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Towards the Synthesis of the Emestrin Family of Natural Products

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Towards the Synthesis of the Emestrin Family of Natural Products Towards the Synthesis of the Emestrin Family of Natural Products Brendan James Fisher ORCID: 0000-0003-0090-8951 Submitted in total fulfilment of the requirements of the degree of Doctor of Philosophy September 2018 School of Chemistry Bio21 Institute The University of Melbourne Abstract A Cope rearrangement of a vinyl pyrrole epoxide (397) was utilised to form the dihydrooxepino[4,3-b]pyrrole core (398) of the emestrin family of natural products which involved the first examples of the dearomatisation of pyrrole in this type of rearrangement. It was found that an electron withdrawing ester substituent on the C2 position of the epoxide was essential for the [3,3]-rearrangement to occur. The vinyl pyrrole epoxides were synthesised in an efficient manner by a vinylogous Darzens reaction. Density functional calculations showed lower transition state energies for Cope rearrangements of epoxides with C2 esters when compared to the unsubstituted substrates which agreed with the observed experimental results. Silyl substituted vinyl bromide esters also participated in the Darzens reactions to give the desired vinyl pyrrole epoxides in good to excellent yields. Only the triethoxysilyl vinyl epoxide 313c underwent Cope rearrangement to provide the fully substituted emestrin core dihydrooxepine. The anion derived from an aryl bromosulfone did not give the Darzens product but underwent a previously unobserved stereoselective trimerization to afford the cyclohexene 343 as a single diastereoisomer. A mechanistic rationale involving SN2’ additions, [3,3]-Cope rearrangements and a stereoselective intramolecular conjugate addition was proposed and this was supported by density functional theory (DFT) calculations. A four-step total synthesis of biaryl ether natural product violaceic acid (11) is described. The steps include an SNAr reaction to afford the biaryl ether 136, tin chloride-mediated chemoselective reduction of the nitro group to amine 135. A Cu-mediated Sandmeyer reaction of 135 gave violaceic acid methyl ester 374 which is hydrolysed to give pure violaceic acid 11. An improved synthesis of the known biaryl iodide 119 is also described via a Sandmeyer reaction of amine 135. i ii iii Declaration This is to certify that: i. The thesis comprises only my original work; ii. Due acknowledgement has been made in the text to all other material used; iii. The thesis is less than 100,000 words in length, exclusive of tables, bibliographies, appendices and footnotes. Brendan James Fisher iv v Preface The synthesis of the dihydrooxepino[4,3‑b]pyrrole core of the emestrin family of natural products via Cope rearrangement of vinyl pyrrole epoxides has been published in a scientific journal (Rizzacasa, M.; Fisher, B.; et al.; Org. Lett. 2015, 17 (24), pp 5998 – 6001) and has been presented at the Royal Australian Chemical Institute, Victorian Branch, 40th Annual Synthesis Symposium, The University of Melbourne, Melbourne, Victoria, Australia on December 4th 2015, the Gordon Research Conference for Heterocyclic Compounds, Salve Regina University, Rhode Island, USA on June 18th – 23rd 2017, and the Royal Australian Chemical Institute, Victorian Branch, 42nd Annual Synthesis Symposium, The University of Melbourne, Victoria, Australia on December 1st 2017. The unprecedented stereoselective base-induced trimerization of an α-bromovinylsulfone has been published in a scientific journal (Rizzacasa, M.; Fisher, B.; et al.; Org. Biomol. Chem. 2017, 15, pp 5529 – 5534) and has been presented at the Gordon Research Conference for Heterocyclic Compounds, Salve Regina University, Rhode Island, USA on June 18th – 23rd 2017 and the Royal Australian Chemical Institute, Victorian Branch, 42nd Annual Synthesis Symposium, The University of Melbourne, Victoria, Australia on December 1st 2017. The synthesis of violaceic acid has been published in a scientific journal (Cameron, A.; Fisher, B.; Rizzacasa, M.; Tetrahedron, 2018, 74, pp 1203 – 1206). vi vii Acknowledgements I’d like to thank my supervisor Professor Mark Rizzacasa for all the help, guidance, support and opportunities given to me throughout my PhD. I’m so lucky that I chose a supervisor so willing to help and be engaged with their students’ learning process. You’re a fantastic supervisor, a brilliant chemist, but most importantly a great person. Acknowledgements and thanks to the contributors to this project, particularly Dr Elizabeth Krenske for providing invaluable computational data that led to two of our publications, and Professor Jonathan White for obtaining many X-ray crystal structures. Thanks to Nick Fisk, Jess Hummel and Alex Cameron for laying the foundations of this project, as well as Angus Robertson, Young Ye and Romain LePage for helping me keep it afloat. Thanks to the University of Melbourne for supporting me financially via the Melbourne Research Scholarship, and to the University and the G.I. Feutrill award for funding my visit to the Gordon Research Conference. Thanks to the Bio21 Institute support staff and students for all the help and friendship. Hamish Grant and Sunnia Rajput were invaluable in the NMR facility, as was everybody in the Bio21 stores, particularly Nick, Alex, Peter and Johanna who were not only a great help but great friends. Thank you to the Rizzacasa group members, both past and present. I’ve never met a brighter bunch of people and I’m so excited to see what all your futures hold in chemistry and beyond. Thanks for putting up with my mood swings and occasionally cleaning up the sintered glass funnels. Thanks to Gajan Santhakumar, Dayna Sturgess and Darran Loits for showing me the ropes in lab management. Thanks to all family and friends for the help and support over the years, particularly those who helped us with the move. Special thanks to my parents for constantly supporting me throughout my education and providing me with many privileges for which I am so fortunate. Finally, thank you to my partner Liv Burnett. There is no way I would have finished this project if it weren’t for your unwavering support and understanding. It’s truly the hardest thing I’ve ever done and knowing you’d be there for me at home to make me happy after a tough day kept me going more often than not. You’re the best. I’d like to take this opportunity to dedicate this body of work to Barbara Phillips and Carlene Fisher, two people who were a tremendous support and inspiration to me throughout my life and PhD. I hope this will serve as a reminder of the place in time that it was written and serve to further inspire me later in life. viii Table of Contents Abstract i Declaration iv Preface vi Acknowledgements viii Table of Contents ix List of Figures xii List of Schemes xiv List of Tables xix Glossary of Abbreviations xx 1. Introduction 1.1 Structure and activity of epipolythiodioxopiperazines (ETPs) 1 1.2 Structure and activity of emestrin (4) and related compounds 1 1.3 Structure and activity of aranotin (12) and related compounds 4 1.4 Biosynthesis of acetylaranotin (3) 5 1.5 Structure and activity of emethallicin A (24) and related compounds 6 1.6 Previous syntheses of dihydrooxepine containing ETPs 7 1.6.1 Clive and Peng’s synthesis of the tricyclic core of the emestrins 7 1.6.2 Reisman and coworkers’ total synthesis of acetylaranotin (3) 10 1.6.3 Reisman and coworkers’ total synthesis of acetylapoaranotin (15) 12 1.6.4 Tokuyama and coworkers’ total synthesis of acetylaranotin (3) 13 1.6.5 Tokuyama and coworkers’ total synthesis of MPC1001B (8) 16 1.7 Biaryl ether synthesis and background 17 1.8 Bibliography 20 ix 2. Retrosynthesis and reaction background 2.1 Retrosynthetic analysis of emestrin-type natural products 24 2.2 Reaction background: Cope rearrangement 27 2.3 Reaction background: vinylogous Darzens reaction 31 2.4 Bibliography 33 3. Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrin natural products 3.1 Synthesis of the dihydrooxepino[4,3-b]pyrrole core of the emestrins via the Cope rearrangement of vinyl pyrrole epoxides 36 3.1.1 Synthesis of vinyl pyrrole epoxides 36 3.1.2 Synthesis of vinyl pyrrole epoxides by a vinylogous Darzens reaction 38 3.1.3 Cope rearrangements of vinyl pyrrole epoxides 42 3.1.4 Computational analyses of Cope rearrangements 47 3.1.5 Preliminary conclusions 49 3.2 Attempts to remove the ester functionality 50 3.3 Towards a synthesis of the fully substituted dihydrooxepine 58 3.3.1 Allylic oxidation approach 58 3.3.2 Extended Darzens reactions 58 3.3.3 Wittig approach 62 3.4 Bibliography 69 4. A novel vinyl sulfone trimerization 4.1 Synthesis of vinyl pyrrole epoxides with alternative electron-withdrawing groups 73 4.1.1 Synthesis of alternative electron-withdrawing groups 73 4.1.2 Darzens reaction with a bromocrotononitrile 73 4.1.3 Attempts to synthesise a sulfone epoxide via a Darzens reaction 74 4.2 A novel vinyl sulfone trimerization 76 x 4.2.1 Characterisation of vinyl sulfone by-product 76 4.2.2 Optimising the trimerisation reaction 81 4.2.3 Proposed mechanisms and computational analyses of transition states 84 4.3 Bibliography 90 5. Synthesis of Violaceic acid (11) 5.1 Biaryl ether coupling 92 5.2 Selective reduction of nitro 136 to amine 135 94 5.3 Sandmeyer hydroxylation and hydrolysis of violaceic acid methyl ester (374) 95 5.4 Attempted modifications of the original route 97 5.5 Formal synthesis of Violaceic acid (11) 99 5.6 Bibliography 101 6. Future work and conclusions 6.1 Synthesis of the tricyclic core of the emestrin family of natural products 104 6.2 Future work and revised route towards the tricyclic core of the emestrins 105 6.3 Conclusion 106 6.4 Bibliography 108 7. Experimental section 7.1 General experimental 110 7.2 Experimental methods 111 7.3 Bibliography 171 xi List of Figures Figure 1.1 Generic structure of ETPs (1), structure of gliotoxin (2) and acetylaranotin (3).
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