PROGRESS TOWARD THE TOTAL SYNTHESIS OF CURCUSONE C AND MECHANISTIC ELUCIDATION OF AN UNEXPECTED REARRANGEMENT Thesis by Chung Whan Lee In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 2015 (Defended May 29, 2015) ii © 2015 Chung Whan Lee All Rights Reserved iii To my teachers iv ACKNOWLEDGEMENTS During my school life since 1993, I have met a lot of great teachers who are not only experts on teaching but are also great mentors and role model. Foremost, I must thank my supervisor, Prof Brian Stoltz. I attended his talk in an ICOS meeting at Daejeon, Korea in 2006, and which was the first moment I dreamed to undertake doctoral studies at Caltech. Throughout my doctoral studies, Brian has been the best teacher and mentor. He has been a generous, supportive advisor who has helped me to overcome obstacles in graduate school and to be an independent researcher. He has been truly enthusiastic in science and professional in research, which has affected me a lot. He has also been respectful to his students and he has exceptional ability to motivate us without relying on his authority. He has kept priorityzed about lab safety all the time as well as doing lab work efficiently. It is truly rare to find an advisor who is talented and creative in operating a giant research lab who also cares deeply about every single student. It is impossible to thank him enough for his sacrifices over the last five years. It was truly fortunate for me to join the Stoltz group in 2010. My committee members Prof. Sarah Reisman, Prof. Theo Agapie, and Prof. Bob Grubbs are acknowledged for their continuing advice and support. Prof. Sarah Reisman has been not only my chairwoman but also a sort of second advisor for us. I sometimes thought her guidance was too strenuous but I finally realized that her comments and directions were tremendously informative, and those hard times she gave me was an extremely valuable period for me. Prof. Theo Agapie is an out-of- v field thesis committee member, but he has offered greatly important comments from a different point of view. The final member of my committee, Prof. Bob Grubbs has been an admirable scientist for me since I learned about his catalyst during undergraduate studies. Furthermore, I was truly surprised when I attended his seminar at Seoul National University in 2009; his contents were filled with completely fresh topics, which was unusual in previous Nobel lectures in Seoul National University. I have been glad to re-meet him and have his guidance at Caltech. I also have to thank my former academic supervisors, including Prof. Eun Lee, Prof. Chulbom Lee, and Prof. Tae-Lim Choi. Prof. Eun Lee, my M.S. thesis advisor, has been a great mentor who has always showed me the way of being a scientist. Prof. Chulbom Lee, alumni of the Eun Lee group, has also been truly supportive of me. When I visited Korea, I always stopped by his office to ask his guidance, and those meetings were always enjoyable. Prof. Tae-Lim Choi, who is a Caltech alumni, was also a great mentor at SNU. In addition to great teachers, I have many co-workers to thank. Dr. Buck Taylor, Ashay Patel and their supervisor Prof. Ken Houk and Dr. Galina Petrova with Prof. Keiji Morokuma are wonderful theoretical chemists. It was impossible to solve ridiculous problems without collaborating with them. Also, Seo-Jung Han for collaboration on the malonates addition project is acknowledged. She has also been one of the very few Korean speakers and it has been quite comfortable to have someone that I can discuss something with in Korean. vi Dr. Jimin Kim, Boram Hong are thanked for helping me settle down in the lab in the early days. It would have been frustrating without their support, but I could get use to Stoltz group life pretty quickly with them. I also want to thank Dr. Chris Henry, Dr. Kristy Tran, Dr. Doug Behenna, and Dr. Alex Goldberg for their kindness in the early days. Dr. Doug Behenna has been my hoodmate for a long time and it was pleasure to have a wonderful scientist next to me all the time. Dr. Alex Goldberg and Dr. Kristy Tran have been my baymates in the early days with Dr. Corey Reeves and Doug Duquette. I sometimes think about the early enjoyable days in the lab when our bay was completely filled every hour with great friends. Special thanks to Alex for drinking Korean liquor together in Korea town and it was fun to meet you again in Tel Aviv. With Corey and Doug, I would like to thank Dr. Rob Craig, Christopher Haley, and Dr. Yiyang Liu, who are the member of my class within the Stoltz group. It was pleasure to be with you over 5 years. I also have to thank Kelly Eunjung Kim, Alex Sun, Steven Loskot, Elizabeth Goldstein, for being my proofreaders of the documents. Special thanks to Kelly who has never hesitated to help me for a long time. In addition, I want to thank Dr. Boger Liu, Dr. Jared Moore and again Alex and Kelly for discussion and correction of my exit proposals. Jared is my current hoodmate who reminded me the early days. I have again been surrounded by wonderful chemists with Jared and Dr. Marc Liniger, and it was truly a pleasure to be with them in my last days. I have to thank Sam Shockley for being a safety officer. It must be the most burdensome group job and I really appreciated that she was willing to take my duty. In addition to Sam, I would like to thank the Caltech safety office for focusing on lab safety. vii I wish there was enough time to thank all the former and present Stoltz group members for their contributions. Every past and present post-doc, and students are great chemists and it has been my luck to be with them all including, Nick O’Connor, Beau Pritchett, Katerina Korch, Kelvin Bates, Jiaming Li, David Schuman, Austin Wright, Max Loewinger, and Drs. Kim Petersen, Koji Chiyoda, Josh Day, Christian Eldamshaus, Vinson Espejo, Michele Gatti, Christian Grünanger, Kathrin Höferl- Prantz Sandoz, Hendrik, F. T. Klare, Guillaume Lapointe, Alex N. Marziale, Kenji Negoro, Yoshitaka Numajiri, Fabian Piller, Grant Shibuya, Hideki Shimizu, Russel Smith, Yuji Sumii, Takeharu, Toyoshima, Florian Vogt, Phil Wu, Xiangyou Xing, Nathan Bennett, Chris Gilmore, Jonny Gordon, Jeff Holder, Allen Hong, Hosea Nelson, Nat Sherden, Pam Tadross, Masaki Hayashi, Kazato Inanaga, Max Klatte, and Noriko Okamoto. Beyond the Stoltz lab, the members past and present of the Reisman and Grubbs labs are acknowledged for supporting the excellent collaborative atmosphere. I especially want to mentions Dr. Roger Nani, and Haoxuan Wang for their kindness and Lauren Chapman for discussing safety matters of 3rd floor Schlinger. I have to thank the technical and support staff in our department. Dr. Scott Virgil has been a tremendous resource during my time here. He has never hesitated to set aside hours of his time to discuss technical or strategic problems and he has kept facility in order every moment. I also want to thank Rick Gerhart for helping repair glassware, Dr. Mike Takase and Larry Henling for X-ray crystal structure determination, Dr. Mona Shahgholi and Naseem for their help obtaining HRMS data, Tony, for his help on the third floor of Schlinger, as well as Agnes Tong, Lynne viii Martinez, and Anne Penny for their help with administrative duties. Especially, Dr. Dave Vander-Velde who runs the best NMR facility and has helped me with difficult experiments. Agnes Tong is the greatest Graduate Program Administrator as well as student counselor. I have feeling at ease when I talk with her. Lynne Martinez does an incredible job of keeping the house in order, she always has answers for every question. I want to thank every member of the Caltech Korean Graduate Student Association. I never had a chance to feel home sick with these fantastic members. Especially Dr. Chang Ho Sohn is acknowledged for important advice and support. Beyond Caltech, it was great pleasure to have a lot of high school classmates around California. I want to thank all of them including, Dr. Hongki Kang, Dr. Yunkyung Kim, Jinwoo Lee, Kyunam Kim, Mihn-jong Lee, and Younghyun Kim. Lastly, I would like to thank the most important people in my life. First of all, my family: Mom, and Dad. They have invested tremendously in my education, and have been truly supportive of me every step. They never pushed me too much as many other Korean parents did, but they have encouraged me to study what I want. Thanks to all who has been a part of my life. Without their support I would not make it here. Chung Whan ix ABSTRACT Curcusone C is tricyclic diterpenoid natural product isolated from Jatropha curcas that exhibits potent biological activity and features a 2,3,7,8- tetrahydroazulene-1,4-dione moiety. Herein, we describe a synthetic approach toward ent-curcusone C. Construction of the tricyclic scaffold of ent-curcusone C is achieved from a cyclopentenol boronate and a vinyl bromide, which was synthesized from (S)-perillaldehyde. Suzuki coupling of the two precursors furnished a dieneol, which was converted to a diazoester via transesterification followed by diazo transfer reaction. A divinylcyclopropane was synthesized from the diazoester by intramolecular cyclopropanation and subsequent Kauffmann olefination. The tricyclic core of ent-curcusone C was accomplished by divinylcyclopropane rearrangement, which was initiated by reduction of the lactone moiety.