 60% trace 25% 25% 70% − − − Conditions: 0.0049 mmol 43, 0.0145 mmol 135, Cu (20 mol %), Ligand (40 mol %), LiOt-Bu (20 mol %), i-Pr2NEt (3 equiv), 0.25 mL CH2Cl2 (0.02 M). Finally, we explored a set of WALPHOS ligands (N1 – N8) under our optimized conditions. Gratifyingly, we observed improved ee by using (Ph,Cy)WALPHOS (Table A4.2.5, entry 5), leading to product formation in 70% ee, whereas other ligands showed diminished selectivity. To date, this is the best result we have, which is a great improvement over the starting point. A4.3. Conclusion Asymmetric alkylation of 3-halooxindoles with malonate esters is an effective method to construct 3,3,-disubstituted oxindole moieties. Herein, we have reported that copper(II) chiral bisphosphine complex demonstrated reactivity with an αarylated malonate ester, which was an unreactive substrate in previously developed Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 327   conditions. This method could be applied to the installation of vicinal quaternary centers on communesin F and perophoramidine and could be useful in the synthesis of a variety of other natural products. A4.4. Selected Experiments A4.4.1. Synthesis of (±)-136 To a flame-dried round-bottomed flask, equipped with a stirbar, was added bromooxindole 43 (20 mg, 0.045 mmol), o-nitrophenyl dimethylmalonate 135 (37 mg, 0.135 mmol) and THF (0.5 mL). To the mixture was added cesium carbonate (47.4 mg, 0.045 mmol) at ambient temperature and the reaction mixture was then stirred for 3 h. The reaction mixture was then treated with saturated NH4Cl aqueous solution, extracted with EtOAc, washed with brine and dried over MgSO4. After concentration in vacuo, the crude product was obtained. Chromatography (6:1 hexanes : ethyl acetate) on silica gel afforded the title compound 136 (23 mg, 80% yield) as colorless oil: 1H NMR (500 MHz, CDCl3) δ 8.0 (d, J = 8.1 Hz, 1H), 7.85 (s, 1H), 7.74 (dd, J = 7.9, 1.7 Hz, 1H), 7.40 (dtd, J = 26.6, 7.4, 1.5 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.14 (td, J = 7.7, 1.3 Hz, 1H), 6.90 (td, J = 7.7, 1.2 Hz ,1H), 6.75 (dd, J = 7.8, 1.1 Hz, 1H), 3.74 (s, 3H), 3.65 (s, 3H), 3.35 (ddd, J = 9.5, 8.4, 6.9 Hz, 1H), 3.06 (td, J = 9.3, 4.5, 1H), 2.93 (ddd, J = 12.6, 8.8, 6.7 Hz, 1H), 2.54 (ddd, J = 12.8, 8.4, 4.4 Hz, 1H), 0.89 (s, 21H). 13C NMR (126 MHz, CDCl3) δ 177.86, 167.63, 167.27, 150.34, 140.67, 132.46, 131.12, 129.49, 129.23, 128.63, 128.61, 126.73, 125.39, 122.45, 109.98, 109.12, 59.52, 56.71, 52.81, 52.80, 38.34, 29.70, 17.85, 17,84, 11.80. IR (Neat Film, NaCl) 2923, 2852, 1722, 1617, 1532, 1463, 1353, 1259, 1097, 992, Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 328   799, 753 cm-1; HRMS (MM) m/z calc’d for C30H40N2O8Si [M+H]+ : 585.2627, found 585.2636. A4.4.2. Ligand Screening Procedure Every step was performed in a nitrogen-filled glove box. Solutions of Copper(II) isoburtyrate (8 mg, 0.034 mmol) in THF (3.5 mL), lithium tert-butoxide (2.72 mg, 0.034 mmol) in THF (3.5 mL), bromooxindole 43 (70 mg, 0.17 mmol) and malonate 135 (129 mg, 0.51 mmol) in CH2Cl2 (1.75 mL), i-Pr2NEt (0.1 ml, 0.57 mmol) in CH2Cl2 (2 mL) were prepared in 2 dram vials prior to reaction setup. To a ligand (1.1 µmol, 22 mol %) in a 1 dram vial equipped with a stirbar was added copper(II) isobutyrate in THF (0.1 mL, 0.97 µmol, 20 mol %). The heterogeneous solution was agitated at room temperature for 10-20 min until a clear homogeneous solution was generated. The reaction mixtures were charged with lithium tert- butoxide in THF (0.1 mL, 0.97 µmol, 20 mol %). Reaction mixtures were allowed to stir for 5 min and concentrated under reduced pressure. A mixture of bromooxindole 43 and malonate 135 in CH2Cl2 (0.05 mL, 4.85 µmol, 14.55 µmol) was dispensed to each vial and allowed to stir for 10 min. After setting the reaction temperature, iPr2NEt in CH2Cl2 (0.05 mL, 14.55 µmol, 3 equiv) was added to the reaction vials and allowed to stir for 48 h. Upon completion, sat. aq ammonium chloride solution (0.1 mL) was added, and the mixture was filtered through silica gel. Each filtrate was diluted by 1 mL of solvent (ethyl acetate or isopropanol) and analyzed by chiral SFC. The mixture was separated by an AD-H column with 20% isopropanol as eluent. Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters A4.5. 329   References and Notes (1) (a) Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med. Chem. 2001, 44, 4641–4649. (b) Woodward, C.; L.; Li, Z.; Kathcart, A. K.; Terrell, J.; Gerena, L.; Lopez-Sanchez, M.; Kyle, D. E.; Bhattacharjee, A. K.; Nichols, D. A.; Ellis, W.; Prigge, S. T.; Geyer, J. A.; Waters, N. C. J. Med. Chem. 2003, 46, 3877– 3882. (c) Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748– 8758. (d) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2219. (e) Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36–51. (f) Trost, B. M.; Brennan, M. K. Synthesis, 2009, 3003–3025. (g) Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49, 3432–3435. (2) Reviews: (a) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal., 2010, 352, 1381– 1407. (b) Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 6821–6841. (c) Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247–7290. (d) Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104–6155. (3) Recent examples: (a) Holmquist, M.; Blay, G.; Pedro, J. R. Chem. Commun., 2014, 50, 9309–9312. (b) Hu, F.-L.; Wei, Y.; Shi, M. Chem. Commun., 2014, 50, 8912–8914. (c) Chen, D.; Xu, M.-H. J. Org. Chem. 2014, 79, 7746–7751. (d) Li, C.; Guo, F.; Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Org. Lett. 2014, 16, 3192– 3195. (e) Zhu, X.-L.; Xu, J.-H.; Cheng, D.-J.; Zhao, L.-J.; Liu, X.-Y. Tan, B. Org. Lett. 2014, 16, 2192–2195. (f) Liu, Z.-M.; Li, N.-K.; Huang, X.-F.; Wu, B.; Li, N.; Kwok, C.-Y.; Wang, Y.; Wang, X.-W. Tetrahedron, 2014, 70, 2406–2415. (g) Cao, Z.-Y.; Wang, Y.-H.; Zeng, X.-P.; Zhou, J. Tetrahedron Lett. 2014, 55, 2571–2584. (h) Zhou, F.; Zeng, X.-P.; Wang, C.; Zhao, X.-L.; Zhou, J. Chem. Commun., 2013, 49, Appendix 4 – Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with a-Arylated Malonate Esters 330   2022–2024. (i) Katayev, D.; Jia, Y.-X. Sharma, A. K.; Banerjee, D.; Besnard, C.; Sunoj, R. B.; Kündig, E. P. Chem. Eur. J. 2013, 19 11916–11927. (j) Zhing, F.; Dou, X.; Han, X.; Yao, W.; Zhu, Q.; Meng, Y.; Lu, Y. Angew. Chem. Int. Ed. 2013, 52, 943–947. (k) Shen, K.; Liu, X.; Feng, X. Chem. Sci., 2012, 3, 327–334. (l) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583–3586. (m) Ding, M.; Zhou, F.; Qian, Z.-Q.; Zhou, J. Org. Biomol. Chem., 2010, 8, 2912–2914. (4) (a) Krishnan, S.; Stoltz, B. M. Tetrahedron Lett. 2007, 48, 7571–7573. (b) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037–8041. (5) Han, S.-J. Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C. Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. (6) (a) Fandrick, D. R., Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Tang, W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.; Yee, N. K.; Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600-7601. (b) Fandrick, K. R.; Fandrick, D. R.; Reeves, J. T.; Ma, S.; Li, W.; Lee, H.; Grinberg, N.; Lu, B.; Senanayake, C. H. J. Am. Chem. Soc. 2011, 133, 10332-10335. (c) Fandrick, K. R.; Ogikubo, J.; Fandrick, D. R.; Patel, N. D.; Saha, J.; Lee, H.; Ma, S.; Grinberg, N.; Busacca, C. A.; Senanayake, C. H. Org. Lett. 2013, 15, 1214-1217.   Appendix 5 – Spectra Relevant to Appendix 4 331 APPENDIX 5 Spectra Relevant to Appendix 4: Stereochemical Evaluation of Bisphosphine Copper Catalysts for the Asymmetric Alkylation of 3-Bromooxindoles with α-Arylated Malonate Esters 136 N H CO2Me O CO2Me NO 2 TIPSO                                                                                                     332   Figure A5.1. 1H NMR (500 MHz, CDCl3) of compound 136. Appendix 5 – Spectra Relevant to Appendix 4 Appendix 5 – Spectra Relevant to Appendix 4     Figure A5.2. Infrared spectrum (Thin Film, NaCl) of compound 136.  Figure A5.3. 13C NMR (125 MHz, CDCl3) of compound 136.   333    Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 334   CHAPTER 2 A New Method for the Cleavage of Nitrobenzyl Amides and Ethers† 2.1. Introduction The selection of protection groups is critical to the synthesis of multifunctional complex molecules. Over the past decades, a wide variety of protecting groups have been developed to mask specific functional groups selectively. 1,2 However, despite considerable effort, relatively few protecting groups have been developed for the amide N–H (e.g., PMB, TBS, Benzyl, SEM, allyl, etc.).3 Consequently, limitations associated with cleavage of amide protecting groups often arise.4 Herein, we report o- and pnitrobenzyl groups as easily introducible and removable protecting groups for both R2N– H (including amides) and RO–H groups.                                                                                                                 †   This work was performed in collaboration with Gabriel Fernando de Melo. Additionally, this work has been published and adapted with permission from Han, S.-J.; Fernando de Melo, G.; Stoltz, B. M. Tetrahedron Lett. 2014, 55, 6467–6469. Copyright 2014 Elsevier. 335   Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 2.2. Results  and  Discussion   In the course of our efforts toward the synthesis of the polycyclic, complex alkaloid perophoramidine, we serendipitously found that the o-nitrobenzyl group was easily removed by using 20% aqueous NaOH in methanol at 75 °C (Scheme 1).5 oNitrobenzyl groups have been used as photocleavable protecting groups for amides and heterocycles such as indoles, benzimidazole, and 6-chlorouracil as well as the more common hydroxyl group.6,7 In addition, a method for removing p-nitrobenzyl groups on hydroxyl groups in two steps by reduction to a p-aminobenzyl group followed by electrochemical oxidation was disclosed by the Kusumoto group.8 To the best of our knowledge, ours was the first example of using simple aqueous NaOH to remove a nitrobenzyl group from a lactam. Scheme 2.2.1. o-Nitrobenzyl group cleavage on perophoramidine intermediate (88) O2N TIPSO TIPSO N NH 20% aq NaOH O O MeOH, 75 °C N O H N Boc 88 Br (50% yield) N N H H Boc Br 80 To explore the general reactivity of nitrobenzyl group cleavage reactions by using simple aqueous NaOH, we initially chose 3,3-dimethyl oxindole as a test substrate (Table 2.2.1). We found that both ortho- and para-nitrobenzyl groups on oxindoles 137a and 137c were smoothly cleaved under our standard conditions (entries 1 and 3). However, a meta-nitrobenzyl group as well as a simple benzyl group on the oxindole 336   Notably, the o- Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers nitrogen (137b and 137d) were both unreactive (entries 2 and 4). nitrobenzyl group was also successfully removed even in the absence of light (entry 5). Interestingly, only trace amounts of product were observed when degassed water and methanol were used (entry 6). Furthermore, we discovered that cleavage of the onitrobenzyl group was successful when the degassed water and methanol were purged with oxygen gas (entry 7). We therefore concluded that oxygen was necessary for the reaction, but light was not. Table 2.2.1. Cleavage of nitrobenzyl groups on 3,3-dimethyloxindole   O N Entry 20% aq NaOH O MeOH, 75 °C R N H 137 138 Substrate R Time (h) Yield (%) 1 137a -o-nitrobenzyl 5 69 2 137b -m-nitrobenzyl 24 0 3 137c -p-nitrobenzyl 1.5 63 4 137d -benzyl 24 0 5a 137a -o-nitrobenzyl 6.5 72 6b 137a -o-nitrobenzyl 12 trace 7b,c 137a -o-nitrobenzyl 6.5 66 a The reaction was performed in the dark. b Degassed water and methanol were used. c Purged with O . 2 With the standard conditions in hand, we explored the scope of the o- and pnitrobenzyl group cleavage reactions with various substrates (Table 2.2.2). o- and pNitrobenzyl protected substrates were easily prepared by a variety of methods, including reductive amination, simple alkylation, EDCI coupling, and acylation. The o-nitrobenzyl group on a highly functionalized communesin F intermediate 79 was smoothly cleaved 337   under our standard conditions in good yield (entry 1). p-Nitrobenzyl groups on amide Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 5 139 and lactam 141 were also cleaved in moderate yields (entries 2 and 3). The pnitrobenzyl group on urea 143 was also successfully cleaved and methyl 4-nitrobenzoate was isolated as a by-product (entry 4). An attempt to remove the p-nitrobenzyl group on secondary carbamate 145 proved unsuccessful (entry 5). Additionally, removal of the pnitrobenzyl group on amine 147 was facile, furnishing aniline 148 in 65% yield (entry 6). Interestingly, 4-nitrobenzaldehyde was isolated as a by-product in this reaction, presumably resulting from the oxidation reaction at the benzylic position by oxygen dissolved in the solution. Furthermore, we successfully removed the p-nitrobenzyl groups from ethers 149 and 151 in moderate yields (entries 7 and 8). This work offers a one-step alternative to previous work by the Kusumoto group.8 In the cases of deprotection reactions from urea 143 and ether 149, the corresponding hemiaminal ether and acetal intermediates were observed (see ref. 9). It is important to note that these deprotection conditions are compatible with free hydroxyl groups, aminals, aryl bromides, methyl carbamates, silyl ethers, and Boc groups present on the substrates. A representative procedure is as follows: To a 20 mL scintillation vial with a magnetic stir bar were added p-nitrobenzyl protected oxindole 137c (30 mg, 0.10 mmol, 1.0 equiv), MeOH (1.0 mL), and 20% aq NaOH (1.0 mL). The reaction mixture was stirred for 1.5 h at 75 °C. The reaction mixture was then cooled to 23 °C, and extracted with EtOAc (3 x 2 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography to afford 3,3-dimethyloxindole 138 (10.3 mg, 63% yield). 338   Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers Table 2.2.2. Scope of the o- and p-nitrobenzyl deprotecion reactions Entry Product Substrate Time (h) Yield (%) 4 70 12 42 1 55 10.5 94a,b 6 0 2 65c 32 59b (74)d 48 48 O2N HO HO 1 N Br NH Br O O N N H N H N CO2Me CO2Me 79 53 O O N 2 NH NO 2 139 140 O O N 3 NH NO 2 142 141 O 4 N O N N NH NO 2 143 144 O O 5 O N H O NH 2 NO 2 146 145 NO 2 6 NH N 147 7 148 O OH 149 8 NO 2 150 O OH NO 2 151 152 a Methyl 4-nitrobenzoate was isolated as a by-product. b See Ref. 9 for detail. c 4-Nitrobenzaldehyde was isolated as a by-product. d Yield based on recovered starting material. Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 2.3. 339   Conclusion   In summary, a mild and efficient deprotection protocol was discovered for the cleavage of o- and p-nitrobenzyl ethers, amides, ureas, and anilines. Since relatively few options for protection of the amide N–H functionality exist, easily introducible and removable o- and p-nitrobenzyl groups could prove useful in the synthesis of alkaloids and biologically active molecules, which possess amide functionalities. In our laboratory, this has already been proven to be the case in our formal syntheses of communesin F and perophoramidine. In addition, p-nitrobenzyl-protected anilines, ureas, and alcohols were also competent substrates for this transformation, which may further its utility as a mild deprotection method in cases where other conditions fail. 2.4. Experimental Methods and Analytical Data 2.4.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Triethylamine was distilled over CaH2 prior to use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Microwave-assisted reactions were 340   performed in a Biotage Initiator 2.5 microwave reactor. Glove box manipulations were Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, panisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and were reported relative to residual CHCl3 (δ 7.26 ppm), or (CD3)2CO (δ 2.05 ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm), or (CD3)2CO (δ 29.84 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). 2.4.2. Experimental Procedures o-nitrobenzyl bromide Cs2CO3 O N H 138 THF, 23 °C (93% yield) O N 137a O2N 341   N–2-nitrobenzyloxindole 137a. To a mixture of 3,3-dimethyloxindole 138 (150 mg, Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 1 0.93 mmol, 1.00 equiv) and Cs2CO3 (606 mg, 1.86 mmol, 2.00 equiv) in THF (4.70 mL) was added o-nitrobenzyl bromide (302 mg, 1.40 mmol, 1.50 equiv). The reaction mixture was stirred overnight. Then, the reaction mixture was extracted with EtOAc (3 x 6 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 → 1:2 EtOAc:hexanes) on silica gel to afford N–2-nitrobenzyl-3,3-dimethyloxindole 137a (258 mg, 93% yield). Rf = 0.35 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.16 (dd, J = 8.1, 1.4 Hz, 1H), 7.51 (td, J = 7.6, 1.4 Hz, 1H), 7.44 (dddt, J = 8.1, 7.4, 1.4, 0.7 Hz, 1H), 7.28 (ddd, J = 7.3, 1.3, 0.6 Hz, 1H), 7.17 (td, J = 7.7, 1.3 Hz, 1H), 7.12 (dq, J = 7.8, 1.0 Hz, 1H), 7.09 (td, J = 7.5, 1.1 Hz, 1H), 6.61 (dt, J = 7.8, 0.8 Hz, 1H), 5.33 (d, J = 0.8 Hz, 2H), 1.48 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 181.8, 148.2, 141.4, 135.8, 134.2, 132.0, 128.5, 128.0, 127.6, 125.7, 123.2, 122.8, 108.8, 77.2, 44.5, 41.2, 24.8; IR (Neat Film NaCl) 2968, 1721, 1615, 1524, 1489, 1385, 1338, 1177, 1008, 858, 761 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H17N2O3 [M+H]+ : 297.1234; found: 297.1236. m-nitrobenzyl bromide Cs2CO3 O N H 138 THF, 23 °C (92% yield) O N 137b NO 2 N–3-nitrobenzyloxindole 137b. To a mixture of 3,3-dimethyloxindole 1381 (100 mg, 0.62 mmol, 1.00 equiv) and Cs2CO3 (403 mg, 1.24 mmol, 2.00 equiv) in THF (3.10 mL)                                                                                                                 1 Vu, A. T.; Cohn, S. T.; Zhang, P.; Kim, C. Y. Mahaney, P. E.; Bray, J. A.; Johnston, G. H.; Koury, E. J.; Cosmi, S. A.; Deecher, D. C.; Smith, V. A.; Harrison, J. E.; Leventhal, L.; Whiteside, G. T.; Kennedy, J. D.; Trybulski, E. J. J. Med. Chem. 2010, 53, 2051–2062. Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers was added m-nitrobenzyl bromide (335 mg, 1.55 mmol, 2.50 equiv). 342   The reaction mixture was stirred overnight. Then, the reaction mixture was extracted with EtOAc (3 x 4 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 → 1:2 EtOAc:hexanes) on silica gel to afford N–3-nitrobenzyl-3,3-dimethyloxindole 137b (170 mg, 92% yield). Rf = 0.35 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.16 – 8.11 (m, 2H), 7.60 (ddt, J = 7.7, 1.8, 0.9 Hz, 1H), 7.53 – 7.48 (m, 1H), 7.26 – 7.24 (m, 1H), 7.17 (td, J = 7.7, 1.3 Hz, 1H), 7.07 (td, J = 7.5, 1.0 Hz, 1H), 5.01 (s, 2H), 1.46 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 181.7, 148.6, 141.1, 138.5, 135.9, 133.3, 130.1, 127.9, 123.2, 122.9, 122.8, 122.2, 108.7, 77.2, 44.4, 43.0, 24.7; IR (Neat Film NaCl) 2969, 1652, 1538, 1348, 1011, 933, 761; HRMS (MM: ESI-APCI+) m/z calc’d for C17H17N2O3 [M+H]+ : 297.1234; found: 297.1241. p-nitrobenzyl bromide Cs2CO3 O N H 138 THF, 23 °C (84% yield) O N 137c NO 2 N–4-nitrobenzyloxindole 137c. To a mixture of 3,3-dimethyloxindole 1381 (50 mg, 0.31 mmol, 1.00 equiv) and Cs2CO3 (202 mg, 0.62 mmol, 2.00 equiv) in THF (1.60 mL) was added p-nitrobenzyl bromide (101 mg, 0.47 mmol, 1.50 equiv). The reaction mixture was stirred overnight. Then, the reaction mixture was extracted with EtOAc (3 x 3 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 → 1:2 343   EtOAc:hexanes) on silica gel to afford N–4-nitrobenzyl-3,3-dimethyloxindole 137c (77.5 Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers mg, 84% yield). Rf = 0.35 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 10.0 Hz, 2H), 7.25 (ddd, J = 7.3, 1.5, 0.7 Hz, 1H), 7.16 (td, J = 7.7, 1.3 Hz, 1H), 7.07 (td, J = 7.5, 1.1 Hz, 1H), 6.65 (dt, J = 7.7, 0.7 Hz, 1H), 5.01 (s, 2H), 1.45 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 181.6, 147.6, 143.7, 141.1, 135.8, 128.0, 127.9, 124.2, 123.2, 122.8, 108.7, 77.2, 44.4, 43.1, 24.7; IR (Neat Film NaCl) 2968, 1707, 1613, 1522, 1343, 1173, 1111, 1009, 760; HRMS (MM: ESI-APCI+) m/z calc’d for C17H17N2O3 [M+H]+ : 297.1234; found: 297.1239. O O OH N H + O2N SI-2-1 SI-2-2 EDCI, HOBt N CH2Cl2, 23 °C (73% yield) NO 2 139 Benzamide 139. To a solution of benzoic acid SI-2-1 (57.0 mg, 0.463 mmol, 1.00 equiv) and propylamine SI-2-22 (90.0 mg, 0.463 mmol, 1.00 equiv) in CH2Cl2 (2.30 mL) were added EDCI (90.0 mg, 0.579 mmol, 1.25 equiv) and HOBt (78.0 mg, 0.579, 1.25 equiv). The reaction mixture was stirred overnight at 23 °C. Then, the reaction mixture was extracted with CH2Cl2 (3 x 3 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 → 1:2 EtOAc:hexanes) on silica gel to afford N–3-nitrobenzyl-3,3dimethyloxindole 139 (101 mg, 73% yield).                                                                                                                 2  Hajipour, A. R.; Fontanilla, D.; Chu, U. B.; Arbabian, M.; Ruoho, A. E. Bioorg. Med. Chem. 2010, 18, 4397–4404.   344   Rf = 0.32 (1:2 EtOAc:hexanes); (due to the distinct presence of rotameric isomers, the 1H Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers NMR and 13C NMR contained extra peaks. See the attached spectrum); 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 10 Hz 2H), 7.53 – 7.35 (m, br, 7H), 4.84 – 4.61 (m, br, 2H), 3.43 – 3.18 (m, br, 2H), 1.68 –1.53 (m, br, 2H), 0.95 – 0.73 (m, br, 3H); 13C NMR (126 MHz, CDCl3) δ 172.47, 147.44, 145.42, 136.17, 129.84, 128.71, 127.49, 126.61, 124.06, 77.16, 52.29, 50.82, 47.59, 46.85, 21.87, 20.34, 11.07; IR (Neat Film NaCl) 3060, 2963, 2874, 1633, 1519, 1461, 1412, 1344, 1258, 1098, 859, 791, 736; HRMS (MM: ESIAPCI+) m/z calc’d for C17H19N2O3 [M+H]+ : 299.1390; found: 299.1396. p-nitrobenzyl bromide LHMDS O NH O N THF, 23 °C (69% yield) 142 NO 2 141 N–4-nitrobenzylpiperidin-2-one 141. To a solution of lactam 142 (34.0 mg, 0.203 mmol, 1.00 equiv) in THF (1.40 mL) was added LHMDS (41.0 mg, 0.244 mmol, 1.20 equiv) at 0 °C. The reaction mixture was stirred for 1 h, and then, p-nitrobenzyl bromide (66.0 mg, 0.305 mmol, 1.50 equiv) was added. The reaction mixture was stirred overnight at 23 °C. Then, the reaction mixture was extracted with EtOAc (3 x 3 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:2 EtOAc:hexanes) on silica gel to afford N–4-nitrobenzylpiperidin-2-one 141 (42.0 mg, 69% yield). Rf = 0.25 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.18 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 5.80 – 5.71 (m, 1H), 5.11 – 5.04 (m, 2H), 4.65 (d, J = 3.8 Hz, 2H), 3.22 (td, J = 6.1, 1.3 Hz, 2H), 2.54 (ddt, J = 13.5, 6.9, 1.3 Hz, 1H), 2.21 (ddt, J = 345   13.4, 8.0, 1.1 Hz, 1H), 1.81 (dddd, J = 11.9, 6.8, 2.9, 1.4 Hz, 3H), 1.76 – 1.72 (m, 2H), Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 1.55 (dq, J = 13.5, 7.4 Hz, 1H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 174.9, 147.4, 145.6, 134.7, 128.7, 124.0, 118.3, 77.2, 50.5, 48.6, 45.5, 43.3, 31.6, 28.9, 19.9, 8.9; IR (Neat Film NaCl) 2939, 1633, 1519, 1344, 1196, 1109; HRMS (MM: ESIAPCI+) m/z calc’d for C17H23N2O3 [M+H]+ : 303.1703; found: 303.1707. O N H + O Et 3N N Cl NO 2 SI-2-2 CH2Cl2, 23 °C (56% yield) N SI-2-3 N NO 2 143 Urea 11. To a solution of propylamine SI-2-22 (100 mg, 0.515 mmol, 1.00 equiv) and Et3N (0.18 mL, 1.29 mmol, 2.50 equiv) in CH2Cl2 (2.60 mL) was added diethylcarbamoyl chloride SI-2-3 (72.0 mL, 0.566 mmol, 1.10 equiv) at 0 °C. The solution was warmed to 23 °C and stirred overnight. Then, the reaction mixture was extracted with CH2Cl2 (3 x 3.5 mL) and washed with brine. The combined organic phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 → 1:4 EtOAc:hexanes) on silica gel to afford urea 143 ( 85 mg, 56% yield). Rf = 0.32 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 4.42 (s, 2H), 3.22 (q, J = 7.1 Hz, 4H), 3.06 – 3.01 (m, 2H), 1.61 – 1.52 (m, 2H), 1.11 (t, J = 7.1 Hz, 6H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 164.9, 147.2, 146.9, 128.4, 123.8, 51.4, 51.2, 42.5, 21.1, 13.4, 11.4; IR (Neat Film NaCl) 2967, 1644, 1520, 1410, 1344, 1251, 1132, 1108; HRMS (MM: ESI-APCI+) m/z calc’d for C15H24N3O3 [M+H]+ : 294.1812; found: 294.1863. Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 2.5. 346   References and Notes                                                                                                                 (1) (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th ed; John Wiley & Sons: New York, 2007. (b) Kocienski, P. J. Protecting Groups; George Thieme Verlag: Stuttgart and New York, 1994. (2) Recent examples: (a) Evans, V.; Mahon, M. F.; Webster, R. L. Tetrahedron, 2014, DOI: 10.1016/j.tet.2014.07.080. (b) Yang, Q.; Njardarson, J. T. Tetrahedron Lett. 2013, 54, 7080–7082. (c) Sugiura, R.; Kozaki, R.; Kitani, S.; Gosho, Y.; Tanimoto, H.; Nishiyama, Y.; Morimoto, T.; Kakiuchi, K. Tetrahedron, 2013, 69, 3984–3990. (3) (a) Williams, R. M.; Kwast, E. Tetrahedron Lett. 1989, 30, 451–454. (b) Pagano, N.; Wong, E. Y. Breiding, T.; Liu, H.; Wilbuer, A.; Bregman, H.; Shen, Q.; Diamond, S. L.; Meggers, E. J. Org. Chem. 2009, 74, 8997–9009. (c) Rodríguez-Vázquez, N.; Salzinger, S.; Silva, L. F.; Amorín, M.; Granja, J. R. Eur. J. Org. Chem. 2013, 17, 3477–3493. (d) Overman, L. E.; Rosen, M. D. Angew. Chem. Int. Ed. 2000, 39, 4596–4599. (e) Würdemann, M.; Christoffers, J. Org. Biomol. Chem. 2010, 8, 1894–1898. (f) Fukuyama, T.; Frank, R. K.; Jewell, C. F., Jr. J. Am. Chem. Soc. 1980, 102, 2122–2123. (4) (a) Hoffmann, R. W.; Breitfelder, S.; Schlapbach, A. Helv. Chim. Acta 1996, 79, 346– 352. (b) Hennessy, E. J.; Buchwald, S. L. J. Org. Chem. 2005, 70, 7371–7375. (c) Madin, A.; O’Donnell, C. J.; Oh, T. Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054–18065. (d) Fetter, J.; Giang, L. T.; Czuppon, T.; Lempert, K.; KajtárPeredy, M; Czira, G. Tetrahedron, 1994, 50, 4185–4200. (e) Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron, 1989, 45, 2431–2449. (5) Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. 347                                                                                                                                                                                                                                                                                                                                             (6) (a) Piloto, A. M.; Costa, S. P. G.; Goncalves, M. S. T. Tetrahedron, 2014, 70, 650– Chapter 2 – A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 657. (b) Voelker, T.; Ewell, T.; Joo, J.; Edstrom, E. D. Tetrahedron Lett. 1998, 39, 359– 362. (c) Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57, 3301–3307. (d) Miknis, G. F.; Williams, R. M. J. Am. Chem. Soc. 1993, 115, 536–547. (7) (a) Stutz, A.; Pitxch, S. Synlett, 1999, 930–934. (b) Pitsch, S. Helv. Chim. Acta 1997, 80, 2286–2314. (8) Fukase, K.; Tanaka, H.; Torii, S.; Kusumoto, S. Tetrahedron Lett. 1990, 31, 389–392. (9) From the deprotection reaction of urea 143, hemiaminal ether intermediate 153 was observed in 1 hour under the standard reaction conditions and intermediate 153 was converted to propyl urea 144 after 10.5 hours. In addition, acetal 154 was observed in 2 hours during the deprotection reaction of ether 149, and the desired phenylethyl alcohol 150 was isolated after 32 hours. O N O 20% aq NaOH N NO 2 N OMe N N MeOH, 75 °C (94% yield) 143 MeOH, 75 °C (59% yield; 74% yield based on recovered 149 ) 144 OMe 20% aq NaOH NO 2 NH NO 2 153 O 149 O O 154 OH NO 2 150 Appendix 6 – Spectra Relevant to Chapter 2 348 APPENDIX 6 Spectra Relevant to Chapter 2: A New Method for the Cleavage of Nitrobenzyl Amides and Ethers 137a O2N O N                                                                                                     349   Figure A6.1. 1H NMR (500 MHz, CDCl3) of compound 137a. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.2. Infrared spectrum (Thin Film, NaCl) of compound 137a.  Figure A6.3. 13C NMR (125 MHz, CDCl3) of compound 137a.   350   NO 2 137b O N                                                                                                     351   Figure A6.4. 1H NMR (500 MHz, CDCl3) of compound 137b. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.5. Infrared spectrum (Thin Film, NaCl) of compound 137b.  Figure A6.6. 13C NMR (125 MHz, CDCl3) of compound 137b.   352   NO 2 137c O N                                                                                                     353   Figure A6.7. 1H NMR (500 MHz, CDCl3) of compound 137c. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.8. Infrared spectrum (Thin Film, NaCl) of compound 137c.  Figure A6.9. 13C NMR (125 MHz, CDCl3) of compound 137c.   354   139 NO 2 N O                                                                                                     355   Figure A6.10. 1H NMR (500 MHz, CDCl3) of compound 139. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.11. Infrared spectrum (Thin Film, NaCl) of compound 139.  Figure A6.12. 13C NMR (125 MHz, CDCl3) of compound 139.   356   141 NO 2 N O                                                                                                     357   Figure A6.13. 1H NMR (500 MHz, CDCl3) of compound 141. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2                                                                                                     Figure A6.14. Infrared spectrum (Thin Film, NaCl) of compound 141.  Figure A6.15. 13C NMR (125 MHz, CDCl3) of compound 141.   358   NO 2 143 N N O                                                                                                     359   Figure A6.16. 1H NMR (500 MHz, CDCl3) of compound 143. Appendix 6 – Spectra Relevant to Chapter 2 Appendix 6 – Spectra Relevant to Chapter 2     Figure A6.17. Infrared spectrum (Thin Film, NaCl) of compound 143.  Figure A6.18. 13C NMR (125 MHz, CDCl3) of compound 143.   360    Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 361   CHAPTER 3 Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.1. Introduction The unique properties of the axially chiral P,N ligand QUINAP (155a) have been employed widely for various transition metal catalyzed asymmetric reactions.1 However, approaches to the synthesis of QUINAP ligands in high enantiomeric purity are limited.2 In 2013, our laboratories explored the palladium-catalyzed atroposelective synthesis of QUINAP and its derivatives via kinetic resolution and dynamic kinetic resolution.3 With a robust method for the synthesis of chiral QUINAP in hand, we turned our attention to the architecturally related PINAP ligands (156). PINAP ligands (156a and 156b), which possess analogous ligation reactivity to QUINAP, were first developed by the Carreira group in 2004.4 Carreira and co-workers separated the two atropoisomeric diastereomers through column chromatography by preparing chiral ether- or amine-substituted PINAP scaffolds. Herein, we disclose synthetic methods for accessing enantiomerically enriched PINAP ligands via dynamic kinetic resolution (156a, 156c). 362   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution Figure 3.1.1. QUINAP (155) and PINAP (156) R1 O N 3.2. Ph HN Ph N N N N OR 2 N N PPh 2 PPh 2 PPh 2 PPh 2 R 1 = alkyl R 2 = achiral alkyl, benzyl QUINAP (155a) O-PINAP (156a) N-PINAP (156b) PINAP (156c) Results  and  Discussion   Our initial attempts to apply the standard QUINAP dynamic kinetic resolution conditions,3 3.0 mol % of Pd[(o-tol)3P]2 and 4.5 mol % of (S, RFc)-Josiphos at 80 °C, to aryl triflate 157 afforded various alkyl- or benzyl-substituted PINAP ligands (Table 3.2.1). Asymmetric C–P couplings via dynamic kinetic resolution on substrates incorporating methoxy, ethoxy, and isopropoxy groups furnished the corresponding PINAP ligands in good yields and selectivities (158a,b,c). Cyclohexyl, 3,3-dimethyl-1butyl, and homoallyl ether groups were also well tolerated under the reaction conditions to give the desired products. (158d,e,f). Additionally, 3,5-dimethyl benzyloxy- substituted PINAP was obtained in good yield and moderate selectivity (158g). Although these initial results were exciting, it was clear that additional optimization was needed to improve the enantioselectivities in the synthesis of these PINAP ligands. 363   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution Table 3.2.1. Scope of dynamic kinetic resolution under initial standard conditions OR OR Pd[(o-tol)3P] 2 (3.0 mol %) (S, RFc )-Josiphos (4.5 mol %) Ph 2PH, DMAP N N N N dioxane, 80 °C OTf PPh 2 157 158 OMe OEt O O N N N N N N N N PPh 2 PPh 2 PPh 2 PPh 2 158a 158b 158c 158d 90% yieldb, 82% eec 48% yieldb, 71% eec 71% yieldb, 86% eec 80% yieldb, 75% eec t-Bu O O O N N N N N N PPh 2 PPh 2 Cy2P PPh 2 Fe PCy 2 (S, RFc )-Josiphos 158e 158f 158g 61% yieldb, 88% eec 63% yieldb, 82% eec 70% yieldb, 60% eec a Reactions performed with 1.0 equiv of triflate 157, 4.0 equiv of DMAP, 3.0 mol % of Pd[(o-tol)3P]2, 4.5 mol % of (S, RFc)-Josiphos, 1.05 equiv of Ph2PH (1.0 M in dioxane) at 0.20 M in dioxane at 80 °C in a glovebox. Ph2PH (1.0 M in dioxane) was added over 4 h. In order to allow more time for the isomerization of the presumed arylpalladium complex before its subsequent phosphination, diphenylphosphine (1.0 M solution in dioxane) was added slowly.5 In addition, we used pre-stirred 1.0 mol % of Pd[(o-tol)3P]2 and 1.5 mol % of (S, RFc)-Josiphos solutions in dioxane. Interestingly, improved enantioselectivity was observed with reduced palladium and Josiphos ligand loadings (1.0 mol % and 1.5 mol %, respectively) (Table 3.2.2, entries 1 and 2). We were pleased to find that higher enantioselectivities were obtained at lower temperatures (Table 3.2.2, 364   entries 3 and 4). However, the conversion rate was dramatically diminished at 50 °C Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution (Table 3.2.2, entry 5). Table 3.2.2. Optimization of reaction parametersa OMe OMe Pd[(o-tol)3P] 2 (S, RFc )-Josiphos Ph 2PH, DMAP N N OTf N Cy2P N dioxane Fe PCy 2 PPh 2 (S, RFc )-Josiphos 157a entry 158a Pd[(o-tol)3P] 2 (S, RFc )-Josiphos T (°C) yield (%)b ee (%) 82c 1 3.0 mol % 4.5 mol % 80 90 2 1.0 mol % 1.5 mol % 80 95 88c 3 1.0 mol % 1.5 mol % 70 75 92c 4 1.0 mol % 1.5 mol % 60 80 96c 5 1.0 mol % 1.5 mol % 50 –d 94c a   Reactions performed with 1.0 equiv of 157a, 4.0 equiv of DMAP, 1.0 mol % of Pd[(o-tol)3P]2, 1.5 mol % of (S, RFc)-Josiphos, 1.05 equiv of Ph2PH (1.0 M in dioxane) at 0.20 M in dioxane in a glovebox. Pd[(otol)3P]2 and (S, RFc)-Josiphos in dioxane were pre-stirred before use. Ph2PH (1.0 M in dioxane) was added over 8 h. bAll yields are isolated yields. cDetermined by chiral SFC analysis. d~50% conversion. With the optimized conditions in hand, we investigated the substrate scope of the reaction (Table 3.2.3). Several alkoxy- and benzyloxy-substituted PINAP ligands were furnished in improved enantioselectivities under the optimized conditions (158a–158h, 57–80% yields and 82–96% ee). Applying our optimized conditions to a (R)- phenylethoxy-substituted substrate, which was previously prepared by the Carreira group by chromatographic separation, generated the corresponding PINAP product in 95% de (158i). Interestingly, diastereomeric PINAP 158j was produced by our method with lower selectivity using the (R, SFc)-Josiphos ligand indicating some balance between substitute and catalyst in the progress (e.g., mismatched pair). Thankfully, nearly enantiopure PINAP 158j was obtained after recrystallization. Unfortunately, in the case of (R)-α-phenethylamine-substituted PINAP, only moderate selectivity was observed 365   (158k). Additionally, application of our conditions to the reaction of triflate 157a with Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution diphenylphosphine oxide or (p-CF3-C6H4)2PH proved unsuccessful, and only low yield and selectivities were observed.6,7 Table 3.2.3. Scope of dynamic kinetic resolution under optimized conditionsa OR OR Pd[(o-tol)3P] 2 (1.0 mol %) (S, RFc )-Josiphos (1.5 mol %) Ph 2PH, DMAP N N N N dioxane, 60 °C OTf PPh 2 157 158 OMe OEt N N N N N N N N O O PPh 2 PPh 2 158a 158b 158c 158d 80% yieldb, 96% eec 73% yieldb, 94% eec 70% yieldb, 82% eec 67% yieldb, 95% eec t-Bu O O PPh 2 PPh 2 O O N N N N N N N N PPh 2 158e PPh 2 PPh 2 PPh 2 158f 158g 158h 57% yieldb, 95% eec 67% yieldb, 94% eec 60% yieldb, 94% eec 72% yieldb, 94% eec O O Ph Ph HN Ph N N N N N N PPh 2 PPh 2 Cy2P Fe PCy 2 PPh 2 (S, RFc )-Josiphos a 158i 158j f 158k 65% yieldb, 95% ded 71% yieldb, 88% dee (57% yield, >99% dee after recrystallization) 79% yieldb, 60% deg   Reactions performed with 1.0 equiv of 157a, 4.0 equiv of DMAP, 1.0 mol % of Pd[(o-tol)3P]2, 1.5 mol % of (S, RFc)-Josiphos, 1.05 equiv of Ph2PH (1.0 M in dioxane) at 0.20 M in dioxane at 60 °C in a glovebox. Pd[(o-tol)3P]2 and (S, RFc)-Josiphos in dioxane were pre-stirred before use. Ph2PH (1.0 M in dioxane) was added over 8 h. bAll yields are isolated yields. cDetermined by chiral SFC analysis. dDetermined by chiral 366   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution SFC analysis; SFC conditions: 40% IPA, 2.5 mL/min, Chiralpak OD-H column, tR (min): major = 2.81, minor = 3.18. eDetermined by chiral HPLC. f(R, SFc)-Josiphos was used. gDetermined by 1H NMR. We applied PINAP ligand 158a (96% ee) to two different reactions (Scheme 3.2.1).8 Copper catalyzed asymmetric phenylacetylene addition to isoquinoline iminium 159 with PINAP ligand 158a afforded propargylamine 160 in 98% yield and 96% ee (Scheme 3.2.1a).1k, 9 In addition, rhodium-catalyzed enantioselective diboration and oxidation of trans-b-methylstyrene 161 with PINAP 158a produced diol 162 in 71% yield and 88% ee (Scheme 3.2.1b).1e,i,10 The enantioselectivities and yields with PINAP 158a ligand are parallel to those with QUINAP 155a. Scheme 3.2.1. Applications (a) OMe phenylacetylene (10 equiv) 5.0 mol % CuBr 5.5 mol % (R)-PINAP Et 3N (1.0 equiv) MeO N MeO Br Br OMe MeO N MeO CH2Cl2, –55 °C Br Ph 159 160 (98% yield, 96% ee with PINAP 158a ; 85% yield, 95% ee with QUINAP, Ref.1k) (b) Me Ph 1. 5.0 mol % (nbd)Rh(acac) 5.0 mol % (R)-PINAP 1.1 equiv B 2(cat)2 THF, 23 °C OH Me Ph 2. 3N NaOH, 30% H 2O2 OH 161 162 (71% yield, 88% ee with PINAP 158a ; 71% yield, 93% ee with QUINAP, Ref. 1e,i) 3.3. Conclusion   In conclusion, the atroposelective synthesis of various achiral alkyl- or benzyloxy-substituted PINAP ligands via dynamic kinetic resolution has been developed. The asymmetric PINAP ligands formed in this communication are envisioned to be useful in several important asymmetric transformations.4 Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.4. Experimental Methods and Analytical Data 3.4.1. Materials and Methods 367   Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm). 13 C NMR spectra are recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a 368   Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution reported in frequency of absorption (cm-1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell and are reported as: [a]DT (concentration in g/100 mL, solvent). Analytical HPLC was performed with an Agilent 1100 Series HPLC utilizing Chiralpak (AD-H or AS) or Chiralcel (OD-H, OJ-H, or OB-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing Chiralpak (AD-H, AS-H or IC) or Chiralcel (OD-H, OJ-H, or OB-H) columns (4.5 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode, or Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). Triflate substrates 157i–157k were prepared by known methods.11 All the data from pinap 158i–158k were confirmed by reported data.1                                                                                                                 (1) (a) Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem. Int., Ed. 2004, 43, 5971–5973. (b) Fujimori, S.; Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635–1657. 369   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.4.2. Experimental Procedures General Procedure for Synthesis of Triflate Substrates Cl OR N N ROH, NaH N OH SI-3-1 OR N Tf2O, DMAP N dioxane, 60 °C OH SI-3-2 N CH2Cl2 OTf 157 To a solution of NaH (2.64 mmol, 2.00 equiv) in dioxane (5.60 mL) was added alcohol (1.39 mmol, 1.05 equiv) in dioxane (1.00 mL) dropwise. The reaction mixture was stirred for 15 min at 23 °C and then SI-3-1 (1.32 mmol, 1.00 equiv) was added portionwise. The solution was stirred for 18 h at 60 °C then diluted with EtOAc (5.00 mL) and water (10.0 mL). The aqueous phase was extracted with EtOAc (3 x 5.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was used in the next step without further purification. To a solution of crude mixture of SI-3-2 (1.32 mmol, 1.00 equiv) and DMAP (2.64 mmol, 2.00 equiv) in CH2Cl2 (13.2 mL) was added Tf2O (1.32 mmol, 1.00 equiv) dropwise at 0 °C. The reaction mixture was stirred at 23 °C until SI-3-2 was fully consumed by TLC analysis. The reaction mixture was diluted with CH2Cl2 (5.00 mL) and water (5.00 mL). The aqueous phase was extracted with CH2Cl2 (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:4 EtOAc:hexanes) on silica gel to give the corresponding triflate substrates. General Procedure of PINAP from Triflates via Dynamic Kinetic Resolution 370   Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution OR N N OR Pd[(o-tol)3P] 2 (1.0 mol %) (S, RFc )-Josiphos (1.5 mol %) Ph 2PH, DMAP OTf N Cy2P N dioxane, 60 °C Fe PCy 2 PPh 2 (S, RFc )-Josiphos 157 158 This reaction was performed in a nitrogen-filled glovebox. Pd[(o-tol)3P]2 (10.8 mg, 0.0151 mmol) and (S, RFc)-Josiphos (13.7 mg, 0.0226 mmol) in dioxane (0.302 mL) were pre-stirred in a vial until all the solids were dissolved. To a solution of triflates 157 (0.211 mmol, 1.00 equiv) in dioxane (1.06 mL) was added DMAP (0.844 mmol, 4.00 equiv) and pre-stirred Pd[(o-tol)3P]2 and (S, RFc)-Josiphos (0.05 M in dioxane; 0.00211 mmol, 0.01 equiv) at 23 °C. The mixture was placed in a reaction well preheated to 60 °C. A solution of Ph2PH (1.00 M in dioxane; 0.317 mmol, 1.50 equiv) was added to the reaction mixture in 20 uL portions every 30 minutes manually. After completion of the addition (8 hours), the reaction was stirred for further 7 hours at which point complete consumption of the starting material was observed. The reaction was cooled, removed from the glovebox and dilulted with EtOAc (1.50 mL) and water (2.00 mL). The aqueous phase was extracted with EtOAc (3 x 1.50 mL). The combined organic phases were washed with brine, dried with MgSO4 and concentrated. The crude material was purified by flash column chromatography on silica gel to afford the corresponding PINAP 158. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 3.4.3. 371   Spectroscopic Data OMe N N OTf 157a 52% (2-step yield); Rf = 0.29 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.35 (dd, J = 8.2, 1.0 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.87 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.70 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.58 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.42 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.31 (dt, J = 8.4, 1.0 Hz, 1H), 4.41 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 160.9, 151.1, 145.6, 133.6, 132.7, 132.6, 132.4, 131.9, 129.2, 128.4, 128.1, 127.4, 126.7, 126.6, 125.7, 123.5, 119.9, 119.6, 117.1, 55.3; IR (Neat Film NaCl) 3063, 2945, 1668, 1581, 1541, 1496, 1457, 1420, 1364, 1247, 1213, 1139, 952, 834 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C20H14F3N2O4S [M+H]+ : 435.0621; found: 435.0625. OEt N N OTf 157b 48% (2-step yield); Rf = 0.33 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, Chloroform-d) δ 8.38 (dd, J = 8.2, 1.2 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.87 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H), 7.69 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.61 (d, J = 9.0 Hz, 1H), 7.57 (ddd, J = 8.2, 6.7, 1.4 Hz, 1H), 7.42 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.29 (dd, J = 8.3, 1.0 Hz, 1H), 4.88 (qd, J = 7.0, 3.9 Hz, 2H), 1.62 (td, J = 372   7.1, 1.6 Hz, 3H); C NMR (126 MHz, CDCl3) δ 160.6, 150.7, 145.6, 133.6, 132.7, 132.5, Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 13 132.3, 131.8, 129.2, 128.4, 128.1, 127.4, 126.7, 126.6, 125.6, 123.6, 120.0, 119.6, 117.1, 63.9, 14.7; IR (Neat Film NaCl) 3066, 2984, 1582, 1540, 1495, 1422, 1381, 1342, 1214, 1140, 1073, 1024, 956, 941, 834 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C21H16F3N2O4S [M+H]+ : 449.0777; found: 449.0780. O N N OTf 157c 37% (2-step yield); Rf = 0.35 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.37 (dd, J = 8.2, 1.0 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.87 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.69 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.58 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.43 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H), 7.40 – 7.35 (m, 1H), 7.30 (dt, J = 8.3, 0.9 Hz, 1H), 5.94 (hept, J = 6.2 Hz, 1H), 1.60 (d, J = 6.1 Hz, 3H), 1.58 (d, J = 6.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 160.3, 150.2, 145.7, 133.5, 132.7, 132.5, 132.4, 132.0, 129.3, 128.5, 128.2, 127.4, 126.6, 126.4, 125.7, 123.7, 120.4, 119.7, 71.1, 22.3, 22.1; IR (Neat Film NaCl) 2981, 1582, 1493, 1417, 1322, 1212, 1140, 1106, 958, 942, 833, 748 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H17F3N2O4S [M+H]+ : 463.0934; found: 463.0964. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 373   O N N OTf 157d 36% (2-step yield); Rf = 0.43 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.2 Hz, 1H), 8.11 (dd, J = 9.1, 1.6 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.85 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.67 (td, J = 7.7, 7.0, 1.4 Hz, 1H), 7.61 (dd, J = 9.1, 2.0 Hz, 1H), 7.57 (ddd, J = 8.2, 6.2, 1.9 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.27 (d, J = 8.3 Hz, 1H), 5.72 (tt, J = 8.7, 3.7 Hz, 1H), 2.25 (d, J = 12.3 Hz, 2H), 1.90 (ddt, J = 13.9, 8.9, 4.5 Hz, 2H), 1.85 – 1.74 (m, 2H), 1.66 (td, J = 8.5, 7.7, 4.2 Hz, 1H), 1.57 (dtt, J = 13.5, 10.2, 3.4 Hz, 2H), 1.45 (ddt, J = 13.3, 10.1, 3.5 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 160.2, 150.3, 145.6, 133.6, 132.7, 132.3, 132.1, 131.7, 129.3, 128.4, 128.1, 127.3, 126.9, 126.7, 125.5, 123.7, 120.3, 119.7, 75.4, 32.0, 31.8, 25.9, 24.1; IR (Neat Film NaCl) 2937, 2858, 1582, 1537, 1493, 1418, 1362, 1342, 1214, 1140, 959, 944, 834 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C25H22F3N2O4S [M+H]+ : 503.1247; found: 503.1248. O N N OTf 157e 49% (2-step yield); Rf = 0.33 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.86 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.69 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.62 (d, J = 9.1 Hz, 1H), 7.57 (ddd, 374   J = 8.2, 6.6, 1.3 Hz, 1H), 7.42 (ddd, J = 8.1, 6.6, 1.2 Hz, 1H), 7.39 – 7.35 (m, 1H), 7.29 Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution (d, J = 8.3 Hz, 1H), 4.88 (t, J = 7.2 Hz, 2H), 1.96 (t, J = 7.2 Hz, 2H), 1.10 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 160.7, 150.7, 145.6, 133.6, 132.7, 132.4, 132.3, 131.8, 129.2, 128.4, 128.1, 127.4, 126.6, 125.6, 123.5, 120.0, 119.6, 117.1, 110.2, 65.8, 42.5, 30.0; IR (Neat Film NaCl) 2958, 1582, 1538, 1495, 1422, 1360, 1214, 1141, 1073, 953, 834, 620 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C25H23F3N2O4S [M+H]+ : 505.1403; found: 505.1436. O N N OTf 157f 52% (2-step yield); Rf = 0.33 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.38 – 8.34 (m, 1H), 8.12 (d, J = 9.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.87 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.69 (ddd, J = 8.4, 7.0, 1.3 Hz, 1H), 7.61 (d, J = 9.1 Hz, 1H), 7.57 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.42 (ddd, J = 8.1, 6.7, 1.2 Hz, 1H), 7.38 – 7.35 (m, 1H), 7.30 (dd, J = 8.3, 1.1 Hz, 1H), 6.04 (ddt, J = 17.1, 10.3, 6.7 Hz, 1H), 5.28 (dq, J = 17.2, 1.7 Hz, 1H), 5.17 (dq, J = 10.3, 1.4 Hz, 1H), 4.94 – 4.83 (m, 2H), 2.78 (dddd, J = 8.1, 6.6, 5.2, 1.4 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 160.6, 150.9, 145.6, 134.6, 133.6, 132.7, 132.5, 132.3, 131.8, 129.2, 128.4, 128.1, 127.4, 126.7, 126.6, 125.6, 123.5, 119.9, 119.6, 117.3, 117.1, 67.0, 33.6; IR (Neat Film NaCl) 1581, 1538, 1494, 1421, 1349, 1213, 1139, 954, 833 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C23H18F3N2O4S [M+H]+ : 475.0934; found: 475.0956. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 375   O N N OTf 157g 35% (2-step yield); Rf = 0.38 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.40 (dt, J = 8.2, 1.0 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.00 (dt, J = 8.3, 0.9 Hz, 1H), 7.86 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.70 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.63 (d, J = 9.1 Hz, 1H), 7.58 (ddd, J = 8.2, 6.6, 1.3 Hz, 1H), 7.43 (ddd, J = 7.9, 6.6, 1.3 Hz, 1H), 7.39 (dd, J = 8.6, 1.2 Hz, 1H), 7.31 (dt, J = 8.4, 1.0 Hz, 1H), 7.04 (s, 1H), 5.80 (d, J = 2.3 Hz, 2H), 2.39 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 160.6, 151.1, 145.6, 138.3, 136.7, 133.6, 132.7, 132.6, 132.3, 131.8, 130.1, 129.3, 128.4, 128.1, 127.4, 126.7, 126.6, 126.6, 125.6, 123.7, 119.9, 119.7, 117.1, 69.8, 21.4; IR (Neat Film NaCl) 2917, 1581, 1494, 1418, 1343, 1213, 1140, 956, 835 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C28H22F3N2O4S [M+H]+ : 539.1247; found: 539.1252. O N N OTf 157h 68% (2-step yield); Rf = 0.37 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.38 (dt, J = 8.2, 1.0 Hz, 1H), 8.13 (d, J = 9.1 Hz, 1H), 8.01 (dt, J = 8.3, 0.9 Hz, 1H), 7.85 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.70 (ddd, J = 8.4, 7.1, 1.3 Hz, 1H), 7.62 (dd, J = 9.1, 1.1 Hz, 1H), 7.58 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.57 – 7.52 (m, 2H), 7.43 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.37 (dt, J = 8.6, 1.0 Hz, 1H), 7.31 (dt, J = 8.3, 1.0 Hz, 1H), 7.27 (d, J = 7.2 376   Hz, 2H), 5.81 (d, J = 7.1 Hz, 2H), 2.41 (s, 3H); C NMR (126 MHz, CDCl3) δ 160.5, Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 13 151.1, 145.5, 138.3, 133.7, 133.5, 132.6, 132.3, 131.9, 129.4, 129.2, 128.90, 128.4, 128.1, 127.4, 126.7, 126.6, 125.6, 123.6, 119.8, 119.6, 119.6, 117.0, 69.6, 21.4; IR (Neat Film NaCl) 3058, 1581, 1538, 1494, 1422, 1342, 1248, 1266, 1140, 1072, 953, 834, 776 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C27H19F3N2O4S [M+H]+ : 525.1090; found: 525.1096. OMe N N PPh 2 158a [a]D25 +124.5 (c 0.51, CHCl3); Rf = 0.42 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.27 (dt, J = 8.3, 1.0 Hz, 1H), 7.91 (dd, J = 8.6, 0.8 Hz, 1H), 7.90 – 7.87 (m, 1H), 7.74 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.49 (ddd, J = 8.2, 6.8, 1.2 Hz, 1H), 7.46 – 7.42 (m, 2H), 7.29 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.27 – 7.14 (m, 11H), 7.07 (dt, J = 8.2, 0.9 Hz, 1H), 4.36 (s, 3H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.4, 156.8, 156.8, 141.5, 141.3, 137.5, 137.4, 137.3, 137.2, 136.0, 135.9, 134.0, 133.9, 133.7, 133.3, 133.2, 133.1, 131.8, 131.7, 130.3, 130.0, 129.9, 129.3, 128.7, 128.4, 128.4, 128.2, 128.1, 127.1, 126.9, 126.7, 126.7, 126.1, 123.2, 119.6, 55.1; 31P NMR (121 MHz, CDCl3) δ -14.3; IR (Neat Film NaCl) 3053, 1582, 1538, 1495, 1456, 1362, 1112, 1018, 744 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C31H23N2OP [M+H]+ : 471.1621; found: 471.1674; SFC conditions: 35% IPA, 2.5mL/min, Chiralcel OD-H column, tR (min): major = 5.81, minor = 5.16. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 377   OEt N N PPh 2 158b [a]D25 +150.3 (c 0.47, CHCl3); Rf = 0.54 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.30 (dd, J = 8.2, 1.0 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.74 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.49 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.47 – 7.41 (m, 2H), 7.29 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.27 – 7.13 (m, 11H), 7.07 (d, J = 8.2 Hz, 1H), 4.83 (qt, J = 7.1, 2.1 Hz, 2H), 1.60 (t, J = 7.1 Hz, 3H); (due to the C–P coupling, the 13 C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.2, 156.5, 156.5, 141.6, 141.3, 137.6, 137.5, 137.3, 137.2, 136.0, 135.9, 134.0, 133.8, 133.7, 133.3, 133.2, 133.1, 131.8, 131.5, 130.3, 130.0, 129.9, 129.2, 128.6, 128.4, 128.4, 128.2, 128.1, 127.1, 126.8, 126.8, 126.7, 126.1, 123.3, 119.6, 63.5, 14.9; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 3053, 2980, 1583, 1538, 1494, 1418, 1378, 1342, 1165, 1110, 1023, 818, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C32H25N2OP [M+H]+ : 485.1777; found: 485.1800; SFC conditions: 30% MeOH, 2.5mL/min, Chiralpak AD-H column, tR (min): major = 2.60, minor = 3.09. O N N PPh 2 158c 378   +131.7 (c 0.57, CHCl3); Rf = 0.54 (1:2 EtOAc:hexanes); H NMR (500 MHz, Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution [a]D 25 1 CDCl3) δ 8.29 (dt, J = 8.1, 1.0 Hz, 1H), 7.90 (t, J = 9.0 Hz, 2H), 7.73 (ddd, J = 8.2, 7.1, 1.1 Hz, 1H), 7.52 – 7.42 (m, 3H), 7.30 (ddd, J = 8.4, 6.6, 1.2 Hz, 1H), 7.28 – 7.15 (m, 11H), 7.08 (dt, J = 8.1, 0.9 Hz, 1H), 5.88 (p, J = 6.2 Hz, 1H), 1.58 (d, J = 5.7 Hz, 3H), 1.56 (d, J = 5.7 Hz, 3H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 159.7, 156.0, 156.0, 141.6, 141.3, 137.6, 137.5, 137.3, 137.2, 136.0, 135.9, 134.0, 133.8, 133.7, 133.4, 133.2, 133.2, 133.1, 131.7, 131.4, 130.2, 130.0, 129.2, 128.6, 128.4, 128.4, 128.4, 128.4, 128.2, 128.1, 127.0, 126.8, 126.0, 123.4, 120.0, 70.1, 22.4, 22.3; 31P NMR (121 MHz, CDCl3) δ -13.9; IR (Neat Film NaCl) 3053, 2978, 1584, 1489, 1413, 1383, 1315, 1106, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C33H27N2OP [M+H]+ : 499.1934; found: 499.1960; SFC conditions: 40% MeOH, 2.5mL/min, Chiralpak AD-H column, tR (min): major = 1.94, minor = 2.22. O N N PPh 2 158d [a]D25 +91.0 (c 0.57, CHCl3); Rf = 0.61 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.29 (dt, J = 8.2, 1.0 Hz, 1H), 7.89 (ddd, J = 9.4, 8.2, 0.8 Hz, 2H), 7.73 (ddd, J = 8.3, 7.0, 1.2 Hz, 1H), 7.49 (ddd, J = 8.1, 6.7, 1.3 Hz, 1H), 7.46 – 7.41 (m, 2H), 7.29 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.26 – 7.14 (m, 11H), 7.07 (dt, J = 8.3, 0.9 Hz, 1H), 5.67 (tt, J = 8.9, 3.8 Hz, 1H), 2.30 – 2.18 (m, 2H), 1.88 (ddtd, J = 9.3, 7.9, 5.4, 4.0 Hz, 2H), 1.76 (qdt, 379   J = 9.9, 6.1, 3.7 Hz, 2H), 1.64 (tt, J = 9.1, 4.9 Hz, 1H), 1.54 (qq, J = 10.2, 3.5 Hz, 2H), Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 1.42 (ddt, J = 13.4, 10.2, 3.5 Hz, 1H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 159.6, 156.0, 155.9, 141.6, 141.4, 137.6, 137.5, 137.3, 137.2, 136.0, 135.9, 134.0, 133.9, 133.7, 133.4, 133.2, 131.7, 131.4, 130.3, 130.0, 129.2, 128.6, 128.4, 128.4, 128.4, 128.4, 128.2, 128.1, 127.0, 126.8, 126.8, 126.8, 126.0, 123.4, 120.0, 74.8, 32.0, 31.9, 25.9, 24.1, 24.0; 31P NMR (121 MHz, CDCl3) δ -13.9; IR (Neat Film NaCl) 3051, 2933, 2856, 1582, 1538, 1490, 1432, 1413, 1361, 1341, 1311, 1263, 1215, 1165, 1113, 1068, 1046, 1019, 744 cm1 ; HRMS (MM: ESI-APCI+) m/z calc’d for C36H31N2OP [M+H]+ : 539.2247; found: 539.2268; SFC conditions: 25% MeOH, 2.5mL/min, Chiralcel OD-H column, tR (min): major = 7.58, minor = 8.13. O N N PPh 2 158e [a]D25 +101.2 (c 0.42, CHCl3); Rf = 0.62 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.27 (dt, J = 8.2, 1.0 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.73 (ddt, J = 8.7, 7.1, 1.4 Hz, 1H), 7.49 (ddt, J = 8.5, 6.9, 1.5 Hz, 1H), 7.46 – 7.40 (m, 2H), 7.29 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.27 – 7.14 (m, 11H), 7.06 (d, J = 8.2 Hz, 1H), 4.87 – 4.77 (m, 2H), 1.94 (td, J = 7.1, 1.9 Hz, 2H), 1.09 (s, 9H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.3, 156.5, 156.4, 141.6, 141.3, 137.6, 137.5, 137.3, 137.2, 136.0, 380   135.9, 134.0, 133.9, 133.7, 133.3, 133.2, 133.1, 131.7, 131.6, 130.3, 129.9, 129.2, 128.7, Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 128.4, 128.4, 128.2, 128.1, 127.1, 126.8, 126.8, 126.7, 126.1, 123.2, 119.7, 77.2, 65.4, 42.5, 30.1; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 3051, 2956, 1418, 1386, 1114, 743 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C36H33N2OP [M+H]+ : 541.2403; found: 541.2409; SFC conditions: 35% IPA, 2.5mL/min, Chiralcel OD-H column, tR (min): major = 4.33, minor = 4.84. O N N PPh 2 158f [a]D25 +117.9 (c 0.52, CHCl3); Rf = 0.62 (1:2 EtOAc:hexanes); 1 H NMR (500 MHz, CDCl3) δ 8.28 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.75 (ddd, J = 8.3, 7.1, 1.2 Hz, 1H), 7.52 – 7.41 (m, 3H), 7.30 (ddd, J = 8.3, 6.8, 1.3 Hz, 1H), 7.26 – 7.14 (m, 11H), 7.08 (dt, J = 8.4, 0.9 Hz, 1H), 6.04 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.28 (dq, J = 17.2, 1.7 Hz, 1H), 5.17 (dt, J = 10.5, 1.6 Hz, 1H), 4.88 – 4.77 (m, 2H), 2.75 (qt, J = 6.8, 1.3 Hz, 2H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.1, 156.7, 156.6, 141.5, 141.2, 137.6, 137.5, 137.2, 137.2, 136.0, 135.9, 134.9, 134.0, 133.8, 133.7, 133.3, 133.2, 133.2, 133.1, 131.9, 131.6, 130.3, 130.0, 130.0, 129.3, 128.7, 128.4, 128.4, 128.2, 128.1, 127.1, 126.9, 126.7, 126.7, 126.1, 123.2, 119.6, 117.2, 77.2, 66.7, 33.7; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 2096, 1642, 1417, 1348, 1113, 1020, 818, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C34H27N2OP [M+H]+ : 511.1934; 381   found: 511.1954; SFC conditions: 35% MeOH, 2.5mL/min, Chiralpak AD-H column, tR Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution (min): major = 3.00, minor = 3.66. O N N PPh 2 158g [a]D25 +40.1 (c 0.31, CHCl3); Rf = 0.56 (1:2 EtOAc:hexanes); 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 8.2 Hz, 1H), 7.91 (t, J = 7.8 Hz, 2H), 7.73 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.54 – 7.41 (m, 3H), 7.35 – 7.13 (m, 14H), 7.12 – 7.03 (m, 2H), 5.74 (d, J = 5.4 Hz, 2H), 2.39 (s, 6H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (75 MHz, CDCl3) δ 160.1, 156.9, 156.8, 141.5, 141.1, 138.3, 137.5, 137.4, 137.3, 137.1, 136.9, 136.0, 135.9, 134.1, 133.8, 133.7, 133.4, 133.2, 133.1, 133.1, 131.9, 131.6, 130.3, 130.0, 130.0, 129.3, 128.7, 128.5, 128.4, 128.4, 128.2, 128.1, 127.1, 126.9, 126.7, 126.7, 126.6, 126.6, 126.1, 123.4, 119.6, 69.5, 21.5; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 3052, 2917, 1608, 1582, 1538, 1492, 1480, 1432, 1414, 1386, 1345, 1264, 1165, 1113, 1019, 962, 851, 818, 777, 743 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C39H31N2OP [M+H]+ : 575.2247; found: 575.2293; SFC conditions: 40% MeOH, 2.5mL/min, Chiralcel OD-H column, tR (min): major = 5.77, minor = 6.82. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 382   O N N PPh 2 158h [a]D25 +118.5 (c 0.33, CHCl3); Rf = 0.61 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 8.29 (dt, J = 8.2, 1.7 Hz, 1H), 7.91 (dd, J = 8.6, 2.5 Hz, 1H), 7.88 (dd, J = 8.2, 1.1 Hz, 1H), 7.71 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.52 (dd, J = 8.2, 2.6 Hz, 2H), 7.48 (ddd, J = 8.2, 6.7, 1.3 Hz, 1H), 7.43 (dddd, J = 9.2, 6.0, 3.4, 1.8 Hz, 2H), 7.32 – 7.13 (m, 14H), 7.10 – 7.06 (m, 1H), 5.76 (q, J = 12.1 Hz, 2H), 2.40 (s, 3H); (due to the C–P coupling, the 13C NMR contained extra peaks. See the attached spectrum); 13C NMR (126 MHz, CDCl3) δ 160.1, 156.9, 156.8, 141.4, 141.2, 138.1, 137.5, 137.4, 137.2, 137.1, 136.0, 135.9, 134.0, 133.9, 133.7, 133.4, 133.2, 133.1, 131.9, 131.6, 130.3, 130.0, 130.0, 129.4, 129.4, 129.3, 128.9, 128.7, 128.4, 128.4, 128.4, 128.4, 128.3, 128.1, 127.1, 126.9, 126.7, 126.7, 126.1, 123.3, 119.6, 69.3, 21.4; 31P NMR (121 MHz, CDCl3) δ -14.2; IR (Neat Film NaCl) 3051, 1583, 1492, 1416, 1345, 1163, 1112, 1019, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C38H29N2OP [M+H]+ : 561.2090; found: 561.2090; SFC conditions: 40% MeOH, 2.5mL/min, Chiralpak AD-H column, tR (min): major = 3.43, minor = 5.21. 3.5. References and Notes                                                                                                                 (1)   (a) Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J. M. Chem. Eur. J. 1999, 5, 1320–1330. (b) Faller, J. W.; Grimmond, B. J. Organometallics 2001, 20, 2454–2458. (c) Maeda, K.; Brown, J. M. Chem. Commun. 2002, 310–311. (d) Gommermann, N.; 383                                                                                                                                                                                                                                                                                                                                             Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763–5766. (e) Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003, 125, 8702–8703. (f) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174–10175. (g) DauraOller, E.; Segarra, A. M.; Poblet, J. M.; Claver, C.; Fernández, E.; Bo, C. J. Org. Chem. 2004, 69, 2669–2680. (h) Black, A.; Brown, J. M.; Pichon, C. Chem. Commun. 2005, 5284–5286. (i) Trudeau, S.; Morgan, J. B.; Shrestha, M.; Morken, J. P. J. Org. Chem. 2005, 70, 9538–9544. (j) Gommermann, N.; Knochel, P. Chem.–Eur. J. 2006, 12, 4380– 4392. (k) Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143–146. (l) Li, X.; Kong, L.; Gao, Y.; Wang, X. Tetrahedron Lett. 2007, 48, 3915–3917. (m) Miura, T.; Yamauchi, M.; Kosaka, A.; Murakami, M. Angew. Chem., Int. Ed. 2010, 49, 4955–4957. (n) Lim, A. D.; Codelli, J. A.; Reisman, S. E. Chem. Sci. 2013, 4, 650–654. (o) Fernández, E. Guiry, P. J.; Connole, K. P. T.; Brown, J. M. J. Org. Chem. 2014, 79, 5391–5400. (2) (a) Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743–756. (b) Lim, C. W.; Tissot, O.; Mattison, A. Hooper, M. W.; Brown, J. M.; Cowley, A. R.; Hulmes, D. I.; Blacker, A. J. Org. Process Res. Dev. 2003, 7, 379–384. (c) Thaler, T.; Geittner, F.; Knochel, P. Synlett 2007, 2655–2658. (d) Clayden, J.; Fletcher, S. P.; McDouall, J. J. W.; Rowbottom, S. J. M. J. Am. Chem. Soc. 2009, 131, 5331–5343. (3) Bhat, V.; Wang, S.; Stoltz, B. M.; Virgil, S. C. J. Am. Chem. Soc. 2013, 135, 16829– 16832. (4) (a) Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971–5973. (b) Fujimori, S.; Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635–1657. (5)  See Ref. 3 for a plausible mechanism of this dynamic kinetic resolution. 384                                                                                                                                                                                                                                                                                                                                               (6)   Attempts to produce PINAP derivatives with diphenylphosphine oxide and (p-CF3Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution C6H4)2PH in high enantioselectivities under our dynamic kinetic resolution conditions were unsuccessful. OMe OMe Pd[(o-tol)3P] 2 (S, RFc )-Josiphos Ar2PH, DMAP N N N N dioxane OTf Cy2P O PCy 2 Fe PAr 2 (S, RFc )-Josiphos 157a 163 O entry Ar2PH T (°C) ee (%) –b 1 diphenylphosphine oxide 60 2 (p-CF3-C6H 4)2PH 60 –c 3 (p-CF3-C6H 4)2PH 70 38d 4 (p-CF3-C6H 4)2PH 80 50d a Reactions performed with 1.0 equiv of 157a , 4.0 equiv of DMAP, 1.0 mol % of Pd[(o-tol) P] , 3 2 1.5 mol % of (S, RFc )-Josiphos, 1.05 equiv of Ar2PH (1.0 M in dioxane) at 0.20 M in dioxane in a b c glovebox. Ar2PH (1.0 M in dioxane) was added over 8 h. No reaction. ~50% conversion. d Determined by chiral SFC analysis; SFC conditions: 35% IPA, 2.5 mL/min, Chiralpak IC column, tR (min): major = 3.06, minor = 3.98.   (7) To demonstrate the scope of our methodology, the enantioselective synthesis of Quinazolinap from triflate 164 was attempted, but our reaction conditions led to poor conversion. Moreover, treatment of triflate 166 with the optimized conditions for PINAP provided the QUINAP ligand in diminished selectivity compared to that with the original reaction conditions3. (a) Pd[(o-tol)3P] 2 (1.0 mol %) (S, RFc )-Josiphos (1.5 mol %) Ph 2PH (1.05 equiv) DMAP (4.0 equiv) N N OTf N N PPh 2 dioxane, 60 °C 164 165 (Low conversion) Pd[(o-tol)3P] 2 (1.0 mol %) (S, RFc )-Josiphos (1.5 mol %) Ph 2PH (1.05 equiv) DMAP (4.0 equiv) (b) N OTf 166 N PPh 2 dioxane, 60 °C 155a (69% yield, 76% ee) 385                                                                                                                                                                                                                                                                                                                                             (8) 96% ee (R)-PINAP 158a was used for both applications. Chapter 3 – Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution (9) Determined by chiral HPLC analysis: conditions: 10% IPA 45 min, AD column, tR: (min): minor = 10.5 min, major = 18.2 min. All the other spectra data were identical to the reported data. (ref. 1k) (10) Determined by chiral SFC analysis: conditions: 20% MeOH, 2.5 mL/min, AD-H column, tR (min): major = 2.46 min, minor = 2.92 min; [a]D25 +38.6 (c 0.19, CHCl3) Appendix 7 – Spectra Relevant to Chapter 3 386 APPENDIX 7 Spectra Relevant to Chapter 3: Enantioselective Synthesis of PINAP via Dynamic Kinetic Resolution 157a OTf N N OMe                                                                                                   387   Figure A7.1. 1H NMR (500 MHz, CDCl3) of compound 157a. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.2. Infrared spectrum (Thin Film, NaCl) of compound 157a.  Figure A7.3. 13C NMR (126 MHz, CDCl 3) of compound 157a.   388   157b OTf N N OEt                                                                                                   389   Figure A7.4. 1H NMR (500 MHz, CDCl3) of compound 157b. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.5. Infrared spectrum (Thin Film, NaCl) of compound 157b.  Figure A7.6. 13C NMR (126 MHz, CDCl3) of compound 157b.   390   157c OTf N N O                                                                                                   391   Figure A7.7. 1H NMR (500 MHz, CDCl3) of compound 157c. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.8. Infrared spectrum (Thin Film, NaCl) of compound 157c.  Figure A7.9. 13C NMR (126 MHz, CDCl 3) of compound 157c.   392   157d OTf N N O                                                                                                   393   Figure A7.10. 1H NMR (500 MHz, CDCl3) of compound 157d. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.11. Infrared spectrum (Thin Film, NaCl) of compound 157d.  Figure A7.12. 13C NMR (126 MHz, CDCl3) of compound 157d.   394   157e OTf N N O                                                                                                   395   Figure A7.13. 1H NMR (500 MHz, CDCl3) of compound 157e. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.14. Infrared spectrum (Thin Film, NaCl) of compound 157e.  Figure A7.15. 13C NMR (126 MHz, CDCl3) of compound 157e.   396   157f OTf N N O                                                                                                   397   Figure A7.16. 1H NMR (500 MHz, CDCl3) of compound 157f. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.17. Infrared spectrum (Thin Film, NaCl) of compound 157f.  Figure A7.18. 13C NMR (126 MHz, CDCl3) of compound 157f.   398   157g OTf N N O                                                                                                   399   Figure A7.19. 1H NMR (500 MHz, CDCl3) of compound 157g. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.20. Infrared spectrum (Thin Film, NaCl) of compound 157g.  Figure A7.21. 13C NMR (126 MHz, CDCl3) of compound 157g.   400   157h OTf N N O                                                                                                   401   Figure A7.22. 1H NMR (500 MHz, CDCl3) of compound 157h. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3   Figure A7.23. Infrared spectrum (Thin Film, NaCl) of compound 157h.  Figure A7.24. 13C NMR (126 MHz, CDCl3) of compound 157h.   402   158a PPh 2 N N OMe                                                                                                   403   Figure A7.25. 1H NMR (500 MHz, CDCl3) of compound 158a. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                     Figure A7.26. Infrared spectrum (Thin Film, NaCl) of compound 158a.  Figure A7.27. 13C NMR (126 MHz, CDCl3) of compound 158a.   404   158b PPh 2 N N OEt                                                                                                   405   Figure A7.28. 1H NMR (500 MHz, CDCl3) of compound 158b. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.29. Infrared spectrum (Thin Film, NaCl) of compound 158b.  Figure A7.30. 13C NMR (126 MHz, CDCl3) of compound 158b.   406   158c PPh 2 N N O                                                                                                   407   Figure A7.31. 1H NMR (500 MHz, CDCl3) of compound 158c. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.32. Infrared spectrum (Thin Film, NaCl) of compound 158c.  Figure A7.33. 13C NMR (126 MHz, CDCl3) of compound 158c.   408   158d PPh 2 N N O                                                                                                   409   Figure A7.34. 1H NMR (500 MHz, CDCl3) of compound 158d. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.35. Infrared spectrum (Thin Film, NaCl) of compound 158d.  Figure A7.36. 13C NMR (126 MHz, CDCl3) of compound 158d.   410   158e PPh 2 N N O                                                                                                   411   Figure A7.37. 1H NMR (500 MHz, CDCl3) of compound 158e. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.38. Infrared spectrum (Thin Film, NaCl) of compound 158e.  Figure A7.39. 13C NMR (126 MHz, CDCl3) of compound 158e.   412   158f PPh 2 N N O                                                                                                   413   Figure A7.40. 1H NMR (500 MHz, CDCl3) of compound 158f. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.41. Infrared spectrum (Thin Film, NaCl) of compound 158f.  Figure A7.42. 13C NMR (126 MHz, CDCl3) of compound 158f.   414   158g PPh 2 N N O                                                                                                   415   Figure A7.43. 1H NMR (300 MHz, CDCl3) of compound 158g. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3                                                                                                   Figure A7.44. Infrared spectrum (Thin Film, NaCl) of compound 158g.  Figure A7.45. 13C NMR (75 MHz, CDCl 3) of compound 158g.   416   158h PPh 2 N N O                                                                                                   417   Figure A7.46. 1H NMR (500 MHz, CDCl3) of compound 158h. Appendix 7 – Spectra Relevant to Chapter 3 Appendix 7 – Spectra Relevant to Chapter 3     Figure A7.47. Infrared spectrum (Thin Film, NaCl) of compound 158h.  Figure A7.48. 13C NMR (126 MHz, CDCl3) of compound 158h.   418    Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   419   CHAPTER 4 Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers† 4.1. Introduction Transition metal-catalyzed cross-coupling reactions have served a powerful tool for efficient carbon–carbon and carbon–heteroatom bond formations over the past several decades. 1 Recently, nickel catalysis has emerged in the synthetic community as an exceptionally useful strategy for cross-coupling. 2 Although tremendous advances in nickel-catalyzed carbon–carbon bond formation have been achieved (e.g., Negishi, Suzuki, Stille, Kumada, Hiyama couplings),3 nickel-catalyzed carbon–oxygen bond forming processes have proven significantly more challenging. The rationale behind this is that reductive elimination of Ni(II) alkoxide complexes is often cited as being significantly challenging even at elevated temperatures. 4 To circumvent this challenge, stoichiometric oxidation of Ni(II) to the less stable Ni(III) analogs has been required. Additionally, reductive elimination of Ni(II) alkoxides is                                                                                                                 †   This work was performed in collaboration with Dr. Ryohei Doi. Additionally, this work has been published and adapted with permission from Han, S.-J.; Doi, R.; Stoltz, B. M. Angew. Chem., Int. Ed. 2016, DOI: 10.1002/anie.201601991; Han, S.-J.; Doi, R.; Stoltz, B. M. Angew. Chem. 2016, DOI: 10.1002/ange.201601991. Copyright 2016 Elsevier. 420     reported to be endothermic via computational analysis. This is in contrast to that of Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers Pd(II) alkoxides, which are exothermic.5 In 1997, Hartwig and co-workers developed the first nickel-catalyzed cross-coupling between electron-deficient aryl halides and pre-formed sodium alkoxides or sodium siloxides.6 In 2014, the Ranu group reported a copper-assisted nickel-catalyzed coupling of phenol derivatives and vinyl halides.7 However, both of these reactions require high temperatures, and the scope of the nucleophiles is limited to pre-formed alkoxides or phenols. Most recently, MacMillan and co-workers developed the nickel-catalyzed intermolecular cross-coupling of aryl bromides and aliphatic alcohols in the presence of light and a photoredox catalyst.8 Importantly, MacMillan and co-workers could not observe their desired C–O coupling products in the absence of either the photocatalyst or light. Although Pd- or Cucatalyzed C–O bond forming reactions have been significantly developed, most of these reactions require high temperature that can limit their utility in the synthesis of multifunctional complex molecules. Moreover, the vast majority of these examples are for aryl ether synthesis, not enol ether synthesis.9,10,11 To our knowledge, a mild and efficient nickel-catalyzed intramolecular cross-coupling cyclization between aliphatic hydroxyl nucleophiles and tethered vinyl halides is unprecedented. 4.2. Results and Discussion In the course of an alkaloid synthesis effort, we attempted a nickel-catalyzed reductive Heck reaction of vinyl iodide 167 with the aim of producing tricycle 168 (Scheme 4.2.1, red arrows).12 Surprisingly, instead of the desired intramolecular C–C bond-forming reaction, a C–O bond-forming cyclization between the vinyl iodide and the free hydroxyl group furnished morpholine derivative 169 (Scheme 4.2.1, blue arrows). Given the lack of precedent in the literature for such a transformation with 421     nickel catalysis, we set out to explore the generality of this reaction. Herein, we Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers describe the first nickel-catalyzed cycloetherification of aliphatic alcohols with pendant vinyl halides. Scheme 4.2.1. Ni-Catalyzed C–O Bond Formation reductive Heck reaction Ni(COD) 2 (50 mol %) Et 3N (10 equiv) O PMB I N H 167 Me H H N N CH3CN, DMF, 23 °C N OH O PMB H C–O bond formation Me H OH 168 (Not Observed) O Ni(COD) 2 (50 mol %) Et 3N (10 equiv) CH3CN, DMF, 23 °C PMB N H N Me O (53% yield) 169 Given this interesting preliminary data, we chose aminocyclohexanols 170a and 170b as simplified substrates for reaction optimization studies (Table 4.2.1). Our initial reaction conditions afforded the corresponding morpholines 171a and 171b in 53% and 42% yield, respectively (entries 1 and 2). A wide variety of bases and additives were investigated to improve the yield and catalytic efficiency (entries 3– 10). We found triethylamine to be superior to others examined (entries 3–5). The use of a 1:1 mixture of triethylamine and DABCO allowed etherification in 69% yield with reduced catalyst loading (i.e., 20 mol % Ni(COD)2, entry 6). Gratifyingly, the use of 2 equiv of zinc powder as an additive resulted in a significant improvement in yield (84%) with only 5 mol % of Ni(COD)2 (entry 10).13,14 ,15,16,17 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   422   Table 4.2.1. Optimization of reaction parametersa OH O I N N Me R R = Me (170a ) R = H (170b ) entry R Ni(COD) 2 bases, additives substrate conc (M) CH3CN, 23 °C Me R = Me (171a ) R = H (171b ) Ni mol % base additive yield (%)b 1c 170a 0.02 50 Et 3N (10 equiv) – 53 2c 170b 0.02 50 Et 3N (10 equiv) – 42 3c 170a 0.02 35 Et 3N (10 equiv) – 42d 4c 170a 0.02 35 Cs2CO3 (3.0 equiv) – 30d 5c 170a 0.02 35 K 3PO 4 (3.0 equiv) – 34d 6 170b 0.10 20 Et 3N (1.0 equiv) DABCO (1.0 equiv) 69 7 170b 0.10 20 Et 3N (1.0 equiv) CsF (1.0 equiv) 51 8 170a 0.04 20 DABCO (1.0 equiv) – 24 9 170a 0.04 20 DABCO (2.0 equiv) – 50d 10 170b 0.15 5 Et 3N (1.1 equiv) Zn (2.0 equiv) 84 a Reactions were performed in a N2-filled glove box. b Yield of isolated product. c DMF (0.04 M) was used as a co-solvent. d The reaction proceeded with incomplete conversion of starting material. With optimized conditions in hand, we investigated the substrate scope of the transformation (Table 4.2.2). In addition to simple vinyl iodides (e.g., 170b, R1 = Me, R2 = H, R3 = H),18 a (Z)-styrenyl iodide (i.e., 170c, R1 = Me, R2 = H, R3 = Ph)19 furnished vinyl ether 171c in high yield and without loss of olefin stereochemical fidelity. Aminocyclohexanols bearing isopropyl and allyl substituents on nitrogen afforded the corresponding products in reduced yields (171d and 171e). Electronically variable benzyl groups were compatible under the reaction conditions, and even an aryl bromide was well tolerated (171f–171h). Additionally, a silyl ether group remained intact, generating substituted morpholine 171i in good yield. Moreover, we discovered that a cis-aminocyclohexanol derived substrate was competent in the reaction, providing the cis-fused bicyclic product 171j.20,21 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   423   Table 4.2.2. Intramolecular cross-coupling of amino-cyclohexanolsa,b OH I N R1 R3 Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M), 23 °C R2 R2 N R3 R1 170 171 Ph O O O N N N 171b 171c 171d 84% yield 93% yield 32% yield O O N N O N MeO F 171e 171f 171g 51% yieldc 76% yield 74% yield O O N N O N TBSO Br a 171h 171i 171j 71% yield 67% yield 55% yield Reactions were performed in a N2-filled glove box. b Yield of isolated product. c 96 h. To our delight, we found that the nickel-catalyzed intramolecular etherification reactions also proceeded with linear aminoalcohol substrates to generate monocyclic morpholine derivatives in moderate to high yields (Table 4.2.3). The steric environment of the alcohol fragment did not hinder the performance, as substrates containing primary, secondary, or highly congested tertiary hydroxyl nucleophiles furnished the corresponding cyclic vinyl ethers in excellent yields (173a–173c). Finally, a benzyl-substituted linear aminoalcohol substrate was transformed to the desired vinyl ether in modest yield (173d). Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   424   Table 4.2.3. Intramolecular cross-coupling of linear aminoalcoholsa,b R2 R3 OH I N Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M), 23 °C R1 R3 R4 O N R4 R1 172 173 Ph a R2 Ph Ph O O O N N N O N 173a 173b 173c 173d 86% yield 94% yield 95% yield 40% yield Reactions were performed in a N2-filled glove box. b Yield of isolated product. We were pleased to discover that additional acyclic substrates undergo the nickel-catalyzed carbon–oxygen cross-coupling to furnish alkylidene tetrahydrofurans and dihydropyrans (Table 4.2.4). Intramolecular etherification of vinyl iodide 174a furnished the cyclic ether 175a in good yield in only 1 h (entry 1). Although less reactive, a vinyl bromide also fared well in the reaction, affording the corresponding product in 52% yield after 12 h (entry 2). Unfortunately, attempts to employ a vinyl chloride as the coupling partner led predominantly to recovery of starting material (entry 3). Mono-methyl and mono-phenyl substituted vinyl iodides (174d and 174e)22 afforded the desired ethers (175d and 175e) in good yields with retention of olefin stereochemistry (entries 4 and 5). Gratifyingly, tetrasubstituted vinyl bromide 174f23 furnished the corresponding tetrahydrofuran product 175f in excellent yield (entry 6). Di-tert-butyl and dibenzyl malonates (174g and 174h) were tolerated under the standard reaction conditions to afford the desired ethers (175g and 175h) in good yields (entries 7 and 8). Additionally, carbon–oxygen bond formations were achieved with nitrile- and amide-containing substituents in 61% and 70% yield, respectively (entries 9 and 10). Formation of a six-membered cyclic vinyl ether (175k) from substrate 174k was found to be challenging with only low levels of conversion (entry 425     11). Interestingly, cycloetherification of 174l did indeed produce a pyran derivative Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers in good yield, but only isomerized product 175l was isolated (entry 12).24,25,26 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   426   Table 4.2.4. Synthesis of substituted tetrahydrofuran and dihydropyran ringsa EWG EWG HO Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) 1-2 X CH3CN (0.15 M), 23 °C R1 EWG EWG 1-2 O R1 R2 R2 174 entry 175 product substrate MeO 2C CO2Me MeO 2C 174a MeO 2C MeO 2C CO2Me MeO 2C HO Cl 174c MeO 2C 174d MeO 2C MeO 2C MeO 2C CO2Me MeO 2C 98 1 87 1 66 12 61 1 70 72 –c 12 76 CO2Me O 174f tBuO C 2 175f CO2tBu tBuO C 2 CO2tBu HO O I 174g BnO 2C 175g CO2Bn BnO 2C CO2Bn HO O I 174h 175h MeO 2C CN MeO 2C CN HO I O 174i 175i O O CO2Me N CO2Me N O O OH MeO 2C 175j MeO 2C CO2Me HO I 174k tBuO C 2 O I 174j CO2tBu CO2Me O 175k tBuO C 2 CO2tBu 12 I O 174l a 48 175e HO Br HO 91 Ph Ph 174e 11 12 CO2Me O I 10 87 175d CO2Me HO 9 2 CO2Me O I 8 –c 175a CO2Me HO 7 60 CO2Me O MeO 2C 6 52 175a 174b 5 12 CO2Me O MeO 2C 4 87 175a CO2Me HO Br 3 1 O I 2 yield (%)b CO2Me HO 1 time (h) 175l Reactions were performed in a N2-filled glove box. b Yield of isolated product. c Low conversion. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   4.3. 427   Conclusion In conclusion, a highly efficient, mild, and operationally simple nickel- catalyzed intramolecular carbon–oxygen bond-forming reaction between vinyl halides and aliphatic alcohols has been developed. We discovered that zinc powder plays an important role in improving catalyst turnover and isolated yields. The reaction is tolerant of many functional groups, affording various cyclic vinyl ethers in good to excellent yields. This work further expands the capability of nickel catalysis in the context of small molecule chemical synthesis. Additional studies are ongoing to expand the scope of the reaction, to understand the mechanism, and to deploy the cyclization in the context of a complex molecular target.27 These efforts will be reported in due course. 4.4. Experimental Methods and Analytical Data 4.4.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, TCI, Oakwood chemicals, Strem, or Alfa Aesar and used as received unless otherwise stated. Ni(COD)2 and NiI2 were purchased from Strem. NiBr2(dme) was purchased from Aldrich. Zinc dust 428     or powder purchased from Aldrich worked well for the reaction but zinc powder Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers (99.999%) purchased from Strem gave poor conversion. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, KMnO4 or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.0400.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), CHDCl2 (δ 5.32) or C6HD6 (δ 7.16 ppm). 13C NMR spectra are recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers (75 MHz, 126 MHz, and 151 MHz, respectively) and are reported relative to CHCl3 (δ 77.16 ppm), CHDCl2 (δ 53.84) or C6HD5 (δ 128.06 ppm). 19 F NMR spectra are recorded on a Varian Mercury 300 MHz (at 282 MHz). 19F NMR spectra are reported relative to CFCl3(δ 0.0 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron 429     ionization (EI+) mode, or Agilent 6200 Series TOF with an Agilent G1978A Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). 4.4.2. Experimental Procedures 1. p-methoxybenzaldehyde 3Å MS; NaBH 4, 0 → 23 °C MeOH O H 2N SI-4-1 O PMB NaHCO 3 N 2. propiolic acid, DCC –20 → 23 °C, CH2Cl2 (65% yield, 2 steps) 1. m-CPBA 0 → 23 °C, CH2Cl2 N SI-4-3 2. aq MeNH 2 80 °C, MeOH 3. (E)-1-bromo-2-iodobut-2-ene 4Å MS, Cs2CO3, THF, DMF (60% yield, 3 steps) 120 °C, toluene (77% yield) PMB SI-4-2 O PMB I N H N OH Me 167 To a solution of amine SI-4-1 (6.66 g, 68.5 mmol, 1.00 equiv), which was prepared according to the literature procedure 1 , in MeOH (171 mL) were added pmethoxybenzaldehyde (10.0 mL, 82.3 mmol, 1.20 equiv) and 3Å MS (18.8 g). The reaction mixture was stirred at 23 °C for 17 h. Then, NaBH4 (5.20g, 0.137 mol, 2.00 equiv) was added to the solution at 0 °C. The solution was stirred at 23 °C for 12 h. After the reaction was done, water (40 mL) was added at 0 °C. The aqueous phase was extracted with EtOAc (3 x 80.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to give the PMB-amine, which was used without further purification. A solution of propiolic acid (4.64 mL, 75.4 mmol, 1.10 equiv) in CH2Cl2 (343 mL) was cooled to 0 °C. DCC (15.6g, 75.4 mmol, 1.10 equiv) and the PMB-amine (68.5                                                                                                                 1  (a) Miller, C. A.; Batey, R. A. Org. Lett. 2004, 6, 699–702. (b) Grieco, P. A.; Galatsis, P.; Spohn, R. F. Tetrahedron 1986, 42, 2847–2853. (c) Nieto-García, O.; Alonso, R. J. Org. Chem. 2013, 78, 2564– 2570. 430     mmol, 1.00 equiv) were added to the reaction mixture sequentially. The mixture was Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers warmed to 23 °C and stirred for 30 min. The solvent was evaporated and the residue was purified by flash column chromatography (1:4 EtOAc:hexanes) on silica gel to give amide SI-4-2 (12.0g, 65% yield, 2 steps). To a stirred solution of amide SI-4-2 (12.0 g, 44.6 mmol, 1.00 equiv) in toluene (558 mL) was added solid NaHCO3 (4.50g, 53.5 mmol, 1.20 equiv). The reaction mixture was heated to 120 °C for 48 h. After the reaction was done, water (200 mL) was added. The aqueous phase was extracted with EtOAc (3 x 120 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:4 EtOAc:hexanes) on silica gel to give lactam SI-4-3 (9.25g, 77% yield). To a stirred solution of lactam SI-4-3 (339 mg, 1.26 mmol, 1.00 equiv) in CH2Cl2 (6.30 mL) at 0 °C was added m-CPBA (≤77%, 1.89 mmol, 424 mg, 1.50 equiv), and the mixture was stirred for 3 h at 23 °C. The reaction mixture was quenched with sat. NaHSO3 and sat. NaHCO3. The aqueous phase was extracted with CH2Cl2 (3 x 6.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to furnish the epoxide, which was used without further purification. To a solution of epoxide (1.26 mmol, 1.00 equiv) in MeOH (6.30 mL) was added aq MeNH2 (40 wt.% in H2O, 12.6 mmol, 10.9 mL, 10.0 equiv). The reaction mixture was stirred at 80 °C for 12 h. After the reaction was done, water (6.00 mL) was added. The aqueous phase was extracted with EtOAc (3 x 8.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the aminoalcohol, which was used without further purification. 431     To a solution of the aminoalcohol (1.26 mmol, 1.00 equiv) in THF (3.15 mL) and Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers DMF (3.15 mL) were added 4Å MS (443 mg), (E)-1-bromo-2-iodobut-2-ene (411 mg, 1.58 mmol, 1.25 equiv) and Cs2CO3 (415 mg, 1.27 mmol, 1.01 equiv) at 23 °C. The reaction mixture was stirred at 23 °C for 24 h. The resulting suspension was filtered and washed with EtOAc (5.00 mL). The combined organic phases were extracted with EtOAc (3 x 6.00 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (2:1 EtOAc:hexane) on silica gel to give vinyl iodide 167 (375 mg, 60% yield, 3 steps). 1 H NMR (500 MHz, CDCl3) δ 7.20 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.75 (dt, J = 6.7, 2.1 Hz, 1H), 6.47 – 6.41 (m, 1H), 4.71 (d, J = 14.4 Hz, 1H), 4.41 (d, J = 14.4 Hz, 1H), 3.96 – 3.89 (m, 2H), 3.80 (s, 3H), 3.35 – 3.27 (m, 2H), 3.20 (d, J = 13.6 Hz, 1H), 3.11 (d, J = 13.6 Hz, 1H), 2.99 – 2.91 (m, 1H), 2.61 (td, J = 10.7, 4.4 Hz, 1H), 2.39 – 2.26 (m, 2H), 2.22 (s, 3H), 2.20 – 2.14 (m, 1H), 1.74 (d, J = 7.1 Hz, 3H), 1.56 – 1.45 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 165.3, 159.1, 139.0, 133.7, 130.3, 129.6, 129.5, 114.1, 103.3, 66.8, 60.1, 57.3, 55.4, 49.7, 46.9, 39.3, 35.6, 23.8, 22.3, 17.1; IR (Neat Film NaCl) 3416, 2927, 1663, 1613, 1512, 1454, 1246, 1175, 1034, 817, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H30IN2O3 [M+H]+ : 497.1296; found: 497.1296. O O PMB PMB N H OH 167 I Ni(COD) 2 (50 mol %) Et 3N N 23 °C, CH3CN, DMF (53% yield) Me N H N O 169 To a solution of vinyl iodide 167 (20.0 mg, 0.0402 mmol, 1.00 equiv) and Et3N (56.0 µL, 0.402 mmol, 10.0 equiv) in CH3CN (2.01 mL) and DMF (1.01 mL) in a 432     scintillation vial at 23 °C was added Ni(COD)2 (6.00 mg, 0.0201 mmol, 0.50 equiv) in Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers a nitrogen-filled glove box. The reaction mixture was stirred at 23 °C for 120 min, and then BHT (18.0 mg, 0.0804 mmol, 2.00 equiv) was added. After being stirred for 20 min, the vial was removed from the glovebox and uncapped. Saturated NaHCO3 aqueous solution was added and the mixture was extracted with Et2O (3 x 2.00 mL), the combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1:20 MeOH:CH2Cl2) to give morpholine derivative 169 (7.85 mg, 53% yield). 1 H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.66 (dt, J = 6.8, 1.9 Hz, 1H), 5.03 (qd, J = 7.1, 1.4 Hz, 1H), 4.63 (d, J = 14.4 Hz, 1H), 4.48 (d, J = 14.4 Hz, 1H), 3.78 (s, 3H), 3.76 (d, J = 7.1 Hz, 1H), 3.54 (d, J = 12.5 Hz, 1H), 3.29 – 3.24 (m, 2H), 2.86 – 2.74 (m, 1H), 2.68 – 2.60 (m, 2H), 2.32 (s, 3H), 2.30 – 2.24 (m, 1H), 2.12 – 1.96 (m, 2H), 1.58 (dd, J = 7.1, 1.3 Hz, 3H), 1.55 – 1.49 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 165.0, 158.9, 148.5, 133.5, 129.5, 129.0, 113.9, 103.5, 77.8, 58.4, 52.2, 49.5, 46.6, 42.4, 37.9, 28.9, 24.3, 11.0; IR (Neat Film NaCl) 3416, 2927, 1663, 1613, 1512, 1454, 1246, 1175, 1034, 817, 732 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C22H29N2O3 [M+H]+ : 369.2173; found: 369.2212. Typical procedure for aminocyclohexanols 170 R2 R3 Br I R 1NH 2 OH 80 °C MeOH NHR1 O SI-4-4 SI-4-5 OH K 2CO3 23 °C, MeCN (32–64% yield, 2 steps) I N R1 R2 170 R3 To a scintillation vial were added cyclohexene oxide SI-4-4 (5.09 mmol, 1.00 equiv), R1NH2 (5.09 mmol, 1.00 equiv), and MeOH (2.50 mL). The reaction mixture was 433     heated to 80 °C for 12 h. The solvent was evaporated to give the corresponding Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers aminocyclohexanols SI-4-5, which were used without further purification. To a solution of aminocyclohexanols SI-4-5 (5.09 mmol, 1.00 equiv) in MeCN (25.0 mL) were added K2CO3 (25.5 mmol, 5.00 equiv) and allyl bromides (5.60 mmol, 1.10 equiv). The reaction mixture was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography, using mixture of hexanes and ethyl acetate as eluent to furnish the product 170. Representative procedure for cross-coupling of aminocyclohexanols 170 OH N I Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) Ph O N Ph 170c 171c Ni-Catalyzed C–O bond formation experiments were performed in a nitrogen-filled glove box. To a solution of aminocyclohexanol 170c (50.0 mg, 0.135 mmol, 1.00 equiv) in MeCN (0.900 mL) in a scintillation vial were added Et3N (21.0 µL, 0.149 mmol, 1.10 equiv), Zn powder (17.7 mg, 0.270 mmol, 2.00 equiv), and Ni(COD)2 (1.90 mg, 0.00673 mmol, 0.05 equiv). The reaction mixture was stirred at 23 °C for 24 h. After the reaction was done, the vial was removed from the glove box and uncapped. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to give 171c (30.7 mg, 93% yield). Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   434   OH N I 170a 1 H NMR (500 MHz, CDCl3) δ 6.41 (q, J = 7.1 Hz, 1H), 4.03 (s, 1H), 3.40 (td, J = 9.8, 4.5 Hz, 1H), 3.15 (d, J = 13.7 Hz, 1H), 3.08 (d, J = 13.9 Hz, 1H), 2.26 (ddd, J = 14.0, 10.2, 3.6 Hz, 1H), 2.18 (s, 3H), 2.15 – 2.11 (m, 1H), 1.79 (dt, J = 8.9, 2.0 Hz, 2H), 1.73 (d, J = 7.2 Hz, 3H), 1.31 – 1.17 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 138.3, 104.4, 69.3, 68.7, 57.3, 35.7, 33.3, 25.6, 24.2, 22.8, 17.0; IR (Neat Film NaCl) 3467, 2930, 2855, 1449, 1282, 1080, 1037 cm-1; HRMS (MM: FAB+) m/z calc’d for C11H21NOI [M+H]+ : 310.0668; found: 310.0654. O N 171a 1 H NMR (400 MHz, CDCl3) δ 5.02 (qd, J = 7.1, 1.6 Hz, 1H), 3.58 (d, J = 12.6 Hz, 1H), 3.35 – 3.23 (m, 1H), 2.62 (d, J = 12.6 Hz, 1H), 2.29 (s, 3H), 2.09 (dtd, J = 12.9, 3.7, 2.0 Hz, 1H), 1.94 (ddt, J = 11.9, 4.5, 2.6 Hz, 1H), 1.85 (s, br, 1H), 1.77 – 1.71 (m, 2H), 1.56 (dd, J = 7.1, 1.5 Hz, 3H), 1.42 – 1.33 (m, 1H), 1.33 – 1.22 (m, 2H), 1.14 – 1.02 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 148.9, 103.3, 81.1, 67.4, 53.0, 42.0, 31.4, 28.1, 24.8, 24.4, 11.1; IR (Neat Film NaCl) 2934, 2861, 2779, 1682, 1451, 1192, 1108, 841 cm-1; HRMS (MM: FAB+) m/z calc’d for C11H20NO [M+H]+ : 182.1545; found: 182.1538. OH N 170b I Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   1 435   H NMR (300 MHz, CDCl3) δ 6.28 (q, J = 1.4 Hz, 1H), 5.86 (dt, J = 0.8, 1.6 Hz, 1H), 3.97 (s, 1H), 3.40 (m, 1H), 3.17 (d, J = 13.7 Hz, 1H), 2.96 (d, J = 13.7 Hz, 1H), 2.28 (m, 1H), 2.18 (s, 3H), 2.13 (m, 1H), 1.75 (m, 3H), 1.20 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 126.8, 113.7, 69.3, 69.1, 64.8, 35.8, 33.1, 25.4, 24.0, 22.6; IR (neat film NaCl) 3470, 2930, 2855, 2796, 1616, 1448, 1079, 1036 cm–1; HRMS (MM: ESIAPCI+) m/z calc’d for C10H19INO, [M+H]+ : 296.0506; found: 296.0499. O N 171b 1 H NMR (300 MHz, CDCl3) δ 4.40 (s, 1H), 4.16 (s, 1H), 3.36 (ddd, J = 2.5, 5.4, 6.7 Hz, 1H), 3.25 (d, J = 7.5 Hz, 1H), 2.81 (7.5 Hz, 1H), 2.24 (s, 3H), 2.09 (m, 1H), 1.98 (m, 1H), 1.84 – 1.73 (m, 3H), 1.43 – 1.07 (m, m, 4H); 13C NMR (75 MHz, CDCl3) δ 156.1, 91.9, 81.1, 66.8, 57.9, 41.7, 31.3, 28.1, 24.3, 24.3; IR (neat film NaCl) 2929, 2858, 2770, 1747, 1653, 1277, 1229, 1074 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H18NO, [M+H]+ : 168.1383; found: 168.1385. OH N 170c 1 I Ph H NMR (400 MHz, CDCl3) δ 7.57 – 7.50 (m, 2H), 7.40 – 7.29 (m, 3H), 6.97 (s, 1H), 4.04 (s, 1H), 3.52 – 3.41 (m, 2H), 3.27 (dd, J = 13.5, 1.1 Hz, 1H), 2.42 – 2.29 (m, 1H), 2.24 (s, 3H), 2.19 – 2.11 (m, 1H), 1.79 (dd, J = 6.9, 3.9 Hz, 2H), 1.75 – 1.64 (m, 1H), 1.35 – 1.15 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 137.4, 135.7, 128.8, 128.3, 128.2, 109.0, 69.5, 69.3, 66.8, 35.8, 33.3, 25.6, 24.2, 22.9; IR (neat film NaCl) 3467, 436     2930, 2855, 1446, 1079, 1058, 1033, 750, 695 cm–1; HRMS (MM: ESI-APCI+) m/z Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers calc’d for C16H23INO, [M+H]+ : 372.0819; found: 372.0859. Ph O N 171c 1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.53 (m, 2H), 7.32 – 7.25 (m, 2H), 7.17 – 7.11 (m, 1H), 5.44 (d, J = 1.7 Hz, 1H), 3.53 (ddd, J = 11.5, 9.1, 4.3 Hz, 1H), 3.32 (d, J = 12.8 Hz, 1H), 3.00 (dd, J = 12.8, 1.6 Hz, 1H), 2.29 (s, 3H), 2.13 (ddtd, J = 12.5, 6.2, 4.3, 3.8, 2.1 Hz, 2H), 1.93 (td, J = 10.2, 9.1, 3.9 Hz, 1H), 1.79 (ddt, J = 13.0, 10.3, 2.9 Hz, 2H), 1.60 – 1.49 (m, 1H), 1.41 – 1.24 (m, 2H), 1.20 – 1.07 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 150.4, 136.0, 128.5, 128.2, 126.0, 107.5, 80.8, 67.0, 59.2, 41.7, 31.4, 28.3, 24.7, 24.4; IR (neat film NaCl) 2935, 2860, 2774, 1664, 1449, 1342, 1179, 1060, 1032, 694 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H22NO, [M+H]+ : 244.1696; found: 244.1716. OH N I 170d 1 H NMR (400 MHz, CDCl3) δ 6.29 (s, 1H), 5.87 (s, 1H), 3.90 (s, 1H), 3.36 – 3.21 (m, 2H), 3.02 (td, J = 13.7, 6.6 Hz, 2H), 2.39 (d, J = 10.5 Hz, 1H), 2.19 – 2.09 (m, 1H), 1.73 (q, J = 10.1 Hz, 3H), 1.35 – 1.17 (m, 4H), 1.14 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.6 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 127.2, 116.0, 69.3, 61.7, 57.4, 48.1, 33.2, 28.0, 26.1, 24.4, 22.9, 18.0; IR (neat film NaCl) 2930, 1614, 1173, 1080, 896 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H23NOI, [M+H]+ : 324.0819; found: 324.0845. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   437   O N 171d 1 H NMR (400 MHz, C6D6) δ 4.64 (d, J = 1.1 Hz, 1H), 4.12 (d, J = 1.5 Hz, 1H), 3.48 (ddd, J = 11.1, 8.9, 4.3 Hz, 1H), 3.23 (d, J = 12.7 Hz, 1H), 3.07 (p, J = 6.6 Hz, 1H), 2.89 (dt, J = 12.7, 1.4 Hz, 1H), 2.14 (ddd, J = 10.8, 8.9, 3.9 Hz, 1H), 2.02 – 1.93 (m, 1H), 1.75 (dq, J = 13.6, 2.9, 2.4 Hz, 1H), 1.48 – 1.33 (m, 4H), 0.99 (s, 3H), 0.96 – 0.79 (m, 2H), 0.65 (s, 3H). 13C NMR (101 MHz, C6D6) δ 158.4, 89.6, 81.0, 62.1, 46.7, 45.8, 31.8, 28.1, 25.0, 24.4, 21.4, 12.4; IR (neat film NaCl) 2933, 1657, 1450, 1280, 1175, 1075, 800 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H22NO, [M+H]+ : 196.1696; found: 196.1697. OH N I 170e 1 H NMR (500 MHz, CDCl3) δ 6.29 (d, J = 1.8 Hz, 1H), 5.92 – 5.81 (m, 2H), 5.23 – 5.10 (m, 2H), 3.83 (s, 1H), 3.41 (td, J = 9.9, 4.5 Hz, 1H), 3.34 (d, J = 14.2 Hz, 1H), 3.31 – 3.23 (m, 1H), 2.94 (dd, J = 14.1, 8.4 Hz, 1H), 2.88 (d, J = 14.2 Hz, 1H), 2.41 (ddd, J = 12.7, 9.9, 3.4 Hz, 1H), 2.13 (ddq, J = 12.2, 4.6, 2.0 Hz, 1H), 1.85 – 1.74 (m, 2H), 1.71 – 1.68 (m, 1H), 1.32 – 1.16 (m, 3H), 1.15 – 1.03 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 136.4, 127.6, 117.9, 113.9, 69.1, 64.9, 60.4, 52.4, 33.2, 25.7, 24.2, 23.5; IR (neat film NaCl) 2930, 2856, 1615, 1450, 1157, 1078, 917 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H21NIO, [M+H]+ : 322.0662; found: 322.0668. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   438   O N 171e 1 H NMR (500 MHz, CDCl3) δ 5.86 (dddd, J = 17.1, 10.2, 8.0, 5.4 Hz, 1H), 5.24 – 5.16 (m, 2H), 4.38 (dt, J = 1.3, 0.7 Hz, 1H), 4.13 (dd, J = 1.6, 0.7 Hz, 1H), 3.48 (ddt, J = 13.6, 5.4, 1.6 Hz, 1H), 3.45 – 3.40 (m, 1H), 3.35 (d, J = 12.9 Hz, 1H), 2.88 – 2.79 (m, 2H), 2.17 – 2.04 (m, 2H), 1.99 (dddd, J = 10.2, 4.8, 3.9, 2.4 Hz, 1H), 1.79 – 1.69 (m, 2H), 1.46 – 1.37 (m, 1H), 1.35 – 1.21 (m, 2H), 1.12 (q, J = 12.3, 11.5 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 156.4, 134.3, 118.8, 91.6, 80.8, 64.6, 56.0, 53.7, 31.5, 28.2, 24.8, 24.3; IR (neat film NaCl) 2935, 2862, 1657, 1280, 1075, 839 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H20NO, [M+H]+ : 194.1539; found: 194.1542. OH N MeO 1 I 170f H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 6.32 (d, J = 1.7 Hz, 1H), 5.90 (t, J = 1.4 Hz, 1H), 3.80 (s, 3H), 3.81 – 3.74 (m, 2H), 3.44 (td, J = 9.8, 4.6 Hz, 1H), 3.36 (d, J = 13.9 Hz, 1H), 3.28 (d, J = 13.2 Hz, 1H), 2.92 (d, J = 14.0 Hz, 1H), 2.42 – 2.29 (m, 1H), 2.13 – 2.04 (m, 1H), 1.90 – 1.81 (m, 1H), 1.75 (ddd, J = 6.7, 4.4, 2.3 Hz, 1H), 1.70 – 1.63 (m, 1H), 1.25 – 1.04 (m, 4H); 13C NMR (126 MHz, CDCl3) δ 159.0, 130.6, 130.5, 128.1, 113.9, 113.5, 68.9, 63.6, 60.5, 55.4, 52.8, 33.3, 25.6, 24.2, 22.6; IR (neat film NaCl) 3483, 2931, 2855, 1612, 1511, 1247, 1036, 813 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H25INO2, [M+H]+ : 402.0924; found: 402.0934. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   439   O N MeO 1 171f H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 4.33 (s, 1H), 4.09 – 3.96 (m, 2H), 3.81 (s, 3H), 3.51 (s, br, 1H), 3.19 (d, J = 13.0 Hz, 1H), 3.09 (d, J = 12.9 Hz, 1H), 2.71 (d, J = 13.0 Hz, 1H), 2.21 (d, J = 12.9 Hz, 1H), 2.13 (s, br, 1H), 2.06 – 1.96 (m, 1H), 1.84 – 1.72 (m, 2H), 1.50 – 1.36 (m, 1H), 1.32 (qd, J = 11.1, 9.7, 5.6 Hz, 2H), 1.22 (d, J = 22.0 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 158.9, 156.5, 130.4, 130.2, 113.8, 91.1, 80.4, 65.2, 56.5, 55.4, 53.4, 31.6, 28.7, 24.8, 24.4; IR (neat film NaCl) 2935, 2861, 1733, 1674, 1611, 1511, 1246, 1036, 843 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H24NO2, [M+H]+ : 274.1802; found: 274.1820. OH N F 1 I 170g H NMR (400 MHz, CDCl3) δ 7.34 (dd, J = 8.4, 5.6 Hz, 2H), 7.01 (t, J = 8.7 Hz, 2H), 6.33 (s, 1H), 5.91 (t, J = 1.4 Hz, 1H), 3.80 (d, J = 13.3 Hz, 1H), 3.73 (s, br, 1H), 3.45 (td, J = 9.7, 4.6 Hz, 1H), 3.35 (t, J = 12.6 Hz, 2H), 2.95 (d, J = 13.9 Hz, 1H), 2.33 (d, J = 10.4 Hz, 1H), 2.14 – 2.04 (m, 1H), 1.92 – 1.83 (m, 1H), 1.81 – 1.72 (m, 1H), 1.67 (dt, J = 7.8, 2.8 Hz, 1H), 1.25 – 1.06 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 162.3 (d, J = 245.2 Hz), 134.2, 131.1 (d, J = 8.0 Hz), 128.4, 115.5 (d, J = 21.3 Hz), 113.1, 68.9, 63.8, 60.6, 52.7, 33.3, 25.5, 24.2, 22.6; 19F NMR (282 MHz, CDCl3) δ -115.5; IR (neat film NaCl) 3485, 2930, 2856, 1602, 1508, 1221, 1152, 1073, 818 cm–1; 440     HRMS (MM: ESI-APCI+) m/z calc’d for C16H22FNOI, [M+H]+ : 390.0725; found: Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 390.0732. O N F 1 171g H NMR (400 MHz, CDCl3) δ 7.37 – 7.25 (m, 2H), 7.08 – 6.93 (m, 2H), 4.34 (s, 1H), 4.04 (d, J = 13.1 Hz, 1H), 3.99 (d, J = 1.5 Hz, 1H), 3.50 (tt, J = 11.8, 10.9, 4.1 Hz, 2H), 3.16 (d, J = 13.0 Hz, 1H), 3.08 (d, J = 13.2 Hz, 1H), 2.72 (d, J = 12.9 Hz, 1H), 2.24 – 2.05 (m, 2H), 2.07 – 1.94 (m, 1H), 1.87 – 1.66 (m, 2H), 1.53 – 1.35 (m, 1H), 1.38 – 1.24 (m, 1H), 1.24 – 1.13 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 162.1 (d, J = 244.7 Hz), 156.3, 134.3, 130.1 (d, J = 6.1 Hz), 115.3 (d, J = 20.9 Hz), 91.2, 80.5, 65.3, 56.4, 53.6, 31.6, 28.8, 24.8, 24.3; 19F NMR (282 MHz, CDCl3) δ -116.0; IR (neat film NaCl) 2936, 2862, 1736, 1673, 1604, 1508, 1222, 1075, 821 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H21FNO, [M+H]+ : 262.1602; found: 262.1629. OH N Br 1 I 170h H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.7 Hz, 2H), 7.27 (d, J = 7.7 Hz, 2H), 6.33 (s, br, 1H), 5.91 (t, J = 1.6 Hz, 1H), 3.78 (d, J = 13.3 Hz, 1H), 3.71 (s, br, 1H), 3.53 – 3.41 (m, 1H), 3.42 – 3.26 (m, 2H), 2.95 (d, J = 14.0 Hz, 1H), 2.33 (s, br, 1H), 2.08 (dd, J = 9.6, 4.3 Hz, 1H), 1.94 – 1.54 (m, 3H), 1.27 – 1.03 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 137.5, 131.7, 131.2, 128.6, 121.4, 112.9, 69.0, 63.9, 60.6, 52.9, 33.3, 25.5, 24.2, 22.6; IR (neat film NaCl) 3486, 2930, 2855, 1615, 1486, 1450, 1403, 1152, 441     1071, 1011, 799 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H22BrNOI, Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers [M+H]+ : 449.9924; found: 449.9937. O N Br 1 171h H NMR (500 MHz, CD2Cl2) δ 7.44 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 4.24 (d, J = 1.1 Hz, 1H), 4.02 (d, J = 13.4 Hz, 1H), 3.93 (d, J = 1.5 Hz, 1H), 3.44 (ddd, J = 11.2, 8.7, 4.2 Hz, 1H), 3.13 (d, J = 12.9 Hz, 1H), 3.02 (d, J = 13.5 Hz, 1H), 2.69 (dt, J = 12.9, 1.5 Hz, 1H), 2.18 – 2.07 (m, 2H), 2.02 – 1.91 (m, 1H), 1.75 (tdd, J = 10.4, 5.5, 2.5 Hz, 2H), 1.47 – 1.34 (m, 1H), 1.36 – 1.22 (m, 2H), 1.19 – 1.06 (m, 1H); 13 C NMR (126 MHz, CD2Cl2) δ 157.1, 138.9, 131.8, 131.2, 121.0, 90.7, 81.0, 65.8, 56.9, 54.2, 31.9, 29.1, 25.2, 24.7; IR (neat film NaCl) 2935, 2861, 1654, 1486, 1280, 1074, 1012, 843, 802 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H21BrNO, [M+H]+ : 322.0801; found: 322.0817. OH N TBSO 1 I 170i H NMR (500 MHz, CDCl3) δ 6.28 (s, 1H), 5.84 (s, 1H), 3.83 (s, 1H), 3.66 (td, J = 6.2, 2.2 Hz, 2H), 3.38 (td, J = 9.9, 4.4 Hz, 1H), 3.29 (d, J = 14.1 Hz, 1H), 2.91 (d, J = 14.2 Hz, 1H), 2.65 (dt, J = 13.0, 8.0 Hz, 1H), 2.43 (ddd, J = 13.1, 7.4, 5.8 Hz, 1H), 2.34 (ddd, J = 12.6, 9.8, 3.3 Hz, 1H), 2.17 – 2.08 (m, 1H), 1.82 – 1.72 (m, 2H), 1.71 (dt, J = 8.4, 6.0 Hz, 3H), 1.32 – 1.14 (m, 3H), 1.10 (tt, J = 12.2, 5.9 Hz, 1H), 0.89 (d, 442     J = 0.9 Hz, 9H), 0.05 (s, 3H), 0.05 (s, 3H); 13C NMR (126 MHz, CDCl 3) δ 127.3, Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 114.2, 69.1, 65.6, 61.6, 61.4, 46.1, 33.3, 31.9, 26.1, 25.7, 24.3, 23.1, 18.4, -5.11, -5.13; IR (neat film NaCl) 3489, 2929, 2856, 1255, 1097, 835, 775 cm–1; HRMS (MM: ESIAPCI+) m/z calc’d for C18H37INO2Si, [M+H]+ : 454.1633; found: 454.1658. O N TBSO 1 171i H NMR (400 MHz, CDCl3) δ 4.38 (s, 1H), 4.13 (s, 1H), 3.63 (td, J = 6.2, 2.2 Hz, 2H), 3.47 – 3.31 (m, 2H), 2.94 – 2.79 (m, 2H), 2.34 (s, br, 1H), 2.15 – 2.04 (m, 2H), 1.98 (ddq, J = 11.8, 4.4, 2.4, 1.9 Hz, 1H), 1.79 – 1.59 (m, 5H), 1.46 – 1.21 (m, 3H), 0.89 (s, 9H), 0.04 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 156.5, 91.4, 80.9, 64.6, 61.4, 53.8, 49.3, 31.5, 28.9, 28.3, 26.1, 24.8, 24.3, 18.4, -5.15, -5.17; IR (neat film NaCl) 2931, 2857, 1739, 1674, 1463, 1256, 1094, 838, 776 cm–1; HRMS (MM: ESIAPCI+) m/z calc’d for C18H36NO2Si, [M+H]+ : 326.2510; found: 326.2544. OH N 170b I benzoic acid PPh 3, DEAD OBz toluene (21% yield, 65% yield based on recovered starting material) N I SI-4-6 A solution of cyclohexanol 170b (500 mg, 1.69 mmol, 1.00 equiv) in toluene (1.20 mL) was added to a cooled solution of PPh3 (532 mg, 2.03 mmol, 1.20 equiv) and benzoic acid (248 mg, 2.03 mmol, 1.20 equiv) in toluene (8.45 mL) at –40 °C. Then, DEAD in toluene (40 wt% in toluene, 0.92 mL, 1.20 equiv) was added dropwise to a solution over 20 min at –40 °C. After stirring for 1.5 h at –40 °C, the solution was warmed to 23 °C. After being stirred for 18 h, saturated NaHCO3 aqueous solution 443     was added and the mixture was extracted with EtOAc (3 x 7.00 mL). The combined Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1:20 EtOAc:hexanes) to give benzoate SI-4-6 (142 mg, 21% yield, 65% yield based on recovered starting material). 1 H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.1 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 6.25 (s, 1H), 5.73 (s, 1H), 5.10 (td, J = 10.4, 4.6 Hz, 1H), 3.29 (d, J = 15.1 Hz, 1H), 3.22 (d, J = 15.1 Hz, 1H), 2.79 – 2.69 (m, 1H), 2.25 (s, 3H), 2.19 – 2.11 (m, 1H), 1.92 (d, J = 13.1 Hz, 1H), 1.83 – 1.72 (m, 2H), 1.40 (dddd, J = 17.5, 10.7, 8.0, 3.7 Hz, 2H), 1.35 – 1.23 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 166.0, 132.9, 131.0, 129.9, 128.4, 125.5, 113.4, 73.5, 67.3, 65.8, 36.2, 32.2, 27.4, 25.3, 24.5; IR (Neat Film NaCl) 2934, 2858, 1714, 1450, 1317, 1273, 1175, 1106, 710 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H23INO2 [M+H]+ : 400.0768; found: 400.0769. OBz N SI-4-6 NaOH I MeOH, H 2O (56% yield) OH N I 170j A solution of benzoate SI-4-6 (140 mg, 0.351 mmol, 1.00 equiv) in MeOH (1.80 mL) and H2O (0.20 mL) was treated with NaOH (28 mg, 0.701 mmol, 2.00 equiv) at 60 °C. After 1 h and 45 min, the solution was poured into H2O and the mixture was extracted with CH2Cl2 (3 x 3.00 mL). The combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1:8 EtOAc:hexanes) to give cyclohexanol 170j (58 mg, 56% yield). Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   1 444   H NMR (400 MHz, CDCl3) δ 6.28 (q, J = 1.4 Hz, 1H), 5.86 (dt, J = 1.6, 0.8 Hz, 1H), 3.96 (s, 1H), 3.40 (td, J = 9.9, 4.5 Hz, 1H), 3.17 (d, J = 13.8 Hz, 1H), 2.95 (d, J = 13.8 Hz, 1H), 2.28 (ddd, J = 11.4, 9.7, 3.5 Hz, 1H), 2.18 (s, 3H), 2.18 – 2.09 (m, 1H), 1.83 – 1.65 (m, 3H), 1.35 – 1.07 (m, 4H); 13C NMR (101 MHz, CDCl3) δ 127.0, 113.8, 69.4, 69.3, 65.0, 35.9, 33.3, 25.6, 24.2, 22.8; IR (Neat Film NaCl) 3468, 2930, 2855, 2796, 1615, 1449, 1282, 1080, 1036, 901 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H19INO [M+H]+ : 296.0506; found: 296.0528. O N 171j 1 H NMR (400 MHz, CD2Cl2) δ 4.28 (dd, J = 1.4, 0.7 Hz, 1H), 4.09 (dd, J = 1.7, 0.5 Hz, 1H), 3.31 (ddd, J = 11.2, 9.0, 4.2 Hz, 1H), 3.21 (d, J = 12.7 Hz, 1H), 2.75 (dt, J = 12.7, 1.6 Hz, 1H), 2.18 (s, 3H), 2.12 – 2.01 (m, 1H), 1.90 (dtd, J = 13.3, 4.7, 2.7 Hz, 1H), 1.81 – 1.66 (m, 3H), 1.43 – 1.23 (m, 3H), 1.03 (tdd, J = 13.0, 11.2, 3.7 Hz, 1H); 13 C NMR (101 MHz, CD2Cl2) δ 157.3, 91.0, 81.4, 67.2, 58.2, 41.9, 31.7, 28.5, 25.1, 24.8; IR (Neat Film NaCl) 2937, 2862, 2770, 1654, 1451, 1339, 1278, 1161, 1075, 1042, 900, 836 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C10H18NO [M+H]+ : 168.1383; found: 168.1396. Typical procedure for linear aminoalcohols 172 R4 Br R2 R3 I OH K 2CO3 NHR1 23 °C, MeCN (48–82% yield) SI-4-7 R2 R3 OH N R1 172 I R4 445     To a solution of aminoalcohols SI-4-7 (1.12 mmol, 1.00 equiv) in MeCN (5.60 mL) Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers were added K2CO3 (11.2 mmol, 10.0 equiv) and allyl bromides (1.23 mmol, 1.10 equiv). The reaction mixture was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography, using mixture of hexanes and ethyl acetate as eluent to give the product 172. Representative procedure for cross-coupling of linear aminoalcohols 172 OH N I Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) Ph O N Ph 172c 173c Ni-Catalyzed C–O bond formation experiments were performed in a nitrogen-filled glove box. To a solution of aminoalcohol 172c (50.0 mg, 0.145 mmol, 1.00 equiv) in MeCN (0.97 mL) in a scintillation vial were added Et3N (22.0 µL, 0.160 mmol, 1.10 equiv), Zn powder (19.0 mg, 0.290 mmol, 2.00 equiv), and Ni(COD)2 (2.00 mg, 0.00724 mmol, 0.05 equiv). The reaction mixture was stirred at 23 °C for 24 h. After the reaction was done, the vial was removed from the glovebox and uncapped. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography, using a mixture of hexanes and ethyl acetate as eluent to furnish the product 173c (30.0 mg, 95% yield). OH I N Ph 172a Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   1 446   H NMR (300 MHz, CDCl3) δ 7.54 (m, 2H), 7.36 (m, 3H), 6.98 (s, 1H), 3.65 (t, J = 5.4 Hz, 2H), 3.36 (s, 2H), 2.95 (br, 1H), 2.66 (t, J = 5.5 Hz, 2H), 2.31 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 137.2, 136.1, 128.7, 128.1, 128.0, 107.1, 70.4, 58.5, 57.8, 40.7; IR (neat film NaCl) 3442, 2946, 2840, 2792, 1490, 1445, 1083, 1066, 1046, 748, 694 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H17INO, [M+H]+ : 318.0349; found: 318.0344. Ph O N 173a 1 H NMR (300 MHz, CDCl3) δ 7.56 (m, 2H), 7.28 (m, 2H), 7.14 (m, 1H), 5.45 (s, 1H), 4.06 (m, 2H), 3.03 (s, 2H), 2.59 (m, 2H), 2.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 149.6, 135.6, 128.4, 128.1, 125.9, 107.9, 67.4, 58.3, 54.1, 46.1; IR (neat film NaCl) 2939. 2790, 1738, 1668, 1452, 1339, 1170, 1051, 695; HRMS (MM: ESI-APCI+) m/z calc’d for C12H16NO, [M+H]+ : 190.1226; found: 190.1228. OH N I Ph 172b 1 H NMR (400 MHz, CDCl3) δ 7.59 – 7.50 (m, 2H), 7.41 – 7.30 (m, 3H), 6.98 (s, 1H), 3.90 (dqd, J = 9.4, 6.1, 3.0 Hz, 1H), 3.75 – 3.53 (m, 1H), 3.47 (d, J = 13.5 Hz, 1H), 3.29 (d, J = 13.5 Hz, 1H), 2.45 (dd, J = 12.3, 3.1 Hz, 1H), 2.41 – 2.36 (m, 1H), 2.32 (s, 3H), 1.16 (d, J = 6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 137.4, 136.4, 128.8, 128.3, 128.3, 128.2, 107.1, 70.8, 64.6, 63.3, 41.3, 19.9; IR (neat film NaCl) 3459, 3054, 3023, 2968, 2930, 2843, 2795, 1598, 1491, 1446, 1408, 1361, 1324, 1291, 447     1209, 1161, 1135, 1065, 1029, 935, 841, 750, 695 cm–1; HRMS (MM: ESI-APCI+) Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers m/z calc’d for C13H19NIO, [M+H]+ : 332.0506; found: 332.0519. Ph O N 173b 1 H NMR (400 MHz, CDCl3) δ 7.65 – 7.56 (m, 2H), 7.33 – 7.26 (m, 2H), 7.19 – 7.10 (m, 1H), 5.46 (d, J = 1.4 Hz, 1H), 4.06 (dqd, J = 9.9, 6.3, 2.6 Hz, 1H), 3.20 (dd, J = 12.5, 1.7 Hz, 1H), 2.85 – 2.72 (m, 2H), 2.31 (s, 3H), 2.06 (dd, J = 11.7, 9.8 Hz, 1H), 1.36 (d, J = 6.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 150.2, 136.0, 128.6, 128.2, 126.0, 107.8, 73.4, 60.9, 58.0, 46.1, 19.2; IR (neat film NaCl) 2973, 2936, 2788, 1666, 1448, 1328, 1154, 1070, 975, 755, 694 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C13H18NO, [M+H]+ : 204.1383; found: 204.1386. OH I N Ph 172c 1 H NMR (400 MHz, CDCl3) δ 7.57 – 7.48 (m, 2H), 7.33 (s, 3H), 6.99 (s, 1H), 3.46 (s, 2H), 3.26 (s, br, 1H), 2.51 (s, 2H), 2.37 (s, 3H), 1.23 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 137.5, 135.8, 129.2, 128.9, 128.2, 108.3, 73.0, 70.9, 68.1, 44.0, 28.0; IR (neat film NaCl) 2969, 2786, 2360, 1446, 1356, 1121, 1031, 970, 749, 695 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H21NIO, [M+H]+ : 346.0662; found: 346.0664. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   448   Ph O N 173c 1 H NMR (400 MHz, CDCl3) δ 7.70 – 7.59 (m, 2H), 7.29 – 7.25 (m, 2H), 7.17 – 7.09 (m, 1H), 5.47 (s, 1H), 2.94 (s, 2H), 2.38 (s, 2H), 2.28 (s, 3H), 1.39 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 149.2, 136.3, 128.3, 128.2, 125.8, 108.7, 76.8, 64.7, 58.3, 46.4, 26.3; IR (neat film NaCl) 2974, 2766, 1663, 1449, 1368, 1346, 1254, 1207, 1152, 1110, 968, 754, 694 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H20NO, [M+H]+ : 218.1539; found: 218.1577. OH N I Ph 172d 1 H NMR (300 MHz, CDCl3) δ 7.38 – 7.25 (m, 5H), 6.33 (q, J = 1.4 Hz, 1H), 5.92 (m, 1H), 3.63 (s, 2H), 3.56 (q, J = 5.4 Hz, 2H), 3.16 (s, 2H), 2.70 (t, J = 5.7 Hz, 1H), 2.65 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 137.8, 129.3, 128.4, 127.9, 127.4, 111.9, 64.8, 58.5, 57.5, 54.1; IR (neat film NaCl) 3435, 3024, 2808, 1616, 1493, 1452, 1257, 1151, 1027, 904, 739, 698 cm–1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H17INO, [M+H]+ : 318.0349; found: 318.0356. O N Ph 173d 1 H NMR (300 MHz, CDCl3) δ 7.33 – 7.24 (m, 5H), 4.39 (s, 1H), 4.11 (s, 1H), 3.90 (m, 2H), 3.50 (s, 2H), 2.98 (s, 2H), 2.52 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 155.9, 137.4, 129.3, 128.5, 127.4, 92.2, 67.9, 63.2, 55.3, 52.1; IR (neat film NaCl) 449     2875, 2807, 1653, 1453, 1313, 1278, 1125, 1079, 1067, 851, 699 cm–1; HRMS (MM: Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers ESI-APCI+) m/z calc’d for C12H16NO, [M+H]+ : 190.1226; found: 190.1229. Typical procedure for malonate substrates 174 EWG R1 EWG EWG + NaH R2 Br X SI-4-8 EWG SI-4-9 50 → 40 °C DMF X 1-2 NaHCO 3 or K 2CO3 37% formaldehyde 23 °C, EtOH, H 2O R1 R2 X = Cl, Br, I SI-4-10 EWG EWG HO 1-2 X R1 R2 174 To a suspension of NaH (60% dispersion in mineral oil, 4.16 mmol, 1.10 equiv) in DMF (19.0 mL) at 0 °C was added malonate SI-4-8 (3.78 mmol, 1.00 equiv) in portions. The reaction mixture was stirred at 50 °C for 1 h. The solution was cooled to 0 °C and allyl bromide (3.78 mmol, 1.00 equiv) in DMF (2 mL) was added in portions over 5 min. Then, the mixture was stirred at 40 °C for 1 h. The reaction was quenched by sat. NH4Cl and the aqueous phase was extracted with Et2O (3 x 10.0 mL). The combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:20 EtOAc:hexanes) on silica gel to give vinyl halide SI-4-10. To a solution of vinyl halide SI-4-10 (0.74 mmol, 1.00 equiv) in EtOH (0.50 mL) and H2O (0.25 mL) were added solid NaHCO3 or K2CO3 (0.15 mmol, 0.20 equiv) and formaldehyde (37wt.% in H2O, 0.89 mmol, 1.20 equiv). The reaction mixture was stirred at 23 °C for 24 h. Then, water (0.40 mL) was added and the aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography, using a mixture of hexanes and ethyl acetate as eluent to furnish the product 174. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   Representative procedure for cross-coupling of malonates 174 MeO 2C CO2Me HO Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) I 174a MeO 2C 450   CO2Me O 175a Ni-Catalyzed C–O bond formation experiments were performed in a nitrogen-filled glove box. To a solution of vinyl iodide 174a (83.9 mg, 0.256 mmol, 1.00 equiv) in MeCN (1.71 mL) in a scintillation vial were added Et3N (39.0 µL, 0.282 mmol, 1.10 equiv), Zn powder (33.0 mg, 0.512 mmol, 2.00 equiv), and Ni(COD)2 (3.50 mg, 0.013 mmol, 0.05 equiv). The reaction mixture was stirred at 23 °C for 1 h. After the reaction was done, the vial was removed from the glovebox and uncapped. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:4 EtOAc:hexanes) to furnish the product 175a (44.5 mg, 87% yield). MeO 2C CO2Me HO I 174a 1 H NMR (500 MHz, C6D6) δ 5.79 (q, J = 1.2 Hz, 1H), 5.61 (d, J = 1.4 Hz, 1H), 4.09 (d, J = 5.8 Hz, 2H), 3.33 (s, 6H), 3.32 (d, J = 1.1 Hz, 2H); 13C NMR (126 MHz, C6D6) δ 169.9, 131.5, 101.2, 63.3, 59.3, 52.4, 45.4; IR (Neat Film NaCl) 3520, 2952, 1731, 1435, 1210, 1033 cm-1; HRMS (MM: FAB+) m/z calc’d for C9H14IO5 [M+H]+ : 328.9886; found: 328.9891. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   MeO 2C 451   CO2Me O 175a 1 H NMR (500 MHz, C6D6) δ 4.53 (q, J = 1.9 Hz, 1H), 4.44 (s, 2H), 3.91 (q, J = 1.7 Hz, 1H), 3.16 (s, 6H), 3.09 (t, J = 1.7 Hz, 2H); 13C NMR (126 MHz, C6D6) δ 169.2, 160.2, 81.8, 74.3, 59.8, 52.6, 37.0; IR (Neat Film NaCl) 2957, 2358, 2340, 1737, 1436, 1280, 1046 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C9H13O5 [M+H]+ : 201.0757; found: 201.0765.   MeO 2C CO2Me HO Br 174b   1   H NMR (500 MHz, CDCl3) δ 5.74 (dt, J = 1.7, 0.9 Hz, 1H), 5.59 (d, J = 1.7 Hz, 1H), 4.09 (s, 2H), 3.79 (s, 6H), 3.25 (d, J = 0.9 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 170.4, 126.6, 122.4, 63.7, 59.0, 53.1, 42.4; IR (Neat Film NaCl) 2953, 1728, 1626, 1435, 1299, 1208, 1032, 902, 857 cm-1; HRMS (MM: FAB+) m/z calc’d for C9H14BrO5 [M+H]+ : 281.0024; found: 281.0036. MeO 2C CO2Me HO Cl 174c 1 H NMR (400 MHz, CDCl3) δ 5.32 (d, J = 1.3 Hz, 1H), 5.30 – 5.28 (m, 1H), 4.07 (s, 2H), 3.78 (s, 6H), 3.13 (d, J = 0.8 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 170.4, 136.6, 117.7, 63.8, 58.7, 53.0, 40.6; IR (Neat Film NaCl) 2955, 1735, 1632, 1437, 1212, 1035, 898 cm-1; HRMS (MM: FAB +) m/z calc’d for C9H14O5Cl [M+H]+ : 237.0530; found: 237.0540. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   MeO 2C 452   CO2Me HO I 174d 1 H NMR (500 MHz, CDCl3) δ 6.50 (qt, J = 7.2, 0.8 Hz, 1H), 4.04 (d, J = 6.6 Hz, 2H), 3.80 (s, 6H), 3.30 (s, br, 2H), 2.36 (t, J = 6.7 Hz, 1H), 1.70 (dt, J = 7.2, 0.7 Hz, 3H); 13 C NMR (126 MHz, CDCl3) δ 170.7, 142.1, 91.5, 63.6, 59.2, 53.1, 38.7, 17.2; IR (Neat Film NaCl) 2952, 1733, 1436, 1299, 1223, 1040 cm-1; HRMS (MM: FAB +) m/z calc’d for C10H16O5I [M+H]+ : 343.0043; found: 343.0048. MeO 2C CO2Me O 175d 1 H NMR (400 MHz, C6D6) δ 4.97 (qt, J = 7.0, 2.2 Hz, 1H), 4.44 (s, 2H), 3.18 (s, 6H), 3.11 (dq, J = 2.8, 1.5 Hz, 2H), 1.40 (dt, J = 7.1, 1.4 Hz, 3H); 13C NMR (101 MHz, C6D6) δ 169.6, 153.8, 92.2, 73.6, 59.7, 52.6, 34.2, 12.2; IR (Neat Film NaCl) 2956, 1740, 1437, 1275, 1169, 1070, 803 cm-1; HRMS (MM: FAB +) m/z calc’d for C10H14O5 [M]+Ÿ: 214.0841; found: 214.0836. MeO 2C CO2Me HO I Ph 174e 1 H NMR (400 MHz, CDCl3) δ 7.42 – 7.28 (m, 5H), 6.88 (s, 1H), 4.15 (s, 2H), 3.81 (s, 6H), 3.57 (d, J = 0.9 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 170.4, 140.1, 138.2, 128.7, 128.3, 128.3, 96.5, 63.6, 59.9, 53.1, 46.9; IR (Neat Film NaCl) 2951, 1727, 1437, 1215, 1032, 696 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C15H18O5I [M+H]+ : 405.0193; found: 405.0195. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   MeO 2C 453   CO2Me O Ph 175e 1 H NMR (400 MHz, C6D6) δ 7.75 – 7.70 (m, 2H), 7.25 (t, J = 7.8 Hz, 2H), 7.05 (ddt, J = 8.6, 7.2, 1.2 Hz, 1H), 5.21 – 5.18 (m, 1H), 4.54 (s, 2H), 3.20 (d, J = 1.6 Hz, 2H), 3.16 (s, 6H); 13C NMR (101 MHz, C6D6) δ 168.8, 153.7, 136.4, 128.2, 127.8, 125.3, 99.4, 75.2, 58.5, 52.3, 38.3; IR (Neat Film NaCl) 2953, 1738, 1678, 1435, 1279, 1210, 1028, 695 cm-1; HRMS (MM: EI +) m/z calc’d for C15H16O5 [M]+Ÿ: 276.0998; found: 276.1012. MeO 2C CO2Me HO Br 174f 1 H NMR (400 MHz, CDCl3) δ 4.02 (s, 2H), 3.78 (s, 6H), 3.37 (s, 2H), 1.88 (d, J = 0.9 Hz, 3H), 1.83 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.0, 136.4, 114.1, 63.7, 59.3, 53.0, 38.8, 25.9, 21.2; IR (Neat Film NaCl) 2952, 1734, 1437, 1209, 1043 cm-1; HRMS (MM: FAB +) m/z calc’d for C11H18O5Br [M+H]+ : 309.0338; found: 309.0325. MeO 2C CO2Me O 175f 1 H NMR (500 MHz, C6D6) δ 4.12 (d, J = 6.0 Hz, 2H), 3.57 (s, 2H), 3.38 (s, 6H), 1.66 (s, 3H), 1.45 (s, 3H); 13C NMR (126 MHz, C6D6) δ 170.6, 136.2, 115.0, 63.6, 59.5, 52.3, 39.0, 25.6, 20.8; IR (Neat Film NaCl) 2952, 1731, 1437, 1301, 1209, 1043 cm-1; HRMS (MM: FAB +) m/z calc’d for C11H17O5 [M+H]+ : 229.1076; found: 229.1074. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   tBuO C 2 454   CO2tBu HO I 174g 1 H NMR (500 MHz, CDCl3) δ 6.18 (q, J = 1.3 Hz, 1H), 5.91 (d, J = 1.5 Hz, 1H), 4.06 (d, J = 3.6 Hz, 2H), 3.20 (d, J = 1.1 Hz, 2H), 2.32 (s, 1H), 1.50 (s, 18H); 13C NMR (126 MHz, CDCl3) δ 169.1, 130.9, 101.6, 82.8, 63.9, 60.7, 45.4, 28.1; IR (Neat Film NaCl) 2978, 1728, 1369, 1256, 1148, 1020, 842 cm-1; HRMS (MM: FAB +) m/z calc’d for C15H26O5I [M+H]+ : 413.0825; found: 413.0821. tBuO C 2 CO2tBu O 175g 1 H NMR (500 MHz, C6D6) δ 4.54 (q, J = 1.8 Hz, 1H), 4.51 (s, 2H), 3.94 (q, J = 1.6 Hz, 1H), 3.14 (t, J = 1.7 Hz, 2H), 1.27 (s, 18H); 13C NMR (126 MHz, C6D6) δ 168.3, 160.9, 81.8, 81.3, 74.5, 61.2, 37.0, 27.7; IR (Neat Film NaCl) 2979, 1732, 1370, 1146, 1050, 844 cm-1; HRMS (MM: FAB +) m/z calc’d for C15H25O5 [M+H]+ : 285.1702; found: 285.1693. BnO 2C CO2Bn HO I 174h 1 H NMR (500 MHz, CDCl3) δ 7.34 – 7.29 (m, 6H), 7.29 – 7.26 (m, 4H), 6.12 (q, J = 1.1 Hz, 1H), 5.87 (d, J = 1.6 Hz, 1H), 5.17 (d, J = 3.2 Hz, 4H), 4.13 (s, 2H), 3.29 (d, J = 1.1 Hz, 2H), 2.27 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 169.6, 135.1, 131.8, 128.7, 128.6, 128.4, 100.3, 67.8, 63.6, 59.5, 45.4; IR (Neat Film NaCl) 2952, 1725, 1455, 455     1214, 695 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C21H22O5I [M+H]+ : Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 481.0506; found: 481.0509. BnO 2C CO2Bn O 175h 1 H NMR (600 MHz, C6D6) δ 7.10 – 6.90 (m, 10H), 4.83 (d, J = 8.0 Hz, 4H), 4.50 (q, J = 1.8 Hz, 1H), 4.46 (s, 2H), 3.87 (q, J = 1.7 Hz, 1H), 3.11 (t, J = 1.7 Hz, 2H); 13C NMR (151 MHz, C6D6) δ 168.7, 148.2, 135.6, 128.7, 128.5, 128.3, 81.9, 74.3, 67.7, 55.8, 37.0; IR (Neat Film NaCl) 2915, 1732, 1455, 1243, 1045, 901, 695 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C21H21O5 [M+H]+ : 353.1384; found: 353.1394. MeO 2C CN HO I 174i 1 H NMR (500 MHz, CDCl3) δ 6.35 (dt, J = 2.2, 1.1 Hz, 1H), 6.05 (d, J = 2.1 Hz, 1H), 4.04 (dd, J = 11.1, 7.6 Hz, 1H), 3.98 (dd, J = 11.1, 6.5 Hz, 1H), 3.90 (s, 3H), 3.13 (dd, J = 14.9, 1.1 Hz, 1H), 3.05 (dd, J = 14.9, 1.1 Hz, 1H), 2.45 (dd, J = 7.6, 6.5 Hz, 1H); 13 C NMR (126 MHz, CDCl3) δ 167.6, 132.6, 117.2, 97.2, 66.0, 54.2, 52.1, 46.9; IR (Neat Film NaCl) 2952, 2359, 1738, 1611, 1434, 1224, 1144, 1060, 910 cm-1; HRMS (MM: FAB +) m/z calc’d for C8H11O3NI [M+H]+ : 295.9784; found: 295.9775. MeO 2C CN O 175i 1 H NMR (500 MHz, C6D6) δ 4.44 (q, J = 2.0 Hz, 1H), 3.84 (d, J = 8.9 Hz, 1H), 3.79 – 3.75 (m, 2H), 3.02 (d, J = 0.7 Hz, 3H), 2.69 (dt, J = 15.9, 1.9 Hz, 1H), 2.42 (dt, J = 456     15.9, 1.6 Hz, 1H); 13C NMR (126 MHz, C6D6) δ 166.1, 158.0, 117.3, 83.6, 75.1, 53.3, Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 46.9, 38.7; IR (Neat Film NaCl) 2959, 2249, 1747, 1682, 1435, 1231, 1046, 819 cm-1; HRMS (MM: FAB +) m/z calc’d for C8H10O3N [M+H]+ : 168.0661; found: 168.0666. O CO2Me N O OH I 174j 1 H NMR (400 MHz, CDCl3) δ 6.22 (q, J = 1.2 Hz, 1H), 5.97 (d, J = 1.6 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.81 (s, 3H), 3.79 – 3.55 (m, 6H), 3.39 (s, br, 2H), 3.30 (dd, J = 15.5, 1.0 Hz, 1H), 3.06 (dd, J = 15.4, 1.1 Hz, 1H), 2.60 (s, br, 1H); 13C NMR (101 MHz, CDCl3) δ 171.9, 167.7, 132.2, 99.9, 66.3, 66.1, 57.4, 53.1, 45.6, 37.2; IR (Neat Film NaCl) 2955, 2859, 1733, 1627, 1436, 1272, 1228, 1115, 1064, 999, 851 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C12H19NO5I [M+H]+ : 384.0302; found: 384.0315. O CO2Me N O O 175j 1 H NMR (500 MHz, C6D6) δ 4.60 (d, J = 9.0 Hz, 1H), 4.55 (q, J = 1.8 Hz, 1H), 4.41 (d, J = 9.0 Hz, 1H), 3.94 (q, J = 1.7 Hz, 1H), 3.22 (s, br, 2H), 3.15 – 2.97 (m, 9H), 2.71 (s, br, 2H); 13C NMR (101 MHz, C6D6) δ 171.6, 165.8, 160.7, 81.4, 75.2, 66.4, 66.0, 58.8, 52.5, 46.0, 43.5, 37.5; IR (Neat Film NaCl) 2857, 1733, 1651, 1435, 1274, 1115, 1018, 804 cm-1; HRMS (MM: ESI-APCI +) m/z calc’d for C12H18NO5 [M+H]+ : 256.1179; found: 256.1196. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   MeO 2C 457   CO2Me HO I 174k 1 H NMR (500 MHz, CDCl3) δ 6.06 (q, J = 1.4 Hz, 1H), 5.72 (d, J = 1.7 Hz, 1H), 3.96 (s, 2H), 3.79 (d, J = 0.6 Hz, 6H), 2.49 – 2.43 (m, 2H), 2.20 – 2.13 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 171.2, 126.4, 109.9, 64.9, 59.0, 52.9, 40.8, 31.5; IR (Neat Film NaCl) 2952, 1729, 1617, 1436, 1205, 1043, 898 cm-1; HRMS (MM: FAB+) m/z calc’d for C10H16IO5 [M+H]+: 343.0043; found: 343.0031. tBuO C 2 CO2tBu I SI-4-10a 1. NaH 2-bromoethyl acetate, THF tBuO C 2 2. K 2CO3, MeOH (38% yield, 2 steps; 65% yields based on recovered starting material) HO CO2tBu I 174l To a solution of NaH (60% dispersion in mineral oil, 78.0 mg, 1.95 mmol, 2.00 equiv) in THF (3.26 mL) was added vinyl iodide SI-4-10a (374 mg, 0.977 mmol, 1.00 equiv), and the solution was stirred until gas evolution was complete. 2-Bromoethyl acetate (0.27 mL, 2.44 mmol, 2.50 equiv) was added to the reaction mixture at 0 °C and then, the solution was stirred at 23 °C for 24 h. The reaction was quenched with sat. NH4Cl at 0 °C and the mixture was extracted with EtOAc (3 x 3.00 mL), the combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (1:20 EtOAc:hexanes) to give dialkylated malonate and recovered SI-4-10a. To a solution of dialkylated malonate intermediate (344 mg, 0.735 mmol, 1.00 equiv) in MeOH (2.50 mL) was added K2CO3 (203 mg, 1.47 mmol, 2.00 equiv) and the solution was stirred at 23 °C for 24 h. The reaction mixture was diluted with CH2Cl2 (3.00 mL) and the mixture was extracted with CH2Cl2 (3 x 2.00 mL), the combined organic phase was washed with brine, dried over MgSO4, filtered and concentrated in Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   vacuo. 458   The residue was purified by silica gel flash chromatography (1:20 → 1:8 → 1:4 EtOAc:hexanes) to give malonate 174l (159 mg, 38% yield, 2 steps). 1 H NMR (500 MHz, CDCl3) δ 6.14 (q, J = 1.4 Hz, 1H), 5.91 (d, J = 1.7 Hz, 1H), 3.72 (t, J = 6.7 Hz, 2H), 3.17 (d, J = 1.2 Hz, 2H), 2.28 (t, J = 6.7 Hz, 2H), 1.65 (s, br, 1H), 1.47 (s, 18H); 13C NMR (126 MHz, CDCl3) δ 170.0, 130.5, 102.2, 82.5, 59.2, 57.7, 46.9, 34.7, 28.1; IR (Neat Film NaCl) 3447, 2977, 1726, 1368, 1250, 1145, 843 cm-1; HRMS (MM: FAB +) m/z calc’d for C16H28IO5 [M+H]+ : 427.0982; found: 427.0985. tBuO C 2 CO2tBu O 175l 1 H NMR (500 MHz, CD2Cl2) δ 4.68 (h, J = 0.9 Hz, 1H), 4.02 – 3.96 (m, 2H), 2.10 – 2.04 (m, 2H), 1.76 (d, J = 1.0 Hz, 3H), 1.43 (s, 18H); 13C NMR (126 MHz, CD2Cl2) δ 170.6, 153.8, 94.6, 81.7, 64.1, 52.5, 28.7, 28.1, 20.6; IR (Neat Film NaCl) 2977, 2933, 1728, 1369, 1266, 1146, 1108, 1088, 847 cm-1; HRMS (MM: FAB +) m/z calc’d for C16H27O5 [M+H]+ : 299.1858; found: 299.1835. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers   4.5. 459   References and Notes                                                                                                                 (1) Selected recent reviews: (a) Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270–5298. (b) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417–1492. (c) Hartwig, J. F. Nature 2008, 455, 314–322. (d) Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79, 663–672. (2) (a) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299–309. (b) Ananikov, V. P. ACS Catal. 2015, 5, 1964–1971. (3) Selected recent reviews: (a) Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525–1532. (b) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346–1416. (c) Hu, X. Chem. Sci. 2011, 2, 1867–1886. (d) Standley, E. A.; Tasker, S. Z.; Jensen, K. L.; Jamison, T. F. Acc. Chem. Res. 2015, 48, 1503–1514. ( 4 ) For fundamental studies involving stoichiometric nickel-alkoxides, see: (a) Matsunaga, P. T.; Hillhouse, G. L.; Rheingold, A. L. J. Am. Chem. Soc. 1993, 115, 2075–2077. (b) Han, R.; Hillhouse, G. L. J. Am. Chem. Soc. 1997, 119, 8135–8136. (5) Macgregor, S. A.; Neave, G. W.; Smith, C. Faraday Discuss. 2003, 124, 111–127. (6) Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413–5418. (7) Kundu, D.; Maity, P.; Ranu, B. C. Org. Lett. 2014, 16, 1040–1043. (8) Terrett, J. A.; Cuthbertson, J. D.; Shurtleff, V. W.; MacMillan, D. W. C. Nature 2015, 524, 330–334. (9) For examples of intramolecular C–O cyclization using non-nickel catalysis, see: (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333– 10334. (b) Torraca, K. E.; Kuwabe, S.-I.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907–12908. (c) Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. 460                                                                                                                                                                                                                                                                                                                                 Soc. 2001, 123, 12202–12206. . (d) Sun, C.; Fang, Y.; Li, S.; Zhang, Y.; Zhao, Q.; Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers Zhu, S.; Li, C. Org Lett. 2009, 11, 4084–4087. (e) Fang, Y.; Li, C. J. Am .Chem. Soc. 2007, 129, 8092–8093. (f) Fang, Y.; Li, C. Chem. Commun. 2005, 3574–3576. (10) For examples of intermolecular C–O cyclization using non-nickel catalysis, see: (a) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224–3225. (b) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369–4378. (c) Burgos, C.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 4321–4326. (d) Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2498–2500. (e) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718–10719. (f) Wu, X.; Fors, B. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9943–9947. (g) Surasani, R.; Kalita, D.; Rao, A. V. D.; Chandrasekhar, K. B. Beilstein J. Org. Chem. 2012, 8, 2004–2018. (h) Maiti, D.; Buchwald, S. L. J. Org. Chem. 2010, 75, 1791–1794. (i) Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2009, 74, 5075–5078. (j) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978–4979. (k) Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am. Chem. Soc. 2010, 132, 1202–1203. (11) For an example of a base-mediated intramolecular synthesis of an alkylidene morpholine by C–O bond formation, see: Bottini, A. T.; Mullikin, J. A.; Morris, C. J. J. Org. Chem. 1964, 29, 373–379. (12) Teng, M.; Zi, W.; Ma, D. Angew. Chem., Int. Ed. 2014, 53, 1814–1817. (13) Lebedev, S. A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya, I. P. J. Organomet. Chem. 1988, 344, 253–259. 461                                                                                                                                                                                                                                                                                                                                 (14) Importantly, if the Ni(COD)2 catalyst was omitted, no carbon–oxygen bond Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers formation was observed. Addition of other additives such as Mg and CuI decreased the yields (36% and 0% yield, respectively). (15) Intramolecular etherification of vinyl iodide 170b proceeded with 5 mol % of NiI2 or NiBr2(dme) to furnish vinyl ether 171b (entries 1 and 2). An increased rate of cycloetherification was observed with 10 mol % of NiBr2(dme) (entries 2 and 3). Unfortunately, attempts to convert vinyl iodide 170b to enol ether 171b outside a N2filled glove box were unsuccessful (entries 4 and 5). OH N I NiLn Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M), 23 °C Me N Me 170b NiLn Ni mol % time yield (%)a 1b NiI 2 5 16 h 60 2b NiBr 2(dme) 5 48 h 53 3b NiBr 2(dme) 10 16 h 51 4c NiI 2 5 24 h 0 5c NiBr 2(dme) 5 24 h 0 entry a 171b Yield of isolated product. b Reactions were performed in a N2-filled glove box. c Reactions were performed under argon outside a N2-filled glove box. (16) No significant improvement in yield or catalyst turnover was observed when various ligands (e.g., various NHC, PYBOX, BOX, diamine, BiOX ligands) were employed. ( 17 ) Since intramolecular etherifications of aminocyclohexanols 170a or 170b proceeded even without Zn powder despite low yields and catalyst turnover (Table 1), we envision that Zn powder likely plays an important role as a scavenger of the forming HI. (18) Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 12248–12249. 462                                                                                                                                                                                                                                                                                                                                 (19) Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.; Leach, D. C. J. Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers Chem. Soc. Perkin. Trans. 1 2002, 58–68. (20) An intramolecular cross-coupling of 170k afforded the desired product 171k in low yield under our standard reaction conditions. Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) (11% yield) OH I N 4k or Ni(COD) 2 (20 mol %) Et 3N (1.0 equiv) DABCO (1.0 equiv) CH3CN (0.04 M) (25% yield) O N 5k ( 21 ) Surprisingly, the cycloetherification of trans- and cis-aminocyclopentanol derived substrates resulted in very low conversion. Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) OH N I 170l OH N I or Ni(COD) 2 (20 mol %) Et 3N (1.0 equiv) DABCO (1.0 equiv) CH3CN (0.04 M) O N 171l (Low conversion) Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M) N 170m 171m (Low conversion) (22) Cao, H.; Yu, J.; Wearing, X. Z.; Zhang, C.; Liu, X.; Deschamps, J.; Cook, J. M. Tetrahedron Lett. 2003, 44, 8013–8017. (23) Gatti, M.; Drinkel, E.; Wu, L.; Pusterla, I.; Gaggia, F.; Dorta, R. J. Am. Chem. Soc. 2010, 132, 15179–15181. (24) Although we attempted to construct 2,3-dihydrobenzofuran 177 from aryl iodide 176 under our standard reaction conditions, only unreacted starting material was recovered. 463                                                                                                                                                                                                                                                                                                                                 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers OH Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) I O 176 177 (Not Observed) (25) Substrates containing alkyl- or mono-ketone substituents instead of a malonate provided a mixture of isomers upon subjection to carbon–oxygen cross-coupling conditions. TBSO Ni(COD) 2 (20 mol %) Et 3N (5.0 equiv) DABCO (1.2 equiv) OH TBSO TBSO O + O CH3CN (0.04 M) (55% combined yield) I 178 179a O Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) OH 179b O O O O + CH3CN (0.15 M) (77% combined yield) I 180 181b 181a (26) Unfortunately, the cyclization reaction of a malonate substrate bearing a nitrogen nucleophile (182) was unsuccessful. MeO 2C BocHN I CO2Me Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) CH3CN (0.15 M) 182 MeO 2C CO2Me BocN 183 (Not Observed) (27) An intermolecular etherification of MacMillan’s substrate 184 (ref. 8) with 1hexanol under our reaction conditions was not successful. Additionally, attempted intermolecular cross-coupling processes of 186 and 188 with 1-hexanol under our standard reaction conditions resulted in no reaction. 464                                                                                                                                                                                                                                                                                                                                 Chapter 4 – Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 1-hexanol (1.0 equiv) Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) Br hex O MeCN (0.15 M) O O 184 185 1-hexanol (1.0 equiv) Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) I N MeCN (0.15 M) O N 187 186 I 1-hexanol (1.0 equiv) Ni(COD) 2 (5.0 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) hex O MeCN (0.15 M) 188 189 hex Appendix 8 – Spectra Relevant to Chapter 4 465 APPENDIX 8 Spectra Relevant to Chapter 4: Ni-Catalyzed Intramolecular C–O Bond Formation: Synthesis of Cyclic Enol Ethers 167 N Me H OH I N O PMB                                                                                                     466   Figure A8.1. 1H NMR (500 MHz, CDCl3) of compound 167. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.2. Infrared spectrum (Thin Film, NaCl) of compound 167.  Figure A8.3. 13C NMR (126 MHz, CDCl3) of compound 167.   467   169 N O H N O PMB                                                                                                     468   Figure A8.4. 1H NMR (400 MHz, CDCl3) of compound 169. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.5. Infrared spectrum (Thin Film, NaCl) of compound 169.  Figure A8.6. 13C NMR (126 MHz, CDCl3) of compound 169.   469   170a I N OH                                                                                                     470   Figure A8.7. 1H NMR (500 MHz, CDCl3) of compound 170a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.8. Infrared spectrum (Thin Film, NaCl) of compound 170a.  Figure A8.9. 13C NMR (126 MHz, CDCl 3) of compound 170a.   471   171a N O                                                                                                     472   Figure A8.10. 1H NMR (400 MHz, CDCl3) of compound 171a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.11. Infrared spectrum (Thin Film, NaCl) of compound 171a.  Figure A8.12. 13C NMR (101 MHz, CDCl3) of compound 171a.   473   170b I N OH                                                                                                     474   Figure A8.13. 1H NMR (300 MHz, CDCl3) of compound 170b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.14. Infrared spectrum (Thin Film, NaCl) of compound 170b.  Figure A8.15. 13C NMR (75 MHz, CDCl3) of compound 170b.   475   171b N O                                                                                                     476   Figure A8.16. 1H NMR (300 MHz, CDCl3) of compound 171b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.17. Infrared spectrum (Thin Film, NaCl) of compound 171b.  Figure A8.18. 13C NMR (75 MHz, CDCl3) of compound 171b.   477   Ph 170c I N OH                                                                                                     478   Figure A8.19. 1H NMR (400 MHz, CDCl3) of compound 170c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.20. Infrared spectrum (Thin Film, NaCl) of compound 170c.  Figure A8.21. 13C NMR (101 MHz, CDCl3) of compound 170c.   479   171c N Ph O                                                                                                     480   Figure A8.22. 1H NMR (400 MHz, CDCl3) of compound 171c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.23. Infrared spectrum (Thin Film, NaCl) of compound 171c.  Figure A8.24. 13C NMR (101 MHz, CDCl3) of compound 171c.   481   170d I N OH                                                                                                     482   Figure A8.25. 1H NMR (400 MHz, CDCl3) of compound 170d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.26. Infrared spectrum (Thin Film, NaCl) of compound 170d.  Figure A8.27. 13C NMR (101 MHz, CDCl3) of compound 170d.   483   171d N O                                                                                                     484   Figure A8.28. 1H NMR (400 MHz, C6D6) of compound 171d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.29. Infrared spectrum (Thin Film, NaCl) of compound 171d.  Figure A8.30. 13C NMR (101 MHz, C6D6) of compound 171d.   485   170e I N OH                                                                                                     486   Figure A8.31. 1H NMR (500 MHz, CDCl3) of compound 170e. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.32. Infrared spectrum (Thin Film, NaCl) of compound 170e.  Figure A8.33. 13C NMR (126 MHz, CDCl3) of compound 170e.   487   171e N O                                                                                                     488   Figure A8.34. 1H NMR (500 MHz, CDCl3) of compound 171e. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.35. Infrared spectrum (Thin Film, NaCl) of compound 171e.  Figure A8.36. 13C NMR (126 MHz, CDCl3) of compound 171e.   489   MeO 170f I N OH                                                                                                     490   Figure A8.37. 1H NMR (500 MHz, CDCl3) of compound 170f. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.38. Infrared spectrum (Thin Film, NaCl) of compound 170f.  Figure A8.39. 13C NMR (126 MHz, CDCl3) of compound 170f.   491   171f MeO N O                                                                                                     492   Figure A8.40. 1H NMR (400 MHz, CDCl3) of compound 171f. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.41. Infrared spectrum (Thin Film, NaCl) of compound 171f.  Figure A8.42. 13C NMR (101 MHz, CDCl3) of compound 171f.   493   F 170g I N OH                                                                                                     494   Figure A8.43. 1H NMR (400 MHz, CDCl3) of compound 170g. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.44. Infrared spectrum (Thin Film, NaCl) of compound 170g.  Figure A8.45. 13C NMR (101 MHz, CDCl3) of compound 170g.   495   171g F N O                                                                                                     496   Figure A8.46. 1H NMR (400 MHz, CDCl3) of compound 171g. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.47. Infrared spectrum (Thin Film, NaCl) of compound 171g.  Figure A8.48. 13C NMR (101 MHz, CDCl3) of compound 171g.   497   Br 170h I N OH                                                                                                     498   Figure A8.49. 1H NMR (400 MHz, CDCl3) of compound 170h. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.50. Infrared spectrum (Thin Film, NaCl) of compound 170h.  Figure A8.51. 13C NMR (101 MHz, CDCl3) of compound 170h.   499   171h Br N O                                                                                                     500   Figure A8.52. 1H NMR (500 MHz, CD2Cl2) of compound 171h. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.53. Infrared spectrum (Thin Film, NaCl) of compound 171h.  Figure A8.54. 13C NMR (126 MHz, CD2Cl2) of compound 171h.   501   TBSO 170i I N OH                                                                                                     502   Figure A8.55. 1H NMR (500 MHz, CDCl3) of compound 170i. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.56. Infrared spectrum (Thin Film, NaCl) of compound 170i.  Figure A8.57. 13C NMR (126 MHz, CDCl3) of compound 170i.   503   171i TBSO N O                                                                                                     504   Figure A8.58. 1H NMR (400 MHz, CDCl3) of compound 171i. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.59. Infrared spectrum (Thin Film, NaCl) of compound 171i.  Figure A8.60. 13C NMR (101 MHz, CDCl3) of compound 171i.   505   SI-4-6 I N OBz                                                                                                     506   Figure A8.61. 1H NMR (500 MHz, CDCl3) of compound SI-4-6. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.62. Infrared spectrum (Thin Film, NaCl) of compound SI-4-6.  Figure A8.63. 13C NMR (126 MHz, CDCl3) of compound SI-4-6.   507   170j I N OH                                                                                                     508   Figure A8.64. 1H NMR (400 MHz, CDCl3) of compound 170j. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.65. Infrared spectrum (Thin Film, NaCl) of compound 170j.  Figure A8.66. 13C NMR (101 MHz, CDCl3) of compound 170j.   509   171j N O                                                                                                     510   Figure A8.67. 1H NMR (400 MHz, CD2Cl2) of compound 171j. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.68. Infrared spectrum (Thin Film, NaCl) of compound 171j.  Figure A8.69. 13C NMR (101 MHz, CD2Cl2) of compound 171j.   511   Ph 172a I N OH                                                                                                     512   Figure A8.70. 1H NMR (300 MHz, CDCl3) of compound 172a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.71. Infrared spectrum (Thin Film, NaCl) of compound 172a.  Figure A8.72. 13C NMR (75 MHz, CDCl 3) of compound 172a.   513   173a N Ph O                                                                                                     514   Figure A8.73. 1H NMR (300 MHz, CDCl3) of compound 173a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.74. Infrared spectrum (Thin Film, NaCl) of compound 173a.  Figure A8.75. 13C NMR (75 MHz, CDCl 3) of compound 173a.   515   Ph 172b I N OH                                                                                                     516   Figure A8.76. 1H NMR (400 MHz, CDCl3) of compound 172b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.77. Infrared spectrum (Thin Film, NaCl) of compound 172b.  Figure A8.78. 13C NMR (101 MHz, CDCl3) of compound 172b.   517   173b N Ph O                                                                                                     518   Figure A8.79. 1H NMR (400 MHz, CDCl3) of compound 173b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.80. Infrared spectrum (Thin Film, NaCl) of compound 173b.  Figure A8.81. 13C NMR (101 MHz, CDCl3) of compound 173b.   519   Ph 172c I N OH                                                                                                     520   Figure A8.82. 1H NMR (400 MHz, CDCl3) of compound 172c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.83. Infrared spectrum (Thin Film, NaCl) of compound 172c.  Figure A8.84. 13C NMR (101 MHz, CDCl3) of compound 172c.   521   173c N Ph O                                                                                                     522   Figure A8.85. 1H NMR (400 MHz, CDCl3) of compound 173c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.86. Infrared spectrum (Thin Film, NaCl) of compound 173c.  Figure A8.87. 13C NMR (101 MHz, CDCl3) of compound 173c.   523   172d I Ph N OH                                                                                                     524   Figure A8.88. 1H NMR (300 MHz, CDCl3) of compound 172d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.89. Infrared spectrum (Thin Film, NaCl) of compound 172d.  Figure A8.90. 13C NMR (75 MHz, CDCl3) of compound 172d.   525   173d Ph N O                                                                                                     526   Figure A8.91. 1H NMR (300 MHz, CDCl3) of compound 173d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.92. Infrared spectrum (Thin Film, NaCl) of compound 173d.  Figure A8.93. 13C NMR (75 MHz, CDCl3) of compound 173d.   527   HO I 174a CO2Me MeO 2C                                                                                                     528   Figure A8.94. 1H NMR (500 MHz, C6D6) of compound 174a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.95. Infrared spectrum (Thin Film, NaCl) of compound 174a.  Figure A8.96. 13C NMR (126 MHz, C6D6) of compound 174a.   529   175a O CO2Me MeO 2C                                                                                                     530   Figure A8.97. 1H NMR (500 MHz, C6D6) of compound 175a. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.98. Infrared spectrum (Thin Film, NaCl) of compound 175a.  Figure A8.99. 13C NMR (126 MHz, C6D6) of compound 175a.   531   HO Br 174b CO2Me MeO 2C                                                                                                     532   Figure A8.100. 1H NMR (500 MHz, CDCl3) of compound 174b. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.101. Infrared spectrum (Thin Film, NaCl) of compound 174b.  Figure A8.102. 13C NMR (126 MHz, CDCl3) of compound 174b.   533   HO Cl 174c CO2Me MeO 2C                                                                                                     534   Figure A8.103. 1H NMR (400 MHz, CDCl3) of compound 174c. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.104. Infrared spectrum (Thin Film, NaCl) of compound 174c.  Figure A8.105. 13C NMR (101 MHz, CDCl3) of compound 174c.   535   HO 174d I CO2Me MeO 2C                                                                                                     536   Figure A8.106. 1H NMR (500 MHz, CDCl3) of compound 174d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.107. Infrared spectrum (Thin Film, NaCl) of compound 174d.  Figure A8.108. 13C NMR (126 MHz, CDCl3) of compound 174d.   537   175d O CO2Me MeO 2C                                                                                                     538   Figure A8.109. 1H NMR (400 MHz, C6D6) of compound 175d. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.110. Infrared spectrum (Thin Film, NaCl) of compound 175d.  Figure A8.111. 13C NMR (101 MHz, C6D6) of compound 175d.   539   HO I 174e Ph CO2Me MeO 2C                                                                                                     540   Figure A8.112. 1H NMR (400 MHz, CDCl3) of compound 174e. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.113. Infrared spectrum (Thin Film, NaCl) of compound 174e.  Figure A8.114. 13C NMR (101 MHz, CDCl3) of compound 174e.   541   175e O Ph CO2Me MeO 2C                                                                                                     542   Figure A8.115. 1H NMR (400 MHz, C6D6) of compound 175e. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.116. Infrared spectrum (Thin Film, NaCl) of compound 175e.  Figure A8.117. 13C NMR (101 MHz, C6D6) of compound 175e.   543   HO Br 174f CO2Me MeO 2C                                                                                                     544   Figure A8.118. 1H NMR (400 MHz, CDCl3) of compound 174f. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.119. Infrared spectrum (Thin Film, NaCl) of compound 174f.  Figure A8.120. 13C NMR (101 MHz, CDCl3) of compound 174f.   545   175f O CO2Me MeO 2C                                                                                                     546   Figure A8.121. 1H NMR (500 MHz, C6D6) of compound 175f. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.122. Infrared spectrum (Thin Film, NaCl) of compound 175f.  Figure A8.123. 13C NMR (126 MHz, C6D6) of compound 175f.   547   HO 174g I CO2tBu tBuO C 2                                                                                                     548   Figure A8.124. 1H NMR (500 MHz, CDCl3) of compound 174g. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                               Figure A8.125. Infrared spectrum (Thin Film, NaCl) of compound 174g.  Figure A8.126. 13C NMR (126 MHz, CDCl3) of compound 174g.   549   CO2tBu 175g O tBuO C 2 Figure A8.127. 1H NMR (500 MHz, C6D6) of compound 175g. Appendix 8 – Spectra Relevant to Chapter 4   550   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.128. Infrared spectrum (Thin Film, NaCl) of compound 175g.  Figure A8.129. 13C NMR (126 MHz, C6D6) of compound 175g.   551   HO CO2Bn 174h I BnO 2C Figure A8.130. 1H NMR (500 MHz, CDCl3) of compound 174h. Appendix 8 – Spectra Relevant to Chapter 4   552   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.131. Infrared spectrum (Thin Film, NaCl) of compound 174h.  Figure A8.132. 13C NMR (126 MHz, CDCl3) of compound 174h.   553   CO2Bn 175h O BnO 2C Figure A8.133. 1H NMR (600 MHz, C6D6) of compound 175h. Appendix 8 – Spectra Relevant to Chapter 4   554   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.134. Infrared spectrum (Thin Film, NaCl) of compound 175h.  Figure A8.135. 13C NMR (151 MHz, C6D6) of compound 175h.   555   I 174i HO MeO 2C CN Figure A8.136. 1H NMR (500 MHz, CDCl3) of compound 174i. Appendix 8 – Spectra Relevant to Chapter 4   556   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.137. Infrared spectrum (Thin Film, NaCl) of compound 174i.  Figure A8.138. 13C NMR (126 MHz, CDCl3) of compound 174i.   557   175i O MeO 2C CN Figure A8.139. 1H NMR (500 MHz, C6D6) of compound 175i. Appendix 8 – Spectra Relevant to Chapter 4   558   Appendix 8 – Spectra Relevant to Chapter 4   Figure A8.140. Infrared spectrum (Thin Film, NaCl) of compound 175i.  Figure A8.141. 13C NMR (126 MHz, C6D6) of compound 175i.   559   O 174j OH I CO2Me N O                                                                                                     560   Figure A8.142. 1H NMR (400 MHz, CDCl3) of compound 174j. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.143. Infrared spectrum (Thin Film, NaCl) of compound 174j  Figure A8.144. 13C NMR (101 MHz, CDCl3) of compound 174j.   561   O 175j O CO2Me N O                                                                                                     562   Figure A8.145. 1H NMR (500 MHz, C6D6) of compound 175j. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.146. Infrared spectrum (Thin Film, NaCl) of compound 175j  Figure A8.147. 13C NMR (101 MHz, C6D6) of compound 175j.   563   I HO 174k CO2Me MeO 2C                                                                                                         564   Figure A8.148. 1H NMR (500 MHz, CDCl3) of compound 174k. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.149. Infrared spectrum (Thin Film, NaCl) of compound 174k.  Figure A8.150. 13C NMR (126 MHz, CDCl3) of compound 174k.   565   HO I 174l CO2tBu tBuO C 2                                                                                                     566   Figure A8.151. 1H NMR (500 MHz, CDCl3) of compound 174l. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4                                                                                                     Figure A8.152. Infrared spectrum (Thin Film, NaCl) of compound 174l.  Figure A8.153. 13C NMR (126 MHz, CDCl3) of compound 174l.   567   175l O CO2tBu tBuO C 2                                                                                                     568   Figure A8.154. 1H NMR (500 MHz, CD2Cl2) of compound 175l. Appendix 8 – Spectra Relevant to Chapter 4 Appendix 8 – Spectra Relevant to Chapter 4     Figure A8.155. Infrared spectrum (Thin Film, NaCl) of compound 175l.  Figure A8.156. 13C NMR (126 MHz, CD2Cl2) of compound 175l.   569   Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement   570   APPENDIX 9 Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement A9.1. Claisen Rearrangement Having successfully investigated Ni-catalyzed intramolecular C–O bond- forming reactions, we envisaged that allyl vinyl ethers prepared under our conditions could be substrates for subsequent Claisen rearrangement. Treatment of epoxide 190 with methylamine followed by alkylation with allyl bromide 191 afforded aminoalcohol 192 (Scheme A9.1.1a). Intramolecular etherification of aminoalcohol 192 furnished the desired allyl vinyl ether 193 (Scheme A9.1.1b). To our delight, microwave-assisted Claisen rearrangement of vinyl ether 193 in m-xylene at 180 °C produced 194 (Scheme A9.1.1c). Further investigation of the substrate scope for Claisen rearrangement is ongoing in our laboratory. Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement   571   Scheme A9.1.1. Ni-Catalyzed C–O Bond Formation and subsequent Claisen Rearrangement (a) 1. MeNH 2 (2M in MeOH) 23 °C O 2. 190 OH I N I Ph Br Ph 192 191 K 2CO3, MeCN, 23 °C (35% yield, 2 steps) (b) OH I N Ph Ni(COD) 2 (5 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M) (72% yield) N Ph 192 193 (c) Ph Ph O microwave N 180 °C, m-xylene (44% yield) 193 O N 194 A9.2. Experimental Methods and Analytical Data A9.2.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, TCI, Oakwood chemicals, Strem, or Alfa Aesar and used as received unless otherwise stated. Ni(COD)2 and NiI2 were purchased from Strem. NiBr2(dme) was purchased from Aldrich. Zinc dust or powder purchased from Aldrich worked well for the reaction but zinc powder (99.999%) purchased from Strem gave poor conversion. Reaction temperatures were 572     controlled by an IKAmag temperature modulator unless otherwise indicated. Glove Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, p-anisaldehyde, KMnO4 or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.0400.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), CHDCl2 (δ 5.32) or C6HD6 (δ 7.16 ppm). 13C NMR spectra are recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers (75 MHz, 126 MHz, and 151 MHz, respectively) and are reported relative to CHCl3 (δ 77.16 ppm), CHDCl2 (δ 53.84) or C6HD5 (δ 128.06 ppm). 19 F NMR spectra are recorded on a Varian Mercury 300 MHz (at 282 MHz). 19F NMR spectra are reported relative to CFCl3(δ 0.0 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app = apparent. Data for 13C are reported in terms of chemical shifts (δ ppm). IR spectra were obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode, or Agilent 6200 Series TOF with an Agilent G1978A 573     Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). A9.2.2. Experimental Procedures O 1. MeNH 2 (2M in MeOH) 23 °C 2. 190 I N I Ph OH Br Ph 192 191 K 2CO3, MeCN, 23 °C (35% yield, 2 steps) To epoxide 190 (300 mg, 4.28 mmol, 1.00 equiv) was added MeNH2 (2M solution in MeOH; 3.71 mL, 42.8 mmol, 10.0 equiv). The solution was stirred for 12 h at 23 °C. The volatile was evaporated and the residue was used without further purification. To a solution of the amine (4.28 mmol, 1.00 equiv) in MeCN (11.0 mL) were added K2CO3 (2.96 g, 21.4 mmol, 5.00 equiv) and allyl bromide 191 (691 mg, 2.14 mmol, 0.50 equiv). The solution was stirred for 12 h at 23 °C. After the reaction was done, water was added. The aqueous phase was extracted with EtOAc (3 x 7.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (1:4 EtOAc:hexanes) on silica gel to give aminoalcohol 192 (257 mg, 35% yield based on equivalent of allyl bromide 191, 2 steps). Rf = 0.65 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.60 – 7.55 (m, 2H), 7.43 – 7.34 (m, 3H), 7.10 – 6.98 (s, br, 1H), 5.84 (ddd, J = 17.2, 10.5, 5.8 Hz, 1H), 5.45 – 5.37 (m, 1H), 5.21 (dt, J = 10.5, 1.5 Hz, 1H), 4.29 (s, br, 1H), 3.54 (s, br, 1H), 3.41 (s, br, 1H), 2.58 (s, br, 2H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 138.0, 137.2, 136.9, 128.8, 128.4, 128.3, 116.3, 70.7, 68.7, 62.8, 61.1, 41.2; IR (Neat Film 574     NaCl) 3435, 2795, 1491, 1446, 1083, 1029, 921, 750, 695 cm-1; HRMS (MM: ESIAppendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement APCI+) m/z calc’d for C14H19NOI [M+H]+ : 344.0506; found: 344.0523. OH I N 192 Ph Ph Ni(COD) 2 (5 mol %) Et 3N (1.1 equiv), Zn (2.0 equiv) O CH3CN (0.15 M) (72% yield) N 193 Ni-Catalyzed C–O bond formation experiments were performed in a nitrogen-filled glove box. To a solution of aminoalcohol 192 (100 mg, 0.291 mmol, 1.00 equiv) in MeCN (1.94 mL) in a scintillation vial were added Et3N (45 µL, 0.320 mmol, 1.10 equiv), Zn powder (38.0 mg, 0.582 mmol, 2.00 equiv), and Ni(COD)2 (4.00 mg, 0.0146 mmol, 0.05 equiv). The reaction mixture was stirred at 23 °C for 24 h. After the reaction was done, the vial was removed from the glovebox and uncapped. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to furnish the product 193 (45.3 mg, 72% yield). Rf = 0.23 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CD2Cl2) δ 7.51 (dd, J = 8.3, 1.4 Hz, 2H), 7.18 (dd, J = 8.4, 7.0 Hz, 2H), 7.08 – 7.01 (m, 1H), 5.89 (ddd, J = 17.3, 10.7, 5.6 Hz, 1H), 5.40 – 5.32 (m, 2H), 5.19 – 5.16 (m, 1H), 4.35 (dddt, J = 9.8, 5.7, 2.9, 1.5 Hz, 1H), 3.09 (dd, J = 12.6, 1.6 Hz, 1H), 2.78 – 2.69 (m, 2H), 2.21 (s, 3H), 2.08 (dd, J = 11.7, 9.5 Hz, 1H); 13C NMR (101 MHz, CD2Cl2) δ 150.5, 136.4, 136.2, 128.9, 128.6, 126.4, 117.1, 107.9, 78.0, 59.5, 58.3, 46.2; IR (Neat Film NaCl) 2939, 2784, 2360, 1666, 1448, 1328, 1239, 1176, 1133, 1047, 985, 937, 755, 694 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H18NO [M+H]+ : 216.1383; found: 216.1399. Appendix 9 – Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement   Ph Ph O microwave N 180 °C, m-xylene (44% yield) 193 575   O N 194 A solution of allyl vinyl ether 193 (11.0 mg, 0.0511 mmol, 1.00 equiv) in m-xylene (1.02 mL) was heated to 180 °C (power: 300 W) by microwave for 6 h. The resultant solution was then allowed to cool to ambient temperature, filtered through a pad of SiO2 using hexanes as the eluent to remove m-xylene, at which time separate fractions were collected, eluting with EtOAc, to isolate reaction products. The filtrate was concentrated in vacuo and the residue was subsequently purified by flash chromatography (1:2 EtOAc:hexanes) to afford the Claisen product, 194 (4.80 mg, 44% yield). Rf = 0.39 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 7.45 – 7.41 (m, 2H), 7.35 (ddd, J = 7.7, 6.8, 1.2 Hz, 2H), 7.30 – 7.27 (m, 1H), 5.94 (m, 1H), 5.61 (dt, J = 10.8, 5.1 Hz, 1H), 3.87 (d, J = 13.9 Hz, 2H), 3.55 (d, J = 15.7 Hz, 1H), 3.42 (d, J = 15.3 Hz, 1H), 3.04 (t, J = 15.5 Hz, 1H), 2.84 (d, J = 15.4 Hz, 1H), 2.47 – 2.42 (m, 1H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 210.7, 138.3, 130.9, 129.0, 128.7, 128.1, 127.6, 66.1, 61.3, 58.1, 45.9, 29.1; IR (Neat Film NaCl) 2928, 2791, 1696, 1493, 1451, 1268, 1126, 699 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H18NO [M+H]+ : 216.1383; found: 216.1398. Appendix 10 – Spectra Relevant to Appendix 9 576 APPENDIX 10 Spectra Relevant to Appendix 9: Ni-Catalyzed C–O Bond Formation and Subsequent Claisen Rearrangement Ph 192 I N OH                                                                                                     577   Figure A10.1. 1H NMR (400 MHz, CDCl3) of compound 192. Appendix 10 – Spectra Relevant to Appendix 9 Appendix 10 – Spectra Relevant to Appendix 9                                                                                                     Figure A10.2. Infrared spectrum (Thin Film, NaCl) of compound 192.  Figure A10.3. 13C NMR (101 MHz, CDCl3) of compound 192.   578   193 N Ph O                                                                                                     579   Figure A10.4. 1H NMR (400 MHz, CD2Cl2) of compound 193. Appendix 10 – Spectra Relevant to Appendix 9 Appendix 10 – Spectra Relevant to Appendix 9                                                                                                     Figure A10.5. Infrared spectrum (Thin Film, NaCl) of compound 193.  Figure A10.6. 13C NMR (101 MHz, CD2Cl2) of compound 193.   580   194 N O Ph                                                                                                     581   Figure A10.7. 1H NMR (500 MHz, CDCl3) of compound 194. Appendix 10 – Spectra Relevant to Appendix 9 Appendix 10 – Spectra Relevant to Appendix 9     Figure A10.8. Infrared spectrum (Thin Film, NaCl) of compound 194.  Figure A10.9. 13C NMR (101 MHz, CDCl3) of compound 194.   582   583   Appendix 11 – Synthetic Studies Toward Alistonitrine A APPENDIX 11 Synthetic Studies Toward Alistonitrine A† A11.1. Introduction The polycyclic monoterpene alkaloid alistonitrine A (195) was isolated from the leaves of Alstonia scholaris in 2014 by the Bai and Jiang groups (Figure A11.1.1).1 The alkaloids extracted from Alstonia scholaris possess interesting biological properties such as anticancer, antibacterial, anti-inflammatory, antiasthmatic, expectorant, analgesic, and antitussive activities. 2 Alistonitrine A (195) possesses intriguing structural features including an unprecedented caged skeleton, consecutive aminals, an epoxide, and a polycyclic system. Synthetic studies toward alistonitrine A have not been reported to date. Herein, we describe our synthetic efforts toward alistonitrine A (195). Figure A11.1.1. Structure of Alistonitrine A (195) MeO 2C H O H N N H ≡ N N H N CO2Me N O Alistonitrine A (195)                                                                                                                 † Portions of this work have been published. Han, S.-J.; Stoltz, B. M. Tetrahedron Lett. 2016, DOI: 10.1016/j.tetlet.2016.04.022 584   Appendix 11 – Synthetic Studies Toward Alistonitrine A A11.2. Results and Discussion Our initial retrosynthetic analysis of alistonitrine A is outlined in Scheme A11.2.1. Disconnection of the aminal at the C21 and epoxide functions in alistonitrine A (195) would afford amide 196. Further cleavage of the C2–C3 bond and the second aminal functional group would provide intermediate 197, in which the acyl telluride would serve as a handle for a decarbonylative radical cyclization.3 We envisioned that the vicinal quaternary centers of intermediate 197 could be constructed by coupling of oxindole 198 and amide 199. Scheme A11.2.1. Retrosynthetic Analysis of Alistonitrine A (195) H O MeO 2C 9 21 7 5 2 12 amide reduction/ aminal formation 3 N N MeO 2C NH N H Alistonitrine A (195) PhthN 196 CO2Me PhthN N 197 allylic alkylation CO2Me N R PhTe OAc O CO2Me O O radical cyclization/ aminal formation O epoxidation N N H H MeO 2C O + N O N H 198 OTIPS 199 The synthesis commenced with the construction of amine 205, which was adapted from Ellman and Nelson protocols (Scheme A11.2.2). Protection of diol 200 with TBSCl furnished bis-silyl ether 201, which was converted to aldehyde 202 by ozonolysis. Condensation with (R)-tert-butanesulfinamide auxiliary produced tert-butylsulfinyl imine 203.4,5 1,2-addition of allylmagnesium bromide to tert-butylsulfinyl imine 203 generated 585   adduct 204 in high diastereoselectivity. Cleavage of the silyl and tert-butanesulfinyl Appendix 11 – Synthetic Studies Toward Alistonitrine A groups under acidic conditions afforded chiral amine 205. Scheme A11.2.2. Synthesis of Chiral Amine 205 OH OTBS TBSCl, imidazole DMAP O 3 then PPh 3 CH2Cl2 (98% yield) CH2Cl2 (97% yield) OH OTBS 200 201 OTBS O 202 OTBS CuSO4 (R)-tert-butanesulfinamide CH2Cl2 (84% yield) allylmagnesium bromide O S N CH2Cl2 (87% yield; single diastereomer) 203 OTBS OH 4N HCl in dioxane O S NH MeOH (90% yield) 204 NH 3Cl 205 With chiral amine 205 in hand, α,β-unsaturated lactam formation was explored (Scheme A11.2.3). Silylation of amine 205 followed by acylation generated metathesis precursor 206. We were delighted to find that ring-closing metathesis of 206 with Hoveyda-Grubbs 2nd generation catalyst smoothly produced lactam 207.6,7 Protection of the nitrogen of amide 207 with MeI or Boc2O afforded the corresponding intermediates 208a and 208b. Unfortunately, attempted Baylis-Hillman reactions to furnish alcohol 209a or 209b, respectively, were unsuccessful.8,9 586   Appendix 11 – Synthetic Studies Toward Alistonitrine A Scheme A11.2.3. Synthesis of α,β-Unsaturated Lactams 208 OH 1. TIPSCl, imidazole, Et 3N DMAP, CH2Cl2 (60% yield) NH 3Cl 2. acryloyl chloride, Et 3N CH2Cl2 (79% yield) OTIPS O 205 206 Hoveyda-Grubbs 2nd generation (5 mol %) CH2Cl2, 45 °C (70% yield) MeI, LHMDS THF (98% yield) O NH OTIPS 207 O or Boc 2O, Et 3N, DMAP CH2Cl2 (89% yield) OH N NH O Baylis-Hillman reactions R N OTIPS R = Me, 208a R = Boc, 208b R OTIPS R = Me, 209a R = Boc, 209b Alternatively, we decided to employ the Baylis-Hillman reaction at an earlier stage (Scheme A11.2.4). Reaction of methyl acrylate (210) with acetaldehyde and subsequent hydrolysis furnished acid 211. Coupling of acid 211 and amine 212 with EDCI and HOBt proceeded smoothly to provide amide 213. To our delight, ring-closing metathesis of 213 occurred with catalyst 214, delivering the desired 2:3 mixture of two diastereomers of lactam 215.10 Coupling of alcohol 215 and acetic acid with EDCI and HOBt generated acetate 199. 587   Appendix 11 – Synthetic Studies Toward Alistonitrine A Scheme A11.2.4. Synthesis of α-Substituted α,β-Unsaturated Lactam 199 1. acetaldehyde DABCO dioxane, H 2O (80% yield) O OMe OH H 2N 211 OH 214 (8 mol %) OH EDCI, HOBt, DIPEA + OH 2. LiOH THF, H 2O (88% yield) 210 O OTIPS N H 213 Cl OAc O NH EDCI, acetic acid DMAP NH CH2Cl2 (90% yield) (73% yield; 78% yield based on recovered starting material) N THF (72% yield) 212 O benzene, 60 °C O OTIPS 215 OTIPS 199 OTIPS N Ru Cl O 214 Having successfully prepared the amide fragment, we began the synthesis of the oxindole fragment 217 (Scheme A11.2.5). The quaternary center of oxindole 198 was constructed by the base-promoted alkylation of 3-bromooxindole 216 with dimethyl malonate, which proceeded via in situ formation of an o-azaxylylene intermediate.11 Boc protection of the oxindole nitrogen generated oxindole fragment 217. Scheme A11.2.5. Synthesis of Oxindole Fragment 217 PhthN PhthN PhthN CO2Me Cs2CO3 dimethyl malonate Br O N H 216 THF (82% yield) CO2Me O N H 198 CO2Me CO2Me Boc 2O, DMAP CH2Cl2 (92% yield) O N Boc 217 With fragments 199 and 217 in hand, we investigated various alkylation reactions of malonate 217 with acetate 199 (Scheme A11.2.6). Unfortunately, only trace amounts 588   of the desired product and some byproducts were observed with palladium catalysts. Appendix 11 – Synthetic Studies Toward Alistonitrine A Additionally, we attempted to form 218 under basic conditions, but only unreacted oxindole 217 and a byproduct were obtained. Scheme A11.2.6. Attempted Coupling of Malonate 217 and Amide 199 PhthN PhthN MeO 2C OAc O CO2Me CO2Me O CO2Me + NH conditions O O N N OTIPS Boc 217 N Boc TIPSO 199 218 (Not observed) Having failed in coupling of oxindole 217 and amide 199, a revised retrosynthesis was devised (Scheme A11.2.7). We envisioned that a late stage Fischer indole synthesis of intermediate 219 would afford the core structure of alistonitrine A. Disconnection of the C15–C20 bond in intermediate 219 provided Heck reaction precursor 220. Vinyl halide 220 was expected to be formed from ketone 221 by reductive amination and subsequent double bond isomerization. Scheme A11.2.7. A Revised Retrosynthesis Toward Alistonitrine A H O MeO 2C 9 15 7 5 2 N H 12 3 H Fischer indole synthesis 20 MeO 2C N N BocHN H O 219 O reductive amination X N N 220 O 20 N Alistonitrine A (195) PMB 15 O O PMB N double bond isomerization O 221 intramolecular reductive Heck reaction 589   Esterification of acid 222 followed by subsequent reductive amination and Appendix 11 – Synthetic Studies Toward Alistonitrine A acylation produced amide 223 (Scheme A11.2.8). Treatment of 223 with NaOMe afforded lactam 224, and a subsequent Robinson annulation furnished bicycle 225.12 Oxidation of enone 225 was accomplished with SeO2 to deliver dienone 226.13 However, an attempted reductive amination of dienone 226 to provide amine 227 resulted in the removal of the ester group and subsequent aromatization, affording phenol 228. Although our synthetic efforts toward alistonitrine A were unsuccessful, we were able to serendipitously discover a novel nickel-catalyzed C–O bond forming reaction (Chapter 4). Scheme A11.2.8. Synthesis of Bicycle 226 1. SOCl2, MeOH 2. p-anisaldehyde Et 3N; NaBH 4, MeOH CO2H H 2N 3. methyl malonyl chloride i-Pr2NEt, CH2Cl2 (74% yield, 3 steps) 222 O PMB CO2Me N 1. 1N KOH in MeOH methyl vinyl ketone 18-crown-6 MeOH O MeO 223 O PMB CO2Me SeO2, AcOH N O 225 O CO2Me MeNH 3Cl, NaBH 3CN N PMB CO2Me N THF, MeOH O NHMe 226 227 (Not observed) O MeNH 3Cl, NaBH 3CN NaOMe toluene, MeOH (70% yield) PMB 224 O CO2Me N 2. pyrrolidine, benzene; AcOH-H2O-NaOAc (46% yield, 2 steps) O PMB O PMB N THF, MeOH (85% yield) OH 228 t-BuOH (40% yield) 590   Appendix 11 – Synthetic Studies Toward Alistonitrine A A11.3. Experimental Methods and Analytical Data A11.3.1. Materials and Methods Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Reaction progress was monitored by thin-layer chromatography (TLC). THF, Et2O, CH2Cl2, toluene, benzene, CH3CN, and dioxane were dried by passage through an activated alumina column under argon. Triethylamine was distilled over CaH2 prior to use. Purified water was obtained using a Barnstead NANOpure Infinity UV/UF system. Brine solutions are saturated aqueous solutions of sodium chloride. Commercially available reagents were purchased from Sigma-Aldrich, Acros Organics, Strem, or Alfa Aesar and used as received unless otherwise stated. Reaction temperatures were controlled by an IKAmag temperature modulator unless otherwise indicated. Microwave-assisted reactions were performed in a Biotage Initiator 2.5 microwave reactor. Glove box manipulations were performed under a N2 atmosphere. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, panisaldehyde, or PMA (phosphomolybdic acid) staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.064 mm) was used for flash column chromatography. 1 H NMR spectra were recorded on a Varian Inova 500 MHz spectrometer and are reported relative to residual CHCl3 (δ 7.26 ppm), or (CD3)2CO (δ 2.05 ppm). 13C NMR spectra are recorded on a Varian Inova 500 MHz spectrometer (125MHz) and are reported relative to CHCl3 (δ 77.16 ppm), or (CD3)2CO (δ 29.84 ppm). Data for 1H NMR are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d= broad doublet, app 591   = apparent. Data for C are reported in terms of chemical shifts (ppm). IR spectra were Appendix 11 – Synthetic Studies Toward Alistonitrine A 13 obtained using a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed ionization mode (MM: ESI-APCI+). A11.3.2. Experimental Procedures OH OTBS TBSCl, imidazole DMAP CH2Cl2 (98% yield) OH OTBS 200 201 To a solution of diol 200 (0.930 mL, 11.3 mmol, 1.00 equiv) in CH2Cl2 (28.3 mL) were added imidazole (7.69 g, 113 mmol, 10.0 equiv) and TBSCl (5.11 g, 33.9 mmol, 3.00 equiv) at 23 °C. The reaction mixture was stirred for 12 h and quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:8 EtOAc:hexanes) to  afford  bis-silyl ether 201 (3.51 g, 98% yield). The spectroscopic data were identical to those previously reported.1 OTBS OTBS O 3 then PPh 3 CH2Cl2 (97% yield) O OTBS 201                                                                                                                 1 Tran, V. T.; Woerpel, K. A. J. Org. Chem. 2013, 78, 6609–6621. 202 592   A solution of bis-silyl ether 201 (1.00 g, 3.16 mmol, 1.00 equiv) in CH2Cl2 (21.1 mL) Appendix 11 – Synthetic Studies Toward Alistonitrine A was cooled to –78 °C and ozone was bubbled through until the solution turned blue. N2 gas was then bubbled through the solution until the reaction mixture turned colorless. PPh3 (0.99 g, 3.79 mmol, 1.20 equiv) was then added and the mixture was warmed to 23 °C slowly. The reaction mixture was stirred under N2 for 1.5 h and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (1:8 EtOAc:hexanes) to  afford  aldehyde 202 (1.07 g, 97% yield). Rf = 0.25 (1:8 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 9.70 (t, J = 0.8 Hz, 1H), 4.22 (d, J = 0.8 Hz, 2H), 0.93 (s, 9H), 0.10 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 202.5, 69.8, 25.9, 18.5, -5.3; IR (Neat Film NaCl) 2955, 2931, 2858, 1740, 1473, 1256, 1128, 838, 779 cm-1; HRMS (MM: FAB+) m/z calc’d for C8H19O2Si [M+H]+: 175.1154; found: 175.1067. OTBS OTBS CuSO4 (R)-tert-butanesulfinamide CH2Cl2 (84% yield) O 202 O S N 203 To a solution of aldehyde 202 (100 mg, 0.574 mmol, 1.00 equiv) in CH2Cl2 (1.91 mL) was added CuSO4 (275 mg, 1.72 mmol, 3.00 equiv) followed by the addition of tertbutanesulfinamide (104 mg, 0.861 mmol, 1.50 equiv). The reaction mixture was stirred at 23 °C for 12 h. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:8 EtOAc:hexanes) to furnish the tert-butylsulfinyl imine 203 (133 mg, 84% yield). 593   –127.8 (c 0.19, CHCl3); Rf = 0.20 (1:8 EtOAc:hexanes); H NMR (400 MHz, Appendix 11 – Synthetic Studies Toward Alistonitrine A [a]D 25 1 CD2Cl2) δ 7.99 (t, J = 3.1 Hz, 1H), 4.53 (d, J = 3.1 Hz, 2H), 1.17 (s, 9H), 0.92 (s, 9H), 0.10 (d, J = 0.6 Hz, 6H); 13C NMR (101 MHz, CD2Cl2) δ 169.1, 66.1, 57.1, 26.1, 22.6, 18.8, -5.1; IR (Neat Film NaCl) 2956, 2930, 2858, 1628, 1473, 1364, 1255, 1089, 838, 779 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H28NO2SSi [M+H]+: 278.1605; found: 278.1606. OTBS OTBS allylmagnesium bromide O S N 203 CH2Cl2 (87% yield; single diastereomer) O S NH 204 To a solution of tert-butylsulfinyl imine 203 (800 mg, 2.88 mmol, 1.00 equiv) in CH2Cl2 (14.4 mL) was added allylmagnesium bromide (1M in diethyl ether; 6.05 mL, 6.05 mmol, 2.10 equiv) dropwise at –78 °C. The reaction mixture was stirred for 5 h at –78 °C and slowly warmed to 23 °C. The reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with CH2Cl2 (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:4 EtOAc:hexanes) to   afford   silyl ether 204 (797 mg, 87% yield). [a]D25 –53.7 (c 0.26, CHCl3); Rf = 0.25 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 5.79 (ddt, J = 17.3, 10.2, 7.2 Hz, 1H), 5.18 – 5.11 (m, 2H), 3.66 (dd, J = 9.9, 4.2 Hz, 1H), 3.54 – 3.51 (m, 1H), 3.48 (s, 1H), 3.34 (t, J = 5.8 Hz, 1H), 2.55 – 2.48 (m, 1H), 2.39 (dtt, J = 13.9, 6.7, 1.3 Hz, 1H), 1.19 (s, 9H), 0.89 (s, 9H), 0.05 (d, J = 0.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 134.5, 118.6, 77.2, 65.1, 56.5, 56.0, 37.2, 26.0, 22.7, 18.4, - 594   5.3, -5.3; IR (Neat Film NaCl) 2955, 2929, 2858, 1472, 1253, 1113, 1072, 836, 777 cm-1; Appendix 11 – Synthetic Studies Toward Alistonitrine A HRMS (MM: FAB+) m/z calc’d for C15H34NO2SSi [M+H]+: 320.2001; found: 320.2084. OTBS OH 4N HCl in dioxane O S NH MeOH (90% yield) 204 NH 3Cl 205 To a solution of silyl ether 204 (126 mg, 0.394 mmol, 1.00 equiv) in MeOH (1.97 mL) was added 4N HCl in dioxane (1.97 mL, 1.97 mmol, 5.00 equiv) at 0 °C. The reaction mixture was warmed to 23 °C and stirred for 2 h. The volatile was evaporated under reduced pressure. The resulting oil was washed with ether revealing a yellow solid. The solid was filtered to give amine hydrochloride 205 (49.0 mg, 90% yield). [a]D25 +9.52 (c 0.06, MeOH); Rf = 0.10 (2:1 EtOAc:hexane); 1H NMR (500 MHz, CD3OD) δ 5.81 (ddt, J = 17.3, 10.2, 7.2 Hz, 1H), 5.29 – 5.19 (m, 2H), 3.76 (dd, J = 11.6, 3.7 Hz, 1H), 3.55 (dd, J = 11.6, 6.7 Hz, 1H), 3.29 – 3.20 (m, 1H), 2.47 – 2.32 (m, 2H); 13 C NMR (126 MHz, CD3OD) δ 133.28, 120.24, 61.92, 53.96, 34.90; IR (Neat Film NaCl) 3369, 2929, 1618, 1508, 1053, 928 cm-1. OH 1. TIPSCl, imidazole, Et 3N DMAP, CH2Cl2 (60% yield) NH 3Cl 2. acryloyl chloride, Et 3N CH2Cl2 (79% yield) 205 OTIPS Hoveyda-Grubbs 2nd generation (5 mol %) O NH 206 O NH CH2Cl2, 45 °C (70% yield) OTIPS 207 To a solution of amine hydrochloride 205 (188 mg, 1.37 mmol, 1.00 equiv) in CH2Cl2 (7.00 mL) were added Et3N (0.38 mL, 2.74 mmol, 2.00 equiv), imidazole (930 mg, 13.7 mmol, 10.0 equiv), DMAP (8.40 mg, 0.0685 mmol, 0.05 equiv), and TIPSCl (0.59 mL, 595   2.74 mmol, 2.00 equiv). The reaction mixture was stirred for 12 h at 23 °C and quenched Appendix 11 – Synthetic Studies Toward Alistonitrine A with water. The aqueous phase was extracted with CH2Cl2 (3 x 8.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (2:1 EtOAc:hexane) to   afford   the   silyl ether (212 mg, 60% yield). To a solution of the resultant silyl ether (100 mg, 0.388 mmol, 1.00 equiv) and Et3N (0.160 mL, 1.16 mmol, 3.00 equiv) in CH2Cl2 (1.94 mL) was added acryloyl chloride (35.0 µL, 0.427 mmol, 1.10 equiv) at 23 °C. The reaction was stirred for 12 h at 23 °C and quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:4 EtOAc:hexanes) to  afford  amide 206 (95.0 mg, 79% yield). To a stirred solution of amide 206 (1.08 g, 3.47 mmol, 1.00 equiv) in CH2Cl2 (116 mL) was added Hoveyda-Grubbs 2nd generation catalyst (0.109 g, 0.173 mmol, 0.05 equiv) at 23 °C. Then, the solution was stirred at 45 °C for 12 h. After the reaction was done, the solution was cooled to 23 °C and water was added. The aqueous phase was extracted with CH2Cl2 (3 x 30.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:2 EtOAc:hexanes) to  afford  lactam 207 (688 mg, 70% yield). [a]D25 –15.6 (c 0.22, CHCl3); Rf = 0.20 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.58 (ddd, J = 9.9, 5.4, 3.0 Hz, 1H), 5.92 (dtd, J = 9.9, 2.4, 1.3 Hz, 1H), 5.87 (s, br, 1H), 3.80 – 3.72 (m, 2H), 3.66 – 3.58 (m, 1H), 2.31 (dtt, J = 17.6, 5.4, 1.2 Hz, 1H), 2.16 (ddt, J = 17.7, 10.9, 2.8 Hz, 1H), 1.21 – 1.00 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 596   166.0, 140.0, 124.8, 66.0, 52.6, 26.0, 18.1, 12.0; IR (Neat Film NaCl) 2943, 2866, 1682, Appendix 11 – Synthetic Studies Toward Alistonitrine A 1615, 1463, 1114, 813 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C15H30NO2Si [M+H]+: 284.2040; found: 284.2045. O O MeI, LHMDS NH OTIPS 207 THF (98% yield) N OTIPS 208a To a solution of lactam 207 (100 mg, 0.353 mmol, 1.00 equiv) in THF (1.80 mL) was added LHMDS (89.0 mg, 0.530 mmol, 1.50 equiv) at 0 °C. The reaction was stirred for 1 h and then MeI (66.0 µL, 1.06 mmol, 3.00 equiv) was added. The solution was stirred for 4 h at 23 °C and quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:2 EtOAc:hexanes) to  afford  amide 208a (103 mg, 98% yield). [a]D25 +46.9 (c 0.12, CHCl3); Rf = 0.27 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.42 – 6.35 (m, 1H), 5.91 (ddd, J = 9.8, 2.7, 1.1 Hz, 1H), 3.74 (dd, J = 9.6, 5.2 Hz, 1H), 3.66 (dd, J = 9.6, 8.6 Hz, 1H), 3.55 – 3.48 (m, 1H), 3.05 (s, 3H), 2.58 (ddt, J = 6.8, 5.0, 2.0 Hz, 2H), 1.15 – 1.00 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 164.1, 137.3, 125.0, 61.6, 59.2, 34.3, 25.0, 18.1, 12.0; IR (Neat Film NaCl) 2942, 2866, 1670, 1618, 1464, 1111, 882 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C16H32NO2Si [M+H]+: 298.2197; found: 298.2199. 597   Appendix 11 – Synthetic Studies Toward Alistonitrine A O O Boc 2O, Et 3N, DMAP NH N Boc CH2Cl2 (89% yield) OTIPS 207 OTIPS 208b To a solution of amide 207 (50.0 mg, 0.176 mmol, 1.00 equiv) and DMAP (32.2 mg, 0.264 mmol, 1.50 equiv) in CH2Cl2 (0.90 mL) at 0 °C were added Et3N (49.1 µL, 0.352 mmol, 2.00 equiv) and Boc anhydride (77.0 mg, 0.353 mmol, 2.00 equiv). The reaction mixture was warmed to 23 °C and stirred for 12 h. The reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with CH2Cl2 (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:8 EtOAc:hexanes) to   afford   carbamate 208b (60.0 mg, 89% yield). [a]D25 +11.5 (c 0.07, CHCl3); Rf = 0.85 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.59 (ddt, J = 9.8, 6.3, 1.9 Hz, 1H), 5.94 (ddd, J = 9.8, 3.1, 0.8 Hz, 1H), 4.45 (ddt, J = 9.6, 4.8, 3.1 Hz, 1H), 3.74 (dd, J = 9.3, 4.8 Hz, 1H), 3.67 (t, J = 9.5 Hz, 1H), 2.76 (dd, J = 18.8, 6.3 Hz, 1H), 2.62 – 2.54 (m, 1H), 1.53 (s, 9H), 1.20 – 0.96 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 163.3, 152.3, 140.9, 126.0, 83.1, 77.2, 61.8, 54.6, 28.2, 24.8, 18.1, 12.0; IR (Neat Film NaCl) 2944, 2867, 1717, 1368, 1297, 1239, 1160, 1114, 810 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C15H30NO2Si [M+H–Boc]+: 284.2040; found: 284.2046. 1. acetaldehyde DABCO dioxane, H 2O (80% yield) O OMe 210 2. LiOH THF, H 2O (88% yield) OH O OH 211 To a solution of acetaldehyde (1.27 mL, 22.7 mmol, 1.00 equiv) in dioxane/water (1.10 mL/1.10 mL) was added methyl acrylate 210 (6.13 mL, 68.1 mmol, 3.00 equiv) and 598   DABCO (2.55 g, 22.7 mmol, 1.00 equiv). The reaction was stirred at 23 °C for 48 h. Appendix 11 – Synthetic Studies Toward Alistonitrine A After the reaction was done, water was added. The aqueous phase was extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:4 EtOAc:hexanes) to   afford   the ester (2.36 g, 80% yield). The spectroscopic data were identical to those previously reported.2 To a solution of the resultant ester (300 mg, 2.31 mmol, 1.00 equiv) in THF (12.0 mL) and H2O (5.00 mL) at 23 °C was added LiOH (88.0 mg, 3.69 mmol, 1.60 equiv). The reaction was stirred at 23 °C for 1 h and then water was added. The aqueous phase was separated and acidified until pH = 1 with 1N HCl. Then, the aqueous phase was extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to   afford   acid 211 (236 mg, 88% yield). Rf = 0.15 (1:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.39 (t, J = 0.8 Hz, 1H), 5.96 (t, J = 1.1 Hz, 1H), 4.65 (q, J = 6.5 Hz, 1H), 1.42 (d, J = 6.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.2, 142.8, 127.0, 67.1, 22.2; IR (Neat Film NaCl) 3390, 1694, 1633, 1416, 1277, 1176, 1093, 962, 928 cm-1; HRMS (MM: FAB+) m/z calc’d for C5H9O3 [M+H]+: 117.0552; found: 117.0521. H 2N OH O OTIPS 212 EDCI, HOBt, DIPEA OH 211 THF (72% yield) OH O N H OTIPS 213                                                                                                                 2 Latorre, A.; Sáez, J. A.; Rodríguez, S.; González, F. V. Tetrahedron 2014, 70, 97–102. 599   To a solution of amine 212 (50.0 mg, 0.194 mmol, 1.00 equiv) in THF (1.00 mL) were Appendix 11 – Synthetic Studies Toward Alistonitrine A added acid 211 (24.0 mg, 0.204 mmol, 1.05 equiv), HOBt (39.3 mg, 0.291 mmol, 1.50 equiv), EDCI (45.2 mg, 0.291 mmol, 1.50 equiv), and DIPEA (41.0 µL. 0.233 mmol, 1.2 equiv). The reaction was stirred for 12 h at 23 °C and then quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (1:4 → 1:2 EtOAc:hexanes)    to  afford   amide 213 (49.7 mg, 72% yield). [a]D25 –29.5 (c 0.07, CHCl3); Rf = 0.35 (1:2 EtOAc:hexanes); (due to the distinct presence of rotameric isomers, the 13C NMR contained extra peaks. See the attached spectrum), 1H NMR (400 MHz, CDCl3) δ 6.65 (dd, J = 18.7, 8.7 Hz, 1H), 5.81 (ddtd, J = 17.2, 10.2, 7.1, 1.5 Hz, 1H), 5.65 (d, J = 6.5 Hz, 1H), 5.45 (s, br, 1H), 5.19 – 5.00 (m, 2H), 4.57 (qt, J = 6.5, 1.2 Hz, 1H), 4.10 (dddddd, J = 8.2, 6.9, 5.1, 3.9, 2.8, 1.2 Hz, 1H), 3.85 – 3.68 (m, 2H), 2.48 – 2.29 (m, 2H), 1.38 (d, J = 6.5 Hz, 3H), 1.16 – 1.02 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 167.7, 167.6, 147.24, 147.17, 134.80, 134.77, 118.0, 117.9, 117.9, 117.7, 69.2, 69.1, 64.12, 64.11, 50.13, 50.12, 36.09, 36.07, 21.94, 21.86, 18.1, 12.0; IR (Neat Film NaCl) 3305, 2943, 2866, 1655, 1618, 1542, 1534, 1460, 1118, 882, 788, 682 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C19H38NO3Si [M+H]+: 356.2615; found: 356.2624. 600   Appendix 11 – Synthetic Studies Toward Alistonitrine A OH 214 (8 mol %) benzene, 60 °C O N H OTIPS 213 (73% yield; 78% yield based on recovered starting material) N Cl OH O NH 215 OTIPS N Ru Cl O 214 To a solution of amide 213 (740 mg, 2.08 mmol, 1.00 equiv) in benzene (104 mL) was added Ru catalyst 214 (95.0 mg, 0.17 mmol, 0.08 equiv). The solution was stirred at 60 °C for 12 h. The solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography (1:2 EtOAc:hexanes) to furnish two diastereomers of lactam 215 (499 mg, 73% yield; 2:3 215a:215b; 78% yield based on recovered starting material). Diastereomer 215a: [a]D25 –1.54 (c 0.78, CHCl3); Rf = 0.35 (1:1 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.44 (ddd, J = 5.7, 3.0, 1.2 Hz, 1H), 5.93 (s, br, 1H), 4.62 – 4.55 (m, 1H), 3.75 (dd, J = 9.2, 4.3 Hz, 1H), 3.61 (dd, J = 9.2, 8.5 Hz, 1H), 2.38 – 2.31 (m, 1H), 2.22 – 2.15 (m, 1H), 1.38 (d, J = 6.5 Hz, 3H), 1.13 – 1.03 (m, 21H); 13C NMR (126 MHz, CDCl3) δ 167.1, 137.0, 132.9, 66.7, 66.0, 52.3, 25.8, 21.1, 18.1, 12.0; IR (Neat Film NaCl) 3408, 2943, 2866, 1678, 1627, 1461, 1117, 1070, 882, 789, 683 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H34NO3Si [M+H]+: 328.2302; found: 328.2306. Diastereomer 215b: [a]D25 –1.77 (c 0.43, CHCl3); Rf = 0.30 (1:1 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.40 (dd, J = 5.8, 3.0 Hz, 1H), 5.92 (s, br, 1H), 4.54 (q, J = 6.5 Hz, 1H), 3.78 – 3.74 (m, 1H), 3.74 – 3.69 (m, 1H), 3.60 (t, J = 8.8 Hz, 1H), 2.31 (dt, J = 17.5, 5.5 Hz, 1H), 2.22 – 2.15 (m, 1H), 1.40 (d, J = 6.4 Hz, 3H), 1.13 – 1.04 (m, 21H); 601   C NMR (126 MHz, CDCl3) δ 166.9, 137.1, 133.2, 67.7, 66.0, 52.2, 25.8, 21.7, 18.1, Appendix 11 – Synthetic Studies Toward Alistonitrine A 13 12.0; IR (Neat Film NaCl) 3294, 2943, 2866, 1678, 1627, 1463, 1115, 882 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C17H34NO3Si [M+H]+: 328.2302; found: 328.2303. OH OAc O O NH EDCI, acetic acid, DMAP NH CH2Cl2 (82% yield) OTIPS OTIPS 199a 215a To a solution of EDCI (960 mg, 6.18 mmol, 10.0 equiv) and DMAP (38.0 mg, 0.309 mmol, 0.50 equiv) in CH2Cl2 (6.18 mL) was added acetic acid (0.354 mL, 6.18 mmol, 10.0 equiv). The solution was stirred for 5 min at 0 °C and then lactam 215a (202 mg, 0.618 mmol, 1.00 equiv) in CH2Cl2 (0.5 mL) was added. The reaction mixture was stirred 12 h at 23 °C and then quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 4.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   acetate 199a (187 mg, 82% yield). 1 H NMR (300 MHz, CDCl3) δ 6.48 (ddd, J = 5.4, 3.3, 1.3 Hz, 1H), 6.06 (s, br, 1H), 5.78 (q, J = 6.6 Hz, 1H), 3.76 – 3.68 (m, 2H), 3.65 – 3.58 (m, 1H), 2.34 (dt, J = 17.5, 5.4 Hz, 1H), 2.26 – 2.15 (m, 1H), 2.07 (s, 3H), 1.40 (d, J = 6.5 Hz, 3H), 1.15 – 0.99 (m, 21H). OH OAc O O NH EDCI, acetic acid, DMAP NH CH2Cl2 (98% yield) OTIPS OTIPS 215b 199b 602   To a solution of EDCI (1.41 g, 9.07 mmol, 10.0 equiv) and DMAP (55.4 mg, 0.454 Appendix 11 – Synthetic Studies Toward Alistonitrine A mmol, 0.50 equiv) in CH2Cl2 (9.07 mL) was added acetic acid (0.520 mL, 9.07 mmol, 10.0 equiv). The solution was stirred for 5 min at 0 °C and then lactam 215b (297 mg, 0.907 mmol, 1.00 equiv) in CH2Cl2 (1.0 mL) was added. The reaction mixture was stirred 12 h at 23 °C and then quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 6.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   acetate 199b (328 mg, 98% yield). 1 H NMR (300 MHz, CDCl3) δ 6.52 (ddd, J = 5.6, 3.2, 1.2 Hz, 1H), 6.07 (s, br, 1H), 5.77 – 5.69 (m, 1H), 3.72 (qd, J = 4.5, 2.0 Hz, 2H), 3.65 – 3.56 (m, 1H), 2.41 – 2.27 (m, 1H), 2.25 – 2.17 (m, 1H), 2.06 (s, 3H), 1.41 (d, J = 6.4 Hz, 3H), 1.14 – 1.00 (m, 21H). PhthN PhthN CO2Me Cs2CO3 dimethyl malonate Br O N H 216 THF (82% yield) CO2Me O N H 198 To a solution of bromooxindole 216 (3.60 g, 9.34 mmol, 1.00 equiv) and dimethyl malonate (2.62 mL, 28.0 mmol, 3.00 equiv) in THF (47.0 mL) was added Cs2CO3 (9.13 g, 28.0 mmol, 3.00 equiv). The reaction mixture was stirred for 12 h at 23 °C. After the reaction was done, water was added. The aqueous phase was extracted with EtOAc (3 x 15.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with 603   mixtures of EtOAc and hexanes to   afford   oxindole 198 (3.34 g, 82% yield). Data for the Appendix 11 – Synthetic Studies Toward Alistonitrine A compound matches reported data.3 PhthN PhthN CO2Me CO2Me O N H CO2Me CO2Me Boc 2O, DMAP O CH2Cl2 (92% yield) N Boc 198 217 To a solution of oxindole 198 (4.08 g, 9.34 mmol, 1.00 equiv) in CH2Cl2 (47.0 mL) were added DMAP (0.114 g, 0.934 mmol, 0.10 equiv) and Boc2O (3.06 g, 14.0 mmol, 1.50 equiv). The reaction mixture was stirred for 12 h at 23 °C. Then, the reaction was quenched with water. The aqueous phase was extracted with CH2Cl2 (3 x 15.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to  afford  carbamate 217 (4.61 g, 92% yield). 1 H NMR (300 MHz, CDCl3) δ 7.82 – 7.76 (m, 1H), 7.74 – 7.68 (m, 2H), 7.68 – 7.62 (m, 2H), 7.61 – 7.56 (m, 1H), 7.18 – 7.11 (m, 1H), 7.01 (td, J = 7.6, 1.2 Hz, 1H), 4.21 (s, 1H), 3.80 (s, 3H), 3.53 (t, J = 7.1 Hz, 2H), 3.49 (s, 3H), 2.51 (dt, J = 14.8, 7.5 Hz, 1H), 2.40 (dt, J = 13.8, 6.8 Hz, 1H), 1.65 (s, 9H). CO2H H 2N 1. SOCl2, MeOH 2. p-anisaldehyde Et 3N; NaBH 4, MeOH 222 PMB N H CO2Me SI-A11-1 β-Alanine (222) (5.00 g, 56.1 mmol, 1.00 equiv) was added to MeOH (94.0 mL) and cooled to 0 °C before dropwise addition of SOCl2 (8.19 mL, 0.112 mol, 2.00 equiv).                                                                                                                 3 Krishnan, S.; Stoltz, B. M. Tetrahedron 2007, 48, 7571–7573. 604   Then, the reaction was stirred for 2 h at 90 °C. The solution was concentrated under Appendix 11 – Synthetic Studies Toward Alistonitrine A reduced pressure and treated with ether. The resulting crystals were removed by filtration to afford the ester, which was used without further purification. To a solution of the resultant ester-HCl salt (2.00 g, 14.4 mmol, 1.00 equiv) and Et3N (4.02 mL, 28.9 mmol, 2.00 equiv) in MeOH (40.0 mL) was added anisaldehyde (1.83 mL, 15.1 mmol, 1.05 equiv) and the reaction mixture was stirred for 1.5 h. Then, NaBH4 (1.09 g, 28.8 mmol, 2.00 equiv) was added in portions in 1 h at 0 °C. The reaction was stirred at 23 °C for 8 h and then quenched with water. The aqueous phase was extracted with EtOAc (3 x 25.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to  afford  amine SI-A11-1. 1 H NMR (300 MHz, CDCl3) δ 7.26 – 7.20 (m, 2H), 6.89 – 6.82 (m, 2H), 3.79 (s, 3H), 3.74 (s, 2H), 3.68 (s, 3H), 2.89 (t, J = 6.5 Hz, 2H), 2.54 (t, J = 6.5 Hz, 2H), 1.87 (s, br, 1H). PMB N H CO2Me methyl malonyl chloride i-Pr2NEt CH2Cl2 (74% yield, 3 steps) SI-A11-1 O MeO O N CO2Me PMB 223 To a solution of amine SI-A11-1 (2.64 g, 11.8 mmol, 1.00 equiv) and i-Pr2NEt (4.22 mL, 24.2 mmol, 2.05 equiv) in CH2Cl2 (59.0 mL) was added methyl malonyl chloride (2.02 mL, 18.9 mmol, 1.60 equiv) at °C. The solution was warmed to 23 °C and stirred for 1 h. Then, the reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with CH2Cl2 (3 x 25.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel 605   chromatography with mixtures of EtOAc and hexanes to  afford  amide 223 (2.82 g, 74% Appendix 11 – Synthetic Studies Toward Alistonitrine A yield, 3 steps). (Due to the distinct presence of rotameric isomers, the 1H NMR contained extra peaks.) 1 H NMR (300 MHz, CDCl3) δ 7.19 (d, J = 8.6 Hz, 1H), 7.14 – 7.06 (m, 1H), 6.93 – 6.87 (m, 1H), 6.87 – 6.82 (m, 1H), 4.57 (s, 1H), 4.52 (s, 1H), 3.80 (s, 2H), 3.79 (s, 1H), 3.76 (s, 1H), 3.72 (s, 2H), 3.68 – 3.58 (m, 5H), 3.52 (t, J = 7.1 Hz, 1H), 3.47 (s, 1H), 2.63 (t, J = 6.9 Hz, 1H), 2.54 (t, J = 7.1 Hz, 1H). O O O MeO N PMB CO2Me NaOMe PMB CO2Me N toluene, MeOH (70% yield) O 223 224 To a solution of NaOMe (95%; 0.87 g, 15.2 mmol, 1.10 equiv) in toluene (69.0 mL) and MeOH (11.0 mL) was added amide 223 (2.81 g, 8.69 mmol, 1.00 equiv) in toluene (1.00 mL) dropwise. The solution was stirred at 90 °C for 6 h. The solution was cooled to 23 °C and water was added. The aqueous phase was extracted with EtOAc (3 x 25.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to  afford  lactam 224 (1.78 g, 70% yield). 1 H NMR (300 MHz, CDCl3) δ 13.91 (s, 1H), 7.24 – 7.17 (m, 2H), 6.87 – 6.81 (m, 2H), 4.57 (s, 2H), 3.93 (s, 3H), 3.79 (s, 3H), 3.31 (t, J = 6.8 Hz, 2H), 2.57 (t, J = 6.8 Hz, 2H). O PMB CO2Me N O 224 1. 1N KOH in MeOH methyl vinyl ketone 18-crown-6 MeOH O PMB CO2Me N 2. pyrrolidine, benzene; AcOH-H2O-NaOAc (46% yield, 2 steps) O 225 606   To a stirred solution of lactam 224 (600 mg, 2.06 mmol, 1.00 equiv) in MeOH (1.60 mL) Appendix 11 – Synthetic Studies Toward Alistonitrine A at 23 °C were added 1N KOH solution in MeOH (0.21 mL, 0.206 mmol, 0.10 equiv) and 18-crown-6 (54.0 mg, 0.206 mmol, 0.10 equiv) under N2. After stirring for 10 min, methyl vinyl ketone (0.55 mL, 6.80 mmol, 3.30 equiv) was added dropwise at 23 °C and stirred for 22 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was treated with sat. aq KCl solution. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the ketone, which was used without further purification. To a stirred solution of the resultant ketone (2.06 mmol, 1.00 equiv) in benzene (20.6 mL) was added pyrrolidine (0.43 mL, 5.15 mmol, 2.50 equiv) and the mixture was stirred at 90 °C for 6 h using Dean-Stark apparatus. The solution was cooled to 23 °C. The reaction mixture was treated with a mixture of AcOH/H2O/NaOAc (2/2/1) (7.92 mL) and stirred at 100 °C for 3 h. The solution was cooled to 23 °C and treated with H2O. The aqueous phase was extracted with EtOAc (3 x 25.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography with mixtures of EtOAc and hexanes to   afford   bicycle 225 (325 mg, 46% yield). 1 H NMR (300 MHz, CDCl3) δ 7.23 – 7.08 (m, 2H), 6.94 – 6.77 (m, 2H), 4.73 (d, J = 14.5 Hz, 1H), 4.41 (d, J = 14.5 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 3.38 (ddd, J = 12.1, 6.3, 3.9 Hz, 1H), 3.24 (ddd, J = 12.2, 9.9, 4.6 Hz, 1H), 3.04 – 2.96 (m, 1H), 2.90 – 2.77 (m, 1H), 2.59 – 2.43 (m, 2H), 2.18 – 2.10 (m, 1H), 2.08 – 2.04 (m, 1H). 607   Appendix 11 – Synthetic Studies Toward Alistonitrine A O PMB O CO2Me SeO2, AcOH N O PMB CO2Me N t-BuOH (40% yield) 225 O 226 To a solution bicycle 225 (28.0 mg, 0.0815 mmol, 1.00 equiv) in t-BuOH (2.04 mL) were added AcOH (0.2 mL) and SeO2 (18.1 mg, 16.3 mmol, 2.00 equiv). The reaction was stirred for 12 h at 100 °C. Solids were removed via a filtration through a celite plug and the resulting solution was concentrated under reduced pressure. The residue was purified by flash column chromatography, using mixture of hexanes and ethyl acetate as eluent to furnish dienone 226 (11.1 mg, 40% yield). 1 H NMR (300 MHz, CDCl3) δ 7.53 (dd, J = 10.1, 0.5 Hz, 1H), 7.24 – 7.19 (m, 2H), 6.90 – 6.85 (m, 2H), 6.45 (ddd, J = 10.1, 1.7, 0.6 Hz, 1H), 6.26 (td, J = 1.7, 0.7 Hz, 1H), 4.89 (d, J = 14.6 Hz, 1H), 4.28 (d, J = 14.6 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.42 (ddd, J = 12.1, 7.0, 3.6 Hz, 1H), 3.26 (ddd, J = 12.2, 9.5, 5.6 Hz, 1H), 2.96 (dddd, J = 14.6, 9.3, 7.0, 1.9 Hz, 1H), 2.63 (ddd, J = 14.5, 5.6, 3.6 Hz, 1H). A11.4. References and Notes                                                                                                                 (1) Zhu, G.-Y.; Yao, X.-J.; Liu, L.; Bai, L.-P.; Jiang, Z.-H. Org. Lett. 2014, 16, 1080– 1083. (2) (a) Shang, J. H.; Cai, X. H.; Feng, T.; Zhao, Y. L.; Wang, J. K.; Zhang, L. Y.; Yan, M.; Luo, X. D. J. Ethnopharmacol. 2010, 129, 174–181. (b) Shang, J.; H.; Cai, X. H.; Zhao, Y. L.; Feng, T.; Luo, X. D. J. Ethnopharmacol. 2010, 129, 293–298. (c) Baliga, M. S. Integr. Cancer Ther. 2010, 9, 261–269. (d) Lee, S. J.; Cho, S. A.; An, S. S.; Na, Y. J.; 608                                                                                                                                                                                                                                                                                                                                             Park, N. H.; Kim, H. S.; Lee, C. W.; Kim, H. K.; Kim, E. K.; Jang, Y. P.; Kim, J. W. Appendix 11 – Synthetic Studies Toward Alistonitrine A Evid. Based Complement Alternat. Med. 2012, 2012, 190370. (3) Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442–6445. (4) (a) Rech, J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso, P. V.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 490–491. (b) Maurya, S. K.; Dow, M.; Warriner, S.; Nelson, A. Beilstein J. Org. Chem. 2013, 9, 775–785. (c) Koriyama, Y.; Nozawa, A.; Hayakawa, R.; Shimizu, M. Tetrahedron 2002, 58, 9621–9628. (5) Although the Ellman group reported that allylmagnesium bromide was added from the Si-face of (S)-tert-butylsulfinyl imine 229 to deliver 230 (ref 3a), the opposite configuration was later confirmed by the Nelson group (ref 3b). The Nelson group prepared (R)-benzamide 231 from both the commercially available (R)-2-amino-4pentenoic acid (232) and using Ellman’s method with (S)-tert-butanesulfinamide. Then they discovered that the retention time of both benzamides (231) was identical on chiral HPLC.   609                                                                                                                                                                                                                                                                                                                                             Appendix 11 – Synthetic Studies Toward Alistonitrine A (a) Ellman (ref 3a) O S OTBS N 1. allylmagnesium bromide CH2Cl2, –78 → 23 °C (92% yield) 2. 4N HCl, CH3OH (94% yield) 229 OH ClH3N 230 (the proposed structure by the Ellman group) (b) Nelson (ref 3b) O S OTBS N 1. allylmagnesium bromide CH2Cl2, –78 → 23 °C (70% yield) 2. 4N HCl, CH3OH (96% yield) 3. benzoyl chloride Et 3N, CH2Cl2 (58% yield) 229 OH BzHN 231 1. acetyl chloride MeOH, reflux OH H 2N O 232 (commercially available) 2. LAH, THF, 0 °C (80% yield, 2 steps) 3. benzoyl chloride Et 3N, CH2Cl2 (58% yield) OH BzHN 231       (6) (a) Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Org. Lett. 2008, 10, 285–288. (b) Hoffmann, T.; Lanig, H.; Waibel, R.; Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40, 3361–3364. (c) Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 65–66. (7) Acidic removal of the silyl and tert-butanesulfinyl groups of 204 followed by carbamate formation with CDI afforded 233. Although acylation of 233 generated metathesis precursor 234, attempted ring-closing metathesis with Hoveyda-Grubbs 2nd generation catalyst to form bicycle 235 led only to double bond isomerization, generating 236.   610                                                                                                                                                                                                                                                                                                                                             Appendix 11 – Synthetic Studies Toward Alistonitrine A OTBS O 1. 4N HCl in dioxane MeOH O S O NH n-BuLi, acryloyl chloride O O N O NH THF (60% yield) 2. CDI, DMAP, Et 3N, THF (62% yield, 2 steps) 204 233 O Hoveyda-Grubbs 2nd generation (5 mol %) O O O N Hoveyda-Grubbs 2nd generation (5 mol %) H H 45 °C, CH2Cl2 (73% yield) 235 236 N O 45 °C, CH2Cl2 234 O     (8) (a) Latorre, A.; Sáez, J. A.; Rodríguez, S.; González, F. V. Tetrahedron 2014, 70, 97– (Not observed) 102. (b) Rao, V. R.; Muthenna, P.; Shankaraiah, G.; Akileshwari, C.; Babu, K. H.; Suresh, G.; Babu, K. S.; Kumar, R. S. C.; Prasad, K. R.; Yadav, P. A.; Petrash, J. M.; Reddy, G. B.; Rao, J. M. Eur. J. Med. Chem. 2012, 57, 344–361. (c) Lee, K. C.; Loh, T. P. Chem. Commun. 2006, 40, 4209–4211. (9) Although a-bromination of lactam 208a produced bromide 237, attempts to prepare the desired alcohol 209a from bromide 237 were unsuccessful. O O 1. Br 2, CH2Cl2 N OTIPS Br 2. Et 3N, CH2Cl2 (42% yield, 2 steps) 208a n-BuLi acetaldehyde N OTIPS 237 THF OH O N OTIPS 209a     (10) The same result of the ring-closing metathesis of amide 213 was obtained with (Not observed) Hoveyda-Grubbs 2nd generation catalyst. (11) (a) Krishnan, S.; Stoltz, B. M. Tetrahedron Lett. 2007, 48, 7571–7573. (b) Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037– 8041. (12) Schultz, A. G.; Lucci, R. D.; Napier, J. J.; Kinoshita, H.; Ravichandran, R.; Shannon, P.; Yee, Y. K. J. Org. Chem. 1985, 50, 217–231. 611                                                                                                                                                                                                                                                                                                                                             (13) Pereira, J.; Barlier, M.; Guillou, C. Org. Lett. 2007, 9, 3101–3103. Appendix 11 – Synthetic Studies Toward Alistonitrine A Appendix 12 – Spectra Relevant to Appendix 11 612 APPENDIX 12 Spectra Relevant to Appendix 11: Synthetic Studies Toward Alistonitrine A O 202 OTBS                                                                                                     613   Figure A12.1. 1H NMR (500 MHz, CDCl3) of compound 202. Appendix 12 – Spectra Relevant to Appendix 11 Appendix 12 – Spectra Relevant to Appendix 11                                                                                                     Figure A12.2. Infrared spectrum (Thin Film, NaCl) of compound 202.  Figure A12.3. 13C NMR (126 MHz, CDCl 3) of compound 202.   614   O S 203 N OTBS                                                                                                     615   Figure A12.4. 1H NMR (400 MHz, CD2Cl2) of compound 203. Appendix 12 – Spectra Relevant to Appendix 11 Appendix 12 – Spectra Relevant to Appendix 11                                                                                                     Figure A12.5. Infrared spectrum (Thin Film, NaCl) of compound 203.  Figure A12.6. 13C NMR (101 MHz, CD2Cl2) of compound 203.   616   204 NH S O OTBS                                                                                                   617   Figure A12.7. 1H NMR (500 MHz, CDCl3) of compound 204. Appendix 12 – Spectra Relevant to Appendix 11 Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.8. Infrared spectrum (Thin Film, NaCl) of compound 204.  Figure A12.9. 13C NMR (126 MHz, CDCl 3) of compound 204.   618   205 NH 3Cl OH Figure A12.10. 1H NMR (500 MHz, CD3OD) of compound 205. Appendix 12 – Spectra Relevant to Appendix 11   619   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.11. Infrared spectrum (Thin Film, NaCl) of compound 205.  Figure A12.12. 13C NMR (126 MHz, CD3OD) of compound 205.   620   O 207 NH OTIPS Figure A12.13. 1H NMR (500 MHz, CDCl3) of compound 207. Appendix 12 – Spectra Relevant to Appendix 11   621   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.14. Infrared spectrum (Thin Film, NaCl) of compound 207.  Figure A12.15. 13C NMR (126 MHz, CDCl3) of compound 207.   622   O OTIPS 208a N Figure A12.16. 1H NMR (500 MHz, CDCl3) of compound 208a. Appendix 12 – Spectra Relevant to Appendix 11   623   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.17. Infrared spectrum (Thin Film, NaCl) of compound 208a.  Figure A12.18. 13C NMR (126 MHz, CDCl3) of compound 208a.   624   O OTIPS Boc 208b N Figure A12.19. 1H NMR (500 MHz, CDCl3) of compound 208b. Appendix 12 – Spectra Relevant to Appendix 11   625   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.20. Infrared spectrum (Thin Film, NaCl) of compound 208b.  Figure A12.21. 13C NMR (126 MHz, CDCl3) of compound 208b.   626   O 211 OH OH Figure A12.22. 1H NMR (400 MHz, CDCl3) of compound 211. Appendix 12 – Spectra Relevant to Appendix 11   627   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.23. Infrared spectrum (Thin Film, NaCl) of compound 211.  Figure A12.24. 13C NMR (101 MHz, CDCl3) of compound 211.   628   OH O 213 N H OTIPS Figure A12.25. 1H NMR (400 MHz, CDCl3) of compound 213. Appendix 12 – Spectra Relevant to Appendix 11   629   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.26. Infrared spectrum (Thin Film, NaCl) of compound 213.  Figure A12.27. 13C NMR (126 MHz, CDCl3) of compound 213.   630   OH OTIPS NH 215a O Figure A12.28. 1H NMR (500 MHz, CDCl3) of compound 215a. Appendix 12 – Spectra Relevant to Appendix 11   631   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.29. Infrared spectrum (Thin Film, NaCl) of compound 215a.  Figure A12.30. 13C NMR (126 MHz, CDCl3) of compound 215a.   632   OH OTIPS NH 215b O Figure A12.31. 1H NMR (500 MHz, CDCl3) of compound 215b. Appendix 12 – Spectra Relevant to Appendix 11   633   Appendix 12 – Spectra Relevant to Appendix 11   Figure A12.32. Infrared spectrum (Thin Film, NaCl) of compound 215b.  Figure A12.33. 13C NMR (126 MHz, CDCl3) of compound 215b.   634    635   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide CHAPTER 5 Synthetic Studies Toward Polycyclic Ineleganolide 5.1. Introduction The complex polycyclic norcembranoid ineleganolide (238) was first isolated from the Taiwanese coral Sinularia inelegans in 1999 by the Duh group (Figure 5.1.1).1,2 The relative stereochemistry of ineleganolide (238) was unambiguously confirmed by X-ray analysis and spectroscopic method. This complex polycyclic norditerpenoid possesses intriguing architectural features including an ether bridge, which connects two carbocyclic rings and an angular fusion of five-, seven,- and sixmembered carbocyclic rings linked with a five-membered lactone ring. Ineleganolide exhibits cytotoxic activity against P-388 murine leukemia cells (ED50 = 3.82 µg/mL).1 Figure 5.1.1. Structure of Ineleganolide (238). (Originally depicted structure shown on the lefthand side; the proposed actual structure from biosynthetic studies shown on the right-hand side.)3 O O H O H O H O O H O O Ineleganolide (238) O H O H 636   A biosynthetic pathway of ineleganolide was proposed by Pattenden and co- Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide workers (Scheme 5.1.1a). 4 It is hypothesized that ineleganolide (238) is biosynthetically constructed by successive transannular Michael reactions of macrocyclic 5-episinuleptolide (239). An initial intramolecular Michael reaction of 5episinuleptolide (239) establishes the C4–C13 bond to furnish cyclohexanone 240. Dehydration of 240 at C11 and subsequent bond formation between C7 and C11 by a second Michael reaction affords ineleganolide (238). The Pattenden group proved this biosynthetic route experimentally by a semisynthesis of ineleganolide (238) from 5-episinuleptolide (239), which was isolated from Sinularia scabra species (Scheme 5.1.1b).5 Acetylation of the hydroxyl group at C11 position of 5-episinuleptolide (239) furnished acetate 242. Ineleganolide (238) was obtained in 26% yield by treatment of acetate 242 with LHMDS. Scheme 5.1.1. Proposed Biosynthesis of Ineleganolide (238) (a) O O O O H 5 4 HO H Michael reaction O 4 11 H (6-exo-trig cyclization) 13 11 H O dehydration O HO H -H2O O O O 5-episinuleptolide (239) 240 O O O 7 H Michael reaction O (5-endo-trig cyclization) 11 H O H H O O O 241 H O Ineleganolide (238) O (b) O O H O O H 5 4 HO Ac2O, Et 3N O 11 H O O 5-episinuleptolide (239) CH2Cl2, 23 °C (92% yield) O H AcO LHMDS O O O 242 O H H THF, –78 → 0 °C (26% yield) O H O H O Ineleganolide (238) 637   Although this intriguing polycyclic norditerpenoid ineleganolide (238) has Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide attracted much attention from the synthetic community over the past decade including extensive efforts from my lab at Caltech,6 a total synthesis of ineleganolide has not been reported. Herein, we describe new synthetic strategies toward an enantioselective synthesis of ineleganolide (238). We chose to pursue the synthesis of the enantiomer of ineleganolide (238), which was depicted in the original isolation paper. 5.2. Results and Discussion We envisioned that a total synthesis of ineleganolide (238) could be achieved by successive transannular Michael reactions (Scheme 5.2.1). Disconnections of the C4–C13 and C11–C12 bonds affords domino double-Michael reaction precursor 243. The 1,4-diketone and ester functional groups of macrocycle 243 can be disassembled into α,β-unsaturated ester 244 and bicycle 245. Scheme 5.2.1. Retrosynthesis of Ineleganolide (238) O H O 4 7 13 12 H O O 11 O Domino Double-Michael Reaction O O H O O 238 O 243 O OTBS X Alkylation + Esterification O CO2Me O X = Leaving Group 244 245 Our synthesis began with the known acetal 2467 to prepare the α,β-unsaturated ester fragment 248 (Scheme 5.2.2). Subjection of acetal 246 to Still-Gennari 638   olefination conditions afforded the (Z)- and (E)-isomers of enoate 248 in ratios Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 8,9 ranging from 10:1 to 2:1, respectively. We were delighted to find that highly (Z)selective olefination occurred to furnish enoate 248 in 54% yield using conditions developed by the Ando group.10 Scheme 5.2.2. Synthesis of (Z)-Selective Enoate 248 OMe O OMe + O F 3C O OMe O P OMe O OMe THF, –20 °C (58% yield, 2 steps) CF3 246 18-crown-6 KHMDS 247 CO2Me 248 (~10:1 to 2:1 Z:E) OMe O OMe + O P O O 246 O OMe NaI, NaH –78 °C, THF (54% yield) OMe OMe or NaI, DBU –78 °C, THF (54% yield) 249 CO2Me 248 (only Z) Acid-mediated acetal hydrolysis of 248 furnished aldehyde 250 in quantitative yield (Scheme 5.2.3a). Methyl Grignard addition to aldehyde 250 produced diastereomeric mixtures of alcohol 251, which was converted to ketone 252 by Swern oxidation. After extensive experimentation, it was found that employing LiTMP (TMP = 2,2,6,6-tetramethylpiperidine) and TMSCl afforded kinetically favored silyl enol ether 253 selectively.11 Silyl enol ether 253 was subsequently transformed to αhydroxyketone 254 by Rubottom oxidation. 12 Surprisingly, tosylation and bromination of α-hydroxyketone 254 proved to be challenging. However, we were delighted to find that treatment of silyl enol ether 253 with NBS furnished αbromoketone 244b (Scheme 5.2.3b). 639   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.3. Synthesis of α-Bromoketone 244b (a) OMe O 50% aq TFA OMe CO2Me OH MeMgBr H CHCl3, 0 → 23 °C (99% yield) CO2Me 248 250 THF, –78 °C (64% yield; 95% yield based on recoverd SM) CO2Me 251 O OTMS DMSO, oxalyl chloride Et 3N 2,2,6,6-tetramethylpiperidine n-BuLi, TMSCl CH2Cl2, –78 °C (88% yield; 90% yield based on recovered SM) THF, –78 °C CO2Me CO2Me 252 253 p-TsCl pyridine 0 → 23 °C O m-CPBA, NaHCO 3 H 2O, toluene; AcOH, H 2O, THF 0 → 23 °C (56% yield based on recovered starting material, 2 steps) OH O X or PPh 3, CBr4 CH2Cl2, 0 °C CO2Me CO2Me 254 X = OTs, 244a X = Br, 244b (Not observed) (b) OTMS O O 2,2,6,6-tetramethylpiperidine n-BuLi, TMSCl THF, –78 °C CO2Me CO2Me 252 Br NBS, NaHCO 3 THF, –78 °C (50% yield based on recovered starting material, 2 steps) 253 CO2Me 244b With α,β-unsaturated ester fragment 244b in hand, we turned our attention to preparing bicyclic fragment 245. Oxidation of known diol 2556a, 13 with MnO2 delivered aldehyde 256 (Scheme 5.2.4a). Methyllithium addition to aldehyde 256 provided secondary alcohol 257, which was oxidized with MnO2 to afford ketone 258. Unfortunately, we explored diazo transfer reactions extensively with various diazo sources (e.g., p-ABSA, 4-dodecylbenzenesulfonyl azide) under Danheiser’s conditions,14 but the desired diazo 259 was not observed. Another strategy was devised to obtain diazo ketone 259 by using Pinnick oxidation of aldehyde 256 to furnish acid 260 (Scheme 5.2.4b). Treatment of acid 260 with ethyl chloroformate or oxalyl chloride generated the corresponding intermediates 261 or 262, respectively. However, attempts to obtain the desired diazo ketone 259 from intermediate 261 or Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 262 with TMS-diazomethane were unsuccessful. 15,16,17 640   Alternatively, we envisioned that the diazo functional group could be inserted by addition of ethyl diazoacetate to aldehyde 256 (Scheme 5.2.4c). Deprotonation of ethyl diazoacetate by LDA followed by addition to aldehyde 256 resulted in an alcohol (263) that could be oxidized to diazo compound 264. Disappointingly, intramolecular O–H insertion of the tertiary alcohol to the diazo in 264 was found to be challenging under Lewis acid conditions. Despite screening numerous rhodium catalysts, solvents, and temperature, only undesired lactonization occurred to form 266.18 641   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.4. Attempts to Synthesize Bicyclic Fragment via Diazo Compounds (a) OTBS OH OH OTBS OTBS MnO 2 MeLi MnO 2 CH2Cl2, 23 °C (92% yield) Et 2O, –15 °C (88% yield) CH2Cl2, 23 °C (89% yield) O OH 255 256 OH 257 OTBS OTBS N2 Danheiser's O OH diazo transfer conditions OH O 258 OH 259 (Not observed) (b) OTBS O OH OTBS NaClO 2, NaH 2PO 4 30% H 2O2 MeCN, H 2O, 0 °C (87% yield) HO O 256 OTBS Et 3N, ethyl chloroformate THF, –10 °C X or oxalyl chloride, Et 3N DMF, CH2Cl2, 0 °C OH O 260 OH X = OCO 2Et, 261 X = Cl, 262 OTBS N2 TMS-diazomethane MeCN, THF, 0 °C O OH 259 (Not observed) (c) OTBS O THF, –78 °C (62% yield) OH OTBS OTBS LDA ethyl diazoacetate N2 MnO 2 EtO O 256 OH CH2Cl2, 23°C (93% yield) OH EtO O O OH 264 263 OTBS OTBS N2 N2 Lewis acids EtO O O OH or Rh 2(OAc)4 catalysts O O EtO 2C 264 265 (Not observed) OTBS Rh 2(OAc)4, toluene 110 °C (36% yield) or Rh 2(OAc)4, benzene 80 °C (36% yield) O O N2 O 266 Having failed to access the bicyclic fragment using diazo strategies, a revised approach was put forward (Scheme 5.2.5). Treatment of methyl ketone 258 with 642   LiTMP (TMP = 2,2,6,6,-tetramethylpiperidine) and TESCl provided silyl ether 267, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide which was transformed to α-hydroxyketone 268 by Rubottom oxidation. However, the desired bicycle 245 was not observed under various basic conditions (e.g., NaOH, KOtBu, NaH, LHMDS, LDA) from benzoate 269 and mesylate 270, which were prepared from α-hydroxyketone 268.19,20 Scheme 5.2.5. Attempted Williamson Etherifications OTBS OTBS 2,2,6,6-tetramethylpiperidine n-BuLi, TESCl O OH THF, –78 °C m-CPBA, NaHCO 3, H 2O, toluene; TESO 258 OH 267 Bz 2O, Et 3N, DMAP CH2Cl2, 0 → 23 °C (85% yield) or MsCl, Et 3N CH2Cl2, 0 °C (71% yield) OTBS AcOH, H 2O, THF, 0 → 23 °C (42% yield based on recovered starting material, 2 steps) OH O OH 268 OTBS OTBS X 11 bases O OH 9 O 6 8 O 5 X = OBz, 269 X = OMs, 270 245 (Not observed) The desired bicycle 245 seemed highly angularly strained due to the α,βunsaturated ketone at the junction of the bicycle. We envisaged that the strain would be reduced by converting the sp2-hybridized carbon to the sp3-hybridized carbon at C6. After considerable experimentation, we found that diastereomeric mixtures of epoxides 271a and 271b could be obtained by a Corey-Chaykovsky reaction (Scheme 5.2.6a).21 Surprisingly, diol 255 was furnished as a major byproduct under these reaction conditions. Treatment of aldehyde 256 with dibromomethane (or chloroiodomethane) and n-BuLi also produced diastereomeric mixtures of epoxides 271a and 271b along with diol 255 (Scheme 5.2.6b).22 643   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.6. Synthesis Epoxides 271a and 271b (a) H OTBS OH THF, 0 °C O (35% combined yield, 271a, 271b; 19% yield, 255 ) 256 (b) OTBS dibromomethane (or ClCH2I) n-BuLi OH THF, –78 → 23 °C O (39% combined yield, 271a, 271b; 34% yield 255 ) OH OH OH 255 OTBS + 271a OH 271b 6 256 O OH OTBS + 271a OTBS O OTBS + 6 O H OTBS trimethylsulfonium iodide KHMDS OTBS + O OH 271b OH OH 255 With epoxide 271 in hand, direct epoxide ring opening reactions were conducted to deliver 272 (Scheme 5.2.7a). Unfortunately, 5-membered ring formation to generate 272 was not observed with various Lewis acids (e.g., CeCl3, TMSOTf, In(OTf)3, PPTS) or bases (e.g., KHMDS, NaH).23 Interestingly, treatment of epoxide 271 with MgI2 at 40 °C generated iodohydrin 273 along with methyl ketone 258 (Scheme 5.2.7b).24,25 Protection of secondary alcohol 273 with TESCl and subsequent intramolecular etherification of iodide 274 with NaH afforded bicyclc 275.26 Selective removal of TES group in 275 with PPTS furnished mono-silyl ether 276. An attempt to oxidize secondary alcohol 276 to ketone 245 shows promise by TLC analysis but to date we have not successfully isolated and characterized 245.27 644   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.7. Formation of Bicyclic Fragment (a) OTBS OTBS Lewis acids O HO or bases OH O 271 (b) 272 (Not observed) OTBS OTBS MgI 2 O HO THF, 40 °C (63% yield, 273; 16% yield, 258 ) OH + HO I 271 O 273 OTBS HO OTBS NaH TESO CH2Cl2, 23 °C (89% yield) I 273 THF, 23 °C (60% yield) HO 274 PPTS TESO O 275 OTBS EtOH, 23 °C (45% yield) OH 258 OTBS TESCl, imidazole DMAP HO I OTBS OTBS MnO 2 HO O CH2Cl2, 23°C 276 O O 245 We next investigated coupling reactions of α-bromoketone 244b and methylketone 258, which could be easily prepared (Scheme 5.2.8a). Despite extensive experimentation, alkylation of methylketone 258 with α-bromoketone 244b failed under basic conditions. 28 Treatment of hydroxyketone 268 with ethyl chloroformate afforded the carbonate intermediate, which was subjected to αbromoketone 244b to generate 1,4-diketone 279 under basic conditions. However, αbromoketone 244b appeared to decompose under the basic conditions and only the unreacted cyclopentene fragment was recovered. 645   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.8. Coupling of the Fragments (a) O O OTBS Br O OH bases + O CO2Me 244b OH O 258 OMe OTBS 277 (Not observed) (b) Et 3N, DMAP ethyl chloroformate OH O EtO OTBS OH 244b O bases CH2Cl2 0 → 23 °C (92% yield) OH OCO 2Et O O O OTBS THF, –78 °C O 268 OH O 278 OMe OTBS 279 (Not observed) Since coupling reactions of α-bromoketone 244b and the cyclopentene fragment by alkylation did not proceed, we next chose to focus on metathesis strategies to combine these two fragments (Scheme 5.2.9). We believed that esterification of acid 280 and secondary alcohol 281 would afford metathesis precursor diene 282. Intramolecular metathesis reaction between the vinyl groups of 282 was expected to produce macrocycle 283. 1,4-Addition of tertiary alcohol to the α,β-unsaturated ketone could deliver 5-membered ether 243, which would proceed domino double-Michael reaction to afford ineleganolide (238). Scheme 5.2.9. Synthetic Plan by Using Metathesis Strategies O O OH metathesis OH O CO2H O esterification + 280 OH O 281 O O O OH O 282 O O Domino Double-Michael 1,4-addition O O H O Reaction H O 283 O O 243 O O H O Ineleganolide (238) 646   1,2-Addition of vinylmagnesium bromide to aldehyde 256 furnished allyl Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide alcohol 284, which was oxidized by MnO2 to deliver vinyl ketone 285 (Scheme 5.2.10a). Removal of silyl group on 285 with TBAF afforded diol 281. Vinyl Grignard addition to aldehyde 250 and subsequent oxidation of the resultant alcohol 286 produced ketone 287 (Scheme 5.2.10b). However, an attempted hydrolysis of methyl ester 287 afforded Michael adduct 288 instead of the desired acid 280. Additionally, transesterifications of ester 287 with alcohol 281 were unsuccessful with Otera’s catalyst (Scheme 5.2.10c). 29 Therefore, we decided to explore esterification reactions with silyl ether 289 (Scheme 5.2.10d). Silylation of secondary alcohol 286 with TBSCl and subsequent hydrolysis produced acid intermediate 289. Disappointingly, esterification of acid 289 and alcohol 281 was found to be challenging under several coupling conditions (e.g., EDCI, DCC, BOPCl).30 647   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.10. Coupling of the Fragments by Esterification (a) OTBS OTBS OTBS vinylmagnesium bromide H O MnO 2 THF, –78 °C (84% yield; 99% yield based on recovered starting material) OH OH 256 CH2Cl2, 23 °C (63% yield) OH O 284 OH 285 OH TBAF THF, 23 °C (46% yield) O OH 281 (b) O OH H CO2Me vinylmagnesium bromide DMSO, oxalyl chloride Et 3N, CH2Cl2, –78 °C (97% yield) THF, –78 °C (66% yield; 88% yield based on recovered starting material) or MnO 2, CH2Cl2, 23 °C (85% yield) CO2Me 250 286 O O LiOH THF, MeOH, H 2O or K 2CO3, MeOH, H 2O CO2Me CO2H 287 280 (Not observed) LiOH THF, MeOH, H 2O, 23 °C (65% yield) O OMe or K 2CO3, MeOH, H 2O, 23 °C (53% yield) CO2Me 288 (c) O O OH O Otera's catalyst + OH toluene CO2Me 287 O OH O 281 O 282 OH (d) OTBS OH 1. TBSCl, imidazole DMAP, CH2Cl2, 23 °C (95% yield) OTBS OH OH 281 2. LiOH THF, MeOH, H 2O, 23 °C CO2Me (97% yield) 286 O O CO2H 289 coupling conditions O O 290 (Not observed) At this stage, we began to investigate intermolecular metathesis between allyl alcohol 286 and vinyl ketone 285 with Grubbs’ catalysts (Scheme 5.2.11a). 31 648   However, intermolecular metathesis of 286 and 285 to deliver 291 proved to be Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide difficult. Alternatively, we attempted to connect allyl alcohol 286 and diol 284 via a silyl tether, but the yield was unsatisfactory (Scheme 5.2.11b). Scheme 5.2.11. Intermolecular Metathesis (a) OH OH OTBS O OH metathesis + CO2Me 286 O OH O 285 OMe OTBS 291 (Not observed) (b) OH Si OTBS dichlorodiethylsilane + O O HO pyridine CO2Me OH OTBS OH CO2Me 286 284 292 (Not observed) Since combining the two fragments appeared to be challenging, we devised a new synthetic strategy that utilized an alkyne functionality (Scheme 5.2.12). Addition of ethynylmagnesium bromide to aldehyde 256 provided intermediate 293, which was oxidized by MnO2 to generate ynone 294 (Scheme 5.2.12a). Although n-BuLi was subjected to alkyne 294 to form lithium acetylide, which was added to aldehyde 250, little or no conversion was observed (Scheme 5.2.11b). We also attempted the lithium acetylide addition reaction with alcohol 293 or silyl ether 296,32 but only trace amounts of the respective coupling products 297 or 298 were observed. 649   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Scheme 5.2.12. Alkyne Addition (a) OTBS H O OH 256 (b) OTBS ethynylmagnesium bromide MnO 2 THF, –78 °C (90% yield, 94% yield based on recovered starting material) CH2Cl2, 23 °C (68% yield) O OH OH O 293 OH 294 HO OTBS H OTBS O HO n-BuLi + THF CO2Me 250 O OH CO2Me 294 OTBS 295 (Not observed) O HO OTBS H OR HO n-BuLi + THF, –78 °C CO2Me 250 OR OH R = H, 293 R = TES, 296 CO2Me OTBS R = H, 297 R = TES, 298 (trace) 5.3. Conclusion We have described our efforts toward the synthesis of ineleganolide. Highly (Z)-selective olefination at C12–C13 was achieved by a method developed by the Ando group. The C–O bond formation at C5, which proved to be challenging in the other strategy investigated in our group,6a was accomplished. Although the entire fragmented carbon framework was constructed from this work, unfortunately, coupling of the two fragments was unsuccessful. We will further investigate a total synthesis of ineleganolide using modified strategies. 5.4. Experimental Methods and Analytical Data 5.4.1. Materials and Methods Unless stated otherwise, reactions were performed at ambient temperature (23 °C) in flame-dried glassware under an argon atmosphere using dry, deoxygentated solvents 650   (distilled or passed over a column of activated alumina) using a Teflon -coated Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide ® magnetic stirring bar. Commercially available reagents were used as received unless otherwise noted. Et3N was distilled from calcium hydride immediately prior to use. MeOH was distilled from magnesium methoxide immediately prior to use. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (250 nm) and visualized by UV fluorescence quenching, potassium permanganate, or p-anisaldehyde staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 40-63 nm) was used for flash chromatography. 1 H NMR spectra were recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), CHDCl2 (δ 5.32) or C6HD6 (δ 7.16 ppm). 13 C NMR spectra are recorded on a Varian Mercury 300 MHz, a Bruker AV III HD 400 MHz spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe, Varian Inova 500 MHz, and 600 MHz spectrometers (75 MHz, 126 MHz, and 151 MHz, respectively) and are reported relative to CHCl3 (δ 77.16 ppm), CHDCl2 (δ 53.84) or C6HD5 (δ 128.06 ppm). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 Spectrometer and are reported in frequency of absorption (cm-1). High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) or electron ionization (EI+) mode or acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in atmospheric pressure 651   chemical ionization (APCI) or mixed (MultiMode ESI/APCI) ionization mode. Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path length cell at 589 nm. 5.4.2. Experimental Procedures OMe O OMe + O P O O 246 249 O OMe NaI, NaH –78 °C, THF (54% yield) OMe OMe or NaI, DBU –78 °C, THF (54% yield) CO2Me 248 (only Z) A solution of phosphate 249 (108 mg, 0.322 mmol, 1.20 equiv) in THF (2.68 mL) was treated with NaI (52.0 mg, 0.349 mmol, 1.30 equiv) and DBU (53.0 mg, 0.348 mmol, 1.30 equiv) at 0 °C and stirred for 10 min. After the mixture was cooled to – 78 °C, aldehyde 246 was added. The reaction was done in 3 min, and quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford α,β-unsaturated ester 248 (35.5 mg, 54% yield). (The same result was obtained by using 1.05 equiv NaH instead of DBU.) Rf = 0.62 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.16 (dt, J = 11.5, 7.2 Hz, 1H), 5.79 (dt, J = 11.5, 1.9 Hz, 1H), 4.79 (ddt, J = 13.6, 2.1, 1.1 Hz, 2H), 4.35 (dd, J = 7.0, 4.7 Hz, 1H), 3.70 (s, 3H), 3.31 (s, 3H), 3.30 (s, 3H), 2.80 – 2.71 (m, 2H), 2.37 (tt, J = 8.5, 6.5 Hz, 1H), 1.76 – 1.64 (m, 2H), 1.65 (dd, J = 1.5, 0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.0, 148.9, 146.3, 120.0, 112.7, 103.0, 53.2, 52.7, 51.2, 43.2, 35.9, 32.6, 18.4; IR (Neat Film NaCl) 2949, 2830, 1723, 1646, 1437, 1408, 1203, 1127, 1053, 892, 819 cm-1; HRMS (MM: FAB+) m/z calc’d for C13H21O4 [M+H]+-H2 : 241.1440; found: 241.1431; [α]D25.0 3.04° (c 0.30, CHCl3). 652   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide OMe O OMe CO2Me 50% aq TFA OH CHCl3, 0 → 23 °C (99% yield) 248 MeMgBr H CO2Me 250 THF, –78 °C (64% yield; 95% yield based on recoverd SM) CO2Me 251 To a solution of acetal 248 (129 mg, 0.494 mmol, 1.00 equiv) in CHCl3 (2.47 mL) was added 50% aq TFA (1.23 mL) at 0 °C. The reaction mixture was stirred for 3 h at 23 °C before it was quenched by the addition of sat. aq NaHCO3. The aqueous phase was extracted with CH2Cl2 (3 x 4.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo to afford aldehyde 250 (95.0 mg, 99% yield), which was used without further purification. To a solution of aldehyde 250 (95.0 mg, 0.484 mmol, 1.00 equiv) in THF (5.00 mL) was added MeMgBr (3.0 M solution in diethyl ether; 0.21 mL, 0.629 mmol, 1.30 equiv) at –78 °C. The mixture was stirred for 1 h at –78 °C. Then, the solution was quenched by the addition of sat. aq NaHCO3. The aqueous phase was extracted with EtOAc (3 x 5.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford secondary alcohol 251 (65.5 mg, 64% yield). Rf = 0.22 (1:4 EtOAc:hexanes); (due to the presence of diastereomeric mixtures, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum) 1H NMR (400 MHz, CDCl3) δ 6.18 (ddt, J = 11.5, 9.8, 7.4 Hz, 2H), 5.82 – 5.76 (m, 2H), 4.86 – 4.76 (m, 4H), 3.92 – 3.83 (m, 1H), 3.77 (ddt, J = 9.4, 6.3, 3.1 Hz, 1H), 3.70 (s, 6H), 2.87 (dddd, J = 15.1, 7.3, 5.0, 1.8 Hz, 1H), 2.74 (dddd, J = 8.3, 7.3, 5.1, 1.8 Hz, 2H), 2.64 – 2.55 (m, 1H), 2.49 (dddd, J = 10.0, 8.6, 6.5, 4.9 Hz, 1H), 2.37 (dddd, J = 9.8, 8.1, 6.7, 5.0 Hz, 1H), 1.68 (t, J = 1.2 Hz, 3H), 1.63 (dd, J = 1.5, 0.8 Hz, 3H), 1.55 – 1.42 (m, 4H), 1.19 (s, 3H), 1.17 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 167.0, 149.2, 653   149.1, 147.7, 146.8, 119.9, 112.9, 112.4, 66.6, 65.9, 51.3, 51.2, 45.1, 44.1, 43.1, 42.4, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 33.0, 32.0, 24.2, 23.5, 18.5, 18.1; IR (Neat Film NaCl) 3421, 2966, 2928, 1724, 1646, 1438, 1408, 1203, 1170, 892, 819 cm-1; HRMS (MM: FAB+) m/z calc’d for C12H21O3 [M+H]+: 213.1491; found 213.1489; [α]D25.0 –9.52° (c 0.11, CHCl3). OH O DMSO, oxalyl chloride Et 3N CO2Me 251 CH2Cl2, –78 °C (88% yield; 90% yield based on recovered SM) CO2Me 252 To a stirred solution of oxalyl chloride (0.21 mL, 2.40 mmol, 1.50 equiv) in CH2Cl2 (8.00 mL) was added DMSO (0.34 mL, 4.79 mmol, 3.00 equiv) dropwise at –78 °C. The reaction mixture was stirred for 15 min, and alcohol 251 (339 mg, 1.60 mmol, 1.00 equiv) in CH2Cl2 (1.00 mL) was added dropwise. The solution was stirred for 2 h and 30 min at –78 °C, then Et3N (1.56 mL, 7.00 equiv) was added. After 90 min at –78 °C, the solution was warmed to 23 °C over 30 min and quenched with H2O. The aqueous phase was extracted with CH2Cl2 (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford ketone 252 (295 mg, 88% yield). Rf = 0.35 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.19 – 6.10 (m, 1H), 5.81 (dt, J = 11.6, 1.7 Hz, 1H), 4.79 (p, J = 1.5 Hz, 1H), 4.74 (dt, J = 1.7, 0.8 Hz, 1H), 3.70 (s, 3H), 2.84 – 2.73 (m, 3H), 2.61 – 2.46 (m, 2H), 2.12 (d, J = 0.5 Hz, 3H), 1.68 (dd, J = 1.5, 0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 207.8, 166.9, 148.3, 146.2, 120.4, 112.3, 51.3, 47.6, 42.1, 32.4, 30.6, 19.5; IR (Neat Film NaCl) 2951, 1718, 1647, 1437, 1204, 1272, 821 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H19O3 [M+H]+: 211.1329; found: 211.1327; [α]D25.0 –9.42° (c 0.15, CHCl3). 654   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide O OTMS m-CPBA, NaHCO 3 H 2O, toluene; THF, –78 °C AcOH, H 2O, THF 0 → 23 °C (56% yield based on recovered starting material, 2 steps) CO2Me 252 O 2,2,6,6-tetramethylpiperidine n-BuLi, TMSCl CO2Me 253 OH CO2Me 254 To a solution of 2,2,6,6-tetramethylpiperidine (50 µL, 0.296 mmol, 1.50 equiv) in THF (2.00 mL) was added n-BuLi (2.5 M in hexane; 0.12 mL, 0.296 mmol, 1.50 equiv) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C, and TMSCl (0.13 mL, 0.990 mmol, 5.00 equiv) was added at –78 °C. Then, methyl ketone 252 (42.0 mg, 0.198 mmol, 1.00 equiv) in THF (1.00 mL) was added dropwise at –78 °C. The solution was stirred for 1 h and quenched with Et3N, followed by sat. aq NaHCO3. The aqueous phase was extracted with EtOAc (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was quickly filtered by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford silyl ether 253, which was used without further purification. To a solution of m-CPBA (75%; 41.0 mg, 0.178 mmol, 0.90 equiv) in toluene (2.74 mL) was added solid NaHCO3 (35.0 mg, 0.411 mmol, 2.08 equiv). The heterogeneous mixture was stirred for 15 min at 23 °C, then H2O (0.40 mL) was added. Silyl ether 253 in toluene (0.50 mL) was added dropwise to the reaction mixture at 0 °C. After the solution was stirred for 30 min at 0 °C, sat. aq NaHCO3 was added and stirred for 10 min at 0 °C. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The combined organic phases were washed with NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo. To the residue dissolved in THF (0.30 mL) and H2O (0.17 mL) was added AcOH (0.17 mL). The mixture was stirred for 2 h at 23 °C. Then, the solution was diluted with EtOAc and H2O, and solid NaHCO3 was added until the gas evolution ceased. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, 655   dried over MgSO4 and concentrated in vacuo. The residue was purified by column Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide chromatography (1:4 EtOAc:hexanes) on silica gel to afford α-hydoxyketone 254 (12.0 mg, 56% yield based on recovered starting material, 2 steps). Rf = 0.35 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.13 (dt, J = 11.5, 7.1 Hz, 1H), 5.83 (ddd, J = 11.6, 2.0, 1.3 Hz, 1H), 4.82 (p, J = 1.5 Hz, 1H), 4.75 (dt, J = 1.6, 0.8 Hz, 1H), 4.20 (d, J = 3.0 Hz, 2H), 3.71 (s, 3H), 3.05 (s, br, 1H), 2.91 – 2.71 (m, 3H), 2.62 – 2.43 (m, 2H), 1.69 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 208.6, 166.8, 147.6, 145.5, 120.8, 112.8, 68.8, 51.3, 42.3, 42.1, 32.4, 19.5; IR (Neat Film NaCl) 2917, 1716, 1440, 1205, 1172 cm-1; HRMS (MM: FAB+) m/z calc’d for C12H19O4 [M+H]+: 227.1283; found: 227.1288; [α]D25.0 –4.11° (c 0.09, CHCl3). OTMS O O 2,2,6,6-tetramethylpiperidine n-BuLi, TMSCl THF, –78 °C CO2Me CO2Me 252 Br NBS, NaHCO 3 253 THF, –78 °C (50% yield based on recovered starting material, 2 steps) CO2Me 244b To a solution of 2,2,6,6-tetramethylpiperidine (0.23 mL, 1.39 mmol, 1.60 equiv) in THF (8.70 mL) was added n-BuLi (1.98 M in hexane; 0.70 mL, 1.39 mmol, 1.60 equiv) at 0 °C. The reaction mixture was stirred for 15 min at 0 °C, and TMSCl (0.55 mL, 4.35 mmol, 5.00 equiv) was added at –78 °C. Then, methyl ketone 252 (183 mg, 0.870 mmol, 1.00 equiv) in THF (1.00 mL) was added dropwise at –78 °C. The solution was stirred for 1 h and quenched with Et3N, followed by sat. aq NaHCO3. The aqueous phase was extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was quickly filtered by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford silyl ether 253, which was used without further purification. 656   A solution of silyl ether 253 in THF (8.70 mL) at –78 °C was treated with solid Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide NaHCO3 (132 mg, 1.57 mmol, 1.80 equiv) and stirred for 10 min at –78 °C. NBS (248 mg, 1.39 mmol, 1.60 equiv) was then added portionwise and stirred for 15 min at –78 °C. The solvent was evaporated and the residue was purified by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford α-bromoketone 244b (55.0 mg, 50% yield based on recovered starting material, 2 steps). Rf = 0.65 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.14 (dt, J = 11.5, 7.2 Hz, 1H), 5.83 (dt, J = 11.6, 1.6 Hz, 1H), 4.82 (p, J = 1.5 Hz, 1H), 4.77 (dt, J = 1.5, 0.8 Hz, 1H), 3.87 (d, J = 1.0 Hz, 2H), 3.71 (s, 3H), 2.89 – 2.68 (m, 6H), 1.72 – 1.69 (m, 3H), 1.56 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 200.9, 166.9, 147.8, 145.7, 120.7, 112.7, 51.3, 43.7, 42.1, 34.8, 32.2, 19.7; IR (Neat Film NaCl) 2949, 2360, 1716, 1645, 1439, 1203, 1172 cm-1; HRMS (MM: FAB+) m/z calc’d for C11H14O2Br [M-OMe]•: 257.0177; found: 257.0170; [α]D25.0 –4.06° (c 0.09, CHCl3). OTBS OTBS MnO 2 OH OH CH2Cl2, 23 °C (92% yield) 255 O OH 256 To a stirred solution of diol 255 (20.0 mg, 0.0774 mmol, 1.00 equiv) in CH2Cl2 (0.80 mL) was added MnO2 (85%; 119 mg, 1.16 mmol, 15.0 equiv). The solution was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford aldehyde 256 (18.3 mg, 92% yield). All the spectrum data matched with those reported in ref 6a. 657   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide OTBS OTBS MeLi O OH Et 2O, –15 °C (88% yield) OTBS MnO 2 OH 256 OH CH2Cl2, 23 °C (89% yield) O 257 OH 258 To a solution of aldehyde 256 (100 mg, 0.390 mmol, 1.00 equiv) in Et2O (2.00 mL) was added MeLi (1.6 M in diethyl ether; 1.95 mL, 3.12 mmol, 8.00 equiv) at –10 °C. The solution was stirred for 2 h and quenched with sat. aq NH4Cl. The solution was poured into H2O. The aqueous phase was extracted with EtOAc (3 x 3.00 mL), washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:2 EtOAc:hexanes) on silica gel to afford alcohol 257 (93.4 mg, 88% yield). To a stirred solution of alcohol 257 (162 mg, 0.594 mmol, 1.00 equiv) in CH2Cl2 (6.00 mL) was added MnO2 (85%; 1.20 g, 11.9 mmol, 20.0 equiv). The solution was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford ketone 258 (143 mg, 89% yield). All the spectrum data matched with those reported in ref 6a. OTBS O OH 256 OTBS NaClO 2, NaH 2PO 4 30% H 2O2 MeCN, H 2O, 0 °C (87% yield) HO O OH 260 To a stirred solution of aldehyde 256 (18.3 mg, 0.0714 mmol, 1.00 equiv) in MeCN (0.70 mL) were added NaH2PO4 (30.0 mg, 0.25 mmol, 3.50 equiv) in H2O (0.50 mL) and 30% H2O2 (10 µL) at 0 °C. Then, a solution of NaClO2 (23.0 mg, 0.25 mmol, 3.50 equiv) in H2O (0.70 mL) was added dropwise in 1 h at 0 °C. The reaction 658   mixture was stirred for 10 min and quenched with sat. aq Na2SO3. The aqueous phase Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide was extracted with EtOAc (2.00 mL). The combined aqueous phases were acidified with 2N HCl to make the solution pH 5–6. The aqueous phase was extracted with EtOAc (3 x 4.00 mL) washed with brine, dried over MgSO4 and concentrated in vacuo to afford acid 260 (17.0 mg, 87% yield). Rf = 0.15 (1:1 EtOAc:hexane); 1H NMR (500 MHz, CDCl3) δ 6.77 (d, J = 1.8 Hz, 1H), 4.75 (td, J = 6.7, 1.9 Hz, 1H), 2.50 (dd, J = 12.9, 6.9 Hz, 1H), 2.09 – 2.03 (m, 1H), 1.48 (d, J = 0.7 Hz, 3H), 0.90 (s, 9H), 0.10 (d, J = 3.0 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 168.2, 147.9, 139.6, 79.5, 72.7, 51.3, 27.7, 25.9, 18.2, -4.5, -4.6; IR (Neat Film NaCl) 2929, 2857, 1701, 1362, 1258, 1097, 898, 837, 778 cm-1; HRMS (MM: FAB+) m/z calc’d for C12H19O4 [M+H]+-H2: 271.1366; found: 271.1357; [α]D25.0 185.9° (c 0.31, CHCl3). OTBS H O OH THF, –78 °C (62% yield) OTBS OTBS LDA ethyl diazoacetate N2 MnO 2 EtO 256 O OH 263 OH CH2Cl2, 23°C (93% yield) N2 EtO O O OH 264 To a solution of aldehyde 256 (15.0 mg, 0.0585 mmol, 1.00 equiv) and ethyl diazoacetate (22 µL, 0.205 mmol, 3.50 equiv) in THF (0.60 mL) was added LDA (0.20 M solution in THF; 0.44 mL, 0.088 mmol, 1.50 equiv) at –78 °C. The reaction mixture was stirred for 10 min and quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.00 mL) washed with brine, dried over MgSO4 and concentrated in vacuo to afford alcohol 263, which was used without further purification (13.5 mg, 62% yield). To a solution of alcohol 263 (13.0 mg, 0.0351 mmol, 1.00 equiv) in CH2Cl2 (0.40 mL) was added MnO2 (85%; 72.0 mg, 0.702 mmol, 20.0 equiv) at 23 °C. The reaction 659   mixture was stirred overnight. Solids were removed via a filtration through a celite Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford diazo 264 (12.0 mg, 93% yield). Rf = 0.56 (1:2 EtOAc:hexane); 1H NMR (400 MHz, CDCl3) δ 6.27 (d, J = 2.0 Hz, 1H), 4.79 (ddd, J = 6.9, 5.6, 2.0 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 2.45 (dd, J = 13.0, 6.9 Hz, 1H), 2.01 (dd, J = 13.0, 5.7 Hz, 1H), 1.39 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H), 0.89 (s, 9H), 0.08 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 185.4, 161.4, 145.4, 141.0, 82.3, 73.8, 62.0, 51.7, 27.3, 26.0, 25.8, 18.3, 14.4, -4.5, -4.6; IR (Neat Film NaCl) 3499, 2930, 2857, 2141, 1728, 1471, 1370, 1300, 1259, 1094, 906, 837 cm-1; HRMS (MM: FAB+) m/z calc’d for C17H29O5N2Si [M+H]+: 369.1846; found 369.1845; [α]D25.0 14.2° (c 0.25, CHCl3). OTBS N2 EtO O O OH Rh 2(OAc)4, toluene 110 °C (36% yield) or Rh 2(OAc)4, benzene 80 °C (36% yield) 264 OTBS O O N2 O 266 To a solution of diazo 264 (12.0 mg, 0.0326 mmol, 1.00 equiv) in toluene (0.30 mL), was added dirhodium tetraacetate (0.70 mg, 0.00163 mmol, 0.05 equiv). The solution was refluxed under argon for 10 min. Solids were removed via a filtration through a celite plug (rinsed with EtOAc) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford lactone 266 (4.0 mg, 36% yield). (Similar result was obtained with benzene solvent at 80 °C.) Rf = 0.30 (1:2 EtOAc:hexane); 1H NMR (400 MHz, CDCl3) δ 6.75 (d, J = 1.6 Hz, 1H), 4.85 (ddd, J = 7.1, 6.4, 1.7 Hz, 1H), 2.72 (dd, J = 12.6, 6.4 Hz, 1H), 2.40 – 2.30 660   (m, 1H), 1.58 (s, 3H), 0.90 (s, 9H), 0.11 (d, J = 4.6 Hz, 6H); C NMR (101 MHz, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 13 CDCl3) δ 198.7, 175.1, 142.6, 138.1, 87.6, 73.5, 51.1, 26.9, 25.8, 18.2, 14.3, -4.6, 4.7; IR (Neat Film NaCl) 2953, 2856, 2146, 1713, 1661, 1330, 1302, 1097, 1066, 837 cm-1; HRMS (MM: FAB+) m/z calc’d for C15H23O4N2Si [M+H]+: 323.1427; found 323.1417; [α]D25.0 7.77° (c 0.20, CHCl3). OTBS OTBS 2,2,6,6-tetramethylpiperidine n-BuLi, TESCl O OH 258 THF, –78 °C OTBS m-CPBA, NaHCO 3, H 2O, toluene; TESO OH 267 AcOH, H 2O, THF, 0 → 23 °C (42% yield based on recovered starting material, 2 steps) OH O OH 268 To a solution of 2,2,6,6-tetramethylpiperidine (0.20 mL, 1.19 mmol, 5.00 equiv) in THF (2.40 mL) was added n-BuLi (1.96 M in hexane; 0.61 mL, 1.19 mmol, 5.00 equiv) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C, and TMSCl (0.20 mL, 1.19 mmol, 5.00 equiv) was added at –78 °C. Methyl ketone 258 (50.0 mg, 0.238 mmol, 1.00 equiv) in THF (0.60 mL) was added dropwise at –78 °C. The solution was stirred for 30 min and quenched with Et3N, followed by sat. aq NaHCO3. The aqueous phase was extracted with EtOAc (3 x 3.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was quickly filtered by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford silyl ether 267, which was used without further purification. To a solution of m-CPBA (75%; 50.0 mg, 0.217 mmol, 0.91 equiv) in toluene (3.34 mL) was added NaHCO3 (55.0 mg, 0.651 mmol, 2.74 equiv). The heterogeneous mixture was stirred for 15 min at 23 °C, then H2O (0.56 mL) was added. Silyl ether 267 in toluene (0.50 mL) was added dropwise to the reaction mixture at 0 °C. After the solution was stirred for 45 min at 0 °C, sat. aq NaHCO3 was added and stirred for 10 min at 0 °C. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The 661   combined organic phases were washed with NaHCO3 and brine, dried over MgSO4 Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide and concentrated in vacuo. To the residue dissolved in THF (0.42 mL) and H2O (0.21 mL) was added AcOH (0.21 mL). The mixture was stirred for 2 h at 23 °C. After the solution was diluted with EtOAc and H2O, solid NaHCO3 was added until the gas evolution ceased. The aqueous phase was extracted with EtOAc (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford α-hydoxyketone 268 (12.0 mg, 42% yield based on recovered starting material, 2 steps). Rf = 0.30 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.55 (d, J = 1.9 Hz, 1H), 4.79 (td, J = 6.9, 1.9 Hz, 1H), 4.59 (d, J = 18.6 Hz, 1H), 4.51 (d, J = 18.6 Hz, 1H), 3.12 (s, br, 1H), 2.44 (dd, J = 12.8, 7.0 Hz, 1H), 2.05 – 1.99 (m, 1H), 1.47 (s, 3H), 0.90 (s, 9H), 0.10 (d, J = 4.1 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 198.4, 145.8, 143.8, 80.5, 73.4, 65.8, 50.9, 28.0, 25.9, 18.2, -4.5, -4.6; IR (Neat Film NaCl) 3418, 2929, 2857, 1682, 1361, 1259, 1093, 912, 835 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H27O4Si [M+H]+:287.1679; found: 287.1677; [α]D25.0 78.9° (c 0.10, CHCl3). OTBS OH O OTBS Bz 2O, Et 3N, DMAP OH 268 CH2Cl2 0 → 23 °C (85% yield) BzO O OH 269 To a solution of α-hydroxyketone 268 (9.80 mg, 0.0342 mmol, 1.00 equiv) in CH2Cl2 (0.30 mL) were added DMAP (8.40 mg, 0.0684 mmol, 2.00 equiv) and Et3N (38 µL, 0.274 mmol, 8.00 equiv). The solution was cooled to 0 °C and benzoic anhydride (15.0 mg, 0.0684 mmol, 2.00 equiv) was added in one portion. After 30 min, the 662   solution was warmed to 23 °C and stirred for 2 h. After the reaction was done, water Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide was added. The aqueous phase was extracted with CH2Cl2 (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford benzoate 269 (11.4 mg, 85% yield). Rf = 0.75 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 8.15 – 8.07 (m, 2H), 7.65 – 7.55 (m, 1H), 7.51 – 7.42 (m, 2H), 6.65 (d, J = 1.9 Hz, 1H), 5.30 (d, J = 16.4 Hz, 1H), 5.18 (d, J = 16.4 Hz, 1H), 4.81 (td, J = 7.1, 1.9 Hz, 1H), 2.44 (dd, J = 12.7, 7.0 Hz, 1H), 2.07 – 1.97 (m, 1H), 1.47 (s, 3H), 0.91 (s, 9H), 0.11 (d, J = 4.4 Hz, 6H); 13 C NMR (101 MHz, CDCl3) δ 192.6, 166.0, 145.5, 144.2, 133.6, 130.1, 129.3, 128.7, 80.6, 73.4, 66.3, 50.7, 28.1, 25.9, 18.3, -4.5, -4.6; IR (Neat Film NaCl) 2928, 1728, 1691, 1259, 1098, 836 cm-1; HRMS (MM: FAB+) m/z calc’d for C21H29O5Si [M+H]+H2: 389.1784; found: 389.1783; [α]D25.0 40.9° (c 0.16, CHCl3). OTBS OH O OTBS MsCl, Et 3N OH 268 CH2Cl2 23 °C (71% yield) MsO O OH 270 To a stirred solution of α-hydroxyketone 268 (49.0 mg, 0.171 mmol, 1.00 equiv) in CH2Cl2 (1.71 mL) were added Et3N (72 µL, 0.513 mmol, 3.00 equiv) and MsCl (20 µL, 0.257 mmol, 1.50 equiv) at 0 °C. The solution was stirred at 0 °C for 2 h and quenched with H2O. The aqueous phase was extracted with CH2Cl2 (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford mesylate 270 (44.0 mg, 71% yield). 663   Rf = 0.43 (1:4 EtOAc:hexanes); H NMR (400 MHz, CDCl3) δ 6.58 (d, J = 1.9 Hz, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 1 1H), 5.15 (s, 2H), 4.78 (td, J = 7.0, 1.9 Hz, 1H), 3.23 (s, 3H), 2.44 (dd, J = 12.8, 7.0 Hz, 1H), 2.05 – 1.95 (m, 1H), 1.95 (s, br, 1H), 1.46 (s, 3H), 0.90 (s, 9H), 0.11 (d, J = 4.6 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 191.2, 146.5, 143.8, 80.6, 73.3, 69.8, 50.7, 39.3, 27.9, 25.9, 18.2, -4.5, -4.7; IR (Neat Film NaCl) 2930, 2856, 1693, 1354, 1259, 1173, 1091, 1042, 959, 912, 835, 777 cm-1; HRMS (MM: FAB+) m/z calc’d for C15H27O5SiS [M-OH]•: 347.1348; found: 347.1357; [α]D25.0 36.3° (c 0.12, CHCl3). OTBS OTBS trimethylsulfonium iodide KHMDS + H O OH THF, 0 °C O (35% combined yield, 271a, 271b; 19% yield, 255 ) 256 OTBS + O OH OTBS 271a OH OH 271b OH 255 To a solution of trimethylsulfonium iodide (18.0 mg, 0.0877 mmol, 1.50 equiv) in THF (0.60 mL) was added dry KHMDS (17.0 mg, 0.0877 mmol, 1.50 equiv) in portions over 30 min at 0 °C. The mixture was stirred for 1 h. Then, a solution of aldehyde 256 in THF (0.30 mL) was added to a reaction vessel. The solution was stirred for 30 min and quenched with H2O. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford epoxide 271a and 271b (5.50 mg, 35% yield). See below for characterization data. OTBS OTBS dibromomethane n-BuLi + H O OH 256 THF, –78 → 23 °C O (39% combined yield, 271a, 271b; 34% yield 255 ) OTBS OH 271a OTBS + O OH 271b OH OH 255 664   To a solution of aldehyde 256 (155 mg, 0.604 mmol, 1.00 equiv) and Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide dibromomethane (51.0 µL, 0.725 mmol, 1.20 equiv) in THF (3.02 mL) was added nBuLi (2.4 M solution in hexane; 0.28 mL, 0.665 mmol, 1.10 equiv) dropwise over 30 min at –78 °C. The reaction mixture was slowly warmed to 23 °C and stirred overnight. Then, the reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 3.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford epoxide 271a and 271b (64.0 mg, 39% yield). Rf = 0.56 (1:2 EtOAc:hexanes); Diastereomer 1: 1H NMR (400 MHz, CDCl3) δ 5.72 (dd, J = 2.2, 1.0 Hz, 1H), 4.61 (ddd, J = 6.5, 3.8, 2.3 Hz, 1H), 3.55 (ddt, J = 4.3, 2.7, 0.8 Hz, 1H), 2.97 (dd, J = 6.0, 4.2 Hz, 1H), 2.74 (dd, J = 6.0, 2.7 Hz, 1H), 2.36 (dd, J = 13.5, 6.5 Hz, 1H), 2.06 (d, J = 15.5 Hz, 1H), 1.89 (dd, J = 13.5, 3.8 Hz, 1H), 1.37 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 148.4, 131.1, 81.3, 73.3, 52.6, 49.7, 48.2, 26.1, 26.0, 18.3, -4.6; IR (Neat Film NaCl) 3408, 2929, 2856, 1361, 1252, 1085, 835 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H25O3Si [M+H]+H2: 269.1573; found: 269.1568; [α]D25.0 44.7° (c 0.08, CHCl3). Diastereomer 2: 1H NMR (400 MHz, CDCl3) δ 5.71 (dd, J = 2.1, 1.0 Hz, 1H), 4.65 (dddd, J = 6.4, 4.4, 2.1, 1.1 Hz, 1H), 3.50 (ddt, J = 3.7, 2.7, 1.0 Hz, 1H), 3.04 (dd, J = 5.7, 4.2 Hz, 1H), 2.88 (dd, J = 5.7, 2.7 Hz, 1H), 2.44 (dd, J = 13.3, 6.5 Hz, 1H), 2.15 (s, 1H), 1.90 (dd, J = 13.3, 4.4 Hz, 1H), 1.44 (s, 3H), 0.90 (s, 9H), 0.09 (d, J = 1.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 148.2, 131.1, 81.1, 73.2, 52.8, 49.5, 47.5, 26.1, 26.0, 18.3, -4.6; IR (Neat Film NaCl) 2956, 2929, 2856, 1361, 1253, 1086, 836, 776 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H25O3Si [M+H]+-H2: 269.1573; found: 269.1577; [α]D25.0 11.5° (c 0.15, CHCl3). 665   Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide OTBS OTBS MgI 2 O OH 271 TESCl, imidazole DMAP HO THF, 40 °C (63% yield) I OTBS HO 273 CH2Cl2, 23 °C (89% yield) TESO I HO 274 To a solution of epoxide 271 (64.0 mg, 0.237 mmol, 1.00 equiv) in THF (1.19 mL) was added MgI2 (69.0 mg, 0.248 mmol, 1.05 equiv). The reaction mixture was stirred overnight at 40 °C and then quenched with H2O. The aqueous phase was extracted with EtOAc (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford iodohydrin 273 (59.0 mg, 63% yield). To a solution of iodohydrin 273 (13.5 mg, 0.0338 mmol, 1.00 equiv) in CH2Cl2 (0.20 mL) were added imidazole (11.5 mg, 0.169 mmol, 5.00 equiv), DMAP (0.20 mg, 0.0016 mmol, 0.05 equiv), and TESCl (6.20 µL, 0.0371 mmol, 1.10 equiv). The reaction mixture was stirred overnight at 23 °C and then H2O was added. The aqueous phase was extracted with CH2Cl2 (3 x 0.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford silyl ether 274 (11.5 mg, 89% yield). Rf = 0.80 (1:4 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 5.89 (ddd, J = 2.1, 1.3, 0.5 Hz, 1H), 4.57 (dtd, J = 5.4, 3.0, 1.4 Hz, 1H), 4.30 (ddt, J = 6.5, 3.9, 1.3 Hz, 1H), 3.59 (dd, J = 10.2, 3.8 Hz, 1H), 3.35 (dd, J = 10.2, 6.4 Hz, 1H), 2.26 – 2.20 (m, 1H), 1.91 – 1.84 (m, 1H), 1.33 (s, 3H), 0.99 – 0.95 (m, 9H), 0.88 (s, 9H), 0.65 – 0.60 (m, 6H), 0.08 (d, J = 0.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 151.8, 132.3, 80.6, 72.8, 69.2, 52.5, 26.0, 25.4, 18.2, 15.4, 7.1, 5.0, -4.4, -4.6; IR (Neat Film NaCl) 2955, 1256, 666   1088, 836, 740 cm ; HRMS (MM: FAB+) m/z calc’d for C20H40O3Si2I [M+H] -H2: Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide -1 + 511.1561; found: 511.1573; [α]D25.0 4.31° (c 0.20, CHCl3). OTBS TESO I OTBS NaH THF, 23 °C (60% yield) HO TESO O 274 275 To a solution of NaH (60%, 1.00 mg, 0.0246 mmol, 1.10 equiv) in THF (1.12 mL) was added silyl ether 274 (11.5 mg, 0.0224 mmol, 1.00 equiv) in THF (0.50 mL) at 23 °C. The solution was stirred overnight and then H2O was added. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:8 EtOAc:hexanes) on silica gel to afford ether 275 (5.20 mg, 60% yield). Rf = 0.23 (1:8 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 5.56 (dd, J = 2.2, 1.1 Hz, 1H), 4.99 (dddd, J = 7.4, 5.4, 3.2, 1.1 Hz, 1H), 4.84 (tdd, J = 7.5, 3.2, 2.2 Hz, 1H), 4.16 (t, J = 7.9 Hz, 1H), 3.56 (dd, J = 8.2, 7.2 Hz, 1H), 2.40 (dd, J = 11.5, 5.4 Hz, 1H), 2.00 (ddd, J = 11.5, 7.3, 1.0 Hz, 1H), 1.21 (d, J = 0.9 Hz, 3H), 0.97 (t, J = 8.0 Hz, 9H), 0.90 (s, 9H), 0.68 – 0.52 (m, 6H), 0.10 – 0.06 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 153.1, 126.0, 89.1, 79.3, 73.6, 68.2, 54.4, 26.0, 6.9, 4.8, -4.5; IR (Neat Film NaCl) 2955, 2927, 2875, 2360, 1459, 1256, 1089, 835 cm-1; HRMS (MM: FAB+) m/z calc’d for C20H39O3Si2 [M+H]+-H2: 383.2438; found: 383.2409; [α]D25.0 12.7° (c 0.15, CHCl3). OTBS OTBS PPTS TESO O 275 EtOH, 23 °C (45% yield) HO O 276 667   To a solution of ether 275 (5.10 mg, 0.0132 mmol, 1.00 equiv) in EtOH (0.13 mL) Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide was added PPTS (0.30 mg, 0.00132 mmol, 0.10 equiv) and stirred at 23 °C for 30 min. The reaction was quenched with sat. aq NaHCO3 and the aqueous phase was extracted with EtOAc (3 x 0.70 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford alcohol 276 (1.61 mg, 45% yield). Rf = 0.23 (1:8 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 5.66 (dd, J = 2.2, 1.2 Hz, 1H), 5.14 – 5.03 (m, 1H), 4.86 (m, br, 1H), 4.35 (dd, J = 9.4, 7.5 Hz, 1H), 3.69 (dd, J = 9.4, 5.5 Hz, 1H), 2.43 (dd, J = 11.7, 5.5 Hz, 1H), 2.02 (ddd, J = 11.7, 7.3, 1.0 Hz, 1H), 1.22 (s, 3H), 0.90 (s, 9H), 0.09 (d, J = 5.8 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 154.7, 126.3, 90.2, 79.9, 75.1, 68.6, 54.0, 26.0, 24.1, -4.5, -4.6; IR (Neat Film NaCl) 2929, 2857, 1361, 1256, 1084, 835, 776 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H27O3Si [M+H]+: 271.1730; found: 271.1734; [α]D25.0 33.7° (c 0.06, CHCl3). OTBS OTBS vinylmagnesium bromide H O OH 256 THF, –78 °C (84% yield; 99% yield based on recovered starting material) OTBS MnO 2 OH OH 284 CH2Cl2, 23 °C (63% yield) O OH 285 A flame-dried flask was charged with aldehyde 256 (399 mg, 1.56 mmol, 1.00 equiv) and THF (7.80 mL). Then, vinylmagnesium bromide (1.0 M solution in THF; 20.5 mL, 20.3 mmol, 13.0 equiv) was added to the solution at –78 °C and stirred for 3 h. The reaction was quenched with sat. aq NH4Cl and the aqueous phase was extracted with EtOAc (3 x 10.0 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column 668   chromatography (1:2 EtOAc:hexanes) on silica gel to afford allyl alcohol 284 (371 Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide mg, 84% yield). To a solution of allyl alcohol 284 (371 mg, 1.30 mmol, 1.00 equiv) in CH2Cl2 (13.0 mL) was added MnO2 (85%; 4.00 g, 39.1 mmol, 30.0 equiv). The mixture was stirred for 12 h. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford vinyl ketone 285 (230 mg, 63% yield). Rf = 0.55 (1:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.88 (dd, J = 17.1, 10.5 Hz, 1H), 6.60 (d, J = 1.9 Hz, 1H), 6.35 (dd, J = 17.1, 1.6 Hz, 1H), 5.80 (dd, J = 10.5, 1.6 Hz, 1H), 4.79 (td, J = 7.1, 1.9 Hz, 1H), 3.67 (s, 1H), 2.44 (dd, J = 12.7, 7.0 Hz, 1H), 2.04 (ddd, J = 12.6, 7.1, 0.9 Hz, 1H), 1.46 (s, 3H), 0.91 (s, 9H), 0.11 (d, J = 4.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 189.7, 147.0, 145.9, 132.3, 129.4, 80.4, 73.2, 51.0, 28.2, 25.9, 18.3, -4.4, -4.6; IR (Neat Film NaCl) 2955, 2929, 2856, 1658, 1605, 1361, 1259, 1091, 911, 837, 777 cm-1; HRMS (MM: FAB+) m/z calc’d for C15H25O3Si [M+H]+-H2: 281.1573; found: 281.1569; [α]D25.0 33.3° (c 0.06, CHCl3). OTBS OH TBAF O OH 285 THF, 23 °C (46% yield) O OH 281 To a solution of ketone 285 (22.1 mg, 0.0782 mmol, 1.00 equiv) in THF (0.80 mL) was added TBAF (1.0 M solution in THF; 0.16 mL, 0.156 mmol, 2.00 equiv) at 23 °C and stirred for 30 min. The reaction was quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was 669   purified by column chromatography (1:1 EtOAc:hexanes) on silica gel to afford diol Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 281 (6.00 mg, 46% yield). Rf = 0.15 (1:1 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.84 (dd, J = 17.1, 10.5 Hz, 1H), 6.68 (d, J = 2.1 Hz, 1H), 6.36 (dd, J = 17.1, 1.5 Hz, 1H), 5.85 (dd, J = 10.5, 1.6 Hz, 1H), 4.82 (ddd, J = 7.4, 5.8, 2.1 Hz, 1H), 3.62 (s, br, 1H), 2.51 (dd, J = 13.4, 7.1 Hz, 1H), 2.01 (dd, J = 13.4, 5.7 Hz, 1H), 1.48 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 190.3, 148.2, 144.3, 132.6, 130.0, 81.2, 73.5, 50.2, 27.7; IR (Neat Film NaCl) 2922, 1657, 1605, 1407, 1264, 1223, 1148, 1067, 961, 796 cm-1; HRMS (MM: FAB+) m/z calc’d for C9H13O3 [M+H]+: 169.0865; found: 169.0864; [α]D25.0 25.8° (c 0.10, CHCl3). O OH vinylmagnesium bromide H CO2Me THF, –78 °C (66% yield; 88% yield based on recovered starting material) 250 CO2Me 286 To a stirred solution of aldehyde 250 (300 mg, 1.53 mmol, 1.00 equiv) in THF (15.3 mL) was added vinylmagnesium bromide (1.0 M solution in THF; 2.29 mmol, 1.50 equiv) at –78 °C. The reaction was stirred for 1 h at –78 °C and quenched with sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 6.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford allyl alcohol 286 (227 mg, 66% yield). Rf = 0.32 (1:4 EtOAc:hexanes); (due to the presence of diastereomeric mixtures, the 1 H NMR and 13C NMR contained extra peaks. See the attached spectrum) 1H NMR (500 MHz, CDCl3) δ 6.23 – 6.14 (m, 2H), 5.92 – 5.82 (m, 2H), 5.82 – 5.77 (m, 2H), 5.23 (ddt, J = 17.2, 5.0, 1.5 Hz, 2H), 5.10 (ddt, J = 13.4, 10.4, 1.4 Hz, 2H), 4.86 – 670   4.74 (m, 4H), 4.17 (q, J = 6.7 Hz, 1H), 4.13 – 4.07 (m, 1H), 3.71 – 3.68 (m, 6H), 2.91 Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide – 2.81 (m, 1H), 2.76 (ddd, J = 7.3, 6.2, 1.8 Hz, 2H), 2.69 – 2.62 (m, 1H), 2.54 (dtd, J = 9.8, 7.6, 4.6 Hz, 2H), 2.37 (ddd, J = 15.1, 9.2, 5.8 Hz, 1H), 1.65 (dq, J = 1.5, 0.8 Hz, 3H), 1.63 – 1.51 (m, 5H); 13C NMR (126 MHz, CDCl3) δ 167.0, 149.1, 149.0, 147.1, 146.5, 141.5, 140.9, 119.9, 115.2, 114.3, 113.2, 112.6, 71.6, 70.9, 51.3, 51.2, 44.2, 40.7, 40.2, 32.9, 32.1, 18.6, 18.2; IR (Neat Film NaCl) 2929, 1722, 1644, 1439, 1202, 1168, 1124, 993 cm-1; HRMS (MM: FAB+) m/z calc’d for C13H21O3 [M+H]+: 225.1491; found: 225.1491. OH O MnO 2 CO2Me CH2Cl2, 23 °C (85% yield) 286 CO2Me 287 To a solution of allyl alcohol 286 (10.0 mg, 0.0446 mmol, 1.00 equiv) in CH2Cl2 (0.45 mL) was added MnO2 (85%; 182 mg, 1.78 mmol, 40.0 equiv). The mixture was stirred for 12 h at 23 °C. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:6 EtOAc:hexanes) on silica gel to afford ketone 287 (8.41 mg, 85% yield). See below for characterization data. OH O DMSO, oxalyl chloride, Et 3N CH2Cl2, –78 °C (97% yield) CO2Me 286 CO2Me 287 To a stirred solution of oxalyl chloride (29 µL, 0.335 mmol, 1.50 equiv) in CH2Cl2 (1.10 mL) was added DMSO (47 µL, 0.669 mmol, 3.00 equiv) at –78 °C. The 671   solution was stirred for 15 min, then alcohol 286 (50.0 mg, 0.223 mmol, 1.00 equiv) Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide in CH2Cl2 (0.6 mL) was added at –78 °C. The mixture was stirred for 3 h and 30 min at –78 °C, and then Et3N (0.22 mL, 1.56 mmol, 7.00 equiv) was added. After 90 min at –78 °C, the solution was slowly warmed to 23 °C over 30 min and H2O was added. The aqueous phase was extracted with CH2Cl2 (3 x 2.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:6 EtOAc:hexanes) on silica gel to afford ketone 287 (47.9 mg, 97% yield). Rf = 0.55 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.34 (dd, J = 17.7, 10.4 Hz, 1H), 6.23 – 6.12 (m, 2H), 5.84 – 5.78 (m, 2H), 4.78 (p, J = 1.5 Hz, 1H), 4.74 (dt, J = 1.7, 0.8 Hz, 1H), 3.70 (s, 3H), 2.88 – 2.77 (m, 3H), 2.73 – 2.61 (m, 2H), 1.69 (dd, J = 1.5, 0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 199.6, 166.9, 148.4, 146.1, 136.8, 128.4, 120.4, 112.3, 51.2, 43.5, 42.2, 32.4, 19.6; IR (Neat Film NaCl) 2950, 1716, 1645, 1439, 1407, 1204, 1173, 992, 895, 818 cm-1; HRMS (MM: FAB+) m/z calc’d for C13H19O3 [M+H]+: 223.1334; found: 223.1325; [α]D25.0 –0.98° (c 0.28, CHCl3). O O OMe LiOH CO2Me 287 THF, MeOH, H 2O, 23 °C (55% yield) CO2Me 288 To a solution of ester 287 (10.0 mg, 0.0449 mmol, 1.00 equiv) in THF (0.50 mL) was added a solution of LiOH (2.20 mg, 0.0898 mmol, 2.00 equiv) in H2O (0.20 mL). After 2 h at 23 °C, the aqueous phase was extracted with EtOAc (3 x 1.00 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 672   EtOAc:hexanes) on silica gel to afford Michael adduct 288 (6.28 mg, 55% yield). See Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide below for characterization data. O O OMe K 2CO3 CO2Me MeOH, H 2O, 23 °C (53% yield) CO2Me 287 288 To a stirred solution of ester 287 (6.80 mg, 0.00306 mmol, 1.00 equiv) in MeOH (0.10 mL) and H2O (0.10 mL) was added K2CO3 (17.0 mg, 0.122 mmol, 4.00 equiv). After 7 h, the aqueous phase was extracted with EtOAc (3 x 0.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford Michael adduct 288 (4.11 mg, 53% yield). Rf = 0.25 (1:4 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 6.14 (dt, J = 11.6, 7.1 Hz, 1H), 5.80 (dt, J = 11.6, 1.7 Hz, 1H), 4.78 (p, J = 1.5 Hz, 1H), 4.77 – 4.70 (m, 1H), 3.70 (s, 3H), 3.61 (t, J = 6.3 Hz, 2H), 3.31 (s, 3H), 2.88 – 2.71 (m, 3H), 2.63 (t, J = 6.3 Hz, 2H), 2.61 – 2.45 (m, 2H), 1.68 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 208.0, 166.9, 148.4, 146.2, 120.3, 112.2, 67.6, 59.0, 51.2, 47.3, 43.3, 41.8, 32.3, 19.6; IR (Neat Film NaCl) 2922, 1719, 1646, 1438, 1203, 1172, 1117, 894, 820 cm-1; HRMS (MM: FAB+) m/z calc’d for C14H23O4 [M+H]+: 255.1596; found: 255.1604; [α]D25.0 – 3.01° (c 0.36, CHCl3). OTBS H O OH 256 OTBS OTBS ethynylmagnesium bromide MnO 2 THF, –78 °C (90% yield, 94% yield based on recovered starting material) CH2Cl2, 23 °C (68% yield) OH OH 293 O OH 294 673   A flame-dried flask was charged with aldehyde 256 (53.4 mg, 0.208 mmol, 1.00 Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide equiv) and THF (1.04 mL). Then, ethynylmagnesium bromide (0.4M solution in THF; 5.20 mL, 2.08 mmol, 10.0 equiv) was added at –78 °C and stirred for 3 h. The reaction mixture was slowly warmed to 23 °C and stirred for 5 h. The reaction was quenched by adding sat. aq NH4Cl. The aqueous phase was extracted with EtOAc (3 x 1.50 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (1:2 EtOAc:hexanes) on silica gel to afford diol 293 (53.0 mg, 90% yield). To a solution of diol 293 (11.1 mg, 0.0392 mmol, 1.00 equiv) in CH2Cl2 (0.40 mL) was added MnO2 (85%; 52.0 mg, 0.510 mmol, 13.0 equiv). The mixture was stirred for 12 h. Solids were removed via a filtration through a celite plug (rinsed with CH2Cl2) and the resulting solution was concentrated under reduced pressure. The residue was purified by column chromatography (1:4 EtOAc:hexanes) on silica gel to afford ketone 294 (7.50 mg, 68% yield). Rf = 0.56 (1:2 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 6.89 (d, J = 1.9 Hz, 1H), 4.79 (tdd, J = 7.2, 1.9, 0.7 Hz, 1H), 3.29 (s, 1H), 3.09 (s, 1H), 2.47 (dd, J = 12.8, 7.0 Hz, 1H), 2.07 (ddt, J = 12.8, 7.1, 0.8 Hz, 1H), 1.58 (s, br, 1H), 1.46 (s, 3H), 0.91 (s, 9H), 0.11 (d, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 176.1, 151.9, 147.9, 79.9, 79.5, 79.3, 72.9, 51.5, 27.8, 25.9, 18.2, -4.6; IR (Neat Film NaCl) 2929, 2955, 2857, 2097, 1638, 1361, 1272, 1259, 1209, 1093, 837, 777 cm-1; HRMS (MM: ESIAPCI+) m/z calc’d for C15H25O3Si [M+H]+: 281.1567; found: 281.1569; [α]D25.0 13.3° (c 0.06, CHCl3). Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide 5.5. 674   References and Notes                                                                                                                 (1)  Duh, C.-Y.; Wang, S.-K.; Chia, M.-C.; Chiang, M. Y. Tetrahedron Lett. 1999, 40, 6033–6035.   (2) Ineleganolide was also isolated from different soft coral species: (a) Thao, N. P.; Nam, N. H.; Cuong, N. X.; Quang, T. H.; Tung, P. T.; Dat, L. D.; Chae, D.; Kim, S.; Koh, Y.-S.; Kiem, P. V.; Minh, C. V.; Kim, Y. H. Bioorg. Med. Chem. Lett. 2013, 23, 228–231. (b) Ahmed, A. F.; Shine, R.-T.; Wang, G.-H.; Dai, C.-F.; Kuo, Y.-H.; Sheu, J.-H. Tetrahedron 2003, 59, 7337–7344. (3) The absolute stereochemistry has yet to be confirmed. (4) (a) Li, Y.; Pattenden, G. Nat. Prod. Rep. 2011, 28, 429–440. (b) Li, Y.; Pattenden, G. Nat. Prod. Rep. 2011, 28, 1269–1310. (c) Chen, W.; Li, Y.; Guo, Y. Acta Pharm. Sin. B 2012, 2, 227–237. (5) Li, Y.; Pattenden, G. Tetrahedron 2011, 67, 10045–10052. (6) (a) Craig, R. A., II Ph.D. Thesis, California Institute of Technology, Pasadena, CA, May 2015. (b) Roizen, J. L. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, Nov 2009. (c) Tang, F. Thesis, Washington University, St. Louis, MO, May 2009. (d) Liu, G.; Romo, D. Abstracts of Papers, 237th ACS National Meeting, Salt Lake City, UT, Mar 22–26, 2009; American Chemical Society, 2009; ORGN083. (e) O’Connell, C. E.; Frontier, A. J. Abstracts of Papers, 32nd Northeast Regional Meeting of the American Chemical Society, Rochester, NY, Oct 31–Nov 3, 2004; American Chemical Society, 2004, GEN-088. (f) Horn, E. J.; Silverston, J. S.; Vanderwal, C. D. J. Org. Chem. 2016, DOI: 10.1021/acs.joc.5b02550. (7) (a) González, M. A.; Ghosh, S.; Rivas, F.; Fischer, D.; Theodorakis, E. A. Tetrahedron Lett. 2004, 45, 5039–5041. (b) Weinstabl, H.; Gaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834–2837. 675                                                                                                                                                                                                                                                                                                                               (8) For a synthetic procedure of phosphonates, see: Messik, F.; Oberthür, M. Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Synthesis 2013, 45, 167–170. (9) (a) Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5–8. (b) Danishefsky, S. J.; DeNinno, M. P.; Chen, S.-h. J. Am. Chem. Soc. 1988, 110, 3929–3940. (c) Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942–10953. (d) Panek, J. S.; Xu, F.; Rondón, A. C. J. Am. Chem. Soc. 1998, 120, 4113–4122. (10) (a) Ando, K. J. Org. Chem. 1997, 62, 1934–1939. (b) Ando, K. J. Org. Chem. 1999, 64, 8406–8408. (c) Ando, K. J. Org. Chem. 2000, 65, 4745–4749. (11) Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 3995–3998. (12) (a) Frontier, A. J.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151–6159. (b) Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2000, 122, 10482–10483. (13) Craig, R. A., II.; Roizen, J. L.; Smith, R. C.; Jones, A. C.; Stoltz, B. M. Org. Lett. 2012, 14, 5716–5719. (14) (a) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959–1964. (b) Arthuis, M.; Beaud, R.; Gandon, V.; Roulland, E. Angew. Chem., Int. Ed. 2012, 51, 10510–10514. (c) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279–9282. (15) Treatment of TMS-diazomethane to acid chloride 262 afforded only methyl ester 299. OTBS HO oxalyl chloride Et 3N TMS-diazomethane Cl MeCN, THF, 0 °C DMF, CH2Cl2, 0 °C O OH OTBS OTBS O OH MeO O OH 299     (16) Addition of diazomethane to intermediate 261 furnished cyclopropane 300. 260 262 676                                                                                                                                                                                                                                                                                                                               Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide OTBS OTBS OTBS Et 3N, ethyl chloroformate HO THF, –10 °C O N2 diazomethane EtO OH O Et 2O, 0 °C O O 260 O OH OH 259 261 (Not observed) OTBS H diazomethane O Et 2O, 0 °C N2 OH 300 (17) (a) Radosevich, A. T.; Chan, V. S.; Shih, H.-W.; Toste, F. D. Angew. Chem., Int. Ed. 2008, 47, 3755–3758. (b) Lam, S. K.; Chiu, P. Chem. Eur. J. 2007, 13, 9589– 9599. (c) Anderluh, M.; Cesar, J.; Štefanič, P.; Kikelj, D.; Janeš, D.; Murn, J.; Nadrah, K.; Tominc, M.; Addicks, E.; Giannis, A.; Stegnar, M.; Dolenc, M. S. Eur. J. Med. Chem. 2005, 40, 25–49. (d) Cesar, J.; Dolenc, M. S.; Tetrahedron Lett. 2001, 42, 7099–7102. (18) (a) Jones, K.; Toutounji, T. Tetrahedron 2001, 57, 2427–2431. (b) Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetrahedron Lett. 1997, 38, 3837–3840. (c) Ziegler, F. E.; Berlin, M. Y.; Lee, K.; Looker, A. R. Org. Lett. 2000, 2, 3619–3621. (d) Calter, M.; Zhu, C. J. Org. Chem. 1999, 64, 1415–1419. (19) (a) Sakai, T.; Matsushita, S.; Arakawa, S.; Kawai, A.; Mori, Y. Tetrahedron Lett. 2014, 55, 6557–6560. (b) Sakai, T; Asano, H.; Fukukawa, K.; Oshima, R.; Mori, Y. Org. Lett. 2014, 16, 2268–2271. (c) Sakai, T.; Sugimoto, A.; Tatematsu, H.; Mori, Y. J. Org. Chem. 2012, 77, 11177–11191. (20) Attempted etherifications of α-bromoketone 301, which was prepared from αhydroxyketone 268, was also unsuccessful.   OTBS OH O OH 268 OTBS OTBS PPh 3, CBr4 CH2Cl2, 0 °C (98% yield) Br bases O OH 301 O O 245 (Not observed)   677                                                                                                                                                                                                                                                                                                                               (21) (a) Garcia, J. A. O. Thesis, The University of British Columbia, Vancouver, Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Canada, Oct 2003. (b) Ebner, C.; Müller, C. A.; Markert, C.; Pfaltz, A. J. Am. Chem. Soc. 2011, 133, 4710–4713. (22) Lautens, M.; Maddess, M. L.; Sauer, E. L. O.; Ouellet, S. G. Org. Lett. 2002, 4, 83–86. (23) (a) Sabitha, G.; Rao, V. R. S.; Sudhakar, K.; Kumar, M. R.; Reddy, E. V.; Yadav, J. S. J. Mol. Catal. A: Chem. 2008, 280, 16–19. (b) Aho, J. E.; Salomäki, E.; Rissanen, K.; Pihko, P. M. Org. Lett. 2008, 10, 4179–4182. (c) Kumaran, R. S.; Mehta, G. Tetrahedron 2015, 71, 1718–1731. (24) Karikomi, M.; Watanabe, S.; Kimura, Y.; Uyehara, T. Tetrahedron Lett. 2002, 43, 1495–1498. (25) Only ketone 258 was observed when the reaction was conducted at 80 °C. (26) Attempts on direct intramolecular etherification of iodohydrin 273 under basic conditions failed to produce 276. In addition, oxidation of iodohydrin 273 with MnO2 produced complex mixtures of byproducts. OTBS OTBS bases HO HO I HO O 273 276 OTBS OTBS MnO 2 HO O CH2Cl2, 23 °C I HO I HO     (27) Because oxidation of secondary alcohol 276 with MnO2 was conducted on small 273 302 scale, the amount of the obtained ketone 245 was too little to be characterized by NMR analysis. (28) Nevar, N. M.; Kel’in, A. V.; Kulinkovich, O. L. Synthesis 2000, 9, 1259–1262. 678                                                                                                                                                                                                                                                                                                                               (29) (a) Trost, B. M.; Stiles, D. T. Org. Lett. 2007, 9, 2763–2766. (b) Trost, B. M.; Chapter 5 – Synthetic Studies Toward Polycyclic Ineleganolide Waser, J.; Meyer, A. J. Am. Chem. Soc. 2008, 130, 16424–16434. (c) Otera, J.; Danoh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307–5311. (30) An attempt to oxidize secondary alcohol 303, which was prepared by hydrolysis of ester 286 using Swern oxidation conditions, caused lactonization to give 305 instead of the desired 304. OH OH O DMSO, oxalyl chloride Et 3N LiOH THF, MeOH, H 2O (98% yield) CH2Cl2, –78 °C CO2Me CO2H 286 CO2H 303 304 DMSO, oxalyl chloride Et 3N O O CH2Cl2, –78 °C (72% yield)     (31) (a) Lin, J.-W.; Kurniawan, Y. D.; Chang, W.-J.; Leu, W.-J.; Chan, S.-H.; Hou, 305 D.-R. Org. Lett. 2014, 16, 5328–5331. (b) Aho, J. E.; Piisola, A.; Krishnan, K. S.; Pihko, P. M. Eur. J. Org. Chem. 2011, 9, 1682–1694. (c) Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513–5516. (32) Silyl ether 296 was prepared from diol 293 with TESCl. OTBS OTBS TESCl, imidazole, DMAP OH OH 293 CH2Cl2 (85% yield) TESO OH 296   Appendix 13 – Spectra Relevant to Chapter 5 679 APPENDIX 13 Spectra Relevant to Chapter 5: Synthetic Studies Toward Polycyclic Ineleganolide 248 CO2Me OMe OMe                                                                                                   680   Figure A13.1. 1H NMR (400 MHz, CDCl3) of compound 248. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.2. Infrared spectrum (Thin Film, NaCl) of compound 248.  Figure A13.3. 13C NMR (101 MHz, CDCl3) of compound 248.   681   CO2Me 251 OH                                                                                                   682   Figure A13.4. 1H NMR (400 MHz, CDCl3) of compound 251. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.5. Infrared spectrum (Thin Film, NaCl) of compound 251.  Figure A13.6. 13C NMR (101 MHz, CDCl3) of compound 251.   683   252 CO2Me O                                                                                                   684   Figure A13.7. 1H NMR (400 MHz, CDCl3) of compound 252. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.8. Infrared spectrum (Thin Film, NaCl) of compound 252.  Figure A13.9. 13C NMR (101 MHz, CDCl3) of compound 252.   685   254 CO2Me OH O                                                                                                   686   Figure A13.10. 1H NMR (400 MHz, CDCl3) of compound 254. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.11. Infrared spectrum (Thin Film, NaCl) of compound 254.  Figure A13.12. 13C NMR (101 MHz, CDCl3) of compound 254.   687   CO2Me 244b Br O                                                                                                   688   Figure A13.13. 1H NMR (400 MHz, CDCl3) of compound 244b. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.14. Infrared spectrum (Thin Film, NaCl) of compound 244b.  Figure A13.15. 13C NMR (101 MHz, CDCl3) of compound 244b.   689   HO O 260 OH OTBS                                                                                                   690   Figure A13.16. 1H NMR (400 MHz, CDCl3) of compound 260. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.17. Infrared spectrum (Thin Film, NaCl) of compound 260.  Figure A13.18. 13C NMR (101 MHz, CDCl3) of compound 260.   691   O EtO 264 O OH OTBS N2                                                                                                   692   Figure A13.19. 1H NMR (400 MHz, CDCl3) of compound 264. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.20. Infrared spectrum (Thin Film, NaCl) of compound 264.  Figure A13.21. 13C NMR (101 MHz, CDCl3) of compound 264.   693   N2 O 266 O O OTBS                                                                                                   694   Figure A13.22. 1H NMR (400 MHz, CDCl3) of compound 266. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.23. Infrared spectrum (Thin Film, NaCl) of compound 266.  Figure A13.24. 13C NMR (101 MHz, CDCl3) of compound 266.   695   O 268 OH OTBS OH                                                                                                   696   Figure A13.25. 1H NMR (400 MHz, CDCl3) of compound 268. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.26. Infrared spectrum (Thin Film, NaCl) of compound 268.  Figure A13.27. 13C NMR (101 MHz, CDCl3) of compound 268.   697   O 269 OH OTBS BzO                                                                                                   698   Figure A13.28. 1H NMR (400 MHz, CDCl3) of compound 269. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.29. Infrared spectrum (Thin Film, NaCl) of compound 269.  Figure A13.30. 13C NMR (101 MHz, CDCl3) of compound 269.   699   O 270 OH OTBS MsO                                                                                                   700   Figure A13.31. 1H NMR (400 MHz, CDCl3) of compound 270. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.32. Infrared spectrum (Thin Film, NaCl) of compound 270.  Figure A13.33. 13C NMR (101 MHz, CDCl3) of compound 270.   701   271a OH O OTBS                                                                                                   702   Figure A13.34. 1H NMR (400 MHz, CDCl3) of compound 271a. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.35. Infrared spectrum (Thin Film, NaCl) of compound 271a.  Figure A13.36. 13C NMR (101 MHz, CDCl3) of compound 271a.   703   271b OH O OTBS                                                                                                   704   Figure A13.37. 1H NMR (400 MHz, CDCl3) of compound 271b. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.38. Infrared spectrum (Thin Film, NaCl) of compound 271b.  Figure A13.39. 13C NMR (101 MHz, CDCl3) of compound 271b.   705   I TESO 274 HO OTBS                                                                                                   706   Figure A13.40. 1H NMR (500 MHz, CDCl3) of compound 274. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.41. Infrared spectrum (Thin Film, NaCl) of compound 274.  Figure A13.42. 13C NMR (126 MHz, CDCl3) of compound 274.   707   TESO 275 O OTBS                                                                                                   708   Figure A13.43. 1H NMR (400 MHz, CDCl3) of compound 275. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.44. Infrared spectrum (Thin Film, NaCl) of compound 275.  Figure A13.45. 13C NMR (101 MHz, CDCl3) of compound 275.   709   HO 276 O OTBS                                                                                                   710   Figure A13.46. 1H NMR (400 MHz, CDCl3) of compound 276. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.47. Infrared spectrum (Thin Film, NaCl) of compound 276.  Figure A13.48. 13C NMR (101 MHz, CDCl3) of compound 276.   711   285 OH O OTBS                                                                                                   712   Figure A13.49. 1H NMR (400 MHz, CDCl3) of compound 285. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.50. Infrared spectrum (Thin Film, NaCl) of compound 285.  Figure A13.51. 13C NMR (101 MHz, CDCl3) of compound 285.   713   OH 281 O OH                                                                                                   714   Figure A13.52. 1H NMR (400 MHz, CDCl3) of compound 281. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.53. Infrared spectrum (Thin Film, NaCl) of compound 281.  Figure A13.54. 13C NMR (101 MHz, CDCl3) of compound 281.   715   CO2Me 286 OH                                                                                                   716   Figure A13.55. 1H NMR (500 MHz, CDCl3) of compound 286. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.56. Infrared spectrum (Thin Film, NaCl) of compound 286.  Figure A13.57. 13C NMR (126 MHz, CDCl3) of compound 286.   717   287 CO2Me O                                                                                                   718   Figure A13.58. 1H NMR (400 MHz, CDCl3) of compound 287. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.59. Infrared spectrum (Thin Film, NaCl) of compound 287.  Figure A13.60. 13C NMR (101 MHz, CDCl3) of compound 287.   719   288 CO2Me OMe O                                                                                                   720   Figure A13.61. 1H NMR (400 MHz, CDCl3) of compound 288. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5                                                                                                   Figure A13.62. Infrared spectrum (Thin Film, NaCl) of compound 288.  Figure A13.63. 13C NMR (101 MHz, CDCl3) of compound 288.   721   294 OH O OTBS                                                                                                   722   Figure A13.64. 1H NMR (500 MHz, CDCl3) of compound 294. Appendix 13 – Spectra Relevant to Chapter 5 Appendix 13 – Spectra Relevant to Chapter 5     Figure A13.65. Infrared spectrum (Thin Film, NaCl) of compound 294.  Figure A13.66. 13C NMR (126 MHz, CDCl3) of compound 294.   723    Appendix 14 – Notebook Cross-Reference for New Compounds 724     APPENDIX 14 Notebook Cross-Reference for New Compounds A14.1. Contents The following notebook cross-reference has been included to facilitate access to the original spectroscopic data obtained for the compounds presented within this thesis. The information is organized by chapter and sequentially by compound number, noting the instrument on which the primary NMR data was collected. All 1H NMR, 13C NMR, and any two-dimensional NMR data available as well as 19F NMF and 31P NMR, if applicable, are electronically stored on the NMR laboratory server (mangia.caltech.edu, most typically under the username ‘shan’) and on the Stoltz group server. All IR spectra were taken on the Stoltz group IR and an electronic copy of each spectrum as a postscript file can be found on the Stoltz group server. A hard copy of each spectrum has been provided with this text, as well. All laboratory notebooks are stored in the Stoltz group archive. 725   Appendix 14 – Notebook Cross-Reference for New Compounds   A14.2. Notebook Cross-Reference Tables Table A14.1. Notebook cross-reference for compounds in Chapter 1 compound chemical structure 1 H NMR 13 C NMR IR JAMX-95 JAMX-95 JAMX-95 JAMX-75ii JAMX-75ii JAMX-75ii JAMXII-75ii JAMXII-75ii JAMXII-75ii JAMXII-75iii JAMXII-75iii JAMXII-75iii JAMXVI-201 JAMXVI-201 JAMXVI-201 JAMXIII-45i JAMXIII-45i JAMXIII-45i JAMXVI-157 JAMXVI-157 JAMXVI-157 JAMXVI-155 JAMXVI-155 JAMXVI-155 JAMXVI-161 JAMXVI-161 JAMXVI-161 JAMXVI-159 JAMXVI-159 JAMXVI-159 OH HO SI-1-2 HN Ts OH MOMO 13 HN Ts CO2Me 16a O N H CO2Me 16b O N H O HO 20 O N H N 5 N N O O 22 N N H N O O 19 N N O 23 N O N H H N H O 24 N O N H H N 726   Appendix 14 – Notebook Cross-Reference for New Compounds   O F 3C N 25 JAMXVI-41i JAMXVI-41i JAMXVI-41i JAMXV243iii JAMXV243iii JAMXV243iii N H N3 SI-1-7 O N H N3 Br 26 JAMXV-243i JAMXV-243i O JAMXV-243i N H O F 3C H N N3 28 JAMXVI85iib JAMXVI35iib JAMXVI35iib JAMXV-233 JAMXV-233 JAMXV-233 JAMXVI47iib JAMXVI47iib JAMXVI47iib JAMXVI85iv JAMXVI85iv JAMXVI-85iv JAMXVI-93 JAMXVI-93 JAMXVI-93 SK-IV-27-2B SK-IV-272B-c13 Communesin_ SI_11_sk-3281_SI-11 NH N H O O F 3C H N N3 Cl 29 N N o-Ns O O F 3C H N N3 30 N H N O H O F 3C H N 31 N3 N3 N N H N H O O H O F 3C H N 32 HN N O NsHN o-Ns Ts N SI-1-11 O N H 727   Appendix 14 – Notebook Cross-Reference for New Compounds   Ts SK-5-201-2A SK-5-2012A_C13 Communesin_ 35_SK-5125-35 SK-7-183f6+7 SK-7-183C13 37_SK-183-37 SK-4-219-2 SK-4-2192_C13 39_SK-4-21939 SK-5-93-2B SK-5-932B_C13 SI-13_SK5_93_SI-13 SK-6-99-2A SK-6-99-2AC13 40_SK-6-9940 SK-6-203-31H SK-6-203-313C 42_SK-6-20342 hsj_ch_comm hsj_ch_comm _nas _nas 44_Comm_ NAS 20130328_ pero_ch_ coupling_ precursor 20130328_ pero_ch_ coupling_ precursor 45_pero_ coupling_ precursor FV-I-091 FV-I-091 46_ coupling_MS 20130403_ pero_ch_ coupling 20130403_ pero_ch_ coupling 47_pero_ coupling FV-I-097-1 FV-I-097-1 48_MeI_MS N 35 Br O N H Ts N CN 37 O N O2N H Ts N CO2Me CO2Me 39 O N H O2N Ts N SI-1-13 O N H Ts H N 40 Br O N H Ts H N CO2Me 42 CO2Me O O 44 N H O O O NO 2 O O AllylO OAllyl 45 NO 2 Br TIPSO NO 2 CO2Allyl 46 CO2Allyl O N H Br TIPSO NO 2 47 CO2Allyl CO2Allyl O N H TIPSO NO 2 CO2Allyl 48 CO2Allyl O N 728   Appendix 14 – Notebook Cross-Reference for New Compounds   Br TIPSO NO 2 49 CO2Allyl CO2Allyl O pero_ch_ methylation pero_ch_ methylation 49_pero_ methylation FV-I-179 FV-I-179 50_ lactonization FV-I-189-1 FV-I-189-1 51_Tsuji_ model study 20130404_ pero_ch_ Tsuji 20130404_ pero_ch_ Tsuji 52_pero_tsuji 03272012_ Oxyalyl_ column 03272012_ Oxyalyl_ column SI-16_Com_ oxalyl 03282012_ Comm_ LAH 03282012_ Comm_ LAH_ reduction_C 59_Com_LAH reduc Comm_TIPS _protection Comm_TIPS _protection SI-17_Com _tips_protec HSJ_ch_ HSJ_ch_ communesin_ communesin_ oxidative_ oxidative_ bromination bromination 57_3-bromo oxindole ch_commune _coupling hsj_comm_ coupling SI-18_comm_ coupling hsj_ch_ comm_ methylation hsj_ch_ comm_ methylation 60_com_ Methylation hsj_ch_TIPS _depro_cycle hsj_ch_TIPS _depro_cycle 61_Tips_ depro_cycle N O O CO2Allyl 50 O NO N 2 O O 51 O NO N 2 Br 52 TIPSO NO 2 CO2Allyl O N O O Br OMe SI-1-16 N H OH Br 59 N H OTIPS Br SI-1-17 N H TIPSO Br Br 57 O N H SI-1-18 TIPSO NO 2 Br CO2Allyl CO2Allyl O N H 60 TIPSO NO 2 Br CO2Allyl CO2Allyl O N O O CO2Allyl Br 61 O NO N 2 729   Appendix 14 – Notebook Cross-Reference for New Compounds   O O Br 62 hsj_Tsuji Tsuji_C 62_tsuji 20131003_ aldehyde_fl _ch 20131003_ aldehyde_fl _ch 63_Floh_ aldehyde 20131001_ Floh_RA 20131001_ Floh_RA 65_FL_ reductive_ amination 1_comm_ nitro reduction_ 02_17 1_comm_ nitro reduction_ 02_17 67_nitro recution TIPS_ protection TIPS_ protection SI-19_ TIPS Protection N CO Me 2 20121017_ CO2Me_ Chara 20121017_ CO2Me_ Chara 68_ CO2Me_ protection N CO Me 2 1_comm_ aldehyde_ 500 1_comm_ aldehyde_ 500 69_ aldehyde Comm_ PMB_ cycle Comm_ PMB_ cycle 54_PMB_ cycle 1_53_ final_ cyclization_ comm 1_53_ final_ cyclization_ comm 71_5,5_ fused_ AlH3 Comm_final_ 2nd_last Communesin _final_C 72_5,5_ fused_depro O NO N 2 O O Br 63 O O NO N 2 PMB HO Br O N 65 N O NO 2 HO Br 67 NH OO N TIPSO Br SI-1-19 NH OO N TIPSO 68 Br OO N TIPSO 69 O Br OO N PMB TIPSO N Br O 54 O N HN CO2Me PMB N H TIPSO 71 CO2Me N Br O N H N HO 72 H CO2Me N Br O N 730   Appendix 14 – Notebook Cross-Reference for New Compounds   PMB TIPSO N H 73 O HN CO2Me N CO2Me O 20120621_ LAH_new 20120621_ LAH_C 73_LAH_ Debro 20130920_ Tf2O_PMB _char 20130920_ Tf2O_PMB _char 74_Tf2O_ PMB 20130926_ pmb_depro 20130926_ PMB_ depro_cage_ C 75_PMB_ depro_cage 20130922_ Dibal_ PMB_ch 20130922_ Dibal_ PMB_ch 76_dibal_ PMB 20130507_ comm_ch_ reductive_ amination 20130507_ comm_ch_ reductive_ amination 78_comm_ nitro_ reductive amination 20130507_ Comm_ Tf2O 20130507_ comm_ Tf2O_C SI-20_ch_ caged nitro 20130322_ dibal_nitro_ rearr 20130322_ dibal_nitro_ rearr 79_dibal_ nitro 20130325finalcommunesinCDCl3 20130325finalcommunesinCDCl3 53_comm_ final 20130405_ 20130405_ pero_Ti_NO2 pero_Ti_NO2 _reduction _reduction 82_pero_Ti_ cyclization N Br 74 O N O N PMB Br 75 O N N CO2Me O NH PMB HO N Br O 76 N N CO2Me O2N TIPSO 78 N Br O O N HN CO2Me Br O N N CO2Me O SI-1-20 N NO 2 O2N HO 79 N Br O N N CO2Me HO NH Br O 53 N N CO2Me Br TIPSO 82 NH OO N 731   Appendix 14 – Notebook Cross-Reference for New Compounds   Br TIPSO 83 NBoc OO 20130407_ pero_Boc_ protection 20130407_ pero_Boc_ protection_ch 83_pero_Boc _protection 20130408_ pero_ch_ aldehyde 20130408_ pero_ch_ aldehyde 81_pero_ aldehyde 20130409_ pero_ nitrobenzyl_ reductive_ amin 20130508_ pero_ reductive_ amination 84_pero_ nitro_ reductive_ amination 20130410_ pero_Tf2O 20130409_ pero_cage_C 86_pero_Tf2O 20130415_ pero_AlH3 20130414_ AlH3_C_ pero 87_pero_AlH3 20130502_ pero_PDC 20130503_ pero_PDC_C 88_pero_pdc 20130521_ pero_final_2 20130521_ pero_final_C 80_pero_final N Br O TIPSO 81 NBoc OO N O2N TIPSO N 84 O O N HN Br Boc O2N Br O 86 N HN N O O2N TIPSO N 87 O N H N Br Boc O2N TIPSO N 88 O N H O TIPSO N Br Boc NH O 80 N N H H Boc Br Table A14.2. Notebook cross-reference for compounds in Appendix 3 compound chemical structure 1 H NMR 13 C NMR IR –– –– O O NH O O 105 Br N O O2N 20131031_ hydrazine 732   Appendix 14 – Notebook Cross-Reference for New Compounds   Br H 2N 20131108_MeNH2 -major –– –– N 20131125_ coupling –– –– N 20131202_ methylation –– –– 20131217_ coupling –– –– NO 2 CO2Allyl 106 CO2Allyl O N O Bn N 112 O N H O Bn N O 114 N O2N AllylO2C O N 130 N H Table A14.3. Notebook cross-reference for compounds in Appendix 4 compound chemical structure TIPSO 1 H NMR 13 C NMR IR CWL-VI-141 CWL-VI-141oxindole NO 2 CO2Me 136 CO2Me O CWL-VI-141 N H Table A14.4. Notebook cross-reference for compounds in Chapter 2 compound chemical structure O 137a N 1 H NMR 13 C NMR IR 20130830_ o-nitro_ch 20130830_ o-nitro_ch 3a_depro_ o-nitro 20130830_ m-nitro 20130830_ m-nitro 3b_depro_ m-nitro O2N O 137b N NO 2 733   Appendix 14 – Notebook Cross-Reference for New Compounds   O 137c N 20130830_ p-nitro_ch 20130830_ p-nitro_ch 3c_depro_ p-nitro CH-EDCI CH-EDCI 7_depro_ propylbenzamide _pt 20131024_ Boger_ substrate_ protection_ ch(C/H) GFMICARBA MOYL 20131024_ Boger_ substrate_ protection_ ch(C/H) GFMICARBA MOYL NO 2 O N 139 NO 2 O 141 N NO 2 O 143 N N NO 2 9_depro_ r-lactam_pt 11_deprotection _urea Table A14.5. Notebook cross-reference for compounds in Chapter 3 compound chemical structure 1 H NMR 13 C NMR IR OTf PINAP_ OMe_OTf PINAP_ OMe_OTf PINAP_ sjh_OMe OTf PINAP_Et_OTf _ch_H_C PINAP_Et_OTf _ch_H_C PINAP_ sjh_Et PINAP_iPr_OTf PINAP_iPr_OTf PINAP_ OTf_iPr_2 SJHXII_127_ A_ch_H_C SJHXII_127_ A_ch_H_C PINAP_ sjh_A_ cyclohexyl PINAP_L_ again_tBu PINAP_L_ again_tBu PINAP_ OTf_L_tBu OMe N N 157a OEt N N 157b O N 157c N OTf O N 157d N OTf O 157e N N OTf 734   Appendix 14 – Notebook Cross-Reference for New Compounds   O N 157f N OTf PINAP_H_ OTf PINAP_H_ OTf PINAP_ sjh_H_ homoallyl PINAP_N_ OTf PINAP_N_ OTf PINAP_ sjh_ 3,5-dimethyl phenyl PINAP_ 4-methylbenzyl _OTf_C_H_ PINAP_ 4-methylbenzyl _OTf_C_H_ PINAP_ OTf_ 4-MeBn PINAP_OMe character_P_ cdcl3_ 20140626_ PINAP_OMe character_P_ cdcl3_ 20140626_ PINAP_ P_OMe PINAP_Et_P _cdcl3_ 20140626_ PINAP_Et_P _cdcl3_ 20140626_ PINAP_P _Et PINAP_iPr_P _cdcl3_ 20140626_ PINAP_iPr_P _cdcl3_ 20140626_ PINAP_P_ iPr PINAP_P_ char_H_c PINAP_P_ char_H_c PINAP_P_ A PINAP_L_ P_HC PINAP_L_ P_HC PINAP_P_ L PINAP_H_P Ch(H,C) PINAP_H_P Ch(H,C) PINAP_P_ H O N N 157g OTf O N 157h N OTf OMe N N 158a PPh 2 OEt N N 158b PPh 2 O N 158c N PPh 2 O N 158d N PPh 2 O N 158e N PPh 2 O N 158f N PPh 2 735   Appendix 14 – Notebook Cross-Reference for New Compounds   O N N 158g PPh 2 PINAP_N_ PPh2_Ch(C,H) PINAP_N_ PPh2_Ch(C,H) PINAP_P_ N PINAP_ 4-methylbenzyl _P(H,C) PINAP_ 4-methylbenzyl _P(H,C) PINAP_P_ 4-methylBn O N N 158h PPh 2 Table A14.6. Notebook cross-reference for compounds in Chapter 4 chemical structure compound 1 H NMR 13 C NMR IR O PMB 167 I N SJHXI_Alisto_ SJHXI_Alisto_ Ni_SM Ni_SM Alistonitrine _iodo_NiSM N SJHXI_ Alistonitrine_ Ni SJHXI_195_ Alisto_Ni_C_ 15 Alistonitrine _Ni_SJHXI_ 195 I SJHXIII_ model substrate_ ch_H_C SJHXIII_ model substrate_ ch_H_C SJHXIII_Ni_ C–O_ch_H SJHXIII_Ni_ C–O_ch_C RD176column RD1-76carbon RD1-76 RD1212column RD1212column RD1-212 N H OH Me O PMB 169 N H O OH 170a N O 171a N OH 170b I N O 171b N OH 170c SJHXV_19_Ph SJHXV_19_Ph _ch_2 _ch_2 I N Ph Ph O 171c N SJHXV_Ph_ PDT SJHXV_Ph_ PDT SJHXIV_281_ isopropyl SJHXIV_281_ isopropyl OH 170d N I Ni_C_O_ Ni_catalyzed SJHXIII_ model substrate Ni_C_O_ SJHXIII_Ni_ C_O_ Ni_C_O_ SJHXV_19_Ph _substrate Ni_C_O_ SJHXV_27_ Ph_PDT Ni_C_O_ SJHXIV_281_ iPr 736   Appendix 14 – Notebook Cross-Reference for New Compounds   O 171d N SJHXIV_297_ iPr_PDT SJHXIV_297_ iPr_PDT Ni_C_O_ SJHXIV_297_ iPr_PDT SJHXIV_281_ allyl SJHXIV_281_ allyl Ni_C_O_ SJHXIV_281_ allyl SJHXIV_245 _allyl_PDT SJHXIV_245 _allyl_PDT Ni_C_O_ SJHXIV_297_ allyl SJHXV_15_ PMB_ch_ H_C_2 SJHXV_15_ PMB_ch_ H_C_2 Ni_C_O_ SJHXV_15_ PMB_substrate SJHXV_25_ PMB_PDT SJHXV_25_ PMB_PDT Ni_C_O_ SJHXV_25_ PMB_PDT SJHXV_29_ 4-fluoro_ substrate SJHXV_29_ 4-fluoro_ substrate Ni_C_O_ SJHXV_29_ 4_F_ substrate SJHXV_37_ 4-Fluoro_ PDT SJHXV_37_ 4-Fluoro_ PDT Ni_C_O_ SJHXV_37_ 4_F-PDT SJHXV_61_ p-Br_ substrate SJHXV_61_ p-Br_ substrate Ni_C_O_ SJHXV_61_ pBr_ substrate SJHXV_65_ 4-Br_char_ inDCM SJHXV_65_ 4-Br_char_ inDCM Ni_C_O_ SJHXV_65_ p-Br_PDT SJHXV_31_ TBS_ substrate SJHXV_31_ TBS_ substrate Ni_C_O_ SJHXV_31_ TBS_substrate SJHXV_37_ TBS_ PDT SJHXV_37_ TBS_ PDT Ni_C_O_ SJHXV_37_ TBS_PDT SJHXV_77_ Mitsunobu_ 6membered SJHXV_77_ Mitsunobu_ 6membered Ni_C_O_ SJHXV_79_ Mitsunobu_ 6_membered OH 170e I N O 171e N OH I N 170f MeO O N 171f MeO OH I N 170g F O N 171g F OH I N 170h Br O N 171h Br OH I N 170i TBSO O N 171i TBSO OBz SI-4-6 N I 737   Appendix 14 – Notebook Cross-Reference for New Compounds   OH 170j I N O 171j N Ni_C_O_ SJHXV_87_ hydrolysis_ 6-membered Ni_C_O_ SJHXV_89_cis _6-membered_ cyclization SJHXV_87_ hydrolysis_ 6_membered SJHXV_87_ hydrolysis_ 6_membered SJHXV_89_6_ membered_cis _cyclization SJHXV_89_6_ membered_cis _cyclization RD1140column RD1140column RD1-230 RD1168column RD1168column RD1-168 OH 172a I N Ph Ph O 173a N OH 172b I N Ph Ph O 173b N OH 172c I N Ph SJHXIV_301_ monomethyl_C SJHXV_13_ monomethyl_ PDT SJHXV_13_ monomethyl_ PDT SJHXIV_299_ dimethyl_ch_ H SJHXIV_299_ dimethyl_ch_C SJHXV_11_ dimethyl_PDT SJHXV_11_ dimethyl_PDT RD1194column RD1194column RD1-194 RD1206column RD1206carbon RD1-206 SJHXIII_289_ SM_ch SJHXIII_289_ SM_ch SJHXIII_289_ benzene SJHXIII_289_ benzene SJHXIV_31_ bromide_ substrate SJHXIV_177_ vinyl_chloride _H SJHXIV_31_ bromide_ substrate SJHXIV_177_ vinyl_chloride _C Ph O 173c N Ni_C_O_ SJHXIV_301_ monomethyl_ substrate Ni_C_O_ SJHXV_13_ mono_PDT Ni_C_O_ SJHXIV_299_ dimethyl_ substrate Ni_C_O_ SJHXV_11_ dimethyl_PDT SJHXIV_301_ monomethyl_ H OH 172d I N Ph O 173d N Ph MeO 2C 174a HO I MeO 2C 175a CO2Me HO Br MeO 2C 174c CO2Me O MeO 2C 174b CO2Me HO Cl CO2Me Ni_C_O_ SJHXIII_289_ cyclization_ SM Ni_C-O_ SJHXIII_289_ cyclization Ni_C-O_ SJHXIV_31_ vinylbromide Ni_C_O_ SJHXIV_177_ vinyl_chloride Appendix 14 – Notebook Cross-Reference for New Compounds 738     MeO 2C 174d CO2Me HO I MeO 2C 175d CO2Me O MeO 2C 174e CO2Me HO I Ph MeO 2C 175e CO2Me O Ph MeO 2C 174f CO2Me HO Br MeO 2C 175f CO2Me O tBuO C 2 174g CO2tBu HO I tBuO C 2 175g CO2tBu O BnO 2C 174h CO2Bn HO I BnO 2C 175h CO2Bn O MeO 2C 174i HO I MeO 2C 175i CN O CN _substrate Ni_C_O_ SJHXIV_151_ SJHXIV_151_ SJHXIV_151_ methyl_vinyl_ methyl_vinyl_ methylsub_ iodide_H_C iodide_H_C vinyliodide_ substrate Ni_C_O_ SJHXIV_157_ SJHXIV_157_ SJHXIV_147_ methylsub_ methylsub_ methylsub_ cyclization cyclization vinyliodide_ cyclization Ni_C_O_ SJHXIV_167_ SJHXIV_167_ SJHXIV_167_ Ph_substituted Ph_substituted Ph_substituted _substrate _substrate _substrate Ni_C_O_ SJHXIV_169_ SJHXIV_169_ SJHXIV_169_ ph_sub_ ph_sub_ Ph_sub_ cyclization cyclization cyclization Ni_C_O_ SJHXIV_77_ SJHXIV_77_ SJHXIV_77_ gemdimethyl_ gemdimethyl_ gemdimethyl_ substrate substrate_C substrate Ni_C_O_ SJHXIV_85_ SJHXIV_85_ SJHXIV_83_ gemdimethyl_ gemdimethyl_ gemdimethyl_ PDT PDT PDT SJHXIV_47_ SJHXIV_47_ Ni_C_O_SJHX tbutyl_ tbutyl_ IV_47_tbutyl_ substrate substrate substrate Ni_C_O_ SJHXIV_47_ SJHXIV_47_ SJHXIV_57_ tbu_cyclization tbu_cyclization tbutyl_ cyclization SJHXIV_113_ SJHXIV_113_ Ni_C_O_ Bn_substrate_ Bn_substrate_ SJHXIV_113_ ch ch Bn_substrate Ni_C_O_ SJHXIV_117_ SJHXIV_117_ SJHXIV_117_ Bn_cyclization Bn_cyclization cyclization Ni_C_O_ SJHXIV_67_ SJHXIV_67_ SJHXIV_67_ cyanatesubstrat cyanatesubstrat cyanate_ e_down e_down substrate Ni_C_O_ SJHXIV_71_ SJHXIV_71_ SJHXIV_71_ cyanate_ cha_proton_2 cyanate_ cyclization cyclization 739   Appendix 14 – Notebook Cross-Reference for New Compounds   O 174j CO2Me N O OH I SJHXIV_191_ morpholine_ substrate_H SJHXIV_191_ morpholine_ substrate SJHXIV_195_ cyclization_H SJHXIV_195_ cyclization_C SJHXIV_37_ CH2CH2_ substrate SJHXIV_37_ CH2CH2_ substrate SJHXV_179_h ydrolysis_H_c h SJHXV_183_ cyclization_ch _H_C SJHXV_179_c h_hydrolysis_ H_C SJHXV_183_ cyclization_ch _H_C O 175j CO2Me N O O MeO 2C 174k CO2Me HO I tBuO C 2 174l HO CO2tBu I tBuO C 2 CO2tBu 175l O Ni_C_O_ SJHXIV_191_ morpholine_ substrate Ni_C_O_ SJHXIV_195_ morpholine_ cyclization Ni_C_O_ SJHXIV_37_C H2CH2vinylio dide_substrate Ni_C_O_ SJHXV_179_ hydrolysis Ni_C_O_ SJHXV_183_ cyclization   Table A14.7. Notebook cross-reference for compounds in Appendix 9 compound 192 chemical structure OH 1 I N Ph Ph O 193 N H NMR 13 C NMR Ni_Claisen_ SJHXV_241_ alkylation SJHXV_243_Ni Ni_Claisen_ SJHXV_243_Ni_ _cyclization_ SJHXV_245_ cyclization_C bottom_major Claisen_sub SJHXV_241_ alkylation_ch SJHXV_241_ C_moretime SJHXV_261_ Claisen_H SJHXV_269_ Claisen_C Ph O 194 N IR Ni_Claisen_ SJHXV_261_ Claisen PDT Table A14.8. Notebook cross-reference for compounds in Appendix 11 compound chemical structure 1 H NMR 13 C NMR IR SJHVII_77_ TBS_protection –– –– SJHXVI_19_ ozonolysis SJHXVI_19_ ozonolysis Alistonitrine_ SJHXVI_19_ ozonolysis OTBS 201 OTBS OTBS 202 O 740   Appendix 14 – Notebook Cross-Reference for New Compounds   OTBS 203 O N S SJHXVI_21_ sulfinamide_H SJHXVI_21_ sulfinamide_C SJHXVI_23_ allyladdn_ major SJHXVI_23_ allyladdn_ major SJHXVI_25_ amine_MeOD SJHXVI_25_ amine_MeOD SJHVII_167_ acylation –– OTBS 204 O NH S OH 205 NH 3Cl OTIPS 206 O NH O 207 NH OTIPS O 208a N OTIPS O 208b Boc N OTIPS 213 OH O OTIPS N H OH SJHXVI_ SJHXVI_ Grubbs_ Grubbs_ pdt pdt SJHXVI_15_ SJHXVI_15_ Me_ Me_ characterization characterization NH NH Alistonitrine_ SJHXVI_ Grubbs_PDT Alistonitrine_ SJHXVI_ 15_Me Alistonitrine_ SJHXVI_ 17_Boc Alistonitrine_ SJHXVI_ 29_amide Alistonitrine_ SJHXVI_ 31_Grubbs_up Alistonitrine_ SJHXVI_ 31_Grubbs_ down SJHXVI_29_ amide_2 SJHXVI_29_ amide_2 SJHXVI_31_ Grubbs_up SJHXVI_31_ Grubbs_up SJHXVI_31_ Grubbs_down SJHXVI_31_ Grubbs_down SJHVIII_29_ up_acetate –– –– SJHVIII_29_ down_acetate –– –– SJHVIII_33_ Boc_protection –– –– SJHIX_211_ RA_PMB –– –– O 215b Alistonitrine_ SJHXVI_27_ amine_TIPS SJHXVI_17_ Boc OTIPS OH Alistonitrine_ SJHXVI_23_ allyl_addnmajor Alistonitrine_ SJHXVI_25_ amine2 SJHXVI_17_ Boc O 215a Alistonitrine_ SJHXVI_21_ sulfinamide OTIPS OAc O NH 199a OTIPS OAc O NH 199b OTIPS PhthN CO2Me CO2Me 217 O N Boc SI-A11-1 PMB N H CO2Me 741   Appendix 14 – Notebook Cross-Reference for New Compounds   O 223 O MeO CO2Me N PMB O PMB 224 CO2Me N O O PMB 225 CO2Me N O O PMB 226 CO2Me N O SJHIX-213Acylation_ PMB SJHIX-215Dieckmannpmb –– –– –– –– SJHIX_221_ Robinson –– –– SJHIX_239_ SeO2 –– ––   Table A14.9. Notebook cross-reference for compounds in Chapter 5 chemical structure compound 1 H NMR C NMR IR SJHXI_201_PDT SJHXI_201_ Still_Gennari _C Ineleganolide _SJHXI_201_ Still_Gennari SJHXI_INELE_ MeAddn_ch SJHXI_INELE_ MeAddn_ch Inele_SJHXI _211_Me_ Addn_PDt SJHXI_211_ swern_H SJHXI_211_ swern_C Ineleganolide_ SJHXI_211_ Swern SJHXI_ Ineleganolide_ mcpba_H SJHXI_ Ineleganolide_ mcpba_C Ineleganolide_ SJHXI_Inele_ mcpba SJHXV_217_ 7_bromide SJHXV_217_ 7_bromide_C Ineleganolide_ SJHXV_217_ NBS SJH_ ineleganolide _acid_ characterization SJH_ ineleganolide _acid_ characterization Ineleganolide_ SJH_ acid SJHXII_235_ MnO2 SJHXII_235_ MnO2_C Ineleganolide_ SJHXII_Rh_ SM_diazo SJHXII_201_H SJHXII_201_C Ineleganolide_ SJHXII_Rh_ TLC_prep OMe OMe 248 13 CO2Me OH 251 CO2Me O 252 CO2Me O OH 254 CO2Me O Br 244b CO2Me OTBS 260 HO O OH OTBS 264 N2 EtO O 266 O OH OTBS O O N2 O 742   Appendix 14 – Notebook Cross-Reference for New Compounds   OTBS 268 OH O OH SJHXIII_25_ Rubottom_ characterization _H SJHXIII_25_ Rubottom_ characterization _C SJHXIII_39_ Benzoylation_H SJHXIII_39_ Benzoylation_C SJHXIII_27_ Mesyl_ characterization _H SJHXIII_27_ Mesyl_ characterization _C SJHXIII_215_ 1_H SJHXIII_215_ 1_C SJHXIII_215_ 2_H SJHXIII_215_ 2_C SJHXV_201_ TES SJHXV_201_ TES SJHXV_221_ cyclization_H SJHXV_221_ cyclization_C SJHXV_239_ TES_depro_H SJHXV_239_ TES_depro_C SJHXIII_MnO2 _ch_H SJHXIII_MnO2 _ch_C SJHXIII_107_ TBAF_H SJHXIII_107_ TBAF_C SJH_vinyl_ addn_ characterization SJH_vinyl_ addn_ characterization SJHXIII_41_ swern_H-ch SJHXIII_41_ swern_C-ch SJHXIII_85_ OMe_addn_H SJHXIII_85_ OMe_addn_c OTBS 269 BzO O OH OTBS 270 MsO O OH OTBS 271a O OH OTBS 271b O OH OTBS 274 TESO HO I OTBS 275 TESO O OTBS 276 HO O OTBS 285 O OH OH 281 O OH OH 286 CO2Me O 287 CO2Me O OMe 288 CO2Me Ineleganolide_ SJHXIII_25_ rubottom_ RobFrag Ineleganolide_ SJHXIII_39_ benzoyl Ineleganolide_ SJHXIII_27_ Mesylate Ineleganolide_ SJHXIII_231 _epoxide_1_ cosy Ineleganolide_ SJHXIII_231 _epoxide2_ corey Ineleganolide_ SJHXV_201 _TES Ineleganolide_ SJHXV_221 _cyclization Ineleganolide_ SJHXV_239 _TES_depro Ineleganolide_ SJHXIII_ MnO2_after vinyladdn Ineleganolide_ SJHXIII_105 _TBAF_ desilylation Ineleganolide_ SJH_vinyl_ addn_left part Ineleganolide_ SJHXIII_ 81_Swern Ineleganolide_ SJHXIII_ 89_OMe_addn _unexpected 743   Appendix 14 – Notebook Cross-Reference for New Compounds   OTBS 294 O OH SJHXV_271_ MnO2_ oxidation SJHXV_271_ MnO2_ oxidation Ineleganolide_ SJHXV_271_ MnO2 Comprehensive Bibliography 744   COMPREHENSIVE BIBLIOGRAPHY Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849. Ahmed, A. F.; Shine, R.-T.; Wang, G.-H.; Dai, C.-F.; Kuo, Y.-H.; Sheu, J.-H. Tetrahedron 2003, 59, 7337–7344. Aho, J. E.; Piisola, A.; Krishnan, K. S.; Pihko, P. M. Eur. J. Org. Chem. 2011, 9, 1682–1694. Aho, J. E.; Salomäki, E.; Rissanen, K.; Pihko, P. M. Org. Lett. 2008, 10, 4179–4182. Alcock, N. W.; Brown, J. M.; Hulmes, D. I. Tetrahedron: Asymmetry 1993, 4, 743– 756. Ananikov, V. P. ACS Catal. 2015, 5, 1964–1971. Anderluh, M.; Cesar, J.; Štefanič, P.; Kikelj, D.; Janeš, D.; Murn, J.; Nadrah, K.; Tominc, M.; Addicks, E.; Giannis, A.; Stegnar, M.; Dolenc, M. S. Eur. J. Med. Chem. 2005, 40, 25–49. Andersen, B.; Smedsgaard, J.; Frisvad, J. C. J. Agric. Food Chem. 2004, 52, 2421. Ando, K. J. Org. Chem. 1997, 62, 1934–1939. Ando, K. J. Org. Chem. 1999, 64, 8406–8408. Ando, K. J. Org. Chem. 2000, 65, 4745–4749. Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369–4378. Arthuis, M.; Beaud, R.; Gandon, V.; Roulland, E. Angew. Chem., Int. Ed. 2012, 51, 10510–10514. Artman, G. D., III; Weinreb, S. M. Org. Lett. 2003, 5, 1523. 745   Asao, N.; Sato, K.; Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682– Comprehensive Bibliography 3685. Baliga, M. S. Integr. Cancer Ther. 2010, 9, 261–269. Belmar, J.; Funk, R. L. J. Am. Chem. Soc. 2012, 134, 16941. Bhat, V.; Wang, S.; Stoltz, B. M.; Virgil, S. C. J. Am. Chem. Soc. 2013, 135, 16829– 16832. Black, A.; Brown, J. M.; Pichon, C. Chem. Commun. 2005, 5284–5286. Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26. Boger, D. L.; Cassidy, K. C.; Nakahara, S. J. Am. Chem. Soc. 1993, 115, 10733– 10741. Bottini, A. T.; Mullikin, J. A.; Morris, C. J. J. Org. Chem. 1964, 29, 373–379. Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M. O.; Leach, D. C. J. Chem. Soc. Perkin. Trans. 1 2002, 58–68. Burgos, C.; Barder, T. E.; Huang, X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 4321–4326. Calter, M. A.; Sugathapala, P. M.; Zhu, C. Tetrahedron Lett. 1997, 38, 3837–3840. Ziegler, F. E.; Berlin, M. Y.; Lee, K.; Looker, A. R. Org. Lett. 2000, 2, 3619–3621. Calter, M.; Zhu, C. J. Org. Chem. 1999, 64, 1415–1419. Cao, H.; Yu, J.; Wearing, X. Z.; Zhang, C.; Liu, X.; Deschamps, J.; Cook, J. M. Tetrahedron Lett. 2003, 44, 8013–8017. Cao, Z.-Y.; Wang, Y.-H.; Zeng, X.-P.; Zhou, J. Tetrahedron Lett. 2014, 55, 2571– 2584. Cesar, J.; Dolenc, M. S.; Tetrahedron Lett. 2001, 42, 7099–7102. Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174–10175. Comprehensive Bibliography 746   Chen, D.; Xu, M.-H. J. Org. Chem. 2014, 79, 7746–7751. Chen, W.; Li, Y.; Guo, Y. Acta Pharm. Sin. B 2012, 2, 227–237. Chen, Y.; Wang, L.; Liu, Y.; Li, Y. Chem. Eur. J. 2011, 17, 12582–12586. Clayden, J.; Fletcher, S. P.; McDouall, J. J. W.; Rowbottom, S. J. M. J. Am. Chem. Soc. 2009, 131, 5331–5343. Craig, R. A., II Ph.D. Thesis, California Institute of Technology, Pasadena, CA, May 2015. Craig, R. A., II.; Roizen, J. L.; Smith, R. C.; Jones, A. C.; Stoltz, B. M. Org. Lett. 2012, 14, 5716–5719. Crawley, S. L.; Funk, R. L. Org. Lett. 2003, 5, 3169. Crawley, S. L.; Funk, R. L. Org. Lett. 2006, 8, 3995. Dakin, L. A.; Panek, J. S. Org. Lett. 2003, 5, 3995–3998. Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Chem. Soc. Rev. 2012, 41, 7247–7290. Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.; Frisvad, J. C.; Christophersen, C. J. Nat. Prod. 2005, 68, 258. Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org. Chem. 1990, 55, 1959–1964. Danishefsky, S. J.; DeNinno, M. P.; Chen, S.-h. J. Am. Chem. Soc. 1988, 110, 3929– 3940. Daura-Oller, E.; Segarra, A. M.; Poblet, J. M.; Claver, C.; Fernández, E.; Bo, C. J. Org. Chem. 2004, 69, 2669–2680. Denault, J.-B.; Salvesen, G. S. Chem. Rev. 2002, 102, 4489. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Wang, G.; Qiu, S.; Shangary, S.; Gao, W.; Qin, D.; Stuckey, J.; Krajewski, K.; Roller, P. P.; Wang, S. J. Med. Chem. 2006, 49, 3432–3435. 747   Ding, M.; Zhou, F.; Qian, Z.-Q.; Zhou, J. Org. Biomol. Chem., 2010, 8, 2912–2914. Comprehensive Bibliography Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Org. Lett. 2008, 10, 285–288. Dou, X.; Yao, W.; Zhou, B.; Lu, Y. Chem. Commun. 2013, 49, 9224. Doucet, H.; Fernandez, E.; Layzell, T. P.; Brown, J. M. Chem. Eur. J. 1999, 5, 1320– 1330. Duh, C.-Y.; Wang, S.-K.; Chia, M.-C.; Chiang, M. Y. Tetrahedron Lett. 1999, 40, 6033–6035. Ebner, C.; Müller, C. A.; Markert, C.; Pfaltz, A. J. Am. Chem. Soc. 2011, 133, 4710– 4713. Eckroth, D. R.; Cochran, T. G. J. Chem. Soc. C 1970, 2660. Evans, M. A.; Sacher, J. R.; Weinreb, S. M. Tetrahedron 2009, 65, 6712. Evans, V.; Mahon, M. F.; Webster, R. L. Tetrahedron, 2014, DOI: 10.1016/j.tet.2014.07.080. Faller, J. W.; Grimmond, B. J. Organometallics 2001, 20, 2454–2458. Fandrick, D. R., Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Tang, W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.; Yee, N. K.; Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600-7601. Fandrick, K. R.; Fandrick, D. R.; Reeves, J. T.; Ma, S.; Li, W.; Lee, H.; Grinberg, N.; Lu, B.; Senanayake, C. H. J. Am. Chem. Soc. 2011, 133, 10332-10335. Fandrick, K. R.; Ogikubo, J.; Fandrick, D. R.; Patel, N. D.; Saha, J.; Lee, H.; Ma, S.; Grinberg, N.; Busacca, C. A.; Senanayake, C. H. Org. Lett. 2013, 15, 1214-1217. Fang, Y.; Li, C. Chem. Commun. 2005, 3574–3576. Fang, Y.; Li, C. J. Am .Chem. Soc. 2007, 129, 8092–8093. Fernandes, R. A.; Yamamoto, Y. J. Org. Chem. 2004, 69, 3562. 748   Fernández, E. Guiry, P. J.; Connole, K. P. T.; Brown, J. M. J. Org. Chem. 2014, 79, Comprehensive Bibliography 5391–5400. Fetter, J.; Giang, L. T.; Czuppon, T.; Lempert, K.; Kajtár-Peredy, M; Czira, G. Tetrahedron, 1994, 50, 4185–4200. Frontier, A. J.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151– 6159. Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068. Fujimori, S.; Knöpfel, T. F.; Zarotti, P.; Ichikawa, T.; Boyall, D.; Carreira, E. M. Bull. Chem. Soc. Jpn. 2007, 80, 1635–1657. Fukase, K.; Tanaka, H.; Torii, S.; Kusumoto, S. Tetrahedron Lett. 1990, 31, 389–392. Fukuyama, T.; Frank, R. K.; Jewell, C. F., Jr. J. Am. Chem. Soc. 1980, 102, 2122– 2123. Fukuyama, T.; Liu, G. J. Am. Chem. Soc. 1996, 118, 7426. Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46, 8748–8758. Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 9279–9282. Garcia, J. A. O. Thesis, The University of British Columbia, Vancouver, Canada, Oct 2003. Gareau, Y.; Zamboni, R.; Wong, A. W. J. Org. Chem. 1993, 58, 1582. Gatti, M.; Drinkel, E.; Wu, L.; Pusterla, I.; Gaggia, F.; Dorta, R. J. Am. Chem. Soc. 2010, 132, 15179–15181. George, J. H.; Adlington, R. M. Synlett 2008, 2093. Gommermann, N.; Knochel, P. Chem.–Eur. J. 2006, 12, 4380–4392. Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763–5766. 749   González, M. A.; Ghosh, S.; Rivas, F.; Fischer, D.; Theodorakis, E. A. Tetrahedron Comprehensive Bibliography Lett. 2004, 45, 5039–5041. Greenberg, A. Mol. Struct. Enegetics 1988, 7, 139. Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270–5298. Han, R.; Hillhouse, G. L. J. Am. Chem. Soc. 1997, 119, 8135–8136. Han, S.-J. Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C. Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. Han, S.-J.; Fernando de Melo, G.; Stoltz, B. M. Tetrahedron Lett. 2014, 55, 6467. Han, S.-J.; Vogt, F.; Krishnan, S.; May, J. A.; Gatti, M.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2014, 16, 3316–3319. Hartwig, J. F. Nature 2008, 455, 314–322. Hayashi, H.; Matsumoto, H.; Akiyama, K. Biosci. Biotechnol. Biochem. 2004, 68, 753. He, L.; Bekkaye, M.; Retailleau, P.; Masson, G. Org. Lett. 2012, 14, 3158. Hegedus, L. S.; Toro, J. L.; Miles, W. H.; Harrington, P. J. J. Org. Chem. 1987, 52, 3319. Hennessy, E. J.; Buchwald, S. L. J. Org. Chem. 2005, 70, 7371–7375. Hoffmann, R. W.; Breitfelder, S.; Schlapbach, A. Helv. Chim. Acta 1996, 79, 346– 352. Hoffmann, T.; Lanig, H.; Waibel, R.; Gmeiner, P. Angew. Chem., Int. Ed. 2001, 40, 3361–3364. Holmquist, M.; Blay, G.; Pedro, J. R. Chem. Commun., 2014, 50, 9309–9312. Horn, E. J.; Silverston, J. S.; Vanderwal, C. D. J. Org. Chem. 2016, DOI: 10.1021/acs.joc.5b02550. Horning, B. D.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 6442–6445. 750   Horvath, A.; Grassberger, M. A.; Schulz, G.; Haidl, E.; Sperner, H.; Steck, A. Comprehensive Bibliography Tetrahedron 2000, 56, 7469. Hrib, N. J.; Jurcak, J. G.; Burgher, K. L.; Conway, P. G.; Hartman, H. B.; Kerman, L. L.; Roehr, J. E.; Woods, A. T. J. Med. Chem. 1994, 37, 2308. Hu, F.-L.; Wei, Y.; Shi, M. Chem. Commun., 2014, 50, 8912–8914. Hu, X. Chem. Sci. 2011, 2, 1867–1886. Huwe, C. M.; Kiehl, O. C.; Blechert, S. Synlett 1996, 65–66. Ishida, T.; Ikota, H.; Kurahashi, K.; Tsukano, C.; Takemoto, Y. Angew. Chem., Int. Ed. 2013, 52, 10204. Ishida, T.; Takemoto, Y. Tetrahedron 2013, 69, 4517. Iwao, M.; Motoi, O. Tetrahedron Lett. 1995, 36, 5929. Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K; Proksch, P. J. Nat. Prod. 2004, 67, 78. Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417–1492. Jones, K.; Toutounji, T. Tetrahedron 2001, 57, 2427–2431. Karikomi, M.; Watanabe, S.; Kimura, Y.; Uyehara, T. Tetrahedron Lett. 2002, 43, 1495–1498. Katayev, D.; Jia, Y.-X. Sharma, A. K.; Banerjee, D.; Besnard, C.; Sunoj, R. B.; Kündig, E. P. Chem. Eur. J. 2013, 19 11916–11927. Kennewell, P. D.; Miller, D. J.; Scrowston, R. M.; Westwood, R. J. Chem. Res. Miniprint 1995, 10, 2380. Klein, J. E. M. N.; Taylor, R. J. K. Eur. J. Org. Chem. 2011, 6821–6841. Klenchin, V. A.; Allingham, J. S.; King, R.; Tanaka, J.; Marriott, G.; Rayment, I. Nat. Struct. Biol. 2003, 10, 1058. 751   Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Comprehensive Bibliography Chem., Int. Ed. 2004, 43, 5971–5973. Kocienski, P. J. Protecting Groups; George Thieme Verlag: Stuttgart and New York, 1994. Koriyama, Y.; Nozawa, A.; Hayakawa, R.; Shimizu, M. Tetrahedron 2002, 58, 9621– 9628. Kotoku, N.; Sumii, Y.; Kobayashi, M. Org. Lett. 2011, 13, 3514. Koyama, J.; Toyokuni, I.; Tagahara, K. Chem. Pharm. Bull. 1998, 46, 332–334. Kozlovskii, A. G.; Solov’eva, T. F.; Sahkarovskii, V. G.; Adanin, V. M. Dokl. Akad. Nauk SSSR 1981, 260, 230. Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C. Ramtohul, Y. K.; Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745. Krishnan, S.; Stoltz, B. M. Tetrahedron Lett. 2007, 48, 7571–7573. Kumaran, R. S.; Mehta, G. Tetrahedron 2015, 71, 1718–1731. Kundu, D.; Maity, P.; Ranu, B. C. Org. Lett. 2014, 16, 1040–1043. Kurosu, M.; Lin, M.-H.; Kishi, Y. J. Am. Chem. Soc. 2004, 126, 12248–12249. Kuwabe, S.-i.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 12202– 12206. . Lam, S. K.; Chiu, P. Chem. Eur. J. 2007, 13, 9589–9599. Latorre, A.; Sáez, J. A.; Rodríguez, S.; González, F. V. Tetrahedron 2014, 70, 97–102. Lautens, M.; Maddess, M. L.; Sauer, E. L. O.; Ouellet, S. G. Org. Lett. 2002, 4, 83– 86. Lebedev, S. A.; Lopatina, V. S.; Petrov, E. S.; Beletskaya, I. P. J. Organomet. Chem. 1988, 344, 253–259. Lee, C. W.; Han, S.-J. Virgil, S. C.; Stoltz, B. M. Tetrahedron 2014, 71, 3666–3670. Comprehensive Bibliography 752   Lee, K. C.; Loh, T. P. Chem. Commun. 2006, 40, 4209–4211. Lee, S. J.; Cho, S. A.; An, S. S.; Na, Y. J.; Park, N. H.; Kim, H. S.; Lee, C. W.; Kim, H. K.; Kim, E. K.; Jang, Y. P.; Kim, J. W. Evid. Based Complement Alternat. Med. 2012, 2012, 190370. Li, C.; Guo, F.; Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Org. Lett. 2014, 16, 3192–3195. Li, P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 6396. Li, X.; Kong, L.; Gao, Y.; Wang, X. Tetrahedron Lett. 2007, 48, 3915–3917. Li, Y.; Pattenden, G. Nat. Prod. Rep. 2011, 28, 429–440. Li, Y.; Pattenden, G. Tetrahedron 2011, 67, 10045–10052. Lim, A. D.; Codelli, J. A.; Reisman, S. E. Chem. Sci. 2013, 4, 650–654. Lim, C. W.; Tissot, O.; Mattison, A. Hooper, M. W.; Brown, J. M.; Cowley, A. R.; Hulmes, D. I.; Blacker, A. J. Org. Process Res. Dev. 2003, 7, 379–384. Lin, H.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 36–51. Lin, J.-W.; Kurniawan, Y. D.; Chang, W.-J.; Leu, W.-J.; Chan, S.-H.; Hou, D.-R. Org. Lett. 2014, 16, 5328–5331. Liu, B.; Hu, L. Bioorg. Med. Chem. 2003, 11, 3889. Liu, G.; Romo, D. Abstracts of Papers, 237th ACS National Meeting, Salt Lake City, UT, Mar 22–26, 2009; American Chemical Society, 2009; ORGN-083. Liu, P.; Seo, J. H.; Weinreb, S. M. Angew. Chem., Int. Ed. 2010, 49, 2000. Liu, Z.-M.; Li, N.-K.; Huang, X.-F.; Wu, B.; Li, N.; Kwok, C.-Y.; Wang, Y.; Wang, X.-W. Tetrahedron, 2014, 70, 2406–2415. Lu, H.; Li, C. Org. Lett. 2006, 8, 5365. Ma, S.; Han, X.; Krishnan, S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037–8041. 753   Macgregor, S. A.; Neave, G. W.; Smith, C. Faraday Discuss. 2003, 124, 111–127. Comprehensive Bibliography Madin, A.; O’Donnell, C. J.; Oh, T. Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 2005, 127, 18054–18065. Maeda, K.; Brown, J. M. Chem. Commun. 2002, 310–311. Maiti, D.; Buchwald, S. L. J. Org. Chem. 2010, 75, 1791–1794. Mann, G.; Hartwig, J. F. J. Org. Chem. 1997, 62, 5413–5418. Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 3224–3225. Marfat, A.; Carta, M. P. Tetrahedron Lett. 1987, 28, 4027. Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209–2219. Martin, D. B. C.; Nguyen, L. Q.; Vanderwal, C. D. J. Org. Chem. 2012, 77, 17–46. Matsunaga, P. T.; Hillhouse, G. L.; Rheingold, A. L. J. Am. Chem. Soc. 1993, 115, 2075–2077. Maurya, S. K.; Dow, M.; Warriner, S.; Nelson, A. Beilstein J. Org. Chem. 2013, 9, 775–785. May, J. A. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, Jul 2005. May, J. A.; Stoltz, B. Tetrahedron 2006, 62, 5262. May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203. Messik, F.; Oberthür, M. Synthesis 2013, 45, 167–170. Michaelis, S.; Blechert, S. Org. Lett. 2005, 7, 5513–5516. Miknis, G. F.; Williams, R. M. J. Am. Chem. Soc. 1993, 115, 536–547. Miura, T.; Yamauchi, M.; Kosaka, A.; Murakami, M. Angew. Chem., Int. Ed. 2010, 49, 4955–4957. Mohr, J. T.; Stoltz, B. M. Chem. Asian J. 2007, 2, 1476. Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003, 125, 8702–8703. Comprehensive Bibliography 754   Moura-Letts, G.; Curran, D. P. Org. Lett. 2007, 9, 5–8. Netherton, M. R.; Fu, G. C. Adv. Synth. Catal. 2004, 346, 1525–1532. Nevar, N. M.; Kel’in, A. V.; Kulinkovich, O. L. Synthesis 2000, 9, 1259–1262. Niu, J.; Guo, P.; Kang, J.; Li, Z.; Xu, J.; Hu, S. J. Org. Chem. 2009, 74, 5075–5078. Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 4978–4979. Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355. O’Connell, C. E.; Frontier, A. J. Abstracts of Papers, 32nd Northeast Regional Meeting of the American Chemical Society, Rochester, NY, Oct 31–Nov 3, 2004; American Chemical Society, 2004, GEN-088. Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991, 56, 5307–5311. Overman, L. E.; Rosen, M. D. Angew. Chem. Int. Ed. 2000, 39, 4596–4599. Pagano, N.; Wong, E. Y. Breiding, T.; Liu, H.; Wilbuer, A.; Bregman, H.; Shen, Q.; Diamond, S. L.; Meggers, E. J. Org. Chem. 2009, 74, 8997–9009. Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 10333– 10334. Panek, J. S.; Xu, F.; Rondón, A. C. J. Am. Chem. Soc. 1998, 120, 4113–4122. Parrish, C. A.; Buchwald, S. L. J. Org. Chem. 2001, 66, 2498–2500. Pereira, J.; Barlier, M.; Guillou, C. Org. Lett. 2007, 9, 3101–3103. Piloto, A. M.; Costa, S. P. G.; Goncalves, M. S. T. Tetrahedron, 2014, 70, 650–657. Pitsch, S. Helv. Chim. Acta 1997, 80, 2286–2314. Radosevich, A. T.; Chan, V. S.; Shih, H.-W.; Toste, F. D. Angew. Chem., Int. Ed. 2008, 47, 3755–3758. 755   Rao, V. R.; Muthenna, P.; Shankaraiah, G.; Akileshwari, C.; Babu, K. H.; Suresh, G.; Comprehensive Bibliography Babu, K. S.; Kumar, R. S. C.; Prasad, K. R.; Yadav, P. A.; Petrash, J. M.; Reddy, G. B.; Rao, J. M. Eur. J. Med. Chem. 2012, 57, 344–361. Ratnayake, A. S.; Yoshida, W. Y.; Mooberry, S. L.; Hemscheidt, T. K. J. Org. Chem. 2001, 66, 8717. Rech, J. C.; Yato, M.; Duckett, D.; Ember, B.; LoGrasso, P. V.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 490–491. Rege, P. D.; Johnson, F. J. Org. Chem. 2003, 68, 6133. Rodríguez-Vázquez, N.; Salzinger, S.; Silva, L. F.; Amorín, M.; Granja, J. R. Eur. J. Org. Chem. 2013, 17, 3477–3493. Roizen, J. L. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, Nov 2009. Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111, 1346–1416. Sabahi, A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006, 45, 4317. Sabitha, G.; Rao, V. R. S.; Sudhakar, K.; Kumar, M. R.; Reddy, E. V.; Yadav, J. S. J. Mol. Catal. A: Chem. 2008, 280, 16–19. Sahkarovskii, V. G.; Aripovskii, A. V.; Baru, M. B.; Kozlovskii, A. G. Khim. Prir. Soedin. 1983, 656. Sakai, T; Asano, H.; Fukukawa, K.; Oshima, R.; Mori, Y. Org. Lett. 2014, 16, 2268– 2271. Sakai, T.; Matsushita, S.; Arakawa, S.; Kawai, A.; Mori, Y. Tetrahedron Lett. 2014, 55, 6557–6560. Sakai, T.; Sugimoto, A.; Tatematsu, H.; Mori, Y. J. Org. Chem. 2012, 77, 11177– 11191. Comprehensive Bibliography 756   Schammel, A. W.; Chiou, G.; Garg, N. K. Org. Lett. 2012, 14, 4556. Schultz, A. G.; Lucci, R. D.; Napier, J. J.; Kinoshita, H.; Ravichandran, R.; Shannon, P.; Yee, Y. K. J. Org. Chem. 1985, 50, 217–231. Seo, J. H.; Artman, G. D., III; Weinreb, S. M. J. Org. Chem. 2006, 71, 8891. Shade, R. E.; Hyde, A. M.; Olsen, J.-C.; Merlic, C. A. J. Am. Chem. Soc. 2010, 132, 1202–1203. Shang, J. H.; Cai, X. H.; Feng, T.; Zhao, Y. L.; Wang, J. K.; Zhang, L. Y.; Yan, M.; Luo, X. D. J. Ethnopharmacol. 2010, 129, 174–181. Shang, J.; H.; Cai, X. H.; Zhao, Y. L.; Feng, T.; Luo, X. D. J. Ethnopharmacol. 2010, 129, 293–298. Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718– 10719. Shen, K.; Liu, X.; Feng, X. Chem. Sci., 2012, 3, 327–334. Siengalewicz, P.; Gaich, T.; Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 8170. Singh, G. S.; Desta, Z. Y. Chem. Rev. 2012, 112, 6104–6155. Smith, A. B., III; Haseltine, J. N.; Visnick, M. Tetrahedron, 1989, 45, 2431–2449. Smith, A. B., III; Minbiole, K. P.; Verhoest, P. R.; Schelhaas, M. J. Am. Chem. Soc. 2001, 123, 10942–10953. Snider, B. B.; Busuyek, M. V. Tetrahedron 2001, 57, 3301–3307. Somei, M.; Yamada, F. Jpn. Patent JP 85-47044 19850308, 1986. Spence, T. W. M.; Tennant, G. J. Chem. Soc. C 1971, 3712. Standley, E. A.; Tasker, S. Z.; Jensen, K. L.; Jamison, T. F. Acc. Chem. Res. 2015, 48, 1503–1514. Steinhagen, H.; Corey, E. J. Angew. Chem., Int. Ed. 1999, 38, 1928. Stutz, A.; Pitxch, S. Synlett, 1999, 930–934. 757   Sugiura, R.; Kozaki, R.; Kitani, S.; Gosho, Y.; Tanimoto, H.; Nishiyama, Y.; Comprehensive Bibliography Morimoto, T.; Kakiuchi, K. Tetrahedron, 2013, 69, 3984–3990. Sun, C.; Fang, Y.; Li, S.; Zhang, Y.; Zhao, Q.; Zhu, S.; Li, C. Org Lett. 2009, 11, 4084–4087. Surasani, R.; Kalita, D.; Rao, A. V. D.; Chandrasekhar, K. B. Beilstein J. Org. Chem. 2012, 8, 2004–2018. Suzuki, T.; Kobayashi, S. Org. Lett. 2010, 12, 2920–2923. Szostak, M.; Aubé, J. Chem. Rev. 2013, 113, 5701. Szostak, M.; Aubé, J. Org. Biomol. Chem. 2011, 9, 27. Tanaka, J.; Yan, Y.; Choi, J.; Bai, J.; Klenchin, V. A.; Rayment, I.; Marriott, G. Proc. Natl. Acad. Sci. 2003, 100, 13851. Tang, F. Thesis, Washington University, St. Louis, MO, May 2009. Tani, K.; Stoltz, B. M. Nature, 2006, 441, 731. Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299–309. Taylor, A. M.; Schreiber, S. L. Org. Lett. 2006, 8, 143–146. Teng, M.; Zi, W.; Ma, D. Angew. Chem., Int. Ed. 2014, 53, 1814–1817. Terao, J.; Kambe, N. Bull. Chem. Soc. Jpn. 2006, 79, 663–672. Terrett, J. A.; Cuthbertson, J. D.; Shurtleff, V. W.; MacMillan, D. W. C. Nature 2015, 524, 330–334. Thaler, T.; Geittner, F.; Knochel, P. Synlett 2007, 2655–2658. Thao, N. P.; Nam, N. H.; Cuong, N. X.; Quang, T. H.; Tung, P. T.; Dat, L. D.; Chae, D.; Kim, S.; Koh, Y.-S.; Kiem, P. V.; Minh, C. V.; Kim, Y. H. Bioorg. Med. Chem. Lett. 2013, 23, 228–231. Thompson, C. F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2000, 122, 10482–10483. 758   Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008, 10, 3583–3586. Comprehensive Bibliography Tokunaga, T.; Hume, W. E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R. J. Med. Chem. 2001, 44, 4641–4649. Torraca, K. E.; Kuwabe, S.-I.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12907– 12908. Trost, B. M.; Brennan, M. K. Synthesis, 2009, 3003–3025. Trost, B. M.; Malhotra, S.; Chan, W. H. J. Am. Chem. Soc. 2011, 133, 7328. Trost, B. M.; Osipov, M.; Krüger, S.; Zhang, Y. Chem. Sci. 2015, 6, 349. Trost, B. M.; Stiles, D. T. Org. Lett. 2007, 9, 2763–2766. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395. Trost, B. M.; Waser, J.; Meyer, A. J. Am. Chem. Soc. 2008, 130, 16424–16434. Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343. Trudeau, S.; Morgan, J. B.; Shrestha, M.; Morken, J. P. J. Org. Chem. 2005, 70, 9538–9544. Tsuda, T.; Chujo, Y.; Nishi, S.; Tawara, K.; Saegusa, T. J. Am. Chem. Soc. 1980, 102, 6381. Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793. Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715. Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124. Voelker, T.; Ewell, T.; Joo, J.; Edstrom, E. D. Tetrahedron Lett. 1998, 39, 359–362. Wang, Y.; Kong, C.; Du, Y.; Song, H.; Zhang, D.; Qin, Y. Org. Biomol. Chem. 2012, 10, 2793. 759   Weaver, J. D.; Recio, A., III; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, Comprehensive Bibliography 1846. Weinstabl, H.; Gaich, T.; Mulzer, J. Org. Lett. 2012, 14, 2834–2837. Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry 2006, 67, 561. Wigley, L. J.; Perry, D. A.; Mantle, P. G. Mycol. Res. 2008, 112, 131. Williams, R. M.; Kwast, E. Tetrahedron Lett. 1989, 30, 451–454. Woodward, C.; L.; Li, Z.; Kathcart, A. K.; Terrell, J.; Gerena, L.; Lopez-Sanchez, M.; Kyle, D. E.; Bhattacharjee, A. K.; Nichols, D. A.; Ellis, W.; Prigge, S. T.; Geyer, J. A.; Waters, N. C. J. Med. Chem. 2003, 46, 3877–3882. Wu, H.; Xue, F.; Xiao, X.; Qin, Y. J. Am. Chem. Soc. 2010, 132, 14052. Wu, X.; Fors, B. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 9943–9947. Würdemann, M.; Christoffers, J. Org. Biomol. Chem. 2010, 8, 1894–1898. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th ed; John Wiley & Sons: New York, 2007. Yamada, F.; Makita, Y.; Suzuki, T.; Somei, M. Chem. Pharm. Bull. 1985, 33, 2162. Yamada, Y.; Arima, S.; Okada, C.; Akiba, A.; Kai, T.; Harigaya, Y. Chem. Pharm. Bull. 2006, 54, 788. Yang, J.; Song, H.; Xiao, X.; Wang, J.; Qin, Y. Org. Lett. 2006, 8, 2187. Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794. Yang, Q.; Njardarson, J. T. Tetrahedron Lett. 2013, 54, 7080–7082. Yokoyama, Y.; Hikawa, H.; Mitsuhashi, M.; Uyama, A.; Hiroki, Y.; Murakami, Y. Eur. J. Org. Chem. 2004, 1244. Yokoyama, Y.; Matsumoto, T.; Murakami, Y. J. Org. Chem. 1995, 60, 1486. Zhang, H.; Hong, L.; Kang, H.; Wang, R. J. Am. Chem. Soc. 2013, 135, 14098. 760   Zhing, F.; Dou, X.; Han, X.; Yao, W.; Zhu, Q.; Meng, Y.; Lu, Y. Angew. Chem. Int. Comprehensive Bibliography Ed. 2013, 52, 943–947. Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal., 2010, 352, 1381–1407. Zhou, F.; Zeng, X.-P.; Wang, C.; Zhao, X.-L.; Zhou, J. Chem. Commun., 2013, 49, 2022–2024. Zhu, G.-Y.; Yao, X.-J.; Liu, L.; Bai, L.-P.; Jiang, Z.-H. Org. Lett. 2014, 16, 1080– 1083. Zhu, X.-L.; Xu, J.-H.; Cheng, D.-J.; Zhao, L.-J.; Liu, X.-Y. Tan, B. Org. Lett. 2014, 16, 2192–2195. Zuo, Z.; Ma, D. Angew. Chem., Int. Ed. 2011, 50, 12008. Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132, 13226. 761   Index INDEX 3 3,3-disubstituted oxindole ......................................................................................................... 12, 19, 318 A acetal .............................................................................................................. 337, 586, 597, 637, 638, 652 alistonitrine A ................................................................................................................ 583, 584, 588, 589 alkaloid .............................................................................................................................. 4, 335, 420, 583 aminal .............................................................................. 2, 18, 26, 27, 28, 31, 85, 86, 91, 94, 95, 96, 584 asymmetric .............................................................................................................. 13, 318, 322, 361, 366 atroposelective ............................................................................................................................... 361, 366 aurantioclavine .................................................................................... 4, 5, 7, 10, 13, 40, 44, 57, 309, 315 B Baylis-Hillman .............................................................................................................................. 585, 586 biosynthesis ............................................................................................................................................... 4 bromooxindole ......................................................... 9, 14, 46, 49, 55, 56, 59, 63, 320, 322, 327, 328, 602 C caged ...................................................................................................................................................... 583 Claisen ................................................................................................................................... 570, 571, 575 communesin ........... 1, 2, 4, 9, 12, 16, 18, 19, 28, 30, 31, 32, 304, 306, 307, 309, 310, 319, 327, 336, 339 copper .............................................................................. 13, 318, 319, 320, 321, 322, 323, 324, 326, 328 Corey-Chaykovsky ................................................................................................................................ 642 cross-coupling ........................................................................................................ 419, 424, 433, 445, 450 cycloaddition ............................................................................................................... 4, 5, 6, 7, 8, 14, 307 cycloetherification ......................................................................................................................... 421, 425 D Danheiser ............................................................................................................................................... 639 decarboxylative allylic alkylation .................................................................................... 16, 18, 20, 29, 33 diastereomer .................................................................................................. 5, 14, 16, 19, 22, 31, 59, 304 Diazo ...................................................................................................................................................... 641 dynamic kinetic resolution .................................................................................................... 361, 362, 366 E enantioselective ......................................................................................................... 5, 318, 319, 366, 637 Index 762   enol ether ....................................................................................................................................... 420, 638 F Fischer indole ........................................................................................................................................ 588 G Grubbs ................................................................................................................................................... 647 H Heck ............................................................................................................................................... 420, 588 I indole ........................................... 2, 5, 7, 9, 14, 33, 38, 43, 44, 46, 49, 53, 57, 58, 73, 314, 315, 316, 321 ineleganolide .......................................................................................................... 635, 636, 637, 645, 649 K kinetic resolution ....................................................................................................................... 5, 361, 362 L lactam 4, 10, 18, 21, 22, 23, 26, 27, 28, 29, 30, 33, 52, 79, 84, 87, 88, 305, 335, 337, 344, 430, 585, 586, 589, 595, 596, 600, 601, 602, 605, 606 lactone .................................................................................... 16, 18, 19, 21, 68, 76, 77, 80, 304, 635, 659 ligand ............................................................................. 318, 320, 321, 323, 324, 328, 361, 363, 364, 366 M Metathesis ...................................................................................................................................... 645, 648 Michael reaction ............................................................................................................................ 636, 637 microwave ......................................................................................................... 33, 76, 311, 340, 575, 590 N nickel ..................................................................................................................................... 419, 421, 427 nitrobenzyl ..................................................................................................................................... 335, 336 nomofungin ................................................................................................................................................ 2 O oxindole9, 12, 13, 14, 15, 18, 19, 21, 22, 24, 26, 27, 28, 29, 30, 32, 36, 54, 58, 59, 65, 66, 67, 75, 76, 87, 89, 94, 96, 312, 318, 326, 335, 337, 584, 587, 588, 603 P palladium ....................................................................................................................................... 363, 588 Index 763   perophoramidine ............................................................ 3, 12, 16, 18, 28, 31, 32, 304, 319, 327, 335, 339 PINAP ............................................................................................................ 361, 362, 364, 366, 369, 370 Pinnick oxidation ................................................................................................................................... 639 Q quaternary .............................................................. 2, 3, 6, 15, 16, 18, 20, 29, 32, 318, 319, 327, 584, 587 QUINAP ................................................................................................................................ 361, 362, 366 R reductive amination ....................................................................................... 21, 22, 27, 33, 336, 588, 589 reductive cyclization .................................................................................................. 22, 24, 26, 27, 31, 33 Robinson annulation .............................................................................................................................. 589 Rubottom ....................................................................................................................................... 638, 642 S stereochemistry .................................................... 5, 8, 13, 15, 16, 20, 29, 32, 59, 309, 319, 424, 635, 674 Still-Gennari .......................................................................................................................................... 637 T tert-butanesulfinyl ................................................................................................................................. 585 U umpolung ........................................................................................................................................... 13, 14 764   About the Author About the Author Seojung Han was born on March 2nd, 1985 in Gumi, Gyeongsang buk-do Province, South Korea. She spent her early life in the company of her parents and her younger brother Sangjun in Gumi. Seojung attended Gyeongbuk Foreign Language High School, where she learned foreign languages such as English, Japanese and Chinese and developed interest in science. In 2004, she began her undergraduate studies at Sogang University in Seoul, Korea. Seojung became attracted to organic chemistry because any of the desired new compounds could be prepared by organic synthesis. Eager to apply the knowledge from her studies, Seojung joined Prof. Duck-Hyung Lee’s laboratory as an undergraduate research assistant and practiced multi-step reactions and synthesized heterocycles related to medicinal chemistry. Seojung received bachelor’s degree in chemistry summa cum laude from Sogang University in 2008. Upon graduation, Seojung joined the research group of Prof. Duck-Hyung Lee for an M.S. degree in organic chemistry at Sogang University and completed the enantioselective synthesis of a C9–C17 fragment of (–)-amphidinolide O and P. In addition, she synthesized fragments of ascospiroketal B and arenicolide A. Upon obtaining an M.S. degree in 2010 summa cum laude, she worked at the Korea Research Institute of Chemical Technology in the medicinal chemistry department to contribute to the development of novel drug candidates for treatment of metabolic diseases and new fluorescent small molecule probes for staining blood vessels. In the fall of 2011, Seojung moved to Pasadena, California in USA, where she began her doctoral studies in synthetic organic chemistry at the California Institute of Technology. In December of 2011, she eagerly joined the research group of Prof. Brian M. Stoltz to study total synthesis of natural products and development of new 765   methodologies. Seojung earned her Ph.D. in chemistry in 2016. In September of About the Author 2016, she will continue her postdoctoral research under the guidance of Prof. F. Dean Toste at University of California, Berkeley.