Studies Towards the Total Synthesis of Eleutherobin and Other Marine Natural Products by Jeffrey Stuart Mowat B.Sc., University of Alberta, 2005 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in the Department of Chemistry Faculty of Science © Jeffrey Stuart Mowat 2012 SIMON FRASER UNIVERSITY Fall 2012 All rights reserved. However, in accordance with the Copyright Act of Canada, this work may be reproduced, without authorization, under the conditions for “Fair Dealing.” Therefore, limited reproduction of this work for the purposes of private study, research, criticism, review and news reporting is likely to be in accordance with the law, particularly if cited appropriately. Approval Name: Jeffrey Stuart Mowat Degree: Doctor of Philosophy Title of Thesis: Studies Towards the Total Synthesis of Eleutherobin and Other Marine Natural Products Examining Committee: Chair: Firstname Surname, Position Dr. Robert Britton Senior Supervisor Associate Professor Dr. Peter Wilson Associate Professor Dr. Hua-Zhong (Hogan) Yu Professor Dr. Robert Young Internal Examiner Professor, Department of Chemistry Simon Fraser University Dr. Louis Barriault External Examiner Professor, Department of Chemistry University of Ottawa Date Defended/Approved: October 05, 2012 ii Partial Copyright Licence Abstract The primary focus of the research described in this thesis relates to the development and application of new synthetic methodologies relevant for the concise construction of four natural products. In Chapter 2, a discussion of our investigation of the total synthesis of eleutherobin (1) is disclosed. Eleutherobin (1), first isolated in 1997 from the rare soft coral Eleutherobia sp., is a member of a class of microtubule stabilising natural products. Although it displays potent cytotoxicity, its development as an anticancer drug has been hampered by the scarcity of material available from the natural source. In an effort to produce quantities of eleutherobin required for further biological testing, four conceptually unique approaches to eleutherobin were investigated which culminated in the development of an unprecedented palladium-catalysed α-arylation reaction/Friedel- Crafts cyclisation methodology for tetralone synthesis. This strategy permitted the production of multi-gram quantities of an advanced tetralone intermediate, and enabled the synthesis of a functionalised epoxyenone intermediate along our intended synthetic route. These investigations have provided a solid foundation for an eventual synthesis of eleutherobin that may also facilitate the evaluation of this natural product as an anticancer drug. In Chapter 3, the total synthesis of two potent anthelmintic oxylipid natural products, isolated from Notheia anomala, is discussed. Specifically, a silver-mediated cyclisation of two chlorodiols afforded two diastereomeric styryl-tetrahydrofurans, which were rapidly elaborated into the desired natural products. In addition, these syntheses featured a remarkable example of inverse-temperature dependence in the diastereoselective addition of Grignard reagents to tetrahydrofurfurals. Ultimately, these natural products were prepared in six synthetic transformations in excellent overall yield and efficiency. The last two topics presented in this thesis are contained in two separate appendices and highlight our interest in the synthesis of ecologically relevant natural products. In Appendix A, we report the synthesis and structure determination of the iii unknown banana volatile, (3R,2’S)-(2’-pentyl)-3-hydroxyhexanoate, and its olfactory recognition by the common fruit fly. The work presented in Appendix B focuses on the development of a scalable synthesis of mathuralure, the sex pheromone of the pink gypsy moth, Lymantria mathura, a potentially devastating invasive species. Keywords: eleutherobin; natural products; total synthesis; antimitotic chemotherapeutics; N. anomala oxylipids; tetrahydrofurans iv Quotation …Having reached this point in life, what chemist, facing the Periodic Table, or the monumental indices of Beilstein or Landolt, does not perceive scattered among them the sad tatters, or trophies, of his own professional past? He only has to leaf through any treatise and memories rise up in bunches: there is among us he who has tied his destiny, indelibly, to bromine or to propylene, or the -NCO group, or glutamic acid; and every chemistry student, faced by almost any treatise, should be aware that on one of those pages, perhaps in a single line, formula, or word, his future is written in indecipherable characters, which however, will become clear “afterward”: after success, error, or guilt, victory, or defeat. Every no longer young chemist, turning again to the verhängnisvoll page in that same treatise, is struck by love or disgust, delights or despairs… - Primo Levi On carbon (from The Periodic Table) v Acknowledgements First of all I would like to acknowledge the support and mentorship of my supervisor Professor Robert Britton. His unwillingness to accept the status quo has given me a unique perspective on synthesis, and his infectious passion for organic chemistry is what lured me to the field during our time together at Merck Frosst. I especially thank Rob for his undying optimism and persistence that kept me persevering in the face of significant obstacles and setbacks. I would also like to thank Profs. Peter Wilson and Hua-Zhong (Hogan) Yu for their support and guidance on my supervisory committee during my Ph.D. studies. Also thanked are Profs. Robert Young and Louis Barriault for serving as the internal and external examiners for my thesis defense. I would like to thank Prof. Gerhard Gries, Regine Gries, and Dr. Grigori Khaskin for their insightful conversations, collaborations, and good spirited demeanour. I have immensely enjoyed learning about the world of insect communication, and hearing about their tireless efforts in chemical ecology. Of course, the flats of German lager and packages of Haribo that appeared in the lab never hurt either. I would also like to acknowledge the staff responsible for NMR, Dr. Andrew Lewis and Colin Zhang, and for mass spectroscopy, Hongwen Chen. Dr. Ken MacFarlane is thanked for ensuring the lab was running smoothly and keeping up with our flood of requests. I would also like to thank the graduate secretaries Susie Smith and especially Lynn Wood for her sunny disposition. To all the members of the Britton group past and present, especially: Dr. Bal Kang, Dr. Kate Ashton, Stanley Chang, Jarod Moore, Jason Draper, Shira Halperin, Hope Fan, Michael Holmes, Milan Bergeron-Brlek, and Vijay Dhand. I am especially grateful to have worked closely with Bal on several projects and enjoyed our collaborations and discussions, be it chemistry related or otherwise. vi I would also like to thank Labros Meimetis, Bal Kang, Matthew Campbell (Esq.), and Pat Chen for their friendship throughout my graduate studies. I especially enjoyed our time outside the lab, sharing good food, beer, and laughs on many occasions at the pub. I would like to thank my parents for their support throughout my PhD studies. Despite their expected lack of understanding of my day-to-day work and perhaps the inability to read this document past these acknowledgement pages, I thank them for their love and support over the years. I know especially my Mom, who now considers me an “author”, will display this book proudly. Finally, for financial support I would like to acknowledge NSERC for the Post-Graduate Scholarship, the Michael Smith Foundation for Health Research for the Junior and Senior Trainee Scholarship, and SFU for their generous contributions. vii Table of Contents Approval ............................................................................................................................. ii Abstract ............................................................................................................................. iii Quotation ........................................................................................................................... v Acknowledgements ........................................................................................................... vi Table of Contents ............................................................................................................ viii List of Tables ...................................................................................................................... x List of Figures ................................................................................................................... xi List of Schemes .............................................................................................................. xiii List of Abbreviations ........................................................................................................ xvi 1. Introduction ............................................................................................................ 1 1.1. Thesis Overview ...................................................................................................... 1 1.2. Introduction to Cancer and Chemotherapy .............................................................. 3 1.2.1. Microtubules as a Target for Cancer Therapy .............................................. 4 1.2.2. Development of Anitimitotics as Chemotherapuetic Agents ......................... 6 1.3. Introduction to Natural Products .............................................................................