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Approaches to Marine-Derived Polycyclic Ether Natural Products: First Total Syntheses of the Asbestinins and a Convergent Strategy for Brevetoxin A

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Approaches to Marine-Derived Polycyclic Ether Natural Products: First Total Syntheses of the Asbestinins and a Convergent Strategy for Brevetoxin A APPROACHES TO MARINE-DERIVED POLYCYCLIC ETHER NATURAL PRODUCTS: FIRST TOTAL SYNTHESES OF THE ASBESTININS AND A CONVERGENT STRATEGY FOR BREVETOXIN A J. Michael Ellis A dissertation submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry Chapel Hill 2007 Approved by: Advisor: Professor Michael T. Crimmins Reader: Professor Michel R. Gagné Reader: Professor Jeffrey S. Johnson © 2007 J. Michael Ellis ii ABSTRACT J. Michael Ellis Approaches to the Marine-derived Polycyclic Ether Natural Products: First Total Syntheses of the Asbestinins and a Convergent Strategy for Brevetoxin A (Under the direction of Professor Michael T. Crimmins) Glycolate aldol reactions and glycolate alkylations, followed by ring-closing metatheses, are used to prepare medium ring ethers used as building blocks for polycyclic ether containing natural products. Using the glycolate aldol/ring-closing metathesis strategy, an approach to a previously unprepared subclass of the C2– C11 cyclized cembranoids known as the asbestinins is described. An oxonene is efficiently synthesized and utilized as a manifold for an intramolecular Diels–Alder cycloaddition to form a hydroisobenzofuran moiety characteristic of the asbestinins. This tricyclic adduct represents the bulk of the framework of the asbestinins. Ultimately, the tricycle was progressed to two different natural products, 11-acetoxy- 4-deoxyasbestinin D and asbestinin-12, via a late-stage divergent route. The completion of these natural products represented the first instance of preparing an asbestinin using chemical synthesis, and served to confirm the absolute configuration of the subclass. Additionally, a glycolate alkylation/ring-closing metathesis strategy was used to prepare the B ring of brevetoxin A on multigram scale. Novel reactivity was discovered and exploited along this route. Namely, it was found that glycolate alkylation adducts can undergo direct Claisen condensation or reduction to the iii aldehyde to provide useful synthons. The B ring has been progressed to the BCDE tetracycle in a convergent fashion, and portions of this supply have been carried forward to provide possible coupling partners for the GHIJ fragment in hopes of completing brevetoxin A in a convergent manner. iv ACKNOWLEDGEMENTS First, I would like to acknowledge Professor Michael T. Crimmins for being an advisor and a friend to me during the past five years. Graduate school can be quite a test of perseverance, and his leadership style made my time here not only tolerable, but enjoyable. I have become an independent thinker and a scientist under his direction, and I owe my professional future to the time and energy he poured into my development. Nearly every member I have overlapped with in the Crimmins laboratory contributed to me reaching this point, but several deserve special thanks. Dr. Brandon Brown and Dr. Jon Parrish were my mentors from day one, and I appreciate all they did to get me off on the right foot and show me how to still enjoy life while in graduate school. The third year is a crucial time for a Ph.D. candidate, and I was fortunate to be surrounded by a number of inspiring postdocs during this portion of my studies. Specifically, Dr. Franck Caussanel and Dr. Hilary Plake motivated me with their strong work ethic and were always there to lend advice. Dr. Hamish Christie brought the entire lab to a new level during his time here, and I was one of the many positively impacted by his contagious passion for science. I would also like to thank Dr. Aaron Smith and Matt Haley for their friendships and for making lab a fun place to be every single day. Special thanks are also extended to Danielle Jacobs for providing this dissertation, and many other things I have written during my time here, with her proofreading prowess. v During the latter half of my time here, I have had the privilege of being part of “Team Brevetoxin”. Many have contributed to this project, but I would like to specifically acknowledge Dr. Patrick McDougall and Luke Zuccarello for allowing me to join them on this task they have poured so much into and take part in the effort toward this natural product. It has been a privilege to be on the same team with such intelligent and talented chemists. Finally, a number of family members have been vital to getting me to this point. My mom and dad have sacrificed countless times to provide me with every opportunity they could. The years put in before getting here equipped me with the abilities to get through this experience. And most importantly, I want to thank my wife Erin. She has been my source of inspiration and energy for the past five years. I could not have done this without all of her love, support, and understanding, which allowed me to focus on the task at hand while she gave our life balance. vi TABLE OF CONTENTS Page List of Tables………………………………………………………..……………………….x List of Figures………………………….……………………………………………………xi List of Abbreviations………………………………….………………...………………….xii Chapter I: An Aldol/Ring-Closing Metatheis/Intramolecular Diels–Alder Approach to the Asbestinins: Total Syntheses of 11-Acetoxy-4-deoxyasbestinin D and Asbestinin-12 ............................................................................................................. 1 A. Background....................................................................................................... 1 B. Previous Total Syntheses of C2–C11 Cyclized Cembranoids........................... 3 1. Prins–pinacol Condensation–rearrangement................................................. 3 2. Claisen Rearrangement Strategy .................................................................. 8 3. A Return to the Prins–pinacol Condensation–rearrangement...................... 12 4. [4+3] Annulation Strategy ............................................................................ 17 5. Intramolecular Amide Enolate Alkylation ..................................................... 19 6. Wittig Rearrangement/Intermolecular Diels–Alder Strategy......................... 23 7. Miscellaneous Strategies............................................................................. 25 C. Medium Ring Ether Synthesis via Ring-closing Metathesis............................ 35 1. Catalyst Development.................................................................................. 35 vii 2. Aldol/Ring-closing Metathesis in the Crimmins Laboratory.......................... 38 3. Alkylation/Ring-closing Metathesis in the Crimmins Laboratory................... 42 4. Total Syntheses of the Eunicellin Diterpenes via Alkylation/........................ 44 D. Total Syntheses of 11-Acetoxy-4-deoxyasbestinin D and............................... 51 1. Background.................................................................................................. 51 2. Retrosynthetic Analysis................................................................................ 52 3. Oxonene Formation ..................................................................................... 54 4. Synthesis of the Diels–Alder Candidate....................................................... 61 5. Revised Retrosynthesis ............................................................................... 76 6. Synthesis of the Revised Diels–Alder Substrate.......................................... 77 7. Refunctionalization of the Six- and Nine-membered Rings.......................... 79 8. Oxepane Formation to Complete 11-Acetoxy-4-deoxyasbestinin D ............ 82 9. Total Synthesis of Asbestinin-12.................................................................. 90 E. Summary......................................................................................................... 93 Chapter II: A Convergent Strategy for the Total Synthesis of Brevetoxin A ............ 97 A. Background..................................................................................................... 97 B. Approaches to Polycyclic Ether Synthesis ...................................................... 99 1. Iterative Ring Formation............................................................................... 99 2. Biomimetic Epoxide Opening..................................................................... 100 3. [X + 1 + X] Approach ................................................................................. 101 4. [X + 2 +X] Strategy .................................................................................... 104 C. Brevetoxin A ................................................................................................. 105 1. Characterization and Biological Activity ..................................................... 105 viii 2. Nicolaou’s Total Synthesis of Brevetoxin A................................................ 108 D. Previous Efforts in the Crimmins Laboratory Toward Brevetoxin A .............. 119 1. Seminal Efforts Toward the BCDE Fragment ............................................ 119 E. Preparation of the BCDE and GHIJ Fragments ............................................ 124 1. A Revised Route to a Homologated B Ring............................................... 125 2. Formation of the BCDE Fragment ................. Error! Bookmark not defined. 3. Formation of the GHIJ Fragment ............................................................... 131 F. Model Studies of F Ring Formation..............................................................
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