Synthesis of Organic Building Blocks and Synthetic Strategies Toward Aleutianamine Citation Sercel, Zachary Patrick (2023) Synthesis of Organic Building Blocks and Synthetic Strategies Toward Aleutianamine. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/3ezw-2h57. https://resolver.caltech.edu/CaltechTHESIS:05312023-053933898 Abstract Described herein are the development of the palladium-catalyzed decarboxylative asymmetric allylic alkylation of medicinally relevant 5- and 7-membered diazaheterocycles and efforts toward the total synthesis of the cytotoxic pyrroloiminoquinone marine alkaloid aleutianamine. The former methodology provides a new tactic to incorporate Csp3 structural complexity into future lead compounds containing diazepane and imidazolidine moieties. The latter project is ongoing. Additionally, Chapter 3 discusses preliminary attempts to improve the synthetic accessibility of minimally substituted corroles, which were conducted during a research internship in the laboratory of Prof. Zeev Gross at the Technion. During the course of this research, the first example of a β-unsubstituted free base monoazaporphyrin was isolated, and its cobalt complex was characterized by x-ray crystallography. Finally, Appendix 8 presents a series of cationic and radical-mediated fragmentations of a derivative of (+)-3-Carene, a chiral pool material. These experiments led to the observation and mechanistic study of an unexpected rearrangement. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: chemistry, organic, synthesis, palladium, allylic alkylation, synthetic methods, natural products 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: Robb, Maxwell J. (chair) Gray, Harry B. Reisman, Sarah E. Stoltz, Brian M. Defense Date: 24 May 2023 Funders: Funding Agency Grant Number NSF Graduate Research Fellowship DGE-1745301 NIH R35GM145239 NIH R01GM080269 Record Number: CaltechTHESIS:05312023-053933898 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:05312023-053933898 DOI: 10.7907/3ezw-2h57 Related URLs: URL URL Type Description https://pubs.acs.org/doi/pdf/10.1021/acs.orglett.9b03530 Related Document Article Adapted for Chapter 1 https://pubs.acs.org/doi/pdf/10.1021/acs.orglett.1c02134 Related Document Article Adapted for Chapter 1 https://doi.org/10.1016/j.tetlet.2021.153496 Related Document Article Adapted for Appendix 8 ORCID: Author ORCID Sercel, Zachary Patrick 0000-0001-7977-8509 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 15242 Collection: CaltechTHESIS Deposited By: Zachary Sercel Deposited On: 02 Jun 2023 15:28 Last Modified: 06 Dec 2023 19:46 Thesis Files PDF (Final Version) - Final Version See Usage Policy. 49MB Repository Staff Only: item control page

SYNTHESIS OF ORGANIC BUILDING BLOCKS AND SYNTHETIC STRATEGIES TOWARD ALEUTIANAMINE Thesis by Zachary Patrick Sercel In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2023 (Defended May 24, 2023) ii © 2023 Zachary Patrick Sercel ORCID: 0000-0001-7977-8509 All Rights Reserved iii To Betty Leifer, my grandmother iv ACKNOWLEDGEMENTS I owe a great deal of gratitude to Professor Brian Stoltz. I first met Brian about 12 years ago when I was a middle schooler seeking to learn more about chemistry. Brian was kind enough to meet with me in his office and give a brief introduction to natural product synthesis. Since then, I have been lucky to have Brian as a strong supporter of my education and am very fortunate to have been able to conduct my Ph.D. studies in his group. In addition to being an incredibly patient, supportive, and personable mentor, Brian has been extremely generous with the creative and scientific freedom he has given me, including the opportunity to spend 5 months conducting research abroad in a different field. The environment Brian has created in his group is a true realization of his vision of “the intellectual adventure of a lifetime.” Professor Maxwell Robb has been an excellent committee chair. I really enjoyed my rotation in the Robb group during my first term of graduate school. Thank you also to Professors Sarah Reisman and Harry Gray for being wonderful committee members. The scientific and career advice that Max, Harry, and Sarah have provided has been very helpful throughout my time at Caltech. I feel fortunate to have had the opportunity to interact with such brilliant chemists. I have enjoyed hearing Harry’s stories and insight, and Sarah’s astute observations and helpful suggestions, especially during our joint group meetings, have been a huge asset. I would also like to thank Professor Matthias Selke, who taught my sophomore organic chemistry course at Cal State LA and supervised my undergraduate thesis research. Prof. Selke’s exemplary teaching and mentorship contributed to my decision to continue studying organic chemistry. I often reflect on his memorable stories and advice. v Additionally, Dr. Richard Maddox, the late director of the Early Entrance Program at Cal State LA, had a profound impact on my life and my education. Rich’s unique program enabled me to pursue my passion for chemistry 5 years earlier than I would otherwise have been able to. I have had the privilege of collaborating with quite a few talented people on an assortment of projects in the Stoltz group. First, I would like to thank Dr. Alexander Sun. Alex mentored me for a summer when I was an undergraduate, taking the time to teach me synthetic lab technique from the ground up, which was no small investment. I also had the opportunity to work with Alex on the allylic alkylation of diazaheterocycles when I started in the group as a graduate student. Dr. Gerit Pototschnig also served as a mentor to me as an undergraduate, specifically during my first foray into total synthesis. Gerit was a fantastic mentor and hoodmate, and her advice helped me to refine my synthetic and analytical technique. I fondly remember Gerit walking me though the (at the time, uniquely terrifying) large-scale preparation and distillation of allyl cyanoformate. Samir Rezgui joined the aleutianamine project at an early stage. Seeing Samir tackle challenges in synthesis and reaction development has been truly inspiring. It is rare to find someone who accepts scientific challenges and curveballs with such grace, determination, and humor. I hope to be able to incorporate some of Samir’s unique attitude and approach into my own science in the future. In addition to being a great project partner, Samir has been a wonderful friend and a positive influence in my life. Hao Yu joined the synthesis the following year and quickly made a profound impact on the project through his tireless work and brilliant, creative ideas. I have really enjoyed vi working with Hao and our chemistry discussions, from which I have learned a great deal. Hao is also extremely generous with the time he spends sharing his vast knowledge with the group by leading denksport exercises and informal problem sessions. We were recently lucky to be joined on a spinoff project by Jonathan Farhi. Mentoring Jonathan in the lab has been a really enjoyable experience, and I am happy that of all the projects he could have worked on, he chose this one. In addition, I have had the chance to collaborate with Adrian Samkian, Alex Cusumano, Youngkyu Park, Dr. Trevor Lohrey, Farbod Moghadam, and Elliot Hicks on various other projects. I am grateful to have worked with and learned from each of these project partners and am looking forward to seeing the great things they will do in the future. I would like to thank Alex Cusumano, with whom I worked in the Spalding basement during the COVID-19 pandemic. Alex has taught me a lot about both chemistry and teamwork, in addition to being a true friend. I have also been privileged to work with some awesome bay-mates in bay 2. Those whom I have not already mentioned include Jay Barbor, Melinda Chan, Dr. Elizabeth Goldstein, Ben Gross, Dr. Carina Jette, Dr. Sebastian Lackner, Dr. Fa Ngamnithiporn, Dr. Beau Pritchett, and Kim Sharp. It is highly motivating to be able to have conversations with such interesting and bright people every day in the lab. In addition to Alex, I thank Alexia Kim and Tyler “TC” Casselman, the other members of our class of four. I have enjoyed getting to know each of them and chatting about the amazing chemistry that they have done. It has been a pleasure to interact with Dr. Scott Virgil, the director of the catalysis center. The instruments expertly maintained by Scott have enabled a large portion of the vii research described in this thesis. Furthermore, Scott has been very generous with his time, making himself available to chat at length about chemistry and help with challenging separations, and has provided invaluable suggestions and advice throughout the course of my graduate studies. In the summer of 2019, I had the chance to serve as a mentor to Liz Park, an undergraduate WAVE fellow. I am grateful to Liz for the opportunity to mentor her, which I really enjoyed. She is a quick learner and demonstrated herself to be a brilliant and highly adaptive researcher. By my count, during my time in the Stoltz lab, I have overlapped with about 100 grad students, postdocs, visiting scholars, and undergraduate researchers. Each of these people has, in some way, contributed to my professional and personal development, and there is no way that I can adequately thank all of them in these pages for the enormous impact that they have had on me. I would like to thank a few additional people in particular though: Besides my baymates, Kevin Gonzalez, Elliot Hicks, Dr. Veronica Hubble, Dr. Trevor Lohrey, Farbod Moghadam, Dr. Brendan O’Boyle, “Teacher Adrian” Samkian, and Christian Strong, among others, have been really fun to chat with and bounce ideas off of. Their suggestions have been extremely helpful, and I’ve enjoyed getting to know many of them outside of the lab as well. Professor Mark Davis and the Davis research group, in addition to collaborating with us on the zeolite project, allowed me to work in their lab space during the COVID-19 pandemic when most of the lab was on a shift schedule. The generosity of the Davis group helped me get back on track after the considerable disruption caused by the pandemic. viii Dr. Dave VanderVelde, Dr. Mona Shagholi, and Dr. Mike Takase maintain excellent NMR, mass spectrometry, and x-ray crystallography facilities, respectively. These facilities have been essential to this research, and advice from Dave, in particular, has greatly contributed to my practical NMR knowledge. Professor Zeev Gross was very kind to invite me to conduct a research internship in his lab at the Technion during my fourth year. It was a great experience to live in Israel and to conduct research in a new subfield. Thanks are also due to the members of the Gross research group, especially Dr. Atif Mahammed, Marcelo Fernandez de la Mora, Arik Raslin, and Dr. Irina Saltsman, with whom I had the chance to collaborate. Outside of the lab, Chabad at Caltech has been like a second home. I owe many thanks to the Stolik family for being so welcoming and generous. I could not imagine grad school without the friends I have met at Chabad, including Sam Davidson, Dr. Simon Mahler, Sophie Miller, Oren Mizrahi, Danielle Resheff, Will Rosencrans, Dr. Lee Rosenthal, Helen Wexler, and Michael Wollman. The roommates with whom I have lived in various apartments during grad school have also been an invaluable source of outside perspective and insight. Thank you, Nicholas Duncan, Aidan Fenwick, and Roey Lazarovits. I have known Nicholas Duncan, in particular, for almost 10 years. His friendship has provided abundant support to me when I have needed it. None of this journey would have been possible without the encouragement to follow my passions and the sense of scientific curiosity and wonder instilled in me from a young age by my parents, Stephanie and Pete. I am really lucky to have grown up in an environment where “do what you love” was a mantra and where I had unconditional ix support for my education and career choices. I am glad that I chose to go to graduate school near my family, which has enabled me to visit home often to see my parents and my siblings, Gregory, Erin, and Jonathan. I am always proud to see the great things constantly being accomplished by my siblings. Each of them teaches me something new almost every time that I visit. The final leg of graduate school has been so much easier thanks to the abundant love and support from my partner, Eva Zanditenas. I thank Eva for braving the distance of almost 7,500 miles so that I can do chemistry, for her unconditional willingness to lend an ear, and for helping me remain focused on what’s truly important. I gratefully acknowledge the National Science Foundation and Rose Hills Foundation for funding my Ph.D. studies. x ABSTRACT Research in the Stoltz group is primarily focused on the total synthesis of complex, bioactive natural products and on the development of reaction methodologies to enable these synthetic endeavors. The majority of the content of this thesis focuses on permutations of this central goal. Chapter 1 describes the development of the palladium-catalyzed decarboxylative asymmetric allylic alkylation of medicinally relevant 5- and 7-membered diazaheterocycles to afford quaternary and gem-disubstituted derivatives. This methodology provides a new tactic to incorporate Csp3 structural complexity into future lead compounds containing diazepane and imidazolidine moieties. Chapter 2 discloses efforts toward the total synthesis of the cytotoxic pyrroloiminoquinone marine alkaloid aleutianamine. Key to the synthetic strategy are rapid assembly of the tricyclic pyrroloiminoquinone core in the arene oxidation state, convergent fragment coupling with a readily accessible aminothiophene derivative, and a powerful new dearomative spirocyclization. This research is ongoing. Chapter 3 discusses preliminary attempts to improve the synthetic accessibility of minimally substituted corroles, which were conducted during a research internship in the laboratory of Prof. Zeev Gross at the Technion. During the course of this research, the first example of a β-unsubstituted free base monoazaporphyrin was isolated, and its cobalt complex was characterized by x-ray crystallography. Finally, Appendix 8 presents a series of cationic and radical-mediated fragmentations of a derivative of (+)-3-Carene, a chiral pool material. These experiments led to the observation and mechanistic study of an unexpected rearrangement. xi PUBLISHED CONTENT AND CONTRIBUTIONS 1. Sercel, Z. P.; Sun, A. W.; Stoltz, B. M. Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 1,4-diazepan-5-ones. Org. Lett. 2019, 21, 9158–9161. DOI: 10.1021/acs.orglett.9b03530 Z. P. S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 2. Sercel, Z. P.; Sun, A. W.; Stoltz, B. M. Synthesis of Enantioenriched gemDisubstituted 4-Imidazolidinones by Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation. Org. Lett. 2021, 23, 6348–6351. DOI: 10.1021/acs.orglett.1c02134 Z. P. S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 3. Samkian, A. E.; Sercel, Z. P.; Virgil, S. C.; Stoltz, B. M. Some Unusual Transformations of a Highly Reactive α-Bromocaranone. Tetrahedron Lett. 2022, 89, 153496. DOI: 10.1016/j.tetlet.2021.153496 Z. P. S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. xii 4. Moghadam, F. A.; Hicks, E. F.; Sercel, Z. P.; Cusumano, A. Q.; Bartberger, M. D.; Stoltz, B. M. Ir-Catalyzed Asymmetric Allylic Alkylation of Dialkyl Malonates Enabling the Construction of Enantioenriched All-Carbon Quaternary Centers. J. Am. Chem. Soc. 2022, 144, 7983–7987. DOI: 10.1021/jacs.2c02960 Z. P. S. participated in experimental work and data acquisition and analysis. 5. Li, C.; Lohrey, T. D.; Nguyen, P.; Min, Z.; Tang, Y.; Ge, C.; Sercel, Z. P.; McLeod, E.; Stoltz, B. M.; Su, J. Part-per-trillion trace selective gas detection using frequency locked whispering gallery mode microtoroids. ACS Appl. Mater. Interfaces 2022, 14, 42430–42440. DOI: 10.1021/acsami.2c11494 Z. P. S. participated in experimental work (synthesis). xiii TABLE OF CONTENTS Dedication ................................................................................................................................ iii Acknowledgements................................................................................................................... iv Abstract ..................................................................................................................................... x Published Content and Contributions ........................................................................................ xi Table of Contents .................................................................................................................... xiii List of Figures ......................................................................................................................... xvii List of Schemes .................................................................................................................... xxvii List of Tables ......................................................................................................................... xxxi List of Abbreviations ........................................................................................................... xxxiii CHAPTER 1 ........................................................................................................... 1 Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 1.1 Introduction ..................................................................................................... 1 1.2 Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 1,4Diazepan-5-ones ............................................................................................. 5 1.3 Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 4Imidazolidinones ........................................................................................... 11 1.4 Conclusion .................................................................................................... 23 1.5 Experimental Section ..................................................................................... 23 1.5.1 Materials and Methods ............................................................................... 23 1.5.2 Experimental Procedures ............................................................................ 25 1.5.3 1.6 1.5.2.1 General Procedure for Allylic Alkylation of Diazepanones ......... 25 1.5.2.2 Synthesis of Diazepanone Allylic Alkylation Substrates .............. 44 1.5.2.3 Derivatization of Diazepane Allylic Alkylation Products ............. 62 1.5.2.4 General Procedure for Allylic Alkylation of Imidazolidinones ..... 66 1.5.2.5 Synthesis of Imidazolidinone Allylic Alkylation Substrates .......... 85 1.5.2.6 Derivatization of Imidazolidinone Allylic Alkylation Products .. 101 Determination of Enantiomeric Excess ...................................................... 105 References and Notes .................................................................................. 109 xiv APPENDIX 1...................................................................................................... 116 Spectra Relevant to Chapter 1 APPENDIX 2...................................................................................................... 242 Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates A2.1 Introduction ................................................................................................. 242 A2.2 Attempts to Access a 1,4-Diazepan-2-one Allylic Alkylation Substrate ......... 243 A2.3 Attempts to Access Benzodiazepane-Derived Allylic Alkylation Substrates .. 244 A2.4 Conclusion .................................................................................................. 246 A2.5 Experimental Section ................................................................................... 246 A2.5.1 Materials and Methods ............................................................................. 246 A2.5.2 Experimental Procedures .......................................................................... 247 A2.6 References and Notes .................................................................................. 252 CHAPTER 2 ....................................................................................................... 254 Progress Toward the Total Synthesis of Aleutianamine 2.1 Introduction ................................................................................................. 254 2.2 Initial Retrosynthetic Analysis ...................................................................... 257 2.3 Strategies Involving Enolate Arylation .......................................................... 258 2.4 2nd-Generation Retrosynthesis ...................................................................... 262 2.5 Preparation of a Versatile Tricyclic Aniline .................................................. 263 2.6 Strategies for Bridged Bicycle Formation ...................................................... 270 2.7 3rd-Generation Retrosynthesis....................................................................... 280 2.8 Pursuit of a Dearomative Cyclization Approach ........................................... 281 2.9 Conclusion .................................................................................................. 295 2.10 Experimental Section ................................................................................... 295 2.11 2.10.1 Materials and Methods ............................................................................. 295 2.10.2 Experimental Procedures .......................................................................... 297 References and Notes .................................................................................. 349 APPENDIX 3...................................................................................................... 360 Synthetic Summary for Chapter 2 APPENDIX 4...................................................................................................... 363 Spectra Relevant to Chapter 2 xv APPENDIX 5...................................................................................................... 447 Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine A5.1 Introduction ................................................................................................. 447 A5.2 Bridgehead Sulfide Installation: Model Studies ............................................. 447 A5.3 Early Strategies Toward a Tricylic Aminoindole ........................................... 450 A5.4 Additional Efforts Toward Key Tetracyclic Quinolone .................................. 453 A5.5 Preliminary Evaluation of a Wacker Oxidation of Internal α,β-Unsaturated Carbonyl Compounds .................................................................................. 457 A5.6 Alkenyl Bromide Installation Via a Functional Handle ................................. 460 A5.7 Spirocycle-First Approach to δ-Oxidized Thioimidate .................................. 462 A5.8 Experimental Section ................................................................................... 464 A5.8.1 Materials and Methods ............................................................................. 464 A5.8.2 Experimental Procedures .......................................................................... 465 A5.9 References and Notes .................................................................................. 480 CHAPTER 3 ....................................................................................................... 484 Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 3.1 Introduction ................................................................................................. 484 3.2 Attempts to Improve Bilane Synthesis ........................................................... 488 3.3 Unexpected Synthesis of a Monoazaporphyrin ............................................ 492 3.4 Conclusion .................................................................................................. 495 3.5 Experimental Section ................................................................................... 496 3.6 3.5.1 Materials and Methods ............................................................................. 496 3.5.2 Experimental Procedures .......................................................................... 497 References and Notes .................................................................................. 501 APPENDIX 6...................................................................................................... 506 Spectra Relevant to Chapter 3 APPENDIX 7...................................................................................................... 509 X-Ray Crystallography Reports Relevant to Chapter 3 A7.1 General Experimental Information ............................................................... 510 A7.2 X-Ray Crystal Structure Analysis of Cobalt Azaporphyrin 306-Co ................. 510 xvi APPENDIX 8...................................................................................................... 524 Some Unusual Transformations of a Highly Reactive α-Bromocaranone A8.1 Introduction ................................................................................................. 524 A8.2 Synthesis and Fragmentations of a Bromocaranone ...................................... 525 A8.3 Conclusion .................................................................................................. 530 A8.4 Experimental Section ................................................................................... 530 A8.5 A8.4.1 Materials and Methods ............................................................................. 530 A8.4.2 Experimental Procedures .......................................................................... 532 References and Notes .................................................................................. 544 APPENDIX 9...................................................................................................... 547 Notebook Cross-Reference for New Compounds Index ............................................................................................................... 553 About the Author ............................................................................................ 557 xvii LIST OF FIGURES CHAPTER 1 Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles Figure 1.1.2. Incorporation of a gem-disubstituted heterocycle into linezolid ................................. 3 Figure 1.2.1. Representative pharmaceuticals containing a diazepane-derived ring system ............ 5 Figure 1.3.1. Representative pharmaceuticals bearing a 4-imidazolidinone moiety ...................... 11 APPENDIX 1 Spectra Relevant to Chapter 1 Figure A1.1. 1H NMR (400 MHz, CDCl3) of compound 20a ............................................................ 117 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound 20a ................................................ 118 Figure A1.3. 13C NMR (100 MHz, CDCl3) of compound 20a............................................................ 118 Figure A1.4. 1H NMR (400 MHz, CDCl3) of compound 20b ............................................................ 119 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 20b ................................................ 120 Figure A1.6. 13C NMR (100 MHz, CDCl3) of compound 20b ........................................................... 120 Figure A1.7. 1H NMR (400 MHz, CDCl3) of compound 20c ............................................................ 121 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 20c ................................................ 122 Figure A1.9. 13C NMR (100 MHz, CDCl3) of compound 20c............................................................ 122 Figure A1.10. 1H NMR (400 MHz, CDCl3) of compound 20d .......................................................... 123 Figure A1.11. Infrared spectrum (Thin Film, NaCl) of compound 20d .............................................. 124 Figure A1.12. 13C NMR (100 MHz, CDCl3) of compound 20d ......................................................... 124 Figure A1.13. 1H NMR (400 MHz, CDCl3) of compound 20e .......................................................... 125 Figure A1.14. Infrared spectrum (Thin Film, NaCl) of compound 20e .............................................. 126 Figure A1.15. 13C NMR (100 MHz, CDCl3) of compound 20e.......................................................... 126 Figure A1.16. 1H NMR (400 MHz, CDCl3) of compound 20f ........................................................... 127 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 20f ............................................... 128 Figure A1.18. 13C NMR (100 MHz, CDCl3) of compound 20f .......................................................... 128 Figure A1.19. 1H NMR (400 MHz, CDCl3) of compound 20g .......................................................... 129 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 20g .............................................. 130 Figure A1.21. 13C NMR (100 MHz, CDCl3) of compound 20g.......................................................... 130 Figure A1.22. 1H NMR (400 MHz, CDCl3) of compound 20h .......................................................... 131 xviii Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 20h .............................................. 132 Figure A1.24. 13C NMR (100 MHz, CDCl3) of compound 20h ......................................................... 132 Figure A1.25. 1H NMR (400 MHz, CDCl3) of compound 20i ........................................................... 133 Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 20i ............................................... 134 Figure A1.27. 13C NMR (100 MHz, CDCl3) of compound 20i .......................................................... 134 Figure A1.28. 1H NMR (400 MHz, CDCl3) of compound 20j ........................................................... 135 Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 20j ............................................... 136 Figure A1.30. 13C NMR (100 MHz, CDCl3) of compound 20j .......................................................... 136 Figure A1.31. 1H NMR (400 MHz, CDCl3) of compound 20k .......................................................... 137 Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 20k .............................................. 138 Figure A1.33. 13C NMR (100 MHz, CDCl3) of compound 20k.......................................................... 138 Figure A1.34. 1H NMR (400 MHz, CDCl3) of compound 20l ........................................................... 139 Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 20l ............................................... 140 Figure A1.36. 13C NMR (100 MHz, CDCl3) of compound 20l .......................................................... 140 Figure A1.37. 1H NMR (400 MHz, CDCl3) of compound 55 ............................................................ 141 Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 55 ................................................ 142 Figure A1.39. 13C NMR (100 MHz, CDCl3) of compound 55 ........................................................... 142 Figure A1.40. 1H NMR (400 MHz, CDCl3) of compound 56 ............................................................ 143 Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 56 ................................................ 144 Figure A1.42. 13C NMR (100 MHz, CDCl3) of compound 56 ........................................................... 144 Figure A1.43. 1H NMR (400 MHz, CDCl3) of compound 57 ............................................................ 145 Figure A1.44. Infrared spectrum (Thin Film, NaCl) of compound 57 ................................................ 146 Figure A1.45. 13C NMR (100 MHz, CDCl3) of compound 57 ........................................................... 146 Figure A1.46. 1H NMR (500 MHz, CDCl3) of compound 18a .......................................................... 147 Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 18a .............................................. 148 Figure A1.48. 13C NMR (125 MHz, CDCl3) of compound 18a.......................................................... 148 Figure A1.49. 1H NMR (400 MHz, CDCl3) of compound 18b .......................................................... 149 Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound 18b .............................................. 150 Figure A1.51. 13C NMR (100 MHz, CDCl3) of compound 18b ......................................................... 150 Figure A1.52. 1H NMR (400 MHz, CDCl3) of compound 18c .......................................................... 151 Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 18c .............................................. 152 Figure A1.54. 13C NMR (100 MHz, CDCl3) of compound 18c.......................................................... 152 Figure A1.55. 1H NMR (400 MHz, CDCl3) of compound 19a .......................................................... 153 Figure A1.56. Infrared spectrum (Thin Film, NaCl) of compound 19a .............................................. 154 Figure A1.57. 13C NMR (100 MHz, CDCl3) of compound 19a.......................................................... 154 xix Figure A1.58. 1H NMR (400 MHz, CDCl3) of compound 19b .......................................................... 155 Figure A1.59. Infrared spectrum (Thin Film, NaCl) of compound 19b .............................................. 156 Figure A1.60. 13C NMR (100 MHz, CDCl3) of compound 19b ......................................................... 156 Figure A1.61. 1H NMR (400 MHz, CDCl3) of compound 19c .......................................................... 157 Figure A1.62. Infrared spectrum (Thin Film, NaCl) of compound 19c .............................................. 158 Figure A1.63. 13C NMR (100 MHz, CDCl3) of compound 19c.......................................................... 158 Figure A1.64. 1H NMR (400 MHz, CDCl3) of compound 19d .......................................................... 159 Figure A1.65. Infrared spectrum (Thin Film, NaCl) of compound 19d .............................................. 160 Figure A1.66. 13C NMR (100 MHz, CDCl3) of compound 19d ......................................................... 160 Figure A1.67. 1H NMR (500 MHz, CDCl3) of compound 19e .......................................................... 161 Figure A1.68. Infrared spectrum (Thin Film, NaCl) of compound 19e .............................................. 162 Figure A1.69. 13C NMR (125 MHz, CDCl3) of compound 19e.......................................................... 162 Figure A1.70. 1H NMR (500 MHz, CDCl3) of compound 19f ........................................................... 163 Figure A1.71. Infrared spectrum (Thin Film, NaCl) of compound 19f ............................................... 164 Figure A1.72. 13C NMR (125 MHz, CDCl3) of compound 19f .......................................................... 164 Figure A1.73. 1H NMR (400 MHz, CDCl3) of compound 19g .......................................................... 165 Figure A1.74. Infrared spectrum (Thin Film, NaCl) of compound 19g .............................................. 166 Figure A1.75. 13C NMR (100 MHz, CDCl3) of compound 19g.......................................................... 166 Figure A1.76. 1H NMR (400 MHz, CDCl3) of compound 19h .......................................................... 167 Figure A1.77. Infrared spectrum (Thin Film, NaCl) of compound 19h .............................................. 168 Figure A1.78. 13C NMR (100 MHz, CDCl3) of compound 19h ......................................................... 168 Figure A1.79. 1H NMR (500 MHz, CDCl3) of compound 19i ........................................................... 169 Figure A1.80. Infrared spectrum (Thin Film, NaCl) of compound 19i ............................................... 170 Figure A1.81. 13C NMR (125 MHz, CDCl3) of compound 19i .......................................................... 170 Figure A1.82. 1H NMR (500 MHz, CDCl3) of compound 19j ........................................................... 171 Figure A1.83. Infrared spectrum (Thin Film, NaCl) of compound 19j ............................................... 172 Figure A1.84. 13C NMR (125 MHz, CDCl3) of compound 19j .......................................................... 172 Figure A1.85. 1H NMR (400 MHz, CDCl3) of compound 19k .......................................................... 173 Figure A1.86. Infrared spectrum (Thin Film, NaCl) of compound 19k .............................................. 174 Figure A1.87. 13C NMR (100 MHz, CDCl3) of compound 19k.......................................................... 174 Figure A1.88. 1H NMR (400 MHz, CDCl3) of compound 19l ........................................................... 175 Figure A1.89. Infrared spectrum (Thin Film, NaCl) of compound 19l ............................................... 176 Figure A1.90. 13C NMR (100 MHz, CDCl3) of compound 19l .......................................................... 176 Figure A1.91. 1H NMR (400 MHz, CDCl3) of compound 21 ............................................................ 177 Figure A1.92. Infrared spectrum (Thin Film, NaCl) of compound 21 ................................................ 178 xx Figure A1.93. 13C NMR (100 MHz, CDCl3) of compound 21 ........................................................... 178 Figure A1.94. 1H NMR (400 MHz, CDCl3) of compound 23 ............................................................ 179 Figure A1.95. Infrared spectrum (Thin Film, NaCl) of compound 23 ................................................ 180 Figure A1.96. 13C NMR (100 MHz, CDCl3) of compound 23 ........................................................... 180 Figure A1.97. 1H NMR (400 MHz, CDCl3) of compound 25 ............................................................ 181 Figure A1.98. Infrared spectrum (Thin Film, NaCl) of compound 25 ................................................ 182 Figure A1.99. 13C NMR (100 MHz, CDCl3) of compound 25 ........................................................... 182 Figure A1.100. 1H NMR (400 MHz, DMSO-d6, 23.3 °C) of compound 20e ...................................... 183 Figure A1.101. 1H NMR (400 MHz, DMSO-d6, 80 °C) of compound 20e ......................................... 184 Figure A1.102. 13C NMR (100 MHz, DMSO-d6, 80 °C) of compound 20e ........................................ 185 Figure A1.103. 1H NMR (400 MHz, CDCl3) of compound 35a ........................................................ 186 Figure A1.104. Infrared spectrum (Thin Film, NaCl) of compound 35a ............................................ 187 Figure A1.105. 13C NMR (100 MHz, CDCl3) of compound 35a ....................................................... 187 Figure A1.106. 1H NMR (400 MHz, CDCl3) of compound 35b ........................................................ 188 Figure A1.107. Infrared spectrum (Thin Film, NaCl) of compound 35b ............................................ 189 Figure A1.108. 13C NMR (100 MHz, CDCl3) of compound 35b ....................................................... 189 Figure A1.109. 1H NMR (400 MHz, CDCl3) of compound 35c ........................................................ 190 Figure A1.110. Infrared spectrum (Thin Film, NaCl) of compound 35c ............................................ 191 Figure A1.111. 13C NMR (100 MHz, CDCl3) of compound 35c ....................................................... 191 Figure A1.112. 1H NMR (400 MHz, CDCl3) of compound 35d ........................................................ 192 Figure A1.113. Infrared spectrum (Thin Film, NaCl) of compound 35d ............................................ 193 Figure A1.114. 13C NMR (100 MHz, CDCl3) of compound 35d ....................................................... 193 Figure A1.115. 1H NMR (400 MHz, CDCl3) of compound 35e ........................................................ 194 Figure A1.116. Infrared spectrum (Thin Film, NaCl) of compound 35e ............................................ 195 Figure A1.117. 13C NMR (100 MHz, CDCl3) of compound 35e ....................................................... 195 Figure A1.118. 1H NMR (400 MHz, CDCl3) of compound 35f ......................................................... 196 Figure A1.119. Infrared spectrum (Thin Film, NaCl) of compound 35f ............................................. 197 Figure A1.120. 13C NMR (100 MHz, CDCl3) of compound 35f ........................................................ 197 Figure A1.121. 1H NMR (400 MHz, CDCl3) of compound 35g ........................................................ 198 Figure A1.122. Infrared spectrum (Thin Film, NaCl) of compound 35g ............................................ 199 Figure A1.123. 13C NMR (100 MHz, CDCl3) of compound 35g ....................................................... 199 Figure A1.124. 1H NMR (400 MHz, CDCl3) of compound 35h ........................................................ 200 Figure A1.125. Infrared spectrum (Thin Film, NaCl) of compound 35h ............................................ 201 Figure A1.126. 13C NMR (100 MHz, CDCl3) of compound 35h ....................................................... 201 Figure A1.127. 1H NMR (400 MHz, CDCl3) of compound 35i ......................................................... 202 xxi Figure A1.128. Infrared spectrum (Thin Film, NaCl) of compound 35i ............................................. 203 Figure A1.129. 13C NMR (100 MHz, CDCl3) of compound 35i ........................................................ 203 Figure A1.130. 1H NMR (400 MHz, CDCl3) of compound 35j ......................................................... 204 Figure A1.131. Infrared spectrum (Thin Film, NaCl) of compound 35j ............................................. 205 Figure A1.132. 13C NMR (100 MHz, CDCl3) of compound 35j ........................................................ 205 Figure A1.133. 1H NMR (400 MHz, CDCl3) of compound 35k ........................................................ 206 Figure A1.134. Infrared spectrum (Thin Film, NaCl) of compound 35k ............................................ 207 Figure A1.135. 13C NMR (100 MHz, CDCl3) of compound 35k ....................................................... 207 Figure A1.136. 1H NMR (400 MHz, CDCl3) of compound 31 .......................................................... 208 Figure A1.137. Infrared spectrum (Thin Film, KBr) of compound 31 ................................................ 209 Figure A1.138. 13C NMR (100 MHz, CDCl3) of compound 31 ......................................................... 209 Figure A1.139. 1H NMR (400 MHz, CDCl3) of compound 32 .......................................................... 210 Figure A1.140. Infrared spectrum (Thin Film, NaCl) of compound 32 .............................................. 211 Figure A1.141. 13C NMR (100 MHz, CDCl3) of compound 32 ......................................................... 211 Figure A1.142. 1H NMR (400 MHz, CDCl3) of compound 33 .......................................................... 212 Figure A1.143. Infrared spectrum (Thin Film, NaCl) of compound 33 .............................................. 213 Figure A1.144. 13C NMR (100 MHz, CDCl3) of compound 33 ......................................................... 213 Figure A1.145. 1H NMR (400 MHz, CDCl3) of compound 60 .......................................................... 214 Figure A1.146. Infrared spectrum (Thin Film, KBr) of compound 60 ................................................ 215 Figure A1.147. 13C NMR (100 MHz, CDCl3) of compound 60 ......................................................... 215 Figure A1.148. 1H NMR (400 MHz, CDCl3) of compound 34a ........................................................ 216 Figure A1.149. Infrared spectrum (Thin Film, NaCl) of compound 34a ............................................ 217 Figure A1.150. 13C NMR (100 MHz, CDCl3) of compound 34a ....................................................... 217 Figure A1.151. 1H NMR (400 MHz, CDCl3) of compound 34b ........................................................ 218 Figure A1.152. Infrared spectrum (Thin Film, NaCl) of compound 34b ............................................ 219 Figure A1.153. 13C NMR (100 MHz, CDCl3) of compound 34b ....................................................... 219 Figure A1.154. 1H NMR (400 MHz, CDCl3) of compound 34c ........................................................ 220 Figure A1.155. Infrared spectrum (Thin Film, NaCl) of compound 34c ............................................ 221 Figure A1.156. 13C NMR (100 MHz, CDCl3) of compound 34c ....................................................... 221 Figure A1.157. 1H NMR (400 MHz, CDCl3) of compound 34d ........................................................ 222 Figure A1.158. Infrared spectrum (Thin Film, NaCl) of compound 34d ............................................ 223 Figure A1.159. 13C NMR (100 MHz, CDCl3) of compound 34d ....................................................... 223 Figure A1.160. 1H NMR (400 MHz, CDCl3) of compound 34e ........................................................ 224 Figure A1.161. Infrared spectrum (Thin Film, NaCl) of compound 34e ............................................ 225 Figure A1.162. 13C NMR (100 MHz, CDCl3) of compound 34e ....................................................... 225 xxii Figure A1.163. 1H NMR (400 MHz, CDCl3) of compound 34f ......................................................... 226 Figure A1.164. Infrared spectrum (Thin Film, NaCl) of compound 34f ............................................. 227 Figure A1.165. 13C NMR (100 MHz, CDCl3) of compound 34f ........................................................ 227 Figure A1.166. 1H NMR (500 MHz, CDCl3) of compound 34g ........................................................ 228 Figure A1.167. Infrared spectrum (Thin Film, NaCl) of compound 34g ............................................ 229 Figure A1.168. 13C NMR (125 MHz, CDCl3) of compound 34g ....................................................... 229 Figure A1.169. 1H NMR (400 MHz, CDCl3) of compound 34h ........................................................ 230 Figure A1.170. Infrared spectrum (Thin Film, NaCl) of compound 34h ............................................ 231 Figure A1.171. 13C NMR (100 MHz, CDCl3) of compound 34h ....................................................... 231 Figure A1.172. 1H NMR (400 MHz, CDCl3) of compound 34i ......................................................... 232 Figure A1.173. Infrared spectrum (Thin Film, NaCl) of compound 34i ............................................. 233 Figure A1.174. 13C NMR (100 MHz, CDCl3) of compound 34i ........................................................ 233 Figure A1.175. 1H NMR (400 MHz, CDCl3) of compound 34j ......................................................... 234 Figure A1.176. Infrared spectrum (Thin Film, NaCl) of compound 34j ............................................. 235 Figure A1.177. 13C NMR (100 MHz, CDCl3) of compound 34j ........................................................ 235 Figure A1.178. 1H NMR (400 MHz, CDCl3) of compound 34k ........................................................ 236 Figure A1.179. Infrared spectrum (Thin Film, NaCl) of compound 34k ............................................ 237 Figure A1.180. 13C NMR (100 MHz, CDCl3) of compound 34k ....................................................... 237 Figure A1.181. 1H NMR (400 MHz, CDCl3) of compound 52 .......................................................... 238 Figure A1.182. Infrared spectrum (Thin Film, NaCl) of compound 52 .............................................. 239 Figure A1.183. 13C NMR (100 MHz, CDCl3) of compound 52 ......................................................... 239 Figure A1.184. 1H NMR (400 MHz, CDCl3) of compound 53 .......................................................... 240 Figure A1.185. Infrared spectrum (Thin Film, NaCl) of compound 53 .............................................. 241 Figure A1.186. 13C NMR (100 MHz, CDCl3) of compound 53 ......................................................... 241 APPENDIX 2 Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates Figure A2.1.1. Scope of diazepanone derivatives discussed herein .................................................... 3 APPENDIX 4 Spectra Relevant to Chapter 2 Figure A4.1. 1H NMR (400 MHz, CDCl3) of compound 96 .............................................................. 364 Figure A4.2. Infrared spectrum (Thin Film, NaCl) of compound 96 .................................................. 365 Figure A4.3. 13C NMR (100 MHz, CDCl3) of compound 96 ............................................................. 365 xxiii Figure A4.4. 1H NMR (400 MHz, CDCl3) of compound 97 .............................................................. 366 Figure A4.5. Infrared spectrum (Thin Film, NaCl) of compound 97 .................................................. 367 Figure A4.6. 13C NMR (100 MHz, CDCl3) of compound 97 ............................................................. 367 Figure A4.7. 1H NMR (400 MHz, CDCl3) of compound 107 ............................................................ 368 Figure A4.8. Infrared spectrum (Thin Film, NaCl) of compound 107 ................................................ 369 Figure A4.9. 13C NMR (100 MHz, CDCl3) of compound 107 ........................................................... 369 Figure A4.10. 1H NMR (400 MHz, CDCl3) of compound 109 .......................................................... 370 Figure A4.11. Infrared spectrum (Thin Film, NaCl) of compound 109 .............................................. 371 Figure A4.12. 13C NMR (100 MHz, CDCl3) of compound 109 ......................................................... 371 Figure A4.13. 1H NMR (400 MHz, CDCl3) of compound 125 .......................................................... 372 Figure A4.14. Infrared spectrum (Thin Film, NaCl) of compound 125 .............................................. 373 Figure A4.15. 13C NMR (100 MHz, CDCl3) of compound 125 ......................................................... 373 Figure A4.16. 1H NMR (400 MHz, CDCl3) of compound 126 .......................................................... 374 Figure A4.17. Infrared spectrum (Thin Film, NaCl) of compound 126 .............................................. 375 Figure A4.18. 13C NMR (100 MHz, CDCl3) of compound 126 ......................................................... 375 Figure A4.19. 1H NMR (400 MHz, CDCl3) of compound 131 .......................................................... 376 Figure A4.20. Infrared spectrum (Thin Film, NaCl) of compound 131 .............................................. 377 Figure A4.21. 13C NMR (100 MHz, CDCl3) of compound 131 ......................................................... 377 Figure A4.22. 1H NMR (400 MHz, CDCl3) of compound 132 .......................................................... 378 Figure A4.23. Infrared spectrum (Thin Film, NaCl) of compound 132 .............................................. 379 Figure A4.24. 13C NMR (100 MHz, CDCl3) of compound 132 ......................................................... 379 Figure A4.25. 1H NMR (400 MHz, CDCl3) of compound 133 .......................................................... 380 Figure A4.26. Infrared spectrum (Thin Film, NaCl) of compound 133 .............................................. 381 Figure A4.27. 13C NMR (100 MHz, CDCl3) of compound 133 ......................................................... 381 Figure A4.28. 1H NMR (400 MHz, CDCl3) of compound 134 .......................................................... 382 Figure A4.29. Infrared spectrum (Thin Film, NaCl) of compound 134 .............................................. 383 Figure A4.30. 13C NMR (100 MHz, CDCl3) of compound 134 ......................................................... 383 Figure A4.31. 1H NMR (400 MHz, CDCl3) of compound 136 .......................................................... 384 Figure A4.32. Infrared spectrum (Thin Film, NaCl) of compound 136 .............................................. 385 Figure A4.33. 13C NMR (100 MHz, CDCl3) of compound 136 ......................................................... 385 Figure A4.34. 1H NMR (400 MHz, CDCl3) of compound 138 .......................................................... 386 Figure A4.35. Infrared spectrum (Thin Film, NaCl) of compound 138 .............................................. 387 Figure A4.36. 13C NMR (100 MHz, CDCl3) of compound 138 ......................................................... 387 Figure A4.37. 1H NMR (400 MHz, CDCl3) of compound 139 .......................................................... 388 Figure A4.38. 13C NMR (100 MHz, CDCl3) of compound 139 ......................................................... 389 xxiv Figure A4.39. 1H NMR (400 MHz, CDCl3) of compound 143 .......................................................... 390 Figure A4.40. Infrared spectrum (Thin Film, NaCl) of compound 143 .............................................. 391 Figure A4.41. 13C NMR (100 MHz, CDCl3) of compound 143 ......................................................... 391 Figure A4.42. 1H NMR (400 MHz, CDCl3) of compound 141 .......................................................... 392 Figure A4.43. Infrared spectrum (Thin Film, NaCl) of compound 141 .............................................. 393 Figure A4.44. 13C NMR (100 MHz, CDCl3) of compound 141 ......................................................... 393 Figure A4.45. 1H NMR (400 MHz, CDCl3) of compound 149 .......................................................... 394 Figure A4.46. Infrared spectrum (Thin Film, NaCl) of compound 149 .............................................. 395 Figure A4.47. 13C NMR (100 MHz, CDCl3) of compound 149 ......................................................... 395 Figure A4.48. 1H NMR (400 MHz, CDCl3) of compound 150 .......................................................... 396 Figure A4.49. Infrared spectrum (Thin Film, NaCl) of compound 150 .............................................. 397 Figure A4.50. 13C NMR (100 MHz, CDCl3) of compound 150 ......................................................... 397 Figure A4.51. 1H NMR (400 MHz, C6D6) of compound 153 ............................................................ 398 Figure A4.52. Infrared spectrum (Thin Film, NaCl) of compound 153 .............................................. 399 Figure A4.53. 13C NMR (100 MHz, C6D6) of compound 153............................................................ 399 Figure A4.54. 1H NMR (400 MHz, C6D6) of compound 154 ............................................................ 400 Figure A4.55. Infrared spectrum (Thin Film, NaCl) of compound 154 .............................................. 401 Figure A4.56. 13C NMR (100 MHz, C6D6) of compound 154............................................................ 401 Figure A4.57. 1H NMR (400 MHz, CDCl3) of compound 156 .......................................................... 402 Figure A4.58. Infrared spectrum (Thin Film, NaCl) of compound 156 .............................................. 403 Figure A4.59. 13C NMR (100 MHz, CDCl3) of compound 156 ......................................................... 403 Figure A4.60. 1H NMR (400 MHz, C6D6) of compound 155 ............................................................ 404 Figure A4.61. Infrared spectrum (Thin Film, NaCl) of compound 155 .............................................. 405 Figure A4.62. 13C NMR (100 MHz, C6D6) of compound 155............................................................ 405 Figure A4.63. 1H NMR (400 MHz, C6D6) of compound 157 ............................................................ 406 Figure A4.64. Infrared spectrum (Thin Film, NaCl) of compound 157 .............................................. 407 Figure A4.65. 13C NMR (100 MHz, C6D6) of compound 157............................................................ 407 Figure A4.66. 1H NMR (400 MHz, C6D6) of compound 160 ............................................................ 408 Figure A4.67. Infrared spectrum (Thin Film, NaCl) of compound 160 .............................................. 409 Figure A4.68. 13C NMR (100 MHz, C6D6) of compound 160............................................................ 409 Figure A4.69. 1H NMR (400 MHz, C6D6) of compound 168 ............................................................ 410 Figure A4.70. Infrared spectrum (Thin Film, NaCl) of compound 168 .............................................. 411 Figure A4.71. 13C NMR (100 MHz, C6D6) of compound 168............................................................ 411 Figure A4.72. 1H NMR (400 MHz, C6D6) of compound 169 ............................................................ 412 Figure A4.73. Infrared spectrum (Thin Film, NaCl) of compound 169 .............................................. 413 xxv Figure A4.74. 13C NMR (100 MHz, C6D6) of compound 169............................................................ 413 Figure A4.75. 1H NMR (400 MHz, DMSO-d6) of compound 214..................................................... 414 Figure A4.76. Infrared spectrum (Thin Film, NaCl) of compound 214 .............................................. 415 Figure A4.77. 13C NMR (100 MHz, DMSO-d6) of compound 214 .................................................... 415 Figure A4.78. 1H NMR (400 MHz, C6D6) of compound 177 ............................................................ 416 Figure A4.79. Infrared spectrum (Thin Film, NaCl) of compound 177 .............................................. 417 Figure A4.80. 13C NMR (100 MHz, C6D6) of compound 177............................................................ 417 Figure A4.81. 1H NMR (400 MHz, C6D6) of compound 179 ............................................................ 418 Figure A4.82. Infrared spectrum (Thin Film, NaCl) of compound 179 .............................................. 419 Figure A4.83. 13C NMR (100 MHz, C6D6) of compound 179............................................................ 419 Figure A4.84. 1H NMR (400 MHz, C6D6) of compound 184 ............................................................ 420 Figure A4.85. Infrared spectrum (Thin Film, NaCl) of compound 184 .............................................. 421 Figure A4.86. 13C NMR (100 MHz, C6D6) of compound 184............................................................ 421 Figure A4.87. 1H NMR (400 MHz, CDCl3) of compound 187 .......................................................... 422 Figure A4.88. Infrared spectrum (Thin Film, NaCl) of compound 187 .............................................. 423 Figure A4.89. 13C NMR (100 MHz, CDCl3) of compound 187 ......................................................... 423 Figure A4.90. 1H NMR (400 MHz, CDCl3) of compound 215 .......................................................... 424 Figure A4.91. Infrared spectrum (Thin Film, NaCl) of compound 215 .............................................. 425 Figure A4.92. 13C NMR (100 MHz, CDCl3) of compound 215 ......................................................... 425 Figure A4.93. 1H NMR (400 MHz, C6D6) of compound 189 ............................................................ 426 Figure A4.94. Infrared spectrum (Thin Film, NaCl) of compound 189 .............................................. 427 Figure A4.95. 13C NMR (100 MHz, C6D6) of compound 189............................................................ 427 Figure A4.96. 1H NMR (400 MHz, CD2Cl2) of compound 186 ......................................................... 428 Figure A4.97. Infrared spectrum (Thin Film, NaCl) of compound 186 .............................................. 429 Figure A4.98. 13C NMR (100 MHz, CD2Cl2) of compound 186 ........................................................ 429 Figure A4.99. 1H NMR (400 MHz, CDCl3) of compound 190 .......................................................... 430 Figure A4.100. Infrared spectrum (Thin Film, NaCl) of compound 190 ............................................ 431 Figure A4.101. 13C NMR (100 MHz, CDCl3) of compound 190 ....................................................... 431 Figure A4.102. 1H NMR (400 MHz, C6D6) of compound 185 .......................................................... 432 Figure A4.103. Infrared spectrum (Thin Film, NaCl) of compound 185 ............................................ 433 Figure A4.104. 13C NMR (100 MHz, C6D6) of compound 185.......................................................... 433 Figure A4.105. 1H NMR (400 MHz, C6D6) of compound 192 .......................................................... 434 Figure A4.106. Infrared spectrum (Thin Film, NaCl) of compound 192 ............................................ 435 Figure A4.107. 13C NMR (100 MHz, C6D6) of compound 192.......................................................... 435 Figure A4.108. 1H NMR (400 MHz, C6D6) of compound 198 .......................................................... 436 xxvi Figure A4.109. Infrared spectrum (Thin Film, NaCl) of compound 198 ............................................ 437 Figure A4.110. 13C NMR (100 MHz, C6D6) of compound 198.......................................................... 437 Figure A4.111. 1H NMR (400 MHz, C6D6) of compound 195 .......................................................... 438 Figure A4.112. Infrared spectrum (Thin Film, NaCl) of compound 195 ............................................ 439 Figure A4.113. 13C NMR (100 MHz, C6D6) of compound 195.......................................................... 439 Figure A4.114. 1H NMR (400 MHz, C6D6) of compound 201 .......................................................... 440 Figure A4.115. Infrared spectrum (Thin Film, NaCl) of compound 201 ............................................ 441 Figure A4.116. 13C NMR (100 MHz, C6D6) of compound 201.......................................................... 441 Figure A4.117. 1H NMR (400 MHz, CD3OD) of compound 206...................................................... 442 Figure A4.118. Infrared spectrum (Thin Film, NaCl) of compound 206 ............................................ 443 Figure A4.119. 13C NMR (100 MHz, CD3OD) of compound 206 ..................................................... 443 Figure A4.120. 19F NMR (376 MHz, CD3OD) of compound 206 ..................................................... 444 Figure A4.121. 1H NMR (400 MHz, C6D6) of compound 207 .......................................................... 445 Figure A4.122. Infrared spectrum (Thin Film, NaCl) of compound 207 ............................................ 446 Figure A4.123. 13C NMR (100 MHz, C6D6) of compound 207.......................................................... 446 CHAPTER 3 Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins Figure 3.1.1. Introduction to the corrole ring system ................................................................... 484 Figure 3.1.2. Select milestones toward the synthesis of minimally substituted corroles ............... 485 Figure 3.3.3. Comparison of the 1H NMR spectra of azaporphyrin 306-H2 and corrole 293 ....... 493 APPENDIX 6 Spectra Relevant to Chapter 3 Figure A6.1. 1H NMR (400 MHz, CDCl3) of compound 306-H2 ....................................................... 507 Figure A6.2. 19F NMR (377 MHz, CDCl3) of compound 306-H2 ....................................................... 508 APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 3 Figure A7.2.1. X-ray crystal structure of azaporphyrin complex 306-Co ........................................ 511 xxvii LIST OF SCHEMES CHAPTER 1 Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles Scheme 1.1.1. Development of the Pd-catalyzed decarboxylative asymmetric allylic alkylation reaction................................................................................................................... 2 Scheme 1.1.3. Prior Pd-catalyzed decarboxylative asymmetric allylic alkylation of diazaheterocycles in the Stoltz group ..................................................................... 4 Scheme 1.2.2. Synthetic route to diazepanone-derived allyl β-amidoesters 19a–l ......................... 7 Scheme 1.2.5. Synthesis of a suvorexant analogue....................................................................... 10 Scheme 1.3.2. Pinza’s route to imidazolidinone .......................................................................... 12 Scheme 1.3.3. Initial synthesis of imidazolidinone allylic alkylation substrates............................ 13 Scheme 1.3.6. Beckmann Rearrangement strategies to access 4-imidazolidinones ...................... 16 Scheme 1.3.7. Attempted cyclization employing Eschenmoser’s Salt as a formaldehyde equivalent ............................................................................................................................. 18 Scheme 1.3.9. Cyclization of an amino alcohol with activated DMSO (Kayser) .......................... 19 Scheme 1.3.11. Previous desulfurization of a protected thiohydantoin (Witkop) ........................... 21 Scheme 1.3.12. Concise and high-yielding route to key allyl ester 33 ........................................... 21 Scheme 1.3.13. Product transformations ........................................................................................ 22 APPENDIX 2 Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates Scheme A2.2.1. Unsuccessful synthesis of a 1,4-diazepan-2-one allylic alkylation substrate ....... 243 Scheme A2.3.1. C–Acylation of diazepam (Wolfe) ....................................................................... 244 Scheme A2.3.2. Unsuccessful synthesis of a benzodiazepine allylic alkylation substrate ............. 245 Scheme A2.3.3. Unsuccessful synthesis of a tetrahydro[1,4]benzodiazepanone allylic alkylation substrate.............................................................................................................. 245 CHAPTER 2 Progress Toward the Total Synthesis of Aleutianamine Scheme 2.1.1. Aleutianamine and examples of related natural products ................................... 254 Scheme 2.1.2. Proposed biosynthetic routes to aleutianamine ................................................... 256 xxviii Scheme 2.2.1. Initial retrosynthetic analysis of aleutianamine ................................................... 258 Scheme 2.3.2. Corey’s addition of a sulfur nucleophile to an α-bromooxime ............................ 260 Scheme 2.3.3. Synthesis of an indole-derived aryl bromide coupling partner ............................ 261 Scheme 2.3.4. Enolate acylation and subsequent unsuccessful bromination.............................. 261 Scheme 2.4.1. Revised retrosynthetic analysis of aleutianamine ................................................ 263 Scheme 2.5.1. Attempts to reduce a pyrroloiminoquinone to aniline 120 ................................. 264 Scheme 2.5.2. Strategies envisioned for the construction of aniline 114 .................................... 265 Scheme 2.5.3. Attempted Fischer indolization of a hydrazone derivative .................................. 266 Scheme 2.5.4. Access to desired tryptophol 126 by Fischer indolization ................................... 267 Scheme 2.5.5. Advancement of tryptophol 126 to a protected tryptamine................................. 268 Scheme 2.6.1. Advancement of tricycle 134 to a tetracyclic quinolone ..................................... 271 Scheme 2.6.4. Ligands tested in entry 4 of Table 2.6.3 .............................................................. 273 Scheme 2.6.5. Preparation of a model Barbier addition substrate .............................................. 274 Scheme 2.6.7. Preparation of a ketal-bearing Michael acceptor................................................. 276 Scheme 2.6.8. Preparation of an oxidized intramolecular Barbier addition substrate ................. 276 Scheme 2.6.9. Cyclization of bromoarene 154 and unexpected rearrangements ....................... 277 Scheme 2.6.10. Attempted allylic oxidation of pentacycle 160.................................................... 278 Scheme 2.6.11. Attempted β-oxidation by a thiol conjugate addition approach .......................... 279 Scheme 2.7.1. 3rd-generation retrosynthetic analysis of aleutianamine....................................... 281 Scheme 2.8.1. Construction of an acetamidothiophene coupling partner .................................. 282 Scheme 2.8.2. Fragment coupling to prepare a dearomative cyclization substrate..................... 283 Scheme 2.8.3. Known dearomative arylation and desired transformation of thiophenes............ 284 Scheme 2.8.4. Key dearomative cyclization of aminothiophene 179 ......................................... 284 Scheme 2.8.5. Attempts to access a thiolactone from acetylthioimidate 184 ............................. 285 Scheme 2.8.6. Synthesis of a TFA-protected aminothiophene .................................................... 286 Scheme 2.8.7. Improved thioimidate synthesis and subsequent tosylation ................................. 287 Scheme 2.8.8. Successful hydrolysis of thioimidate 190 ............................................................ 287 Scheme 2.8.9. Demonstration of the feasibility of thioaminal formation .................................... 288 Scheme 2.8.10. Installation of the final nitrogen atom by azidation and reduction ...................... 289 Scheme 2.8.12. Desaturation of thiolactone 185 to diene 195..................................................... 291 Scheme 2.8.13. Thioester δ-functionalization and unsuccessful downstream chemistry .............. 292 Scheme 2.8.14. Inefficient azidation of dienone 195 ................................................................... 292 Scheme 2.8.15. Benefits of an early oxidation event .................................................................... 293 Scheme 2.8.16. Proof-of-concept for an oxidative strategy........................................................... 294 Scheme 2.8.17. Toward desired pyrroloiminoquinone 208 ......................................................... 294 xxix Scheme 2.8.18. Planned completion of synthesis......................................................................... 295 APPENDIX 3 Synthetic Summary for Chapter 2 Scheme A3.1. Synthesis of tricyclic aniline 134......................................................................... 361 Scheme A3.2. Synthesis of hydroxyketone 157 ......................................................................... 361 Scheme A3.3. Synthesis of aminothiophene 188 ....................................................................... 361 Scheme A3.4. Synthesis of thiolactol 207 .................................................................................. 362 APPENDIX 5 Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine Scheme A5.2.1. Planned bridgehead sulfide installation toward aleutianamine ........................... 448 Scheme A5.2.2. A model system for bridgehead sulfide installation ............................................. 449 Scheme A5.2.3. Alternative strategy for sulfide installation........................................................... 450 Scheme A5.3.1. Late-stage arene amination disconnection .......................................................... 451 Scheme A5.3.2. Preparation of nitroaniline 231 and failed Fischer Indolization........................... 451 Scheme A5.3.3. Intramolecular aryl C–H amination (Falck, 2016) ............................................... 452 Scheme A5.3.4. Attempts to access tricyclic aminoindoles by intramolecular C–H amination ..... 453 Scheme A5.4.1. Unexpected tosyl group migration during quinolone synthesis........................... 454 Scheme A5.4.2. Attempted preparation of N-allyl tetracycle 247 ................................................. 454 Scheme A5.4.3. Evaluation of a pivaloyl indole protecting group................................................. 455 Scheme A5.4.4. A julolidine desymmetrization approach to quinolone 252 ................................ 455 Scheme A5.4.5. Unsuccessful preparation of diketojulolidine 250 ............................................... 456 Scheme A5.5.1. Desired enone β-oxidation and challenging Wacker oxidation of internal α,βunsaturated carbonyl compounds ....................................................................... 458 Scheme A5.6.1. A functional handle approach to alkenyl bromide installation............................ 460 Scheme A5.6.2. Evaluation of a cyanide functional handle .......................................................... 461 Scheme A5.6.3. Attempted Gewald reaction of a cyclopentadiene Diels–Alder adduct ............... 462 Scheme A5.7.1. A spirocyclization–Michael addition approach to the oxidized ring system of aleutianamine ..................................................................................................... 463 Scheme A5.7.2. Access to a 2-bromoketone electrophile ............................................................. 463 Scheme A5.7.3. Attempts to access a spirocyclization substrate ................................................... 464 xxx CHAPTER 3 Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins Scheme 3.1.3. Approaches to complexes of unsubstituted corrole 294 (Gross, 2021) ............... 487 Scheme 3.2.1. Evaluation of sublimation as a means for oligopyrrane separation ...................... 488 Scheme 3.2.2. AcOH-promoted oligomerization of pyrrole and paraformaldehyde .................. 489 Scheme 3.2.3. A tetrapyrrane from a meso-free dipyrrane (Tanaka and Osuka, 2015) ............... 490 Scheme 3.2.4. Attempted controlled assembly of tetrapyrrane 297............................................ 491 Scheme 3.3.1. Corrole synthesis by oxidation with K3Fe(CN)6 (Dolphin et al., 1966)................. 492 Scheme 3.3.2. Unexpected oxidation of a bilane to a monoazaporphyrin ................................. 493 Scheme 3.3.4. Previous synthesis of a β-free monoazaporphyrin complex (Palmer, Gross, and Gray, 2011) ........................................................................................................ 494 Scheme 3.3.5. Metallation of monoazaporphyrin 306-H2 .......................................................... 495 APPENDIX 8 Some Unusual Transformations of a Highly Reactive α-Bromocaranone Scheme A8.1.1. Carene and the desired transformation ............................................................... 524 Scheme A8.2.1. Synthesis of a reactive α-bromocaranone ........................................................... 526 Scheme A8.2.3. Radical-mediated cyclopropane fragmentation of 313 ....................................... 528 Scheme A8.2.4. Proposed mechanism for the formation of racemic 321 ..................................... 529 Scheme A8.2.5. Synthesis of bromide 328 and control reaction in benzene ................................ 530 xxxi LIST OF TABLES CHAPTER 1 Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles Table 1.2.3. Reaction optimization............................................................................................. 8 Table 1.2.4. 1,4-Diazepan-5-one substrate scope ...................................................................... 9 Table 1.3.4. Reaction optimization........................................................................................... 14 Table 1.3.5. Imidazolidinone substrate scope........................................................................... 15 Table 1.3.8. Unsuccessful cyclization employing Eschenmoser’s Salt as a formaldehyde equivalent ............................................................................................................. 18 Table 1.3.10. Cyclization employing activated DMSO as a methylene equivalent..................... 20 Table 1.5.3.1. Determination of enantiomeric excess ................................................................ 105 Table 1.5.3.2. Determination of enantiomeric excess (continued) ............................................. 106 Table 1.5.3.3. Determination of enantiomeric excess (continued) ............................................. 107 Table 1.5.3.4. Determination of enantiomeric excess (continued) ............................................. 108 CHAPTER 2 Progress Toward the Total Synthesis of Aleutianamine Table 2.3.1. Investigation of the α-arylation of model vinylogous ester 96 ............................. 259 Table 2.5.6. Evaluation of the intramolecular C–N coupling of 133 ....................................... 269 Table 2.6.2. Unsuccessful aza-Michael addition of aniline 134 into cyclohexenone ............. 272 Table 2.6.3. A model system for aza-Michael addition........................................................... 273 Table 2.6.6. Barbier-type addition into a model ketone.......................................................... 275 Table 2.8.11. Conditions tested for direct desaturation of thiobutenolide 185 .......................... 290 APPENDIX 5 Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine Table A5.5.2. Evaluation of solvents for positive control substrate 264 ..................................... 459 Table A5.5.3. Evaluation of Lewis-acidic additives ................................................................... 459 xxxii APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 3 Table A7.2.2. Crystal data and structure refinement for complex 306-Co ..................................... 511 Table A7.2.3. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 306-Co. U(eq) is defined as 1/3 of the trace of the orthogonalized UIJ tensor ........................................................................................ 512 Table A7.2.4. Anisotropic Displacement Parameters (Å2×103) for 306-Co. The Anisotropic displacement factor exponent takes the form: –2π2[h2a*2U11+2hka*b*U12+…] ...... 514 Table A7.2.5. Bond Lengths for 306-Co ........................................................................................ 516 Table A7.2.6. Bond Angles for 306-Co ......................................................................................... 517 Table A7.2.7. Torsion Angles for 306-Co ...................................................................................... 520 Table A7.2.8. Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for 306-Co .............................................................................................................. 522 APPENDIX 8 Some Unusual Transformations of a Highly Reactive α-Bromocaranone Table A8.2.2. AgI-mediated reactions of 313 ............................................................................ 527 APPENDIX 9 Notebook Cross-Reference for New Compounds Table A9.1. Notebook cross-reference for Chapter 1 ............................................................. 548 Table A9.2. Notebook cross-reference for Chapter 1 (continued) .......................................... 549 Table A9.3. Notebook cross-reference for Chapter 2 ............................................................. 550 Table A9.4. Notebook cross-reference for Chapter 2 (continued) .......................................... 551 Table A9.5. Notebook cross-reference for Appendix 2 .......................................................... 551 Table A9.6. Notebook cross-reference for Appendix 5 .......................................................... 552 xxxiii LIST OF ABBREVIATIONS Å Ångstrom λ wavelength µ micro µwave microwave [a]D specific rotation at wavelength of sodium D line [H] reduction [O] oxidation °C degrees Celsius Ac acetyl AcOH acetic acid An para-anisoyl APCI atmospheric pressure chemical ionization aq aqueous Ar aryl atm atmosphere Bn benzyl Boc tert-butyloxycarbonyl bp boiling point br broad Bu butyl Bz benzoyl c calc’d concentration for specific rotation measurements (g/100 mL) calculated xxxiv CAN ceric ammonium nitrate cat catalytic cm–1 wavenumber(s) COD 1,5-cyclooctadiene Cp cyclopentadienyl CPME cyclopentyl methyl ether CuTC copper(I) thiophene-2-carboxylate Cy cyclohexyl d doublet D deuterium dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIAD diisopropyl azodicarboxylate DIBAL diisobutylaluminum hydride DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide DPPF 1,1′-bis(diphenylphosphino)ferrocene dr diastereomeric ratio e.g. for example (Latin exempli gratia) ee enantiomeric excess equiv equivalent(s) xxxv ESI electrospray ionization esp α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid Et ethyl EtOAc ethyl acetate FAB fast atom bombardment FD field desorption g gram(s) G4 fourth-generation Buchwald precatalyst GC gas chromatography h hour(s) HFIP 1,1,1,3,3,3-hexafluoropropan-2-ol HMDS 1,1,1,3,3,3-hexamethyldisilazane HMPA hexamethylphosphoramide HPLC high-performance liquid chromatography HRMS high-resolution mass spectroscopy Hz hertz i-Bu isobutyl i.e. that is (Latin id est) IBX 2-iodoxybenzoic acid IPA isopropanol, 2-propanol i-Pr isopropyl IR infrared (spectroscopy) J coupling constant K Kelvin(s) (absolute temperature) kcal kilocalorie L liter; neutral ligand LC–MS liquid chromatography–mass spectrometry xxxvi LDA lithium diisopropylamide m multiplet; milli m meta M metal; molar; molecular ion m/z mass to charge ratio m-CPBA meta-chloroperoxybenzoic acid Me methyl mg milligram(s) MHz megahertz min minute(s) MM mixed method mol mole(s) mp melting point Ms methanesulfonyl (mesyl) MS molecular sieves MTBE methyl tert-butyl ether n nano N normal NBS N-bromosuccinimide n-Bu butyl NCS N-chlorosuccinimide ND not determined NHK Nozaki–Hiyama–Kishi NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance NR no reaction detected Nu– nucleophile xxxvii o ortho p para Pd/C palladium on carbon PEG polyethylene glycol PG protecting group Ph phenyl pH hydrogen ion concentration in aqueous solution PHOX phosphinooxazoline ligand Phth phthaloyl PIFA (bis(trifluoroacetoxy)iodo)benzene Piv pivaloyl pmdba bis(4-methoxybenzylidene)acetone PPA polyphosphoric acid ppm parts per million Pr propyl PTSA para-toluenesulfonic acid Py pyridine q quartet R generic for any atom or functional group Ref. reference s singlet SFC supercritical fluid chromatography t triplet TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBHP tert-butyl hydroperoxide TBS tert-butyldimethylsilyl xxxviii t-Bu tert-butyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFE 2,2,2-trifluoroethanol THF tetrahydrofuran TLC thin-layer chromatography TMG 1,1,3,3-tetramethylguanidine TMP 2,2,6,6-tetramethylpiperidine TMS trimethylsilyl TOF time-of-flight TosMIC para-toluenesulfonylmethyl isocyanide tR retention time Ts p-toluenesulfonyl (tosyl) TTMSS tris(trimethylsilyl)silane UV ultraviolet v/v volume to volume w weak w/v weight to volume w/w weight to weight X anionic ligand or electronegative element Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 1 CHAPTER 1 Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7-Membered Diazaheterocycles † 1.1 INTRODUCTION In 1983, Tsuji and coworkers reported the first example of a palladium-catalyzed decarboxylative allylic alkylation reaction (Scheme 1.1.1A).1 Treatment of cyclohexanonederived allyl enol carbonate 1 with catalytic Pd0 in the presence of triphenylphosphine provided α-quaternary ketone (±)-2. In 2004, our laboratory reported the first enantioselective example of such a palladium-catalyzed decarboxylative allylic alkylation,2 employing allyl enol carbonate substrates 3 similar to those utilized in Tsuji’s seminal work (Scheme 1.1.1B). The Pfaltz-type chiral ligand (S)-t-BuPHOX led to consistently high ee in this reaction. In the following years, this chemistry has been extensively explored by our group,3 the Trost group,4 and others. The use of allyl β-ketoester masked enolate synthons in place of allyl enol carbonates allowed the same enantioenriched products to be obtained, but facilitated the late-stage diversification of allylic alkylation substrates by a more divergent synthetic route.3a Seeking to broaden the substrate scope of the palladium-catalyzed decarboxylative asymmetric allylic alkylation beyond ketones, our group reported that this † This research was conducted in collaboration with Dr. Alexander Sun. Portions of this chapter have been reproduced with permission from Sercel, Z. P.; Sun, A. W.; Stoltz, B. M. Org. Lett. 2019, 21, 9158–9161. and Sercel, Z. P.; Sun, A. W.; Stoltz, B. M. Org. Lett. 2021, 23, 6348–6351. © 2019, 2021 American Chemical Society. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 2 method could also be used to access α-quaternary lactams 6 in excellent yield and enantioselectivity (Scheme 1.1.1C).3b Scheme 1.1.1. Development of the Pd-catalyzed decarboxylative asymmetric allylic alkylation reaction. A) Initial report by Tsuji and coworkers. O O O Pd2(dba)3•CHCl3 PPh3 Me DME, 0 °C O Me (±)-2 1 B) Pd-catalyzed decarboxylative asymmetric allylic alkylation (Stoltz, 2004). R2 O O O Pd2(dba)3 (5 mol %) L1 (12.5 mol %) R1 THF, 25 °C O R2 R1 O Ph2P t-Bu (S)-t-BuPHOX (L1) 4 up to 99% yield up to 92% ee 3 N C) Pd-catalyzed decarboxylative asymmetric allylic alkylation of lactams (Stoltz, 2012). CF3 O R1 R2 O BzN O Pd2(pmdba)3 (5 mol %) L2 (12.5 mol %) THF, 25 °C O R2 R1 O BzN P 5 6 up to 97% yield up to 99% ee N t-Bu F3C 2 (S)-(CF3)3-t-BuPHOX (L2) In addition to simple lactams, other gem-disubstituted heterocycles, such as substituted morpholinones, could be accessed. Access to these heterocycles presents a notable advantage in the context of medicinal chemistry. A higher degree of saturation and the presence of sp3-stereogenic centers in lead molecules are correlated with greater clinical success and fewer off-target effects, which can be attributed to a greater number of accessible 3D conformers.5 In order to explore medicinal applications, our group reported Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 3 the incorporation of a variety of gem-disubstituted morpholine derivatives into the oxazolidinone antibiotic linezolid (7, Figure 1.1.2).6 Linezolid is an important treatment for antibiotic-resistant infections, but it possesses various side effects as a result of its offtarget inhibition of human mitochondrial protein synthesis. Furthermore, the rapid metabolism of linezolid by oxidation of its morpholine ring necessitates frequent administration, which presents issues regarding patient-compliance with the dosing regimen. Figure 1.1.2. Incorporation of a gem-disubstituted heterocycle into linezolid. F O F O N N O N 7 O O N O NHAc 8 O NHAc Ultimately, linezolid derivative 8 was found to be the most promising of the initial candidates, exhibiting decreased inhibition of human mitochondrial protein synthesis, although a reduction in IC50 against S. aureus ATCC 43300 was also observed. To expand the scope of chiral heterocycles that can be prepared by palladiumcatalyzed decarboxylative asymmetric allylic alkylation, our group reported the synthesis of gem-disubstituted piperazin-2-ones (Scheme 1.1.3A).3d The choice of protecting group for the secondary amine proved key to obtaining high enantioselectivity: an electronwithdrawing benzyl group resulted in low ee (10), which was hypothesized to be a result of stabilization of the palladium enolate. Our group has previously reported that stabilized enolates lead to low or no enantioselectivity under our reaction conditions.7 These compounds are thought to favor an outer-sphere mechanism of C–C bond formation that is Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 4 not well-controlled by the PHOX ligand steric environment, in contrast to the inner-sphere mechanism favored for less stabilized enolates. Scheme 1.1.3. Prior Pd-catalyzed decarboxylative asymmetric allylic alkylation of diazaheterocycles in the Stoltz group. A) Korch et. al., 2015: O R1 R2 O BzN O Pd2(pmdba)3 (5 mol %) L2 (12.5 mol %) PhCH3, 40 °C R2 O R1 BzN NR3 NR3 9 Representative substrates: O O Me BzN O Me Me BzN BzN NBz NBn NBn 10 89% yield 52% ee 11 89% yield 91% ee 12 89% yield 59% ee B) Sun et. al., 2019: O R O BzN O Pd2(dba)3 (4 mol %) L2 (10 mol %) 2:1 hexanes/PhCH3, 40 °C O NBoc NBoc 13 O R 14 up to 93% yield up to 97% ee O BzN O N Boc R BzN Pd2(pmdba)3 (4 mol %) L2 (10 mol %) 2:1 hexanes/PhCH3, 40 °C O R BzN N Boc 15 16 up to 85% yield up to 95% ee Thus, the use of a benzyl group (as in 11) resulted in a dramatic boost in enantioselectivity. However, the presence of a basic amine presented challenges during substrate synthesis, limiting the scope of this transformation. Nevertheless, in addition to piperazinones, this report included a single example of the asymmetric allylic alkylation of a 7-membered diazepanone heterocycle (12), albeit in a modest 59% ee. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 5 Recently, our group reported the use of an N-Boc protecting group to expand the scope of piperazin-2-ones (14) accessible by palladium-catalyzed decarboxylative asymmetric allylic alkylation (Scheme 1.1.3B).3e The more electron-rich nature of carbamate protecting groups, in comparison with acyl groups, enabled the allylic alkylation to proceed in high ee while facilitating a more general substrate synthesis. This methodology was applied in the same report to the preparation of the isomeric enantioenriched gem-disubstituted tetrahydropyrimidin-4-ones (16). 1.2 PALLADIUM-CATALYZED DECARBOXYLATIVE ASYMMETRIC ALLYLIC ALKYLATION OF 1,4-DIAZEPAN-5-ONES Figure 1.2.1. Representative pharmaceuticals containing a diazepane-derived ring system. NMe R O N N R1 Ar Benzodiazepine Anxiolytics Cl N N Cl N X Me O N H Clozapine N N N N O N Me Suvorexant Seeking to expand the accessible chemical space of chiral gem-disubstituted heterocycles with potential applications in medicinal chemistry, we identified 1,4diazepanes as an underutilized substrate class. Diazepanes are common structural motifs found in a variety of pharmaceuticals (Figure 1.2.1), including the benzodiazepine anxiolytics,8 the antipsychotic clozapine,9 and the anti-insomnia drug suvorexant.10 Notably, many of these compounds lack Csp3 complexity. Suvorexant is a notable Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 6 exception as the only FDA-approved drug to date bearing a stereodefined chiral center in a diazepane ring. The lack of stereochemically complex diazepanes in the drug landscape, especially those bearing all-carbon quaternary stereocenters, is likely due to a lack of asymmetric methods available for their synthesis, leading to a reliance on kinetic resolution, either of a quaternary building block or of the diazepane itself.11 The efficient and enantioselective incorporation of gem-disubstitution into diazepane heterocycles could enable the development of pharmaceutical agents with enhanced properties, due to the precedented benefits of increasing saturation in drug molecules.5,6 Furthermore, increasing substitution on the diazepane ring could potentially block metabolically labile sites, thus improving the pharmacokinetic profile of a drug candidate. Palladium-catalyzed decarboxylative asymmetric allylic alkylation represents a promising method for the synthesis of enantioenriched gem-disubstituted diazepane derivatives. Starting from the commercially available N-Boc diazepanone 17, substrates were readily accessible in a 3-step sequence analogous to that previously reported by our group (Scheme 1.2.2).3e N-Acylation of 17 with an acyl chloride, followed by C-acylation with allyl cyanoformate, yielded allyl esters 18a–c. It is notable that this enolate acylation proceeded smoothly despite the presence of a potential carbamate leaving group at the amide β-position. Subsequent functionalization of 18a–c was conducted with a variety of electrophiles, providing substrates 19a–l which bear diverse functional groups. The divergence put in place by late-stage functionalization of dicarbonyls 18 could enable rapid analoging in the context of medicinal chemistry. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 7 Scheme 1.2.2. Synthetic route to diazepanone-derived allyl β-amidoesters 19a–l. O 1) n-BuLi, R1Cl, THF, –78 °C HN 2) O NBoc 17 NC O Base THF, –78 °C O O O O O R2 Enolate Functionalization R 1N O R 1N NBoc 18a–c up to >99% yield NBoc 19a–l up to 95% yield We began by examining conditions for the asymmetric allylic alkylation of diazepanone 19a (R2 = Bn), utilizing Pd2(pmdba)3 as a palladium source and (S)-(CF3)3-tBuPHOX as a chiral ligand (Table 1.2.3). Polar solvents and toluene led to only modest ee of product 20a (entries 1−4). In prior research by our laboratory, 2:1 hexanes/toluene proved to be an effective solvent system for achieving high ee with a variety of lactam substrates.3e Indeed, compound 20a was obtained in 87% ee under these conditions (entry 6). Finally, we were pleased to discover that an even more nonpolar solvent, methylcyclohexane,12 further enhanced enantioselectivity, yielding 20a in 89% ee (entry 9). Despite its lack of polarity, methylcyclohexane affords homogeneous reaction mixtures. While examining reaction conditions, we also discovered that use of the highly electrondeficient ligand (S)-Ty-PHOX13 resulted in reduced ee (entry 8). This is in contrast with previous results indicating that more electron-deficient ligands often lead to higher enantioselectivity in related systems.3b–e Using a more electron-rich ligand, (S)-t-BuPHOX, also sharply decreased the ee of the product (entry 11). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 8 Table 1.2.3. Reaction optimization.a O Bn O O Bn Pd2(pmdba)3 (4 mol %) ligand (10 mol %) O BzN BzN solvent, 40 °C NBoc NBoc 20a 19a entry solvent ligand eeb (%) 1 THF (S)-(CF3)3-t-BuPHOX 20 2 1,4-dioxane (S)-(CF3)3-t-BuPHOX 38 3 MTBE (S)-(CF3)3-t-BuPHOX 70 4 PhCH3 (S)-(CF3)3-t-BuPHOX 66 5 2:1 hexanes/benzene (S)-(CF3)3-t-BuPHOX 84 6 2:1 hexanes/PhCH3 (S)-(CF3)3-t-BuPHOX 87c 7 cyclohexane (S)-(CF3)3-t-BuPHOX 88 8 cyclohexane (S)-Ty-PHOX 80 9 methylcyclohexane (S)-(CF3)3-t-BuPHOX 89c 10 2:1 methylcyclohexane/PhCH3 (S)-(CF3)3-t-BuPHOX 86 11 methylcyclohexane 50 (S)-t-BuPHOX [a] Reaction optimization was performed on a 0.01-0.02 mmol scale. [b] Values determined by chiral SFC analysis. [c] Average over 4 trials, values consistent within 1% ee. CF3 CF3 O O P O Ph2P N P F3C 2 N t-Bu t-Bu N t-Bu (S)-t-BuPHOX F F3C 2 (S)-(CF3)3-t-BuPHOX (S)-Ty-PHOX We then applied the optimized reaction conditions to a variety of diazepanone substrates (Table 1.2.4). First, the effect of the electronics of the lactam protecting group on the reaction outcome was investigated. Switching from a benzoyl group (20b) to a more electron-poor p-CF3-benzoyl group (20c) had a minor effect on enantioselectivity. Interestingly, the use of an electron-rich p-anisoyl (An) group delivered product 20d in an excellent 94% ee. It is worth noting that use of the p-anisoyl protecting group was not beneficial to enantioselectivity in all cases (20a/20e, 20f/20g) and was often on par with the unsubstituted benzoyl group. A variety of functional groups at the quaternary carbon Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 9 were tolerated, including groups bearing an alkenyl chloride (20h) and a tert-butyl carbamate (20l). This method also proved reliable for the formation of tertiary alkyl fluorides (20f, 20g). The low yield of propargyl lactam 20i and the necessity for elevated reaction temperatures are also noteworthy–allylic alkylation of other α-propargyl lactams studied by our group has proceeded smoothly.3e It is possible that the geometry of the diazepanone substrate promotes coordination of the alkyne to palladium, hindering the desired reactivity. Additionally, this method allowed for the preparation of benzoyl lactam 20e on a 1 mmol scale, albeit in somewhat diminished yield and ee (see Table 1.2.4, footnote c). Table 1.2.4. 1,4-Diazepan-5-one substrate scope.a O O R2 O R2 Pd2(dba)3 (4 mol %) L2 (10 mol %) O R 1N methylcyclohexane, 40 °C, 2–24 h R 1N NBoc NBoc 20a–l 19a–l 20b: R = Bz, 93% yield, 90% eeb O Me 90% yield, 92% ee RN RN 20d: R = An, NBoc 20a: R = Bz, 93% yield, 90% eeb O Bn 20c: R = p-CF3-Bz, NBoc O F 20e: R = An, >99% yield, 89% eec RN CO2Me CN NBoc 20f: R = Bz, 84% yield, 90% eeb 20g: R = An, 84% yield, 83% ee 94% yield, 94% ee Cl O O AnN AnN NBoc AnN AnN NBoc BocHN O O O NBoc BzN NBoc NBoc 20h 20i 20j 20k 84% yield 90% ee 44% yield,b,d 94% ee 20l 96% yield, 95% ee 86% yield,e 84% ee 76% yield, 93% ee [a] Reactions were performed on a 0.1 mmol scale at a 0.014 M concentration. An = p-anisoyl. [b] Pd2(pmdba)3 was used instead of Pd2(dba)3. [c] 1 mmol scale: 82% yield, 83% ee. [d] Conducted at 50 °C for 17 h. [e] Performed in 9:1 methylcyclohexane/PhCH3 to improve substrate solubility. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 10 Having demonstrated the functional group tolerance of this methodology, we performed a short synthesis of an enantioenriched quaternary stereocenter-containing analogue of suvorexant, an FDA-approved sedative used to treat insomnia (Scheme 1.2.5). Diazepanone 20a was subjected to selective debenzoylation under basic conditions, followed by reduction with LiAlH4 to yield diazepane 21 bearing a free secondary amine. Then, nucleophilic aromatic substitution of aryl bromide 22 with 21, followed by Boc deprotection with in situ generated HCl furnished secondary amine 23. A final coupling with the benzoyl chloride derived from carboxylic acid 2414 in the same pot provided target compound 25, an analogue of suvorexant bearing an all-carbon quaternary stereocenter. The rapid synthesis of this drug analogue illustrates the ease with which gem-substituted diazepane units can be incorporated into pharmaceutically relevant molecules to produce new agents with potentially improved biological properties. Scheme 1.2.5. Synthesis of a suvorexant analogue. O 1) O Bn Bn BzN NBoc 1) LiOH·H2O, i-PrOH 23 °C, 5 h 2) LiAlH4, THF, 0 °C, 4 h 22 N K2CO3, MeCN, 23 °C, 24 h HN 2) AcCl, MeOH, 23 °C, 5 h NBoc 44% yield over 2 steps 20a Br Cl 21 39% yield over 2 steps O CO2H N N O N 23 NH (COCl)2, cat. DMF, CH2Cl2 23 °C, 1 h N N N 24 N Cl Bn N Me Bn N Me O N 34% yield Cl 25 N Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 1.3 PALLADIUM-CATALYZED DECARBOXYLATIVE 11 ASYMMETRIC ALLYLIC ALKYLATION OF 4-IMIDAZOLIDINONES With a robust strategy for the synthesis of quaternary-substituted 7-membered diazepanones by Pd-catalyzed decarboxylative asymmetric allylic alkylation having been developed, our attention was drawn to the related 5-membered 4-imidazolidinone substrate class, which also occurs in pharmaceuticals (Figure 1.3.1). Interestingly, several of these pharmaceuticals, such as spiperone, bear a fully substituted (albeit achiral) tertiary carbon atom at the 5-position of the heterocycle. Figure 1.3.1. Representative pharmaceuticals bearing a 4-imidazolidinone moiety. O O NH O N N F O NH N H Ph Spiperone Phenytoin Me Me O F3C NC O F HN N N NHMe O O N NO2 N S Enzalutamide O Dantrolene Given the prevalence of this substitution pattern, we reasoned that drug design would potentially benefit from a method that delivers chiral 4-imidazolidinones bearing fully substituted tertiary stereocenters. 4-Imidazolidinones have also been used as chiral auxiliaries in the preparation of artificial amino acids15 and have found applications in popular organic catalysts,16 but to our knowledge, preparation of these species has been largely restricted to processes involving the use of chiral pool materials or kinetic resolution. While 4-imidazolidinone is commercially available, it is prohibitively expensive (>$100 /g for the hydrochloride salt from Combi Blocks at the time of writing). We thus set Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 12 out to develop a scalable synthesis of imidazolidinone allylic alkylation substrates. Although these heterocycles appear trivial to prepare at first glance, the development of a practical synthetic route proved to be quite challenging. A synthetic route to unsubstituted imidazolidinone 30 was published in 1988 by Pinza and coworkers (Scheme 1.3.2).17 Glycinamide hydrochloride (26) was subjected to benzylation by reductive amination with benzaldehyde to provide secondary amine 27. Cyclization with formaldehyde proceeded rapidly, but over-addition was observed, and hemiaminal 28 was isolated. Heating under vacuum provided N-benzyl imidazolidinone 29 in reasonable yield. Finally, removal of the undesired benzyl protecting group by hydrogenolysis furnished 4-imidazolidinone 30 in quantitative yield. Scheme 1.3.2. Pinza’s route to imidazolidinone.a O H 2N NH3Cl 26 benzaldehyde NaBH4, Et3N CH2Cl2, 2 d 57% yield OH O CH2O H2O, reflux, 30 min H 2N 71% yield over 2 steps HN N Bn O H2, Pd/C EtOH, 23 °C >99% yield 29 N N Bn NHBn 27 O 150 °C hi-vac, 28 h O 28 HN N H 30 [a] Reported yields were obtained in our laboratory. After replicating Pinza’s synthesis of 4-imidazolidinone, we set out to derivatize this compound and prepare substrates for Pd-catalyzed decarboxylative asymmetric allylic alkylation (Scheme 1.3.3). Beginning with 4-imidazolidinone 30, Boc protection proceeded smoothly to provide carbamate 31 in high yield. Subsequent benzoylation with n-BuLi and BzCl provided fully protected heterocycle 32, albeit in mediocre yield. Acylation of 32 proved to be challenging. The enolate of this compound is highly reactive Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 13 and nucleophilic, as evidenced by its putative intractable addition into the benzoyl protecting group of another equivalent of starting material. This pathway dominates even at –78 °C, precluding the isolation of desired allyl ester 33. Only by cooling the base solution to –116 °C and allowing the THF solvent to begin to freeze during dropwise addition of the starting material, followed by warming the enolate solution to –96 °C prior to electrophile addition, was desired product 33 produced. Unfortunately, this reaction exhibited highly variable yields, particularly when conducted on a larger scale. The yields obtained were generally in the range of 23–50%, but sometimes reached as high as 89%. Overall, key intermediate 33 could be obtained by this route in 8 steps from glycinamide hydrochloride 26 in 3–12% overall yield. Scheme 1.3.3. Initial synthesis of imidazolidinone allylic alkylation substrates. O O Boc2O, Et3N THF, 23 °C, 20 min HN N H HN N Boc 79% yield O n-BuLi, BzCl THF, –78 °C, 5 min 43% yield 31 30 BzN N Boc 32 O CN O LiHMDS THF, –116→–96 °C 23–89% yield O O BzN N Boc 33 O O O BzN N Boc + undesired benzoyl transfer O 33 NaH, R-X, DMF, 23 °C or Michael acceptor, acetone, 50 °C O BzN R O N Boc O 34a–k While this route suffered from excessive length and inconsistency, access to 33 nevertheless enabled us to begin evaluating the Pd-catalyzed decarboxylative asymmetric allylic alkylation of 4-imidazolidinone substrates. Treatment of 33 with NaH or K2CO3 and Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 14 an appropriate electrophile enabled the expedient preparation of diverse allylic alkylation substrates 34a–k. A brief solvent evaluation (Table 1.3.4) revealed that while ethereal and aromatic solvents predictably led to low to moderate enantioselectivities (entries 1–4), our group’s conditions for the Pd-catalyzed decarboxylative asymmetric allylic alkylation of analogous tetrahydropyrimidin-4-ones3e employing 2:1 hexanes/PhCH3 led to 91% ee. Distinct allylic alkylation conditions developed by Trost and coworkers were also tested,4c but led to low ee and sluggish reactivity (entry 6). Table 1.3.4. Reaction optimization.a O BzN Pd2(pmdba)3 (4 mol %) (S)-(CF3)3-t-BuPHOX (10 mol %) Bn O N Boc O BzN solvent, 40 °C, 45 h O Bn N Boc 35a 34a eeb (%) entry solvent 1 THFc 51 2 1,4-dioxane 68 3 benzene 89 4 PhCH3 87 5 2:1 hexanes/PhCH3 91 6d 1,4-dioxane –43 [a] Reaction optimization was performed on a 0.01 mmol scale at 0.014 M concentration. Reactions proceeded to completion unless otherwise noted. [b] Values determined by chiral SFC analysis. [c] Reaction incomplete after 45 h. [d] (R,R)-ANDEN-Ph Trost ligand (12 mol %) was used in place of (S)-(CF3)3-t-BuPHOX. Reaction was conducted at 60 °C and 0.1 M concentration, and was incomplete after 38 h. CF3 O P O N O NH HN t-Bu F3C 2 (S)-(CF3)3-t-BuPHOX PPh2 Ph2P (R,R)-ANDEN-Ph We were pleased to discover that applying the optimal conditions from Table 1.3.4 to a variety of substrates furnished chiral gem-disubstituted 4-imidazolidinones 35a–k in Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 15 high yields and levels of ee (Table 1.3.5). Various nonpolar side chains proved to be welltolerated, such as benzyl (35a), p-trifluoromethylbenzyl (35b), methyl (35c), prenyl (35d), and cinnamyl (35e) groups. A propargyl group was also tolerated with high enantioselectivity (35f), albeit with a reduction in yield. We were pleased to observe that the reaction proceeded smoothly with a methyl group at the 2-position of the allyl fragment (35g). Lastly, several polar functional groups were also well-tolerated in the allylic alkylation (35h–k), including an alkenyl chloride and a carbamate. In particular, nitrile substrate 35j was obtained in quantitative yield and an excellent 95% ee. Table 1.3.5. Imidazolidinone substrate scope.a O BzN R1 N Boc O Pd2(pmdba)3 (4 mol %) (S)-(CF3)3-t-BuPHOX (10 mol %) 2:1 hexanes/PhCH3, 60 °C R O BzN R N Boc O 34a–k 35a–k Me O O BzN Bn BzN N Boc O p-CF3-Ph BzN N Boc O Me Ph BzN N Boc O Me O BzN N Boc BzN N Boc N Boc 35a 35b 35c 35d 35e 35f 76% yieldb,c 92% ee 76% yield 89% ee 88% yield 86% ee 80% yield 80% ee 97% yieldb 85% ee 46% yield 91% ee O Cl O O BzN Bn N Boc Me BzN O NHCbz BzN N Boc O CN BzN N Boc O Me BzN N Boc N Boc 35g 35h 35i 35j 35k 83% yield 89% ee 93% yieldb 86% ee 75% yield 85% ee >99% yieldb,d 95% ee 79% yieldd 93% ee [a] Reactions were performed on a 0.1 mmol scale at 0.014 M concentration. ee values were determined by chiral SFC analysis. [b] Conducted at 40 °C. [c] 1.86 mmol scale: 86% yield, 95% ee. [d] Pd2(dba)3 was used instead of Pd2(pmdba)3 to facilitate product purification. With the knowledge that 4-imidazolidinones were a competent substrate class for Pdcatalyzed decarboxylative asymmetric allylic alkylation, we set out to shorten and improve Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 16 the synthetic route to these substrates. We were aware of a synthetic route to imidazolidinones relying on the Beckmann rearrangement of 3-azetidinones (Scheme 1.3.6A) and hoped to use this strategy to prepare 1-Boc-4-imidazolidinone 31, thereby intercepting our existing synthetic route. Nitta and coworkers prepared O-tosyloxime 38 in 2 steps from carbamate 36 and found that this oxime derivative underwent a facile Beckmann rearrangement when simply passed through a column of neutral or basic alumina, yielding imidazolidinone 39.18 Analogous oxime 41 was easily accessible from commercially available 3-azetidinone 40 in 2 steps (Scheme 1.3.6B), but in our hands, a column of basic alumina was unable to affect rearrangement following tosylation. Incomplete conversion was observed under heating with basic alumina in wet acetone. Scheme 1.3.6. Beckmann Rearrangement strategies to access 4-imidazolidinones. A) Nitta, 1986: O NOH NH2OH•HCl, NaOAc H2O/EtOH N CO2Et 98% yield 36 NOTs N NaH, TsCl Et2O N CO2Et 57% yield CO2Et 37 O Al2O3 EtOAc 67% yield 38 HN N CO2Et 39 B) Synthesis of N-Boc imidazolidinone 31. O O NOH N Boc 40 NH2OH•HCl, NaOAc i-PrOH/H2O, 50 °C, 2 h 90% yield 1. NaH, TsCl, Et2O X 2. Al2O3, EtOAc N Boc Beckmann Rearrangement did not occur 41 TsCl, K2CO3 41 N Boc 31 O NOH N Boc HN CH3CN/H2O, 80 °C, 1.5 h 12% yield HN N Boc 31 We were, however, pleased to discover that free oxime 41 could undergo a 1-pot Beckmann rearrangement with TsCl and K2CO3 to deliver product 31 in 12% yield. This Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 17 set of conditions was found to be uniquely effective for the Beckmann Rearrangement of 41, and unfortunately, the yield of this key step could not be increased—imidazolidinone 31 degrades under the reaction conditions. Nevertheless, the low cost of N-Boc-3azetidinone 40 enabled the synthetic route depicted in Scheme 1.3.6B to be harnessed to provide enough material to evaluate most of the substrate scope depicted in Table 1.3.5. Given the poor results of a Beckmann Rearrangement strategy to access key intermediate 31, we instead began reevaluating cyclization approaches analogous to that of Pinza.17 Direct treatment of N-Boc glycinamide 42 with formaldehyde resulted in no desired cyclization product. Instead, Eschenmoser’s Salt, generated in situ from tetramethylmethylenediamine 43, was envisioned to be a promising formaldehyde equivalent (Scheme 1.3.7). In the presence of an acylating agent, Eschenmoser’s Salt B could form via loss of an amide from A. Nucleophilic attack by substrate 42 could produce intermediate C, whose only basic amine could attack another equivalent of acylating agent to provide charged species D. This species could eject an amide and produce Nacyliminium E, which could undergo cyclization, and following deprotonation, yield desired product 31. Unfortunately, while putative intermediate C was observed by mass spectrometry, no desired product was observed under any of the conditions explored (Table 1.3.8). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 18 Scheme 1.3.7. Attempted cyclization employing Eschenmoser’s Salt as a formaldehyde equivalent. Me2N O O NMe2 43 H 2N HN acyl electrophile N Boc NHBoc 42 31 O Me2N R NMe2 Me2 N R Me2N X 43 Me2N B O A O O H 2N O O NHBoc H 2N H 2N 42 R X NBoc NBoc Me2N NMe2 C O O O –H+ H 2N R D HN N Boc NBoc E 31 Table 1.3.8. Unsuccessful cyclization employing Eschenmoser’s Salt as a formaldehyde equivalent. Me2N O NMe2 43 H 2N NHBoc X electrophile CH3CN, 23 °C O HN N Boc 42 31 entry conditions % yield 1 Ac2O (2 equiv) 0 2 AcCl (2 equiv), K2CO3 0 3 Ac2O (1 equiv), then MeI 0 4 TFAA (2 equiv), K2CO3 0 Reluctant to abandon a cyclization approach to key intermediate 31, we began to explore other formaldehyde equivalents and became aware of a report that showed promise in our system. In 2007, Kayser and coworkers disclosed that amino alcohol 44, when Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 19 subjected to activated DMSO oxidation conditions, failed to deliver the desired 1,2dicarbonyl product, instead furnishing oxazolidine 45 in high yield (Scheme 1.3.9).19 Phosphorous pentoxide was a uniquely effective activating agent for this transformation. Mechanistically, Kayser and coworkers propose that activation of DMSO with phosphorous pentoxide leads to intermediate F. Deprotonation with concominant loss of PO3– provides sulfenium ion G, a key intermediate in the Pummerer Rearrangment and the MTM protection of alcohols.20 Trapping of this ion by the aniline moiety of 44 is thought to produce methylthiomethylaniline H, which can eject methanethiolate, leading to iminium ion I. A final cyclization and proton transfer yields oxazolidine 45. Scheme 1.3.9. Cyclization of an amino alcohol with activated DMSO (Kayser). MeO MeO NH N P4O10, DMSO O O 25 °C, 24 h OEt OEt O 85% yield OH 45 44 O O P O H 3C S O O P P O O S O H CH3 F H 2C O CH3 O P OH Ph CO2Et I PT CH3 G PMP NH PT PMP N SMe OH OH Ph O Ph O PMP N S 44 PMP N CO2Et CO2Et H O Ph CO2Et 45 Hopeful that the sulfonium ion G derived from activated DMSO could also affect the cyclization of carbamate 42, we subjected this compound to the conditions reported by Kayser and coworkers (Table 1.3.10) and were pleased to observe a 9% yield of product 31 (entry 1). P4O10 proved to be uniquely effective in promoting this transformation. Two Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 20 sets of conditions for the α-methylenation of ketones resulted in only decomposition (entries 5, 6).20,21 Interestingly, Ac2O resulted in no reaction even at 60 °C, despite its precedent as a popular DMSO activating agent for the MTM protection of alcohols (entry 3).22 Unfortunately, yields higher than 13% (entry 2) were never observed. Hence, a strategically different approach to access imidazolidinone 31 was necessitated. Table 1.3.10. Cyclization employing activated DMSO as a methylene equivalent. O O DMSO, conditions HN H 2N N Boc NHBoc 42 31 entry conditions % yield 1 P4O10 (2 equiv), 1.5 h, 23 °C 9 2 P4O10 (1.1 equiv), 20 h, 23 °C 13 3 Ac2O, 60 °C NR 4 TFAA, NaH or Et3N, 23 °C 0 5 K2S2O8, NaOAc, 120 °C 0 (decomp) 6 PhI(OAc)2, Na2CO3, 120 °C 0 (decomp) 7 POCl3, Et3N, 23 °C trace In 1957, Witkop and coworkers reported that when 2-thiohydantoin derivative 46 was subjected to desulfurization conditions with Raney Nickel, the undesired 4imidazolidinone 47 was obtained in poor yields (Scheme 1.3.11).23 The desired imidazolone 48 was not detected. Pinza later reported that Witkop’s reaction was hard to reproduce and consistently low-yielding.17 However, aware of the success of nickel boridepromoted reductive desulfurization of other cyclic thioureas,24 including aryl-substituted imidazolidinones,25 we began to develop an improved route to 4-imidazolidinones from thiohydantoins (Scheme 1.3.12). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 21 Scheme 1.3.11. Previous desulfurization of a protected thiohydantoin (Witkop). O HN S N Cbz O Raney Nickel EtOH, reflux 23–34% yield 46 O HN N N Cbz N Cbz 47 48 not observed A precedented Boc protection of inexpensive 2-thiohydantoin 49 provided carbamate 50, which bears similarity to Witkop’s substrate 46.26 Subjecting 50 to nickel boride-mediated reductive desulfurization conditions provided key 4-imidazolidinone intermediate 31. Direct quenching of this reaction with glacial acetic acid to dissolve insoluble byproducts followed by filtration and biphasic extraction enabled the preparation of 31 in multi-gram quantities and in excellent yield, with no chromatography. Scheme 1.3.12. Concise and high-yielding route to key allyl ester 33. O O HN N H S Boc2O, DMAP THF, 23 °C, 2 h 93% yield HN N Boc S 50 49 O NiCl2, NaBH4 MeOH, 0→23 °C, 1 h then AcOH HN N Boc 31 96% yield O O O HN N Boc 31 O BzCl, Et3N CH2Cl2, 23 °C, 9 h 56% yield BzN N Boc 32 N 51 N + LiHMDS (pre-mixed) THF, –78 °C, 13 min 50% yield up to 4.8 g product O O BzN N Boc O 33 Then, yields for the benzoyl protection of free lactam 31 were improved by switching to milder conditions, providing imide 32. Previously, acylation of 32 using LiHMDS and allyl cyanoformate proved challenging and resulted in inconsistent yields due to the high reactivity of the enolate intermediate (vide supra). It was discovered that by switching to acylimidazole electrophile 51, the electrophile and base were stable when Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 22 pre-mixed at –78 °C, and addition of starting material to the electrophile-base mixture provided target allyl ester 33 in 50% yield, which was consistent upon scale-up to produce 4.8 g of 33. The new synthetic route depicted in Scheme 1.3.12 generates key intermediate 33 in 25% overall yield over only 4 steps. Having demonstrated the broad functional group tolerance of the reported method, we sought to explore the feasibility of further functionalization of the 4-imidazolidinone products (Scheme 1.3.13). The selective removal of either protecting group would likely prove essential for applications in medicinal chemistry. Toward this end, treatment of chiral benzyl imidazolidinone 35a with TFA led to facile Boc cleavage, affording free secondary amine 52. Similarly, treatment of 35a with lithium hydroxide readily affected benzoyl group removal, providing free lactam 53. Scheme 1.3.13. Product transformations. O TFA BzN CH2Cl2, 23 °C, 22 h N H 81% yield 52 O BzN Bn O Bn LiOH•H2O N Boc i-PrOH/H2O, 70 °C, 1 h 35a 80% yield HN Bn N Boc 53 O H2SO4/MeOH (4 M) 70 °C, 3 d highly variable yield maximum 25% MeO H2N Bn 54 α,α-disubstituted α-amino acid derivative At the outset of this research, we had planned to explore the conversion of 4imidazolidinone allylic alkylation products 35a–k to useful derivatives of biologically relevant and synthetically challenging α,α-disubstituted α-amino acids.27 Imidazolidinones Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 23 were envisioned as surrogates for these desirable compounds based on prior examples of imidazolidinone chiral auxiliary–based strategies to access α,α-disubstituted α-amino acids,15 as well as our own group’s preparation of α-quaternary substituted β-amino acids from the analogous tetrahydropyrimidinones.3e Unfortunately, the presence of olefinic functionality hampered the feasibility of converting 35a–k into amino acid derivatives due to the harsh conditions required for ring opening. Despite extensive experimentation, the highest-yielding conditions identified for the conversion of imidazolidinone 35a to amino ester 54 (H2SO4/MeOH) provided highly variable results, with the maximum observed yield of 54 being only 25%. 1.4 CONCLUSION 1,4-Diazepan-5-ones and 4-imidazolidinones bearing gem-disubstitution were prepared in moderate to high levels of yield and enantioselectivity by palladium-catalyzed decarboxylative asymmetric allylic alkylation. Applying this methodology to these nitrogen-rich substrate classes enabled access to enantioenriched diazaheterocycles bearing diverse functionality. As illustrated by our synthesis of suvorexant analogue 25 (Scheme 1.2.5) and the demonstrated orthogonality of the imidazolidinone protecting groups (Scheme 1.3.13), the chemistry reported herein can be adapted for applications in drug design. 1.5 EXPERIMENTAL SECTION 1.5.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 24 by passage through an activated alumina column under argon.28 Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 nm) was used for flash chromatography. 1H NMR spectra were recorded on Varian Inova 500 MHz, Varian 400 MHz, and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (125 MHz), a Varian 400 MHz spectrometer (100 MHz), and Bruker 400 MHz spectrometers (100 MHz) and are reported relative to CHCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities 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. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra include minor solvent impurities of water (δ 1.56 ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), acetone (δ 2.17 ppm), grease (δ 1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm), which do not impact product assignments. Most NMR spectra are complicated by rotational isomerism about amide bonds. This behavior is illustrated by variable-temperature NMR spectra of compound 20e in DMSO (p. 183). IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR spectrometer using thin films deposited on NaCl or KBr plates and 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 path-length cell. Analytical SFC was performed with a Mettler Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 25 SFC supercritical CO2 analytical chromatography system utilizing Chiralpak (AD-H, ASH or IC) or Chiralcel (OD-H, OJ-H, or OB-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. 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+), or from the Caltech Mass Spectrometry Laboratory using a JMS600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) mode. Absolute stereochemistry is assigned by analogy to previous results by our group.3 Reagents were purchased from commercial sources and used as received unless otherwise stated. Ligands (S)-(CF3)3-t-BuPHOX and (S)-Ty-PHOX were prepared according to literature procedures.29,13 1.5.2 EXPERIMENTAL PROCEDURES 1.5.2.1 General Procedure for Allylic Alkylation of Diazepanones O O R 1 O Pd2(dba)3 or Pd2(pmdba)3 (4 mol %) (S)-(CF3)3-t-BuPHOX (10 mol %) methylcyclohexane, 40 °C RN NBoc O R 1 RN NBoc CF3 O P N t-Bu F3C 2 (S)-(CF3)3-t-BuPHOX In a N2 filled glovebox, Pd2(dba)3 (4 mol %) or Pd2(pmdba)3 (4 mol %) and (S)(CF3)3-t-BuPHOX (10 mol %) were suspended in methylcyclohexane (2 mL) in a 20 mL glass vial. After stirring for 20 minutes at 25 °C, the appropriate diazepanone (1.0 equiv) Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 26 and methylcyclohexane (5.2 mL, total substrate concentration 0.014 M) were added to the pre-stirred catalyst solution. The vial was then sealed and heated to 40 °C. After full consumption of starting material, as monitored by TLC, the reaction mixture was exposed to air. The crude reaction mixture was loaded directly onto a flash column and the product was isolated by silica gel flash chromatography. O Bn BzN NBoc tert-butyl (S)-6-allyl-4-benzoyl-6-benzyl-5-oxo-1,4-diazepane-1-carboxylate (20a) Prepared according to the general procedure with allyl ester 19a (51.2 mg, 0.104 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (15% EtOAc/hexanes) to provide benzyl diazepanone 20a as a colorless oil (43.4 mg, 0.0967 mmol, 93% yield, 90% ee); 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.40 (m, 3H), 7.40 – 7.32 (m, 2H), 7.32 – 7.19 (m, 3H), 7.19 – 7.00 (m, 2H), 5.88 (br s, 1H), 5.26 – 5.07 (m, 2H), 4.26 – 4.03 (m, 1H), 3.94 (d, J = 15.4 Hz, 1H), 3.73 (d, J = 42.2 Hz, 1H), 3.54 (d, J = 15.3 Hz, 1H), 3.40 (s, 2H), 3.09 (dd, J = 61.0, 13.7 Hz, 1H), 2.94 – 2.34 (m, 3H), 1.48 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 179.2, 174.8, 156.0, 155.4, 136.6, 136.4, 133.0, 131.5, 130.8, 128.6, 128.4, 127.8, 127.1, 120.0, 119.7, 80.8, 54.3, 53.9, 49.1, 47.4, 46.9, 42.5, 42.0, 41.5, 40.3, 28.5; IR (Neat Film, NaCl) 3062, 2975, 2928, 1693, 1682, 1601, 1452, 1415, 1392, 1365, 1322, 1283, 1246, 1156, 1044, 978, 917, 865, 728, 697 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C27H33N2O4 [M+H]+: 449.2435, found 449.2429; [α]D22.4 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 27 +14.19 (c 0.66, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 3.51, minor = 2.71. O Me BzN NBoc tert-butyl (R)-6-allyl-4-benzoyl-6-methyl-5-oxo-1,4-diazepane-1-carboxylate (20b) Prepared according to the general procedure with allyl ester 19b (39.0 mg, 0.0937 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide methyl diazepanone 20b as a colorless, waxy solid (32.3 mg, 0.868 mmol, 93% yield, 90% ee); 1H NMR (400 MHz, CDCl3) δ 7.54 – 7.43 (m, 3H), 7.43 – 7.32 (m, 2H), 5.74 (ddt, J = 17.1, 9.9, 7.4 Hz, 1H), 5.19 – 5.06 (m, 2H), 4.30 – 3.89 (m, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 28 3H), 3.85 – 3.69 (m, 1H), 3.66 – 3.34 (m, 2H), 2.63 – 2.20 (m, 2H), 1.50 (s, 9H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 180.8, 174.5, 155.4, 155.0, 136.3, 132.9, 131.4, 128.3, 127.5, 119.5, 80.7, 50.9, 49.9, 47.2, 46.5, 42.5, 42.1, 41.8, 28.4, 23.5, 23.1; IR (Neat Film, NaCl) 2976, 2933, 1694, 1450, 1418, 1392, 1366, 1323, 1284, 1246, 1146, 1057, 983, 917, 868, 768, 729, 696 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C21H29N2O4 [M+H]+: 373.2122, found 373.2117; [α]D22.31 –12.69 (c 1.0, CHCl3); SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): minor = 4.31, major = 5.68. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 29 O Me (p-F3C-Bz)N NBoc tert-butyl (R)-6-allyl-6-methyl-5-oxo-4-(4-(trifluoromethyl)benzoyl)-1,4-diazepane-1carboxylate (20c) Prepared according to the general procedure with allyl ester 19c (55.3 mg, 0.114 mmol, 1.0 equiv), Pd2(dba)3 (4.2 mg, 4.57 µmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (6.7 mg, 0.011 mmol, 10 mol %). Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide methyl diazepanone 20c as a colorless oil (45.1 mg, 0.102 mmol, 90% yield, 92% ee); 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 5.71 (ddt, J = 17.2, 10.1, 7.4 Hz, 1H), 5.23 – 5.07 (m, 2H), 4.21 – 4.03 (m, 2H), 4.02 – 3.64 (m, 2H), 3.58 – 3.38 (m, 2H), 2.59 – 2.21 (m, 2H), 1.49 (s, 9H), 1.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 181.0, 180.8, 173.1, 155.4, 155.1 140.0, 132.8 (q, JC-F = 32.9 Hz), 132.7, 127.6, 125.5 (q, JC-F = 3.7 Hz), 123.7 (q, JC-F = 272.5 Hz), 119.9, 81.0, 50.9, 50.0, 47.2, 46.4, 42.4, 42.0, 41.8, 28.5, 23.6, 23.3; IR (Neat Film, NaCl) 3366, 3077, 2978, 2934, 1694, 1452, 1410, 1394, 1367, 1326, 1248, 1167, 1147, 1066, 1014, 984, 925, 852, 764 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H31F3N3O4 [M+NH4]+: 458.2261, found 458.2250; [α]D22.6 –12.32 (c 1.0, CHCl3); SFC Conditions: 5% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): minor = 4.49, major = 5.86. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 30 O Me AnN NBoc tert-butyl (R)-6-allyl-4-(4-methoxybenzoyl)-6-methyl-5-oxo-1,4-diazepane-1carboxylate (20d) Prepared according to the general procedure with allyl ester 19d (45.8 mg, 0.103 mmol, 1.0 equiv), Pd2(dba)3 (3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide methyl diazepanone 20d as a colorless oil (38.9 mg, 0.0966 mmol, 94% yield, 94% ee); 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.44 (m, 2H), 6.95 – 6.75 (m, 2H), 5.76 (m, 1H), 5.26 – 4.99 (m, 2H), 4.24 – 3.87 (m, 3H), 3.83 (s, 3H), 3.75 (m, 1H), 3.59 – 3.37 (m, 2H), 2.60 – 2.25 (m, 2H), 1.49 (s, 9H), 1.31 (s, 3H); 13C NMR (100 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 31 MHz, CDCl3) δ 180.7, 180.6, 174.3, 162.5, 155.4, 155.0, 133.0, 130.1, 128.1, 119.4, 113.6, 80.7, 55.4, 50.8, 49.8, 47.4, 46.6, 42.7, 42.4, 28.4, 23.5, 23.1; IR (Neat Film, NaCl) 3352, 3076, 2975, 2932, 2841, 2568, 1690, 1605, 1579, 1542, 1511, 1458, 1420, 1392, 1366, 1322, 1284, 1256, 1214, 1168, 1146, 1056, 1032, 984, 924, 868, 842, 807, 762, 743, 736, 650, 633, 621, 608 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H31N2O5 [M+H]+: 403.2227, found 403.2225; [α]D22.45 –40.51 (c 1.0, CHCl3); SFC Conditions: 20% MeOH, 2.5 mL/min, Chiralpak IC column, λ = 210 nm, tR (min): minor = 5.11, major = 5.66. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 32 O Bn AnN NBoc tert-butyl (S)-6-allyl-6-benzyl-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1carboxylate (20e) Prepared according to the general procedure with allyl ester 19e (52.3 mg, 0.100 mmol, 1.0 equiv), Pd2(dba)3 (3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide benzyl diazepanone 20e as a colorless oil (48.1 mg, 0.100 mmol, >99% yield, 89% ee); 1H NMR (400 MHz, CDCl3) δ 7.51 – 7.44 (m, 2H), 7.32 – 7.20 (m, 3H), 7.18 – 7.09 (m, 2H), 6.87 – 6.81 (m, 2H), 5.93 (br s, 1H), 5.26 – 5.12 (m, 2H), 4.09 – 3.88 (m, 2H), 3.84 (s, 3H), 3.78 – 2.41 (m, 8H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 179.0, 174.6, 162.6, 156.0, 155.4, 136.7, 133.1, 130.8, 130.5, 128.5, 128.2, 127.0, 119.9, 119.6, 113.7, 80.9, 80.7, 55.5, 54.2, 53.8, 49.1, 47.5, 47.3, 42.4, 42.0, 41.2, 40.9, 40.0, 28.5; IR (Neat Film, NaCl) 3374, 2974, 2927, 1694, 1604, 1581, 1510, 1454, 1416, 1392, 1365, 1320, 1282, 1256, 1211, 1166, 1028, 979, 925, 838, 762, 742, 705, 678, 636, 610 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C28H35N2O5 [M+H]+: 479.2540, found 479.2533; [α]D22.81 +19.02 (c 1.0, CHCl3); SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): minor = 3.94, major = 6.20. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 33 O F BzN NBoc tert-butyl (S)-6-allyl-4-benzoyl-6-fluoro-5-oxo-1,4-diazepane-1-carboxylate (20f) Prepared according to the general procedure with allyl ester 19f (43.2 mg, 0.103 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide alkyl fluoride 20f as a white, amorphous solid (32.6 mg, 0.0866 mmol, 84% yield, 90% ee); 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.53 (m, 2H), 7.53 – 7.45 (m, 1H), 7.45 – 7.34 (m, 2H), 5.94 – 5.72 (m, 1H), 5.34 – 5.17 (m, 2H), 4.58 – 4.38 (m, 1H), 4.26 – 4.02 (m, 2H), 3.99 – 3.74 (m, 1H), 3.39 – 3.10 (m, 2H), 2.96 – 2.74 (m, 1H), 2.73 – 2.43 (m, 1H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.9, 173.9 (d, JC-F = 26.3 Hz), 155.1, 135.2, 132.1, 130.3, 128.4, 128.2, 121.0, 97.7 (dd, JC-F = 193.9, 47.2 Hz), 81.1, 49.8 (dd, JC-F = 35.3, 23.1 Hz), 47.2, 46.6, 42.6, 39.7 (dd, JC-F = 27.6, 21.9 Hz), 28.3; IR (Neat Film, NaCl) 2978, 2926, 1694, 1450, 1414, 1393, 1367, 1329, 1246, 1152, 1042, 999, 979, 926, 857, 766, 724, 694, 672, 648 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 34 C20H29FN3O4 [M+NH4]+: 438.2035, found 438.2040; [α]D22.85 +28.89 (c 1.0, CHCl3); SFC Conditions: 10% IPA, 2.5 mL/min, Chiralcel OD-H column, λ = 210 nm, tR (min): minor = 6.26, major = 4.99. O F AnN NBoc tert-butyl (S)-6-allyl-6-fluoro-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1carboxylate (20g) Prepared according to the general procedure with allyl ester 19g (60 mg, 0.133 mmol, 1.0 equiv), Pd2(dba)3 (4.9 mg, 0.0053 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (7.9 mg, 0.013 mmol, 10 mol %). Purified by automated silica gel flash chromatography (0→50% acetone/hexanes) to provide alkyl fluoride 20g as a colorless oil (45 mg, 0.111 mmol, 84% yield, 83% ee); 1H NMR (400 MHz, CDCl3) δ 7.61 – 7.53 (m, 2H), 6.92 – 6.84 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 35 (m, 2H), 5.93 – 5.78 (m, 1H), 5.30 – 5.21 (m, 2H), 4.35 (t, J = 16.0 Hz, 1H), 4.22 – 4.02 (m, 2H), 3.96 – 3.85 (m, 1H), 3.84 (s, 3H), 3.40 – 3.19 (m, 2H), 2.94 – 2.78 (m, 1H), 2.71 – 2.48 (m, 1H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.9, 173.7, 163.1, 155.3, 131.0, 130.6, 127.1, 121.0, 113.8, 97.8 (dd, JC-F = 193.7, 52.5 Hz), 81.2, 55.5, 49.8 (dd, JCF = 33.5, 23.3 Hz), 47.5, 46.9, 43.2, 39.8 (dd, JC-F = 32.1, 21.8 Hz), 28.3; IR (Neat Film, NaCl) 2977, 2932, 1696, 1603, 1578, 1511, 1448, 1413, 1366, 1327, 1256, 1169, 1152, 1029, 1000, 977, 923, 835, 766 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C21H28FN2O5 [M+H]+: 407.1977, found 407.1973; [α]D22.5 +46.99 (c 1.7, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralcel OD-H column, λ = 210 nm, tR (min): major = 2.69, minor = 3.25. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles Cl 36 O AnN NBoc tert-butyl (S)-6-allyl-6-(2-chloroallyl)-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1carboxylate (20h) Prepared according to the general procedure with allyl ester 19h (48.1 mg, 0.0949 mmol, 1.0 equiv), Pd2(dba)3 (3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide alkenyl chloride 20h as a colorless oil (36.7 mg, 0.0793 mmol, 84% yield, 90% ee); 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.93 – 5.71 (m, 1H), 5.36 – 5.07 (m, 4H), 4.36 – 3.84 (m, 4H), 3.83 (s, 3H), 3.82 – 3.51 (m, 2H), 3.00 – 2.33 (m, 4H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.2, 174.6, 162.7, 155.8, 155.2, 137.5, 132.9, 130.5, 128.3, 120.1, 118.2, 113.7, 81.1, 80.9, 55.5, 52.6, 49.2, 47.7, 47.4, 47.0, 44.5, 43.8, 42.8, 42.0, 41.8, 40.3, 28.5; IR (Neat Film, NaCl) 2976, 2930, 1694, 1631, 1604, 1580, 1510, 1456, 1421, 1393, 1366, 1320, 1282, 1256, 1212, 1167, 1150, 1030, 980, 928, 840, 765, 682, 636, 610 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C24H32ClN2O5 [M+H]+: 463.1994, found 463.2005; [α]D22.68 – 24.10 (c 0.5, CHCl3); SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): minor = 2.52, major = 2.77. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 37 O AnN NBoc tert-butyl (S)-6-allyl-4-(4-methoxybenzoyl)-5-oxo-6-(prop-2-yn-1-yl)-1,4-diazepane1-carboxylate (20i) Prepared according to the general procedure with allyl ester 19i (70.0 mg, 0.149 mmol, 1.0 equiv), Pd2(pmdba)3 (5.4 mg, 4.9 µmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (8.8 mg, 0.015 mmol, 10 mol %) at 50 °C. Purification by automated silica gel flash chromatography (Teledyne ISCO, 0→40% acetone/hexanes) provided alkyne 20i as a colorless oil (28.0 mg, 0.0656 mmol, 44% yield, 94% ee); 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 8.2 Hz, 2H), 6.89 – 6.82 (m, 2H), 5.93 – 5.63 (m, 1H), 5.30 – 5.10 (m, 2H), 4.36 – 4.15 (m, 1H), 4.09 – 3.68 (m, 4H), 3.83 (s, 3H), 3.62 – 3.37 (m, 1H), 2.83 – 2.43 (m, 4H), 2.20 – 1.99 (m, 1H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 177.5, 174.6, 162.9, 155.6, 155.2, 132.1, 130.7, 127.9, 120.0, 113.7, 81.1, 80.9, 80.5, 72.1, 55.6, 52.7, 49.1, 46.9, 47.7, 43.0, 42.3, 39.1, 37.5, 28.5, 26.5, 25.9; IR (Neat Film, NaCl) 3283, 2972, 2922, 1692, 1603, 1511, 1454, 1418, 1365, 1322, 1255, 1169, 1031, 980, 926, 839, 766, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 38 670 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C24H31N2O5 [M+H]+: 427.2227, found 427.2238; [α]D22.1 –7.69 (c 1.0, CHCl3); SFC conditions: 10% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): major = 10.85, minor = 10.29. CO2Me O AnN NBoc tert-butyl (R)-6-allyl-6-(3-methoxy-3-oxopropyl)-4-(4-methoxybenzoyl)-5-oxo-1,4diazepane-1-carboxylate (20j) Prepared according to the general procedure with allyl ester 19j (51.9 mg, 0.100 mmol, 1.0 equiv), Pd2(dba)3 (3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %). Purified by silica gel flash chromatography (33% Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 39 EtOAc/hexanes) to provide methyl ester 20j as a white, amorphous solid (45.8 mg, 0.0965 mmol, 96% yield, 95% ee); 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.48 (m, 2H), 6.92 – 6.83 (m, 2H), 5.80 – 5.64 (m, 1H), 5.22 – 5.09 (m, 2H), 4.21 (ddd, J = 15.7, 6.6, 2.1 Hz, 1H), 4.13 – 3.85 (m, 3H), 3.83 (s, 3H), 3.62 (s, 3H), 3.51 (d, J = 15.2 Hz, 1H), 3.42 – 3.29 (m, 1H), 2.64 – 2.20 (m, 4H), 2.20 – 1.86 (m, 2H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 179.2, 174.7, 173.6, 173.4, 162.7, 155.4, 155.0, 132.7, 132.5, 130.3, 128.3, 120.0, 113.8, 81.1, 80.9, 55.5, 51.8, 50.1, 48.9, 47.6, 46.8, 43.2, 42.9, 40.3, 39.7, 29.3, 28.8, 28.5; IR (Neat Film, NaCl) 2975, 2360, 1736, 1694, 1605, 1580, 1510, 1426, 1393, 1366, 1321, 1283, 1254, 1167, 1031, 980, 927, 842, 811, 762, 647, 610 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C25H35N2O7 [M+H]+: 475.2439, found 475.2438; [α]D22.52 +7.73 (c 1.0, CHCl3); SFC conditions: 15% IPA, 2.5 mL/min, Chiralcel OD-H column, λ = 210 nm, tR (min): major = 5.27, minor = 4.84. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 40 CN O AnN NBoc tert-butyl (R)-6-allyl-6-(2-cyanoethyl)-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1carboxylate (20k) Prepared according to the general procedure with allyl ester 19k (62.2 mg, 0.128 mmol, 1.0 equiv), Pd2(dba)3 (4.7 mg, 0.00512 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (7.6 mg, 0.0128 mmol, 10 mol %), using 9:1 methylcyclohexane-toluene as the reaction solvent. Purified by silica gel flash chromatography (33% EtOAc/hexanes) to provide nitrile 20k as a white, amorphous solid (48.6 mg, 0.110 mmol, 86% yield, 84% ee); 1H NMR (400 MHz, CDCl3) δ 7.59 – 7.47 (m, 2H), 6.96 – 6.85 (m, 2H), 5.82 – 5.64 (m, 1H), 5.30 – 5.11 (m, 2H), 4.09 – 3.93 (m, 2H), 3.93 – 3.72 (m, 2H), 3.85 (s, 3H), 3.70 – 3.38 (m, 2H), 2.60 – 2.25 (m, 4H), 2.22 – 1.93 (m, 2H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.0, 174.5, 163.0, 155.6, 154.9, 131.7, 130.3, 127.9, 120.7, 119.7, 113.9, 81.4, 55.6, 52.2, 49.6, 48.0, 47.4, 46.8, 43.0, 42.6, 39.9, 39.0, 32.1, 31.5, 28.4, 12.4; IR (Neat Film, NaCl) 2975, 2931, 2361, 2246, 1690, 1604, 1579, 1510, 1456, 1419, 1366, 1321, 1256, 1168, 1148, 1031, 980, 926, 840, 811, 766, 607 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C24H35N4O5 [M+NH4]+: 459.2602, found 459.2602; [α]D22.4 +9.31 (c 0.5, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralcel OD-H column, λ = 310 nm, tR (min): major = 8.33, minor = 6.18. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 41 BocHN O BzN NBoc tert-butyl (S)-6-allyl-4-benzoyl-6-(((tert-butoxycarbonyl)amino)methyl)-5-oxo-1,4diazepane-1-carboxylate (20l) Prepared according to the general procedure with allyl ester 19l (53 mg, 0.0997 mmol, 1.0 equiv) and Pd2(dba)3. Purification by automated silica gel flash chromatography (0→50% EtOAc/hexanes) provided carbamate 20l as a white foam (37 mg, 0.0759 mmol, 76% yield, 93% ee). 1H NMR (400 MHz, CDCl3) δ 7.55 – 7.44 (m, 3H), 7.44 – 7.35 (m, 2H), 5.74 (ddt, J = 15.7, 10.5, 7.4 Hz, 1H), 5.35 (br s, 0.5H), 5.21 – 5.06 (m, 2H), 4.79 (br s, 0.5H), 4.48 – 4.28 (m, 1H), 4.14 – 3.09 (m, 7H), 2.69 – 2.18 (m, 2H), 1.50 (s, 9H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 179.3, 178.8, 174.5, 156.3, 155.9, 155.1, 136.3, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 42 132.5, 132.1, 131.7, 128.5, 127.7, 120.1, 81.3, 81.1, 79.5, 54.8, 48.9, 47.3, 46.8, 46.3, 42.6, 41.1, 38.7, 37.1, 28.5, 28.5; IR (Neat Film, NaCl) 2977, 1687, 1502, 1422, 1391, 1365, 1322, 1282, 1245, 1168, 978, 916, 753 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C26H37N3O6 [M+H]+: 488.2755, found 488.2747; [α]D23.2 –3.70 (c 1.85, CHCl3); SFC conditions: 20% IPA, 2.5 mL/min, Chiralpak IC column, λ = 254 nm, tR (min): major = 5.85, minor = 4.65. O Bn AnN NBoc Procedure for the large-scale preparation of diazepanone 20e To a 500 mL Schlenk flask was added Pd2(dba)3 (37 mg, 0.04 mmol, 4 mol %), (S)(CF3)3-t-BuPHOX (59 mg, 0.1 mmol, 10 mol %), and MeCy (20 mL). After stirring for 20 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 43 minutes at 25 °C, allyl ester 19e (523 mg, 1.0 mmol, 1.0 equiv) and methylcyclohexane (52 mL, total substrate concentration 0.014 M) were added to the pre-stirred catalyst solution. After stirring for 23 h at 40 °C, the reaction mixture was directly loaded onto a flash column and purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide benzyl diazepanone 20e as a colorless oil (393 mg, 0.82 mmol, 82% yield, 83% ee); All characterization data matched those reported above for compound 20e; [α]D21.96 +14.757 (c 1.0, CHCl3); SFC Conditions: 20% IPA, 2.5 mL/min, Chiralpak AD-H column, λ = 210 nm, tR (min): minor = 3.76, major = 5.90. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 1.5.2.2 44 Synthesis of Diazepanone Allylic Alkylation Substrates O BzN NBoc tert-butyl 4-benzoyl-5-oxo-1,4-diazepane-1-carboxylate (55) To a solution of tert-butyl 5-oxo-1,4-diazepane-1-carboxylate (5.00 g, 23.3 mmol, 1.0 equiv) in THF (230 mL, 0.1 M) at –78 °C was slowly added n-BuLi (2.18 M in hexanes, 12.8 mL, 27.9 mmol, 1.2 equiv). The opaque mixture was allowed to warm to ambient temperature until the solution became homogeneous, at which point it was again cooled to –78 °C. Then, benzoyl chloride (3.52 mL, 30.3 mmol, 1.3 equiv) was added dropwise and the reaction turned light orange over several minutes. The reaction was stirred for 1 h at – 78 °C, then poured into saturated aqueous NH4Cl (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (20% acetone/hexanes) to afford benzoyl-protected lactam 55 as a white solid (7.43 g, 23.3 mmol, >99% yield); 1H NMR (400 MHz, CDCl3) δ 7.57 – 7.49 (m, 2H), 7.49 – 7.41 (m, 1H), 7.41 – 7.32 (m, 2H), 4.03 – 3.96 (m, 2H), 3.71 (m, 4H), 2.82 – 2.75 (m, 2H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.6, 173.7, 154.5, 135.9, 131.7, 128.2, 127.9, 80.7, 47.8, 47.10, 45.4, 41.6, 41.0, 40.6, 28.3; IR (Neat Film, NaCl) 2976, 2932, 2251, 1682, 1599, 1582, 1450, 1422, 1392, 1366,1327, 1285, 1247, 1229, 1157, 1115, 1032, 1018, 976, 954, 915,862, 793,769, 729, 696, 647 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C17H26N3O4 [M+NH4]+: 336.1918, found 336.1912. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 45 O (p-F3C-Bz)N NBoc tert-butyl 5-oxo-4-(4-(trifluoromethyl)benzoyl)-1,4-diazepane-1-carboxylate (56) To a solution of tert-butyl 5-oxo-1,4-diazepane-1-carboxylate (500 mg, 2.33 mmol, 1 equiv) in THF (25 mL, 0.1 M) at –78 °C was slowly added n-BuLi (2.5 M in hexanes, 1.02 mL, 2.56 mmol, 1.1 equiv), and the reaction mixture was stirred at –78 °C for 15 min. Then, 4-trifluoromethylbenzoyl chloride (450 µL, 3.03 mmol, 1.3 equiv) was added dropwise, and the reaction was stirred for 30 min at –78 °C. The reaction mixture was then poured into saturated aqueous NH4Cl (20 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (25% EtOAc/hexanes) to afford the title compound as a white solid (698 mg, 1.81 mmol, 77% yield); 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 4.14 – 4.02 (m, 2H), 3.84 – 3.66 (m, 4H), 2.91 – 2.77 (m, 2H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.7, 172.5, 154.6, 139.6, 133.0 (q, JC-F = 32.8 Hz), 130.6, 128.0, 125.5 (q, JC-F = 3.8 Hz), 123.7 (q, JC-F = 272.6 Hz), 81.2, 47.7 (br), 45.3, 41.4 (br), 40.8, 28.5; IR (Neat Film, NaCl) 2981, 1689, 1455, 1422, 1367, 1326, 1301, 1249, 1230, 1159, 1127, 1066, 1028, 1015, 977, 955, 852, 832, 769 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C18H25F3N3O4 [M+NH4]+: 404.1742, found 404.1797. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 46 O AnN NBoc tert-butyl 4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1-carboxylate (57) To a solution of tert-butyl 5-oxo-1,4-diazepane-1-carboxylate (800 mg, 3.73 mmol, 1 equiv) in THF (37 mL, 0.1 M) at –78 °C was slowly added n-BuLi (2.5 M in hexanes, 1.64 mL, 4.1 mmol, 1.1 equiv). The opaque mixture was allowed to warm to ambient temperature until the solution became homogeneous, at which point it was again cooled to –78 °C. Then, 4-methoxybenzoyl chloride (657 µL, 4.85 mmol, 1.3 equiv) was added dropwise and the reaction was stirred for 30 min at –78 °C. The reaction mixture was then poured into saturated aqueous NH4Cl (30 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→100% EtOAc/hexanes) to afford the title compound as a white solid (1.2 g, 3.44 mmol, 92% yield); 1H NMR (400 MHz, CDCl3) δ 7.62 – 7.54 (m, 2H), 6.93 – 6.84 (m, 2H), 4.00 – 3.93 (m, 2H), 3.83 (s, 3H), 3.78 – 3.69 (m, 4H), 2.85 – 2.78 (m, 2H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 175.7, 173.4, 162.9, 154.6, 130.9, 130.6, 127.7, 113.7, 80.8, 55.5, 48.0, 47.4, 46.1, 41.9, 41.3, 40.8, 28.5; IR (Neat Film, NaCl) 2974, 2936, 1774, 1687, 1604, 1578, 1510, 1458, 1420, 1391, 1366, 1327, 1284, 1249, 1166, 1114, 1023, 977, 956, 916, 860, 842, 809, 767, 632 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C18H25N2O5 [M+H]+: 349.1758, found 349.1760. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles O 47 O O BzN NBoc 6-allyl 1-(tert-butyl) 4-benzoyl-5-oxo-1,4-diazepane-1,6-dicarboxylate (18a) To a solution of diisopropylamine (266 µL, 1.88 mmol, 1.2 equiv) in THF (10 mL) at –78 °C in a flame-dried round-bottom flask was added n-BuLi (2.5 M in hexanes, 792 µL, 1.73 mmol, 1.1 equiv), the resulting solution was stirred at –78 °C for 45 min. To this solution was then added lactam 55 (500 mg, 1.57 mmol, 1.0 equiv) in THF (6 mL, 0.1 M total concentration) dropwise while stirring at −78 °C. The reaction mixture was stirred for 75 min at −78 °C. Allyl cyanoformate (201 μL, 1.88 mmol, 1.2 equiv) was then added dropwise at −78 °C. After stirring for 3 h at −78 °C, the reaction mixture was poured into saturated aqueous NH4Cl (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were concentrated under reduced pressure onto silica (4 g). The silica-adsorbed crude mixture was purified by silica gel flash chromatography (20→30% EtOAc/hexanes) to provide allyl ester 18a as an off-white solid (550 mg, 1.37 mmol, 87% yield); 1H NMR (500 MHz, CDCl3) δ 7.65 – 7.57 (m, 2H), 7.53 – 7.45 (m, 1H), 7.42 – 7.34 (m, 2H), 5.92 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.40 – 5.22 (m, 2H), 4.79 – 4.59 (m, 2H), 4.33 – 4.03 (m, 2H), 4.02 – 3.88 (m, 3H), 3.87 – 3.66 (m, 1H), 3.55 – 3.40 (m, 1H), 1.48 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 173.7, 171.4, 167.5, 154.7, 135.3, 132.2, 131.4, 128.4, 128.4, 119.5, 81.3, 66.6, 56.0, 46.7 (br), 44.5, 43.3 (br), 28.4; IR (Neat Film, NaCl) 3374, 3062, 2977, 2934, 1746, 1694, 1600, 1582, 1450, 1419, 1393, 1367, 1327, 1246, 1156, 1037, 1020, 995, 968, 939, 857, 792, 769, 727, 695, 616 cm–1; HRMS (MM: ESIAPCI): m/z calc’d for C21H30N3O6 [M+NH4]+: 420.2129, found 420.2109. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles O 48 O O (p-F3C-Bz)N NBoc 6-allyl 1-(tert-butyl) 5-oxo-4-(4-(trifluoromethyl)benzoyl)-1,4-diazepane-1,6- dicarboxylate (18b) To a solution of lactam 56 (500 mg, 1.29 mmol, 1.0 equiv) in THF (8 mL, 0.1 M total concentration) at −78 °C was added LiHMDS (303 mg, 1.81 mmol, 1.4 equiv) in THF (5 mL) dropwise. The resulting yellow reaction mixture was stirred for 15 min at −78 °C. Then, allyl cyanoformate (166 μL, 1.55 mmol, 1.2 equiv) was added dropwise at −78 °C, after which the solution slowly became colorless. After stirring for 1 h at −78 °C, the reaction was poured into 2 M HCl (20 mL) and extracted with ethyl acetate (4 x 20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and NaHCO3, passed through filter paper, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (20→33% EtOAc/hexanes) to provide allyl ester 18b as a white solid (266 mg, 0.565 mmol, 44% yield); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 5.92 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 5.42 – 5.23 (m, 2H), 4.79 – 4.59 (m, 2H), 4.46 – 3.63 (m, 6H), 3.52 (m, 1H), 1.47 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 172.4, 171.4, 167.4, 154.6, 138.9, 133.3 (q, JC-F = 32.6 Hz), 131.2, 128.3, 125.4 (q, JC-F = 3.8 Hz), 123.7 (q, JC-F = 272.5 Hz), 119.8, 81.5, 66.8, 56.0, 47.4, 46.3, 44.2, 43.0, 28.4; IR (Neat Film, NaCl) 3377, 3083, 2980, 2935, 2463, 2358, 1928, 1798, 1747, 1694, 1652, 1619, 1584, 1513, 1455, 1414, 1394, 1368, 1327, 1246, 1156, 1131, 1067, 1034, 1016, 994, 970, 940, 879, 853, 824, 770, 723, 679, 639, 630, 612 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 49 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H29F3N3O6 [M+NH4]+: 488.2003, found 488.2022. O O O AnN NBoc 6-allyl 1-(tert-butyl) 4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1,6-dicarboxylate (18c) To a solution of lactam 57 (1.00 g, 2.87 mmol, 1.0 equiv) in THF (20 mL, 0.1 M total concentration) at −78 °C was added LiHMDS (528 mg, 3.16 mmol, 1.1 equiv) in THF (9 mL) dropwise. The resulting pale yellow reaction mixture was stirred for 15 min at −78 °C. Allyl cyanoformate (368 μL, 3.44 mmol, 1.2 equiv) was then added dropwise at −78 °C, resulting in a clear solution. After stirring for 1.5 h at −78 °C, the reaction was poured into 1 M HCl (10 mL) and diluted with ethyl acetate (20 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and NaHCO3, filtered, and concentrated under reduced pressure onto silica. The silica-adsorbed crude mixture was purified by silica gel flash chromatography (10→20% EtOAc/hexanes) to provide allyl ester 18c as a colorless oil (600 mg, 1.39 mmol, 48% yield); 1H NMR (400 MHz, CDCl3) δ 7.72 – 7.60 (m, 2H), 6.91 – 6.79 (m, 2H), 5.92 (ddt, J = 17.3, 10.4, 5.9 Hz, 1H), 5.42 – 5.20 (m, 2H), 4.77 – 4.56 (m, 2H), 4.40 – 3.92 (m, 4H), 3.92 – 3.62 (m, 2H), 3.82 (s, 3H), 3.58 – 3.24 (m, 1H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.1, 171.3, 167.6, 163.2, 154.6, 131.4, 131.2, 127.0, 119.4, 113.7, 81.1, 66.5, 55.9, 55.4, 47.7 and 46.7, 45.1, 43.3, 42.8, 28.3; IR (Neat Film, NaCl) 2977, 1746, 1693, 1603, 1578, 1511, 1454, 1419, 1392, 1366, 1324, 1255, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 50 1168, 1025, 995, 965, 842, 766 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H28N2O7 [M+H]+: 433.1969, found 433.1966. O Bn O O BzN NBoc 6-allyl 1-(tert-butyl) 4-benzoyl-6-benzyl-5-oxo-1,4-diazepane-1,6-dicarboxylate (19a) To a flame-dried round bottom flask containing a solution of allyl ester 18a (1.00 g, 2.49 mmol, 1.0 equiv) in THF (25 mL, 0.1 M) at 0 °C was added NaH (60% dispersion in mineral oil, 107 mg, 2.74 mmol, 1.1 equiv) and the mixture was stirred at 0 °C for 30 min. BnBr (1.50 mL, 12.45 mmol, 5.0 equiv) was then added dropwise and the reaction mixture was warmed to 45 °C. After 16 h, the temperature was further increased to 53 °C due to sluggish reactivity. After another 45 min of stirring at 53 °C, the reaction mixture was cooled to 23 °C and poured into saturated aqueous NH4Cl (25 mL), the layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide the title compound as a colorless foam (922 mg, 1.87 mmol, 75% yield); 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz, 2H), 7.55 – 7.46 (m, 1H), 7.37 (t, J = 7.7 Hz, 2H), 7.31 – 7.25 (m, 3H), 7.24 – 7.12 (m, 2H), 5.86 (tq, J = 22.8, 6.5 Hz, 1H), 5.42 – 5.26 (m, 2H), 4.71 – 4.55 (m, 2H), 4.22 (dd, J = 75.3, 15.5 Hz, 1H), 4.05 – 3.57 (m, 4H), 3.57 – 3.36 (m, 2H), 3.22 (dd, J = 68.5, 13.7 Hz, 1H), 1.45 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ (174.4, 174.0, 172.2, 172.0, 170.8, 170.2, 155.5, 155.0, 135.7, 135.6, 135.5, 132.0, 131.1, 130.9, 130.8, 130.6, 128.5, 128.5, 128.3, 127.5, 127.4, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 51 120.6, 120.2, 81.2, 81.0, 67.0, 66.9, 62.6, 62.2, 47.3, 46.7, 46.2, 45.8, 42.4, 42.1, 42.0, 28.5; IR (Neat Film, NaCl) 3063, 3030, 2977, 2933, 1694, 1601, 1583, 1495, 1450, 1416, 1393, 1366, 1325, 1280, 1247, 1154, 1132, 1092, 1041, 1023, 980, 939, 868, 796, 768, 728, 703, 662 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C24H25N2O6 [M–tBu+2H]+: 437.1707, found 437.1697. O Me O O BzN NBoc 6-allyl 1-(tert-butyl) 4-benzoyl-6-methyl-5-oxo-1,4-diazepane-1,6-dicarboxylate (19b) To a solution of allyl ester 18a (240 mg, 0.596 mmol, 1.0 equiv) in THF (6 mL, 0.1 M) at 0 °C was added 60 % NaH (26 mg, 0.657 mmol, 1.1 equiv). The solution was stirred at 0 °C for 40 min, after which MeI (186 µL, 2.98 mmol, 5.0 equiv) was added rapidly. The reaction was heated to 45 °C and stirred for 16 h, cooled to 23 °C, poured into saturated aqueous NH4Cl (5 mL), and extracted with EtOAc (3 x 3 mL). The combined organic extracts were dried over Na2SO4 and concentrated onto silica gel. The silica-adsorbed crude product was purified by silica gel flash chromatography (20% EtOAc/hexanes) to afford the title compound as a light yellow oil (200 mg, 0.480 mmol, 81% yield). 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.63 (m, 2H), 7.58 – 7.43 (m, 1H), 7.38 (t, J = 7.6 Hz, 2H), 5.96 (ddt, J = 16.6, 10.4, 6.0 Hz, 1H), 5.49 – 5.26 (m, 2H), 4.85 – 4.64 (m, 2H), 4.46 – 4.22 (m, 1H), 4.10 (br d, J = 14.8 Hz, 1H), 3.86 – 3.42 (m, 4H), 1.57 (s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.5 174.1, 173.0, 171.7, 155.1, 154.9, 135.7, 132.0, 131.2, 128.3, 128.2, 120.2, 81.1, 66.9, 57.7, 49.8, 49.0, 47.1, 46.0, 43.2, 28.4, 23.6; IR (Neat Film, NaCl) 2977, 1693, 1449, 1416, 1366, 1325, 1281, 1249, 1139, 1104, 1047, 983, 938, 768, 727, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 52 694 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H29N2O6 [M+H]+: 417.2020, found 417.2010. O Me O O (p-F3C-Bz)N NBoc 6-allyl 1-(tert-butyl) 6-methyl-5-oxo-4-(4-(trifluoromethyl)benzoyl)-1,4-diazepane1,6-dicarboxylate (19c) To a suspension of allyl ester 18b (150 mg, 0.319 mmol, 1.0 equiv) and Cs2CO3 (208 mg, 0.638 mmol, 2.0 equiv) in acetonitrile (3.2 mL, 0.1 M) was added MeI (99 µL, 1.59 mmol, 5.0 equiv) at 23 °C. The reaction was heated to 45 °C and stirred for 5 h, then cooled to 23 °C, poured into saturated aqueous NH4Cl (6 mL), and extracted with EtOAc (3 x 3 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (15% EtOAc/petroleum ether) to provide the title compound as a colorless oil (146 mg, 0.301 mmol, 95% yield); 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 5.97 (ddt, J = 17.3, 10.3, 6.1 Hz, 1H), 5.48 – 5.29 (m, 2H), 4.84 – 4.68 (m, 2H), 4.49 – 4.30 (m, 1H), 4.18 – 3.98 (m, 1H), 3.90 – 3.39 (m, 4H), 1.57 (s, 3H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 173.2, 172.7, 171.7, 154.9, 139.2, 133.1 (q, JC-F = 32.5 Hz), 131.1, 128.2, 125.4, 123.8 (q, JC-F = 272.7 Hz), 120.5, 81.3, 67.0, 57.7, 49.7, 49.0, 46.9, 45.8, 43.1, 42.9, 28.4, 23.7; IR (Neat Film, NaCl) 3384, 3083, 2979, 2937, 1698, 1619, 1584, 1514, 1478, 1453, 1416, 1394, 1367, 1326, 1285, 1250, 1207, 1166, 1136, 1110, 1066, 1022, 1012, 985, 938, 855, 832, 817, 790, 769, 740, 722, 680 cm– Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 1 53 ; HRMS (MM: ESI-APCI): m/z calc’d for C23H28F3N2O6 [M+H]+: 485.1894, found 485.1907. O Me O O AnN NBoc 6-allyl 1-(tert-butyl) 4-(4-methoxybenzoyl)-6-methyl-5-oxo-1,4-diazepane-1,6dicarboxylate (19d) To a suspension of allyl ester 18c (200 mg, 0.462 mmol, 1.0 equiv), Cs2CO3 (301 mg, 0.925 mmol, 2.0 equiv) in acetonitrile (4.6 mL, 0.1 M) was added MeI (143 µL, 2.31 mmol, 5.0 equiv) at 23 °C. The reaction was heated to 45 °C and stirred for 40 min, then cooled to 23 °C, poured into saturated aqueous NH4Cl (10 mL), and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→90% EtOAc/hexanes) to provide the title compound as a colorless oil (70 mg, 0.157 mmol, 34% yield). 1H NMR (400 MHz, CDCl3) δ 7.75 – 7.65 (m, 2H), 6.90 – 6.82 (m, 2H), 5.96 (ddt, J = 17.3, 10.4, 6.0 Hz, 1H), 5.44 – 5.29 (m, 2H), 4.77 – 4.66 (m, 2H), 4.27 – 4.15 (m, 1H), 4.14 – 4.04 (m, 1H), 3.83 (s, 3H), 3.80 – 3.70 (m, 1H), 3.67 – 3.58 (m, 2H), 3.56 – 3.46 (m, 1H), 1.57 (s, 3H), 1.44 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.0, 173.6, 172.9, 172.0, 171.8, 162.9, 155.2, 154.9, 131.2, 131.2, 131.0, 127.6, 120.1, 120.0, 113.6, 81.0, 66.8, 57.5, 55.5, 49.6, 48.9, 47.2, 46.1, 43.7, 28.4, 23.7; IR (Neat Film, NaCl) 2974, 2937, 1698, 1604, 1578, 1511, 1453, 1416, 1392, 1366, 1324, 1280, 1256, 1169, 1139, 1103, 1031, 1001, 983, 929, 840, 768, 733 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C23H31N2O7 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 54 [M+H]+: 447.2126, found 447.2128. O Bn O O AnN NBoc 6-allyl 1-(tert-butyl) 6-benzyl-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1,6- dicarboxylate (19e) To a flame-dried round bottom flask containing a solution of allyl ester 18c (300 mg, 0.694 mmol, 1.0 equiv) in THF (7 mL, 0.1 M) at 0 °C was added NaH (60% dispersion in mineral oil, 38 mg, 0.972 mmol, 1.4 equiv) and the mixture was stirred at 0 °C for 15 min and then allowed to warm to 23 °C over 15 min. BnBr (412 µL, 3.47 mmol, 5.0 equiv) was then added dropwise and the reaction mixture was heated to 50 °C. After stirring for 8 h, the reaction mixture was allowed to cool to 23 °C and poured into saturated aqueous NH4Cl (5 mL), the layers were separated, and the aqueous phase was extracted with ethyl acetate (3 x 2 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide the title compound as a colorless foam (303 mg, 0.580 mmol, 84% yield); 1H NMR (500 MHz, CDCl3) δ 7.72 (d, J = 8.5 Hz, 2H), 7.31 – 7.12 (m, 5H), 6.90 – 6.80 (m, 2H), 5.95 – 5.75 (m, 1H), 5.41 – 5.26 (m, 2H), 4.69 – 4.54 (m, 2H), 4.21 – 4.05 (m, 1H), 4.02 – 3.86 (m, 2H), 3.83 (s, 3H), 3.78 – 3.62 (m, 2H), 3.56 – 3.49 (m, 1H), 3.43 – 3.10 (m, 2H), 1.45 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 173.7, 173.4, 172.0, 171.7, 170.8, 170.2, 162.9, 155.4, 154.8, 135.7, 135.6, 131.1, 130.9, 130.7, 130.5, 128.5, 128.3, 128.2, 127.5, 127.3, 127.0, 120.2, 119.9, 113.5, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 55 80.9, 80.7, 66.6, 62.4, 62.0, 55.3, 47.1, 46.8, 46.0, 45.8, 42.8, 42.5, 41.9, 28.3; IR (Neat Film, NaCl) 2976, 2359, 1698, 1604, 1512, 1455, 1416, 1366, 1324, 1258, 1155, 1028, 979, 840, 741, 703, 671, 634 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C29H35N2O7 [M+H]+: 523.2439, found 523.2446. O F O O BzN NBoc 6-allyl 1-(tert-butyl) 4-benzoyl-6-fluoro-5-oxo-1,4-diazepane-1,6-dicarboxylate (19f) To a 20 mL vial containing allyl ester 18a (250 mg, 0.621 mmol, 1.0 equiv) in THF (7.4 mL, 0.1 M) at 23 °C was added NaH (60% dispersion in mineral oil, 27.3 mg, 0.683 mmol, 1.1 equiv). After stirring for 12 min, Selectfluor™ (264 mg, 0.745 mmol, 1.2 equiv) was added in a single portion, and the reaction mixture was warmed to 50 °C and stirred for 24 h, after which starting material remained as judged by TLC. Additional Selectfluor™ (264 mg, 0.745 mmol, 1.2 equiv) was then added, and the reaction mixture was stirred for an additional 8 h at 50 °C. The reaction mixture was allowed to cool to 23 °C and water (5 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel flash chromatography (25% EtOAc/hexanes) to provide the title compound (167 mg, 0.397 mmol, 64% yield); 1H NMR (500 MHz, CDCl3) δ 7.64 – 7.56 (m, 2H), 7.52 – 7.43 (m, 1H), 7.36 (t, J = 7.7 Hz, 2H), 5.99 – 5.80 (m, 1H), 5.43 – 5.19 (m, 2H), 4.83 – 4.56 (m, 2H), 4.52 – 4.17 (m, 3H), 4.03 – 3.56 (m, 2H), 3.27 – 3.08 (m, 1H), 1.47 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 173.1, 169.6, 169.4, 164.8, 164.6, 154.9, 134.3, 132.5, 130.7, 128.5, 128.4, 119.7, 95.7 (d, J = Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 56 204.8 Hz), 81.5, 67.2, 47.6 (dd, JC-F = 137.5, 24.1 Hz), 47.3, 46.4, 42.8, 28.3; IR (Neat Film, NaCl) 2978, 2926, 1694, 1450, 1414, 1393, 1367, 1329, 1246, 1152, 1042, 999, 979, 926, 857, 766, 724, 694, 672, 648 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C21H29FN3O6 [M+NH4]+: 438.2035, found 438.2040. O F O O AnN NBoc 6-allyl 1-(tert-butyl) 6-fluoro-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1,6- dicarboxylate (19g) To a 20 mL vial containing allyl ester 18c (320 mg, 0.740 mmol, 1.0 equiv) and NaH (60% dispersion in mineral oil, 32.5 mg, 0.814 mmol, 1.1 equiv) was added THF (7.4 mL, 0.1 M) at 23 °C. After stirring for 30 min, Selectfluor™ (315 mg, 0.889 mmol, 1.2 equiv) was added in a single portion, and the reaction mixture was warmed to 50 °C and stirred for 5 h. The crude reaction mixture was then concentrated under reduced pressure and purified by silica gel flash chromatography (30% acetone/hexanes) to provide the title compound (290 mg, 0.644 mmol, 87% yield); 1H NMR (400 MHz, CDCl3) δ 7.66 – 7.58 (m, 2H), 6.90 – 6.82 (m, 2H), 5.91 (ddt, J = 16.3, 10.9, 5.7 Hz, 1H), 5.43 – 5.21 (m, 2H), 4.84 – 4.40 (m, 3H), 4.40 – 4.16 (m, 2H), 4.00 – 3.86 (m, 1H), 3.82 (s, 3H), 3.77 – 3.56 (m, 1H), 3.22 – 3.09 (m, 1H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.6, 169.6 (dd, JC-F = 48.2, 25.4 Hz), 164.9 (d, JC-F = 25.8 Hz), 163.4, 155.0, 131.3, 130.8, 126.1, 119.8, 113.9, 95.7 (dd, JC-F = 205.6, 14.6 Hz), 81.5, 67.3, 55.5, 47.5 (dd, JC-F = 109.0, 23.7 Hz), 47.2 (d, JC-F = 92.2 Hz), 43.4, 28.3; IR (Neat Film, NaCl) 2976, 2936, 2844, 1759, 1698, 1603, 1578, 1512, 1449, 1414, 1367, 1327, 1258, 1168, 1151, 1076, 1030, 997, 977, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 57 942, 929, 841, 817, 770, 760, 730, 698 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H28FN2O7 [M+H]+: 451.1875, found 451.1877. Cl O O O AnN NBoc 6-allyl 1-(tert-butyl) 6-(2-chloroallyl)-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1,6dicarboxylate (19h) To a suspension of allyl ester 18c (300 mg, 0.694 mmol, 1.0 equiv) and Cs2CO3 (453 mg, 1.39 mmol, 2.0 equiv) in acetonitrile (7 mL, 0.1 M) was added 2,3dichloropropene (320 µL, 3.47 mmol, 5.0 equiv) at 23 °C. The reaction mixture was heated to 50 °C and stirred for 19 h, after which starting material remained as judged by TLC. Tetrabutylammonium iodide (25.6 mg, 0.0694 mmol, 0.1 equiv) was added and the reaction mixture was stirred at 50 °C for an additional 9 h, then allowed to cool to 23 °C. The mixture was filtered through a cotton plug and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (20% EtOAc/petroleum ether) to provide the title compound as a colorless oil (196 mg, 0.387 mmol, 56% yield); 1 H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 6.12 – 5.94 (m, 1H), 5.60 – 5.25 (m, 4H), 4.78 (qdt, J = 12.8, 6.0, 1.2 Hz, 2H), 4.25 (br t, J = 13.9 Hz, 1H), 4.17 – 3.87 (m, 3H), 3.84 (s, 3H), 3.76 – 3.51 (m, 1H), 3.48 – 3.30 (m, 1H), 3.29 – 2.99 (m, 2H), 1.43 (d, J = 16.9 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 173.9, 173.3, 170.3, 163.1, 155.9, 155.1, 137.0, 136.7, 131.1, 127.2, 120.6, 120.3, 119.4, 118.4, 113.6, 81.4, 81.0, 67.5, 60.0, 55.5, 47.1, 45.9, 46.0, 45.2, 45.6, 44.7, 43.1, 42.8, 28.4; IR (Neat Film, NaCl) 3356, 3080, 2977, 2933, 2841, 2568, 2254, 1700, 1629, 1605, 1579, 1512, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 58 1456, 1417, 1393, 1367, 1326, 1281, 1257, 1217, 1196, 1153, 1029, 988, 910, 842, 811, 780, 757, 732, 668, 634, 621 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C25H32ClN2O7 [M+H]+: 507.1893, found 507.1902. O O O AnN NBoc 6-allyl 1-(tert-butyl) 4-(4-methoxybenzoyl)-5-oxo-6-(prop-2-yn-1-yl)-1,4-diazepane1,6-dicarboxylate (19i) To a solution of allyl ester 18c (250 mg, 0.578 mmol, 1.0 equiv) in THF (5.8 mL, 0.1 M) was added NaH (60% dispersion in mineral oil, 25 mg, 0.636 mmol, 1.1 equiv) at 0 °C. After stirring for 30 min at 0 °C, propargyl bromide (80% wt/wt in toluene, 125 μL, 1.16 mmol, 2.0 equiv) was added at 0 °C. The reaction mixture was heated to 50 °C and stirred for 16 h. The mixture was allowed to cool to 23 °C, quenched with aqueous NaHCO3 (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→50% acetone/hexanes) to provide propargyl allyl ester 19i as a colorless oil (220 mg, 0.468 mmol, 81% yield). 1H NMR (500 MHz, CDCl3) δ 7.73 – 7.59 (m, 2H), 6.84 (d, J = 8.6 Hz, 2H), 5.99 (ddt, J = 17.3, 10.4, 6.0 Hz, 1H), 5.54 – 5.27 (m, 2H), 4.85 – 4.69 (m, 2H), 4.33 – 3.85 (m, 4H), 3.82 (s, 3H), 3.76 – 3.56 (m, 1H), 3.56 – 3.39 (m, 1H), 3.14 – 2.90 (m, 2H), 2.08 (s, 1H), 1.42 (d, J = 14.3 Hz, 9H); 13C NMR (125 MHz, CDCl3) δ 173.7, 173.2, 170.5, 170.3, 169.7, 169.3, 163.0, 155.6, 154.9, 131.2, 131.0, 127.1, 120.3, 120.0, 113.6, 81.1, 81.0, 78.9, 78.6, 72.3, 67.3, 60.7, 60.4, 55.5, 47.1, 46.5, 46.2, 46.0, 43.0, 28.3, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 59 27.0, 26.9; IR (Neat Film, NaCl) 3280, 2975, 2936, 1737, 1694, 1604, 1579, 1547, 1512, 1454, 1416, 1393, 1366, 1326, 1280, 1258, 1156, 1134, 1030, 994, 980, 841, 778, 770, 737, 706, 677, 634, 622 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C25H31N2O7 [M+H]+: 471. 2126, found 471.2130. CO2Me O O O AnN NBoc 6-allyl 1-(tert-butyl) 6-(3-methoxy-3-oxopropyl)-4-(4-methoxybenzoyl)-5-oxo-1,4- diazepane-1,6-dicarboxylate (19j) To a 20 mL vial containing allyl ester 18c (300 mg, 0.694 mmol, 1.0 equiv) and K2CO3 (480 mg, 3.47 mmol, 5.0 equiv) was added acetone (2.8 mL, 0.25 M) and methyl acrylate (126 µL, 1.39 mmol, 2.0 equiv) at 23 °C. The vessel was sealed and heated to 50 °C. After stirring for 5 h, additional methyl acrylate (126 µL, 1.39 mmol, 2.0 equiv) was added and the reaction was stirred for an additional 14 h. The reaction mixture was then filtered through a plug of cotton, concentrated under reduced pressure, and purified by silica gel flash chromatography (33% EtOAc/petroleum ether) to provide diester 19j as a colorless, waxy solid (185 mg, 0.357 mmol, 51% yield); 1H NMR (500 MHz, CDCl3) δ 7.77 – 7.65 (m, 2H), 6.92 – 6.79 (m, 2H), 5.96 (ddt, J = 17.2, 10.3, 6.1 Hz, 1H), 5.48 – 5.27 (m, 2H), 4.82 – 4.63 (m, 2H), 4.32 – 3.84 (m, 3H), 3.83 (s, 3H), 3.81 – 3.66 (m, 1H), 3.62 (s, 3H), 3.58 – 3.40 (m, 2H), 2.56 – 2.13 (m, 4H), 1.44 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 173.8, 173.5, 173.0, 171.9, 170.9, 170.6, 163.0, 155.1, 154.8, 131.1, 131.0, 127.5, 120.6, 113.6, 81.2, 67.0, 60.4, 55.5, 51.7, 48.7, 47.8, 47.0, 46.0, 43.4, 31.4, 29.8, 28.3; IR Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 60 (Neat Film, NaCl) 3354, 2976, 2843, 2568, 2255, 2044, 1694, 1605, 1579, 1556, 1513, 1416, 1393, 1367, 1260, 1168, 1030, 982, 916, 843, 811, 782, 766, 732, 648, 634 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C26H38N3O9 [M+NH4]+: 536.2603, found 536.2603. CN O O O AnN NBoc 6-allyl 1-(tert-butyl) 6-(2-cyanoethyl)-4-(4-methoxybenzoyl)-5-oxo-1,4-diazepane-1,6dicarboxylate (19k) To a 20 mL vial containing allyl ester 18c (300 mg, 0.694 mmol, 1.0 equiv) and K2CO3 (480 mg, 3.47 mmol, 5.0 equiv) was added acetone (2.8 mL, 0.25 M) and acrylonitrile (182 µL, 2.78 mmol, 4.0 equiv) at 23 °C. The vessel was sealed and heated to 50 °C. After 17 h of stirring, the reaction mixture was filtered through a plug of cotton, concentrated under reduced pressure, and purified by silica gel flash chromatography (33% EtOAc/petroleum ether) to provide 19k as a colorless foam (176 mg, 0.362 mmol, 52% yield); 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 6.01 (ddt, J = 16.7, 10.3, 6.3 Hz, 1H), 5.51 – 5.36 (m, 2H), 4.89 – 4.75 (m, 2H), 4.32 – 3.88 (m, 3H), 3.86 (s, 3H), 3.84 – 3.34 (m, 3H), 2.71 – 2.09 (m, 4H), 1.53 – 1.34 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 170.8, 170.3, 163.2, 155.3, 131.0, 130.6, 127.1, 121.4, 121.1, 119.1, 113.7, 81.4, 67.5, 60.2, 55.5, 47.5, 46.8, 43.6, 32.9, 28.3, 13.6; IR (Neat Film, NaCl) 2975, 2934, 2250, 1694, 1605, 1579, 1512, 1455, 1419, 1393, 1367, 1326, 1255, 1164, 1031, 1000, 979, 941, 916, 842, 813, 781, 762, 733, 648, 634 cm–1; HRMS (MM: ESIAPCI): m/z calc’d for C25H35N4O7 [M+NH4]+: 503.2500, found 503.2505. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles BocHN O 61 O O BzN NBoc 6-allyl 1-(tert-butyl) 4-benzoyl-6-(((tert-butoxycarbonyl)amino)methyl)-5-oxo-1,4diazepane-1,6-dicarboxylate (19l) A solution of allyl ester 18a (200 mg, 0.497 mmol, 1.0 equiv) and tert-butyl ((phenylsulfonyl)methyl)carbamate30,31 (162 mg, 0.597 mmol, 1.2 equiv) in CH2Cl2 (2.5 mL, 0.2 M) at 23 °C was stirred for 5 min, after which time Cs2CO3 (405 mg, 1.24 mmol, 2.5 equiv) was added at the same temperature. After an additional 30 min of stirring, saturated aqueous NH4Cl (1 mL) was added, and the biphasic mixture was vigorously stirred for 20 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 3 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure onto silica gel (2 g). The silica-adsorbed crude reaction mixture was purified by automated silica gel flash chromatography (Teledyne ISCO, 10→40% acetone/hexanes) to provide carbamate 19l as a white foam (200 mg, 0.376 mmol, 76% yield): 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.71 (m, 2H), 7.59 – 7.46 (m, 1H), 7.46 – 7.36 (m, 2H), 6.00 (ddt, J = 16.6, 10.3, 6.1 Hz, 1H), 5.51 – 5.25 (m, 2H), 5.17 (br s, 1H), 4.79 – 4.64 (m, 2H), 4.48 – 4.23 (m, 1H), 4.14 – 3.20 (m, 7H), 1.44 (s, 9H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 174.1, 173.8, 172.7, 170.1, 169.6, 156.0, 155.2, 154.7, 135.5, 132.2, 131.4, 128.5, 128.4, 120.2, 81.4, 79.6, 67.4, 62.7, 47.1, 46.8, 45.9, 43.2, 28.5, 28.4; IR (Neat Film, NaCl) 3457, 2977, 2934, 2253, 1704, 1600, 1503, 1450, 1417, 1392, 1367, 1325, 1283, 1248, 1158, 1042, 980, 913,77 860, 767, 729, 693, 663 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C27H38N3O8 [M+H]+: 532.2653, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 62 found 532.2664. 1.5.2.3 Derivatization of Diazepane Allylic Alkylation Products O Br Cl N 2-bromo-5-chlorobenzo[d]oxazole (22) Prepared according to the literature procedure by Mangion and coworkers14 and used directly in the synthesis of 23. CO2H N Me N N 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (24) Prepared according to the literature procedure by Mangion and coworkers.14 All characterization data matched those reported in the literature. O Bn i-PrOH/H2O, 23 °C, 5 h BzN O Bn LiOH·H2O THF, 0 °C, 4 h HN NBoc 20a Bn LiAlH4 HN NBoc 58 NBoc 21 tert-butyl (S)-6-allyl-6-benzyl-5-oxo-1,4-diazepane-1-carboxylate (58) To a flask containing benzoyl-protected diazepanone 20a (460 mg, 1.03 mmol, 1.0 equiv) was added isopropyl alcohol (100 mL, 0.01 M) and water (10 mL), followed by LiOH·H2O (61 mg, 1.45 mmol, 1.5 equiv) at 23 °C. After stirring for 4 h at 23 °C, the isopropyl alcohol was removed under reduced pressure and the resulting aqueous mixture extracted with EtOAc (4 x 50 mL). The combined organic extracts were dried with sodium Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 63 sulfate, filtered, and concentrated under reduced pressure to yield a crude oil (400 mg) that was used without further purification. tert-butyl (R)-6-allyl-6-benzyl-1,4-diazepane-1-carboxylate (21) Crude lactam 58 (350 mg [theoretical maximum 310 mg lactam], 0.903 mmol, 1 equiv) was dissolved in THF (10.2 mL, 0.1 M) and cooled to 0 °C. LiAlH4 (77 mg, 2.03 mmol, 2.25 equiv) was then added, and the reaction mixture was stirred at 0 °C for 4 h, over the course of which an additional 3.37 equiv (116 mg, 3.05 mmol) of LiAlH4 were added in total (77 mg, followed by 39 mg, at equal intervals). The reaction mixture was then diluted with diethyl ether (10 mL) and water (300 µL) was added. After gas generation subsided, 15% aqueous NaOH (300 µL) was added, followed by additional water (900 µL). After stirring at 0 °C for 15 min, anhydrous MgSO4 was added, and the mixture was stirred for an additional 10 min, whereafter it was filtered through celite and concentrated under reduced pressure. Purification by automated silica gel flash chromatography (Teledyne ISCO, 0→20% MeOH/CH2Cl2) provided the product as a light yellow oil (130 mg, 0.393 mmol, 44% yield); 1H NMR (400 MHz, CDCl3) δ 7.40 – 7.14 (m, 5H), 6.01 (dq, J = 17.1, 7.8 Hz, 1H), 5.18 (d, J = 15.9 Hz, 2H), 3.67 – 3.30 (m, 4H), 2.97 (m, 2H), 2.88 – 2.48 (m, 4H), 2.30 – 2.06 (m, 3H), 1.50 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 155.8, 138.1, 134.6, 130.7, 128.0, 126.2, 118.2, 79.8, 79.5, 57.9, 57.2, 55.3, 54.2, 50.9, 49.8, 49.3, 43.5, 41.3, 39.8, 39.4, 28.5; IR (Neat Film, NaCl) 3357, 3066, 3028, 2976, 2928, 1694, 1602, 1464, 1455, 1416, 1391, 1365, 1334, 1302, 1248, 1166, 1031, 996, 952, 912, 866, 771, 733, 703, 685, 672, 659, 644, 612 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C20H31N2O2 [M+H]+: 331.2380, found 331.2399; [α]D22.24 –6.496 (c 2.0, CHCl3). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles Bn Bn HN 22, K2CO3 N O N MeCN, 23 °C, 24 h Bn NBoc AcCl, MeOH 64 NH N O 23 °C, 5 h N 23 NBoc 21 59 Cl Cl tert-butyl (R)-6-allyl-6-benzyl-4-(5-chlorobenzo[d]oxazol-2-yl)-1,4-diazepane-1carboxylate (59) To a 1-dram vial containing diazepane 21 (9.5 mg, 0.0287 mmol, 1.0 equiv), aryl bromide 22 (10.0 mg, 0.0431 mmol, 1.5 equiv), and K2CO3 (7.9 mg, 0.0574 mmol, 2 equiv) was added MeCN (0.3 mL, 0.1 M) at 23 °C. After stirring for 24 h at 23 °C, saturated aqueous NH4Cl (1 mL) was added, and the mixture was extracted with EtOAc (3 x 1 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material (15.4 mg) thus obtained was carried forward without further purification. (S)-2-(6-allyl-6-benzyl-1,4-diazepan-1-yl)-5-chlorobenzo[d]oxazole (23) Crude carbamate 59 was dissolved in MeOH (0.3 mL, 0.1 M) and AcCl (20.5 µL, 0.288 mmol, 10 equiv) was added at 23 °C. After stirring for 5 h at 23 °C, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (66% EtOAc/benzene + 1% Et3N) to provide 23 as a beige, amorphous solid (4.3 mg, 0.0113 mmol, 39% yield from 21) of sufficient purity for use in the next reaction, however, further purification was possible by silica gel flash chromatography with 2% Et3N in Et2O; 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.27 (m, 3H), 7.25 – 7.17 (m, 3H), 7.12 (d, J = 8.4 Hz, 1H), 6.94 (dd, J = 8.4, 2.3 Hz, 1H), 5.99 (ddt, J = 14.5, 10.4, 7.2 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 65 Hz, 1H), 5.30 (d, J = 3.1 Hz, 1H), 5.20 – 5.10 (m, 1H), 3.87 – 3.61 (m, 3H), 3.15 – 3.00 (m, 2H), 2.90 – 2.66 (m, 3H), 2.57 (d, J = 13.9 Hz, 1H), 2.22 – 2.10 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 147.5, 137.8, 134.1, 130.8, 129.4, 128.2, 126.4, 120.1, 118.8, 116.2, 109.2, 57.8, 56.5, 53.3, 49.2, 43.8, 41.3, 39.8; IR (Neat Film, NaCl) 2922, 1638, 1570, 1458, 1249, 1167, 921, 792, 710 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H25ClN3O [M+H]+: 382.1681, found 382.1695; [α]D21.89 +7.524 (c 0.07, CHCl3). Bn O N Cl N N O N N N Me (R)-(6-allyl-6-benzyl-4-(5-chlorobenzo[d]oxazol-2-yl)-1,4-diazepan-1-yl)(5-methyl-2(2H-1,2,3-triazol-2-yl)phenyl)methanone (25) To a vial containing carboxylic acid 24 (35 mg, 0.172 mmol, 1.0 equiv) in CH2Cl2 (1.8 mL) at 23 °C was added DMF (4 µL, 0.0517 mmol, 0.3 equiv) and oxalyl chloride (18 µL, 0.207 mmol, 1.2 equiv). After stirring for 1 h, Et3N (48 µL, 0.344 mmol, 2.0 equiv) was added, followed by amine 23 (60 mg, 0.155 mmol, 0.9 equiv) in CH2Cl2 (1.8 mL, 0.05 M total concentration). After stirring for an additional 1 h at 23 °C, the reaction mixture was quenched with saturated aqueous NaHCO3 (3 mL), the layers were separated, and the aqueous layer was extracted with CH2Cl2 (3 x 2 mL). The combined organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→40% Et2O/hexanes) to provide amide 25 as a beige oil (29.6 mg, 0.0522 mmol, 34% yield); 1H NMR (400 MHz, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 66 CDCl3) δ 7.73 (s, 1H), 7.55 (s, 1H), 7.34 – 7.27 (m, 6H), 7.20 – 7.09 (m, 3H), 7.04 – 6.92 (m, 2H), 6.11 (ddt, J = 17.6, 10.4, 7.3 Hz, 1H), 5.26 – 5.12 (m, 2H), 4.24 – 4.07 (m, 1H), 3.96 (dd, J = 17.1, 14.4 Hz, 1H), 3.90 – 3.75 (m, 1H), 3.70 – 3.40 (m, 4H), 3.38 – 3.12 (m, 2H), 2.99 – 2.80 (m, 2H), 2.43 – 2.38 (m, 2H), 2.38 – 2.33 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 170.7, 170.5, 170.0, 163.0, 147.2, 144.4, 138.7, 138.6, 138.5, 136.9, 135.9, 135.8, 135.8, 135.7, 135.7, 135.6, 135.6, 134.2, 133.9, 133.8, 133.6, 133.5, 133.2, 132.9, 130.9, 130.8, 130.6, 130.6, 130.4, 130.4, 129.9, 129.5, 129.5, 129.0, 129.0, 128.3, 128.3, 128.2, 128.2, 128.2, 128.1, 128.1, 126.6, 126.6, 122.2, 122.0, 121.9, 120.5, 120.5, 119.2, 119.1, 119.0, 116.3, 116.3, 109.3, 109.2, 56.2, 56.1, 55.5, 54.3, 52.9, 52.2, 49.5, 49.3, 49.2, 48.9, 47.6, 45.0, 43.5, 43.1, 42.4, 42.2, 42.0, 41.8, 39.5, 39.5, 37.6, 21.0, 21.0, 20.9; IR (Neat Film, NaCl) 3431, 2923, 2854, 2356, 1644, 1634, 1574, 1568, 1538, 1505, 1462, 1454, 1428, 1372, 1308, 1251, 1216, 1172, 1054, 952, 921, 852, 822, 794, 737, 704 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C32H32ClN6O2 [M+H]+: 567.2270, found 567.2294; [α]D22.24 +41.90 (c 1.0, CHCl3). 1.5.2.4 General Procedure for Allylic Alkylation of Imidazolidinones O BzN R O N Boc Pd2(dba)3 or Pd2(pmdba)3 (4 mol %) (S)-(CF3)3-t-BuPHOX (10 mol %) 2:1 hexanes/PhMe O R BzN N Boc O CF3 O P N t-Bu F3C 2 (S)-(CF3)3-t-BuPHOX In a N2 filled glovebox, Pd2(dba)3 (4 mol %) or Pd2(pmdba)3 (4 mol %) and (S)- Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 67 (CF3)3-t-BuPHOX (10 mol %) were suspended in 2:1 hexanes:PhMe (2 mL) in a 20 mL glass vial. After stirring for 20 minutes at 25 °C, the appropriate imidazolidinone (1.0 equiv) and 2:1 hexanes:PhMe (5.1 mL, total substrate concentration 0.014 M) were added to the pre-stirred catalyst solution. The vial was then sealed and heated to the appropriate temperature in a heating block. After full consumption of starting material, as monitored by TLC, the reaction mixture was exposed to air. The crude reaction mixture was loaded directly onto a flash column and the product was isolated by silica gel flash chromatography. O Bn BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-5-benzyl-4-oxoimidazolidine-1-carboxylate (35a) Prepared according to the general procedure with allyl ester 34a (49.0 mg, 0.105 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 50 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide benzyl imidazolidinone 35a as a colorless oil (33.7 mg, 0.0801 mmol, 76% yield, 92% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 2:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.52 (dtd, J = 9.6, 6.5, 2.5 Hz, 1H), 7.44 – 7.30 (m, 4H), 7.31 – 7.23 (m, 3H), 7.12 (ddt, J = 8.8, 7.2, 2.0 Hz, 2H), 5.77 – 5.56 (m, 1H), 5.27 – 5.13 (m, 2H), 4.93 (d, J = 7.6 Hz, 1H#), 4.85 (d, J = 7.4 Hz, 1H*), 4.31 (d, J = 7.6 Hz, 1H#), 4.18 (d, J = 7.4 Hz, 1H*), 3.62 (d, J = 13.4 Hz, 1H*), 3.40 (d, J = 13.5 Hz, 1H#), 3.27 (dd, J = 13.6, 7.7 Hz, 1H*), 3.02 (dd, J = 13.8, 7.4 Hz, 1H#), 2.95 (dd, J = 13.5, 4.4 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 68 Hz, 1H), 2.69 – 2.52 (m, 1H), 1.65 (s, 9H#), 1.54 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 171.5, 171.4, 168.4, 168.1, 152.6, 151.9, 135.9, 135.3, 133.3, 133.3, 132.6, 132.5, 131.9, 131.5, 130.0, 129.9, 128.9, 128.9, 128.8, 128.6, 127.9, 127.9, 127.8, 127.6, 120.6, 120.5, 82.2, 81.3, 71.5, 71.1, 61.3, 61.3, 41.7, 40.9, 40.6, 39.7, 28.8, 28.5; IR (Neat Film, NaCl) 2927, 1758, 1707, 1390, 1368, 1295, 1167, 702, 660 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C25H29N2O4 [M+H]+: 421.2122, found 421.2108; [α]D21.7 +19.50 (c 1.0, CHCl3); SFC (AD-H, IPA/CO2 = 7/93, flow rate = 2.5 mL/min, λ = 210 nm) tR = 5.13 min (major), 6.29 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles O 69 p-CF3-Ph BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-4-oxo-5-(4-(trifluoromethyl)benzyl)imidazolidine-1carboxylate (35b) Prepared according to the general procedure with allyl ester 34b (53.8 mg, 0.101 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 23 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide 4-trifluorobenzyl imidazolidinone 35b as a colorless oil (37.7 mg, 0.0772 mmol, 76% yield, 89% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 3:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.60 – 7.52 (m, 3H), 7.47 – 7.37 (m, 3H), 7.36 – 7.22 (m, 3H), 5.82 – 5.59 (m, 1H), 5.31 – 5.19 (m, 2H), 4.96 (d, J = 7.7 Hz, 1H#), 4.89 (d, J = 7.5 Hz, 1H*), 4.42 (d, J = 7.7 Hz, 1H#), 4.34 (d, J = 7.5 Hz, 1H*), 3.72 (d, J = 13.4 Hz, 1H*), 3.48 (d, J = 13.5 Hz, 1H#), 3.29 (ddt, J = 13.7, 7.8, 1.0 Hz, 1H), 3.05 (dd, J = 13.3, 1.8 Hz, 1H), 2.72 – 2.55 (m, 1H), 1.67 (s, 9H#), 1.56 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 171.1, 171.1, 168.3, 168.0, 152.5, 152.0, 140.2, 139.6, 133.1, 133.1, 132.8, 132.8, 131.5, 131.1, 130.4, 130.4, 130.0, 129.7, 128.9, 128.0, 128.0, 125.7, 125.7, 125.6, 125.5, 125.5, 125.4, 125.4, 122.9, 121.1, 121.0, 82.5, 81.7, 71.3, 70.9, 61.4, 61.4, 41.4, 41.1, 40.3, 39.9, 28.8, 28.5; IR (Neat Film, NaCl) 2977, 1754, 1707, 1391, 1369, 1326, 1294, 1263, 1226, 1165, 1126, 1068, 1019, 858, 700, 662 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C26H31F3N3O4 [M+NH4]+: 506.2261, found 506.2254; [α]D21.5 +25.45 (c 1.0, CHCl3); SFC (OJ-H, IPA/CO2 = 10/90, flow rate = 2.5 mL/min, λ = 254 nm) tR = 1.55 min (major), Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 70 1.71 min (minor). O Me BzN N Boc tert-butyl (S)-5-allyl-3-benzoyl-5-methyl-4-oxoimidazolidine-1-carboxylate (35c) Prepared according to the general procedure with allyl ester 34c (40.7 mg, 0.105 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 19 h. Purified by silica gel flash chromatography (15% EtOAc/hexanes) to provide methyl imidazolidinone 35c as a colorless oil (31.3 mg, 0.0909 mmol, 88% yield, 86% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 4:3 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.65 – 7.50 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H), Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 71 5.70 (ddt, J = 17.3, 9.9, 7.5 Hz, 1H), 5.25 – 5.13 (m, 3H), 5.07 (dd, J = 13.8, 7.7 Hz, 1H), 3.16 (dd, J = 13.7, 7.8 Hz, 1H*), 2.90 (dd, J = 13.8, 7.2 Hz, 1H#), 2.56 – 2.38 (m, 1H), 1.63 – 1.48 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 172.7, 168.8, 168.6, 152.8, 151.7, 133.3, 132.7, 132.1, 131.9, 129.1, 128.1, 120.5, 81.8, 81.3, 66.2, 65.8, 60.9, 60.8, 41.3, 40.0, 28.6, 28.5, 23.6, 22.7; IR (Neat Film, NaCl) 3076, 2977, 2931, 1759, 1702, 1602, 1477, 1450, 1388, 1368, 1297, 1263, 1227, 1168, 1124, 1059, 998, 965, 928, 906, 879, 859, 823, 792, 774, 733, 704, 662, 614 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C19H25N2O4 [M+H]+: 345.1809, found 345.1805; [α]D21.6 +4.82 (c 1.0, CHCl3); SFC (AD-H, IPA/CO2 = 7/93, flow rate = 2.5 mL/min, λ = 210 nm) tR = 3.40 min (major), 3.04 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 72 Me O Me BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-5-(3-methylbut-2-en-1-yl)-4-oxoimidazolidine-1carboxylate (35d) Prepared according to the general procedure with allyl ester 34d (42.2 mg, 0.0954 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 24 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide prenyl imidazolidinone 35d as a colorless oil (30.3 mg, 0.0760 mmol, 80% yield, 80% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 3:2 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.62 – 7.50 (m, 3H), 7.42 (td, J = 7.7, 4.8 Hz, 2H), 5.75 – 5.58 (m, 1H), 5.24 – 4.96 (m, 5H), 3.17 (dd, J = 13.6, 7.8 Hz, 1H*), 3.06 (dd, J = 14.3, 7.9 Hz, 1H*), 2.90 (dd, J = 13.8, 7.2 Hz, 1H#), 2.78 (dd, J = 14.4, 6.9 Hz, 1H#), 2.58 – 2.36 (m, 2H), 1.73 (d, J = 1.5 Hz, 3H), 1.64 (d, J = 1.4 Hz, 3H), 1.56 (s, 9H#), 1.51 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 172.1, 168.7, 168.5, 152.7, 151.7, 137.3, 137.2, 133.3, 132.7, 132.7, 132.1, 131.7, 129.1, 129.1, 128.0, 128.0, 120.4, 120.3, 117.3, 117.0, 81.8, 81.2, 70.4, 70.0, 61.7, 61.6, 40.6, 39.4, 35.3, 34.3, 28.6, 28.5, 26.4, 26.3, 18.3, 18.2; IR (Neat Film, NaCl) 2976, 1758, 1702, 1449, 1396, 1368, 1305, 1264, 1223, 1168, 1143, 924, 858, 772, 702, 665 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C23H30N2O4 [M+H]+: 399.2278, found 399.2275; [α]D21.7 –3.75 (c 1.0, CHCl3); SFC (OJ-H, IPA/CO2 = 1/99, flow rate = 2.5 mL/min, λ = 254 nm) tR = 2.98 min (major), 3.34 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 73 Ph O BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-5-cinnamyl-4-oxoimidazolidine-1-carboxylate (35e) Prepared according to the general procedure with allyl ester 34e (47.6 mg, 0.0970 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 48 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide cinnamyl imidazolidinone 35e as a colorless oil (41.9 mg, 0.0938 mmol, 97% yield, 85% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 1.8:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.61 – 7.48 (m, 3H), 7.42 – 7.35 (m, 2H), 7.35 – 7.29 (m, 4H), 7.25 (dtd, J = 6.6, 3.5, 1.5 Hz, 1H), 6.60 – 6.48 (m, 1H), 6.14 – 6.00 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 74 (m, 1H), 5.79 – 5.64 (m, 1H), 5.27 – 5.17 (m, 2H), 5.17 – 4.99 (m, 2H), 3.30 (ddd, J = 13.7, 7.6, 1.3 Hz, 1H*), 3.18 (dd, J = 13.6, 7.8 Hz, 1H*), 3.05 (ddd, J = 13.8, 6.8, 1.4 Hz, 1H#), 2.93 (dd, J = 13.8, 7.4 Hz, 1H#), 2.71 – 2.45 (m, 2H), 1.62 (s, 9H#), 1.53 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 171.8, 168.6, 168.4, 152.7, 151.8, 137.0, 136.7, 135.6, 135.5, 133.2, 132.8, 132.7, 131.8, 131.4, 129.1, 129.1, 128.9, 128.8, 128.0, 128.0, 127.9, 126.4, 126.3, 122.8, 122.3, 120.8, 120.7, 82.0, 81.4, 70.4, 70.0, 61.6, 61.6, 40.7, 40.1, 39.5, 38.9, 28.7, 28.5; IR (Neat Film, NaCl) 2974, 1755, 1703, 1398, 1296, 1172, 703 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C27H34N3O4 [M+NH4]+: 464.2544, found 464.2521; [α]D21.6 +30.48 (c 1.0, CHCl3); SFC (AD-H, IPA/CO2 = 10/90, flow rate = 2.5 mL/min, λ = 210 nm) tR = 5.15 min (major), 4.77 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 75 O BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-4-oxo-5-(prop-2-yn-1-yl)imidazolidine-1-carboxylate (35f) Prepared according to the general procedure with allyl ester 34f (43.8 mg, 0.106 mmol, 1.0 equiv), Pd2(pmdba)3 (4.7 mg, 0.00425 mmol, 4 mol %), and (S)-(CF3)3-tBuPHOX (6.3 mg, 0.0106 mmol, 10 mol %) at 60 °C for 45 h. Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide propargyl imidazolidinone 35f as a colorless oil (18.1 mg, 0.0491 mmol, 46% yield, 91% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 1.8:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.75 – 7.61 (m, 2H), 7.60 – 7.50 (m, 1H), 7.49 – 7.38 (m, 2H), 5.81 – 5.59 (m, 1H), 5.32 – 5.03 (m, 4H), 3.39 – 2.75 (m, 2H), 2.66 (dd, J = 16.7, 2.6 Hz, 1H#), 2.59 (dd, J = 16.7, 2.6 Hz, 1H*), 2.52 – 2.36 (m, 1H), 2.09 (t, J = 2.6 Hz, 1H#), 2.06 (t, J = 2.6 Hz, 1H*), 1.57 (s, 9H#), 1.53 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 171.0, 170.9, 168.6, 168.4, 152.4, 151.8, 133.1, 132.8, 132.8, 131.4, 131.1, 129.3, 129.2, 128.1, 128.1, 121.0, 120.9, 116.2, 82.2, 81.7, 79.1, 78.3, 72.0, 71.3, 69.6, 69.1, 62.2, 62.1, 40.1, 39.9, 38.7, 38.6, 28.6, 28.5, 28.5, 27.2, 25.9; IR (Neat Film, NaCl) 3276, 2980, 2930, 1760, 1704, 1642, 1602, 1478, 1449, 1392, 1369, 1306, 1266, 1228, 1172, 1091, 1015, 928, 878, 857, 768, 739, 704, 664 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C21H28N3O4 [M+NH4]+: 386.2074, found 386.2066; [α]D21.4 –14.43 (c 1.0, CHCl3); SFC (OJ-H, IPA/CO2 = 7/93, flow rate = 2.5 mL/min, λ = 210 nm) tR = 2.43 min (major), 2.11 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 76 O Bn BzN Me N Boc tert-butyl (R)-3-benzoyl-5-benzyl-5-(2-methylallyl)-4-oxoimidazolidine-1-carboxylate (35g) Prepared according to the general procedure with allyl ester 34g (48.1 mg, 0.101 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 26 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide benzyl imidazolidinone 35g as a colorless oil (36.4 mg, 0.0838 mmol, 83% yield, 89% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 2.5:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.57 – 7.48 (m, 1H), 7.40 (d, J = 4.4 Hz, 3H), 7.35 – 7.22 (m, 4H), 7.16 – 7.08 (m, 2H), 4.98 – 4.75 (m, 3H), 4.36 (d, J = 7.7 Hz, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 77 1H#), 4.21 (d, J = 7.5 Hz, 1H*), 3.66 (d, J = 13.3 Hz, 1H*), 3.45 (d, J = 13.4 Hz, 1H#), 3.22 (d, J = 13.5 Hz, 1H*), 3.01 – 2.88 (m, 1H), 2.62 (d, J = 13.7 Hz, 1H#), 2.56 (d, J = 13.5 Hz, 1H*), 1.72 (s, 3H), 1.66 (s, 9H#), 1.54 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 171.5, 171.3, 168.5, 168.2, 152.6, 152.0, 140.7, 140.3, 135.8, 135.2, 133.5, 133.4, 132.5, 132.5, 130.0, 130.0, 128.9, 128.8, 128.6, 127.9, 127.9, 127.8, 127.6, 116.6, 116.4, 82.3, 81.3, 71.6, 71.1, 61.2, 61.1, 43.6, 42.5, 42.2, 41.1, 28.8, 28.6, 23.9, 23.8; IR (Neat Film, NaCl) 2974, 1755, 1708, 1450, 1397, 1368, 1295, 1216, 1171, 1141, 1076, 901, 703 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C26H30N2NaO4 [M+Na]+: 457.2098, found 457.2083; [α]D21.8 +26.68 (c 1.5, CHCl3); SFC (OD-H, IPA/CO2 = 10/90, flow rate = 2.5 mL/min, λ = 254 nm) tR = 3.79 min (major), 3.47 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 78 Cl O BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-5-(2-chloroallyl)-4-oxoimidazolidine-1-carboxylate (35h) Prepared according to the general procedure with allyl ester 34h (44.6 mg, 0.0994 mmol, 1.0 equiv), Pd2(pmdba)3 (4.4 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 5.5 h. Purified by silica gel flash chromatography (10% EtOAc/hexanes) to provide alkenyl chloride 35h as a colorless oil (37.4 mg, 0.0924 mmol, 93% yield, 86% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 2.7:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.64 (ddt, J = 8.5, 2.9, 1.7 Hz, 2H), 7.55 (ddt, J = 7.6, 6.9, 1.3 Hz, 1H), 7.46 – 7.38 (m, 2H), 5.75 – 5.60 (m, 1H), 5.38 – 5.28 (m, 2H), 5.27 – 5.08 (m, 4H), 3.40 (d, J = 14.3 Hz, 1H), 3.20 – 3.06 (m, 1H), 2.94 – 2.76 (m, 1H), 2.54 – 2.38 (m, 1H), 1.57 (s, 9H#), 1.50 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 170.9, 170.9, 168.4, 168.1, 152.2, 151.6, 136.7, 136.7, 133.2, 133.2, 132.6, 132.6, 131.1, 130.7, 129.0, 129.0, 127.9, 121.1, 121.0, 117.9, 117.8, 82.0, 81.3, 68.8, 68.6, 61.6, 61.5, 44.8, 44.1, 41.0, 39.6, 28.5, 28.3; IR (Neat Film, NaCl) 2976, 1758, 1707, 1394, 1368, 1295, 1266, 1140, 704 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C21H29ClN3O4 [M+NH4]+: 422.1841, found 422.1825. [α]D21.7 –3.52 (c 1.0, CHCl3); SFC (OJ-H, IPA/CO2 = 7/93, flow rate = 2.5 mL/min, λ = 210 nm) tR = 2.19 min (major), 1.99 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles O 79 NHCbz BzN N Boc tert-butyl (R)-5-allyl-3-benzoyl-5-((((benzyloxy)carbonyl)amino)methyl)-4oxoimidazolidine-1-carboxylate (35i) Prepared according to the general procedure with allyl ester 34i (53.7 mg, 0.0100 mmol, 1.0 equiv), Pd2(dba)3 (3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 22 h. Purified by silica gel flash chromatography (25% EtOAc/hexanes) to provide carbamate 35i as a colorless foam (37.2 mg, 0.0754 mmol, 75% yield, 85% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 2:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.73 – 7.59 (m, 2H), 7.55 (td, J = 7.3, 1.4 Hz, 1H), 7.42 (q, J = Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 80 7.4 Hz, 2H), 7.36 – 7.27 (m, 5H), 5.75 – 5.55 (m, 1H), 5.26 – 4.97 (m, 6H), 3.80 – 3.62 (m, 2H), 3.02 (dd, J = 13.5, 8.0 Hz, 1H*), 2.85 (dd, J = 13.7, 7.3 Hz, 1H#), 2.51 (dd, J = 13.8, 7.5 Hz, 1H#), 2.41 (dd, J = 13.5, 7.0 Hz, 1H*), 1.58 (s, 9H#), 1.50 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 171.2, 170.8, 168.5, 168.2, 156.4, 156.3, 152.4, 152.2, 136.5, 136.2, 133.1, 133.0, 132.8, 132.7, 131.0, 130.7, 129.3, 129.2, 128.7, 128.4, 128.3, 128.0, 121.2, 82.6, 81.8, 69.5, 67.3, 67.2, 61.6, 61.5, 45.7, 45.5, 37.9, 37.1, 28.6, 28.4; IR (Neat Film, NaCl) 3347, 2977, 1704, 1519, 1449, 1392, 1369, 1304, 1166, 1073, 927, 858, 733, 698, 662 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C27H31N3NaO6 [M+Na]+: 516.2105, found 516.2087; [α]D21.8 –18.93 (c 1.0, CHCl3); SFC (AD-H, IPA/CO2 = 20/80, flow rate = 2.5 mL/min, λ = 210 nm) tR = 6.15 min (major), 3.52 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 81 CN O BzN N Boc tert-butyl (S)-5-allyl-3-benzoyl-5-(2-cyanoethyl)-4-oxoimidazolidine-1-carboxylate (35j) Prepared according to the general procedure with allyl ester 34j (41.4 mg, 0.0970 mmol, 1.0 equiv), Pd2(dba)3 (3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 40 °C for 22 h. Purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide nitrile 35j as a colorless oil (37.2 mg, 0.0970 mmol, >99% yield, 95% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 2.5:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.69 – 7.61 (m, 2H), 7.61 – 7.54 (m, 1H), 7.49 – 7.38 (m, 2H), 5.74 – 5.60 (m, 1H), 5.30 – 5.18 (m, 3H), 5.17 – 5.06 (m, 1H), 3.11 (dd, J = 13.6, 8.1 Hz, 1H*), 2.86 (dd, J = 13.7, 7.4 Hz, 1H#), 2.63 (dt, J = 13.8, 6.8 Hz, 1H*), 2.53 – 2.14 (m, 4H), 1.57 (s, 9H#), 1.53 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 170.7, 170.6, 168.2, 168.0, 152.2, 151.9, 133.0, 132.9, 132.8, 132.7, 130.5, 130.1, 129.0, 129.0, 128.0, 121.7, 121.6, 118.4, 118.2, 82.7, 82.1, 68.6, 68.3, 61.5, 61.5, 41.1, 39.7, 31.6, 30.4, 28.5, 28.3, 12.9, 12.7; IR (Neat Film, NaCl) 2976, 1756, 1705, 1390, 1295, 1164, 704 cm–1; HRMS (MM: ESIAPCI): m/z calc’d for C21H29N4O4 [M+NH4]+: 401.2183, found 401.2182; [α]D21.7 –33.24 (c 1.0, CHCl3); SFC (IC, IPA/CO2 = 15/85, flow rate = 2.5 mL/min, λ = 210 nm) tR = 5.49 min (major), 4.78 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 82 O O Me BzN N Boc tert-butyl (S)-5-allyl-3-benzoyl-4-oxo-5-(3-oxobutyl)imidazolidine-1-carboxylate (35k) Prepared according to the general procedure with allyl ester 34k (44.4 mg, 0.010 mmol, 1.0 equiv), Pd2(dba)3 (3.7 mg, 0.004 mmol, 4 mol %), and (S)-(CF3)3-t-BuPHOX (5.9 mg, 0.01 mmol, 10 mol %) at 60 °C for 19 h. Purified by silica gel flash chromatography (25% EtOAc/hexanes) to provide ketone 35k as a colorless oil (31.4 mg, 0.0784 mmol, 79% yield, 93% ee); 1H NMR (400 MHz, CDCl3; compound exists as a 1.3:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.67 – 7.60 (m, 2H), 7.59 – 7.52 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 83 5.76 – 5.60 (m, 1H), 5.25 – 5.17 (m, 2H), 5.13 – 5.02 (m, 2H), 3.15 (dd, J = 13.6, 8.0 Hz, 1H*), 2.89 (dd, J = 13.8, 7.2 Hz, 1H#), 2.59 – 2.27 (m, 4H), 2.21 – 2.00 (m, 4H), 1.54 (s, 9H#), 1.51 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 207.3, 206.6, 171.7, 171.6, 168.6, 168.3, 152.6, 151.7, 133.2, 133.1, 132.8, 132.7, 131.5, 131.2, 129.1, 129.1, 128.1, 121.0, 121.0, 82.3, 81.6, 69.0, 68.7, 61.5, 61.4, 41.2, 39.6, 39.0, 38.2, 30.5, 30.1, 29.6, 28.5, 28.5; IR (Neat Film, NaCl) 2974, 1755, 1708, 1450, 1397, 1368, 1295, 1216, 1171, 1141, 1076, 901, 703 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H32N3O5 [M+NH4]+: 418.2336, found 418.2347; [α]D21.7 +3.65 (c 1.0, CHCl3); SFC (IC, IPA/CO2 = 20/80, flow rate = 2.5 mL/min, λ = 210 nm) tR = 2.42 min (major), 3.23 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 84 O Bn BzN N Boc Procedure for the large-scale preparation of compound 35a In a N2 filled glovebox, Pd2(pmdba)3 (82 mg, 0.0744 mmol, 4 mol %) and (S)(CF3)3-t-BuPHOX (110 mg, 0.186 mmol, 10 mol %) were suspended in 2:1 hexanes:PhMe (45 mL) in a 500 mL Schlenk flask. After stirring for 20 minutes at 25 °C, imidazolidinone 34a (864 mg, 1.86 mmol, 1.0 equiv) and 2:1 hexanes:PhMe (90 mL, total substrate concentration 0.014 M) were added to the pre-stirred catalyst solution. The flask was then sealed and heated at 40 °C in an oil bath for 64 h. The reaction mixture was then cooled to 23 °C and exposed to air. The crude reaction mixture was loaded directly onto a flash column and the product was isolated by silica gel flash chromatography (10% EtOAc/hexanes) to provide 35a as a colorless oil (674 mg, 1.60 mmol, 86% yield, 95% ee); All characterization data matched those reported above for compound 35a; [α]D22.1 +21.69 (c 1.0, CHCl3); SFC (AD-H, IPA/CO2 = 7/93, flow rate = 2.5 mL/min, λ = 210 nm) tR = 5.07 min (major), 6.31 min (minor). Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 1.5.2.5 85 Synthesis of Imidazolidinone Allylic Alkylation Substrates NOH N Boc tert-butyl 3-(hydroxyimino)azetidine-1-carboxylate (41) Prepared from tert-butyl 3-oxoazetidine-1-carboxylate according to the literature procedure of Xiang, Yang, and coworkers, substituting i-PrOH for MeOH.32 All characterization data matched those reported in the literature. O HN S N Boc tert-butyl 4-oxo-2-thioxoimidazolidine-1-carboxylate (50) Prepared from 2-thiohydantoin according to the literature procedure of Tatibouët under an atmosphere of air.26 All characterization data matched those reported in the literature. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 86 O HN N Boc tert-butyl 4-oxoimidazolidine-1-carboxylate (31) Compound 50 (10.43 g, 48.23 mmol, 1.0 equiv) and anhydrous NiCl2 (31.25 g, 241.1 mmol, 5.0 equiv) were added to a round-bottom flask, MeOH (dried by distillation over 3 Å molecular sieves, 480 mL, 0.1 M) was added, and the mixture was subjected to rapid magnetic stirring to form a suspension. This suspension was cooled to 0 °C in an ice bath, and NaBH4 (27.37 g, 723.4 mmol, 15 equiv) was added portionwise. Care should be taken, as this step is highly exothermic and results in the rapid generation of a large volume of gas. Following complete addition of NaBH4, the reaction mixture was removed from the ice bath and allowed to warm to 23 °C. After 1 h of stirring, glacial acetic acid (10 mL) was added, and the reaction mixture was filtered through a plug of celite under pressurized air. A steel rod was periodically used to break up the plug of nickel salts and accelerate filtration. The resulting bright green solution was concentrated under reduced pressure. The resulting solids were dissolved in a mixture of deionized water (500 mL), EtOAc (300 mL), and glacial acetic acid (20 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (4x200 mL). The combined organic phases were washed with a solution of NaHCO3 and NaCl (100 mL, equal parts saturated NaHCO3 and NaCl solutions), dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as an off-white solid (8.58 g, 46.08 mmol, 96% yield) of sufficient purity for use in the next step; an analytically pure sample could be obtained by silica gel flash chromatography (90% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.01 (m, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 87 1H), 4.78 (d, J = 11.6 Hz, 2H), 3.89 (d, J = 15.2 Hz, 2H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 172.3, 153.1, 152.7, 81.2, 59.1, 58.9, 47.6, 47.1, 28.4; IR (Neat Film, KBr) 3213, 3120, 2978, 2934, 1714, 1456, 1414, 1366, 1326, 1294, 1257, 1171, 1128, 1080, 898, 855, 771, 700, 575, 491, 461 cm–1; HRMS (FAB+): m/z calc’d for C8H15N2O3 [M+H]+: 187.1083, found 187.1086. O BzN N Boc tert-butyl 3-benzoyl-4-oxoimidazolidine-1-carboxylate (32) To a solution of 31 (8.58 g, 46.08 mmol, 1.0 equiv) in CH2Cl2 (400 mL, 0.12 M) at 23 °C was added Et3N (11.6 mL, 82.94 mmol, 1.8 equiv) followed by BzCl (8.03 mL, 69.12 mmol, 1.5 equiv). After 9 h of stirring, the reaction mixture was washed with water (200 mL) and brine (100 mL) and the combined aqueous washes were extracted with CH2Cl2 (2x50 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (25% EtOAc/hexanes) to afford the title compound as a white solid (7.47 g, 25.73 mmol, 56% yield); 1H NMR (400 MHz, CDCl3) δ 7.68 – 7.60 (m, 2H), 7.59 – 7.52 (m, 1H), 7.49 – 7.39 (m, 2H), 5.29 (s, 2H), 4.17 (s, 2H), 1.51 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.6, 167.5, 152.6, 133.1, 132.8, 129.2, 128.1, 81.9, 61.8, 49.9, 49.4, 28.4; IR (Neat Film, NaCl) 2980, 1763, 1708, 1477, 1448, 1411, 1368, 1305, 1212, 1163, 1127, 895, 858, 768, 727, 704, 662 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C15H22N3O4 [M+NH4]+: 308.1600, found 308.1605. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 88 O O BzN N Boc O 5-allyl 1-(tert-butyl) 3-benzoyl-4-oxoimidazolidine-1,5-dicarboxylate (33) To a solution of LiHMDS (9.43 g, 56.38 mmol, 2.2 equiv) in THF (150 mL) at –78 °C in a flame-dried round-bottom flask was added allyl 1H-imidazole-1-carboxylate33 (4.68 g, 30.76 mmol, 1.2 equiv) by syringe with rapid stirring. Immediately thereafter, a solution of imidazolidinone 32 (7.44 g, 25.63 mmol, 1.0 equiv) in THF (100 mL, 0.1 M total concentration) was added over 15 min by cannula while stirring at −78 °C. After an additional 13 min of stirring, the reaction mixture was poured into 1 N aqueous HCl (200 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were dried over a mixture of NaHCO3 and Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (20→35% Et2O/hexanes) to provide allyl ester 33 as a viscous oil that solidified upon standing to form a white solid (4.80 g, 12.82 mmol, 50% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1.1:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.61 (dd, J = 8.3, 1.3 Hz, 2H), 7.56 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 5.98 – 5.80 (m, 1H), 5.43 – 5.18 (m, 4H), 4.96 (s, 1H#), 4.88 (s, 1H*), 4.81 – 4.62 (m, 2H), 1.52 (s, 9H#), 1.46 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 168.4, 168.2, 165.7, 165.6, 163.5, 163.2, 152.1, 151.9, 133.0, 132.6, 131.0, 130.9, 129.2, 128.1, 119.8, 119.2, 82.8, 82.6, 67.2, 63.5, 63.0, 61.5, 28.3, 28.2; IR (Neat Film, NaCl) 2977, 1748, 1716, 1449, 1405, 1369, 1302, 1250, 1167, 1135, 987, 939, 770, 725, 696, 668 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 89 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C19H26N3O6 [M+NH4]+: 392.1816, found 392.1822. O O BzN Me N Boc O 1-(tert-butyl) 5-(2-methylallyl) 3-benzoyl-4-oxoimidazolidine-1,5-dicarboxylate (60) To a solution of methallyl 1H-imidazole-1-carboxylate34 (286 mg, 1.72 mmol, 2 equiv) in THF (5.2 mL) at –78 °C in a flame-dried round-bottom flask was added LiHMDS solution (1 M in THF, 1.89 mL, 1.89 mmol, 2.2 equiv) by syringe. Immediately thereafter, a solution of imidazolidinone 32 (250 mg, 0.861 mmol, 1.0 equiv) in THF (3.4 mL, 0.1 M total concentration) was added dropwise by syringe with rapid stirring at −78 °C. After an additional 10 min of stirring, the reaction mixture was poured into 1 N aqueous HCl (20 mL) and extracted with ethyl acetate (4 x 15 mL). The combined organic extracts were dried over a mixture of NaHCO3 and Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (40% Et2O/hexanes) to provide methallyl ester 60 as a viscous oil that solidified upon standing to form a white solid (149 mg, 0.384 mmol, 45% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1:1 mixture of rotamers. Fully resolved rotamer peaks are denoted by *) δ 7.65 – 7.59 (m, 2H), 7.59 – 7.53 (m, 1H), 7.43 (t, J = 7.8 Hz, 2H), 5.48 – 5.27 (m, 2H), 5.06 – 4.84 (m, 3H), 4.75 – 4.51 (m, 2H), 1.75 (s, 3H), 1.52 (s, 9H*), 1.46 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 168.5, 168.3, 165.7, 165.6, 163.5, 163.3, 152.1, 151.9, 138.9, 138.8, 133.0, 132.7, 132.7, 129.2, 128.2, 114.5, 114.1, 82.8, 82.7, 69.8, 63.5, 63.1, 61.5, 28.4, 28.3, 19.6, 19.5, 19.5, 19.5; IR (Neat Film, KBr) 3064, 2978, 2934, 1772, 1750, 1716, 1602, 1583, 1477, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 90 1449, 1406, 1369, 1303, 1251, 1170, 1137, 1085, 1027, 1000, 964, 908, 858, 787, 770, 726, 699, 665, 629, 591, 519, 411 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C27H30N2NaO6 [M+Na]+: 411.1527, found 411.1544; O BzN Bn O N Boc O 5-allyl 1-(tert-butyl) 3-benzoyl-5-benzyl-4-oxoimidazolidine-1,5-dicarboxylate (34a) To a solution of lactam 33 (500 mg, 1.34 mmol, 1.0 equiv) in DMF (13.4 mL, 0.1 M) at 23 °C was added NaH (60% dispersion in mineral oil, 64 mg, 1.60 mmol, 1.2 equiv). The reaction mixture was stirred for 25 min, resulting in a bright yellow solution. BnBr (477 μL, 4.02 mmol, 3.0 equiv) was then added and the reaction mixture was stirred at 23 °C for 55 min. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (4x15 mL). The combined organic extracts were washed with saturated aq. LiCl (2x10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (7.5→15% acetone/hexanes) to provide the title compound as a colorless oil (291 mg, 0.626 mmol, 47% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1.2:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.59 – 7.49 (m, 1H), 7.47 – 7.26 (m, 7H), 7.21 – 7.14 (m, 2H), 6.02 – 5.80 (m, 1H), 5.42 – 5.26 (m, 2H), 5.24 (d, J = 7.1 Hz, 1H*), 5.16 (d, J = 7.0 Hz, 1H#), 4.83 – 4.61 (m, 2H), 4.46 (d, J = 7.2 Hz, 1H#), 4.40 (d, J = 7.0 Hz, 1H*), 3.86 – 3.50 (m, 2H), 1.56 (s, 9H#), 1.56 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 168.2, 168.0, 166.7, 166.6, 166.2, 166.1, 152.0, 151.8, 134.7, 134.1, 132.8, 132.8, 132.6, 132.6, 131.2, 130.9, 130.3, 130.2, 128.9, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 91 128.9, 128.8, 128.6, 128.0, 127.9, 127.9, 127.7, 119.7, 119.1, 82.9, 82.4, 72.9, 72.8, 67.2, 67.2, 61.2, 61.2, 38.0, 37.1, 28.4, 28.3; IR (Neat Film, NaCl) 2977, 1771, 1712, 1602, 1450, 1393, 1294, 1230, 1147, 1075, 1010, 768, 701 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C26H32N3O6 [M+NH4]+: 482.2286, found 482.2284. CF3 O O BzN NBoc O 5-allyl 1-(tert-butyl) 3-benzoyl-4-oxo-5-(4-(trifluoromethyl)benzyl)imidazolidine-1,5dicarboxylate (34b) To a solution of lactam 33 (128.4 mg, 0.343 mmol, 1.0 equiv) in DMF (3.4 mL, 0.1 M) at 23 °C was added NaH (60% dispersion in mineral oil, 16.5 mg, 0.412 mmol, 1.2 equiv). The reaction mixture was stirred for 15 min, resulting in a bright yellow solution. 4-trifluoromethylbenzyl bromide (159 μL, 1.03 mmol, 3.0 equiv) was then added and the reaction mixture was stirred at 23 °C for 35 min. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (4x5 mL). The combined organic extracts were washed with saturated aq. LiCl (2x3 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (15% EtOAc/hexanes) to provide the title compound as a colorless oil (122 mg, 0.229 mmol, 67% yield); 1H NMR (400 MHz, CDCl3) δ 7.64 – 7.51 (m, 3H), 7.44 – 7.27 (m, 6H), 5.99 – 5.84 (m, 1H), 5.43 – 5.15 (m, 3H), 4.84 – 4.63 (m, 2H), 4.55 (dd, J = 7.2, 2.8 Hz, 1H), 3.92 – 3.59 (m, 2H), 1.56 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 168.3, 168.0, 166.6, 166.5, 165.9, 165.7, 152.4, 152.0, 139.2, 138.6, 133.1, 132.6, 131.2, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 92 130.8, 130.3, 129.9, 129.0, 128.2, 128.1, 125.8, 125.7, 125.6, 125.5, 120.1, 119.5, 83.4, 82.9, 72.8, 72.7, 67.5, 67.5, 61.5, 61.4, 37.8, 37.0, 28.5, 28.4; IR (Neat Film, NaCl) 2977, 1772, 1710, 1389, 1325, 1291, 1228, 1164, 1068, 1019, 857, 697, 665 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C27H31F3N3O6 [M+NH4]+: 550.2159, found 550.2139. O BzN Me O N Boc O 5-allyl 1-(tert-butyl) 3-benzoyl-5-methyl-4-oxoimidazolidine-1,5-dicarboxylate (34c) To a suspension of NaH (60% dispersion in mineral oil, 32 mg, 0.801 mmol, 1.2 equiv) in THF (6.7 mL, 0.1 M) at −78 °C was added lactam 33 (250 mg, 0.668 mmol, 1.0 equiv). The reaction mixture was warmed to 0 °C and stirred for 45 min, resulting in a bright yellow solution. MeI (208 μL, 3.34 mmol, 5.0 equiv) was then added and the reaction mixture was stirred at 23 °C for 2 h. The reaction mixture was poured into saturated aq. NaHCO3 (10 mL) and extracted with ethyl acetate (3x6 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Telodyne ISCO, 0→50% acetone/hexanes) to provide the title compound as a colorless oil (90 mg, 0.232 mmol, 35% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1.2:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.63 – 7.52 (m, 3H), 7.42 (t, J = 7.6 Hz, 2H), 5.96 – 5.80 (m, 1H), 5.41 – 5.19 (m, 4H), 4.75 – 4.57 (m, 2H), 1.83 (s, 3H#), 1.78 (s, 3H*), 1.50 (s, 9H#), 1.46 (s, 9H*); 13 C NMR (100 MHz, CDCl3) δ 168.6, 168.4, 167.5, 167.2, 152.3, 152.2, 133.0, 132.7, 131.3, 131.0, 129.1, 128.1, 119.6, 119.1, 82.6, 82.4, 68.4, 68.2, 67.1, 61.1, 61.0, 28.4, 28.2, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 93 20.5, 19.9; IR (Neat Film, NaCl) 2979, 1773, 1740, 1714, 1602, 1477, 1450, 1386, 1370, 1305, 1244, 1162, 1124, 1067, 913, 859, 770, 732, 702, 667 cm–1; HRMS (MM: ESIAPCI): m/z calc’d for C20H28N3O6 [M+NH4]+: 406.1973, found 406.1975. Me Me O O BzN N Boc 5-allyl O 1-(tert-butyl) 3-benzoyl-5-(3-methylbut-2-en-1-yl)-4-oxoimidazolidine-1,5- dicarboxylate (34d) To a solution of lactam 33 (300 mg, 0.801 mmol, 1.0 equiv) in DMF (8 mL, 0.1 M) at 23 °C was added NaH (60% dispersion in mineral oil, 38.5 mg, 0.962 mmol, 1.2 equiv). The reaction mixture was stirred for 13 min, resulting in a bright yellow solution. Prenyl bromide (280 μL, 2.40 mmol, 3.0 equiv) was then added and the reaction mixture was stirred at 23 °C for 1 h. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (4x15 mL). The combined organic extracts were washed with saturated aq. LiCl (2x10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (15% EtOAc/hexanes) to provide the title compound as a colorless oil (230 mg, 0.520 mmol, 65% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1.1:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.61 – 7.51 (m, 3H), 7.45 – 7.37 (m, 2H), 5.98 – 5.76 (m, 1H), 5.43 – 5.19 (m, 3H), 5.16 – 4.99 (m, 2H), 4.77 – 4.52 (m, 2H), 3.26 – 2.93 (m, 2H), 1.77 (s, 3H), 1.67 (d, J = 1.4 Hz, 3H*), 1.66 (d, J = 1.5 Hz, 3H#), 1.51 (s, 9H#), 1.47 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 168.6, 168.4, 166.9, 166.9, 166.8, 166.7, 152.1, 152.1, 138.5, 138.4, 133.0, 132.8, 131.4, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 94 131.0, 129.1, 129.1, 128.1, 128.1, 119.6, 119.1, 116.1, 115.8, 82.6, 82.3, 72.1, 72.0, 67.1, 67.0, 61.7, 31.7, 30.8, 28.4, 28.3, 26.4, 26.3, 18.3, 18.2; IR (Neat Film, NaCl) 2978, 2931, 1771, 1746, 1713, 1601, 1450, 1388, 1293, 1228, 1167, 1030, 993, 940, 859, 792, 772, 701, 665 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C24H30N2NaO6 [M+Na]+: 465.1996, found 465.1984; Ph O O BzN N Boc O 5-allyl 1-(tert-butyl) 3-benzoyl-5-cinnamyl-4-oxoimidazolidine-1,5-dicarboxylate (34e) To a solution of lactam 33 (157.2 mg, 0.420 mmol, 1.0 equiv) in DMF (4.2 mL, 0.1 M) at 23 °C was added NaH (60% dispersion in mineral oil, 20.2 mg, 0.504 mmol, 1.2 equiv). The reaction mixture was stirred for 14 min, resulting in a bright yellow solution. Cinnamyl bromide (186 μL, 1.26 mmol, 3.0 equiv) was then added and the reaction mixture was stirred at 23 °C for 20 min. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (4x6 mL). The combined organic extracts were washed with saturated aq. LiCl (2x5 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (15% EtOAc/hexanes) to provide the title compound as a colorless oil (154 mg, 0.314 mmol, 75% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1.1:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.55 – 7.49 (m, 3H), 7.41 – 7.30 (m, 6H), 7.28 – 7.24 (m, 1H), 6.61 (dd, J = 15.9, 2.9 Hz, Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 95 1H), 6.16 – 6.02 (m, 1H), 5.98 – 5.82 (m, 1H), 5.42 – 5.12 (m, 4H), 4.81 – 4.58 (m, 2H), 3.53 – 3.42 (m, 1H*), 3.29 (ddd, J = 14.3, 6.5, 1.5 Hz, 1H#), 3.23 – 3.10 (m, 1H), 1.54 (s, 9H*), 1.52 (s, 9H#); 13C NMR (100 MHz, CDCl3) δ 168.6, 168.3, 166.7, 166.7, 166.5, 166.2, 152.3, 152.2, 136.8, 136.5, 136.4, 136.3, 133.0, 133.0, 132.7, 131.3, 131.0, 129.2, 128.9, 128.8, 128.2, 128.1, 128.1, 128.0, 126.4, 121.7, 121.2, 119.8, 119.2, 82.9, 82.6, 72.3, 72.1, 67.2, 61.7, 36.5, 35.6, 29.8, 28.4, 28.4; IR (Neat Film, NaCl) 2975, 1772, 1709, 1388, 1290, 1226, 1168, 752, 694 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C28H34N3O6 [M+NH4]+: 508.2442, found 508.2426. O O BzN N Boc O 5-allyl 1-(tert-butyl) 3-benzoyl-4-oxo-5-(prop-2-yn-1-yl)imidazolidine-1,5dicarboxylate (34f) To a solution of lactam 33 (250 mg, 0.668 mmol, 1.0 equiv) in THF (6.7 mL, 0.1 M) at 23 °C was added NaH (60% dispersion in mineral oil, 32 mg, 0.801 mmol, 1.2 equiv). The reaction mixture was stirred for 15 min, resulting in a bright yellow solution. Propargyl bromide (80% in PhMe, 252 μL, 2.67 mmol, 4.0 equiv) was then added and the reaction mixture was stirred at 23 °C for 1 h. The reaction mixture was poured into saturated aq. NaHCO3 (10 mL) and extracted with ethyl acetate (3x6 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Telodyne ISCO, 0→30% acetone/hexanes) to provide the title compound as a colorless oil (158 mg, 0.383 mmol, 57% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1:1 mixture of Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 96 rotamers. Fully resolved rotamer peaks are denoted by *) δ 7.72 – 7.63 (m, 2H), 7.59 – 7.52 (m, 1H), 7.48 – 7.37 (m, 2H), 5.96 – 5.75 (m, 1H), 5.44 (d, J = 7.1 Hz, 1H*), 5.40 (d, J = 6.9 Hz, 1H*), 5.36 – 5.20 (m, 3H), 4.76 – 4.53 (m, 2H), 3.46 (dd, J = 17.2, 2.7 Hz, 1H*), 3.27 (dd, J = 17.3, 2.7 Hz, 1H*), 3.23 – 3.15 (m, 1H), 2.12 (dt, J = 5.4, 2.6 Hz, 1H), 1.52 (s, 9H*), 1.47 (s, 9H*); 13C NMR (100 MHz, CDCl3) δ 168.4, 168.1, 165.9, 165.8, 165.6, 165.6, 151.9, 151.5, 133.0, 132.5, 131.0, 130.7, 129.2, 128.1, 119.9, 119.3, 82.9, 82.7, 78.2, 77.5, 72.3, 71.8, 71.1, 70.8, 67.3, 67.3, 62.0, 28.3, 28.2, 24.2, 23.3; IR (Neat Film, NaCl) 3280, 2977, 1771, 1747, 1714, 1602, 1450, 1392, 1370, 1296, 1229, 1152, 1059, 1019, 858, 790, 770, 740, 701, 665 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H28N3O6 [M+NH4]+: 430.1973, found 430.1969. O Bn O Me BzN NBoc O 1-(tert-butyl) 5-(2-methylallyl) 3-benzoyl-5-benzyl-4-oxoimidazolidine-1,5- dicarboxylate (34g) To a solution of lactam 60 (76.1 mg, 0.196 mmol, 1.0 equiv) in THF (2 mL, 0.1 M) at 23 °C was added NaH (60% dispersion in mineral oil, 9.4 mg, 0.235 mmol, 1.2 equiv). The reaction mixture was stirred for 5 min, resulting in a bright yellow solution. BnBr (93 μL, 0.784 mmol, 4.0 equiv) was then added and the reaction mixture was stirred at 23 °C for 5 h. The reaction mixture was poured into saturated aq. NaHCO3 (5 mL) and extracted with ethyl acetate (4x3 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (15% EtOAc/hexanes) to provide the title compound as a colorless oil (50.6 mg, 0.106 mmol, 54% yield); 1H NMR (500 MHz, CDCl3; compound Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 97 exists as a 4:3 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.58 – 7.51 (m, 1H), 7.43 – 7.36 (m, 3H), 7.36 – 7.29 (m, 4H), 7.20 – 7.15 (m, 2H), 5.24 (d, J = 7.2 Hz, 1H#), 5.16 (d, J = 7.1 Hz, 1H*), 5.03 – 4.94 (m, 2H), 4.76 – 4.56 (m, 2H), 4.48 (d, J = 7.2 Hz, 1H#), 4.41 (d, J = 7.0 Hz, 1H*), 3.84 (d, J = 14.0 Hz, 1H*), 3.63 (d, J = 14.1 Hz, 1H#), 3.59 – 3.54 (m, 1H), 1.77 (s, 3H), 1.57 (s, 9H#), 1.56 (s, 9H*); 13C NMR (125 MHz, CDCl3) δ 168.2, 168.0, 166.6, 166.6, 166.2, 166.1, 152.0, 151.8, 139.1, 138.6, 134.7, 134.1, 132.8, 132.8, 132.6, 130.2, 128.9, 128.9, 128.8, 128.6, 128.0, 127.9, 127.9, 127.7, 114.4, 114.0, 82.9, 82.4, 72.9, 69.9, 69.8, 61.3, 61.2, 37.9, 37.1, 28.4, 28.3, 19.6, 19.5; IR (Neat Film, NaCl) 2977, 1770, 1714, 1453, 1392, 1294, 1223, 1168, 1075, 1008, 857, 703, 665 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C27H34N3O6 [M+NH4]+: 496.2442, found 496.2423. Cl O O BzN N Boc 5-allyl O 1-(tert-butyl) 3-benzoyl-5-(2-chloroallyl)-4-oxoimidazolidine-1,5- dicarboxylate (34h) To a vial containing lactam 33 (250 mg, 0.668 mmol, 1.0 equiv), NaH (60% dispersion in mineral oil, 32 mg, 0.802 mmol, 1.2 equiv), and TBAI (25 mg, 0.0668 mmol, 0.1 equiv) was added THF (6.7 mL, 0.1 M) at 23 °C. The reaction mixture was stirred for 20 min, resulting in a bright yellow solution. 2,3-dichloropropene (246 μL, 2.67 mmol, 4.0 equiv) was then added and the reaction mixture was stirred at 23 °C for 27 h. The mixture was then heated to 40 °C using a heating block and stirred for an additional 4 h, then poured into saturated aq. NaHCO3 (10 mL) and extracted with ethyl acetate (4x5 mL). The Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 98 combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (15% EtOAc/hexanes) to provide the title compound as a colorless oil (163.9 mg, 0.365 mmol, 55% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1.2:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.66 – 7.61 (m, 2H), 7.59 – 7.53 (m, 1H), 7.46 – 7.39 (m, 2H), 5.97 – 5.80 (m, 1H), 5.48 – 5.19 (m, 6H), 4.81 – 4.56 (m, 2H), 3.67 (d, J = 14.8 Hz, 1H*), 3.43 (d, J = 14.9 Hz, 1H#), 3.36 – 3.23 (m, 1H), 1.50 (s, 9H*), 1.47 (s, 9H#); 13C NMR (100 MHz, CDCl3) δ 168.3, 168.1, 166.5, 166.4, 166.0, 165.8, 151.9, 151.6, 136.0, 135.9, 132.9, 132.8, 132.6, 132.6, 131.0, 130.7, 129.1, 128.0, 120.0, 119.3, 118.4, 82.8, 82.5, 70.6, 70.6, 67.4, 67.3, 61.6, 61.5, 41.5, 41.0, 31.0, 28.2; IR (Neat Film, NaCl) 3062, 2980, 2931, 2909, 2360, 1770, 1747, 1714, 1694, 1651, 1634, 1602, 1583, 1477, 1450, 1392, 1370, 1322, 1295, 1231, 1172, 1145, 1099, 1050, 1013, 989, 936, 888, 857, 792, 769, 724, 703, 682, 665, 634 cm– 1 ; HRMS (MM: ESI-APCI): m/z calc’d for C22H29ClN3O6 [M+NH4]+: 466.1739, found 466.1750. O NHCbz O N Boc O BzN 5-allyl 1-(tert-butyl) 3-benzoyl-5-((((benzyloxy)carbonyl)amino)methyl)-4- oxoimidazolidine-1,5-dicarboxylate (34i) To a vial containing lactam 33 (199 mg, 0.532 mmol, 1.0 equiv), and benzyl ((phenylsulfonyl)methyl)carbamate31 (195 mg, 0.638 mmol, 1.2 equiv) was added CH2Cl2 (2.7 mL, 0.2 M). Cs2CO3 (433 mg, 1.33 mmol, 2.5 equiv) was then added in a single portion Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 99 and the reaction mixture was stirred at 23 °C for 4 h. Saturated aq. NH4Cl (3 mL) was then added, and the resulting mixture was stirred vigorously for 30 min. The layers were then separated, and the aqueous layer was extracted with CH2Cl2 (3 x 3 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (20% EtOAc/hexanes) to provide the title compound as a colorless oil (149 mg, 0.341 mmol, 64% yield); 1H NMR (400 MHz, CDCl3) δ 7.82 – 7.58 (m, 2H), 7.54 (td, J = 7.0, 1.6 Hz, 1H), 7.40 (q, J = 7.9 Hz, 2H), 7.32 (q, J = 2.3 Hz, 5H), 5.99 – 5.73 (m, 1H), 5.46 – 4.82 (m, 7H), 4.76 – 4.53 (m, 2H), 4.17 – 3.95 (m, 2H), 1.49 (d, J = 5.9 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 168.4, 168.1, 166.2, 166.1, 165.5, 165.1, 156.8, 156.6, 152.5, 151.8, 136.4, 136.2, 132.9, 132.9, 132.6, 132.5, 131.0, 130.7, 129.4, 129.3, 128.7, 128.6, 128.4, 128.3, 128.2, 128.0, 120.0, 119.3, 83.1, 82.8, 71.2, 70.7, 67.2, 67.2, 67.1, 61.5, 61.3, 43.2, 43.0, 29.8, 28.3, 28.2; IR (Neat Film, NaCl) 3380, 3066, 2978, 1714, 1601, 1519, 1454, 1393, 1304, 1166, 1068, 989, 941, 855, 737, 698, 666 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C28H31N3NaO8 [M+Na]+: 560.2003, found 560.1998. CN O O BzN N Boc 5-allyl O 1-(tert-butyl) 3-benzoyl-5-(2-cyanoethyl)-4-oxoimidazolidine-1,5- dicarboxylate (34j) To a vial containing lactam 33 (250 mg, 0.668 mmol, 1.0 equiv) and K2CO3 (462 mg, 3.34 mmol, 5 equiv) were added acetone (2.7 mL, 0.25 M) and acrylonitrile (175 µL, 2.67 mmol, 4 equiv). The vial was sealed and the reaction mixture was heated to 50 °C Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 100 using a heating block, stirred for 20 h, and allowed to cool to 23 °C. The crude mixture was filtered through cotton and concentrated under reduced pressure. The product was purified by silica gel flash chromatography (25% EtOAc/hexanes) to provide the title compound as a colorless oil (94.6 mg, 0.221 mmol, 33% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1.7:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.70 – 7.61 (m, 2H), 7.61 – 7.54 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H), 5.96 – 5.78 (m, 1H), 5.48 – 5.21 (m, 4H), 4.78 – 4.56 (m, 2H), 2.94 – 2.59 (m, 2H), 2.53 – 2.34 (m, 2H), 1.52 (s, 9H*), 1.47 (s, 9H#); 13C NMR (100 MHz, CDCl3) δ 168.4, 168.1, 166.4, 165.5, 165.3, 152.9, 152.2, 133.1, 132.6, 130.9, 130.6, 129.3, 128.2, 120.4, 119.7, 118.5, 118.2, 83.7, 83.4, 70.9, 70.8, 67.6, 67.6, 61.8, 61.8, 28.3, 28.3, 27.6, 12.7, 12.5; IR (Neat Film, NaCl) 3065, 2979, 2936, 2343, 2249, 1770, 1745, 1714, 1698, 1651, 1602, 1582, 1477, 1449, 1386, 1372, 1301, 1245, 1225, 1173, 1154, 1114, 1081, 1048, 1028, 994, 939, 894, 858, 845, 793, 781, 770, 733, 701, 672, 664, 621 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C22H29N4O6 [M+NH4]+: 445.2082, found 445.2085. O Me O O BzN N Boc O 5-allyl 1-(tert-butyl) 3-benzoyl-4-oxo-5-(3-oxobutyl)imidazolidine-1,5-dicarboxylate (34k) To a vial containing lactam 33 (250 mg, 0.668 mmol, 1.0 equiv) and K2CO3 (462 mg, 3.34 mmol, 5 equiv) were added acetone (3 mL, 0.25 M) and methyl vinyl ketone (223 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 101 µL, 2.67 mmol, 4 equiv). The vial was sealed, and the reaction mixture was heated to 50 °C using a heating block, stirred for 6 h, and allowed to cool to 23 °C. The crude mixture was filtered through cotton and concentrated under reduced pressure. The product was purified by silica gel flash chromatography (33% EtOAc/hexanes) to provide the title compound as a colorless oil (228 mg, 0.513 mmol, 77% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1.1:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.62 (d, J = 7.7 Hz, 2H), 7.55 – 7.48 (m, 1H), 7.39 (t, J = 7.7 Hz, 2H), 5.95 – 5.75 (m, 1H), 5.41 – 5.05 (m, 4H), 4.73 – 4.52 (m, 2H), 2.75 – 2.35 (m, 4H), 2.11 (d, J = 3.0 Hz, 3H), 1.47 (s, 9H*), 1.43 (s, 9H#); 13C NMR (100 MHz, CDCl3) δ 207.5, 206.7, 168.4, 168.2, 166.9, 166.8, 166.4, 166.2, 152.5, 152.2, 132.8, 132.8, 132.7, 132.7, 131.1, 130.8, 129.1, 128.0, 119.7, 119.1, 82.9, 82.6, 70.9, 67.1, 67.1, 61.4, 61.3, 38.5, 37.8, 29.8, 29.4, 28.2, 28.1, 27.8, 26.9; IR (Neat Film, NaCl) 3074, 2977, 2931, 1757, 1703, 1642, 1602, 1583, 1478, 1448, 1393, 1368, 1304, 1226, 1168, 1091, 1061, 999, 970, 928, 880, 858, 826, 795, 768, 731, 701, 664 cm–1; HRMS (MM: ESIAPCI): m/z calc’d for C23H32N3O7 [M+NH4]+: 462.2235, found 462.2251. 1.5.2.6 Derivatization of Imidazolidinone Allylic Alkylation Products O Bn BzN NH (R)-5-allyl-3-benzoyl-5-benzylimidazolidin-4-one (52) To a solution of benzyl imidazolidinone 35a (15 mg, 0.0357 mmol, 1.0 equiv) in CH2Cl2 (0.36 mL, 0.1 M) was added trifluoroacetic acid (41 µL, 0.536 mmol, 15 equiv), and the reaction mixture was stirred in a sealed vial at 23 °C for 22 h. The resulting solution was concentrated under reduced pressure and the residue taken up in Et2O (0.5 mL), Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 102 washed with 5% aq. K2CO3 (1 mL), dried with Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (33% EtOAc/hexanes) to provide free amine 52 as a white solid (9.3 mg, 0.0290 mmol, 81% yield); 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.49 (m, 3H), 7.46 – 7.40 (m, 2H), 7.38 – 7.29 (m, 3H), 7.29 – 7.22 (m, 2H), 5.85 (dddd, J = 17.0, 10.2, 8.6, 6.2 Hz, 1H), 5.31 – 5.17 (m, 2H), 4.71 (d, J = 9.6 Hz, 1H), 4.32 (d, J = 9.6 Hz, 1H), 3.15 (d, J = 13.6 Hz, 1H), 2.76 (d, J = 13.6 Hz, 1H), 2.63 (ddt, J = 14.0, 6.1, 1.4 Hz, 1H), 2.32 (ddt, J = 13.9, 8.5, 0.9 Hz, 1H), 2.21 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 176.0, 169.7, 135.6, 133.4, 132.5, 132.1, 130.5, 129.3, 128.8, 128.0, 127.6, 120.9, 68.4, 61.9, 42.1, 41.1; IR (Neat Film, NaCl) 2921, 1743, 1674, 1494, 1449, 1380, 1306, 1235, 922, 796, 732, 700 cm–1; HRMS (MM: ESIAPCI): m/z calc’d for C20H21N2O2 [M+H]+: 321.1598, found 321.1590; [α]D21.7 +69.27 (c 0.5, CHCl3). O HN Bn NBoc tert-butyl (R)-5-allyl-5-benzyl-4-oxoimidazolidine-1-carboxylate (53) To a solution of benzyl imidazolidinone 35a (15 mg, 0.0357 mmol, 1.0 equiv) in 50% MeOH/H2O (0.36 mL, 0.1 M) was added LiOH·H2O (22 mg, 0.536 mmol, 15 equiv) and the reaction mixture was heated with stirring in a sealed vial at 70 °C for 1 h using a heating block. MeOH was removed under reduced pressure and the solution was diluted with H2O (0.5 mL) and extracted with ethyl acetate (4 x 0.5 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (40% EtOAc/hexanes) to provide Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 103 free lactam 53 as a colorless film (9.0 mg, 0.0284 mmol, 80% yield); 1H NMR (400 MHz, CDCl3; compound exists as a 1.1:1 mixture of rotamers. For fully resolved peaks, the major rotamer is denoted by *, and the minor rotamer by #) δ 7.26 – 7.12 (m, 5H), 6.38 (d, J = 32.9 Hz, 1H), 5.74 – 5.53 (m, 1H), 5.24 – 5.04 (m, 2H), 4.41 (d, J = 5.5 Hz, 1H#), 4.32 (d, J = 5.4 Hz, 1H*), 3.79 (d, J = 5.5 Hz, 1H#), 3.68 (d, J = 5.3 Hz, 1H*), 3.50 (d, J = 13.3 Hz, 1H*), 3.27 (d, J = 13.4 Hz, 1H#), 3.16 (dd, J = 13.6, 8.4 Hz, 1H#), 3.01 (dd, J = 13.3, 1.7 Hz, 1H), 2.93 (dd, J = 13.8, 8.2 Hz, 1H*), 2.71 – 2.54 (m, 1H), 1.64 (s, 9H#), 1.49 (s, 9H*); 13 C NMR (100 MHz, CDCl3) δ 174.4, 174.2, 152.9, 151.9, 136.5, 135.9, 132.4, 132.0, 130.0, 129.9, 128.5, 128.3, 127.1, 126.9, 119.7, 119.6, 81.7, 80.5, 68.6, 68.4, 58.1, 57.9, 41.1, 40.0, 38.8, 28.8, 28.5; IR (Neat Film, NaCl) 3242, 2976, 2930, 1708, 1454, 1402, 1368, 1341, 1257, 1174, 1143, 1078, 996, 920, 768, 702 cm–1; HRMS (MM: ESI-APCI): m/z calc’d for C18H25N2O3 [M+H]+: 317.1860, found 317.1852; [α]D21.8 –67.38 (c 0.5, CHCl3). O MeO H2N Bn methyl (R)-2-amino-2-benzylpent-4-enoate (54) To a solution of benzyl imidazolidinone 35a (10 mg, 0.0238 mmol, 1.0 equiv) in MeOH (0.4 mL, 0.06 M) was added concentrated H2SO4 (85 µL). The reaction vessel was sealed, and the reaction mixture was stirred at 70 °C in a heating block for 3 days. Care should be taken, as gas pressure is generated over the course of the reaction. The crude mixture was then added to saturated aq. NaHCO3 (10 mL, gas evolution) and extracted with ethyl acetate (4 x 4 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 104 chromatography (20% EtOAc/hexanes + 0.1% Et3N) to provide amino ester 11 as a colorless film (1.3 mg, 0.00593 mmol, 25% yield). 1H NMR (500 MHz, CDCl3) δ 7.31 – 7.26 (m, 2H), 7.26 – 7.22 (m, 1H), 7.18 – 7.08 (m, 2H), 5.77 – 5.64 (m, 1H), 5.24 – 5.11 (m, 2H), 3.71 (s, 3H), 3.19 (d, J = 13.2 Hz, 1H), 2.80 (dd, J = 13.2, 6.9 Hz, 1H), 2.73 (ddt, J = 13.3, 6.4, 1.3 Hz, 1H), 2.33 (dd, J = 13.5, 8.4 Hz, 1H). All characterization data matched those reported in the literature.35 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 1.5.3 DETERMINATION OF ENANTIOMERIC EXCESS Table 1.5.3.1. Determination of enantiomeric excess. entry compound O Bn 1 BzN assay conditions tR of major isomer (min) tR of minor isomer (min) % ee SFC Chiralpak AD-H 20% IPA isocratic, 2.5 mL/min 3.51 2.71 90 SFC Chiralpak IC 20% IPA isocratic, 2.5 mL/min 5.68 4.31 90 SFC Chiralpak AD-H 5% IPA isocratic, 2.5 mL/min 5.86 4.49 92 SFC Chiralpak IC 20% MeOH isocratic, 2.5 mL/min 5.66 5.11 94 SFC Chiralpak AD-H 20% IPA isocratic, 2.5 mL/min 6.20 3.94 89 SFC Chiralpak AD-H 20% IPA isocratic, 2.5 mL/min 4.99 6.26 90 SFC Chiralcel OD-H 20% IPA isocratic, 2.5 mL/min 2.69 3.25 83 NBoc 20a O Me 2 BzN NBoc 20b O Me 3 (p-F3C-Bz)N NBoc 20c O Me 4 AnN NBoc 20d O Bn 5 AnN NBoc 20e O F 6 BzN NBoc 20f O F 7 AnN NBoc 20g 105 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles Table 1.5.3.2. Determination of enantiomeric excess (continued). entry compound Cl 8 O AnN assay conditions tR of major isomer (min) tR of minor isomer (min) % ee SFC Chiralpak AD-H 20% IPA isocratic, 2.5 mL/min 2.77 2.52 90 SFC Chiralpak AD-H 10% IPA isocratic, 2.5 mL/min 10.85 10.29 94 SFC Chiralcel OD-H 15% IPA isocratic, 2.5 mL/min 5.27 4.84 95 SFC Chiralcel OD-H 20% IPA isocratic, 2.5 mL/min 8.33 6.18 84 SFC Chiralpak IC 20% IPA isocratic, 2.5 mL/min 5.85 4.65 93 SFC Chiralpak AD-H 7% IPA isocratic, 2.5 mL/min 5.13 6.29 92 SFC Chiralcel OJ-H 10% IPA isocratic, 2.5 mL/min 1.55 1.71 89 NBoc 20h O 9 BzN NBoc 20i CO2Me O 10 AnN NBoc 20j CN O 11 AnN NBoc 20k BocHN O 12 AnN NBoc 20l O BzN 13 Bn N Boc 35a O 14 BzN N Boc 35b p-CF3-Ph 106 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles Table 1.5.3.3. Determination of enantiomeric excess (continued). entry compound assay conditions tR of major isomer (min) tR of minor isomer (min) % ee SFC Chiralpak AD-H 7% IPA isocratic, 2.5 mL/min 3.40 3.04 86 SFC Chiralcel OJ-H 1% IPA isocratic, 2.5 mL/min 2.98 3.34 80 SFC Chiralpak AD-H 10% IPA isocratic, 2.5 mL/min 5.15 4.77 85 SFC Chiralcel OJ-H 7% IPA isocratic, 2.5 mL/min 2.43 2.11 91 SFC Chiralcel OD-H 10% IPA isocratic, 2.5 mL/min 3.79 3.47 89 SFC Chiralcel OJ-H 7% IPA isocratic, 2.5 mL/min 2.19 1.99 86 O BzN 15 Me N Boc 35c Me O 16 Me BzN N Boc 35d Ph O 17 BzN N Boc 35e O 18 BzN N Boc 35f O 19 Me Bn BzN N Boc 35g O Cl BzN 20 N Boc 35h 107 Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 108 Table 1.5.3.4. Determination of enantiomeric excess (continued). entry compound O tR of major isomer (min) tR of minor isomer (min) % ee SFC Chiralpak AD-H 20% IPA isocratic, 2.5 mL/min 6.15 3.52 85 SFC Chiralpak IC 15% IPA isocratic, 2.5 mL/min 5.49 4.78 95 SFC Chiralpak IC 20% IPA isocratic, 2.5 mL/min 2.42 3.23 93 NHCbz BzN 21 assay conditions N Boc 35i O CN BzN 22 N Boc 35j O O 23 BzN N Boc 35k Me Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 1.6 (1) 109 REFERENCES AND NOTES Tsuji, J.; Minami, I.; Shimizu, I. Palladium-catalyzed allylation of ketones and aldehydes via allyl enol carbonates. Tetrahedron Lett. 1983, 24, 1793–1796. (2) Behenna, D. C.; Stoltz, B. M. The Enantioselective Tsuji Allylation. J. Am. Chem. Soc. 2004, 126, 15044–15045. (3) a) Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. 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Nature 2018, 562, 105–109. d) Abas, H.; Mas-Roselló, J.; Amer, M. M.; Durand, D. J.; Groleau, R. R.; Fey, N.; Clayden, J. Asymmetric and Geometry-Selective α-Alkenylation of α-Amino Acids. Angew. Chem. Int. Ed. 2019, 58, 2418–2422. (16) Cozzi, P. G.; Gualandi, A.; Mengozzi, L.; Wilson, C. M. Imidazolidinones as Asymmetric Organocatalysts. In Sustainable Catalysis: Without Metals or Other Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles 113 Endangered Elements, Part 2; North, M., Ed.; Royal Society of Chemistry: Cambridge, 2016; 164–195. (17) Pfeiffer, U.; Riccaboni, M. T.; Erba, R.; Pinza, M. A short synthesis of 4imidazolidinone. Liebigs Ann. Chem. 1988, 993–995. (18) Nitta, Y.; Yamaguchi, T.; Tanaka, T. First Synthesis of 4-Imidazolidinone. Heterocycles 1986, 24, 25–28. (19) Wang, J.; Rochon, F. D.; Yang, Y.; Hua, L.; Kayser, M. M. Synthesis of oxazolidines using DMSO/P4O10 as a formaldehyde equivalent. Tetrahedron: Asymmetry 2007, 18, 1115–1123. (20) Liu, Y.; Ji, P.; Xu, J.; Hu, Y.; Liu, Q.; Luo, W.; Guo, C. Transition Metal-Free αCsp3-H Methylenation of Ketones to Form C═C Bond Using Dimethyl Sulfoxide as Carbon Source. J. Org. Chem. 2017, 82, 7159–7164. (21) Pothikumar, R.; Sujatha, C.; Namitharan, K. Transition-Metal-Free In Situ Generation of Terminal Alkenes: Synthesis of Multisubstituted Acrylamidines via Tandem sp3 C–H Olefination/sp2 C–H Arylation Reactions. ACS Catal. 2017, 7, 7783–7787. (22) Pojer, P. M.; Angyal, S. J. Methylthiomethyl ethers: Their use in the protection and methylation of hydroxyl groups. Aust. J. Chem. 1978, 31, 1031–1040. (23) Freter, K.; Rabinowitz, J. C.; Witkop, B. Labile Stoffwechselprodukte V. Zur Biogenese Des Formiminoglycins Aus 4(5H)-Imidazolon. Liebigs Ann. Chem. 1957, 607, 174–187. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles (24) 114 Khurana, J. M.; Kukreja, G. Nickel boride mediated reductive desulfurization of 2-thioxo-4(3H)-quinazolinones: A new synthesis of quinazolin-4(3H)-ones and 2,3-dihydro-4(1H)-quinazolinones. J. Heterocyclic Chem. 2003, 40, 677–679. (25) Khurana, J. M.; Agrawal, A.; Bansal, G. 5,5-diaryl and 5-alkyl-3-phenyl-4imidazolidones: A novel synthesis. J. Heterocyclic Chem. 2009, 46, 1007–1010. (26) Gosling, S.; Rollin, P.; Tatibouët, A. Thiohydantoins: Selective N- and SFunctionalization for Liebeskind-Srogl Reaction Study Synthesis 2011, 3649– 3660. (27) Recent reviews: a) Vogt, H.; Bräse, S. Recent approaches towards the asymmetric synthesis of α,α-disubstituted α-amino acids. Org. Biomol. Chem. 2007, 5, 406– 430. b) Bera, K.; Namboothiri, I. N. N. Asymmetric Synthesis of Quaternary αAmino Acids and Their Phosphonate Analogues. Asian J. Org. Chem. 2014, 3, 1234–1260. c) Metz, A. E.; Kozlowski, M. C. Recent Advances in Asymmetric Catalytic Methods for the Formation of Acyclic α,α-Disubstituted α-Amino Acids. J. Org. Chem. 2015, 80, 1–7. d) Cativiela, C.; Ordóñez, M.; Viveros-Ceballos, J. L. Stereoselective synthesis of acyclic α,α-disubstituted α-amino acids derivatives from amino acids templates. Tetrahedron 2020, 76, 130875. (28) Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. Chapter 1 – Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7Membered Diazaheterocycles (29) 115 McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Rapid synthesis of an electron-deficient t-BuPHOX ligand: cross-coupling of aryl bromides with secondary phosphine oxides. Tetrahedron Lett. 2010, 51, 5550– 5554. (30) Klepacz, A.; Zwierzak, A. An expeditious one-pot synthesis of diethyl N-Boc-1aminoalkylphosphonates. Tetrahedron Lett. 2002, 43, 1079–1080. (31) Sikriwal, D.; Kant, R.; Maulik, P. R.; Dikshit, D. K. A short formal synthesis of three epimers of penmacric acid. Tetrahedron 2010, 66, 6167–6173. (32) Jia, P.; Hu, Y.; Ye, Z.; Li, X.; Xiang, H.; Yang, H. O-Perfluoropyridin-4-yl Oximes: Iminyl Radical Precursors for Photo- or Thermal-Induced N–O Cleavage in C(sp2)– C(sp3) Bond Formation. J. Org. Chem. 2020, 85, 3538–3547. (33) Trost, B. M.; Xu, J. The O-Acylation of Ketone Enolates by Allyl 1H-Imidazole1-carboxylate Mediated with Boron Trifluoride Etherate – A Convenient Procedure for the Synthesis of Substituted Allyl Enol Carbonates. J. Org. Chem. 2007, 72, 9372–9375. (34) Heller, S. T.; Schultz, E. E.; Sarpong, R. Chemoselective N-Acylation of Indoles and Oxazolidinones with Carbonylazoles. Angew. Chem. Int. Ed. 2012, 51, 8304– 8308. (35) Wei, L.; Xu, S.; Zhu, Q.; Che, C.; Wang, C. Synergistic Cu/Pd Catalysis for Enantioselective Allylic Alkylation of Aldimine Esters: Access to α,αDisubstituted α-Amino Acids. Angew. Chem. Int. Ed. 2017, 56, 12312–12316. Appendix 1 – Spectra Relevant to Chapter 1 116 APPENDIX 1 Spectra Relevant to Chapter 1: Palladium-Catalyzed Decarboxylative Asymmetric Allylic Alkylation of 5- and 7-Membered Diazaheterocycles BzN 9 NBoc O Bn 8 6 5 ppm 4 3 2 Figure A1.1. 1H NMR (400 MHz, CDCl3) of compound 20a. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 117 Appendix 1 – Spectra Relevant to Chapter 1 118 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound 20a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.3. 13C NMR (100 MHz, CDCl3) of compound 20a. 0 BzN NBoc O Me 9 8 6 5 ppm 4 3 Figure A1.4. 1H NMR (400 MHz, CDCl3) of compound 20b. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 119 Appendix 1 – Spectra Relevant to Chapter 1 120 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 20b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.6. 13C NMR (100 MHz, CDCl3) of compound 20b. 0 (p-F3C-Bz)N 9 NBoc O Me 8 6 5 ppm 4 3 2 Figure A1.7. 1H NMR (400 MHz, CDCl3) of compound 20c. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 121 Appendix 1 – Spectra Relevant to Chapter 1 122 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 20c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.9. 13C NMR (100 MHz, CDCl3) of compound 20c. 0 AnN 9 NBoc O Me 8 6 5 ppm 4 3 2 Figure A1.10. 1H NMR (400 MHz, CDCl3) of compound 20d. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 123 Appendix 1 – Spectra Relevant to Chapter 1 124 Figure A1.11. Infrared spectrum (Thin Film, NaCl) of compound 20d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.12. 13C NMR (100 MHz, CDCl3) of compound 20d. 0 AnN 9 NBoc O Bn 8 6 5 ppm 4 3 2 Figure A1.13. 1H NMR (400 MHz, CDCl3) of compound 20e. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 125 Appendix 1 – Spectra Relevant to Chapter 1 126 Figure A1.14. Infrared spectrum (Thin Film, NaCl) of compound 20e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.15. 13C NMR (100 MHz, CDCl3) of compound 20e. 0 BzN 9 NBoc O F 8 6 5 ppm 4 3 Figure A1.16. 1H NMR (400 MHz, CDCl3) of compound 20f. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 127 Appendix 1 – Spectra Relevant to Chapter 1 128 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 20f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.18. 13C NMR (100 MHz, CDCl3) of compound 20f. 0 AnN 9 NBoc O F 8 6 5 ppm 4 3 2 Figure A1.19. 1H NMR (400 MHz, CDCl3) of compound 20g. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 129 Appendix 1 – Spectra Relevant to Chapter 1 130 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 20g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.21. 13C NMR (100 MHz, CDCl3) of compound 20g. 0 AnN Cl O NBoc 9 8 6 5 ppm 4 3 2 Figure A1.22. 1H NMR (400 MHz, CDCl3) of compound 20h. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 131 Appendix 1 – Spectra Relevant to Chapter 1 132 Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 20h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.24. 13C NMR (100 MHz, CDCl3) of compound 20h. 0 AnN O 9 NBoc 8 6 5 ppm 4 3 Figure A1.25. 1H NMR (400 MHz, CDCl3) of compound 20i. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 133 Appendix 1 – Spectra Relevant to Chapter 1 134 Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 20i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.27. 13C NMR (100 MHz, CDCl3) of compound 20i. 0 AnN O 9 NBoc CO2Me 8 6 5 ppm 4 3 2 Figure A1.28. 1H NMR (400 MHz, CDCl3) of compound 20j. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 135 Appendix 1 – Spectra Relevant to Chapter 1 136 Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 20j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.30. 13C NMR (100 MHz, CDCl3) of compound 20j. 0 AnN O 9 NBoc CN 8 6 5 ppm 4 3 2 Figure A1.31. 1H NMR (400 MHz, CDCl3) of compound 20k. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 137 Appendix 1 – Spectra Relevant to Chapter 1 138 Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 20k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.33. 13C NMR (100 MHz, CDCl3) of compound 20k. 0 BzN BocHN O 9 NBoc 8 6 5 ppm 4 3 Figure A1.34. 1H NMR (400 MHz, CDCl3) of compound 20l. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 139 Appendix 1 – Spectra Relevant to Chapter 1 140 Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 20l. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.36. 13C NMR (100 MHz, CDCl3) of compound 20l. 0 BzN O 9 NBoc 8 6 5 ppm 4 3 Figure A1.37. 1H NMR (400 MHz, CDCl3) of compound 55. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 141 Appendix 1 – Spectra Relevant to Chapter 1 142 Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 55. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.39. 13C NMR (100 MHz, CDCl3) of compound 55. 0 (p-F3C-Bz)N O 9 NBoc 8 6 5 ppm 4 3 Figure A1.40. 1H NMR (400 MHz, CDCl3) of compound 56. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 143 Appendix 1 – Spectra Relevant to Chapter 1 144 Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 56. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.42. 13C NMR (100 MHz, CDCl3) of compound 56. 0 AnN O 9 NBoc 8 6 5 ppm 4 3 Figure A1.43. 1H NMR (400 MHz, CDCl3) of compound 57. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 145 Appendix 1 – Spectra Relevant to Chapter 1 146 Figure A1.44. Infrared spectrum (Thin Film, NaCl) of compound 57. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.45. 13C NMR (100 MHz, CDCl3) of compound 57. 0 BzN O O 9 NBoc O 8 6 5 ppm 4 3 Figure A1.46. 1H NMR (500 MHz, CDCl3) of compound 18a. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 147 Appendix 1 – Spectra Relevant to Chapter 1 148 Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 18a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.48. 13C NMR (125 MHz, CDCl3) of compound 18a. 0 (p-F3C-Bz)N O 9 NBoc O O 8 6 5 ppm 4 3 2 Figure A1.49. 1H NMR (400 MHz, CDCl3) of compound 18b. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 149 Appendix 1 – Spectra Relevant to Chapter 1 150 Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound 18b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.51. 13C NMR (100 MHz, CDCl3) of compound 18b. 0 AnN O 9 NBoc O O 8 6 5 ppm 4 3 2 Figure A1.52. 1H NMR (400 MHz, CDCl3) of compound 18c. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 151 Appendix 1 – Spectra Relevant to Chapter 1 152 Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 18c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.54. 13C NMR (100 MHz, CDCl3) of compound 18c. 0 BzN O O 9 NBoc O Bn 8 6 ppm 5 4 3 Figure A1.55. 1H NMR (400 MHz, CDCl3) of compound 19a. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 1 153 Appendix 1 – Spectra Relevant to Chapter 1 154 Figure A1.56. Infrared spectrum (Thin Film, NaCl) of compound 19a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.57. 13C NMR (100 MHz, CDCl3) of compound 19a. 0 BzN O 9 NBoc O Me O 8 6 5 ppm 4 3 2 Figure A1.58. 1H NMR (400 MHz, CDCl3) of compound 19b. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 155 Appendix 1 – Spectra Relevant to Chapter 1 156 Figure A1.59. Infrared spectrum (Thin Film, NaCl) of compound 19b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.60. 13C NMR (100 MHz, CDCl3) of compound 19b. 0 (p-F3C-Bz)N 9 O NBoc O Me O 8 6 5 ppm 4 3 2 Figure A1.61. 1H NMR (400 MHz, CDCl3) of compound 19c. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 157 Appendix 1 – Spectra Relevant to Chapter 1 158 Figure A1.62. Infrared spectrum (Thin Film, NaCl) of compound 19c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.63. 13C NMR (100 MHz, CDCl3) of compound 19c. 0 AnN O 9 NBoc O Me O 8 6 5 ppm 4 3 2 Figure A1.64. 1H NMR (400 MHz, CDCl3) of compound 19d. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 159 Appendix 1 – Spectra Relevant to Chapter 1 160 Figure A1.65. Infrared spectrum (Thin Film, NaCl) of compound 19d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.66. 13C NMR (100 MHz, CDCl3) of compound 19d. 0 AnN O 9 NBoc O Bn O 8 6 5 ppm 4 3 Figure A1.67. 1H NMR (500 MHz, CDCl3) of compound 19e. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 161 Appendix 1 – Spectra Relevant to Chapter 1 162 Figure A1.68. Infrared spectrum (Thin Film, NaCl) of compound 19e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.69. 13C NMR (125 MHz, CDCl3) of compound 19e. 0 BzN 9 O NBoc O F O 8 6 5 ppm 4 3 2 Figure A1.70. 1H NMR (500 MHz, CDCl3) of compound 19f. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 163 Appendix 1 – Spectra Relevant to Chapter 1 164 Figure A1.71. Infrared spectrum (Thin Film, NaCl) of compound 19f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.72. 13C NMR (125 MHz, CDCl3) of compound 19f. 0 AnN O 9 NBoc O F O 8 6 5 ppm 4 3 2 Figure A1.73. 1H NMR (400 MHz, CDCl3) of compound 19g. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 165 Appendix 1 – Spectra Relevant to Chapter 1 166 Figure A1.74. Infrared spectrum (Thin Film, NaCl) of compound 19g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.75. 13C NMR (100 MHz, CDCl3) of compound 19g. 0 AnN Cl O 9 NBoc O O 8 6 5 ppm 4 3 2 Figure A1.76. 1H NMR (400 MHz, CDCl3) of compound 19h. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 167 Appendix 1 – Spectra Relevant to Chapter 1 168 Figure A1.77. Infrared spectrum (Thin Film, NaCl) of compound 19h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.78. 13C NMR (100 MHz, CDCl3) of compound 19h. 0 AnN O 9 NBoc O O 8 7 5 ppm 4 3 2 Figure A1.79. 1H NMR (500 MHz, CDCl3) of compound 19i. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 169 Appendix 1 – Spectra Relevant to Chapter 1 170 Figure A1.80. Infrared spectrum (Thin Film, NaCl) of compound 19i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.81. 13C NMR (125 MHz, CDCl3) of compound 19i. 0 AnN O 9 NBoc O CO2Me O 8 6 5 ppm 4 3 Figure A1.82. 1H NMR (500 MHz, CDCl3) of compound 19j. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 171 Appendix 1 – Spectra Relevant to Chapter 1 172 Figure A1.83. Infrared spectrum (Thin Film, NaCl) of compound 19j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.84. 13C NMR (125 MHz, CDCl3) of compound 19j. 0 AnN O 9 NBoc O CN O 8 6 5 ppm 4 3 2 Figure A1.85. 1H NMR (400 MHz, CDCl3) of compound 19k. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 173 Appendix 1 – Spectra Relevant to Chapter 1 174 Figure A1.86. Infrared spectrum (Thin Film, NaCl) of compound 19k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.87. 13C NMR (100 MHz, CDCl3) of compound 19k. 0 BzN BocHN O 9 NBoc O O 8 6 5 ppm 4 3 2 Figure A1.88. 1H NMR (400 MHz, CDCl3) of compound 19l. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 175 Appendix 1 – Spectra Relevant to Chapter 1 176 Figure A1.89. Infrared spectrum (Thin Film, NaCl) of compound 19l. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.90. 13C NMR (100 MHz, CDCl3) of compound 19l. 0 HN 9 NBoc Bn 8 6 5 ppm 4 3 Figure A1.91. 1H NMR (400 MHz, CDCl3) of compound 21. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 177 Appendix 1 – Spectra Relevant to Chapter 1 178 Figure A1.92. Infrared spectrum (Thin Film, NaCl) of compound 21. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.93. 13C NMR (100 MHz, CDCl3) of compound 21. 0 Cl 9 N O N Bn NH 8 6 5 ppm 4 3 Figure A1.94. 1H NMR (400 MHz, CDCl3) of compound 23. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 179 Appendix 1 – Spectra Relevant to Chapter 1 180 Figure A1.95. Infrared spectrum (Thin Film, NaCl) of compound 23. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.96. 13C NMR (100 MHz, CDCl3) of compound 23. 0 Cl O Bn 9 N N N O N Me N 8 N 6 5 ppm 4 3 2 Figure A1.97. 1H NMR (400 MHz, CDCl3) of compound 25. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 181 Appendix 1 – Spectra Relevant to Chapter 1 182 Figure A1.98. Infrared spectrum (Thin Film, NaCl) of compound 25. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.99. 13C NMR (100 MHz, CDCl3) of compound 25. 0 AnN 9 NBoc O Bn 8 6 5 ppm 4 3 2 Figure A1.100. 1H NMR (400 MHz, DMSO-d6, 23.3 °C) of compound 20e. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 183 Variable-Temperature NMR of Diazepanone 20e AnN 9 NBoc O Bn 7 6 5 ppm 4 3 2 Figure A1.101. 1H NMR (400 MHz, DMSO-d6, 80 °C) of compound 20e. 8 1 0 Appendix 1 – Spectra Relevant to Chapter 1 184 Appendix 1 – Spectra Relevant to Chapter 1 200 180 160 140 120 185 100 ppm 80 60 40 20 Figure A1.102. 13C NMR (100 MHz, DMSO-d6, 80 °C) of compound 20e. 0 BzN N Boc O 9 Bn 8 6 5 ppm 4 3 2 Figure A1.103. 1H NMR (400 MHz, CDCl3) of compound 35a. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 186 Appendix 1 – Spectra Relevant to Chapter 1 187 Figure A1.104. Infrared spectrum (Thin Film, NaCl) of compound 35a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.105. 13C NMR (100 MHz, CDCl3) of compound 35a. 0 BzN N Boc O 9 p-CF3-Ph 8 6 5 ppm 4 3 2 Figure A1.106. 1H NMR (400 MHz, CDCl3) of compound 35b. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 188 Appendix 1 – Spectra Relevant to Chapter 1 189 Figure A1.107. Infrared spectrum (Thin Film, NaCl) of compound 35b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.108. 13C NMR (100 MHz, CDCl3) of compound 35b. 0 BzN N Boc O 9 Me 8 6 5 ppm 4 3 2 Figure A1.109. 1H NMR (400 MHz, CDCl3) of compound 35c. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 190 Appendix 1 – Spectra Relevant to Chapter 1 191 Figure A1.110. Infrared spectrum (Thin Film, NaCl) of compound 35c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.111. 13C NMR (100 MHz, CDCl3) of compound 35c. 0 9 BzN N Boc O Me 8 Me 6 5 ppm 4 3 2 Figure A1.112. 1H NMR (400 MHz, CDCl3) of compound 35d. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 192 Appendix 1 – Spectra Relevant to Chapter 1 193 Figure A1.113. Infrared spectrum (Thin Film, NaCl) of compound 35d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.114. 13C NMR (100 MHz, CDCl3) of compound 35d. 0 BzN N Boc O 9 Ph 8 6 5 ppm 4 3 2 Figure A1.115. 1H NMR (400 MHz, CDCl3) of compound 35e. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 194 Appendix 1 – Spectra Relevant to Chapter 1 195 Figure A1.116. Infrared spectrum (Thin Film, NaCl) of compound 35e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.117. 13C NMR (100 MHz, CDCl3) of compound 35e. 0 BzN N Boc O 9 8 6 5 ppm 4 3 2 Figure A1.118. 1H NMR (400 MHz, CDCl3) of compound 35f. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 196 Appendix 1 – Spectra Relevant to Chapter 1 197 Figure A1.119. Infrared spectrum (Thin Film, NaCl) of compound 35f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.120. 13C NMR (100 MHz, CDCl3) of compound 35f. 0 BzN N Boc O 9 Bn Me 8 6 5 ppm 4 3 2 Figure A1.121. 1H NMR (400 MHz, CDCl3) of compound 35g. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 198 Appendix 1 – Spectra Relevant to Chapter 1 199 Figure A1.122. Infrared spectrum (Thin Film, NaCl) of compound 35g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.123. 13C NMR (100 MHz, CDCl3) of compound 35g. 0 BzN N Boc Cl O 9 8 6 5 ppm 4 3 2 Figure A1.124. 1H NMR (400 MHz, CDCl3) of compound 35h. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 200 Appendix 1 – Spectra Relevant to Chapter 1 201 Figure A1.125. Infrared spectrum (Thin Film, NaCl) of compound 35h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.126. 13C NMR (100 MHz, CDCl3) of compound 35h. 0 BzN N Boc O 9 NHCbz 8 6 5 ppm 4 3 2 Figure A1.127. 1H NMR (400 MHz, CDCl3) of compound 35i. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 202 Appendix 1 – Spectra Relevant to Chapter 1 203 Figure A1.128. Infrared spectrum (Thin Film, NaCl) of compound 35i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.129. 13C NMR (100 MHz, CDCl3) of compound 35i. 0 BzN N Boc O 9 CN 8 6 5 ppm 4 3 2 Figure A1.130. 1H NMR (400 MHz, CDCl3) of compound 35j. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 204 Appendix 1 – Spectra Relevant to Chapter 1 205 Figure A1.131. Infrared spectrum (Thin Film, NaCl) of compound 35j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.132. 13C NMR (100 MHz, CDCl3) of compound 35j. 0 BzN N Boc O 9 O Me 8 6 5 ppm 4 3 2 Figure A1.133. 1H NMR (400 MHz, CDCl3) of compound 35k. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 206 Appendix 1 – Spectra Relevant to Chapter 1 207 Figure A1.134. Infrared spectrum (Thin Film, NaCl) of compound 35k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.135. 13C NMR (100 MHz, CDCl3) of compound 35k. 0 HN 9 N Boc O 8 6 5 ppm 4 3 2 Figure A1.136. 1H NMR (400 MHz, CDCl3) of compound 31. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 208 Appendix 1 – Spectra Relevant to Chapter 1 209 Figure A1.137. Infrared spectrum (Thin Film, KBr) of compound 31. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.138. 13C NMR (100 MHz, CDCl3) of compound 31. 0 BzN 9 N Boc O 8 6 5 ppm 4 3 2 Figure A1.139. 1H NMR (400 MHz, CDCl3) of compound 32. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 210 Appendix 1 – Spectra Relevant to Chapter 1 211 Figure A1.140. Infrared spectrum (Thin Film, NaCl) of compound 32. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.141. 13C NMR (100 MHz, CDCl3) of compound 32. 0 BzN N Boc O 9 O O 8 6 5 ppm 4 3 2 Figure A1.142. 1H NMR (400 MHz, CDCl3) of compound 33. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 212 Appendix 1 – Spectra Relevant to Chapter 1 213 Figure A1.143. Infrared spectrum (Thin Film, NaCl) of compound 33. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.144. 13C NMR (100 MHz, CDCl3) of compound 33. 0 BzN N Boc O 9 O O Me 8 6 5 ppm 4 3 2 Figure A1.145. 1H NMR (400 MHz, CDCl3) of compound 60. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 214 Appendix 1 – Spectra Relevant to Chapter 1 215 Figure A1.146. Infrared spectrum (Thin Film, KBr) of compound 60. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.147. 13C NMR (100 MHz, CDCl3) of compound 60. 0 BzN 9 O Bn O N Boc O 8 6 5 ppm 4 3 2 Figure A1.148. 1H NMR (400 MHz, CDCl3) of compound 34a. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 216 Appendix 1 – Spectra Relevant to Chapter 1 217 Figure A1.149. Infrared spectrum (Thin Film, NaCl) of compound 34a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.150. 13C NMR (100 MHz, CDCl3) of compound 34a. 0 BzN NBoc O 9 O O CF3 8 6 5 ppm 4 3 2 Figure A1.151. 1H NMR (400 MHz, CDCl3) of compound 34b. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 218 Appendix 1 – Spectra Relevant to Chapter 1 219 Figure A1.152. Infrared spectrum (Thin Film, NaCl) of compound 34b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.153. 13C NMR (100 MHz, CDCl3) of compound 34b. 0 9 BzN O Me O N Boc O 8 6 5 ppm 4 3 2 Figure A1.154. 1H NMR (400 MHz, CDCl3) of compound 34c. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 220 Appendix 1 – Spectra Relevant to Chapter 1 221 Figure A1.155. Infrared spectrum (Thin Film, NaCl) of compound 34c. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.156. 13C NMR (100 MHz, CDCl3) of compound 34c. 0 BzN N Boc O Me 9 O O Me 8 6 5 ppm 4 3 2 Figure A1.157. 1H NMR (400 MHz, CDCl3) of compound 34d. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 222 Appendix 1 – Spectra Relevant to Chapter 1 223 Figure A1.158. Infrared spectrum (Thin Film, NaCl) of compound 34d. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.159. 13C NMR (100 MHz, CDCl3) of compound 34d. 0 BzN N Boc O 9 O O Ph 8 6 5 ppm 4 3 2 Figure A1.160. 1H NMR (400 MHz, CDCl3) of compound 34e. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 224 Appendix 1 – Spectra Relevant to Chapter 1 225 Figure A1.161. Infrared spectrum (Thin Film, NaCl) of compound 34e. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.162. 13C NMR (100 MHz, CDCl3) of compound 34e. 0 BzN N Boc O 9 O O 8 6 5 ppm 4 3 2 Figure A1.163. 1H NMR (400 MHz, CDCl3) of compound 34f. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 226 Appendix 1 – Spectra Relevant to Chapter 1 227 Figure A1.164. Infrared spectrum (Thin Film, NaCl) of compound 34f. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.165. 13C NMR (100 MHz, CDCl3) of compound 34f. 0 BzN 9 O Bn O NBoc O Me 8 6 5 ppm 4 3 2 Figure A1.166. 1H NMR (500 MHz, CDCl3) of compound 34g. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 228 Appendix 1 – Spectra Relevant to Chapter 1 229 Figure A1.167. Infrared spectrum (Thin Film, NaCl) of compound 34g. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.168. 13C NMR (125 MHz, CDCl3) of compound 34g. 0 BzN Cl N Boc O 9 O O 8 6 5 ppm 4 3 2 Figure A1.169. 1H NMR (400 MHz, CDCl3) of compound 34h. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 230 Appendix 1 – Spectra Relevant to Chapter 1 231 Figure A1.170. Infrared spectrum (Thin Film, NaCl) of compound 34h. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.171. 13C NMR (100 MHz, CDCl3) of compound 34h. 0 BzN N Boc O 9 O NHCbz O 8 6 5 ppm 4 3 2 Figure A1.172. 1H NMR (400 MHz, CDCl3) of compound 34i. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 232 Appendix 1 – Spectra Relevant to Chapter 1 233 Figure A1.173. Infrared spectrum (Thin Film, NaCl) of compound 34i. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.174. 13C NMR (100 MHz, CDCl3) of compound 34i. 0 10 BzN N Boc O 9 O O CN 8 6 5 ppm 4 3 2 Figure A1.175. 1H NMR (400 MHz, CDCl3) of compound 34j. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 234 Appendix 1 – Spectra Relevant to Chapter 1 235 Figure A1.176. Infrared spectrum (Thin Film, NaCl) of compound 34j. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.177. 13C NMR (100 MHz, CDCl3) of compound 34j. 0 BzN N Boc O O O 9 O Me 8 6 5 ppm 4 3 2 Figure A1.178. 1H NMR (400 MHz, CDCl3) of compound 34k. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 236 Appendix 1 – Spectra Relevant to Chapter 1 237 Figure A1.179. Infrared spectrum (Thin Film, NaCl) of compound 34k. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.180. 13C NMR (100 MHz, CDCl3) of compound 34k. 0 BzN NH O 9 Bn 8 6 5 ppm 4 3 2 Figure A1.181. 1H NMR (400 MHz, CDCl3) of compound 52. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 238 Appendix 1 – Spectra Relevant to Chapter 1 239 Figure A1.182. Infrared spectrum (Thin Film, NaCl) of compound 52. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.183. 13C NMR (100 MHz, CDCl3) of compound 52. 0 HN Bn NBoc O 9 8 6 5 ppm 4 3 2 Figure A1.184. 1H NMR (400 MHz, CDCl3) of compound 53. 7 1 0 Appendix 1 – Spectra Relevant to Chapter 1 240 Appendix 1 – Spectra Relevant to Chapter 1 241 Figure A1.185. Infrared spectrum (Thin Film, NaCl) of compound 53. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.186. 13C NMR (100 MHz, CDCl3) of compound 53. 0 Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates 242 APPENDIX 2 Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates † A2.1 INTRODUCTION Having developed a tolerant Pd-catalyzed decarboxylative asymmetric allylic alkylation approach to enantioenriched gem-disubstituted 1,4-diazepan-5-ones (Chapter 1), we sought to apply this methodology to structurally related diazepane heterocycles (Figure A2.1.1). Figure A2.1.1. Scope of diazepanone derivatives discussed herein. O R1 R2 BzN NBoc 1,4-diazepan-5-ones (Chapter 1) This appendix: O R1 R2 BzN NBoc 1,4-diazepan-2-ones O R N R1 N Bz N R2 N Boc O R1 R2 Ph benzo-fused derivatives We had hoped to revisit the allylic alkylation of isomeric 1,4-diazepan-2-ones. Our group had previously reported a single example of the allylic alkylation of a 1,4-diazepan2-one substrate bearing an N-benzyl amine protecting group, which resulted in a modest 59% ee.1 Additionally, the allylic alkylation of benzo-fused derivatives of both 1,4- † This research was conducted in collaboration with Dr. Alexander Sun. Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates 243 diazepan-5-ones and 1,4-diazepan-2-ones is a desirable transformation, as both of these motifs have found medicinal applications.2 A2.2 ATTEMPTS TO ACCESS A 1,4-DIAZEPAN-2-ONE ALLYLIC ALKYLATION SUBSTRATE Compared to our group’s previous isolated example of a N-benzyl 1,4-diazepan2-one substrate, replacement of the N-benzyl group with an N-Boc group was expected to ease substrate synthesis. Thus, synthesis of this related substrate was attempted by a method analogous to the synthesis of 1,4-diazepan-5-ones 19a–l (see Chapter 1, Scheme 1.2.2). Commercial Boc-protected 1,4-diazepan-2-one 61 smoothly underwent deprotonation with n-BuLi and benzoylation to afford protected diazepanone 62 (Scheme A2.2.1). C-acylation under our standard conditions resulted in a mixture of 1,3-dicarbonyl 63 and unreacted starting material. Scheme A2.2.1. Unsuccessful synthesis of a 1,4-diazepan-2-one allylic alkylation substrate. O O HN O NBoc n-BuLi, BzCl THF, –78 °C, 20 min BzN NBoc 91% yield 61 62 O R base X MeI or Michael acceptor BzN CN O LiHMDS THF, –78 °C, 3 h 19% yield (+ 68% recovered starting material) O BzN O O NBoc 63 O O NBoc 64 Unfortunately, all attempts to prepare allylic alkylation substrates 64 were unsuccessful in our hands, resulting in either no reaction or putative O-alkylation to provide Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates 244 products which hydrolyzed back to 63 upon aqueous workup. Direct alkylation of 62 also resulted in putative O-alkylation. This behavior may be due to the proximity of the bulky tert-butyl carbamate to the nucleophilic enolate carbon, coupled with the substrate geometry. This undesired reactivity stands in stark contrast to the facile preparation of analogous piperazin-2-ones 13 (Chapter 1).3 A2.3 ATTEMPTS TO ACCESS BENZODIAZEPANE-DERIVED ALLYLIC ALKYLATION SUBSTRATES Seeking to remove the steric bulk of the Boc protecting group while maintaining medicinal relevance, we reasoned that close derivatives of the benzodiazepine anxiolytics could themselves be competent substrates for Pd-catalyzed decarboxylative asymmetric allylic alkylation. In 1981, Wolfe and coworkers reported that the FDA-approved anxiolytic diazepam (65) could be lithiated with 2 equivalents of LDA and acylated by treatment with ethyl acetate to provide dicarbonyl 66, albeit in poor yield (Scheme A2.3.1).4 Treatment of diazepam with fewer than 2 equivalents of LDA resulted in incomplete deprotonation—the enolate may be destabilized by antiaromaticity. Scheme A2.3.1. C–Acylation of diazepam (Wolfe). O Me N N Cl Ph diazepam (65) LDA (2 equiv) then EtOAc THF, –20→25 °C, 1 h 12% yield O Me N O N Cl Me Ph 66 While conjugated enolates generally result in poor enantioselectivity in our group’s Pd-catalyzed decarboxylative asymmetric allylic alkylation,5 we were interested in testing whether the destabilized enolate of a benzodiazepine would result in a higher ee. Toward this end, benzodiazepine 67 was prepared in two steps by a literature procedure (Scheme Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates 245 A2.3.2).6 This compound was subjected to routine benzoylation to yield protected benzodiazepine 68, but 1,3-dicarbonyl 69 was not observed under any of the acylation conditions tested. The use of LDA or LiHMDS as a base led to unidentified decomposition products, while LiTMP resulted in recovery of starting material. Scheme A2.3.2. Unsuccessful synthesis of a benzodiazepine allylic alkylation substrate. O O H N N O Bz N n-BuLi, BzCl THF, –78→23 °C, 30 min Ph NC O Bz N O base X O N 58% yield 67 O N Ph Ph 68 69 Finally, isomeric tetrahydrobenzodiazepanones 71 were evaluated as a potential substrate class due to their demonstrated applications in medicinal chemistry (Scheme A2.3.3).2b Scheme A2.3.3. Unsuccessful synthesis of a tetrahydro[1,4]benzodiazepanone allylic alkylation substrate. NH2 NH2 70 H N acrylic acid neat, 100 °C N H 24% yield Bz N 1) Boc2O, DMAP THF, 50 °C 2) n-BuLi, BzCl THF, –78 °C, 20 min N Boc 72 71 O O Bz N N LiTMP THF, –78 °C N Boc Ph NBoc 73 74 O N O 75 O O Ph N Boc 76 O Ph N Boc Bz N N aq. workup 14% yield O N Boc O 77 not observed O Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates 246 Treatment of 1,2-phenylenediamine 70 with acrylic acid provided cyclized product 71,7 and both nitrogen atoms could be protected over two steps to furnish carbamate 72. However, ester 77 was discovered not to be accessible by enolate acylation of 72. Instead, the highly fluorescent benzimidazole side-product 76 was isolated in 14% yield. This material probably arises from β-elimination of the carbamate from enolate 73, facilitated by the altered electronics of the aniline moiety. The resulting intermediate 74 can then undergo 5-exo-trig ring closure with the N-benzoyl group, leading to intermediate alkoxide 75. Finally, during aqueous workup, aromatization with loss of acrylate provides the observed product 76. A2.4 CONCLUSION Attempts were made to prepare several additional diazepane-derived allylic alkylation substrates but were unsuccessful. In two cases (1,4-diazepan-2-ones and benzodiazepines), the necessary prefunctionalization of the enolate was thwarted by steric or electronic factors. In the third case (benzo-fused 1,4-diazepan-5-ones), an unexpected fragmentation of the ring system precluded the synthesis of allylic alkylation substrates. A2.5 EXPERIMENTAL SECTION A2.5.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.8 Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or KMnO4 staining. Silicycle SiliaFlash® P60 Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates 247 Academic Silica gel (particle size 40–63 nm) was used for flash chromatography. 1H NMR spectra were recorded on Varian Inova 500 MHz and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CHCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities 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. Many NMR spectra are complicated by rotational isomerism about amide bonds. Reagents were purchased from commercial sources and used as received unless otherwise stated. A2.5.2 EXPERIMENTAL PROCEDURES O HN O NBoc 61 n-BuLi, BzCl THF, –78 °C BzN NBoc 62 tert-butyl 4-benzoyl-3-oxo-1,4-diazepane-1-carboxylate (62) To a flame-dried round bottom flask containing lactam 61 (300 mg, 1.40 mmol, 1.0 equiv) was added THF (14 mL). The flask was cooled to –78 °C and n-BuLi (2.5 M in hexanes, 0.59 mL, 1.47 mmol, 1.05 equiv) was added dropwise with stirring. Immediately following addition, BzCl (211 µL, 1.82 mmol, 1.3 equiv) was added dropwise. The reaction mixture was stirred at –78 °C for 20 min, whereafter it was quenched with saturated aq. NaHCO3. The resulting suspension was extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash chromatography (40% EtOAc/hexanes) to afford the title compound (403 mg, 1.27 mmol, 91% yield); 1H NMR (500 MHz, CDCl3) δ 7.65 – 7.53 (m, 2H), 7.52 – Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates 248 7.43 (m, 1H), 7.42 – 7.33 (m, 2H), 4.21 (s, 2H), 4.17 – 4.03 (m, 2H), 3.81 – 3.61 (m, 2H), 2.01 – 1.88 (m, 2H), 1.55 (d, J = 8.2 Hz, 9H). O O BzN NBoc 62 CN O LiHMDS THF, –78 °C, 3 h O BzN O O NBoc 63 2-allyl 1-(tert-butyl) 4-benzoyl-3-oxo-1,4-diazepane-1,2-dicarboxylate (63) To a flame-dried 20 mL glass vial were added imide 62 (150 mg, 0.471 mmol, 1.0 equiv) and THF (3 mL). The vial was cooled to –78 °C and a freshly prepared solution of LiHMDS (87 mg, 0.52 mmol, 1.1 equiv) in THF (1.7 mL) was added dropwise with stirring. The reaction mixture was stirred at –78 °C for 25 min, after which allyl cyanoformate (65 µL, 0.61 mmol, 1.3 equiv) was added dropwise. After 1 h at –78 °C, additional allyl cyanoformate (50 µL, 0.47 mmol, 1.0 equiv) was added. Following an additional 2 h of stirring, the reaction mixture was quenched by addition to 2 N aq. HCl. The solution was extracted with EtOAc (3x). Na2SO4 was added to the aqueous layer to accelerate separation between the phases. The combined organic extracts were dried over a mixture of Na2SO4 and NaHCO3 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (33% EtOAc/hexanes) to afford recovered starting imide 62 (102 mg, 0.320 mmol, 68%) and the title compound as a white solid (35.7 mg, 0.0887 mmol, 19% yield); 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 7.8 Hz, 2H), 7.54 – 7.44 (m, 1H), 7.42 – 7.35 (m, 2H), 5.91 (ddq, J = 16.4, 11.5, 5.6 Hz, 1H), 5.77 (s, 1H, first rotamer), 5.56 (s, 1H, second rotamer), 5.40 – 5.32 (m, 1H), 5.27 (t, J = 10.7 Hz, 1H), 4.78 – 4.67 (m, 2H), 4.40 – 4.15 (m, 1H), 4.15 – 3.77 (m, 2H), 3.32 – 3.13 (m, 1H), 2.05 – 1.92 (m, 2H), 1.52 (d, J = 16.1 Hz, 9H). Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates O H N N O Bz N n-BuLi, BzCl THF, –78→23 °C 249 N Ph Ph 67 68 1-benzoyl-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]diazepin-2-one (68) To a flame-dried 100 mL round bottom flask were added benzodiazepine 676 (462 mg, 1.96 mmol, 1.0 equiv) and THF (20 mL). The flask was cooled to –78 °C and n-BuLi (2.5 M in hexanes, 0.86 mL, 2.15 mmol, 1.1 equiv) was added dropwise. Immediately following addition, BzCl (296 µL, 2.55 mmol, 1.3 equiv) was added dropwise. The cooling bath was then removed, and the flask was allowed to warm to 23 °C over 30 min. Then, the reaction mixture was quenched with saturated aq. NH4Cl, and the resulting suspension was extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was combined with material from an earlier 0.212 mmol batch and purified by silica gel flash chromatography (33% EtOAc/hexanes) to afford the title compound as a pastel yellow solid (427 mg, 1.25 mmol, 58% combined yield); 1H NMR (400 MHz, CDCl3) δ 7.76 – 7.62 (m, 4H), 7.55 – 7.42 (m, 6H), 7.41 – 7.29 (m, 4H), 4.87 (d, J = 11.0 Hz, 1H), 4.02 (d, J = 11.1 Hz, 1H). H N O N H 71 1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one (71) Prepared according to a patent procedure.7 All characterization data matched those reported in the patent. Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates O H N N H 1) Boc2O, DMAP THF, 50 °C 2) n-BuLi, BzCl THF, –78 °C, 20 min Bz N 250 O N Boc 72 71 tert-butyl 5-benzoyl-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-1- carboxylate (72) To a flame-dried 500 mL round bottom flask were added benzodiazepanone 71 (5 g, 31 mmol, 1.0 equiv), Boc2O (7.39 g, 33.9 mmol, 1.1 equiv), and THF (310 mL). The reaction mixture was stirred at 50 °C for 5 h, after which TLC analysis indicated no conversion. DMAP (379 mg, 3.1 mmol, 0.1 equiv) was then added, followed by additional Boc2O (3.9 g, 18 mmol, 0.6 equiv). Following cessation of reaction conversion as judged by TLC analysis, the reaction mixture was concentrated under reduced pressure and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→20→100% acetone/CH2Cl2) to provide an intermediate carbamate containing an isomeric impurity. 6.3 g (24.0 mmol, 1.0 equiv) of this intermediate were dissolved in THF (130 mL) in a flame-dried 250 mL round bottom flask. The flask was cooled to –78 °C and n-BuLi (2.5 M in hexanes, 11.5 mL, 28.8 mmol, 1.2 equiv) was added dropwise with stirring. After 5 min, BzCl (3.6 mL, 31.0 mmol, 1.3 equiv) was added dropwise. After an additional 20 min at –78 °C, the reaction mixture was quenched with aq. NaH2PO4 and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure, and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→100% EtOAc/hexanes) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J = 8.1, 1.3 Hz, 1H), 7.69 – 7.64 (m, 2H), 7.50 – 7.45 (m, 1H), 7.43 – 7.38 (m, 2H), 7.30 (ddd, J = 8.2, 6.8, 2.1 Hz, 1H), 7.20 – 7.13 (m, 2H), 3.70 (t, J = 4.6 Hz, 2H), 3.01 (t, J = 4.6 Hz, 2H), 1.20 (s, 9H). Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates Bz N N Boc 72 O 251 N LiTMP THF, –78 °C then aq. workup Ph N Boc 76 tert-butyl 2-phenyl-1H-benzo[d]imidazole-1-carboxylate To a flame-dried 1-dram glass vial were added THF (0.4 mL) and TMP (27.5 µL, 0.163 mmol, 1.2 equiv). The vial was cooled to –78 °C and n-BuLi (2.5 M in hexanes, 65.2 µL, 0.163 mmol, 1.2 equiv) was added. The vial was then warmed to 0 °C in an ice bath. To a second flame-dried 1-dram glass vial were added benzodiazepanone 72 (50 mg, 0.136 mmol, 1.0 equiv) and THF (1 mL). The vial was cooled to –78 °C and the freshly prepared LiTMP solution was added dropwise. The reaction mixture was stirred for 15 min at –78 °C, whereafter allyl cyanoformate (18.9 µL, 0.177 mmol, 1.3 equiv) was added. After an additional hour of stirring, the reaction mixture was quenched with saturated aq. NH4Cl and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was combined with material from a second 0.136 mmol scale reaction conducted with LDA in place of LiTMP and purified by silica gel flash chromatography (15% EtOAc/hexanes) to provide the title compound as a fluorescent yellow film (11 mg, 0.037 mmol, 14% combined yield); 1H NMR (400 MHz, CDCl3) δ 8.07 – 8.02 (m, 1H), 7.82 – 7.77 (m, 1H), 7.66 – 7.60 (m, 2H), 7.50 – 7.44 (m, 3H), 7.42 – 7.35 (m, 2H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 154.0, 148.7, 142.7, 134.0, 132.6, 129.7, 129.3, 128.1, 125.1, 124.6, 120.3, 114.8, 85.4, 27.7. Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates A2.6 (1) 252 REFERENCES AND NOTES Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.; Stoltz, B. M. Enantioselective Synthesis of α-Secondary and α-Tertiary Piperazin-2-ones and Piperazines by Catalytic Asymmetric Allylic Alkylation. Angew. Chem. Int. Ed. 2015, 54, 179−183. (2) a) Gates, M. New synthesis of diazepam. J. Org. Chem. 1980, 45, 1675−1681. b) Hussenether, T.; Hübner, H.; Gmeiner, P.; Troschütz, R. Clozapine derived 2,3dihydro-1H-1,4- and 1,5-benzodiazepines with D4 receptor selectivity: synthesis and biological testing. Bioorg. Med. Chem. 2004, 12, 2625–2637. (3) Sun, A. W.; Hess, S. N.; Stoltz, B. M. Enantioselective synthesis of gemdisubstituted N-Boc diazaheterocycles via decarboxylative asymmetric allylic alkylation. Chem. Sci. 2019, 10, 788−792. (4) Reitter, B. E.; Sachdeva, Y. P.; Wolfe, J. F. Metalation of diazepam and use of the resulting carbanion intermediate in a new synthesis of 3-substituted diazepam derivatives. J. Org. Chem. 1981, 46, 3945–3949. (5) Behenna, D. C. et. al. Enantioselective Decarboxylative Alkylation Reactions: Catalyst Development, Substrate Scope, and Mechanistic Studies. Chem. Eur. J. 2011, 17, 14199–14223. (6) Bock, M. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber, D. F.; Freidinger, R. M.; Hirshfield, J.; Springer, J. P. Synthesis and resolution of 3-amino-1,3dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones. J. Org. Chem. 1987, 52, 3232– 3239. Appendix 2 – Attempts to Effect the Allylic Alkylation of Additional Diazepanone Substrates (7) 253 Albright, J. D.; Reich, M. F.; Sum, F.; Santos, E. G. D. Tricyclic diazepine vasopressin antagonists and oxytocin antagonists. US Patent US5733905A, March 31, 1998. (8) Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 254 CHAPTER 2 Progress Toward the Total Synthesis of Aleutianamine† 2.1 INTRODUCTION In 2019, Hamann and coworkers reported the isolation of the pyrroloiminoquinone alkaloid aleutianamine (78, Scheme 2.1.1) from the sea sponge Latrunculia (Latrunculia) austini found off the coast of the Aleutian Islands.1 Scheme 2.1.1. Aleutianamine and examples of related natural products. O HN O H N O H N HN HN S S N NH NH Br Br NH 80 Discorhabdin B Synthesis: Kita, 2002 O HN H N NH HN HN H N S OH S NH N Br O 83 Discorhabdin C Me 82 Atkamine Br 81 Makaluvamine F O H N Br † HO Synthesis: Kita, 1999 O Br O S O 79 Discorhabdin A 78 Aleutianamine H N HN S O Br O H N O 84 Discorhabdin D Syntheses: Yamamura, 1991; Kita, 1992; Heathcock, 1999 This research was performed in collaboration with Samir Rezgui and Hao Yu and is ongoing. Portions of this chapter are reproduced from a grant proposal submitted to the NSF. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 255 This compound was found to possess potent cytotoxicity against several human solid tumor cell lines, with exceptional selectivity for pancreatic cancer (25 nM IC50 against PANC-1). The structure of aleutianamine was elucidated by a combination of spectroscopic and density functional theory methods. Structurally, aleutianamine bears a highly fused heptacyclic ring system, which consists of a planar pyrroloiminoquinone unit, a bridged [3.3.1]bicycle, and another bridging thioaminal linkage. The pyrroloiminoquinone moiety of aleutianamine is shared with related natural products including the discorhabdins and makaluvamines. Specifically, discorhabdins A (79) and B (80) are proposed to have a biosynthetic relationship to aleutianamine (vide infra), as they also share the alkenyl bromide and thioaminal linkage. Makaluvamine F (81), which bears a tethered aryl bromide, may also be a biosynthetic precursor. Aleutianamine also bears some structural resemblance to atkamine (82) and other discorhabdins (e.g 83, 84). Pyrroloiminoquinones have been longstanding targets for total synthesis.2,3 The congested tertiary sulfide at C(5) of aleutianamine is a unique structural motif and presents a considerable synthetic challenge. The multi-bridged ring system of the natural product bears two stereocenters in addition to the tertiary sulfide and is highly strained due to extensive unsaturation. The unusual structure of aleutianamine, coupled with its potent biological activity, makes this compound an attractive synthetic target of considerable challenge. Aleutianamine is proposed to biosynthetically arise from makaluvamine F (81) by oxidation to p-quinone methide 85, which could then cyclize to hemiaminal 86 (Scheme 2.1.2).1 Reduction would lead to aleutianamine (78). Alternatively, either S-bromination of discorhabdin A (79) followed by HBr elimination or protonation of discorhabdin B (80) Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 256 would lead to sulfenium intermediate 87. Then, enamine-like reactivity (blue) would lead to cyclopropane 88, or a σ-bond shift (red) would afford tertiary carbocation 89. Both 88 and 89 could finally undergo an elimination reaction, which following cyclization would lead to common intermediate 86, one biosynthetic step away from aleutianamine (78). Scheme 2.1.2. Proposed biosynthetic routes to aleutianamine. O O H N HN HN S O H N HN NH Br HO O O HN Br O H N HN HN “Br ” N S N H Br Br Br O O Discorhabdin A (79) O Discorhabdin B (80) 87 O HN O H N HN S –H+ [H] O H N –H+ 86 N Br 88 H N –H S –HBr N Br Aleutianamine (78) 86 O S N HO Br 85 H N H N S [H] N NH Makaluvamine F (81) HN S S [O] O H N 78 S N Br 89 O We set out to develop a synthetic route to aleutianamine that was orthogonal to these biosynthetic proposals, as this exercise was expected to provide a unique opportunity for organic methods development and would lead to new strategies that could be applied to the synthesis of other pyrroloiminoquinone alkaloids. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 2.2 257 INITIAL RETROSYNTHETIC ANALYSIS In designing a total synthesis of aleutianamine, we recognized the need to orchestrate the introduction of reactive functional groups to minimize the potential for deleterious reactivity. The alkenyl bromide was identified as one such reactive moiety, and the introduction of this functional group was therefore planned for the latest possible stage. Additionally, while syntheses of the related discorhabdins have often involved early oxidation of an arene precursor to the quinone oxidation state,2 we imagined that delaying this oxidation would enable more diverse strategies for functionalizing the 6-membered core. Thus, retrosynthetically, aleutianamine (78) was expected to arise from keto-arene 90 by arene oxidation, enol triflate formation, and late stage triflate-halogen exchange.4 An olefination of vinylogous ester 91 followed by intramolecular thioaminal formation could produce 90. Primary aniline 91 could be disconnected by arene C–H amination—the relatively late-stage introduction of this electron-donating group would render earlier arene intermediates more stable and more easily accessible, although we recognized that the requisite amination would present a challenge. Additionally, we planned to construct the remaining bridged bicycle at this stage by a formal γ-amination of the vinylogous ester, inspired by a related sequence used to access Securinega alkaloids.5 These disconnections lead back to secondary aniline 92. The aryl C–N bond could be disconnected by a second C–H amination, now intramolecular, and tryptophol precursor 93 could be prepared by an asymmetric α-arylation of vinylogous ester 95 with aryl bromide 94. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 258 Scheme 2.2.1. Initial retrosynthetic analysis of aleutianamine. O HN OMe H N TsN S triflate-halogen exchange 78 90 SPG O olefination thioacetal formation N Br N O 91 OR OMe arene C–H amination TsN NH2 TsN S oxidation N OMe H N OMe Ts N SPGO SPGO arene C–H amination ketone γ-amination NH OH OR 92 93 OMe O H N asymmetric α-arylation PGS Br HO 2.3 OR + OR 95 94 STRATEGIES INVOLVING ENOLATE ARYLATION As the α-arylation of α-thioketone 95 is unprecedented, this transformation was first investigated in the context of a model system using α-thioketone 96 (Table 2.3.1). Despite the variation of solvent, palladium source, aryl halide, and base, formation of desired αarylated product 98 was never observed. Instead, γ-arylated product 97 was isolated in low yields. The use of (R)-SEGPHOS (99) as a ligand shut down the formation of 97.6 As vinylogous esters have been previously arylated to form quaternary centers under conditions similar to those tested,7 we hypothesize that the sulfide moiety of 96 inhibits the desired reaction. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 259 Table 2.3.1. Investigation of the α-arylation of model vinylogous ester 96.a O O O Pd source/ligand Ph–X, base solvent, 18 h MeS MeS MeS Ph O OMe OMe OMe Ph 96 98 97 not detected O PPh2 O PPh2 O (R)-SEGPHOS (99) entry solvent temp (°C) Pd source added ligand Ph–X base % SM % 97 1 1,4-dioxane 80 Pd(Pt-Bu3)2 — PhBr NaHMDS 34 16 2 1,4-dioxane 80 Pd(Pt-Bu3)2 — PhBrb NaHMDS 31 10 3 1,4-dioxane 60 Pd(Pt-Bu3)2 — PhBr NaHMDS 19 6.5 4 1,4-dioxane 100 Pd(Pt-Bu3)2 — PhBr NaHMDS 19 6.3 5 1,4-dioxane 80 Pd(Pt-Bu3)2 — PhBr LiHMDS 28 11 6 1,4-dioxane 80 Pd(Pt-Bu3)2 — PhBr LDA 26 21 7 1,4-dioxane 80 Pd(Pt-Bu3)2 — PhBr KHMDS 5.7 1 8 1,4-dioxane 80 Pd(Pt-Bu3)2 — PhBr NaH 4.9 1.6 9 PhCH3 60 Pd(dba)2 99 PhOTf NaOt-Buc ND 0 10 PhCH3 60 Pd(dba)2 99 PhOTf LDA ND 0 11 1,4-dioxane 80 Pd(Pt-Bu3)2 — PhOTf LDA ND 0 12 1,4-dioxane 80 Pd(Pt-Bu3)2 — PhCl LDA ND 0 13 1,4-dioxane 80 Pd(Pt-Bu3)2 — PhI LDA 11 15 14 PhCH3 60 Pd(dba)2 99 PhBr NaOt-Buc ND 0 15 PhCH3 60 Pd(dba)2 99 PhBr LDA ND 0 16 PhCH3 80 Pd(Pt-Bu3)2 — PhBr LDA 29 9.4 17 2:1 hexanes/PhCH3 80 Pd(Pt-Bu3)2 — PhBr LDA 22 8 18 DMF 80 Pd(Pt-Bu3)2 — PhBr LDA 27 3.3 19 2-MeTHF 80 Pd(Pt-Bu3)2 — PhBr LDA 27 12 20 n-Bu2O 80 Pd(Pt-Bu3)2 — PhBr LDA 15 trace 21 CPME 80 Pd(Pt-Bu3)2 — PhBr LDA 21 6.9 22 1,4-dioxane 80 Pd(dba)2 99 PhBr LDA ND 0 23 1,4-dioxane 80 Pd(dba)2 Pt-Bu3d PhBr LDA 28 13 [a] Unless otherwise indicated, reactions were conducted at 0.1 M concentration with 1 equiv 96, 1 equiv Ar– X, 1 equiv base, and 10 mol % Pd. Reactions with (R)-SEGPHOS were conducted with 12 mol % ligand. All yields were determined by 1H NMR analysis with 1,3,5-trimethoxybenzene as an internal standard. [b] 3 equiv PhBr. [c] 2 equiv NaOt-Bu. d 20 mol %. In order to circumvent the deleterious effect of the sulfur atom on α-arylation, an alternative order of events involving sulfide installation subsequent to α-arylation was envisioned. Corey reported an enantioselective phase transfer-catalyzed addition of nucleophiles to α-bromooximes,8 including an example of the addition of a sulfur nucleophile (Scheme 2.3.2). Treatment of oxime 100 with base led to intermediate Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 260 unsaturated nitrosamine 102, which underwent addition of PhCOS– catalyzed by chiral ammonium salt 101 to afford enantioenriched α-thioketone 103. Scheme 2.3.2. Corey’s addition of a sulfur nucleophile to an α-bromooxime. H Br Ph Br NOH 100 101 (15 mol %) PhCOSNa, TMG H2O/PhF, –20 °C N Ph O PhCOS Ph O H N 80% yield, 81% ee 102 N O 103 101 An appropriate tryptophol-derived aryl bromide was necessary for the α-arylation reaction toward a substrate to which Corey’s chemistry could be applied. The Bartoli indolization was first examined as a method to prepare indole 105, which could potentially be advanced to a tryptamine (Scheme 2.3.3A). Aryl fluoride 104 underwent a precedented SNAr reaction with NaOMe,9 but subjection of the product to Bartoli indolization conditions led only to nonspecific decomposition despite its similarity to known substrates.10 Instead, known arylhydrazine 10611 underwent a Fischer indolization with 2,3dihydrofuran,12 and subsequent bis-silylation by repeated deprotonation and silyl chloride addition afforded fully protected aryl bromide 107. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 261 Scheme 2.3.3. Synthesis of an indole-derived aryl bromide coupling partner. A) Unsuccessful Bartoli Indolization. Br Br 1. NaOMe, MeOH, 23 °C X 2. vinylMgBr (3 equiv), THF, –46 °C NO2 N H OMe F 105 104 not detected B) Fischer Indolization and subsequent bis-silylation. OTBS Br 1. 2,3-dihydrofuran, H2SO4, DMA/H2O, 60 °C NHNH2 OMe Br 2. n-BuLi, TBSCl, then n-BuLi, TBSCl, THF, –78→23→–78→23 °C 106 N TBS OMe 11% over 2 steps 107 Satisfyingly, treatment of aryl bromide 107 with known vinylogous ester 108,13 base, and Pd(Pt-Bu3)2 led to the formation of α-arylated product 109 in 43% yield (Scheme 2.3.4).14 The silyl-protected indole was found to be optimal for this transformation—a tosyl indole led to a complex reaction profile, while a Boc-protected indole led to acylation of the enolate of vinylogous ester 108. Unfortunately, α-bromination of arylated ketone 109 could not be effected under any conditions tested, with aromatized or γ-brominated products being isolated. Scheme 2.3.4. Enolate acylation and subsequent unsuccessful bromination. O OMe Oi-Bu TBS N 108 OMe TBS N , LiHMDS O Pd(Pt-Bu3)2 (5 mol %) PhCH3, 70 °C Br 43% yield TBSO 107 TBSO OMe TBS N conditions X Br TBSO 110 not detected O Oi-Bu 109 Oi-Bu Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 262 As access to bromoketone 110 would be necessary in order to install the sulfide by Corey’s method, the synthetic plan depicted in Scheme 2.2.1 was abandoned at this relatively early stage. The challenges encountered with Pd-catalyzed arylation of sulfidecontaining substrate 96 and the facile nature of the aromatization of the cyclohexenone moiety of 109, did, however, inform later synthetic plans—the sulfide installation was delayed to a later stage, and care was taken to introduce/construct the 6-membered carbocycle in a lower oxidation state to prevent aromatization. 2.4 2ND-GENERATION RETROSYNTHESIS At this stage, a revised retrosynthetic analysis of aleutianamine that would circumvent the issues encountered with enolate arylation strategies was envisioned (Scheme 2.4.1). As in the first retrosynthesis, aleutianamine was planned to arise from keto-arene 90, which could be prepared by olefination of vinylogous ester 91 and thioaminal formation. In contrast to the earlier synthetic plan, however, vinylogous ester 91 was disconnected to saturated hydroxyketone 111 by sulfide installation via bridgehead carbocation chemistry (demonstrated in a model system, see Appendix 5) and oxidation. This approach would enable a wider array of strategies for construction of the bridged bicycle, including methods that would not tolerate a sulfide. Additionally, as the feasibility of installing N(9) (aleutianamine numbering), the protected aniline group of pentacycle 111, by late-stage arene amination was uncertain, strategies involving precursors both with and without this nitrogen atom were investigated. The bridged bicyclic ketone of pentacycle 111 could be traced back either to 4quinolone 112 by a formal [3+3] cycloaddition approach,15 or to a protected derivative of Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 263 1,2-diketone 113 by halogenation and an intramolecular Barbier–type addition. Both of these intermediates would arise from tricyclic aniline 114. Scheme 2.4.1. Revised retrosynthetic analysis of aleutianamine. O HN OMe H N TsN S triflate-halogen exchange 78 oxidation N 112 OMe O N 91 OR O 9 OH sulfide installation NHR TsN NHR TsN N OMe O formal [3+3] OMe SPG O olefination N 90 Br NH2 TsN thioacetal formation S oxidation N OMe H N ketone 1,2addition NHR TsN 111 N OMe O NHR TsN 113 O NH 114 2.5 PREPARATION OF A VERSATILE TRICYCLIC ANILINE As aniline 114 is essentially a reduced and protected variant of tricyclic pyrroloiminoquinones already well-studied in the discorhabdin and makaluvamine literature,2,3 we set out to intercept a pyrroloiminoquinone intermediate and study its reduction. Methoxypyrroloiminoquinone 117 was prepared by the method of Kita from vanillin (115) via dimethoxyindole 116 (Scheme 2.5.1A).2b Unfortunately, addition of phthalimide to afford derivative 118, which would obviate later aniline protection, was unsuccessful (Scheme 2.5.1B). Instead, a substitution reaction with ammonium chloride afforded known aminopyrroloiminoquinone 119, previously accessed by White.16 While addition of NaBH4 did lead to rapid disappearance of the deep purple color of 119, selective Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 264 methylation of the resulting putative phenoxide could not be effected, and the reduced intermediate was not stable to air. Scheme 2.5.1. Attempts to reduce a pyrroloiminoquinone to aniline 120. A) Kita’s synthesis of pyrroloiminoquinone intermediate 117. O OMe OH 5 steps OMe H N O 5 steps OMe N 116 Vanillin (115) OMe TsN 117 B) Attempts to access a reduced dianiline from pyrroloiminoquinone 117. O O OMe TsN KNPhth, PhthNH X MeOH or DMF, 23 °C NPhth TsN N N 117 118 O O OMe TsN NH4Cl (10 equiv) OMe NH2 TsN MeOH, 40 °C N 117 49% yield NaBH4, MeOH, 23 °C X then methylating agent NH2 TsN N NH 119 120 Due to the challenges associated with reducing known pyrroloiminoquinone 119 to a stable arene intermediate, we instead opted to develop a strategically unique synthesis of tricyclic aniline 114 (Scheme 2.5.2). Instead of the risky C–H amination proposed in our first retrosynthesis (i.e., 93→92), the secondary aniline could arise from an intramolecular C–N cross coupling of a halogenated tryptamine 121. This tryptamine would be prepared by either Fischer indolization of arylhydrazine 122 or Larock indolization of dianiline derivative 123. Early experiments revealed that the preparation of a Fischer indolization substrate bearing the additional N(9) was impractical, so this transformation was only explored in the context of des-amino arene 122. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 265 Scheme 2.5.2. Strategies envisioned for the construction of aniline 114. Fischer indolization OMe OMe NHR TsN C–N coupling H 2N 9 NHR TsN OMe H N 122 X OMe NH 114 X H 2N 121 Larock indolization RHN NHR Y X 123 Investigation of the Larock indolization of 123 led to the development of a powerful cascade cyclization that afforded a derivative of tricycle 114 in a single step. While the advancement of the resulting dianiline intermediate did not bear fruit in the context of the total synthesis of aleutianamine, efforts are ongoing to employ this Larock cascade in the syntheses of other pyrroloiminoquinone alkaloids. This research is outside the scope of this thesis chapter. An arylhydrazine substrate for Fischer indolization toward tricycle 114 was first prepared by Pd-catalyzed Buchwald–Hartwig coupling of aryl iodide 124 with benzophenone hydrazone under Eilbracht’s conditions (Scheme 2.5.3),17 as this strategy would circumvent the intermediacy of a potentially explosive arenediazonium salt. The Fischer indolization of benzophenone arylhydrazones was reported by Buchwald,18 but treatment of hydrazone 125 with 2,3-dihydrofuran and acid led to nonspecific decomposition. Desired tryptophol 126 was not detected. Indeed, Buchwald and coworkers noted that the C(2)-unsubstituted indoles derived from aldehydes were unstable under their reaction conditions.18b Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 266 Scheme 2.5.3. Attempted Fischer indolization of a hydrazone derivative. N OMe I NH2 Ph Ph Pd(OAc)2 (5 mol %), (±)-BINAP (10 mol %), NaOt-Bu OMe Ph Ph N H N 2,3-dihydrofuran, PTSA X EtOH, 80 °C PhCH3, 100 °C Cl 124 54% yield H N OMe Cl 125 Cl HO 126 not detected Fischer indolization was instead performed on a free arylhydrazine (Scheme 2.5.4A). Hydrochloride salt 127 was available in 1 step (diazotization and reduction) by a patent procedure.19 Satisfyingly, treatment with 2,3-dihydrofuran and excess acid in a mixture of water and dimethylacetamide afforded desired tryptophol product 126. While the 29% yield of tryptophol 126 from 127 could not be increased, our attention was drawn to Schmidt’s report that terminal methylation of arylhydrazines could facilitate Fischer indolization (Scheme 2.5.4B).20 Copper-catalyzed cross coupling of aryl bromide 128 with hydrazine derivative 129 was accomplished under the conditions developed by Singer and successfully employed by Schmidt using ligand 130,21 and Boc cleavage yielded methylated arylhydrazine salt 131. Interestingly, while the Fischer indolization of 131 now proceeded to afford tryptophol 126 at ambient temperature, the yield of the product was not improved. Moving forward, we opted to continue employing the classical Fischer indolization of arylhydrazine salt 127, since no chromatography was required in this sequence prior to indolization. Thus, despite the low indolization yield, tryptophol 126 could be prepared in the multigram quantities necessary for synthetic route development. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 267 Scheme 2.5.4. Access to desired tryptophol 126 by Fischer indolization. A) Successful Fischer indolization with 2,3-dihydrofuran. H 3N OMe OMe H N Cl H2SO4, 2,3-dihydrofuran DMA/H2O 60 °C Cl 29% yield 127 H N Cl HO known in 1 step from commercial material 126 B) Low-temperature Fischer indolization of an N-methyl substrate. OMe Br 1. 129, CuI (5 mol %), 130 (6 mol %), K2CO3, DMSO, 80 °C MeH2N H N OMe Boc H 2N 2. TMSCl, MeOH, 0→23 °C Cl 75% over 2 steps OMe 23% yield H N Cl Me O N OH NH Me Cl HO Me 129 131 128 H2SO4, 2,3-dihydrofuran DMA/H2O 23 °C Cl N 130 126 Advancement of tryptophol 126 to a derivative of key tricyclic aniline 114 would require protection of the indole and conversion of the tryptophol to a tryptamine (Scheme 2.5.5A). Simultaneous tosylation of the indole and primary alcohol was followed by SN2 displacement of the primary tosylate with Boc2NH to afford protected tryptamine 132. Biphasic tosylation conditions with a tetrabutylammonium phase transfer catalyst were uniquely effective for the bis-tosylation of 126; NaH in THF led to monotosylation of the indole while Et3N and DMAP in CH2Cl2 led to monotosylation of the alcohol. Other sets of conditions tested led only to nonspecific decomposition. Treatment of imide 132 with TFA led to deprotection to afford free tryptamine 133. While this sequence enabled access to sufficient quantities of 133 for the investigation of downstream chemistry, the yield of the bis-tosylation step was inconsistent and dropped sharply at a higher scale. An improved sequence to access tryptamine 133 was Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 268 therefore developed (Scheme 2.5.5B). Azidation of tryptophol 126 by a Mitsunobu reaction provided an intermediate azide, the indole was tosylated under biphasic conditions, and a final Staudinger reduction provided primary amine 133 in moderate yield over 3 steps. Scheme 2.5.5. Advancement of tryptophol 126 to a protected tryptamine. A) Initial advancement to a primary tryptamine. OMe OMe H N 1. TsCl, NaOH, Bu4NHSO4, CH2Cl2/H2O, 23 °C Cl OMe Ts N Ts N TFA 2. Boc2NH, Cs2CO3, DMF, 80 °C Cl CH2Cl2, 23 °C Cl 69% yield HO 126 58% over 2 steps Boc2N 132 H 2N 133 B) Improved sequence to access a primary tryptamine. OMe H N 1. DIAD, PPh3, DPPA, THF, 0→23 °C 2. TsCl, Bu4NHSO4, NaOH, CH2Cl2/H2O, 23 °C OMe Ts N 3. PPh3, H2O, THF, 23 °C Cl Cl 52% over 3 steps HO 126 H 2N 133 Conditions for the intramolecular C–N coupling of the amine and aryl chloride of 133 were then evaluated (Table 2.5.6). The array of methods at our disposal was limited by the challenge associated with oxidative addition into an aryl chloride rather than a more reactive aryl bromide or iodide. Buchwald–Hartwig coupling using LiHMDS as a base provided only trace product (entry 1).22 Other nickel-23 or copper-catalyzed24 methods failed to deliver an appreciable quantity of the desired product (entries 2/3). Control experiments revealed that heating tryptamine 133 with NaOt-Bu led to detosylation, while heating with LiHMDS led to tosyl group migration to the primary amine. Optimization efforts were thereafter limited to the use of weak bases. Buchwald–Hartwig coupling in dioxane using either K3PO4 or Cs2CO3 as the base led to slow formation of tricycle 134, but the sluggish nature of the reactions (a likely result of low inorganic base solubility in Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 269 dioxane) precluded their use (entries 4/5). Satisfyingly, the copper-catalyzed Ullman-type coupling of aryl chlorides developed by Ma afforded 134 in 51% yield with the use of oxalamide ligand 135 (entry 6).25 Table 2.5.6. Evaluation of the intramolecular C–N coupling of 133.a OMe OMe Ts N metal source, ligand, base OMe MeO TsN solvent, temp Cl NH H 2N 133 134 Ar OMe O OMe PCy2 N H 135 OMe 2 BrettPhos Ar = 2,4,6-(i-Pr)3-Ph temp (°C) reagents entry solvent 1 1,4-dioxane 100 Pd(OAc)2 (2 mol %), BrettPhos (4 mol %), LiHMDS trace 2 PhCH3 100 Ni(COD)2 (5 mol %), DPPF (10 mol %), NaOt-Bu –– 3 NMP 120 Cu2O (5 mol %), NaOt-Bu trace 4 1,4-dioxane 100 BrettPhos Pd G4 (2 mol %), BrettPhos (2 mol %), K3PO4 NDb 5 1,4-dioxane 100 BrettPhos Pd G4 (2 mol %), BrettPhos (2 mol %), Cs2CO3 NDb 6 DMSO CuI (5 mol %), 135 (10 mol %), K3PO4 51c 7 1,4-dioxane 100 BrettPhos Pd G4 (4 mol %), BrettPhos (4 mol %), K3PO4, 18-C-6 33 8 t-BuOH 70 BrettPhos Pd G4 (2 mol %), BrettPhos (2 mol %), K3PO4 –– 9 t-BuOH 100 BrettPhos Pd G4 (2 mol %), BrettPhos (2 mol %), K3PO4 63 10 t-BuOH 100 BrettPhos Pd G4 (2 mol %), BrettPhos (2 mol %), Cs2CO3 60 11 t-BuOH 100 BrettPhos Pd G4 (5 mol %), BrettPhos (5 mol %), K3PO4 90 120 % yield [a] All reported yields are isolated yields unless otherwise noted. [b] Slight conversion to the desired product was observed by LC–MS analysis of the crude reaction mixture after 18 h, but the reactions were not driven to completion. [c] Yield on a 0.396 mmol scale. Yield decreased to 38% on a 1.50 mmol scale. Unfortunately, this yield decreased at higher scales, so optimization efforts were continued. Addition of 18-crown-6 to a Buchwald–Hartwig coupling employing K3PO4 did accelerate the reaction, but 134 was obtained in only 33% yield (entry 7). Instead, to improve base solubility, t-BuOH was tested as a solvent. The reaction did not proceed at 70 °C (entry 8) but conducting the coupling at 100 °C in a sealed tube afforded 134 in synthetically useful yields (entries 9/10), with K3PO4 slightly outcompeting Cs2CO3 as a base. Raising the palladium loading to 5 mol % improved the consistency of the reaction and increased the yield to 90%. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 2.6 270 STRATEGIES FOR BRIDGED BICYCLE FORMATION Now enabled by a scalable route to tricyclic aniline 134, the formation of the bridged [3.3.1]bicycle of the natural product was investigated. First, we set out to advance aniline 134 to a tetracyclic quinolone that could undergo a formal [3+3] cycloaddition (Scheme 2.6.1). Aniline 134 was condensed with trimethyl orthoformate and Meldrum’s Acid to yield bright yellow adduct 136. The cyclization of related adducts by pyrolysis is known to afford 4-quinolones.26 Pyrolysis of 136 led only to nonspecific decomposition, while treatment with TiCl4 led to inefficient reversion to aniline 134. Aniline 134 was instead heated with methyl propiolate, inducing an aza-Michael reaction to yield “push-pull” olefin 138 in high yield. Ultimately, cyclization did proceed in Eaton’s Reagent at 60 °C, but concomitant migration of the indole tosyl group to the C(2) position was observed and the product was only isolated in 34% yield. To our knowledge, the migration of a tosyl group from an indole nitrogen to C(2) is not precedented. Other indole protecting groups that were expected to be less likely to migrate were briefly evaluated (see Appendix 5). A Piv group spontaneously migrated to the primary amine of the Piv-protected derivative of 133, while an N-allyl indole derivative of “push-pull” olefin 138 did not survive the harsh conditions of the cyclization. This formal [3+3] approach was therefore abandoned in favor of a ketone 1,2-addition strategy for the construction of the [3.3.1]bicycle. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 271 Scheme 2.6.1. Advancement of tricycle 134 to a tetracyclic quinolone. OMe OMe HC(OMe)3, Meldrum’s Acid DMF, 80 °C TsN NH OMe TsN ∆ or TiCl4 X 72% yield TsN O N 134 N O 137 O not detected O O Me Me 136 OMe OMe TsN methyl propiolate TsN Eaton’s Reagent DMF, 80 °C NH 134 88% yield OMe 60 °C N HN Ts O N CO2Me 34% yield 138 139 • Unusual Tosyl group migration Early model studies revealed that assembly of a 1,2-diketone system and Friedel– Crafts-type addition of the arene into one of the ketones was not feasible. A strategy involving intramolecular Barbier-type addition was therefore pursued. This strategy would necessitate tethering a 6-membered ketone to the aniline nitrogen. The aza-Michael reaction was identified as an optimal tactic for this C–N bond formation. Reports of the aza-Michael addition of secondary anilines into α,β-unsaturated carbonyl compounds bearing β-substitution are relatively scare. Cyclohexene (140) was used as a model enone for this addition, as it was anticipated that some optimization would be necessary. While heating aniline 134 with enone 140 in DCE did lead to trace product (by LC–MS analysis), we were unable to drive this reaction to a higher degree of conversion (Table 2.6.2, entry 1). The addition of Lewis acids also failed to promote the reaction (entries 2–4). While HFIP is known to promote the addition of anilines into acyclic Michael acceptors,27 it did not effect the coupling of 134 and 140 (entry 5). A set of DMAP- Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 272 catalyzed conditions utilized for aza-Michael additions of indoline also failed to promote the desired reaction (entry 6).28 Table 2.6.2. Unsuccessful aza-Michael addition of aniline 134 into cyclohexenone.a O OMe OMe TsN TsN 140 conditions N O NH 134 141 entry solvent temp (°C) additive equiv enone result 1 DCE 80 N/A 10 traceb 2 CH2Cl2 23 BF3•OEt2 5 traceb 3 CH2Cl2/Et2O 23 Cu(OTf)2 (20 mol %) 5 decomp 4 CH2Cl2 23 TiCl4 5 trace 5 HFIP 60 N/A 5 NR 6 MeCN 23 DMAP 5 NR [a] Reaction outcomes were determined by LC–MS analysis. [b] Reaction led to a complex mixture containing unreacted 134 and nonspecific decomposition products. Realizing that additional optimization would be necessary, we directed our efforts to a model system, utilizing tetrahydroquinoline (142) as a nucleophile in order to preserve valuable material (Table 2.6.3). Conducting the reaction at elevated temperature in aqueous Na2CO3 led to only slight conversion but did enable the isolation and characterization of an authentic standard of product 143 in 4% yield (entry 1). Interestingly, heating 142 and 140 in AcOH, with or without a CuI additive, led to the formation of a different major product (entries 2/3). This product was not fully characterized, although LC–MS analysis indicated that it may be an isomer of desired product 143. Lee reported an aza-Michael addition of anilines to acyclic Michael acceptors catalyed by CuCl and NHC or phosphine ligands.29 Although 5 ligands were tested (entry 4, 144–148, Scheme 2.6.4), no reactivity was observed in the system at hand. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 273 Table 2.6.3. A model system for aza-Michael addition.a O 140 conditions N O NH 142 143 entry solvent temp (°C) additive equiv enone result 1 H 2O 80 Na2CO3 1 4% yieldb 2 AcOH 75 N/A 2.5 unidentified major pdt 3 AcOH 75 CuCl 2.5 unidentified major pdt 4c PhCH3 23 CuCl, 144–148, KOt-Bu 1 NR 5 PEG400 50 RuCl3 (5 mol %) 1 trace 6 Et3N/HOAc 23 N/A 5 41% yieldb [a] Reaction outcomes were determined by LC–MS analysis unless otherwise noted. [b] Isolated yields. [c] 7 mol % CuCl, 7 mol % ligand, 14 mol % KOt-Bu. Scheme 2.6.4. Ligands tested in entry 4 of Table 2.6.3. Me NCy Me P Me PPh2 •BF4 CyN P Me n-Bu P n-Bu Fe PPh2 n-Bu 144 145 ICy•BF4 (R,R)-Me-DuPhos 146 Ph2P PPh2 147 148 DPPF DPPP The RuCl3-catalyzed reaction conditions reported by Wang led to only trace product (entry 5). Finally, to our delight, when 142 and 140 were combined in a mixture of triethylamine and acetic acid, as described for basic amines and primary anilines by Verma et al., the desired tertiary aniline 143 was obtained in 41% isolated yield (entry 6).30 Intriguingly, this model aza-Michael addition appeared qualitatively to proceed to a higher degree of conversion at lower reaction temperatures, and an excess of cyclohexenone was necessary to drive the reaction forward. Around the same time that these experiments were conducted, a report was published by Condakes detailing the Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 274 equilibrium nature of related aza-Michael additions of π-excessive heterocycles into βsubstituted unsaturated esters catalyzed by base.31 The reactions reported by Condakes appear to exhibit a similar thermodynamic profile to the formation of 143 –– increasing the reaction temperature led to a more reactant-favored equilibrium. The ionic liquid-promoted aza-Michael reaction to form model compound 143 translated well to tricycle 134 (Scheme 2.6.5). Aza-Michael reaction with cyclohexenone was followed by selective ortho-bromination of the aniline with NBS to afford model cyclization substrate 149. Scheme 2.6.5. Preparation of a model Barbier addition substrate. OMe OMe 1. cyclohexenone, Et3N/AcOH, 23 °C TsN 2. NBS, CH2Cl2, 23 °C NH 134 42% over 2 steps TsN Br N O 149 With model substrate 149 in hand, we evaluated conditions for a Barbier-type addition of the aryl bromide into the cyclic ketone (Table 2.6.6). Lithium-halogen exchange did not provide the desired tertiary alcohol 150––we hypothesize that the generated aryllithium species could be protonated intramolecularly to form an enolate (entry 1). Formation of an aryl Grignard species could not be effected (entries 2–3). While the Nozaki–Hiyama–Kishi reaction is generally selective for addition into aldehydes, the use of forcing reaction conditions was anticipated to provide an opportunity to achieve the desired ketone addition. Subjecting bromide 149 to standard NHK conditions at elevated temperature led to the formation of trace amounts of desired alcohol 150, but primarily led to retro-aza-Michael fragmentation to tricycle 134 with accompanying protodebromination (entry 4). The use of neocuproine as a ligand for nickel was hypothesized to promote Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 275 reactivity under milder conditions,32 but only protodebromination was observed in this case (entry 5). Switching the catalyst from nickel to palladium and employing a stoichiometric variant of Yamamoto’s conditions for the intramolecular addition of aryl bromides to ketones resulted, satisfyingly, in the formation of desired alcohol 150 (entry 6).33 This reaction was then conducted at a larger scale with catalytic palladium (entry 7)—while the low yield obtained suggests poor or no catalyst turnover despite the addition of 1-hexanol (used by Yamamoto as a stoichiometric reductant), a sufficient quantity of 150 was obtained to confirm the structure of the product. We therefore decided to move forward with a Pd-mediated approach to construction of the azabicyclononane moiety and set out to prepare an analogue of cyclization substrate 149 in a higher oxidation state. Table 2.6.6. Barbier-type addition into a model ketone.a OMe OMe OMe TsN conditions Br N O 149 OMe TsN TsN TsN OH + N 150 + N O NH 141 134 entry conditions result 1 t-BuLi, THF, –95 °C partial protodebromination 2 i-PrMgCl•LiCl, THF, –78 °C no Mg–Br exchange 3 4 Mg0, THF, 50 °C NiCl2 (0.4 equiv), CrCl2, DMF, 125 °C NR 150 (trace) + 134 (major) 5 NiCl2 (0.4 equiv), CrCl2, neocuproine, DMF, 23 °C 141 (major) 6 Pd(OAc)2 (1 equiv), PCy3 (2 equiv), K2CO3, DMF, 135 °C 150 (major) 7 Pd(OAc)2 (0.3 equiv), PCy3 (0.4 equiv), K2CO3, 1-hexanol, DMF, 135 °C 150 (17% yield) + 134 (29% yield)b [a] Reaction outcomes were determined by LC–MS analysis unless otherwise noted. [b] Isolated yields. An additional functional handle could be introduced in the desired oxidation state as a ketal, which would obviate later redox manipulations. Toward this aim, 1,2-dione 151 was subjected to known monoketalization (Scheme 2.6.7).34 Subsequent desaturation of ketone 152 was complicated by the propensity of desired enone 153 to undergo Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 276 aromatization by elimination of methanol. While IBX oxidation, selenide installation and selenoxide elimination, and Saegusa–Ito oxidation all failed to deliver the desired enone, the copper-catalyzed method developed by Dong provided enone 153 in modest yield.35 Desaturation with N-t-butylbenzenesulfinimidoyl chloride also provided the desired product, but Dong’s conditions were favored due to the ready availability of the reagents. Scheme 2.6.7. Preparation of a ketal-bearing Michael acceptor. O O O 151 44% yield O CuTC (20 mol %), CyPPh2 (20 mol %), t-BuOOt-Bu OMe OMe TMSCl MeOH, 23 °C OMe OMe PhH, 80 °C 39% yield 152 153 Subsequent aza-Michael addition of aniline 134 and bromination proceeded smoothly to afford Barbier addition substrate 154 (Scheme 2.6.8). Unfortunately, Yamamoto’s conditions failed to provide tertiary alcohol 155 despite the successful application of this method toward the cyclization of model substrate 149. Scheme 2.6.8. Preparation of an oxidized intramolecular Barbier addition substrate. OMe OMe 1. 153, Et3N/AcOH, 23 °C 2. NBS, CH2Cl2, 23 °C TsN 75% over 2 steps OMe TsN Br N TsN N NH 134 O Pd(OAc)2, PCy3, K2CO3 X DMF, 135 °C 154 OMe OMe OH OMe OMe 155 not detected While several additional sets of Ni-catalyzed conditions were tested, providing only trace cyclized product,36 the simple conditions developed by Reissig for Pd-catalyzed addition of aryl iodides to ketones led to efficient cyclization of aryl bromide 154 (Scheme 2.6.9).37 Interestingly, however, the major product of this cyclization was found to be azabicyclo[3.2.2]nonane 156, arising from formal addition of the arene to the ketal instead of the ketone. It is uncertain if this addition occurs directly to the ketal or if 156 is formed Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 277 by addition of an arylpalladium species to the ketone with concomitant semipinacol rearragement of a [3.2.1]bicycle. In any case, allowing ketone 156 to stand overnight in CDCl3 (likely containing catalytic acid formed by decomposition, and concievably containing at least 1 equivalent of water) effected complete rearrangement to desired bicyclic ketone 157 bearing a bridgehead alcohol. Alternatively, rearrangement of 156 to bicyclic ketal 155 was promoted by acidic methanol. Finally, employing a stoichiometric quantity of Pd(PPh3)4 in the Barbier-type addition rather than using Et3N as a stoichiometric reductant directly afforded bicyclic ketal 155, the initially anticipated product. The structure of 155 was confirmed by x-ray crystallography. Scheme 2.6.9. Cyclization of bromoarene 154 and unexpected rearrangements. OMe OMe TsN Pd(PPh3)4 (15 mol %), Et3N (10 equiv) Br N O OMe OMe 154 TsN OMe DMF, 110 °C O N 62% yield 156 OMe TsN OH CDCl3 OMe O 23 °C, 16 h N TsN 157 OMe ` OMe O N TMSCl TsN OH OMe OMe MeOH, 23 °C 156 46% yield N 155 OMe OMe TsN TsN Pd(PPh3)4 (1.2 equiv) Br N 154 O DMF, 110 °C OMe OMe 86% yield N 155 OH OMe OMe • Unexpected [3.2.2]bicycle Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 278 With desired pentacyclic intermediate 155 in hand, strategies were evaluated for the installation of the 1,3-dicarbonyl equivalent (e.g., 158, Scheme 2.6.10A) that would be required for eventual formation of the alkenyl bromide of aleutianamine. In general, elaboration of a saturated ketone or enone to a 1,3-dicarbonyl equivalent is challenging to perform directly, with Wacker-type oxidations failing in all but the simplest cases (see Appendix 5 for preliminary evaluation of a relevant oxidation). We first imagined that a vinylogous ester could be installed by allylic oxidation of an enol ether (Scheme 2.6.10B).38 Thus, ketal 155 was treated with TMSOTf and i-Pr2NEt, leading to silylation of the tertiary alcohol and elimination of the ketal to afford methyl enol ether 160. Unfortunately, under selenium- or hypervalent iodine-mediated allylic oxidation conditions, nonspecific decomposition was observed with no detectable trace of the desired compound 161. Scheme 2.6.10. Attempted allylic oxidation of pentacycle 160. A) General strategy. OMe OMe OMe TsN TsN N TsN OH OH OMe OMe OH O 155 O N N 158 O 159 Br B) Attempted access to a vinylogous ester by allylic oxidation. OMe TsN N 155 OMe OMe OH OMe OMe TMSOTf, i-Pr2NEt TsN TsN OTMS OMe CH2Cl2, 23 °C 69% yield N 160 OTMS OMe allylic [O] X N nonspecific decomposition 161 O in all cases examined not detected Another demonstrated, albeit lengthier strategy to accomplish the desired transformation involves desaturation of a ketone followed by thiol conjugate addition and further desaturation to a vinylogous thioester, another 1,3-diketone equivalent. Precedent Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 279 for this sequence was reported by d’Angelo (Scheme 2.6.11A), wherein sulfide 162 was converted to vinylogous thioester 163 with NCS, and subsequent treatment with NaOMe and acidic hydrolysis afforded 1,3-diketone 164.39 Similarly, Kakisawa reported the desaturation of sulfide 165 with concomitant ketal hydrolysis (Scheme 2.6.11B).40 The product 166 underwent direct alkaline hydrolysis to diketone 167. In our system, ketal 155 underwent hydrolysis to the ketone under biphasic conditions, double silylation to afford an intermediate TMS enol ether that was surprisingly stable to silica, and Saegusa–Ito oxidation to afford enone 168 (Scheme 2.6.11C). Scheme 2.6.11. Attempted β-oxidation by a thiol conjugate addition approach. A) Precedent for desaturation of a β-thioketone and subsequent solvolysis (d’Angelo, 1994). O CO2Me O Et NCS CO2Me Et 1. NaOMe, MeOH, reflux 2. HCl, H2O/THF, 22 °C CCl4, 0 °C PhS 82% yield 162 O 59% over 2 steps PhS CO2Me Et O 163 164 B) Precedent for an analogous transformation of a ketal (Kakisawa, 1987). O O O O NCS, H2O KOH H2O, reflux CCl4, rt 165 89% yield SPh SPh 166 99% yield 167 O C) Efforts to prepare a vinylogous thioester by a 1,4-addition/oxidation sequence. OMe OMe TsN N OH OMe OMe TsN 1. TFA, CH2Cl2/H2O, 23 °C N 65% over 3 steps 155 168 OMe OMe TsN OTMS O N TsN various halogenating agents X • arene halogenation and decomposition 169 OTMS O 2. TMSOTf, i-Pr2NEt, CH2Cl2, 23 °C 3. Pd(OAc)2, DMSO, 28 °C SPh • the analogous ketal exhibited similar reactivity OTMS O N 170 SPh not detected PhSH, cat. Et3N CCl4, 23 °C >99% yield Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 280 Conjugate addition of PhSH afforded sulfide 169. Unfortunately, treatment of 169 or the derived ethylene ketal with various halogenating reagents did not effect the necessary desaturation to vinylogous thioester 170, unlike in the systems of d’Angelo and Kakisawa. While the evaluation of further reaction conditions could indeed lead to a synthetically useful derivative of 1,3-dicarbonyl 158, at this point, we had several concerns about the synthetic route leading up to sulfide 169. Namely, the route was highly linear, proceeding in a longest linear sequence of 13 steps. Although the feasibility of bridgehead sulfide installation had been demonstrated in a model system (see Appendix 5), we realized that the plan to subject a late-stage intermediate to the harsh carbocation chemistry necessary for this transformation bore excessive risk. Additionally, having already required 13 steps to access an intermediate lacking both the bridgehead sulfide and the alkenyl bromide of the natural product, the synthetic sequence would probably become inelegantly lengthy over the course of the installation of these challenging motifs. We therefore conceived of a 3rd-generation retrosynthetic analysis of aleutianamine. 2.7 3rd-GENERATION RETROSYNTHESIS An ideal synthesis of aleutianamine would: 1) be convergent and enable rapid assembly of structural complexity, 2) provide a robust strategy for the construction of the tertiary bridgehead sulfide moiety of the natural product, and 3) take advantage of the scalable early-stage chemistry already developed during our previous synthetic efforts. A retrosynthetic analysis that would meet all of these requirements could, like our previous strategies, invoke a late-stage arene oxidation, but now, aleutianamine would be tracked back to doubly unsaturated thiolactone 171, which could undergo reduction and ring closure (Scheme 2.7.1). Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 281 Structural simplification of hexacycle 171 by disconnection of the acyclic aniline and alkenyl bromide leads back to thiobutenolide precursor 172—while we aimed to install the bromide in a selective fashion, carrying a functional handle R1 through the synthetic sequence was envisioned as an alternative strategy. From this point, in a highly simplifying disconnection, 172 could arise from haloarene 173 by an unprecedented cyclization reaction involving dearomatization of the thiophene ring. This cyclization would establish the full carbon skeleton of the natural product as well as the bridgehead sulfide in a single step. Tertiary aniline 173 would arise from a convergent fragment coupling of tricyclic aniline 134 and keto-thiophene 174 by reductive amination followed by arene halogenation. Rapid access to material to test the key cyclization step would be facilitated by the access to tricycle 134 already enabled by our previous synthetic efforts and by facile preparation of 2-aminothiophenes by the Gewald reaction. Scheme 2.7.1. 3rd-generation retrosynthetic analysis of aleutianamine. O HN NHR O TsN S oxidation Br 171 dearomative cyclization N N Br reductive amination 172 NHAc 173 O TsN + halogenation S R1 2.8 arene C–H amination R1 OMe TsN X hydrolysis S oxidation alkenyl bromide installation N OMe O TsN S thioaminal formation N 78 OMe OMe H N NH S NHAc R1 174 134 • already prepared • 2-aminothiophenes: readily prepared by (this research) the Gewald reaction PURSUIT OF A DEAROMATIVE CYCLIZATION APPROACH To realize this new synthetic plan, we developed an expedient synthesis of a thiophene coupling partner (Scheme 2.8.1). Monoketal 175 smoothly underwent the Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 282 Gewald aminothiophene synthesis in the presence of ethyl cyanoacetate to afford 2aminothiophene 176 under published conditions.41 Saponification and TFA-promoted decarboxylation then served to remove the ester group, and the resulting amine was readily acetylated to provide amide 177. Finally, the ketal could undergo acidic hydrolysis to provide desired ketone 178. As ketone 178 was found to undergo oxidation in air, this compound was prepared just prior to use or stored in the glovebox. Syntheses of analogues of 178 bearing functional handles for alkenyl bromide installation were also attempted (see Appendix 5), but each functional handle tested presented its own synthetic obstacles and these approaches were eventually abandoned in favor of planned late-stage alkenyl bromide installation. Scheme 2.8.1. Construction of an acetamidothiophene coupling partner. NC O CO2Et O S8 morpholine O S O NH2 EtOH, 75 °C O 175 93% yield CO2Et 176 1. KOH, EtOH/H2O, reflux 2. TFA, then Ac2O, Et3N, DMAP, CH2Cl2, 23 °C 58% over 2 steps O HCl S O NHAc 177 O S NHAc THF/H2O, 66 °C 178 • Unstable to prolonged handling under air Now with access to both fragments, the key reductive amination was tested. While the potentially low nucleophilicity of secondary aniline 134 was an initial concern, we were please to observe that the InCl3/Et3SiH system reported by Yang smoothly promoted reductive amination between aniline 134 and ketone 178 (Scheme 2.8.2).42 Subsequent bromination at the aniline ortho-position was initially challenging due to competitive bromination at the C(3)-position of the thiophene and the formation of dibrominated Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 283 products prior to complete consumption of the starting material. The use of THF as the reaction solvent was crucial to maximally (albeit not completely) suppress this undesired reactivity, allowing for the preparation of key bromoarene cyclization substrate 179. Note that bromination of tricycle 134 prior to coupling completely shut down the reductive amination. Scheme 2.8.2. Fragment coupling to prepare a dearomative cyclization substrate. OMe OMe O TsN S NHAc + NH 178 1. InCl3, Et3SiH, MeOH, 23 °C 2. NBS, THF, –78→23 °C 48% yield over 2 steps TsN Br N S NHAc 134 179 • Bromination must be performed after reductive amination • Other solvents led to increased dibromination While Pd-catalyzed dearomative Heck-type transformations of furans have been reported,43 related transformations of thiophenes are scarce and have not been performed by transition metal catalysis. A possible explanation for the lack of reports of thiophene dearomatization by Heck-type reactivity is the high degree of aromaticity of thiophenes compared to other π-excessive heterocycles.44 We therefore opted to model the desired transformation on reported dearomative intramolecular arylations of phenols 180, which lead to ketones 181 (Scheme 2.8.3). Buchwald’s initial report of this transformation has inspired further development by other groups45 and synthetic applications.46 Examples exist of related dearomative transformations of anilines, albeit with a limited scope.47 Based on this combined precedent, we envisioned that the dearomative arylation of aminothiophenes 182 to access thioimidates 183 would be feasible, driven by deprotonation of the aminothiophene to render the heterocycle more electron-rich and by the formation of an additional C=N π-bond. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 284 Scheme 2.8.3. Known dearomative arylation and desired transformation of thiophenes. OH O NHR S Pd S Pd n Br NR n n 180 Br 181 n 182 183 • Analogous, unknown transformation • Several examples (Buchwald, You, Tang) • Employed in total synthesis Indeed, gratifyingly, treatment of brominated acetamide 179 with Pd0, ligand, and base under conditions derived from those used by Buchwald for the dearomative arylation of phenols provided desired cyclized thioimidate 184 on the first attempt with protodebromination as the primary side product (Scheme 2.8.4).45a The successful application of this transformation completes the carbon skeleton of the natural product. Scheme 2.8.4. Key dearomative cyclization of aminothiophene 179. OMe OMe TsN Pd(dba)2 (15 mol %) XPhos (45 mol %), K2CO3 Br N S dioxane, 120 °C S NHAc 179 NAc TsN 65% yield N 184 • Tertiary sulfide assembled in high yield • Full carbon skeleton of aleutianamine established Following the preparation of thioimidate 184, experiments were conducted to effect C–H amination and subsequent closure of the final ring of the natural product. While amination could occur, albeit in low yield, ring closure was unsuccessful. Furthermore, a path toward alkenyl bromide installation from thioimidate 184 was unclear. Our efforts therefore shifted to hydrolysis of the thioimidate to the corresponding thiolactone. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 285 Interestingly, attempts to effect acidic or basic hydrolysis of acetylthioimidate 184 to thiolactone 185 led only to deacetylation with no further reactivity (Scheme 2.8.5). Under acidic conditions, prolonged heating led to nonspecific decomposition after deacetylation. This behavior was rather surprising given the generally facile hydrolysis of imines. Deacetylated thioimidate 186 (prepared independently, vide infra) was exposed to several electrophilic nitrogen sources in an attempt to render the nitrogen a better leaving group, unsuccessfully. Scheme 2.8.5. Attempts to access a thiolactone from acetylthioimidate 184. OMe OMe NAc TsN S aqueous H+ or OH– X only deacetylation – thioimidate is stable to hydrolysis N 184 O TsN S N 185 not detected OMe NH TsN S electrophilic [N] reagents X nonspecific decomposition N 186 We imagined that a derivative of thioimidate 184 bearing a more electronwithdrawing thioimidate protecting group could be more hydrolytically labile. Furthermore, a more electron-poor 2-aminothiophene might be less prone to undesired competitive bromination. Therefore, following hydrolysis of Gewald product 176, the resulting acid was decarboxylated and treated with TFAA and base in the same pot, leading to TFA-protected aminothiophene 187 (Scheme 2.8.6). Ketal removal provided an intermediate ketone (188) that was used directly in the following step to prevent oxidation. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 286 Scheme 2.8.6. Synthesis of a TFA-protected aminothiophene. O S O NH2 176 CO2Et 1. KOH, EtOH, reflux 2. TFA, CH2Cl2, 23 °C, then TFAA, Py, 0→23 °C 51% over 2 steps O O S O NHTFA 187 S HCl NHTFA • Used directly THF/H2O, reflux 188 Coupling of tricycle 134 and ketone 188 proceeded smoothly by reductive amination, and bromination provided cyclization substrate 189 (Scheme 2.8.7A). Orthobrominated product 189 was the only product isolated from the reaction mixture, with the more electron-deficient TFA-protected aminothiophene not undergoing competitive bromination. Satisfyingly, 189 underwent dearomative cyclization under the conditions applied earlier to acetyl-protected substrate 179, but the product isolated was free thioimidate 186—TFA cleavage appears to be effected under the reaction conditions, possibly due to adventitious water originating from the hygroscopic base. It was thus clear that the TFA group would not facilitate hydrolysis. Instead, free thioimidate 186 was sulfonylated with TsCl to provide tosyl-protected derivative 190. While this improved synthetic sequence was sufficient to access useful quantities of 190, we hypothesized that the yield of polar thioimidate 186 was reduced during chromatographic purification. To circumvent this purification, the dearomative cyclization and protection steps were combined (Scheme 2.8.7B). For consistency, the product of the dearomative cyclization was stirred with alkali prior to tosylation, as TFA cleavage was not always complete after the cyclization. To date, this step has enabled the preparation of up to 2.66 g of tosylthioimidate 190 in a single batch. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 287 Scheme 2.8.7. Improved thioimidate synthesis and subsequent tosylation. A) Advancement of TFA-protected aminothiophene and access to a tosylated thioimidate. OMe OMe O TsN 1. InCl3, Et3SiH, MeOH, 23 °C 2. NBS, THF, –78→23 °C S NHTFA + Br 49% yield over 2 steps 188 NH TsN N NHTFA 134 • No thiophene bromination! 189 OMe Pd(dba)2 (15 mol %) XPhos (25 mol %), K2CO3 S OMe NH TsN dioxane, 100 °C NTs TsN TsCl, Py S S CH2Cl2, 23 °C N 60% yield • TFA group is labile under the reaction conditions N 90% yield 186 190 B) Improved, telescoped sequence. OMe Pd(dba)2 (15 mol %), XPhos (25 mol %), K2CO3, dioxane, 100 °C; TsN Br N S OMe NTs TsN S then NaOH, CH2Cl2/H2O, 23 °C; then TsCl, DMAP, Py, CH2Cl2, 23 °C NHTFA N 71% yield [multi-gram scale] 189 190 Subjecting tosylthioimidate 190 to basic hydrolysis led to desired thiolactone 185 in 68% yield with 11% recovered starting material (Scheme 2.8.8). Notably, the yield of 185 varied significantly depending on the solvent ratio (excluding THF led to inconsistent results due to low solubility), temperature (a low yield was obtained at 60 °C, with LC– MS evidence for partial hydrolysis products that did not convert to 185 upon further subjection to alkali), and air exposure (the electron-rich arene appears to undergo nonspecific decomposition by an oxidative pathway). Scheme 2.8.8. Successful hydrolysis of thioimidate 190. OMe OMe NTs TsN S NaOH O TsN S THF/EtOH/H2O, 75 °C N 190 68% yield 11% recovered 190 N 185 Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 288 Prior to studying alkenyl bromide installation or arene amination, a test reaction was conducted to determine the feasibility of condensation to form the thioaminal moiety of the natural product (Scheme 2.8.9). Thiolactone 185 was treated with DIBAL to afford an intermediate thiolactol as a mixture of diastereomers. Heating this intermediate with panisidine, a model aniline, formed a trace amount of putative thioaminal 191, as detected by LC–MS. Scheme 2.8.9. Demonstration of the feasibility of thioaminal formation. OMe OMe O TsN S 1. DIBAL, CH2Cl2, 23 °C HN TsN Me S 2. p-anisidine, EtOH, 80 °C N 185 N 191 trace, observed by LC–MS (tentative assignment) Following this promising result, installation of the final nitrogen atom of the natural product was attempted (Scheme 2.8.10). Reactions of thioimidate 184 studied at an earlier stage indicated that a modified version of Kita’s oxidative arene azidation conditions were uniquely effective for installation of the nitrogen atom at the desired position ortho to the methoxy group.48 These conditions were found to be applicable to thiolactone 185, and reduction of the aryl azide under silane-mediated radical conditions49 afforded desired aniline 192.50 Unfortunately, treatment of aniline 192 with DIBAL failed to provide the desired thiolactol 193: Evidently, the aniline can form ate complex 194, which preferentially leads to 1,4-reduction. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 289 Scheme 2.8.10. Installation of the final nitrogen atom by azidation and reduction. OMe OMe TsN S N 185 O 1. PIFA, TMSN3, CH2Cl2, –78→23 °C 2. TTMSS, BEt3, t-dodecanethiol, PhCH3, 23 °C 49% over 2 steps • Successful installation of final nitrogen atom OMe NH2 O TsN DIBAL X CH2Cl2, –78 °C S N NH2 OH TsN S N 192 193 OMe Al(i-Bu)2H NH2 O TsN S • Aniline precludes 1,2-reduction 1,4-reduction via ate complex N 194 While further optimization may enable access to thiolactol 193, we instead directed our efforts to further desaturation of the thiolactone and installation of the alkenyl bromide. Direct desaturation of thiobutenolide 185 to the doubly unsaturated derivative 195 was explored under a variety of reaction conditions (Table 2.8.11). IBX led to nonspecific decomposition (entry 1), while N-t-butylbenzenesulfinimidoyl chloride (196) failed to effect desaturation (entry 2). Dong’s Cu-catalyzed conditions provided very little reactivity with only trace product formation (entry 3), perhaps unsurprisingly due to the proposed involvement of a 6-membered transition state in this reaction, which would not be possible for vinylogous desaturation.35 Newhouse’s Pd-catalyzed conditions provided some conversion, but the reaction stalled (entry 4).51 A control experiment with Pd(OAc)2 revealed that the [Pd(allyl)Cl2] precatalyst is necessary for this reaction (entry 5), but the use of stoichiometric [Pd(allyl)Cl2] led to a mixture of putative allylation products (entry 6). Stahl reported a method for mono-desaturation of cyclic ketones, finding during optimization that Pd(TFA)2 in DMSO led to high amounts of doubly unsaturated (aromatized) product.52 While these conditions did lead to trace quantities of desired diene 195 (entry 7), useful levels of conversion were not achieved even after prolonged stirring. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 290 Stahl’s Pd/diazafluorenone (197) conditions,53 reported to lead to rapid aromatization of cyclohexanone, did not lead to any reactivity (entry 8). Table 2.8.11. Conditions tested for direct desaturation of thiobutenolide 185. Ph OMe OMe O TsN S conditions X O TsN N 185 195 N t-Bu 196 O S N S Cl N N 197 entry conditions result 1 IBX, MeCN, 50 °C decomp 2 LiHMDS, 196, THF, –78→23 °C SM + decomp 3 CuTC, CyPPh2, (t-BuO)2, PhH, 80 °C trace product 4 LiTMP, ZnCl2, [Pd(allyl)Cl]2 (5 mol %), allyl acetate, THF, –40→28 °C stalled 5 LiTMP, ZnCl2, Pd(OAc)2, THF, –40→28 °C NR 6 LiTMP, ZnCl2, [Pd(allyl)Cl]2 (1.1 equiv), THF, –40→28 °C putative allylation 7 Pd(TFA)2 (1 equiv), DMSO, 80 °C trace product 8 Pd(TFA)2 (20 mol %), 197 (20 mol %), O2, DMSO, 80 °C NR Diene 195 can, fortunately, be accessed by a 2-step oxidation protocol (Scheme 2.8.12). Soft enolization with i-Pr2NEt and TMSOTf leads to an unstable silyl ketene thioacetal. Upon workup and chromatography, this intermediate appears to undergo protonation at the α-carbon, affording deconjugated olefin 198. Then, treatment with stoichiometric Pd(OAc)2 provides desired diene 195 in modest yield. This desaturation likely proceeds by initial coordination of the palladium to the carbonyl, as in intermediate 199. Soft enolization would be enabled by the acidic nature of the ketone α-position, leading to extended palladium enolate 200. A hydride elimination would provide the desired product. Support for this proposed mechanism is provided by the failure of thiobutenolide 185 to directly afford diene 195 upon treatment with Pd(OAc)2—acidified α-protons are likely necessary for formation of palladium enolate 200. Unfortunately, we have been unable to render the desaturation of deconjugated ketone 198 catalytic. Further Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 291 efforts will be made in the future to circumvent the requirement of this process for stoichiometric palladium. Scheme 2.8.12. Desaturation of thiolactone 185 to diene 195. OMe OMe OMe O TsN S i-Pr2NEt, TMSOTf O TsN CH2Cl2, 23 °C N O TsN S Pd(OAc)2 S DMSO, 28 °C N 94% yield 185 40% yield N 195 198 Proposed mechanism: OMe OMe O Pd(OAc)2 TsN soft enolization –HOAc S N O PdOAc TsN S H– elimination N 199 200 Control experiment: OMe OMe O TsN S N 185 Pd(OAc)2 X DMSO, 23 °C NR O TsN S N 195 not observed Toward the desired alkenyl bromide, diene 195 underwent conjugate addition of thiophenol followed by oxidation to the sulfoxide and Pummerer rearrangement to afford doubly vinylogous dithiocarbonate 201 (Scheme 2.8.13). We imagined that hydrolysis to the doubly vinylogous acid could enable bromide installation by [COBr]2/DMF54 or by triflate formation and triflate-halogen exchange,4 or that access to a vinylogous amide could enable bromide installation by radical chemistry.55 To our dismay, 201 was Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 292 recalcitrant to sulfide displacement by a variety of nucleophiles, and the phenyl sulfide did not undergo selective oxidation to render it a better leaving group. Scheme 2.8.13. Thioester δ-functionalization and unsuccessful downstream chemistry. OMe OMe TsN O TsN S N OMe O 1. PhSH, PhH, 23 °C 2. m-CPBA, CH2Cl2, 0 °C 3. TFAA, Py, CH2Cl2, 0→23 °C 38% over 3 steps 195 S N TsN Nu–, H3O+, oxidants X (NH3, N2H4, NaOMe, LiOOH, HN3, m-CPBA) 201 SPh O S N 202 X X = [O], [N] Around the same time, we discovered that unlike thiobutenolide 185, diene 195 was not an efficient substrate for oxidative arene azidation (Scheme 2.8.14). Putative aryl azide 203 was detected in the reaction mixture by LC–MS, but a low yield was obtained upon isolation. As desaturation of the thiobutenolide following azidation may present a functional group compatibility challenge, we reevaluated the synthetic plan for arene amination and bromide installation. Scheme 2.8.14. Inefficient azidation of dienone 195. OMe OMe O TsN S PIFA, TMSN3 N3 TsN O S CH2Cl2, –78→23 °C N 195 <10% yield N 203 (tentative assignment) Throughout the synthetic sequence leading up to 195, most intermediates were found to be somewhat oxidatively unstable, especially in the presence of acid, undergoing discoloration in air and decomposition in CDCl3. This behavior hinted that arene 195 may be readily oxidized to the corresponding pyrroloiminoquinone. While conducting the Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 293 synthetic sequence in the arene oxidation state enabled aniline alkylation by reductive amination, dearomative thiophene functionalization, and subsequent transformations, we realized that it could be beneficial to oxidize the arene to the quinone oxidation state prior to installation of the final nitrogen atom and the alkenyl bromide (Scheme 2.8.15). The electrophilic nature of pyrroloiminoquinone 204 could facilitate direct amination and circumvent the low-yielding azidation step. Additionally, the thiolactone could be reduced to a thiolactol, altering the diene electronics and potentially enabling direct bromination at the desired position. Although the exploration of backup strategies for earlier installation of the alkenyl bromide is ongoing, we have begun to explore this strategy. Scheme 2.8.15. Benefits of an early oxidation event. OMe O O TsN OH TsN S N S N 195 204 • Unstable electron-rich arene • δ-functionalization of dienone is challenging • Oxidative conditions are already necessary for arene amination • Electrophilic nature of iminoquinone may facilate amination • Isolated diene could undergo direct bromination To evaluate the key arene oxidation, thiolactone 185 was subjected to the CANmediated conditions described by White (Scheme 2.8.16).16 Addition of CAN to the substrate led to rapid formation of orange putative cationic pyrroloiminoquinone 205. This intermediate was not isolated; instead, gratifyingly, addition of aqueous ammonia led to purple, aminated pyrroloiminoquinone 206, isolated as the TFA salt after HPLC purification. The second oxidation event after ammonia addition is likely mediated by atmospheric oxygen. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 294 Scheme 2.8.16. Proof-of-concept for an oxidative strategy. O OMe TsN S CAN MeCN/H2O, 0 °C S O O TsN O then NH4OH S 64% yield N N N 205 185 TFA NH2 O TsN 206 observed by LC/MS • 2 oxidation events and amination in a single step To translate this promising result to a synthetically relevant system, desaturated thiobutenolide 195 was treated with DIBAL, which led to the formation of thiolactol 207 as a 5:1 mixture of diastereomers (inseparable on silica gel) (Scheme 2.8.17). Oxidation of 207 with CAN and ammonia addition did indeed lead to putative desired pyrroloiminoquinone 208. Efforts to isolate this intermediate and effect its cyclization are ongoing. Scheme 2.8.17. Toward desired pyrroloiminoquinone 208. OMe O TsN S N 195 O OMe DIBAL CH2Cl2, –78 °C 95% yield 5:1 dr S N 207 NH TsN OH TsN CAN, then NH4OH MeCN/H2O, 0 °C OH S N 208 detected by LC–MS and crude 1H NMR We plan to treat 208 with a Lewis acid to effect dehydrative cyclization to heptacycle 209 (Scheme 2.8.18). Bromination will then be attempted with NBS—the electron-poor nature of the pyrroloiminoquinone and additional electron-withdrawing effect of the tosyl protecting group should favor bromination of the diene instead of the pyrrole moiety. If desired bromonium ion 210 forms, elimination from the more stable allylic carbocation 211 should afford alkenyl bromide 212 with the necessary Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 295 regioselectivity. Finally, detosylation of the electron-poor heterocycle by mild ammoniamediated conditions16 and formation of the TFA salt could provide aleutianamine (78). Scheme 2.8.18. Planned completion of synthesis. O NH TsN OH Lewis Acid S N TsN S N N 208 209 N TsN S NBS N N O S S –H+ 211 Br N 212 Br 210 N TsN N TsN O O 2.9 O O 1. NH4OH 2. TFA HN H N S N Br Br Aleutianamine (78) CONCLUSION Efforts toward the first total synthesis of the marine alkaloid aleutianamine have been conducted. Our strategy has evolved through three distinct major synthetic plans. To date, a hexacyclic intermediate bearing the entire carbon skeleton and all three nitrogen atoms of aleutianamine has been prepared by a strategy involving Pd-catalyzed dearomative spirocyclization of an aminothiophene intermediate. Efforts to advance this intermediate to the natural product are ongoing. 2.10 EXPERIMENTAL SECTION 2.10.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.56 NBS was recrystallized from boiling water prior to use, amines and TMSCl were distilled under nitrogen prior to use, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 296 and K2CO3 was flame-dried under vacuum and stored in a nitrogen-filled glovebox prior to use. All other reagents were purchased from commercial sources and used as received unless otherwise indicated. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 nm) was used for flash chromatography. Preparative HPLC was performed on an Agilent 1100 Series HPLC system using a 9.4 x 250 mm Agilent Eclipse XDB-C18 column, or on an Agilent 1200 Series HPLC system using a 9.4 x 250 mm Agilent Zorbax Rx-SIL column. 1H NMR spectra were recorded on Varian Inova 500 MHz, Varian 600 MHz, and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), C6D6 (δ 7.16 ppm), DMSO-d6 (δ 2.50 ppm), CD2Cl2 (δ 5.32 ppm), or CD3OD (δ 3.31 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometer (100 MHz) and are reported relative to CHCl3 (δ 77.16 ppm), C6D6 (δ 128.06 ppm), DMSO-d6 (δ 39.52 ppm), CD2Cl2 (δ 53.84 ppm), or CD3OD (δ 49.00 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities 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. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Some reported spectra include minor solvent impurities of water, ethyl acetate, diethyl ether, methylene chloride, acetone, grease, and/or silicon grease, which do not impact product assignments. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). High resolution Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 297 mass spectra (HRMS) were obtained from an Agilent 6230 LC/TOF with an Agilent Jet Stream ion source in electrospray ionization (ESI+ or ESI–) mode, or from the Caltech Mass Spectrometry Laboratory using a JEOL JMS-T2000GC AccuTOF™ GC-Alpha in field desorption (FD+) mode. 2.10.2 EXPERIMENTAL PROCEDURES O O LDA, MeSTs THF, –78→0 °C MeS OMe 213 OMe 96 3-methoxy-6-(methylthio)cyclohex-2-en-1-one (96) To a 20 mL glass vial equipped with a septum cap were added THF (8 mL) and iPr2NH (0.29 mL, 2.1 mmol, 1.3 equiv). The solution was cooled to –78 °C and n-BuLi (2.5 M in hexanes, 0.76 mL, 1.9 mmol, 1.2 equiv) was added slowly with stirring. The mixture was then allowed to warm to 23 °C and cooled back to –78 °C. A solution of 3methoxycyclohex-2-en-1-one (213, 200 mg, 1.59 mmol, 1.0 equiv)57 in THF (1 mL) was then added dropwise and the resulting light-yellow solution was stirred at –78 °C for 5 min. Subsequently, a solution of methyl thiotosylate58 (384 mg, 1.90 mmol, 1.2 equiv) in THF (1 mL) was added slowly. After stirring for an additional 5 min at –78 °C, the reaction mixture was warmed to 0 °C in an ice bath, resulting in a pink, milky suspension. Saturated aq. NH4Cl (5 mL) was then added, and the resulting biphasic suspension was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (33% EtOAc/hexanes) to afford the title compound as a yellow solid (210 mg, 1.22 mmol, 77% yield); 1H NMR (400 MHz, CDCl3) δ 5.29 (d, J = 0.97 Hz, 1H), 3.69 (s, 3H), 3.25 (t, J = 4.3 Hz, 1H), 2.75 – 2.61 (m, 1H), 2.40 – 2.24 (m, 2H), 2.16 (s, 3H), 2.16 – 2.06 (m, 1H); Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 13 298 C NMR (100 MHz, CDCl3) δ 195.5, 177.2, 100.0, 55.8, 48.4, 27.1, 26.0, 14.6; IR (Neat Film, NaCl) 2920, 2851, 1651, 1607, 1446, 1381, 1317, 1228, 1185, 1075, 1002, 837, 786 cm–1; HRMS (ESI+): m/z calc’d for C8H13O2S [M+H]+: 173.0631, found 173.0629. O O LDA, PhI, Pd(Pt-Bu3)2 (10 mol %) MeS MeS dioxane, 80 °C OMe 96 OMe Ph 97 6-methoxy-3-(methylthio)-2,3-dihydro-[1,1'-biphenyl]-4(1H)-one (97) To a 20 mL glass vial in a nitrogen-filled glovebox were added Pd(t-Bu3)2 (15 mg, 0.029 mmol, 10 mol %) and 1,4-dioxane (1.5 mL). The mixture was stirred at 28 °C to dissolve the palladium complex. PhI (32.5 µL, 0.290 mmol, 1.0 equiv) was then added rapidly. Separately, a solution of sulfide 96 (50 mg, 0.290 mmol, 1.0 equiv) in 1,4-dioxane (1 mL) was prepared in a 1-dram glass vial. Solid LDA (31 mg, 0.290 mmol, 1.0 equiv) was then added and the mixture was shaken to effect dissolution. The resulting enolate solution was then added to the 20 mL vial containing the Pd/PhI mixture, and additional dioxane (0.4 mL) was used to quantitatively transfer the enolate. The vial was sealed with a PTFE-lined cap, removed from the glovebox, and stirred at 80 °C in a metal heating block for 20 h. The reaction mixture was allowed to cool to 23 °C, saturated aq. NaHCO3 (5 mL) was added, and the biphasic mixture was extracted with Et2O (4x3 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (33% EtOAc/hexanes) to afford the title compound as a yellow solid (12.1 mg, 0.0487 mmol, 17% yield); 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.31 (m, 2H), 7.31 – 7.27 (m, 1H), 7.20 – 7.13 (m, 2H), 5.53 (d, J = 1.1 Hz, 1H), 3.96 (dd, J = 8.5, 5.6 Hz, 1H), 3.67 (s, 3H), 3.33 (t, J = 5.1 Hz, 1H), Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 299 2.46 – 2.34 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.5, 177.1, 140.1, 128.9, 128.2, 127.4, 101.8, 56.3, 47.6, 43.4, 37.1, 14.7; IR (Neat Film, NaCl) 3027, 2918, 1651, 1602, 1454, 1358, 1220, 1076, 1011, 838, 750, 704 cm–1; HRMS (ESI+): m/z calc’d for C14H17O2S [M+H]+: 249.0944, found 249.0942. OTBS Br 1. 2,3-dihydrofuran, H2SO4, DMA/H2O, 60 °C NHNH2 OMe 106 2. n-BuLi, TBSCl, then n-BuLi, TBSCl, THF, –78→23→–78→23 °C Br N TBS OMe 107 Silyl indole 107 To a 20 mL glass vial was added (4-bromo-2-methoxyphenyl)hydrazine11 (106, 832 mg, 3.83 mmol, 1.0 equiv), DMA (5 mL), deionized water (3.6 mL), and 25% (v/v) aq. H2SO4 (1.85 mL, 8.62 mmol, 2.25 equiv). 2,3-dihydrofuran (290 µL, 3.83 mmol, 1.0 equiv) was then added and the vial was sealed and heated to 60 °C in a metal heating block. After 4 h of stirring at 60 °C, the reaction mixture was transferred to a separatory funnel containing 1:1 saturated aq. NaHCO3/brine. The resulting suspension was extracted with EtOAc (4x5 mL). The combined organic extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (50% EtOAc/hexanes) to afford an intermediate tryptophol as a viscous brown oil (351 mg, 1.30 mmol, 34% yield); 1H NMR (400 MHz, CDCl3) δ 8.27 (br s, 1H), 7.36 (dd, J = 1.5, 0.6 Hz, 1H), 7.05 (d, J = 2.2 Hz, 1H), 6.75 (d, J = 1.5 Hz, 1H), 3.94 (s, 3H), 3.88 (t, J = 6.3 Hz, 2H), 2.96 (td, J = 6.3, 0.8 Hz, 2H). The intermediate tryptophol (320 mg, 1.18 mmol, 1.0 equiv) was transferred to a 20 mL glass vial. Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation, the headspace of the vial was evacuated and Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 300 flushed with nitrogen, and THF (10 mL) was added. The solution was cooled to –78 °C. nBuLi (2.5 M in hexanes, 0.47 mL, 1.18 mmol, 1.0 equiv) was added slowly and the reaction mixture was subsequently allowed to warm to 23 °C. Then, TBSCl (187 mg, 1.24 mmol, 1.05 equiv) in THF (1 mL) was added and the reaction mixture was allowed to stir at 23 °C for 15 min. After cooling back to –78 °C, additional n-BuLi (2.5 M in hexanes, 0.47 mL, 1.18 mmol, 1.0 equiv) was added slowly and the reaction mixture was subsequently allowed to warm back to 23 °C. Additional TBSCl (187 mg, 1.24 mmol, 1.05 equiv) in THF (1 mL) was then added. After an additional 1 h of stirring, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (5% EtOAc/hexanes) to afford the title compound as a colorless oil (183 mg, 0.367 mmol, 31% yield); 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 1.7 Hz, 1H), 7.04 (s, 1H), 6.69 (d, J = 1.7 Hz, 1H), 3.87 (s, 3H), 3.83 (t, J = 7.0 Hz, 2H), 2.87 (td, J = 7.0, 0.9 Hz, 2H), 0.89 (s, 9H), 0.85 (s, 9H), 0.51 (s, 6H), 0.01 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 147.6, 134.6, 131.1, 129.9, 115.0, 114.4, 112.8, 105.6, 63.7, 54.5, 29.0, 26.9, 26.1, 19.7, 18.5, –1.5, – 5.2; IR (Neat Film, NaCl) 2927, 2856, 1572, 1462, 1367, 1300, 1254, 1104, 992, 911, 824, 683 cm–1; HRMS (ESI+): m/z calc’d for C23H41BrNO2Si2 [M+H]+: 498.1854, found 498.1844. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 301 O OTBS Oi-Bu 108 Br OMe TBS N , LiHMDS O Pd(Pt-Bu3)2 (5 mol %) PhMe, 70 °C N TBS OMe TBSO 109 Oi-Bu 107 Vinylogous ester 109 To a 20 mL glass vial were added silyl indole 107 (173 mg, 0.347 mmol, 1.0 equiv) and 3-isobutoxycyclohex-2-en-1-one13 (108, 58 mg, 0.347 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation and the vial was transferred to a nitrogen-filled glovebox. Pd(t-Bu3)2 (8.9 mg, 0.0174 mmol, 5 mol %) was added followed by PhCH3 (3.5 mL). A solution of LiHMDS (116 mg, 0.694 mmol, 2.0 equiv) in PhCH3 (1 mL) was added dropwise with manual swirling. Additional PhCH3 (0.2 mL) was used to quantitatively transfer the remaining base. The vial was sealed with a PTFE-lined cap, removed from the glovebox, and heated to 70 °C in a metal heating block for 75 min. The reaction mixture was subsequently cooled to 23 °C and saturated aq. NH4Cl (5 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3x2 mL). The combined organic phases were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (20% EtOAc/hexanes) to afford the title compound as a colorless film (87.5 mg, 0.149 mmol, 43% yield); 1H NMR (400 MHz, CDCl3) δ 7.02 (s, 1H), 6.98 (s, 1H), 6.44 (s, 1H), 5.54 (s, 1H), 3.86 (s, 3H), 3.86 – 3.82 (m, 2H), 3.66 (d, J = 6.5 Hz, 2H), 3.64 – 3.58 (m, 1H), 2.91 (t, J = 7.3 Hz, 2H), 2.55 (t, J = 6.1 Hz, 2H), 2.33 (q, J = 6.6 Hz, 2H), 2.11 – 2.02 (m, 1H), 1.00 (d, J = 6.7 Hz, 6H), 0.91 (s, 9H), 0.90 (s, 9H), 0.51 (s, 6H), 0.05 (s, 6H); 13C NMR Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 302 (100 MHz, CDCl3) δ 200.2, 177.6, 147.1, 133.3, 131.8, 130.2, 130.1, 114.8, 110.7, 103.4, 102.7, 74.9, 63.8, 54.0, 52.4, 29.9, 29.2, 28.3, 27.8, 26.9, 26.1, 19.6, 19.2, 18.4, –1.5, –5.1; IR (Neat Film, NaCl) 2927, 2856, 1654, 1609, 1469, 1382, 1313, 1252, 1177, 1098, 994, 910, 838, 682 cm–1; HRMS (ESI+): m/z calc’d for C33H56NO4Si2 [M+H]+: 586.3742, found 586.3752. O O OMe TsN NH4Cl (10 equiv) NH2 TsN MeOH, 40 °C N N 117 119 Pyrroloiminoquinone 119 Conditions for the preparation of 119 were adapted from a procedure for the synthesis of a related compound by Tokuyama.59 To a 1-dram glass vial containing pyrroloiminoquinone 1172c (24.8 mg, 0.0696 mmol, 1.0 equiv) and NH4Cl (37 mg, 0.696 mmol, 10 equiv) was added degassed MeOH (2.3 mL). The vial was sealed with a PTFElined cap and stirred at 23 °C for 21 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (10% MeOH/CH2Cl2) to afford the title compound as a dark purple solid (11.6 mg, 0.0340 mmol, 49% yield). All characterization data matched those reported by White and coworkers.16 Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine N OMe I 303 NH2 Ph Ph Pd(OAc)2 (5 mol %), (±)-BINAP (10 mol %), NaOt-Bu Ph Ph N H N OMe PhCH3, 100 °C Cl 125 Cl 124 Arylhydrazone 125 Conditions for the synthesis of 125 were adapted from those reported for a related compound by Eilbracht.17 To a 20 mL glass vial in a nitrogen-filled glovebox were added Pd(OAc)2 (17 mg, 0.075 mmol, 5 mol %), rac-BINAP (93 mg, 0.15 mmol, 10 mol %), and PhCH3 (3.5 mL). The vial was sealed with a PTFE-lined cap and heated to 100 °C in a metal block for 5 min, followed by cooling to 28 °C. To a separate 20 mL glass vial in the glovebox were added aryl iodide 124 (403 mg, 1.50 mmol, 1.0 equiv), NaOt-Bu (202 mg, 2.10 mmol, 1.4 equiv), and PhCH3 (0.8 mL). The Pd/BINAP solution was then added to the aryl iodide/base mixture, the vial was sealed and removed from the glovebox, and the reaction mixture was stirred at 100 °C in a metal heating block for 14 h. The vial was then allowed to cool to 23 °C. The resulting dark orange suspension was diluted with Et2O (3 mL), filtered through a short SiO2 plug with EtOAc, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (10% Et2O/hexanes, dry-loaded with Celite) to afford the title compound as a light-yellow solid (273 mg, 0.811 mmol, 54% yield); 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.66 – 7.48 (m, 6H), 7.38 – 7.28 (m, 5H), 6.73 (dd, J = 8.5, 2.6 Hz, 1H), 6.64 (d, J = 8.5 Hz, 1H), 3.66 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.1, 144.0, 138.2, 135.1, 132.8, 129.6, 129.3, 128.9, 128.3, 128.2, 126.9, 126.7, 118.3, 112.3, 110.8, 55.8; IR (Neat Film, NaCl) 3345, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 304 3057, 2937, 2835, 2352, 1598, 1514, 1422, 1322, 1254, 1217, 1133, 1026, 857, 767, 695 cm–1; HRMS (ESI+): m/z calc’d for C20H18ClN2O [M+H]+: 337.1102, found 337.1099. H 2N OMe OMe H N H2SO4, 2,3-dihydrofuran DMA/H2O 60 °C Cl H N Cl Cl 127 HO 126 Tryptophol 126 To a 250 mL round bottom flask were added (5-chloro-2-methoxyphenyl)hydrazine hydrochloride19 (127, 8.60 g, 41.1 mmol, 1.0 equiv), DMA (65 mL), H2O (65 mL), and 25% (v/v) aq. H2SO4 (11.0 mL, 51.4 mmol, 1.25 equiv). 2,3-dihydrofuran (3.42 mL, 45.2 mmol, 1.1 equiv) was added slowly with stirring, resulting in a slow color change to yellow, whereafter the flask was equipped with an air-cooled reflux condenser and heated to 60 °C in an oil bath for 6 h. The reaction mixture was then allowed to cool to 23 °C and transferred to a separatory funnel containing 1:1 saturated aq. NaHCO3/brine (250 mL). The mixture was then extracted with EtOAc (4x100 mL), and the combined organic extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (60% EtOAc/hexanes) to afford the title compound as a thick, red-brown syrup that slowly crystallized upon storage at –20 °C (2.66 g, 11.79 mmol, 29% yield); 1H NMR (400 MHz, CDCl3) δ 8.54 (br s, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.50 (d, J = 8.2 Hz, 1H), 3.94 (t, J = 6.4 Hz, 2H), 3.91 (s, 3H), 3.23 (td, J = 6.4, 0.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 145.2, 128.4, 124.8, 123.8, 120.2, 118.2, 113.1, 102.4, 63.7, 55.7, 29.5; IR (Neat Film, NaCl) 3416, 2935, 2580, 1786, 1703, 1626, 1571, 1494, 1452, 1339, 1230, 1115, 1052, 937, 789, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 305 736, 694, 628 cm–1; HRMS (FD+): m/z calc’d for C11H13ClNO2 [M+H]+: 225.0557, found 225.0552. OMe 1. 129, CuI (5 mol %), 130 (6 mol %), K2CO3, DMSO, 80 °C Br MeH2N H N OMe Me Cl 131 128 N OH NH 2. TMSCl, MeOH, 0→23 °C Cl O Cl Me Boc H 2N 130 N Me 129 N-methylarylhydrazine hydrochloride 131 Conditions for the synthesis of 131 were adapted from those reported for related compounds by Schmidt.20 To a 20 mL glass vial in a nitrogen-filled glovebox were added CuI (34 mg, 0.179 mmol, 5 mol %), hydroxypicolinamide ligand 13021 (53 mg, 0.22 mmol, 6 mol %), K2CO3 (762 mg, 5.51 mmol, 1.5 equiv), aryl bromide 128 (0.50 mL, 3.67 mmol, 1.0 equiv), and carbazate 129 (0.68 mL, 4.59 mmol, 1.25 equiv), followed by DMSO (3.7 mL). The vial was sealed with a PTFE cap and removed from the glovebox. The reaction mixture was stirred at 80 °C for 17 h, whereafter the resulting gray suspension was filtered through a Celite plug with EtOAc and transferred to a separatory funnel containing pH 7 phosphate buffer (20 mL). The layers were shaken and separated, the aqueous phase was extracted with EtOAc (10 mL), and the combined organic phases were washed with water, then brine, and finally dried over Na2SO4. The crude product was purified by silica gel flash chromatography (15% EtOAc/hexanes) to afford an intermediate aryl carbazate as an off-white solid (902 mg, 3.15 mmol, 86% yield); 1H NMR (500 MHz, CDCl3) δ 6.77 (dd, J = 8.5, 2.4 Hz, 1H), 6.70 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.44 (br s, 1H), 3.83 (s, 3H), 3.23 (s, 3H), 1.45 (s, 9H). This intermediate carbazate (900 mg, 3.15 mmol, 1.0 equiv) was added to a 20 mL glass vial, followed by MeOH (1.8 mL). Upon complete dissolution of the intermediate Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 306 compound, the solution was cooled to 0 °C and the headspace of the vial was purged with nitrogen. TMSCl (0.64 mL, 5.05 mmol, 1.60 equiv) was added dropwise over 6 min, whereafter the reaction mixture was allowed to warm to 23 °C. After stirring for 19 h, PhCH3 (3.6 mL) was added, and the solvent was removed under reduced pressure. The resulting solid was suspended in additional PhCH3 (5 mL) and placed in a –20 °C freezer for 2 h. The solid was collected by vacuum filtration, washed with PhCH3, and dried under high vacuum to afford the title compound as a beige solid (612 mg, 2.74 mmol, 87% yield); 1 H NMR (400 MHz, DMSO-d6) δ 11.31 (br s, 2H), 8.07 (br s, 1H), 7.39 (q, J = 1.1 Hz, 1H), 7.02 (d, J = 1.3 Hz, 2H), 3.82 (s, 3H), 2.78 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 147.1, 133.5, 124.3, 122.1, 115.5, 112.6, 56.0, 34.0; IR (Neat Film, NaCl) 3180, 3028, 2928, 2653, 2469, 2350, 2244, 2093, 1919, 1822, 1695, 1587, 1494, 1414, 1336, 1220, 1126, 1022, 952, 874, 792, 748, 670 cm–1; HRMS (ESI+): m/z calc’d for C8H12ClN2O [M+H]+: 187.0633, found 187.0627. OMe OMe H N 1. TsCl, NaOH, Bu4NHSO4, CH2Cl2/H2O, 23 °C Cl HO Ts N 2. Boc2NH, Cs2CO3, DMF, 80 °C 126 Cl Boc2N 132 Protected tryptamine 132 To a 50 mL round bottom flask under air were added tryptophol 126 (500 mg, 2.22 mmol, 1.0 equiv), Bu4NHSO4 (75 mg, 0.222 mmol, 10 mol %), and CH2Cl2 (9 mL), followed by 50% w/v aq. NaOH (2 mL). After stirring for 5 min, TsCl (1.69 g, 8.88 mmol, 4.0 equiv) was added in a single portion. The reaction mixture was subjected to vigorous magnetic stirring for 20 min, then diluted with H2O (15 mL) and CH2Cl2 (10 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3x10 mL). The Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 307 combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (33% EtOAc/hexanes) to afford an intermediate tosylate as an orange solid (0.80 g, 1.50 mmol, 67% yield); 1H NMR (500 MHz, CDCl3) δ 7.73 – 7.64 (m, 4H), 7.62 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.5 Hz, 1H), 6.54 (d, J = 8.5 Hz, 1H), 4.36 (t, J = 6.6 Hz, 2H), 3.65 (s, 3H), 3.28 (t, J = 6.6 Hz, 2H), 2.41 (s, 3H), 2.35 (s, 3H). This intermediate (0.80 g, 1.50 mmol, 1.0 equiv) was transferred to a 20 mL glass vial. Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation. Boc2NH (391 mg, 1.8 mmol, 1.2 equiv) and Cs2CO3 (586 mg, 1.8 mmol, 1.2 equiv) were added, and the headspace of the vial was evacuated and backfilled with nitrogen. DMF (7.5 mL) was added, and the reaction mixture was stirred at 23 °C for 11 h, after which TLC analysis indicated no conversion. The vial was sealed with a PTFE cap and stirred vigorously at 80 °C in a metal heating block for 2 h, after which TLC analysis indicated complete consumption of the starting material. The reaction mixture was cooled to 23 °C, diluted with H2O (50 mL), and extracted with EtOAc (4x15 mL). The combined organic extracts were washed twice with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (25% EtOAc/hexanes) to afford the title compound as a peach solid (751 mg, 1.30 mmol, 87% yield); 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.66 (m, 2H), 7.62 (s, 1H), 7.26 (dd, J = 7.4, 1.4 Hz, 2H), 7.05 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 8.5 Hz, 1H), 4.00 (t, J = 6.8 Hz, 2H), 3.62 (s, 3H), 3.28 – 3.18 (m, 2H), 2.39 (s, 3H), 1.38 (s, 18H); 13C NMR (100 MHz, CDCl3) δ 152.5, 146.5, 144.3, 137.4, 129.9, 129.5, 128.1, 127.3, 126.3, 124.5, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 308 118.7, 117.1, 107.6, 82.3, 55.9, 46.7, 28.0, 25.7, 21.7; IR (Neat Film, NaCl) 3120, 2978, 1740, 1698, 1574, 1488, 1368, 1250, 1173, 1000, 854, 813, 661 cm–1; HRMS (ESI+): m/z calc’d for C28H35ClN2NaO7S [M+Na]+: 601.1746, found 601.1758. OMe H N 1. DIAD, PPh3, DPPA, THF, 0→23 °C 2. TsCl, Bu4NHSO4, NaOH, CH2Cl2/H2O, 23 °C 3. PPh3, H2O, THF, 23 °C Cl Ts N TFA Cl Method A CH2Cl2, 23 °C Cl Method B H2N 133 HO 126 OMe OMe Ts N Boc2N 132 Tryptamine 133 Method A: To a 250 mL round bottom flask was added tryptophol 126 (3.36 g, 14.89 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation. PPh3 (4.69 g, 17.87 mmol, 1.2 equiv) was added, and the headspace of the flask was evacuated and backfilled with nitrogen. THF (60 mL) was added, and the reaction mixture was cooled to 0 °C. Then, DIAD (3.52 mL, 17.87 mmol, 1.2 equiv) was added dropwise over 4 min. The reaction mixture was stirred at 0 °C for an additional 15 min, after which DPPA (3.85 mL, 17.87 mmol, 1.2 equiv) was added rapidly and the reaction mixture was allowed to warm to 23 °C. The reaction mixture became cloudy over several minutes. TLC analysis after 16 h indicated a high degree of conversion to product. Stirring for another 24 h led to no change in the reaction profile by TLC analysis. The reaction mixture was concentrated under reduced pressure and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→40% EtOAc/hexanes) to afford an intermediate azide as an orange-brown solid (2.50 g, 9.97 mmol, 67% yield); 1 H NMR (500 MHz, CDCl3) δ 8.32 (br s, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 8.2 Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 309 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 3.94 (s, 3H), 3.59 (t, J = 7.1 Hz, 2H), 3.27 (td, J = 7.1, 0.8 Hz, 2H). To a 250 mL round bottom flask under air were added this intermediate azide (5.11 g, 20.4 mmol, 1.0 equiv), CH2Cl2 (41 mL), and Bu4NHSO4 (69 mg, 0.204 mmol, 1 mol %), followed by 50% w/v aq. NaOH (14 mL). After stirring for 5 min, TsCl (7.78 g, 40.8 mmol, 2.0 equiv) was added in a single portion. The reaction mixture was subjected to vigorous magnetic stirring for 10 min, then diluted with H2O (100 mL) and CH2Cl2 (30 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3x50 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→45% EtOAc/hexanes) to afford an intermediate tosyl indole as a white solid (6.77 g, 16.7 mmol, 82% yield); 1H NMR (400 MHz, CDCl3) δ 7.74 (t, J = 1.0 Hz, 1H), 7.73 – 7.67 (m, 2H), 7.30 – 7.26 (m, 2H), 7.08 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 3.64 (s, 3H), 3.65 – 3.59 (m, 2H), 3.26 (td, J = 7.1, 0.9 Hz, 2H), 2.40 (s, 3H). To a 500 mL round bottom flask under air were added this intermediate tosyl indole (11.73 g, 28.97 mmol, 1.0 equiv), PPh3 (9.88 g, 37.66 mmol, 1.3 equiv), and THF (190 mL). The reaction mixture was stirred at 23 °C for 15 h, whereafter deionized water (9.5 mL) was added. After an additional 30 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (10% MeOH/CH2Cl2 + 1% Et3N) to afford the title compound as a white solid (10.41 g, 27.48 mmol, 95% yield); 1 H NMR (400 MHz, CDCl3) δ 7.72 – 7.65 (m, 3H), 7.29 – 7.23 (m, 2H), 7.05 (d, J = 8.5 Hz, 1H), 6.56 (d, J = 8.5 Hz, 1H), 3.62 (s, 3H), 3.14 – 3.00 (m, 4H), 2.39 (s, 3H); 13C NMR Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 310 (100 MHz, CDCl3) δ 146.5, 144.4, 137.4, 129.7, 129.5, 127.4, 127.2, 126.5, 124.6, 118.5, 118.1, 107.5, 55.8, 42.9, 30.7, 21.7; IR (Neat Film, NaCl) 2938, 2686, 2595, 2515, 2363, 1574, 1487, 1366, 1290, 1237, 1171, 1092, 1052, 997, 937, 809, 662 cm–1; HRMS (ESI+): m/z calc’d for C18H20ClN2O3S [M+H]+: 379.0878, found 379.0877. Method B: To a 50 mL round bottom flask under air were added imide 132 (750 mg, 1.30 mmol, 1.0 equiv), CH2Cl2 (13 mL), and TFA (1.5 mL, 19.4 mmol, 15 equiv). The reaction mixture was stirred at 23 °C for 11 h, then transferred to a separatory funnel containing aq. K2CO3 (20 mL). The funnel was shaken, the layers were separated, and the aqueous phase was extracted with CH2Cl2 (3x10 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (10% MeOH/CH2Cl2 + 1% Et3N) to afford the title compound as a white solid (341 mg, 0.90 mmol, 69% yield). For characterization data, see above. OMe OMe Ts N BrettPhos Pd G4 (5 mol %), BrettPhos (5 mol %), K3PO4 TsN t-BuOH, 100 °C Cl NH H 2N 133 134 Tricycle 134 A 20 mL glass vial containing tryptamine 133 (1.0 g, 2.64 mmol, 1.0 equiv) was brought into a nitrogen-filled glovebox. To this vial were added BrettPhos Pd G4 (121 mg, 0.132 mmol, 5 mol %), BrettPhos (71 mg, 0.132 mmol, 5 mol %), and K3PO4 (784 mg, 3.70 mmol, 1.4 equiv), followed by t-BuOH (6.6 mL). The vial was sealed with a PTFElined cap, removed from the glovebox, and stirred at 100 °C in a metal heating block. After 3 days, the reaction mixture was partitioned between CH2Cl2 and water and the layers were Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 311 separated. The aqueous phase was extracted with CH2Cl2 (3x), and the combined organic phases were concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (40% EtOAc/hexanes) to afford the title compound as a beige foam (816 mg, 2.38 mmol, 90% yield); 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.76 (m, 2H), 7.33 (d, J = 1.4 Hz, 1H), 7.25 – 7.20 (m, 2H), 6.56 (d, J = 8.1 Hz, 1H), 6.27 (d, J = 8.1 Hz, 1H), 3.70 (s, 3H), 3.37 (t, J = 5.9 Hz, 2H), 2.91 (ddd, J = 6.9, 5.5, 1.4 Hz, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 144.1, 140.5, 137.1, 135.8, 129.4, 127.7, 124.0, 122.6, 120.2, 115.2, 110.7, 105.0, 57.5, 43.0, 22.8, 21.7; IR (Neat Film, NaCl) 3384, 2956, 2834, 1595, 1512, 1421, 1356, 1260, 1170, 1103, 1035, 977, 937, 795, 664 cm–1; HRMS (ESI+): m/z calc’d for C18H19N2O3S [M+H]+: 343.1111, found 343.1127. OMe OMe HC(OMe)3, Meldrum’s Acid DMF, 80 °C TsN TsN NH 134 N O O O O Me Me 136 Diester 136 To a ½ dram vial were added tricycle 134 (10 mg, 0.0292 mmol, 1 equiv) and Meldrum’s acid (5.0 mg, 0.035 mmol, 1.2 equiv). The headspace of the vial was evacuated and backfilled with nitrogen. Then, DMF (0.06 mL) and trimethyl orthoformate (6.4 µL, 0.0584 mmol, 2 equiv) were added. The vial was sealed with a PTFE-lined cap and stirred at 80 °C in a metal heating block. Upon heating, the reaction mixture slowly turned from beige to yellow to dark red. After 2 h, the reaction mixture was allowed to cool to 23 °C, diluted with H2O (1 mL), and extracted with EtOAc (5x0.5 mL). The combined organic Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 312 phases were washed with water (2x0.5 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (50% EtOAc/hexanes) to afford the title compound as an intensely yellow foam (10.5 mg, 0.0211 mmol, 72% yield); 1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.82 – 7.76 (m, 2H), 7.57 (t, J = 1.3 Hz, 1H), 7.30 – 7.27 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.23 (t, J = 6.1 Hz, 2H), 3.80 (s, 3H), 3.17 – 3.06 (m, 2H), 2.40 (s, 3H), 1.78 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.9, 160.9, 154.7, 146.7, 144.9, 136.5, 129.7, 127.9, 127.8, 125.6, 123.3, 122.8, 112.7, 111.9, 107.9, 103.5, 88.4, 56.2, 52.3, 27.1, 22.6, 21.8; IR (Neat Film, NaCl) 2939, 1688, 1567, 1511, 1438, 1359, 1278, 1190, 1108, 967, 785, 660 cm–1; HRMS (ESI+): m/z calc’d for C25H24N2NaO7S [M+Na]+: 519.1196, found 519.1192. OMe OMe TsN methyl propiolate TsN DMF, 80 °C NH 134 N CO2Me 138 “Push-pull” olefin 138 To a 1-dram glass vial were added tricycle 134 (43.5 mg, 0.127 mmol, 1.0 equiv), DMF (0.25 mL), and methyl propiolate (113 µL, 1.27 mmol, 10 equiv). The vial was sealed with a PTFE-lined cap and stirred at 80 °C in a metal heating block for 15 h. The reaction mixture was then diluted with water (2 mL) and extracted with EtOAc (5x0.5 mL). The combined organic extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→100% EtOAc/hexanes) to afford the title compound as a yellow foam (47.6 mg, 0.112 mmol, 88% yield); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 13.3 Hz, 1H), 7.82 – 7.73 (m, 2H), 7.46 (t, J = 1.4 Hz, 1H), 7.28 – 7.24 (m, 2H), Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 313 6.81 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.17 (d, J = 13.3 Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.72 – 3.68 (m, 2H), 3.02 (td, J = 6.1, 1.4 Hz, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.8, 145.0, 144.4, 143.3, 136.7, 129.4, 129.1, 127.7, 124.0, 123.2, 121.6, 113.0, 108.9, 107.7, 90.0, 56.5, 51.0, 44.9, 21.8, 21.6; IR (Neat Film, NaCl) 2948, 1695, 1605, 1511, 1440, 1359, 1275, 1171, 1108, 998, 801, 662 cm–1; HRMS (ESI+): m/z calc’d for C22H23N2O5S [M+H]+: 427.1322, found 427.1322. OMe OMe TsN Eaton’s Reagent 60 °C N CO2Me 138 HN Ts O N 139 Quinolone 139 To a 1-dram glass vial were added ester 138 (25.6 mg, 0.060 mmol, 1.0 equiv) and Eaton’s reagent (0.6 mL). The vial was sealed with a PTFE-lined cap and stirred at 60 °C in a metal heating block for 2 h. The reaction mixture was then quenched with saturated aqueous K2CO3. The resulting solution was extracted with 1:1 EtOAc/CH2Cl2 (2x3 mL) and CH2Cl2 (2x3 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (10% MeOH/CH2Cl2) to afford the title compound as a light brown solid (8.1 mg, 0.0205 mmol, 34% yield); 1H NMR (400 MHz, CD2Cl2) δ 10.05 (br s, 1H), 7.93 – 7.84 (m, 2H), 7.51 (d, J = 7.5 Hz, 1H), 7.37 – 7.31 (m, 3H), 6.29 (d, J = 7.5 Hz, 1H), 4.27 (t, J = 6.6 Hz, 2H), 3.93 (s, 3H), 3.50 (t, J = 6.6 Hz, 2H), 2.38 (s, 3H); 13C NMR (100 MHz, CD2Cl2) δ 176.9, 145.4, 145.2, 139.2, 139.0, 130.9, 130.5, 128.2, 127.8, 127.5, 120.1, 118.9, 116.1, 112.3, 100.1, 56.4, 50.4, 22.5, 21.7; An IR spectrum could not be Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 314 obtained due to the difficulty associated with depositing a thin film of this compound; HRMS (ESI+): m/z calc’d for C21H19N2O4S [M+H]+: 395.1060, found 395.1067. O 140 Et3N/HOAc, 23 °C N O NH 142 143 Model aza-Michael adduct 143 To a 1-dram glass vial under air were added 1:1 (v/v) Et3N/HOAc (0.65 mL), tetrahydroquinoline (142, 0.07 mL, 0.52 mmol, 1.0 equiv), and cyclohexenone (140, 0.25 mL, 2.58 mmol, 5.0 equiv). After stirring at 23 °C for 19 h, the reaction mixture was diluted with water (7 mL), extracted with EtOAc (3x3 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→50% EtOAc/hexanes) to afford the title compound as a colorless oil that crystallized upon standing to form a white solid (49.1 mg, 0.214 mmol, 41% yield); 1H NMR (400 MHz, CDCl3) δ 7.09 – 7.01 (m, 1H), 7.01 – 6.93 (m, 1H), 6.68 – 6.57 (m, 2H), 4.09 – 3.95 (m, 1H), 3.29 (ddd, J = 11.5, 7.4, 4.3 Hz, 1H), 3.19 (ddd, J = 11.2, 7.1, 4.3 Hz, 1H), 2.75 (t, J = 6.4 Hz, 2H), 2.62 – 2.54 (m, 2H), 2.49 – 2.38 (m, 1H), 2.29 (td, J = 13.9, 6.4 Hz, 1H), 2.16 – 2.08 (m, 1H), 2.03 (dddd, J = 11.8, 8.2, 4.3, 2.3 Hz, 1H), 2.00 – 1.84 (m, 3H), 1.72 – 1.57 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 210.0, 144.6, 129.5, 127.3, 123.6, 116.4, 110.9, 56.2, 45.1, 41.6, 41.1, 28.8, 28.4, 22.7, 22.6; IR (Neat Film, NaCl) 2939, 2861, 1709, 1601, 1496, 1456, 1303, 1271, 1219, 1192, 1058, 745 cm–1; HRMS (ESI+): m/z calc’d for C15H20NO [M+H]+: 230.1539, found 230.1546. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 315 O OMe OMe TsN TsN 140 Et3N/HOAc, 23 °C N O NH 134 141 Aza-Michael adduct 141 To a 1/2-dram glass vial under air were added tricycle 134 (40 mg, 0.117 mmol, 1.0 equiv), 1:1 (v/v) Et3N/HOAc (0.23 mL), and cyclohexenone (140, 0.11 mL, 1.17 mmol, 10 equiv). After stirring at 23 °C for 30 h, the reaction mixture was quenched with saturated aq. NaHCO3 (7 mL). The resulting suspension was extracted with EtOAc (3x2 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 40→100% Et2O/hexanes) to afford the title compound as a beige foam (30 mg, 0.0684 mmol, 58% yield); 1H NMR (400 MHz, CDCl3) δ 7.82 – 7.73 (m, 2H), 7.33 (d, J = 1.4 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 6.58 (d, J = 8.3 Hz, 1H), 6.25 (d, J = 8.3 Hz, 1H), 3.92 (tt, J = 11.8, 4.0 Hz, 1H), 3.69 (s, 3H), 3.36 – 3.28 (m, 1H), 3.20 – 3.12 (m, 1H), 2.98 – 2.91 (m, 2H), 2.61 (ddt, J = 13.3, 4.3, 1.9 Hz, 1H), 2.58 – 2.50 (m, 1H), 2.44 (ddq, J = 14.3, 4.3, 2.0 Hz, 1H), 2.36 (s, 3H), 2.29 (td, J = 13.8, 6.3 Hz, 1H), 2.17 – 2.02 (m, 2H), 1.90 (qd, J = 12.5, 3.5 Hz, 1H), 1.66 (tdt, J = 12.4, 8.4, 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 209.9, 144.2, 140.2, 137.1, 135.5, 129.4, 127.7, 124.1, 123.2, 119.8, 115.2, 110.2, 102.9, 57.2, 55.8, 44.7, 41.9, 41.2, 28.5, 23.3, 22.8, 21.7; IR (Neat Film, NaCl) 2936, 2835, 1709, 1596, 1509, 1357, 1281, 1171, 1106, 914, 780, 733, 661 cm–1; HRMS (ESI+): m/z calc’d for C24H27N2O4S [M+H]+: 439.1686, found 439.1692. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine OMe 316 OMe TsN TsN N O NBS CH2Cl2, 23 °C 141 Br N O 149 Bromoarene 149 To a 1-dram glass vial under air were added tertiary aniline 141 (21.8 mg, 0.0497 mmol, 1.0 equiv) and CH2Cl2 (2 mL). Recrystallized NBS (9.3 mg, 0.0522 mmol, 1.05 equiv) was added rapidly with stirring, resulting in a brown color. After 15 mins, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (40% EtOAc/hexanes) to afford the title compound as a beige foam (18.8 mg, 0.0363 mmol, 73% yield); 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.73 (m, 2H), 7.41 (t, J = 1.4 Hz, 1H), 7.28 – 7.23 (m, 2H), 6.77 (s, 1H), 3.88 (tdd, J = 12.0, 4.9, 3.6 Hz, 1H), 3.71 (s, 3H), 3.43 – 3.29 (m, 2H), 2.84 – 2.70 (m, 2H), 2.67 – 2.53 (m, 2H), 2.38 (s, 3H), 2.38 – 2.32 (m, 1H), 2.23 (td, J = 14.0, 6.5 Hz, 1H), 2.11 (dtd, J = 11.3, 3.2, 1.8 Hz, 1H), 2.04 – 1.98 (m, 1H), 1.86 (qd, J = 12.4, 3.6 Hz, 1H), 1.49 (qt, J = 13.4, 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 209.9, 144.5, 142.7, 136.8, 133.3, 129.6, 127.7, 127.3, 122.3, 122.2, 114.5, 113.4, 106.2, 61.5, 56.7, 48.0, 43.0, 40.9, 30.8, 22.5, 22.2, 21.8; IR (Neat Film, NaCl) 2939, 2863, 1709, 1596, 1490, 1439, 1344, 1284, 1229, 1174, 1111, 1032, 993, 804, 735, 665, 608 cm–1; HRMS (ESI+): m/z calc’d for C24H26BrN2O4S [M+H]+: 517.0791, found 517.0806. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine OMe OMe TsN Pd(OAc)2 (0.3 equiv), PCy3 (0.4 equiv), K2CO3, 1-hexanol Br N 317 O 149 TsN OH DMF, 135 °C N 150 Tertiary alcohol 150 To a 1-dram glass vial was added bromoarene 149 (12 mg, 0.0232 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation. The vial was transferred to a nitrogen-filled glovebox. K2CO3 (6.4 mg, 0.0464 mmol, 2 equiv), Pd(OAc)2 (1.4 mg, 0.00624 mmol, 0.3 equiv), and PCy3 (2.6 mg, 0.00927 mmol, 0.4 equiv) were added to the vial. Then, DMF (1.15 mL) and 1-hexanol (14 µL, 0.116 mmol, 5.0 equiv) were added, the vial was sealed with a PTFE-lined cap and removed from the glovebox, and the reaction mixture was stirred at 135 °C in a metal heating block. After 25 h, the reaction mixture was allowed to cool to 23 °C, diluted with water (10 mL), and extracted with EtOAc (4x3 mL). The combined organic extracts were washed with water (2x3 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (50% EtOAc/hexanes) to afford tricycle 134 (2.3 mg, 0.00672 mmol, 29% yield) and the title compound as a brown film (1.7 mg, 0.00388 mmol, 17% yield); 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.79 (m, 2H), 7.29 (t, J = 1.5 Hz, 1H), 7.25 – 7.21 (m, 2H), 6.74 (s, 1H), 3.71 (d, J = 1.9 Hz, 3H), 3.60 – 3.56 (m, 1H), 3.28 – 3.19 (m, 1H), 3.18 – 3.08 (m, 1H), 2.99 – 2.94 (m, 2H), 2.37 (s, 3H), 2.20 – 2.13 (m, 1H), 2.09 (d, J = 2.7 Hz, 1H), 1.95 (dd, J = 11.7, 2.9 Hz, 1H), 1.74 – 1.69 (m, 2H), 1.36 (tdd, J = 13.8, 4.9, 2.7 Hz, 1H), 1.11 (dtt, J = 17.5, 6.4, 3.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 144.1, 139.5, 137.2, 133.2, 129.4, 129.4, 127.9, 122.9, 120.8, 120.2, 114.6, 105.8, 70.0, 57.5, 56.1, 47.0, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 318 40.8, 40.8, 29.0, 23.2, 21.7, 20.4; IR (Neat Film, NaCl) 3385, 2930, 2851, 1596, 1505, 1450, 1404, 1360, 1286, 1225, 1170, 1105, 978, 814, 735, 662 cm–1; HRMS (ESI+): m/z calc’d for C24H27N2O4S [M+H]+: 439.1686, found 439.1689. O O O OMe OMe TMSCl MeOH, 23 °C 151 152 Ketal 152 Prepared according to the procedure of Caubere starting with 1.0 g (8.92 mmol) of dione 151.34 Purification by silica gel flash chromatography (20% EtOAc/hexanes, fractions were analyzed by TLC with DNP staining) afforded ketal 152 as a colorless, fragrant oil (619 mg, 3.91 mmol, 44% yield). All characterization data matched those reported in the literature.34 O OMe OMe CuTC (20 mol %), CyPPh2 (20 mol %), t-BuOOt-Bu O OMe OMe PhH, 80 °C 153 152 Enone 153 Conditions for the synthesis of 153 were adapted from those reported for related compounds by Dong.35 To a 20 mL glass vial in a nitrogen-filled glovebox were added CuTC (24 mg, 0.126 mmol, 20 mol %), CyPPh2 (34 mg, 0.126 mmol, 20 mol %), benzene (6.3 mL), and a magnetic stir bar. The vial was sealed with a septum cap and removed from the glovebox. Ketal 152 (100 mg, 0.632 mmol, 1.0 equiv) and di-tert-butyl peroxide (0.17 mL, 0.948 mmol, 1.5 equiv) were added by injection. The reaction mixture was then heated to 80 °C in a metal heating block, resulting in a deep green solution. After 23 h, the reaction mixture was allowed to cool to 23 °C, concentrated under reduced pressure, and purified Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 319 by silica gel flash chromatography (33% EtOAc/hexanes) to afford the title compound as a colorless oil (38.1 mg, 0.244 mmol, 39% yield); 1H NMR (400 MHz, C6D6) δ 6.2 – 6.1 (m, 1H), 5.8 (dtd, J = 10.0, 2.0, 0.9 Hz, 1H), 3.1 (d, J = 1.0 Hz, 6H), 1.9 – 1.8 (m, 2H), 1.8 – 1.7 (m, 2H); 13C NMR (100 MHz, C6D6) δ 192.1, 148.9, 128.1, 97.0, 49.6, 31.1, 24.6; IR (Neat Film, NaCl) 2940, 2834, 1694, 1623, 1437, 1388, 1310, 1231, 1160, 1117, 1060, 916, 850, 801 cm–1; HRMS (ESI+): m/z calc’d for C8H12NaO3 [M+Na]+: 179.0679, found 179.0678. OMe OMe 1. 153, Et3N/AcOH, 23 °C 2. NBS, CH2Cl2, 23 °C TsN TsN Br N NH 134 154 O OMe OMe Bromoarene 154 To a 1-dram glass vial under air were added tricycle 134 (50 mg, 0.146 mmol, 1.0 equiv), enone 153 (114 mg, 0.730 mmol, 5.0 equiv), and 1:1 (v/v) Et3N/HOAc (0.15 mL). The reaction mixture was stirred at 23 °C for 21 h, then partitioned between water and EtOAc. The layers were separated, and the aqueous phase was extracted with EtOAc (3x). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (80% Et2O/hexanes) to afford an intermediate tertiary aniline as a beige foam (59 mg, 0.118 mmol, 81% yield); 1H NMR (400 MHz, CDCl3) δ 7.81 – 7.76 (m, 2H), 7.33 (t, J = 1.4 Hz, 1H), 7.25 – 7.21 (m, 2H), 6.58 (d, J = 8.3 Hz, 1H), 6.27 – 6.21 (m, 1H), 3.90 (tt, J = 11.8, 3.7 Hz, 1H), 3.69 (s, 3H), 3.41 – 3.37 (m, 1H), 3.36 (s, 3H), 3.22 (s, 3H), 3.15 (dt, J = 11.2, 6.3 Hz, 1H), 2.98 – 2.87 (m, 3H), 2.61 (ddd, J = 12.0, 3.9, 2.3 Hz, 1H), Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 320 2.41 (dt, J = 14.3, 3.7 Hz, 1H), 2.37 (s, 3H), 2.17 (qd, J = 13.1, 4.0 Hz, 1H), 1.95 – 1.85 (m, 1H), 1.60 – 1.55 (m, 1H). To a sample of this intermediate aniline (19.5 mg, 0.0391 mmol, 1.0 equiv) also containing secondary aniline 134 as a major impurity (7.6 mg, 0.0222 mmol) in a 1-dram glass vial was added CH2Cl2 (2.5 mL). Recrystallized NBS (11 mg, 0.0613 mmol, 1.0 equiv w.r.t. combined total aniline) was added rapidly with stirring, resulting in a brown color. After 10 mins, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (80% Et2O/hexanes) to afford the title compound as an off-white foam (21.1 mg, 0.0365 mmol, 93% yield); 1H NMR (400 MHz, C6D6) δ 7.84 – 7.78 (m, 2H), 7.47 (t, J = 1.5 Hz, 1H), 6.70 (s, 1H), 6.66 – 6.60 (m, 2H), 3.99 (tt, J = 12.4, 4.0 Hz, 1H), 3.28 (s, 3H), 3.18 (s, 3H), 2.97 (s, 3H), 2.96 – 2.91 (m, 1H), 2.88 (ddd, J = 6.6, 5.3, 2.8 Hz, 2H), 2.77 (ddd, J = 11.7, 4.2, 2.2 Hz, 1H), 2.23 – 2.10 (m, 2H), 1.94 (dt, J = 14.5, 3.4 Hz, 1H), 1.86 – 1.76 (m, 1H), 1.75 (s, 3H), 1.57 (dq, J = 13.0, 3.4 Hz, 1H), 1.18 (td, J = 14.0, 4.0 Hz, 1H); 13C NMR (100 MHz, C6D6) δ 202.6, 144.0, 143.1, 137.9, 133.8, 129.4, 127.4, 123.0, 122.5, 114.8, 114.1, 106.2, 100.9, 62.0, 56.3, 49.9, 48.5, 45.8, 42.8, 30.6, 27.4, 22.2, 21.1; IR (Neat Film, NaCl) 2936, 2835, 1732, 1692, 1597, 1490, 1360, 1285, 1222, 1172, 1111, 1057, 992, 933, 806, 666 cm–1; HRMS (ESI+): m/z calc’d for C26H30BrN2O6S [M+H]+: 577.1002, found 577.1015. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 321 OMe OMe TsN Pd(PPh3)4 (15 mol %), Et3N (10 equiv) Br N 154 O TsN OMe DMF, 110 °C OMe OMe N O 156 Aza[3.2.2]bicyclononene 156 To a flame-dried 1-dram glass vial was added bromoarene 154 (5 mg, 0.00866 mmol, 1.0 equiv) as a stock solution in benzene. Traces of water were azeotropically removed by addition of two additional portions of benzene followed by rotary evaporation. The vial was transferred to a nitrogen-filled glovebox and Pd(PPh3)4 (1.5 mg, 0.0013 mmol, 15 mol %), DMF (0.22 mL), and Et3N (12 µL, 0.0866 mmol, 10 equiv) were added. The vial was sealed with a PTFE-lined cap, removed from the glovebox, and stirred at 110 °C in a metal heating block for 18 h. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (4x0.5 mL). The combined organic extracts were washed with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative TLC on basic alumina (60% EtOAc/hexanes) to afford the title compound as a beige film (2.5 mg, 0.00536 mmol, 62% yield); 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 1.3 Hz, 1H), 7.22 (d, J = 8.0 Hz, 2H), 6.84 (s, 1H), 3.68 (d, J = 1.0 Hz, 3H), 3.56 – 3.50 (m, 1H), 3.43 (d, J = 1.1 Hz, 3H), 3.32 (qdd, J = 11.1, 6.7, 5.1 Hz, 2H), 3.01 – 2.86 (m, 3H), 2.71 – 2.62 (m, 1H), 2.55 (td, J = 11.6, 4.7 Hz, 1H), 2.42 (dd, J = 10.0, 4.9 Hz, 1H), 2.37 (s, 3H), 2.32 (dd, J = 5.2, 2.6 Hz, 1H), 2.04 – 1.95 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 204.3, 144.2, 140.7, 137.0, 132.0, 129.4, 127.8, 124.0, 123.6, 120.3, 116.8, 115.0, 106.6, 82.8, 56.8, 56.6, 51.9, 51.8, 44.2, 31.2, 26.3, 23.5, 21.7; IR (Neat Film, NaCl) 2926, 2851, 1727, 1494, 1366, 1285, 1171, 1108, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 322 1019, 807, 670 cm–1; HRMS (ESI+): m/z calc’d for C25H27N2O5S [M+H]+: 467.1635, found 467.1636. OMe OMe TsN TsN Pd(PPh3)4 (1.2 equiv) Br N O DMF, 110 °C N 154 OMe OMe OH OMe OMe 155 Bicyclic ketal 155 To a 1-dram glass vial was added bromoarene 154 (53.7 mg, 0.0930 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation. The vial was transferred to a nitrogen-filled glovebox, and Pd(PPh3)4 (125 mg, 0.108 mmol, 1.16 equiv) and DMF (2.4 mL) were added. The vial was sealed with a PTFE-lined cap, removed from the glovebox, and heated to 110 °C in a metal heating block. After stirring for 17 h, the reaction mixture was allowed to cool to 23 °C, diluted with water and brine, and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash chromatography (45% EtOAc/hexanes) to afford the desired product as a beige film (40 mg, 0.0802 mmol, 86% yield); 1H NMR (400 MHz, C6D6) δ 7.97 – 7.91 (m, 2H), 7.47 (s, 1H), 7.19 (s, 1H), 6.62 – 6.57 (m, 2H), 3.63 (s, 3H), 3.34 (s, 3H), 3.04 (s, 3H), 2.99 (q, J = 2.4 Hz, 1H), 2.79 (td, J = 9.8, 4.1 Hz, 1H), 2.65 (ddd, J = 15.2, 4.8, 1.8 Hz, 1H), 2.58 – 2.46 (m, 2H), 2.11 (dd, J = 11.8, 2.9 Hz, 1H), 1.98 (ddd, J = 11.9, 3.5, 2.2 Hz, 1H), 1.73 (s, 3H), 1.59 – 1.50 (m, 2H), 1.28 – 1.11 (m, 2H); 13C NMR (100 MHz, C6D6) δ 143.4, 139.6, 138.1, 133.7, 129.4, 124.3, 121.1, 120.3, 118.0, 114.9, 110.5, 102.7, 75.7, 58.2, 54.7, 51.3, 48.8, 46.7, 38.2, 27.4, 27.0, 23.3, 21.1 (an additional Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 13 323 C resonance associated with the tosyl group is likely obscured by the solvent signal); IR (Neat Film, NaCl) 2934, 2832, 1504, 1451, 1406, 1360, 1283, 1227, 1169, 1103, 967, 913, 813, 663 cm–1; HRMS (ESI+): m/z calc’d for C26H31N2O6S [M+H]+: 499.1897, found 499.1890. OMe OMe TsN TsN N OH OMe OMe TFA CH2Cl2/H2O, 23 °C 155 OH O N 157 α-Hydroxyketone 157 To a 1-dram glass vial under air were added ketal 155 (10 mg, 0.020 mmol, 1.0 equiv), CH2Cl2 (1 mL), water (0.1 mL), and TFA (6.0 µL, 0.078 mmol, 3.9 equiv). The reaction mixture was stirred at 23 °C for 40 min, then neutralized with saturated aq. NaHCO3 (1 mL) and stirred for an additional 10 min. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3x0.5 mL). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound as a beige film (9.0 mg, 0.020 mmol, >99% yield); 1H NMR (400 MHz, C6D6) δ 7.72 – 7.67 (m, 2H), 7.29 (t, J = 1.3 Hz, 1H), 6.66 (s, 1H), 6.44 – 6.36 (m, 2H), 4.55 (s, 1H), 3.20 (s, 3H), 2.61 (td, J = 3.6, 1.8 Hz, 1H), 2.55 – 2.46 (m, 1H), 2.45 – 2.33 (m, 1H), 2.32 – 2.23 (m, 2H), 2.15 (dt, J = 12.5, 3.4 Hz, 1H), 1.89 – 1.72 (m, 2H), 1.52 (s, 3H), 1.47 (dd, J = 12.4, 2.8 Hz, 2H), 0.84 (tdd, J = 13.8, 6.0, 2.8 Hz, 1H); 13C NMR (100 MHz, C6D6) δ 209.9, 143.7, 140.4, 138.0, 133.2, 129.4, 124.3, 121.8, 120.9, 116.3, 114.2, 107.0, 75.9, 57.2, 54.6, 46.8, 39.6, 33.5, 32.3, 23.1, 21.1 (an additional 13C resonance associated with the tosyl group is obscured by the solvent signal); IR (Neat Film, NaCl) 3466, 2925, 2853, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 324 1712, 1596, 1505, 1462, 1435, 1367, 1285, 1223, 1171, 1105, 1010, 970, 892, 816, 735, 665 cm–1; HRMS (ESI+): m/z calc’d for C24H25N2O5S [M+H]+: 453.1479, found 453.1472. OMe OMe TsN N OH OMe OMe TMSOTf, i-Pr2NEt TsN OTMS OMe CH2Cl2, 23 °C 155 N 160 Methyl enol ether 160 To a 1-dram glass vial was added ketal 155 (5 mg, 0.010 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation. The headspace of the vial was evacuated and backfilled with nitrogen. CH2Cl2 (1 mL) and i-Pr2NEt (27 µL, 0.16 mmol, 16 equiv) were added, followed by the addition of TMSOTf (18 µL, 0.10 mmol, 10 equiv). The reaction mixture was stirred at 23 °C for 30 min, then quenched with aq. NaOH (0.3 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (1x). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative TLC on silica gel (50% EtOAc/hexanes) to afford the title compound as a beige film (3.7 mg, 0.00687 mmol, 69% yield); 1H NMR (400 MHz, C6D6) δ 7.94 – 7.87 (m, 2H), 7.40 (t, J = 1.7 Hz, 1H), 7.27 (s, 1H), 6.58 (d, J = 8.2 Hz, 2H), 4.15 (dd, J = 4.9, 2.4 Hz, 1H), 3.63 (s, 3H), 3.20 (dt, J = 4.6, 2.9 Hz, 1H), 2.94 (s, 3H), 2.91 – 2.84 (m, 1H), 2.68 – 2.55 (m, 2H), 2.53 – 2.43 (m, 1H), 2.20 – 1.99 (m, 4H), 1.73 (s, 3H), 0.29 (s, 9H); 13C NMR (100 MHz, C6D6) δ 159.3, 143.2, 139.5, 138.2, 131.5, 129.3, 123.8, 121.5, 121.4, 120.3, 114.8, 109.0, 90.9, 71.6, 58.3, 54.1, 53.6, 47.3, 38.5, 30.3, 23.2, 21.1, 2.1 (an additional 13C resonance associated with the tosyl group is likely obscured by the solvent signal); IR (Neat Film, NaCl) 2932, 2834, 1657, 1597, 1505, 1463, 1406, 1361, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 325 1285, 1249, 1172, 1104, 1024, 932, 843, 682 cm–1; HRMS (ESI+): m/z calc’d for C28H35N2O5SSi [M+H]+: 539.2030, found 539.2028. OMe OMe TsN 1. TMSOTf, i-Pr2NEt, CH2Cl2, 23 °C OH O TsN OTMS O 2. Pd(OAc)2, DMSO, 28 °C N N 157 168 Enone 168 To a 1-dram glass vial was added ketone 157 (9 mg, 0.020 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation. The headspace of the vial was evacuated and backfilled with nitrogen. CH2Cl2 (0.5 mL) and i-Pr2NEt (40 µL, 0.23 mmol, 11 equiv) were added, followed by the addition of TMSOTf (28 µL, 0.15 mmol, 7.5 equiv). The reaction mixture was stirred at 23 °C for 1 h, after which LC–MS analysis indicated incomplete conversion. Additional i-Pr2NEt (14 µL, 0.080 mmol, 4 equiv) and TMSOTf (10 µL, 0.055 mmol, 2.8 equiv) were therefore added, and stirring was continued for an additional 40 min, after which LC–MS analysis indicated complete conversion. The reaction mixture was loaded directly onto a silica gel preparative TLC plate. Elution with 25% EtOAc/hexanes afforded a silyl enol ether that was used directly in the following step. This intermediate was transferred to a 20 mL glass vial and brought into a nitrogenfilled glovebox. Pd(OAc)2 (9 mg, 0.040 mmol, 2.0 equiv) and DMSO (1.2 mL) were added. The reaction mixture was stirred at 28 °C for 4 days, whereafter the vial was removed from the glovebox and the reaction mixture diluted with water and extracted with CH2Cl2 (4x). The combined organic extracts were washed with 1 M aq. LiCl, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative TLC Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 326 on silica gel (70% EtOAc/hexanes) to afford the title compound as a yellow solid (7 mg, 0.013 mmol, 65% yield over 2 steps); 1H NMR (400 MHz, C6D6) δ 7.87 – 7.78 (m, 2H), 7.47 (d, J = 1.6 Hz, 1H), 7.04 (s, 1H), 6.57 (d, J = 8.0 Hz, 2H), 5.87 (d, J = 9.9 Hz, 1H), 5.81 (ddd, J = 10.0, 5.1, 1.8 Hz, 1H), 3.43 (s, 3H), 3.32 (td, J = 4.4, 2.8 Hz, 1H), 2.65 – 2.57 (m, 2H), 2.41 – 2.29 (m, 1H), 2.23 (ddd, J = 12.0, 2.7, 1.8 Hz, 1H), 2.15 – 1.99 (m, 2H), 1.71 (s, 3H), 0.37 (s, 9H); 13C NMR (100 MHz, C6D6) δ 196.0, 143.7, 142.0, 141.0, 137.9, 130.8, 129.6, 129.4, 124.5, 123.0, 121.1, 115.7, 114.0, 107.3, 77.0, 56.8, 54.6, 47.2, 38.6, 23.1, 21.1, 2.7 (an additional 13C resonance associated with the tosyl group is likely obscured by the solvent signal); IR (Neat Film, NaCl) 2925, 2854, 1693, 1504, 1463, 1352, 1263, 1173, 1107, 1024, 963, 932, 844, 759, 666 cm–1; HRMS (ESI+): m/z calc’d for C27H31N2O5SSi [M+H]+: 523.1717, found 523.1718. OMe OMe TsN TsN OTMS O N 168 OTMS O PhSH, cat. Et3N CCl4, 23 °C N 169 SPh Phenyl sulfide 169 To a 1-dram glass vial was added enone 168 (12.4 mg, 0.024 mmol, 1.0 equiv), CCl4 (0.1 mL), thiophenol (6 µL, 0.059 mmol, 2.5 equiv), and Et3N (2.0 µL, 0.014 mmol, 0.6 equiv). The reaction mixture was stirred at 23 °C for 35 min, during which time the yellow color of the starting material disappeared. The reaction mixture was loaded directly onto a silica gel preparative TLC plate. Elution with 40% EtOAc/hexanes afforded the title compound as a colorless film (15.6 mg, 0.024 mmol, >99% yield); 1H NMR (400 MHz, C6D6) δ 7.92 – 7.86 (m, 2H), 7.49 (d, J = 1.3 Hz, 1H), 7.30 – 7.25 (m, 2H), 7.02 – 6.87 (m, 4H), 6.63 – 6.58 (m, 2H), 3.67 (dq, J = 6.1, 2.1 Hz, 1H), 3.46 (s, 3H), 3.31 (dt, J = 4.9, 2.3 Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 327 Hz, 1H), 2.94 (dd, J = 12.5, 2.9 Hz, 1H), 2.72 – 2.61 (m, 1H), 2.56 – 2.42 (m, 4H), 2.37 (dt, J = 15.8, 1.8 Hz, 1H), 2.09 (ddd, J = 12.5, 3.4, 2.3 Hz, 1H), 1.72 (s, 3H), 0.51 (s, 9H); 13 C NMR (100 MHz, C6D6) δ 204.7, 143.8, 140.7, 137.9, 134.1, 132.7, 131.2, 129.5, 129.4, 127.9, 124.3, 121.8, 121.0, 117.3, 114.0, 107.4, 79.4, 58.3, 57.2, 50.2, 46.8, 40.2, 35.2, 23.1, 21.1, 3.0 (an additional 13C resonance associated with the tosyl group is likely obscured by the solvent signal); IR (Neat Film, NaCl) 2934, 2847, 1725, 1502, 1358, 1285, 1249, 1172, 1106, 963, 845, 665 cm–1; HRMS (ESI+): m/z calc’d for C33H37N2O5S2Si [M+H]+: 633.1908, found 633.1895. O S O NH2 176 CO2Et Aminothiophene 176 Prepared according to the procedure of Andersen, Møller, and coworkers from 1,4cyclohexandione monoethylene ketal (175).41 All characterization data matched those reported in the literature. O O S O NH2 176 KOH S NH3+ Cl– O EtOH, reflux CO2Et 214 CO2H Amino acid hydrochloride 214 To a 350 mL glass pressure vessel under air were added aminothiophene 176 (22.2 g, 78.35 mmol, 1.0 equiv), KOH (17.6 g, 313.4 mmol, 4.0 equiv), EtOH (165 mL), and water (33 mL). The flask was sealed, and the reaction mixture was stirred at 75 °C in an oil bath for 12 h. The reaction mixture was subsequently transferred to an Erlenmeyer flask and cooled to 0 °C in an ice bath. The solution was acidified with 1 N aq. HCl (375 mL), Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 328 resulting in the formation of a thick precipitate. The product was collected by vacuum filtration and washed with water. The resulting clay-like material was transferred to a round bottom flask with MeOH. The solvent was removed under reduced pressure and the product was dried under high vacuum to afford the title compound as a cream-colored powder (17.95 g, 61.53 mmol, 79% yield assuming complete conversion to hydrochloride); 1 H NMR (400 MHz, DMSO) δ 11.81 (br s, 1H), 7.20 (br s, 2H), 3.90 (s, 4H), 2.72 (t, J = 6.4 Hz, 2H), 2.59 (s, 2H), 1.75 (t, J = 6.5 Hz, 2H); 13C NMR (100 MHz, DMSO) δ 166.7, 163.4, 130.9, 112.4, 107.6, 102.6, 63.9, 34.3, 31.0, 25.1; IR (Neat Film, NaCl) 3409, 2890, 1635, 1580, 1474, 1451, 1353, 1294, 1267, 1105, 1054, 1036, 926, 642 cm–1; HRMS (ESI– ): m/z calc’d for C11H12NO4S [M–H]–: 254.0493, found 254.0494. O S NH3+ Cl– O 214 TFA, then Ac2O, Et3N, DMAP CO2H CH2Cl2, 23 °C O S O NHAc 177 Acetamidothiophene 177 To a 500 mL round bottom flask containing hydrochloride salt 214 (10.78 g, 37.0 mmol, 1.0 equiv) were added CH2Cl2 (186 mL) and TFA (8.6 mL, 111 mmol, 3.0 equiv). After stirring for 2 h at 23 °C, DMAP (230 mg, 1.86 mmol, 5 mol %) and Et3N (26 mL, 185 mmol, 5.0 equiv) were added rapidly, followed by acetic anhydride (5.25 mL, 56.0 mmol, 1.5 equiv). After an additional 4 h, the reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (35% acetone/hexanes) to afford a crude product. Repurification by silica gel flash chromatography (30% acetone/hexanes) provided the title compound as a cream-colored solid (6.95 g, 27.4 mmol, 74% yield); 1H NMR (400 MHz, C6D6) δ 6.64 (br s, 1H), 6.14 (s, 1H), 3.52 – 3.40 (m, 4H), 2.85 (s, 2H), 2.74 (tt, J = 6.5, 1.6 Hz, 2H), 1.86 (t, J = 6.5 Hz, 2H), 1.39 (s, 3H); 13C NMR Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 329 (100 MHz, C6D6) δ 165.7, 137.5, 130.9, 125.4, 111.7, 108.9, 64.5, 35.1, 34.9, 32.5, 32.4, 24.4, 22.7; IR (Neat Film, NaCl) 3260, 3089, 3046, 2931, 2892, 1650, 1583, 1434, 1370, 1301, 1263, 1114, 1060, 986, 946, 837, 737 cm–1; HRMS (ESI+): m/z calc’d for C12H16NO3S [M+H]+: 254.0845, found 254.0847. OMe OMe O TsN S NHAc + NH 1. InCl3, Et3SiH, MeOH, 23 °C 2. NBS, THF, –78→23 °C 178 134 TsN Br N S NHAc 179 Bromoarene 179 To a 40 mL glass vial were added ketal 177 (500 mg, 1.97 mmol, 1.0 equiv). The vial was sealed with a PTFE/silicone septum, and the headspace was evacuated and backfilled with nitrogen. THF (13 mL) and 4 N aq. HCl (1.98 mL, 7.92 mmol, 4.0 equiv) were added and the vial was sealed and stirred at 66 °C in a metal heating block. After 1.5 h, the reaction mixture was allowed to cool to 23 °C, neutralized with saturated aq. NaHCO3, and extracted with CH2Cl2 (3x). The combined organic extracts were concentrated under reduced pressure and dried under high vacuum with a P4O10 trap to remove water, providing 420 mg of crude ketone 178 containing ~10% of an unknown impurity, but that was sufficiently pure to use in the next step. To a 20 mL glass vial were added tricycle 134 (182 mg, 0.532 mmol, 1.0 equiv), the crude ketone prepared from ketal 177 (144 mg, 0.692 mmol, 1.3 equiv assuming a pure compound), and InCl3 (235 mg, 1.06 mmol, 2.0 equiv). The headspace of the vial was evacuated and backfilled with nitrogen. Dry MeOH (3.6 mL) and triethylsilane (0.26 mL, 1.6 mmol, 3.0 equiv) were added by syringe and the reaction mixture was allowed to stir Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 330 at 23 °C for 19 h. At this point, additional triethylsilane (0.26 mL, 1.6 mmol, 3.0 equiv) was added. After 2 more days, additional triethylsilane (0.26 mL, 1.6 mmol, 3.0 equiv) and intermediate ketone 178 (50 mg, 0.24 mmol, 0.45 equiv assuming a pure compound) were added. After stirring for an additional 21 h at 23 °C, the reaction mixture was diluted with saturated aq. NaHCO3 and extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash chromatography (35% acetone/hexanes) to afford an intermediate tertiary aniline as an off-white foam (231 mg, 0.431 mmol, 81% yield); 1H NMR (400 MHz, C6D6) δ 7.95 – 7.87 (m, 2H), 7.48 (s, 1H), 6.64 (d, J = 8.1 Hz, 2H), 6.50 (d, J = 8.3 Hz, 1H), 6.19 (s, 1H), 6.04 (d, J = 8.4 Hz, 1H), 3.90 – 3.74 (m, 1H), 3.56 (s, 3H), 2.79 – 2.61 (m, 3H), 2.57 – 2.40 (m, 5H), 1.73 (s, 3H), 1.71 – 1.64 (m, 1H), 1.62 – 1.56 (m, 1H), 1.55 (s, 3H). To a 50 mL round bottom flask was added this intermediate tertiary aniline (103.4 mg, 0.193 mmol, 1.0 equiv), and the headspace of the flask was evacuated and backfilled with nitrogen. THF (5 mL) was added, and the flask was cooled to –78 °C. Subsequently, a solution of NBS (34.3 mg, 0.193 mmol, 1.0 equiv) was added by syringe pump over a period of 1 h with rapid stirring. After completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to 23 °C. The reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (30% acetone/hexanes) to afford the title compound as an off-white foam of sufficient purity for use in the next step (70 mg, 0.114 mmol, 59% yield); a nearly pure sample for analysis was obtained by preparative HPLC (SiO2 column, 30→100% acetone/hexanes over 18 min at 12 mL/min). 1H NMR (400 MHz, C6D6) δ 7.86 – 7.80 (m, 2H), 7.52 (s, 1H), 7.35 (s, 1H), 6.75 (s, 1H), 6.65 (d, J = 8.1 Hz, 2H), 6.28 (s, 1H), 4.24 (ddq, J = 13.9, 7.9, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 331 2.6 Hz, 1H), 3.21 (s, 3H), 3.05 – 2.91 (m, 2H), 2.86 (ddd, J = 13.9, 7.8, 4.9 Hz, 1H), 2.72 (ddd, J = 14.5, 11.3, 2.4 Hz, 1H), 2.55 – 2.36 (m, 2H), 2.35 – 2.18 (m, 2H), 1.87 – 1.69 (m, 1H), 1.76 (s, 3H), 1.59 – 1.49 (m, 1H), 1.56 (s, 3H); 13C NMR (100 MHz, C6D6) δ 166.1, 144.0, 142.8, 137.9, 137.6, 134.8, 131.1, 129.5, 128.0, 127.7, 126.8, 123.1, 122.3, 115.4, 114.3, 112.2, 106.1, 59.9, 56.4, 43.1, 29.6, 28.8, 26.3, 22.8, 22.6, 21.1. Additional peaks in the 1H NMR spectrum at 1.60 ppm and in the 13C NMR spectrum at 29.2 and 176.8 ppm arise from an unknown impurity; correlations to the resonances of bromoarene 179 are not observed in a 1H/13C HMBC experiment; IR (Neat Film, NaCl) 3256, 2932, 2842, 1713, 1582, 1487, 1347, 1288, 1228, 1169, 1112, 804, 684 cm–1; HRMS (ESI+): m/z calc’d for C28H29BrN3O4S2 [M+H]+: 614.0777, found 614.0786. OMe OMe TsN Pd(dba)2 (15 mol %) XPhos (45 mol %), K2CO3 Br N NAc TsN S dioxane, 120 °C S NHAc 179 N 184 Thioimidate 184 To a 1-dram glass vial in a nitrogen-filled glovebox were added bromoarene 179 (18 mg, 0.0293 mmol, 1.0 equiv), 1,4-dioxane (0.3 mL), and K2CO3 (6.1 mg, 0.0441 mmol, 1.5 equiv). Pd(dba)2 (2.5 mg, 0.0043 mmol, 0.15 equiv) and XPhos (3.5 mg, 0.0132 mmol, 0.45 equiv) were added as a stock solution in 1,4-dioxane (0.44 mL, prestirred for 10 min at 28 °C). The vial was sealed with a PTFE-lined cap, removed from the glovebox, and stirred at 120 °C in a metal heating block for 6 h. Then, the reaction mixture was allowed to cool to 23 °C and concentrated under reduced pressure. The crude product was purified by preparative TLC on silica gel (100% EtOAc) to afford the title compound as a brown Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 332 solid (11.2 mg of material containing 10 wt % EtOAc by 1H NMR analysis, 0.0189 mmol, 65% yield); 1H NMR (400 MHz, C6D6) δ 7.87 – 7.82 (m, 2H), 7.47 (s, 1H), 6.86 (s, 1H), 6.62 – 6.56 (m, 2H), 6.11 (d, J = 1.4 Hz, 1H), 3.24 (s, 3H), 2.74 (p, J = 2.9 Hz, 1H), 2.72 – 2.55 (m, 2H), 2.51 – 2.42 (m, 2H), 2.38 (dt, J = 12.3, 2.7 Hz, 1H), 2.33 (s, 3H), 1.91 (dt, J = 13.9, 6.5 Hz, 1H), 1.72 (s, 3H), 1.69 – 1.58 (m, 3H), 0.84 – 0.70 (m, 1H); 13C NMR (100 MHz, C6D6) δ 184.5, 183.6, 175.0, 143.8, 140.1, 137.9, 133.4, 129.4, 124.3, 123.2, 121.9, 120.9, 114.4, 112.4, 109.1, 63.5, 57.2, 52.9, 47.1, 40.3, 31.5, 27.6, 25.1, 23.0, 21.1 (an additional 13C resonance associated with the tosyl group is likely obscured by the solvent signal); IR (Neat Film, NaCl) 2924, 1665, 1503, 1362, 1285, 1234, 1172, 1106, 1004, 672 cm–1; HRMS (ESI+): m/z calc’d for C28H28N3O4S2 [M+H]+: 534.1516, found 534.1524. O S NH3+ Cl– O 214 TFA, 23 °C then TFAA, Py, 0→23 °C CH2Cl2 CO2H O S O NHTFA 187 Trifluoroacetamidothiophene 187 To a 500 mL round bottom flask was added hydrochloride salt 214 (14.29 g, 48.98 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation. Then, the headspace of the flask was evacuated and backfilled with nitrogen, and CH2Cl2 (150 mL) and TFA (11.2 mL, 146.9 mmol, 3.0 equiv) were added. After 15 min, additional CH2Cl2 (50 mL) was added to reduce the viscosity of the mixture. The reaction mixture was stirred for 2.5 h at 23 °C, whereafter it was cooled to 0 °C in an ice bath and pyridine (19.7 mL, 244.9 mmol, 5.0 equiv) was added rapidly. TFAA (10.2 mL, 73.47 mmol, 1.5 equiv) was then added, and the ice bath was removed. After stirring for an additional 16 h at 23 °C, silica gel was Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 333 added, and the reaction mixture was concentrated under reduced pressure and purified by silica gel flash chromatography (33% EtOAc/hexanes) to afford the title compound as an orange solid (9.67 g, 31.47 mmol, 64% yield); 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 6.59 (s, 1H), 4.06 – 3.98 (m, 4H), 2.91 (d, J = 1.5 Hz, 2H), 2.74 (tt, J = 6.5, 1.6 Hz, 2H), 1.94 (t, J = 6.5 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 154.2, 153.8, 153.4, 153.0, 133.4, 131.8, 127.9, 120.1, 117.2, 116.1, 114.4, 111.5, 108.5, 64.8, 34.9, 31.7, 24.0; IR (Neat Film, NaCl) 3248, 3097, 2894, 1713, 1589, 1434, 1362, 1250, 1169, 1060, 946, 905, 842, 739 cm–1; HRMS (ESI+): m/z calc’d for C12H13F3NO3S [M+H]+: 308.0563, found 308.0561. OMe OMe O TsN NHTFA + NH 134 TsN S InCl3, Et3SiH MeOH, 23 °C 188 N S NHTFA 215 Tertiary aniline 215 To a 100 mL round bottom flask containing thiophene-ketal 187 (1.64 g, 5.34 mmol, 1.5 equiv) under nitrogen and equipped with a reflux condenser were added THF (27 mL) and 4 N aq. HCl (5.3 mL, 21.2 mmol, 4.0 equiv w.r.t. ketal). The reaction mixture was heated to reflux and stirred for 1.5 h, then allowed to cool to 23 °C and quenched with saturated aq. NaHCO3 (100 mL). The resulting mixture was extracted with CH2Cl2 (3x40 mL). The combined organic extracts were washed with brine, and the brine phase was back-extracted once with CH2Cl2. The combined organic phases were dried over a mixture of Na2SO4 and MgSO4 and concentrated under reduced pressure to afford crude ketone 188 as an orange solid that was used directly without further purification. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 334 To a 50 mL round bottom flask were added tricyclic aniline 134 (1.22 g, 3.56 mmol, 1.0 equiv), the crude ketone resulting from hydrolysis of ketal 187 (5.34 mmol assuming pure compound), and InCl3 (1.57 g, 7.12 mmol, 2.0 equiv). The headspace of the flask was evacuated and backfilled with nitrogen. MeOH (12 mL) and Et3SiH (5.7 mL, 35.6 mmol, 10 equiv) were added and the reaction mixture was stirred at 23 °C for 24 h, whereafter it was transferred to a separatory funnel containing saturated aq. NaHCO3 (200 mL). The resulting suspension was extracted with CH2Cl2 (3x70 mL). The combined organic extracts (still containing a significant quantity of water and indium salts) were dried over Na2SO4, concentrated under reduced pressure, and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→60% EtOAc/hexanes) to afford the title compound as a golden-colored foam of sufficient purity for use in the next step (1.80 g, 3.05 mmol, 86% yield). A sample for analysis was obtained by preparative TLC on silica gel (33% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.40 (br s, 1H), 7.82 – 7.75 (m, 2H), 7.34 (t, J = 1.5 Hz, 1H), 7.26 – 7.21 (m, 2H), 6.60 (s, 1H), 6.58 (d, J = 8.3 Hz, 1H), 6.30 (d, J = 8.8 Hz, 1H), 4.15 – 4.01 (m, 1H), 3.68 (s, 3H), 3.33 (dt, J = 11.0, 5.4 Hz, 1H), 3.21 (dt, J = 11.5, 6.2 Hz, 1H), 2.99 – 2.92 (m, 3H), 2.91 – 2.66 (m, 3H), 2.37 (s, 3H), 2.07 – 1.98 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 153.8, 153.4, 144.2, 140.0, 137.1, 136.3, 133.2, 132.4, 129.5, 129.4, 127.7, 124.2, 123.2, 119.7, 117.2, 116.5, 115.4, 114.4, 110.3, 102.7, 57.3, 53.5, 42.2, 27.0, 26.0, 25.9, 23.5, 21.7; IR (Neat Film, NaCl) 3281, 3126, 3058, 2935, 2841, 1714, 1588, 1510, 1442, 1356, 1251, 1169, 1108, 1056, 996, 903, 739, 663 cm–1; HRMS (ESI+): m/z calc’d for C28H27F3N3O4S2 [M+H]+: 590.1390, found 590.1404. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine OMe 335 OMe TsN TsN NBS THF, –78→23 °C N S Br N S NHTFA 215 NHTFA 189 Bromoarene 189 To a 250 mL round bottom flask was added tertiary aniline 215 (1.78 g, 3.02 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation, and the headspace of the flask was evacuated and backfilled with nitrogen. The starting material was taken up in THF (50 mL), and the flask was cooled to –78 °C and protected from light. A solution of NBS (484 mg, 2.72 mmol, 0.9 equiv) in THF (50 mL) was added as a slow stream with rapid stirring. Following addition, the reaction mixture was allowed to stir at –78 °C for 5 additional min, whereafter the cooling bath was removed and the reaction mixture allowed to warm to 23 °C. The reaction mixture was concentrated under reduced pressure and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→50% EtOAc/hexanes) to afford the title compound as a brown foam (1.16 g, 1.74 mmol, 57% yield from tertiary aniline 215 or 64% from NBS); 1H NMR (400 MHz, C6D6) δ 7.86 – 7.80 (m, 2H), 7.54 (t, J = 1.5 Hz, 1H), 6.75 (s, 1H), 6.67 – 6.57 (m, 2H), 6.01 (s, 1H), 4.17 (dddd, J = 13.7, 11.3, 5.3, 2.6 Hz, 1H), 3.19 (s, 3H), 2.99 – 2.75 (m, 3H), 2.58 (tdd, J = 11.7, 3.9, 2.0 Hz, 1H), 2.36 – 2.09 (m, 4H), 1.80 – 1.71 (m, 1H), 1.76 (s, 3H), 1.45 (tdd, J = 12.2, 10.7, 6.7 Hz, 1H); 13C NMR (100 MHz, C6D6) δ 153.6, 153.2, 144.1, 143.0, 137.8, 134.6, 133.6, 131.9, 129.6, 129.5, 128.0, 127.7, 123.1, 122.4, 117.7, 116.6, 116.2, 115.2, 114.2, 106.2, 59.5, 56.3, 43.0, 29.5, 28.5, 26.0, 22.6, 21.1; IR (Neat Film, NaCl) 3295, 2931, 1714, 1588, 1490, 1438, 1347, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 336 1251, 1172, 1111, 908, 804, 737, 665 cm–1; HRMS (ESI+): m/z calc’d for C28H26BrF3N3O4S2 [M+H]+: 668.0495, found 668.0502. OMe OMe TsN Pd(dba)2 (15 mol %) XPhos (25 mol %), K2CO3 Br N S dioxane, 100 °C S NHTFA 189 NH TsN N 186 Thioimidate 186 To a 40 mL glass vial was added bromoarene 189 (331 mg, 0.495 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation and the vial was transferred to a nitrogen-filled glovebox. Solid K2CO3 (96 mg, 0.695 mmol, 1.4 equiv) was added to the vial. In a separate vial, a stock solution of Pd(dba)2 (46.2 mg) and XPhos (64.2 mg) in 1,4-dioxane (13.3 mL) was prepared and stirred at 28 °C for 10 min. Then, 12.4 mL of this solution were transferred to the vial containing bromoarene 189 (for 43 mg Pd(dba)2 [0.0748 mmol, 15 mol %] and 59.1 mg XPhos [0.124 mmol, 25 mol %]). The vial was sealed with a PTFE/silicone septum cap, removed from the glovebox, and stirred at 100 °C for 6 h. The reaction mixture was then allowed to cool to 23 °C and passed through a PTFE syringe filter, which was subsequently rinsed with EtOAc. The solution was concentrated under reduced pressure and purified by silica gel flash chromatography (100% EtOAc → 100% acetone) to afford the title compound as an off-white solid (145 mg, 0.295 mmol, 60% yield); 1H NMR (400 MHz, CD2Cl2) δ 7.81 – 7.72 (m, 2H), 7.32 – 7.24 (m, 3H), 6.81 (s, 1H), 5.78 (d, J = 1.7 Hz, 1H), 3.64 (s, 3H), 3.59 (p, J = 2.7 Hz, 1H), 3.35 (ddd, J = 11.1, 9.7, 5.7 Hz, 1H), 3.25 (ddd, J = 11.1, 4.8, 3.5 Hz, 1H), 3.04 – 2.94 (m, 2H), 2.65 (dt, J = 12.5, 2.9 Hz, 1H), 2.54 Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 337 – 2.47 (m, 1H), 2.40 (qd, J = 5.3, 3.1 Hz, 1H), 2.37 (s, 3H), 2.33 (dd, J = 12.5, 2.9 Hz, 1H), 2.06 – 1.97 (m, 1H), 1.61 (tdd, J = 13.7, 5.3, 2.9 Hz, 1H); 13C NMR (100 MHz, CD2Cl2) δ 178.5, 168.3, 144.9, 139.3, 137.2, 133.5, 129.7, 128.0, 123.5, 122.3, 121.7, 120.6, 115.2, 114.5, 109.1, 63.5, 57.4, 47.6, 41.9, 31.9, 24.8, 23.2, 21.7 (the bridgehead methine 13C resonance is obscured by the solvent peak); IR (Neat Film, NaCl) 2925, 2851, 1595, 1503, 1462, 1349, 1284, 1226, 1174, 1106, 1011, 898, 808, 738, 704, 672 cm–1; HRMS (ESI+): m/z calc’d for C26H26N3O3S2 [M+H]+: 492.1410, found 492.1416. OMe OMe NH TsN S TsCl, Py NTs TsN S CH2Cl2, 23 °C N N 186 190 N-tosylthioimidate 190 To a 1-dram glass vial containing TsCl (16 mg, 0.0814 mmol, 2.0 equiv) under nitrogen was added thioimidate 186 (20 mg, 0.0407 mmol, 1.0 equiv) as a stock solution in CH2Cl2 (1 mL), followed by pyridine (10 µL, 0.122 mmol, 3.0 equiv). The reaction mixture was stirred at 23 °C for 3 days, after which it was concentrated under reduced pressure and purified by silica gel flash chromatography (50% EtOAc/hexanes) to afford the title compound as an orange film (23.7 mg, 0.0367 mmol, 90% yield); 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.1 Hz, 2H), 7.83 – 7.74 (m, 2H), 7.36 – 7.28 (m, 3H), 7.28 – 7.22 (m, 2H), 6.49 (s, 1H), 5.97 (d, J = 1.6 Hz, 1H), 3.65 – 3.61 (m, 1H), 3.59 (s, 3H), 3.37 (dt, J = 10.9, 7.6 Hz, 1H), 3.27 (dt, J = 11.1, 4.2 Hz, 1H), 3.06 – 2.97 (m, 2H), 2.83 (dt, J = 12.6, 2.8 Hz, 1H), 2.68 – 2.58 (m, 1H), 2.49 – 2.44 (m, 1H), 2.43 (s, 3H), 2.38 (s, 3H), 2.21 – 2.04 (m, 2H), 1.59 – 1.51 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 184.5, 175.3, 144.4, 144.0, 139.4, 137.3, 136.9, 133.1, 129.6, 129.5, 127.9, 127.6, 123.6, 122.7, 121.6, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 338 120.7, 114.2, 111.1, 107.8, 65.4, 57.2, 53.0, 47.4, 40.4, 31.7, 25.4, 23.0, 21.7; IR (Neat Film, NaCl) 2924, 2850, 1596, 1519, 1449, 1286, 1228, 1167, 1107, 1010, 867, 813, 734, 664 cm–1; HRMS (ESI+): m/z calc’d for C33H32N3O5S3 [M+H]+: 646.1499, found 646.1500. OMe Pd(dba)2 (15 mol %), XPhos (25 mol %), K2CO3, dioxane, 100 °C; TsN Br N S 189 then NaOH, CH2Cl2/H2O, 23 °C; then TsCl, DMAP, Py, CH2Cl2, 23 °C NHTFA OMe NTs TsN S N 190 Procedure for the direct preparation of N-tosylthioimidate 190 from bromoarene 189 To a 500 mL Schlenk bomb in a nitrogen-filled glovebox was added bromoarene 189 (3.88 g, 5.80 mmol, 1.0 equiv) as a solution in a minimal amount of benzene. The benzene was removed under reduced pressure, and K2CO3 (1.12 g, 8.12 mmol, 1.4 equiv) and 1,4-dioxane (110 mL) were added. In a separate vial, Pd(dba)2 (500 mg, 0.870 mmol, 15 mol %) and XPhos (691 mg, 1.45 mmol, 25 mol %) were combined. 1,4-dioxane (35 mL) was added and the mixture was stirred at 28 °C for 10 min. Then, the Pd/ligand solution was transferred by pipette to the Schlenk bomb. The vessel was sealed, removed from the glovebox, and stirred at 100 °C for 7 h. The reaction mixture was allowed to cool to 23 °C, filtered through a Celite plug with EtOAc, and concentrated under reduced pressure. The residue was taken up in CH2Cl2 (70 mL). 1 N aq. NaOH was added, and the biphasic mixture was subjected to vigorous magnetic stirring for 1 h. The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3x20 mL). The combined Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 339 organic phases were dried over Na2SO4 and concentrated under reduced pressure in a 500 mL round bottom flask. Traces of water were azeotropically removed by addition of three portions of PhCH3 followed by rotary evaporation. DMAP (71 mg, 0.58 mmol, 10 mol %) was added and the headspace of the flask was evacuated and backfilled with nitrogen. CH2Cl2 (115 mL) was added, followed by pyridine (1.4 mL, 17.4 mmol, 3.0 equiv). TsCl (2.21 g, 11.6 mmol, 2.0 equiv) was added in a single portion under a stream of nitrogen. The reaction mixture was stirred at 23 °C for 58 h, then concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→40→75% EtOAc/hexanes) to afford N-tosylthioimidate 190 as an orange foam that crystallized upon standing (2.66 g, 4.12 mmol, 71% yield). For characterization data, see above. OMe OMe NTs TsN S NaOH O TsN S THF/EtOH/H2O, 75 °C N N 190 185 Thiolactone 185 To a 20 mL glass vial containing thioimidate 190 (200 mg, 0.310 mmol, 1.0 equiv) under nitrogen were added THF (2.5 mL), a degassed mixture of water (2 mL) and ethanol (10 mL), and 2 N aq. NaOH (0.62 mL, 1.24 mmol, 4.0 equiv). The vial was opened and sealed with a PTFE/silicone septum under a stream of argon. The reaction mixture was stirred at 80 °C at 490 rpm in a metal heating block for 25 min, after which the solution was nearly homogenous. The vial was immediately removed from the heating block and allowed to cool to approximately 35 °C, at which point the reaction mixture was quenched Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 340 with glacial acetic acid (0.3 mL) and diluted with water (40 mL), leading to the formation of a beige precipitate. The suspension was extracted with EtOAc (4x30 mL), and the combined organic phases were dried over Na2SO4 concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (2.5% EtOAc/CH2Cl2) to afford recovered thioimidate 190 (23.5 mg of material containing 10 wt % TsNH2 by 1H NMR analysis, 0.0328 mmol, 11% yield) and the title compound (104 mg, 0.211 mmol, 68% yield); 1H NMR (400 MHz, C6D6) δ 7.86 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 1.6 Hz, 1H), 6.89 (t, J = 1.3 Hz, 1H), 6.67 – 6.59 (m, 2H), 5.50 (d, J = 1.7 Hz, 1H), 3.32 (s, 3H), 2.87 – 2.78 (m, 1H), 2.78 – 2.59 (m, 2H), 2.59 – 2.45 (m, 2H), 2.40 (dt, J = 12.4, 2.8 Hz, 1H), 1.91 – 1.81 (m, 1H), 1.81 – 1.76 (m, 1H), 1.74 (s, 3H), 1.73 – 1.66 (m, 1H), 1.66 – 1.56 (m, 1H), 0.97 – 0.81 (m, 1H); 13C NMR (100 MHz, C6D6) δ 196.3, 177.3, 143.9, 140.0, 137.8, 133.5, 129.4, 124.2, 121.9, 121.7, 121.0, 114.6, 112.8, 108.9, 60.8, 60.8, 57.0, 53.0, 47.1, 40.9, 31.4, 24.8, 23.0, 21.1 (an additional 13C resonance associated with the tosyl group is likely obscured by the solvent signal); IR (Neat Film, NaCl) 2931, 2851, 1682, 1504, 1348, 1284, 1227, 1169, 1107, 1011, 897, 851, 814, 738, 662 cm–1; HRMS (ESI+): m/z calc’d for C26H25N2O4S2 [M+H]+: 493.1250, found 493.1251. OMe OMe TsN S N O 1. PIFA, TMSN3, CH2Cl2, –78→23 °C 2. TTMSS, BEt3, t-dodecanethiol, PhCH3, 23 °C 185 NH2 O TsN S N 192 Primary aniline 192 To a 1-dram glass vial containing thiolactone 185 (22.6 mg, 0.0459 mmol, 1.0 equiv) under nitrogen were added CH2Cl2 (2.3 mL) and TMSN3 (30 µL, 0.23 mmol, 5.0 equiv). The reaction mixture was cooled to –78 °C and a solution of PIFA (18.8 mg, 0.0437 Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 341 mmol, 0.95 equiv) in CH2Cl2 (0.5 mL) was added dropwise. After stirring for 10 min at – 78 °C, the reaction mixture was allowed to warm to 23 °C, concentrated under reduced pressure, and purified by preparative TLC on silica gel (90% Et2O/hexanes, eluted twice) to afford an intermediate aryl azide as a brown film (15.3 mg, 0.0287 mmol, 62% yield); 1 H NMR (600 MHz, C6D6) δ 7.95 – 7.91 (m, 2H), 7.34 (s, 1H), 6.56 (d, J = 8.2 Hz, 2H), 5.66 (d, J = 1.6 Hz, 1H), 3.81 (s, 3H), 2.61 – 2.56 (m, 2H), 2.53 – 2.46 (m, 1H), 2.41 – 2.32 (m, 2H), 2.24 (dt, J = 12.7, 2.8 Hz, 1H), 1.82 – 1.77 (m, 1H), 1.63 (dd, J = 12.7, 3.1 Hz, 1H), 1.58 (s, 3H), 1.54 – 1.43 (m, 2H), 0.79 (tdd, J = 13.0, 5.7, 3.2 Hz, 1H). To a ½-dram glass vial under air was added this intermediate aryl azide (7.3 mg, 0.0137 mmol, 1.0 equiv) as a stock solution in CH2Cl2. The solvent was removed by blowing a stream of nitrogen over the surface of the solution. Then, PhCH3 (0.36 mL), tris(trimethylsilyl)silane (21 µL, 0.0684 mmol, 5.0 equiv), tert-dodecanethiol (1.6 µL, 0.0069 mmol, 0.5 equiv), and triethylborane (1 M in hexanes, 41 µL, 0.0411 mmol, 3.0 equiv) were added under air. After 5 min, the reaction mixture was concentrated under reduced pressure and purified by preparative TLC on silica gel (100% EtOAc) to afford the title compound as a brown film (5.5 mg, 0.0108 mmol, 79% yield); 1H NMR (400 MHz, C6D6) δ 8.02 – 7.97 (m, 2H), 7.26 (d, J = 1.6 Hz, 1H), 6.59 – 6.54 (m, 2H), 5.60 (d, J = 1.5 Hz, 1H), 4.53 (s, 2H), 3.77 (s, 3H), 2.63 – 2.50 (m, 3H), 2.42 – 2.34 (m, 3H), 1.75 – 1.67 (m, 2H), 1.65 (s, 3H), 1.58 – 1.53 (m, 2H), 0.75 – 0.63 (m, 1H); 13C NMR (100 MHz, C6D6) δ 194.9, 175.9, 143.9, 139.9, 136.8, 136.6, 129.6, 127.5, 127.2, 122.7, 117.8, 116.5, 112.2, 100.0, 60.3, 60.3, 52.8, 48.0, 44.0, 30.9, 25.2, 22.9, 21.0 (an additional 13C resonance associated with the tosyl group is likely obscured by the solvent signal); IR (Neat Film, NaCl) 3440, 3347, 2921, 2854, 1682, 1486, 1367, 1294, 1177, 1136, 1094, 967, 828, 738, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 342 683 cm–1; HRMS (ESI+): m/z calc’d for C26H26N3O4S2 [M+H]+: 508.1359, found 508.1374. OMe OMe O TsN S i-Pr2NEt, TMSOTf CH2Cl2, 23 °C O TsN S N N 185 198 Deconjugated olefin 198 To a 1-dram glass vial was added thiolactone 185 (50 mg, 0.102 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation, and the headspace of the vial was evacuated and flushed with nitrogen. The starting material was taken up in CH2Cl2 (1 mL), and i-Pr2NEt (0.18 mL, 1.02 mmol, 10 equiv) and TMSOTf (0.13 µL, 0.714 mmol, 7.0 equiv) were injected. The reaction mixture was stirred at 23 °C for 20 h, then loaded directly onto a silica gel flash column and eluted (hexanes → 30% EtOAc/hexanes) to afford the title compound as a beige solid containing starting material as a minor impurity (47.3 mg, 0.0960 mmol, 94% yield); 1H NMR (400 MHz, C6D6) δ 7.92 – 7.85 (m, 2H), 7.43 (s, 1H), 7.04 (s, 1H), 6.62 (d, J = 8.2 Hz, 2H), 4.83 (q, J = 3.2 Hz, 1H), 3.46 (s, 3H), 3.12 – 3.00 (m, 2H), 2.77 – 2.67 (m, 1H), 2.66 – 2.49 (m, 3H), 2.48 – 2.39 (m, 1H), 2.07 (dd, J = 11.7, 3.8 Hz, 1H), 1.96 – 1.86 (m, 2H), 1.78 (q, J = 3.9 Hz, 1H), 1.72 (s, 3H); 13C NMR (100 MHz, C6D6) δ 202.0, 143.8, 139.6, 139.0, 137.9, 131.5, 129.4, 124.1, 121.9, 120.8, 119.0, 116.4, 114.6, 109.0, 58.1, 56.3, 52.2, 47.3, 45.8, 35.6, 31.4, 22.9, 21.1 (an additional 13C resonance associated with the tosyl group is likely obscured by the solvent signal); IR (Neat Film, NaCl) 2928, 2836, 1713, 1596, 1504, 1361, 1285, 1172, 1108, 895, 811, 731, 667, 616 cm–1; HRMS (ESI+): m/z calc’d for C26H25N2O4S2 [M+H]+: 493.1250, found 493.1248. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 343 OMe OMe O TsN S O TsN S Pd(OAc)2 DMSO, 28 °C N N 198 195 Diene 195 To a 20 mL glass vial was added deconjugated thiolactone 198 (19.9 mg, 0.0404 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation, the vial was transferred to a nitrogenfilled glovebox, and Pd(OAc)2 (9.5 mg, 0.0424 mmol, 1.05 equiv) and DMSO (2.4 mL) were added. The vial was sealed with a PTFE/silicone septum and stirred at 28 °C for 24 h, then removed from the glovebox and stirred at 23 °C for an additional 24 h. Then, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (4x15 mL). The combined organic extracts were washed with brine (2x15 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by preparative TLC (100% Et2O, eluted twice) to afford the title compound as a bright orange film (8.0 mg, 0.0163 mmol, 40% yield); 1H NMR (400 MHz, C6D6) δ 7.83 – 7.78 (m, 2H), 7.44 (d, J = 1.6 Hz, 1H), 6.92 (s, 1H), 6.62 – 6.53 (m, 2H), 5.87 (ddd, J = 9.7, 1.9, 0.9 Hz, 1H), 5.52 (s, 1H), 5.46 – 5.38 (m, 1H), 3.29 (s, 3H), 3.19 (dtt, J = 4.7, 3.3, 2.0 Hz, 1H), 2.67 – 2.55 (m, 3H), 2.40 – 2.32 (m, 2H), 1.93 (dd, J = 12.3, 3.9 Hz, 1H), 1.71 (s, 3H); 13C NMR (100 MHz, C6D6) δ 196.1, 171.8, 143.8, 141.3, 137.8, 132.8, 131.8, 129.4, 128.0, 125.1, 124.1, 123.4, 121.6, 121.2, 114.3, 113.6, 108.7, 58.2, 56.8, 53.0, 47.9, 37.6, 23.0, 21.1; IR (Neat Film, NaCl) 3060, 2934, 2841, 1681, 1622, 1504, 1347, 1287, 1226, 1177, 1106, 1016, 967, 898, 856, 813, 732, 662, 623 cm–1; HRMS (ESI+): m/z calc’d for C26H23N2O4S2 [M+H]+: 491.1094, found 491.1098. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine OMe OMe S O TsN O TsN N 344 S 1. PhSH, PhH, 23 °C 2. m-CPBA, CH2Cl2, 0 °C 3. TFAA, Py, CH2Cl2, 0→23 °C 195 N 201 SPh Doubly vinylogous dithiocarbonate 201 To a ½-dram glass vial containing diene 195 (5.0 mg, 0.0102 mmol, 1.0 equiv) under nitrogen were added benzene (0.2 mL), thiophenol (5.2 µL, 0.051 mmol, 5.0 equiv), and Et3N (14.2 µL, 0.102 mmol, 10 equiv). The reaction mixture was stirred at 23 °C for 75 min, whereafter it was loaded directly onto a silica gel flash column. Elution (10 → 25% EtOAc/hexanes) provided an intermediate sulfide as a colorless film (4.7 mg, 0.00782 mmol, 77% yield); 1H NMR (600 MHz, C6D6) δ 7.86 (d, J = 8.0 Hz, 2H), 7.47 (s, 1H), 7.21 (d, J = 7.6 Hz, 2H), 7.04 – 6.94 (m, 3H), 6.90 (s, 1H), 6.62 (d, J = 8.0 Hz, 2H), 5.66 (d, J = 1.7 Hz, 1H), 3.62 – 3.52 (m, 1H), 3.31 (s, 3H), 3.14 (q, J = 3.1 Hz, 1H), 2.79 (dd, J = 12.8, 2.8 Hz, 1H), 2.67 – 2.60 (m, 1H), 2.51 – 2.38 (m, 3H), 2.33 (d, J = 14.8 Hz, 1H), 2.19 (dt, J = 12.5, 2.4 Hz, 1H), 2.10 (ddd, J = 14.8, 6.0, 1.8 Hz, 1H), 1.72 (s, 3H). To a 1-dram glass vial containing this intermediate sulfide (3.2 mg, 0.00533 mmol, 1.0 equiv) under nitrogen was added CH2Cl2 (133 µL), and the vial was cooled to 0 °C in an ice bath. m-CPBA (77 wt %, 1.2 mg, 0.00535 mmol, 1.0 equiv) was added dropwise as a solution in CH2Cl2 (133 µL) and the reaction mixture was allowed to stir at 0 °C for 100 min. The solution was then diluted with EtOAc (1 mL), washed with saturated aq. K2CO3 (3x), dried over Na2SO4, and concentrated to provide a crude sulfoxide that was used directly in the next step. To a ½-dram glass vial was added the crude sulfoxide as a solution in dry CH2Cl2 (0.25 mL). The vial was cooled to 0 °C, and pyridine (7.0 µL, 0.087 mmol, 16 equiv) and Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 345 TFAA (7.5 µL, 0.054 mmol, 10 equiv) were added. The reaction mixture was stirred for 5 min at 0 °C, then allowed to warm to 23 °C and stirred for an additional 14 h. MeOH (7 µL) was then added to quench excess TFAA, and the reaction mixture was loaded directly onto a silica gel flash column and eluted (25% EtOAc/hexanes). The product was combined with the product of another reaction conducted on a 0.0118 mmol scale to provide the title compound as an orange-red film (5.0 mg, 0.00835 mmol, 49% combined yield); 1H NMR (400 MHz, C6D6) δ 7.83 – 7.76 (m, 2H), 7.47 (d, J = 1.7 Hz, 1H), 7.08 – 7.01 (m, 2H), 6.96 – 6.86 (m, 4H), 6.55 (d, J = 8.1 Hz, 2H), 5.80 (s, 1H), 5.11 (s, 1H), 3.54 (t, J = 3.2 Hz, 1H), 3.46 (td, J = 11.6, 3.9 Hz, 1H), 3.25 (s, 3H), 2.93 (ddd, J = 11.1, 4.9, 2.6 Hz, 1H), 2.68 – 2.57 (m, 1H), 2.53 (dt, J = 15.6, 3.3 Hz, 1H), 2.34 (dd, J = 12.2, 2.6 Hz, 1H), 2.00 (dd, J = 12.3, 3.8 Hz, 1H), 1.72 (s, 3H); 13C NMR (100 MHz, C6D6) δ 195.4, 171.3, 145.0, 143.7, 141.4, 137.8, 134.4, 130.1, 129.8, 129.6, 129.3, 124.2, 123.0, 121.3, 118.5, 118.4, 114.3, 112.9, 108.8, 57.1, 56.8, 56.8, 50.1, 37.8, 23.2, 21.1 (2 additional aryl 13C resonances are likely obscured by the solvent signal); IR (Neat Film, NaCl) 2924, 2853, 1678, 1593, 1503, 1348, 1281, 1173, 1108, 1022, 897, 810, 675 cm–1; HRMS (ESI+): m/z calc’d for C32H27N2O4S3 [M+H]+: 599.1127, found 599.1120. OMe O O TsN S N CAN, then NH4OH MeCN/H2O, 0 °C 64% yield 185 TsN TFA NH2 O S N 206 Pyrroloiminoquinone 206 To a 1-dram glass vial containing thiolactone 185 (7.0 mg, 0.014 mmol, 1.0 equiv) was added MeCN (0.42 mL). The solution was cooled to 0 °C and CAN (15.6 mg, 0.0284 mmol, 2.0 equiv) was added dropwise as a solution in water (0.28 mL). The solution Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 346 became deep purple during addition, and the color rapidly faded to bright orange upon completion of the addition. After stirring for 3 min at 0 °C, concentrated aq. NH4OH (50 µL) was added rapidly, leading to a dark purple color and a brown precipitate. The reaction mixture was stirred for an additional 30 min at 0 °C, then diluted with water (1 mL) and extracted with EtOAc (3x0.5 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C18 column, 40→100% MeCN/H2O with 0.1% TFA over 10 min at 5 mL/min) to afford the title compound as a purple film (5.3 mg, 0.0090 mmol, 64% yield); 1H NMR (400 MHz, CD3OD) δ 8.14 – 8.07 (m, 2H), 7.94 (t, J = 1.0 Hz, 1H), 7.49 – 7.40 (m, 2H), 6.19 (d, J = 1.3 Hz, 1H), 4.31 – 4.20 (m, 2H), 3.99 (ddd, J = 13.9, 5.9, 4.3 Hz, 1H), 3.17 – 3.09 (m, 2H), 2.97 (dt, J = 13.1, 2.8 Hz, 1H), 2.85 (dd, J = 13.6, 4.7 Hz, 1H), 2.56 – 2.46 (m, 2H), 2.44 (s, 3H), 2.34 (dd, J = 13.1, 2.5 Hz, 1H), 2.07 – 1.93 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 194.0, 173.7, 164.9, 155.0, 150.1, 147.4, 133.2, 129.8, 128.9, 128.5, 127.4, 124.3, 122.6, 118.3, 94.2, 57.7, 56.6, 51.5, 42.2, 31.5, 23.4, 20.3, 18.3; 19F NMR (376 MHz, CD3OD) δ –77.2 (s); IR (Neat Film, NaCl) 3416, 3296, 3146, 2955, 1728, 1693, 1607, 1556, 1510, 1438, 1407, 1379, 1338, 1292, 1195, 1179, 1168, 1141, 1123, 1093, 1068, 991, 955, 785, 706, 666, 642, 626 cm–1; HRMS (ESI+): m/z calc’d for C25H22N3O4S2 [M+H]+: 492.1046, found 492.1057. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine OMe 347 OMe O TsN S OH TsN DIBAL S CH2Cl2, –78 °C N N 195 207 Thiolactol 207 To a 1-dram glass vial was added diene 195 (2.0 mg, 0.00408 mmol, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by rotary evaporation, the headspace of the vial was evacuated and flushed with nitrogen, and the starting material was taken up in CH2Cl2 (200 µL). The vial was cooled to –78 °C, and freshly prepared DIBAL solution (0.4 M in CH2Cl2, 0.10 mL, 0.040 mmol, 10 equiv) was added dropwise. A dark brown color initially formed and slowly faded to yield a colorless solution. After 5 min, 0.5 mL saturated aq. Rochelle’s salt was injected at –78 °C. The cooling bath was then removed at the mixture stirred vigorously at 23 °C for 30 min. The layers were separated, and the aqueous phase was extracted with EtOAc (3x). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure to provide the title compound as a 5:1 mixture of diastereomers of sufficient purity for use in the next step (1.9 mg, 0.00386 mmol, 95% yield); 1H NMR (400 MHz, C6D6) δ 7.91 – 7.86 (m, 2H), 7.57 (s, 1H), 7.45 (s, 1H), 6.59 (dd, J = 8.3, 4.3 Hz, 2H), 6.03 (d, J = 9.8 Hz, 1H, major diastereomer), 5.98 (d, J = 9.8 Hz, 1H, minor diastereomer), 5.84 – 5.79 (m, 1H), 5.55 – 5.45 (m, 1H), 5.25 (d, J = 3.2 Hz, 1H, major diastereomer), 5.16 (d, J = 2.1 Hz, 1H, minor diastereomer), 3.64 (s, 3H), 3.35 (ddd, J = 5.1, 3.9, 2.3 Hz, 1H), 2.73 – 2.62 (m, 3H), 2.55 (dt, J = 12.0, 1.7 Hz, 1H), 2.46 – 2.36 (m, 1H), 2.02 (dd, J = 12.0, 3.9 Hz, 1H), 1.95 – 1.84 (m, 1H), 1.71 (s, 3H); 13C NMR (100 MHz, C6D6) δ 151.2, 143.5, 141.1, 138.1, 130.7, 129.4, 129.4, 129.0, 125.6, 124.0, 123.1, 122.5, 120.9, 119.4, 115.0, 112.1, Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 348 84.1, 59.6, 57.2, 53.9, 48.1, 38.8, 23.1, 21.1; IR (Neat Film, NaCl) 2927, 2856, 1684, 1500, 1460, 1361, 1285, 1225, 1173, 1107, 970, 897, 813, 755, 663 cm–1; HRMS (ESI+): m/z calc’d for C26H25N2O4S2 [M+H]+: 493.1250, found 493.1250. Chapter 2 – Progress Toward the Total Synthesis of Aleutianamine 2.11 (1) 349 REFERENCES AND NOTES Zou, Y.; Wang, X.; Sims, J.; Wang, B.; Pandey, P.; Welsh, C. 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Total synthesis of makaluvamine A/D, damirone B, batzelline C, makaluvone, and isobatzelline C featuring one-pot benzyne-mediated cyclizationefunctionalization. Tetrahedron 2012, 68, 9376–9383. Appendix 3 – Synthetic Summary for Chapter 2 360 APPENDIX 3 Synthetic Summary for Chapter 2: Progress Toward the Total Synthesis of Aleutianamine Appendix 3 – Synthetic Summary for Chapter 2 361 Scheme A3.1. Synthesis of tricyclic aniline 134. OMe H 3N H N H2SO4, 2,3-dihydrofuran DMA/H2O 60 °C Cl 1. DIAD, PPh3, DPPA, THF, 0→23 °C 2. TsCl, Bu4NHSO4, NaOH, CH2Cl2/H2O, 23 °C H N OMe 3. PPh3, H2O, THF, 23 °C Cl 52% over 3 steps Cl 29% yield 127 HO 126 [ref. 19] OMe OMe Ts N BrettPhos Pd G4 (5 mol %), BrettPhos (5 mol %), K3PO4 TsN t-BuOH, 100 °C Cl NH H2N 133 134 Scheme A3.2. Synthesis of hydroxyketone 157. OMe OMe 1. Et3N/AcOH, 23 °C 2. NBS, CH2Cl2, 23 °C O TsN OMe OMe + NH TsN Br 75% over 2 steps N O 153 134 OMe OMe 154 OMe OMe TsN Pd(PPh3)4 (1.2 equiv) OH OMe OMe DMF, 110 °C N 86% yield TsN TFA CH2Cl2/H2O, 23 °C OH O N 157 155 Scheme A3.3. Synthesis of aminothiophene 188. O S O 1. KOH, EtOH, reflux 2. TFA, CH2Cl2, 23 °C, then TFAA, Py, 0→23 °C NH2 176 CO2Et 51% over 2 steps O S HCl NHTFA THF/H2O, reflux 188 O S O NHTFA 187 Appendix 3 – Synthetic Summary for Chapter 2 362 Scheme A3.3. Synthesis of thiolactol 207. OMe OMe O TsN TsN S InCl3, Et3SiH NHTFA + MeOH, 23 °C N 188 NH S NHTFA 134 215 OMe NBS Br THF, –78→23 °C OMe Pd(dba)2 (15 mol %), XPhos (25 mol %), K2CO3, dioxane, 100 °C; TsN N S S then NaOH, CH2Cl2/H2O, 23 °C; then TsCl, DMAP, Py, CH2Cl2, 23 °C NHTFA N 71% yield 189 190 OMe OMe O TsN NaOH S N N 185 198 OMe O TsN S DMSO, 28 °C 40% yield S 94% yield OMe Pd(OAc)2 O TsN i-Pr2NEt, TMSOTf CH2Cl2, 23 °C THF/EtOH/H2O, 75 °C 68% yield 11% recovered 190 N 195 NTs TsN OH TsN DIBAL CH2Cl2, –78 °C 95% yield 5:1 dr S N 207 Appendix 4 – Spectra Relevant to Chapter 2 363 APPENDIX 4 Spectra Relevant to Chapter 2: Progress Toward the Total Synthesis of Aleutianamine MeS 9 O OMe 8 7 5 ppm 4 3 2 Figure A4.1. 1H NMR (400 MHz, CDCl3) of compound 96. 6 1 0 Appendix 4 – Spectra Relevant to Chapter 2 364 Appendix 4 – Spectra Relevant to Chapter 2 365 Figure A4.2. Infrared spectrum (Thin Film, NaCl) of compound 96. 200 180 160 140 120 100 ppm 80 60 40 Figure A4.3. 13C NMR (100 MHz, CDCl3) of compound 96. 20 0 MeS 9 Ph O OMe 8 7 5 ppm 4 3 Figure A4.4. 1H NMR (400 MHz, CDCl3) of compound 97. 6 2 1 0 Appendix 4 – Spectra Relevant to Chapter 2 366 Appendix 4 – Spectra Relevant to Chapter 2 367 Figure A4.5. Infrared spectrum (Thin Film, NaCl) of compound 97. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.6. 13C NMR (100 MHz, CDCl3) of compound 97. 0 Br OMe 9 N TBS OTBS 8 6 5 ppm 4 3 2 Figure A4.7. 1H NMR (400 MHz, CDCl3) of compound 107. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 368 Appendix 4 – Spectra Relevant to Chapter 2 369 Figure A4.8. Infrared spectrum (Thin Film, NaCl) of compound 107. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.9. 13C NMR (100 MHz, CDCl3) of compound 107. 0 TBSO 9 TBS N OMe O 8 Oi-Bu 6 5 ppm 4 3 2 Figure A4.10. 1H NMR (400 MHz, CDCl3) of compound 109. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 370 Appendix 4 – Spectra Relevant to Chapter 2 371 Figure A4.11. Infrared spectrum (Thin Film, NaCl) of compound 109. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.12. 13C NMR (100 MHz, CDCl3) of compound 109. 0 Ph Ph N 9 H N Cl OMe 8 6 5 ppm 4 3 2 Figure A4.13. 1H NMR (400 MHz, CDCl3) of compound 125. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 372 Appendix 4 – Spectra Relevant to Chapter 2 373 Figure A4.14. Infrared spectrum (Thin Film, NaCl) of compound 125. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.15. 13C NMR (100 MHz, CDCl3) of compound 125. 0 HO H N 9 Cl OMe 8 6 5 ppm 4 3 2 Figure A4.16. 1H NMR (400 MHz, CDCl3) of compound 126. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 374 Appendix 4 – Spectra Relevant to Chapter 2 375 Figure A4.17. Infrared spectrum (Thin Film, NaCl) of compound 126. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.18. 13C NMR (100 MHz, CDCl3) of compound 126. 0 MeH2N 9 Cl H N Cl OMe 8 6 5 ppm 4 3 2 Figure A4.19. 1H NMR (400 MHz, DMSO-d6) of compound 131. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 376 Appendix 4 – Spectra Relevant to Chapter 2 377 Figure A4.20. Infrared spectrum (Thin Film, NaCl) of compound 131. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.21. 13C NMR (100 MHz, DMSO-d6) of compound 131. 0 Boc2N Ts N 9 Cl OMe 8 6 5 ppm 4 3 2 Figure A4.22. 1H NMR (400 MHz, CDCl3) of compound 132. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 378 Appendix 4 – Spectra Relevant to Chapter 2 379 Figure A4.23. Infrared spectrum (Thin Film, NaCl) of compound 132. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.24. 13C NMR (100 MHz, CDCl3) of compound 132. 0 H 2N Ts N 9 Cl OMe 8 6 5 ppm 4 3 2 Figure A4.25. 1H NMR (400 MHz, CDCl3) of compound 133. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 380 Appendix 4 – Spectra Relevant to Chapter 2 381 Figure A4.26. Infrared spectrum (Thin Film, NaCl) of compound 133. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.27. 13C NMR (100 MHz, CDCl3) of compound 133. 0 TsN 9 NH OMe 8 6 5 ppm 4 3 2 Figure A4.28. 1H NMR (400 MHz, CDCl3) of compound 134. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 382 Appendix 4 – Spectra Relevant to Chapter 2 383 Figure A4.29. Infrared spectrum (Thin Film, NaCl) of compound 134. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.30. 13C NMR (100 MHz, CDCl3) of compound 134. 0 TsN O O 9 Me Me O N OMe O 8 6 5 ppm 4 3 2 Figure A4.31. 1H NMR (400 MHz, CDCl3) of compound 136. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 384 Appendix 4 – Spectra Relevant to Chapter 2 385 Figure A4.32. Infrared spectrum (Thin Film, NaCl) of compound 136. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.33. 13C NMR (100 MHz, CDCl3) of compound 136. 0 TsN N 9 OMe CO2Me 8 6 5 ppm 4 3 2 Figure A4.34. 1H NMR (400 MHz, CDCl3) of compound 138. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 386 Appendix 4 – Spectra Relevant to Chapter 2 387 Figure A4.35. Infrared spectrum (Thin Film, NaCl) of compound 138. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.36. 13C NMR (100 MHz, CDCl3) of compound 138. 0 10 Ts HN N 9 OMe O 8 6 5 ppm 4 3 2 Figure A4.37. 1H NMR (400 MHz, CD2Cl2) of compound 139. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 388 Appendix 4 – Spectra Relevant to Chapter 2 200 180 160 140 120 389 100 ppm 80 60 40 20 Figure A4.38. 13C NMR (100 MHz, CD2Cl2) of compound 139. 0 N 9 O 8 6 5 ppm 4 3 2 Figure A4.39. 1H NMR (400 MHz, CDCl3) of compound 143. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 390 Appendix 4 – Spectra Relevant to Chapter 2 391 Figure A4.40. Infrared spectrum (Thin Film, NaCl) of compound 143. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.41. 13C NMR (100 MHz, CDCl3) of compound 143. 0 TsN N 9 OMe O 8 6 5 ppm 4 3 2 Figure A4.42. 1H NMR (400 MHz, CDCl3) of compound 141. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 392 Appendix 4 – Spectra Relevant to Chapter 2 393 Figure A4.43. Infrared spectrum (Thin Film, NaCl) of compound 141. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.44. 13C NMR (100 MHz, CDCl3) of compound 141. 0 TsN N 9 OMe Br O 8 6 5 ppm 4 3 2 Figure A4.45. 1H NMR (400 MHz, CDCl3) of compound 149. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 394 Appendix 4 – Spectra Relevant to Chapter 2 395 Figure A4.46. Infrared spectrum (Thin Film, NaCl) of compound 149. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.47. 13C NMR (100 MHz, CDCl3) of compound 149. 0 TsN 9 N OMe OH 8 6 5 ppm 4 3 2 Figure A4.48. 1H NMR (400 MHz, CDCl3) of compound 150. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 396 Appendix 4 – Spectra Relevant to Chapter 2 397 Figure A4.49. Infrared spectrum (Thin Film, NaCl) of compound 150. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.50. 13C NMR (100 MHz, CDCl3) of compound 150. 0 9 O OMe OMe 8 6 5 ppm 4 3 2 Figure A4.51. 1H NMR (400 MHz, C6D6) of compound 153. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 398 Appendix 4 – Spectra Relevant to Chapter 2 399 Figure A4.52. Infrared spectrum (Thin Film, NaCl) of compound 153. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.53. 13C NMR (100 MHz, C6D6) of compound 153. 0 TsN N 9 OMe Br OMe OMe O 8 6 5 ppm 4 3 2 Figure A4.54. 1H NMR (400 MHz, C6D6) of compound 154. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 400 Appendix 4 – Spectra Relevant to Chapter 2 401 Figure A4.55. Infrared spectrum (Thin Film, NaCl) of compound 154. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.56. 13C NMR (100 MHz, C6D6) of compound 154. 0 TsN N 9 OMe O OMe 8 6 5 ppm 4 3 2 Figure A4.57. 1H NMR (400 MHz, CDCl3) of compound 156. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 402 Appendix 4 – Spectra Relevant to Chapter 2 403 Figure A4.58. Infrared spectrum (Thin Film, NaCl) of compound 156. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.59. 13C NMR (100 MHz, CDCl3) of compound 156. 0 TsN N 9 OMe OH OMe OMe 8 6 5 ppm 4 3 2 Figure A4.60. 1H NMR (400 MHz, C6D6) of compound 155. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 404 Appendix 4 – Spectra Relevant to Chapter 2 405 Figure A4.61. Infrared spectrum (Thin Film, NaCl) of compound 155. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.62. 13C NMR (100 MHz, C6D6) of compound 155. 0 TsN N 9 OMe OH O 8 7 5 ppm 4 3 2 Figure A4.63. 1H NMR (400 MHz, C6D6) of compound 157. 6 1 0 Appendix 4 – Spectra Relevant to Chapter 2 406 Appendix 4 – Spectra Relevant to Chapter 2 407 Figure A4.64. Infrared spectrum (Thin Film, NaCl) of compound 157. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.65. 13C NMR (100 MHz, C6D6) of compound 157. 0 TsN N 9 OMe OTMS OMe 8 6 5 ppm 4 3 2 Figure A4.66. 1H NMR (400 MHz, C6D6) of compound 160. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 408 Appendix 4 – Spectra Relevant to Chapter 2 409 Figure A4.67. Infrared spectrum (Thin Film, NaCl) of compound 160. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.68. 13C NMR (100 MHz, C6D6) of compound 160. 0 TsN N 9 OMe OTMS O 8 6 5 ppm 4 3 2 Figure A4.69. 1H NMR (400 MHz, C6D6) of compound 168. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 410 Appendix 4 – Spectra Relevant to Chapter 2 411 Figure A4.70. Infrared spectrum (Thin Film, NaCl) of compound 168. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.71. 13C NMR (100 MHz, C6D6) of compound 168. 0 TsN 9 N OMe SPh OTMS O 8 6 5 ppm 4 3 2 Figure A4.72. 1H NMR (400 MHz, C6D6) of compound 169. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 412 Appendix 4 – Spectra Relevant to Chapter 2 413 Figure A4.73. Infrared spectrum (Thin Film, NaCl) of compound 169. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.74. 13C NMR (100 MHz, C6D6) of compound 169. 0 12 O O NH3Cl 11 CO2H S 10 8 7 ppm 6 5 4 3 Figure A4.75. 1H NMR (400 MHz, DMSO-d6) of compound 214. 9 2 1 0 Appendix 4 – Spectra Relevant to Chapter 2 414 Appendix 4 – Spectra Relevant to Chapter 2 415 Figure A4.76. Infrared spectrum (Thin Film, NaCl) of compound 214. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.77. 13C NMR (100 MHz, DMSO-d6) of compound 214. 0 O O 9 S NHAc 8 6 5 ppm 4 3 2 Figure A4.78. 1H NMR (400 MHz, C6D6) of compound 177. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 416 Appendix 4 – Spectra Relevant to Chapter 2 417 Figure A4.79. Infrared spectrum (Thin Film, NaCl) of compound 177. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.80. 13C NMR (100 MHz, C6D6) of compound 177. 0 TsN 9 N OMe Br S 8 NHAc 6 5 ppm 4 3 2 Figure A4.81. 1H NMR (400 MHz, C6D6) of compound 179. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 418 Appendix 4 – Spectra Relevant to Chapter 2 419 Figure A4.82. Infrared spectrum (Thin Film, NaCl) of compound 179. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.83. 13C NMR (100 MHz, C6D6) of compound 179. 0 TsN 9 N OMe S NAc 8 6 5 ppm 4 3 2 Figure A4.84. 1H NMR (400 MHz, C6D6) of compound 184. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 420 Appendix 4 – Spectra Relevant to Chapter 2 421 Figure A4.85. Infrared spectrum (Thin Film, NaCl) of compound 184. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.86. 13C NMR (100 MHz, C6D6) of compound 184. 0 O O 9 S 8 NHTFA 6 5 ppm 4 3 2 Figure A4.87. 1H NMR (400 MHz, CDCl3) of compound 187. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 422 Appendix 4 – Spectra Relevant to Chapter 2 423 Figure A4.88. Infrared spectrum (Thin Film, NaCl) of compound 187. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.89. 13C NMR (100 MHz, CDCl3) of compound 187. 0 TsN N 9 OMe S 8 NHTFA 6 5 ppm 4 3 2 Figure A4.90. 1H NMR (400 MHz, CDCl3) of compound 215. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 424 Appendix 4 – Spectra Relevant to Chapter 2 425 Figure A4.91. Infrared spectrum (Thin Film, NaCl) of compound 215. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.92. 13C NMR (100 MHz, CDCl3) of compound 215. 0 TsN N 9 OMe Br S 8 NHTFA 6 5 ppm 4 3 2 Figure A4.93. 1H NMR (400 MHz, C6D6) of compound 189. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 426 Appendix 4 – Spectra Relevant to Chapter 2 427 Figure A4.94. Infrared spectrum (Thin Film, NaCl) of compound 189. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.95. 13C NMR (100 MHz, C6D6) of compound 189. 0 TsN 9 N OMe S NH 8 6 5 ppm 4 3 2 Figure A4.96. 1H NMR (400 MHz, CD2Cl2) of compound 186. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 428 Appendix 4 – Spectra Relevant to Chapter 2 429 Figure A4.97. Infrared spectrum (Thin Film, NaCl) of compound 186. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.98. 13C NMR (100 MHz, CD2Cl2) of compound 186. 0 TsN 9 N OMe S NTs 8 6 5 ppm 4 3 2 Figure A4.99. 1H NMR (400 MHz, CDCl3) of compound 190. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 430 Appendix 4 – Spectra Relevant to Chapter 2 431 Figure A4.100. Infrared spectrum (Thin Film, NaCl) of compound 190. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.101. 13C NMR (100 MHz, CDCl3) of compound 190. 0 TsN N 9 OMe S O 8 6 5 ppm 4 3 2 Figure A4.102. 1H NMR (400 MHz, C6D6) of compound 185. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 432 Appendix 4 – Spectra Relevant to Chapter 2 433 Figure A4.103. Infrared spectrum (Thin Film, NaCl) of compound 185. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.104. 13C NMR (100 MHz, C6D6) of compound 185. 0 TsN N 9 OMe S NH2 O 8 6 5 ppm 4 3 2 Figure A4.105. 1H NMR (400 MHz, C6D6) of compound 192. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 434 Appendix 4 – Spectra Relevant to Chapter 2 435 Figure A4.106. Infrared spectrum (Thin Film, NaCl) of compound 192. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.107. 13C NMR (100 MHz, C6D6) of compound 192. 0 TsN N 9 OMe S O 8 6 5 ppm 4 3 2 Figure A4.108. 1H NMR (400 MHz, C6D6) of compound 198. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 436 Appendix 4 – Spectra Relevant to Chapter 2 437 Figure A4.109. Infrared spectrum (Thin Film, NaCl) of compound 198. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.110. 13C NMR (100 MHz, C6D6) of compound 198. 0 TsN 9 N OMe S O 8 6 5 ppm 4 3 2 Figure A4.111. 1H NMR (400 MHz, C6D6) of compound 195. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 438 Appendix 4 – Spectra Relevant to Chapter 2 439 Figure A4.112. Infrared spectrum (Thin Film, NaCl) of compound 195. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.113. 13C NMR (100 MHz, C6D6) of compound 195. 0 TsN N 9 OMe SPh S O 8 6 5 ppm 4 3 2 Figure A4.114. 1H NMR (400 MHz, C6D6) of compound 201. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 440 Appendix 4 – Spectra Relevant to Chapter 2 441 Figure A4.115. Infrared spectrum (Thin Film, NaCl) of compound 201. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.116. 13C NMR (100 MHz, C6D6) of compound 201. 0 TsN 9 N O S TFA NH2 O 8 6 5 ppm 4 3 2 Figure A4.117. 1H NMR (400 MHz, CD3OD) of compound 206. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 442 Appendix 4 – Spectra Relevant to Chapter 2 443 Figure A4.118. Infrared spectrum (Thin Film, NaCl) of compound 206. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.119. 13C NMR (100 MHz, CD3OD) of compound 206. 0 Appendix 4 – Spectra Relevant to Chapter 2 0 -20 -40 -60 444 -80 ppm -100 -120 -140 -160 Figure A4.120. 19F NMR (376 MHz, CD3OD) of compound 206. -180 TsN 9 N OMe S OH 8 6 5 ppm 4 3 2 Figure A4.121. 1H NMR (400 MHz, C6D6) of compound 207. 7 1 0 Appendix 4 – Spectra Relevant to Chapter 2 445 Appendix 4 – Spectra Relevant to Chapter 2 446 Figure A4.122. Infrared spectrum (Thin Film, NaCl) of compound 207. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A4.123. 13C NMR (100 MHz, C6D6) of compound 207. 0 Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 447 APPENDIX 5 Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine† A5.1 INTRODUCTION Over the course of our synthetic studies toward aleutianamine, several strategies were briefly pursued and abandoned at a relatively early stage, and several synthetic tactics were studied in simplified systems to demonstrate their applicability prior to pursuit of a synthetic strategy. These strategies and tactics are reported in this appendix. A5.2 BRIDGEHEAD SULFIDE INSTALLATION: MODEL STUDIES Upon conceiving of our 2nd-generation retrosynthesis of aleutianamine, we recognized that installation of the bridgehead tertiary sulfide of the natural product would represent a synthetic challenge (Scheme A5.2.1). Ideally, hydroxyketone intermediate 111 would undergo a short synthetic sequence involving a substitution reaction, establishing bridgehead α-thioketone 216 which could be advanced to the natural product. Many strategies for tertiary sulfide construction from alcohols involve either harsh, acidic conditions necessary to ionize the alcohol and effect an SN1 reaction,1 rely on an SN2 reaction at the α-position of a carbonyl compound,2,3 or employ conjugate addition strategies.3 An SN2 approach for the synthesis of sulfide 216 would be rendered ineffective † This research was performed in collaboration with Samir Rezgui and Hao Yu and is ongoing. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 448 by the constrained nature of the bicyclic system. We therefore planned to utilize an SN1type approach employing a mild Lewis acid such as the method reported by Baba for indium-catalyzed substitution of alkyl acetates with silyl thioethers.4 Scheme A5.2.1. Planned bridgehead sulfide installation toward aleutianamine. OMe NHR TsN O OMe HN NHR TsN H N S SR1 OH O O N N 111 216 N Br 78 Aleutianamine Streuff reported an elegant method for the synthesis of a relevant model system (Scheme A5.2.2A).5 4-quinolone 217 (and related substrates) underwent Ti(III)-catalyzed single-electron reductive coupling with acrylonitrile to afford keto-nitrile 218. This intermediate then underwent a related reductive coupling, now intramolecularly, to afford α-hydroxyketone 219. After replicating Streuff’s synthesis of bridgehead alcohol 219, the alcohol was acetylated to afford ester 220 (Scheme A5.2.2B). Then, encouragingly, Baba’s conditions for acetate-sulfide exchange provided desired sulfide 222, presumably via tertiary carbocation 221. This cation may be somewhat stabilized by resonance donation from the aniline. Although this donation would increase the ring strain of 221, related strained bicyclo[3.3.1]octenes have been implicated as reactive intermediates.6 Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 449 Scheme A5.2.2. A model system for bridgehead sulfide installation. A) Reductive formal [3+3] cycloaddition between 4-quinolones and acrylonitrile (Streuff, 2015). CN Cp2TiCl2 (10 mol %) Zn0, Et3N•HCl, TMSCl THF, 35 °C, then aq. HCl O N Me O O CN N Me 77% yield Cp2TiCl2 (10 mol %) Zn0, Et3N•HCl, TMSCl THF, 23 °C, then TBAF N Me 63% yield 218 217 HO 219 B) Model study for bridgehead sulfide installation. O O HO AcO Ac2O, Et3N, DMAP CH2Cl2, 23 °C N Me 91% yield 219 O PhS–TMS InI3 (20 mol %) PhCH3, 90 °C N Me 28% yield 220 N Me 221 O PhS • Key bridgehead sulfide installation demonstrated in a model context N Me 222 Although the yield for sulfide installation in this model system was only 28%, this proof-of-concept provided impetus to proceed with the synthesis of a bridgehead alcohol substrate in the real system. Simultaneously, however, an alternative method for sulfide installation that would obviate carbocation chemistry was briefly explored (Scheme A5.2.3A). Tetracylic quinolone 137, which would also be the substrate for Streuff’s bicyclization method, could undergo conjugate addition of a ketone equivalent, homologation to a nitrile, and installation of the sulfide prior to bicyclization to afford ketone 223. Bicyclization could then occur by a Dieckmann-type reaction to directly afford 1,3-diketone 224. Again using 4-quinolone 217 as a model substrate, lithiated 1,3-dithiane underwent conjugate addition by a literature procedure to yield saturated ketone 225.7 Unfortunately, homologation of 225 by the van Leusen reaction was unsuccessful in our hands. Ketone 226 may simply be too electron-rich to undergo the desired reaction. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 450 Scheme A5.2.3. Alternative strategy for sulfide installation. A) Synthetic strategy: Sulfide installation prior to bicyclization. OMe OMe OMe TsN TsN SR CN TsN O SR base N O N N O 137 Me 224 223 O B) Synthetic strategy thwarted by unsuccessful van Leusen reaction. O O CN 1,3-dithiane, n-BuLi, HMPA N Me THF, –78→23 °C Me 217 S N 225 S TosMIC, KOt-Bu, conditions X EtOH, DME/THF -orMeOH, DMSO 0→23 °C S N Me S 226 not detected Further efforts to access nitrile 226 or derivatives thereof may be merited, but we planned to continue the synthetic sequence with the goal of utilizing Streuff’s bicyclization and Baba’s sulfide exchange, not yet realizing the synthetic challenge associated with accessing tetracyclic quinolone 137. A5.3 EARLY STRATEGIES TOWARD A TRICYLIC AMINOINDOLE Uncertain if the retrosynthetic disconnection of dianiline 91 to tertiary aniline 227 was indeed feasible (Scheme A5.3.1A), we invested considerable synthetic efforts into developing an alternative synthetic route that would incorporate the final nitrogen atom of the natural product at an early stage via nitrogen-rich tricycle 228 (Scheme A5.3.1B). Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 451 Scheme A5.3.1. Late-stage arene amination disconnection. A) Proposed disconnection. OMe OMe NH2 TsN TsN SPG O SPG O arene C–H amination N N 91 OR 227 OR B) Alternative strategy: Early incorporation of 3rd nitrogen atom. O HN H N OMe S NPG TsN N NH Br 228 78 Aleutianamine In our initial approach (Scheme A5.3.2), known brominated salicylic acid derivative 2298 underwent precedented nitration to afford nitroarene 230.9 DPPA-mediated Curtius rearrangement in t-BuOH and cleavage of the resulting t-butyl carbamate afforded nitroaniline 231, an anticipated precursor to tricycle 228. Unfortunately, attempted conversion to arylhydrazine 232 by diazotization and reduction was unsuccessful in our hands, thwarting access to necessary tryptophol 233. The electron-poor nature of the arene may accelerate side reactions of the diazonium salt. Scheme A5.3.2. Preparation of nitroaniline 231 and failed Fischer Indolization. OMe HO2C OMe HNO3/H2SO4 OMe HO2C NO2 0 °C Br NO2 2. TFA, CH2Cl2, 23 °C 78% yield Br 229 NaNO2, then SnCl2•2H2O X aq. HCl, –20→23 °C 1. DPPA, Et3N, t-BuOH, 80 °C H 2N Br 42% over 2 steps 230 H 2N H N 231 OMe H N OMe NO2 NO2 Fischer Br Br 232 not detected HO 233 Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 452 While tricycle 228 was ultimately synthesized via Larock indolization, the need for this nitrogen-rich intermediate was obviated by the discovery that late-stage formal arene C–H amination is indeed a facile process (see Chapter 2). We also briefly investigated a route to simplified derivatives of this tricyclic intermediate relying on intramolecular Rh-catalyzed C–H amination. A catalytic system for this transformation was reported by Falck and found to enable both inter- and intramolecular C–N bond formation (Scheme A5.3.3).10 In the intramolecular sense, Osulfonylhydroxylamines such as 234 could cyclize to afford anilines such as 142. Falck’s report did not include examples of substrates bearing heterocycles. Scheme A5.3.3. Intramolecular aryl C–H amination (Falck, 2016). Rh2(esp)2 (2 mol %), TFA N TsO Boc 234 TFE, 0→23 °C 81% yield N H 142 • 9 intramolecular examples • no heterocyclic examples Toward an analogous indolyl system, tryptophol (235) underwent a Mitsunobu reaction with known hydroxycarbamate derivative 23611 to afford tryptamine 237 (Scheme A5.3.4). Subsequent tosylation was attempted but using triethylamine as a base failed to effect the reaction, and the O-sulfonyl hydroxycarbamate did not survive NaH. The indole was instead protected as pivaloyl amide 239. Unfortunately, neither 239 nor free indole 237 underwent Falck’s Rh-catalyzed C–H amination, instead undergoing unproductive side reactions. Following these observations, a route toward a tosyl-protected tricycle involving a Buchwald–Hartwig amination was developed (see Chapter 2). Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 453 Scheme A5.3.4. Attempts to access tricyclic aminoindoles by intramolecular C–H amination. TsO H N N H Boc Ts N H N 236 base, TsCl X PPh3, DIAD THF, 0→23 °C 44% yield HO Boc N 235 Boc N OTs OTs 238 237 not detected H N Piv N PivN Rh2(esp)2 (2 mol %), TFA X TFE, 0→23 °C PivCl, Et3N, DMAP CH2Cl2, 0→23 °C NH Boc N 53% yield OTs Boc N 240 OTs not detected 239 237 H N HN Rh2(esp)2 (2 mol %), TFA X TFE or TFE/AcOH, 0→23 °C NH Boc N 241 OTs not detected 237 A5.4 ADDITIONAL EFFORTS TOWARD KEY TETRACYCLIC QUINOLONE As discussed in Chapter 2, attempts to cyclize methyl ester 138 to afford a tetracyclic quinolone led to concomitant tosyl group migration, yielding unexpected product 139 (Scheme A5.4.1). Given the low yield of this cyclization, rather than incorporating additional steps to remove and reinstall the tosyl group, we evaluated alternative indole protecting groups. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 454 Scheme A5.4.1. Unexpected tosyl group migration during quinolone synthesis. OMe OMe TsN HN Eaton’s Reagent Ts 60 °C N O N CO2Me 34% yield 138 139 • Unusual Tosyl group migration First, azide 242 was N-allylated to afford azide 243, which underwent a Staudinger reduction to tryptamine 244 (Scheme A5.4.2). Ma’s Cu-catalyzed C–N coupling employing oxalamide ligand 135 provided desired tricycle 245, albeit in low yield.12 This tricycle was found to be oxidatively unstable, particularly on silica gel, due to its electronrich nature. Aza-Michael reaction with methyl propiolate afforded “push-pull” olefin 246, but this substrate did not survive acidic conditions, likely also due to the electron-rich nature of the indole. Scheme A5.4.2. Attempted preparation of N-allyl tetracycle 247. OMe OMe H N N NaH, allyl iodide Cl THF, 23 °C 68% yield Cl 242 N3 CuI (5 mol %), OMe 135 (10 mol %), K3PO4 N PPh3, H2O DMF, 23 °C N3 OMe 86% yield Cl H 2N 243 244 OMe CO2Me N N DMSO, 120 °C DMF, 80 °C unstable on silica 22% over 2 steps NH N 245 CO2Me 246 OMe Eaton’s Reagent or PPA X OMe O MeO N O N 247 not detected OMe 135 N H 2 Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 455 Realizing that an electron-withdrawing indole protecting group would be necessary, we evaluated the use of a Piv group (Scheme A5.4.3). Azide 242 underwent efficient pivaloylation, but subsequent Staudinger reduction of azidoindole 248 lead to concomitant migration of the Piv group from the indole to the unveiled primary amine to yield amide 249. Following this result, the direct cyclization approach to a tetracylic quinolone intermediate was abandoned, and a sulfonyl indole protecting group was recognized as essential. Scheme A5.4.3. Evaluation of a pivaloyl indole protecting group. OMe OMe OMe Piv N H N H N PivCl, Et3N, DMAP PPh3, H2O CH2Cl2, 23→45 °C Cl N3 THF, 23 °C Cl 79% yield N3 242 67% yield 248 Cl PivHN 249 • Undesired pivalate migration Finally, a strategically distinct approach to a tetracyclic quinolone structurally related to 139 was envisioned (Scheme A5.4.4). Diketojulolidine derivative 250 could be advanced to diaminoquinolone 251 by nitration, reduction, and desaturation. The latter transformation proceeds readily for a related compound simply by heating in the presence of Pd/C.13 Finally, installation of an additional methine could establish the indole moiety of 252. This synthetic route would also have the advantage of enabling early incorporation of the final nitrogen atom of the natural product. Scheme A5.4.4. A julolidine desymmetrization approach to quinolone 252. OMe OMe H 2N O O OMe NH2 O NH2 HN O O N N N 250 251 252 Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 456 Toward the requisite diketojulolidine starting material 250, p-anisidine (253) underwent known double aza-Michael addition into acrylonitrile to afford dinitrile 254 (Scheme A5.4.5).14 Treatment of 254 with several Brønsted and Lewis acids failed to effect the desired cyclization. Bromination was attempted in order to access 255, a substrate for an anionic cyclization, but concomitant loss of acrylonitrile was observed. This retro-azaMichael fragmentation was not suppressed by the addition of base. Finally, the cyclization of known diacid 256 was attempted under the conditions of Kantminene et al.15 Desired tricycle 250 was not detected, with retro-aza-Michael fragmentation again being observed. At this point, we abandoned the quinolone cyclization approach to aleutianamine, shifting our efforts instead to the intramolecular Barbier approach outlined in Chapter 2. Scheme A5.4.5. Unsuccessful preparation of diketojulolidine 250. OMe OMe various Brønsted or Lewis acids X acrylonitrile, AcOH, cat. CuCl AcOH, 75 °C, 20 h 46% yield NH2 N NC O O N CN 254 253 OMe 250 not detected OMe OMe Br2 X CH2Cl2/MeOH, 23 °C NC N CN • Desired product undergoes retro-aza-Michael Br Br N NC CN 255 254 not detected OMe OMe PPA or acid chloride formation X HO2C N 256 CO2H O O N 250 not detected Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine A5.5 457 PRELIMINARY EVALUATION OF A WACKER OXIDATION OF INTERNAL α,β-UNSATURATED CARBONYL COMPOUNDS Toward the installation of the alkenyl bromide moiety of aleutianamine, the synthetic transformation of enone 257 or a derivative thereof to a 1,3-diketone equivalent (e.g., ketal 258 or vinylogous ester 259) was identified as desirable (Scheme A5.5.1A). Existing methods to effect this transformation are outlined in Chapter 2, generally requiring around 3 steps. A potential alternative one-step transformation is the Wacker oxidation. While Pd-catalyzed Wacker oxidation leads to efficient oxidation of terminal α,βunsaturated esters to acetals,16 oxidation of β-substituted unsaturated esters is typically slow and low-yielding. Interestingly, Sturgess reported that while unsaturated ester 260 undergoes Pd-catalyzed oxidative ketalization to afford 261 in only 20% yield in 14 days, substrate 262, which bears a tethered alcohol group, undergoes Wacker oxidation to ketal 263 in improved yield in only 22 hours.17 This result suggests that the slow rate of the oxidation of β-substituted unsaturated esters is due to slow conjugate addition of the alcohol to afford an intermediate than can undergo further oxidation. We therefore hypothesized that the addition of an appropriate Lewis-acidic additive could accelerate oxa-Michael addition and promote faster oxidation of relevant substrates. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 458 Scheme A5.5.1. Desired enone β-oxidation and challenging Wacker oxidation of internal α,β-unsaturated carbonyl compounds. A) Desired reactivity. OMe OMe OMe one-step transformation TsN X TsN TsN X X -or- O O O N N N RO OR 257 259 258 X = OR, SR OR B) Challenging Wacker oxidation of β-substituted enones and rate enhancement by intramolecular ketalization (Sturgess, 1992). O OMe O PdCl2, CuCl, CuCl2 DME, 50 °C, O2, 14 d C6H13 C6H13 20% yield 261 260 O OMe O PdCl2, CuCl, CuCl2 OH DME, 50 °C, O2, 22 h 262 OMe MeO MeO 62% yield OMe O OMe 263 Acyl oxazolidinones were identified as a desirable substrate class for the evaluation of reaction conditions due to their crystallinity and lack of volatility. Acryloyl substrate 264 was synthesized by a reported procedure as a positive control and a brief solvent screen was conducted (Table A5.5.2).18 Among solvents tested, DME (entries 1, 2) was found to perform well, in line with previous research,16,17 but dioxane provided an optimal yield (entry 4). HFIP (entry 5) led to a slightly higher yield but required a longer reaction time (the reaction was conducted at a lower temperature due to the high volatility of the solvent). Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 459 Table A5.5.2. Evaluation of solvents for positive control substrate 264.a O O O PdCl2 (30 mol %), CuCl, MeOH, O2 O N O O N solvent, 50 °C, 13 h 264 OMe 265 entry solvent % yield 1 2 3 4 5 6 DME DME MeCN 1,4-dioxane HFIP DMA 52b 73 56 79 82c 21 OMe [a] Reactions were conducted at 0.035 mmol scale at 0.25 M using 0.3 equiv PdCl2, 1.0 equiv CuCl, and 25 equiv MeOH. Yields were determined by 1H NMR analysis with 1,3,5-trimethoxybenzene as an internal standard unless otherwise noted. [b] Isolated yield on a 0.142 mmol scale with 10 mol % PdCl2. [c] Conducted at 23 °C for 3 days. Having validated acyloxazolidinones as a competent substrate class, β-substituted substrate 266 was also prepared and tested (Table A5.5.3). Unfortunately, all additives tested either failed to improve the reaction outcome (trace product, entry 1) or resulted in nonspecific decomposition. Indium triflate led to putative oxa-Michael addition without oxidation (entry 5). Table A5.5.3. Evaluation of Lewis-acidic additives.a O O PdCl2 (30 mol %), CuCl, MeOH, O2 1,4-dioxane, 50 °C O N O O Me 266 O N 267 entry additiveb result 1 2 3 4 –– +6 equiv CuCl 6 equiv LiCl 6 equiv LiI trace (3 d) trace (3 d) trace (3 d) decomp decomp + oxa-Michael decomp decomp 5 In(OTf)3 6 7 Bi(OTf)3 Sc(OTf)3 OMe Me OMe [a] Reactions were conducted at 0.035 mmol scale at 0.25 M using 0.3 equiv PdCl2, 1.0 equiv CuCl, and 25 equiv MeOH. Reaction progress was monitored by LC–MS. [b] 2.0 equiv unless otherwise noted. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 460 At this stage, development of the Wacker oxidation of unsaturated imide 266 was shelved in favor of development of other aspects of the total synthesis. Nevertheless, further development of the Wacker oxidation of electron-poor internal olefins could facilitate future synthetic studies. A5.6 ALKENYL BROMIDE INSTALLATION VIA A FUNCTIONAL HANDLE In parallel to efforts toward late-stage alkenyl bromide installation, which have thus far proved unfruitful, we have evaluated early incorporation of a functional handle R1 into thiophene coupling fragment 174 (Scheme A5.6.1). Advancement to functionalized thiobutenolide 172 would enable installation of the alkenyl bromide moiety of 268 without selective δ-oxidation chemistry. Scheme A5.6.1. A functional handle approach to alkenyl bromide installation. OMe O TsN S 174 O TsN S NHAc R1 OMe O N 172 S N R1 268 Br A suitable functional handle should be stable to the conditions for reductive amination and be a sufficiently poor leaving group to prevent aromatization of ketone 174. Given these constraints, a nitrile was first tested as a potential functional handle. Known ketal 26919 was subjected to precedented allylic oxidation to enone 270 (Scheme A5.6.2).20 Conjugate addition of cyanide in the presence of triethylamine hydrochloride led to a complex mixture of intermediates suspected to contain cyanohydrins, which underwent Gewald thiophene synthesis to afford aminothiophene 271 in low yield as a mixture of isomers. Removal of the methyl ester would be necessary to employ this Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 461 intermediate as a coupling fragment toward the synthesis of aleutianamine. Previous experiments examining the hydrolytic cleavage of the ester led to competitive hydrolysis of the nitrile, so alternative anionic decarboxylation conditions were tested. Treatment with NaCl at elevated temperature in DMSO led to nonspecific decomposition, while milder conditions employing NaCN in HMPA21 led to no reaction. The challenge of selective methyl ester removal coupled with the low yield and unselective synthesis of nitrile 271 led us to abandon this route. Scheme A5.6.2. Evaluation of a cyanide functional handle. O O 269 Mn(OAc)3•2H2O, TBHP, 3 Å MS EtOAc, 23 °C 49% yield NH2 MeO2C O 1. KCN, Et3N•HCl MeOH/H2O, 23 °C O 270 O 2. methyl cyanoacetate, S8, morpholine, MeOH, 60 °C 16% over 2 steps NaCl X DMSO, 180 °C NH2 S NC O O S NaCN X HMPA, 80 °C NC O O 271 272 mixture of isomers not detected Instead, a cyclopentadiene Diels–Alder adduct was anticipated to be a suitable removable handle, as this bulkier group could result in a more selective Gewald reaction and no potentially problematic leaving group would be present. Diketone 273 was prepared by a literature procedure22 and underwent precedented monoketalization to afford ketal 274 (Scheme A5.6.3A).23 Unfortunately, Gewald thiophene synthesis of aminothiophene 275 could not be effected. Significant recovery of starting material was observed at 75 °C, and the desired product was not generated even at 90 °C. Likely, the initial Knoevenagel condensation of 274 with ethyl cyanoacetate is thwarted by the increase in strain of condensation product 277 relative to initial adduct 276, as the bridgehead methine would sterically clash with the cyano group (Scheme A5.6.3B). Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 462 Scheme A5.6.3. Attempted Gewald reaction of a cyclopentadiene Diels–Alder adduct. A) Attempted Gewald thiophene synthesis of aminothiophene 275. NC HO OH , PTSA•H2O PhH, reflux (Dean-Stark) O 76% yield O 273 CO2Et , S , morpholine 8 X EtOH, 75 °C O O NC HO O 274 O 275 not detected B) Rationale for failure of Gewald thiophene synthesis. NC S O 274 O NH2 EtO2C O O H CO2Et NC CO2Et CO2Et , base O O 276 –H2O O O 277 SPIROCYCLE-FIRST APPROACH TO δ-OXIDIZED THIOIMIDATE A5.7 As an alternative strategy to circumvent a challenging late-stage δ-oxidation of a thiobutenolide, it was anticipated that 2-aminoketone 278 could undergo the dearomative cyclization previously developed during the course of our synthetic efforts to provide spirocyclic thioimidate 279 (Scheme A5.7.1). Then, the installation of an oxidation handle such as an epoxide or vinyl bromide would enable intramolecular Michael-type addition with concomitant elimination to afford hexacycle 280 with the desired ketone in place, setting the stage for functional group interconversion to the alkenyl bromide of aleutianamine. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 463 Scheme A5.7.1. A spirocyclization–Michael addition approach to the oxidized ring system of aleutianamine. OMe OMe TsN OMe NAc TsN N Br O [Pd] O S 2. Michael addition or epoxide opening N 278 NAc TsN 1. epoxidation or bromination Me S AcHN S N Me 280 279 O δ-oxidation in place A strategy to prepare aminoketone 280 was not immediately clear due to the dissonant oxidation pattern of this species, but a potential SN2 approach was identified. Thus, commercially available aldehyde 281 underwent Horner–Wadsworth–Emmons olefination with phosphonate 282 to afford enone 283 (Scheme A5.7.2). The hydrosilylation-bromination reaction developed by Toy afforded bromoketone electrophile 284.24 Scheme A5.7.2. Access to a 2-bromoketone electrophile. O O2N O Me 282 O S P OMe OMe , NaH O O2N S Me THF, 0→23 °C 281 85% yield 283 Cl3SiH, Ph3PO (20 mol %) then NBS CH2Cl2, 23 °C 27% yield Br O2N O S Me 284 Unfortunately, SN2 displacement of the bromide with secondary aniline 134 could not be effected in our hands (Scheme A5.7.3A)—undesired elimination of the bromide was observed, and aminoketone 285 was not detected. As an alternative, epoxyketone 287 was prepared by a DBU-mediated Darzens reaction25 between aldehyde 281 and chloroacetone (286) (Scheme A5.7.3B). Epoxide opening with aniline 134 to provide enaminone 288 also did not occur, however. Epoxide opening with a basic amine led to opening at the undesired benzylic position. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 464 Scheme A5.7.3. Attempts to access a spirocyclization substrate. A) Unsuccessful SN2 displacement of bromide. OMe OMe TsN Br O2N O TsN 134 S O X NaOAc, EtOH, 75 °C -orEt3N, CH2Cl2, 23 °C Me 284 N Me NH S AcHN 134 285 not detected B) Synthesis of an epoxide electrophile. O2N O2N S O O + Cl 281 Me 286 S O DBU CH2Cl2, –20 °C Me 25% yield 287 O C) Unsuccessful enaminone synthesis from epoxide 287. OMe O2N TsN S O 134 O X N Me 287 O Me S AcHN 288 not detected The spirocyclization-first synthetic route was abandoned at this stage due to the difficulty associated with accessing aminoketone 285. A5.8 EXPERIMENTAL SECTION A5.8.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.26 NBS was recrystallized from boiling water prior to use and amines were distilled under nitrogen prior to use. All other reagents were purchased from commercial sources and used as received unless otherwise indicated. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 465 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 nm) was used for flash chromatography. 1H NMR spectra were recorded on Varian Inova 500 MHz and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities 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. A5.8.2 EXPERIMENTAL PROCEDURES O O HO AcO Ac2O, Et3N, DMAP CH2Cl2, 23 °C N Me 219 N Me 220 Tertiary acetate 220 To a 1-dram glass vial under air were added tertiary alcohol 2195 (25 mg, 0.115 mmol, 1.0 equiv), DMAP (1.6 mg, 0.013 mmol, 0.12 equiv), and CH2Cl2 (0.6 mL), followed by Et3N (36 µL, 0.26 mmol, 2.25 equiv) and Ac2O (24 µL, 0.26 mmol, 2.25 equiv). The reaction mixture was stirred at 23 °C for 46 h, then washed with water (2x). The combined aqueous phases were extracted once with CH2Cl2, and the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (60% Et2O/hexanes) to afford the title compound (27 mg, 0.10 mmol, 91% yield); 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 7.8, 1.7 Hz, 1H), 7.21 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 6.72 – 6.63 (m, 2H), 3.77 (tt, J = Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 466 4.5, 3.1 Hz, 1H), 3.22 (dd, J = 12.0, 2.8 Hz, 1H), 3.09 (s, 3H), 2.52 – 2.43 (m, 1H), 2.41 – 2.35 (m, 1H), 2.35 – 2.26 (m, 1H), 2.24 (s, 3H), 2.23 – 2.19 (m, 1H), 2.05 – 1.94 (m, 1H). O AcO O PhS–TMS InI3 (20 mol %) PhS PhCH3, 90 °C N Me 220 N Me 222 Tertiary sulfide 222 To a 1-dram glass vial in a nitrogen-filled glovebox were added InI3 (2 mg, 0.004 mmol, 0.2 equiv), PhCH3 (0.2 mL), and PhSTMS (7.3 µL, 0.0386 mmol, 2.0 equiv). Then, acetate 220 (5.0 mg, 0.0193 mmol, 1.0 equiv) was added as a solution in PhCH3 (0.25 mL), the vial was sealed with a PTFE/silicone septum and removed from the glovebox, and the reaction mixture was stirred at 90 °C in a metal heating block for 3 h. Then, the reaction mixture was allowed to cool to 23 °C and saturated aq. NaHCO3 (1 mL) was added. The resulting suspension was extracted with Et2O (4x0.5 mL) and the combined organic extracts were dried over Na2SO4. The crude product was purified by preparative TLC on silica gel (33% EtOAc/hexanes) to afford the crude product as a brown film (1.7 mg, 0.0055 mmol, 28% yield); 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J = 7.8, 1.7 Hz, 1H), 7.37 – 7.32 (m, 2H), 7.24 – 7.13 (m, 4H), 6.69 (ddd, J = 7.8, 7.3, 1.2 Hz, 1H), 6.57 (dd, J = 8.3, 1.2 Hz, 1H), 3.53 (ddd, J = 3.8, 2.8, 1.1 Hz, 1H), 3.01 (s, 3H), 2.46 – 2.32 (m, 3H), 2.23 – 2.11 (m, 2H), 1.90 – 1.75 (m, 1H). Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 467 OMe HO2C NO2 Br 230 Nitroarene 230 Prepared according to the procedure of Hofmann and Sanjayan.9 All characterization data matched those reported in the literature. OMe HO2C OMe NO2 1. DPPA, Et3N, t-BuOH, 80 °C H 2N NO2 2. TFA, CH2Cl2, 23 °C Br Br 230 231 Nitroaniline 231 To a 20 mL glass vial containing nitroarene 230 under nitrogen were added t-BuOH (0.72 mL) and Et3N (76 µL, 0.54 mmol, 3.0 equiv) followed by DPPA (59 µL, 0.27 mmol, 1.5 equiv). The vial was sealed with a PTFE/silicone septum and stirred at 80 °C in a metal heating block for 3 h. The reaction mixture was then cooled to 23 °C, concentrated under reduced pressure, and purified by silica gel flash chromatography (10% EtOAc/hexanes) to afford an intermediate carbamate (36 mg, 0.10 mmol, 58% yield); 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.14 (br s, 1H), 3.91 (s, 3H), 1.54 (s, 9H). To a 1-dram glass vial were added this intermediate carbamate (20 mg, 0.0576 mmol, 1.0 equiv), CH2Cl2 (0.6 mL), and TFA (66 µL, 0.86 mmol, 15 equiv). The reaction mixture was stirred at 23 °C. Upon complete conversion as judged by TLC analysis, the reaction mixture was concentrated under reduced pressure and Et3N (1 drop) was added to neutralize any remaining TFA. The crude product was purified by silica gel flash Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 468 chromatography (60% Et2O/hexanes) to afford the title compound as a yellow film (10.4 mg, 0.0421 mmol, 73% yield); 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 4.16 (br s, 2H), 3.89 (s, 3H). TsO H N N H Boc H N 236 PPh3, DIAD THF, 0→23 °C Boc N HO 235 OTs 237 O-tosylhydroxylamine 237 To a flame-dried 20 mL vial containing PPh3 (294 mg, 1.12 mmol, 1.2 equiv) under nitrogen was added THF (2 mL). The vial was cooled to 0 °C and DIAD (0.22 mL, 1.1 mmol, 1.2 equiv) was added dropwise, whereafter additional THF (1 mL) was added to reduce the viscosity of the heterogeneous mixture and the reaction mixture was stirred at 0 °C for 30 min. Then a solution of tryptamine (235, 150 mg, 0.930 mmol, 1.0 equiv) and nucleophile 23611 (322 mg, 1.12 mmol, 1.2 equiv) in THF (1.7 mL) was added dropwise and additional THF (1 mL) was used to quantitatively transfer the residual nucleophile solution. The reaction mixture was stirred at 0 °C for 1 h, then allowed to warm to 23 °C and stirred for an additional 20 h. The reaction mixture was concentrated under reduced pressure and purified twice by silica gel flash chromatography (50% Et2O/hexanes, then CH2Cl2) to afford the title compound as a white foam (177 mg, 0.411 mmol, 44% yield); 1 H NMR (400 MHz, CDCl3) δ 7.96 (br s, 1H), 7.89 – 7.85 (m, 2H), 7.60 – 7.55 (m, 1H), 7.35 – 7.29 (m, 3H), 7.18 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.11 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 3.94 (br s, 2H), 3.10 (td, J = 7.5, 0.8 Hz, 2H), 2.43 (s, 3H), 1.05 (s, 9H). Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine H N 469 Piv N PivCl, Et3N, DMAP CH2Cl2, 0→23 °C Boc N OTs 237 Boc N OTs 239 N-pivaloyltryptamine 239 To a flame-dried 1-dram glass vial were added O-tosylhydroxylamine 237 (10 mg, 0.0232 mmol, 1.0 equiv) and DMAP (0.3 mg, 0.002 mmol, 0.1 equiv). The vial was evacuated and backfilled with nitrogen. CH2Cl2 (0.23 mL) and Et3N (5.0 µL, 0.035 mmol, 1.5 equiv) were added and the vial was cooled to 0 °C. PivCl (3.4 µL, 0.028 mmol, 1.2 equiv) was added dropwise with stirring and the reaction mixture was allowed to warm to 23 °C and sealed with a PTFE-lined cap. After stirring for 15 h, the reaction mixture was warmed to 45 °C and stirring was continued. After an additional 24 h, the reaction mixture was allowed to cool to 23 °C, diluted with CH2Cl2 (0.5 mL), and washed once with water. The aqueous phase was extracted once with CH2Cl2, and the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (15% EtOAc/hexanes) to afford the title compound as a colorless film (6.3 mg, 0.0122 mmol, 53% yield); 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.57 (s, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.36 – 7.27 (m, 4H), 3.99 (br s, 2H), 3.06 (t, J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.51 (s, 9H), 1.02 (s, 9H). Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 470 OMe H N Cl N3 242 Azide 242 Prepared according to the procedure described in Chapter 2 for the synthesis of tryptamine 133 by a Mitsunobu reaction without subsequent tosylation and reduction. 1H NMR (500 MHz, CDCl3) δ 8.32 (br s, 1H), 7.06 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 3.94 (s, 3H), 3.59 (t, J = 7.1 Hz, 2H), 3.27 (td, J = 7.1, 0.8 Hz, 2H). OMe OMe H N N NaH, allyl iodide DMF, 23 °C Cl N3 242 Cl N3 243 N-allylindole 243 To a flame-dried 1-dram glass vial containing azide 242 (50 mg, 0.199 mmol, 1.0 equiv) under nitrogen was added DMF (1 mL) followed by NaH (60% dispersion in mineral oil, 9.6 mg, 0.24 mmol, 1.2 equiv) at 23 °C. The reaction mixture was stirred for 1 h, after which allyl iodide (22 µL, 0.24 mmol, 1.2 equiv) was added. After 4 h, the reaction mixture was diluted with saturated aq. NaHCO3 (7 mL) and extracted with EtOAc (4x2mL). The combined organic extracts were washed twice with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→20% EtOAc/hexanes) to afford the title compound (39.5 mg, 0.136 mmol, 68% yield); 1H NMR (400 MHz, CDCl3) Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 471 δ 6.93 (d, J = 8.2 Hz, 1H), 6.88 (s, 1H), 6.51 (d, J = 8.3 Hz, 1H), 6.07 – 5.92 (m, 1H), 5.13 – 5.07 (m, 1H), 4.99 – 4.92 (m, 3H), 3.88 (s, 3H), 3.56 (t, J = 7.2 Hz, 2H), 3.24 (t, J = 7.2 Hz, 2H). OMe N OMe N PPh3, H2O THF, 23 °C Cl N3 Cl H 2N 243 244 N-allyltryptamine 244 To a 1-dram vial under air were added PPh3 (47 mg, 0.179 mmol, 1.5 equiv), THF (0.2 mL), and a solution of azide 243 (34.7 mg, 0.119 mmol, 1.0 equiv) in THF (0.6 mL) followed by H2O (40 µL, 5% v/v). The reaction mixture was stirred at 23 °C for 18 h, then concentrated under reduced pressure. Excess water was removed azeotropically with benzene under reduced pressure. The crude product was purified by silica gel flash chromatography (10% MeOH/CH2Cl2 + 1% Et3N) to afford the title compound (27.1 mg, 0.102 mmol, 86% yield); 1H NMR (400 MHz, CDCl3) δ 6.91 (d, J = 8.2 Hz, 1H), 6.87 (s, 1H), 6.49 (d, J = 8.3 Hz, 1H), 6.05 – 5.93 (m, 1H), 5.11 – 5.06 (m, 1H), 4.98 – 4.90 (m, 3H), 3.88 (s, 3H), 3.16 – 3.11 (m, 2H), 3.07 (td, J = 6.2, 1.5 Hz, 2H). OMe N OMe CuI (5 mol %), 135 (10 mol %), K3PO4 OMe O MeO N DMSO, 120 °C OMe Cl H 2N 244 NH 135 N H 2 245 Secondary aniline 245 To a ½-dram glass vial in a nitrogen-filled glovebox were added CuI (0.9 mg, 0.0048 mmol, 0.05 equiv), oxalamide 13512 (2.0 mg, 0.0048 mmol, 0.05 equiv), and K3PO4 Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 472 (20.3 mg, 0.0956 mmol, 1.0 equiv), followed by a solution of tryptamine 244 (25.3 mg, 0.0956 mmol, 1.0 equiv) in DMSO (0.2 mL). The vial was sealed with a PTFE-lined cap, removed from the glovebox, and heated to 120 °C in a metal heating block. After stirring for 24 h, the reaction mixture was cooled to 23 °C, diluted with EtOAc (2 mL), and washed twice with brine. The combined brine phases were extracted once with EtOAc, and the combined organic phases were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on basic alumina (10→20% EtOAc/hexanes) to afford the title compound as an impure, oxidatively unstable brown film (7.6 mg, NMR analysis indicates 0.025 mmol, 26% yield desired product); 1H NMR (400 MHz, CDCl3) δ 6.58 (s, 1H), 6.43 (d, J = 7.8 Hz, 1H), 6.14 – 5.92 (m, 2H), 5.13 – 5.00 (m, 2H), 4.92 (dt, J = 5.6, 1.7 Hz, 2H), 3.84 (s, 3H), 3.43 (t, J = 5.6 Hz, 2H), 2.98 – 2.93 (m, 2H). OMe OMe CO2Me N N DMF, 80 °C NH N 245 246 CO2Me “Push-Pull” olefin 246 To a 1-dram vial was added impure aniline 245 (7.6 mg, 0.033 mmol assuming pure material, 1.0 equiv). Traces of water were azeotropically removed by addition of three portions of benzene followed by concentration under reduced pressure, and the vial was evacuated and backfilled with nitrogen. DMF (0.33 mL) and methyl propiolate (30 µL, 0.33 mmol, 10 equiv) were added, and the vial was sealed with a PTFE-lined cap and stirred at 80 °C in a metal heating block. After 18 h, the reaction mixture was cooled to 23 °C, diluted with water (2 mL), and extracted with EtOAc (3x0.5 mL). The combined organic Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 473 extracts were washed twice with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (20% EtOAc/hexanes) to afford the title compound as a yellow film (6.6 mg, 0.021 mmol, 22% yield over 2 steps); 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 13.3 Hz, 1H), 6.68 (t, J = 1.2 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 8.2 Hz, 1H), 6.03 (ddt, J = 17.0, 10.1, 5.6 Hz, 1H), 5.17 (d, J = 13.2 Hz, 1H), 5.12 (dq, J = 10.3, 1.5 Hz, 1H), 5.03 (dq, J = 17.0, 1.6 Hz, 1H), 4.94 (dt, J = 5.5, 1.5 Hz, 2H), 3.89 (s, 3H), 3.75 – 3.71 (m, 5H), 3.03 (td, J = 6.1, 1.2 Hz, 2H). OMe OMe Piv N H N PivCl, Et3N, DMAP CH2Cl2, 23→45 °C Cl N3 242 Cl N3 248 N-Pivaloyl indole 248 To a flame-dried 1-dram glass vial were added azide 242 (50 mg, 0.199 mmol, 1.0 equiv) and DMAP (2.4 mg, 0.020 mmol, 0.1 equiv). The vial was evacuated and backfilled with nitrogen. CH2Cl2 (2 mL) and Et3N (42 µL, 0.30 mmol, 1.5 equiv) were added followed by the addition of PivCl (29 µL, 0.24 mmol, 1.2 equiv). The vial was sealed with a PTFElined cap and stirred at 45 °C in a metal heating block. After 1 day, the reaction mixture was allowed to cool to 23 °C, washed twice with water, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→25% EtOAc/hexanes) to afford the title compound as a white solid (52.7 mg, 0.157 mmol, 79% yield); 1H NMR (400 MHz, CDCl3) δ 7.18 (t, J = 0.9 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H), 3.89 (s, 3H), 3.59 (t, J = 7.0 Hz, 2H), 3.23 (td, J = 7.0, 0.9 Hz, 2H), 1.43 (s, 9H). Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine OMe 474 OMe Piv N H N PPh3, H2O THF, 23 °C Cl N3 Cl PivHN 248 249 Secondary amide 249 To a 1-dram glass vial under air were added PPh3 (60 mg, 0.23 mmol, 1.5 equiv) and a solution of azide 248 (51.3 mg, 0.153 mmol, 1.0 equiv) in THF (1 mL) followed by water (50 µL). The reaction mixture was stirred at 23 °C for 22 h, then concentrated under reduced pressure and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→40→100% EtOAc/hexanes) to afford the title compound as a white solid (31.5 mg, 0.102 mmol, 67% yield); 1H NMR (400 MHz, CDCl3) δ 8.34 (br s, 1H), 7.00 (br d, J = 2.4 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 8.2 Hz, 1H), 5.76 (br s, 1H), 3.93 (s, 3H), 3.60 (td, J = 6.7, 5.6 Hz, 2H), 3.18 (t, J = 6.7 Hz, 2H), 1.13 (s, 9H). O O O N PdCl2 (10 mol %), CuCl, MeOH, O2 DME, 50 °C 264 O O O N OMe 265 OMe Dimethyl acetal 265 To a flame-dried 1-dram glass vial was added imide 26418 (20 mg, 0.142 mmol, 1.0 equiv). The vial was transferred to a nitrogen-filled glovebox and PdCl2 (2.5 mg, 0.014 mmol, 0.1 equiv), CuCl (14 mg, 0.142 mmol, 1.0 equiv), and DME (0.57 mL) were added. The vial was sealed with a PTFE/silicone septum and removed from the glovebox. MeOH (0.14 mL, 3.55 mmol, 25 equiv) was injected, whereafter the reaction mixture was sparged with O2, heated to 50 °C in a metal vial block, and stirred under a positive pressure of O2 from a balloon. After 16 h, the reaction mixture was cooled to 23 °C, filtered through a Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 475 plug of basic alumina with EtOAc, concentrated under reduced pressure, and purified by silica gel flash chromatography (67% EtOAc/hexanes) to afford the title compound as a white solid (14.9 mg, 0.0733 mmol, 52% yield); 1H NMR (400 MHz, CDCl3) δ 4.94 (t, J = 5.6 Hz, 1H), 4.41 (dd, J = 8.7, 7.5 Hz, 2H), 4.02 (dd, J = 8.7, 7.5 Hz, 2H), 3.37 (s, 6H), 3.30 (d, J = 5.7 Hz, 2H). O O O crotonoyl chloride, Et3N NH THF, 0→23 °C O O N 266 289 Me Crotonoyl imide 266 To a flame-dried 40 mL vial containing 2-oxazolidinone (289, 1.0 g, 11.5 mmol, 1.0 equiv) under nitrogen were added THF (20 mL) and Et3N (4.0 mL, 28.8 mmol, 2.5 equiv). The vial was cooled to 0 °C and crotonoyl chloride (2.2 mL, 23.0 mmol, 2.0 equiv) was added dropwise with stirring. After 30 min, the reaction mixture was allowed to warm to 23 °C and stirring was continued. After 22 h, the reaction mixture was partitioned between saturated aq. NH4Cl and CH2Cl2. The layers were separated, and the aqueous phase was extracted once with CH2Cl2 and washed once with 1 N aq. HCl. The HCl phase was back-extracted once with CH2Cl2, and the combined organic phases were dried over a mixture of NaHCO3 and Na2SO4 and concentrated under reduced pressure. The crude product was purified twice by automated silica gel flash chromatography (Teledyne ISCO, 0→60% EtOAc/hexanes, then 0→80% EtOAc/hexanes) to afford the title compound as a white solid (159 mg, 1.02 mmol, 9% yield). All characterization data matched those reported in the literature.27 Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 476 O O O 270 Enone 270 Prepared according to the procedure of Shing.20 All characterization data matched those reported in the literature. NH2 MeO2C O 1. KCN, Et3N•HCl MeOH/H2O, 23 °C O O 2. methyl cyanoacetate, S8, morpholine, MeOH, 60 °C 270 S NC O O 271 mixture of isomers Nitrile 271 To a 2-dram glass vial were added KCN (201 mg, 3.09 mmol, 1.17 equiv), Et3N•HCl (429 mg, 3.12 mmol, 1.18 equiv), water (0.59 mL) and methanol (0.73 mL). Enone 270 (407 mg, 2.64 mmol, 1.0 equiv) was added dropwise with stirring as a solution in methanol (1.3 mL). After 27 h, the reaction mixture was diluted with water and extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4 and purified by silica gel flash chromatography (50% EtOAc/hexanes) to afford an uncharacterized complex mixture of nitrile adducts (207 mg) as a waxy substance. To a 20 mL glass vial were added this mixture (192 mg, 0.922 mmol, 1.0 equiv assuming mass of cyanohydrin), S8 (30 mg, 0.115 mmol, 0.125 equiv), and MeOH (1.8 mL), followed by methyl cyanoacetate (82 µL, 0.92 mmol, 1.0 equiv) and morpholine (80 µL, 0.92 mmol, 1.0 equiv). The vial was sealed with a PTFE/silicone septum and the reaction mixture was stirred at 60 °C in a metal heating block for 20 h, resulting in a deep Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 477 red color. After 20 h, the reaction mixture was concentrated under reduced pressure and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→90% EtOAc/hexanes) to afford the title compound as a mixture of constitutional isomers (117 mg, 0.398 mmol, 16% yield over 2 steps); 1H NMR (400 MHz, CDCl3) δ 4.29 – 4.21 (m, 3H), 4.16 – 3.98 (m, 5H), 3.96 – 3.85 (m, 2H), 3.81 (s, 3H), 3.36 (ddt, J = 17.1, 5.9, 1.3 Hz, 1H), 3.24 – 3.15 (m, 1H), 3.09 (dd, J = 9.1, 5.8 Hz, 1H), 2.99 – 2.89 (m, 1H), 2.87 – 2.77 (m, 2H). O O O 274 Ketal 274 Prepared according to the procedure of Liao.23 All characterization data matched those reported in the literature. O O2N Me S O 282 O P OMe OMe , NaH O O2N S Me THF, 0→23 °C 281 283 Enone 283 To a flame-dried 250 mL round bottom flask containing NaH (60% dispersion in mineral oil, 611 mg, 15.3 mmol, 1.2 equiv) under nitrogen was added THF (25 mL). The flask was cooled to 0 °C and phosphonate 282 (3.5 mL, 25.5 mmol, 2.0 equiv) was added rapidly with stirring. Gas evolution was accompanied by the formation of a thick white precipitate. After 15 min, aldehyde 281 (2.0 g, 12.7 mmol, 1.0 equiv) was added as a solution in THF (25 mL) by cannula, whereafter the reaction mixture was allowed to warm Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 478 to 23 °C and stirred for 1.5 h. Then, the reaction mixture was quenched with saturated aq. NH4Cl (100 mL), the layers were separated, and the aqueous phase was extracted with EtOAc (2x20mL). The combined organic phases were dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel flash chromatography (40% EtOAc/hexanes) to afford the title compound as a yellow solid (2.13 g, 10.8 mmol, 85% yield); 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 4.3 Hz, 1H), 7.51 (dd, J = 16.0, 0.7 Hz, 1H), 7.22 (dt, J = 4.3, 0.5 Hz, 1H), 6.68 (d, J = 16.0 Hz, 1H), 2.38 (s, 3H). O O2N S Me 283 Cl3SiH, Ph3PO (20 mol %) then NBS CH2Cl2, 23 °C Br O2N O S Me 284 Bromoketone 284 To a flame-dried 1-dram glass vial were added enone 283 (200 mg, 1.01 mmol, 1.0 equiv) and PPh3O (56 mg, 0.202 mmol, 0.2 equiv). The vial was evacuated and backfilled with nitrogen, and CH2Cl2 (2 mL) was added followed by Cl3SiH (0.15 mL, 1.52 mmol, 1.5 equiv). The reaction mixture was stirred at 23 °C for 7 h, then transferred by syringe into a separate 2-dram glass vial containing a suspension of NBS (270 mg, 1.52 mmol, 1.5 equiv) in CH2Cl2 (3 mL). The reaction mixture quickly became dark red and an exotherm occurred. After stirring for 13 h, the reaction mixture was quenched with saturated aq. Na2CO3 (50 mL). The resulting suspension was extracted with CH2Cl2 (2x20 mL), and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→50% EtOAc/hexanes) to afford the title compound as a thick yellow oil (75 mg, 0.27 mmol, 27% yield); 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 4.2 Hz, 1H), Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine 479 6.87 (dt, J = 4.2, 0.9 Hz, 1H), 4.46 (t, J = 7.0 Hz, 1H), 3.65 (ddd, J = 15.5, 6.8, 1.0 Hz, 1H), 3.38 (ddd, J = 15.5, 7.1, 0.9 Hz, 1H), 2.41 (s, 3H). O2N O2N S O O + Cl 281 Me 286 DBU CH2Cl2, –20 °C S O Me 287 O Epoxyketone 287 To a flame-dried 100 mL round bottom flask under nitrogen were added CH2Cl2 (12.5 mL) and DBU (1.4 mL, 9.5 mmol, 3.0 equiv). The flask was cooled to –20 °C in an ice/NaCl bath. Then, a solution of aldehyde 281 (500 mg, 3.18 mmol, 1.0 equiv) and chloroacetone (286, 0.29 mL, 3.5 mmol, 1.1 equiv) in CH2Cl2 (12.5 mL) was added dropwise over 8 min with stirring, resulting in a color change to deep purple. After stirring for 1 h at –20 °C, the reaction mixture was combined with water (50 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2x15 mL). The combined organic phases were washed with diluted brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (33% EtOAc/hexanes) to afford the title compound as a light brown solid (169 mg, 0.793 mmol, 25% yield); 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 4.3 Hz, 1H), 7.10 (dd, J = 4.2, 0.6 Hz, 1H), 4.23 (dd, J = 1.8, 0.5 Hz, 1H), 3.62 (d, J = 1.8 Hz, 1H), 2.21 (s, 3H). Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine A5.9 (1) 480 REFERENCES AND NOTES See, for example: Ipatieff, V. N.; Pines, H.; Friedman, B. S. Reaction of Aliphatic Olefins with Thiophenol. J. Am. Chem. Soc. 1938, 60, 2731–2734. (2) See, for example: Blom, J.; Reyes-Rodríguez, G. J.; Tobiesen, H. N.; Lamhauge, J. N.; Iversen, M. V.; Barløse, C. L.; Hammer, N.; Rusbjerg, M.; Jørgensen, K. A. Umpolung Strategy for α-Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles. Angew. Chem. Int. Ed. 2019, 58, 17856–17862. (3) For a relevant review, see: Clayden, J.; MacLellan, P. Asymmetric synthesis of tertiary thiols and thioethers. Beilstein J. Org. Chem. 2011, 7, 582–595. (4) Nishimoto, Y.; Okita, A.; Yasuda, M.; Baba, A. Synthesis of a Wide Range of Thioethers by Indium Triiodide Catalyzed Direct Coupling between Alkyl Acetates and Thiosilanes. Org. Lett. 2012, 14, 1846–1849. (5) Bichovski, P.; Haas, T. M.; Kratzert, D.; Streuff, J. Synthesis of Bridged Benzazocines and Benzoxocines by a Titanium-Catalyzed Double-Reductive Umpolung Strategy. Chem. Eur. J. 2015, 21, 2339–2342. (6) House, H. O.; Kleschick, W. A.; Zaiko, E. J. Enones with Strained Double Bonds: The Bicyclo[3.3.1] System. J. Org. Chem. 1978, 43, 3653–3661. (7) Griera, R.; Rigat, L.; Alvarez, M.; Joule, J. A. Reactions of 1-Methyl-4-quinolone with 2-Lithio-1,3-dithianes. J. Chem. Soc. Perkin Trans. 1 1992, 1223–1227. (8) Nowick, J. S.; Pairish, M.; Lee, I. Q.; Holmes, D. L.; Ziller, J. W. An Extended βStrand Mimic for a Larger Artificial β-Sheet. J. Am. Chem. Soc. 1997, 119, 5413– 5424. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine (9) 481 Baruah, P. K.; Sreedevi, N. K.; Gonnade, R.; Ravindranathan, S.; Damodaran, K.; Hofmann, H.; Sanjayan, G. J. Enforcing Periodic Secondary Structures in Hybrid Peptides: A Novel Hybrid Foldamer Containing Periodic γ-Turn Motifs. J. Org. Chem. 2007, 72, 636–639. (10) Paudyal, M. P.; Adebesin, A. M.; Burt, S. R.; Ess, D. H.; Ma, Z.; Kürti, L.; Falck, J. R. Dirhodium-catalyzed C-H arene amination using hydroxylamines. Science 2016, 353, 1144–1147. (11) Ma, X.; Hazelden, I. R.; Langer, T.; Munday, R. H.; Bower, J. F. Enantioselective Aza-Heck Cyclizations of N-(Tosyloxy)carbamates: Synthesis of Pyrrolidines and Piperidines. J. Am. Chem. Soc. 2019, 141, 3356–3360. (12) Zhou, W.; Fan, M.; Yin, J.; Jiang, Y.; Ma, D. CuI/Oxalic Diamide Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amines. J. Am. Chem. Soc. 2015, 137, 11942–11945. (13) Ittyerah, P. I.; Mann, F. G. Cyclic keto-amines. Part III. The reactions of substituted 1 : 2 : 3 : 4-tetrahydro-4-oxoquinolines and of 1 : 6-dioxojulolidines. J. Chem. Soc. 1958, 467–480. (14) Braunholtz, J. T.; Mann, F. G. The preparation of bis-2-cyanoethyl derivatives of aromatic primary amines, and their conversion into 1 : 6-diketojulolidines. Part II. J. Chem. Soc. 1953, 1817–1824. (15) Kantminene, K.; Mikul'skene, G.; Hormi, O.; Beresnevicius, Z. I. Synthesis of Tetrahydro-1H,7H-benzo[ij]quinolizine-1,7-dione Derivatives. Chem. Heterocycl. Compd. 2002, 38, 422–428. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine (16) 482 a) Hosokawa, T.; Ohta, T.; Murahashi, S. Palladium(II)-catalysed acetalization of terminal olefins bearing electron-withdrawing substituents with 1,3- and 1,2-diols. J. Chem. Soc., Chem. Commun. 1983, 848–849. b) Hosokawa, T.; Ohta, T.; Kanayama, S.; Murahashi, S. Palladium(II)-catalyzed acetalization of terminal olefins bearing electron-withdrawing substituents with optically active diols. J. Org. Chem. 1987, 52, 1758–1764. (17) Auclair, S. X.; Morris, M.; Sturgess, M. A. Rate Enhancement in the Wacker Oxidation of Hydroxy-α,β unsaturated Esters: A Fast Neutral Method for the Preparation of Masked β-Ketoesters. Tetrahedron Lett. 1992, 33, 7739–7742. (18) Li, M.; Carreras, V.; Jalba, A.; Ollevier, T. Asymmetric Diels–Alder Reaction of α,β-Unsaturated Oxazolidin-2-one Derivatives Catalyzed by a Chiral Fe(III)Bipyridine Diol Complex. Org. Lett. 2018, 20, 995–998. (19) Otera, J.; Dan-oh, N.; Nozaki, H. Distannoxane-catalyzed acetilization of carbonyls. Tetrahedron 1992, 48, 1449–1456. (20) Shing, T. K. M.; Yeung, Y.; Su, P. L. Mild Manganese(III) Acetate Catalyzed Allylic Oxidation: Application to Simple and Complex Alkenes. Org. Lett. 2006, 8, 3149–3151. (21) Müller, P.; Siegfried, B. SN2 Reactions with Carboxylic Esters. Selective cleavage of methyl esters. Helv. Chim. Acta 1974, 57, 987–994. (22) Oda, M.; Kawase, T.; Okada, T.; Enomoto, T. 2-Cyclohexene-1,4-dione. Org. Synth. 1996, 73, 253. Appendix 5 – Additional Strategies and Tactics Toward the Total Synthesis of Aleutianamine (23) 483 Hung, S.; Liao, C. Double Michael Additions of Lithium Enolate of 1,4Dioxaspiro[4.5]dec-6-en-8-One to Acrylates. J. Chin. Chem. Soc. 1994, 41, 191– 194. (24) Lao, Z.; Zhang, H.; Toy, P. H. Reductive Halogenation Reactions: Selective Synthesis of Unsymmetrical α-Haloketones. Org. Lett. 2019, 21, 8149–8152. (25) Luo, J.; Hu, L.; Zhang, M.; Tang, Q. An efficient Darzens reaction promoted by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Tetrahedron Lett. 2019, 60, 1949– 1951. (26) Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (27) Lauzon, S.; Keipour, H.; Gandon, V.; Ollevier, T. Asymmetric FeII-Catalyzed ThiaMichael Addition Reaction to α,β-Unsaturated Oxazolidin-2-one Derivatives. Org. Lett. 2017, 19, 6324–6327. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 484 CHAPTER 3 Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins† 3.1 INTRODUCTION Porphyrinoids and their transition metal complexes have demonstrated numerous applications in catalysis (including electrocatalysis),1 as sensitizers for photodynamic therapy,2 and as drugs.3 Corroles are a class of aromatic, ring-contracted porphyrinoid heterocycles that differ from the parent porphyrins by the absence of one meso carbon atom (Figure 3.1.1). The carbon skeleton of corroles is shared with the corrin moiety of vitamin B12. Compared to L2X2 porphyrins, LX3 corroles have been found to stabilize high metal oxidation states and often preferentially bind to trivalent metals.4 Figure 3.1.1. Introduction to the corrole ring system. N HN NH N Porphyrins • L2X2 ligands • D4h symmetry † N HN NH HN Corroles • LX3 ligands • Stabilize high oxidation states • Lower symmetry This research was performed under the supervision of Prof. Zeev Gross in the Schulich Faculty of Chemistry at the Technion in collaboration with Arik Raslin, Marcelo Fernandez de la Mora, and Dr. Atif Mahammed and is unpublished. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 485 The first corroles (290, Figure 3.1.2) were prepared in 1965 by Johnson and Kay.5,6 These compounds were unsubstituted at the meso positions but fully substituted at the ortho positions. Later research by Paolesse in 1993 demonstrated the synthesis of mesosubstituted corroles such as 291.7 In 1999, Gross8 and Paolesse9 simultaneously reported dramatically simplified synthetic procedures toward corroles, wherein pyrrole and an aromatic aldehyde could undergo direct condensation followed by oxidation in a modified Rothemund reaction to afford meso-substituted, β-unsubstituted corroles 292. This architecture, analogous to that of meso-tetrasubstituted porphyrins,10 is attractive due to its smaller geometric size, electronic tunability, and potential for further functionalization. Figure 3.1.2. Select milestones toward the synthesis of minimally substituted corroles. Johnson and Kay, 1965: corroles Paolesse, 1993: meso-substituted corroles Ph Me N Co L Ph N Me Me N HN N Ph Ar 293 Me 291 N N HN Ar NH HN CF3 NH HN Me Me HN F3C N Me Ar NH HN Me Gross, 2021: parent, unsubstituted corrole CF3 Me N R Ghosh, 2011: CF3-substituted β-free corrole Me Me R Gross, Paolesse, 1999: β-free corroles from pyrrole and aldehydes HN NH HN Me Me Me 290 a) R = Et b) R = CH2CH2CO2Me 292 294 Gross: Ar = C6F6, C6H4F2 Paolesse: Ar = Ph Additional seminal research: Gryko, Gross, Paolesse, Ghosh, others The reports by Gross and Paolesse prompted a renaissance in the field of corrole synthesis and applications, and numerous syntheses of corrole derivatives and their Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 486 transition and main group metal complexes have since been reported: the “periodic table of corroles” continues to expand.11 In 2011, moving toward smaller corrole derivatives, Ghosh reported the synthesis of tris(trifluoromethyl)corrole 293 from pyrrole and trifluoroacetaldehyde hydrate.12 A single example of a rhenium complex of this corrole had previously been reported by a unique porphyrin ring contraction,13 but Ghosh’s report represented the first synthesis of the free base and of other metal complexes. The synthesis of this corrole was later improved upon by Gross, Gray, and Virgil.14 Corrole 293 is somewhat unique due to its small size and the fully sp3-hybridized nature of the meso substituents. Most recently, in 2021, the Gross group succeeded in synthesizing corrole 294, the fully unsubstituted parent heterocycle.15 While the electron-rich nature of the free heterocycle was found to render it unstable, several metal complexes of corrole 294 were prepared and characterized. Gross’s synthesis of unsubstituted corrole 294 could proceed by two methods.15 First, tris(trifluoromethyl)corrole 293 underwent basic hydrolysis to tricarboxylate derivative 295 (Scheme 3.1.3A).16 Interestingly, esters of 295 were not competent precursors to the triacid. Thermolysis of triacid 295 in decalin led to efficient decarboxylation. The free corrole was isolated as Mo or Re oxo complexes to circumvent the unstable nature of the heterocycle. In a more rapid fashion, complexes of 294 could be prepared by a pyrrole oligomerization approach (Scheme 3.1.3B). Similar approaches have achieved wide adoption by the community for the synthesis of meso-substituted corroles from pyrrole and aryl aldehydes.6a Combination of excess pyrrole (296) with formaldehyde afforded a Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 487 statistical mixture of oligomers, from which tetrapyrromethane (or “bilane”) 297 was isolated in 12% yield. Lastly, oxidation with PIFA in the presence of a suitable metal salt directly afforded corrole complexes 294. Scheme 3.1.3. Approaches to complexes of unsubstituted corrole 294 (Gross, 2021). A) Free corrole 294 by a decarboxylative approach. CF3 N CO2H HN F3C CF3 NH HN NaOH, then HCl H2O, reflux N HO2C then Mo(CO)6 or Re2(CO)10 CO2H NH HN 93% yield N O N M decalin, 160 °C HN N M = Re: 18% yield M = Mo: 26% yield 293 295 N 294-ReO 294-MoO B) Free corrole 294 by a classical oligomerization-cyclization approach. H N + CH2O H2O, µwave, 60 °C 12% yield NH HN NH HN 296 PIFA excess [M] pyridine, 60 °C N N M N N M = Co(Py)2: 15% yield M = Mn: 8% yield (4 equiv) 297 294-Co 294-Mn Excitingly, the Co(PPh3) complex of 294 was found to undergo sublimation at 220 °C and 40 mTorr, a property unique among porphyrinoid metal complexes, which are generally much more challenging to sublimate. Furthermore, the molybdenum oxo complex efficiently underwent adsorption to Vulcan XC72R carbon and was shown to be an excellent electrocatalyst for proton reduction to H2. Given the unique properties of corrole complexes 294, an efficient and scalable synthetic route is desirable as it would enable further exploration of the potential applications of these complexes. Unfortunately, the cyclooligomerization approach to 294 proceeds in only up to 1.8% yield over 2 steps. We therefore set out to develop an improved procedure for the synthesis of these compounds and other minimally substituted corroles. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 3.2 488 ATTEMPTS TO IMPROVE BILANE SYNTHESIS The two key factors complicating the synthesis of bilane 297 are low chemical yield and a slow and laborious chromatographic separation. We first attempted to solve the latter problem, aiming to replace chromatography with sublimation. The volatilities of pyrrole (296) and isolated dipyrrane 298, tripyrrane 299, and desired tetrapyrrane 297, each chromatographically isolated from a statistical oligomerization reaction of pyrrole and formaldehyde, were therefore compared (Scheme 3.2.1). Scheme 3.2.1. Evaluation of sublimation as a means for oligopyrrane separation. H N Easily removable by rotary evaporation 296 (excess) NH HN Smooth sublimation at 40 °C, 2•10–4 torr. 298 H N + CH2O H2O, µwave, 60 °C N H NH Slow, incomplete sublimation from 60–80 °C at 6.4•10–5 torr. HN 299 NH HN NH HN Began sublimating at 70 °C (3.4•10–5 torr), melted at 130 °C, decomp. at 250 °C 297 + larger oligomers While pyrrole was readily removed by rotary evaporation and dipyrrane 298 sublimated in an efficient manner, tripyrrane 299 and tetrapyrrane 297 could not be separated by sublimation. The slow sublimation of the latter two compounds occurred at similar temperatures and pressures. As such, chromatography on silica gel remained the primary means of oligopyrrane isolation. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 489 We then directed our efforts to improving the chemical process for the synthesis of bilane 297. In addition to the low yield of 297, the existing procedure (Scheme 3.1.3B) is inherently limited in scale as the oligomerization must be conducted in a microwave vessel to enable rapid, brief heating. The use of paraformaldehyde as a less reactive formaldehyde surrogate was envisioned as a possible method to improve the robustness and scalability of the oligomerization. To our delight, applying a modified version of Bruce’s conditions for the synthesis of dipyrromethane 298 enabled the isolation of tetrapyrromethane 297 in 13% yield (Scheme 3.2.2).17 Scheme 3.2.2. AcOH-promoted oligomerization of pyrrole and paraformaldehyde. NH HN H N 298 (CH2O)n 30% yield NH HN MeOH/AcOH, 23 °C N H 296 (20 equiv) recovered 37% NH NH HN HN 299 19% yield 297 13% yield Unfortunately, the use of 20 equivalents of pyrrole were necessary to maximize the yield of the reaction. While the use of fewer equivalents was expected to favor the formation of tetrapyrrane over di- and tripyrrane, this appeared to simply favor the formation of putative polymeric material. The product ratio for the oligomerization of pyrrole and aldehydes is likely biased by the increased electron-richness of the oligomers relative to free pyrrole.6a For oligomerizations of pyrrole with certain aryl aldehydes, the yield can be tuned by exploiting the reduced solubility of the tetrapyrrane relative to smaller oligomers. In the correct solvent mixture (typically a water/MeOH mixture), under acid catalysis, Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 490 tetrapyrrane precipitates out of solution upon formation, minimizing the formation of longer oligomers.18 Unfortunately, the higher aqueous solubility of bilane 297 would prevent the use of such a method to control the oligomerization. We instead took inspiration from well-established controlled bilane formations used to synthesize A2B corroles. Specifically, in 2015, Tanaka and Osuka reported that diol 300, which bears an unsubstituted meso-methylene linker, could undergo Lewis acid-promoted substitution with pyrrole to afford tetrapyrrane 301 in excellent yield (Scheme 3.2.3).19 This compound could be oxidized to a trans-A2B-type corrole. Scheme 3.2.3. A tetrapyrrane from a meso-free dipyrrane (Tanaka and Osuka, 2015). F F F H N F NH HN F HO OH F F F F 300 F F F , BF3•OEt2 neat, 23 °C 91% yield F F NH HN F NH HN F F F F F 301 We aimed to access dialdehyde 303 as a precursor to a des-aryl derivative of diol 300 (Scheme 3.2.4A). Dimerization of aldehyde 302 using formaldehyde as a linker was attempted by acid catalysis, but the electron-poor nature of the heterocycle inhibited the reaction. Instead, dipyrrane 298 was formylated with the Villsmeier reagent, providing 303 in 49% yield (Scheme 3.2.4B). NaBH4 reduction provided a crude diol that was directly treated with pyrrole and either TFA or BF3•Et2O, but in either case, nonspecific decomposition was observed with no conversion to desired tetrapyrrane 297. Subjecting the crude diol to the conditions used for the mild oligomerization of pyrrole with paraformaldehyde (AcOH/MeOH) led to scrambling, as judged by TLC – both di- and tripyrranes were observed, suggesting reversable loss of formaldehyde. This phenomenon Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 491 in well-known in the porphyrin literature, occurring to a greater extent in systems with small substituents.20 Scheme 3.2.4. Attempted controlled assembly of tetrapyrrane 297. A) Unsuccessful dimerization of 2-formylpyrrole. O H N + cat. HCl X MeOH/H2O, 23 °C CH2O NH HN O O 303 302 not detected B) Preparation of dialdehyde 303 by dipyrrane acylation. POCl3, DMF NH HN CH2Cl2, 23 °C 298 49% yield NH HN O O 303 C) Unsuccessful selective formation of tetrapyrrane. NH HN O 303 O NaBH4, MeOH/CH2Cl2 then pyrrole, TFA, CH2Cl2 -or- BF3•OEt2, CH2Cl2, pyrrole X 23 °C NH HN NH HN 297 NH HN O 303 not detected NaBH4, MeOH then pyrrole (100 equiv), AcOH/MeOH scrambling –– di- and tripyrranes observed by TLC 23 °C O D) Low-yielding dimerization of dipyrromethane. (CH2O)n NH HN MeOH/AcOH, 23 °C 298 6% yield 22% recovery NH HN NH HN 297 As a final resort, the dimerization of dipyrrane 298 was attempted (Scheme 3.2.4D). While the standard conditions with paraformaldehyde led to formation of tetrapyrrane 297, it was only isolated in 6% yield, with the recovery of 22% of the starting material. The remainder of the mass balance appeared to consist of higher-order oligomers. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 492 Further evaluation of reaction conditions could result in a procedure for the synthesis of tetrapyrrane 297 in higher yield, but at this stage, we refocused our efforts toward the synthesis of additional minimally substituted porphyrinoids. 3.3 UNEXPECTED SYNTHESIS OF A MONOAZAPORPHYRIN Over the course of previous synthetic efforts toward minimally substituted corroles by the Gross group, PIFA was consistently demonstrated to be the most robust oxidant for cyclization of the bilane intermediate.14b,15 We embarked on a campaign to evaluate further chemical oxidants, both with and without metal templating agents, in order to maximize the yields for bilane cyclization. During this campaign, our attention was drawn to an early report from the corrole literature wherein K3Fe(CN)6 was used to oxidize acyclic biladienes (e.g., 304) to corroles (e.g., 290a, Scheme 3.3.1).21 Scheme 3.3.1. Corrole synthesis by oxidation with K3Fe(CN)6 (Dolphin et al., 1966). Et Et Et Me Me Me N HN NH N •2HBr Me Me Me 304 Me Et MeOH/H2O, ∆ 84% yield Me N K3Fe(CN)6, NH4OH HN NH HN Me Me Me Me 290a Using tris(trifluoromethyl)bilane 305 as a model substrate to evaluate oxidation to corroles, the K3Fe(CN)6-mediated conditions reported by Dolphin et al., which include aqueous ammonia, were evaluated (Scheme 3.3.2). Interestingly, known free base corrole 293 was not isolated from the reaction mixture—instead, a new porphyrinoid was isolated and found to be monoazaporphyrin 306-H2. Replacement of NH4OH with NaOH suppressed macrocycle formation entirely. To our knowledge, 306-H2 is only the second Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 493 reported example of a monoazaporphyrin lacking β-substituents, and the first example of such a compound as the free base. Scheme 3.3.2. Unexpected oxidation of a bilane to a monoazaporphyrin. CF3 CF3 K3Fe(CN)6 (8 equiv) NH HN F3C NH HN CF3 MeOH/aq. NH4OH, 65 °C 4.0% yield CF3 HN N N CF3 F3C N NH HN F3C CF3 NH HN N 305 306-H2 293 not observed Examination of the 1H NMR spectrum of 306-H2 in CDCl3 (Figure 3.3.3A) revealed the presence of 3 multiplets and one clean doublet (J = 5.1 Hz) in the aromatic region, consistent with the expected 2-fold symmetry of the molecule and similar to the spectra of corroles. The 2 N-H ring protons appear upfield at –2.41 ppm. Compared to the analogous corrole 293 (Figure 3.3.3B), the aryl C–H protons appear somewhat downshifted. Figure 3.3.3. Comparison of the 1H NMR spectra of A) azaporphyrin 306-H2 and B) corrole 293. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 494 The preparation of monoazaporphyrins was reported as early as 1936,22 and since then, several targeted syntheses of these macrocycles have been developed.23,24 While related diazaporphyrins have been used in catalysis,25 monoazaporphyrins have not found applications, and nearly all reported examples of these compounds are fully alkylated at the pyrrole β positions. Compared to porphyrins, monoazaporphyrins possess a red-shifted Q-band and a blue-shifted Soret band and their copper complexes are more prone to reduction and less prone to oxidation.26 An iron(III) monoazaporphyrin complex was shown to have a different electronic ground state than the corresponding porphyrin.27 In 2011, Palmer, Gross, and Gray reported the first example of a β-unsubstituted monoazaporphyrin as an iridium complex (308) by oxidative nitrogen insertion into a corrole ring (Scheme 3.3.4).28 This compound was isolated as a mixture with mono- and dibrominated derivatives. Scheme 3.3.4. Previous synthesis of a β-free monoazaporphyrin complex (Palmer, Gross, and Gray, 2011). C6F5 C6F5 F5C6 N L N Ir N L N N C6F5 NBS, NH4OH MeCN/H2O N Br 307 L = NH3 L N Ir F5C6 C6F5 L N N Br 308 L = NH3 We were therefore thrilled to have discovered a procedure to prepare a β-free monoazaporphyrin as the free base, as access to this material would enable the preparation of metalated derivatives and their characterization and comparison with similar classic porphyrins. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 495 Heating monoazaporphyrin 306-H2 in methanol/chloroform solution in the presence of cobalt(II) acetate tetrahydrate led to formation of the corresponding cobalt(II) monoazaporphyrin complex 306-Co (Scheme 3.3.5).29 An x-ray quality crystal of this complex was grown by slow evaporation from a THF/heptane mixture. The crystal structure of 306-Co revealed considerable ruffling, similar to the reported structure of an analogous 4-fold symmetric copper porphyrin. The average Co–N bond distance was 1.928 Å, compared to 1.971 Å for (octaethylporphyrinato)cobalt(II).30 Scheme 3.3.5. Metallation of monoazaporphyrin 306-H2. CF3 CF3 Co(OAc)2•4H2O HN N CF3 F3C N NH MeOH/CHCl3, 61 °C 95% yield N F3C N Co N CF3 N N N 306-H2 306-Co Future research will involve the synthesis of additional metal complexes of monoazaporphyrin 306, the study of these complexes’ photophysical and electrochemical properties, and the exploration of potential catalytic applications. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 3.4 496 CONCLUSION Studies toward improved syntheses of minimally substituted corrole macrocycles were performed, primarily focusing on optimization of the synthetic procedure toward bilane (tetrapyrrane) macrocyclization substrates. Although the synthesis of these substrates was not substantially improved in our hands, we inadvertently prepared the first known example of a free base β-free monoazaporphyrin. The cobalt complex of this ligand was prepared and characterized by x-ray crystallography. Future studies will involve the preparation of additional metal monoazaporphyrin complexes and characterization of their photo- and electrochemical properties and potential applications in catalysis. 3.5 EXPERIMENTAL SECTION 3.5.1 MATERIALS AND METHODS Unless otherwise noted, reagents and solvents were purchased from commercial sources and used as received. Pyrrole was passed through a column of basic alumina immediately prior to use. Reaction progress was monitored by thin-layer chromatography (TLC). TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or Br2 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 nm) was used for flash chromatography. 1H and 19F NMR spectra were recorded on Bruker Avance III 400 spectrometer (400 MHz for 1 H and 377 MHz for 19F). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities 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. High-resolution mass spectra were recorded on a Bruker MaXis Impact mass spectrometer. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 3.5.2 497 EXPERIMENTAL PROCEDURES H N (CH2O)n MeOH/AcOH, 23 °C NH HN NH 298 296 NH HN N H + + HN 299 NH HN 297 Procedure for the oligomerization of pyrrole (296) with paraformaldehyde To a 250 mL round bottom flask were added paraformaldehyde (541 mg, 18.0 mmol [calculated for monomer], 1.0 equiv), pyrrole (25.0 mL, 360 mmol, 20 equiv), glacial acetic acid (75 mL), and methanol (25 mL). The reaction mixture was sparged with nitrogen for 25 min, then sealed and stirred for 17 h at 23 °C. After 17 h, the reaction mixture was diluted with CH2Cl2 (250 mL), washed once with water and twice with dilute aq. KOH, dried over Na2SO4, and concentrated under reduced pressure. Pyrrole (9.3 mL, 134 mmol, 37% recovery) was recovered by distillation under high vacuum. The residue was subjected to silica gel flash chromatography (5→10→15→20% EtOAc/hexanes) to afford dipyrrane 298 (780 mg, 5.34 mmol, 30% yield), tripyrrane 299 (390 mg, 1.73 mmol, 19% yield), and tetrapyrrane 297 (244 mg, 0.802 mmol, 13% yield). All characterization data matched those reported in the literature.31 (CH2O)n NH HN MeOH/AcOH, 23 °C NH HN NH HN 298 297 Tetrapyrrane 297 by dimerization of dipyrrane 298 To a 2-dram glass vial were added dipyrrane 298 (50 mg, 0.342 mmol, 2.0 equiv) and paraformaldehyde (5 mg, 0.171 mmol, 1.0 equiv) followed by glacial acetic acid (0.75 mL) and methanol (0.25 mL). The reaction mixture was stirred at 23 °C for 23 h, then Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 498 diluted with CH2Cl2, washed with water (2x) and saturated aq. KOH (1x), and dried over Na2SO4. The solution was concentrated under reduced pressure and purified by silica gel flash chromatography (10→20% EtOAc/hexanes) to afford recovered dipyrrane 298 (11 mg, 0.075 mmol, 22% recovery) and tetrapyrrane 297 (3.3 mg, 0.011 mmol, 6% yield). All characterization data matched those reported in the literature.31 POCl3, DMF NH HN 298 NH HN CH2Cl2, 23 °C O O 303 Dialdehyde 303 To a flame-dried 25 mL round bottom flask under nitrogen in an ice bath were added DMF (0.26 mL, 3.37 mmol, 9.9 equiv) and POCl3 (0.32 mL, 3.43 mmol, 10 equiv). The ice bath was removed, and after 10 min, CH2Cl2 (1 mL) was added. Dipyrrane 298 (50 mg, 0.342 mmol, 1.0 equiv) was added as a solution in CH2Cl2 (2.4 mL), and the reaction mixture was allowed to stir for 28 h. Then, the reaction mixture was quenched with 5% aq. NaOH (30 mL). The resulting biphasic suspension was stirred for 15 min at 23 °C, then diluted with water and extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (50% EtOAc/hexanes) to afford the title compound as a white solid (34 mg, 0.168 mmol, 49% yield). All characterization data matched those reported in the literature.32 Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins CF3 CF3 K3Fe(CN)6 (8 equiv) NH HN F3C 499 NH HN CF3 N HN NH N CF3 F3C MeOH/aq. NH4OH, 65 °C N 305 306-H2 10,15,20-tris(trifluoromethyl)-5-azaporphyrin (306-H2): To a solution of tetrapyrromethane 30514b (247 mg, 0.486 mmol, 1.0 equiv) in methanol (49 mL) was added a solution of potassium hexacyanoferrate(III) (1.28 g, 3.89 mmol, 8.0 equiv) in 25% aq. NH3 (99 mL) rapidly with magnetic stirring. The reaction mixture was placed in a hot water bath and heated to reflux. After 1.5 h, the reaction mixture was cooled to 23 °C, diluted with water (50 mL), extracted with dichloromethane (3x50 mL), dried over solid Na2SO4, and filtered. The solvent was removed by rotary evaporation and the crude product was purified by silica gel flash chromatography (10% EtOAc/hexanes, pink fractions collected) to afford monoazaporphyrin 306-H2 as a dark brown solid (9.9 mg, 0.0192 mmol, 4.0% yield); 1H NMR (400 MHz, CDCl3) δ 9.81 – 9.67 (m, 4H), 9.65 – 9.55 (m, 2H), 9.32 (d, J = 5.1 Hz, 2H), –2.41 (s, 2H); 19F NMR (377 MHz, CDCl3) δ –36.44 (s, 3F), –38.18 (t, J = 2.8 Hz, 6F); HRMS (APCI–): m/z calc’d for C22H10F9N5 [M–]: 515.0792, found 515.0802. CF3 CF3 Co(OAc)2•4H2O HN N CF3 F3C N NH MeOH/CHCl3, 61 °C N F3C N Co N CF3 N N N 306-H2 306-Co 10,15,20-tris(trifluoromethyl)-5-azaporphyrin cobalt(II) (306-Co): To a solution of monoazaporphyrin 306-H2 (7.8 mg, 0.0151 mmol, 1.0 equiv.) in CHCl3 (2.2 mL) in a 25 mL round-bottom flask was added a solution of cobalt(II) acetate Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 500 tetrahydrate (38 mg, 0.151 mmol, 10.0 equiv.) in methanol (0.3 mL) rapidly with stirring. The reaction mixture was heated to a gentle reflux and stirred for 16 h, then cooled to 23 °C. The solvent was removed under reduced pressure and the crude reaction mixture was purified by silica gel flash chromatography (CHCl3) to afford 306-Co as a black solid (8.2 mg, 0.0143 mmol, 95% yield); NMR data was not collected due to the paramagnetic nature of cobalt(II). HRMS (APCI–): m/z calc’d for C22H8CoF9N5 [M–]: 571.9968, found 571.9973. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 3.6 (1) 501 REFERENCES AND NOTES a) Barona-Castaño, J. C.; Carmona-Vargas, C. C.; Brocksom, T. J.; De Oliveira, K. T. Porphyrins as Catalysts in Scalable Organic Reactions. Molecules 2016, 21, 310. b) Liang, Z.; Wang, H.; Zheng, H.; Zhang, W.; Cao, R. Porphyrin-based frameworks for oxygen electrocatalysis and catalytic reduction of carbon dioxide. Chem. Soc. Rev. 2021, 50, 2540–2581. (2) Ethirajan, M.; Chen, Y.; Joshi, P.; Pandey, R. K. The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem. Soc. Rev. 2011, 40, 340–362. (3) Teo, R. D.; Hwang, J. Y.; Termini, J.; Gross, Z.; Gray, H. B. Fighting Cancer with Corroles. Chem. Rev. 2017, 117, 2711–2729. (4) Peters, J. C.; Thomas, J. C. Ligands, Reagents, and Methods in Organometallic Synthesis. In Comprehensive Organometallic Chemistry III; Mingos, D. M. 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Synthesis of an oxorhenium(v) corrolate from porphyrin with detrifluoromethylation and ring contraction. Chem. Commun. 1998, 1199–1200. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins (14) 503 a) Chen, Q.; Soll, M.; Mizrahi, A.; Saltsman, I.; Fridman, N.; Saphier, M.; Gross, Z. One-Pot Synthesis of Contracted and Expanded Porphyrins with mesoCF3 Groups. Angew. Chem. Int. Ed. 2018, 57, 1006–1010. b) Yadav, P.; Khoury, S.; Mahammed, A.; Morales, M.; Virgil, S. C.; Gray, H. B.; Gross, Z. Enhanced Synthetic Access to Tris-CF3‐Substituted Corroles. Org. Lett. 2020, 22, 3119– 3122. (15) Kumar, A.; Yadav, P.; Majdoub, M.; Saltsman, I.; Fridman, N.; Kumar, S.; Kumar, A.; Mahammed, A.; Gross, Z. Corroles: The Hitherto Elusive Parent Macrocycle and its Metal Complexes. Angew. Chem. Int. Ed. 2021, 60, 25097–25103. (16) Yadav, P.; Khoury, S.; Fridman, N.; Sharma, V. K.; Kumar, A.; Majdoub, M.; Kumar, A.; Diskin-Posner, Y.; Mahammed, A.; Gross, Z. Trifluoromethyl Hydrolysis En Route to Corroles with Increased Druglikeness. Angew. Chem. Int. Ed. 2021, 60, 12829–12834. (17) Wang, Q. M.; Bruce, D. W. One-Step Synthesis of β, meso-Unsubstituted Dipyrromethane. Synlett 1995, 1267–1268. (18) Koszarna, B.; Gryko, D. T. Efficient Synthesis of meso-Substituted Corroles in a H2O-MeOH Mixture. J. Org. Chem. 2006, 71, 3707–3717. (19) Ooi, S.; Yoneda, T.; Tanaka, T.; Osuka, A. meso-Free Corroles: Syntheses, Structures, Properties, and Chemical Reactivities. Chem. Eur. J. 2015, 21, 7772– 7779. Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins (20) 504 Littler, B. J.; Ciringh, Y.; Lindsey, J. S. Investigation of Conditions Giving Minimal Scrambling in the Synthesis of trans-Porphyrins from Dipyrromethanes and Aldehydes. J. Org. Chem. 1999, 64, 2864–2872. (21) Dolphin, D.; Johnson, A. W.; Leng, J.; van den Broek, P. The base-catalysed cyclisations of 1,19-dideoxybiladienes-ac. J. Chem. Soc. C 1966, 880–884. (22) Fischer, H.; Friedrich, W. Synthese von Mono-imido-ätio- und Mono-imidokoproporphyrin. II. Mitteilung über Imidoporphyrine. Justus Liebigs Ann. Chem. 1936, 523, 154–164. (23) Representative examples: a) Harris, R. L. N.; Johnson, A. W.; Kay, I. T. A stepwise synthesis of unsymmetrical porphyrins. J. Chem. Soc. C 1966, 22–29. b) Neya, S.; Sato, T.; Hoshino, T. A concise synthesis of monoazaporphyrin from 1,19dideoxybiladiene-ac. Tetrahedron Lett. 2008, 49, 1613–1615. (24) For a comprehensive review, see: Matano, Y. Synthesis of Aza‐, Oxa‐, and Thiaporphyrins and Related Compounds. Chem. Rev. 2017, 117, 3138–3191. (25) a) Nishimura, T.; Ikeue, T.; Shoji, O.; Shinokubo, H.; Miyake, Y. Iron(III) 5,15Diazaporphyrin Catalysts for the Direct Oxidation of C(sp3)–H Bonds. Inorg. Chem. 2020, 59, 15751–15756. b) Nishimura, T.; Sakurai, T.; Shinokubo, H.; Miyake, Y. Iron hexamesityl-5,15-diazaporphyrin: synthesis, structure and catalytic use for direct oxidation of sp3 C–H bonds. Dalton Trans. 2021, 50, 6343– 6348. (26) Ogata, H.; Fukuda, T.; Nakai, K.; Fujimura, Y.; Neya, S.; Stuzhin, P. A.; Kobayashi, N. Absorption, Magnetic Circular Dichroism, IR Spectra, Chapter 3 – Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins 505 Electrochemistry, and Molecular Orbital Calculations of Monoaza- and Opposite Diazaporphyrins. Eur. J. Inorg. Chem. 2004, 1621–1629. (27) Nakamura, K.; Ikezaki, A.; Ohgo, Y.; Ikeue, T.; Neya, S.; Nakamura, M. Electronic Structure of Six-Coordinate Iron(III) Monoazaporphyrins. Inorg. Chem. 2008, 47, 10299–10307. (28) Palmer, J. H.; Brock-Nannestad, T.; Mahammed, A.; Durrell, A. C.; VanderVelde, D.; Virgil, S.; Gross, Z.; Gray, H. B. Nitrogen Insertion into a Corrole Ring: Iridium Monoazaporphyrins. Angew. Chem. Int. Ed. 2011, 50, 9433–9436. (29) Sonkar, P. K.; Prakash, K.; Yadav, M.; Ganesan, V.; Sankar, M.; Gupta, R.; Yadav, D. K. Co(II)-porphyrin-decorated carbon nanotubes as catalysts for oxygen reduction reactions: an approach for fuel cell improvement. J. Mater. Chem. A 2017, 5, 6263–6276. (30) Scheidt, W. R.; Turowska-Tyrk, I. Crystal and Molecular Structure of (Octaethylporphinato)cobalt(II). Comparison of the Structures of Four-Coordinate M(TPP) and M(OEP) Derivatives (M = Fe-Cu). Use of Area Detector Data. Inorg. Chem. 1994, 33, 1314–1318. (31) Saltsman, I.; Gross, Z. Microwave-assisted synthesis of non-substituted tripyrrane, tetrapyrrane and pentapyrrane. Tetrahedron Lett. 2008, 49, 247–249. (32) de Groot, J. A.; van der Steen, R.; Fokkens, R.; Lugtenburg, J. Synthesis and photochemical reactivity of bilirubin model compounds. Recl. Trav. Chim. PaysBas 1982, 101, 35–40. Appendix 6 – Spectra Relevant to Chapter 3 506 APPENDIX 6 Spectra Relevant to Chapter 3: Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins F3C 9 NH N N N HN CF3 8 CF3 7 5 4 ppm 3 2 1 0 Figure A6.1. 1H NMR (400 MHz, CDCl3) of compound 306-H2. 6 -1 -2 -3 Appendix 6 – Spectra Relevant to Chapter 3 507 Appendix 6 – Spectra Relevant to Chapter 3 0 -20 -40 -60 508 -80 ppm -100 -120 -140 -160 Figure A6.2. 19F NMR (377 MHz, CDCl3) of compound 306-H2. -180 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 509 APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 3: Synthetic Strategies Toward Minimally Substituted Corroles and Azaporphyrins Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 A7.1 510 GENERAL EXPERIMENTAL INFORMATION A single crystal was immersed in Paratone–N oil and mounted on a Rigaku Oxford Diffraction XtaLAB Synergy-S at 100 K. Data collection was performed using monochromated Mo Kα radiation, l = 0.71073 Å, using φ and ω scans to cover the Ewald sphere. Accurate cell parameters were obtained with the amount of indicated reflections. Using Olex2,1 the structure was solved with the olex2.solve2 structure solution program using Charge Flipping and refined with the ShelXL3 refinement package using Least Squares minimization. All non-hydrogen atoms were refined with anisotropic displacement parameters. The hydrogen atoms were refined isotropically on calculated positions using a riding model with their Uiso values constrained to 1.5 times the Ueq of their pivot atoms for terminal sp3 carbon atoms and 1.2 times for all other carbon atoms. Software used for molecular graphics: Mercury 4.3.1.4 A7.2 X-RAY CRYSTAL STRUCTURE ANALYSIS OF COBALT AZAPORPHYRIN 306-Co Co(II) azaporphyrin 306-Co was recrystallized by slow evaporation from THF/heptane (liquid/liquid diffusion) at 23 °C to provide suitable crystals for X-ray analysis. Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 Figure A7.2.1. X-ray crystal structure of azaporphyrin complex 306-Co. Table A7.2.2. Crystal data and structure refinement for complex 306-Co. Empirical formula C22H8CoF9N5 Formula weight Temperature/K 572.26 140.15 Crystal system triclinic Space group P-1 a/Å b/Å 12.2205(2) 13.5302(2) c/Å 14.1720(3) α/° β/° 115.4873(18) 110.9276(18) γ/° 90.5835(15) Volume/Å 3 1938.02(7) Z 4 3 ρcalcg/cm μ/mm-1 1.961 0.997 F(000) Crystal size/mm Radiation 1132.0 3 2Θ range for data collection/° 0.24 × 0.15 × 0.15 MoKα (λ = 0.71073) 4.47 to 59.468 511 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 512 Index ranges -16 ≤ h ≤ 16, -17 ≤ k ≤ 18, -18 ≤ l ≤ 18 Reflections collected 28085 Independent reflections Data/restraints/parameters 8920 [Rint = 0.0364, Rsigma = 0.0377] 8920/772/667 Goodness-of-fit on F2 1.059 Final R indexes [I>=2σ (I)] R1 = 0.0335, wR2 = 0.0785 Final R indexes [all data] Largest diff. peak/hole / e Å–3 R1 = 0.0421, wR2 = 0.0826 0.44/-0.41 Table A7.2.3. Fractional Atomic Coordinates (×104) and Equivalent Isotropic Displacement Parameters (Å2×103) for 306-Co. U(eq) is defined as 1/3 of the trace of the orthogonalized UIJ tensor. Atom Co1 F1 F2 F3 F4 F5 F6 F7 F8 F9 N1 N2 N3 N4 N5 C1 C2 C3 C4 C5 C6 x 3868.3(2) 934.9(12) 1955.9(15) 2688.4(12) -640.2(14) 394.3(13) -353.2(14) 6119.8(14) 5259.6(12) 6947.8(12) 2236.7(14) 3359.9(14) 5506.6(14) 4416.0(14) 6463.2(15) 2558.9(18) 1817.9(17) 537.4(19) 199.7(19) 1256.8(17) 1292.3(17) y 3311.6(2) 4085.3(13) 5720.5(11) 4571.1(10) 1524.0(13) 2399.6(12) 3309.8(13) 1446.3(12) 24.1(10) 941.5(11) 3285.3(12) 2295.0(12) 3373.8(12) 4313.6(12) 4981.2(13) 4225.6(15) 3653.2(15) 3515.6(17) 3139.8(17) 2983.6(15) 2529.0(15) z 9273.0(2) 11690.6(12) 12381.4(12) 12982.5(10) 5645.0(14) 5204.8(11) 6376.1(12) 6274.2(12) 6229.7(11) 7566.7(11) 9137.1(13) 7670.4(13) 9438.4(13) 10879.7(13) 11302.8(13) 11154.7(16) 9992.0(17) 9489.1(18) 8363.5(18) 8134.1(17) 7054.7(16) U(eq) 15.29(7) 43.6(4) 42.5(4) 31.0(3) 57.8(5) 40.9(3) 46.4(4) 42.8(4) 36.1(3) 36.8(3) 17.8(3) 17.5(3) 15.7(3) 16.5(3) 20.1(3) 20.2(4) 20.3(4) 27.0(4) 27.0(4) 20.7(4) 21.3(4) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 Atom C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18 C19 C20 C21 C22 Co1A F1A F2A F3A F4A F5A F6A F7A F8A F9A N1A N2A N3A N4A N5A C1A C2A C3A C4A C5A C6A x 2249.7(17) 2234.3(19) 3312.5(19) 4036.9(18) 5277.2(18) 5978.1(17) 7250.5(18) 7530.3(18) 6453.0(17) 5528.1(17) 5594.1(19) 4530.6(19) 3773.3(18) 2023(2) 177.8(19) 5903(2) 4461.3(2) 75.5(11) 312.8(11) -465.4(11) 2680(2) 4153.1(14) 2481.4(13) 8250.9(12) 8999.0(12) 9096.9(13) 2896.0(14) 5201.8(14) 6011.3(14) 3754.2(14) 5521.5(15) 1638.8(17) 1793.2(17) 874.9(19) 1424.5(19) 2686.4(18) 3571.4(19) y 2103.9(15) 1347.0(16) 1064.5(16) 1690.9(15) 1816.4(15) 2691.6(15) 3112.7(16) 4044.7(16) 4183.1(15) 4976.3(14) 5713.7(15) 5475.1(15) 4611.4(15) 4637.5(17) 2431.5(17) 1060.5(17) 1675.2(2) -906.8(10) 286.2(10) 671.8(12) 3235.5(14) 2479.5(13) 1466.3(12) 5113.5(10) 4211.0(11) 3766.4(13) 1623.6(12) 2700.9(12) 1685.8(12) 675.0(12) 90.6(13) 663.3(15) 1217.7(15) 1275.0(17) 1641.7(17) 1880.1(15) 2367.2(15) z 6828.2(16) 5731.8(17) 5909.1(17) 7117.0(15) 7631.2(16) 8691.5(16) 9146.3(17) 10131.2(17) 10329.7(16) 11561.5(15) 12689.3(16) 12694.2(16) 11556.6(15) 12037.5(18) 6069.8(18) 6933.5(17) 700.9(2) -2612.1(11) -3178.6(10) -1965.3(11) 4121.0(17) 4646.4(12) 3395.5(11) 3871.0(12) 2683.3(12) 3988.3(14) 733.3(13) 2308.6(13) 644.6(13) -909.6(13) -1205.2(14) -1313.2(16) -163.2(17) 261.5(18) 1393.2(19) 1701.7(17) 2806.3(17) 513 U(eq) 20.2(4) 24.7(4) 25.2(4) 18.9(4) 19.1(4) 17.9(4) 21.0(4) 21.1(4) 17.9(4) 18.0(4) 22.3(4) 22.1(4) 18.0(4) 26.3(4) 27.8(4) 26.3(4) 15.82(7) 31.7(3) 32.2(3) 39.8(3) 71.8(6) 49.9(4) 39.0(3) 39.2(3) 41.2(3) 51.5(4) 18.1(3) 18.1(3) 16.7(3) 16.6(3) 21.4(3) 20.0(4) 20.6(4) 26.5(4) 27.2(4) 21.3(4) 22.0(4) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 Atom C7A C8A C9A C10A C11A C12A C13A C14A C15A C16A C17A C18A C19A C20A C21A C22A x 4722.3(18) 5557(2) 6527(2) 6329.6(18) 7205.0(17) 7086.4(17) 8033.9(18) 7537.5(18) 6279.2(17) 4353.7(17) 3536.4(19) 2445.4(18) 2561.4(17) 392.9(18) 3226(2) 8389(2) y 2863.9(15) 3662.7(17) 3987.7(16) 3357.4(15) 3272.8(15) 2406.8(15) 2034.9(16) 1093.3(16) 902.1(15) 49.0(15) -690.0(16) -490.8(16) 339.0(15) 193.4(17) 2401.3(17) 4086.7(17) z 3096.8(16) 4215.4(17) 4102.2(17) 2916.3(16) 2476.5(16) 1439.4(16) 1059.4(18) 65.7(18) -205.6(16) -1539.0(16) -2693.5(16) -2776.3(16) -1652.3(16) -2253.2(18) 3743.4(18) 3251.8(18) 514 U(eq) 21.6(4) 27.3(4) 27.0(4) 20.7(4) 21.2(4) 19.5(4) 23.4(4) 23.1(4) 18.9(4) 18.8(4) 22.5(4) 23.0(4) 19.6(4) 25.3(4) 30.0(5) 28.9(5) Table A7.2.4. Anisotropic Displacement Parameters (Å2×103) for 306-Co. The Anisotropic displacement factor exponent takes the form: –2π2[h2a*2U11+2hka*b*U12+…]. Atom U11 Co1 16.77(13) F1 31.2(8) F2 68.6(10) F3 39.2(7) F4 38.9(9) F5 44.8(8) F6 43.8(9) F7 60.1(10) F8 39.2(8) F9 30.9(7) N1 20.1(8) N2 19.6(8) N3 19.8(8) U22 15.14(12) 67.3(10) 36.7(7) 40.0(7) 59.6(10) 58.1(9) 61.6(9) 46.7(8) 23.2(6) 35.9(7) 15.5(7) 16.3(7) 15.1(7) U33 11.42(12) 32.6(7) 44.9(8) 22.6(6) 47.5(9) 24.4(7) 31.7(7) 39.3(8) 31.0(7) 31.6(7) 15.0(7) 15.2(7) 12.6(7) U23 4.42(9) 17.8(7) 23.0(7) 17.3(6) 33.6(8) 24.8(7) 23.1(7) 20.9(7) -1.5(5) 5.7(6) 4.8(6) 6.3(6) 6.6(6) U13 5.15(10) 19.9(6) 41.2(8) 18.1(6) -21.7(7) 11.6(6) 10.7(7) 37.5(8) 15.7(6) 11.9(6) 6.8(6) 6.7(6) 6.6(6) U12 2.18(9) 3.0(7) 33.5(7) 12.1(6) -23.7(7) 19.9(7) 30.4(7) 18.4(7) 7.8(5) 17.4(6) 2.6(6) 2.5(6) 4.2(6) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 Atom U11 N4 19.1(8) N5 22.5(8) C1 26.9(10) C2 21.7(10) C3 22.1(10) C4 17.4(10) C5 19.9(10) C6 20.0(10) C7 22.3(10) C8 25.4(11) C9 31.1(11) C10 26.9(10) C11 24.9(10) C12 22.1(10) C13 20.5(10) C14 19.2(10) C15 20.5(9) C16 22.4(10) C17 29.2(11) C18 31.2(11) C19 25.1(10) C20 29.4(11) C21 25.5(11) C22 30.7(11) Co1A 15.88(13) F1A 27.4(7) F2A 25.9(7) F3A 19.3(7) F4A 142.6(19) F5A 51.5(9) F6A 38.5(8) F7A 37.4(8) F8A 33.5(8) F9A 32.2(8) N1A 19.8(8) N2A 20.6(8) N3A 18.8(8) U22 16.3(7) 18.9(8) 19.4(9) 19.1(9) 30.7(11) 30.9(11) 18.0(9) 19.7(9) 17.8(9) 25.6(10) 23.2(10) 15.5(8) 18.6(9) 17.5(8) 23.4(9) 22.5(9) 17.2(8) 16.0(8) 18.8(9) 20.6(9) 16.9(8) 28.8(10) 30.1(11) 25.7(10) 15.50(12) 27.2(6) 38.6(7) 48.2(8) 53.7(10) 66.3(10) 47.8(8) 22.8(6) 35.8(7) 51.0(9) 15.7(7) 14.8(7) 15.1(7) U33 14.0(7) 16.4(8) 18.8(9) 22.6(10) 27.6(11) 25.0(10) 19.8(9) 17.7(9) 15.2(9) 13.2(9) 15.7(9) 13.6(9) 16.3(9) 17.8(9) 22.8(10) 22.3(10) 15.7(9) 13.4(9) 13.4(9) 12.6(9) 13.6(9) 24.1(10) 21.1(10) 20.0(10) 12.32(12) 29.0(7) 24.3(6) 33.5(7) 80.5(13) 21.9(7) 32.2(7) 36.3(7) 41.3(8) 50.1(9) 15.7(8) 15.8(7) 14.1(7) U23 7.0(6) 6.8(6) 9.9(7) 10.1(8) 10.2(9) 8.8(9) 7.1(7) 6.9(7) 6.7(7) 4.4(8) 3.5(8) 5.4(7) 8.3(7) 10.0(7) 12.6(8) 11.7(8) 8.6(7) 7.0(7) 4.7(7) 6.1(7) 7.9(7) 11.8(9) 10.3(9) 6.6(8) 5.01(10) 10.4(5) 18.3(5) 10.0(6) 42.2(10) 21.2(7) 21.1(6) 0.8(5) 7.5(6) 30.6(8) 5.5(6) 6.2(6) 7.0(6) 515 U13 6.5(6) 6.9(7) 12.6(8) 10.9(8) 13.3(9) 5.6(8) 5.3(8) 2.9(8) 3.3(8) 3.1(8) 10.2(8) 9.1(8) 10.7(8) 9.5(8) 10.1(8) 7.6(8) 5.7(7) 4.6(7) 6.3(8) 8.8(8) 8.2(8) 15.0(9) 4.2(9) 12.8(9) 3.49(10) 2.8(5) -2.7(5) 2.2(6) 95.1(14) 4.1(6) 13.1(6) 8.9(6) 14.7(6) -14.4(7) 5.9(6) 5.2(6) 4.1(6) U12 4.6(6) 3.0(6) 8.2(7) 6.0(7) 6.7(8) 3.3(8) 2.9(7) 0.1(7) -0.5(7) -1.0(8) 3.7(8) 3.2(7) 6.9(7) 8.0(7) 7.3(7) 3.5(7) 3.0(7) 3.8(7) 2.5(7) 6.8(8) 7.9(7) 10.1(8) 4.0(8) 7.5(8) 1.15(9) -8.6(5) -2.0(5) 8.3(6) 58.5(11) -18.4(8) -5.8(6) -9.8(5) -13.4(6) -8.6(6) 2.5(6) 2.3(6) 1.4(6) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 Atom U11 N4A 17.6(8) N5A 24.0(9) C1A 18.8(9) C2A 19.4(10) C3A 18.9(10) C4A 25.4(11) C5A 24.5(10) C6A 28.9(11) C7A 27.4(10) C8A 33.6(12) C9A 32.0(12) C10A 23.7(10) C11A 19.7(10) C12A 17.6(9) C13A 17.7(10) C14A 21.8(10) C15A 21.7(10) C16A 23.0(10) C17A 29.5(11) C18A 25.5(11) C19A 20.3(10) C20A 19.1(10) C21A 40.3(13) C22A 25.6(11) U22 16.3(7) 20.5(8) 17.9(9) 19.0(9) 28.5(10) 30.1(11) 18.0(9) 17.6(9) 19.4(9) 24.1(10) 21.7(9) 16.9(9) 18.9(9) 20.3(9) 27.9(10) 25.8(10) 18.8(9) 16.5(8) 19.1(9) 22.2(9) 17.4(9) 27.7(10) 26.8(10) 27.1(10) U33 13.9(7) 19.1(8) 18.1(9) 21.6(10) 29.7(11) 29.5(11) 21.7(10) 18.8(9) 14.5(9) 15.3(9) 16.2(9) 16.1(9) 18.6(9) 20.3(9) 28.8(11) 26.8(10) 18.1(9) 16.7(9) 14.9(9) 12.9(9) 16.3(9) 23.5(10) 23.9(11) 24.6(11) U23 7.2(6) 8.5(7) 8.8(7) 9.1(8) 12.8(9) 13.1(9) 8.2(8) 6.1(7) 6.8(7) 4.9(8) 5.0(8) 6.8(7) 8.8(7) 13.3(7) 18.2(9) 14.9(8) 10.7(7) 7.8(7) 5.5(7) 6.6(7) 7.6(7) 11.4(8) 10.0(9) 10.9(9) 516 U13 4.0(6) 8.8(7) 1.4(7) 6.7(8) 8.0(9) 15.5(9) 10.9(8) 11.8(8) 6.3(8) 5.8(9) 2.8(8) 3.6(8) 0.8(8) 2.6(7) 7.3(8) 11.7(8) 7.5(8) 7.4(8) 7.8(8) 1.0(8) 2.6(7) 3.1(8) 16.3(10) 1.5(9) U12 0.3(6) 4.1(6) 0.3(7) 3.1(7) 3.8(8) 7.2(8) 5.3(7) 5.1(7) 4.2(7) -1.1(8) -2.6(8) 0.6(7) -1.9(7) 0.1(7) 3.1(7) 6.3(8) 4.2(7) 2.1(7) 0.9(7) -3.1(7) -1.5(7) 1.2(8) 5.3(9) -2.9(8) Table A7.2.5. Bond Lengths for 306-Co. Atom Co1 Co1 Co1 Co1 F1 F2 F3 F4 F5 F6 Atom N1 N2 N3 N4 C20 C20 C20 C21 C21 C21 Length/Å 1.9319(16) 1.9293(15) 1.9273(16) 1.9253(15) 1.328(3) 1.345(2) 1.338(2) 1.333(3) 1.327(3) 1.340(2) Atom Co1A Co1A Co1A Co1A F1A F2A F3A F4A F5A F6A Atom N1A N2A N3A N4A C20A C20A C20A C21A C21A C21A Length/Å 1.9310(16) 1.9277(15) 1.9244(16) 1.9226(15) 1.349(2) 1.340(2) 1.333(2) 1.325(3) 1.334(3) 1.338(3) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 F7 F8 F9 N1 N1 N2 N2 N3 N3 N4 N4 N5 N5 C1 C1 C1 C2 C3 C4 C5 C6 C6 C7 C8 C9 C10 C11 C11 C12 C13 C14 C16 C17 C18 C22 C22 C22 C2 C5 C7 C10 C12 C15 C16 C19 C15 C16 C2 C19 C20 C3 C4 C5 C6 C7 C21 C8 C9 C10 C11 C12 C22 C13 C14 C15 C17 C18 C19 1.345(2) 1.339(2) 1.331(3) 1.381(2) 1.377(2) 1.379(2) 1.376(2) 1.382(2) 1.368(2) 1.370(2) 1.383(2) 1.332(2) 1.320(3) 1.399(3) 1.387(3) 1.516(3) 1.440(3) 1.342(3) 1.437(3) 1.399(3) 1.388(3) 1.517(3) 1.440(3) 1.342(3) 1.444(3) 1.399(3) 1.387(3) 1.515(3) 1.452(3) 1.338(3) 1.439(3) 1.446(3) 1.339(3) 1.453(3) F7A F8A F9A N1A N1A N2A N2A N3A N3A N4A N4A N5A N5A C1A C1A C1A C2A C3A C4A C5A C6A C6A C7A C8A C9A C10A C11A C11A C12A C13A C14A C16A C17A C18A C22A C22A C22A C2A C5A C7A C10A C12A C15A C16A C19A C15A C16A C2A C19A C20A C3A C4A C5A C6A C7A C21A C8A C9A C10A C11A C12A C22A C13A C14A C15A C17A C18A C19A 517 1.338(3) 1.333(3) 1.333(3) 1.376(2) 1.383(2) 1.378(3) 1.378(2) 1.385(2) 1.368(2) 1.371(2) 1.385(2) 1.332(2) 1.325(3) 1.407(3) 1.382(3) 1.516(3) 1.439(3) 1.345(3) 1.435(3) 1.394(3) 1.389(3) 1.514(3) 1.439(3) 1.345(3) 1.443(3) 1.401(3) 1.384(3) 1.518(3) 1.452(3) 1.343(3) 1.436(3) 1.442(3) 1.337(3) 1.454(3) Table A7.2.6. Bond Angles for 306-Co. Atom N2 N3 N3 N4 N4 N4 Atom Co1 Co1 Co1 Co1 Co1 Co1 Atom N1 N1 N2 N1 N2 N3 Angle/˚ 91.72(7) 178.62(6) 89.48(6) 89.67(7) 178.48(7) 89.13(6) Atom N2A N3A N3A N4A N4A N4A Atom Co1A Co1A Co1A Co1A Co1A Co1A Atom N1A N1A N2A N1A N2A N3A Angle/˚ 91.74(7) 178.53(6) 89.33(7) 89.56(7) 178.35(7) 89.39(6) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 Atom C2 C5 C5 C7 C10 C10 C12 C15 C15 C16 C16 C19 C16 C2 C19 C19 N1 N1 C1 C4 C3 N1 N1 C6 C5 C7 C7 N2 N2 C6 C9 C8 N2 N2 C11 C10 C12 Atom N1 N1 N1 N2 N2 N2 N3 N3 N3 N4 N4 N4 N5 C1 C1 C1 C2 C2 C2 C3 C4 C5 C5 C5 C6 C6 C6 C7 C7 C7 C8 C9 C10 C10 C10 C11 C11 Atom Co1 Co1 C2 Co1 Co1 C7 Co1 Co1 C12 Co1 C19 Co1 C15 C20 C2 C20 C1 C3 C3 C2 C5 C4 C6 C4 C21 C5 C21 C6 C8 C8 C7 C10 C9 C11 C9 C22 C10 Angle/˚ 128.67(13) 124.77(13) 106.27(16) 126.00(13) 127.93(13) 105.86(15) 129.27(13) 125.31(12) 105.30(15) 125.25(13) 105.62(15) 128.80(13) 120.48(17) 120.27(18) 122.86(17) 115.98(17) 123.65(18) 109.02(17) 126.58(18) 107.72(18) 107.21(19) 109.65(17) 124.41(18) 125.82(18) 117.19(18) 123.93(18) 118.75(18) 123.20(17) 109.75(17) 126.88(18) 107.40(18) 107.08(17) 109.78(17) 124.05(16) 125.41(17) 118.42(17) 123.03(17) Atom C2A C2A C5A C7A C7A C10A C12A C15A C15A C16A C16A C19A C16A C2A C19A C19A N1A N1A C1A C4A C3A N1A N1A C6A C5A C7A C7A N2A N2A C6A C9A C8A N2A N2A C11A C10A C12A Atom N1A N1A N1A N2A N2A N2A N3A N3A N3A N4A N4A N4A N5A C1A C1A C1A C2A C2A C2A C3A C4A C5A C5A C5A C6A C6A C6A C7A C7A C7A C8A C9A C10A C10A C10A C11A C11A 518 Atom Co1A C5A Co1A Co1A C10A Co1A Co1A Co1A C12A Co1A C19A Co1A C15A C20A C2A C20A C1A C3A C3A C2A C5A C4A C6A C4A C21A C5A C21A C6A C8A C8A C7A C10A C9A C11A C9A C22A C10A Angle/˚ 129.02(13) 106.09(16) 124.47(13) 125.96(13) 106.08(15) 127.83(13) 129.52(13) 125.17(13) 105.21(16) 125.28(13) 105.28(15) 129.13(13) 120.67(16) 120.12(18) 123.32(18) 115.58(17) 123.21(18) 109.61(17) 126.33(18) 107.18(19) 107.57(19) 109.40(17) 124.37(18) 126.09(19) 117.37(18) 123.79(18) 118.76(18) 123.37(17) 109.76(18) 126.75(19) 107.28(18) 107.29(18) 109.48(17) 124.24(17) 125.46(18) 117.39(18) 122.79(17) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 Atom C12 N3 N3 C11 C14 C13 N3 N5 N5 N4 N5 N5 C18 C17 N4 N4 C1 F1 F1 F1 F2 F3 F3 F4 F4 F5 F5 F5 F6 F7 F8 F8 F9 F9 F9 Atom C11 C12 C12 C12 C13 C14 C15 C15 C15 C16 C16 C16 C17 C18 C19 C19 C19 C20 C20 C20 C20 C20 C20 C21 C21 C21 C21 C21 C21 C22 C22 C22 C22 C22 C22 Atom C22 C11 C13 C13 C12 C15 C14 N3 C14 C17 N4 C17 C16 C19 C1 C18 C18 F2 F3 C1 C1 F2 C1 F6 C6 F4 F6 C6 C6 C11 F7 C11 F7 F8 C11 Angle/˚ 117.98(18) 122.81(18) 109.50(16) 127.40(17) 107.43(17) 106.65(17) 111.02(16) 127.67(18) 121.22(17) 110.67(17) 128.15(17) 121.18(17) 106.76(17) 107.46(17) 124.05(17) 109.45(17) 126.10(17) 107.01(18) 105.57(17) 114.69(18) 111.15(17) 105.67(17) 112.16(17) 106.76(19) 112.76(17) 106.75(18) 104.62(17) 113.31(18) 112.05(17) 111.64(17) 106.39(16) 112.66(17) 106.73(18) 105.51(16) 113.40(17) Atom C12A N3A C11A C11A C14A C13A N3A N5A N5A N4A N5A N5A C18A C17A N4A C1A C1A F1A F2A F2A F3A F3A F3A F4A F4A F4A F5A F5A F6A F7A F8A F8A F8A F9A F9A Atom C11A C12A C12A C12A C13A C14A C15A C15A C15A C16A C16A C16A C17A C18A C19A C19A C19A C20A C20A C20A C20A C20A C20A C21A C21A C21A C21A C21A C21A C22A C22A C22A C22A C22A C22A 519 Atom C22A C13A N3A C13A C12A C15A C14A N3A C14A C17A N4A C17A C16A C19A C18A N4A C18A C1A F1A C1A F1A F2A C1A F5A F6A C6A F6A C6A C6A C11A F7A F9A C11A F7A C11A Angle/˚ 119.32(18) 109.64(17) 122.82(18) 127.25(18) 107.13(17) 106.81(18) 111.11(17) 127.66(18) 121.11(17) 110.84(17) 127.77(17) 121.37(17) 106.95(17) 107.30(17) 109.54(17) 123.57(17) 126.47(18) 111.06(17) 105.89(16) 112.30(17) 106.42(17) 105.68(16) 114.88(17) 107.17(19) 106.3(2) 113.23(18) 104.46(17) 113.18(19) 111.91(17) 112.32(18) 105.40(16) 107.09(19) 113.10(17) 106.74(18) 111.73(17) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 520 Table A7.2.7. Torsion Angles for 306-Co. A Co1 Co1 Co1 Co1 Co1 Co1 Co1 Co1 Co1 Co1 Co1 Co1 Co1 Co1 Co1 Co1 N1 N1 N1 N2 N2 N2 N3 N4 N5 C1 C2 C2 C2 C2 C2 C2 C2 C2 C3 B C N1 C2 N1 C2 N1 C5 N1 C5 N2 C7 N2 C7 N2 C10 N2 C10 N3 C12 N3 C12 N3 C15 N3 C15 N4 C16 N4 C16 N4 C19 N4 C19 C2 C3 C5 C6 C5 C6 C7 C8 C10 C11 C10 C11 C12 C13 C16 C17 C16 C17 C2 C3 N1 C5 N1 C5 C1 C19 C1 C19 C1 C20 C1 C20 C1 C20 C3 C4 C4 C5 D C1 C3 C4 C6 C6 C8 C9 C11 C11 C13 N5 C14 N5 C17 C1 C18 C4 C7 C21 C9 C12 C22 C14 C18 C18 C4 C4 C6 N4 C18 F1 F2 F3 C5 N1 Angle/˚ 6.5(3) 177.16(13) -175.78(13) 7.9(3) -8.3(3) 176.19(13) -177.94(13) -7.5(3) 1.4(3) 175.63(12) 9.4(3) -174.02(12) -7.7(3) 173.53(12) -1.2(3) -174.42(12) -3.8(2) 14.5(3) -169.72(17) 1.3(2) -11.5(3) 177.44(17) -1.6(2) 1.5(2) -177.34(18) 166.6(2) -1.5(2) -177.77(18) -11.7(3) 160.39(18) 24.0(3) -97.5(2) 144.45(18) 2.8(2) -0.9(2) A Co1A Co1A Co1A Co1A Co1A Co1A Co1A Co1A Co1A Co1A Co1A Co1A Co1A Co1A Co1A Co1A N1A N1A N1A N2A N2A N2A N3A N4A N5A C1A C2A C2A C2A C2A C2A C2A C2A C2A C3A B C N1A C2A N1A C2A N1A C5A N1A C5A N2A C7A N2A C7A N2A C10A N2A C10A N3A C12A N3A C12A N3A C15A N3A C15A N4A C16A N4A C16A N4A C19A N4A C19A C2A C3A C5A C6A C5A C6A C7A C8A C10A C11A C10A C11A C12A C13A C16A C17A C16A C17A C2A C3A N1A C5A N1A C5A C1A C19A C1A C19A C1A C20A C1A C20A C1A C20A C3A C4A C4A C5A D Angle/˚ C1A 5.7(3) C3A 175.69(13) C4A -174.07(13) C6A 10.0(3) C6A -6.0(3) C8A 177.72(13) C9A -179.16(13) C11A -9.1(3) C11A 1.6(3) C13A 175.77(12) N5A 9.8(3) C14A -174.28(12) N5A -7.5(3) C17A 174.30(12) C1A -2.7(3) C18A -175.77(12) C4A -4.0(2) C7A 14.0(3) C21A -169.24(17) C9A 0.6(2) C12A -10.0(3) C22A 178.13(17) C14A -1.3(2) C18A 1.8(2) C18A -176.48(18) C4A 165.65(19) C4A -0.9(2) C6A -176.78(18) N4A -10.6(3) C18A 161.31(19) F1A -97.6(2) F2A 144.06(18) F3A 23.2(3) C5A 3.3(2) N1A -1.6(2) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 A C3 C4 C4 C5 C5 C5 C5 C5 C5 C5 C6 C7 C7 C7 C7 C7 C7 C8 C8 C9 C9 C10 C10 C10 C10 C10 C10 C10 C11 C12 C12 C12 C12 C12 C12 C13 C13 B C C4 C5 C5 C6 C5 C6 N1 C2 N1 C2 C6 C7 C6 C7 C6 C21 C6 C21 C6 C21 C7 C8 N2 C10 N2 C10 C6 C21 C6 C21 C6 C21 C8 C9 C9 C10 C9 C10 C10 C11 C10 C11 N2 C7 N2 C7 C11 C12 C11 C12 C11 C22 C11 C22 C11 C22 C12 C13 N3 C15 N3 C15 C11 C22 C11 C22 C11 C22 C13 C14 C14 C15 C14 C15 D C6 C7 C21 C1 C3 N2 C8 F4 F5 F6 C9 C9 C11 F4 F5 F6 C10 N2 C11 C12 C22 C6 C8 N3 C13 F7 F8 F9 C14 N5 C14 F7 F8 F9 C15 N3 N5 Angle/˚ 175.36(19) -161.2(2) 14.6(3) -167.56(18) 3.1(2) -14.3(3) 160.4(2) -82.2(2) 156.37(18) 38.3(3) -174.04(19) -3.0(2) 167.45(18) 93.8(2) -27.6(3) -145.73(19) -3.0(2) 3.9(2) -166.42(19) 157.54(19) -13.6(3) 176.67(18) 1.1(2) 14.5(3) -158.69(19) 83.0(2) -36.6(3) -156.41(18) 172.34(19) -174.22(18) 2.3(2) -88.6(2) 151.80(17) 32.0(3) 2.9(2) -3.4(2) 173.44(17) A C3A C4A C4A C5A C5A C5A C5A C5A C5A C5A C6A C7A C7A C7A C7A C7A C7A C8A C8A C9A C9A C10A C10A C10A C10A C10A C10A C10A C11A C12A C12A C12A C12A C12A C12A C13A C13A B C C4A C5A C5A C6A C5A C6A N1A C2A N1A C2A C6A C7A C6A C7A C6A C21A C6A C21A C6A C21A C7A C8A N2A C10A N2A C10A C6A C21A C6A C21A C6A C21A C8A C9A C9A C10A C9A C10A C10A C11A C10A C11A N2A C7A N2A C7A C11A C12A C11A C12A C11A C22A C11A C22A C11A C22A C12A C13A N3A C15A N3A C15A C11A C22A C11A C22A C11A C22A C13A C14A C14A C15A C14A C15A 521 D Angle/˚ C6A 174.21(19) C7A -161.26(19) C21A 15.6(3) C1A -167.10(17) C3A 2.9(2) N2A -16.1(3) C8A 159.5(2) F4A -81.3(2) F5A 156.49(18) F6A 38.8(3) C9A -175.5(2) C9A -3.1(2) C11A 166.91(18) F4A 95.7(3) F5A -26.5(3) F6A -144.24(19) C10A -2.5(2) N2A 3.6(2) C11A -166.3(2) C12A 158.43(19) C22A -13.4(3) C6A 177.90(18) C8A 1.6(2) N3A 13.8(3) C13A -159.36(19) F7A -39.6(3) F8A -158.76(18) F9A 80.3(2) C14A 172.59(19) N5A -173.47(18) C14A 2.4(2) F7A 148.28(18) F8A 29.1(3) F9A -91.8(2) C15A 2.7(2) N3A -3.3(2) N5A 172.89(18) Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 A C15 C15 C15 C15 C16 C16 C16 C16 C16 C17 C17 C19 C19 C19 C19 C19 C19 C19 C20 C20 C20 C20 C21 C21 C22 C22 B C N3 C12 N3 C12 N5 C16 N5 C16 N4 C19 N4 C19 N5 C15 N5 C15 C17 C18 C18 C19 C18 C19 N4 C16 N4 C16 C1 C2 C1 C2 C1 C20 C1 C20 C1 C20 C1 C2 C1 C2 C1 C19 C1 C19 C6 C7 C6 C7 C11 C12 C11 C12 D C11 C13 N4 C17 C1 C18 N3 C14 C19 N4 C1 N5 C17 N1 C3 F1 F2 F3 N1 C3 N4 C18 N2 C8 N3 C13 Angle/˚ -174.76(17) -0.53(19) -9.5(3) 169.11(17) 172.40(17) -0.8(2) 8.6(3) -167.64(17) -1.9(2) 1.8(2) -171.26(18) 178.37(18) -0.4(2) 9.0(3) -160.02(19) -166.47(17) 72.0(2) -46.1(2) 177.77(17) 8.7(3) 179.11(17) -8.8(3) 169.99(17) -15.3(3) -174.40(17) 12.5(3) A C15A C15A C15A C15A C16A C16A C16A C16A C16A C17A C17A C19A C19A C19A C19A C19A C19A C19A C20A C20A C20A C20A C21A C21A C22A C22A B C N3A C12A N3A C12A N5A C16A N5A C16A N4A C19A N4A C19A N5A C15A N5A C15A C17A C18A C18A C19A C18A C19A N4A C16A N4A C16A C1A C2A C1A C2A C1A C20A C1A C20A C1A C20A C1A C2A C1A C2A C1A C19A C1A C19A C6A C7A C6A C7A C11A C12A C11A C12A 522 D Angle/˚ C11A -174.93(17) C13A -0.7(2) N4A -9.6(3) C17A 168.37(17) C1A 171.15(18) C18A -1.9(2) N3A 8.4(3) C14A -167.12(18) C19A -2.9(2) N4A 3.1(2) C1A -169.71(19) N5A 178.31(18) C17A 0.2(2) N1A 9.1(3) C3A -159.24(19) F1A 71.5(2) F2A -46.9(2) F3A -167.72(17) N1A 177.24(17) C3A 8.9(3) N4A -179.23(17) C18A -7.3(3) N2A 167.11(18) C8A -17.3(3) N3A -174.53(17) C13A 12.3(3) Table A7.2.8. Hydrogen Atom Coordinates (Å×104) and Isotropic Displacement Parameters (Å2×103) for 306-Co. Atom H3 H4 H8 H9 H13 x 24 -591 1581 3554 7786 y 3664 3003 1094 550 2786 z 9883 7820 5015 5346 8807 U(eq) 32 32 30 30 25 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 3 Atom H14 H17 H18 H3A H4A H8A H9A H13A H14A H17A H18A x 8292 6263 4311 37 1046 5445 7214 8851 7941 3735 1727 A7.3 (1) y 4522 6262 5809 1089 1727 3914 4531 2391 641 -1218 -829 z 10607 13308 13326 -176 1897 4906 4693 1442 -373 -3283 -3445 523 U(eq) 25 27 26 32 33 33 32 28 28 27 28 REFERENCES AND NOTES Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. OLEX2: a complete structure solution, refinement and analysis program. J. Appl. Cryst. 2009, 42, 339–341. (2) Bourhis, L. J.; Dolomanov, O. V.; Gildea, R. J.; Howard, J. A. K.; Puschmann, H. The anatomy of a comprehensive constrained, restrained refinement program for the modern computing environment – Olex2 dissected. Acta Cryst. 2015, A71, 59– 75. (3) Sheldrick, G. M. Crystal structure refinement with SHELXL. Acta Cryst. 2015, C71, 3–8. (4) Mercury Software from CCDC: Solutions/CSDSystem/Pages/Mercury.aspx. http://www.ccdc.cam.ac.uk/ Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 524 APPENDIX 8 Some Unusual Transformations of a Highly Reactive α-Bromocaranone† A8.1 INTRODUCTION The advent of asymmetric catalysis has greatly increased the number and variety of synthetically accessible chiral building blocks.1 Nevertheless, the syntheses of many natural products and consumer commodities continue to rely on starting materials from the readily available chiral pool and derivatives thereof.2,3 As such, strategies for the derivatization of chiral building blocks remain vital in organic synthesis. (+)-3-Carene (309, Scheme A8.1.1) is one such building block: the defining dimethylcyclopropane moiety of this molecule coupled with its widespread availability and conveniently rigid structure have made it a popular chiral feedstock.2,4 Scheme A8.1.1. Carene and the desired transformation. Me Me (+)-3-Carene (309) Conditions 51% over 2 steps Me Me (–)-4-Caranone (310) † Me Me Me Ref. 6, 7 O O O Me or Me 311 Me Me R 312 This research was conducted in collaboration with Adrian Samkian and Dr. Scott Virgil. This appendix has been modified and reproduced with permission from Samkian, A. E.; Sercel, Z. P.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2022, 89, 153496. © 2021 Published by Elsevier Ltd. Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 525 However, among the numerous syntheses beginning from 309, most feature the presence of the intact dimethylcyclopropane moiety in the target. This is due in part to the lack of mild and selective methods for the fragmentation of the strained ring. Although such fragmentations have been performed on carene (309) and related dimethylcyclopropane-containing compounds, the vast majority rely on strongly acidic conditions.5 In the course of a total synthesis effort, we identified the fragmentation of a βketodimethylcyclopropane (310) as a valuable transformation for revealing a reactive γisopropenyl group (311) from the relatively unreactive, “protected” cyclopropane. Furthermore, we aimed to develop a method to trap the species immediately after ring fragmentation to access the challenging γ-gem-dimethyl synthon (312). A8.2 SYNTHESIS AND FRAGMENTATIONS OF A BROMOCARANONE We realized that in order to affect this transformation in a mild and efficient fashion, a synthetic handle would be necessary at the α-position. α-Bromocaranone 313 was selected as a promising model system to study the feasibility of this synthetic transformation due to its straightforward synthesis from carene (Scheme A8.2.1). Hydroboration of commercially available (+)-3-carene (309) followed by oxidation afforded (–)-4-caranone (310) in modest yields on a >10 g scale.6,7 Enolization of (–)-310 with LiHMDS and direct bromination with NBS led to the production of several inseparable side products,8 however, formation of the silyl enol ether with LDA and TMSCl followed by quenching with NBS led to diminished side product formation, affording (–)-313.9 Although bromide (–)-313 decomposes rapidly on silica, purification was possible via chromatography on neutral alumina. While this compound can be stored Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 526 for at least several weeks at –15 °C as a solution in benzene, neat samples of bromide (–)313 stored at ambient temperature undergo spontaneous, exothermic decomposition to isocarvacrol (314), with the release of HBr, after several hours. Despite the unstable nature of bromide (–)-313, it was possible to manipulate neat samples of this intermediate for short periods of time. Scheme A8.2.1. Synthesis of a reactive α-bromocaranone. O LDA, TMSCl NBS THF, –78 °C Me Me (–)-310 OH O Me 48% yield Me Br Me Me Me (–)-313 Me Me 314 We began by treating bromide (–)-313 with AgI reagents in order to effect a carbocation-mediated fragmentation. Treatment of (–)-313 with AgClO4 or AgOTf in THF afforded dienone (+)-315 (Table A8.2.2, entries 1 and 2) in modest yields. Trace quantities of the desired compound featuring an isopropenyl group ((–)-311) were also observed. Attempts to favor the formation of (–)-311 by performing the reaction in the presence of a bulky base were not successful. The rapid elimination of tertiary carbocation 314 toward (+)-315 would appear to impede formation of (–)-311 or trapping with nucleophiles. Despite this, we were surprised to observe tertiary fluoride (–)-316 as the major product when AgBF4 was used as a AgI source (entry 3). Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 527 Table A8.2.2. AgI-mediated reactions of 313. O O Me Br O O O Me Me Me Me Ag salt (2.1 equiv) THF, 20 °C + + Me Me Me (–)-313 Me Me Me (+)-315 314 F Me Me (–)-311 (–)-316 entry Ag salt % yield 315 % yield 311 % yield 316 1 AgOTf 55 <5 –– 2 AgClO4 67 <5 –– 3 AgBF4 10 5 35 Me The lack of control observed in carbocation-mediated reactions led us to study radical-mediated fragmentations next. Treatment of (–)-313 with AIBN and Bu3SnH afforded isopropyl enone (–)-317 (Scheme A8.2.3) in excellent yield. Allyltributylstannane (318) was used in place of Bu3SnH in an attempt to prepare the allylated product (–)-320.10 Pleasingly, (–)-320 was observed, though in moderate yields (<40%), with the tertiary bromide (–)-319 instead being the major product. Using catalytic amounts of 318 led to high yields of (–)-319, which could then be isolated and subjected to similar conditions, albeit with an excess of 318, to afford the desired allylated species (–)-320. It is noteworthy that treatment of dienone (+)-315 with 318 and AIBN did not afford (–)-320, suggesting (+)-315 is not an intermediate en route to (–)-320. The presence of catalytic stannane radicals proved vital for the production of (–)-319. Indeed, a control experiment performed by simply heating a solution of (–)-313 in benzene provided racemic carvone derivative (±)-321 in high yields, with phenol 314 being observed as a minor product. To explain this surprising divergence in reactivity between (–)-319 and (±)-321, further mechanistic studies were performed. Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 528 Scheme A8.2.3. Radical-mediated cyclopropane fragmentation of 313. O AIBN, Bu3SnH PhH, 86 °C, 1 h Me 89% yield Me Me (–)-317 O O Me O Me Br Me 318 (0.4 equiv), AIBN PhH, 86 °C, 4 h Me Me 318 (6 equiv), AIBN PhH, 86 °C, 48 h 72% yield Me (–)-313 Me 63% yield Br Me (–)-319 Me (–)-320 O Me Br PhH, 86°C, 25 min 73% yield Me Me SnBu3 318 (±)-321 We initially suspected that the mechanism to form (±)-321 may be radicalmediated, perhaps through the homolysis of the carbon-bromine bond followed by 1,4HAT. However, such a mechanism would not explain a racemic product. Furthermore, DFT calculations11,12,13 suggested that the barriers for such a transformation are kinetically inaccessible (>31 kcal/mol). Instead, we propose a polar mechanism (Scheme A8.2.4) that, through elimination of the bromide through enol 322, could afford diene 323. Such a system is precedented to rapidly racemize through an electrocyclic reaction via cycloheptatriene 324.14 Ultimately, 323 may be protonated in its keto form (325), eventually leading to tertiary cation 326, which is trapped by bromide, affording (±)-321. Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 529 Scheme A8.2.4. Proposed mechanism for the formation of racemic 321. O OH Me Br Me OH Br Me Me Me Me Me Me Me (–)-313 322 323 O Me Me Me Br (±)-321 324 Me Me Me Me Me OH OH Me HO Me Me 326 Me 325 The conversion of (–)-313 to (±)-321 is likely catalyzed by HBr formed via the decomposition of (–)-313 to 314. Interestingly, despite the formation of (–)-319 requiring longer reaction times (4 h vs. 25 min), carvone derivative (±)-321 is not observed. Indeed, heating bromide (–)-313 in PhH in the presence of allylstannane 318 with no radical initiator entirely suppressed the formation of (±)-321. We propose that this observation is due to the quenching of HBr by 318. Another reaction performed with (–)-313 and bis(tributylstannane), which exists in equilibrium with two tributyltin radicals,15 also suppressed the formation of (±)-321 whilst producing (–)-319, albeit in lower yields. No reaction was observed when (–)-313 was heated in hexanes, but (±)-321 was produced rapidly in dioxane or 1,2-dichloroethane with greater quantities of phenol 314, further implicating a polar mechanism. Finally, control compound (–)-328 (Scheme A8.2.5), featuring an additional gemdimethyl group, was prepared in two steps from (–)-310. This compound was found to be significantly more stable than (–)-313, decomposing neither on silica nor spontaneously as a solid compound. Importantly, only clean starting material was observed when (–)-328 Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 530 was heated in benzene for extended periods of time, providing further evidence that the reaction leading to (±)-321 proceeds via the mechanism proposed in Scheme A8.2.4. Scheme A8.2.5. Synthesis of bromide 328 and control reaction in benzene. O O NaH, HMDS, MeI THF, reflux→0→20 °C Me Me LDA, TMSCl NBS THF, –78 °C Me 29% yield Me (–)-310 89% yield Br Me Me (–)-328 O Br PhH, 86 °C X Me Me Me Me Me Me (–)-328 A8.3 Me Me (–)-327 O Me Me O Me Me Me Br 329 not detected CONCLUSION Over the course of this study, readily available (+)-3-carene was derivatized into an array of useful chiral building blocks through a highly reactive α-bromocaranone as a synthetic branching point. These chiral products are expected to be useful in future synthetic efforts, and we believe that the convenient fragmentation of β-cyclopropyl ketones will also find applications outside of carene-derived systems. A8.4 EXPERIMENTAL SECTION A8.4.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.16 (+)-3-Carene was purchased from TCI and used as received, N-bromosuccinimide (NBS) was recrystallized from boiling water prior to use, trimethylsilyl chloride (TMSCl) was distilled under argon prior to use, all other reagents and solvents were purchased from various commercial suppliers Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 531 and used as received. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or panisaldehyde staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 µm) or Sigma-Aldrich aluminum oxide (activated, neutral, Brockmann Activity I) were used for flash chromatography. Preparative HPLC was performed on an Agilent 1200 preparative HPLC system using a 9.4 x 250 mm Eclipse XDB-C18 column. A water/MeCN gradient was used as the mobile phase and the compounds were detected at 230.8 nm and 254.4 nm. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing a Chiralpak AD-H column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. 1H NMR spectra were recorded on Varian Inova 500 MHz, Varian 400 MHz, and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (125 MHz), a Varian 400 MHz spectrometer (100 MHz), and Bruker 400 MHz spectrometers (100 MHz) and are reported relative to CHCl3 (δ 77.16 ppm). Data for 1 H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities 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. Data for 13C NMR are reported in terms of chemical shifts (δ ppm) Some reported spectra include minor solvent impurities of water (δ 1.56 ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), acetone (δ 2.17 ppm), grease (δ 1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm), which do not impact product assignments. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 532 films deposited on NaCl plates and 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 path-length cell. High-resolution mass spectrometry was performed by the Multi User Mass Spectrometry Laboratory at the California Institute of Technology using a JMS-T200 GC AccuTOF GC-Alpha mass spectrometer. A8.4.2 EXPERIMENTAL PROCEDURES OH Me Me Me 330 (1R,3R,4R,6S)-4,7,7-trimethylbicyclo[4.1.0]heptan-3-ol (330) The procedure was adapted from the literature:6 To a dried 500 mL round bottom flask was added NaBH4 (6.94 g, 183 mmol, 1.0 equiv), THF (60 mL), and (+)-3-carene (25 g, 180 mmol, 1.0 equiv). The reaction flask was cooled to 0 °C in an ice bath, and BF3•OEt2 (26 g, 160 mmol, 1.0 equiv) was added dropwise over 30 min. The reaction was stirred at this temperature for 4 h, after which the reaction was cooled to –10 °C and aq. NaOH (3 M, 60 mL) was added dropwise over 40 min. H2O2 (30 wt %, 100 mL) was then added dropwise over 1 h, and the reaction allowed to warm to 20 °C. The solution was concentrated under reduced pressure to remove THF, and the aqueous layer was extracted with CH2Cl2 (3 x 40 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and filtered. Concentration under reduced pressure afforded an oil that was distilled under vacuum (0.5 mmHg, 150 °C) to afford the title compound (22 g, 78%) as a colorless oil that solidified upon cooling. 1H NMR (CDCl3, 400 MHz): δ = 3.07 (ddd, J = 10.3, 9.3, 6.6 Hz, 1H), 2.10 (ddd, J = 14.1, 6.6, 0.9 Hz, 1H), Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 533 2.01 – 1.92 (m, 1H), 1.61 – 1.51 (m, 1H), 1.29 – 1.17 (m, 1H), 0.97 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.90 (s, 3H), 0.86 – 0.77 (m, 1H), 0.75 – 0.67 (m, 2H). Spectral data are in agreement with previously reported values.17 O Me Me Me (–)-310 (1R,4R,6S)-4,7,7-trimethylbicyclo[4.1.0]heptan-3-one (310) A procedure from the literature7 was modified as follows: To a 1 L round bottom flask was added alcohol 330 (20 g, 130 mmol, 1.0 equiv) and Et2O (280 mL). The solution was cooled in an ice bath, and Brown–Garg (BG) reagent18,19 (70 mL) was added dropwise over 20 min with vigorous stirring, maintaining the reaction temperature below 20 °C. The ice bath was then removed, and the solution stirred for 1 h. Additional BG reagent (70 mL) was added slowly, and the reaction was left to stir for 18 h. The organic layer was then separated, and the aqueous layer was extracted with Et2O (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual oil was distilled under vacuum (0.5 mmHg, 130 °C) to yield the title compound (12.8 g, 65%) as a fragrant, yellow oil. 1H NMR (CDCl3, 400 MHz): δ = 2.52 (ddd, J = 18.0, 8.4, 0.9 Hz, 1H), 2.41 – 2.32 (m, 1H), 2.32 – 2.25 (m, 2H), 1.31 – 1.19 (m, 1H), 1.07 (m, 1H), 1.04 (s, 3H), 1.02 – 0.97 (m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.84 (s, 3H). Spectral data are in agreement with previously reported values.7 Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 534 O Me Br Me Me (–)-313 (1R,2R,4R,6S)-2-bromo-4,7,7-trimethylbicyclo[4.1.0]heptan-3-one (313) To a flame-dried 250 mL Schlenk flask was added THF (29 mL) and diisopropylamine (1.59 g, 15.8 mmol, 1.2 equiv). The solution was cooled to –78 °C and n-butyllithium (2.5 M in hexanes, 5.5 mL, 13.8 mmol, 1.05 equiv) was added dropwise over 8 min. After stirring for 30 min, a solution of ketone 310 (2 g, 13.1 mmol, 1.0 equiv) in THF (2 mL) was added dropwise over 5 min and the reaction mixture allowed to stir at –78 °C for 1.5 h. TMSCl (2.14 g, 19.7 mmol, 1.5 equiv) was added and the reaction was allowed to warm to 0 °C in an ice bath, and further stirred at 0 °C for 1 h. The reaction flask was then wrapped in Al foil to exclude light and NBS (3.5 g, 19.7 mmol, 1.5 equiv) was added in a single portion. After stirring for a further 30 min in the dark, the reaction was quenched* with saturated aq. NaHCO3 (50 mL) and extracted with Et2O (2 x 20 mL). The combined organic layers were washed with water (2 x 40 mL) and brine (40 mL), dried over Na2SO4, and filtered. The solution was concentrated under reduced pressure to yield 2.1 g of residue. A small amount of this residue (255 mg) was purified via flash chromatography on neutral alumina (hexanes) to yield 313 (173 mg, extrapolated to 48% overall yield) as an unstable straw-colored oil which crystallized when pure. 313 was used immediately or stored as a frozen solution in benzene. 1H NMR (CDCl3, 400 MHz): δ = 4.37 (d, J = 1.2 Hz, 1H), 3.22 (ddq, J = 13.0, 7.7, 6.5 Hz, 1H), 2.45 (ddd, J = 14.7, 9.7, 7.6 Hz, 1H), 1.52 (dd, J = 8.6, 1.3 Hz, 1H), 1.40 (ddd, J = 14.8, 13.0, 4.3 Hz, 1H), 1.18 (td, J = 8.9, 4.2 Hz, 1H), 1.07 (s, 3H), 1.00 (d, J = 6.5 Hz, 3H), 0.84 (s, 3H); 13C{1H} NMR Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 535 (CDCl3, 100 MHz): δ = 209.7, 48.2, 36.2, 33.7, 30.7, 28.2, 22.2, 20.5, 14.7, 14.1; IR (Neat Film, NaCl) 2933, 1719, 1455, 1378, 1162, 848, 776, 622 cm–1; HRMS (FI+): m/z calc’d for C10H15OBr [M]+: 230.0301 found, 230.0308; [α]D 22.16 –278.99 (c 1.0, CHCl3). *Due to the light-sensitivity of the product, it is recommended to perform the work-up in the dark. O Me Me Me (–)-317 (4R,6R)-4-isopropyl-6-methylcyclohex-2-en-1-one (317) AIBN (20 mg, 0.121 mmol, 0.2 equiv) was loaded into a 20 mL vial with septum cap. A solution of bromide 313 (140 mg, 0.606 mmol, 1.0 equiv) and Bu3SnH (353 mg, 1.21 mmol, 2.0 equiv) in anhydrous benzene (6 mL) was added. The reaction mixture was stirred at 86 °C for 1 h, after which the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica (0–10% EtOAc in hexanes) to afford the title compound (82 mg, 89%) as a colorless oil. The resulting product is pure enough for most purposes, but a sample of higher purity for analysis was obtained by distillation. 1H NMR (CDCl3, 400 MHz): δ = 6.82 (dt, J = 10.2, 2.2 Hz, 1H), 6.01 (dd, J = 10.2, 3.0 Hz, 1H), 2.39 (m, 2H), 1.96 (dtd, J = 13.0, 4.5, 2.0 Hz, 1H), 1.80 (pd, J = 6.9, 4.8 Hz, 1H), 1.54 – 1.49 (ddd, J = 13.9, 13.0, 11.4 Hz, 1H), 1.15 (d, J = 6.6, 3H), 0.96 (d, J = 7.1, 3H), 0.94 (d, J = 6.9, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 202.7, 153.5, 129.7, 43.5, 41.7, 34.2, 31.8, 19.6, 19.3, 15.2; IR (Neat Film, NaCl) 2959, 2872, 1684, 1458, 1386, 1219, 803 cm–1; HRMS (FI+): m/z calc’d for C10H16O [M]+: 152.1196 found, 152.1198; [α]D 22.31 –35.30 (c 1.0, CHCl3). Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 536 O Me Me Me Br (–)-319 (4S,6R)-4-(2-bromopropan-2-yl)-6-methylcyclohex-2-en-1-one (319). To a 4 mL vial was added bromide 313 (36 mg, 0.156 mmol, 1.0 equiv) in anhydrous benzene (1.5 mL). To this solution was added allyltributyltin (21 mg, 0.062 mmol, 0.4 equiv) and AIBN (5 mg, 0.03 mmol, 0.2 equiv). The vial was sealed, and the reaction mixture stirred at 86 °C for 4 h. The reaction was then allowed to cool to 20 °C and concentrated under reduced pressure. The residue was purified via flash chromatography on silica (5–10% EtOAc in hexanes) to afford the title compound (26 mg, 72%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ = 7.09 (dt, J = 10.3, 2.1 Hz, 1H), 6.09 (dd, J = 10.3, 2.8 Hz, 1H), 2.85 (dddd, J = 11.4, 4.6, 2.9, 2.0 Hz, 1H), 2.41 (dqd, J = 13.4, 6.7, 4.5 Hz, 1H), 2.24 (dtd, J = 12.7, 4.4, 2.2 Hz, 1H), 1.89 (s, 3H), 1.74 (s, 3H), 1.67 – 1.58 (m, 1H), 1.17 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 201.3, 150.1, 130.2, 68.3, 50.5, 41.0, 34.2, 32.9, 30.9, 15.1; IR (Neat Film, NaCl) 2967, 1682, 1455, 1372, 1213, 1125, 803, 644, 601 cm–1; HRMS (FI+): m/z calc’d for C10H15OBr [M]+: 230.0301, found 230.0300; [α]D 22.13 –62.67 (c 1.0, CHCl3). Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 537 O Me Me Me (–)-320 (4S,6R)-6-methyl-4-(2-methylpent-4-en-2-yl)cyclohex-2-en-1-one (320). To a 20 mL vial was added bromide 319 (45 mg, 0.195 mmol, 1.0 equiv) in anhydrous benzene (4 mL). To this was added allyltributyltin (390 mg, 1.17 mmol, 6.0 equiv) and AIBN (6.4 mg, 0.039 mmol, 0.2 equiv). The vial was sealed, and the reaction mixture stirred at 86 °C for 48 h. The solution was concentrated under reduced pressure and the residue purified via flash chromatography on silica (5% EtOAc in hexanes) to afford the title compound (24 mg, 63%) as a colorless oil. The compound is pure enough for most purposes, but a sample of higher purity for analysis was obtained by preparative HPLC (60–80% MeCN in H2O over 5 min at 12 mL/min). 1H NMR (CDCl3, 400 MHz): δ = 6.96 (dt, J = 10.3, 2.1 Hz, 1H), 6.03 (dd, J = 10.3, 3.0 Hz, 1H), 5.83 (ddt, J = 16.8, 10.2, 7.4 Hz, 1H), 5.13 – 5.02 (m, 2H), 2.36 (m, 2H), 2.11 – 2.06 (m, 2H), 2.03 (ddq, J = 11.0, 4.4, 2.2 Hz, 1H), 1.55 – 1.46 (m, 1H), 1.15 (d, J = 6.7 Hz, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13 C{1H} NMR (CDCl3, 100 MHz): δ = 202.4, 151.7, 134.7, 130.0, 118.0, 45.7, 44.5, 41.8, 35.7, 33.1, 24.9, 24.6, 15.3; IR (Neat Film, NaCl) 2961, 1683, 1385, 1222, 914, 802 cm–1; HRMS (FI+): m/z calc’d for C13H20O [M]+: 192.1509, found 192.1509; [α]D 22.49 –25.44 (c 0.25, CHCl3). Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 538 O Me Br Me Me (±)-321 (S)-5-(2-bromopropan-2-yl)-2-methylcyclohex-2-en-1-one (321) To a 4 mL vial was added bromide 313 (86 mg, 0.372 mmol, 1.0 equiv) in anhydrous benzene (1.6 mL). The vial was sealed, and the reaction mixture stirred at 86 °C for 25 min. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography on neutral alumina (5% EtOAc in hexanes) to afford the title compound (63 mg, 73%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ = 6.75 (ddq, J = 5.4, 2.8, 1.4 Hz, 1H), 2.74 (ddd, J = 16.0, 3.7, 1.8 Hz, 1H), 2.59 (dddt, J = 18.2, 6.2, 4.6, 1.5 Hz, 1H), 2.41 (m, 2H), 2.05 (dddd, J = 13.5, 11.1, 4.6, 3.7 Hz, 1H), 1.79 (m, 3H), 1.79 (s, 3H), 1.77 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 199.2, 144.3, 135.4, 70.1, 48.3, 41.2, 32.5, 32.2, 29.2, 15.7; IR (Neat Film, NaCl) 2972, 1674, 1451, 1370, 1254, 1103, 1062, 904, 690 cm–1; HRMS (FI+): m/z calc’d for C10H15OBr [M]+: 230.0301, found 230.0302. 321 was determined to be racemic by chiral SFC analysis (AD-H, EtOH/CO2 = 5/95, flow rate = 3.5 mL/min, l = 210 nm) tR = 3.39, 3.95. Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 539 Procedure for the AgI–mediated fragmentation of bromide 313. To a solution of the indicated silver salt (0.182 mmol, 2.1 equiv) in THF (0.6 mL) was added a solution of bromoketone 313 (20 mg, 0.0865 mmol, 1.0 equiv) in THF (0.3 mL, 0.1 M total concentration) dropwise over 1 min with stirring at 20 °C. In all cases, a thick precipitate immediately formed. Stirring was continued for an additional 20 min, after which the reaction mixture was quenched with saturated aq. NaHCO3 (1 mL) and filtered through a plug of celite with EtOAc. The layers were separated and the organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to provide a crude product that was purified by silica gel flash chromatography (5% EtOAc in hexanes). O Me Me Me (+)-315 (R)-6-methyl-4-(propan-2-ylidene)cyclohex-2-en-1-one (315) 8.7 mg (67%) yield with AgClO4; 7.1 mg (55%) yield with AgOTf; 1H NMR (CDCl3, 400 MHz): δ = 7.42 (dd, J = 10.1, 0.9 Hz, 1H), 5.80 (d, J = 10.0 Hz, 1H), 2.84 (dd, J = 14.6, 5.4 Hz, 1H), 2.48 (dqd, J = 10.9, 6.8, 5.4 Hz, 1H), 2.39 – 2.27 (m, 1H), 1.93 (dd, J = 1.6, 0.8 Hz, 3H), 1.90 (s, 3H), 1.14 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 203.0, 143.1, 139.4, 126.7, 124.0, 40.9, 34.1, 21.9, 20.8, 15.9; IR (Neat Film, NaCl) 2927, 1672, 1623, 1453, 1216, 812 cm–1; HRMS (FI+): m/z calc’d for C10H14O [M]+: 150.1039, found 150.1039; [α]D 21.95 +137.36 (c 0.5, CHCl3). Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 540 O Me Me (–)-311 (4S,6R)-6-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-one (311) Isopropenyl enone 311 was observed in trace quantities in the AgI-mediated fragmentation of bromide 313. 0.7 mg (5% yield) with AgBF4. A sample suitable for characterization, albeit containing a minor impurity, could be obtained by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc in hexanes) on a 100 mg scale. 1 H NMR (CDCl3, 400 MHz): δ = 6.81 (dt, J = 10.1, 2.0 Hz, 1H), 6.03 (dd, J = 10.1, 3.0 Hz, 1H), 4.86 (p, J = 1.5 Hz, 1H), 4.81 (dq, J = 1.6, 0.8 Hz, 1H), 3.21 – 3.12 (m, 1H), 2.42 (dqd, J = 13.5, 6.7, 4.5 Hz, 1H), 2.13 (dtd, J = 13.0, 4.5, 2.0 Hz, 1H), 1.77 (dd, J = 1.4, 0.9 Hz, 3H), 1.72 – 1.61 (m, 1H), 1.15 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 202.0, 152.5, 146.9, 129.6, 112.0, 45.2, 41.8, 37.7, 20.8, 15.1; IR (Neat Film, NaCl) 2964, 2934, 2862, 1683, 1649, 1454, 1376, 1215, 1188, 1118, 895, 804 cm–1; HRMS (FI+): m/z calc’d for C10H14O [M]+: 150.1039, found 150.1030; [α]D 21.23 –92.59 (c 0.33, CHCl3). O Me Me Me F (–)-316 (4S,6R)-4-(2-fluoropropan-2-yl)-6-methylcyclohex-2-en-1-one (316) 6.6 mg of a 3.4:1 (w/w) mixture of fluoride 316 and dienone 315 was isolated, corresponding to a 35% yield of fluoride 316. While this mixture was inseparable by silica gel flash chromatography, an analytical sample of 316 was isolated by reverse-phase Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 541 preparative HPLC (50–70% MeCN in H2O over 3.5 min at 10 mL/min); 1H NMR (CDCl3, 400 MHz): δ = 6.96 (dt, J = 10.3, 2.0 Hz, 1H), 6.09 (dd, J = 10.3, 3.0 Hz, 1H), 2.88 – 2.75 (m, 1H), 2.41 (dqd, J = 13.5, 6.7, 4.6 Hz, 1H), 2.08 (dtdd, J = 12.8, 4.5, 2.1, 0.9 Hz, 1H), 1.53 – 1.45 (m, 1H), 1.42 (d, J = 22.0 Hz, 3H), 1.32 (d, J = 22.0 Hz, 3H), 1.16 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 201.6, 148.9, 148.8, 130.5, 97.3, 95.6, 47.4, 47.2, 41.3, 33.4, 33.4, 25.6, 25.4, 23.7, 23.4, 15.1; IR (Neat Film, NaCl) 2930, 1682, 1453, 1376, 1219, 878, 812, 522 cm–1; HRMS (FI+): m/z calc’d for C10H15FO [M]+: 170.1101, found 170.1099; [α]D 21.82 –37.10 (c 0.167, CHCl3). O Me Me Me Me (–)-327 (1R,6S)-4,4,7,7-tetramethylbicyclo[4.1.0]heptan-3-one (327) To a rapidly stirred suspension of NaH (60% dispersion in mineral oil, 289 mg, 7.23 mmol, 1.1 equiv) in THF (5.6 mL, 1 M final substrate concentration) in a 50 mL 2neck flask equipped with a reflux condenser was added ketone 310 (1.00 g, 6.57 mmol, 1.0 equiv) through the top of the condenser. Additional THF (1 mL) was used to rinse the ketone into the reaction mixture. The suspension was then heated to reflux in an oil bath and stirred for 1.5 h. Then, HMDS (0.21 mL, 0.986 mmol, 0.15 equiv) was added through the top of the condenser and the reaction mixture was stirred under reflux for an additional 25 min. The flask was then cooled to 0 °C in an ice bath, and the reflux condenser was replaced with a septum. MeI (0.45 mL, 7.23 mmol, 1.1 equiv) was added dropwise, after which the ice bath was removed. After stirring at 20 °C for 17 h, the reaction mixture was quenched with H2O (20 mL), the layers were separated, and the aqueous layer was Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 542 extracted with Et2O (4x10 mL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified via silica gel flash chromatography (10% Et2O in hexanes). The resulting oil was purified again by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc in hexanes) to provide dimethyl ketone 327 (361 mg, 29% yield desired isomer) as a fragrant, colorless oil containing 11% of an inseparable isomeric impurity; 1H NMR (CDCl3, 400 MHz): δ = 2.65 – 2.52 (m, 1H), 2.19 – 2.07 (m, 1H), 1.94 (ddt, J = 14.9, 9.3, 1.4 Hz, 1H), 1.39 (ddt, J = 14.9, 6.2, 0.9 Hz, 1H), 1.22 (s, 3H), 1.11 – 1.06 (m, 1H), 1.04 (s, 3H), 0.94 (s, 3H), 0.90 – 0.80 (m, 4H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 218.9, 42.4, 35.1, 34.6, 28.0, 24.8, 24.3, 22.4, 19.5, 18.2, 14.9; IR (Neat Film, NaCl) 2930, 2867, 1709, 1460, 1412, 1379, 1111, 1051, 986, 808 cm– 1 ; m/z calc’d for C11H18O [M]+: 166.1352, found 166.1358; [α]D 21.48 –68.91 (c 1.0, CHCl3). O Me Me Br Me Me (–)-328 (1R,2S,6S)-2-bromo-4,4,7,7-tetramethylbicyclo[4.1.0]heptan-3-one (328) To a solution of diisopropylamine (0.10 mL, 0.722 mmol, 1.2 equiv) in THF (1.3 mL, 0.45 M substrate concentration) was added n-butyllithium (2.5 M in hexanes, 0.25 mL, 0.632 mmol, 1.05 equiv) dropwise at –78 °C. The solution was allowed to warm to 0 °C and immediately cooled back to –78 °C, whereafter ketone 327 (100 mg, 0.602 mmol, 1.0 equiv) was added dropwise and the solution stirred at –78 °C for 1 h. TMSCl (0.11 mL, 0.903 mmol, 1.5 equiv) was added and the reaction was allowed to warm to 0 °C in an ice bath and stirred for an additional 45 min. The reaction was then protected from light and NBS (161 mg, 0.903 mmol, 1.5 equiv) was added in one portion. After stirring for a further Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 543 30 min in the dark, the reaction was quenched with saturated aq. NaHCO3 (1 mL), the layers were separated, and the aqueous layer was extracted with Et2O (1 mL). The combined organic layers were washed with water (1 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel flash chromatography to afford α-bromoketone 328 (126 mg, 89% yield desired isomer) as a white crystalline solid containing 8% of an inseparable isomeric impurity; 1H NMR (CDCl3, 400 MHz): δ = 4.23 (dd, J = 6.0, 0.8 Hz, 1H), 1.91 (ddd, J = 15.1, 8.3, 0.9 Hz, 1H), 1.44 (ddd, J = 15.0, 8.4, 0.8 Hz, 1H), 1.40 – 1.35 (m, 4H), 1.13 (s, 3H), 1.11 – 1.05 (m, 4H), 1.03 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz): δ = 209.2, 49.2, 44.4, 33.7, 30.4, 27.7, 26.6, 26.0, 21.8, 21.5, 14.2; IR (Neat Film, NaCl) 2954, 2869, 1721, 1462, 1376, 1244, 1054, 911, 742 cm–1; m/z calc’d for C11H17OBr [M]+: 244.0457, found 244.0459; [α]D 21.55 –148.50 (c 1.0, CHCl3). OH Me Me Me 314 4-isopropyl-2-methylphenol (314) 313 (39 mg, 0.17 mmol) was left in a sealed 4 mL vial under ambient conditions for 24 h. During this time, the oil was found to spontaneously decompose with notable exotherm20 and change in consistency. The blackened tar was purified via flash chromatography on silica (5% EtOAc in hexanes) to afford 314 (8 mg, 32%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ = 6.99 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 8.1, 2.2 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 4.62 (s, 1H), 2.83 (hept, J = 7.0 Hz, 1H), 2.26 (s, 3H), 1.23 (d, J = 6.9 Hz, 6H). Spectral data are in agreement with previously reported values.21 Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone A8.5 (1) 544 REFERENCES AND NOTES Nugent, W. A.; Rajanbabu, T. V.; Burk, M. J. Beyond Nature’s Chiral Pool: Enantioselective Catalysis in Industry. Science 1993, 259, 479–483. (2) Brill, Z. G.; Condakes, M. L.; Ting, C. P.; Maimone, T. J. Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products. Chem. Rev. 2017, 117, 11753–11795. (3) Carreira, E. M.; Yamamoto, H. Comprehensive Chirality; 2012. (4) Curlat, S. Recent studies of (+)-3-carene transformations with the retention of the native framework. Chem. J. Mold. 2019, 14, 32–55. (5) Ohloff, G.; Giersch, W. Säurekatalysierte Isomerisierung von α,β-CyclopropylOxiranen. Helv. Chim. Acta 1968, 51, 1328–1342. (6) Kilbas, B.; Azizoglu, A.; Balci, M. Incorporation of an Allene Unit into α-Pinene via β-Elimination. Helv. Chim. Acta 2006, 89, 1449–1456. (7) Kozioł, A.; Frątczak, J.; Grela, E.; Szczepanik, M.; Gabryś, B.; Dancewicz, K.; Lochyński, S. Synthesis and Biological Activity of New Derivatives with the Preserved Carane System. Nat. Prod. Res. 2020, 34, 1399–1403. (8) Zhang, X.; Cai, X.; Huang, B.; Guo, L.; Gao, Z.; Jia, Y. Enantioselective Total Syntheses of Pallambins A–D. Angew. Chem. Int. Ed. 2019, 58, 13380–13384. (9) Wu, K. K. Y. The Diels-Alder reaction in the synthesis of qinghaosu analogues. PhD Thesis, Hong Kong University of Science and Technology, 2002. Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone (10) 545 Bruncko, M.; Crich, D.; Samy, R. Chemistry of Cyclic Tautomers of Tryptophan: Formation of a Quaternary Center at C3a and Total Synthesis of the Marine Alkaloid (+)-Ent-Debromoflustramine B. J. Org. Chem. 1994, 59, 5543–5549. (11) DFT Calculations Were Carried out with the ORCA Program (See Supporting Information) at the M06-2X/Def2-TZVPP/SMD(Benzene)//M06-2X/Def2-TZVP Level of Theory. (12) Neese, F. The ORCA Program System. WIREs Computational Molecular Science 2012, 2, 73–78. (13) Neese, F. Software Update: The ORCA Program System, Version 4.0. WIREs Computational Molecular Science 2018, 8, e1327. (14) Marvell, E. Thermal Electrocyclic Reactions; Elsevier, 2012; pp 283–288. (15) Davies, A. G. Radical Chemistry of Tin. In Chemistry of Tin; Smith, P. J., Ed.; Springer Netherlands: Dordrecht, 1998; pp 265–289. (16) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (17) Ramachandran, P. V.; Drolet, M. P.; Kulkarni, A. S. A Non-Dissociative OpenFlask Hydroboration with Ammonia Borane: Ready Synthesis of Ammonia– Trialkylboranes and Aminodialkylboranes. Chem. Commun. 2016, 52, 11897– 11900. (18) Brown–Garg reagent was prepared as follows: H2SO4 (21.2 mL) was added to Na2Cr2O7 (28 g). Water was slowly added to this slurry until a final volume of 141 Appendix 8 – Some Unusual Transformations of a Highly Reactive α-Bromocaranone 546 mL was attained. The mixture was stirred until homogeneous and used immediately. (19) Brown, H. C.; Garg, C. P.; Liu, K.-T. Oxidation of secondary alcohols in diethyl ether with aqueous chromic acid. Convenient procedure for the preparation of ketones in high epimeric purity. J. Org. Chem. 1971, 36, 387–390. (20) On large scales (>200 mg) the exotherm and release of HBr can lead to dangerous pressure build up, this can be avoided by leaving the vial open to atmosphere. (21) Kamat, S. P.; D’Souza, A. M.; Paknikar, S. K. Sodium Metaperiodate Oxidation of Isocarvacrol. J. Chem. Res. 2003, 395–397. Appendix 9 – Notebook Cross-Reference for New Compounds 547 APPENDIX 9 Notebook Cross-Reference for New Compounds Appendix 9 – Notebook Cross-Reference for New Compounds 548 Table A9.1. Notebook cross-reference for Chapter 1. compound 1H NMR (instrument) 13C NMR (instrument) yield/procedure 20a AWS-XII-77 (Florence) AWS-XII-77 (Florence) ZPS-III-115 20b AWS-XII-65 (Florence) AWS-XII-65 (Florence) ZPS-III-117 20c ZPS-I-297 (Florence) ZPS-I-297 (Florence) ZPS-III-119 20d ZPS-I-279 (Florence) ZPS-I-279 (Florence) ZPS-I-279 20e ZPS-II-83 (Florence) ZPS-II-83 (Florence) ZPS-II-83 20f ZPS-II-13 (Florence) ZPS-II-13 (Florence) ZPS-II-13 20g AWS-XIV-61 (Florence) AWS-XIV-61 (Florence) AWS-XIV-61 20h ZPS-II-65 (Florence) ZPS-II-65 (Florence) ZPS-III-121 20i AWS-XIV-63 (Florence) AWS-XIV-63 (Florence) AWS-XIV-63 20j ZPS-II-67 (Florence) ZPS-II-67 (Florence) ZPS-II-67 20k ZPS-II-69 (Florence) ZPS-II-69 (Florence) ZPS-II-101 20l AWS-XIV-13 (Florence) AWS-XIV-13 (Florence) AWS-XIV-13 55 AWS-XII-47 (Florence) AWS-XII-47 (Florence) AWS-XII-47 56 ZPS-I-287 (Florence) ZPS-I-287 (Florence) ZPS-I-287 57 AWS-XII-287 (Florence) AWS-XII-287 (Florence) AWS-XII-287 18a KY81 (Indy, zsercel2 folder) KY81 (Indy, zsercel2 folder) AWS-XII-49, 51, 67 18b ZPS-I-289 (Florence) ZPS-I-289 (Florence) ZPS-I-289 18c AWS-XII-289 (Florence) AWS-XII-289 (Florence) AWS-XII-289 19a AWS-XII-55 (Florence) AWS-XII-55 (Florence) ZPS-I-241 19b AWS-XII-53 (Florence) AWS-XII-53 (Florence) AWS-XII-53, 59 19c ZPS-I-293 (Florence) ZPS-I-293 (Florence) ZPS-I-293 19d AWS-XII-291 (Florence) AWS-XII-291 (Florence) AWS-XII-291 19e ZPS-II-75 (Indy) ZPS-II-75 (Indy) ZPS-II-75 19f ZPS-III-111 (Indy) ZPS-III-111 (Indy) ZPS-III-111 19g AWS-XIV-55 (Florence) AWS-XIV-55 (Florence) AWS-XIV-55 19h ZPS-II-51 (Florence) ZPS-II-51 (Florence) ZPS-II-51 19i AWS-XIV-53 (Indy) AWS-XIV-53 (Indy) AWS-XIV-53 19j ZPS-II-53 (Indy) ZPS-II-53 (Indy) ZPS-II-53 19k ZPS-II-61 (Florence) ZPS-II-61 (Florence) ZPS-II-61 19l AWS-XII-57 (Florence) AWS-XII-57 (Florence) AWS-XII-57 21 AWS-XIV-171 (Florence) AWS-XIV-171 (Florence) AWS-XIV-171 Appendix 9 – Notebook Cross-Reference for New Compounds 549 Table A9.2. Notebook cross-reference for Chapter 1 (continued). compound 1H NMR (instrument) 13C NMR (instrument) yield/procedure 23 ZPS-III-127 (Florence) ZPS-III-127 (Florence) ZPS-III-127 25 AWS-XIV-199 (Florence) AWS-XIV-199 (Florence) AWS-XIV-199 35a ZPS-III-159 (Florence) ZPS-III-159 (Florence) ZPS-III-159 35b ZPS-III-69 (Florence) ZPS-III-69 (Florence) ZPS-III-69 35c AWS-XIV-123 (Florence) AWS-XIV-123 (Florence) ZPS-IV-65 35d ZPS-III-155 (Florence) ZPS-III-155 (Florence) ZPS-III-155 35e ZPS-III-97 (Florence) ZPS-III-97 (Florence) ZPS-III-97 35f ZPS-III-287 (Florence) ZPS-III-287 (Florence) ZPS-III-287 35g ZPS-III-141 (Florence) ZPS-III-141 (Florence) ZPS-III-141 35h ZPS-II-191 (Florence) ZPS-II-191 (Florence) ZPS-II-191 35i ZPS-V-43 (Florence) ZPS-V-43 (Florence) ZPS-V-43 35j ZPS-II-239 (Florence) ZPS-II-239 (Florence) ZPS-II-239 35k ZPS-III-303 (Florence) ZPS-III-303 (Florence) ZPS-III-303 31 ZPS-III-199 (Florence) ZPS-III-259B (Florence) ZPS-III-285 32 AWS-XIV-23 (Florence) AWS-XIV-23 (Florence) ZPS-III-289 33 AWS-XIV-115 (Florence) AWS-XIV-115 (Florence) ZPS-IV-25 60 ZPS-V-277 (Florence) ZPS-V-277 (Florence) ZPS-V-277 34a AWS-XIV-125 (Florence) AWS-XIV-125 (Florence) ZPS-IV-83 34b ZPS-III-43 (Florence) ZPS-III-43 (Florence) ZPS-III-43 34c AWS-XIV-85 (Florence) AWS-XIV-85 (Florence) AWS-XIV-85 34d ZPS-III-79 (Florence) ZPS-III-79 (Florence) ZPS-III-79 34e ZPS-II-203 (Florence) ZPS-II-203 (Florence) ZPS-III-45 34f AWS-XIV-127 (Florence) AWS-XIV-127 (Florence) AWS-XIV-127 34g ZPS-II-193 (Indy) ZPS-II-193 (Indy) ZPS-II-193 34h ZPS-II-129 (Florence) ZPS-II-129 (Florence) ZPS-II-129 34i ZPS-IV-205 (Florence) ZPS-IV-205 (Florence) ZPS-IV-205 34j ZPS-II-141 (Florence) ZPS-II-141 (Florence) ZPS-II-141 34k ZPS-III-163 (Florence) ZPS-III-163 (Florence) ZPS-III-163 52 ZPS-V-109 (Florence) ZPS-V-109 (Florence) ZPS-V-109 53 ZPS-V-111 (Florence) ZPS-V-111 (Florence) ZPS-V-111 Appendix 9 – Notebook Cross-Reference for New Compounds 550 Table A9.3. Notebook cross-reference for Chapter 2. compound 1H NMR (instrument) 13C NMR (instrument) yield/procedure 96 ZPS-II-229 (Florence) ZPS-II-229 (Florence) ZPS-II-229 97 ZPS-VIII-251 (Florence) ZPS-VIII-251 (Florence) ZPS-V-203 107 ZPS-IV-215 (Florence) ZPS-IV-215 (Florence) ZPS-IV-231 109 ZPS-IV-243 (Florence) ZPS-IV-243 (Florence) ZPS-IV-243 125 ZPS-VI-13 (Florence) ZPS-VI-13 (Florence) ZPS-VI-13 126 ZPS-IX-127 (Florence) ZPS-IX-127 (Florence) ZPS-VI-89 131 ZPS-VI-169 (Florence) ZPS-VI-169 (Florence) ZPS-VI-169 132 ZPS-VI-113 (Florence) ZPS-VI-113 (Florence) ZPS-VI-125 133 ZPS-VIII-59 (Florence) ZPS-VIII-59 (Florence) ZPS-VIII-59 (from 132: ZPS-VI-129) 134 ZPS-IX-65 (Florence) ZPS-IX-65 (Florence) HY-III-213 136 ZPS-VI-153 (Florence) ZPS-VI-153 (Florence) ZPS-VI-153 138 ZPS-VI-193 (Florence) ZPS-VI-193 (Florence) ZPS-VI-211 139 ZPS-VI-261 (Florence) ZPS-VI-261 (Florence) ZPS-VI-261 141 ZPS-IX-117 (Florence) ZPS-IX-117 (Florence) ZPS-IX-117 143 ZPS-IX-115 (Florence) ZPS-IX-115 (Florence) ZPS-VII-69A 149 ZPS-VII-93 (Florence) ZPS-VII-93 (Florence) ZPS-VII-93 150 ZPS-VII-129 (Florence) ZPS-VII-129 (Florence) ZPS-VII-129 153 ZPS-VII-141 (Florence) ZPS-VII-141 (Florence) ZPS-VII-141 154 HY-I-83 (Florence, zsercel folder) HY-I-83 (Florence, zsercel folder) ZPS-VII-155 155 HY-I-221 (Florence, zsercel folder) HY-I-221 (Florence, zsercel folder) HY-I-107 (from 156: HY-I-81) 156 ZPS-VII-193 (Florence) ZPS-VII-193 (Florence) ZPS-VII-193 157 ZPS-VII-197 (Florence) ZPS-VII-197 (Florence) HY-I-121 160 HY-I-111 (Florence, zsercel folder) HY-I-111 (Florence, zsercel folder) HY-I-111 168 HY-I-251 (Florence, zsercel folder) HY-I-251 (Florence, zsercel folder) HY-I-251 169 HY-I-163 (Florence, zsercel folder) HY-I-163 (Florence, zsercel folder) HY-I-163 214 ZPS-VIII-301 (Florence) ZPS-VIII-301 (Florence) ZPS-VIII-301 177 HY-II-10 (Florence) HY-II-10 (Florence) HY-II-25 179 ZPS-IX-125 (Florence) ZPS-IX-125 (Florence) HY-II-187 184 ZPS-VIII-185 (Florence) ZPS-VIII-185 (Florence) HY-I-239 187 ZPS-VIII-303 (Florence) ZPS-VIII-303 (Florence) ZPS-VIII-303 Appendix 9 – Notebook Cross-Reference for New Compounds 551 Table A9.4. Notebook cross-reference for Chapter 2 (continued). compound 1H NMR (instrument) 13C NMR (instrument) yield/procedure 215 ZPS-IX-91 (Florence) ZPS-IX-91 (Florence) ZPS-VIII-209 189 ZPS-IX-123 (Florence) ZPS-IX-123 (Florence) ZPS-VIII-215 186 HY-III-281 (Florence) HY-III-281 (Florence) HY-III-303 190 ZPS-VIII-199 (Florence) ZPS-VIII-199 (Florence) ZPS-IX-111 185 HY-V-29 (Florence) HY-V-29 (Florence) ZPS-IX-131 192 HY-IV-61 (Florence) SPR-VII-17 (Florence, zsercel folder) SPR-VII-17 198 ZPS-IX-71 (Florence) ZPS-IX-71 (Florence) HY-IV-243 195 HY-IV-97 (Florence) HY-IV-97 (Florence) ZPS-IX-73 201 HY-IV-147 (Florence) HY-IV-147 (Florence) HY-IV-147 206 ZPS-IX-133 (Florence) ZPS-IX-133 (Florence) ZPS-IX-133 207 ZPS-IX-103 (Florence) ZPS-IX-103 (Florence) HY-IV-271 Table A9.5. Notebook cross-reference for Appendix 2. compound yield/procedure NMR instrument 62 ZPS-II-163 Indy 63 ZPS-II-167 Indy 68 ZPS-II-95 Florence 72 AWS-XIV-33 Florence 76 ZPS-II-109 Florence Appendix 9 – Notebook Cross-Reference for New Compounds Table A9.6. Notebook cross-reference for Appendix 5. compound yield/procedure NMR instrument 220 ZPS-V-69 Florence 222 ZPS-V-79 Florence 231 ZPS-IV-241 Florence 237 ZPS-VI-41 Florence 239 ZPS-VI-55 Indy 243 ZPS-VI-277 Florence 244 ZPS-VI-279 Florence 245 ZPS-VI-281 Florence 246 ZPS-VI-287 Florence 248 ZPS-VI-283 Florence 249 ZPS-VI-289 Florence 265 ZPS-VII-51 Florence 271 ZPS-VIII-43 Florence 283 ZPS-VIII-97 Florence 284 ZPS-VIII-115 Florence 287 ZPS-VIII-157 Florence 552 553 INDEX A Allyl Cyanoformate .............................................................................................. 6, 21, 47–49, 248, 251 Allylic Oxidation ............................................................................................................... 278, 460–461 ANDEN ............................................................................................................................................... 14 Aniline ........................ 19, 246, 257, 262–265, 267, 270–276, 281–283, 288–289, 293, 448–452, 463 Aza-Michael Addition .......................................................................270–274, 276, 314–315, 454, 456 B Barbier Addition ................................................................................................263, 271, 274–277, 456 Bartoli Indolization .................................................................................................................... 260–261 Beckmann Rearrangement ..................................................................................................... 16–17, 249 Benzodiazepine ..................................................................................................................... 5, 244–245 BINAP........................................................................................................................................ 266–303 BrettPhos ................................................................................................................................... 269, 310 C CAN .................................................................................................................................. 293–294, 345 D Desaturation ...................................................................................... 275–276, 278–280, 289–292, 455 Desulfurization .............................................................................................................................. 20–21 Dianiline............................................................................................................................ 264–265, 450 Diazepane ............................................................................................................................... 5–6, 9–10 Diazonium ........................................................................................................................ 265–266, 451 Dieckmann Condensation ................................................................................................................. 449 E Enolate.................................1, 3–4, 6–7, 12–13, 21, 244–246, 258, 261–262, 274, 290–291, 298, 525 Epoxide.............................................................................................................................. 462–464, 479 554 Eschenmoser’s Salt......................................................................................................................... 17–18 F Fischer Indolization ........................................................................................... 260–261, 264–267, 451 Fluoride ............................................................................................................. 9, 33–34, 260, 526, 540 G Grignard ............................................................................................................................................ 274 Gewald Aminothiophene Synthesis ................................................................... 281–282, 285, 460–462 H Hydrogenolysis .................................................................................................................................... 12 Hydrolysis......................................................................... 279, 281–282, 284–287, 291, 334, 461, 486 Hydroxyketone .......................................................................................................... 262, 323, 447–448 I Indium ...................................................................................... 282–283, 287, 329, 333–334, 448, 459 J Julolidine ................................................................................................................................... 455–456 K KHMDS ............................................................................................................................................. 259 L LDA .......................................................................................... 244–245, 251, 259, 297–298, 526, 530 LiAlH4 ...................................................................................................................................... 10, 62–63 LiTMP ................................................................................................................................ 245, 251, 290 M Methylcyclohexane ................................................................................................... 7–9, 25–26, 40, 43 555 Methylation ............................................................................................................................... 264, 266 Mitsunobu Reaction........................................................................................................... 268, 452, 470 N NBS .. 274, 276, 283, 287, 294–295, 316, 319–320, 329–330, 335, 463–464, 478, 494, 525–526, 530, 534, 542 NHK Reaction ..................................................................................................................................................... 274 Nitration.......................................................................................................................................................451, 455 N-Methylarylhydrazine ...............................................................................................................................267, 305 N-t-Butylbenzenesulfinimidoyl Chloride ....................................................................................... 276, 289 P PIFA ......................................................................................................... 289, 292, 340, 357, 487, 492 Pummerer Rearrangement .............................................................................................................. 19, 291 Pyrroloiminoquinone ...................................................................254–256, 263–265, 292–294, 302, 345 Q Quinolone .................................................................................262, 270–271, 313, 448–450, 453–456 R Raney Nickel ................................................................................................................................. 20–21 Reductive Amination ........................................................................................... 12, 281–283, 286, 293 S Silane ......................................................................................................................... 288, 329–330, 341 Sulfide ....................................................................................................... 255, 258–260, 447–450, 466 T Tetrapyrrane .............................................................................................................. 488–492, 496–498 Thiolactone............................................... 280, 284–285, 287–294, 339–340, 342–343, 345, 460, 462 Titanium .................................................................................................................... 270–272, 448–449 Triethylsilane ..................................................................................................... 282–283, 287, 329–330 Ty-PHOX ..................................................................................................................................... 7–8, 25 556 W Wacker Oxidation ..................................................................................................................... 457–460 X X-Ray ................................................................................................................................. 495, 509–523 557 ABOUT THE AUTHOR Zachary Patrick Sercel was born to Stephanie Leifer and Pete Sercel in Pasadena, California, where he was raised together with his three younger siblings. He attended elementary school at Don Benito Fundamental School and was then homeschooled for 3 years. A book given to him by his grandmother when he was 10 years old inspired his passion for chemistry. After a few years of performing experiments in his parents’ garage, Zachary was accepted to the Early Entrance Program at California State University, Los Angeles in 2013. At Cal State LA, Zachary conducted research with Professor Matthias Selke in the area of singlet oxygen chemistry as a CSULA-Penn State NSF PREM fellow. He also spent two summers conducting research in organic synthesis in the laboratory of Professor Brian Stoltz at Caltech. After completing his B.S. in chemistry in 2018, Zachary returned to the Stoltz lab to complete his graduate studies. As a Ph.D. student, Zachary has primarily focused on the development of palladium-catalyzed decarboxylative asymmetric allylic alkylation of medicinally relevant heterocycles and the total synthesis of the marine alkaloid aleutianamine. In his fourth year of graduate school, Zachary conducted a research internship in the laboratory of Professor Zeev Gross at the Technion, where he studied the synthesis of minimally substituted porphyrinoids and their metal complexes. After completing his Ph.D., Zachary will travel back to Israel to conduct postdoctoral research at the Technion with Professor Ilan Marek as an Azrieli and Fulbright postdoctoral fellow.