SYNTHESIS OF SESQUITERPENE-TROPOLONES BY CHRISTOPHER YNGWIE BEMIS DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate College of the University of Illinois at Urbana-Champaign, 2019 Urbana, Illinois Doctoral Committee: Assistant Professor David Sarlah, Chair Professor Scott E. Denmark Professor Paul J. Hergenrother Professor Scott K. Silverman ABSTRACT A modular synthetic platform for the synthesis of the multi-bioactive sesquiterpene- tropolone natural products has been developed in an effort to provide general synthetic access to this class of compounds and related structures. In this work, the convergence of the sesquiterpene and tropolone fragments is enabled by a hetero-Diels–Alder reaction between a tropolone ortho- quinone methide and derivatives of α–humulene. Concise and scalable syntheses of both fragments are described, as well as alternative approaches to key intermediates. During the development of the tropolone synthesis, an unprecedented photochemical fragmentation was discovered. Two natural products, epolone B and deoxypycnidione have been synthesized employing this strategy, as well as two diastereomers of pycnidione. In these studies, a correction to the originally reported structure of epolone B is suggested based upon X-ray crystallographic data. The synthetic compounds were found to be cytotoxic to A459 and HCT116 cell lines. Current efforts are focused on synthesizing pycnidione in its correct relative stereochemical configuration. Future directions include application of these fragments in hetero- Diels–Alder reactions to synthesize related sesquiterpene-tropolones, other tropolone containing natural products, and bistropolone congeners for biological evaluation. ii ACKNOWLEDGEMENTS I thank Prof. David Sarlah for accepting me into his research group as part of his first class of graduate students, for supporting and advising me in my work at UIUC, and for teaching me the skills required to be a successful chemist. I thank my committee consisting of Prof. Scott Denmark, Prof. M. Christina White, and Prof. Scott Silverman, as well as Prof. Paul Hergenrother for agreeing to serve in Prof. White’s absence during my defense. I appreciate the insight these professors have provided at the various stages of my graduate studies. I also want to thank the OCB office and the rest of the SCS faculty and staff for all of their work in helping the department operate efficiently. I thank Prof. Phyllis Leber for her continued mentorship and for teaching me how to conduct rigorous research as an undergraduate student. I thank Prof. Claude Yoder, Prof. Scott Brewer, and Prof. Ed Fenlon for the guidance that led me to UIUC and beyond. I thank Mrs. Marie Yagel for introducing me to chemistry and giving me an appreciation for the joys that it can bring. I thank Mrs. Michele Newberry, who was the first teacher to give me the space to explore my passions, which contributed a great deal to making me into the person that I am. None of my work would have been possible without the love of my family. They have always enabled the pursuit of my interests, trusted my judgement, and showed an incredible amount of empathy in the best and worst of times. My gratitude for their support is immeasurable. I would like to thank Emma, Mikiko, Carrie, Dan, and Bryan for joining me in taking the risk of being the first class in a new research group. There are very few experiences quite like this one, but I am so glad we could support each other in the early days. I thank Chad and Matt for joining me on this project. Having co-workers with a deep understanding of your project iii means there is always someone with whom you can celebrate about achievements and commiserate about setbacks. It has been a pleasure to teach my undergraduate co-workers, Jiawen, Yingzhe, Marko, Tae, Renyu, and Linxiao. I am grateful for their enthusiasm and willingness to provide assistance wherever it was needed in this project. I thank Emma and Aaron for being my personal support system for most of graduate school. I thank Sarah for being a voice of reason when I needed it most. I also thank my old housemates not yet mentioned here, Siraj, Andy, and Connor, for helping me decompress during our second year. There are a few friends outside of UIUC who have helped me through graduate school from afar. I consider myself lucky to have these people in my life, as well as so many others. I am thankful for Eric’s limitless optimism, compassion, late-night phone calls, music suggestions, and for always giving me a place to sleep when I am passing through Pittsburgh. I am thankful for Vanessa’s devoted friendship and for allowing me to escape to St. Louis when I needed a break. I thank Joe for the encouraging note he left on my desk when we worked together in the Leber Lab. I still keep that note in my desk and read it when I need a boost in motivation. I thank Andrew for making Illinois feel a little more like home. I thank Maggie, Liz, and Maia for always being understanding and able to maintain our close friendships despite our incongruent schedules. Finally, I thank Kevin Barnes, Brian Wilson, Elliott Smith, John Darnielle, The Smiths, Pocket Vinyl, Buddy Holly, Conor Oberst, and George Clinton for providing most of the soundtrack to my graduate studies that kept me working through late nights and early mornings. iv To Mariah, Caleb, and my parents v TABLE OF CONTENTS CHAPTER 1: INTRODUCTION TO THE SESQUITERPENE-TROPOLONES .............1 1.1. Isolation and Characterization of the Pycnidione Series ..................................1 1.2. Isolation and Characterization of the Eupenifeldin Series ................................3 1.3. Isolation and Characterization of Fusariocin C and the Malettinins.................5 1.4. Biological Activity of the Sesquiterpene-Tropolones .......................................6 1.5. Biosyntheses Related to the Sesquiterpene-Tropolones ................................15 1.5.1. Biosynthesis of the Xenovulenes .....................................................15 1.5.2. Biosynthesis of the Sesquiterpene-Tropolones ................................16 1.6. References .......................................................................................................19 CHAPTER 2: PREVIOUS SYNTHETIC APPROACHES TO SESQUITERPENE- TROPOLONES AND FRAGMENTS ........................................................24 2.1. ortho-Quinone Methide Approach by Baldwin ..............................................24 2.2. Synthesis of 10-Hydroxy-α–Humulene by Takahashi ....................................28 2.3. References .......................................................................................................30 CHAPTER 3: SYNTHESIS OF SESQUITERPENE-TROPOLONES .............................33 3.1. Retrosynthetic Analysis ..................................................................................33 3.2. Synthesis of Tropolone Fragment ...................................................................40 3.2.1. Büchner Reaction Strategy ..............................................................40 3.2.2. Biomimetic Semi-Pinacol Reaction Strategy...................................43 3.2.3. De Mayo Fragmentation Strategy ....................................................45 3.2.4. Synthesis of Deoxyepolone B ..........................................................54 3.3. Synthesis of 10-Hydroxy-α–Humulene ..........................................................56 vi 3.3.1. Ring Closing Metathesis Strategies .................................................56 3.3.2. Nozaki-Hiyama-Kishi Reaction Strategies ......................................60 3.3.3. McMurry Reaction Strategies ..........................................................64 3.3.4. Hydrogen Atom Transfer Strategy...................................................66 3.4. Synthesis of Sesquiterpene-Tropolones ..........................................................69 3.4.1. Synthesis of Deoxypycnidione ........................................................69 3.4.2. Synthesis of Epolone B ....................................................................72 3.4.3. Synthesis of Pycnidione ...................................................................76 3.5. References .......................................................................................................95 CHAPTER 4: SUMMARY AND FUTURE DIRECTIONS...........................................102 4.1. Summary .......................................................................................................102 4.2. Synthesis of Eupenifeldin Series Natural Products ......................................103 4.3. Synthesis of Tropolone-Containing Natural Products ..................................105 4.4. Synthesis of Bistropolones for Biological Studies........................................107 4.5. Development of the Photochemical Fragmentation ......................................110 4.6. References .....................................................................................................111 CHAPTER 5: EXPERIMENTAL....................................................................................113 vii CHAPTER 1: INTRODUCTION TO THE SESQUITERPENE-TROPOLONES 1.1. Isolation and Characterization of the Pycnidione Series Cultures of a Phoma sp. (MF 4726) recovered from soil on Kosrae Island, Federated States of Micronesia, in 1993 were discovered to produce the first sesquiterpene-tropolone natural