The Total Synthesis of (+)-Ineleganolide, the Lycojapomine Alkaloids, and a New Strategy for Radical Deoxygenation Citation Gross, Benjamin Martin (2026) The Total Synthesis of (+)-Ineleganolide, the Lycojapomine Alkaloids, and a New Strategy for Radical Deoxygenation. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/4sc5-0e50. https://resolver.caltech.edu/CaltechTHESIS:02112026-184323225 Abstract Organic chemistry is an enabling science, that has given scientist the ability to construct and manipulate small molecules. The relationship that bridges the classic study of chemical reactivity and synthesis at the molecular level with the broader field of the life sciences continues to flourish and has expanded its impact tremendously. The study of complex, bioactive small molecules, their synthesis, and the development of new reactions has laid the foundation for many of these advancements to build upon. The contents of this thesis contribute to this goal and hope to be of use for future generations and the development of the field. The first chapter describes the total synthesis of the furanobutenolide-derived norcembranoid diterpenoid ineleganolide, a secondary metabolite produced by sinularia soft corals. Displaying cytotoxic bioactivity, the chemical structure has intrigued chemists for several decades. We describe a successful synthesis of the natural product in 14 steps, enabled by several unique cascade reactions. The second chapter details the total synthesis of Lycojapomine A and B, two members of the lycopodium alkaloids. To achieve a practical and concise synthetic route, we developed a photoreaction for the stepwise dearomatization of a pyrrole heterocycle. Building off the simple and easily accessible starting material, we can synthesize each of the complex target molecule in 13 steps. Inspired by the previously utilized photochemistry, the third chapter details a new catalytic method for the generation of alkyl radicals directly from alcohols. We achieved this transformation by photo irradiation of a titanium porphyrin catalyst and showcase its ability to deoxygenate several different alcohols, by generation of the carbon-centered radical. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Organic chemistry, total synthesis, natural products Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Awards: Bristol Myers Squibb Graduate Student Fellowship Thesis Availability: Public (worldwide access) Research Advisor(s): Stoltz, Brian M. Thesis Committee: Nelson, Hosea M. (chair) Semlow, Daniel R. Fu, Gregory C. Stoltz, Brian M. Defense Date: 26 January 2026 Funders: Funding Agency Grant Number NIH-NIGMS R35GM145239 NSF CHE-2247315 Record Number: CaltechTHESIS:02112026-184323225 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:02112026-184323225 DOI: 10.7907/4sc5-0e50 Related URLs: URL URL Type Description https://doi.org/10.1021/jacs.3c02142 DOI Portions of article adapted for ch.1 https://doi.org/10.1016/j.tetlet.2024.155011 DOI Portions of article adapted for ch.1 https://doi.org/10.1021/jacs.5c05721 DOI Article adapted for ch.2 ORCID: Author ORCID Gross, Benjamin Martin 0000-0002-9124-2317 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 17881 Collection: CaltechTHESIS Deposited By: Benjamin Gross Deposited On: 09 Mar 2026 17:44 Last Modified: 17 Mar 2026 23:48 Thesis Files PDF - Final Version See Usage Policy. 22MB Repository Staff Only: item control page

THE TOTAL SYNTHESIS OF (+)-INELEGANOLIDE, THE LYCOJAPOMINE ALKALOIDS, AND A NEW STRATEGY FOR RADICAL DEOXYGENATION Thesis by Benjamin Martin Gross In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2026 (Defended January 26, 2026) ii © 2026 Benjamin Martin Gross ORCID: 0000-0002-9124-2317 All Rights Reserved iii Dedicated to my family, friends, professors and mentors that supported me throughout the years iv ACKNOWLEDGEMENTS I want to thank Prof. Brian Stoltz for serving as my PhD advisor. My time at Caltech, including my scientific as well as personal progress, would not have been the same without him. Over the course of my graduate studies, I have come to realize and cherish how special it is to have an advisor that wants the best for you. I thank him for wholeheartedly taking me into his research group and encouraging me in the many ways he has. I have come to be in awe of what it means to keep a research group like his running successfully for over 20 years (I can imagine it’s not always easy!). His approach to leadership and his patience has been an inspiration, especially towards the later years of my graduate school. I will always remain grateful for his unwavering support. I would also like to thank Erna, Harry and Teddy, for always welcoming Somya and me with open arms and for all the conversations we got to share. I would like to thank Prof. Hosea Nelson, Prof. Daniel Semlow and Prof. Greg Fu for serving as my thesis committee. I appreciate the time that they have all put in, sitting through my ideas in candidacy and proposal exams and supporting me throughout my time at Caltech. I would also like to thank Prof. Sarah Reisman, who played a crucial role in recruiting me to Caltech in the first place. Even though I was not a member of her research group, the interactions we had over the years meant a lot to me. I want to thank her for always believing in me and taking an interest in the science I conducted. Even though she likes to say: “You don’t owe me anything, Ben!”- I will always be grateful for her support. When I started on the ineleganolide project, people always told me: “You should talk to Scott.”- and I did. Scott always took an interest in my ideas and the project with pure enthusiasm and joy. I want to thank him for his support on all the HPLC runs and v excitement we shared when isolating natural products. I had so much fun working alongside him, joking and talking. Thank you also to his wife Silva for always welcoming Somya and me- I will miss the wonderful Christmas parties. I would like to thank Dr. David Vander Velde, and Dr. Rajan Paranji, for maintaining and running the NMR facility. It has been great to get to know both and work as a GLA alongside them, learning about the intricacies of NMR instruments. I would also like thank Dr. Michael Takase for running the X-ray facility and his persistence when collecting data from my often ‘very small’ crystals. I would like to thank all the members of the Stoltz and Reisman group that I have interacted with over the years. I want to thank Yujia, Jordan, Emily, Simon, and many more for first welcoming me to Caltech during my summer rotation and helping me get set up in lab. I want to thank Nick Hafeman, for selling me on the ‘cembranoid natural products’ and for his enthusiasm and openness when I first joined the group. I would also especially like to thank my ‘hood mates’ Elliot and Hao. Both of them are exceptional scientists that take a real, dedicated interest in chemistry- which I have always appreciated. I will think fondly of all the times they would both listen to my ideas (sometimes more philosophical), and all the laughs we shared. I would also like to thank Samir, for his friendliness and endless encouragement. I miss just going over a bay and shooting the breeze with him. I want to thank Elijah for joining the lab, and the adjacent bay, taking a chance in listening to my suggestions. It has been great to interact with him- his enthusiasm and interest for synthesis has been motivating and I am sure he will continue to do great in graduate school. I am excited to follow the future of the lab and the next generation of graduate students. vi Adrian, Chloe, Jonathan, Bryce, Sara, Maddie- I am excited to see all of their projects unfold. I would also like to thank Sophia Razavi, for her dedication and enthusiasm while working on the titanium project with me over the summer. It has been a great time working with her- I am sure she will continue to do great things. There are many more people that I can think of: Adrian de Almenara, Christian, Kevin, Jay, Farbod, Kali, Angel, Melinda, Veronica, Trevor Butcher, Yutaro, Liam and the list goes on and on. Thank you all for the support, great or small, and talks, short or long, that have shaped my time throughout graduate school. I would like to thank Prof. Martin Oestreich, for teaching me organic chemistry from the ground-up and shaping me in a way that has made my career in chemistry possible. I think fondly of my time in Berlin and looking back am always grateful for all the chances and support that he has provided me with. I would like to thank Prof. Christopher Vanderwal, for welcoming me into his lab at UCI and for his tremendous support in applying for graduate school and beyond. The time at UCI was transformative for me and has forever shaped my interest in total synthesis and chemistry as a whole. I would also like to thank Darius Vrubliauskas for mentoring me during that time and building me up with his unwavering determination. I consider myself fortunate to have worked alongside him and all the things he has taught me. All throughout, graduate studies and life in general would not have been possible without the help and guidance of my family. I want to thank Margie and John for taking me in during my time in Irvine and for always being there for Somya and me. It is so special to have you in my life. Thank you for all the love you have shown us and for always having vii an open door and ear for us. Thank you also to Leslie, Greg, Laura, Dean, Amy, Jack, Will, Tommy, Lulu, Ben and Macy. I am fortunate to have you all as part of my family here in California. I want to thank Tanya and Drew for welcoming me into their family and for their support. I am thankful for all the time, the laughter, and holidays we got to share together with Winston and Olive and look forward to many more. I want to thank my parents, Kathrin and Dietmar, for their support throughout my PhD and everything that they have done for me. I know it is not always easy being so far apart- their love, encouragement and faith we share shaped me in a way that is beyond words. I want to also thank my brothers, Maximilian and Jonathan, and Marie and Madeleine for their support. I am so thankful to have you all in my life. It has been a blessing, and I look forward to many more memories together. Last, but not least, I would like to express my love for my wife, Somya. I never thought we would be where we are today. I am so thankful to have you alongside me and for all the times you stood by me throughout my PhD. It would be pretty lonely without you, and I feel so blessed to have you in my life. viii ABSTRACT Organic chemistry is an enabling science, that has given scientist the ability to construct and manipulate small molecules. The relationship that bridges the classic study of chemical reactivity and synthesis at the molecular level with the broader field of the life sciences continues to flourish and has expanded its impact tremendously. The study of complex, bioactive small molecules, their synthesis, and the development of new reactions has laid the foundation for many of these advancements to build upon. The contents of this thesis contribute to this goal and hope to be of use for future generations and the development of the field. The first chapter describes the total synthesis of the furanobutenolide-derived norcembranoid diterpenoid ineleganolide, a secondary metabolite produced by sinularia soft corals. Displaying cytotoxic bioactivity, the chemical structure has intrigued chemists for several decades. We describe a successful synthesis of the natural product in 14 steps, enabled by several unique cascade reactions. The second chapter details the total synthesis of Lycojapomine A and B, two members of the lycopodium alkaloids. To achieve a practical and concise synthetic route, we developed a photoreaction for the stepwise dearomatization of a pyrrole heterocycle. Building off the simple and easily accessible starting material, we can synthesize each of the complex target molecule in 13 steps. Inspired by the previously utilized photochemistry, the third chapter details a new catalytic method for the generation of alkyl radicals directly from alcohols. We achieved this transformation by photo irradiation of a titanium porphyrin catalyst and showcase its ability to deoxygenate several different alcohols, by generation of the carbon-centered radical. ix PUBLISHED CONTENT AND CONTRIBUTIONS 1. Gross, B. M.; Han, S.-J.; Stoltz, B. M. A Convergent Total Synthesis of (+)Ineleganolide. J. Am. Chem. Soc. 2023, 145, 7763–7767. DOI: 10.1021/jacs.3c02142 B.M.G. contributed to project conceptualization, experimental investigation, data analysis and preparation of the manuscript. 2. Gross, B. M.; Stoltz, B. M. Convenient access to a strained bicyclic enone: A concise and improved formal synthesis of ineleganolide. Tetrahedron Lett. 2024, 140, 155011. DOI: 10.1016/j.tetlet.2024.155011 B.M.G. contributed to project conceptualization, experimental investigation, data analysis and preparation of the manuscript. 3. Gross, B. M.; Stoltz, B. M. Concise Syntheses of Lycojapomine Alkaloids Enabled by Radical Dearomatization of a Pyrrole. J. Am. Chem. Soc. 2025, 147, 20200–20204. DOI: 10.1021/jacs.5c05721 B.M.G. contributed to project conceptualization, experimental investigation, data analysis and preparation of the manuscript. 4. Gross, B. M.; Razavi, S.; de Almenara, A. J.; Stoltz, B. M. Radical Deoxygenation of Alcohols via Visible Light Irradiation of a Titanium Porphyrin Catalyst. Submitted for publication. B.M.G. contributed to project conceptualization, experimental investigation, data analysis and preparation of the manuscript. x TABLE OF CONTENTS Dedication ................................................................................................................................iii Acknowledgements ................................................................................................................... iv Abstract................................................................................................................................... viii Published Content and Contributions ........................................................................................ ix Table of Contents ....................................................................................................................... x List of Figures .......................................................................................................................... xiii List of Schemes ..................................................................................................................... xviii List of Tables ........................................................................................................................... xix List of Abbreviations................................................................................................................ xxi CHAPTER 1 ........................................................................................................... 1 The Total Synthesis of Ineleganolide 1.1 Introduction .....................................................................................................1 1.2 Previous Research Considerations ....................................................................2 1.3 Retrosynthetic Analysis ....................................................................................5 1.4 Synthesis of Fragments .....................................................................................6 1.5 Fragment Coupling and Completion of the Synthesis ......................................10 1.6 Conclusion .....................................................................................................14 1.7 Experimental Section ......................................................................................15 1.8 1.7.1 Materials and Methods ................................................................................15 1.7.2 Synthesis of Starting Materials .....................................................................16 1.7.3 Experimental Procedures .............................................................................17 References and Notes .....................................................................................40 APPENDIX 1 ........................................................................................................ 46 Spectra Relevant to Chapter 1 APPENDIX 2 ........................................................................................................ 83 X-Ray Crystallography Reports Relevant to Chapter 1 A2.1 General Experimental Information ..................................................................84 A2.2 X-Ray Crystal Structure Analysis of 31 ............................................................84 A2.3 X-Ray Crystal Structure Analysis of 33 ..........................................................105 xi X-Ray Crystal Structure Analysis of 1 ............................................................117 A2.4 CHAPTER 2 ....................................................................................................... 128 Total Synthesis of Lycojapomine A & B 2.1 Introduction .................................................................................................128 2.2 Retrosynthetic Strategy: Pyrrole Dearomatization .........................................129 2.3 Photocatalytic Radical Addition ...................................................................130 2.4 Annulation Cascade to form the Core Structure ............................................133 2.5 Divergent Aldol Reaction and Completion of the Synthesis ..........................136 2.6 Conclusion ...................................................................................................137 2.7 Experimental Section ....................................................................................138 2.7.1 Materials and Methods ..............................................................................138 2.7.2 Experimental Procedures ...........................................................................139 2.8 References and Notes ...................................................................................154 APPENDIX 3 ...................................................................................................... 159 Spectra Relevant to Chapter 2 CHAPTER 3 ....................................................................................................... 182 Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 3.1 Introduction .................................................................................................182 3.2 Reaction Optimization .................................................................................185 3.3 Evaluation of Substrate Generality ................................................................187 3.4 Mechanistic Investigations ...........................................................................190 3.5 Use in Giese Addition and Cross-coupling ...................................................193 3.6 Conclusion ...................................................................................................193 3.7 Experimental Section ....................................................................................194 3.7.1 Materials and Methods ..............................................................................194 3.7.2 Experimental Procedures ...........................................................................196 3.7.2.1 Syntheis of Ti(TPP)Cl2 ............................................................................196 3.7.2.2 General Reaction Procedure A ..............................................................197 3.7.2.3 Substrates for Deoxygenation ................................................................198 3.7.2.4 Synthetic Derivatives ............................................................................214 3.7.2.5 Mechanistic Experiments ......................................................................218 3.7.2.6 Giese Addition and Cross-coupling .......................................................220 xii 3.8 References and Notes ...................................................................................223 APPENDIX 4 ...................................................................................................... 234 Spectra Relevant to Chapter 3 ABOUT THE AUTHOR ...................................................................................... 272 xiii LIST OF FIGURES CHAPTER 1 The Total Synthesis of Ineleganolide Figure 1.1.1. Structures of representative furanobutenolide-derived diterpenoids............................ 1 Figure 1.5.3. X-ray structure of 1 ................................................................................................... 14 APPENDIX 1 Spectra Relevant to Chapter 1 Figure A1.1. 1H NMR (600 MHz, CDCl3) of compound 18 ................................................................ 47 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound 18 .................................................... 48 Figure A1.3. 13C NMR (100 MHz, CDCl3) of compound 18 ............................................................... 48 Figure A1.4. 1H NMR (600 MHz, CDCl3) of compound 19 ................................................................ 49 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 19 .................................................... 50 Figure A1.6. 13C NMR (100 MHz, CDCl3) of compound 19 ............................................................... 50 Figure A1.7. 1H NMR (600 MHz, CDCl3) of compound 39 ................................................................ 51 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 39 .................................................... 52 Figure A1.9. 13C NMR (100 MHz, CDCl3) of compound 39 ............................................................... 52 Figure A1.10. 1H NMR (600 MHz, CDCl3) of compound 21 .............................................................. 53 Figure A1.11. Infrared spectrum (Thin Film, NaCl) of compound 21 .................................................. 54 Figure A1.12. 13C NMR (125 MHz, CDCl3) of compound 21 ............................................................. 54 Figure A1.13. 1H NMR (600 MHz, CDCl3) of compound 22 .............................................................. 55 Figure A1.14. Infrared spectrum (Thin Film, NaCl) of compound 22 .................................................. 56 Figure A1.15. 13C NMR (125 MHz, CDCl3) of compound 22 ............................................................. 56 Figure A1.16. 1H NMR (600 MHz, CDCl3) of compound 28 .............................................................. 57 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 28 .................................................. 58 Figure A1.18. 13C NMR (100 MHz, CDCl3) of compound 28 ............................................................. 58 Figure A1.19. 1H NMR (600 MHz, CDCl3) of compound 16 .............................................................. 59 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 16 .................................................. 60 Figure A1.21. 13C NMR (100 MHz, CDCl3) of compound 16 ............................................................. 60 Figure A1.22. 1H NMR (400 MHz, CDCl3) of compound 26 .............................................................. 61 Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 26 .................................................. 62 Figure A1.24. 13C NMR (100 MHz, CDCl3) of compound 26 ............................................................. 62 xiv Figure A1.25. 1H NMR (400 MHz, CDCl3) of compound 27 .............................................................. 63 Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 27 .................................................. 64 Figure A1.27. 13C NMR (100 MHz, CDCl3) of compound 27 ............................................................. 64 Figure A1.28. 1H NMR (400 MHz, CDCl3) of compound 41 .............................................................. 65 Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 41 .................................................. 66 Figure A1.30. 13C NMR (100 MHz, CDCl3) of compound 41 ............................................................. 66 Figure A1.31. 1H NMR (400 MHz, CDCl3) of compound 42 .............................................................. 67 Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 42 .................................................. 68 Figure A1.33. 13C NMR (100 MHz, CDCl3) of compound 42 ............................................................. 68 Figure A1.34. 1H NMR (600 MHz, CDCl3) of compound 15 .............................................................. 69 Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 15 .................................................. 70 Figure A1.36. 13C NMR (100 MHz, CDCl3) of compound 15 ............................................................. 70 Figure A1.37. 1H NMR (600 MHz, CDCl3) of compound 31 .............................................................. 71 Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 31 .................................................. 72 Figure A1.39. 13C NMR (100 MHz, CDCl3) of compound 31 ............................................................. 72 Figure A1.40. 1H NMR (600 MHz, CDCl3) of compound 43 .............................................................. 73 Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 43 .................................................. 74 Figure A1.42. 13C NMR (125 MHz, CDCl3) of compound 43 ............................................................. 74 Figure A1.43. 1H NMR (600 MHz, CDCl3) of compound 32 .............................................................. 75 Figure A1.44. Infrared spectrum (Thin Film, NaCl) of compound 32 .................................................. 76 Figure A1.45. 13C NMR (125 MHz, CDCl3) of compound 32 ............................................................. 76 Figure A1.46. 1H NMR (400 MHz, CDCl3) of compound 33 .............................................................. 77 Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 33 .................................................. 78 Figure A1.48. 13C NMR (100 MHz, CDCl3) of compound 33 ............................................................. 78 Figure A1.49. 1H NMR (600 MHz, CDCl3) of compound 34 .............................................................. 79 Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound 34 .................................................. 80 Figure A1.51. 13C NMR (100 MHz, CDCl3) of compound 34 ............................................................. 80 Figure A1.52. 1H NMR (400 MHz, CDCl3) of compound 1 ................................................................ 81 Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 1 .................................................... 82 Figure A1.54. 13C NMR (100 MHz, CDCl3) of compound 1 ............................................................... 82 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1 Figure A2.2.1. X-ray crystal structure of compound 31 ....................................................................... 84 Figure A2.3.1. X-ray crystal structure of compound 33 ..................................................................... 105 xv Figure A2.4.1. X-ray crystal structure of compound 1 ....................................................................... 117 CHAPTER 2 Total Synthesis of Lycojapomine A & B Figure 2.2.1. (A) Structure of Lycojapomine A (44) and B (45) and proposed retrosynthetic elements. (B) Concept of reductive functionalization of a pyrrole. .......................................... 129 Figure 2.3.1. Synthesis of starting material 48 .............................................................................. 131 Figure 2.4.2. Potential pathways and considerations for cascade ring annulation ....................... 134 APPENDIX 3 Spectra Relevant to Chapter 2 Figure A3.1. 1H NMR (400 MHz, CDCl3) of compound 46 .............................................................. 160 Figure A3.2. Infrared spectrum (Thin Film, NaCl) of compound 46 .................................................. 161 Figure A3.3. 13C NMR (101 MHz, CDCl3) of compound 46 ............................................................. 161 Figure A3.4. 1H NMR (400 MHz, CDCl3) of compound 48 .............................................................. 162 Figure A3.5. Infrared spectrum (Thin Film, NaCl) of compound 48 .................................................. 163 Figure A3.6. 13C NMR (101 MHz, CDCl3) of compound 48 ............................................................. 163 Figure A3.7. 1H NMR (600 MHz, CDCl3) of compound 49 (trans).................................................... 164 Figure A3.8. Infrared spectrum (Thin Film, NaCl) of compound 49 (trans) ....................................... 165 Figure A3.9. 13C NMR (101 MHz, CDCl3) of compound 49 (trans) ................................................... 165 Figure A3.10. 1H NMR (400 MHz, CDCl3) of compound 49 (cis) ..................................................... 166 Figure A3.11. Infrared spectrum (Thin Film, NaCl) of compound 49 (cis) ......................................... 167 Figure A3.12. 13C NMR (101 MHz, CDCl3) of compound 49 (cis) .................................................... 167 Figure A3.13. 1H NMR (400 MHz, CDCl3) of compound 52 ............................................................ 168 Figure A3.14. Infrared spectrum (Thin Film, NaCl) of compound 52 ................................................ 169 Figure A3.15. 13C NMR (101 MHz, CDCl3) of compound 52 ........................................................... 169 Figure A3.16. 1H NMR (400 MHz, CDCl3) of compound 53 ............................................................ 170 Figure A3.17. Infrared spectrum (Thin Film, NaCl) of compound 53 ................................................ 171 Figure A3.18. 13C NMR (101 MHz, CDCl3) of compound 53 ........................................................... 171 Figure A3.19. 1H NMR (400 MHz, CDCl3) of compound 59 ............................................................ 172 Figure A3.20. Infrared spectrum (Thin Film, NaCl) of compound 59 ................................................ 173 Figure A3.21. 13C NMR (101 MHz, CDCl3) of compound 59 ........................................................... 173 Figure A3.22. 1H NMR (400 MHz, CDCl3) of compound 60 ............................................................ 174 Figure A3.23. Infrared spectrum (Thin Film, NaCl) of compound 60 ................................................ 175 xvi Figure A3.24. 13C NMR (101 MHz, CDCl3) of compound 60 ........................................................... 175 Figure A3.25. 1H NMR (600 MHz, CD3OD) of compound 61.......................................................... 176 Figure A3.26. Infrared spectrum (Thin Film, NaCl) of compound 61 ................................................ 177 Figure A3.27. 13C NMR (101 MHz, CD3OD) of compound 61 ......................................................... 177 Figure A3.28. 1H NMR (600 MHz, CD3OD) of compound 45.......................................................... 178 Figure A3.29. Infrared spectrum (Thin Film, NaCl) of compound 45 ................................................ 179 Figure A3.30. 13C NMR (101 MHz, CD3OD) of compound 45 ......................................................... 179 Figure A3.31. 1H NMR (600 MHz, CD3OD) of compound 44.......................................................... 180 Figure A3.32. Infrared spectrum (Thin Film, NaCl) of compound 44 ................................................ 181 Figure A3.33. 13C NMR (101 MHz, CD3OD) of compound 44 ......................................................... 181 CHAPTER 3 Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst Figure 3.1.1. Evolution of a titanium porphyrin catalyst for deoxygenation ................................. 183 Figure 3.3.1. Substrate scope for radical deoxygenation .............................................................. 188 Figure 3.3.2. Implementation of deoxygenation method in synthesis .......................................... 190 Figure 3.4.1. Mechanistic control experiments ............................................................................ 191 Figure 3.4.2. Preliminary mechanistic proposal ........................................................................... 192 Figure 3.5.1. Interception of radical for Giese addition and Nickel cross-coupling ..................... 193 Figure 3.7.2.1.1. UV-Vis spectrum of Ti(TPP)Cl2 ................................................................................ 197 Figure 3.7.2.5.1. Mass trace analysis of adduct 69e........................................................................... 219 APPENDIX 4 Spectra Relevant to Chapter 3 Figure A4.1. 1H NMR (600 MHz, C6D6) of Ti(TPP)Cl2 ...................................................................... 235 Figure A4.2. 1H NMR (400 MHz, CDCl3) of compound 69b ............................................................ 236 Figure A4.3. 1H NMR (400 MHz, CDCl3) of compound 69c ............................................................ 237 Figure A4.4. 1H NMR (400 MHz, CDCl3) of compound 71b ............................................................ 238 Figure A4.5. 1H NMR (400 MHz, CDCl3) of compound 72b ............................................................ 239 Figure A4.6. 1H NMR (400 MHz, CDCl3) of compound 73b ............................................................ 240 Figure A4.7. 1H NMR (400 MHz, CDCl3) of compound 74b ............................................................ 241 Figure A4.8. 1H NMR (400 MHz, CDCl3) of compound 76b ............................................................ 242 Figure A4.9. 1H NMR (400 MHz, CDCl3) of compound 77b ............................................................ 243 Figure A4.10. 1H NMR (400 MHz, CDCl3) of compound 78b .......................................................... 244 Figure A4.11. 1H NMR (500 MHz, CDCl3) of compound 79b .......................................................... 245 xvii Figure A4.12. 1H NMR (600 MHz, CDCl3) of compound 80b .......................................................... 246 Figure A4.13. 1H NMR (600 MHz, CDCl3) of compound 81b .......................................................... 247 Figure A4.14. 1H NMR (400 MHz, CDCl3) of compound 82b .......................................................... 248 Figure A4.15. 1H NMR (400 MHz, CDCl3) of compound 83b .......................................................... 249 Figure A4.16. 1H NMR (400 MHz, CDCl3) of compound 84b .......................................................... 250 Figure A4.17. 1H NMR (400 MHz, CDCl3) of compound 88b, 88c, 88d .......................................... 251 Figure A4.18. 1H NMR (600 MHz, CDCl3) of compound 90b, 90c, 90d .......................................... 252 Figure A4.19. 1H NMR (400 MHz, CDCl3) of compound 93b .......................................................... 253 Figure A4.20. Infrared spectrum (Thin Film, NaCl) of compound 93b .............................................. 254 Figure A4.21. 13C NMR (101 MHz, CDCl3) of compound 93b ......................................................... 254 Figure A4.22. 1H NMR (400 MHz, CDCl3) of compound 95b .......................................................... 255 Figure A4.23. 1H NMR (400 MHz, CDCl3) of compound 97b .......................................................... 256 Figure A4.24. 13C NMR (101 MHz, CDCl3) of compound 97b ......................................................... 257 Figure A4.25. 1H NMR (400 MHz, CDCl3) of compound 98a .......................................................... 258 Figure A4.26. Infrared spectrum (Thin Film, NaCl) of compound 98a .............................................. 259 Figure A4.27. 13C NMR (101 MHz, CDCl3) of compound 98a.......................................................... 259 Figure A4.28. 1H NMR (400 MHz, CDCl3) of compound 98b .......................................................... 260 Figure A4.29. Infrared spectrum (Thin Film, NaCl) of compound 98b .............................................. 261 Figure A4.30. 13C NMR (101 MHz, CDCl3) of compound 98b ......................................................... 261 Figure A4.31. 1H NMR (400 MHz, CDCl3) of compound 99 ............................................................ 262 Figure A4.32. 1H NMR (600 MHz, CDCl3) of compound 100a ........................................................ 263 Figure A4.33. 1H NMR (600 MHz, CDCl3) of compound 101 .......................................................... 264 Figure A4.34. 1H NMR (600 MHz, CDCl3) of HE-d2 ......................................................................... 265 Figure A4.35. 1H NMR (400 MHz, CDCl3) of compound 69d .......................................................... 266 Figure A4.36. 1H NMR (400 MHz, CDCl3) of compound 102 .......................................................... 267 Figure A4.37. Infrared spectrum (Thin Film, NaCl) of compound 102 .............................................. 268 Figure A4.38. 13C NMR (101 MHz, CDCl3) of compound 102 ......................................................... 268 Figure A4.39. 1H NMR (400 MHz, CDCl3) of compound 103 .......................................................... 269 Figure A4.40. Infrared spectrum (Thin Film, NaCl) of compound 103 .............................................. 270 Figure A4.41. 13C NMR (101 MHz, CDCl3) of compound 103 ......................................................... 270 Figure A4.42. 1H NMR (600 MHz, CDCl3) of compound 104 .......................................................... 271 xviii LIST OF SCHEMES CHAPTER 1 The Total Synthesis of Ineleganolide Scheme 1.2.1. Biomimetic and bioinspired synthesis of 1 by Pattenden and Wood ...................... 2 Scheme 1.2.2. Previous approach to (-)-1 by Stoltz and co-workers............................................... 4 Scheme 1.2.3. Previous approach to (-)-1 by Vanderwal and co-workers ...................................... 4 Scheme 1.2.4. Successful oxa-Michael and epimerization cascade by Fürstner in 2024................ 5 Scheme 1.3.1. Retrosynthesis of (+)-ineleganolide ......................................................................... 6 Scheme 1.4.1. First-generation synthesis of enone 16. ................................................................... 7 Scheme 1.4.2. Second-generation synthesis of enone 16 ............................................................... 9 Scheme 1.5.1. Completion of the total synthesis of Ineleganolide (1) ........................................... 11 Scheme 1.5.2. Mechanistic proposal for air-oxidation to intermediate 33.................................... 12 Scheme 1.7.2.1. Route to carboxylic acid 5, Ref [17] ..................................................................... 16 Scheme 1.7.2.2. Route to aldehyde 17, Ref [20] and [21] ............................................................... 17 CHAPTER 2 Total Synthesis of Lycojapomine A & B Scheme 2.4.1. Synthetic sequence to access the Lycojapomine core structure .......................... 133 Scheme 2.5.1. Oxidative cleavage and divergent aldol reaction to access 44 and 45 ................ 136 xix LIST OF TABLES APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1 Table A2.2.2. Crystal data and structure refinement for compound 31 ........................................... 84 Table A2.2.3. Atomic coordinates (×104) and equivalent isotropic displacement parameters (Å2×103) for compound 31. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ................................................................................................................... 85 Table A2.2.4. Bond lengths [Å] and angles [°] for compound 31 .................................................... 87 Table A2.2.5. Anisotropic displacement parameters (Å2×103) for compound 31. The anisotropic displacement factor exponent takes the form: –2p2[h2a*2U11 + … + 2hka*b*U12] ..... 96 Table A2.2.6. Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2×103) for compound 31 ........................................................................................................... 98 Table A2.2.7. Torsion angles [°] for compound 31 ......................................................................... 99 Table A2.2.8. Hydrogen bonds for compound 31 [Å and °] ......................................................... 104 Table A2.3.2. Crystal data and structure refinement for compound 33 ......................................... 105 Table A2.3.3. Atomic coordinates (×104) and equivalent isotropic displacement parameters (Å2×103) for compound 33. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ................................................................................................................. 106 Table A2.3.4. Bond lengths [Å] and angles [°] for compound 31 .................................................. 107 Table A2.3.5. Anisotropic displacement parameters (Å2×103) for compound 33. The anisotropic displacement factor exponent takes the form: –2p2[h2a*2U11 + … + 2hka*b*U12] ... 111 Table A2.3.6. Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2×103) for compound 33 ......................................................................................................... 112 Table A2.3.7. Torsion angles [°] for compound 33 ....................................................................... 113 Table A2.3.8. Hydrogen bonds for compound 33 [Å and °] ......................................................... 116 Table A2.4.2. Crystal data and structure refinement for compound 1 ........................................... 117 Table A2.4.3. Atomic coordinates (×104) and equivalent isotropic displacement parameters (Å2×103) for compound 1. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor ................................................................................................................. 118 Table A2.4.4. Bond lengths [Å] and angles [°] for compound 1 .................................................... 119 Table A2.4.5. Anisotropic displacement parameters (Å2×103) for compound 1. The anisotropic displacement factor exponent takes the form: –2p2[h2a*2U11 + … + 2hka*b*U12] ... 123 xx Table A2.4.6. Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2×103) for compound 1 ........................................................................................................... 124 Table A2.4.7. Torsion angles [°] for compound 1 ......................................................................... 125 CHAPTER 2 Total Synthesis of Lycojapomine A & B Table 2.3.2. Optimization of dearomative intramolecular radical addition ............................ 132 CHAPTER 3 Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst Table 3.2.1. Optimization of reaction conditions ................................................................... 186 xxi LIST OF ABBREVIATIONS Å Ångstrom λ wavelength µ micro µwave microwave [a]D specific rotation at wavelength of sodium D line °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 concentration for specific rotation measurements (g/100 mL) calc’d calculated CAN ceric ammonium nitrate cat catalytic xxii cm–1 wavenumber(s) COD 1,5-cyclooctadiene Cp cyclopentadienyl Cy cyclohexyl d doublet D deuterium dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DIBAL diisobutylaluminum hydride DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMP Dess-Martin periodinane DMSO dimethyl sulfoxide dr diastereomeric ratio e.g. for example (Latin exempli gratia) ee enantiomeric excess equiv equivalent(s) ESI electrospray ionization Et ethyl EtOAc ethyl acetate FAB fast atom bombardment FD field desorption g gram(s) GC gas chromatography h hour(s) xxiii HE Hantzsch ester 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 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 xxiv min minute(s) MM mixed method mol mole(s) mp melting point Ms methanesulfonyl (mesyl) MS molecular sieves MTBE methyl tert-butyl ether NBS N-bromosuccinimide n-Bu butyl NCS N-chlorosuccinimide ND not determined NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance NR no reaction detected Nu– nucleophile o ortho p para Pd/C palladium on carbon PG protecting group Ph phenyl pH hydrogen ion concentration in aqueous solution Phth phthaloyl Piv pivaloyl ppm parts per million Pr propyl p-TsOH para-toluenesulfonic acid Py pyridine xxv q quartet R generic for any atom or functional group Ref. reference s singlet t triplet TBAF tetrabutylammonium fluoride 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 TMP 2,2,6,6-tetramethylpiperidine TMS trimethylsilyl TOF time-of-flight TosMIC para-toluenesulfonylmethyl isocyanide tR retention time Ts p-toluenesulfonyl (tosyl) 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 – The Total Synthesis of Ineleganolide 1 CHAPTER 1 The Total Synthesis of Ineleganolide † 1.1 INTRODUCTION The cembranoid and norcembranoid diterpenoids represent a large family of natural products isolated from soft coral species.1 Because of their unique, highly complex structures, the furanobutenolide-derived diterpenoids have received considerable attention from synthetic chemists over the past decades, which has given rise to new reaction developments in synthetic chemistry.2 They have furthermore served as a proving ground in retrosynthetic planning and in delivering useful amounts of material for potential further investigations into their bioactivity.3 A subclass of these molecules contain a macrocyclic structure, as represented by the neurotoxin lophotoxin (3), which functions as an irreversible inhibitor of the nicotinic acetylcholine receptor (Figure 1.1.1).4,5 Figure 1.1.1 Structures of representative furanobutenolide-derived diterpenoids. O O H H O H O H Ineleganolide (1) H O O H H O O Horiolide (2) HO CHO H H H O O O OH O O O OAc Lophotoxin (3) H OH H H H O O O H OH O OAc Bielschowskysin (4) Biosynthetically, these macrocycles are suggested to engage in further modifications to give rise to more dense polycyclic structures. Showcase examples of these architectures † Portions of this chapter have been reproduced and modified with permission from Gross, B. M.; Han, S.-J.; Stoltz, B. M. J. Am. Chem. Soc. 2023, 145, 7763–7767 under CC-BY 4.0; Gross, B. M.; Stoltz, B. M. Tetrahedron Lett. 2024, 140, 155011. © 2023 American Chemical Society, 2024 Elsevier Ltd. Chapter 1 – The Total Synthesis of Ineleganolide 2 are reflected in horiolide (2) or bielschowskysin (4), which shows promising cytotoxicity against non-small cell lung cancer and renal cancer.6 Another flagship member of this class, ineleganolide (1), was isolated from the Formosan soft coral Sinularia inelegans by Duh and co-workers in 1999.7 It has shown preliminary cytotoxicity against P-380 leukeumia cell lines, but further insights into its bioactivity remain undisclosed. 1.2 PREVIOUS RESEARCH CONSIDERATIONS Structurally, ineleganolide contains a highly rigid oxidized framework that bears a key central seven-membered ring, a remote isopropenyl group, and a bridging β-keto tetrahydrofuran moiety. Because of its unique and challenging framework, the synthesis of ineleganolide had remained an unsolved challenge over the past two decades, despite efforts by the groups of Vanderwal,8 Nicolaou,9 Gaich,10 Romo,11 Moeller,12 and our group.13 Only in 2022, shortly before our published research, did Wood and co-workers showcase the first total synthesis of ineleganolide (Scheme 1.2.1).14 Scheme 1.2.1 Biomimetic and bioinspired synthesis of 1 by Pattenden and Wood. Pattenden (2011) O H LiHMDS O OAc O 26% yield THF, −78 to 0°C 5-Episinuleptolide Acetate O O H Wood (2022) O O H O LiHMDS THF, −78°C H O H O O O O O H H O 10% yield H H O O O + O H H H Ineleganolide O Sinulochmodin C 11% yield 35% yield Chapter 1 – The Total Synthesis of Ineleganolide 3 As one of the earliest reports on synthetic success to target ineleganolide, Pattenden and co-workers had shown the conversion of the natural product 5-episinuleptolide acetate to ineleganolide upon treatment with strong base.15 Believed to undergo a double Michael addition cascade, they isolated ineleganolide along with its isomer sinulochmodin C. The Wood group achieved the first total synthesis of ineleganolide in 2022, by elegantly constructing a macrocyclic precursor from commercial starting materials. They were able to form the last bond by inducing a similar transannular Michael addition, which gave rise to sinulochmodin C in 35% yield and ineleganolide in 11% yield, respectively. In our own research group, the effort to achieve the synthesis of ineleganolide had been a long-standing project that led to numerous advances in reaction development (Scheme 1.2.2).16,17 Previous group members established a route to carboxylic acid (R)-5 from (R)norcarvone, and displayed diol 6 over a 15-step sequence from commercial starting materials. Esterification with carbodiimide gave the ester 7 in excellent yield, which can be converted to the diazo species 8. To construct the cycloheptane core of the target molecule, 8 was treated with a rhodium catalyst which induced carbenoid formation and cyclopropanation, giving strained intermediate 9. This intermediate subsequently underwent divinyl cyclopropane rearrangement to give compound 10 upon olefin isomerization. Using oxidation state manipulations, 10 was converted to 11 over a multistep sequence. However, the advanced structure 11 proved challenging to manipulate, namely isomerization of the alkene into conjugation with both ketones failed under numerous conditions. This step was viewed as crucial to complete the synthesis, having proposed oxa-Michael addition of the tertiary alcohol to complete the synthesis of 1. It was later found computationally that this exact approach was flawed.16 Chapter 1 – The Total Synthesis of Ineleganolide 4 Scheme 1.2.2 Previous approach to (-)-1 by Stoltz and co-workers. O HO + O O CH2Cl2 OH (R)-5 O EDC•HCl DMAP (cat.) OH 75% yield 7 O O OH OH Cope [3,3] 10 9 X H 59% yield O OH O O 8 O H OH failed isomerization H N2 CH2Cl2 O O Rh2OAc4 (1 mol %) then isomerization O O CH3CN, 0 °C O O O p-ABSA, Et3N >99% yield 6 H OH O H OH O oxa-Michael O H O H H H O H O H O O 11 H H O O (–)-Ineleganolide 12 Complementary to our group’s research, Vanderwal and co-workers had published their extensive efforts to synthesize 1 (Scheme 1.2.3).8 Having constructed the advanced intermediate 13, they proposed to close the central seven-membered ring by addition of the silyl enol ether into a latent oxocarbenium ion. Scheme 1.2.3 Previous approach to (-)-1 by Vanderwal and co-workers. TfO H H O H C12 O TIPSO 13 H O failed epimerization at C12 TIPSO TfO X C12 H H O 14 O H O H O O H H O H H H O O (–)-Ineleganolide Before attempting to achieve this transformation, they ran into a stereochemical problem with compound 13. Having synthesized the incorrect epimer at the C12 carbon, they were unable to invert the stereocenter to give the desired conformation depicted in structure 14. Chapter 1 – The Total Synthesis of Ineleganolide 5 Due to presumed steric clash of the C4 and C5 carbon, they deemed this epimerization and strategic approach systematically flawed. Following the publication of our total synthesis detailed in this chapter, the group of Fürstner reported successful conversion of the revised structure of scabrolide B to ineleganolide in 2024, by an oxa-Michael and epimerization cascade (Scheme 1.2.4).18 Key to this success was the epimeric carbon at C12 of scabrolide B, which presumably allowed for oxa-Michael addition to occur. Followingly, the product undergoes a final epimerization to the correct stereochemical configuration found in ineleganolide. Scheme 1.2.4 Successful oxa-Michael and epimerization cascade by Fürstner in 2024. OH H O O C12 O H H O O O H H Et3N, 60°C O MeOH/MeCN 20% yield (brsm) Scabrolide B [revised structure] O C12 H O H H Ineleganolide (1) Maimone and co-workers independently followed up with their own unique strategy for the synthesis of 1, published in 2025.19 1.3 RETROSYNTHETIC ANALYSIS In our own research, issues surrounding the central seven-membered ring and constructing the ether bridge at a late stage had halted previous efforts.16,17 This sparked the idea of constructing the central seven-membered ring at a later stage, and instead having the tetrahydrofuran motif introduced early. Therefore, we envisioned disconnecting through the C4−C5 bond as the final step and constructing the seven-membered ring last (Scheme Chapter 1 – The Total Synthesis of Ineleganolide 6 1.3.1). Originally, we imagined this bond formation could potentially be achieved by a cross-enolate coupling process. Scheme 1.3.1 Retrosynthesis of (+)-ineleganolide. O O H H O C5 O H O H O O O C5 C4 C12 O O C4 + C11 C12 O H O (+)-Ineleganolide (1) O vinylogous 𝝱-ketoester at C12 15 HO HO O 16 5 from (R)-linalool from (S)-norcarvone Inspired by our previous research and, specifically, the work of Vanderwal and co-workers, we planned our route back to the precursor 15 to set the stereochemistry at C12 through a Michael addition.8 As a vinylogous β-keto ester, we envisioned that the lowered acidity of the C12 proton would thereby provide an epimerizable handle. Disconnecting 15 through an esterification, we were left with two fragments, carboxylic acid 5 and alcohol 16. 1.4 SYNTHESIS OF FRAGMENTS We were able to derive these from (−)-linalool and (+)-norcarvone, respectively, which resulted in an overall convergent and stereospecific synthesis. To synthesize bicyclic enone 16, we began from (R)-linalool (Scheme 1.4.1). Aldehyde 17 was readily available through previously developed chemistry established by the Maimone group and our group, respectively.20,21 This route proved to be highly scalable to access aldehyde 17 in sufficient quantities (>70 g prepared). We next focused our attention on building the essential β-keto tetrahydrofuran moiety present in bicycle 16. This proved challenging because of the highly strained nature of enone 16. Initially, extensive efforts of an intra-molecular cyclization of the tertiary alcohol onto an α-functionalized ketone showed no success. We Chapter 1 – The Total Synthesis of Ineleganolide 7 envisioned that oxidizing to the ketone later would alleviate the induced strain and allow for the intramolecular cyclization to occur. This idea proved to be successful, as the cyclization onto a β-functionalized secondary alcohol was possible. Scheme 1.4.1 First-generation synthesis of enone 16. O O HO 7 steps H TBSO CH2Br2, n-BuLi THF, –78 to 23 °C TBSO 72% yield (R)-linalool 56% yield over 2 steps OTES OTES 17 OH O PPTS, EtOH OTES O 76% yield 1. TESCl, imid, CH2Cl2 66% yield over 2 steps 1. TBAF, THF, 60 °C 2. TBSCl, imid, DMAP, CH2Cl2 18 HO O I MgI2 THF, 40 °C HO HO 2. NaH, THF, 98% yield OTBS OTBS OTBS OTBS 22 21 20 19 1. (COCl)2, DMSO, CH2Cl2 then Et3N, 72% yield O O 16 steps 2. HF (aq), THF, 81% yield OH 16 We converted aldehyde 17 to the corresponding epoxide 18 using dibromomethane as the one carbon source. Removal of both silyl groups by treatment of 18 with TBAF, followed by selective silylation of the resulting secondary alcohol with TBSCl, revealed the tertiary alcohol 19. Treatment of epoxide 19 with magnesium diiodide revealed the intermediary iodohydrin 20. Protection of the incipient secondary alcohol as the corresponding silyl ether proved necessary since cyclization in the presence of the unprotected secondary alcohol failed, even with excess amounts of base. Upon silylation, however, intramolecular substitution of the alkyl iodide by the tertiary alkoxide occurred at room temperature to afford bicycle 21 in excellent yield (98%). Selective deprotection of the triethyl silyl ether Chapter 1 – The Total Synthesis of Ineleganolide 8 under mild acidic conditions gave alcohol 22, which was oxidized to the enone under Swern conditions in 72% yield. Lastly, deprotection employing aqueous HF yielded 16 in 81% yield. Other deprotection conditions proved unsuccessful because of the presumed high reactivity and instability of enone 16 as an electrophilic Michael acceptor. Although this route allowed us to introduce chirality at the tertiary alcohol early in the sequence, the excessive use of protecting groups and redox manipulations led to a lengthy sequence of 16 steps to get to compound 16. One of the challenges in constructing building block 16 is its highly strained structure. Presumably, the planar conformation of the enone required for π-orbital overlap induces significant strain into the fused [5-5] ring system. The shorter C–O bond lengths of the embedded tetrahydrofuran moiety serve to further intensify this effect. In our hands, enone 16 often behaved as the chemical equivalent of a wound-up spring. As an exceptional Michael-acceptor, we observed 1,4-addition with numerous nucleophiles or rapid decomposition, even under mild reaction conditions. However, when the allylic alcohol was protected as a bulky silyl ether, the compounds stability was significantly improved. In looking for a better route, we considered how we could simultaneously construct the enone and !-keto tetrahydrofuran. We imagined that retrosynthetic disconnection of the Csp2/C-sp2 bond through an intramolecular 1,2-addition could lead to a more direct synthesis of 16. We hypothesized that collapse of the tetrahedral intermediate would provide a sufficient thermodynamic driving force to induce the strain of the enone moiety. Ultimately this proved to be a successful strategy, reducing the length of our route to only seven steps from commercial starting materials, employing only two protecting group (PG) manipulations (Scheme 1.4.2). Chapter 1 – The Total Synthesis of Ineleganolide 9 Scheme 1.4.2 Second-generation synthesis of enone 16. O OH TBSCl (1.5 equiv) imidazole (2.0 equiv) DMAP (0.2 equiv) O KH2PO4/H3PO4 pH ~ 4.1 OH 35% yield I O I2 (1.7 equiv) pyridine:CH2Cl2 (1:1) CH2Cl2 H2O, reflux Furfuryl alcohol O OTBS 90% yield 23 OTBS 80% yield 24 25 O NaH (2.0 equiv) OMe I O t-BuLi (1.5 equiv) O (1.5 equiv) Cl Et2O, –78 ºC OTBS OTBS 72% yield 26 O O HF (aq.) 7 steps THF racemic 81 % yield MeMgBr (2.2 equiv) Et2O, –78 ºC to –30 ºC 16:1 d.r. 21% yield 69% recovered 9 OTBS 27 O I THF 79% yield O HO OMe OH 16 28 Our sequence was initiated in targeting the intermediate tertiary alcohol 26, which was previously known in the literature.22 Starting from furfuryl alcohol, we can readily display cyclopentenone 23 via the known Piancatelli-rearrangement.23 Due to the ease of access, we set out with the racemic mixture of compound 23 to investigate the forward route. The allylic alcohol of 23 can be converted to the silyl ether 24. Subsequent α-iodination of the enone occurred in great yield to give vinyl iodide 25.24 Next, we preformed 1,2-addition using methyl magnesium bromide. Under cryogenic conditions, we could achieve an excellent diastereoselectivity of 16:1, favoring the syn-arrangement of oxygenation in 26. With the tertiary alcohol in place, we sought to alkylate using methyl chloroacetate. Deprotonation with sodium hydride followed by allylation was successful, producing compound 27 in 21% yield, with 69% recovered starting material. In trying to improve this yield, we evaluated numerous solvents and different conditions, such as K2CO3/acetonitrile, potassium hydride/18-crown-6 or methyl bromoacetate as electrophile Chapter 1 – The Total Synthesis of Ineleganolide 10 for example. Unfortunately, most of these conditions led to no product formation and complete decomposition of the starting material. With the vinyl iodide 27 in place, lithiumhalogen exchange occurred rapidly and gave clean conversion to our desired enone 28 in 79% isolated yield. It is noteworthy to point out that we had initially synthesized the analogous vinyl bromide, where lithium-halogen exchange and 1,2-addition occurred to give product 28 successfully, yet in a diminished 18% yield. Deprotecting with our previously developed conditions, we can now access the racemic building block 16 in only seven steps from commercial starting materials. 1.5 FRAGMENT COUPLING AND COMPLETION OF THE SYNTHESIS Carboxylic acid 5 could be accessed through a protocol previously employed by our group, which utilizes (S)-norcarvone as an enantioenriched starting material.17 With acid 5 and alcohol 16 in hand, we turned to develop conditions for esterification. This proved challenging because of (1) the acidic α-proton of the acid 5 and (2) the instability of enone 16 toward a amine bases or nucleophiles (Et3N, DIPEA, DMAP, pyridine, etc.), thereby leading to decomposition within minutes. As such, a broad range of esterification reagents were evaluated (i.e., EDC, DIC, Yamaguchi’s reagent, Otera’s catalyst, etc.) but failed to yield any desired product. We eventually developed specific conditions to overcome these issues by activating the acid as the triphenylphosphonium salt at low temperatures,25 which reacted with alcohol 16 within seconds upon addition of a base, to afford ester 15 in 87% yield. Next, we investigated the intramolecular Michael addition. While we were evaluating conditions, ester 15 appeared unstable to various bases and induced the formation of an array of unidentified side products upon reaction. Chapter 1 – The Total Synthesis of Ineleganolide 11 Scheme 1.5.1 Completion of the total synthesis of Ineleganolide (1). O Ph3P=O, (COCl)2 then 16 then DIPEA CH2Cl2 –30 °C to –78 °C O 3 steps O O O C6 O O (S)-norcarvone DMF, 120 °C then DBU C12 84% yield C11 87% yield HO C4 5 O 15 OH O O OH O O O O C6 O H H O H H H O H O H 2. SmI2, H2O THF, –78 °C 63% yield O H H O 29 OH O DBU, O2 C6H6, 70 °C O H 67% yield H O H 30 O O O O 31 1. TESCl, imid THF, 60 °C 83% yield 15% rsm H C12 O 32 H O H H O 33 Ac2O, Et3N DMAP, CH2Cl2 85% yield O O H H AcO SmI2 O O O O H O H O H (+)-ineleganolide (1) H 45% yield O H SmI2 THF:NaOH (1M) (8:1), –78 to 23 °C OAc O O H H H O 35 O H O H H O 34 To our surprise, treatment of ester 15 with DBU at 23 °C gave trace amounts of an unexpected pentacycle (31), the structure of which was determined by X-ray crystallography and resulted from not only Michael addition but a subsequent aldol cyclization, as well. We were able to optimize this process by preheating a solution of the ester 15 in DMF at high temperatures (i.e., 120 °C) and adding DBU in one portion. Under this protocol the reaction then proceeded within minutes to smoothly give 31 in 84% yield, thereby suppressing previous side products. Mechanistically, we believe that a Michael Chapter 1 – The Total Synthesis of Ineleganolide 12 addition occurs first to form the C12−C11 bond. The second proton at C12 can be abstracted again to give the conjugated enolate 29. The extended enolate can then undergo aldol addition at C4 with the neighboring ketone and isomerize to give rise to intermediate 30. Being sp2-hybridized, the enolate at C12 is preferentially protonated from the convex face, thereby giving 31 as a single diastereomer. Overall, this Michael addition and aldol cascade forges two bonds and four stereocenters as a single diastereomer in high yield, which crucially provides the correct stereochemistry at C12. With this result in hand, we could envision a path toward ring expansion and completion of the natural product. To this end, protection of the tertiary alcohol as the silyl ether facilitated reduction of the tetrasubstituted enone under samarium diiodide conditions and subsequent elimination to enone 32.17 While attempting an allylic oxidation at C5, we discovered that enone 32 undergoes a unique air oxidation under basic conditions to produce the epoxide hemiacetal 33 (Scheme 1.5.2). Scheme 1.5.2 Mechanistic proposal for air-oxidation to intermediate 33. O OH O O O O O O C–H oxidation H H O H H O H O H H O 36 H 37 DBU–H+ nucleophilic epoxidation OH O O O O O O O H O H H O H H 33 O H H O H 38 Chapter 1 – The Total Synthesis of Ineleganolide 13 We were surprised by this nearly unprecedented reaction26 and speculate that triplet oxygen can facilitate a radical H atom abstraction to form the highly stabilized captodative radical 36 on the γ-position of the enone. Upon radical recombination, an initial peroxide can be formed, which can be deprotonated to form compound 37. Under basic conditions, the peroxyanion 37 can then undergo intramolecular nucleophilic epoxidation with the enone to give intermediate 38, which converts to the final product 33. After optimization, 33 could be reliably obtained in 67% yield, because it is highly sensitive to the stirring rate and oxygen atmosphere. Having the correct oxidation pattern in place, we planned to construct the crucial C4−C5 bond through reductive opening of the epoxide and a subsequent semipinacol shift. We deemed the odds in our favor and predicted good antiperiplanar orbital overlap between the shifting carbon−carbon bond and hemiacetal leaving group. Additionally, the ability to form a stabilized oxocarbenium ion could also be beneficial. Initial investigations showed that epoxide opening typically leads to elimination of the resulting tertiary alcohol. Conversion of hemiacetal 33 to the acetate 34 provided the initial lead, and reductive opening of 34 with samarium diiode provided trace amounts of ineleganolide, which indicates that the semipinacol rearrangement proceeded in the same pot as the epoxide opening. We then extensively evaluated additives and temperatures and found that addition of an aqueous 1 M sodium hydroxide solution as relatively high pH proton source significantly improved the yield. Although several mechanistic scenarios are possible, we deemed the existence of intermediate 35 to be crucial, with samarium potentially engaging as a Lewis acid to promote the rearrangement.27 The basicity of the proton source could provide improved conditions to protonate the initially forming samarium enolate without Chapter 1 – The Total Synthesis of Ineleganolide 14 protonating the tertiary alcohol too rapidly and forcing elimination. Quickly warming up from−78 to 23 °C gave (+)-ineleganolide 1 in 45% isolated yield. While the isolation paper initially provides an X-ray structure of ineleganolide, lower resolution prevented determination of absolute stereochemistry.7 This led us to obtain a higher- resolution crystal structure that further confirms the absolute stereochemistry of the naturally occurring enantiomer (+)-ineleganolide, in accordance with observations by Wood14 and Pattenden15 (Figure 1.5.3). Figure 1.5.3 X-ray structure of 1. 1.6 CONCLUSION In conclusion, we have completed the total synthesis of (+)-ineleganolide in an overall longest linear sequence of 23 steps from (−)-linalool and 14 steps with a revised route starting from furfuryl alcohol. We based our convergent strategy on the union of two fragments, thereby providing a concise endgame with only seven total steps from our coupling partners 5 and 16. We were able to access a highly strained enone 16 and develop Chapter 1 – The Total Synthesis of Ineleganolide 15 underutilized esterification conditions for sensitive substrates by employing triphenyl phosphine oxide and oxalyl chloride as activating reagents. Furthermore, we realized an exceptional Michael addition and aldol cascade by constructing a crucial pentacyclic intermediate as a single diastereomer (i.e., 15 → 31). In the later stage, we discovered a unique air oxidation and epoxidation sequence to install the needed oxidation pattern (i.e., 32 → 33). Reductive opening of acetoxy epoxide 34 with samarium diiode induced a semipinacol shift in the same pot to furnish (+)-ineleganolide (1) in good yield. We envision that the developed chemistry can be utilized in solving future problems in the synthesis of related compounds and enable further investigations into the bioactivity of the cembranoid and norcembranoid diterpenoids, specifically (+)-ineleganolide. 1.7 EXPERIMENTAL SECTION 1.7.1 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.28 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, panisaldehyde, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 μm) was used for flash chromatography. 1H NMR spectra were recorded on Varian Inova 500 MHz and 600 MHz and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), C6D6 (δ 7.16 ppm) or CD3OD (δ 3.31 ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (125 MHz) and Chapter 1 – The Total Synthesis of Ineleganolide 16 Bruker 400 MHz spectrometers (100 MHz) and are reported relative to CHCl3 (δ 77.16 ppm), C6D6 (δ 128.06 ppm) or CD3OD (δ 49.01 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 13 C NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR 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 using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+) mode. 1.7.2 SYNTHESIS OF STARTING MATERIALS Scheme 1.7.2.1 Route to carboxylic acid 5, Ref [17]. CeCl3 (2.0 equiv.) O OLi (2.06 equiv.) OEt EtO O OH O PCC (1.5 equiv.) CH2Cl2 THF, –78°C O EtO (S)-norcarvone O K2CO3 O MeOH/H2O HO 5 Chapter 1 – The Total Synthesis of Ineleganolide 17 Scheme 1.7.2.2 Route to aldehyde 17, Ref [20] and [21]. HG-II (0.075 mol%) then NaH (3.0 equiv.) TBSCl (1.5 equiv.) HO RuCl3 x H2O (0.01 equiv.) MgOAc2 x 4H2O (2.0 equiv.) tBuOOH (9.0 equiv.) TBSO TBSO CH2Cl2/H2O THF, 65°C O (R)-linalool Br2 (1.1 equiv.) Et3N (1.5 equiv.) CH2Cl2 CN TBSO CeCl3 (1.1 equiv.) NaBH4 (1.01 equiv.) CN TBSO NaCN (2.2 equiv.) TBSO TBAI (0.17 equiv.) MeOH TESCl (1.2 equiv.) Imidazole (2.0 equiv.) CH2Cl2 H2O/CH2Cl2 OH O Br O O CN DIBAL-H (1.5 equiv.) TBSO H TBSO CH2Cl2, –78°C OTES OTES 17 1.7.3 EXPERIMENTAL PROCEDURES O O H CH2Br2 (1.2 equiv.) n-BuLi (1.1 equiv.) TBSO TBSO THF, –78 °C to 23 °C OTES 17 OTES 18 Epoxide 18: In a flame dried round-bottom flask, Aldehyde 17 (9.4 g, 25.3 mmol, 1.0 equiv.) was dissolved in THF (125 mL, 0.2 M) and CH2Br2 (2.1 mL, 30.1 mmol, 1.2 equiv.) was added in one portion. The solution was cooled to –78 °C in a dry ice/acetone bath and n-BuLi (2.5 M in hexanes, 10.6 mL, 27.6 mmol, 1.1 equiv.) was added dropwise over the course of one hour. The reaction mixture was left to stir in the dry ice/acetone bath and let warm to 23 °C overnight (12 h). After consumption of starting material as determined by TLC, saturated aqueous NH4Cl was added, the layers separated, and the aqueous layer was Chapter 1 – The Total Synthesis of Ineleganolide 18 extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes → 5% Et2O/hexanes) to afford the title compound 18 as a pale-yellow oil (7.0 g, 18.2 mmol, 72% yield). 18 was isolated as an inconsequential mixture of diastereomers (ratio ~2:1). Signals for the major diastereomer are reported; 1H NMR (600 MHz, CDCl3) δ 5.47 (s, 1H), 4.62 – 4.58 (m, 1H), 3.37 (s, 1H), 2.98 – 2.95 (m, 1H), 2.74 (dd, J = 6.0, 2.7 Hz, 1H), 2.44 (dd, J = 12.2, 6.8 Hz, 1H), 1.95 (dd, J = 12.2, 6.5 Hz, 1H), 1.38 (s, 3H), 0.95 (t, J = 7.9 Hz, 9H), 0.86 (s, 9H), 0.60 (q, J = 7.9 Hz, 6H), 0.11 (s, 3H), 0.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 149.8, 127.3, 82.1, 73.3, 53.1, 49.9, 47.0, 28.6, 25.8, 18.0, 6.9, 4.8, -2.0, -2.4; IR (neat film, NaCl) 2955, 2885, 2855, 1471, 1461, 1359, 1251, 1118, 1004, 834, 739, 671, 645 cm–1; HRMS (ESI+): m/z calc’d for C14H25SiO2 [M–OTBS]+: 253.1618, found 253.1610; [a]D23 + 7.7 (c 0.20, CHCl3). O O TBAF (2.0 equiv.) TBSO HO 18 O HO CH2Cl2, 0 °C THF, 60 °C OTES TBSCl (1.2 equiv.) imid (2.0 equiv.) DMAP (0.2 equiv.) OH OTBS 19 Tertiary Alcohol 19: A round-bottom flask was charged with 18 (12.1 g, 31.4 mmol, 1.0 equiv.) and dissolved in THF (314 mL, 0.1 M). TBAF (1M in THF, 62.9 mL, 2.0 equiv.) was added and the solution heated to 60 °C. After 3h, full consumption of starting material was observed by TLC and the solution was left to cool to 23 °C. The reaction mixture was diluted with hexanes (50 mL) and flushed over a plug of silica gel, eluting with a mixture Chapter 1 – The Total Synthesis of Ineleganolide 19 of EtOAc/Hexanes (9:1). The solvent was evaporated under reduced pressure, and the crude diol (3.8 g) isolated as a yellow oil which was directly used in the next step. The intermediate diol (3.8 g, 24.3 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (243 mL, 0.1 M), and imidazole (3.3 g, 48.6 mmol, 2.0 equiv.) added in one portion. The solution was cooled to 0°C, after which TBSCl (4.4 g, 29.2 mmol, 1.2 equiv.) and DMAP (0.59 g, 4.86 mmol, 0.2 equiv.) were subsequently added. The solution was stirred for 1 h, quenched with a saturated aqueous solution of NaHCO3, and the aqueous layer extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (20% EtOAc/hexanes), to yield tertiary alcohol 19 (4.8 g, 17.7 mmol, 56% over two steps) as a yellow oil. 19 was isolated as an inconsequential mixture of diastereomers (ratio ~2:1). Signals for the major diastereomer are reported; 1H NMR (600 MHz, CDCl3) δ 5.68 (s, 1H), 4.63 – 4.58 (m, 1H), 3.47 (s, 1H), 3.02 – 2.98 (m, 1H), 2.87 – 2.82 (m, 1H), 2.41 (dd, J = 13.3, 6.5 Hz, 1H), 2.21 – 2.13 (m, 1H), 1.90 – 1.83 (m, 1H), 1.41 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 148.1, 131.1, 81.0, 73.2, 52.7, 49.4, 47.4, 25.9, 18.2, -4.5, -4.5; IR (neat film, NaCl) 2956, 2855, 1614, 1460, 1422, 1360, 1252, 1166, 1079, 1064, 898, 834, 776, 759, 748, 662 621 cm–1; HRMS (ESI+): m/z calc’d for C14H25SiO2 [M–OH]+: 253.1618, found 253.1611; [a]D25 + 11.5 (c 0.15, CHCl3). Chapter 1 – The Total Synthesis of Ineleganolide O HO MgI2 (1.05 equiv.) HO HO 20 I TESCl (1.2 equiv.) imid (2.0 equiv.) TESO I HO CH2Cl2, 23 °C THF, 40 °C OTBS OTBS OTBS 19 20 39 Alkyliodide 39: A flame dried round-bottom flask was charged with 19 (4.8 g, 17.7 mmol, 1.0 equiv.) and transferred into a glovebox. The starting material was dissolved in THF (89 mL, 0.2 M) and anhydrous MgI2 (5.17 g, 18.6 mmol, 1.05 equiv.) was added in one portion. The flask was sealed with a rubber septum and transferred outside the glovebox. The flask was kept under N2, placed in a heating mantel set to 40 °C and the reaction mixture stirred for 14 h. H2O was added, and the aqueous phase extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried over Na2SO4 and the solvent evaporated under reduced pressure to yield the crude diol 20 (7.05 g) as a yellow oil, which was directly used in the next step. Diol 10 (7.05 g, 17.7 mmol, 1.0 equiv.) was dissolved in CH2Cl2 (177 mL, 0.1 M), imidazole (2.4 g, 35.4 mmol, 2.0 equiv.) added in one portion and the reaction mixture cooled to 0 °C. TESCl (3.5 mL, 21.2 mmol, 1.2 equiv.) was added dropwise and the reaction mixture stirred for 10 minutes. Brine was added, the phases separated, and the aqueous phase extracted with Et2O (3x). The combined organic extracts were dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes → 10% Et2O/hexanes) to yield alkyliodide 39 (5.94 g, 11.6 mmol, 66% over two steps) as a yellow oil. 39 was isolated as an inconsequential mixture of diastereomers. Signals for the major diastereomer are reported; 1H NMR (600 MHz, CDCl3) δ 5.89 (s, 1H), 4.58 – 4.55 (m, 1H), 4.31 – 4.28 (m, Chapter 1 – The Total Synthesis of Ineleganolide 21 1H), 3.59 (dd, J = 10.2, 3.9 Hz, 1H), 3.35 (dd, J = 10.1, 6.4 Hz, 1H), 2.23 (dd, J = 13.2, 6.0 Hz, 1H), 1.88 (dd, J = 13.2, 3.0 Hz, 1H), 1.33 (s, 3H), 0.97 (t, J = 7.9 Hz, 9H), 0.88 (s, 9H), 0.66 – 0.58 (m, 6H), 0.08 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 151.7, 132.3, 80.5, 72.7, 69.1, 52.5, 25.9, 25.3, 18.2, 15.3, 7.0, 5.0, -4.3, -4.6; IR (neat film, NaCl) 2956, 2929, 2879, 1362, 1098, 1004, 834, 736, 652 cm–1; HRMS (ESI+): m/z calc’d for C20H40ISi2O2 [M–OH]+: 495.1606, found 495.1600; [a]D25 + 4.31 (c 0.20, CHCl3). TESO HO I NaH (3.0 equiv.) OTES O THF, 0 °C to 23 °C OTBS OTBS 39 21 Bicycle 21: A flame dried round-bottom flask was charged with alkyl iodide 39 (5.94 g, 11.59 mmol, 1.0 equiv.), dissolved in THF (0.013 M, 891 mL) and cooled to 0°C. NaH (60% in mineral oil, 1.4 g, 34.7 mmol, 3.0 equiv.) was added portion wise, after which the ice bath was removed and the reaction stirred at 23°C for 2.5 hours, until full consumption of starting material as determined by TLC. The reaction was quenched with a saturated aqueous solution of NH4Cl, and the aqueous layer extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes → 10% Et2O/hexanes) to yield the title compound 21 (4.4 g, 11.4 mmol, 98%) as a colorless oil; 21 was isolated as an inconsequential mixture of diastereomers. Signals for the major diastereomer are reported; 1H NMR (600 MHz, CDCl3) δ 5.61 (s, 1H), 5.02 (t, J = 6.3 Hz, 1H), 4.62 (d, J = 3.1 Hz, 1H), 4.11 (dd, J = 9.5, 4.7 Hz, 1H), 4.00 (dd, J = 9.6, Chapter 1 – The Total Synthesis of Ineleganolide 22 1.8 Hz, 1H), 2.44 (dd, J = 11.6, 5.5 Hz, 1H), 1.87 (dd, J = 11.6, 7.4 Hz, 1H), 1.39 (s, 3H), 0.95 (t, J = 7.9 Hz, 9H), 0.89 (s, 9H), 0.60 (q, J = 7.9 Hz, 6H), 0.09 (s, 3H), 0.07 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 151.3, 128.7, 90.0, 79.3, 78.2, 68.1, 54.5, 26.0, 24.9, 18.3, 6.8, 4.8, -4.4, -4.6; IR (neat film, NaCl) 2955, 2878, 2856, 1463, 1456, 1362, 1251, 1102, 1051, 1003, 895, 862, 831, 779, 728 cm–1; HRMS (ESI+): m/z calc’d for C20H41Si2O3 [M+H]+: 385.2589, found 385.2579; [a]D25 + 12.7 (c 0.15, CHCl3). OTES O PPTS (0.1 equiv.) OH O EtOH, 23 °C OTBS OTBS 21 22 Allylic alcohol 22: A round-bottom flask was charged with 21 (2.25g, 5.85 mmol, 1.0 equiv.) and dissolved in EtOH (58 mL, 0.1 M). PPTS (147.0 mg, 0.585 mmol, 0.1 equiv.) was added in one portion and the reaction mixture stirred for 1 h. After nearly full consumption of starting material as determined by TLC, a saturated aqueous solution of NaHCO3 was added. The aqueous layer was extracted with EtOAc (3x), the combined organic extracts dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes → 20% EtOAc/hexanes) to yield the title compound 22 (1.2 g, 4.4 mmol, 76%) as a colorless oil; 22 was isolated as an inconsequential mixture of diastereomers. Signals for the major diastereomer are reported; 1H NMR (600 MHz, CDCl3) δ 5.74 (s, 1H), 5.03 (t, J = 6.5 Hz, 1H), 4.73 (dd, J = 4.8, 1.9 Hz, 1H), 4.15 (dd, J = 10.0, 4.9 Hz, 1H), 4.06 (dd, J = 10.1, 1.8 Hz, 1H), 2.45 (dd, J = 11.6, 5.5 Hz, 1H), 1.93 (s, 1H), 1.90 (dd, J = 11.6, 7.5 Hz, 1H), 1.41 (s, 3H), 0.89 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 150.7, Chapter 1 – The Total Synthesis of Ineleganolide 23 130.2, 89.9, 79.3, 77.2, 68.0, 54.7, 25.9, 25.1, 18.3, -4.4, -4.6; IR (neat film, NaCl) 3402, 2931, 2857, 1471, 1360, 1260, 1213, 1185, 1097, 1047, 977, 828, 775, 674 cm–1; HRMS (ESI+): m/z calc’d for C14H27SiO3 [M+H]+: 271.1724, found 271.1719; [a]D25 + 33.7 (c 0.06, CHCl3). OH O (COCl)2 (1.2 equiv.) DMSO (2.5 equiv.) Et3N (5.0 equiv.) O O CH2Cl2, –78 °C to 23 °C OTBS OTBS 22 28 Enone 28: In a flame dried round-bottom, a solution of DMSO (0.78 mL, 11.0 mmol, 2.5 equiv.) in CH2Cl2 (44.3 mL) was cooled to –78 °C and oxalyl chloride (0.45 mL, 5.31 mmol, 1.2 equiv.) was added dropwise. After stirring at the same temperature for 15 minutes, alcohol 22 (1.2 g, 4.4 mmol, 1.0 equiv.) was added as a solution in CH2Cl2 (44.3 mL). The reaction mixture was stirred for 1 hour at –78 °C, after which Et3N (3.1 mL, 22.1 mmol, 5.0 equiv.) was added and the reaction mixture let warm to 23 °C. The solvent was evaporated under reduced pressure and the crude mixture purified by flash chromatography on silica gel (hexanes → 10% EtOAc/hexanes). The title compound 28 (854 mg, 3.18 mmol, 72%) was obtained as a colorless oil; 1H NMR (600 MHz, CDCl3) δ 6.48 (s, 1H), 5.18 (t, J = 6.6 Hz, 1H), 4.26 (d, J = 17.1 Hz, 1H), 4.21 (d, J = 17.1 Hz, 1H), 2.64 (dd, J = 11.8, 5.6 Hz, 1H), 2.27 (dd, J = 11.9, 8.0 Hz, 1H), 1.39 (s, 3H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.1, 146.4, 138.8, 90.5, 80.0, 74.0, 55.6, 25.8, 22.9, 18.2, -4.5, -4.7; IR (neat film, NaCl) 2955, 2930, 2857, 1732, 1645, 1362, 1258, 1103, 1035, 865, 834, 779, 651 cm–1; HRMS (ESI+): m/z calc’d for C14H25SiO3 [M+H]+: 269.1567, found 269.1561; [a]D23 – 48.0 (c 0.50, CHCl3). Chapter 1 – The Total Synthesis of Ineleganolide 24 O O HF (aq) O O THF, 23 °C OTBS OH 28 16 Alcohol 16: A round-bottom flask was charged with 28 (420 mg, 1.56 mmol, 1.0 equiv.) and dissolved in THF (15 mL, 0.1 M), after which an aqueous solution of HF (45%, 0.6 mL) was added dropwise. After stirring at 23 °C for 5 hours, the reaction was quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x), the combined organic extracts dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (30% EtOAc/hexanes) to yield the title compound 16 (196 mg, 1.27 mmol, 81%) as a white solid; 1H NMR (600 MHz, CDCl3) δ 6.55 (s, 1H), 5.22 (t, J = 6.9 Hz, 1H), 4.28 (d, J = 17.2 Hz, 1H), 4.23 (d, J = 17.2 Hz, 1H), 2.78 (dd, J = 12.0, 5.7 Hz, 1H), 2.20 (dd, J = 12.1, 8.0 Hz, 1H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 200.0, 147.3, 137.6, 90.7, 79.9, 74.0, 55.0, 22.7; IR (neat film, NaCl) 3435, 2921, 2852, 1749, 1220 cm–1; HRMS (ESI+): m/z calc’d for C8H11O3 [M+H]+: 155.0703, found 155.0700; [a]D23 – 15.0 (c 0.30, CHCl3). KH2PO4/H3PO4 pH ~ 4.1 O OH O H2O, reflux OH Furfuryl alcohol 23 Cyclopentenone 23: Prepared according to a known literature procedure.2 Deionized water (509 mL, 0.4M), furfuryl alcohol (20 g, 203.8 mmol, 1.0 equiv.) and 6.25 g of Chapter 1 – The Total Synthesis of Ineleganolide 25 KH2PO4 were placed in a round bottom flask equipped with a reflux condenser. The pH was measured with a handheld pH-Meter and H3PO4 was added until the pH was measured to be ~4.1. The solution was placed under inert atmosphere and was degassed by bubbling argon through the solution for 1 hour. Subsequently the reaction mixture was heated to reflux for 72 hours, and complete consumption of starting material was observed by GCMS. The reaction mixture was cooled to room temperature and washed once with EtOAc. The aqueous layer was evaporated under reduced pressure, diluted with EtOAc and the salts filtered off. The organic layer was evaporated under reduced pressure to yield product 23 (6.9 g, 70.3 mmol, 35% yield) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 7.57 (dd, J = 5.7, 2.3 Hz, 1H), 6.22 (dd, J = 5.7, 1.3 Hz, 1H), 5.05 (dtd, J = 6.0, 2.3, 1.3 Hz, 1H), 3.44 (br s, 1H), 2.78 (dd, J = 18.5, 6.1 Hz, 1H), 2.28 (dd, J = 18.5, 2.2 Hz, 1H). The spectroscopic data matches those previously reported.23 TBSCl (1.5 equiv) imidazole (2.0 equiv) DMAP (0.2 equiv) O O CH2Cl2 OH 23 OTBS 24 Silyl Ether 24: Prepared according to a known literature procedure.3 Allylic alcohol 23 (7.0 g, 71 mmol, 1.0 equiv.) was placed in a round bottom flask and dissolved in dichloromethane (355 mL, 0.2 M). Imidazole (9.6 g, 142 mmol, 2.0 equiv.), TBSCl (16 g, 107 mmol, 1.5 equiv.) and DMAP (1.7 g, 14.2 mmol, 0.2 equiv.) were added and the reaction mixture stirred at 20 °C for 6 hours. After complete consumption of starting material, water was added to the reaction mixture and the aqueous phase extracted with Chapter 1 – The Total Synthesis of Ineleganolide 26 Et2O (3x). The combined organic layers were washed with brine, dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (0 → 10% EtOAc/Hexanes) to yield product 24 (13.5 g, 64 mmol, 90% yield) as a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 7.45 (ddd, J = 5.7, 2.3, 0.7 Hz, 1H), 6.18 (ddd, J = 5.6, 1.3, 0.7 Hz, 1H), 4.98 (dd, J = 3.7, 1.6 Hz, 1H), 2.70 (ddd, J = 18.2, 5.9, 0.7 Hz, 1H), 2.24 (ddd, J = 18.2, 2.2, 0.7 Hz, 1H), 0.90 (s, 9H), 0.13 (s, 3H), 0.12 (s, 3H). The spectroscopic data matches those previously reported.29 O I O I2 (1.7 equiv) pyridine:CH2Cl2 (1:1) OTBS OTBS 24 25 Vinyl iodide 25: Prepared according to a known literature procedure.4 Starting material 24 (1.0 g, 4.7 mmol, 1.0 equiv.) was dissolved in a mixture of dichloromethane/pyridine (8 mL/8 mL) and cooled to 0 °C in an ice bath. A solution of iodine (2.0 g, 8.0 mmol, 1.7 equiv.) in a mixture of dichloromethane/pyridine (9.5 mL/9.5 mL) was added dropwise over the course of 1 h. The mixture was then allowed to warm to room temperature and stirred for another hour. Upon complete consumption of starting material as determined by TLC, aqueous HCl (1M) was added and the aqueous layer extracted with CH2Cl2 (2x). The combined organic layers were washed with a sat. aqueous solution of Na2S2O3, brine and dried over Na2SO4. The crude product was purified by flash column chromatography on silica gel (0 → 10% EtOAc/Hexanes) to yield the product 25 as a yellow oil (1.28 g, 3.8 mmol, 80% yield). Chapter 1 – The Total Synthesis of Ineleganolide 1 27 H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 2.5 Hz, 1H), 4.95 (d, J = 6.1 Hz, 1H), 2.86 (dd, J = 18.2, 6.0 Hz, 1H), 2.35 (ddd, J = 18.2, 2.2, 0.7 Hz, 1H), 0.91 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H). The spectroscopic data matches those previously reported.30 I O MeMgBr (2.2 equiv) THF, –78 ºC to –30 ºC HO I 16:1 d.r. OTBS OTBS 25 26 Alcohol 26: Vinyl iodide 25 (300 mg, 0.88 mmol, 1.0 equiv.) was placed in a vial equipped with a stir bar, sealed, evacuated, and backfilled with N2 (3x). The starting material was dissolved in THF (8.8 mL, 0.1 M) and cooled to –78 °C in a dry ice/acetone bath. MeMgBr (3M in Et2O, 0.35 mL, 1.05 mmol, 1.2 equiv) was added dropwise over the course of 5 min and the reaction mixture warmed and kept at temperature between –40 °C and –30 °C. After 1 h, another equivalent of MeMgBr (3M in Et2O, 0.3 mL) was added and the reaction stirred for another hour at the same temperature. After full consumption of SM as indicated by TLC, a solution of sat. aq. NH4Cl was added, and the reaction mixture warmed to room temperature. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers dried over Na2SO4. The crude product was purified by flash column chromatography on silica gel (0 → 15% EtOAc/Hexanes) to yield the product 26 as a yellow oil (225 mg, 0.64 mmol, 72% yield). 1 H NMR (400 MHz, CDCl3) δ 6.16 (d, J = 2.2 Hz, 1H), 4.60 (ddd, J = 6.6, 4.4, 2.1 Hz, 1H), 2.48 (dd, J = 13.3, 6.8 Hz, 1H), 2.17 (s, 1H), 1.91 (dd, J = 13.3, 4.4 Hz, 1H), 1.24 (s, 3H), 0.88 (s, 9H), 0.07 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 143.2, 113.8, 82.7, 75.6, Chapter 1 – The Total Synthesis of Ineleganolide 28 48.2, 27.4, 25.9, 18.2, -4.6, -4.6; IR (neat film, NaCl) 3423, 2954, 2929, 2856, 1743, 1604, 1471, 1359, 1255, 1087, 960, 824, 776, 681, 651 cm–1; HRMS (ESI+): m/z calc’d for C12H22SiOI [M–OH]+: 337.0480, found 337.0482. O NaH (5.0 equiv) HO I O Cl (3.0 equiv) OMe I O OMe THF, 60 ºC OTBS OTBS 26 27 Methyl Ester 27: Starting material 26 (183 mg, 0.516 mmol, 1.0 equiv.) was placed in a vial and dissolved in THF (3.4 mL, 0.15 M). Sodium hydride (60% in mineral oil, 103 mg, 2.58 mmol, 5.0 equiv.) was added and the reaction stirred for 10 minutes at room temperature. Methyl chloroacetate (0.135 mL, 1.55 mmol, 3.0 equiv.) was added dropwise and the reaction mixture heated to 60 °C for 3 hours. The reaction mixture was cooled to room temperature and quenched with a sat. aq. solution of NaHCO3. The aqueous layer was extracted with Et2O (3x), the combined organic layers dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (0 → 10% EtOAc/Hexanes) to yield the product 27 as a colorless oil (44.5 mg, 0.11 mmol, 21% yield) along with reisolated starting material 26 (126 mg, 0.35 mmol, 69% yield). 1 H NMR (600 MHz, CDCl3) δ 6.31 (dd, J = 2.3, 0.5 Hz, 1H), 4.75 – 4.31 (m, 1H), 4.12 (d, J = 16.4 Hz, 1H), 3.99 (d, J = 16.4 Hz, 1H), 3.73 (s, 3H), 2.35 (dd, J = 14.7, 7.5 Hz, 1H), 1.92 (dd, J = 14.7, 3.0 Hz, 1H), 1.34 (s, 3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 171.3, 146.1, 109.7, 88.9, 75.1, 61.9, 51.9, 42.3, 28.1, 25.9, Chapter 1 – The Total Synthesis of Ineleganolide 29 18.2, -4.6, -4.7; IR (neat film, NaCl) 2955, 2928, 2856, 1741, 1648, 1462, 1361, 1257, 1103, 1035, 837, 778 cm–1; HRMS (ESI+): m/z calc’d for C12H22SiOI [M– OCH2COOMe]+: 337.0480, found 337.0488. O OMe I O t-BuLi (1.5 equiv) O O Et2O, –78 ºC OTBS 27 OTBS 28 Enone 28: Starting material 27 (20 mg, 0.048 mmol, 1.0 equiv.) was placed in a vial, capped, equipped with a stir bar, evacuated, and backfilled with N2 (3x). Et2O (4.8 mL, 0.01 M) was added, and the reaction mixture cooled to –78 °C in a dry ice/acetone bath. A solution of t-BuLi (1.7M in pentane, 0.072 mmol, 0.042 mL) was added dropwise to the reaction mixture and the solution stirred for 30 minutes, before the reaction was quenched with a sat. aq. solution of NaHCO3 and subsequently warmed to room temperature. The aqueous layer was extracted with Et2O (3x), and the combined organic layers dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product purified by flash column chromatography on silica gel (0 → 10% EtOAc/Hexanes) to yield the product 28 as a colorless oil (10.2 mg, 0.038 mmol, 79% yield). 1 H NMR (600 MHz, CDCl3) δ 6.48 (s, 1H), 5.18 (t, J = 6.6 Hz, 1H), 4.26 (d, J = 17.1 Hz, 1H), 4.21 (d, J = 17.1 Hz, 1H), 2.64 (dd, J = 11.8, 5.6 Hz, 1H), 2.27 (dd, J = 11.9, 8.0 Hz, 1H), 1.39 (s, 3H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H). The spectroscopic data matches those previously reported.5 Chapter 1 – The Total Synthesis of Ineleganolide Br O MeMgBr (2.5 equiv) THF, –78 ºC to –30 ºC 30 HO Br 10:1 d.r. OTBS OTBS 40 41 Alcohol 41: Vinyl bromide 40 (500 mg, 1.71 mmol, 1.0 equiv.) was placed in a round bottom flask with a stir bar, sealed, evacuated, and backfilled with N2 (3x). The starting material was dissolved in Et2O (17 mL, 0.1 M) and cooled to –78 °C in a dry ice/acetone bath. MeMgBr (3M in Et2O, 0.85 mL, 2.56 mmol, 1.5 equiv) was added dropwise over the course of 5 min and the reaction mixture warmed and kept at temperature between –40 °C and –30 °C. After 1 h another equivalent of MeMgBr (3M in Et2O, 0.3 mL) was added and the reaction stirred for another hour at the same temperature. After full consumption of SM as indicated by TLC, a solution of sat. aq. NH4Cl was added, and the reaction mixture warmed to room temperature. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers dried over Na2SO4. The crude product was purified by flash column chromatography on silica gel (0 → 15% EtOAc/Hexanes) to yield the product 41 as a yellow oil (363 mg, 1.18 mmol, 69% yield). 1 H NMR (400 MHz, CDCl3) δ 5.94 (d, J = 2.2 Hz, 1H), 4.60 (ddd, J = 6.5, 3.9, 2.2 Hz, 1H), 2.49 (dd, J = 13.4, 6.8 Hz, 1H), 1.95 (dd, J = 13.4, 4.0 Hz, 1H), 1.32 (s, 3H), 0.88 (s, 9H), 0.08 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 134.9, 81.1, 73.2, 49.6, 26.2, 25.9, 18.2, -4.6, -4.6; IR (neat film, NaCl) 3423, 2954, 2930, 2857, 1618, 1358, 1254, 1087, 970, 901, 820, 777 cm–1; HRMS (ESI+): m/z calc’d for C12H22SiOBr [M–OH]+: 291.0598, found 291.0605. Chapter 1 – The Total Synthesis of Ineleganolide 31 O NaH (5.0 equiv) HO Br O Cl (3.0 equiv) O OMe Br OMe THF, 60 ºC OTBS OTBS 41 42 Methyl Ester 42: Starting material 41 (220 mg, 0.714 mmol, 1.0 equiv.) was placed in a vial and dissolved in THF (7 mL, 0.1 M). Sodium hydride (60% in mineral oil, 142 mg, 3.57 mmol, 5.0 equiv.) was added and the reaction stirred for 10 minutes at room temperature. Methyl chloroacetate (0.183 mL, 2.1 mmol, 3.0 equiv.) was added dropwise and the reaction mixture heated to 60 °C for 3 hours. The reaction mixture was cooled to room temperature and quenched with a sat. aq. solution of NaHCO3. The aqueous layer was extracted with Et2O (3x), the combined organic layers dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (0 → 10% EtOAc/Hexanes) to yield the product 42 as a colorless oil (67 mg, 0.18 mmol, 25% yield) along with reisolated starting material 41 (132 mg, 0.43 mmol, 60% yield). 1 H NMR (600 MHz, CDCl3) δ 6.08 (dd, J = 2.4, 0.6 Hz, 1H), 4.56 (d, J = 7.3 Hz, 1H), 4.15 (d, J = 16.3 Hz, 1H), 4.00 (d, J = 16.3 Hz, 1H), 3.73 (s, 3H), 2.38 (dd, J = 14.8, 7.4 Hz, 1H), 1.97 (dd, J = 14.8, 2.7 Hz, 1H), 1.41 (s, 3H), 0.87 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13 C NMR (125 MHz, CDCl3) δ 171.3, 137.9, 131.5, 87.3, 72.5, 62.0, 52.0, 44.0, 26.8, 25.9, 18.1, -4.6, -4.7; IR (neat film, NaCl) 3503, 2954, 2857, 1740, 1619, 1471, 1359, 1251, 1118, 1060, 1036, 972, 900, 840, 777 cm–1; HRMS (ESI+): m/z calc’d for C12H22SiOBr [M–OCH2COOMe]+: 291.0598, found 291.0602. Chapter 1 – The Total Synthesis of Ineleganolide O O O O + Ph3P=O (2.1 equiv.) (COCl)2 (2.0 equiv.) DIPEA (4.0 equiv.) 32 O O O CH2Cl2, –40 °C to –78 °C HO OH 5 16 O O 15 Ester 15: A flame dried round-bottom flask was charged with triphenylphosphine oxide (478 mg, 1.7 mmol, 2.1 equiv.) and dissolved in CH2Cl2 (3.3 mL). The reaction mixture was cooled to –10 °C using a dry ice/acetone bath, and oxalyl chloride (0.14 mL, 1.65 mmol, 2.0 equiv.) was added dropwise. After stirring at the same temperature for 10 minutes, the reaction mixture was cooled to –40 °C, after which acid 5 (323 mg, 1.65 mmol, 2.0 equiv.) was added dropwise as a solution in CH2Cl2 (1.0 mL). The mixture was stirred for exactly 10 minutes, while the temperature of the dry ice/acetone bath was monitored with a thermostat and kept between –35 °C to –40 °C. Subsequently, the reaction mixture was cooled to –78 °C, after which alcohol 16 (127 mg, 0.8 mmol, 1.0 equiv.) was added as a solution in CH2Cl2 (1.0 mL). Following directly, a solution of diisopropylethylamine (0.53 mL, 3.3 mmol, 4.0 equiv.) in CH2Cl2 (0.5 mL) was added dropwise to the reaction mixture and stirred at –78 °C for 10 minutes. The reaction mixture was quenched at the same temperature with a saturated aqueous solution of NH4Cl and let warm to 23 °C. The aqueous layer was extracted with EtOAc (3x), the combined organic extracts dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (30% EtOAc/hexanes) to yield the title compound 15 (235 mg, 0.71 mmol, 87%) as a colorless oil; 1H NMR (600 MHz, CDCl3) δ 6.45 (s, 1H), 6.04 (t, J = 7.1 Hz, 1H), 5.96 (s, 1H), 4.83 (s, 1H), 4.77 (s, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.25 (d, J = 17.2 Hz, 1H), 3.29 (s, 2H), 2.81 (dd, J = 12.2, 6.0 Hz, 1H), 2.72 (ddt, J = 14.1, 9.6, 4.9 Hz, 1H), 2.54 (dd, J = 16.3, 3.9 Hz, 1H), 2.46 – 2.39 (m, 2H), 2.35 Chapter 1 – The Total Synthesis of Ineleganolide 33 – 2.28 (m, 2H), 1.76 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 199.1, 198.8, 168.6, 155.4, 149.3, 146.0, 132.4, 128.9, 111.2, 90.5, 81.5, 74.3, 50.9, 43.0, 42.2, 41.9, 34.9, 22.9, 20.6; IR (neat film, NaCl) 2976, 1660, 1136, 1028, 988, 889, 735, 658 cm–1; HRMS (ESI+): m/z calc’d for C19H23O5 [M+H]+: 331.1540, found 331.1535; [a]D23 – 91.6 (c 0.50, CHCl3). O O OH O O DBU (0.5 equiv.) O H DMF, 120 °C O O 15 O H H O 31 Tertiary Alcohol 31: In a flame dried round-bottom flask, 15 (228 mg, 0.69 mmol, 1.0 equiv.) was dissolved in dry DMF (69 mL, 0.01 M) under N2 atmosphere and heated in a heating mantel set to 120°C for 10 minutes. DBU (51.6 µL, 0.34 mmol, 0.5 equiv.) was added in one portion via syringe and the reaction mixture stirred for 5 minutes. The reaction mixture was consequently cooled to 23°C and a saturated aqueous solution of NH4Cl and EtOAc was added. The phases were separated, and the aqueous layer extracted with EtOAc (3x). The combined organic extracts were washed with a 10% aqueous solution of LiCl (3x), then brine, dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified via flash chromatography on silica gel (50% EtOAc/hexanes) and the title compound 31 (193 mg, 0.58 mmol, 84%) isolated as a white solid. 1H NMR (600 MHz, CDCl3) δ 5.52 (s, 1H), 5.03 (t, J = 6.1 Hz, 1H), 4.85 (s, 1H), 4.79 (s, 1H), 4.20 (d, J = 9.9 Hz, 1H), 3.62 (d, J = 10.0 Hz, 1H), 3.53 (d, J = 9.8 Hz, 1H), 3.26 (ddd, J = 12.3, 9.9, 6.4 Hz, 1H), 3.06 (dd, J = 18.0, 4.7 Hz, 1H), 2.84 (ddt, J = Chapter 1 – The Total Synthesis of Ineleganolide 34 14.8, 9.0, 4.2 Hz, 1H), 2.63 – 2.51 (m, 4H), 2.50 – 2.41 (m, 1H), 2.01 (dd, J = 15.9, 5.8 Hz, 1H), 1.78 (s, 3H), 1.55 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 201.9, 173.9, 151.4, 145.7, 134.8, 111.3, 95.0, 85.7, 83.5, 80.6, 59.7, 46.1, 44.4, 43.7, 41.2, 40.3, 36.4, 24.2, 20.5; IR (neat film, NaCl) 3458, 3082, 2971, 1755, 1655, 1360, 1114, 1062, 897, 733 cm–1; HRMS (ESI+): m/z calc’d for C19H21O4 [M–OH]+: 313.1434, found 331.1435; [a]D23 + 14.3 (c 1.00, CHCl3). OH O O H O H OR O O TESCl (3.0 equiv.) imid. (5.0 equiv.) H O 31 H THF, 60 °C O H H O R = TES 43 Silyl ether 43: In a vial, 31 (100 mg, 0.3 mmol, 1.0 equiv.) was dissolved in THF (3 mL, 0.1 M) and imidazole (102 mg, 1.5 mmol, 5.0 equiv.) added in one portion. Subsequently, TESCl (152 µL, 0.9 mmol, 3.0 equiv.) was added dropwise. The vial was sealed with a plastic cap and placed in a heating block set to 60 °C. After stirring for exactly 3 h, the reaction mixture was flushed over a plug of silica gel, eluting with EtOAc. After the solvent was removed under reduced pressure, the crude product was purified by flash chromatography on silica gel (20% EtOAc/hexanes → 60% EtOAc/hexanes) to give the title compound 43 (112 mg, 0.25 mmol, 83%) as a white solid, along with reisolated starting material 31 (15 mg, 0.045 mmol, 15%); 1H NMR (600 MHz, CDCl3) δ 5.01 (t, J = 6.4 Hz, 1H), 4.84 (s, 1H), 4.79 (s, 1H), 4.28 (d, J = 10.2 Hz, 1H), 3.86 (d, J = 10.2 Hz, 1H), 3.41 (d, J = 10.4 Hz, 1H), 3.24 (td, J = 11.2, 6.8 Hz, 1H), 3.15 (dd, J = 17.7, 4.8 Hz, 1H), 2.95 – 2.77 (m, 1H), 2.66 – 2.43 (m, 4H), 2.36 (dd, J = 17.7, 11.3 Hz, 1H), 1.97 (dd, J = Chapter 1 – The Total Synthesis of Ineleganolide 35 15.6, 6.0 Hz, 1H), 1.78 (s, 3H), 1.50 (s, 3H), 0.90 (t, J = 7.9 Hz, 9H), 0.50 (q, J = 7.9 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 197.4, 174.1, 146.4, 146.2, 138.1, 110.6, 93.7, 85.1, 83.6, 80.1, 60.8, 44.6, 44.5, 43.3, 42.1, 38.3, 35.8, 22.8, 20.5, 7.1, 6.2; IR (neat film, NaCl) 2955, 1766, 1682, 1372, 1116, 1004, 735, 627 cm–1; HRMS (ESI+): m/z calc’d for C19H21O4 [M–OTES]+: 313.1434, found 331.1442; [a]D23 + 10.4 (c 0.20, CHCl3). OR O O H O H O O SmI2 (6.0 equiv.) H2O (26 equiv.) H THF, –78 °C H O O R = TES 43 H H H O 32 Preparation of Samariumdiiode (0.1 M in THF): Samarium metal (325 mg, 2.16 mmol, 1.7 equiv.) was freshly filed and the resulting fine powder submitted in a Schlenk tube. The tube was set under vacuum and flame-dried, letting it cool back down to 23 °C. THF (125 mL, 0.1 M) was added, followed by EtI2 (350 mg, 1.24 mmol, 1.0 equiv.). The reaction mixture was stirred for 10 h, becoming dark blue in color, before it was used. The stock solution was kept under N2 and sealed with a stopcock, storing it for up to two months without observing any loss of reactivity. Enone 32: A vial was charged with Silylether 43 (19.2 mg, 0.04 mmol, 1.0 equiv.), dissolved in dry THF (0.4 mL, 0.1 M), the reaction mixture cooled to –78 °C with a dry ice/acetone bath and H2O (17.3 µL, 0.96 mmol, 24.0 equiv.) added dropwise. SmI2 (0.1 M in THF, 2.6 mL, 6.0 equiv.) was slowly added down the side of the reaction flask and the dark blue reaction mixture stirred for exactly 2 hours at the same temperature. The dry ice/acetone bath was removed and replaced with an ice bath to let the reaction mixture Chapter 1 – The Total Synthesis of Ineleganolide 36 slowly warm up to 0 °C. After one hour, the reaction was quenched with a mixture of a saturated aqueous solution of Na2S2O3 and hexanes (4 mL, 1:8). After stirring for 2 minutes, Na2SO4 was added and the mixture filtered over a plug of silica gel, eluting with EtOAc. The solvent was evaporated under reduced pressure and the crude product purified by flash chromatography on silica gel (20% EtOAc/hexanes → 30% EtOAc/hexanes) to yield the title compound 32 (8.0 mg, 0.025 mmol, 63%) as a white foam; 1H NMR (600 MHz, CDCl3) δ 4.96 – 4.89 (m, 2H), 4.85 (td, J = 7.6, 3.8 Hz, 1H), 4.82 (s, 1H), 4.51 (s, 1H), 3.38 (td, J = 9.7, 7.8 Hz, 1H), 2.99 (dd, J = 10.0, 3.9 Hz, 1H), 2.94 (ddd, J = 14.3, 10.7, 4.0 Hz, 1H), 2.82 (s, 1H), 2.71 – 2.50 (m, 4H), 2.21 (dd, J = 15.6, 7.5 Hz, 1H), 2.14 – 2.07 (m, 1H), 2.01 (dd, J = 15.7, 4.0 Hz, 1H), 1.80 (s, 3H), 1.48 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 197.4, 177.2, 156.8, 146.0, 127.5, 111.9, 89.9, 82.6, 71.0, 53.6, 44.2, 43.7, 43.5, 42.2, 38.0, 34.7, 26.5, 25.9, 22.2; IR (neat film, NaCl) 2922, 1761, 1616, 1315, 1110, 950, 798, 637 cm–1; HRMS (ESI+): m/z calc’d for C19H23O4 [M+H]+: 315.1591, found 315.1588; [a]D23 + 10.1 (c 0.15, CHCl3). OH O O H O H H H O 32 DBU (5.0 equiv.) O2 O O O H benzene, 70 °C O H H H O 33 Hemiacetal 33: A vial was charged with starting material 32 (8.0 mg, 0.025 mmol, 1.0 equiv.), dissolved in benzene (2.5 mL, 0.01 M) and DBU (20 µL, 0.12 mmol, 5.0 equiv.) added dropwise. The head space of the vial was briefly flushed with a blow of oxygen (1 second) and sealed shut with a plastic cap. The vial was placed in a preheated Chapter 1 – The Total Synthesis of Ineleganolide 37 heating block set to 70 °C and stirred for 3 h until full consumption of starting material was observed as determined by TLC. The reaction mixture was directly purified by flash chromatography on silica gel (hexanes → EtOAc/hexanes/acetone, 4:5:1) to yield the title compound 33 (5.8 mg, 0.016 mmol, 67%) as a white foam. Note: The reaction was very sensitive to the speed of stirring; being kept low (around 200 to 300 rpm), as a loss in yield was observed at higher rates; 1H NMR (400 MHz, CDCl3) δ 5.60 (s, 1H), 4.98 (s, 1H), 4.87 (t, J = 5.0 Hz, 1H), 4.71 (s, 1H), 3.19 (ddd, J = 10.8, 8.1, 5.0 Hz, 1H), 3.07 (dd, J = 17.2, 5.0 Hz, 1H), 2.99 (dt, J = 6.3, 3.2 Hz, 2H), 2.86 – 2.75 (m, 1H), 2.74 – 2.62 (m, 2H), 2.54 (d, J = 10.8 Hz, 1H), 2.37 (dddd, J = 14.0, 9.6, 4.3, 2.6 Hz, 1H), 2.13 – 2.02 (m, 1H), 1.87 (dd, J = 16.1, 5.0 Hz, 1H), 1.81 (s, 3H), 1.71 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 205.6, 176.6, 145.3, 112.7, 95.2, 93.7, 85.1, 74.4, 60.6, 50.4, 45.6, 45.4, 44.9, 44.5, 38.2, 35.5, 29.2, 28.6, 22.1; IR (neat film, NaCl) 3335, 2929, 1756, 1600, 1124, 1007, 735, 624 cm–1; HRMS (ESI+): m/z calc’d for C19H21O5 [M+H]+: 329.1384, found 329.1383; [a]D23 + 7.5 (c 0.23, CHCl3). OH O O H O H O H H O 33 Ac2O (1.5 equiv.) Et3N (2.0 equiv.) DMAP (0.1 equiv.) OAc O O H CH2Cl2, 23 °C O H O H H O 34 Acetal 34: A vial was charged with 33 (26.3 mg, 0.076 mmol, 1.0 equiv.) and dissolved in CH2Cl2 (0.76 mL, 0.1 M). Et3N (21.2 µL, 0.15 mmol, 2.0 equiv.) and Acetic anhydride (10.7 µL, 0.11 mmol, 1.5 equiv.) were added dropwise. Subsequently, DMAP (0.9 mg, 0.0076 mmol, 0.1 equiv.) was added and the reaction stirred at 23 °C for 1.5 h. The crude Chapter 1 – The Total Synthesis of Ineleganolide 38 reaction mixture was directly purified by flash chromatography on silica gel (hexanes → EtOAc/hexanes/acetone, 4:5:1) and the title compound 34 (26.8 mg, 0.065 mmol, 85% yield) isolated as a white foam; 1H NMR (600 MHz, CDCl3) δ 6.56 (s, 1H), 4.97 (s, 1H), 4.87 (t, J = 5.0 Hz, 1H), 4.71 (s, 1H), 3.20 (ddd, J = 11.9, 8.0, 5.1 Hz, 1H), 3.06 (dd, J = 17.4, 5.1 Hz, 1H), 3.00 (dd, J = 8.3, 2.6 Hz, 1H), 2.99 – 2.95 (m, 1H), 2.79 (dt, J = 17.7, 3.1 Hz, 1H), 2.74 – 2.65 (m, 2H), 2.57 (d, J = 10.8 Hz, 1H), 2.43 – 2.32 (m, 1H), 2.11 (s, 3H), 2.10 – 2.04 (m, 1H), 1.87 (dd, J = 16.2, 5.0 Hz, 1H), 1.80 (s, 3H), 1.64 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 204.4, 176.3, 169.6, 145.3, 112.6, 94.6, 93.8, 84.9, 72.0, 59.9, 50.4, 45.3, 45.1, 44.8, 44.6, 38.1, 35.6, 28.6, 28.5, 22.0, 21.4; IR (neat film, NaCl) 2929, 1748, 1715, 1362, 1228, 1131, 1080, 1005, 940, 736 cm–1; HRMS (ESI+): m/z calc’d for C21H24O7Na [M+Na]+: 411.1414, found 411.1412; [a]D23 + 18.6 (c 0.12, CHCl3). OAc O O O H O H H H O 34 O O H H SmI2 (3.0 equiv.) THF:NaOH (1M in H2O), (8:1) –78 °C to 23 °C O H O H O H (+)-Ineleganolide (1) (+)-Ineleganolide (1): A vial was charged with 34 (11.0 mg, 0.026 mmol, 1.0 equiv.), dissolved in THF (1.07 mL, 0.025 M) and the reaction mixture cooled to –78 °C in a dry ice/acetone bath. Aqueous NaOH (1M, 133 µL) was added dropwise, before SmI2 (0.1 M in THF, 801 µL, 0.08 mmol, 3.0 equiv.) was added dropwise. The reaction mixture was stirred for 3 minutes, before the dry ice/acetone bath was removed. The reaction mixture was stirred for a total of another 3 minutes, while warming up to 23 °C, before it was quenched with a mixture of a saturated aqueous solution of Na2S2O3 and hexanes (2 mL, Chapter 1 – The Total Synthesis of Ineleganolide 39 1:8). After stirring for 2 minutes, Na2SO4 was added and the mixture filtered over a plug of silica gel, eluting with EtOAc. The solvent was evaporated under reduced pressure and the crude product purified by preparative HPLC (Agilent Zorbax RX-SIL 5µm (SiO2), Hexanes:CH2Cl2 (3:1) / iPrOH (10% → 25% over 7.5 min), flowrate: 7 mL/min, monitor wavelength = 206 nm, retention time = 3.9 min) to yield (+)-ineleganolide (1, 4.0 mg, 0.012 mmol, 45%) as a white solid; 1H NMR (400 MHz, CDCl3) δ 5.12 (t, J = 7.4 Hz, 1H), 5.07 (s, 1H), 4.94 (s, 1H), 4.62 (s, 1H), 3.42 (ddd, J = 12.1, 9.2, 7.6 Hz, 1H), 3.02 (dd, J = 12.0, 2.4 Hz, 1H), 3.00 (m, 1H), 2.78 (br s, 1H), 2.70 (d, J = 13.0 Hz, 1H), 2.64 (m, 1H), 2.59 (d, J = 9.3 Hz, 1H), 2.52 (d, J = 15.6 Hz, 1H), 2.25 (tt, J = 12.4, 2.8 Hz, 1H), 2.10 (dd, J = 15.5, 7.3 Hz, 1H), 1.78 (dq, J = 13.0, 2.8 Hz, 1H), 1.71 (s, 2H), 1.28 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 212.2, 206.4, 176.1, 146.0, 113.8, 91.1, 83.1, 77.4, 62.5, 49.8, 47.0, 45.5, 44.4, 43.8, 40.4, 33.2, 32.7, 22.7, 20.2; IR (neat film, NaCl) 2935, 1759, 1705, 1372, 1322, 1213, 1184, 1026, 905, 835, 736 cm–1; HRMS (ESI+): m/z calc’d for C19H23O5 [M+H]+: 331.1540, found 331.1538; [a]D23 + 25.1 (c 0.22, CHCl3). Chapter 1 – The Total Synthesis of Ineleganolide 40 1.8 REFERENCES AND NOTES (1) Li, Y.; Pattenden, G. Perspectives on the Structural and Biosynthetic Interrelationships Between Oxygenated Furanocembranoids and Their Polycyclic Congeners Found in Corals. Nat. Prod. Rep. 2011, 28, 1269−1310. (2) Craig, R. A., II; Stoltz, B. M. Polycyclic Furanobutenolide-Derived Cembranoid and Norcembranoid Natural Products: Biosynthetic Connections and Synthetic Efforts. Chem. Rev. 2017, 117, 7878−7909. (3) For recent and selected examples of syntheses of the polycyclic furanobutenolidederived diterpenoids, see: (a) Tang, B.; Bray, C. D.; Pattenden, G. A Biomimetic Total Synthesis of (+)-Intricarene. Tetrahedron Lett. 2006, 47, 6401−6404. (b) Roethle, P. A.; Hernandez, P. T.; Trauner, D. Exploring Biosynthetic Relationships Among Furanocembranoids: Synthesis of (−)-Bipinnatin J, (+)-Intricarene, (+)-Rubifolide, and (+)-Isoepilophodione B. Org. Lett. 2006, 8, 5901−5904. (c) Stichnoth, D.; Kölle, P.; Kimbrough, T. J.; Riedle, E.; de Vivie-Riedle, R.; Trauner, D. Photochemical Formation of Intricarene. Nat. Commun. 2014, 5, 5597. (d) Hafeman, N. J.; Loskot, S. A.; Reimann, C. E.; Pritchett, B. P.; Virgil, S. C.; Stoltz, B. M. The Total Synthesis of (−)-Scabrolide A. J. Am. Chem. Soc. 2020, 142, 8585−8590. (e) Meng, Z.; Fürstner, A. Total Syntheses of Scabrolide A and Nominal Scabrolide B. J. Am. Chem. Soc. 2022, 144, 1528−1533. (f) Truax, N. J.; Ayinde, S.; Liu, J. O.; Romo, D. Total Synthesis of Rameswaralide Utilizing a Pharmacophore- Directed Retrosynthetic Strategy. J. Am. Chem. Soc. 2022, 144, 18575−18585. Chapter 1 – The Total Synthesis of Ineleganolide (4) 41 Fenical, W.; Okuda, R.K.; Bandurraga, M.W.; Culver, P.; Jacobs, R.S. Lophotoxin: a Novel Neuromuscular Toxin from Pacific Sea Whips of the Genus Lophogorgia, Science, 1981, 212, 1512−1514. (5) Groebe, D. R.; Abramson, S. N. Lophotoxin Is a Slow Binding Irreversible Inhibitor of Nicotinic Acetylcholine Receptors, The Journal of Biological Chemistry, 1995, 270, 281−286. (6) Marrero, J.; Rodríguez, A. D.; Baran, P.; Raptis, R. G.; Sánchez, J. A.; Ortega-Barria, E.; Capson, T. L. Bielschowskysin, a Gorgonian-Derived Biologically Active Diterpene with an Unprecedented Carbon Skeleton, Org. Lett. 2006, 10, 1661−1664. (7) (a) Duh, C. Y.; Wang, S. K.; Chia, M. C.; Chiang, M. Y. A Novel Cytotoxic Norditerpenoid from the Formosan Soft Coral Sinularia Inelegans, Tetrahedron Lett. 1999, 40, 6033– 6035. An additional isolation report of compound 1 was recently published: (b) Cui W.; Yang, M.; Li, H.; Li, S.; Yao, L.; Li, G.; Tang, W.; Wang, C.; Liang, L.; Guo, Y. Polycyclic furanobutenolide-derived norditerpenoids from the South China Sea soft corals Sinularia scabra and Sinularia polydactyla with immunosuppressive activity, Bioorg. Chem. 2019, 94, 103350. (8) Horn, E. J.; Silverston, J. S.; Vanderwal, C. D. A Failed Late- Stage Epimerization Thwarts an Approach to Ineleganolide, J. Org. Chem. 2016, 81, 1819−1838. (9) Pratt, B. A. The Design and Synthesis of Highly Potent Epothilone B Analogues and Progress toward the Total Synthesis of Sinularia Natural Products. Ph.D. Dissertation, The Scripps Research Institute, La Jolla, CA, 2008. Chapter 1 – The Total Synthesis of Ineleganolide 42 (10) Breunig, M. Studies toward the Total Synthesis of Macro- and Polycyclic Furanobutenolides and Formal Synthesis of (±)-Strictamine. Ph.D. Dissertation, Universität Konstanz, Konstanz, Germany, 2019. (11) Liu, G. Beta-Lactones as Synthetic Vehicles in Natural Product Synthesis: Total Syntheses of Schulzeines B & C and Omphadiol, and Studies toward the Total Syntheses of Scabrolides A & B and Sinulochmodin C. Ph.D. Dissertation, Texas A & M University, College Station, TX, 2012. (12) (a) Tang, F.; Moeller, K. D. Anodic Oxidations and Polarity: Exploring the Chemistry of Olefinic Radical Cations. Tetrahedron 2009, 65, 10863−10875. (b) Tang, F.; Moeller, K. D. Intramolecular Anodic Olefin Coupling Reactions: The Effect of Polarization on Carbon−Carbon Bond Formation. J. Am. Chem. Soc. 2007, 129, 12414−12415. (13) For the previous work of our group see: (a) Roizen, J. L.; Jones, A. C.; Smith, R. C.; Virgil, S. C.; Stoltz, B. M. Model Studies To Access the [6,7,5,5]-Core of Ineleganolide Using Tandem Translactonization−Cope or Cyclopropanation−Cope Rearrangements as Key Steps. J. Org. Chem. 2017, 82, 13051−13067. (b) Craig, R. A.; Smith, R. C.; Roizen, J. L.; Jones, A. C.; Virgil, S. C.; Stoltz, B. M. Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade. J. Org. Chem. 2018, 83, 3467−3485. (c) Craig, R. A.; Smith, R. C.; Roizen, J. L.; Jones, A. C.; Virgil, S. C.; Stoltz, B. M. Unified Enantioselective, Convergent Synthetic Approach toward the Furanobutenolide-Derived Polycyclic Chapter 1 – The Total Synthesis of Ineleganolide 43 Norcem- branoid Diterpenes: Synthesis of a Series of Ineleganoloids by OxidationState Manipulation of the Carbocyclic Core. J. Org. Chem. 2019, 84, 7722−7746. (14) (a) Tuccinardi, J. P.; Wood J. L. Total Syntheses of (+)-Ineleganolide and (−)Sinulochmodin C. J. Am. Chem. Soc. 2022, 144, 20539−20547. (b) A similar macrocycle was also prepared by Sarlah and coworkers: Nesic, M.; Kincanon, M. M.; Ryffel, D. B.; Sarlah, D. A New Approach towards the Synthesis of Bielschowskysin: Synthesis and Photochemistry of an Advanced Macrocyclic Enedione Intermediate. Tetrahedron 2020, 76, No. 131318. (15) Li, Y.; Pattenden, G. Biomimetic Syntheses of Ineleganolide and Sinulochmodin C from 5-Episinuleptolide via Sequences of Transannular Michael Reactions. Tetrahedron 2011, 67, 10045−10052. (16) Cusumano, A. Q.; Houk, K. N.; Stoltz, B. M. Synthetic Strategy toward Ineleganolide: A Cautionary Tale. Tetrahedron 2021, 93, No. 132289. (17) Craig, R. A.; Roizen, J. L.; Smith, R. C.; Jones, A. C.; Virgil, S. C.; Stoltz, B. M. Enantioselective, convergent synthesis of the ineleganolide core by a tandem annulation cascade. Chem. Sci. 2017, 8, 507−514. (18) (a) Lin, D. S.; Späth, G.; Meng, Z.; Wieske, L. H. E.; Farès, C.; Fürstner, A. Total Synthesis of the Norcembranoid Scabrolide B and Its Transformation into Sinuscalide C, Ineleganolide, and Horiolide. J. Am. Chem. Soc. 2024, 146, 24250−24256. Also see: (b) Simmons, E. J.; Ryffel, D. B.; Lopez, D. A.; Boyko, Y. D.; Sarlah, D. Total Syntheses of Scabrolide B, Ineleganolide, and Related Norcembranoids. J. Am. Chem. Soc. 2025, 147, 130−135. Chapter 1 – The Total Synthesis of Ineleganolide 44 (19) Yu, K.; Gorou, A.; Huang, D.; Maimone, T. J. Short, Enantioselective Total Synthesis of (+)-Ineleganolide, J. Am. Chem. Soc. 2025, ASAP. (20) Brill, Z. G.; Grover, H. K.; Maimone, T. J. Enantioselective Synthesis of an Ophiobolin Sesterterpene via a Programmed Radical Cascade. Science 2016, 352, 1078−1082. (21) Hafeman, N. J.; Chan, M.; Fulton, T. J.; Alexy, E. J.; Loskot, S. A.; Virgil, S. C.; Stoltz, B. M. Asymmetric Total Synthesis of Havellockate. J. Am. Chem. Soc. 2022, 144, 20232−20236. (22) Saitman, A.; Theodorakis, E. A.; Synthesis of a Highly Functionalized Core of Verrillin. Org. Lett. 2013, 15, 2410–2413. (23) Watson, T. J. N.; Curran, T. T.; Hay, D. A.; Shah, R. S.; Wenstrup, D. L.; Webster, M. E. Development of the Carbocyclic Nucleoside MDL 201449A: A Tumor Necrosis Factor-α Inhibitor. Org. Proc. Res. Dev. 1998, 2, 357–365. (24) Myers, A. G.; Dragovich, P. S.; A Reaction Cascade Leading to 1,6Didehydro[10]annulene → 1,5-Dehydronaphthalene Initiated by Thiol Addition. J. Am. Chem. Soc. 1993, 115, 7021–7022. (25) Jia, M.; Jiang, L.; Niu, F.; Zhang, Y.; Sun, X. A novel and highly efficient esterification process using triphenylphosphine oxide with oxalyl chloride. R. Soc. Open Sci. 2018, 5, 171988. (26) To the best of our knowledge, the only similar observations we found were (a) by Vanderwal and co-workers during the synthesis of the pseudopterosins and (b) by Newhouse, Yin and co-workers during the development of a copper-catalyzed aerobic oxidation: (a) Ramella, V.; Roosen, P. C.; Vanderwal, C. D. Concise Formal Chapter 1 – The Total Synthesis of Ineleganolide 45 Synthesis of the Pseudopterosins via Anionic Oxy-Cope/Transannular Michael Addition Cascade. Org. Lett. 2020, 22, 2883–2886. (b) Zhang, H.-J.; Schuppe, A. W.; Pan, S.-T.; Chen, J.-X.; Wang, B.-R.; Newhouse, T. R.; Yin, L. Copper-Catalyzed Vinylogous Aerobic Oxidation of Unsaturated Compounds with Air. J. Am. Chem. Soc. 2018, 140, 5300−5310. (27) For a review on the semi-pinacol shift in natural product synthesis see: Song, Z. L.; Fan, C. A.; Tu, Y. Q. Semipinacol Rearrangement in Natural Product Synthesis. Chem. Rev. 2011, 111, 7523. (28) Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (29) Jacobo, S. H. et al. Total Synthesis of 8,12-iso-iPF3α-VI, an EPA-Derived Isoprostane: Stereoselective Introduction of the Fifth Asymmetric Center. J. Org. Chem. 2006, 71, 1370–1379. (30) Kimbrough, J. R. et al. Synthesis of tetranor-PGE1: A urinary metabolite of prostaglandins E1 and E2, Tetrahedron Lett. 2020, 61, 151922. Appendix 1 – Spectra Relevant to Chapter 1 46 APPENDIX 1 Spectra Relevant to Chapter 1: The Total Synthesis of Ineleganolide 9 TBSO 8 OTES O 7 5 ppm 4 3 2 Figure A1.1. 1H NMR (600 MHz, CDCl3) of compound 18. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 47 Appendix 1 – Spectra Relevant to Chapter 1 48 Figure A1.2. Infrared spectrum (Thin Film, NaCl) of compound 18. 200 150 100 ppm 50 Figure A1.3. 13C NMR (100 MHz, CDCl3) of compound 18. 0 9 HO OTBS O 8 7 5 ppm 4 3 2 Figure A1.4. 1H NMR (600 MHz, CDCl3) of compound 19. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 49 Appendix 1 – Spectra Relevant to Chapter 1 50 Figure A1.5. Infrared spectrum (Thin Film, NaCl) of compound 19. 180 160 140 120 100 ppm 80 60 40 20 Figure A1.6. 13C NMR (100 MHz, CDCl3) of compound 19. 0 9 HO 8 OTBS TESO I 7 5 4 ppm 3 2 Figure A1.7. 1H NMR (600 MHz, CDCl3) of compound 39. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 51 Appendix 1 – Spectra Relevant to Chapter 1 52 Figure A1.8. Infrared spectrum (Thin Film, NaCl) of compound 39. 180 160 140 120 100 ppm 80 60 40 20 Figure A1.9. 13C NMR (100 MHz, CDCl3) of compound 39. 0 9 O 8 OTBS OTES 7 5 ppm 4 3 2 Figure A1.10. 1H NMR (600 MHz, CDCl3) of compound 21. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 53 Appendix 1 – Spectra Relevant to Chapter 1 54 Figure A1.11. Infrared spectrum (Thin Film, NaCl) of compound 21. 180 160 140 120 100 ppm 80 60 40 20 Figure A1.12. 13C NMR (125 MHz, CDCl3) of compound 21. 0 9 O OTBS OH 8 6 5 ppm 4 3 Figure A1.13. 1H NMR (600 MHz, CDCl3) of compound 22. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 55 Appendix 1 – Spectra Relevant to Chapter 1 56 Figure A1.14. Infrared spectrum (Thin Film, NaCl) of compound 22. 200 ppm 100 Figure A1.15. 13C NMR (125 MHz, CDCl3) of compound 22. 0 O 8 OTBS O 7 5 ppm 4 3 2 Figure A1.16. 1H NMR (600 MHz, CDCl3) of compound 28. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 57 Appendix 1 – Spectra Relevant to Chapter 1 58 Figure A1.17. Infrared spectrum (Thin Film, NaCl) of compound 28. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.18. 13C NMR (100 MHz, CDCl3) of compound 28. 0 O OH 8 O 7 5 ppm 4 3 Figure A1.19. 1H NMR (600 MHz, CDCl3) of compound 16. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 59 Appendix 1 – Spectra Relevant to Chapter 1 60 Figure A1.20. Infrared spectrum (Thin Film, NaCl) of compound 16. 200 180 160 140 120 ppm 100 80 60 40 Figure A1.21. 13C NMR (100 MHz, CDCl3) of compound 16. 20 0 9 HO 8 OTBS I 7 5 ppm 4 3 2 Figure A1.22. 1H NMR (400 MHz, CDCl3) of compound 26. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 61 Appendix 1 – Spectra Relevant to Chapter 1 62 Figure A1.23. Infrared spectrum (Thin Film, NaCl) of compound 26. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A1.24. 13C NMR (100 MHz, CDCl3) of compound 26. 0 9 O OTBS 8 OMe I O 7 5 ppm 4 3 Figure A1.25. 1H NMR (400 MHz, CDCl3) of compound 27. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 63 Appendix 1 – Spectra Relevant to Chapter 1 64 Figure A1.26. Infrared spectrum (Thin Film, NaCl) of compound 27. 200 150 100 ppm 50 Figure A1.27. 13C NMR (100 MHz, CDCl3) of compound 27. 0 9 HO OTBS Br 8 7 5 ppm 4 3 2 Figure A1.28. 1H NMR (400 MHz, CDCl3) of compound 41. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 65 Appendix 1 – Spectra Relevant to Chapter 1 66 Figure A1.29. Infrared spectrum (Thin Film, NaCl) of compound 41. 180 160 140 120 100 ppm 80 60 40 20 Figure A1.30. 13C NMR (100 MHz, CDCl3) of compound 41. 0 9 O OTBS OMe Br O 8 7 5 ppm 4 3 2 Figure A1.31. 1H NMR (400 MHz, CDCl3) of compound 42. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 67 Appendix 1 – Spectra Relevant to Chapter 1 68 Figure A1.32. Infrared spectrum (Thin Film, NaCl) of compound 42. 180 160 140 120 100 ppm 80 60 40 20 Figure A1.33. 13C NMR (100 MHz, CDCl3) of compound 42. 0 9 O O O O 8 O 6 5 ppm 4 3 Figure A1.34. 1H NMR (600 MHz, CDCl3) of compound 15. 7 2 1 Appendix 1 – Spectra Relevant to Chapter 1 69 Appendix 1 – Spectra Relevant to Chapter 1 70 Figure A1.35. Infrared spectrum (Thin Film, NaCl) of compound 15. 200 180 160 140 120 100 ppm 80 60 40 Figure A1.36. 13C NMR (100 MHz, CDCl3) of compound 15. 20 9 O O H 8 H O H OH O 7 5 ppm 4 3 Figure A1.37. 1H NMR (600 MHz, CDCl3) of compound 31. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 71 Appendix 1 – Spectra Relevant to Chapter 1 72 Figure A1.38. Infrared spectrum (Thin Film, NaCl) of compound 31. 200 150 100 ppm 50 Figure A1.39. 13C NMR (100 MHz, CDCl3) of compound 31. 0 9 H R = TES O O 8 H O H OR O 7 5 ppm 4 3 Figure A1.40. 1H NMR (600 MHz, CDCl3) of compound 43. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 73 Appendix 1 – Spectra Relevant to Chapter 1 74 Figure A1.41. Infrared spectrum (Thin Film, NaCl) of compound 43. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1.42. 13C NMR (125 MHz, CDCl3) of compound 43. 20 0 9 O O H H O H 8 H O 6 5 ppm 4 3 Figure A1.43. 1H NMR (600 MHz, CDCl3) of compound 32. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 75 Appendix 1 – Spectra Relevant to Chapter 1 76 Figure A1.44. Infrared spectrum (Thin Film, NaCl) of compound 32. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A1.45. 13C NMR (125 MHz, CDCl3) of compound 32. 20 0 9 O O H H O H O OH 8 H O 6 5 ppm 4 3 Figure A1.46. 1H NMR (400 MHz, CDCl3) of compound 33. 7 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 77 Appendix 1 – Spectra Relevant to Chapter 1 78 Figure A1.47. Infrared spectrum (Thin Film, NaCl) of compound 33. 200 180 160 140 120 ppm 100 80 60 40 Figure A1.48. 13C NMR (100 MHz, CDCl3) of compound 33. 20 0 9 O O H H O H O OAc 8 H O 7 5 ppm 4 3 2 Figure A1.49. 1H NMR (600 MHz, CDCl3) of compound 34. 6 1 0 Appendix 1 – Spectra Relevant to Chapter 1 79 Appendix 1 – Spectra Relevant to Chapter 1 80 Figure A1.50. Infrared spectrum (Thin Film, NaCl) of compound 34. 200 180 160 140 120 ppm 100 80 60 40 Figure A1.51. 13C NMR (100 MHz, CDCl3) of compound 34. 20 0 9 O H O H O H 8 H O O H 7 5 ppm 4 3 Figure A1.52. 1H NMR (400 MHz, CDCl3) of compound 1. 6 2 1 0 Appendix 1 – Spectra Relevant to Chapter 1 81 Appendix 1 – Spectra Relevant to Chapter 1 82 Figure A1.53. Infrared spectrum (Thin Film, NaCl) of compound 1. 200 180 160 140 120 ppm 100 80 60 40 Figure A1.54. 13C NMR (100 MHz, CDCl3) of compound 1. 20 0 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 83 APPENDIX 2 X-Ray Crystallography Reports Relevant to Chapter 1: The Total Synthesis of Ineleganolide Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.1 84 GENERAL EXPERIMENTAL INFORMATION Low-temperature diffraction data (f-and w-scans) were collected a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON II CPAD detector with Cu Ka radiation (l = 1.54178 Å) from an IμS micro-source. The structure was solved by direct methods using SHELXS and refined against F2 on all data by full-matrix least squares with SHELXL-2019 using established refinement techniques. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). A2.2 X-RAY CRYSTAL STRUCTURE OF COMPOUND 31 Figure A2.2.1 X-ray crystal structure of compound 31. Table A2.2.2 Crystal data and structure refinement for compound 31. Empirical formula C38H44O10 Formula weight 660.73 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 85 Space group P21 Unit cell dimensions a = 5.4379(6) Å a= 90°. b = 20.759(2) Å b= 93.475(6)°. c = 14.7956(10) Å g = 90°. Volume 1667.2(3) Å3 Z 2 Density (calculated) 1.316 Mg/m3 Absorption coefficient 0.778 mm-1 F(000) 704 Crystal size 0.200 x 0.100 x 0.050 mm3 Theta range for data collection 2.992 to 74.571°. Index ranges -6<=h<=6, -25<=k<=25, -18<=l<=18 Reflections collected 30860 Independent reflections 6591 [R(int) = 0.0626] Completeness to theta = 67.679° 98.8 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7538 and 0.5987 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6591 / 123 / 472 Goodness-of-fit on F2 1.043 Final R indices [I>2sigma(I)] R1 = 0.0388, wR2 = 0.0957 R indices (all data) R1 = 0.0462, wR2 = 0.0984 Absolute structure parameter 0.12(13) Extinction coefficient n/a Largest diff. peak and hole 0.186 and -0.159 e.Å-3 Table A2.2.3 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for compound 31. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ O(1) 2700(3) 6720(1) 8394(1) 27(1) C(1) 3494(5) 6439(1) 9236(2) 25(1) C(2) 6328(5) 6329(1) 9210(2) 22(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 86 O(4) 6584(5) 5571(1) 10834(2) 43(1) C(3) 6938(5) 5612(1) 9244(2) 23(1) C(4) 7106(6) 5292(2) 10141(2) 34(1) O(5) 7629(4) 6666(1) 9937(1) 29(1) C(5) 7989(9) 4600(2) 10171(2) 49(1) C(6) 6818(8) 4217(2) 9379(2) 39(1) C(16) 7455(9) 3504(2) 9376(3) 51(1) C(17) 9389(9) 3264(2) 9859(3) 58(1) C(18) 5771(12) 3102(2) 8797(3) 68(1) C(7) 7501(6) 4538(1) 8501(2) 28(1) C(8) 7088(5) 5255(1) 8494(2) 22(1) C(9) 6734(5) 5546(1) 7575(2) 21(1) C(10) 4061(5) 5489(1) 7203(2) 22(1) O(2) 3443(4) 6002(1) 6691(1) 24(1) O(3) 2636(4) 5057(1) 7311(1) 30(1) C(11) 5399(5) 6489(1) 6739(2) 23(1) C(12) 4431(5) 7127(1) 7064(2) 26(1) C(13) 4713(5) 7103(1) 8087(2) 23(1) C(19) 4785(6) 7765(1) 8531(2) 32(1) C(14) 6959(5) 6675(1) 8331(2) 20(1) C(15) 7323(5) 6258(1) 7481(2) 21(1) O(201) -2721(3) 3099(1) 4780(1) 26(1) C(201) -2411(5) 3593(1) 4137(2) 22(1) C(202) 340(5) 3599(1) 3953(2) 22(1) O(204) 476(6) 4016(1) 2088(2) 46(1) C(203) 1184(5) 4260(1) 3646(2) 24(1) C(204) 1242(7) 4400(2) 2668(2) 34(1) O(205) 857(4) 3101(1) 3328(1) 25(1) C(205) 2297(9) 5037(2) 2402(2) 47(1) C(206) 1569(8) 5574(2) 3041(2) 44(1) C(216) 2690(30) 6220(6) 2760(11) 52(3) C(217) 4390(17) 6547(4) 3206(8) 56(3) C(218) 1320(30) 6465(5) 1912(7) 76(4) C(16B) 1970(40) 6256(9) 2640(20) 37(4) C(17B) 290(30) 6633(6) 2235(13) 45(4) C(18B) 4630(30) 6430(7) 2733(18) 50(4) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 87 C(207) 2438(7) 5404(2) 4000(2) 36(1) C(208) 1749(5) 4727(1) 4253(2) 26(1) C(209) 1661(5) 4603(1) 5250(2) 25(1) C(210) -888(5) 4742(1) 5581(2) 26(1) O(202) -1542(4) 4272(1) 6152(1) 27(1) O(203) -2238(4) 5184(1) 5384(2) 33(1) C(211) 464(5) 3816(1) 6337(2) 26(1) C(212) -466(6) 3128(1) 6262(2) 29(1) C(213) -401(5) 2938(1) 5261(2) 24(1) C(219) 15(6) 2217(1) 5126(2) 30(1) C(214) 1552(5) 3379(1) 4862(2) 22(1) C(215) 2197(5) 3910(1) 5567(2) 24(1) ________________________________________________________________________________ Table A2.2.4 Bond lengths [Å] and angles [°] for compound 31. _____________________________________________________ O(1)-C(1) 1.419(3) O(1)-C(13) 1.449(3) C(1)-C(2) 1.561(4) C(1)-H(1A) 0.9900 C(1)-H(1B) 0.9900 C(2)-O(5) 1.433(3) C(2)-C(3) 1.524(4) C(2)-C(14) 1.543(4) O(4)-C(4) 1.225(4) C(3)-C(8) 1.342(4) C(3)-C(4) 1.483(4) C(4)-C(5) 1.515(4) O(5)-H(5O) 0.83(3) C(5)-C(6) 1.523(5) C(5)-H(5A) 0.9900 C(5)-H(5B) 0.9900 C(6)-C(16) 1.520(4) C(6)-C(7) 1.526(4) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(6)-H(6) 1.0000 C(16)-C(17) 1.333(7) C(16)-C(18) 1.474(7) C(17)-H(17A) 0.9500 C(17)-H(17B) 0.9500 C(18)-H(18A) 0.9800 C(18)-H(18B) 0.9800 C(18)-H(18C) 0.9800 C(7)-C(8) 1.506(4) C(7)-H(7A) 0.9900 C(7)-H(7B) 0.9900 C(8)-C(9) 1.489(4) C(9)-C(15) 1.522(4) C(9)-C(10) 1.527(4) C(9)-H(9) 1.0000 C(10)-O(3) 1.203(3) C(10)-O(2) 1.338(3) O(2)-C(11) 1.465(3) C(11)-C(12) 1.515(4) C(11)-C(15) 1.545(4) C(11)-H(11) 1.0000 C(12)-C(13) 1.513(4) C(12)-H(12A) 0.9900 C(12)-H(12B) 0.9900 C(13)-C(19) 1.522(4) C(13)-C(14) 1.536(4) C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800 C(14)-C(15) 1.548(4) C(14)-H(14) 1.0000 C(15)-H(15) 1.0000 O(201)-C(201) 1.416(3) O(201)-C(213) 1.450(3) C(201)-C(202) 1.537(4) C(201)-H(20A) 0.9900 88 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(201)-H(20B) 0.9900 C(202)-O(205) 1.427(3) C(202)-C(203) 1.525(4) C(202)-C(214) 1.532(4) O(204)-C(204) 1.224(4) C(203)-C(208) 1.345(4) C(203)-C(204) 1.479(4) C(204)-C(205) 1.504(5) O(205)-H(05O) 0.82(3) C(205)-C(206) 1.528(5) C(205)-H(20C) 0.9900 C(205)-H(20D) 0.9900 C(206)-C(207) 1.510(5) C(206)-C(216) 1.541(10) C(206)-C(16B) 1.556(16) C(206)-H(206) 1.0000 C(216)-C(217) 1.296(14) C(216)-C(218) 1.507(14) C(217)-H(21A) 0.9500 C(217)-H(21B) 0.9500 C(218)-H(21C) 0.9800 C(218)-H(21D) 0.9800 C(218)-H(21E) 0.9800 C(16B)-C(17B) 1.32(2) C(16B)-C(18B) 1.49(2) C(17B)-H(17C) 0.9500 C(17B)-H(17D) 0.9500 C(18B)-H(18D) 0.9800 C(18B)-H(18E) 0.9800 C(18B)-H(18F) 0.9800 C(207)-C(208) 1.506(4) C(207)-H(20E) 0.9900 C(207)-H(20F) 0.9900 C(208)-C(209) 1.502(4) C(209)-C(210) 1.526(4) C(209)-C(215) 1.536(4) 89 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(209)-H(209) 1.0000 C(210)-O(203) 1.200(4) C(210)-O(202) 1.352(4) O(202)-C(211) 1.458(4) C(211)-C(212) 1.518(4) C(211)-C(215) 1.534(4) C(211)-H(211) 1.0000 C(212)-C(213) 1.535(4) C(212)-H(21F) 0.9900 C(212)-H(21G) 0.9900 C(213)-C(219) 1.530(4) C(213)-C(214) 1.545(4) C(219)-H(21H) 0.9800 C(219)-H(21I) 0.9800 C(219)-H(21J) 0.9800 C(214)-C(215) 1.543(4) C(214)-H(214) 1.0000 C(215)-H(215) 1.0000 C(1)-O(1)-C(13) 107.8(2) O(1)-C(1)-C(2) 106.7(2) O(1)-C(1)-H(1A) 110.4 C(2)-C(1)-H(1A) 110.4 O(1)-C(1)-H(1B) 110.4 C(2)-C(1)-H(1B) 110.4 H(1A)-C(1)-H(1B) 108.6 O(5)-C(2)-C(3) 110.8(2) O(5)-C(2)-C(14) 106.3(2) C(3)-C(2)-C(14) 115.0(2) O(5)-C(2)-C(1) 110.7(2) C(3)-C(2)-C(1) 110.8(2) C(14)-C(2)-C(1) 102.9(2) C(8)-C(3)-C(4) 119.3(2) C(8)-C(3)-C(2) 122.4(3) C(4)-C(3)-C(2) 117.9(2) O(4)-C(4)-C(3) 122.2(3) 90 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(4)-C(4)-C(5) 120.8(3) C(3)-C(4)-C(5) 117.0(3) C(2)-O(5)-H(5O) 105(3) C(4)-C(5)-C(6) 110.8(3) C(4)-C(5)-H(5A) 109.5 C(6)-C(5)-H(5A) 109.5 C(4)-C(5)-H(5B) 109.5 C(6)-C(5)-H(5B) 109.5 H(5A)-C(5)-H(5B) 108.1 C(16)-C(6)-C(5) 115.2(3) C(16)-C(6)-C(7) 110.8(3) C(5)-C(6)-C(7) 108.4(3) C(16)-C(6)-H(6) 107.4 C(5)-C(6)-H(6) 107.4 C(7)-C(6)-H(6) 107.4 C(17)-C(16)-C(18) 122.8(4) C(17)-C(16)-C(6) 122.4(4) C(18)-C(16)-C(6) 114.8(4) C(16)-C(17)-H(17A) 120.0 C(16)-C(17)-H(17B) 120.0 H(17A)-C(17)-H(17B) 120.0 C(16)-C(18)-H(18A) 109.5 C(16)-C(18)-H(18B) 109.5 H(18A)-C(18)-H(18B) 109.5 C(16)-C(18)-H(18C) 109.5 H(18A)-C(18)-H(18C) 109.5 H(18B)-C(18)-H(18C) 109.5 C(8)-C(7)-C(6) 113.2(2) C(8)-C(7)-H(7A) 108.9 C(6)-C(7)-H(7A) 108.9 C(8)-C(7)-H(7B) 108.9 C(6)-C(7)-H(7B) 108.9 H(7A)-C(7)-H(7B) 107.8 C(3)-C(8)-C(9) 121.4(2) C(3)-C(8)-C(7) 123.9(3) C(9)-C(8)-C(7) 114.7(2) 91 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(8)-C(9)-C(15) 117.4(2) C(8)-C(9)-C(10) 111.4(2) C(15)-C(9)-C(10) 104.0(2) C(8)-C(9)-H(9) 107.8 C(15)-C(9)-H(9) 107.8 C(10)-C(9)-H(9) 107.8 O(3)-C(10)-O(2) 121.8(2) O(3)-C(10)-C(9) 128.0(2) O(2)-C(10)-C(9) 110.1(2) C(10)-O(2)-C(11) 111.3(2) O(2)-C(11)-C(12) 110.7(2) O(2)-C(11)-C(15) 106.3(2) C(12)-C(11)-C(15) 106.2(2) O(2)-C(11)-H(11) 111.2 C(12)-C(11)-H(11) 111.2 C(15)-C(11)-H(11) 111.2 C(13)-C(12)-C(11) 105.8(2) C(13)-C(12)-H(12A) 110.6 C(11)-C(12)-H(12A) 110.6 C(13)-C(12)-H(12B) 110.6 C(11)-C(12)-H(12B) 110.6 H(12A)-C(12)-H(12B) 108.7 O(1)-C(13)-C(12) 107.4(2) O(1)-C(13)-C(19) 111.2(2) C(12)-C(13)-C(19) 113.6(2) O(1)-C(13)-C(14) 102.3(2) C(12)-C(13)-C(14) 106.5(2) C(19)-C(13)-C(14) 115.0(2) C(13)-C(19)-H(19A) 109.5 C(13)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 C(13)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 C(13)-C(14)-C(2) 104.7(2) C(13)-C(14)-C(15) 105.8(2) 92 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(2)-C(14)-C(15) 118.1(2) C(13)-C(14)-H(14) 109.3 C(2)-C(14)-H(14) 109.3 C(15)-C(14)-H(14) 109.3 C(9)-C(15)-C(11) 103.2(2) C(9)-C(15)-C(14) 115.5(2) C(11)-C(15)-C(14) 106.9(2) C(9)-C(15)-H(15) 110.3 C(11)-C(15)-H(15) 110.3 C(14)-C(15)-H(15) 110.3 C(201)-O(201)-C(213) 111.2(2) O(201)-C(201)-C(202) 106.3(2) O(201)-C(201)-H(20A) 110.5 C(202)-C(201)-H(20A) 110.5 O(201)-C(201)-H(20B) 110.5 C(202)-C(201)-H(20B) 110.5 H(20A)-C(201)-H(20B) 108.7 O(205)-C(202)-C(203) 112.6(2) O(205)-C(202)-C(214) 105.2(2) C(203)-C(202)-C(214) 114.1(2) O(205)-C(202)-C(201) 110.0(2) C(203)-C(202)-C(201) 111.9(2) C(214)-C(202)-C(201) 102.3(2) C(208)-C(203)-C(204) 119.6(3) C(208)-C(203)-C(202) 120.8(3) C(204)-C(203)-C(202) 119.5(2) O(204)-C(204)-C(203) 122.1(3) O(204)-C(204)-C(205) 120.6(3) C(203)-C(204)-C(205) 117.3(3) C(202)-O(205)-H(05O) 108(3) C(204)-C(205)-C(206) 111.3(3) C(204)-C(205)-H(20C) 109.4 C(206)-C(205)-H(20C) 109.4 C(204)-C(205)-H(20D) 109.4 C(206)-C(205)-H(20D) 109.4 H(20C)-C(205)-H(20D) 108.0 93 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(207)-C(206)-C(205) 109.4(3) C(207)-C(206)-C(216) 110.6(6) C(205)-C(206)-C(216) 110.3(8) C(207)-C(206)-C(16B) 121.8(11) C(205)-C(206)-C(16B) 112.4(12) C(207)-C(206)-H(206) 108.8 C(205)-C(206)-H(206) 108.8 C(216)-C(206)-H(206) 108.8 C(217)-C(216)-C(218) 123.2(8) C(217)-C(216)-C(206) 126.9(9) C(218)-C(216)-C(206) 109.7(9) C(216)-C(217)-H(21A) 120.0 C(216)-C(217)-H(21B) 120.0 H(21A)-C(217)-H(21B) 120.0 C(216)-C(218)-H(21C) 109.5 C(216)-C(218)-H(21D) 109.5 H(21C)-C(218)-H(21D) 109.5 C(216)-C(218)-H(21E) 109.5 H(21C)-C(218)-H(21E) 109.5 H(21D)-C(218)-H(21E) 109.5 C(17B)-C(16B)-C(18B) 122.7(14) C(17B)-C(16B)-C(206) 127.2(15) C(18B)-C(16B)-C(206) 110.1(12) C(16B)-C(17B)-H(17C) 120.0 C(16B)-C(17B)-H(17D) 120.0 H(17C)-C(17B)-H(17D) 120.0 C(16B)-C(18B)-H(18D) 109.5 C(16B)-C(18B)-H(18E) 109.5 H(18D)-C(18B)-H(18E) 109.5 C(16B)-C(18B)-H(18F) 109.5 H(18D)-C(18B)-H(18F) 109.5 H(18E)-C(18B)-H(18F) 109.5 C(208)-C(207)-C(206) 112.5(3) C(208)-C(207)-H(20E) 109.1 C(206)-C(207)-H(20E) 109.1 C(208)-C(207)-H(20F) 109.1 94 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(206)-C(207)-H(20F) 109.1 H(20E)-C(207)-H(20F) 107.8 C(203)-C(208)-C(209) 120.8(3) C(203)-C(208)-C(207) 123.9(3) C(209)-C(208)-C(207) 115.3(2) C(208)-C(209)-C(210) 111.5(2) C(208)-C(209)-C(215) 116.4(2) C(210)-C(209)-C(215) 103.7(2) C(208)-C(209)-H(209) 108.3 C(210)-C(209)-H(209) 108.3 C(215)-C(209)-H(209) 108.3 O(203)-C(210)-O(202) 121.5(3) O(203)-C(210)-C(209) 128.4(3) O(202)-C(210)-C(209) 110.1(2) C(210)-O(202)-C(211) 111.3(2) O(202)-C(211)-C(212) 110.8(2) O(202)-C(211)-C(215) 105.3(2) C(212)-C(211)-C(215) 106.4(2) O(202)-C(211)-H(211) 111.4 C(212)-C(211)-H(211) 111.4 C(215)-C(211)-H(211) 111.4 C(211)-C(212)-C(213) 106.5(2) C(211)-C(212)-H(21F) 110.4 C(213)-C(212)-H(21F) 110.4 C(211)-C(212)-H(21G) 110.4 C(213)-C(212)-H(21G) 110.4 H(21F)-C(212)-H(21G) 108.6 O(201)-C(213)-C(219) 106.9(2) O(201)-C(213)-C(212) 110.2(2) C(219)-C(213)-C(212) 112.9(2) O(201)-C(213)-C(214) 105.9(2) C(219)-C(213)-C(214) 114.8(2) C(212)-C(213)-C(214) 105.9(2) C(213)-C(219)-H(21H) 109.5 C(213)-C(219)-H(21I) 109.5 H(21H)-C(219)-H(21I) 109.5 95 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(213)-C(219)-H(21J) 109.5 H(21H)-C(219)-H(21J) 109.5 H(21I)-C(219)-H(21J) 109.5 C(202)-C(214)-C(215) 116.6(2) C(202)-C(214)-C(213) 104.1(2) C(215)-C(214)-C(213) 107.3(2) C(202)-C(214)-H(214) 109.5 C(215)-C(214)-H(214) 109.5 C(213)-C(214)-H(214) 109.5 C(211)-C(215)-C(209) 103.4(2) C(211)-C(215)-C(214) 106.6(2) C(209)-C(215)-C(214) 115.6(2) C(211)-C(215)-H(215) 110.3 C(209)-C(215)-H(215) 110.3 C(214)-C(215)-H(215) 110.3 96 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.2.5 Anisotropic displacement parameters (Å2x 103) for compound 31. The anisotropic displacement factor exponent takes the form: -2p2[h2 a*2U11 + ... + 2hka* b* U12] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ O(1) 16(1) 38(1) 28(1) 5(1) 2(1) 1(1) C(1) 20(1) 29(1) 27(1) 2(1) 8(1) 3(1) C(2) 17(1) 23(1) 24(1) -3(1) 1(1) 2(1) O(4) 73(2) 36(1) 21(1) -1(1) 9(1) 7(1) C(3) 20(1) 26(1) 23(1) -1(1) 2(1) 3(1) C(4) 46(2) 33(2) 23(2) 0(1) 3(1) 9(1) O(5) 32(1) 32(1) 22(1) -6(1) -3(1) -2(1) C(5) 86(3) 38(2) 22(2) 6(1) 5(2) 24(2) C(6) 63(2) 26(1) 31(2) 4(1) 16(2) 10(1) C(16) 91(3) 26(2) 40(2) 9(1) 34(2) 15(2) C(17) 78(3) 34(2) 66(3) 16(2) 29(2) 22(2) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 97 C(18) 122(4) 28(2) 56(3) -5(2) 12(3) 5(2) C(7) 36(2) 24(1) 24(1) 0(1) 6(1) 7(1) C(8) 20(1) 24(1) 23(1) 1(1) 4(1) 4(1) C(9) 22(1) 21(1) 20(1) -3(1) 4(1) 2(1) C(10) 26(1) 23(1) 17(1) -4(1) 0(1) -2(1) O(2) 22(1) 27(1) 25(1) 1(1) -1(1) -4(1) O(3) 32(1) 28(1) 29(1) -1(1) 0(1) -11(1) C(11) 21(1) 25(1) 24(1) 1(1) 2(1) -3(1) C(12) 22(1) 25(1) 30(1) 6(1) 1(1) 1(1) C(13) 16(1) 24(1) 30(1) 1(1) 2(1) 1(1) C(19) 36(2) 24(1) 36(2) -3(1) 3(1) 7(1) C(14) 13(1) 21(1) 26(1) -2(1) 2(1) -2(1) C(15) 15(1) 24(1) 23(1) 1(1) 5(1) 0(1) O(201) 15(1) 28(1) 34(1) 1(1) 1(1) -2(1) C(201) 15(1) 22(1) 29(1) -4(1) -1(1) 1(1) C(202) 19(1) 24(1) 24(1) -6(1) 1(1) 1(1) O(204) 80(2) 31(1) 26(1) -5(1) -6(1) -8(1) C(203) 18(1) 27(1) 26(1) -5(1) 3(1) 0(1) C(204) 42(2) 32(2) 27(2) -6(1) 4(1) -1(1) O(205) 28(1) 24(1) 25(1) -7(1) 4(1) 2(1) C(205) 75(3) 41(2) 25(2) -6(1) 15(2) -19(2) C(206) 69(2) 30(2) 35(2) -2(1) 13(2) -14(2) C(216) 91(9) 37(4) 30(4) 1(3) 11(5) -22(5) C(217) 93(5) 33(3) 40(5) -2(3) 5(4) -28(3) C(218) 137(11) 47(5) 42(5) 12(4) -9(6) -33(6) C(16B) 55(8) 27(6) 31(10) -7(5) 19(7) -6(5) C(17B) 74(8) 23(5) 37(8) 3(5) 5(6) -4(5) C(18B) 64(7) 40(6) 46(11) -2(6) 13(6) -14(5) C(207) 51(2) 30(2) 28(2) -7(1) 14(1) -16(1) C(208) 22(1) 29(1) 27(1) -5(1) 6(1) -5(1) C(209) 24(1) 26(1) 26(1) -8(1) 5(1) -7(1) C(210) 26(1) 28(1) 23(1) -10(1) 3(1) -3(1) O(202) 24(1) 28(1) 29(1) -6(1) 7(1) -4(1) O(203) 35(1) 32(1) 33(1) -6(1) 6(1) 6(1) C(211) 24(1) 31(1) 24(1) -2(1) 4(1) -3(1) C(212) 29(2) 29(1) 30(2) 1(1) 4(1) 0(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 98 C(213) 17(1) 26(1) 30(1) -2(1) 1(1) 1(1) C(219) 31(2) 26(1) 35(2) -2(1) 2(1) 4(1) C(214) 13(1) 26(1) 28(1) -3(1) 3(1) 2(1) C(215) 14(1) 34(1) 23(1) -3(1) 1(1) -3(1) ______________________________________________________________________________ Table A2.2.6 Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2x 103) for compound 31. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(1A) 2639 6024 9321 30 H(1B) 3134 6730 9741 30 H(5O) 7220(80) 6480(20) 10400(20) 44 H(5A) 7560 4399 10747 59 H(5B) 9804 4590 10147 59 H(6) 4990 4252 9408 47 H(17A) 9729 2815 9838 70 H(17B) 10427 3540 10223 70 H(18A) 6176 2647 8896 103 H(18B) 5949 3212 8160 103 H(18C) 4068 3181 8950 103 H(7A) 9259 4451 8409 34 H(7B) 6510 4343 7988 34 H(9) 7784 5301 7161 25 H(11) 6153 6537 6143 28 H(12A) 5394 7489 6830 31 H(12B) 2680 7184 6857 31 H(19A) 3242 7993 8372 48 H(19B) 6172 8012 8317 48 H(19C) 4989 7715 9190 48 H(14) 8444 6953 8456 24 H(15) 9028 6316 7275 25 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 99 H(20A) -2911 4014 4381 27 H(20B) -3424 3505 3572 27 H(05O) 470(70) 3231(19) 2813(19) 38 H(20C) 1691 5144 1776 56 H(20D) 4115 5005 2416 56 H(206) -267 5613 3006 53 H(21A) 4833 6962 3000 67 H(21B) 5195 6371 3738 67 H(21C) 1823 6910 1799 114 H(21D) -453 6450 1987 114 H(21E) 1719 6194 1398 114 H(17C) 762 7033 1986 54 H(17D) -1387 6504 2191 54 H(18D) 5558 6145 2350 75 H(18E) 5239 6381 3366 75 H(18F) 4839 6877 2542 75 H(20E) 4252 5450 4069 43 H(20F) 1709 5710 4422 43 H(209) 2872 4896 5578 30 H(211) 1333 3899 6941 31 H(21F) -2168 3099 6461 35 H(21G) 602 2838 6645 35 H(21H) -1373 1976 5350 46 H(21I) 1543 2086 5461 46 H(21J) 140 2127 4480 46 H(214) 3061 3121 4755 27 H(215) 3952 3868 5802 29 ________________________________________________________________________________ Table A2.2.7 Torsion angles [°] for compound 31. ________________________________________________________________ C(13)-O(1)-C(1)-C(2) -31.1(3) O(1)-C(1)-C(2)-O(5) 121.4(2) O(1)-C(1)-C(2)-C(3) -115.2(2) O(1)-C(1)-C(2)-C(14) 8.2(3) O(5)-C(2)-C(3)-C(8) -145.2(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(14)-C(2)-C(3)-C(8) -24.7(4) C(1)-C(2)-C(3)-C(8) 91.5(3) O(5)-C(2)-C(3)-C(4) 41.3(3) C(14)-C(2)-C(3)-C(4) 161.9(2) C(1)-C(2)-C(3)-C(4) -82.0(3) C(8)-C(3)-C(4)-O(4) -167.8(3) C(2)-C(3)-C(4)-O(4) 5.9(5) C(8)-C(3)-C(4)-C(5) 13.0(5) C(2)-C(3)-C(4)-C(5) -173.4(3) O(4)-C(4)-C(5)-C(6) 138.4(4) C(3)-C(4)-C(5)-C(6) -42.3(5) C(4)-C(5)-C(6)-C(16) -176.3(3) C(4)-C(5)-C(6)-C(7) 59.0(4) C(5)-C(6)-C(16)-C(17) -18.4(5) C(7)-C(6)-C(16)-C(17) 105.1(4) C(5)-C(6)-C(16)-C(18) 161.7(4) C(7)-C(6)-C(16)-C(18) -74.9(5) C(16)-C(6)-C(7)-C(8) -175.7(3) C(5)-C(6)-C(7)-C(8) -48.4(4) C(4)-C(3)-C(8)-C(9) 175.2(3) C(2)-C(3)-C(8)-C(9) 1.8(4) C(4)-C(3)-C(8)-C(7) -2.0(4) C(2)-C(3)-C(8)-C(7) -175.3(3) C(6)-C(7)-C(8)-C(3) 21.0(4) C(6)-C(7)-C(8)-C(9) -156.4(3) C(3)-C(8)-C(9)-C(15) 26.5(4) C(7)-C(8)-C(9)-C(15) -156.1(2) C(3)-C(8)-C(9)-C(10) -93.3(3) C(7)-C(8)-C(9)-C(10) 84.1(3) C(8)-C(9)-C(10)-O(3) -35.0(4) C(15)-C(9)-C(10)-O(3) -162.5(3) C(8)-C(9)-C(10)-O(2) 146.4(2) C(15)-C(9)-C(10)-O(2) 18.9(3) O(3)-C(10)-O(2)-C(11) 174.3(2) C(9)-C(10)-O(2)-C(11) -7.0(3) C(10)-O(2)-C(11)-C(12) -122.5(2) 100 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(10)-O(2)-C(11)-C(15) -7.7(3) O(2)-C(11)-C(12)-C(13) 87.4(3) C(15)-C(11)-C(12)-C(13) -27.5(3) C(1)-O(1)-C(13)-C(12) 152.7(2) C(1)-O(1)-C(13)-C(19) -82.4(3) C(1)-O(1)-C(13)-C(14) 40.8(3) C(11)-C(12)-C(13)-O(1) -78.7(3) C(11)-C(12)-C(13)-C(19) 157.9(2) C(11)-C(12)-C(13)-C(14) 30.3(3) O(1)-C(13)-C(14)-C(2) -33.9(2) C(12)-C(13)-C(14)-C(2) -146.4(2) C(19)-C(13)-C(14)-C(2) 86.8(3) O(1)-C(13)-C(14)-C(15) 91.6(2) C(12)-C(13)-C(14)-C(15) -21.0(3) C(19)-C(13)-C(14)-C(15) -147.8(2) O(5)-C(2)-C(14)-C(13) -100.7(2) C(3)-C(2)-C(14)-C(13) 136.3(2) C(1)-C(2)-C(14)-C(13) 15.8(3) O(5)-C(2)-C(14)-C(15) 142.1(2) C(3)-C(2)-C(14)-C(15) 19.1(3) C(1)-C(2)-C(14)-C(15) -101.5(2) C(8)-C(9)-C(15)-C(11) -145.6(2) C(10)-C(9)-C(15)-C(11) -21.9(3) C(8)-C(9)-C(15)-C(14) -29.4(3) C(10)-C(9)-C(15)-C(14) 94.3(2) O(2)-C(11)-C(15)-C(9) 18.7(3) C(12)-C(11)-C(15)-C(9) 136.6(2) O(2)-C(11)-C(15)-C(14) -103.5(2) C(12)-C(11)-C(15)-C(14) 14.4(3) C(13)-C(14)-C(15)-C(9) -110.1(2) C(2)-C(14)-C(15)-C(9) 6.6(3) C(13)-C(14)-C(15)-C(11) 4.0(3) C(2)-C(14)-C(15)-C(11) 120.7(2) C(213)-O(201)-C(201)-C(202) 20.2(3) O(201)-C(201)-C(202)-O(205) 80.4(3) O(201)-C(201)-C(202)-C(203) -153.6(2) 101 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(201)-C(201)-C(202)-C(214) -31.0(3) O(205)-C(202)-C(203)-C(208) -154.0(3) C(214)-C(202)-C(203)-C(208) -34.2(4) C(201)-C(202)-C(203)-C(208) 81.4(3) O(205)-C(202)-C(203)-C(204) 29.6(4) C(214)-C(202)-C(203)-C(204) 149.4(3) C(201)-C(202)-C(203)-C(204) -95.0(3) C(208)-C(203)-C(204)-O(204) -171.4(3) C(202)-C(203)-C(204)-O(204) 5.0(5) C(208)-C(203)-C(204)-C(205) 8.8(5) C(202)-C(203)-C(204)-C(205) -174.8(3) O(204)-C(204)-C(205)-C(206) 142.0(4) C(203)-C(204)-C(205)-C(206) -38.2(5) C(204)-C(205)-C(206)-C(207) 57.7(5) C(204)-C(205)-C(206)-C(216) 179.6(7) C(204)-C(205)-C(206)-C(16B) -163.7(9) C(207)-C(206)-C(216)-C(217) 9(2) C(205)-C(206)-C(216)-C(217) -112(2) C(207)-C(206)-C(216)-C(218) -165.5(10) C(205)-C(206)-C(216)-C(218) 73.3(13) C(207)-C(206)-C(16B)-C(17B) -128(3) C(205)-C(206)-C(16B)-C(17B) 99(3) C(207)-C(206)-C(16B)-C(18B) 55(2) C(205)-C(206)-C(16B)-C(18B) -78(2) C(205)-C(206)-C(207)-C(208) -48.7(4) C(216)-C(206)-C(207)-C(208) -170.3(8) C(16B)-C(206)-C(207)-C(208) 177.4(11) C(204)-C(203)-C(208)-C(209) 178.9(3) C(202)-C(203)-C(208)-C(209) 2.5(4) C(204)-C(203)-C(208)-C(207) 0.5(5) C(202)-C(203)-C(208)-C(207) -175.9(3) C(206)-C(207)-C(208)-C(203) 20.7(5) C(206)-C(207)-C(208)-C(209) -157.8(3) C(203)-C(208)-C(209)-C(210) -89.1(3) C(207)-C(208)-C(209)-C(210) 89.5(3) C(203)-C(208)-C(209)-C(215) 29.6(4) 102 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(207)-C(208)-C(209)-C(215) -151.8(3) C(208)-C(209)-C(210)-O(203) -42.0(4) C(215)-C(209)-C(210)-O(203) -168.1(3) C(208)-C(209)-C(210)-O(202) 136.9(2) C(215)-C(209)-C(210)-O(202) 10.8(3) O(203)-C(210)-O(202)-C(211) -175.8(2) C(209)-C(210)-O(202)-C(211) 5.2(3) C(210)-O(202)-C(211)-C(212) -133.8(2) C(210)-O(202)-C(211)-C(215) -19.2(3) O(202)-C(211)-C(212)-C(213) 86.5(3) C(215)-C(211)-C(212)-C(213) -27.5(3) C(201)-O(201)-C(213)-C(219) -123.5(2) C(201)-O(201)-C(213)-C(212) 113.4(2) C(201)-O(201)-C(213)-C(214) -0.7(3) C(211)-C(212)-C(213)-O(201) -89.9(3) C(211)-C(212)-C(213)-C(219) 150.6(2) C(211)-C(212)-C(213)-C(214) 24.2(3) O(205)-C(202)-C(214)-C(215) 156.8(2) C(203)-C(202)-C(214)-C(215) 32.9(3) C(201)-C(202)-C(214)-C(215) -88.3(3) O(205)-C(202)-C(214)-C(213) -85.2(2) C(203)-C(202)-C(214)-C(213) 150.8(2) C(201)-C(202)-C(214)-C(213) 29.7(3) O(201)-C(213)-C(214)-C(202) -18.9(3) C(219)-C(213)-C(214)-C(202) 98.8(3) C(212)-C(213)-C(214)-C(202) -136.0(2) O(201)-C(213)-C(214)-C(215) 105.3(2) C(219)-C(213)-C(214)-C(215) -137.0(2) C(212)-C(213)-C(214)-C(215) -11.8(3) O(202)-C(211)-C(215)-C(209) 24.6(3) C(212)-C(211)-C(215)-C(209) 142.2(2) O(202)-C(211)-C(215)-C(214) -97.7(2) C(212)-C(211)-C(215)-C(214) 19.9(3) C(208)-C(209)-C(215)-C(211) -144.1(2) C(210)-C(209)-C(215)-C(211) -21.2(3) C(208)-C(209)-C(215)-C(214) -27.9(3) 103 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(210)-C(209)-C(215)-C(214) 94.9(3) C(202)-C(214)-C(215)-C(211) 111.3(3) C(213)-C(214)-C(215)-C(211) -4.9(3) C(202)-C(214)-C(215)-C(209) -3.0(3) C(213)-C(214)-C(215)-C(209) -119.2(3) 104 ________________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.2.8 Hydrogen bonds for compound 31 [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ O(5)-H(5O)...O(4) 0.83(3) 2.04(3) 2.710(3) 138(4) C(5)-H(5A)...O(204)#1 0.99 2.59 3.299(4) 128.6 C(9)-H(9)...O(202)#2 1.00 2.65 3.542(3) 149.2 C(9)-H(9)...O(203)#2 1.00 2.64 3.406(3) 133.5 C(12)-H(12A)...O(205)#3 0.99 2.43 3.342(3) 153.7 C(14)-H(14)...O(1)#2 1.00 2.37 3.119(3) 130.8 C(15)-H(15)...O(1)#2 1.00 2.65 3.288(3) 121.6 O(205)-H(05O)...O(204) 0.82(3) 1.95(3) 2.640(3) 141(4) C(209)-H(209)...O(3) 1.00 2.60 3.206(3) 119.2 C(211)-H(211)...O(3) 1.00 2.56 3.146(3) 117.5 C(214)-H(214)...O(201)#2 1.00 2.29 3.178(3) 147.0 C(215)-H(215)...O(202)#2 1.00 2.61 3.542(3) 154.9 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x+1,y,z+1 #2 x+1,y,z #3 -x+1,y+1/2,-z+1 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.3 105 X-RAY CRYSTAL STRUCTURE OF COMPOUND 33 Figure A2.3.1 X-ray crystal structure of compound 33. Table A2.3.2 Crystal data and structure refinement for compound 33. Empirical formula C19H22O6 Formula weight 346.36 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P212121 Unit cell dimensions a = 6.0176(4) Å a= 90°. b = 12.9933(17) Å b= 90°. c = 20.752(2) Å g = 90°. Volume 1622.6(3) Å3 Z 4 Density (calculated) 1.418 Mg/m3 Absorption coefficient 0.874 mm-1 F(000) 736 Crystal size 0.300 x 0.300 x 0.050 mm3 Theta range for data collection 4.014 to 74.419°. Index ranges -7<=h<=7, -14<=k<=16, -25<=l<=22 Reflections collected 17915 Independent reflections 3315 [R(int) = 0.0964] Completeness to theta = 67.679° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7538 and 0.4675 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3315 / 1 / 231 Goodness-of-fit on F2 1.068 Final R indices [I>2sigma(I)] R1 = 0.0516, wR2 = 0.1264 R indices (all data) R1 = 0.0594, wR2 = 0.1320 Absolute structure parameter 0.02(14) Extinction coefficient n/a Largest diff. peak and hole 0.457 and -0.323 e.Å-3 106 Table A2.3.3. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for compound 33. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ O(1) 2960(4) 4788(2) 8897(1) 25(1) O(2) 1892(4) 6270(2) 8370(1) 27(1) C(1) 2981(6) 5314(2) 8307(2) 21(1) C(2) 1690(5) 4607(2) 7847(2) 19(1) O(3) 633(4) 5051(2) 7295(1) 23(1) C(3) 2389(5) 4301(2) 7184(2) 19(1) C(4) 4363(5) 4811(2) 6862(2) 20(1) O(4) 5136(5) 5596(2) 7076(1) 30(1) C(5) 5223(5) 4335(2) 6245(2) 23(1) C(6) 3506(6) 3683(2) 5891(2) 22(1) C(16) 1575(6) 4278(3) 5608(2) 23(1) C(17) 1223(6) 5275(3) 5695(2) 29(1) C(18) 80(7) 3656(3) 5173(2) 33(1) C(7) 2766(6) 2818(2) 6349(2) 22(1) C(8) 1674(5) 3218(2) 6976(2) 18(1) C(9) 2147(5) 2494(2) 7547(2) 18(1) C(10) 4520(5) 2638(2) 7789(2) 19(1) O(5) 4575(4) 2656(2) 8443(1) 23(1) O(6) 6185(4) 2784(2) 7481(1) 23(1) C(11) 2371(6) 2430(2) 8699(2) 24(1) C(12) 1785(6) 3126(3) 9261(2) 27(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 107 C(13) 1006(6) 4139(2) 8956(2) 24(1) C(19) -769(7) 4696(3) 9340(2) 31(1) C(14) 314(5) 3881(2) 8254(2) 20(1) C(15) 800(5) 2712(2) 8150(2) 20(1) ________________________________________________________________________________ Table A2.3.4 Bond lengths [Å] and angles [°] for compound 33. _____________________________________________________ O(1)-C(1) 1.403(4) O(1)-C(13) 1.452(4) O(2)-C(1) 1.410(4) O(2)-H(2O) 0.85(3) C(1)-C(2) 1.536(5) C(1)-H(1) 1.0000 C(2)-O(3) 1.432(4) C(2)-C(3) 1.492(5) C(2)-C(14) 1.513(4) O(3)-C(3) 1.456(4) C(3)-C(4) 1.516(4) C(3)-C(8) 1.533(4) C(4)-O(4) 1.206(4) C(4)-C(5) 1.512(5) C(5)-C(6) 1.525(5) C(5)-H(5A) 0.9900 C(5)-H(5B) 0.9900 C(6)-C(16) 1.514(5) C(6)-C(7) 1.538(4) C(6)-H(6) 1.0000 C(16)-C(17) 1.325(5) C(16)-C(18) 1.510(5) C(17)-H(17A) 0.9500 C(17)-H(17B) 0.9500 C(18)-H(18A) 0.9800 C(18)-H(18B) 0.9800 C(18)-H(18C) 0.9800 C(7)-C(8) 1.547(5) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(7)-H(7A) 0.9900 C(7)-H(7B) 0.9900 C(8)-C(9) 1.540(4) C(8)-H(8) 1.0000 C(9)-C(15) 1.518(5) C(9)-C(10) 1.525(4) C(9)-H(9) 1.0000 C(10)-O(6) 1.203(4) C(10)-O(5) 1.358(4) O(5)-C(11) 1.458(4) C(11)-C(12) 1.519(5) C(11)-C(15) 1.524(5) C(11)-H(11) 1.0000 C(12)-C(13) 1.534(5) C(12)-H(12A) 0.9900 C(12)-H(12B) 0.9900 C(13)-C(19) 1.516(5) C(13)-C(14) 1.552(5) C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800 C(14)-C(15) 1.563(4) C(14)-H(14) 1.0000 C(15)-H(15) 1.0000 C(1)-O(1)-C(13) 111.3(3) C(1)-O(2)-H(2O) 116(4) O(1)-C(1)-O(2) 110.1(3) O(1)-C(1)-C(2) 104.3(2) O(2)-C(1)-C(2) 110.5(3) O(1)-C(1)-H(1) 110.6 O(2)-C(1)-H(1) 110.6 C(2)-C(1)-H(1) 110.6 O(3)-C(2)-C(3) 59.7(2) O(3)-C(2)-C(14) 117.1(3) C(3)-C(2)-C(14) 120.2(3) O(3)-C(2)-C(1) 118.7(2) 108 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(3)-C(2)-C(1) 126.1(3) C(14)-C(2)-C(1) 107.6(3) C(2)-O(3)-C(3) 62.2(2) O(3)-C(3)-C(2) 58.11(19) O(3)-C(3)-C(4) 110.2(2) C(2)-C(3)-C(4) 120.8(3) O(3)-C(3)-C(8) 117.1(3) C(2)-C(3)-C(8) 115.2(3) C(4)-C(3)-C(8) 119.8(3) O(4)-C(4)-C(5) 121.8(3) O(4)-C(4)-C(3) 120.6(3) C(5)-C(4)-C(3) 117.6(3) C(4)-C(5)-C(6) 113.8(3) C(4)-C(5)-H(5A) 108.8 C(6)-C(5)-H(5A) 108.8 C(4)-C(5)-H(5B) 108.8 C(6)-C(5)-H(5B) 108.8 H(5A)-C(5)-H(5B) 107.7 C(16)-C(6)-C(5) 115.0(3) C(16)-C(6)-C(7) 113.0(3) C(5)-C(6)-C(7) 107.7(3) C(16)-C(6)-H(6) 106.9 C(5)-C(6)-H(6) 106.9 C(7)-C(6)-H(6) 106.9 C(17)-C(16)-C(18) 120.7(3) C(17)-C(16)-C(6) 124.7(3) C(18)-C(16)-C(6) 114.6(3) C(16)-C(17)-H(17A) 120.0 C(16)-C(17)-H(17B) 120.0 H(17A)-C(17)-H(17B) 120.0 C(16)-C(18)-H(18A) 109.5 C(16)-C(18)-H(18B) 109.5 H(18A)-C(18)-H(18B) 109.5 C(16)-C(18)-H(18C) 109.5 H(18A)-C(18)-H(18C) 109.5 H(18B)-C(18)-H(18C) 109.5 109 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(6)-C(7)-C(8) 113.4(2) C(6)-C(7)-H(7A) 108.9 C(8)-C(7)-H(7A) 108.9 C(6)-C(7)-H(7B) 108.9 C(8)-C(7)-H(7B) 108.9 H(7A)-C(7)-H(7B) 107.7 C(3)-C(8)-C(9) 107.0(2) C(3)-C(8)-C(7) 115.2(3) C(9)-C(8)-C(7) 111.3(2) C(3)-C(8)-H(8) 107.7 C(9)-C(8)-H(8) 107.7 C(7)-C(8)-H(8) 107.7 C(15)-C(9)-C(10) 101.9(3) C(15)-C(9)-C(8) 115.0(2) C(10)-C(9)-C(8) 110.6(3) C(15)-C(9)-H(9) 109.7 C(10)-C(9)-H(9) 109.7 C(8)-C(9)-H(9) 109.7 O(6)-C(10)-O(5) 120.5(3) O(6)-C(10)-C(9) 128.6(3) O(5)-C(10)-C(9) 110.7(3) C(10)-O(5)-C(11) 109.7(3) O(5)-C(11)-C(12) 111.7(3) O(5)-C(11)-C(15) 104.2(3) C(12)-C(11)-C(15) 106.7(3) O(5)-C(11)-H(11) 111.3 C(12)-C(11)-H(11) 111.3 C(15)-C(11)-H(11) 111.3 C(11)-C(12)-C(13) 105.3(3) C(11)-C(12)-H(12A) 110.7 C(13)-C(12)-H(12A) 110.7 C(11)-C(12)-H(12B) 110.7 C(13)-C(12)-H(12B) 110.7 H(12A)-C(12)-H(12B) 108.8 O(1)-C(13)-C(19) 109.7(3) O(1)-C(13)-C(12) 106.6(3) 110 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(19)-C(13)-C(12) 114.1(3) O(1)-C(13)-C(14) 105.3(3) C(19)-C(13)-C(14) 114.0(3) C(12)-C(13)-C(14) 106.5(3) C(13)-C(19)-H(19A) 109.5 C(13)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 C(13)-C(19)-H(19C) 109.5 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 C(2)-C(14)-C(13) 104.1(3) C(2)-C(14)-C(15) 115.3(3) C(13)-C(14)-C(15) 106.8(3) C(2)-C(14)-H(14) 110.1 C(13)-C(14)-H(14) 110.1 C(15)-C(14)-H(14) 110.1 C(9)-C(15)-C(11) 103.8(3) C(9)-C(15)-C(14) 113.3(3) C(11)-C(15)-C(14) 104.3(3) C(9)-C(15)-H(15) 111.6 C(11)-C(15)-H(15) 111.6 C(14)-C(15)-H(15) 111.6 111 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A.2.3.5 Anisotropic displacement parameters (Å2x 103) for V22369. The anisotropic displacement factor exponent takes the form: -2p2[h2 a*2U11 + ... + 2 h k a* b* U12]. ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ O(1) 22(1) 23(1) 31(1) 0(1) -3(1) -1(1) O(2) 29(1) 15(1) 37(1) -2(1) 5(1) 1(1) C(1) 20(2) 16(1) 28(2) 1(1) 2(1) -1(1) C(2) 14(1) 14(1) 28(2) 0(1) -2(1) 2(1) O(3) 21(1) 15(1) 31(1) 2(1) -2(1) 5(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 112 C(3) 16(1) 14(1) 26(2) -1(1) -1(1) 4(1) C(4) 19(1) 11(1) 30(2) 0(1) 0(1) 1(1) O(4) 33(1) 20(1) 37(1) -2(1) 4(1) -11(1) C(5) 17(2) 21(1) 30(2) -2(1) 2(1) -2(1) C(6) 21(2) 17(1) 28(2) -2(1) 1(1) 2(1) C(16) 20(2) 23(2) 27(2) 3(1) 0(1) 0(1) C(17) 28(2) 23(2) 35(2) 3(1) -1(2) 5(1) C(18) 28(2) 31(2) 41(2) -2(2) -10(2) 1(2) C(7) 20(2) 15(1) 30(2) -3(1) -2(1) 1(1) C(8) 13(1) 12(1) 29(2) 1(1) -4(1) 0(1) C(9) 13(1) 11(1) 30(2) 0(1) -2(1) 0(1) C(10) 18(2) 11(1) 29(2) 0(1) -4(1) 1(1) O(5) 16(1) 25(1) 29(1) 1(1) -4(1) 2(1) O(6) 14(1) 21(1) 35(1) 0(1) -2(1) 1(1) C(11) 20(2) 19(1) 32(2) 4(1) 1(1) 2(1) C(12) 24(2) 27(2) 30(2) 2(1) 0(1) 5(1) C(13) 17(2) 23(2) 32(2) -1(1) -1(1) -1(1) C(19) 29(2) 30(2) 34(2) -1(1) 4(2) 4(2) C(14) 14(1) 17(1) 29(2) -1(1) 0(1) 2(1) C(15) 14(1) 15(1) 32(2) 2(1) -1(1) 0(1) ______________________________________________________________________________ Table A.2.3.6 Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2x 10 3) for compound 33. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(2O) 2370(80) 6750(30) 8130(20) 40 H(1) 4540 5413 8152 26 H(5A) 6525 3900 6348 27 H(5B) 5732 4892 5955 27 H(6) 4294 3346 5523 26 H(17A) 18 5605 5483 34 H(17B) 2174 5660 5970 34 H(18A) -1046 4107 4981 50 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 113 H(18B) -653 3115 5424 50 H(18C) 968 3340 4830 50 H(7A) 4076 2395 6463 26 H(7B) 1696 2369 6121 26 H(8) 30 3230 6906 22 H(9) 1920 1763 7411 22 H(11) 2228 1687 8818 28 H(12A) 3099 3242 9539 32 H(12B) 587 2817 9525 32 H(19A) -202 4850 9772 46 H(19B) -2089 4258 9375 46 H(19C) -1163 5338 9121 46 H(14) -1304 4024 8191 24 H(15) -594 2293 8164 24 ________________________________________________________________________________ Table A2.3.7 Torsion angles [°] for compound 33. ________________________________________________________________ C(13)-O(1)-C(1)-O(2) 90.2(3) C(13)-O(1)-C(1)-C(2) -28.4(3) O(1)-C(1)-C(2)-O(3) 155.4(3) O(2)-C(1)-C(2)-O(3) 37.1(4) O(1)-C(1)-C(2)-C(3) -132.8(3) O(2)-C(1)-C(2)-C(3) 108.9(3) O(1)-C(1)-C(2)-C(14) 19.5(3) O(2)-C(1)-C(2)-C(14) -98.8(3) C(14)-C(2)-O(3)-C(3) -110.9(3) C(1)-C(2)-O(3)-C(3) 117.3(3) C(2)-O(3)-C(3)-C(4) -114.4(3) C(2)-O(3)-C(3)-C(8) 104.2(3) C(14)-C(2)-C(3)-O(3) 105.6(3) C(1)-C(2)-C(3)-O(3) -105.2(3) O(3)-C(2)-C(3)-C(4) 95.9(3) C(14)-C(2)-C(3)-C(4) -158.5(3) C(1)-C(2)-C(3)-C(4) -9.3(4) O(3)-C(2)-C(3)-C(8) -107.4(3) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(14)-C(2)-C(3)-C(8) -1.8(4) C(1)-C(2)-C(3)-C(8) 147.3(3) O(3)-C(3)-C(4)-O(4) 50.0(4) C(2)-C(3)-C(4)-O(4) -14.2(5) C(8)-C(3)-C(4)-O(4) -169.8(3) O(3)-C(3)-C(4)-C(5) -126.5(3) C(2)-C(3)-C(4)-C(5) 169.3(3) C(8)-C(3)-C(4)-C(5) 13.7(4) O(4)-C(4)-C(5)-C(6) -153.6(3) C(3)-C(4)-C(5)-C(6) 22.9(4) C(4)-C(5)-C(6)-C(16) 67.8(4) C(4)-C(5)-C(6)-C(7) -59.2(3) C(5)-C(6)-C(16)-C(17) -5.8(5) C(7)-C(6)-C(16)-C(17) 118.4(4) C(5)-C(6)-C(16)-C(18) 171.0(3) C(7)-C(6)-C(16)-C(18) -64.8(4) C(16)-C(6)-C(7)-C(8) -67.3(3) C(5)-C(6)-C(7)-C(8) 60.9(3) O(3)-C(3)-C(8)-C(9) -109.9(3) C(2)-C(3)-C(8)-C(9) -44.4(3) C(4)-C(3)-C(8)-C(9) 112.5(3) O(3)-C(3)-C(8)-C(7) 125.8(3) C(2)-C(3)-C(8)-C(7) -168.7(3) C(4)-C(3)-C(8)-C(7) -11.8(4) C(6)-C(7)-C(8)-C(3) -25.9(4) C(6)-C(7)-C(8)-C(9) -147.9(3) C(3)-C(8)-C(9)-C(15) 64.2(3) C(7)-C(8)-C(9)-C(15) -169.1(2) C(3)-C(8)-C(9)-C(10) -50.4(3) C(7)-C(8)-C(9)-C(10) 76.2(3) C(15)-C(9)-C(10)-O(6) -161.4(3) C(8)-C(9)-C(10)-O(6) -38.7(4) C(15)-C(9)-C(10)-O(5) 14.2(3) C(8)-C(9)-C(10)-O(5) 136.8(3) O(6)-C(10)-O(5)-C(11) -178.4(3) C(9)-C(10)-O(5)-C(11) 5.6(3) 114 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(10)-O(5)-C(11)-C(12) -137.9(3) C(10)-O(5)-C(11)-C(15) -23.1(3) O(5)-C(11)-C(12)-C(13) 80.8(3) C(15)-C(11)-C(12)-C(13) -32.4(3) C(1)-O(1)-C(13)-C(19) -97.2(3) C(1)-O(1)-C(13)-C(12) 138.8(3) C(1)-O(1)-C(13)-C(14) 25.9(3) C(11)-C(12)-C(13)-O(1) -91.1(3) C(11)-C(12)-C(13)-C(19) 147.7(3) C(11)-C(12)-C(13)-C(14) 20.9(3) O(3)-C(2)-C(14)-C(13) -141.2(3) C(3)-C(2)-C(14)-C(13) 149.8(3) C(1)-C(2)-C(14)-C(13) -4.4(3) O(3)-C(2)-C(14)-C(15) 102.3(3) C(3)-C(2)-C(14)-C(15) 33.2(4) C(1)-C(2)-C(14)-C(15) -121.0(3) O(1)-C(13)-C(14)-C(2) -11.7(3) C(19)-C(13)-C(14)-C(2) 108.6(3) C(12)-C(13)-C(14)-C(2) -124.6(3) O(1)-C(13)-C(14)-C(15) 110.7(3) C(19)-C(13)-C(14)-C(15) -129.0(3) C(12)-C(13)-C(14)-C(15) -2.3(3) C(10)-C(9)-C(15)-C(11) -27.0(3) C(8)-C(9)-C(15)-C(11) -146.6(3) C(10)-C(9)-C(15)-C(14) 85.5(3) C(8)-C(9)-C(15)-C(14) -34.1(4) O(5)-C(11)-C(15)-C(9) 31.1(3) C(12)-C(11)-C(15)-C(9) 149.4(3) O(5)-C(11)-C(15)-C(14) -87.8(3) C(12)-C(11)-C(15)-C(14) 30.6(3) C(2)-C(14)-C(15)-C(9) -14.2(4) C(13)-C(14)-C(15)-C(9) -129.3(3) C(2)-C(14)-C(15)-C(11) 98.0(3) C(13)-C(14)-C(15)-C(11) -17.1(3) ________________________________________________________________ 115 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 116 Table A2.3.8 Hydrogen bonds for compound 33 [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ O(2)-H(2O)...O(6)#1 0.85(3) 2.04(3) 2.887(3) 173(5) C(1)-H(1)...O(4) 1.00 2.27 2.887(4) 118.5 C(9)-H(9)...O(4)#2 1.00 2.56 3.060(4) 110.5 C(14)-H(14)...O(6)#3 1.00 2.65 3.283(4) 121.0 C(15)-H(15)...O(6)#3 1.00 2.48 3.106(4) 119.9 ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 -x+1,y+1/2,-z+3/2 #2 -x+1,y-1/2,-z+3/2 #3 x-1,y,z Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 A2.4 117 X-RAY CRYSTAL STRUCTURE OF COMPOUND 1 Figure A2.4.1 X-ray crystal structure of compound 1. Table A2.4.2 Crystal data and structure refinement for compound 1. Empirical formula C19H22O5 Formula weight 330.36 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P212121 Unit cell dimensions a = 10.5762(8) Å a= 90°. b = 10.7831(11) Å b= 90°. c = 13.8667(15) Å g = 90°. Volume 1581.4(3) Å3 Z 4 Density (calculated) 1.388 Mg/m3 Absorption coefficient 0.820 mm-1 F(000) 704 Crystal size 0.300 x 0.150 x 0.100 mm3 Theta range for data collection 5.196 to 74.559°. Index ranges -13<=h<=13, -13<=k<=13, -17<=l<=17 Reflections collected 25211 Independent reflections 3240 [R(int) = 0.0504] Completeness to theta = 67.679° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7538 and 0.6138 Refinement method Full-matrix least-squares on F2 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 Data / restraints / parameters 3240 / 0 / 219 Goodness-of-fit on F2 1.045 Final R indices [I>2sigma(I)] R1 = 0.0306, wR2 = 0.0791 R indices (all data) R1 = 0.0324, wR2 = 0.0803 Absolute structure parameter -0.02(5) Extinction coefficient n/a Largest diff. peak and hole 0.756 and -0.188 e.Å-3 118 Table A.2.4.3 Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2x 103) for compound 1. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ C(1) 5052(2) 2908(2) 4104(1) 15(1) O(1) 4757(1) 1706(1) 4235(1) 18(1) O(2) 4325(1) 3602(1) 3709(1) 20(1) C(2) 6325(2) 3210(2) 4553(1) 13(1) C(3) 6950(2) 1924(2) 4738(1) 15(1) C(4) 5836(2) 997(2) 4568(1) 19(1) C(5) 6253(2) 118(2) 3766(2) 22(1) C(6) 7333(2) 769(2) 3257(2) 18(1) C(16) 8121(2) -69(2) 2615(2) 23(1) O(3) 6826(1) 1824(1) 2717(1) 16(1) C(7) 8042(2) 1445(2) 4071(1) 16(1) C(8) 8704(2) 2428(2) 3493(1) 14(1) O(4) 9762(1) 2839(1) 3584(1) 18(1) C(9) 7777(2) 2781(2) 2698(1) 14(1) C(10) 7158(2) 4030(2) 2932(1) 14(1) C(11) 7806(2) 5120(2) 2425(1) 18(1) O(5) 8613(2) 4967(2) 1815(1) 27(1) C(12) 7301(2) 6387(2) 2684(2) 23(1) C(13) 7166(2) 6591(2) 3779(1) 18(1) C(17) 8417(2) 6814(2) 4290(1) 18(1) C(18) 9522(2) 6846(2) 3848(2) 26(1) C(19) 8333(2) 7048(3) 5360(2) 31(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 119 C(14) 6397(2) 5522(2) 4216(1) 17(1) C(15) 7033(2) 4260(2) 4032(1) 12(1) ________________________________________________________________________________ Table A2.4.4 Bond lengths [Å] and angles [°] for compound 1. _____________________________________________________ C(1)-O(2) 1.205(2) C(1)-O(1) 1.345(2) C(1)-C(2) 1.519(2) O(1)-C(4) 1.450(2) C(2)-C(15) 1.538(2) C(2)-C(3) 1.558(2) C(2)-H(2) 1.0000 C(3)-C(4) 1.562(2) C(3)-C(7) 1.567(2) C(3)-H(3) 1.0000 C(4)-C(5) 1.526(3) C(4)-H(4) 1.0000 C(5)-C(6) 1.514(3) C(5)-H(5A) 0.9900 C(5)-H(5B) 0.9900 C(6)-O(3) 1.464(2) C(6)-C(16) 1.519(3) C(6)-C(7) 1.538(2) C(16)-H(16A) 0.9800 C(16)-H(16B) 0.9800 C(16)-H(16C) 0.9800 O(3)-C(9) 1.440(2) C(7)-C(8) 1.502(3) C(7)-H(7) 1.0000 C(8)-O(4) 1.210(2) C(8)-C(9) 1.524(2) C(9)-C(10) 1.532(2) C(9)-H(9) 1.0000 C(10)-C(11) 1.532(3) C(10)-C(15) 1.552(2) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(10)-H(10) 1.0000 C(11)-O(5) 1.213(3) C(11)-C(12) 1.510(3) C(12)-C(13) 1.540(3) C(12)-H(12A) 0.9900 C(12)-H(12B) 0.9900 C(13)-C(17) 1.521(3) C(13)-C(14) 1.536(2) C(13)-H(13) 1.0000 C(17)-C(18) 1.320(3) C(17)-C(19) 1.507(3) C(18)-H(18A) 0.9500 C(18)-H(18B) 0.9500 C(19)-H(19A) 0.9800 C(19)-H(19B) 0.9800 C(19)-H(19C) 0.9800 C(14)-C(15) 1.539(2) C(14)-H(14A) 0.9900 C(14)-H(14B) 0.9900 C(15)-H(15) 1.0000 O(2)-C(1)-O(1) 120.78(16) O(2)-C(1)-C(2) 128.23(17) O(1)-C(1)-C(2) 110.92(15) C(1)-O(1)-C(4) 111.62(14) C(1)-C(2)-C(15) 113.41(14) C(1)-C(2)-C(3) 104.63(14) C(15)-C(2)-C(3) 121.73(15) C(1)-C(2)-H(2) 105.2 C(15)-C(2)-H(2) 105.2 C(3)-C(2)-H(2) 105.2 C(2)-C(3)-C(4) 102.99(14) C(2)-C(3)-C(7) 120.57(14) C(4)-C(3)-C(7) 104.81(14) C(2)-C(3)-H(3) 109.3 C(4)-C(3)-H(3) 109.3 120 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(7)-C(3)-H(3) 109.3 O(1)-C(4)-C(5) 108.84(16) O(1)-C(4)-C(3) 107.71(15) C(5)-C(4)-C(3) 106.80(15) O(1)-C(4)-H(4) 111.1 C(5)-C(4)-H(4) 111.1 C(3)-C(4)-H(4) 111.1 C(6)-C(5)-C(4) 105.65(15) C(6)-C(5)-H(5A) 110.6 C(4)-C(5)-H(5A) 110.6 C(6)-C(5)-H(5B) 110.6 C(4)-C(5)-H(5B) 110.6 H(5A)-C(5)-H(5B) 108.7 O(3)-C(6)-C(5) 108.81(15) O(3)-C(6)-C(16) 111.30(17) C(5)-C(6)-C(16) 114.30(16) O(3)-C(6)-C(7) 100.67(14) C(5)-C(6)-C(7) 104.23(16) C(16)-C(6)-C(7) 116.41(15) C(6)-C(16)-H(16A) 109.5 C(6)-C(16)-H(16B) 109.5 H(16A)-C(16)-H(16B) 109.5 C(6)-C(16)-H(16C) 109.5 H(16A)-C(16)-H(16C) 109.5 H(16B)-C(16)-H(16C) 109.5 C(9)-O(3)-C(6) 108.09(13) C(8)-C(7)-C(6) 99.87(14) C(8)-C(7)-C(3) 115.22(14) C(6)-C(7)-C(3) 103.31(14) C(8)-C(7)-H(7) 112.5 C(6)-C(7)-H(7) 112.5 C(3)-C(7)-H(7) 112.5 O(4)-C(8)-C(7) 129.37(16) O(4)-C(8)-C(9) 125.40(17) C(7)-C(8)-C(9) 105.15(15) O(3)-C(9)-C(8) 104.91(14) 121 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(3)-C(9)-C(10) 109.12(14) C(8)-C(9)-C(10) 109.92(14) O(3)-C(9)-H(9) 110.9 C(8)-C(9)-H(9) 110.9 C(10)-C(9)-H(9) 110.9 C(11)-C(10)-C(9) 112.76(15) C(11)-C(10)-C(15) 111.51(14) C(9)-C(10)-C(15) 112.63(14) C(11)-C(10)-H(10) 106.5 C(9)-C(10)-H(10) 106.5 C(15)-C(10)-H(10) 106.5 O(5)-C(11)-C(12) 122.55(18) O(5)-C(11)-C(10) 122.04(18) C(12)-C(11)-C(10) 115.25(16) C(11)-C(12)-C(13) 113.38(15) C(11)-C(12)-H(12A) 108.9 C(13)-C(12)-H(12A) 108.9 C(11)-C(12)-H(12B) 108.9 C(13)-C(12)-H(12B) 108.9 H(12A)-C(12)-H(12B) 107.7 C(17)-C(13)-C(14) 113.26(15) C(17)-C(13)-C(12) 113.68(16) C(14)-C(13)-C(12) 109.33(16) C(17)-C(13)-H(13) 106.7 C(14)-C(13)-H(13) 106.7 C(12)-C(13)-H(13) 106.7 C(18)-C(17)-C(19) 120.33(19) C(18)-C(17)-C(13) 123.89(17) C(19)-C(17)-C(13) 115.75(17) C(17)-C(18)-H(18A) 120.0 C(17)-C(18)-H(18B) 120.0 H(18A)-C(18)-H(18B) 120.0 C(17)-C(19)-H(19A) 109.5 C(17)-C(19)-H(19B) 109.5 H(19A)-C(19)-H(19B) 109.5 C(17)-C(19)-H(19C) 109.5 122 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 H(19A)-C(19)-H(19C) 109.5 H(19B)-C(19)-H(19C) 109.5 C(13)-C(14)-C(15) 111.50(14) C(13)-C(14)-H(14A) 109.3 C(15)-C(14)-H(14A) 109.3 C(13)-C(14)-H(14B) 109.3 C(15)-C(14)-H(14B) 109.3 H(14A)-C(14)-H(14B) 108.0 C(2)-C(15)-C(14) 111.08(14) C(2)-C(15)-C(10) 112.70(14) C(14)-C(15)-C(10) 109.96(14) C(2)-C(15)-H(15) 107.6 C(14)-C(15)-H(15) 107.6 C(10)-C(15)-H(15) 107.6 123 _____________________________________________________________ Symmetry transformations used to generate equivalent atoms: Table A2.4.5 Anisotropic displacement parameters (Å2x 103) for compound 1. The anisotropic displacement factor exponent takes the form: -2p2[h2 a*2U11 + ... + 2hka* b* U12] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ C(1) 12(1) 16(1) 16(1) -1(1) 2(1) -1(1) O(1) 14(1) 17(1) 24(1) 1(1) -2(1) -3(1) O(2) 13(1) 21(1) 25(1) 2(1) -2(1) 0(1) C(2) 11(1) 14(1) 14(1) -1(1) 0(1) -1(1) C(3) 15(1) 14(1) 15(1) 3(1) -2(1) -2(1) C(4) 17(1) 15(1) 23(1) 3(1) -1(1) -3(1) C(5) 22(1) 12(1) 31(1) -1(1) -2(1) -3(1) C(6) 17(1) 13(1) 23(1) -2(1) -4(1) 2(1) C(16) 22(1) 17(1) 30(1) -8(1) -2(1) 4(1) O(3) 16(1) 14(1) 20(1) -2(1) -4(1) 1(1) C(7) 15(1) 12(1) 20(1) 0(1) -3(1) 2(1) C(8) 13(1) 15(1) 15(1) -4(1) 1(1) 3(1) O(4) 13(1) 21(1) 21(1) -1(1) 1(1) 0(1) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 124 C(9) 13(1) 15(1) 15(1) -1(1) 1(1) 1(1) C(10) 15(1) 14(1) 14(1) 1(1) -2(1) 1(1) C(11) 23(1) 18(1) 14(1) 1(1) -6(1) -4(1) O(5) 34(1) 28(1) 19(1) 1(1) 6(1) -9(1) C(12) 31(1) 15(1) 22(1) 4(1) -7(1) -1(1) C(13) 20(1) 10(1) 22(1) 0(1) -1(1) 2(1) C(17) 23(1) 13(1) 19(1) -1(1) 1(1) -4(1) C(18) 23(1) 32(1) 22(1) -1(1) 2(1) -7(1) C(19) 30(1) 43(1) 20(1) -7(1) 4(1) -13(1) C(14) 15(1) 12(1) 24(1) -2(1) 2(1) 1(1) C(15) 12(1) 10(1) 15(1) 0(1) 1(1) -1(1) ______________________________________________________________________________ Table A2.4.6 Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2x 103) for compound 1. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(2) 6125 3546 5208 16 H(3) 7227 1873 5426 18 H(4) 5630 530 5171 22 H(5A) 6539 -683 4038 26 H(5B) 5548 -40 3313 26 H(16A) 7579 -441 2120 35 H(16B) 8505 -726 3006 35 H(16C) 8789 419 2304 35 H(7) 8646 890 4419 19 H(9) 8209 2808 2057 17 H(10) 6278 3990 2671 17 H(12A) 6463 6498 2377 27 H(12B) 7875 7026 2419 27 H(13) 6650 7361 3865 21 H(18A) 10269 7018 4204 31 H(18B) 9569 6697 3174 31 H(19A) 9168 7282 5606 47 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 125 H(19B) 8045 6293 5686 47 H(19C) 7732 7721 5482 47 H(14A) 5539 5518 3931 20 H(14B) 6309 5653 4920 20 H(15) 7907 4300 4307 15 __________________________________________________________________ Table A2.4.7 Torsion angles [°] for compound 1. ________________________________________________________________ O(2)-C(1)-O(1)-C(4) 170.04(17) C(2)-C(1)-O(1)-C(4) -12.7(2) O(2)-C(1)-C(2)-C(15) -32.8(3) O(1)-C(1)-C(2)-C(15) 150.19(15) O(2)-C(1)-C(2)-C(3) -167.69(18) O(1)-C(1)-C(2)-C(3) 15.34(18) C(1)-C(2)-C(3)-C(4) -11.45(17) C(15)-C(2)-C(3)-C(4) -141.55(16) C(1)-C(2)-C(3)-C(7) 104.72(17) C(15)-C(2)-C(3)-C(7) -25.4(2) C(1)-O(1)-C(4)-C(5) -110.86(17) C(1)-O(1)-C(4)-C(3) 4.6(2) C(2)-C(3)-C(4)-O(1) 4.94(18) C(7)-C(3)-C(4)-O(1) -122.00(15) C(2)-C(3)-C(4)-C(5) 121.72(16) C(7)-C(3)-C(4)-C(5) -5.22(19) O(1)-C(4)-C(5)-C(6) 97.19(17) C(3)-C(4)-C(5)-C(6) -18.8(2) C(4)-C(5)-C(6)-O(3) -70.65(19) C(4)-C(5)-C(6)-C(16) 164.26(16) C(4)-C(5)-C(6)-C(7) 36.09(19) C(5)-C(6)-O(3)-C(9) 148.40(15) C(16)-C(6)-O(3)-C(9) -84.77(18) C(7)-C(6)-O(3)-C(9) 39.23(17) O(3)-C(6)-C(7)-C(8) -45.18(16) C(5)-C(6)-C(7)-C(8) -157.91(14) C(16)-C(6)-C(7)-C(8) 75.23(19) Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 O(3)-C(6)-C(7)-C(3) 73.87(16) C(5)-C(6)-C(7)-C(3) -38.85(17) C(16)-C(6)-C(7)-C(3) -165.72(16) C(2)-C(3)-C(7)-C(8) 19.3(2) C(4)-C(3)-C(7)-C(8) 134.58(16) C(2)-C(3)-C(7)-C(6) -88.48(18) C(4)-C(3)-C(7)-C(6) 26.75(18) C(6)-C(7)-C(8)-O(4) -140.98(19) C(3)-C(7)-C(8)-O(4) 109.1(2) C(6)-C(7)-C(8)-C(9) 35.84(17) C(3)-C(7)-C(8)-C(9) -74.05(17) C(6)-O(3)-C(9)-C(8) -16.76(18) C(6)-O(3)-C(9)-C(10) -134.50(15) O(4)-C(8)-C(9)-O(3) 163.79(17) C(7)-C(8)-C(9)-O(3) -13.19(18) O(4)-C(8)-C(9)-C(10) -79.0(2) C(7)-C(8)-C(9)-C(10) 104.00(16) O(3)-C(9)-C(10)-C(11) -148.60(14) C(8)-C(9)-C(10)-C(11) 96.86(17) O(3)-C(9)-C(10)-C(15) 84.12(17) C(8)-C(9)-C(10)-C(15) -30.4(2) C(9)-C(10)-C(11)-O(5) 8.8(2) C(15)-C(10)-C(11)-O(5) 136.61(18) C(9)-C(10)-C(11)-C(12) -175.67(15) C(15)-C(10)-C(11)-C(12) -47.8(2) O(5)-C(11)-C(12)-C(13) -136.2(2) C(10)-C(11)-C(12)-C(13) 48.2(2) C(11)-C(12)-C(13)-C(17) 75.3(2) C(11)-C(12)-C(13)-C(14) -52.4(2) C(14)-C(13)-C(17)-C(18) 126.3(2) C(12)-C(13)-C(17)-C(18) 0.7(3) C(14)-C(13)-C(17)-C(19) -55.8(2) C(12)-C(13)-C(17)-C(19) 178.63(18) C(17)-C(13)-C(14)-C(15) -68.85(19) C(12)-C(13)-C(14)-C(15) 59.0(2) C(1)-C(2)-C(15)-C(14) 71.42(19) 126 Appendix 2 – X-Ray Crystallography Reports Relevant to Chapter 1 C(3)-C(2)-C(15)-C(14) -162.34(15) C(1)-C(2)-C(15)-C(10) -52.49(19) C(3)-C(2)-C(15)-C(10) 73.76(19) C(13)-C(14)-C(15)-C(2) 174.67(15) C(13)-C(14)-C(15)-C(10) -59.88(18) C(11)-C(10)-C(15)-C(2) 177.06(14) C(9)-C(10)-C(15)-C(2) -55.01(19) C(11)-C(10)-C(15)-C(14) 52.53(18) C(9)-C(10)-C(15)-C(14) -179.54(14) ________________________________________________________________ 127 Chapter 2 – Total Synthesis of Lycojapomine A & B 128 CHAPTER 2 Total Synthesis of Lycojapomine A & B † 2.1 INTRODUCTION The synthesis of alkaloids has been an ongoing area of research and innovation in organic chemistry over the past century.1,2 Dating back to landmark studies, such as Robinson’s highly efficient synthesis of tropinone in 1917,3,4 chemists have enabled access to these natural products by providing new and concise strategies for their synthesis. This is not only due to their intriguing and abundant chemical structures, but more importantly their biological activity and use in medicine.5 Among them, the Lycopodium alkaloids represent one of the largest alkaloid families, possessing anti-inflammatory and neuroprotective effects.6 Two unusual members of this class, Lycojapomine A (44) and Lycojapomine B (45) were recently isolated from the club-moss Lycopodium japonicum, the extracts of which are used in traditional Chinese medicine (Figure 2.2.1, A).7,8 Ongoing research into the medicinal efficacy of these extracts and the low abundance of 44 and 45 (0.000017 - 0.000018% isolation yield) necessitates the synthesis of these key chemical components to enable further biological investigations. From a structural perspective, both 44 and 45 possess unprecedented molecular frameworks, with Lycojapomine A (44) bearing an unusual aza[3.3.3]propellane motif and Lycojapomine B (45) having an isomeric structural relationship. † Portions of this chapter have been reproduced and modified with permission from Gross, B. M.; Stoltz, B. M. J. Am. Chem. Soc. 2025, 147, 20200–20204. © 2025 American Chemical Society. Chapter 2 – Total Synthesis of Lycojapomine A & B 2.2 129 RETROSYNTHETIC STRATEGY: PYRROLE DEAROMATIZATION Due to the aliphatic nature of these caged ring systems, they are often traced back to saturated starting materials. This retrosynthetic logic has been well established, however necessitates the synthesis of complicated sp3-rich precursors.9 These often include complex stereochemical information and necessitate protection of reactive functional groups, inflating the step-count and decreasing synthetic efficiency. Instead, we sought to design a route for 44 and 45 from a simple sp2-hybridized aromatic heterocycle, streamlining the synthesis and avoiding unnecessary protecting groups.10 Figure 2.2.1 (A) Structure of Lycojapomine A (44) and B (45) and proposed retrosynthetic elements. (B) Concept of reductive functionalization of a pyrrole. A H H H H N N N H O OH N 44 R’ TMS CO2Me R H O N O N H OH H N O Pyrrole 45 Lycojapomine alkaloids • isolated from Chinese club moss Lycopodium japonicum • inhibition of TGF-𝛽1-induced fibronectin deposition (anti-renal fibrosis) A Simple heterocyclic starting material Dearomative strategy B • No protecting groups used • 11 steps for A & B Divergent aldol reaction B Sequential pyrrole dearomatization and functionalization N R R2 1e- radical 3 2e- ionic R2 3R H H N 2 Dearomatization reductive C–C bond formation N R R1 “Enamine reactivity” 4R N R stereocenter-guided diasteroselectivity R1 N H O Alkene oxidation unified Lycojapomine framework Retrosynthetically, we identified the central pyrrolidine ring of 44 and 45 as a linchpin that could be derived from a heterocyclic pyrrole precursor. While dearomatization of other nitrogen-containing heterocycles (i.e. pyridines, quinolines, isoquinolines) is well established through hydrogenation methodologies,11 controlled dearomatization of electron- Chapter 2 – Total Synthesis of Lycojapomine A & B 130 rich pyrroles represents an underdeveloped challenge.12,13 Additionally, execution of this strategy would require not only saturation, but also introduction of additional substituents to build the fully substituted pyrrolidine and surrounding three-dimensional nitrogen and carbon framework. To begin our synthetic approach, we planned a radical addition to initially break the aromaticity of the pyrrole (Figure 2.2.1, B). Upon successful addition, the first two stereocenters are generated, revealing a dihydropyrrole. The chiral information would then be transferred to establish the remaining five stereocenters with the correct relative configuration. We identified the intermediate as having a reactive functional group, similar to an enamine, and envisioned leveraging it for an ionic two-electron annulation. Upon successfully setting the stereocenters around the pyrrolidine ring system, we imagined divergent aldol reactions to access both 44 and 45, controlling bond formation and stereoselectivity to access the two alkaloids. 2.3 PHOTOCATALYTIC RADICAL ADDITION The substituted pyrrole 46 was prepared in two steps from commercial materials in 74% yield (Figure 2.3.1).14 Aminal formation with 46 under acidic conditions proved challenging, preferentially alkylating at the C2 carbon. We instead proceeded using carbonyl diimidazole and commercially available N-methyl-b-alanine to form urea 47 in 66% yield. We imagined that the urea motif would additionally aid in providing electronwithdrawing character to facilitate radical addition and provide the necessary stabilization of the product as the resulting enamide. While carboxylic acid 47 could be envisioned as a primary radical precursor in its own right, we elected to convert it to the N-hydroxy Chapter 2 – Total Synthesis of Lycojapomine A & B 131 phthalimide ester 48 in 72% yield, completing the synthesis of two potential radical precursors. Figure 2.3.1 Synthesis of starting material 48. O OMe CDI, DMAP then N-methyl-𝜷-alanine i-Pr2EtN OMe 2 steps from commercial 66% yield (30% recovered 46) 46 CO2H N MeCN, 80 ºC N H O O O N 47 OMe NHPhth DIC 72% yield O N CH2Cl2 O N ONPhth 48 Building on reports published by Wang and co-workers, we proceeded to investigate radical formation from the carboxylic acid 47 and reductive addition to generate 49 (Table 2.3.2).15 We were quickly faced with the challenge of generating the primary radical, which is significantly high in energy and short-lived. Upon irradiation of the carboxylic acid 47 with an Iridium-photocatalyst and K2HPO4, we isolated trace amounts of 50, which conceptually proved that radical addition is feasible (Entry 1).16 Upon employing Ironcatalyzed Ligand-to-Metal charge transfer,17 we were able to observe increased radical formation, and isolation of 50, along with decarboxylated product 51 in 50% overall yield (Entry 2). While decarboxylation was successful, we were unable to access dearomatized product 49. This led us to investigate the redox active N-hydroxy phthalimide ester 48, which can be activated at much lower reduction potentials, possibly circumventing the undesired oxidation and rearomatization to pyrrole 50. Irradiation with photocatalyst Eosin Y,18 as well transition-metal induced decarboxylation initially failed to yield any improvement19 (Entry 3-4). The first successful reactivity was observed using Ru(bpy)3 and Hantzsch Ester (HE) as reductant to isolate product 49 in 11% yield (Entry 5).20 Increasing the equivalents of HE Chapter 2 – Total Synthesis of Lycojapomine A & B 132 did not improve these results, instead resulting in premature reduction of the primary radical to give increased yields of 51. Upon evaluating solvents, we observed that the formation of 6 preferentially occurred in polar solvents, such as DMSO or NMP. While Et3N did not yield any improvement, we hypothesized that the redox potential of the photocatalyst determined the reaction pathway, potentially contributing to oxidation of the generated radical and rearomatization to 50.21 We therefore opted to investigate Ir(ppy)3, which possesses one of the lower oxidation potentials of commercially known photocatalysts. As put forth, irradiation with Ir(ppy)3 increased the yield substantially (Entry 17). While dimethyl sulfoxide proved to be poorly miscible with iPr2EtN, we proceeded with NMP, delivering the product 49 in 81% yield (Entry 18). Table 2.3.2 Optimization of dearomative intramolecular radical addition. O O OMe O 47, R = H 48, R = NPhth Catalyst Base N H N solvent O N O OMe + N O OR O OMe 49 OMe + N N O H N O 50 N 51 Entry Catalyst Additive Solvent 49 e 50 e 51 e 1 (R=H) 2a Ir[dF(CF3)ppy)]2(dtbbpy)PF6 K2HPO4 TRIP disulfide (5 mol%), Na2CO3 (0.1 equiv) DMF DCE: H2O (1:1) - 5 25 25 DIPEA (2.5 equiv) Zn (50 equiv), LiCl (20 equiv), 50ºC HE (1.5 equiv), DIPEA (2.0 equiv) HE (1.5 equiv) DIPEA (2.0 equiv) DIPEA (2.0 equiv) DIPEA (2.0 equiv) DIPEA (2.0 equiv) DIPEA (2.0 equiv) DIPEA (2.0 equiv) Et3N (2.0 equiv) Et3N (10.0 equiv) Et3N (5.0 equiv) DIPEA (10.0 equiv) DIPEA (10.0 equiv) DIPEA (10.0 equiv) CH2Cl2 DMF CH2Cl2 CH2Cl2 CH2Cl2 MeCN DMF DMA DMSO NMP DMSO DMSO DMSO DMSO DMSO NMP 11 1 10 8 11 18 15 10 14 25 42 d 53 d 81 10 6 8 7 12 24 32 23 17 24 20 35 33 10 15 22 11 10 12 11 13 5 8 5 4 2 3 Fe(NO3)3 • 9 H2O (5 mol %) di(2-picolyl)amine (5.1 mol %) b 3c (R=NPhth) Eosin Y (10 mol %) Ni(acac)2 (2.0 equiv) 4c 5c Ru(bpy)3(PF6)2 c 6 Ru(bpy)3(PF6)2 c 7 Ru(bpy)3(PF6)2 c 8 Ru(bpy)3(PF6)2 c 9 Ru(bpy)3(PF6)2 c 10 Ru(bpy)3(PF6)2 c 11 Ru(bpy)3(PF6)2 c 12 Ru(bpy)3(PF6)2 13c Ru(bpy)3(PF6)2 14c Ru(bpy)3(PF6)2 15c Ir(dtbbpy)(ppy)2PF6 16c Ir(dtbbpy)(ppy)2PF6 17c Ir(ppy)3 18c Ir(ppy)3 Reactions were performed with 10 mg of starting material. Yield determined by 1H-NMR with internal standard. aIrratiated with purple LED (390 nm); bIrratiated with CFL; c1 mol % catalyst used, irratiated with blue LED (450 nm); d200 mg scale, isolated yield, d.r. = 3:1; 1 eYield given in Reactions were %. performed with 10 mg of starting material. Yield determined by H-NMR with internal standard. aIrradiated with purple LED (390 nm); bIrradiated with CFL; c1 mol % catalyst used, irradiated with blue LED (450 nm); d200 mg scale, isolated yield, d.r. = 3:1; eYield given in %. Chapter 2 – Total Synthesis of Lycojapomine A & B 2.4 133 ANNULATION CASCADE TO FORM THE CORE STRUCTURE With the optimized conditions in hand, we could access dihydropyrrole 49 in high yield, setting the first two stereocenters of our synthesis (Scheme 2.4.1). Scheme 2.4.1 Synthetic sequence to access the Lycojapomine core structure. OMe OMe Ir(ppy)3 (1 mol %) DIPEA O N N 48 H N CH2Cl2, –20 ºC N O 81% yield OMe N HCl•MeHN OMe i-PrMgCl H NMP, blue LED ONPhth N O O O O N O 64% yield 49 52 d.r. = 3:1 d.r. = 10:1 TMS Br TMS 53 O OMe N Br 4 steps from commercial H TMS 54 THF, 0 ºC N N MgCl i-PrMgCl•LiCl AgBF4 (10 mol %) O N N O HFIP H 42% yield (over two steps) O 55 TMS 5-endo-dig cyclization O N H Aza-silyl-Prins O N H O N H SmI2 2-Naphthalenethiol N THF, –10 ºC H 59 O O 83% yield O H H [Ag] N H O – [Ag] – [TMS] O 58 C7 H N N H N 57 56 O [Ag] N [Ag] N TMS TMS H H OH 60 1) LiAlH4 THF, 55 ºC 2) DMP, NaHCO3 CH2Cl2 77% yield (over two steps) H H N N H O 61 We observed preferential formation of the desired trans product (3:1 d.r.), which could be enriched upon isomerization under basic conditions. This proved to be inconsequential as Weinreb amide formation with i-PrMgCl formed 52 with a greater than 10:1 d.r. in 64% yield. With a functional electrophile for 1,2-addition (i.e. Weinreb amide 52), we Chapter 2 – Total Synthesis of Lycojapomine A & B 134 envisioned introducing the alkyl chain to construct the cyclohexene moiety via an intramolecular annulation. While several different pathways could be imagined to construct the cyclohexene present in 59, we were faced with several constraints (Figure 2.4.2). Mainly, Diels-Alder reaction would likely provide the wrong double bond isomer, and cyclization of the enamide onto an enone would require an unfavorable 5-endo-trig cyclization. Figure 2.4.2 Potential pathways and considerations for cascade ring annulation. intramolecular Diels-Alder N O H O X H incorrect alkene isomer O H N O H O X H unfavorable 5-endo-trig cyclization H N O N N Enone substrate TMS H Prins reaction N O N H H X N O conjugated alkene formation reduced nucleophilicity N H H H N tailored cascade O H N O N Me3Si O O H O N O N H H O H favorable 5-endo-dig Silyl aza-prins N O H N We therefore devised a tailored cascade, that would begin with constructing intermediate ynone 55 (Scheme 2.4.1). To do so, we utilized dibromide 53 as an alkyne precursor, which we accessed in four steps from commercial materials.22,23 Dibromide 53 could successfully undergo Fritsch-Buttenberg-Wiechell rearrangement, to generate the metalated acetylide in-situ. We then introduced Weinreb amide 52 in the same step leading to nucleophilic addition and production of ynone 55. With the use of n-BuLi, we observed diminished yields of product formation, likely due to the high basicity of the lithium acetylide. Isolating the alkyne before addition proved problematic, as rapid decomposition was observed. The use of the less basic turbo-Grignard (iPrMgCl·LiCl) significantly improved H H Chapter 2 – Total Synthesis of Lycojapomine A & B 135 the reaction profile,24 as 1,2-shift was smoothly induced and addition of the acetylide 54 to form 55 proceeded without the formation of any significant side products. The ynone 55 was unstable upon purification on silica gel, which led to its direct use in the annulation cascade. Having the alkyne preinstalled, we envisioned selective activation with metal p-acids.25 While the use of gold catalysts did not provide any appreciable results, silver salts proved competent in the reaction with ynone 55. Upon employing catalytic AgBF4, the alkyne in 56 can be primed for 5-endo-dig cyclization of the enamide, to reveal iminium ion 57. The formation of the first 5/5 ring fusion is favored as the cis over the strained trans fused 5/5 system, directing the annulation to occur from the top-face of the molecule. Thus, the predominant formation of 57 leads to intramolecular Aza-Prins reaction with the vinyl silane from the same face. With carbocationic intermediate 58 being stabilized by the bsilicon effect, desilylation directs double bond formation to afford 59 with the alkene installed at the desired position. Forging three carbon-carbon bonds and two stereocenters, we isolate 59 as a single diastereomer in an appreciable yield of 42% over two steps from amide 52. The use of hexafluroisopropanol (HFIP) proved essential to facilitate the cascade, acting as a proton source to turn over the catalyst and likely contributing to the stabilization of cationic intermediates. With the tetracyclic core in hand, SmI2 facilitated complete reduction of the cyclopentenone moiety to give 60 in 83% yield,26 delivering the proton at C7 from the desired convex face with excellent diastereoselectivity. Reduction of the urea proceeded with lithium aluminum hydride and oxidation of the cyclopentanol delivered tetracyclic ketone 61 in 77% yield over two steps. Chapter 2 – Total Synthesis of Lycojapomine A & B 2.5 136 DIVERGENT ALDOL REACTION AND COMPLETION OF THE SYNTHESIS With the pendant terminal alkene present in 61, we envisioned chemoselective oxidative cleavage and subsequent aldol reaction, proposing to access both isomers (Lycojapomine A and B) by control of enolate formation. Careful reaction control enabled selective oxidation of the terminal (over the tri-substituted) alkene, but revealed significant instability of the expected aldehyde, which rapidly decomposed. Due to the potential susceptibility of the hexahydro pyrimidine to oxidation, we decided to protonate it as an HCl salt that could be used directly in the subsequent oxidation. Dihydroxylation with OsO4 proceeded to generate the corresponding diol, however concurrent oxidative cleavage only resulted in decomposition. We ultimately succeeded by trapping out the unstable aldehyde as the methanol adduct following ozonolysis, yielding an isolable product, the structure of which is proposed to be 62 (Scheme 2.5.1). By titrating a saturated solution of ozone into the reaction at cryogenic temperatures, we could achieve excellent selectivity to access the oxidized intermediate in high yield.27 Scheme 2.5.1 Oxidative cleavage and divergent aldol reaction to access 44 and 45. kinetic product H H N N H O HCl in Et2O then O3 in CH2Cl2 H MeOH, –78 ºC N N H MeOH, 21 ºC 30 min N 63% yield (over two steps) H O H H OH H N H O 62 thermodynamic product MeOH, 55 ºC 6h OH O Lycojapomine B (45) H KOH 61 H KOH H N N H OH O 57% yield (over two steps) Lycojapomine A (44) Chapter 2 – Total Synthesis of Lycojapomine A & B 137 To complete the synthesis, we attempted a range of aldol reactions of 62. Initially, treatment of 62 with various mild bases (i.e. DBU, Et3N, K2CO3, Cs2CO3 etc.) led to non-specific decomposition. Alternatively, exposing 62 to acid resulted in recovery of starting material. Interestingly, upon exposure to methanolic potassium hydroxide, we can direct clean and selective collapse of 62 to Lycojapomine B (45) in 63% yield over two steps, without observing 44. While different conditions did not lead to the formation of Lycojapomine A (44), we found that simply heating the solution of 62 in KOH/MeOH for an extended period exclusively delivered 44 in 57% yield over two steps, likely proceeding through an aldol/retro-aldol mechanism. In a control experiment, heating a solution of 45 in KOH/MeOH cleanly converted the natural product to its isomer 44. We achieved precise control, funneling aldol product formation to either the kinetic or thermodynamic product, attributing this selectivity to the lower ground-state energy of 44. Overall, we can successfully access both natural products 44 and 45 in excellent yields, highlighting the power of late stage divergency in our retrosynthesis. 2.6 CONCLUSION Previous syntheses of complex alkaloids and related natural products have often relied on aliphatic precursors, that can be tedious to prepare and often necessitate protecting groups to mask reactive functional groups. The retrosynthetic approach that is disclosed instead begins with a sp2-hybridized aromatic nitrogen heterocycle. This strategy is enabled by a photo-induced radical cyclization to selectively dearomatize a pyrrole, manipulating its inherent reactivity. Utilizing the generated enamine, we achieve a silver-catalyzed cyclization cascade to annulate two rings and assemble the core carbon framework in a Chapter 2 – Total Synthesis of Lycojapomine A & B 138 single step. By controlling divergent product formation of a late-stage aldol reaction, we can access both Lycojapomine A and B in 13 steps from commercial starting materials. We believe this concept of sequential pyrrole functionalization can be applied in different settings and enables a new retrosynthetic tool for the synthesis of different members of the Lycopodium alkaloids. 2.7 EXPERIMENTAL SECTION 2.7.1 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.28 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, panisaldehyde, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 μm) was used for flash chromatography. 1H NMR spectra were recorded on Varian Inova 500 MHz and 600 MHz and Bruker 400 MHz spectrometers and are reported relative to residual CHCl3 (δ 7.26 ppm), C6D6 (δ 7.16 ppm) or CD3OD (δ 3.31 ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (125 MHz) and Bruker 400 MHz spectrometers (100 MHz) and are reported relative to CHCl3 (δ 77.16 ppm), C6D6 (δ 128.06 ppm) or CD3OD (δ 49.01 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 Chapter 2 – Total Synthesis of Lycojapomine A & B 13 139 C NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR 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 using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+) mode. 2.7.2 EXPERIMENTAL PROCEDURES MeO2C O H 63 PPh3 CH2Cl2, 21 ºC OMe 64 O NaH TosMIC O THF, 0 ºC OMe N H 46 Ester 64: In a round-bottom flask, Aldehyde 63 (24.4 g, 0.29 mol, 1.0 equiv) was dissolved in CH2Cl2 (1.1 L, 0.25 M) and Methyl(triphenylphosphoranylidene)acetate (106 g, 0.32 mol, 1.1 equiv) was added portionwise. The reaction was stirred for 15 h, after which no more starting material was present as determined by TLC analysis. A mixture of Et2O and hexanes (1:1, 500 mL) was added, upon which a white solid crashed out (O=PPh3). The mixture was filtered, and the filtrate concentrated under reduced pressure. The crude oil was purified by flash column chromatography on silica gel (10% Et2O/hexanes) to yield Ester 64 (38 g, 0.27 mol, 93% yield) as a colorless oil. The spectroscopic data was in accordance with the values previously reported in the literature;29 1H NMR (500 MHz, CDCl3) δ 6.98 (dt, J = 16.0 Hz, 6.5 Hz, 1H), 5.84 (d, J = 16.0 Hz, 1H), 5.79 (ddt, J = 16.5 Chapter 2 – Total Synthesis of Lycojapomine A & B 140 Hz, 10.0 Hz, 6.5 Hz, 1H), 5.05 (dd, J = 16.5 Hz, 2.0 Hz, 1H), 5.00 (dd, J = 10.0 Hz, 2.0 Hz, 1H), 3.72 (s, 3H), 2.31 – 2.29 (m, 2H), 2.24 – 2.21 (m, 2H). Pyrrole 46: In a flame dried round-bottom flask under N2, NaH (60% in mineral oil, 2.86 g, 71.4 mmol, 2.0 equiv) was dissolved in THF (35.7 mL, 1M). The reaction mixture was cooled to 0 °C in an ice bath, and a solution of Ester 64 (5.0 g, 35.7 mmol, 1.0 equiv) and TosMIC (7.3 g, 37.5 mmol, 1.05 equiv) in THF (37.5 mL, 1M) was added semi-dropwise. Upon completion of addition, the reaction was stirred for 30 min and the ice bath removed. After 13 h, the starting material was consumed as determined by TLC analysis and saturated aqueous NaHCO3 was added. The aqueous layer was extracted with EtOAc (3x), the combined organic extracts dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (30% EtOAc/hexanes) and the product 46 (5.1 g, 28.6 mmol, 80% yield) isolated as a pale-yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.45 (brs, 1H), 7.38 (dd, J = 3.2, 2.2 Hz, 1H), 6.56 (s, 1H), 5.89 (ddt, J = 16.9, 10.3, 6.6 Hz, 1H), 5.20 – 4.90 (m, 1H), 3.80 (s, 3H), 2.87 – 2.80 (m, 2H), 2.36 (tdt, J = 7.8, 6.4, 1.4 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 165.9, 139.0, 125.7, 124.7, 117.0, 114.5, 114.1, 50.9, 34.5, 25.7; IR (neat film, NaCl) 3272, 2916, 1686, 1436, 1398, 1338, 1236, 1160, 1090, 918, 743 cm–1; HRMS (ESI+): m/z calc’d for C10H14NO2 [M+H]+: 180.1019, found 180.1020. O OMe CDI, DMAP then N-Methyl propionic acid, DIPEA OMe 46 CO2H N MeCN, 80 ºC N H O O O N 47 OMe NHPhth DIC O N CH2Cl2, 21 ºC O N 48 ONPhth Chapter 2 – Total Synthesis of Lycojapomine A & B 141 Carboxylic acid 47: A round-bottom flask equipped with a reflux condenser was flushed with Argon, and charged with pyrrole 46 (4.82 g, 26.8 mmol, 1.0 equiv). Acetonitrile (107 mL, 0.25 M) was added, followed by CDI (6.54 g, 40.2 mmol, 1.5 equiv) and DMAP (326 mg, 0.1 mmol, 0.1 equiv). The reaction flask was heated to 80 °C for 3 h, after which it was cooled to ambient temperature. N-Methyl propionic acid (5.38 g, 53.6 mmol, 2.0 equiv) and iPr2EtN (4.65 mL, 80.3 mmol, 3.0 equiv) were added and the flask heated to 80 °C for 12 h. The reaction mixture was cooled to ambient temperature, quenched with 1M aqueous HCl and the aqueous layer extracted with EtOAc (3x). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude product was separated from left-over starting material 46 (1.4 g, 8.0 mmol, 30% yield) by flash column chromatography on silica gel (30% EtOAc/hexanes → 1% AcOH/10% MeOH/CH2Cl2) to provide carboxylic acid 47 (5.4 g, 17.5 mmol, 66% yield) which was used in the next step without further purification. The yield for 47 was calculated based on an 80% purity of the crude product as determined by quantitative 1H-NMR with 1,3,5trimethoxybenzene as an internal standard. N-Hydroxy phthalimide ester 48: Crude carboxylic acid 47 (5.9 g, ~80% purity) was placed in a round-bottom flask and dissolved in CH2Cl2 (87 mL, 0.2 M). N-Hydroxy phthalimide (3.1 g, 19.3 mmol, 1.1 equiv) and DMAP (106 mg, 0.87 mmol, 0.05 equiv) were added, after which DIC (3.56 mL, 22.8 mmol, 1.3 equiv) was added semi-dropwise. Upon addition was finished, the reaction mixture was stirred for 15 min, after which it was directly loaded onto a flash column with silica gel for purification (33% EtOAc/hexanes). The N-Hydroxy phthalimide ester 48 (5.7 g, 12.6 mmol, 72% yield) was isolated as a white solid. It is noteworthy to point out that prolonged reaction time led to significant Chapter 2 – Total Synthesis of Lycojapomine A & B 142 decomposition and lower isolated yields of the product 48; 1H NMR (400 MHz, CDCl3) δ1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 5.6, 3.0 Hz, 2H), 7.82 – 7.79 (m, 2H), 7.66 (d, J = 2.4 Hz, 1H), 6.86 (dt, J = 2.1, 1.0 Hz, 1H), 5.87 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.04 (dd, J = 17.1, 1.9 Hz, 1H), 4.97 – 4.93 (m, 1H), 3.86 (t, J = 6.5 Hz, 2H), 3.79 (s, 3H), 3.19 (s, 3H), 3.08 (t, J = 6.5 Hz, 2H), 2.80 (td, J = 7.5, 1.0 Hz, 2H), 2.36 (dd, J = 7.7, 1.4 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 168.1, 164.9, 161.8, 153.7, 138.6, 135.0, 128.9, 127.0, 126.6, 124.2, 119.3, 116.6, 114.8, 51.1, 46.4, 38.9, 33.9, 29.6, 25.6; IR (neat film, NaCl) 2947, 1814, 1787, 1745, 1708, 1520, 1486, 1399, 1371, 1243, 1186, 1150, 1081, 973, 698 cm–1; HRMS (ESI+): m/z calc’d for C23H24N3O7 [M+H]+: 454.1614, found 454.1645. O O OMe O N O N 48 OMe Ir(ppy)3 (1 mol %) DIPEA ONPhth H N NMP, 21 ºC blue LED N O 49 d.r. = 3:1 Dihydropyrrole 49: A 50 mL eggplant-shaped flask was charged with a magnetic stir bar, 48 (200 mg, 0.44 mmol, 1.0 equiv) and Ir(ppy3) (2.9 mg, 0.004 mmol, 1 mol %) and sealed with a rubber septum. The flask was evacuated and backfilled with N2 (3x), after which the solids were dissolved in NMP (8.8 mL, 0.05 M). The solution was degassed by placing the flask under vacuum for 15 min and backfilled with N2. Freshly distilled iPr2EtN (0.77 mL, 4.4 mmol, 10 equiv) was added and the septum secured and covered with electrical tape. The reaction flask was fastened in a Penn PhD Photoreactor M2 with copper wire (~1.5 cm above the light source) and irradiated with blue LEDs for 10h (450 nm, 1000 rpm, 6870 Chapter 2 – Total Synthesis of Lycojapomine A & B 143 fan, 100% LED intensity). The flask was removed from the photoreactor and the solvent removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (33% acetone/hexanes) to deliver the product 49 (94 mg, 0.36 mmol, 81% yield) in a diastereomeric ratio of 3:1 (trans:cis) as a yellow oil. The diastereomers were separated on preparative HPLC (Agilent Zorbax Eclipse XDB-C18 column, 5 µm, 32% MeCN/H2O + 1% AcOH) and assigned based on the NOE as observed by 2D-NOESY NMR analysis. Major diastereomer of 49 (trans): 1 H NMR (600 MHz, CDCl3) δ 6.58 (d, J = 2.0 Hz, 1H), 5.86 – 5.69 (m, 1H), 5.02 (dd, J = 17.2, 1.7 Hz, 1H), 4.96 (ddd, J = 10.2, 1.7, 1.1 Hz, 1H), 4.40 (ddd, J = 11.8, 9.6, 3.4 Hz, 1H), 3.75 (s, 3H), 3.66 – 3.57 (m, 1H), 3.40 (td, J = 12.3, 4.2 Hz, 1H), 3.18 (ddd, J = 12.0, 5.3, 1.8 Hz, 1H), 2.94 (s, 3H), 2.30 – 2.14 (m, 3H), 2.13 – 2.04 (m, 2H), 1.88 (qd, J = 12.5, 5.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 172.5, 151.9, 138.0, 127.0, 116.8, 115.2, 59.7, 57.3, 52.4, 47.4, 34.9, 31.7, 27.9, 26.6; IR (neat film, NaCl) 3346, 2937, 1732, 1536, 1510, 1443, 1405, 1335, 1236, 914, 740 cm–1; HRMS (ESI+): m/z calc’d for C14H21N2O3 [M+H]+: 265.1552, 265.1551 found. Minor diastereomer of 49 (cis): 1 H NMR (400 MHz, CDCl3) δ 6.67 (d, J = 1.8 Hz, 1H), 5.98 – 5.62 (m, 1H), 5.02 (dd, J = 17.1, 1.6 Hz, 1H), 4.96 (d, J = 10.5 Hz, 1H), 4.25 (ddd, J = 12.2, 10.5, 3.5 Hz, 1H), 3.69 (s, 3H), 3.62 (d, J = 10.4 Hz, 1H), 3.35 (td, J = 12.2, 4.2 Hz, 1H), 3.20 (ddd, J = 12.1, 5.3, 2.0 Hz, 1H), 2.92 (s, 3H), 2.28 – 2.13 (m, 3H), 2.08 (dd, J = 12.0, 6.4 Hz, 1H), 2.01 (d, J = 12.8 Hz, 1H), 1.87 (qd, J = 12.4, 5.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 171.3, 151.9, 138.0, 127.9, 117.7, 115.2, 58.6, 54.7, 52.0, 47.5, 34.8, 32.0, 26.9, 24.2; IR (neat Chapter 2 – Total Synthesis of Lycojapomine A & B 144 film, NaCl) 3339, 2922, 1689, 1505, 1452, 1406, 1330, 1249, 1082, 996, 913, 743 cm–1; HRMS (ESI+): m/z calc’d for C14H21N2O3 [M+H]+: 265.1552, 265.1548 found. O O OMe H N H N CH2Cl2, –20 ºC N O OMe N HCl•MeHN OMe i-PrMgCl O N 49 52 d.r. = 3:1 d.r. = 10:1 Amide 52: A flame-dried vial under N2 was charged with ester 49 (278 mg, 1.05 mmol, 1.0 equiv) and HN(Me)OMe·HCl (153 mg, 1.58 mmol, 1.5 equiv). The reactants were dissolved in THF (3.5 mL, 0.3 M) and the vial cooled to –35 °C in an acetonitrile/dry ice bath. A solution of i-PrMgCl (2M in THF, 2.1 mL, 4.2 mmol, 4.0 equiv) was added dropwise and the reaction mixture stirred for 1.5 h. After this time the cooling bath had reached a temperature of –10 °C and the starting material was consumed as determined by TLC analysis. The reaction was quenched by addition of saturated aqueous NH4Cl (0.5 mL), filtered through a plug of Na2SO4 and loaded directly onto a flash column with silica gel for purification (60% acetone/hexanes). The amide 52 (196 mg, 0.67mmol, 64% yield) was isolated as a white film; 1H NMR (400 MHz, C6D6) δ 6.99 (s, 1H), 5.80 – 5.65 (m, 1H), 5.00 (dd, J = 17.1, 1.9 Hz, 1H), 4.96 – 4.91 (m, 1H), 4.40 (ddd, J = 11.6, 9.9, 3.8 Hz, 1H), 3.86 (d, J = 10.1 Hz, 1H), 2.97 (s, 3H), 2.86 (s, 3H), 2.76 (s, 3H), 2.52 (td, J = 12.0, 4.4 Hz, 1H), 2.34 (ddd, J = 11.8, 5.1, 2.0 Hz, 1H), 2.18 – 2.04 (m, 4H), 1.40 – 1.34 (m, 1H), 1.30 (td, J = 12.1, 5.2 Hz, 1H); 13C NMR (101 MHz, C6D6) δ 173.1, 151.6, 138.5, 118.3, 117.2, 115.0, 60.9, 60.8, 58.6, 54.7, 47.0, 34.6, 32.1, 27.7, 27.0; IR (neat film, NaCl) Chapter 2 – Total Synthesis of Lycojapomine A & B 145 2926, 1647, 1504, 1453, 1398, 1078 cm–1; HRMS (ESI+): m/z calc’d for C15H24N3O3 [M+H]+: 294.1818, found 294.1823. nBuLi TMSCl then HCl HO THF TMS CH2Cl2 HO 65 AlMe3 ZrCp2Cl2 TMS HO 66 67 Vinylsilane 67: Vinylsilane 67 was prepared according to literature procedures in two steps from 3-Butin-1-ol 65.30,31 The spectroscopic data for 67 was in accordance with the values previously reported in the literature; 1H NMR (500 MHz, CDCl3) δ 5.30 (s, 1H), 3.71 (t, J = 7.2 Hz, 2H), 2.35 (t, J = 7.2 Hz, 2H), 1.80 (s, 3H), 1.60 (bs, 1H), 0.12 (s, 9H). DMP TMS HO 67 CH2Cl2 TMS O CBr4 PPh3 Zn CH2Cl2 68 Br TMS Br 53 Aldehyde 68: A round-bottom flask was charged with alcohol 67 (948 mg, 6 mmol, 1.0 equiv) and CH2Cl2 (60 mL, 0.1 M). Dess-Martin periodinane (2.8 g, 6.6 mmol, 1.1 equiv) was added portion wise and the reaction stirred for 45 min until the starting material was consumed as determined by TLC analysis. The reaction was concentrated to near dryness under reduced pressure and the crude product filtered over a plug of silica gel eluting with pentane. The solvent was evaporated to near dryness under reduced pressure and the solution of aldehyde 68 was directly used in the next step without further purification. Aldehyde 68 proved to be inherently volatile and was therefore only concentrated under slightly reduced pressure to avoid diminished yields. Chapter 2 – Total Synthesis of Lycojapomine A & B 146 Dibromide 53: A flame-dried round-bottom flask under N2 was charged with Zn powder (780 mg, 12 mmol, 2.0 equiv), carbon tetrabromide (3.97 g, 12 mmol, 2.0 equiv) and PPh3 (3.14 g, 12 mmol, 2.0 equiv). The contents were dissolved in CH2Cl2 (17 mL, 0.35 M) and vigorously stirred for 16 h, upon which the reaction mixture had turned to a pastel light pink color. The aldehyde 68 was added as a solution with CH2Cl2 and the reaction stirred for 2 hours. After the starting material was consumed as determined by TLC analysis, the reaction mixture was diluted with pentanes and flushed over a plug of celite. The solvent was removed under reduced pressure and the crude product purified by flash column chromatography on silica gel (pentane). The dibromide 53 (1.0 g, 3.3 mmol, 55% yield over two steps) was isolated as a colorless oil. Dibromide 53 proved to be volatile under high vacuum and unstable upon extended storage at –20 °C. It was therefore used in the following reaction on the same day; 1H NMR (400 MHz, CDCl3) δ 6.42 (t, J = 7.4 Hz, 1H), 5.25 (q, J = 1.1 Hz, 1H), 2.85 (dd, J = 7.4, 1.3 Hz, 2H), 1.79 (d, J = 1.0 Hz, 3H), 0.11 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 149.9, 136.6, 125.9, 90.0, 45.7, 21.9, 0.1; IR (neat film, NaCl) 2953, 1700, 1427, 1249, 844, 780 cm–1; HRMS (ESI+): m/z calc’d for C9H17Br2Si [M+H]+: 310.9466, found 310.9462. O N H N O TMS OMe Dibromide 53 i-PrMgCl•LiCl THF, 0 ºC N 52 AgBF4 (10 mol %) O N H 55 H N HFIP, 21 ºC N N O H O O 59 Tetracycle 59: A flame-dried vial under N2 was charged with dibromide 53 (231 mg, 0.74 mmol, 1.5 equiv) and THF (1.65 mL, 0.3 M). The vial was placed in an ice bath at 0 °C Chapter 2 – Total Synthesis of Lycojapomine A & B 147 and a solution of iPrMgCl·LiCl (1.3 M in THF, 1.52 mL, 1.98 mmol, 4.0 equiv) was added dropwise. The reaction was stirred for 1 h, after which a solution of starting material 52 (145 mg, 0.49 mmol, 1.0 equiv) in THF (1.5 mL) was added semi-dropwise. The reaction was stirred for an additional hour at 0 °C, after which it was quenched with saturated aqueous NH4Cl (0.5 mL) and warmed to ambient temperature. The reaction mixture was diluted with EtOAc, filtered over a plug of Na2SO4 and celite, and the solvent evaporated under reduced pressure. The crude product 55 was obtained as a brown oil and directly used in the next step without further purification. The intermediate 55 was transferred into a vial and moved into a glovebox under N2. AgBF4 (9.6 mg, 0.049 mmol, 0.1 equiv) was added and the reactants dissolved in HFIP (9.9 mL, 0.05 M). The reaction was transferred outside the glovebox and stirred for an additional 30 min. Upon full consumption of the starting material as determined by LC-MS, the reaction was diluted with saturated aqueous NH4Cl and the aqueous layer extracted with EtOAc (4x). The combined organic extracts were dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (33% acetone/hexanes) to yield the product 59 (65.5 mg, 0.21 mmol, 42% yield) as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 5.98 (ddt, J = 3.8, 3.0, 1.5 Hz, 1H), 5.80 (s, 1H), 5.72 (ddt, J = 17.2, 10.3, 5.9 Hz, 1H), 5.02 – 4.89 (m, 2H), 4.38 (s, 1H), 3.46 (ddd, J = 11.6, 8.1, 3.9 Hz, 1H), 3.26 (td, J = 12.3, 3.4 Hz, 1H), 3.13 (ddd, J = 12.1, 4.9, 2.2 Hz, 1H), 3.01 – 2.96 (m, 2H), 2.91 (s, 3H), 2.50 (d, J = 7.9 Hz, 1H), 2.24 (dtd, J = 12.9, 3.6, 2.2 Hz, 1H), 1.88 – 1.83 (m, 4H), 1.82 (s, 3H), 1.78 – 1.68 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 206.3, 179.4, 154.6, 137.1, 132.4, 125.0, 122.6, 115.7, 62.9, 62.5, 58.5, 55.6, 47.2, 35.9, 35.1, 32.3, 29.7, 28.4, 23.6; IR (neat film, NaCl) 2922, 1695, 1634, 1503, 1446 Chapter 2 – Total Synthesis of Lycojapomine A & B 148 cm–1; HRMS (ESI+): m/z calc’d for C19H25N2O2 [M+H]+: 313.1916, found 313.1950. O N H SmI2 2-Naphthalenethiol N THF, –10 ºC H 59 O N N O H H H H OH 60 Alcohol 60: A vial under N2 was charged with enone 59 (37 mg, 0.12 mmol, 1.0 equiv) and 2-Naphthalenethiol (381 mg, 2.4 mmol, 20.0 equiv) and the reactants dissolved in THF (2.4 mL, 0.05 M). The vial was cooled to –10 °C in a brine/ice bath and a solution of SmI2 in THF (0.1 M, 11.9 mL, 1.19 mmol, 10.0 equiv) was added dropwise over the course of 1 h via syringe pump. Upon completion of addition, the ice bath was removed and the reaction stirred for an additional 30 minutes at ambient temperature. The reaction was quenched with a 1:1 mixture of aqueous saturated Na2S2O3 and hexanes, the aqueous layer extracted with EtOAc (3x), the combined organic extracts dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (50% acetone/hexanes) to yield the alcohol 60 (31.3 mg, 0.099 mmol, 83% yield) as a colorless foam; 1H NMR (400 MHz, CDCl3) δ 5.75 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H), 5.57 – 5.46 (m, 1H), 4.98 (dd, J = 17.1, 1.7 Hz, 1H), 4.91 (dd, J = 10.2, 1.7 Hz, 1H), 4.25 (s, 1H), 4.24 – 4.12 (m, 1H), 3.60 (ddd, J = 10.8, 8.5, 3.9 Hz, 1H), 3.31 (td, J = 12.3, 3.8 Hz, 1H), 3.07 (ddd, J = 11.9, 5.0, 2.1 Hz, 1H), 2.91 (s, 3H), 2.44 (brs, 1H), 2.27 – 2.12 (m, 2H), 2.11 – 1.87 (m, 5H), 1.84 – 1.73 (m, 2H), 1.69 (s, 3H), 1.67 – 1.60 (m, 1H), 1.55 (dd, J = 9.5, 7.3 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 155.0, 138.6, 133.8, 122.9, 114.6, 71.5, 62.4, 59.8, 55.9, 51.3, 47.5, 42.6, 39.7, 37.7, 34.9, 30.6, 29.9, Chapter 2 – Total Synthesis of Lycojapomine A & B 149 29.6, 24.2; IR (neat film, NaCl) 2920, 2852, 1734, 1636, 1506, 1444, 1073, 802 cm–1; HRMS (ESI+): m/z calc’d for C19H29N2O2 [M+H]+: 317.2224, found 317.2107. O H H N N H H OH 60 1.) LiAlH4 THF, 55 ºC 2.) DMP NaHCO3 CH2Cl2, 21 ºC H H N N H O 61 Ketone 61: A vial under N2 was charged with starting material 60 (31.3 mg, 0.099 mmol, 1.0 equiv) and THF (3.3 mL, 0.03 M). LiAlH4 (22.5 mg, 0.59 mmol, 6.0 equiv) was added in one portion, the reaction vial sealed and placed in a heating block at 55 °C. After 2 h, the starting material had been consumed as determined by LC-MS analysis and the reaction cooled to 0 °C. The reaction was quenched with saturated aqueous NaHCO3 (0.3 mL) and diluted with CH2Cl2. The contents were filtered over a plug of Na2SO4 and celite and the solvent evaporated under reduced pressure. The crude product was used in the next step without further purification. The intermediate was dissolved in CH2Cl2 (2 mL, 0.05 M) and NaHCO3 (25 mg, 0.297 mmol, 3.0 equiv) and Dess-Martin periodinane (45 mg, 0.129 mmol, 1.3 equiv) were added sequentially. After 1 h, full consumption of starting material was observed by LC-MS analysis and the reaction mixture directly loaded onto a flash column packed with silica gel for purification (3-5% MeOH/CH2Cl2 + 0.1% NH4OH). The product 61 (23 mg, 0.077 mmol, 77% yield over two steps) was isolated as a pale yellow solid; 1H NMR (600 MHz, CD3OD) δ 5.84 (ddt, J = 16.8, 10.1, 6.5 Hz, 1H), 5.73 – 5.65 (m, 1H), 5.04 (dd, J = 17.1, 1.8 Hz, 1H), 4.95 (dd, J = 10.2, 1.7 Hz, 1H), 3.97 (dd, J = 12.1, 2.0 Hz, 1H), 3.65 (d, J = Chapter 2 – Total Synthesis of Lycojapomine A & B 150 4.1 Hz, 1H), 3.28 (dd, J = 12.4, 3.9 Hz, 1H), 3.17 (d, J = 12.2 Hz, 1H), 3.05 (d, J = 11.4 Hz, 1H), 2.50 – 2.41 (m, 1H), 2.37 – 2.24 (m, 5H), 2.22 (s, 3H), 2.19 – 2.09 (m, 2H), 2.05 – 1.97 (m, 1H), 1.95 (dd, J = 13.1, 4.1 Hz, 1H), 1.87 – 1.79 (m, 2H), 1.77 (s, 3H), 1.51 (dq, J = 13.5, 3.0 Hz, 1H); 13C NMR (101 MHz, CD3OD) δ 221.8, 139.8, 135.5, 120.1, 115.1, 70.5, 64.0, 62.3, 61.8, 55.9, 50.8, 46.0, 42.5, 41.6, 36.9, 32.0, 30.7, 27.3, 24.2; IR (neat film, NaCl) 3382, 2921, 1694, 1632, 1503, 1450, 1309, 1092 cm–1; HRMS (ESI+): m/z calc’d for C19H29N2O [M+H]+: 301.2280, found 301.2353. H H N N H 61 O HCl in Et2O then O3 in CH2Cl2 H MeOH, –78 ºC N N H O H H OH O 62 Compound 62: In a vial, starting material 61 (10 mg, 0.033 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.5 mL) and HCl (1M in Et2O, 0.04 mL, 1.2 equiv) was added dropwise. The solvent was evaporated under reduced pressure, leaving behind a white salt. The contents were dissolved in MeOH (0.66 mL, 0.05 M) and the vial flushed and equipped with an argon balloon (This step was done to avoid excess condensation of water during the reaction). The vial was cooled at –78 °C in a dry ice/acetone bath. Simultaneously, ozone was bubbled through a test tube filled with CH2Cl2 at –78 °C for 3 min, to create a saturated solution, as indicated by the blue color. The saturated solution of ozone in CH2Cl2 (~1.5 mL) was added to the reaction mixture portion wise (0.1–0.5 mL). The reaction was carefully monitored by TLC analysis (10% MeOH/CH2Cl2 + 1% Et3N) every 5 minutes after addition, until the starting material had been completely consumed. P(OMe)3 (0.3 mL) Chapter 2 – Total Synthesis of Lycojapomine A & B 151 and Et3N (0.5 mL) were added, the reaction warmed to ambient temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the residue purified by flash column chromatography on silica gel (10% MeOH/CH2Cl2 + 1% Et3N) to give crude intermediate 62 (7.7 mg) as a colorless film. Intermediate 62 proved to be unstable and decomposed upon extended storage. It was therefore used on the same day in the following reaction. H H O N N H H 62 OH O KOH H MeOH, 21 ºC 30 min N N H H H OH O Lycojapomine B (45) Lycojapomine B: A vial was charged with starting material 62 (4.0 mg, 0.01 mmol, 1.0 equiv), which was dissolved in MeOH (0.5 mL, 0.02 M). A solution of KOH (11.2 mg) in MeOH (0.14 mL) was added and the reaction stirred at ambient temperature for 30 min. The reaction was adjusted to pH ~9-10 with aqueous saturated NH4Cl, diluted with CH2Cl2 and flushed over a plug of Na2SO4 and silica gel. The solvent was removed under reduced pressure and the crude product purified by preparatory HPLC (Agilent Zorbax Eclipse XDB-C18 column, 5 µm, 25% MeCN/H2O + 0.2% Et2NH, flowrate: 5 mL/min, monitor wavelength = 209 nm, retention time = 7.5 min) to give Lycojapomine B (45, 2.7 mg, 0.009 mmol, 63% yield over two steps) as a white solid; 1H NMR (600 MHz, CD3OD) δ 5.50 (dt, J = 5.0, 1.9 Hz, 1H), 3.98 (ddd, J = 10.8, 6.5, 4.3 Hz, 1H), 3.69 (d, J = 8.7 Hz, 1H), 3.44 (d, J = 5.0 Hz, 1H), 2.83 (brd, J = 11.9 Hz, 1H), 2.76 (d, J = 8.7 Hz, 1H), 2.55 (d, J = 4.2 Hz, 1H), 2.32 (td, J = 9.9, 2.9 Hz, 1H), 2.28 (d, J = 9.6 Hz, 1H), 2.24 (s, 3H), 2.18 (dt, J = Chapter 2 – Total Synthesis of Lycojapomine A & B 152 13.7, 6.2 Hz, 1H), 2.03 – 1.91 (m, 3H), 1.91 – 1.82 (m, 2H), 1.78 (s, 3H), 1.74 – 1.70 (m, 2H), 1.64 – 1.50 (m, 2H); 13C NMR (101 MHz, CD3OD) δ 217.7, 140.1, 122.5, 73.6, 72.0, 67.5, 63.1, 62.0, 61.7, 54.4, 50.4, 45.2, 42.7, 37.5, 34.1, 32.0, 31.0, 23.9; IR (neat film, NaCl) 3349, 2930, 1729, 1445, 1131 cm–1; HRMS (ESI+): m/z calc’d for C18H27N2O2 [M+H]+: 303.2067, found 303.2070. H H N N KOH O H H 62 OH O MeOH, 55 ºC 6h H H N N H O OH Lycojapomine A (44) Lycojapomine A: A vial was charged with starting material 62 (2.2 mg, 0.007 mmol, 1.0 equiv), which was dissolved in MeOH (0.36 mL, 0.02 M). A solution of KOH (8.0 mg) in MeOH (0.1 mL) was added and the reaction stirred at 55 °C for 6 h. The reaction was adjusted to pH ~9-10 with aqueous saturated NH4Cl, diluted with CH2Cl2 and flushed over a plug of Na2SO4 and silica gel. The solvent was removed under reduced pressure and the crude product purified by preparatory HPLC (Agilent Zorbax Eclipse XDB-C18 column, 5 µm, 25% MeCN/H2O + 0.2% Et2NH, flowrate: 5 mL/min, monitor wavelength = 209 nm, retention time = 9.0 min) to give Lycojapomine A (44, 1.7 mg, 0.0057 mmol, 57% yield over two steps) as a white solid; 1H NMR (600 MHz, CD3OD) δ 5.65 (brs, 1H), 4.27 (dd, J = 5.8, 4.5 Hz, 1H), 3.78 (dd, J = 11.6, 2.0 Hz, 1H), 3.57 (brs, 1H), 3.21 (dd, J = 12.4, 3.8 Hz, 1H), 2.99 (d, J = 11.7 Hz, 1H), 2.94 (d, J = 11.6 Hz, 1H), 2.47 (dd, J = 17.5, 8.4 Hz, 1H), 2.40 – 2.34 (m, 1H), 2.26 – 2.20 (m, 2H), 2.17 (dd, J = 17.5, 9.5 Hz, 1H), 2.13 (s, 3H), 2.10 – 1.93 (m, 4H), 1.79 – 1.75 (m, 1H), 1.77 (s, 3H), 1.76 – 1.67 (m, 1H), 1.45 Chapter 2 – Total Synthesis of Lycojapomine A & B 153 (dddd, J = 12.9, 3.9, 2.8, 2.4 Hz, 1H); 13C NMR (101 MHz, CD3OD) δ 222.8, 136.9, 120.1, 75.9, 75.1, 70.9, 64.4, 63.2, 61.8, 56.1, 47.4, 42.9, 39.3, 38.6, 38.5, 31.8, 25.1, 24.3; IR (neat film, NaCl) 3340, 2931, 1729, 1445, 1121, 1055, 867, 805 cm–1; HRMS (ESI+): m/z calc’d for C18H27N2O2 [M+H]+: 303.2073, found 303.2060. Chapter 2 – Total Synthesis of Lycojapomine A & B 154 2.8 REFERENCES AND NOTES (1) Alkaloids: Biochemistry, Ecology, and Medicinal Applications (eds. Roberts, M.F.; Wink, M.); Springer US, Boston, MA, 1998. doi:10.1007/978-1-4757-2905-4. (2) Heinrich, M.; Mah, J.; Amirkia, V. Alkaloids Used as Medicines: Structural Phytochemistry Meets Biodiversity—An Update and Forward Look. Molecules 2021, 26, 1836. (3) Robinson, R. LXIII.—A synthesis of tropinone. J. Chem. Soc., Trans. 1917, 111, 762–768. (4) Medley, J. W.; Movassaghi, M. Robinson’s landmark synthesis of tropinone. Chem. Commun. 2013, 49, 10775–10777. (5) Pereira, A. G. et al. Plant Alkaloids: Production, Extraction, and Potential Therapeutic Properties. In Natural Secondary Metabolites: From Nature, Through Science, to Industry (eds. Carocho, M.; Heleno, S. A.; Barros, L.); Springer International Publishing, Cham, 2023; pp 157–200. doi: 10.1007/978-3-031-185878_6. (6) For reviews on Lycopodium alkaloids see: (a) Ma, X.; Gang, D. R. The Lycopodium alkaloids. Nat. Prod. Rep. 2004, 21, 752–772. (b) Zhang, Z.-J.; Jiang, S.; Zhao, Q.S. The Chemistry and Biology of Lycopodium Alkaloids. Chemistry & Biodiversity 2024, 21 e202400954. (7) Xia, D. et al. Lycojapomines A–E: Lycopodium Alkaloids with Anti-Renal Fibrosis Potential from Lycopodium japonicum. Org. Lett. 2022, 24, 4684–4688. (8) Olafsdóttir, E. S.; Halldorsdottir, E. S.; Pich, N. M.; Omarsdottir, S. Lycopodium Alkaloids: Pharmacology. In Natural Products: Phytochemistry, Botany and Chapter 2 – Total Synthesis of Lycojapomine A & B 155 Metabolism of Alkaloids, Phenolics and Terpenes (eds. Ramawat, K. G.; Mérillon, J.-M.); Springer, Berlin, Heidelberg, 2013; pp 1239–1262. doi:10.1007/978-3-64222144-6_42. (9) For recent examples of Lycopodium alkaloid syntheses see: (a) Zhao, X.-H. et al. Total Synthesis of (±)-Lycojaponicumin D and Lycodoline-Type Lycopodium Alkaloids. J. Am. Chem. Soc. 2017, 139, 7095–7103. (b) Wang, F.-X. et al. Total Synthesis of Lycopodium Alkaloids Palhinine A and Palhinine D. J. Am. Chem. Soc. 2017, 139, 4282–4285. (c) Zhang, J. et al. Diversity-oriented synthesis of Lycopodium alkaloids inspired by the hidden functional group pairing pattern. Nat Commun 2014, 5, 4614. (d) Williams, B. M.; Trauner, D. Expedient Synthesis of (+)Lycopalhine A. Angew. Chem. Int. Ed. 2016, 55, 2191–2194. (e) Kurose, T.; Tsukano, C.; Nanjo, T.; Takemoto, Y. Total Synthesis of Lyconesidine B, a Lycopodium Alkaloid with an Oxygenated, Amine-Type Fawcettimine Core. Org. Lett. 2021, 23, 676–681. (10) Huck, C. J.; Sarlah, D. Shaping Molecular Landscapes: Recent Advances, Opportunities, and Challenges in Dearomatization. Chem 2020, 6, 1589–1603. (11) (a) Escolano, M. et al. Recent Strategies in the Nucleophilic Dearomatization of Pyridines, Quinolines, and Isoquinolines. Chem. Rev. 124, 1122–1246 (2024). For recent selected examples in synthesis see: (b) Landwehr, E. M. et al. Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction. Science 2022, 375, 1270–1274. (c) Welin, E. R. et al. Concise total syntheses of (-)jorunnamycin A and (-)-jorumycin enabled by asymmetric catalysis. Science 2019, 363, 270–275. Chapter 2 – Total Synthesis of Lycojapomine A & B 156 (12) For a recent review see: (a) Olivier, W. J.; Smith, J. A.; Bissember, A. C. Synthesis of Pyrrolidine- and γ-Lactam-Containing Natural Products and Related Compounds from Pyrrole Scaffolds. The Chemical Record 2022, 22, e202100277. For a recent selected example in synthesis see: (b) Parr, B. T.; Economou, C.; Herzon, S. B. A concise synthesis of (+)-batzelladine B from simple pyrrole-based starting materials. Nature 2015, 525, 507–510. (13) For reviews on dearomatization strategies in synthesis see: (a) Roche, S. P.; Porco, J. A. Dearomatization Strategies in the Synthesis of Complex Natural Products. Angew. Chem. Int. Ed. 2011, 55, 4068–4093. (b) Huck, C. J.; Boyko, Y. D.; Sarlah, D. Dearomative logic in natural product total synthesis. Nat. Prod. Rep. 2022, 39, 2231–2291. (14) Pavri, N. P.; Trudell, M. L. An Efficient Method for the Synthesis of 3-Arylpyrroles. J. Org. Chem. 1997, 62, 2649–2651. (15) (a) Zhang, Y. et al. Photoredox Asymmetric Nucleophilic Dearomatization of Indoles with Neutral Radicals. ACS Catal. 2021, 11, 998–1007; Zhang, Y. et al. Organophotocatalytic dearomatization of indoles, pyrroles and benzo(thio)furans via a Giese-type transformation. Commun Chem 2021, 4, 1–13. (16) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322–5363. (17) Lu, Y.-C.; West, J. G. Chemoselective Decarboxylative Protonation Enabled by Cooperative Earth-Abundant Element Catalysis. Angew. Chem. Int. Ed. 2023, 23, e202213055. Chapter 2 – Total Synthesis of Lycojapomine A & B 157 (18) Yin, H. et al. Stereoselective and Divergent Construction of β-Thiolated/Selenolated Amino Acids via Photoredox-Catalyzed Asymmetric Giese Reaction. J. Am. Chem. Soc. 2020, 142, 14201–14209. (19) Qin, T. et al. Nickel-Catalyzed Barton Decarboxylation and Giese Reactions: A Practical Take on Classic Transforms. Angew. Chem. Int. Ed. 2017, 56, 260–265. (20) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. Direct Construction of Quaternary Carbons from Tertiary Alcohols via Photoredox-Catalyzed Fragmentation of tertAlkyl N-Phthalimidoyl Oxalates. J. Am. Chem. Soc. 2013, 135, 15342–15345. (21) Alpers, D.; Brasholz, M.; Rehbein, J. Photoredox-Induced Radical 6-exo-trig Cyclizations onto the Indole Nucleus: Aromative versus Dearomative Pathways. European Journal of Organic Chemistry 2017, 2017, 2186–2193. (22) Ma, S.; Negishi, E. Anti-Carbometalation of Homopropargyl Alcohols and Their Higher Homologues via Non-Chelation-Controlled Syn-Carbometalation and Chelation-Controlled Isomerization. J. Org. Chem. 1997, 62, 784–785. (23) Suzuki, K.; Tomooka, K.; Katayama, E.; Matsumoto, T.; Tsuchihashi, G. Stereocontrolled asymmetric total synthesis of protomycinolide IV. J. Am. Chem. Soc. 1986, 108, 5221–5229. (24) Krasovskiy, A.; Knochel, P. A LiCl-Mediated Br/Mg Exchange Reaction for the Preparation of Functionalized Aryl- and Heteroarylmagnesium Compounds from Organic Bromides. Angew. Chem. Int. Ed. 2004, 43, 3333–3336. (25) Liddon, J. T. R. et al. Catalyst-Driven Scaffold Diversity: Selective Synthesis of Spirocycles, Carbazoles and Quinolines from Indolyl Ynones. Chemistry – A European Journal 2016, 22, 8777–8780. Chapter 2 – Total Synthesis of Lycojapomine A & B 158 (26) Nakayama, Y. et al. Total Synthesis of Ritterazine B. J. Am. Chem. Soc. 2021, 143, 4187–4192. (27) Holton, R. A. et al. First total synthesis of taxol. 2. Completion of the C and D rings. J. Am. Chem. Soc. 1994, 116, 1599–1600. (28) Pangborn, A. M.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Safe and Convenient Procedure for Solvent Purification. Organometallics 1996, 15, 1518–1520. (29) Tsimelzon, A.; Braslau, R. Radical [n + 1] Annulations with Sulfur Dioxide, J. Org. Chem. 2005, 70, 10854–10859. (30) Davies, J. A. et al; Total Synthesis of Kalimantacin A, Org. Lett. 2020, 22, 6349– 6353. (31) Ma, S.; Negishi, E.; Anti-Carbometalation of Homopropargyl Alcohols and Their Higher Homologues via Non-Chelation-Controlled Syn-Carbometalation and Chelation-Controlled Isomerization, J. Org. Chem. 1997, 62, 784–785. Appendix 3 – Spectra Relevant to Chapter 2 159 APPENDIX 3 Spectra Relevant to Chapter 2: Total Synthesis of Lycojapomine A & B 9 N H O OMe 8 6 5 ppm 4 3 Figure A3.1. 1H NMR (400 MHz, CDCl3) of compound 46. 7 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 160 Appendix 3 – Spectra Relevant to Chapter 2 161 Figure A3.2. Infrared spectrum (Thin Film, NaCl) of compound 46. 200 150 100 ppm 50 Figure A3.3. 13C NMR (101 MHz, CDCl3) of compound 46. 0 9 O N 8 N O OMe O O O N 7 6 5 ppm 4 3 Figure A3.4. 1H NMR (400 MHz, CDCl3) of compound 48. O 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 162 Appendix 3 – Spectra Relevant to Chapter 2 163 Figure A3.5. Infrared spectrum (Thin Film, NaCl) of compound 48. 200 180 160 140 120 100 ppm 80 60 40 Figure A3.6. 13C NMR (101 MHz, CDCl3) of compound 48. 20 0 9 8 O N N O H OMe 7 5 ppm 4 3 2 Figure A3.7. 1H NMR (600 MHz, CDCl3) of compound 49 (trans). 6 1 0 Appendix 3 – Spectra Relevant to Chapter 2 164 Appendix 3 – Spectra Relevant to Chapter 2 165 Figure A3.8. Infrared spectrum (Thin Film, NaCl) of compound 49 (trans). 180 160 140 120 100 ppm 80 60 40 20 Figure A3.9. 13C NMR (101 MHz, CDCl3) of compound 49 (trans). 0 9 8 O N N O H OMe 7 5 ppm 4 3 2 Figure A3.10. 1H NMR (400 MHz, CDCl3) of compound 49 (cis). 6 1 0 Appendix 3 – Spectra Relevant to Chapter 2 166 Appendix 3 – Spectra Relevant to Chapter 2 167 Figure A3.11. Infrared spectrum (Thin Film, NaCl) of compound 49 (cis). 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.12. 13C NMR (101 MHz, CDCl3) of compound 49 (cis). 0 9 O 8 N N O H N OMe 7 5 ppm 4 3 Figure A3.13. 1H NMR (400 MHz, C6D6) of compound 52. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 168 Appendix 3 – Spectra Relevant to Chapter 2 169 Figure A3.14. Infrared spectrum (Thin Film, NaCl) of compound 52. 180 160 140 120 100 ppm 80 60 40 Figure A3.15. 13C NMR (101 MHz, C6D6) of compound 52. 20 0 9 Br Br 8 TMS 6 5 ppm 4 3 2 Figure A3.16. 1H NMR (400 MHz, CDCl3) of compound 53. 7 1 0 Appendix 3 – Spectra Relevant to Chapter 2 170 Appendix 3 – Spectra Relevant to Chapter 2 171 Figure A3.17. Infrared spectrum (Thin Film, NaCl) of compound 53. 180 160 140 120 100 ppm 80 60 40 20 Figure A3.18. 13C NMR (101 MHz, CDCl3) of compound 53. 0 9 N O N H 8 H O 7 5 ppm 4 3 2 Figure A3.19. 1H NMR (400 MHz, CDCl3) of compound 59. 6 1 0 Appendix 3 – Spectra Relevant to Chapter 2 172 Appendix 3 – Spectra Relevant to Chapter 2 173 Figure A3.20. Infrared spectrum (Thin Film, NaCl) of compound 59. 200 180 160 140 120 ppm 100 80 60 40 Figure A3.21. 13C NMR (101 MHz, CDCl3) of compound 59. 20 0 N O 8 N H H OH H 7 5 4 ppm 3 2 Figure A3.22. 1H NMR (400 MHz, CDCl3) of compound 60. 6 1 0 Appendix 3 – Spectra Relevant to Chapter 2 174 Appendix 3 – Spectra Relevant to Chapter 2 175 Figure A3.23. Infrared spectrum (Thin Film, NaCl) of compound 60. 180 160 140 120 100 ppm 80 60 40 Figure A3.24. 13C NMR (101 MHz, CDCl3) of compound 60. 20 0 N N H 8 H O H 7 5 ppm 4 3 Figure A3.25. 1H NMR (600 MHz, CD3OD) of compound 61. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 2 176 Appendix 3 – Spectra Relevant to Chapter 2 177 Figure A3.26. Infrared spectrum (Thin Film, NaCl) of compound 61. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A3.27. 13C NMR (101 MHz, CD3OD) of compound 61. 20 0 9 N H O H 8 Lycojapomine B N H OH H 7 5 ppm 4 3 Figure A3.28. 1H NMR (600 MHz, CD3OD) of compound 45. 6 2 1 0 Appendix 3 – Spectra Relevant to Chapter 2 178 Appendix 3 – Spectra Relevant to Chapter 2 179 Figure A3.29. Infrared spectrum (Thin Film, NaCl) of compound 45. 220 200 180 160 140 120 100 ppm 80 60 40 20 Figure A3.30. 13C NMR (101 MHz, CD3OD) of compound 45. 0 -20 N H O OH H 7 Lycojapomine A N H 5 4 ppm 3 Figure A3.31. 1H NMR (600 MHz, CD3OD) of compound 44. 6 2 1 Appendix 3 – Spectra Relevant to Chapter 2 180 Appendix 3 – Spectra Relevant to Chapter 2 181 Figure A3.32. Infrared spectrum (Thin Film, NaCl) of compound 44. 220 200 180 160 140 120 ppm 100 80 60 40 Figure A3.33. 13C NMR (101 MHz, CD3OD) of compound 44. 20 0 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 182 CHAPTER 3 Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 3.1 INTRODUCTION The use of radical intermediates in synthetic organic chemistry has seen an increased rise in popularity over the last decade.1,2 Due to the development of new reaction methodology, carbon-centered radicals have become valuable synthetic intermediates that give way to a variety of downstream manipulations (Figure 3.1.1, A).2 These have led to a certain generality in single-electron logic, with reactions such as hydrogen-atom transfer, Giese additions or metal-mediated cross-couplings being well-established. Their complementary nature to ionic transformations has opened doors for new chemical reactivity, making them popular in industrial and academic settings alike. To gain accessibility to these reactions however, selective generation of the carbon-centered radical from ubiquitous precursors is necessary. One of the longer standing challenges in this area has been the radical deoxygenation of alcohols, by generation of the corresponding alkyl radical.3 Due to the strong nature of the C–O bond and lack of driving force for homolytic bond cleavage, traditional methods rely on a two-step protocol, via preactivation of the alcohol. This is exemplified by the original protocol in the Barton deoxygenation, forming the xanthate ester before being able to induce radical C–O bond cleavage.4 Many groups Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 183 have evolved this logic through the introduction of more easily accessible redox active esters that can be preformed or generated in-situ and employed for radical formation.5 To address this challenge, we sought to identify a new catalyst that provides convenient entry to the generation of carbon-centered radicals directly from the alcohol. This would provide the blueprint for a catalytic, one-step protocol, making the direct radical deoxygenation of alcohols more accessible. Figure 3.1.1 Evolution of a titanium porphyrin catalyst for deoxygenation. B Alkyl radical formation in C–H oxidation by P450 iron porphyrin A Generation of radicals from alcohols OH O-RE 1.) 2.) O N N ? catalytic, one-step protocol N N N N Fe IV N N R–H III Fe N N R–OH “H2”, – H2O R = alkyl substituent RE = Redox active ester D This research: Titanium porphyrin complex as deoxygenation catalyst C Seminal Report: Cp2TiCl2 (Barrero, 2010) OH OH N Fe IV N carbon-centered radical R–OH R R–H Ph Cp2TiCl2 (2.0 equiv) Me OH N Cl Ph N Mn (1.5 equiv) THF, reflux 79% yield allylic and benzylic alcohols Ti H N Cl N Ph purple LED (390 nm) & Hantzsch Ester Ph via alkyl radical formation Trying to identify a possible transition-metal catalyst for deoxygenation, we were inspired by the intriguing reactivity of the iron porphyrin active site found in P450 enzymes (Figure 3.1.1, B).6 Looking closer at the mechanism, the iron metal center undergoes oxygen rebound chemistry and generates a carbon-centered radical in the process.7 The enzyme essentially performs the opposite reaction to our desired process, selectively oxidizing inert C–H bonds. An iron(IV)-oxo radical cation abstracts an H atom from the substrate to generate the alkyl radical intermediate. This radical rebounds with the iron(IV)-oxo Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 184 complex, which is reduced to iron(III) in the process, and releases the alcohol. Within the laws of microscopic reversibility, we envisioned adapting this mechanism to perform the opposite reaction. This would involve coordination of the alcohol to a metal(III) center, which now must be reducing, to cleave the C–O bond, generate a metal (IV)-oxo complex and release the alkyl radical. Our catalyst would have to be turned over by an equivalent of H2, to release water and regenerate the active metal(III) complex. To overturn the reactivity of the oxidizing heme, we deemed to switch out the iron metal for an alternate transition metal that can be reducing in its nature. A seminal report by Barrero and co-workers in 2010 introduced the ability of Nugent’s reagent (Cp2TiCl2) to directly deoxygenate various alcohols (Figure 3.1.1, C).8 While its ability to reductively open epoxides had been well established, the authors were able to demonstrate direct C–O bond cleavage of an alcohol by the reagent for the first time. Interestingly, they observed the necessity to employ two equivalents of titanium metal to give full conversion of starting material. Believed to first undergo reduction to Ti(III) by excess manganese, the metal binds to the alcohol, undergoing oxidation to a Ti(IV)-oxo species and releasing the carbon-centered radical. However, excess Ti(III) can recombine with the alkyl radical to give a semi-stable carbon-Ti(IV) bond. This species is formed after deoxygenation and is later hydrolyzed during work-up, showcasing the challenge of achieving catalytic turnover for a titanium catalyst. In an impressive preliminary result, the group was able to succeed in the use of catalytic Cp2TiCl2 (0.3 equiv), turning over the catalyst with excess manganese (8.0 equiv) and TMSCl (4.0 equiv).8 This system was later adapted by Shu and co-workers for activation of tertiary alcohols for Giese addition.9 Following their reports, several studies have been presented that employ titanium metal Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 185 complexes in similar fashion for deoxygenation reactions.10 These seminal findings and reports led us to further investigate titanium as a deoxygenation catalyst. 3.2 REACTION OPTIMIZATION We proposed synthesizing a titanium porphyrin complex, analogous to the iron porphyrin complex present in P450 enzymes. The porphyrin framework provides a stable ligand with potential photoabsorbance for activation and reduction. To our benefit, the group of Woo et al. has reported the synthesis and characterization of various transition-metal porphyrin complexes, including titanium analogs.11 Based on their literature precedent, we were able to successfully prepare the phenyl-substituted titanium porphyrin complex Ti(TPP)Cl2 (Table 3.2.1). The complex would serve as our Ti(IV) precatalyst, which could undergo initial reduction to the active Ti(III) species. While metal reductants can realize this transformation, we wanted to circumvent the use of excess reagents, such as silyl chlorides, to turn over the catalyst. Gänsauer and co-workers showed the successful implementation of photochemistry for reduction, by excitation of Cp2TiCl2 in the presence of iPr2EtN with green light.12 However, the short lifetime of the photoexcited species and slow decomposition of Cp2TiCl2 render the catalyst problematic for direct photoexcitation. The photoabsorbance of porphyrins is well established, and we sought to realize direct photoexcitation of our catalyst with visible light. If successful, it could undergo the desired Ti(IV) to Ti(III) redox cycle. To facilitate reduction with an electron donor, we investigated different wavelengths for photoexcitation in the presence of Hantzsch Ester (HE). We chose substrate 69a as a practical model substrate for deoxygenation (Table 3.2.1). To our delight, upon irradiation Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 186 of the reaction mixture with purple LEDs (390 nm) in DMA as solvent, we observed deoxygenation to product 69b in 45% yield (Entry 2). Table 3.2.1 Optimization of reaction conditions. Ti(TPP)Cl2 (15 mol%) HE (2.0 equiv) OH + purple LED (390 nm) 4Å mol sieves DMA:THF (1:1) 69a entry Me deviation from standard conditions 69b 69c yield of 69a yield of 69c 1 none 84% trace 2 DMA 45% - 3 THF - 90% 4 CH2Cl2 - 89% 5 HE (4.0 equiv) 64% trace 6 10 mol% Ti-catalyst 61% trace 7 blue LED (450 nm) 5% - 8 no Ti-catalyst - - 9 no purple LED - - 10 no HE - - 11 no 4Å mol sieves - - Ph N Cl Ph N Ti N Cl N Ph Ph Ti(TPP)Cl2 H H EtO2C Me CO2Et N H Me Hantzsch Ester (HE) Most of the left-over mass balance was unreacted starting material 69a. Irradiation with blue LEDs resulted in zero to minimal turnover (Entry 7). When switching solvents to dichloromethane or THF, the reaction was pushed to full conversion and delivered a clean reaction profile (Entry 3 & 4). In these cases, however, we observed sole formation of the dimeric product 69c. This result can potentially be attributed to different aggregation of catalyst transition states or the rate of hydrogen atom transfer. When employing a 1:1 mixture of DMA and THF, we preserved full consumption of starting material and observed only trace amount of dimer formation, isolating the desired product 69b in 84% yield. Alternating the equivalents of Hantzsch ester or catalyst loading did not produce an Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 187 improvement (Entry 5 & 6). In control reactions, omitting any of the additives, including molecular sieves, resulted in no conversion and shutdown of reactivity (Entry 8-11). 3.3 EVALUATION OF SUBSTRATE GENERALITY With these results in hand, we set out to investigate the functional group tolerance of the catalytic system and ability to deoxygenate various substrates (Figure 3.3.1). Expanding on benzylic alcohols, we observed good conversion of benzyl alcohol 70a, and slightly lower conversion going to secondary (71a) and tertiary (72a) benzylic alcohols. Biphenyl 74a gave excellent conversion, isolating the product in 78% yield. Interestingly, the ethyl naphthalene substrate 73a gave lower conversion than the model substrate 69a, suggesting the presence of !-alkyl substituents to hinder turnover of the catalyst. When switching to diarylmethanes, we observed more general activation on a variety of substrates (77a-84a). Substituents such as methoxy, methyl, fluorine or phenols (83a) were widely compatible. Interestingly, we observed lower yield due to partial dimer formation in some cases, likely depending on the specific electronics of the system. Esters also proved to be well tolerated, isolating the deoxygenated product of mandelic acid ethyl ester 76a in 69% yield. Expanding on the scope, we sought out to test allylic systems. We were pleased to observe full conversion of cinnamyl alcohol 85a. Our catalyst achieved the deoxygenation on a wide range of cinnamyl alcohols, showing little side reaction to dimerized byproducts in most cases. Electron-withdrawing groups in the halogen series (86a-88a) were well tolerated, as were electron-donating groups, such as unprotected phenol substrate 89a, and the dimethoxy-substituted substrate 90a. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 188 Figure 3.3.1 Substrate scope for radical deoxygenation. Ph Ti(TPP)Cl2 (15 mol%) Hantzsch Ester (2.0 equiv) OH 69b–97b N Ti N purple LED (390 nm) 4Å mol sieves DMA:THF (1:1) 69a–97a N Cl Ph H Cl N Ph Ph Ti(TPP)Cl2 benzylic alcohols OH OH OH OH OH Me OH 69a 70a 71a 72a 73a 74a 84% yield 56% yielda 39% yield 15% yield 27% yield 78% yield OH OH OH OH HO OEt MeO O OMe 75a 76a 77a 78a 25% yielda 69% yield 58% yield 93% yield OH OH MeO 80a OH F 81a OMe 51% yield OH OH Me 79a 88% yield Me 75% yield OH O 83a 84a 62% yield 37% yield 82a F 33% yield cinnamyl alcohols OH OH OH Cl F OH OH HO Br 85a 86a 87a 88a 89a 76% yielda (E/Z/iso = 2/1/1.2) 79% yielda (E/Z/iso = 4.5/1/1.1) 80% yielda (E/Z/iso = 7.8/1/2.5) 69% yield (E/Z/iso = 8.9/1/2.8) 52% yielda (E/Z/iso = 2/1/1.5) OH OH OH MeO MeO S OH N Me O Me O 90a 91a 92a 48% yield (E/Z/iso = 3.3/1/1.7) 82% yielda (E/Z/iso = 2.5/1/1.3) 77% yielda (E/Z/iso = 1.4/1.2/1) Me Stiripentol (93a) 47% yield natural products (allylic alcohols) Me Geraniol (94a) 51% yielda (E/Z = 2/1) Me HO a Me Me Me Me OH Me Me Me Me HO Geranylgeraniol (95a) Me Me 48% yield (E/Z = 2.1/1) OH (-)-perillyl alcohol (96a) Nootkatol (97a) 28% yielda 21% yield Yield determined by quantitative 1H-NMR with 1,3,5-trimethoxybenzene as internal standard. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 189 In most cases we observed a mixture of olefin isomers, namely the E/Z styrene, and the migration of the double bond to the allylic substituted benzene. We generally noted preferential formation of the (E)-isomer in most derivates, yet substrate control seems to play a crucial part in determining product distribution. To our delight, even heterocycles such as pyridine or thiophene (91a and 92a) were well tolerated and gave high yields of product. The neopentylic, secondary alcohol in the anticonvulsant medication Stiripentol (93a) could be activated by our catalytic system as well, giving the deoxygenated derivative in decent yield. Lastly, we asked the question if non-conjugated allylic alcohols could be utilized as well. Testing the deoxygenation on geraniol and geranylgeraniol (94a & 95a), we were pleased to find good turnover and isolation of the product in 51% and 48% yield respectively. Further advancements on different terpenes, such as perillyl alcohol (96a) and secondary alcohol nootkatol (97a), gave deoxygenated product in both cases, yet in modest yields. In preliminary findings, we observed trace amounts of product formation on tertiary, secondary or primary alcohols, highlighting the potential of this catalytic system to expand on more general aliphatic alcohols. With the substrate scope evaluated, we identified an opportunity to showcase the new method in synthetic scenarios. Observing generally good reactivity on the diarylmethane derivates, these motifs are found in a variety of pharmaceutical and natural products.13 Retrosynthetically, we sought out addition of a Grignard or metalated starting material to the corresponding aldehyde and subsequently directly deoxygenating the resulting alcohol using our titanium catalyst (Figure 3.3.2). Targeting the lipoprotein regulator beclobrate (99), we alkylated 4-hydroxybenzaldehyde 98, following addition of 4-chloro- Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 190 phenylmagnesium chloride in good yield. The intermediate was well tolerated in our catalytic system, giving the deoxygenated target 99 in 67% yield, completing the threestep sequence. Figure 3.3.2 Implementation of deoxygenation method in synthesis. K2CO3 Me Me Br O Ti CO2Et 67% yield 35% yield CO2Et H Cl OH MgCl beclobrate (99) 98 Cl 78% yield N TMPMgCl LiCl O then 100 H Me Me Ti 77% yield MeO MeO O OMe MeO MeO N OMe papaverine (101) OMe OMe 69% yield Synthesis of the opium alkaloid and antispasmodic drug papaverine (101) commenced from commercial isoquinoline 100. Metalation with turbo-Hauser base and addition into veratraldehyde gave an intermediate secondary alcohol in 69% yield.14 Our standard deoxygenation conditions proceeded, displaying the natural product 101 in 77% yield. With Grignard and metal additions being robust and straightforward transformations, our system displays convenient utility for the synthesis of diarylmethane motifs. As exemplified in these cases, our deoxygenation method may present enhanced chemoselectivity and functional group tolerance, compared to analogous deoxygenations with hydrosilanes or heterogeneous hydrogenations. 3.4 MECHANISTIC INVESTIGATIONS Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 191 To gain further insight into our catalytic method, we conducted several preliminary mechanistic experiments (Figure 3.4.1). To rule out any solvent, such as DMA, water or other reagents participating as H atom source, we synthesized a deuterated Hantzsch ester derivative.15 Employing it in our standard reaction conditions with substrate 69a, we isolated deuterated product 69d in 78% yield, suggesting Hantzsch ester as the exclusive H atom source. Figure 3.4.1 Mechanistic control experiments. D D EtO2C CO2Et H (2 equiv) N H Ti(TPP)Cl2 (15 mol%) OH purple LED (390 nm) 4Å mol sieves, DMA:THF (1:1) 69a D H 69d 78% yield >99% Deuterium incorporation N OH O (1 equiv) O N Ti(TPP)Cl2 (15 mol%) HE (2.0 equiv) 69e purple LED (390 nm) 4Å mol sieves, DMA:THF (1:1) 69a Ti O O OEt O N Detected by HRMS m/z calc’d for C20H28NO+ [M+H]+ = 298.2165 found: 298.2165 standard conditions no conversion observed X N.R. 102 To support our hypothesis of a radical intermediate, we added TEMPO as a radical trap to our standard conditions. The reaction shut down, and we only observed trace dimer formation. Subjecting the mixture to HRMS analysis, we detected the adduct 69e, with a match on its exact mass (see Experimental Section). Lastly, we wanted to rule out any Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 192 potential in-situ activation of our alcohol by the Hantzsch ester, as observed by Sato, Morisaki, and co-workers.16 We therefore synthesized the adduct 102 and subjected it to our reaction conditions. We observed no conversion of the substrate, cleanly isolating unreacted starting material. Given these results, we propose a potential catalytic cycle, starting from our Ti(IV) precatalyst (Figure 3.4.2). As shown in literature precedent, the Ti(IV) species can easily be reduced to Ti(III). In our case, we propose photoexcitation of the porphyrin framework by purple LEDs through ligand to metal charge transfer (LMCT), making the titanium center viable for reductive quenching by the Hantzsch ester.17,18 The reduced Ti(III) species can coordinate the alcohol starting material, initiating homolytic C– O bond cleavage. This results in generation of the alkyl radical intermediate, which can undergo H atom transfer with the Hantzsch ester radical cation. The Ti(IV)-oxo species can be turned over with the two equivalents of HCl generated in the course of the reaction, producing water as a byproduct, and closing the catalytic cycle with regeneration of our precatalyst.19 Figure 3.4.2 Preliminary mechanistic proposal. H H Cl Ph Ph LMCT & reductive quenching N IV N N Ti N H 2O HCl + py HCl Ph N Ti IV Me H H EtO2C Cl Ph Ph N N N III N N Ti N Ph Ph Me Ph Ph R Me N H HE HE Cl Ph Cl N CO2Et HE O Ph Ph EtO2C CO2Et Me N H Cl HE Cl OH R H – py HCl EtO2C O Ph HE Cl R Ph N III N N Ti N Ph CO2Et R Me Ph HCl N H Me Cl py HCl Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 3.5 193 USE IN GIESE ADDITION AND CROSS-COUPLING Building on the value of the carbon-centered radical, we tested interception of the intermediate for downstream functionalization (Figure 3.5.1). When adding an excess of methyl methacrylate to the reaction, we could isolate the Giese addition product 103 in 48% yield. Furthermore, when adding one equivalent of phenyl bromide and 10 mol% of nickel catalyst to substrate 74a, we were delighted to observe formation of the crosscoupled product 104 in 13% yield.20,21 These results further validate our radical mechanism and present the generality of this system to be employed in radical transformations, greatly increasing its synthetic value. Figure 3.5.1 Interception of radical for Giese addition and Nickel cross-coupling. O O OH Me Me OMe OMe (10 equiv) Ti standard conditions 69a 103 48% yield Ni(dtbbpy)Br2 (10 mol%) Br OH (1 equiv) Ti 74a 3.6 standard conditions 104 13% yield CONCLUSION In summary, we present the unique catalytic activity of a titanium porphyrin complex and its ability to activate C–O bonds, presumed by generation of an alkyl radical. While usually a two-step process, we present a novel catalytic system that achieves the direct Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 194 transformation with minimal additives. Unlike other titanium deoxygenations, we harness the photoabsorption of a porphyrin framework to photoexcite the catalyst, using Hantzsch ester as mild reductant. This creates reaction conditions with high functional group tolerance, excluding the addition of metal reductants or chlorosilanes to turn over the catalyst. We demonstrated our reaction on a variety of substrates, showcasing the synthetic utility for diarylmethanes, cinnamyl alcohols, as well as allylic alcohols. In preliminary investigations we intercept the radical intermediate, employing it successfully for Giese addition and nickel-catalyzed cross coupling. This demonstrates the compatibility of the method for general entry into radical chemistry directly from alcohols. With the ability to manipulate the porphyrin framework and conduct further in-depth mechanistic interrogations, the potential of the titanium catalyst is extensive, with future studies aimed at the activation of aliphatic alcohols as well. 3.7 EXPERIMENTAL SECTION 3.7.1 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.22 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, panisaldehyde, or KMnO4 staining. Silicycle SiliaFlash® P60 Academic Silica gel (particle size 40–63 μm) was used for flash chromatography. 1H NMR spectra were recorded on Varian Inova 500 MHz and 600 MHz and Bruker 400 MHz spectrometers and are reported Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 195 relative to residual CHCl3 (δ 7.26 ppm), C6D6 (δ 7.16 ppm) or CD3OD (δ 3.31 ppm). 13C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer (125 MHz) and Bruker 400 MHz spectrometers (101 MHz) and are reported relative to CHCl3 (δ 77.16 ppm), C6D6 (δ 128.06 ppm) or CD3OD (δ 49.01 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 13 C NMR are reported in terms of chemical shifts (δ ppm). IR spectra were obtained by use of a Perkin Elmer Spectrum BXII spectrometer or Nicolet 6700 FTIR spectrometer using thin films deposited on NaCl plates and reported in frequency of absorption (cm-1). UVVis spectra were obtained by use of a Doube Beam Thermo Fisher Evolution 201 UV-Vis Spectrophotometer and reported in absorbance over wavelength (nm). High resolution mass spectra (HRMS) were obtained using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI+) mode or a JOEL JMS-T2000 AccuTOF GC-Alpha high resolution mass spectrometer using field desorption (FD+) ionization, or field ionization (FI+). Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 3.7.2 EXPERIMENTAL PROCEDURES 3.7.2.1 Synthesis of Ti(TPP)Cl2: Ph Ph NH NH n-BuLi, hexanes then THF then TiCl4 N N 196 Ph N Cl Ph N Ph Ph N Ti Cl N Ph Ph TPP Ti(TPP)Cl2 Ti(TPP)Cl2: A Schlenk flask was flame-dried under vacuum and charged with TPP (1 g, 1.6 mmol, 1.0 equiv), which had previously been suspended with benzene (2x), the solvent evaporated under reduced pressure and dried under high-vacuum. The starting material was suspended in toluene (40 mL), which had previously been degassed using the freeze-pumpthaw method (3x). A solution of n-BuLi (2.5 M in hexanes, 1.3 mL, 3.28 mmol, 2.05 equiv) was added dropwise at room temperature, upon which the solution turned bright “forest green”. After stirring for 10 min, TiCl4 (0.7 mL, 6.4 mmol, 4.0 equiv) was added dropwise, the reaction mixture heated to 50 ºC in an oil bath and stirred for an additional 2 h. The reaction mixture was cooled to room temperature and the solvent evaporated to near dryness under reduced pressure. The residue was redissolved in a minimal amount of methylene chloride and layered with a surplus of hexanes. After diffusion over 72 h, a dark solid had crystallized, which was filtered off in a glovebox under inert atmosphere. The crystals were washed with hexanes to yield the product Ti(TPP)Cl2 (0.84 g, 1.15 mmol, 72% yield) as a dark-green solid. UV-Vis (CH2Cl2): 315, 374, 400, 424 (Soret), 552 nm; 1H NMR (600 MHz, C6D6) δ 8.91 (s, 8H), 7.91 (d, J = 7.6 Hz, 8H), 7.45 (t, J = 7.7 Hz, 4H), 7.37 (t, J = 7.6 Hz, 8H); HRMS (FD+): m/z calc’d for C44H28Cl2N4Ti [M]+•: 730.1165, found 730.1158. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 197 Figure 3.7.2.1.1: UV-Vis spectrum of Ti(TPP)Cl2. Data collected at room temperature (21 ºC). Sample prepared under inert atmosphere in a 4mm quartz cuvette in CH2Cl2. 3.7.2.2 GENERAL REACTION PROCEDURE A: Ph OH Phenyl(POR)TiCl2 (15 mol%) Hantzsch Ester (2.0 equiv) purple LED (390 nm) 4Å mol sieves DMA:THF (1:1) H N Cl Ph N Ti N Cl N Ph Ph Ti(TPP)Cl2 A 5mL microwave-vial was charged with a magnetic stir bar, the starting material alcohol (0.05 mmol, 1.0 equiv) and Hantzsch ester (25.6 mg, 0.1 mmol, 2.0 equiv) and transferred into a glovebox under N2. The titanium catalyst Ti(TPP)Cl2 (5.6 mg, 0.0075 mmol, 15 mol %) was weighed out, transferred into the reaction vial and the contents dissolved using a solvent mixture of THF:DMA (1:1, 1.0 mL, 0.05 M). Previously activated mol sieves (4Å, 300 mg, 6g/mmol) were added and the vial sealed with an aluminum cap using the appropriate crimper. The sealed reaction vial was transferred out of the glovebox and Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 198 fastened above a Kessil lamp (PR160L-390nm), approximately 2-3 cm above the light source. The lamp was equipped with a reflective mirror and stirred using a magnetic stir plate set at 800 rpm. The reaction mixture was irradiated for 12-16h, under ventilation with two fans and a fume hood exhaust. Upon completion, the internal temperature of the reaction mixture had reached between 35-40 ºC. The vial was transferred to a fume hood, the reaction quenched with an aqueous solution of LiCl (10% w/v, 2 mL) and extracted with organic solvent. The extract was directly analyzed by quantitative 1H-NMR or concentrated under reduced pressure and purified using flash chromatography on silica gel. 3.7.2.3 SUBSTRATES FOR DEOXYGENATION OH Me A 69a 69b Reaction performed according to General Procedure A, using starting material 69a (7.9 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 69b (6.0 mg, 0.042 mmol, 84% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.18 – 7.97 (m, 1H), 7.92 – 7.83 (m, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.62 – 7.45 (m, 2H), 7.44 – 7.30 (m, 2H), 2.72 (s, 3H). The spectroscopic data is in agreement with the values previously reported.23 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 199 OH A THF 69a 69c Reaction performed according to General Procedure A, using starting material 69a (7.9 mg, 0.05 mmol) and THF (1.0 mL) as solvent. The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 69c (6.3 mg, 0.023 mmol, 90% yield) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 7.9 Hz, 2H), 7.93 – 7.87 (m, 2H), 7.76 (d, J = 8.1 Hz, 2H), 7.62 – 7.46 (m, 4H), 7.45 – 7.33 (m, 4H), 3.52 (s, 4H). The spectroscopic data is in agreement with the values previously reported.24 OH A 70a Me 70b Reaction performed according to General Procedure A, using starting material 70a (5.4 mg, 0.05 mmol). The aqueous layer was extracted with CDCl3 (2 x 0.5 mL) and the combined organic layers spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 mL) was directly transferred into an NMR tube and the yield of 70b (0.028 mmol, 56% yield) determined by quantitative 1H-NMR with 1,3,5-trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.25 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst OH 200 A 71a 71b Reaction performed according to General Procedure A, using starting material 71a (6.7 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 71b (2.3 mg, 0.02 mmol, 39% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.24 (dt, J = 7.2, 3.6 Hz, 2H), 7.17 – 7.12 (m, 2H), 2.93 (t, J = 7.4 Hz, 4H), 2.08 (p, J = 7.4 Hz, 2H). The spectroscopic data is in agreement with the values previously reported.26 A OH 72a 72b Reaction performed according to General Procedure A, using starting material 72a (8.8 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 72b (1.2 mg, 0.0075 mmol, 15% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.33 – 7.27 (m, 2H), 7.23 – 7.14 (m, 3H), 2.56 – 2.45 (m, 1H), 1.86 (tddd, J = 11.0, 6.4, 3.1, 1.6 Hz, 4H), 1.75 (dtt, J = 12.5, 3.1, 1.5 Hz, 1H), 1.50 – 1.32 (m, 4H), 1.32 – 1.14 (m, 1H). Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 201 The spectroscopic data is in agreement with the values previously reported.27 OH A 73a 73b Reaction performed according to General Procedure A, using starting material 73a (8.6 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 73b (2.1 mg, 0.014 mmol, 27% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.83 – 7.74 (m, 3H), 7.63 (s, 1H), 7.49 – 7.38 (m, 2H), 7.36 (dd, J = 8.4, 1.8 Hz, 1H), 2.82 (q, J = 7.6, 2H), 1.33 (t, J = 7.6 Hz, 3H). The spectroscopic data is in agreement with the values previously reported.26 Me OH A 74a 74b Reaction performed according to General Procedure A, using starting material 74a (9.2 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 74b (6.6 mg, 0.039 mmol, 78% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.60 – 7.56 (m, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.36 – 7.30 (m, 1H), 7.27 – 7.23 (m, 2H), 2.40 (s, 3H). Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 202 The spectroscopic data is in agreement with the values previously reported.28 OH Me A MeO OMe MeO 75a OMe 75b Reaction performed according to General Procedure A, using starting material 75a (8.4 mg, 0.05 mmol). The aqueous layer was extracted with CDCl3 (2 x 0.5 mL) and the combined organic layers spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 mL) was directly transferred into an NMR tube and the yield of 75b (0.013 mmol, 25% yield) determined by quantitative 1H-NMR with 1,3,5-trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.29 OH OEt OEt A O 76a O 76b Reaction performed according to General Procedure A, using starting material 76a (9.0 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes/diethyl ether), to give product 76b (5.7 mg, 0.035 mmol, 69% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.35 – 7.24 (m, 5H), 4.15 (q, J = 7.1 Hz, 2H), 3.61 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H). The spectroscopic data is in agreement with the values previously reported.30 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 203 OH A 77a 77b Reaction performed according to General Procedure A, using starting material 77a (9.2 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 77b (4.9 mg, 0.029 mmol, 58% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.32 – 7.26 (m, 4H), 7.23 – 7.16 (m, 6H), 3.99 (s, 2H). The spectroscopic data is in agreement with the values previously reported.31 OH A 78a 78b Reaction performed according to General Procedure A, using starting material 78a (9.1 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 78b (7.7 mg, 0.047 mmol, 93% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.4 Hz, 2H), 7.55 (dt, J = 7.4, 1.0 Hz, 2H), 7.40 – 7.35 (m, 2H), 7.30 (td, J = 7.4, 1.2 Hz, 2H), 3.91 (s, 2H). The spectroscopic data is in agreement with the values previously reported.32 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 204 HO A 79a 79b Reaction performed according to General Procedure A, using starting material 79a (10.4 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 79b (8.4 mg, 0.044 mmol, 88% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3) δ 7.34 – 7.25 (m, 6H), 7.20 (td, J = 7.0, 1.8 Hz, 2H), 7.03 (s, 2H), 3.74 (s, 2H). The spectroscopic data is in agreement with the values previously reported.33 OH A MeO OMe MeO 80a OMe 80b Reaction performed according to General Procedure A, using starting material 80a (12.2 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes/diethyl ether), to give product 80b (5.8 mg, 0.025 mmol, 51% yield) as a colorless oil. 1 H NMR (600 MHz, CDCl3) δ 7.09 (d, J = 8.6 Hz, 4H), 6.82 (d, J = 8.6 Hz, 4H), 3.87 (s, 2H), 3.78 (s, 6H). The spectroscopic data is in agreement with the values previously reported.34 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 205 OH A 81a 81b Reaction performed according to General Procedure A, using starting material 81a (10.6 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 81b (7.3 mg, 0.038 mmol, 75% yield) as a colorless oil. 1 H NMR (600 MHz, CDCl3) δ 7.12 – 7.02 (m, 8H), 3.90 (s, 2H), 2.31 (s, 6H). The spectroscopic data is in agreement with the values previously reported.35 OH A F F 82a F F 82b Reaction performed according to General Procedure A, using starting material 82a (11.0 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 82b (3.5 mg, 0.017 mmol, 33% yield) as a colorless oil. 1 H NMR (600 MHz, CDCl3) δ 7.11 (dd, J = 8.6, 5.4 Hz, 4H), 6.97 (t, J = 8.7 Hz, 4H), 3.92 (s, 2H). The spectroscopic data is in agreement with the values previously reported.36 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 206 OH A OH OH 83a 83b Reaction performed according to General Procedure A, using starting material 83a (10.0 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes/ethyl acetate), to give product 83b (5.7 mg, 0.031 mmol, 62% yield) as a colorless oil. 1 H NMR (600 MHz, CDCl3) δ 7.32 – 7.27 (m, 2H), 7.25 – 7.18 (m, 3H), 7.15 – 7.10 (m, 2H), 6.89 (td, J = 7.4, 1.2 Hz, 1H), 6.79 (dd, J = 7.9, 1.2 Hz, 1H), 4.66 (brs, 1H), 4.00 (s, 2H). The spectroscopic data is in agreement with the values previously reported.37 OH A O O 84a 84b Reaction performed according to General Procedure A, using starting material 84a (9.9 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes/diethyl ether), to give product 84b (3.4 mg, 0.019 mmol, 37% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 7.22 – 7.13 (m, 4H), 7.06 – 6.97 (m, 4H), 4.06 (s, 2H). The spectroscopic data is in agreement with the values previously reported.38 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst OH 207 A + 85a + 85b (E) 85d iso 85c (Z) Reaction performed according to General Procedure A, using starting material 85a (6.7 mg, 0.05 mmol). The aqueous layer was extracted with CDCl3 (2 x 0.5 mL) and the combined organic layers spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 mL) was directly transferred into an NMR tube and the yield of 85b:85c:85d (2:1:1.2, 0.038 mmol, 76% yield) determined by quantitative 1H-NMR with 1,3,5-trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.39-41 OH A + F F 86a + F 86b (E) F 86d iso 86c (Z) Reaction performed according to General Procedure A, using starting material 86a (7.6 mg, 0.05 mmol). The aqueous layer was extracted with CDCl3 (2 x 0.5 mL) and the combined organic layers spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 mL) was directly transferred into an NMR tube and the yield of 86b:86c:86d (4.5:1:1.1, 0.04 mmol, 79% yield) determined by quantitative 1H-NMR with 1,3,5-trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.42-44 OH Cl A + 87a + Cl Cl 87b (E) Cl 87c (Z) 87d iso Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 208 Reaction performed according to General Procedure A, using starting material 87a (8.4 mg, 0.05 mmol). The aqueous layer was extracted with CDCl3 (2 x 0.5 mL) and the combined organic layers spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 mL) was directly transferred into an NMR tube and the yield of 87b:87c:87d (7.8:1:2.5, 0.04 mmol, 80% yield) determined by quantitative 1H-NMR with 1,3,5-trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.45,46 OH Br A + 88a + Br Br 88b (E) Br 88c (Z) 88d iso Reaction performed according to General Procedure A, using starting material 88a (10.7 mg, 0.05 mmol). The aqueous layer was extracted with diethyl ether (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give a mixture of products 88b:88c:88d (8.9:1:2.8, 6.9 mg, 0.035 mmol, 69% yield) as a colorless oil. 88b, (E): 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.33 (dd, J = 15.8, 1.6 Hz, 1H), 6.23 (dq, J = 15.7, 6.3 Hz, 1H), 1.87 (dd, J = 6.4, 1.4 Hz, 3H). 88c, (Z): 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.5 Hz, 2H), 7.20 – 7.13 (m, 2H), 6.35 (dd, J = 11.7, 1.9 Hz, 1H), 5.82 (dq, J = 11.6, 7.2 Hz, 1H), 1.71 (d, J = 6.5 Hz, 3H). 88d, iso: 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 5.93 (ddt, J = 17.0, 10.5, 6.6 Hz, 1H), 5.10 – 5.08 (m, 1H), 5.06 (dd, J = 8.8, 1.6 Hz, 1H), 3.34 (d, J = 6.7 Hz, 2H). Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 209 The spectroscopic data is in agreement with the values previously reported.47-49 OH A + HO 89a + HO HO 89b (E) HO 89d iso 89c (Z) Reaction performed according to General Procedure A, using starting material 89a (7.5 mg, 0.05 mmol). The aqueous layer was extracted with CDCl3 (2 x 0.5 mL) and the combined organic layers spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 mL) was directly transferred into an NMR tube and the yield of 89b:89c:89d (2:1:1.5, 0.026 mmol, 52% yield) determined by quantitative 1H-NMR with 1,3,5-trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.50-52 MeO OH MeO A MeO MeO + MeO MeO 90a MeO + 90b (E) MeO 90c (Z) 90d iso Reaction performed according to General Procedure A, using starting material 90a (9.7 mg, 0.05 mmol). The aqueous layer was extracted with diethyl ether (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes/diethyl ether), to give a mixture of products 90b:90c:90d (3.3:1:1.7, 4.3 mg, 0.024 mmol, 48% yield) as a colorless oil. 90b, (E): 1H NMR (600 MHz, CDCl3) δ 6.91 – 6.82 (m, 2H), 6.80 (d, J = 8.2 Hz, 1H), 6.34 (dd, J = 15.6, 1.8 Hz, 1H), 6.11 (dq, J = 15.5, 6.6 Hz, 1H), 3.89 (s, 3H), 3.87 (s, 3H), 1.87 (dd, J = 6.6, 1.7 Hz, 3H). Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 210 90c, (Z): 1H NMR (600 MHz, CDCl3) δ 6.91 – 6.82 (m, 2H), 6.80 (m, 1H), 6.39 – 6.36 (m, 1H), 5.72 (dq, J = 11.5, 7.2 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 1.91 (dd, J = 7.2, 1.9 Hz, 3H). 90d, iso: 1H NMR (600 MHz, CDCl3) δ 6.84 (m, 1H), 6.75 – 6.71 (m, 2H), 5.96 (ddt, J = 16.7, 9.9, 6.7 Hz, 1H), 5.11 – 5.00 (m, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 3.34 (d, J = 6.7 Hz, 2H). The spectroscopic data is in agreement with the values previously reported.53-55 OH A + N + N N 91a 91b (E) N 91d iso 91c (Z) Reaction performed according to General Procedure A, using starting material 91a (6.8 mg, 0.05 mmol). The aqueous layer was extracted with CDCl3 (2 x 0.5 mL) and the combined organic layers spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 mL) was directly transferred into an NMR tube and the yield of 91b:91c:91d (2.5:1:1.3, 0.041 mmol, 82% yield) determined by quantitative 1H-NMR with 1,3,5-trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.56,57 S OH 92a A S S + + 92b 92c S 92d Reaction performed according to General Procedure A, using starting material 92a (7.0 mg, 0.05 mmol). The aqueous layer was extracted with CDCl3 (2 x 0.5 mL) and the combined organic layers spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 211 mL) was directly transferred into an NMR tube and the yield of 92b:92c:92d (1.4:1.2:1, 0.039 mmol, 77% yield) determined by quantitative 1H-NMR with 1,3,5-trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.58-60 OH O O A O O Stiripentol (93a) 93b Reaction performed according to General Procedure A, using starting material 93a (11.7 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes/diethyl ether), to give product 93b (5.2 mg, 0.024 mmol, 47% yield) as a colorless solid. 1 H NMR (400 MHz, CDCl3) δ 6.73 (d, J = 7.9 Hz, 1H), 6.69 – 6.56 (m, 2H), 5.92 (s, 2H), 5.54 (dt, J = 15.5, 1.3 Hz, 1H), 5.41 (dt, J = 15.4, 6.7 Hz, 1H), 3.23 (dq, J = 6.6, 0.6 Hz, 2H), 1.01 (s, 9H). 13 C NMR (101 MHz, CDCl3) δ 147.7, 145.8, 143.3, 135.3, 123.6, 121.2, 109.1, 108.2, 100.9, 38.9, 33.1, 29.9. IR (neat film, NaCl) 2954, 2927, 1503, 1487, 1361, 1245, 1095, 1040, 970, 940, 799 cm– 1 . HRMS (FI+): m/z calc’d for C14H18O2 [M]+•: 218.1301, found 218.1295. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 212 A HO Geraniol (94a) 94b Reaction performed according to General Procedure A, using starting material 94a (7.7 mg, 0.05 mmol). The aqueous layer was extracted with a mixture of pentane (0.3 mL) and CDCl3 (0.5 mL) and the organic layer spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 mL) was directly transferred into an NMR tube and the yield of 94b (E/Z = 2/1, 0.026 mmol, 51% yield) determined by quantitative 1H-NMR with 1,3,5trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.61 A HO Geranylgeraniol (95a) 95b Reaction performed according to General Procedure A, using starting material 95a (14.5 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 95b (E/Z = 2.1/1, 6.6 mg, 0.024 mmol, 48% yield) as a colorless solid. Major isomer of 3ba (E): 1H NMR (400 MHz, CDCl3) δ 5.17 – 5.06 (m, 4H), 2.12 – 2.02 (m, 7H), 2.02 – 1.94 (m, 5H), 1.68 (s, 3H), 1.60 (s, 12H), 1.57 (d, J = 6.8, 3H). The spectroscopic data is in agreement with the values previously reported.62 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst OH 213 A (-)-perillyl alcohol (96a) 96b Reaction performed according to General Procedure A, using starting material 96a (7.6 mg, 0.05 mmol). The aqueous layer was extracted with a mixture of pentane (0.3 mL) and CDCl3 (0.5 mL) and the organic layer spiked with 1,3,5-trimethoxy benzene (1.0 equiv). An aliquot (0.5 mL) was directly transferred into an NMR tube and the yield of 96b (0.014 mmol, 28% yield) determined by quantitative 1H-NMR with 1,3,5-trimethoxy benzene as an internal standard. The spectroscopic data aligned with the values previously reported.63 A OH Nootkatol (97a) 97b Reaction performed according to General Procedure A, using starting material 97a (11 mg, 0.05 mmol). The aqueous layer was extracted with pentane (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes), to give product 97b (2.1 mg, 0.01 mmol, 21% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 5.37 – 5.29 (m, 1H), 4.68 (m, 2H), 2.38 – 2.15 (m, 2H), 2.08 (ddd, J = 13.9, 4.2, 2.6 Hz, 1H), 2.04 – 1.90 (m, 2H), 1.87 (dt, J = 12.8, 2.8 Hz, 1H), 1.76 (m, 2H), 1.71 (s, 3H), 1.44 – 1.37 (m, 3H), 1.19 (m, 1H), 0.95 (s, 3H), 0.88 (d, J = 6.3 Hz, 3H). Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 13 214 C NMR (101 MHz, CDCl3) δ 150.9, 143.3, 120.3, 108.4, 45.1, 41.2, 41.1, 38.0, 33.3, 32.8, 27.3, 26.1, 21.0, 18.6, 15.8. The spectroscopic data is in agreement with the values previously reported.64 3.7.2.4 SYNTHETIC DERIVATIVES K2CO3 O O Br H OH 98 CO2Et CO2Et H 35% yield O 98a In a round-bottom flask equipped with a reflux condenser, aldehyde 98 (200 mg, 1.64 mmol, 1.0 equiv) was dissolved in acetonitrile (2.4 mL, 0.7M). K2CO3 (452 mg, 3.28 mmol, 2.0 equiv) and ethyl 2-bromo-2-methylbutanoate (514 mg, 2.46 mmol, 1.5 equiv) were added and the reaction mixture refluxed for 72 h. The reaction mixture was cooled to room temperature and quenched with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with ethyl acetate (3x), the combined organic layers dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (10-20% ethyl acetate/hexanes) to give the product 98a (143 mg, 0.57 mmol, 35% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 2.12 – 1.91 (m, 2H), 1.60 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 190.9, 173.3, 161.2, 131.7, 130.4, 117.9, 82.4, 61.7, 32.9, 20.9, 14.2, 7.8. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 215 IR (neat film, NaCl) 2979, 2943, 2737, 1731, 1694, 1599, 1578, 1504, 1463, 1379, 1309, 1238, 1156, 1126, 1016, 934, 838, 620 cm–1. HRMS (ESI+): m/z calc’d for C14H19O4+ [M+H]+: 251.1278, found 251.1278. MgCl O OH CO2Et H O Cl CO2Et 78% yield Cl 98a O 98b In a vial under inert atmosphere, 1-chloro-4-iodobenzene (48 mg, 0.2 mmol, 1.0 equiv) was dissolved in THF (1.3 mL, 0.15 M) and the solution cooled to –78 ºC. iPrMgCl•LiCl (1.3M in THF, 0.15 mL, 0.2 mmol, 1.0 equiv) was added dropwise and the reaction mixture stirred for 15 min. A solution of aldehyde 98a (50 mg, 0.2 mmol, 1.0 equiv) in THF (0.25 mL) was added dropwise and the reaction warmed up to room temperature over the course of 16 h. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl, extracted with ethyl acetate (3x), the combined organic layers dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (20% ethyl acetate/hexanes) to give the product 98b (56 mg, 0.16 mmol, 78% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.29 (s, 4H), 7.18 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 8.7 Hz, 2H), 5.74 (s, 1H), 4.22 (qd, J = 7.1, 1.5 Hz, 2H), 2.27 (brs, 1H), 1.96 (qd, J = 14.0, 7.5 Hz, 2H), 1.48 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 174.0, 155.3, 142.4, 137.0, 133.3, 128.6, 127.9, 127.7, 119.1, 119.1, 82.1, 75.3, 61.4, 32.7, 20.9, 20.8, 14.3, 7.9. IR (neat film, NaCl) 3444, 2978, 1729, 1608, 1504, 1228, 1168, 1126, 1013, 823 cm–1. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 216 HRMS (ESI+): m/z calc’d for C20H22ClO3+ [M–OH]+: 345.1252, found 345.1254. OH CO2Et Cl A CO2Et Cl O O beclobrate (99) 98b Reaction performed according to General Procedure A, using starting material 98b (18 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes/diethyl ether), to give beclobrate (99, 11.6 mg, 0.034 mmol, 67% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 4.23 (q, J = 7.2 Hz, 2H), 3.87 (s, 2H), 2.06 – 1.86 (m, 2H), 1.47 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.5 Hz, 3H). The spectroscopic data is in agreement with the values previously reported.65 TMPMgCl LiCl O then H MeO N MeO 100 69% yield OMe MeO OMe MeO N HO 100a OMe OMe In a Schlenk flask under inert atmosphere, isoquinoline 100 (100 mg, 0.53 mmol, 1.0 equiv) was dissolved in THF (2.1 mL, 0.25 M) and a solution of TMPMgCl•LiCl (1.0 M in THF, 0.8 mL, 0.8 mmol, 1.5 equiv) was added dropwise. The reaction was stirred at room temperature for 4 h, after which it was cooled to 0 ºC and a solution of 3,4-dimethoxy benzaldehyde (133 mg, 0.8 mmol, 1.5 equiv) in THF (1 mL) was added dropwise. The Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 217 reaction mixture was stirred for 16 h at room temperature, after which a 1 M aqueous solution of HCl was added. The aqueous layer was extracted with ethyl acetate (3x), the combined organic layers dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (acetone/hexanes) to give the product 100a (130 mg, 0.37 mmol, 69% yield) as a yellow solid. 1 H NMR (600 MHz, CDCl3) δ 8.40 (d, J = 5.7 Hz, 1H), 7.52 (d, J = 5.6 Hz, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 6.91 (dd, J = 8.2, 2.1 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.17 (s, 1H), 3.99 (s, 3H), 3.82 (s, 3H), 3.81 (s, 3H), 3.76 (s, 3H). The spectroscopic data is in agreement with the values previously reported.66 MeO MeO A N MeO HO 100a OMe OMe MeO N OMe papaverine (101) OMe Reaction performed according to General Procedure A, using starting material 100a (17.8 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (acetone/hexanes), to give papaverine (101, 13 mg, 0.039 mmol, 77% yield) as a white solid. 1 H NMR (600 MHz, CDCl3) δ 8.37 (d, J = 5.7 Hz, 1H), 7.43 (d, J = 5.7 Hz, 1H), 7.35 (s, 1H), 7.05 (s, 1H), 6.84 – 6.78 (m, 2H), 6.76 (d, J = 8.5 Hz, 1H), 4.53 (s, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H), 3.77 (s, 3H). The spectroscopic data is in agreement with the values previously reported.66 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 3.7.2.5 218 MECHANISTIC EXPERIMENTS D D O paraformaldehyde-d2 CO2Et EtO2C CO2Et + NH4OAc N H A round-bottom flask was charged with ethyl acetoacetate (2.6 g, 20 mmol, 4.0 equiv), paraformaldehyde-d2 (162 mg, 5 mmol, 1.0 equiv) and NH4OAc (771 mg, 10 mmol, 2.0 equiv). The contents were suspended in water (6 mL) and the reaction mixture heated at 90 ºC for 17 h. The heating source was removed and the reaction mixture left to slowly cool to ambient temperature. The resulting solid was filtered off and the crystals consecutively washed with H2O and a minimal amount of ethanol to give the deuterated Hantzsch ester (701 mg, 2.75 mmol, 55% yield) as a yellow solid. 1 H NMR (600 MHz, CDCl3) δ 5.12 (s, 1H), 4.17 (q, J = 7.1 Hz, 4H), 2.19 (s, 6H), 1.28 (t, J = 7.1 Hz, 6H). The spectroscopic data is in agreement with the values previously reported.67 D D EtO2C OH CO2Et (2 equiv) N H Ti(TPP)Cl2 (15 mol%) H H D purple LED (390 nm) 4Å mol sieves, DMA:THF (1:1) 69a 69d Reaction performed according to General Procedure A, using d2-Hantzsch ester (25.5 mg, 0.1 mmol, 2.0 equiv) and starting material 69a (7.9 mg, 0.05 mmol). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 219 chromatography on silica gel (hexanes) to give deuterated product 69d (5.6 mg, 0.039 mmol, 78% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.04 – 7.98 (m, 1H), 7.88 – 7.83 (m, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.55 – 7.45 (m, 2H), 7.42 – 7.30 (m, 2H), 2.70 (s, 2H). The spectroscopic data is in agreement with the values previously reported.68 N OH O (1 equiv) Phenyl(POR)TiCl2 (15 mol%) HE (2.0 equiv) O N purple LED (390 nm) 4Å mol sieves, DMA:THF (1:1) 69a 69e Reaction performed according to General Procedure A, using starting material 69a (7.9 mg, 0.05 mmol) with the addition of TEMPO (7.8 mg, 0.05 mmol, 1.0 equiv). The aqueous layer was extracted with ethyl acetate and the extract submitted for analysis of 69e by mass spectrometry. HRMS (ESI+): m/z calc’d for C20H28NO+ [M+H]+: 298.2165, found 298.2165. Figure 3.7.2.5.1: Mass trace and analysis of adduct 69e. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst OH O O + OEt EtO OEt O N 69a O O Cs2CO3 DMF 220 N 102 In a reaction vial starting material 69a (16 mg, 0.1 mmol, 1.0 equiv), oxidized Hantzsch ester (100 mg, 0.4 mmol, 4.0 equiv) and Cs2CO3 (130 mg, 0.4 mmol, 4.0 equiv) were suspended in DMF (1.0 mL) and the reaction mixture stirred for 15 h. An aqueous solution of LiCl (10% w/v) was added and the aqueous layer extracted with diethyl ether (3x). The combined organic layers were dried over Na2SO4, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (5-10% diethyl ether/hexanes) to give the product 102 (19.2 mg, 0.053 mmol, 53% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.12 (dt, J = 8.7, 1.0 Hz, 1H), 7.94 – 7.87 (m, 2H), 7.64 (dd, J = 7.0, 1.2 Hz, 1H), 7.62 – 7.45 (m, 3H), 5.83 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 2.82 (d, J = 1.7 Hz, 6H), 1.34 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.9, 162.7, 162.5, 141.3, 133.9, 131.9, 131.2, 129.7, 129.0, 128.0, 126.8, 126.2, 125.4, 123.6, 123.2, 122.9, 65.7, 61.5, 25.2, 25.1, 14.3. IR (neat film, NaCl) 2927, 1721, 1594, 1553, 1442, 1368, 1282, 1225, 1101, 1039, 770 cm–1. HRMS (ESI+): m/z calc’d for C22H22NO4+ [M+H]+: 364.1543, found 364.1671. 3.7.2.6 GIESE ADDITON AND CROSS-COUPLING Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 221 O O OH OMe OMe (10 equiv) A 103 69a Reaction performed according to General Procedure A, using starting material 69a (7.9 mg, 0.05 mmol) with addition of methyl methacrylate (50 mg, 0.5 mmol, 10.0 equiv). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (diethyl ether/hexanes) to give 103 (5.8 mg, 0.024 mmol, 48% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.07 – 8.01 (m, 1H), 7.85 (dd, J = 7.7, 1.5 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.55 – 7.44 (m, 2H), 7.39 (dd, J = 8.2, 7.0 Hz, 1H), 7.32 (dd, J = 7.2, 1.3 Hz, 1H), 3.72 (s, 3H), 3.16 – 2.99 (m, 2H), 2.65 – 2.54 (m, 1H), 2.15 (dddd, J = 13.8, 10.2, 8.2, 5.8 Hz, 1H), 1.85 (ddt, J = 13.5, 10.2, 5.9 Hz, 1H), 1.25 (d, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 177.2, 138.0, 134.0, 131.9, 128.9, 126.9, 126.2, 126.0, 125.7, 125.6, 123.9, 51.8, 39.6, 34.9, 30.9, 17.5. IR (neat film, NaCl) 2928, 1731, 1459, 1360, 1202, 779, 745 cm–1. HRMS (FI+): m/z calc’d for C16H18O2 [M] +•: 242.1301, found 242.1299. Ni(dtbbpy)Br2 (10 mol %) Br OH (1 equiv) A 74a 104 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 222 Reaction performed according to General Procedure A, using starting material 74a (9.2 mg, 0.05 mmol) with the addition of bromobenzene (7.9 mg, 0.05 mmol, 1.0 equiv) and Ni(dtbbpy)Br2 (2.4 mg, 0.005 mmol, 0.1 equiv). The aqueous layer was extracted with ethyl acetate (3 x 1.5 mL), dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel (hexanes) to give 104 (1.6 mg, 0.0065 mmol, 13% yield) as a colorless film. 1 H NMR (600 MHz, CDCl3) δ 7.59 – 7.55 (m, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.34 – 7.28 (m, 3H), 7.27 – 7.26 (m, 2H), 7.25 – 7.19 (m, 3H), 4.03 (s, 2H). The spectroscopic data is in agreement with the values previously reported.69 Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 223 3.8 REFERENCES AND NOTES (1) Zard, S. Z. Radical Reactions in Organic Synthesis; Oxford University Press, 2003. (2) For selected reviews see: (a) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. Radicals: Reactive Intermediates with Translational Potential. J. Am. Chem. Soc. 2016, 138 (39), 12692–12714. (b) Parsaee, F.; Senarathna, M. C.; Kannangara, P. B.; Alexander, S. N.; Arche, P. D. E.; Welin, E. R. Radical Philicity and Its Role in Selective Organic Transformations. Nat. Rev. Chem. 2021, 5 (7), 486–499. (3) Anwar, K.; Merkens, K.; Aguilar Troyano, F. J.; Gómez-Suárez, A. Radical Deoxyfunctionalisation Strategies. Eur. J. Org. Chem. 2022, 2022 (26), e202200330. (4) McCombie, S. W.; Motherwell, W. B.; Tozer, M. J. The Barton-McCombie Reaction. In Organic Reactions; John Wiley & Sons, Ltd, 2012; pp 161–432. https://doi.org/10.1002/0471264180.or077.02. (5) For selected seminal examples see: (a) Barton, D. H. R.; McCombie, S. W. A New Method for the Deoxygenation of Secondary Alcohols. J. Chem. Soc. Perkin 1 1975, No. 16, 1574–1585. (b) Dong, Z.; MacMillan, D. W. C. Metallaphotoredox-Enabled Deoxygenative Arylation of Alcohols. Nature 2021, 598 (7881), 451–456. (c) Togo, H.; Matsubayashi, S.; Yamazaki, O.; Yokoyama, M. Deoxygenative Functionalization of Hydroxy Groups via Xanthates with Tetraphenyldisilane. J. Org. Chem. 2000, 65 (9), 2816–2819. (d) Lackner, G. L.; Quasdorf, K. W.; Overman, L. E. Direct Construction of Quaternary Carbons from Tertiary Alcohols via Photoredox-Catalyzed Fragmentation of Tert-Alkyl N-Phthalimidoyl Oxalates. J. Am. Chem. Soc. 2013, 135 (41), 15342–15345. (e) Nawrat, C. C.; Jamison, C. R.; Slutskyy, Y.; MacMillan, D. W. C.; Overman, L. E. Oxalates as Activating Groups Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 224 for Alcohols in Visible Light Photoredox Catalysis: Formation of Quaternary Centers by Redox-Neutral Fragment Coupling. J. Am. Chem. Soc. 2015, 137 (35), 11270– 11273. (f) Ye, Y.; Chen, H.; Sessler, J. L.; Gong, H. Zn-Mediated Fragmentation of Tertiary Alkyl Oxalates Enabling Formation of Alkylated and Arylated Quaternary Carbon Centers. J. Am. Chem. Soc. 2019, 141 (2), 820–824. (g) Yu, L.; Li, S.; Ogawa, H.; Ma, Y.; Chen, Q.; Yamazaki, K.; Nagata, Y.; Nakamura, H. FeElectrocatalytic Deoxygenative Giese Reaction. Nat. Commun. 2025, 16 (1), 8379. (h) Pan, Q.; Yu, R.; Cai, Z.; Chen, Y. Direct Deoxyarylation of Non-Activated Alcohols. Angew. Chem. Int. Ed. (n/a), e20148. https://doi.org/10.1002/anie.202520148. (6) Cytochrome P450; Ortiz De Montellano, P. R., Ed.; Springer US: Boston, MA, 2005. (7) Schlichting, I.; Berendzen, J.; Chu, K.; Stock, A. M.; Maves, S. A.; Benson, D. E.; Sweet, R. M.; Ringe, D.; Petsko, G. A.; Sligar, S. G. The Catalytic Pathway of Cytochrome P450cam at Atomic Resolution. Science 2000, 287 (5458), 1615–1622. https://doi.org/10.1126/science.287.5458.1615. (8) Diéguez, H. R.; López, A.; Domingo, V.; Arteaga, J. F.; Dobado, J. A.; Herrador, M. M.; Quílez del Moral, J. F.; Barrero, A. F. Weakening C−O Bonds: Ti(III), a New Reagent for Alcohol Deoxygenation and Carbonyl Coupling Olefination. J. Am. Chem. Soc. 2010, 132 (1), 254–259. https://doi.org/10.1021/ja906083c. (9) Xie, H.; Guo, J.; Wang, Y.-Q.; Wang, K.; Guo, P.; Su, P.-F.; Wang, X.; Shu, X.-Z. Radical Dehydroxylative Alkylation of Tertiary Alcohols by Ti Catalysis. J. Am. Chem. Soc. 2020, 142 (39), 16787–16794. https://doi.org/10.1021/jacs.0c07492. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 225 (10) For selected examples employing titanium in deoxygenation of alcohols see: (a) Sumiyama, K.; Toriumi, N.; Iwasawa, N. Use of Isopropyl Alcohol as a Reductant for Catalytic Dehydoxylative Dimerization of Benzylic Alcohols Utilizing Ti−O Bond Photohomolysis. Eur. J. Org. Chem. 2021, 2021 (17), 2474–2478. (b) Lin, Q.; Tong, W.; Shu, X.-Z.; Chen, Y. Ti-Catalyzed Dehydroxylation of Tertiary Alcohols. Org. Lett. 2022, 24 (46), 8459–8464. (c) Suga, T.; Takahashi, Y.; Miki, C.; Ukaji, Y. Direct and Unified Access to Carbon Radicals from Aliphatic Alcohols by Cost-Efficient Titanium-Mediated Homolytic C−OH Bond Cleavage. Angew. Chem. Int. Ed. 2022, 61 (10), e202112533. (d) Suga, T.; Shimazu, S.; Ukaji, Y. Low-Valent Titanium-Mediated Radical Conjugate Addition Using Benzyl Alcohols as Benzyl Radical Sources. Org. Lett. 2018, 20 (17), 5389–5392. (e) Căciuleanu, A.; Vöhringer, F.; Fleischer, I. Titanium-Catalysed Deoxygenation of Benzylic Alcohols and Lignin Model Compounds. Org. Chem. Front. 2023, 10 (12), 2927–2935. (11) Berreau, L. M.; Hays, J. A.; Young, V. G. Jr.; Woo, L. K. Synthesis of Early Transition Metal Porphyrin Halide Complexes: First Structural Characterization of a Vanadium(III) Porphyrin Complex. Inorg. Chem. 1994, 33 (1), 105–108. (12) Zhang, Z.; Hilche, T.; Slak, D.; Rietdijk, N. R.; Oloyede, U. N.; Flowers II, R. A.; Gansäuer, A. Titanocenes as Photoredox Catalysts Using Green-Light Irradiation. Angew. Chem. Int. Ed. 2020, 59 (24), 9355–9359. (13) Seki, M.; Tapkir, S. R.; Nadiveedhi, M. R.; Mulani, S. K.; Mashima, K. New Synthesis of Diarylmethanes, Key Building Blocks for SGLT2 Inhibitors. ACS Omega 2023, 8 (19), 17288–17295. https://doi.org/10.1021/acsomega.3c01972. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 226 (14) Melzer, B.; Bracher, F. A Divergent Approach to Benzylisoquinoline-Type and Oxoaporphine Alkaloids via Regioselective Direct Ring Metalation of Alkoxy Isoquinolines. Org. Biomol. Chem. 2015, 13 (28), 7664–7672. (15) Larraufie, M.-H.; Pellet, R.; Fensterbank, L.; Goddard, J.-P.; Lacôte, E.; Malacria, M.; Ollivier, C. Visible-Light-Induced Photoreductive Generation of Radicals from Epoxides and Aziridines. Angew. Chem. Int. Ed. 2011, 50 (19), 4463–4466. (16) Yagi, S.; Morisaki, K.; Sato, Y. Direct Site-Selective Deoxygenation of Benzylalcohol Derivatives. Adv. Synth. Catal. 2025, 367 (14), e9590. (17) Chaudhuri, A.; Denkler, L. M.; Zhuo, Q.; Mandal, A.; Bunescu, A. LMCT-Driven Iron Photocatalysis: Mechanistic Insights and Synthetic Applications. Chem. – Eur. J. 2025, 31 (58), e02185. (18) Büchner, R.; Fondell, M.; Haverkamp, R.; Pietzsch, A.; Cruz, V. V. da; Föhlisch, A. The Porphyrin Center as a Regulator for Metal–Ligand Covalency and π Hybridization in the Entire Molecule. Phys. Chem. Chem. Phys. 2021, 23 (43), 24765–24772. (19) Li, H.; Li, Y.; Yuan, W.; Qu, A.; Chen, K.; Zhu, Y. Photoredox/Ti Dual-Catalyzed Dehydroxylative Ring-Opening Giese Reaction of Cyclobutanone Oximes. Green Synth. Catal. 2024, 5 (3), 159–164. (20) Suga, T.; Ukaji, Y. Nickel-Catalyzed Cross-Electrophile Coupling between Benzyl Alcohols and Aryl Halides Assisted by Titanium Co-Reductant. Org. Lett. 2018, 20 (24), 7846–7850. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 227 (21) Chen, F.; Xu, X.-H.; Chu, L.; Qing, F.-L. Visible-Light-Induced Nickel-Catalyzed Radical Cross-Couplings to Access α-Aryl-α-Trifluoromethyl Alcohols. Org. Lett. 2022, 24 (50), 9332–9336. (22) 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 (5), 1518–1520. (23) Molander, G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B. B-Alkyl Suzuki−Miyaura Cross-Coupling Reactions with Air-Stable Potassium Alkyltrifluoroborates. J. Org. Chem. 2003, 68 (14), 5534–5539. (24) Sahoo, S. K. An Unprecedented Oxidative Intermolecular Homo Coupling Reaction between Two sp3C–sp3C Centers under Metal-Free Condition. Tetrahedron Lett. 2016, 57 (31), 3476–3480. (25) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. NMR Chemical Shifts of Trace Impurities: Common Laboratory Solvents, Organics, and Gases in Deuterated Solvents Relevant to the Organometallic Chemist. Organometallics 2010, 29 (9), 2176–2179. (26) Saito, K.; Kondo, K.; Akiyama, T. B(C6F5)3-Catalyzed Hydrodesulfurization Using Hydrosilanes – Metal-Free Reduction of Sulfides. Org. Lett. 2015, 17 (13), 3366– 3369. (27) Cahiez, G.; Chaboche, C.; Duplais, C.; Moyeux, A. A New Efficient Catalytic System for the Chemoselective Cobalt-Catalyzed Cross-Coupling of Aryl Grignard Reagents with Primary and Secondary Alkyl Bromides. Org. Lett. 2009, 11 (2), 277– 280. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 228 (28) Karthikeyan, P.; Vanitha, A.; Radhika, P.; Suresh, K.; Sugumaran, A. Imidazolium Supported Palladium–Chloroglycine Complex: Recyclable Catalyst for Suzuki– Miyaura Coupling Reactions. Tetrahedron Lett. 2013, 54 (52), 7193–7197. (29) Koch, K.; Podlech, J.; Pfeiffer, E.; Metzler, M. Total Synthesis of Alternariol. J. Org. Chem. 2005, 70 (8), 3275–3276. (30) Xu, J.-X.; Wu, X.-F. Palladium-Catalyzed Decarboxylative Carbonylative Transformation of Benzyl Aryl Carbonates: Direct Synthesis of Aryl 2-Arylacetates. Org. Lett. 2018, 20 (18), 5938–5941. (31) Burns, M. J.; Fairlamb, I. J. S.; Kapdi, A. R.; Sehnal, P.; Taylor, R. J. K. Simple Palladium(II) Precatalyst for Suzuki−Miyaura Couplings: Efficient Reactions of Benzylic, Aryl, Heteroaryl, and Vinyl Coupling Partners. Org. Lett. 2007, 9 (26), 5397–5400. (32) Liu, T.-P.; Xing, C.-H.; Hu, Q.-S. Synthesis of Fluorene and Indenofluorene Compounds: Tandem Palladium-Catalyzed Suzuki Cross-Coupling and Cyclization. Angew. Chem. Int. Ed. 2010, 49 (16), 2909–2912. (33) Schmuck, C.; Wienand, W. The First Efficient Synthesis and Optical Resolution of Monosubstituted Cyclotribenzylenes. Synthesis 2002, 2002 (05), 0655–0663. (34) Suga, T.; Ukaji, Y. Nickel-Catalyzed Cross-Electrophile Coupling between Benzyl Alcohols and Aryl Halides Assisted by Titanium Co-Reductant. Org. Lett. 2018, 20 (24), 7846–7850. (35) Bedford, R. B.; Brenner, P. B.; Carter, E.; Clifton, J.; Cogswell, P. M.; Gower, N. J.; Haddow, M. F.; Harvey, J. N.; Kehl, J. A.; Murphy, D. M.; Neeve, E. C.; Neidig, M. L.; Nunn, J.; Snyder, B. E. R.; Taylor, J. Iron Phosphine Catalyzed Cross-Coupling Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 229 of Tetraorganoborates and Related Group 13 Nucleophiles with Alkyl Halides. Organometallics 2014, 33 (20), 5767–5780. (36) Tandiary, M. A.; Masui, Y.; Onaka, M. Deoxygenation of Tertiary and Secondary Benzylic Alcohols into Alkanes with Triethylsilane Catalyzed by Solid Acid Tin(IV) Ion-Exchanged Montmorillonite. Tetrahedron Lett. 2014, 55 (30), 4160–4162. (37) Maity, P.; Shacklady-McAtee, D. M.; Yap, G. P. A.; Sirianni, E. R.; Watson, M. P. Nickel-Catalyzed Cross Couplings of Benzylic Ammonium Salts and Boronic Acids: Stereospecific Formation of Diarylethanes via C–N Bond Activation. J. Am. Chem. Soc. 2013, 135 (1), 280–285. (38) Wang, Y.; McGonigal, P. R.; Herlé, B.; Besora, M.; Echavarren, A. M. Gold(I) Carbenes by Retro-Buchner Reaction: Generation and Fate. J. Am. Chem. Soc. 2014, 136 (2), 801–809. (39) Yu, J.; Zhou, Y.; Lin, Z.; Tong, R. Regioselective and Stereospecific CopperCatalyzed Deoxygenation of Epoxides to Alkenes. Org. Lett. 2016, 18 (18), 4734– 4737. (40) Singh, K.; Staig, S. J.; Weaver, J. D. Facile Synthesis of Z-Alkenes via Uphill Catalysis. J. Am. Chem. Soc. 2014, 136 (14), 5275–5278. (41) López-Pérez, A.; Adrio, J.; Carretero, J. C. Palladium-Catalyzed Cross-Coupling Reaction of Secondary Benzylic Bromides with Grignard Reagents. Org. Lett. 2009, 11 (23), 5514–5517. (42) Qin, L.; Sharique, M.; Tambar, U. K. Controllable, Sequential, and Stereoselective C–H Allylic Alkylation of Alkenes. J. Am. Chem. Soc. 2019, 141 (43), 17305–17313. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 230 (43) Yu, J.; Gaunt, M. J.; Spencer, J. B. Convenient Preparation of Trans-Arylalkenes via Palladium(II)-Catalyzed Isomerization of Cis-Arylalkenes. J. Org. Chem. 2002, 67 (13), 4627–4629. (44) Kim, H.; Choi, S. Y.; Shin, S. Asymmetric Synthesis of Dihydropyranones via Gold(I)-Catalyzed Intermolecular [4+2] Annulation of Propiolates and Alkenes. Angew. Chem. Int. Ed. 2018, 57 (40), 13130–13134. (45) McNulty, J.; Keskar, K. Stereoselective Wittig Olefination Reactions Employing a Novel Ortho-P-Aryl Alkoxide Effect. Tetrahedron Lett. 2008, 49 (49), 7054–7057. https://doi.org/10.1016/j.tetlet.2008.09.150. (46) Kohler, D. G.; Gockel, S. N.; Kennemur, J. L.; Waller, P. J.; Hull, K. L. PalladiumCatalysed Anti-Markovnikov Selective Oxidative Amination. Nat. Chem. 2018, 10 (3), 333–340. (47) Ek, F.; Axelsson, O.; Wistrand, L.-G.; Frejd, T. Aromatic Allylation via Diazotization: Metal-Free C−C Bond Formation. J. Org. Chem. 2002, 67 (18), 6376–6381. (48) Lu, X.-L.; Shannon, M.; Peng, X.-S.; Wong, H. N. C. Stereospecific Iron-Catalyzed Carbon(Sp2)–Carbon(Sp3) Cross-Coupling with Alkyllithium and Alkenyl Iodides. Org. Lett. 2019, 21 (8), 2546–2549. (49) Colomer, I.; Coura Barcelos, R.; Donohoe, T. J. Catalytic Hypervalent Iodine Promoters Lead to Styrene Dimerization and the Formation of Tri- and Tetrasubstituted Cyclobutanes. Angew. Chem. Int. Ed. 2016, 55 (15), 4748–4752. (50) Furuyama, T.; Yonehara, M.; Arimoto, S.; Kobayashi, M.; Matsumoto, Y.; Uchiyama, M. Development of Highly Chemoselective Bulky Zincate Complex, Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 231 tBu4ZnLi2: Design, Structure, and Practical Applications in Small-/Macromolecular Synthesis. Chem. – Eur. J. 2008, 14 (33), 10348–10356. (51) Angle, S. R.; Arnaiz, D. O. Synthesis of Dihydro-1H-Indenes via a Formal 3 + 2 Cycloaddition of Para-Quinone Methides and Styrenes. J. Org. Chem. 1990, 55 (12), 3708–3710. (52) Payer, S. E.; Pollak, H.; Schmidbauer, B.; Hamm, F.; Juričić, F.; Faber, K.; Glueck, S. M. Multienzyme One-Pot Cascade for the Stereoselective Hydroxyethyl Functionalization of Substituted Phenols. Org. Lett. 2018, 20 (17), 5139–5143. (53) Tlahuext-Aca, A.; Candish, L.; Garza-Sanchez, R. A.; Glorius, F. Decarboxylative Olefination of Activated Aliphatic Acids Enabled by Dual Organophotoredox/Copper Catalysis. ACS Catal. 2018, 8 (3), 1715–1719. (54) Movahhed, S.; Westphal, J.; Dindaroğlu, M.; Falk, A.; Schmalz, H.-G. Low-Pressure Cobalt-Catalyzed Enantioselective Hydrovinylation of Vinylarenes. Chem. – Eur. J. 2016, 22 (22), 7381–7384. (55) Nielsen, A. J.; Jenkins, H. A.; McNulty, J. Asymmetric Organocatalytic Stepwise [2+2] Entry to Tetra-Substituted Heterodimeric and Homochiral Cyclobutanes. Chem. – Eur. J. 2016, 22 (27), 9111–9115. (56) Mayer, M.; Czaplik, W. M.; Jacobi von Wangelin, A. Practical Iron-Catalyzed Allylations of Aryl Grignard Reagents. Adv. Synth. Catal. 2010, 352 (13), 2147– 2152. (57) Tomita, R.; Yasu, Y.; Koike, T.; Akita, M. Combining Photoredox-Catalyzed Trifluoromethylation and Oxidation with DMSO: Facile Synthesis of α- Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 232 Trifluoromethylated Ketones from Aromatic Alkenes. Angew. Chem. Int. Ed. 2014, 53 (28), 7144–7148. (58) Race, N. J.; Bower, J. F. Palladium Catalyzed Cyclizations of Oxime Esters with 1,2Disubstituted Alkenes: Synthesis of Dihydropyrroles. Org. Lett. 2013, 15 (17), 4616–4619. (59) Siddiki, S. M. A. H.; Touchy, A. S.; Kon, K.; Shimizu, K. Direct Olefination of Alcohols with Sulfones by Using Heterogeneous Platinum Catalysts. Chem. – Eur. J. 2016, 22 (17), 6111–6119. (60) Lara, M.; Mutti, F. G.; Glueck, S. M.; Kroutil, W. Biocatalytic Cleavage of Alkenes with O2 and Trametes Hirsuta G FCC 047. Eur. J. Org. Chem. 2008, 2008 (21), 3668–3672. (61) Matsushita, H.; Negishi, E. Palladium-Catalyzed Reactions of Allylic Electrophiles with Organometallic Reagents. A Regioselective 1,4-Elimination and a Regio- and Stereoselective Reduction of Allylic Derivatives. J. Org. Chem. 1982, 47 (21), 4161– 4165. (62) Kim, H. J.; Su, L.; Jung, H.; Koo, S. Selective Deoxygenation of Allylic Alcohol: Stereocontrolled Synthesis of Lavandulol. Org. Lett. 2011, 13 (10), 2682–2685. (63) Nakamura, H.; Ishihara, K.; Yamamoto, H. Lewis Acid-Activated Chiral Leaving Group: Enantioselective Electrophilic Addition to Prochiral Olefins. J. Org. Chem. 2002, 67 (15), 5124–5137. (64) Sauer, A. M.; Crowe, W. E.; Henderson, G.; Laine, R. A. Hydrogenation Selectivity of the Bicyclo[4.4.0]Decane Ring System of Valencanes. Synlett 2010, 2010 (03), 445–448. Chapter 3 – Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 233 (65) He, Z.; Song, F.; Sun, H.; Huang, Y. Transition-Metal-Free Suzuki-Type CrossCoupling Reaction of Benzyl Halides and Boronic Acids via 1,2-Metalate Shift. J. Am. Chem. Soc. 2018, 140 (7), 2693–2699. (66) Melzer, B.; Bracher, F. A Divergent Approach to Benzylisoquinoline-Type and Oxoaporphine Alkaloids via Regioselective Direct Ring Metalation of Alkoxy Isoquinolines. Org. Biomol. Chem. 2015, 13 (28), 7664–7672. (67) Larraufie, M.-H.; Pellet, R.; Fensterbank, L.; Goddard, J.-P.; Lacôte, E.; Malacria, M.; Ollivier, C. Visible-Light-Induced Photoreductive Generation of Radicals from Epoxides and Aziridines. Angew. Chem. Int. Ed. 2011, 50 (19), 4463–4466. (68) Liu, Y.; Xiao, S.; Qi, Y.; Du, F. Reductive Homocoupling of Organohalides Using Nickel(II) Chloride and Samarium Metal. Chem. – Asian J. 2017, 12 (6), 673–678. (69) Keaveney, S. T.; Kundu, G.; Schoenebeck, F. Modular Functionalization of Arenes in a Triply Selective Sequence: Rapid C(Sp2) and C(Sp3) Coupling of C−Br, C−OTf, and C−Cl Bonds Enabled by a Single Palladium(I) Dimer. Angew. Chem. Int. Ed. 2018, 57 (38), 12573–12577. Appendix 4 – Spectra Relevant to Chapter 3 234 APPENDIX 4 Spectra Relevant to Chapter 3: Radical Deoxygenation of Alcohols by a Titanium Porphyrin Catalyst 12 Ph Cl N Ti 11 Ph N N Cl N Ph 10 Ph 8 8.6 7 6 ppm 8.4 8.2 8.8 5 8.0 8.6 ppm 4 7.92 7.92 7.91 8.04 8.91 8.00 8.91 8.00 7.88.4 Figure A.4.1. 1H NMR (600 MHz, C6D6) of Ti(TPP)Cl2. 9 8.8 3 7.68.2 8.04 4.02 2 7.48.0 ppm 1 7.27.8 0 7.07.6 7.4 4.02 7.46 7.45 7.43 7.38 7.37 7.35 7.92 7.92 7.91 8.04 7.46 7.45 7.43 7.38 7.37 7.35 8.04 Appendix 4 – Spectra Relevant to Chapter 3 235 7. 10 Me 9 8 6 5 ppm 4 3 Figure A.4.2. 1H NMR (400 MHz, CDCl3) of compound 69b. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 236 10 9 7 6 ppm 5 4 Figure A.4.3. 1H NMR (400 MHz, CDCl3) of compound 69c. 8 3 2 Appendix 4 – Spectra Relevant to Chapter 3 237 9 8 6 5 ppm 4 3 Figure A.4.4. 1H NMR (400 MHz, CDCl3) of compound 71b. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 238 9 8 6 5 ppm 4 3 Figure A.4.5. 1H NMR (400 MHz, CDCl3) of compound 72b. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 239 9 8 7 5 ppm 4 3 Figure A.4.6. 1H NMR (400 MHz, CDCl3) of compound 73b. 6 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 240 9 8 Me 6 5 ppm 4 3 Figure A.4.7. 1H NMR (400 MHz, CDCl3) of compound 74b. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 241 9 O OEt 8 6 5 ppm 4 3 Figure A.4.8. 1H NMR (400 MHz, CDCl3) of compound 76b. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 242 9 8 7 5 ppm 4 3 Figure A.4.9. 1H NMR (400 MHz, CDCl3) of compound 77b. 6 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 243 10 9 8 6 5 ppm 4 3 Figure A.4.10. 1H NMR (400 MHz, CDCl3) of 78b. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 244 8 6 ppm 5 Figure A.4.11. 1H NMR (500 MHz, CDCl3) of 79b. 7 4 3 Appendix 4 – Spectra Relevant to Chapter 3 245 9 MeO 8 OMe 7 5 ppm 4 3 Figure A.4.12. 1H NMR (600 MHz, CDCl3) of 80b. 6 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 246 9 8 7 5 ppm 4 3 Figure A.4.13. 1H NMR (600 MHz, CDCl3) of 81b. 6 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 247 9 F 8 F 6 ppm 5 4 Figure A.4.14. 1H NMR (600 MHz, CDCl3) of 82b. 7 3 2 Appendix 4 – Spectra Relevant to Chapter 3 248 9 OH 8 6 ppm 5 4 Figure A.4.15. 1H NMR (600 MHz, CDCl3) of 83b. 7 3 2 Appendix 4 – Spectra Relevant to Chapter 3 249 9 O 8 7 ppm 5 4 Figure A.4.16. 1H NMR (400 MHz, CDCl3) of 84b. 6 3 2 Appendix 4 – Spectra Relevant to Chapter 3 250 9 (E) 8 + Br (Z) Br 6 iso 5 Br (E) 6.25 ppm Br (E) 4 6.20 + 6.15 Br + 3 (Z) 6.10 Br 6.05 Br (Z) + 6.00 ppm Br (E) + Figure A.4.17. 1H NMR (400 MHz, CDCl3) of 88b, 88c, 88d. 7 + 2 5.95 Br iso 2.86 6.27 6.25 6.24 6.23 6.22 6.22 6.20 6.18 8.95 5.90 + Br iso 5.85 1 (Z) 5.98 5.96 5.95 5.94 5.93 5.92 5.91 5.90 5.89 5.88 5.86 5.84 5.83 5.82 5.81 5.81 5.79 5.78 5.80 1.00 Br 5.75 + 0 Br iso Appendix 4 – Spectra Relevant to Chapter 3 251 8 MeO MeO MeO (E) (E) + 7 MeO MeO + 6.20 MeO MeO MeO MeO 6.10 (E) + MeO MeO MeO MeO 6.05 6 6.00 MeO MeO MeO MeO + + iso 5.95 ppm (E) 5.90 (Z) iso 5.85 + MeO MeO ppm 5.80 MeO MeO 5 + 5.75 (Z) iso 5.70 5.65 + 4 MeO MeO iso Figure A.4.18. 1H NMR (600 MHz, CDCl3) of 90b, 90c, 90d. 6.15 (Z) (Z) 6.14 6.12 6.11 6.11 6.10 6.10 6.09 6.08 3.33 5.99 5.98 5.98 5.97 5.97 5.96 5.95 5.94 5.94 5.93 1.71 5.75 5.73 5.73 5.72 5.71 5.71 5.70 5.69 1.00 MeO 3 2 Appendix 4 – Spectra Relevant to Chapter 3 252 8 O O 7 6 4 ppm 3 2 Figure A.4.19. 1H NMR (400 MHz, CDCl3) of 93b. 5 1 0 Appendix 4 – Spectra Relevant to Chapter 3 253 Appendix 4 – Spectra Relevant to Chapter 3 254 Figure A.4.20. Infrared spectrum (Thin Film, NaCl) of compound 93b. 180 160 140 120 100 ppm 80 60 40 20 Figure A.4.21. 13C NMR (101 MHz, CDCl3) of compound 93b. 0 10 9 8 6 5 ppm 4 3 Figure A.4.22. 1H NMR (400 MHz, CDCl3) of 95b. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 255 9 8 7 5 ppm 4 3 Figure A.4.23. 1H NMR (400 MHz, CDCl3) of 97b. 6 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 256 180 160 120 100 ppm 80 Figure A.4.24. 13C NMR (101 MHz, CDCl3) of 97b. 140 60 40 20 0 Appendix 4 – Spectra Relevant to Chapter 3 257 12 H O 11 O 10 CO2Et 9 7 6 ppm 5 4 Figure A.4.25. 1H NMR (400 MHz, CDCl3) of 98a. 8 3 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 258 Appendix 4 – Spectra Relevant to Chapter 3 259 Figure A.4.26. Infrared spectrum (Thin Film, NaCl) of compound 98a. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A.4.27. 13C NMR (101 MHz, CDCl3) of compound 98a. 0 Cl 9 OH 8 O CO2Et 6 5 ppm 4 3 Figure A.4.28. 1H NMR (400 MHz, CDCl3) of 98b. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 260 Appendix 4 – Spectra Relevant to Chapter 3 261 Figure A.4.29. Infrared spectrum (Thin Film, NaCl) of compound 98b. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A.4.30. 13C NMR (101 MHz, CDCl3) of compound 98b. 0 9 Cl 8 O 7 CO2Et 5 ppm 4 3 Figure A.4.31. 1H NMR (400 MHz, CDCl3) of 99. 6 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 262 MeO MeO 9 HO N 8 OMe OMe 6 5 ppm 4 3 Figure A.4.32. 1H NMR (600 MHz, CDCl3) of 100a. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 263 10 MeO MeO 9 N OMe OMe 8 6 ppm 5 Figure A.4.33. 1H NMR (600 MHz, CDCl3) of 101. 7 4 3 2 Appendix 4 – Spectra Relevant to Chapter 3 264 EtO2C 8 N H D D CO2Et 7 5.12 0.88 5 4.18 4.17 4.16 4.15 4 4.05 ppm 3 2.19 2 5.97 Figure A.4.34. 1H NMR (600 MHz, CDCl3) of HE-d2. 6 1 0 Appendix 4 – Spectra Relevant to Chapter 3 265 1.29 1.28 1.27 6.00 10 H H 9 D 8 6 ppm 5 Figure A.4.35. 1H NMR (400 MHz, CDCl3) of 69d. 7 4 3 2 Appendix 4 – Spectra Relevant to Chapter 3 266 10 9 O O 8 N O OEt 6 5 ppm 4 3 Figure A.4.36. 1H NMR (400 MHz, CDCl3) of 102. 7 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 267 Appendix 4 – Spectra Relevant to Chapter 3 268 Figure A.4.37. Infrared spectrum (Thin Film, NaCl) of compound 102. 180 160 140 120 100 ppm 80 60 40 20 Figure A.4.38. 13C NMR (101 MHz, CDCl3) of compound 102. 0 9 8 O OMe 7 5 ppm 4 3 Figure A.4.39. 1H NMR (400 MHz, CDCl3) of 103. 6 2 1 0 Appendix 4 – Spectra Relevant to Chapter 3 269 Appendix 4 – Spectra Relevant to Chapter 3 270 Figure A.4.40. Infrared spectrum (Thin Film, NaCl) of compound 103. 200 180 160 140 120 100 ppm 80 60 40 20 Figure A.4.41. 13C NMR (101 MHz, CDCl3) of compound 103. 0 9 8 6 ppm 5 4 Figure A.4.42. 1H NMR (600 MHz, CDCl3) of 104. 7 3 2 Appendix 4 – Spectra Relevant to Chapter 3 271 272 ABOUT THE AUTHOR Benjamin Martin Gross was born in Berlin, Germany, where he spent the beginning of his childhood, moving to New York with his family at the age of six. He returned to Berlin to finish high school, graduating from the John F. Kennedy International School with an emphasis in math and physics. Originally planning to attend medical school, he instead enrolled at the Technische Universität in Berlin as a chemistry undergraduate. He was quickly captivated by the organic chemistry classes taught by Prof. Martin Oestreich and taken under his wing. He completed his bachelor’s degree in 2018, where he gained his first research experience in teaching labs and within the research group. He additionally completed a summer stay within the medicinal chemistry department at Merck, KGaA in Darmstadt, Germany. Staying on for his master’s degree in Berlin, he embarked on a five-month research stay with Prof. Christopher D. Vanderwal at the University of California, Irvine. He contributed to the application of a cobalt-catalyzed radical polyene cyclization, further developing his interest in natural product total synthesis. With the start of the COVID pandemic, he returned to Berlin in 2020, completing his master thesis with Prof. Martin Oestreich in the spring of 2021. After a 3-month research internship in medicinal chemistry at the Bayer campus in Berlin, he returned to Southern California in August 2021, to begin graduate studies at Caltech under the guidance of Prof. Brian M. Stoltz. During his PhD, Benjamin further nurtured his passion for the synthesis of complex small molecules and the applications of new reaction development. Upon completing his PhD, Benjamin will move to South San Francisco to start a job in the medicinal chemistry department at Genentech.