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The Total Synthesis of Securinine and Other Methodology Studies University of Windsor Scholarship at UWindsor Electronic Theses and Dissertations Theses, Dissertations, and Major Papers 2010 The total synthesis of securinine and other methodology studies Bhartesh Dhudshia University of Windsor Follow this and additional works at: https://scholar.uwindsor.ca/etd Recommended Citation Dhudshia, Bhartesh, "The total synthesis of securinine and other methodology studies" (2010). Electronic Theses and Dissertations. 8275. https://scholar.uwindsor.ca/etd/8275 This online database contains the full-text of PhD dissertations and Masters’ theses of University of Windsor students from 1954 forward. These documents are made available for personal study and research purposes only, in accordance with the Canadian Copyright Act and the Creative Commons license—CC BY-NC-ND (Attribution, Non-Commercial, No Derivative Works). Under this license, works must always be attributed to the copyright holder (original author), cannot be used for any commercial purposes, and may not be altered. Any other use would require the permission of the copyright holder. Students may inquire about withdrawing their dissertation and/or thesis from this database. For additional inquiries, please contact the repository administrator via email ([email protected]) or by telephone at 519-253-3000ext. 3208. The Total Synthesis of Securinine and Other Methodology Studies by Bhartesh Dhudshia A Dissertation Submitted to the Faculty of Graduate Studies through the Department of Chemistry and Biochemistry in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Windsor Windsor, Ontario, Canada 2010 Copyright © 2010 Bhartesh Dhudshia. Library and Archives Bibliotheque et 1*1 Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington OttawaON K1A0N4 Ottawa ON K1A0N4 Canada Canada Your file Votre r6f6rence ISBN: 978-0-494-62763-1 Our file Notre r6f6rence ISBN: 978-0-494-62763-1 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library and permettant a la Bibliotheque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par Nnternet, prefer, telecommunication or on the Internet, distribuer et vendre des theses partout dans le loan, distribute and sell theses monde, a des fins commerciales ou autres, sur worldwide, for commercial or non­ support microforme, papier, electronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in this et des droits moraux qui protege cette these. Ni thesis. Neither the thesis nor la these ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent etre imprimes ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author's permission. In compliance with the Canadian Conformement a la loi canadienne sur la Privacy Act some supporting forms protection de la vie privee, quelques may have been removed from this formulaires secondaires ont ete enleves de thesis. cette these. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n'y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. 1+1 Canada Ill Declaration of CoAuthorship I hereby declare that this thesis incorporates material that is a result of joint research under the supervision of Dr. Avinash Thadani, as follows: Ben Cooper, Dr. Charles Macdonald and Dr. Jorge Tiburcio solved crystal structures presented in both Chapter 1 and Chapter 3. I am aware of the University of Windsor Senate Policy on Authorship and I certify that I have properly acknowledged the contribution of other researchers to my thesis. I certify that, with the above qualification, this thesis, and the research to which it refers, is the product of my own work. Declaration of Previous Publication This thesis includes three original papers that has been previously published in peer reviewed journals, as follows: (1) Bhartesh Dhudshia, Benjamin F. T. Cooper, Charles L. B. Macdonald, Avinash N. Thadani; The asymmetric total synthesis of (-)-securinine, Chem. Commun., 2009, (4), 463-465 (2) Dhudshia, Bhartesh; Thadani, Avinash N. Acyclic diaminocarbenes: simple, versatile ligands for cross-coupling reactions, Chem. Commun., (2006), (6), 668-670. (3) Dhudshia, Bhartesh; Tiburcio, Jorge; Thadani, Avinash N.; Diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones, Chem. Commun., (2005), (44), 5551-5553. I certify that the above material describes work completed during my registration as graduate student at the University of Windsor. I declare that, to the best of my knowledge, my thesis does not infringe upon anyone's copyright nor violate any proprietary rights and that any ideas, techniques, quotations, or any other material from the work of other people included in my thesis, published or otherwise, are fully acknowledged in accordance with the standard referencing practices. IV I declare that this is a true copy of my thesis, including any final revisions, as approved by my thesis committee and the Graduate Studies office, and that this thesis has not been submitted for a higher degree to any other University or Institution. V Abstract Chapter 1 presents a flexible synthesis of (-)-securinine in 18 steps and 16% overall isolated yield from the commercially available frvms-4-hydroxy-L-proline. Securinine is the major Securinega alkaloid isolated from the Securinega, which has been associated with a number of interesting biological activities. The key steps of the synthesis include the highly diastereoselective preparation of the spirocyclic a,P- unsaturated y-lactone intermediate and the intramolecular Heck cyclization to complete the tetracyclic skeleton. We anticipate that the synthetic route can be readily modified to access other Securinega alkaloids {e.g. norsecurinine). In chapter 2 Acyclic Diaminocarbene (ADC) were studied as lignads in various C-C bond formation reactions (e.g. Suzuki-Miyaura, Sonogashira and Heck). ADCs are more basic than their counterpart NHCs and can be easily synthesized from the formamidinium salt precursors. The resulting coupling products obtained in good to excellent yields. Homoallylic amines are very useful synthons for numerous biologically active compounds. Chapter 3 presents facile syntheses of homoallylic amines using an easily executable three component system of ketone, ammonia, and allylboronates. The resulting homoallylic amines were isolated in good to excellent yields through simple acid-base extraction. The crotylation of N-unsubstituted ketimines was also shown to be highly diastereoselective. VI To My Family VII Acknowledgements First and foremost, I would like to thank my advisor Professor Avinash Thadani for his guidance and support over my tenure at the University of Windsor. His inspiration and enthusiasm made this work possible. I am very grateful to his continuous encouragement, which always motivated me to think deeper and try harder. Professor James R. Green and Stephen J. Loeb are sincerely acknowledged for serving on my thesis committee. I would like to thank Professor Kerr for agreeing to be external examiner for my thesie and defense. I feel blessed to work with Prof. K. C. Nicolaou as post doctoral fellow before defense of this thesis. I am also very appreciative of the help provided to me by Mr. Mike Fuerth in NMR spectroscopy and Drs. Jorge Tuburcio, Charles Macdonald, Bobby Ellis and Mr. Ben Cooper for solving the relevant X-ray structures. I owe many thanks to my parents and family members for supporting my educational path. I would not have made it through without all their immense support. A heartfelt and sincere thank goes to my wife, Sejal, for always being there. Finally, I would like to express my gratitude to all the Thadani group members for their friendship and help through the past several years. VIII Table of Contents Declaration of Co-authorship and Previous Publications Hi Abstract v Dedication vi Acknowledgements vii List of Figures ix List of Schemes x List of Tables xiii List of Abbreviations xvi Chapter 1: Asymmetric Total Synthesis of Securinine 1 1.1 Introduction 1 1.2 Results and Discussion 20 1.3 Conclusion and Future Work 40 1.4 Experimental 41 1.5 References 55 Chapter 2: Acyclic Diaminocarbene: Simple, Versatile Ligand for Cross-Coupling Reactions 61 2.1 Introduction 61 2.2 Results and Discussion 81 2.3 Conclusion and Future Work 99 2.4 Experimental 100 2.5 References 112 Chapter 3: Diastereoselective Allylation and Crotylation of N-Unsubstituted Imines Derived from Ketones 121 3.1 Introduction 121 3.2 Results and Discussion 135 3.3 Conclusion and Future Work 142 3.4 Experimental 143 3.5 References 154 Vita Auctoris, 158 ix List of Figures Figure 1.1 Structures of Various Securinega Alkaloids 2 Figure 1.2 Ring Labeling of (-)-Securinine and (-)-Norsecurinine 6 Figure 1.3 Grubbs' 1st and 2nd Generation RCM Catalysts 30 Figure 1.4 Hoveyda-Grubbs' 2nd Generation Catalyst 36 Figure 2.1 Carbene Electronics 61 Figure 2.2 Examples of Fischer and Shrock Carbene Complexes 62 Figure 2.3 Examples
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