Applications of the Enantioselective Allylic Alkylation Toward the Synthesis of Complex Natural Products Citation Loskot, Steven Anthony (2019) Applications of the Enantioselective Allylic Alkylation Toward the Synthesis of Complex Natural Products. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/TZHG-9B35. https://resolver.caltech.edu/CaltechTHESIS:05132019-092701701 Abstract The Stoltz group, and moreover the synthetic community at large, has long been interested in the development of methods for the synthesis of enantioenriched all-carbon quaternary stereocenters. This thesis present three projects all unified by the development and use of the palladium-catalyzed decarboxylative allylic alkylation to synthesize enantioenriched all-carbon quaternary stereocenter containing cyclopentanones as well as the natural product total synthesis. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Natural Product; Total Synthesis; Asymmetric Allylic Alkylation Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Stoltz, Brian M. Thesis Committee: Reisman, Sarah E. (chair) Stoltz, Brian M. Grubbs, Robert H. Agapie, Theodor Defense Date: 3 May 2019 Record Number: CaltechTHESIS:05132019-092701701 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:05132019-092701701 DOI: 10.7907/TZHG-9B35 Related URLs: URL URL Type Description https://doi.org/10.1002/9780470682531.pat0858 DOI Book section adapted for Chapter 1. https://doi.org/10.1021/acs.orglett.5b02376 DOI Article adapted for Chapter 2. https://doi.org/10.1021/jacs.7b05196 DOI Article adapted for Chapter 3. Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 11510 Collection: CaltechTHESIS Deposited By: Steven Loskot Deposited On: 23 May 2019 20:03 Last Modified: 08 Nov 2023 00:39 Thesis Files Preview PDF - Final Version See Usage Policy. 16MB Repository Staff Only: item control page

APPLICATIONS OF THE ENANTIOSELECTIVE ALLYLIC ALKYLATION TOWARD THE SYNTHESIS OF COMPLEX NATURAL PRODUCTS Thesis by Steven Anthony Loskot In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2019 (Defended May 3, 2019) ii ã 2019 Steven A. Loskot All Rights Reserved iii To my family, for their constant love and support iv ACKNOWLEDGEMENTS Reflecting on the past 5 and half years of life at Caltech, I’ve learned that going it alone is not a possibility. There are so many people that I need to thank and acknowledge for their help and support that allowed me to reach this point in my life and achieved this surreal feat. First I need to acknowledge Professor Brian Stoltz, my advisor, mentor, and friend. I was lucky to have such a kind and understanding advisor who knew exactly the right time to challenge and when to support me throughout my doctoral studies. It has been a pleasure working in his lab, and I would not be the scientist I am today without his guidance. It was great having such an active advisor as well. When he was in town over the summer, Brian made sure he was able to participate on our softball team “Ru-Tang Clan”. Not only did he play softball, but also came out a couple times to play tennis with us as well as being our substitute for the volleyball team (we lost that game, but I’m not pointing any fingers). Needless to say, I cannot thank him enough for what he has done and the impact he has had on my life. I would also like to thank the chair of my committee, Professor Sarah Reisman, for all her help and advice over the past five and half years at Caltech. Sarah, like Brian, always had her door open, and was willing to talk about chemistry anytime. I probably did not take advantage of this enough, but her insightful questions and advice during my formal presentation were immensely helpful and gave me a new perspective on the problems at hand. In addition, I am deeply appreciative of the valuable career advice the rest of my thesis committee, Professors Bob Grubbs and Theodor Agapie, have given me over my graduate career. v Of course, I wouldn’t have even attended Caltech if it wasn’t for the great mentorship and guidance I received at Seattle University from Professor Joe Langenhan. Joe’s passion for chemistry and teaching truly inspired me to be where I am today. At Seattle University I had the pleasure of meeting some of my closest friends, Leo Rozal and Nick Martinez, who have continued to support me through my doctoral studies. I also had the pleasure of research with Professor Neil Garg at UCLA prior to graduate school as an Amgen Scholar. Working in Neil’s lab showed me firsthand what it would be like working in a top research institution and I cannot thank him enough for the opportunity and experience he gave me. During my time at Caltech, I was extremely lucky to have had excellent mentors over the years. First I’d like to thank Rob Craig, whom I only overlapped with for about 6 months. During that time learned the Stoltz lab way and hopefully continued the tradition after he left. I’d also like to thank Matt Hesse for his constant support and willingness to talk about chemistry. Even though we were in different labs, he was always willing to set time aside and help. Finally I’d like to thank Eric Welin for his constant wisdom and seemingly endless knowledge of chemistry and sports. During my time at Caltech, I was fortunate to be able to work with great project partners. First, I would like to thank Dr. Rob Craig, who asked me to join his project in my first year here. I need to thank Katerina Korch for working with me on the book chapter review as well as being one of the friendliest people I know. I also would like to thank Dr. David Romney and the Arnold lab for all their help in completing the total synthesis of nigelladine A. Without the use of directed evolution, the synthesis would have been significantly less impactful. Finally I’d like to thank Nick Hafeman, Chris Reimann, and vi Dr. Beau Pritchett for putting up with me on the Scabtrain. Hopefully the Scabtrain will reach its final stop soon. I’d like to thank every Stoltz group member, past and present, for their helpful discussions, thoughtfulness, and contributions to my development as a chemist. Specifically, I’d like to thank again everyone I have mention above, as well as David Schuman, Tyler Fulton, Nick Hafeman, Fa Ngamnithiporn, Austin Wright, Dr. Max Klatte, Dr. Marc Liniger, Dr. Wen-bo Liu, Dr. Jared Moore (creator of the “Dirty SAL” nickname), Dr. Gerit Potoschnig, and Dr. Marc Liniger. Moreover I’d like to thank David Schuman for being a great roommate for three–plus years and having to deal with me basically 24/7 during that time, and Tyler Fulton for being such a tolerant hoodmate. Beyond the Stoltz lab, many thanks to the members past and present of the Reisman, Grubbs, and Fu labs for supporting the excellent collaborative atmosphere that is characteristic of the chemistry department at Caltech. I especially want to acknowledge Carson Matier, Alice Wong, Meaghan Deegan, Nina Gu, Chris Reed, and Dr. Nick Cowper for their friendship and comradery. I want to thank all of the Caltech staff for all of their assistance and aide throughout the years, specifically Dr. Scott Virgil for all of his help maintaining the catalysis center, prepping numerous compounds, and helping me learn how to grow X-ray quality crystals. I’d also like to thank Scott and his wife Silva for hosting their Christmas party every year, which was always fun to attend. Additionally, Dr. David VanderVelde for his constant maintenance of the NMR lab as well as assistance in structure determination of a number of tricky diastereomers. I’d also like to thank Mike Takase and Larry Henling for their assistance with obtaining X-ray diffraction data, as well as Dr. Mona Shahgholi and vii Naseem Torian for their tireless efforts with mass spectrometry. I would also like to thank Rick Gerhart and Jeff Groseth for their great work in the glass and electronic shops. Finally, I need to acknowledge my family. Without them I know I would not be here completing my graduate studies. I always enjoyed when my family visited, and wished it happened more frequently than it did. I need to thank my brother for always being up for an adventure, whether it was to blow off steam and get drunk in Las Vegas or lounge around all day playing Crash Bandicoot and other video games. The life advice he has given me has helped me become the man I am today. I need to thank my mother, Annette, and late father, Victor, for being such wonderful parents. As they know I am not the most elegant writer, all I can say is that the person I am today and everything I have accomplished is because of you and your love. I also need to thank them for dealing with my late night phone calls on my walks back home from lab. I think family is the most important thing in life and I had the pleasure to expand my family during my doctoral studies by marrying the love of my life Danielle Loskot. There are no words that can describe the love and support I have received from her. Every day she is my rock and is what keeps me sane knowing that when I go home I get to see her. I also need to thank my in-laws, Thomas and Kelly Bright, for being so supportive and welcoming me into their family. The work presented in this thesis would not have been possible without the neverending support, friendship, and love from all of these people and many others I do not have space to name. To you all, thank you. I am eternally grateful. viii ABSTRACT The Stoltz group, and moreover the synthetic community at large, has long been interested in the development of methods for the synthesis of enantioenriched all-carbon quaternary stereocenters. This thesis present three projects all unified by the development and use of the palladium-catalyzed decarboxylative allylic alkylation to synthesize enantioenriched all-carbon quaternary stereocenter containing cyclopentanones as well as the natural product total synthesis. An enantioselective total synthesis of the norditerpenoid alkaloid nigelladine A utilizing the asymmetric allylic alkylation to set the central all-carbon quaternary center is described. Strategically, the synthesis relies on a late-stage C–H oxidation of an advanced intermediate. While traditional chemical methods failed to deliver the desired outcome, an engineered cytochrome P450 enzyme was employed to effect a chemo- and regioselective allylic C–H oxidation in the presence of at least four oxidizable positions. The enzyme variant was readily identified from a focused library of three enzymes, allowing for completion of the synthesis without the need for extensive screening. Lastly, we describe a unified synthetic approach toward scabrolide A. The first generation route to scabrolide A hinged upon the asymmetric allylic alkylation reaction to synthesis the key hydroxymethyl-cis-1,3-cyclopentenediol fragment. Ultimately, assembly of the tetracyclic scaffold is accomplished in a convergent manner from (–)-carvone and (–)-linalool. A key intramolecular Diels–Alder reaction and a photocatalytic [2+2]-ring expansion construct the [5,5,6,7] carbocyclic core of scabrolide A. Various other synthetic strategies, including transannular Diels–Alder and oxidative enolate coupling, are also discussed. ix PUBLISHED CONTENT AND CONTRIBUTIONS 1. Craig, II, R. A. ‡; Loskot, S. A. ‡; Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. “Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones” Org. Lett. 2015, 17, 5160–5163. DOI: 10.1021/acs.orglett.5b02376 S.A.L. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 2. Korch, K.; Loskot, S. A.; Stoltz, B. M. (2017) Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates. In PATAI’S Chemistry of Functional Groups, Rappoport, Z. (Ed.). doi: 10.1002/9780470682531.pat0858. S.A.L. participated in book chapter preparation, including the introduction and asymmetric allylic alkylation section. S.A.L. performed the editing process, as well as updating this review to 2018. 3. Loskot, S. A.; Romney, D. K.; Arnold, F. H.; Stoltz, B. M. “Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme” J. Am. Chem. Soc. 2017, 139, 10196–10199. DOI: 10.1021/jacs.7b05196. S.A.L. lead project design, experimental work, data acquisition and analysis, and manuscript preparation. x TABLE OF CONTENTS Acknowledgements .........................................................................................iv Abstract ........................................................................................................viii Published Content and Contributions ...............................................................ix Table of Contents ............................................................................................ x List of Figures ................................................................................................ xvi List of Schemes............................................................................................. xxv List of Tables ............................................................................................... xxix List of Abbreviations .................................................................................. xxxiv CHAPTER 1........................................................................................................... 1 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 1.1 Introduction ................................................................................................. 1 1.2 Enolate Types and Their Formation ............................................................... 3 1.2.1 Alkali and Alkaline Earth Metal Enolates .................................................... 4 1.2.2 Silyl Enol Ethers ........................................................................................ 6 1.2.3 Boron Enolates .......................................................................................... 9 1.2.4 Transition Metal Enolates......................................................................... 11 1.3 Aldol Reaction ........................................................................................... 12 1.3.1 Introduction ............................................................................................ 12 1.3.2 Rhodium-Catalyzed Reactions ................................................................. 12 1.3.3 Palladium-, Platinum-, and Nickel-Catalyzed Reactions ............................ 13 1.3.4 Scandium- and Neodymium-Catalyzed Reactions .................................... 15 1.3.5 Reactions Proceeding Through Boron Enolates ......................................... 17 1.4 Mannich Reaction ...................................................................................... 18 1.4.1 Introduction ............................................................................................ 18 1.4.2 Copper-Catalyzed Reactions.................................................................... 19 1.4.3 Palladium-Catalyzed Reactions................................................................ 19 1.4.4 Scandium-Catalyzed Reactions ................................................................ 22 1.4.5 Nickel-Catalyzed Reactions ..................................................................... 23 1.4.6 Lithium-Catalyzed Reactions ................................................................... 23 1.4.7 Calcium-Catalyzed Reactions .................................................................. 25 xi 1.5. Conjugate Addition and Michael Reaction .................................................. 25 1.5.1 Michael Additions Involving Potassium Enolates....................................... 25 1.5.2 Michael Additions Involving Cobalt Enolate ............................................. 26 1.5.3 Michael Additions Involving Nickel Enolates ............................................ 28 1.5.4 Michael Additions Involving Copper Enolates........................................... 31 1.5.5 Michael Additions Involving Europium Enolates ....................................... 32 1.5.6 Michael Additions Involving Rhodium Enolates ........................................ 33 1.5.7 Michael Additions Using Lanthanum–BINOL Complexes.......................... 36 1.5.8 Michael Additions Involving Platinum and Iron Enolates ........................... 41 1.5.9 Michael Additions Involving Palladium Enolates....................................... 42 1.5.10 Michael Additions Involving Scandium and Yttrium Enolates .................... 47 1.5.11 Michael Additions Involving Calcium Enolates ......................................... 49 1.5.12 Conjugate Addition Reactions Involving Manganese Enolates ................... 50 1.6 Allylic Alkylation........................................................................................ 51 1.6.1 Introduction ............................................................................................ 51 1.6.2 Palladium-Catalyzed Asymmetric Allylic Alkylations of Non-Stabilized Enolates ......................................................................... 52 1.6.3 Molybdenum-Catalyzed Asymmetric Allylic Alkylations ........................... 59 1.6.4 Iridium-Catalyzed Allylic Alkylations ....................................................... 60 1.6.5 Rhodium-Catalyzed Allylic Alkylations .................................................... 63 1.6.6 Nickel-Catalyzed Allylic Alkylations ........................................................ 64 1.7 Miscellaneous Alkylations .......................................................................... 64 1.7.1 Asymmetric Alkylations of Chromium Enolates......................................... 64 1.7.2 Asymmetric Alkylations of Lithium Enolates ............................................. 66 1.8 a-Arylation and a-Alkenylation.................................................................. 67 1.8.1 Introduction ............................................................................................ 67 1.8.2 Palladium-Catalyzed Reactions................................................................ 68 1.8.3 Nickel-Catalyzed Reactions ..................................................................... 79 1.8.4 Copper-Catalyzed Reactions.................................................................... 83 1.9 Pericyclic Reactions ................................................................................... 84 1.9.1 Claisen-Type Reactions ........................................................................... 84 1.9.2 Conia-Ene Reactions ............................................................................... 88 1.10 Notes and References ................................................................................. 93 xii CHAPTER 2....................................................................................................... 109 Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 2.1 Introduction ............................................................................................. 109 2.2 Initial Reaction Optimization .................................................................... 111 2.3 Exploration of Reaction Scope .................................................................. 114 2.4 Adapting the Low Catalyst Loading Allylic Alkylation ................................ 118 2.5 Conclusion .............................................................................................. 118 2.6 Experimental Methods and Analytical Data ............................................... 119 2.6.1 Materials and Methods .......................................................................... 119 2.6.2 Experimental Procedures ....................................................................... 121 2.6.3 Methods for the Determination of Enantiomeric Excess ........................... 154 2.6.4 Notes and References............................................................................ 156 APPENDIX 1 ..................................................................................................... 161 Spectra Relevant to Chapter 2 CHAPTER 3....................................................................................................... 217 Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 3.1 Introduction ............................................................................................. 217 3.2 Retrosynthetic Analysis ............................................................................. 219 3.3 Synthesis of Cross-Coupling Fragments...................................................... 220 3.4 Cross-Coupling and Elaboration to the Carbocyclic Core ........................... 222 3.5 Chemical Oxidation of Desoxy-Nigelladine A ........................................... 224 3.6 Enzymatic Oxidation of Desoxy-Nigelladine A .......................................... 225 3.7 Conclusion .............................................................................................. 228 3.8 Experimental Methods and Analytical Data ............................................... 228 3.8.1 Materials and Methods .......................................................................... 228 3.8.2 Protocols for Protein Expression and Lysis .............................................. 230 3.8.3 Experimental Procedures ....................................................................... 231 3.8.4 Enzymatic Screens and Enantiomer Screen ............................................. 246 3.8.5 Chemical Oxidation Tables ................................................................... 248 3.8.6 Comparison of Natural and Synthetic Nigelladine A ............................... 250 xiii 3.8.7 Notes and References............................................................................ 251 APPENDIX 2 ..................................................................................................... 256 Synthetic Summary of Chapter 3 APPENDIX 3 ..................................................................................................... 258 Spectra Relevant of Chapter 3 APPENDIX 4 ..................................................................................................... 285 X-Ray Crystallography Reports Relevant to Chapter 3 A4.1 X-Ray Crystal Structure Analysis of Triene 401........................................... 286 A4.2 Notes and References ............................................................................... 316 CHAPTER 4....................................................................................................... 317 Progress Toward the Total Synthesis of Scabrolide A 4.1 Introduction ............................................................................................. 317 4.2 Retrosynthetic Analysis; Transannular Diels–Alder ..................................... 318 4.3 Synthesis of Convergent Coupling Fragments ............................................. 319 4.4 Fragment Coupling and Ring Closing Metathesis........................................ 321 4.5 Retrosynthetic Analysis; Oxidative Enolate Coupling.................................. 324 4.6 Second Generation Synthesis of the Cyclopentene Diol Fragment............... 325 4.7 Alkyne Synthesis and Fragment Coupling .................................................. 327 4.8 Intramolecular Diels–Alder Reaction and Late-Stage Functionalization ....... 327 4.9 Third Generation Retrosynthetic Analysis; Ring Expansion ......................... 329 4.10 Synthesis of [2+2] Precursor...................................................................... 330 4.11 [2+2] Photocycloaddition and Ring Expansion........................................... 331 4.12 Future Directions...................................................................................... 333 4.13 Conclusion .............................................................................................. 334 4.14 Experimental Methods and Analytical Data ............................................... 334 4.14.1 Material and Methods ........................................................................... 334 4.14.2 Experimental Procedures ....................................................................... 336 4.14.3 Notes and References............................................................................ 369 xiv APPENDIX 5 ..................................................................................................... 372 Synthetic Summary for Chapter 4 APPENDIX 6 ..................................................................................................... 377 Spectra Relevant to Chapter 4 APPENDIX 7 ..................................................................................................... 444 X-Ray Crystallography Reports Relevant to Chapter 4 A7.1 X-Ray Crystal Structure Analysis of Tetracycle 452 ..................................... 445 A7.2 X-Ray Crystal Structure Analysis of Cyclobutane 465 ................................. 465 A7.3 X-Ray Crystal Structure Analysis of Cyclobutane 466 ................................. 485 A7.4 X-Ray Crystal Structure Analysis of Cycloheptane 468 ............................... 503 A7.5 Notes and References ............................................................................... 528 APPENDIX 8 ..................................................................................................... 529 Alternative Strategy Toward the Total Synthesis of Scabrolide A A8.1 Alternative Approach to Scabrolide A........................................................ 529 A8.2 Synthesis of Diisopropyl Carbamate .......................................................... 530 A8.3 Umpolung Aldehyde Addition .................................................................. 531 A8.4 Experimental Methods and Analytical Data ............................................... 531 A8.4.1 Materials and Methods .......................................................................... 531 A8.4.2 Experimental Procedures ....................................................................... 533 A8.4.3 Notes and References............................................................................ 538 APPENDIX 9 ..................................................................................................... 539 Spectra Relevant to Appendix 8 APPENDIX 10 ................................................................................................... 546 Notebook Cross-Reference for New Compounds A10.1 Contents ............................................................................................... 546 A10.2 Notebook Cross-Reference Tables.......................................................... 546 xv Comprehensive Bibliography ....................................................................... 552 Index .......................................................................................................... 581 About the Author......................................................................................... 588 xvi LIST OF FIGURES CHAPTER 1 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Figure 1.1.1. Commonly Mislabeled Tetrasubstituted C-Centers........................................................2 Figure 1.1.2. Natural Products Containing Quaternary Centers Possessing Potent Biological Activities .........................................................................................2 Figure 1.3.2.1. Transition State of Zwitterionic (Enolato)Rhodium Intermediate ................................ 13 Figure 1.3.3.1. Scope of Palladium- and Platinum-Catalyzed Hydroxymethylation of Substituted b-Ketoesters ..................................................................................... 14 Figure 1.5.7.1 Proposed Mechanism of the Lanthanum-BINOL Complex-Catalyzed Asymmetric Michael Reaction................................................................................. 37 Figure 1.6.2.1. Representative Products of the Palladium-Catalyzed Asymmetric Allylic Alkylation Reaction Developed by Stoltz and Coworkers .............................. 55 Figure 1.6.2.2. Scope of Chiral Ferrocenylphosphine-Palladium Complex-Catalyzed Allylic Alkylation................................................................................................... 59 Figure 1.8.2.1. Aminophosphine and Desamino Ligands for a-Vinylation........................................ 69 Figure 1.8.2.2. Proposed Mechanism of Palladium-Catalyzed Intramolecular a-Arylation Reaction Forming Oxindoles ................................................................ 74 Figure 1.8.2.3. NHC Ligands Screened in Intramolecular a-Arylation Reaction Reported by Kond, Aoyama, and Coworkers ........................................................... 76 CHAPTER 2 Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones Figure 2.1.1. Natural Products Characterized by Cyclopentane Rings Containing Chiral All-Carbon Quaternary Centers ..................................................................... 111 APPENDIX 1 Spectra Relevant to Chapter 2 Figure A1.1. 1H NMR (400 MHz, CDCl3) of compound 331 ........................................................ 162 xvii Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound 331.............................................. 163 Figure A1.3. 13C NMR (101 MHz, CDCl3) of compound 331........................................................ 163 Figure A1.4. 1H NMR (400 MHz, CDCl3) of compound 332 ......................................................... 164 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 332.............................................. 165 Figure A1.6. 13C NMR (101 MHz, CDCl3) of compound 332 ........................................................ 165 Figure A1.7. 1H NMR (400 MHz, CDCl3) of compound 336 ......................................................... 166 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 336.............................................. 167 Figure A1.9. 13C NMR (101 MHz, CDCl3) of compound 336 ........................................................ 167 Figure A1.10. 1H NMR (400 MHz, CDCl3) of compound 339 ....................................................... 168 Figure A1. 11. Infrared spectrum (Thin Film, NaCl) of compound 339 ........................................... 169 Figure A1. 12. 13C NMR (101 MHz, CDCl3) of compound 339...................................................... 169 Figure A1.13. 1H NMR (400 MHz, CDCl3) of compound 346 ....................................................... 170 Figure A1. 14. Infrared spectrum (Thin Film, NaCl) of compound 346 ........................................... 171 Figure A1.15. 13C NMR (101 MHz, CDCl3) of compound 346 ...................................................... 171 Figure A1.16. 1H NMR (400 MHz, CDCl3) of compound 347 ....................................................... 172 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 347 ............................................ 173 Figure A1.18. 13C NMR (101 MHz, CDCl3) of compound 347 ...................................................... 173 Figure A1.19. 1H NMR (400 MHz, CDCl3) of compound 348 ....................................................... 174 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 348 ............................................ 175 Figure A1.21. 13C NMR (101 MHz, CDCl3) of compound 348....................................................... 175 Figure A1.22. 1H NMR (400 MHz, CDCl3) of compound 349. ...................................................... 176 Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 349 ............................................ 177 Figure A1.24. 13C NMR (101 MHz, CDCl3) of compound 349 ...................................................... 177 Figure A1.25. 1H NMR (400 MHz, CDCl3) of compound 351 ....................................................... 178 Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 351 ............................................ 179 Figure A1.27. 13C NMR (101 MHz, CDCl3) of compound 351 ...................................................... 179 Figure A1.28. 1H NMR (400 MHz, CDCl3) of compound 353 ....................................................... 180 Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 353 ............................................ 181 Figure A1.30. 13C NMR (101 MHz, CDCl3) of compound 353 ...................................................... 181 Figure A1.31. 1H NMR (400 MHz, CDCl3) of compound 354 ....................................................... 182 Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 354 ............................................ 183 Figure A1.33. 13C NMR (101 MHz, CDCl3) of compound 354 ...................................................... 183 Figure A1.34. 1H NMR (400 MHz, CDCl3) of compound 355 ....................................................... 184 Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 355 ............................................ 185 Figure A1.36. 13C NMR (101 MHz, CDCl3) of compound 355 ...................................................... 185 xviii Figure A1.37. 1H NMR (400 MHz, CDCl3) of compound 359 ....................................................... 186 Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 359 ............................................ 187 Figure A1.39. 13C NMR (101 MHz, CDCl3) of compound 359 ...................................................... 187 Figure A1.40. 1H NMR (400 MHz, C6D6) of compound 361 ......................................................... 188 Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 361 ............................................ 189 Figure A1.42. 13C NMR (101 MHz, C6D6) of compound 361 ........................................................ 189 Figure A1.43. 1H NMR (400 MHz, CDCl3) of compound 363 ....................................................... 190 Figure A1. 44. Infrared spectrum (Thin Film, NaCl) of compound 363 ........................................... 191 Figure A1. 45. 13C NMR (101 MHz, CDCl3) of compound 363...................................................... 191 Figure A1.46. 1H NMR (400 MHz, CDCl3) of compound 364 ....................................................... 192 Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 364 ............................................ 193 Figure A1.48. 13C NMR (101 MHz, CDCl3) of compound 364 ...................................................... 193 Figure A1.49. 1H NMR (400 MHz, CDCl3) of compound 365 ....................................................... 194 Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound 365 ............................................ 195 Figure A1.51. 13C NMR (101 MHz, CDCl3) of compound 365 ...................................................... 195 Figure A1.52. 1H NMR (400 MHz, CDCl3) of compound 366 ....................................................... 196 Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 366 ............................................ 197 Figure A1.54. 13C NMR (101 MHz, CDCl3) of compound 366 ...................................................... 197 Figure A1.55. 1H NMR (400 MHz, CDCl3) of compound 367 ....................................................... 198 Figure A1.56. Infrared spectrum (Thin Film, NaCl) of compound 367 ............................................ 199 Figure A1.57. 13C NMR (101 MHz, CDCl3) of compound 367 ...................................................... 199 Figure A1.58. 1H NMR (400 MHz, CDCl3) of compound 370 ....................................................... 200 Figure A1.59. Infrared spectrum (Thin Film, NaCl) of compound 370 ............................................ 201 Figure A1.60. 13C NMR (101 MHz, CDCl3) of compound 370 ...................................................... 201 Figure A1.61. 1H NMR (400 MHz, CDCl3) of compound 377 ....................................................... 202 Figure A1.62. Infrared spectrum (Thin Film, NaCl) of compound 377 ............................................ 203 Figure A1.63. 13C NMR (101 MHz, CDCl3) of compound 377 ...................................................... 203 Figure A1.64. 19F NMR (470 MHz, CDCl3) of compound 377 ....................................................... 204 Figure A1.65. 1H NMR (400 MHz, CDCl3) of compound 378 ....................................................... 205 Figure A1.66. Infrared spectrum (Thin Film, NaCl) of compound 378 ............................................ 206 Figure A1.67. 13C NMR (101 MHz, CDCl3) of compound 378 ...................................................... 206 Figure A1.68. 1H NMR (400 MHz, CDCl3) of compound 379 ....................................................... 207 Figure A1.69. Infrared spectrum (Thin Film, NaCl) of compound 379 ............................................ 208 Figure A1.70. 13C NMR (101 MHz, CDCl3) of compound 379 ...................................................... 208 Figure A1.71. 1H NMR (400 MHz, CDCl3) of compound 380 ....................................................... 209 xix Figure A1.72. Infrared spectrum (Thin Film, NaCl) of compound 380 ............................................ 210 Figure A1.73. 13C NMR (101 MHz, CDCl3) of compound 380 ...................................................... 210 Figure A1.74. 1H NMR (400 MHz, CDCl3) of compound 382 ....................................................... 211 Figure A1.75. Infrared spectrum (Thin Film, NaCl) of compound 382 ............................................ 212 Figure A1.76. 13C NMR (101 MHz, CDCl3) of compound 382 ...................................................... 212 Figure A1.77. 1H NMR (400 MHz, CDCl3) of compound 383 ....................................................... 213 Figure A1.78. Infrared spectrum (Thin Film, NaCl) of compound 383 ............................................ 214 Figure A1.79. 13C NMR (101 MHz, CDCl3) of compound 383 ...................................................... 214 Figure A1.80. 1H NMR (400 MHz, CDCl3) of compound 384 ....................................................... 215 Figure A1.81. Infrared spectrum (Thin Film, NaCl) of compound 384 ............................................ 216 Figure A1.82. 13C NMR (101 MHz, CDCl3) of compound 384 ...................................................... 216 CHAPTER 3 Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme Figure 3.1.1. Structures of Nigelladines A–C and Nigellaquinomine .............................................. 218 APPENDIX 3 Spectra Relevant of Chapter 3 Figure A3.1. 1H NMR (400 MHz, CDCl3) of compound 395 ......................................................... 259 Figure A3.2. Infrared spectrum (Thin Film, NaCl) of compound 395.............................................. 260 Figure A3.3. 13C NMR (101 MHz, CDCl3) of compound 395 ........................................................ 260 Figure A3.4. 1H NMR (500 MHz, CDCl3) of compound 396 ......................................................... 261 Figure A3.5. Infrared spectrum (Thin Film, NaCl) of compound 396.............................................. 262 Figure A3.6. 13C NMR (126 MHz, CDCl3) of compound 396 ........................................................ 262 Figure A3.7. 1H NMR (500 MHz, CDCl3) of compound 393 ......................................................... 263 Figure A3.8. Infrared spectrum (Thin Film, NaCl) of compound 393.............................................. 264 Figure A3.9. 13C NMR (126 MHz, CDCl3) of compound 393 ........................................................ 264 Figure A3.10. 1H NMR (500 MHz, CDCl3) of compound 392 ....................................................... 265 Figure A3.11. Infrared spectrum (Thin Film, NaCl) of compound 392 ............................................ 266 Figure A3.12. 13C NMR (126 MHz, CDCl3) of compound 392 ...................................................... 266 Figure A3.13. 1H NMR (400 MHz, CDCl3) of compound 397 ....................................................... 267 Figure A3.14. Infrared spectrum (Thin Film, NaCl) of compound 397 ............................................ 268 Figure A3.15. 13C NMR (101 MHz, CDCl3) of compound 397 ...................................................... 268 xx Figure A3.16. 1H NMR (400 MHz, CDCl3) of compound 391 ....................................................... 269 Figure A3.17. Infrared spectrum (Thin Film, NaCl) of compound 391 ............................................ 270 Figure A3.18. 13C NMR (101 MHz, CDCl3) of compound 391 ...................................................... 270 Figure A3.19. 1H NMR (400 MHz, CDCl3) of compound 400 ....................................................... 271 Figure A3.20. Infrared spectrum (Thin Film, NaCl) of compound 400 ............................................ 272 Figure A3.21. 13C NMR (101 MHz, CDCl3) of compound 400 ...................................................... 272 Figure A3.22. 1H NMR (400 MHz, CDCl3) of compound 390 ....................................................... 273 Figure A3.23. Infrared spectrum (Thin Film, NaCl) of compound 390 ............................................ 274 Figure A3.24. 13C NMR (101 MHz, CDCl3) of compound 390 ...................................................... 274 Figure A3.25. 1H NMR (400 MHz, CDCl3) of compound 401 ....................................................... 275 Figure A3.26. Infrared spectrum (Thin Film, NaCl) of compound 401 ............................................ 276 Figure A3.27. 13C NMR (101 MHz, CDCl3) of compound 401 ...................................................... 276 Figure A3.28. 1H NMR (400 MHz, CDCl3) of compound 389 ....................................................... 277 Figure A3.29. Infrared spectrum (Thin Film, NaCl) of compound 389 ............................................ 278 Figure A3.30. 13C NMR (101 MHz, CDCl3) of compound 389 ...................................................... 278 Figure A3.31. 1H NMR (400 MHz, CDCl3) of compound 385 ....................................................... 279 Figure A3.32. Infrared spectrum (Thin Film, NaCl) of compound 385 ............................................ 280 Figure A3.33. 13C NMR (101 MHz, CDCl3) of compound 385 ...................................................... 280 Figure A3.34. 1H NMR (400 MHz, C6D6) of compound 385 ......................................................... 281 Figure A3.35. 13C NMR (101 MHz, C6D6) of compound 385 ........................................................ 282 Figure A3.36. 1H NMR (400 MHz, CD3OD) of compound 385•DCl ............................................. 283 Figure A3.37. 13C NMR (101 MHz, CD3OD) of compound 385•DCl ............................................ 284 APPENDIX 4 X-Ray Crystallography Reports Relevant to Chapter 3 Figure A4.1.1. X-Ray Crystal Structure of Triene 401 .................................................................... 286 CHAPTER 4 Progress Toward the Total Synthesis of Scabrolide A Figure 4.1.1. Select Examples of Polycyclic Furanobutenolide-Derived Norcembranoid Diterpenes..................................................................................... 318 xxi APPENDIX 6 ........................................................................................................... Spectra Relevant to Chapter 4 Figure A6.1. 1H NMR (500 MHz, CDCl3) of compound 422 ......................................................... 378 Figure A6.2. 13C NMR (126 MHz, CDCl3) of compound 422 ........................................................ 379 Figure A6.3. 1H NMR (500 MHz, CDCl3) of compound ent•416 .................................................. 380 Figure A6.4. 13C NMR (126 MHz, CDCl3) of compound ent•416 ................................................. 381 Figure A6.5. 1H NMR (400 MHz, CDCl3) of compound 423 ......................................................... 382 Figure A6.6. Infrared spectrum (Thin Film, NaCl) of compound 423.............................................. 383 Figure A6.7. 13C NMR (101 MHz, CDCl3) of compound 423 ........................................................ 383 Figure A6.8. 1H NMR (400 MHz, CDCl3) of compound 430 ......................................................... 384 Figure A6.9. 13C NMR (101 MHz, CDCl3) of compound 430 ........................................................ 385 Figure A6.10. 1H NMR (400 MHz, CDCl3) of compound 432 ....................................................... 386 Figure A6.11. Infrared spectrum (Thin Film, NaCl) of compound 432 ............................................ 387 Figure A6.12. 13C NMR (101 MHz, CDCl3) of compound 432 ...................................................... 387 Figure A6.13. 1H NMR (400 MHz, CDCl3) of compound 434 ....................................................... 388 Figure A6.14. Infrared spectrum (Thin Film, NaCl) of compound 434 ............................................ 389 Figure A6.15. 13C NMR (101 MHz, CDCl3) of compound 434 ...................................................... 389 Figure A6.16. 1H NMR (400 MHz, CDCl3) of compound 441 ....................................................... 390 Figure A6.17. Infrared spectrum (Thin Film, NaCl) of compound 441 ............................................ 391 Figure A6.18. 13C NMR (101 MHz, CDCl3) of compound 441 ...................................................... 391 Figure A6.19. 1H NMR (400 MHz, CDCl3) of compound 442 ....................................................... 392 Figure A6.20. Infrared spectrum (Thin Film, NaCl) of compound 442 ............................................ 393 Figure A6.21. 13C NMR (101 MHz, CDCl3) of compound 442 ...................................................... 393 Figure A6.22. 1H NMR (400 MHz, CDCl3) of compound 470 ....................................................... 394 Figure A6.23. Infrared spectrum (Thin Film, NaCl) of compound 470 ............................................ 395 Figure A6.24. 13C NMR (101 MHz, CDCl3) of compound 470 ...................................................... 395 Figure A6.25. 1H NMR (400 MHz, CDCl3) of compound 443 ....................................................... 396 Figure A6.26. Infrared spectrum (Thin Film, NaCl) of compound 443 ............................................ 397 Figure A6.27. 13C NMR (101 MHz, CDCl3) of compound 443 ...................................................... 397 Figure A6.28. 1H NMR (400 MHz, CDCl3) of compound 444 ....................................................... 398 Figure A6.29. Infrared spectrum (Thin Film, NaCl) of compound 444 ............................................ 399 Figure A6.30. 13C NMR (101 MHz, CDCl3) of compound 444 ...................................................... 399 Figure A6.31. 1H NMR (400 MHz, CDCl3) of compound 445 ....................................................... 400 Figure A6.32. Infrared spectrum (Thin Film, NaCl) of compound 445 ............................................ 401 Figure A6.33. 13C NMR (101 MHz, CDCl3) of compound 445 ...................................................... 401 xxii Figure A6.34. 1H NMR (400 MHz, CDCl3) of compound 446 ....................................................... 402 Figure A6.35. Infrared spectrum (Thin Film, NaCl) of compound 446 ............................................ 403 Figure A6.36. 13C NMR (101 MHz, CDCl3) of compound 446 ...................................................... 403 Figure A6.37. 1H NMR (400 MHz, CDCl3) of compound 447 ....................................................... 404 Figure A6.38. Infrared spectrum (Thin Film, NaCl) of compound 447 ............................................ 405 Figure A6.39. 13C NMR (101 MHz, CDCl3) of compound 447 ...................................................... 405 Figure A6.40. 1H NMR (400 MHz, CDCl3) of compound 448 ....................................................... 406 Figure A6.41. Infrared spectrum (Thin Film, NaCl) of compound 448 ............................................ 407 Figure A6.42. 13C NMR (101 MHz, CDCl3) of compound 448 ...................................................... 407 Figure A6.43. 1H NMR (400 MHz, CDCl3) of compound 449 ....................................................... 408 Figure A6.44. Infrared spectrum (Thin Film, NaCl) of compound 449 ............................................ 409 Figure A6.45. 13C NMR (101 MHz, CDCl3) of compound 449 ...................................................... 409 Figure A6.46. 1H NMR (400 MHz, CDCl3) of compound 450 ....................................................... 410 Figure A6.47. Infrared spectrum (Thin Film, NaCl) of compound 450 ............................................ 411 Figure A6.48. 13C NMR (101 MHz, CDCl3) of compound 450 ...................................................... 411 Figure A6.49. 1H NMR (400 MHz, CDCl3) of compound 451 ....................................................... 412 Figure A6.50. Infrared spectrum (Thin Film, NaCl) of compound 451 ............................................ 413 Figure A6.51. 13C NMR (101 MHz, CDCl3) of compound 451 ...................................................... 413 Figure A6.52. 1H NMR (400 MHz, CDCl3) of compound 452 ....................................................... 414 Figure A6.53. Infrared spectrum (Thin Film, NaCl) of compound 452 ............................................ 415 Figure A6.54. 13C NMR (101 MHz, CDCl3) of compound 452 ...................................................... 415 Figure A6.55. 1H NMR (400 MHz, CDCl3) of compound 437 ....................................................... 416 Figure A6.56. Infrared spectrum (Thin Film, NaCl) of compound 437 ............................................ 417 Figure A6.57. 13C NMR (101 MHz, CDCl3) of compound 437 ...................................................... 417 Figure A6.58. 1H NMR (400 MHz, CDCl3) of compound 453 ....................................................... 418 Figure A6.59. Infrared spectrum (Thin Film, NaCl) of compound 453 ............................................ 419 Figure A6.60. 13C NMR (101 MHz, CDCl3) of compound 453 ...................................................... 419 Figure A6.61. 1H NMR (400 MHz, C6D6) of compound 454 ......................................................... 420 Figure A6.62. Infrared spectrum (Thin Film, NaCl) of compound 454 ............................................ 421 Figure A6.63. 13C NMR (101 MHz, C6D6) of compound 454 ........................................................ 421 Figure A6.64. 1H NMR (400 MHz, CDCl3) of compound 455 ....................................................... 422 Figure A6.65. Infrared spectrum (Thin Film, NaCl) of compound 455 ............................................ 423 Figure A6.66. 13C NMR (101 MHz, CDCl3) of compound 455 ...................................................... 423 Figure A6.67. 1H NMR (400 MHz, CDCl3) of compound 458 ....................................................... 424 Figure A6.68. Infrared spectrum (Thin Film, NaCl) of compound 458 ............................................ 425 xxiii Figure A6.69. 13C NMR (101 MHz, CDCl3) of compound 458 ...................................................... 425 Figure A6.70. 1H NMR (400 MHz, CDCl3) of compound 461 ....................................................... 426 Figure A6.71. Infrared spectrum (Thin Film, NaCl) of compound 461 ............................................ 427 Figure A6.72. 13C NMR (101 MHz, CDCl3) of compound 461 ...................................................... 427 Figure A6.73. 1H NMR (400 MHz, CDCl3) of compound 462 ....................................................... 428 Figure A6.74. Infrared spectrum (Thin Film, NaCl) of compound 462 ............................................ 429 Figure A6.75. 13C NMR (101 MHz, CDCl3) of compound 462 ...................................................... 429 Figure A6.76. 1H NMR (400 MHz, CDCl3) of compound 463 ....................................................... 430 Figure A6.77. Infrared spectrum (Thin Film, NaCl) of compound 463 ............................................ 431 Figure A6.78. 13C NMR (101 MHz, CDCl3) of compound 463 ...................................................... 431 Figure A6.79. 1H NMR (400 MHz, CDCl3) of compound 464 ....................................................... 432 Figure A6.80. Infrared spectrum (Thin Film, NaCl) of compound 464 ............................................ 433 Figure A6.81. 13C NMR (101 MHz, CDCl3) of compound 464 ...................................................... 433 Figure A6.82. 1H NMR (400 MHz, CDCl3) of compound 457 ....................................................... 434 Figure A6.83. Infrared spectrum (Thin Film, NaCl) of compound 457 ............................................ 435 Figure A6.84. 13C NMR (101 MHz, CDCl3) of compound 457 ...................................................... 435 Figure A6.85. 1H NMR (400 MHz, CDCl3) of compound 465 ....................................................... 436 Figure A6.86. Infrared spectrum (Thin Film, NaCl) of compound 465 ............................................ 437 Figure A6.87. 13C NMR (101 MHz, CDCl3) of compound 465 ...................................................... 437 Figure A6.88. 1H NMR (400 MHz, CDCl3) of compound 466 ....................................................... 438 Figure A6.89. Infrared spectrum (Thin Film, NaCl) of compound 466 ............................................ 439 Figure A6.90. 13C NMR (101 MHz, CDCl3) of compound 466 ...................................................... 439 Figure A6.91. 1H NMR (400 MHz, CDCl3) of compound 456 ....................................................... 440 Figure A6.92. Infrared spectrum (Thin Film, NaCl) of compound 456 ............................................ 441 Figure A6.93. 13C NMR (101 MHz, CDCl3) of compound 456 ...................................................... 441 Figure A6.94. 1H NMR (400 MHz, CDCl3) of compound 468 ....................................................... 442 Figure A6.95. Infrared spectrum (Thin Film, NaCl) of compound 468 ............................................ 443 Figure A6.96. 13C NMR (101 MHz, CDCl3) of compound 468 ...................................................... 443 APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 4 Figure A7.1.1. X-Ray Crystal Structure of Tetracycle 452 .............................................................. 445 Figure A7.2.1. X-Ray Crystal Structure of Cyclobutane 465........................................................... 465 Figure A7.3.1. X-Ray Crystal Structure of Cyclobutane 466........................................................... 485 xxiv Figure A7.4.1. X-Ray Crystal Structure of Cycloheptane 468 ......................................................... 503 APPENDIX 9 Spectra Relevant to Appendix 8 Figure A9.1. 1H NMR (400 MHz, CDCl3) of compound 476 ......................................................... 540 Figure A9.2. Infrared spectrum (Thin Film, NaCl) of compound 476.............................................. 541 Figure A9.3. 13C NMR (101 MHz, CDCl3) of compound 476 ........................................................ 541 Figure A9.4. 1H NMR (400 MHz, CDCl3) of compound 475 ......................................................... 542 Figure A9.5. Infrared spectrum (Thin Film, NaCl) of compound 475.............................................. 543 Figure A9.6. 13C NMR (101 MHz, CDCl3) of compound 475 ........................................................ 543 Figure A9.7. 1H NMR (400 MHz, CDCl3) of compound 473 ......................................................... 544 Figure A9.8. 13C NMR (101 MHz, CDCl3) of compound 473 ........................................................ 545 xxv LIST OF SCHEMES CHAPTER 1 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Scheme 1.2.1. Zimmerman-Traxler Transition States for Aldol Reactions of (Z)- and (E)-Enolates .....................................................................4 Scheme 1.2.1.1. Ireland’s Model for Selective Enolate Geometry Formation ......................................5 Scheme 1.2.1.2. Selective Ester Enolate Isomer Formation ................................................................6 Scheme 1.2.2.1. Standard Conditions for Silyl Enol Ether Formation ..................................................8 Scheme 1.2.4.1. Common Methods to Form Transition Metal Enolates............................................ 11 Scheme 1.2.4.2. Equilibrium Between Transition Metal Enolate Coordination Sites .......................... 12 Scheme 1.3.4.1. Proposed Catalytic Cycle of Scandium-Catalyzed Aldol Reaction........................... 16 Scheme 1.3.5.1. Transition State and Substrate Scope of Aldol Reaction of Aldehydes and Stereochemically Defined Tetrasubstituted Enol Borinates ............................... 18 Scheme 1.4.5.1. Nickel-Catalyzed Asymmetric Reaction................................................................ 23 Scheme 1.5.2.1. Cobalt-Catalyzed Asymmetric Michael Reaction Reported by Brunner and Hammer..................................................................................... 27 Scheme 1.5.2.2. Cobalt-Catalyzed Asymmetric Michael Reaction Reported by Botteghi and Boga.......................................................................................... 28 Scheme 1.5.3.1. Nickel-Catalyzed Asymmetric Michael Reaction................................................... 29 Scheme 1.5.7.1. Lanthanum-BINOL Complex-Catalyzed Asymmetric Michael Reaction .................. 37 Scheme 1.5.9.1. The First Palladium Catalyzed Asymmetric Michael Reaction Forming Quaternary Centers ............................................................................... 42 Scheme 1.5.9.2. Palladium N-Heterocyclic Carbene Diaqua Complexes in Asymmetric Michael Reaction of b-Ketoesters and Methyl Vinyl Ketone.................................... 45 Scheme 1.5.11.1. Calcium-Octahydro-BINOL Complex-Catalyzed Asymmetric Michael Reaction ............................................................................................. 50 Scheme 1.6.2.1. Palladium Catalyzed Asymmetric Allylic Alkylation of Non-Stabilized Enolates Bearing Other Enolizable Positions Reported by Stoltz and Coworkers.................... 52 Scheme 1.6.2.2. Proposed Mechanism of the Palladium-Catalyzed Asymmetric Allylic Alkylation Reaction ............................................................................................ 53 Scheme 1.6.2.3. Asymmetric Allylic Alkylation of Cyclobutanones and Protected Lactams ............... 54 xxvi Scheme 1.7.2.1. Asymmetric Alkylation of Cyclic Lithium Enolates Utilizing Tetradentate Amine Ligands ................................................................................ 66 Scheme 1.7.2.2. Asymmetric Alkylation of Acyclic Acids Using Tetradentate Amines....................... 67 Scheme. 1.8.1.1. a-Arylation In the Synthesis of Cephalotaxinone (218) .......................................... 67 Scheme 1.8.2.1. NHC-Palladium Complex-Catalyzed Intramolecular a-Arylation ............................ 75 Scheme 1.8.2.2. Palladium-Catalyzed Intramolecular a-Arylation of Aldehydes Reported by Buchwald and Coworkers............................................................................... 77 Scheme 1.8.2.3. Palladium-Catalyzed Asymmetric a-Arylation of Ketones Using Aryl Triflates.......... 79 Scheme 1.8.3.1. Nickel-Catalyzed Asymmetric a-Arylation of Indanones ........................................ 80 Scheme 1.8.4.1. Copper-Catalyzed Asymmetric a-Arylation Reported by Ma and Coworkers ........... 84 Scheme 1.9.1.1. Corey’s Synthesis of (+)-b-Elemene ...................................................................... 85 Scheme 1.9.1.2. Enantioselective Ireland-Claisen Rearrangement in Corey’s Synthesis of Dolabellatrienone ........................................................................................... 85 Scheme 1.9.1.3. Asymmetric Claisen-Type Reaction Using Aluminum Reported by Krebs and Kazmaier ............................................................................................ 86 Scheme 1.9.1.4. Generic Asymmetric Ketene-Claisen Rearrangement ............................................. 87 Scheme. 1.9.1.5. Asymmetric Ketene-Claisen Rearrangement ......................................................... 88 Scheme 1.9.2.1. Mechanism of the Conia-Ene Reaction ................................................................. 88 Scheme 1.9.2.2. Proposed Mechanism of Copper-Catalyzed Asymmetric Conia-Ene Reaction .......... 91 Scheme 1.9.2.3. Use of Cooperative Catalysis in the Asymmetric Conia-Ene Reaction...................... 92 Scheme 1.9.2.4. Iron-Catalyzed Asymmetric Conia-Ene Reported by Shaw and White ..................... 93 CHAPTER 2 Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones Scheme 2.1.1. Cyclic Ketone Substrates in Transition Metal-Catalyzed Enantioselective Decarboxylative Allylic Alkylation ............................................... 110 Scheme 2.3.1. Substrate Scope of Cyclopentanone Substitution in Enantioselective Allylic Alkylation ........................................................................ 116 Scheme. 2.3.2 Enantioselective Allylic Alkylation of Indanone Substrates ..................................... 117 Scheme 2.3.3. Enantioselective Allylic Alkylation of Cyclopentanone Substrates with 2-Substituted Allyl Fragments ........................................................ 117 Scheme 2.4.1. Low Catalyst Loading Palladium(II)-Catalyzed Enantioselective Allylic Alkylation ........................................................................ 118 xxvii CHAPTER 3 Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme Scheme 3.2.1. Retrosynthetic Analysis of Nigelladine A ............................................................... 220 Scheme 3.3.1. Synthesis of Asymmetric Allylic Alkylation Precursor ............................................. 221 Scheme 3.3.2. Synthesis of Electrophilic Cross-Coupling Fragment ............................................... 221 Scheme 3.3.3. Synthesis of the Nucleophilic Cross-Coupling Fragment ......................................... 222 Scheme 3.4.1. Cross-Coupling of Dienone 391 and Vinyl Boronic Ester 390 ................................. 223 Scheme 3.4.2. Synthesis of the Tricyclic Core of Nigelladine A ..................................................... 224 Scheme. 3.6.1. Completion of the Synthesis of Nigelladine A ....................................................... 228 APPENDIX 2 Synthetic Summary of Chapter 3 Scheme A2.1. Synthetic Summary for Construction of Nigelladine A 385 ...................................... 257 CHAPTER 4 Progress Toward the Total Synthesis of Scabrolide A Scheme 4.2.1. Retrosynthetic Analysis of Scabrolide A via Transannular Diels–Alder ..................... 319 Scheme 4.3.1. Synthesis of Carvone Isocarvone........................................................................... 319 Scheme. 4.3.2. Synthesis of Alkyne 423 from Carvone ................................................................. 320 Scheme 4.3.3. 1st Generation Synthesis of Cyclopentenyl Diol ent•415 ........................................ 321 Scheme 4.4.1. Convergent Coupling of RCM Precursor 430 ......................................................... 322 Scheme 4.4.2. Ring-Closing Metathesis of Ester 430..................................................................... 323 Scheme 4.4.3. Intramolecular Diels–Alder of Ester 430 ................................................................ 324 Scheme 4.5.1. 2nd Generation Retrosynthetic Analysis of Scabrolide A .......................................... 324 Scheme 4.5.2. Development of Modified Synthesis of Diol 415 .................................................... 325 Scheme 4.6.1. Terpene-Derived Synthesis Toward Diol 415......................................................... 326 Scheme 4.6.2. Synthesis of Cyclopentene Diol 415 ..................................................................... 326 Scheme 4.7.1. Synthesis of Methyl Ketone Diels–Alder Precursor ................................................. 327 Scheme 4.8.1. Unexpected Aldol Condensation of Tricycle 450 ................................................... 328 Scheme 4.8.2. Selective Oxidation of Deprotected Tricycle 437 ................................................... 329 xxviii Scheme 4.9.1. 3rd Generation Retrosynthetic Analysis Utilizing Energy of a Strained Cyclobutane Ring......................................................................................................... 330 Scheme 4.10.1. Convergent Esterification of Diol 415 and Ester 460 ............................................. 330 Scheme 4.10.2. Diels–Alder and Oxidation of Model System 458................................................. 331 Scheme 4.11.1. [2+2] Cyclization of Enone 457 .......................................................................... 332 Scheme 4.11.2. Ring Expansion of Cyclobutanol 466 .................................................................. 333 Scheme. 4.12.1. Future Directions Toward the Completion of Scabrolide A................................... 334 APPENDIX 5 Synthetic Summary for Chapter 4 Scheme A5.1. Synthetic Summary for Construction of Tricycle 434............................................... 373 Scheme A5.2. Synthetic Summary for 2nd Generation Synthesis of Diol 415................................... 374 Scheme A5.3 Synthetic Summary for Undesired Aldol Products 451 and 452 ................................ 375 Scheme A5.4 Synthetic Summary for Late-Stage Functionalization of Diels–Alder Adduct 453 ....................................................................................... 375 Scheme A5.5 Synthetic Summary for Ring Expansion Model System 458....................................... 376 APPENDIX 8 Alternative Strategy Toward the Total Synthesis of Scabrolide A Scheme A8.1.1. Retrosynthetic Analysis of Scabrolide A .............................................................. 530 Scheme A8.2.1. Derivatization of Weinreb Amide ent•422 to Carbamate 475 .............................. 530 Scheme A8.3.1. Coupling of Carbamate 475 and Aldehyde 444 ................................................... 531 xxix LIST OF TABLES CHAPTER 1 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.2.3.1. Enolate Selectivity Due to Leaving Group, Alkyl Substituents, and Amine Base .................................................................................................... 10 Table 1.3.2.1. Substrate Scope of Rhodium-Catalyzed Aldol Reaction ............................................. 13 Table 1.3.3.1 Scope of Nickel-Catalyzed Hydroxymethylation Reaction of Substituted b-Ketoesters ........................................................................................... 15 Table 1.3.4.1. Substrate Scope of Scandium-Catalyzed Asymmetric Aldol Reaction ......................... 16 Table 1.3.4.2. Scope of Neodymium-Catalyzed Asymmetric Aldol Reaction .................................... 17 Table 1.4.2.1. Substrate Scope of Copper-Catalyzed Asymmetric Mannich Reaction ........................ 19 Table 1.4.3.1. Scope of Palladium-Catalyzed Asymmetric Mannich Reaction Reported by Sodeoka, and Coworkers ................................................................................... 20 Table 1.4.3.2. Scope of Palladium-Catalyzed Mannich Reaction Reported by Kim and Coworkers ............................................................................................... 21 Table 1.4.3.3. Palladium-Catalyzed Mannich Reaction Reported by Shi and Coworkers ................... 22 Table 1.4.4.1. Scandium-Catalyzed Asymmetric Mannich Reaction ................................................ 23 Table 1.4.6.1 Scope of Lithium BINOLate-Catalyzed Asymmetric Mannich Reaction ....................... 24 Table 1.4.7.1. Scope of Calcium-Catalyzed Asymmetric Mannich Reaction..................................... 25 Table 1.5.3.1. Scope of Nickel-Diamine Catalyzed Asymmetric Michael Reaction ........................... 30 Table 1.5.3.2. Scope of Nickel-Diamine Catalyzed Conjugate Addition of 3-Substituted Oxindoles and Nitroolefins .................................................................................... 31 Table 1.5.4.1. Copper(II)-Catalyzed Reaction of Methyl Vinyl Ketone and Methyl 1-Oxo-2-Indanecarboxylate .................................................................................... 32 Table 1.5.6.1. Scope of the First Asymmetric Michael Reaction using Chiral Rhodium Catalysts................................................................................................. 33 Table1.5.6.2. Rhodium-Catalyzed Asymmetric Michael Reaction of a-Cyano Weinreb Amides....................................................................................... 34 Table 1.5.6.3. Scope of Rhodium-Catalyzed Asymmetric Michael Reaction of a-Cyanocarboxylates .......................................................................................... 35 Table 1.5.6.4. First Example of Rhodium-Catalyzed Asymmetric Michael Reaction with b-Ketoesters ..................................................................................... 36 xxx Table 1.5.7.1. LSB-Catalyzed Asymmetric Michael Reaction .......................................................... 38 Table 1.5.7.2. Lanthanum NR-Linked-BINOL-Catalyzed Asymmetric Michael Reaction ................... 40 Table 1.5.7.3. Scope of Michael Reaction of Cyclic b-Ketoesters and Methyl Vinyl Ketone Using Podand-Type Alkali Metal 2’-Substituted 1,1’-Binaphthalene-2-Oxides ............. 41 Table 1.5.9.1. Palladium Pincer Complex-Catalyzed Asymmetric Michael Reaction......................... 43 Table 1.5.9.2. Palladium-Catalyzed Michael Reaction Reported by Sodeoka and Coworkers ............ 44 Table 1.5.9.3. Palladium Diaqua Complex-Catalyzed Michael Reaction with o-Quinone Methides ............................................................................................. 46 Table 1.5.10.1. Chiral Scandium-N,N’-Dioxide-Catalyzed Asymmetric Michael Reaction ................ 48 Table 1.5.10.2. Asymmetric Michael Reaction of 4-Substituted-5-Pyrazolones and 1,4-Dicarbonyl But-2-enes ................................................................................... 49 Table 1.5.12.1. Homodinuclear Manganese-Schiff Base Complex-Catalyzed Conjugate Addition Reaction................................................................................ 51 Table 1.6.2.1. Asymmetric Allylic Alkylation of b-Ketoesters Using LDA, Palladium, and the Trost Ligand ..................................................................................................... 56 Table 1.6.2.2. Formation of Aryl Substituted Cyclic Ketones Using NaHMDS, Allylpalladium(II) Chloride Dimer, a Trost Ligand, and Allyl Acetate .......................... 57 Table 1.6.2.3. Asymmetric Allylic Alkylation of Lithium Enolates in the Presence of a Tin Lewis Acid, Palladium Source, and a Trost Ligand ........................................ 57 Table 1.6.2.4. 3-Aryloxindoles In the Asymmetric Allylic Alkylation Reaction.................................. 58 Table 1.6.2.5. Allyl Enol Carbonates In the Asymmetric Allylic Alkylation Reaction Using Trost Ligand 182 ........................................................................................... 59 Table 1.6.3.1. Molybdenum-Catalyzed Asymmetric Allylic Alkylation ............................................ 60 Table 1.6.4.1. Iridium-Catalyzed Intramolecular Allylic Alkylation Generating Six-Membered Rings............................................................................................... 61 Table 1.6.4.2. Iridium-Catalyzed Intramolecular Allylic Alkylation Generating Five-Membered Rings ............................................................................................. 61 Table 1.6.4.3 Intermolecular Iridium-Catalyzed Allylic Alkylation to Generate Compounds Bearing Vicinal Quaternary and Tertiary Stereocenters ............................ 62 Table 1.6.5.1. Scope of the Rhodium-Catalyzed Asymmetric Allylic Alkylation of Acyclic Aldehydes .............................................................................................. 64 Table 1.7.1.1. Scope of Asymmetric Alkylation of Cyclic Tin Enolates Using Chromium Complexes ............................................................................................ 65 Table 1.7.1.2. Scope of Asymmetric Alkylation of Acyclic Tine Enolates Using Chromium Complexes .................................................................................. 65 xxxi Table 1.8.2.1. Scope of Palladium BINAP-Catalyzed a-Arylation Reaction....................................... 68 Table 1.8.2.2. Scope of Palladium-Catalyzed a-Vinylation Reaction ............................................... 70 Table 1.8.2.3. Scope of Palladium MOP-Derived Ligand-Catalyzed a-Arylation .............................. 71 Table 1.8.2.4. Scope of Palladium P-Chirogenic Binaphthyl Monophosphine Ligand-Catalyzed a-Arylation and a-Vinylation Reactions ........................................ 71 Table 1.8.2.5. Scope of Palladium-Catalyzed a-Arylation and a-Vinylation of 3-Substituted Oxindoles ......................................................................................... 72 Table 1.8.2.6. Scope of Palladium-Catalyzed Intramolecular a-Arylation Reaction to Form Oxindoles.................................................................................... 73 Table 1.8.2.7. Scope of Palladium Carbene Ligand-Catalyzed Intramolecular a-Arylation Reaction to Form Oxindoles .................................................................. 74 Table 1.8.2.8. Ligand Screen for Palladium-Catalyzed Intramolecular a-Arylation Reaction Reported by Kündig and Coworkers ........................................................... 76 Table 1.8.2.9. Scope of Asymmetric Intramolecular a-arylation of Aldehydes Forming Indanes ......... 78 Table 1.8.3.1. Nickel-Catalyzed Intermolecular a-Heteroarylation of Cyclic Ketones ....................... 81 Table 1.8.3.2. Asymmetric a-Arylation of Lactones Using Nickel BINAP Catalysts ........................... 82 Table 1.8.3.3. Asymmetric Nickel Catalyzed a-Arylation Reaction Using P-Phos Ligand .................. 83 Table 1.9.2.1. Scope of Palladium DTBM-SEGPHOS 64 Catalyzed Conia-Ene Reaction ................... 89 Table 1.9.2.2. Scope of Copper-Catalyzed Asymmetric Conia-Ene Reaction ................................... 90 CHAPTER 2 Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones Table 2.2.1. PHOX Ligand Screen .............................................................................................. 112 Table 2.2.2. Solvent Effect on Enantiomeric Excess of Cyclopentanone Product (S)-332 .................. 114 CHAPTER 3 Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme Table 3.5.1. Attempted Chemical Oxidations .............................................................................. 225 Table 3.6.1. Screening of Focused Library for Allylic Oxidation .................................................... 227 Table 3.8.5.1. Oxidations of Imine 389....................................................................................... 248 xxxii Table 3.8.5.2. Oxidations of Enone 397 ...................................................................................... 249 Table 3.8.6.1.Comparison of Synthetic and Natural Nigelladine A ................................................ 250 APPENDIX 4 X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.1.Experimental Details for X-Ray Structure Determination of Triene 401....................... 287 Table A4.1.2.Crystal Data and Structure Refinement for Triene 401 .............................................. 288 Table A4.1.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Triene 401 ....................................................................... 289 Table A4.1.4. Bond Lengths [Å] and angles [°] for Triene 401 ....................................................... 291 Table A4.1.5. Anisotropic Displacement Parameters (Å2x103) for Triene 401.................................. 306 Table A4.1.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Triene 401 ......................................................................................... 308 Table A4.1.7. Torsion Angles [°] for Triene 401 ........................................................................... 311 Table A4.1.8. Hydrogen Bonds for Triene 401 [Å and °] .............................................................. 315 APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.1.1. Experimental Details for X-Ray Structure Determination of Tetracycle 452 ................ 446 Table A7.1.2. Crystal Data and Structure Refinement for Tetracycle 452........................................ 447 Table A.7.1.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Tetracycle 452 ................................................................. 448 Table A7.1.4. Bond Lengths [Å] and angles [°] for Tetracycle 452 ................................................. 450 Table A7.1.5. Anisotropic Displacement Parameters (Å2x103) for Tetracycle 452............................ 457 Table A7.1.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Tetracycle 452 .................................................................................... 459 Table A7.1.7. Torsion Angles [°] for Tetracycle 452 ..................................................................... 461 Table A7.1.8. Hydrogen Bonds for Tetracycle 452 [Å and °]......................................................... 464 Figure A7.2.1. X-Ray Crystal Structure of Cyclobutane 465........................................................... 466 Table A7.2.2.Crystal Data and Structure Refinement for Cyclobutane 465 ..................................... 467 Table A.7.2.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Cyclobutane 465 ........................................ 468 Table A7.2.4. Bond Lengths [Å] and angles [°] for Cyclobutane 465.............................................. 470 xxxiii Table A7.2.5. Anisotropic Displacement Parameters (Å2x103) for Cyclobutane 465 ........................ 476 Table A7.2.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Cyclobutane 465 ................................................................................ 478 Table A7.2.7. Torsion Angles [°] for Cyclobutane 465.................................................................. 480 Table A7.2.8. Hydrogen Bonds for Cyclobutane 465 [Å and °] ..................................................... 484 Table A7.3.1. Experimental Details for X-Ray Structure Determination of Cyclobutane 466.................................................................................................. 486 Table A7.3.2.Crystal Data and Structure Refinement for Cyclobutane 466 ..................................... 487 Table A.7.3.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Cyclobutane 466 .............................................................................. 488 Table A7.3.4. Bond Lengths [Å] and angles [°] for Cycloheptane 466 ............................................ 490 Table A7.3.5. Anisotropic Displacement Parameters (Å2x103) for Cyclobutane 466 ........................ 496 Table A7.3.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Cyclobutane 466 ................................................................................ 497 Table A7.3.7. Torsion Angles [°] for Cyclobutane 466.................................................................. 499 Table A7.3.8. Hydrogen Bonds for Cyclobutane 466 [Å and °] ..................................................... 502 Table A7.4.1. Experimental Details for X-Ray Structure Determination of Cyclobutane 468.................................................................................................. 504 Table A7.4.2. Crystal Data and Structure Refinement for Cycloheptane 468 .................................. 505 Table A.7.4.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Cycloheptane 468 ........................................................... 506 Table A7.4.4. Bond Lengths [Å] and angles [°] for Cycloheptane 468 ............................................ 508 Table A7.4.5. Anisotropic Displacement Parameters (Å2x103) for Cycloheptane 468....................... 518 Table A7.4.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Cycloheptane 468 .............................................................................. 520 Table A7.4.7. Torsion Angles [°] for Cycloheptane 468 ................................................................ 522 Table A7.4.8. Hydrogen Bonds for Cycloheptane 468 [Å and °].................................................... 527 APPENDIX 10 Notebook Cross-Reference for New Compounds Table A10.2.1. Notebook Cross-Reference For Compounds in Chapter 2 ...................................... 546 Table A10.2.2. Notebook Cross-Reference For Compounds in Chapter 3 ...................................... 548 Table A10.2.3. Notebook Cross-Reference For Compounds in Chapter 4 ...................................... 549 Table A10.2.4. Notebook Cross-Reference For Compounds in Appendix 8 .................................... 551 xxxiv LIST OF ABBREVIATIONS [a]D specific rotation at wavelength of sodium D line °C degrees Celsius Å Ångstrom Ac acetyl Acac acetylacetonate AcOH acetic acid ADH alcohol dehydrogenase Adm adamantyl ALB aluminum-lanthanum-BINOL complex All allyl An anisole APCI atmospheric pressure chemical ionization app apparent aq aqueous Ar aryl atm atmosphere BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BINOL 1,1-binaphthol bmim 1-Butyl-3-methylimidazolium Bn benzyl Boc tert-butyloxycarbonyl BOX bis(oxazoline) bp boiling point br broad xxxv Bu butyl Bz benzoyl c concentration for specific rotation measurements (g/100 mL) ca. about (Latin circa) calc’d calculated cat catalytic CDI 1,1'-carbonyldiimidazole cm–1 wavenumber(s) cod 1,5-cyclooctadiene Cp cyclopentadienyl Cp* pentamethyl-cyclopentadienyl CSA camphorsulfonic acid Cy cyclohexyl d doublet D deuterium DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N'-Dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIBAL diisobutylaluminum hydride DIC N,N′-Diisopropylcarbodiimide DIFLUORPHOS 5,5'-Bis(diphenylphosphino)-2,2,2',2'-tetrafluoro4,4'-bi-1,3-benzodioxole xxxvi DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine dmdba bis(3,5-dimethoxybenzylidene)acetone DMDO dimethyldioxirane DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMP Dess–Martin periodinane DMPU N, N′-Dimethylpropyleneurea DMS dimethyl sulfide DMSO dimethyl sulfoxide DPPA diphenyl phosphoryl azide dr diastereomeric ratio DTBM di-t-butyl-methoxy e.g. for example (Latin exempli gratia) EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ee enantiomeric excess EI+ electron impact equiv equivalent(s) ESI electrospray ionization Et ethyl EtOAc ethyl acetate EWG electron withdrawing group FAB fast atom bombardment Fu furanyl g gram(s) xxxvii G-I Grubbs catalyst 1st generation G-II Grubbs catalyst 2nd generation GC gas chromatography gCOSY gradient-selected correlation spectroscopy h hour(s) HG-II Hoveyda-Grubbs catalyst 2nd generation hmim 2-methylimidazole HMBC heteronuclear multiple bond correlation HMDS 1,1,1,3,3,3-hexamethyldisilazane HMPA hexamethylphosphoramide (HMPT) HPLC high-performance liquid chromatography HRMS high-resolution mass spectroscopy HSQC heteronuclear single quantum correlation Hz hertz hn light i- iso- i-Pr isopropyl i.e. that is (Latin id est) IBX 2-iodoxybenzoic acid IL-6 interleukin 6 IPA isopropanol, 2-propanol Ipc diisopinocampheyl IR infrared (spectroscopy) J coupling constant K Kelvin(s) (absolute temperature) kcal kilocalorie KPi potassium phosphate xxxviii L liter; ligand L* chiral ligand LDA lithium diisopropylamide LG leaving group lit. literature value LSB lanthanum-sodium-BINOL m multiplet; milli m meta M metal; molar; molecular ion; Mega m-CPBA meta-chloroperoxybenzoic acid m/z mass to charge ratio Me methyl mg milligram(s) min minute(s) MM mixed method MOC methoxycarbonyl mol mole(s) MOP 2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl mp melting point Ms methanesulfonyl (mesyl) MS molecular sieves MTBE methyl tert-butyl ether n nano N normal n- normal- NADP nicotinamide adenine dinucleotide phosphate Naph naphthyl xxxix NBS N-bromosuccinimide NHC N-heterocyclic carbene NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance Nu nucleophile o ortho p para P450 cytochrome P450 Pd/C palladium on carbon pen pentyl Ph phenyl pH hydrogen ion concentration in aqueous solution PHOX phosphinooxazoline Pin 2,3-dimethylbutane-2,3-diol (pinacol) Piv trimethylacetyl, pivaloyl pKa pK for association of an acid pmdba bis(4-methoxybenzylidene)acetone PMP para-methoxy phenyl ppm parts per million PPTS pyridinium p-toluenesulfonate Pr propyl Proton sponge 1,8-bis(dimethylamino)naphthalene Py pyridine q quartet R generic for any atom or functional group RCM ring-closing metathesis Ref. reference xl Rf retention factor RRCM relay ring-closing metathesis s singlet s- sec- sat. saturated SEGPHOS 5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3benzodioxole SFC supercritical fluid chromatography Solv solvent t triplet t- tert- T-Hydro 70% TBHP in water TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBAT tetrabutylammonium difluorotriphenylsilicate TBD 1,3,4-triazabicyclo[4.4.0]dec-5-ene TBDPS tert-butyldiphenylsilyl TBHP tert-butyl hydroperoxide TBS tert-butyldimethylsilyl TES triethylsilyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFE 2,2,2-trifluoroethanol THF tetrahydrofuran TIPS triisopropylsilyl TLC thin-layer chromatography xli TMEDA N,N,N’,N’-tetramethylethylenediamine TMS trimethylsilyl TMP tetramethylpiperidine TOF time-of-flight Tol tolyl tR retention time TRAP 2,2"-bis[1 -(diphenylphosphino)ethyl]-1,1"biferrocene TRIS tris(hydroxymethyl)aminomethane Ts p-toluenesulfonyl (tosyl) UV ultraviolet v/v volume to volume Val valine w weak w/v weight to volume X anionic ligand or halide XPhos 2-dicyclohexylphosphino-2′,4′,6′triisopropylbiphenyl l wavelength µ micro Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 1 CHAPTER 1 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates† 1.1 INTRODUCTION By definition, a quaternary center is a carbon atom bonded to four other carbon atoms by single bonds.1,2 Due to the multitude of names for quaternary centers—all-carbon quaternary centers, all-carbon quaternary carbon, quaternary compound, and quaternary carbon—some functional groups have been falsely labeled as quaternary centers in the literature. Common moieties that are misrepresented as quaternary centers include tertiary alcohols (1) and tertiary centers bonded to other heteroatoms (2,3). Quaternary centers as used in this chapter must have the general structure of compound 4, where R1–R4 are any carbon substituted group (Figure 1.1.1). † This research was performed in collaboration with Katerina Korch, an alumni of the Stoltz group. Additionally, this research has been published and adapted with permission Korch, K. M., Loskot, S. A. and Stoltz, B. M. (2017). Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates. In PATAI'S Chemistry of Functional Groups, Z. Rappoport (Ed.). doi:10.1002/9780470682531.pat0858 2 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Figure 1.1.1. Commonly Mislabeled Tetrasubstituted C-Centers R2 R2 R1 R3 OH R1 R3 NH2 R2 R2 R3 R1 R1 X R3 R4 Tertiary Alcohol Tertiary Center Tertiary Halide Quaternary Center 1 2 3 4 Tetrasubstituted Tertiary Centers Quaternary Center The ubiquitous nature of quaternary centers in pharmaceuticals and biologically active natural products (5–7) creates the need for their efficient and stereoselective synthesis.3 Because of their significance, the synthesis of chiral quaternary centers has garnered much attention in chemical research (Figure 1.1.2). Although great advances have been made, quaternary center synthesis remains an active research topic due to the difficulty of synthesizing and functionalizing these centers.4 Figure 1.1.2. Natural Products Containing Quaternary Centers Possessing Potent Biological Activities OH N OH H N H MeO2C HO O H OAc N H Vinblastine (5) Chemotherapuetic CO2Me O O HO O O O AcO N H H O O Pleuromutilin (6) Antibiotic O O Wortmannin (7) Potent PI3K inhibitor Since all the substituents on a quaternary center are carbon-linked, there is a large steric encumbrance during the C–C bond-forming event compared to less substituted centers. Elevated steric congestion creates high-energy transition states that must be overcome with the use of harsh forcing conditions or catalytic methods. To accomplish this stereospecificity, an endogenous (e.g., chiral auxiliary) or exogenous (e.g., chiral catalyst) chiral source is needed. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 3 In most cases, metal enolates are sufficiently strong nucleophiles to overcome the energy barrier required to form sterically hindered quaternary centers. Because of this, metal enolates are commonly employed in the asymmetric formation of quaternary centers at the a-position of a ketone, aldehyde, ester, or amide (a-quaternary centers). Moreover, enolates strongly coordinate with Lewis acids, thereby facilitating stereoinduction through the use of chiral Lewis acids. This chapter will review common methods to prepare metal enolates and, more importantly, the stereoselective synthesis of a-quaternary centers that they facilitate. 1.2 ENOLATE TYPES AND THEIR FORMATION The most common method used to form enolates is through the a-deprotonation of a carbonyl compound. With an asymmetric ketone in hand, a regioselective deprotonation can occur depending on the conditions used.5 If the reaction is performed at low, typically below 0 °C, in aprotic ethereal solvents, and over short reaction times, deprotonation will occur at the most accessible position (i.e., lowest transition state energy) to obtain the socalled ‘kinetic’ enolate. On the other hand, if the deprotonation is performed at warmer temperatures, in protic solvents, and over increased reaction times, the deprotonation is allowed to reach equilibrium and will form the thermodynamically stable enolate. Other factors must be taken into account when considering the stereoselectivity in enolate formation. Metal enolates can exist in either the (Z)- or (E)- configuration (8 and 9 respectively, Scheme 1.2.1). Each stereoisomer has its own unique steric and electronic characteristics that dictate reactivity. Over the past several decades, the conditions needed to dictate enolate geometry have been extensively studied, particularly for the 4 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates diastereoselective aldol reaction.6 Both enolates form different Zimmerman–Traxler transition states, in order to minimize 1,3-diaxial interactions (10 and 11), ultimately resulting in the production of syn- (12) and anti- (13) diastereomers. Thermodynamic enolates predominantly exist in the Z conformation excluding the small- and mid-sized rings, in order to minimize A1,3-strain.7 Kinetic enolates, on the other hand, depend on an array of variables, including base, solvent, counterion, co-solvents, and various additives. Scheme 1.2.1. Zimmerman-Traxler Transition States for Aldol Reactions of (Z)- and (E)-Enolates R1 H H R2 Me favored OML2 Me R1 L O M L O R2CHO (Z)-enolate OH R1 R2 Me syn 12 10 L R1 R2 M L O H O H Me 8 O O OH R1 R2 Me anti disfavored 13 R1 H Me R2CHO R1 R2 O OH R1 R2 favored Me anti 11 ent•12 H OML2 L O M L O Me (E)-enolate 9 Me H L R1 R2 O M L O H disfavored O OH R1 R2 Me syn ent•13 1.2.1 ALKALI AND ALKALINE EARTH METAL ENOLATES Alkali metal bases are one of the most common reagents used to form kinetic enolates. Typical conditions employ subzero temperatures (–78 °C), ethereal solvents, and 5 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates strong amide bases or metal hydrides. Common alkali bases include lithium diisopropylamide (LDA), lithium hexamethyldisilazide (LiHMDS), lithium 2,2,6,6tetramethylpiperidide (LiTMP), lithium t-butyl-t-octyl amide (LOBA), lithium bis(dimethylphenylsilyl)amide, and N-t-butyl-N-tritylamide, as well as their sodium and potassium analogs. The first model used to describe the inherent selectivity of enolate formation was postulated by Ireland in 1975,8 and stated that the deprotonation occurred through a closed, chair-like transition state (Scheme 1.2.1.1). Ireland demonstrated that treating ketones 14 with strong bases LiNR22 can result in two potential closed transition states. When R1 is small and R2 is large, the steric interaction between R2 and the methyl (Me) is greater than the interaction between R1 and Me (transition state 15). Consequently, the (E)-enolate 16, is favored. On the other hand if R2 is small and R1 is large, the steric interaction between R1 and Me is greater than the interaction between R2 and Me (transition state 17), and the (Z)-enolate 18 is favored. Scheme 1.2.1.1. Ireland’s Model for Selective Enolate Geometry Formation H R2 R1 O Me Li N OLi R1 H Me R2 O Me R1 16 15 LiNR22 14 Me R2 O OLi H Li N R1 H R2 Me R1 18 17 While the Ireland model is predictive for most systems, it is important to realize that it is a simple model. In reality, lithium amide bases can form aggregates in solutions; 6 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates usually di-, tetra-, or hexameric structures.9 Treatment of esters (e.g. 19) and amides, with a strong alkali base, tends to result in the E- (20) and Z-enolates (21), respectively. It is possible, however, to reverse the selectivity of esters by adding a strong solvating cosolvent (i.e., HMPA), which can reverse this trend by disturbing the aggregates (Scheme 1.2.1.2), albeit with diminished selectivity.10 Scheme 1.2.1.2. Selective Ester Enolate Isomer Formation. O LDA, TBSCl OMe THF, –78 °C OMe OTBS E-20 19 O LDA, TBSCl OMe 23% HMPA-THF –78 °C 19 OTBS + OMe 91:9 OMe Z-21 OTBS + OTBS E-20 OMe 16:84 Z-21 While alkali metal (Group 1) enolates are commonly used, their counterparts, alkali earth metal (Group 2) enolates, are far less common, largely due to their attenuated reactivity. These enolates can be formed by the same methods as the alkali enolates, using strong basic amides like bromomagnesium diisopropylamide.11 Other methods of alkaline earth metal enolate formation include the transmetalation of lithium enolate by addition of a magnesium(II) salt,12 the Cu-catalyzed conjugate addition of a Grignard reagent to an a,b-unsaturated ketone,13 or the insertion into an a-bromoketone.14 1.2.2 SILYL ENOL ETHERS Silyl enol ethers are considered masked enolate equivalents. The increased stability allows these trapped or protected enolates to be carried through multiple steps in a synthesis.15 Another advantage is that silyl enol ether can be purified by distillation or column chromatography over neutralized silica. Because of the versatility of silyl enol ethers, chemists have developed various methods for their synthesis, under a variety of Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 7 conditions, using a wide range of silyl sources (Scheme 1.2.2.1). These methods include silylation of enolates,16 silylation of enols,17 hydrosilylation of a,b unsaturated ketones,17 trapping the intermediate enolate formed during a 1,4-conjugate addition to an a,bunsaturated ketone,18 isomerization of allyl silyl ethers,19 reaction of vinyllithiums with silyl peroxides, 20 simultaneous carbonylation and silylation of alkyl acetates,21 and Brooklike rearrangements.22 Common silylating reagents include silyl chlorides, silyl iodides (often formed in situ), and silyl triflates. 8 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Scheme 1.2.2.1. Standard Conditions for Silyl Enol Ether Formation Enolate Silylation Me Na+ Me NaH Me TMSCl O O OTMS Enol Silylation O OTMS TMSI or TMSCl, NaI OTMS + HMDS or Et3N 90% Enone Hydrosilylation O 10% O OSiPhMe2 M (Ph3P)3RhH (0.4% mol) Me2PhSiH, 23 °C M = RHSiMe2Ph Enolate Trapping OMgBr O MeMgBr i-Pr OTMS TMSCl i-Pr CuCl, Et2O i-Pr Et3N, HMPT Olefin Isomerization OTMS H2Ru(PPh3)4, OTMS + OTMS benzene, 150 °C 55% 45% Vinyl Anion Quenching with Silyl Peroxide Ph Ph 1. s-BuLi, –78 °C 2. (TMSO)2 Br Ph + TMSO TMSO 8% 92% Reductive Carbonylation OAc Co2(CO)8, TMSH OTMS CO (50 Atm) Brook-Type Rearrangement O MeLi + PhS TMS OTMS OTMS 99.5% 0.5% Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 1.2.3 9 BORON ENOLATES While the versatility of boron enolates is significantly decreased compared to silyl vinyl ethers, boron enolates are heavily relied on in aldol, and aldol-like reactions.23 The breadth of boron enolates has been extensively explored by Evans, Masamune, Mukaiyama, and Brown with their use in aldol chemistry, which shows excellent diastereoand enantioselectivity. A considerable amount of research, performed by Evans, Masamune, Mukaiyama, and Brown, has enabled stereoselective boron enolate formation. Numerous factors play a role in forming boron enolates stereoselectively, including substituents on the ketone and boron precursor, the leaving group X on the latter, and the amine base (Table 1.2.3.1).24 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 10 Table 1.2.3.1. Enolate Selectivity Due to Leaving Group, Alkyl Substituents, and Amine Base O Me R1 R2 + B R2 OBR22 base + R1 X OBR22 R1 X Cy B B Cy X 22 Boron Source 22 23 23 X R1 Base Yield (%) Z (%) E (%) OTf t-Bu NEt3 90 10 90 Ms t-Bu NEt3 87 <3 >97 I t-Bu NEt3 95 >97 <3 Br t-Bu NEt3 94 <3 >97 Cl t-Bu NEt3 94 <3 >97 OTf Ph NEt3 97 >97 <3 Ms Ph NEt3 96 >97 <3 I Ph NEt3 98 >97 <3 Br Ph NEt3 96 83 17 Cl Ph NEt3 97 52 48 OTf t-Bu NEt3 85 <3 >97 Ms t-Bu NEt3 66 <3 >97 I t-Bu NEt3 96 >97 <3 Br t-Bu NEt3 82 10 90 Cl t-Bu NEt3 60 <3 >97 OTf Ph NEt3 96 67 33 OTf Pha Hunigs ND >99 <1 Ms Ph NEt3 95 62 38 I Ph NEt3 97 >97 <3 Br Ph NEt3 97 5 95 Cl Ph NEt3 97 <3 >97 Cl Phb Hunigs ND 51 49 a Aldol product with benzaldehyde, syn:anti = 5:95. b Aldol product with benzaldehyde, syn:anti = 98:2. 11 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 1.2.4 TRANSITION METAL ENOLATES Research on transition metal enolates has gained much attention over the past several years. At least 23 different transition metal enolates have been prepared25 and used in organic synthesis, especially those of palladium, zinc, copper, titanium, and nickel. Transition metal enolates are synthesized using a wide variety of methods26 including ion exchange, oxidative addition, carbene insertion, conjugate addition, and metal alkylation (Scheme 1.2.4.1). Scheme 1.2.4.1. Common Methods to Form Transition Metal Enolates Ion Exchange OLi OTi(Oi-Pr)3 ClTi(Oi-Pr)3 THF, –78 °C Oxidative Addition O O OAll OPd(All)(PPh3)2 O Pd2(dba)3•CHCl3 PPh3, DME Carbene Insertion N2 Ph Et Rh2(DIEA)4 (1 mol %) Ph Et2Zn, PhMe CO2Me OMe Et D 2O Ph OZnEt D CO2Me Conjugate Addition O O CH3(CH2)7Br O Cu H+ CuI (CH2)7CH3 (CH2)7CH3 Metal Alkylation O Et2Zn OZnEt Br The three main types of binding modes that transition metal enolates can adopt are h1-O-bound 24, h3-oxa-p-allyl (25), or h1-C-bound (26, Scheme 1.2.4.2). All three Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 12 configurations are capable of interconversion, but each complex has a preferred one, depending on multiple factors, including the hardness or softness of the metal, the steric and electronic environments of the ligands, and the solvent. Although there are exceptions, the general trend for preferred enolate configurations is that early transition metals tend to primarily adopt the h1-O-bound configuration (24), while late transition metals primarily adopt the h1-C-bound (26).27 Since transition metals generally have higher coordination numbers, chiral ligands can be used to control the stereochemical outcome. Scheme 1.2.4.2. Equilibrium Between Transition Metal Enolate Coordination Sites O M M R R 24 1.3 ALDOL REACTION 1.3.1 INTRODUCTION O O R M 25 26 First discovered in 1872 by Wurtz,28 the aldol reaction has long served as an important method of carbon–carbon bond formation. Due to the highly organized cyclic transition state, diastereoselective aldol methodologies including those utilizing chiral auxiliaries29 have long been employed in organic synthesis. 30 More recently catalytic asymmetric aldol reactions relying on organic catalysts31 or metal complex catalysts have been explored. Although many examples of metal-catalyzed asymmetric aldol reactions exist in the literature, few methods tolerate the construction of quaternary centers. 1.3.2 RHODIUM-CATALYZED REACTIONS First reported in 1998 by Kuwano and Ito, the asymmetric aldol reaction of aldehydes (27) with 2-cyanopropionates (28) catalyzed by trans-chelating chiral diphosphine ligands (R,R)-TRAP (29)–rhodium(I) complex generates b-hydroxy-a- 13 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates cyanocarboxylate products (30 and 31) bearing two vicinal stereocenters, one of which is quaternary (Table 1.3.2.1).32 Good anti to syn ratios were achieved only for a few substrates although with poor to good enantioselectivities. Table 1.3.2.1. Substrate Scope of Rhodium-Catalyzed Aldol Reaction + R1 Rh(acac)(CO)2 (R,R)-29 (1 mol %) O O NC OR2 H 27 OH O R1 Bu2O, 0 °C + OR2 Me 28 R2 Me Et 24 Me i-Pr 24 61 Me CH(i-Pr)2 24 67 Et CH(i-Pr)2 48 76 CO2Et CH(i-Pr)2 40 88 time (h) Yield (%) 63 anti/syn ee-anti ee-syn 45/55 31 23 47/53 55 50 81/19 86 33 75/25 57 10 68/32 91 63 O Me CN R1 CN OR2 31 30 R1 OH Ph2P H Fe Fe PPh2 H (R,R)-TRAP (29) In order to explain the anti-selectivity of their system, Kuwano and Ito propose several possible transition state structures of the zwitterionic (enolato)rhodium intermediate and suggest that an antiperiplanar transition state (32) in which the steric interaction between the aldehyde substituent (R1) and the alkyl group (R2) of the ester is minimized is most likely (Figure 1.3.2.1). Figure 1.3.2.1. Transition State of Zwitterionic (Enolato)Rhodium Intermediate CO Ph2P O R 2O H OH O Rh R1 N PPh2 R1 OR2 CN O 30 32 1.3.3 PALLADIUM- PLATINUM- AND NICKEL-CATALYZED REACTIONS Sodeoka and coworkers have reported an asymmetric hydroxymethylation of substituted b-ketoesters with formaldehyde produced in situ, using chiral palladium or platinum bisphosphine catalysts (33 and 34).33 They also found that chiral platinum 14 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates bisphosphine catalysts were able to affect the same reactivity. Their proposed mechanism for the reaction proceeds through the enolization of the substituted b-ketoester (35 and 36) to form a chiral palladium enolate that reacts with the highly electrophilic aldehyde in a selective fashion to produce the chiral quaternary center containing products (37 and 38) in good yield (up to 92% yield) and enantioselectivity (up to 80% ee, Scheme 1.3.3.1). The reaction was also found to work for less acidic ketones such as β-tetralone (39), with more electrophilic aldehydes such as ethyl glyoxalate, albeit only to form tertiary centers (40). Figure 1.3.3.1. Scope of Palladium- and Platinum-Catalyzed Hydroxymethylation of Substituted b-Ketoesters O O O 33 or 34 (5 mol %) (CH2O)n, THF Ot-Bu O * PPh2 Ot-Bu 0 to 23 °C (70h) M OH 35 PPh2 OH2 OH2 37 for 33: 84% yield, 60% ee for 34: 92% yield, 71% ee O 33 or 34 (5 mol %) (CH2O)n, THF O Ot-Bu 36 R-33 R-34 O M = Pt2+ O * for 33: 23 °C, 110 h for 34: 0 °C, 56 h 23 °C, 24 h M = Pd2+ Ot-Bu OH 38 for 33: 65% yield, 67% ee for 34: 54% yield, 80% ee O O O 33 (10 mol %) + H 39 CO2Et OH OEt * O THF, 0 °C, 38 h 40 50%, dr= 1:1, 43% ee In 2009, Matsunaga and Shibasaki reported the synthesis of asymmetric hydroxymethylated derivatives (43) of substituted b-ketoesters with formaldehyde, but their catalyst was a homodinuclear Ni2-Schiff base complex (42).34 With relatively low catalyst loading (0.1–1.0 mol %) they were able to obtain a variety of hydroxymethylated, Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 15 quaternary carbon containing products in modest to good yields, featuring enantioselectivities of 66% ee or better (Table 1.3.3.1). Table 1.3.3.1 Scope of Nickel-Catalyzed Hydroxymethylation Reaction of Substituted b-Ketoesters O O O R1 42, aq. HCHO Ot-Bu R2 i-Pr2O, 40 °C 1.3.4 R2 R1 Ot-Bu R2 OH 41 R1 O 43 Yield (%) ee (%) –(CH2)3– 94 93 –(CH2)4– 91 85 –(CH2)5– 81 66 Me Me 79 81 Me Et 79 89 Me Bn 84 90 Ph Me 40 89 O N O Ni N Ni O O (R)-42 SCANDIUM- AND NEODYMIUM-CATALYZED REACTIONS Feng and coworkers, in 2010, disclosed an asymmetric aldol reaction where a Sc(OTf)3 complex, formed from chiral ligand 46, catalyzes the reaction of 3-substituted-2oxindoles (44) and glyoxal derivatives (45) to form enantioenriched 3-(a-hydroxy-bcarbonyl)oxindoles (47).35 The reaction’s mild conditions tolerate a variety of substituents on both the glyoxal electrophile as well as on the oxindole substrate with yields ranging from 62% to 92%, enantioselectivities ranging from 82% to 99%, and diastereoselectivities as high as 99:1 (Table 1.3.4.1). They also found that the reaction was scalable with no major loss in yield, ee, or dr. 16 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.3.4.1. Substrate Scope of Scandium-Catalyzed Asymmetric Aldol Reaction R1 + O R2 H N H O 44 45 * * * * * O i-Pr O OH i-Pr N O H N H O N 82%, 90:10 dr 99% ee 88%, 83:17 dr 99% ee O O O N O * OH O O N H 79%, 86:14 dr 98% ee * F OH * N H 3 Å MS, CH2Cl2, 0 °C * * 47 O OH 46-Sc(OTf)3 (5 mol %) R1 N H O O O R2 O Bn OH * O N H Ph * OH N H 75%, 79:21 dr 92% ee N i-Pr * * O H OH O i-Pr O N H 72%, 64:36 dr 99% ee 46 62%, 80:20 dr 98% ee The mechanism proposed feature a scandium enolate (48) which serves to coordinate the glyoxal electrophile in a bidentate fashion (49), thereby allowing the aldol reaction to form the enantioenriched products (47) with vicinal stereocenters (Figure 1.3.4.1). Scheme 1.3.4.1. Proposed Catalytic Cycle of Scandium-Catalyzed Aldol Reaction 46 + Sc(OTf)3 O R2 R1 R1 Sc(46)(OTf)3 O * * N H N H 44 47 HOTf R1 R1 O N H O Sc(46)(OTf) 48 N H 49 O H R2 O 45 O H O R2 Sc-46 OTf OH O Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 17 In another report, Feng and coworkers disclosed the use of chiral neodymium catalysts in the asymmetric aldol reaction of 3-substituted-2-oxindoles and formalin.36 Again, N,N’-dioxide ligands were utilized, and the optimal ligand for this transformation was found to be 50. Good yields ranging from 60% to 93% and excellent enantioselectivities all above 87% were obtained, producing enantioenriched 1,3bis(hydroxymethyl)-2-oxindoles (51, Table 1.3.4.2). Table 1.3.4.2. Scope of Neodymium-Catalyzed Asymmetric Aldol Reaction HO R1 50-Nd(OTf)3 (2 mol %) aq. HCHO (2.0 equiv) R1 O N H O 3 Å MS, DCE, 0 °C N 44 HO Me i-Pr O HO Ph O N O N OH N i-Pr H O N OH 81%, 89% ee 91%, 90% ee HO Bn HO i-Pr H O N N O O i-Pr OH 87%, 93% ee 50 O N N OH 85%, 95% ee 1.3.5 OH 51 REACTIONS PROCEEDING THROUGH BORON ENOLATES The aldol reaction of aldehydes and stereochemically defined tetrasubstituted enol borinates generated by the 1,4-hydroboration of a,b-unsaturated morpholine carboxamides with diisopinocampheylborane, (L-Ipc)2BH, has been reported by Roush and coworkers in 2013.37 Based on the stereochemistry of product (55), they propose that the reaction proceeds through an organized six-membered transition state (54) of a Z(O)-enolborinate (53, Scheme 1.3.5.1). Depending on the configuration of the starting acrylamide (52), both 18 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates syn and anti products could both be predictably obtained. Moderate to good yields (40 to 90%) were obtained for almost all of the quaternary carbon containing products with diastereoselectivities greater than 20:1 and enantioselectivities above 92%. Scheme 1.3.5.1. Transition State and Substrate Scope of Aldol Reaction of Aldehydes and Stereochemically Defined Tetrasubstituted Enol Borinates ‡ O O O (i-Ipc)2BH N O R1CHO B O O N Et2O 23 °C, 3 h O 52 1. 50 °C, sealed tube overnight B(i-Ipc)2 54 O R1 N R1 53 OH H R1 yield dr ee 90% >20:1 >95% 40% >20:1 93% 78% >20:1 >95% 68% >20:1 95% N 2. pH 7 buffer, MeOH, THF, 23 °C, 6h O 55 TMS 1.4 MANNICH REACTION 1.4.1 INTRODUCTION A C–C bond forming reaction that has been used by chemists since the nineteenth century is the aminoalkylation reaction known as the Mannich reaction, named after German chemist Carl Mannich, who played a pivotal role in developing this reaction for broad synthetic use. The Mannich reaction produces b-amino carbonyl compounds by nucleophilic attack if an enol or enolate on a n electrophilic iminium salt.38 This reaction has been employed in the synthesis of several bioactive compounds39 and a number of asymmetric variants have been developed utilizing organic catalysts40 or metal-based Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 19 catalysts. 41 To date, direct asymmetric Mannich reactions employing transition metal catalysts are limited to stabilized enolates (1,3-dicarbonyl, b-keto nitriles, or oxindoles). 1.4.2 COPPER-CATALYZED REACTIONS Jørgensen and coworkers first reported the direct catalytic asymmetric Mannich reaction of malonates and b-ketoesters in 2003.42 They found that by using Cu(OTf)2 and the (S)-t-Bu-BOX ligand (57) in the reaction between substituted b-ketoesters (41) and Ntosyl-a-imino ester (56), they could obtain the quaternary carbon-containing products (58) in modest to good yields, diastereoselectivities as high as 99:1, and enantioselectivities ranging from 86% to 95% (Table 1.4.2.1). Although the best enantioselectivities were observed at –20 °C, these reactions were also plagued with low yields. The yields could be greatly improved upon warming to room temperature with only a slight decrease in ee. Table 1.4.2.1. Substrate Scope of Copper-Catalyzed Asymmetric Mannich Reaction O O R1 Ot-Bu OEt R2 O 41 56 Cu(OTf)2 57 (10 mol %) yield (%) dr ee (%) Me Me Et Me i-Pr Me Me Me Et Me i-Pr Me –(CH2)4– –20 –20 –20 23 23 23 23 23 23 55 17 15 87 80 55 89 83 69 97:3 98:2 84:16 93:7 98:2 84:16 99:1 96:4 92:8 95 93 92 88 92 91 86 93 87 Me All NHTs R2 CO2t-Bu CO2Et 58 T (°C) Bn i-Pr O R1 CH2Cl2 R2 R1 1.4.3 NTs + O O N t-Bu N (R,R) 57 t-Bu PALLADIUM-CATALYZED REACTIONS Chiral palladium enolates have also found use in the asymmetric Mannich reaction, such as one reported by Jørgensen, Sodeoka and coworkers for b-ketoesters.43 However, they utilize palladium catalysts and are able to extend their reaction to a variety of imine 20 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates electrophiles. Two palladium catalysts one with BINAP ligand (61) and the other with SEGPHOS ligand (62), were used to optimize their substrate scope that features a variety of b-ketoesters and imines (Table 1.4.3.1). Good to excellent yields of the vicinal quaternary and secondary stereocenter-containing products (60) could be obtained with good diastereoselectivity for most b-ketoester/imine combinations. The enantioselectivity of the reaction is also excellent, with enantioselectivities as high 99%. After assigning the absolute stereochemistry of their products by comparison to previously published results, they propose that the excellent enantioselectivity comes from the face selection of the chiral palladium-enolate. Table 1.4.3.1. Scope of Palladium-Catalyzed Asymmetric Mannich Reaction Reported by Sodeoka, and Coworkers O PPh2 O R1 Ot-Bu R2 41 NR4 + [Pd-61]OTf2 NHR4 R2 R3 CO2t-Bu R1 THF R3 O 59 PPh2 60 61 X NHPMP O * Me Me CO2Et CO2t-Bu 63%, 74:26 dr 86% ee major 55% ee minor NHBoc O Ph * CO2t-Bu 93%, 88:12 dr 99% ee major 97% ee minor NHBoc O * Me Me X 2-furyl CO2t-Bu 71%, 82:18 dr 96% ee major 99% ee minor X 62 63 64 O O PAr2 O PAr2 X O X = H, Ar = Ph, SEGPHOS X = F, Ar = Ph, DIFLUORPHOS X = H, Ar, = 3,5-t-Bu2-4-MeOC6H2, DTBM-SEGPHOS Another Pd-BINAP catalyst system utilized in an asymmetric Mannich reaction was reported by Kim and coworkers in 2009.44 This time the targeted substrates were acyanoketones (65) and N-Boc protected aldimines (66). The reaction was tolerant of a variety of aromatic substituted aldimines as well as a number of cyclic a-cyanoketones 21 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates with yields ranging from 71–95% (Table 1.4.3.2). The enantioselectivity of the reaction was also good with enantioselectivities as high as 91%. Several products could be obtained with complete diastereoselectivity, selective for the syn product. Table 1.4.3.2. Scope of Palladium-Catalyzed Mannich Reaction Reported by Kim and Coworkers O CN R1 NBoc + 65 O NHBoc R2 CN R1 THF Ar R2 O [Pd-61](PF6)2 2,6-di-t-Bu-4-Me-pyridine Ar 66 NHBoc O NHBoc 67 O NHBoc Ph CN NHBoc O Ph CN Ph CN CN MeO 78%, 83:17 dr 91% ee 95%, 100:0 dr 77% ee 81%, 100:0 dr 90% ee 71%, 100:0 dr 70% ee N-heterocyclic carbene Pd2+ diaqua complex (70) has been utilized as a catalyst by Shi and coworkers, who found that under mild conditions cyclic b-ketoesters (68) and NBoc imines (66) could ne reacted with these complexes to form Mannich adducts (69) in good yield (80–95%) and good enantioselectivity (70–96%, Table 1.4.3.3).45 The reaction, however, was not very diastereoselective for many of the substrate combinations; the diastereoselectivities ranged from 2:1 to 1:20. They propose a mechanism almost identical to that of Sodeoka43 with the reaction proceeding through a chelated palladium enolate, which directs the stereochemical outcome of the nucleophilic addition through an open transition state. 22 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.4.3.3. Palladium-Catalyzed Mannich Reaction Reported by Shi and Coworkers O O O Ot-Bu NBoc + Ar n 68 O 70, CH2Cl2 Ot-Bu NHBoc n Ar 66 69 n Ar Yield (%) dr ee (%) 1 3-ClC6H4 95 1:20 91 1 2 4-BrC6H4 3-CF3C6H4 89 85 2:1 1:10 70 88 NMe N 2+ OH Pd N 2 OH2 NMe 2TfO– R-70 1.4.4 SCANDIUM-CATALYZED REACTIONS Prior to Kim and coworkers’ report44 on the asymmetric Mannich reaction of a- cyanoketones and N-Boc protected aldimines, a similar reaction was reported by Shibasaki and coworkers.46 Unlike Kim and coworkers, Shibasaki’s conditions were able to preferentially form the anti-product. By using scandium complex with amide ligand (73), the quaternary carbon-containing products (72) could be obtained in good to excellent yields (80–99% and good to excellent enantioselectivities for most substrate combinations (77–96%) at a broad range of temperatures (Table 1.4.4.1). The anti-selectivity of the reaction was excellent, with diastereoselectivities as high as 97:3. Mechanistic investigations were not conclusive and suggested that the catalyst exists in solution as a conglomerate without order or regularity that must dissociate in order to form the highly ordered transition state necessary for the high enantioselectivity and diastereoselectivity observed in the reaction. 23 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.4.4.1. Scandium-Catalyzed Asymmetric Mannich Reaction O O CN + CH2Cl2 Ar n 71 O NHBoc OH 73, Sc(Oi-Pr)3 NBoc 66 O CN n N H 72 NHBoc O NHBoc H N R O OH O 73 O NHBoc NHBoc O CN CN 90%, 94:6 dr (anti:syn) 94% ee 92%, 95:5 dr 91% ee CN CN OMe 1.4.5 97%, 85:15 dr 77% ee 94%, 75:25 dr 82% ee NICKEL-CATALYZED REACTIONS Shibasaki and Matsunaga reported a second asymmetric Mannich reaction of N- Boc protected aldimines in 2008.47 However this reaction utilized a homodinuclear nickel Schiff base complex catalyst instead of a scandium complex. The targeted nucleophilic partner in this reaction was substituted nitroacetates resulting in tertiary stereocentercontaining products, but they also showed two examples of a b-ketoester 74 with aldimine (66) resulting in quaternary stereocenter-containing products. These two products (75) were obtained in good yields (82% and 92%) and with great enantioselectivities (91% and 99%, Scheme 1.4.5.1). Scheme 1.4.5.1. Nickel-Catalyzed Asymmetric Reaction O NBoc + MeO2C R1 O 42, THF BocN Ar 74 1.4.6 MeO2C 66 (a) R= Ph (b) R= 2-Fu 75 (a) R= Ph 92%, syn:anti 20:1, 99% ee (b) R= 2-Fu 82%, syn:anti 20:1, 91% ee LITHIUM-CATALYZED REACTIONS An asymmetric Mannich reaction of cyclic and acyclic 1,3-dicarbonyl compounds (76) and N-Boc aldimines (77) using BINOL (79) lithium salts as the chiral catalyst was 24 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates reported by Ishihara and coworkers.48 All products (78) were obtained in good yield (above 90%), good diastereoselectivity (most greater than 9:1), and good to excellent enantioselectivities (82%–97%, Table 1.4.6.1). Interestingly they found that the syn/anti selectivity of the reaction and the absolute stereochemistry at the newly formed aminocarbon stereocenter switched depending on whether the 1,3-dicarbonyl substrate was cyclic or acyclic. Cyclic substrates resulted in high syn selectivities whereas acyclic substrates exhibited high anti selectivity with the exception of the ketolactone. Two mechanistic pathways were purposed for the reaction. In pathway A, the aldimine is activated by the Lewis acidic lithium center, allowing for the conformational flexibility preferred by acyclic substrates, and in pathway B the pronucleophile is activated as a lithium enolate, forming a more rigid structure promoting chelation by the 1,3-dicarbonyl. Pathway A would most likely result in attack of the pronucleophile, coordinated by a naphtholate oxygen, on the re face of the lithium-coordinated aldimine resulting in anti-products, whereas in the pathway B the aldimine is activated by the naphthol proton and the lithium enolate attacks the aldimine on the si face resulting in syn products. Table 1.4.6.1 Scope of Lithium BINOLate-Catalyzed Asymmetric Mannich Reaction O O R1 NR4 + R3 t-BuOH, toluene Ar R2 76 77 R4 Ar Yield (%) dr ee (%) –(CH2)4– CO2Me Boc Ph 98 88:12 91 –(CH2)4– CO2Me Boc p-An 95 96:4 95 –(CH2)4– CO2Me CBz Ph 91 95:5 87 –OCH2CH2– Ac Boc Ph >99 39:61 85 –(CH2)2S(CH2)2– CO2Me Boc Ph 90 88:12 93 R2 R1 Ar R2 R3 78 R3 R1 NHR4 O 79, n-BuLi Me H CO2Me Boc Ph 97 5:95 85 Me H CONMe2 Boc p-An 93 9:91 97 F F F OH OH F F R-79 F 25 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 1.4.7 CALCIUM-CATALYZED REACTIONS Kobayashi and coworkers reported an asymmetric Mannich reaction of 3- substituted oxindoles (80) and N-Boc-imines (59) in 2015.49 Their optimized conditions utilized catalytic triethylamine, CaI2, and a PyBOX ligand (83) to generate 3tetrasubstituted oxindoles (81, 82) with vicinal quaternary and secondary stereocenters. Yields as high as 99% and enantioselectivities greater than 99% could be obtained for some substrate combinations (Table 1.4.7.1). The diastereoselectivity of the reaction was excellent, ranging from 93:7 to 98:2 with preferential formation of diastereomer 81. Table 1.4.7.1. Scope of Calcium-Catalyzed Asymmetric Mannich Reactiona R2 R1 O N Boc 80 R1 a NR3 + R1 CaI2, 83 NHBoc 59 R2 yield (%)2 dr XX:XX2 ee XX2 Me Ph 87 95:5 98 Me 2-tol 93 97:3 97 Me i-Bu 99 94:6 84 Bn 2-thi 84 96:4 98 n-Pr Et 43 97:3 72 i-Pr Ph 80 95:5 >99 NHBoc + O NEt3, CH2Cl2 –78 °C R2 R2 R1 O N Boc N Boc 81 82 O O N Ph N Ph N MeO OMe S,S-83 R3 = Boc. 1.5. CONJUGATE ADDITION AND MICHAEL REACTION 1.5.1 MICHAEL ADDITIONS INVOLVING POTASSIUM ENOLATES The earliest example of an asymmetric Michael reaction50 resulting in the formation of a quaternary center was published in 1973 by Långström and Bergson,51 relying on the use of 2-(hydroxymethyl)-quinuclidine enantiomer as the chiral organic catalyst to obtain optically active products. Their substrate scope was very limited and no conclusions could be reached regarding the mechanism of asymmetric induction. In 1981, the first example Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 26 of an asymmetric Michael reaction proceeding through a metal enolate was reported by Cram and Sogah,52 using potassium enolates in conjunction with chiral crown ethers to effect this transformation. Although the enantioselectivity of the products was fair (low 60’s) for most reactant combinations, one exceptional case resulted in an enantioselectivity of 99%. The chiral crown ether hosts could be recovered and reused many times. 1.5.2 MICHAEL ADDITIONS INVOLVING COBALT ENOLATES The use of cobalt catalysts in the asymmetric Michael reaction first appears in the literature in 1984, where Brunner and Hammer, investigated the Michael reaction of cyclicb-ketoesters and methyl vinyl ketone with Co(acac)2 in the presence of enantiomeric diamines (e.g. 87, Scheme 1.5.2.1).53 Subzero temperatures were required to obtain modest enantioselectivities (up to 66%). However, lowered temperatures also resulted in diminished yields. The highest enantioselectivity obtained corresponded to only a 50% yield at –50 °C. In a subsequent publication the substrate scope of this reaction was of this reaction was explored and it was found that substrate architecture played an enormous role in the selectivity of the reaction.54 The highest enantioselectivity obtained in the substrate scope study was only 39%, which was the result for the reaction of cyclohexanone derived b-ketoester with acrolein at 20 °C. 27 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Scheme 1.5.2.1. Cobalt-Catalyzed Asymmetric Michael Reaction Reported by Brunner and Hammer O O O Co(acac)2 (R,R)-87 O + 84 O toluene –50 °C, 64 h Me OMe Me O 85 OMe 86 50%, 66% ee H O O Co(acac)2 (S,S)-87 O OEt + toluene 20 °C, 189 h H 88 O O O * OEt 89 90 41%, 39% ee Ph NH2 H 2N Ph (R,R)-87 In 1991, Botteghi, Boga, and coworkers reported the asymmetric Michael reaction using cobalt catalysts derived from a number of ligand architectures (Scheme 1.5.2.2).55 For the formation of the quaternary carbon-containing product the optimal ligand was found to be a tetradentate diaminodiol ligand 91. Under optimized conditions the reaction only proceeded with 38% enantioselectivity accompanied by a low 46% yield. Higher yields could be achieved but only at the cost of lowered enantioselectivity. Brunner revisited the asymmetric Michael reaction again in 1999. In this report a number of chiral transition metal complexes are utilized as the catalyst.56 Although cobalt was only one of several metals tested, its complex with 1,2-diphenylethylenediamine gave the highest enantioselectivity (47%) for this reaction. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 28 Scheme 1.5.2.2. Cobalt-Catalyzed Asymmetric Michael Reaction Reported by Botteghi and Boga Botteghi & Boga (1991) O O O O Co(acac)2, 91 85 toluene –80 to –50 °C 42 h + OMe 84 O O OMe 86 46%, 38% ee Brunner (1999) O H O Co(acac)2 (S,S)-91 O OEt + toluene 23 °C, 250 h H 88 O O O * OEt 89 90 100%, 47% ee OH NH2 H 2N OH 91 1.5.3 MICHAEL ADDITIONS INVOLVING NICKEL ENOLATES Chiral nickel complexes of various ligand architectures have found use in asymmetric Michael reactions since the early 1990s. Botteghi and coworkers first reported the use of nickel chiral Schiff base complexes in a Michael addition of methyl vinyl ketone and ethyl 2-methylacetoacetate with slight asymmetric induction topping out at 6% for the quaternary carbon-containing product.57 Their intention was not to optimize the reaction conditions but rather to study the mechanism of the reaction which they propose proceeds through a chelated nickel enolate intermediate. The use of tridentate ligands in coordination with nickel centers in the asymmetric Michael reaction has been explored by Christoffers and coworkers. A series of tridentate diamino thioethers (94), diimino thioethers, and oxazolines (95)58 were screened with a variety of metal salts in reaction of 1,3-dicarbonyl (e.g. 92) with methyl vinyl ketone (Scheme 1.5.3.1).59 They concluded that the nickel complexes with diamino thioether ligand 94 and pyridine, or the methionine derived 29 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates oxazoline ligand 95 produced the best results in terms of both conversion and enantioselectivity. However enantioselectivities of the product 93 did not exceed 19% for any of the tested combinations and optimized reaction conditions with these ligands. Scheme 1.5.3.1. Nickel-Catalyzed Asymmetric Michael Reaction O O O OEt + NiCl2•6H2O 94 CH2Cl2 23 °C, 12 h O O S O NH2 OEt 92 85 NH2 94 93 17% ee Ph O O O OEt + O Ni(OAc)2•4H2O 95 CH2Cl2 23 °C, 16 h O 85 N O N OEt 92 Ph O MeS 95 93 19% ee Instead Christoffers and coworkers have reported mild conditions utilizing nickel diamine complexes for the asymmetric Michael reaction of cyclic b-ketoesters and methyl vinyl ketone.60 The enantioselectivity of the reaction was hugely dependent on the ring size of the cyclic b-ketoester; the cyclohexanone derived product could be obtained in 91% ee but the cycloheptanone derived product was nearly racemic with an ee of only 2% (Table 1.5.3.1). The other disadvantage of this reaction is that the chiral diamine is not catalytic, but the authors note that some of the auxiliary can be recovered after workup. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 30 Table 1.5.3.1. Scope of Nickel-Diamine Catalyzed Asymmetric Michael Reaction O O O O R1 + Ni(OAc)2•4H2O 98, CH2Cl2 O O 23 °C, 12 h n R1 n 96 85 n R1 97 ee (%) 2 OEt 91 1 1 Ot-Bu Oi-Pr 74 6 3 2 OMe Me 2 41 H 2N NH2 R,R-98 More recently chiral diamine complexes have also been utilized in the conjugate addition of 3-substituted oxindoles (99) and nitroolefins (100).61 These mild conditions employ Ni(OAc)2 with ligand 102 and deliver the products (101) in good yield, diastereoselectivity, and enantioselectivity for a range of substrates (Table 1.5.3.2). Aliphatic nitroolefins were note tolerated and the oxindole nitrogen needed to be substituted as a carbamate; free N–H oxindole as well as N-benzyl substituted oxindole produced no reaction. This suggests that the 1,3-dicarbonyl motif is critical for reactivity and the reaction likely proceeds through a chelated nickel enolate. 31 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.5.3.2. Scope of Nickel-Diamine Catalyzed Conjugate Addition of 3Substituted Oxindoles and Nitroolefins R2 R3 O + Ni(OAc)2 102, toluene R4 NO2 R3 23 °C NR1 NO2 O NR1 99 1.5.4 R4 R2 100 Yield (%) 101 ee (%) Ph Ph 99:1 95 HN NH 75:25 71 Ph Ph dr R1 R2 R3 CO2Et Me H Ph 91 CO2Et Me H o-An 74 CO2Et Me H p-An 74 99:1 89 CO2Et Bn H Ph 79 90:10 76 CO2Et Me F Ph 94 90:10 80 H Me H Ph 0 0 0 R4 R,R-102 MICHAEL ADDITIONS INVOLVING COPPER ENOLATES Chiral copper(II) complexes (103–107) were used by Desimoni and coworkers62 in the reaction of methyl 1-indanone-2-carboxylate (84) and methyl vinyl ketone 85 to yield the chiral Michael adduct 86 (Table 1.5.4.1). Initially tridentate Schiff base ligands bearing ethyl or phenyl substituents were investigated along with carious solvents and it was found that the ethyl-substituted ligand (103) gave the highest ee when carbon tetrachloride was used as the solvent. Based on these results, they reasoned that catalysts with increased rigidity would result in higher ee’s and thus tetradentate ligands should be investigated. Two tetradentate ligands, one derived from (S)-2-amino-1,5-pentandiol (104) and the other derived from (S,S)-2-amino-1,3-propandiol, were screened with a variety of solvents; although there was no clear difference between the two ligands and that the highest ee’s were obtained from reactions carried out in carbon tetrachloride. The highest ee obtained was 70% which corresponded to a stoichiometric use of the copper catalyst; although the catalyst loading could be dropped to 10 mol % with only a minor loss of enantioselectivity. Subsequent work in the Desimoni group focused on designing new ligands to improve the 32 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates efficiency of the copper catalyzed asymmetric Michael reaction.63 Eight new Schiff base ligands were investigated and the ligand 105 derived from (S)-aspartic acid gave the highest ee value of 75% which outperformed the ligands investigated in their previous publication. Unlike 104 and 105, the methionine derived methyl thiol (106) and its gem-dimethyl analog (107) result in enantioselectivities equal to or worse than the original ligand 103, suggesting the pendant alcohol acts as an axial coordinating ligand. It was concluded that minor modifications in the ligand structure will not be enough to significantly improve the enantioselectivity of the reaction and alternative avenues will need to be investigated to obtain better results. Table 1.5.4.1. Copper(II)-Catalyzed Reaction of Methyl Vinyl Ketone and Methyl 1Oxo-2-Indanecarboxylate Me O O O O * 84 85 OH N N Cu O 2 O 103 •H2O Cu O 2 104 OH 1.5.5 Yield (%) ee 103 104 105 106 107 99 99 99 99 99 54 70 75 61 20 SMe N Cu O 2 105 complex SMe N O OMe 86 Et O O CCl4 Me OMe O 103–107 + O N Cu O 2 106 O Cu O Me Me 2 107 MICHAEL ADDITIONS INVOLVING EUROPIUM ENOLATES Scettri and coworkers reported in 199364 an early example of the Michael reaction of a 1,3-dicarbonyl compound and methyl vinyl ketone to produce various quaternary carbon-containing products, using the commercially available europium(III) tris(3- Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 33 (trifluoromethylhydroxymethylene-d-camphorate)) as the catalyst under very mild conditions. The yields were modest to good but only with modest enantioselectivities up to 36%. 1.5.6 MICHAEL ADDITIONS INVOLVING RHODIUM ENOLATES Ito and coworkers reported in 199265 the first asymmetric Michael reaction of vinyl ketones (108) using chiral rhodium–TRAP (29) catalysts. The products (109) were in quantitative yields and enantioselectivities as high as 89% (Table 1.5.6.1). The nucleophilic partner in this reaction was an a-cyanocarboxylate (28) which they propose is key to the selectivity of the reaction because of coordination of the cyano group to the rhodium center forming a cationic rhodium species, which serves as the counterion for the enolate. The trans-chelating TRAP ligand66 (29) was also essential to the selectivity of the reaction as cis-chelating chiral diphosphines such as BINAP produced very little asymmetric induction. Table 1.5.6.1. Scope of the First Asymmetric Michael Reaction using Chiral Rhodium Catalysts + NC OR2 R1 108 O RhH(CO)(PPh3)3 (R,R)-TRAP (29) O O O R1 benzene OR2 CN 28 109 R2 Time (h) Yield (%) ee (%) Me Me 10 99 72 Me i-Pr 10 99 84 p-An i-Pr 1.5 99 89 4-ClC6H4 i-Pr 4 98 85 Ph i-Pr 1.5 95 83 H i-Pr 2.5 88 87 Me t-Bu 10 95 81 Me CH(i-Pr)2 23 99 93 H CH(i-Pr)2 3.5 88 92 R1 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates In a followup publication, 34 addition substrates were investigated and enantioselectivities up to 93% were obtained.67 Considering the potential synthetic use of the quaternary carbon containing Michael adducts, subsequent product elaborations were also conducted. The use of a-cyano Weinreb amides (110) as the nucleophilic partner was also investigated and enantioselectivities up to 94% could be obtained (Table 1.5.6.2).68 These highly useful enantioenriched products (111) could also be further elaborated. Table1.5.6.2. Rhodium-Catalyzed Asymmetric Michael Reaction of a-Cyano Weinreb Amides O O + R1 108 NC N Me OMe Rh(acac)(CO)2 (R,R)-TRAP (29) O O R benzene CN 110 N Me OMe 111 R1 Yield (%) ee(%) Me Ph H 98 99 94 93 94 89 Takaya and coworkers69 reported about the rhodium catalyzed asymmetric Michael addition of a-cyanocarboxylates (112). They used a bisphosphine ligand (114) with large bite angles capable of forming trans-chelating metal complexes to obtain good yields of the quaternary carbon-containing products (113, Table 1.5.6.3). Temperature played a large role in the enantioselectivity of the reaction, with the best enantioselectivities (up to 73% ee) were obtained at 0 °C. Interestingly, lower temperatures resulted in sluggish reactions with decreased enantioselectivities. 35 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.5.6.3. Scope of Rhodium-Catalyzed Asymmetric Michael Reaction of aCyanocarboxylates O O + R3 NC R1 108 R1 R2 O Rh(acac)(CO)2 OR2 O R3 114, solvent OR2 R1 CN 112 113 R3 Solvent Temp (°C) Time (h) Yield (%) ee (%) Me Et Me Me Et Me Me Et Me Et Et Me Me Et OMe Me i-Pr Me Me t-Bu Me PhH PhMe PhMe PhH PhH PhH PhMe 30 0 –30 30 30 0 0 4 13 20 13 212 6 11 90 86 88 89 0 93 95 55 73 11 14 ND 72 66 Ph2P OMe OMe Ph2P R-114 Suzuki and Torii70 in early 2000’s reported another rhodium-catalyzed asymmetric Michael reaction yielding products bearing quaternary centers that likely proceeded through a metal enolate. This was the first example of a Michael reaction with a b-ketoester (115) rather than an a-cyanocarboxylate serving as the nucleophilic partner in conjunction with a rhodium catalyst (Table 1.5.6.4). Using a chiral rhodium complex, prepared in situ from [Cp*RhCl2]2 and partially sulfonated diamine 117, enantioenriched products (116) were obtained from cyclic b-ketoesters and methyl vinyl ketone in quantitative yield with enantioselectivities as high as 67%. Acyclic b-ketoesters also exhibited good reactivity but very poor selectivity. Iridium and osmium catalysts were also investigated in this report, but provided inferior yields and enantioselectivities. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 36 Table 1.5.6.4. First Example of Rhodium-Catalyzed Asymmetric Michael Reaction with b-Ketoesters O O R1 OR3 O [Cp*RhCl2]2 117, KOH O + O CH2Cl2 R2 O R1 OR3 R2 115 R1 R2 R3 yield (%) 116 ee (%) O O S HN –C6H3-2-CH2– Me >99 –(CH2)3– Et >99 67 –(CH2)4– Et 30 34 NH2 Me Et 73 10 S,S-117 Et 1.5.7 85 67 Me MICHAEL ADDITIONS USING LANTHANUM–BINOL COMPLEXES Lanthanum–BINOL complexes, 71 initially developed by Shibasaki and coworkers for the asymmetric nitroaldol reaction,72 have found use in the asymmetric Michael reaction of malonates and β-ketoesters. 73 First reported in 1994, the asymmetric Michael reaction of several symmetrical malonates with cyclic enones using lithium-free lanthanum BINOL catalysts proceeds in up to quantitative yield and up to 95% ee.74 In this initial report, one example of a quaternary carbon-containing product (119) is shown; the reaction of methyl vinyl ketone with benzyl 2-methyl-3-oxobutanoate (118) proceeds in good yield (86%) but with only a 62% ee; the lowest value reported in the initial publication (Scheme 1.5.7.1). Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 37 Scheme 1.5.7.1. Lanthanum-BINOL Complex-Catalyzed Asymmetric Michael Reaction O O O + OBn La(Oi-Pr)3, (S)-BINOL O O O THF, –50 °C, 48 h OBn 118 85 119 86% yield 62% ee The proposed mechanism for this reaction features a chelated lanthanum enolate (120) that undergoes the conjugate addition to yield lanthanum enolate product (121) that is then turned over by deprotonating 1,3-dicarbonyl (118, Figure 1.5.7.1) Figure 1.5.7.1 Proposed Mechanism of the Lanthanum-BINOL Complex-Catalyzed Asymmetric Michael Reaction * O O O La * O La O O H O * La O O O * OBn O O La O O O * O BnO OBn * O O O O * 120 119 O O * O OBn * O O OH OH OBn * 118 OH = OH (S)-BINOL La O 121 O The asymmetric Michael addition of β-ketoesters (115) with vinyl ketones (108) producing quaternary carbon-containing products (122) was the focus of a later report from the Shibasaki group.75 Of their three lanthanum-BINOL catalysts developed at the time (the alkali metal free La–BINOL complex (123), the La–Na–BINOL complex (124, LSB), Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 38 and the Al–Li–BINOL complex (125, ALB)), the highest enantioselectivities were observed when using the LSB catalyst. The catalyst loading could be decreased from 10 to 5 mol % and an increased enantioselectivity of 91% could be observed when using dichloromethane as the solvent, without the slow substrate addition necessary for high enantioselectivities when using toluene as the solvent (Table 1.5.7.1). The reaction was not very sensitive to the choice of rare earth metal and praseodymium, samarium, gadolinium, and dysprosium could all be substituted for the lanthanum with only minor drops in yield and enantioselectivity. Cyclic and acyclic β-ketoesters were both tolerated in this reaction and methyl vinyl ketone as well as acrylates were competent Michael electrophiles, all proceeding in good yield and enantioselectivity. The proposed mechanism of this reaction proceeds through a chelated sodium enolate rather than a lanthanum enolate, as was suggested for the reaction using alkali metal-free lanthanum–BINOL catalyst (123). Table 1.5.7.1. LSB-Catalyzed Asymmetric Michael Reaction R4 O O R1 O O OR3 123 + R2 O R1 OR3 108 115 O CH2Cl2 R4 R2 122 * M2 R3 R4 yield (%) ee (%) –(CH2)4– Bn Me 73 91 Me Me Bn Me 93 Me Et Bn Me 98 83 89 –(CH2)4– Et OEt 60 76 * O O M1 M2 O O O M2 * R2 R1 O 123 M1 = La, M2 = none 124 M1 = La, M2 = Na 125 M1 = Al, M2 = Li In efforts to improve the stability and reusability of the lanthanum–BINOL catalysts, Shibasaki and coworkers prepared in 200076 a lanthanum complex from La(iPrO)3 and the amino-linked BINOL ligand 129, which exhibits no deliquescence and can Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 39 be stored under air with no decrease in enantioselectivity after four weeks of storage. At 10 mol % catalyst loading, 97% yield and 75% ee can be obtained from the reaction of methyl vinyl ketone and ethyl 2-oxocyclohexane-1-carboxylate. Thanks to solubility differences between the catalyst and the Michael adducts the catalyst can easily be recovered and reused. Very minor decreases in enantioselectivity were observed upon using recycled catalyst. In 2005, Shibasaki and coworkers reported an enantioselective diastereoselective Michael reaction of substituted b-ketoesters (126) and cyclic enones (127) yielding products (128) containing vicinal tertiary and quaternary stereocenters (Table 1.5.7.2).77 After optimization of the amino-linked BINOL ligand (129), modest to excellent yields (37–100%) were obtained for a diverse array of substrates. The diastereoselectivity also was somewhat substrate dependent with dr’s ranging from 68:32 up to 86:14. The enantioselectivity of the reaction was good for a few substrates with ee’s as high as 86% for the major isomer but many substrate combinations result in enantioselectivities around 60% with some as low as 39% for the major isomer. 40 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.5.7.2. Lanthanum NR-Linked-BINOL-Catalyzed Asymmetric Michael Reaction O O O R1 OMe O La(Oi-Pr)3 129 + H DME R2 n n 126 127 O R1 R2 CO2Me 128 n R1 R2 Yield (%) dr ee major (%) ee minor (%) 0 0 0 1 1 Me Me i-Pr Me Me Me All Me Me (CH2)3Ph 100 86 71 92 37 76:24 77:23 86:14 86:14 68:32 79 56 63 86 56 73 63 16 80 86 1 2 2 2 i-Pr Me Me Me Me Me All (CH2)3Ph 42 89 69 45 84:16 86:14 74:26 81:19 80 82 42 39 35 82 72 67 OH HO N Et OH HO 129 The use of chiral alkali metal base catalysts in the asymmetric Michael reaction to form quaternary centers extends beyond the work of Shibasaki. Tamai and Miyano reported the asymmetric Michael addition of cyclic-b-ketoesters (115) and methyl vinyl ketone using podand-type alkali metal 2’-substituted 1,1’-binapthalene-2-oxides (Table 1.5.7.3).78 A number of alkali metals were investigated but sodium provided the products (116) in the highest yields and enantioselectivities in combination with the optimized oligoether bearing ligand 130. Cooling the reaction to –78 °C provided an additional boost in enantioselectivity up to 64%. 41 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.5.7.3. Scope of Michael Reaction of Cyclic b-Ketoesters and Methyl Vinyl Ketone Using Podand-Type Alkali Metal 2’-Substituted 1,1’-Binaphthalene-2-Oxides O O R1 OR3 O + 115 85 O R1 OR3 R2 116 O O O O O OMe 98%, 28% ee at 20 °C 81%, 57% ee at –78 °C 1.5.8 O 4 Å MS, CH2Cl2 –78 °C R2 O O NaOH, 130 O O O O O OH OEt OEt MeO 130 93%, 64% ee 97%, 51% ee MICHAEL ADDITIONS INVOLVING PLATINUM AND IRON ENOLATES Williams and coworkers have reported the use of platinum catalysts in the asymmetric Michael reaction. Although the major focus of their report was the synthesis and characterization of novel platinum phosphino-oxazoline complexes, they did demonstrate the use of two cationic platinum complexes in the asymmetric Michael addition of ethyl cyanopropionate and methyl vinyl ketone.79 Although good yields were obtained, the reaction proceeded with low enantioselectivity (up to 25%). Iron has also found use in the asymmetric Michael reaction of β-ketoesters and methyl vinyl ketone with the use of a dipeptide ligand.80 Although several metals work to catalyze this reaction, the highest enantioselectivity, 18%, was observed using iron(III). This was a surprising result because at the time iron was not typically used in enantioselective transformations.81 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 1.5.9 42 MICHAEL ADDITIONS INVOLVING PALLADIUM ENOLATES One metal that has found widespread use in a symmetric addition reactions is palladium.82 The first palladium catalyzed asymmetric Michael reaction forming quaternary stereocenters was reported in 2000 by Richards and coworkers.83 A number of cationic palladium pincer complexes were screened in the reaction of a-cyanocarboxylates and methyl vinyl ketone. Modest to good yields of 132 were obtained in most reactions however the enantioselectivities were generally low. The best ee obtained was 34% for the reaction of ethyl 2-cyanopropanoate 131 and methyl vinyl ketone, in the presence of DIPEA, catalyzed by 133 (Scheme 1.5.9.1). Scheme 1.5.9.1. The First Palladium Catalyzed Asymmetric Michael Reaction Forming Quaternary Centers O NC OEt 131 + O 133, DIPEA O O toluene, –78 °C NC OEt 132 85 86% yield, 34% ee SbF6– O O N H Pd OH2 N H 133 The use of palladium pincer complexes in the asymmetric Michael reaction was further explored by Uozumi and coworkers in 2004.84 They also investigated the asymmetric Michael reaction of vinyl ketones (108) and a-cyanocarboxylates (28), but 43 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates their palladium pincer complexes had pyrroloimidazolone coordinating groups. With low loading of their optimal catalyst 134 (0.5 mol %), they were able to obtain enantioenriched products (ent•109) in up to 91% yield and 83% ee (Table 1.5.9.1). The use of palladium pincer complexes was revisited again in 2007 by Fossey and coworkers. 85 They used chiral palladium bis-aldimine NCN–pincer complexes in the reaction of vinyl ketones and acyanocarboxylates. Although the reaction proceeded in nearly quantitative yield the product was completely racemic due to the conformational flexibility of the halideabstracted catalyst. Table 1.5.9.1. Palladium Pincer Complex-Catalyzed Asymmetric Michael Reaction O O + NC R1 O 134, DIPEA OR2 benzene or toluene 25 °C OR2 CN 28 108 O R1 ent•109 R1 R2 Yield (%) Time (h) ee (%) Et Me 89 4 81 i-Pr Me 90 4 80 CH(i-Pr)2 Me 93 24 80 91 4 83 t-Bu N N O O H N Pd OTf OH i-Pr Et N H HO 134 The first highly enantioselective palladium catalyzed Michael reaction was reported in 2002 by Sodeoka and coworkers.86 They targeted β-diketones as their nucleophilic partner in the reaction because no work prior had attempted to utilize this type of dicarbonyl compound. The reaction of ketone 76 and 135, which proceeds through a chelated chiral palladium enolate,87 as evidenced by NMR and ESI-MS, is promoted by triflic acid and capable of generating product 136 in good yield and enantioselectivity at 10 mol % catalyst loading (33, Table 1.5.9.2). They extended their optimized conditions to Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 44 β-ketoesters and their substrate scope features both cyclic and acyclic b-ketoesters bearing bulky t-butyl or phenyl groups on the ester. Yields ranging from 69% to 93% and ee’s narrowly ranging from 86% to 93% were obtained for several substrate combinations. Revealed in a subsequent full paper, the reaction is somewhat sensitive to substitution on the β-ketoester with some substrates proceeding in yields as low as 8% and ee’s as low as 30%.88 β-substituted trans-enones were also competent substrates in combination with tbutyl-2-oxocyclopentane-1-carboxylate, yielding vicinal stereocenter-containing products in good yield and excellent enantioselectivity as high as 99% for the major isomer with diastereoselectivities of 3.6:1 for (E)-4-phenylbut-3-en-2-one and 8:1 for (E)-pent-3-en-2one. Good enantioselectivities but poor diastereoselectivities were observed for βsubstituted cis-enones. Table 1.5.9.2. Palladium-Catalyzed Michael Reaction Reported by Sodeoka and Coworkers O O O R1 O R3 + R2 76 R1 R5 R4 –20 °C R5 135 R2 R3 R4 O 33, THF R3 R2 O R1 136 R4 R5 Yield (%) dr ee, major (%) –(CH2)3– CH2t-Bu H Me 89 ND 90 Me Me Ot-Bu H Me 88 ND 90 Me Me OPh H Me 69 ND 93 –(CH2)3– Ot-Bu H Me 92 ND 92 –(CH2)4– Ot-Bu H Me 92 ND 90 –(CH2)3– Ot-Bu H Et 84 ND 88 –(CH2)3– Ot-Bu Ph Me 83 3.6:1 97 –(CH2)3– Ot-Bu Me Me 89 8:1 99 Et Me Ot-Bu H Me 8 ND 35 Me –(CH2)2– H Me 88 ND 30 In a follow-up paper, Sodeoka and coworkers report the use of their palladium catalysts immobilized in ionic liquids in the asymmetric Michael reaction, allowing for Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 45 catalyst recycling.89 The optimal ionic liquid for single use was 1-hexyl-3methylimidazolium tetrafluoroborate ([hmim][BF4]), generating products with yields as high as 97% and ee’s as high as 88%, which is comparable to the results obtained in usual organic solvents. The optimal ionic liquid for recycling was found to be 1-butyl-3methylimidazolium trifluoromethanesulfonate ([bmim][OTf]); unfortunately, the catalyst could be recycled only once before a significant drop in reaction rate took place. They could preserve the reactivity by using a palladium catalyst recycled previously in an asymmetric fluorination reaction, but only five cycles could be completed with this pretreated catalyst before a significant drop in reaction rate was observed. Shi and coworkers demonstrated the use of palladium(II)-N-heterocyclic carbene– diaqua complexes in the asymmetric Michael reaction of b-ketoesters (137) and methyl vinyl ketone.45 Using complex 70 they were able to obtain enantioenriched products (138) in up 98% yield and 71% ee (Scheme 1.5.9.2) They did not broadly explore the substrate scope of the asymmetric Michael reaction but instead investigated the use of complex 70 in the asymmetric Mannich reaction. (See Section 1.4). Scheme 1.5.9.2. Palladium N-Heterocyclic Carbene Diaqua Complexes in Asymmetric Michael Reaction of b-Ketoesters and Methyl Vinyl Ketone O O Ot-Bu + O 70 (5 mol %) O O O 4Å MS, CH2Cl2 * 137 85 Ot-Bu 138 98%, 71% ee More recently in 2018, Schneider and coworkers were able to utilize a palladiumaqua–BINAP complex 33 in order to perform an asymmetric Michael reaction with ortho quinone methides and cyclic b-ketoesters.90 The reaction of cyclic phenol 139 and b- 46 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates ketoesters 140 is believed to proceed through a chelated chiral palladium enolate which is then capable of undergoing a conjugate addition to ortho quinone methide, generated in situ with trifluoromethyl sulfonic acid, to form tricyclic chroman cores bearing vicinal tertiary and quaternary stereocenters (Table 1.5.9.3). The enantioenriched chroman products 141 were obtained in excellent yield (up to 99%), enantioselectivity (as high as 99%), and diastereoselectivity (as great as 95:5). Mechanistically, the reaction is believed to progress through a stepwise process. Palladium coordinated complex 33 first undergoes a conjugate addition to the Re-face of ortho-quinone methide through an open transition state. The initial addition product can then rearomatize through the hemi-ketalization to form the desired chroman core 141. Table 1.5.9.3. Palladium Diaqua Complex-Catalyzed Michael Reaction with oQuinone Methides R2 R2 O O + OH R1 33 (5 mol %) Ot-Bu X CO2t-Bu toluene, 23 °C n X R1 O OH 139 140 141 R1 R2 X n Yield (%) dr ee (%) H p-OMe O 1 95 90:10 98 H p-Me O 1 99 89:11 98 p-OMe H O 1 96 90:10 >99 p-t-Bu Thi CH2 2 94 88:12 99 H p-OMe S 1 83 88:12 99 p-t-Bu p-OMe S 1 92 >95:5 >99 p-OMe p-OMe NMoc 1 78 87:13 >99 H p-OMe CH2 1 99 84:16 99 p-t-Bu H CH2 1 93 86:14 99 n OH Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 1.5.10 47 MICHAEL ADDITIONS INVOLVING SCANDIUM AND YTTRIUM ENOLATES Chiral N,N’-dioxides have been used in a number of asymmetric transformations as organic catalysts or as tetradentate ligands for metal-catalyzed reactions.91 Nakajima and coworkers in 200192 first utilized chiral N,N’-dioxides in the scandium-catalyzed asymmetric Michael reaction of indanone-2-carboxylates (142) and methyl vinyl ketone. By using a 1:1 mixture of ligand 144 and Sc(OTf)3 in dichloromethane the enantioenriched products 143 could be obtained in good yield but with variable enantioselectivities. The highest ee observed was for the reaction of 142 and methyl acrylate, which proceeded with 89% yield and 84% ee although ee’s as low as 38% were observed for some indan-2carboxylate substrate combinations (Table 1.5.10.1).93 The indanone-2-carboxylate skeleton appears to be important in the enantiocontrol of the reaction, as using substrate 145–147 instead of 142 afforded good yields of totally racemic products. 48 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.5.10.1. Chiral Scandium-N,N’-Dioxide-Catalyzed Asymmetric Michael Reaction R2 O O O O Sc(OTf)3, 144 + R2 OR1 O N O CH2Cl2, 23 °C OR1 142 O OMe H O O O O O Ot-Bu Ot-Bu O O O OBn Oi-Pr 85% yield 38% ee O OMe O O 73% yield 75% ee O OMe O O 89% yield 84% ee 144 143 108 N O O 94% yield 47% ee O O O OMe OBn 145 146 147 Feng and coworkers utilized scandium N,N’-dioxide complexes in the asymmetric Michael reaction and their targeted substrates were 4-substititued-5-pyrazolones (148) and 4-aryl-4-oxo-butenoic esters (149, Table 1.5.10.2).94 Interestingly, they were able to use one enantiomer of their optimized (S)-pipecolic acid-derived ligand 151 to obtain either enantiomer of the Michael adduct by switching the metal from scandium to yttrium. With scandium yields ranging from 83–97% and enantioselectivities from 86–95%. The diastereoselectivity of the reaction was also good with dr’s as high as 19:1, with yttrium the yields ranged from 75–95% and enantioselectivities from –83 to –98% with significantly improved diastereoselectivity, usually greater than 49:1. This reaction was also scalable up to gram-scale without loss of reactivity or selectivity. 49 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.5.10.2. Asymmetric Michael Reaction of 4-Substituted-5-Pyrazolones and 1,4-Dicarbonyl But-2-enes O O R1 NPh + OR3 R2 M(OTf)3 (M = Sc, Y) 151 O solvent, temp N O 148 R1 R1 Bn Ph Et 95 4.6:1 86 Et Ph i-Pr 97 19:1 93 Bn 3-ClC6H4 i-Pr 83 13.3:1 92 Bn 85 5.7:1 92 yield (%) dr i-Pr O N H O N 151 O N With Y(OTf)3 in CH2Cl2 at 0 °C 1.5.11 150 ee (%) With Sc(OTf)3 in EtOH at 30 °C p-An NPh N R2 149 R1 OR3 O R1 O H Bn Ph Et 95 >49:1 –96 Bn p-An i-Pr 75 >49:1 –91 Et Ph Et 93 >49:1 –83 Ph 4-BrC6H4 i-Pr 95 >49:1 –98 N O MICHAEL ADDITIONS INVOLVING CALCIUM ENOLATES An example of a calcium catalyzed Michael addition that generates products bearing quaternary stereocenters comes from Kumaraswamy and coworkers.95 Their calcium–octahydro-BINOL complex 154 catalyzed the addition of a variety of cyclic bketoesters 152 to methyl vinyl ketone 85 in good yield and moderate to good enantioselectivities (Scheme 1.5.11.1). Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 50 Scheme 1.5.11.1. Calcium-Octahydro-BINOL Complex-Catalyzed Asymmetric Michael Reaction O O O n + O R-154 O O toluene, –40 °C OR * n 152 85 OR 153 O Ca•2KCl O R-154 1.5.12 CONJUGATE ADDITION REACTIONS INVOLVING MANGANESE ENOLATES An Asymmetric conjugate addition reaction of 3-substittuted oxindoles 155 and nitroolefins 100, similar to that in Table 1.5.3.2 was reported by Shibasaki and coworkers in 2009.96 A homodinuclear manganese–Schiff base complex (157) catalyzed the conjugate addition of a variety of substrate combinations in high yields and excellent enantioselectivities ranging from 87–96% (Table 1.5.12.1). The diastereoselectivity of the reaction was also good with dr’s ranging from 5:1 to greater than 30:1. 51 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.5.12.1. Homodinuclear Manganese-Schiff Base R-Mn2-157 R1 Complex-Catalyzed Conjugate Addition Reaction R3 R1 R2 + O R3 NO2 N Boc R2 EtOAc, 23 °C NO2 O N Boc 155 100 156 R1 R2 R3 Yield (%) dr ee (%) Me H Ph 99 22:1 95 Me H 2-BrC6H4 92 >30:1 96 Me H CH2=C(Ph)CH2 85 13:1 87 Bn H Ph 90 6:1 95 Me F Ph 99 11:1 85 Me H 2-Fu 92 13:1 91 O N O M N M O O R-157 [M] = Mn(III)(OAc) 1.6 ALLYLIC ALKYLATION 1.6.1 INTRODUCTION Asymmetric transition metal-catalyzed allylic alkylation has been an area of interest to many organic chemists.97 Specifically, the use of palladium catalyzed allylic alkylation to asymmetrically generate stereocenters has received much attention over the last 30 years, but the generation of quaternary stereocenters using this strategy has only been utilized in the last 20 years.98 In 1992, Ito and coworkers published a palladiumcatalyzed asymmetric allylation of b-diketones using chiral phosphine ligands modified by crown ethers. Enantioselectivities up to 75% were obtained for a limited number of substrates. 99 Similarly in 2000, Tenaglia, Buono, and coworkers published a palladiumcatalyzed asymmetric allylic alkylation reaction that generated a quaternary stereocenter using a chiral QUIPHOS ligand and a stabilized prochiral nucleophile derived from bketoesters.100 Good yields and enantioselectivities were obtained for some select substrate combinations but in general their conditions resulted in poor enantioselectivities. Hamada Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 52 and coworkers were able to get consistently good enantioselectivities for the palladiumcatalyzed allylic alkylation of their b-ketoester substrates using P-chirogenic diaminophosphine oxide ligands.101 1.6.2 PALLADIUM-CATALYZED ASYMMETRIC ALLYLIC ALKYLATION OF NON-STABILIZED ENOLATES The first example of palladium-catalyzed asymmetric allylic alkylation of nonstabilized enolates bearing other enolizable positions was reported by Behenna and Stoltz in 2004.102 In this initial report, both cyclic enol carbonates (159) and cyclic silyl enol ethers (160), in the presence of TBAT, a diallyl carbonate, a palladium(0) complex, and tbutyl-PHOX ligand 158 to give the enantioenriched product 161 in good yields and enantioselectivities (Scheme 1.6.2.1). This work was later extended to include b-ketoesters substrates 162 as well.103 Scheme 1.6.2.1. Palladium Catalyzed Asymmetric Allylic Alkylation of NonStabilized Enolates Bearing Other Enolizable Positions Reported by Stoltz and Coworkers O O O O PPh2 N 159 t-Bu Pd2(dba)3 158 THF 25 °C 158 90% yield, 89% ee OTMS 160 Pd2(dba)3 158 TBAT diallyl carbonate THF 25 °C 95% yield, 87% ee O Pd2(dba)3 158 O O O THF 25 °C 161 85% yield, 88% ee 162 53 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates The proposed mechanism for the enantioselective decarboxylative allylic alkylation of a racemic allyl b-ketoester (162) to a chiral a-allyl ketone (161) catalyzed by Pdphosphine complex 158, proceeds through a number of intermediate steps (Scheme 1.6.2.2). Initial p-coordination of the allyl moiety to Pd generates complex (163), which then allows for oxidative insertion of the ester bond to for Pd(II) complex (164). Complex 164 is then able to undergo decarboxylation to form chiral Pd-enolate (165) followed by an inner-sphere sigmatropic reductive elimination to generate the desired product.104 Scheme 1.6.2.2. Proposed Mechanism of the Palladium-Catalyzed Asymmetric Allylic Alkylation Reaction. Solv O O t-Bu Pd Ph2P O O N O 162 158 161 Solv O O O Ph2P O t-Bu Pd t-Bu Pd N Ph2P N O O 163 165 O O O t-Bu Pd Ph2P N CO2 O 164 Stoltz and coworkers also found that the use of the more electron deficient (CF3)3t-Bu-PHOX (168) was found to give excellent yields and enantioselectivities with benzoylprotected lactam substrates (e.g. 169) as well as strained cyclobutanones (e.g. 166) (Scheme 1.6.2.3).105,106s 54 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Scheme 1.6.2.3. Asymmetric Allylic Alkylation of Cyclobutanones and Protected Lactams O Et Ph O [Pd(pmdba)3] 168 O Et toluene CF3 Ph O O 166 O Me 167 62%, 99% ee O BzN O O [Pd(pmdba)3] 168 F3C P N t-Bu Me BzN toluene CF3 168 169 170 85%, 99% ee Utilize the PHOX ligand scaffold the Stoltz group has been able to perform the asymmetric decarboxylative allylic alkylation on a wide variety of substrates exhibiting great functional group tolerance (Figure 1.6.2.1). Recently the Stoltz group has been able to expand the scope of the asymmetric allylic alkylation chemistry to encompass Mannich adduct products,107 as well as create chiral acyclic quaternary centers for the first time from stabilized palladium enolates utilizing the PHOX ligand scaffold.108 Moreover, the catalyst loading could be dropped as low as 0.125 mol % Pd(OAc)2 without greatly diminishing the yield or enantioselectivity of the reaction.109 55 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Figure 1.6.2.1. Representative Products of the Palladium-Catalyzed Asymmetric Allylic Alkylation Reaction Developed by Stoltz and Coworkers O O 90%, 89% ee O O 94%, 92% ee 55%, 82% ee OTBDPS O F 86%, 81% ee 80%, 91% ee O O O O O O t-Bu O Et Cl N Bn 94%, 86% ee 77%, 90% ee O 83%, 87% ee O 71%, 92% ee t-BuO 91%, 88% ee 87%, 91% ee CHO N O t-BuO PhS 91%, 92% ee O t-BuO 97%, 85% ee 90%, 80% ee TMS OMe O O Ph O O Bn Ph 86%, 92% ee 92%, 90% ee 89%, 95% ee 91%, 92% ee O O CO2Me O O BzN 85%, 99% ee O BzN BzN O 92%, 99% ee O Et Ph F BzN BzN 86%, 98% ee O Bn Ph O Et 4-MeO-Ph Ph Ph Ph 97%, 91% ee 99%, 76% ee 99%, 87% ee O 81%, 94% ee Bu Ph O O 91%, 99% ee Ph Bn O Bn 90%, 93% ee O O Bn Ph 99%, 90% ee O Et O Bn BzN S 92%, 94% ee S 74%, 93% ee NBoc S S 70%, 82% ee 29%, 80% ee O O 90%, 96% ee CN O 81%, 86% ee O Et 79%, 88% ee NPhth 92%, 93% ee i-Pr 62%, 87% ee O >99%, 90% ee 56 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Work by Trost and coworkers in the area of palladium catalyzed allylic alkylation to form quaternary stereocenters was first published in 1997.110 Their initial work was on the asymmetric allylic alkylation through stabilized enolates of tetralone-derived βketoesters using palladium and the Trost ligand 173. In 1999, they pursued ketone substrates that would give non-stabilized enolate intermediates.111 LDA was used to generate the lithium enolate in situ in the presence of the Lewis acid trimethyltin chloride, allyl acetate, a palladium source, and the Trost ligand 173. An a-blocking group was required but thioacetals, benzylidene, furanylidene, and tetralones were all tolerated and generated their corresponding quaternary centered products (Table 1.6.2.1). Table 1.6.2.1. Asymmetric Allylic Alkylation of b-Ketoesters Using LDA, Palladium, and the Trost Ligand O AllOAc LDA, Me3SnCl [AllPdCl]2, 173 O O 171 O HN PPh2 Ph2P 172 O O NH DME, 23 °C 173 O Ph SMe O MeS O 99% yield 88% ee 98% yield 82% ee 89% yield 79% ee 64% yield 70% ee In 2002, Trost showed that aryl substituted cyclic ketones (174) could be subjected to a base like NaHMDS in the presence of allylpalladium(II) chloride dimer, a Trost ligand 176, and allyl acetate to give good yields and enantioselectivities of the allyl-substituted enantioenriched product (175, Table 1.6.2.2).112 57 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.6.2.2. Formation of Aryl Substituted Cyclic Ketones Using NaHMDS, Allylpalladium(II) Chloride Dimer, a Trost Ligand, and Allyl Acetate O Ar AllOAc NaHMDS, 176 [AllPdCl]2 O Ar DME, 0 °C O n n 174 175 F NH PPh2 NH PPh2 O O O 90% yield 88% ee 90% yield 83% ee O 176 77% yield 90% ee In 2005, Trost demonstrated that lithium enolates could be generated in situ in the presence of a tin Lewis acid, palladium source, and a Trost Ligand 173 to effect the asymmetric allylic alkylation of a variety of substituted tetralones.113 Good yields and enantioselectivities were obtained for a variety of allyl sources and for a variety of substituted tetralones 177 (Table 1.6.2.3).114 Other substrates with blocking groups were also tolerated including the dithioacetal. This method was featured in the synthesis of hamigeran B 179. Table 1.6.2.3. Asymmetric Allylic Alkylation of Lithium Enolates in the Presence of a Tin Lewis Acid, Palladium Source, and a Trost Ligand O R1 O LDA, n-Bu3SnCl [AllPdCl]2, 173 * DME, 23 °C n R3 R1 R4 R2 n 177 O * 99% yield 88% ee 84% yield 90% ee HN 173 O * O NH PPh2 Ph2P 178 O O Bn O O OH * 98% yield 73% ee Br H 179 58 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Trost investigated the use of 3-aryloxindoles (180) as substrates for asymmetric allylic alkylation.115 The anthracenyl-Trost ligand 182 was found to be optimal, with no need to form the lithium enolate in order to obtain good yield and enantioselectivity of the corresponding products (181, Table 1.6.2.4). Table 1.6.2.4. 3-Aryloxindoles In the Asymmetric Allylic Alkylation Reaction Ar t-BuOH, AllOAc [AllPdCl]2, 182 O N Me Ar toluene –78 to 4 °C O O N Me 180 181 O NH HN PPh2 Ph2P 182 O O O N Me 93% yield 81% ee O N Me 68% yield 79% ee O N Me 96% yield 77% ee This work has also been extended to b-ketoesters and allyl enol carbonates (183).116 For the latter, Trost Ligand 182 was found to be optimal although a-blocking groups were necessary to obtain good yields of the quaternary stereocenter-containing product, for example, as in the 2,3-benzo cyclic ketones (Scheme 1.6.2.5), or in 2- benzylidenecyclohexanone undergoing the same process (yields 99%, 95% ee). Allylated products bearing tertiary stereocenters could also be generated using these reaction conditions from unsubstituted all enol carbonates. Vinylogous esters were also found to be good substrates for this chemistry.117 59 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.6.2.5. Allyl Enol Carbonates In the Asymmetric Allylic Alkylation Reaction Using Trost Ligand 182 O O O O Pd2(dba)3•CHCl3 182 toluene, 23 °C n n 183 184 O O O O Ph 88% yield >99% ee 94% yield 91% ee 98% yield 76% ee 99% yield 95% ee Hayashi and coworkers found that sodium enolates could be subjected to chiral ferrocenylphosphine-palladium complexes and allyl acetate to form quaternary stereocenters bearing allyl substituents in good yields and modest enantioselectivities.118 Unfortunately, no ee’s exceeding 82% were observed for any of the substrates tested and some of them yielded nearly racemic products (185–189, Figure 1.6.2.2). Figure 1.6.2.2. Scope of Chiral Ferrocenylphosphine-Palladium Complex-Catalyzed Allylic Alkylation O O * O O * O O O * OEt O O * OMe Ph * H 185 186 187 188 189 88% yield 81% ee 94% yield 82% ee 82% yield 3% ee 70% yield 22% ee 88% yield 47% ee 1.6.3 MOLYBDENUM-CATALYZED ASYMMETRIC ALLYLIC ALKYLATIONS In 2006, the first example of molybdenum-catalyzed asymmetric allylation of oxindoles (190) to create quaternary stereocenters was reported by Trost.119 A variety of quaternary stereocenter-containing oxindoles 191 were obtained in good yields and 60 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates enantioselectivities when using catalyst [Mo(C7H8)(CO)3] and ligand 192 (Table 1.6.3.1). This method was also applied in the formal synthesis of (–)-physostigmine. Table 1.6.3.1. Molybdenum-Catalyzed Asymmetric Allylic Alkylation OCO2t-Bu R1 R1 Mo(C7H8)(CO)3 192, LiOt-Bu O N Me O N Me 190 N 192 NC Bn 1.6.4 HN N 191 O O NH O THF, 23 °C O O N Me N Me N Me 99% yield 81% ee 95% yield 93% ee 99% yield 93% ee O N Me 95% yield 80% ee IRIDIUM-CATALYZED ALLYLIC ALKYLATIONS You and coworkers have reported in 2010120 on the iridium-catalyzed intramolecular allylic alkylation reaction generating vicinal quaternary and tertiary stereocenters. Using [Ir(cod)Cl]2, phosphoramidite ligand 195 and cesium carbonate in dichloromethane they were able to transform indoles (193) into spirocyclic quaternary stereocenter-containing products (194) with good yields, diastereoselectivities, and enantioselectivities (Table 1.6.4.1). 61 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.6.4.1. Iridium-Catalyzed Intramolecular Allylic Alkylation Generating SixMembered Rings NR2 NR2 [Ir(cod)Cl]2, 195 R1 Cs2CO3, CH2Cl3 N H OCO2Me R1 N 193 194 Me N Bn N Bn N O F P N O N N 95%, >99:1 96% ee 95%, >99:1 96% ee N Me 93%, 97:3 88% ee 195 You and coworkers also targeted Spirocyclic products (197) bearing fivemembered rings in 2012. These products originated from indoles (196), this time using a BINOL-phosphoramidite derived ligand (198, Table 1.6.4.2).121 Table 1.6.4.2. Iridium-Catalyzed Intramolecular Allylic Alkylation Generating FiveMembered Rings R2 R2 R1 2. NaBH3CN, MeOH N H 196 R1 N OCO2Me CO2Me MeO2C R2 R2 1. [Ir(cod)Cl]2, 198 Cs2Co3, dioxane 197 CO2Me MeO2C Ph O P N Me N N N 93% yield 16:1 d.r. 98% ee 71% yield 4.5:1 d.r. 92% ee 96% yield 15:1 d.r. 97% ee O Ph 198 Initial work in the area of intermolecular iridium-catalyzed allylic alkylation by Takemoto and coworkers was focused on the generation of products bearing a tertiary stereocenter vicinal to a quaternary one.122 Stoltz and coworkers used iridium catalysis in the asymmetric allylic alkylation of cyclic β-ketoesters (199) to generate on reaction with 62 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 3-phenynylallyl acetate compounds bearing vicinal quaternary and tertiary stereocenters (201, 202, Table 1.6.4.3).123 [Ir(cod)Cl]2 and phosphoramidite ligand 195 in the presence of the TBD base were used to preferentially generate these branched products by electrophilic attack of position 3 of the allyl group with good regio-, diastereo-, and enantioselectivity. Linear allylation products 202 were also obtained but as minor byproducts. Branched to linear ratios as high as 95:5, diastereoselectivities greater than 20:1 and enantioselectivities exceeding 99% ee were obtained. Acyclic substrates were targeted in a later publication with some products being obtained in >99% ee and 20:1 diastereoselectivity.124 Table 1.6.4.3 Intermolecular Iridium-Catalyzed Allylic Alkylation to Generate Compounds Bearing Vicinal Quaternary and Tertiary Stereocenters O O OR1 199 O R2 CO2R1 LiBr, THF + R2 O [Ir(cod)Cl]2 195, TBD X R2 X X OCO2Me CO2R1 + 201 202 200 O Ph O CO2Me Ph CO2Me O b:l 95:5 98%, >20:1 >99% ee b:l 90:10 88%, 16:1 98% ee Ph O CO2Me t-BuO b:l 91:9 99%, 20:1 >99% ee Hartwig and coworkers have reported on an intermolecular iridium-catalyzed allylic alkylation reaction of tetralones and cyclohexanones and allylcarbonates using Ba(Ot-Bu)2 in tetrahydrofuran. The vicinal quaternary and tertiary stereocenter-containing products were obtained in diastereoselectivities up to >20:1 and enantioselectivities up to >99% ee using a preformed iridium phosphoramidite catalyst. 63 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Finally Stoltz and coworkers reported the enantioselective synthesis of acyclic aquaternary-containing carboxylic acid derivatives through iridium-catalysis (equation 1).125 Masked acyl cyanides were used as the stabilized nucleophile to add into the Ir pallyl complex formed from allylic carbonates and a phosphoramidite ligand. After an acidic workup, a-quaternary-center containing carboxylic acids were obtained in high yields and enantioselectivities. OMOM OCO2Me + NC CN Ar 1. BEt3 (200 mol %) [Ir(COD)Cl]2 (2 mol %) Ligand (4.2 mol %) TBD (10 mol%) THF, 60 °C 2. 6 N HCl, 80 °C O (1) HO 32 – 90% yield 85 – 95% ee Ar O P N O Ligand 1.6.5 RHODIUM-CATALYZED ALLYLIC ALKYLATIONS In 2016, Evans and coworkers reported the first example of a rhodium-catalyzed allylic alkylation of acyclic a-alkyl-benzaldehydes to form a quaternary center.126 Utilizing a BINOL-derived phosphite ligand (205), DMPU additive, and LiHMDS, Evans and coworkers successfully generated a,a’-disubstituted benzaldehydes in excellent yields and enantioselectivities (Table 1.6.5.1). While the substrate scope is fairly limited, reaction conditions tolerate a variety of steric bulk a- to the aldehyde as well as electron rich and deficient benzyl substitutions. 64 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.6.5.1. Scope of the Rhodium-Catalyzed Asymmetric Allylic Alkylation of Acyclic Aldehydes R2 R2 CHO i. RhCl(PPh3)3 (10 mol %) (R)-BINOL-MeOP (205) CHO DMPU, AllOBz, THF, 23 °C ii. LiHMDS R1 R1 203 1.6.6 204 R1 R2 Yield (%) ee (%) H H H Et i-Pr Cy 74 64 62 92 92 91 OMe Me F Br Et Et Et Et 79 75 72 83 91 92 86 77 O O P OMe 205 NICKEL-CATALYZED ALLYIC ALKYLATION In 2018, the Stotlz group reported the first example of a nickel-catalyzed intermolecular allylic alkylation of b-ketoesters with allyl alcohols (equation 2).127 Utilizing P-PHOS and Ni(COD)2 in Et2O at 10 °C Stoltz and coworkers successfully generated a-quaternary-center containing d-valerolactone in moderate yield and excellent yields. This method was further explored with benzoyl protected d-valerolactams to afford excellent yields and enantioselectivities. O O O OH O OR1 + R2 Ni(COD)2 (10 mol %) P-PHOS (12 mol %) O O OR1 (2) Et2O, 10 °C 60 – 90% yield 64 – 90% ee R2 1.7 MISCELLANEOUS ALKYLATIONS 1.7.1 ASYMMETRIC ALKYLATIONS OF CHROMIUM ENOLATES The first asymmetric alkylation of cyclic tin enolates using chromium. Complexes to generate quaternary stereocenters was reported in 2004 by Jacobsen.128 Preformed tin 65 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates enolates (206) were exposed to an alkyl halide (bromide or iodide) electrophile and a chiral salen-chromium complex catalyst (208) in benzene at 0 °C to give the enantioenriched alkylated cyclic ketone product (207) in good yield and enantioselectivity (Table 1.7.1.1). Table 1.7.1.1. Scope of Asymmetric Alkylation of Cyclic Tin Enolates Using Chromium Complexes R2X (X = Br, I) 208 OSnBu3 R1 O R2 R1 benzene, 0 °C n n 206 207 yield (%)2 ee (%) n R1 R2 1 Me CH2CCH 81 96 1 Me Bn 91 93 2 Me Et 43 90 2 CH2CO2Et Et 72 89 2 Bn 80 85 Me N N Cr t-Bu t-Bu O Cl O t-Bu t-Bu R,R-208 This work was extended to acyclic tin enolates (209) in 2007.129 Using a modified chiral (salen)–chromium complex catalyst (211), to generate a variety of linear quaternary stereocenter-containing products (210) in good yield and enantioselectivity, although the latter were not as high as those observed in the cyclic case (Table 1.7.1.2). Table 1.7.1.2. Scope of Asymmetric Alkylation of Acyclic Tine Enolates Using Chromium Complexes R2X (X = Br, I) 211 OSnBu3 O R2 o-xylene, –27 °C R1 R1 209 R1 R2 Et Bn 210 yield (%)2 ee (%) 86 Et CH2CO2Et 73 76 n-Bu Bn 83 86 97 78 n-Bu CH2CCSiMe3 N 81 N Cr Me2PhSiO O I t-Bu O t-Bu R,R-211 OSiPhMe2 66 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 1.7.2 ASYMMETRIC ALKYLATION OF LITHIUM ENOLATES Asymmetric alkylation to construct quaternary stereocenters has also been achieved from achiral lithium enolates using chiral tetradentate ligands. Reported in 1999 by Koga and coworkers, Lithium enolates were generated from the silyl enol ethers (212) and were subjected to a chiral tetradentate amine ligand (214) and a bromide electrophile to achieve the asymmetric alkylation product (213) in good yield and enantioselectivity for some of the ligands tested (Scheme 1.7.2.1).130 The scope of the reaction was not investigated in detail and although catalytic conditions were investigated, the best yields and enantioselectivities were observed when using the chiral ligand in stoichiometric ratio. Scheme 1.7.2.1. Asymmetric Alkylation of Cyclic Lithium Enolates Utilizing Tetradentate Amine Ligands OTMS OLi O PhCH2Br 214 (1 equiv) MeLi•LiBr Bn toluene –45 °C, 48h 213 212 93%, 94% ee Ph Ph N HN N NH R,R-214 In 2017, Zakarian and coworkers utilized similar conditions to perform the asymmetric alkylation of carboxylic acid 215 with various electrophiles to generate allcarbon quaternary center containing products 216.131 Double deprotonation of the acid 215 by n-BuLi in the presence of stoichiometric chiral amine 214 followed by addition of the electrophile generated the products 216 in good yield (80%) and enantioselectivity (90%, Scheme 1.7.2.2). 67 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Scheme 1.7.2.2. Asymmetric Alkylation of Acyclic Acids Using Tetradentate Amines O Ph HO O i. 214, n-BuLi THF, 0 °C II. EtX, –78 °C, THF Ph HO Et 215 216 80% yield 90% ee 1.8 a-ARYLATION AND a-ALKENYLATION 1.8.1 INTRODUCTION The first metal-catalyzed a-arylation reaction132 of a carbonyl compound was reported in 1973 by Semmelhack and coworkers,133 using [Ni(cod)2] to effect the ringclosure of 217 to obtain cephalotaxinone (218) in 25–30% yield (Scheme 1.8.1.1). In 1992 Musco, Santi, and coworkers reported the first asymmetric α-arylation reaction,134 using palladium–(R)-BINAP complex generated in situ to obtain in 68% yield and 54% ee from a silyl ketene acetal and bromobenzene. Other chiral phosphine ligands provided reduced enantioselectivities. In 1997 Muratake and Natsume135, Buchwald,136 Hartwig,137 and Miura138 independently reported palladium-catalyzed catalyzed a-arylation reactions that produced racemic or achiral products from readily available ketones; these methods served as a foundation for the development of an asymmetric a-arylation reaction that forms asymmetric quaternary stereocenters. Scheme. 1.8.1.1. a-Arylation In the Synthesis of Cephalotaxinone (218) O O O O I O 217 O N N OMe H N O Ni O OMe O OMe 218 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 1.8.2 68 PALLADIUM-CATALYZED REACTIONS In 1998, the first asymmetric a-arylation reaction of ketone enolates yielding quaternary stereocenter-containing products was reported by Buchwald and coworkers.139 Using 10–20 mol % of a palladium(0)–(R)-BINAP complex catalyst in toluene at elevated temperatures, 2-methyl- a-tetralone (220) could be a-arylated with a variety of aryl bromides giving modest to good yields (40–74%) and enantioselectivities (61–88% ee) of the quaternary stereocenter-containing products 224 (Table 1.8.2.1). 2-Methyl-1-indanone and 2-methylcyclopentanone derivative could also be obtained in high yields and enantioselectivities. Interestingly, a-arylated 2-methylcyclohexanone derivative could only be obtained with low enantioselectivity and no clear explanation was provided for this phenomenon. An intramolecular variation of this method was applied in Zhang’s synthesis of physovenine albeit proceeding in extremely low enantioselectivity and only moderate yield.140 Table 1.8.2.1. Scope of Palladium BINAP-Catalyzed a-Arylation Reaction O O R1 Pd(0)/BINAP NaOt-Bu Br * R1 + toluene, 100 °C 219 220 O 221 O * O * * O O 40% yield 61% ee CN 73% yield 88% ee t-Bu 74% yield 84% ee Buchwald and coworkers extended this methodology to the asymmetric αvinylation of ketone enolates.141 Considering that the palladium–BINAP catalyst led to the desired product in low yield and enantioselectivity, additional ligands were investigated. Prior work142 on the racemic a-arylation reaction identified 2aminophosphine ligand 222 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 69 and simpler desamino ligands 223 and 224 as efficient ligands for a-arylation (Figure 1.8.2.1). Figure 1.8.2.1. Aminophosphine and Desamino Ligands for a-Vinylation NMe2 R' R' NMe2 PCy2 PR2 PR2 PCy2 222 223 224 225 DavePhos R = t-Bu, Cy R' = H, Me, i-Pr JohnPhos R = t-Bu, Cy R' = H, Me, i-Pr KenPhos Therefore, enantiomerically pure analogs of these ligands were synthesized and screened in the asymmetric a-vinylation reaction. Aminophosphine ligand 225 was found to provide the best yields and enantioselectivities in the synthesis of asymmetric vinylated ketones 228, in combination with [Pd2(dba)3] for the reaction of cyclic ketones 226 (R1 = Me) and trans-1-bromopropene (227, R2 = H, R3 = Me, Table 1.8.2.2). Lower temperatures provided increased enantioselectivities, but room temperature was found to provide the best balance of reactivity and selectivity. The scope of the reaction was quite broad with, a-vinylated derivates of 2-alkylcyclopentanones, 2-methylcyclohexanone, 2methyl-a-tetralone (229), and 2-methyl-1-indanone (230) all being obtained in good to excellent yields (76–96%) and modest to good enantioselectivities (50–92%). 70 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.8.2.2. Scope of Palladium-Catalyzed a-Vinylation Reaction Ph O N Me R1 + [Pd2(dba)]3 225 R2 Br R3 Ph NaOt-Bu, toluene O N Me R1 R2 * n n 226 n R1 227 228 R2 R3 yield (%) ee (%) Me H Me H Me H Me Me n-Pr H n-Pen H Me H Me Ph H Me H H H 95 92 94 95 86 84 78 90 89 92 71 90 92 50 O O 1 1 1 1 1 1 2 R3 * * 229 230 96% yield 80% ee 95% yield 74% ee Following the success of enantiomerically pure aminophosphine and desamino phosphine ligands in the asymmetric a-vinylation reaction, they were also utilized in the asymmetric a-arylation reaction.143 Aminophosphine ligand 233, the optimal ligand found for the asymmetric a-vinylation reaction, was found to give the highest combined yield and enantioselectivity in the a-arylation reaction. The reaction with aminophosphine ligand 225 could be conducted at room temperature rather than the elevated temperatures required in the initial system, and a lower catalyst loading was also possible. Some ligands that were not previously screened in the asymmetric a-vinylation reaction, namely MOPderived ligands, were also tested in the a-arylation reaction. Ligand 233 outperformed aminophosphine ligand 225 in the a-arylation reaction of cyclopentanone 231 with 3bromotoluene, consistently giving higher yields and better enantioselectivities (up to 94% ee) under the same mild conditions (Table 1.8.2.3). 71 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.8.2.3. Scope of Palladium MOP-Derived Ligand-Catalyzed a-Arylation Br O Ph R1 + N Me O [Pd2(dba)3] 233 R Ph t-BuONa, toluene N Me * 232 231 R1 yield (%)2 ee (%) Me 85 94 n-Pr 85 88 n-Pen 85 88 O P(i-Pr)2 R-233 Further work by Buchwald and coworkers investigated P-chirogenic binaphthyl substituted monophosphine ligands in palladium-catalyzed asymmetric a-arylation and avinylation reactions.144 Diastereomeric ligand 236 was found to give similar results as 225 for the a-vinylation reaction of 234 but reactions with 236 or its diastereomer 237 tested in the a-arylation of 234 were unable to exceed 10% ee of ketone 235 (Table 1.8.2.4) Table 1.8.2.4. Scope of Palladium P-Chirogenic Binaphthyl Monophosphine LigandCatalyzed a-Arylation and a-Vinylation Reactions Pd2(dba)3 236 or 237 O Ph + O RBr NaOt-Bu, toluene N Me Ph N Me * R 235 234 RBr Br Br 236 237 96% 86% ee 91% 34% ee 57% 5% ee 83% 10% ee NMe2 NMe2 P P t-Bu Ph 236 Ph t-Bu 237 These ligands were studied again in the context of palladium-catalyzed a-arylation and a-vinylation of 3-substituted oxindoles with more satisfying results.145 For the a- Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 72 arylation reaction of oxindoles (e.g. 238) using 237 as the chiral ligand, good yields and ee values greater than 99% could be obtained of 239 (Table 1.8.2.5). Table 1.8.2.5. Scope of Palladium-Catalyzed a-Arylation and a-Vinylation of 3-Substituted Oxindoles R1 O R1 + NaOt-Bu, cyclohexane Br N Me TMEDA•PdMe2 237 O N Me 238 239 CF3 O O O O N Me N Me N Me N Me 63% yield 95% ee 79% yield 97% ee 70% yield >99% ee trans- 87% yield 54% ee cis- 79% yield 94% ee Enantioenriched 3-alkyl-3-aryloxindoles (240) were also the targeted products of Aoyama and coworkers. however, they were interested in an asymmetric intramolecular aarylation reaction to close the oxindole ring in N-arylamides (241) rather than intermolecular arylation on an existing oxindole skeleton.146 Using palladium and the (S)H8-BINAP ligand (242), they were able to effect this ring closing reaction (Table 1.8.2.6) in good yields (up to 97%) but only moderate enantioselectivities (51–67%) for a small collection of substrates. 73 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Table 1.8.2.6. Scope of Palladium-Catalyzed Intramolecular a-Arylation Reaction to Form Oxindoles R R Pd(OAc)2 242 PPh2 NaOt-Bu, toluene Br N Me PPh2 O O N Me 240 241 242 i-Pr O N Me 81% yield 51% ee O N Me 92% yield 67% ee O O N Me N Me 87% yield 59% ee 97% yield 63% ee In addition to the success of phosphine and aminophosphine ligands, carbene ligands have also found widespread use in the palladium catalyzed asymmetric a-arylation reaction (Table 1.8.2.7). The first report of carbene ligands in a palladium-catalyzed asymmetric a-arylation reaction generating quaternary stereocenter-containing products is by Lee and Hartwig in 2001,147 who investigated N-heterocyclic carbene (NHC) ligands 245–247 in the intramolecular a-arylation reaction of N-(2-bromophenyl)-a- arylpropionamides (243) to form enantioenriched 3,3-disubstituted oxindoles 244 (Table 1.8.2.7). Ligand 245, derived from trans-1,2 diaminocyclohexane, performed as well as the phosphine ligands that were also investigated, although the enantioselectivities for both did not exceed 61%. Ligands 246 and 247, derived from (–)isopinocamphenylamine and (+)-bornylamine respectively, gave slightly higher enantioselectivities. Additionally, reactions with ligand 247 proceeded quite rapidly at room temperature allowing for even greater selectivities. After optimization of the base and solvent, the substrate scope was investigated for ligands 246 and 247. Good yields and enantioselectivities ranging from Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 74 33% to 69% were obtained when using ligand 246 at room temperature or above. Ligand 247 performed slightly better, with enantioselectivities ranging from 40% to 76% at room temperature or below, but yields were highly variable, ranging from 5% to 95%. Table 1.8.2.7. Scope of Palladium Carbene Ligand-Catalyzed Intramolecular aArylation Reaction to Form Oxindoles X Pd2(dba)3 Ligand O NR1 Ar Ar * NaOt-Bu DME O N NR1 243 N BF4 244 245 R1 Ar X Ligand Yield (%) ee (%) Bn Bn Me Me Me Me Me Me 1-Naph 1-Naph 1-Naph 1-Naph 1-Naph 1-Naph Ph Ph Br Br Cl Cl I I Br Br 246 247 246 247 246 247 246 247 88 75 91 5 75 30 94 74 67 76 69 58 0 40 34 57 Me N N BF4 246 N N BF4 247 Further studies suggest the mechanism consists of oxidative addition of the catalyst to form palladacycle 249, base-mediated formation of a C-bound palladium enolate (250), and reductive elimination to form the achiral product (251, Figure 1.8.2.2). Figure 1.8.2.2. Proposed Mechanism of Palladium-Catalyzed Intramolecular aArylation Reaction Forming Oxindoles Br O Pd(PCy3)L O N Me N Me 248 251 Cy3P PCy3 Br Pd Pd O N Me N Me O 250 NaBr + HOt-Bu 249 NaOt-Bu 75 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates The use of chiral carbene ligands in the palladium-catalyzed intramolecular aarylation reaction to form enantioenriched 3,3-disubstituted oxindoles has also been investigated by Glorius and coworkers.148 Although the major focus of this report was the synthesis and characterization of enantioenriched oxazoline-derived imidazolium salts, their subsequent deprotonation, and coordination to palladium, they also demonstrate the use of their novel NHC-palladium complex in the enantioselective synthesis of oxindole 253 (Scheme 1.8.2.1). Compound 253 has been previously synthesized by Lee and Hartwig, also via a palladium-catalyzed intramolecular a-arylation reaction, using 5 mol % of their palladium/NHC (247) catalyst to obtain a 74% yield of 253 with 57% ee at room temperature. Glorius and coworker’s oxazoline-derived imidazolinium triflate 254 in combination with Pd2(dba)3 and sodium tert-butoxide was able to catalyze the formation of 253 in an improved 95% yield but with slightly diminished 43% ee at room temperature. Scheme 1.8.2.1. NHC-Palladium Complex-Catalyzed Intramolecular a-Arylation Br O N Me 252 Ph NaOt-Bu, DME * N Me 253 95%, 43%ee O O Ph Pd2(dba)3, 254 N O t-Bu + N TfO– t-Bu 254 An asymmetric palladium-catalyzed intramolecular a-arylation reaction to form enantioenriched 3,3-disubstituted oxindoles using carbene ligands was also reported by Kondo, Aoyama, and coworkers.149 They screened a number of NHC ligands 255 and 256 in the synthesis of 253, a product targeted by Hartwig and Glorius. Using 255 as the NHC ligand precursor and sodium t-butoxide as the base, they were able to obtain the product in 67% ee, but the yield was only 14%. The yield could be increased to 62% by switching the 76 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates base to lithium t-butoxide but the enantioselectivity was slightly diminished to 61% ee (Figure 1.8.2.3). Figure 1.8.2.3. NHC Ligands Screened in Intramolecular a-Arylation Reaction Reported by Kond, Aoyama, and Coworkers Ph N R Ph – N BF4 R 255 R= adamantyl (Adm) 256 R= adamantylmethyl 257 R= t-butyl 258 R= t-butylmethyl N N Adm BF4– Adm 259 In 2007, Kündig and coworkers150 synthesized five novel imidazolium salts 260– 264 and screened them in the palladium-catalyzed ring-closing reaction of 252 to form 253 (Table 1.8.2.8). Previously the highest enantioselectivity seen in this reaction was 67% by using Kondo and Aoyama’s 255 as the NHC ligand precursor. Kündig and coworker’s NHC ligand precursor 264 in combination with Pd(dba)2 and sodium tert-butoxide was able to catalyze the formation of 253 in 94% ee and quantitative yield. The scope of this reaction was also investigated and found to be quite broad, with only ortho- or electronwithdrawing substituents on the aniline ring resulting in low reactivity. Table 1.8.2.8. Ligand Screen for Palladium-Catalyzed Intramolecular a-Arylation Reaction Reported by Kündig and Coworkers Br Ph N Me Ph Pd(dba)2 Ligand, NaOt-Bu O * DME O N Me 252 253 BF4– I– R R Ligand Yield (%) ee (%) 260 261 262 263 264 72 93 96 98 99 16 77 87 57 94 I– t-Bu t-Bu N N N N N N O O O O R R 260 261 R= i-Pr 262 R= t-Bu 263 R= H 264 R= Me Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 77 The asymmetric a-arylation of aldehydes was first reported in 2008 by Buchwald and coworkers.151 Initial optimization of reaction conditions concluded that the use of tBu-PHOX ligand 158 in t-BuOH with Pd(OAc)2 and excess Cs2CO3 provided the highest yield (92%) and best enantioselectivity (81% ee) for the cyclization product (266) of 265 (Scheme 1.8.2.2). Scheme 1.8.2.2. Palladium-Catalyzed Intramolecular a-Arylation of Aldehydes Reported by Buchwald and Coworkers CHO Pd(OAc)2 158 Cs2CO3 t-BuOH Br 265 OHC 266 92% yield, 81% ee Additional PHOX ligands with varied steric and electronic properties were screened. No clear trend in ligand electronics could be seen but steric factors did play a major role in selectivity; bulky substituents on the phosphine leading to reduced enantioselectivities. Using t-Bu-PHOX ligand 269 a number of enantioenriched indane derivatives 268 bearing alkyl or aryl substituents were obtained in moderate to good yields and good to excellent enantioselectivities from aryl bromide 267 (Table 1.8.2.9). Tetrahydronaphthalene derivatives proved to be more challenging products to obtain in high enantioselectivities using these conditions. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 78 Table 1.8.2.9. Scope of Asymmetric Intramolecular a-arylation of Aldehydes Forming Indanes R1 Pd(OAc)2, 269 CHO * Cs2CO3, t-BuOH 1 OHC R Br 267 R1 Yield (%) 268 ee (%) O Me 64 87 i-Pr 86 94 t-Bu 88 96 Cy 87 96 Ph 81 98 MeO P N t-Bu HBF4 OMe 269 Hartwig and coworkers were the first to report on the a-arylation of ketones using aryl triflates rather than aryl halides.152 Using DIFLUOROPHOS ligand and Pd(dba)2 catalyst in the presence of two equivalents of sodium tert-butoxide, the arylation of tetralone 220 using bromobenzene or phenyl trifluoromethanesulfonate was investigated (Scheme 1.8.2.3). Although both reactions yielded product in 85% ee at 80 °C, the reaction of the aryl triflate proceeded faster allowing this reaction to be carried out at a lower temperature. At 60 °C, arylation of tetralone 220 with phenyl triflate provided the product in 90% ee. These optimized conditions were then applied in a substrate scope study. A variety of cyclic ketones were a-arylated with electron-rich and electron-neutral aryl triflates yielding quaternary stereocenter-containing products in good yields and enantioselectivities. a-Arylation using electron-poor aryl triflates required switching the palladium(0) catalyst to Ni(cod). Tetralone 220 and the analogous indanone were aarylated under these nickel-catalyzed conditions to yield products in moderate to good yields and good to excellent enantioselectivities. 79 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Scheme 1.8.2.3. Palladium-Catalyzed Asymmetric a-Arylation of Ketones Using Aryl Triflates O O Pd(dba)2 DIFLUOROPHOS 63 X + X = Br, OTf 220 Ph * NaOt-Bu, toluene 270 X= OTf at 80 °C: 85% ee X= Br at 80 °C: 85% ee X= OTf at 60 °C: 90% ee Finally in 2019, Stoltz and coworkers reported the first enantioselective a-arylation glactams (equation 3).153 Using dialkylferrocelane type ligands with Pd2(pmdba)3 and a strong base in dioxane, a-quaternary containing g-lactams were obtained in moderate to good yield and great enantioselectivities. Interestingly depending on the choice of base both aryl chlorides and aryl bromides could successfully undergo the desired transformation. Pd2(pmdba)2 (2.5 mol %) Ligand (7.5 mol %) O PMP N R1 + ArX O PMP LiHMDS or NaHMDS dioxane, 80 – 100 °C X = Cl, Br Ar N (3) R1 44 – 88% yield 78 – 95% ee R2 R2 P Fe R2 P R2 Ligand R = Et or Me 1.8.3 NICKEL-CATALYZED REACTIONS In addition to the nickel-catalyzed a-arylation using electron-poor aryl triflates discussed in relation to Scheme 1.8.5.3, Hartwig and coworkers have utilized nickel also in the catalytic asymmetric intermolecular a-arylation and heteroarylation of ketones using aryl chlorides.154 Aryl halides and triflates were investigated in the nickel-catalyzed a- 80 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates arylation of indanone 271 to form 272 using a variety of bidentate phosphine ligands (Scheme 1.8.3.1). For all ligands tested the yields and enantioselectivities of the reactions using phenyl chloride (X = Cl) exceeded the results obtained for the other electrophiles (X = Br, I, OTf). BINAP (61), SEGPHOS (62), DIFLUORPHOS (63), and P-PHOS (273) complexes of nickel were all able to catalyze the formation of 272 with yields ranging from 67% to 80% and enantioselectivities from 93% to 96%. Because of its availability and low cost, BINAP was selected as the ligand in further substrate scope studies. Scheme 1.8.3.1. Nickel-Catalyzed Asymmetric a-Arylation of Indanones OMe N O X + 271 [Ni(cod)2] Ligand (L) NaOt-Bu, toluene X = Cl, Br, I, OTf L = 61, 62, 63, 273 O * 272 MeO PPh2 MeO PPh2 Ph N OMe 273 P-PHOS Electron-neutral, electron-rich, and electron-poor aryl chlorides were all competent substrates for the a-arylation of alkyl-substituted indanones and tetralones 274 with yields ranging from 58% to 89% and enantioselectivities from 90% to 99%. When heteroaryl bromides were investigated, no product was observed with BINAP (61) as the ligand; however, switching to DIFLUORPHOS (63) recovered the reactivity, albeit only in moderate yield and enantioselectivity (Table 1.8.3.2). Switching from heteroaryl bromides to heteroaryl chlorides boosted the yield and enantioselectivity dramatically. Several chloropyridine derivatives bearing electron-donating and electron-withdrawing groups, as well as 3-chlorothiophene, were successfully coupled with methyl-substituted indanone and tetralone 274 with moderate to good yields (54–93%) and moderate to excellent 81 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates enantioselectivities (81–99%). Reactions of 2-chloro-6-methoxypyridine proceeded in low enantioselectivity presumably due to chelation to the nickel center and two of the electrondeficient 2-chloropyridines proceeded in low enantioselectivity due to competing uncatalyzed nucleophilic aromatic substitution.154 Table 1.8.3.1. Nickel-Catalyzed Intermolecular a-Heteroarylation of Cyclic Ketones O + ArCl Ni(cod)2 63, NaOt-Bu O toluene, 70 °C * n Ar n 274 275 O O * O * OMe * N 54% yield 91% ee CF3 76% yield 96% ee OMe O N N O 86% yield 98% ee F O N F CF3 N 68% yield 94% ee N 84% yield 93% ee 89% yield 99% ee Prior to Hartwig’s work on the asymmetric α-arylation of ketones using nickel– BINAP complex catalysts and aryl chlorides, Buchwald and coworkers reported the asymmetric a-arylation of g-lactones (276) using nickel–BINAP complex catalysts and both aryl bromides and aryl chlorides.155 The optimized conditions included the use of catalytic [Ni(cod)2], BINAP, and ZnBr2 along with 2.3 equiv of NaHMDS and an excess of the lactone in toluene–THF (3:1) solution at elevated temperatures. It is postulated that the ZnBr2 acts as a Lewis acid facilitating halide abstraction generating a cationic nickel complex that undergoes transmetalation more rapidly resulting in the observed rate increase as well as the improved yield. The scope of this reaction was studied and it was found that o-substitution on the aryl halide is not tolerated, but both electron-rich and Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 82 electron-poor aryl halides can be coupled with yields of g-lactones (277) ranging from 57% to 95% and enantioselectivities ranging from 90% to 99% (Table 1.8.3.2). Various alkyl substitution on the lactone were tolerated with yields as high as 91% and enantioselectivities up to 98%. Table 1.8.3.2. Asymmetric a-Arylation of Lactones Using Nickel BINAP Catalysts O R1 O + ArX Ni(cod)2 BINAP NaHMDS ZnBr2 toluene/THF 276 O R1 O * Ar 277 R1 Ar X yield (%) ee (%) Me 2-Naph Br 33 98 Me 2-Naph Cl 95 94 Me 3-Me2N Cl 81 >97 Me 3-CO2Bu-t Br 58 93 Bn 2-Naph Cl 91 96 All 2-Naph Cl 80 89 Bn 3-Me2N Cl 58 96 i-Pr Ph Cl 84 98 The asymmetric nickel-catalyzed a-arylation reaction leading to quaternary stereocenters (Table 1.8.3.3) was reported by Kwong, Chan, and coworkers in 2006.156 The P-PHOS (273)–nickel complex in combination with sodium t-butoxide in toluene was able to effect the a-arylation of tetralone 274 with bromobenzene in 85% yield and 92% ee at elevated temperatures. Bromobenzene, chlorobenzene, and iodobenzene were all competent aryl coupling partners although yields were diminished when using chlorobenzene. A variety of meta- and para-substituted aryl bromides could be coupled in moderate to good yield and good to excellent enantioselectivities. Indanone 274 and benzosuberone containing a cycloheptanone moiety were also competent substrates. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 83 Table 1.8.3.3. Asymmetric Nickel Catalyzed a-Arylation Reaction Using P-Phos Ligand Ni(cod)2 273 NaOt-Bu O + ArX * toluene, 100 °C X = Cl, Br, I n 274 n = 1, 2, 3 1.8.4 O Ar n 275 n = 1, 2, 3 n Ar X yield (%) ee (%) 1 Ph Br 85 92 1 Ph I 97 92 1 Ph Cl 59 91 1 4-t-BuC6H4 Br 92 95 0 Ph Br 78 88 0 4-Tol Br 69 87 2 Ph Br 70 73 COPPER-CATALYZED REACTIONS One example of an asymmetric copper-catalyzed a-arylation was reported by Ma and coworkers in 2006.157 This Ullman-type reaction involves the use of CuI and trans-4hydroxy-l-proline, the chiral ligand, with sodium hydroxide as the base and aqueous DMF as the optimal solvent (Scheme 1.8.4.1). Notably these reactions are performed at low temperatures which is rare for Ullman-type reactions. Substituted b-ketoester 279 could be a-arylated with aryl iodides 278 under optimized conditions to generate 280 in yields ranging from 70% to 82% and enantioselectivities ranging from 60% to 93%. The NHCOCF3 group on the aryl iodide is necessary as it promotes the Ullman-type reaction. Additional substitution on the aryl ring is tolerated although aryl iodides bearing electronwithdrawing groups require increased temperatures to ensure complete conversion and suffer from reduced yields due to competing reductive homo-coupling. Ethyl, isopropyl, and t-butyl ester substituents were also well tolerated, although the scope of the reaction in regards to the a-substituent on the b-ketoester was not examined. 84 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Scheme 1.8.4.1. Copper-Catalyzed Asymmetric a-Arylation Reported by Ma and Coworkers NHCOCF3 O CuI (2S,4R)-4-hydroxyproline O NaOH, DMF/H2O, –45 °C + Y I RO 278 279 NHCOCF3 O Y O OR 280 70–82% yield 60–93% ee 1.9 PERICYCLIC REACTIONS 1.9.1 CLAISEN-TYPE REACTIONS Pericyclic reactions have long served as important carbon-carbon bond forming reactions especially fir the generation of quaternary centers. The Claisen rearrangement, discovered in 1912,158 has seen over 100 years of use and many variations have been developed, including asymmetric methods.159 Three asymmetric Claisen-type reactions yielding quaternary stereocenter-containing products that proceed through a metal enolate intermediate have been reported. The first one was reported by Corey and coworkers in 1995.160 Their enantioselective Ireland-Claisen rearrangement relies on the use of chiral boron reagent 283, which provides good control over the geometry of the intermediate boron enolate. Previous work with this reagent found that use of triethylamine as the base in toluene resulted in the formation of the (Z)-boron enolate.161 Corey applied this method to the synthesis of (+)-b-elemene (283). Compound 284 was treated with chiral boron reagent 283 and triethylamine in toluene to yield 282 as a mixture of two diastereomers (Scheme 1.9.1.1). After reduction of the carboxylic acid to a primary alcohol and purification to separate the two diastereomers, 284 was obtained in 70% yield and >99% ee. 85 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Scheme 1.9.1.1. Corey’s Synthesis of (+)-b-Elemene CF3 CF3 Ph F3C S O2 Ph N B Br N S O2 CF3 O 283 O NEt3, toluene –70 °C to 4 °C 85% yield of two diastereomers 281 LiAlH4, Et2O, 23 °C H CO2H 282 4 Steps 70% yield of single diastereomer 99% ee H H OH H 285 284 (+)-β-elemene Corey also applied this method in the synthesis of dolabellatrienone in which 286 was reacted with chiral boron reagent 283 and Hünig’s base affording 287 in >97:3 dr and >99% ee but only a 31% yield (Scheme 1.9.1.2).162 The yield could be increased to 86% with no major loss in enantioselectivity or diastereoselectivity by switching to the more hindered base penta-isopropylguanidine. Scheme 1.9.1.2. Enantioselective Ireland-Claisen Rearrangement in Corey’s Synthesis of Dolabellatrienone 283, i-Pr2NEt O O 286 CO2H H –78 °C 31% yield, >97:3 dr >99% ee 287 The second example of an asymmetric Claisen-type reaction yielding quaternary stereocenter-containing products that proceeds through a metal enolate was reported by Krebs and Kazmaier in 1996.163 Addition of LHMDS and excess Al(Oi-Pr)3 to trifluoroacetyl-protected disubstituted allylic glycine ester 288 in the presence of quinine (291) in THF at −78 °C results in the formation of chiral chelated aluminum enolate 289 86 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates which, upon warming to room temperature undergoes an ester enolate Claisen rearrangement forming enantioenriched amino acid 290 (Scheme 1.9.1.3), containing a bquaternary carbon stereocenter in high diastereoselectivity and good enantioselectivity. A variety of alkyl and aryl substituents were tolerated at the R1 position with diastereoselectivities ranging from 9:1 to 49:1 dr and enantioselectivities from 81% to 93%, although the yields were quite low with none exceeding 51% and some as low as 12%. The only substituent investigated at the R2 position was methyl because Z-configured esters failed to give the desired rearranged product, indicating that large cis-oriented substituents sterically crowd the quinine ligand in the coordination sphere. Scheme 1.9.1.3. Asymmetric Claisen-Type Reaction Using Aluminum Reported by Krebs and Kazmaier R1 R2 O F3C N H O O R1 LHMDS, Al(Oi-Pr)3 O 291 THF, –78 °C F3C 288 O R2 N [Al] R2 R1 O O 289 0 °C F3C N H OH O 290 N HO MeO N 291 The third example is an asymmetric ketene-Claisen rearrangement, also known as a Belluš–Claisen rearrangement, reported by MacMillan and coworkers in 2001. The Belluš-Claisen rearrangement, discovered in 1978,164 is the reaction of an allylic ether, thioether, or amine (292) with a ketene (293), producing a zwitterionic intermediate (294) that undergoes a [3,3] sigmatropic bond reorganization yielding an E unsaturated ester, 87 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates thioester, or amide (295) (Scheme 1.9.1.4).165 Prior work by MacMillan and coworkers found that Lewis acids could serve to coordinate and activate the in situ formed ketene resulting in high yields and excellent diastereoselectivities of racemic rearranged products.166 They envisioned that chiral Lewis acids may be able to effect enantioinduction in this rearrangement and in a subsequent publication they reported an asymmetric keteneClaisen rearrangement.167 Scheme 1.9.1.4. Generic Asymmetric Ketene-Claisen Rearrangement R1 C O R2 X 292 R1 293 X R2 R1, R2 = H, alkyl, Cl, CN [3,3] X O O 294 295 R1 R2 X = O, S, NR Optimized reaction conditions of the acyl-Claisen rearrangement using Nallylmorpholines (e.g. 296) included the use of an excess of chiral Lewis acid [MgARBOX](I)2 complex 300 in CH2Cl2 with Hünig’s base and acid chloride 297 serving as the ketene surrogate (Scheme 1.9.1.5).167 The -OBn group of 297 was crucial to obtaining good yields and enantioselectivities of the rearranged products as it serves to chelate the magnesium center in the intermediate magnesium enolate 298. Although the reaction optimization was conducted on substrates yielding enantioenriched products bearing tertiary stereocenters, these conditions were also readily applied to 3,3-disubstituted allyl morpholine 271 which undergoes the acyl-Claisen rearrangement with acid chloride 297 to yield quaternary stereocenter-containing 299 in 75% yield, 97% ee, and 94:6 syn:anti diastereoselectivity. 88 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates Scheme. 1.9.1.5. Asymmetric Ketene-Claisen Rearrangement O OBn Cl O O 297 N N+ CO2Et 300, i-Pr2NEt –20 °C O O CO2Et 298 Cl O Mg N I MeO 299 Cl O 1.9.2 OBn Bn Mg 296 N O O CO2Et N I R,R-300 [Mg-ARBOX](I)2 OMe CONIA-ENE REACTION The Conia-ene reaction was first reported in 1968 by Conia and coworkers as the thermal intramolecular cyclization of a ketone or aldehyde with a tethered terminal alkene or alkyne.168 Mechanistically, the reaction proceeds by two distinct steps (Scheme 1.9.2.1): first the ketone or aldehyde (301) is tautomerized at elevated temperatures to form the enol (302), which then undergoes a hydrogen shift from the enol group to the terminal double or triple bond with simultaneous formation of the new carbon–carbon bond (303).169 A number of metals have been utilized in the asymmetric Conia-ene reaction including palladium, copper, lanthanum, and iron. Scheme 1.9.2.1. Mechanism of the Conia-Ene Reaction R H R O 301 R = H, Alk R O O H 302 303 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 89 Toste and coworkers reported the first palladium-catalyzed Conia-ene reaction in 2005.170 Stemming from their interest in the gold(I)-catalyzed intramolecular addition of b-ketoesters to alkynes,171 they envisioned that a chiral gold complex may be able to catalyze an asymmetric Conia-ene reaction. Although good yields were observed for this gold-catalyzed transformation the product was racemic. A screen of other metals identified the palladium complex with DTBM-SEGPHOS (64) as a competent catalyst for this reaction with moderate enantioselectivity, although the yield was low and the reaction proceeded slowly. Further optimization identified Yb(OTf)3 as a co-catalyst which boosted the rate of the reaction and excess acetic acid as an additive which improved the asymmetric Conia-ene reactivity with good yields of 305 ranging from 70% to 97% and enantioselectivities ranging from 70% to 94%, with the exception of the aliphatic bketoester 305 (R1 = Cy, R2 = OEt), which proceeded in only 44% ee (Table 1.9.2.1). Mechanistically they propose the reaction proceeds through a palladium enolate that undergoes Lewis acid-promoted addition to the alkyne. Table 1.9.2.1. Scope of Palladium DTBM-SEGPHOS 64 Catalyzed Conia-Ene Reaction O O R1 (DTBM-SEGPHOS)Pd(OTf)2 Yb(OTf)3 R2 R1 O R2 O AcOH, Et2O, 23 °C 304 305 R2 yield (%) ee (%) Ph OEt 86 89 Ph Ot-Bu 94 80 Cy OEt 97 44 90 70 R1 Ph Me Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 90 Dixon and coworkers reported a copper-catalyzed asymmetric Conia-ene reaction in 2009.172 Their cooperative catalysis approach aimed to utilize a cinchona-derived bifunctional catalyst (306) as well as a “soft” transition-metal ion. After optimization copper(I) triflate in combination with 306 was found transform 305 to b-ketoester 305 yielding up to a 92% ee and 98% conversion (Table 1.9.2.2). A number of pentynyl bketoesters with varying substituents on the ester and ketone groups were subjected to this reaction. Aliphatic, electron-rich, and electron-poor aromatic substrates were all competent participants in the cyclization reaction, with yields ranging from 67% to 98% and enantioselectivities ranging from 79% to 93%. b-Ketoamides were also found to be good substrates. Homologation of the carbon chain leading to the terminal alkyne was not tolerated in the reaction and products bearing six- or seven-membered rings could not be generated. Detailed kinetic and computational studies were completed in order to elucidate the mechanism of this transformation.173 Table 1.9.2.2. Scope of Copper-Catalyzed Asymmetric Conia-Ene Reaction O O R1 CuOTf•1/2C6H6 306 R2 O R2 R1 O CH2Cl2, 23 °C 304 305 R1 R2 yield (%) ee (%) Ph OMe 98 92 Ph OBn 95 89 Me OEt 85 83 Ph NHPh 85 83 N NH N O F3C NH CF3 S-306 The proposed mechanism (Scheme 1.9.2.2) begins with rate-determining enolization of the b-ketoester 307 forming copper enolate 308. Coordination of the Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 91 cinchona-derived pre-catalyst to the copper center is followed by the stereo-determining syn-carbocupration generating 309, which undergoes protonation–demetallation to form the product 310 and regenerate the catalyst. Scheme 1.9.2.2. Proposed Mechanism of Copper-Catalyzed Asymmetric Conia-Ene Reaction O O Ph OEt CuOTf•1/2 C6H6 306 L D Cu CH2Cl2, 23 °C D Ph CO2Et 307 D O 308 L H O Ph CO2Et 310 H+ D Cu O Ph CO2Et 309 Another example of the use of cooperative catalysis in the asymmetric Conia-ene reaction of malonic ester amide 311 comes from Kumagai, Shibasaki, and coworkers.174 Their initial catalyst system used the combination of La(NO3)3, an amide-based chiral ligand 313, and the protonated amino acid ester H-l-Val-Ot-Bu, in 1:1:3 ratio, in the presence of a soft Lewis acid. Screening of soft Lewis acids found that AgOAc in the presence of phosphine ligand 314 gave the desired product 312 in 55% yield, albeit with only slight enantioinduction (Scheme 1.9.2.3). The selectivity of the reaction was improved by modifying the metal to ligand ratios, switching from 314 to triphenylphosphine, and cooling the reaction down to 0 °C. With optimized conditions in hand a variety of substrates were subjected to the asymmetric Conia-ene reaction. Yields ranging from 63% up to 100% and enantioselectivities ranging from 83% to 96% were obtained for a variety Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 92 of substrates, with the exception of one bearing an electron-donating methoxy substituent which gave only 26% yield despite extended reaction time. Scheme 1.9.2.3. Use of Cooperative Catalysis in the Asymmetric Conia-Ene Reaction O La(NO3)3•6H2O 313 H-L-Val-Ot-Bu 314 O H 2N OMe H 2N O OMe O AgOAc, EtOAc 50 °C 311 OH 312 i-Pr O N H H N OH H 2P PhN O 313 314 Shaw and White recently reported an iron-catalyzed asymmetric Conia-ene reaction with a broader substrate scope than that of the previous reports.175 Their initial screen of metal–salen complexes identified iron salen complex 317 as able to catalyze the transformation of 315 to 316 in moderate yield and selectivity. Addition of silver trifluoroacetate or silver triflate boosted the yields of these reactions; however, the enantioselectivity of the reaction remained unsatisfactory (Scheme 1.9.2.4). New salen ligands were synthesized and investigated in this reaction and the optimal reaction conditions were found to be 7.5 mol% 317 in chloroform. A variety of b-ketoesters, thioesters, and ketones bearing the pentynyl group were found to be good substrates for this reaction, forming the products in good yields and excellent enantioselectivities. Unlike any previous asymmetric method, b-ketoesters bearing hexynyl and heptynyl groups at the a-position could be cyclized to give the exo-methylenecyclohexene and exomethylenecycloheptene with no loss of reactivity or selectivity. Even a b-ketoesters Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 93 bearing a butynyl group at that position could be cyclized to yield the cyclobutane, although the yield and ee were somewhat diminished. Scheme 1.9.2.4. Iron-Catalyzed Asymmetric Conia-Ene Reported by Shaw and White O O Ph O OEt 317, AgO2CCF3 O Ph ClCH2CH2Cl, 70 °C OEt * 315 316 91% yield 53% ee N N t-Bu Fe O Cl O t-Bu t-Bu t-Bu R,R-317 1.10 NOTES AND REFERENCES 1. This chapter includes reported research up to and including the year 2018. 2. A. Jay in Dictionary of Chemistry, 2nd Edition (Ed. E Geller), McGraw-Hill, 2003, p. 317. 3. (a) Sears, J. E.; Boger, D. L. Acc. Chem. Res. 2015, 48, 653–662. (b) Giner, J.-L.; Kehbein, K. A.; Cook, J. A.; Smith, M. C.; Vlahos, C. J.; Badwey, J. A. Bioorg. Med. Chem. Lett. 2006, 16, 2518–2521. (c) Egger, H.; Reinshagen, H. J. Antibiot. 1976, 29, 923–927. 4. For reviews see: (a) Prakash, J.; Marek, I. Chem. Commun. 2011, 47, 4593–4623. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. 2004, 101, 5363–5367. (c) Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I. Nature 2012, 490, 522–526. 5. d’Angelo J. Tetrahedron 1976, 32, 2979–2990. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 6. 94 Evans, D. A.; Nelson, J. V.; Taber, T. R., Top. Stereochem., 13, 1 (1982); Heathcock, C. H. in Asymmetric Synthesis, Vol. 3 (Ed. J. D. Morrison), Chap. 2, Academic Press, 1984, p. 111–212. 7. Mekelburger, H. B.; Wilcox, C. S. in Comprehensive Organic Synthesis, 2nd Edition (Eds. Knochel, P. and Molander, G. A.), Chap. 2, Elsevier, 2014, p. 243– 272. 8. (a) Ireland, R. E.; Willard, A. K. Tetrahedron Lett. 1975, 16, 3975–3978. (b) Ireland, R. E.; Wipf, P. (c) Armstrong, J. D. III, J. Org. Chem. 1991, 56, 650–657. 9. Seebach, S. Angew. Chem. Int. Ed. Engl. 1988, 27, 1624–1654. 10. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868– 2877. 11. Frostick, F. C.; Hauser, C. R. J. Am. Chem. Soc. 1949, 71, 1350–1352. 12. Boechman, Jr., R. K.; Chinn, R. L. Tetrahedron 1985, 26, 5005–5008. 13. Taylor, R. J. K. Synthesis 1985, 364–392. 14. Collman, J. P. J. Org. Chem. 1961, 26, 3162–3166. 15. Jung, M. E.; Nishimura, N. Org. Lett. 2001, 3, 2113–2115. 16. House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chem. 1969, 34, 2324–2336. 17. (a) Cazeau, P.; Moulines, F.; Laporte, O.; Duboudin, F. J. Organomet. Chem. 1980, 201, C9–C13. (b) Miller, R. D.; McKean, D. R. Synthesis 1979, 730–732. (c) Chan, T. H.; Zheng, G. Z. Tetrahedron Lett. 1993, 34, 3095–3098. 18. Shrestham R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751–762. 19. Suzuki, H.; Koyama, Y. Tetrahedron Lett. 1979, 20, 1415–1418. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 95 20. Davis, F. A.; Lal, G. S.; Wei, J. Tetrahedron Lett. 1988, 29, 4269–4272. 21. Chantani, N. Murai, S.; Sonoda, N. J. Am. Chem. Soc. 1983, 105, 1370–1372. 22. Reich, H. J.; Holtan, R. C.; Borkowsky, S. L. J. Org. Chem. 1987, 52, 312–314. 23. (a) T. Mukaiyama and J.-I. Matsuo in Modern Aldol Reactions, 1st Edition (Ed. R. Mahrwald), Chap. 3, Wiley, 2004, p. 127–160. (b) C. J. Cowden and I. Paterson in Organic Reactions, Vol. 51, Chap. 1, Wiley, 1997, p. 1–200. (c) Masamune, S.; Choy, W.; Kerdesky, F. A. J.; Imperiali, B. J. Am. Chem. Soc. 1981, 103, 1566– 1568. 24. (a) Brown H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 1993, 58, 147–153. (b) Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441–3442. 25. (a) Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nature Chem. 2010, 2, 192– 196. (b) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976– 4985. (c) Ohtsuka, Y.; Ikeno, T.; Yamada, T. Tetrahedron: Asymmetry 2003, 14, 967–970. (d) Hirano, M.; Ito, Y.; Hirai, M.; Fukuoka, A.; Komiya, S. Chem. Lett. 1993, 22, 2057–2060. (e) Burkhardt, E. R.; Bergman, R. G.; Heathcock, C. H. Organometallics 1990, 9, 30–44. (f) Yanagisawa, A.; Lin, Y.; Miyake, R.; Yoshida, K. Org. Lett. 2014, 16, 86–89. (g) Herrmann, A. T.; Smith, L. L.; Zakarian, A. J. Am. Chem. Soc. 2012, 134, 6976–6979. (h) Kalek, M.; Himo, F. J. Am. Chem. Soc. 2012, 134, 19159–19169. (i) Noda, D.; Sunada, Y.; Hatakeyama, T.; Nakamura, M.; Nagashima, H. Chem. Commun. 2012, 48, 12231–12233. (j) Yoshikai, N.; Zhang, S.-L.; Yamagata, K.-I.; Tsuji, H.; Nakamura, E. J. Am. Chem. Soc. 2009, 131, 4099–4109. (k) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548– Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 96 14549. (l) Sibi, M. P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571–2573. (m) Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 12236–12237. (n) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5644–5645. (o) Murahashi, S.-I.; Take, K.; Naota, T.; Takaya, H. Synlett 2000, 1016–1018. (p) Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032–10039. (q) Nerz-Stormes, M.; Thronton, E. R. J. Org. Chem. 1991, 56, 2489–2498. (r) Meyer, T. Y.; Garner, L. R.; Baenziger, N. C.; Messerie, L. Inorg. Chem. 1990, 29, 4045–4050. (s) Masahiro, M.; Masahiko, I.; Michinori, S.; Yoshihiko, I. Bull. Chem. Soc. Jpn. 1988, 61, 3649–3652. (t) Bassner, S. L.; Morrison, E. D.; Geoffroy, G. L.; Rheingold, A. L. J. Am. Chem. Soc. 1986, 108, 5358–5359. (u) Evans, W. J.; Dominguez, R.; Hanusa, T. P. Organometallics 5, 1291–1296. 26. (a) Reetz, M. T.; Peter, R. Tetrahedron Lett. 1981, 22, 4691–4694. (b) Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793–1796. (c) Panish, R.; Selvaraj, R.; Fox, J. M. Org. Lett. 2015, 17, 3978–3981. (d) Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1987, 52, 5056–5057. (e) Hansen, M. M.; Bartlett, P. A.; Heathcock, C. H. Organometallics 1987, 6, 2069–2074. 27. Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1998, 60, 1–6. 28. Wurtz, A. C. Bull. Soc. Chim. Fr. 1872, 17, 436–442. 29. (a) Heravi, M. M.; Zadsirjan, V. Tetrahedron: Asymmetry 2013, 24, 1149–1188. (b) Heravi, M. M.; Zadsirjan, V. Tetrahedron: Asymmetry 2014, 25, 1061–1090. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 30. 97 (a) Brodmann, T.; Lorenz, M.; Schäckel, R.; Simsek, S.; Kalesse, M. Synlett 2009 174–192. (b) Schetter, B.; Mahrwald, R. Angew. Chem. Int. Ed. 2006, 45, 7506– 7525. 31. (a) Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry 2012, 23, 1431–1465. (b) Bhanushali, M.; Zhao, C.-G. Synthesis 2011, 1815–1830. (c) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138–5175. (d) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569. (e) Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580–591. (f) Bisai, V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541–4580. 32. (a) Kuwano, R.; Miyazaki, H.; Ito, Y. J. Organomet. Chem. 2000, 603, 18–29. (b) Kuwano, R.; Miyazaki, H.; Ito, Y. Chem. Commun. 1998, 71–72. 33. Fukuchi, I.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2007, 349, 509–512. 34. Mouri, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Chem. Commun. 2009, 5138– 5140. 35. Shen, K.; Liu, X.; Zheng, K.; Li, W.; Hu, X.; Lin, L.; Feng, X. Chem. Euro. J. 2010, 16, 3736–3742. 36. Shen, K.; Liu, X.; Wang, W.; Wang, G.; Cao, W.; Li, W.; Hu, X.; Lin, L.; Feng, X. Chem. Sci. 2010, 1, 590–595. 37. Allais, C.; Tsai, A. S.; Nuhant, P.; Roush, W. R. Angew. Chem. Int. Ed. 2013, 52, 12880–12891. 38. Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044–1070. 39. Subramaniapillai, S. G. J. Chem. Sci. 2013, 125, 467–482. 98 Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 40. (a) A. Córdova, in Stereoselective Organocatalysis: Bond Formation Methodologies and Activation Modes, 1st Edition (Ed. R. R. Torres), Chap. 4, Wiley, 2013, p. 129–146 (b) Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem Soc. Rev. 2008, 37, 29–41. (c) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797–5815. 41. (a) Arrayás, R. G.; Carretero, J. C. Chem. Soc, Rev. 2009, 38, 1940–1948. (b) Manuel, M.; Marques, M. B. Angew. Chem. Int. Ed. 2006, 45, 348–352. (c) Karimi, B.; Ender, D.; Jafari, E. Synthesis 2013, 45, 2769–2812. (d) Córdova, A. Acc. Chem Res. 2004, 37, 102–112. (d) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626–2704. (e) Greco, S. J.; Lacerda, V. Jr.; dos Santos, R. B. Aldrichimica Acta 2011, 44, 15–24. 42. Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359–2367. 43. Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem. Int. Ed. 2005, 44, 1525–1529. 44. Kim, E. J.; Kang, Y. K.; Kim, D. Y. Bull. Korean Chem.Soc. 2009, 30, 1437–1438. 45. Liu, Z.; Shi, M. Organometallics 2010, 29, 2831–2834. 46. Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 5630–5631. 47. Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170–2171. 48. Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010, 132, 56–57. 49. Shimizu, S.; Tsubogo, T.; Xu, P.; Kobayashi, S. Org. Lett. 2015, 17, 2006–2008. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 50. 99 For reviews on the asymmetric Michael reaction see: (a) Christoffer, J.; Baro, A. Angew. Chem. Int. Ed. 2003, 42, 1688–1690. (b) Krause, N.; Hoffmann-Röder, A. Synthesis 2001, 171–196. (c) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033– 8061. (d) Leonard, J.; Díez-Barra, E.; Merino, S. Eur. J. Org. Chem. 1998 2051– 2061. (e) Christoffers, J. Eur. J. Org. Chem. 1998, 1259–1266. 51. Långström, B.; Göran, B. Acta Chem. Scand. 1973, 27, 3118–3119. 52. Cram, D. J.; Sogah, G. D. Y. J. Chem. Soc., Chem. Commun. 1981, 625–628. 53. Brunner, H.; Hammer, B. Angew. Chem. Int. Ed. 1984, 23, 312–313. 54. Brunner, H.; Kraus, J. J. Mol. Catal. 1989, 49, 133–142. 55. Botteghi, C.; Paganelli, S.; Schionate, A; Boga, C; Fava, A. J. Mol. Catal. 1991, 66, 7–21. 56. Brunner, H.; Krumey, C. J. Mol Catal. A: Chem. 1999, 142, 7–15. 57. Botteghi, C.; Schionanto, A.; Rosini, C.; Salvadori, R. P. J. Mol. Catal. 1990, 63, 155–165. 58. For a review on thioether ligands see: Masdeu-Bultó, A. M.; Diéguez, M.; Martin, E.; Gómez, M. Coord. Chem. Rev. 2003, 242, 159–201. 59. (a) Christoffers, J.; Mann, A. Eur. J. Org. Chem. 1999, 1475–1479. (b) Christoffers, J.; Mann, A.; Pickardt, J. Tetrahedron 1999, 55, 5377–5388. 60. Christoffers, J.; Röβler, U.; Werner, T. Eur. J. Org. Chem. 2000, 701–705. 61. Han, Y.-Y.; Wu, Z.-J.; Chen, W.-B.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2011, 13, 5064–5067. 62. Desimoni, G.; Quadrelli, P.; Righetti, P. P. Tetrahedron 1990, 46, 2927–2934. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 63. 100 Desimoni, G.; Dusi, G.; Faita, G.; Quadrelli, P.; Righetti, P. P. Tetrahedron 1995, 51, 4131–4144. 64. Bonadies, F.; Lattanzi, A.; Orelli, L. R.; Pesci, S.; Scettri, A. Tetrahedron Lett. 1993, 34, 7649–7650. 65. Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 8295–8296. 66. Freixa, Z.; van Leeuwen, P. W. N. M. Coord. Chem. Rev. 2008, 252, 1755–1786. 67. Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron 1994, 50, 4439–4454. 68. Sawamura, M.; Hamashima, H.; Shinoto, H.; Ito, Y. Tetrahedron Lett. 1995, 36, 6479–6482. 69. Inagaki, K.; Nozaki, K.; Takaya, H. Synlett 1997, 119–120. 70. Suzuki, T.; Torii, T. Tetrahedron: Asymmetry 2001, 12, 1077–1081. 71. For a review on lanthanide complexes in asymmetric catalysis see: Shibasaki, M.; Yoshikawa, N. Chem Rev. 2002, 102, 2187–2210. 72. (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418–4420. (b) Sasai, H.; Suzuki, T.; Itoh, N.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 851–854. (c) Sasai, H.; Itoh, N.; Suzuki, T.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 855–858. (d) Sasai, H.; Suzuki, T.; Itoh, N.; Arai, S.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 2657–2660. (e) Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura, K.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 10372– 10373. 73. For reviews on heterobimetallic catalysts see: (a) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem. Int. Ed. 1997, 36, 1236–1256. (b) Matsunaga, S.; Ohshima, T.; Shibasaki, M. Adv. Synth. Catal. 2002, 344, 3–15. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 101 74. Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1571–1572. 75. Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 5561– 5564. 76. Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506–6507. 77. Majima, K.; Tosaki, S.-Y.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2005, 46, 5377–5381. 78. Yasufumi, T.; Atsushi, K.; Eiji, K.; Sotaro, M. Chem. Lett. 1995, 24, 957–958. 79. Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Mahon, M. F.; Williams, J. M. Organometallics 1999, 18, 2867–2873. 80. Christoffers, J. Prakt. Chem. (Weinheim, Ger.), 1999, 341, 495. 81. For a review on chiral iron catalysts see: Gopalaiah, K. Chem. Rev. 2013, 113, 3248–3296. 82. For a review on palladium catalyzed asymmetric addition reactions see: Sun, Y.W.; Zhu, P.-L.; Xu, Q.; Shi, M. RSC Adv. 2013, 3, 3153–3168. 83. Stark, M. A.; Jones, G.; Richards, C. J. Organometallics 2000, 19, 1282–1291. 84. (a) Takenaka, K.; Uozumi, Y. Org. Lett. 2004, 6, 1833–1835. (b) Takenaka, K.; Minakawa, M.; Uozumi, Y. J. Am. Chem. Soc. 2005, 127, 12273–12281. 85. Fossey, J. S.; Russell, M. L.; Malik, K. M. A.; Richards, C. J. J. Organomet. Chem. 2007, 692, 4843–4848. 86. (a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240– 11241. (b) Mikiko, S.; Yoshitaka, H. Bull. Chem. Soc. Jpn. 2005, 78, 941–956. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 87. 102 For a review on the use of chiral palladium enolates in asymmetric reactions see: Hamashima, Y.; Sodeoka, M. Chem. Rec. 2004, 4, 231–242. 88. Hamashima, Y.; Hotta, D.; Umebayahi, N.; Tsuchiya, Y.; Suzuki, T.; Sodeoka, M. Adv. Synth. Catal. 2005, 347, 1576–1586. 89. Hamashima, Y.; Takano, H.; Hotta, D.; Sodeoka, M. Org. Lett. 2003, 5, 3225–3228. 90. Göricke, F.; Schneider, C. Angew. Chem. Int. Ed. 2018, 57, 14736–14741. 91. Liu, X.; Lin, L.; Feng, X. Acc. Chem. Res. 2011, 44, 574–587. 92. Nakajima, M.; Yamaguchi, Y.; Hashimoto, S. Chem. Commun. 2001, 1596–1597. 93. Nakajima, M.; Yamamoto, S.; Yamaguchi, Y.; Nakamura, S.; Hashimoto, S. Tetrahedron 2003, 59, 7307–7313. 94. Wang, Z.; Yang, Z.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2011, 50, 4928–4932. 95. Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Padmaja, M.; Markondaiah, B. Adv. Synth. Catal. 2005, 347, 867–871. 96. Kato, Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168–9169. 97. (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395–422. (b) Trost, B. M. J. Org. Chem. 2004, 69, 5813–5837. 98. You, S.-L.; Dai, L.-X. Angew. Chem. Int. Ed. 2006, 45, 5246–5248. 99. Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 2586–2592. 100. Brunel, J. M.; Tenaglia, A.; Buono, G. Tetrahedron: Asymmetry 2000, 11, 3585– 3590. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 101. 103 Nemoto, T.; Matsumoto, T.; Masuda, T.; Hitoma, T.; Hatano, K.; Hamada, Y. J. Am. Chem. Soc. 2004, 126, 3690–2691. 102. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. 2004, 126, 15044–15045. 103. Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2005, 44, 6924–6927. 104. (a) Sherden, N. H.; Behenna, D. C.; Virgil, S. C.; Stoltz, B. M. Angew. Chem. Int. Ed. 2009, 48, 6840–6843. (b) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2007, 129, 11876–11877. 105. Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nature Chemistry 2012, 4, 130–133. 106. Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Angew. Chem. Int. Ed. 2013, 52, 6718–6721. 107. Numajiri, Y.; Pritchett, B. P.; Chiyoda, K.; Stotlz, B. M. J. Am. Chem. Soc. 2015, 137, 1040–1043. 108. Alexy, E. J.; Zhang, H.; Stoltz, B. M. J. Am. Chem. Soc. 2018, 140, 10109–10112. 109. (a) Marziale, A. N.; Duquette, D. C.; Craig, II, R. A.; Kim, K. E.; Liniger, M.; Numajiri, Y.; Stoltz, B. M. Adv. Synth. Catal. 2015, 357, 2238–2245. (b) Hong, A. Y.; Bennett, N. B.; Krout, M. R.; Jensen, T.; Harned, A. M.; Stoltz, B. M. Tetrahedron 2011, 67, 10234–10248. (c) Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2009, 11, 292–295. (d) Craig, II, R. A.; Loskot, S. A.; Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Org. Lett. 2015, 17, 5160–5163. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 110. 104 Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997, 119, 7879– 7880. 111. Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759–6760. 112. Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem. Int. Ed. 2002, 41, 3492–3495. 113. Trost, B. M.; Schroeder, G. M. Chem. Eur. J. 2005, 11, 174–184. 114. Trost, B. M.; Pissot-Soldermann, C.; Chen, I. Chem. Eur. J. 2005, 11 951–959. 115. Trost, B. M.; Frederiksen, M. U. Angew. Chem. Int. Ed. 2005, 44, 308–310. 116. Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343–18357. 117. Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem. Int. Ed. 2006, 45, 3109–3112. 118. Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113– 120. 119. Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590–4591. 120. Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418– 11419. 121. Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem. Int. Ed. 2012, 51, 1680–1683. 122. Kanayama, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew. Chem. Int. Ed. 2003, 42, 2054–2056. 123. Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 10626–10629. 124. Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 17298– 17301. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 125. 105 Shockley, S. E.; Hethcox, J. C.; Stoltz, B. M. Angew. Chem. Int. Ed. 2017, 56, 11545–11548. 126. Wright, T. B.; Evans, P. A. J. Am. Chem. Soc. 2016, 138, 1503–15306. 127. Ngamnithiporn, A.; Jette, C. I.; Bachman, S.; Virgil, S. C.; Stoltz, B. M. Chem. Sci, 2018, 9, 2547–2551. 128. Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 62–63. 129. Doyle, A. G.; Jacobsen, E.N. Angew. Chem. Int. 2007, 46, 3701–3705. 130. Yamashita, Y.; Odashima, K.; Koga, K. Tetrahedron Lett. 1999, 40, 2803–2806. 131. Yu, K.; Jackson, J. J.; Nguyen, T. D.; Alvatado, J.; Stivala, C. E.; Ma, Y.; Mack, K. A.; Hayton, T. W.; Collum, D. B.; Zakarian, A. J. Am. Chem. Soc. 2017, 139, 527–533. 132. For reviews on a-arylation see: (a) Johansson, C. C. C.; Colacot, T. J. Angew. Chem. Int. Ed. 2010, 49, 676–707. (b) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082–1146. (c) Mazet, C. Synlett, 2012, 23, 1999–2004. (d) Burtoloso, A. C. B. Synlett 2009, 320–327. 133. (a) Semmelhack, M. F.; Stauffer, R. D.; Rogerson, T. D. Tetrahdron Lett. 1973, 14, 4519–4522. (b) Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507–2516. 134. Galarini, R.; Musco, A.; Pontellini, R.; Santi, R. J. Mol. Catal. 1992, 72, L11–L13. 135. (a) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581–7582. (b) Muratake, H.; Hayakawa, A.; Natsume, M. Tetrahedron Lett. 1997, 38, 7577–7580. 136. Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108–11109. 137. Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382–12383. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 138. 106 Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem. Int. Ed. 1997, 36, 1740–1742. 139. Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918–1919. 140. Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 1363–1365. 141. Chieffi, A.; Kamikawa, K.; Åhman, J.; Fox, J. M.; Buchwald, S. L. Org. Lett. 2001, 3, 1897–1900. 142. Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360–1370. 143. Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261–1268. 144. Hamada, T.; Buchwald, S. L. Org. Lett. 2002, 4, 999–1001. 145. Taylor, A. M.; Altman, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900– 9901. 146. Arao, T.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1743–1744. 147. (a) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402–3415. (b) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245. 148. Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002, 2704– 2705. 149. Arao, T.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2006, 47, 1417–1420. 150. Kündig, E. P.; Seidel, T. M.; Jia, Y.; Bernardinelli, G. Angew. Chem. Int. Ed. 2007, 46, 8484–8487. 151. García-Fortanet, J.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 8108–8111. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 107 152. Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195–200. 153. Jette, C. I.; Geibel, I.; Bachman, S.; Hayashi, M.; Sakurai, S.; Shimizu, H.; Morgan, J. B.; Stoltz, B. M. Angew. Chem. Int. Ed. 2019, 58, 1–6. 154. Ge, S.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 16330–16333. 155. (a) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500–3501. (b) Spielvogel, D. J.; Davis, W. M.; Buchwald, S. L. Organometallics 2002, 21, 3833– 3836. 156. Chen, G.; Kwong, F. Y.; Chan, H. O.; Yu, W.-Y.; Chan, A. S. C. Chem. Commun. 2006, 1413–1415. 157. Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050–16051. 158. Claisen, L. Chem. Ber. 1912, 45, 3157–3166. 159. For reviews on the Claisen rearrangement see: (a) Rehbein, J.; Hiersemann, M. Synthesis 2013, 45, 1121–1159. (b) Castro, A. M. M. Chem. Rev. 2004, 104, 2939– 3002. (c) Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43–50. (d) Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry 1996, 7, 1847–1882. (e) Ziegler, F. E. Chem. Rev. 1988, 88, 1423–1452. 160. Corey, E. J.; Roberts, B. E.; Dixon, B. R. J. Am. Chem. Soc. 1995, 117, 193–196. 161. Corey, E. J.; Lee, D. H. J. Am. Chem. Soc. 1991, 113, 4026–4028. 162. Corey, E. J.; Kania, R. S.J. Am. Chem. Soc. 1996, 118, 1229–1230. 163. Krebs, A.; Kazmaier, U. Tetrahedron Lett. 1996, 37, 7945–7946. 164. (a) Malherbe, R.; Belluš, D. Helv. Chim. Acta 1978, 61, 3096–3099. (b) Malherbe, R.; Rist, G.; Belluš, D. J. Org. Chem. 1983, 48, 860–869. Asymmetric Synthesis of Quaternary Stereocenters via Metal Enolates 165. 108 For a review on the Belluš–Claisen rearrangement see: Gonda, J. Angew. Chem. Int. Ed. 2004, 43, 3516–3524. 166. Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121, 9726–9727. 167. Yoon, T. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 2911–2912. 168. Bloch, R.; Le Perchec, P.; Rouessac, F.; Conia, J.-M. Tetrahedron 1968, 24, 5971– 5989. 169. Conia, J.-M.; Le Perchec, P. Synthesis 1975, 1–19. 170. Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168–17169. 171. (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526–4527. (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem. Int. Ed. 2004, 43, 5350–5352. 172. Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 9140–9141. 173. Sladojevich, F.; Fuentes de Arriba, Á. L.; Ortín, I.; Yang, T.; Ferrali, A.; Paton, R. S.; Dixon, D. J. Chem. Eur. J. 2013, 19, 14286–14295. 174. Matsuzawa, A.; Mashiko, T.; Kumagai, N.; Shibasaki, M. Angew. Chem. Int. Ed. 2011, 50, 7616–7619. 175. Shaw, S.; White, J. D. J. Am. Chem. Soc. 2014, 136, 13578–13581. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 109 CHAPTER 2 Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones† 2.1 INTRODUCTION The efficient construction of all-carbon quaternary centers remains a challenge for the modern synthetic chemist.1 The difficulty associated with forming all-carbon quaternary centers arises from the inherent steric congestion during the C–C bond forming event. Toward this end, our laboratory disclosed the first palladium-catalyzed enantioselective decarboxylative allylic alkylation for the construction of all-carbon quaternary centers of non-stabilized enolates.2 Over the past decade we have continued to explore the breadth of our reaction manifold,3 including the development of new ligands based on the original PHOX scaffold.4 Cyclic ketones generally represent the most explored class of substrates, from the initially reported cyclohexanones (Scheme 2.1.1A),2,5 † This research was performed in collaboration with Robert A. Craig, II, Justin T. Mohr, Douglas C. Behenna, and Andrew M. Harned, all alumni of the Stoltz group. Additionally, this research has been published and adapted with permission Craig, II, R. A.; Loskot, S. A.; Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Org. Lett. 2015, 17, 5160–5163. R.A.C. and S.A.L. contributed equally. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 110 cycloheptanones,2,3d,5b,c and cyclooctanones2,3d,5b to the highly strained cyclobutanones (Scheme 2.1.1B).6 Scheme 2.1.1. Cyclic Ketone Substrates in Transition Metal-Catalyzed Enantioselective Decarboxylative Allylic Alkylation O R1 O O A) O Pd0 (cat.) (S)-t-BuPHOX ((S)-158, cat.) R2 R2 up to 92% ee 318 B) R1 O R1 (S)-319 Pd0 (cat.) (S)-(p-CF3)3-t-BuPHOX ((S)-168, cat.) O O R1 O up to 99% ee R2 R2 320 O (S)-321 Pd0 or PdII (cat.) O O PHOX Ligand (cat.) C) R1 O R1 up to 94% ee R2 322 R2 (S)-323 CF3 O O P F3C N P N t-Bu t-Bu CF3 (S)-158 (S)-168 Interestingly, cyclopentanones have typically performed worse than the corresponding 6-membered substrates, often furnishing the a-quaternary ketone products in comparatively reduced yields and ee.3d Only a few examples with limited substrate scope exist for the formation of a-quaternary cyclopentanones by transition metal-catalyzed enantioselective allylic alkylation.7 Yet cyclopentanes containing enantioenriched quaternary centers characterize a number of biologically pertinent and chemically fascinating natural products, including polycyclic terpenoids8 1799 and 710 as well as Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 111 alkaloids 324,11 325,11 and 32612 (Figure 2.1.1). As part of our continued efforts to extend the utility of our reaction methodology, we revisited the problematic cyclopentanone substrate class, striving to develop the first general method for the construction of aquaternary center cyclopentanones and 5-membered cyclic ketone substrates by transition metal-catalyzed enantioselective decarboxylative allylic alkylation (Scheme 2.1.1C). Figure 2.1.1. Natural Products Characterized by Cyclopentane Rings Containing Chiral All-Carbon Quaternary Centers OH O O Br O O O O O H H O O O Hamigeran B (179) Anti-Herpes and Anti-Polio HO H Wortmannin (7) PI3K Covalent Inhibitor HO H O O OH O N Lycoposerramine-D (324) 2.2 O H O H N H HH N Lycoposerramine-U (325) Chaetochalasin A (326) Antibacterial and Antitumor INITIAL REACTION OPTIMIZATION Initial reaction development employed p-Me-benzyl-substituted b-ketoester 327, using catalytic Pd2(dba)3 at 20 °C in toluene in the presence of a chiral PHOX ligand, affording enantioenriched a-quaternary cyclopentanone 328 (Table 2.2.1).13,14 Using the classic (S)-t-BuPHOX ligand ((S)-158), cyclopentanone (S)-340 was provided in 87% ee (entry 1). Switching to the electron-deficient (S)-(p-CF3)3-t-BuPHOX ((S)-168) furnished product (S)-340 in an improved 89% ee (entry 2). The recently disclosed, cost-effective Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 112 alternative to 168, (R)-(p-CF3)3-i-PrPHOXMe2 ((R)-329) provided cyclic ketone (R)-340 in a decreased 83% ee (entry 3).4a Similarly to (R)-329, geminally disubstituted valinederived (S)-(p-CF3)2-i-PrPHOXPh2 ((S)-330) afforded ketone (S)-340 with nearly equivalent ee (82%, entry 4). Switching to ester-substituted b-ketoester 331, we confirmed (S)-(p-CF3)3-t-BuPHOX ((S)-168) was indeed the optimal ligand for the desired enantioselective decarboxylative allylic alkylation, providing enantioenriched aquaternary cyclopentanone (S)-332 in 91% ee (entry 6). The remaining PHOX ligands (S)158, (R)-329, and (S)-330 furnished the desired product (332) in reduced ee’s, ranging between 80% and 82% (entries 5, 7, and 8, respectively). Table 2.2.1. PHOX Ligand Screen O O R1 O Pd2(dba)3 (2.75 mol %) ligand (6.00 mol %) O R1 toluene (0.033 M), 20 °C (S)-328 327 entry R1 product ligand ee (%)b 1 p-Me-C6H4CH2– (S)-340 (S)-158 87 2 p-Me-C6H4CH2– (S)-340 (S)-168 89 3 p-Me-C6H4CH2– (S)-340 (R)-329 83 4 p-Me-C6H4CH2– (S)-340 (S)-330 82 5 EtO2CCH2CH2– (S)-332 (S)-158 82 6 EtO2CCH2CH2– (S)-332 (S)-168 91 7 EtO2CCH2CH2– (S)-332 (R)-329 82 8 EtO2CCH2CH2– (S)-332 (S)-330 80 CF3 O O F3C P F3C N P (S)-329 Ph i-Pr i-Pr CF3 N Ph CF3 (S)-330 Conditions: b-Ketoester 331 (0.19 mmol), Pd2(dba)3 (2.75 mol %), (S)-168 (6.00 mol %), toluene (5.8 mL). b Measured by analytical chiral SFC. a Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 113 Having identified the optimal ligand for the enantioselective decarboxylative allylic alkylation, we next examined the solvent effect using b-ketoester 331 (Table 2.2.2). Employing identical reaction conditions from our ligand screen, using toluene as the solvent, we isolated a-quaternary center cyclopentanone (S)-332 in 91% ee, achieving complete consumption of starting material 331 in 8.0 h (entry 1). Switching to the less polar solvent mixture 2:1 hexanes:toluene, which has previously provided increased ee’s for other a-quaternary cyclic ketones constructed through palladium-catalyzed enantioselective decarboxylative allylic alkylation,15 did not affect the reaction time, but furnished ketone (S)-332 in a diminished 88% ee (entry 2). Changing to ethereal solvents (entries 3 and 4) drastically decreased the reaction time, facilitating the full consumption of b-ketoester 331 in 1.0 h. While the use of MTBE (entry 3) afforded cyclopentanone (S)332 in nearly identical ee to the mixed nonpolar solvent system (entry 2), switching to THF (entry 4) proved deleterious. Ultimately, the use of Pd2(dba)3 (2.75 mol %) with (S)-(pCF3)3-t-BuPHOX ((S)-168, 6.00 mol %) in toluene (0.033 M in b-ketoester 331) at 20 °C proved optimal. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 114 Table 2.2.2. Solvent Effect on Enantiomeric Excess of Cyclopentanone Product (S)332a O O Pd2(dba)3 (2.75 mol %) (S)-(p-CF3)3-t-BuPHOX ((S)-168, 6.00 mol %) O O solvent (0.033 M), 20 °C CO2Et CO2Et 331 (S)-332 entry solvent time (h) ee (%)(b) 1 2 3 4 toluene 2:1 hexane:toluene MTBE THF 8.0 8.0 1.0 1.0 91 88 87 81 Conditions: b-ketoester 331 (0.19 mmol), Pd2(dba)3 (2.75 mol %), (S)-168 (6.00 mol %), toluene (5.8 mL). b Measured by analytical chiral SFC. a 2.3 EXPLORATION OF REACTION SCOPE Subsequently, we explored the substrate scope of the enantioselective allylic alkylation of cyclopentanones. We found that our reaction manifold was tolerant of a variety of substitution at the a-position of the cyclopentanone (Scheme 2.3.1).16 Alkylsubstituted a-quaternary cyclopentanones (S)-333, (S)-334, and (S)-335 were each produced over reaction times greater than 30 hours with ee’s ranging from 86% to 88%, providing the more sterically congested cyclopentanone (S)-335 over a slightly longer reaction time.13 Along with ester-substituted cyclopentanone (S)-332, nitrile (S)-336 and phthalimide (S)-337 were both produced quite rapidly at 20 °C in excellent yield with good ee (2.5 h, 97% yield, 87% ee and 3 h, 93% yield, 88% ee, respectively). We found that we could increase the ee of these two products significantly by lowering the temperature without any deleterious effect on the yield, providing cyclopentanones (S)-336 and (S)-337 in an improved 90% ee and 93% ee, respectively, at 0 °C over 23 h. This result represents a dramatic improvement in the formation of (S)-337 compared to our previously reported Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 115 system, employing THF as the solvent with (S)-158 as the ligand, which provided (S)-337 in only 67% yield with 48% ee.3d Comparatively, benzyl-substituted cyclopentanones proved to have a correlation between the electronics of the aryl substituent and the overall reaction time. Electron rich p-OMe-benzyl cyclopentanone (S)-338 was furnished in only 8 h, while the electron neutral benzyl and p-Me-benzyl products ((S)-339 and (S)-340) were each produced over a slightly extended reaction time (13 h). Interestingly, the reaction producing electron poor p-CF3-benzyl-substitued (S)-341 failed to proceed to full conversion over 96 h, affording the product in a reduced 56% overall yield (83% yield based on recovered b-ketoester). Interestingly, despite the variable reaction times, the ee of the benzyl-substituted cyclopentanone products was largely consistent (88%–89% ee), with a slight boost for the electron-rich p-OMe-benzyl product ((S)-338) to 92% ee. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 116 Scheme 2.3.1. Substrate Scope of Cyclopentanone Substitution in Enantioselective Allylic Alkylation O Pd2(dba)3 (2.75 mol %) (S)-(p-CF3)3-t-BuPHOX ((S)-168, 6.00 mol %) O R1 O O R1 toluene (0.033 M), 20 °C 327 (S)-328 O O O O (S)-333 (S)-334 (S)-335 (S)-336 31 h, 81% yieldb 86% ee 31 h, 79% yieldb 88% ee 36 h, 62% yieldb 87% ee 23 h,c 97% yield 90% ee CN O O O O O N R2 = O OEt R2 (S)-332 (S)-337 8 h, 93% yield 91% ee 23 h,c 92% yield 93% ee (S)-338 OMe 8 h, >99% yield 92% ee (S)-339 H 13 h, 95% yield 88% ee (S)-340 CH3 13 h, 93% yield 89% ee (S)-341 CF3 96 h, 83% yieldd 88% ee Unless otherwise noted, all reported yields are isolated yields. Enantiomeric excess (ee) was determined by either analytical chiral SFC or HPLC. a Conditions: b-ketoester 327 (0.19 mmol), Pd2(dba)3 (2.75 mol %), (S)-168 (6.00 mol %), toluene (5.8 mL). b Cyclopentanone product was volatile, resulting in a reduced isolated yield compared to other substrates. c Reaction performed at 0 C. d Isolated yield was 56%. Additionally, we found that indanones were competent substrates within our reaction manifold (Scheme 2.3.2).3d,5a,d,7g Methyl-substituted indanone product (S)-344 was furnished over a greatly shortened 4.5 h compared to the methyl-substituted cyclopentanone product ((S)-333, see Scheme 2.3.1). Additionally, bicycle (S)-344 was provided in 94% yield with 84% ee. Comparatively, the fluorinated analog (S)-345 was produced in an improved >99% yield and 87% ee, albeit over a longer reaction time (13 h). Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 117 Scheme. 2.3.2 Enantioselective Allylic Alkylation of Indanone Substrates O Pd2(dba)3 (2.75 mol %) (S)-(p-CF3)3-t-BuPHOX ((S)-168, 6.00 mol %) O R1 O O R1 toluene (0.033 M), 20 °C (S)-344, R1 = Me, 4.5 h, 94% yield, 84% ee (S)-345, R1 = F, 13 h, >99% yield, 87% ee 342 (S)-343 Having investigated the tolerance of our reaction manifold to a variety of substitution on the cyclopentanone ring, we next evaluated the potential to use 2-substituted allyl fragments in the enantioselective allylic alkylation of cyclopentanones (Scheme 2.3.3). Methyl- and ethyl-substituted cyclopentanone products (S)-346 and (S)-347 containing a 2-phenylallyl fragment were both produced in excellent yield and with 90% and 94% ee, respectively. Comparatively, cyclopentanones (S)-348 and (S)-349, each containing a 2-chloroallyl fragment, were produced with similar ee’s in slightly reduced yield. Interestingly, each of the alkyl-substituted cyclopentanone products possessing a 2substituted allyl fragment were produced over a shorter reaction time than the same substrates containing an unsubstituted allyl fragment (see Scheme 2.3.1). Scheme 2.3.3. Enantioselective Allylic Alkylation of Cyclopentanone Substrates with 2-Substituted Allyl Fragmentsa O O R1 O 321 R1 toluene (0.033 M), 20 °C R2 R2 (S)-322 O O O Ph Ph a O Pd2(dba)3 (2.75 mol %) (S)-(p-CF3)3-t-BuPHOX ((S)-168, 6.00 mol %) O Cl Cl CO2Et (S)-346 (S)-347 (S)-348 (S)-349 27.5 h, 95% yield 90% ee 20 h, 98% yield 94% ee 28.5 h, 72% yield 90% ee 21 h, 85% yield 88% ee All reported yields are isolated yields. Enantiomeric excess (ee) was determined by analytical chiral SFC. Conditions: b-ketoester 321 (0.19 mmol), Pd2(dba)3 (2.75 mol %), (S)-168 (6.00 mol %), toluene (5.8 mL). Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 2.4 118 ADAPTING THE LOW CATALYST LOADING ALLYLIC ALKYLATION Lastly, we examined the potential to apply our recently disclosed palladium(II) low catalyst loading protocol for enantioselective decarboxylative allylic alkylation to this new substrate class.17 We discovered that on small scale, ester-substituted cyclopentanone (S)332 was provided in an identical 91% ee and an improved 98% yield at 20 °C using only 0.15 mol % palladium catalyst (Scheme 2.4.1) compared to our palladium(0)-mediated reaction conditions, which employ 5.50 mol % palladium (vide supra). Increasing the scale of the reaction slightly (0.22 mmol) as well as the temperature (28 °C) and catalyst loading (0.30 mol % Pd) furnished (S)-332 over a reduced 18 h in 96% yield with 89% ee. Using these reaction conditions and increasing the scale 17 times (3.73 mmol) provided (S)-332 with identical 89% ee, although in a slightly diminished 82% yield. Scheme 2.4.1. Low Catalyst Loading Palladium(II)-Catalyzed Enantioselective Allylic Alkylation O O Pd(OAc)2 (0.30 mol %) (S)-(p-CF3)3-t-BuPHOX ((S)-168, 3.00 mol %) O O toluene (0.10 M) CO2Et 331 0.19 mmol 17, 20 °C, 28 h, 98% yield, 91% eea 0.22 mmol 17, 28 °C, 18 h, 96% yield, 89% ee 3.73 mmol 17, 28 °C, 15 h, 82% yield, 89% ee CO2Et (S)-332 All reported yields are isolated yields. Enantiomeric excess (ee) was determined by analytical chiral SFC. a Pd(OAc)2 (0.15 mol %), (S)168 (1.50 mol %) used. 2.5 CONCLUSION In conclusion, we have disclosed the first general method for the construction of a- quaternary-containing cyclopentanones by enantioselective palladium-catalyzed decarboxylative allylic alkylation. The reaction manifold proved optimal when electrondeficient (S)-(p-CF3)3-t-BuPHOX ((S)-168) was employed, providing a variety of Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 119 substituted cyclopentanone products in up to near-quantitative yield and with up to 94% ee. Additionally, the enantioselective allylic alkylation was found to be tolerant of allyl fragments substituted at the 2-position. Employment of low-catalyst loading, palladium(II)-mediated reaction conditions was successfully accomplished, facilitating the synthesis of a-quaternary cyclopentanones on increased scale in a cost-effective manner. Currently, our lab is pursuing the further development of this technology through substrate scope extension and application in natural product synthesis. 2.6 EXPERIMENTAL METHODS AND ANALYTICAL DATA 2.6.1 MATERIALS AND METHODS Unless stated otherwise, reactions were performed at ambient temperature (23 °C) in flame-dried or oven-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents (distilled or passed over a column of activated alumina).18 Commercially obtained reagents were used as received with the exception of Pd(OAc)2, Pd2(dba)3, tetrakis(triphenylphosphine)palladium(0), and TBAT, which were stored in a nitrogen-filled glovebox. (S)-t-BuPHOX,4c (S)-(CF3)3-t-BuPHOX,4b (R)-(CF3)3-i- PrPHOXMe2,4a,19 (S)-(CF3)2-i-PrPHOXPh2,20 allyl 2-oxocyclopentanecarboxylate,21 2phenylallyl alcohol,22 2-(p-methylbenzyl)-cyclopentanone,23 and 2,2-dimethyl-5-oxocyclopenanecarboxylic acid methyl ester24 were prepared by known methods. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. Reaction progress was monitored by TLC, which was performed using E. Merck silica gel 60 F254 precoated glass plated (0.25 mm) and visualized by UV fluorescence quenching, potassium permanganate, or p-anisaldehyde staining. Silicycle Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 120 SiliaFlash® P60 Academic Silica gel (particle size 40-63 nm) was used for column chromatography. 1H and 13C NMR spectra were recorded on a Varian Inova 500 (500 MHz and 126 MHz, respectively), Varian Mercury 300 spectrometer (300 MHz and 75 MHz, respectively), and a Bruker AV III HD spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe (400 MHz and 101 MHz, respectively) and are reported in terms of chemical shift relative to CHCl3 (d 7.26 and d 77.16, respectively). 19F NMR spectra were recorded on a Varian Inova 500 spectrometer (470 MHz) and are reported in terms of absolute chemical shift according to IUPAC standard recommendations from CFCl3.25 Data for 1H NMR are reported as follows: chemical shift (d ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septet, m = multiplet, and br s = broad singlet. Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and are 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 and are reported as: [a]DT (concentration in g/100 mL, solvent). Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing Chiralpak (AD-H) or Chiracel (OD-H, OJ-H or OB-H) columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. Analytical chiral HPLC was performed with an Agilent 1100 Series HPLC utilizing chiralcel OD-H or OJ (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd., with visualization at 254 and 210 nm. High resolution mass spectra were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 121 High Resolution Mass Spectrometer in fast atom bombardment (FAB+) ionization mode or a Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed (ESI/APCI) ionization mode. Julabo Presto LH45 was used to control reaction temperatures inside the nitrogen-filled glovebox. 2.6.2 EXPERIMENTAL PROCEDURES Cl OH 350 adipic acid p-TsOH PhH, reflux >99% yield Cl O O O O 351 Cl 2-Chlorodiallyl adipate (351): Esterification using alcohol S1 was adapted from the literature.3d Adipic acid (800 mg, 5.47 mmol, 1.00 equiv), 2-chloroallyl alcohol (350, 1.30 mL, 16.4 mmol, 3.00 equiv), and p-TsOH (3.0 mg, 0.03 mmol, 0.03 equiv) were added to a flask and diluted in benzene (8.00 mL, 0.68 M). The flask was then fitted with a DeanStark trap filled with additional benzene. The reaction flask was heated to reflux with stirring for 16 h, at which time the starting material had been completely consumed (determined by TLC analysis, 9:1 Pentane:Et2O). The reaction solution was cooled to 23 °C, washed with saturated aqueous NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude oil was purified by column chromatography (SiO2, 10% Et2O in pentane) to afford ester 351 (1.62 g, >99% yield) as a pale yellow oil; Rf = 0.21 (9:1 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 5.49–5.38 (m, 4H), 4.68–4.63 (m, 4H), 2.46–2.37 (m, 4H), 1.78–1.65 (m, 4H); 13C NMR (101 MHz, CDCl3) d 172.5 (C), 136.1 (C), 115.2 (CH2), 66.1 (CH2), 33.8 (CH2), 24.4 (CH2); IR (thin film, NaCl) 2943, 2873, Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 122 1740, 1637, 1419, 1374, 1134, 1077, 899, 720, 640 cm-1; HRMS (FAB+) m/z calc’d for C12H16Cl2O4 [M+H]+: 295.0504, found: 295.0516. Ph OH 352 adipic acid DIC, DMAP CH2Cl2 93% yield Ph O O O O 353 Ph 2-Phenyldiallyl adipate (353): Esterification of 352 was adapted from the literature.3d A flask charged with alcohol 352 (5.10 g, 38.0 mmol, 1.90 equiv), adipic acid (2.93 g 20.0 mmol, 1.00 equiv), and 4-(dimethylamino)-pyridine (DMAP, 1.88 g, 15.4 mmol, 0.77 equiv), was evacuated and filled with argon (3 x 5 minutes). Dichloromethane (77 mL, 0.26 M) was added and the solution was cooled to 0 °C (ice/H2O bath) with stirring. Diisopropylcarbodiimide (DIC, 6.20 mL, 39.6 mmol, 1.98 equiv) was added dropwise and the reaction mixture was allowed to stir for 5 minutes. The cooling bath was then removed and the solution was allowed to warm to ambient temperature (ca. 23 °C). After 11 h, the consumption of starting material was complete (as determined by TLC analysis, 12:1 hexanes:EtOAc) and the reaction was filtered through filter paper and then diluted with dichloromethane (200 mL). The solution was washed with 0.1 M aqueous HCl (200 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiO2, 7.7% EtOAc in hexanes) to provided diallyladipate 353 (7.06 g, 93% yield) as a pale orange oil; Rf = 0.15 (12:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) d 7.45–7.37 (m, 4H), 7.41–7.24 (m, 6H), 5.54 (d, J = 0.9 Hz, 2H), 5.35 (q, J = 1.2 Hz, 2H), 4.98 (d, J = 1.2 Hz, 4H), 2.36–2.23 (m, 4H), 1.61–1.56 (m, 4H); 13C NMR (101 MHz, CDCl3) d 173.0 (C), 142.6 (C), 138.0 (C), 128.5 (CH), 128.1 (CH), 126.0 (CH), Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 123 115.3 (CH2), 65.6 (CH2), 33.9 (CH2), 24.3 (CH2); IR (thin film, NaCl) 2943, 1734, 1631, 1496, 1444, 1387, 1165. 1076, 1026, 910, 709, 778 cm-1; HRMS (FAB+) m/z calc’d for C24H26O4 [M+H]+: 379.1904, found: 379.1908. Cl O O O NaH, THF O O O 351 Cl 40 °C 73% yield 2-Chloroallyl 2-oxocyclopentanecarboxylate (354): O 354 Cl Dieckmann condensation was adapted from the literature.21 A flask was charged with NaH (60% dispersion in mineral oil, 140 mg, 3.5 mmol, 1.04 equiv) and subsequently evacuated and re-filled with argon (3 x 5 minutes). THF (17 mL, 0.20 M) was added followed by 2-chlorodiallyl adipate (351, 1.00 g, 3.40 mmol, 1.00 equiv). The reaction was then placed into a preheated 40 °C oil bath. After 16 h, the consumption of starting material was complete (as determined by TLC analysis, 9:1 hexanes:EtOAc) and the reaction was removed from the heating bath and allowed to cool to ambient temperature (ca. 23 °C). After cooling, the reaction was quenched with 1.0 M aqueous HCl (20 mL). The resultant solution was extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (90 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 10% EtOAc in hexanes) to furnish b-ketoester 354 (502 mg, 73% yield) as a clear colorless oil; Rf = 0.27 (9:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) d 5.56 (q, J = 1.4 Hz, 1H), 5.44 (dd, J = 1.9, 0.9 Hz, 1H), 4.74 (qt, J = 13.9, 1.0 Hz, 2H), 3.35–3.17 (m, 1H), 2.45–2.27 (m, 4H), 2.19 (ddq, J = 13.2, 7.8, 5.3 Hz, 1H), 2.01–1.82 (m, 1H); 13C NMR (101 MHz, CDCl3) d 211.9 (C), 168.6 (C), 135.3 (C), 115.1 (CH2), 66.5 (CH2), 54.7 (CH), 38.2 (CH2), 21.1 (CH2); IR (thin film, NaCl) 2971, 2883, 1757, 1734, Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 124 1730, 1656, 1639, 1405, 1333, 1295, 1248, 1179, 1108, 1003, 961, 901, 833 cm-1; HRMS (FAB+) m/z calc’d for C9H12O3Cl [M+H]+: 203.0475, found: 203.0470. Ph O O O NaH, toluene O O O 353 Ph 100 °C 77% yield 2-Phenylallyl 2-oxocyclopentanecarboxylate (355): O 355 Ph Dieckmann condensation was adapted from the literature.3d A flask was charged with NaH (60% dispersion in mineral oil, 216 mg, 9.02 mmol, 1.10 equiv) and subsequently evacuated and re-filled with argon (3 x 5 minutes). Toluene (31.0 mL, 0.26 M) was added followed by 2-phenyldiallyl adipate (353, 3.10 g, 8.20 mmol, 1.00 equiv). The reaction was then placed in a preheated 100 °C oil bath. After 16 h, the consumption of starting material was complete (as determined by TLC analysis, 8:2 hexanes:EtOAc) and the reaction was removed from the heating bath and allowed to cool to ambient temperature (ca. 23 °C). After cooling, the reaction was quenched with 1 M HCl (12.5 mL) and saturated aqueous NH4Cl (25 mL). The resultant solution was extracted with Et2O (3 x 30 mL). The combined organics were washed with a 50:50 mixture of H2O and brine (90 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude solution was purified by column chromatography (SiO2, 20% EtOAc in hexanes) to afford b-ketoester 355 (1.54 g, 77% yield) as a faint pink oil; Rf = 0.42 (8:2 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) d 7.45–7.40 (m, 2H), 7.39–7.28 (m, 3H), 5.56 (d, J = 0.9 Hz, 1H), 5.40 (q, J = 1.2 Hz, 1H), 5.12–4.96 (m, 2H), 3.28–3.06 (m, 1H), 2.38–2.18 (m, 4H), 2.15–1.98 (m, 1H), 1.93–1.76 (m, 1H); 13C NMR (101 MHz, CDCl3) d 212.2 (C), 169.2 (C), 142.2 (C), 138.0 (C), 128.6 (CH), 128.2 (CH), 126.2 (CH), 115.5 (CH2), 66.6 (CH2), 54.9 (CH), 38.2 (CH2), 27.5 (CH2), 21.1 (CH2); IR (thin film, NaCl) Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 125 3467, 3083, 3056, 2962, 1725, 1574, 1496, 1450, 1400, 1341, 1294, 1249, 1180, 1106, 1025, 959, 914, 833, 778, 708 cm-1; HRMS (APCI/ESI) m/z calc’d for C15H17O3 [M+H]+: 245.1182, found: 245.1173. O NaH diallyl carbonate O O O THF 91% yield 356 357 Allyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (357): Acylation of 356 was adapted from the literature.3d A flask was charged with NaH (60% dispersion in mineral oil, 500 mg, 20.8 mmol, 2.50 equiv) and subsequently evacuated and re-filled with argon (3 x 5 minutes). THF (10.8 mL, 1.92 M) was added and the resultant solution was cooled to 0 °C (ice/H2O bath). A solution of 1-indanone (356, 1.10 g, 8.30 mmol, 1.00 equiv) in THF (2.6 mL, 3.20 M) was added dropwise. The solution was allowed to warm to room temperature (ca. 23 °C). After 15 minutes, diallyl carbonate (1.79 mL, 12.5 mmol, 1.50 equiv) was added dropwise. After 16 h, the consumption of starting material was complete (as determined by TLC analysis, 12:1 hexanes:EtOAc) and the solution was quenched with saturated aqueous NH4Cl and extracted with EtOAc (3 x 20 mL). The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 7.7% EtOAc in hexanes) to provided bketoester 357 (1.62 g, 91% yield) as a purple oil; Rf = 0.25 (12:1 hexanes:EtOAc). bketoester 357 was carried on without any further characterization. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones O O OMe 358 O allyl alcohol zinc powder tol. reflux 67% yield 126 O O 359 Allyl 2,2-dimethyl-5-oxocyclopentane-1-carboxylate (359): A solution of 358 (400 mg, 2.35 mmol, 1.00 equiv) in toluene (1.96 mL, 1.20 M) was added zinc powder (31 mg, 0.47 mmol, 0.20 equiv) and allyl alcohol (799 µL, 11.8 mmol, 5.00 equiv). The reaction mixture was allowed to stir at reflux. After 24 h the consumption of starting material was complete (as determined by TLC analysis, 9:1 hexanes:EtOAc). The crude solution was directly purified by column chromatography (SiO2, 10% Et2O in hexanes) to furnish cyclopentanone 359 (309 mg, 67% yield) as a clear colorless oil; Rf = 0.24 (9:1 hexanes:Et2O); 1H NMR (400 MHz, CDCl3) d 5.91 (ddt, J = 17.2, 10.4, 5.8 Hz, 1H), 5.34 (dq, J = 17.2, 1.5 Hz, 1H), 5.25 (dq, J = 10.4, 1.2 Hz, 1H), 4.62 (ddt, J = 5.9, 3.0, 1.4 Hz, 2H), 2.97–2.91 (m, 1H), 2.55–2.31 (m, 2H), 2.01 (ddd, J = 12.8, 9.1, 5.7 Hz, 1H), 1.82– 1.65 (m, 1H), 1.22 (s, 3H), 1.10 (s, 3H); 13C NMR (101 MHz, CDCl3) d 213.0 (C), 168.6 (C), 131.8 (CH), 118.9 (CH2), 65.8 (CH), 65.7 (CH2), 41.0 (C), 36.8 (CH2), 36.1 (CH2), 29.1 (CH3), 24.1 (CH3); IR (thin film, NaCl) 2959, 2872, 1757, 1761, 1734, 1729, 1647, 1610, 1616, 1458, 1390, 1370, 1363, 1319, 1234, 1219, 1190, 1159, 1112, 1032, 991, 934, 810, 772, 736 cm–1; HRMS (APCI/ESI) m/z calc'd for C11H16O3 [M+H]+: 197.1172, found 197.1169. 127 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones O OTES TESCl, NaI Et3N, MeCN 34% yield 360 2-(p-methylbenzyl)-1-triethylsiloxy-1-cyclopentene 361 (361): To a solution of cyclopentanone 360 (300 mg, 1.59 mmol, 1.00 equiv) and sodium iodide (310 mg, 2.00 mmol, 1.30 equiv) in acetonitrile (2.65 mL, 0.60 M) had Et3N (357 µL, 2.54 mmol, 1.60 equiv) added dropwise. After 5 minutes of stirring, TESCl (347 µL, 2.07 mmol, 1.30 equiv) was added dropwise. After 6 hours of stirring, consumption of starting was complete (as determined by TLC analysis, 19:1 hexanes:Et2O). Crude solution was extracted with pentane (4 x 5 mL), the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 0.5% Et3N, 1% Et2O in hexanes) to provide silyl enol ether 361 (164 mg, 34%) as a pale yellow oil; Rf = 0.62 (19:1 hexanes:Et2O); 1H NMR (400 MHz, C6D6) d 7.21 (d, J = 7.9 Hz, 2H), 7.03 (d, J = 7.7 Hz, 2H), 3.52 (s, 2H), 2.30 (dddd, J = 8.6, 7.3, 3.4, 1.7 Hz, 2H), 2.19 (dddd, J = 9.5, 7.2, 3.0, 1.3 Hz, 2H), 2.13 (s, 3H), 1.72 – 1.61 (m, 2H), 1.01 (t, J = 7.9 Hz, 9H), 0.65 (q, J = 7.8 Hz, 6H); 13C NMR (101 MHz, C6D6) d 147.6 (C), 138.2 (C), 135.1 (C), 129.3 (CH), 129.0 (CH), 115.8 (C), 34.2 (CH2), 33.0 (CH2), 31.2 (CH2), 21.1 (CH3), 20.1 (CH2), 7.1 (CH3), 5.9 (CH2); IR (thin film, NaCl) 3044, 2954, 2876, 2845, 1895, 1681, 1512, 1458, 1412, 1378, 1341, 1306, 1240, 1107, 1045, 1016, 974, 888, 859, 746, 680 cm–1; HRMS (FAB+) m/z calc'd for C19H30OSi [M]+: 302.2066, found 302.2075. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 128 General Procedure A: a-Quaternary b-Ketoester Cyclopentanone Synthesis O O MeI O 362 K2CO3, acetone, 50 °C 88% yield O O O 363 The alkylation b-ketoester 362 was adapted from the literature.3d b-ketoester 262 (500 mg, 2.97 mmol, 1.00 equiv) was added to a suspension of anhydrous K2CO3 (822 mg, 5.95 mmol, 2.00 equiv) in acetone (3.00 mL, 1.00 M). To the reaction mixture was added iodomethane (0.370 mL, 5.95 mmol, 2.00 equiv). The resultant solution was placed in a preheated 50 °C oil bath. After 14 h, the consumption of starting material was complete (as determined by TLC analysis, 9:1 Pentane:Et2O) and the reaction was removed from the heating bath and allowed to cool to ambient temperature (ca. 23 °C). After cooling, the solution was filtered with grade 4 filter paper and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 10% Et2O in pentane) to furnish bketoester 363 (477 mg, 88% yield) as a clear colorless oil; Rf = 0.23 (9:1 Pentane:Et2O); 1 H NMR (400 MHz, CDCl3) d 5.88 (ddt, J = 17.3, 10.5, 5.6 Hz, 1H), 5.29 (dq, J = 17.2, 1.6 Hz, 1H), 5.23 (dq, J = 10.5, 1.3 Hz, 1H), 4.60 (dq, J = 5.6, 1.4 Hz, 2H), 2.61–2.38 (m, 2H), 2.39–2.26 (m, 1H), 2.14–1.98 (m, 1H), 2.02–1.80 (m, 2H), 1.33 (s, 3H); 13C NMR (101 MHz, CDCl3) d 215.8 (C), 172.0 (C), 131.7 (CH), 118.3 (CH2), 65.8 (CH2), 56.0 (C), 37.7 (CH2), 36.2 (CH2), 19.6 (CH3), 19.5 (CH2). IR (thin film, NaCl) 3462, 3086, 2973, 2886, 1752, 1731, 1648, 1457, 1406, 1375, 1316, 1273, 1153, 1064, 976, 939, 842, 814, 770 cm-1; HRMS (FAB+) m/z calc’d for C10H15O3 [M+H]+: 183.1021, found 183.1022. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones O 129 O O 364 Ph 2-Phenylallyl 1-methyl)-2-oxocyclopentanecarboxylate (364): Prepared by using general procedure A above from 2-phenylallyl 2-oxocyclopentanecarboxylate (355, 1.64 mmol), using iodomethane as the electrophile, and purified by column chromatography (SiO2, 10% Et2O in pentane) to afford b-ketoester 364 (292 mg, 69% yield) as a clear colorless oil; Rf = 0.25 (9:1 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 7.43–7.28 (m, 5H), 5.52 (q, J = 0.8 Hz, 1H), 5.33 (q, J = 1.3 Hz, 1H), 5.06 (ddd, J = 13.4, 1.5, 0.7 Hz, 1H), 4.96 (ddd, J = 13.3, 1.3, 0.7 Hz, 1H), 2.46–2.34 (m, 1H), 2.31–2.18 (m, 2H), 1.94– 1.74 (m, 3H), 1.29 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 215.8 (C), 172.1 (C), 142.5 (C), 138.0 (C), 128.6 (CH), 128.2 (CH), 126.2 (CH), 115.4 (CH2), 66.6 (CH2), 56.1 (C), 37.7 (CH2), 36.3 (CH2), 19.61 (CH3), 19.59 (CH2); IR (thin film, NaCl) 3467, 2972, 1750, 1729, 1496, 1457, 1405, 1374, 1316, 1262, 1230, 1150, 1063, 1027, 973, 911, 840, 778, 709 cm-1; HRMS (FAB+) m/z calc’d for C16H19O3 [M+H]+: 259.1334, found: 259.1347. O O Et O 365 Ph 2-Phenylallyl 1-ethyl)-2-oxocyclopentanecarboxylate (365): Prepared by using general procedure A above from 2-phenylallyl 2-oxocyclopentanecarboxylate (355, 1.63 mmol), using iodoethane as the electrophile, and purified by column chromatography (SiO2, 10% Et2O in pentane) to provide b-ketoester 365 (288 mg, 65% yield) as a clear colorless oil; Rf = 0.29 (9:1 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 7.42–7.28 (m, 5H), 5.52 (d, J = 0.8 Hz, 1H), 5.34 (q, J = 1.3 Hz, 1H), 5.04 (ddd, J = 13.3, 1.4, 0.7 Hz, 1H), 4.99 (ddd, J Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 130 = 13.4, 1.3, 0.6 Hz, 1H), 2.50–2.32 (m, 1H), 2.32–2.11 (m, 2H), 1.94 (dq, J = 14.1, 7.5 Hz, 1H), 1.89–1.78 (m, 3H), 1.62 (dq, J = 14.0, 7.4 Hz, 1H), 0.83 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 215.0 (C), 170.9 (C), 142.6 (C), 138.1 (C), 128.6 (CH), 128.2 (CH), 126.2 (CH), 115.5 (CH2), 66.5 (CH2), 61.0 (C), 38.2 (CH2), 32.3 (CH2), 26.9 (CH2), 19.6 (CH2), 9.3(CH3); IR (thin film, NaCl) 3460, 2968, 2881, 1749, 1725, 1635, 1496, 1457, 1405, 1318, 1294, 1223, 1142, 1078, 1027, 977, 915, 824, 779, 709 cm-1; HRMS (FAB+) m/z calc’d for C17H21O3 [M+H]+: 273.1491, found: 273.1480. O O Et O 366 Cl 2-Chloroallyl 1-ethyl)-2-oxocyclopentanecarboxylate (366): Prepared by using general procedure A above from 2-chloroallyl 2-oxocyclopentanecarboxylate (354, 0.99 mmol), using iodoethane as the electrophile, and purified by column chromatography (SiO2, 5% Et2O in pentane) to furnish b-ketoester 366 (228 mg, 80% yield) as a clear colorless oil; Rf = 0.3 (8:2 Pentane:Et2O); 1H NMR d 5.46 (q, J = 1.4 Hz, 1H), 5.39 (dd, J = 1.8, 0.8 Hz, 1H), 4.75–4.59 (m, 2H), 2.60–2.49 (m, 1H), 2.49–2.38 (m, 1H), 2.34–2.21 (m, 1H), 2.14– 1.90 (m, 4H), 1.67 (dq, J = 13.9, 7.4 Hz, 1H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 214.7 (C), 170.4 (C), 135.5 (C), 115.3 (CH2), 66.5 (CH2), 61.0 (C), 38.3 (CH2), 32.3 (CH2), 26.9 (CH2), 19.7 (CH2), 9.3 (CH3); IR (thin film, NaCl) 3466, 3115, 2970, 2882, 1755, 1732, 1639, 1458, 1405, 1382, 1319, 1294, 1222, 1132, 1082, 1030, 904, 820, 797, 765, 705, 643 cm-1; HRMS (FAB+) m/z calc’d for C11H16O3Cl [M+H]+: 231.0788, found: 231.0794. 131 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones O O O Cl OEt O 367 2-Chloroallyl 1-(3-ethoxy-3-oxopropyl)-2-oxocyclopentanecarboxylate Prepared using by general procedure A above from (367): 2-chloroallyl 2- oxocyclopentanecarboxylate (354, 0.99 mmol), using ethyl acrylate as the electrophile, and purified by column chromatography (SiO2, 20% Et2O in pentane) to afford b-ketoester 367 (132 mg, 44% yield) as a clear colorless oil; Rf = 0.1 (8:2 Pentane:Et2O); 1H NMR d 5.46 (dt, J = 2.2, 1.2 Hz, 1H), 5.43–5.39 (m, 1H), 4.75–4.61 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.58–2.47 (m, 2H), 2.47–2.39 (m, 1H), 2.39–2.19 (m, 3H), 2.13–1.88 (m, 4H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 214.1 (C), 173.0 (C), 170.3 (C), 135.4 (C), 115.7 (CH2), 66.7 (CH2), 60.7 (CH2), 59.4 (C), 38.1 (CH2), 33.8 (CH2), 29.9 (CH2), 28.5 (CH2), 19.8 (CH2), 14.3 (CH3); IR (thin film, NaCl) 3459, 2978, 1730, 1638, 1448, 1377, 1180, 1109, 1023, 905, 642 cm-1; HRMS (FAB+) m/z calc’d for C14H20O5Cl [M+H]+: 303.0999, found: 303.0986. O O O OEt O 331 Allyl 1-(3-ethoxy-3-oxopropyl)-2-oxocyclopentanecarboxylate (331): Prepared by using general procedure A above from allyl 2-cyclopentanonecarboxylate (362, 8.97 mmol), using ethyl acrylate as the electrophile, and purified by column chromatography (SiO2, 10% Et2O in pentane) to provide b-ketoester 331 (1.83 g, 76% yield) as a clear Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 132 colorless oil; Rf = 0.20 (8:2 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 5.83 (ddt, J = 17.2, 10.4, 5.6 Hz, 1H), 5.33–5.11 (m, 2H), 4.55 (dt, J = 5.6, 1.4 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 2.54–2.38 (m, 2H), 2.36 (ddd, J = 8.7, 6.3, 1.1 Hz, 1H), 2.32–2.12 (m, 3H), 2.08– 1.77 (m, 4H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 214.2 (C), 172.9 (C), 170.7 (C), 131.5 (CH), 118.6 (CH2), 65.9 (CH2), 60.6 (CH2), 59.3 (C), 37.9 (CH2), 33.7 (CH2), 29.8 (CH2), 28.4 (CH2), 19.6 (CH2), 14.2 (CH3); IR (thin film, NaCl) 3453, 3086, 2979, 1731, 1648, 1451, 1377, 1182, 1113, 1025, 985, 939, 852 cm-1; HMRS (APCI) m/z calc’d for C14H21O5 [M+H]+: 269.1384, found: 269.1389. O O Et O 368 Allyl 1-ethyl-2-oxocyclopentanecarboxylate (368): Prepared by using general procedure A above from allyl 2-cyclopentanonecarboxylate (362, 9.17 mmol), using iodoethane as the electrophile, and purified by column chromatography (SiO2, 10% Et2O in hexanes) to afford b-ketoester 368 (1.53 g, 85% yield) as a clear colorless oil; Rf = 0.23 (9:1 hexanes:Et2O); characterization data match known literature values.3d O O O i-Pr 369 Allyl 1-isopropyl-2-oxocyclopentanecarboxylate (369): Prepared by using general procedure A above from allyl 2-cyclopentanonecarboxylate (362, 8.99 mmol), using 2iodopropane as the electrophile, and purified by column chromatography (SiO2, 10% to 30% Et2O in hexanes) to provide b-ketoester 369 (1.55 g, 82% yield) as a clear colorless oil; Rf = 0.32 (10:1 hexanes:EtOAc); characterization data match known literature values.3d Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones O 133 O O CN 370 Allyl 1-(cyanomethyl)-2-oxocyclopentanecarboxylate (370): Prepared by using general procedure A above from allyl 2-cyclopentanonecarboxylate (362, 2.66 mmol), using acrylonitrile as the electrophile, and purified by column chromatography (SiO2, 50% Et2O in pentane) to afford b-ketoester 370 (589 mg, 30% yield) as a clear colorless oil; Rf = 0.20 (8:2 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 5.96–5.76 (m, 1H), 5.37–5.20 (m, 2H), 4.67–4.54 (m, 2H), 2.67–2.41 (m, 4H), 2.41–2.26 (m, 1H), 2.26–2.15 (m, 1H), 2.14–1.88 (m, 4H); 13C NMR (101 MHz, CDCl3) d 213.7 (C), 170.1 (C), 131.2 (CH), 119.4 (C), 119.3 (CH2), 66.4 (CH2), 58.7 (C), 37.9 (CH2), 34.1 (CH2), 29.5 (CH2), 19.8 (CH2), 13.2 (CH2); IR (thin film, NaCl) 2962, 2247, 1748, 1726, 1648, 1451, 1362, 1261, 1232, 1164, 1115, 938, 824 cm-1; HMRS (ESI+) m/z calc’d for C12H16O3N [M+H]+: 222.1125, found: 222.1127. O O O NPhth 371 Allyl 1-((1,3-dioxoisoindolin-2-yl)methyl)-2-oxocyclopentanecarboxylate (371): Prepared by using general procedure A above from allyl 2-cyclopentanonecarboxylate (362, 8.83 mmol), using (N-chloromethyl)phthalimide as the electrophile, and purified by column chromatography (SiO2, 20% to 30% EtOAc in hexanes) to furnish b-ketoester 371 (1.56 g, 54% yield) as a white amorphous solid; Rf = 0.27 (6:3 hexanes:EtOAc); characterization data match known literature values.3d Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones O 134 O O OMe 372 Allyl 1-(4-methoxybenzyl)-2-oxocyclopentanecarboxylate (372): Prepared by using general procedure A above from allyl 2-cyclopentanonecarboxylate (362, 8.88 mmol), using 4-methoxybenzyl chloride as the electrophile, and purified by column chromatography (SiO2, 9% EtOAc in hexanes) to provide b-ketoester 372 (2.56 g, 95% yield) as a clear colorless oil; Rf = 0.17 (11:1 hexanes:EtOAc); characterization data match known literature values.3d O O O 373 Allyl 1-benzyl-2-oxocyclopentanecarboxylate (373): Prepared by using general procedure A above from allyl 2-cyclopentanonecarboxylate (362, 8.86 mmol). using benzyl bromide as the electrophile, and purified by column chromatography (SiO2, 10% Et2O in pentane) to furnish b-ketoester 373 (824 mg, 36% yield) as a clear colorless oil; Rf = 0.17 (9:1 Pentane:Et2O); characterization data match known literature values.26 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones O 135 O O 374 Allyl 1-(4-methylbenzyl)-2-oxocyclopentanecarboxylate (374): Prepared by using general procedure A above from allyl 2-cyclopentanonecarboxylate (362, 8.79 mmol), using 4-methylbenzyl bromide as the electrophile, and purified by column chromatography (SiO2, 10% Et2O in pentane) to afford b-ketoester 374 (2.13 g, 89% yield) as a clear colorless oil; Rf = 0.20 (9:1 Pentane:Et2O); characterization data match known literature values.3d O O O CF3 375 Allyl 2-oxo-1-(4-(trifluoromethyl)benzyl)cyclopentanecarboxylate (375): Prepared by using general procedure A above from allyl 2-cyclopentanonecarboxylate (362, 9.10 mmol), using 4-trifluoromethylbenzyl bromide as the electrophile, and purified by column chromatography (SiO2, 10% Et2O in pentane) to furnish b-ketoester 375 (1.93 g, 65% yield) as an amorphous solid; Rf = 0.20 (9:1 Pentane:Et2O); characterization data match known literature values.3d Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones O 136 O O 376 Allyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (376): Prepared by using general procedure A above from allyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (357, 1.84 mmol), using iodomethane as the electrophile, and purified by column chromatography (SiO2, 7.7% EtOAc in hexanes) to provide b-ketoester 376 (361 mg, 85% yield) as a pale yellow oil; Rf = 0.23 (12:1 hexanes:EtOAc); characterization data match known literature values.26 O O O 357 TiCl4 Selectfluor“ O O F MeCN 97% yield O 377 Allyl 2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (377): TiCl4 (18 µL, 167 µmol, 0.09 equiv) was added to a solution of indanone 357 (400 mg, 1.85 mmol, 1.00 equiv) in acetonitrile (18.5 mL, 0.10 M). After 10 minutes, Selectfluor® (786 mg, 2.22 mmol, 1.20 equiv) was added. After 3 h, the starting material had been completely consumed (determined by TLC analysis, 8:2 Pentane:Et2O) The solution was partitioned between H2O (100 mL) and Et2O (25 mL), extracted with Et2O (3 x 30 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. Crude product was filtered through a silica plug (Et2O) to provide b-ketoester 377 (421 mg, 97% yield) as an amorphous orange solid; Rf = 0.23 (8:2 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 7.84 (dt, J = 7.7, 1.0 Hz, 1H), 7.70 (td, J = 7.5, 1.3 Hz, 1H), 7.59–7.39 (m, 2H), 5.84 (ddt, J = 17.2, 10.5, 5.7 Hz, 1H), 5.35–5.16 (m, 2H), 4.70 (dq, J = 5.7, 1.3 Hz, 2H), 3.92–3.72 (m, 1H), 3.59–3.32 (m, 1H); 19F NMR (470 MHz, CDCl3) –164.6 (dd, J =11.6, 23.2 Hz); 13C Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 137 NMR (101 MHz, CDCl3) d 195.2 (d, J = 18.2 Hz, C), 167.1 (d, J = 28.0 Hz, C), 150.9 (d, J = 3.7 Hz, C), 136.9 (CH), 133.4 (C), 130.8 (CH), 128.8 (CH), 126.7 (d, J = 1.5 Hz, CH), 125.8 (CH), 119.4 (CH2), 94.7 (d, J = 201.8 Hz, C), 66.8 (CH2), 38.4 (d, J = 23.7 Hz, CH2); IR (thin film, NaCl) 3585, 3435, 3078, 2943, 1761, 1720, 1603, 1465, 1423, 1363, 1272, 1181, 1155, 1067, 994, 917, 806, 751, 721, 692 cm-1; HRMS (ESI+) m/z calc’d for C13H12FO3 [M+H]+: 235.0765, found: 235.0768. O O O 378 Allyl 2,2-dimethyl-1-(4-methylbenzyl)-5-oxocyclopentane-1-carboxylate (378): Prepared by using general procedure A above from allyl 2,2-dimethyl-5-oxocyclopentane1-carboxylate (359, 1.48 mmol) and using 4-methylbenzyl chloride as the electrophile. Purified by column chromatography (SiO2, 10% Et2O in hexanes) to furnish b-ketoester 378 (61 mg, 14% yield) as a clear colorless oil; Rf = 0.12 (9:1 hexanes:Et2O); 1H NMR d 7.29 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 5.99 (ddt, J = 17.2, 10.6, 5.4 Hz, 1H), 5.35 (dq, J = 17.2, 1.7 Hz, 1H), 5.19 (dq, J = 10.5, 1.5 Hz, 1H), 5.08 (s, 2H), 4.68 (dt, J = 5.4, 1.6 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.37 (s, 3H), 1.69 (t, J = 7.4 Hz, 2H), 1.24 (s, 6H); 13C NMR (101 MHz, CDCl3) d 167.7 (C), 165.0 (C), 137.8 (CH), 133.9 (CH), 133.0 (CH), 129.3, 127.0, 117.3 (CH2), 113.4 (C), 71.5 (CH2), 64.1 (CH2), 43.0 (C), 37.2 (CH2), 29.1 (CH2), 27.9 (CH3), 21.3 (CH3); IR (thin film, NaCl) 2948, 1685, 1617, 16517, 1457, 1370, 1356, 1283, 1224, 1170, 1087, 1047, 1020, 994, 929, 801, 788 cm–1; HRMS (FAB+) m/z calc'd for C19H25O3 [M+H]+: 301.1798, found 301.1803. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones O O O 138 O O O NaH, MeI DME, 55 °C 52% yield 374 379 Allyl 3,3-dimethyl-1-(4-methylbenzyl)-2-oxocyclopentane-1-carboxylate (379): The alkylation of 374 was adapted from the literature.27 A flask was charged with sodium hydride (60% dispersion in mineral oil, 61.7 mg, 1.54 mmol, 3.00 equiv) and subsequently evacuated and re-filled with argon (3 x 5 minutes). DME (6 mL, 0.63 M) was added followed by methyliodide (0.16 mL, 2.57 mmol, 5.00 equiv) and b-ketoester 374 (140 mg, 0.514 mmol, 1 equiv). The heterogeneous solution was heated to 55 °C with stirring. After 2 hours, the consumption of starting was complete (as determined by TLC analysis, 9:1 Pentane:Et2O). The solution was poured into water, and extracted with Et2O (3 x 5 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solution was purified by flash chromatography (SiO2, 5% Et2O in hexanes) to afford b-ketoester 379 (80 mg, 52% yield) as a clear colorless oil; Rf = 0.60 (9:1 Pentane:Et2O); 1H NMR d 7.05 (d, J = 7.9 Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 5.89 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H), 5.32 (dq, J = 17.2, 1.5 Hz, 1H), 5.24 (dq, J = 10.4, 1.3 Hz, 1H), 4.62 (ddt, J = 5.6, 2.7, 1.4 Hz, 2H), 3.14 (s, 2H), 2.38–2.31 (m, 1H), 2.30 (s, 3H), 1.97 (ddd, J = 13.6, 8.5, 7.2 Hz, 1H), 1.78 (ddd, J = 12.8, 8.4, 7.2 Hz, 1H), 1.41 (ddd, J = 12.7, 7.2, 5.4 Hz, 1H), 1.08 (s, 3H), 0.70 (s, 3H); 13C NMR (101 MHz, CDCl3) d 218.5 (C), 171.3 (C), 136.6 (C), 133.5 (C), 131.7 (CH), 130.6 (CH), 129.1 (CH), 118.8 (CH2), 66.2 (CH2), 62.4 (C), 46.2 (C), 39.1 (CH2), 35.5 (CH2), 28.1 (CH2), 25.1 (CH3), 24.0 (CH3), 21.2 (CH3); IR (thin film, NaCl) 2963, 2870, 1747, 1726, Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 139 1515, 1457, 1380, 1361, 1315, 1252, 1197, 1183, 1130, 1061, 993, 977, 931, 888, 817, 775 cm–1; HRMS (FAB+) m/z calc'd for C19H25O3 [M+H]+: 301.1798, found 301.1808. General Procedure B: Pd-Catalyzed Enantioselective Allylic Alkylation O Pd2(dba)3 (2.75 mol %) (S)-(p-CF3)3-t-BuPHOX ((S)-168, 6.00 mol %) O Et O 365 toluene (0.033 M), 20 °C Ph 98% yield 94% ee O Et Ph (S)-347 In a nitrogen-filled glovebox, separate stock solutions of Pd2(dba)3 (2.50 mg/mL), (S)(CF3)3-t-Bu-PHOX ((S)-168, 10.0 mg/mL), and b-ketoester 365 (100. mg/mL) in toluene were prepared. Pd2(dba)3 (1.92 mL, 4.8 mg, 5.20 µmol, 0.0275 equiv) and (S)-(CF3)3-t-BuPHOX ((S)-168, 0.67 mL, 6.7 mg, 11.4 µmol, 0.06 equiv) were added to a 20 mL scintillation vial and placed in a pre-chilled 20 °C stirrer. After 20 minutes, the solution was diluted with toluene (2.69 mL, 20 °C) followed by b-ketoester 365 (0.517 mL, 51.7 mg, 0.19 mmol, 1.00 equiv) in one portion (total volume 5.8 mL, 0.033 M). After 20 h, the consumption of starting material was complete (as determined by TLC analysis, 19:1 Pentane:Et2O). The crude solution was directly purified by column chromatography (SiO2, 100% pentane then 5% Et2O in pentane) to furnish cyclopentanone (S)-347 (43 mg, 98% yield) as a clear colorless oil; Rf = 0.20 (19:1 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 7.37–7.26 (m, 5H), 5.26 (d, J = 1.7 Hz, 1H), 5.07 (dt, J = 1.8, 0.9 Hz, 1H), 2.77 (dd, J = 13.8, 1.1 Hz, 1H), 2.62 (d, J = 13.8 Hz, 1H), 2.17–2.04 (m, 1H), 1.99–1.84 (m, 1H), 1.82– 1.66 (m, 3H), 1.66–1.60 (m, 1H), 1.51–1.31 (m, 2H), 0.79 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 223.2 (C), 146.1 (C), 142.3 (C), 128.3 (CH), 127.6 (CH), 126.8 (CH), 117.4 (CH2), 52.8 (C), 40.0 (CH2), 38.4 (CH2), 31.9 (CH2), 28.8 (CH2), 18.8 (CH2), 8.8 (CH3); IR (thin film, NaCl) 3079, 3054, 2963, 2879, 1734, 1623, 1572, 1491, 1457, 1405, Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 140 1380, 1306, 1268, 1160, 1083, 1028, 902, 778, 700 cm–1; HRMS (APCI/ESI) m/z calc'd for C16H21O [M+H]+: 229.1587, found 229.1589; [a]D 25 –40.78 (c 0.510, CHCl3, 94% ee). O Ph (S)-346 2-(2-Phenyl)allyl-2-methylcyclopentanone ((S)-346): Prepared by using general procedure B from b-ketoester 364 (0.19 mmol), reaction time = 27.5 h. Purified by column chromatography (SiO2, 5% Et2O in pentane) to provide cyclopentanone (S)-346 (39 mg, 95% yield) as a clear colorless oil; Rf = 0.11 (19:1 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 7.37–7.26 (m, 5H), 5.27 (d, J = 1.7 Hz, 1H), 5.08 (dt, J = 1.8, 1.0 Hz, 1H), 2.74 (dd, J = 13.7, 1.1 Hz, 1H), 2.62 (d, J = 13.8 Hz, 1H), 2.29–2.14 (m, 1H), 2.04–1.90 (m, 1H), 1.88–1.65 (m, 3H), 1.51–1.37 (m, 1H), 0.91 (s, 3H); 13C NMR (101 MHz, CDCl3) d 223.3 (C), 146.1 (C), 142.5 (C), 128.4 (CH), 127.6 (CH), 126.8 (CH), 117.3 (CH2), 49.0 (C), 41.8 (CH2), 37.6 (CH2), 35.4 (CH2), 22.6 (CH3), 18.8 (CH2); IR (thin film, NaCl) 3078, 2960, 1734, 1623, 1491, 1457, 1405, 1160, 1061, 900, 778, 701 cm–1; HRMS (APCI/ESI) m/z calc'd for C15H19O [M+H]+: 215.21436, found 215.21430; [a]D 25 –99.32 (c 0.445, CHCl3, 90% ee). O Et Cl (S)-348 2-(2-Chloro)allyl-2-ethylcyclopentanone ((S)-348): Prepared by using general procedure B from b-ketoester 366 (0.19 mmol), reaction time = 28.5 h. Purified by column chromatography (SiO2, 10% Et2O in pentane) to furnish cyclopentanone (S)-348 (26 mg, 72% yield) as a clear colorless oil; Rf = 0.71 (8:2 Pentane:Et2O); 1H NMR (400 MHz, Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 141 CDCl3) d 5.24 (t, J = 0.9 Hz, 1H), 5.15 (t, J = 1.1 Hz, 1H), 2.61 (dd, J = 14.4, 1.1 Hz, 1H), 2.49 (d, J = 14.4 Hz, 1H), 2.34–2.21 (m, 2H), 2.16–2.00 (m, 1H), 1.98–1.79 (m, 3H), 1.48 (qd, J = 7.4, 3.1 Hz, 2H), 0.84 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 222.1 (C), 139.5 (C), 116.3 (CH2), 51.8 (C), 44.1 (CH2), 38.2 (CH2), 32.1 (CH2), 28.6 (CH2), 18.9 (CH2), 8.6 (CH3); IR (thin film, NaCl) 2965, 1734, 1629, 1458, 1405, 1382, 1260, 1158, 1115, 1085, 886 cm–1. HRMS (FAB+) m/z calc'd for C10H16ClO [M+H]+: 187.0890, found 187.0897; [a]D 25 –38.57 (c 0.165, CHCl3, 90% ee). O Cl O OEt (S)-349 2-(2-Chloro)allyl-2-(3-ethoxy-3oxopropyl)cyclopentanone ((S)-349): Prepared by using general procedure B from b-ketoester 367 (0.19 mmol), reaction time = 21 h. Purified by column chromatography (SiO2, 20% Et2O in pentane) to afford cyclopentanone (S)-349 (42 mg, 85% yield) as a clear colorless oil Rf = 0.32 (8:2 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 5.33–5.23 (m, 1H), 5.18 (t, J = 1.2 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 2.59 (dd, J = 14.4, 1.1 Hz, 1H), 2.51 (d, J = 14.4 Hz, 1H), 2.40–2.21 (m, 4H), 2.19–2.05 (m, 1H), 2.03–1.72 (m, 5H), 1.24 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 221.1 (C), 173.3 (C), 138.9 (C), 116.7 (CH2), 60.7 (CH2), 50.7 (C), 43.9 (CH2), 37.8 (CH2), 33.5 (CH2), 30.1 (CH2), 29.1 (CH2), 18.8 (CH2), 14.3 (CH3); IR (thin film, NaCl) 2962, 1734, 1629, 1375, 1304, 1267, 1191, 1025, 888 cm–1; HRMS (ESI) m/z calc'd for C13H20ClO3 [M+H]+: 259.1095, found 259.1108; [a]D 25 –26.99 (c 0.255, CHCl3, 88% ee). Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 142 O O OEt (S)-332 2-Allyl-2-(3-ethoxy-3-oxopropyl)cyclopentanone ((S)-332): Prepared by using general procedure B above from b-ketoester 331 (0.19 mmol), reaction time = 8 h. Purified by column chromatography (SiO2, 20% Et2O in pentane) to provide cyclopentanone (S)-332 (40 mg, 93% yield) as a clear colorless oil; Rf = 0.30 (8:2 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 5.66 (ddt, J = 16.4, 10.6, 7.4 Hz, 1H), 5.11–5.01 (m, 2H), 4.09 (q, J = 7.1 Hz, 2H), 2.39–2.10 (m, 6H), 1.95–1.67 (m, 4H), 1.23 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 221.9 (C), 173.5 (C), 133.4 (CH), 118.7 (CH2), 60.6 (CH2), 50.9 (C), 39.1 (CH2), 38.3 (CH2), 33.3 (CH2), 29.7 (CH2), 29.2 (CH2), 18.7 (CH2), 14.3 (CH3); IR (thin film, NaCl) 3076, 2961, 1734, 1639, 1445, 1406, 1376, 1303, 1252, 1190, 1096, 1028, 919 cm–1; HRMS (FAB+) m/z calc'd for C13H21O3 [M+H]+: 225.1491, found 225.1498; [a]D 25 –18.69 (c 1.950, CHCl3, 91% ee). O (S)-333 2-Allyl-2-methylcyclopentanone ((S)-333): Prepared by using general procedure B from b-ketoester 363 (0.38 mmol), reaction time = 31 h. Purified by column chromatography (SiO2, 5% Et2O in pentane) to furnish cyclopentanone (S)-333 (43 mg, 81% yield) as a clear colorless oil; Rf = 0.24 (19:1 Pentane:Et2O); [a]D 25 –72.21 (c 0.245, CHCl3, 86% ee); characterization data match known literature values.7i Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 143 O Et (S)-334 2-Allyl-2-ethylcyclopentanone ((S)-334): Prepared by using general procedure B from bketoester 368 (0.38 mmol), reaction time = 31 h. Purified by column chromatography (SiO2, 7% Et2O in pentane) to afford cyclopentanone (S)-334 (69 mg, 79% yield) as a clear colorless oil; Rf = 0.44 (10:1 hexanes:EtOAc); [a]D 25 –20.22 (c 0.340, Et2O, 88% ee); characterization data match known literature values.3d O i-Pr (S)-335 2-Allyl-2-isopropylcyclopentanone ((S)-335): Prepared by using general procedure B from b-ketoester 369 (0.38 mmol), reaction time = 36 h. Purified by column chromatography (SiO2, 5% Et2O in pentane) to provide cyclopentanone (S)-335 (39 mg, 62% yield) as a clear colorless oil; Rf = 0.44 (10:1 hexanes:EtOAc); [a]D 25 +33.57 (c 0.315, CHCl3, 87% ee); characterization data match known literature values.3d O CN (S)-336 2-Allyl-2-(cyanomethyl)cyclopentanone ((S)-336): Prepared by using general procedure B from b-ketoester 370 (0.19 mmol), except catalyst pre-stir ran for 40 minutes (20 minutes at 30 °C followed by another 20 minutes at 0 °C) and the reaction was run at 0 °C, reaction time = 23 h. Purified by column chromatography (SiO2, 40% Et2O in pentane) to afford cyclopentanone (S)-336 (35 mg, 97% yield) as a clear colorless oil; Rf = 0.32 (1:1 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 144 hexanes:Et2O); 1H NMR (400 MHz, CDCl3) d 5.68 (ddt, J = 16.9, 10.2, 7.4 Hz, 1H), 5.26– 5.07 (m, 2H), 2.52–2.21 (m, 4H), 2.18 (dt, J = 7.4, 1.2 Hz, 2H), 2.10–1.79 (m, 6H); 13C NMR (101 MHz, CDCl3) d 221.0 (C), 132.4 (CH), 119.7 (C), 119.5 (CH2), 50.6 (C), 38.4 (CH2), 38.0 (CH2), 33.2 (CH2), 30.2 (CH2), 18.6 (CH2), 12.3 (CH2); IR (thin film, NaCl) 2961, 2246, 1731, 1444, 1159, 921 cm–1; HRMS (EI+) m/z calc'd for C11H15NO [M]+: 177.1154, found 177.1171; [a]D 25 –13.41 (c 0.450, CHCl3, 90% ee). O NPhth (S)-337 2-Allyl-((1,3-dioxoisoindolin-2-yl)methyl)cyclopentanone ((S)-337): Prepared by using general procedure B from b-ketoester 371 (0.19 mmol), except catalyst pre-stir ran for 40 minutes (20 minutes at 30 °C followed by another 20 minutes at 0 °C) and the reaction was run at 0 °C, reaction time = 23 h. Purified by column chromatography (SiO2, 20% Et2O in pentane) to afford cyclopentanone (S)-337 (48 mg, 93% yield) as a white amorphous solid; Rf = 0.50 (1:1 Pentane:Et2O); [a]D 25 –25.16 (c 0.305, CHCl3, 92% ee); characterization data match known literature values.3d O OMe (S)-338 2-Allyl-2-(4-methoxybenzyl)cyclopentanone ((S)-338): Prepared by using general procedure B from b-ketoester 372 (0.19 mmol), reaction time = 8 h. Purified by column chromatography (SiO2, 10% Et2O in pentane) to provide cyclopentanone (S)-338 (46 mg, Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 145 >99% yield) as a clear colorless oil; Rf = 0.25 (9:1 Pentane:Et2O); [a]D 25 +6.40 (c 0.275, CHCl3, 92% ee); characterization data match known literature values.3d O (S)-339 2-Allyl-2-benzylcyclopentanone ((S)-339): Prepared by using general procedure B from b-ketoester 373 (0.19 mmol), reaction time = 13 h. Purified by column chromatography (SiO2, 7% Et2O in pentane) to furnish cyclopentanone (S)-339 (39 mg, 95% yield) as a clear colorless oil; Rf = 0.41 (9:1 Pentane:Et2O); 1H NMR (400 MHz, CDCl3) d 7.32–7.15 (m, 3H), 7.16–7.08 (m, 2H), 5.75 (dddd, J = 17.0, 10.2, 7.8, 6.9 Hz, 1H), 5.18–5.05 (m, 2H), 2.94 (d, J = 13.3 Hz, 1H), 2.62 (d, J = 13.3 Hz, 1H), 2.31 (ddt, J = 13.8, 7.0, 1.3 Hz, 1H), 2.24–2.11 (m, 2H), 2.07–1.93 (m, 1H), 1.97–1.81 (m, 2H), 1.75 (ddq, J = 12.8, 8.7, 7.0 Hz, 1H), 1.56–1.41 (m, 1H); 13C NMR (101 MHz, CDCl3) d 223.0 (C), 137.9 (C), 133.8 (CH), 130.4 (CH), 128.3 (CH), 126.5 (CH), 118.8 (CH2), 53.3 (C), 41.8 (CH2), 41.0 (CH2), 39.0 (CH2), 31.1 (CH2), 18.8 (CH2); IR (thin film, NaCl) 3027, 2960, 1733, 1639, 1495, 1453, 1404, 1156, 997, 920, 757 cm–1; HRMS (FAB+) m/z calc'd for C15H19O [M+H]+: 215.1436, found 215.1433; [a]D 25 +6.88 (c 1.950, CHCl3, 88% ee). Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 146 O (S)-340 2-Allyl-2-(4-methylbenzyl)cyclopentanone ((S)-340): Prepared by using general procedure B from b-ketoester 374 (0.19 mmol), reaction time = 13 h. Purified by column chromatography (SiO2, 5% Et2O in pentane) to afford cyclopentanone (S)-340 (50 mg, 93% yield) as a clear colorless oil; Rf = 0.39 (9:1 Pentane:Et2O); [a]D 25 +12.78 (c 0.835, CHCl3, 89% ee); characterization data match known literature values.3d O CF3 (S)-341 2-Allyl-2-(4-(trifluoromethyl)benzyl)cyclopentanone ((S)-341): Prepared by using general procedure B from b-ketoester 375 (0.19 mmol), reaction time = 96 h. Purified by column chromatography (SiO2, 7% Et2O in pentane) to furnish cyclopentanone (S)-341 (30 mg, 54% yield (83% yield based on recovered starting material 375) as a clear colorless oil; Rf = 0.59 (6:3 Pentane:Et2O); [a]D 25 +10.22 (c 0.540, CHCl3, 88% ee); characterization data match known literature values.3d O (S)-344 2-Allyl-2-methyl-2,3-dihydro-1H-inden-1-one ((S)-344): Prepared by using general procedure B from b-ketoester 376 (0.19 mmol), reaction time = 4.5 h. Purified by column Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 147 chromatography (SiO2, 10% Et2O in pentane) to afford cyclopentanone (S)-344 (33 mg, 93% yield) as a clear colorless oil; Rf = 0.36 (9:1 hexanes:EtOAc); [a]D 25 –59.24 (c 0.595, CHCl3, 84% ee); characterization data match known literature values.3d O F (S)-345 2-Allyl-2-Fluoro-2,3-dihydro-1H-inden-1-one ((S)-345): Prepared by using general procedure B above from b-ketoester 377 (0.19 mmol), reaction time = 13 h. Purified by column chromatography (SiO2, 5% Et2O in pentane) to provide cyclopentanone (S)-345 (36 mg, >99% yield) as a clear colorless oil; Rf = 0.19 (19:1 Pentane:Et2O); [a]D 25 –75.79 (c 0.585, CHCl3, 87% ee); characterization data match known literature values.7g O (S)-380 (S)-2-allyl-5,5-dimethyl-2-(4-methylbenzyl)cyclopentan-1-one ((S)-380): Prepared by using general procedure B from b-ketoester 379 (0.19 mmol), reaction time = 48 h. Purified by column chromatography (SiO2, 3% Et2O in hexanes) to afford cyclopentanone (S)-380 (32 mg, 66% yield) as a clear colorless oil Rf = 0.24 (19:1 hexanes:Et2O); 1H NMR (400 MHz, CDCl3) d 7.07–7.03 (m, 2H), 6.97 (d, J = 8.0 Hz, 2H), 5.73 (dddd, J = 17.0, 10.1, 7.8, 7.0 Hz, 1H), 5.14–5.01 (m, 2H), 2.87 (d, J = 13.3 Hz, 1H), 2.55 (d, J = 13.3 Hz, 1H), 2.30 (s, 3H), 2.26 (ddt, J = 13.7, 7.0, 1.3 Hz, 1H), 2.17 – 2.10 (m, 1H), 1.89–1.72 (m, 2H), 1.63 (dt, J = 12.8, 7.2 Hz, 1H), 1.39 (ddd, J = 12.8, 7.3, 6.3 Hz, 1H), 0.98 (s, 3H), 0.67 (s, 148 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 3H); 13C NMR (101 MHz, CDCl3) d 136.1 (C), 134.8 (C), 134.1 (CH), 130.6 (CH), 128.9 (CH), 118.7 (CH2), 54.5 (C), 45.6 (C), 41.7 (CH2), 41.6 (CH2), 35.0 (CH2), 27.4 (CH2), 24.7 (CH3), 23.9 (CH3), 21.2 (CH3); IR (thin film, NaCl) 2958, 2867, 1731, 1513, 1459, 1379, 1061, 997, 916, 812, 752 cm–1; HRMS (ESI) m/z calc'd for C18H25O [M+H]+: 257.1900, found 275.1901; [a]D 25 +13.67 (c 0.58, CHCl3, 73% ee). General Procedure C: Phenyl Ester Derivative Synthesis O (S)-333 NaIO4 RuCl3•H2O H2O, MeCN, EtOAc O O O O DIC, DMAP OPh OH phenol, CH2Cl2 (S)-381 (S)-382 57% yield over 2 steps Ketone (S)-333 (34 mg, 0.25 mmol, 1.00 equiv) was diluted in H2O (2.34 mL, 0.11 M), acetonitrile (1.50 mL, 0.160 M), and EtOAc (1.50 mL, 0.16 M). Sodium periodate (NaIO4, 342 mg, 1.60 mmol, 6.40 equiv) and ruthenium(III) trichloride (RuCl3, 4.7 µL, 0.1 M solution in H2O, 0.019 equiv) were added in single portions. The reaction was allowed to stir at ambient temperature (ca. 23 °C) for 4 h, at which time consumption of starting material was complete (as determined by TLC analysis, 19:1 Pentane:Et2O). Crude reaction mixture was filtered through a celite plug and extracted with a saturated solution of NaHCO3. The aqueous solution was acidified to pH 1 with 1 M HCl. Acidified aqueous solution was extracted with dichloromethane, dried over Na2SO4, filtered, and concentrated in vacuo. Crude solution was carried on with no further purification. A flask charged with carboxylic acid (S)-381 (0.25 mmol, 1.00 equiv), phenol (14 mg, 0.27 mmol, 1.10 equiv), and 4-(dimethylamino)-pyridine (DMAP, 14 mg, 0.11 mol, 0.45 equiv) was evacuated and re-filled with argon (3 x 5 minutes). Dichloromethane (946 µL, 0.26 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 149 M) was added and the solution was cooled to 0 °C (ice/H2O bath). Diisopropylcarbodiimide (DIC, 42.0 µL, 0.27 mmol, 1.10 equiv) was added dropwise and allowed to stir for 5 minutes. The cooling bath was then removed and the solution was allowed to warm to ambient temperature (ca. 23 °C). After 11 h, the consumption of starting material was complete (as determined by TLC analysis, 9:1 hexanes:EtOAc) and the reaction was filtered through filter paper and then diluted with dichloromethane (200 mL). The solution was washed with 0.1 M aqueous HCl (200 mL), 1 M aqueous NaOH, saturated aqueous NaHCO3 (100 mL), and brine (100 mL). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by column chromatography (SiO2, 10% hexanes in EtOAc) to provide ester (S)-382 (33 mg, 57% yield over 2 steps) as a clear colorless oil; Rf = 0.24 (9:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) d 7.42–7.31 (m, 2H), 7.22 (ddt, J = 7.9, 6.9, 1.2 Hz, 1H), 7.09–6.99 (m, 2H), 2.92 (d, J = 16.6 Hz, 1H), 2.72 (d, J = 16.6 Hz, 1H), 2.45–2.30 (m, 2H), 2.27–2.13 (m, 1H), 2.09–1.94 (m, 1H), 1.97–1.81 (m, 2H), 1.13 (s, 3H); 13C NMR (101 MHz, CDCl3) d 221.7 (C), 170.2 (C), 150.5 (C), 129.6 (CH), 126.1 (CH), 121.6 (CH), 46.5 (C), 41.6 (CH2), 37.3 (CH2), 35.1 (CH2), 22.8 (CH3), 18.9 (CH2); IR (thin film, NaCl) 3459, 3066, 2964, 2873, 1756, 1738, 1592, 1493, 1456, 1404, 1375, 1350, 1317, 1266, 1242, 1193, 1162, 1127, 1070, 1023, 1006, 969, 925, 896, 817, 800, 772, 749, 772, 722, 698, 687 cm–1; HRMS (FAB+) m/z calc'd for C14H17O3 [M+H]+: 233.1178, found 233.1176; [a]D 25 –45.05 (c 0.280, CHCl3, 86% ee). Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 150 O O Et OPh (S)-383 (1-Ethyl-2-oxo-cyclopentyl)-acetic acid phenyl ester ((S)-383): Prepared by using general procedure C from cyclopentanone (S)-334 (0.25 mmol). Purified by column chromatography (SiO2, 10% EtOAc in hexanes) to furnish ester (S)-383 (46 mg, 75% yield over 2 steps) as an amorphous solid; Rf = 0.28 (9:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) d 7.39–7.33 (m, 2H), 7.21 (tt, J = 7.1, 1.1 Hz, 1H), 7.07–7.02 (m, 2H), 2.90 (d, J = 16.7 Hz, 1H), 2.73 (d, J = 16.7 Hz, 1H), 2.48– 2.27 (m, 2H), 2.14 (ddd, J = 13.1, 10.3, 7.8 Hz, 1H), 2.06–1.94 (m, 2H), 1.95–1.80 (m, 1H), 1.53 (p, J = 7.4 Hz, 2H), 0.93 (t, J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 221.8 (C), 170.5 (C), 150.5 (C), 129.6 (CH), 126.0 (CH), 121.6 (CH), 50.0 (C), 39.5 (CH2), 37.6 (CH2), 32.4 (CH2), 28.6 (CH2), 18.8 (CH2), 8.6 (CH3); IR (thin film, NaCl) 3455, 3066, 2965, 2881, 1733, 1592, 1492, 1456, 1404, 1383, 1349, 1262, 1238, 1190, 1161, 1125, 1024, 1006, 951, 926, 895, 810, 768, 721, 688 cm–1; HRMS (APCI/ESI) m/z calc'd for C15H19O3 [M+H]+: 247.1329, found 247.1327; [a]D 25 +2.45 (c 0.445, CHCl3, 88% ee). O O OPh i-Pr (S)-384 (1-(1-Methylethyl)-2-oxo-cyclopentyl)-acetic acid phenyl ester ((S)-384): Prepared by using general procedure C from cyclopentanone (S)-335 (0.20 mmol). Purified by column chromatography (SiO2, 10% EtOAc in hexanes) to afford ester (S)-384 (27 mg, 52% yield over 2 steps) as an amorphous white solid; Rf = 0.36 (9:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) d 7.40 – 7.33 (m, 2H), 7.21 (dd, J = 7.0, 1.1 Hz, 1H), 7.08–7.01 (m, 2H), Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 151 2.94 (d, J = 16.6 Hz, 1H), 2.73 (d, J = 16.6 Hz, 1H), 2.56–2.42 (m, 1H), 2.33–2.20 (m, 1H), 2.20–1.80 (m, 5H), 0.95 (d, J = 6.9 Hz, 3H), 0.90 (d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 223.1 (C), 170.8 (C), 150.5 (C), 129.6 (CH), 126.0 (CH), 121.6 (CH), 52.9 (C), 39.8 (CH2), 38.5 (CH2), 33.4 (CH), 29.7 (CH2), 18.9 (CH2), 18.4 (CH3), 17.6 (CH3); IR (thin film, NaCl) 2963, 1757, 1734, 1592, 1492, 1404, 1389, 1372, 1350, 1271, 1237, 1193, 1162, 1127, 1069, 1023, 932, 898, 818, 764, 719, 687 cm–1; HRMS (FAB+) m/z calc'd for C16H21O3 [M+H]+: 261.1491, found 261.1495; [a]D 25 –45.05 (c 0.280, CHCl3, 88% ee). Low-Catalyst Loading, Pd(II)-Catalyzed Enantioselective Allylic Alkylation O O O Pd(OAc)2 (0.15 mol %) (S)-(p-CF3)3-t-BuPHOX ((S)-168, 1.50 mol %) O toluene (0.10 M), 20 °C CO2Et 331 CO2Et (S)-332 In a nitrogen-filled glovebox, stock solutions of Pd(OAc)2 (1.00 mg/mL), (S)-(CF3)3-t-BuPHOX ((S)-168, 10.0 mg/mL), and b-ketoester 331 (100. mg/mL) in toluene were prepared. Pd(OAc)2 (64.0 µL, 0.064 mg, 0.285 µmol, 0.0015 equiv) and (S)-(CF3)3-t-BuPHOX (0.17 mL, 1.69 mg, 2.85 µmol, 0.015 equiv) were added to a 20 mL scintillation vial and placed in a pre-chilled 20 °C stirrer. After 40 minutes, the solution was diluted with toluene (1.16 mL, 20 °C) followed by b-ketoester 331 (0.51 mL, 51.0 mg, 0.19 mmol, 1.00 equiv) in one portion (total volume 1.9 mL, 0.10 M). After 28 h, the consumption of starting material was complete (as determined by TLC analysis, 19:1 Pentane:Et2O). The crude solution was directly purified by column chromatography (SiO2, 100% pentane then 20% Et2O in pentane) to furnish (S)-332 (42 mg, 98% yield) as a clear colorless oil; Rf = 0.30 (8:2 Pentane:Et2O); characterization data match those that are reported above. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 152 Large Scale Low-Catalyst Loading, Pd(II)-Catalyzed Enantioselective Allylic Alkylation O O O Pd(OAc)2 (0.30 mol %) (S)-(p-CF3)3-t-BuPHOX ((S)-168, 3.00 mol %) O toluene (0.10 M), 30 °C CO2Et CO2Et 331 (S)-332 In a nitrogen filled glovebox, Pd(OAc)2 (2.49 mg, 11.1 µmol, 0.003 equiv) and (S)-(CF3)3t-Bu-PHOX 168 (65.7 mg, 0.111 µmol, 0.03 equiv) were added to a flask and diluted with toluene (37.3 mL, 0.10M). The solution stirred in the ambient glovebox atmosphere (ca. 30 °C) for 40 minutes. b-ketoester 331 (1.00 g, 3.73 mmol, 1.00 equiv) was then added in one portion. After 15 h, the consumption of starting material was complete (as determined by TLC analysis, 19:1 Pentane:Et2O). The crude solution was directly purified by column chromatography (SiO2, 100% pentane then 20% Et2O in pentane) to furnish (S)-332 (682 mg, 82% yield, 89% ee) as a clear colorless oil; Rf = 0.30 (8:2 Pentane:Et2O); characterization data match those that are reported above. Fluoride Triggered, Pd(0)-Catalyzed Enantioselective Allylic Alkylation O OTES Pd2(dba)3 (2.75 mol %) (S)-(p-CF3)3-t-BuPHOX ((S)-168, 6.00 mol %) TBAT (1 equiv) toluene (0.033 M), 20 °C 361 (S)-340 In a nitrogen-filled glovebox, separate stock solutions of Pd2(dba)3 (2.50 mg/mL), (S)(CF3)3-t-Bu-PHOX ((S)-168, 10.0 mg/mL), and silyl enol ether 361 (100. mg/mL) in toluene were prepared. Pd2(dba)3 (1.92 mL, 4.8 mg, 5.20 µmol, 0.0275 equiv), (S)-(CF3)3t-Bu-PHOX ((S)-168, 0.67 mL, 6.7 mg, 11.4 µmol, 0.06 equiv), and TBAT (103 mg, 0.19 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 153 mmol, 1.00 equiv) were added to a 20 mL scintillation vial and placed in a pre-chilled 20 °C well with stirring. After 20 minutes, the solution was diluted with toluene (2.69 mL, 20 °C) followed by the addition of diallyl carbonate (28.7 µL, 0.20 mmol, 1.05 equiv) and silyl enol ether 361 (0.574 mL, 57.4 mg, 0.19 mmol, 1.00 equiv) in one portion (total volume 5.8 mL, 0.033 M). After 48 h, the consumption of starting material appeared stalled (as determined by TLC analysis, 19:1 Pentane:Et2O). The crude solution was directly purified by column chromatography (SiO2, 100% hexanes then 5% Et2O in hexanes) to furnish cyclopentanone (S)-340 (17 mg, 40% yield, 75% ee) as a clear colorless oil; characterization data match those that are reported above. 154 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 2.6.3 METHODS FOR THE DETERMINATION OF ENANTIOMERIC EXCESS product compound assayed O O entry Ph 1 Ph (S)-346 assay conditions retention time of major isomer (min) retention time of minor isomer (min) % ee SFC Chiracel OJ-H 2% IPA isocratic 2.5 mL/min 7.11 8.59 90 SFC Chiracel OJ-H 1% IPA isocratic 2.5 mL/min 8.03 10.18 94 SFC 2 Chiralpak AD-H 3% IPA isocratic 2.5 mL/min 5.40 5.14 90 SFC Chiralpak AD-H 3% IPA isocratic 2.5 mL/min 5.05 6.35 88 SFC Chiralpak AD-H 3% IPA isocratic 2.5 mL/min 3.57 4.58 91 (S)-346 O O Ph 2 Ph (S)-347 (S)-347 O O Cl 3 Cl (S)-348 (S)-348 O O Cl Cl 4 O O OEt OEt (S)-349 O (S)-349 O 5 O OEt (S)-332 O OEt (S)-332 155 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones entry product compound assayed O O 6 Me (S)-333 (S)-382 O O Et (S)-334 (S)-383 O O O % ee OPh SFC Chiracel OB-H 5% IPA isocratic 2.5 mL/min 11.37 7.36 86 OPh SFC Chiracel OB-H 3% IPA isocratic 2.5 mL/min 12.19 11.18 88 SFC Chiracel OB-H 5% IPA isocratic 2.5 mL/min 7.35 6.65 88 SFC Chiracel OD-H 10% IPA isocratic 2.5 mL/min 2.87 2.48 90 HPLC Chiracel OD-H 4% IPA in hexanes isocratic; 1 mL/min 20.82 27.11 92 SFC Chiracel OJ-H 1% IPA isocratic 2.5 mL/min 9.87 9.20 92 O OPh i-Pr i-Pr (S)-335 retention time of minor isomer (min) O Et 8 retention time of major isomer (min) O Me 7 assay conditions (S)-384 O 9 CN CN (S)-336 (S)-336 O O 10 NPhth NPhth (S)-337 (S)-337 O O 11 OMe (S)-338 OMe (S)-338 156 Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones entry O retention time of major isomer (min) retention time of minor isomer (min) % ee HPLC Chiracel OJ 0.1% EtOH in hexanes isocratic; 1 mL/min 14.61 13.26 88 HPLC Chiracel OJ 0.1% EtOH in hexanes isocratic;1 mL/min 12.90 11.43 89 SFC Chiralpak AD-H 1% IPA isocratic 2.5 mL/min 5.61 6.03 88 SFC Chiralpak AD-H 2% IPA isocratic 2.5 mL/min 7.17 6.30 84 SFC Chiracel OB-H 2% IPA isocratic 2.5 mL/min 7.18 4.46 87 9.50 6.12 73 O 12 13 assay conditions compound assayed product Bn Bn (S)-339 (S)-339 O O p-tol p-tol (S)-340 O (S)-340 O 14 CF3 CF3 (S)-341 (S)-341 O O 15 (S)-344 (S)-344 O O 16 F F (S)-345 (S)-345 O O 17 2.6.4 1. p-tol p-tol (S)-380 (S)-380 SFC Chiralpak IC 3% IPA isocratic 2.5 mL/min NOTES & REFERENCES (a) Liu, Y.; Han, S. J.; Lui, W. B.; Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740– 751. (b) Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I. Nature 2012, 490, 522–526. (c) Das, J. P; Marek, I. Chem. Commun. 2011, 47, 4593–4623. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 157 (d) Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846–1913. (e) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363–5367. (f) Martin, S. F. Tetrahedron 1980, 36, 419–460. 2. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044–15045. 3. (a) Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.; Stoltz, B. M. Angew. Chem. Int. Ed. 2015, 54, 179–183. (b) Numajiri, Y.; Pritchett, B. P.; Chiyoda, K.; Stoltz, B. M. J. Am. Chem. Soc. 2015, 137, 1040–1043. (c) Reeves, C. M.; Behenna, D. C.; Stoltz, B. M. Org. Lett. 2014, 16, 2314–2317. (d) Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marunescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist Jr., J. A.; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. – Eur. J. 2011, 17, 14199–14223. 4. (a) Craig, II, R. A.; Stoltz, B. M. Tetrahedron Lett. 2015, 56, 4670–4673. (b) McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2010, 51, 5550–5554. (c) Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth. 2009, 86, 181–205. (d) Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769–1772. (e) Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993,
34, 3149–3150. (f) Von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566–568. 5. (a) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343–18357. (b) Burger, E.; Barron, B.; Tunge, J. Synlett 2006, 17, 2824–2826. (c) Mohr, J. T.; Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 158 Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2005, 44, 6924–6927. (d) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846–2847. 6. Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Angew. Chem. Int. Ed. 2013, 52, 6718–6721. 7. (a) Trost, B. M. Tetrahedron 2015, 71, 5708–5733. (b) Nahra, F.; Macé, Y.; Boreux, A.; Billard, F.; Riant, O. Chem. – Eur. J. 2014, 20, 10970–10981. (c) Rambla, M.; Duroure, L.; Chabaud, L.; Guillou, C. Eur. J. Org. Chem. 2014, 7716– 7720. (d) Nahra, F.; Macé, Y.; Lambin, D.; Riant, O. Angew. Chem. Int. Ed. 2013, 52, 3208–3212. (e) Huang, J. Z.; Jie, X. K.; Wei, K.; Zhang, H.; Wang, M. C.; Yang, Y. R. Synlett 2013, 24, 1303–1306. (f) Nahra, F.; Macé, Y.; Lambin, D.; Riant, O. Angew. Chem. Int. Ed. 2013, 52, 3208–3212. (g) Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem. Int. Ed. 2005, 44, 7248–7251. (h) Trost, B. M.; Pissot-Soldermann, C.; Chen, I. Chem – Eur. J. 2005, 11, 951–959. (i) Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 62–63. (j) Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 2586–2592. 8. Asai, R.; Mitsuhashi, S.; Shigetomi, K.; Miyamoto, T.; Ubukata, M. J. Antibiot. 2011, 64, 693–696. 9. Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist, P. R. J. Nat. Prod. 2000, 63, 79–85. 10. Abbas, H. K.; Mirocha, C. J. Appl. Environ. Microbiol. 1988, 54, 1268–1274. 11. Takayama, H.; Katakawa, K.; Kitajima, M.; Yamaguchi, K.; Aimi, N. Tetrahedron Lett. 2002, 43, 8307–8311. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 12. 159 Oh, H.; Swenson, D. C.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. Tetrahedron Lett. 1998, 39, 7633–7636. 13. Absolute stereochemistry of cyclopentanone (S)-333 was determined by comparison of optical rotation of the methyl ketone Wacker product to the known literature value, see: Thominiaux, C.; Roussé, S.; Desmaële, D.; d’Angelo, J.; Riche, C. Tetrahedron: Asymmetry 1999, 10, 2015–2021. The absolute stereochemistry of all other products generated herein was assigned by analogy to the absolute stereochemistry of (S)-333. 14. Additionally, silyl enol ether derivatives of cyclopentanones were found to be suitable enolate precursors for the formation of a-quaternary cyclopentanones under similar reaction conditions with an external allyl electrophile. 15. McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Synlett 2010, 11, 1712–1716. 16. Additionally, a’, a’-disubstituted cyclopentanones were suitable substrates within the disclosed reaction manifold, albeit generally giving the a-quaternary cyclopentanone products in reduced yields and with slightly diminished ee. a,adisubstituted cyclopentanones were not suitable substrates under the optimized conditions. 17. Marziale, A. N.; Duquette, D. C.; Craig, II, R. A.; Kim, K. E.; Liniger, M.; Numajiri, Y.; Stoltz, B. M. Adv. Synth. Catal. 2015, 357, 2238–2245. 18. Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520. 19. Craig, II, R. A.; Stoltz, B. M. Tetrahedron Lett. 2015, 56, 4670–4673. Chapter 2 – Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 160 20. McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Synlett 2010, 1712–1716. 21. Doran, R.; Guiry, P. J. J. Org. Chem. 2014, 79, 9112–9124. 22. Garzan, A.; Jaganathan, A.; Salehi Marzijarani, N.; Yousefi, R.; Whitehead. D. C.; Jackson, J. E.; Borhan, B. Chem. – Eur. J. 2013, 19, 9015–9021. 23. Corbin, N. C.; Fraher, P.; McChesney, J. D. J. Pharm. Sci. 1979, 68, 1501–1504. 24. Zou, Y.; Millar, J. G. J. Org. Chem. 2009, 74, 7207–7209. 25. (a) Harris, R. K.; Becker, E. D.; Cabral de Menezes, S. M.; Granger, P.; Hoffman, R. E.; Zilm, K. W. Pure Appl. Chem. 2008, 80, 59–84. (b) Harris, R. K.; Becker, E. D.; Cabral de Menezes, S. M.; Goodfellow, R.; Granger, P. Pure Appl. Chem. 2001, 73, 1795–1818. 26. Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039–1042. 27. Keana, J. F.; Seyedrezai, S. E. J. Org. Chem. 1982, 42, 347–352. Appendix 1 – Spectra Relevant to Chapter 2 161 APPENDIX 1 Spectra Relevant to Chapter 2: Palladium-Catalyzed Enantioselective Decarboxylative Allylic Alkylation of Cyclopentanones 8 O CO2Et O 331 O 7 6 4 ppm 3 Figure A1.1. 1H NMR (400 MHz, CDCl3) of compound 331. 5 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 162 163 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound 331. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.3. 13C NMR (101 MHz, CDCl3) of compound 331. 20 0 8 O 7 (S)-332 CO2Et 6 4 ppm 3 2 Figure A1.4. 1H NMR (400 MHz, CDCl3) of compound 332. 5 1 0 Appendix 1 – Spectra Relevant to Chapter 2 164 165 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 332. 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.6. 13C NMR (101 MHz, CDCl3) of compound 332. 0 -20 8 CN (S)-336 O 7 6 4 ppm 3 Figure A1.7. 1H NMR (400 MHz, CDCl3) of compound 336. 5 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 166 167 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 336. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1.9. 13C NMR (101 MHz, CDCl3) of compound 336. 20 0 8 (S)-339 O 7 5 4 ppm 3 Figure A1.10. 1H NMR (400 MHz, CDCl3) of compound 339. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 168 169 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1. 11. Infrared spectrum (Thin Film, NaCl) of compound 339. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1. 12. 13C NMR (101 MHz, CDCl3) of compound 339. 20 0 8 (S)-346 O Ph 7 5 4 ppm 3 Figure A1.13. 1H NMR (400 MHz, CDCl3) of compound 346. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 170 171 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1. 14. Infrared spectrum (Thin Film, NaCl) of compound 346. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.15. 13C NMR (101 MHz, CDCl3) of compound 346. 20 0 8 (S)-347 O 7 Ph 6 4 3 ppm 2 1 0 Figure A1.16. 1H NMR (400 MHz, CDCl3) of compound 347. 5 -1 -2 -3 Appendix 1 – Spectra Relevant to Chapter 2 172 173 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 347. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.18. 13C NMR (101 MHz, CDCl3) of compound 347. 20 0 8 (S)-348 O Cl 7 5 4 ppm 3 Figure A1.19. 1H NMR (400 MHz, CDCl3) of compound 348. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 174 175 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 348. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1.21. 13C NMR (101 MHz, CDCl3) of compound 348. 20 0 8 (S)-349 O CO2Et Cl 7 5 4 ppm 3 Figure A1.22. 1H NMR (400 MHz, CDCl3) of compound 349. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 176 177 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 349. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1.24. 13C NMR (101 MHz, CDCl3) of compound 349. 20 0 8 Cl O O 7 351 O O Cl 5 4 ppm 3 Figure A1.25. 1H NMR (400 MHz, CDCl3) of compound 351. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 178 179 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 351. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.27. 13C NMR (101 MHz, CDCl3) of compound 351. 20 0 8 Ph O O 7 353 O O Ph 5 4 ppm 3 Figure A1.28. 1H NMR (400 MHz, CDCl3) of compound 353. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 180 181 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 353. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.30. 13C NMR (101 MHz, CDCl3) of compound 353. 20 0 8 O O 7 354 O Cl 6 4 ppm 3 2 Figure A1.31. 1H NMR (400 MHz, CDCl3) of compound 354. 5 1 0 Appendix 1 – Spectra Relevant to Chapter 2 182 183 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 354. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.33. 13C NMR (101 MHz, CDCl3) of compound 354. 20 0 8 O O 355 O Ph 7 5 4 ppm 3 Figure A1.34. 1H NMR (400 MHz, CDCl3) of compound 355. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 184 185 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 355. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1.36. 13C NMR (101 MHz, CDCl3) of compound 355. 20 0 8 O 359 O O 7 5 4 ppm 3 Figure A1.37. 1H NMR (400 MHz, CDCl3) of compound 359. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 186 187 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 359. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.39. 13C NMR (101 MHz, CDCl3) of compound 359. 20 0 8 OTES 361 7 6 4 ppm 3 Figure A1.40. 1H NMR (400 MHz, C6D6) of compound 361. 5 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 188 189 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 361. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.42. 13C NMR (101 MHz, C6D6) of compound 361. 20 0 8 O O 363 O 7 5 4 ppm 3 Figure A1.43. 1H NMR (400 MHz, CDCl3) of compound 363. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 190 191 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1. 44. Infrared spectrum (Thin Film, NaCl) of compound 363. 220 200 180 160 140 120 100 ppm 80 60 40 Figure A1. 45. 13C NMR (101 MHz, CDCl3) of compound 363. 20 0 8 O O 364 O 7 Ph 5 4 ppm 3 Figure A1.46. 1H NMR (400 MHz, CDCl3) of compound 364. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 192 193 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 364. 220 200 180 160 140 120 100 ppm 80 60 40 Figure A1.48. 13C NMR (101 MHz, CDCl3) of compound 364. 20 0 8 O O 365 Et O 7 Ph 5 4 ppm 3 Figure A1.49. 1H NMR (400 MHz, CDCl3) of compound 365. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 194 195 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound 365. 220 200 180 160 140 120 100 ppm 80 60 40 Figure A1.51. 13C NMR (101 MHz, CDCl3) of compound 365. 20 0 8 O O 366 Et O Cl 7 5 4 ppm 3 Figure A1.52. 1H NMR (400 MHz, CDCl3) of compound 366. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 196 197 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 366. 220 200 180 160 140 120 100 ppm 80 60 40 Figure A1.54. 13C NMR (101 MHz, CDCl3) of compound 366. 20 0 8 O Cl CO2Et O 367 O 7 5 4 ppm 3 Figure A1.55. 1H NMR (400 MHz, CDCl3) of compound 367. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 198 199 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.56. Infrared spectrum (Thin Film, NaCl) of compound 367. 220 200 180 160 140 120 100 ppm 80 60 40 Figure A1.57. 13C NMR (101 MHz, CDCl3) of compound 367. 20 0 8 O CN O 370 O 7 5 4 ppm 3 Figure A1.58. 1H NMR (400 MHz, CDCl3) of compound 370. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 200 201 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.59. Infrared spectrum (Thin Film, NaCl) of compound 370. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.60. 13C NMR (101 MHz, CDCl3) of compound 370. 20 0 8 O 377 F O O 7 5 4 ppm 3 Figure A1.61. 1H NMR (400 MHz, CDCl3) of compound 377. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 202 203 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.62. Infrared spectrum (Thin Film, NaCl) of compound 377. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.63. 13C NMR (101 MHz, CDCl3) of compound 377. 20 0 O 377 F O O Figure A1.64. 19F NMR (470 MHz, CDCl3) of compound 377. Appendix 1 – Spectra Relevant to Chapter 2 204 8 O O 378 O 7 5 4 ppm 3 Figure A1.65. 1H NMR (400 MHz, CDCl3) of compound 378. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 205 206 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.66. Infrared spectrum (Thin Film, NaCl) of compound 378. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.67. 13C NMR (101 MHz, CDCl3) of compound 378. 20 0 8 O O 379 O 7 5 4 ppm 3 Figure A1.68. 1H NMR (400 MHz, CDCl3) of compound 379. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 207 208 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.69. Infrared spectrum (Thin Film, NaCl) of compound 379. 220 200 180 160 140 120 100 ppm 80 60 40 Figure A1.70. 13C NMR (101 MHz, CDCl3) of compound 379. 20 0 8 (S)-380 O 7 5 4 ppm 3 Figure A1.71. 1H NMR (400 MHz, CDCl3) of compound 380. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 209 210 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.72. Infrared spectrum (Thin Film, NaCl) of compound 380. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.73. 13C NMR (101 MHz, CDCl3) of compound 380. 20 0 8 O (S)-382 OPh O 7 5 4 ppm 3 Figure A1.74. 1H NMR (400 MHz, CDCl3) of compound 382. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 211 212 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.75. Infrared spectrum (Thin Film, NaCl) of compound 382. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1.76. 13C NMR (101 MHz, CDCl3) of compound 382. 20 0 8 Et (S)-383 O OPh O 7 5 4 ppm 3 Figure A1.77. 1H NMR (400 MHz, CDCl3) of compound 383. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 213 214 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.78. Infrared spectrum (Thin Film, NaCl) of compound 383. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1.79. 13C NMR (101 MHz, CDCl3) of compound 383. 20 0 8 O OPh i-Pr (S)-384 O 7 5 4 ppm 3 Figure A1.80. 1H NMR (400 MHz, CDCl3) of compound 384. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 2 215 216 Appendix 1 – Spectra Relevant to Chapter 2 Figure A1.81. Infrared spectrum (Thin Film, NaCl) of compound 384. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1.82. 13C NMR (101 MHz, CDCl3) of compound 384. 20 0 Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 217 CHAPTER 3 Enantioselective Total Synthesis of Nigelladine A Via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme† 3.1 INTRODUCTION The field of organic synthetic chemistry has benefited greatly from the many recent advances in selective C–H functionalization.1 Indeed, chemical oxidations of C–H bonds are some of the most important transformations in synthetic chemistry because they allow for direct access to oxidized intermediates, without the need for synthetic handles or functional group interconversions. Despite recent advances, there remain significant limitations regarding the regioselectivity of non-directed C–H oxidation reactions. We envisioned that the recently isolated norditerpenoid alkaloids nigelladines A–C (385–387) and pyrroloquinoline alkaloid nigellaquinomine (388) (Figure 3.1.1)2 would present a challenging test bed to evaluate the viability of late-stage C–H oxidation methods. † This research was performed in collaboration with David K. Romney, an postdoctoral scholar of the Arnold group. Additionally, this research has been published and adapted with permission Loskot, S. A.; Romney, D. K.; Arnold, F. A.; Stoltz, B. M. J. Am. Chem. Soc. 2017, 139, 10196–10199. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 218 Figure 3.1.1. Structures of Nigelladines A–C and Nigellaquinomine N N 10 N N 7 O Nigelladine A (385) N O Nigelladine B (386) O O Nigelladine C (387) Nigellaquinomine (388) With respect to nigelladine A, we believed that late-stage installation of the C7 ketone would offer significant flexibility in how we chose to construct the highly conjugated core of alkaloid 385. However, despite the abundance of chemical allylic oxidation conditions, there are relatively few examples of selective oxidation at a 2° carbon (e.g., C7) in the presence of a non-bridging 3° carbon (e.g., C10),3 since oxidation generally occurs at the position where hydrogen abstraction is most favorable.4 On the other hand, enzymes are well known to catalyze oxidation reactions with regioselectivity that defies conventional trends of chemical reactivity. Despite this, enzymatic methods are often overlooked in total synthesis efforts due to a typically narrow substrate scope deriving from their exceptional specificity. Fortunately, recent progress in the field of directed evolution has greatly increased the viability of biocatalysis in total synthesis by increasing the reactivity and selectivity of enzymes for non-native transformations.5,6 Biocatalytic C–H oxidations with engineered enzymes thus present an alternative approach that can circumvent the limitations of traditional chemical oxidations. Nonetheless, even though there have been examples of the use of engineered enzymes for the functionalization of complex molecules,7 their application in total syntheses is still very limited. Herein we describe the first enantioselective total synthesis of tricyclic alkaloid 385, enabled by the Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 219 selective late-stage allylic oxidation of unsaturated imine 389 via an engineered P450 enzyme. 3.2 RETROSYNTHETIC ANALYSIS Retrosynthetically, we surmised that selective late-stage allylic oxidation of 389 at C7 would be essential to the synthesis of enone 385 (Scheme 3.2.1). Imine 389 could be generated by the cross-coupling of vinyl boronic ester 390 and bromide dienone 391. Vinyl bromide 391 was envisioned to arise via annulation of enone 392, with the quaternary stereocenter constructed by an asymmetric allylic alkylation reaction from b-ketoester 393.8 With this retrosynthetic analysis, we recognized that the strategically planned C–H oxidation would be particularly challenging due to issues of site selectivity. Imine 389 contains three different allylic carbon centers that could be susceptible to oxidation, a 1°, 2°, and 3°, in addition to a relatively acidic α–carbon adjacent to the imine. Together, the natural product combined with our strategic analysis unveiled a challenging problem for selective C–H functionalization that would need to be addressed in a successful synthesis. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 220 Scheme 3.2.1. Retrosynthetic Analysis of Nigelladine A N N late-stage enzymatic [O] Suzuki-Miyaura cross-coupling imine formation 7 O 389 Nigelladine A (385) O Br O Tsuji–Wacker NHBoc + aldol BPin 390 enantioselective allylic alkylation 391 O 392 O O O 393 3.3 394 SYNTHESIS OF CROSS-COUPLING FRAGMENTS In the forward direction, known enone 394 can be synthesized in excellent yield through a Stork-Danheiser transposition from 1,3-cyclohexanedione.9,10 Unfortunately, attempts to directly acylate the a-carbon of 394 resulted in low yields due to competing self-aldol additions. To avoid these issues, we chose to increase the reactivity and steric environment of the enolate by synthesizing the 1,1-dimethyl hydrazone 395.11 Hydrazone 395 was readily acylated then hydrolyzed, and the resulting b-ketoester 396 was subsequently methylated, providing our desired asymmetric allylic alkylation substrate (393) in good yield (Scheme 3.3.1). Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 221 Scheme 3.3.1. Synthesis of Asymmetric Allylic Alkylation Precursor O O N N Cl O 1. LDA, THF, –78 °C Me2NNH2, TFA 2. 1M HCl, THF, 50 °C benzene, 80 °C 79% yield over 2 steps 91% yield 1.7:1 E/Z 394 O 395 O O O O NaH, MeI O DMF, 0 °C 396 92% yield 393 With b-ketoester 393 in hand, we evaluated a variety of reaction parameters for the key quaternary stereocenter-forming asymmetric allylic alkylation and determined that the use of (CF3)3-t-Bu-PHOX (168)12 in 2:1 hexanes–toluene with Pd2(dba)3 was optimal, generating desired enone 392 in 96% yield and 87% ee. Standard Tsuji–Wacker oxidation of enone 392 using PdCl2 and CuCl under an atmosphere of oxygen generated the desired ketone,13 which subsequently underwent an aldol condensation to provide dienone 397 in good yield (76% yield over 2 steps).14 Enone 397 was then selectively mono-brominated to form vinyl bromide 391, the desired electrophilic cross-coupling fragment, in 83% yield on gram scale (Scheme 3.3.2).15 Scheme 3.3.2. Synthesis of Electrophilic Cross-Coupling Fragment O O O Pd2(dba)3 (2.75 mol %) (R)-CF3-t-BuPHOX (6.0 mol %) O (2:1) hexanes:toluene, 40 °C 393 96% yield, 87% ee O 1. PdCl2 (20 mol %) CuCl (2 equiv) DMF:H2O (9:1), 23 °C 392 Br NBS (1.1 equiv) 2. KOH, xylenes 110 °C MeCN, 0 °C 76% yield over 2 steps 83% yield 397 391 O Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 222 The nucleophilic cross-coupling fragment, Vinyl boronic ester 390, was readily prepared in three steps from commercially available ethyl isobutyrate (398 ,scheme 3.3.3). Propargylation of ethyl isobutyrate followed by concomitant saponification yielded known acid 399. Curtius rearrangement of acid 399 followed by a Markovnikov hydroboration of the resultant alkyne 400 generated the desired nucleophilic cross-coupling fragment 390 in three steps. Scheme 3.3.3. Synthesis of the Nucleophilic Cross-Coupling Fragment 1. LDA, Propargyl bromide THF, –78 °C O O OEt OH 2. 4 N KOH, EtOH, 23 °C t-BuOH, 85 °C 82% yield over 2 steps 398 59% yield 399 NHBoc B2Pin2 (1.2 equiv) CuCl (1.2 equiv) LiCl (1.2 equiv) KOAc (1.2 equiv) DMF, 50 °C 400 3.4 DPPA (1.1 equiv) Et3N (1.5 equiv) 53% yield NHBoc BPin 390 CROSS-COUPLING AND ELABORATION TO THE CARBOCYCLIC CORE The cross coupling of 390 and 391 was next evaluated for optimal reaction conditions. Ultimately, we found that Buchwald’s 2nd generation precatalyst with XPhos (XPhos Pd G2)16 allowed for the union of 390 and 391 in 88% yield using only a slight excess (1.1 equiv) of 390 (Scheme 3.4.1). Furthermore, triene 401 provided crystals suitable for X-ray diffraction and allowed us to ascertain absolute stereochemistry.17 Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 223 Scheme 3.4.1. Cross-Coupling of Dienone 391 and Vinyl Boronic Ester 390 Br BocHN O + 0.5M K3PO4, THF, 50 °C BPin 391 O XPhos Pd G2 (3 mol %) NHBoc 88% yield 401 390 H2N Pd Cl P i-Pr i-Pr i-Pr XPhos Pd G2 With triene 401 in hand, we turned our attention to the synthesis of the heterocyclic portion of the alkaloid and the final stages of the synthesis. Toward that end, triene 401 was treated with trifluoroacetic acid (TFA) in CH2Cl2 to deprotect the amine, which spontaneously cyclized to form the requisite imine upon quenching with aqueous sodium bicarbonate (Scheme 3.4.2). Fortuitously, upon removal of the aqueous layer, treatment with silica gel promoted isomerization of the exocyclic olefin into the ring, which, after purification, afforded the TFA salt of 389 in 75% yield (25% over 10 steps from enone 394).18 Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 224 Scheme 3.4.2. Synthesis of the Tricyclic Core of Nigelladine A BocHN NH O TFA, DCM, 23 °C; OTFA then NaHCO3 (aq); then SiO2 75% yield 389•TFA 401 (25% yield from 10, over 10 steps) TFA H 3N NH O NaHCO3 (aq) 3.5 SiO2 CHEMICAL OXIDATION OF DESOXY-NIGELLADINE A With only an allylic oxidation separating tricycle 389 from nigelladine A (385), we initiated a broad exploration of oxidation methods for installing an oxidation handle at the desired C7 position. Unfortunately, the required site-selective C–H oxidation of 389 or the intermediate enone 397 proved intractable for traditional synthetic methods (Table 3.5.1). While numerous conditions were probed on both substrates,19,20 only a limited few effected oxidation at the desired position. These reactions also exhibited poor selectivity, generating an inseparable mixture of mono-oxidation products, along with over-oxidized byproducts that constituted the majority of the product mixture. We thus turned our attention to enzymes as a potential means to achieve the desired oxidation. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 225 Table 3.5.1. Attempted Chemical Oxidationsa O O 14 N N 1 1 or R''' 10 10 7 7 389 Oxidation Conditions R' R' = H, OH, or t-BuOO R'' =H, OH, t-BuOO, or O R' R''' =H, OH, t-BuOO, or O R''' or R'' R'' 397 Substrate Conditions SM HPLC Yield of Oxygenation Products (%)b,c,d C1 C7 C10 Polyoxygenation 389 SeO2, DCM, 40 °C 21 79 (57)e – – – 397 SeO2, DCM, 40 °C 5 26 (22) – – 15 389 Pd/C (10 wt%), TBHP, 0 °C 7 – 3 44 46 397 Pd/C (10 wt%), TBHP, 0 °Cf 46 – 2 42 4 389 Cr(V) (1 equiv), MnO2 CF3C6H5, 15-crown-5, 80 °C 55 3 35g – 6 389 Rh2(esp)2, T-HYDRO, 23 °C 2 8 21(10) – 34 397 Rh2(esp)2, T-HYDRO, 23 °C – – 15 16 43 a See section 3.8 for reaction conditions and description of the product distribution. b Approximated by separating the products on UHPLC-MS and comparing ion count of the various oxidation products. c Remaining percent balance were unidentified side products. d Numbers given in parenthesis indicate isolated yields of the oxidized product. e Protection of 389 as an Nacyl enamide results in oxidation at C-14. f Shortened reaction time used to observe inherent regioselectivity without over oxidation. g Oxidation at C-5 occurred. 3.6 ENZYMATIC OXIDATION OF DESOXY-NIGELLADINE A The cytochrome P450 enzyme from Bacillus megaterium (P450BM3) is a workhorse of protein engineering studies because it is soluble and self-contained, exhibits one of the fastest reaction rates of any P450-catalyzed hydroxylation (17,000 min–1 for arachidonic acid),5a and possesses good stability (t1/2 = 68 min at 50 °C).21 Since the substrate scope of the wild-type protein is mostly limited to long-chain fatty acids, many engineering efforts have focused on expanding the substrate scope of P450BM3 to accept larger and more complex substrates. To this end, various approaches have been applied to develop biocatalysts derived from P450BM3 that perform regioselective C–H oxygenation of complex molecules for which the wild-type enzyme exhibits minimal activity.6c,22 Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 226 However, these approaches involved extensive screening endeavors, often requiring highthroughput screening and limiting them to substrates that were readily available. For biocatalysis to be a viable strategy for the late-stage of a total synthesis, it is desirable to identify a synthetically useful catalyst with minimal screening. Thus, we elected to screen a focused library of variants that had been previously engineered to accept large substrates,22 but had otherwise never encountered substrate 389. To compare the catalysts, we chose to allow the reactions to proceed to only low conversion and compare the ratio of desired to undesired oxidation products (Table 3.6.1). Encouragingly, wildtype P450BM3 exhibited some selectivity for C7, although oxidation of the isopropyl C–H bond was favored 1.2:1 (Table 3.6.1, entry 1). We then probed a small selection of engineered variants that all derive from the same parent (12 mutations from P450BM3). These enzymes were previously evolved for regioselective oxidation of methoxymethylprotected glycosides, but are distinct in that different combinations of active-site residues have been mutated to alanine. The variant 2A1, in which leucine residues 75, 181, and 437 are mutated to alanine, exhibited a worse selectivity compared to wild-type, favoring the isopropyl oxidation product, as well as an unidentified oxidation product (Table 3.6.1, entry 2). The two other variants, however, exhibited a reversal in selectivity, favoring oxidation at the desired position in excess of 2:1 (Table 3.6.1, entries 3–4). The best variant proved to be 8C7, which is identical to 2A1, but lacks the L437A mutation. This variant favors oxidation at the desired position in a 2.8:1 ratio (Table 3.6.1, entry 4). Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 227 Table 3.6.1. Screening of Focused Library for Allylic Oxidation Entry Catalysta Active-Site Ala Substitutions Desired/ Undesiredb 1 P450BM3 – 0.86 2 2A1 L75A, L181A, L437A 0.37 3 4H5 L75A, L177A, L181A 2.1 4 8C7 L75A, L181A 2.8 a See section 3.8 for full list of mutations. b Approximated by separating the products on UHPLC-MS and comparing ion count of C-7 oxidation product to all other monooxygenation products (m/z = 286). See section 3.8 for more details. Since enzyme active sites are well known to bind substrate enantiomers differently, we wished to test if the stereochemistry of 389 would affect the activity or selectivity of 8C7. Using the Pd-catalyzed alkylation, we obtained both enantiomers of 389, which were then enriched to enantiopurity by chiral preparative HPLC. Each enantiomer was then subjected to oxidation by catalyst 8C7. Interestingly, at both short (15 min) and long (12 h) reaction times, the enantiomers gave nearly identical results, although the R enantiomer exhibited a slightly higher initial rate by a factor of 1.3. Having achieved the desired regioselectivity, we then needed to improve the yield. Furthermore, we wished to supplant the stoichiometric use of NADPH, which is required if oxygen is used as the terminal oxidant. Fortunately, we could use NADPH in catalytic amounts by regenerating it in situ with an alcohol dehydrogenase (ADH) and isopropanol as the terminal reductant.23 With these new conditions, we conducted the oxidation on a 160 mg scale, followed by subjecting the crude product mixture to oxidation with DessMartin periodinane, thus affording the natural product in 21% yield over both steps (43% yield based on recovered 389, Scheme 3.6.1). The recovered starting material (389) was Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 228 competent in the same two-step procedure with no loss in efficiency (26% yield).24 Under these conditions, we observed up to 1700 turnovers to the C7 mono-oxygenation product. Scheme. 3.6.1. Completion of the Synthesis of Nigelladine A NH OTFA 1. P450 8C7 (0.02 to 0.04 mol %) NADP (10 mol %), i-PrOH, ADH 2.5% DMSO in KPi buffer (pH 8) 23 °C , 12h N 2. DMP, CH2Cl2, 0 °C, 4h 389•TFA 3.7 21% yield over 2 steps 43% yield based on recovered 389 O 385 CONCLUSION In summary, we have completed the first total synthesis of nigelladine A in an expedient 12 steps and 5% overall yield (11% yield based on recovered 389). The asymmetric allylic alkylation allowed for the construction of the quaternary center in high yield and enantioselectivity. Expedient identification of engineered enzymes allowed for a site-selective 2° allylic oxidation without the need for extensive generational screening or reaction optimization. These results demonstrate that enzymatic transformations are capable of defying standard chemical limitations and should be included in the repertoire of reactions that are traditionally considered for the late stages of total syntheses. 3.8 EXPERIMENTAL METHODS AND ANALYTICAL DATA 3.8.1 MATERIALS AND METHODS Unless stated otherwise, reactions were performed at ambient temperature (23 °C) in flame-dried or oven-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents (distilled or passed over a column of activated alumina).25 Commercially obtained reagents were used as received with the exception of anhydrous cerium trichloride (CeCl3)10 dipalladium tris(dibenzylideneacetone) (Pd2(dba)3), palladium Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 229 (II) chloride (PdCl2), anhydrous copper (I) chloride (CuCl), bis(pinacolato)diboron (B2Pin2), anhydrous lithium chloride (LiCl), and anhydrous potassium acetate (KOAc), which were stored in a nitrogen-filled glovebox. Triethylamine (Et3N) and Diisopropylethylamine (i-Pr2NH) were distilled over potassium hydride prior to use, while allyl chloroformate was freshly distilled prior to use. N-bromosuccinimide was recrystallized prior to use.26 (S)-(CF3)3-t-BuPHOX,12 (R)-(CF3)3-t-BuPHOX,12 and Dess– Martin periodinane27 were prepared by known methods. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. Reaction progress was monitored by thin-layer chromatography (TLC), which was performed using E. Merck silica gel 60 F254 precoated glass plated (0.25 mm) and visualized by UV fluorescence quenching, potassium permanganate, p-anisaldehyde, or iodine staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40-63 nm) was used for column chromatography. 1H and 13C NMR spectra were recorded on a Varian Inova 500 (500 MHz and 126 MHz, respectively), Varian Mercury 300 spectrometer (300 MHz and 75 MHz, respectively), Varian 600 MHz Spectrometer (600 MHz), and a Bruker AV III HD spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe (400 MHz and 101 MHz, respectively) and are reported in terms of chemical shift relative to CHCl3 (d 7.26 and d 77.16, respectively) and CH3OH (d 3.31 and d 39.00 respectively). 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, sext = sextet, sept = septet, m = multiplet, and br s = broad singlet. Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and are reported in frequency of Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 230 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 and are reported as: [a]DT (concentration in g/100 mL, solvent). Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing CHIRALCEL OB-H and CHIRALPAK IC columns (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. with visualization at 254, 230, and 210 nm. High resolution mass spectra were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) ionization mode or a Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed (ESI/APCI) ionization mode. 3.8.2 PROTOCOLS FOR PROTEIN EXPRESSION AND LYSIS The genes for wild-type P450BM3 and the variants were previously cloned into the pCWori vector, which was used to transform Escherichia coli DH5a.21 In addition to the mutations listed in Table 3.6.1, all variants had the following mutations: V78A F87V P142S T175I A184V S226R H236Q E252G A290V L353V I366V E442K. For protein expression, a culture (typically 5 mL) of lysogeny broth with 100 µg/mL of ampicillin (LBamp) was inoculated with a glycerol stock of E. coli DH5a containing the desired plasmid. This culture was shaken at 37 °C and 230 rpm. After 12 hours, the culture was used to inoculate an expression culture (1:100 v/v) of Terrific Broth containing 100 µg/mL of ampicillin (TBamp) plus 0.1% by volume of trace metal mix (aqueous solution of 50 mM FeCl3, 20 mM CaCl2, 10 mM MnSO4, 10 mM ZnSO4, 2 mM CoSO4, 2 mM CuCl2, Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 231 2 mM NiCl2, 2 mM Na2MoO4, 2 mM H3BO3). The expression culture was shaken at 37 °C and 230 rpm. After ~3 hours, the OD600 was 0.6–0.8, whereupon the culture was chilled in ice for 30 minutes, then induced with the addition of aminolevulinic acid (1 mM final concentration) and isopropyl b-d-thiogalactopyranoside (0.5 mM final concentration). The culture was then shaken at 230 rpm and 20 °C. After 16–20 hours, the culture was subjected to centrifugation at 5,000×g and 4 °C for 10 minutes. The supernatant was discarded, and then the cell pellet was stored at –30 °C until further use. For lysis, the cell pellet was thawed, and then suspended in 4 mL/mg of potassium phosphate buffer (100 mM, pH 8) that contained 1 mg/mL of hen egg white lysozyme and 0.1 mg/mL of bovine pancreas DNase I. The suspension was shaken at 37 °C and 230 rpm (19 mm radius). After 1 hour, the culture was cooled on ice, then subjected to centrifugation at 15,000×g and 4 °C for 10 min. The supernatant was used directly in the biocatalytic transformation. To determine protein concentration, 900 µL of fivefold-diluted lysate was treated with a spatula tip of dithionite, then exposed to an atmosphere of carbon monoxide (CO) for 30 minutes. The absorbance of the CO-bound lysate at 450 nm minus the absorbance at 490 nm was converted to protein concentration using the extinction coefficient ε = 91 mM–1cm–1. 3.8.3 EXPERIMENTAL PROCEDURES O O i-BuOH, p-TsOH benzene, 90 °C 92% yield O 402 i-BuO 403 3-isobutoxycyclohex-2-en-1-one (403):28 1,3-cyclohexadione (402, 22.4 g, 200 mmol, 1.0 equiv), iso-butyl alcohol (55 mL, 600 mmol, 3 equiv), and p-TsOH (190 mg, 1.0 mmol, Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 232 0.005 equiv) were added to a flask and diluted in benzene (123 mL, 1.6 M). The flask was then fitted with a Dean–Stark trap filled with additional benzene. The reaction flask was heated to reflux with stirring for 8 h, at which time the starting material had been completely consumed (determined by TLC analysis, 8:1 hexanes:EtOAc). The reaction mixture was cooled to ambient temperature (ca. 23 °C) and Et3N (0.7 mL, 5 mmol, 0.025 equiv) was added. The crude reaction mixture was then concentrated in vacuo and distilled by short path distillation (Pressure 1.0 torr, neck temperature 118 °C, bath temperature 150 °C) to provide vinylogous ester 403 (32.6 g, 97% yield) as a clear colorless oil; Rf = 0.5 (8:1 hexanes:EtOAc); 1H NMR (300 MHz, CDCl3) δ 5.34 (s, 1H), 3.59 (d, J = 6.5 Hz, 2H), 2.41 (t, J = 6.3 Hz, 2H), 2.34 (dd, J = 7.2, 6.0 Hz, 2H), 2.10–1.91 (m, 3H), 0.97 (dd, J = 6.7, 0.7 Hz, 6H). All other characterization matches literature values.29 O O i-PrMgCl, CeCl3 THF, –78 °C i-BuO 403 91% yield 394 3-isopropylcyclohex-2-en-1-one (394): In a nitrogen-filled glovebox, CeCl3 (49g, 200 mmol, 1.5 equiv) was added to a round bottom flask with a magnetic stir bar. The flask was sealed with a rubber septum and removed from the glovebox. The flask was heated at 140 °C under vacuum (ca. 1 Torr) with stirring for 8 h. CeCl3 was allowed to cool to ambient temperature (23 °C) and the flask was refilled with Ar. The CeCl3 was then cooled to 0 °C (H2O:ice bath) and diluted with THF (444 mL, 0.3 M) with vigorous stirred for 3 h. The reaction flask was then cooled to –78 °C (dry ice:acetone bath) whereupon ester 403 (22.4 g, 133 mmol, 1 equiv) was added. After 1h at –78 °C, i-PrMgCl (2.0 M in THF, 100 mL, 1.5 equiv) was added dropwise via cannula and allowed to stir for 1h, at which time Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 233 the starting material had been completely consumed (determined by TLC, 8:1 hexanes:Et2O). The reaction was then quenched with 1 M HCl (300 mL) and allowed to warm to ambient temperature. The product was extracted from the biphasic mixture with Et2O (3 × 200 mL), and then the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product can be purified by either flash chromatography (SiO2, 4:1 hexanes:Et2O) or by Kugelrohr distillation (pressure 1.0 Torr, 115 °C) to provide enone 394 (16.8 g, 91% yield) as a pale yellow oil, which solidifies to a white solid upon cooling to –20 °C; Rf = 0.29 (4:1 hexanes:Et2O); 1H NMR (500 MHz, C6D6) δ 5.95 (q, J = 1.4 Hz, 1H), 2.17–2.10 (m, 2H), 1.88 (pd, J = 6.8, 1.0 Hz, 1H), 1.66– 1.60 (m, 2H), 1.47–1.38 (m, 2H), 0.74 (d, J = 6.9 Hz, 6H). All other characterization matches literature values.30 O Me2NNH2, TFA N N benzene 90°C 91% yield 394 395 1.7:1 E:Z 2-(3-isopropylcyclohex-2-en-1-ylidene)-1,1-dimethylhydrazine (395): Hydrazone condensation was adapted from the literature.31 Enone 394 (8.2g, 59.0 mmol, 1 equiv), N,N-dimethylhydrazine (9 mL, 118 mmol, 2 equiv), TFA (0.1 mL), and benzene (120 mL, 0.4 M) were added to a round-bottom flask. The flask was fitted with a Dean-Stark trap filled with additional benzene. The reaction flask was heated to reflux with stirring for 8 h, at which time the starting material had been completely consumed (determined by TLC analysis, 1:1 hexanes:EtOAc). The crude reaction mixture was then cooled to ambient temperature and concentrated in vacuo. The crude product can be purified by either flash Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 234 chromatography (SiO2, 1:1 hexanes:EtOAc) or short path distillation (pressure 1 Torr, neck temperature 130 °C, bath temperature 160 °C) to generate hydrazone 395 (9.7 g, 91% yield, 1.7:1 E:Z ratio) as a yellow oil; Rf = 0.5 (E); 0.26 (Z) (1:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) (E) δ 6.00 (q, J = 1.4 Hz, 1H), 2.59 (dd, J = 7.5, 5.8 Hz, 2H), 2.52 (s, 6H), 2.33 (sept, J = 6.9 Hz, 1H), 2.20–2.16 (m, 2H), 1.79 (dtd, J = 7.5, 6.4, 5.6 Hz, 2H), 1.08 (d, J = 6.9 Hz, 6H), (Z) δ 6.54 (q, J = 1.5 Hz, 1H), 2.49 (s, 6H), 2.43–2.33 (m, 3H), 2.21– 2.17 (m, 2H), 1.85–1.78 (m, 2H), 1.08 (d, J = 6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) (E) δ 164.9, 157.3, 121.1, 47.4, 35.6, 27.7, 26.2, 22.5, 21.0, (Z) δ 162.5, 160.2, 113.6, 47.9, 36.0, 31.9, 27.7, 22.9, 21.1; IR thin film, NaCl) 2960, 2857, 2816, 2771, 1634, 1589, 1466, 1436, 1383, 1362, 1327, 1304, 1267, 1251, 1222, 1200, 1154, 1142, 1089, 1022, 980, 969, 890, 790 cm-1; HRMS (ES/APCI) m/z calc’d C11H21N2 [M+H]+: 181.1699, found: 181.1705. O N N Cl O 1. LDA, THF, –78 °C O O O 2. 1 M HCl, THF, 50 °C 79% yield over 2 steps 395 396 Allyl 4-isopropyl-2-oxocyclohex-3-ene-1-carboxylate (396): A flame-dried round bottom flask was charged with diisopropylamine (i-Pr2NH, 9.58 mL, 68.4 mmol, 1.5 equiv) in THF (61 mL, 1.1 M) and cooled to 0 °C. A solution of n-BuLi in hexanes (2.3 M, 29.7 mL, 68.4 mmol, 1.5 equiv) was added dropwise and the resulting solution was allowed to stir for 0.5 h at 0 °C. Hydrazone 395 (8.22 g, 45.6 mmol, 1 equiv) was added dropwise to the LDA solution, which was then stirred for 1 h at 0 °C. The reaction mixture was cannulated to a separate flame dried flask containing allyl chloroformate (7.3 mL, 68.4 mL, Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 235 1.5 equiv) in THF (320 mL, 0.2 M) at –78 °C. The solution was stirred for 1 h, at which time the starting material had been completely consumed (determined by TLC analysis, 4:1 hexanes:EtOAc). The solution was quenched at –78 °C with aqueous NH4Cl (200 mL) and allowed to warm to ambient temperature. The product was extracted from the biphasic solution with Et2O (3 × 150 mL), and the combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude compound was diluted with THF (230 mL, 0.2 M) and 1 M HCl (91.2 mL, 91.2 mmol, 2.0 equiv) and heated to 50 °C for 12 h, at which time the starting material had been completely consumed (determined by TLC analysis, 4:1 pentane:Et2O). The product was extracted with Et2O (3 × 100 mL) and the combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 9:1 hexanes:EtOAc) to yield b-Ketoester 396 (7.96 g, 79% yield) as a pale yellow oil; Rf = 0.2 (4:1 pentane:Et2O); 1H NMR (500 MHz, CDCl3) δ 5.98–5.85 (m, 2H), 5.32 (dd, J = 17.2, 1.6 Hz, 1H), 5.22 (dd, J = 10.5, 1.3 Hz, 1H), 4.71–4.58 (m, 2H), 3.42–3.32 (m, 1H), 2.50– 2.29 (m, 4H), 2.24–2.17 (m, 1H), 1.09 (dd, J = 6.8, 0.9 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 194.3, 172.2, 170.1, 131.9, 123.0, 118.5, 65.8, 53.2, 35.8, 26.3, 26.0, 20.8, 20.6; IR thin film, NaCl) 2965, 2940, 2875, 1741, 1650, 1624, 1457, 1425, 1375, 1364, 1307, 1275, 1216, 1166, 1151, 1050, 1027, 989, 884, 767 cm-1; HRMS (ES/APCI) m/z calc’d C13H19O3 [M+H]+: 223.1329, found: 223.1329. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme O O O O 236 O NaH, MeI O DMF, 0 °C 92% yield 396 393 Allyl 4-isopropyl-1-methyl-2-oxocyclohex-3-ene-1-carboxylate (393): NaH (60% dispersion, 3.3 g, 81.9 mmol, 1.4 equiv) was added to DMF (31.5 mL, 2.6 M) at 0 °C. The solution was then charged with b-Ketoester 396 (13 g, 58.4 mmol, 1.0 equiv) in a solution of DMF (25 mL, 2.3 M) and allowed to stir for 1 h at 0 °C. MeI (12.7 mL, 204.4 mmol, 3.5 equiv) was added, followed by additional DMF (20 mL). The reaction was allowed to stir for 1.5 h, at which time the starting material had been completely consumed (determined by TLC analysis, 9:1 hexanes:EtOAc). The reaction was then quenched with water and the product was extracted with Et2O (40 mL × 3). The combined organic layers were washed with brine (3 × 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 9:1 hexanes:EtOAc) to generate b-Ketoester 393 (12.7 g, 92% yield) as a pale yellow oil; Rf = 0.30 (9:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 5.92 (dt, J = 2.1, 1.1 Hz, 1H), 5.86 (ddt, J = 17.2, 10.5, 5.5 Hz, 1H), 5.28 (dq, J = 17.2, 1.6 Hz, 1H), 5.20 (dq, J = 10.5, 1.3 Hz, 1H), 4.64 (ddt, J = 13.4, 5.6, 1.5 Hz, 1H), 4.56 (ddt, J = 13.4, 5.5, 1.5 Hz, 1H), 2.53–2.37 (m, 3H), 2.33–2.26 (m, 1H), 1.87 (ddd, J = 13.0, 8.4, 5.0 Hz, 1H), 1.39 (s, 3H), 1.09 (d, J = 6.9 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 197.4, 172.7, 170.7, 131.9, 122.8, 118.3, 65.7, 52.9, 35.7, 33.6, 25.3, 20.9, 20.7, 20.5; IR thin film, NaCl) 2965, 2935, 2875, 1731, 16678, 1626, 1456, 1425, 1375, 1302, 1248, 1217, 1170, 1105, 987, 26, 882, 771, 749 cm-1; HRMS (ES/APCI) m/z calc’d C14H21O3 [M+H]+: 237.1485, found: 237.1482. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme O O O Pd2(dba)3 (2.4 mol %) (R)-(CF3)3-t-Bu-Phox (6.5 mol %) 237 O 2:1 hexanes:toluene, 40 °C 96% yield, 87% ee 393 392 (R)-6-allyl-3-isopropyl-6-methylcyclohex-2-en-1-one (392): In a nitrogen filled glovebox, Pd2(dba)3 (725 mg, 0.79 mmol, 0.024 equiv) and (R)-(CF3)3-t-Bu-PHOX (1.3 g, 2.2 mmol, 0.065 equiv) were added to a flask. The flask was sealed and removed from the glovebox. The catalyst and ligand were then diluted with a 2:1 hexanes:toluene (1 L, 0.033M) and allowed to stir for 40 minutes at 40 °C. b-Ketoester 393 (8.0 g, 33.9 mmol, 1.0 equiv) was then added in one portion. After 62 h, the consumption of starting material was complete (as determined by TLC analysis, 9:1 hexanes:EtOAc). The crude solution was directly purified by column chromatography (SiO2, 100% hexanes then 12:1 hexanes:Et2O) to furnish enone 392 (6.25 g, 96% yield, 87% ee) as a pale yellow oil; Rf = 0.46 (9:1 hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 5.79 (q, J = 1.4 Hz, 1H), 5.73 (ddt, J = 16.8, 10.3, 7.4 Hz, 1H), 5.09–5.01 (m, 2H), 2.43–2.35 (m, 1H), 2.35–2.29 (m, 3H), 2.16 (ddt, J = 13.7, 7.7, 1.2 Hz, 1H), 1.90 (ddd, J = 13.6, 6.9, 5.6 Hz, 1H), 1.71 (ddd, J = 13.6, 6.6, 5.4 Hz, 1H), 1.09 (d, J = 6.8 Hz, 6H), 1.05 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 204.3, 169.8, 134.4, 122.4, 118.0, 43.7, 41.3, 35.6, 33.4, 24.8, 21.9, 20.9, 20.9; IR thin film, NaCl) 2964, 2929, 2873, 1663, 1627, 461, 1428, 1373, 1323, 1274, 1213, 1126, 1107, 999, 912, 881, 613 cm-1; HRMS (ES/APCI) m/z calc’d C13H21O [M+H]+: 193.1587, found: 193.1582; (R): [a]D25 +3.15° (c 1.215, CDCl3, 87% ee); (S): [a]D25 – 1.34° (c 0.675, CDCl3, 87% ee); SFC (OB-H (4 x 25 cm), 1% i-PrOH) (R) retention time: 1.93 min, (S) retention time: 2.30 min. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 238 O O PdCl2 (20 mol %) CuCl (2 equiv) O O 9:1 DMF:H2O, O2 KOH xylenes, 110 °C 76% yield over 2 steps 392 397 404 (R)-5-isopropyl-7a-methyl-1,6,7,7a-tetrahydro-2H-inden-2-one (397): A flask containing enone 392 (1.0 g, 5.2 mmol, 1.0 equiv) in 9:1 DMF:H2O (52 mL, 0.1 M) was charged with PdCl2 (0.18 g, 1 mmol, 0.2 equiv) and CuCl2 (1.0 g, 10.4 mmol, 2.0 equiv). The reaction was evacuated/backfilled (vacuum/O2) and allowed to stir for 14 h, at which time the consumption of starting material was complete (as determined by TLC analysis, 8:2 hexanes:EtOAc). The reaction was then diluted with H2O and brine and the product was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 9:1 hexanes:EtOAc to 8:2 hexanes:EtOAc) to generate ketone 404 (1.02 g, 7:1 ketone:aldehyde) as a pale yellow oil which was carried on to the next reaction without further purification. Enone 404 (1.0 g, 4.8 mmol, 1.0 equiv) was dissolved in xylenes (53 mL) in a flask fitted with a Dean–Stark trap and a reflux condenser. Freshly powdered KOH (300 mg, 5.3 mmol, 1.1 equiv) was added in one portion. The reaction was allowed to stir for 14 h at 110 °C, at which time the consumption of starting material was complete (as determined by TLC analysis, 4:1 hexanes:EtOAc). The crude solution was directly purified by flash chromatography (SiO2, 100% hexanes then 9:1 hexanes:EtOAc) to furnish enone 397 (674 mg, 76% yield over 2 steps) as a yellow oil; Rf = 0.24 (4:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.36 (d, J = 2.4 Hz, 1H), 5.69 (s, 1H), 2.46–2.28 (m, 4H), 2.20 (d, J = 17.4 Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 239 Hz, 1H), 1.92 (ddd, J = 12.9, 5.3, 1.7 Hz, 1H), 1.71–1.62 (m, 1H), 1.15 (s, 3H), 1.11 (dd, J = 6.9, 0.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 208.1, 179.2, 159.3, 122.7, 116.4, 51.7, 40.4, 35.9, 34.2, 25.8, 25.6, 21.5, 21.1; IR thin film, NaCl) 2962, 2927, 2872, 1698, 1622, 1581, 1464, 1414, 1375, 1329, 1288, 1266, 1247, 1179, 1143, 898 882 cm-1; HRMS (ES/APCI) m/z calc’d C13H19O [M+H]+: 191.1430, found: 191.1440; (R): [a]D25 –435.36° (c 0.93, CDCl3, 87% ee); (S): [a]D25 +302.67° (c 0.59, CDCl3, 87% ee). O Br O NBS (1.1 equiv) MeCN, 0 °C 83% yield 397 391 (R)-3-bromo-5-isopropyl-7a-methyl-1,6,7,7a-tetrahydro-2H-inden-2-one (391): A flask covered in aluminum foil with enone 397 (100 mg, 0.53 mmol, 1.0 equiv) diluted with MeCN (16 mL, 0.03 M) and cooled to 0 °C. NBS (104 mg, 0.58 mmol, 1.1 equiv) dissolved in MeCN (1.6 mL, 0.3 M) was added dropwise to the reaction over 4 h via syringe pump. After complete addition of NBS, the reaction was allowed to stir for 1 h at 0 °C, at which time complete consumption of starting material was observed (determined by TLC analysis, 4:1hexanes:EtOAc). The reaction was concentrated in vacuo and purified directly by flash chromatography (9:1 hexanes:EtOAc) to yield vinyl bromide 391 (118 mg, 83% yield) as a yellow oil; Rf = 0.36 (4:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.43 (dq, J = 2.5, 0.9 Hz, 1H), 2.53–2.23 (m, 5H), 1.92 (ddd, J = 13.1, 5.1, 2.0 Hz, 1H), 1.64 (ddd, J = 13.0, 11.1, 6.1 Hz, 1H), 1.17 (s, 3H), 1.15 (d, J = 6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 199.8, 173.6, 162.2, 115.4, 114.8, 49.6, 40.7, 36.2, 34.2, 26.2, 25.7, 21.5, 21.1; IR thin film, NaCl) 2963, 2928, 2872, 1712, 1614, 1579, 1458, 1421, 1374, 1314, 1259, 1245, 1211, 1175, 955, 881 cm-1; HRMS (ES/APCI) m/z calc’d C13H18OBr [M+H]+: Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 240 269.0536, found: 269.0547; (R): [a]D25 –311.57° (c 0.875, CDCl3, 87% ee); (S): [a]D25 +329.26° (c 1.245, CDCl3, 87% ee). O O 1. LDA, Propargyl bromide THF, –78 °C OH OEt 2. 4 N KOH, EtOH, 23 °C 82% yield over 2 steps 398 399 2,2-dimethylpent-4-ynoic acid (399): Acid 399 was formed using known literature procedures32 as a pale orange amorphous solid; 1H NMR (400 MHz, CDCl3) δ 11.52 (bs, 1H), 2.47 (d, J = 2.7 Hz, 2H), 2.04 (t, J = 2.7 Hz, 1H), 1.32 (s, 6H). All other characterization data match known literature values.32 O OH DPPA (1.1 equiv) Et3N (1.5 equiv) NHBoc t-BuOH, 85 °C 59% yield 399 400 tert-butyl (2-methylpent-4-yn-2-yl)carbamate (400): A flask containing alkyne 399 (3.5 g, 28 mmol, 1.0 equiv) in anhydrous t-BuOH (100 mL, 0.28 M) was charged with Et3N (5.9 mL, 42 mmol, 1.5 equiv) and diphenyl phosphoryl azide (DPPA, 6.7 mL, 30.8 mmol, 1.1 equiv). The reaction was heated to reflux and allowed to stir for 24 h. The reaction was then concentrated in vacuo, dissolved in EtOAc (100 mL), and washed sequentially with 5% citric acid and saturated NaHCO3. The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 5% EtOAc in hexanes) to generate alkyne 400 (3.3 g, 59% yield) as a white amorphous solid; Rf = 0.35 (12:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 4.59 (bs, 1H), 2.59 (d, J = 2.7 Hz, 2H), 2.00 (t, J = 2.7 Hz, 1H), 1.43 (s, 9H), 1.35 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 154.7, 81.3, 79.2, 70.5, 51.9, 30.6, 28.6, 26.9; IR thin Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 241 film, NaCl) 3361, 3310, 2977, 2932, 1718, 1501, 1457, 1390, 1367, 1290, 1247, 1170, 1079, 865 cm-1; HRMS (FAB+) m/z calc’d C11H20NO2 [M+H]+: 198.1494, found: 198.1482. NHBoc B2Pin2 (1.2 equiv) CuCl (1.2 equiv) LiCl (1.2 equiv) KOAc (1.2 equiv) DMF, 50 °C 400 tert-butyl 53% yield NHBoc BPin 390 (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-en-2- yl)carbamate (390): Hydroboration of 400 was adapted from a known procedure.33 In a nitrogen-filled glovebox, CuCl (420 mg, 4.3 mmol, 1.2 equiv) and LiCl (175 mg, 4.3 mmol, 1.2 equiv) were distributed evenly between seven 1-dram vials (60 mg and 25 mg per vial respectively). DMF (0.85 mL, 0.6 M) was added to each vial and the resulting suspensions were stirred vigorously for 1 h. Each vial was then charged sequentially with KOAc (60 mg, 0.61 mmol, 1.2 equiv), B2Pin2 (154 mg, 0.61 mmol, 1.2 equiv), and alkyne 400 (100 mg, 0.51 mmol, 1.0 equiv) dissolved in DMF (0.2 mL). The reactions were heated to 50 °C and stirred for 24 h. The vials were combined and diluted with saturated aqueous solution of NH4Cl (40 mL) and EtOAc (50 mL). The product was extracted from the biphasic solution with EtOAc (3 × 50 mL) and the combined organic layers were washed with brine (3 × 100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude solution was purified by flash chromatography (SiO2, 5% Et2O in hexanes) to generate vinyl boronic ester 390 (610 mg, 53% yield) as a white amorphous solid; Rf = 0.33 (12:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.98 (d, J = 3.6 Hz, 1H), 5.65 (d, J = 3.6 Hz, 1H), 5.40 (bs, 1H), 2.33 (d, J = 1.0 Hz, 2H), 1.41 (s, 9H), 1.28 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 134.8, 84.1, 78.3, 52.8, 51.0, 47.7, 29.9, 28.7, 26.7, 24.8; IR thin film, Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 242 NaCl) 3396, 2976, 2930, 1719, 1517, 1447, 1365, 1305, 1269, 1252, 1165, 1142, 1064, 960, 951, 861, 733 cm-1; HRMS (ES/APCI) m/z calc’d C17H3311BO4N [M+H]+: 326.2497, found: 326.2507. Br BocHN O G2 Pd XPhos (3 mol %) O 390 (1.1 equiv), 0.5M K3PO4 THF, 50 °C 88% yield 391 401 tert-butyl (R)-(4-(5-isopropyl-7a-methyl-2-oxo-2,6,7,7a-tetrahydro-1H-inden-3-yl)-2methylpent-4-en-2-yl)carbamate (401): A flask was charged with vinyl bromide 391 (300 mg, 1.11 mmol, 1.0 equiv), vinyl boronic acid 390 (387 mg, 1.22 mmol, 1.1 equiv), 0.5 M K3PO4 in degassed H2O (4.4 mL, 0.25 M), and THF (2.2 mL, 0.5 M). Buchwald’s 2nd generation precatalyst XPhos (26 mg, 0.03 mmol, 0.03 equiv) was added to the reaction with an overpressure of Ar. The reaction was allowed to stir for 16 h at 60 °C, at which time complete consumption of starting material was observed (determined by TLC analysis, 9:1 hexanes:EtOAc). The product was extracted with Et2O (3 x 10 mL) and the combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2 9:1 hexanes:EtOAc) to furnish enone 401 (377 mg, 88% yield) as a white crystalline solid; Rf = 0.17 (9:1 hexanes:EtOAc); mp: 97.7 – 98.5 °C; 1H NMR (400 MHz, CDCl3) δ 6.49 (d, J = 2.5 Hz, 1H), 5.24 (d, J = 2.3 Hz, 1H), 5.00 (d, J = 2.4 Hz, 1H), 4.49 (s, 1H), 2.79 (d, J = 13.6 Hz, 1H), 2.66 (d, J = 13.5 Hz, 1H), 2.49–2.24 (m, 4H), 2.20 (d, J = 17.4 Hz, 1H), 1.93 (ddd, J = 12.9, 5.4, 1.6 Hz, 1H), 1.62 (dt, J = 12.5, 6.2 Hz, 1H), 1.41 (s, 9H), 1.22 (s, 3H), 1.20 (s, 3H), 1.13 (s, 3H), 1.13 (d, J = 0.9 Hz, 3H), 1.11 (d, J = 0.9 Hz, 3H); 13C NMR (101 Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 243 MHz, CDCl3) δ 206.2, 171.3, 159.1, 137.9, 135.2, 121.0, 115.5, 78.5, 52.7, 51.4, 45.7, 38.4, 36.0, 34.1, 28.5, 27.5, 25.5, 25.1, 21.6, 21.0; IR thin film, NaCl) cm-1; HRMS (ES/APCI) m/z calc’d C24H38NO3 [M+H]+: 388.2846, found: 388.2864; (R): [α]D25 –256.26° (c 0.45, CDCl3, 87% ee); (S): [α]D25 +265.13° (c 0.27, CDCl3, 87% ee); SFC (IC, 30% IPA) (R) retention time: 6.385, (S) retention time: 5.691. The ee of 401 can be increased to 99% through preparative HPLC (IC, 20 x 250 µm, 30% IPA in hexanes, (R) retention time: 18.2 min, (S) retention time: 16.6 min); (R): [a]D25 –297.74° (c 0.51, CHCl3, 99% ee); (S): [a]D25 +294.25° (c 0.44, CHCl3, 99% ee). BocHN O NH TFA CH2Cl2, 0 °C 75% yield 401 389•TFA (R)-6-isopropyl-2,2,4,8a-tetramethyl-7,8,8a,9-tetrahydro-2H-indeno[2,1-b]pyridine (389): TFA (0.34 mL, 0.4 M) was added to enone 401 (53 mg, 0.14 mmol) in CH2Cl2 (1.4 mL, 0.1 M) at 0 °C. The reaction was allowed to warm to ambient temperature and stirred for an additional 1 h, at which time complete consumption of starting material was observed (determined by TLC analysis (4:1 hexanes:EtOAc). The reaction was quenched with saturated aqueous NaHCO3 until the solution was neutralized and allowed to stir for 1 h, at which time complete cyclization occurred (determined through LC-MS analysis, m/z = 270.1 [M+H]+). The product was extracted from the biphasic mixture with CH2Cl2 (3 × 30 mL), dried over Na2SO4, and filtered. SiO2 was added and the suspension was stirred for 1 h. The solution was concentrated and purified by flash chromatography (SiO2, 0–10% methanol in EtOAc) to generate imine 389•TFA as a tan amorphous solid. 389•TFA Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 244 can be deprotonated by washing a 10% aqueous solution of potassium carbonate to afford 389 (28 mg, 75% yield) as a viscous yellow oil; Rf = 0.25 (8% methanol in EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.56 (d, J = 2.4 Hz, 1H), 5.56 (d, J = 1.5 Hz, 1H), 2.51 – 2.27 (m, 4H), 2.24 – 2.15 (m, 1H), 2.02 (d, J = 1.5 Hz, 3H), 1.88 (ddd, J = 12.7, 5.6, 1.7 Hz, 1H), 1.59 (td, J = 12.3, 5.8 Hz, 1H), 1.24 (d, J = 4.1 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H), 1.06 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 171.1, 152.2, 150.5, 135.6, 125.0, 119.3, 115.1, 58.4, 45.9, 39.3, 34.9, 33.6, 30.3, 30.1, 27.4, 24.1, 24.0, 20.6, 20.2, 20.1; IR thin film, NaCl) 2962, 2922, 2177, 1660, 1615, 1456, 1407, 1374, 1286, 1261, 1154, 1048, 873, 842, 811, 732 cm-1; HRMS (ES/APCI) m/z calc’d C19H28N [M+H]+: 270.2216, found: 270.2228; (R): [a]D25 –223.18 (c 0.3, CHCl3, 87% ee); (S): [a]D25 +250.16° (c 0.28, CDCl3, 87% ee); (R): [a]D25 –340.60° (c 0.6, CHCl3, 99% ee); (S): [a]D25 +391.68° (c 1.39, CHCl3, 99% ee). OTFA NH N P450 8C7, NADP (10 mol %) i-PrOH (100 equiv), ADH N DMP CH2Cl2 2.5% DMSO in KPi buffer (pH 8) 23 °C , 12h OH 389•TFA 405 O 385 21% yield over 2 steps 43% yield based on recovered 389 Nigelladine A (385): Lysate containing the enzyme “8C7” was prepared from a 500-mL TBamp expression culture as described above. The concentration of 8C7 was determined to be 8.5 µM. A 1-L Erlenmeyer flask was charged with 5•trifluoroacetate (160 mg, 417 µmol), followed by NADP disodium salt (33 mg, 41.7 µmol). The solids were dissolved in 10 mL Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 245 of DMSO and 400 mL of potassium phosphate buffer (100 mM, pH 8). Next, isopropanol (3.2 mL) and lysate (21 mL) were added. Finally, alcohol dehydrogenase (recombinant from E. coli, 49641 Sigma) was added. The reaction was shaken at ambient temperature and 100 rpm (19 mm radius). After 12 hours, the reaction volume was reduced in vacuo to ~100 mL, then the products were extracted with ethyl acetate (250 mL plus 2×100 mL). An emulsion formed on the third extraction, so the mixture was subjected to centrifugation (5,000×g, 20 °C, 2 minutes) in order to separate the layers. The combined organic extracts were dried over sodium sulfate, filtered, and then concentrated in vacuo. The crude reaction was subjected to column chromatography (SiO2, 0–15% methanol in ethyl acetate) yielding free imine 389 (57 mg, 0.21 mmol, 51% recovery) and an inseparable mixture of diastereomers and constitutional isomers of oxidation products, which were carried on to the next reaction without further purification. Crude alcohol 405 (55.4 mg, 0.19 mmol, 1.0 equiv) was dissolved in wet CH2Cl2 (4 mL, 0.05M). DMP (98.7 mg, 0.23 mmol, 1.2 equiv) was added in one portion and allowed to stir at ambient temperature. After 3 hours, the reaction was quenched with saturated aqueous Na2S2O3 and the product was extracted with CH2Cl2 (3 × 15 mL). The organic layers were combined and washed with a saturated aqueous solution of K2CO3 dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 0–16% methanol in ethyl acetate) to generate nigelladine A (385) (25 mg, 21% yield) as an orange oil; Rf = 0.54 (8% methanol in ethyl acetate); 1H NMR (400 MHz, C6D6) δ 7.22 (d, J = 1.0 Hz, 1H), 5.63 (q, J = 1.4 Hz, 1H), 3.16 (pd, J = 6.8, 1.1 Hz, 1H), 2.47 (d, J = 15.4 Hz, 1H), 2.42 (d, J = 16.9 Hz, 1H), 2.27 (d, J = 16.9 Hz, 1H), 2.09 (dd, J = 15.4, 0.9 Hz, 1H), 1.77 (d, J = 1.4 Hz, 3H), 1.40 (s, 3H), 1.35 (s, 3H), 1.06 Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 246 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.93 (s, 3H); 13C NMR (101 MHz, C6D6) δ 196.1, 170.2, 147.2, 147.0, 141.9, 130.6, 126.0, 125.1, 61.2, 51.7, 46.5, 43.6, 31.1, 30.8, 27.5, 26.8, 22.1, 21.7, 21.0; IR thin film, NaCl) 2962, 2926, 2872, 1670, 1618, 1458, 1375, 1303, 1230, 1147, 1045, 920, 840 cm-1; HRMS (ES/APCI) m/z calc’d C19H26NO [M+H]+: 284.2009, found: 284.2021; (R): [a]D25 –200.3 (c 0.10, MeOH). 3.8.4 ENZYMATIC SCREENS AND ENANTIOMER SCREEN Initial screen of enzymes: Lysates containing the desired enzymes were prepared from 5-mL expression cultures according to the procedure described above. A 2-mL vial was charged with 5•trifluoroacetate as a solution in DMSO (5 µL, 280 mM). Potassium phosphate buffer (100 mM, pH 8, 35 µL) was added, followed by lysate (80 µL). The reactions were initiated by the addition of NADPH (80 µL, 50 mM aqueous solution) and shaken at ambient temperature and 450 rpm (Labnet Orbit P4 shaker). After 1 hour, the reactions were diluted with 1:1 CH3CN/H2O (800 µL), and subjected to centrifugation at 20,000×g and 4 °C (10 minutes). The supernatant was analyzed by LCMS (ESI, positive mode) with a C-18 column (1.8 µm, 2.1 × 50 mm). The compounds were eluted with water (0.1% acetic acid by volume) and acetonitrile at a gradient of 5% to 95% acetonitrile over 4 minutes. Selectivity was approximated by extracting m/z = 286 from the total ion count, and comparing the integration of the desired product (1.6 min) to the isopropyl oxidation product (1.3 min) and an additional product (1.8 min). Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 247 Comparison of enantiomers: Lysates containing the desired enzymes were prepared from 5-mL expression cultures according to the procedure described above. Reactions were conducted in duplicate. A 2-mL vial was charged with 5•trifluoroacetate as a solution in DMSO (10 µL, 200 mM). Potassium phosphate buffer (100 mM, pH 8, 290 µL) was added, followed by lysate (20 µL). Finally, the reactions were initiated by the addition of NADPH (80 µL, 50 mM aqueous solution) and shaken at ambient temperature and 500 rpm (Labnet Orbit P4 shaker). After 15 minutes, the reactions were diluted fivefold with 1:1 CH3CN/H2O, and subjected to centrifugation at 20,000×g and 4 °C (10 minutes). The supernatant was analyzed by LCMS using the method described above. Selectivity was approximated by extracting m/z from 269.5 to 286.5, so as to include residual starting material and all monooxygenation products. The desired product peak partially overlapped with a trace oxidation byproduct formed during preparation of the starting material, therefore the % integration of the peak at 1.4 minutes was subtracted by the % integration of the corresponding peak in the unreacted starting material. This gave % integrations of the desired product of 2.763% and 3.144% for the S enantiomer, and 3.828% and 4.069% for the R enantiomer. The krel was approximated as the ratio of the average % integration for each enantiomer. 248 Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 3.8.5 CHEMICAL OXIDATION TABLES Table 3.8.5.1. Oxidations of Imine 389 14 N N Oxidation Conditions 1 10 R''' R' = H, OH, or t-BuOO R'' =H, OH, t-BuOO, or O R''' =H, OH, t-BuOO, or O 7 R' R'' 389 HPLC Yield of Oxygenation Products (%)a,b,c Entry a Conditions SM C1 M/z= (270) (284) (286) (284) C10 Polyoxygenation (286) (358) (302) (300) (298) (314) (374) (316) (390) C7 1 SeO2, DCM, 40 °C 21 79 (57)d – – – – – – – – – – – 2 SeO2 (anhydrous), dioxane, 80 °C – – – – – – – – 60 (24) 12 – 5 – 3 Pd/C (10 wt%), TBHP, 0 °C 3 – – 3 – 44 – – 4 – 35 – 7 4 Cr(V) (5 equiv), MnO2, CF3C6H5, 15-crown-5, 80 °C – – – 5 – – 6 – 55 10 – 19 – 5 Cr(V) (1 equiv), MnO2, CF3C6H5, 15-crown-5, 80 °C 55 3 – 35e – – 2 1 3 – – – – 6 Rh2(esp)2, T-HYDRO, 23 °C 2 8 – 21 (10) – – 4 – – – – 4 – 7 CrO3, 3,5-dimethylpyrazole,f – – – – – – – – – – – – – 8 8C7 P450 oxidation 47 – 32 – 11 – – 1 – – – – – DCE, 80 °C Approximated by separating the products on UHPLC-MS and comparing ion counts of the various oxidation products. b Remaining percent balance remaining were unidentified side products. c Numbers given in parenthesis indicate isolated yields of the oxidized product. d Protection of 389 as an N-acyl enamide results in oxidation at C-14. e Observed C-7 olefin isomerization yielding oxidation at C-5. f No reaction was observed. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 249 Table 3.8.5.2. Oxidations of Enone 397 O O 1 10 R''' Oxidation Conditions R' R' = H, OH, or t-BuOO R'' =H, OH, t-BuOO, or O R''' =H, OH, t-BuOO, or O 7 R'' 397 Entry C1 M/z= (191) (205) (205) (207) (279) (207) (223) (295) (367) (221) (238) 1 SeO2, DCM, 40 °C 5 26 (22) – – – – – – – 15 – 2 Pd/C (10 wt%), TBHP, 0 °Cd 46 – 2 – 40 (23) 2 3 1 – – – 3 Rh2(esp)2, T-HYDRO, 23 °C – – 10 5 14 2 9 9 15 10 – 4 Cr(V) (5 equiv), MnO2, CF3C6H5, 15-crown-5, 80 °C 58 2 7 – – 15 – – – 4 – 5 Cr(V) (1 equiv), MnO2, CF3C6H5, 15-crown-5, 80 °C 84 – 4 – – 5 – – – – 1 6 PIFA, TBHP, Cs2CO3, O2, 4 Å mol sieves, EtOAc, –78 to – 15 °C 76 – – – 24e – – – – – – 7 Cl4-NHPI, LiClO4, acetone TBHP, pyridine, e- 68 – – – 5 – 4 – – – – 8 PCC, NaOAc benzene, celite, 80 °C 79 9 4 – – – – – – – – 9 CrO3, 3,5-dimethylpyrazole,f DCE, 80 °C – – – – – – – – – – – 10 Pd(OAc)2, 406, AcOH,f dioxane, air – – – – – – – – – – – 11 Pd(OAc)2, oxone,g AcOH, 95 °C – – – – – – – – – – – 12 BTC, KOH, EtOH, 80 °Cg – – – – – – – – – – – 13 Pd(OH)2/C (10 wt%),f – – – – – – – – – – – trityl peroxide,0 °C CH2Cl2 O Me Et OO O Cr O O Cr(V) a HPLC Yield of Oxygenation Products (%)a,b,c Polyoxygenation C7 C10 SM Conditions Me Et O MeO Ph OMe N N O Ph N N N N Ph N Cl BTC Cl Ph S S N O 406 Approximated by separating the products on UHPLC-MS and comparing ion count of the various oxidation products. b Remaining percent balance were unidentified side products. c Numbers given in parentheses indicate isolated yields of the oxidized product. d Shortened reaction time used to observe inherent regioselectivity without over oxidation. e Site-selectivity determined by analogy from Table 3.8.5.1 entry 3. f No reaction observed. g Decomposition was observed. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 3.8.6 250 COMPARISON OF NATURAL AND SYNTHETIC NIGELLADINE A Table 3.8.6.1.Comparison of Synthetic and Natural Nigelladine A34 Synthetic mono-deuterated, DCl salt of Nigelladine A (385) 1 H NMR (400 MHz, methanol-d4) 7.64 (br, 1H) 5.97 (q, J = 1.5 Hz, 1H) 3.05 (pd, J = 6.8, 1.1 Hz, 1H) 2.99 (s, 1H) 2.84 (s, 2H) 2.25 (d, J = 1.5 Hz, 3H) 1.55 (s, 3H) 1.53 (s, 3H) 1.17 (d, J = 6.8 Hz, 3H) 1.14 (d, J = 6.9 Hz, 3H) 13 C NMR (101 MHz, Methanol-d4) 197.5 184.3 165.8 154.6 136.2 130.1 126.6 125.9 61.3 51.4 49.7 44.0 29.3 29.0 29.0 27.7 22.0 21.5 20.5 Optical Rotation 26 [a]D = –200.3 (c 0.10, MeOH) Isolated Nigelladine A2a 1 H NMR (600 MHz, methanol-d4) 7.64 (br, 1H) 5.97 (q, J = 1.2 Hz, 1H) 3.05 (pd, J = 6.9, 0.8 Hz, 1H) 3.01 (s, 1H) 2.84 (s, 2H) 2.25 (d, J = 1.2 Hz, 3H) 1.55 (s, 3H) 1.54 (s, 3H) 1.17 (d, J = 6.9 Hz, 3H) 1.14 (d, J = 7.2 Hz, 3H) 13 C NMR (150 MHz, Methanol-d4) 197.6 184.3 165.8 154.7 136.4 130.1 126.7 126.0 61.5 51.6 49.6 44.2 29.5 29.2 29.1 27.8 22.1 21.6 20.6 Optical Rotation [a]D20 = –53 (c 0.10, MeOH) Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 3.8.8 1. 251 NOTES & REFERENCES For recent reviews on direct C–H functionalization see: (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169. (b) Wencel-Delord, J.; Dröge, T. Chem. Soc. Rev. 2011, 40, 4740–4761. (c) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802. (d) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. Engl. 2011, 50, 11062–11087. (e) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976–1991. (f) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. Engl. 2012, 51, 8960–9009. (g) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424 2. (a) Chen, Q. B.; Xin, X. L.; Yang, Y.; Lee, S. S.; Aisa, H. A. J. Nat. Prod. 2014, 77, 807–812. (b) Zhang, S.; Zhang, Z. Y. Drug Discovery Today 2007, 373–381. 3. Nakamura, A.; Nakada, M. Synthesis 2013, 45, 1421–1451. 4. Weidmann, V.; Maison, W. Synthesis 2013, 45, 2201–2221. 5. For reviews of biocatalysis and directed evolution see: (a) Arnold, F. H. Acc. Chem. Res. 1998, 31, 125–131. (b) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 2001, 40, 284–310. (c) Turner N. J. Nat. Chem. Biol. 2009, 5, 567–573. (d) Wohlgemuth, R. Curr. Opin. Biotechnol. 2010, 21, 713–724. (e) Reetz, M. T. J. Am. Chem. Soc. 2013, 135, 12480–12496. (f) Nestl, B. M.; Hammer, S. C.; Nebel, B. A.; Hauer, B. Angew. Chem., Int. Ed. Engl. 2014, 53, 3070–3095. (g) Denard, C. A.; Ren, H.; Zhao, H. Curr. Opin. Chem. Biol. 2015, 25, 55–64. 6. (a) Jung, S. T.; Lauchli, R.; Arnold, F. H. Curr. Opin. Biotechnol. 2011, 22, 809– 817. (b) Whitehouse, C. J.; Bell, S. G.; Wong, L. L. Chem. Soc. Rev. 2012, 41, Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 1218–1260. (c) Janocha, S.; Schmitz, D.; 252 Bernhardt, R. Adv. Biochem. Eng./Biotechnol. 2015, 148, 215–250. (d) Roiban, G.-D.; Reetz, M. T. Chem. Commun. 2015, 51, 2208–2224. 7. (a) Hoffmeister, D.; Yang, J.; Liu, L.; Thorson, J. S. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 13184–13189. (b) Whitehouse, C. J. C.; Bell, S. G.; Tufton, H. G.; Kenny, R. J. P.; Ogilvie, L. C. I.; Wong, L. L. Chem. Commun. 2008, 966–968. (c) Zhang, K.; Shafer, B. M.; Demars, M. D., II; Stern, H. A.; Fasan, R. J. Am. Chem. Soc. 2012, 134, 18695–18704. (d) Abreu, M.; Alvaro-Benito, M.; Sanz-Aparicio, J.; Plou, F. J.; Fernandez-Lobato, M.; Alcalde, M. Adv. Synth. Catal. 2013, 355, 1698–1702. 8. Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marinescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist, J. A., Jr.; White, D. E.; Levine, S. R.; Petrova, K.V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. – Eur. J. 2011, 17, 14199–14223. 9. Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775–1776. 10. Dimitrov, V.; Kostova, K.; Genov, M. Tetrahedron Lett. 1996, 37, 6787–6790. 11. Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 17, 3–6. 12. McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2010, 51, 5550–5554. 13. Mehta, G.; Shinde, H. M. J. Org. Chem. 2012, 77, 8056–8070. 14. Day, J. J.; McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed. Engl. 2011, 50, 6814–6818. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 15. 253 Zhu, J.; Germain, A. R.; Porco, J. A. Jr. Angew. Chem., Int. Ed. Engl. 2004, 43, 1239–1243. 16. Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4, 916–920. 17. Crystals grown for X-ray crystallography were synthesized in the enantiomeric series using (S)-CF3-t-Bu-PHOX for the asymmetric allylic alkylation of 393. BocHN O ent-401 18. The TFA salt of 389 can be deprotonated to the free imine by an aqueous wash with 10% potassium carbonate. 19. See Appendix 4 for full list of conditions and results. 20. (a) Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43, 2057– 2059. (b) Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, C. M. J. Am. Chem. Soc. 2005, 127, 6970–6971. (c) Yu, J.-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727– 2730. (d) Xing, X.; O’Connor, N. R.; Stoltz, B. M. Angew. Chem., Int. Ed. Engl. 2015, 54, 11186–11190. (e) Sparling, B. A.; Moebius, D. C.; Shair, M. D. J. Am. Chem. Soc. 2013, 135, 644–647. (f) Schmuff, N. R.; Trost, B. M. J. Org. Chem. 1983, 48, 1404–1412. (g) Zhao, Y.; Yeung, Y.-Y. Org. Lett. 2010, 12, 2128–2131. (h) Wang, Y.; Kuang, Y.; Wang, Y. Chem. Commun. 2015, 51, 5852–5855. (i) Wilde, N. C.; Isomura, M.; Mendoza, A.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 4909–4912. (j) Young, W. B.; Masters, J. J.; Danishefsky, S. J. Am. Chem. Soc. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 254 1995, 117, 5228–5234. (k) Jasiczak, J. J. Chem. Soc., Perkin Trans. 1 1988, 2687– 2692. (l) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.; Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77–81. (m) Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351–352. (n) Quinn, R. K.; Könst, Z. A.; Michalak, S. E.; Schmidt, Y.; Szklarski, A. R.; Flores, A. R.; Nam, S.; Horne, D. A.; Vanderwal, C. D.; Alexanian, E. J. Am. Chem. Soc. 2016, 138, 696–702. 21. Lewis, J. C.; Mantovani, S. M.; Fu, Y.; Snow, C. D.; Komor, R. S. Wong, C.-H.; Arnold, F. H. ChemBioChem 2010, 11, 2502–2505. 22. (a) Rentmeister, A.; Arnold, F. H.; Fasan, R. Nat. Chem. Biol. 2009, 5, 26–28. (b) Lewis, J. C.; Bastian, S.; Bennett, C. S.; Fu, Y.; Mitsuda, Y.; Chen, M. M.; Greenberg, W. A.; Wong, C.-H.; Arnold, F. H. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 16550–16555. (c) Kille, S.; Zilly, F. E.; Acevedo, J. P.; Reetz, M. T. Nat. Chem. 2011, 3, 738–743. 23. Wolberg, M.; Hummel, W.; Wandrey, C.; Müller, M. Angew. Chem., Int. Ed. Engl. 2000, 39, 4306–4308. 24. The TFA salt of 389 was used to avoid deleterious aerobic oxidation of 389. Both the TFA salt and the free base of 389 were competent substrates and reacted identically for the enzymatic oxidation. 25. Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520. 26. Dauben, H. J.; McCoy, L. L. J. Am. Chem. Soc. 1959, 81, 4863–4873. 27. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899–2899. Chapter 3 – Enantioselective Total Synthesis of Nigelladine A via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 28. 255 Liu, Y.; Liniger, M.; McFadden, R. M.; Roizen, J. L.; Malette, J.; Reeves, C. M.; Behenna, D. C.; Seto, M.; Kim, J.; Mohr, J. T. Beilstein J. Org. Chem. 2014, 10, 2501–2512. 29. Gulias, M.; Rodriguez, J. R.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2003, 5, 1975–1977. 30. Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 12268–13369. 31. Mino, T.; Masuda, S.; Nishio, M; Yamashita, M. J. Org. Chem. 1997, 62, 2633– 2635. 32. Doering, W. V. E.; Yamashita, Y. J. Am. Chem. Soc. 1983, 105, 5368–5372. 33. Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001, 47–53. 34. Nigelladine A 385 was repurified by preparative HPLC prior to optical rotation and therefore we believe that nigelladine A is either possibly isolated as a scalemic mixture or the isolation chemists isolated a mixture of protonated and free imine. Appendix 2 – Synthetic Summary of Chapter 3 256 APPENDIX 2 Synthetic Summary of Chapter 3: Enantioselective Total Synthesis of Nigelladine A Via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 257 Appendix 2 – Synthetic Summary of Chapter 3 Scheme A2.1. Synthetic Summary for Construction of Nigelladine A 385 O O N O Me2NNH2, TFA Cl O 1. LDA, THF, –78 °C benzene, 80 °C 2. 1M HCl, THF, 50 °C 91% yield 1.7:1 E/Z 79% yield over 2 steps N O O 396 395 394 O O NaH, MeI O Pd2(dba)3 (2.75 mol %) (R)-CF3-t-BuPHOX (6.0 mol %) O DMF, 0 °C (2:1) hexanes:toluene, 40 °C 92% yield 96% yield, 87% ee 393 392 O 1. PdCl2 (20 mol %) CuCl (2 equiv) DMF:H2O (9:1), 23 °C 2. KOH, xylenes 110 °C 76% yield over 2 steps Br NBS (1.1 equiv) 390, XPhos Pd G2 (3 mol %) MeCN, 0 °C 0.5M K3PO4, THF, 50 °C 83% yield BocHN NH TFA, DCM, 23 °C OTFA then NaHCO3 (aq) then SiO2 1. P450 8C7 (0.02 to 0.04 mol %) NADP (10 mol %), i-PrOH, ADH 2.5% DMSO in KPi buffer (pH 8) 23 °C , 12h N 2. DMP, CH2Cl2, 0 °C, 4h 21% yield over 2 steps 43% yield based on recovered 389 75% yield 401 88% yield 391 397 O O 389•TFA O 385 Appendix 3 – Spectra Relevant to Chapter 3 258 APPENDIX 3 Spectra Relevant to Chapter 3: Enantioselective Total Synthesis of Nigelladine A Via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme 8 N 1.7:1 E:Z 395 N 7 6 4 ppm 3 Figure A3.1. 1H NMR (400 MHz, CDCl3) of compound 395. 5 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 259 260 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.2. Infrared spectrum (Thin Film, NaCl) of compound 395. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.3. 13C NMR (101 MHz, CDCl3) of compound 395. 20 0 8 O 396 O O 7 6 4 ppm 3 Figure A3.4. 1H NMR (500 MHz, CDCl3) of compound 396. 5 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 261 262 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.5. Infrared spectrum (Thin Film, NaCl) of compound 396. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.6. 13C NMR (126 MHz, CDCl3) of compound 396. 20 0 8 O 393 O O 7 6 4 ppm 3 Figure A3.7. 1H NMR (500 MHz, CDCl3) of compound 393. 5 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 263 264 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.8. Infrared spectrum (Thin Film, NaCl) of compound 393. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.9. 13C NMR (126 MHz, CDCl3) of compound 393. 20 0 8 392 O 7 5 4 ppm 3 Figure A3.10. 1H NMR (500 MHz, CDCl3) of compound 392. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 265 266 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.11. Infrared spectrum (Thin Film, NaCl) of compound 392. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.12. 13C NMR (126 MHz, CDCl3) of compound 392. 20 0 8 397 O 7 5 4 ppm 3 Figure A3.13. 1H NMR (400 MHz, CDCl3) of compound 397. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 267 268 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.14. Infrared spectrum (Thin Film, NaCl) of compound 397. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.15. 13C NMR (101 MHz, CDCl3) of compound 397. 20 0 8 391 Br O 7 5 4 ppm 3 Figure A3.16. 1H NMR (400 MHz, CDCl3) of compound 391. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 269 270 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.17. Infrared spectrum (Thin Film, NaCl) of compound 391. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.18. 13C NMR (101 MHz, CDCl3) of compound 391. 20 0 8 400 NHBoc 7 5 4 ppm 3 Figure A3.19. 1H NMR (400 MHz, CDCl3) of compound 400. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 271 272 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.20. Infrared spectrum (Thin Film, NaCl) of compound 400. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.21. 13C NMR (101 MHz, CDCl3) of compound 400. 20 0 8 390 BPin NHBoc 7 5 4 ppm 3 Figure A3.22. 1H NMR (400 MHz, CDCl3) of compound 390. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 273 274 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.23. Infrared spectrum (Thin Film, NaCl) of compound 390. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.24. 13C NMR (101 MHz, CDCl3) of compound 390. 20 0 8 BocHN 401 O 7 5 4 ppm 3 Figure A3.25. 1H NMR (400 MHz, CDCl3) of compound 401. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 275 276 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.26. Infrared spectrum (Thin Film, NaCl) of compound 401. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.27. 13C NMR (101 MHz, CDCl3) of compound 401. 20 0 8 389 N 7 5 4 ppm 3 Figure A3.28. 1H NMR (400 MHz, CDCl3) of compound 389. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 277 278 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.29. Infrared spectrum (Thin Film, NaCl) of compound 389. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.30. 13C NMR (101 MHz, CDCl3) of compound 389. 20 0 8 385 O N 7 5 4 ppm 3 Figure A3.31. 1H NMR (400 MHz, CDCl3) of compound 385. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 279 280 Appendix 3 – Spectra Relevant to Chapter 3 Figure A3.32. Infrared spectrum (Thin Film, NaCl) of compound 385. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.33. 13C NMR (101 MHz, CDCl3) of compound 385. 20 0 8 385 O N 7 6 4 ppm 3 Figure A3.34. 1H NMR (400 MHz, C6D6) of compound 385. 5 2 1 0 Appendix 3 – Spectra Relevant to Chapter 3 281 282 Appendix 3 – Spectra Relevant to Chapter 3 200 180 160 140 120 100 ppm 80 60 40 Figure A3.35. 13C NMR (101 MHz, C6D6) of compound 385. 20 0 8 385•DCl O D 7 ND Cl 5 4 ppm 3 2 Figure A3.36. 1H NMR (400 MHz, CD3OD) of compound 385•DCl. 6 1 0 Appendix 3 – Spectra Relevant to Chapter 3 283 284 Appendix 3 – Spectra Relevant to Chapter 3 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.37. 13C NMR (101 MHz, CD3OD) of compound 385•DCl. 0 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 285 APPENDIX 4 X-Ray Crystallography Reports Relevant to Chapter 3: Enantioselective Total Synthesis of Nigelladine A Via Late-Stage C–H Oxidation Enabled by an Engineered P450 Enzyme Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 A4.1 X-RAY CRYSTAL STRUCTURE ANALYSIS OF TRIENE 401 BocHN O 401 Contents Table A4.1.1. Experimental Details Table A4.1.2. Crystal Data Table A4.1.3. Atomic Coordinates Table A4.1.4. Full Bond Distances and Angles Table A4.1.5. Anisotropic Displacement Parameters Table A4.1.6. Hydrogen Atomic Coordinates Table A4.1.7. Torsion Angles Table A4.1.8. Hydrogen Bond Distances and Angle Figure A4.1.1. X-Ray Crystal Structure of Triene 401 286 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.1. 287 Experimental Details for X-Ray Structure Determination of Triene 401 Low-temperature diffraction data (f-and w-scans) were collected on a Bruker AXS KAPPA APEX II diffractometer coupled to a APEX II CCD detector with graphite monochromated Mo Ka radiation (l = 0.71073 Å) for the structure of triene 401. The structure was solved by direct methods using SHELXS1 and refined against F2 on all data by full-matrix least squares with SHELXL-20142 using established refinement techniques.3 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). 288 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.2. Crystal Data and Structure Refinement for Triene 401 Empirical formula C24 H37 N O3 Formula weight 387.54 Temperature 100 K Wavelength 1.54178 Å Crystal system Triclinic Space group P1 Unit cell dimensions a = 9.6892(11) Å a = 89.402(8)° b = 10.0478(9) Å b = 77.360(8)° c = 11.9882(11) Å g = 89.745(8)° Volume 1138.76(19) Å3 Z 2 Density (calculated) 1.130 Mg/m3 Absorption coefficient 0.574 mm-1 F(000) 424 Crystal size 0.31 x 0.15 x 0.15 mm3 Theta range for data collection 3.779 to 79.188°. Index ranges -12<=h<=12, -12<=k<=12, -15<=l<=15 Reflections collected 44144 Independent reflections 9136 [R(int) = 0.0587] Completeness to theta = 67.000° 99.6 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9470 and 0.8656 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 9136 / 3 / 521 Goodness-of-fit on F2 1.062 Final R indices [I>2sigma(I)] R1 = 0.0497, wR2 = 0.1066 R indices (all data) R1 = 0.0568, wR2 = 0.1114 Absolute structure parameter 0.08(8) Extinction coefficient n/a Largest diff. peak and hole 0.318 and -0.238 e.Å-3 289 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Triene 401. U(eq) is Defined as One Third of the Trace of the Orthogonalized Uij Tensor. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ O(1) 6427(3) 5529(2) 4290(2) 25(1) O(2) 1594(2) 3334(2) 8236(2) 24(1) O(3) 2950(3) 2423(2) 9381(2) 24(1) N(1) 3663(3) 4279(3) 8426(2) 19(1) C(1) 8553(4) 3624(3) 5846(3) 22(1) C(2) 9499(4) 2396(4) 5692(3) 27(1) C(3) 9318(4) 1614(3) 6823(3) 26(1) C(4) 7794(4) 1450(3) 7447(3) 23(1) C(5) 6748(4) 2160(3) 7164(3) 21(1) C(6) 7031(4) 3176(3) 6278(3) 19(1) C(7) 6109(3) 3839(3) 5775(3) 19(1) C(8) 6912(4) 4726(3) 4874(3) 21(1) C(9) 8471(4) 4390(3) 4741(3) 25(1) C(10) 8980(4) 4589(4) 6705(3) 28(1) C(11) 7516(4) 404(3) 8396(3) 28(1) C(12) 6811(5) 994(4) 9543(3) 40(1) C(13) 6667(5) -743(4) 8076(4) 45(1) C(14) 4548(3) 3702(3) 6030(2) 18(1) C(15) 3982(4) 2511(3) 5934(3) 24(1) C(16) 3632(3) 4898(3) 6411(3) 18(1) C(17) 3666(3) 5403(3) 7625(3) 19(1) C(18) 5001(4) 6206(3) 7619(3) 22(1) C(19) 2376(4) 6285(3) 8055(3) 24(1) C(20) 2632(3) 3355(3) 8639(3) 19(1) C(21) 1988(4) 1295(3) 9736(3) 26(1) C(22) 1986(4) 410(3) 8715(3) 31(1) C(23) 2671(5) 576(4) 10590(3) 37(1) 290 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.3 Cont’d C(24) 514(5) 1766(4) 10308(4) 47(1) O(1B) 6314(3) 4207(2) -587(2) 25(1) O(2B) 1567(2) 6339(2) 3346(2) 23(1) O(3B) 3051(2) 7332(2) 4333(2) 21(1) N(1B) 3720(3) 5462(3) 3414(2) 20(1) C(1B) 8278(3) 6485(3) 780(3) 21(1) C(2B) 8972(4) 6488(4) 1797(3) 27(1) C(3B) 8775(4) 7833(4) 2410(3) 30(1) C(4B) 7286(4) 8363(3) 2592(3) 23(1) C(5B) 6354(4) 7851(3) 2047(3) 21(1) C(6B) 6729(3) 6804(3) 1209(3) 19(1) C(7B) 5858(3) 6011(3) 769(3) 19(1) C(8B) 6728(4) 5017(3) 34(3) 22(1) C(9B) 8233(4) 5137(4) 190(3) 27(1) C(10B) 8957(4) 7542(4) -132(3) 29(1) C(11B) 6859(4) 9458(3) 3462(3) 26(1) C(12B) 7716(4) 10730(4) 3123(4) 38(1) C(13B) 6903(5) 8998(5) 4671(3) 39(1) C(14B) 4297(3) 6029(3) 1009(3) 19(1) C(15B) 3619(4) 7141(3) 826(3) 24(1) C(16B) 3495(3) 4785(3) 1467(3) 21(1) C(17B) 3681(4) 4317(3) 2662(3) 21(1) C(18B) 5065(4) 3555(3) 2590(3) 24(1) C(19B) 2448(4) 3397(3) 3194(3) 27(1) C(20B) 2677(3) 6368(3) 3662(3) 19(1) C(21B) 2079(4) 8434(3) 4721(3) 22(1) C(22B) 2867(4) 9229(3) 5458(3) 28(1) C(23B) 1886(4) 9273(4) 3704(3) 33(1) C(24B) 690(4) 7918(4) 5439(3) 29(1) ___________________________________________________________________________ Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. Bond Lengths [Å] and angles [°] for Triene 401 _____________________________________________________ O(1)-C(8) 1.221(4) O(2)-C(20) 1.208(4) O(3)-C(20) 1.365(4) O(3)-C(21) 1.470(4) N(1)-H(1) 0.8800 N(1)-C(17) 1.475(4) N(1)-C(20) 1.348(4) C(1)-C(2) 1.522(5) C(1)-C(6) 1.520(5) C(1)-C(9) 1.542(4) C(1)-C(10) 1.543(5) C(2)-H(2A) 0.9900 C(2)-H(2B) 0.9900 C(2)-C(3) 1.537(5) C(3)-H(3A) 0.9900 C(3)-H(3B) 0.9900 C(3)-C(4) 1.510(5) C(4)-C(5) 1.337(5) C(4)-C(11) 1.522(4) C(5)-H(5) 0.9500 C(5)-C(6) 1.450(4) C(6)-C(7) 1.351(4) C(7)-C(8) 1.478(4) C(7)-C(14) 1.484(4) C(8)-C(9) 1.520(5) 291 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(9)-H(9A) 0.9900 C(9)-H(9B) 0.9900 C(10)-H(10A) 0.9800 C(10)-H(10B) 0.9800 C(10)-H(10C) 0.9800 C(11)-H(11) 1.0000 C(11)-C(12) 1.520(6) C(11)-C(13) 1.520(5) C(12)-H(12A) 0.9800 C(12)-H(12B) 0.9800 C(12)-H(12C) 0.9800 C(13)-H(13A) 0.9800 C(13)-H(13B) 0.9800 C(13)-H(13C) 0.9800 C(14)-C(15) 1.335(4) C(14)-C(16) 1.505(4) C(15)-H(15A) 0.9500 C(15)-H(15B) 0.9500 C(16)-H(16A) 0.9900 C(16)-H(16B) 0.9900 C(16)-C(17) 1.554(4) C(17)-C(18) 1.526(4) C(17)-C(19) 1.526(5) C(18)-H(18A) 0.9800 C(18)-H(18B) 0.9800 C(18)-H(18C) 0.9800 292 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800 C(21)-C(22) 1.520(5) C(21)-C(23) 1.512(5) C(21)-C(24) 1.519(6) C(22)-H(22A) 0.9800 C(22)-H(22B) 0.9800 C(22)-H(22C) 0.9800 C(23)-H(23A) 0.9800 C(23)-H(23B) 0.9800 C(23)-H(23C) 0.9800 C(24)-H(24A) 0.9800 C(24)-H(24B) 0.9800 C(24)-H(24C) 0.9800 O(1B)-C(8B) 1.234(4) O(2B)-C(20B) 1.217(4) O(3B)-C(20B) 1.365(4) O(3B)-C(21B) 1.463(4) N(1B)-H(1B) 0.8800 N(1B)-C(17B) 1.474(4) N(1B)-C(20B) 1.343(4) C(1B)-C(2B) 1.516(5) C(1B)-C(6B) 1.510(5) C(1B)-C(9B) 1.539(5) C(1B)-C(10B) 1.557(4) 293 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(2B)-H(2BA) 0.9900 C(2B)-H(2BB) 0.9900 C(2B)-C(3B) 1.536(5) C(3B)-H(3BA) 0.9900 C(3B)-H(3BB) 0.9900 C(3B)-C(4B) 1.507(5) C(4B)-C(5B) 1.333(5) C(4B)-C(11B) 1.516(5) C(5B)-H(5B) 0.9500 C(5B)-C(6B) 1.451(4) C(6B)-C(7B) 1.355(4) C(7B)-C(8B) 1.473(5) C(7B)-C(14B) 1.477(4) C(8B)-C(9B) 1.515(5) C(9B)-H(9BA) 0.9900 C(9B)-H(9BB) 0.9900 C(10B)-H(10D) 0.9800 C(10B)-H(10E) 0.9800 C(10B)-H(10F) 0.9800 C(11B)-H(11B) 1.0000 C(11B)-C(12B) 1.529(5) C(11B)-C(13B) 1.526(5) C(12B)-H(12D) 0.9800 C(12B)-H(12E) 0.9800 C(12B)-H(12F) 0.9800 C(13B)-H(13D) 0.9800 294 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(13B)-H(13E) 0.9800 C(13B)-H(13F) 0.9800 C(14B)-C(15B) 1.334(5) C(14B)-C(16B) 1.509(4) C(15B)-H(15C) 0.9500 C(15B)-H(15D) 0.9500 C(16B)-H(16C) 0.9900 C(16B)-H(16D) 0.9900 C(16B)-C(17B) 1.551(4) C(17B)-C(18B) 1.528(5) C(17B)-C(19B) 1.534(4) C(18B)-H(18D) 0.9800 C(18B)-H(18E) 0.9800 C(18B)-H(18F) 0.9800 C(19B)-H(19D) 0.9800 C(19B)-H(19E) 0.9800 C(19B)-H(19F) 0.9800 C(21B)-C(22B) 1.523(4) C(21B)-C(23B) 1.520(5) C(21B)-C(24B) 1.520(5) C(22B)-H(22D) 0.9800 C(22B)-H(22E) 0.9800 C(22B)-H(22F) 0.9800 C(23B)-H(23D) 0.9800 C(23B)-H(23E) 0.9800 C(23B)-H(23F) 0.9800 295 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(24B)-H(24D) 0.9800 C(24B)-H(24E) 0.9800 C(24B)-H(24F) 0.9800 C(20)-O(3)-C(21) 119.5(3) C(17)-N(1)-H(1) 118.6 C(20)-N(1)-H(1) 118.6 C(20)-N(1)-C(17) 122.9(3) C(2)-C(1)-C(9) 115.8(3) C(2)-C(1)-C(10) 110.7(3) C(6)-C(1)-C(2) 108.4(3) C(6)-C(1)-C(9) 102.1(3) C(6)-C(1)-C(10) 110.1(3) C(9)-C(1)-C(10) 109.4(3) C(1)-C(2)-H(2A) 109.6 C(1)-C(2)-H(2B) 109.6 C(1)-C(2)-C(3) 110.5(3) H(2A)-C(2)-H(2B) 108.1 C(3)-C(2)-H(2A) 109.6 C(3)-C(2)-H(2B) 109.6 C(2)-C(3)-H(3A) 108.8 C(2)-C(3)-H(3B) 108.8 H(3A)-C(3)-H(3B) 107.7 C(4)-C(3)-C(2) 113.7(3) C(4)-C(3)-H(3A) 108.8 C(4)-C(3)-H(3B) 108.8 296 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(3)-C(4)-C(11) 116.0(3) C(5)-C(4)-C(3) 122.1(3) C(5)-C(4)-C(11) 121.9(3) C(4)-C(5)-H(5) 119.3 C(4)-C(5)-C(6) 121.4(3) C(6)-C(5)-H(5) 119.3 C(5)-C(6)-C(1) 118.0(3) C(7)-C(6)-C(1) 113.0(3) C(7)-C(6)-C(5) 128.9(3) C(6)-C(7)-C(8) 108.8(3) C(6)-C(7)-C(14) 127.2(3) C(8)-C(7)-C(14) 123.9(3) O(1)-C(8)-C(7) 127.0(3) O(1)-C(8)-C(9) 125.5(3) C(7)-C(8)-C(9) 107.3(3) C(1)-C(9)-H(9A) 110.8 C(1)-C(9)-H(9B) 110.8 C(8)-C(9)-C(1) 104.7(3) C(8)-C(9)-H(9A) 110.8 C(8)-C(9)-H(9B) 110.8 H(9A)-C(9)-H(9B) 108.9 C(1)-C(10)-H(10A) 109.5 C(1)-C(10)-H(10B) 109.5 C(1)-C(10)-H(10C) 109.5 H(10A)-C(10)-H(10B) 109.5 H(10A)-C(10)-H(10C) 109.5 297 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d H(10B)-C(10)-H(10C) 109.5 C(4)-C(11)-H(11) 107.4 C(12)-C(11)-C(4) 112.1(3) C(12)-C(11)-H(11) 107.4 C(13)-C(11)-C(4) 110.5(3) C(13)-C(11)-H(11) 107.4 C(13)-C(11)-C(12) 111.8(4) C(11)-C(12)-H(12A) 109.5 C(11)-C(12)-H(12B) 109.5 C(11)-C(12)-H(12C) 109.5 H(12A)-C(12)-H(12B) 109.5 H(12A)-C(12)-H(12C) 109.5 H(12B)-C(12)-H(12C) 109.5 C(11)-C(13)-H(13A) 109.5 C(11)-C(13)-H(13B) 109.5 C(11)-C(13)-H(13C) 109.5 H(13A)-C(13)-H(13B) 109.5 H(13A)-C(13)-H(13C) 109.5 H(13B)-C(13)-H(13C) 109.5 C(7)-C(14)-C(16) 119.6(3) C(15)-C(14)-C(7) 119.2(3) C(15)-C(14)-C(16) 121.2(3) C(14)-C(15)-H(15A) 120.0 C(14)-C(15)-H(15B) 120.0 H(15A)-C(15)-H(15B) 120.0 C(14)-C(16)-H(16A) 108.5 298 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(14)-C(16)-H(16B) 108.5 C(14)-C(16)-C(17) 114.9(3) H(16A)-C(16)-H(16B) 107.5 C(17)-C(16)-H(16A) 108.5 C(17)-C(16)-H(16B) 108.5 N(1)-C(17)-C(16) 110.9(2) N(1)-C(17)-C(18) 106.7(2) N(1)-C(17)-C(19) 109.6(3) C(18)-C(17)-C(16) 111.5(3) C(18)-C(17)-C(19) 108.8(3) C(19)-C(17)-C(16) 109.1(3) C(17)-C(18)-H(18A) 109.5 C(17)-C(18)-H(18B) 109.5 C(17)-C(18)-H(18C) 109.5 H(18A)-C(18)-H(18B) 109.5 H(18A)-C(18)-H(18C) 109.5 H(18B)-C(18)-H(18C) 109.5 C(17)-C(19)-H(19A) 109.5 C(17)-C(19)-H(19B) 109.5 C(17)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 O(2)-C(20)-O(3) 124.8(3) O(2)-C(20)-N(1) 126.1(3) N(1)-C(20)-O(3) 109.1(3) 299 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d O(3)-C(21)-C(22) 109.7(3) O(3)-C(21)-C(23) 102.3(3) O(3)-C(21)-C(24) 111.4(3) C(23)-C(21)-C(22) 110.2(3) C(23)-C(21)-C(24) 110.4(3) C(24)-C(21)-C(22) 112.4(4) C(21)-C(22)-H(22A) 109.5 C(21)-C(22)-H(22B) 109.5 C(21)-C(22)-H(22C) 109.5 H(22A)-C(22)-H(22B) 109.5 H(22A)-C(22)-H(22C) 109.5 H(22B)-C(22)-H(22C) 109.5 C(21)-C(23)-H(23A) 109.5 C(21)-C(23)-H(23B) 109.5 C(21)-C(23)-H(23C) 109.5 H(23A)-C(23)-H(23B) 109.5 H(23A)-C(23)-H(23C) 109.5 H(23B)-C(23)-H(23C) 109.5 C(21)-C(24)-H(24A) 109.5 C(21)-C(24)-H(24B) 109.5 C(21)-C(24)-H(24C) 109.5 H(24A)-C(24)-H(24B) 109.5 H(24A)-C(24)-H(24C) 109.5 H(24B)-C(24)-H(24C) 109.5 C(20B)-O(3B)-C(21B) 119.7(2) C(17B)-N(1B)-H(1B) 118.3 300 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(20B)-N(1B)-H(1B) 118.3 C(20B)-N(1B)-C(17B) 123.3(3) C(2B)-C(1B)-C(9B) 116.2(3) C(2B)-C(1B)-C(10B) 111.3(3) C(6B)-C(1B)-C(2B) 107.8(3) C(6B)-C(1B)-C(9B) 102.6(3) C(6B)-C(1B)-C(10B) 109.4(3) C(9B)-C(1B)-C(10B) 109.1(3) C(1B)-C(2B)-H(2BA) 109.3 C(1B)-C(2B)-H(2BB) 109.3 C(1B)-C(2B)-C(3B) 111.4(3) H(2BA)-C(2B)-H(2BB) 108.0 C(3B)-C(2B)-H(2BA) 109.3 C(3B)-C(2B)-H(2BB) 109.3 C(2B)-C(3B)-H(3BA) 108.9 C(2B)-C(3B)-H(3BB) 108.9 H(3BA)-C(3B)-H(3BB) 107.7 C(4B)-C(3B)-C(2B) 113.2(3) C(4B)-C(3B)-H(3BA) 108.9 C(4B)-C(3B)-H(3BB) 108.9 C(3B)-C(4B)-C(11B) 117.7(3) C(5B)-C(4B)-C(3B) 121.4(3) C(5B)-C(4B)-C(11B) 120.9(3) C(4B)-C(5B)-H(5B) 118.9 C(4B)-C(5B)-C(6B) 122.2(3) C(6B)-C(5B)-H(5B) 118.9 301 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(5B)-C(6B)-C(1B) 118.1(3) C(7B)-C(6B)-C(1B) 113.5(3) C(7B)-C(6B)-C(5B) 128.4(3) C(6B)-C(7B)-C(8B) 108.4(3) C(6B)-C(7B)-C(14B) 128.1(3) C(8B)-C(7B)-C(14B) 123.4(3) O(1B)-C(8B)-C(7B) 126.6(3) O(1B)-C(8B)-C(9B) 125.4(3) C(7B)-C(8B)-C(9B) 107.9(3) C(1B)-C(9B)-H(9BA) 110.8 C(1B)-C(9B)-H(9BB) 110.8 C(8B)-C(9B)-C(1B) 104.9(3) C(8B)-C(9B)-H(9BA) 110.8 C(8B)-C(9B)-H(9BB) 110.8 H(9BA)-C(9B)-H(9BB) 108.8 C(1B)-C(10B)-H(10D) 109.5 C(1B)-C(10B)-H(10E) 109.5 C(1B)-C(10B)-H(10F) 109.5 H(10D)-C(10B)-H(10E) 109.5 H(10D)-C(10B)-H(10F) 109.5 H(10E)-C(10B)-H(10F) 109.5 C(4B)-C(11B)-H(11B) 106.7 C(4B)-C(11B)-C(12B) 112.2(3) C(4B)-C(11B)-C(13B) 112.2(3) C(12B)-C(11B)-H(11B) 106.7 C(13B)-C(11B)-H(11B) 106.7 302 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(13B)-C(11B)-C(12B) 111.8(3) C(11B)-C(12B)-H(12D) 109.5 C(11B)-C(12B)-H(12E) 109.5 C(11B)-C(12B)-H(12F) 109.5 H(12D)-C(12B)-H(12E) 109.5 H(12D)-C(12B)-H(12F) 109.5 H(12E)-C(12B)-H(12F) 109.5 C(11B)-C(13B)-H(13D) 109.5 C(11B)-C(13B)-H(13E) 109.5 C(11B)-C(13B)-H(13F) 109.5 H(13D)-C(13B)-H(13E) 109.5 H(13D)-C(13B)-H(13F) 109.5 H(13E)-C(13B)-H(13F) 109.5 C(7B)-C(14B)-C(16B) 119.1(3) C(15B)-C(14B)-C(7B) 119.8(3) C(15B)-C(14B)-C(16B) 121.1(3) C(14B)-C(15B)-H(15C) 120.0 C(14B)-C(15B)-H(15D) 120.0 H(15C)-C(15B)-H(15D) 120.0 C(14B)-C(16B)-H(16C) 108.5 C(14B)-C(16B)-H(16D) 108.5 C(14B)-C(16B)-C(17B) 115.1(2) H(16C)-C(16B)-H(16D) 107.5 C(17B)-C(16B)-H(16C) 108.5 C(17B)-C(16B)-H(16D) 108.5 N(1B)-C(17B)-C(16B) 111.0(3) 303 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d N(1B)-C(17B)-C(18B) 106.7(3) N(1B)-C(17B)-C(19B) 110.0(3) C(18B)-C(17B)-C(16B) 111.8(3) C(18B)-C(17B)-C(19B) 108.5(3) C(19B)-C(17B)-C(16B) 108.8(3) C(17B)-C(18B)-H(18D) 109.5 C(17B)-C(18B)-H(18E) 109.5 C(17B)-C(18B)-H(18F) 109.5 H(18D)-C(18B)-H(18E) 109.5 H(18D)-C(18B)-H(18F) 109.5 H(18E)-C(18B)-H(18F) 109.5 C(17B)-C(19B)-H(19D) 109.5 C(17B)-C(19B)-H(19E) 109.5 C(17B)-C(19B)-H(19F) 109.5 H(19D)-C(19B)-H(19E) 109.5 H(19D)-C(19B)-H(19F) 109.5 H(19E)-C(19B)-H(19F) 109.5 O(2B)-C(20B)-O(3B) 124.9(3) O(2B)-C(20B)-N(1B) 125.7(3) N(1B)-C(20B)-O(3B) 109.4(3) O(3B)-C(21B)-C(22B) 102.6(3) O(3B)-C(21B)-C(23B) 110.0(3) O(3B)-C(21B)-C(24B) 110.6(3) C(23B)-C(21B)-C(22B) 109.9(3) C(24B)-C(21B)-C(22B) 110.3(3) C(24B)-C(21B)-C(23B) 113.0(3) 304 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.4. cont’d C(21B)-C(22B)-H(22D) 109.5 C(21B)-C(22B)-H(22E) 109.5 C(21B)-C(22B)-H(22F) 109.5 H(22D)-C(22B)-H(22E) 109.5 H(22D)-C(22B)-H(22F) 109.5 H(22E)-C(22B)-H(22F) 109.5 C(21B)-C(23B)-H(23D) 109.5 C(21B)-C(23B)-H(23E) 109.5 C(21B)-C(23B)-H(23F) 109.5 H(23D)-C(23B)-H(23E) 109.5 H(23D)-C(23B)-H(23F) 109.5 H(23E)-C(23B)-H(23F) 109.5 C(21B)-C(24B)-H(24D) 109.5 C(21B)-C(24B)-H(24E) 109.5 C(21B)-C(24B)-H(24F) 109.5 H(24D)-C(24B)-H(24E) 109.5 H(24D)-C(24B)-H(24F) 109.5 H(24E)-C(24B)-H(24F) 109.5 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: 305 306 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.5. Anisotropic Displacement Parameters (Å2x103) for Triene 401. The Anisotropic Displacement Factor Exponent Takes the Form: -2p2[h2a*2U11 + … + 2hka*b*U12]. ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ O(1) 24(1) 28(1) 23(1) 8(1) -7(1) -1(1) O(2) 21(1) 26(1) 26(1) 6(1) -8(1) -4(1) O(3) 32(1) 18(1) 23(1) 6(1) -12(1) -4(1) N(1) 21(1) 19(1) 17(1) 2(1) -6(1) -1(1) C(1) 22(2) 22(2) 24(2) 3(1) -6(1) -1(1) C(2) 23(2) 29(2) 27(2) 0(1) -4(1) 2(2) C(3) 26(2) 25(2) 31(2) -1(1) -10(2) 5(1) C(4) 27(2) 20(2) 23(2) -1(1) -7(1) 1(1) C(5) 23(2) 21(2) 19(2) 2(1) -4(1) -1(1) C(6) 22(2) 16(1) 17(1) -3(1) -2(1) 1(1) C(7) 24(2) 14(1) 17(1) 0(1) -1(1) -1(1) C(8) 23(2) 21(2) 20(2) -1(1) -5(1) -3(1) C(9) 20(2) 28(2) 27(2) 6(1) -6(1) -5(1) C(10) 28(2) 27(2) 32(2) 1(2) -10(2) -3(2) C(11) 34(2) 21(2) 31(2) 8(1) -11(2) 0(2) C(12) 50(3) 38(2) 30(2) 11(2) -7(2) 4(2) C(13) 55(3) 31(2) 54(3) 16(2) -27(2) -14(2) C(14) 20(2) 20(1) 14(1) 2(1) -2(1) -1(1) C(15) 23(2) 24(2) 25(2) 0(1) -4(1) -2(1) C(16) 18(2) 18(1) 19(1) 3(1) -4(1) 0(1) C(17) 21(2) 17(1) 18(1) 2(1) -4(1) 0(1) C(18) 26(2) 20(2) 20(2) 0(1) -5(1) -2(1) C(19) 26(2) 22(2) 24(2) 0(1) -3(1) 4(1) C(20) 21(2) 17(1) 17(1) 0(1) -2(1) 2(1) C(21) 33(2) 17(2) 26(2) 6(1) -1(2) -2(1) C(22) 33(2) 21(2) 42(2) 0(2) -13(2) -5(2) C(23) 57(3) 20(2) 34(2) 9(2) -12(2) -1(2) 307 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.5. cont’d C(24) 43(3) 35(2) 50(3) 18(2) 16(2) 8(2) O(1B) 27(1) 24(1) 24(1) -6(1) -6(1) 4(1) O(2B) 20(1) 27(1) 24(1) -6(1) -7(1) 2(1) O(3B) 22(1) 20(1) 23(1) -6(1) -8(1) 4(1) N(1B) 21(1) 21(1) 19(1) -5(1) -5(1) 2(1) C(1B) 19(2) 23(2) 19(2) 1(1) -1(1) 0(1) C(2B) 22(2) 31(2) 28(2) 0(1) -7(1) 2(2) C(3B) 26(2) 36(2) 32(2) -6(2) -12(2) 0(2) C(4B) 25(2) 22(2) 22(2) 1(1) -5(1) -1(1) C(5B) 21(2) 20(2) 20(2) 1(1) -1(1) -1(1) C(6B) 21(2) 19(2) 16(1) 3(1) -2(1) -2(1) C(7B) 23(2) 19(1) 16(1) 2(1) -3(1) 1(1) C(8B) 26(2) 19(2) 19(2) 2(1) -4(1) 2(1) C(9B) 24(2) 27(2) 31(2) -7(1) -6(1) 6(2) C(10B) 26(2) 28(2) 31(2) 6(2) 2(2) 2(2) C(11B) 27(2) 25(2) 27(2) -5(1) -8(1) -1(2) C(12B) 34(2) 33(2) 45(2) -10(2) -3(2) -2(2) C(13B) 45(3) 45(2) 30(2) -7(2) -10(2) 11(2) C(14B) 21(2) 20(2) 15(1) -3(1) -4(1) -1(1) C(15B) 25(2) 23(2) 25(2) 2(1) -6(1) 0(1) C(16B) 20(2) 23(2) 19(2) -5(1) -3(1) -1(1) C(17B) 24(2) 20(2) 18(2) -4(1) -3(1) 0(1) C(18B) 31(2) 19(2) 21(2) 1(1) -4(1) 4(1) C(19B) 29(2) 23(2) 25(2) 1(1) 1(1) -5(2) C(20B) 20(2) 20(2) 16(1) -2(1) -2(1) 0(1) C(21B) 25(2) 16(1) 26(2) -2(1) -5(1) -1(1) C(22B) 27(2) 22(2) 32(2) -9(1) -2(2) -4(1) C(23B) 34(2) 23(2) 43(2) 6(2) -13(2) 2(2) C(24B) 26(2) 28(2) 31(2) -9(2) 0(2) -4(2) ______________________________________________________________________________ 308 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Triene 401. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(1) 4366 4207 8780 22 H(2A) 10499 2670 5430 32 H(2B) 9253 1819 5100 32 H(3A) 9749 721 6664 32 H(3B) 9838 2079 7328 32 H(5) 5799 1993 7553 25 H(9A) 9048 5210 4663 30 H(9B) 8810 3830 4061 30 H(10A) 8415 5405 6742 43 H(10B) 9985 4809 6455 43 H(10C) 8810 4167 7463 43 H(11) 8453 39 8472 34 H(12A) 7392 1723 9724 60 H(12B) 6712 304 10138 60 H(12C) 5873 1337 9504 60 H(13A) 5734 -419 8004 67 H(13B) 6551 -1434 8672 67 H(13C) 7167 -1115 7346 67 H(15A) 4578 1765 5703 29 H(15B) 2983 2410 6095 29 H(16A) 2643 4676 6392 22 H(16B) 3935 5632 5855 22 H(18A) 4964 6554 8386 33 H(18B) 5063 6949 7074 33 H(18C) 5833 5631 7394 33 H(19A) 1512 5767 8092 36 H(19B) 2392 7042 7531 36 H(19C) 2396 6611 8819 36 309 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.6. cont’d H(22A) 1610 910 8140 47 H(22B) 1391 -370 8965 47 H(22C) 2954 120 8383 47 H(23A) 3615 266 10207 55 H(23B) 2089 -189 10912 55 H(23C) 2753 1185 11206 55 H(24A) 576 2379 10925 71 H(24B) -67 998 10624 71 H(24C) 83 2225 9743 71 H(1B) 4464 5557 3715 24 H(2BA) 9994 6299 1534 32 H(2BB) 8554 5774 2340 32 H(3BA) 9033 7732 3161 36 H(3BB) 9429 8489 1953 36 H(5B) 5412 8182 2213 25 H(9BA) 8914 5122 -557 33 H(9BB) 8462 4400 674 33 H(10D) 8543 7468 -805 44 H(10E) 9979 7390 -355 44 H(10F) 8774 8435 190 44 H(11B) 5851 9685 3469 31 H(12D) 8713 10555 3115 57 H(12E) 7359 11429 3676 57 H(12F) 7623 11020 2359 57 H(13D) 6310 8206 4871 59 H(13E) 6548 9711 5211 59 H(13F) 7880 8782 4707 59 H(15C) 4140 7918 543 29 H(15D) 2615 7157 980 29 H(16C) 3803 4057 918 25 H(16D) 2476 4943 1507 25 H(18D) 5865 4149 2300 36 H(18E) 5101 2802 2071 36 310 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.6. cont’d H(18F) 5116 3225 3352 36 H(19D) 2575 3069 3938 40 H(19E) 2426 2642 2688 40 H(19F) 1556 3892 3296 40 H(22D) 3045 8663 6083 41 H(22E) 2293 9998 5777 41 H(22F) 3769 9539 4990 41 H(23D) 2813 9553 3259 49 H(23E) 1315 10060 3976 49 H(23F) 1405 8746 3220 49 H(24D) 188 7418 4952 44 H(24E) 105 8670 5780 44 H(24F) 881 7332 6046 44 ________________________________________________________________________________ Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.7. Torsion Angles [°] for Triene 401. ________________________________________________________________ O(1)-C(8)-C(9)-C(1) 165.9(3) C(1)-C(2)-C(3)-C(4) 44.6(4) C(1)-C(6)-C(7)-C(8) 4.9(4) C(1)-C(6)-C(7)-C(14) -176.8(3) C(2)-C(1)-C(6)-C(5) 43.1(4) C(2)-C(1)-C(6)-C(7) -138.5(3) C(2)-C(1)-C(9)-C(8) 137.0(3) C(2)-C(3)-C(4)-C(5) -13.6(5) C(2)-C(3)-C(4)-C(11) 164.9(3) C(3)-C(4)-C(5)-C(6) -3.1(5) C(3)-C(4)-C(11)-C(12) 121.6(4) C(3)-C(4)-C(11)-C(13) -113.0(4) C(4)-C(5)-C(6)-C(1) -12.6(5) C(4)-C(5)-C(6)-C(7) 169.3(3) C(5)-C(4)-C(11)-C(12) -59.8(5) C(5)-C(4)-C(11)-C(13) 65.6(5) C(5)-C(6)-C(7)-C(8) -176.9(3) C(5)-C(6)-C(7)-C(14) 1.4(5) C(6)-C(1)-C(2)-C(3) -57.7(4) C(6)-C(1)-C(9)-C(8) 19.6(3) C(6)-C(7)-C(8)-O(1) -175.4(3) C(6)-C(7)-C(8)-C(9) 8.6(3) C(6)-C(7)-C(14)-C(15) -58.0(5) C(6)-C(7)-C(14)-C(16) 121.0(3) C(7)-C(8)-C(9)-C(1) -18.0(3) C(7)-C(14)-C(16)-C(17) -69.5(3) C(8)-C(7)-C(14)-C(15) 120.0(3) C(8)-C(7)-C(14)-C(16) -60.9(4) C(9)-C(1)-C(2)-C(3) -171.6(3) C(9)-C(1)-C(6)-C(5) 165.8(3) C(9)-C(1)-C(6)-C(7) -15.8(4) C(10)-C(1)-C(2)-C(3) 63.1(4) 311 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.7. cont’d C(10)-C(1)-C(6)-C(5) -78.1(4) C(10)-C(1)-C(6)-C(7) 100.3(3) C(10)-C(1)-C(9)-C(8) -97.0(3) C(11)-C(4)-C(5)-C(6) 178.4(3) C(14)-C(7)-C(8)-O(1) 6.2(5) C(14)-C(7)-C(8)-C(9) -169.8(3) C(14)-C(16)-C(17)-N(1) -40.6(4) C(14)-C(16)-C(17)-C(18) 78.2(3) C(14)-C(16)-C(17)-C(19) -161.5(3) C(15)-C(14)-C(16)-C(17) 109.5(3) C(17)-N(1)-C(20)-O(2) -1.4(5) C(17)-N(1)-C(20)-O(3) 177.9(3) C(20)-O(3)-C(21)-C(22) 66.4(4) C(20)-O(3)-C(21)-C(23) -176.6(3) C(20)-O(3)-C(21)-C(24) -58.7(4) C(20)-N(1)-C(17)-C(16) -58.1(4) C(20)-N(1)-C(17)-C(18) -179.7(3) C(20)-N(1)-C(17)-C(19) 62.6(4) C(21)-O(3)-C(20)-O(2) 0.1(5) C(21)-O(3)-C(20)-N(1) -179.2(3) O(1B)-C(8B)-C(9B)-C(1B) 165.9(3) C(1B)-C(2B)-C(3B)-C(4B) 45.3(4) C(1B)-C(6B)-C(7B)-C(8B) 2.9(4) C(1B)-C(6B)-C(7B)-C(14B) 179.1(3) C(2B)-C(1B)-C(6B)-C(5B) 42.3(4) C(2B)-C(1B)-C(6B)-C(7B) -135.5(3) C(2B)-C(1B)-C(9B)-C(8B) 133.4(3) C(2B)-C(3B)-C(4B)-C(5B) -13.9(5) C(2B)-C(3B)-C(4B)-C(11B) 163.2(3) C(3B)-C(4B)-C(5B)-C(6B) -3.1(5) C(3B)-C(4B)-C(11B)-C(12B) 63.3(4) C(3B)-C(4B)-C(11B)-C(13B) -63.5(4) C(4B)-C(5B)-C(6B)-C(1B) -12.2(5) C(4B)-C(5B)-C(6B)-C(7B) 165.2(3) 312 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.7. cont’d C(5B)-C(4B)-C(11B)-C(12B) -119.5(4) C(5B)-C(4B)-C(11B)-C(13B) 113.7(4) C(5B)-C(6B)-C(7B)-C(8B) -174.6(3) C(5B)-C(6B)-C(7B)-C(14B) 1.6(5) C(6B)-C(1B)-C(2B)-C(3B) -57.8(4) C(6B)-C(1B)-C(9B)-C(8B) 16.0(3) C(6B)-C(7B)-C(8B)-O(1B) -173.1(3) C(6B)-C(7B)-C(8B)-C(9B) 8.2(3) C(6B)-C(7B)-C(14B)-C(15B) 57.4(5) C(6B)-C(7B)-C(14B)-C(16B) -122.1(3) C(7B)-C(8B)-C(9B)-C(1B) -15.4(3) C(7B)-C(14B)-C(16B)-C(17B) 63.7(4) C(8B)-C(7B)-C(14B)-C(15B) -126.9(3) C(8B)-C(7B)-C(14B)-C(16B) 53.6(4) C(9B)-C(1B)-C(2B)-C(3B) -172.3(3) C(9B)-C(1B)-C(6B)-C(5B) 165.5(3) C(9B)-C(1B)-C(6B)-C(7B) -12.3(4) C(10B)-C(1B)-C(2B)-C(3B) 62.1(4) C(10B)-C(1B)-C(6B)-C(5B) -78.8(4) C(10B)-C(1B)-C(6B)-C(7B) 103.4(3) C(10B)-C(1B)-C(9B)-C(8B) -99.9(3) C(11B)-C(4B)-C(5B)-C(6B) 179.9(3) C(14B)-C(7B)-C(8B)-O(1B) 10.4(5) C(14B)-C(7B)-C(8B)-C(9B) -168.3(3) C(14B)-C(16B)-C(17B)-N(1B) 38.7(4) C(14B)-C(16B)-C(17B)-C(18B) -80.3(3) C(14B)-C(16B)-C(17B)-C(19B) 159.9(3) C(15B)-C(14B)-C(16B)-C(17B) -115.8(3) C(17B)-N(1B)-C(20B)-O(2B) 3.0(5) C(17B)-N(1B)-C(20B)-O(3B) -177.3(3) C(20B)-O(3B)-C(21B)-C(22B) 178.2(3) C(20B)-O(3B)-C(21B)-C(23B) -64.9(3) C(20B)-O(3B)-C(21B)-C(24B) 60.5(4) C(20B)-N(1B)-C(17B)-C(16B) 57.1(4) 313 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.7. cont’d C(20B)-N(1B)-C(17B)-C(18B) 179.1(3) C(20B)-N(1B)-C(17B)-C(19B) -63.4(4) C(21B)-O(3B)-C(20B)-O(2B) -0.1(4) C(21B)-O(3B)-C(20B)-N(1B) -179.8(2) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: 314 315 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 Table A4.1.8. Hydrogen Bonds for Triene 401 [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ N(1)-H(1)...O(1B)#1 0.88 2.18 3.054(4) 170.5 N(1B)-H(1B)...O(1) 0.88 2.16 3.032(4) 171.0 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x,y,z+1 Appendix 4 – X-Ray Crystallography Reports Relevant to Chapter 3 A4.2 NOTES AND REFERENCES 1. Sheldrick, G. M. Acta Cryst. 1990, A46, 467–473. 2. Sheldrick, G. M. Acta Cryst. 2008, A64, 112–122. 3. Müller, P. Crystallography Reviews 2009, 15, 57–83. 316 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 317 CHAPTER 4 Progress Toward the Total Synthesis of Scabrolide A† 4.1 INTRODUCTION Throughout history, natural products have played an integral role in the development of new medicines.1 These products have been used to treat a number of different ailments including cancer, pain, and infectious bacteria.2 Despite the numerous medical advances attributed to natural products, there remains a need for new and more effective therapies for the treatment of diseases. The norcembranoid class of natural products is a vast family of highly oxygenated diterpenoids, some of which display biological activity including antileukemic and anti-inflammatory activity of IL-6.3 While the polycyclic norcembranoids have been known since 1975,4 there has only been one reported de novo synthesis of any norcembranoid diterpenoid, Pavidolide B, by Yang and coworkers.5 The lack of completed total syntheses of this family of natural products is a testament to the inherent synthetic challenges that are associated with their highly congested structures. Some examples of the polycyclic norcembranoids are scabrolide A (407), scabrolide B (408), yonarolide (409), sinolochmodin C (410), and ineleganolide † This research was performed in collaboration with Dr. Beau Pritchett, Chris Reimann, and Nick Hafeman 318 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A (411) (Figure 4.1.1). All except ineleganolide consist of a [5,5,6,7]-tetracyclic core containing a high degree of oxygenation and 4–7 stereocenters. We are drawn to the unique scaffold of these norcembranoid diterpenoids and sought to design a convergent synthesis of late-stage intermediate 412 which would allow for divergent access to a number of the norcembranoid diterpenoids including 407, 408, 409, and 410. Figure 4.1.1. Select Examples of Polycyclic Furanobutenolide-Derived Norcembranoid Diterpenes H HO O O O H HO H O H H O O O scabrolide B (408) O O H O O yonarolide (409) H O H O O O O O O scabrolide A (407) H H H O sinolochmodin C (410) 4.2 O O H H O ineliganolide (411) RETROSYNTHETIC ANALYSIS; TRANSANNULAR DIELS–ALDER From a retrosynthetic perspective, we believed that construction of scabrolide A (407), can be achieved through the oxidation and olefin isomerization of 1,6-hexadiene 412 (Scheme 4.2.1). The central cyclohexadiene ring in 412 may be generated from an intramolecular Diels–Alder reaction of macrocycle 413 in order to form the core carbon skeleton. Ring-closing metathesis (RCM) of tetraene 414 would allow access to requisite macrocycle 413. Finally, tetraene 414 can be convergently synthesized from the coupling of alkyne 416 and cyclopentene diol 415. 319 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A Scheme 4.2.1. Retrosynthetic Analysis of Scabrolide A via Transannular Diels–Alder H HO O O [O] O O HO O HO Diels–Alder H O O H O O Scabrolide A (407) 412 HO O 413 O O RCM Esterification HO + O OH O 414 4.3 415 416 SYNTHESIS OF CONVERGENT COUPLING FRAGMENTS In 2005, Theodorakis and coworkers reported the synthesis of isocarvone (421) from carvone (417) .6 Starting from (+)-carvone (417), they were able to perform a nucleophilic epoxidation with hydrogen peroxide to generate epoxy ketone 418 (Scheme 4.3.1). Epoxide 418 is then hydrolyzed followed by oxidative cleavage with NaIO4 to afford acid 419 in a modest yield. Amidation of acid 419 with methoxy methylamine generates Weinreb amide 420 can be progressed to isocarvone in 5 further steps. Scheme 4.3.1. Synthesis of Isocarvone From Carvone Theodorakis (2005) O O H2O2, NaOH 1. H2SO4 THF:H2O, 65°C O MeOH:H2O 2. NaIO4, SiO2 DCM:H2O 0 °C 98% yield (+)-carvone (417) 418 O 38% yield 2 steps O (MeO)NHMe•HCl Et3N, EDC•HCl HO MeO O 5 steps N Me CH2Cl2, 0 °C to 23 °C O H 419 75% yield O 420 H (+)-isocarvone (421) 320 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A By utilizing Theodorakis’ key Weinreb amide intermediate (420), we can expediently synthesize alkyne ent•416 with the isopropenyl stereocenter set (Scheme 4.3.2). Treatment of aldehyde 420 with the Ohira–Bestmann reagent furnishes alkyne 422,7 which upon addition of allyl magnesium bromide affords our desired ketone ent•416 in a 71% yield over 2 steps. Unfortunately, protection of the ketone moiety is necessary to couple ent•416 with diol 415, in order to avoid competing enolate formation and subsequent olefin isomerization during the carboxylation. Gratifyingly, treatment of ketone ent•416 with ethylene glycol and anhydrous oxalic acid in triethylorthoformate and acetonitrile affords 1,3-dioxolane 423 in 83% yield and without any observable olefin isomerization.8 Scheme. 4.3.2. Synthesis of Alkyne 423 from Carvone O O O 4 steps MeO MeO N Me Ohira-Bestmann Reagent N Me K2CO3, MeOH 82% yield O (+)-Carvone (417) H 420 422 O HO MgBr OH O O oxalic acid THF, –78 to 0 °C CH(OCH2CH3)3 MeCN, 23 °C 87% yield 83% yield ent•416 423 Fortunately in 2017, our lab reported the utility of the key cyclopentene diol ent•415 in a convergent synthesis of ineleganoloids.9 The first generation enantioselective synthesis of diol ent•415 starts from dimethyl ketal 424 and TRIS•HCl (425) through a 6 step sequence (28% yield) to generate silyl enol ether 426 (Scheme 4.3.3). Silyl enol ether 426 then undergoes an asymmetric allylic alkylation, setting the tertiary stereocenter of 427 in 92% ee. The 2-chloroallyl moiety is then oxidized to the a-bromo ketone followed 321 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A by an aldol condensation to afford enone 428. Ketone 428 is then subjected to a 1,2 reduction, benzoyl protection, and acetonide cleavage to provide triol 429, in an excellent yield over three steps. DMP oxidation of the primary alcohol, followed by Wittig olefination and benzoyl deprotection affords the desired diol ent•415 in a 15 step sequence and 18% overall yield. Scheme 4.3.3. 1st Generation Synthesis of Cyclopentene Diol ent•415 Stoltz (2017) Cl OMs MeO OMe + NH3 –Cl HO O O OH toluene, 35 °C OH 28% yield 424 OTES 425 426 1. NaOBr, AcOH acetone, 0 °C O O Cl O O 3. fumaric acid, HC(OMe)3 MeOH, 0 to 35 °C 94% yield 2 steps 96% yield 3 steps O 428 OH 1. DMP, CH2Cl2, 0 to 23 °C 2. Ph3PMeBr, KOt-Bu, THF, 23 °C HO 18% yield over 15 steps 3. NaOH, MeOH, 23 °C OBz 429 4.4 82% yield 92% ee 1. DIBAL, THF, –78 to 0 °C 2. Bz2O, DMAP, Et3N CH2Cl2, 0 °C O 2. (n-Bu)3P, Et3N toluene, 110 °C 427 HO TBAT, Pd2(pmdba)3 (S)-t-Bu-PHOX 6 steps 84% yield 3 steps OH ent•415 FRAGMENT COUPLING AND RING CLOSING METATHESIS Having successfully synthesized both fragments ent•415 and 423, we turned our attention to investigating the coupling of these two compounds to form macrocycle 430. Carboxylation of alkyne 423 was performed followed by Yamaguchi esterification with diol ent•415 to afford our desired RCM substrate, ester 430 (Scheme 4.4.1).10 322 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A Scheme 4.4.1. Convergent Coupling of RCM Precursor 430 O O HO O 1. n-BuLi, CO2, THF, –78 °C 2. 2,4,5 trichlorobenzoyl chloride ent•415, Et3N, DMAP, toluene, 23 °C 46% yield 2 steps 423 O O O 430 We anticipated that the RCM of tetraene 430 would be challenging due to the presence of 3 terminal olefins, a diene, and an ynoate moiety. We Subjected tetraene 430 to a variety of RCM catalysts (e.g. Grubbs I, Grubbs II, Hoveyda-Grubbs II, and Stewart– Grubbs), solvent, and temperatures, but unfortunately no desired RCM was observed (i.e. 431, Scheme 4.4.2). Instead, cyclohexenone 432 is observed as the sole product. We suspect this selectivity problem arises from the fact that the catalyst preferentially inserts into the most accessible olefin, as is common with Ru-based catalysts.11 Although both the diene and allyl moieties possess mono-substituted olefins, the vinyl diene is electronically deactivated through conjugation. Therefore, the allyl group is the preferred initial site of metathesis in order to form Ru carbenoid 433. Carbenoid 433 then undergoes olefin metathesis with the undesired isopropenyl fragment to form cyclohexene 432. Due to these factors, we presumed that controlling the site selectivity for the initial insertion of the Ru catalyst will be crucial to the success to the RCM. Relay ring-closing metathesis (RRCM) offers an appealing solution to this challenge. Initially disclosed by Hoye and coworkers,12 RRCM has been shown to overcome inherent selectivity bias as well as to allow traditionally inert olefins such as dienes to react smoothly under standard RCM conditions. Unfortunately, any attempt to direct Rh insertion into the diene moiety preferentially failed, and we observed either no reaction or the removal of the relay handle. 323 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A Scheme 4.4.2. Ring-Closing Metathesis of Ester 430 HO O HO O HO O O O O toluene, 23 °C O O Grubbs II (20 mol %) O O 430 431 O HO 432 31% yield O O O [Ru] [Ru] O HO O HO HO O O O O + O O O O O O 430 O O 431 Desired RCM 432 Undesired RCM 433 IMes PCy3 Cl Ru Ph Cl PCy3 Grubbs I IMes Ru Cl Ru Cl PCy3 Cl N Ru Cl Ph Grubbs II O Cl Cl O Hoveyda–Grubbs II Stewart–Grubbs Even though we have yet to successfully perform the desired RCM to generate macrocycle 431, obtaining these late-stage intermediates allowed us to test whether an intramolecular Diels–Alder reaction would be able to generate the central cyclohexane ring of the norcembranoid diterpenes. Indeed, heating ester 430 at 130 °C in xylenes furnished the desired intramolecular Diels–Alder product 434 in an unoptimized 40% yield (Scheme 4.4.3). 324 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A Scheme 4.4.3. Intramolecular Diels–Alder of Ester 430 O HO O HO O xylenes O 130 °C O O 40% yield H O O 430 4.5 434 RETROSYNTHETIC ANALYSIS; OXIDATIVE ENOLATE COUPLING The potential challenges associated with the late stage RCM have incentivized the formulation an alternative retrosynthetic analysis. Thus, scabrolide A (407), can arise from the olefin isomerization of 435, which itself may be generated from an intramolecular oxidative enolate coupling of 436 (Scheme 4.5.1). Tricycle 436 may arise from the oxidation of the intramolecular Diels–Alder reaction of diene 437, which will be formed from the convergent esterification of the previous diol fragment 415 and methyl ketone 438. Scheme 4.5.1. 2nd Generation Retrosynthetic Analysis of Scabrolide A H HO O O O Olefin Isomerization H H HO O O O Oxidative Enolate-Coupling H HO H O O O H O O O Scabrolide A (407) 435 436 HO O O Diels–Alder Esterification HO + O OH O 437 415 R 438 At this time we also were interested in developing a second generation synthesis of diol 415. The first generation route hinged upon the previously developed asymmetric allylic alkylation in the Stoltz lab to obtain the desired diol in a high 92% ee but required 325 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 15 steps and afforded an 18% overall yield of the desired product (Scheme 4.5.2). We believed that by taking advantage of readily available chiral terpenes, we would be able to not only decrease the number of synthetic steps and increase the yield, but also obtain the diol product enantiopure. Scheme 4.5.2. Development of Modified Synthesis of Diol 415 1st generation MeO OMe + NH3 –Cl HO OH OH 2nd generation 15 steps HO cheap chiral terpene 18% yield OH 415 4.6 SECOND GENERATION SYNTHESIS OF THE CYCLOPENTENE DIOL FRAGMENT In 2016, Maimone and coworkers disclosed the enantioselective synthesis of ophiobolin N, and showed that commercially available (–)-linalool can afford cyclopentenone 440 in a two-step sequence.13 Linalool (339) first undergoes an RCM with Hoveyda–Grubbs II and TBS protection of the tertiary alcohol followed by a RuCl3catalyzed allylic oxidation generates the desired enone 440 (Scheme 4.6.1). We believed enone 440 would allow rapid access to our desired diol 415. a-Bromonation generates abromo enone 441, allowing for tandem phase-transfer mediated sodium cyanide conjugate addition and halide elimination to afford vinylogous ketonitrile 442.14 Unfortunately we observed low yields and diastereoselectivity upon double reduction of the nitrile and ketone moieties in 442. Instead using a Luche reduction at low temperatures performs a diastereoselective reduction of the enone to the syn-diol, which can subsequently be TESprotected, generating diol 443. 326 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A Scheme 4.6.1. Terpene-Derived Synthesis Toward Diol 415 1. HG-II (0.1 mol %), neat then, NaH, THF, TBSCl TBSO O 68% yield 2 steps (–)-linalool (439) NaCN, TBAI (17 mol %) O 90% yield 440 CN TBSO 1. NaBH4, CeCl3•7H2O MeOH, –78 °C 1:1 H2O:CH2Cl2 91% yield 10:1 dr 2 steps 442 441 CN TBSO 2. TESCl, imidazole CH2Cl2, 23 °C O 72% yield Br CH2Cl2, 0 to 23 °C 2. RuCl3, t-BuOOH, Mg(OAc)2 CH2Cl2, H2), 0 °C HO TBSO Br2, Et3N OTES 443 After initial reduction and protection of enone 442, a reduction of nitrile 443 with DIBAL, affords enal 444 in excellent yield (Scheme 4.6.2). Enal 444 then undergoes a Wittig olefination to yield bis-protected diol 445. Due to the judicious choice of protecting groups, we next selectively deprotected the secondary alcohol in the presence of the tertiary to afford diene 446. Treating diol 445 with harsh deprotection conditions such as an excess of TBAF in refluxing THF, we can obtain the same cyclopentene diol 415 fragment as the first generation route. This second generation synthesis not only decreased the number of steps required from 15 to 9 but also increased the overall yield to 30%. Scheme 4.6.2. Synthesis of Cyclopentene Diol 415 O CN TBSO DIBAL OTES H TBSO Ph3PMeBr, KOt-Bu CH2Cl2, –78 °C THF, 23 °C 91% yield 68% yield 443 OTES TBSO OTES 444 HO TBAF (2.7 equiv) 445 TBSO TBAF (1.1 equiv) THF, 65 °C OH 415 81% yield TBSO THF, 23 °C, 15 min OTES 445 87% yield OH 446 327 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 4.7 ALKYNE SYNTHESIS AND FRAGMENT COUPLING Alkyne ent•422 was synthesized in 5 steps from (–)-carvone following previously described methods (Scheme 4.7.1). The Weinreb amide moiety was then monomethylated with methyl magnesiumbromide to afford ketone 447, which then undergoes a palladiumcatalyzed oxidative carbonylation using one atmosphere of a 1:1 mixture of CO:O2 in a methanol:DMF solution, affording methyl ester 448.15 Saponification of ester 448 followed by Steglich esterification with DIC yields the Diels–Alder precursor 449. Scheme 4.7.1. Synthesis of Methyl Ketone Diels–Alder Precursor O MeO O N Me Pd(OAc)2 (30 mol %) Ph3P (60 mol %) MeMgBr THF, –78 to 0 °C DMF:MeOH 1:1 CO:O2 (1 atm) 79% yield 72% yield ent•422 447 O TBSO O 1. LiOH, 1:1 THF:H2O 2. 446, DIC, DMAP CH2Cl2, 0 °C MeO O 448 4.8 57% yield 2 steps O O 449 INTRAMOLECULAR DIELS–ALDER REACTION AND LATE-STAGE FUNCTIONALIZATION Similar to tetraene 430, heating triene 449 to 140 °C in rigorously degassed xylenes produces the desired Diels–Alder products as a single diastereomer (450) in excellent yield (75%, Scheme 4.8.1). Having synthesized 3 of the 4 rings of the carbocyclic core of scabrolide A, we intended to deprotect the tertiary alcohol of 450 in order to set the stage for a directed oxidation of the 1,4-cyclohexadiene moiety. Unfortunately, after subjecting tricycle 450 to TBAF, we observed spontaneous and quantitative conversion to tetracycle 328 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 451 and 452 as a mixture of diastereomers. Tricycle 450 and analogous compounds appear to be extremely sensitive to base, treatment with milder bases such as triethylamine at 0 °C still result in quantitative aldol reaction. Any attempt to functionalize, protect, or anneal the final ring onto tricycle 450 again resulted in the deleterious aldol product. Scheme 4.8.1. Unexpected Aldol Condensation of Tricycle 450 TBSO O TBSO O xylenes 140 °C O O H O 82% yield O 450 449 TBSO O TBSO TBSO TBAF O THF, 23 °C H O 450 >99% yield 1:1.8 dr O OH H + O H OH O O 451 452 X-ray Crystal Structure of 452 In order to avoid the problematic aldol reaction, double deprotection of the cyclopentene diol fragment is required prior to the requisite coupling and Diels–Alder reaction. Ester 437 successfully undergoes the Diels–Alder reaction at 140 °C in xylenes to afford tricycle 453 (Scheme 4.8.2). The free alcohol is now able to participate in a directed epoxidation utilizing vanadyl acetylacetonate to generate the syn-epoxy alcohol 454 in an excellent 91% yield. Epoxide 454 can be selectively reduced to the 1,3 diol employing in situ-generated titanocene(III) chloride.9,16 With 1,3-diol 455 in hand, we 329 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A investigated possible oxidation conditions to obtain oxidative enolate coupling precursor 436. Unfortunately we have yet to determine optimal conditions to effect the desired transformation. Basic oxidation conditions such as the Swern oxidation17 again resulted in an undesired aldol product. Neutral oxidations, such as the Ley oxidation18 and Stahl oxidation,19 afforded recovered starting material due to the large steric encumbrance posed by the caged tricyclic core. Moreover, acidic oxidation primarily resulted in decomposition. Ultimately we were unable to obtain sufficient quantities of enone 436 to investigate the oxidative enolate coupling, necessitating the development of a new retrosynthetic analysis. Scheme 4.8.2. Selective Oxidation of Deprotected Tricycle 437 HO O HO O VO(acac)2 xylenes 140 °C O O TBHP, benzene H O 79% yield O H 91% yield O 437 O 454 453 H HO OH 4.9 THIRD O H HO O O [O] conditions TiCp*2Cl2, Zn° H2O, THF, –78 °C 92% yield O O HO O H O H O O 455 436 GENERATION RETROSYNTHETIC ANALYSIS; RING EXPANSION Learning from our previous synthetic routes, direct construction of the 7-membered ring would likely require the avoidance of ketone functionalities on the carvone fragment in order to prevent the problematic aldol reaction. Retrosynthetically, we believed that using the inherit energy in a strained small membered ring would facilitate the synthesis of the cycloheptanone ring.20 We believed this could be achieved by the ring fission of 330 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A cyclobutanol 456, which itself can be formed through a photocatalytic [2+2] cycloaddition of enone 457 (Scheme 4.9.1). Tricycle 457 again can be synthesized through the redox manipulation of the Diels–Alder adduct of ester 458. Finally, ester 458 can be convergently synthesized from diol 415 and diyne 459. Scheme 4.9.1. 3rd Generation Retrosynthetic Analysis Utilizing Energy of a Strained Cyclobutane Ring H HO O O H HO O H H HO Ring expansion O SiMe2Ph [2+2] OH O H O H O O O Scabrolide A 407 456 H O 457 HO Diels–Alder HO Esterification + O OH O 458 4.10 415 459 SYNTHESIS OF [2+2] PRECURSOR In order to provide more facile access to late stage material, a model system was constructed. Employing 1,6-heptadiyne as the starting material instead of carvone, we could rapidly access ester 460 in a single known step instead of 6 steps (Scheme 4.10.1).21 Ester 460 then undergoes saponification and Steglich esterification with diol 415 to afford the Diels–Alder precursor 458 efficiently and in excellent yield. Scheme 4.10.1. Convergent Esterification of Diol 415 and Ester 460 HO 1. LiOH, THF:H2O 2. DIC, DMAP, 415 CH2Cl2, 0 °C MeO O 460 64% yield O O 458 331 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A Cyclization of ester 458 was again performed in xylenes at 140 °C to furnish the desired tricycle 461 (Scheme 4.10.2). By utilizing the double deprotected diol 415 instead of 446, we can perform a directed epoxidation utilizing vanadyl acetylacetonate and TBHP to afford the syn-epoxy alcohol 462. Epoxide 462 can be selectively opened using in situgenerated titanocene(III) chloride to form the syn-1,3 diol 463, which upon treatment with DMP is oxidized to afford enone 464, a moiety that strongly absorbs UV light at 350 nm. Scheme 4.10.2. Diels–Alder and Oxidation of Model System 458 HO HO VO(acac)2 xylenes 140 °C O O 84% yield TBHP, benzene H 458 O 77% yield O O H HO 462 OH H HO O DMP, NaHCO3 TiCp2Cl2, Zn° H2O, THF, –78 °C O CH2Cl2 H O 47% yield 463 4.11 H O 461 96% yield O HO O H O 464 [2+2] PHOTOCYCLOADDITION AND RING EXPANSION The successful installation of the enone moiety of tricycle 464 allowed us to perform the Markovnikov hydrosilylation using RuCp*(MeCN)3PF6 and dimethylphenylsilane (Scheme 4.11.1).22 While other hydrosilanes are competent in the hydrosilylation reaction,23 the presence of an aryl group was paramount to the success of the subsequent Tamao–Fleming oxidation. [2+2] cyclization of enone 457, affords a 2:1 mixture of diastereomers 465 and 466 in quantitative yield. The structures of 465 and 466 have both been confirmed by single crystal X-ray diffraction. 332 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A Scheme 4.11.1. [2+2] Cyclization of Enone 457 H HO O O H HO HSiMe2Ph [RuCp*(MeCN)3]PF6 O 84% yield O SIMe2Ph hν CH2Cl2, 0 to 23 °C H O benzene H >99% yield 1:2 dr O 464 457 H HO O H SiMe2Ph O H HO H O H + SiMe2Ph O H O O 465 466 X-ray Crystal Structure of 465 X-ray Crystal Structure of 466 Oxidation of 466 using conditions developed by Fleming, using Hg(OAc)2 in peracetic acid generated the desired cyclobutanol 456 in moderate yield (30%, Scheme 4.11.2).24 Interestingly only diastereomer 466 reacted under these oxidation conditions, while 465 required harsher conditions.25 Finally, having synthesized cyclobutanol 456, we focused our attention on the strain-release-driven ring expansion. Multiple attempts to form the hypoiodite of 456 in-situ followed by homolytic cleavage by thermal or photochemical means, resulted in either no reaction or decomposition.26 Fortunately in 2016, Xhang and coworkers reported the AgOTf-catalyzed b-scission of cyclic alcohols to the corresponding chloroketone.27 Subjecting cyclobutanol 456 to these reaction conditions (Scheme 4.11.2), we hoped to obtain the tetracyclic core of scabrolide A 467, but unfortunately these conditions also failed to afford the expected product. Fortunately, concentration of this product in CDCl3 provided a crystalline solid, from which we were able to obtain an X-ray 333 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A crystal structure. From this data we determined that the product of this reaction was actually furan 468. Similar to expected tetracycle 467, furan 468 possesses the key seven membered ring, thus completing the carbocyclic skeleton of scabrolide A. Scheme 4.11.2. Ring Expansion of Cyclobutanol 466 H HO O H SiMe2Ph O H HO H H AcOOH, Hg(OAc)2 AgOTf (40 mol %) 1,4 phenanthroline O t-BuOCl, MeCN H O 466 H O O 49% yield 456 HO H HO O O OH AcOH, 23 °C 30% yield O O H O 467 Not Observed Cl H O O H O 468 4.12 Observed X-ray Crystal Structure of 468 FUTURE DIRECTIONS Having achieved the successful synthesis of the carbocyclic skeleton of scabrolide A through the use of the ring expansion of a four-membered ring on model system 458, we can now focus on the late-stage functionalization to complete the total synthesis. Currently we envision furan 468 to undergo a retro-oxa-Michael reaction to afford cycloheptenone followed by selective enolization, Segusa–Ito oxidation, and diastereoselective conjugate addition of isopropenyl organometallic to complete the synthesis of scabrolide A (Scheme 4.12.1). If derivatization of model system 458 fails it may be possible to synthesize the carvone fragment with the isopropenyl fragment already installed. Early introduction of the isopropenyl stereocenter removes the need for late-stage functionalize of tetracycle 468 and only requires a retro-oxa-Michael reaction to complete the synthesis. 334 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A Scheme. 4.12.1. Future Directions Toward the Completion of Scabrolide A H HO O Cl H O 1. retro-oxa-Michael 2. Segua–Ito [O] H HO O O 3. conjugate addition O 4.13 H O H O O 468 407 CONCLUSION We have reported significant progress toward the total synthesis of scabrolide A. A key ring expansion of a strained small ring allowed for the synthesis of the [5,5,6,7] tetracyclic core in an expedient 16 steps (longest linear) from known enone 440 and in an overall yield of 1.1 %. Current endeavors include early introduction of the isopropenyl fragment by adapting the carvone route yet again. Moreover we are also investigating the oxidation of furan 468 to allow for a diastereoselective conjugate addition of isopropenyl organometallic reagent, thus completing the synthesis of scabrolide A. 4.14 EXPERIMENTAL METHODS AND ANALYTICAL DATA 4.14.1 MATERIALS AND METHODS Unless stated otherwise, reactions were performed at ambient temperature (23 °C) in flame-dried or oven-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents (distilled or passed over a column of activated alumina).28 Commercially obtained reagents were used as received with the exception of [RuCp*(MeCN)3]PF6 and Ph3PMeBr which were stored in a nitrogen-filled glovebox. Triethylamine (Et3N) was distilled over potassium hydride prior to use. Dess–Martin periodinane29 were prepared by known methods. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. Reaction progress was monitored by thin-layer chromatography (TLC), which was performed using Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 335 E. Merck silica gel 60 F254 precoated glass plated (0.25 mm) and visualized by UV fluorescence quenching, potassium permanganate, p-anisaldehyde, or iodine staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40-63 nm) was used for column chromatography. 1H and 13C NMR spectra were recorded on a Varian Inova 500 (500 MHz and 126 MHz, respectively), Varian Mercury 300 spectrometer (300 MHz and 75 MHz, respectively), Varian 600 MHz Spectrometer (600 MHz), and a Bruker AV III HD spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe (400 MHz and 101 MHz, respectively) and are reported in terms of chemical shift relative to CHCl3 (d 7.26 and d 77.16, respectively) and C6H6 (d 7.16 and d 128.4 respectively). Data for 1H NMR are reported as follows: chemical shift (d ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sext = sextet, sept = septet, m = multiplet, and br s = broad singlet. Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and are 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 and are reported as: [a]DT (concentration in g/100 mL, solvent). High resolution mass spectra were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H High Resolution Mass Spectrometer in fast atom bombardment (FAB+) ionization mode or a Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed (ESI/APCI) ionization mode. Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 4.14.2 336 EXPERIMENTAL PROCEDURES O O O MeO P OMe OMe N Me N2 O MeO N Me K2CO3, MeOH 82% yield O H 420 422 (S)-N-methoxy-N-methyl-3-(prop-1-en-2-yl)hex-5-ynamide (422): In a round-bottom flask, known aldehyde 420 (6.27 g, 31.5 mmol, 1.0 equiv) and K2CO3 (8.7 g, 62.9 mmol, 2.0 equiv) was diluted with dry methanol (52.5 mL, 0.6 M) and cooled to 0 °C (ice/water bath). Neat Ohira–Bestmann reagent (7.25 g, 37.8 mmol, 1.2 equiv) was added dropwise via syringe and the resultant solution was allowed to stir for 12 h and warm to ambient temperature (23 °C). Upon complete consumption of starting material (determined by TLC analysis, 9:1 CH2Cl2:EtOAc), the reaction was diluted with Et2O and washed with a saturated solution of NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 9:1 CH2Cl2:EtOAc) to generate alkyne 422 (5.0 g, 82% yield) as a pale yellow oil; Rf = 0.71 (9:1 CH2Cl2:EtOAc); 1H NMR (500 MHz, CDCl3) d 4.85 (p, J = 1.5 Hz, 1H), 4.82 (dp, J = 1.7, 0.9 Hz, 1H), 3.70 (s, 3H), 3.17 (s, 3H), 2.92–2.82 (m, 1H), 2.76–2.60 (m, 2H), 2.38 (ddd, J = 6.4, 3.5, 2.7 Hz, 2H), 1.99 (t, J = 2.7 Hz, 1H), 1.77 (dd, J = 1.6, 0.8 Hz, 3H); 13C NMR (126 MHz, CDCl3) d 173.0, 146.2, 111.6, 82.4, 69.9, 61.3, 40.8, 34.8, 32.2, 23.0, 20.7; IR (thin film, NaCl) 3293, 3250, 3076, 2967, 2938, 2820, 2116, 1661, 1430, 1384, 1334, 1175, 1175, 1108, 1002, 936, 894 cm-1; HRMS (ES/APCI) m/z calc’d C11H18O2N [M+H]+: 196.1332, found: 196.1336. Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A O MeO N Me 337 O MgBr THF, –78 to 0 °C 87% yield 422 ent•416 (S)-6-(prop-1-en-2-yl)non-1-en-8-yn-4-one ent•416: In a flame dried round bottom flask, amide 422 (50 mg, 0.26 mmol, 1.0 equiv) was dissolved in THF (0.8 mL, 0.3 M) and cooled to –78 °C. Allyl magnesium bromide (0.52 mL, 0.52 mmol, 1.0 M, 2.0 equiv) was added dropwise to the reaction solution. The reaction was allowed to stir for 15 min at –78 °C and then warmed to 0 °C and stirred for 16 h. Upon complete consumption of starting material (determined by TLC analysis, 9:1 hexanes:Et2O), the reaction was quenched with a saturated solution of NH4Cl and the product was extracted from the biphasic mixture with Et2O (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 9:1 hexanes:Et2O) to generate alkyne ent•416 (39 mg, 87% yield) as a pale yellow oil; 1H NMR (500 MHz, CDCl3) d 5.91 (ddt, J = 17.2, 10.2, 7.0 Hz, 1H), 5.18 (dq, J = 10.2, 1.3 Hz, 1H), 5.14 (dq, J = 17.1, 1.5 Hz, 1H), 4.82 (p, J = 1.5 Hz, 1H), 4.78 (dt, J = 1.5, 0.8 Hz, 1H), 3.18 (dt, J = 6.9, 1.4 Hz, 2H), 2.86–2.77 (m, 1H), 2.74 (dd, J = 16.7, 6.6 Hz, 1H), 2.62 (dd, J = 16.7, 7.4 Hz, 1H), 2.32 (ddd, J = 14.5, 6.5, 2.7 Hz, 2H), 1.99 (t, J = 2.7 Hz, 1H), 1.73 (dd, J = 1.5, 0.8 Hz, 3H); 13C NMR (126 MHz, CDCl3) d 207.3, 145.9, 130.52, 119.1, 111.8, 82.2, 70.3, 48.2, 45.1, 40.2, 23.0, 20.7; IR (thin film, NaCl) 3297, 3078, 2969, 2917, 2117, 1715, 1646, 1430, 1376, 993, 920, 895 cm-1; HRMS (ESI) m/z calc’d C12H16O [M•]+: 176.1201, found: 176.1191. [a]D25 – 24.90 (c 3.7, CDCl3). Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A O HO OH O 338 O oxalic acid CH(OCH2CH3)3 MeCN, 23 °C 83% yield ent•416 423 (S)-2-allyl-2-(2-(prop-1-en-2-yl)pent-4-yn-1-yl)-1,3-dioxolane (423): Dried oxalic acid (109 mg, 1.2 mmol, 8.5 equiv) was dissolved in a solution of ethylene glycol (0.27 mL, 4.69 mmol, 33 equiv), triethyl orthoformate (0.14 mL, 0.85 mmol, 6 equiv), and MeCN (1.95 mL, 0.073 M). After complete dissolution of the oxalic acid, ketone ent•416 (25 mg, 0.14 mmol, 1 equiv) was added. The reaction was sealed and allowed to stir at ambient temperature (23 °C) for 36 h. Upon complete consumption of starting material (as determined by TLC analysis, 4:1 hexanes: Et2O), the reaction was diluted with H2O and the product was extracted with Et2O (3 x 5 mL). The combined organic layers were washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 4:1 hexanes:Et2O) to afford dioxolane 423 (26 mg, 83% yield) as a pale yellow oil (Rf = 0.68, 4:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) d = 5.81 (ddt, J = 16.9, 10.5, 7.2 Hz, 1H), 5.12 (ddt, J = 8.2, 2.2, 1.3 Hz, 1H), 5.08 (t, J = 1.3 Hz, 1H), 4.79 (q, J = 1.3 Hz, 2H), 3.94 (q, J = 1.3 Hz, 4H), 2.52 (dq, J = 8.2, 6.3 Hz, 1H), 2.43–2.34 (m, 3H), 2.26 (ddd, J = 16.7, 8.1, 2.7 Hz, 1H), 1.97 (t, J = 2.6 Hz, 1H), 1.83 (d, J = 6.5 Hz, 2H), 1.70 (t, J = 1.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) d = 147.5, 133.3, 118.4, 111.4, 110.8, 83.3, 69.4, 65.0, 65.0, 42.5, 41.3, 39.2, 24.1, 19.2; IR (thin film, NaCl) 3302, 3075, 2949, 2888, 2117, 1643, 1433, 1374, 1311, 1124, 1100, 996, 918, 890, 862, 837, 635 cm-1; HRMS (FAB+) m/z calc’d C14H21O2 [M+H]+: 221.1536, found: 221.1531; [a]23D = –2.45 (c = 0.79, CHCl3). 339 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A Cl O Cl O O O O Cl n-BuLi, CO2 415, Et3N, DMAP THF, –78 °C toluene, 23 °C CO2H 423 Cl 469 O HO O O O 430 46% yield 2 steps (1R,4S)-4-hydroxy-4-methyl-3-vinylcyclopent-2-en-1-yl (S)-5-((2-allyl-1,3-dioxolan-2 yl)methyl)-6-methylhept-6-en-2-ynoate (430): Dioxolane 423 (95 mg, 0.43 mmol, 1 equiv) was dissolved in THF (4.3 mL, 0.1 M) and cooled –78 °C. The solution was allowed to stir for 5 min followed by the addition powdered dry ice (0.56 g, 1.3 g/mmol of 423). After 10 min, the reaction was quenched with a saturated solution of NH4Cl and was allowed to warm to ambient temperature (23°C). The solution was acidified with a 5% solution of citric acid (5 mL) and the product was extracted with EtOAc (5 x 15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product 469 (103 mg, 93%) was used crude in the following reaction. To a solution of acid 469 (58 mg, 0.22 mmol, 1.1 equiv) in THF (2 mL, 0.1 M), Et3N (92 µL, 0.66 mmol, 3.3 equiv) and 2,4,6-trichlorobenzoyl chloride (34 µL, 0.22 mmol, 1.1 equiv) was added. The reaction was allowed to stir for 1 h followed by the addition of a THF solution (2 mL, 0.1 M) of diol 415 (28 mg, 0.2 M, 1 equiv) and DMAP (24 mg, 0.2 mmol, 1 equiv). The reaction was allowed to stir at ambient temperature (23 °C) until complete. Upon complete consumption of diol 415 (as determined by TLC analysis, 4:1 hexanes:EtOAc) the reaction was directly purified by column chromatography (SiO2, 100% hexanes then 1:1 hexanes:EtOAc) to afford ester 430 (43 mg, 50%) as a yellow oil (Rf = 0.22); 1H NMR (400 MHz, CDCl3) d 6.31 (dd, J = 17.8, 340 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 11.3 Hz, 1H), 5.87–5.73 (m, 3H), 5.53 (ddd, J = 7.1, 4.5, 2.3 Hz, 1H), 5.32 (dd, J = 11.3, 1.6 Hz, 1H), 5.16–5.10 (m, 1H), 5.08 (t, J = 1.3 Hz, 1H), 4.80 (d, J = 1.2 Hz, 2H), 3.94 (s, 4H), 2.65–2.53 (m, 3H), 2.45–2.39 (m, 1H), 2.36 (dq, J = 6.1, 1.2 Hz, 2H), 2.08–2.01 (m, 1H), 1.92 (s, 1H), 1.85 (dd, J = 14.7, 6.1 Hz, 1H), 1.77 (dd, J = 14.7, 6.2 Hz, 1H), 1.69 (t, J = 1.2 Hz, 3H), 1.43 (s, 3H); 13C NMR (101 MHz, CDCl3) d 153.6, 151.7, 146.6, 133.2, 129.0, 126.2, 119.5, 118.6, 112.1, 110.7, 88.9, 81.0, 77.0, 74.2, 65.1, 65.0, 49.0, 42.5, 40.6, 39.4, 26.7, 24.2, 19.4; IR (thin film, NaCl) 3369lm2956, 2918, 2847, 2232, 1705, 1633, 1460, 1418, 1372, 1258, 1063, 801 cm-1; HRMS (FAB+) m/z calc’d C23H31O5 [M+H]+: 387.2171, found: 387.2158; [a]25D = + 26.7 (c = 0.045, CHCl3). HO O HO O toluene, 23 °C O O Grubbs II (20 mol %) O O 31% yield O O 430 (1R,4S)-4-hydroxy-4-methyl-3-vinylcyclopent-2-en-1-yl 432 3-((S)-8-methyl-1,4- dioxaspiro[4.5]dec-8-en-7-yl)propiolate (432): To a stirred, Ar sparged solution of ester 430 (6 mg, 0.016 mmol, 1.0 equiv) in toluene (1 mL, 0.016 M) had Grubbs II (2.6 mg, 3.1 µmol, 0.2 equiv) added in one portion. The reaction was allowed to stir for 2 h followed by direct purification of column chromatography (SiO2, 100% hexanes to 4:1 hexanes:EtOAc) to afford ester 432 (1.7 mg, 31 %) as a pale yellow oil (Rf = 0.17); 1H NMR (400 MHz, CDCl3) d 6.26 (ddt, J = 17.8, 11.3, 0.7 Hz, 1H), 5.76 (d, J = 2.4 Hz, 1H), 5.75–5.68 (m, 1H), 5.52–5.45 (m, 1H), 5.35 (ddt, J = 4.6, 3.2, 1.5 Hz, 1H), 5.27 (dd, J = 11.3, 1.6 Hz, 1H), 3.94–3.87 (m, 4H), 2.58 (dd, J = 14.3, 7.3 Hz, 1H), 2.50 (d, J = 1.9 Hz, 3H), 2.26–2.11 (m, 2H), 2.00 (dd, J = 14.2, 4.4 Hz, 1H), 1.90–1.76 (m, 2H), 1.64 (q, J = 2.0 Hz, 3H), 1.38 (s, 3H); 13C NMR (101 MHz, CDCl3) d 153.6, 151.8, 133.9, 128.9, 126.1, 341 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 121.8, 119.6, 108.0, 88.5, 81.1, 77.1, 74.4, 64.7, 64.5, 49.0, 38.1, 36.2, 36.1, 26.8, 22.6, 21.1; IR (thin film, NaCl) 3447, 2926, 2233, 1734, 1701, 1559, 1540, 1420, 1372, 1248, 1122, 1072, 988, 948, 874, 810, 753, 731; HRMS (ESI) m/z calc’d C21H27O5 [M+H]+: 358.1853, found: 358.1833; [a]D23 + 125.4 (c 0.75, CHCl3). O HO O HO O O xylenes 130 °C O O 40% yield O 430 H O 434 (2a1R,6S,7aR)-3-((S)-2-((2-allyl-1,3-dioxolan-2-yl)methyl)-3-methylbut-3-en-1-yl)-6hydroxy-6-methyl-4,6,7,7a-tetrahydroindeno[1,7-bc]furan-2(2a1H)-one (434): Ester 430 (5.3 mg, 13.7 µmol, 1 equiv) was dissolved xylenes (0.5 mL), sparged with Ar, sealed, and heated to 130 °C for 1 h. Upon complete consumption of starting material (as determined by TLC analysis, 1:1 hexanes: EtOAc), the reaction was loaded directly flash column (SiO2, 100% hexanes to 1:1 hexanes:EtOAc) to afford tricycle 434 (2.1 mg, 40% yield) as an amorphous solid; 1H NMR (400 MHz, CDCl3) d 5.91–5.72 (m, 2H), 5.16–5.03 (m, 2H), 4.96 (ddd, J = 9.1, 8.0, 7.0 Hz, 1H), 4.64 (dq, J = 2.9, 1.5 Hz, 1H), 4.57 (dd, J = 2.3, 1.0 Hz, 1H), 4.01–3.86 (m, 4H), 3.30 (t, J = 9.7 Hz, 1H), 3.10–2.90 (m, 2H), 2.75– 2.59 (m, 3H), 2.50 (ddd, J = 12.7, 7.0, 0.9 Hz, 1H), 2.39 (dq, J = 7.2, 1.5 Hz, 2H), 1.90 (dd, J = 14.8, 7.9 Hz, 1H), 1.72–1.64 (m, 4H), 1.64–1.60 (m, 1H), 1.40 (d, J = 1.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) d 168.3, 156.7, 152.0, 148.6, 133.5, 124.9, 118.4, 116.6, 111.3, 110.9, 80.0, 75.2, 65.1, 65.0, 49.8, 45.7, 42.5, 41.9, 39.4, 36.8, 35.3, 26.6, 18.3; IR (thin film, NaCl) 3458, 2924, 1749, 1642, 1432, 1210, 1093, 1044, 823 cm-1; HRMS (FAB+) m/z calc’d C23H31O5 [M+H]+: 387.2171, found: 387.2188; [a]D23 + 37.5 (c 0.12, CHCl3). Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A TBSO Br2, Et3N TBSO Br CH2Cl2, 0 to 23 °C O 440 342 O 90% yield 441 (R)-2-bromo-4-((tert-butyldimethylsilyl)oxy)-4-methylcyclopent-2-en-1-one (441): In a flame dried round-bottom flask, Enone 440 (2.76g, 12.2 mmol, 1.0 equiv) dissolved in CH2Cl2 (122 mL, 0.1 M) was cooled to 0 °C (ice: water bath). Br2 (0.687 mL, 13.4 mmol, 1.1 equiv) was added dropwise over 10 min and the resultant solution stirred for 30 min. Upon complete consumption of starting material (as determined by TLC analysis, 9:1 hexanes:EtOAc), Et3N (2.5 mL, 18.3 mmol, 1.5 equiv) was added and allowed to stir for 1 h at ambient temperature (23 °C). The reaction was diluted with a saturated solution of Na2S2O3 and the product was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 9:1 hexanes:EtOAc) to afford enone 441 (3.3 g, 90% yield) as a colorless oil (Rf = 0.45); 1H NMR (400 MHz, CDCl3) d = 7.51 (s, 1H), 2.64 (d, J = 3.6 Hz, 2H), 1.51 (s, 3H), 0.85 (d, J = 0.5 Hz, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 198.9, 165.0, 125.4, 50.4, 29.2, 25.7, 18.0, -2.3, -2.4; IR (thin film, NaCl) 2956, 2930, 2888, 2858, 1733, 1593, 1472, 1463, 1374, 1292, 1254, 1205, 1106, 1081, 1018, 922, 837, 776 cm-1; HRMS (ESI) m/z calc’d C12H22BrO2Si [M+H]+: 305.0567, found: 305.0567; [a]D23 + 2.3 (c 0.21, CHCl3). Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A TBSO NaCN, TBAI (17 mol %) Br O 441 343 CN TBSO 1:1 H2O:CH2Cl2 72% yield O 442 (R)-5-((tert-butyldimethylsilyl)oxy)-5-methyl-3-oxocyclopent-1-ene-1-carbonitrile (442): In a round-bottom flask, NaCN (2.3 g, 47 mmol, 2.2 equiv) and TBAI (1.1 g, 3.6 mmol, 0.17 equiv) is dissolved in H2O (66 mL, 0.32 M). Upon complete dissolution, a solution of enone 441 (6.5 g, 21.3 mmol, 1 equiv) in CH2Cl2 (107 mL, 0.2 M) was added and the biphasic mixture was stirred vigorously for 16 h. Upon completion of starting material (as determined by TLC analysis, 9:1 hexanes:EtOAc), the reaction was allowed to stand until complete separation of the biphasic mixture occured. The organic layer was separated and the aqueous layer was extracted with EtOAc (5 x 100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 9:1 hexanes:EtOAc) to afford enone 442 (3.8 g, 72% yield) as a pale yellow oil (Rf = 0.43); 1H NMR (400 MHz, CDCl3) d = 6.56 (s, 1H), 2.65 (d, J = 3.7 Hz, 2H), 1.64 (s, 3H), 0.88 (s, 9H), 0.17 (s, 3H), 0.13 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 203.0, 149.6, 139.6, 113.3, 78.8, 51.1, 28.1, 25.6, 18.1, -2.4, -2.7; IR (thin film, NaCl) 3449, 3087, 2957, 2932, 2888, 2859, 2231, 2736, 1606, 1473, 1378, 1290, 1254, 1217, 1170, 1093, 1006, 838, 778, 673 cm-1; HRMS (FAB+) m/z calc’d C13H22O2NSi [M+H]+: 252.1420, found: 252.1416; [a]D23 – 34.6 (c 0.34, CHCl3). 344 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A CN TBSO CN TBSO NaBH4, CeCl3•7H2O CH2Cl2, 23 °C MeOH, –78 °C O 442 CN TBSO TESCl, imidazole OH 470 OTES 91% yield over 2 steps 443 (3S,5R)-5-((tert-butyldimethylsilyl)oxy)-3-hydroxy-5-methylcyclopent-1-ene-1carbonitrile (470): In a round bottom flask, enone 442 (9.4 g, 37.3 mmol, 1 equiv) was dissolved in methanol (373 mL, 0.1 M). The solution was stirred for 5 min followed by the addition of CeCl3•7H2O (13.2 g, 41 mmol, 1.1 equiv). Once the reaction is homogeneous, the solution is cooled to – 78 °C and allowed to stir for 1 h. NaBH4 (1.4 g, 37.3 mmol, 1 equiv) was added slowly in portions to the reaction and was allowed to stir until completion (as determined by TLC analysis 4:1 hexanes:EtOAc). Upon complete consumption of starting material, the reaction was quenched with a saturated solution of NH4Cl (300 mL) and the biphasic mixture was allowed to warm to room temperature. The biphasic mixture was extracted with 2:1 Et2O:hexanes (3 x 300 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was assumed to have quantitative conversion and was used directly into the next reaction without further purification. Alcohol 470 could be purified by column chromatography (SiO2, 9:1 hexanes:EtOAc) to afford pure alcohol 470 as a white amorphous powder; Rf = 0.74 (4:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) d = 6.40 (d, J = 2.1 Hz, 1H), 4.60 (dddd, J = 8.1, 7.1, 5.2, 2.2 Hz, 1H), 2.34 (dd, J = 13.3, 6.9 Hz, 1H), 1.80 (dd, J = 13.2, 5.2 Hz, 1H), 1.65 (d, J = 8.2 Hz, 1H), 1.29 (d, J = 0.6 Hz, 3H), 0.72 (s, 9H), 0.00 (s, 3H), -0.01 (s, 3H); 13 C NMR (101 MHz, CDCl3) d 146.6, 127.2, 114.7, 83.0, 74.2, 50.8, 27.8, 25.7, 18.0, -2.2, -2.4; IR (thin film, NaCl) 3429, 2956, 2930, 2887, 2858, 2229, 1472, 1255, 1176, 1126, Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 345 1082, 1031, 868, 838, 777, 668 cm-1; HRMS (ESI) m/z calc’d C13H27N2O2Si [M+NH4]+: 271.1836; found: 271.1842; [a]D23 – 53.0 (c 0.28, CHCl3). (3S,5R)-5-((tert-butyldimethylsilyl)oxy)-5-methyl-3-((triethylsilyl)oxy)cyclopent-1ene-1-carbonitrile (443): Crude alcohol 470 (37.3 mmol, 1 equiv) was dissolved in CH2Cl2 (266 mL, 0.14 M). Once the solution is homogeneous Imidazole (7.6 g, 111.9 mmol, 3 equiv) and TESCl (7.1 mL, 55.9 mL, 1.5 equiv) was added. The reaction was allowed to stir until completion at 23 °C. Upon complete consumption of starting material (as determined by TLC analysis, 9:1 hexanes:EtOAc), the reaction was quenched with H2O (200 mL) and the biphasic mixture was extracted with Et2O (3 x 400 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The resultant crude product was the purified by column chromatography (SiO2, 9:1 hexanes:EtOAc) to afford nitrile 443 (12.5 g, 91% yield, 11:1 dr) as a pale yellow oil (Rf = 0.5); 1H NMR (400 MHz, CDCl3) d = 6.41 (d, J = 2.0 Hz, 1H), 4.72 (ddd, J = 7.0, 6.2, 2.0 Hz, 1H), 2.49 (dd, J = 12.8, 7.0 Hz, 1H), 1.98 (ddd, J = 12.8, 6.3, 0.8 Hz, 1H), 1.40 (d, J = 0.8 Hz, 3H), 0.96 (t, J = 7.9 Hz, 9H), 0.89 (s, 9H), 0.61 (q, J = 7.8 Hz, 6H), 0.14 (s, 3H), 0.13 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 147.3, 126.1, 114.9, 82.4, 73.8, 51.5, 28.7, 25.8, 18.1, 6.8, 4.8, -2.2, -2.6; IR (thin film, NaCl) 2957, 2879, 2858, 2224, 1463, 1414, 1360, 1308, 1254, 1198, 1177, 1132, 1099, 1047, 1006, 893, 869, 837, 809, 777 cm1 ; HRMS (ESI) m/z calc’d C19H38NO2Si2 [M+H]+: 268.2436; found: 368.2449; [a]D23 – 52.0 (c 0.40, CHCl3). Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A O CN TBSO 346 DIBAL H TBSO CH2Cl2, –78 °C OTES 443 91% yield OTES 444 (3S,5R)-5-((tert-butyldimethylsilyl)oxy)-5-methyl-3-((triethylsilyl)oxy)cyclopent-1ene-1-carbaldehyde (444): Nitrile 443 (250 mg, 0.68 mmol, 1 equiv) was added to CH2Cl2 (6.8 mL, 0.1M) and cooled to –78 °C. DIBAL (1.36 mL, 1 M in DCM, 2 equiv) was added dropwise and allowed to stir for 1 h at –78 °C. Upon complete consumption of starting material (as determined by TLC analysis, 19:1 hexanes:Et2O) the reaction was quenched with EtOAc (0.5 mL), diluted with Et2O and warmed to room temperature. A 50% solution of Rochelle’s salt (10 mL) was added and the biphasic mixture was allowed to stir for 0.5 h. If the biphasic mixture does not separate completely, another portion of Rochelle’s salt is add and stirred for another 0.5 h. The biphasic mixture is separated and the aqueous layer is extracted with Et2O (3 x 10 mL). The combined organic layers are dried over MgSO4, filtered, and concentrated in vacuo. The resultant crude product was the purified by column chromatography (SiO2, 19:1 hexanes:Et2O) to afford enal 444 (252 mg, 91% yield, 17:1 dr) as a pale yellow oil (Rf = 0.46); 1H NMR (400 MHz, CDCl3) d = 9.77 (s, 1H), 6.53 (d, J = 1.8 Hz, 1H), 4.70 (td, J = 6.9, 1.9 Hz, 1H), 2.49 (dd, J = 12.7, 7.1 Hz, 1H), 2.08 (dd, J = 12.6, 6.6 Hz, 1H), 1.45 (s, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.84 (d, J = 0.9 Hz, 9H), 0.63 (q, J = 7.9 Hz, 6H), 0.11 (s, 3H), 0.07 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 189.7, 149.8, 147.8, 80.6, 72.9, 53.9, 28.6, 25.8, 18.1, 6.9, 4.9, -2.2, -2.4; IR (thin film, NaCl) 2956, 2936, 2879, 2857, 2805, 2708, 1698, 1627, 1472, 1462, 1414, 1359, 1253, 1203, 1172, 1103, 1058, 975, 897, 837, 806, 775, 746, 671; HRMS (FAB+) m/z calc’d C19H37O3Si2 [M+H-H2]+: 369.2250, found: 369.2262; [a]D23 – 117.2 (c 0.20, CHCl3). Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 347 O H TBSO Ph3PMeBr, KOt-Bu TBSO THF, 23 °C OTES 444 95% yield OTES 445 tert-butyldimethyl(((1R,4S)-1-methyl-4-((triethylsilyl)oxy)-2-vinylcyclopent-2-en-1yl)oxy)silane (445): To a round-bottom flask in an N2-filled glovebox were charged Ph3PMeBr (1.7 g, 4.86 mmol, 3.00 equiv) and KOt-Bu (490 mg, 4.37 mmol, 2.70 equiv) as solids followed by THF (162 mL, 0.01 M). The bright yellow reaction mixture was then sealed with a rubber septum, removed from the glovebox, and placed under an argon atmosphere with stirring. After 2 h, a solution of aldehyde 444 in THF (3.00 mL) was added dropwise, causing the reaction mixture to become dark orange-brown. After the consumption of starting material was complete (as determined by TLC analysis, 19:1 hexanes:EtOAc). The reaction was poured onto a mixture of H2O (90 mL) and Et2O (30 mL). The organics were separated and the aqueous layer was extracted with Et2O (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude dark brown residue was purified by column chromatography (SiO2, 19:1 hexanes:Et2O) to afford diene 445 (567 mg, 95% yield) as a colorless oil (Rf = 0.80); 1H NMR (400 MHz, CDCl3) d = 6.24 (dd, J = 17.3, 11.2 Hz, 1H), 5.68 (dd, J = 18.2, 2.0 Hz, 1H), 5.62 (d, J = 1.9 Hz, 1H), 5.18 (ddt, J = 11.3, 2.2, 0.6 Hz, 1H), 4.60 (dddd, J = 6.7, 6.0, 2.0, 0.9 Hz, 1H), 2.43 (dd, J = 12.2, 6.8 Hz, 1H), 2.00 (ddd, J = 12.1, 6.6, 0.9 Hz, 1H), 1.34 (d, J = 0.9 Hz, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.86 (s, 9H), 0.61 (q, J = 7.9 Hz, 6H), 0.11 (s, 3H), 0.08 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 149.4, 130.0, 129.9, 117.4, 82.1, 73.2, 53.5, 29.0, 26.0, 18.2, 7.0, 5.0, -2.0, -2.5; IR (thin film, NaCl) 2956,2935, 2877, 2857, 1591, 1462, 1414, 1359, 1252, 1171, 1126, 1079, 1055, Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 348 1018, 1004, 855, 836, 774, 744 cm-1; HRMS (FAB+) m/z calc’d C20H44NO2Si [M+NH4]+: 386.2905, found: 386.2889; [a]D23 – 3.87 (c 0.35, CHCl3). TBSO TBAF (1.1 equiv) TBSO THF, 23 °C, 15 min OTES 445 87% yield OH 446 (1S,4R)-4-((tert-butyldimethylsilyl)oxy)-4-methyl-3-vinylcyclopent-2-en-1-ol (446): A solution of Diene 445 (195 mg, 0.53 mmol, 1 equiv) in THF (7.6 mL, 0.07 M) had a THF solution of TBAF (0.58 mL, 0.58 mmol, 1 M, 1.1 equiv). The reaction was allowed to stir for 15 min at which time total consumption of starting material occur (as determined by TLC analysis, 3:1 hexanes:Et2O). The reaction was diluted with water (10 mL) and the aqueous layer was extracted with Et2O (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 3:1 hexanes:Et2O) to afford diene 446 (117 mg, 87%) as a viscous colorless oil which solidifies at –20 °C (Rf = 0.2); 1H NMR (400 MHz, CDCl3) d = 6.32–6.22 (m, 1H), 5.75–5.67 (m, 2H), 5.25–5.19 (m, 1H), 4.64– 4.55 (m, 1H), 2.53 (dd, J = 12.7, 6.9 Hz, 1H), 1.93 (ddd, J = 12.7, 6.0, 0.8 Hz, 1H), 1.59 (s, 1H), 1.36 (d, J = 0.9 Hz, 3H), 0.86 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 150.6, 129.8, 129.1, 118.1, 82.5, 73.5, 53.2, 28.7, 25.9, 18.2, -2.0, -2.4; IR (thin film, NaCl) 3324, 2957, 2929, 2886, 2857, 1590, 1472, 1462, 1370, 1254, 1204, 1170, 1134, 1042, 1017, 835, 774, 679; HRMS (FAB+) m/z calc’d C14H30NO2Si [M+NH4]+: 272.204, found 272.2027; [a]D23 + 25.4 (c 0.19, CHCl3). Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A TBSO TBAF (2.7 equiv) 349 HO THF, 23 °C, 3 h OTES 81% yield 445 OH 415 (1R,3S)-1-methyl-5-vinylcyclopent-4-ene-1,3-diol (415): A solution of Diene 445 (270 mg, 0.57 mmol, 1 equiv) in THF (8.1 mL, 0.07 M) had a THF solution of TBAF (1.25 mL, 1.25 mmol, 1 M, 2.2 equiv). The reaction was allowed to stir for 2 h at 65 °C at which time another solution of TBAF (0.25 mL, 0.25 mmol, 0.5 equiv) was added. Upon total consumption of starting material (as determined by TLC analysis, 3:1 hexanes:Et2O), the reaction was diluted with water (10 mL) and the aqueous layer was extracted with Et2O (5 x 25 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 1:3 hexanes:EtOAc) to afford diene 415 (64 mg, 81%) as a white amorphous solid; 1H NMR (300 MHz, CDCl3) d 6.30 (dd, J = 17.8, 11.3, 1H), 5.82 (d, J = 2.1, 1H), 5.73 (dd, J = 17.9, 1.7, 1H), 5.26 (dd, J = 11.2, 1.7, 1H), 4.65 (dd, J = 11.5, 5.1, 1H), 2.54 (dd, J = 13.6, 6.8, 1H), 1.85 (dd, J = 13.6, 4.8, 2H), 1.68 (d, J = 6.6, 1H), 1.40 (s, 3H). All other characterization data matched known values.9 O MeO N Me O MeMgBr THF, –78 to 0 °C 79% yield ent•422 447 (S)-4-(prop-1-en-2-yl)hept-6-yn-2-one (447): Amide ent•422 (2.0 g, 10.2 mmol, 1 equiv) in THF (51 mL, 0.2 M) was cooled to –78 °C. A solution of MeMgBr in Et2O(7.1 mL, 21.5 mmol, 3 M, 2.1 equiv) was added dropwise. The reaction was allowed to stir for 12 h, gradually warming up to ambient temperature (23 °C). Upon complete consumption of Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 350 starting material (as determined by TLC analysis, 4:1 hexanes:Et2O), the reaction was quenched with a saturated solution of NH4Cl (50 mL), and diluted with Et2O (25 mL). The organics were separated and the aqueous layer was extracted with Et2O (3 x 40 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 4:1 hexanes, Et2O) to afford ketone 447 (1.2 g, 79%) as a pale yellow oil (Rf = 0.6); 1H NMR (400 MHz, CDCl3) d = 4.83 (p, J = 1.5 Hz, 1H), 4.78 (dt, J = 1.6, 0.8 Hz, 1H), 2.81 (p, J = 6.7 Hz, 1H), 2.73 (dd, J = 16.5, 6.6 Hz, 1H), 2.59 (dd, J = 16.5, 7.5 Hz, 1H), 2.36 (ddd, J = 16.9, 6.3, 2.7 Hz, 1H), 2.29 (ddd, J = 16.9, 6.6, 2.7 Hz, 1H), 2.15 (s, 3H), 1.99 (t, J = 2.6 Hz, 1H), 1.73 (dd, J = 1.5, 0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) d = 207.6, 145.9, 111.9, 82.2, 70.2, 46.5, 40.5, 30.5, 23.1, 20.6; IR (thin film, NaCl) 3294, 3078, 2970, 2918, 2117, 1715, 1648, 1433, 1360, 1233, 1160, 1059, 997, 896, 641; HRMS (ESI) m/z calc’d C10H15O [M+H]+: 151.1197, found: 151.1115; [a]D23 + 22.2 (c 0.59, CHCl3). O O Pd(OAc)2 (30 mol %) Ph3P (60 mol %) DMF:MeOH 1:1 CO:O2 (1 atm) 86% yield 447 CO2Me 448 methyl (S)-7-oxo-5-(prop-1-en-2-yl)oct-2-ynoate (448): Palladium acetate (112 mg, 0.5 mmol, 0.3 equiv) and triphenylphosphine (260 mg, 1.0 mmol, 0.6 equiv) were mixed in dimethylformamide (17 mL, 0.1 M) in a round-bottomed flask under N2 and allowed to stir for 5 min. Methanol (1.7 mL, 41.5 mmol, 25 equiv) and ketone 447 (250 mg, 1.66 mmol, 1 equiv) were added, followed by attachment of 2 rubber balloons, one filled with oxygen and the other CO, to the flask. The reaction was sparged with both CO andO2 balloons for 351 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 5 min and allowed to stir at ambient temperature (23 °C) for 16 h. Upon complete consumption of starting material (as determined by TLC, 4:1 hexanes:EtOAc), the mixture was diluted with Et2O and a saturated solution of LiCl and the aqueous layer was extracted with Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 4:1 hexanes:EtOAc) to afford ester 448 (249 mg, 86%) as a colorless oil (Rf = 0.25); 1H NMR (400 MHz, CDCl3) d =4.86 (t, J = 1.4 Hz, 1H), 4.81 (q, J = 0.9 Hz, 1H), 3.75 (s, 3H), 2.85 (p, J = 6.7 Hz, 1H), 2.66 (dd, J = 9.4, 7.1 Hz, 2H), 2.48 (dd, J = 6.5, 4.9 Hz, 2H), 2.16 (s, 3H), 1.73 (dd, J = 1.4, 0.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) d =207.0, 154.2, 145.2, 112.5, 87.3, 74.6, 52.8, 46.3, 39.7, 30.6, 23.1, 20.7; IR (thin film, NaCl) 2923, 2236, 1714, 1647, 1434, 1361, 1259, 1158, 1074, 942, 901, 752, 679 cm-1, HRMS (FAB+) m/z calc’d C12H17O3 [M+H]+: 209.1172; found 209.1164; [a]D23 + 46.5 (c 0.18, CHCl3). O O TBSO CO2Me 448 LiOH 446, DIC, DMAP 1:1 THF:H2O CH2Cl2, 0 °C CO2H 471 67% yield 2 steps O O O 449 (1S,4R)-4-((tert-butyldimethylsilyl)oxy)-4-methyl-3-vinylcyclopent-2-en-1-yl (R)-7- oxo-5-(prop-1-en-2-yl)oct-2-ynoate (471): Ester 448 (1.5 g, 5.7 mmol, 1 equiv) in a solution of THF (28 mL, 0.2M), was added to a solution of LiOH (205 mg, 8.6 mmol, 1.5 equiv) in H2O (28 mL, 0.2M). The reaction was stirred vigorously for 4 h when complete consumption of starting material was observed (as determined by TLC analysis 4:1 hexanes:EtOAc). The reaction was washed with EtOAc (1 X 20 mL) and the aqueous layer Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 352 was subsequently acidified to a pH of 1 with 1 N HCl. The acidic aqueous layer was then extracted with EtOAc (5 x 30 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude acid 471 (1.3 g, 81%) was used without further purification or characterization. Diol 446 (10 mg, 0.039 mmol, 1 equiv), acid 471 (15 mg, 0.079 mmol 2 equiv), and DMAP (16 mg, 0.039 mmol, 1 equiv) were added to a solution of CH2Cl2 (0.4 mL, 0.1 M) and cooled to 0 °C. DIC (12 µL, 0.079 mmol, 2 equiv) was added dropwise and the reaction was allowed to stir for 2 h. Upon complete consumption of starting material (as determined by TLC analysis, 4:1 hexanes:EtOAc), the reaction was diluted with H2O (5 mL) and extracted with Et2O (3 x 5 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 4:1 hexanes:EtOAc) to afford ester 449 (12 mg, 70%) as a pale yellow oil (Rf = 0.4); 1H NMR (400 MHz, CDCl3) d = 6.27 (ddd, J = 17.8, 11.2, 0.8 Hz, 1H), 5.75–5.69 (m, 2H), 5.53 (dddd, J = 7.3, 5.9, 2.3, 0.8 Hz, 1H), 5.27 (dd, J = 11.3, 1.9 Hz, 1H), 4.86–4.83 (m, 1H), 4.83–4.77 (m, 1H), 2.93–2.81 (m, 1H), 2.67 (dd, J = 13.2, 7.1 Hz, 2H), 2.63–2.56 (m, 1H), 2.48 (dd, J = 7.5, 6.4 Hz, 2H), 2.16 (s, 3H), 2.10 (ddd, J = 13.1, 5.9, 0.8 Hz, 1H), 1.73 (dd, J = 1.5, 0.8 Hz, 3H), 1.38 (d, J = 0.8 Hz, 3H), 0.86 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 207.1, 153.7, 152.7, 145.2, 129.3, 123.9, 119.0, 112.4, 87.2, 82.3, 74.9, 48.9, 46.3, 39.7, 30.5, 29.2, 25.9, 23.2, 20.7, 18.2, -2.2, -2.6; IR (thin film, NaCl) 2956, 2929, 2856, 2234, 1711, 1649, 1472, 1439, 1359, 1250, 1169, 1069, 1022, 837, 774, 752 cm-1; HRMS (FAB+) m/z calc’d C25H39O4Si [M+H]+: 431.2612; found 431.2629; [a]D23 –71.1 (c 0.59, CHCl3). 353 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A TBSO O TBSO O xylenes 140 °C O O 82% yield O 449 H O 450 (2a1S,6R,7aS)-6-((tert-butyldimethylsilyl)oxy)-6-methyl-3-((R)-4-oxo-2-(prop-1-en-2yl)pentyl)-4,6,7,7a-tetrahydroindeno[1,7-bc]furan-2(2a1H)-one (450): Ester 449 (65 mg, 0.15 mmol) was transferred to a Schlenk bomb with xylenes (15 mL, 0.01 M). The Schlenk was the rigorously degassed by standard freeze-pump-thaw technique and upon reaching ambient temperature (23 °C) the flask was sealed and heat to 140 °C. The reaction was allowed to stir at this temperature of 2 h at which time complete consumption of starting material was observed (as determined by TLC analysis, 4:1 hexanes:EtOAc). The reaction was allowed to cool to room temperature and was directly purified by column chromatography (SiO2, 100% hexanes then 4:1 hexanes:EtOAc) to furnish tricycle 450 (53 mg, 82%) as a white amorphous solid (Rf = 0.35); 1H NMR (400 MHz, CDCl3) d = δ 5.78 (ddd, J = 6.4, 2.9, 1.9 Hz, 1H), 4.93 (ddd, J = 9.0, 8.1, 7.0 Hz, 1H), 4.68 (p, J = 1.5 Hz, 1H), 4.63 (dt, J = 1.8, 0.8 Hz, 1H), 3.19 (t, J = 9.6 Hz, 1H), 3.13–3.04 (m, 1H), 2.93 (p, J = 7.1 Hz, 1H), 2.84 (dddd, J = 10.7, 7.1, 2.4, 1.3 Hz, 1H), 2.75 (ddd, J = 12.7, 7.7, 1.2 Hz, 1H), 2.66 (ddt, J = 18.1, 10.1, 1.6 Hz, 1H), 2.59 (d, J = 1.4 Hz, 1H), 2.57 (d, J = 1.5 Hz, 1H), 2.42–2.34 (m, 1H), 2.12 (s, 3H), 1.70–1.63 (m, 4H), 1.36 (d, J = 1.0 Hz, 3H), 0.86 (s, 9H), 0.10 (s, 3H), 0.03 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 208.0, 168.7, 156.7, 151.8, 146.4, 125.4, 116.5, 112.3, 81.2, 76.2, 48.8, 47.3, 44.8, 40.9, 35.7, 34.8, 30.8, 28.1, 25.8, 19.5, 18.1, -2.1, -2.3; IR (thin film, NaCl) 2957, 2929, 2857, 1753, 1714, 1645, 1442, 1359, 1327, 1291, 1257, 1209, 1177, 1028, 856, 836, 774, 680 cm-1; HRMS (FAB+) m/z calc’d C25H39O4Si [M+H]+: 431.2612, found; 431.2643; [a]D23 –64.5 (c 0.39, CHCl3). 354 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A TBSO O TBSO TBSO DBU O THF, 0 °C H O 450 >99% yield 1:1.8 dr O OH H + O H OH O O 451 452 (2R,2a1S,6R,8R,8aS,10aS)-2-((tert-butyldimethylsilyl)oxy)-8-hydroxy-2,8-dimethyl6-(prop-1-en-2-yl)-1,2,2a1,5,6,7,8,10a-octahydro-9H-benzo[6,7]indeno[1,7-bc]furan9-one (451) and (2R,2a1S,6R,8S,8aS,10aS)-2-((tert-butyldimethylsilyl)oxy)-8- hydroxy-2,8-dimethyl-6-(prop-1-en-2-yl)-1,2,2a1,5,6,7,8,10a-octahydro-9Hbenzo[6,7]indeno[1,7-bc]furan-9-one (452): Tricycle XXX (3 mg, 7.2 µmol, 1 equiv) in THF (0.2 mL) had DBU (1.7 µL, 7.2 µmol, 1 equiv). After 5 min, the reaction was concentrated and directly purified by column chromatography (SiO2, 4:1 hexanes:EtOAc) to afford tetracycle 451 and 452 (1:1.8 dr, 3 mg, >99%) as an amorphous film (Rf = 0.48 452 and 0.34 451) 452: 1H NMR (400 MHz, CDCl3) d = 5.99 (dd, J = 5.7, 2.5 Hz, 1H), 5.83 (ddd, J = 5.8, 2.8, 1.1 Hz, 1H), 4.89 – 4.68 (m, 3H), 3.76–3.69 (m, 1H), 2.88–2.76 (m, 1H), 2.47 (dd, J = 13.7, 7.4 Hz, 1H), 2.39–2.27 (m, 2H), 2.27–2.04 (m, 1H), 1.86 (dd, J = 13.7, 3.9 Hz, 1H), 1.78 (dd, J = 1.5, 0.8 Hz, 3H), 1.71 (dt, J = 13.0, 2.6 Hz, 1H), 1.40 (d, J = 1.0 Hz, 3H), 1.25 (s, 3H), 0.89 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 176.6, 148.1, 142.2, 131.1, 123.2, 112.7, 110.2, 80.0, 79.7, 74.4, 56.7, 49.0, 42.0, 40.7, 40.0, 35.7, 29.9, 28.5, 25.9, 24.9, 20.6, 18.2, 14.3, -2.0, -2.2; IR (thin film, NaCl) 3523, 2925, 2856, 2759, 1461, 1372, 1292, 1257, 1153, 1065, 964, 833, 771, 732, 705, 655 cm1 ; HRMS (FAB+) m/z calc’d C25H42O4SiN [M+NH4]+ 448.2878, found: 448.2889; [a]D23 +4.12 (c 0.235, CHCl3). 355 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 451: 1H NMR (400 MHz, CDCl3) d = 5.86 (dd, J = 5.7, 2.6 Hz, 1H), 5.82 (ddd, J = 5.8, 2.7, 1.0 Hz, 1H), 4.89 (td, J = 7.2, 3.2 Hz, 1H), 4.80 (dq, J = 1.8, 0.9 Hz, 1H), 4.78 (q, J = 1.5 Hz, 1H), 3.47 (d, J = 7.4 Hz, 1H), 2.86–2.73 (m, 1H), 2.48–2.36 (m, 2H), 2.31 (ddd, J = 15.0, 4.4, 1.9 Hz, 1H), 2.20 (tt, J = 12.8, 3.8 Hz, 1H), 1.94 (dd, J = 14.0, 3.1 Hz, 1H), 1.78 (s, 3H), 1.66 (ddd, J = 12.0, 3.4, 1.9 Hz, 1H), 1.39 (d, J = 1.1 Hz, 3H), 1.29 (d, J = 0.8 Hz, 3H), 0.88 (d, J = 1.1 Hz, 9H), 0.12 (s, 3H), 0.08 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 177.3, 148.1, 142.1, 132.2, 121.3, 113.4, 110.1, 80.1, 80.0, 76.2, 57.8, 48.7, 42.7, 42.3, 41.3, 35.5, 29.2, 26.7, 25.9, 20.5, 18.2, -2.0, -2.3; IR (thin film, NaCl) 3462, 2956, 2928, 2856, 1739, 1643, 1450, 1375, 1293,1257, 1163, 1132, 1018, 837, 809, 773 cm-1; HRMS (FAB+) m/z calc’d C25H42O4SiN [M+NH4]+ 448.2878, found: 448.2890; [a]D23 –33.7 (c 0.1, CHCl3). O HO O 415, DIC, DMAP CH2Cl2, 0 °C CO2H O 73% yield 471 (1S,4R)-4-hydroxy-4-methyl-3-vinylcyclopent-2-en-1-yl O 437 (R)-7-oxo-5-(prop-1-en-2- yl)oct-2-ynoate (437): Diol 415 (18 mg, 0.13 mmol, 1 equiv), acid 471 (56 mg, 0.28 mmol 2.2 equiv), and DMAP (17 mg, 0.17 mmol, 1.1 equiv) were added to a solution of CH2Cl2 (1.4 mL, 0.09 M) and cooled to 0 °C. DIC (44 µL, 0.28 mmol, 2.2 equiv) was added dropwise and the reaction was allowed to stir for 1 h. Upon complete consumption of starting material (as determined by TLC analysis, 1:1 hexanes:EtOAc), the reaction was diluted with H2O (5 mL) and extracted with Et2O (3 x 5 mL). The combined organic layers 356 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 1:1 hexanes:EtOAc) to afford ester 437 (30 mg, 73%) as a colorless oil (Rf = 0.27); 1H NMR (400 MHz, CDCl3) d = 6.32 (ddt, J = 17.8, 11.3, 0.8 Hz, 1H), 5.85–5.75 (m, 2H), 5.54 (ddd, J = 7.1, 4.7, 2.5 Hz, 1H), 5.33 (dd, J = 11.3, 1.6 Hz, 1H), 4.90–4.82 (m, 1H), 4.80 (q, J = 0.9 Hz, 1H), 2.86 (p, J = 6.6 Hz, 1H), 2.74–2.59 (m, 3H), 2.55–2.41 (m, 2H), 2.16 (s, 3H), 2.06 (dd, J = 14.3, 4.4 Hz, 1H), 1.73 (dd, J = 1.4, 0.8 Hz, 3H), 1.44 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 207.1, 153.5, 151.9, 145.2, 129.0, 126.1, 119.6, 112.5, 87.5, 81.1, 77.4, 74.8, 48.9, 46.4, 39.7, 30.6, 26.8, 23.2, 20.7; IR (thin film, NaCl) 3462, 2969, 2926, 2233, 1704, 1422, 1249, 1163, 1071, 944, 751; HRMS (ESI) m/z calc’d C19H26O5 [M+H2O]+: 334.1775, found: 334.1785; [a]D23 –65.9 (c 0.18, CHCl3). HO O HO O xylenes 140 °C O O O 437 79% yield H O 453 (2a1S,6R,7aS)-6-hydroxy-6-methyl-3-((R)-4-oxo-2-(prop-1-en-2-yl)pentyl)-4,6,7,7atetrahydroindeno[1,7-bc]furan-2(2a1H)-one (453): Ester 437 (100 mg, 0.32 mmol) was transferred to a Schlenk bomb with xylenes (32 mL, 0.01 M). The Schlenk was the rigorously degassed by standard freeze-pump-thaw technique and upon reaching ambient temperature (23 °C) the flask was sealed and heat to 140 °C. The reaction was allowed to stir at this temperature of 2 h at which time complete consumption of starting material was observed (as determined by TLC analysis, 1:1 hexanes:EtOAc). The reaction was allowed to cool to room temperature and was directly purified by column chromatography (SiO2, 100% hexanes then 1:1 hexanes:EtOAc) to furnish tricycle 453 (79 mg, 79%) as a white 357 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A amorphous solid (Rf = 0.27); 1H NMR (400 MHz, CDCl3) d = δ 5.84 (dt, J = 6.4, 2.3 Hz, 1H), 5.02–4.91 (m, 1H), 4.75–4.69 (m, 1H), 4.67 (d, J = 1.9 Hz, 1H), 3.26 (t, J = 9.6 Hz, 1H), 3.12–2.98 (m, 2H), 2.97–2.87 (m, 1H), 2.74 (ddt, J = 18.2, 10.1, 1.6 Hz, 1H), 2.59 (dd, J = 6.7, 4.1 Hz, 2H), 2.57–2.44 (m, 2H), 2.11 (s, 3H), 1.69 (d, J = 1.3 Hz, 3H), 1.64 (dd, J = 12.8, 8.0 Hz, 1H), 1.40 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 207.9, 168.4, 156.5, 151.6, 146.9, 125.2, 116.6, 112.0, 80.0, 75.4, 49.7, 47.2, 45.6, 41.1, 36.2, 35.4, 30.7, 26.7, 19.6; IR (thin film, NaCl) 3440, 2968, 1746, 1713, 1644, 1442, 1418, 1359, 1289, 1213, 1117, 1042, 1021, 995, 973, 913, 810, 732; HRMS (ESI) m/z calc’d C19H25O4 [M+H]+: 317.1747, found: 317.1733; [a]D23 –99.1 (c 0.375, CHCl3). O HO O O HO VO(acac)2 O TBHP, benzene H O O 453 91% yield H O 454 (1aR,1a1S,2R,3aS,7aS)-2-hydroxy-2-methyl-6-((R)-4-oxo-2-(prop-1-en-2-yl)pentyl)1a1,2,3,3a,7,7a-hexahydro-5H-oxireno[2',3':3a,4]indeno[1,7-bc]furan-5-one (454): To a pale yellow stirred solution of diene 453 (80 mg, 0.25 mmol, 1.0 equiv) in a round-bottom flask in benzene (8.4 mL, 0.044M) and CH2Cl2 (0.2 mL, 1 M) was added VO(acac)2 (6.7 mg, 0.025 mmol, 0.1 equiv). After 15 minutes, to this dark green solution was added tbutyl hydroperoxide (TBHP, 76 µL, 0.38 mmol, 1.5 equiv) as a 5 M solution in decane dropwise causing the reaction to immediately become deep ruby red. After 1 hour, the reaction had lost all red color and became pale yellow, and complete consumption of starting material was observed (as determined by TLC analysis, 1:1 hexanes:EtOAc). The crude reaction was directly purified by column chromatography (SiO2, 100% hexanes then 1:1 hexanes:EtOAc) to furnish epoxide 454 (76.3 mg, 91%) as a white amorphous solid 358 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A (Rf = 0.11); 1H NMR (400 MHz, C6D6) d 4.83 (q, J = 0.9 Hz, 1H), 4.75 (t, J = 1.6 Hz, 1H), 4.08 (ddd, J = 8.5, 7.4, 6.3 Hz, 1H), 3.38–3.31 (m, 1H), 3.05 (d, J = 3.4 Hz, 1H), 2.90 (dq, J = 9.3, 6.3 Hz, 1H), 2.41 (dd, J = 17.0, 6.8 Hz, 3H), 2.29–2.20 (m, 3H), 2.11 (ddd, J = 12.7, 5.4, 1.9 Hz, 1H), 2.05 (dd, J = 13.5, 7.5 Hz, 1H), 1.86 (dd, J = 16.7, 2.4 Hz, 1H), 1.82–1.74 (m, 1H), 1.70 (s, 3H), 1.63 (t, J = 1.2 Hz, 3H), 0.99 (s, 3H); 13C NMR (101 MHz, C6D6) d = 206.0, 168.9, 149.6, 147.7, 120.8, 111.5, 76.3, 73.3, 69.5, 51.6, 50.2, 47.0, 44.5, 41.0, 37.6, 36.0, 30.2, 22.4, 20.0; IR (thin film, NaCl) 3469, 2933, 1746, 1711, m1645, 1360, 1294, 1200, 1114, 1029, 967, 792 cm,-1; HRMS (ESI) m/z calc’d C19H25O5 [M+H]+: 333.1697, found: 333.1703; [a]D23 –88.9 (c 0.375, CHCl3). O O HO H HO OH O TiCp*2Cl2, Zn° O H2O, THF, –78 °C H 92% yield O H O O 454 455 (2a1S,5S,5aR,6R,7aS)-5,6-dihydroxy-6-methyl-3-((R)-4-oxo-2-(prop-1-en-2yl)pentyl)-4,5,5a,6,7,7a-hexahydroindeno[1,7-bc]furan-2(2a1H)-one (455): Preparation of a 0.50 M Stock Solution: of Titanocene Monochloride (Cp2TiCl): Into a thoroughly flame-dried Schlenk tube under an overpressure of argon was charged with zinc(0) dust (647 mg, 9.90 mmol, 3.00 equiv) and titanocene dichloride (Cp2TiCl2, 822 mg, 3.30 mmol, 1.00 equiv). The flask was then evacuated and back filled with argon (3 x 5 minute cycles). To the reaction vessel was then added THF (6.6 mL). After 1.5 h, the bright red reaction mixture had become dark green and stirring was halted. After 30 minutes, the supernatant was used as a 0.50 M stock solution of Cp2TiCl. A stirred solution of epoxide 454 (15 mg, 0.045 mmol, 1.0 equiv) in THF (1.5 mL, 0.03 M). The homogeneous reaction mixture was then cooled to –78 °C followed by the Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 359 addition of H2O (62 µL, 3.46 mmol, 76.9 equiv). After stirring for 5 minutes, Cp2TiCl (0.87 mmol, 0.50 M in THF, 19.2 equiv) was added dropwise. After 2 h, was allowed to warm to ambient temperature (23 °C). After an additional 12 h, the complete consumption of starting material was observed (as determined by TLC 3:1 EtOAc:hexanes). The reaction was quenched by the addition of saturated NaH2PO4 (1.0 mL) and brine (1.0 mL), sparged with compressed air for 5 minutes, and allowed to stir for an additional 15 minutes. The reaction mixture was then filtered through a Celite® plug, washing with H2O and EtOAc. The biphasic mixture was separated and the aqueous layer was extracted with EtOAc (3 X 3 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 3:1 EtOAc:hexanes), furnishing diol 455 (14 mg, 92% yield) as a white amorphous solid (Rf = 0.22); 1H NMR (400 MHz, CDCl3) d = 4.90 (ddd, J = 8.2, 6.6, 4.1 Hz, 1H), 4.80 (dt, J = 1.7, 0.8 Hz, 1H), 4.76 (p, J = 1.5 Hz, 1H), 4.69 (dt, J = 7.8, 3.2 Hz, 1H), 3.35–3.25 (m, 1H), 3.05 (ddd, J = 9.9, 8.0, 2.0 Hz, 1H), 2.94 (dq, J = 9.2, 6.5 Hz, 1H), 2.67–2.49 (m, 3H), 2.41–2.29 (m, 2H), 2.14–1.98 (m, 6H), 1.75 (dd, J = 1.5, 0.8 Hz, 3H), 1.43 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 208.3, 169.7, 151.7, 147.8, 124.9, 111.5, 81.7, 79.2, 68.5, 49.6, 48.5, 47.2, 44.4, 41.3, 40.6, 37.7, 30.8, 28.8, 20.1; IR (thin film, NaCl) 3384, 2966, 1738, 1666, 1420, 1359, 1304, 1222, 1200, 1145, 1105, 1040, 1020, 910, 733 cm-1; HRMS (ESI) m/z calc’d C19H27O5 [M+H]+: 335.1853, found: 335.1844; [a]D23 –15.4 (c 0.205, CHCl3). 360 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A HO HO 1. LiOH, THF:H2O 2. DIC, DMAP, 415 CH2Cl2, 0 °C MeO O 460 xylenes 140 °C O O 458 84% yield over 3 steps O H O 461 (2a1S,6R,7aS)-6-hydroxy-6-methyl-3-(pent-4-yn-1-yl)-4,6,7,7a-tetrahydroindeno[1,7bc]furan-2(2a1H)-one (461): Ester 460 was saponified under the same conditions reported above for ester 448. A stirred solution of Diol 415 (250 mg, 1.8 mmol, 1 equiv), octa-2,7-diynoic acid (435 mg, 3.2 mmol, 1.8 equiv), and DMAP (21.8 mg, 0.18 mmol, 0.1 equiv) in CH2Cl2 (18 mL, 0.1 M) and THF (10 mL, 0.18 M) was cooled to 0 °C. DIC (0.50 mL, 3.2 mmol, 1.8 equiv) was added dropwise via syringe and the resultant solution was allowed to stir for 2 h. Upon complete consumption of starting material (as determined by TLC analysis, 4:1 hexanes:EtOAc), the reaction was diluted with H2O (20 mL) and extracted with Et2O (3 x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 4:1 hexanes:EtOAc) to afford a mixture of triphenylphosphine oxide and ester 458 which is used directly in the next reaction. Ester 458 can be further purified by another column of the same eluent to obtain pure ester 458 (Rf = 0.22); 1H NMR (400 MHz, CDCl3) d = 6.32 (ddt, J = 17.8, 11.3, 0.8 Hz, 1H), 5.82 (dd, J = 2.3, 0.8 Hz, 1H), 5.81–5.75 (m, 1H), 5.55 (dddd, J = 7.4, 4.4, 2.3, 0.7 Hz, 1H), 5.33 (dd, J = 11.3, 1.5 Hz, 1H), 2.64 (dd, J = 14.3, 7.3 Hz, 1H), 2.48 (t, J = 7.1 Hz, 2H), 2.32 (td, J = 6.9, 2.7 Hz, 2H), 2.06 (dd, J = 14.3, 4.4 Hz, 1H), 1.98 (t, J = 2.6 Hz, 1H), 1.80 (p, J = 7.0 Hz, 2H), 1.44 (s, 3H); 13C NMR (101 MHz, CDCl3) d =. 153.5, 151.9, 128.9, 126.0, 119.6, 88.7, 82.8, 81.1, 77.1, 73.7, 69.6, 48.9, 26.8, 26.5, 17.8, 17.7; IR (thin film, NaCl) 3295, Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 361 2972, 2236, 1703, 1432, 1252, 1073, 990, 950, 872, 752, 641 cm-1; HRMS (ESI) m/z calc’d C16H22NO3 [M+NH4]+: 276.1595, found: 276.1581l; [a]D23 –155.1 (c 0.57, CHCl3). Crude ester 458 (460 mg, 1.78 mmol) was transferred to a Schlenk bomb with xylenes (178 mL, 0.01 M). The Schlenk was the rigorously degassed by standard freezepump-thaw technique and upon reaching ambient temperature (23 °C) the flask was sealed and heat to 140 °C. The reaction was allowed to stir at this temperature of 2 h at which time complete consumption of starting material was observed (as determined by TLC analysis, 1:1 hexanes:EtOAc). The reaction was allowed to cool to room temperature and was directly purified by column chromatography (SiO2, 100% hexanes then 1:1 hexanes:EtOAc) to furnish tricycle 461 (560 mg, 84% over 3 steps) as a pale yellow solid (Rf = 0.25); 1H NMR (400 MHz, CDCl3) d = 5.85 (ddd, J = 6.3, 2.9, 1.9 Hz, 1H), 4.97 (ddd, J = 9.0, 7.9, 7.1 Hz, 1H), 3.30 (ttd, J = 9.2, 1.9, 1.0 Hz, 1H), 3.11–2.96 (m, 2H), 2.75 (ddt, J = 18.4, 10.1, 1.5 Hz, 1H), 2.62–2.54 (m, 1H), 2.51 (ddd, J = 12.8, 7.1, 0.8 Hz, 1H), 2.22 (tt, J = 7.1, 2.5 Hz, 2H), 1.98 (t, J = 2.6 Hz, 1H), 1.78 (td, J = 6.6, 5.5, 3.3 Hz, 1H), 1.76– 1.63 (m, 3H), 1.41 (d, J = 1.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) d =. 168.2, 157.1, 152.1, 124.4, 116.4, 84.0, 80.0, 75.4, 69.1, 49.7, 45.5, 35.2, 31.0, 27.2, 26.8, 18.4; IR (thin film, NaCl) 3425, 3288, 2971, 1738, 1643, 1439, 1326, 1288, 1256, 1218, 1194, 1117, 1041, 996, 967, 817, 742, 638 cm-1; HRMS (ESI) m/z calc’d C16H19O3 [M+H]+: 259.1329, found: 259.1323; [a]D23 –120.3 (c 0.635, CHCl3). Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A HO 362 O HO VO(acac)2 O TBHP, benzene H O 461 77% yield O H O 462 (1aR,1a1S,2R,3aS,7aS)-2-hydroxy-2-methyl-6-(pent-4-yn-1-yl)-1a1,2,3,3a,7,7ahexahydro-5H-oxireno[2',3':3a,4]indeno[1,7-bc]furan-5-one (462): To a pale yellow stirred solution of diene 461 (376 mg, 1.5 mmol, 1.0 equiv) in a round-bottom flask in benzene (49 mL, 0.03M) was added VO(acac)2 (29 mg, 0.11 mmol, 0.075 equiv). After 15 minutes, to this dark green solution was added t-butyl hydroperoxide (TBHP, 0.58 mL, 2.9 mmol, 2.0 equiv) as a 5 M solution in decane dropwise causing the reaction to immediately become deep ruby red. After 2 hours, the reaction had lost all red color and become pale yellow and complete consumption of starting material was observed (as determined by TLC analysis, 3:7 hexanes:EtOAc). The crude reaction was directly purified by column chromatography (SiO2, 100% hexanes then 3:7 hexanes:EtOAc) to furnish epoxide 462 (307 mg, 77%) as a white amorphous solid (Rf = 0.3); 1H NMR (400 MHz, CDCl3) d = 4.83 (ddd, J = 8.5, 7.4, 6.3 Hz, 1H), 3.81 (dd, J = 3.3, 0.8 Hz, 1H), 3.28 (d, J = 8.1 Hz, 1H), 2.88 (dd, J = 16.7, 3.4 Hz, 1H), 2.84–2.68 (m, 2H), 2.59 (ddd, J = 13.6, 7.4, 0.6 Hz, 1H), 2.55–2.45 (m, 2H), 2.35–2.12 (m, 2H), 2.08–1.99 (m, 1H), 1.98 (t, J = 2.6 Hz, 1H), 1.81– 1.62 (m, 2H), 1.44 (d, J = 1.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) d = 169.1, 150.9, 119.9, 84.1, 76.6, 73.6, 70.0, 69.0, 51.8, 50.1, 44.8, 35.7, 31.6, 26.9, 22.7, 18.3; IR (thin film, NaCl) 3529, 3270, 2976, 2938, 2116, 1742, 1649, 1454, 1422, 1391, 1348, 1324, 1296, 1268, 1195, 1113, 1093, 1030, 964, 923, 899, 795, 756, 733, 678 cm-1; HRMS (ESI) m/z calc’d C16H19O4 [M+H]+: 275.1278, found: 275.1268; [a]D23 –179.9 (c 0.39, CHCl3). Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A O HO H HO 363 OH TiCp2Cl2, Zn° O H2O, THF, –78 °C H O 462 96% yield O H O 463 (2a1S,5S,5aR,6R,7aS)-5,6-dihydroxy-6-methyl-3-(pent-4-yn-1-yl)-4,5,5a,6,7,7ahexahydroindeno[1,7-bc]furan-2(2a1H)-one (463): A stirred solution of epoxide 462 (278 mg, 1.01 mmol, 1.0 equiv) in THF (34 mL, 0.03 M). The homogeneous reaction mixture was then cooled to –78 °C followed by the addition of H2O (0.9 mL, 50.0 mmol, 50 equiv). After stirring for 5 minutes, Cp2TiCl (11.1 mmol, 0.50 M in THF, 11 equiv) was added dropwise. After 2 h, was allowed to slowly warm to ambient temperature (23 °C). After an additional 12 h, the complete consumption of starting material was observed (as determined by TLC 3:1 EtOAc:hexanes). The reaction was quenched by the addition of saturated NaH2PO4 (20 mL) and brine (10 mL), sparged with compressed air for 5 minutes, and allowed to stir for an additional 15 minutes. The reaction mixture was then filtered through a Celite® plug, washing with H2O and EtOAc. The biphasic mixture was separated and the aqueous layer was extracted with EtOAc (3 X 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 3:1 EtOAc:hexanes), furnishing diol 463 (270 mg, 96% yield) as a viscous colorless oil (Rf = 0.3); 1H NMR (400 MHz, CDCl3) d = 4.91 (ddd, J = 8.1, 6.7, 3.1 Hz, 1H), 4.69 (ddd, J = 8.1, 3.5, 2.8 Hz, 1H), 3.43 (s, 2H), 3.08 (ddd, J = 9.7, 7.9, 2.0 Hz, 1H), 2.98–2.88 (m, 1H), 2.70 (dtd, J = 12.6, 7.4, 1.8 Hz, 1H), 2.58 (dd, J = 14.9, 2.8 Hz, 1H), 2.39 (dd, J = 9.4, 8.0 Hz, 1H), 2.23 (qd, J = 7.2, 2.6 Hz, 2H), 2.13 (dd, J = 14.4, 3.1 Hz, 1H), 2.10–2.03 (m, 1H), 1.99 (dd, J = 14.3, 6.6 Hz, 1H), 1.95 (t, J = 2.6 Hz, 1H), 1.72 (p, J = 7.4 Hz, 2H), 1.44 (s, 3H); 13C NMR (101 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 364 MHz, CDCl3) d = 169.9, 152.5, 124.3, 84.4, 82.0, 79.5, 68.8, 68.3, 49.8, 48.6, 44.6, 41.4, 31.9, 28.6, 26.5, 18.5; IR (thin film) 3302, 2966, 2930, 2251, 1738, 1731, 1668, 1454, 1427, 1358, 1336, 1305, 1278, 1248, 1222, 1198, 1144, 1119, 1104, 1069, 1045, 1018, 989, 926, 912, 874, 853, 768, 737, 650; HRMS (ESI) m/z calc’d C16H21O4 [M+H]+: 277.1434, found: 277.1430; [a]D23 –16.0 (c 0.72, CHCl3). H HO OH H HO O DMP, NaHCO3 O CH2Cl2 H O 463 47% yield O H O 464 (2aS,2a1S,5aS,6R,7aS)-6-hydroxy-6-methyl-3-(pent-4-yn-1-yl)-2a,2a1,5a,6,7,7ahexahydroindeno[1,7-bc]furan-2,5-dione (464): Diol 463 (270 mg, 0.98 mmol, 1.0 equiv) in CH2Cl2 (27 mL, 0.036 M) was added NaHCO3 (330 mg, 3.9 mmol, 4 equiv) and DMP (538 mg, 1.3 mmol, 1.3 equiv) at ambient temperature (23 °C) with stirring. The reaction vessel was then sealed and stirred for 3 h. Each subsequent hour, more DMP was added (1 equiv) until complete consumption of starting material (as determined by TLC analysis, 1:3 hexanes:EtOAc). The reaction was then quenched by the addition of saturated NaS2O3 (30 mL) and saturated NaHCO3 (20 mL). After stirring for 10 minutes, the reaction mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organics were then dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then purified by column chromatography (SiO2, 1:3 hexanes:EtOAc) to afford enone 464 (117 mg, 47%) as a colorless viscous oil (Rf = 0.6); 1H NMR (400 MHz, CDCl3) d = 6.07 (q, J = 1.5 Hz, 1H), 5.12 (dd, J = 7.1, 5.4 Hz, 1H), 3.63 (dddd, J = 10.9, 10.2, 7.1, 0.6 Hz, 1H), 3.51–3.45 (m, 1H), 2.90–2.78 (m, 1H), 2.78–2.66 (m, 1H), 2.53 (d, J = 10.2 Hz, 1H), 2.33 (d, J = 15.0 Hz, 1H), 2.27 (tdd, J = 7.1, 6.1, 2.7 Hz, 2H), 1.99 (t, J = 2.6 Hz, 1H), 1.91 (dd, J = 15.0, 365 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 5.5 Hz, 1H), 1.87–1.74 (m, 2H), 1.51 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 196.0, 173.5, 157.6, 127.5, 83.6, 82.8, 82.5, 69.4, 55.2, 47.4, 42.5, 42.2, 34.7, 26.4, 25.6, 18.2; IR (thin film, NaCl) 3442, 3282, 2966, 1757, 1649, 1375, 1289, 1255, 1214, 1179, 1104, 1033, 1017, 993, 938; HRMS (ESI) m/z calc’d C16H19O4 [M+H]+: 275.1278, found: 275.1269; [a]D23 –195 (c 0.32, CHCl3). H HO O O HSiMe2Ph [RuCp*(MeCN)3]PF6 H HO CH2Cl2, 0 to 23 °C H O 464 84% yield O O SIMe2Ph H O 457 (2aS,2a1S,5aS,6R,7aS)-3-(4-(dimethyl(phenyl)silyl)pent-4-en-1-yl)-6-hydroxy-6methyl-2a,2a1,5a,6,7,7a-hexahydroindeno[1,7-bc]furan-2,5-dione (457): Alkyne 464 (28 mg, 0.1 mmol, 1 equiv) and dimethylphenylsilane (18 µL, 0.12 mmol, 1.2 equiv) was dissolved in CH2Cl2 (0.5 mL, 0.2 M) and sparged with Ar for 5 min. A stock solution of [RuCp*(MeCN)3]PF6 (0.5 mg, 1mg/mL, 0.01 equiv) prepared in the gloved box and was added to the reaction. The reaction was allowed to stir for 15 min, at which time complete consumption of starting material was observed (as determined by TLC analysis, 1:3 hexanes:EtOAc). The solution was then concentrated and directly purified by column chromatography (SiO2, 1:3 hexanes:EtOAc) to afford vinyl silane 457 (19 mg, 64%) as a colorless amorphous solid (Rf = 0.55); 1H NMR (400 MHz, CDCl3) d = 7.60–7.48 (m, 2H), 7.44–7.30 (m, 3H), 5.94 (q, J = 1.4 Hz, 1H), 5.70 (dt, J = 2.9, 1.5 Hz, 1H), 5.46 (dt, J = 2.7, 1.0 Hz, 1H), 5.07 (dd, J = 7.2, 5.4 Hz, 1H), 3.48 (dddd, J = 10.9, 10.2, 7.1, 0.6 Hz, 1H), 3.16 (dd, J = 11.1, 1.5 Hz, 1H), 2.66–2.50 (m, 2H), 2.48 (d, J = 10.2 Hz, 1H), 2.30 (d, J = 15.0 Hz, 1H), 2.24–2.08 (m, 2H), 1.89 (dd, J = 15.0, 5.5 Hz, 1H), 1.67–1.51 (m, 2H), 1.49 (s, 3H), 0.37 (s, 6H); 13C NMR (101 MHz, CDCl3) d = 196.0, 173.4, 158.7, 149.7, 366 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 138.4, 134.1, 129.1, 128.0, 127.3, 126.7, 82.7, 82.4, 55.2, 47.4, 42.2, 41.9, 35.7, 35.4, 26.5, 26.1, -2.8, -2.9; IR (thin film, NaCl) 3450, 2958, 1759, 1650, 1378, 1290, 1248, 1173, 1107, 992, 818 cm-1; HRMS (ESI) m/z calc’d C23H31O4Si [M+H]+: 411.1986, found: 411.1972; [a]D23 –115.3 (c 0.25, CHCl3). H HO O SIMe2Ph H HO O H hν O SiMe2Ph benzene H >99% yield 1:2 dr O 457 O H H HO O H + SiMe2Ph O H O O 465 466 (2aS,2a1S,4R,4aS,5aR,6aS,9aS,9bS)-6a-(dimethyl(phenyl)silyl)-4-hydroxy-4methyldodecahydrocyclopenta[2',3']cyclobuta[1',2':5,6]indeno[1,7-bc]furan-1,5dione (465) and (2aS,2a1S,4R,4aS,5aR,6aR,9aR,9bS)-6a-(dimethyl(phenyl)silyl)-4hydroxy-4-methyldodecahydrocyclopenta[2',3']cyclobuta[1',2':5,6]indeno[1,7bc]furan-1,5-dione (466): Enone 457 (19 mg, 0.0465 mmol, 1 equiv) in a 20 mL vial was dissolved in benzene (4.65 mL, 0.01 M) and was sparged with Ar for 10 min. The reaction vessel was sealed and irradiated with UVB light. After 2 hours complete consumption of starting material was observed (as determined by TLC analysis, 1:1 hexanes:EtOAc) and was directly purified by column chromatography (SiO2, 100% hexanes then 1:1 hexanes:EtOAc) to afford a 2:1 mixture of pentacycle 465 and 466 (19 mg, >99%) as a colorless amorphous solid which crystalizes in benzene (Rf = 0.85, 465, and 0.65, 366). 465: 1H NMR (400 MHz, CDCl3) d = 7.66–7.53 (m, 2H), 7.45–7.37 (m, 3H), 4.59 (ddd, J = 6.6, 5.6, 2.0 Hz, 1H), 3.02 (s, 1H), 2.92 (ddd, J = 11.1, 9.8, 6.7 Hz, 1H), 2.74–2.66 (m, 2H), 2.41–2.33 (m, 2H), 2.31–2.21 (m, 1H), 2.17 (s, 1H), 2.13 (dd, J = 14.6, 2.0 Hz, 1H), 2.03–1.82 (m, 4H), 1.81–1.72 (m, 1H), 1.66–1.59 (m, 1H), 1.18 (s, 3H), 0.41 (s, 3H), 0.30 (s, 3H); 13C NMR (101 MHz, CDCl3) d =215.6, 174.9, 138.3, 134.4, 129.9, 128.5, 80.9, 367 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 80.9, 55.4, 53.3, 48.4, 45.8, 44.5, 43.4, 39.7, 39.0, 38.7, 29.0, 28.6, 24.5, -2.9, -3.9; IR (thin film, NaCl) 3416, 2957, 1759, 1673, 1359, 1107, 731 cm-1; HRMS (ESI) m/z calc’d C23H31O4Si [M+H]+: 411.1986, found: 411.1976; [a]D23 –17.7 (c 0.3, CHCl3). 466: 1H NMR (400 MHz, CDCl3) d = 7.57–7.47 (m, 2H), 7.37–7.28 (m, 3H), 4.91 (dd, J = 6.1, 4.5 Hz, 1H), 3.60–3.52 (m, 1H), 3.52–3.48 (m, 1H), 2.94 (dd, J = 9.0, 0.7 Hz, 1H), 2.56 (d, J = 10.6 Hz, 1H), 2.36 (d, J = 15.2 Hz, 1H), 2.21–2.14 (m, 2H), 2.08–2.00 (m, 1H), 1.96–1.88 (m, 2H), 1.88–1.76 (m, 1H), 1.73–1.59 (m, 2H), 1.45 (s, 3H), 1.32 (dd, J = 11.9, 6.6 Hz, 1H), 0.55 (s, 3H), 0.52 (s, 3H); 13C NMR (101 MHz, CDCl3) d =205.7, 174.8, 141.4, 134.2, 128.5, 127.6, 82.1, 81.4, 60.6, 60.1, 51.3, 50.1, 48.6, 47.7, 43.9, 39.9, 37.1, 27.6, 27.1, 24.5, -2.1, -4.7; IR (thin film, NaCl) 3393, 2949, 1769, 1687, 1373, 1242, 1209, 1147, 1104, 1089, 826, 783, 733; HRMS (ESI) m/z calc’d C23H31O4Si [M+H]+: 411.1986, found: 411.1972; [a]D23 –19.7 (c 0.35, CHCl3). H HO O H SiMe2Ph O H O H HO O H AcOOH, Hg(OAc)2 OH AcOH, 23 °C 30% yield 466 O H O 456 (2aS,2a1S,4R,4aS,5aR,6aR,9aR,9bS)-4,6a-dihydroxy-4methyldodecahydrocyclopenta[2',3']cyclobuta[1',2':5,6]indeno[1,7-bc]furan-1,5dione (456): To a solution of lactone 466 (25 mg, 0.061 mmol) in 35% AcOOH-AcOH (3.05 mL, 0.02 M) at 23 °C was added Hg(OAc)2 (92 mg, 0.29 mmol, 4.8 equiv), and the clear solution was stirred for 1 h at which time complete consumption of starting material was observed (as determined by TLC analysis, 1:3 hexanes:EtOAc). The reaction mixture was diluted with Et2O (5 mL), washed sequentially with 10% aq Na2S2O3 (7 mL), H2O (7 mL), saturated solution of NaHCO3 (7 mL), and brine (7 mL), dried over MgSO4, filtered, 368 Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 1:3 hexanes:EtOAc) to afford diol 456 (6 mg, 30%) as a white amorphous powder (Rf = 0.20) 1H NMR (400 MHz, CDCl3) d = 6.16 (s, 1H), 5.13 (dd, J = 5.9, 4.6 Hz, 1H), 3.90 (t, J = 9.5 Hz, 1H), 3.57–3.43 (m, 1H), 3.21 (dd, J = 9.0, 0.8 Hz, 1H), 2.58 (d, J = 10.6 Hz, 1H), 2.47–2.34 (m, 2H), 2.07–1.94 (m, 2H), 1.94–1.87 (m, 1H), 1.87–1.78 (m, 1H), 1.78–1.68 (m, 3H), 1.48 (s, 3H), 1.25 (d, J = 2.5 Hz, 1H); 13C NMR (101 MHz, CDCl3) d =205.5, 179.1, 88.5, 86.1, 81.5, 60.8, 55.4, 52.3, 49.4, 47.7, 47.1, 38.1, 36.4, 34.5, 27.8, 23.1; IR (thin film, NaCl) 3421, 2972, 2923, 1741, 1686, 1448, 1400, 1377, 1305, 1276, 1211, 1161, 1112, 1088, 1069, 1010, 921, 850, 813, 777, 733, 719; HRMS (ESI) m/z calc’d C16H21O5 [M+H]+: 293.1384, found: 293.1372; [a]D23 –40.4 (c 0.13, CHCl3). H HO O H AgOTf (40 mol %) 1,4 phenanthroline H HO O O OH O Cl H t-BuOCl, MeCN H O 456 49% yield O H O 468 (2aS,2a1S,4R,4aS,5aR,7R,10aR,10bS)-7-chloro-4-hydroxy-4-methyldodecahydro7,10a-epoxycyclohepta[5,6]indeno[1,7-bc]furan-1,5-dione (468): Diol 456 (10 mg, 0.034 mmol, 1 equiv), AgOTf (1.2 mg, 0.012 mmol, 0.4 equiv), and 1,10-phenanthroline (4.8 mg, 0.024 mmol, 0.8 equiv) were placed in a round-bottom flask and dissolved in MeCN (1 mL, 0.034 M) followed by the addition of t-BuOCl (7.8 µL, 0.068 mmol, 2 equiv). The reaction mixture was stirred at ambient temperature (23 °C) for 6 h. The reaction was the quenched with saturated solution of Na2S2O3 and extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 1:3 hexanes:EtOAc) to obtain furan 468 (5.4 mg, 49%) as a white amorphous solid Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 369 which can be crystalized in CHCl3 (Rf = 0.26); 1H NMR (400 MHz, CDCl3) d = 5.02 (dd, J = 5.9, 4.5 Hz, 1H), 3.79–3.66 (m, 1H), 3.42 (dddd, J = 10.3, 9.5, 5.9, 0.6 Hz, 1H), 3.34 (dd, J = 9.5, 0.7 Hz, 1H), 2.88 (ddd, J = 13.8, 7.4, 0.9 Hz, 1H), 2.71 (d, J = 10.4 Hz, 1H), 2.42 (d, J = 15.4 Hz, 1H), 2.35 (ddd, J = 13.8, 11.6, 1.1 Hz, 1H), 2.29–2.09 (m, 1H), 2.07– 1.96 (m, 2H), 1.75–1.64 (m, 3H), 1.49 (s, 3H), 1.46–1.34 (m, 1H); 13C NMR (101 MHz, CDCl3) d =202.8, 172.0, 101.8, 85.2, 82.7, 82.3, 60.6, 56.4, 48.6, 47.5, 45.9, 40.1, 36.3, 33.1, 27.6, 18.9; IR (thin film, NaCl) 3472, 2921, 1766, 1713, 1359, 1243, 1214, 1171, 1126, 1093, 1000, 953, 905, 845, 759, 731; HRMS (ESI) m/z calc’d C16H20O5Cl [M+H]+: 327.0994, found: 327.0980; [a]D23 –43.3 (c 0.13, CHCl3). 4.15 NOTES & REFERENCES 1. Newman, D. J.; Cragg, G. M.; Snader, K. M. Nat Prod. Rep. 2000, 17, 215–234. 2. Dias, D. A.; Urban, S.; Roessner, U. Metabolites 2012, 2, 303–336. 3. Kamel, H. N.; Slattery, M. Pharmaceutical Biology 2005, 43, 253–269. 4. Missakian, M. G.; Burreson, B. J.; Scheuer, P. J. Tetrahedron 1975, 31, 2513–2515. 5. Zhang, P.-P.; Yan, Z.-M.; Li, Y.-H.; Gong, J.-X.; Yang, Z. J. Am. Chem. Soc. 2017, 139, 13989–13992. 6. González, M. A.; Ghosh, S.; Rivas, F.; Fischer, D.; Theodorakis, E. A. Tetrahedron Lett. 2004, 45, 5039–5041. 7. Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521–522. 8. Anderson, N. H.; Uh, H.-S. Synth. Commun. 1973, 3, 125–128. 9. Craig, II, R. A.; Roizen, J. L.; Smith, R. C.; Jones, A. C.; Virgil, S. C.; Stoltz, B. M. Chem. Sci. 2017, 8, 507–514. Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 10. 370 Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993. 11. (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140. (b) Gradillas, A.; PérezCastells, J. Angew. Chem. Int. Ed. 2006, 45, 6086–610. 12. Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004, 126, 10210–10211. 13. Brill, Z. G.; Grover, H. K.; Maimone, T. J. Science 2016, 27, 1078–1082. 14. Bauta, W.; Booth, J.; Bos, M. E.; DeLuca, M.; Diorazio, L.; Donohoe, T.; Magnus, N.; Magnus, P.; Mendoza, J.; Pye, P.; Tarrant, J.; Thom, S.; Ujjainwalla, F. Tetrahedron Lett. 1995, 36, 5327–5330. 15. Yusuke, I.; Isao, S.; Akio, Y. Bull Chem. Soc. Jpn. 2004, 77, 2033–2045. 16. Jiménez, T.; Campaña, A. G.; Bazdi, B.; Paradas, M.; Arráez-Román, D.; SeguraCarretero, A.; Fernández-Gutiérrez, A.; Oltra, J. E.; Robles, R.; Justicia, J.; Cuerva, J. M. Eur. J. Org. Chem. 2010, 4288–4295. 17. Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198–2200. 18. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639–666. 19. Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901–16910. 20. Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317–4353 21. Piers, E.; Wong, T.; Ellis, K. A. Can. J. Chem. 1992, 70, 2058–2064. 22. Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726–12727. 23. Hydrosilylation with triethoxysilane has been performed as well 24. Stoltz, B. M; Kano, T.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9044–9045. Chapter 4 – Progress Toward the Total Synthesis of Scabrolide A 25. 371 Preliminary results suggest that heat the solution to 60 °C allows for conversion to the desired product. 26. (a) Hiroshi, S.; Masahito, I.; Kazuhiro, K. Chem. Lett. 1987, 16, 1527–1530. (b) Renata, H.; Zhou, Q.; Dünstl, G.; Felding, J.; Merchant, R., R.; Yeh, C.-H.; Baran, P. S. J. Am. Chem. Soc. 2015, 137, 1330–1340. (c) Takasu, K.; Nagao, S.; Ihara, M. Tetrahedron Lett. 2005, 46, 1005–1008. 27. Huang, F.-Q., Sun J.-G.; Wang, Y.-W.; Dong, X.; Qi, L.-W.; Zhang, B. Org. Lett. 2016, 18, 684–687. 28. Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520. 29. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899–2899. Appendix 5 – Synthetic Summary of Chapter 4 372 APPENDIX 5 Synthetic Summary of Chapter 4: Progress Toward the Total Synthesis of Scabrolide A 373 Appendix 5 – Synthetic Summary of Chapter 4 Scheme A5.1. Synthetic Summary for Construction of Tricycle 434 O O O 1. H2SO4 THF:H2O, 65°C H2O2, NaOH O MeOH:H2O (+)-Carvone (417) HO 2. NaIO4, SiO2 DCM:H2O 0 °C 98% yield 418 H O 38% yield 2 steps 419 O O (MeO)NHMe•HCl Et3N, EDC•HCl MeO MeO N Me Ohira-Bestmann Reagent K2CO3, MeOH CH2Cl2, 0 °C to 23 °C 75% yield 82% yield H O 420 422 O OH HO MgBr O CH(OCH2CH3)3 MeCN, 23 °C 87% yield 83% yield ent•416 423 O HO 1. n-BuLi, CO2, THF, –78 °C 46% yield 2 steps O oxalic acid THF, –78 to 0 °C 2. 2,4,5 trichlorobenzoyl chloride 415, Et3N, DMAP, toluene, 23 °C N Me O HO O O xylenes 130 °C O O O 40% yield 430 H O 434 374 Appendix 5 – Synthetic Summary of Chapter 4 Scheme A5.2. Synthetic Summary for 2nd Generation Synthesis of Diol 415 1. HG II (0.1 mol %), neat then, NaH, THF, TBSCl TBSO O 68% yield 2 steps (–)-linalool (439) NaCN, TBAI (17 mol %) 440 CN TBSO 1:1 H2O:CH2Cl2 O 90% yield 1. NaBH4, CeCl3•7H2O MeOH, –78 °C 441 CN TBSO 2. TESCl, imidazole CH2Cl2, 23 °C O 72% yield Br CH2Cl2, 0 to 23 °C 2. RuCl2, t-BuOOH, Mg(OAc)2 CH2Cl2, H2), 0 °C HO TBSO Br2, Et3N OTES 91% yield 10:1 dr 2 steps 442 443 O H TBSO DIBAL Ph3PMeBr, KOt-Bu CH2Cl2, –78 °C THF, 23 °C 91% yield 68% yield OTES TBSO OTES 444 conditions a) TBAF (2.7 equiv), THF, 65 °C b) TBAF (1.1 equiv), THF, 23 °C 445 HO TBSO OH OH conditions a conditions b 81% yield 87% yield 415 446 375 Appendix 5 – Synthetic Summary of Chapter 4 Scheme A5.3 Synthetic Summary for Undesired Aldol Products 451 and 452 O O MeO O N Me Pd(OAc)2 (30 mol %) Ph3P (60 mol %) MeMgBr THF, –78 to 0 °C DMF:MeOH 1:1 CO:O2 (1 atm) 79% yield 72% yield ent•422 MeO 447 TBSO O 448 O TBSO O 1. LiOH, 1:1 THF:H2O xylenes 2. 446, DIC, DMAP CH2Cl2, 0 °C 140 °C O 57% yield 2 steps O O H O 82% yield 449 450 TBSO TBSO TBAF THF, 23 °C O >99% yield 1:1.8 dr + OH H O H OH O O 451 452 Scheme A5.4 Synthetic Summary for Late-Stage Functionalization of Diels–Alder Adduct 453 HO O HO O VO(acac)2 xylenes 140 °C O O 79% yield O 437 91% yield O 453 O O HO TBHP, benzene H H HO OH TiCp*2Cl2, Zn° O H2O, THF, –78 °C H O 454 92% yield O H O 455 O 376 Appendix 5 – Synthetic Summary of Chapter 4 Scheme A5.5 Synthetic Summary for Ring Expansion Model System 458 HO HO 1. LiOH, THF:H2O xylenes 2. 415, DIC, DMAP CH2Cl2, 0 °C MeO 140 °C O O 64% yield O 458 461 O HO TiCp2Cl2, Zn° TBHP, benzene H2O, THF, –78 °C O 77% yield H HO VO(acac)2 H O 96% yield O H O HSiMe2Ph [RuCp*(MeCN)3]PF6 H O O SIMe2Ph hν O 84% yield benzene H >99% yield 1:2 dr O 457 H H HO SiMe2Ph O H HO 464 HO 47% yield O CH2Cl2, 0 to 23 °C O CH2Cl2 H 463 O H OH DMP, NaHCO3 462 HO O 84% yield O 460 H O H + SiMe2Ph H O H O 465 466 AgOTf (40 mol %) 1,4 phenanthroline H HO Cl H O t-BuOCl, MeCN 49% yield O O H O 468 O H AcOOH, Hg(OAc)2 OH AcOH, 23 °C 30% yield O H HO O H O 456 Appendix 6 – Spectra Relevant to Chapter 4 377 APPENDIX 6 Spectra Relevant to Chapter 4: Progress Toward the Total Synthesis of Scabrolide A 8 MeO 422 N Me O 7 6 4 ppm 3 Figure A6.1. 1H NMR (500 MHz, CDCl3) of compound 422. 5 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 378 379 Appendix 6 – Spectra Relevant to Chapter 4 200 180 160 140 120 100 ppm 80 60 40 Figure A6.2. 13C NMR (126 MHz, CDCl3) of compound 422. 20 0 8 ent•416 O 7 5 4 ppm 3 2 Figure A6.3. 1H NMR (500 MHz, CDCl3) of compound ent•416. 6 1 0 Appendix 6 – Spectra Relevant to Chapter 4 380 381 Appendix 6 – Spectra Relevant to Chapter 4 200 180 160 140 120 100 ppm 80 60 40 Figure A6.4. 13C NMR (126 MHz, CDCl3) of compound ent•416. 20 0 8 423 O O 7 6 4 ppm 3 Figure A6.5. 1H NMR (400 MHz, CDCl3) of compound 423. 5 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 382 383 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.6. Infrared spectrum (Thin Film, NaCl) of compound 423. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.7. 13C NMR (101 MHz, CDCl3) of compound 423. 20 0 8 HO O O 430 7 O O 6 4 ppm 3 Figure A6.8. 1H NMR (400 MHz, CDCl3) of compound 430. 5 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 384 385 Appendix 6 – Spectra Relevant to Chapter 4 200 180 160 140 120 100 ppm 80 60 40 Figure A6.9. 13C NMR (101 MHz, CDCl3) of compound 430. 20 0 8 HO O O 432 7 O 5 4 ppm 3 Figure A6.10. 1H NMR (400 MHz, CDCl3) of compound 432. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 386 387 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.11. Infrared spectrum (Thin Film, NaCl) of compound 432. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.12. 13C NMR (101 MHz, CDCl3) of compound 432. 20 0 8 HO O H 434 O 7 O O 5 4 ppm 3 Figure A6.13. 1H NMR (400 MHz, CDCl3) of compound 434. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 388 389 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.14. Infrared spectrum (Thin Film, NaCl) of compound 434. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.15. 13C NMR (101 MHz, CDCl3) of compound 434. 20 0 8 TBSO 441 O Br 7 5 4 ppm 3 Figure A6.16. 1H NMR (400 MHz, CDCl3) of compound 441. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 390 391 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.17. Infrared spectrum (Thin Film, NaCl) of compound 441. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.18. 13C NMR (101 MHz, CDCl3) of compound 441. 20 0 8 O 442 TBSO CN 7 5 4 ppm 3 Figure A6.19. 1H NMR (400 MHz, CDCl3) of compound 442. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 392 393 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.20. Infrared spectrum (Thin Film, NaCl) of compound 442. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.21. 13C NMR (101 MHz, CDCl3) of compound 442. 20 0 8 OH 470 TBSO CN 7 5 4 ppm 3 Figure A6.22. 1H NMR (400 MHz, CDCl3) of compound 470. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 394 395 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.23. Infrared spectrum (Thin Film, NaCl) of compound 470. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.24. 13C NMR (101 MHz, CDCl3) of compound 470. 20 0 8 CN OTES 443 TBSO 7 5 4 ppm 3 Figure A6.25. 1H NMR (400 MHz, CDCl3) of compound 443. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 396 397 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.26. Infrared spectrum (Thin Film, NaCl) of compound 443. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.27. 13C NMR (101 MHz, CDCl3) of compound 443. 20 0 10 TBSO 444 9 OTES O H 8 6 5 ppm 4 3 Figure A6.28. 1H NMR (400 MHz, CDCl3) of compound 444. 7 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 398 399 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.29. Infrared spectrum (Thin Film, NaCl) of compound 444. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.30. 13C NMR (101 MHz, CDCl3) of compound 444. 20 0 8 TBSO 445 OTES 7 5 4 ppm 3 Figure A6.31. 1H NMR (400 MHz, CDCl3) of compound 445. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 400 401 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.32. Infrared spectrum (Thin Film, NaCl) of compound 445. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.33. 13C NMR (101 MHz, CDCl3) of compound 445. 20 0 8 TBSO 446 OH 7 5 4 ppm 3 Figure A6.34. 1H NMR (400 MHz, CDCl3) of compound 446. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 402 403 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.35. Infrared spectrum (Thin Film, NaCl) of compound 446. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.36. 13C NMR (101 MHz, CDCl3) of compound 446. 20 0 8 O 447 7 5 4 ppm 3 Figure A6.37. 1H NMR (400 MHz, CDCl3) of compound 447. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 404 405 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.38. Infrared spectrum (Thin Film, NaCl) of compound 447. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.39. 13C NMR (101 MHz, CDCl3) of compound 447. 20 0 8 448 CO2Me O 7 5 4 ppm 3 Figure A6.40. 1H NMR (400 MHz, CDCl3) of compound 448. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 406 407 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.41. Infrared spectrum (Thin Film, NaCl) of compound 448. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.42. 13C NMR (101 MHz, CDCl3) of compound 448. 20 0 8 TBSO O O 449 7 O 5 4 ppm 3 Figure A6.43. 1H NMR (400 MHz, CDCl3) of compound 449. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 408 409 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.44. Infrared spectrum (Thin Film, NaCl) of compound 449. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.45. 13C NMR (101 MHz, CDCl3) of compound 449. 20 0 8 TBSO O H 450 O 7 O 5 4 ppm 3 Figure A6.46. 1H NMR (400 MHz, CDCl3) of compound 450. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 410 411 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.47. Infrared spectrum (Thin Film, NaCl) of compound 450. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.48. 13C NMR (101 MHz, CDCl3) of compound 450. 20 0 8 TBSO O O OH 451 H 7 5 4 ppm 3 Figure A6.49. 1H NMR (400 MHz, CDCl3) of compound 451. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 412 413 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.50. Infrared spectrum (Thin Film, NaCl) of compound 451. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.51. 13C NMR (101 MHz, CDCl3) of compound 451. 20 0 8 TBSO O O 452 H OH 7 5 4 ppm 3 Figure A6.52. 1H NMR (400 MHz, CDCl3) of compound 452. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 414 415 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.53. Infrared spectrum (Thin Film, NaCl) of compound 452. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.54. 13C NMR (101 MHz, CDCl3) of compound 452. 20 0 8 HO O O 437 7 O 5 4 ppm 3 Figure A6.55. 1H NMR (400 MHz, CDCl3) of compound 437. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 416 417 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.56. Infrared spectrum (Thin Film, NaCl) of compound 437. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.57. 13C NMR (101 MHz, CDCl3) of compound 437. 20 0 8 HO O H 453 O 7 O 5 4 ppm 3 Figure A6.58. 1H NMR (400 MHz, CDCl3) of compound 453. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 418 419 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.59. Infrared spectrum (Thin Film, NaCl) of compound 453. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.60. 13C NMR (101 MHz, CDCl3) of compound 453. 20 0 8 HO O H O 454 O 7 O 6 4 ppm 3 Figure A6.61. 1H NMR (400 MHz, C6D6) of compound 454. 5 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 420 421 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.62. Infrared spectrum (Thin Film, NaCl) of compound 454. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.63. 13C NMR (101 MHz, C6D6) of compound 454. 20 0 8 HO O H H 455 O OH 7 O 5 4 ppm 3 Figure A6.64. 1H NMR (400 MHz, CDCl3) of compound 455. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 422 423 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.65. Infrared spectrum (Thin Film, NaCl) of compound 455. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.66. 13C NMR (101 MHz, CDCl3) of compound 455. 20 0 8 HO O 458 O 7 5 4 ppm 3 Figure A6.67. 1H NMR (400 MHz, CDCl3) of compound 458. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 424 425 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.68. Infrared spectrum (Thin Film, NaCl) of compound 458. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.69. 13C NMR (101 MHz, CDCl3) of compound 458. 20 0 8 HO O O 461 H 7 5 4 ppm 3 Figure A6.70. 1H NMR (400 MHz, CDCl3) of compound 461. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 426 427 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.71. Infrared spectrum (Thin Film, NaCl) of compound 461. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.72. 13C NMR (101 MHz, CDCl3) of compound 461. 20 0 8 HO O O 462 H O 7 5 4 ppm 3 Figure A6.73. 1H NMR (400 MHz, CDCl3) of compound 462. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 428 429 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.74. Infrared spectrum (Thin Film, NaCl) of compound 462. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.75. 13C NMR (101 MHz, CDCl3) of compound 462. 20 0 8 HO O O OH 463 H H 7 5 4 ppm 3 Figure A6.76. 1H NMR (400 MHz, CDCl3) of compound 463. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 430 431 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.77. Infrared spectrum (Thin Film, NaCl) of compound 463. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.78. 13C NMR (101 MHz, CDCl3) of compound 463. 20 0 8 HO O O O 464 H H 7 5 4 ppm 3 Figure A6.79. 1H NMR (400 MHz, CDCl3) of compound 464. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 432 433 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.80. Infrared spectrum (Thin Film, NaCl) of compound 464. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.81. 13C NMR (101 MHz, CDCl3) of compound 464. 20 0 8 HO O H H O O 457 7 SIMe2Ph 5 4 ppm 3 Figure A6.82. 1H NMR (400 MHz, CDCl3) of compound 457. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 434 435 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.83. Infrared spectrum (Thin Film, NaCl) of compound 457. 200 180 160 140 120 ppm 100 80 60 Figure A6.84. 13C NMR (101 MHz, CDCl3) of compound 457. 40 20 8 HO O H H H 465 O O 7 SiMe2Ph 5 4 ppm 3 Figure A6.85. 1H NMR (400 MHz, CDCl3) of compound 465. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 436 437 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.86. Infrared spectrum (Thin Film, NaCl) of compound 465. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.87. 13C NMR (101 MHz, CDCl3) of compound 465. 20 0 8 HO O H H H 466 O O 7 SiMe2Ph 5 4 ppm 3 Figure A6.88. 1H NMR (400 MHz, CDCl3) of compound 466. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 438 439 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.89. Infrared spectrum (Thin Film, NaCl) of compound 466. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.90. 13C NMR (101 MHz, CDCl3) of compound 466. 20 0 8 HO O H H H 456 O O 7 OH 5 4 ppm 3 Figure A6.91. 1H NMR (400 MHz, CDCl3) of compound 456. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 440 441 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.92. Infrared spectrum (Thin Film, NaCl) of compound 456. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.93. 13C NMR (101 MHz, CDCl3) of compound 456. 20 0 8 HO O H H H 468 O O O 7 Cl 5 4 ppm 3 Figure A6.94. 1H NMR (400 MHz, CDCl3) of compound 468. 6 2 1 0 Appendix 6 – Spectra Relevant to Chapter 4 442 443 Appendix 6 – Spectra Relevant to Chapter 4 Figure A6.95. Infrared spectrum (Thin Film, NaCl) of compound 468. 200 180 160 140 120 100 ppm 80 60 40 Figure A6.96. 13C NMR (101 MHz, CDCl3) of compound 468. 20 0 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 444 APPENDIX 7 X-Ray Crystallography Reports Relevant to Chapter 4: Progress Toward the Total Synthesis of Scabrolide A Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 A7.1 X-RAY CRYSTAL STRUCTURE ANALYSIS OF TETRACYCLE 452 TBSO O H OH O 452 Contents Table A7.1.1. Experimental Details Table A7.1.2. Crystal Data Table A7.1.3. Atomic Coordinates Table A7.1.4. Full Bond Distances and Angles Table A7.1.5. Anisotropic Displacement Parameters Table A7.1.6. Hydrogen Atomic Coordinates Table A7.1.7. Torsion Angles Table A7.1.8. Hydrogen Bond Distances and Angle Figure A7.1.1. X-Ray Crystal Structure of Tetracycle 452 445 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 446 Table A7.1.1. Experimental Details for X-Ray Structure Determination of Tetracycle 452 Low-temperature diffraction data (f-and w-scans) were collected a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON II CPAD detector with Cu Ka radiation (l = 1.54178 Å) from an IµS micro-source for the structure of compound V18139. The structure was solved by direct methods using SHELXS1 and refined against F2 on all data by full-matrix least squares with SHELXL-20162 using established refinement techniques.3 All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Compound 452 crystallizes in the orthorhombic space group P212121 with one molecule in the asymmetric unit. The coordinates for the hydrogen atom bound to O4 were located in the difference Fourier synthesis and refined semi-freely with the help of a restraint on the O-H distance (0.84(4) Å). 447 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.1.2. Crystal Data and Structure Refinement for Tetracycle 452 Empirical formula C25 H38 O4 Si Formula weight 430.64 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P212121 Unit cell dimensions a = 6.3347(3) Å a= 90°. b = 12.3768(5) Å b= 90°. c = 30.9537(13) Å g = 90°. Volume 2426.87(18) Å3 Z 4 Density (calculated) 1.179 Mg/m3 Absorption coefficient 1.064 mm-1 F(000) 936 Crystal size 0.300 x 0.150 x 0.100 mm3 Theta range for data collection 2.855 to 74.566°. Index ranges -7<=h<=7, -15<=k<=14, -38<=l<=38 Reflections collected 25153 Independent reflections 4954 [R(int) = 0.0480] Completeness to theta = 67.679° 99.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7538 and 0.6036 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4954 / 1 / 282 Goodness-of-fit on F2 1.045 Final R indices [I>2sigma(I)] R1 = 0.0315, wR2 = 0.0776 R indices (all data) R1 = 0.0341, wR2 = 0.0795 Absolute structure parameter 0.001(10) Extinction coefficient n/a Largest diff. peak and hole 0.271 and -0.190 e.Å-3 448 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Tetracycle 452. U(eq) is Defined as One Third of the Orthogonalized Uij Tensor. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ C(1) 2853(3) 1349(2) 3662(1) 17(1) C(15) 4285(4) 511(2) 3878(1) 27(1) O(2) 2611(2) 1129(1) 3218(1) 19(1) Si(1) 1788(1) 60(1) 2947(1) 16(1) C(20) 4027(3) -872(2) 2822(1) 24(1) C(21) -250(4) -722(2) 3251(1) 27(1) C(22) 679(3) 665(2) 2435(1) 22(1) C(23) -1264(4) 1358(2) 2539(1) 34(1) C(24) 2358(4) 1396(2) 2225(1) 27(1) C(25) 61(4) -241(2) 2120(1) 31(1) C(2) 716(3) 1448(2) 3904(1) 23(1) C(3) 1072(3) 2289(2) 4263(1) 21(1) O(1) -488(2) 3141(1) 4231(1) 24(1) C(4) 390(3) 4128(2) 4204(1) 18(1) O(3) -697(2) 4922(1) 4186(1) 26(1) C(5) 2811(3) 4065(2) 4224(1) 14(1) C(6) 3546(3) 4471(2) 4685(1) 15(1) O(4) 5671(2) 4121(1) 4755(1) 17(1) C(16) 2269(3) 3954(2) 5047(1) 18(1) C(7) 3408(3) 5707(1) 4721(1) 16(1) C(8) 4719(3) 6285(2) 4379(1) 16(1) C(17) 4820(3) 7503(2) 4426(1) 18(1) C(18) 3432(4) 8079(2) 4649(1) 24(1) C(19) 6667(4) 8017(2) 4198(1) 24(1) C(9) 3849(3) 5956(2) 3933(1) 20(1) C(10) 3843(3) 4750(2) 3871(1) 16(1) C(11) 4656(3) 4292(2) 3517(1) 20(1) 449 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.3. Cont’d C(12) 4409(3) 3144(2) 3418(1) 18(1) C(13) 3699(3) 2478(2) 3720(1) 15(1) C(14) 3205(3) 2845(1) 4173(1) 15(1) ________________________________________________________________________________ Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.1.4. Bond Lengths [Å] and angles [°] for Tetracycle 452 _____________________________________________________ C(1)-O(2) 1.412(2) C(1)-C(13) 1.507(3) C(1)-C(15) 1.530(3) C(1)-C(2) 1.551(3) C(15)-H(15A) 0.9800 C(15)-H(15B) 0.9800 C(15)-H(15C) 0.9800 O(2)-Si(1) 1.6507(14) Si(1)-C(21) 1.868(2) Si(1)-C(20) 1.869(2) Si(1)-C(22) 1.887(2) C(20)-H(20A) 0.9800 C(20)-H(20B) 0.9800 C(20)-H(20C) 0.9800 C(21)-H(21A) 0.9800 C(21)-H(21B) 0.9800 C(21)-H(21C) 0.9800 C(22)-C(23) 1.534(3) C(22)-C(25) 1.537(3) C(22)-C(24) 1.540(3) C(23)-H(23A) 0.9800 C(23)-H(23B) 0.9800 C(23)-H(23C) 0.9800 C(24)-H(24A) 0.9800 C(24)-H(24B) 0.9800 C(24)-H(24C) 0.9800 C(25)-H(25A) 0.9800 C(25)-H(25B) 0.9800 C(25)-H(25C) 0.9800 C(2)-C(3) 1.541(3) C(2)-H(2A) 0.9900 C(2)-H(2B) 0.9900 450 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.4. Cont’d C(3)-O(1) 1.448(3) C(3)-C(14) 1.542(3) C(3)-H(3) 1.0000 O(1)-C(4) 1.345(3) C(4)-O(3) 1.201(3) C(4)-C(5) 1.537(2) C(5)-C(10) 1.529(2) C(5)-C(14) 1.538(2) C(5)-C(6) 1.585(2) C(6)-O(4) 1.430(2) C(6)-C(16) 1.522(3) C(6)-C(7) 1.535(2) O(4)-H(4O) 0.84(2) C(16)-H(16A) 0.9800 C(16)-H(16B) 0.9800 C(16)-H(16C) 0.9800 C(7)-C(8) 1.524(3) C(7)-H(7A) 0.9900 C(7)-H(7B) 0.9900 C(8)-C(17) 1.515(3) C(8)-C(9) 1.540(3) C(8)-H(8) 1.0000 C(17)-C(18) 1.326(3) C(17)-C(19) 1.506(3) C(18)-H(18A) 0.9500 C(18)-H(18B) 0.9500 C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800 C(9)-C(10) 1.505(3) C(9)-H(9A) 0.9900 C(9)-H(9B) 0.9900 C(10)-C(11) 1.336(3) C(11)-C(12) 1.462(3) 451 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.4. Cont’d C(11)-H(11) 0.9500 C(12)-C(13) 1.325(3) C(12)-H(12) 0.9500 C(13)-C(14) 1.505(2) C(14)-H(14) 1.0000 O(2)-C(1)-C(13) 109.48(15) O(2)-C(1)-C(15) 111.00(16) C(13)-C(1)-C(15) 111.47(16) O(2)-C(1)-C(2) 112.91(16) C(13)-C(1)-C(2) 100.35(15) C(15)-C(1)-C(2) 111.20(17) C(1)-C(15)-H(15A) 109.5 C(1)-C(15)-H(15B) 109.5 H(15A)-C(15)-H(15B) 109.5 C(1)-C(15)-H(15C) 109.5 H(15A)-C(15)-H(15C) 109.5 H(15B)-C(15)-H(15C) 109.5 C(1)-O(2)-Si(1) 133.20(12) O(2)-Si(1)-C(21) 112.17(9) O(2)-Si(1)-C(20) 111.08(9) C(21)-Si(1)-C(20) 107.95(10) O(2)-Si(1)-C(22) 103.08(8) C(21)-Si(1)-C(22) 111.81(10) C(20)-Si(1)-C(22) 110.76(10) Si(1)-C(20)-H(20A) 109.5 Si(1)-C(20)-H(20B) 109.5 H(20A)-C(20)-H(20B) 109.5 Si(1)-C(20)-H(20C) 109.5 H(20A)-C(20)-H(20C) 109.5 H(20B)-C(20)-H(20C) 109.5 Si(1)-C(21)-H(21A) 109.5 Si(1)-C(21)-H(21B) 109.5 H(21A)-C(21)-H(21B) 109.5 452 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.4. Cont’d Si(1)-C(21)-H(21C) 109.5 H(21A)-C(21)-H(21C) 109.5 H(21B)-C(21)-H(21C) 109.5 C(23)-C(22)-C(25) 109.66(19) C(23)-C(22)-C(24) 108.29(18) C(25)-C(22)-C(24) 109.73(18) C(23)-C(22)-Si(1) 110.17(15) C(25)-C(22)-Si(1) 109.73(14) C(24)-C(22)-Si(1) 109.24(14) C(22)-C(23)-H(23A) 109.5 C(22)-C(23)-H(23B) 109.5 H(23A)-C(23)-H(23B) 109.5 C(22)-C(23)-H(23C) 109.5 H(23A)-C(23)-H(23C) 109.5 H(23B)-C(23)-H(23C) 109.5 C(22)-C(24)-H(24A) 109.5 C(22)-C(24)-H(24B) 109.5 H(24A)-C(24)-H(24B) 109.5 C(22)-C(24)-H(24C) 109.5 H(24A)-C(24)-H(24C) 109.5 H(24B)-C(24)-H(24C) 109.5 C(22)-C(25)-H(25A) 109.5 C(22)-C(25)-H(25B) 109.5 H(25A)-C(25)-H(25B) 109.5 C(22)-C(25)-H(25C) 109.5 H(25A)-C(25)-H(25C) 109.5 H(25B)-C(25)-H(25C) 109.5 C(3)-C(2)-C(1) 105.86(16) C(3)-C(2)-H(2A) 110.6 C(1)-C(2)-H(2A) 110.6 C(3)-C(2)-H(2B) 110.6 C(1)-C(2)-H(2B) 110.6 H(2A)-C(2)-H(2B) 108.7 O(1)-C(3)-C(2) 110.00(17) 453 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.4. Cont’d O(1)-C(3)-C(14) 105.10(15) C(2)-C(3)-C(14) 107.37(15) O(1)-C(3)-H(3) 111.4 C(2)-C(3)-H(3) 111.4 C(14)-C(3)-H(3) 111.4 C(4)-O(1)-C(3) 112.56(15) O(3)-C(4)-O(1) 120.61(18) O(3)-C(4)-C(5) 128.00(19) O(1)-C(4)-C(5) 111.32(17) C(10)-C(5)-C(4) 111.75(15) C(10)-C(5)-C(14) 113.68(15) C(4)-C(5)-C(14) 102.01(15) C(10)-C(5)-C(6) 109.99(15) C(4)-C(5)-C(6) 108.18(15) C(14)-C(5)-C(6) 110.88(14) O(4)-C(6)-C(16) 105.17(15) O(4)-C(6)-C(7) 110.16(16) C(16)-C(6)-C(7) 109.63(15) O(4)-C(6)-C(5) 108.43(14) C(16)-C(6)-C(5) 111.94(15) C(7)-C(6)-C(5) 111.31(15) C(6)-O(4)-H(4O) 112.7(19) C(6)-C(16)-H(16A) 109.5 C(6)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16B) 109.5 C(6)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 C(8)-C(7)-C(6) 112.79(15) C(8)-C(7)-H(7A) 109.0 C(6)-C(7)-H(7A) 109.0 C(8)-C(7)-H(7B) 109.0 C(6)-C(7)-H(7B) 109.0 H(7A)-C(7)-H(7B) 107.8 454 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.4. Cont’d C(17)-C(8)-C(7) 115.09(16) C(17)-C(8)-C(9) 111.31(15) C(7)-C(8)-C(9) 107.63(15) C(17)-C(8)-H(8) 107.5 C(7)-C(8)-H(8) 107.5 C(9)-C(8)-H(8) 107.5 C(18)-C(17)-C(19) 122.07(19) C(18)-C(17)-C(8) 123.84(19) C(19)-C(17)-C(8) 114.09(17) C(17)-C(18)-H(18A) 120.0 C(17)-C(18)-H(18B) 120.0 H(18A)-C(18)-H(18B) 120.0 C(17)-C(19)-H(19A) 109.5 C(17)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 C(17)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 C(10)-C(9)-C(8) 112.16(15) C(10)-C(9)-H(9A) 109.2 C(8)-C(9)-H(9A) 109.2 C(10)-C(9)-H(9B) 109.2 C(8)-C(9)-H(9B) 109.2 H(9A)-C(9)-H(9B) 107.9 C(11)-C(10)-C(9) 121.61(17) C(11)-C(10)-C(5) 120.96(17) C(9)-C(10)-C(5) 117.41(16) C(10)-C(11)-C(12) 122.87(18) C(10)-C(11)-H(11) 118.6 C(12)-C(11)-H(11) 118.6 C(13)-C(12)-C(11) 119.56(17) C(13)-C(12)-H(12) 120.2 C(11)-C(12)-H(12) 120.2 C(12)-C(13)-C(14) 122.60(17) 455 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.4. Cont’d C(12)-C(13)-C(1) 127.85(17) C(14)-C(13)-C(1) 108.49(15) C(13)-C(14)-C(5) 115.21(15) C(13)-C(14)-C(3) 102.49(15) C(5)-C(14)-C(3) 106.08(15) C(13)-C(14)-H(14) 110.9 C(5)-C(14)-H(14) 110.9 C(3)-C(14)-H(14) 110.9 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: 456 457 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.1.5. Anisotropic Displacement Parameters (Å2x103) for Tetracycle 452. The Anisotropic Displacement Factor Exponent Takes the Form: -2p2[h2a*2U11 + … + 2hka*b*U12]. ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ C(1) 20(1) 18(1) 13(1) -1(1) 0(1) -3(1) C(15) 38(1) 19(1) 24(1) -3(1) -8(1) 4(1) O(2) 25(1) 18(1) 14(1) -2(1) 0(1) -4(1) Si(1) 16(1) 15(1) 17(1) -2(1) 0(1) -1(1) C(20) 20(1) 19(1) 34(1) -5(1) -2(1) 3(1) C(21) 28(1) 25(1) 28(1) -2(1) 4(1) -10(1) C(22) 24(1) 21(1) 21(1) -2(1) -5(1) 0(1) C(23) 28(1) 29(1) 47(1) 0(1) -10(1) 7(1) C(24) 35(1) 26(1) 20(1) -1(1) 0(1) -2(1) C(25) 38(1) 31(1) 25(1) -5(1) -11(1) -6(1) C(2) 25(1) 23(1) 22(1) -4(1) 6(1) -9(1) C(3) 22(1) 23(1) 18(1) -1(1) 5(1) -6(1) O(1) 16(1) 28(1) 27(1) -7(1) 5(1) -5(1) C(4) 13(1) 26(1) 15(1) -5(1) -1(1) 1(1) O(3) 16(1) 31(1) 32(1) -6(1) -4(1) 6(1) C(5) 13(1) 17(1) 12(1) -1(1) 0(1) 1(1) C(6) 15(1) 19(1) 13(1) -1(1) 1(1) 1(1) O(4) 14(1) 21(1) 15(1) 1(1) -2(1) 2(1) C(16) 20(1) 21(1) 13(1) 1(1) 3(1) -1(1) C(7) 16(1) 18(1) 13(1) -2(1) 0(1) 2(1) C(8) 16(1) 16(1) 16(1) -1(1) 0(1) 2(1) C(17) 21(1) 18(1) 16(1) 1(1) -4(1) 0(1) C(18) 28(1) 17(1) 28(1) -1(1) 1(1) 2(1) C(19) 27(1) 18(1) 28(1) 0(1) 3(1) -3(1) C(9) 27(1) 18(1) 15(1) 2(1) 0(1) 0(1) C(10) 16(1) 18(1) 13(1) 2(1) -2(1) -1(1) C(11) 25(1) 20(1) 16(1) 1(1) 5(1) -5(1) 458 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.5. Cont’d C(12) 19(1) 22(1) 15(1) -4(1) 5(1) -2(1) C(13) 13(1) 17(1) 16(1) -3(1) -1(1) 2(1) C(14) 15(1) 16(1) 13(1) 1(1) 1(1) 0(1) ______________________________________________________________________________ 459 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.1.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Tetracycle 452. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(15A) 3655 -209 3848 41 H(15B) 4443 685 4185 41 H(15C) 5674 519 3738 41 H(20A) 5104 -483 2656 37 H(20B) 3507 -1485 2653 37 H(20C) 4646 -1136 3092 37 H(21A) 372 -1007 3517 41 H(21B) -752 -1323 3072 41 H(21C) -1437 -247 3322 41 H(23A) -1856 1647 2270 52 H(23B) -850 1957 2728 52 H(23C) -2326 914 2685 52 H(24A) 1858 1638 1942 40 H(24B) 3675 990 2190 40 H(24C) 2611 2026 2410 40 H(25A) -1010 -704 2254 47 H(25B) 1310 -674 2050 47 H(25C) -513 76 1855 47 H(2A) -408 1691 3704 28 H(2B) 300 743 4029 28 H(3) 1053 1945 4555 25 H(4O) 6480(40) 4290(20) 4552(8) 20 H(16A) 2464 3169 5040 27 H(16B) 771 4125 5008 27 H(16C) 2751 4236 5326 27 H(7A) 1914 5930 4691 19 H(7B) 3899 5931 5011 19 H(8) 6195 6004 4400 19 460 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.6. Cont’d H(18A) 3586 8841 4669 29 H(18B) 2284 7730 4788 29 H(19A) 6682 8794 4258 36 H(19B) 6537 7900 3886 36 H(19C) 7982 7690 4302 36 H(9A) 2391 6233 3902 24 H(9B) 4723 6293 3705 24 H(11) 5428 4732 3322 24 H(12) 4756 2877 3140 22 H(14) 4310 2591 4380 18 ________________________________________________________________________________ Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.1.7. Torsion Angles [°] for Tetracycle 452. ________________________________________________________________ C(13)-C(1)-O(2)-Si(1) 179.54(13) C(15)-C(1)-O(2)-Si(1) 56.1(2) C(2)-C(1)-O(2)-Si(1) -69.6(2) C(1)-O(2)-Si(1)-C(21) 31.7(2) C(1)-O(2)-Si(1)-C(20) -89.25(19) C(1)-O(2)-Si(1)-C(22) 152.10(17) O(2)-Si(1)-C(22)-C(23) -65.50(17) C(21)-Si(1)-C(22)-C(23) 55.18(18) C(20)-Si(1)-C(22)-C(23) 175.62(15) O(2)-Si(1)-C(22)-C(25) 173.66(15) C(21)-Si(1)-C(22)-C(25) -65.66(18) C(20)-Si(1)-C(22)-C(25) 54.79(18) O(2)-Si(1)-C(22)-C(24) 53.33(15) C(21)-Si(1)-C(22)-C(24) 174.01(14) C(20)-Si(1)-C(22)-C(24) -65.55(16) O(2)-C(1)-C(2)-C(3) -147.14(16) C(13)-C(1)-C(2)-C(3) -30.70(19) C(15)-C(1)-C(2)-C(3) 87.3(2) C(1)-C(2)-C(3)-O(1) 125.61(17) C(1)-C(2)-C(3)-C(14) 11.8(2) C(2)-C(3)-O(1)-C(4) -125.15(17) C(14)-C(3)-O(1)-C(4) -9.8(2) C(3)-O(1)-C(4)-O(3) -178.16(17) C(3)-O(1)-C(4)-C(5) -0.9(2) O(3)-C(4)-C(5)-C(10) -50.1(3) O(1)-C(4)-C(5)-C(10) 132.92(16) O(3)-C(4)-C(5)-C(14) -171.86(19) O(1)-C(4)-C(5)-C(14) 11.1(2) O(3)-C(4)-C(5)-C(6) 71.2(2) O(1)-C(4)-C(5)-C(6) -105.85(17) C(10)-C(5)-C(6)-O(4) -74.73(17) C(4)-C(5)-C(6)-O(4) 162.96(15) 461 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.7. Cont’d C(14)-C(5)-C(6)-O(4) 51.88(19) C(10)-C(5)-C(6)-C(16) 169.70(15) C(4)-C(5)-C(6)-C(16) 47.4(2) C(14)-C(5)-C(6)-C(16) -63.7(2) C(10)-C(5)-C(6)-C(7) 46.6(2) C(4)-C(5)-C(6)-C(7) -75.7(2) C(14)-C(5)-C(6)-C(7) 173.21(15) O(4)-C(6)-C(7)-C(8) 62.5(2) C(16)-C(6)-C(7)-C(8) 177.78(15) C(5)-C(6)-C(7)-C(8) -57.8(2) C(6)-C(7)-C(8)-C(17) -174.09(17) C(6)-C(7)-C(8)-C(9) 61.2(2) C(7)-C(8)-C(17)-C(18) -20.2(3) C(9)-C(8)-C(17)-C(18) 102.6(2) C(7)-C(8)-C(17)-C(19) 159.28(17) C(9)-C(8)-C(17)-C(19) -77.9(2) C(17)-C(8)-C(9)-C(10) 177.00(17) C(7)-C(8)-C(9)-C(10) -56.0(2) C(8)-C(9)-C(10)-C(11) -130.3(2) C(8)-C(9)-C(10)-C(5) 51.3(2) C(4)-C(5)-C(10)-C(11) -103.3(2) C(14)-C(5)-C(10)-C(11) 11.5(3) C(6)-C(5)-C(10)-C(11) 136.48(19) C(4)-C(5)-C(10)-C(9) 75.0(2) C(14)-C(5)-C(10)-C(9) -170.19(16) C(6)-C(5)-C(10)-C(9) -45.2(2) C(9)-C(10)-C(11)-C(12) -171.04(19) C(5)-C(10)-C(11)-C(12) 7.2(3) C(10)-C(11)-C(12)-C(13) -12.7(3) C(11)-C(12)-C(13)-C(14) -2.5(3) C(11)-C(12)-C(13)-C(1) 164.33(19) O(2)-C(1)-C(13)-C(12) -8.9(3) C(15)-C(1)-C(13)-C(12) 114.3(2) C(2)-C(1)-C(13)-C(12) -127.8(2) 462 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.1.7. Cont’d O(2)-C(1)-C(13)-C(14) 159.42(15) C(15)-C(1)-C(13)-C(14) -77.38(19) C(2)-C(1)-C(13)-C(14) 40.45(18) C(12)-C(13)-C(14)-C(5) 20.8(3) C(1)-C(13)-C(14)-C(5) -148.21(16) C(12)-C(13)-C(14)-C(3) 135.51(19) C(1)-C(13)-C(14)-C(3) -33.52(19) C(10)-C(5)-C(14)-C(13) -24.1(2) C(4)-C(5)-C(14)-C(13) 96.36(18) C(6)-C(5)-C(14)-C(13) -148.65(16) C(10)-C(5)-C(14)-C(3) -136.71(15) C(4)-C(5)-C(14)-C(3) -16.25(18) C(6)-C(5)-C(14)-C(3) 98.75(17) O(1)-C(3)-C(14)-C(13) -104.81(16) C(2)-C(3)-C(14)-C(13) 12.3(2) O(1)-C(3)-C(14)-C(5) 16.37(18) C(2)-C(3)-C(14)-C(5) 133.48(17) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: 463 464 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.1.8. Hydrogen Bonds for Tetracycle 452 [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ C(3)-H(3)...O(4)#1 1.00 2.52 3.514(2) 171.9 O(4)-H(4O)...O(1)#2 0.84(2) 2.59(3) 3.167(2) 127(2) O(4)-H(4O)...O(3)#2 0.84(2) 2.25(2) 3.062(2) 162(3) C(7)-H(7A)...O(3) 0.99 2.59 3.231(2) 122.0 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x-1/2,-y+1/2,-z+1 #2 x+1,y,z Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 A7.2 465 X-RAY CRYSTAL STRUCTURE ANALYSIS OF CYCLOBUTANE 465 H HO O H SiMe2Ph O H O 465 Contents Table A7.2.1. Experimental Details Table A7.2.2. Crystal Data Table A7.2.3. Atomic Coordinates Table A7.2.4. Full Bond Distances and Angles Table A7.2.5. Anisotropic Displacement Parameters Table A7.2.6. Hydrogen Atomic Coordinates Table A7.2.7. Torsion Angles Table A7.2.8. Hydrogen Bond Distances and Angle Figure A7.2.1. X-Ray Crystal Structure of Cyclobutane 465 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 466 Table A7.2.1. Experimental Details for X-Ray Structure Determination of Cyclobutane 465 Low-temperature diffraction data (f-and w-scans) were collected on a Bruker AXS KAPPA APEX II diffractometer coupled to an PHOTON 100 CMOS detector with graphite monochromated Mo Ka radiation (l = 0.71073 Å) for the structure of compound 465. The structure was solved by direct methods using SHELXS and refined against F2 on all data by full-matrix least squares with SHELXL-2017 using established refinement techniques. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Compound 465 crystallizes in the monoclinic space group P21 with one molecule in the asymmetric unit. The molecule was refined with a disordered hydroxide. 467 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.2. Crystal Data and Structure Refinement for Cyclobutane 465 Empirical formula C24 H30 O4.16 Si Formula weight 413.21 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P21 Unit cell dimensions a = 7.267(3) Å a= 90°. b = 9.667(3) Å b= 99.237(16)°. c = 15.436(4) Å g = 90°. Volume 1070.3(7) Å3 Z 2 Density (calculated) 1.282 Mg/m3 Absorption coefficient 0.138 mm-1 F(000) 443 Crystal size 0.300 x 0.100 x 0.050 mm3 Theta range for data collection 2.495 to 30.501°. Index ranges -10<=h<=9, -13<=k<=13, -22<=l<=22 Reflections collected 16781 Independent reflections 5995 [R(int) = 0.0322] Completeness to theta = 25.242° 99.7 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7466 and 0.6535 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5995 / 2 / 280 Goodness-of-fit on F2 1.024 Final R indices [I>2sigma(I)] R1 = 0.0392, wR2 = 0.0861 R indices (all data) R1 = 0.0494, wR2 = 0.0897 Absolute structure parameter 0.04(4) Extinction coefficient n/a Largest diff. peak and hole 0.316 and -0.247 e.Å-3 468 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.2.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Cyclobutane 465. U(eq) is Defined as One Third of the Trace of the Orthogonalized Uij Tensor. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ Si(1) 4386(1) 6279(1) 8522(1) 15(1) C(1) 3245(3) 4685(2) 7973(1) 12(1) C(2) 3535(3) 3370(2) 8547(1) 17(1) C(3) 2928(3) 2185(2) 7909(1) 16(1) C(4) 3789(3) 2600(2) 7113(1) 12(1) C(5) 3459(3) 4173(2) 7001(1) 10(1) C(6) 4859(3) 4923(2) 6488(1) 12(1) O(6B) 6250(11) 5648(9) 7055(5) 9(3) C(7) 6204(3) 3975(2) 6103(2) 17(1) O(1) 6138(2) 4182(2) 5238(1) 20(1) O(2) 7296(2) 3157(2) 6489(1) 24(1) C(8) 5001(3) 5372(2) 4925(1) 17(1) C(9) 3445(3) 4958(2) 4187(1) 18(1) C(10) 1752(3) 4665(2) 4626(1) 13(1) C(18) -89(3) 4728(2) 4002(1) 19(1) O(3) 1978(2) 3371(2) 5078(1) 15(1) C(11) 1954(3) 5803(2) 5343(1) 12(1) C(12) 4054(3) 5873(2) 5706(1) 13(1) C(13) 749(3) 5568(2) 6031(1) 12(1) O(4) -691(2) 6223(2) 6041(1) 17(1) C(14) 1345(3) 4496(2) 6715(1) 11(1) C(15) 1116(3) 4936(2) 7652(1) 14(1) C(16) 6926(3) 6088(3) 8901(2) 27(1) C(17) 3947(4) 7835(3) 7791(2) 26(1) C(21) 3208(3) 6548(2) 9508(1) 19(1) C(22) 1903(3) 7607(3) 9547(2) 25(1) C(23) 1014(4) 7768(3) 10273(2) 35(1) 469 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.2.3. Cont’d C(24) 1401(4) 6871(3) 10974(2) 37(1) C(25) 2668(4) 5819(3) 10955(2) 30(1) C(26) 3574(3) 5662(3) 10235(1) 23(1) ________________________________________________________________________________ Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.4. Bond Lengths [Å] and angles [°] for Cyclobutane 465 _____________________________________________________ Si(1)-C(16) 1.853(2) Si(1)-C(17) 1.877(3) Si(1)-C(21) 1.881(2) Si(1)-C(1) 1.886(2) C(1)-C(2) 1.545(3) C(1)-C(15) 1.566(3) C(1)-C(5) 1.611(3) C(2)-C(3) 1.529(3) C(2)-H(2A) 0.9900 C(2)-H(2B) 0.9900 C(3)-C(4) 1.520(3) C(3)-H(3A) 0.9900 C(3)-H(3B) 0.9900 C(4)-C(5) 1.545(3) C(4)-H(4A) 0.9900 C(4)-H(4B) 0.9900 C(5)-C(14) 1.561(3) C(5)-C(6) 1.564(3) C(6)-O(6B) 1.412(8) C(6)-C(7) 1.529(3) C(6)-C(12) 1.554(3) C(6)-H(6) 1.0000 O(6B)-H(6OB) 0.8400 C(7)-O(2) 1.207(3) C(7)-O(1) 1.343(3) O(1)-C(8) 1.452(3) C(8)-C(9) 1.525(3) C(8)-C(12) 1.558(3) C(8)-H(8) 1.0000 C(9)-C(10) 1.524(3) C(9)-H(9A) 0.9900 C(9)-H(9B) 0.9900 470 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.4. Cont’d C(10)-O(3) 1.430(2) C(10)-C(18) 1.519(3) C(10)-C(11) 1.551(3) C(18)-H(18A) 0.9800 C(18)-H(18B) 0.9800 C(18)-H(18C) 0.9800 O(3)-H(3O) 0.81(2) C(11)-C(13) 1.499(3) C(11)-C(12) 1.541(3) C(11)-H(11) 1.0000 C(12)-H(12) 1.0000 C(13)-O(4) 1.225(2) C(13)-C(14) 1.492(3) C(14)-C(15) 1.542(3) C(14)-H(14) 1.0000 C(15)-H(15A) 0.9900 C(15)-H(15B) 0.9900 C(16)-H(16A) 0.9800 C(16)-H(16B) 0.9800 C(16)-H(16C) 0.9800 C(17)-H(17A) 0.9800 C(17)-H(17B) 0.9800 C(17)-H(17C) 0.9800 C(21)-C(26) 1.403(3) C(21)-C(22) 1.403(3) C(22)-C(23) 1.390(3) C(22)-H(22) 0.9500 C(23)-C(24) 1.380(5) C(23)-H(23) 0.9500 C(24)-C(25) 1.375(4) C(24)-H(24) 0.9500 C(25)-C(26) 1.387(3) C(25)-H(25) 0.9500 C(26)-H(26) 0.9500 471 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.4. Cont’d C(16)-Si(1)-C(17) 109.50(13) C(16)-Si(1)-C(21) 108.58(11) C(17)-Si(1)-C(21) 108.67(11) C(16)-Si(1)-C(1) 113.85(11) C(17)-Si(1)-C(1) 111.37(10) C(21)-Si(1)-C(1) 104.63(10) C(2)-C(1)-C(15) 110.28(17) C(2)-C(1)-C(5) 104.92(16) C(15)-C(1)-C(5) 89.47(14) C(2)-C(1)-Si(1) 113.87(14) C(15)-C(1)-Si(1) 110.89(13) C(5)-C(1)-Si(1) 124.62(14) C(3)-C(2)-C(1) 104.36(16) C(3)-C(2)-H(2A) 110.9 C(1)-C(2)-H(2A) 110.9 C(3)-C(2)-H(2B) 110.9 C(1)-C(2)-H(2B) 110.9 H(2A)-C(2)-H(2B) 108.9 C(4)-C(3)-C(2) 102.09(17) C(4)-C(3)-H(3A) 111.4 C(2)-C(3)-H(3A) 111.4 C(4)-C(3)-H(3B) 111.4 C(2)-C(3)-H(3B) 111.4 H(3A)-C(3)-H(3B) 109.2 C(3)-C(4)-C(5) 105.86(16) C(3)-C(4)-H(4A) 110.6 C(5)-C(4)-H(4A) 110.6 C(3)-C(4)-H(4B) 110.6 C(5)-C(4)-H(4B) 110.6 H(4A)-C(4)-H(4B) 108.7 C(4)-C(5)-C(14) 110.87(16) C(4)-C(5)-C(6) 114.26(16) C(14)-C(5)-C(6) 117.03(16) 472 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.4. Cont’d C(4)-C(5)-C(1) 103.58(15) C(14)-C(5)-C(1) 87.97(14) C(6)-C(5)-C(1) 119.85(16) O(6B)-C(6)-C(7) 95.7(4) O(6B)-C(6)-C(12) 109.3(4) C(7)-C(6)-C(12) 103.69(16) O(6B)-C(6)-C(5) 112.1(4) C(7)-C(6)-C(5) 115.31(17) C(12)-C(6)-C(5) 118.24(16) C(7)-C(6)-H(6) 106.2 C(12)-C(6)-H(6) 106.2 C(5)-C(6)-H(6) 106.2 C(6)-O(6B)-H(6OB) 109.5 O(2)-C(7)-O(1) 120.3(2) O(2)-C(7)-C(6) 127.7(2) O(1)-C(7)-C(6) 111.93(18) C(7)-O(1)-C(8) 112.11(17) O(1)-C(8)-C(9) 110.79(18) O(1)-C(8)-C(12) 106.70(16) C(9)-C(8)-C(12) 107.08(18) O(1)-C(8)-H(8) 110.7 C(9)-C(8)-H(8) 110.7 C(12)-C(8)-H(8) 110.7 C(10)-C(9)-C(8) 105.72(17) C(10)-C(9)-H(9A) 110.6 C(8)-C(9)-H(9A) 110.6 C(10)-C(9)-H(9B) 110.6 C(8)-C(9)-H(9B) 110.6 H(9A)-C(9)-H(9B) 108.7 O(3)-C(10)-C(18) 111.44(17) O(3)-C(10)-C(9) 110.04(17) C(18)-C(10)-C(9) 113.72(17) O(3)-C(10)-C(11) 106.37(15) C(18)-C(10)-C(11) 113.38(17) 473 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.4. Cont’d C(9)-C(10)-C(11) 101.23(16) C(10)-C(18)-H(18A) 109.5 C(10)-C(18)-H(18B) 109.5 H(18A)-C(18)-H(18B) 109.5 C(10)-C(18)-H(18C) 109.5 H(18A)-C(18)-H(18C) 109.5 H(18B)-C(18)-H(18C) 109.5 C(10)-O(3)-H(3O) 110.9(19) C(13)-C(11)-C(12) 113.93(16) C(13)-C(11)-C(10) 113.52(17) C(12)-C(11)-C(10) 105.39(16) C(13)-C(11)-H(11) 107.9 C(12)-C(11)-H(11) 107.9 C(10)-C(11)-H(11) 107.9 C(11)-C(12)-C(6) 118.97(16) C(11)-C(12)-C(8) 103.86(16) C(6)-C(12)-C(8) 105.05(16) C(11)-C(12)-H(12) 109.5 C(6)-C(12)-H(12) 109.5 C(8)-C(12)-H(12) 109.5 O(4)-C(13)-C(14) 120.14(18) O(4)-C(13)-C(11) 121.80(18) C(14)-C(13)-C(11) 118.06(17) C(13)-C(14)-C(15) 114.11(17) C(13)-C(14)-C(5) 119.99(17) C(15)-C(14)-C(5) 92.24(14) C(13)-C(14)-H(14) 109.7 C(15)-C(14)-H(14) 109.7 C(5)-C(14)-H(14) 109.7 C(14)-C(15)-C(1) 90.25(15) C(14)-C(15)-H(15A) 113.6 C(1)-C(15)-H(15A) 113.6 C(14)-C(15)-H(15B) 113.6 C(1)-C(15)-H(15B) 113.6 474 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.4. Cont’d H(15A)-C(15)-H(15B) 110.9 Si(1)-C(16)-H(16A) 109.5 Si(1)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16B) 109.5 Si(1)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 Si(1)-C(17)-H(17A) 109.5 Si(1)-C(17)-H(17B) 109.5 H(17A)-C(17)-H(17B) 109.5 Si(1)-C(17)-H(17C) 109.5 H(17A)-C(17)-H(17C) 109.5 H(17B)-C(17)-H(17C) 109.5 C(26)-C(21)-C(22) 117.0(2) C(26)-C(21)-Si(1) 120.69(17) C(22)-C(21)-Si(1) 122.26(19) C(23)-C(22)-C(21) 121.4(3) C(23)-C(22)-H(22) 119.3 C(21)-C(22)-H(22) 119.3 C(24)-C(23)-C(22) 120.0(3) C(24)-C(23)-H(23) 120.0 C(22)-C(23)-H(23) 120.0 C(25)-C(24)-C(23) 120.0(2) C(25)-C(24)-H(24) 120.0 C(23)-C(24)-H(24) 120.0 C(24)-C(25)-C(26) 120.3(3) C(24)-C(25)-H(25) 119.9 C(26)-C(25)-H(25) 119.9 C(25)-C(26)-C(21) 121.4(2) C(25)-C(26)-H(26) 119.3 C(21)-C(26)-H(26) 119.3 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: 475 476 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.5. Anisotropic Displacement Parameters (Å2x103) for Cyclobutane 465. The Anisotropic Displacement Factor Exponent Takes the Form: -2p2[h2a*2U11 + … + 2hka*b*U12]. ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Si(1) 15(1) 15(1) 14(1) -4(1) 1(1) 1(1) C(1) 13(1) 14(1) 10(1) -1(1) 1(1) 3(1) C(2) 20(1) 17(1) 13(1) 1(1) 3(1) 2(1) C(3) 18(1) 14(1) 16(1) 2(1) 5(1) 1(1) C(4) 14(1) 10(1) 14(1) -1(1) 3(1) 1(1) C(5) 11(1) 10(1) 10(1) -1(1) 1(1) -1(1) C(6) 10(1) 10(1) 16(1) -1(1) 1(1) -3(1) O(6B) 4(4) 15(5) 9(4) -3(3) 2(3) -1(3) C(7) 11(1) 14(1) 28(1) 0(1) 7(1) -5(1) O(1) 16(1) 22(1) 24(1) -4(1) 8(1) 1(1) O(2) 12(1) 21(1) 42(1) 7(1) 8(1) 1(1) C(8) 17(1) 18(1) 18(1) 1(1) 8(1) -3(1) C(9) 22(1) 19(1) 14(1) -1(1) 6(1) -2(1) C(10) 15(1) 11(1) 12(1) 1(1) 2(1) 1(1) C(18) 21(1) 21(1) 16(1) 0(1) -1(1) 1(1) O(3) 21(1) 10(1) 13(1) -1(1) 1(1) -1(1) C(11) 14(1) 9(1) 13(1) 1(1) 2(1) 0(1) C(12) 14(1) 11(1) 15(1) -1(1) 5(1) -2(1) C(13) 14(1) 8(1) 13(1) -3(1) -1(1) 0(1) O(4) 14(1) 18(1) 18(1) 2(1) 3(1) 5(1) C(14) 10(1) 11(1) 11(1) -1(1) 2(1) 0(1) C(15) 16(1) 15(1) 12(1) 0(1) 3(1) 2(1) C(16) 16(1) 35(2) 29(1) -1(1) 2(1) -2(1) C(17) 37(2) 18(1) 24(1) -2(1) 3(1) -1(1) C(21) 14(1) 23(1) 18(1) -10(1) 2(1) -2(1) C(22) 16(1) 29(1) 29(1) -14(1) 0(1) -1(1) C(23) 18(1) 41(2) 47(2) -23(1) 11(1) -4(1) 477 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.5. Cont’d C(24) 26(1) 51(2) 38(1) -24(1) 21(1) -12(1) C(25) 32(1) 38(2) 23(1) -10(1) 11(1) -13(1) C(26) 21(1) 29(1) 19(1) -9(1) 5(1) -4(1) ______________________________________________________________________________ 478 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Cyclobutane 465. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(2A) 4860 3268 8816 20 H(2B) 2760 3400 9019 20 H(3A) 3424 1287 8151 19 H(3B) 1553 2127 7765 19 H(4A) 3185 2097 6584 15 H(4B) 5140 2390 7209 15 H(6) 5647 5529 6924 15 H(6OB) 6985 6026 6759 90(90) H(8) 5785 6123 4729 20 H(9A) 3177 5718 3754 21 H(9B) 3801 4124 3881 21 H(18A) -81 4048 3531 29 H(18B) -260 5657 3747 29 H(18C) -1113 4520 4324 29 H(3O) 1630(40) 2740(20) 4749(16) 22 H(11) 1581 6705 5049 15 H(12) 4418 6853 5851 15 H(14) 646 3617 6555 13 H(15A) 297 4314 7928 17 H(15B) 733 5913 7695 17 H(16A) 7531 5787 8409 40 H(16B) 7141 5397 9371 40 H(16C) 7449 6978 9122 40 H(17A) 4148 8677 8147 40 H(17B) 2659 7815 7483 40 H(17C) 4805 7824 7362 40 H(22) 1622 8227 9066 30 H(23) 140 8495 10287 42 479 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.6. Cont’d H(24) 792 6979 11471 44 H(25) 2924 5197 11436 36 H(26) 4461 4941 10235 27 ________________________________________________________________________________ Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.7. Torsion Angles [°] for Cyclobutane 465. ________________________________________________________________ C(16)-Si(1)-C(1)-C(2) 56.33(18) C(17)-Si(1)-C(1)-C(2) -179.28(15) C(21)-Si(1)-C(1)-C(2) -62.05(17) C(16)-Si(1)-C(1)-C(15) -178.59(14) C(17)-Si(1)-C(1)-C(15) -54.20(17) C(21)-Si(1)-C(1)-C(15) 63.02(15) C(16)-Si(1)-C(1)-C(5) -74.03(18) C(17)-Si(1)-C(1)-C(5) 50.4(2) C(21)-Si(1)-C(1)-C(5) 167.59(16) C(15)-C(1)-C(2)-C(3) 67.9(2) C(5)-C(1)-C(2)-C(3) -27.2(2) Si(1)-C(1)-C(2)-C(3) -166.73(14) C(1)-C(2)-C(3)-C(4) 42.6(2) C(2)-C(3)-C(4)-C(5) -42.0(2) C(3)-C(4)-C(5)-C(14) -68.47(19) C(3)-C(4)-C(5)-C(6) 156.67(16) C(3)-C(4)-C(5)-C(1) 24.6(2) C(2)-C(1)-C(5)-C(4) 1.8(2) C(15)-C(1)-C(5)-C(4) -109.09(16) Si(1)-C(1)-C(5)-C(4) 135.63(15) C(2)-C(1)-C(5)-C(14) 112.77(17) C(15)-C(1)-C(5)-C(14) 1.90(15) Si(1)-C(1)-C(5)-C(14) -113.38(16) C(2)-C(1)-C(5)-C(6) -126.96(19) C(15)-C(1)-C(5)-C(6) 122.16(18) Si(1)-C(1)-C(5)-C(6) 6.9(2) C(4)-C(5)-C(6)-O(6B) -102.5(4) C(14)-C(5)-C(6)-O(6B) 125.6(4) C(1)-C(5)-C(6)-O(6B) 21.3(4) C(4)-C(5)-C(6)-C(7) 5.6(2) C(14)-C(5)-C(6)-C(7) -126.37(19) C(1)-C(5)-C(6)-C(7) 129.33(19) 480 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.7. Cont’d C(4)-C(5)-C(6)-C(12) 129.03(18) C(14)-C(5)-C(6)-C(12) -2.9(2) C(1)-C(5)-C(6)-C(12) -107.2(2) O(6B)-C(6)-C(7)-O(2) 60.3(4) C(12)-C(6)-C(7)-O(2) 171.8(2) C(5)-C(6)-C(7)-O(2) -57.4(3) O(6B)-C(6)-C(7)-O(1) -116.5(4) C(12)-C(6)-C(7)-O(1) -5.0(2) C(5)-C(6)-C(7)-O(1) 125.80(18) O(2)-C(7)-O(1)-C(8) -169.35(19) C(6)-C(7)-O(1)-C(8) 7.8(2) C(7)-O(1)-C(8)-C(9) -123.23(18) C(7)-O(1)-C(8)-C(12) -7.0(2) O(1)-C(8)-C(9)-C(10) 94.2(2) C(12)-C(8)-C(9)-C(10) -21.8(2) C(8)-C(9)-C(10)-O(3) -74.5(2) C(8)-C(9)-C(10)-C(18) 159.71(18) C(8)-C(9)-C(10)-C(11) 37.8(2) O(3)-C(10)-C(11)-C(13) -50.7(2) C(18)-C(10)-C(11)-C(13) 72.2(2) C(9)-C(10)-C(11)-C(13) -165.64(17) O(3)-C(10)-C(11)-C(12) 74.70(19) C(18)-C(10)-C(11)-C(12) -162.48(17) C(9)-C(10)-C(11)-C(12) -40.28(19) C(13)-C(11)-C(12)-C(6) 36.0(2) C(10)-C(11)-C(12)-C(6) -89.1(2) C(13)-C(11)-C(12)-C(8) 152.21(17) C(10)-C(11)-C(12)-C(8) 27.10(19) O(6B)-C(6)-C(12)-C(11) -142.6(4) C(7)-C(6)-C(12)-C(11) 116.25(18) C(5)-C(6)-C(12)-C(11) -12.8(3) O(6B)-C(6)-C(12)-C(8) 101.8(4) C(7)-C(6)-C(12)-C(8) 0.6(2) C(5)-C(6)-C(12)-C(8) -128.44(18) 481 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.7. Cont’d O(1)-C(8)-C(12)-C(11) -122.18(17) C(9)-C(8)-C(12)-C(11) -3.5(2) O(1)-C(8)-C(12)-C(6) 3.5(2) C(9)-C(8)-C(12)-C(6) 122.15(18) C(12)-C(11)-C(13)-O(4) 135.85(19) C(10)-C(11)-C(13)-O(4) -103.5(2) C(12)-C(11)-C(13)-C(14) -44.4(2) C(10)-C(11)-C(13)-C(14) 76.2(2) O(4)-C(13)-C(14)-C(15) -42.7(3) C(11)-C(13)-C(14)-C(15) 137.55(18) O(4)-C(13)-C(14)-C(5) -150.63(19) C(11)-C(13)-C(14)-C(5) 29.6(3) C(4)-C(5)-C(14)-C(13) -138.52(18) C(6)-C(5)-C(14)-C(13) -5.0(3) C(1)-C(5)-C(14)-C(13) 117.72(18) C(4)-C(5)-C(14)-C(15) 101.83(17) C(6)-C(5)-C(14)-C(15) -124.68(17) C(1)-C(5)-C(14)-C(15) -1.93(15) C(13)-C(14)-C(15)-C(1) -122.46(17) C(5)-C(14)-C(15)-C(1) 1.98(16) C(2)-C(1)-C(15)-C(14) -107.64(17) C(5)-C(1)-C(15)-C(14) -1.92(15) Si(1)-C(1)-C(15)-C(14) 125.28(14) C(16)-Si(1)-C(21)-C(26) -49.7(2) C(17)-Si(1)-C(21)-C(26) -168.77(18) C(1)-Si(1)-C(21)-C(26) 72.18(19) C(16)-Si(1)-C(21)-C(22) 131.85(19) C(17)-Si(1)-C(21)-C(22) 12.8(2) C(1)-Si(1)-C(21)-C(22) -106.24(19) C(26)-C(21)-C(22)-C(23) -0.1(3) Si(1)-C(21)-C(22)-C(23) 178.40(18) C(21)-C(22)-C(23)-C(24) -0.3(4) C(22)-C(23)-C(24)-C(25) 0.1(4) C(23)-C(24)-C(25)-C(26) 0.6(4) 482 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.7. Cont’d C(24)-C(25)-C(26)-C(21) -1.0(4) C(22)-C(21)-C(26)-C(25) 0.8(3) Si(1)-C(21)-C(26)-C(25) -177.75(18) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: 483 484 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.2.8. Hydrogen Bonds for Cyclobutane 465 [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ C(9)-H(9A)...O(2)#1 0.99 2.40 3.280(3) 147.2 C(18)-H(18C)...O(1)#2 0.98 2.64 3.622(3) 175.1 O(3)-H(3O)...O(4)#3 0.81(2) 1.96(2) 2.766(2) 177(3) C(14)-H(14)...O(2)#2 1.00 2.46 3.182(3) 128.6 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,y+1/2,-z+1 #2 x-1,y,z #3 -x,y-1/2,-z+1 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 A7.3 485 X-RAY CRYSTAL STRUCTURE ANALYSIS OF CYCLOBUTANE 466 H HO O H SiMe2Ph O H O 466 Contents Table A7.3.1. Experimental Details Table A7.3.2. Crystal Data Table A7.3.3. Atomic Coordinates Table A7.3.4. Full Bond Distances and Angles Table A7.3.5. Anisotropic Displacement Parameters Table A7.3.6. Hydrogen Atomic Coordinates Table A7.3.7. Torsion Angles Table A7.3.8. Hydrogen Bond Distances and Angle Figure A7.3.1. X-Ray Crystal Structure of Cyclobutane 466 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.3.1. 486 Experimental Details for X-Ray Structure Determination of Cyclobutane 466 Low-temperature diffraction data (f-and w-scans) were collected on a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON II CPAD detector with Cu Ka radiation (l = 1.54178 Å) from an IµS micro-source for the structure of compound V19015. The structure was solved by direct methods using SHELXS1 and refined against F2 on all data by full-matrix least squares with SHELXL-20172 using established refinement techniques.3 All non-hydrogen atoms were refined anisotropically. Unless otherwise noted, all hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Compound 466 crystallizes in the monoclinic space group P21 with one molecule in the asymmetric unit. The coordinates for the hydrogen atom bound to O2 were located in the difference Fourier synthesis and refined semi-freely with the help of a restraint on the O-H distance (0.84(4) Å). The structure was refined as a twin [-1 0 0 0 -1 0 1 0 1]. 487 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.3.2. Crystal Data and Structure Refinement for Cyclobutane 466 Empirical formula C24 H30 O4 Si Formula weight 410.57 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P21 Unit cell dimensions a = 6.7649(5) Å a= 90°. b = 10.9273(9) Å b= 103.394(5)°. c = 14.4629(14) Å g = 90°. Volume 1040.05(15) Å3 Z 2 Density (calculated) 1.311 Mg/m3 Absorption coefficient 1.224 mm-1 F(000) 440 Crystal size 0.200 x 0.150 x 0.050 mm3 Theta range for data collection 3.141 to 74.630°. Index ranges -7<=h<=8, -13<=k<=13, -18<=l<=17 Reflections collected 17179 Independent reflections 4172 [R(int) = 0.0797] Completeness to theta = 67.679° 99.7 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7504 and 0.5626 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4172 / 2 / 269 Goodness-of-fit on F2 1.071 Final R indices [I>2sigma(I)] R1 = 0.0880, wR2 = 0.2288 R indices (all data) R1 = 0.0893, wR2 = 0.2312 Absolute structure parameter 0.03(6) Extinction coefficient n/a Largest diff. peak and hole 0.686 and -0.364 e.Å-3 488 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Cyclobutane 466. U(eq) is Defined as One Third of the Trace of the Orthogonalized Uij Tensor. _______________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ Si(1) 5500(3) 3644(2) 3733(2) 26(1) C(1) 5454(13) 4028(8) 5009(6) 28(2) C(2) 3622(15) 4276(9) 5275(7) 34(2) C(3) 3582(16) 4570(10) 6208(8) 38(2) C(4) 5409(17) 4598(10) 6909(8) 37(2) C(5) 7217(15) 4334(10) 6668(7) 35(2) C(6) 7249(16) 4064(9) 5719(7) 34(2) C(7) 3130(15) 2738(10) 3256(7) 34(2) C(8) 7879(13) 2754(9) 3754(8) 33(2) C(11) 5539(13) 5208(8) 3156(6) 26(2) C(12) 3363(14) 5841(9) 3012(7) 32(2) C(13) 2992(13) 5596(8) 1937(6) 26(2) C(14) 2128(13) 6460(8) 1150(6) 26(2) O(1) 1187(12) 7376(6) 1210(5) 34(2) C(15) 2743(13) 6116(8) 223(6) 27(2) C(16) 1075(14) 5330(8) -431(6) 28(2) C(26) -690(15) 6100(9) -971(7) 34(2) O(2) 321(10) 4436(6) 135(5) 31(1) C(17) 2279(15) 4700(8) -1074(6) 28(2) C(18) 4326(15) 4391(8) -447(6) 29(2) C(19) 4824(13) 5439(8) 283(6) 26(2) C(20) 5848(13) 4788(8) 1237(6) 27(2) C(21) 5101(13) 3456(8) 1047(6) 27(2) O(3) 4251(10) 3301(6) 116(5) 30(1) O(4) 5290(12) 2622(6) 1593(5) 34(2) C(22) 5312(13) 5490(8) 2053(6) 27(2) C(23) 6384(15) 6755(8) 2115(7) 30(2) 489 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.3. Cont’d C(24) 8208(15) 6643(10) 2960(8) 39(2) C(25) 7315(15) 5980(9) 3715(7) 34(2) ________________________________________________________________________________ Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.3.4. Bond Lengths [Å] and angles [°] for Cyclobutane 466 Si(1)-C(8) 1.874(9) Si(1)-C(7) 1.875(10) Si(1)-C(1) 1.900(9) Si(1)-C(11) 1.905(9) C(1)-C(6) 1.397(13) C(1)-C(2) 1.406(13) C(2)-C(3) 1.393(14) C(2)-H(2) 0.9500 C(3)-C(4) 1.406(15) C(3)-H(3) 0.9500 C(4)-C(5) 1.378(15) C(4)-H(4) 0.9500 C(5)-C(6) 1.409(14) C(5)-H(5) 0.9500 C(6)-H(6) 0.9500 C(7)-H(7A) 0.9800 C(7)-H(7B) 0.9800 C(7)-H(7C) 0.9800 C(8)-H(8A) 0.9800 C(8)-H(8B) 0.9800 C(8)-H(8C) 0.9800 C(11)-C(25) 1.535(12) C(11)-C(12) 1.596(12) C(11)-C(22) 1.598(12) C(12)-C(13) 1.541(13) C(12)-H(12A) 0.9900 C(12)-H(12B) 0.9900 C(13)-C(14) 1.489(12) C(13)-C(22) 1.544(12) C(13)-H(13) 1.0000 C(14)-O(1) 1.201(12) C(14)-C(15) 1.541(12) C(15)-C(16) 1.552(12) 490 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.4. Cont’d C(15)-C(19) 1.574(12) C(15)-H(15) 1.0000 C(16)-O(2) 1.441(11) C(16)-C(26) 1.521(13) C(16)-C(17) 1.534(12) C(26)-H(26A) 0.9800 C(26)-H(26B) 0.9800 C(26)-H(26C) 0.9800 O(2)-H(2A) 0.83(3) C(17)-C(18) 1.508(13) C(17)-H(17A) 0.9900 C(17)-H(17B) 0.9900 C(18)-O(3) 1.450(11) C(18)-C(19) 1.541(12) C(18)-H(18) 1.0000 C(19)-C(20) 1.565(12) C(19)-H(19) 1.0000 C(20)-C(22) 1.520(12) C(20)-C(21) 1.544(12) C(20)-H(20) 1.0000 C(21)-O(4) 1.193(11) C(21)-O(3) 1.347(11) C(22)-C(23) 1.554(13) C(23)-C(24) 1.527(13) C(23)-H(23A) 0.9900 C(23)-H(23B) 0.9900 C(24)-C(25) 1.545(14) C(24)-H(24A) 0.9900 C(24)-H(24B) 0.9900 C(25)-H(25A) 0.9900 C(25)-H(25B) 0.9900 C(8)-Si(1)-C(7) 112.9(5) C(8)-Si(1)-C(1) 107.8(4) 491 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.4. Cont’d C(7)-Si(1)-C(1) 105.7(4) C(8)-Si(1)-C(11) 111.9(4) C(7)-Si(1)-C(11) 114.2(4) C(1)-Si(1)-C(11) 103.4(4) C(6)-C(1)-C(2) 117.7(9) C(6)-C(1)-Si(1) 120.9(7) C(2)-C(1)-Si(1) 121.4(7) C(3)-C(2)-C(1) 121.7(9) C(3)-C(2)-H(2) 119.2 C(1)-C(2)-H(2) 119.2 C(2)-C(3)-C(4) 119.5(10) C(2)-C(3)-H(3) 120.2 C(4)-C(3)-H(3) 120.2 C(5)-C(4)-C(3) 119.7(10) C(5)-C(4)-H(4) 120.1 C(3)-C(4)-H(4) 120.1 C(4)-C(5)-C(6) 120.4(9) C(4)-C(5)-H(5) 119.8 C(6)-C(5)-H(5) 119.8 C(1)-C(6)-C(5) 121.0(9) C(1)-C(6)-H(6) 119.5 C(5)-C(6)-H(6) 119.5 Si(1)-C(7)-H(7A) 109.5 Si(1)-C(7)-H(7B) 109.5 H(7A)-C(7)-H(7B) 109.5 Si(1)-C(7)-H(7C) 109.5 H(7A)-C(7)-H(7C) 109.5 H(7B)-C(7)-H(7C) 109.5 Si(1)-C(8)-H(8A) 109.5 Si(1)-C(8)-H(8B) 109.5 H(8A)-C(8)-H(8B) 109.5 Si(1)-C(8)-H(8C) 109.5 H(8A)-C(8)-H(8C) 109.5 H(8B)-C(8)-H(8C) 109.5 492 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.4. Cont’d C(25)-C(11)-C(12) 114.6(7) C(25)-C(11)-C(22) 107.6(7) C(12)-C(11)-C(22) 85.0(6) C(25)-C(11)-Si(1) 110.5(6) C(12)-C(11)-Si(1) 109.9(6) C(22)-C(11)-Si(1) 127.1(6) C(13)-C(12)-C(11) 89.2(7) C(13)-C(12)-H(12A) 113.8 C(11)-C(12)-H(12A) 113.8 C(13)-C(12)-H(12B) 113.8 C(11)-C(12)-H(12B) 113.8 H(12A)-C(12)-H(12B) 111.0 C(14)-C(13)-C(12) 127.2(8) C(14)-C(13)-C(22) 109.9(7) C(12)-C(13)-C(22) 88.8(7) C(14)-C(13)-H(13) 109.5 C(12)-C(13)-H(13) 109.5 C(22)-C(13)-H(13) 109.5 O(1)-C(14)-C(13) 126.4(8) O(1)-C(14)-C(15) 121.4(8) C(13)-C(14)-C(15) 111.9(7) C(14)-C(15)-C(16) 111.1(7) C(14)-C(15)-C(19) 119.0(7) C(16)-C(15)-C(19) 106.8(7) C(14)-C(15)-H(15) 106.4 C(16)-C(15)-H(15) 106.4 C(19)-C(15)-H(15) 106.4 O(2)-C(16)-C(26) 109.1(8) O(2)-C(16)-C(17) 110.3(7) C(26)-C(16)-C(17) 113.6(7) O(2)-C(16)-C(15) 109.4(7) C(26)-C(16)-C(15) 112.3(7) C(17)-C(16)-C(15) 101.8(7) C(16)-C(26)-H(26A) 109.5 493 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.4. Cont’d C(16)-C(26)-H(26B) 109.5 H(26A)-C(26)-H(26B) 109.5 C(16)-C(26)-H(26C) 109.5 H(26A)-C(26)-H(26C) 109.5 H(26B)-C(26)-H(26C) 109.5 C(16)-O(2)-H(2A) 106(10) C(18)-C(17)-C(16) 106.2(7) C(18)-C(17)-H(17A) 110.5 C(16)-C(17)-H(17A) 110.5 C(18)-C(17)-H(17B) 110.5 C(16)-C(17)-H(17B) 110.5 H(17A)-C(17)-H(17B) 108.7 O(3)-C(18)-C(17) 112.0(7) O(3)-C(18)-C(19) 104.9(7) C(17)-C(18)-C(19) 105.7(7) O(3)-C(18)-H(18) 111.3 C(17)-C(18)-H(18) 111.3 C(19)-C(18)-H(18) 111.3 C(18)-C(19)-C(20) 104.4(7) C(18)-C(19)-C(15) 105.1(7) C(20)-C(19)-C(15) 118.0(7) C(18)-C(19)-H(19) 109.7 C(20)-C(19)-H(19) 109.7 C(15)-C(19)-H(19) 109.7 C(22)-C(20)-C(21) 119.2(7) C(22)-C(20)-C(19) 108.6(6) C(21)-C(20)-C(19) 102.2(7) C(22)-C(20)-H(20) 108.8 C(21)-C(20)-H(20) 108.8 C(19)-C(20)-H(20) 108.8 O(4)-C(21)-O(3) 121.4(8) O(4)-C(21)-C(20) 128.5(8) O(3)-C(21)-C(20) 110.1(7) C(21)-O(3)-C(18) 113.3(7) 494 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.4. Cont’d C(20)-C(22)-C(13) 111.9(7) C(20)-C(22)-C(23) 107.6(7) C(13)-C(22)-C(23) 112.9(8) C(20)-C(22)-C(11) 133.8(7) C(13)-C(22)-C(11) 89.0(6) C(23)-C(22)-C(11) 100.2(7) C(24)-C(23)-C(22) 104.8(8) C(24)-C(23)-H(23A) 110.8 C(22)-C(23)-H(23A) 110.8 C(24)-C(23)-H(23B) 110.8 C(22)-C(23)-H(23B) 110.8 H(23A)-C(23)-H(23B) 108.9 C(23)-C(24)-C(25) 103.1(8) C(23)-C(24)-H(24A) 111.1 C(25)-C(24)-H(24A) 111.1 C(23)-C(24)-H(24B) 111.1 C(25)-C(24)-H(24B) 111.1 H(24A)-C(24)-H(24B) 109.1 C(11)-C(25)-C(24) 105.8(8) C(11)-C(25)-H(25A) 110.6 C(24)-C(25)-H(25A) 110.6 C(11)-C(25)-H(25B) 110.6 C(24)-C(25)-H(25B) 110.6 H(25A)-C(25)-H(25B) 108.7 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: 495 496 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.3.5. Anisotropic Displacement Parameters (Å2x103) for Cyclobutane 466. The Anisotropic Displacement Factor Exponent Takes the Form: -2p2[h2a*2U11 + … + 2hka*b*U12]. U11 U22 U33 U23 U13 U12 Si(1) 19(1) 29(1) 32(1) 0(1) 7(1) -1(1) C(1) 26(4) 33(4) 24(4) 2(3) 7(3) 0(3) C(2) 31(5) 36(5) 35(4) 3(4) 11(4) -4(4) C(3) 26(4) 44(5) 44(5) -1(4) 10(4) -13(4) C(4) 42(6) 32(4) 39(5) -4(4) 15(4) -2(4) C(5) 27(4) 41(5) 34(5) 2(4) 4(4) -8(4) C(6) 30(4) 34(5) 37(5) 2(3) 5(4) -2(4) C(7) 27(4) 41(5) 37(5) -3(4) 10(4) -1(4) C(8) 20(4) 34(5) 47(5) 1(4) 11(4) 7(3) C(11) 21(4) 31(4) 30(4) -2(3) 10(3) 4(3) C(12) 26(4) 32(4) 37(5) 3(4) 10(4) 7(4) C(13) 21(4) 29(4) 31(4) -1(3) 11(3) 0(3) C(14) 15(3) 30(4) 34(4) -1(3) 7(3) -2(3) O(1) 32(3) 38(4) 36(3) 0(3) 12(3) 9(3) C(15) 22(4) 31(4) 28(4) 2(3) 7(3) 2(3) C(16) 24(4) 28(4) 31(4) 2(3) 7(3) -3(4) C(26) 26(4) 35(5) 42(5) -2(4) 9(4) -1(4) O(2) 25(3) 34(3) 35(3) 1(2) 12(3) 0(3) C(17) 30(4) 24(4) 34(4) -1(3) 12(3) -1(3) C(18) 30(4) 26(4) 33(4) -2(3) 13(3) -2(4) C(19) 21(4) 29(4) 29(4) 0(3) 8(3) 2(3) C(20) 20(4) 22(4) 40(4) -2(3) 10(3) 5(3) C(21) 22(4) 29(4) 31(4) -1(3) 9(3) 6(3) O(3) 27(3) 29(3) 32(3) -1(2) 7(2) 2(2) O(4) 35(4) 31(3) 37(3) 3(3) 9(3) -1(3) C(22) 20(4) 28(4) 33(4) 3(3) 6(3) 5(3) C(23) 29(4) 28(4) 34(4) 0(3) 7(4) 0(4) C(24) 26(5) 41(5) 48(6) 2(4) 4(4) -9(4) C(25) 32(4) 31(4) 35(4) 1(4) 3(4) -6(4) ______________________________________________________________________________ 497 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.3.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Cyclobutane 466. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(2) 2380 4242 4806 40 H(3) 2330 4751 6369 45 H(4) 5397 4799 7547 44 H(5) 8449 4333 7144 42 H(6) 8510 3903 5559 41 H(7A) 1946 3280 3161 52 H(7B) 3004 2092 3709 52 H(7C) 3201 2367 2647 52 H(8A) 8045 2119 4244 50 H(8B) 9051 3307 3897 50 H(8C) 7785 2371 3133 50 H(12A) 2417 5398 3324 38 H(12B) 3426 6721 3180 38 H(13) 2354 4772 1789 31 H(15) 2817 6900 -124 32 H(26A) -1691 5569 -1381 51 H(26B) -188 6704 -1362 51 H(26C) -1329 6524 -518 51 H(2A) -100(200) 3860(90) -230(80) 46 H(17A) 1573 3948 -1357 34 H(17B) 2433 5255 -1594 34 H(18) 5385 4317 -825 35 H(19) 5814 6014 96 31 H(20) 7355 4806 1316 32 H(23A) 6832 6932 1524 36 H(23B) 5462 7416 2222 36 H(24A) 8746 7459 3189 47 H(24B) 9308 6156 2792 47 498 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.6. Cont’d H(25A) 8353 5450 4119 40 H(25B) 6829 6579 4125 40 ________________________________________________________________________________ Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.3.7. Torsion Angles [°] for Cyclobutane 466. ________________________________________________________________ C(8)-Si(1)-C(1)-C(6) 23.2(9) C(7)-Si(1)-C(1)-C(6) 144.2(8) C(11)-Si(1)-C(1)-C(6) -95.5(8) C(8)-Si(1)-C(1)-C(2) -156.3(8) C(7)-Si(1)-C(1)-C(2) -35.2(9) C(11)-Si(1)-C(1)-C(2) 85.1(8) C(6)-C(1)-C(2)-C(3) 1.2(15) Si(1)-C(1)-C(2)-C(3) -179.4(8) C(1)-C(2)-C(3)-C(4) -1.3(15) C(2)-C(3)-C(4)-C(5) -0.1(16) C(3)-C(4)-C(5)-C(6) 1.5(16) C(2)-C(1)-C(6)-C(5) 0.3(15) Si(1)-C(1)-C(6)-C(5) -179.2(8) C(4)-C(5)-C(6)-C(1) -1.6(16) C(25)-C(11)-C(12)-C(13) 127.8(8) C(22)-C(11)-C(12)-C(13) 20.7(6) Si(1)-C(11)-C(12)-C(13) -107.0(6) C(11)-C(12)-C(13)-C(14) -135.6(8) C(11)-C(12)-C(13)-C(22) -21.4(7) C(12)-C(13)-C(14)-O(1) -17.2(15) C(22)-C(13)-C(14)-O(1) -121.5(10) C(12)-C(13)-C(14)-C(15) 157.4(8) C(22)-C(13)-C(14)-C(15) 53.1(10) O(1)-C(14)-C(15)-C(16) -89.6(11) C(13)-C(14)-C(15)-C(16) 95.4(8) O(1)-C(14)-C(15)-C(19) 145.8(9) C(13)-C(14)-C(15)-C(19) -29.2(11) C(14)-C(15)-C(16)-O(2) -42.2(10) C(19)-C(15)-C(16)-O(2) 89.0(8) C(14)-C(15)-C(16)-C(26) 79.1(9) C(19)-C(15)-C(16)-C(26) -149.6(8) C(14)-C(15)-C(16)-C(17) -159.0(7) 499 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.7. Cont’d C(19)-C(15)-C(16)-C(17) -27.8(8) O(2)-C(16)-C(17)-C(18) -77.6(9) C(26)-C(16)-C(17)-C(18) 159.5(7) C(15)-C(16)-C(17)-C(18) 38.5(8) C(16)-C(17)-C(18)-O(3) 79.1(8) C(16)-C(17)-C(18)-C(19) -34.6(9) O(3)-C(18)-C(19)-C(20) 22.3(8) C(17)-C(18)-C(19)-C(20) 140.8(7) O(3)-C(18)-C(19)-C(15) -102.6(7) C(17)-C(18)-C(19)-C(15) 16.0(9) C(14)-C(15)-C(19)-C(18) 134.4(8) C(16)-C(15)-C(19)-C(18) 7.8(9) C(14)-C(15)-C(19)-C(20) 18.7(11) C(16)-C(15)-C(19)-C(20) -107.9(8) C(18)-C(19)-C(20)-C(22) -147.5(7) C(15)-C(19)-C(20)-C(22) -31.4(10) C(18)-C(19)-C(20)-C(21) -20.7(8) C(15)-C(19)-C(20)-C(21) 95.4(8) C(22)-C(20)-C(21)-O(4) -51.9(12) C(19)-C(20)-C(21)-O(4) -171.5(9) C(22)-C(20)-C(21)-O(3) 132.0(8) C(19)-C(20)-C(21)-O(3) 12.4(8) O(4)-C(21)-O(3)-C(18) -174.6(8) C(20)-C(21)-O(3)-C(18) 1.9(9) C(17)-C(18)-O(3)-C(21) -129.8(7) C(19)-C(18)-O(3)-C(21) -15.7(9) C(21)-C(20)-C(22)-C(13) -59.4(10) C(19)-C(20)-C(22)-C(13) 57.0(9) C(21)-C(20)-C(22)-C(23) 176.1(7) C(19)-C(20)-C(22)-C(23) -67.6(8) C(21)-C(20)-C(22)-C(11) 51.8(13) C(19)-C(20)-C(22)-C(11) 168.1(9) C(14)-C(13)-C(22)-C(20) -71.5(10) C(12)-C(13)-C(22)-C(20) 159.0(7) 500 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.3.7. Cont’d C(14)-C(13)-C(22)-C(23) 50.1(10) C(12)-C(13)-C(22)-C(23) -79.4(8) C(14)-C(13)-C(22)-C(11) 150.8(7) C(12)-C(13)-C(22)-C(11) 21.3(7) C(25)-C(11)-C(22)-C(20) 105.0(10) C(12)-C(11)-C(22)-C(20) -140.7(10) Si(1)-C(11)-C(22)-C(20) -29.5(13) C(25)-C(11)-C(22)-C(13) -134.9(7) C(12)-C(11)-C(22)-C(13) -20.6(7) Si(1)-C(11)-C(22)-C(13) 90.6(8) C(25)-C(11)-C(22)-C(23) -21.8(8) C(12)-C(11)-C(22)-C(23) 92.4(7) Si(1)-C(11)-C(22)-C(23) -156.3(7) C(20)-C(22)-C(23)-C(24) -103.1(8) C(13)-C(22)-C(23)-C(24) 132.9(8) C(11)-C(22)-C(23)-C(24) 39.6(9) C(22)-C(23)-C(24)-C(25) -43.1(10) C(12)-C(11)-C(25)-C(24) -96.0(9) C(22)-C(11)-C(25)-C(24) -3.4(10) Si(1)-C(11)-C(25)-C(24) 139.2(7) C(23)-C(24)-C(25)-C(11) 28.0(10) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: 501 502 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.3.8. Hydrogen Bonds for Cyclobutane 466 [Å and °]. D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ C(13)-H(13)...O(2) 1.00 2.49 3.079(11) 116.9 C(15)-H(15)...O(3)#1 1.00 2.50 3.246(11) 130.8 O(2)-H(2A)...O(1)#2 0.83(3) 2.16(3) 2.996(10) 178(15) C(17)-H(17A)...O(1)#2 0.99 2.58 3.430(11) 143.8 C(19)-H(19)...O(3)#1 1.00 2.52 3.267(11) 131.5 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,y+1/2,-z #2 -x,y-1/2,-z Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 A7.4 503 X-RAY CRYSTAL STRUCTURE ANALYSIS OF CYCLOHEPTANE 468 O H HO Cl H O O H O 468 Contents Table A7.4.1. Experimental Details Table A7.4.2. Crystal Data Table A7.4.3. Atomic Coordinates Table A7.4.4. Full Bond Distances and Angles Table A7.4.5. Anisotropic Displacement Parameters Table A7.4.6. Hydrogen Atomic Coordinates Table A7.4.7. Torsion Angles Table A7.4.8. Hydrogen Bond Distances and Angle Figure A7.4.1. X-Ray Crystal Structure of Cycloheptane 468 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.1. 504 Experimental Details for X-Ray Structure Determination of Cycloheptane 468 Refinement details A crystal was mounted on a polyimide MiTeGen loop with STP Oil Treatment and placed under a nitrogen stream. Low temperature (100K) X-ray data were collected with a Bruker AXS D8 VENTURE KAPPA diffractometer running at 50 kV and 1mA (Cu Ka = 1.54178 Å; PHOTON II CPAD detector and Helios focusing multilayer mirror optics). All diffractometer manipulations, including data collection, integration, and scaling were carried out using the Bruker APEX3 software. An absorption correction was applied using SADABS. The space group was determined and the structure solved by intrinsic phasing using XT. Refinement was full-matrix least squares on F2 using XL. All nonhydrogen atoms (except the carbon of a disordered chloroform) were refined using anisotropic displacement parameters. Hydrogen atoms were placed in idealized positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed at 1.2 times (1.5 times for methyl groups) the Ueq value of the bonded atom. Special refinement details Compound 468 crystallizes in the monoclinic space group C2 with two molecules, one water molecule, and 38% of a chloroform in the asymmetric unit. The structure was refined as a two-component twin (refined ratio of 85:15) on an HKLF 5 file generated by PLATON. 505 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.2. Crystal Data and Structure Refinement for Cycloheptane 468 Empirical formula C16.19 H20.19 Cl1.59 O5.50 Formula weight 359.09 Temperature 100 K Wavelength 1.54178 Å Crystal system Monoclinic Space group C121 Unit cell dimensions a = 34.102(5) Å a= 90° b = 14.485(2) Å b= 94.960(10)° c = 6.6087(11) Å g = 90° Volume 3252.2(9) Å3 Z 8 Density (calculated) 1.467 g/cm3 Absorption coefficient 3.208 mm-1 F(000) 1507 Crystal size 0.11 x 0.04 x 0.03 mm3 Theta range for data collection 3.317 to 76.122°. Index ranges -41 £ h £ 40, -17 £ k £ 17, 0 £ l £ 8 Reflections collected 6144 Independent reflections 6144 [R(int) = ?] Completeness to theta = 67.679° 98.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9904 and 0.7072 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6144 / 4 / 434 Goodness-of-fit on F2 1.065 Final R indices [I>2sigma(I)] R1 = 0.0840, wR2 = 0.2207 R indices (all data) R1 = 0.0969, wR2 = 0.2291 Absolute structure parameter [Flack] 0.163(12) Extinction coefficient n/a Largest diff. peak and hole 0.708 and -0.538 e.Å-3 506 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.3. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (Å2x 103) for Cycloheptane 468. U(eq) is Defined as One Third of the Trace of the Orthogonalized Uij Tensor. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ Cl(1) 6462(1) 349(2) 11229(4) 36(1) O(1) 6294(2) 1950(4) 12668(10) 25(1) O(2) 5281(2) 2980(5) 8327(10) 29(2) O(3) 6853(2) 3559(5) 11901(10) 28(1) O(4) 6508(2) 4844(4) 11323(10) 25(1) O(5) 6000(2) 4396(5) 7538(10) 27(1) C(1) 6013(2) 2698(6) 12313(13) 23(2) C(2) 5664(3) 2506(7) 13588(15) 31(2) C(3) 5480(3) 1561(8) 13098(18) 38(2) C(4) 5790(3) 823(7) 12868(19) 40(3) C(5) 6094(3) 1208(7) 11574(16) 30(2) C(6) 5924(3) 1617(7) 9532(16) 32(2) C(7) 5919(3) 2650(6) 10038(12) 21(2) C(8) 5562(3) 3240(7) 9446(13) 25(2) C(9) 5591(2) 4203(6) 10287(12) 21(2) C(10) 5876(3) 4396(6) 12246(13) 19(2) C(11) 6178(2) 3656(6) 12938(13) 20(2) C(12) 6543(3) 3974(7) 12019(13) 23(2) C(13) 6124(2) 5226(6) 11765(12) 20(2) C(14) 5911(3) 5671(6) 9851(14) 24(2) C(15) 5723(2) 4889(7) 8647(13) 23(2) C(16) 5371(3) 5187(8) 7186(16) 37(2) Cl(1B) 5600(1) 7225(2) 14099(5) 54(1) O(1B) 6287(2) 7010(5) 16090(11) 35(2) O(2B) 7121(2) 8559(5) 12394(11) 41(2) O(3B) 6650(2) 5146(5) 15897(10) 31(2) O(4B) 7290(2) 5266(6) 15553(12) 43(2) 507 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.3. Cont’d O(5B) 7372(2) 6411(5) 11759(11) 33(2) C(1B) 6692(4) 7307(8) 16092(16) 42(3) C(2B) 6754(5) 8185(9) 17260(18) 64(4) C(3B) 6466(5) 8945(9) 16450(19) 65(4) C(4B) 6047(5) 8570(9) 15850(20) 63(4) C(5B) 6081(3) 7679(8) 14762(17) 42(3) C(6B) 6326(3) 7773(7) 12972(15) 33(2) C(7B) 6725(3) 7396(7) 13782(13) 30(2) C(8B) 7108(3) 7877(7) 13444(13) 32(2) C(9B) 7466(3) 7454(8) 14569(15) 40(3) C(10B) 7409(3) 6845(10) 16518(15) 46(3) C(11B) 6992(3) 6573(9) 16972(16) 42(3) C(12B) 6950(3) 5610(8) 16141(16) 36(2) C(13B) 7614(3) 5924(10) 16200(20) 55(4) C(14B) 7873(3) 6067(10) 14504(19) 51(3) C(15B) 7675(3) 6800(8) 13096(15) 35(2) C(16B) 7962(3) 7313(9) 11897(15) 44(3) O(6) 7478(2) 4630(5) 10479(12) 41(2) Cl(2) 5193(2) -332(5) 7527(14) 100(5) Cl(3) 4852(3) -647(9) 11220(19) 169(12) Cl(4) 5237(3) -2147(5) 9390(20) 147(9) C(17) 4947(2) -1158(6) 8908(16) 130(30) ________________________________________________________________________________ Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.4. Bond Lengths [Å] and angles [°] for Cycloheptane 468 _____________________________________________________ Cl(1)-C(5) 1.796(10) O(1)-C(1) 1.452(10) O(1)-C(5) 1.435(11) O(2)-C(8) 1.217(11) O(3)-C(12) 1.224(11) O(4)-C(12) 1.343(11) O(4)-C(13) 1.473(10) O(5)-H(5) 0.8400 O(5)-C(15) 1.434(10) C(1)-C(2) 1.542(12) C(1)-C(7) 1.512(12) C(1)-C(11) 1.541(12) C(2)-H(2A) 0.9900 C(2)-H(2B) 0.9900 C(2)-C(3) 1.528(15) C(3)-H(3A) 0.9900 C(3)-H(3B) 0.9900 C(3)-C(4) 1.521(15) C(4)-H(4A) 0.9900 C(4)-H(4B) 0.9900 C(4)-C(5) 1.505(15) C(5)-C(6) 1.540(13) C(6)-H(6A) 0.9900 C(6)-H(6B) 0.9900 C(6)-C(7) 1.533(13) C(7)-H(7) 1.0000 C(7)-C(8) 1.511(13) C(8)-C(9) 1.501(13) C(9)-H(9) 1.0000 C(9)-C(10) 1.576(12) C(9)-C(15) 1.564(12) C(10)-H(10) 1.0000 508 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.4. Cont’d C(10)-C(11) 1.528(12) C(10)-C(13) 1.520(12) C(11)-H(11) 1.0000 C(11)-C(12) 1.504(12) C(13)-H(13) 1.0000 C(13)-C(14) 1.544(12) C(14)-H(14A) 0.9900 C(14)-H(14B) 0.9900 C(14)-C(15) 1.497(13) C(15)-C(16) 1.534(13) C(16)-H(16A) 0.9800 C(16)-H(16B) 0.9800 C(16)-H(16C) 0.9800 Cl(1B)-C(5B) 1.788(13) O(1B)-C(1B) 1.447(13) O(1B)-C(5B) 1.448(13) O(2B)-C(8B) 1.210(12) O(3B)-C(12B) 1.223(12) O(4B)-C(12B) 1.350(14) O(4B)-C(13B) 1.495(14) O(5B)-H(5B) 0.8400 O(5B)-C(15B) 1.416(12) C(1B)-C(2B) 1.494(16) C(1B)-C(7B) 1.546(13) C(1B)-C(11B) 1.553(18) C(2B)-H(2C) 0.9900 C(2B)-H(2D) 0.9900 C(2B)-C(3B) 1.54(2) C(3B)-H(3C) 0.9900 C(3B)-H(3D) 0.9900 C(3B)-C(4B) 1.55(2) C(4B)-H(4D) 0.9900 C(4B)-H(4C) 0.9900 C(4B)-C(5B) 1.487(18) 509 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.4. Cont’d C(5B)-C(6B) 1.513(15) C(6B)-H(6C) 0.9900 C(6B)-H(6D) 0.9900 C(6B)-C(7B) 1.519(15) C(7B)-H(7B) 1.0000 C(7B)-C(8B) 1.514(13) C(8B)-C(9B) 1.504(16) C(9B)-H(9B) 1.0000 C(9B)-C(10B) 1.586(14) C(9B)-C(15B) 1.572(16) C(10B)-H(10B) 1.0000 C(10B)-C(11B) 1.531(15) C(10B)-C(13B) 1.53(2) C(11B)-H(11B) 1.0000 C(11B)-C(12B) 1.502(17) C(13B)-H(13B) 1.0000 C(13B)-C(14B) 1.503(18) C(14B)-H(14C) 0.9900 C(14B)-H(14D) 0.9900 C(14B)-C(15B) 1.531(16) C(15B)-C(16B) 1.510(13) C(16B)-H(16D) 0.9800 C(16B)-H(16E) 0.9800 C(16B)-H(16F) 0.9800 O(6)-H(6E) 0.8689 O(6)-H(6F) 0.9962 Cl(2)-Cl(3)#1 0.969(17) Cl(2)-C(17) 1.7602 Cl(3)-Cl(4)#1 2.227(5) Cl(3)-C(17) 1.7534 Cl(4)-C(17) 1.7546 C(17)-H(17) 0.9198 C(5)-O(1)-C(1) 101.4(6) 510 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.4. Cont’d C(12)-O(4)-C(13) 109.9(7) C(15)-O(5)-H(5) 109.5 O(1)-C(1)-C(2) 107.9(7) O(1)-C(1)-C(7) 102.0(7) O(1)-C(1)-C(11) 114.1(7) C(7)-C(1)-C(2) 115.3(8) C(7)-C(1)-C(11) 110.5(7) C(11)-C(1)-C(2) 107.3(7) C(1)-C(2)-H(2A) 109.3 C(1)-C(2)-H(2B) 109.3 H(2A)-C(2)-H(2B) 108.0 C(3)-C(2)-C(1) 111.5(8) C(3)-C(2)-H(2A) 109.3 C(3)-C(2)-H(2B) 109.3 C(2)-C(3)-H(3A) 109.2 C(2)-C(3)-H(3B) 109.2 H(3A)-C(3)-H(3B) 107.9 C(4)-C(3)-C(2) 112.1(8) C(4)-C(3)-H(3A) 109.2 C(4)-C(3)-H(3B) 109.2 C(3)-C(4)-H(4A) 110.0 C(3)-C(4)-H(4B) 110.0 H(4A)-C(4)-H(4B) 108.4 C(5)-C(4)-C(3) 108.3(8) C(5)-C(4)-H(4A) 110.0 C(5)-C(4)-H(4B) 110.0 O(1)-C(5)-Cl(1) 105.9(6) O(1)-C(5)-C(4) 108.2(9) O(1)-C(5)-C(6) 106.3(8) C(4)-C(5)-Cl(1) 109.7(7) C(4)-C(5)-C(6) 114.6(8) C(6)-C(5)-Cl(1) 111.7(7) C(5)-C(6)-H(6A) 111.5 C(5)-C(6)-H(6B) 111.5 511 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.4. Cont’d H(6A)-C(6)-H(6B) 109.3 C(7)-C(6)-C(5) 101.2(8) C(7)-C(6)-H(6A) 111.5 C(7)-C(6)-H(6B) 111.5 C(1)-C(7)-C(6) 104.9(7) C(1)-C(7)-H(7) 106.9 C(1)-C(7)-C(8) 109.2(7) C(6)-C(7)-H(7) 106.9 C(8)-C(7)-C(6) 121.3(7) C(8)-C(7)-H(7) 106.9 O(2)-C(8)-C(7) 123.7(9) O(2)-C(8)-C(9) 122.4(9) C(9)-C(8)-C(7) 113.8(7) C(8)-C(9)-H(9) 107.2 C(8)-C(9)-C(10) 119.0(7) C(8)-C(9)-C(15) 110.3(7) C(10)-C(9)-H(9) 107.2 C(15)-C(9)-H(9) 107.2 C(15)-C(9)-C(10) 105.3(7) C(9)-C(10)-H(10) 109.2 C(11)-C(10)-C(9) 118.3(7) C(11)-C(10)-H(10) 109.2 C(13)-C(10)-C(9) 106.4(7) C(13)-C(10)-H(10) 109.2 C(13)-C(10)-C(11) 104.2(7) C(1)-C(11)-H(11) 108.9 C(10)-C(11)-C(1) 109.3(7) C(10)-C(11)-H(11) 108.9 C(12)-C(11)-C(1) 117.6(7) C(12)-C(11)-C(10) 103.0(7) C(12)-C(11)-H(11) 108.9 O(3)-C(12)-O(4) 119.4(8) O(3)-C(12)-C(11) 128.7(9) O(4)-C(12)-C(11) 111.8(7) 512 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.4. Cont’d O(4)-C(13)-C(10) 105.3(7) O(4)-C(13)-H(13) 111.5 O(4)-C(13)-C(14) 110.9(7) C(10)-C(13)-H(13) 111.5 C(10)-C(13)-C(14) 105.8(7) C(14)-C(13)-H(13) 111.5 C(13)-C(14)-H(14A) 110.6 C(13)-C(14)-H(14B) 110.6 H(14A)-C(14)-H(14B) 108.7 C(15)-C(14)-C(13) 105.7(7) C(15)-C(14)-H(14A) 110.6 C(15)-C(14)-H(14B) 110.6 O(5)-C(15)-C(9) 106.2(7) O(5)-C(15)-C(14) 112.1(7) O(5)-C(15)-C(16) 109.3(7) C(14)-C(15)-C(9) 104.4(7) C(14)-C(15)-C(16) 113.5(8) C(16)-C(15)-C(9) 111.1(7) C(15)-C(16)-H(16A) 109.5 C(15)-C(16)-H(16B) 109.5 C(15)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 C(1B)-O(1B)-C(5B) 102.4(8) C(12B)-O(4B)-C(13B) 108.3(10) C(15B)-O(5B)-H(5B) 109.5 O(1B)-C(1B)-C(2B) 110.3(11) O(1B)-C(1B)-C(7B) 100.1(8) O(1B)-C(1B)-C(11B) 113.2(8) C(2B)-C(1B)-C(7B) 114.9(9) C(2B)-C(1B)-C(11B) 109.3(11) C(7B)-C(1B)-C(11B) 109.0(9) C(1B)-C(2B)-H(2C) 109.3 513 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.4. Cont’d C(1B)-C(2B)-H(2D) 109.3 C(1B)-C(2B)-C(3B) 111.7(12) H(2C)-C(2B)-H(2D) 107.9 C(3B)-C(2B)-H(2C) 109.3 C(3B)-C(2B)-H(2D) 109.3 C(2B)-C(3B)-H(3C) 109.1 C(2B)-C(3B)-H(3D) 109.1 C(2B)-C(3B)-C(4B) 112.7(11) H(3C)-C(3B)-H(3D) 107.8 C(4B)-C(3B)-H(3C) 109.1 C(4B)-C(3B)-H(3D) 109.1 C(3B)-C(4B)-H(4D) 110.0 C(3B)-C(4B)-H(4C) 110.0 H(4D)-C(4B)-H(4C) 108.3 C(5B)-C(4B)-C(3B) 108.7(11) C(5B)-C(4B)-H(4D) 110.0 C(5B)-C(4B)-H(4C) 110.0 O(1B)-C(5B)-Cl(1B) 106.8(7) O(1B)-C(5B)-C(4B) 110.0(10) O(1B)-C(5B)-C(6B) 105.2(9) C(4B)-C(5B)-Cl(1B) 109.2(10) C(4B)-C(5B)-C(6B) 111.8(10) C(6B)-C(5B)-Cl(1B) 113.5(8) C(5B)-C(6B)-H(6C) 111.1 C(5B)-C(6B)-H(6D) 111.1 C(5B)-C(6B)-C(7B) 103.3(8) H(6C)-C(6B)-H(6D) 109.1 C(7B)-C(6B)-H(6C) 111.1 C(7B)-C(6B)-H(6D) 111.1 C(1B)-C(7B)-H(7B) 106.9 C(6B)-C(7B)-C(1B) 103.8(8) C(6B)-C(7B)-H(7B) 106.9 C(8B)-C(7B)-C(1B) 108.8(8) C(8B)-C(7B)-C(6B) 122.6(8) 514 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.4. Cont’d C(8B)-C(7B)-H(7B) 106.9 O(2B)-C(8B)-C(7B) 122.5(10) O(2B)-C(8B)-C(9B) 123.2(9) C(9B)-C(8B)-C(7B) 114.3(8) C(8B)-C(9B)-H(9B) 107.8 C(8B)-C(9B)-C(10B) 118.5(9) C(8B)-C(9B)-C(15B) 109.3(8) C(10B)-C(9B)-H(9B) 107.8 C(15B)-C(9B)-H(9B) 107.8 C(15B)-C(9B)-C(10B) 105.1(9) C(9B)-C(10B)-H(10B) 108.9 C(11B)-C(10B)-C(9B) 118.9(9) C(11B)-C(10B)-H(10B) 108.9 C(13B)-C(10B)-C(9B) 106.6(9) C(13B)-C(10B)-H(10B) 108.9 C(13B)-C(10B)-C(11B) 104.2(10) C(1B)-C(11B)-H(11B) 108.6 C(10B)-C(11B)-C(1B) 110.1(9) C(10B)-C(11B)-H(11B) 108.6 C(12B)-C(11B)-C(1B) 117.4(9) C(12B)-C(11B)-C(10B) 103.2(10) C(12B)-C(11B)-H(11B) 108.6 O(3B)-C(12B)-O(4B) 119.2(10) O(3B)-C(12B)-C(11B) 127.7(10) O(4B)-C(12B)-C(11B) 113.0(9) O(4B)-C(13B)-C(10B) 105.1(9) O(4B)-C(13B)-H(13B) 111.6 O(4B)-C(13B)-C(14B) 109.9(11) C(10B)-C(13B)-H(13B) 111.6 C(14B)-C(13B)-C(10B) 106.6(10) C(14B)-C(13B)-H(13B) 111.6 C(13B)-C(14B)-H(14C) 110.3 C(13B)-C(14B)-H(14D) 110.3 C(13B)-C(14B)-C(15B) 107.0(11) 515 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.4. Cont’d H(14C)-C(14B)-H(14D) 108.6 C(15B)-C(14B)-H(14C) 110.3 C(15B)-C(14B)-H(14D) 110.3 O(5B)-C(15B)-C(9B) 106.4(8) O(5B)-C(15B)-C(14B) 111.3(9) O(5B)-C(15B)-C(16B) 109.8(8) C(14B)-C(15B)-C(9B) 104.0(9) C(16B)-C(15B)-C(9B) 112.2(9) C(16B)-C(15B)-C(14B) 112.8(9) C(15B)-C(16B)-H(16D) 109.5 C(15B)-C(16B)-H(16E) 109.5 C(15B)-C(16B)-H(16F) 109.5 H(16D)-C(16B)-H(16E) 109.5 H(16D)-C(16B)-H(16F) 109.5 H(16E)-C(16B)-H(16F) 109.5 H(6E)-O(6)-H(6F) 111.1 Cl(3)#1-Cl(2)-C(17) 28.3(8) Cl(2)#1-Cl(3)-Cl(4)#1 125.8(10) Cl(2)#1-Cl(3)-C(17) 176.6(7) C(17)-Cl(3)-Cl(4)#1 57.4(6) Cl(2)-C(17)-Cl(4)#1 170.4(6) Cl(2)-C(17)-H(17) 109.8 Cl(3)-C(17)-Cl(2) 107.2 Cl(3)#1-C(17)-Cl(2) 26.9(11) Cl(3)#1-C(17)-Cl(3) 86.6(10) Cl(3)#1-C(17)-Cl(4)#1 146.3(17) Cl(3)#1-C(17)-Cl(4) 103.7(6) Cl(3)-C(17)-Cl(4)#1 73.5(5) Cl(3)-C(17)-Cl(4) 109.3 Cl(3)#1-C(17)-H(17) 134.5 Cl(3)-C(17)-H(17) 109.0 Cl(4)-C(17)-Cl(2) 111.4 Cl(4)-C(17)-Cl(4)#1 60.1(6) Cl(4)#1-C(17)-H(17) 78.5 516 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A.7.4.4. Cont’d Cl(4)-C(17)-H(17) 110.1 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,y,-z+2 517 518 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.5. Anisotropic Displacement Parameters (Å2x103) for Cycloheptane 468. The Anisotropic Displacement Factor Exponent Takes the Form: -2p2[h2a*2U11 + … + 2hka*b*U12]. ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Cl(1) 36(1) 26(1) 42(1) -7(1) -7(1) 4(1) O(1) 21(3) 22(3) 31(3) -2(3) -3(3) 3(2) O(2) 21(3) 42(4) 22(3) 2(3) -10(2) -9(3) O(3) 24(3) 28(3) 33(4) -11(3) 1(3) 6(3) O(4) 24(3) 20(3) 32(3) -2(3) 2(3) 3(3) O(5) 28(3) 32(4) 22(3) -4(3) 10(3) -6(3) C(1) 22(4) 22(4) 23(4) 2(4) 3(3) 1(4) C(2) 27(5) 30(5) 36(5) 11(4) 8(4) 3(4) C(3) 30(5) 38(6) 47(6) 20(5) 5(4) 4(4) C(4) 41(6) 24(5) 56(7) 10(5) -2(5) -5(4) C(5) 25(5) 28(5) 36(5) 3(4) -9(4) -1(4) C(6) 32(5) 26(5) 34(5) -2(4) -16(4) 2(4) C(7) 27(4) 15(4) 19(4) -5(3) -4(3) -2(4) C(8) 24(5) 35(5) 17(4) 0(4) 1(3) -2(4) C(9) 18(4) 31(5) 14(4) 2(4) 0(3) 1(4) C(10) 28(4) 14(4) 14(4) 1(3) -1(3) 4(3) C(11) 20(4) 24(4) 16(4) -7(3) 2(3) -1(3) C(12) 23(4) 28(5) 18(4) -12(4) -4(3) 1(4) C(13) 21(4) 21(4) 18(4) -8(3) 1(3) 0(3) C(14) 26(4) 21(4) 24(5) 0(4) -2(4) 1(3) C(15) 22(4) 32(5) 15(4) 1(4) 3(3) -1(4) C(16) 37(5) 42(6) 30(5) 12(5) -6(4) -1(5) Cl(1B) 45(2) 40(2) 77(2) 16(2) 14(1) 11(1) O(1B) 44(4) 32(4) 31(4) 9(3) 9(3) -5(3) O(2B) 65(5) 26(4) 34(4) -2(3) 13(4) -15(3) O(3B) 27(3) 37(4) 27(3) 5(3) -3(3) -5(3) O(4B) 20(3) 52(5) 55(5) 28(4) -6(3) -6(3) 519 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.5. Cont’d O(5B) 35(4) 26(4) 37(4) 0(3) -9(3) -1(3) C(1B) 58(7) 38(6) 29(5) -10(5) 4(5) -19(5) C(2B) 122(13) 46(7) 27(6) -11(6) 20(7) -34(8) C(3B) 129(14) 37(7) 32(6) -17(5) 28(8) -16(8) C(4B) 97(11) 37(7) 59(8) 7(6) 39(8) 10(7) C(5B) 50(6) 35(6) 42(6) 5(5) 8(5) 1(5) C(6B) 50(6) 19(5) 28(5) 2(4) 3(4) -6(4) C(7B) 42(5) 32(6) 17(4) -6(4) 7(4) -12(4) C(8B) 50(6) 32(5) 12(4) 2(4) 2(4) -15(5) C(9B) 50(6) 45(7) 23(5) -2(5) -2(4) -32(5) C(10B) 43(6) 75(9) 19(5) 4(5) -8(4) -38(6) C(11B) 45(6) 59(8) 23(5) 2(5) 5(4) -29(6) C(12B) 29(5) 47(7) 31(5) 14(4) -7(4) -13(4) C(13B) 34(6) 79(10) 50(7) 32(7) -12(5) -24(6) C(14B) 30(6) 75(9) 46(7) 27(6) -10(5) -20(6) C(15B) 36(5) 43(6) 25(5) 13(4) -4(4) -14(5) C(16B) 53(7) 59(8) 20(5) 5(5) 6(4) -22(6) O(6) 39(4) 37(4) 49(5) -11(4) 14(3) -6(3) Cl(2) 78(8) 64(7) 162(16) 5(8) 34(9) 31(6) Cl(3) 74(10) 310(40) 120(15) 28(19) 16(10) -12(15) Cl(4) 100(10) 200(20) 148(15) 93(14) 27(10) 74(12) ______________________________________________________________________________ 520 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.6. Hydrogen Coordinates (x104) and Isotropic Displacement Parameters (Å2x103) for Cycloheptane 468. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(5) 6187 4747 7314 40 H(2A) 5756 2532 15049 37 H(2B) 5462 2991 13313 37 H(3A) 5316 1380 14197 46 H(3B) 5307 1603 11821 46 H(4A) 5916 646 14219 49 H(4B) 5667 266 12218 49 H(6A) 6096 1485 8433 38 H(6B) 5656 1381 9136 38 H(7) 6145 2937 9406 25 H(9) 5321 4391 10601 25 H(10) 5717 4553 13399 23 H(11) 6226 3680 14452 24 H(13) 6152 5671 12926 24 H(14A) 5710 6117 10229 29 H(14B) 6101 5999 9056 29 H(16A) 5464 5588 6130 56 H(16B) 5182 5525 7941 56 H(16C) 5244 4640 6555 56 H(5B) 7454 5921 11262 49 H(2C) 7028 8401 17168 77 H(2D) 6719 8068 18709 77 H(3C) 6568 9239 15249 78 H(3D) 6451 9426 17506 78 H(4D) 5906 8475 17082 75 H(4C) 5896 9019 14961 75 H(6C) 6347 8427 12557 39 H(6D) 6213 7408 11798 39 521 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.6. Cont’d H(7B) 6744 6755 13237 36 H(9B) 7653 7965 14989 48 H(10B) 7542 7158 17739 55 H(11B) 6981 6547 18479 51 H(13B) 7768 5712 17474 66 H(14C) 7903 5483 13754 61 H(14D) 8138 6279 15048 61 H(16D) 8113 6870 11152 66 H(16E) 8143 7671 12826 66 H(16F) 7818 7732 10933 66 H(6E) 7684 4303 10257 62 H(6F) 7299 4281 11315 62 H(17) 4712 -1315 8203 155 ________________________________________________________________________________ Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.7. Torsion Angles [°] for Cycloheptane 468. Cl(1)-C(5)-C(6)-C(7) -135.7(7) O(1)-C(1)-C(2)-C(3) -56.0(10) O(1)-C(1)-C(7)-C(6) 36.0(9) O(1)-C(1)-C(7)-C(8) 167.4(7) O(1)-C(1)-C(11)-C(10) 172.7(7) O(1)-C(1)-C(11)-C(12) 55.9(10) O(1)-C(5)-C(6)-C(7) -20.7(10) O(2)-C(8)-C(9)-C(10) 159.3(8) O(2)-C(8)-C(9)-C(15) -78.9(10) O(4)-C(13)-C(14)-C(15) 81.2(8) C(1)-O(1)-C(5)-Cl(1) 162.9(6) C(1)-O(1)-C(5)-C(4) -79.5(8) C(1)-O(1)-C(5)-C(6) 44.0(9) C(1)-C(2)-C(3)-C(4) 41.8(12) C(1)-C(7)-C(8)-O(2) -131.9(9) C(1)-C(7)-C(8)-C(9) 50.8(10) C(1)-C(11)-C(12)-O(3) -49.2(12) C(1)-C(11)-C(12)-O(4) 133.0(8) C(2)-C(1)-C(7)-C(6) -80.7(10) C(2)-C(1)-C(7)-C(8) 50.8(10) C(2)-C(1)-C(11)-C(10) -67.8(8) C(2)-C(1)-C(11)-C(12) 175.4(8) C(2)-C(3)-C(4)-C(5) -45.3(12) C(3)-C(4)-C(5)-Cl(1) -179.1(8) C(3)-C(4)-C(5)-O(1) 65.8(11) C(3)-C(4)-C(5)-C(6) -52.5(12) C(4)-C(5)-C(6)-C(7) 98.7(10) C(5)-O(1)-C(1)-C(2) 72.7(8) C(5)-O(1)-C(1)-C(7) -49.1(8) C(5)-O(1)-C(1)-C(11) -168.2(7) C(5)-C(6)-C(7)-C(1) -9.4(9) C(5)-C(6)-C(7)-C(8) -133.5(8) C(6)-C(7)-C(8)-O(2) -9.8(14) 522 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.7. Cont’d C(6)-C(7)-C(8)-C(9) 172.9(8) C(7)-C(1)-C(2)-C(3) 57.1(11) C(7)-C(1)-C(11)-C(10) 58.6(9) C(7)-C(1)-C(11)-C(12) -58.2(10) C(7)-C(8)-C(9)-C(10) -23.3(11) C(7)-C(8)-C(9)-C(15) 98.5(8) C(8)-C(9)-C(10)-C(11) 13.5(11) C(8)-C(9)-C(10)-C(13) 130.2(8) C(8)-C(9)-C(15)-O(5) -36.7(9) C(8)-C(9)-C(15)-C(14) -155.2(7) C(8)-C(9)-C(15)-C(16) 82.1(9) C(9)-C(10)-C(11)-C(1) -29.8(10) C(9)-C(10)-C(11)-C(12) 96.0(8) C(9)-C(10)-C(13)-O(4) -102.0(7) C(9)-C(10)-C(13)-C(14) 15.5(8) C(10)-C(9)-C(15)-O(5) 93.0(7) C(10)-C(9)-C(15)-C(14) -25.6(9) C(10)-C(9)-C(15)-C(16) -148.3(8) C(10)-C(11)-C(12)-O(3) -169.4(8) C(10)-C(11)-C(12)-O(4) 12.8(9) C(10)-C(13)-C(14)-C(15) -32.4(9) C(11)-C(1)-C(2)-C(3) -179.4(7) C(11)-C(1)-C(7)-C(6) 157.5(7) C(11)-C(1)-C(7)-C(8) -71.0(9) C(11)-C(10)-C(13)-O(4) 23.8(8) C(11)-C(10)-C(13)-C(14) 141.3(7) C(12)-O(4)-C(13)-C(10) -16.8(8) C(12)-O(4)-C(13)-C(14) -130.7(7) C(13)-O(4)-C(12)-O(3) -175.7(7) C(13)-O(4)-C(12)-C(11) 2.4(9) C(13)-C(10)-C(11)-C(1) -147.6(7) C(13)-C(10)-C(11)-C(12) -21.9(8) C(13)-C(14)-C(15)-O(5) -78.7(9) C(13)-C(14)-C(15)-C(9) 35.7(9) 523 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.7. Cont’d C(13)-C(14)-C(15)-C(16) 156.8(7) C(15)-C(9)-C(10)-C(11) -110.8(8) C(15)-C(9)-C(10)-C(13) 5.9(8) Cl(1B)-C(5B)-C(6B)-C(7B) -135.5(7) O(1B)-C(1B)-C(2B)-C(3B) -55.2(13) O(1B)-C(1B)-C(7B)-C(6B) 37.4(10) O(1B)-C(1B)-C(7B)-C(8B) 169.4(8) O(1B)-C(1B)-C(11B)-C(10B) 168.1(9) O(1B)-C(1B)-C(11B)-C(12B) 50.5(12) O(1B)-C(5B)-C(6B)-C(7B) -19.1(10) O(2B)-C(8B)-C(9B)-C(10B) 155.9(10) O(2B)-C(8B)-C(9B)-C(15B) -83.8(11) O(4B)-C(13B)-C(14B)-C(15B) 83.0(13) C(1B)-O(1B)-C(5B)-Cl(1B) 165.3(7) C(1B)-O(1B)-C(5B)-C(4B) -76.3(11) C(1B)-O(1B)-C(5B)-C(6B) 44.3(10) C(1B)-C(2B)-C(3B)-C(4B) 39.5(14) C(1B)-C(7B)-C(8B)-O(2B) -126.1(11) C(1B)-C(7B)-C(8B)-C(9B) 52.1(11) C(1B)-C(11B)-C(12B)-O(3B) -48.0(15) C(1B)-C(11B)-C(12B)-O(4B) 129.5(9) C(2B)-C(1B)-C(7B)-C(6B) -80.8(13) C(2B)-C(1B)-C(7B)-C(8B) 51.3(15) C(2B)-C(1B)-C(11B)-C(10B) -68.5(12) C(2B)-C(1B)-C(11B)-C(12B) 173.9(9) C(2B)-C(3B)-C(4B)-C(5B) -42.0(14) C(3B)-C(4B)-C(5B)-Cl(1B) 179.0(9) C(3B)-C(4B)-C(5B)-O(1B) 62.0(12) C(3B)-C(4B)-C(5B)-C(6B) -54.5(14) C(4B)-C(5B)-C(6B)-C(7B) 100.3(11) C(5B)-O(1B)-C(1B)-C(2B) 71.4(11) C(5B)-O(1B)-C(1B)-C(7B) -50.0(10) C(5B)-O(1B)-C(1B)-C(11B) -165.8(9) C(5B)-C(6B)-C(7B)-C(1B) -11.2(10) 524 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.7. Cont’d C(5B)-C(6B)-C(7B)-C(8B) -134.6(9) C(6B)-C(7B)-C(8B)-O(2B) -5.0(14) C(6B)-C(7B)-C(8B)-C(9B) 173.2(9) C(7B)-C(1B)-C(2B)-C(3B) 57.0(15) C(7B)-C(1B)-C(11B)-C(10B) 57.7(11) C(7B)-C(1B)-C(11B)-C(12B) -59.9(11) C(7B)-C(8B)-C(9B)-C(10B) -22.3(13) C(7B)-C(8B)-C(9B)-C(15B) 98.0(9) C(8B)-C(9B)-C(10B)-C(11B) 10.3(16) C(8B)-C(9B)-C(10B)-C(13B) 127.5(10) C(8B)-C(9B)-C(15B)-O(5B) -33.4(10) C(8B)-C(9B)-C(15B)-C(14B) -151.0(8) C(8B)-C(9B)-C(15B)-C(16B) 86.7(10) C(9B)-C(10B)-C(11B)-C(1B) -27.7(14) C(9B)-C(10B)-C(11B)-C(12B) 98.3(12) C(9B)-C(10B)-C(13B)-O(4B) -101.6(9) C(9B)-C(10B)-C(13B)-C(14B) 15.1(11) C(10B)-C(9B)-C(15B)-O(5B) 94.9(9) C(10B)-C(9B)-C(15B)-C(14B) -22.7(10) C(10B)-C(9B)-C(15B)-C(16B) -145.0(9) C(10B)-C(11B)-C(12B)-O(3B) -169.2(10) C(10B)-C(11B)-C(12B)-O(4B) 8.2(11) C(10B)-C(13B)-C(14B)-C(15B) -30.4(13) C(11B)-C(1B)-C(2B)-C(3B) 179.8(10) C(11B)-C(1B)-C(7B)-C(6B) 156.3(8) C(11B)-C(1B)-C(7B)-C(8B) -71.6(10) C(11B)-C(10B)-C(13B)-O(4B) 25.0(11) C(11B)-C(10B)-C(13B)-C(14B) 141.7(9) C(12B)-O(4B)-C(13B)-C(10B) -20.7(11) C(12B)-O(4B)-C(13B)-C(14B) -135.1(11) C(13B)-O(4B)-C(12B)-O(3B) -174.5(9) C(13B)-O(4B)-C(12B)-C(11B) 7.8(11) C(13B)-C(10B)-C(11B)-C(1B) -146.2(9) C(13B)-C(10B)-C(11B)-C(12B) -20.1(11) 525 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.7. Cont’d C(13B)-C(14B)-C(15B)-O(5B) -81.1(12) C(13B)-C(14B)-C(15B)-C(9B) 33.1(12) C(13B)-C(14B)-C(15B)-C(16B) 154.9(10) C(15B)-C(9B)-C(10B)-C(11B) -112.2(12) C(15B)-C(9B)-C(10B)-C(13B) 5.0(10) Cl(3)#1-Cl(2)-C(17)-Cl(3) 41.5(13) Cl(3)#1-Cl(2)-C(17)-Cl(4) -78.0(13) Cl(4)#1-Cl(3)-C(17)-Cl(2) -170.0(7) Cl(4)#1-Cl(3)-C(17)-Cl(3)#1 -152.5(14) Cl(4)#1-Cl(3)-C(17)-Cl(4) -49.2(7) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,y,-z+2 526 527 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 Table A7.4.8. Hydrogen Bonds for Cycloheptane 468 [Å and °]. D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ O(5)-H(5)...O(3B)#2 0.84 1.99 2.772(9) 154.9 O(5B)-H(5B)...O(6) 0.84 1.94 2.749(10) 160.2 O(6)-H(6E)...O(2B)#3 0.87 2.21 2.886(10) 134.6 O(6)-H(6F)...O(3) 1.00 1.91 2.858(9) 157.8 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,y,-z+2 #2 x,y,z-1 #3 -x+3/2,y-1/2,-z+2 Appendix 7 – X-Ray Crystallography Reports Relevant to Chapter 4 A7.5 NOTES AND REFERENCES 1. Sheldrick, G. M. Acta Cryst. 1990, A46, 467-473. 2. Sheldrick, G. M. Acta Cryst. 2015, C71, 3-8. 3. Müller, P. Crystallography Reviews 2009, 15, 57-83. 528 Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A 529 Appendix 8 Alternative Strategy Toward the Total Synthesis of Scabrolide A A8.1 ALTERNATIVE APPROACH TO SCABROLIDE A During the development of the ultimately successful ring expansion of a small- membered ring for the synthesis of the cycloheptanone ring in the core of scabrolide A, we concurrently investigated numerous alternative routes (Scheme A8.1.1). Retrosynthetically, we envisioned access to scabrolide A 407 through an intramolecular transannular Diels–Alder reaction from intermediate 472. We believed intermediate 472 could be formed through a Yamaguchi macrolactonization from masked 1,4-diketone 473. The key masked 1,4 diketone moiety of 473 is believed to be generated from an umpolung 1,2 addition of allyl carbamate 475 and aldehyde 444. 530 Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A Scheme A8.1.1. H HO Retrosynthetic Analysis of Scabrolide A O O HO O O Diels–Alder O Esterification O H O O 472 Scabrolide A 407 O NH(i-Pr)2 O TMS O H TBSO 1,2 Addition N(i-Pr)2 O O O + TBSO OTES OTES TMS 444 473 A8.2 475 SYNTHESIS OF DIISOPROPYL CARBAMATE Exploration of the proposed synthetic route began with the derivatization of key carvone derived Weinreb amide ent•422 (Scheme A8.2.1). Single addition of vinyl Grignard followed by subsequent Luche reduction of the resultant ketone, afforded allylic alcohol 476 in 51% yield over 2 steps as a 1:1 mixture of diastereomers. The mixture of diastereomers can then be TMS protected at the terminal alkyne followed by the carbamoylation of the allylic alcohol generating carbamate 475 in a 70% yield over 2 steps in a 1:1 mixture of diastereomers. Ultimately, silyl protection of the alkyne is required to avoid statistical mixtures of the desired carbamate and the undesired acetylated alkyne. Scheme A8.2.1. Derivatization of Weinreb Amide ent•422 to Carbamate 475 O O MeO N Me OH 1. Vinyl Grignard THF, –78 to 0 °C 2. NaBH4, CeCl3•7H2O MeOH, 0 °C ent•422 51% yield over 2 steps 1:1 dr 1. n-BuLi, TMSCl THF –78 to 0 °C then 1 N HCl N(i-Pr)2 O 2. NaH, DMAP toluene, 110 °C O 476 Cl N(i-Pr)2 79% yield over 2 steps 1:1 dr TMS 475 531 Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A A8.3 UMPOLUNG ALDEHYDE ADDITION Successful synthesis of allylic carbamate 475, allows for the investigation of the synthesis of the 1,4-diketone moiety of scabrolide A. Deprotonation of the allylic carbamate 475 with n-BuLi in the presence of TMEDA at low temperatures, generates a stabilized allylic carbanion, which are known to undergo selective 1,2 additions into aldehydes (Scheme A8.3.1).1 Addition of previously synthesized aldehyde 444 to the stabilized allylic anion followed by an oxidation with DMP affords our desired masked 1,4-diketone 473 in 20% yield over 2 steps. While we were able to selective generate enol carbamate 473, albeit in low yield, we were unable to progress this intermediate toward macrocycle 472. Attempts to deprotect the alkyne and affect Yamaguchi esterification resulted in decomposition. Deprotection of the enol carbamate moiety similarly resulted in decomposition. Ultimately we were unable to advance this interesting intermediate any further in the synthesis. Scheme A8.3.1. Coupling of Carbamate 475 and Aldehyde 444 O + 2. DMP, CH2Cl2, 23 °C OTES 20% yield over 2 steps TMS 444 O 1. n-BuLI, TMEDA Et2O, –78 °C H TBSO NH(i-Pr)2 O N(i-Pr)2 O O 475 TMS O TBSO OTES 473 A8.4 EXPERIMENTAL METHODS AND ANALYTICAL DATA A8.4.1 MATERIALS AND METHODS Unless stated otherwise, reactions were performed at ambient temperature (23 °C) in flame-dried or oven-dried glassware under an argon or nitrogen atmosphere using dry, Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A 532 deoxygenated solvents (distilled or passed over a column of activated alumina).2 Commercially obtained reagents were used as received. Triethylamine (Et3N) and trimethylsilyl chloride (TMSCl) were distilled over potassium hydride prior to use. Reactions requiring external heat were modulated to the specified temperatures using an IKAmag temperature controller. Reaction progress was monitored by thin-layer chromatography (TLC), which was performed using E. Merck silica gel 60 F254 precoated glass plated (0.25 mm) and visualized by UV fluorescence quenching, potassium permanganate, p-anisaldehyde, or iodine staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40-63 nm) was used for column chromatography. 1H and 13C NMR spectra were recorded on a Varian Inova 500 (500 MHz and 126 MHz, respectively), Varian Mercury 300 spectrometer (300 MHz and 75 MHz, respectively), Varian 600 MHz Spectrometer (600 MHz), and a Bruker AV III HD spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe (400 MHz and 101 MHz, respectively) and are reported in terms of chemical shift relative to CHCl3 (d 7.26 and d 77.16, respectively) and C6H6 (d 7.16 and d 128.4 respectively). 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, sext = sextet, sept = septet, m = multiplet, and br s = broad singlet. Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer using thin films deposited on NaCl plates and are 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 and are reported as: [a]DT (concentration in g/100 mL, solvent). High resolution mass spectra were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-600H Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A 533 High Resolution Mass Spectrometer in fast atom bombardment (FAB+) ionization mode or a Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+), atmospheric pressure chemical ionization (APCI+), or mixed (ESI/APCI) ionization mode. A8.4.2 EXPERIMENTAL PROCEDURES O MeO N Me OH 1. Vinyl Grignard THF, –78 to 0 °C 2. NaBH4, CeCl3•7H2O MeOH, 0 °C ent•422 51% yield over 2 steps 1:1 dr 476 (5R)-5-(prop-1-en-2-yl)oct-1-en-7-yn-3-ol (476): In a flame dried round bottom flask, amide ent•422 (250 mg, 1.3 mmol, 1.0 equiv) was dissolved in THF (4.2 mL, 0.3 M) and cooled to –78 °C. Allyl magnesium bromide (2.6 mL, 2.6 mmol, 1.0 M, 2.0 equiv) was added dropwise to the reaction solution. The reaction was allowed to stir for 15 min at –78 °C and then warmed to 0 °C and stirred for 16 h. Upon complete consumption of starting material (determined by TLC analysis, 9:1 hexanes:EtOAc), the reaction was quenched with a saturated solution of NH4Cl and the product was extracted from the biphasic mixture with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 9:1 hexanes:EtOAc) to generate an intermediate enone (128 mg, 62% yield) as a pale yellow oil which was used without further characterization. In a round bottom flask, crude enone (490 mg, 3 mmol, 1 equiv) was dissolved in methanol (30 mL, 0.1 M). The solution was stirred for 5 min followed by the addition of CeCl3•7H2O (1.1 g, 3.3 mmol, 1.1 equiv). Once the reaction is homogeneous, the solution is cooled to – 78 °C and allowed to stir for 1 h. NaBH4 (164 mg, 3 mmol, 1 equiv) was Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A 534 added slowly in portions to the reaction and was allowed to stir until completion (as determined by TLC analysis 4:1 hexanes:EtOAc). Upon complete consumption of starting material, the reaction was quenched with a saturated solution of NH4Cl (30 mL) and the biphasic mixture was allowed to warm to room temperature. The biphasic mixture was extracted with 2:1 Et2O:hexanes (3 x 30 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was assumed to have quantitative conversion and was used directly into the next reaction without further purification. Alcohol 476 could be purified by column chromatography (SiO2, 9:1 hexanes:EtOAc) to afford pure alcohol 476 as a colorless oil; Rf = 0.44 (4:1 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) d = 5.89 (ddd, J = 17.2, 10.4, 5.8 Hz, 1H), 5.23 (dt, J = 17.2, 1.5 Hz, 1H), 5.10 (dt, J = 10.4, 1.4 Hz, 1H), 4.84 (ddt, J = 5.6, 2.0, 1.1 Hz, 2H), 2.58 (dtd, J = 9.6, 7.1, 4.9 Hz, 1H), 2.31 (d, J = 1.4 Hz, 1H), 2.29 (s, 1H), 1.69 (dd, J = 1.5, 0.8 Hz, 3H), 1.68–1.63 (m, 2H), 1.25 (s, 2H); 5.84 (ddd, J = 17.0, 10.4, 6.5 Hz, 1H), 5.24 (dt, J = 17.2, 1.4 Hz, 1H), 5.13 (dt, J = 10.4, 1.3 Hz, 1H), 4.84–4.78 (m, 2H), 4.19 – 4.11 (m, 2H), 2.45–2.34 (m, 1H), 2.32 (d, J = 2.3 Hz, 1H), 2.30 (d, J = 3.8 Hz, 1H), 1.77–1.69 (m, 5H); 13C NMR (101 MHz, CDCl3) d = 146.7, 146.1, 141.3, 140.7, 115.5, 114.4, 113.0, 112.6, 82.8, 82.8, 71.9, 70.9, 69.7, 69.6, 42.9, 42.5, 39.5, 39.4, 23.8, 23.5, 19.1, 18.8; IR (thin film, NaCl) 3305, 3076, 2972, 2935, 2117, 1645, 1429, 1376, 1122, 992, 924, 895, 633 cm-1; HRMS (ESI) m/z calc’d C11H17O [M+H]+: 165.1279, found: 165.1299; [a]D23 +17.3 (c 0.125, CHCl3). Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A 535 O OH 1. n-BuLi, TMSCl THF –78 to 0 °C then 1 N HCl N(i-Pr)2 O 2. NaH, DMAP toluene, 110 °C O 476 Cl N(i-Pr)2 79% yield over 2 steps 1:1 dr TMS 475 (5R)-5-(prop-1-en-2-yl)-8-(trimethylsilyl)oct-1-en-7-yn-3-yl diisopropylcarbamate (475): To a stirred solution of alcohol 476 (58 mg, 0.35 mmol, 1.0 equiv) in THF (2.2 mL, 0.15 M) at –78 °C has n-BuLi (0.35 mL, 0.812 mmol, 2.16 M, 2.3 equiv) added. The reaction was warmed to 0 °C, stirred for 10 min, and cooled back to –78 °C. TMSCl (89 µL, 0.71 mmol, 2 equiv) was added and allowed to for 1 h. Upon complete consumption of starting material (as determined by TLC analysis, 4:1 hexanes:EtOAc), 1 N HCl (1.8 mL, 0.2 M) was added and allowed to stir for 20 min. The organic layer was separated and the aqueous layer was extracted with Et2O (3 X 5 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 4:1 hexanes:EtOAc) and carried onto the next reaction without further purification. To a stirred solution of alcohol (68 mg, 0.29 mmol, 1 equiv) in toluene (2.9 mL, 0.1 M) had NaH (23 mg, 0.58 mmol, 2 equiv), DMAP (3.5 mg, 0.03 mmol, 0.1 equiv), and diisopropyl carbamoyl chloride (118 mg, 0.72 mg, 2.5 equiv) added. The reaction was sealed and heated go 110 °C. Upon complete consumption of starting material (as determined by TLC analysis, 4:1 hexanes:EtOAc) , the reaction was cooled to 23 °C and quenched with a saturated solution of NH4Cl (5 mL). The biphasic mixture was extracted Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A 536 with Et2O (3 x 5 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 9:1 hexanes:EtOAc) to afford carbamate 475 (86 mg, 98%) as a viscous colorless oil (Rf = 057, 4:1 hexanes:EtOAc) 1H NMR (400 MHz, CDCl3) d = 5.79 (ddd, J = 17.3, 10.4, 6.9 Hz, 1H), 5.26 (dt, J = 17.2, 1.4 Hz, 1H), 5.20–5.05 (m, 2H), 4.82–4.73 (m, 2H), 4.20–3.64 (bd, 1H), 2.36–2.24 (m, 3H), 2.06 (s, 1H), 1.93–1.75 (m, 2H), 1.71 (dd, J = 1.5, 0.8 Hz, 3H), 1.20 (dd, J = 7.0, 2.9 Hz, 12H), 0.13 (s, 9H); 6.00–5.65 (m, 1H), 5.33–5.07 (m, 3H), 4.84 (q, J = 1.6 Hz, 1H), 4.76–4.73 (m, 1H), 4.06 (bs, 1H), 3.80 (bs, 1H), 2.45 (dddd, J = 10.4, 8.0, 6.1, 4.1 Hz, 1H), 2.38–2.18 (m, 2H), 2.07–1.91 (m, 1H), 1.74–1.57 (m, 4H), 1.32–1.16 (m, 12H), 0.13 (s, 9H); 13C NMR (101 MHz, CDCl3) d = 155.12, 145.77, 137.20, 117.01, 112.61, 105.71, 86.41, 73.82, 69.76, 46.24, 42.50, 36.87, 25.19, 21.26, 19.17, 0.22; 155.05, 145.52, 138.16, 137.12, 117.09, 115.45, 112.87, 112.83, 105.84, 86.10, 73.00, 42.77, 37.30, 25.42, 19.31, 0.23; IR (thin film, NaCl) 3076, 2967, 2175, 1742, 1693, 1646, 1435, 1368, 1285, 1249, 1157, 1133, 1048, 842, 760, 694 cm-1; HRMS (FAB+) m/z calc’d C21H37NO2SiNa [M+Na]+: 386.2486, found: 386.2470; [a]D23 +5.6 (c 0.305, CHCl3). 537 Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A O + 2. DMP, CH2Cl2, 23 °C OTES 20% yield over 2 steps TMS 444 O 1. n-BuLI, TMEDA Et2O, –78 °C H TBSO NH(i-Pr)2 O N(i-Pr)2 O O TMS O TBSO OTES 475 473 (R,Z)-1-((3S,5R)-5-((tert-butyldimethylsilyl)oxy)-5-methyl-3((triethylsilyl)oxy)cyclopent-1-en-1-yl)-1-oxo-6-(prop-1-en-2-yl)-9(trimethylsilyl)non-3-en-8-yn-4-yl diisopropylcarbamate (473): To a stirred solution of carbamate 475 (16 mg, 0.0275 mmol, 1 equiv) and TMEDA ( 6 µL, 0.04225 mmol, 1.3 equiv) in Et2O (0.33 mL, 0.1 M) was cooled to –78 °C. n-BuLi (0.02 mL, 0.04 mmol, 2.16 M, 1.3 equiv) was added and stirred for 2 h. Aldehyde 444 ( 27.4 mg, 0.98 mmol, 2.2 equiv) in a solution of Et2O (0.33 mL, 0.1 M) was added dropwise and allowed to stir for 2 h. Upon complete consumption of starting material (as determined by TLC, 9:1 hexanes:EtOAc) the reaction was quenched with H2O (3 mL) and extracted with Et2O (3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 9:1 hexanes:EtOAc) and carried on to the next reaction. The crude alcohol product (8 mg, 0.011 mmol, 1 equiv) in wet CH2Cl2 (0.55 mL, 0.02 M) had DMP (9 mg, 0.022 mmol, 2 equiv) added. The reaction was allowed to stir for 2 h, at which time complete consumption of starting material was observed (by TLC analysis, 9:1 hexanes:EtOAc). The reaction was quenched with Na2S2O3, poured into a saturated solution of NaHCO3, and extracted with Et2O (3 x 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, 9:1 hexanes:EtOAc) to afford enone 473 (4 mg, Appendix 8 – Alternative Strategy Toward the Total Synthesis Scabrolide A 538 20% over 2 steps) as a colorless oil (Rf = 0.46); 1H NMR (400 MHz, CDCl3) d = 6.33 (d, J = 1.8 Hz, 1H), 5.34 (t, J = 6.5 Hz, 1H), 4.79 (q, J = 1.6 Hz, 1H), 4.75 (d, J = 1.6 Hz, 1H), 4.60 (td, J = 7.0, 1.8 Hz, 1H), 3.93 (s, 2H), 3.45 (dd, J = 18.7, 6.5 Hz, 1H), 3.26 (dd, J = 18.8, 6.7 Hz, 1H), 2.55 – 2.26 (m, 6H), 2.03 – 1.96 (m, 1H), 1.69 (dd, J = 1.5, 0.9 Hz, 3H), 1.52 – 1.43 (m, 3H), 1.26 (d, J = 6.7 Hz, 12H), 0.96 (t, J = 7.9 Hz, 9H), 0.82 (s, 9H), 0.67 – 0.56 (m, 6H), 0.12 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (101 MHz, CDCl3) d = 196.0, 152.5, 149.3, 148.5, 145.9, 141.9, 112.2, 110.3, 105.8, 86.2, 81.9, 72.6, 53.9, 46.6, 43.4, 37.8, 37.2, 28.6, 25.9, 24.4, 21.7, 20.7, 19.9, 18.2, 6.9, 4.9, 0.3, 0.2, -2.3, -2.4; HRMS (FAB+) m/z calc’d C40H74NO5Si3 [M+H]+: 732.4875, found: 732.4869. A8.5 NOTES AND REFERENCES 1. Hoppe, D. Synthesis, 2009 43–55. 2. Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520. Appendix 9 – Spectra Relevant to Appendix 8 539 APPENDIX 9 Spectra Relevant to Appendix 8: Alternative Strategy Toward the Total Synthesis of Scabrolide A 8 476 OH 7 6 4 ppm 3 Figure A9.1. 1H NMR (400 MHz, CDCl3) of compound 476. 5 2 1 0 Appendix 9 – Spectra Relevant to Appendix 8 540 541 Appendix 9 – Spectra Relevant to Appendix 8 Figure A9.2. Infrared spectrum (Thin Film, NaCl) of compound 476. 200 180 160 140 120 100 ppm 80 60 40 Figure A9.3. 13C NMR (101 MHz, CDCl3) of compound 476. 20 0 8 N(i-Pr)2 475 TMS O O 7 6 4 ppm 3 Figure A9.4. 1H NMR (400 MHz, CDCl3) of compound 475. 5 2 1 0 Appendix 9 – Spectra Relevant to Appendix 8 542 543 Appendix 9 – Spectra Relevant to Appendix 8 Figure A9.5. Infrared spectrum (Thin Film, NaCl) of compound 475. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A9.6. 13C NMR (101 MHz, CDCl3) of compound 475. 0 8 TBSO O O 7 473 NH(i-Pr)2 OTES O TMS 6 4 ppm 3 Figure A9.7. 1H NMR (400 MHz, CDCl3) of compound 473. 5 2 1 0 Appendix 9 – Spectra Relevant to Appendix 8 544 545 Appendix 9 – Spectra Relevant to Appendix 8 200 180 160 140 120 100 ppm 80 60 40 Figure A9.8. 13C NMR (101 MHz, CDCl3) of compound 473. 20 0 546 Appendix 10 – Notebook Cross-Reference APPENDIX 10 Notebook Cross-Reference for New Compounds A10.1 CONTENTS The following notebook cross-reference provides the file name for all original spectroscopic data obtained for new compounds presented within this thesis. The information is organized by chapter or appendix and sequentially by compound number. All 1H NMR, 13C NMR, as well as 19F NMR and any two-dimensional NMR data, if applicable, are electronically stored on the Caltech NMR laboratory server (mangia.caltech.edu, most typically under the usernames ‘sloskot’, ‘nhafeman’, ‘bpritche’, or ‘rcraig’) and on the Stoltz group server. Electronic copies of all IR spectra can also be found on the Stoltz group server. All laboratory notebooks are stored in the Stoltz group archive. A10.2 NOTEBOOK CROSS-REFERENCE TABLES Table A10.2.1. Notebook Cross-Reference For Compounds in Chapter 2 Compound 331 332 1 H NMR (instrument) RAC-XIII-165 (Florence) RAC-XIII-141 (Florence) 13 C NMR (instrument) RAC-XIII-165 (Florence RAC-XIII-141 (Florence) IR Yield and Procedure RAC-XIII-165 JTM-VII-237 RAC-XIII-141 RAC-XIII141 Appendix 10 – Notebook Cross-Reference Compound 336 339 346 347 348 349 351 353 354 355 359 361 363 364 365 366 367 370 377 378 1 13 H NMR C NMR IR (instrument) (instrument) RAC-XIII-175 RAC-XIII-175 RAC-XIII-175 (Florence) (Florence) RAC-XIII-179 RAC-XIII-179 RAC-XIII-179 (Florence) (Florence) SAL-II-149 SAL-II-149 SAL-II-149 (Florence) (Florence) SAL-II-151 SAL-II-151 SAL-II-151 (Florence) (Florence) SAL-II-187 SAL-II-187 SAL-II-187 (Florence) (Florence) SAL-II-191 SAL-II-191 SAL-II-191 (Florence) (Florence) SAL-II-131 SAL-II-131 SAL-II-131 (Florence) (Florence) SAL-II-121 SAL-II-121 SAL-II-121 (Florence) (Florence) SAL-II-141 SAL-II-141 SAL-II-141 (Florence) (Florence) SAL-II-125 SAL-II-125 SAL-II-125 (Florence) (Florence) SAL-III-161 SAL-III-161 SAL-III-161 (Florence) (Florence) SAL-III-169 SAL-III-169 SAL-III-169 (Florence) (Florence) SAL-JAE-XSAL-JAE-XSAL-JAE-X167B 167B 167B (Florence) (Florence) SAL-II-133 SAL-II-133 SAL-II-133 (Florence) (Florence) SAL-II-135 SAL-II-135 SAL-II-135 (Florence) (Florence) SAL-II-179 SAL-II-179 SAL-II-179 (Florence) (Florence) SAL-II-181 SAL-II-181 SAL-II-181 (Florence) (Florence) RAC-XIII-CH- RAC-XIII-CHRAC-XIII-CHCH2CH2CO2Et CH2CH2CO2Et CH2CH2CO2Et (Florence) (Florence) SAL-II-123 SAL-II-123 SAL-II-123 (Florence) (Florence) SAL-III-167 SAL-III-167 SAL-III-167 (Florence) (Florence) 547 Yield and Procedure RAC-XIII175 RAC-XIII179 SAL-II-149 SAL-II-151 SAL-II-187 SAL-II-191 SAL-II-131 SAL-II-121 SAL-II-141 SAL-II-125 SAL-III-161 SAL-III-169 JAE-X-167B SAL-II-133 SAL-II-135 SAL-II-179 SAL-II-181 RAC-XIII167 SAL-II-123 SAL-III-167 548 Appendix 10 – Notebook Cross-Reference Compound 379 380 382 383 384 1 H NMR (instrument) SAL-III-165 (Florence) SAL-III-173 (Florence) SAL-II-169 (Florence) SAL-II-173 (Florence) SAL-II-177 (Florence) 13 C NMR (instrument) SAL-III-165 (Florence) SAL-III-173 (Florence) SAL-II-169 (Florence) SAL-II-173 (Florence) SAL-II-177 (Florence) IR Yield and Procedure SAL-III-165 SAL-III-165 SAL-III-173 SAL-III-173 SAL-II-169 SAL-II-169 SAL-II-173 SAL-II-173 SAL-II-177 SAL-II-177 Table A10.2.2. Notebook Cross-Reference For Compounds in Chapter 3 Compound 385 389 390 391 392 393 395 396 397 400 401 1 H NMR (instrument) SAL-V-271-3 (Florence) SAL-IV-177 (Florence) SAL-IV-063 (Florence) SAL-IV-111 (Florence) SAL-I-101 (Indy) SAL-I-073 (Indy) SAL-I-289 (Florence) SAL-I-061 (Indy) SAL-IV-101 (Florence) SAL-IV-061 (Florence) SAL-IV-169 (Florence) 13 C NMR (instrument) SAL-V-271-3 (Florence) SAL-IV-177 (Florence) SAL-IV-063 (Florence) SAL-IV-111 (Florence) SAL-I-101 (Indy) SAL-I-073 (Indy) SAL-I-289 (Florence) SAL-I-061 (Indy) SAL-IV-101 (Florence) SAL-IV-061 (Florence) SAL-IV-169 (Florence) SAL-V-271 Yield and Procedure SAL-VI-241 SAL-IV-177 SAL-VI-075 SAL-IV-063 SAL-IV-193 SAL-IV-111 SAL-IV-155 SAL-VI-037 SAL-V-265 SAL-VI-023 SAL-VI-023 SAL-IV-107 SAL-IV-107 SAL-I-061 SAL-IV-191 SAL-IV-101 SAL-VI-021 SAL-IV-061 SAL-V-281 SAL-IV-169 SAL-VI-051 IR 549 Appendix 10 – Notebook Cross-Reference Table A10.2.3. Notebook Cross-Reference For Compounds in Chapter 4 Compound 422 416 423 430 432 434 437 441 442 443 444 445 446 447 448 449 450 451 1 13 H NMR C NMR IR (instrument) (instrument) BPP-V-287 BPP-V-287 BPP-V-287 (Indy) (Indy) BPP-V-295 BPP-V-295 BPP-V-295 (Indy) (Indy) SAL-VII-051 SAL-VII-051 SAL-VII-051 (Florence) (Florence) BPP-VI-197 BPP-VI-197 BPP-VI-197 (Florence) (Florence) SALVI-267 SALVI-267 SALVI-267 (Florence) (Florence) BPP-VI-197BPP-VI-197BPP-VI-197-col1col1-A col1-A A (Florence) (Florence) SAL-IX-263 SAL-IX-263 SAL-IX-263 (Florence) (Florence) NJH-II-083 NJH-II-083 NJH-II-083 (Florence) (Florence) SAL-VIIISAL-VIIINJH-enoneNJH-enoneSAL-VIII-enoneCN CN CN (Florence) (Florence) SAL-VIII-153 SAL-VIII-153 SAL-VIII-153 (Florence) (Florence) NJH-II-089 NJH-II-089 NJH-II-089 (Florence) (Florence) SAL-TBSTES- SAL-TBSTESSAL-VII(Florence) (Florence) doubleprotecteddiol SAL-TBSOH- SAL-TBSOHSAL-VIII(Florence) (Florence) monoprotecteddiol SAL-VIII-155 SAL-VIII-155 SAL-VIII-155 (Florence) (Florence) SAL-X-203 SAL-X-203 SAL-X-203 (Florence) (Florence) SAL-VIII-229 SAL-VIII-229 SAL-VII-229 (Florence) (Florence) SAL-VIII-195 SAL-VIII-195 SAL-VIII-195 (Florence) (Florence) SAL-VIII-215 SAL-VIII-215 bottom bottom SAL-VIII-215 (Florence) (Florence) Yield and Procedure NJH-II-221 SAL-VI-245 SAL-VII051 SAL-VI-261 SALVI-267 SAL-VI-279 SAL-IX-197 SAL-VIII279 SAL-VIII143 SAL-IX-141 SAL-VIII043 SAL-VIII245 SAL-VIII219 SAL-VIII155 NJH-II-093 SAL-VIII229 SAL-VIII233 SAL-VIII209 550 Appendix 10 – Notebook Cross-Reference Compound 452 453 454 455 456 457 458 461 462 463 464 465 466 468 470 1 H NMR (instrument) SAL-VIII-209 crystals Florence SAL-IX-267 (Florence) SAL-IX-271-2 (Florence) SAL-IX-243 (Florence) SAL-X-201 (Florence) SAL-X-197 (Florence) SAL-X-183 (Florence) SAL-X-185 (Florence) SAL-X-189 (Florence) SAL-X-193 (Florence) SAL-X-195 (Florence) SAL-X-199-1 (Florence) SAL-X-199-2 (Florence) SAL-X-163 (Florence) SAL-VIIINJH-alcoholCN (Florence) 13 C NMR (instrument) SAL-VIII-209 crystals Florence SAL-IX-267 (Florence) SAL-IX-271-2 (Florence) SAL-IX-243 (Florence) SAL-X-201 (Florence) SAL-X-197 (Florence) SAL-X-183 (Florence) SAL-X-185 (Florence) SAL-X-189 (Florence) SAL-X-193 (Florence) SAL-X-195 (Florence) SAL-X-199-1 (Florence) SAL-X-199-2 (Florence) SAL-X-163 (Florence) SAL-VIIINJH-alcoholCN (Florence) IR Yield and Procedure SAL-VIII-209toptbsaldol SAL-VIII209 SAL-IX-267 SAL-IX-197 SAL-IX-271-2 SAL-IX-241 SAL-IX-243 SAL-IX-031 SAL-X-201 SAL-X-201 SAL-X-197 SAL-X-197 SAL-X-183 SAL-X-183 SAL-X-185 SAL-X-185 SAL-X-189 SAL-X-189 SAL-X-193 SAL-X-079 SAL-X-195 SAL-X-091 SAL-X-199-1 SAL-X-119 SAL-X-199-2 SAL-X-119 SAL-X-163 SAL-X-163 SAL-VIII-NJHalcohol-CN SAL-IX-139 551 Appendix 10 – Notebook Cross-Reference Table A10.2.4. Notebook Cross-Reference For Compounds in Appendix 8 Compound 473 475 476 1 13 H NMR C NMR (instrument) (instrument) SAL-VIII-091- SAL-VIII-0914 4 (Florence) (Florence) SAL-VIII-121 SAL-VIII-121 (Florence) (Florence) SAL-VIII-117 SAL-VIII-117 (Florence) (Florence) IR Yield and Procedure – SAL-VIII091 SAL-VIII-121 SAL-VIII-117 SAL-VIII087 SAL-VIII117 552 COMPREHENSIVE BIBLIOGRAPHY Abbas, H. K.; Mirocha, C. J. Appl. Environ. Microbiol. 1988, 54, 1268–1274. Abreu, M.; Alvaro-Benito, M.; Sanz-Aparicio, J.; Plou, F. J.; Fernandez-Lobato, M.; Alcalde, M. Adv. Synth. Catal. 2013, 355, 1698–1702. Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918–1919. Alexy, E. J.; Zhang, H.; Stoltz, B. M. J. Am. Chem. Soc. 2018, 140, 10109–10112. Allais, C.; Tsai, A. S.; Nuhant, P.; Roush, W. R. Angew. Chem. Int. Ed. 2013, 52, 1288– 12891. Allen, J. G.; Danishefsky, S. J. J. Am. Chem. Soc. 2001, 123, 351–352. Anderson, N. H.; Uh, H.-S. Synth. Commun. 1973, 3, 125–128. d’Angelo J. Tetrahedron 1976, 32, 2979–2990. Arao, T.; Kondo, K.; Aoyama, T. Chem. Pharm. Bull. 2006, 54, 1743–1744. Arao, T.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2006, 47, 1417–1420. Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044–1070. Arnold, F. H. Acc. Chem. Res. 1998, 31, 125–131. Arrayás, R. G.; Carretero, J. C. Chem. Soc, Rev. 2009, 38, 1940–1948. 553 Asai, R.; Mitsuhashi, S.; Shigetomi, K.; Miyamoto, T.; Ubukata, M. J. Antibiot. 2011, 64, 693–696. Bassner, S. L.; Morrison, E. D.; Geoffroy, G. L.; Rheingold, A. L. J. Am. Chem. Soc. 1986, 108, 5358–5359. Bauta, W.; Booth, J.; Bos, M. E.; DeLuca, M.; Diorazio, L.; Donohoe, T.; Magnus, N.; Magnus, P.; Mendoza, J.; Pye, P.; Tarrant, J.; Thom, S.; Ujjainwalla, F. Tetrahedron Lett. 1995, 36, 5327–5330. Behenna, D. C.; Liu, Y.; Yurino, T.; Kim, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nature Chemistry 2012, 4, 130–133. Behenna, D. C.; Mohr, J. T.; Sherden, N. H.; Marunescu, S. C.; Harned, A. M.; Tani, K.; Seto, M.; Ma, S.; Novak, Z.; Krout, M. R.; McFadden, R. M.; Roizen, J. L.; Enquist Jr., J. A.; White, D. E.; Levine, S. R.; Petrova, K. V.; Iwashita, A.; Virgil, S. C.; Stoltz, B. M. Chem. – Eur. J. 2011, 17, 14199–14223. Behenna, D. C.; Stoltz, B. M. J. Am. Chem. 2004, 126, 15044–15045. Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082–1146. Bisai, V.; Bisai, A.; Singh, V. K. Tetrahedron 2012, 68, 4541–4580. Bhanushali, M.; Zhao, C.-G. Synthesis 2011, 1815–1830. Blacker, A. J.; Clarke, M. L.; Loft, M. S.; Mahon, M. F.; Williams, J. M. Organometallics 1999, 18, 2867–2873. Bloch, R.; Le Perchec, P.; Rouessac, F.; Conia, J.-M. Tetrahedron, 1968, 24, 5971–5989. 554 Boechman, Jr., R. K.; Chinn, R. L. Tetrahedron, 1985, 26, 5005–5008. Bonadies, F.; Lattanzi, A.; Orelli, L. R.; Pesci, S.; Scettri, A. Tetrahedron Lett. 1993, 34, 7649–7650. Botteghi, C.; Paganelli, S.; Schionate, A; Boga, C; Fava, A. J. Mol. Catal. 1991, 66, 7–21. Botteghi, C.; Schionanto, A.; Rosini, C.; Salvadori, R. P. J. Mol. Catal. 1990, 63, 155–165. Brill, Z. G.; Grover, H. K.; Maimone, T. J. Science 2016, 27, 1078–1082. Brodmann, T.; Lorenz, M.; Schäckel, R.; Simsek, S.; Kalesse, M. Synlett 2009 174–192. Brown, H. C.; Dhar, R. K.; Bakshi, R. K.; Pandiarajan, P. K.; Singaram, B. J. Am. Chem. Soc. 1989, 111, 3441–3442. Brown H. C.; Ganesan, K.; Dhar, R. K. J. Org. Chem. 1993, 58, 147–153. Brunel, J. M.; Tenaglia, A.; Buono, G. Tetrahedron: Asymmetry 2000, 11, 3585–3590. Brunner, H.; Kraus, J. J. Mol. Catal. 1989, 49, 133–142. Brunner, H.; Krumey, C. J. Mol Catal. A: Chem. 1999, 142, 7–15. Brunner, H.; Hammer, B. Angew. Chem. Int. Ed. 1984, 23, 312–313. Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013, 4, 916–920. Burger, E.; Barron, B.; Tunge, J. Synlett 2006, 17, 2824–2826. Burkhardt, E. R.; Bergman, R. G.; Heathcock, C. H. Organometallics 1990, 9, 30–44. 555 Burkhardt, E. R.; Doney, J. J.; Slough, G. A.; Stack, J. M.; Heathcock, C. H.; Bergman, R. G. Pure Appl. Chem. 1998, 60, 1–6. Burtoloso, A. C. B. Synlett 2009, 320–327. Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002. Cazeau, P.; Moulines, F.; Laporte, O.; Duboudin, F. J. Organomet. Chem. 1980, 201, C9– C13. Chan, T. H.; Zheng, G. Z. Tetrahedron Lett. 1993, 34, 3095–3098. Chantani, N. Murai, S.; Sonoda, N. J. Am. Chem. Soc. 1983, 105, 1370–1372. Chen, G.; Kwong, F. Y.; Chan, H. O.; Yu, W.-Y.; Chan, A. S. C. Chem. Commun. 2006, 1413–1415. Chen, M. S.; Prabagaran, N.; Labenz, N. A.; White, C. M. J. Am. Chem. Soc. 2005, 127, 6970–6971. Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170– 2171. Chen, Q. B.; Xin, X. L.; Yang, Y.; Lee, S. S.; Aisa, H. A. J. Nat. Prod. 2014, 77, 807–812. b) Zhang, S.; Zhang, Z. Y. Drug Discovery Today 2007, 373–381. Chieffi, A.; Kamikawa, K.; Åhman, J.; Fox, J. M.; Buchwald, S. L. Org. Lett. 2001, 3, 1897–1900. Christoffers, J. Eur. J. Org. Chem. 1998, 1259–1266. 556 Christoffers, J. Prakt. Chem. (Weinheim, Ger.), 1999, 341, 495. Christoffer, J.; Baro, A. Angew. Chem. Int. Ed. 2003, 42, 1688–1690. Christoffers, J.; Mann, A. Eur. J. Org. Chem. 1999, 1475–1479. Christoffers, J.; Mann, A.; Pickardt, J. Tetrahedron, 1999, 55, 5377–5388. Christoffers, J.; Röβler, U.; Werner, T. Eur. J. Org. Chem. 2000, 701–705. Claisen, L. Chem. Ber., 1912, 45, 3157–3166. Collman, J. P. J. Org. Chem. 1961, 26, 3162–3166. Conia, J.-M.; Le Perchec, P. Synthesis 1975, 1–19. Corbin, N. C.; Fraher, P.; McChesney, J. D. J. Pharm. Sci. 1979, 68, 1501–1504. Córdova, A. Acc. Chem Res. 2004, 37, 102–112. Córdova, A. in Stereoselective Organocatalysis: Bond Formation Methodologies and Activation Modes, 1st Edition (Ed. R. R. Torres), Chap. 4, Wiley, 2013, p. 129–146 Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 17, 3–6. Corey, E. J.; Kania, R. S.J. Am. Chem. Soc. 1996, 118, 1229–1230. Corey, E. J.; Lee, D. H. J. Am. Chem. Soc. 1991, 113, 4026–4028. Corey, E. J.; Roberts, B. E.; Dixon, B. R. J. Am. Chem. Soc. 1995, 117, 193–196. 557 Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168–17169. Cowden, C. J.; Paterson, I. in Organic Reactions, Vol. 51, Chap. 1, Wiley, 1997, p. 1–200. Craig, II, R. A.; Loskot, S. A.; Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Org. Lett. 2015, 17, 5160–5163. Craig, II, R. A.; Roizen, J. L.; Smith, R. C.; Jones, A. C.; Virgil, S. C.; Stoltz, B. M. Chem. Sci. 2017, 8, 507–514. Craig, II, R. A.; Stoltz, B. M. Tetrahedron Lett. 2015, 56, 4670–4673. Cram, D. J.; Sogah, G. D. Y. J. Chem. Soc., Chem. Commun. 1981, 625–628. Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–245. Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43, 5138–5175. Das, J. P; Marek, I. Chem. Commun. 2011, 47, 4593–4623. Dauben, H. J.; McCoy, L. L. J. Am. Chem. Soc. 1959, 81, 4863–4873. Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424. Davis, F. A.; Lal, G. S.; Wei, J. Tetrahedron Lett. 1988, 29, 4269–4272. Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993,
34, 3149–3150. 558 Day, J. J.; McFadden, R. M.; Virgil, S. C.; Kolding, H.; Alleva, J. L.; Stoltz, B. M. Angew. Chem., Int. Ed. Engl. 2011, 50, 6814–6818. Denard, C. A.; Ren, H.; Zhao, H. Curr. Opin. Chem. Biol. 2015, 25, 55–64. Desimoni, G.; Dusi, G.; Faita, G.; Quadrelli, P.; Righetti, P. P. Tetrahedron 1995, 51, 4131–4144. Desimoni, G.; Quadrelli, P.; Righetti, P. P. Tetrahedron 1990, 46, 2927–2934. Dias, D. A.; Urban, S.; Roessner, U. Metabolites 2012, 2, 303–336. Dimitrov, V.; Kostova, K.; Genov, M. Tetrahedron Lett. 1996, 37, 6787–6790. Doering, W. V. E.; Yamashita, Y. J. Am. Chem. Soc. 1983, 105, 5368–5372. Doran, R.; Guiry, P. J. J. Org. Chem. 2014, 79, 9112–9124. Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. 2004, 101, 5363–5367. Doyle, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 62–63. Doyle, A. G.; Jacobsen, E.N. Angew. Chem. Int. 2007, 46, 3701–3705. Egger, H.; Reinshagen, H. J. Antibiot. 1976, 29, 923–927. Enders, D.; Knopp, M.; Schiffers, R. Tetrahedron: Asymmetry 1996, 7, 1847–1882. Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788–802. Evans, D. A.; Nelson, J. V.; Taber, T. R., Top. Stereochem., 13, 1 (1982) 559 Evans, W. J.; Dominguez, R.; Hanusa, T. P. Organometallics, 5, 1291–1296. Fossey, J. S.; Russell, M. L.; Malik, K. M. A.; Richards, C. J. J. Organomet. Chem. 2007, 692, 4843–4848. Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360– 1370. Freixa, Z.; van Leeuwen, P. W. N. M. Coord. Chem. Rev. 2008, 252, 1755–1786. Frostick, F. C.; Hauser, C. R. J. Am. Chem. Soc. 1949, 71, 1350–1352. Fujimura, O. J. Am. Chem. Soc. 1998, 120, 10032–10039. Fukuchi, I.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2007, 349, 509–512. Galarini, R.; Musco, A.; Pontellini, R.; Santi, R. J. Mol. Catal. 1992, 72, L11–L13. García-Fortanet, J.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 8108–8111. Garzan, A.; Jaganathan, A.; Salehi Marzijarani, N.; Yousefi, R.; Whitehead. D. C.; Jackson, J. E.; Borhan, B. Chem. – Eur. J. 2013, 19, 9015–9021. Ge, S.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 16330–16333. Giner, J.-L.; Kehbein, K. A.; Cook, J. A.; Smith, M. C.; Vlahos, C. J.; Badwey, J. A. Bioorg. Med. Chem. Lett. 2006, 16, 2518–2521. Glorius, F.; Altenhoff, G.; Goddard, R.; Lehmann, C. Chem. Commun. 2002, 2704–2705. 560 Göricke, F.; Schneider, C. Angew. Chem. Int. Ed. 2018, 57, 14736–14741. Gonda, J. Angew. Chem. Int. Ed. 2004, 43, 3516–3524. González, M. A.; Ghosh, S.; Rivas, F.; Fischer, D.; Theodorakis, E. A. Tetrahedron Lett. 2004, 45, 5039–5041. Gopalaiah, K. Chem. Rev. 2013, 113, 3248–3296. Gradillas, A.; Pérez-Castells, J. Angew. Chem. Int. Ed. 2006, 45, 6086–6101. Greco, S. J.; Lacerda, V. Jr.; dos Santos, R. B. Aldrichimica Acta, 2011, 44, 15–24. Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140. Gulias, M.; Rodriguez, J. R.; Castedo, L.; Mascarenas, J. L. Org. Lett. 2003, 5, 1975–1977. Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976–1991. Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976–4985. Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261– 1268. Hamada, T.; Buchwald, S. L. Org. Lett. 2002, 4, 999–1001. Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382–12383. Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124, 11240–11241. 561 Hamashima, Y.; Sasamoto, N.; Hotta, D.; Somei, H.; Umebayashi, N.; Sodeoka, M. Angew. Chem. Int. Ed. 2005, 44, 1525–1529. Hamashima, Y.; Hotta, D.; Umebayahi, N.; Tsuchiya, Y.; Suzuki, T.; Sodeoka, M. Adv. Synth. Catal. 2005, 347, 1576–1586. Hamashima, Y.; Sodeoka, M. Chem. Rec. 2004, 4, 231–242. Hamashima, Y.; Takano, H.; Hotta, D.; Sodeoka, M. Org. Lett. 2003, 5, 3225–3228. Han, Y.-Y.; Wu, Z.-J.; Chen, W.-B.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2011, 13, 5064–5067. Hansen, M. M.; Bartlett, P. A.; Heathcock, C. H. Organometallics, 1987, 6, 2069–2074. Harris, R. K.; Becker, E. D.; Cabral de Menezes, S. M.; Goodfellow, R.; Granger, P. Pure Appl. Chem. 2001, 73, 1795–1818. Harris, R. K.; Becker, E. D.; Cabral de Menezes, S. M.; Granger, P.; Hoffman, R. E.; Zilm, K. W. Pure Appl. Chem. 2008, 80, 59–84. Hatano, M.; Horibe, T.; Ishihara, K. J. Am. Chem. Soc. 2010, 132, 56–57. Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113–120. Heathcock, C. H. in Asymmetric Synthesis, Vol. 3 (Ed. J. D. Morrison), Chap. 2, Academic Press, 1984, p. 111–212. Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry 2012, 23, 1431–1465. Heravi, M. M.; Zadsirjan, V. Tetrahedron: Asymmetry 2013, 24, 1149–1188. 562 Heravi, M. M.; Zadsirjan, V. Tetrahedron: Asymmetry 2014, 25, 1061–1090. Herrmann, A. T.; Smith, L. L.; Zakarian, A. J. Am. Chem. Soc, 2012, 134, 6976–6979. Hirano, M.; Ito, Y.; Hirai, M.; Fukuoka, A.; Komiya, S. Chem. Lett. 1993, 22, 2057–2060. Hiroshi, S.; Masahito, I.; Kazuhiro, K. Chem. Lett. 1987, 16, 1527–1530. Hoffmeister, D.; Yang, J.; Liu, L.; Thorson, J. S. Proc. Natl. Acad. Sci. U. S. A. 2003, 100, 13184–13189. Hong, A. Y.; Bennett, N. B.; Krout, M. R.; Jensen, T.; Harned, A. M.; Stoltz, B. M. Tetrahedron, 2011, 67, 10234–10248. Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901–16910. Hoppe, D. Synthesis, 2009, 43–55. Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.; Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77–81. House, H. O.; Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chem. 1969, 34, 2324–2336. Hoye, T. R.; Jeffrey, C. S.; Tennakoon, M. A.; Wang, J.; Zhao, H. J. Am. Chem. Soc. 2004, 126, 10210–10211. Huang, F.-Q., Sun J.-G.; Wang, Y.-W.; Dong, X.; Qi, L.-W.; Zhang, B. Org. Lett. 2016, 18, 684–687. 563 Huang, J. Z.; Jie, X. K.; Wei, K.; Zhang, H.; Wang, M. C.; Yang, Y. R. Synlett 2013, 24, 1303–1306. Inagaki, K.; Nozaki, K.; Takaya, H. Synlett, 1997, 119–120. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993. Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899–2899. Ireland, R. E.; Mueller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868–2877. Ireland, R. E.; Norbeck, D. W. J. Org. Chem. 1985, 50, 2198–2200. Ireland, R. E.; Willard, A. K. Tetrahedron Lett. 1975, 16, 3975–3978. Ireland, R. E.; Wipf, P.; Armstrong, J. D. III, J. Org. Chem. 1991, 56, 650–657. Ishikawa, S.; Hamada, T.; Manabe, K.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 12236– 12237. Ito, H.; Taguchi, T. Chem. Soc. Rev. 1999, 28, 43–50. Janocha, S.; Schmitz, D.; Bernhardt, R. Adv. Biochem. Eng./Biotechnol..2015, 148, 215– 250. Jasiczak, J. J. Chem. Soc., Perkin Trans. 1 1988, 2687–2692. Jay, A. in Dictionary of Chemistry, 2nd Edition (Ed. E Geller), McGraw-Hill, 2003, p. 317. 564 Jette, C. I.; Geibel, I.; Bachman, S.; Hayashi, M.; Sakurai, S.; Shimizu, H.; Morgan, J. B.; Stoltz, B. M. Angew. Chem. Int. Ed. 2019, 58, 1–6 Jiménez, T.; Campaña, A. G.; Bazdi, B.; Paradas, M.; Arráez-Román, D.; SeguraCarretero, A.; Fernández-Gutiérrez, A.; Oltra, J. E.; Robles, R.; Justicia, J.; Cuerva, J. M. Eur. J. Org. Chem. 2010, 4288–4295. Johansson, C. C. C.; Colacot, T. J. Angew. Chem. Int. Ed. 2010, 49, 676–707. Jung, M. E.; Nishimura, N. Org. Lett. 2001, 3, 2113–2115. Jung, S. T.; Lauchli, R.; Arnold, F. H. Curr. Opin. Biotechnol. 2011, 22, 809–817. Kalek, M.; Himo, F. J. Am. Chem. Soc. 2012, 134, 19159–19169. Kamel, H. N.; Slattery, M. Pharmaceutical Biology 2005, 43, 253–269. Kanayama, T.; Yoshida, K.; Miyabe, H.; Takemoto, Y. Angew. Chem. Int. Ed. 2003, 42, 2054–2056. Kantorowski, E. J.; Kurth, M. J. Tetrahedron 2000, 56, 4317–4353 Karimi, B.; Ender, D.; Jafari, E. Synthesis, 2013, 45, 2769–2812. Kato, Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168–9169. Keana, J. F.; Seyedrezai, S. E. J. Org. Chem. 1982, 42, 347–352. Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.; Oxgaard, J.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2007, 129, 11876–11877. 565 Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526–4527. Kille, S.; Zilly, F. E.; Acevedo, J. P.; Reetz, M. T. Nat. Chem. 2011, 3, 738–743. Kim, E. J.; Kang, Y. K.; Kim, D. Y. Bull. Korean Chem.Soc. 2009, 30, 1437–1438. Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506–6507. Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626–2704. Korch, K. M.; Eidamshaus, C.; Behenna, D. C.; Nam, S.; Horne, D.; Stoltz, B. M. Angew. Chem. Int. Ed. 2015, 54, 179–183. Krause, N.; Hoffmann-Röder, A. Synthesis 2001, 171–196. Krebs, A.; Kazmaier, U. Tetrahedron Lett. 1996, 37, 7945–7946. Krout, M. R.; Mohr, J. T.; Stoltz, B. M. Org. Synth. 2009, 86, 181–205. Kündig, E. P.; Seidel, T. M.; Jia, Y.; Bernardinelli, G. Angew. Chem. Int. Ed. 2007, 46, 8484–8487. Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Padmaja, M.; Markondaiah, B. Adv. Synth. Catal. 2005, 347, 867–871. Kuwano, R.; Miyazaki, H.; Ito, Y. Chem Commun. 1998, 71–72. Kuwano, R.; Miyazaki, H.; Ito, Y. J. Organomet. Chem. 2000, 603, 18–29. 566 Långström, B.; Göran, B. Acta Chem. Scand. 1973, 27, 3118–3119. Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402–3415. Leonard, J.; Díez-Barra, E.; Merino, S. Eur. J. Org. Chem. 1998 2051–2061. Lewis, J. C.; Bastian, S.; Bennett, C. S.; Fu, Y.; Mitsuda, Y.; Chen, M. M.; Greenberg, W. A.; Wong, C.-H.; Arnold, F. H. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 16550– 16555. Lewis, J. C.; Mantovani, S. M.; Fu, Y.; Snow, C. D.; Komor, R. S. Wong, C.-H.; Arnold, F. H. ChemBioChem 2010, 11, 2502–2505. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639–666. Liao, X.; Weng, Z.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 195–200. Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 10626– 10629. Liu, W.-B.; Reeves, C. M.; Stoltz, B. M. J. Am. Chem. Soc. 2013, 135, 17298–17301. Liu, X.; Lin, L.; Feng, X. Acc. Chem. Res. 2011, 44, 574–587. Liu, Y.; Han, S. J.; Lui, W. B.; Stoltz, B. M. Acc. Chem. Res. 2015, 48, 740–751. Liu, Y.; Liniger, M.; McFadden, R. M.; Roizen, J. L.; Malette, J.; Reeves, C. M.; Behenna, D. C.; Seto, M.; Kim, J.; Mohr, J. T. Beilstein J. Org. Chem. 2014, 10, 2501–2512. Liu, Z.; Shi, M. Organometallics, 2010, 29, 2831–2834. 567 Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–1169. Majima, K.; Tosaki, S.-Y.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2005, 46, 5377– 5381. Malherbe, R.; Belluš, D. Helv. Chim. Acta 1978, 61, 3096–3099. Malherbe, R.; Rist, G.; Belluš, D. J. Org. Chem. 1983, 48, 860–869. Manuel, M.; Marques, M. B. Angew. Chem. Int. Ed. 2006, 45, 348–352. Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen, K. A. Chem. Eur. J. 2003, 9, 2359–2367. Marinescu, S. C.; Nishimata, T.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2008, 10, 1039–1042. Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 12268–13369. Martin, S. F. Tetrahedron 1980, 36, 419–460. Marziale, A. N.; Duquette, D. C.; Craig, II, R. A.; Kim, K. E.; Liniger, M.; Numajiri, Y.; Stoltz, B. M. Adv. Synth. Catal. 2015, 357, 2238–2245. Masamune, S.; Choy, W.; Kerdesky, F. A. J.; Imperiali, B. J. Am. Chem. Soc. 1981, 103, 1566–1568. Masahiro, M.; Masahiko, I.; Michinori, S.; Yoshihiko, I. Bull. Chem. Soc. Jpn. 1988, 61, 3649–3652. Masdeu-Bultó, A. M.; Diéguez, M.; Martin, E.; Gómez, M. Coord. Chem. Rev. 2003, 242, 159–201. 568 Matsunaga, S.; Ohshima, T.; Shibasaki, M. Adv. Synth. Catal. 2002, 344, 3–15. Matsuzawa, A.; Mashiko, T.; Kumagai, N.; Shibasaki, M. Angew. Chem. Int. Ed. 2011, 50, 7616–7619. Mazet, C. Synlett 2012, 23, 1999–2004. McDougal, N. T.; Virgil, S. C.; Stoltz, B. M. Synlett 2010, 11, 1712–1716. McDougal, N. T.; Streuff, J.; Mukherjee, H.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2010, 51, 5550–5554. Mehta, G.; Shinde, H. M. J. Org. Chem. 2012, 77, 8056–8070. Mekelburger, H. B.; Wilcox, C. S. in Comprehensive Organic Synthesis, 2nd Edition (Eds. Knochel, P. and Molander, G. A.), Chap. 2, Elsevier, 2014, p. 243–272. Meyer, T. Y.; Garner, L. R.; Baenziger, N. C.; Messerie, L. Inorg. Chem. 1990, 29, 4045– 4050. Mikiko, S.; Yoshitaka, H. Bull. Chem. Soc. Jpn. 2005, 78, 941–956. Miller, R. D.; McKean, D. R. Synthesis, 1979, 730–732. Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I. Nature, 2012, 490, 522– 526. Mino, T.; Masuda, S.; Nishio, M; Yamashita, M. J. Org. Chem. 1997, 62, 2633–2635. Missakian, M. G.; Burreson, B. J.; Scheuer, P. J. Tetrahedron 1975, 31, 2513–2515. 569 Mohr, J. T.; Behenna, D. C.; Harned, A. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2005, 44, 6924–6927. Mouri, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Chem Commun, 2009, 5138–5140. Müller, P. Crystallography Reviews 2009, 15, 57–83. Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521–522. Mukaiyama, T.; Matsuo, J.-I. in Modern Aldol Reactions, 1st Edition (Ed. R. Mahrwald), Chap. 3, Wiley, 2004, p. 127–160. Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471–5569. Murahashi, S.-I.; Take, K.; Naota, T.; Takaya, H. Synlett 2000, 1016–1018. Muratake, H.; Hayakawa, A.; Natsume, M. Tetrahedron Lett. 1997, 38, 7577–7580. Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38, 7581–7582. Nahra, F.; Macé, Y.; Boreux, A.; Billard, F.; Riant, O. Chem. – Eur. J. 2014, 20, 10970– 10981. Nahra, F.; Macé, Y.; Lambin, D.; Riant, O. Angew. Chem. Int. Ed. 2013, 52, 3208–3212. Nakajima, M.; Yamaguchi, Y.; Hashimoto, S. Chem. Commun. 2001, 1596–1597. Nakajima, M.; Yamamoto, S.; Yamaguchi, Y.; Nakamura, S.; Hashimoto, S. Tetrahedron, 2003, 59, 7307–7313. 570 Nakamura, M.; Hajra, A.; Endo, K.; Nakamura, E. Angew. Chem. Int. Ed. 2005, 44, 7248– 7251. Nakamura, A.; Nakada, M. Synthesis 2013, 45, 1421–1451. Nahra, F.; Macé, Y.; Lambin, D.; Riant, O. Angew. Chemie Int. Ed. 2013, 52, 3208–3212. Nemoto, T.; Matsumoto, T.; Masuda, T.; Hitoma, T.; Hatano, K.; Hamada, Y. J. Am. Chem. Soc. 2004, 126, 3690–2691. Nerz-Stormes, M.; Thronton, E. R. J. Org. Chem. 1991, 56, 2489–2498. Nestl, B. M.; Hammer, S. C.; Nebel, B. A.; Hauer, B. Angew. Chem., Int. Ed. Engl. 2014, 53, 3070–3095. Newman, D. J.; Cragg, G. M.; Snader, K. M. Nat Prod. Rep. 2000, 17, 215–234. Ngamnithiporn, A.; Jette, C. I.; Bachman, S.; Virgil, S. C.; Stoltz, B. M. Chem. Sci, 2018, 9, 2547–2551. Noda, D.; Sunada, Y.; Hatakeyama, T.; Nakamura, M.; Nagashima, H. Chem. Commun. 2012, 48, 12231–12233. Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 5630–5631. Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37, 580–591. Numajiri, Y.; Pritchett, B. P.; Chiyoda, K.; Stotlz, B. M. J. Am. Chem. Soc. 2015, 137, 1040–1043. 571 Oh, H.; Swenson, D. C.; Gloer, J. B.; Wicklow, D. T.; Dowd, P. F. Tetrahedron Lett. 1998, 39, 7633–7636. Ohtsuka, Y.; Ikeno, T.; Yamada, T. Tetrahedron: Asymmetry, 2003, 14, 967–970. Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5644–5645. Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108–11109. Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518–1520. Panish, R.; Selvaraj, R.; Fox, J. M. Org. Lett. 2015, 17, 3978–3981. Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Org. Lett. 2009, 11, 292–295. Piers, E.; Wong, T.; Ellis, K. A. Can. J. Chem. 1992, 70, 2058–2064. Prakash, J.; Marek, I. Chem. Commun. 2011, 47, 4593–4623. Quinn, R. K.; Könst, Z. A.; Michalak, S. E.; Schmidt, Y.; Szklarski, A. R.; Flores, A. R.; Nam, S.; Horne, D. A.; Vanderwal, C. D.; Alexanian, E. J. Am. Chem. Soc. 2016, 138, 696–702. Rambla, M.; Duroure, L.; Chabaud, L.; Guillou, C. Eur. J. Org. Chem. 2014, 7716–7720. Reetz, M. T. Angew. Chem., Int. Ed. Engl. 2001, 40, 284–310. Reetz, M. T. J. Am. Chem. Soc. 2013, 135, 12480–12496. Reetz, M. T.; Peter, R. Tetrahedron, Lett. 1981, 22, 4691–4694. 572 Reeves, C. M.; Behenna, D. C.; Stoltz, B. M. Org. Lett. 2014, 16, 2314–2317. Reeves, C. M.; Eidamshaus, C.; Kim, J.; Stoltz, B. M. Angew. Chem. Int. Ed. 2013, 52, 6718–6721. Rehbein, J.; Hiersemann, M. Synthesis 2013, 45, 1121–1159. Reich, H. J.; Holtan, R. C.; Borkowsky, S. L. J. Org. Chem. 1987, 52, 312–314. Renata, H.; Zhou, Q.; Dünstl, G.; Felding, J.; Merchant, R., R.; Yeh, C.-H.; Baran, P. S. J. Am. Chem. Soc. 2015, 137, 1330–1340. Rentmeister, A.; Arnold, F. H.; Fasan, R. Nat. Chem. Biol. 2009, 5, 26–28. Roiban, G.-D.; Reetz, M. T. Chem. Commun. 2015, 51, 2208–2224. Salmond, W. G.; Barta, M. A.; Havens, J. L. J. Org. Chem. 1978, 43, 2057–2059. Sasai, H.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 1571–1572. Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 5561–5564. Sasai, H.; Itoh, N.; Suzuki, T.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 855–858. Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418– 4420. Sasai, H.; Suzuki, T.; Itoh, N.; Arai, S.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 2657– 2660. 573 Sasai, H.; Suzuki, T.; Itoh, N.; Shibasaki, M. Tetrahedron Lett. 1993, 34, 851–854. Sasai, H.; Suzuki, T.; Itoh, N.; Tanaka, K.; Date, T.; Okamura, K.; Shibasaki, M. J. Am. Chem. Soc. 1993, 115, 10372–10373. Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem. Int. Ed. 1997, 36, 1740– 1742. Sawamura, M.; Hamashima, H.; Ito, Y. J. Am. Chem. Soc, 1992, 114, 8295–8296. Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron, 1994, 50, 4439–4454. Sawamura, M.; Hamashima, H.; Shinoto, H.; Ito, Y. Tetrahedron, Lett. 1995, 36, 6479– 6482. Sawamura, M.; Nagata, H.; Sakamoto, H.; Ito, Y. J. Am. Chem. Soc. 1992, 114, 2586– 2592. Schetter, B.; Mahrwald, R. Angew. Chem. Int. Ed. 2006, 45, 7506–7525. Schmuff, N. R.; Trost, B. M. J. Org. Chem. 1983, 48, 1404–1412. Sears, J. E.; Boger, D. L. Acc. Chem. Res. 2015, 48, 653–662. Seebach, S. Angew. Chem. Int. Ed. Engl. 1988, 27, 1624–1654. Semmelhack, M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T. D.; Chong, A.; Jones, L. D. J. Am. Chem. Soc. 1975, 97, 2507–2516. Semmelhack, M. F.; Stauffer, R. D.; Rogerson, T. D. Tetrahdron Lett. 1973, 14, 4519– 4522. 574 Shaw, S.; White, J. D. J. Am. Chem. Soc. 2014, 136, 13578–135 Sheldrick, G. M. Acta Cryst. 1990, A46, 467–473. Sheldrick, G. M. Acta Cryst. 2008, A64, 112–122. Shen, K.; Liu, X.; Wang, W.; Wang, G.; Cao, W.; Li, W.; Hu, X.; Lin, L.; Feng, X. Chem. Sci. 2010, 1, 590–595. Shen, K.; Liu, X.; Zheng, K.; Li, W.; Hu, X.; Lin, L.; Feng, X. Chem. Euro. J. 2010, 16, 3736–3742. Sherden, N. H.; Behenna, D. C.; Virgil, S. C.; Stoltz, B. M. Angew. Chem. Int. Ed. 2009, 48, 6840–6843. Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem. Int. Ed. 1997, 36, 1236–1256. Shibasaki, M.; Yoshikawa, N. Chem Rev. 2002, 102, 2187–2210. Shimizu, S.; Tsubogo, T.; Xu, P.; Kobayashi, S. Org. Lett. 2015, 17, 2006–2008. Shrestham R.; Dorn, S. C. M.; Weix, D. J. J. Am. Chem. Soc. 2013, 135, 751–762. Shockley, S. E.; Hethcox, J. C.; Stoltz, B. M. Angew. Chem. Int. Ed. 2017, 56, 11545– 11548. Sibi, M. P.; Manyem, S. Tetrahedron, 2000, 56, 8033–8061 Sibi, M. P.; Tatamidani, H.; Patil, K. Org. Lett. 2005, 7, 2571–2573. 575 Sladojevich, F.; Fuentes de Arriba, Á. L.; Ortín, I.; Yang, T.; Ferrali, A.; Paton, R. S.; Dixon, D. J. Chem. Eur. J. 2013, 19, 14286–14295. Sparling, B. A.; Moebius, D. C.; Shair, M. D. J. Am. Chem. Soc. 2013, 135, 644–647. Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 3500–3501. Spielvogel, D. J.; Davis, W. M.; Buchwald, S. L. Organometallics 2002, 21, 3833–3836. Sprinz, J.; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769–1772. Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem. Int. Ed. 2004, 43, 5350– 5352. Stark, M. A.; Jones, G.; Richards, C. J. Organometallics, 2000, 19, 1282–1291. Stoltz, B. M; Kano, T.; Corey, E. J. J. Am. Chem. Soc. 2000, 122, 9044–9045. Stork, G.; Danheiser, R. L. J. Org. Chem. 1973, 38, 1775–1776. Streuff, J.; White, D. E.; Virgil, S. C.; Stoltz, B. M. Nature Chem. 2010, 2, 192–196. Subramaniapillai, S. G. J. Chem. Sci. 2013, 125, 467–482. Sun, Y.-W.; Zhu, P.-L.; Xu, Q.; Shi, M. RSC Adv. 2013, 3, 3153–3168. Suzuki, H.; Koyama, Y. Tetrahedron Lett. 1979, 20, 1415–1418. Suzuki, T.; Torii, T. Tetrahedron: Asymmetry 2001, 12, 1077–1081. 576 Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001, 47–53. Takasu, K.; Nagao, S.; Ihara, M. Tetrahedron Lett. 2005, 46, 1005–1008. Takayama, H.; Katakawa, K.; Kitajima, M.; Yamaguchi, K.; Aimi, N. Tetrahedron Lett. 2002, 43, 8307–8311. Takenaka, K.; Minakawa, M.; Uozumi, Y. J. Am. Chem. Soc. 2005, 127, 12273–12281. Takenaka, K.; Uozumi, Y. Org. Lett. 2004, 6, 1833–1835. Taylor, A. M.; Altman, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900–9901. Taylor, R. J. K. Synthesis 1985, 364–392. Thominiaux, C.; Roussé, S.; Desmaële, D.; d’Angelo, J.; Riche, C. Tetrahedron: Asymmetry 1999, 10, 2015–2021. Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797–5815. Trost, B. M. Tetrahedron 2015, 71, 5708–5733. Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2001, 123, 12726–12727. Trost, B. M.; Bream, R. N.; Xu, J. Angew. Chem. Int. Ed. 2006, 45, 3109–3112. Trost, B. M.; Frederiksen, M. U. Angew. Chem. Int. Ed. 2005, 44, 308–310. Trost, B. M.; Pissot-Soldermann, C.; Chen, I. Chem. Eur. J. 2005, 11 951–959. Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc. 1997, 119, 7879–7880. 577 Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121, 6759–6760. Trost, B. M.; Schroeder, G. M. Chem. Eur. J. 2005, 11, 174–184. Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem. Int. Ed. 2002, 41, 3492–3495. Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395–422. (b) Trost, B. M. J. Org. Chem. 2004, 69, 5813–5837. Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127, 2846–2847. Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131, 18343–18357. Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590–4591. Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129, 14548–14549. Tsuji, J.; Minami, I.; Shimizu, I. Tetrahedron Lett. 1983, 24, 1793–1796. Turner N. J. Nat. Chem. Biol. 2009, 5, 567–573. Verkade, J. M. M.; van Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem Soc. Rev. 2008, 37, 29–41. Von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 566–568. Wang, Y.; Kuang, Y.; Wang, Y. Chem. Commun. 2015, 51, 5852–5855. Wang, Z.; Yang, Z.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2011, 50, 4928–4932. 578 Weaver, J. D.; Recio, A.; Grenning, A. J.; Tunge, J. A. Chem. Rev. 2011, 111, 1846–1913. Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1987, 52, 5056–5057. Weidmann, V.; Maison, W. Synthesis 2013, 45, 2201–2221. Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist, P. R. J. Nat. Prod. 2000, 63, 79–85. Wencel-Delord, J.; Dröge, T. Chem. Soc. Rev. 2011, 40, 4740–4761. Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. Engl. 2011, 50, 11062–11087. Whitehouse, C. J. C.; Bell, S. G.; Tufton, H. G.; Kenny, R. J. P.; Ogilvie, L. C. I.; Wong, L. L. Chem. Commun. 2008, 966–968. Whitehouse, C. J.; Bell, S. G.; Wong, L. L. Chem. Soc. Rev. 2012, 41, 1218–1260. Wilde, N. C.; Isomura, M.; Mendoza, A.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 4909– 4912. Wohlgemuth, R. Curr. Opin. Biotechnol. 2010, 21, 713–724. Wolberg, M.; Hummel, W.; Wandrey, C.; Müller, M. Angew. Chem., Int. Ed. Engl. 2000, 39, 4306–4308. Wright, T. B.; Evans, P. A. J. Am. Chem. Soc. 2016, 138, 1503–15306. Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418–11419. 579 Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem. Int. Ed. 2012, 51, 1680–1683. Wurtz, A. C. Bull. Soc. Chim. Fr. 1872, 17, 436–442. Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050–16051. Xing, X.; O’Connor, N. R.; Stoltz, B. M. Angew. Chem., Int. Ed. Engl. 2015, 54, 11186– 11190. Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem. Int. Ed. Engl. 2012, 51, 8960– 9009. Yamashita, Y.; Odashima, K.; Koga, K. Tetrahedron Lett. 1999, 40, 2803–2806. Yanagisawa, A.; Lin, Y.; Miyake, R.; Yoshida, K. Org. Lett. 2014, 16, 86–89. Yang, T.; Ferrali, A.; Sladojevich, F.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 9140–9141. Yasufumi, T.; Atsushi, K.; Eiji, K.; Sotaro, M. Chem. Lett. 1995, 24, 957–958. Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121, 9726–9727. Yoon, T. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 2911–2912. Yoshikai, N.; Zhang, S.-L.; Yamagata, K.-I.; Tsuji, H.; Nakamura, E. J. Am. Chem. Soc. 2009, 131, 4099–4109. You, S.-L.; Dai, L.-X. Angew. Chem. Int. Ed. 2006, 45, 5246–5248. 580 Young, W. B.; Masters, J. J.; Danishefsky, S. J. Am. Chem. Soc. 1995, 117, 5228–5234. Yu, J.-Q.; Corey, E. J. Org. Lett. 2002, 4, 2727–2730. Yu, K.; Jackson, J. J.; Nguyen, T. D.; Alvatado, J.; Stivala, C. E.; Ma, Y.; Mack, K. A.; Hayton, T. W.; Collum, D. B.; Zakarian, A. J. Am. Chem. Soc. 2017, 139, 527–533. Yusuke, I.; Isao, S.; Akio, Y. Bull Chem. Soc. Jpn. 2004, 77, 2033–2045. Zhang, K.; Shafer, B. M.; Demars, M. D., II; Stern, H. A.; Fasan, R. J. Am. Chem. Soc. 2012, 134, 18695–18704. Zhang, P.-P.; Yan, Z.-M.; Li, Y.-H.; Gong, J.-X.; Yang, Z. J. Am. Chem. Soc. 2017, 139, 13989–13992. Zhang, T. Y.; Zhang, H. Tetrahedron Lett. 2002, 43, 1363–1365. Zhao, Y.; Yeung, Y.-Y. Org. Lett. 2010, 12, 2128–2131. Zhu, J.; Germain, A. R.; Porco, J. A. Jr. Angew. Chem., Int. Ed. Engl. 2004, 43, 1239– 1243. Ziegler, F. E. Chem. Rev. 1988, 88, 1423–1452. Zou, Y.; Millar, J. G. J. Org. Chem. 2009, 74, 7207–7209. 581 INDEX # 1,3 dicarbonyl ...................................................................................................... 19, 23–24, 28, 30, 32, 37, a a-alkenylation ........................................................................................................................................ 67 a- arylation................................................................................................................................ 67–84, 105 a-bromo ............................................................................................................................ 6, 221, 320, 325 a-vinylation...................................................................................................................................... 68–72 a,b-unsaturated.................................................................................................................. 6–7, 17, 86, 219 b b-ketoester............................................ 13–15, 19–21, 23, 26, 29, 35–46, 49–53, 56, 58, 61, 64, 83, 89–90, ............................................................... 92, 111–117, 123–125, 128–147, 151–152, 219–221, 235–237 b-scission ............................................................................................................................................. 332 p p-allyl............................................................................................................................................... 11, 53 A acetonide .............................................................................................................................................. 321 acyclic ...................................................................................................... 23–24, 35, 38, 44, 54, 62–65, 67 ADH.............................................................................................................................. 227–228, 244, 257 aldimine ......................................................................................................................................20, 22–25 aldol ................................................................ 4, 9–10, 12–13, 15–18, 36, 95, 220–221, 321, 328–329, 375 alkylation........................................................... 11, 18, 51–67, 109–119, 219–221, 227–228, 253, 320, 324 alkyne.................................................... 88–90, 222, 240–241, 318, 320–321, 327, 336–337, 365, 530–531 allylic alkylation ....................................................... 51–57, 59–64–109–161, 219–221, 228, 253, 320, 324 allylic anion .......................................................................................................................................... 531 amide ................................. 3–6, 17, 22, 34, 72–73, 87, 90–91, 319–320, 327, 336–337, 349–350, 530, 533 582 aminophosphine ligand .......................................................................................................... 52, 68–70, 73 asymmetric ............................................................1–108, 219–221, 228, 253, 320, 324, 446, 466, 486, 504 B bidentate ligand ................................................................................................................................ 16, 80 BINAP .......................................................................................... 20, 33, 40–41, 45, 67–68, 71–72, 80–82 BINOL ..................................................................................................... 23–24, 36–40, 49–50, 61, 63–64 bioactive .................................................................................................................................. 18, 110, 317 boron .................................................................................... 9–10, 17, 84–85, 219, 222–223, 229, 241–242 BOX ligand ........................................................................................................................... 19, 25, 87–88 C calcium ........................................................................................................................................25, 49–50 carbon monoxide .......................................................................................................................... 231, 327 carboxylic acid ............................... 32, 48, 63, 65, 84, 91, 119, 121–122, 148, 150, 222, 225, 231, 240, 319 carvone ................................................................................... 319–320, 327–328, 330, 333–334, 373, 530 cerium ..................................................................................................... 228, 232, 326, 344, 374, 530, 533 chelate (chelation) .................................................................................... 21, 28, 30, 37–38, 43, 46, 85, 87 chromium ......................................................................................................................................... 64–65 Claisen ............................................................................................................................................. 84–88 co-catalyst .............................................................................................................................................. 89 cobalt ............................................................................................................................................... 26–28 Conia-ene ......................................................................................................................................... 88–93 conjugate addition.................................................................... 6–7, 11, 25, 30–31, 37, 46, 50–51, 333–334 copper ............................................................................................... 11, 19, 31–32, 83–84, 88, 90–91, 229 cross-coupling .............................................................................................................................. 219–223 cyanoketones .................................................................................................................................... 20, 22 cyclic .................................................... 12, 20–24, 26, 29, 35–36, 38–41, 44–45, 49, 52, 56–58, 61, 64–66 ............................................................................................................................... 69, 78, 81, 109–113 cycloaddition, [2+2] ...................................................................................................................... 330–332 cyclohexadiene ............................................................................................................................. 318, 327 cyclopentanone .................................................................................................................. 68, 70, 109–161 cyclopentene ............................................................................................ 127, 318, 320–321, 325–326, 328 583 D decarboxylative.................................................................................................................. 53–54, 109–161 desamino ligand ............................................................................................................................... 69–70 diamine ligand ................................................................................................................. 26–27, 29–31, 35 diastereoselective ............................................................................................... 4,12, 21, 39, 325, 333–334 DIBAL .......................................................................................................................... 321, 326, 346, 374 Dieckmann ................................................................................................................................... 123–124 Diels–Alder .............................................................. 318–319, 323–324, 327–328, 330–331, 375, 529–530 dienone .................................................................................................................................. 219, 221, 223 directed epoxidation...................................................................................................................... 328, 331 diyne .................................................................................................................................................... 330 DMAP ...................................... 122, 148, 321, 327, 330, 339, 351–352, 3550, 360, 373, 375–376, 530, 535 DMP......................................................................... 227–229, 244–245, 257, 321, 334, 364, 276, 531, 537 E enantioselective ..................................39, 41, 43, 53, 63, 75, 79, 84, 109–161, 217–256, 258, 285, 320, 325 enolate ........................................................................................................ 1–109, 159, 220, 320, 324, 329 enzymatic ....................................................................................................... 218, 220, 225, 228, 246, 254 epoxidation ............................................................................................................................ 319, 328, 331 epoxide .................................................................................................... 319, 328, 331, 357–358, 362–363 europium ................................................................................................................................................ 32 F ferrocenylphosphine ligand ..................................................................................................................... 59 G gold ........................................................................................................................................................ 89 Grignard .................................................................................................................................... 6, 530, 533 H HMDS ............................................................................................... 5, 8, 56–57, 63–64, 79, 81–82, 85–86 homologation.......................................................................................................................................... 90 hydroboration .......................................................................................................................... 17, 222, 241 584 hydrolysis ..................................................................................................................................... 220, 319 hydrosilylation ....................................................................................................................... 7–8, 331, 370 I ineleganolide ......................................................................................................................... 317–318, 320 ionic liquid ....................................................................................................................................... 44–45 iridium.........................................................................................................................................35, 60–63 iron................................................................................................................................ 41, 88, 92–92, 101 isocarvone ............................................................................................................................................ 319 J Jonhphos ................................................................................................................................................ 69 K ketal ..................................................................................................................................................... 320 ketalization ............................................................................................................................................. 46 L lactam.................................................................................................................................... 53–54, 64, 79 lactone ........................................................................................................................... 24, 64, 81–82, 367 lanthanum .............................................................................................................................. 36–38, 40, 88 LDA .................................................................................................... 5–6, 56–57, 221–222, 234, 240, 257 Lewis acid ........................................................................................................ 3, 24, 56–57, 81, 87, 89, 91 ligand screen................................................................. 28, 31, 42, 69, 71, 75–77, 89, 91–92, 112–113, 226 linalool .................................................................................................................................. 325–326, 374 low catalyst loading ................................................................................. 14, 43, 54, 70, 118–119, 151–152 Luche ........................................................................................................................................... 325, 530 M macrocycle .................................................................................................................... 318, 321, 323, 531 manganese ........................................................................................................................................ 50–51 Mannich reaction ................................................................................................................... 19–25, 45, 54 585 metathesis...................................................................................................................... 318, 321, 323, 531 methyl vinyl ketone ...................................................... 26, 28–29, 31–32, 35–36, 38–39, 40–42, 45, 47, 49 Michael addition ................................................................................................................ 25–50, 333–334 molybdenum ..................................................................................................................................... 59–60 monophosphine ligand ............................................................................................................................ 71 MOP ligand ...................................................................................................................................... 70–71 N N-heterocyclic carbene (NHC) ........................................................................................ 21, 45, 73, 75–76 N,N’-dioxide ligand .....................................................................................................................17, 47–48 NADPH ................................................................................................................................. 227, 246–247 natural product ............................................................................................ 2, 110–111, 119, 219, 227, 317 neodymium....................................................................................................................................... 15, 17 nickel ....................................................................................................... 11, 13, 15, 23, 28–31, 64, 78–83 nigelladine A ......................................................................................................................... 217–258, 285 norcembranoid ....................................................................................................................... 317, 318, 323 O Ohira–Bestmann .................................................................................................................... 320, 336, 373 olefin isomerization ............................................................................................ 8, 223, 248, 318, 320, 324 oxa–Michael ................................................................................................................................. 333–334 oxidation ................................................... 217–256, 258, 285, 318, 321, 324–325, 327–329, 331–334, 531 oxidative enolate coupling............................................................................................................. 324, 329 oxindole ........................................................................................ 15, 17, 19, 25, 30–31, 50, 58–59, 71–75 P P-PHOS (ligand) ................................................................................................................... 64, 80, 82–83 palladium...................................... 11, 13, 14, 19–22, 42–46, 51–59, 67–79, 88–89, 109–161, 228, 327, 350 Pavidolide ............................................................................................................................................ 317 Pericyclic reaction .................................................................................................................................. 84 phosphinooxazoline (PHOX) ..................................................52–54, 77, 109–114, 116–119, 139, 151–152 ................................................................................................................. 221, 229, 237, 253, 257, 321 photocycloaddition ............................................................................................................................... 331 pincer complex ligand ....................................................................................................................... 42–43 586 platinum ......................................................................................................................................13–14, 41 Q quaternary center ......................................................................... 1–114, 118–119, 128, 159, 219, 221, 228 R rearrangement ..................................................................................................... 7–8, 84–88, 107–108, 222 reduction .................................................................................................................. 84, 321, 325–326, 530 regioselective ............................................................................................................................. 3, 225–226 retrosynthetic analysis ...................................................................... 219–220, 318–319, 324, 329–330, 530 rhodium ......................................................................................................................12–13, 33–36, 63–64 ring expansion ............................................................................................................... 329–334, 376, 529 S saponification ........................................................................................................................ 222, 327, 330 scabrolide A ................................................................................................... 317–372, 377, 444, 529–539 scabrolide B.................................................................................................................................. 317–318 scandium ....................................................................................................................15–16, 22–23, 47–48 SEGPHOS ligand ........................................................................................................................20, 80, 89 selectivity ......................... 3, 5–6, 9–10, 13–14, 20–27, 29–35, 38–41, 43–44, 46, 48, 50, 54, 58, 62, 65–66 ........................................ 68–70, 80–81, 85–87, 89, 91–92, 217–219, 224–228, 246–247, 249, 322, 325 silver .............................................................................................................................................. 92, 332 silyl enol ether ..................................................................................... 6–8, 52, 66, 127, 152–153, 159, 320 sinolochmodin C........................................................................................................................... 317–318 Stork–Danheiser ................................................................................................................................... 220 T tautomerization ....................................................................................................................................... 88 transition state............................................................................................... 2–5, 12–13, 17–18, 21–22, 46 TRAP ligand.......................................................................................................................... 12–13, 33–34 Trost ligand ...................................................................................................................................... 56–59 587 U UHPLC ......................................................................................................................... 225, 227, 248, 249 V vinylogous ............................................................................................................................... 58, 232, 325 W Wacker oxidation................................................................................................................... 159, 220–221 Wittig olefination.......................................................................................................................... 321, 326 X XPhos ligand ................................................................................................................. 222–223, 242, 257 X-ray ....................................................................................... 222, 253, 285–316, 328, 331–333, 444–528 Y Yamaguchi esterification........................................................................................................ 321, 529, 531 yonarolide..................................................................................................................................... 317–318 yttrium.............................................................................................................................................. 47–48 Z Zimmerman–Traxler transition state .......................................................................................................... 4 zwitterionic....................................................................................................................................... 13, 86 588 ABOUT THE AUTHOR Steven Anthony Loskot was born in San Jose, California on October 7th, 1991 to Victor and Annette Loskot. Steven was raised in San Jose with his older brother, Daniel Loskot. Steven’s love for science and engineering stemmed from his father, who was an engineer. Originally Steven was interested in biology thanks to his AP biology teacher, Mr. Wong, at Bellarmine College Preparatory, but was convinced by him to pursue a degree in biochemistry. In the fall of 2010, Steven moved to Seattle, Washington to attend the University of Seattle, a small Jesuit, liberal arts college for a B.S. in biochemistry. After the first organic chemistry class taken, instructed by Professor Joe Langenhan, Steven immediately fell in love with it and sought to perform research with Professor Langenhan. Under the tutelage of Professor Langenhan, Steven performed research in a number of subfields of organic chemistry, specifically with natural product total synthesis being is favorite area of research. In the summer of 2013, Steven solidified his interest and intent to study the field of organic synthesis when he conduct research under Professor Neil Garg at UCLA as an Amgen Scholar. During his time there, he learned what it was truly like to be on the forefront of research in pursuit of the total synthesis of the complex natural product tubingensin A. Following his undergraduate education, Steven moved to Pasadena, California to pursue his doctoral studies at the California Institute of Technology with Professor Brian Stoltz. His doctoral research has focused on the pursuit of the asymmetric total synthesis 589 of alkaloids and terpenoids. Upon completion of his doctoral research in May, 2019, Steven will begin his professional career as a medicinal chemist at Janssen, San Diego.