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Strategic Redox Relay Enables A Scalable Synthesis of Ouabagenin, A Bioactive Cardenolide A thesis presented by Hans Renata to The Scripps Research Institute Graduate Program in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Chemistry for The Scripps Research Institute La Jolla, California February 2013 UMI Number: 3569793 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. UMI 3569793 Published by ProQuest LLC (2013). Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, MI 48106 - 1346 © 2013 by Hans Renata All rights reserved ! ii! ACKNOWLEDGEMENTS To Phil, thank you for taking me under your wing, the past five years have been a wonderful learning experience. You truly are a fantastic teacher, both in and out of the fumehood and your unbridled enthusiasm, fearlessness and passion for chemistry are second to none. In the words of Kurt Cobain, I am “forever indebted to your priceless advice.” To the members of the Baran lab, in the words of Kurt Cobain, “Our little (?) group has always been and always will until the end.” See what I did there? Oh well, whatever, nevermind. To my committee members, Prof. K. C. Nicolaou, Prof. Floyd Romesberg, and Prof. Jin- Quan Yu, thank you for overseeing my graduate education for the past five years. To Prof. Breslow and Prof. Katz, thank you for introducing me to the wonderful world of organic chemistry, you both were fabulous teachers to me, especially in the field of physical organic chemistry. Tristan, thank you for letting me join your lab as one of your first students when you started. Scott, thank you for agreeing to serve as my external committee member and the various advices that you have given to me. To the early members of the Baran lab, I am grateful for the opportunity to learn from you guys as a naïve first year student. You guys played an influential role in establishing a superb lab culture and showed me what hard work really means. Your passion for chemistry is truly contagious. I will always regard Baran lab as the Eames office (Charles and Ray Eames anyone?) equivalent of organic chemistry and you guys definitely play a big part in establishing that notion for me. ! iii! To the Worrell household (Williams and B), thank you for your nonpareil hospitality and provision of various alternative entertainments. Being one of the founding fathers of O’Briens Wednesday is probably one of my proudest achievements in grad school, next to spelling the alphabets backwards. And don’t worry, from the scale of 1 to 10, I’m still a 6. To Dane, thank you for watching A Serbian Film with me and for having a similar taste in music (although I still maintain that War All The Time is better than Full Collapse). To Aaron Sather, thank you for inviting me to your place on multiple occasions to watch sports on TV. I wish you and Lupita all the best. Danny Wansen, thank you for initiating Don Diego’s Monday and for always having bottomless supply of candies whenever we need one. Brosen, thank you for taking turns to carpool to O’Briens and Don Diego’s. I hope you find a great future project that’s better than quassin, but also with the funding. PEmily, thank you for your hospitality during Thanksgiving for the past few years. Taycoh, the lab will be forever grateful for the Jelly Belly machine you got. JG, thank you for being such an enabler when it comes to beers. To Qianghui, I am very grateful to have you as my teammate in the ouabagenin project. Thank you for your help and valuable scientific discussions throughout the project. I wish you all the best for your future career. To Ian Young and Sarah Tully, thank you for being such great friends during the ‘dark Cheetah’s days’ of the Baran lab, and for the many Papa John’s pizzas and Sour Patch Kids. Thank you for Per Se too! I eagerly wait to be driven around in your (future) R8. ! iv! To my parents, you guys recently made a passing comment to me, “Never did we imagine we would have a Ph.D. graduate in the family.” Well, neither did I. But I am really thankful for your love and support throughout my education. The following non-scientists have played a huge role in coloring my worldview: Mark Rothko, Richard Serra, Joseph Beuys, Le Corbusier, Dieter Rams, Robert Mapplethorpe, Rick Owens, Yohji Yamamoto, Andrei Tarkovsky, and Béla Tarr. Their creative output has been a wellspring of inspiration for me. As Beuys once said, “Creativity is not limited to people practicing one of the traditional forms of art, and even in the case of artists, creativity is not confined to the exercise of their art.” ! v! Dieter Rams: ten principles for good design Good design is innovative Good design makes a product useful Good design is aesthetic Good design makes a product understandable Good design is unobtrusive Good design is honest Good design is long-lasting Good design is thorough down to the last detail Good design is environmentally-friendly Good design is as little design as possible ! vi! Decades Here are the young men, the weight on their shoulders Here are the young men, well where have they been? We knocked on the doors of hell’s darker chamber Pushed to the limit, we dragged ourselves in Watched from the wings as the scenes were replaying We saw ourselves now as we never had seen Potrayal of the trauma and degeneration The sorrows we suffered and never were free Where have they been? Weary inside, now our heart’s lost forever Can’t replace the fear, or the thrill of the chase Each ritual showed up the door for our wanderings Open then shut, then slammed in our face Where have they been? Ian Curtis L.W.T.U.A., 07/15/56–05/18/80 ! vii! Table of contents Chapter 1 Introduction: Historical background of the cardiac glycosides .................. 1 1.1. Structure, history and bioactivity of the cardiac glycosides and related natural product ........................................................................................................................... 2 1.2. Syntheses of cardenolides, bufadienolides and the batrachotoxins ........................ 5 1.3. Recent semisyntheses of other complex, bioactive steroidal natural products .... 18 1.4. Other polyoxygenated steroids ............................................................................. 24 1.5. References ............................................................................................................ 25 Chapter 2 A scalable synthesis of ouabagenin .............................................................. 30 2.1. Synthesis planning part 1: additional lessons from literature .............................. 31 2.2. Synthesis planning part 2: cyclase-oxidase approach .......................................... 33 2.3. C19 methyl oxidation literature ............................................................................ 36 2.4. Norrish photochemistry ........................................................................................ 40 2.5. Cyclobutanol fragmentation and diepoxide synthesis .......................................... 43 2.6. Diepoxide fragmentation and synthesis of protected ouabageninone .................. 46 2.7. Model study development for butenolide attachment .......................................... 51 2.8. Back to the real system ......................................................................................... 54 2.9. Reinventing your exit ........................................................................................... 57 2.10. Conclusion and future direction ......................................................................... 58 2.11. Distribution of credit .......................................................................................... 61 2.12. References .......................................................................................................... 62 2.13. Supplementary information ................................................................................ 67 Appendix 1: Spectra ...................................................................................................... 109 ! viii! Appendix 2: X-ray crystal structures .......................................................................... 196 Appendix 3: Curriculum Vitae ...................................................................................... 214 ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ix! List of Figures and Schemes Figure 1-1. Selected examples of cardiotonic steroid natural products .............................. 2 Scheme 1-1. Wiesner’s synthesis of digitoxigenin from testosterone ................................ 6 Scheme 1-2. Kabat’s formal synthesis of digitoxigenin ..................................................... 7 Scheme 1-3. Stork’s total synthesis of digitoxigenin .......................................................... 8 Scheme 1-4. Yoshii’s synthesis of strophanthidol .............................................................. 9 Scheme 1-5. Jung’s total synthesis of rhodexin A ............................................................ 10 Scheme
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