Synthetic Studies Toward Aziridinomitosenes and 9-Oxo-Pyrrolo[1,2-A]Indole Mitosanes Related to the Mitomycin and FR Heterocycles

Synthetic Studies Toward Aziridinomitosenes and 9-Oxo-pyrrolo[1,2-a]indole Mitosanes Related to the Mitomycin and FR Heterocycles by Susan D. Wiedner A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Chemistry) in The University of Michigan 2009 Doctoral Committee: Professor Edwin Vedejs, Chair Professor David Sherman Associate Professor Anna Mapp Associate Professor John Wolfe © Susan D. Wiedner 2009 To my grandfather, Francis Jerome Trick ii Acknowledgements I would first like to thank my advisor, Professor Edwin Vedejs, for advising me over the last six years. His drive for understanding chemical problems and discovering new chemistry imparted on me a desire to understand, analyze, and circumvent multiple synthetic difficulties which I encountered during my graduate work. Without his guidance and example, I would not have been successful. Furthermore, I would like to thank him for the opportunity to discover my “talents” during this incredibly challenging and rewarding research experience. I also want to thank past and present Vedejs group members. A special thanks goes to Tim, Trisha, and Drew for helping me transition into the lab during my first and second year. Thank you Jeremy and Musong for your previous work on the FK317 project. Thanks John, Aleks, Li, Dan and Eoghan for many discussions about chemistry. I especially want to thank Bob and Val for their insightful suggestions regarding my project, for reading and editing my thesis, and for their friendship. Most importantly, I would like to thank my family. My husband Eric has been by my side for most of my graduate career and I could not have gotten through this challenging process without his support and love. And finally, my parents, grandparents, siblings, and extended family have all been supportive of me during my graduate studies, and a special thanks goes to them for understanding that during graduate school my time has not always been my own. iii Table of Contents Dedication ii Acknowledgements iii List of Figures vi List of Tables vii List of Schemes viii List of Appendices xi Abstract xii Chapter 1. The Antitumor Antibiotic Mitomycins and FR Compounds 1 The Antitumor Antibiotic Mitomycin Family 1 Events Leading to DNA Cross-linking by Mitomycin C 3 Monoalkylation of DNA by Mitomycin C 9 Formation of 2,7-Diaminomitosene and its DNA adduct 13 Summary of Mitomycin C Activation 15 The Antitumor Antibiotic FR Family of Compounds 16 The Promising Semi-synthetic Candidate FK317 21 Asymmetric Syntheses of Aziridinomitosenes Derived from the FR Compounds 23 Summary 29 Chapter 1 Bibliography 32 iv 2. Synthesis of a Fully Functionalized Aziridinomitosene 40 Introduction 40 The Synthesis of a fully functionalized Aziridinomitosene 42 Deprotection Attempts on Fully Functionalized 36 53 Disscussion 59 Chapter 2 Bibliography 80 3. Synthesis of a 9-Oxo-pyrrolo[1,2-a]indole Related to FR900482 84 Brief Overview of Mitomycin C and FR900482 84 The Relationship between Mitomycin C and FR900482 85 Racemic syntheses of the pyrrolo[1,2-a]indole core 89 Asymmetric syntheses of the pyrrolo[1,2-a]indole core 94 Part 1. Enantioselective synthesis of 3,6-diazabicyclo[3.1.0]hexanes 99 Route A: Tin-Lithium exchange and intramolecular 1,2-addition 99 Route B: Dianion formation and trapping studies 104 Route C: Transition metal-catalyzed coupling 107 Part 2. Enantioselective synthesis of a 9-oxo-pyrrolo[1,2-a]indole 114 Tetracycle Formation 114 Synthesis of the fully functionalized 9-oxo-pyrrolo[1,2-a]indole 96 122 Conclusion 129 Chapter 3 Bibliography 162 Appendices 169 v List of Figures Figures: Chapter 1 1-1. Mitomycins A, B, C and Poriformycin 2 1-2. DNA Lesion of 3 and schematic of interstrand and intrastrand cross linking 7 1-3. Monoalkylated adduct 6 and schematic of precomplexing hydrogen bonding 10 1-4. The FR antitumor antibiotics 17 1-5. Isolated peracetylated DNA lesion of 30 and schematic of orientation isomers 19 1-6. Hydrogen bonding facilitating monoalkylation and quinone methides 41 and 11 21 1-7. Target aziridinomitosene derived from FK317 30 Figures: Chapter 2 2-1. The FR compounds, aziridinomitosene 5 and Mitomycin C 41 2-2. Selected aziridinomitosenes 55 Figures: Chapter 3 3-1. Diamine ligands used in Cu catalyzed coupling 113 3-2. X-ray crystal structure of tetracycle 90 121 vi List of Tables Tables: Chapter 2 2-1. Preparation of 9a from 10 43 2-2. Characteristic 1H NMR Signals of 29 – 36 51 2-3. Characteristic 1H NMR signals of key tetracycles 55 2-4. Deprotection of Aziridine 45 57 Tables: Chapter 3 3-1. Tin-lithium exchange on 36 102 3-2. Dianion formation on model carbamate 44 106 3-3. Copper catalyzed coupling of aryl iodides with 19 112 3-4. Transition metal catalyzed coupling of aryl triflate with 19 125 vii List of Schemes Schemes: Chapter 1 1-1. Main DNA adducts of 3 3 1-2. Reductive activation and DNA alkylation of 3 by guanine nucleosides (dG) 5 1-3. Mono- and Bis-alkylation of reduced 3 with exogenous nucleophiles 6 1-4. One electron reduction to initiate the activation cascade of N-methylmitomycin A 8 1-5. Mono-alkylation vs. Bis-alkylation pathways 12 1-6. C(1) alkylation of aziridinomitosene 25 13 1-7. Formation of the 2,7-DAM 8 and the DNA mono-adduct 7 14 1-8. Summary of three activation pathways of mitomycin C 16 1-9. Bioreductive activation cascade for FR-66979 30 19 1-10. Activation of FK317 32 23 1-11. Sulikowski’s synthesis of the aziridinomitosene 56 24 1-12. Michael’s Heck arylation to form tetracycle 63 25 1-13. Miller’s asymmetric synthesis of unprotected aziridinomitosene 72 26 1-14. Ziegler’s convergent synthesis of aziridinomitosene 81 28 1-15. Vedejs and Little’s asymmetric synthesis of the deprotected aziridinomitosene 91 29 viii Schemes: Chapter 2 2-1. Retrosynthetic analysis of the aziridinomitosene 7 derived from FK317 42 2-2. Alkylation of 10 with aziridines 12 and 13 42 2-3. Tetracycle formation 45 2-4. Removal of the trityl protecting group from 8 46 2-5. Pyrrole carbinol installation on m-Anisaldehyde 21 47 2-6. Installation of pyrrole carbinol and enoate reduction 48 2-7. Synthesis of fully functionalized aziridinomitosene 36 50 2-8. Formation of mitosene 47 during final deprotection 59 2-9. Solvolysis of aziridinomitosene 49 60 2-10. Deprotection studies on aziridinomitosene 51 60 2-11. Summary of the reactivity of the C(10) carbamate of 36 and 39 61 Schemes: Chapter 3 3-1. Biosynthetic intermediates leading to 1 and 2 85 3-2. Conversion of pyrrolo[1,2-a]indole 8 to dihydrobenzoxazine 12 88 3-3. Retrosynthesis of targeted probes 13a,b 89 3-A. Danishefsky’s synthesis of (±)-mitomycin K 91 3-B. Shibisaki’s synthesis of the decarbamoyloxymitomycin 7B 92 3-C. Jimenez’s synthesis of the mitosane 6C and 8C 93 3-D. Jimenez’s racemic synthesis of (±)-mitomycin K 94 ix 3-E. Miller’s asymmetric synthesis of mitosane 7E 95 3-F. Ziegler’s asymmetric synthesis of dihydrobenzoxazine 9F 96 3-G. Trost’s asymmetric synthesis of epi-(+)-FR900482 97 3-4. Retrosynthetic analysis of 14a,b 98 3-5. Synthesis of 25 and attempted tin-lithium exchange 100 3-6. Synthesis of 36 and tin-lithium exchange 102 3-7. Formation of ketone 38 104 3-8. Dianion formation on model 44 105 3-9. Dianion formation on fully functionalized 50 107 3-10. Dianion formation and trapping to form aziridinolactam 19 109 3-11. Synthesis of ortho-functionalized aryl iodides 112 3-12. INAS reaction of TMS-acetylenes 116 3-13. Modified Kulinkovich reaction to form the mitosane core 116 3-14. INAS reaction of TMS-acetylene 67 117 3-15. Protected cyanohydrin addition into lactam 69 119 3-16. Installation of the C(10) carbon 122 3-17. Retrosynthetic analysis of thioesters 13a,b 123 3-18. Synthesis of aryl triflate 98 124 3-19. Palladium catalyzed coupling of 98 and 19 125 3-20. Cyclization of 104 128 x List of Appendices Appendix A. X-Ray Crystal Structure of 90 169 B. Selected NMR Specta 187 xi Abstract The aminobenzoquinone mitomycins and the dihydrobenzoxazine FR compounds are potent antitumor antibiotics. Despite structural differences, the compounds are reductively activated to analogous reactive metabolites known as leucoaziridinomitosenes. Leucoaziridinomitosenes contain two electrophilic sites at the C(1) and C(10) positions which are selectively attacked by two guanosines on complementary strands of DNA, thereby resulting in cross-link formation and cell death. Much has been learned about the complex mechanism of action of these compounds, but a better understanding of their mechanisms of action and biological origins is required in order to produce more potent and less cytotoxic synthetic analogs. The leucoaziridinomitosene derived from the semisynthetic derivative FK317 was targeted for total syntheses. The tetracyclic core of the target was accessed via intramolecular Michael addition of a chiral lithioaziridine into a vinylogous amide. Temporary protection of a stabilizing formyl group, reduction of an enoate, and subsequent transformation of the resulting alcohol provides the free C(10) carbamate. The C(10) carbamate of the intact leucoaziridinomitosene proved to be extremely labile as it was lost under acidic, basic, and neutral conditions which were explored to remove the final aziridine protecting group. Surprisingly, in contrast to the mitomycin leucoaziridinomitosenes, C(10) heterolysis of the FR leucoaziridinomitosenes was more facile than C(1) heterolysis. Nonetheless, a fully functionalized leucoaziridinomitosene derivative of FK317 was obtained. In order to probe the related biosynthetic pathways of mitomcyin C and FR900482, a mitosane derivative that could be a common precursor of both structural families was targeted for synthesis.

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