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Progress Toward the Total Synthesis of Terpenoid Natural Products: the Neomangicols and the Yohimbine Alkaloids

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Progress Toward the Total Synthesis of Terpenoid Natural Products: the Neomangicols and the Yohimbine Alkaloids Progress Toward the Total Synthesis of Terpenoid Natural Products: the Neomangicols and the Yohimbine Alkaloids By Jessica Louise Wood A dissertation in submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Richmond Sarpong, Chair Professor F. Dean Toste Professor Leonard Bjeldanes Fall 2011 Abstract Progress Toward the Total Synthesis of Terpenoid Natural Products: the Neomangicols and the Yohimbine Alkaloids by Jessica Louise Wood Doctor of Philosophy in Chemistry University of California, Berkeley Professor Richmond Sarpong, Chair Progress has been made toward the total synthesis of a diverse array of natural products. Chapter 1 begins by introducing the isolation, bioactivity, and biosynthesis of the neomangicol and mangicol sesterterpenoids. Subsequent to that introduction, a summary of previous synthetic approaches to these natural products is presented. In the third section, our synthetic approaches are detailed, beginning with a first generation synthesis of the ABD tricycle, followed by a description of our revised route to the neomangicol tetracyclic core and our work toward the rearrangement of that core to the mangicol spirocyclic core. This chapter concludes with a summary of our accomplishments in this natural product area and outlines several strategies to achieve the desired rearrangement. The last section also includes our initial studies into the formation of the mangicol core. Preliminary work toward the synthesis of the ABD tricycle was performed by Dr. Brian Pujanauski. Chapter 2 details our work in the area of the yohimbine alkaloids. It begins with an introduction to these pentacyclic indole-containing natural products, discussing their isolation, proposed biosynthesis and giving a brief overview of the rich bioactivity that has been ascertained for these molecules. Closely related synthetic approaches are also described. Finally, our divergent approach to the synthesis of several yohimbine alkaloids, as well as strategic analogs, is delineated. Our proposal for rendering this route enantioselective is also detailed. This work was done in collaboration with Dr. Terry Lebold and Josh Deitch. 1 For Matthew, I think of you every day. i Table of Contents Acknowledgements .................................................................................................................... iv Chapter 1 Synthetic Progress Toward the Neomangicol and Mangicol Natural Products ......... 1 1.1 Isolation and Bioactivity of the Mangicols and Neomangicols ............................................ 1 1.2 Biosynthesis of the Mangicols and Neomangicols ............................................................... 2 1.3 Approaches to the Mangicol Natural Products ..................................................................... 7 1.3.1 Uemura’s Transannular Diels-Alder Approach to Mangicol A ......................................... 7 1.3.2 Paquette’s First Generation Approach to Mangicol A ....................................................... 9 1.3.3 Paquette’s Second Generation Approach to Mangicol A ................................................ 13 1.4 Our First Generation Route to the Tetracyclic Neomangicol Core .................................... 15 1.4.1 Introduction ...................................................................................................................... 15 1.4.2 Synthetic Plan .................................................................................................................. 16 1.4.3 Forward Synthesis ............................................................................................................ 16 1.5 Second Generation Approach to the Neomangicol Tetracyclic Core ................................. 22 1.5.1 Revised Retrosynthesis .................................................................................................... 22 1.5.2 Synthesis of A-Ring Coupling Partner ............................................................................ 23 1.5.3 Synthesis of C/D Ring Coupling Partners ....................................................................... 26 1.5.4 Indene Acylation Substrate .............................................................................................. 31 1.5.5 Alternative Indene Alkylation Substrates ........................................................................ 32 1.5.6 Tetracycle Functionalization ............................................................................................ 35 1.5.7 Cis A/B Ring Tetracycle .................................................................................................. 41 1.5.8 Conclusions and Future Directions .................................................................................. 42 1.6 Proposed Direct Approach to Mangicol A .......................................................................... 43 1.6.1 Introduction ...................................................................................................................... 44 1.6.2 Preliminary Studies .......................................................................................................... 44 1.7 Conclusions ......................................................................................................................... 46 1.8 References ........................................................................................................................... 46 1.9 Experimental Methods ........................................................................................................ 49 1.10 X-ray crystallographic data for 1.218: .............................................................................. 68 1.11 Selected Spectra ............................................................................................................... 69 1.12 Experimental References ................................................................................................ 120 Chapter 2 A Unified Approach to the Yohimbine Alkaloids ................................................. 121 ii 2.1 Isolation and Biosynthesis of the Yohimbinoid Alkaloids ............................................... 121 2.2 Synthetic Background ....................................................................................................... 125 2.3 Model Studies for the Synthesis of the Pentacyclic Core ................................................. 127 2.4 Synthesis of the Aminonitrile Intermediates..................................................................... 133 2.5 Synthesis of β-C(3) Natural Products ............................................................................... 134 2.6 Synthesis of α-C(3) Natural Products ............................................................................... 137 2.7 Summary & Future Directions .......................................................................................... 140 2.8 References ......................................................................................................................... 141 2.9 Experimental Methods ...................................................................................................... 143 2.10 X-ray crystal data for 2.82: ............................................................................................. 161 2.11 Selected Spectra ............................................................................................................. 163 2.12 Experimental References ................................................................................................ 205 iii Acknowledgements First, I would like to thank my advisor, Professor Richmond Sarpong, for being a wonderful mentor and an outstanding role model. His enthusiasm for teaching his students is truly inspirational. Not only has he taught me an enormous amount about synthetic organic chemistry, he’s helped me to learn what questions to ask and how to think about fundamental reactivity. His genuine concern for his student’s overall well-being is something that I am grateful for. By emphasizing a strong group dynamic and a culture of helping one another, he has established a group environment that makes it a wonderful place to learn and grow as a graduate student. I appreciate everything that he has done as my advisor to make my experience here at Berkeley a great one. I would also like to thank my first three labmates here at Cal; Kimberly Larson, Scott West, and Jesse Cortez, for teaching me so much in the beginning. Kimberly showed me that persistence and careful consideration does pay off, Scott demonstrated that you can have fun and accomplish a great deal during grad school, and Jesse’s upbeat attitude made it a pleasure to come to work. I think back on my times in 847 Latimer and smile, especially whenever a Garth Brooks song comes on the radio. Eric Bunnelle, Andrew Marcus, and Laura Miller were fantastic, and always willing to take time to answer questions or offer opinions on how best to attack a problem. Alison Hardin-Narayan kept things interesting with her good idea/bad idea sessions. Eric Simmons’ phenomenal patience with my constant questions was truly admirable. I am grateful to have him as a role model as well as a friend. His ability to listen to my tirades is phenomenal, and I am indebted to him for his infallible advice. Dr. Daniel Fischer was a great resource during his time here, and
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