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Towards a Formal Total Synthesis of Triptolide Via a Gold-Catalyzed Cyclization Cascade

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Towards a Formal Total Synthesis of Triptolide Via a Gold-Catalyzed Cyclization Cascade By Travis R. Schwantje A thesis submitted to the Faculty of Graduate and Postdoctoral Studies In partial fulfillment of the requirements for the Master of Science (M.Sc.) degree in Chemistry Candidate Supervisor Travis Schwantje Dr. Louis Barriault Ottawa-Carelton Chemistry Institute Faculty of Science University of Ottawa © Travis Schwantje, Ottawa, Canada, 2013 Table of Contents ii Abstract This thesis discusses the progress made towards a formal total synthesis of triptolide, a naturally occurring diterpenoid triepoxide molecule. Isolated from a Chinese vine, triptolide features some interesting structural characteristics and has demonstrated a broad range of interesting medicinal effects. It has demonstrated remarkable cytotoxicity against a number of cancer cell lines, immunosuppressive activity, and reversible male sterility. This biological activity has made it a target of a number of total syntheses spanning from 1980 to 2010. Gold-catalyzed transformations are an emerging field in synthetic organic chemistry, but their efficacy and potential uses are gaining much recognition among the synthetic organic community. Our research group is extremely interested in the applications of such gold-catalyzed organic transformations in natural product synthesis. Here, we discuss our investigations towards accessing the tetracyclic core of triptolide using a gold-catalyzed cyclization cascade reaction. We explored a number of synthetic routes towards a common linear precursor, and our successes and failures are discussed herein. We also report numerous unsuccessful efforts towards an oxidative gold-catalyzed cyclization cascade to form the tetracyclic core of triptolide. Finally, we investigated the use of a photocatalytic radical cyclization cascade to access the desired core. We report some promising preliminary results, and this study is ongoing in the Barriault group. Table of Contents iii Acknowledgements First and foremost, I want to extend the warmest of thanks to my supervisor, Dr. Louis Barriault, for taking me into his research group and providing guidance. Without an honours thesis, I had little experience in a synthetic chemistry lab when I entered grad school, but Louis took a chance on me and I am so grateful for this. He gave me freedom to pursue my own goals for this project, encouraged me to investigate new ideas and push my creativity as far as I possibly could. He let me make my own mistakes and learn from them, which I feel has helped me grow both as a chemist and as a person. Finally, under his guidance, my passion for organic chemistry has grown more than I ever imagined. Thank you, Louis. The students in the Barriault group are equally important to recognize. From my first day in group, everyone was warm, welcoming, and willing to provide advice and assistance. Jason Poulin and Kassandra Lepack were the first two people I met when I toured the uOttawa campus in March 2010. Their warm reception went a long way in convincing me to join the group. My fumehood neighbours, Daniel Newbury and Geneviève Bétournay, were such great people to hang around and never failed to put a smile on my face. I greatly enjoyed working with Joel Marcotte and Boubacar Sow, with whom I had lively debates about the merits of iPhone vs. Android – by the way, Android is still better. During my time in the group, I had the opportunity to improve my French, and much of this is due to Francis Barabé; merci beaucoup pour l’expérience! Huge thanks go to our resident post-doc, Guillaume Révol, and former PhD student David Lapointe (now at U.C Berkeley) for all their input and suggestions. My office neighbours, Patrick Levesque and Mathieu Morin, were two great labmates and truly wonderful friends. Pat always encouraged me to keep pushing and to never give up when I was facing challenges. Mathieu never failed to put a smile on my face and, during my writing, helped out greatly by sending me some spectral data I had forgotten. Finally, I got to work with a great bunch of undergraduate students: Table of Contents iv Stephanie Lanoix, Terry McCallum and Anika Tarasewicz were all such a pleasure to work with and I wish them all the best! During my time at the University of Ottawa, I was privileged to interact with excellent faculty and support staff. I would like to first thank my committee members, Professors Christopher Boddy and Jeffrey Keillor, for their valuable input and comments on my work. On numerous occasions, I associated with Professors André Beauchemin and Derek Pratt, who were always willing to lend advice or suggestions when needed. Glenn Facey, our NMR Manager, is invaluable to the department: his organization and dedication kept the NMR facilities running smoothly. I want to thank also the crew in science stores for their hard work and cheery disposition, day in and out. I would never have even gone to graduate school without the inspiration of a number of my teachers and professors from my undergraduate degree and before. First, I want to thank Professors Dennis Hore and Fraser Hof at the University of Victoria for being such excellent instructors and inspiring me to pursue a career in chemistry. To Professor Robin Hicks at UVic and Professor Mark McLachlan at UBC, I am grateful for giving me my first experiences in research labs, which helped me so much throughout both my undergraduate and graduate work. Finally, I want to thank Mr. Ray Mar, my high school chemistry teacher, who, though his excellent teaching and wonderful personality first ignited my passion for chemistry. I am fortunate to have had a great support system of friends and family throughout my schooling. I want to extend thanks to my amazing friends back home in Ladner – Fabian Juren, Andrew Isaak, and Ryan Coleman, as well as all my friends from the University of Victoria, especially Emma Nicholls-Allison, whose drive and perseverance I admire in the utmost. I thank my brother, Kevin Schwantje, and my mother, Gayle Hubbard, for always supporting me and encouraging me to pursue my dreams. Finally, I want to give my deepest thanks to my best friend in the world, Claire Gilmour. She means the world to me and I would have had a tough time getting through graduate school without her love and support. Table of Contents v Table of Contents Abstract ................................................................................................................................... ii Acknowledgements................................................................................................................ iii Table of Contents ................................................................................................................... v List of Schemes ..................................................................................................................... vii List of Figures ........................................................................................................................ ix List of Tables ....................................................................................................................... xiv List of Symbols and Abbreviations.................................................................................... xvi Experimental Index............................................................................................................. xix 1 Introduction ................................................................................................................. 1 1.1 Triptolide ................................................................................................................... 1 1.1.1 Biosynthesis ........................................................................................................................... 3 1.1.2 Medicinal Activity ................................................................................................................. 5 1.1.3 Previous Syntheses ................................................................................................................ 8 1.1.4 Our Approach ...................................................................................................................... 17 1.2 Proposed Gold Catalyzed Cyclization Cascade ...................................................... 18 1.2.1 Introduction to Gold(I) Catalyzed Organic Transformations .............................................. 18 1.2.2 Oxidative Gold Transformations ......................................................................................... 23 1.2.3 Gouverneur Oxidative Cyclization ...................................................................................... 25 2 Synthesis ..................................................................................................................... 28 2.1 Retrosynthetic Analysis ........................................................................................... 28 2.1.1 Proposed extension of Gouverneur mechanism .................................................................. 28 2.1.2 Construction of Linear Precursor ........................................................................................ 31 2.2 Synthesis of Starting Materials ............................................................................... 32 2.3 Cyclopropanation and Brady-Julia Olefination ....................................................... 35 2.3.1 Oxidative Cleavage of Terminal Alkene ............................................................................
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