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Vinylogous Sulfonamides in the Total Synthesis of Indolizidine Alkaloids from Amphibians and Ants

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Vinylogous Sulfonamides in the Total Synthesis of Indolizidine Alkaloids from Amphibians and Ants VINYLOGOUS SULFONAMIDES IN THE TOTAL SYNTHESIS OF INDOLIZIDINE ALKALOIDS FROM AMPHIBIANS AND ANTS Susan Winks A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg in fulfilment of the requirements for the Degree of Doctor of Philosophy. January 2010 i Declaration I declare that the work presented in this thesis was carried out exclusively by me under the supervision of Professor J. P. Michael and Professor C. B. de Koning. It is being submitted for the degree of Doctor of Philosophy at the University of the Witwatersrand, Johannesburg. It has not been submitted before for any degree or examination in any other university. ______________________ 15th day of January 2010. ii Abstract This thesis describes the application of vinylogous sulfonamides in a generalised synthetic protocol for the synthesis of indolizidine alkaloids, viz. monomorine I, 5-epi-monomorine I and the key precursor to indolizidine 209D. Chapter one puts the work into perspective with a review of the different classes of amphibian alkaloids, with specific emphasis on previous syntheses of indolizidine 209D and monomorine I. This is followed by a brief overview of previous synthetic strategies employed for alkaloid synthesis in the Wits laboratories and an introduction to vinylogous sulfonamides. Chapter 2 concludes with our aims and proposed strategies for the project. The attempted total synthesis of (−)-indolizidine 209D is described in Chapter 3. The initial three steps to prepare t-butyl (3R)-3-{benzyl[(1R)-1- phenylethyl]amino}nonanoate (274) proceeded well, but the fourth step, deprotecting the nitrogen, gave inconsistent results and hindered the completion of the synthesis. The free amine that we succeeded in isolating, t- butyl (3R)-3-aminononanoate (275), reacted with chlorobutyryl chloride to give us lactam, t-butyl (3R)-3-(2-oxo-1-pyrrolidinyl)nonanoate (277) in addition to the unusual by-product N-(cyclopropanecarbonyl)cyclopropanecarboxamide (327). From the lactam (277) we successfully prepared the key intermediate, vinylogous sulfonamide t-butyl (3R)-3-{2-[(E)-(p-toluenesulfonyl)methylene-1- pyrrolidinyl} nonanoate (280). The vinylogous sulfonamide effectively facilitated a high-yielding cyclisation reaction to produce the bicyclic hexahydroindolizine (282). Unfortunately the failing debenzylation reaction prevented the completion of the synthesis as no more material was available. The total syntheses of (±)-monomorine I and (±)-5-epi-monomorine I are described in Chapter 4. Notable intermediates include the enamide, ethyl 3- [(2E)-2-butylidene-5-oxopyrrolidinyl]butanoate (293), which we prepared from a condensation reaction between the ketoester (292) and the racemic amine (291). The diastereoselective reduction of the enamide (293) was optimised to give ethyl 3-(2-butyl-5-oxo-1-pyrrolidinyl)butanoate (294) as a 1:5 mixture of iii isomers. After thionation, the two isomers were separable, (295A) was the intermediate for (±)-monomorine I and (295B) the intermediate for (±)-5-epi- monomorine I. Following the formation of the vinylogous sulfonamide, the key cyclisation step proceeded well for both the diastereomers to give the hexahydroindolizines (298A) and (298B). We obtained crystal structures of both hexahydroindolizines and were able to confirm the relative stereochemistry of the isomers. Defunctionalisation of the vinylogous sulfonamide included a stereoselective platinum-catalysed reduction of the alkene, followed by desulfonylation. Conditions were optimized and the synthesis was completed to give (±)-monomorine I in an overall yield of 3% and (±)-5-epi-monomorine I in an overall yield of 7%. Approaches towards the enantioselective synthesis were explored but, unfortunately, we experienced difficulties with the debenzylation reaction required to produce the chiral amine (291). In the process of trying to circumvent this problem a side route involving monobenzylated analogues was investigated. While the side route produced some interesting products, we were unable to direct the synthetic path back towards enantiopure monomorine I. The feasibility of extending this methodology to more complex alkaloids was briefly investigated. Initial experimentation involving allylated analogues of the ketoester (292) was investigated and was found to be incompatible with our reaction conditions. iv In memory of my grandmother Edna Robins Sept 1927 – Aug 2009 v Personal acknowledgements Firstly, Professor J. P. Michael, thank you for giving me the freedom to explore organic chemistry and for nurturing my love of the subject. You were always there providing me with complete support, guidance and confidence. In addition, I would like to thank my second supervisor, Professor C. B. de Koning, for many useful discussions and reminding me that there is more to life than chemistry. I would also like to thank the other organic chemistry members of staff, Professor W. A. L. van Otterlo and Dr. S. Pelly for support and encouragement. Richard Mampa, thank you for your endless patience and assistance with my many, many NMR samples, and thank you for taking the time to train and guide me in the use of the 300 MHz instrument. I would like to express my sincere gratitude to Manuel Fernandes for constantly encouraging me to grow crystals, even when the majority of my products stubbornly remained as oils, and also, of course, for doing the crystallographic analyses when I did succeed. Thank you also to Andreas Lemmerer for crystallographic analyses. A big thank you to Chris Perry, who is responsible for all the MD/SA results, and many fruitful discussions on stereoselectivity. Thank you also for proof- reading my thesis and supporting me through-out this project. I would like to thank Tommy van der Merwe, Martin Brits and Marelize Ferreira for running low and high resolution mass spectrometry. The Organic Group, past and present, thank you for all the fun and encouragement, especially to my lab mates, mentors and friends; Garreth, Sameshnee, Siyanda and Jeremy. vi Acknowledgements for funding Without all the funding I have received, this PhD would not have been possible. I would like to express my sincere appreciation to the Andrew Mellon Mentorship Programme for their substantial financial contribution, the University of the Witwatersrand for the Post Graduate Merit Award and the School of Chemistry for the Teaching Assistantship bursaries; I thoroughly enjoyed the classes I taught and the experience I gained from lecturing was invaluable. The financial assistance of the National Research Foundation (NRF) towards this research is hereby acknowledged. Opinions expressed and conclusions arrived at are those of the author and are not necessarily to be attributed to the NRF. vii CONTENTS Chapter 1: An overview of amphibian alkaloids, and reported syntheses of indolizidine 209D and monomorine I..........................................................1 1.1 Definition, occurrence and classification of alkaloids....................................1 1.2 Indolizidine alkaloids in nature......................................................................4 1.3 Major classes of “amphibian” alkaloids..........................................................7 1.3.1 Steroidal alkaloids............................................................................7 1.3.2 Monocyclic alkaloids........................................................................8 1.3.3 Bicyclic alkaloids..............................................................................9 1.3.4 Tricyclic alkaloids...........................................................................15 1.3.5 Pyridine alkaloids...........................................................................17 1.3.6 Indole alkaloids..............................................................................17 1.4 Indolizidines of interest in this project..........................................................18 1.4.1 Indolizidine 209D...........................................................................18 1.4.2 Monomorine I.................................................................................27 1.4.3 Tricyclic alkaloids...........................................................................52 Chapter 2: Background, aims and scope of this project.............................56 2.1 The “Wits Approach” to indolizidine alkaloids .............................................56 2.1.1 Introduction to the “Wits Approach”...............................................56 2.1.2 Preparation of enaminones............................................................57 2.1.3 Enaminones in action at Wits........................................................59 2.2 Vinylogous sulfonamides.............................................................................67 2.2.1 Preparation of vinylogous sulfonamides........................................67 2.2.2 Uses of vinylogous sulfonamides..................................................68 2.3 Aims and proposed strategies of this project...............................................71 2.3.1 (−)-Indolizidine 209D......................................................................71 2.3.2 Monomorine I and diastereomers..................................................74 2.3.3 Accessing tricyclic alkaloids...........................................................79 2.3.4 Summary of aims...........................................................................83 viii Chapter 3: The attempted total synthesis of (−)-indolizidine
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