Total Synthesis of Hypersampsone M and Studies of Related Polycyclic Polyprenylated Acylphloroglucinol Systems Citation Samkian, Adrian Eduard (2026) Total Synthesis of Hypersampsone M and Studies of Related Polycyclic Polyprenylated Acylphloroglucinol Systems. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/hd4h-sk15. https://resolver.caltech.edu/CaltechTHESIS:08122025-011509478 Abstract Research in the Stoltz group is primarily focused on the total synthesis of complex, bioactive natural products and on the development of reaction methodologies to enable these synthetic endeavors. This thesis focuses on the homoadamantane polycyclic polyprenylated acylphloroglucinol (PPAP) class of natural products, our efforts toward their synthesis, and discoveries made along the way. Chapter 1 describes the completed synthesis of hypersampsone M, while Chapter 2 describes ongoing efforts toward wilsonglucinol G and hypersampsone A. Appendix 5 presents the culmination of optimization studies and unsuccessful routes toward these natural products. Chapter 3 describes selective fragmentations of a-bromocaranones, reactions that were tailored to the synthesis of PPAPs. Chapter 4 discloses the synthesis and characterization of an unexpected, caged side product isolated during an unsuccessful route to the homoadamantane PPAPs. Chapter 5 discusses the development and scope of the key cyclopentene annulation methodology that enabled the installation of the challenging, hindered 5-membered ring on the homoadamantane PPAPs. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Synthesis PPAPs organic chemistry 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: Fu, Gregory C. (chair) Reisman, Sarah E. Goddard, William A., III Virgil, Scott C. Stoltz, Brian M. Defense Date: 22 May 2025 Funders: Funding Agency Grant Number NIH-NIGMS R35GM145239 NSF Graduate Research Fellowship UNSPECIFIED Record Number: CaltechTHESIS:08122025-011509478 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:08122025-011509478 DOI: 10.7907/hd4h-sk15 Related URLs: URL URL Type Description https://doi.org/10.1016/j.tetlet.2021.153496 DOI Article adapted for ch.3 https://doi.org/10.1021/jacs.4c07007 DOI Article adapted for ch.2 https://doi.org/10.1016/j.tetlet.2025.155591 DOI Article adapted for ch.4 https://doi.org/10.1021/acs.orglett.5c01750 DOI Article adapted for ch.5 ORCID: Author ORCID Samkian, Adrian Eduard 0000-0002-0068-3572 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 17616 Collection: CaltechTHESIS Deposited By: Adrian Samkian Deposited On: 21 Aug 2025 21:44 Last Modified: 28 Aug 2025 09:10 Thesis Files PDF - Final Version See Usage Policy. 50MB Repository Staff Only: item control page

TOTAL SYNTHESIS OF HYPERSAMPSONE M AND STUDIES OF RELATED POLYCYCLIC POLYPRENYLATED ACYLPHLOROGLUCINOL SYSTEMS Thesis by Adrian Eduard Samkian In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2026 (Defended May 21, 2025) ii © 2025 Adrian Eduard Samkian ORCID: 0000-0002-0068-3572 All Rights Reserved iii To my partner, parents, and brother iv ACKNOWLEDGEMENTS A Ph.D. marks the culmination of several years of research, learning, and personal growth. While the research presented herein represents countless hours’ worth of experimentation and analysis, it would not have been possible without the support, guidance, and encouragement of many individuals and organizations. I am deeply grateful to all who have played a role in helping me come to this point, and I dedicate this section to recognizing their contributions. First, I would like to thank Professor Brian Stoltz. Without a doubt, the most significant factor in shaping the experiences I’ve had these past few years has been Brian’s guidance. While his research expertise and knowledge in the field needs no elaboration, I have been continually impressed by—and sought to learn from—his interpersonal skills and his ability to tailor guidance to an incredibly varied group of individuals. The patience and trust he has afforded me has been immense: from embarking on unusual research avenues, to spending months at industrial internships, and even providing support for me to start a company, Brian’s priority was always my personal growth and development. I felt confident that joining the Stoltz lab was the right decision five years ago and I am still confident that was the right call. I would also like to thank my committee chair, Professor Greg Fu, for both his research and life advice. His Chem 104 class has continually proved vital during my research, and it was fairly common for me to reference my class notes when making mechanistic analysis. Professors William (Bill) Goddard, Sarah Reisman, and Dr. Scott Virgil are also thanked for being incredibly wonderful committee members. Their advice v and comments on my research were clearly always from a place of curiosity, and I feel incredibly lucky to have had regular meetings with them. Scott and Silva Virgil have also had a profound impact on my graduate experience. Scott was introduced to me by Bob, and early on we spent many hours in his office talking about fundamental and applied chemistry. Silva and I connected early in my graduate studies, with our shared interest in fine dining being a consistent talking point. Their generosity is appreciated by many graduate students during the holidays, where the Virgils host a superb Christmas party at their house. I will miss these events and our times together, but I am certain opportunities to meet will present themselves in our future. I would like to extend my gratitude to Dr. Mike Takase and Dr. Mona Shahgholi for their assistance with X-ray structure determination and mass spectrometry. I need to thank Beth Marshal, Tomomi Kano, Allison Ross, and Suri Pourmodheji for keeping Schlinger running and all the events organized. I would also like to thank Dr. Dave VanderVelde, whose discussions over coffee I have appreciated immensely. Joe Drew has done a stellar job in keeping the chemistry buildings safe and operational, and I have also enjoyed our lunches talking about his past a great deal. I wish Mona, Allison, Dave, and Joe a very happy retirement. Throughout the years at Caltech, I have collaborated with a number of incredibly talented project partners. When I joined the Stoltz Lab, I immediately joined a collaboration with Zack Sercel and Alex Cusumano synthesizing organic structure directing agents (OSDAs) for a collaboration with Youngkyu Park and Professor Mark Davis, as well as Stacy Zones from Chevron. Zack and Alex also joined me studying the chemistry of abromocaranones, an experience that was incredibly rewarding. vi I am thankful to have had the opportunity to mentor Kasam Poonswat on the cyclopentene annulation method. Kasam was a visiting student from the Chulabhorn Graduate Institute (CGI) in Thailand, and the months he spent at Caltech were incredibly rewarding. I enjoyed learning about his past and have found him to be one of the kindest people I have ever met. I was also fortunate to join Farbod Moghadam, Chloe Cerione, Igor Beckers, and Hanh Nguyen on various other projects. Each of them has contributed to my learning and has made my time at Caltech that much more enjoyable. I was lucky to be in a cohort of seven other talented students: Jay Barbor, Kali Flesch, Kevin Gonzalez, Elliot Hicks, Farbod Moghadam, and Samir Rezgui. I have had fond interactions with each of them, and I particularly want to point out the help that Kevin has given me, at essentially every turn through graduate school. He has been my bay mate since early on, and every idea, reaction, and document that I have worked on has been touched by him in some way. The friendship I have formed with Kevin is very important to me, and I wish him nothing but the best in his future endeavors. Similarly, I would like to thank Farbod and Samir, whose friendship has been a comfort during stressful days and whose presence never failed to leave me with a smile. The following class consisted of another large group of talented chemists: Ruby Chen, Ben Gross, Kimberly Sharp, Christian Strong, Camila Suarez, Marva Tariq, and Hao Yu. Christian’s hood was geographically proximal to me, and I have many fond memories of the discussions we have had (chemistry and otherwise). I am often humbled by Christian’s selfless attitude, and he has on more than one occasion offered a compelling perspective that reshaped my stance on a topic. We were then joined by Adrian de Almenara, Chloe Cerione, and Jonathan vii Farhi, followed by Bryce Gaskins, Sara Siddiqui, and Elijah Gonzalez the following year. Both Chloe and “student” Adrian have been delightful bay mates. I have had countless conversations with both of them, and they were a big contributor in making going into lab each day a truly fun experience. Jonathan and I grew very close, almost without my realizing it. We see eye to eye on most topics, and there was always something interesting or insightful to discuss when we were together. Over time, I came to really value his presence and developed a deep trust in him. I will miss our regular walks and dinners, but I’m confident we’ll continue to catch up regularly in the future. I would also like to thank the classes above me consisting of Tyler Fulton, Nick Hafeman, Alexia Kim, Tyler Casselman, Zack Sercel, Alex Cusumano, Melinda Chan, and Ally Stanko. Both Tyler and Nick offered tons of advice early in my Ph.D., and Ally was a phenomenal bay mate, always ready to cheer me up when I was stressed. Zack was actually one of the first people I met at Caltech, and the advice and experience he offered me was always appreciated. I want to point out the contributions of Alex “Cus” in particular. Everything I know about DFT and in silico modeling was taught to me by Cus. From the beginning, Cus has treated me with utmost respect and kindness, and he has never hesitated to take time from his busy schedule to offer me advice. I anticipate the soon-to-be Professor Cusumano will make quite a splash in the scientific community. Looking back, I have had many excellent mentors at multiple institutions that have shaped the chemist I am today. I want to start by thanking Sarah Kuroic and Daniel, with whom I worked under Dr. Marc Baum with at the Oakcrest Institute of Science. Here I learned NMR, the basics of research and I’m really very fortunate to have had such an opportunity during high school. I am very thankful to my mentor Dr. Gavin Kiel, whom I viii worked with at UC Berkeley under Professor Tilley and who taught me the importance of rigor and care in all aspects of research, from setting up reactions, to taking notes, to analyzing data. In additional Gavin was, and still is, a good friend and someone whose conversations with I always look forward to. Finally, I want to thank Dr. Yan Xu, who I worked with whilst in the Grubbs Group at Caltech. Yan gave me a very different perspective in organic chemistry, heavily emphasizing efficiency and strategic project planning to maximize the chance of success. I also want to thank Dr. Marc Baum, who saw my passion for chemistry as a high school student and gave me the opportunity to explore the field much, much earlier than would be possible in most cases. Additionally, I would like to thank Professor Don Tilley who gave me the opportunity to work in his lab very early during my undergraduate studies. In my interactions with him, he treated me with only respect and kindness, and at times I felt more like his research colleague than his student. Finally, I would like to acknowledge Professor Grubbs. Bob took me in as a visiting student following my undergraduate studies and gave me incredible support during the year I worked with him. In addition to strongly advocating for Caltech to provide me with a stipend, he was instrumental in guiding both Hanh and I through our graduate school decisions and played a key role in rekindling my trust and love for academic research. I see many similar qualities in Brian and Bob— putting their student needs above their own is a defining trait. Outside of the academic setting, many people have helped me get to this point. I would like to start by acknowledging my parents, Emik and Mario Samkian, who have supported my love for chemistry since a young age. They have never questioned, stopped, or tried to dissuade me from doing what I love, something I didn’t appreciate until later in ix my studies. Similarly, I would like to thank my brother for his unconditional love for me. I have fond memories of our times cooking together and foresee many more such occurrences. I would like to thank Chris Olmassakian, a close friend I’ve had since early high school, for his continued support and encouragement. Talking weekly during my Ph.D. has been a significant stress release and was something to look forward to at the end of each week. In addition, his help in the founding and running of Silver Point Labs LLC was instrumental. I look forward to our continued conversations in the future. I would like to end the acknowledgments by thanking Hanh T. Nguyen, my collaborator, partner, mentor, mentee, roommate, and fiancé. I met Hanh during my undergraduate studies at UC Berkley and we have been inseparable since. Traversing graduate school together, especially during the lonely COVID days, made day to day life much less stressful. Having someone to discuss chemistry with has been an irreplaceable resource, and the trust and support Hanh provided me with was without a doubt crucial in making graduate school the fantastic experience it was. I very much look forward to our life and future together. x ABSTRACT Research in the Stoltz group is primarily focused on the total synthesis of complex, bioactive natural products and on the development of reaction methodologies to enable these synthetic endeavors. This thesis focuses on the homoadamantane polycyclic polyprenylated acylphloroglucinol (PPAP) class of natural products, our efforts toward their synthesis, and discoveries made along the way. Chapter 1 describes the completed synthesis of hypersampsone M, while Chapter 2 describes ongoing efforts toward wilsonglucinol G and hypersampsone A. Appendix 5 presents the culmination of optimization studies and unsuccessful routes toward these natural products. Chapter 3 describes selective fragmentations of a-bromocaranones, reactions that were tailored to the synthesis of PPAPs. Chapter 4 discloses the synthesis and characterization of an unexpected, caged side product isolated during an unsuccessful route to the homoadamantane PPAPs. Chapter 5 discusses the development and scope of the key cyclopentene annulation methodology that enabled the installation of the challenging, hindered 5-membered ring on the homoadamantane PPAPs. xi PUBLISHED CONTENT AND CONTRIBUTIONS 1. Samkian, A. E.; Sercel, Z. P.; Virgil, S. C.; Stoltz, B. M. Some unusual transformation of a highly reactive a-bromocaranone. Tetrahedron. Lett. 2022, 89, 153496. DOI: 10.1016/j.tetlet.2021.153496 A. E. S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 2. Samkian, A. E.; Virgil, S. C.; Stoltz, B. M. Total Synthesis of Hypersampsone M. J. Am. Chem. Soc. 2024, 146, 18886–18891. DOI: 10.1021/jacs.4c07007 A. E. S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 3. Samkian, A. E.; Nguyen, H. T.; Vanderwal, C. D.; Stoltz, B. M. On the unexpected formation of [2.2.1]- and [2.1.1]homotriblattanes. Tetrahedron. Lett. 2025, 164, 155591. DOI: 10.1016/j.tetlet.2025.155591 A. E. S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. 4. Samkian, A. E.; Poonswat, K.; Virgil, S. C.; Stoltz, B. M. A Modular Cyclopentene Annulation. Org. Lett. 2025, 27, 5876–5879. DOI: 10.1021/acs.orglett.5c01750 A. E. S. participated in project design, experimental work, data acquisition and analysis, and manuscript preparation. xii TABLE OF CONTENTS Dedication ................................................................................................................................iii Acknowledgements ................................................................................................................... iv Abstract...................................................................................................................................... x Published Content and Contributions ........................................................................................ xi Table of Contents ..................................................................................................................... xii List of Figures .......................................................................................................................... xvi List of Schemes ...................................................................................................................... xxv List of Tables ....................................................................................................................... xxviii List of Abbreviations............................................................................................................... xxx CHAPTER 1 ........................................................................................................... 1 Total Synthesis of Hypersampsone M 1.1 Introduction .....................................................................................................1 1.2 Retrosynthetic Analysis ....................................................................................2 1.3 Unsuccessful Chiral Pool Route .......................................................................3 1.4 Total Synthesis of Hypersampsone M ...............................................................4 1.5 Conclusion .....................................................................................................10 1.6 Experimental Section ......................................................................................10 1.7 1.6.1 Materials and Methods ................................................................................10 1.6.2 Experimental Procedures .............................................................................12 References and Notes .....................................................................................37 APPENDIX 1 ........................................................................................................ 48 Synthetic Summary for Chapter 1 APPENDIX 2 ........................................................................................................ 50 Spectra Relevant to Chapter 1 CHAPTER 2 ......................................................................................................... 89 Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 2.1 Introduction ...................................................................................................89 2.2 Retrosynthetic Analysis ..................................................................................91 2.3 Development of a 3-component Cyclopentene Annulation ............................92 xiii 2.4 Current Progress Toward Wilsonglucinol G ....................................................94 2.5 Conclusion .....................................................................................................98 2.6 Experimental Section ......................................................................................98 2.6.1 Materials and Methods ................................................................................98 2.6.2 Experimental Procedures ...........................................................................100 2.7 References and Notes ...................................................................................122 APPENDIX 3 ...................................................................................................... 126 Synthetic Summary for Chapter 2 APPENDIX 4 ...................................................................................................... 128 Spectra Relevant to Chapter 2 APPENDIX 5 ...................................................................................................... 164 Early Strategies Toward the Synthesis of Homoadamantane PPAPs A5.1 Introduction .................................................................................................164 A5.2 Chiral Pool Efforts Starting from Limonene ...................................................164 A5.3 Chiral Pool Efforts Starting from (+)-Carene ..................................................168 A5.4 Eastern Ring-First Strategy ............................................................................173 A5.5 Cyclohexenone Strategy: Hydroindene Formation ........................................176 A5.6 Cyclohexenone Strategy: Hydroindene Ring Expansion ................................179 A5.7 Cyclohexenone Strategy: Forming the C5–C9 Bond......................................183 A5.8 Cyclohexenone Strategy: Opening the Caged Lactone..................................186 A5.9 Experimental Section ....................................................................................192 A5.9.1 Materials and Methods ..............................................................................192 A5.9.2 Experimental Procedures ...........................................................................193 A5.10 References and Notes ...............................................................................233 CHAPTER 3 ....................................................................................................... 238 Some Unusual Transformations of a Highly Reactive a-Bromocaranone 3.1 Introduction .................................................................................................238 3.2 Cationic Fragmentations of the Bromocaranone ...........................................240 3.3 Radical Fragmentations of the Bromocaranone.............................................241 3.4 Conclusion ...................................................................................................244 3.5 Experimental Section ....................................................................................244 3.5.1 Materials and Methods ..............................................................................244 xiv 3.5.2 Experimental Procedures ...........................................................................246 3.5.3 Computational Details ..............................................................................258 3.6 References and Notes ...................................................................................260 APPENDIX 6 ...................................................................................................... 264 Spectra Relevant to Chapter 3 CHAPTER 4 ....................................................................................................... 288 On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 4.1 Introduction .................................................................................................288 4.2 Synthesis of the Homotriblattanes ................................................................289 4.3 Conclusion ...................................................................................................293 4.4 Experimental Section ....................................................................................293 4.5 4.4.1 Materials and Methods ..............................................................................293 4.4.2 Experimental Procedures ...........................................................................295 4.4.3 Computational Details ..............................................................................307 References and Notes ...................................................................................308 APPENDIX 7 ...................................................................................................... 312 Spectra Relevant to Chapter 4 APPENDIX 8 ...................................................................................................... 349 X-Ray Crystallography Reports Relevant to Chapter 4 A8.1 General Experimental Information ................................................................350 A8.2 X-Ray Structure Analysis of 236 ...................................................................351 A8.3 X-Ray Structure Analysis of 255 ...................................................................365 A8.4 References and Notes ...................................................................................375 CHAPTER 5 ....................................................................................................... 376 A Modular Cyclopentene Annulation 5.1 Introduction .................................................................................................377 5.2 Reaction Optimization .................................................................................378 5.3 Scope and Limitations ..................................................................................379 5.4 Product Derivatization .................................................................................382 5.5 Conclusion ...................................................................................................383 5.6 Experimental Section ....................................................................................384 xv 5.7 5.6.1 Materials and Methods ..............................................................................384 5.6.2 Experimental Procedures ...........................................................................386 References and Notes ...................................................................................410 APPENDIX 9 ...................................................................................................... 413 Spectra Relevant to Chapter 5 APPENDIX 10 .................................................................................................... 474 Notebook Cross-Reference for New Compounds About the Author .............................................................................................480 xvi LIST OF FIGURES CHAPTER 1 Total Synthesis of Hypersampsone M Figure 1.1.1. Hypersampsone M and representative PPAP classes. .............................................. 2 Figure 1.6.3.1. Synthetic and natural 1H NMR of Hypersampsone M (1), CDCl3........................... 35 Figure 1.6.3.2. Synthetic and natural 13C NMR of Hypersampsone M (1), CDCl3 .......................... 35 APPENDIX 2 Spectra Relevant to Chapter 1 Figure A2.1. 1 Figure A2.2. Infrared spectrum (Thin Film, NaCl) of compound 26 ........................................... 52 Figure A2.3. 13 Figure A2.4. 1 Figure A2.5. 1 Figure A2.6. Infrared spectrum (Thin Film, NaCl) of compound 10 ........................................... 55 Figure A2.7. 13 Figure A2.8. COSY NMR (400 MHz, C6D6) of compound 10 .................................................... 56 Figure A2.9. HSQC NMR (400 MHz, C6D6) of compound 10 ................................................... 57 Figure A2.10. NOESY NMR (400 MHz, C6D6) of compound 10 .................................................. 58 Figure A2.11. 1 Figure A2.12. Infrared spectrum (Thin Film, NaCl) of compound 12 ........................................... 60 Figure A2.13. 13 Figure A2.14. 1 Figure A2.15. Infrared spectrum (Thin Film, NaCl) of compound 28 ........................................... 62 Figure A2.16. 13 Figure A2.17. 1 Figure A2.18. 1 Figure A2.19. Infrared spectrum (Thin Film, NaCl) of compound 14 ........................................... 65 Figure A2.20. 13 Figure A2.21. 1 Figure A2.22. Infrared spectrum (Thin Film, NaCl) of compound 29 ........................................... 67 Figure A2.23. 13 H NMR (400 MHz, C6D6) of compound 26 ......................................................... 51 C NMR (100 MHz, C6D6) of compound 26......................................................... 52 H NMR (500 MHz, CDCl3) of compound 7 ......................................................... 53 H NMR (400 MHz, C6D6) of compound 10 ......................................................... 54 C NMR (100 MHz, C6D6) of compound 10......................................................... 55 H NMR (400 MHz, C6D6) of compound 12 ......................................................... 59 C NMR (100 MHz, C6D6) of compound 12......................................................... 60 H NMR (400 MHz, CDCl3) of compound 28 ....................................................... 61 C NMR (100 MHz, CDCl3) of compound 28 ...................................................... 62 H NMR (400 MHz, CDCl3) of compound 13 ....................................................... 63 H NMR (400 MHz, CDCl3) of compound 14 ....................................................... 64 C NMR (100 MHz, CDCl3) of compound 14 ...................................................... 65 H NMR (400 MHz, C6D6) of compound 29 ......................................................... 66 C NMR (100 MHz, C6D6) of compound 29......................................................... 67 xvii Figure A2.24. 1 Figure A2.25. Infrared spectrum (Thin Film, NaCl) of compound 16 ........................................... 69 Figure A2.26. 13 Figure A2.27. 1 Figure A2.28. 1 Figure A2.29. Infrared spectrum (Thin Film, NaCl) of compound 18 ........................................... 72 Figure A2.30. 13 Figure A2.31. 1 Figure A2.32. Infrared spectrum (Thin Film, NaCl) of compound 30 ........................................... 74 Figure A2.33. 13 Figure A2.34. 1 Figure A2.35. Infrared spectrum (Thin Film, NaCl) of compound 19 ........................................... 76 Figure A2.36. 13 Figure A2.37. 1 Figure A2.38. Infrared spectrum (Thin Film, NaCl) of compound 21 ........................................... 78 Figure A2.39. 13 Figure A2.40. 1 Figure A2.41. Infrared spectrum (Thin Film, NaCl) of compound 25 ........................................... 80 Figure A2.42. 13 Figure A2.43. 1 Figure A2.44. Infrared spectrum (Thin Film, NaCl) of compound 31 ........................................... 82 Figure A2.45. 13 Figure A2.46. 1 Figure A2.47. Infrared spectrum (Thin Film, NaCl) of compound 22 ........................................... 84 Figure A2.48. 13 Figure A2.49. 1 Figure A2.50. Infrared spectrum (Thin Film, NaCl) of compound 2 ............................................. 86 Figure A2.51. 13 Figure A2.52. 1 Figure A2.53. Infrared spectrum (Thin Film, NaCl) of compound 1 ............................................. 88 Figure A2.54. 13 H NMR (400 MHz, C6D6) of compound 16 ......................................................... 68 C NMR (100 MHz, C6D6) of compound 16......................................................... 69 H NMR (400 MHz, C6D6) of compound 17 ......................................................... 70 H NMR (400 MHz, C6D6) of compound 18 ......................................................... 71 C NMR (100 MHz, C6D6) of compound 18......................................................... 72 H NMR (400 MHz, C6D6) of compound 30 ......................................................... 73 C NMR (100 MHz, C6D6) of compound 30......................................................... 74 H NMR (400 MHz, C6D6) of compound 19 ......................................................... 75 C NMR (100 MHz, C6D6) of compound 19......................................................... 76 H NMR (400 MHz, C6D6) of compound 21 ......................................................... 77 C NMR (100 MHz, C6D6) of compound 21......................................................... 78 H NMR (400 MHz, C6D6) of compound 25 ......................................................... 79 C NMR (100 MHz, C6D6) of compound 25......................................................... 80 H NMR (400 MHz, C6D6) of compound 31 ......................................................... 81 C NMR (100 MHz, C6D6) of compound 31......................................................... 82 H NMR (400 MHz, C6D6) of compound 22 ......................................................... 83 C NMR (100 MHz, C6D6) of compound 22......................................................... 84 H NMR (400 MHz, C6D6) of compound 2 ........................................................... 85 C NMR (100 MHz, C6D6) of compound 2 ........................................................... 86 H NMR (400 MHz, CDCl3) of compound 1 ......................................................... 87 C NMR (100 MHz, CDCl3) of compound 1 ........................................................ 88 CHAPTER 2 Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G Figure 2.1.1. Hypersonin A, wilsonglucinol G and representative PPAP classes ........................ 90 xviii APPENDIX 4 Spectra Relevant to Chapter 2 Figure A4.1. 1 Figure A4.2. Infrared spectrum (Thin Film, NaCl) of compound 62 ......................................... 130 Figure A4.3. 13 Figure A4.4. 1 Figure A4.5. Infrared spectrum (Thin Film, NaCl) of compound 64 ......................................... 132 Figure A4.6. 13 Figure A4.7. 1 Figure A4.8. Infrared spectrum (Thin Film, NaCl) of compound 51 ......................................... 134 Figure A4.9. 13 Figure A4.10. 1 Figure A4.11. Infrared spectrum (Thin Film, NaCl) of compound 65 ......................................... 136 Figure A4.12. 13 Figure A4.13. 1 Figure A4.14. Infrared spectrum (Thin Film, NaCl) of compound 66 ......................................... 138 Figure A4.15. 13 Figure A4.16. 1 Figure A4.17. Infrared spectrum (Thin Film, NaCl) of compound 52 ......................................... 140 Figure A4.18. 13 Figure A4.19. 1 Figure A4.20. Infrared spectrum (Thin Film, NaCl) of compound 54 ......................................... 142 Figure A4.21. 13 Figure A4.22. 1 Figure A4.23. Infrared spectrum (Thin Film, NaCl) of compound 56 ......................................... 144 Figure A4.24. 13 Figure A4.25. 1 Figure A4.26. Infrared spectrum (Thin Film, NaCl) of compound 57 ......................................... 146 Figure A4.27. 13 Figure A4.28. 1 Figure A4.29. Infrared spectrum (Thin Film, NaCl) of compound 67 ......................................... 148 Figure A4.30. 13 Figure A4.31. 1 H NMR (600 MHz, CDCl3) of compound 62 ..................................................... 129 C NMR (100 MHz, CDCl3) of compound 62 .................................................... 130 H NMR (400 MHz, C6D6) of compound 64 ....................................................... 131 C NMR (100 MHz, C6D6) of compound 64....................................................... 132 H NMR (400 MHz, C6D6) of compound 51 ....................................................... 133 C NMR (100 MHz, C6D6) of compound 51....................................................... 134 H NMR (400 MHz, C6D6) of compound 65 ....................................................... 135 C NMR (100 MHz, C6D6) of compound 65....................................................... 136 H NMR (400 MHz, C6D6) of compound 66 ....................................................... 137 C NMR (100 MHz, C6D6) of compound 66....................................................... 138 H NMR (400 MHz, C6D6) of compound 52 ....................................................... 139 C NMR (100 MHz, C6D6) of compound 52....................................................... 140 H NMR (400 MHz, C6D6) of compound 54 ....................................................... 141 C NMR (100 MHz, C6D6) of compound 54....................................................... 142 H NMR (400 MHz, C6D6) of compound 56 ....................................................... 143 C NMR (100 MHz, C6D6) of compound 56....................................................... 144 H NMR (400 MHz, C6D6) of compound 57 ....................................................... 145 C NMR (100 MHz, C6D6) of compound 57....................................................... 146 H NMR (400 MHz, C6D6) of compound 67 ....................................................... 147 C NMR (100 MHz, C6D6) of compound 67....................................................... 148 H NMR (400 MHz, C6D6) of compound 58 ....................................................... 149 xix Figure A4.32. Infrared spectrum (Thin Film, NaCl) of compound 58 ......................................... 150 Figure A4.33. 13 Figure A4.34. 1 Figure A4.35. Infrared spectrum (Thin Film, NaCl) of compound 68 ......................................... 152 Figure A4.36. 13 Figure A4.37. 1 Figure A4.38. 1 Figure A4.39. Infrared spectrum (Thin Film, NaCl) of compound 60 ......................................... 155 Figure A4.40. 13 Figure A4.41. 1 Figure A4.42. Infrared spectrum (Thin Film, NaCl) of compound 69 ......................................... 157 Figure A4.43. 13 Figure A4.44. 1 Figure A4.45. Infrared spectrum (Thin Film, NaCl) of compound 61 ......................................... 159 Figure A4.46. 13 Figure A4.47. 1 Figure A4.48. Infrared spectrum (Thin Film, NaCl) of compound 38 ......................................... 161 Figure A4.49. 13 Figure A4.50. 1 Figure A4.51. Infrared spectrum (Thin Film, NaCl) of compound 37 ......................................... 163 Figure A4.52. 13 C NMR (100 MHz, C6D6) of compound 58....................................................... 150 H NMR (400 MHz, C6D6) of compound 68 ....................................................... 151 C NMR (100 MHz, C6D6) of compound 68....................................................... 152 H NMR (400 MHz, C6D6) of compound 59 ....................................................... 153 H NMR (400 MHz, C6D6) of compound 60 ....................................................... 154 C NMR (100 MHz, C6D6) of compound 60....................................................... 155 H NMR (400 MHz, C6D6) of compound 69 ....................................................... 156 C NMR (100 MHz, C6D6) of compound 69....................................................... 157 H NMR (400 MHz, C6D6) of compound 61 ....................................................... 158 C NMR (100 MHz, C6D6) of compound 61....................................................... 159 H NMR (400 MHz, C6D6) of compound 38 ....................................................... 160 C NMR (100 MHz, C6D6) of compound 38....................................................... 161 H NMR (400 MHz, C6D6) of compound 37 ....................................................... 162 C NMR (100 MHz, C6D6) of compound 37....................................................... 163 CHAPTER 3 Some Unusual Transformations of a Highly Reactive a-Bromocaranone Figure 3.5.3.1. Minimum free energy pathway from 226 toward 224 and 235 ........................... 259 APPENDIX 6 Spectra Relevant to Chapter 3 Figure A6.1. 1 Figure A6.2. 1 Figure A6.3. 1 Figure A6.4. Infrared spectrum (Thin Film, NaCl) of compound 207 ....................................... 268 Figure A6.5. 13 Figure A6.6. 1 Figure A6.7. 1 H NMR (400 MHz, CDCl3) of compound 223 ................................................... 265 H NMR (400 MHz, CDCl3) of compound 204 ................................................... 266 H NMR (400 MHz, CDCl3) of compound 207 ................................................... 267 C NMR (100 MHz, CDCl3) of compound 207 .................................................. 268 H NMR (400 MHz, CDCl3) of compound 208 ................................................... 269 H NMR (400 MHz, CDCl3) of compound 210 ................................................... 270 xx Figure A6.8. Infrared spectrum (Thin Film, NaCl) of compound 210 ....................................... 271 Figure A6.9. 13 Figure A6.10. 1 Figure A6.11. Infrared spectrum (Thin Film, NaCl) of compound 205 ....................................... 273 Figure A6.12. 13 Figure A6.13. 1 Figure A6.14. Infrared spectrum (Thin Film, NaCl) of compound 211 ....................................... 275 Figure A6.15. 13 Figure A6.16. 1 Figure A6.17. Infrared spectrum (Thin Film, NaCl) of compound 212 ....................................... 277 Figure A6.18. 13 Figure A6.19. 1 Figure A6.20. Infrared spectrum (Thin Film, NaCl) of compound 213 ....................................... 279 Figure A6.21. 13 Figure A6.22. 1 Figure A6.23. Infrared spectrum (Thin Film, NaCl) of compound 214 ....................................... 281 Figure A6.24. 13 Figure A6.25. 1 Figure A6.26. Infrared spectrum (Thin Film, NaCl) of compound 215 ....................................... 283 Figure A6.27. 13 Figure A6.28. 1 Figure A6.29. Infrared spectrum (Thin Film, NaCl) of compound 220 ....................................... 285 Figure A6.30. 13 Figure A6.31. 1 Figure A6.32. Infrared spectrum (Thin Film, NaCl) of compound 221 ....................................... 287 Figure A6.33. 13 C NMR (100 MHz, CDCl3) of compound 210 .................................................. 271 H NMR (400 MHz, CDCl3) of compound 205 ................................................... 272 C NMR (100 MHz, CDCl3) of compound 205 .................................................. 273 H NMR (400 MHz, CDCl3) of compound 211 ................................................... 274 C NMR (100 MHz, CDCl3) of compound 211 .................................................. 275 H NMR (400 MHz, CDCl3) of compound 212 ................................................... 276 C NMR (100 MHz, CDCl3) of compound 212 .................................................. 277 H NMR (400 MHz, CDCl3) of compound 213 ................................................... 278 C NMR (100 MHz, CDCl3) of compound 213 .................................................. 279 H NMR (400 MHz, CDCl3) of compound 214 ................................................... 280 C NMR (100 MHz, CDCl3) of compound 214 .................................................. 281 H NMR (400 MHz, CDCl3) of compound 215 ................................................... 282 C NMR (100 MHz, CDCl3) of compound 215 .................................................. 283 H NMR (400 MHz, CDCl3) of compound 220 ................................................... 284 C NMR (100 MHz, CDCl3) of compound 220 .................................................. 285 H NMR (400 MHz, CDCl3) of compound 221 ................................................... 286 C NMR (100 MHz, CDCl3) of compound 221 .................................................. 287 APPENDIX 7 Spectra Relevant to Chapter 4 Figure A7.1. 1 Figure A7.2. Infrared spectrum (Thin Film, NaCl) of compound 130 ....................................... 314 Figure A7.3. 13 Figure A7.4. 1 Figure A7.5. COSY NMR (400 MHz, CDCl3) of compound 131.............................................. 316 Figure A7.6. NOESY NMR (400 MHz, CDCl3) of compound 131 ........................................... 317 H NMR (400 MHz, CDCl3) of compound 130 ................................................... 313 C NMR (100 MHz, CDCl3) of compound 130 .................................................. 314 H NMR (400 MHz, CDCl3) of compound 131 ................................................... 315 xxi Figure A7.7. Infrared spectrum (Thin Film, NaCl) of compound 131 ....................................... 318 Figure A7.8. 13 Figure A7.9. 1 Figure A7.10. COSY NMR (400 MHz, CDCl3) of compound 245.............................................. 320 Figure A7.11. HSQC NMR (400 MHz, CDCl3) of compound 245 ............................................. 321 Figure A7.12. Infrared spectrum (Thin Film, NaCl) of compound 245 ....................................... 322 Figure A7.13. 13 Figure A7.14. 1 Figure A7.15. Infrared spectrum (Thin Film, NaCl) of compound 246 ....................................... 324 Figure A7.16. 13 Figure A7.17. 1 Figure A7.18. Infrared spectrum (Thin Film, NaCl) of compound 133 ....................................... 326 Figure A7.19. 13 Figure A7.20. 1 Figure A7.21. Infrared spectrum (Thin Film, NaCl) of compound 236 ....................................... 328 Figure A7.22. 13 Figure A7.23. 1 Figure A7.24. Infrared spectrum (Thin Film, NaCl) of compound 242 ....................................... 330 Figure A7.25. 13 Figure A7.26. 1 Figure A7.27. COSY NMR (400 MHz, CDCl3) of compound 244.............................................. 332 Figure A7.28. HSQC NMR (400 MHz, CDCl3) of compound 244 ............................................. 333 Figure A7.29. NOESY NMR (400 MHz, CDCl3) of compound 244 ........................................... 334 Figure A7.30. Infrared spectrum (Thin Film, NaCl) of compound 244 ....................................... 335 Figure A7.31. 13 Figure A7.32. 1 Figure A7.33. COSY NMR (400 MHz, CDCl3) of compound 255.............................................. 337 Figure A7.34. HSQC NMR (400 MHz, CDCl3) of compound 255 ............................................. 338 Figure A7.35. Infrared spectrum (Thin Film, NaCl) of compound 255 ....................................... 339 Figure A7.36. 13 Figure A7.37. 1 Figure A7.38. Infrared spectrum (Thin Film, NaCl) of compound 256 ....................................... 341 Figure A7.39. 13 Figure A7.40. 1 Figure A7.41. Infrared spectrum (Thin Film, NaCl) of compound 241 ....................................... 343 C NMR (100 MHz, CDCl3) of compound 131 .................................................. 318 H NMR (400 MHz, CDCl3) of compound 245 ................................................... 319 C NMR (100 MHz, CDCl3) of compound 245 .................................................. 322 H NMR (400 MHz, CDCl3) of compound 246 ................................................... 323 C NMR (100 MHz, CDCl3) of compound 246 .................................................. 324 H NMR (400 MHz, CDCl3) of compound 133 ................................................... 325 C NMR (100 MHz, CDCl3) of compound 133 .................................................. 326 H NMR (400 MHz, CDCl3) of compound 236 ................................................... 327 C NMR (100 MHz, CDCl3) of compound 236 .................................................. 328 H NMR (400 MHz, CDCl3) of compound 242 ................................................... 329 C NMR (100 MHz, CDCl3) of compound 242 .................................................. 330 H NMR (400 MHz, CDCl3) of compound 244 ................................................... 331 C NMR (100 MHz, CDCl3) of compound 244 .................................................. 335 H NMR (400 MHz, CDCl3) of compound 255 ................................................... 336 C NMR (100 MHz, CDCl3) of compound 255 .................................................. 339 H NMR (400 MHz, CDCl3) of compound 256 ................................................... 340 C NMR (100 MHz, CDCl3) of compound 256 .................................................. 341 H NMR (400 MHz, CDCl3) of compound 241 ................................................... 342 xxii Figure A7.42. 13 Figure A7.43. 1 Figure A7.44. COSY NMR (400 MHz, CDCl3) of compound 243.............................................. 345 Figure A7.45. HSQC NMR (400 MHz, CDCl3) of compound 243 ............................................. 346 Figure A7.46. NOESY NMR (400 MHz, CDCl3) of compound 243 ........................................... 347 Figure A7.47. Infrared spectrum (Thin Film, NaCl) of compound 243 ....................................... 348 Figure A7.48. 13 C NMR (100 MHz, CDCl3) of compound 241 .................................................. 343 H NMR (400 MHz, CDCl3) of compound 243 ................................................... 344 C NMR (100 MHz, CDCl3) of compound 243 .................................................. 348 APPENDIX 8 X-Ray Crystallography Reports Relevant to Chapter 4 Figure A8.2.1. X-ray crystal structure of 236 ............................................................................... 351 Figure A8.3.1. X-ray crystal structure of 255 ............................................................................... 365 APPENDIX 9 Spectra Relevant to Chapter 5 Figure A9.1. 1 Figure A9.2. HMBC NMR (600 MHz, CDCl3) of compound 269 ........................................... 415 Figure A9.3. Infrared spectrum (Thin Film, NaCl) of compound 269 ..................................... 416 Figure A9.4. 13 Figure A9.5. 1 Figure A9.6. Infrared spectrum (Thin Film, NaCl) of compound 270 ..................................... 418 Figure A9.7. 13 Figure A9.8. 1 Figure A9.9. Infrared spectrum (Thin Film, NaCl) of compound 275 ..................................... 420 Figure A9.10. 13 Figure A9.11. 1 Figure A9.12. Infrared spectrum (Thin Film, NaCl) of compound 276 ..................................... 422 Figure A9.13. 13 Figure A9.14. 1 Figure A9.15. COSY NMR (400 MHz, CDCl3) of compound 89 .............................................. 424 Figure A9.16. NOESY NMR (400 MHz, CDCl3) of compound 89 ............................................ 425 Figure A9.17. Infrared spectrum (Thin Film, NaCl) of compound 89 ....................................... 426 Figure A9.18. 13 Figure A9.19. 1 H NMR (600 MHz, CDCl3) of compound 269 ................................................. 414 C NMR (100 MHz, CDCl3) of compound 269 ................................................. 416 H NMR (500 MHz, CDCl3) of compound 270 ................................................. 417 C NMR (100 MHz, CDCl3) of compound 270 ................................................. 418 H NMR (400 MHz, CDCl3) of compound 275 ................................................. 419 C NMR (100 MHz, CDCl3) of compound 275 ................................................. 420 H NMR (400 MHz, CDCl3) of compound 276 ................................................. 421 C NMR (100 MHz, CDCl3) of compound 276 ................................................. 422 H NMR (400 MHz, CDCl3) of compound 89.................................................... 423 C NMR (100 MHz, CDCl3) of compound 89 ................................................... 426 H NMR (400 MHz, CDCl3) of compound 277 ................................................. 427 xxiii Figure A9.20. Infrared spectrum (Thin Film, NaCl) of compound 277 ..................................... 428 Figure A9.21. 13 Figure A9.22. 1 Figure A9.23. Infrared spectrum (Thin Film, NaCl) of compound 278 ..................................... 430 Figure A9.24. 13 Figure A9.25. 1 Figure A9.26. Infrared spectrum (Thin Film, NaCl) of compound 279 ..................................... 432 Figure A9.27. 13 Figure A9.28. 1 Figure A9.29. Infrared spectrum (Thin Film, NaCl) of compound 280 ..................................... 434 Figure A9.30. 13 Figure A9.31. 1 Figure A9.32. Infrared spectrum (Thin Film, NaCl) of compound 281 ..................................... 436 Figure A9.33. 13 Figure A9.34. 1 Figure A9.35. Infrared spectrum (Thin Film, NaCl) of compound 282 ..................................... 438 Figure A9.36. 13 Figure A9.37. 1 Figure A9.38. Infrared spectrum (Thin Film, NaCl) of compound 283 ..................................... 440 Figure A9.39. 13 Figure A9.40. 1 Figure A9.41. Infrared spectrum (Thin Film, NaCl) of compound 271 ..................................... 442 Figure A9.42. 13 Figure A9.43. 1 Figure A9.44. Infrared spectrum (Thin Film, NaCl) of compound 288 ..................................... 444 Figure A9.45. 13 Figure A9.46. 1 Figure A9.47. Infrared spectrum (Thin Film, NaCl) of compound 289 ..................................... 446 Figure A9.48. 13 Figure A9.49. 1 Figure A9.50. Infrared spectrum (Thin Film, NaCl) of compound 290 ..................................... 448 Figure A9.51. 13 Figure A9.52. 1 Figure A9.53. Infrared spectrum (Thin Film, NaCl) of compound 291 ..................................... 450 Figure A9.54. 13 C NMR (100 MHz, CDCl3) of compound 277 ................................................. 428 H NMR (400 MHz, CDCl3) of compound 278 ................................................. 429 C NMR (100 MHz, CDCl3) of compound 278 ................................................. 430 H NMR (400 MHz, CDCl3) of compound 279 ................................................. 431 C NMR (100 MHz, CDCl3) of compound 279 ................................................. 432 H NMR (400 MHz, CDCl3) of compound 280 ................................................. 433 C NMR (100 MHz, CDCl3) of compound 280 ................................................. 434 H NMR (500 MHz, CDCl3) of compound 281 ................................................. 435 C NMR (100 MHz, CDCl3) of compound 281 ................................................. 436 H NMR (400 MHz, CDCl3) of compound 282 ................................................. 437 C NMR (100 MHz, CDCl3) of compound 282 ................................................. 438 H NMR (400 MHz, CDCl3) of compound 283 ................................................. 439 C NMR (100 MHz, CDCl3) of compound 283 ................................................. 440 H NMR (400 MHz, CDCl3) of compound 271 ................................................. 441 C NMR (100 MHz, CDCl3) of compound 271 ................................................. 442 H NMR (400 MHz, CDCl3) of compound 288 ................................................. 443 C NMR (100 MHz, CDCl3) of compound 288 ................................................. 444 H NMR (400 MHz, CDCl3) of compound 289 ................................................. 445 C NMR (100 MHz, CDCl3) of compound 289 ................................................. 446 H NMR (400 MHz, CDCl3) of compound 290 ................................................. 447 C NMR (100 MHz, CDCl3) of compound 290 ................................................. 448 H NMR (400 MHz, CDCl3) of compound 291 ................................................. 449 C NMR (100 MHz, CDCl3) of compound 291 ................................................. 450 xxiv Figure A9.55. 1 Figure A9.56. Infrared spectrum (Thin Film, NaCl) of compound 292 ..................................... 452 Figure A9.57. 13 Figure A9.58. 1 Figure A9.59. Infrared spectrum (Thin Film, NaCl) of compound 293 ..................................... 454 Figure A9.60. 13 Figure A9.61. 1 Figure A9.62. COSY NMR (400 MHz, CDCl3) of compound 294 ............................................ 456 Figure A9.63. HSQC NMR (400 MHz, CDCl3) of compound 294 ........................................... 457 Figure A9.64. NOESY NMR (400 MHz, CDCl3) of compound 294 .......................................... 458 Figure A9.65. Infrared spectrum (Thin Film, NaCl) of compound 294 ..................................... 459 Figure A9.66. 13 Figure A9.67. 1 Figure A9.68. COSY NMR (400 MHz, CDCl3) of compound 295 ............................................ 461 Figure A9.69. HSQC NMR (400 MHz, CDCl3) of compound 295 ........................................... 462 Figure A9.70. NOESY NMR (400 MHz, CDCl3) of compound 295 .......................................... 463 Figure A9.71. Infrared spectrum (Thin Film, NaCl) of compound 295 ..................................... 464 Figure A9.72. 13 Figure A9.73. 1 Figure A9.74. COSY NMR (400 MHz, CDCl3) of compound 296 ............................................ 466 Figure A9.75. HSQC NMR (400 MHz, CDCl3) of compound 296 ........................................... 467 Figure A9.76. NOESY NMR (400 MHz, CDCl3) of compound 296 .......................................... 468 Figure A9.77. Infrared spectrum (Thin Film, NaCl) of compound 296 ..................................... 469 Figure A9.78. 13 Figure A9.79. 1 Figure A9.80. Infrared spectrum (Thin Film, NaCl) of compound 297 ..................................... 471 Figure A9.81. 13 Figure A9.82. 1 Figure A9.83. Infrared spectrum (Thin Film, NaCl) of compound 298 ..................................... 473 Figure A9.84. 13 H NMR (400 MHz, CDCl3) of compound 292 ................................................. 451 C NMR (100 MHz, CDCl3) of compound 292 ................................................. 452 H NMR (400 MHz, CDCl3) of compound 293 ................................................. 453 C NMR (100 MHz, CDCl3) of compound 293 ................................................. 454 H NMR (400 MHz, CDCl3) of compound 294 ................................................. 455 C NMR (100 MHz, CDCl3) of compound 294 ................................................. 459 H NMR (400 MHz, CDCl3) of compound 295 ................................................. 460 C NMR (100 MHz, CDCl3) of compound 295 ................................................. 464 H NMR (400 MHz, CDCl3) of compound 296 ................................................. 465 C NMR (100 MHz, CDCl3) of compound 296 ................................................. 469 H NMR (400 MHz, CDCl3) of compound 297 ................................................. 470 C NMR (100 MHz, CDCl3) of compound 297 ................................................. 471 H NMR (400 MHz, CDCl3) of compound 298 ................................................. 472 C NMR (100 MHz, CDCl3) of compound 298 ................................................. 473 xxv LIST OF SCHEMES CHAPTER 1 Total Synthesis of Hypersampsone M Scheme 1.2.1. Retrosynthetic strategy toward hypersampsone M .................................................. 3 Scheme 1.3.1. Cyclopentene annulation of enone 7 ...................................................................... 4 Scheme 1.4.1. Cyclopentene annulation of enone 13 .................................................................... 5 Scheme 1.4.2. Synthesis of aldehyde 19 ........................................................................................ 6 Scheme 1.4.3. Cyclization of aldehyde 19 to lactone 21 ............................................................... 7 Scheme 1.4.4. Attempts to functionalize Weinreb amide 25.......................................................... 8 Scheme 1.4.5. Completion of hypersampsone M (1) ...................................................................... 9 APPENDIX 1 Synthetic Summary for Chapter 1 Scheme A1.1. Total synthesis of hypersampsone M .................................................................... 49 CHAPTER 2 Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G Scheme 2.2.1. Retrosynthetic strategy toward wilsonglucinol G .................................................. 91 Scheme 2.3.1. Toward a functionalized cyclopentene annulation ............................................... 92 Scheme 2.4.1. Scalable preparation of ketone 12 ........................................................................ 94 Scheme 2.4.2. Installing the hydroindene core ............................................................................ 95 Scheme 2.4.3. Synthetic sequence advancing ketone 56 to lactone 38........................................ 96 Scheme 2.4.4. Proposed completion of wilsonglucinol G (36) and hypersonin A (32) ................. 97 APPENDIX 3 Synthetic Summary for Chapter 2 Scheme A3.1. Synthesis of intermediate 37 en route to Wilsonglucinol G (36) ......................... 127 APPENDIX 5 Early Strategies Toward the Synthesis of Homoadamantane PPAPs Scheme A5.2.1. Limonene-based approach toward the homoadamantane PPAPs ....................... 164 xxvi Scheme A5.2.2. Synthesis of isopropenyl-flanked cycloheptenone 7 ........................................... 165 Scheme A5.2.3. Unsuccessful cyclopentene annulation of ester 7 ............................................... 166 Scheme A5.2.4. Selective reduction of the enone in hydrazulene 10 ........................................... 168 Scheme A5.3.1. Yang’s anti-addition into ester 75 ....................................................................... 169 Scheme A5.3.2. Cyclopentene annulation and other nucleophilic additions to 75....................... 170 Scheme A5.3.3. Additions involving cycloheptenone 95 and 75 ................................................. 171 Scheme A5.3.4. Danheiser annulation of cycloheptenone 75 ...................................................... 172 Scheme A5.4.1. Eastern ring first approach to the homoadamantane PPAPs ................................ 173 Scheme A5.4.2. Unexpected formation of rearranged allylketone 118 ......................................... 174 Scheme A5.4.3. Attempts to destabilize captodative radical 121.................................................. 175 Scheme A5.4.4. Cyclopentadiene protected enone radical fragmentation .................................... 176 Scheme A5.5.1. Unsuccessful tertiary conjugate additions to 11 .................................................. 177 Scheme A5.5.2. Unsuccessful strategies toward the key hydroindene .......................................... 178 Scheme A5.6.1. Early unsuccessful ring expansion strategies ....................................................... 180 Scheme A5.6.2. Successful diazo-mediated ring expansion of 149 .............................................. 181 Scheme A5.6.3. Diazoacetate-mediated ring expansion of 58...................................................... 182 Scheme A5.7.1. Lactonization of aldehyde 61 ............................................................................. 183 Scheme A5.7.2. Synthesis and deployment of Claisen substrates.................................................. 185 Scheme A5.7.3. Synthesis and deployment of des-prenyl ester 178 ............................................. 186 Scheme A5.8.1. Proposed future steps for lactone 38 ................................................................... 186 Scheme A5.8.2. Weinreb amide opening of lactone 38 ............................................................... 188 Scheme A5.8.3. Studies carried out on model Weinreb amide 186.............................................. 189 CHAPTER 3 Some Unusual Transformations of a Highly Reactive a-Bromocaranone Scheme 3.1.1. Synthesis of an a-bromocaranone (207) from (+)-3-carene (73) .......................... 239 Scheme 3.3.1. Radical mediated cyclopropane fragmentation of 207........................................ 241 Scheme 3.3.2. Proposed mechanism and control study for the formation of 215 ....................... 242 CHAPTER 4 On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes Scheme 4.1.1. Unexpected cyclization of bromide 131 to cage 133 ......................................... 289 Scheme 4.2.1. Synthesis of a-brominated cycloheptanones....................................................... 290 Scheme 4.2.2. Proposed mechanism and minimum free energy pathway to 240 ...................... 291 xxvii Scheme 4.2.3. Synthesis of other homotriblattanes .................................................................... 292 CHAPTER 5 A Modular Cyclopentene Annulation Scheme 5.1.1. Cyclopentane-Containing Natural Products and a Previous Propargyl Zinc Cyclopentene Annulation ................................................................................... 377 Scheme 5.3.1. Enone and Propargyl Bromide Scope.................................................................. 380 Scheme 5.3.2. Electrophile Scope .............................................................................................. 382 Scheme 5.4.1. Product Derivatizations ...................................................................................... 383 xxviii LIST OF TABLES CHAPTER 1 Total Synthesis of Hypersampsone M Table 1.4.1. Attempts to open lactone 21 ................................................................................... 7 Table 1.6.3.1. Comparison of 1H and 13C NMR shifts of Hypersampsone M (1), CDCl3 .............. 36 CHAPTER 2 Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G Table 2.3.1. Optimization of the intercepted cyclopentene annulation .................................... 93 APPENDIX 5 Early Strategies Toward the Synthesis of Homoadamantane PPAPs Table A5.5.1. Attempts to reduce the enone olefin in hydrazulene 10...................................... 167 Table A5.7.1. Unsuccessful aldol reaction of aldehyde 61 ....................................................... 184 Table A5.8.1. Attempts to open lactone 38 to tricycle 180 ....................................................... 187 Table A5.8.2. Other amines used to open the caged lactones 171 and 38 ............................... 191 CHAPTER 3 Some Unusual Transformations of a Highly Reactive a-Bromocaranone Table 3.2.1. AgI-mediated reactions of 207 ............................................................................ 240 APPENDIX 8 X-Ray Crystallography Reports Relevant to Chapter 4 Table A8.2.1. Crystal data and structure refinement for 236 (CCDC# 2430670) ........................... 351 Table A8.2.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 236. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor . 352 Table A8.2.3. Bond lengths [Å] and angles [°] for 236 .................................................................. 353 Table A8.2.4. Anisotropic displacement parameters (Å2x 103) for 236. The anisotropic displacement factor exponent takes the form: -2p2[h2 a*2U11 + ... + 2 h k a* b* U12] .................... 359 Table A8.2.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for 236 ............................................................................................................................... 360 xxix Table A8.2.6. Torsion angles [°] for 236 ....................................................................................... 361 Table A8.2.7. Hydrogen bonds for 236 [Å and °].......................................................................... 364 Table A8.3.1. Crystal data and structure refinement for 255 (CCDC# 2430671) ........................... 365 Table A8.3.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 255. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ............................................................................................................................... 366 Table A8.3.3. Bond lengths [Å] and angles [°] for 255 .................................................................. 367 Table A8.3.4. Anisotropic displacement parameters (Å2x 103) for 255. The anisotropic displacement factor exponent takes the form: -2p2[h2 a*2U11 + ... + 2 h k a* b* U12] .................... 371 Table A8.3.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for 255 ............................................................................................................................... 372 Table A8.3.6. Torsion angles [°] for 255 ....................................................................................... 373 CHAPTER 5 A Modular Cyclopentene Annulation Table 5.2.1. Optimization of Reaction Conditions ................................................................. 379 APPENDIX 10 Notebook Cross-Reference for New Compounds Table A10.1. Notebook cross-reference for Chapter 1 ............................................................. 475 Table A10.2. Notebook cross-reference for Chapter 2 ............................................................. 476 Table A10.3. Notebook cross-reference for Appendix 5 .......................................................... 477 Table A10.4. Notebook cross-reference for Chapter 3 ............................................................. 478 Table A10.5. Notebook cross-reference for Chapter 4 ............................................................. 478 Table A10.6. Notebook cross-reference for Chapter 5 ............................................................. 479 xxx LIST OF ABBREVIATIONS Å Ångstrom λ wavelength µ micro µwave microwave [a]D specific rotation at wavelength of sodium D line [H] reduction [O] oxidation °C degrees Celsius Ac acetyl AcOH acetic acid An para-anisoyl APCI atmospheric pressure chemical ionization aq aqueous Ar aryl atm atmosphere Bn benzyl Boc tert-butyloxycarbonyl bp boiling point br broad Bu butyl Bz benzoyl c calc’d concentration for specific rotation measurements (g/100 mL) calculated xxxi CAN ceric ammonium nitrate cat catalytic cm–1 wavenumber(s) COD 1,5-cyclooctadiene Cp cyclopentadienyl CPME cyclopentyl methyl ether CuTC copper(I) thiophene-2-carboxylate Cy cyclohexyl d doublet D deuterium dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIAD diisopropyl azodicarboxylate DIBAL diisobutylaluminum hydride DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide DPPF 1,1′-bis(diphenylphosphino)ferrocene dr diastereomeric ratio e.g. for example (Latin exempli gratia) ee enantiomeric excess equiv equivalent(s) xxxii ESI electrospray ionization esp α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid Et ethyl EtOAc ethyl acetate FAB fast atom bombardment FD field desorption g gram(s) G4 fourth-generation Buchwald precatalyst GC gas chromatography h hour(s) HFIP 1,1,1,3,3,3-hexafluoropropan-2-ol HMDS 1,1,1,3,3,3-hexamethyldisilazane HMPA hexamethylphosphoramide HPLC high-performance liquid chromatography HRMS high-resolution mass spectroscopy Hz hertz i-Bu isobutyl i.e. that is (Latin id est) IBX 2-iodoxybenzoic acid IPA isopropanol, 2-propanol i-Pr isopropyl IR infrared (spectroscopy) J coupling constant K Kelvin(s) (absolute temperature) kcal kilocalorie L liter; neutral ligand LC–MS liquid chromatography–mass spectrometry xxxiii LDA lithium diisopropylamide m multiplet; milli m meta M metal; molar; molecular ion m/z mass to charge ratio m-CPBA meta-chloroperoxybenzoic acid Me methyl mg milligram(s) MHz megahertz min minute(s) MM mixed method mol mole(s) mp melting point Ms methanesulfonyl (mesyl) MS molecular sieves MTBE methyl tert-butyl ether n nano N normal NBS N-bromosuccinimide n-Bu butyl NCS N-chlorosuccinimide ND not determined NHK Nozaki–Hiyama–Kishi NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance NR no reaction detected Nu– nucleophile xxxiv o ortho p para Pd/C palladium on carbon PEG polyethylene glycol PG protecting group Ph phenyl pH hydrogen ion concentration in aqueous solution PHOX phosphinooxazoline ligand Phth phthaloyl PIFA (bis(trifluoroacetoxy)iodo)benzene Piv pivaloyl pmdba bis(4-methoxybenzylidene)acetone PPA polyphosphoric acid PPAP polycyclic polyprenylated acylphloroglucinol ppm parts per million Pr propyl PTSA para-toluenesulfonic acid Py pyridine q quartet R generic for any atom or functional group Ref. reference s singlet SFC supercritical fluid chromatography t triplet TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBHP tert-butyl hydroperoxide xxxv TBS tert-butyldimethylsilyl t-Bu tert-butyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFE 2,2,2-trifluoroethanol THF tetrahydrofuran TLC thin-layer chromatography TMG 1,1,3,3-tetramethylguanidine TMP 2,2,6,6-tetramethylpiperidine TMS trimethylsilyl TOF time-of-flight TosMIC para-toluenesulfonylmethyl isocyanide tR retention time Ts p-toluenesulfonyl (tosyl) TTMSS tris(trimethylsilyl)silane UV ultraviolet v/v volume to volume w weak w/v weight to volume w/w weight to weight X anionic ligand or electronegative element Chapter 1 – Total Synthesis of Hypersampsone M 1 CHAPTER 1 Total Synthesis of Hypersampsone M † 1.1 INTRODUCTION Since their discovery, the polycyclic polyprenylated acylphloroglucinols (PPAPs) have provided scientists a continuous reservoir of diverse natural products with a broad spectrum of bioactivities and structural architectures.1 A large part of why the PPAP class of compounds has attracted continued interest from synthetic chemists is that a viable structure– activity relationship (SAR) has not yet been established for them, and in many cases, small structural changes lead to unexpected “turn on” or “turn off” effects on biological activity.2 With over 400 isolated compounds as of 2018, it becomes useful to further subdivide the PPAP class of compounds into the bicylic polyprenylated acylphloroglucinols (BPAPs), the caged adamantane and homoadamantane PPAPs, and other spirocyclic or otherwise rearranged PPAPs (Figure 1.1.1).1e This interest has led dozens of researchers to develop synthetic approaches to PPAPs, with many having completed sophisticated total syntheses. The bicyclo[3.3.1]nonane subclass (BPAPs) in particular has enjoyed significant attention in the realm of natural product synthesis, reflecting their overall prevalence within the PPAP family, well-established structural diversity, and medicinal potential.3 Despite these †This research was conducted in collaboration with Dr. Scott Virgil. Portions of this chapter have been reproduced with permission from Samkian, A. E.; Virgil, S. C.; Stoltz, B. M. J. Am. Chem. Soc. 2024, 146, 18886–18891. © 2024 American Chemical Society. Chapter 1 – Total Synthesis of Hypersampsone M 2 extensive efforts, to date there exist only three syntheses of adamantane PPAP natural products.4 Moreover, there are no homoadamantane PPAP syntheses, which is surprising in relation to the subclasses’ substantial scope of at least 70 members.1e,5 Figure 1.1.1. Hypersampsone M and representative PPAP classes. OH R R R O O R O R R O O O O O R R R R R O O O O O R O Ph H BPAPs Adamantane PPAPs >250 compounds >20 syntheses >40 compounds 3 syntheses Homoadamantane PPAPs Hypersampsone M (1) >70 compounds no syntheses –Prototypical homoadamantane PPAP –Fully substituted cyclohexatrione core –No prior syntheses in class We identified hypersampsone M (1), isolated from Hypericum sampsonii in 2014, to be a prototypical representative of this subclass, making it an excellent target for our initial investigations into this family of PPAPs.6 Many homoadamantane PPAPs have been known for decades7 and many more have provided glimpses into the promising bioactivity of this class, with several being implicated to inflammatory/immunosuppressive,5i,8 hepatoprotective,5c and have antitumor,7c antiantiadipogenesis9 properties. Like other homoadamantane PPAPs, the phloroglucinol moiety in hypersampsone M (1) is clearly conserved (Figure 1.1.1, highlighted in blue), yet the unsymmetrical homoadamantane core and fused cyclopentane make it difficult to utilize an alkylative dearomatization strategy such as was cleverly applied to an adamantane PPAP by Porco and co-workers.4b 1.2 RETROSYNTHETIC ANALYSIS We devised a retrosynthetic strategy that centers on the C4-cycloheptanone ring (Scheme 1.2.1, highlighted in blue), electing to employ a late stage Claisen condensation Chapter 1 – Total Synthesis of Hypersampsone M 3 and bridgehead benzoylation on C1 from tricycle 3. Utilizing the C4 ketone as a handle, prenylation and cyclization would allow access to tricycle 3 from simplified hydrazulene 4, which could finally be traced back to cycloheptenone 5 through a key cyclopentene annulation. Scheme 1.2.1. Retrosynthetic strategy toward hypersampsone M. O O O O benzoylation O O2 Ph H O 4 1 Claisen condensation 2 MeO2C H 1 H MeO2C O H cyclopentene annulation O MeO2C R R 5 4 1.3 H 3 2 prenylation/ cyclization O 4 H 1 O UNSUCCESSFUL CHIRAL POOL ROUTE We began by targeting cycloheptenone 7 (Scheme 1.3.1). Acylation of known ketone 610 with NaH and dimethyl carbonate provides access to the required β-ketoester. Cleavage of the acetal, followed by a Knoevenagel condensation, delivers cycloheptenone 7. While several cyclopentene annulation reactions were considered, the demanding gem-dimethyl moiety excluded most obvious options.11 After significant optimization, our observations indicated that 1,1-dimethylpropargylzinc bromide 8 undergoes facile 1,4-addition to enone 7, providing zinc enolate 9 as a single isomer.12 Subsequent heating of zinc enolate 9 following conjugate addition was sufficient to effect cyclization, affording the hydrazulene product (10) in a single step.13 To our surprise,14 NOESY studies indicated that the undesired syn-isomer (i.e., C20 and C7) was Chapter 1 – Total Synthesis of Hypersampsone M 4 exclusively isolated as a 4:1 mixture of diastereomers at C3 (i.e., cis and trans ring junctures). Attempts to control the addition temperature or alter solvents did not invert the stereochemical outcome, and we propose that the bulky nature of the nucleophile was likely responsible for the undesired initial syn conjugate addition stereochemistry, perhaps through torsional steering effects. Further investigation of this reaction and other attempts with chiral starting materials are discussed in Appendix 3. Scheme 1.3.1. Cyclopentene annulation of enone 7. O 1. NaH, O=C(OMe)2 THF, 50 ºC O MeO2C 2. HClO4, THF, 18 ºC 3. piperidine, AcOH PhH, 80 ºC MeO OMe 30% over 3 steps 6 7 [Zn] O 8 BrZn syn O addition MeO DME, –15 ºC O 3 then 80 ºC 31% yield 4:1 dr at C3 9, single isomer 1.4 MeO2C 20 H NOE 7 H 10 TOTAL SYNTHESIS OF HYPERSAMPSONE M We rationalized that a cyclohexenone substrate would provide a more predictable stereochemical outcome in the cyclopentene annulation and a successive ring expansion would intercept the original retrosynthesis at hydrazulene 4. We began by targeting the annulation substrate (13, Scheme 1.4.1). We were able to access ketone 12 from cyclohexenone (11) in a single step using a radical HAT coupling.15 Acylation and selenoxide elimination provided activated enone 13 in 73% yield over 2 steps. Proceeding to the key cyclopentene annulation, we were surprised to still observe the presence of the syn addition product at C7. Fortunately, further lowering the temperature to −40 °C Chapter 1 – Total Synthesis of Hypersampsone M 5 during the propargylzinc (8) addition resulted in the formation of the desired antiisomer 14 (6.3:1) with exclusively cis ring fusion. Scheme 1.4.1. Cyclopentene annulation of enone 13. O O OTBS Fe(acac)3, PhSiH3 1. NaH, O=C(OMe)2 THF, reflux OTBS Ethylene glycol/ DCE, 60 ºC 2. PhSeCl, py then, H2O2 (aq.) CH2Cl2, 0 ºC 48% yield 11 73% over 2 steps 12 O 8 MeO2C OTBS BrZn DME 0 → –40 → 80 ºC 65% yield 6.3:1 d.r. 13 O MeO2C OTBS 7 H 14 Following hydrogenation of the cyclopentene, we shifted our focus to ringexpansion of the hydroindene system to access the required hydrazulene (4). Significant effort was made on this front, and it was found necessary to use a designer diazoacetate (15, Scheme 1.4.2).16 Deprotonation of 15 with LDA enabled nucleophilic addition to the neopentylic ketone furnished alcohol 16.17 Catalytic Rh2(TFA)4 was found to be uniquely effective in initiating the ring-expansion rearrangement, resulting in β-ketoester 17 as a mixture of three inseparable isomers, which were putatively assigned to the enol and two ketone diastereomers. Commercially available ethyl diazoacetate and tert-butyl diazoacetate undergo similar rearrangements but ultimately proved to be synthetic impasses, as selective decarboxylation of the newly installed esters could not be accomplished in the presence of the neighboring, preexistent methyl ester. The trimethylsilylethyl ester thus proved vital, as following prenylation to form bicycle 18, treatment with TBAF resulted in the selective decarboxylation of the trimethylsilylethyl Chapter 1 – Total Synthesis of Hypersampsone M 6 ester. Concomitant TBS cleavage produces the desired primary alcohol as a single diastereomer, which upon DMP oxidation results in aldehyde 19 in excellent yield (79%, 2 steps).17 Scheme 1.4.2. Synthesis of aldehyde 19. O O MeO2C OTBS 1. Pd/C (10 wt %) H2, EtOAc, 18 ºC MeO2C H 15 O 88% over 2 steps single diastereomer 14 MeO2C Rh2(TFA)4 (1 mol %) O N2 SiMe3 HO N2 4 2. LDA, THF, –78 ºC O Me3Si 7 O OTBS H 16 O O SiMe3 NaH, prenyl bromide THF, 0 → 18 ºC pentane/CH2Cl2, 18 ºC OTBS 92% yield mixture of tautomers H 89% yield single diastereomer 17 MeO2C O O 1. TBAF, THF, 18 ºC O SiMe3 79% over 2 steps single diastereomer 18 O 5 2. DMP, CH2Cl2, 18 ºC OTBS H MeO2C O H 19 With a scalable route to aldehyde 19 established, we were optimistic about the aldol reaction proposed to provide tricycle 20 (Scheme 1.4.3). Unfortunately, classic aldol conditions lead to decomposition or, in most cases, return the starting aldehyde without any trace of desired tricycle 20. In fact, TsOH·H2O in CH2Cl2 was the only set of conditions evaluated that resulted in a product of interest, forging caged lactone 21 slowly in moderate yield. We hypothesized that the aldol reaction to form tricycle 20 is likely highly reversible under most conditions, and perhaps even favors aldehyde 19 due to strain induced upon cyclization. Further lactonization of the aldol product (20) provides a Chapter 1 – Total Synthesis of Hypersampsone M 7 powerful thermodynamic driving force for cyclization and highlights the opportune placement of the methyl ester. Scheme 1.4.3. Cyclization of aldehyde 19 to lactone 21. MeO2C O 5 HO MeO2C H TsOH•H2O O O (-MeOH) O H H CH2Cl2, 18 ºC O H 46% yield 30% recovered 19 H H O H 20, not isolated 19 21 Formation of the lactone (21) seemed so favorable that attempts to reopen or saponify it (Table 1.4.1, 21 → 24) with any number of acidic or basic conditions resulted in no reaction or decomposition (entries 1–4). We concluded that the lactone would need to be opened in an irreversible fashion and hypothesized that an amide would be suitably stable. While this approach seemed promising, it introduced the eventual synthetic challenge of needing to activate an extremely hindered amide in order to progress with our plans. Table 1.4.1. Attempts to open lactone 21. O O H R H HO O H H conditions O H O H 21 24 entry conditions R resulta 1 NaOMe/MeOH -OMe decomp. 2 Bu3SnOMe -OMe 0% 3 Al(Oi-Pr)3/MeOH -OMe 0% 4 KOH/H2O -OH decomp. 5 NHMe(OMe)•HCl/AlMe3 -NMe(OMe) 85% 6 NH4Cl/AlMe3 -NH2 73% 7 NHMe2•HCl/AlMe3 -NMe2 0% 8 PhNH2•HCl/AlMe3 -NHPh 84%b aDetermined by 1H NMR analysis. bIsolated yield. Chapter 1 – Total Synthesis of Hypersampsone M 8 For example, opening the lactone with AlMe3/N,O-dimethylhydroxylamine to afford the Weinreb amide proceeded smoothly (entry 5), but following oxidation, we were unable to further transform amide 25 (Scheme 1.4.4) in a useful fashion (25 → 2). Some amides, such as the unsubstituted ammonia-derived amide, were also formed successfully (entry 6), but subsequent oxidation resulted in decomposition. Many disubstituted amides simply failed Scheme 1.4.4. Attempts to functionalize Weinreb amide 25. O O H H O H 1. NHMe(OMe)•HCl AlMe3, PhMe 2. DMP, CH2Cl2, 18 ºC 26% over 2 steps 21 MeO MeN O O O O H X H 25 H O O H 2 to form, as was the case with dimethylamide (entry 7). Fortunately, we were able to install aniline (entry 8) and oxidize the revealed alcohol, providing anilide 22 (Scheme 1.4.5) in good yield (70%, 2 steps). We next aimed to methanolyze the anilide (22) to the methyl ester, targeting homoadamantane 2 via Dieckmann cyclization. The direct installation of a methyl ester with MeOH/H+ was not successful; however, we believed that treatment with Me3OBF4 (methyl-Meerwein’s salt) would form the methyl imidate, which could then be hydrolyzed to the methyl ester.18 Excitingly, we observed direct cyclization to the homoadamantane cage instead, isolating imine 23. Mechanistically, we propose that methyl imidate formation likely occurs first. We then envision that one of two scenarios is likely for bond construction. In one case, enol addition would occur directly to the imidate to form a particularly sterically hindered tetrahedral intermediate. Alternatively, Chapter 1 – Total Synthesis of Hypersampsone M 9 elimination of MeOH or Me2O could form a nitrilium that can cyclize to the observed imine (23). Following optimization, 2,6-di-tert-butylpyridine (DTBP) was added to suppress decomposition of the prenyl group, and an acidic workup was performed to hydrolyze the imine product and provide access to trione 2 in a single step. Scheme 1.4.5. Completion of hypersampsone M (1). O O 1. PhNH2•HCl AlMe3, PhMe 0 → 18 ºC H H 1 PhHN O 2 ≡ H 2. DMP, CH2Cl2 18 ºC O H O O PhHN H 70% over 2 steps 67% yield O O 1 O H H 22 21 Me3OBF4 2,6-di-(t-Bu)py CH2Cl2, 18 ºC 2 2 O Ph N O 1 H then EtOAc/HCl O 23 O O LiTMP, BzCl H (-PhNH2) O THF, –78 → –35 ºC 20% yield 22% recovered 2 H H O O 2 O Ph H 1 To install the final benzoyl group, we attempted variations of the Danishefsky protocol involving an intermediate bridgehead iodide,3b as well as Shair’s direct bridgehead acylation protocol.3p Deuterium incorporation experiments with LiTMP showed that no deprotonation occurs at −78 °C, whereas complete decomposition is observed at 0 °C. A screen of several intermediary temperatures established that 40% deuterium incorporation could be achieved at −35 °C. It has been shown that deprotonation of bridgehead homoadamantane protons is challenging compared to those on bicyclo[3.3.1]nonane systems.19 Interestingly, the challenge associated with bridgehead acylations in the sister BPAP systems seems to stem from lack of anion reactivity, rather than generation of the stabilized anion itself.3h This was found to be in stark contrast with homoadamantane 2, as despite the difficulty in generating the required anion, treatment Chapter 1 – Total Synthesis of Hypersampsone M 10 with BzCl directly affords hypersampsone M (1) in moderate yield with an equivalent amount of isolated starting trione (2). 1.5 CONCLUSION To conclude, we have completed the synthesis of hypersampsone M (1) in 15 steps starting from cyclohexenone, thus achieving the first total synthesis of a homoadamantane PPAP natural product. Additionally, the enabling cyclopentene annulation provides an orthogonal method for installing highly substituted five-membered rings using simple reagents and techniques. This strategy is likely of sufficient generality to allow access to other homoadamantane PPAPs. Biological studies and further development of this route to synthesize additional PPAPs are in progress. 1.6 EXPERIMENTAL SECTION 1.6.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.20 Cyclohexenone was distilled prior to use. Pyridine and 2,2,6,6-Tetramethylpiperidine were distilled from CaH2 prior to use. Freshly purchased TsOH•H2O was stored in a desiccator and dried under high vacuum for several hours prior to use. Activated zinc dust was prepared according to a previously reported procedure.21 All other reagents were purchased from commercial sources and used as received unless otherwise stated. Reaction progress was monitored by thin-layer chromatography (TLC), or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, CAM stain, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel Chapter 1 – Total Synthesis of Hypersampsone M 11 (particle size 40–63 µm) was used for flash chromatography. Teledyne ISCO CombiFlashRf+, Teledyne ISCO CombiFlashRf+ LumenTM, or Teledyne ISCO CombiFlashRf NEXTGEN+ systems were used for automated flash chromatography using Luknova SuperSepTM silica columns or RediSepRf GOLD C18 columns. Agilent 1100 or 1200 preparatory HPLC systems were used for high-performance reverse phase separations. 1H NMR spectra were recorded on Varian Inova 500 MHz and Bruker 400 MHz spectrometers and are reported relative to residual non-deuterated solvent CHCl3 (δ 7.26 ppm) or C6H6 (δ 7.16 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometers (100 MHz) and are reported relative to residual non-deuterated solvent CHCl3 (δ 77.16 ppm) or C6H6 (δ 128.06). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Diastereomeric ratios were calculated based on ratios of integrals from crude 1H NMR spectra. Some spectra contain minor solvent impurities of water, ethyl acetate, dichloromethane, diethyl ether, acetone, grease, and/or silicone grease, which do not impact product assignments. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell. High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-T2000GC AccuTOFTM GC-Alpha High Resolution Chapter 1 – Total Synthesis of Hypersampsone M 12 Mass Spectrometer in field ionization (FI+) or field desorption (FD+) mode, or an Agilent 6230 Series TOF with and Agilent Jet Stream ion source in electrospray ionization (ESI+). 1.6.2 EXPERIMENTAL PROCEDURES O O NaH, O=C(OMe)2 MeO THF, 50 ºC O MeO MeO OMe OMe 6 26 methyl (R)-6-(2,2-dimethoxyethyl)-7-methyl-3-oxooct-7-enoate 26. A 100 mL flask with reflux condenser under Ar was charged with NaH (1.4 g, 58.3 mmol, 2.5 equiv), THF (25 mL), (OMe)2CO (5.25 g, 58.3 mmol, 2.5 equiv) and a drop of MeOH. The reaction was heated to 50 °C and ketone 6 (prepared according to a previously reported procedure10)(5 g, 23.3 mmol, 1.0 equiv) was added dropwise, neat, over 1 min and the reaction was allowed to stir at this temperature for 1 h. The apparatus was allowed to cool slightly, and the entire contents of the flask were poured into a cold saturated aqueous NH4Cl solution with stirring. The mixture was extracted 3x with ether, and the combined organics were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified via flash column chromatography (20% acetone/hexanes) to afford 26 (4.64 g, 74% yield) as a colorless oil. Note: 26 was isolated as a 6.7:1 mixture of keto/enol tautomers. Keto tautomer: 1H NMR (400 MHz, C6D6) δ = 4.75 – 4.73 (m, 1H), 4.73 – 4.72 (m, 1H), 4.40 – 4.34 (m, 1H), 3.28 (s, 3H), 3.17 (s, 3H), 3.13 (s, 3H), 2.95 (s, 2H), 2.25 – 2.17 (m, 1H), 2.09 – 2.01 (m, 2H), 1.69 – 1.56 (m, 3H), 1.51 – 1.44 (m, 1H), 1.44 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 201.31, 167.44, 146.74, 112.84, 103.08, 52.58, 52.08, 51.63, 48.97, 42.86, 40.66, 36.62, 26.86, 17.87. Enol tautomer: 1H NMR (400 MHz, C6D6) δ = 12.72 (s, 1H), 5.02 (s, 1H), 4.80 – 4.76 (m, 1H), Chapter 1 – Total Synthesis of Hypersampsone M 13 4.76 – 4.74 (m, 1H), 4.40 – 4.34 (m, 1H), 3.34 (s, 3H), 3.15 (s, 3H), 3.12 (s, 3H), 2.29 – 2.18 (m, 1H), 2.13 – 1.98 (m, 2H), 1.70 – 1.55 (m, 3H), 1.52 – 1.45 (m, 1H), 1.44 – 1.43 (m, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 179.57, 146.36, 113.67, 113.08, 89.12, 52.57, 52.03, 50.79, 43.05, 36.81, 36.58, 33.18, 29.90; IR (Neat Film, NaCl) 2951, 1747, 1716, 1438, 1126, 1062, 894 cm–1; HRMS (ESI+): m/z calc’d for C14H24O5Na [M+Na]+: 295.1516, found 295.1520; [α]D 23.20 13.44 (c 1.0, CHCl3). O O O HClO4 MeO MeO THF, 18 ºC O MeO O OMe 26 27 methyl (R)-7-methyl-3-oxo-6-(2-oxoethyl)oct-7-enoate 27. A solution of acetal 26 (3 g, 11 mmol, 1.0 equiv) in THF (30 mL) was added to HClO4 (3% aq., 30 mL) at 0 °C under air. The solution was stirred vigorously and allowed to warm to 18 °C, after which it was further stirred for 2 h. The solution was then poured into brine (10 mL) and extracted 2x with ether. The combined organics were washed with brine, dried over Na2SO4, and concentrated gently under reduced pressure, leaving 20 mL of solvent remaining. Note: This material was directly carried forward to the next step as a solution in THF/Et2O. 27 degrades rapidly upon concentration or on silica/alumina and cannot be easily purified. Chapter 1 – Total Synthesis of Hypersampsone M O 14 O O piperidine, AcOH MeO O MeO2C PhH, 80 ºC 27 7 methyl (R)-7-oxo-4-(prop-1-en-2-yl)cyclohept-1-ene-1-carboxylate 7. A 500 mL flask equipped with a Dean-Stark apparatus was charged with PhH (210 mL) and the solution of aldehyde (27, theoretical: 11 mmol in 20 mL THF/Et2O). A solution of piperidine (375 mg, 4.4 mmol, 0.4 equiv) and AcOH (1.59 g, 26.4 mmol, 2.4 equiv) in PhH (20 mL) was added rapidly and the flask was heated to reflux for 30 min and then cooled to 18 °C. The solution was concentrated under reduced pressure, saturated aqueous NaHCO3 was added, and the mixture then extracted 3x with ether. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography (5→10% acetone/hexanes) to furnish 7 as a yellow oil (730 mg, 40% yield, two steps). Note: This material was directly carried forward to the next step. Additionally, 7 is not stable for extended periods of time, even when stored at –15 °C. 1H NMR spectral data and HRMS data is provided as a courtesy. HRMS (ESI+): m/z calc’d for C12H16O3Na [M+Na]+; 231.0992, found 231.0998. Chapter 1 – Total Synthesis of Hypersampsone M 15 O BrZn MeO2C DME, –15 ºC then 80 ºC 7 methyl MeO2C O H 10 H (3aS,7R,8aS)-1,1-dimethyl-4-oxo-7-(prop-1-en-2-yl)-4,5,6,7,8,8a- hexahydroazulene-3a(1H)-carboxylate 10. To a dry 2 dram vial under N2 was added activated Zn dust (94 mg, 1.44 mmol, 2.5 equiv) and DME (1.2 mL). The mixture was cooled to 0 °C and 3-bromo-3-methylbut-1-yne (prepared according to a previously reported procedure22)(212 mg, 1.44 mmol, 2.5 equiv) was added in one portion. After 1 h most of the Zn has dissolved and the mixture was cooled to –15 °C at which point enone 7 (120 mg, 0.58 mmol, 1.0 equiv) in DME (1.2 mL) was added dropwise over 10 min. The cloudy solution was then stirred at –15 °C for 12 h. The reaction was then allowed to warm to 18 °C and filtered into a fresh flask via a Teflon syringe filter to yield a perfectly homogeneous, yellow solution. The solution was heated to 80 °C for 4 h without stirring and then cooled to 0 °C and quenched with saturated, aqueous NH4Cl. The mixture was extracted with EtOAc, and the combined organic extracts were washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 10 (50 mg, 31% yield) as a 4:1 mixture of diastereomers. Characterization data for the major diastereomer is given. 1H NMR (400 MHz, C6D6) δ = 5.83 (d, J = 5.7 Hz, 1H), 5.51 (d, J = 5.6 Hz, 1H), 4.70 – 4.68 (m, 1H), 4.66 (p, J = 1.5 Hz, 1H), 3.24 (s, 3H), 3.14 (dd, J = 13.2, 3.5 Hz, 1H), 2.47 – 2.33 (m, 2H), 2.33 – 2.27 (m, 1H), 1.78 (dt, J = 14.5, 3.0 Hz, 1H), 1.71 – 1.62 (m, 1H), 1.53 (d, J = 1.9 Hz, 3H), 1.51 – 1.39 (m, 1H), 1.38 – 1.25 (m, 1H), 1.06 (s, 3H), 0.80 (s, 3H); 13C{1H} Chapter 1 – Total Synthesis of Hypersampsone M 16 NMR (101 MHz, C6D6) δ = 205.53, 172.92, 150.40, 145.03, 126.20, 109.39, 77.77, 52.32, 50.51, 49.20, 45.85, 40.18, 33.72, 30.68, 29.93, 24.53, 20.69; IR (Neat Film, NaCl) 2953, 1743, 1711, 1445, 1247, 1213, 1018, 886, 799 cm–1; HRMS (ESI+): m/z calc’d for C17H25O3 [M+H]+: 277.1798, found 277.1787; [α]D 23.23 66.63 (c 0.4, CHCl3). O O OTBS Fe(acac)3, PhSiH3 OTBS Ethylene glycol/ DCE, 60 ºC 12 3-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)cyclohexan-1-one 12. A procedure from the literature23 was modified as follows: a flask with stir bar under N2 was charged with Fe(acac)3 (7.3 g, 20.8 mmol, 1.0 equiv), DCE (58 mL) and ethylene glycol (11 mL). Cyclohexenone (2.0 g, 20.8 mmol, 1.0 equiv) and tert-butyldimethyl((3methylbut-3-en-1-yl)oxy)silane24 (7.5 g, 37.5 mmol, 1.8 equiv) were added sequentially, followed by PhSiH3 (4.0 g, 37.5 mmol, 1.8 equiv). The solution was stirred at 60 °C for 20 h, cooled to 18 °C, and additional Fe(acac)3 (3.1 g, 8.8 mmol, 0.4 equiv) was added. The mixture was then heated to 60 °C for 20 h and the DCE was removed under reduced pressure. Water (100 mL) was added to the red residue, and this mixture was extracted with hexanes (5 x 50 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 12 (2.9 g, 48% yield) as a colorless oil. A small sample was further purified via silica gel chromatography to obtain an analytical sample. 1H NMR (400 MHz, C6D6) δ = 3.56 (t, J = 7.2 Hz, 2H), 2.39 – 2.31 (m, 1H), 2.21 (ddq, J = 13.9, 4.1, 2.1 Hz, 1H), 1.76 (tdd, J = 13.9, Chapter 1 – Total Synthesis of Hypersampsone M 17 6.4, 1.0 Hz, 1H), 1.67 (td, J = 13.4, 1.0 Hz, 1H), 1.57 (dddd, J = 13.1, 6.1, 3.3, 2.4 Hz, 1H), 1.54 – 1.46 (m, 1H), 1.39 (td, J = 7.0, 3.4 Hz, 2H), 1.28 (ddt, J = 13.3, 11.9, 3.3 Hz, 1H), 1.22 – 1.08 (m, 1H), 0.98 (s, 9H), 0.90 – 0.78 (m, 1H), 0.67 (s, 3H), 0.66 (s, 3H), 0.07 (s, 6H); 13C{1H} NMR (101 MHz, C6D6) δ = 209.32, 59.86, 47.75, 43.20, 42.59, 41.29, 34.49, 26.19, 25.86, 25.64, 24.85, 24.65, 18.46, -5.13; IR (Neat Film, NaCl) 2955, 2930, 2858, 1714, 1471, 1388, 1253, 1092, 835, 777 cm–1; HRMS (ESI+): m/z calc’d for C17H35O2Si [M+H]+: 299.2401, found 299.2396. O O OTBS NaH, O=C(OMe)2 OH OTBS MeO THF, 50 ºC 12 methyl 28 4-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-2-hydroxycyclohex- 1-ene-1-carboxylate 28. To a 100 mL flask fitted with a reflux condenser under N2 was added NaH (60% dispersion in mineral oil, 1.3 g, 24 mmol, 5.0 equiv), THF (30 mL), and CO(OMe)2 (2.4 g, 26.8 mol, 4.0 equiv). The vigorously stirred solution was brought to a reflux at which point a solution of ketone 12 (2.0 g, 6.7 mmol, 1.0 equiv) in THF (15 mL) was added dropwise over 2 h with a syringe pump. After a further 2 h at reflux the solution was cooled to 0 °C and saturated aqueous NH4Cl (10 mL) was added slowly (Warning – H2 evolution!). Once gas evolution ceased, H2O (50 mL) and ether (20 mL) were added and the organic layer was separated, washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude oil was purified by automated silica gel flash chromatography (5→7.5% EtOAc/hexanes) to furnish 28 as a yellow oil (1.78 g, 75% yield). 1H NMR (400 MHz, Chapter 1 – Total Synthesis of Hypersampsone M 18 CDCl3) δ = 12.08 (s, 1H), 3.75 (s, 3H), 3.66 (t, J = 7.5 Hz, 2H), 2.41 (ddt, J = 15.9, 5.1, 1.8 Hz, 1H), 2.27 (ddt, J = 17.7, 5.2, 1.4 Hz, 1H), 2.16 – 2.01 (m, 2H), 1.84 (ddt, J = 14.6, 4.3, 2.0 Hz, 1H), 1.52 (td, J = 7.3, 2.6 Hz, 2H), 1.44 (tdd, J = 11.9, 5.3, 2.1 Hz, 1H), 1.10 (qd, J = 12.2, 5.1 Hz, 1H), 0.89 – 0.88 (m, 15H), 0.05 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ = 173.04, 172.53, 97.59, 59.95, 51.50, 42.52, 42.42, 34.09, 30.71, 26.12, 24.78, 24.47, 23.64, 23.27, 18.45, -5.13; IR (Neat Film, NaCl) 2954, 2856, 1660, 1620, 1441, 1360, 1282, 1220, 1093, 833, 774 cm–1; HRMS (ESI+): m/z calc’d for C19H37O4Si [M+H]+: 357.2456, found 357.2465. O OH OTBS MeO PhSeCl, py then, H2O2 (aq.) O MeO2C OTBS CH2Cl2, 0 ºC 28 13 methyl 4-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-6-oxocyclohex-1-ene1-carboxylate 13. Pyridine (1.32 g, 16.8 mmol, 1.5 equiv) was added dropwise to a solution of PhSeCl (5.9 g, 30.8 mmol, 1.1 equiv) in CH2Cl2 (40 mL) at 0 °C in a 250 mL flask under N2. A solution of ester 28 (4.0 g, 11.2 mmol, 1.0 equiv) in CH2Cl2 (20 mL) was added dropwise over 30 min and the resulting solution was stirred at 0 °C for a further 2 h. Saturated aqueous NH4Cl (80 mL) was added, and the organic layer separated. The aqueous layer was extracted with CH2Cl2 (20 mL x 2), and the combined organic extracts were concentrated under reduced pressure into a 250 mL flask. CH2Cl2 (140 mL) was added to the residue and the solution was cooled to 0 °C followed by addition of 35% H2O2 (5 mL). The mixture was stirred vigorously for 2.5 h, then H2O (20 mL) was added, and the organic layer separated. The Chapter 1 – Total Synthesis of Hypersampsone M 19 aqueous layer was further extracted with CH2Cl2 (20 mL), and the combined organic extracts were washed with saturated aqueous NaHCO3 and dried with Na2SO4. The solution was concentrated under reduced pressure to yield a yellow residue that was agitated with pentane (40 mL), filtered to remove solids, and concentrated to yield the title compound (13) as a yellow oil (3.9 g, 97% yield). Note: This material was directly carried forward to the next step. While this material is sufficiently pure for most purposes, 13 degrades rapidly on silica or alumina and cannot be easily purified. Additionally, 13 is not stable for extended periods of time, even when stored at –15 °C. 1H NMR and HRMS data is provided as a courtesy. 1H NMR (600 MHz, CDCl3) δ = 7.73 (dd, J = 6.3, 2.3 Hz, 1H), 3.79 (s, 3H), 3.65 (t, J = 7.1 Hz, 2H), 2.63 – 2.56 (m, 2H), 2.27 (ddd, J = 19.8, 11.4, 2.2 Hz, 1H), 2.24 – 2.18 (m, 1H), 1.99 (ddt, J = 14.9, 11.5, 3.9 Hz, 1H), 1.53 – 1.43 (m, 2H), 0.90 (s, 6H), 0.86 (s, 9H), 0.02 (s, 6H); HRMS (ESI+): m/z calc’d for C19H35O4Si [M+H]+: 355.2313, found 355.2299. O MeO2C MeO2C OTBS OTBS BrZn DME 0 → –40 → 80 ºC 13 methyl O H 14 6-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-1,1-dimethyl-4-oxo- 1,4,5,6,7,7a-hexahydro-3aH-indene-3a-carboxylate 14. To a dry flask under N2 was added activated Zn dust (2.12 g, 32.43 mmol, 2.5 equiv) and DME (46 mL). The mixture was cooled to 0 °C and 3-bromo-3-methylbut-1-yne (prepared according to a previously reported procedure22)(4.77 g, 32.43 mmol, 2.5 equiv) was added in one portion. After 1 h most of the Zn had dissolved and the mixture was cooled to –40 Chapter 1 – Total Synthesis of Hypersampsone M 20 °C at which point enone 13 (4.6 g, 12.97 mmol, 1.0 equiv) in DME (46 mL) was added dropwise over 1 h. The cloudy solution was then gradually allowed to warm to –15 °C and stirred at that temperature for 16 h. The reaction was then allowed to warm to 18 °C and filtered into a fresh flask via a glass fritted cannula filter to yield a perfectly homogeneous, yellow solution. The solution was heated to 80 °C for 5 h without stirring and then cooled to 0 °C and quenched with saturated, aqueous NH4Cl. The mixture was extracted with EtOAc (75 mL x 3), and the combined organic extracts were washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→15% EtOAc/hexanes) to furnish 14 (3.54 g, 65% yield) as a 6.3:1 mixture of diastereomers. 1H NMR (400 MHz, CDCl3) δ = 5.82 (d, J = 5.7 Hz, 1H), 5.80 (d, J = 5.8 Hz, 1H), 3.74 (s, 3H), 3.65 (t, J = 7.5 Hz, 2H), 2.84 (dd, J = 6.8, 1.7 Hz, 1H), 2.41 (ddd, J = 12.8, 3.8, 1.9 Hz, 1H), 2.32 (t, J = 12.4 Hz, 1H), 1.95 – 1.74 (m, 3H), 1.52 (tt, J = 13.4, 6.7 Hz, 2H), 1.10 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H), 0.89 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ = 210.02, 171.52, 144.92, 126.45, 71.21, 59.76, 52.91, 52.61, 48.28, 45.41, 41.95, 41.34, 35.11, 28.63, 25.99, 24.72, 24.55, 24.36, 22.59, 18.34, -5.25; IR (Neat Film, NaCl) 2954, 2858, 1740, 1715, 1471, 1254, 1092, 836, 775 cm–1; HRMS (ESI+): m/z calc’d for C24H43O4Si [M+H]+: 423.2925, found 423.2929. Note: The presence of the minor diastereomer does not impede future steps, but an analytical sample was prepared through reverse phase chromatography (Teledyne ISCO, MeCN/water). Chapter 1 – Total Synthesis of Hypersampsone M MeO2C O 21 MeO2C OTBS O Pd/C (10 wt %), H2 OTBS EtOAc, 18 ºC H H 14 methyl 29 6-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-1,1-dimethyl-4- oxooctahydro-3aH-indene-3a-carboxylate 29. A 50 mL flask under N2 was charged with Pd/C (30 mg, 10%w loading) and a solution of compound 14 (310 mg, 0.73 mmol, 1 equiv) in EtOAc (10 mL) was added. A H2 filled balloon was used to purge the solution for 10 min, at which point a fresh H2 balloon was installed, and the mixture was stirred vigorously for 3 h. The mixture was filtered through celite and concentrated under reduced pressure to furnish 29 as a colorless oil (310 mg, >98% yield). 1H NMR (400 MHz, C6D6) δ = 3.62 (t, J = 7.2 Hz, 2H), 3.24 (s, 3H), 3.04 (ddd, J = 14.2, 10.9, 8.2 Hz, 1H), 2.74 (dd, J = 5.4, 3.6 Hz, 1H), 2.61 – 2.54 (m, 1H), 2.28 (dd, J = 13.1, 12.1 Hz, 1H), 1.95 (ddd, J = 14.2, 8.7, 2.8 Hz, 1H), 1.85 – 1.73 (m, 1H), 1.69 (tdd, J = 5.7, 3.3, 1.7 Hz, 2H), 1.56 – 1.31 (m, 4H), 0.99 (s, 9H), 0.89 (s, 3H), 0.74 (s, 3H), 0.71 (s, 3H), 0.68 (s, 3H), 0.09 (s, 6H); 13C{1H} NMR (101 MHz, C6D6) δ = 207.29, 173.64, 65.12, 59.90, 54.55, 52.22, 45.62, 43.08, 42.53, 41.88, 40.79, 35.02, 29.06, 29.04, 26.20, 24.64, 24.33, 23.77, 23.06, 18.48, -5.11; IR (Neat Film, NaCl) 2952, 2860, 1739, 1714, 1469, 1250, 1206, 1092, 837, 774 cm–1; HRMS (ESI+): m/z calc’d for C24H45O4Si [M+H]+: 425.3082, found 425.3070. Chapter 1 – Total Synthesis of Hypersampsone M MeO2C OTBS Me3Si O O 15 LDA, O 22 O N2 MeO2C 4 THF, –78 ºC H 29 methyl O HO N2 SiMe3 OTBS H 16 6-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-4-(1-diazo-2-oxo-2- (2-(trimethylsilyl)ethoxy)ethyl)-4-hydroxy-1,1-dimethyloctahydro-3aH-indene-3acarboxylate 16. To a 100 mL Schlenk flask under N2 was added NH(i-Pr)2 (1.37 g, 13.5 mmol, 4.5 equiv) and THF (7 mL). The flask was cooled to –78 °C in a dry ice/acetone bath. n-BuLi (2.5M in hexanes, 4.2 mL, 10.5 mmol, 3.5 equiv) was added dropwise over 15 min and the solution was left to stir at –78 °C for 15 min. A solution of diazoacetate 15 (prepared according to a previously reported procedure25)(2.23 g, 12 mmol, 4.0 equiv) in THF (7 mL) was added dropwise over 15 min and the blood-red solution was stirred for a further 30 min. A solution of ketone 29 (1.26 g, 3.0 mmol, 1.0 equiv) in THF (24 mL) was then added dropwise over 30 min and the reaction was left to stir for an additional 45 min. A solution of AcOH (810 mg) in Et2O (4 mL) was added slowly and the reaction was removed from the cold bath. Water (80 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→15% EtOAc/hexanes) to furnish a yellow oil. The oil was dried in vacuo overnight to remove residual diazoacetate (15), furnishing 16 (1.63 g, 89% yield) as a yellow oil. We have been unable to unambiguously determine the stereochemistry at C4 to date. 1H NMR (400 MHz, C6D6) δ = 5.88 (br s, 1H), 4.12 (qdd, J = 10.9, 9.0, 7.5 Hz, 2H), 3.91 – 3.75 (m, 2H), 3.39 (s, 3H), 2.74 (ddd, J = 13.8, 7.8, 3.6 Hz, Chapter 1 – Total Synthesis of Hypersampsone M 23 1H), 2.52 (ddd, J = 13.7, 10.3, 7.7 Hz, 1H), 2.25 – 2.04 (m, 4H), 1.80 – 1.66 (m, 3H), 1.61 (ddt, J = 11.3, 7.6, 4.3 Hz, 2H), 1.49 (ddd, J = 12.3, 10.4, 7.8 Hz, 1H), 1.07 (s, 3H), 1.01 (s, 9H), 0.98 (s, 3H), 0.94 (s, 6H), 0.76 (ddd, J = 9.2, 7.2, 1.5 Hz, 2H), 0.13 (d, J = 2.1 Hz, 6H), -0.14 (s, 9H); 13C{1H} NMR (101 MHz, C6D6) δ = 176.51, 168.61, 72.10, 63.71, 63.58, 60.10, 53.42, 51.65, 43.26, 42.57, 41.21, 35.73, 35.55, 34.81, 34.27, 30.78, 28.83, 26.24, 25.19, 24.83, 23.44, 22.34, 18.51, 17.51, -1.64, -5.03; IR (Neat Film, NaCl) 3419, 2952, 2089, 1667, 1386, 1305, 1090, 840, 775 cm–1; HRMS (ESI+): m/z calc’d for C31H58N2O6Si2Na [M+Na]+: 633.3726, found 633.3719. O MeO2C O SiMe3 HO N2 OTBS MeO2C O Rh2(TFA)4 (1 mol %) O O SiMe3 OTBS pentane/CH2Cl2, 18 ºC H H 16 3a-methyl 17 5-(2-(trimethylsilyl)ethyl)-7-(4-((tert-butyldimethylsilyl)oxy)-2- methylbutan-2-yl)-1,1-dimethyl-4-oxooctahydroazulene-3a,5(1H)-dicarboxylate 17 To a solution of diazoacetate 16 (97 mg, 0.16 mmol, 1 equiv) in pentane/CH2Cl2 (4:1, 5 mL) under Ar was added Rh2(TFA)4 (1 mg, 0.0016 mmol, 0.01 equiv). The reaction was stirred at 18 °C for 24 h, concentrated under reduced pressure and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 17 (85 mg, 92% yield) as a colorless oil. Note: Title compound 17 was isolated as a mixture of dynamically interconverting tautomers and was used directly in the next step. 1H NMR spectral data (See page S36) and HRMS data is provided as a courtesy. HRMS (ESI+): m/z calc’d for C31H58O6Si2Na [M+Na]+: 605.3664, found 605.3656. Chapter 1 – Total Synthesis of Hypersampsone M MeO2C O 24 O O SiMe3 NaH, prenyl bromide OTBS H MeO2C O O O THF, 0 → 18 ºC SiMe3 OTBS H 17 18 3a-methyl 5-(2-(trimethylsilyl)ethyl)-7-(4-((tert-butyldimethylsilyl)oxy)-2- methylbutan-2-yl)-1,1-dimethyl-5-(3-methylbut-2-en-1-yl)-4-oxooctahydroazulene3a,5(1H)-dicarboxylate 18. A 25 mL flask under N2 was charged with ester 17 (85 mg, 0.14 mmol, 1.0 equiv) and THF (4.5 mL). The solution was cooled to 0 °C and NaH (60% dispersion in mineral oil, 16 mg, 0.41 mmol, 4 equiv) was added in one portion and the cold bath was removed. After stirring at 18 °C for 1 h, the solution was cooled to 0 °C and prenyl bromide (101 mg, 0.68 mmol, 5 equiv) was added dropwise. The reaction was allowed to warm to 18 °C and stirred at this temperature for 2.5 h after which it was cooled to 0 °C and quenched slowly with saturated aqueous NH4Cl (1 mL). The mixture was extracted with EtOAc (1 mL x 3), and the combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure.a The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% Et2O/hexanes) to furnish 18 (79 mg, 89% yield) as colorless oil. Note: aCare should be taken to completely remove excess prenyl bromide before loading onto silica as prenyl bromide may decompose to HBr with significant exotherm resulting in a drastically decreased yield. 1H NMR (400 MHz, C6D6) δ = 5.62 (dddd, J = 6.9, 5.5, 2.8, 1.4 Hz, 1H), 4.34 – 4.20 (m, 2H), 3.78 (ddt, J = 10.9, 7.2, 3.6 Hz, 2H), 3.27 (s, 3H), 3.26 – 3.21 (m, 1H), 3.11 (td, J = 13.9, 6.2 Hz, 1H), 3.03 (dd, J = 14.9, 8.2 Hz, 1H), 2.46 (ddt, J = 14.9, 4.8, 1.5 Hz, 1H), 2.26 – 2.11 (m, 2H), 2.01 – 1.94 (m, 1H), 1.94 – 1.70 (m, Chapter 1 – Total Synthesis of Hypersampsone M 25 5H), 1.69 (d, J = 1.5 Hz, 3H), 1.67 (s, 3H), 1.39 (ddd, J = 13.8, 12.0, 6.2 Hz, 1H), 1.27 (ddd, J = 12.1, 6.2, 1.6 Hz, 1H), 1.08 (d, J = 1.2 Hz, 6H), 1.06 (s, 3H), 1.02 (s, 11H), 0.78 (s, 3H), 0.15 (s, 3H), 0.15 (s, 3H), -0.10 (s, 9H); 13C{1H} NMR (101 MHz, C6D6) δ = 201.68, 174.33, 171.83, 133.43, 120.43, 70.21, 63.35, 63.20, 59.84, 51.90, 48.32, 44.69, 43.70, 40.81, 39.08, 38.84, 36.31, 34.55, 33.95, 28.68, 26.74, 26.59, 26.23, 26.23, 24.05, 22.77, 18.50, 18.31, 17.83, -1.71, -4.95, -4.99; IR (Neat Film, NaCl) 2953, 2860, 1731, 1703, 1458, 1386, 1367, 1304, 1250, 1093, 838, 776, 671; HRMS (ESI+): m/z calc’d for C36H66O6Si2Na [M+Na]+: 673.4298, found 673.4301. MeO2C O O TBAF O SiMe3 OTBS MeO2C O 5 THF, 18 ºC H 18 OH H 30 methyl 7-(4-hydroxy-2-methylbutan-2-yl)-1,1-dimethyl-5-(3-methylbut-2-en-1-yl)-4oxooctahydroazulene-3a(1H)-carboxylate 30. To a solution of compound 18 (73 mg, 0.11 mmol, 1 equiv) in THF (1.1 mL) at 0 °C under N2 was slowly added TBAF (1M in THF, 0.39 mL, 0.39 mmol, 3.5 equiv). The solution warmed to 18 °C and stirred at this temperature for 18 h. Saturated aqueous NH4Cl (1 mL) was added, and the mixture extracted with EtOAc (1 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→50% EtOAc/hexanes) to furnish 30 (43 mg, 98% yield) as colorless oil. We have been unable to unambiguously determine the stereochemistry at C5 to date. 1H NMR (400 MHz, Chapter 1 – Total Synthesis of Hypersampsone M 26 C6D6) δ = 5.09 (ddq, J = 8.7, 5.8, 1.5 Hz, 1H), 3.43 (t, J = 7.5 Hz, 2H), 3.28 (s, 3H), 3.21 (td, J = 13.5, 6.4 Hz, 1H), 3.07 – 2.98 (m, 1H), 2.96 (dd, J = 12.4, 2.9 Hz, 1H), 2.77 (dq, J = 9.6, 4.7 Hz, 1H), 2.17 (dt, J = 14.9, 9.5 Hz, 1H), 1.74 – 1.66 (m, 3H), 1.65 (d, J = 1.8 Hz, 3H), 1.64 – 1.57 (m, 2H), 1.55 (d, J = 1.2 Hz, 3H), 1.54 – 1.43 (m, 3H), 1.37 – 1.32 (m, 1H), 1.21 (ddd, J = 15.7, 7.9, 4.5 Hz, 1H), 1.04 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.73 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 207.27, 175.50, 132.68, 123.42, 68.22, 59.19, 52.10, 48.69, 48.20, 43.79, 43.74, 40.14, 38.62, 36.05, 32.18, 28.26, 27.24, 26.08, 25.99, 25.86, 25.68, 24.77, 22.17, 17.97; IR (Neat Film, NaCl) 3392, 2957, 1703, 1462, 1366, 1251, 1199, 1120, 1051, 1018; HRMS (ESI+): m/z calc’d for C24H41O4 [M+H]+: 393.2999, found 393.3008. MeO2C O DMP OH O CH2Cl2, 18 ºC H O H 30 methyl MeO2C 19 1,1-dimethyl-7-(2-methyl-4-oxobutan-2-yl)-5-(3-methylbut-2-en-1-yl)-4- oxooctahydroazulene-3a(1H)-carboxylate 19. To an 8 mL vial was added alcohol 30 (43 mg, 0.11 mmol, 1.0 equiv) and CH2Cl2 (4 mL). DMP (116 mg, 0.28 mmol, 2.5 equiv) was added, and the vial was stirred under Ar for 3 h. The reaction was concentrated under reduced pressure and hexanes (1 mL) was added. The heterogeneous mixture was agitated and concentrated under reduced pressure. Hexanes (4 mL) was added, and the mixture was sonicated for 2 min. The mixture was filtered over celite, and the filter cake rinsed with hexanes (4 mL). The combined organic fractions were concentrated under reduced pressure to and purified by flash silica gel Chapter 1 – Total Synthesis of Hypersampsone M 27 chromatography (0→20% EtOAc/hexanes) to provide aldehyde 19 (35 mg, 81% yield) as a colorless oil. 1H NMR (400 MHz, C6D6) δ = 9.51 (t, J = 2.9 Hz, 1H), 5.07 (ddq, J = 8.8, 5.8, 1.5 Hz, 1H), 3.27 (s, 3H), 3.19 (td, J = 13.7, 6.4 Hz, 1H), 3.05 – 2.94 (m, 1H), 2.86 (dd, J = 12.5, 2.7 Hz, 1H), 2.73 (dq, J = 9.5, 4.6 Hz, 1H), 2.10 (dt, J = 14.9, 9.4 Hz, 1H), 2.02 (dd, J = 14.6, 2.9 Hz, 1H), 1.90 (dd, J = 14.6, 2.9 Hz, 1H), 1.66 (d, J = 1.6 Hz, 3H), 1.65 – 1.55 (m, 4H), 1.55 (d, J = 1.2 Hz, 3H), 1.54 – 1.49 (m, 2H), 1.36 – 1.28 (m, 1H), 1.14 (ddd, J = 16.3, 12.6, 6.6 Hz, 1H), 0.98 (s, 3H), 0.90 (s, 3H), 0.86 (s, 3H), 0.69 (s, 3H); 13 C{1H} NMR (101 MHz, C6D6) δ = 206.82, 201.24, 175.38, 132.94, 123.08, 68.15, 53.91, 52.12, 48.52, 48.08, 43.69, 40.06, 39.22, 37.19, 32.15, 28.18, 27.16, 25.97, 25.96, 25.82, 25.70, 24.68, 22.06, 17.92; IR (Neat Film, NaCl) 2957, 1703, 1460, 1255, 1196, 1120; HRMS (ESI+): m/z calc’d for C24H39O4 [M+H]+: 391.2843, found 391.2841. MeO2C O O TsOH•H2O O O H H CH2Cl2, 18 ºC H 19 O H 21 1,1,8,8-tetramethyl-5-(3-methylbut-2-en-1-yl)decahydro-4H-6,3a-(epoxymethano)5,9-methanocyclopenta[9]annulene-4,13-dione 2. A 250 mL flask was charged with aldehyde 19 (57 mg, 0.15 mmol, 1.0 equiv), pTsOH•H2O (111 mg, 0.58 mmol, 4.0 equiv) and CH2Cl2 (15 mL). The vial was sealed under Ar and stirred at 18 °C for 36 h. The solution was concentrated under reduced pressure, hexanes (20 mL) was added, and the solution was filtered to remove pTsOH•H2O. The crude residue was purified by flash silica gel chromatography (0→30% Et2O/hexanes) to furnish 21 (24 mg, 46% yield) as a colorless oil. Starting aldehyde 19 (17 Chapter 1 – Total Synthesis of Hypersampsone M 28 mg, 30%) could also be recovered. 1H NMR (400 MHz, C6D6) δ = 5.15 (ddp, J = 8.4, 7.0, 1.5 Hz, 1H), 4.57 (dd, J = 10.4, 7.8 Hz, 1H), 2.84 (td, J = 12.8, 6.1 Hz, 1H), 2.64 (dd, J = 14.4, 8.3 Hz, 1H), 2.31 (tdd, J = 11.6, 7.6, 4.5 Hz, 2H), 2.21 (dd, J = 13.4, 4.0 Hz, 1H), 2.14 (td, J = 12.3, 6.2 Hz, 1H), 1.90 (ddd, J = 15.9, 10.4, 1.4 Hz, 1H), 1.78 (ddd, J = 14.2, 3.1, 1.8 Hz, 1H), 1.65 (dddd, J = 15.2, 6.1, 3.8, 1.8 Hz, 1H), 1.58 (d, J = 1.2 Hz, 3H), 1.58 – 1.53 (m, 2H), 1.53 (d, J = 1.4 Hz, 3H), 1.40 (dd, J = 14.1, 3.6 Hz, 1H), 1.13 – 1.00 (m, 2H), 0.86 (s, 3H), 0.69 (s, 3H), 0.66 (s, 3H), 0.59 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 207.83, 175.98, 136.30, 118.95, 74.24, 67.24, 51.49, 49.52, 44.59, 43.79, 42.76, 40.22, 37.41, 36.99, 32.62, 31.49, 30.62, 30.55, 28.83, 28.30, 26.09, 23.34, 17.96; IR (Neat Film, NaCl) 2957, 1748, 1708, 1458, 1366, 1247; HRMS (ESI+): m/z calc’d for C23H35O3 [M+H]+: 359.2581, found 359.2571. O O H O H 21 H 1. NHMe(OMe)•HCl AlMe3, PhMe 2. DMP, CH2Cl2, 18 ºC MeO MeN O O H O H 25 N-methoxy-N,1,1,8,8-pentamethyl-5-(3-methylbut-2-en-1-yl)-4,6-dioxodecahydro5,9-methanocyclopenta[9]annulene-3a(1H)-carboxamide 25. A small test tube equipped with a septum under N2 was charged with N,Odimethylhydroxylamine hydrochloride (27 mg, 0.28 mmol, 10 equiv) and PhMe (0.3 mL). The reaction was cooled to 0 °C and AlMe3 (0.14 mL, 2M in PhMe, 0.28 mmol, 10 equiv) was added dropwise. The homogenous solution was stirred at 0 °C for 45 min, at which point lactone 21 (10 mg, 28 µmol, 1.0 equiv) in PhMe (0.3 mL) was added dropwise and the reaction was left to warm naturally over 20 h. The reaction was quenched by Chapter 1 – Total Synthesis of Hypersampsone M 29 sequentially adding a saturated solution of potassium sodium tartrate (1 mL), water (0.2 mL), CH2Cl2 (1 mL), and stirring for 3 h. The organic layer was separated, and the aqueous layer extracted further with CH2Cl2 (2x2 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by preparatory TLC (18% EtOAc in hexanes) and directly used in the next step. The crude residue was transferred to a 4 mL vial, and CH2Cl2 (1 mL) was added. DMP (30 mg, 0.07 mmol, 2.5 equiv) was added, and the solution was stirred under Ar for 2 h. The reaction was concentrated under reduced pressure and hexanes (1 mL) was added. The mixture was agitated and filtered over celite, and the filter cake rinsed with hexanes (1 mL). The combined organic fractions were concentrated under reduced pressure to and purified by preparatory TLC (10% EtOAc in hexanes) to provide amide 25 (3 mg, 26% yield) as a colorless oil. 1H NMR (400 MHz, C6D6) δ = 5.35 (ddp, J = 9.6, 5.4, 1.4 Hz, 1H), 3.28 – 3.03 (m, 5H), 2.94 (s, 3H), 2.88 (s, 3H), 2.43 (ddd, J = 14.0, 3.6, 1.7 Hz, 1H), 2.29 (dd, J = 19.2, 1.8 Hz, 1H), 1.89 (dddd, J = 15.1, 6.0, 4.0, 1.7 Hz, 1H), 1.73 (dd, J = 12.5, 5.6 Hz, 1H), 1.68 (t, J = 1.4 Hz, 3H), 1.64 (d, J = 3.2 Hz, 1H), 1.64 – 1.62 (m, 3H), 1.55 (ddd, J = 13.0, 5.7, 2.3 Hz, 1H), 1.43 – 1.36 (m, 2H), 1.29 (td, J = 14.6, 2.1 Hz, 1H), 1.23 (s, 3H), 0.89 (s, 3H), 0.84 (s, 3H), 0.76 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 210.01, 201.59, 176.51, 134.80, 121.66, 70.70, 67.17, 59.18, 53.04, 46.09, 43.64, 40.76, 39.72, 38.83, 35.31, 34.73, 34.41, 33.41, 31.96, 31.62, 29.15, 27.05, 26.08, 24.40, 18.27; IR (Neat Film, NaCl) 2960, 2868, 1684, 1654, 1458, 1364, 1185, 1005, 983, 941, 844; HRMS (ESI+): m/z calc’d for C25H40NO4 [M+H]+: 418.2952, found 418.2968. Chapter 1 – Total Synthesis of Hypersampsone M O O H PhNH2•HCl, AlMe3 H 30 O O OH PhHN PhMe, 0 → 18 ºC O H H 21 H 31 6-hydroxy-1,1,8,8-tetramethyl-5-(3-methylbut-2-en-1-yl)-4-oxo-N-phenyldecahydro5,9-methanocyclopenta[9]annulene-3a(1H)-carboxamide 31. A small test tube equipped with a septum under N2 was charged with aniline hydrochloride (86 mg, 0.66 mmol, 10 equiv) and PhMe (1.2 mL). The reaction was cooled to 0 °C and AlMe3 (0.33 mL, 2M in PhMe, 0.66 mmol, 10 equiv) was added dropwise. The homogenous solution was stirred at 0 °C for 45 min, at which point lactone 21 (24 mg, 66 µmol, 1.0 equiv) in PhMe (1.2 mL) was added dropwise and the reaction was left to warm naturally over 20 h. The reaction was quenched by sequentially adding a saturated solution of potassium sodium tartrate (8 mL), water (5 mL), CH2Cl2 (10 mL), and stirring for 1 h. The entire mixture was filtered over celite, the organic layer separated, and the aqueous layer extracted further with CH2Cl2 (2x5 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography (0→15% EtOAc/hexanes) to furnish 31 (25 mg, 84% yield) as a colorless oil. 1H NMR (400 MHz, C6D6) δ = 7.55 – 7.49 (m, 2H), 7.35 (s, 1H), 7.10 – 7.04 (m, 2H), 6.91 – 6.79 (m, 1H), 5.49 (ddt, J = 7.7, 6.1, 1.5 Hz, 1H), 3.71 (dt, J = 11.6, 5.6 Hz, 1H), 3.63 (dd, J = 11.7, 4.3 Hz, 1H), 2.76 (dd, J = 14.3, 7.9 Hz, 1H), 2.47 (dd, J = 14.3, 7.5 Hz, 1H), 2.43 – 2.28 (m, 3H), 1.98 (d, J = 5.2 Hz, 1H), 1.87 – 1.79 (m, 1H), 1.73 (ddd, J = 14.8, 4.4, 1.4 Hz, 1H), 1.63 (d, J = 1.4 Hz, 3H), 1.60 – 1.50 (m, 4H), 1.39 (dd, J = 14.8, 2.5 Hz, 1H), 1.35 – 1.21 (m, 7H), 0.97 (s, 3H), 0.86 (s, 3H), 0.81 (s, 3H); 13C{1H} Chapter 1 – Total Synthesis of Hypersampsone M 31 NMR (101 MHz, C6D6) δ = 215.13, 169.34, 139.31, 134.79, 129.06, 123.98, 121.95, 120.12, 76.36, 72.63, 58.83, 44.76, 42.93, 40.57, 40.08, 39.48, 38.00, 37.78, 35.51, 34.46, 32.11, 31.17, 29.68, 27.84, 26.27, 25.97, 18.06; IR (Neat Film, NaCl) 3338; 2934, 1660, 1598, 1529, 1439, 1311, 1246, 1030, 752; HRMS (ESI+): m/z calc’d for C29H42NO3 [M+H]+: 452.3159, found 452.3163. O O O OH PhHN DMP O O PhHN CH2Cl2, 18 ºC H H 31 H H 22 1,1,8,8-tetramethyl-5-(3-methylbut-2-en-1-yl)-4,6-dioxo-N-phenyldecahydro-5,9methanocyclopenta[9]annulene-3a(1H)-carboxamide 22. To a 4 mL vial was added alcohol 31 (25 mg, 0.055 mmol, 1.0 equiv) and CH2Cl2 (1.1 mL). DMP (52 mg, 0.12 mmol, 2.2 equiv) was added, and the solution was stirred under Ar for 2 h. The reaction was concentrated under reduced pressure and hexanes (0.5 mL) was added. The heterogeneous mixture was agitated and concentrated under reduced pressure. Hexanes (2 mL) was added, and the mixture was sonicated for 2 min. The mixture was filtered over celite, and the filter cake rinsed with hexanes (2 mL). The combined organic fractions were concentrated under reduced pressure and the crude residue purified by silica gel plug (10% EtOAc/hexanes) to provide dione 22 (20 mg, 80% yield) as a white foam. 1H NMR (400 MHz, C6D6) δ = 7.38 – 7.34 (m, 2H), 7.07 – 7.02 (m, 2H), 6.88 – 6.81 (m, 1H), 6.70 (s, 1H), 5.36 (ddp, J = 8.0, 6.4, 1.5 Hz, 1H), 3.42 – 3.32 (m, 2H), 2.97 (dd, J = 14.0, 6.5 Hz, 1H), 2.80 (dd, J = 13.9, 8.6 Hz, 1H), 2.64 (td, J = 13.6, 5.8 Hz, 1H), 2.32 – Chapter 1 – Total Synthesis of Hypersampsone M 32 2.22 (m, 2H), 1.94 (dtd, J = 13.4, 5.7, 2.6 Hz, 2H), 1.64 (d, J = 1.4 Hz, 3H), 1.59 (d, J = 1.4 Hz, 3H), 1.58 – 1.51 (m, 1H), 1.41 – 1.33 (m, 2H), 1.28 – 1.22 (m, 4H), 1.21 – 1.12 (m, 1H), 0.89 (s, 3H), 0.79 (s, 3H), 0.72 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 208.86, 206.64, 168.81, 138.12, 135.52, 128.99, 124.87, 121.20, 121.17, 75.03, 67.36, 52.31, 44.06, 43.56, 40.40, 39.10, 38.64, 35.69, 35.18, 32.27, 31.85, 29.88, 29.67, 27.13, 26.14, 24.86, 18.25; IR (Neat Film, NaCl) 3363, 2960, 1694, 1671, 1599, 1524, 1438, 1312, 1236, 1170, 1117, 748; HRMS (ESI+): m/z calc’d for C29H40NO3 [M+H]+: 450.3003, found 450.3016. O O O PhHN Me3OBF4 2,6-di-(t-Bu)py CH2Cl2, 18 ºC O then EtOAc/HCl H H 22 O H O H 2 1,1,8,8-tetramethyl-5-(3-methylbut-2-en-1-yl)octahydro-4H-3a,7:5,9dimethanocyclopenta[9]annulene-4,6,12(5H)-trione 2. In a glovebox, an 8 mL vial was charged with finely ground Me3OBF4 (132 mg, 0.89 mmol, 10 equiv) and a solution of amide 22 (40 mg, 89 µmol, 1.0 equiv) and 2,6-di-tertbutylpyridine (187 mg, 0.98 mmol, 11 equiv) in CH2Cl2 (4 mL) was added in one portion. The reaction was sealed with a Teflon cap and electrical tape, brought out of the glovebox, sonicated for 3 min, and then vigorously stirred at 18 °C for 45 h. Saturated NaHCO3 (10 mL) was added, and the organic layer was separated and further extracted with CH2Cl2 (3x3 mL). The combined organic fractions were concentrated under reduced pressure, EtOAc (4 mL) and 1M aq. HCl (4 mL) were added, and the mixture stirred at 35 °C for 18 Chapter 1 – Total Synthesis of Hypersampsone M 33 h. The reaction was cooled to 18 °C and saturated NaHCO3 was added dropwise until effervescence stopped at which point the reaction was extracted with EtOAc (3x2 mL), dried with Na2SO4, and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→15% EtOAc/hexanes) to furnish 2 (24 mg, 67% yield) as a colorless oil. 1H NMR (400 MHz, C6D6) δ = 5.51 (tp, J = 7.4, 1.5 Hz, 1H), 3.36 (s, 1H), 2.68 (d, J = 7.4 Hz, 2H), 2.56 (ddd, J = 13.6, 10.6, 8.3 Hz, 1H), 2.44 (ddd, J = 13.5, 9.5, 2.6 Hz, 1H), 2.21 (ddd, J = 14.1, 5.9, 1.3 Hz, 1H), 1.76 (dd, J = 11.6, 8.4 Hz, 1H), 1.72 – 1.64 (m, 5H), 1.63 (d, J = 1.4 Hz, 3H), 1.56 (dt, J = 12.2, 10.0 Hz, 1H), 1.41 (ddd, J = 7.4, 5.7, 1.6 Hz, 1H), 1.34 – 1.30 (m, 1H), 1.10 (ddd, J = 14.4, 11.6, 1.5 Hz, 1H), 0.83 (s, 3H), 0.82 (s, 3H), 0.73 (s, 3H), 0.70 (s, 3H); 13 C{1H} NMR (101 MHz, C6D6) δ = 204.42, 203.37, 200.98, 133.78, 120.30, 77.99, 75.21, 66.65, 54.69, 44.24, 44.03, 42.74, 41.66, 38.40, 30.04, 29.34, 29.02, 28.71, 26.55, 25.81, 24.78, 20.06, 17.75; IR (Neat Film, NaCl) 2953, 1739, 1702, 1690, 1460, 1223, 1205; HRMS (ESI+): m/z calc’d for C23H33O3 [M+H]+: 357.2424, found 357.2429. O O LiTMP, BzCl H THF, –78 → –35 ºC O O H O O O Ph H 2 1 Hypersampsone M 1. To a freshly prepared solution of LiTMP26 (0.5M, 225 µL, 0.112 mM, 4.0 equiv) at –78 °C in a test tube was added triketone 2 (10 mg, 28 µM, 1.0 equiv) in THF (350 uL) dropwise over 5 min. The reaction was warmed to –35 °C over 10 min, and this temperature was Chapter 1 – Total Synthesis of Hypersampsone M 34 maintained for 1 h. The reaction was then cooled to –78 °C and BzCl (0.4 M in THF, 295 µL, 0.118 mmol, 4.2 equiv) was added dropwise. The brown solution was warmed to –25 °C over 10 min, and this temperature was maintained for 15 min. The reaction was quenched cold with sat. aq. NaHCO3 an extracted 3x with EtOAc. The crude residue was purified by preparatory TLC (10% Et2O in hexanes) followed by preparatory HPLC (9.4x250mm XDB-C18 column, 70 – 100% MeCN/water over 5 min, then held at 100% MeCN for 3 min. The title compound eluted at 6.49 min and was observed at 254 nm. 1 (2.5 mg, 20% yield) was isolated as a crystalline solid and unreacted 2 was also recovered (2.2 mg, 22% rsm). 1H NMR (400 MHz, CDCl3) δ = 7.39 (ddt, J = 7.9, 6.7, 1.2 Hz, 1H), 7.29 – 7.23 (m, 2H), 7.14 – 7.06 (m, 2H), 5.04 – 4.96 (m, 1H), 2.60 – 2.46 (m, 4H), 2.36 (ddd, J = 13.5, 10.2, 5.1 Hz, 1H), 2.32 – 2.24 (m, 1H), 2.15 – 2.10 (m, 1H), 2.06 (dd, J = 11.0, 9.6 Hz, 1H), 2.02 – 1.95 (m, 1H), 1.87 – 1.75 (m, 2H), 1.66 (s, 3H), 1.65 (d, J = 1.0 Hz, 3H), 1.49 (s, 3H), 1.44 (s, 3H), 1.01 (s, 3H), 0.89 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 205.94, 205.38, 205.21, 193.04, 135.23, 134.93, 132.10, 129.26, 128.03, 119.27, 81.35, 76.32, 68.64, 57.71, 51.51, 44.75, 44.19, 43.64, 41.64, 30.32, 30.02, 29.07, 28.81, 26.20, 25.91, 22.91, 22.02, 18.25; IR (Neat Film, NaCl) 2954, 2930, 1732, 1694, 1446, 1393, 1370, 1243, 1223, 1123, 684; HRMS (ESI+): m/z calc’d for C30H37O4 [M+H]+: 461.2686, found 461.2690. Analytical data are in agreement with those reported in the literature.6 Chapter 1 – Total Synthesis of Hypersampsone M 1.6.3 35 COMPARISON OF NATURAL AND SYNTHETIC HYPERSAMPSONE M Figure 1.6.3.1. Synthetic and natural 1H NMR of Hypersampsone M (1), CDCl3. Figure 1.6.3.2. Synthetic and natural 13C NMR of Hypersampsone M (1), CDCl3. Chapter 1 – Total Synthesis of Hypersampsone M 36 Table 1.6.3.1. Comparison of 1H and 13C NMR shifts of Hypersampsone M (1), CDCl3. 33 31 32 30 O 3 25 20 H 22 5 9 2 1 O 6 21 23 O O 29 4 24 19 7 10 18 11 12 8 13 16 17 15 14 *A shift for the second vicinal proton on carbon #24 was not provided in the original isolation report.6 The proton was found to be in an overlapping multiplet centered at 2.50 ppm. The integration value supporting this can be seen in both the natural and synthetic spectra. Chapter 1 – Total Synthesis of Hypersampsone M 1.7 (1) 37 REFERENCES AND NOTES For insightful reviews of PPAPs, see: (a) Ciochina, R.; Grossman, R. B. Polycyclic Polyprenylated Acylphloroglucinols. Chem. Rev. 2006, 106, 3963– 3986. (b) Singh, I. P.; Sidana, J.; Bharate, S. B.; Foley, W. J. Phloroglucinol Compounds of Natural Origin: Synthetic Aspects. Nat. Prod. Rep. 2010, 27, 393– 416. (c) Njardarson, J. T. Synthetic Efforts Toward [3.3.1] Bridged Bicyclic Phloroglucinol Natural products. Tetrahedron 2011, 67, 7631– 7666. (d) Richard, J.-A.; Pouwer, R. H.; Chen, D. Y.-K. The Chemistry of the Polycyclic Polyprenylated Acylphloroglucinols. Angew. Chem., Int. Ed. 2012, 51, 4536– 4561. (e) Yang, X.-W.; Grossman, R. B.; Xu, G. Research Progress of Polycyclic Polyprenylated Acylphloroglucinols. Chem. Rev. 2018, 118, 3508– 3558. (f) Phang, Y. L.; Liu, S.; Zheng, C.; Xu, H. Recent Advances in the Synthesis of Natural Products Containing the Phloroglucinol Motif. Nat. Prod. Rep. 2022, 39, 1766– 1802. (2) For some examples, see: (a) Zhang, J.-S.; Zou, Y.-H.; Guo, Y.-Q.; Li, Z.-Z.; Tang, G.-H.; Yin, S. Polycyclic Polyprenylated Acylphloroglucinols: Natural Phosphodiesterase-4 Inhibitors from Hypericum Sampsonii. RCS Adv. 2016, 6, 53469–53476. (b) Nedialkov, P. T.; Momekov, G.; Kokanova-Nedialkova; Z. K., Heilmann; J. Polyprenylated Phloroglucinols from Hypericum maculatum. Nat. Prod. Commun. 2015, 10, 1231–1235. (c) Xiao, Z. Y.; Mu, Q.; Shiu, W. K. P.; Zeng, Y. H., Gibbons, S. Polyisoprenylated Benzoylphloroglucinol Derivatives from Hypericum sampsonii. J. Nat. Prod. 2007, 70, 1779–1782. (d) Zhou, Z.-B.; Chapter 1 – Total Synthesis of Hypersampsone M 38 Li, Z.-R.; Wang, X.-B.; Luo, J.-G.; Kong, L.-Y. Polycyclic Polyprenylated Derivatives from Hypericum uralum: Neuroprotective Effects and Antidepressantlike Activity of Uralodin A. J. Nat. Prod. 2016, 79, 1231–1240. (e) Weng, J.-R.; Tsao, L.-T.; Wang, J.-P.; Wu, R.-R.; Lin, C.-N. Anti-inflammatory Phloroglucinols and Terpenoids from Garcinia subelliptica. J. Nat. Prod. 2004, 67, 1796–1799. 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(11) The Danheiser annulation, trimethylenemethane cycloaddition, and additions of 2(bromoisopropyl)acrylates were unsuccessful on these systems. (12) Determined by 1H NMR analysis following a protic quench. (13) Ballassoued, M.; Frangin, Y.; Gaudemar, M. A New, Convenient Synthesis of Cyclopentene Derivatives. Synthesis 1978, 150–152. (14) Yang and coworkers had previously carried out a successful anti-addition of a methyl cuprate reagent on an analogous cyclopropyl-flanked system (i→ii), see: Shi, L.; He, Y.; Gong, J.; Yang, Z. Concise Gram-Scale Synthesis of Euphorikanin A Skeleton Through A Domino Ring-Closing Metathesis Strategy. Chem. Commun. 2020, 56, 531–534. O O MeO2C H CuI, MeLi, HMPA then, allyl iodide MeO2C H Et2O, –78 ºC H i (15) 50% yield H anti H ii Lo, J. C.; Kim, D.; Pan, C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.; Qin, T.; Gutierrez, S.; Giacoboni, J.; Smith, M. W.; Holland, P. L.; Baran, P. S. Fe-Catalyzed C–C Bond Construction from Olefins via Radicals. J. Am. Chem. Soc. 2017, 139, 2484– 2503. Chapter 1 – Total Synthesis of Hypersampsone M (16) 46 Zhu, K.; Cao, M.; Zhao, G.; Zhao, J.; Li, P. Visible Light-Promoted Diazoacetates and Nitriles Generating Nitrilium Ions Trapped by Benzotriazoles and Carboxylic Acids. Org. Lett. 2022, 24, 5855–5859. (17) To date, we have been unable to unambiguously determine the stereochemistry at C4 and C5 for compounds 16 and 19, respectively. (18) Costello, G.; Saxton, J. E. Approaches to the Synthesis of Aspidosperma Alkaloids. Part I. Preliminary Studies in the Vincadifformine Group. Tetrahedron 1986, 42, 6047–6069. (19) Schleyer, P. v. R.; Funke, E.; Liggero, S. H. Homoadamantane. I. A new synthesis. Conformational evidence. Degenerate 4-homoadamantyl cation. J. Am. Chem. Soc. 1969, 91, 3965–3967. (20) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (21) Yamamura, S.; Toda, M.; Hirata, Y. Modified Clemmensen Reduction: Cholestane. Org. Synth. 1973, 53, 86. (22) Smith, B. R.; Njardarson, J. T. Double-Diels–Alder Approach to Maoecrystal V. Unexpected C–C Bond-Forming Fragmentations of the [2.2.2]-Bicyclic Core. Org. Lett. 2017, 19, 5316–5319. (23) Lo, J. C.; Kim, D.; Pan, C.-M.; Edwards, J. T.; Yabe, Y.; Gui, J.; Qin, T.; Gutierrez, S.; Giacoboni, J.; Smith, M. W.; Holland, P. L.; Baran, P. S. Fe-Catalyzed C–C Chapter 1 – Total Synthesis of Hypersampsone M 47 Bond Construction from Olefins via Radicals. J. Am. Chem. Soc. 2017, 139, 2484– 2503. (24) Siu, J. C.; Parry, J. B.; Lin, S. Aminoxyl-Catalyzed Electrochemical Diazidation of Alkenes Mediated by a Metastable Charge-Transfer Complex. J. Am. Chem. Soc. 2019, 141, 2825–2831. (25) Zhu, K.; Cao, M.; Zhao, G.; Zhao, J.; Li, P. Visible Light-Promoted Diazoacetates and Nitriles Generating Nitrilium Ions Trapped by Benzotriazoles and Carboxylic Acids. Org. Lett. 2022, 24, 5855–5859. (26) Reddy. R. E.; Kowalski, C. J. Ethyl 1-Naphthylacetate: Ester Homologation Via Ynolate Anions. Org. Synth. 1993, 71, 146. Appendix 1 – Synthetic Summary for Chapter 1 48 APPENDIX 1 Synthetic Summary for Chapter 1: Total Synthesis of Hypersampsone M Appendix 1 – Synthetic Summary for Chapter 1 49 Scheme A1.1 Total synthesis of hypersampsone M O O O OTBS Fe(acac)3, PhSiH3 OTBS Ethylene glycol/ DCE, 60 ºC 8 BrZn 12 OTBS 7 MeO2C O O pentane/CH2Cl2, 18 ºC O O SiMe3 OTBS OTBS H 16 SiMe3 NaH, prenyl bromide THF, 0 → 18 ºC H 89% yield single diastereomer 17 MeO2C O O 5 2. DMP, CH2Cl2, 18 ºC 79% over 2 steps single diastereomer H N2 4 N2 OTBS 1. TBAF, THF, 18 ºC O SiMe3 HO O Rh2(TFA)4 (1 mol %) MeO2C MeO2C 2. LDA, THF, –78 ºC O Me3Si 14 O O 15 O 88% over 2 steps single diastereomer 92% yield mixture of tautomers 13 1. Pd/C (10 wt %) H2, EtOAc, 18 ºC H 65% yield 6.3:1 d.r. OTBS 73% over 2 steps O MeO2C DME 0 → –40 → 80 ºC MeO2C 2. PhSeCl, py then, H2O2 (aq.) CH2Cl2, 0 ºC 48% yield 11 1. NaH, O=C(OMe)2 THF, reflux ≡ O MeO2C H O H H 18 19 HO MeO2C H TsOH•H2O H O O (-MeOH) 1. PhNH2•HCl AlMe3, PhMe 0 → 18 ºC H H CH2Cl2, 18 ºC 46% yield 30% recovered 19 O H 2. DMP, CH2Cl2 18 ºC O H 20, not isolated 21 70% over 2 steps 1 PhHN 2 O O O ≡ H PhHN 2 O O Me3OBF4 2,6-di-(t-Bu)py CH2Cl2, 18 ºC 1 H 22 O H H 23 O O O O LiTMP, BzCl H O H 2 THF, –78 → –35 ºC 20% yield 22% recovered 2 O H Ph 1 O 1 Ph N 67% yield O H 2 O H then EtOAc/HCl (-PhNH2) Appendix 2 – Spectra Relevant to Chapter 1 50 APPENDIX 2 Spectra Relevant to Chapter 1: Total Synthesis of Hypersampsone M 16 15 MeO MeO 14 26 OMe O O 13 12 11 9 8 7 6 ppm 5 4 3 2 Figure A2.1 1H NMR (400 MHz, C6D6) of compound 26. 10 1 0 -1 -2 -3 Appendix 2 – Spectra Relevant to Chapter 1 51 Appendix 2 – Spectra Relevant to Chapter 1 52 Figure A2.2 Infrared spectrum (Thin Film, NaCl) of compound 26. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.3 13C NMR (100 MHz, C6D6) of compound 26. 20 10 0 -10 10.5 MeO2C 10.0 O 7 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 ppm 5.0 4.5 4.0 3.5 Figure A2.4 1H NMR (500 MHz, CDCl3) of compound 7. 8.0 3.0 2.5 2.0 1.5 1.0 0.5 Appendix 2 – Spectra Relevant to Chapter 1 53 9.0 8.5 O 10 H MeO2C 8.0 H 7.5 7.0 6.5 5.5 5.0 4.5 4.0 ppm 3.5 3.0 2.5 2.0 1.5 Figure A2.5 1H NMR (400 MHz, C6D6) of compound 10. 6.0 1.0 0.5 0.0 -0.5 -1.0 Appendix 2 – Spectra Relevant to Chapter 1 54 Appendix 2 – Spectra Relevant to Chapter 1 55 Figure A2.6 Infrared spectrum (Thin Film, NaCl) of compound 10. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.7 13C NMR (100 MHz, C6D6) of compound 10. 20 10 0 -10 6.5 6.0 5.5 4.5 4.0 3.5 3.0 ppm 2.5 2.0 1.5 Figure A2.8 1COSY NMR (400 MHz, C6D6) of compound 10. 5.0 1.0 0.5 0.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 2 – Spectra Relevant to Chapter 1 56 ppm 10.5 10.0 9.5 9.0 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 ppm 4.0 3.5 3.0 2.5 2.0 1.5 Figure A2.9 HSQC NMR (400, 100 MHz, C6D6) of compound 10. 8.5 1.0 0.5 0.0 -0.5 -1.0 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 Appendix 2 – Spectra Relevant to Chapter 1 57 ppm 9.0 8.5 8.0 7.0 6.5 6.0 5.5 5.0 4.5 ppm 4.0 3.5 3.0 2.5 2.0 Figure A2.10 NOESY NMR (400 MHz, C6D6) of compound 10. 7.5 1.5 1.0 0.5 0.0 9 8 7 6 5 4 3 2 1 0 Appendix 2 – Spectra Relevant to Chapter 1 58 ppm 10.5 12 O 10.0 9.5 OTBS 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.11 1H NMR (400 MHz, C6D6) of compound 12. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 59 Appendix 2 – Spectra Relevant to Chapter 1 60 Figure A2.12 Infrared spectrum (Thin Film, NaCl) of compound 12. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A2.13 13C NMR (100 MHz, C6D6) of compound 12. 10 0 -10 MeO 10.5 O 10.0 28 OH 9.5 9.0 OTBS 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.14 1H NMR (400 MHz, CDCl3) of compound 28. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 61 Appendix 2 – Spectra Relevant to Chapter 1 62 Figure A2.15 Infrared spectrum (Thin Film, NaCl) of compound 28. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A2.16 13C NMR (100 MHz, CDCl3) of compound 28. 10 0 -10 10.5 MeO2C 10.0 13 O 9.5 9.0 OTBS 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.17 1H NMR (400 MHz, CDCl3) of compound 13. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 63 10.5 10.0 H MeO2C 14 9.5 O 9.0 8.5 OTBS 8.0 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.18 1H NMR (400 MHz, CDCl3) of compound 14. 7.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 64 Appendix 2 – Spectra Relevant to Chapter 1 65 Figure A2.19 Infrared spectrum (Thin Film, NaCl) of compound 14. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.20 13C NMR (100 MHz, CDCl3) of compound 14. 20 10 0 -10 10.5 O 10.0 29 H MeO2C 9.5 9.0 OTBS 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.21 1H NMR (400 MHz, C6D6) of compound 29. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 66 Appendix 2 – Spectra Relevant to Chapter 1 67 Figure A2.22 Infrared spectrum (Thin Film, NaCl) of compound 29. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.23 13C NMR (100 MHz, C6D6) of compound 29. 20 10 0 -10 10.5 H MeO2C O 10.0 16 HO 9.5 N2 O 9.0 OTBS SiMe3 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.24 1H NMR (400 MHz, C6D6) of compound 16. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 68 Appendix 2 – Spectra Relevant to Chapter 1 69 Figure A2.25 Infrared spectrum (Thin Film, NaCl) of compound 16. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.26 13C NMR (100 MHz, C6D6) of compound 16. 20 10 0 -10 10.5 H MeO2C 10.0 17 O O 9.5 O 9.0 OTBS 8.5 SiMe3 8.0 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.27 1H NMR (400 MHz, C6D6) of compound 17. 7.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 70 18 O 10.5 H MeO2C 10.0 O O 9.5 9.0 OTBS SiMe3 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.28 1H NMR (400 MHz, C6D6) of compound 18. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 71 Appendix 2 – Spectra Relevant to Chapter 1 72 Figure A2.29 Infrared spectrum (Thin Film, NaCl) of compound 18. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.30 13C NMR (100 MHz, C6D6) of compound 18. 20 10 0 -10 10.5 H MeO2C 10.0 30 O 9.5 9.0 OH 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.31 1H NMR (400 MHz, C6D6) of compound 30. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 73 Appendix 2 – Spectra Relevant to Chapter 1 74 Figure A2.32 Infrared spectrum (Thin Film, NaCl) of compound 30. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.33 13C NMR (100 MHz, C6D6) of compound 30. 20 10 0 -10 10.5 O 19 10.0 H MeO2C 9.5 9.0 O 8.5 8.0 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.34 1H NMR (400 MHz, C6D6) of compound 19. 7.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 75 Appendix 2 – Spectra Relevant to Chapter 1 76 Figure A2.35 Infrared spectrum (Thin Film, NaCl) of compound 19. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.36 13C NMR (100 MHz, C6D6) of compound 19. 20 10 0 -10 10.5 H O 10.0 21 O H O 9.5 H 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.37 1H NMR (400 MHz, C6D6) of compound 21. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 77 Appendix 2 – Spectra Relevant to Chapter 1 78 Figure A2.38 Infrared spectrum (Thin Film, NaCl) of compound 21. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.39 13C NMR (100 MHz, C6D6) of compound 21. 20 10 0 -10 10.5 10.0 MeO MeN H O H 9.5 25 O 9.0 O 8.5 8.0 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.40 1H NMR (400 MHz, C6D6) of compound 25. 7.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 79 Appendix 2 – Spectra Relevant to Chapter 1 80 Figure A2.41 Infrared spectrum (Thin Film, NaCl) of compound 25. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.42 13C NMR (100 MHz, C6D6) of compound 25. 20 10 0 -10 10.5 PhHN 31 O 10.0 H O 9.5 H 9.0 OH 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.43 1H NMR (400 MHz, C6D6) of compound 31. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 81 Appendix 2 – Spectra Relevant to Chapter 1 82 Figure A2.44 Infrared spectrum (Thin Film, NaCl) of compound 31. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.45 13C NMR (100 MHz, C6D6) of compound 31. 20 10 0 -10 10.5 PhHN 22 O 10.0 H O 9.5 H O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.46 1H NMR (400 MHz, C6D6) of compound 22. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 83 Appendix 2 – Spectra Relevant to Chapter 1 84 Figure A2.47 Infrared spectrum (Thin Film, NaCl) of compound 22. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.48 13C NMR (100 MHz, C6D6) of compound 22. 20 10 0 -10 10.5 2 O 10.0 H O 9.5 H O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.49 1H NMR (400 MHz, C6D6) of compound 2. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 85 Appendix 2 – Spectra Relevant to Chapter 1 86 Figure A2.50 Infrared spectrum (Thin Film, NaCl) of compound 2. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.51 13C NMR (100 MHz, C6D6) of compound 2. 20 10 0 -10 10.5 O 1 10.0 H O 9.5 Ph O O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A2.52 1H NMR (400 MHz, CDCl3) of compound 1. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 2 – Spectra Relevant to Chapter 1 87 Appendix 2 – Spectra Relevant to Chapter 1 88 Figure A2.53 Infrared spectrum (Thin Film, NaCl) of compound 1. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A2.54 13C NMR (100 MHz, CDCl3) of compound 1. 20 10 0 -10 Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 89 CHAPTER 2 Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G † 2.1 INTRODUCTION The polycyclic polyprenylated acylphloroglucinols (PPAPs) are a vast and diverse class of natural products comprised of over 400 members.1 The notable bioactivity and range of fundamentally different structures have fueled the attention PPAPs have received, both in synthetic chemistry and chemical biology communities. The sheer number and complexity of these natural products necessitates a further subdivision—namely into the bicyclic polyprenylated acylphloroglucinols (BPAPs), the adamantane and homoadamantane PPAPs, and the spirocyclic or otherwise rearranged PPAPs (Figure 2.1.1).1e While the BPAPs, homoadamantane, and rearranged PPAPs have all received significant attention in the context of total synthesis, a homoadamantane PPAP (hypersampsone M, 1, Figure 1.1.1) was only recently synthesized by our lab in 2024.2,3 During our studies of the homoadamantane PPAPs we became interested in hypersonin A (32), isolated from Hypericum wilsonii in 2020 alongside three other closely related natural products (33–35).4 Hypersonin A displays moderate immunosuppressive bioactivity in preliminary murine studies (IC50 = 8.3 µM), but we found the most striking feature to be its 5-7-6 tricyclic core: a rare example of a seco-homoadamantane PPAP. †This research was conducted in collaboration with Kasem Poonswat. Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 90 Indeed, of over 70 homoadamantane PPAPs isolated to date,1e,5 the hypersonins are the only compounds featuring a disconnection between the C1 and C2 positions. Interestingly, the cyclized, homoadamantane version of hypersonin A, wilsonglucinol G (36), is also a natural product isolated from the same flowering plant Hypericum wilsonii in 2019.6 Figure 2.1.1. Hypersonin A, wilsonglucinol G and representative PPAP classes. O OH R O R R O O O R R R R O O O R R R H R R O OH O R O O R R H O R R HO BPAPs Adamantane PPAPs >250 compounds >20 syntheses >40 compounds 3 syntheses 2 MeO2C O 1 O Adamantane PPAPs >75 compounds >5 syntheses >70 compounds no syntheses 2 OH HO Homoadamantane PPAPs MeO2C O R1 OH HO 1 O O HO O R2 H H Hypersonin A (32) H H Hypersonin B (33), R1 = prenyl, R2 = i-Bu Hypersonin C (34), R1 = geranyl, R2 = i-Pr Hypersonin D (35), keto tautamer of 33 O O 2 1 H Wilsonglucinol G (36) Furthermore, both compounds are implicated to have similar immunosuppressive bioactivity (albeit the IC50 is > 40 µM for 36), and the hypersonins are isolated via methanol chromatography. These points seemed coincidental and led us to hypothesize that the hypersonins are potentially isolation artifacts arising during extraction or chromatography of the wilsonglucinols. The hypersonins are significantly more potent immunosuppressants than their ring-closed counterparts, likely due to increased conformational flexibility and enhanced polar interactions at the biological target. This suggests that subtle structural changes in the PPAP scaffold can have a profound impact on bioactivity. Hoping to showcase the applicability of our previous 15-step route, Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 91 potentially address this isolation puzzle, and shed light on the biochemistry of this class of PPAPs we set out to synthesize wilsonglucinol G, hoping to access hypersonin A (32) via subsequent ring opening. 2.2 RETROSYNTHETIC ANALYSIS The retrosynthetic strategy for wilsonglucinol G (36, Scheme 2.2.1) is analogous to that of hypersampsone M (1). Wilsonglucinol G (36) features an exocyclic 3° alcohol on the 5-membered ring. To avoid elimination of this alcohol throughout the synthesis, this alcohol will be masked as an isopropenyl group. A late-stage bridgehead acylation and olefin hydration follows cyclization of amide 37 after amidation of lactone 38. Lactone 38 will be formed through prenylation and cyclization of aldehyde 39, which can arise from ring-expansion of cyclohexanone 40. The key challenge in this synthesis will be installation of the exocyclic functionality on this 5-membered ring, which ultimately should be accessible from enone 41. Scheme 2.2.1. Retrosynthetic strategy toward wilsonglucinol G. O O O HO acylation/ cyclization 2 PhHNOC O O H H 2 MeO2C O O 4 ring expansion 39 H 2 O H 1 38 MeO2C O cyclopentane annulation 1 H H O H H 37 36 O 4 1 O prenylation/ lactonization lactone opening 4 H 40 O MeO2C R R 41 Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 2.3 DEVELOPMENT OF A 3-COMPONENT 92 CYCLOPENTENE ANNULATION Significant efforts were made to install functionality that could later be advanced to the requisite, exocyclic 3° alcohol. Disappointingly, installation of any functionality following construction of the cyclopentene (14®42, Scheme 2.3.1A) proved difficult. These attempts, as well as other unsuccessful cyclopentane installation attempts are discussed in more detail in Appendix 5. The conclusion we made in those efforts was that installation of functionality at the C16 position needs to occur during the construction of the cyclopentene. Scheme 2.3.1. Toward a functionalized cyclopentene annulation. A) Unsuccessful attempts to functionalize cyclopentene 14. MeO2C O MeO2C 16 R OTBS O 16 OTBS H H 42 14 B) Potential intercepted vinyl zinc functionalization. [Zn] O O 8 O O BrZn MeO MeO MeO2C Δ O 44 O R [Zn] 43 MeO2C R–X 45 46 To this end we revisited the cyclopentene annulation developed by Bellassoued and coworkers,7 and that we previously used in the synthesis of hypersampsone M.2 Mechanistically, addition of propargyl zinc 8 (Scheme 2.3.1B) to enone 43 results in zinc enolate 44. Heating of this enolate results in cyclization resulting in the olefin product, presumably via vinyl zinc intermediate 45. We hypothesized that interception of this vinyl zinc moiety, for example with an electrophile, could lead to a functionalized product (46). Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 93 Investigations commenced into the tandem annulation using ketoester 47 as a model (Table 2.3.1). Propargyl zinc bromide 8 underwent clean 1,4-addition to ketoester 47 (determined via complete consumption of starting material), and further heating of the solution resulted in partial conversion to vinyl zinc intermediate 48, identified by a protic quench (entry 1). Direct addition into electrophiles (e.g., acetone, entry 2) was unsuccessful due to the low reactivity of vinyl zinc 48. Instead, coupling with AcCl was explored, resulting in desired hydrazulene 49 (E = Ac, entries 3,4). Several solvents were next evaluated, and it was found that 1,2-dimethoxyethane (DME) improves the thermal cyclization significantly, although the subsequent acetylation still proceeds in low yield (entry 5). After further investigation, it was discovered that excess AcCl slowly decomposes vinyl zinc 48 and changing the order of addition (i.e. adding 48 dropwise into Pd(PPh3)4/AcCl, entry 6) led to greatly improved yield (65%). Table 2.3.1. Optimization of the intercepted cyclopentene annulation. 8 O MeO2C BrZn MeO2C O MeO2C conditions then, Δ [Zn] 47 O E 48 49 entry conditions E yield XXa,b 1 THF/H+/H2O H 44% 2 THF/acetone 3 Pd(PPh3)4 (5 mol%) THF/AcCl Ac 15% 4 CuBr (1 equiv) THF/AcCl Ac 11% 5 Pd(PPh3)4 (5 mol%) DME/AcCl Ac 27% 6 Pd(PPh3)4 (5 mol%) DME/AcCl inverse addition Ac 65% OH a yield determined by 1H NMR; b yields represent a 6:1 ratio of cis to trans fused hydrazulenes. 0% Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 94 This reaction stands as an enabling step on route to wilsonglucinol G (36). It forges three C–C bonds (all of which are neopentylic) and forms two stereocenters and a tetrasubstituted center. Further discussion of this reaction is presented in Chapter 5. With these promising results on model substrate 47, we turned our attention to the substituted cyclohexenone on route to wilsonglucinol G. 2.4 CURRENT PROGRESS TOWARD WILSONGLUCINOL G Enone 13 was previously synthesized via acylation and desaturation of cyclohexanone 12, which itself was accessible through an Fe-mediated HAT coupling from cyclohexenone (11, see Scheme 1.4.1). Though concise, this route suffers from poor material throughput due to the low yield and difficult isolation of the HAT coupling. To address this, a longer, more scalable route was developed. Scheme 2.4.1. Scalable preparation of ketone 12. 50 MeO OMe Me3Si O 1. TiCl4, Ch2Cl2, –78 ºC 2. HCl (aq.), THF 3. TBSCl, imidazole CH2Cl2 2. (OMe)3CH, p-TsOH MeOH, 65 ºC 11 1. BH3•DMS, THF then NAOH, H2O2 51 75% over 5 steps >125 g scale O O 1. NaH, O=C(OMe)2 THF, reflux OTBS 12 MeO2C 2. PhSeCl, py then H2O2 CH2Cl2, 0 ºC 73% over 2 steps OTBS 13 Starting again from cyclohexenone (11, Scheme 2.4.1), a Sakurai allylation with prenyl silane 50 followed by protection of the ketone afforded acetal 51. Hydroboration/oxidation, ketone deprotection, and TBS protection of the alcohol afforded Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 95 cyclohexanone 12 in 75% over 5 steps with no intermediate chromatography. This route allowed for >125 g of ketone 12 to be prepared in a single pass. With a scalable route to 13 secured we proceeded on to the intercepted cyclopentene annulation. Starting with the optimized conditions from Table 2.3.1 (entry 6), using Pd(PPh3)4, unfortunately resulted in irreproducible yields and very difficult purification sequences. Further optimization led to the conclusion that using stoichiometric Cu led to simpler reaction protocols avoiding dropwise additions and producing reproducible yields. This enabled the synthesis of hydroindene 52 in up to 45% isolated yield (Scheme 2.4.2A). Scheme 2.4.2. Installing the hydroindene core. A) Intercepted cyclopentene annulation of enone 13. 8 O MeO2C BrZn TBSO MeO2C DME, –40 ºC, 2 h then, 80 ºC, 3 h then, 0 ºC, CuBr, 40 min then, AcCl, 25 min TBSO O O H 44% yield 52 MeO2C 53 2 OTBS OTBS Crabtree’s catalyst (55), (15 mol %) H2/N2 (balloon) CH2Cl2, 18 ºC, 17 min H 54 OH + O O TBSO H 52 1:1 CH2Cl2/MeOH 0 °C, 2 h H O 16 B) Successful enone reduction setting the C16 stereocenter. O OH MeO2C MeO2C TBSO KBH4 (9 equiv) 16 MeO2C H2, [M] 3 O 45% isolated yield 11:1 d.r. at C3 13 O H O OTBS CO2Me H H H 56 90% yield 57 trace PCy3 Ir N PF6- Crabtree’s Catalyst (55) Our efforts to set the C16 stereocenter via hydrogenation of 52 unfortunately did not provide the desired diketone 53. Instead, NOE experiments pointed to a structure tentatively assigned as the incorrect C16 epimer (not shown). Efforts to epimerize this site Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 96 were not fruitful, and eventual DFT calculations indicated that the desired epimer 53 is neither the kinetic, nor the thermodynamic product, forcing us to adjust our strategy. Attempting to execute a directed hydrogenation, a thorough screen of ketone reductions allowed isolation of ketoalcohol 54 (Scheme 2.4.2B) in 44% yield using KBH4. As the newly installed 2° alcohol was positioned inside the concave portion of the bowllike structure of 54, we were confident that a directed hydrogenation would provide the correct stereochemistry at C16. Gratifyingly, reduction with 15 mol % Crabtree’s catalyst (55) under rigorously anhydrous conditions in a carefully controlled H2/N2 atmosphere allowed for an excellent 90% yield of the desired enone reduction product 56. This reaction is unfortunately very sensitive to setup and execution. Scheme 2.4.3. Synthetic sequence advancing ketone 56 to lactone 38. OH MeO2C O MeO2C OTBS 1. H2C=PPh3 THF, 18 ºC, 1 h O O OTBS 2. DMP, NaHCO3 H 67% over 2 steps 56 MeO2C O N2 15 SiMe3 O 1. LDA, THF, –78 ºC H 2. Rh2(TFA)4 (1 mol %) pentane/CH2Cl2, 18 ºC 58 86% over 2 steps O O SiMe3 OTBS MeO2C NaH, prenyl bromide O SiMe3 O THF, 0 → 18 ºC H OTBS 98% yield H 60 59 MeO2C O O 1. TBAF, THF, 18 ºC O 2. DMP, CH2Cl2, 18 ºC 82% over 2 steps O H 61 TsOH•H2O O H H CH2Cl2, 18 ºC 42% yield O H 38 Ketone 56 is unstable and will epimerize during the reaction resulting in a hemiacetal (not shown) as the 2° alcohol engages the nearby ketone. The hemiacetal can be further reduced to side-product 57 with liberation of water. The extra water causes decomposition of Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 97 Crabtree’s catalyst and further epimerization of ketone 56, a situation that must be carefully avoided. Thus, wet solvent, performing the reaction for even a few minutes too long or too short (unreacted 54 is not separable from 56), and high H2 concentrations (cutting the H2 with N2 results in a slower and more controllable reaction rate) are deleterious, resulting in almost exclusive formation of ether 57. With ketoalcohol 56 in hand, we proceeded to olefinate the exocyclic ketone using salt-free Wittig conditions and oxidized the 2° alcohol to afford ketone 58 (Scheme 2.4.3). Ketone 58 is analogous to ketone 29 en route to hypersampsone M (1) and was advanced in a similar fashion. Addition of diazoacetate 15 followed by Rh-catalyzed ring-expansion resulted in b-ketoester 59, isolated as a mixture of tautomers. Then, prenylation (60), deprotection, and oxidation resulted in desired aldehyde 61. As with hypersampsone M (1), aldol/lactonization with TsOH resulted in caged lactone 38 in moderate yield. Scheme 2.4.4. Proposed completion of wilsonglucinol G (36) and hypersonin A (32). O O H 1. PhNH2•HCl, AlMe3 2. DMP, CH2Cl2 H 77% over 2 steps O H PhHNOC H 38 1. cyclization 2. acylation 3. olefin hydration O O 2 1 H Wilsonglucinol G (36) O 37 H 2 O O HO O MeO2C MeOH O OH HO 1 H O H Hypersonin A (32) Currently, we have been successful in advancing lactone 38 to amide 37 (Scheme 2.4.4). From amide 37, we anticipate cyclization with Me-Meerwine salt, bridgehead Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 98 acylation, and olefin hydration directly providing wilsonglucinol G (36) and hypersonin A (32). 2.5 CONCLUSION To conclude, we have developed an enabling 3-component cyclopentene annulation that incorporates two stereocenters and forms three C–C bonds in a single step. Additionally, a late-stage intermediate (37) just three steps away from wilsonglucinol G has been accessed. Current efforts are focused on completion of wilsonglucinol G, with the anticipation that the retro-Claisen ring-opening to hypersonin A will provide invaluable insight into the biosynthesis of this class of PPAPs. 2.6 EXPERIMENTAL SECTION 2.6.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.8 Cyclohexenone was distilled prior to use. Pyridine and 2,2,6,6-Tetramethylpiperidine were distilled from CaH2 prior to use. Freshly purchased TsOH•H2O was stored in a desiccator and dried under high vacuum for several hours prior to use. Activated zinc dust was prepared according to a previously reported procedure.9 3-bromo-3-methylbut-1-yne was prepared according to a previously reported procedure.10 All other reagents were purchased from commercial sources and used as received unless otherwise stated. Reaction progress was monitored by thin-layer chromatography (TLC), or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, CAM stain, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 99 (particle size 40–63 µm) was used for flash chromatography. Teledyne ISCO CombiFlashRf+, Teledyne ISCO CombiFlashRf+ LumenTM, or Teledyne ISCO CombiFlashRf NEXTGEN+ systems were used for automated flash chromatography using Luknova SuperSepTM silica columns or RediSepRf GOLD C18 columns. Agilent 1100 or 1200 preparatory HPLC systems were used for high-performance reverse phase separations. 1H NMR spectra were recorded on Varian Inova 500 MHz and Bruker 400 MHz spectrometers and are reported relative to residual non-deuterated solvent CHCl3 (δ 7.26 ppm) or C6H6 (δ 7.16 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometers (100 MHz) and are reported relative to residual non-deuterated solvent CHCl3 (δ 77.16 ppm) or C6H6 (δ 128.06). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Diastereomeric ratios were calculated based on ratios of integrals from crude 1H NMR spectra. Some spectra contain minor solvent impurities of water, ethyl acetate, dichloromethane, diethyl ether, acetone, grease, and/or silicone grease, which do not impact product assignments. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm pathlength cell. High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-T2000GC AccuTOFTM GC-Alpha High Resolution Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 100 Mass Spectrometer in field ionization (FI+) or field desorption (FD+) mode, or an Agilent 6230 Series TOF with and Agilent Jet Stream ion source in electrospray ionization (ESI+). 2.6.2 EXPERIMENTAL PROCEDURES 8 BrZn O MeO2C DME, –40 ºC then, 80 ºC MeO2C O H 47 62 methyl 1,1-dimethyl-4-oxo-4,5,6,7,8,8a-hexahydroazulene-3a(1H)-carboxylate 62. A 4 mL vial was charged with Zn (65 mg, 1.0 mmol, 5 equiv) and DME (1 mL) and cooled to –15 °C. 3-bromo-3-methylbut-1-yne (147 mg, 1.0 mmol, 5 equiv) was added in one portion. After 1 h, a solution of enone 47 (prepared according to a previously reported procedure11)(33 mg, 0.2 mmol, 1.0 equiv) was added dropwise and the solution was stirred at –15 °C. After 2 days, the mixture was filtered into a fresh vial and heated to 65 °C without stirring. After 3 days, the solution was cooled to 20 °C, then quenched with saturated aqueous NH4Cl, and extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (10–20% EtOAc/hexanes) to furnish ketone 62 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 5.73 (d, J = 5.6 Hz, 1H), 5.51 (d, J = 5.6 Hz, 1H), 3.75 (s, 3H), 2.82 (dd, J = 13.4, 3.3 Hz, 1H), 2.53 (ddd, J = 13.7, 9.3, 4.3 Hz, 1H), 2.44 – 2.32 (m, 1H), 1.92 – 1.73 (m, 3H), 1.56 (s, 3H), 1.14 (s, 3H), 0.90 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ = 208.4, 173.0, 145.9, 125.3, 77.2, 53.0, 50.0, 49.2, 41.4, 30.0, 26.9, 26.3, 24.6, 24.3; IR (Neat Film, NaCl) 2949, 1742, 1706, 1454, 1241, 1225, 799 cm–1; HRMS (EI+): m/z calc’d for C14H20O3 [M]+: 236.1407, found 236.1411. Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 101 50 O Me3Si TiCl4, Ch2Cl2, –78 ºC 11 O 64 3-(2-methylbut-3-en-2-yl)cyclohexan-1-one 64. To a dry 5 L flask under N2 was added CH2Cl2 (2.23 L) and cyclohexenone (11) (42.8 g, 0.445 mol, 1.0 equiv). The reaction flask was cooled to –78 °C in a dry ice/acetone bath and prenyltrimethylsilane 50 (prepared according to a previously reported procedure12)(76 g, 0.534 mol, 1.2 equiv) was added in one portion. TiCl4 (92.9 g, 0.490 mol, 1.1 equiv) was then added slowly over 15 min, resulting in a deep-red solution. After an additional 15 min, H2O (250 mL) was slowly added, and the flask was removed from the cold bath. Additional H2O (1.5 L) was added, and the flask was allowed to warm to 23 °C. The organic layer was separated, and the aqueous layer was further extracted with CH2Cl2 (300 mL x 2). The combined organic layers were concentrated under reduced pressure to a volume of 1.5 L, washed with brine, dried with Na2SO4, and then further concentrated under reduced pressure to yield 64 as yellow oil (97 g). The crude oil was used directly in the next step, but an analytical sample was obtained via basic alumina chromatography (CH2Cl2). 1H NMR (400 MHz, C6D6) δ = 5.49 (ddt, J = 17.4, 10.8, 1.7 Hz, 1H), 4.90 (dt, J = 10.8, 1.3 Hz, 1H), 4.80 (dt, J = 17.4, 1.4 Hz, 1H), 2.42 – 2.31 (m, 1H), 2.21 (dddt, J = 13.9, 3.4, 2.3, 1.3 Hz, 1H), 1.78 – 1.68 (m, 1H), 1.64 (tt, J = 13.5, 1.2 Hz, 1H), 1.55 (dddd, J = 10.7, 9.7, 5.1, 2.3 Hz, 1H), 1.47 (dtd, J = 11.1, 3.5, 1.6 Hz, 1H), 1.22 – 1.06 (m, 2H), 0.84 – 0.76 (m, 1H), 0.74 (s, 6H); 13C{1H} NMR (101 MHz, C6D6) δ = 209.23, 146.58, 111.85, 48.12, 43.53, 41.25, 38.91, 26.23, 25.49, 24.16, 23.74; IR (Neat Film, NaCl) 2964, 2865, 1713, Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 102 1229, 1004, 912, 682 cm–1; HRMS (FI+): m/z calc’d for C11H18O [M]+: 166.1358 found, 166.1363. O MeO OMe (OMe)3CH, p-TsOH MeOH, 65 ºC 64 51 1,1-dimethoxy-3-(2-methylbut-3-en-2-yl)cyclohexane 51. To a 1 L flask under N2 was added ketone 64 (97 g), MeOH (450 mL), p-TsOH•H2O (1.7 g, 8.9 mmol, 0.02 equiv), and CH(OMe)3 (94 g, 0.89 mol, 2 equiv). The flask was heated in an Al heating block at 75 °C until complete conversion was observed by TLC (usually 2 h). The reaction was allowed to cool to 23 °C and NaOMe was added until a litmus test returned an alkaline result. The solution was concentrated under reduced pressure and the residue was dissolved in hexanes and filtered to remove salts. The hexanes solution was concentrated to yield 51 as a colorless oil. The crude oil was used directly in the next step, but an analytical sample was obtained via silica gel chromatography. 1H NMR (400 MHz, C6D6) δ = 5.72 (dd, J = 17.5, 10.8 Hz, 1H), 4.95 (dd, J = 10.9, 1.5 Hz, 1H), 4.91 (dd, J = 17.5, 1.5 Hz, 1H), 3.13 (s, 3H), 3.04 (s, 3H), 2.16 (dq, J = 13.1, 2.8 Hz, 1H), 2.05 – 1.98 (m, 1H), 1.64 (ddd, J = 12.5, 4.4, 2.3 Hz, 1H), 1.58 – 1.51 (m, 1H), 1.46 (dt, J = 13.5, 3.9 Hz, 1H), 1.39 (dt, J = 12.5, 3.2 Hz, 1H), 1.14 (td, J = 13.2, 4.9 Hz, 1H), 1.04 (t, J = 12.9 Hz, 1H), 0.91 (s, 3H), 0.90 (s, 3H), 0.78 (qd, J = 12.5, 4.4 Hz, 1H); 13C{1H} NMR (101 MHz, C6D6) δ = 147.91, 111.15, 101.06, 47.22, 47.09, 43.66, 38.79, 34.37, 33.15, 27.01, 24.57, 23.86, 23.01; IR (Neat Film, NaCl) 2948, 2867, 1458, 1365, 1139, 1089, 1054, 910, 843 cm–1; HRMS (FI+): m/z calc’d for C13H24O2 [M]+: 212.1776 found, 212.1777. Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G MeO OMe BH3•DMS, THF then NaOH, H2O2 103 MeO OMe OH 51 65 3-(3,3-dimethoxycyclohexyl)-3-methylbutan-1-ol 65. To a 12 L flask equipped with an overhead stirrer and under N2 was added olefin 51 and THF (3 L). The solution was cooled to 0 °C and BH3•SMe2 (135 g, 1.78 mol, 4 equiv) was added slowly. The solution was then warmed to 23 °C and stirred for 4 h. After cooling to 0 °C, aqueous 3M NaOH (770 mL) was added slowly (Warning – violent H2 evolution!) followed by 30% H2O2 (770 mL). The solution was allowed to warm to 23 °C overnight and hexanes (2 L) and H2O (2L) was added. The combined organic/aqueous mixture is filtered through a coarse filter to remove solids. The organic layer was separated, and the aqueous layer was stirred with ether (1 L) overnight. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure to yield 65 as colorless oil. The crude oil was used directly in the next step, but an analytical sample was obtained via silica gel chromatography. 1H NMR (400 MHz, C6D6) δ = 3.53 – 3.41 (m, 2H), 3.13 (s, 3H), 3.04 (s, 3H), 2.12 (dq, J = 13.0, 2.7 Hz, 1H), 2.06 – 1.98 (m, 1H), 1.63 – 1.50 (m, 2H), 1.49 – 1.31 (m, 4H), 1.15 (td, J = 13.3, 4.6 Hz, 1H), 1.03 (t, J = 12.9 Hz, 1H), 0.79 – 0.74 (m, 1H), 0.76 (s, 3H), 0.76 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 101.12, 59.33, 47.22, 47.14, 43.07, 34.07, 33.92, 33.08, 26.58, 25.17, 25.04, 23.03; IR (Neat Film, NaCl) 3408, 2947, 1469, 1367, 1089, 1049, 923 cm–1; HRMS (ESI+): m/z calc’d for C13H26O3K [M+K]+: 269.1514, found 269.1516. Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 104 O MeO OMe HCl (aq), THF OH 65 OH 66 3-(4-hydroxy-2-methylbutan-2-yl)cyclohexan-1-one 66. To a 2 L flask was added alcohol 65 and THF (1 L). 1M aq. HCl (112 mL) was added, and the solution was stirred at 23 °C for 2 h. The THF was removed under reduced pressure and the residue was extracted with CH2Cl2 (200 mL x 3). The combined organic extracts were washed with brine, dried with Na2SO4, and concentrated under reduced pressure to yield 66 as colorless oil. The crude oil was used directly in the next step, but an analytical sample was obtained via silica gel chromatography. 1H NMR (400 MHz, C6D6) δ = 3.44 (t, J = 7.9 Hz, 2H), 2.36 (ddt, J = 13.4, 3.7, 2.2 Hz, 1H), 2.22 (ddq, J = 14.0, 4.2, 2.0 Hz, 1H), 1.76 (tdd, J = 13.9, 6.5, 1.0 Hz, 1H), 1.67 (td, J = 13.4, 1.0 Hz, 2H), 1.61 – 1.52 (m, 1H), 1.51 – 1.43 (m, 1H), 1.40 – 1.29 (m, 2H), 1.29 – 1.21 (m, 1H), 1.21 – 1.08 (m, 1H), 0.87 – 0.77 (m, 1H), 0.65 (s, 3H), 0.63 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 210.45, 58.98, 47.66, 43.21, 42.64, 41.29, 34.38, 25.79, 25.63, 24.73, 24.69; IR (Neat Film, NaCl) 3428, 2958, 2868, 1708, 1448, 1267, 1233, 1041, 1029 cm–1; HRMS (FI+): m/z calc’d for C11H20O2 [M]+: 184.1463, found 184.1466. Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G O TBSCl, imidazole CH2Cl2 O OH 66 105 OTBS 12 3-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)cyclohexan-1-one 12. To a 1 L flask under N2 was added ketone 66, CH2Cl2 (760 mL), and imidazole (75.6 g, 1.11 mol, 2.4 equiv). The solution was cooled to 0 °C and TBSCl (84 g, 0.556 mol, 1.25 equiv) was added in one portion. The solution was allowed to warm to 23 °C and stirred at this temperature for 3 h. H2O (800 mL) was added, and the organic layer was separated. The aqueous layer was further extracted with CH2Cl2 (200 mL), and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure to yield 12 as colorless oil (125 g). This material is sufficiently pure for the next step, having only various silyl impurities. The purity was determined to be 54–57% by weight using 1H NMR and 1,3,5-trimethoxybenzene as an internal standard. A small sample was further purified via silica gel chromatography to obtain an analytical sample. Characterization data were consistent with previously reported data (see Chapter 1). Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 106 8 O MeO2C BrZn TBSO then, 0 ºC, CuBr then, AcCl 13 methyl MeO2C DME, –40 ºC then, 80 ºC O O TBSO H 52 2-acetyl-6-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-1,1- dimethyl-4-oxo-1,4,5,6,7,7a-hexahydro-3aH-indene-3a-carboxylate 52. To a dry 500 mL flask under N2 was added activated Zn dust (4.6 g, 70.5 mmol, 2.5 equiv) and DME (140 mL). The mixture was cooled to 0 °C and 3-bromo-3-methylbut-1-yne (10.36 g, 70.5 mmol, 2.5 equiv) was added in one portion. After 1.5 h most of the Zn has dissolved and the mixture was cooled to –40 °C at which point enone 13 (10 g, 28.2 mmol, 1.0 equiv) in DME (140 mL) was added dropwise over 15 min. The cloudy solution was then gradually allowed to warm to –15 °C and stirred at that temperature for 16 h. The reaction was then allowed to warm to 23 °C and filtered into a fresh 500 mL flask via a glass fritted cannula filter to yield a perfectly homogeneous, yellow solution. The solution was then heated to 80 °C for 4 h and cooled to 0 °C, followed by addition of CuBr (17.9 g, 70.5 mmol, 2.5 equiv). The mixture was stirred at 0 °C for 1.5 h, and AcCl (5.53 g. 70.5 mmol, 2.5 equiv) was added slowly. The reaction flask was rapidly warmed in a 23 °C water bath and stirred at this temperature for 30 min before being cooled to 0 °C and quenched with saturated, aqueous NH4Cl. The mixture was extracted with EtOAc (75 mL x 3) and the combined organic extracts were washed with brine, dried with Na2SO4, and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→15% EtOAc/hexanes) to furnish 52 as a colorless oil (3.9 g, 30% yield). 1H NMR (400 MHz, CDCl3) δ = 6.77 (s, 1H), 3.79 (s, 3H), 3.65 (t, J = 7.4 Hz, 2H), 2.87 (t, J = 4.2 Hz, 1H), 2.41 – 2.38 (m, 1fH), 2.34 – 2.33f (m, Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 107 4H), 1.97 – 1.84 (m, 3H), 1.61 – 1.43 (m, 3H), 1.38 (s, 3H), 1.04 (s, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.88 (s, 9H), 0.05 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ = 208.53, 196.41, 170.07, 152.69, 140.07, 59.70, 53.88, 53.31, 49.07, 45.71, 41.94, 35.19, 32.91, 28.09, 26.71, 25.99, 24.90, 24.53, 24.39, 23.69, 21.78, 18.34, -5.26; IR (Neat Film, NaCl) 2954, 2857, 1743, 1713, 1677, 1364, 1252, 1223, 1090, 837, 778 cm–1; HRMS (ESI+): m/z calc’d for C26H45O5Si [M+H]+: 465.3031, found 465.3027. MeO2C O MeO2C TBSO OH OTBS KBH4 (9 equiv) O CH2Cl2/ MeOH, 0 °C H 52 methyl O H 54 2-acetyl-6-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-4-hydroxy- 1,1-dimethyl-1,4,5,6,7,7a-hexahydro-3aH-indene-3a-carboxylate 54. To a dry 100 mL flask under N2 was added CH2Cl2 (19 mL), MeOH (23 mL), and KBH4 (523 mg, 9.7 mmol, 12 equiv). The solution was cooled to 0 °C, and a solution of enone 52 (500 mg, 75% purity, 0.81 mmol, 1.0 equiv) in CH2Cl2 (5 mL) was added over 5 min. The solution was stirred at 0 °C for 2.5 h before adding saturated aqueous NH4Cl (10 mL) followed by H2O (50 mL). The mixture was stirred for an hour to ensure complete deborylation and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (30 mL x 2), and the combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→30% EtOAc/hexanes) to furnish 54 as a colorless oil (164 mg, 44%) that solidified into a waxy solid. 1H NMR (400 MHz, CDCl3) δ = 6.65 (s, 1H), 4.31 (dt, J = 6.4, 3.4 Hz, 1H), 3.74 (s, 3H), 3.65 (t, J = 7.5 Hz, 2H), 2.50 Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 108 (dd, J = 7.4, 1.4 Hz, 1H), 2.34 (s, 3H), 1.71 – 1.55 (m, 5H), 1.53 – 1.45 (m, 4H), 1.28 (s, 3H), 1.20 (s, 3H), 0.88 (s, 9H), 0.87 (s, 3H), 0.84 (s, 3H), 0.04 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ = 196.79, 175.41, 154.12, 141.42, 69.91, 62.08, 60.11, 52.67, 49.78, 48.99, 42.37, 35.24, 34.65, 30.03, 29.45, 28.46, 26.16, 24.81, 24.39, 22.11, 21.56, 18.52, -5.06, 5.07; IR (Neat Film, NaCl) 3466, 2952, 2858, 1732, 1673, 1366, 1248, 1228, 1084, 835, 773 cm–1; HRMS (ESI+): m/z calc’d for C26H47O5Si [M+H]+: 467.3187, found 467.3195. MeO2C O OH OTBS Crabtrees catalyst (55) (15 mol %) H2/N2 (balloon) CH2Cl2, 18 ºC, 17 min H 54 MeO2C OH OTBS O + H O H OTBS CO2Me H H 56 57 Ketoalcohol 56 and ether 57. To a dry 500 mL flask was added a large football-shaped stir bar, alcohol 54 (1.13 g, 2.4 mmol, 1.0 equiv), and Crabtree’s catalyst (55) (480 mg, 0.6 mmol, 0.25 equiv) in a N2 glovebox. The flask was sealed with a white, silicone septum and the joint wrapped in electrical tape. The flask was removed from the glovebox (do not connect to Schlenk line or inert gas balloon), CH2Cl2 (96 mL) was added, and the stirring adjusted to 500 rpm. Two concentric balloons fitted with a 1.5 in x 21G needle are filled with H2 and inserted into the septum, resulting in a pressure release from the flask into the balloons. A 60 mL syringe fitted with a 26G needle was used to remove 240 mL of headspace from inside the flask.a The reaction was left to stir at 23 °C for 19 min during which time the bright orange color fades to a yellow or colorless, followed by the return of a muted brown orange. After this time the solution is concentrated under reduced pressure as quickly as possible, and the crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 109 0→35% EtOAc/hexanes) to separate 57 (54 mg, 5% yield) from 56b (990 mg, 88% yield) as a colorless oil.c Notes: aA headspace of pure H2 was found to decompose Crabtree’s catalyst rapidly, resulting in excessive formation of 57. b56 is not stable in long term storage, especially neat. The material should be used right away or stored as a frozen solution in benzene. cThe reaction is highly reproducible when run in this fashion, however, small changes in reaction time, water contamination, and H2/N2 ratio can either lead to incomplete conversion or loss in yield due to decomposition to ether 57. Characterization data for ketoalcohol 56: 1H NMR (400 MHz, C6D6) δ = 4.15 (dd, J = 6.9, 3.4 Hz, 1H), 3.77 – 3.69 (m, 2H), 3.34 (s, 3H), 2.91 – 2.74 (m, 2H), 2.55 (t, J = 5.0 Hz, 1H), 2.16 (dd, J = 12.3, 6.0 Hz, 1H), 1.80 (s, 3H), 1.70 – 1.62 (m, 1H), 1.63 – 1.54 (m, 2H), 1.52 – 1.41 (m, 3H), 1.38 – 1.31 (m, 1H), 1.18 (s, 3H), 1.02 – 1.00 (m, 1H), 1.01 (s, 9H), 0.90 (s, 3H), 0.86 (s, 3H), 0.83 (s, 3H), 0.12 (s, 6H); 13C{1H} NMR (101 MHz, C6D6) δ = 207.97, 177.44, 70.81, 61.43, 60.23, 55.78, 51.90, 50.86, 45.10, 42.80, 36.26, 35.08, 33.02, 31.47, 30.13, 27.48, 26.23, 25.83, 24.78, 24.46, 22.37, 18.53, -5.02, -5.05; IR (Neat Film, NaCl) 3503, 2954, 2857, 1728, 1707, 1467, 1364, 1250, 1087, 835, 773 cm–1; HRMS (ESI+): m/z calc’d for C26H49O5Si [M+H]+: 469.3344, found 469.3349. Characterization data for ether 57: 1H NMR (400 MHz, C6D6) δ = 4.34 (dd, J = 3.7, 2.1 Hz, 1H), 3.86 – 3.73 (m, 2H), 3.57 (q, J = 6.9 Hz, 1H), 3.34 (s, 3H), 2.37 (dt, J = 6.3, 1.7 Hz, 1H), 2.09 (td, J = 11.2, 5.4 Hz, 2H), 2.00 – 1.90 (m, 1H), 1.75 – 1.57 (m, 5H), 1.34 (s, 3H), 1.27 – 1.19 (m, 4H), 1.15 (d, J = 5.1 Hz, 1H), 1.02 (s, 9H), 0.96 (s, 3H), 0.88 (s, 3H), 0.87 (s, 3H), 0.12 (d, J = 3.2 Hz, 6H); 13C{1H} NMR (101 MHz, C6D6) δ = 174.33, 77.75, 75.29, 59.81, 53.11, 50.91, 49.48, 47.77, 43.08, 41.62, 41.43, 35.62, 35.29, 34.03, 29.04, 25.89, 24.85, 24.59, 22.38, 21.57, 18.15, -5.36; IR (Neat Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 110 Film, NaCl) 2954, 1732, 1471, 1255, 1088, 1066, 835, 774 cm–1; HRMS (ESI+): m/z calc’d for C26H49O4Si [M+H]+: 453.3395, found 453.3401. MeO2C OTBS H2C=PPh3 MeO2C OH OTBS THF, 18 ºC O H 56 methyl OH H 67 6-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-4-hydroxy-1,1- dimethyl-2-(prop-1-en-2-yl)octahydro-3aH-indene-3a-carboxylate 67. A conical flask was charged with NaNH2 (2.18 g, 56 mmol), MePPh3Br (8.0 g, 22 mmol), PhMe (75 mL), and heated to reflux for 2 h. The heating and stirring were then turned off, and the heterogeneous mixture was left overnight, allowing the solids to settle. To a 250 mL flask at 0 °C under N2 was added alcohol 56 (990 mg, 2.11 mmol, 1.0 equiv) and PhMe (75 mL). The prepared solution of CH2=PPh3 (0.3M, 48 mL, 14.4 mmol, 6.8 equiv) was added dropwise over 5 min, and the solution was left to stir at 0 °C for 5 h. Silica gel (16 g) was added slowly, and the solution was further stirred for 20 min at 0 °C. The heterogeneous mixture was filtered, and the silica cake was rinsed (30% EtOAc in hexanes, 200 mL). The combined organic fractions were concentrated under reduced pressure and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→25% EtOAc/hexanes) to furnish 67 (460 mg, 47% yield) as a colorless oil. 1H NMR (400 MHz, C6D6) δ = 4.96 (t, J = 1.7 Hz, 1H), 4.89 – 4.86 (m, 1H), 4.23 (dt, J = 8.0, 5.4 Hz, 1H), 3.72 (t, J = 7.2 Hz, 2H), 3.38 (s, 3H), 2.60 (d, J = 7.7 Hz, 2H), 2.49 (dd, J = 6.2, 3.9 Hz, 1H), 2.28 – 2.16 (m, 1H), 1.74 (d, J = 1.3 Hz, 3H), 1.73 – 1.64 (m, 1H), 1.59 (q, J = 7.0 Hz, 2H), 1.55 – 1.47 (m, 2H), 1.43 (dd, J = 7.7, 5.6 Hz, 2H), 1.30 (d, J = 4.8 Hz, 1H), 1.07 (s, Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 111 3H), 1.01 (s, 9H), 0.93 (s, 3H), 0.86 (s, 3H), 0.82 (s, 3H), 0.11 (s, 6H); 13C{1H} NMR (101 MHz, C6D6) δ = 178.39, 145.05, 112.76, 70.96, 60.22, 55.36, 55.21, 52.18, 51.88, 45.38, 42.57, 37.90, 35.60, 33.21, 29.15, 26.92, 26.22, 25.09, 24.54, 24.25, 24.06, 22.36, 18.51, 5.05, -5.07; IR (Neat Film, NaCl) 3458, 2955, 1730, 1470, 1252, 1089, 836, 775 cm–1; HRMS (ESI+): m/z calc’d for C27H51O4Si [M+H]+: 467.3551, found 467.3551. MeO2C OH OTBS DMP, NaHCO3 MeO2C O H H 67 58 OTBS methyl 6-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-1,1-dimethyl-4-oxo-2(prop-1-en-2-yl)octahydro-3aH-indene-3a-carboxylate 58. To a 100 mL flask was added alcohol 67 (460 mg, 0.99 mmol, 1.0 equiv) and CH2Cl2 (44 mL). NaHCO3 (500 mg, 5.91 mmol, 6 equiv) and DMP (835 mg, 1.97 mmol, 2 equiv) were added sequentially, and the flask was stirred under Ar for 3 h. The reaction was concentrated under reduced pressure and hexanes (15 mL) was added. The heterogeneous mixture was agitated and concentrated under reduced pressure. Hexanes (40 mL) was added, and the mixture was sonicated for 2 min. The mixture was filtered over celite and the filter cake rinsed with hexanes (20 mL). The combined organic fractions were concentrated under reduced pressure to afford 58 (440 mg, 96% yield) as a colorless oil. 1 H NMR (600 MHz, C6D6) δ = 4.87 (p, J = 1.5 Hz, 1H), 4.76 – 4.73 (m, 1H), 3.63 (t, J = 7.1 Hz, 2H), 3.25 (s, 3H), 3.19 (dd, J = 13.3, 7.2 Hz, 1H), 2.99 (dd, J = 6.9, 2.1 Hz, 1H), 2.55 (ddd, J = 12.3, 3.5, 2.0 Hz, 1H), 2.35 (dd, J = 9.5, 7.1 Hz, 1H), 2.26 (dd, J = 13.2, 12.3 Hz, 1H), 2.04 (dd, J = 13.3, 9.6 Hz, 1H), 1.87 (tt, J = 12.9, 3.7 Hz, 1H), 1.78 (ddd, J Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 112 = 14.4, 12.5, 6.9 Hz, 1H), 1.67 (ddt, J = 14.5, 4.2, 2.2 Hz, 1H), 1.65 – 1.59 (m, 3H), 1.49 (td, J = 7.0, 3.0 Hz, 2H), 1.00 (s, 9H), 0.90 (s, 3H), 0.83 (s, 3H), 0.78 (s, 3H), 0.74 (s, 3H), 0.10 (s, 6H); 13C{1H} NMR (101 MHz, C6D6) δ = 206.82, 172.92, 145.92, 112.65, 64.67, 59.93, 56.00, 54.06, 52.25, 46.03, 44.45, 42.40, 41.51, 35.21, 34.72, 27.25, 27.19, 26.20, 24.54, 24.38, 23.96, 23.95, 18.49, -5.11; IR (Neat Film, NaCl) 2952, 2857, 1740, 1715, 1470, 1388, 1367, 1248, 1093, 890, 835, 775 cm–1; HRMS (ESI+): m/z calc’d for C27H49O4Si [M+H]+: 465.3395, found 465.3395. O MeO2C N2 O OTBS 15 O LDA SiMe3 MeO2C HO 58 O OTBS O THF, –78 ºC H SiMe3 N2 H 68 methyl 6-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-4-(1-diazo-2-oxo-2-(2(trimethylsilyl)ethoxy)ethyl)-4-hydroxy-1,1-dimethyl-2-(prop-1-en-2-yl)octahydro3aH-indene-3a-carboxylate 68. To a 100 mL Schlenk flask under N2 was added NH(i-Pr)2 (480 mg, 4.73 mmol, 5 equiv) and THF (1.2 mL). The flask was cooled to –78 °C in a dry ice/acetone bath. n-BuLi (2.5M in hexanes, 1.5 mL, 3.79 mmol, 4 equiv) was added dropwise over 5 min and the solution was left to stir at –78 °C for 15 min. A solution of diazoacetate 15 (prepared according to a previously reported procedure13)(792 mg, 4.26 mmol, 4.5 equiv) in THF (1.2 mL) was added dropwise over 15 min and the blood-red solution was stirred for a further 10 min. A solution of ketone 58 (440 mg, 0.95 mmol, 1.0 equiv) in THF (5 mL) was then added dropwise over 20 min and the reaction was left to stir an additional 20 min. A solution of AcOH (270 mg) in Et2O (4.5 mL) was added slowly and the reaction was removed from Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 113 the cold bath. Water (10 mL) was added, and the mixture was extracted with EtOAc (5 mL x 3). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→20% EtOAc/hexanes) to furnish a yellow oil. The oil was dried in vacuo overnight to remove residual diazoacetate 15, furnishing 68 (547 mg, 88% yield) as a yellow oil. 1H NMR (600 MHz, C6D6) δ = 5.95 (s, 1H), 4.94 (t, J = 1.7 Hz, 1H), 4.91 (s, 1H), 4.11 (t, J = 8.4 Hz, 2H), 3.84 – 3.78 (m, 2H), 3.43 (s, 3H), 2.97 (dd, J = 13.4, 11.5 Hz, 1H), 2.90 – 2.78 (m, 2H), 2.51 (dd, J = 9.7, 6.1 Hz, 1H), 2.28 (pd, J = 11.8, 4.0 Hz, 2H), 2.02 (dd, J = 10.6, 4.2 Hz, 1H), 1.85 (ddd, J = 14.0, 9.7, 6.8 Hz, 1H), 1.81 – 1.67 (m, 6H), 1.10 (s, 3H), 1.02 (s, 9H), 1.01 (s, 3H), 0.98 (s, 3H), 0.83 (s, 3H), 0.75 (tt, J = 8.4, 4.3 Hz, 2H), 0.13 (s, 6H), -0.15 (s, 9H); 13C{1H} NMR (151 MHz, C6D6) δ = 177.06, 168.82, 145.12, 128.35, 112.52, 73.50, 63.69, 62.16, 60.19, 54.37, 53.95, 52.11, 44.45, 43.10, 36.19, 35.64, 34.02, 32.63, 26.49, 26.23, 25.51, 24.96, 24.95, 24.07, 22.26, 18.50, 17.52, -1.65, -5.02; IR (Neat Film, NaCl) 3420, 2955, 2088, 1719, 1667, 1305, 1250, 1095, 837 cm–1; HRMS (ESI+): m/z calc’d for C34H62N2O6Si2Na [M+Na]+: 673.4039, found 673.4038. Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G MeO2C HO SiMe3 N2 O MeO2C Rh2(TFA)4 (1 mol %) O 114 O O SiMe3 OTBS O OTBS pentane/CH2Cl2, 18 ºC H H 68 3a-methyl 5-(2-(trimethylsilyl)ethyl) 59 7-(4-((tert-butyldimethylsilyl)oxy)-2- methylbutan-2-yl)-1,1-dimethyl-4-oxo-2-(prop-1-en-2-yl)octahydroazulene-3a,5(1H)dicarboxylate 59. To a solution of diazoacetate 68 (547 mg, 0.84 mmol, 1 equiv) in pentane/CH2Cl2 (4:1, 100 mL) under Ar was added Rh2(TFA)4 (6 mg, 0.009 mmol, 0.01 equiv). The reaction was stirred at 23 °C for 24 h, concentrated under reduced pressure and purified by automated silica gel flash chromatography (Teledyne ISCO, 0→15% EtOAc/hexanes) to furnish 59 (502 mg, 96% yield) as a colorless oil. Note: Title compound 59 was isolated as a mixture of dynamically interconverting tautomers and was used directly in the next step. 1H NMR and HRMS data is provided as a courtesy. HRMS (ESI+): m/z calc’d for C34H62O6Si2Na [M+Na]+: 645.3977, found 645.3996. Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G MeO2C O O O SiMe3 OTBS MeO2C O NaH, prenyl bromide O O THF, 0 → 18 ºC H 115 SiMe3 OTBS H 60 59 3a-methyl 5-(2-(trimethylsilyl)ethyl) 7-(4-((tert-butyldimethylsilyl)oxy)-2- methylbutan-2-yl)-1,1-dimethyl-5-(3-methylbut-2-en-1-yl)-4-oxo-2-(prop-1-en-2yl)octahydroazulene-3a,5(1H)-dicarboxylate 60. An 8 mL vial under N2 was charged with ester 59 (19 mg, 0.03 mmol, 1.0 equiv) and THF (1.1 mL). The solution was cooled to 0 °C and NaH (60% dispersion in mineral oil, 6 mg, 0.15 mmol, 5 equiv) was added in one portion and the cold bath was removed. After stirring at 23 °C for 1 h, the solution was cooled to 0 °C and prenyl bromide (27 mg, 0.18 mmol, 6 equiv) was added dropwise. The reaction was allowed to warm to 23 °C and stirred at this temperature for 2 h after which it was cooled to 0 °C and quenched slowly with saturated aqueous NH4Cl (1 mL). The mixture was extracted with EtOAc (1 mL x 3), and the combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure.a The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→20% EtOAc/hexanes) to furnish 60 (20 mg, 98% yield) as colorless oil. Note: aCare should be taken to completely remove excess prenyl bromide before loading onto silica as prenyl bromide may exothermically decompose to HBr. 1H NMR (400 MHz, C6D6) δ = 5.46 (tt, J = 6.4, 1.6 Hz, 1H), 4.90 (t, J = 1.7 Hz, 1H), 4.72 – 4.68 (m, 1H), 4.37 – 4.22 (m, 2H), 3.79 (dd, J = 8.3, 6.8 Hz, 2H), 3.61 (dd, J = 13.5, 6.5 Hz, 1H), 3.38 (dd, J = 13.2, 1.7 Hz, 1H), 3.29 (s, 3H), 2.98 (dd, J = 15.0, 8.6 Hz, 1H), 2.55 (dd, J = 14.3, 12.8 Hz, 1H), 2.38 (dd, J = 13.3, 6.5 Hz, 1H), 2.29 – 2.20 (m, 1H), 2.20 – 2.07 Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 116 (m, 3H), 2.07 – 1.99 (m, 1H), 1.92 – 1.72 (m, 3H), 1.67 (d, J = 2.0 Hz, 6H), 1.57 (s, 3H), 1.11 – 1.02 (m, 17H), 1.00 (s, 3H), 0.96 (s, 3H), 0.16 (d, J = 1.9 Hz, 6H), -0.11 (s, 9H); 13 C{1H} NMR (101 MHz, C6D6) δ = 200.73, 173.88, 171.92, 143.49, 133.95, 119.94, 113.25, 68.34, 64.41, 63.39, 59.81, 52.32, 51.90, 50.68, 46.62, 44.63, 40.81, 37.55, 37.45, 36.51, 33.41, 26.71, 26.60, 26.23, 26.20 26.19, 25.38, 24.99, 24.06, 18.50, 18.42, 17.87, 1.70, -4.94, -4.98; IR (Neat Film, NaCl) 2954, 1730, 1704, 1470, 1454, 1250, 1223, 1088, 838, 777 cm–1; HRMS (ESI+): m/z calc’d for C39H70O6Si2Na [M+Na]+: 713.4603, found 713.4630. MeO2C O O TBAF O SiMe3 OTBS H 60 MeO2C O OH THF, 18 ºC H 69 methyl 7-(4-hydroxy-2-methylbutan-2-yl)-1,1-dimethyl-5-(3-methylbut-2-en-1-yl)-4oxo-2-(prop-1-en-2-yl)octahydroazulene-3a(1H)-carboxylate 69. To a solution of compound 60 (56 mg, 82 µmol, 1 equiv) in THF (0.8 mL) at 0 °C under N2 was slowly added TBAF (1M in THF, 0.29 mL, 0.29 mmol, 3.5 equiv). The solution warmed to 23 °C and stirred at this temperature for 18 h. Saturated aqueous NH4Cl (1 mL) was added, and the mixture extracted with EtOAc (1 mL x 3). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→50% EtOAc/hexanes) to furnish 69 (31 mg, 89% yield) as colorless oil. 1H NMR (600 MHz, C6D6) δ = 5.10 (t, J = 7.4 Hz, 1H), 4.95 (t, J = 1.7 Hz, 1H), 4.75 (s, 1H), 3.40 (t, J = Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 117 7.5 Hz, 2H), 3.32 – 3.27 (m, 4H), 3.12 (dd, J = 13.1, 2.5 Hz, 1H), 2.96 (d, J = 15.0 Hz, 1H), 2.68 (dq, J = 9.4, 4.7 Hz, 1H), 2.43 (dd, J = 12.5, 6.5 Hz, 1H), 2.21 (dt, J = 15.2, 9.2 Hz, 1H), 2.09 – 2.00 (m, 2H), 1.82 (d, J = 15.8 Hz, 1H), 1.66 (s, 3H), 1.65 (s, 3H), 1.58 (s, 3H), 1.49 (q, J = 7.2 Hz, 1H), 1.46 – 1.43 (m, 2H), 1.22 – 1.15 (m, 2H), 1.03 (s, 3H), 0.93 (s, 3H), 0.86 (s, 3H), 0.84 (s, 3H), 0.45 (br s, 1H); 13C{1H} NMR (151 MHz, C6D6) δ = 206.39, 175.03, 143.99, 132.80, 123.28, 113.38, 66.61, 59.21, 53.63, 52.11, 50.12, 48.64, 46.45, 43.58, 39.19, 36.95, 36.42, 27.31, 26.11, 26.07, 25.98, 25.86, 25.71, 25.69, 25.67, 24.10, 18.03; IR (Neat Film, NaCl) 3385, 2963, 1740, 1705, 1453, 1235,1023, 889 cm–1; HRMS (ESI+): m/z calc’d for C27H45O4 [M+H]+: 433.3312, found 433.3316. MeO2C O DMP MeO2C O O OH H H 69 61 methyl 1,1-dimethyl-7-(2-methyl-4-oxobutan-2-yl)-5-(3-methylbut-2-en-1-yl)-4-oxo2-(prop-1-en-2-yl)octahydroazulene-3a(1H)-carboxylate 61. To a 4 mL vial was added alcohol 69 (6.8 mg, 16 µmol, 1.0 equiv) and CH2Cl2 (1.5 mL). DMP (17 mg, 39 µmol, 2.5 equiv) was added, and the flask was stirred under Ar for 3 h. The reaction was concentrated under reduced pressure and hexanes (1 mL) was added. The heterogeneous mixture was agitated and concentrated under reduced pressure. Hexanes (2 mL) was added, and the mixture was sonicated for 2 min. The mixture was filtered over celite, and the filter cake rinsed with hexanes (2 mL). The combined organic fractions were concentrated under reduced pressure to and purified by flash silica gel chromatography (0→10% EtOAc/hexanes) to provide aldehyde 61 (6 mg, 88% yield) as a colorless oil. 1H Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 118 NMR (400 MHz, C6D6) δ = 9.51 (t, J = 2.9 Hz, 1H), 5.06 (dddt, J = 7.3, 5.8, 2.8, 1.4 Hz, 1H), 4.94 (h, J = 1.7 Hz, 1H), 4.74 (dt, J = 2.0, 0.9 Hz, 1H), 3.30 – 3.23 (m, 4H), 3.01 (dd, J = 13.0, 2.6 Hz, 1H), 2.91 (dd, J = 13.6, 6.6 Hz, 1H), 2.63 (tt, J = 9.3, 4.2 Hz, 1H), 2.38 (dd, J = 12.5, 6.5 Hz, 1H), 2.14 (dt, J = 14.9, 9.2 Hz, 1H), 2.04 – 1.99 (m, 1H), 1.99 – 1.86 (m, 3H), 1.73 – 1.66 (m, 1H), 1.64 (dt, J = 5.5, 1.4 Hz, 6H), 1.59 – 1.53 (m, 4H), 1.53 – 1.47 (m, 1H), 1.11 (ddd, J = 15.9, 13.0, 7.4 Hz, 1H), 0.99 (s, 3H), 0.87 (s, 6H), 0.85 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 206.03, 201.21, 174.92, 143.88, 133.03, 122.98, 113.45, 66.55, 53.74, 53.57, 52.16, 49.89, 48.47, 46.38, 39.75, 37.52, 36.90, 27.25, 26.06, 25.96, 25.80, 25.78, 25.77, 25.72, 25.64, 24.08, 18.00; IR (Neat Film, NaCl) 2963, 1706. 1455, 1374,1234, 890 cm–1; HRMS (ESI+): m/z calc’d for C27H43O4 [M+H]+: 431.3156, found 431.3150. MeO2C O O TsOH•H2O O H O H H CH2Cl2, 18 ºC O H 38 61 1,1,8,8-tetramethyl-5-(3-methylbut-2-en-1-yl)-2-(prop-1-en-2-yl)decahydro-4H-6,3a(epoxymethano)-5,9-methanocyclopenta[9]annulene-4,13-dione 38. A 100 mL flask was charged with aldehyde 61 (180 mg, 0.42 mmol, 1.0 equiv), pTsOH•H2O (400 mg, 2.1 mmol, 5.0 equiv) and CH2Cl2 (60 mL). The flask was sealed under Ar and stirred at 23 °C for 4 d. The solution was concentrated under reduced pressure, hexanes (20 mL) was added, and the solution was filtered to remove p-TsOH•H2O. The crude residue was purified by flash silica gel chromatography (0→10% EtOAc/hexanes). Impure 38 was further purified by preparatory SFC (silica gel, 1% i-PrOH/CO2, 25 Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 119 mL/min) to furnish 38 (45 mg, 25% yield) as a colorless, crystalline solid. 1H NMR (400 MHz, C6D6) δ = 5.14 (dddt, J = 6.8, 5.8, 2.9, 1.5 Hz, 1H), 4.99 (p, J = 1.5 Hz, 1H), 4.87 (dt, J = 2.0, 0.9 Hz, 1H), 4.59 (dd, J = 10.9, 7.2 Hz, 1H), 3.22 (dd, J = 13.9, 13.0 Hz, 1H), 2.78 (dd, J = 12.9, 6.4 Hz, 1H), 2.62 (dd, J = 14.2, 8.6 Hz, 1H), 2.44 (dd, J = 13.9, 6.3 Hz, 1H), 2.38 (dd, J = 13.9, 3.5 Hz, 1H), 2.27 – 2.2c40 (m, 1H), 1.93 – 1.82 (m, 2H), 1.77 (ddd, J = 14.1, 2.9, 1.5 Hz, 1H), 1.71 (s, 3H), 1.64 – 1.57 (m, 4H), 1.53 (d, J = 1.3 Hz, 3H), 1.44 (dd, J = 14.0, 3.9 Hz, 1H), 1.14 (d, J = 4.6 Hz, 1H), 1.10 (s, 3H), 0.96 (ddd, J = 15.5, 13.9, 1.9 Hz, 1H), 0.76 (s, 3H), 0.67 (s, 3H), 0.60 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 207.66, 174.34, 143.42, 136.30, 118.85, 114.10, 74.33, 64.30, 52.68, 52.22, 50.34, 47.81, 43.59, 40.58, 37.63, 36.78, 34.05, 32.91, 32.82, 31.40, 28.22, 26.29, 26.09, 24.87, 23.93, 17.96; IR (Neat Film, NaCl) 2961, 1745, 1708, 1457, 1244, 1162, 1087, 1027, 889 cm–1; HRMS (ESI+): m/z calc’d for C26H39O3 [M+H]+: 399.2894, found 399.2902. O O H O H 38 H 1. PhNH2•HCl, AlMe3 2. DMP, CH2Cl2 PhHN H O O 37 H 1,1,8,8-tetramethyl-5-(3-methylbut-2-en-1-yl)-4,6-dioxo-N-phenyl-2-(prop-1-en-2yl)decahydro-5,9-methanocyclopenta[9]annulene-3a(1H)-carboxamide 37. A small test tube equipped with a septum under N2 was charged with aniline hydrochloride (18 mg, 0.13 mmol, 10 equiv) and PhMe (0.6 mL). The reaction was cooled to 0 °C and AlMe3 (63 mL, 2M in PhMe, 0.13 mmol, 10 equiv) was added dropwise. The homogenous solution was stirred at 0 °C for 1 h, at which point lactone 38 (5 mg, 12.6 µmol, 1.0 equiv) in PhMe (0.6 mL) was added dropwise and the reaction was left to warm naturally over 20 h. The Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 120 reaction was quenched by sequentially adding a saturated solution of potassium sodium tartrate (8 mL), water (5 mL), CH2Cl2 (10 mL), and stirring for 1 h. The entire mixture was filtered over celite, the organic layer separated, and the aqueous layer extracted further with CH2Cl2 (2x5 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography (0→15% EtOAc/hexanes) and the resulting oil directly subjected to the next step. To a 4 mL vial charged with the alcohol was added CH2Cl2 (0.4 mL) and DMP (9 mg, 21 mmol, 2.0 equiv). The vial was stirred under Ar for 2 h. The reaction was concentrated under reduced pressure and hexanes (0.5 mL) was added. The heterogeneous mixture was agitated and concentrated under reduced pressure. EtOAc (2 mL) was added, and the mixture was sonicated for 2 min. The mixture was filtered over celite, and the filter cake rinsed with EtOAc (2 mL). The combined organic fractions were concentrated under reduced pressure to and purified by flash silica gel chromatography (10% EtOAc/hexanes) to provide dione 37 (4.8 mg, 77% over 2 steps) as a white foam. 1H NMR (400 MHz, C6D6) δ = 7.40 – 7.35 (m, 2H), 7.09 – 7.02 (m, 2H), 6.89 – 6.81 (m, 1H), 6.47 (s, 1H), 5.44 (ddq, J = 9.0, 7.4, 1.5 Hz, 1H), 4.95 (p, J = 1.5 Hz, 1H), 4.73 – 4.67 (m, 1H), 3.55 (d, J = 19.0 Hz, 1H), 3.42 – 3.28 (m, 2H), 2.92 (dd, J = 13.8, 7.2 Hz, 1H), 2.75 (dd, J = 13.8, 7.9 Hz, 1H), 2.40 – 2.30 (m, 2H), 2.28 – 2.15 (m, 2H), 2.09 (t, J = 13.1 Hz, 1H), 1.69 (d, J = 1.4 Hz, 3H), 1.62 (s, 3H), 1.58 (d, J = 1.4 Hz, 3H), 1.52 (dd, J = 14.0, 3.4 Hz, 1H), 1.40 (s, 1H), 1.13 (ddd, J = 15.1, 14.0, 2.5 Hz, 1H), 1.06 (s, 3H), 0.90 (d, J = 1.9 Hz, 6H), 0.73 (s, 3H); 13C{1H} NMR (101 MHz, C6D6) δ = 208.99, 205.08, 169.19, 143.07, 138.06, 135.32, 129.02, 124.95, 121.54, 121.35, 113.73, 70.77, 68.23, 52.58, 52.53, 47.73, 47.33, 41.00, 39.94, 38.59, 35.85, 35.48, 33.16, 31.73, 27.22, 26.22, 25.70, 25.50, 23.93, 18.23; IR (Neat Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 121 Film, NaCl) 3366, 2964, 1694, 1674, 1522, 1438, 1311, 750 cm–1; HRMS (ESI+): m/z calc’d for C32H44NO3 [M+H]+: 490.3316, found 490.3313. Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 2.7 (1) 122 REFERENCES AND NOTES For insightful reviews of PPAPs, see: (a) Ciochina, R.; Grossman, R. B. Polycyclic Polyprenylated Acylphloroglucinols. Chem. Rev. 2006, 106, 3963– 3986. (b) Singh, I. P.; Sidana, J.; Bharate, S. B.; Foley, W. J. Phloroglucinol Compounds of Natural Origin: Synthetic Aspects. Nat. Prod. Rep. 2010, 27, 393– 416. (c) Njardarson, J. T. Synthetic Efforts Toward [3.3.1] Bridged Bicyclic Phloroglucinol Natural products. Tetrahedron 2011, 67, 7631– 7666. (d) Richard, J.-A.; Pouwer, R. H.; Chen, D. Y.-K. The Chemistry of the Polycyclic Polyprenylated Acylphloroglucinols. Angew. Chem., Int. Ed. 2012, 51, 4536– 4561. (e) Yang, X.-W.; Grossman, R. B.; Xu, G. Research Progress of Polycyclic Polyprenylated Acylphloroglucinols. Chem. Rev. 2018, 118, 3508– 3558. (f) Phang, Y. L.; Liu, S.; Zheng, C.; Xu, H. Recent Advances in the Synthesis of Natural Products Containing the Phloroglucinol Motif. Nat. Prod. Rep. 2022, 39, 1766– 1802. (2) Samkian, A. E.; Virgil, S. C.; Stoltz, B. M. Total Synthesis of Hypersampsone M. J. Am. Chem. Soc. 2024, 147, 18886–18891. (3) Tian, W.-J.; Yu, Y.; Yao, X.-J.; Chen, H.-F.; Dai, Y.; Zhang, X.-K.; Yao, X.-S. Norsampsones A–D, Four New Decarbonyl Polycyclic Polyprenylated Acylphloroglucinols from Hypericum sampsonii. Org. Lett. 2014, 16, 3448–3451. (4) Xie, S.; Tan, X.; Liu, Y., Duan, Y.; Chen, G.; Feng, H.; Sun, L.; Huang, Y.; Guo, Y.; Shi, Z.; Zhou, Y.; Qi, C.; Zhang, Y. Hypersonins A−D, Polycyclic Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 123 Polyprenylated Acylphloroglucinols with a 1,2-seco-Homoadamantane Architecture from Hypericum wilsonii. J. Nat. Prod., 2020, 83, 1804–1809. (5) For compounds isolated prior to 2018, see reference 1e. For compounds isolated after 2018, see: (a) Ye, Y.; Yang, X.-W.; Zhou, Y.; Xu, G. Homo-Adamantane Type Polycyclic Polyprenylated Acylphloroglucinols from Hypericum hookerianum. Fitoterapia 2019, 133, 43–50. (b) Xie, S.; Qi, C.; Duan, Y.; Hao, X.; Guo, Y.; Deng, M.; Qio, Y.; Shi, Z.; Tao, L.; Cao, Y.; Gu, L.; Zhou, Y.; Zhang, Y. Wilsonglucinols A–C, Homoadamantane-Type Polycyclic Polyprenylated Acylphloroglucinols with Unusual Fused Epoxy Ring Skeletons from Hypericum wilsonii. Org. Chem. Front. 2020, 7, 464–471. (c) Wang, X.; Shi, M.; Wang, J.; Suo, X.; Sun, H.; Zhen, B.; Sun, H.; Li, J.; Ji, T. Hyperacmosins E-G, Three New Homoadamantane-Type Polyprenylated Acylphloroglucinols from Hypericum acmosepalum. Fitoterapia 2020, 142, 104535. (d) Zhang, H.-B.; Zhang, X.; Jiang, K.; Qu, S.-J.; Meng, L.-H. Lu, Q. Polycyclic Polyprenylated Acylphloroglucinols from Hypericum choisianum. Nat. Prod. Res. 2021, 35, 195–202. (e) Cheng, H.; Zhang, L.; Wang, S.; Deng, J.; Zhou, X.; Liu, Y.; Yang, X. Four New Polycyclic Polyprenylated Acylphloroglucinols from Hypericum wilsonii and their Glucose Uptake Bioactivities. Fitoterapia 2022, 159, 105137. (f) Li, Y.-W.; Lu, W.-J.; Zhou, X.; Zhang, C.; Li, X.-Y.; Tang, P.-F.; Kong, L.-Y.; Xu, W.-J. Diverse Polycyclic Polyprenylated Acylphloroglucinols with Anti-Neuroinflammatory Activity from Hypericum beanie. Bioorganic Chemistry 2022, 127, 106005. (g) Ma, Y.; Suo, X.; Li, X.; Zhu, T.; Li, J.; Ji, T.; Liu, B. Polycyclic Polyprenylated Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 124 Acylphloroglucinols from Hypericum beanii and their Hepatoprotective Activity. Phytochemistry 2022, 203, 113413. (h) Li, Y.; Wang, M.; Su, J.; Wang, Y.; Zhao, Z.; Sun, Z. Polycyclic Polyprenylated Acylphloroglucinols from Hypericum sampsonii Hance and their Anti-Inflammatory Activity. Fitoterapia 2023, 169, 105610. (i) Tao, B.; Li, Y., Shi, Z.; Duan, Y.; Guo, Y.; Huang, X.; Li, J.; Zhang, Y.; Chen, M.; Song, F.; Lan, X.; Sun, W.; Gu, L.; Qi, C.; Zhang, Y. Discovery of Bioactive Polycyclic Adamantine/Homoadamantane Polyprenylated Skeletons Acylphloroglucinols from Hypericum with wilsonii. Phytochemistry 2024, 218, 113953. (6) Xie, S., Qi, C., Duan, Y., Hao, X., Guo, Y., Deng, M., Qiao, Y., Shi, Z., Tao, L., Cao, Y., Gu, L., Zhou, Y., Zhang, Y. Wilsonglucinols A-C, homoadamantanetype polycyclic polyprenylated acylphloroglucinols with unusual fused epoxy ring skeletons from Hypericum wilsonii. Org. Chem. Front. 2020, 7, 464–471. (7) Ballassoued, M.; Frangin, Y.; Gaudemar, M. A New, Convenient Synthesis of Cyclopentene Derivatives. Synthesis 1978, 150–152. (8) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (9) Yamamura, S.; Toda, M.; Hirata, Y. Modified Clemmensen Reduction: Cholestane. Org. Synth. 1973, 53, 86. Chapter 2 – Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G (10) 125 Smith, B. R.; Njardarson, J. T. Double-Diels–Alder Approach to Maoecrystal V. Unexpected C–C Bond-Forming Fragmentations of the [2.2.2]-Bicyclic Core. Org. Lett. 2017, 19, 5316–5319. (11) Ikeda, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. Synthetic Studies on Daphnicyclidin A: Enantiocontrolled Construction of the BCD Ring System. Org. Lett. 2009, 11, 1833–1836. (12) Dubac, J.; Laporterie, A.; Iloughmane, H.; Pillot, J. P.; Déléris, G.; Dunoguès, J. Ène-réactivité d’allylsilanes: Fonctionnalisation et régiochimie. J. Organomet. Chem. 1985, 281, 149–162. (13) Zhu, K.; Cao, M.; Zhao, G.; Zhao, J.; Li, P. Visible Light-Promoted Diazoacetates and Nitriles Generating Nitrilium Ions Trapped by Benzotriazoles and Carboxylic Acids. Org. Lett. 2022, 24, 5855–5859. Appendix 3 – Synthetic Summary for Chapter 2 126 APPENDIX 3 Synthetic Summary for Chapter 2: Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G Appendix 3 – Synthetic Summary for Chapter 2 127 Scheme 3.1 Synthesis of intermediate 37 en route to Wilsonglucinol G (36). A) Both sequences to protected ketoalcohol 12. 50 O MeO OMe Me3Si O 1. BH3•DMS, THF then NAOH, H2O2 1. TiCl4, Ch2Cl2, –78 ºC OTBS 2. HCl (aq.), THF 3. TBSCl, imidazole CH2Cl2 2. (OMe)3CH, p-TsOH MeOH, 65 ºC 11 51 12 75% over 5 steps >125 g scale O O OTBS Fe(acac)3, PhSiH3 OTBS Ethylene glycol/ DCE, 60 ºC 48% yield 11 12 B) Steps en route to benzamide 37. 8 BrZn O O 1. NaH, O=C(OMe)2 THF, reflux OTBS 12 MeO2C 2. PhSeCl, py then, H2O2 (aq.) CH2Cl2, 0 ºC then, 0 ºC, CuBr, 40 min then, AcCl, 25 min O 45% isolated yield 11:1 d.r. at C3 13 73% over 2 steps MeO2C 1:1 CH2Cl2/MeOH 0 °C, 2 h H OTBS CH2Cl2, 18 ºC, 17 min O H 44% yield 52 Crabtrees catalyst (55) (15 mol %) H2/N2 (balloon) OH MeO2C TBSO KBH4 (9 equiv) O DME, –40 ºC, 2 h then, 80 ºC, 3 h OTBS 90% yield 53 O OH MeO2C O OTBS O MeO2C 1. H2C=PPh3 THF, 18 ºC, 1 h N2 OTBS 2. DMP, NaHCO3 H MeO2C O 86% over 2 steps 58 O O SiMe3 OTBS H NaH prenyl bromide MeO2C O O O THF, 0 → 18 ºC SiMe3 OTBS 98% yield H 1. TBAF, THF, 18 ºC 2. DMP, CH2Cl2, 18 ºC 82% over 2 steps 60 59 MeO2C O 61 O O O H SiMe3 2. Rh2(TFA)4 (1 mol %) pentane/CH2Cl2, 18 ºC H 67% over 2 steps 56 15 O 1. LDA, THF, –78 ºC TsOH•H2O H 1. PhNH2•HCl AlMe3 PhHNOC O O 2. DMP, CH2Cl2 CH2Cl2, 18 ºC 42% yield H O H 38 77% over 2 steps H 37 H Appendix 4 – Spectra Relevant to Chapter 2 128 APPENDIX 4 Spectra Relevant to Chapter 2: Toward the Total Synthesis of Hypersonin A and Wilsonglucinol G 10.5 O 10.0 62 H MeO2C 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.1 1H NMR (600 MHz, CDCl3) of compound 62. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 129 Appendix 4 – Spectra Relevant to Chapter 2 130 Figure A4.2 Infrared spectrum (Thin Film, NaCl) of compound 62. 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm Figure A4.3 13C NMR (100 MHz, CDCl3) of compound 62. 20 10 0 10.5 10.0 64 O 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.4 1H NMR (400 MHz, C6D6) of compound 64. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 131 Appendix 4 – Spectra Relevant to Chapter 2 132 Figure A4.5 Infrared spectrum (Thin Film, NaCl) of compound 64. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.6 13C NMR (100 MHz, C6D6) of compound 64. 20 10 0 -10 10.5 10.0 51 MeO OMe 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.7 1H NMR (400 MHz, C6D6) of compound 51. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 133 Appendix 4 – Spectra Relevant to Chapter 2 134 Figure A4.8 Infrared spectrum (Thin Film, NaCl) of compound 51. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.9 13C NMR (100 MHz, C6D6) of compound 51. 20 10 0 -10 10.5 10.0 65 MeO OMe 9.5 OH 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.10 1H NMR (400 MHz, C6D6) of compound 65. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 135 Appendix 4 – Spectra Relevant to Chapter 2 136 Figure A4.11 Infrared spectrum (Thin Film, NaCl) of compound 65. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.12 13C NMR (100 MHz, C6D6) of compound 65. 20 10 0 -10 10.5 O 10.0 66 9.5 OH 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.13 1H NMR (400 MHz, C6D6) of compound 66. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 137 Appendix 4 – Spectra Relevant to Chapter 2 138 Figure A4.14 Infrared spectrum (Thin Film, NaCl) of compound 66. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.15 13C NMR (100 MHz, C6D6) of compound 66. 20 10 0 -10 10.5 O 10.0 52 H MeO2C O 9.5 TBSO 9.0 8.5 8.0 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.16 1H NMR (400 MHz, C6D6) of compound 52. 7.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 139 Appendix 4 – Spectra Relevant to Chapter 2 140 Figure A4.17 Infrared spectrum (Thin Film, NaCl) of compound 52. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.18 13C NMR (100 MHz, C6D6) of compound 52. 20 10 0 -10 O 10.0 OH 54 10.5 H MeO2C 9.5 9.0 OTBS 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.19 1H NMR (400 MHz, C6D6) of compound 54. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 141 Appendix 4 – Spectra Relevant to Chapter 2 142 Figure A4.20 Infrared spectrum (Thin Film, NaCl) of compound 54. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.21 13C NMR (100 MHz, C6D6) of compound 54. 20 10 0 -10 O OH 10.5 56 H MeO2C 10.0 9.5 9.0 OTBS 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.22 1H NMR (400 MHz, C6D6) of compound 56. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 143 Appendix 4 – Spectra Relevant to Chapter 2 144 Figure A4.23 Infrared spectrum (Thin Film, NaCl) of compound 56. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.24 13C NMR (100 MHz, C6D6) of compound 56. 20 10 0 -10 H H 10.0 CO2Me 10.5 57 H O 9.5 OTBS 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.25 1H NMR (400 MHz, C6D6) of compound 57. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 145 Appendix 4 – Spectra Relevant to Chapter 2 146 Figure A4.26 Infrared spectrum (Thin Film, NaCl) of compound 57. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.27 13C NMR (100 MHz, C6D6) of compound 57. 20 10 0 -10 OH 10.5 67 H MeO2C 10.0 9.5 OTBS 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.28 1H NMR (400 MHz, C6D6) of compound 67. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 147 Appendix 4 – Spectra Relevant to Chapter 2 148 Figure A4.29 Infrared spectrum (Thin Film, NaCl) of compound 67. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.30 13C NMR (100 MHz, C6D6) of compound 67. 20 10 0 -10 O 10.5 58 H MeO2C 10.0 9.5 9.0 OTBS 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.31 1H NMR (400 MHz, C6D6) of compound 58. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 149 Appendix 4 – Spectra Relevant to Chapter 2 150 Figure A4.32 Infrared spectrum (Thin Film, NaCl) of compound 58. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.33 13C NMR (100 MHz, C6D6) of compound 58. 20 10 0 -10 N2 10.5 68 H MeO2C HO 10.0 O O 9.5 OTBS SiMe3 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.34 1H NMR (400 MHz, C6D6) of compound 68. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 151 Appendix 4 – Spectra Relevant to Chapter 2 152 Figure A4.35 Infrared spectrum (Thin Film, NaCl) of compound 68. 230 220 210 200 190 180 170 160 150 140 130 120 110 ppm 100 90 80 70 60 50 40 30 Figure A4.36 13C NMR (100 MHz, C6D6) of compound 68. 20 10 0 -10 O 10.5 59 H MeO2C 10.0 O O 9.5 OTBS 9.0 SiMe3 8.5 8.0 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.37 1H NMR (400 MHz, C6D6) of compound 59. 7.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 153 O 60 H MeO2C 10.5 O 10.0 O 9.5 OTBS 9.0 SiMe3 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.38 1H NMR (400 MHz, C6D6) of compound 60. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 154 Appendix 4 – Spectra Relevant to Chapter 2 155 Figure A4.39 Infrared spectrum (Thin Film, NaCl) of compound 60. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.40 13C NMR (100 MHz, C6D6) of compound 60. 20 10 0 -10 O 10.5 69 H MeO2C 10.0 9.5 OH 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.41 1H NMR (400 MHz, C6D6) of compound 69. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 156 Appendix 4 – Spectra Relevant to Chapter 2 157 Figure A4.42 Infrared spectrum (Thin Film, NaCl) of compound 69. 230 220 210 200 190 180 170 160 150 140 130 120 110 ppm 100 90 80 70 60 50 40 30 Figure A4.43 13C NMR (100 MHz, C6D6) of compound 69. 20 10 0 -10 O 10.5 61 H MeO2C 10.0 O 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.44 1H NMR (400 MHz, C6D6) of compound 61. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 158 Appendix 4 – Spectra Relevant to Chapter 2 159 Figure A4.45 Infrared spectrum (Thin Film, NaCl) of compound 61. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.46 13C NMR (100 MHz, C6D6) of compound 61. 20 10 0 -10 10.0 O H O 38 10.5 H O H 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.47 1H NMR (400 MHz, C6D6) of compound 38. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 160 Appendix 4 – Spectra Relevant to Chapter 2 161 Figure A4.48 Infrared spectrum (Thin Film, NaCl) of compound 38. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.49 13C NMR (100 MHz, C6D6) of compound 38. 20 10 0 -10 10.5 O H 10.0 37 H PhHNOC 9.5 O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A4.50 1H NMR (400 MHz, C6D6) of compound 37. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 4 – Spectra Relevant to Chapter 2 162 Appendix 4 – Spectra Relevant to Chapter 2 163 Figure A4.51 Infrared spectrum (Thin Film, NaCl) of compound 37. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A4.52 13C NMR (100 MHz, C6D6) of compound 37. 20 10 0 -10 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 164 APPENDIX 5 Early Strategies Toward the Synthesis of Homoadamantane PPAPs A5.1 INTRODUCTION Over the course of our synthetic studies toward hypersampsone M, wilsonglucinol G, and hypersonin A, several strategies were pursued and abandoned as new data came to light. These early strategies, as well as the model studies and optimizations that eventually led to the route in Chapters 1 and 2, are reported in this appendix. A5.2 CHIRAL POOL EFFORTS STARTING FROM LIMONENE Our initial approach to the homoadamantane PPAPs (70, Scheme A5.2.1) involved the same early disconnections to tricycle 71. From there, we imagined opening the eastern 6-membered ring and removing the prenyl group in a fashion analogous to that in Chapters 1 and 2, resulting in hydrazulene 72. Scheme A5.2.1. Limonene-based approach toward the homoadamantane PPAPs. O R 2 O O O 2 1 R1 Homoadamantane PPAPs (70) MeO2C O R H O O O MeO2C 1 MeO2C R H H H 71 72 7 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 165 The key distinction is that hydrazulene 72 would be accessed via cyclopentene annulation of cycloheptenone 7, derived from the chiral pool (limonene). This also means that the two carbons in the eastern ring (71, highlighted in red) would be installed after the cyclopentene annulation, through functionalization of the isopropenyl group in hydrazulene 72. We started by developing a route toward cycloheptenone 7, taking inspiration from Yang’s approach to ester 75 (Scheme A5.2.2A),1 involving oxidative cleavage of (+)Carene (73), followed by acetal protection and acylation to afford b-ketoester 74. They report that a Lewis acid-mediated cyclization of 74 directly resulted in cycloheptenone 75. Starting from (+)-limonene oxide (76, Scheme A5.2.2B), we followed a procedure by Renaud and coworkers who demonstrated its oxidative cleavage and protection to form acetal 6.2 Scheme A5.2.2. Synthesis of isopropenyl-flanked cycloheptenone 7. A) Previously reported route to cyclopropyl-bearing 75. (Yang, 2020) O 1. ozonolysis 2. acetal protection 3. acylation 56% over 3 steps O O MeO TiCl4 CH2Cl2, –78 ºC MeO 85% yield OMe (+)-Carene (73) MeO2C 74 75 B) Synthesis of isopropenyl-bearing cyclohepteneone 7. O 1. NaIO4, THF/H2O 18 ºC 2. CeCl3•7H2O (MeO)3CH, MeOH (+)-limonene oxide (76) OMe NaH, (OMe)2CO OMe THF, 50 ºC O 86% over 2 steps 74% yield 6 O OMe MeO OMe O O 26 1. 3% aq. HClO4 THF, 18 ºC MeO2C 2. piperidine (10 mol %) PhH, AcOH, reflux 53% over 2 steps 7 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 166 This was followed by acetylation to afford b-ketoester 26. Unfortunately, direct cyclization with TiCl4 did not result in the formation of the desired ester 7. Instead, a two-step procedure involving deprotection of acetal 26 followed by a Knoevenagel condensation successfully provided ester 7. We subjected this substrate (7) to an early version of our cyclopentene annulation conditions but were met with multiple complications (Scheme A5.2.3). First, a significantly decreased yield was observed, with diacetylated 78 being the major product. We believe that the introduction of the isopropenyl group may have congested the system, resulting in a decreased aptitude for cyclization. Second, a diminished 3:1 cis to trans ratio (10 and 77) was isolated, a noticeable reduction from the 6:1 ratio isolated in the model system (See Table 2.3.1). Finally, both diastereomers were isolated as the undesired synaddition product in relation to the isopropenyl group. This surprising outcome prevented us from advancing through our intended route. After some consideration, we reasoned that oxidative cleavage of the isopropenyl group in hydrazulene 10 would provide an epimerizable site at C7 that could be used to attain the correct diastereomer required for the synthesis. Scheme A5.2.3. Unsuccessful cyclopentene annulation of ester 7. O MeO2C 8 O BrZn DME, –10 ºC, 48 h then, 65 ºC, 72 h then Pd(PPh3)4 AcCl, 18 ºC H NOE 7 MeO2C 7 O + 7 O H H + AcO MeO2C H NOE 10 13% yield 10 AcO O MeO2C 77 3:1 cis/trans 78 major product Before oxidative cleavage, we needed to reduce and methylate the enone olefin (10) and realized this may be a good opportunity to investigate the conjugate reduction and Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 167 selective methylation. We were dismayed to see that a variety of 1,4-selective reduction conditions were unsuccessful on our system: L-selectride resulted in a complex mixture while Cu-hydride reductants instead reduced the cycloheptanone carbonyl to give alcohol 80 (Table A5.2.1). 3,4,5 Interestingly using Birch conditions did result in the reduction of the enone olefin, however this was accompanied by migration of the methyl ester to afford hydrazulene 81. More exotic reducing conditions involving Si6 Table A5.2.1. Attempts to reduce the enone olefin in hydrazulene 10. O O O MeO2C conditions O MeO2C PPh2 L= H 10 79 conditions L-selectride THF, –78 ºC, 1 h Cu(OAc)2, PMHS, L PhMe, t-BuOH, 18 ºC, 12 h – OR – CuI, MeLi, HMPA, DIBAL THF, –45 ºC, 3h Li0, t-BuOH, NH PPh2 H 3 O outcome conditions outcome complex mixture PPh3O, SiCl3H CH2Cl2, 18 ºC, 2h – OR – ZnCl2, Pd(PPh3)4 Bu3SnH, THF, 18 ºC, 1 h no reaction Pd/C or Rh/C or Pt/C EtOAc, H2 (10 bar), 48 h complex mixture HO MeO2C O Raney Ni THF, 18 ºC, 5 h O MeO2C H H 80 82 O MeO2C O O Rh/alumina, EtOAc H2 (10 bar), 48 h Et2O, –78 ºC, 30 min O MeO2C H H 81a 83 a isolated as a mixture of diastereomers or Sn7 did not have any effect on our system. This string of failures led us to focus on heterogenous hydrogenation catalysts. We found that Pd, Pt, or Rh on C gave complex mixtures, and Raney Nickel8 selectively reduced the isopropenyl group to afford enone 82. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 168 We were happy to see that Rh/alumina resulted in smooth reduction of the enone and isopropenyl group, allowing us to isolate dione 83. Since we intended to oxidatively cleave the isopropenyl group eventually, it was decided to preemptively dihydroxylate and protect this olefin as the acetonide (84, Scheme A5.2.4). This allowed us to selectively reduce the enone olefin using Rh/alumina to afford dione 85. These steps were high yielding, however, what was two diastereomers after the cyclopentene annulation became eight following reduction. Some of these diastereomers are inconsequential, however due to the challenges involved in trying to isolate and characterize anything at this stage, it was decided to reevaluate the current route. Scheme A5.2.4. Selective reduction of the enone in hydrazulene 10. O O 1. K2OsO4, NMO acetone, H2O 18 ºC, 24 h O MeO2C 3 O 2. p-TsOH•H2O dimethoxyacetone acetone, 18 ºC, 24 h H MeO2C H O 84 O (4 diastereomers) 10 3:1 dr at C3 O O MeO2C Rh/alumina, H2 (10 bar) EtOAc, 18 ºC, 24 h H 85 (8 diastereomers) A5.3 O O CHIRAL POOL EFFORTS STARTING FROM (+)-CARENE Initially, we had made the assumption that the cyclopentene annulation would occur anti to the isopropenyl group, both based on our intuition of analogous 6-membered systems, as well as a recent report by Yang and coworkers.1 In their report, unsaturated bketoester 75 (Scheme A5.3.1) was treated with cuprate reagents which resulted in isolation of the anti-addition product 86. While it is true that the dimethylcyclopropyl group is Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 169 significantly more rigid than an isopropenyl group, we were initially hesitant to use the cyclopropyl appended ester 75 for two reasons. First, it is derived from (+)-carene (73) which exists naturally only as a single enantiomer, meaning we would need to target the ent-PPAPs. Second, even if we could get the cyclopentene annulation to proceed as desired and isolate hydrazulene 87, we would have no way of functionalizing the cyclopropane in a useful fashion. There are a multitude of cyclopropane fragmentation conditions in the literature,9,10 but many rely on strong acids, or simply do not provide us with a handle (88) that we could advance to the PPAPs. It was thus decided to invest time in studying this type of b,g-cyclopropyl ketone fragmentation so that we could use the bulkier ketoester 75 in our synthesis. The results of this fragmentation study are presented in Chapter 3. Scheme A5.3.1. Yang’s anti-addition into ester 75. O O H MeO O MeLi, CuI, HMPA then allyl iodide MeO2C H Et2O, THF, –78 ºC 50% yield H (+)-Carene (73) H 75 86 O O MeO2C MeO2C H R H 87 H ? R OR1 H 88 Ester 75 was prepared as outlined previously by Yang and coworkers, providing access to several grams of material.1 Ester 75 was subjected to the first two steps of the cyclopentene annulation resulting in the formation of a single diastereomer of hydrazulene 89 (Scheme A5.3.2A). Unfortunately, this diastereomer (89) was the undesired synaddition product (cis-fused) once again, indicating that a more rigid backbone does not seem to affect the stereochemical outcome in this case. We reasoned that the Yang group’s Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 170 use of Cu nucleophiles may instead have been the deciding factor, prompting us to test different propargylic nucleophiles. Using a propargyl Mg nucleophile (90, Scheme A5.3.2B) resulted in quantitative, irreversible deprotonation of ester 75 to the enol tautomer (91)—this is not entirely surprising given the basicity of Mg reagents. Attempting to make a propargyl cuprate delivered a complex mixture, likely due to the interaction of the Cu with the terminal alkyne.11 A protected alkyne (92) was used instead, delivering the expected conjugate addition products. We isolated a mixture of four isomers, two propargylic (93) and two allene (94) products, each as two diastereomers at the methyl ester. However, all four compounds were isolated as the syn-addition products with respect to the cyclopropyl ring. Scheme A5.3.2. Cyclopentene annulation and other nucleophilic additions to 75. A) Cyclopentene annulation of ester 75. O 8 O H MeO O BrZn DME, –10 ºC, 48 h MeO2C H then 65 ºC, 72 h 75 H 68% yield > 20:1 cis/trans H 89 H NOE B) Alternative dimethyl-propargyl nucleophiles. O HO 90 75 BrMg 90 BrMg MeO THF, 0 ºC, 30 min CuI 75 THF, –30 ºC, 30 min 91 ClMg 75 O 92 CuI SiMe3 Me3Si O O MeO THF, –40 ºC, 30 min + decomposition O MeO SiMe3 93, mixture of diastereomers 94, mixture of diastereomers In an attempt to drastically change the substrate, we elected to use cycloheptenone 95 (Scheme A5.3.3A), previously reported by Wood and coworkers.12 The lack of the Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 171 methyl ester prevents chelation via a bidentate interaction, possibly affecting the transition state during addition, and thus, the subsequent stereochemical outcome. However, without the highly activated dicarbonyl, propargyl zinc 8 undergoes the undesired 1,2-addition affording tertiary alcohol 96 cleanly. Using the Cu reagent 92 instead led to no reaction. Scheme A5.3.3. Additions involving cycloheptenone 95 and 75. A) Additions into enone 95. 8 HO BrZn DME, –15 ºC, 1 h O 96 92 BrMg 95 SiMe3 CuI no reaction THF, –40 ºC, 30 min B) Mukaiyama aldol additions using silane 97. 97 O O O TMSO MeO 75 TiCl4, Ti(Oi-Pr)4 MeO CH2Cl2, –78 ºC, 1 h O > 50% conversion 97 95 TiCl4, Ti(Oi-Pr)4 CH2Cl2, –78 ºC, 1 h < 25% conversion 98, synproduct only O TMSO O O + O O 99 2:1 100 Several Mukaiyama Michael additions were attempted next (Scheme A5.3.3B).13 Using vinyloxysilane 97, we were able to effect the desired transformation with ester 75 to afford aldol product 98, isolated exclusively as the syn-product. Using heptanone 95 instead led to a mixture of the undesired syn-aldehyde (99) and the desired anti-aldehyde (100). This reaction has been the only example thus far that has provided any anti-addition product from these 7-membered systems with bulky carbo-nucleophiles. However, due to Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 172 the low yield and poor selectivity, we did not see this result as particularly promising and pressed forward. A Danheiser annulation14 was attempted next using ester 75 and allenylsilane 101 (Scheme A5.3.4A), to access hydrazulene 102. Although the substitution pattern on hydrazulene 102 is not ideal, we nonetheless believed that it would be worth attempting. However, we observed no reaction at decreased temperatures, and a mixture of chloride 103 and cycloheptatriene 104 at elevated temperatures. Mechanistically, we propose that coordination of ester 75 to TiCl4 could generate a strong positive charge at the beta position (105, Scheme A5.3.4B). This could then fragment the neighboring cyclopropane internally (red) resulting in cation 106, which is trapped, or externally (blue), leading to tertiary cation 107. A 1,2-hydride shift to 108 followed by fragmentation of the cyclopropane and tautomerization could result in ester 109. Scheme A5.3.4. Danheiser annulation of cycloheptenone 75. A) Danheiser annulation of ester 75. SiMe3 101 O O At increased temperatures: O MeO X 75 Cl + 103 H no reaction OH MeO2C Me3Si CH2Cl2, –78 ºC, 1 h CO2Me HO MeO2C TiCl4 104 102 B) Mechanistic rational for the formation of 103 and 104. [Ti] [Ti] O O O 75 MeO MeO 105 [Ti] O O Cl TiCl4 103 106 [Ti] O MeO O O 104 MeO MeO 107 O O 108 109 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs A5.4 173 EASTERN RING-FIRST STRATEGY It became clear at this point that the intrinsic bias for bulky nucleophiles on esters 75 or 95 was not to give the desired anti-addition products, and our continued efforts to force this were not productive. We instead imagined an alternate approach where we would first construct the eastern 6-membered ring (110, Scheme A5.4.1), thereby rigidifying and increasing the steric bulk to a point where it could be reasonably assumed that nucleophiles would attack on the anti-face, providing 111. The remaining steps to ent-36 would be mostly unchanged. Retrosynthetically, the unsaturated b-ketoester moiety is very reactive and must be installed directly before use. We elected to use a silane as a temporary placeholder and blocking group in ketone 112. Ketone 112 could be accessed from bromoketone 113 via a cyclopropyl fragmentation, prenylation, and cyclization. Finally, enone protection and bromination of 95 would afford bromoketone 113. Scheme A5.4.1. Eastern ring first approach to the homoadamantane PPAPs. O O O OPG MeO O H 110 H H 111 O OPG R3Si O HO R H O O OPG MeO2C ent-36 O cyclopropyl fragmentation/ prenylation/cyclization Br O enone protection/ bromination R3Si 112 H 113 95 Starting from enone 95 (Scheme A5.4.2A), we were able to protect the enone as a b-silylketone (114) by addition of a silylcuprate, following a procedure by Patel and Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 174 coworkers.15 Curiously, in this case we isolated the anti-addition product. Bromination afforded bromide 115 in excellent yield, however our radical fragmentation conditions with stannane 116 did not result in desired allyl enone 117. Instead, undesired enone 118 was isolated. Mechanistically, we reasoned that generation of secondary radical 119 (Scheme A5.4.2B) would be followed by fragmentation to form tertiary radical 120. This radical is nucleophilic in nature and would thus be slow to engage with the kinetically mismatched stannane (116), which would also provide a nucleophilic radical. Instead, a facile 1,5-HAT could occur: this would not only be kinetically matched but would also generate a highly stabilized push-pull radical (121).16 Scheme A5.4.2. Unexpected formation of rearranged allylketone 118. A) Synthesis and radical fragmentation of bromide 115. O O O LDA, then TMSCl then NBS THF, –78→0 ºC CuI, Me2PhSiLi THF, –23 ºC, 4 h 67% yield 95 SnBu3 Me2PhSi Me2PhSi 96% yield 114 115 O O 116 Br ACHN X PhH, 86 ºC, 48 h Me2PhSi Me2PhSi 118 sole product 117 B) Mechanistic rational for the formation of enone 118. O O O 115 Me2PhSi Me2PhSi 119 Me2PhSi 120 121 We reasoned that in order to destabilize this push-pull, “captodative” radical, and thus shut down this side reaction, we need to either remove the pulling group (carbonyl) or the pushing group (b-Si effect). We were able to reduce bromide 115 to the corresponding secondary alcohol (122, Scheme A5.4.3A), however this only resulted in decomposition Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 175 products upon treatment with our radical fragmentation conditions (123 was not observed). We next tried to make the desilylated version of bromide 115. Starting from enone 95, we were able to selectively brominate alpha to the carbonyl, yielding bromide 124. Unfortunately, all reductive conditions that were tried in order to reduce the enone olefin resulted in concomitant reduction of the bromide as well. Next, we tried to subject bromide 124 to the radical fragmentation conditions directly (Scheme A5.4.3B). We isolated a mixture of two isomers, the desired allyldieneone 126 as well as a curious dimethylcyclobutane (127) byproduct. It was not entirely surprising to observe this undesired isomer, as following fragmentation, the resulting tertiary radical 128 has three viable pathways to termination. It could directly engage an allyl group forming allyl dienone 126, it could engage the neighboring olefin regenerating the intial enone (these two species are likely in equilibrium), or it could engage the second enone, resulting in cyclobutane 127 after termination with allyl stannane 116. Scheme A5.4.3. Attempts to destabilize captodative radical 121. A) Attempts to destabilize radical 121. HO HO 115 Br NaBH4 ACHN, 116 MeOH, 0 ºC PhH, 86 ºC, 48 h X Me2PhSi 122 O 95 LDA, then TMSCl then NBS THF, –78→0 ºC Me2PhSi decomposition 123 O Br Br [H] reduction results in debromination X 124 125 B) Radical fragmentation of bromide 124. O 124 ACHN, 116 O via: O + PhH, 86 ºC, 48 h 45 : 55 126 127 128 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 176 At this point we elected to try cyclopentadiene (cp, 120, Scheme A5.4.4) as an enone protecting group, hoping to avoid the issues we observed with the silyl group.17 We were pleased to find that simple Diels-Alder conditions with enone 95 and cp (129) resulted in the desired adduct 130. This could then be brominated to afford bromide 131 which we subjected to the radical fragmentation conditions. Unfortunately, we did not isolate the desired allyl enone 132 and instead found the major product to be an unusual cage (133). Further studies of this reaction, 133, and its relevance, is explored in Chapter 4. Scheme A5.4.4. Cyclopentadiene protected enone radical fragmentation. 129 95 AlCl3 H O PhMe, 18 ºC 50% yield H LDA, then TMSCl then NBS O Br THF, –78→0 ºC 66% yield H H 130 131 H O ACHN, 116 O PhH, 86 ºC, 48 h H 132 not observed A5.5 133, sole product ca. 50% yield CYCLOHEXENONE STRATEGY: HYDROINDENE FORMATION Due to the challenges faced in both the first and second approaches, a third route was targeted, focusing specifically on omitting the seven membered ring until necessary. Ultimately, this strategy proved successful, with the key outcomes presented in Chapters 1 and 2. Additional efforts, including unsuccessful attempts, are discussed in these sections (A5.5–A5.9). Initial attempts to synthesize a 6-membered substrate for the cyclopentene annulation were met with limited success (Scheme A5.5.1). Starting from 3° alkyl bromides 134 and 136, various radical and organometallic additions were attempted with Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 177 only trace product being observed in most cases. Only two routes, a Sakurai allylation and Fe-mediated HAT addition ultimately proved successful (see. Scheme 1.4.1 and Scheme 2.4.1). Scheme A5.5.1. Unsuccessful tertiary conjugate additions to 11. O 134 BzO O O BnO Br X conditions 11 136 Br X conditions OBz 135 O 11 OBn 137 Unsuccessful attempts: Unsuccessful attempts: • Zn, CuI, EtOH/H2O, sonication • Zn, CuI, EtOH/H2O, sonication • AIBN, Bu3SnH, PhH, 65 ºC • Mg, CuI, THF, 0 ºC • Zn, 2-thienyllithium, TMSCl, –50 ºC, THF • Zn-Cu couple, dioxane, sonication for all reactions: trace or no reaction Having access to cyclohexanones 13 and 138, multiple strategies to install the cyclopentane ring were attempted (Scheme A5.5.2). Despite having developed a cyclopentene annulation for this purpose, the challenging reaction protocols and moderate yields led us to question whether more suitable methodologies exist. Allylic bromide 139 was initially selected with the expectation that Zn-mediated metalation would enable branched addition into enone 138, followed by a formally forbidden 5-endo-trig cyclization to form hydroindene 140.18 While the cyclization was anticipated to be challenging, we were disappointed to see that metalation of bromide 139 resulted in decomposition, leaving enone 138 unreacted. Attempts to run this reaction under aqueous (Reformatsky) conditions or with CrII were also unsuccessful. Hypothesizing that the acrylate was leading to premature decomposition we attempted this reaction using bromide 141, now bearing an isolated acetate. Several new compounds were Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 178 observed by TLC; however, these were formed in trace quantities and were not stable to isolation. Scheme A5.5.2. Unsuccessful strategies toward the key hydroindene. O OMe O 139 MeO2C X OTBDPS OTBDPS Unsuccessful conditions: H • Zn, THF, –40 ºC • Zn, THF, 0 ºC • Zn OR In, THF/H2O, 18 ºC • CrCl3, LiAlH4, THF, 18 ºC 138 140 Observed only decomposition of 139 OAc OH 141 O Br MeO2C MeO2C OTBS Zn, THF, –40 ºC 13 OTBS X AcO observed only undesired side-products 142 O(CO)OMe OH 143 13 O MeO2C Br MeO2C MeO2C OTBS X Fe(acac)3, PhSiH2(Oi-Pr) CH2Cl2, i-PrOH, 18 ºC MeO(OC)O 144 no reaction of 13 O(CO)OMe OH 145 147 O O MeO2C O 13 X LiHMDS, Pd2(dba)3 PPh3, DMF, 18 ºC observed only 147 OTBS HO 146 OH SiMe3 13 O MeO2C 50 X OTBS TiCl4 OR SnCl4 CH2Cl2/pentane, –78 ºC 148 not observed 148 Carbonate 143 was synthesized with the aim of using an iron catalyzed HAT coupling to generate b-ketoester 144.19 Ideally, the nucleophilic ketoester could then displace the carbonate in an SN2 reaction to generate the cyclopentane. However, this HAT Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 179 coupling provided mainly unreacted starting material (13). It is possible the symmetric allylic radical formed is too stable and hindered to engage in a Giese type addition to ester 13. Deprotonation of enone 13 at the γ-position using LHMDS, followed by treatment with a mixture of Pd and allylic carbonate 145, was expected to result in allylation to form diene 146.20 Unfortunately, carbonate 145 is not stable to base and cyclic carbonate 147 was isolated. A final attempt was made to extend the previously successful Sakurai allylation to the synthesis of b-ketoester 148, using either a Ti or Sn Lewis acid. Surprisingly, Ti resulted in no reaction while Sn produced non-specific decomposition. The combined outcome of these efforts underscored the challenges associated with constructing this hindered cyclopentane ring and reinforced the notion that our previously developed 3-component cyclopentane annulation (see Chapter 5) remains among the most effective ways to construct this motif. A5.6 CYCLOHEXENONE STRATEGY: HYDROINDENE RING EXPANSION Following preparation of hydroindenes 149 and 14 (bearing an OTBS group), it became necessary to perform a ring expansion to access the respective hydrazulenes (Scheme A5.6.1). Several reactions were investigated to this end. After successful preparation of silyl enol ether 150, a cyclopropanation using dibromocarbene was attempted in order to access dibromide 151, which is anticipated to undergo spontaneous rearrangement to hydrazulene 152.21 This reaction resulted in a complex mixture with several unidentified species. To mitigate potential interference from the cyclopentyl olefin, cyclopentene 149 was hydrogenated to form the saturated hydroindene (153), followed by silylation to form enol ether 154. Subjection to dibromocarbene resulted in no reaction, likely due to the steric congestion near the silyl enol ether. We also attempted a Tiffeneau- Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 180 Demjanov ring expansion which requires primary amine 158.22 While cyanohydrin 157 was formed successfully, we were unable to reduce the cyanide in the presence of the neighboring ester (158). Hydrogenation resulted in no reaction, while LiAlH4 resulted in decomposition. This strategy would likely also have been plagued by undesired lactam cyclization of the primary amine. Scheme A5.6.1. Early unsuccessful ring expansion strategies. MeO2C O TMSOTf Et3N MeO2C OTMS KOt-Bu CHBr3 R hexanes CH2Cl2, 18 ºC R H Br TMSO MeO2C 149 MeO2C R 150 Br X H H H >80% yield O Br 151 R 152 Pd/C (5 wt. %), H2, EtOAc, 18 ºC 92% yield MeO2C O TMSOTf Et3N R H MeO2C O KCN, TMSCN 18-crown-6 R H OTMS CH2Cl2, 18 ºC 85% yield 153 MeO2C 154 Raney Ni H2, EtOH R 157 MeO2C R OR X LiAlH4 Br X H 155 TMSO CN MeO2C Et2O, 18 ºC O Br H H H 149 KOt-Bu CHBr3 hexanes R Br TMSO MeO2C TMSO MeO2C R 156 NH2 R R= OTBDPS H 158 We next investigated diazo-mediated ring expansion strategies. Although various conditions were unsuccessful (see Scheme A5.6.2), the reaction of 149 with trimethylsilyldiazomethane, BF3, and molecular sieves resulted in desired hydrazulene 159 in a modest 31% yield with smaller amounts of the undesired ketone isomer (160).23 Separation of isomers 159 and 160 was possible with reverse phase preparatory HPLC enabling 159 to be advanced to aldehyde 161 via prenylation, deprotection, and oxidation. Treatment of aldehyde 161 with acidic conditions then allowed isolation of lactone 162 in small quantities. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 181 Scheme A5.6.2. Successful diazo-mediated ring expansion of 149. O MeO2C OTBDPS Me3SiCHN2 BF3•Et2O, CH2Cl2 4Å mol. sieves O MeO2C OTBDPS then, PPTS MeOH/CH2Cl2 H 149 O MeO2C OTBDPS H 43% yield 31% rsm H 159 160 2.5 : 1 Unsuccessful conditions: Me3SiCHN2, n-BuLi; Me3SiCHN2, TiCl4 Me3SiCHN2, AlMe3; CH2N2 O 159 1. LDA, prenyl Br THF, –78 ºC 2. TBAF, THF 3. DMP, CH2Cl2 71% over 3 steps single diastereomer MeO2C TsOH•H2O O H O O H H CH2Cl2, 35 ºC low conversion 161 O H 162 The success of trimethylsilyldiazomethane ring expansion and subsequent advancement to lactone 162 gave us confidence in this overall strategy, however, we decided to invest more time into developing a more practical ring expansion. This set of conditions resulted in low yields and reproducibility due to the heterogenous nature of the reaction. Additionally, separation of isomers 159 and 160 via HPLC was only feasible on a small scale (<100 mg), and finally, this set of conditions was unsuccessful on substituted cyclopentane rings, such as ketone 58 (Scheme A5.6.3A). Effecting a ring expansion of substituted hydroindene 58 became a necessity as we set out to target wilsonglucinol G (36) and hypersonin A (32). The isopropenyl group, although oriented away from the concave face, is currently believed to further compress the bowl-like topology of 58 and hinder the ability of the neutral diazomethane nucleophile to engage the ketone. To address this, neutral diazoacetate nucleophiles were employed in conjunction with Lewis acids, while anionic diazoacetates were generated under basic conditions with LDA (Scheme A5.6.3B). Unsurprisingly, the neutral nucleophiles were similarly ineffective, however both anionic ethyl and t-butyl diazoacetate reacted smoothly Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 182 with 58, resulting in 3° alcohols 165 and 166, respectively. Both alcohols underwent tentative ring expansion with Rh2(OAc)4 to afford b-ketoesters 167 and 168. Unfortunately, 167 and 168 both exist as a mixture of dynamically interconverting isomers, preventing characterization. Scheme A5.6.3. Diazoacetate-mediated ring expansion of 58. A) Unsuccesssful ring expansion of hydroindene 58 using trimethylsilyldiazomethane. O MeO2C OTBS Me3SiCHN2 BF3•Et2O, CH2Cl2 4Å mol. sieves H then, PPTS MeOH/CH2Cl2 58 no reaction O MeO2C X OTBS H No reaction with TBDPS protecting group 163 B) Ring expansion attempts using diazoacetates. OR conditions 58 result conditions O N2 HO MeO2C N2 OR OTBS O H R = Et, Meerwine’s salt R = Et, SbCl5 R = Et, LDA R = t-Bu, LDA R = Bn, LDA R = (CH2)2SiMe3, LDA no reaction complex mixture > 80% yield (165) > 80% yield (166) no reaction 91% yield (68) OR MeO2C 164 HO MeO2C N2 O OR OTBS O MeO2C O Rh2(OAc)4 TBAF OTBS pentane H O H OH THF mixture of tautomers 93% yield 165, R = Et tentative assignment 167, R = Et (only from 59) 166, R = t-Bu 168, R = t-Bu 68, R = (CH2)2SiMe3 59, R = (CH2)2SiMe3 H 169 Attempts to selectively decarboxylate either 167 or 168 to hydrazulene 163 proved exceedingly challenging in the presence of the neighboring methyl ester. Custom diazoacetates bearing benzyl and trimethylsilyl ethyl esters were synthesized to facilitate the selective decarboxylation step. Deprotonation of benzyl diazoacetate resulted in decomposition and alcohol 164 bearing a benzyl group was never observed. Ultimately, trimethylsilyl ethyl diazoacetate added cleanly to hydroindene 58 forming 68, and following ring expansion with Rh, the resulting tautomeric mixture (59) could be Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 183 selectively decarboxylated with TBAF, providing a high-yielding and scalable route to hydrazulene 169. A5.7 CYCLOHEXENONE STRATEGY: FORMING THE C5–C9 BOND Hydroindene 58 was advanced to aldehyde 61 (Scheme A5.7.1) in five steps, outlined in Chapter 2. Previous model studies with 161 to form 162 (Scheme A5.6.2) led us to believe that a similar set of conditions could be used to access lactone 38 from aldehyde 61. Indeed, lactone 38 could be isolated, albeit in low yield and with significant amounts of isomerized 171, which proved inseparable without preparatory HPLC. Significant efforts were made to forge the C5–C9 bond (61) without lactonization, to yield 170. These efforts are described in this section. Scheme A5.7.1. Lactonization of aldehyde 61. MeO2C O O MeO2C OTBS O 5 TsOH•H2O 5 steps H H 58 61 MeO2C O OH 9 O H H O CH Cl , 18 ºC 2 2 O H 45% yield 1.45 : 1 38 : 171 38 + O O H H H 170 H O H 171 A variety of aldol conditions (at multiple temperatures) were employed in an attempt to isolate aldol product 170 from aldehyde 61 (Table A5.7.1). Unfortunately, essentially all of conditions resulted in no reaction. Various bases (entries 1–5), including TBD, and acids (entries 7–11), including dpp, returned starting material. Interestingly Mukaiyama aldol conditions (entry 6) resulted in formation of silyl enol ether 172, but not condensation products. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 184 Table A5.7.1. Unsuccessful aldol reaction of aldehyde 61. O MeO2C MeO2C O OH conditions X O H H 61 entry conditionsa H 170 result entry conditionsa TsOH•H2O Et2O OR PhH N result 1 TBD, THF no reaction 7 2 DBU, CH2Cl2 no reaction 8 3 pyrrolidine, DMF no reaction 9 BF3•Et2O OR TFA, CH2Cl2 no reaction 4 NaOMe, MeOH no reaction 10 PPTS, CH2Cl2 no reaction 5 CsCO3, PhH no reaction 11 dpp, PhMe, 65 ºC no reaction no reaction CSA, CH2Cl2 OR no reaction Et2O OR PhH N O N H PhO dpp P OH OPh TBD O MeO2C OTMS H 6 TMSOTf, EtN(i-Pr)2 isolated 172 172 aAll reactions performed at 18 ºC and heated until reflux unless otherwise stated. Anticipating that perhaps this aldol reaction is reversible, acid (173), ester (174), and acid chloride (176) substrates were prepared (Scheme 5.7.2A). Literature precedent suggested it may be possible to directly cyclize the carboxylic acid (173) using forcing acidic conditions.24,25 Targeting Claisen product 177, we treated acid 173 with Amberlyst 15 in PhMe, which unfortunately resulted in decomposition of the isoproprenyl group (Scheme A5.7.2B). Polyphosphoric acid in AcOH resulted in nonspecific decomposition. All attempts to utilize ester 174 under basic or Lewis acidic conditions resulted in no reaction.26 Next, acid chloride 176 was treated with AlCl3 to generate the highly electrophilic oxocarbenium/ketene. Unfortunately, this also resulted in a complex mixture. Finally, dimethyl acetal 175 was prepared and treated with Lewis acids, resulting in elimination to the methyl enol ether (not shown) with TMSOTf/Hunig’s base, and hydrolysis to the aldehyde (61) with SnCl4. Elimination of 175 to the methyl enol ether Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 185 suggests that the oxocarbenium electrophile was formed, but cyclization was unfavorable, possibly due to an insurmountable steric interaction. Scheme A5.7.2. Synthesis and deployment of Claisen substrates. A) Synthesis of Claisen substrates. O 61 O MeO2C NaClO2, NaH2PO4 2-methyl-2-butene MeO2C Me3SiCHN2 t-BuOH/H2O, 18 ºC CO2H Et2O/MeOH H 94% yield CO2Me H 95% yield 173 174 O 61 CeCl3 (OMe)3CH O MeO2C MeO2C (COCl)2, DMF MeOH, 18 ºC CH2Cl2, 18 ºC COCl H 175 H OMe 176 MeO B) Attempts to close the C5–C9 bond irreversibly. 173 174 Amberlyst 15 PhMe, 100 ºC X OR polyphorphoric acid AcOH, 100 ºC NaOMe, PhH, 65 ºC OR LiTMP, THF, –78 ºC OR EtSAlMe2 CH2Cl2, 50 ºC X X MeO2C O H 177 O H X AlCl3 CH2Cl2, 18 ºC 176 TMSOTf, EtN(Oi-Pr)2 CH2Cl2, 18 ºC OR, SnCl4 MeCN, 0 ºC 175 At this stage we hypothesized that perhaps the prenyl group was responsible for a deleterious steric interaction and elected to synthesis ester 178 (Scheme A5.7.3). Ester 178 was prepared via sequential oxidation and methylation of alcohol 169 (Scheme A5.6.3). Cyclization of 178 to dione 179 was anticipated to proceed more readily, with the acidic 1,3-diketone serving as a handle for subsequent installation of the prenyl group. However, a range of basic conditions resulted in no reaction, while EtSAlMe2 resulted in decomposition. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 186 Scheme A5.7.3. Synthesis and deployment of des-prenyl ester 178. O DMP 169 O CH2Cl2 39 O H O conditions X No reaction or complex mixture (EtSAlMe2) CO2Me H 178 55% over 2 steps MeO2C 178 MeO2C 2. Me3SiCHN2 Et2O/MeOH H 87% yield O 1. NaClO2, NaH2PO4 2-methyl-2-butene t-BuOH/H2O, 18 ºC MeO2C H H Unsuccessful conditions: • NaOMe, PhH OR MeOH, 70 ºC • NaOMe, MeOH, µw, 125 ºC • LiTMP OR LHMDS, THF • EtSAlMe2, CH2Cl2, 50 ºC 179 The accumulated results from attempts to forge the C5–C9 bond led to the conclusion that cyclization was unlikely to be favorable thermodynamically due to the strain induced in the tricyclic system. The isolation of lactone 38 was recognized as a fortunate outcome, arising from the serendipitous lactonization of the aldol product, which acted as a thermodynamic sink. At this point, rather than continuing to pursue cyclization of these systems to the aldol/Claisen products, efforts were redirected toward utilizing lactone 38 as a synthetic intermediate. A5.8 CYCLOHEXENONE STRATEGY: OPENING THE CAGED LACTONE Proceeding with lactone 38 (Scheme A5.8.1), a lactone opening followed by oxidation was anticipated to provide tricycle 177, intercepting the original retrosynthesis for the homoadamantane PPAPs. Scheme A5.8.1. Proposed future steps for lactone 38. O O H H 1. lactone opening 2. [O] MeO2C O O H H 38 177 O H Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 187 Targeting alcohol 180 (Table A5.8.1), where R = ester, a variety of lactone opening conditions were attempted (entries 1–5).27,28 In all cases, even at greatly elevated temperatures, no reaction was observed. Our current hypothesis is that lactone opening is not prohibitively challenging, rather, the rigid backbone of alcohol 180 provides a strong driving force for cyclization back to lactone 38. It was determined that to proceed with lactone 38, ester opening must lead to a thermodynamically favorable product, making the process effectively irreversible. A set of unique conditions using Na2RuO4 published by Corey could potentially saponify the ester to the potassium salt using KOH, followed by basic oxidation of the 2° alcohol to afford ketone 181.29 Table A5.8.1. Attempts to open lactone 38 to tricycle 180. O O H R O OH conditions H X O H H 38 180 H entry conditions R result 1 NaOMe, MeOH -CO2Me no reaction 2 Al(Oi-Pr)3, MeOH -CO2Me no reaction 3 AlMe3, MeOH, PhMe -CO2Me no reaction 4 Bu3SnOMe -CO2Me no reaction 5 Mg(OEt)2, EtOH -CO2Et no reaction 6 LiAlH4, THF -CH2OH complex mixture KOH (1M aq.) then, Na2RuO4 38 X observed decarboxylation HO2C O H 181 O H Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 188 Unfortunately, the only product identified by mass spectrometry was the decarboxylated species, suggesting a potentially favorable pathway for relieving strain in this compound. Moving beyond esters, it was decided to try opening lactone 38 using an AlMe3mediated Weinreb amine amidation, a reaction that has significant precedent for opening stubborn lactones.30 We were happy to see that indeed, a small sample could be progressed to ketone 183 via amide 182 following oxidation (Scheme A5.8.2). This material was then subjected to both hard and soft enolization conditions with the hopes of accessing 1,3diketone 184, however this dione was never observed.31,32 Scheme A5.8.2. Weinreb amide opening of lactone 38. O O H HNMe(OMe)•HCl, AlMe3 H O MeO O OH N PhMe/CH2Cl2, 0 ºC O H H 38 182 O MeO O O N H H 183 (<1 mg) O MeO LHMDS, i-Pr(CO)CN THF, –78 ºC OR X MgBr2•OEt2, EtN(i-Pr) 185, CH2Cl2, 18 ºC DMP CH2Cl2, 18 ºC H O O O N N H 184 O 185 N N H The challenges associated with these late-stage intermediates were exasperated by difficulties in scalability and material throughput. To alleviate these challenges, isomer 171 was deemed a viable model system for investigating future steps following amidation and oxidation to dione 186 (Scheme A5.8.3A). Functionalization of both the amide and the eastern ketone was attempted. The Weinreb amide had sufficient thermodynamic drive to open lactone 171, however this stability also proved problematic for further functionalization. Both esterification of the amide to ester 187 or cyclization to homoadamantane 188 were unsuccessful, with the amide remaining unaffected (Scheme Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 189 A5.8.3B). We also attempted to acylate dione 186 to install the final four carbons required in the natural product (Scheme A.5.8.4C). Scheme A5.8.3. Studies carried out on model Weinreb amide 186. A) Synthesis of model amide 186. O O O MeO H 1. HNMe(OMe)•HCl, AlMe3, PhMe/CH2Cl2, 0 ºC H O O N 2. DMP, CH2Cl2, 18 ºC O H H 51% over 2 steps 171 H 186 B) Attempts to functionalize the Weinreb amide in 186. HCl (aq.) MeOH, 100 ºC 186 O 186 OR X p-TsOH MeOH, 100 ºC H desired mass not detected 187 O LHMDS THF, 18 ºC O MeO2C H O H OR X TFA MeCN, 18 ºC O H desired mass not detected 188 C) Attempts to install the acyl group on the eastern 6-membered ring on amide 186. O MeO 186 LDA, 185 OR 193 THF, –78→18 ºC 186 O H O MeO 186 H OTMS NBS NaHCO3 O H 189 H 192 O O O N O Br N THF, –78 ºC CH2Cl2, 18 ºC 54% yield O O X new species after step 1, starting material after step 2 MeO O N O N 1. LDA, 192 THF, –78→18 ºC 2. DMP, CH2Cl2 189 TMSOTf Et3N O N X decomposition O MeO O H 190 H observed mass H 191 H 193 N Using acyl imidazole (193) with LDA resulted in no reaction, however using benzotriazole 185 resulted in a new species with the desired mass. Although the newly formed species could not be fully assigned upon isolation, it was clear that it was not the desired trione (189). It was also attempted to access trione 189 through an aldol reaction with aldehyde 192 followed by oxidation. Following the aldol step, several new species were observed, however, these reverted to dione 186 upon oxidation. Finally, silyl enol Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 190 ether 190 was prepared to access bromide 191. Although bromination of 190 appeared promising, this pathway was ultimately abandoned due to the challenges associated with the Weinreb amide. Several other nucleophiles were tried in the hope that some of these compounds (194–197) would be more labile and amenable to further transformation (Table A5.8.2A). Treatment with propanethiol to access thioester 194 proved unfruitful, resulting in only starting material (entry 1).33 Using a combination of NH4Cl/AlMe3 resulted in isolation of acetamide 195 (entry 2), however subsequent oxidation of the 2° alcohol resulted in decomposition. Dimethylamine and pyrrolidine led to unidentified side-products and no reaction, respectively (entries 3,4). An interesting report by Barrett and Barton outlines the use of indoline as a nucleophilic 2° amine whose amides are stable, but become labile indoles following oxidation with DDQ.34 To our delight, indoline successfully afforded a mixture of desired amide 198 and over reduced diol 199, indicating an unusual ketone reduction in which indoline may be acting as a reducing agent (Table 5.8.2B). This mixture could be oxidized with DMP to yield the dione (not shown), followed by DDQ oxidation to yield acyl indole 200. With a tricyclic ring system bearing a labile leaving group in hand, dione 200 was subjected to basic methanolysis. Excitingly, this allowed us to observe ester 201 by mass spectrometry. Despite the indoline strategy showing promise, concomitant studies done with aniline proved far more fruitful, leading to the final route presented in Chapters 1 and 2. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 191 Table A5.8.2. Other amines used to open the caged lactones 171 and 38. A) Opening of lactone 171 with selected amines. O O H H conditions O H 171 entry product 1 conditions AlMe3, PrSH, CH2Cl2 194 no reaction 2 AlMe3, NH4Cl, PhMe 195 decomposition following oxidation 3 AlMe3, HNMe2•HCl, PhMe 196 two unidentified side products 4 AlMe3, pyrrolidine, PhMe 197 no reaction O O O OH PrS H O O OH H 2N H H 194 result O O OH Me2N H H 195 O OH N H H 196 H 197 B) Opening lactone 38 using indoline. O O H H O AlMe3 indoline O O OH N + PhMe, 0 ºC OH OH N O H H 38 198 O H H 199 O O O N 1. DMP, CH2Cl2 O O MeO NaOMe THF 2. DDQ, PhH, 75 ºC H 200 H H 201 H H Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs A5.9 EXPERIMENTAL SECTION A5.9.1 MATERIALS AND METHODS 192 Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.35 NBS was recrystallized from boiling water prior to use and amines were distilled under nitrogen prior to use. 3-bromo3-methylbut-1-yne was prepared according to a previously reported procedure.36 Activated zinc dust was prepared according to a previously reported procedure.37 Allene 10138 was prepared according to a previously reported procedure. All other reagents were purchased from commercial sources and used as received unless otherwise indicated. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLCMS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 nm) was used for flash chromatography. 1H NMR spectra were recorded on Varian Inova 500 MHz, 600MHz, and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs A5.9.2 193 EXPERIMENTAL PROCEDURES 8 O BrZn then Pd(PPh3)4 AcCl, 18 ºC 7 methyl AcO DME, –10 ºC, 48 h then, 65 ºC, 72 h MeO2C MeO2C AcO 78 (5R)-2-acetoxy-7-(4-acetoxy-2-methylbut-3-yn-2-yl)-5-(prop-1-en-2- yl)cyclohept-1-ene-1-carboxylate 78. A 500 mL Teflon-stoppered flask under Ar was charged with Zn (1.56 g, 24 mmol, 2.5 equiv) and DME (50 mL). The reaction was cooled to –10 °C and 3-bromo-3-methylbut1-yne (3.5 g, 24 mmol, 2.5 equiv) was added in one portion. The solution was stirred at this temperature for 2 days, after which the mixture was brought into a glovebox and filtered. A solution of 7 (2.0 g, 9.6 mmol, 1 equiv) in DME (50 mL) was added dropwise and the reaction was stirred at 76 °C for 2 d. A separate solution of Pd(PPh3)4 (665 mg, 0.576 mmol, 0.06 equiv) and AcCl (11 g, 144 mmol, 15 equiv) in DME (50 mL) was prepared, and the zinc reagent solution was added dropwise over several minutes. The reaction was stirred for 15 min and quenched with ice-cold saturated aqueous NH₄Cl. The mixture was neutralized with potassium phosphate and water, extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (5→15% EtOAc/hexanes) to furnish 78 as a colorless oil. 1H NMR (500 MHz, CDCl3) δ = 4.75 – 4.67 (m, 2H), 3.73 (s, 3H), 3.16 – 3.07 (m, 2H), 2.34 (s, 3H), 2.25 (td, J = 10.8, 6.8 Hz, 1H), 2.15 (s, 3H), 2.02 (ddd, J = 14.6, 5.8, 1.9 Hz, 1H), 1.95 (dd, J = 13.8, 8.7 Hz, 1H), 1.87 (tt, J = 13.0, 6.3 Hz, 1H), 1.73 (s, 3H), 1.71 – 1.63 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 194 (m, 1H), 1.54 – 1.46 (m, 1H), 1.30 (s, 3H), 1.27 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 185.1, 168.9, 168.9, 155.2, 149.7, 120.2, 109.7, 98.7, 82.3, 52.1, 47.2, 40.8, 37.4, 32.9, 30.0, 29.4, 28.3, 26.7, 26.6, 20.9, 20.4. O O methyl methyl MeO2C Cu(OAc)2, o-Ph(PPH2)2 PMHS O HO MeO2C H H 10 80 (3aS,7R,8aS)-2-acetyl-4-hydroxy-1,1-dimethyl-7-(prop-1-en-2-yl)- 4,5,6,7,8,8a-hexahydroazulene-3a(1H)-carboxylate 80. A vial was charged with Cu(OAc)2 (6 mg, 0.03 mmol, 1.0 equiv) and o-Ph(PPh2)2 (1.3 mg, 0.003 mmol, 0.1 equiv), purged with N2, and then PhMe/t-BuOH (4:1, 2.6 mL) was added. After the solids dissolved, PMHS (400 µL, 6 mmol, 200 equiv) was added and the reaction was stirred for 1 h. Enone 10 (10 mg, 0.031 mmol, 1.0 equiv) in PhH (0.2 mL) was then added. After 2 days, the reaction was quenched with water and hexanes, extracted with EtOAc, and the solvent was removed under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (25% EtOAc in hexanes) to furnish 80. 1 H NMR (400 MHz, CDCl3) δ = 6.46 (s, 1H), 4.67 (s, 1H), 4.61 (dq, J = 2.9, 1.4 Hz, 1H), 4.47 – 4.41 (m, 1H), 3.76 (s, 3H), 3.04 (dd, J = 12.8, 6.3 Hz, 1H), 2.31 (s, 3H), 2.25 – 2.17 (m, 1H), 2.03 (ddt, J = 14.9, 6.0, 3.7 Hz, 1H), 1.87 – 1.76 (m, 1H), 1.74 (dd, J = 1.5, 0.8 Hz, 3H), 1.73 – 1.64 (m, 2H), 1.42 (dddd, J = 14.8, 13.4, 4.6, 1.4 Hz, 1H), 1.27 (s, 4H), 1.17 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 196.5, 174.5, 153.3, 152.7, 143.7, 107.8, 73.3, 68.7, 52.9, 51.4, 49.3, 44.1, 33.9, 31.9, 30.6, 28.8, 28.5, 23.2, 20.4. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O O methyl MeO2C Li0, t-BuOH, NH 3 195 O MeO2C O H H 10 81 (3aR,5R)-2-acetyl-8-hydroxy-3,3-dimethyl-5-(prop-1-en-2- yl)decahydroazulene-1-carboxylate 81. A solution of enone 10 (100 mg, 0.31 mmol, 1.0 equiv), t-BuOH (23.3 mg, 0.31 mmol, 1.0 equiv), and Et2O (0.4 mL) was prepared under Ar. Separately, Li (4.79 mg, 0.69 mmol, 2.2 equiv) was added to NH3 (4 mL, 0.25 M) at –78 °C. The ether solution was added dropwise to the stirred ammonia solution at –78 °C and stirred for 30 min. The reaction was quenched with saturated aqueous NH4Cl and allowed to warm to 23 °C. The mixture was extracted with EtOAc and filtered, and the solvent was removed under reduced pressure. Purification by preparative thin-layer chromatography (30% EtOAc in hexanes) furnished 81. 1H NMR (400 MHz, CDCl3) δ = 4.70 (dq, J = 10.7, 1.3 Hz, 2H), 3.93 (dd, J = 9.6, 6.5 Hz, 1H), 3.65 – 3.59 (m, 4H), 2.80 (d, J = 9.6 Hz, 1H), 2.69 (dt, J = 18.7, 3.9 Hz, 1H), 2.55 – 2.43 (m, 1H), 2.19 (s, 3H), 1.94 – 1.84 (m, 3H), 1.79 – 1.71 (m, 4H), 1.51 – 1.42 (m, 1H), 1.34 (s, 1H), 1.11 (s, 3H), 0.89 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 211.1, 207.4, 174.2, 150.9, 109.2, 63.0, 57.5, 53.9, 52.2, 48.2, 45.7, 44.4, 42.6, 35.9, 32.2, 29.0, 28.1, 20.5, 17.5. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O O O methyl MeO2C 196 Raney Ni O MeO2C H H 10 82 (3aS,7R,8aS)-2-acetyl-7-isopropyl-1,1-dimethyl-4-oxo-4,5,6,7,8,8a- hexahydroazulene-3a(1H)-carboxylate 82. A vial was charged with enone 10 (15 mg, 0.047 mmol, 1.0 equiv) and THF (1.5 mL). Raney-Ni (0.25 g) was added and the reaction was stirred. After 1 h, an additional portion of Raney-Ni (0.25 g) was added and stirring was continued. After 3 h, the reaction was removed from the glovebox and the solvent was removed under reduced pressure to yield 82. 1H NMR (400 MHz, CDCl3) δ = 6.50 (s, 1H), 4.12 (q, J = 7.1 Hz, 1H), 3.80 (s, 3H), 2.89 (dd, J = 13.2, 3.7 Hz, 1H), 2.60 – 2.51 (m, 1H), 2.45 (td, J = 6.6, 4.1 Hz, 1H), 2.33 (s, 3H), 2.04 (s, 1H), 1.93 – 1.82 (m, 2H), 0.96 (d, J = 6.6 Hz, 6H). Note: only key peaks are provided, indicating the absence of the isopropenyl protons, but not the enone resonance. O O methyl MeO2C O Rh/alumina, H2 O MeO2C H H 10 83 (3aS,7R,8aS)-2-acetyl-7-isopropyl-1,1-dimethyl-4-oxooctahydroazulene- 3a(1H)-carboxylate 84. A vial was charged with enone 10 (10 mg, 0.031 mmol, 1.0 equiv), 5% Rh/Alumina (6 mg), and EtOAc (1 mL). The reaction was placed in a Parr bomb and pressurized to 10 atm with hydrogen and stirred for 2 days. The pressure was released and the reaction mixture was filtered and concentrated under reduced pressure. The crude residue was passed Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 197 through a short silica plug (15% EtOAc/hexanes) to yield 83. Major diastereomer: 1H NMR (400 MHz, CDCl3) δ = 3.74 (s, 3H), 3.20 (t, J = 14.0 Hz, 1H), 2.67 (ddd, J = 13.7, 8.7, 4.5 Hz, 2H), 2.47 – 2.42 (m, 2H), 2.16 (s, 3H), 1.75 – 1.67 (m, 1H), 0.87 (d, J = 1.6 Hz, 3H), 0.85 (d, J = 1.6 Hz, 3H); Minor diastereomer: 1H NMR (400 MHz, CDCl3) δ = 3.69 (s, 3H), 2.87 (dd, J = 13.8, 7.6 Hz, 1H), 2.81 – 2.72 (m, 1H), 2.57 (dd, J = 12.1, 7.5 Hz, 1H), 2.17 (s, 3H), 1.75 – 1.67 (m, 1H), 0.89 (d, J = 1.5 Hz, 3H), 0.88 (d, J = 3.3 Hz, 3H). Note: only key peaks are provided, indicating the absence of all olefinic resonances. 8 O O H MeO BrZn DME, –10 ºC, 48 h O MeO2C H then 65 ºC, 72 h 75 methyl H H 89 H (1aR,2aR,5aR,7aS)-1,1,3,3-tetramethyl-6-oxo-1,1a,2,2a,3,6,7,7a-octahydro- 5aH-cyclopropa[f]azulene-5a-carboxylate 89. A 4 mL vial was charged with zinc powder (39 mg, 0.60 mmol, 2.5 equiv) and DME (1 mL) and cooled to –15 °C. 3-bromo-3-methylbut-1-yne (80 μL, 88.2 mg, 0.60 mmol, 2.5 equiv) was added and the mixture was stirred. After 1 hour, most of the zinc had dissolved and ester 75 (50 mg, 0.24 mmol, 1.0 equiv) was added. The mixture was stirred at –15 °C overnight, then warmed to 60 °C the following day. After stirring at this temperature for 2 days, the reaction was quenched with saturated aqueous NH4Cl. The mixture was extracted, and the organic layer was concentrated. Purification by silica gel flash chromatography (5→10% EtOAc/hexanes) yielded 89. 1H NMR (400 MHz, CDCl3) δ = 5.90 (d, J = 5.7 Hz, 1H), 5.44 (dd, J = 5.7, 0.7 Hz, 1H), 3.78 (s, 3H), 3.08 (dd, J = 13.5, 4.4 Hz, 1H), 2.98 (dd, J = 19.9, 8.8 Hz, 1H), 2.15 (dd, J = 19.9, 8.1 Hz, 1H), 1.90 (dt, J = 14.1, 4.0 Hz, 1H), 1.12 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 198 (s, 3H), 1.06 (s, 3H), 0.98 (s, 3H), 0.90 (ddd, J = 12.1, 8.5, 3.6 Hz, 1H), 0.84 – 0.76 (m, 1H), 0.75 (s, 3H), 0.49 (q, J = 8.5 Hz, 1H). O 90 O H MeO 75 H O HO BrMg MeO 91 methyl (1R,7S)-5-hydroxy-8,8-dimethylbicyclo[5.1.0]octa-2,4-diene-4-carboxylate 91. A 1 M solution of propargylmagnesium bromide (90) in THF was prepared by charging a flame-dried Schlenk flask with magnesium turnings (97 mg, 4.0 mmol, 2.0 equiv) under vacuum. Anhydrous THF (1.7 mL) was added, followed by 3-bromo-3-methylbut-1-yne (294 mg, 2.00 mmol, 1.0 equiv) at room temperature. The reaction mixture was stirred and gently warmed to 38 °C, at which point it turned yellow and began to evolve gas. A white precipitate formed, and the mixture was heated to 50 °C for 1 hour, then allowed to cool. The resulting 1 M solution of the Grignard reagent was used directly in the next step without further purification. To a solution of the enone 75 (25 mg, 0.12 mmol, 1.0 equiv) in THF (1 mL) under argon at 0 °C was added the freshly prepared propargylmagnesium bromide (0.144 mL, 0.144 mmol, 1.2 equiv) in one portion. The reaction mixture turned slightly yellow and was stirred for 30 minutes, after which TLC analysis showed complete consumption of the starting material. The reaction was quenched by concentration under reduced pressure to afford 91. 1H NMR (500 MHz, CDCl3) δ = 12.93 (s, 1H), 6.08 (dd, J = 11.1, 2.4 Hz, 1H), 5.84 (ddd, J = 11.1, 2.1, 0.7 Hz, 1H), 3.78 (s, 3H), 2.49 – 2.36 (m, 2H), 1.36 – 1.32 (m, 1H), 1.11 (s, 3H), 1.08 (dt, J = 8.2, 2.3 Hz, 1H), 1.05 (s, 3H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O O H MeO 75 ClMg CuI SiMe3 H Me3Si MeO O O O O 92 + 199 MeO SiMe3 93 94 b-ketoesters 93 and 94. To a test tube charged with magnesium turnings (42 mg, 1.7 mmol, 1.5 equiv) under nitrogen was added anhydrous THF (1 mL), followed by (3-Chloro-3-methyl-1-butyn-1yl)trimethylsilane (250 mg, 1.1 mmol, 1.0 equiv). The mixture was heated to 60 °C, initiating the Grignard reaction, which proceeded rapidly to give a homogenous yellow solution with excess Mg settling at the bottom. After stirring at 60 °C for 20–30 minutes, the reaction was cooled to room temperature, resulting in the precipitation of a solid. The mixture was cooled to 0 °C, and CuI (130 mg, 0.68 mmol, 0.6 equiv) was added in one portion. In a separate vessel, a solution of enone 75 (40 mg, 0.21 mmol, 0.15 equiv) was prepared in THF (0.25 mL). The Gilman reagent was transferred to the enone solution. After stirring for 30 minutes at 0 °C, the reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (2→5% EtOAc in hexanes) to afford 93 and 94. Clean NMR spectra were not attained for 93 and 94. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O 8 BrZn 95 200 HO 96 (1S,7R)-8,8-dimethyl-3-(2-methylbut-3-yn-2-yl)bicyclo[5.1.0]oct-4-en-3-ol 96. To a test tube charged with zinc dust (27 mg, 0.415 mmol, 2.5 equiv) and anhydrous DME (1.6 mL) was added 3-bromo-3-methylbut-1-yne (61 mg, 0.415 mmol, 2.5 equiv) at –15 °C under inert atmosphere. The mixture was stirred for 1 hour, after which a solution of enone 95 (25 mg, 0.166 mmol, 1.0 equiv) in Et2O (0.4 mL) was added dropwise. The reaction was allowed to stir at –15 °C for an additional 1 hour and monitored by TLC, showing full consumption of starting material and formation of a clean new product spot. The reaction was quenched with saturated aqueous NH4Cl and extracted with hexanes. The organic layer was dried over Na2SO4, filtered, and concentrated to yield 96. 1H NMR (500 MHz, CDCl3) δ = 5.95 (ddd, J = 11.8, 8.6, 4.1 Hz, 1H), 5.61 (dt, J = 11.8, 2.8 Hz, 1H), 2.23 (s, 1H), 2.16 – 2.12 (m, 1H), 2.02 (s, 1H), 1.86 (dddd, J = 15.6, 11.1, 4.1, 2.9 Hz, 1H), 1.64 – 1.56 (m, 2H), 1.26 (d, J = 1.3 Hz, 6H), 1.11 (s, 3H), 1.04 (s, 3H), 1.02 – 0.97 (m, 1H), 0.85 – 0.79 (m, 1H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 201 97 O O TMSO O O TiCl4, Ti(Oi-Pr)4 MeO MeO O 98 75 methyl (1R,3S,7S)-8,8-dimethyl-3-(2-methyl-1-oxopropan-2-yl)-5- oxobicyclo[5.1.0]octane-4-carboxylate 98. A test tube under N2 was charged with CH2Cl2 (3.0 mL) and cooled to –78 °C. TiCl4 (143 mg, 0.75 mmol, 1.9 equiv) was added, followed by Ti(Oi-Pr)4 (142.1 mg, 0.50 mmol, 1.3 equiv). After 5 min, a solution of enone 75 (83 mg, 0.4 mmol, 1.0 equiv) in CH2Cl2 (0.8 mL) was added dropwise, and the mixture was stirred for 30 min before a solution of 97 (86 mg, 0.6 mmol, 1.4 equiv) in CH2Cl2 (0.8 mL) was added over 1 min. The reaction was stirred at –78 °C for 30 min before removing the cold bath and allowing the mixture to warm to 18 °C. The reaction was quenched with saturated aqueous NaHCO3 (1 mL) and extracted with Et2O (3 x 1 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure to yield 98. 1H NMR (400 MHz, C6D6) δ = 9.41 (s, 1H), 3.72 (p, J = 1.7 Hz, 1H), 3.66 (s, 3H), 2.87 (dd, J = 11.9, 10.7 Hz, 1H), 2.40 (ddd, J = 11.9, 6.5, 1.7 Hz, 1H), 2.19 – 2.10 (m, 2H), 1.69 (s, 1H), 1.13 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H), 0.73 – 0.66 (m, 1H), 0.62 (ddd, J = 10.8, 8.9, 6.5 Hz, 1H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 202 97 O O O TMSO O TiCl4, Ti(Oi-Pr)4 MeO + O O 99 75 100 Ketones 99 and 100. A test tube under N2 was charged with CH2Cl2 (3.0 mL) and cooled to –78 °C. TiCl4 (143 mg, 0.75 mmol, 1.9 equiv) was added, followed by Ti(Oi-Pr)4 (142.1 mg, 0.50 mmol, 1.3 equiv). After 5 min, a solution of enone 75 (60 mg, 0.4 mmol, 1.0 equiv) in CH2Cl2 (0.8 mL) was added dropwise, and the mixture was stirred for 30 min before a solution of 97 (86 mg, 0.6 mmol, 1.4 equiv) in CH2Cl2 (0.8 mL) was added over 1 min. The reaction was stirred at –78 °C for 30 min before removing the cold bath and allowing the mixture to warm to 18 °C. The reaction was quenched with saturated aqueous NaHCO3 (1 mL) and extracted with Et2O (3 x 1 mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (0→15% EtOAc in hexanes) to afford a mixture of 99 and 100. Clean NMR spectra were not attained for 99 and 100. O O 101 SiMe3 TiCl4 MeO CO2Me HO OH MeO2C Cl 75 103 + 104 Chloride 103 and Enol 104. A 4 mL vial under N2 was charged with allene 101 (20 mg, 0.14 mmol, 1.0 equiv) and CH2Cl2 (0.75 mL). Ester 75 (30 mg, 0.14 mmol, 1.0 equiv) was then added, and the solution was cooled to –78 °C. TiCl4 (41 mg, 0.22 mmol, 1.5 equiv) was added dropwise. The Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 203 reaction was stirred as it gradually warmed to 18 °C over 2 h. Upon completion by TLC, the reaction was quenched with water and extracted with CH2Cl2, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (5% EtOAc/hexanes) to furnish 103 and 104 as colorless oils. Characterization data for chloride 103: 1H NMR (400 MHz, CDCl3) δ = 11.92 (s, 1H), 3.81 (s, 3H), 2.44 (ddd, J = 17.1, 5.7, 1.9 Hz, 1H), 2.38 – 2.28 (m, 1H), 2.01 (dd, J = 17.0, 12.3 Hz, 1H), 1.78 (td, J = 8.5, 4.6 Hz, 1H), 1.68 (s, 3H), 1.67 (s, 3H), 1.49 – 1.38 (m, 1H), 0.89 (td, J = 8.3, 5.1 Hz, 1H), 0.45 (dtd, J = 5.9, 4.9, 0.8 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ = 172.6, 169.1, 99.0, 73.8, 51.8, 43.2, 30.9, 30.3, 27.5, 13.3, 10.3, 7.3. Characterization data for enol 104: 1H NMR (400 MHz, CDCl3) δ = 12.50 (d, J = 1.0 Hz, 1H), 6.71 (d, J = 11.3 Hz, 1H), 6.24 (ddd, J = 11.4, 5.5, 0.6 Hz, 1H), 5.95 (dd, J = 5.5, 1.1 Hz, 1H), 3.81 (d, J = 1.0 Hz, 3H), 2.66 (s, 2H), 2.55 – 2.45 (m, 1H), 1.12 (s, 3H), 1.10 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 172.4, 166.6, 140.9, 124.7, 124.1, 120.4, 101.1, 51.9, 36.6, 35.9, 21.1. O O CuI, Me2PhSiLi Me2PhSi 95 114 (1S,5R,7R)-5-(dimethyl(phenyl)silyl)-8,8-dimethylbicyclo[5.1.0]octan-3-one 114. A 25 mL Schlenk flask under N2 was charged with CuI (757 mg, 3.4 mmol, 1.3 equiv) and THF (3 mL) and cooled to –23 °C. Dimethyl(phenyl)silyllithium (0.86 M in THF, 9.23 mL, 7.9 mmol, 2.7 equiv) was added slowly over 5 min and the mixture was stirred at –23 °C for 4 h. Enone 95 (448 mg, 2.99 mmol, 1.0 equiv) in THF (3 mL) was then added, and the reaction was stirred for an additional 30 min. The reaction was poured into 25 g crushed Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 204 ice with concentrated aq. HCl (5 mL) and extracted with CH2Cl2 (3x). The combined organic extarctes were washed with aq. 3M HCl, saturated NaHCO3, water, and dried over Na2SO4. After concentration under reduced pressure the crude residue was purified by silica gel chromatography (3→7.5% EtOAc/hexanes) to furnish 114 as an oil. 1H NMR (500 MHz, CDCl3) δ = 7.52 – 7.49 (m, 2H), 7.38 – 7.36 (m, 3H), 2.91 (t, J = 11.8 Hz, 1H), 2.62 (dd, J = 17.6, 8.0 Hz, 1H), 2.19 (dd, J = 12.0, 4.9 Hz, 1H), 2.13 (dd, J = 17.6, 9.4 Hz, 1H), 1.94 (ddd, J = 14.9, 5.4, 2.7 Hz, 1H), 1.45 – 1.38 (m, 1H), 1.37 – 1.30 (m, 1H), 1.04 (s, 3H), 0.96 (s, 3H), 0.77 – 0.71 (m, 1H), 0.60 (ddd, J = 11.2, 8.9, 5.3 Hz, 1H), 0.37 (s, 3H), 0.35 (s, 3H). Note: a minor diastereomer was also observed (1 : 0.3) but is inseparable from the major diastereomer. O Me2PhSi O LDA, then TMSCl then NBS Br Me2PhSi 114 115 (1S,5R,7R)-2-bromo-5-(dimethyl(phenyl)silyl)-8,8-dimethylbicyclo[5.1.0]octan-3-one 115. A test tube under N2 was charged with i-Pr2NH (85 mg, 0.84 mmol, 1.2 equiv) and THF (1.7 mL) and cooled to –78 °C. n-BuLi (2.5 M in hexanes, 0.3 mL, 0.735 mmol, 1.05 equiv) was added dropwise. After 30 min, ketone 114 (200 mg, 0.70 mmol, 1.0 equiv) in THF (0.6 mL) was added slowly. After another 30 min, TMSCl (114 mg, 1.05 mmol, 1.5 equiv, 0.133 mL) was added slowly and the reaction was allowed to warm to 18 °C. After 1 h, nbromosuccinimide (187 mg, 1.05 mmol, 1.5 equiv) was added in one portion and the reaction was stirred at 18 °C for 20 minutes. The reaction was quenched with saturated aqueous NaHCO3 and poured into Et2O, and the aqueous phase was extracted once more Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 205 with Et2O. The combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (0→5% EtOAc/hexanes) to furnish 115 as an oil. 1H NMR (400 MHz, CDCl3) δ = 7.52 – 7.49 (m, 2H), 7.40 – 7.36 (m, 3H), 4.30 (d, J = 10.1 Hz, 1H), 2.82 (dd, J = 13.7, 9.1 Hz, 1H), 2.41 (dd, J = 13.7, 5.0 Hz, 1H), 2.06 – 2.00 (m, 1H), 1.53 – 1.44 (m, 2H), 1.10 (s, 3H), 1.08 (s, 3H), 1.07 – 1.01 (m, 1H), 0.84 – 0.73 (m, 1H), 0.35 (d, J = 6.0 Hz, 6H). O 116 Br O SnBu3 ACHN Me2PhSi Me2PhSi 115 118 (4S,6R)-7-allyl-6-(dimethyl(phenyl)silyl)-4-isopropylcyclohept-2-en-1-one 118. A Teflon-stoppered flask was charged with bromide 115 (74 mg, 0.20 mmol, 1.0 equiv), ACHN (9.8 mg, 0.04 mmol, 0.2 equiv), allylstannane 116 (265 mg, 0.80 mmol, 4.0 equiv), and PhH (2.8 mL) and heated to 76 °C in an oil bath. After 48 h, an additional portion of ACHN (10 mg) was added and the reaction was heated at 76 °C overnight. The flask was removed from the oil bath and allowed to cool before the solvent was removed under reduced pressure. The crude residue was purified by silica gel chromatography (2→6% EtOAc/hexanes) to furnish 118 as an oil. 1H NMR (400 MHz, CDCl3) δ = 7.53 – 7.49 (m, 2H), 7.38 – 7.34 (m, 3H), 6.31 (ddd, J = 12.4, 3.2, 0.8 Hz, 1H), 5.91 (dd, J = 12.4, 2.5 Hz, 1H), 5.64 – 5.51 (m, 1H), 4.95 – 4.86 (m, 2H), 2.79 (ddd, J = 9.1, 6.9, 5.1 Hz, 1H), 2.43 (dddt, J = 14.1, 9.1, 6.5, 1.3 Hz, 1H), 2.23 (ddt, J = 11.6, 5.7, 2.9 Hz, 1H), 2.14 (dddt, J = 13.8, 7.4, 5.1, 1.1 Hz, 1H), 1.83 – 1.75 (m, 1H), 1.74 – 1.67 (m, 2H), 1.33 – 1.29 (m, 1H), Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 206 0.83 (dd, J = 6.9, 5.6 Hz, 6H), 0.36 (s, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ = 13C NMR (101 MHz, CDCl3) δ = 206.8, 147.3, 138.1, 136.2, 134.0, 131.5, 129.4, 128.1, 116.5, 54.2, 46.9, 37.2, 32.8, 29.3, 25.2, 20.1, 19.4, -2.7, -2.9. O Me2PhSi Br HO NaBH4 Br Me2PhSi 115 122 (1S,5R,7R)-2-bromo-5-(dimethyl(phenyl)silyl)-8,8-dimethylbicyclo[5.1.0]octan-3-ol 122. A 4 mL vial under N2 was charged with bromide 115 (23 mg, 0.063 mmol, 1.0 equiv) and MeOH (0.4 mL) and cooled to 0 °C. NaBH4 (29 mg, 0.78 mmol, 12 equiv) was added in one portion and the cold bath was removed after 20 min. After an additional 20 min, the reaction was quenched with saturated aqueous NH4Cl. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2, filtered again, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (2→10% EtOAc/hexanes) to furnish 122 as a single diastereomer. 1H NMR (400 MHz, CDCl3) δ = 7.51 (dddd, J = 6.9, 4.7, 3.2, 1.5 Hz, 2H), 7.39 – 7.34 (m, 3H), 4.05 (dddd, J = 9.6, 5.9, 4.0, 2.2 Hz, 1H), 3.80 (dd, J = 11.3, 9.4 Hz, 1H), 2.27 (dd, J = 2.2, 1.1 Hz, 1H), 2.20 (dddd, J = 13.4, 8.1, 3.5, 1.1 Hz, 1H), 1.94 – 1.86 (m, 1H), 1.62 (ddd, J = 14.5, 5.5, 3.4 Hz, 1H), 1.42 (ddt, J = 9.0, 7.4, 3.8 Hz, 1H), 1.32 (dt, J = 11.3, 3.7 Hz, 1H), 1.11 – 1.07 (m, 1H), 1.06 (d, J = 4.7 Hz, 6H), 0.69 – 0.60 (m, 1H), 0.33 (d, J = 2.3 Hz, 6H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O LDA, then TMSCl then NBS 95 O 207 Br 124 (1S,7R)-2-bromo-8,8-dimethylbicyclo[5.1.0]oct-4-en-3-one (124). A test tube under N2 was charged with i-Pr2NH (76 mg, 0.75 mmol, 1.2 equiv) and THF (1.5 mL) and cooled to –78 °C. n-BuLi (2.5M in hexanes0.27 mL, 0.66 mmol, 1.05 equiv) was added slowly. After 30 min, enone 95 (101 mg, 0.63 mmol, 1.0 equiv) was added slowly. After an additional 1.5 h, TMSCl (103 mg, 0.95 mmol, 1.5 equiv) was added and the reaction was allowed to warm to 18 °C. n-Bromosuccinimide (168 mg, 0.95 mmol, 1.5 equiv) was added and the mixture was stirred for 40 min. The reaction was quenched with saturated aqueous NaHCO3, extracted with Et2O (2x), washed with water and brine, and dried over Na2SO4 before concentration under reduced pressure. The crude residue was purified by silica gel chromatography (5→10% EtOAc/hexanes) to furnish 124 as an oil. 1 H NMR (400 MHz, CDCl3) δ = 6.86 (ddd, J = 12.0, 8.7, 3.5 Hz, 1H), 6.20 (dd, J = 11.7, 3.2 Hz, 1H), 4.48 (d, J = 11.7 Hz, 1H), 2.69 (ddd, J = 17.0, 8.7, 6.4 Hz, 1H), 2.10 (ddt, J = 17.3, 10.9, 3.4 Hz, 1H), 1.32 – 1.27 (m, 4H), 1.20 – 1.12 (m, 4H). O O Br O ACHN, 116 + 124 126 127 Trienone 126 and cyclobutane 127. A flame-dried 8 mL vial was charged with bromide 124 (65 mg, 0.28 mmol, 1.0 equiv), PhH (3.75 mL), and ACHN (14 mg, 0.057 mmol, 0.2 equiv) under N₂. Allylstannane 116 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 208 (370 mg, 1.1 mmol, 4.0 equiv) was added, and the mixture was heated to 84 °C. After 48 hours, the reaction mixture was concentrated, and the crude residue was purified by silica gel chromatography (5→12% EtOAc/hexanes). The pure fractions consisted of a mixture of 126 and 127 which were further separated by preparatory HPLC (65→75 MeCN/H2O, 12 mL/min, C18 column). Characterization data for trienone 126: 1H NMR (400 MHz, CDCl3) δ =6.78 – 6.70 (m, 1H), 6.70 – 6.64 (m, 1H), 6.13 (ddt, J = 12.9, 9.7, 2.2 Hz, 2H), 5.77 (ddt, J = 16.9, 10.2, 7.5 Hz, 1H), 5.11 – 5.01 (m, 2H), 2.56 – 2.45 (m, 2H), 2.31 (dddd, J = 16.5, 12.8, 4.9, 2.3 Hz, 1H), 2.10 (ddt, J = 7.5, 6.4, 1.2 Hz, 2H), 0.96 (d, J = 1.7 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ = 146.3, 145.2, 134.4, 133.5, 133.0, 118.2, 46.1, 44.7, 36.1, 28.6, 24.9, 24.8. Note: the ketone carbon resonance for 126 is not visible due to low sample concentration. Characterization data for cyclobutane 127: 1H NMR (400 MHz, CDCl3) δ = 7.01 (dd, J = 9.7, 6.8 Hz, 1H), 5.89 (dd, J = 9.7, 1.7 Hz, 1H), 5.74 (ddt, J = 16.9, 10.2, 6.7 Hz, 1H), 5.08 – 4.98 (m, 2H), 2.47 – 2.29 (m, 3H), 2.25 (q, J = 1.5 Hz, 1H), 2.04 – 1.90 (m, 2H), 1.79 (dd, J = 12.6, 8.4 Hz, 1H), 1.11 (s, 3H), 1.04 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 203.7, 153.1, 137.3, 127.6, 116.1, 65.0, 48.6, 48.3, 39.9, 38.9, 34.1, 27.5, 22.4. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 145 209 O(CO)OMe OH O O MeO2C LiHMDS, Pd2(dba)3, PPh3 O O + 13 OTBS 13 147 4,4-dimethyl-5-(propan-2-ylidene)-1,3-dioxan-2-one 147. A 4 mL vial under N2 was charged with enone 13 (50 mg, 0.141 mmol, 1.0 equiv) and DMF (0.22 mL), then cooled to 0 °C. LHMDS (1.0 M in THF, 0.18 mL, 0.183 mmol, 1.3 equiv) was added dropwise to the solution. In a separate 4 mL vial, Pd2(dba)3 (3.2 mg, 0.0035 mmol, 0.025 equiv) and PPh3 (3.7 mg, 0.014 mmol, 0.1 equiv) were dissolved in DMF (1.2 mL) and stirred at 18 °C to form a homogeneous solution. Carbonate 145 (35 mg, 0.17 mmol, 1.2 equiv) was added neat to the Pd solution, after which the enolate solution was added slowly. The reaction was stirred 20 h after which the reaction mixture was cooled to 0 °C and quenched with saturated aqueous NH4Cl (1 mL). EtOAc and water were added, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash chromatography (10% EtOAc/hexanes) to furnish 147 and a mixture of enol and keto tautomers of 13. 1H NMR (500 MHz, CDCl3) δ = 4.73 (dt, J = 2.4, 1.3 Hz, 2H), 1.82 (t, J = 1.3 Hz, 3H), 1.74 (d, J = 0.8 Hz, 3H), 1.65 (s, 6H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs MeO2C O TMSOTf Et3N MeO2C OTMS OTBDPS H OTBDPS H 149 methyl 210 150 6-(4-((tert-butyldiphenylsilyl)oxy)-2-methylbutan-2-yl)-1,1-dimethyl-4- ((trimethylsilyl)oxy)-1,6,7,7a-tetrahydro-3aH-indene-3a-carboxylate 150. A 4 mL vial under N2 was charged with ketone 149 (15 mg, 0.027 mmol, 1.0 equiv) and CH2Cl2 (0.35 mL), then cooled to 0 °C. Et3N (56 mg, 0.5 mmol, 20 equiv) was added, followed by slow addition of TMSOTf (50 mg, 0.2 mmol, 8 equiv). The reaction was stirred at 0 °C for 5 minutes and then allowed to warm to 23 °C and stirred for 24 h. The reaction mixture was cooled to 0 °C and quenched slowly with saturated aqueous NaHCO3 (1 mL). The mixture was extracted with hexanes (3x), and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to furnish 150 as an oil. 1H NMR (600 MHz, CDCl3) δ = 7.84 (ddd, J = 7.4, 2.7, 1.8 Hz, 4H), 7.28 – 7.24 (m, 6H), 6.22 (d, J = 5.7 Hz, 1H), 5.52 (d, J = 5.7 Hz, 1H), 4.99 (d, J = 2.6 Hz, 1H), 3.90 (ddd, J = 8.0, 6.6, 1.2 Hz, 2H), 3.38 (s, 3H), 2.35 (dd, J = 6.7, 2.0 Hz, 1H), 1.81 (s, 3H), 1.59 (ddd, J = 14.3, 6.8, 2.1 Hz, 1H), 1.22 – 1.20 (m, 10H), 0.96 (s, 3H), 0.95 (s, 3H), 0.94 (s, 3H), 0.91 (s, 3H), 0.19 (s, 9H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs MeO2C O Pd/C (5 wt. %), H2 O MeO2C OTBDPS OTBDPS H H 149 methyl 211 153 6-(4-((tert-butyldiphenylsilyl)oxy)-2-methylbutan-2-yl)-1,1-dimethyl-4- oxooctahydro-3aH-indene-3a-carboxylate 153. A 25 mL round-bottom flask was charged with ketone 149 (81 mg, 0.15 mmol, 1.0 equiv) and EtOAc (1 mL), then purged with N2. Pd/C (16 mg) was added, and the flask was purged with H2 and stirred at 18 °C for 20 h. The reaction mixture was filtered through a pad of Celite and concentrated under reduced pressure to furnish 153 as an oil. 1H NMR (500 MHz, C6D6) δ = 7.81 – 7.77 (m, 4H), 7.28 – 7.23 (m, 6H), 3.73 (ddt, J = 10.1, 6.1, 3.1 Hz, 2H), 3.24 (s, 3H), 3.01 (ddd, J = 14.2, 10.9, 8.1 Hz, 1H), 2.71 (dd, J = 5.7, 2.6 Hz, 1H), 2.54 – 2.48 (m, 1H), 2.23 (t, J = 12.3 Hz, 1H), 1.94 (ddd, J = 14.1, 8.9, 2.7 Hz, 1H), 1.73 – 1.57 (m, 4H), 1.51 (ddd, J = 13.8, 8.1, 6.3 Hz, 1H), 1.44 – 1.37 (m, 1H), 1.34 (ddd, J = 12.3, 8.1, 2.6 Hz, 1H), 1.19 (s, 9H), 0.83 (s, 3H), 0.67 (s, 3H), 0.63 (s, 3H), 0.59 (s, 3H). MeO2C O TMSOTf Et3N MeO2C OTMS OTBDPS H 153 methyl OTBDPS H 154 6-(4-((tert-butyldiphenylsilyl)oxy)-2-methylbutan-2-yl)-1,1-dimethyl-4- ((trimethylsilyl)oxy)-1,2,3,6,7,7a-hexahydro-3aH-indene-3a-carboxylate 154. A 25 mL flask under N2 was charged with ketone 153 (75 mg, 0.14 mmol, 1.0 equiv) and CH2Cl2 (0.85 mL) and cooled to 0 °C. Et3N (139 mg, 1.37 mmol, 10.0 equiv) was added, followed by slow addition of TMSOTf (122 mg, 0.55 mmol, 4.0 equiv). After 5 minutes, Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 212 the cold bath was removed and the reaction was stirred at 18 °C for 24 h. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous NaHCO3. The mixture was extracted with Et2O (3 × 1 mL), the combined organic layers were dried over Na2SO4, and the solvent was removed under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 5–7.5% EtOAc/hexanes) to furnish 154 as an oil. 1H NMR (400 MHz, CDCl3) δ = 7.73 – 7.65 (m, 4H), 7.46 – 7.34 (m, 6), 4.80 (d, J = 2.3 Hz, 1H), 3.79 – 3.69 (m, 2H), 3.63 (d, J = 0.8 Hz, 3H), 2.46 – 2.37 (m, 1H), 2.05 (ddd, J = 9.4, 6.7, 2.3 Hz, 1H), 1.92 – 1.82 (m, 2H), 1.67 – 1.58 (m, 2H), 1.56 – 1.43 (m, 4H), 1.05 (d, J = 1.0 Hz, 9H), 0.96 (s, 3H), 0.88 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H), 0.16 (d, J = 0.8 Hz, 9H). MeO2C O OTBDPS Me3SiCHN2 BF3•Et2O, CH2Cl2 4Å mol. sieves O OTBDPS then, PPTS H 149 MeO2C MeO2C + O OTBDPS H H 159 160 Ketones 159 and 160. A vial was charged with 4Å molecular sieves (450 mg) in a glovebox, followed by a solution of ketone 149 (100 mg, 0.27 mmol, 1.0 equiv) in CH2Cl2 (3 mL), and the mixture was cooled to –78 °C. BF3·OEt2 (43 mg, 0.30 mmol, 1.1 equiv) was added, followed by slow addition of Me3SiCHN2 (2 M in CH2Cl2, 0.41 mL, 0.82 mmol, 3.0 equiv). After 2 h the cold bath was removed and the reaction was stirred at 18 °C for 10 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (3 × 1 mL), and the combined organic extracts were centrifuged. The resulting solution was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was dissolved in 1:1 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 213 MeOH/CH2Cl2 (3 mL) containing PPTS (15 mg, 0.06 mmol, 0.22 equiv), and the mixture was stirred at 18 °C for 18 h. A drop of dimethylethylamine was added, and the solvent was removed under reduced pressure. The residue was purified by a short silica gel plug followed by preparative HPLC (C18, 100% MeCN, 14 mL/min, eluted at 2–4 min) to furnish ketones 159 and 160. Characterization data for 159: 1H NMR (400 MHz, C6D6) δ = 7.84 – 7.79 (m, 4H), 7.25 (ddt, J = 6.3, 3.3, 1.1 Hz, 6H), 5.77 (d, J = 5.6 Hz, 1H), 5.49 (d, J = 5.6 Hz, 1H), 3.74 (dddd, J = 26.0, 10.1, 8.2, 6.6 Hz, 2H), 3.26 – 3.21 (m, 4H), 2.59 (ddd, J = 17.8, 4.5, 3.4 Hz, 1H), 2.07 (ddd, J = 17.6, 13.8, 3.5 Hz, 1H), 1.78 – 1.59 (m, 4H), 1.34 – 1.27 (m, 1H), 1.26 – 1.22 (m, 1H), 1.21 – 1.78 (m, 10H), 1.14 (s, 3H), 0.83 (s, 3H), 0.82 (s, 3H), 0.80 (s, 3H). Characterization data for 160: 1H NMR (400 MHz, C6D6) δ = 7.83 (ddd, J = 7.0, 5.2, 2.1 Hz, 4H), 7.27 – 7.23 (m, 6H), 5.65 (d, J = 5.8 Hz, 1H), 5.43 (d, J = 5.8 Hz, 1H), 3.87 (t, J = 7.5 Hz, 2H), 3.29 (s, 3H), 2.73 (d, J = 5.0 Hz, 1H), 2.72 – 2.69 (m, 1H), 2.30 (d, J = 4.9 Hz, 1H), 1.86 – 1.62 (m, 6H), 1.20 (s, 9H), 1.16 (s, 3H), 1.08 – 1.03 (m, 1H), 0.99 (s, 3H), 0.81 (s, 3H), 0.77 (s, 3H). O O MeO2C MeO2C LDA, prenyl Br OTBDPS OTBDPS H 159 methyl H 202 7-(4-((tert-butyldiphenylsilyl)oxy)-2-methylbutan-2-yl)-1,1-dimethyl-5-(3- methylbut-2-en-1-yl)-4-oxo-4,5,6,7,8,8a-hexahydroazulene-3a(1H)-carboxylate 202. A test tube under N2 was charged with i-Pr2NH (11 mg, 0.108 mmol, 12 equiv), THF (0.2 mL), and the mixture was cooled to −78 °C. n-BuLi (2.5 M in hexanes, 36 µL, 0.09 mmol, 10 equiv) was added slowly. After 15 min, ketone 159 (5 mg, 0.009 mmol, 1.0 equiv) in Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 214 THF (0.05 mL) was added dropwise. After 1.5 h, prenyl bromide (27 mg, 0.18 mmol, 20 equiv) was added dropwise. After 5 min, the reaction was transferred to an ice bath at 0 °C. After 45 min, the reaction was quenched with saturated aqueous NH4Cl (1 mL), extracted with EtOAc (1 mL × 3), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by passing through a short silica gel plug (20% EtOAc/hexanes) to furnish 202 as an oil. 1H NMR (500 MHz, C6D6) δ = 7.82 (dp, J = 6.2, 2.2 Hz, 4H), 7.26 (ddd, J = 9.8, 4.9, 2.9 Hz, 6H), 5.93 (d, J = 5.6 Hz, 1H), 5.47 (d, J = 5.6 Hz, 1H), 5.23 (dddd, J = 7.8, 6.2, 2.8, 1.4 Hz, 1H), 3.79 (ddd, J = 8.3, 6.6, 1.7 Hz, 2H), 3.41 – 3.36 (m, 1H), 3.30 (s, 3H), 2.63 – 2.54 (m, 1H), 2.32 (tt, J = 9.6, 5.0 Hz, 1H), 2.18 (dt, J = 14.2, 8.9 Hz, 1H), 1.80 – 1.68 (m, 3H), 1.66 (d, J = 1.4 Hz, 3H), 1.57 (s, 3H), 1.52 – 1.46 (m, 1H), 1.35 (t, J = 6.3 Hz, 1H), 1.30 (dd, J = 9.3, 3.1 Hz, 1H), 1.21 (s, 9H), 1.19 (d, J = 3.3 Hz, 1H), 1.14 (s, 3H), 0.89 (d, J = 1.2 Hz, 6H), 0.86 (s, 3H). O O MeO2C 1. TBAF 2. DMP MeO2C OTBDPS O H H 202 161 methyl 7-(4-hydroxy-2-methylbutan-2-yl)-1,1-dimethyl-5-(3-methylbut-2-en-1-yl)-4oxo-4,5,6,7,8,8a-hexahydroazulene-3a(1H)-carboxylate 161. A 4 mL vial under N2 was charged with ketone 202 (5.5 mg, 0.009 mmol, 1.0 equiv) and THF (0.5 mL), and the solution was cooled to 0 °C. TBAF (1 M in THF, 30 µL, 0.027 mmol, 3.0 equiv) was added dropwise. The ice bath was removed and the reaction was allowed to warm to 18 °C. After 24 h, the reaction was quenched with saturated aqueous NH4Cl (1 mL), extracted with EtOAc (1 mL × 3), dried over Na2SO4, and concentrated Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 215 under reduced pressure to furnish the alcohol as a colorless oil that was directly used in the next step. A 4 mL vial was charged with DMP (11 mg, 0.023 mmol, 2.5 equiv), followed by a solution of crude alcohol (0.009 mmol, 1.0 equiv) in CH2Cl2 (0.4 mL). The mixture was stirred at 18 °C for 1 h. The crude reaction mixture was purified by passing through a short silica gel plug (20% EtOAc/hexanes) followed by preparative thin-later chromatography (20% EtOAc/hexanes) to furnish 161 as an oil. 1H NMR (400 MHz, C6D6) δ = 9.51 – 9.46 (m, 1H), 5.88 (d, J = 5.6 Hz, 1H), 5.46 (d, J = 5.6 Hz, 1H), 5.22 (ddp, J = 7.7, 6.0, 1.5 Hz, 1H), 3.29 (s, 3H), 3.29 – 3.25 (m, 1H), 2.64 – 2.54 (m, 1H), 2.32 (dddd, J = 12.4, 9.5, 5.1, 2.9 Hz, 1H), 2.21 – 2.12 (m, 1H), 2.02 (dd, J = 14.6, 3.1 Hz, 1H), 1.90 (dd, J = 14.6, 2.9 Hz, 1H), 1.68 (d, J = 1.2 Hz, 3H), 1.66 – 1.58 (m, 3H), 1.57 (d, J = 1.1 Hz, 3H), 1.34 – 1.27 (m, 2H), 1.08 (s, 3H), 0.89 (s, 3H), 0.86 (s, 3H), 0.84 (s, 3H). O MeO2C TsOH•H2O O O H H O H O H 161 162 1,1,8,8-tetramethyl-5-(3-methylbut-2-en-1-yl)-1,5,6,7,8,9,10,10a-octahydro-4H-6,3a(epoxymethano)-5,9-methanocyclopenta[9]annulene-4,13-dione 162. A 4 mL vial under N2 was charged with TsOH·H2O (1.7 mg, 0.009 mmol, 1.0 equiv), dissolved in CH2Cl2 (0.1 mL). Aldehyde 161 (2.5 mg, 0.009 mmol, 1.0 equiv) in CH2Cl2 (0.2 mL) was added. The mixture was heated to 35 °C for 24 h, after which the crude mixture was passed through a short silica gel plug. The residue was purified by preparative thin-later chromatography to furnish an impure sample of 162. 1H NMR (400 MHz, C6D6) δ = 5.90 – 5.87 (m, 1H) 5.38 (d, J = 5.6 Hz, 1H), 4.77 (d, J = 12.9 Hz, 3H), 4.35 – 4.26 (m, Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 216 1H), 1.46 (s, 3H), 1.43 (s, 3H), 1.00 (s, 3H), 0.99 (d, J = 1.9 Hz, 3H), 0.80 (s, 3H), 0.78 (s, 3H). Note: only key peaks are provided, indicating the presence of 6 methyl groups, the 3 olefin resonances, the notable the a-hydroxy proton at 4.26 ppm, and the absence of the methyl ester peak. O MeO2C TsOH•H2O O O H H O + O O H H H O H O H 61 38 171 Lactones 38 and 171. A 100 mL flask was charged with aldehyde 61 (180 mg, 0.42 mmol, 1.0 equiv), pTsOH•H2O (400 mg, 2.1 mmol, 5.0 equiv) and CH2Cl2 (60 mL). The flask was sealed under Ar and stirred at 23 °C for 4 d. The solution was concentrated under reduced pressure, hexanes (20 mL) was added, and the solution was filtered to remove p-TsOH•H2O. The crude residue was purified by flash silica gel chromatography (0→10% EtOAc/hexanes) to provide a 3:2 mixture of olefin isomers 38 and 171, respectively. This mixture was further purified by preparatory SFC (silica gel, 1% i-PrOH/CO2, 25 mL/min) to furnish 38 (45 mg, 25% yield) and 171 (31 mg, 17% yield) as a colorless, crystalline solid. Characterization data for 38 is provided in Chapter 2. Characterization data for 171: 1H NMR (600 MHz, C6D6) δ = 5.22 – 5.14 (m, 1H), 4.59 (dd, J = 10.5, 7.4 Hz, 1H), 3.58 (d, J = 15.8 Hz, 1H), 3.16 (d, J = 15.7 Hz, 1H), 2.69 (dd, J = 14.4, 8.3 Hz, 1H), 2.43 (dd, J = 13.4, 3.6 Hz, 1H), 2.28 (dd, J = 14.4, 6.9 Hz, 1H), 1.90 (dd, J = 16.1, 10.6 Hz, 1H), 1.82 – 1.77 (m, 4H), 1.73 – 1.67 (m, 4H), 1.62 – 1.57 (m, 4H), 1.55 (s, 3H), 1.44 (dd, J = 14.2, 3.7 Hz, 1H), 1.21 (s, 3H), 1.17 – 1.08 (m, 2H), 0.90 (s, 3H), 0.68 (s, 3H), 0.61 (s, 3H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs MeO2C O O OTBS N2 OEt HO MeO2C N2 OEt OTBS O LDA H 217 H 58 165 methyl 6-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutan-2-yl)-4-(1-diazo-2-ethoxy2-oxoethyl)-4-hydroxy-1,1-dimethyl-2-(prop-1-en-2-yl)octahydro-3aH-indene-3acarboxylate 165. A small test tube under N2 was charged with i-Pr2NH (24 mg, 0.234 mmol, 20 equiv) and THF (50 µL), and the mixture was cooled to −78 °C. n-BuLi (2.5 M in hexanes, 75 µL, 0.187 mmol, 16 equiv) was added slowly. After 15 min, ethyl diazoacetate (23.5 mg, 0.176 mmol, 15 equiv) in THF (50 µL) was added slowly. After 20 min, ketone 58 (4 mg, 0.012 mmol, 1.0 equiv) in THF (0.1 mL) was added dropwise. After 20 min, AcOH (50 µL) in THF (0.1 mL) was added. The reaction mixture was extracted with water (1 mL) and EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→20% EtOAc/hexanes) to furnish 165 as a yellow oil. 1H NMR (400 MHz, C6D6) δ = 5.79 (s, 1H), 4.95 (t, J = 1.7 Hz, 1H), 4.90 (d, J = 2.0 Hz, 1H), 3.90 – 3.76 (m, 4H), 3.37 (s, 3H), 2.94 (dd, J = 12.8, 11.1 Hz, 1H), 2.87 – 2.71 (m, 2H), 2.50 (dd, J = 9.8, 6.1 Hz, 1H), 2.30 – 2.20 (m, 2H), 1.96 (d, J = 6.5 Hz, 1H), 1.87 – 1.77 (m, 1H), 1.76 – 1.64 (m, 6H), 1.08 (s, 3H), 1.02 (s, 9H), 1.01 – 0.99 (m, 3H), 0.96 (s, 3H), 0.83 – 0.77 (m, 6H), 0.12 (s, 6H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs MeO2C O O OTBS N2 Ot-Bu HO MeO2C N2 H 58 methyl Ot-Bu OTBS O LDA H 218 166 4-(2-(tert-butoxy)-1-diazo-2-oxoethyl)-6-(4-((tert-butyldimethylsilyl)oxy)-2- methylbutan-2-yl)-4-hydroxy-1,1-dimethyl-2-(prop-1-en-2-yl)octahydro-3aHindene-3a-carboxylate 166. A small test tube under N2 was charged with i-Pr2NH (47 mg, 0.47 mmol, 20 equiv) and THF (0.1 mL), and the mixture was cooled to −78 °C. n-BuLi (2.5 M in hexanes, 0.15 mL, 0.37 mmol, 16 equiv) was added slowly. After 15 min, t-butyl diazoacetate (60 mg, 0.42 mmol, 18 equiv) in THF (0.1 mL) was added slowly. After 20 min, ketone 58 (8 mg, 0.023 mmol, 1.0 equiv) in THF (0.2 mL) was added dropwise. After 20 min, AcOH (0.1 mL) in THF (0.2 mL) was added. The reaction mixture was extracted with water (1 mL) and EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→20% EtOAc/hexanes) to furnish 166 as a yellow oil. 1H NMR (600 MHz, C6D6) δ = 5.82 (s, 1H), 4.95 (t, J = 1.7 Hz, 1H), 4.91 (s, 1H), 3.79 (t, J = 7.2 Hz, 2H), 3.40 (s, 3H), 2.93 (dd, J = 13.5, 11.4 Hz, 1H), 2.86 – 2.74 (m, 2H), 2.50 (dd, J = 9.8, 6.0 Hz, 1H), 2.23 (td, J = 8.0, 3.8 Hz, 2H), 1.97 (d, J = 6.3 Hz, 1H), 1.82 (ddd, J = 15.8, 9.6, 6.4 Hz, 1H), 1.77 – 1.64 (m, 6H), 1.27 (s, 9H), 1.09 (s, 3H), 1.02 (s, 9H), 0.99 (s, 3H), 0.96 (s, 3H), 0.83 (s, 3H), 0.12 (s, 6H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O MeO2C SiMe3 O O MeO2C O TBAF OtBS H 59 methyl 219 OH H 169 7-(4-hydroxy-2-methylbutan-2-yl)-1,1-dimethyl-4-oxo-2-(prop-1-en-2- yl)octahydroazulene-3a(1H)-carboxylate 169. A small test tube under N2 was charged with ketoester 59 (1 mg, 1.6 µmol, 1.0 equiv) and THF (16 µL). TBAF (1 M in THF, 5 µL, 4.8 µmol, 3.0 equiv) was added and the reaction mixture was stirred at 18 °C for 20 h. The reaction was quenched with saturated aqueous NH4Cl (0.2 mL) and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by pipette column chromatography (10→30% EtOAc/hexanes) to furnish 169 as a colorless oil. 1H NMR (600 MHz, C6D6) δ = 4.94 (t, J = 1.7 Hz, 1H), 4.73 (s, 1H), 3.35 (dt, J = 8.6, 6.5 Hz, 2H), 3.26 (s, 3H), 3.22 (dd, J = 12.8, 6.4 Hz, 1H), 3.06 (dd, J = 13.2, 2.4 Hz, 1H), 2.59 (dt, J = 17.2, 3.9 Hz, 1H), 2.39 (dd, J = 13.1, 6.4 Hz, 1H), 2.27 (ddd, J = 17.5, 13.9, 3.9 Hz, 1H), 1.98 (t, J = 12.9 Hz, 1H), 1.85 – 1.80 (m, 1H), 1.76 (qd, J = 14.1, 3.8 Hz, 1H), 1.63 (s, 3H), 1.46 – 1.34 (m, 6H), 1.02 (s, 3H), 0.90 (s, 3H), 0.83 (s, 3H), 0.80 (s, 3H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O TMSOTf, EtN(i-Pr)2 MeO2C O MeO2C OTMS O methyl 220 H H 61 172 1,1-dimethyl-7-((E)-2-methyl-4-((trimethylsilyl)oxy)but-3-en-2-yl)-5-(3- methylbut-2-en-1-yl)-4-oxo-2-(prop-1-en-2-yl)octahydroazulene-3a(1H)-carboxylate 172. A small vial under N2 was charged with aldehyde 61 (0.5 mg, 0.0012 mmol, 1.0 equiv) and CH2Cl2 (24 µL). EtNi-Pr2 (0.23 mg, 0.0018 mmol, 1.5 equiv) and TMSOTf (0.4 mg, 0.0018 mmol, 1.5 equiv) were added sequentially and the reaction mixture was stirred at 18 °C for 20 h. The solvent was removed under reduced pressure and the crude residue was purified by preparative TLC to furnish 172 as an oil. 1H NMR (600 MHz, C6D6) δ = 6.02 (d, J = 6.7 Hz, 1H), 5.20 (s, 1H), 4.95 (q, J = 1.7 Hz, 2H), 4.76 (d, J = 1.9 Hz, 1H), 4.27 (d, J = 6.6 Hz, 1H), 3.30 (s, 3H), 3.05 – 2.99 (m, 2H), 2.79 – 2.73 (m, 1H), 2.50 (dd, J = 12.4, 6.5 Hz, 1H), 2.31 – 2.25 (m, 1H), 0.07 (s, 9H). Note: only key peaks are provided, indicating the presence of a silyl enol ether and the absence of an aldehyde resonance Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs NaClO2, NaH2PO4 2-methyl-2-butene O MeO2C 221 O MeO2C O CO2H H H 61 173 3-(8a-(methoxycarbonyl)-3,3-dimethyl-7-(3-methylbut-2-en-1-yl)-8-oxo-2-(prop-1en-2-yl)decahydroazulen-5-yl)-3-methylbutanoic acid 173. A 4 mL vial open to air was charged with aldehyde 61 (8 mg, 0.0186 mmol, 1.0 equiv) and t-BuOH/H2O 5:1 (0.6 mL), followed by NaH2PO4 (9 mg, 0.074 mmol, 4.0 equiv) and methyl butene (80 mg, 1.12 mmol, 60 equiv). NaClO2 (80%, 5 mg, 0.056 mmol, 3.0 equiv) was then added and the reaction was stirred at 18 °C for 1.5 h. The reaction was quenched with brine and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by pipette column chromatography (20→50% EtOAc/hexanes) to furnish 173 (7.8 mg, 97% yield). 1H NMR (600 MHz, C6D6) δ = 5.15 – 5.10 (m, 1H), 4.94 (t, J = 1.8 Hz, 1H), 4.74 (s, 1H), 3.29 – 3.24 (m, 4H), 3.07 (dd, J = 13.0, 2.4 Hz, 1H), 2.96 (d, J = 14.8 Hz, 1H), 2.66 (dq, J = 9.4, 4.7 Hz, 1H), 2.40 (dd, J = 12.4, 6.6 Hz, 1H), 2.22 (dt, J = 14.6, 9.1 Hz, 2H), 2.17 (s, 2H), 2.05 – 1.95 (m, 2H). Note: only key peaks are provided; note the presence of the broad singlet at 2.22 ppm corresponding to the methylene a to the carboxylic acid and the absence of an aldehyde resonance Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O Me3SiCHN2 MeO2C 222 O MeO2C CO2H CO2Me H H 173 174 methyl 7-(4-methoxy-2-methyl-4-oxobutan-2-yl)-1,1-dimethyl-5-(3-methylbut-2-en1-yl)-4-oxo-2-(prop-1-en-2-yl)octahydroazulene-3a(1H)-carboxylate 174. A 4 mL vial was charged with carboxylic acid 173 (4 mg, 0.0089 mmol, 1.0 equiv) and Et2O/MeOH 1:1 (0.4 mL) and cooled to 0 °C. Me3SiCHN2 (2 M in hexanes, 70 µL, 0.14 mmol, 16 equiv) was added slowly and the reaction was stirred for 10 min at 0 °C, then allowed to warm to 18 °C. AcOH (1 equiv) was added and the solvent was removed under reduced pressure. The crude residue was purified by pipette column chromatography (0→10% EtOAc/hexanes) to furnish 174 as an oil. 1H NMR (600 MHz, C6D6) δ = 5.12 (dt, J = 14.7, 1.5 Hz, 1H), 4.94 (t, J = 1.7 Hz, 1H), 4.74 (d, J = 1.9 Hz, 1H), 3.34 (s, 3H), 3.31 – 3.23 (m, 4H), 3.08 (dd, J = 12.9, 2.6 Hz, 1H), 2.97 (d, J = 15.0 Hz, 1H), 2.67 (dq, J = 9.3, 4.7 Hz, 1H), 2.41 (dd, J = 12.4, 6.6 Hz, 1H), 2.23 (dd, J = 14.9, 8.7 Hz, 1H), 2.20 (s, 2H), 2.05 – 1.97 (m, 2H), 1.83 (dt, J = 16.0, 2.6 Hz, 1H), 1.79 – 1.73 (m, 1H), 1.69 (dt, J = 14.3, 4.0 Hz, 1H), 1.64 (s, 3H), 1.63 (s, 3H), 1.60 (s, 3H), 1.28 – 1.20 (m, 1H), 1.06 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.91 (s, 3H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs CeCl3 (OMe)3CH O MeO2C O MeO2C O H H 61 methyl 223 175 OMe MeO 7-(4,4-dimethoxy-2-methylbutan-2-yl)-1,1-dimethyl-5-(3-methylbut-2-en-1- yl)-4-oxo-2-(prop-1-en-2-yl)octahydroazulene-3a(1H)-carboxylate 175. A 2 mL vial was charged with aldehyde 61 (2 mg, 0.0046 mmol, 1.0 equiv) and MeOH (0.1 mL), followed by trimethyl orthoformate (24 mg, 0.23 mmol, 50 equiv). CeCl3 (1.7 mg, 0.0046 mmol, 1.0 equiv) was then added and the reaction was stirred at 18 °C for 20 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to furnish 175. 1H NMR (600 MHz, C6D6) δ = 5.16 – 5.11 (m, 1H), 4.94 (dt, J = 5.3, 1.7 Hz, 1H), 4.75 (s, 1H), 4.49 (t, J = 5.0 Hz, 1H), 3.32 – 3.28 (m, 4H), 3.17 (s, 3H), 3.16 (s, 3H), 3.03 – 2.95 (m, 1H), 2.70 (dq, J = 9.3, 4.7 Hz, 1H), 2.44 (dd, J = 12.5, 6.6 Hz, 1H), 2.24 (dt, J = 14.9, 9.1 Hz, 1H). Note: only key peaks are provided; note the presence of the triplet at 4.49 ppm, the two additional methyl ester peaks corresponding to the dimethyl acetal and the absence of the aldehyde resonance. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O (COCl)2, DMF MeO2C O MeO2C COCl CO2H methyl 224 H H 173 176 7-(4-chloro-2-methyl-4-oxobutan-2-yl)-1,1-dimethyl-5-(3-methylbut-2-en-1- yl)-4-oxo-2-(prop-1-en-2-yl)octahydroazulene-3a(1H)-carboxylate 176. A 2 mL vial was charged with carboxylic acid 173 (2 mg, 0.0045 mmol, 1.0 equiv) and CH2Cl2 (225 µL), followed by DMF (2 µL). Oxalyl chloride (7 mg, 0.054 mmol, 12 equiv) was added dropwise and the reaction was stirred at 18 °C for 1.5 h. The solvent was removed under reduced pressure followed by high vacuum to afford 176 as an oil. 1H NMR (600 MHz, C6D6) δ = 5.04 (tdd, J = 5.7, 2.8, 1.4 Hz, 1H), 4.95 (q, J = 1.6 Hz, 1H), 4.74 (d, J = 1.9 Hz, 1H), 3.28 (s, 3H), 3.27 – 3.22 (m, 1H), 2.98 – 2.90 (m, 2H), 2.61 (dq, J = 9.5, 4.7 Hz, 1H), 2.52 (d, J = 17.0 Hz, 1H), 2.46 (d, J = 17.0 Hz, 1H), 2.39 – 2.34 (m, 1H), 2.20 – 2.16 (m, 1H), 1.99 (t, J = 12.8 Hz, 1H), 1.89 – 1.82 (m, 1H), 1.69 (d, J = 1.8 Hz, 4H), 1.65 – 1.62 (m, 3H), 1.61 (d, J = 1.3 Hz, 3H), 1.60 – 1.56 (m, 1H), 1.45 (dt, J = 14.1, 3.9 Hz, 1H), 1.09 (ddd, J = 16.0, 13.1, 7.6 Hz, 1H), 0.97 (s, 3H), 0.86 (s, 3H), 0.84 (s, 3H), 0.80 (s, 3H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs O 225 O MeO2C MeO2C DMP OH methyl O H H 169 39 1,1-dimethyl-7-(2-methyl-4-oxobutan-2-yl)-4-oxo-2-(prop-1-en-2- yl)octahydroazulene-3a(1H)-carboxylate 39. A 4 mL vial was charged with alcohol 169 (30 mg, 0.082 mmol, 1.0 equiv) and CH2Cl2 (0.2 mL), and the solution was cooled to 0 °C. A separate solution of DMP (56 mg, 0.13 mmol, 1.6 equiv) in CH2Cl2 (0.6 mL) was prepared and added to the reaction mixture. After 2 h, additional DMP (33 mg, 0.0823 mmol, 1.0 equiv) was added. After stirring, pentane was added and the mixture was filtered, the solvent was removed, additional pentane was added, and the mixture was filtered again. The combined organic layers were concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→60% EtOAc/hexanes) to furnish 39 (26 mg, 87% yield) as a colorless oil. 1H NMR (600 MHz, C6D6) δ = 9.41 (t, J = 2.9 Hz, 1H), 4.87 (h, J = 1.8 Hz, 1H), 4.67 – 4.64 (m, 1H), 3.19 (s, 3H), 3.16 – 3.09 (m, 1H), 2.89 (dd, J = 13.6, 2.4 Hz, 1H), 2.46 (dt, J = 17.3, 3.9 Hz, 1H), 2.28 (dd, J = 13.1, 6.4 Hz, 1H), 2.14 (ddd, J = 17.5, 13.9, 3.9 Hz, 1H), 1.92 – 1.80 (m, 3H), 1.64 – 1.54 (m, 5H), 1.23 – 1.13 (m, 2H), 1.04 (ddd, J = 16.0, 13.5, 7.7 Hz, 1H), 0.92 (s, 3H), 0.78 (s, 3H), 0.78 (s, 3H), 0.74 (s, 3H). Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 1. NaClO2, NaH2PO4 2-methyl-2-butene 2. Me3SiCHN2 O MeO2C 226 O MeO2C O CO2Me H H 39 178 methyl 7-(4-methoxy-2-methyl-4-oxobutan-2-yl)-1,1-dimethyl-4-oxo-2-(prop-1-en-2yl)octahydroazulene-3a(1H)-carboxylate 178. A 4 mL vial was charged with aldehyde 39 (20 mg, 0.055 mmol, 1.0 equiv), t-BuOH/H2O 5:1 (0.6 mL), NaH2PO4 (25 mg, 0.22 mmol, 4.0 equiv), and methyl butene (232 mg, 3.31 mmol, 60 equiv). NaClO2 (80%, 15 mg, 0.17 mmol, 3.0 equiv) was then added and the reaction mixture was stirred at room temperature. After 2.5 h, the reaction was quenched with brine and extracted with EtOAc. The combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→70% EtOAc/hexanes) to furnish the acid. The acid was dissolved in Et2O/MeOH 1:1 (0.5 mL) and cooled to 0 °C. TMSCHN2 (2M in hexanes, 0.1 mL, 0.2 mmol, 16 equiv) was added slowly. After 15 min, the cold bath was removed and the mixture was stirred at room temperature. After 1.5 h, AcOH (0.2 mmol) was added followed by EtOAc and water. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by pipette column chromatography (10→20% EtOAc/hexanes) to furnish ester 178 as an oil. 1 H NMR (600 MHz, C6D6) δ = 4.93 (p, J = 1.6 Hz, 1H), 4.73 – 4.69 (m, 1H), 3.34 (s, 3H), 3.25 (s, 3H), 3.22 – 3.18 (m, 1H), 3.02 (dd, J = 13.4, 2.4 Hz, 1H), 2.57 (dt, J = 17.3, 3.9 Hz, 1H), 2.37 (dd, J = 13.0, 6.4 Hz, 1H), 2.29 (ddd, J = 17.5, 13.8, 3.9 Hz, 1H), 2.20 (d, J = 13.7 Hz, 1H), 2.13 (d, J = 13.7 Hz, 1H), 1.96 (t, J = 12.9 Hz, 1H), 1.81 (dd, J = 16.0, 2.5 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 227 Hz, 1H), 1.73 (tdd, J = 13.9, 12.3, 3.8 Hz, 1H), 1.61 (t, J = 1.0 Hz, 3H), 1.51 (dddd, J = 12.1, 7.6, 3.8, 1.9 Hz, 1H), 1.45 (dq, J = 13.9, 4.0 Hz, 1H), 1.26 – 1.18 (m, 1H), 1.03 (s, 3H), 0.99 (s, 6H), 0.88 (s, 3H). O O H H 1. HNMe(OMe)•HCl, AlMe3 2. DMP O MeO O O N O H H 38 H 183 N-methoxy-N,1,1,8,8-pentamethyl-5-(3-methylbut-2-en-1-yl)-4,6-dioxo-2-(prop-1-en2-yl)decahydro-5,9-methanocyclopenta[9]annulene-3a(1H)-carboxamide 183. An 8 mL vial under N2 was charged with (OMe)NMeH•HCl (17 mg, 0.18 mmol, 20 equiv) and PhMe (240 µL), and the solution was cooled to 0 °C. Me3Al (2M in PhMe, 86 µL, 0.17 mmol, 19.6 equiv) was added dropwise. After 10 min, a solution of lactone 38 (2 mg, 0.0088 mmol, 1.0 equiv) in CH2Cl2 (0.4 mL) was added dropwise, and the reaction mixture was removed from the ice bath. After 24 h, the mixture was cooled to 0 °C, and saturated aqueous potassium sodium tartrate and CH2Cl2 were added. The mixture was allowed to warm to 18 °C and stirred vigorously for 3 h. The mixture was extracted with CH2Cl2 (2x) and Et2O (2x). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by pipette column chromatography (10→20% EtOAc/hexanes) to furnish the alcohol which was directly used in the next step. A 4 mL vial was charged with the alcohol (1.3 mg, 0.0028 mmol, 1.0 equiv) and CH2Cl2 (0.3 mL). The vial was brought into the glovebox and DMP (2.5 mg, 0.006 mmol, 2.0 equiv) was added. The reaction mixture was stirred at room temperature with an additional Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 228 portion of DMP (2.5 mg, 0.006 mmol, 2.0 equiv) being added after 1 h. After 3.5 h, the solvent was removed under reduced pressure. Hexanes/EtOAc was added, the mixture was filtered, and the solution was concentrated under reduced pressure. The crude residue was purified by preparative TLC (20% EtOAc/hexanes) to furnish 183. 1H NMR (600 MHz, C6D6) δ = 5.37 – 5.31 (m, 1H), 4.99 (t, J = 1.7 Hz, 1H), 4.78 (d, J = 1.9 Hz, 1H), 3.37 – 3.29 (m, 2H), 3.23 (dd, J = 12.4, 6.5 Hz, 1H), 3.05 (dd, J = 14.0, 10.1 Hz, 1H), 2.94 (s, 3H), 2.92 (s, 3H), 2.55 (dd, J = 13.3, 6.5 Hz, 1H), 2.48 – 2.42 (m, 1H), 2.33 (dd, J = 19.5, 1.7 Hz, 1H), 2.22 – 2.14 (m, 1H), 1.93 (t, J = 12.8 Hz, 1H), 1.75 (dd, J = 13.9, 3.5 Hz, 1H), 1.69 (d, J = 5.6 Hz, 7H), 1.64 (s, 3H), 1.46 (s, 1H), 1.24 (td, J = 13.7, 2.5 Hz, 1H), 1.17 (s, 3H), 0.92 (d, J = 8.0 Hz, 6H), 0.78 (s, 3H). O O H H 1. HNMe(OMe)•HCl, AlMe3 2. DMP O MeO O O N O H H 171 H 186 N-methoxy-N,1,1,8,8-pentamethyl-5-(3-methylbut-2-en-1-yl)-4,6-dioxo-2-(propan-2ylidene)decahydro-5,9-methanocyclopenta[9]annulene-3a(1H)-carboxamide 186. A 25 mL flask under N2 was charged with (OMe)NMeH•HCl (152 mg, 1.56 mmol, 20 equiv) and PhMe (3.6 mL), and the solution was cooled to 0 °C. Me3Al (2 M in PhMe, 765 µL, 1.53 mmol, 19.6 equiv) was added dropwise. After completion of addition, the mixture was cooled to 0 °C and lactone 171 (31 mg, 0.078 mmol, 1.0 equiv) was added in CH2Cl2 (6 mL) dropwise over 5 min. The mixture was allowed to gradually warm to room temperature and stirred for 20 h. The reaction was cooled to 0 °C and quenched with Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 229 saturated aqueous potassium sodium tartrate. The mixture was extracted with CH2Cl2 (3x), and the combined organic layers were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was used directly in the next step. Crude amide in CH2Cl2 (5 mL) were added to a 20 mL vial and brought into the glovebox. NaHCO3 (39 mg, 0.468 mmol, 6 equiv) and DMP (34 mg, 0.078 mmol, 2.5 equiv) were added sequentially. The vial was removed from the glovebox and stirred at 1 8°C for 2 h. The solvent was removed under reduced pressure, hexanes were added, and the mixture was filtered. The crude residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→25% EtOAc/hexanes) to furnish 186. 1H NMR (600 MHz, C6D6) δ = 5.44 – 5.26 (m, 1H), 3.79 (d, J = 16.5 Hz, 1H), 3.52 (s, 1H), 3.22 (dd, J = 14.2, 5.1 Hz, 1H), 3.06 (s, 3H), 2.98 (t, J = 12.0 Hz, 1H), 2.92 (s, 4H), 2.85 – 2.71 (m, 1H), 2.40 – 2.25 (m, 1H), 2.19 (d, J = 18.3 Hz, 1H), 1.86 (s, 2H), 1.71 (d, J = 1.7 Hz, 3H), 1.67 (s, 3H), 1.63 (d, J = 1.5 Hz, 3H), 1.62 (d, J = 1.3 Hz, 3H), 1.50 (s, 4H), 1.35 (d, J = 27.9 Hz, 1H), 1.13 (s, 3H), 0.79 (d, J = 16.2 Hz, 6H). O MeO O O N H 186 H TMSOTf Et3N O MeO O OTMS N H H 190 N-methoxy-N,1,1,8,8-pentamethyl-5-(3-methylbut-2-en-1-yl)-4-oxo-2-(propan-2ylidene)-6-((trimethylsilyl)oxy)-2,3,4,5,8,9,10,10a-octahydro-5,9methanocyclopenta[9]annulene-3a(1H)-carboxamide 190. A 2 mL vial was charged with amide 186 (2 mg, 0.0056 mmol, 1.0 equiv), CH2Cl2 (0.4 mL), and Et3N (25 mg, 0.224 mmol, 40.0 equiv). The solution was cooled to 0 °C and Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 230 TMSOTf (16 µL, 0.090 mmol, 16 equiv) was added. The reaction mixture was allowed to warm gradually to 18 °C and stirred. After 2 d, the mixture was cooled to 0 °C, quenched with saturated NaHCO3 and EtOAc, and extracted. The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure. The crude residue was purified by pipette column chromatography on alumina (10% EtOAc/hexanes) to furnish 190 as an oil. 1H NMR (600 MHz, C6D6) δ = 5.23 (d, J = 7.5 Hz, 1H), 4.80 (s, 1H), 3.54 (d, J = 13.9 Hz, 1H), 3.38 (d, J = 15.4 Hz, 1H), 3.25 (s, 3H), 3.06 – 2.96 (m, 2H), 2.90 (s, 3H), 2.76 (d, J = 15.6 Hz, 1H), 2.37 (d, J = 13.8 Hz, 1H), 1.93 (dd, J = 14.6, 5.9 Hz, 1H), 1.72 (d, J = 2.9 Hz, 6H), 1.70 (dd, J = 5.5, 2.1 Hz, 6H), 1.66 (s, 3H), 1.54 (dd, J = 13.4, 3.5 Hz, 1H), 1.44 (s, 1H), 1.23 (t, J = 14.6 Hz, 1H), 1.17 (s, 3H), 1.09 (s, 3H), 1.04 (s, 3H), 0.29 (s, 9H). O O H H 1. AlMe3 indoline 2. DMP O O O N O H H 38 203 H 3a-(indoline-1-carbonyl)-1,1,8,8-tetramethyl-5-(3-methylbut-2-en-1-yl)-2-(prop-1en-2-yl)octahydro-5,9-methanocyclopenta[9]annulene-4,6(1H,5H)-dione 203. A small test tube under N2 was charged with indoline (36 mg, 0.3 mmol, 40 equiv) and PhMe (0.4 mL), and the solution was cooled to 0 °C. Me3Al (1 M in hexanes, 0.3 mL, 0.3 mmol, 40 equiv) was added dropwise, and the ice bath was removed. After 1 h, a solution of lactone 38 (3 mg, 0.0075 mmol, 1.0 equiv) in PhMe (0.4 mL) was added dropwise at 0 °C, and the reaction was allowed to warm 18 °C. After 20 h, the mixture was cooled to 0 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 231 °C and quenched with saturated aqueous potassium sodium tartrate. The mixture was stirred, extracted with EtOAc, dried with Na2SO4, and concentrated under reduced pressure. The crude residue was purified by preparative TLC (20% EtOAc/hexanes) to furnish the product which was directly used in the next step. A 20 mL vial was charged with the crude alcohol (0.0075 mmol, 1.0 equiv) and CH2Cl2 (1 mL). The vial was brought into the glovebox and DMP (5 mg, 0.019 mmol, 2.5 equiv) was added. The reaction was stirred for 2 h, then diluted with CH2Cl2/hexanes, filtered, and concentrated under reduced pressure to furnish 203 as an oil. 1H NMR (600 MHz, C6D6) δ = 8.71 (d, J = 8.1 Hz, 1H), 7.10 (s, 1H), 6.87 (d, J = 6.0 Hz, 2H), 5.16 (s, 1H), 4.97 (s, 1H), 4.73 (s, 1H), 3.74 – 3.67 (m, 2H), 3.61 (d, J = 6.8 Hz, 1H), 3.52 – 3.44 (m, 1H), 3.34 (dd, J = 12.5, 6.9 Hz, 1H), 3.06 (d, J = 9.9 Hz, 1H), 3.00 (s, 1H), 2.58 (d, J = 6.6 Hz, 1H), 2.49 – 2.42 (m, 2H), 2.38 (s, 1H), 1.64 (s, 3H), 1.63 (s, 3H), 1.57 (s, 3H), 1.13 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 0.76 (s, 3H). Note: only key peaks are provided; note the presence of the four aromatic resonances and the four resonances between 3.75 – 3.40 ppm corresponding to the incorporated indoline. O O O O N H 203 H DDQ O O N H 200 H 3a-(1H-indole-1-carbonyl)-1,1,8,8-tetramethyl-5-(3-methylbut-2-en-1-yl)-2-(prop-1en-2-yl)octahydro-5,9-methanocyclopenta[9]annulene-4,6(1H,5H)-dione 200. A 2 mL vial was charged with dione 203 (0.0013 mmol, 1.0 equiv) and PhH (0.1 mL). DDQ (3 mg, 0.0132 mmol, 10 equiv) was added and the reaction mixture was stirred at 18 Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs 232 °C for 3 days. The solvent was then removed under reduced pressure. The crude residue was purified by preparative TLC (20% Et2O/hexanes) to furnish 200. 1H NMR (600 MHz, C6D6) δ = 8.95 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 3.9 Hz, 1H), 7.11 (s, 1H), 6.28 (d, J = 3.9 Hz, 1H), 4.87 (s, 1H), 4.57 (s, 1H). Note: this sample was very dilute, and only key peaks are provided. Note the presence of the six aromatic protons corresponding to the oxidized indole. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs A5.10 (1) 233 REFERENCES AND NOTES Shi, L.; He, Y.; Gong, J.; Yang, Z. 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Methylcopper(I)catalyzed selective conjugate reduction of .alpha.,.beta.-unsaturated carbonyl compounds by di-iso-butylaluminum hydride in the presence of hexamethylphosphoric triamide. J. Org. Chem. 1986, 51, 537–540. (6) Lao, Z.; Zhang, H.; Toy, P. H. Reductive Halogenation Reactions: Selective Synthesis of Unsymmetrical a-Haloketones. Org. Lett. 2019, 21, 8149–8152. (7) Keinan, E.; Gleize, P. A. Organo tin nucleophiles IV. Palladium catalyzed conjugate reduction with tin hydride. Tetrahedron Lett. 1982, 23, 477–480. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs (8) 234 Palanichamy, K.; Subrahmanyam, A. V.; Kaliappan, K. P. Org. Biomol. Chem. 2011, 9, 7877. (9) Ohloff, G.; Giersch, W. Säurekatalysierte Isomerisierung von a,b-Cyclopropyloxiranen. Helv. Chim. Acta 1968, 51, 1328–1342. (10) Newcomb, M. Radical Kinetics and Clocks. In Encyclopedia of Radicals in Chemistry, Biology and Materials; John Wiley & Sons, Ltd, 2012. (11) Posner, G. H. Modern Organocopper Chemistry; Krause, N., Ed.; Wiley VCH: Weinheim. 2002. (12) Jackson, R. K.; Wood, J. L. Total Synthesis of ent-Plagiochianin B. Org. Lett. 2021, 23, 1243–1246. (13) Molander, G. A.; Eastwood, P. R. Total Synthesis of (+)-Dactylol via a Novel [3 + 5] Annulation Approach. J. Org. Chem. 1995, 60, 4559–4565. (14) Danheiser, R. L.; Dixon, B. R.; Gleason, R. W. Five-membered ring annulation via propargyl- and allylsilanes. J. Org. Chem. 1992, 57, 6094–6097. (15) Ager, D. J.; Fleming, I.; Patel, S. K. The conjugate addition of a silyl group to enones and its removal with copper(II) bromide: a protecting group for the abunsaturation of ab-unsaturated ketones. J. Chem. Soc., Perkin Trans. 1 1981, 2520– 2526. (16) Viehe, H. G.; Janousek, Z.; Merenyi, R.; Stella, L. The captodative effect. Acc. Chem. Res. 1985, 18, 148–154. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs (17) 235 Cimarusti, C. M.; Wolinsky, J. Synthesis and bisdecarboxylation of oxygenated bicyclo[2.2.X]alkanedicarboxylic anhydrides. J. Am. Chem. Soc. 1968, 90, 113– 120. (18) Baldwin, J. E. Rules for Ring Closure. J. Chem. Soc. Chem. Commun. 1976, No. 18, 734. (19) Obradors, C.; Martinez, R. M.; Shenvi, R. A. Ph(i-PrO)SiH2: An Exceptional Reductant for Metal-Catalyzed Hydrogen Atom Transfers. J. Am. Chem. Soc. 2016, 138, 4962–4971. (20) Sato, Y.; Oonishi, Y.; Mori, M. Novel Synthesis of Conjugated Dienes Attached to a Quaternary Carbon Center via Pd(0)-Catalyzed Deconjugative Allylation of Alkenylidenemalonates. J. Org. Chem. 2003, 68, 9858–9860. (21) Yuan, P.; Gerlinger, C. K. G.; Herberger, J.; Gaich, T. Ten-Step Asymmetric Total Synthesis of (+)-Pepluanol A. J. Am. Chem. Soc. 2021, 143, 11934–11938. (22) Smith, P. A. S.; Baer, D. R. The Demjanov and Tiffeneau-Demjanov ring expansions. Org. React. 1960, 11, 157–188. (23) Sakai, T.; Ito, S.; Furuta, H.; Kawahara, Y.; Mori, Y. Mechanism of the Regio- and Diastereoselective Ring Expansion Reaction Using Trimethylsilyldiazomethane. Org. Lett. 2012, 14, 4564–4567. (24) Gerlach, H.; Müller, W. Synthesis of Non‐enolizable b‐diketones by Acid‐ catalyzed Intramolecular Claisen Condensation. Angew. Chem., Int. Ed. Engl. 1972, 11, 1030–1031. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs (25) 236 Brünner, R.; Gerlach, H. Synthesis and Resolution of the Enantiomeric Trans,Trans-Spiro[5.5]Undecane-1,7-Diols and Determination of Their Absolute Configuration; (S)-(−)-Spiro[5.5]Undecane-1,7-Dione. Tetrahedron Asymmetry 1994, 5, 1613–1620. (26) Wang, X.; Phang, Y.; Feng, J.; Liu, S.; Zhang, H.; Fu, W.; Zhou, H.; Xu, G.; Xu, H.; Zheng, C. Stereodivergent Strategy in Structural Determination: Asymmetric Total Synthesis of Garcinol, Cambogin, and Related Analogues. Org. Lett. 2021, 23, 4203–4208. (27) Yimthachote, S.; Phomphrai, K. Rapid Alcoholysis of Cyclic Esters Using Metal Alkoxides: Access to Linear Lactyllactate-Grafted Polyglycidol. New J Chem 2023, 47, 2701–2705. (28) Lovely, C. J.; Brueggemeier, R. W. Synthesis of 7a-Substituted Androstenediones by a 1,4-Conjugate Addition Approach. Bioorg. Med. Chem. Lett. 1995, 5, 2513– 2516. (29) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Keck, G. E.; Gopalan, B.; Larsen, S. D.; Siret, P.; Gras, J. L. Stereospecific Total Synthesis of Gibberellic Acid. J. Am. Chem. Soc. 1978, 100, 8034–8036. (30) Sidler, D. R.; Lovelace, T. C.; McNamara, J. M.; Reider, P. J. Aluminum-Amine Complexes for the Conversion of Carboxylic Esters to Amides. Application to the Synthesis of LTD4 Antagonist MK-0679. J. Org. Chem. 1994, 59, 1231–1233. (31) Jang, D.; Choi, M.; Chen, J.; Lee, C. Enantioselective Total Synthesis of (+)Garsubellin A. Angew. Chem. Int. Ed Engl. 2021, 60, 22735–22739. Appendix 5 – Early Strategies Toward the Synthesis of Homoadamantane PPAPs (32) 237 Coltart, D.; Lim, D.; Zhou, G.; Livanos, A.; Fang, F. MgBr2·OEt2-Promoted Coupling of Ketones and Activated Acyl Donors via Soft Enolization: A Practical Synthesis of 1,3-Diketones. Synthesis (Mass.) 2008, 2008, 2148–2152. (33) Gong, J.; Chen, H.; Liu, X.-Y.; Wang, Z.-X.; Nie, W.; Qin, Y. Total Synthesis of Atropurpuran. Nat. Commun. 2016, 7, 12183. (34) de Oliveira Baptista, M. J.; Barrett, A. G.; Barton, D. H.; Girijavallabhan, M.; Jennings, R. C.; Kelly, J.; Papadimitriou, V. J.; Turner, J. V.; Usher, N. A. Transformations of Penicillin. Part 8. Preparation of 2-Acetylceph-3-Em Derivatives from Carboxy-Protected Penicillin S-Oxides. J. Chem. Soc. Perkin 1 1977, No. 12, 1477–1500. (35) Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (36) Smith, B. R.; Njardarson, J. T. Double-Diels–Alder Approach to Maoecrystal V. Unexpected C–C Bond-Forming Fragmentations of the [2.2.2]-Bicyclic Core. Org. Lett. 2017, 19, 5316–5319. (37) Yamamura, S.; Toda, M.; Hirata, Y. Modified Clemmensen Reduction: Cholestane. Org. Synth. 1973, 53, 86. (38) Pillot, J.-P.; Bennetau, B.; Dunogues, J.; Calas, R. Nouvelle voie d’acces aux cetones a-alleniques. Tetrahedron Lett. 1981, 22, 3401–3404. Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 238 CHAPTER 3 Some Unusual Transformations of a Highly Reactive a-Bromocaranone† 3.1 INTRODUCTION The advent of asymmetric catalysis has greatly increased the number and variety of synthetically accessible chiral building blocks.1 Nevertheless, the syntheses of many natural products and consumer commodities continue to rely on starting materials from the readily available chiral pool and derivatives thereof.2,3 As such, strategies for the derivatization of chiral building blocks remain vital in organic synthesis. (+)-3-Carene (73, Scheme 3.1.1A) is one such building block: the defining dimethylcyclopropane moiety of this molecule coupled with its widespread availability and conveniently rigid structure have made it a popular chiral feedstock.2,4 However, among the numerous syntheses beginning from 73, most feature the presence of the intact dimethylcyclopropane moiety in the target. This is due in part to the lack of mild and selective methods for the fragmentation of the strained ring. Although such fragmentations have been performed on carene (73) and related dimethylcyclopropane-containing compounds, the vast majority rely on strongly acidic conditions.5 In the course of a total synthesis effort, we identified the fragmentation of a,bketodimethylcyclopropane (204) as a valuable transformation for revealing a reactive g†This research was conducted in collaboration with Zachary P. Sercel and Dr. Scott Virgil. Portions of this chapter have been reproduced with permission from Samkian, A. E.; Sercel, Z. P.; Virgil, S. C.; Stoltz, B. M. Tetrahedron Lett. 2022, 89, 153496. © 2021 Elsevier. Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 239 isopropenyl group (205) from the relatively unreactive, “protected” cyclopropane. Furthermore, we aimed to develop a method to trap the species immediately after ring fragmentation to access the challenging g-gem-dimethyl synthon (206). We realized that in order to affect this transformation in a mild and efficient fashion, a synthetic handle would be necessary at the a-position. a-Bromocaranone 207 was selected as a promising model system to study the feasibility of this synthetic transformation due to its straightforward synthesis from carene (73) (Scheme 3.1.1B). Scheme 3.1.1. Synthesis of an a-bromocaranone (207) from (+)-3-carene (73). A) Fragmentation of a β-ketocyclopropane to afford γ-substituted ketones O O Ref. 6, 7 (+)-3-Carene (73) O Conditions or R (–)-4-Caranone (204), 51% over 2 steps 206 205 B) Synthesis of α-bromocaranone (207) O OH O LDA, TMSCl NBS THF, –78 °C Br 48% yield (–)-204 (–)-207 208 Hydroboration of commercially available (+)-3-carene (73) followed by oxidation afforded (–)-4-caranone (204) in modest yields on a >10 g scale.6,7 Enolization of (–)-204 with LiHMDS and direct bromination with NBS led to the production of several inseparable side products,8 however, formation of the silyl enol ether with LDA and TMSCl followed by quenching with NBS led to diminished side product formation, affording (–)-207.9 Although bromide (–)-207 decomposes rapidly on silica, purification was possible via chromatography on neutral alumina. While this compound can be stored for at least several weeks at –15 °C as a solution in benzene, neat samples of bromide (–)- Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 240 207 stored at ambient temperature undergo spontaneous, exothermic decomposition to isocarvacrol (208), with the release of HBr, after several hours. Despite the unstable nature of bromide (–)-207, it was possible to manipulate neat samples of this intermediate for short periods of time. 3.2 CATIONIC FRAGMENTATIONS OF THE BROMOCARANONE We began by treating bromide (–)-207 with AgI reagents in order to effect a carbocation-mediated fragmentation. Treatment of (–)-207 with AgClO4 or AgOTf in THF afforded dienone (+)-210 (Table 3.2.1, entries 1 and 2) in modest yields. Trace quantities of the desired compound featuring an isopropenyl group (205) were also observed. Attempts to favor the formation of (–)-205 by performing the reaction in the presence of a bulky base were not successful. The rapid elimination of tertiary carbocation 209 toward (+)-210 would appear to impede formation of (–)-205 or trapping with nucleophiles. Despite this, we were surprised to observe tertiary fluoride (–)-211 as the major product when AgBF4 was used as a AgI source (entry 3). Table 3.2.1. AgI-mediated reactions of 207. O O O O O Br Ag salt (2.1 equiv) THF, 20 °C + + F (–)-207 209 (+)-210 (–)-205 (–)-211 entry Ag salt Yield 209 Yield 210 Yield 211 1 AgOTf 55% <5% — 2 AgClO4 67% <5% — 3 AgBF4 10% 5% 35% Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 241 3.3 RADICAL FRAGMENTATIONS OF THE BROMOCARANONE The lack of control observed in carbocation-mediated reactions led us to study radical-mediated fragmentations next. Treatment of (–)-207 with AIBN and Bu3SnH afforded isopropyl enone (–)-212 (Scheme 3.3.1) in excellent yield. Allyltributylstannane (116) was used in place of Bu3SnH, in an attempt to prepare the allylated product (–)-214.10 Pleasingly, (–)-214 was observed, though in moderate yields (<40%), with the tertiary bromide (–)-213 instead being the major product. Using catalytic amounts of 116 led to high yields of (–)-213, which could then be isolated and subjected to similar conditions, albeit with an excess of 116, to afford the desired allylated species (–)-214. Scheme 3.3.1. Radical mediated cyclopropane fragmentation of 207. O AIBN, Bu3SnH PhH, 86 °C, 1 h 89% yield (–)-212 O O O Br 116 (0.4 equiv), AIBN PhH, 86 °C, 4 h 116 (6 equiv), AIBN PhH, 86 °C, 48 h 72% yield (–)-207 63% yield Br (–)-213 (–)-214 O Br PhH, 86°C, 25 min 73% yield SnBu3 116 (±)-215 It is noteworthy that treatment of dienone (+)-210 with 116 and AIBN did not afford (–)214, suggesting (+)-210 is not an intermediate on route to (–)-214. The presence of catalytic stannane radicals proved vital for the production of (–)-213. Indeed, a control experiment Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 242 performed by simply heating a solution of (–)-207 in benzene provided racemic carvone derivative (±)-215 in high yields, with phenol 208 being observed as a minor product. To explain this surprising divergence in reactivity between (–)-213 and (±)-215, further mechanistic studies were performed. Scheme 3.3.2. Proposed mechanism and control study for the formation of 215. A) Proposed mechanism for the formation of racmic 215 from 207 O OH Br OH HO Br (–)-207 216 O 217 218 OH OH Br (±)-215 220 219 A) Synthesis of bromide 221 and control reaction in benzene O O O NaH, HMDS, MeI LDA, TMSCl NBS THF, reflux→0→20 °C THF, –78 °C 29% yield 89% yield (–)-204 (–)-220 O Br (–)-221 O Br PhH, 86 °C X Br (–)-221 222 We initially suspected that the mechanism to form (±)-215 may be radical mediated, perhaps through the homolysis of the carbon-bromine bond followed by 1,4-HAT. However, such a mechanism would not explain a racemic product. Furthermore, DFT calculations11,12,13 (see Section 3.5.3 for details) suggested that the barriers for such a transformation are kinetically inaccessible (>31 kcal/mol). Instead, we propose a polar mechanism (Scheme 3.3.2A) that, through elimination of the bromide through enol 216, Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 243 could afford diene 217. Such a system is precedented to rapidly racemize through an electrocyclic reaction via cycloheptatriene 218.14 Ultimately, 217 may be protonated in its keto form (219), eventually leading to tertiary cation 220, which is trapped by bromide, affording (±)-215. The conversion of (–)-207 to (±)-215 is likely catalyzed by HBr formed via the decomposition of (–)-207 to 208. Interestingly, despite the formation of (–)-213 requiring longer reaction times (4 h vs. 25 min), carvone derivative (±)-215 is not observed. Indeed, heating bromide (–)-207 in PhH in the presence of allylstannane 116 with no radical initiator entirely suppressed the formation of (±)-215. We propose that this observation is due to the quenching of HBr by 116. Another reaction performed with (–)-207 and bis(tributylstannane), which exists in equilibrium with two tributyltin radicals,15 also suppressed the formation of (±)-215 whilst producing (–)-213, albeit in lower yields. No reaction was observed when (–)-207 was heated in hexanes, but (±)-215 was produced rapidly in dioxane or 1,2-dichloroethane with greater quantities of phenol 208, further implicating a polar mechanism. Finally, control compound (–)-221 (Scheme 3.3.2B), featuring an additional gem-dimethyl group, was prepared in two steps from (–)-204. This compound was found to be significantly more stable than (–)-207, decomposing neither on silica nor spontaneously as a solid compound. Importantly, only clean starting material was observed when (–)-204 was heated in benzene for extended periods of time, providing further evidence that the reaction leading to (±)-215 proceeds via the mechanism proposed in Scheme 3.3.2A. Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 244 3.4 CONCLUSION Over the course of this study, readily available (+)-3-carene was derivatized into an array of useful chiral building blocks through a highly reactive a-bromocaranone as a synthetic branching point. These chiral products are expected to be useful in future synthetic efforts, and we believe that the convenient fragmentation of b-cyclopropyl ketones will also find applications outside of carene-derived systems. 3.5 EXPERIMENTAL SECTION 3.5.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.16 (+)-3-Carene was purchased from TCI and used as received, N-bromosuccinimide (NBS) was recrystallized from boiling water prior to use, trimethylsilyl chloride (TMSCl) was distilled under argon prior to use, all other reagents and solvents were purchased from various commercial suppliers and used as received. Reaction progress was monitored by thin-layer chromatography (TLC) or Agilent 1290 UHPLC-MS. TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching or panisaldehyde staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 µm) or Sigma-Aldrich aluminum oxide (activated, neutral, Brockmann Activity I) were used for flash chromatography. Preparatory HPLC was performed on an Agilent 1200 preparatory HPLC system using a 9.4 x 250 mm Eclipse XDB-C18 column. A water/MeCN gradient was used as the mobile phase and the compounds were detected at 230.8 nm and 254.4 nm. Analytical SFC was performed with a Mettler SFC supercritical Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 245 CO2 analytical chromatography system utilizing a Chiralpak AD-H column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. 1H NMR spectra were recorded on Varian Inova 500 MHz, Varian 400 MHz, and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (125 MHz), a Varian 400 MHz spectrometer (100 MHz), and Bruker 400 MHz spectrometers (100 MHz) and are reported relative to CHCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm) Some reported spectra include minor solvent impurities of water (δ 1.56ppm), ethyl acetate (δ 4.12, 2.05, 1.26 ppm), methylene chloride (δ 5.30 ppm), acetone (δ 2.17 ppm), grease (δ 1.26, 0.86 ppm), and/or silicon grease (δ 0.07 ppm), which do not impact product assignments. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell. High-resolution mass spectrometry was performed by the Multi User Mass Spectrometry Laboratory at the California Institute of Technology using a JMS-T200 GC AccuTOF GC-Alpha mass spectrometer. Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 246 3.5.2 EXPERIMENTAL PROCEDURES OH NaBH4, BF3•Et2O 73 223 (1R,3R,4R,6S)-4,7,7-trimethylbicyclo[4.1.0]heptan-3-ol 223. The procedure was adapted from the literature:6 To a dried 500 mL round bottom flask was added NaBH4 (6.94 g, 183 mmol, 1.0 equiv), THF (60 mL), and (+)-3-carene (73)(25 g, 180 mmol, 1.0 equiv). The reaction flask was cooled to 0 °C in an ice bath, and BF3•OEt2 (26 g, 160 mmol, 1.0 equiv) was added dropwise over 30 min. The reaction was stirred at this temperature for 4 h, after which the reaction was cooled to –10 °C and aq. NaOH (3M, 60 mL) was added dropwise over 40 min. H2O2 (30 wt %, 100 mL) was then added dropwise over 1 h, and the reaction allowed to warm to 20 °C. The solution was concentrated under reduced pressure to remove THF, and the aqueous layer was extracted with CH2Cl2 (3 x 40 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, and filtered. Concentration under reduced pressure afforded an oil that was distilled under vacuum (0.5 mmHg, 150 °C) to afford 223 (22 g, 78%) as a colorless oil that solidified upon cooling. 1H NMR (chloroform-d, 400 MHz): δ = 3.07 (ddd, J = 10.3, 9.3, 6.6 Hz, 1H), 2.10 (ddd, J = 14.1, 6.6, 0.9 Hz, 1H), 2.01 – 1.92 (m, 1H), 1.61 – 1.51 (m, 1H), 1.29 – 1.17 (m, 1H), 0.97 (s, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.90 (s, 3H), 0.86 – 0.77 (m, 1H), 0.75 – 0.67 (m, 2H). Spectral data are in agreement with previously reported values.17 Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 247 OH O Brown-Garg reagent 223 204 (1R,4R,6S)-4,7,7-trimethylbicyclo[4.1.0]heptan-3-one 204. A procedure from the literature7 was modified as follows: To a 1 L round bottom flask was added alcohol 223 (20 g, 130 mmol, 1.0 equiv) and Et2O (280 mL). The solution was cooled in an ice bath, and Brown–Garg (BG) reagent18,19 (70 mL) was added dropwise over 20 min with vigorous stirring, maintaining the reaction temperature below 20 °C. The ice bath was then removed, and the solution stirred for 1 h. Additional BG reagent (70 mL) was added slowly, and the reaction was left to stir for 18 h. The organic layer was then separated, and the aqueous layer was extracted with Et2O (2 x 50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual oil was distilled under vacuum (0.5 mmHg, 130 °C) to yield 204 (12.8 g, 65%) as fragrant, yellow oil. 1H NMR (chloroformd, 400 MHz): δ = 2.52 (ddd, J = 18.0, 8.4, 0.9 Hz, 1H), 2.41 – 2.32 (m, 1H), 2.32 – 2.25 (m, 2H), 1.31 – 1.19 (m, 1H), 1.07 (m, 1H), 1.04 (s, 3H), 1.02 – 0.97 (m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.84 (s, 3H). Spectral data are in agreement with previously reported values.7 Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 248 O O LDA, then TMSCl then NBS 204 Br 207 (1R,2R,4R,6S)-2-bromo-4,7,7-trimethylbicyclo[4.1.0]heptan-3-one 207. To a flame-dried 250 mL Schlenk flask was added THF (29 mL) and diisopropylamine (1.59 g, 15.8 mmol, 1.2 equiv). The solution was cooled to –78 °C and n-butyllithium (2.5 M in hexanes, 5.5 mL, 13.8 mmol, 1.05 equiv) was added dropwise over 8 min. After stirring for 30 min, a solution of ketone 204 (2 g, 13.1 mmol, 1.0 equiv) in THF (2 mL) was added dropwise over 5 min and the reaction mixture allowed to stir at –78 °C for 1.5 h. TMSCl (2.14 g, 19.7 mmol, 1.5 equiv) was added and the reaction was allowed to warm to 0 °C in an ice bath, and further stirred at 0 °C for 1 h. The reaction flask was then wrapped in Al foil to exclude light and NBS (3.5 g, 19.7 mmol, 1.5 equiv) was added in a single portion. After stirring for a further 30 min in the dark, the reaction was quenched* with saturated aq. NaHCO3 (50 mL) and extracted with Et2O (2 x 20 mL). The combined organic layers were washed with water (2 x 40 mL) and brine (40 mL), dried over Na2SO4, and filtered. The solution was concentrated under reduced pressure to yield 2.1 g of residue. A small amount of this residue (255 mg) was purified via flash chromatography on neutral alumina (hexanes) to yield 207 (173 mg, extrapolated to 48% overall yield) as an unstable straw-colored oil which crystallized when pure. 207 was used immediately or stored as a frozen solution in benzene. 1H NMR (chloroform-d, 400 MHz): δ = 4.37 (d, J = 1.2 Hz, 1H), 3.22 (ddq, J = 13.0, 7.7, 6.5 Hz, 1H), 2.45 (ddd, J = 14.7, 9.7, 7.6 Hz, 1H), 1.52 (dd, J = 8.6, 1.3 Hz, 1H), 1.40 (ddd, J = 14.8, 13.0, 4.3 Hz, 1H), 1.18 (td, J = 8.9, 4.2 Hz, 1H), 1.07 (s, 3H), 1.00 (d, J = 6.5 Hz, 3H), 0.84 (s, 3H); 13C{1H} NMR (chloroform-d, 100 Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 249 MHz): δ = 209.7, 48.2, 36.2, 33.7, 30.7, 28.2, 22.2, 20.5, 14.7, 14.1; IR (Neat Film, NaCl) 2933, 1719, 1455, 1378, 1162, 848, 776, 622 cm–1; HRMS (FI+): m/z calc’d for C10H15OBr [M]+: 230.0301 found, 230.0308; [α]D 22.16 –278.99 (c 1.0, CHCl3). *Due to the lightsensitivity of the product, it is recommended to perform the work-up in the dark. OH O Br 207 208 4-isopropyl-2-methylphenol 208. 207 (39 mg, 0.17 mmol) was left in a sealed 4 mL vial under ambient conditions for 24 h. During this time, the oil was found to spontaneously decompose with notable exotherm* and change in consistency. The blackened tar was purified via flash chromatography on silica (5% EtOAc in hexanes) to afford 208 (8 mg, 32%) as a colorless oil. 1H NMR (chloroform-d, 400 MHz): δ = 6.99 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 8.1, 2.2 Hz, 1H), 6.71 (d, J = 8.1 Hz, 1H), 4.62 (s, 1H), 2.83 (hept, J = 7.0 Hz, 1H), 2.26 (s, 3H), 1.23 (d, J = 6.9 Hz, 6H). Spectral data are in agreement with previously reported values.20 *On large scales (>200 mg) the exotherm and release of HBr can lead to dangerous pressure build up; this can be avoided by leaving the vial open to atmosphere. Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 250 Br O O O O AgI + + F 207 210 205 211 Enones 210, 205, and 211. To a solution of the indicated silver salt (0.182 mmol, 2.1 equiv) in THF (0.6 mL) was added a solution of bromoketone 207 (20 mg, 0.0865 mmol, 1.0 equiv) in THF (0.3 mL, 0.1 M total concentration) dropwise over 1 min with stirring at 20 °C. In all cases, a thick precipitate immediately formed. Stirring was continued for an additional 20 min, after which the reaction mixture was quenched with saturated aq. NaHCO3 (1 mL) and filtered through a plug of celite with EtOAc. The layers were separated and the organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to provide a crude product that was purified by silica gel flash chromatography (5% EtOAc in hexanes). Characterization data for (R)-6-methyl-4-(propan-2-ylidene)cyclohex-2-en-1-one (210). 8.7 mg (67%) yield with AgClO4; 7.1 mg (55%) yield with AgOTf; 1H NMR (chloroformd, 400 MHz): δ = 7.42 (dd, J = 10.1, 0.9 Hz, 1H), 5.80 (d, J = 10.0 Hz, 1H), 2.84 (dd, J = 14.6, 5.4 Hz, 1H), 2.48 (dqd, J = 10.9, 6.8, 5.4 Hz, 1H), 2.39 – 2.27 (m, 1H), 1.93 (dd, J = 1.6, 0.8 Hz, 3H), 1.90 (s, 3H), 1.14 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (chloroform-d, 100 MHz): δ = 203.0, 143.1, 139.4, 126.7, 124.0, 40.9, 34.1, 21.9, 20.8, 15.9; IR (Neat Film, NaCl) 2927, 1672, 1623, 1453, 1216, 812 cm–1; HRMS (FI+): m/z calc’d for C10H14O [M]+: 150.1039, found 150.1039; [α]D 21.95 +137.36 (c 0.5, CHCl3). Characterization data for (4S,6R)-6-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-one (205). Isopropenyl enone 205 was observed in trace quantities in the AgI-mediated fragmentation of bromide 207. 0.7 mg (5% yield) with AgBF4. A sample suitable for Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 251 characterization, albeit containing a minor impurity, could be obtained by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc in hexanes) on a 100 mg scale. 1 H NMR (chloroform-d, 400 MHz): δ = 6.81 (dt, J = 10.1, 2.0 Hz, 1H), 6.03 (dd, J = 10.1, 3.0 Hz, 1H), 4.86 (p, J = 1.5 Hz, 1H), 4.81 (dq, J = 1.6, 0.8 Hz, 1H), 3.21 – 3.12 (m, 1H), 2.42 (dqd, J = 13.5, 6.7, 4.5 Hz, 1H), 2.13 (dtd, J = 13.0, 4.5, 2.0 Hz, 1H), 1.77 (dd, J = 1.4, 0.9 Hz, 3H), 1.72 – 1.61 (m, 1H), 1.15 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (chloroformd, 100 MHz): δ = 202.0, 152.5, 146.9, 129.6, 112.0, 45.2, 41.8, 37.7, 20.8, 15.1; IR (Neat Film, NaCl) 2964, 2934, 2862, 1683, 1649, 1454, 1376, 1215, 1188, 1118, 895, 804 cm–1; HRMS (FI+): m/z calc’d for C10H14O [M]+: 150.1039, found 150.1030; [α]D 21.23 –92.59 (c 0.33, CHCl3). Characterization data for (4S,6R)-4-(2-fluoropropan-2-yl)-6-methylcyclohex-2-en-1one (211). 6.6 mg of a 3.4:1 (w/w) mixture of fluoride 211 and dienone 210 was isolated with AgBF4, corresponding to a 35% yield of fluoride 211. While this mixture was inseparable by silica gel flash chromatography, an analytical sample of 211 was isolated by reverse-phase preparative HPLC (50–70% MeCN in H2O over 3.5 min at 10 mL/min); 1 H NMR (chloroform-d, 400 MHz): δ = 6.96 (dt, J = 10.3, 2.0 Hz, 1H), 6.09 (dd, J = 10.3, 3.0 Hz, 1H), 2.88 – 2.75 (m, 1H), 2.41 (dqd, J = 13.5, 6.7, 4.6 Hz, 1H), 2.08 (dtdd, J = 12.8, 4.5, 2.1, 0.9 Hz, 1H), 1.53 – 1.45 (m, 1H), 1.42 (d, J = 22.0 Hz, 3H), 1.32 (d, J = 22.0 Hz, 3H), 1.16 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (chloroform-d, 100 MHz): δ = 201.6, 148.9, 148.8, 130.5, 97.3, 95.6, 47.4, 47.2, 41.3, 33.4, 33.4, 25.6, 25.4, 23.7, 23.4, 15.1; IR (Neat Film, NaCl) 2930, 1682, 1453, 1376, 1219, 878, 812, 522 cm–1; HRMS (FI+): m/z calc’d for C10H15FO [M]+: 170.1101, found 170.1099; [α]D 21.82 –37.10 (c 0.167, CHCl3). Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 252 O O Br AIBN, Bu3SnH 207 212 (4R,6R)-4-isopropyl-6-methylcyclohex-2-en-1-one 212. AIBN (20 mg, 0.121 mmol, 0.2 equiv) was loaded into a 20 mL vial with septum cap. A solution of bromide 207 (140 mg, 0.606 mmol, 1.0 equiv) and Bu3SnH (353 mg, 1.21 mmol, 2.0 equiv) in anhydrous benzene (6 mL) was added. The reaction mixture was stirred at 86 °C for 1 h, after which the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica (0–10% EtOAc in hexanes) to afford 212 (82 mg, 89%) as a colorless oil. The resulting product is pure enough for most purposes, but a sample of higher purity for analysis was obtained by distillation. 1H NMR (chloroform-d, 400 MHz): δ = 6.82 (dt, J = 10.2, 2.2 Hz, 1H), 6.01 (dd, J = 10.2, 3.0 Hz, 1H), 2.39 (m, 2H), 1.96 (dtd, J = 13.0, 4.5, 2.0 Hz, 1H), 1.80 (pd, J = 6.9, 4.8 Hz, 1H), 1.54 – 1.49 (ddd, J = 13.9, 13.0, 11.4 Hz, 1H), 1.15 (d, J = 6.6, 3H), 0.96 (d, J = 7.1, 3H), 0.94 (d, J = 6.9, 3H); 13C{1H} NMR (chloroform-d, 100 MHz): δ = 202.7, 153.5, 129.7, 43.5, 41.7, 34.2, 31.8, 19.6, 19.3, 15.2; IR (Neat Film, NaCl) 2959, 2872, 1684, 1458, 1386, 1219, 803 cm–1; HRMS (FI+): m/z calc’d for C10H16O [M]+: 152.1196 found, 152.1198; [α]D 22.31 –35.30 (c 1.0, CHCl3). Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 253 O O Br SnBu3 AIBN 116 Br 207 213 (4S,6R)-4-(2-bromopropan-2-yl)-6-methylcyclohex-2-en-1-one 213. To a 4 mL vial was added bromide 207 (36 mg, 0.156 mmol, 1.0 equiv) in anhydrous benzene (1.5 mL). To this solution was added allyltributyltin 116 (21 mg, 0.062 mmol, 0.4 equiv) and AIBN (5 mg, 0.03 mmol, 0.2 equiv). The vial was sealed, and the reaction mixture stirred at 86 °C for 4 h. The reaction was then allowed to cool to 20 °C and concentrated under reduced pressure. The residue was purified via flash chromatography on silica (5–10% EtOAc in hexanes) to afford 213 (26 mg, 72%) as a colorless oil. 1H NMR (chloroform-d, 400 MHz): δ = 7.09 (dt, J = 10.3, 2.1 Hz, 1H), 6.09 (dd, J = 10.3, 2.8 Hz, 1H), 2.85 (dddd, J = 11.4, 4.6, 2.9, 2.0 Hz, 1H), 2.41 (dqd, J = 13.4, 6.7, 4.5 Hz, 1H), 2.24 (dtd, J = 12.7, 4.4, 2.2 Hz, 1H), 1.89 (s, 3H), 1.74 (s, 3H), 1.67 – 1.58 (m, 1H), 1.17 (d, J = 6.7 Hz, 3H); 13C{1H} NMR (chloroform-d, 100 MHz): δ = 201.3, 150.1, 130.2, 68.3, 50.5, 41.0, 34.2, 32.9, 30.9, 15.1; IR (Neat Film, NaCl) 2967, 1682, 1455, 1372, 1213, 1125, 803, 644, 601 cm–1; HRMS (FI+): m/z calc’d for C10H15OBr [M]+: 230.0301, found 230.0300; [α]D 22.13 –62.67 (c 1.0, CHCl3). Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 254 O O SnBu3 AIBN 116 Br 213 214 (4S,6R)-6-methyl-4-(2-methylpent-4-en-2-yl)cyclohex-2-en-1-one 214. To a 20 mL vial was added bromide 213 (45 mg, 0.195 mmol, 1.0 equiv) in anhydrous benzene (4 mL). To this was added allyltributyltin 116 (390 mg, 1.17 mmol, 6.0 equiv) and AIBN (6.4 mg, 0.039 mmol, 0.2 equiv). The vial was sealed, and the reaction mixture stirred at 86 °C for 48 h. The solution was concentrated under reduced pressure and the residue purified via flash chromatography on silica (5% EtOAc in hexanes) to afford 214 (24 mg, 63%) as a colorless oil. The compound is pure enough for most purposes, but a sample of higher purity for analysis was obtained by preparatory HPLC (60–80% MeCN in H2O over 5 min at 12 mL/min). 1H NMR (chloroform-d, 400 MHz): δ = 6.96 (dt, J = 10.3, 2.1 Hz, 1H), 6.03 (dd, J = 10.3, 3.0 Hz, 1H), 5.83 (ddt, J = 16.8, 10.2, 7.4 Hz, 1H), 5.13 – 5.02 (m, 2H), 2.36 (m, 2H), 2.11 – 2.06 (m, 2H), 2.03 (ddq, J = 11.0, 4.4, 2.2 Hz, 1H), 1.55 – 1.46 (m, 1H), 1.15 (d, J = 6.7 Hz, 3H), 0.95 (s, 3H), 0.92 (s, 3H); 13C{1H} NMR (chloroform-d, 100 MHz): δ = 202.4, 151.7, 134.7, 130.0, 118.0, 45.7, 44.5, 41.8, 35.7, 33.1, 24.9, 24.6, 15.3; IR (Neat Film, NaCl) 2961, 1683, 1385, 1222, 914, 802 cm–1; HRMS (FI+): m/z calc’d for C13H20O [M]+: 192.1509, found 192.1509; [α]D 22.49 –25.44 (c 0.25, CHCl3). Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 255 O O Br Δ Br 207 215 5-(2-bromopropan-2-yl)-2-methylcyclohex-2-en-1-one 215. To a 4 mL vial was added bromide 207 (86 mg, 0.372 mmol, 1.0 equiv) in anhydrous benzene (1.6 mL). The vial was sealed, and the reaction mixture stirred at 86 °C for 25 min. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography on neutral alumina (5% EtOAc in hexanes) to afford 215 (63 mg, 73%) as a colorless oil. 1H NMR (chloroform-d, 400 MHz): δ = 6.75 (ddq, J = 5.4, 2.8, 1.4 Hz, 1H), 2.74 (ddd, J = 16.0, 3.7, 1.8 Hz, 1H), 2.59 (dddt, J = 18.2, 6.2, 4.6, 1.5 Hz, 1H), 2.41 (m, 2H), 2.05 (dddd, J = 13.5, 11.1, 4.6, 3.7 Hz, 1H), 1.79 (m, 3H), 1.79 (s, 3H), 1.77 (s, 3H); 13C{1H} NMR (chloroform-d, 100 MHz): δ = 199.2, 144.3, 135.4, 70.1, 48.3, 41.2, 32.5, 32.2, 29.2, 15.7; IR (Neat Film, NaCl) 2972, 1674, 1451, 1370, 1254, 1103, 1062, 904, 690 cm–1; HRMS (FI+): m/z calc’d for C10H15OBr [M]+: 230.0301, found 230.0302. 215 was determined to be racemic by chiral SFC analysis (AD-H, EtOH/CO2 = 5/95, flow rate = 3.5 mL/min, l = 210 nm) tR = 3.39, 3.95. Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 256 O O NaH, HMDS, MeI 204 220 (1R,6S)-4,4,7,7-tetramethylbicyclo[4.1.0]heptan-3-one 220. To a rapidly stirred suspension of NaH (60% dispersion in mineral oil, 289 mg, 7.23 mmol, 1.1 equiv) in THF (5.6 mL, 1 M final substrate concentration) in a 50 mL 2-neck flask equipped with a reflux condenser was added ketone 204 (1.00 g, 6.57 mmol, 1.0 equiv) through the top of the condenser. Additional THF (1 mL) was used to rinse the ketone into the reaction mixture. The suspension was then heated to reflux in an oil bath and stirred for 1.5 h. Then, HMDS (0.21 mL, 0.986 mmol, 0.15 equiv) was added through the top of the condenser and the reaction mixture was stirred under reflux for an additional 25 min. The flask was then cooled to 0 °C in an ice bath, and the reflux condenser was replaced with a septum. MeI (0.45 mL, 7.23 mmol, 1.1 equiv) was added dropwise, after which the ice bath was removed. After stirring at 20 °C for 17 h, the reaction mixture was quenched with H2O (20 mL), the layers were separated, and the aqueous layer was extracted with Et2O (4x10 mL). The combined organic layers were dried over MgSO4, concentrated under reduced pressure, and purified via silica gel flash chromatography (10% Et2O in hexanes). The resulting oil was purified again by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc in hexanes) to provide dimethyl ketone 220 (361 mg, 29% yield desired isomer) as a fragrant, colorless oil containing 11% of an inseparable isomeric impurity; 1H NMR (chloroform-d, 400 MHz): δ = 2.65 – 2.52 (m, 1H), 2.19 – 2.07 (m, 1H), 1.94 (ddt, J = 14.9, 9.3, 1.4 Hz, 1H), 1.39 (ddt, J = 14.9, 6.2, 0.9 Hz, 1H), 1.22 (s, Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 257 3H), 1.11 – 1.06 (m, 1H), 1.04 (s, 3H), 0.94 (s, 3H), 0.90 – 0.80 (m, 4H); 13C{1H} NMR (chloroform-d, 100 MHz): δ = 218.9, 42.4, 35.1, 34.6, 28.0, 24.8, 24.3, 22.4, 19.5, 18.2, 14.9; IR (Neat Film, NaCl) 2930, 2867, 1709, 1460, 1412, 1379, 1111, 1051, 986, 808 cm– 1 ; m/z calc’d for C11H18O [M]+: 166.1352, found 166.1358; [α]D 21.48 –68.91 (c 1.0, CHCl3). O O LDA, then TMSCl then NBS 220 Br 221 (1R,2S,6S)-2-bromo-4,4,7,7-tetramethylbicyclo[4.1.0]heptan-3-one 221. To a solution of diisopropylamine (0.10 mL, 0.722 mmol, 1.2 equiv) in THF (1.3 mL, 0.45 M substrate concentration) was added n-butyllithium (2.5 M in hexanes, 0.25 mL, 0.632 mmol, 1.05 equiv) dropwise at –78 °C. The solution was allowed to warm to 0 °C and immediately cooled back to –78 °C, whereafter ketone 220 (100 mg, 0.602 mmol, 1.0 equiv) was added dropwise and the solution stirred at –78 °C for 1 h. TMSCl (0.11 mL, 0.903 mmol, 1.5 equiv) was added and the reaction was allowed to warm to 0 °C in an ice bath and stirred for an additional 45 min. The reaction was then protected from light and NBS (161 mg, 0.903 mmol, 1.5 equiv) was added in one portion. After stirring for a further 30 min in the dark, the reaction was quenched with saturated aq. NaHCO3 (1 mL), the layers were separated, and the aqueous layer was extracted with Et2O (1 mL). The combined organic layers were washed with water (1 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified via silica gel flash chromatography to afford a-bromoketone 221 (126 mg, 89% yield desired isomer) as a white crystalline solid containing 8% of an inseparable isomeric impurity; 1H NMR Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 258 (chloroform-d, 400 MHz): δ = 4.23 (dd, J = 6.0, 0.8 Hz, 1H), 1.91 (ddd, J = 15.1, 8.3, 0.9 Hz, 1H), 1.44 (ddd, J = 15.0, 8.4, 0.8 Hz, 1H), 1.40 – 1.35 (m, 4H), 1.13 (s, 3H), 1.11 – 1.05 (m, 4H), 1.03 (s, 3H); 13C{1H} NMR (chloroform-d, 100 MHz): δ = 209.2, 49.2, 44.4, 33.7, 30.4, 27.7, 26.6, 26.0, 21.8, 21.5, 14.2; IR (Neat Film, NaCl) 2954, 2869, 1721, 1462, 1376, 1244, 1054, 911, 742 cm–1; m/z calc’d for C11H17OBr [M]+: 244.0457, found 244.0459; [α]D 21.55 –148.50 (c 1.0, CHCl3). 3.5.3 COMPUTATIONAL DETAILS All quantum mechanical calculations were carried out with the ORCA program.12,13 DFT geometry optimizations and harmonic frequency calculations were carried out in the gas phase with the M06-2X functional21 and def2-TZVP basis set22 on all atoms. Thermodynamic corrections from harmonic frequency calculations employ the quasiridged rotor harmonic oscillator approach to correct for the breakdown of the harmonic oscillator approximation at low vibrational frequencies.23 Stationary points are characterized by the correct number of imaginary vibrational modes (zero for minima and one for saddle points). Intrinsic reaction coordinate (IRC) analysis24 confirms the nature of transition states. Electronic energies are further refined with single point calculations at the M06-2X/def2-TZVPP level of theory employing the SMD implicit solvation model for benzene.25 Final Gibbs free energies were obtained by applying thermodynamic corrections obtained at the optimization level of theory to these refined solvated electronic energies. The resolution of identity (RI) and Chain-of-Spheres (COS) approximations are employed for efficient evaluation of Coulomb and exchange integrals, respectively.26 The Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 259 def2/J auxiliary basis27 and very fine grid settings are employed in all calculations (keyword: DefGrid3). Calculations on open-shell systems employ unrestricted Kohn– Sham orbitals (UKS). Spin contamination is generally minor. Figure 3.5.3.1. Minimum free energy pathway from 226 toward 224 and 235.a 55.2 H 3C H ‡ H CH3 H O H 3C CH3 H TS(230) ‡ ‡ O H H H H 3C TS(231) ‡ H CH3 TS(230) 40.3 TS(229) 34.1 TS(231) TS(227) 31.0 TS(227) TS(229) TS(233) 15.4 Grel kcal/mol TS(225) 9.2 10.6 4.2 6.7 0.2 O Tautomerization 0.0 –2.4 O O O O 224 226 Towards compound 212, 213, 214 228 232 O 234 235 Towards compound 215 aRelative free energies (in blue) provided in kcal/mol obtained at the M06-2X/def2-TZVPP/SMD(Benzene)//M06-2X/def2-TZVP level of theory. Note that 224 and 226 exist in a rapid equilibrium. Direct 1,4-HAT over (TS(230)) or under (TS(231)) the ring, as well as indirect HAT through primary radical 228, involve barriers that are kinetically inaccessible at the temperatures at which these reactions were performed. Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 260 3.6 (1) REFERENCES AND NOTES Nugent, W. A.; Rajanbabu, T. V.; Burk, M. J. Beyond Nature’s Chiral Pool: Enantioselective Catalysis in Industry. Science 1993, 259, 479–483. (2) Brill, Z. G.; Condakes, M. L.; Ting, C. P.; Maimone, T. J. Navigating the Chiral Pool in the Total Synthesis of Complex Terpene Natural Products. Chem. Rev. 2017, 117, 11753–11795. (3) Carreira, E. M.; Yamamoto, H. Comprehensive Chirality; 2012. (4) Curlat, S. RECENT STUDIES OF (+)-3-CARENE TRANSFORMATIONS WITH THE RETENTION OF THE NATIVE FRAMEWORK. 2019. (5) Ohloff, G.; Giersch, W. Säurekatalysierte Isomerisierung von α,β-CyclopropylOxiranen. Helvetica Chimica Acta 1968, 51, 1328–1342. (6) Kilbas, B.; Azizoglu, A.; Balci, M. Incorporation of an Allene Unit into α-Pinene via β-Elimination. Helvetica Chimica Acta 2006, 89, 1449–1456. (7) Kozioł, A.; Frątczak, J.; Grela, E.; Szczepanik, M.; Gabryś, B.; Dancewicz, K.; Lochyński, S. Synthesis and Biological Activity of New Derivatives with the Preserved Carane System. Natural Product Research 2020, 34, 1399–1403. (8) Zhang, X.; Cai, X.; Huang, B.; Guo, L.; Gao, Z.; Jia, Y. Enantioselective Total Syntheses of Pallambins A–D. Angewandte Chemie International Edition 2019, 58, 13380–13384. (9) Wu, K. K. Y. The Diels-Alder reaction in the synthesis of qinghaosu analogues. Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 261 (10) Bruncko, M.; Crich, D.; Samy, R. Chemistry of Cyclic Tautomers of Tryptophan: Formation of a Quaternary Center at C3a and Total Synthesis of the Marine Alkaloid (+)-Ent-Debromoflustramine B. J. Org. Chem. 1994, 59, 5543–5549. (11) DFT Calculations Were Carried out with the ORCA Program (See Supporting Information) at the M06-2X/Def2-TZVPP/SMD(Benzene)//M06-2X/Def2-TZVP Level of Theory. (12) Neese, F. The ORCA Program System. WIREs Computational Molecular Science 2012, 2, 73–78. (13) Neese, F. Software Update: The ORCA Program System, Version 4.0. WIREs Computational Molecular Science 2018, 8, e1327. (14) Marvell, E. Thermal Electrocyclic Reactions; Elsevier, 2012; pp 283–288. (15) Davies, A. G. Radical Chemistry of Tin. In Chemistry of Tin; Smith, P. J., Ed.; Springer Netherlands: Dordrecht, 1998; pp 265–289. (16) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (17) Ramachandran, P. V.; Drolet, M. P.; Kulkarni, A. S. A Non-Dissociative OpenFlask Hydroboration with Ammonia Borane: Ready Synthesis of Ammonia– Trialkylboranes and Aminodialkylboranes. Chem. Commun. 2016, 52, 11897– 11900. (18) Brown–Garg reagent was prepared as follows: H2SO4 (21.2 mL) was added to Na2Cr2O7 (28 g). Water was slowly added to this slurry until a final volume of 141 Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 262 mL was attained. The mixture was stirred until homogeneous and used immediately. (19) Brown, H. C.; Garg, C. P.; Liu, K.-T. Oxidation of secondary alcohols in diethyl ether with aqueous chromic acid. Convenient procedure for the preparation of ketones in high epimeric purity. J. Org. Chem. 1971, 36, 387–390. (20) Kamat, S. P.; D’Souza, A. M.; Paknikar, S. K. Sodium Metaperiodate Oxidation of Isocarvacrol. Journal of Chemical Research 2003, 2003, 395–397. (21) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor Chem Account 2008, 120, 215–241. (22) Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297–3305. (23) Grimme, S. Supramolecular Binding Thermodynamics by Dispersion-Corrected Density Functional Theory. Chemistry – A European Journal 2012, 18, 9955–9964. (24) Ishida, K.; Morokuma, K.; Komornicki, A. The Intrinsic Reaction Coordinate. An Ab Initio Calculation for HNC→HCN and H−+CH4→CH4+H−. J. Chem. Phys. 1977, 66, 2153–2156. (25) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by Chapter 3 – Some Unusual Transformations of a Highly Reactive a-Bromocaranone 263 the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378–6396. (26) Neese, F.; Wennmohs, F.; Hansen, A.; Becker, U. Efficient, Approximate and Parallel Hartree–Fock and Hybrid DFT Calculations. A ‘Chain-of-Spheres’ Algorithm for the Hartree–Fock Exchange. Chemical Physics 2009, 356, 98–109. (27) Weigend, F. Accurate Coulomb-Fitting Basis Sets for H to Rn. Phys. Chem. Chem. Phys. 2006, 8, 1057–1065. Appendix 6 – Spectra Relevant to Chapter 3 264 APPENDIX 6 Spectra Relevant to Chapter 3: Some Unusual Transformations of a Highly Reactive a-Bromocaranone 10.5 10.0 223 OH 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A6.1 1H NMR (400 MHz, CDCl3) of compound 223. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 265 10.5 10.0 204 O 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A6.2 1H NMR (400 MHz, CDCl3) of compound 204. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 266 10.5 10.0 207 O 9.5 Br 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A6.3 1H NMR (400 MHz, CDCl3) of compound 207. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 267 Appendix 6 – Spectra Relevant to Chapter 3 268 Figure A6.4 Infrared spectrum (Thin Film, NaCl) of compound 207. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A6.5 13C NMR (100 MHz, CDCl3) of compound 207. 20 10 0 -10 10.5 10.0 208 OH 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A6.6 1H NMR (400 MHz, CDCl3) of compound 208. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 269 10.5 10.0 210 O 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A6.7 1H NMR (400 MHz, CDCl3) of compound 210. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 270 Appendix 6 – Spectra Relevant to Chapter 3 271 Figure A6.8 Infrared spectrum (Thin Film, NaCl) of compound 210. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A6.9 13C NMR (100 MHz, CDCl3) of compound 210. 10 0 -10 10.5 10.0 205 O 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A6.10 1H NMR (400 MHz, CDCl3) of compound 205. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 272 Appendix 6 – Spectra Relevant to Chapter 3 273 Figure A6.11 Infrared spectrum (Thin Film, NaCl) of compound 205. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A6.12 13C NMR (100 MHz, CDCl3) of compound 205. 10 0 -10 10.5 10.0 211 O F 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A6.13 1H NMR (400 MHz, CDCl3) of compound 211. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 274 Appendix 6 – Spectra Relevant to Chapter 3 275 Figure A6.14 Infrared spectrum (Thin Film, NaCl) of compound 211. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A6.15 13C NMR (100 MHz, CDCl3) of compound 211. 10 0 -10 10.5 10.0 9.5 212 O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A6.16 1H NMR (400 MHz, CDCl3) of compound 212. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 276 Appendix 6 – Spectra Relevant to Chapter 3 277 Figure A6.17 Infrared spectrum (Thin Film, NaCl) of compound 212. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A6.18 13C NMR (100 MHz, CDCl3) of compound 212. 20 10 0 -10 10.5 10.0 Br 9.5 213 O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A6.19 1H NMR (400 MHz, CDCl3) of compound 213. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 278 Appendix 6 – Spectra Relevant to Chapter 3 279 Figure A6.20 Infrared spectrum (Thin Film, NaCl) of compound 213. 210 200 190 180 170 160 150 140 130 120 110 ppm 100 90 80 70 60 50 40 Figure A6.21 13C NMR (100 MHz, CDCl3) of compound 213. 30 20 10 10.5 10.0 9.5 214 O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A6.22 1H NMR (400 MHz, CDCl3) of compound 214. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 280 Appendix 6 – Spectra Relevant to Chapter 3 281 Figure A6.23 Infrared spectrum (Thin Film, NaCl) of compound 214. 210 200 190 180 170 160 150 140 130 120 110 ppm 100 90 80 70 60 50 40 Figure A6.24 13C NMR (100 MHz, CDCl3) of compound 214. 30 20 10 10.5 10.0 9.5 215 O 9.0 Br 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A6.25 1H NMR (400 MHz, CDCl3) of compound 215. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 282 Appendix 6 – Spectra Relevant to Chapter 3 283 Figure A6.26 Infrared spectrum (Thin Film, NaCl) of compound 215. 210 200 190 180 170 160 150 140 130 120 110 ppm 100 90 80 70 60 50 40 Figure A6.27 13C NMR (100 MHz, CDCl3) of compound 215. 30 20 10 10.5 10.0 9.5 220 O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A6.28 1H NMR (400 MHz, CDCl3) of compound 220. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 284 Appendix 6 – Spectra Relevant to Chapter 3 285 Figure A6.29 Infrared spectrum (Thin Film, NaCl) of compound 220. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A6.30 13C NMR (100 MHz, CDCl3) of compound 220. 10 0 -10 10.5 10.0 221 O 9.5 Br 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A6.31 1H NMR (400 MHz, CDCl3) of compound 221. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 6 – Spectra Relevant to Chapter 3 286 Appendix 6 – Spectra Relevant to Chapter 3 287 Figure A6.32 Infrared spectrum (Thin Film, NaCl) of compound 221. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A6.33 13C NMR (100 MHz, CDCl3) of compound 221. 10 0 -10 Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 288 CHAPTER 4 On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes† 4.1 INTRODUCTION Polycyclic caged structures have interested chemists since the advent of organic chemistry. Several such systems have played a crucial role in elucidating phenomena like fluxionality,1,2 nonclassical carbocations,3,4 and the reactivity of strained, conformationally restricted systems.5 More recently, polycyclic caged compounds have attracted interest in medicinal chemistry with many derivatives finding themselves utilized as bioisosteres or alternate scaffolds for drug molecules.6,7,8,9 In our investigations toward a polycyclic polyprenylated acylphloroglucinol (PPAP) natural product, we sought to generate allyl cycloheptenone 132 (Scheme 4.1.1A) from a protected bromocycloheptenone (131). We previously developed a radical cyclopropane fragmentation/allylation using allyltributylstannane that we believed could be applied to this system.10 Surprisingly, upon treatment of 131 with a radical initiator (ACHN) and allyl tributylstannane (116), 132 was not observed, and instead caged compound 133 was isolated in excellent yield (confirmed via X-ray structure of compound 236).11 Cage 133 is a homotriblattane featuring an additional carbon (red) compared to the previously known [2.1.1]triblattane (239, Scheme 4.1.1B).12 To our knowledge, this represents the first †This research was conducted in collaboration with Hanh T. Nguyen and Christopher D. Vanderwal. Portions of this chapter have been reproduced with permission from Samkian, A. E.; Nguyen, H. T.; Vanderwal, C. D.; Stoltz, B. M. Tetrahedron Lett. 2025, 164, 155591. © 2025 Elsevier. Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 289 isolation of a homotriblattane (240), a framework that expands on the chemical space of the known triblattanes (238), which are defined as [2.2.2]-bicycles with three helically arranged carbon bridges (in blue). Given that derivatives of Cookson’s cage (237) have been shown to exhibit notable neuroprotective bioactivity,13,14 we were intrigued by the similarity of cage 133 and elected to synthesize several derivatives. Scheme 4.1.1. Unexpected cyclization of bromide 131 to cage 133. A) Unexpected formation of allyl ketone 133. O H Br H ACHN (0.2 equiv) SnBu3 116 (4 equiv) H O PhH, 86 ºC H O H H 132 not observed 131 ACHN NC N N N H N 133, sole product 74% yield NO2 ≡ CN 236 NO2 X-ray structure of 236 2,4-DNPH and hydrogens hidden for clarity B) Homotriblattane 240 and similar polycyclic caged compounds. n n n n ≡ n 237 Cookson’s Cage 4.2 n n 238 [n.n.n]triblattane 240, this work 239 [2.1.1]triblattane [2.n.1]homotriblattane SYNTHESIS OF THE HOMOTRIBLATTANES Bromide 131 (Scheme 4.2.1) was prepared via an AlCl3-catalyzed Diels–Alder reaction of cyclopentadiene with known enone 95 (prepared from (+)-carene, (73)).15 Bromination of the respective silyl enol ether, generated in situ, provided bromide 131 in good yield. The stereochemical assignment of bromide 131 was accomplished via NOE analysis (see Appendix 7). Two other closely related bromides, 243 and 244, were synthesized in a similar fashion, utilizing 1,3-butadiene or 1,3-cyclohexadiene as the diene. Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 290 Scheme 4.2.1. Synthesis of a-brominated cycloheptanones. O H PhMe, 23–40 ºC 95 H H AlCl3 (0.25 equiv) diene (10 equiv) diene: 1,3-butadiene cyclopentadiene 1,3-cyclohexadiene O H R H NH(i-Pr)2, n-BuLi then TMSCl then NBS THF, –78→0 ºC O Br H R H H 241, 43% yield, R = H, H 130, 48% yield, R = –CH2– 242, 69% yield, R = –CH2CH2– H H 243, 59% yield, R = H, H 131, 67% yield, R = –CH2– 244, 70% yield, R = –CH2CH2– We began by attempting to access des-allyl cage 245 (Scheme 4.2.2A) using a hydrogen atom donor. Initial radical cyclization experiments with n-Bu3SnH did not deliver the desired cage, instead providing enone 246. To form the desired cage 245, we hypothesized that bromine abstraction leads to a-ketoradical 247 (Scheme 4.2.2B) which undergoes cyclopropyl fragmentation to afford tertiary radical 248. Addition of this radical into the proximal olefin affords secondary radical 249, which can cyclize with the enone to generate the observed polycyclic ring system (250), followed by radical termination through either H• abstraction or trapping with an allyl group. Given the unexpected formation of cage 133 and the competing pathway leading to enone 246, we proceeded to investigate this sequence via DFT analysis to better understand the radical intermediates involved (Scheme 4.2.2C, see Section 4.4.3 for more details). As we have found in previous studies involving a similar bromocarene system,10 a- ketoradical 247 and 3° radical 248 are close in energy and separated by a shallow barrier, indicating equilibrium behavior. Presumably, the 6-exo cyclization of 248 is slow due to the formation of a strained intermediate (249), but subsequent 5-exo (or 6-endo) ring closure to cage 250 is rapid and thermodynamically favored, driven by geometric constraints and an electronically matched Giese addition. Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 291 Scheme 4.2.2. Proposed mechanism and minimum free energy pathway to 240. A) Attempts to access homotriblattane 245. O H Br H H ACHN (0.2 equiv) n-Bu3SnH (4.0 equiv) PhH, 86 ºC H 131 O H 245 not observed O H 246 major product B) Proposed mechanism for the formation of the caged ketone. H O Br H H H 131 O H –Br• H H H H 247 H 248 SnBu3 H• or O H O O O 249 R 250 133 or 245 Grel (kcal/mol) C) Minimum free energy pathway from 247 toward 250.a 18.4 20 11.2 10 0.0 3.1 0.0 –6.7 –10 –14.7 –20 –30 –40 –35.1 247 TS(251) 248 TS(252) 249 TS(253) Reaction Intermediate 250 aRelative Gibbs free energies in kcal/mol at the M06-2X/def2-TZVPP/SMD(Benzene)// M06-2X/def2-TZVP level of theory. The proposed mechanism is consistent with the observed formation of enone 246, which arises from premature hydrogen atom transfer (HAT) quenching of the equilibrium mixture of intermediates 247 and 248. Although this outcome was initially desired with allyltributylstannane, allylated enone 132 was never observed, likely due to the significantly lower rate of radical addition to an allyl group.16 To mitigate premature HAT, we utilized triethylborane as the initiator at much lower reaction temperatures,17 as well as n- Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 292 Bu3SnCl/sodium cyanoborohydride mixtures to minimize the concentration of available nBu3SnH.18 Unfortunately, both strategies resulted in enone 246 or complex mixtures. We next attempted to attenuate the reactivity of the hydrogen atom donor by employing super silane ((Me3Si)3SiH) or n-Bu3GeH, which have hydrogen abstraction rates that are approximately 5- and 10-fold slower than n-Bu3SnH, respectively.19 We anticipated that the decreased rate of H• abstraction would reduce premature quenching of intermediate 248, allowing the subsequent cyclization to 249 to occur. Gratifyingly, in both cases cage 245 was observed, with n-Bu3GeH providing an excellent 82% isolated yield of 245 with only minimal enone 246 observed (Scheme 4.2.3A). Scheme 4.2.3. Synthesis of other homotriblattanes. A) Hydrogen atom donor screen for cyclization of bromide 131 (NMR yields, isolated yields in parentheses).a O O H Br H ACHN (0.2 equiv) H• source (2.0 equiv) H H H 131 C6D6, 86 ºC O H• source n-Bu3SnH (TMS)3SiH n-Bu3GeH 245 0% yield 34% yield 88% (82%) yield H 246 53% yield 38% yield 9% yield B) Attempts to synthesize cages 254 and 255. H O Br H ACHN n-Bu3GeH O PhH, 80 ºC H 243 H 254 not observed H O Br H ACHN n-Bu3GeH ≡ PhH, 80 ºC H 244 H 12% yield O X-ray structure of 255 Hydrogens hidden for clarity 255 aNMR yields were determined using 1,3,5-trimethoxybenzene as an internal standard in C D . 6 6 Interestingly, while these conditions with bromide 243 resulted in a complex mixture, bromide 244 provided [2.2.1]homotriblattane 255 (Scheme 4.2.3B), albeit in decreased yield. Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 293 It is possible that the rigid nature of the bicycles in bromides 131 and 244 is necessary to facilitate cyclization. 4.3 CONCLUSION In conclusion, we have developed a facile sequence to access a new class of enantiomerically pure polycyclic cages from readily available chiral pool starting materials. Given the similarity of the trihomoblattane scaffolds to bioactive caged systems such as Cookson’s cage (237), we believe these structures, and derivatives thereof, warrant further exploration. 4.4 EXPERIMENTAL SECTION 4.4.1 MATERIALS AND METHODS Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.20 Enone 95 was prepared according to a previously reported procedure.15 All other reagents were purchased from commercial sources and used as received unless otherwise stated. Reaction progress was monitored by thin-layer chromatography (TLC). TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, CAM stain, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 µm) was used for flash chromatography. Teledyne ISCO CombiFlashRf+, Teledyne ISCO CombiFlashRf+ LumenTM, or Teledyne ISCO CombiFlashRf NEXTGEN+ systems were used for automated flash chromatography using Luknova SuperSepTM silica columns. 1H NMR spectra were recorded on Varian Inova 600 MHz and Bruker 400 MHz spectrometers and are reported relative to residual non-deuterated solvent Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 294 CHCl3 (δ 7.26 ppm). 13C NMR spectra were recorded on a Bruker 400 MHz spectrometers (100 MHz) and are reported relative to residual non-deuterated solvent CDCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Diastereomeric ratios were calculated based on ratios of integrals from crude 1H NMR spectra. Some spectra contain minor solvent impurities of water, ethyl acetate, dichloromethane, diethyl ether, acetone, grease, and/or silicone grease, which do not impact product assignments. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell. High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-T2000GC AccuTOFTM GC-Alpha High Resolution Mass Spectrometer in field ionization (FI+) or field desorption (FD+) mode, or an Agilent 6230 Series TOF with and Agilent Jet Stream ion source in electrospray ionization (ESI+). Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 4.4.2 295 EXPERIMENTAL PROCEDURES O H AlCl3 cyclopentadiene H O H PhMe, 23 ºC H 95 H H 130 (1aR,2aR,3S,6R,6aS,8aS)-1,1-dimethyl-1a,2,2a,3,6,6a,8,8a-octahydro-3,6methanobenzo[a]cyclopropa[d][7]annulen-7(1H)-one 130. A 100 mL flask under N2 was charged with enone 95 (450 mg, 3.0 mmol, 1.0 equiv) and PhMe (12 mL). With good stirring, a suspension of anhydrous AlCl3 (100 mg, 0.75 mmol, 0.25 equiv) in PhMe (12 mL) was slowly added at 23 °C, and the orange suspension stirred for 45 min. Freshly cracked cyclopentadiene (1.94 g, 29.4 mmol, 9.8 equiv) in PhMe (6 mL) was then added and the reaction monitored by TLC until the disappearance of enone 95 was observed (1.5 h). The reaction was rapidly poured into 100 mL of ice cold 1% NaHCO3 solution, and the layers vigorously mixed. The mixture was extracted with Et2O (2 x 25 mL), and the combined organic extracts washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→100% PhMe/hexanes) to furnish 130 (312 mg, 48% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 6.26 (dd, J = 6.0, 2.5 Hz, 1H), 5.98 (dd, J = 5.7, 3.0 Hz, 1H), 3.17 – 3.11 (m, 2H), 2.74 (s, 1H), 2.70 – 2.59 (m, 2H), 2.11 (dd, J = 16.4, 7.3 Hz, 1H), 1.90 (ddd, J = 14.2, 5.3, 3.0 Hz, 1H), 1.40 (dt, J = 8.3, 1.8 Hz, 1H), 1.30 (d, J = 8.3 Hz, 1H), 1.02 (s, 3H), 0.92 – 0.84 (m, 4H), 0.66 – 0.51 (m, 2H); 13 C{1H} NMR (101 MHz, CDCl3) δ = 213.6, 137.6, 133.2, 56.0, 48.7, 47.6, 47.1, 43.4, 41.2, 28.6, 27.5, 27.3, 19.6, 18.5, 15.3; IR (Neat Film, NaCl) 2927, 2863, 1688, 1454, 1124, Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 296 711 cm–1; HRMS (ESI+): m/z calc’d for C15H21O [M+H]+: 217.1587, found 217.1580; [α]D 22.75 +70.5 (c = 0.1, CHCl3). H O H NH(i-Pr)2, n-BuLi TMSCl, NBS H O Br H THF, –78→0 ºC H 130 H H H 131 (1aR,2aR,3S,6R,6aS,8S,8aS)-8-bromo-1,1-dimethyl-1a,2,2a,3,6,6a,8,8a-octahydro3,6-methanobenzo[a]cyclopropa[d][7]annulen-7(1H)-one 131. To a solution of diisopropylamine (112 mg, 1.11 mmol, 1.2 equiv) in THF (2 mL) at –78 °C, n-BuLi (2.5M, 0.39 mL, 0.97 mmol, 1.05 equiv) was added dropwise and the solution stirred at this temperature for 20 min. A solution of ketone 130 (200 mg, 0.925 mmol, 1.0 equiv) in THF (1.5 mL) was added dropwise over 10 minutes and the resulting solution stirred for 1.5 h. Trimethylsilyl chloride (151 mg, 1.39 mmol, 1.5 equiv) was added dropwise and the reaction was warmed to 0 °C in an ice bath and stirred for 1 h. Solid Nbromosuccinimide (248 mg, 1.39 mmol, 1.5 equiv) was added in one portion and the reaction was stirred at 0 °C for 30 min in the dark. The reaction was quenched with sat. aq. NaHCO3 (5 mL) and extracted with Et2O (2 x 10 mL). The combined organic extracts were washed with water (2 x 5 mL) and brine (10 mL), then dried of Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→5% EtOAc/hexanes) to furnish 131 (272 mg, 67% yield) as a colorless oil. Frozen solutions of 131 in PhH could be stored at –15 °C for months without degradation. However, 131 is sensitive to light and will discolor in its presence. 1H NMR (400 MHz, CDCl3) δ = 6.20 (dd, J = 5.7, 2.8 Hz, 1H), 6.15 (dd, J = 5.8, Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 297 2.9 Hz, 1H), 4.06 (d, J = 9.5 Hz, 1H), 3.42 (dd, J = 9.5, 3.6 Hz, 1H), 3.28 – 3.22 (m, 1H), 2.84 (tp, J = 3.0, 1.5 Hz, 1H), 2.66 (ddt, J = 13.2, 9.5, 3.9 Hz, 1H), 2.08 – 1.98 (m, 1H), 1.47 (dt, J = 8.4, 1.9 Hz, 1H), 1.40 (dt, J = 8.4, 1.5 Hz, 1H), 1.09 (s, 3H), 1.08 – 1.01 (m, 4H), 0.97 (t, J = 9.2 Hz, 1H), 0.73 (ddd, J = 14.6, 13.2, 11.9 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ = 204.3, 136.2, 135.7, 56.6, 53.0, 49.5, 49.5, 48.0, 44.0, 29.3, 28.7, 28.1, 27.6, 22.1, 14.3; IR (Neat Film, NaCl) 2924, 1703, 1456, 1254, 1137, 743 cm–1; HRMS (ESI+): m/z calc’d for C15H20OBr [M+H]+: 295.0692, found 295.0683; [α]D 22.95 +92.7 (c = 0.2, CHCl3). H O Br H ACHN, n-Bu3GeH PhH, 80 ºC H 131 O H 245 3,3-dimethyldecahydro-6H-2,7,4-(epiethane[1,1,2]triyl)cyclopenta[cd]inden-6-one 245. In a glovebox, a solution of bromide 131 (5 mg, 17.0 µmol, 1.0 equiv) in PhH (0.5 mL) was added to 1,1′-azobis(cyclohexanecarbonitrile) (0.8 mg, 3.4 µmol, 0.2 equiv) in a 1dram vial with a stir bar. n-Bu3GeH (8.3 mg, 34.0 µmol, 2.0 equiv) was added, and the vial was carefully sealed with a Teflon lined cap. The vial was taken out of the glovebox and heated to 80 °C for 24 h with stirring. After cooling to 23 °C, the solution was concentrated under reduced pressure and the residue was purified by preparative TLC (25% Et2O/hexanes) to furnish 245 (3.0 mg, 82% yield) as a waxy solid. 1H NMR (400 MHz, CDCl3) δ = 2.77 – 2.70 (m, 1H), 2.56 (tdd, J = 9.7, 6.8, 1.8 Hz, 1H), 2.47 (dt, J = 10.7, 2.3 Hz, 1H), 2.38 – 2.31 (m, 3H), 2.31 – 2.21 (m, 2H), 1.93 – 1.85 (m, 2H), 1.56 – 1.44 (m, Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 298 3H), 1.37 – 1.28 (m, 1H), 1.05 (s, 3H), 0.95 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 217.2, 58.6, 58.1, 47.4, 42.6, 40.3, 40.2, 39.1, 38.7, 38.1, 35.5, 33.8, 27.7, 24.5, 22.6; IR (Neat Film, NaCl) 2930, 1711, 1465, 1231 cm–1; HRMS (ESI+): m/z calc’d for C15H21O [M+H]+: 217.1587, found 217.1585; [α]D 22.92 +11.3 (c = 0.3, CHCl3). H O Br H ACHN n-Bu3SnH H O PhH, 86 ºC H H H 131 246 (1S,4R,4aS,8S,9aR)-8-isopropyl-1,4,4a,8,9,9a-hexahydro-5H-1,4methanobenzo[7]annulen-5-one 246. In a glovebox, a solution of bromide 131 (100 mg, 0.169 mmol, 1.0 equiv) in PhH (4.5 mL) was added to 1,1′-azobis(cyclohexanecarbonitrile) (16 mg, 0.068 mmol, 0.2 equiv) in a 2-dram vial with a stir bar. n-Bu3SnH (394 mg, 1.36 mmol, 4.0 equiv) was added, and the vial was carefully sealed with a Teflon lined cap. The vial was taken out of the glovebox and heated to 86 °C for 48 h with stirring. After cooling to 23 °C, the solution was concentrated under reduced pressure and the residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% Et2O/hexanes) to furnish 246 (8.3 mg, 23% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 6.35 (dd, J = 5.9, 2.6 Hz, 1H), 6.23 (dt, J = 12.5, 2.1 Hz, 1H), 6.01 (dd, J = 5.7, 3.0 Hz, 1H), 5.94 (dd, J = 12.5, 3.3 Hz, 1H), 3.20 – 3.11 (m, 2H), 2.77 (tq, J = 3.3, 1.4 Hz, 1H), 2.48 (dddd, J = 13.7, 9.8, 3.5, 1.7 Hz, 1H), 2.32 – 2.23 (m, 1H), 1.84 – 1.71 (m, 2H), 1.45 (dt, J = 8.3, 1.8 Hz, 1H), 1.33 (dt, J = 8.0, 1.5 Hz, 1H), 0.95 – 0.87 (m, 1H), 0.85 (dd, J = 7.0, 5.3 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ = 204.1, 147.5, 137.9, 132.7, 131.3, 59.9, 48.8, 48.4, 48.3, 45.5, 43.0, Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 299 34.0, 33.7, 19.3, 19.1; IR (Neat Film, NaCl) 2957, 1665, 1458, 1335, 728 cm–1; HRMS (ESI+): m/z calc’d for C15H21O [M+H]+: 217.1587, found 217.1580; [α]D 22.72 –16.9 (c = 0.9, CHCl3). H O SnBu3 Br H ACHN 116 O PhH, 86 ºC H 131 H 133 5-allyl-3,3-dimethyldecahydro-6H-2,7,4-(epiethane[1,1,2]triyl)cyclopenta[cd]inden6-one 133. In a glovebox, a solution of bromide 131 (50 mg, 0.169 mmol, 1.0 equiv) in PhH (2.25 mL) was added to 1,1′-azobis(cyclohexanecarbonitrile) (8.2 mg, 0.034 mmol, 0.2 equiv) in a 1-dram vial with a stir bar. Allyltributylstannane 116 (224 mg, 0.676 mmol, 4.0 equiv) was added, and the vial was carefully sealed with a Teflon lined cap. The vial was taken out of the glovebox and heated to 86 °C for 48 h with stirring. After cooling to 23 °C, the solution was concentrated under reduced pressure and the residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→15% Et2O/hexanes) to furnish 133 (32 mg, 74% yield) as a colorless oil. The stereochemistry of the allyl group was assigned based on the X-ray crystal structure of compound 236. However, we acknowledge the possibility of epimerization during the hydrazine condensation step. 1H NMR (600 MHz, CDCl3) δ = 5.79 (dddd, J = 16.4, 10.3, 8.4, 5.8 Hz, 1H), 5.09 – 5.05 (m, 1H), 5.04 (t, J = 1.2 Hz, 1H), 2.68 – 2.63 (m, 1H), 2.51 (tdd, J = 9.9, 6.8, 1.9 Hz, 1H), 2.45 (dt, J = 10.6, 2.4 Hz, 1H), 2.39 – 2.34 (m, 2H), 2.29 – 2.19 (m, 3H), 2.15 – 2.08 (m, 1H), 1.91 – 1.86 (m, 2H), 1.55 – 1.49 (m, 2H), 1.46 (dt, J = 9.9, 1.5 Hz, 1H), 1.31 (dd, J = 15.0, Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 300 4.2 Hz, 1H), 1.04 (s, 3H), 0.94 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 218.8, 136.4, 116.9, 58.4, 57.9, 48.5, 47.2, 42.8, 40.5, 40.2, 38.8, 38.4, 37.5, 35.9, 34.3, 27.7, 24.6, 22.6; IR (Neat Film, NaCl) 2946, 1701, 1463, 910 cm–1; HRMS (ESI+): m/z calc’d for C18H25O [M+H]+: 257.1900, found 257.1896; [α]D 22.74 –24.6 (c = 1.1, CHCl3). DNPH, H2SO4 O 133 N EtOH/H2O, 80 ºC 236 H N NO2 NO2 (Z)-1-((5R)-5-allyl-3,3-dimethyldecahydro-6H-2,7,4-(epiethane[1,1,2]triyl)cyclopenta [cd]inden-6-ylidene)-2-(2,4-dinitrophenyl)hydrazine 236. A solution of 2,4-dinitrophenylhydrazine (140 mg) and H2SO4 (0.5 mL) was prepared in EtOH/H2O (5:1, 6 mL). Ketone 133 (16 mg, 0.06 mmol, 1 equiv) was dissolved in this solution in a 20 mL vial. The reaction was heated to 80 °C for 3 h, cooled to 23 °C, quenched with sat. aq. NaHCO3 (16 mL) and extracted with CH2Cl2 (20 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (5→10% EtOAc/hexanes) to afford 236 (26 mg, 96% yield) as an orange solid. Compound 236 was isolated as a 1.1:1 mixture of inseparable isomers, 1H, 13C, IR, HRMS, and polarimetry data is provided for this mixture. IR (Neat Film, NaCl) 3315, 2926, 1616, 1590, 1517, 1334, 1133, 1073, 918 cm–1; HRMS (ESI+): m/z calc’d for C24H29N4O4 [M+H]+: 437.2183, found 437.2202; [α]D 22.68 –64.4 (c 0.9, CHCl3). Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes O H AlCl3 1,3-cyclohexadiene H 301 O H PhMe, 40 ºC H 95 H H 242 (1aR,2aR,3S,6R,6aS,8aS)-1,1-dimethyl-1a,2,2a,3,6,6a,8,8a-octahydro-3,6ethanobenzo[a]cyclopropa[d][7]annulen-7(1H)-one 242. In a glovebox, a 20 mL vial was charged with enone 95 (200 mg, 1.3 mmol, 1.0 equiv) and PhMe (7 mL). With good stirring, a suspension of anhydrous AlCl3 (89 mg, 0.67 mmol, 0.50 equiv) in PhMe (3 mL) was slowly added at 20 °C, and the suspension was stirred rigorously for 1.5 h. 1,3-cyclohexadiene (1.09 g, 13.6 mmol, 10 equiv), dried over neutral alumina, diluted in PhMe (3 mL), and then added to the reaction vial. The reaction was heated to 40 °C and monitored by TLC until the disappearance of enone 95 was observed (18 h). The reaction was rapidly poured into 50 mL of ice cold 5% NaHCO3 solution, and the layers vigorously mixed. The mixture was extracted with Et2O (2 x 25 mL), and the combined organic extracts washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (10→50% PhMe/hexanes) to furnish 242 (210 mg, 69% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 6.42 – 6.34 (m, 1H), 6.07 – 5.98 (m, 1H), 3.08 (dd, J = 10.5, 2.2 Hz, 1H), 2.83 – 2.67 (m, 2H), 2.49 – 2.31 (m, 3H), 1.70 (ddd, J = 14.4, 5.8, 1.9 Hz, 1H), 1.60 – 1.53 (m, 1H), 1.46 – 1.37 (m, 1H), 1.23 (m, J = 9.7, 3.0 Hz, 2H), 1.00 (s, 3H), 0.92 (ddd, J = 11.4, 9.1, 5.8 Hz, 1H), 0.85 (s, 3H), 0.78 – 0.63 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ = 212.5, 135.1, 129.8, 57.0, 43.2, 42.5, 37.0, 32.4, 29.8, 29.2, 28.5, 26.6, 23.5, 19.5, 17.8, 15.4; IR (Neat Film, NaCl) 2941, 2864, 1698, 1451, 1313, 1127, 680 cm–1; HRMS (ESI+): Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 302 m/z calc’d for C16H23O [M+H]+: 231.1743, found 231.1742; [α]D 23.83 –35.2 (c = 1.0, CHCl3). H O H NH(i-Pr)2, n-BuLi TMSCl, NBS H O Br H THF, –78→0 ºC H H 242 H H 244 (1aR,2aR,3S,6R,6aS,8S,8aS)-8-bromo-1,1-dimethyl-1a,2,2a,3,6,6a,8,8a-octahydro3,6-ethanobenzo[a]cyclopropa[d][7]annulen-7(1H)-one 244. To a solution of diisopropylamine (79 mg, 0.78 mmol, 1.2 equiv) in THF (3 mL) at –78 °C, titrated nBuLi (0.36 mL, 0.72 mmol, 1.1 equiv) was added dropwise and the solution stirred at this temperature for 30 min. A solution of ketone 242 (150 mg, 0.65 mmol, 1.0 equiv) in THF (1.5 mL) was added dropwise over 10 minutes and the resulting solution stirred for 1.5h. Trimethylsilyl chloride (106 mg, 0.98 mmol, 1.5 equiv) was added dropwise and the reaction was warmed to 0 °C in an ice bath and stirred for 1 h. Nbromosuccinimide (174 mg, 0.98 mmol, 1.5 equiv) in THF (1.5 mL) was added slowly and the reaction was stirred at 0 °C for 30 min in the dark. The reaction was quenched with sat. aq. NaHCO3 (5 mL) and extracted with Et2O (2 x 10 mL). The combined organic extracts were washed with water (2 x 5 mL) and brine (10 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (10→20% PhMe/hexanes) to furnish 244 (140 mg, 70% yield) as a colorless oil. Frozen solutions of in PhH could be stored at –15 °C for several days without degradation. 1H NMR (400 MHz, CDCl3) δ = 6.38 (m, J = 8.3, 6.2, 0.9 Hz, 1H), 6.10 (m, J = 8.3, 6.3, 1.1 Hz, 1H), 4.26 – 4.20 (m, 1H), 3.67 (dd, J = 10.4, 2.1 Hz, 1H), 2.75 (dd, J Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 303 = 6.4, 3.5, 1.8 Hz, 1H), 2.45 – 2.34 (m, 2H), 1.77 (dq, J = 15.3, 2.6 Hz, 1H), 1.63 – 1.52 (m, 2H), 1.33 – 1.20 (m, 2H), 1.08 (m, 5H), 0.92 (s, 3H), 0.87 – 0.74 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ = 205.5, 134.6, 130.9, 53.6, 51.9, 43.9, 37.0, 33.4, 29.7, 29.4, 28.3, 27.9, 25.9, 24.3, 21.8, 15.0; IR (Neat Film, NaCl) 2941, 2866, 1700, 1458, 1311, 1165, 705 cm–1; HRMS (ESI+): m/z calc’d for C16H22BrO [M+H]+: 309.0849, found 309.0846; [α]D 23.97 +40.0 (c = 1.0, CHCl3). H O Br H H ACHN, n-Bu3GeH + PhH, 80 ºC H 244 O O H H 255 256 2,2-dimethyldecahydro-3,6,1-(epiethane[1,1,2]triyl)acenaphthylen-7(2a1H)-one 255. In a glovebox, a solution of bromide 244 (30 mg, 97 µmol, 1.0 equiv) in PhH (1.3 mL) was added to 1,1′-azobis(cyclohexanecarbonitrile) (6.3 mg, 26 µmol, 0.27 equiv) in a 1-dram vial with a stir bar. n-Bu3GeH (47 mg, 50 µL, 0.26 mmol, 2.0 equiv) was added, and the vial was carefully sealed with a Teflon lined cap. The vial was taken out of the glovebox and heated to 80 °C for 24 h with stirring. After cooling to 23 °C, the solution was concentrated under reduced pressure and the residue was purified by preparatory TLC (20% Et2O/hexanes) to furnish cage 255 (2.6 mg, 12% yield) as a colorless crystalline solid. Characterization data for 255: 1H NMR (400 MHz, CDCl3) δ = 2.83 – 2.74 (m, 1H), 2.54 – 2.39 (m, 3H), 2.33 – 2.23 (m, 1H), 1.97 (m, 1H), 1.93 – 1.76 (m, 3H), 1.57 – 1.38 (m, 6H), 1.34 (ddd, J = 15.0, 4.1, 1.8 Hz, 1H), 1.06 (s, 3H), 0.99 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 216.3, 52.1, 48.2, 47.4, 41.5, 39.3, 37.5, 36.5, 31.7, 28.5, 27.9, 27.8, 26.8, 24.3, 22.2, 21.0; IR (Neat Film, NaCl) 2922, 2888, 1710, 1466, 1403, 1381, 1196 Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 304 cm–1; HRMS (ESI+): m/z calc’d for C16H23O [M+H]+: 231.1743, found 231.1742; [α]D 23.56 –40.3 (c = 0.05, CHCl3). (1S,4R,4aS,8S,9aR)-8-isopropyl-1,4,4a,8,9,9a-hexahydro-5H-1,4ethanobenzo[7]annulen-5-one 256. Further purification of the crude residue yielded enone 256 (8.6 mg, 38% yield) as a colorless oil. Characterization data for 256: 1H NMR (400 MHz, CDCl3) δ = 6.44 – 6.32 (m, 1H), 6.17 – 6.07 (m, 2H), 5.94 (dd, J = 12.3, 3.2 Hz, 1H), 3.01 – 2.91 (m, 2H), 2.47 – 2.39 (m, 1H), 2.27 (dp, J = 11.2, 2.9 Hz, 1H), 2.18 (ddt, J = 12.2, 10.4, 2.0 Hz, 1H), 1.76 (dtq, J = 10.5, 7.0, 3.5 Hz, 1H), 1.62 – 1.50 (m, 2H), 1.48 – 1.38 (m, 1H), 1.27 (m, J = 11.8, 9.1, 3.2 Hz, 2H), 1.13 (ddd, J = 13.9, 11.9, 10.8 Hz, 1H), 0.85 (s, 3H), 0.83 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ = 204.6, 144.7, 134.7, 131.5, 131.1, 60.0, 50.1, 43.2, 38.5, 36.3, 33.8, 31.3, 26.0, 23.6, 19.3, 19.3; IR (Neat Film, NaCl) 2953, 2931, 2867, 1674, 1461, 1371, 704 cm–1; HRMS (ESI+): m/z calc’d for C16H23O [M+H]+: 231.1743, found 231.1742; [α]D 23.35 –11.7 (c = 0.5, CHCl3). O H AlCl3 1,3-butadiene H O H PhMe, 40 ºC H 95 H H 241 (1aR,2aS,6aS,8aS)-1,1-dimethyl-1a,2,2a,3,6,6a,8,8aoctahydrobenzo[a]cyclopropa[d][7]annulen-7(1H)-one 241. A 2-dram vial was charged with AlCl3 (33.3 mg, 0.0.25 mmol, 0.25 equiv) and PhMe (3.6 mL) under a N2 atmosphere. A solution of enone 95 (150 mg, 1.0 mmol, 1.0 equiv) in PhMe (3 mL) was added dropwise with good stirring resulting in a cloudy, orange solution Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 305 that was stirred for 40 min further. Butadiene (80 wt% in PhMe, 3.38 mL, 10 mmol, 10 equiv) is then added and the reaction was heated to 40 °C and stirred at this temperature for 24 h. The reaction was rapidly poured into 40 mL of ice cold 2.5% NaHCO3 solution, a sat. aq. solution of Rochelle salt (10 mL) was added, and the layers vigorously mixed. The mixture was extracted with Et2O (2 x 20 mL), and the combined organic extracts washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 241 (89 mg, 43% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 5.72 – 5.65 (m, 1H), 5.65 – 5.58 (m, 1H), 3.53 (td, J = 6.2, 4.1 Hz, 1H), 2.59 – 2.51 (m, 1H), 2.34 (dtt, J = 18.2, 3.9, 1.7 Hz, 1H), 2.24 (dddd, J = 10.9, 8.6, 5.1, 1.1 Hz, 1H), 2.18 – 2.02 (m, 3H), 2.02 – 1.94 (m, 1H), 1.66 – 1.56 (m, 1H), 1.09 (s, 3H), 1.03 (s, 3H), 1.00 – 0.77 (m, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 214.6, 125.2, 125.1, 46.9, 37.9, 34.4, 31.2, 28.8, 28.7, 25.1, 25.0, 21.9, 20.4, 15.3; IR (Neat Film, NaCl) 2917, 1703, 1458, 1138, 655 cm–1; HRMS (ESI+): m/z calc’d for C14H21O [M+H]+: 205.1587, found 205.1580; [α]D 22.81 +83.3 (c = 1.0, CHCl3). H O H NH(i-Pr)2, n-BuLi TMSCl, NBS H O Br H THF, –78→0 ºC H 241 H H H 243 (1aR,2aS,6aS,8S,8aS)-8-bromo-1,1-dimethyl-1a,2,2a,3,6,6a,8,8aoctahydrobenzo[a]cyclopropa[d][7]annulen-7(1H)-one 243. To a solution of diisopropylamine (39 mg, 0.38 mmol, 1.2 equiv) in THF (0.7 mL) at –78 °C, nBuLi (2.5M, 0.13 mL, 0.34 mmol, 1.05 equiv) was added dropwise and the solution Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 306 stirred at this temperature for 20 min. A solution of ketone 241 (69 mg, 0.32 mmol, 1.0 equiv) in THF (0.5 mL) was added dropwise over 10 minutes and the resulting solution stirred for 2 h. Trimethylsilyl chloride (52 mg, 0.48 mmol, 1.5 equiv) was added dropwise and the reaction was warmed to 0 °C in an ice bath and stirred for 1 h. Solid Nbromosuccinimide (85 mg, 0.48 mmol, 1.5 equiv) was added in one portion and the reaction was stirred at 0 °C for 30 min in the dark. The reaction was quenched with 5% aq. NaHCO3 (2 mL) and extracted with Et2O (2 x 5 mL). The combined organic extracts were washed with water (2 x 2 mL) and brine (2 mL), then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→15% EtOAc/hexanes) to furnish 243 (53 mg, 59% yield) as a colorless oil. Frozen solutions of 243 in PhH could be stored at –15 °C for several days without degradation. However, 243 is sensitive to light and will discolor in its presence. 1H NMR (400 MHz, CDCl3) δ = 5.71 – 5.58 (m, 2H), 4.34 (d, J = 10.5 Hz, 1H), 3.32 (td, J = 6.7, 4.4 Hz, 1H), 2.37 – 2.22 (m, 3H), 2.17 (dddd, J = 15.7, 6.1, 3.6, 1.4 Hz, 1H), 1.88 (ddd, J = 15.0, 5.8, 3.6 Hz, 1H), 1.77 (dddd, J = 17.5, 7.0, 4.8, 2.2 Hz, 1H), 1.29 – 1.20 (m, 1H), 1.19 – 1.12 (m, 7H), 1.07 – 0.95 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ = 204.8, 125.1, 124.3, 51.1, 47.9, 34.8, 32.0, 31.4, 29.5, 28.1, 27.8, 24.9, 22.8, 14.3; IR (Neat Film, NaCl) 2920, 1715, 1456, 1135, 680 cm–1; HRMS (ESI+): m/z calc’d for C14H20BrO [M+H]+: 283.0692, found 283.0693; [α]D 24.00 +54.3 (c = 0.5, CHCl3). Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 4.4.3 307 COMPUTATIONAL DETAILS All quantum mechanical calculations were carried out with the ORCA program.21,22 DFT geometry optimizations and harmonic frequency calculations were carried out in the gas phase with the M06-2X functional23 and def2-TZVP basis set24 on all atoms. Thermodynamic corrections from harmonic frequency calculations employ the quasiridged rotor harmonic oscillator approach to correct for the breakdown of the harmonic oscillator approximation at low vibrational frequencies.25 Stationary points are characterized by the correct number of imaginary vibrational modes (zero for minima and one for saddle points). Intrinsic reaction coordinate (IRC) analysis26 confirms the nature of transition states. Electronic energies are further refined with single point calculations at the M06-2X/def2-TZVPP level of theory employing the SMD implicit solvation model for benzene.27 Final Gibbs free energies were obtained by applying thermodynamic corrections obtained at the optimization level of theory to these refined solvated electronic energies. The resolution of identity (RI) and Chain-of-Spheres (COS) approximations are employed for efficient evaluation of Coulomb and exchange integrals, respectively.28 The def2/J auxiliary basis29 and very fine grid settings are employed in all calculations (keyword: DefGrid3). Calculations on open-shell systems employ unrestricted Kohn– Sham orbitals (UKS). Spin contamination is generally minor. Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 4.5 (1) 308 REFERENCES AND NOTES Ault, A. The Bullvalene Story. The Conception of Bullvalene, a Molecule That Has No Permanent Structure. J. Chem. Educ. 2001, 78, 924–927. (2) Schröder, G. Preparation and Properties of Tricyclo[3,3,2,04,6]deca-2,7,9-triene (Bullvalene). Angew. Chem. Int. Ed. 1963, 2, 481–482. (3) H. C. Brown, The Nonclassical Ion Problem, with comments by P. v. R. Schleyer (Springer, New York, 1977). (4) Scholz, F.; Himmel, D.; Heinemann, F. W.; Schleyer, P. V. R.; Meyer, K.; Krossing, I. Crystal Structure Determination of the Nonclassical 2-Norbornyl Cation. Science 2013, 341, 62–64. (5) Lerman, B. M. Skeletal rearrangements of cage compounds with medium rings. Russ. Chem. Rev. 1991, 60, 736–763. (6) Biegasiewicz, K. F.; Griffiths, J. R.; Savage, G. P.; Tsanaktsidis, J.; Priefer, R. Cubane: 50 Years Later. Chem. Rev. 2015, 115, 6719–6745. (7) Smith, E.; Jones, K. D.; O’Brien, L.; Argent, S. P.; Salome, C.; Lefebvre, Q.; Valery, A.; Böcü, M.; Newton, G. N.; Lam, H. W. Silver(I)-Catalyzed Synthesis of Cuneanes from Cubanes and Their Investigation as Isosteres. J. Am. Chem. Soc. 2023, 145, 16365–16373. (8) Van der Schyf, C. J.; Geldenhuys, W. J. Polycyclic Compounds: Ideal Drug Scaffolds for the Design Drugs? Neurotherapeutics 2009, 6, 175–186. of Multiple Mechanism Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes (9) 309 Joubert, J.; Geldenhuys, W. J.; Van der Schyf, C. J.; Oliver, D. W.; Kruger, H. G.; Govender, T.; Malan, S. F. Polycyclic Cage Structures as Lipophilic Scaffolds for Neuroactive Drugs. ChemMedChem 2012, 7, 375–384. (10) Samkian, A. E.; Sercel, Z. P.; Virgil, S. C.; Stoltz, B. M. Some Unusual Transformations of a Highly Reactive α-Bromocaranone. Tetrahedron Lett. 2022, 89, 153496. (11) The stereochemistry of the allyl group was assigned based on the X-ray crystal structure of compound 4. However, we acknowledge the possibility of epimerization during the hydrazine condensation step. (12) Müller-Bötticher, H.; Fessner, W.-D.; Melder, J.-P.; Prinzbach, H.; Gries, S.; Irngartinger, H. Functionalized Enantiomerically Pure [1.1.1]‐, [2.1.1]‐, [2.2.1]‐, and [2.2.2]Triblattanes. Chem. Ber. 1993, 126, 2275–2297. (13) Cookson, R.C., Grundwell, E., Hudec, J. Synthesis of cage-like molecules by irradiation of Diels-Alder adducts. Chem. Ind. 1958, 1003–1004 (14) Geldenhuys, W. J.; Malan, S. F.; Bloomquist, J. R.; Marchand, A. P.; Van der Schyf, C. J. Pharmacology and Structure-Activity Relationships of Bioactive Polycyclic Cage Compounds: A Focus on Pentacycloundecane Derivatives. Med. Res. Rev. 2005, 25, 21–48. (15) Jackson III, R. K.; Wood, J. L. Total Synthesis of ent-Plagiochianin B. Org. Lett. 2021, 23, 1243–1246. Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes (16) 310 Curran, D. P.; v. Elburd, P. A.; Giese, B.; Gilges, S. Approximate rate constants for the addition of alkyl radicals to allylstannanes. Tetrahedron Lett. 1990, 31, 2861– 2864. (17) Ollivier, C.; Renaud, P. Organoboranes as a Source of Radicals. Chem. Rev. 2001, 101, 3415–3434. (18) Srikrishna, A.; Viswajanani, R.; Yelamaggad, C. V. Tributyltin Chloride-Sodium Cyanoborohydride Mediated Tandem Radical Cyclisation-Reductive Demethoxylation Sequence. Tetrahedron 1997, 53, 10479–10488. (19) Chatgilialoglu, C. (Me3Si)3SiH: Twenty Years after Its Discovery as a RadicalBased Reducing Agent. Chemistry 2008, 14, 2310–2320. (20) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (21) Neese, F. The ORCA Program System. WIREs Computational Molecular Science 2012, 2, 73–78. (22) Neese, F. Software Update: The ORCA Program System, Version 4.0. WIREs Computational Molecular Science 2018, 8, e1327. (23) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals. Theor Chem Account 2008, 120, 215–241. Chapter 4 – On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes (24) 311 Weigend, F.; Ahlrichs, R. Balanced Basis Sets of Split Valence, Triple Zeta Valence and Quadruple Zeta Valence Quality for H to Rn: Design and Assessment of Accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297–3305. (25) Grimme, S. Supramolecular Binding Thermodynamics by Dispersion-Corrected Density Functional Theory. Chemistry – A European Journal 2012, 18, 9955–9964. (26) Ishida, K.; Morokuma, K.; Komornicki, A. The Intrinsic Reaction Coordinate. An Ab Initio Calculation for HNC→HCN and H−+CH4→CH4+H−. J. Chem. Phys. 1977, 66, 2153–2156. (27) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J. Phys. Chem. B 2009, 113, 6378–6396. (28) Neese, F.; Wennmohs, F.; Hansen, A.; Becker, U. Efficient, Approximate and Parallel Hartree–Fock and Hybrid DFT Calculations. A ‘Chain-of-Spheres’ Algorithm for the Hartree–Fock Exchange. Chemical Physics 2009, 356, 98–109. (29) Weigend, F. Accurate Coulomb-Fitting Basis Sets for H to Rn. Phys. Chem. Chem. Phys. 2006, 8, 1057–1065. Appendix 7 – Spectra Relevant to Chapter 4 312 APPENDIX 7 Spectra Relevant to Chapter 4: On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes 10.5 O 10.0 130 H H H 9.5 H 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A7.1 1H NMR (400 MHz, CDCl3) of compound 130. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 313 Appendix 7 – Spectra Relevant to Chapter 4 314 Figure A7.2 Infrared spectrum (Thin Film, NaCl) of compound 130. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A7.3 13C NMR (100 MHz, CDCl3) of compound 130. 10 0 -10 10.5 O H 10.0 131 H H 9.5 H Br 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A7.4 1H NMR (400 MHz, CDCl3) of compound 131. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 315 7.5 7.0 6.0 5.5 5.0 4.5 4.0 3.5 ppm 3.0 2.5 2.0 1.5 1.0 Figure A7.5 COSY NMR (400 MHz, CDCl3) of compound 131. 6.5 0.5 0.0 -0.5 -1.0 7 6 5 4 3 2 1 0 -1 Appendix 7 – Spectra Relevant to Chapter 4 316 ppm 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 4.5 ppm 4.0 3.5 3.0 2.5 2.0 Figure A7.6 NOESY NMR (400 MHz, CDCl3) of compound 131. 8.0 1.5 1.0 0.5 0.0 9 8 7 6 5 4 3 2 1 0 Appendix 7 – Spectra Relevant to Chapter 4 317 ppm Appendix 7 – Spectra Relevant to Chapter 4 318 Figure A7.7 Infrared spectrum (Thin Film, NaCl) of compound 131. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A7.8 13C NMR (100 MHz, CDCl3) of compound 131. 20 10 0 -10 10.5 10.0 245 9.5 O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A7.9 1H NMR (400 MHz, CDCl3) of compound 245. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 319 3.0 2.9 2.8 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 ppm 1.6 1.5 1.4 1.3 1.2 1.1 1.0 Figure A7.10 COSY NMR (400 MHz, CDCl3) of compound 245. 2.7 0.9 0.8 0.7 0.6 0.5 0.4 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 Appendix 7 – Spectra Relevant to Chapter 4 320 ppm 3.1 3.0 2.9 2.8 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 1.8 1.7 ppm 1.6 1.5 1.4 1.3 1.2 1.1 1.0 Figure A7.11 HSQC NMR (400 MHz, CDCl3) of compound 245. 2.7 0.9 0.8 0.7 0.6 0.5 0.4 60 55 50 45 40 35 30 25 20 Appendix 7 – Spectra Relevant to Chapter 4 321 ppm Appendix 7 – Spectra Relevant to Chapter 4 322 Figure A7.12 Infrared spectrum (Thin Film, NaCl) of compound 245. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A7.13 13C NMR (100 MHz, C6D6) of compound 245. 10 0 -10 10.5 O 10.0 246 H H 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A7.14 1H NMR (400 MHz, CDCl3) of compound 246. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 323 Appendix 7 – Spectra Relevant to Chapter 4 324 Figure A7.15 Infrared spectrum (Thin Film, NaCl) of compound 246. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A7.16 13C NMR (100 MHz, CDCl3) of compound 246. 10 0 -10 10.5 10.0 133 9.5 O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A7.17 1H NMR (400 MHz, CDCl3) of compound 133. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 325 Appendix 7 – Spectra Relevant to Chapter 4 326 Figure A7.18 Infrared spectrum (Thin Film, NaCl) of compound 133. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A7.19 13C NMR (100 MHz, CDCl3) of compound 133. 20 10 0 -10 11.5 236 11.0 N 10.5 H N 10.0 NO2 9.5 NO2 8.5 8.0 7.5 7.0 6.5 6.0 ppm 5.5 5.0 4.5 4.0 3.5 3.0 Figure A7.20 1H NMR (400 MHz, CDCl3) of compound 236. 9.0 2.5 2.0 1.5 1.0 0.5 Appendix 7 – Spectra Relevant to Chapter 4 327 Appendix 7 – Spectra Relevant to Chapter 4 328 Figure A7.21 Infrared spectrum (Thin Film, NaCl) of compound 236. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A7.22 13C NMR (100 MHz, CDCl3) of compound 236. 20 10 0 -10 10.5 10.0 O 9.5 242 H H H 9.0 H 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A7.23 1H NMR (400 MHz, CDCl3) of compound 242. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 329 Appendix 7 – Spectra Relevant to Chapter 4 330 Figure A7.24 Infrared spectrum (Thin Film, NaCl) of compound 242. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A7.25 13C NMR (100 MHz, CDCl3) of compound 242. 10 0 -10 10.5 O 10.0 244 H H 9.5 H 9.0 H Br 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A7.26 1H NMR (400 MHz, CDCl3) of compound 244. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 331 8.0 7.5 7.0 6.0 5.5 5.0 4.5 4.0 ppm 3.5 3.0 2.5 2.0 Figure A7.27 COSY NMR (400 MHz, CDCl3) of compound 244. 6.5 1.5 1.0 0.5 0.0 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 7 – Spectra Relevant to Chapter 4 332 ppm 6.5 6.0 5.0 4.5 4.0 3.5 ppm 3.0 2.5 2.0 Figure A7.28 HSQC NMR (400 MHz, CDCl3) of compound 244. 5.5 1.5 1.0 0.5 140 130 120 110 100 90 80 70 60 50 40 30 20 10 Appendix 7 – Spectra Relevant to Chapter 4 333 ppm 7.5 7.0 6.0 5.5 5.0 4.5 4.0 ppm 3.5 3.0 2.5 2.0 1.5 Figure A7.29 NOESY NMR (400 MHz, CDCl3) of compound 244. 6.5 1.0 0.5 0.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 7 – Spectra Relevant to Chapter 4 334 ppm Appendix 7 – Spectra Relevant to Chapter 4 335 Figure A7.30 Infrared spectrum (Thin Film, NaCl) of compound 244. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A7.31 13C NMR (100 MHz, C6D6) of compound 244. 10 0 -10 10.5 10.0 9.5 255 9.0 O 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A7.32 1H NMR (400 MHz, CDCl3) of compound 255. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 336 8.0 7.5 7.0 6.0 5.5 5.0 4.5 4.0 ppm 3.5 3.0 2.5 2.0 Figure A7.33 COSY NMR (400 MHz, CDCl3) of compound 255. 6.5 1.5 1.0 0.5 0.0 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 7 – Spectra Relevant to Chapter 4 337 ppm 3.1 3.0 2.9 2.7 2.6 2.5 2.4 2.3 2.2 2.1 2.0 1.9 ppm 1.8 1.7 1.6 1.5 1.4 1.3 Figure A7.34 HSQC NMR (400 MHz, CDCl3) of compound 255. 2.8 1.2 1.1 1.0 0.9 0.8 55 50 45 40 35 30 25 20 15 Appendix 7 – Spectra Relevant to Chapter 4 338 ppm Appendix 7 – Spectra Relevant to Chapter 4 339 Figure A7.35 Infrared spectrum (Thin Film, NaCl) of compound 255. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A7.36 13C NMR (100 MHz, CDCl3) of compound 255. 10 0 -10 8.5 O 8.0 256 H H 7.5 7.0 6.0 5.5 5.0 4.5 ppm 4.0 3.5 3.0 2.5 Figure A7.37 1H NMR (400 MHz, CDCl3) of compound 256. 6.5 2.0 1.5 1.0 0.5 Appendix 7 – Spectra Relevant to Chapter 4 340 Appendix 7 – Spectra Relevant to Chapter 4 341 Figure A7.38 Infrared spectrum (Thin Film, NaCl) of compound 256. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A7.39 13C NMR (100 MHz, CDCl3) of compound 256. 10 0 -10 10.5 O 10.0 241 H H 9.5 H H 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A7.40 1H NMR (400 MHz, CDCl3) of compound 241. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 342 Appendix 7 – Spectra Relevant to Chapter 4 343 Figure A7.41 Infrared spectrum (Thin Film, NaCl) of compound 241. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 Figure A7.42 13C NMR (100 MHz, CDCl3) of compound 241. 20 10 0 -10 10.5 O 10.0 243 H H 9.5 H H Br 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 2.0 Figure A7.43 1H NMR (400 MHz, CDCl3) of compound 243. 8.0 1.5 1.0 0.5 0.0 -0.5 Appendix 7 – Spectra Relevant to Chapter 4 344 6.0 5.5 4.5 4.0 3.5 3.0 ppm 2.5 2.0 1.5 Figure A7.44 COSY NMR (400 MHz, CDCl3) of compound 243. 5.0 1.0 0.5 0.0 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 7 – Spectra Relevant to Chapter 4 345 ppm 6.0 5.5 4.5 4.0 3.5 3.0 ppm 2.5 2.0 1.5 1.0 Figure A7.45 HSQC NMR (400 MHz, CDCl3) of compound 243. 5.0 0.5 0.0 130 120 110 100 90 80 70 60 50 40 30 Appendix 7 – Spectra Relevant to Chapter 4 346 ppm 6.0 5.5 4.5 4.0 3.5 ppm 3.0 2.5 2.0 Figure A7.46 NOESY NMR (400 MHz, CDCl3) of compound 243. 5.0 1.5 1.0 0.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Appendix 7 – Spectra Relevant to Chapter 4 347 ppm Appendix 7 – Spectra Relevant to Chapter 4 348 Figure A7.47 Infrared spectrum (Thin Film, NaCl) of compound 243. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A7.48 13C NMR (100 MHz, CDCl3) of compound 243. 10 0 -10 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 349 APPENDIX 8 X-Ray Crystallography Reports Relevant to Chapter 4: On the Unexpected Formation of [2.2.1]- and [2.1.1]Homotriblattanes Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 A8.1 350 GENERAL EXPERIMENTAL INFORMATION 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 compounds 236 and 255. The structure was solved by direct methods using SHELXS1 and refined against F2 on all data by full-matrix least squares with SHELXL-20172 (for 236) or SHELXL20192 (for 255) 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). Software used for molecular graphics: Mercury 4.1.0.4 Compound 236 crystallizes in the orthorhombic space group P212121 with one molecule in the asymmetric unit. The coordinates for the hydrogen atom bound to N1 were located in the difference Fourier synthesis and refined semi-freely with the help of a restraint on the N-H distance (0.91(4) Å). Compound 255 crystallizes in the orthorhombic space group P212121 with one molecule in the asymmetric unit. Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 A8.2 351 X-RAY CRYSTAL STRUCTURE ANALYSIS OF 236 Hydrazine 236 was recrystallized by slow evaporation at 23 °C to provide suitable crystals for X-ray analysis. Figure A8.2.1. X-ray crystal structure of 236. Table A8.2.1. Crystal data and structure refinement for 236 (CCDC# 2430670). Identification code V21331 Empirical formula C24 H28 N4 O4 Formula weight 436.50 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P212121 Unit cell dimensions a = 7.6098(6) Å a= 90°. b = 16.6020(16) Å b= 90°. c = 17.229(2) Å g = 90°. Volume 2176.6(4) Å3 Z 4 Density (calculated) 1.332 Mg/m3 Absorption coefficient 0.751 mm-1 F(000) 928 Crystal size 0.250 x 0.150 x 0.150 mm3 Theta range for data collection 3.697 to 74.373°. Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 Index ranges Reflections collected Independent reflections Completeness to theta = 67.679° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Absolute structure parameter Extinction coefficient Largest diff. peak and hole 352 -9<=h<=9, -20<=k<=20, -20<=l<=21 37438 4456 [R(int) = 0.0459] 100.0 % Semi-empirical from equivalents 0.7538 and 0.6621 Full-matrix least-squares on F2 4456 / 1 / 294 1.037 R1 = 0.0294, wR2 = 0.0763 R1 = 0.0305, wR2 = 0.0769 0.03(4) n/a 0.343 and -0.188 e.Å-3 Table A8.2.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 236. U(eq) is defined as one-third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________ Atom x y z U(eq) ________________________________________________________________________ N(1) 3840(2) 6403(1) 6198(1) 18(1) C(1) 4045(2) 7178(1) 5986(1) 15(1) C(2) 2618(2) 7733(1) 5954(1) 16(1) N(3) 844(2) 7506(1) 6155(1) 19(1) O(1) 544(2) 6802(1) 6364(1) 25(1) O(2) -322(2) 8014(1) 6112(1) 29(1) C(3) 2850(2) 8525(1) 5710(1) 17(1) C(4) 4498(2) 8770(1) 5494(1) 17(1) N(4) 4741(2) 9592(1) 5226(1) 20(1) O(3) 3574(2) 10084(1) 5360(1) 31(1) O(4) 6109(2) 9757(1) 4876(1) 30(1) C(5) 5952(2) 8256(1) 5539(1) 16(1) Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 353 C(6) N(2) C(7) C(8) C(20) C(21) C(22) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(23) C(24) C(17) C(18) 5737(2) 5278(2) 5023(2) 3357(2) 3138(2) 1251(3) 667(3) 3376(2) 5086(2) 6767(2) 6533(2) 6312(2) 4419(3) 3176(2) 3762(3) 2453(3) 4023(3) 5476(2) 6980(3) 7481(1) 5885(1) 5188(1) 4906(1) 5349(1) 5384(1) 5148(1) 3989(1) 3656(1) 4176(1) 4615(1) 3882(1) 3798(1) 3489(1) 2638(1) 2266(1) 2030(1) 2862(1) 3152(1) 5794(1) 6176(1) 6478(1) 6876(1) 7665(1) 7927(1) 8603(1) 6985(1) 7371(1) 7241(1) 6464(1) 5888(1) 5594(1) 6230(1) 6496(1) 7073(1) 5833(1) 6909(1) 6384(1) 16(1) 18(1) 17(1) 16(1) 21(1) 29(1) 36(1) 17(1) 18(1) 20(1) 20(1) 23(1) 24(1) 21(1) 24(1) 31(1) 38(1) 21(1) 24(1) C(19) 8159(2) 3553(1) 6994(1) 27(1) Table A8.2.3. Bond lengths [Å] and angles [°] for 236. _____________________________________________________ N(1)-C(1) 1.346(2) N(1)-N(2) 1.3920(19) N(1)-H(1N) 0.888(19) C(1)-C(6) 1.421(2) C(1)-C(2) 1.426(2) C(2)-C(3) 1.391(2) C(2)-N(3) 1.443(2) N(3)-O(2) 1.2267(19) N(3)-O(1) 1.244(2) C(3)-C(4) 1.370(2) C(3)-H(3) 0.9500 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(4)-C(5) C(4)-N(4) N(4)-O(3) N(4)-O(4) C(5)-C(6) C(5)-H(5) C(6)-H(6) N(2)-C(7) C(7)-C(12) C(7)-C(8) C(8)-C(9) C(8)-C(20) C(8)-H(8) C(20)-C(21) C(20)-H(20A) C(20)-H(20B) C(21)-C(22) C(21)-H(21) C(22)-H(22A) C(22)-H(22B) C(9)-C(15) C(9)-C(10) C(9)-H(9) 1.400(2) 1.454(2) 1.228(2) 1.234(2) 1.369(2) 0.9500 0.9500 1.284(2) 1.492(2) 1.516(2) 1.533(2) 1.555(2) 1.0000 1.506(3) 0.9900 0.9900 1.307(3) 0.9500 0.9500 0.9500 1.551(2) 1.563(2) 1.0000 C(10)-C(11) C(10)-C(17) C(10)-H(10) C(11)-C(12) C(11)-C(19) C(11)-H(11) C(12)-C(13) C(12)-H(12) C(13)-C(14) C(13)-C(18) C(13)-H(13) C(14)-C(15) 1.559(2) 1.567(2) 1.0000 1.535(2) 1.540(3) 1.0000 1.579(2) 1.0000 1.533(3) 1.567(2) 1.0000 1.536(3) 354 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(14)-H(14A) C(14)-H(14B) C(15)-C(16) C(15)-H(15) C(16)-C(17) C(16)-C(24) C(16)-C(23) C(23)-H(23A) C(23)-H(23B) C(23)-H(23C) C(24)-H(24A) C(24)-H(24B) C(24)-H(24C) C(17)-C(18) C(17)-H(17) C(18)-C(19) C(18)-H(18) C(19)-H(19A) C(19)-H(19B) 0.9900 0.9900 1.550(2) 1.0000 1.532(3) 1.537(3) 1.537(3) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.536(3) 1.0000 1.534(3) 1.0000 0.9900 0.9900 C(1)-N(1)-N(2) C(1)-N(1)-H(1N) N(2)-N(1)-H(1N) 119.45(14) 119.8(15) 120.6(15) N(1)-C(1)-C(6) N(1)-C(1)-C(2) C(6)-C(1)-C(2) C(3)-C(2)-C(1) C(3)-C(2)-N(3) C(1)-C(2)-N(3) O(2)-N(3)-O(1) O(2)-N(3)-C(2) O(1)-N(3)-C(2) C(4)-C(3)-C(2) C(4)-C(3)-H(3) C(2)-C(3)-H(3) 120.43(14) 122.70(15) 116.86(14) 121.72(15) 115.96(14) 122.30(14) 122.03(14) 118.87(14) 119.10(13) 118.62(15) 120.7 120.7 355 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(3)-C(4)-C(5) C(3)-C(4)-N(4) C(5)-C(4)-N(4) O(3)-N(4)-O(4) O(3)-N(4)-C(4) O(4)-N(4)-C(4) C(6)-C(5)-C(4) C(6)-C(5)-H(5) C(4)-C(5)-H(5) C(5)-C(6)-C(1) C(5)-C(6)-H(6) C(1)-C(6)-H(6) C(7)-N(2)-N(1) N(2)-C(7)-C(12) N(2)-C(7)-C(8) C(12)-C(7)-C(8) C(7)-C(8)-C(9) C(7)-C(8)-C(20) C(9)-C(8)-C(20) C(7)-C(8)-H(8) C(9)-C(8)-H(8) C(20)-C(8)-H(8) C(21)-C(20)-C(8) 121.86(15) 118.81(15) 119.32(15) 123.76(15) 118.15(15) 118.09(14) 119.71(15) 120.1 120.1 121.07(15) 119.5 119.5 115.29(14) 116.88(14) 126.04(14) 117.03(14) 110.76(13) 109.82(13) 111.27(14) 108.3 108.3 108.3 112.54(15) C(21)-C(20)-H(20A) C(8)-C(20)-H(20A) C(21)-C(20)-H(20B) C(8)-C(20)-H(20B) H(20A)-C(20)-H(20B) C(22)-C(21)-C(20) C(22)-C(21)-H(21) C(20)-C(21)-H(21) C(21)-C(22)-H(22A) C(21)-C(22)-H(22B) H(22A)-C(22)-H(22B) C(8)-C(9)-C(15) 109.1 109.1 109.1 109.1 107.8 125.4(2) 117.3 117.3 120.0 120.0 120.0 115.33(14) 356 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(8)-C(9)-C(10) C(15)-C(9)-C(10) C(8)-C(9)-H(9) C(15)-C(9)-H(9) C(10)-C(9)-H(9) C(11)-C(10)-C(9) C(11)-C(10)-C(17) C(9)-C(10)-C(17) C(11)-C(10)-H(10) C(9)-C(10)-H(10) C(17)-C(10)-H(10) C(12)-C(11)-C(19) C(12)-C(11)-C(10) C(19)-C(11)-C(10) C(12)-C(11)-H(11) C(19)-C(11)-H(11) C(10)-C(11)-H(11) C(7)-C(12)-C(11) C(7)-C(12)-C(13) C(11)-C(12)-C(13) C(7)-C(12)-H(12) C(11)-C(12)-H(12) C(13)-C(12)-H(12) 114.30(13) 104.39(13) 107.5 107.5 107.5 115.25(13) 103.74(13) 103.87(13) 111.2 111.2 111.2 99.03(14) 107.00(13) 103.43(14) 115.2 115.2 115.2 112.20(14) 114.81(15) 101.22(13) 109.4 109.4 109.4 C(14)-C(13)-C(18) C(14)-C(13)-C(12) C(18)-C(13)-C(12) C(14)-C(13)-H(13) C(18)-C(13)-H(13) C(12)-C(13)-H(13) C(13)-C(14)-C(15) C(13)-C(14)-H(14A) C(15)-C(14)-H(14A) C(13)-C(14)-H(14B) C(15)-C(14)-H(14B) H(14A)-C(14)-H(14B) 114.49(15) 112.19(14) 102.64(14) 109.1 109.1 109.1 111.92(14) 109.2 109.2 109.2 109.2 107.9 357 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(14)-C(15)-C(16) C(14)-C(15)-C(9) C(16)-C(15)-C(9) C(14)-C(15)-H(15) C(16)-C(15)-H(15) C(9)-C(15)-H(15) C(17)-C(16)-C(24) C(17)-C(16)-C(23) C(24)-C(16)-C(23) C(17)-C(16)-C(15) C(24)-C(16)-C(15) C(23)-C(16)-C(15) C(16)-C(23)-H(23A) C(16)-C(23)-H(23B) H(23A)-C(23)-H(23B) C(16)-C(23)-H(23C) H(23A)-C(23)-H(23C) H(23B)-C(23)-H(23C) C(16)-C(24)-H(24A) C(16)-C(24)-H(24B) H(24A)-C(24)-H(24B) C(16)-C(24)-H(24C) H(24A)-C(24)-H(24C) 109.74(15) 111.02(14) 102.27(13) 111.2 111.2 111.2 113.30(17) 110.38(15) 107.49(16) 99.26(13) 114.59(15) 111.74(16) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 H(24B)-C(24)-H(24C) C(16)-C(17)-C(18) C(16)-C(17)-C(10) C(18)-C(17)-C(10) C(16)-C(17)-H(17) C(18)-C(17)-H(17) C(10)-C(17)-H(17) C(19)-C(18)-C(17) C(19)-C(18)-C(13) C(17)-C(18)-C(13) C(19)-C(18)-H(18) C(17)-C(18)-H(18) 109.5 115.84(15) 106.22(14) 100.19(14) 111.3 111.3 111.3 99.69(15) 103.13(15) 108.76(15) 114.6 114.6 358 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 359 C(13)-C(18)-H(18) 114.6 C(18)-C(19)-C(11) 94.51(14) C(18)-C(19)-H(19A) 112.8 C(11)-C(19)-H(19A) 112.8 C(18)-C(19)-H(19B) 112.8 C(11)-C(19)-H(19B) 112.8 H(19A)-C(19)-H(19B) 110.3 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table 8.2.4. Anisotropic displacement parameters (Å2x 103) for 236. The anisotropic displacement factor exponent takes the form: -2p2[h2 a*2U11 + ... + 2 h k a* b* U12]. ________________________________________________________________________ Atom U11 U22 U33 U23 U13 U12 ________________________________________________________________________ N(1) 15(1) 16(1) 25(1) 1(1) 3(1) 1(1) C(1) C(2) N(3) O(1) O(2) C(3) C(4) N(4) O(3) O(4) C(5) C(6) N(2) C(7) C(8) 17(1) 14(1) 15(1) 19(1) 14(1) 18(1) 21(1) 25(1) 31(1) 32(1) 16(1) 16(1) 17(1) 17(1) 16(1) 16(1) 19(1) 21(1) 21(1) 28(1) 17(1) 16(1) 17(1) 18(1) 25(1) 20(1) 17(1) 17(1) 17(1) 17(1) 13(1) 17(1) 21(1) 36(1) 45(1) 16(1) 14(1) 19(1) 43(1) 33(1) 14(1) 16(1) 22(1) 16(1) 17(1) -2(1) -2(1) -2(1) 2(1) 5(1) -3(1) 0(1) 0(1) 4(1) 7(1) -2(1) -2(1) 0(1) -1(1) -1(1) -1(1) -2(1) -2(1) 4(1) -2(1) -5(1) -2(1) -3(1) -2(1) 6(1) 0(1) 0(1) 2(1) 1(1) 0(1) 1(1) 0(1) 1(1) -2(1) 5(1) 3(1) -1(1) 0(1) 6(1) -4(1) -1(1) 3(1) 4(1) 0(1) 0(1) C(20) 23(1) 21(1) 21(1) -4(1) 4(1) -4(1) Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 360 C(21) C(22) C(9) C(10) C(11) C(12) C(13) C(14) C(15) C(16) C(23) C(24) C(17) C(18) 26(1) 31(1) 18(1) 20(1) 18(1) 18(1) 31(1) 40(1) 27(1) 34(1) 35(1) 58(1) 27(1) 30(1) 31(1) 43(1) 18(1) 19(1) 21(1) 19(1) 18(1) 18(1) 17(1) 16(1) 18(1) 20(1) 16(1) 18(1) 28(1) 33(1) 15(1) 15(1) 21(1) 24(1) 20(1) 14(1) 19(1) 23(1) 39(1) 35(1) 19(1) 24(1) -4(1) -3(1) 0(1) 2(1) 4(1) 3(1) 4(1) 0(1) -2(1) 0(1) 4(1) -6(1) 4(1) 4(1) 6(1) 11(1) -1(1) -1(1) -2(1) 5(1) 8(1) -2(1) -6(1) -4(1) -4(1) -10(1) -1(1) 6(1) 1(1) -3(1) -2(1) -1(1) 0(1) 3(1) 7(1) 7(1) 0(1) 0(1) -6(1) 4(1) 2(1) 9(1) C(19) 21(1) 26(1) 34(1) 10(1) 1(1) 5(1) Table A8.2.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 103) for 236. ________________________________________________________________________ Atom x y z U(eq) ________________________________________________________________________ H(1N) H(3) H(5) H(6) H(8) 2780(30) 1886 7084 6734 2335 6219(13) 8888 8443 7141 5048 6318(13) 5693 5393 5844 6538 22 20 20 20 20 H(20A) H(20B) H(21) H(22A) H(22B) 3844 3599 417 1458 -548 5067 5904 5597 4931 5192 8064 7616 7572 8976 8722 26 26 34 43 43 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 361 H(9) H(10) H(11) H(12) H(13) H(14A) H(14B) H(15) H(23A) H(23B) H(23C) H(24A) H(24B) H(24C) H(17) H(18) H(19A) 2369 4899 7109 7635 7114 4396 3999 1929 2895 1312 2318 4936 2918 4382 5874 7564 9220 3847 3542 4527 4914 3959 3420 4328 3485 1742 2194 2624 2228 1966 1510 2422 2716 3805 7332 7934 7688 6334 5434 5150 5408 6047 7247 6818 7521 5480 5547 6049 7264 6078 6766 20 22 24 24 27 29 29 25 46 46 46 57 57 57 25 29 33 H(19B) 8493 3183 7420 33 Table A8.2.6. Torsion angles [°] for 236. ________________________________________________________________ N(2)-N(1)-C(1)-C(6) -4.5(2) N(2)-N(1)-C(1)-C(2) 176.63(14) N(1)-C(1)-C(2)-C(3) -177.89(16) C(6)-C(1)-C(2)-C(3) 3.2(2) N(1)-C(1)-C(2)-N(3) 0.5(2) C(6)-C(1)-C(2)-N(3) -178.37(15) C(3)-C(2)-N(3)-O(2) -1.3(2) C(1)-C(2)-N(3)-O(2) -179.76(15) C(3)-C(2)-N(3)-O(1) 178.66(15) C(1)-C(2)-N(3)-O(1) 0.2(2) C(1)-C(2)-C(3)-C(4) 0.1(2) N(3)-C(2)-C(3)-C(4) -178.44(15) C(2)-C(3)-C(4)-C(5) -2.3(2) Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(2)-C(3)-C(4)-N(4) C(3)-C(4)-N(4)-O(3) C(5)-C(4)-N(4)-O(3) C(3)-C(4)-N(4)-O(4) C(5)-C(4)-N(4)-O(4) C(3)-C(4)-C(5)-C(6) N(4)-C(4)-C(5)-C(6) C(4)-C(5)-C(6)-C(1) N(1)-C(1)-C(6)-C(5) C(2)-C(1)-C(6)-C(5) C(1)-N(1)-N(2)-C(7) N(1)-N(2)-C(7)-C(12) N(1)-N(2)-C(7)-C(8) N(2)-C(7)-C(8)-C(9) C(12)-C(7)-C(8)-C(9) N(2)-C(7)-C(8)-C(20) C(12)-C(7)-C(8)-C(20) C(7)-C(8)-C(20)-C(21) C(9)-C(8)-C(20)-C(21) C(8)-C(20)-C(21)-C(22) C(7)-C(8)-C(9)-C(15) C(20)-C(8)-C(9)-C(15) C(7)-C(8)-C(9)-C(10) 179.03(14) 15.7(2) -163.03(16) -164.25(15) 17.0(2) 1.0(2) 179.68(14) 2.6(2) 176.57(15) -4.5(2) 171.66(15) 179.88(14) -2.8(2) 166.32(16) -16.3(2) -70.4(2) 106.94(17) 155.54(15) -81.47(19) 126.8(2) -70.42(18) 167.13(14) 50.59(18) C(20)-C(8)-C(9)-C(10) C(8)-C(9)-C(10)-C(11) C(15)-C(9)-C(10)-C(11) C(8)-C(9)-C(10)-C(17) C(15)-C(9)-C(10)-C(17) C(9)-C(10)-C(11)-C(12) C(17)-C(10)-C(11)-C(12) C(9)-C(10)-C(11)-C(19) C(17)-C(10)-C(11)-C(19) N(2)-C(7)-C(12)-C(11) C(8)-C(7)-C(12)-C(11) N(2)-C(7)-C(12)-C(13) -71.85(18) -27.0(2) 99.93(16) -139.73(14) -12.84(16) -28.46(19) 84.38(15) -132.46(15) -19.61(16) 135.89(16) -41.7(2) -109.26(18) 362 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(8)-C(7)-C(12)-C(13) C(19)-C(11)-C(12)-C(7) C(10)-C(11)-C(12)-C(7) C(19)-C(11)-C(12)-C(13) C(10)-C(11)-C(12)-C(13) C(7)-C(12)-C(13)-C(14) C(11)-C(12)-C(13)-C(14) C(7)-C(12)-C(13)-C(18) C(11)-C(12)-C(13)-C(18) C(18)-C(13)-C(14)-C(15) C(12)-C(13)-C(14)-C(15) C(13)-C(14)-C(15)-C(16) C(13)-C(14)-C(15)-C(9) C(8)-C(9)-C(15)-C(14) C(10)-C(9)-C(15)-C(14) C(8)-C(9)-C(15)-C(16) C(10)-C(9)-C(15)-C(16) C(14)-C(15)-C(16)-C(17) C(9)-C(15)-C(16)-C(17) C(14)-C(15)-C(16)-C(24) C(9)-C(15)-C(16)-C(24) C(14)-C(15)-C(16)-C(23) C(9)-C(15)-C(16)-C(23) 73.16(19) 170.89(14) 63.76(18) 48.00(16) -59.13(16) -13.1(2) 108.00(15) -136.46(15) -15.39(17) 44.5(2) -71.99(18) -61.89(18) 50.43(19) 47.8(2) -78.49(16) 164.76(15) 38.51(17) 69.34(16) -48.57(16) -51.7(2) -169.59(17) -174.24(15) 67.85(18) C(24)-C(16)-C(17)-C(18) C(23)-C(16)-C(17)-C(18) C(15)-C(16)-C(17)-C(18) C(24)-C(16)-C(17)-C(10) C(23)-C(16)-C(17)-C(10) C(15)-C(16)-C(17)-C(10) C(11)-C(10)-C(17)-C(16) C(9)-C(10)-C(17)-C(16) C(11)-C(10)-C(17)-C(18) C(9)-C(10)-C(17)-C(18) C(16)-C(17)-C(18)-C(19) C(10)-C(17)-C(18)-C(19) 52.7(2) 173.29(15) -69.27(18) 162.90(15) -76.50(17) 40.95(16) -138.62(14) -17.78(16) -17.72(16) 103.12(15) 163.10(15) 49.38(15) 363 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 364 C(16)-C(17)-C(18)-C(13) 55.6(2) C(10)-C(17)-C(18)-C(13) -58.16(17) C(14)-C(13)-C(18)-C(19) -144.46(15) C(12)-C(13)-C(18)-C(19) -22.62(17) C(14)-C(13)-C(18)-C(17) -39.3(2) C(12)-C(13)-C(18)-C(17) 82.55(17) C(17)-C(18)-C(19)-C(11) -60.85(15) C(13)-C(18)-C(19)-C(11) 51.16(16) C(12)-C(11)-C(19)-C(18) -61.39(15) C(10)-C(11)-C(19)-C(18) 48.63(15) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A8.2.7. Hydrogen bonds for 236 [Å and °]. ________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ________________________________________________________________________ N(1)-H(1N)...O(1) 0.888(19) 1.96(2) 2.6098(19) 129.0(19) C(5)-H(5)...O(2)#1 0.95 2.44 3.029(2) 120.3 C(8)-H(8)...O(4)#2 1.00 2.63 3.513(2) 147.7 ________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x+1,y,z #2 x-1/2,-y+3/2,-z+1 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 A8.3 365 X-RAY CRYSTAL STRUCTURE ANALYSIS OF 255 Ketone 255 was recrystallized by slow evaporation from CH2Cl2 at 4 °C to provide suitable crystals for X-ray analysis. Figure A8.3.1. X-ray crystal structure of 255. Table A8.3.1. Crystal data and structure refinement for 255 (CCDC# 2430671). Identification code V25098 Empirical formula C16 H22 O Formula weight 230.33 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P212121 Unit cell dimensions a = 8.0806(8) Å a= 90°. b = 11.9089(11) Å c = 12.6284(10) Å b= 90°. g = 90°. Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 67.679° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Absolute structure parameter Extinction coefficient Largest diff. peak and hole 366 1215.24(19) Å3 4 1.259 Mg/m3 0.578 mm-1 504 0.300 x 0.300 x 0.200 mm3 5.105 to 74.416°. -10<=h<=9, -14<=k<=14, -15<=l<=14 16253 2480 [R(int) = 0.0621] 100.0 % Semi-empirical from equivalents 0.7538 and 0.5044 Full-matrix least-squares on F2 2480 / 0 / 156 1.045 R1 = 0.0454, wR2 = 0.1193 R1 = 0.0464, wR2 = 0.1199 -0.1(3) n/a 0.271 and -0.301 e.Å-3 Table A8.3.2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 255. U(eq) is defined as one-third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________ Atom x y z U(eq) ________________________________________________________________________ C(1) 6329(3) 7818(2) 3103(2) 16(1) C(2) 8056(3) 7279(2) 3196(2) 17(1) C(3) 8157(3) 6332(2) 4063(2) 16(1) Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 367 C(4) 6735(3) 6440(2) 4829(2) 16(1) O(1) 6878(2) 6827(1) 5712(1) 23(1) C(5) 5112(3) 5989(2) 4407(2) 17(1) C(6) 5062(3) 5884(2) 3194(2) 14(1) C(7) 5039(3) 7024(2) 2614(2) 15(1) C(8) 5570(3) 6693(2) 1478(2) 15(1) C(15) 4283(3) 5933(2) 942(2) 18(1) C(16) 5833(3) 7688(2) 728(2) 21(1) C(9) 7136(2) 6009(2) 1743(2) 14(1) C(10) 8575(3) 6753(2) 2126(2) 17(1) C(11) 10119(3) 6019(2) 2270(2) 23(1) C(12) 9658(3) 4960(2) 2905(2) 23(1) C(13) 8038(3) 5184(2) 3498(2) 17(1) C(14) 6599(3) 5262(2) 2706(2) 14(1) ________________________________________________________________________ Table A8.3.3. Bond lengths [Å] and angles [°] for 255. _____________________________________________________ C(1)-C(7) 1.537(3) C(1)-C(2) 1.540(3) C(1)-H(1A) 0.9900 C(1)-H(1B) 0.9900 C(2)-C(10) 1.547(3) C(2)-C(3) 1.574(3) C(2)-H(2) 1.0000 C(3)-C(4) 1.507(3) C(3)-C(13) 1.546(3) C(3)-H(3) C(4)-O(1) C(4)-C(5) C(5)-C(6) 1.0000 1.212(3) 1.514(3) 1.538(3) Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(5)-H(5A) C(5)-H(5B) C(6)-C(7) C(6)-C(14) C(6)-H(6) C(7)-C(8) C(7)-H(7) C(8)-C(16) C(8)-C(15) C(8)-C(9) C(15)-H(15A) C(15)-H(15B) C(15)-H(15C) C(16)-H(16A) C(16)-H(16B) C(16)-H(16C) C(9)-C(10) C(9)-C(14) C(9)-H(9) C(10)-C(11) C(10)-H(10) C(11)-C(12) C(11)-H(11A) 0.9900 0.9900 1.542(3) 1.573(3) 1.0000 1.548(3) 1.0000 1.532(3) 1.536(3) 1.541(3) 0.9800 0.9800 0.9800 0.9800 0.9800 0.9800 1.539(3) 1.568(3) 1.0000 1.534(3) 1.0000 1.541(4) 0.9900 C(11)-H(11B) C(12)-C(13) C(12)-H(12A) C(12)-H(12B) C(13)-C(14) C(13)-H(13) C(14)-H(14) 0.9900 1.532(3) 0.9900 0.9900 1.536(3) 1.0000 1.0000 C(7)-C(1)-C(2) C(7)-C(1)-H(1A) C(2)-C(1)-H(1A) C(7)-C(1)-H(1B) 112.89(17) 109.0 109.0 109.0 368 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(2)-C(1)-H(1B) H(1A)-C(1)-H(1B) C(1)-C(2)-C(10) C(1)-C(2)-C(3) C(10)-C(2)-C(3) C(1)-C(2)-H(2) C(10)-C(2)-H(2) C(3)-C(2)-H(2) C(4)-C(3)-C(13) C(4)-C(3)-C(2) C(13)-C(3)-C(2) C(4)-C(3)-H(3) C(13)-C(3)-H(3) C(2)-C(3)-H(3) O(1)-C(4)-C(3) O(1)-C(4)-C(5) C(3)-C(4)-C(5) C(4)-C(5)-C(6) C(4)-C(5)-H(5A) C(6)-C(5)-H(5A) C(4)-C(5)-H(5B) C(6)-C(5)-H(5B) H(5A)-C(5)-H(5B) 109.0 107.8 110.32(17) 113.51(17) 107.68(17) 108.4 108.4 108.4 108.95(18) 110.23(17) 108.00(16) 109.9 109.9 109.9 123.4(2) 122.8(2) 113.83(18) 113.72(18) 108.8 108.8 108.8 108.8 107.7 C(5)-C(6)-C(7) C(5)-C(6)-C(14) C(7)-C(6)-C(14) C(5)-C(6)-H(6) C(7)-C(6)-H(6) C(14)-C(6)-H(6) C(1)-C(7)-C(6) C(1)-C(7)-C(8) C(6)-C(7)-C(8) C(1)-C(7)-H(7) C(6)-C(7)-H(7) C(8)-C(7)-H(7) 113.74(17) 114.07(18) 103.77(16) 108.3 108.3 108.3 110.02(17) 109.91(17) 102.29(16) 111.4 111.4 111.4 369 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(16)-C(8)-C(15) C(16)-C(8)-C(9) C(15)-C(8)-C(9) C(16)-C(8)-C(7) C(15)-C(8)-C(7) C(9)-C(8)-C(7) C(8)-C(15)-H(15A) C(8)-C(15)-H(15B) H(15A)-C(15)-H(15B) C(8)-C(15)-H(15C) H(15A)-C(15)-H(15C) H(15B)-C(15)-H(15C) C(8)-C(16)-H(16A) C(8)-C(16)-H(16B) H(16A)-C(16)-H(16B) C(8)-C(16)-H(16C) H(16A)-C(16)-H(16C) H(16B)-C(16)-H(16C) C(10)-C(9)-C(8) C(10)-C(9)-C(14) C(8)-C(9)-C(14) C(10)-C(9)-H(9) C(8)-C(9)-H(9) 106.06(17) 115.42(18) 109.91(18) 114.48(18) 111.75(17) 99.28(16) 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 109.5 112.59(17) 106.97(17) 103.94(16) 111.0 111.0 C(14)-C(9)-H(9) C(11)-C(10)-C(9) C(11)-C(10)-C(2) C(9)-C(10)-C(2) C(11)-C(10)-H(10) C(9)-C(10)-H(10) C(2)-C(10)-H(10) C(10)-C(11)-C(12) C(10)-C(11)-H(11A) C(12)-C(11)-H(11A) C(10)-C(11)-H(11B) C(12)-C(11)-H(11B) 111.0 108.90(19) 110.33(17) 107.61(17) 110.0 110.0 110.0 109.37(18) 109.8 109.8 109.8 109.8 370 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 371 H(11A)-C(11)-H(11B) 108.2 C(13)-C(12)-C(11) 108.56(18) C(13)-C(12)-H(12A) 110.0 C(11)-C(12)-H(12A) 110.0 C(13)-C(12)-H(12B) 110.0 C(11)-C(12)-H(12B) 110.0 H(12A)-C(12)-H(12B) 108.4 C(12)-C(13)-C(14) 109.84(17) C(12)-C(13)-C(3) 109.07(18) C(14)-C(13)-C(3) 107.11(17) C(12)-C(13)-H(13) 110.3 C(14)-C(13)-H(13) 110.3 C(3)-C(13)-H(13) 110.3 C(13)-C(14)-C(9) 109.24(17) C(13)-C(14)-C(6) 111.80(17) C(9)-C(14)-C(6) 104.77(16) C(13)-C(14)-H(14) 110.3 C(9)-C(14)-H(14) 110.3 C(6)-C(14)-H(14) 110.3 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A8.3.4. Anisotropic displacement parameters (Å2x 103) for 255. The anisotropic displacement factor exponent takes the form: -2p2[ h2 a*2U11 + ... + 2 h k a* b* U12]. ________________________________________________________________________ Atom U11 U22 U33 U23 U13 U12 ________________________________________________________________________ C(1) 20(1) 10(1) 19(1) 0(1) 2(1) 1(1) C(2) 16(1) 16(1) 19(1) -1(1) 1(1) -5(1) C(3) 14(1) 18(1) 17(1) -1(1) -2(1) 1(1) C(4) 19(1) 12(1) 16(1) 3(1) 0(1) 1(1) O(1) 26(1) 25(1) 18(1) -4(1) 0(1) 0(1) Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 372 C(5) C(6) C(7) C(8) C(15) C(16) C(9) C(10) C(11) C(12) C(13) 16(1) 12(1) 14(1) 12(1) 16(1) 22(1) 12(1) 13(1) 12(1) 17(1) 17(1) 17(1) 13(1) 12(1) 16(1) 21(1) 20(1) 16(1) 21(1) 38(1) 30(1) 15(1) 19(1) 18(1) 18(1) 18(1) 18(1) 20(1) 14(1) 17(1) 20(1) 21(1) 18(1) 2(1) 1(1) 2(1) 2(1) 1(1) 5(1) -1(1) 1(1) -4(1) -4(1) -1(1) 4(1) 1(1) 3(1) 1(1) -1(1) 1(1) 1(1) 2(1) 2(1) -2(1) -2(1) -1(1) -1(1) 2(1) 1(1) -1(1) 0(1) 2(1) -3(1) 3(1) 11(1) 3(1) C(14) 15(1) 11(1) 18(1) -1(1) 0(1) 1(1) Table A8.3.5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for 255. ________________________________________________________________________ x y z U(eq) ________________________________________________________________________ H(1A) H(1B) H(2) H(3) H(5A) H(5B) H(6) H(7) 5950 6412 8870 9231 4206 4908 4041 3909 8048 8502 7880 6387 6492 5240 5460 7366 3816 2661 3382 4453 4638 4722 2994 2621 20 20 20 19 21 21 17 18 H(15A) H(15B) H(15C) H(16A) H(16B) 3223 4142 4662 6245 6641 6330 5246 5738 7414 8206 896 1359 228 45 1037 28 28 28 31 31 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 373 H(16C) H(9) H(10) H(11A) H(11B) H(12A) H(12B) H(13) 4780 7481 8800 10984 10565 9520 10549 7824 8080 5535 7358 6447 5802 4314 4778 4573 622 1128 1596 2652 1569 2420 3415 4024 31 17 20 28 28 28 28 20 H(14) 6276 4495 2458 17 Table A8.3.6. Torsion angles [°] for 255. ________________________________________________________________ C(7)-C(1)-C(2)-C(10) 50.4(2) C(7)-C(1)-C(2)-C(3) -70.6(2) C(1)-C(2)-C(3)-C(4) -18.8(2) C(10)-C(2)-C(3)-C(4) -141.19(18) C(1)-C(2)-C(3)-C(13) C(10)-C(2)-C(3)-C(13) C(13)-C(3)-C(4)-O(1) C(2)-C(3)-C(4)-O(1) C(13)-C(3)-C(4)-C(5) C(2)-C(3)-C(4)-C(5) O(1)-C(4)-C(5)-C(6) C(3)-C(4)-C(5)-C(6) C(4)-C(5)-C(6)-C(7) C(4)-C(5)-C(6)-C(14) C(2)-C(1)-C(7)-C(6) C(2)-C(1)-C(7)-C(8) C(5)-C(6)-C(7)-C(1) C(14)-C(6)-C(7)-C(1) C(5)-C(6)-C(7)-C(8) C(14)-C(6)-C(7)-C(8) C(1)-C(7)-C(8)-C(16) C(6)-C(7)-C(8)-C(16) C(1)-C(7)-C(8)-C(15) 100.1(2) -22.3(2) 138.2(2) -103.4(2) -40.1(2) 78.2(2) 162.0(2) -19.7(3) -69.3(2) 49.5(2) 50.8(2) -61.1(2) 45.2(2) -79.27(19) 162.00(18) 37.5(2) -57.3(2) -174.13(17) -177.88(17) Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 C(6)-C(7)-C(8)-C(15) C(1)-C(7)-C(8)-C(9) C(6)-C(7)-C(8)-C(9) C(16)-C(8)-C(9)-C(10) C(15)-C(8)-C(9)-C(10) C(7)-C(8)-C(9)-C(10) C(16)-C(8)-C(9)-C(14) C(15)-C(8)-C(9)-C(14) C(7)-C(8)-C(9)-C(14) C(8)-C(9)-C(10)-C(11) C(14)-C(9)-C(10)-C(11) C(8)-C(9)-C(10)-C(2) C(14)-C(9)-C(10)-C(2) C(1)-C(2)-C(10)-C(11) C(3)-C(2)-C(10)-C(11) C(1)-C(2)-C(10)-C(9) C(3)-C(2)-C(10)-C(9) C(9)-C(10)-C(11)-C(12) C(2)-C(10)-C(11)-C(12) C(10)-C(11)-C(12)-C(13) C(11)-C(12)-C(13)-C(14) C(11)-C(12)-C(13)-C(3) C(4)-C(3)-C(13)-C(12) 65.3(2) 66.23(19) -50.61(18) 51.4(2) 171.27(17) -71.4(2) 166.82(18) -73.33(19) 43.97(18) -174.77(16) 71.7(2) 65.6(2) -47.9(2) -168.78(18) -44.4(2) -50.1(2) 74.3(2) -48.0(2) 69.9(2) -19.7(2) 69.4(2) -47.7(2) -167.89(17) C(2)-C(3)-C(13)-C(12) C(4)-C(3)-C(13)-C(14) C(2)-C(3)-C(13)-C(14) C(12)-C(13)-C(14)-C(9) C(3)-C(13)-C(14)-C(9) C(12)-C(13)-C(14)-C(6) C(3)-C(13)-C(14)-C(6) C(10)-C(9)-C(14)-C(13) C(8)-C(9)-C(14)-C(13) C(10)-C(9)-C(14)-C(6) C(8)-C(9)-C(14)-C(6) C(5)-C(6)-C(14)-C(13) 72.4(2) 73.3(2) -46.4(2) -44.9(2) 73.4(2) -160.43(18) -42.1(2) -22.0(2) -141.30(17) 97.94(19) -21.4(2) -16.0(2) 374 Appendix 8 – X-Ray Crystallography Reports Relevant to Chapter 4 375 C(7)-C(6)-C(14)-C(13) 108.30(18) C(5)-C(6)-C(14)-C(9) -134.19(18) C(7)-C(6)-C(14)-C(9) -9.9(2) ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: A8.4 (1) REFERENCES AND NOTES Sheldrick, G. M. Phase Annealing in SHELX-90: Direct Methods for Larger Structures. Acta Cryst. 1990, A46, 467-473. (2) Sheldrick, G. M. Crystal structure refinement with SHELXL. Acta Cryst. 2015, C71, 3–8. (3) Müller, P. Practical suggestions for better crystal structures. Crystallography Reviews 2009, 15, 57-83. (4) Mercury Software from CCDC: Solutions/CSDSystem/Pages/Mercury.aspx. http://www.ccdc.cam.ac.uk/ Chapter 5 – A Modular Cyclopentene Annulation 376 CHAPTER 5 A Modular Cyclopentene Annulation† 5.1 INTRODUCTION Reactions that construct complex, substituted carbocyclic ring systems sit at the heart of natural product synthesis, often leveraged as key transformations. Among these, the construction of 5-membered rings has been particularly important in the synthesis of countless natural products including steroids,1 prostaglandins,2 triquinanes,3 and more recently, the polycyclic polyprenylated acylphloroglucinols (PPAPs) (257–260, Scheme 5.1.1A).4 Several reactions for the construction of 5-membered rings have been employed successfully toward the synthesis of these challenging natural products.5,6 Notable examples include the Danheiser annulation,7 the Pauson–Khand reaction,8 and trimethylenemethane chemistry.9 Despite their success, these methods often yield products with highly specific oxidation patterns, which can render them unsuitable for many synthetic applications. In our efforts toward a homoadamantane PPAP natural product, we were unable to construct the sterically demanding cyclopentane (e.g., in 260) using conventional approaches.10 Our attention was drawn to the work of Bellassoued and coworkers, who reported that propargyl zinc nucleophiles (261, Scheme 5.1.1B) react with unsaturated 1,3-diesters (262) to afford substituted cyclopentenes (265).11 Despite the long reaction times and modest yields, we †This research was conducted in collaboration with Kasam Poonswat and Scott C. Virgil. Portions of this chapter have been reproduced with permission from Samkian, A. E.; Poonswat, K.; Virgil, S. C.; Stoltz, B. M. Org. Lett. 2025, 27, 5876–5879. © 2025 American Chemical Society. Chapter 5 – A Modular Cyclopentene Annulation 377 recognized the potential of this transformation to construct diverse cyclopentenes, including those bearing the substitution pattern required for the PPAPs, and thus embarked on a study to improve the yield, increase the operational simplicity, and examine its generality. Scheme 5.1.1. Cyclopentane-Containing Natural Products and a Previous Propargyl Zinc Cyclopentene Annulation. A) Cyclopentane containing natural products. R O O R1 O R1 O HO R2 HO H Prosteglandins (259) Polyquinanes (258) Steroids (257) R2 PPAPs (260) B) Prior propargyl zinc mediated cyclopentene annulation by Bellassoued (1978). [Zn] O O MeO2C CO2Me + BrZn 261 Δ 24 h –15 ºC 48 h MeO 262 CO2Me CO2Me [Zn] 264 OMe 263 H+ H CO2Me CO2Me 265, 24% yield mixture of diastereomers The mechanism proposed by Bellassoued involves a conjugate addition of the propargyl zinc nucleophile (261) into the activated enone (262) to form zinc enolate 263. Upon heating, this enolate is proposed to cyclize to form vinyl zinc intermediate 264. While all iterations of this reaction in Bellassoued’s work in-volve a protic quench, we hypothesized that the vinyl zinc intermediate (264) is persistent and could potentially be intercepted by various electrophiles. Chapter 5 – A Modular Cyclopentene Annulation 5.2 378 REACTION OPTIMIZATION To probe this, we initiated an optimization campaign targeting vinyl iodide 271 (Table 5.2.1). We selected chromone 266 as an optimization substrate due to its stability and favorable isolation properties. We found that performing this reaction in 1,2dimethoxyethane (DME) with 2.5 equivalents of propargyl zinc 8 at 0.1 M provided the optimal yield at 0.1 mmol scale. (entry 1). The reaction sequence involves dropwise addition of enone 266 into a solution of propargyl zinc 8 at 0 °C followed by heating to affect cyclization at 85 °C, and finally quenching with a solution of I2 in Et2O at 0 °C. Tracking the reaction led us to identifying enol 269 and cyclopentene 270 as byproducts, likely formed via protic quench of intermediates 267 and 268. Under the optimal conditions, cyclization of the zinc enolate is highly efficient, with the major side reaction being protodemetalation. Both iodide 271 and cyclopentene 270 were isolated exclusively as the cis fused isomer. Unsurprisingly, a protic quench with NH4Cl provided cyclopentene 270 in excellent yield (entry 2). Changing either the solvent or running the reaction at higher concentration significantly reduces the yield (entries 4 and 5). Interestingly, using only 1.5 equivalents of 8 resulted in no iodide 271 being observed, suggesting that significant protodemetalation occurred, and that propargyl zinc 8 possibly plays a role beyond a simple nucleophile. Performing the cyclization at lower temperature (60 °C) results in incomplete cyclization (entry 6), while increasing the temperature (105 °C) results in significant protodemetalation and non-specific decomposition (entry 7). Excitingly, the yield of iodide 271 increased significantly at 1 mmol scale, resulting in a 62% isolated yield for this 3-component coupling. Chapter 5 – A Modular Cyclopentene Annulation 379 Table 5.2.1. Optimization of Reaction Conditions. O 8 (2.5 equiv) MeO2C BrZn DME, t1 = 0 ºC, 1 h O 266 [Zn] O O MeO2C MeO O t2 = 85 ºC 3h O I2 (3 equiv) [Zn] H 267 H+ Et2O t3 = 0 ºC 10 min O 268 H+ OH MeO2C MeO2C O MeO2C O I O H 269 O H 270 O 271 entry variation from standard conditionsa yield 269b yield 270b yield 271b 1 none < 5% 39% 43% 2 NH4Cl quench < 5% 87% 0% 3 THF < 5% 7% 15% 4 0.3 M 0% 39% 27% 5 1.5 equiv 8 0% 40% 0% 6 t2 = 60 ºC 36% 16% 18% 7 t2 = 105 ºC 0% 55% 12% 8 1 mmol scale 0% 15% 68% (62%)c aConditions: 0.1 mmol 266 in 1.0 mL solvent (0.1M). bYields determined by 1H NMR with respect to 1,3,5-trimethoxybenzene or Si(SiMe3)4 (entry 8) as internal standard. cIsolated yield. 5.3 SCOPE AND LIMITATIONS With optimal conditions in hand (Scheme 5.3.1A), we set about exploring the scope of this reaction using a protic quench (NH4Cl) for simplicity (Scheme 5.3.1B). In addition to chromone 270 coumarin 275 and nitrile bearing chromone 276 were both accessible, Chapter 5 – A Modular Cyclopentene Annulation 380 though in decreased yield. Several cycloalkyl b-ketoesters were competent, and hydropentalene 277, hydroindene 278, and hydrazulenes 62 and 89 could all be formed in moderate yields. The lower yields in some cases (e.g. 278) were partially due to the poor stability of the starting enones, which have a propensity to tautomerize to the unproductive enol tautomer (See Section 5.6.2). Scheme 5.3.1. Enone and Propargyl Bromide Scope.a A) Optimized reaction conditions. R R2 Zn (2.5 equiv), 0 ºC, 1 h then, 274, 0→85 ºC, 3–5 h R1 2.5 equiv 1 R2 O DME, 0.1M Br R1 R1 272 R5 R3 O R3 R5 R4 R4 274 273 B) Scope of enones and propargyl bromides. MeO2C O MeO2C O NC O H 270, 74% yield O MeO2C 275, 56% yield MeO2C O MeO2C O H H O H O O H 276, 33% yield MeO2C O H 89, 61% yield > 20 : 1 dr CO2Et CO2Et CO2Me CO2Me Ph H H H 277, 52% yield 278, 31% yield 62, 64% yield MeO2C O TBSO MeO2C H H 14, 65% yield 6.3 : 1 dr MeO2C O O H 281, 49% yield 279, 84% yield O 280, 22% yield TBSO MeO2C O 282, 41% yield H O O N N H Bn H 284 285 O MeO2C C5H11 H aIsolated yield reported. See section 5.6.2 for more details. O MeO2C O Me3Si O H 286 O 283, 15% yield C) Challenging substrates. MeO2C O O 287 Chapter 5 – A Modular Cyclopentene Annulation 381 Substitution can fortuitously attenuate this decomposition, as seen for the enone used to prepare hydroindene 14. Both hydroindene 14 and hydrazulene 89 indicate that the initial conjugate addition is diastereoselective, affording the anti and syn cis-cyclized products, respectively. We also attempted to use acyclic diester 262 (Scheme 5.1.1B), resulting in cyclopentene 279 in excellent yield. Interestingly, the phenyl substituted substrate resulted in a drastically decreased yield (280). Attempts to use vinylogous amides or ketoamides (284, 285) unfortunately resulted in no reaction and allenyl addition, respectively (Scheme 5.3.1C). Next exploring the propargyl bromide scope, we were pleased to find that unsubstituted propargyl bromide was competent (281), albeit in moderate yield. During isolation several allenyl products were observed: a decomposition pathway not seen with dimethylpropargyl nucleophiles. Monosubstituted propargyl bromides did result in cyclopentene product (286), however this resulted in an inseparable mixture of diastereomers, limiting synthetic utility. Additionally, terminally substituted alkynes were also successful (282 and 283). Hindered alkynes inhibit cyclization, an effect that was obvious with trimethylsilylpropargyl bromide, resulting in conjugate addition (not shown), but not cyclization (287). Finally, we attempted to expand the electrophile scope (Scheme 5.3.2), finding that in addition to iodine, NBS and Me3SnCl could be used to access vinyl bromide 288 and vinyl stannane 289 in good yield.12 We were pleased to find that a variety of reactions generally compatible with organozinc reagents worked well for this system. For example, transmetalation with CuBr enabled access to acetylated cyclopentene 52, and using CuCN•2LiCl to generate the “mixed cuprate” also enabled acylation (290) and allylation Chapter 5 – A Modular Cyclopentene Annulation 382 (291).13 We were also excited to find that the vinylzinc reagents were competent nucleophiles in Negishi couplings, and a combination of Pd(dba)2 and tri(2furyl)phosphine (tfp) generated styrene 292.14 Unfortunately, treatment with TsCN did not afford the desired acrylonitrile, despite previous precedent for vinylzinc cyanation using this reagent.14 Scheme 5.3.2. Electrophile Scope.a R1 R1 2.5 equiv R2 Br Zn (2.5 equiv), 0 ºC, 1 h then, 274, 0→85 ºC, 3–5 h then, R6–X, 0 ºC DME, 0.1M O MeO2C I O O MeO2C O H R4 R5 R4 274 273 O MeO2C O O O TBSO MeO2C H 52, 45% yield 6.3 : 1 dr with CuBr/AcCl 289, 55% yield with Me3SnCl 288, 46% yield with NBS O O R3 Me3Sn H 271, 62% yield with I2 O R5 R3 R6 MeO2C Br H O R1 R1 272 MeO2C R2 O MeO2C O MeO2C H O 290, 54% yield with CuCN•2LiCl/Ph–AcCl H O 291, 49% yield with CuCN•2LiCl/allyl Br H O 292, 47% yield with Pd(dba)2, tfp, 4-I-BzOMe aIsolated yield reported. See section 5.6.2 for more details. 5.4 PRODUCT DERIVATIZATION Having demonstrated the scope of this 3-component cyclopentene annulation, we aimed to evaluate the potential synthetic applications of these scaffolds (Scheme 5.4.1). Starting from hydrazulene 89, a range of transformations on the olefin and ketone functional groups resulted in the expected products. Hydrogenation (293) and epoxidation (294) of the olefin proceeded smoothly, as did prenylation (295) and a-bromination of the ketone (296). Using hydropentalene 277 as the starting material, exhaustive reduction Chapter 5 – A Modular Cyclopentene Annulation 383 resulted in diol 298, albeit in only modest yield due to undesired ring-opening side reactions. Subjecting 277 to the Vilsmeier reagent provided b-bromoenone 297, a highly substituted hydropentalene accessed from an activated cyclopentenone in only two steps. Scheme 5.4.1. Product Derivatizations. MeO2C O H H 293 Pd/C (5 wt. %), H2 mCPBA (2.0 equiv) EtOAc, 18 ºC, 24 h CH2Cl2, 0→18 ºC, 12 h 94% yield 92% yield H MeO2C MeO2C O O H H 294 O H H H 89 MeO2C O H H 295 H H LDA (2.5 equiv) then, prenyl Br (2.6 equiv) LDA (1.2 equiv) then, TMSCl (1.7 equiv) then, NBS (1.7 equiv) THF, –78 ºC, 2 h THF, –78 ºC, 3 h 37% yield 87% yield O Br O DMF (20 equiv) PBr3 (12 equiv) MeO2C O CHCl3, 18 ºC, 4 d H 297 31% yield 38% rsm L-selectride (1.5 equiv) then, LiAlH4 (2 equiv) Br H H 296 MeO2C 5.5 MeO2C HO H OH THF, 0 ºC, 3 h H 277 45% yield H 298 CONCLUSION To conclude, a new 3-component cyclopentene annulation is presented herein. The components are commercially available or readily synthesized, providing access to a wide array of substituted cyclopentenes. While several substrates afford only moderate yields, we provide these results as a foundation, noting that reaction times and temperatures can often be adjusted to improve outcomes for specific substrate combinations. We anticipate this reaction will prove valuable in natural product synthesis, and current efforts are focused toward development of an asymmetric variant. Chapter 5 – A Modular Cyclopentene Annulation 5.6 EXPERIMENTAL SECTION 5.6.1 MATERIALS AND METHODS 384 Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Unless otherwise stated, reactions were performed in flame-dried glassware under an argon or nitrogen atmosphere using dry, deoxygenated solvents. Solvents were dried by passage through an activated alumina column under argon.15 Activated Zn was prepared according to a previously reported procedure.16 3-bromo-3-methylbut-1-yne17 and propargyl bromide 30418 were prepared according to previously reported procedures. Enones 1310, 47,19 75,20 266,21 299,22 301,23 and 30224 were prepared according to previously reported procedures. Procedures for compounds 14 and 52 were previously presented in Chapters 1, and 2, respectively, and are therefore not reproduced here. Anhydrous 1,2-dimethoxyethane (DME) was purchased from Chem-Impex, used as received, and stored in a glovebox. All other reagents were purchased from commercial sources and used as received unless otherwise stated. Reaction progress was monitored by thin-layer chromatography (TLC). TLC was performed using E. Merck silica gel 60 F254 precoated glass plates (0.25 mm) and visualized by UV fluorescence quenching, CAM stain, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 µm) was used for flash chromatography. Teledyne ISCO CombiFlashRf+, Teledyne ISCO CombiFlashRf+ LumenTM, or Teledyne ISCO CombiFlashRf NEXTGEN+ systems were used for automated flash chromatography using Luknova SuperSepTM silica columns. 1H NMR spectra were recorded on Varian Inova 600 MHz, Varian Inova 500 MHz, and Bruker 400 MHz spectrometers and are reported relative to residual non-deuterated solvent CHCl3 (δ Chapter 5 – A Modular Cyclopentene Annulation 385 7.26 ppm). 13C NMR spectra were recorded on Bruker 400 MHz and Varian Inova 600 MHz spectrometers (100 MHz) and are reported relative to residual non-deuterated solvent CDCl3 (δ 77.16 ppm). Data for 1H NMR are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, sept = septuplet, m = multiplet, br s = broad singlet, br d = broad doublet. Data for 13C NMR are reported in terms of chemical shifts (δ ppm). Diastereomeric ratios were calculated based on ratios of integrals from crude 1H NMR spectra. Some spectra contain minor solvent impurities of water, ethyl acetate, dichloromethane, diethyl ether, acetone, grease, and/or silicone grease, which do not impact product assignments. IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm–1). Optical rotations were measured with a Jasco P-2000 polarimeter operating on the sodium D-line (589 nm), using a 100 mm path-length cell. High resolution mass spectra (HRMS) were obtained from the Caltech Mass Spectral Facility using a JEOL JMS-T2000GC AccuTOFTM GC-Alpha High Resolution Mass Spectrometer in field ionization (FI+), electron impact (EI+), or field desorption (FD+) mode, or an Agilent 6230 Series TOF with and Agilent Jet Stream ion source in electrospray ionization (ESI+). Chapter 5 – A Modular Cyclopentene Annulation 5.6.2 386 EXPERIMENTAL PROCEDURES O 8 ZnBr MeO2C DME, 0 ºC O 266 1 MeO2C OH 4 O 269 methyl 4-hydroxy-2-(2-methylbut-3-yn-2-yl)-2H-chromene-3-carboxylate 269. In a glovebox, a 1-dram vial was charged with activated Zn (16.4 mg, 0.25 mmol, 2.5 equiv) and DME (0.5 mL) and sealed with a septum cap. The vial was brought out of the glovebox, put under N2, and cooled to 0 ºC in an ice bath. 3-bromo-3-methylbut-1-yne (37 mg, 0.25 mmol, 2.5 equiv) was added in one portion and the resulting suspension was stirred vigourously for 2 h. A solution of 266 (20 mg, 0.1 mmol, 1 equiv) in DME (0.5 mL) was added dropwise over 5 min, and the solution was stirred for 1 h at 0 ºC and 2 h at 18 ºC. The reaction was quenched with sat. aq. NH4Cl, extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 269 as a colorless oil. This compound was characterized to be used as a standard in the optimization studies and a yield was thus not recorded. 1H NMR (600 MHz, CDCl3) δ = 12.40 (s, 1H), 7.61 (dd, J = 7.8, 1.7 Hz, 1H), 7.31 (ddd, J = 8.2, 7.3, 1.7 Hz, 1H), 6.95 (td, J = 7.5, 1.0 Hz, 1H), 6.88 (dd, J = 8.2, 1.1 Hz, 1H), 5.14 (s, 1H), 3.81 (s, 3H), 1.87 (s, 1H), 1.26 (s, 3H), 1.17 (s, 3H); NMR (101 MHz, CDCl3) δ = 171.3, 164.1, 157.4, 133.5, 124.3, 121.1, 118.7, 116.2, 88.5, 78.9, 70.9, 51.5, 39.8, 25.9, 25.8; IR (Neat Film, NaCl) 3292, 2976, 1652, 1626, 1441, 1351, 1268, 761 cm–1; HRMS (ESI+): m/z calc’d for C16H17O4 [M+H]+: 273.1121, found 273.1125. Note: the carbon peaks at 171.3 ppm and 164.1 ppm corresponding to C1 and C4 are not Chapter 5 – A Modular Cyclopentene Annulation 387 visible in the 13C spectrum, possibly due to tautomer effects. However, the presence of these peaks can easily be observed on the HMBC spectrum. General Procedure A: Zn-mediated Cyclopentene Annulation (Protic Quench). The requisite propargyl bromide (2.5 equiv) was added to a suspension of activated Zn (2.5 equiv) in DME (0.5 M with respect to propargyl bromide) at 0 ºC under N2. After 1 h of stirring at 0 ºC, a solution of the requisite a,b-unsaturated carbonyl compound (1.0 equiv) in DME (0.2 M with respect to dicarbonyl) was added dropwise. The suspension was stirred at this temperature for 1 h, and then at 18 ºC for 2 h before being heated to 85 ºC for 4 h without stirring.* After cooling to 0 ºC, the reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to yield a crude residue which was purified according to the listed conditions (vide infra). *Stirring during the heating step was found to significantly increase the rate of protodemetalation of the vinyl zinc intermediate. While this is less important for reactions that are to eventually be quenched with H+, we found it was beneficial to eliminate stirring at this stage altogether. Chapter 5 – A Modular Cyclopentene Annulation 388 8 O ZnBr MeO2C O MeO2C DME, 0 ºC then, 85 ºC O H 266 O 270 methyl 3,3-dimethyl-9-oxo-3,3a-dihydrocyclopenta[b]chromene-9a(9H)-carboxylate 270. Prepared according to General Procedure A using enone 266 (50 mg, 0.24 mmol) and 3bromo-3-methylbut-1-yne (90 mg, 0.61 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to yield 270 (48 mg, 74% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ = 7.85 (dd, J = 7.9, 1.7 Hz, 1H), 7.51 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 7.03 – 6.94 (m, 2H), 6.04 (d, J = 6.0 Hz, 1H), 5.88 (d, J = 6.0 Hz, 1H), 4.95 (s, 1H), 3.73 (s, 3H), 1.29 (s, 3H), 0.87 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 188.13, 170.82, 161.14, 142.59, 136.97, 127.35, 126.19, 121.08, 119.41, 117.93, 88.82, 64.92, 53.38, 50.17, 27.23, 23.68; IR (Neat Film, NaCl) cm–1; HRMS (ESI+): m/z calc’d for C16H17O4 [M+H]+: 273.1121, found 273.1125. 8 O MeO2C O ZnBr DME, 0 ºC then, 85 ºC 299 MeO2C O O H 275 methyl 1,1-dimethyl-4-oxo-1,9b-dihydrocyclopenta[c]chromene-3a(4H)-carboxylate 275. Prepared according to General Procedure A using enone 299 (50 mg, 0.24 mmol) and 3bromo-3-methylbut-1-yne (90 mg, 0.61 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to yield 275 (37 mg, 56% Chapter 5 – A Modular Cyclopentene Annulation 389 yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.32 (ddd, J = 8.2, 6.8, 2.3 Hz, 1H), 7.21 – 7.14 (m, 2H), 7.14 – 7.10 (m, 1H), 6.05 (d, J = 5.5 Hz, 1H), 6.02 (d, J = 5.6 Hz, 1H), 3.68 (s, 3H), 3.45 (s, 1H), 1.33 (s, 3H), 0.63 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 170.6, 166.5, 151.4, 145.8, 129.0, 128.8, 126.6, 124.9, 120.2, 117.2, 62.5, 55.4, 53.6, 50.5, 27.5, 23.3; IR (Neat Film, NaCl) 2958, 1764, 1739, 1456, 1254, 1233, 1164, 760 cm–1; HRMS (FD+): m/z calc’d for C16H16O4 [M]+: 272.1043, found 272.1036. 8 O ZnBr NC O NC O DME, 0 ºC then, 85 ºC 300 H O 276 3,3-dimethyl-9-oxo-3,3a-dihydrocyclopenta[b]chromene-9a(9H)-carbonitrile 276. Prepared according to General Procedure A using enone 300 (51 mg, 0.3 mmol) and 3bromo-3-methylbut-1-yne (110 mg, 0.75 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to yield 276 (24 mg, 33% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.92 – 7.84 (m, 1H), 7.57 (ddd, J = 8.5, 7.2, 1.8 Hz, 1H), 7.09 – 6.99 (m, 2H), 6.03 (d, J = 5.8 Hz, 1H), 5.88 (d, J = 5.9 Hz, 1H), 5.01 (s, 1H), 1.36 (s, 3H), 0.96 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 183.1, 160.8, 145.3, 137.9, 128.0, 123.6, 122.1, 118.3, 118.3, 118.2, 89.3, 52.7, 50.8, 27.0, 23.2; IR (Neat Film, NaCl) 2922, 1687, 1604, 1459, 1296, 751 cm–1; HRMS (FD+): m/z calc’d for C15H13NO2 [M]+: 239.0941, found 239.0929. Chapter 5 – A Modular Cyclopentene Annulation 8 O ZnBr MeO2C MeO2C O H H DME, 0 ºC then, 85 ºC H 75 methyl 390 H H 89 (1aR,2aR,5aR,7aS)-1,1,3,3-tetramethyl-6-oxo-1,1a,2,2a,3,6,7,7a-octahydro- 5aH-cyclopropa[f]azulene-5a-carboxylate 89. Prepared according to General Procedure A using enone 75 (42 mg, 0.2 mmol) and 3bromo-3-methylbut-1-yne (74 mg, 0.5 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% Et2O/hexanes) to yield 22 (34 mg, 61% yield) as a colorless oil. The stereochemistry of 89 was assigned based on diagnostic NOESY correlations. 1H NMR (400 MHz, CDCl3) δ = 5.91 (d, J = 5.6 Hz, 1H), 5.45 (d, J = 5.7 Hz, 1H), 3.79 (s, 3H), 3.08 (dd, J = 13.5, 4.3 Hz, 1H), 2.99 (dd, J = 19.9, 8.8 Hz, 1H), 2.16 (dd, J = 19.9, 8.1 Hz, 1H), 1.90 (dt, J = 14.0, 4.0 Hz, 1H), 1.13 (s, 3H), 1.06 (s, 3H), 0.99 (s, 3H), 0.96 – 0.87 (m, 1H), 0.85 – 0.77 (m, 1H), 0.75 (s, 3H), 0.50 (q, J = 8.5 Hz, 1H); 13 C{1H} NMR (101 MHz, CDCl3) δ = 210.2, 172.1, 146.7, 126.3, 73.7, 52.9, 52.6, 46.9, 38.4, 28.5, 28.0, 27.1, 23.5, 21.5, 20.8, 18.7, 15.0; IR (Neat Film, NaCl) 2952, 1744, 1701, 1241, 1227, 796 cm–1; HRMS (FD+): m/z calc’d for C17H24O3 [M]+: 276.1720, found 276.1712; [α]D 22.90 –72.5 (c = 0.2, CHCl3). Chapter 5 – A Modular Cyclopentene Annulation 391 8 O MeO2C ZnBr DME, 0 ºC then, 85 ºC 301 MeO2C O H 277 methyl 6,6-dimethyl-3-oxo-2,3,6,6a-tetrahydropentalene-3a(1H)-carboxylate 277. Prepared according to General Procedure A using enone 301 (42 mg, 0.3 mmol) and 3bromo-3-methylbut-1-yne (110 mg, 0.75 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to yield 277 (33 mg, 52% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ = 5.68 (d, J = 5.4 Hz, 1H), 5.58 (d, J = 5.4 Hz, 1H), 3.72 (s, 3H), 2.89 (t, J = 8.4 Hz, 1H), 2.54 – 2.33 (m, 2H), 2.06 (dddd, J = 12.5, 8.7, 7.9, 3.7 Hz, 1H), 1.75 – 1.64 (m, 1H), 1.10 (s, 3H), 1.06 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 212.2, 172.1, 144.8, 124.3, 73.5, 55.7, 52.8, 48.1, 39.8, 30.41, 22.9, 21.9; IR (Neat Film, NaCl) 2955, 1750, 1732, 1258, 1162, 792, 750 cm–1; HRMS (ESI+): m/z calc’d for C12H17O3 [M+H]+: 209.1172, found 209.1165. 8 O ZnBr MeO2C O MeO2C DME, 0 ºC then, 85 ºC 302 H 278 methyl 1,1-dimethyl-4-oxo-1,4,5,6,7,7a-hexahydro-3aH-indene-3a-carboxylate 278. Prepared according to General Procedure A using enone 302 (50 mg, 0.32 mmol) and 3bromo-3-methylbut-1-yne (120 mg, 0.81 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to yield 278 (22 mg, 31% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 5.79 (d, J = 5.7 Hz, 1H), 5.77 – 5.74 (m, 1H), 3.74 (d, J = 0.7 Hz, 3H), 2.83 (t, J = 6.9 Hz, 1H), 2.62 (dtd, J = 15.7, 7.1, 0.9 Chapter 5 – A Modular Cyclopentene Annulation 392 Hz, 1H), 2.30 (dt, J = 15.6, 6.1 Hz, 1H), 2.06 – 1.89 (m, 3H), 1.61 – 1.51 (m, 1H), 1.10 (s, 3H), 0.93 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 209.6, 172.3, 145.1, 126.3, 72.0, 53.8, 53.1, 48.2, 39.4, 28.9, 24.5, 23.5, 22.8; IR (Neat Film, NaCl) 2953, 1714, 1246, 1223 cm–1; HRMS (FD+): m/z calc’d for C13H18O3 [M]+: 222.1251, found 222.1246. Note that 302 is prone to tautomerization to the enol form, at which point it is inactive toward this chemistry. 302 should be prepared immediately before use to ensure reproducible yield. O 8 ZnBr MeO2C O MeO2C DME, 0 ºC then, 85 ºC 47 H 62 methyl 1,1-dimethyl-4-oxo-4,5,6,7,8,8a-hexahydroazulene-3a(1H)-carboxylate 62. Prepared according to General Procedure A using enone 47 (50 mg, 0.30 mmol) and 3bromo-3-methylbut-1-yne (110 mg, 0.74 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% Et2O/hexanes) to yield 62 (45 mg, 64% yield) as a colorless oil. Characterization data for compound 62 is presented in Chapter 2. 8 MeO2C CO2Me ZnBr CO2Me CO2Me DME, 0 ºC then, 85 ºC 262 279 dimethyl 4,4,5-trimethylcyclopent-2-ene-1,1-dicarboxylate 279. Prepared according to General Procedure A using enone 262 (48 mg, 0.3 mmol) and 3bromo-3-methylbut-1-yne (110 mg, 0.75 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to yield 279 (57 mg, 84% Chapter 5 – A Modular Cyclopentene Annulation 393 yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 5.87 (d, J = 5.7 Hz, 1H), 5.66 (d, J = 5.7 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 2.62 (q, J = 7.4 Hz, 1H), 1.08 (s, 3H), 1.02 (d, J = 7.4 Hz, 3H), 0.93 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 171.8, 171.3, 146.9, 125.9, 77.4, 70.4, 52.7, 52.3, 48.3, 47.5, 28.4, 23.1, 10.8; IR (Neat Film, NaCl) 2955, 1731, 1434, 1261, 798 cm–1; HRMS (ESI+): m/z calc’d for C12H18NaO4 [M+Na]+: 249.1097, found 249.1090. 8 EtO2C ZnBr CO2Et Ph DME, 0 ºC then, 85 ºC 303 CO2Et CO2Et Ph 280 diethyl 4,4-dimethyl-5-phenylcyclopent-2-ene-1,1-dicarboxylate 280. Prepared according to General Procedure A using enone 303 (74 mg, 0.3 mmol) and 3bromo-3-methylbut-1-yne (110 mg, 0.75 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to yield 280 (21 mg, 22% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.22 – 7.14 (m, 5H), 5.92 (d, J = 5.6 Hz, 1H), 5.89 (d, J = 5.6 Hz, 1H), 4.27 – 4.10 (m, 2H), 3.99 (s, 1H), 3.80 (dq, J = 10.7, 7.1 Hz, 1H), 3.64 (dq, J = 10.7, 7.1 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H), 1.19 (s, 3H), 0.82 (s, 3H), 0.77 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 170.7, 170.2, 145.8, 139.3, 130.1, 127.6, 126.9, 126.5, 72.5, 61.8, 61.2, 60.0, 49.6, 30.6, 25.7, 14.1, 13.5; IR (Neat Film, NaCl) 2958, 1731, 1253, 1191, 1091 cm–1; HRMS (ESI+): m/z calc’d for C19H25O4 [M+H]+: 317.1747, found 317.1748. Chapter 5 – A Modular Cyclopentene Annulation O ZnBr 394 O MeO2C MeO2C DME, 0 ºC then, 85 ºC O 266 O H 281 methyl 9-oxo-3,3a-dihydrocyclopenta[b]chromene-9a(9H)-carboxylate 281. Prepared according to General Procedure A using enone 266 (100 mg, 0.49 mmol) and 3bromoprop-1-yne (147 mg, 1.22 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→20% EtOAc/hexanes) to yield 281 (59 mg, 49% yield) as a yellow oil. 1H NMR (500 MHz, CDCl3) δ = 7.92 (dd, J = 7.9, 1.8 Hz, 1H), 7.52 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 7.03 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.98 (dd, J = 8.4, 1.2 Hz, 1H), 6.06 (dt, J = 5.9, 2.3 Hz, 1H), 5.99 (dt, J = 6.0, 2.0 Hz, 1H), 5.39 (dd, J = 7.2, 6.1 Hz, 1H), 3.76 (s, 3H), 2.86 (dddd, J = 16.8, 7.2, 2.6, 1.8 Hz, 1H), 2.66 (ddt, J = 16.8, 6.1, 2.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ = 187.1, 170.6, 159.8, 136.9, 132.8, 130.0, 127.9, 121.8, 121.0, 118.9, 82.7, 66.9, 53.3, 38.2; IR (Neat Film, NaCl) 2953, 1745, 1681, 1606, 1462, 1311, 1248, 945, 769 cm–1; HRMS (ESI+): m/z calc’d for C14H12NaO4 [M+Na]+: 267.0628, found 267.0621. MeO2C O O ZnBr MeO2C DME, 0 ºC then, 85 ºC O H 266 O 282 methyl 1-methyl-9-oxo-3,3a-dihydrocyclopenta[b]chromene-9a(9H)-carboxylate 282. Prepared according to General Procedure A using enone 266 (50 mg, 0.24 mmol) and 1bromobut-2-yne (81 mg, 0.61 mmol). Purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to yield 282 (26 mg, 41% Chapter 5 – A Modular Cyclopentene Annulation 395 yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 7.91 – 7.86 (m, 1H), 7.52 (ddd, J = 8.1, 7.3, 1.8 Hz, 1H), 7.06 – 6.98 (m, 2H), 5.66 – 5.58 (m, 2H), 3.72 (s, 3H), 3.21 – 3.10 (m, 1H), 3.07 – 2.94 (m, 1H), 1.66 (dd, J = 2.8, 1.4 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 190.0, 170.8, 158.6, 137.6, 136.8, 127.7, 127.4, 121.7, 120.7, 118.5, 88.4, 62.5, 53.2, 38.6, 13.6; IR (Neat Film, NaCl) 2953, 1742, 1681, 1606, 1463, 1311, 1247, 768 cm– 1 ; HRMS (FD+): m/z calc’d for C15H14O4 [M]+: 258.0887, found 258.0890. O TBSO TBSO Br DME, 0 ºC then, 85 ºC O 266 O ZnBr MeO2C methyl MeO2C H O OTBS 304 283 1-(((tert-butyldimethylsilyl)oxy)methyl)-9-oxo-3,3a- dihydrocyclopenta[b]chromene-9a(9H)-carboxylate 283. Prepared according to General Procedure A using enone 266 (61 mg, 0.3 mmol) and propargyl bromide 304 (198 mg, 0.75 mmol). Purified by preparatory thin layer chromatography (10% EtOAc/hexanes) to yield 283 (17 mg, 15% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 7.92 (dd, J = 7.9, 1.8 Hz, 1H), 7.51 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 7.04 – 7.00 (m, 1H), 6.99 – 6.94 (m, 1H), 6.02 (p, J = 2.2 Hz, 1H), 5.42 (t, J = 6.3 Hz, 1H), 4.52 – 4.37 (m, 2H), 3.74 (s, 3H), 2.82 – 2.67 (m, 1H), 2.67 – 2.53 (m, 1H), 0.89 (s, 9H), 0.06 (d, J = 4.0 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ = 186.7, 170.3, 159.9, 142.0, 136.8, 127.8, 126.5, 121.7, 121.4, 118.8, 84.2, 67.0, 60.9, 53.2, 36.1, 26.0, 18.5, 5.3; IR (Neat Film, NaCl) 2953, 2854, 1742, 1681, 1606, 1462, 1249, 837 cm–1; HRMS (ESI+): m/z calc’d for C21H29O5Si [M+H]+: 389.1779, found 389.1789. Chapter 5 – A Modular Cyclopentene Annulation 8 O MeO2C ZnBr MeO2C DME, 0 ºC then, 85 ºC then, I2, 0 ºC O 266 methyl 396 O I H O 271 2-iodo-3,3-dimethyl-9-oxo-3,3a-dihydrocyclopenta[b]chromene-9a(9H)- carboxylate 271. Activated Zn (164 mg, 2.5 mmol, 2.5 equiv) and DME (5 mL) were added to a 40 mL vial in a glovebox. The vial was fitted with a septum cap and cooled to 0 ºC under N2. 3-bromo3-methylbut-1-yne (368 mg, 2.5 mmol, 2.5 equiv) was added in one portion and the suspension was left to stir at the same temperature. After 1 h, a solution of enone 266 (204 mg, 1.0 mmol, 1.0 equiv) in DME (5 mL) was added dropwise over 10 min. The suspension was stirred at 0 °C for 1 h, and then at 18 ºC for 2 h before being heated to 85 ºC for 3 h without stirring. After cooling to 0 ºC, a solution of I2 (761 mg, 3.0 mmol, 3.0 equiv) in Et2O (3 mL) was added slowly and the brown solution allowed to stir for a further 10 min. The reaction was quenched with sat. aq. Na2S2O3 and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 271 (285 mg, 72% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 7.89 – 7.82 (m, 1H), 7.52 (ddd, J = 8.4, 7.2, 1.8 Hz, 1H), 7.06 – 6.95 (m, 2H), 6.50 (s, 1H), 5.03 (s, 1H), 3.74 (s, 3H), 1.23 (s, 3H), 0.81 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 186.2, 169.4, 160.8, 137.3, 133.6, 127.4, 121.5, 119.1, 117.9, 113.7, 85.4, 65.7, 54.7, 53.6, 27.8, 23.0; IR (Neat Film, NaCl) 2962, 1736, 1679, 1607, 1460, 1301, 1249, 764 cm–1; HRMS (FD+): m/z calc’d for C16H15IO4 [M]+: 398.0010, found 397.9990. Chapter 5 – A Modular Cyclopentene Annulation 8 O MeO2C ZnBr MeO2C DME, 0 ºC then, 85 ºC then, NBS, 0 ºC O 266 methyl 397 O Br H O 288 2-bromo-3,3-dimethyl-9-oxo-3,3a-dihydrocyclopenta[b]chromene-9a(9H)- carboxylate 288. Activated Zn (50 mg, 0.75 mmol, 2.5 equiv) and DME (1.5 mL) were added to a test tube in a glovebox. The test tube was fitted with a septum and cooled to 0 ºC under N2. 3-bromo3-methylbut-1-yne (110 mg, 0.75 mmol, 2.5 equiv) was added in one portion and the suspension was left to stir at –15 °C for 18 h.* The solution was warmed to 0 °C and a solution of enone 266 (61 mg, 0.3 mmol, 1.0 equiv) in DME (1.5 mL) was added dropwise over 10 min. The suspension was stirred at 0 °C for 1 h, and then at 18 ºC for 2 h before being heated to 85 ºC for 3 h without stirring. After cooling to 0 ºC, NBS (160 mg, 0.9 mmol, 3.0 equiv) was added as a solid in one portion and the reaction was allowed to stir for a further 10 min at the same temperature. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 288 (48 mg, 46% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ = 7.85 (dd, J = 8.2, 1.8 Hz, 1H), 7.53 (ddd, J = 8.4, 7.2, 1.8 Hz, 1H), 7.04 – 6.96 (m, 2H), 6.24 (s, 1H), 5.03 (s, 1H), 3.74 (s, 3H), 1.29 (s, 3H), 0.90 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 186.6, 169.7, 160.8, 137.3, 136.2, 127.4, 125.9, 121.5, 119.2, 117.9, 87.0, 63.7, 53.6, 53.1, 26.2, 22.3; IR (Neat Film, NaCl) 2968, 1741, 1681, 1607, 1460, 1302, 1252, 1213, 761 Chapter 5 – A Modular Cyclopentene Annulation 398 cm–1; HRMS (ESI+): m/z calc’d for C16H16BrO4 [M+H]+: 351.0226, found 351.0219. *Metalation of the propargyl bromide is generally complete after 1 h. However, solutions of the propargyl zinc bromide are stable at –15 °C for at least 24 h allowing operators to pause the reaction if required. O 8 MeO2C O MeO2C ZnBr DME, 0 ºC then, 85 ºC then, Me3SnCl, 0 ºC Me3Sn 266 methyl O H O 289 3,3-dimethyl-9-oxo-2-(trimethylstannyl)-3,3a- dihydrocyclopenta[b]chromene-9a(9H)-carboxylate 289. Activated Zn (50 mg, 0.75 mmol, 2.5 equiv) and DME (1.5 mL) were added to a test tube in a glovebox. The test tube was fitted with a septum and cooled to 0 ºC under N2. 3-bromo3-methylbut-1-yne (110 mg, 0.75 mmol, 2.5 equiv) was added in one portion and the suspension left to stir at the same temperature. After 1 h, a solution of enone 266 (61 mg, 0.3 mmol, 1.0 equiv) in DME (1.5 mL) was added dropwise over 10 min. The suspension was stirred at 0 °C for 1 h, and then at 18 ºC for 2 h before being heated to 85 ºC for 3 h without stirring. After cooling to 18 ºC, Me3SnCl (179 mg, 0.9 mmol, 3.0 equiv) was added as a solution in THF (0.3 mL) and the reaction was allowed to stir for a further 18 h. The reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 289 (71 mg, 55% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ = 7.86 (dd, J = 7.9, 1.8 Hz, 1H), 7.50 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), Chapter 5 – A Modular Cyclopentene Annulation 399 7.03 – 6.93 (m, 2H), 6.11 (s, 1H), 4.95 (s, 1H), 3.72 (s, 3H), 1.29 (s, 3H), 0.81 (s, 3H), 0.21 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ = 187.7, 170.7, 161.2, 158.2, 136.8, 134.5, 127.4, 120.9, 119.6, 117.9, 89.1, 66.0, 56.0, 53.4, 28.4, 24.4, -8.6; IR (Neat Film, NaCl) 2958, 1739, 1678, 1605, 1461, 1245, 766 cm–1; HRMS (ESI+): m/z calc’d for C19H25O4Sn [M+H]+: 437.0769, found 437.0778. 8 O ZnBr MeO2C DME, 0 ºC then, 85 ºC then, CuCN•2LiCl, PhAcCl, 0 ºC O 266 O MeO2C H O O 290 methyl 3,3-dimethyl-9-oxo-2-(2-phenylacetyl)-3,3a-dihydrocyclopenta[b]chromene9a(9H)-carboxylate 290. Activated Zn (50 mg, 0.75 mmol, 2.5 equiv) and DME (1.5 mL) were added to a 2 dram vial in a glovebox. The vial was fitted with a septum cap and cooled to 0 ºC under N2. 3bromo-3-methylbut-1-yne (110 mg, 0.75 mmol, 2.5 equiv) was added in one portion and the suspension left to stir at the same temperature. After 1 h, a solution of enone 266 (61 mg, 0.3 mmol, 1.0 equiv) in DME (1.5 mL) was added dropwise over 10 min. The suspension was stirred at 0 °C for 1 h, and then at 18 ºC for 2 h before being heated to 85 ºC for 3 h without stirring. After cooling to 0 ºC, CuCN•2LiCl (1M in THF, 0.3 mL, 0.3 mmol, 1.0 equiv) and phenylacetyl chloride (139 mg, 0.9 mmol, 3.0 equiv) were added sequentially and the reaction was allowed to stir for a further 18 h at 18 °C. The reaction was quenched with sat. aq. NH4Cl and extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→20% Chapter 5 – A Modular Cyclopentene Annulation 400 EtOAc/hexanes) to furnish 290 (63 mg, 54% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ = 7.84 (dd, J = 7.9, 1.8 Hz, 1H), 7.54 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 7.32 (td, J = 7.4, 1.5 Hz, 3H), 7.21 – 7.16 (m, 2H), 7.04 – 6.97 (m, 3H), 4.92 (s, 1H), 4.02 (d, J = 2.0 Hz, 2H), 3.77 (s, 3H), 1.37 (s, 3H), 0.99 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 195.7, 186.5, 169.5, 161.2, 150.0, 137.5, 137.3, 133.9, 129.7, 129.5, 128.8, 128.8, 127.3, 127.1, 121.4, 119.3, 118.1, 88.7, 63.9, 53.7, 51.2, 46.7, 25.7, 22.4; IR (Neat Film, NaCl) 2956, 1738, 1678, 1605, 1460, 1304, 1217, 767 cm–1; HRMS (ESI+): m/z calc’d for C24H23O5 [M+H]+: 391.1540, found 391.1551. 8 O ZnBr MeO2C O MeO2C O 266 methyl DME, 0 ºC then, 85 ºC then, CuCN•2LiCl, allyl Br, 0 ºC H O 291 2-allyl-3,3-dimethyl-9-oxo-3,3a-dihydrocyclopenta[b]chromene-9a(9H)- carboxylate 291. Activated Zn (50 mg, 0.75 mmol, 2.5 equiv) and DME (1.5 mL) were added to a 2 dram vial in a glovebox. The vial was fitted with a septum cap and cooled to 0 ºC under N2. 3bromo-3-methylbut-1-yne (110 mg, 0.75 mmol, 2.5 equiv) was added in one portion and the suspension left to stir at the same temperature. After 1 h, a solution of enone 266 (61 mg, 0.3 mmol, 1.0 equiv) in DME (1.5 mL) was added dropwise over 10 min. The suspension was stirred at 0 °C for 1 h, and then at 18 ºC for 2 h before being heated to 85 ºC for 3 h without stirring. After cooling to 0 ºC, CuCN•2LiCl (1M in THF, 0.3 mL, 0.3 mmol, 1.0 equiv) and allyl bromide (109 mg, 0.9 mmol, 3.0 equiv) were added sequentially and the reaction was allowed to stir for a further 18 h at 18 °C. The reaction was quenched Chapter 5 – A Modular Cyclopentene Annulation 401 with sat. aq. NH4Cl and extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparatory HLPC (60→76% MeCN/H2O, 10 mL/min, 254 nm) to furnish 291 (46 mg, 49% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 7.85 (dd, J = 7.9, 1.8 Hz, 1H), 7.50 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 7.03 – 6.94 (m, 2H), 5.86 (ddt, J = 18.0, 9.4, 6.9 Hz, 1H), 5.73 (t, J = 1.7 Hz, 1H), 5.13 (dq, J = 6.1, 1.6 Hz, 1H), 5.09 (t, J = 1.3 Hz, 1H), 4.95 (s, 1H), 3.71 (s, 3H), 2.84 – 2.67 (m, 2H), 1.24 (s, 3H), 0.84 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 188.6, 171.0, 161.3, 152.0, 136.9, 134.5, 127.3, 121.0, 120.7, 119.7, 117.9, 117.5, 89.1, 63.1, 53.3, 51.3, 31.8, 25.5, 22.7; IR (Neat Film, NaCl) 1960, 1739, 1679, 1605, 1460, 1300, 1213, 765 cm–1; HRMS (ESI+): m/z calc’d for C19H21O4 [M+H]+: 313.1434, found 313.1443. 8 O MeO2C O 266 methyl MeO2C ZnBr DME, 0 ºC then, 85 ºC then, Pd(dba)2, tfp, 4-I-BzOMe, 0 ºC O MeO2C H O 292 2-(4-(methoxycarbonyl)phenyl)-3,3-dimethyl-9-oxo-3,3a- dihydrocyclopenta[b]chromene-9a(9H)-carboxylate 292. Activated Zn (50 mg, 0.75 mmol, 2.5 equiv) and DME (1.5 mL) were added to a 2-dram vial in a glovebox. The vial was fitted with a septum cap and cooled to 0 ºC under N2. 3bromo-3-methylbut-1-yne (110 mg, 0.75 mmol, 2.5 equiv) was added in one portion and the suspension left to stir at the same temperature. After 1 h, a solution of enone 266 (61 mg, 0.3 mmol, 1.0 equiv) in DME (1.5 mL) was added dropwise over 10 min. The suspension was stirred at 0 °C for 1 h, and then at 18 ºC for 2 h before being heated to 85 Chapter 5 – A Modular Cyclopentene Annulation 402 ºC for 3 h without stirring. A separate 1-dram vial in a glovebox was charged with Pd(dba)2 (5.2 mg, 0.009 mmol, 3 mol %), tri(2-furyl)phosphine (tfp, 4.2 mg, 0.018 mmol, 6 mol %), and THF (0.8 mL). This suspension was stirred in the glovebox at 18 °C for 5 min and methyl 4-iodobenzoate (157 mg, 0.6 mmol, 2.0 equiv) was added to the catalyst solution and stirred until complete dissolution (20 min). The catalyst solution was then added to the vinyl zinc solution and the reaction was allowed to stir for 20 h. The reaction was quenched with sat. aq. NH4Cl and extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 10→20% EtOAc/hexanes) to furnish 292 (57 mg, 47% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.02 – 7.97 (m, 2H), 7.88 (dd, J = 7.9, 1.8 Hz, 1H), 7.54 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 7.42 – 7.37 (m, 2H), 7.08 – 6.98 (m, 2H), 6.23 (s, 1H), 5.08 (s, 1H), 3.92 (s, 3H), 3.76 (s, 3H), 1.33 (s, 3H), 1.07 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 188.1, 170.5, 166.9, 161.2, 152.0, 140.1, 137.1, 129.8, 129.7, 127.3, 125.2, 121.3, 119.7, 117.9, 89.2, 63.2, 53.5, 52.3, 51.9, 26.1, 23.5; IR (Neat Film, NaCl) 2954, 1722, 1680, 1606, 1461, 1280, 1240, 1105, 771 cm–1; HRMS (ESI+): m/z calc’d for C24H23O6 [M+H]+: 407.1489, found 407.1492. Chapter 5 – A Modular Cyclopentene Annulation MeO2C O 403 MeO2C H O Pd/C, H2 H EtOAc, 18 ºC H H 89 methyl H H 293 (1aR,2aR,5aR,7aS)-1,1,3,3-tetramethyl-6-oxodecahydro-5aH- cyclopropa[f]azulene-5a-carboxylate 293. A 1-dram vial was charged with cyclopentene 89 (53 mg, 0.19 mmol, 1.0 equiv), Pd/C (10 wt. % loading on C, 5 mg, 10 wt. %), and cycled under N2. EtOAc (1 mL) was added, and the vial was purged with H2 (balloon) and stirred vigorously for 24 h. The suspension was filtered over celite and the filtrate was concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 293 (50 mg, 94% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 3.74 (s, 3H), 3.04 – 2.88 (m, 2H), 2.82 (dd, J = 13.5, 3.8 Hz, 1H), 2.18 (dd, J = 19.8, 8.0 Hz, 1H), 1.79 (dt, J = 14.2, 3.8 Hz, 1H), 1.59 – 1.44 (m, 3H), 1.04 (s, 3H), 1.01 (s, 3H), 0.96 (s, 3H), 0.84 (ddd, J = 12.4, 8.7, 3.9 Hz, 1H), 0.66 – 0.54 (m, 4H), 0.44 (q, J = 8.5 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ = 208.7, 175.0, 66.3, 55.7, 52.5, 42.0, 40.6, 38.7, 30.5, 28.6, 28.2, 27.3, 21.6, 20.8, 20.6, 18.4, 15.2; IR (Neat Film, NaCl) 2948, 1700, 1460, 1212 cm–1; HRMS (ESI+): m/z calc’d for C17H27O3 [M+H]+: 279.1955, found 279.1942; [α]D 22.81 –29.4 (c = 0.9, CHCl3). Chapter 5 – A Modular Cyclopentene Annulation MeO2C O H mCPBA 404 MeO2C O O H CH2Cl2, 0→18 ºC H H H 89 methyl H 294 (1aS,1bS,3aS,4aR,5aR,6aR)-4,4,6,6-tetramethyl-2-oxodecahydro-1bH- cyclopropa[5,6]azuleno[1,2-b]oxirene-1b-carboxylate 294. A 2-dram vial under N2 was charged with cyclopentene 89 (24 mg, 88 µmol, 1.0 equiv), CH2Cl2 (1.75 mL), and cooled to 0 °C. Solid mCPBA (45 mg, 0.27 mmol, 3.0 equiv) was added in one portion and the reaction was allowed to warm to 18 °C and stirred at this temperature for 18 h. The crude reaction was quenched with saturated aq. Na2S2O3 solution and extracted with CH2Cl2. The combined organic extracts were washed with saturated aq. NaHCO3, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified via a silica plug to yield epoxide 294 (24 mg, 92 % yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 3.82 (s, 3H), 3.76 (d, J = 2.6 Hz, 1H), 3.25 (d, J = 2.6 Hz, 1H), 2.94 (dd, J = 20.1, 8.7 Hz, 1H), 2.67 (dd, J = 13.8, 4.8 Hz, 1H), 2.13 (dd, J = 20.1, 8.3 Hz, 1H), 1.79 (dt, J = 14.2, 4.3 Hz, 1H), 1.12 (s, 3H), 1.04 (s, 3H), 0.97 (s, 3H), 0.88 (ddd, J = 12.3, 8.6, 3.8 Hz, 1H), 0.73 (s, 3H), 0.67 (td, J = 14.0, 12.3 Hz, 1H), 0.43 (q, J = 8.5 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ = 209.9, 169.9, 66.6, 65.9, 60.3, 52.9, 48.8, 40.8, 38.7, 28.6, 27.2, 23.9, 21.4, 21.3, 19.6, 18.8, 15.0; IR (Neat Film, NaCl) 2952, 1752, 1698, 1227, 1164 cm–1; HRMS (ESI+): m/z calc’d for C17H25O4 [M+H]+: 293.1747, found 293.1743; [α]D 22.80 –42.7 (c = 0.9, CHCl3). Chapter 5 – A Modular Cyclopentene Annulation MeO2C O H LDA then, prenyl Br 405 MeO2C O H THF, –78 ºC H H 89 H H 295 methyl (1aR,2aR,5aR,7S,7aR)-1,1,3,3-tetramethyl-7-(3-methylbut-2-en-1-yl)-6-oxo1,1a,2,2a,3,6,7,7a-octahydro-5aH-cyclopropa[f]azulene-5a-carboxylate 295. A small test tube fitted with a septum under N2 was charged with i-Pr2NH (29 mg, 0.28 mmol, 3.0 equiv), THF (0.15 mL), and cooled to –78 °C. n-BuLi (2.5 M in hexanes, 95 µL, 0.24 mmol, 2.5 equiv) was added dropwise and the solution was stirred at this temperature for a further 20 min. A solution of cyclopentene 89 (26 mg, 95 µmol, 1.0 equiv) in THF (0.20 mL) was added dropwise and the reaction was stirred at this temperature for 1 h. Prenyl bromide (37 mg, 0.25 mmol, 2.6 equiv) was added in one portion and the reaction was stirred at –78 °C for 30 min, then quenched with saturated aq. NH4Cl, and extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated silica gel flash chromatography (Teledyne ISCO, 0→10% EtOAc/hexanes) to furnish 295 (12 mg, 37% yield) as a colorless oil. The stereochemistry of 295 was assigned based on diagnostic NOESY correlations. 1H NMR (400 MHz, CDCl3) δ = 5.88 (d, J = 5.7 Hz, 1H), 5.51 (d, J = 5.7 Hz, 1H), 5.09 (ddt, J = 8.4, 7.0, 1.4 Hz, 1H), 3.77 (s, 3H), 3.11 (dd, J = 13.0, 4.8 Hz, 1H), 2.76 – 2.65 (m, 1H), 2.20 (dt, J = 13.9, 9.3 Hz, 1H), 1.99 – 1.85 (m, 2H), 1.72 (d, J = 1.5 Hz, 3H), 1.64 – 1.61 (m, 3H), 1.12 (s, 3H), 1.02 (s, 3H), 0.93 (s, 3H), 0.90 – 0.76 (m, 2H), 0.72 (s, 3H), 0.13 (dd, J = 9.7, 8.3 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ = 212.0, 172.2, 146.1, 132.8, 127.2, 122.2, 73.8, 54.0, 52.4, 49.8, 46.6, 33.0, 28.7, 27.7, 27.2, Chapter 5 – A Modular Cyclopentene Annulation 406 26.1, 25.6, 23.6, 21.6, 21.0, 18.0, 15.4; IR (Neat Film, NaCl) 2953, 2925, 1745, 1697, 1456, 1223, 1146, 800 cm–1; HRMS (ESI+): m/z calc’d for C22H33O3 [M+H]+: 345.2424, found 345.2423; [α]D 22.87 –60.3 (c = 0.8, CHCl3). MeO2C O H LDA then, TMSCl then, NBS MeO2C O Br H THF, –78 ºC H H 89 H H 296 methyl (1aR,2aR,5aR,7S,7aS)-7-bromo-1,1,3,3-tetramethyl-6-oxo-1,1a,2,2a,3,6,7,7aoctahydro-5aH-cyclopropa[f]azulene-5a-carboxylate 296. A small test tube fitted with a septum under N2 was charged with i-Pr2NH (18 mg, 0.18 mmol, 1.4 equiv), THF (0.35 mL), and cooled to –78 °C. n-BuLi (2.5 M in hexanes, 63 µL, 0.16 mmol, 1.2 equiv) was added dropwise and the solution was stirred at this temperature for a further 20 min. A solution of cyclopentene 89 (37 mg, 0.13 µmol, 1.0 equiv) in THF (0.25 mL) was added dropwise and the reaction was stirred at this temperature for 1.5 h. TMSCl (24 mg, 0.23 mmol, 1.7 equiv) was added dropwise and the reaction was warmed to 0 °C in an ice bath and stirred at this temperature for 1 h. NBS (40 mg, 0.23 mmol, 1.7 equiv) was added as a solid in one portion and the reaction was stirred at 0 °C for 30 min.* The reaction was quenched with saturated aq. NaHCO3, extracted with EtOAc (3x), and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0→10% EtOAc/hexanes) to afford bromide 296 (40 mg, 87 % yield) as a colorless oil. The stereochemistry of 296 was assigned based on diagnostic NOESY correlations. 1H NMR (400 MHz, CDCl3) δ = 5.91 (d, J = 5.6 Hz, 1H), 5.57 (d, J = 5.7 Hz, 1H), 4.03 (d, J = 10.1 Chapter 5 – A Modular Cyclopentene Annulation 407 Hz, 1H), 3.82 (s, 3H), 3.18 (dd, J = 13.5, 5.0 Hz, 1H), 1.94 (dt, J = 14.3, 4.5 Hz, 1H), 1.17 – 1.12 (m, 9H), 1.09 (ddd, J = 12.8, 9.0, 4.0 Hz, 1H), 1.00 – 0.78 (m, 2H), 0.72 (s, 3H); 13 C{1H} NMR (101 MHz, CDCl3) δ = 203.8, 171.2, 146.6, 126.6, 73.8, 54.5, 52.8, 48.9, 46.6, 30.2, 29.5, 28.3, 27.4, 23.7, 22.5, 21.4, 14.2; IR (Neat Film, NaCl) 2923, 1739, 1706, 1221, 1150, 786 cm–1; HRMS (ESI+): m/z calc’d for C17H27BrNO3 [M+NH4]+: 372.1169, found 372.1166; [α]D 22.51 –119.7 (c = 0.1, CHCl3). *a-bromoketones can be light sensitive, so this step, including purification, was performed in the dark. MeO2C O DMF, PBr3 MeO2C Br O CHCl3, 18 ºC methyl H H 277 297 4-bromo-5-formyl-1,1-dimethyl-6,6a-dihydropentalene-3a(1H)-carboxylate 297. A 1-dram vial under N2 was charged with DMF (56 mg, 0.76 mmol, 20 equiv), CHCl3 (1.2 mL) and cooled to 0 °C. PBr3 (123 mg, 0.46 mmol, 12 equiv) was added and the reaction was allowed to stir at 18 °C for 30 min. A solution of ketone 277 (8 mg, 38 µmol, 1.0 equiv) in CHCl3 (1.2) mL was added dropwise and the resulting solution was allowed to stir for 4 d. The reaction was then quenched with ice cold saturated aq. NaHCO3 and extracted with CH2Cl2 (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparatory thin-layer chromatography (10% EtOAc/hexanes) to afford starting ketone 277 (3.0 mg, 38% yield) and bromide 297 (3.5 mg, 31% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ = 9.86 (s, 1H), 5.81 (d, J = 5.6 Hz, 1H), 5.79 (d, J = 5.6 Hz, 1H), 3.77 (s, 3H), 2.85 (dd, J = Chapter 5 – A Modular Cyclopentene Annulation 408 8.6, 3.4 Hz, 1H), 2.72 (dd, J = 16.8, 8.6 Hz, 1H), 2.64 (dd, J = 16.8, 3.4 Hz, 1H), 1.12 (s, 3H), 0.97 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 189.5, 172.8, 146.7, 140.9, 139.3, 124.7, 78.7, 54.1, 53.0, 48.5, 30.6, 30.6, 23.9; IR (Neat Film, NaCl) 2955, 1735, 1677, 1239, 795 cm–1; HRMS (ESI+): m/z calc’d for C13H16BrO3 [M+H]+: 299.0277, found 299.0273. MeO2C O L-selectride then, LiAlH4 HO OH THF, 0 ºC H H 277 298 6a-(hydroxymethyl)-4,4-dimethyl-1,2,3,3a,4,6a-hexahydropentalen-1-ol 298. A 1dram vial under N2 was charged with ketone 277 (8.4 mg, 40 µmol, 1.0 equiv), THF (0.2 mL), and cooled to 0 °C. L-Selectride (1 M in THF, 60 µL, 60 µmol, 1.5 equiv) was added dropwise and the reaction was allowed to stir at 0 °C for 45 min. Solid LiAlH4 (3.0 mg, 80 mmol, 2.0 equiv) was added in one portion and the reaction was stirred for another 2 h. The reaction was quenched by adding H2O (10 µL), aq. NaOH (2 M, 30 µL), and H2O (10 µL), sequentially and then filtered over celite. The filtrate was extracted with EtOAc (3x) and the combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by preparatory thin-layer chromatography (33% EtOAc/hexanes) to afford diol 298 (3.3 mg, 45% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ = 5.73 (d, J = 5.6 Hz, 1H), 5.51 (d, J = 5.7 Hz, 1H), 4.00 (t, J = 6.5 Hz, 1H), 3.71 (d, J = 10.1 Hz, 1H), 3.62 (d, J = 10.2 Hz, 1H), 1.94 – 1.88 (m, 1H), 1.83 – 1.69 (m, 2H), 1.68 – 1.58 (m, 2H), 1.54 – 1.46 (m, 2H), 1.08 (s, 3H), 1.04 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 147.1, 125.9, 78.3, 70.1, 67.5, 53.2, 47.7, 34.4, 32.6, 24.3, Chapter 5 – A Modular Cyclopentene Annulation 409 23.8; IR (Neat Film, NaCl) 3233, 2923, 1359, 1008 cm–1; HRMS (FI+): m/z calc’d for C11H18O2 [M+]+: 182.1301, found 182.1307. Chapter 5 – A Modular Cyclopentene Annulation 5.7 (1) 410 REFERENCES AND NOTES Woodward, R. B.; Sondheimer, F.; Taub, D.; Heusler, K.; McLamore, W. M. The Total Synthesis of Steroids1. J. Am. Chem. Soc. 1952, 74, 4223–4251. (2) Das, S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R. 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E.; Majid, T. N.; Knochel. P.; Venegas, P.; Cahiez, G. Preparation of polyfunctional aryl and alkenyl zinc halides from functionalized unsaturated organolithiums and their reactivity in cross-coupling and conjugated addition reactions. Tetrahedron, 1996, 52, 7201–7220. (15) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (16) Yamamura, S.; Toda, M.; Hirata, Y. Modified Clemmensen Reduction: Cholestane. Org. Synth. 1973, 53, 86. (17) Trost, B. M.; Hu, Y.; Horne, D. B. Total Synthesis of (+)-Frondosin A. Application of the Ru-Catalyzed [5+2] Cycloaddition. J. Am. Chem. Soc. 2007, 129, 11781– 11790. Chapter 5 – A Modular Cyclopentene Annulation (18) 412 Cera, G.; Crispino, P.; Monari, M.; Bandini, M. Stereoselective Synthesis of Tetracyclic Indolines viaGold-Catalyzed Cascade Cyclization Reactions. Chem. Commun. 2011, 47, 7803-7805. (19) Ikeda, S.; Shibuya, M.; Kanoh, N.; Iwabuchi, Y. Synthetic Studies on Daphnicyclidin A: Enantiocontrolled Construction of the BCD Ring System. Org. Lett. 2009, 11, 1833–1836. (20) Jackson III, R. K.; Wood, J. L. Total Synthesis of ent-Plagiochianin B. Org. Lett. 2021, 23, 1243–1246. (21) Li, Y.-J.; Wu, Z.-L.; Gu, Q.-S.; Fan, T.; Duan, M.-H.; Wu, L.; Wang, Y.-T.; Wu, J.-P.; Fu, F.-L.; Sang, F.; Peng, A.-T.; Jiang, Y.; Liu, X.-Y.; Lin, J.-S. Catalytic Intermolecular Asymmetric [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]Butanes: Practical Synthesis of Enantioenriched Highly Substituted Bicyclo[2.1.1]Hexanes. J. Am. Chem. Soc. 2024, 146, 34427–34441. (22) Pramanik, A.; Haldar, D. Packing-Induced Solid-State Fluorescence and Thermochromic Behavior of Peptidic Luminophores. RSC Adv. 2017, 7, 389–395. (23) Ley, S. V.; Murray, P. J.; Palmer, B. D. Total Synthesis of the Sesquiterpene (±)Hirsutene Using an Organoselenium-Mediated Cyclization Reaction. Tetrahedron 1985, 41, 4765–4769. (24) Liotta, D.; Barnum, C.; Puleo, R.; Zima, G.; Bayer, C.; Kezar, H. S., III. A Simple Method for the Efficient Synthesis of Unsaturated Compounds. J. Org. Chem. 1981, 46, 2920–2923. .Beta.-Dicarbonyl Appendix 9 – Spectra Relevant to Chapter 5 413 APPENDIX 9 Spectra Relevant to Chapter 5: A Modular Cyclopentene Annulation 12.5 12.0 MeO2C 11.5 269 O OH 11.0 10.5 10.0 9.0 8.5 8.0 7.5 7.0 6.5 6.0 ppm 5.5 5.0 4.5 4.0 3.5 3.0 Figure A9.1 1H NMR (600 MHz, CDCl3) of compound 269. 9.5 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 414 8.5 8.0 7.5 6.5 6.0 5.5 5.0 4.5 ppm 4.0 3.5 3.0 2.5 Figure A9.2 HMBC NMR (600 MHz, CDCl3) of compound 269. 7.0 2.0 1.5 1.0 0.5 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 Appendix 9 – Spectra Relevant to Chapter 5 415 ppm Appendix 9 – Spectra Relevant to Chapter 5 416 Figure A9.3 Infrared spectrum (Thin Film, NaCl) of compound 269. 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm Figure A9.4 13C NMR (100 MHz, CDCl3) of compound 269. 20 10 0 10.5 270 O O 10.0 H MeO2C 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.5 1H NMR (500 MHz, CDCl3) of compound 270. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 417 Appendix 9 – Spectra Relevant to Chapter 5 418 Figure A9.6 Infrared spectrum (Thin Film, NaCl) of compound 270. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.7 13C NMR (100 MHz, CDCl3) of compound 270. 10 0 -10 10.5 O 275 O 10.0 H MeO2C 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.8 1H NMR (400 MHz, CDCl3) of compound 275. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 419 Appendix 9 – Spectra Relevant to Chapter 5 420 Figure A9.9 Infrared spectrum (Thin Film, NaCl) of compound 275. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.10 13C NMR (100 MHz, CDCl3) of compound 275. 10 0 -10 10.5 276 O O 10.0 H NC 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.11 1H NMR (400 MHz, CDCl3) of compound 276. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 421 Appendix 9 – Spectra Relevant to Chapter 5 422 Figure A9.12 Infrared spectrum (Thin Film, NaCl) of compound 276. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.13 13C NMR (100 MHz, CDCl3) of compound 276. 10 0 -10 10.5 O 10.0 89 H MeO2C 9.5 H H 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.14 1H NMR (400 MHz, CDCl3) of compound 89. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 423 6.5 6.0 5.0 4.5 4.0 3.5 3.0 ppm 2.5 2.0 1.5 Figure A9.15 COSY NMR (400 MHz, CDCl3) of compound 89. 5.5 1.0 0.5 0.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 9 – Spectra Relevant to Chapter 5 424 ppm 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 4.5 ppm 4.0 3.5 3.0 2.5 2.0 Figure A9.16 NOESY NMR (400 MHz, CDCl3) of compound 89. 8.0 1.5 1.0 0.5 0.0 9 8 7 6 5 4 3 2 1 0 Appendix 9 – Spectra Relevant to Chapter 5 425 ppm Appendix 9 – Spectra Relevant to Chapter 5 426 100 95 90 85 % Transmittance 80 75 70 65 60 55 50 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 Wavenumber [cm-1] 1800 1600 1400 1200 1000 800 Figure A9.17 Infrared spectrum (Thin Film, NaCl) of compound 89. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.18 13C NMR (100 MHz, CDCl3) of compound 89. 10 0 -10 10.5 10.0 277 H MeO2C 9.5 O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.19 1H NMR (400 MHz, CDCl3) of compound 277. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 427 Appendix 9 – Spectra Relevant to Chapter 5 428 Figure A9.20 Infrared spectrum (Thin Film, NaCl) of compound 277. 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm Figure A9.21 13C NMR (100 MHz, CDCl3) of compound 277. 20 10 0 10.5 O 10.0 278 H MeO2C 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.22 1H NMR (400 MHz, CDCl3) of compound 278. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 429 Appendix 9 – Spectra Relevant to Chapter 5 430 Figure A9.23 Infrared spectrum (Thin Film, NaCl) of compound 278. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.24 13C NMR (100 MHz, CDCl3) of compound 278. 10 0 -10 10.5 10.0 279 9.5 CO2Me CO2Me 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.25 1H NMR (400 MHz, CDCl3) of compound 279. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 431 Appendix 9 – Spectra Relevant to Chapter 5 432 Figure A9.26 Infrared spectrum (Thin Film, NaCl) of compound 279. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.27 13C NMR (100 MHz, CDCl3) of compound 279. 10 0 -10 10.5 10.0 280 9.5 Ph CO2Et CO2Et 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.28 1H NMR (400 MHz, CDCl3) of compound 280. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 433 Appendix 9 – Spectra Relevant to Chapter 5 434 Figure A9.29 Infrared spectrum (Thin Film, NaCl) of compound 280. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.30 13C NMR (100 MHz, CDCl3) of compound 280. 10 0 -10 10.5 281 O O 10.0 H MeO2C 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.31 1H NMR (500 MHz, CDCl3) of compound 281. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 435 Appendix 9 – Spectra Relevant to Chapter 5 436 Figure A9.32 Infrared spectrum (Thin Film, NaCl) of compound 281. 230 220 210 200 190 180 170 160 150 140 130 120 110 ppm 100 90 80 70 60 50 40 30 20 Figure A9.33 13C NMR (100 MHz, CDCl3) of compound 281. 10 0 -10 10.5 H 282 O O 10.0 MeO2C 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.34 1H NMR (400 MHz, CDCl3) of compound 282. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 437 Appendix 9 – Spectra Relevant to Chapter 5 438 Figure A9.35 Infrared spectrum (Thin Film, NaCl) of compound 282. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.36 13C NMR (100 MHz, CDCl3) of compound 282. 10 0 -10 H 283 O O 8.0 MeO2C 8.5 TBSO 7.5 7.0 6.0 5.5 5.0 4.5 4.0 ppm 3.5 3.0 2.5 2.0 Figure A9.37 1H NMR (400 MHz, CDCl3) of compound 283. 6.5 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 439 Appendix 9 – Spectra Relevant to Chapter 5 440 Figure A9.38 Infrared spectrum (Thin Film, NaCl) of compound 283. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.39 13C NMR (100 MHz, CDCl3) of compound 283. 10 0 -10 10.5 I O O 10.0 271 H MeO2C 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 ppm 5.0 4.5 4.0 3.5 3.0 2.5 Figure A9.40 1H NMR (400 MHz, CDCl3) of compound 271. 8.0 2.0 1.5 1.0 0.5 0.0 Appendix 9 – Spectra Relevant to Chapter 5 441 Appendix 9 – Spectra Relevant to Chapter 5 442 98 96 94 92 90 % Transmittance 88 86 84 82 80 78 76 74 72 3800 3600 3400 3200 3000 2800 2600 2400 2200 2000 Wavenumber [cm-1] 1800 1600 1400 1200 1000 800 Figure A9.41 Infrared spectrum (Thin Film, NaCl) of compound 271. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.42 13C NMR (100 MHz, CDCl3) of compound 271. 10 0 -10 10.5 Br O O 9.5 288 10.0 H MeO2C 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.43 1H NMR (400 MHz, CDCl3) of compound 288. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 443 Appendix 9 – Spectra Relevant to Chapter 5 444 Figure A9.44 Infrared spectrum (Thin Film, NaCl) of compound 288. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.45 13C NMR (100 MHz, CDCl3) of compound 288. 10 0 -10 Me3Sn 10.5 289 O O 10.0 H MeO2C 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.46 1H NMR (400 MHz, CDCl3) of compound 289. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 445 Appendix 9 – Spectra Relevant to Chapter 5 446 Figure A9.47 Infrared spectrum (Thin Film, NaCl) of compound 289. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.48 13C NMR (100 MHz, CDCl3) of compound 289. 10 0 -10 10.5 O 10.0 O O 9.5 290 H MeO2C 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.49 1H NMR (400 MHz, CDCl3) of compound 290. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 447 Appendix 9 – Spectra Relevant to Chapter 5 448 Figure A9.50 Infrared spectrum (Thin Film, NaCl) of compound 290. 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 ppm Figure A9.51 13C NMR (100 MHz, CDCl3) of compound 290. 20 10 0 10.5 291 O O 10.0 H MeO2C 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.52 1H NMR (400 MHz, CDCl3) of compound 291. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 449 Appendix 9 – Spectra Relevant to Chapter 5 450 Figure A9.53 Infrared spectrum (Thin Film, NaCl) of compound 291. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.54 13C NMR (100 MHz, CDCl3) of compound 291. 10 0 -10 MeO2C 10.5 10.0 H MeO2C 9.5 292 O O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.55 1H NMR (400 MHz, CDCl3) of compound 292. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 451 Appendix 9 – Spectra Relevant to Chapter 5 452 Figure A9.56 Infrared spectrum (Thin Film, NaCl) of compound 292. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.57 13C NMR (100 MHz, CDCl3) of compound 292. 10 0 -10 10.5 O 10.0 293 H MeO2C H 9.5 H 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.58 1H NMR (400 MHz, CDCl3) of compound 293. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 453 Appendix 9 – Spectra Relevant to Chapter 5 454 Figure A9.59 Infrared spectrum (Thin Film, NaCl) of compound 293. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.60 13C NMR (100 MHz, CDCl3) of compound 293. 10 0 -10 10.5 294 O 10.0 H MeO2C O 9.5 H H 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.61 1H NMR (400 MHz, CDCl3) of compound 294. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 455 4.0 3.0 2.5 ppm 2.0 1.5 1.0 Figure A9.62 COSY NMR (400 MHz, CDCl3) of compound 294. 3.5 0.5 0.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 9 – Spectra Relevant to Chapter 5 456 ppm 4.2 4.0 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 ppm 2.0 1.8 1.6 1.4 1.2 1.0 Figure A9.63 HSQC NMR (400 MHz, CDCl3) of compound 294. 3.8 0.8 0.6 0.4 0.2 0.0 75 70 65 60 55 50 45 40 35 30 25 20 15 10 Appendix 9 – Spectra Relevant to Chapter 5 457 ppm 4.6 4.4 4.2 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 ppm 2.0 1.8 1.6 1.4 1.2 1.0 Figure A9.64 NOESY NMR (400 MHz, CDCl3) of compound 294. 4.0 0.8 0.6 0.4 0.2 0.0 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 9 – Spectra Relevant to Chapter 5 458 ppm Appendix 9 – Spectra Relevant to Chapter 5 459 Figure A9.65 Infrared spectrum (Thin Film, NaCl) of compound 294. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.66 13C NMR (100 MHz, CDCl3) of compound 294. 10 0 -10 H 10.0 295 O 10.5 H MeO2C H 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.67 1H NMR (400 MHz, CDCl3) of compound 295. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 460 8.0 7.5 7.0 6.0 5.5 5.0 4.5 4.0 3.5 ppm 3.0 2.5 2.0 1.5 1.0 Figure A9.68 COSY NMR (400 MHz, CDCl3) of compound 295. 6.5 0.5 0.0 -0.5 -1.0 -1.5 8 7 6 5 4 3 2 1 0 -1 Appendix 9 – Spectra Relevant to Chapter 5 461 ppm 6.0 5.5 4.5 4.0 3.5 3.0 ppm 2.5 2.0 1.5 1.0 Figure A9.69 HSQC NMR (400 MHz, CDCl3) of compound 295. 5.0 0.5 0.0 -0.5 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 Appendix 9 – Spectra Relevant to Chapter 5 462 ppm 6.0 5.5 4.5 4.0 3.5 3.0 ppm 2.5 2.0 1.5 Figure A9.70 NOESY NMR (400 MHz, CDCl3) of compound 295. 5.0 1.0 0.5 0.0 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Appendix 9 – Spectra Relevant to Chapter 5 463 ppm Appendix 9 – Spectra Relevant to Chapter 5 464 Figure A9.71 Infrared spectrum (Thin Film, NaCl) of compound 295. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.72 13C NMR (100 MHz, CDCl3) of compound 295. 10 0 -10 10.5 O 10.0 H MeO2C 9.5 296 H H Br 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.73 1H NMR (400 MHz, CDCl3) of compound 296. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 465 6.5 6.0 5.0 4.5 4.0 3.5 ppm 3.0 2.5 2.0 1.5 Figure A9.74 COSY NMR (400 MHz, CDCl3) of compound 296. 5.5 1.0 0.5 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Appendix 9 – Spectra Relevant to Chapter 5 466 ppm 10.5 10.0 9.5 9.0 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 ppm 4.0 3.5 3.0 2.5 2.0 1.5 Figure A9.75 HSQC NMR (400 MHz, CDCl3) of compound 296. 8.5 1.0 0.5 0.0 -0.5 -1.0 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 Appendix 9 – Spectra Relevant to Chapter 5 467 ppm 9.5 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 4.5 ppm 4.0 3.5 3.0 2.5 2.0 Figure A9.76 NOESY NMR (400 MHz, CDCl3) of compound 296. 8.0 1.5 1.0 0.5 0.0 9 8 7 6 5 4 3 2 1 0 Appendix 9 – Spectra Relevant to Chapter 5 468 ppm Appendix 9 – Spectra Relevant to Chapter 5 469 Figure A9.77 Infrared spectrum (Thin Film, NaCl) of compound 296. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.78 13C NMR (100 MHz, CDCl3) of compound 296. 10 0 -10 10.5 Br 10.0 297 H MeO2C 9.5 O 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.79 1H NMR (400 MHz, CDCl3) of compound 297. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 470 Appendix 9 – Spectra Relevant to Chapter 5 471 Figure A9.80 Infrared spectrum (Thin Film, NaCl) of compound 297. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.81 13C NMR (100 MHz, CDCl3) of compound 297. 10 0 -10 10.5 H 298 10.0 HO 9.5 OH 9.0 8.5 7.5 7.0 6.5 6.0 5.5 5.0 ppm 4.5 4.0 3.5 3.0 2.5 Figure A9.82 1H NMR (400 MHz, CDCl3) of compound 298. 8.0 2.0 1.5 1.0 0.5 0.0 -0.5 Appendix 9 – Spectra Relevant to Chapter 5 472 Appendix 9 – Spectra Relevant to Chapter 5 473 Figure A9.83 Infrared spectrum (Thin Film, NaCl) of compound 298. 210 200 190 180 170 160 150 140 130 120 110 100 ppm 90 80 70 60 50 40 30 20 Figure A9.84 13C NMR (100 MHz, CDCl3) of compound 298. 10 0 -10 Appendix 10 – Notebook Cross-Reference for New Compounds 474 APPENDIX 10 Notebook Cross-Reference for New Compounds Appendix 10 – Notebook Cross-Reference for New Compounds Table A10.1. Notebook cross-reference for Chapter 1. 1 AS429 2 AS426 7 AS141 10 AS144 12 AS226/AS264 13 AS266 14 AS308 16 AS418 17 AS419 18 AS420 19 AS422 21 AS423 22 AS425 25 AS437 26 AS136 27 AS140 28 AS265 29 AS416 30 AS421 31 AS424 475 Appendix 10 – Notebook Cross-Reference for New Compounds Table A10.2. Notebook cross-reference for Chapter 2. 12 AS226/AS264 37 AS411/AS412 38 AS363 51 AS261 52 AS308 54 AS318 56 AS319 57 AS319 58 AS342 59 AS358 60 AS360 61 AS362 62 AS117 64 AS243 65 AS262 66 AS263 67 AS334 68 AS355 69 AS361 476 Appendix 10 – Notebook Cross-Reference for New Compounds 477 Table A10.3. Notebook cross-reference for Appendix 5. 38 AS363 147 AS298 39 AS374 150 AS240 78 AS144 153 AS244 80 AS147 154 AS245 81 AS147 159 AS247 82 AS147 160 AS247 83 AS147 161 AS254/AS255 89 AS160 162 AS256 91 AS173 165 AS346 93 AS206 166 AS349 94 AS206 169 AS359 96 AS189 171 AS363 98 AS197 172 AS363 99 AS196 173 AS364 100 AS196 174 AS365 103 AS172 175 AS370 104 AS172 176 AS372 114 AS179 178 AS376/AS377 115 AS180 183 AS384/AS385 118 AS182 186 AS388/AS389 122 AS186 190 AS394 124 AS185 200 AS408 126 AS191 202 AS253 127 AS191 203 AS406/AS409 Appendix 10 – Notebook Cross-Reference for New Compounds Table A10.4. Notebook cross-reference for Chapter 3. 204 AS149 205 ZPS-VI-239 207 AS151 208 AS151 210 ZPS-VI-171 211 ZPS-VI-171 212 AS153 213 AS153 214 AS153 215 AS153 220 ZPS-VI-213 221 ZPS-VI-231 223 AS148 Table A10.5. Notebook cross-reference for Chapter 4. 130 AS193/AS-C-4 131 AS194/AS-C-5 133 AS195/AS-C-7 236 AS195 241 AS-C-1 242 HN-473A 243 AS-C-8 244 HN02-489A 245 AS-C-6 246 AS-C-6 255 HN02-491A 256 HN02-491A 478 Appendix 10 – Notebook Cross-Reference for New Compounds Table A10.6. Notebook cross-reference for Chapter 5. 62 AS117/KP95 89 AS160/KP88 269 ASCA70b 270 KP86 271 ASCA70/KP91 275 KP89 276 ASCA25 277 ASCA26 278 KP93 279 ASCA20 280 ASCA24 281 KP62 282 KP90 283 ASCA35 288 ASCA40 289 ASCA57 290 ASCA60 291 ASCA59 292 ASCA68 293 ASCA49 294 ASCA42 295 ASCA52 296 ASCA54 297 ASCA67 298 ASCA65 479 480 ABOUT THE AUTHOR Adrian Eduard Samkian was born in Frankfurt am Main, Germany on December 13th, 1997 to Mario and Emik Samkian. After he turned five, Adrian, his parents, and his younger brother moved to Los Angeles, California. His interest in chemistry began around this time, and his early grade school years were spent studying chemistry textbooks and collecting laboratory glassware. In high school he developed an interest in organic chemistry, spending many hours synthesizing dye and fragrance chemicals in his parent’s garage. In the last two years of high school, Adrian joined the Oakcrest Institute of Science, where he conducted research under Dr. Marc Baum, developing a method to synthesize cyclic carbamates using nickel catalysis. In the fall of 2016, he started attending UC Berkeley as a chemistry major in the College of Chemistry. While an undergraduate at Cal, he conducted research in the lab of Professor Don Tilley, where he studied expanded helicenes and other polycyclic aromatic hydrocarbons in the context of organic materials. In 2019, Adrian completed his studies at Cal and moved back to Southern California where he studied olefin metathesis catalysts in the lab of Professor Robert Grubbs. Having enjoyed his experience at Caltech immensely, he decided to start his graduate studies in the lab of Professor Brian Stoltz. His research there centered on the synthesis of complex natural products, specifically targeting the homoadamantane polycyclic polyprenylated acylphloroglucinols. In his fourth year of graduate study, he completed an internship at Merck & Co., which solidified his interest in industrial process chemistry. After completing his Ph.D., Adrian will work at Bristol Myers Squibb in New Jersey as an industrial process chemist.