UC Irvine UC Irvine Electronic Theses and Dissertations Title Studies Toward the Synthesis of Exiguaquinol Permalink https://escholarship.org/uc/item/2466q0vq Author Schwarzwalder, Gregg Martin Publication Date 2015 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, IRVINE Studies Toward the Synthesis of Exiguaquinol DISSERTATION submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Chemistry by Gregg Martin Schwarzwalder Dissertation Committee: Professor Christopher D. Vanderwal, Chair Professor Elizabeth R. Jarvo Professor Sergey V. Pronin 2015 © 2015 Gregg Martin Schwarzwalder DEDICATION To my parents, siblings, Erica, the Ross family, and Casey ii TABLE OF CONTENTS Page LIST OF FIGURES v LIST OF TABLES vi LIST OF SCHEMES vii ACKNOWLEDGMENTS xii CURRICULUM VITAE xiii ABSTRACT OF THE DISSERTATION xv CHAPTER 1: INTRODUCTION TO EXIGUAQUINOL 1 1.1 Introduction 1 1.2 Isolation and Structure Determination of Exiguaquinol 1 1.3 H. pylori MurI Enzyme and AstraZeneca's Selective Inhibitors 3 1.4 Exiguaquinol’s Biological Properties 10 1.5 Proposed Biosynthesis of Exiguaquinol 11 1.6 Previous Syntheses of Related Furanosteroid Natural Products 13 1.6.1 Harada’s Syntheses of Halenaquinol, Xestoquinol, and Adociaquinones A & B 14 1.6.2 Kanematsu’s Synthesis of Xestoquinone 16 1.6.3 Keay’s Synthesis of the Xestoquinone 17 1.6.4 Shibasaki’s Synthesis of Halenaquinone 19 1.6.5 Rodrigo’s Syntheses of Halenaquinone and Xestoquinone 21 1.6.6 Trauner’s Synthesis of Halenaquinone 22 1.6.7 Wipf’s Synthesis of Thiohalenaquinone 24 1.6.8 Crews’s Syntheses of Halenaquinone and Xestoquinone Analogues 26 1.6.9 Nemoto’s Synthesis of the Halenaquinone Core 28 1.6.10 Ahn’s Synthesis of the Xestoquinone Core 29 1.7 Goals for the Synthesis of Exiguaquinol and Analogues 30 1.8 Notes and References 33 CHAPTER 2: SYNTHESIS OF THE TETRACYCLIC CORE OF EXIGUAQUINOL 36 2.1 Introduction 36 2.2 Retrosynthetic Analysis 36 2.3 Synthetic Efforts Toward an Acylmaleimide Diels–Alder Strategy 37 2.4 Second Generation Retrosynthetic Analysis 41 2.5 Synthesis of the Tetracyclic Core of Exiguaquinol 42 2.5.1 Diels–Alder Cycloaddition and Aldol Reaction 42 iii 2.5.2 Sulfoxide Elimination and Closure of the C-Ring 44 2.5.3 Hemiaminal Formation 55 2.5.4 Completion of the Exiguaquinol Core 58 2.6 Ground State Energy Calculations of Hemiaminal Epimers 61 2.7 Conclusions 63 2.8 Experimental Procedures 65 2.9 Notes and References 92 CHAPTER 3: PROGRESS TOWARD THE SYNTHESIS OF EXIGUAQUINOL 95 3.1 Introduction 95 3.2 Retrosynthetic Analysis 95 3.3 Strategies to Access an Appropriately Substituted Naphthaldehyde 96 3.3.1 o-Quinodimethane Diels–Alder Strategy 97 3.3.2 3,5-Dihydroxy-2-naphthoic Acid Strategy 102 3.3.3 Cycloaddition/Iododesilylation Strategy 104 3.3.4 Other Strategies 105 3.3.5 Thiophene Dioxide Diels–Alder Strategy 107 3.4 Synthesis of the Pentacyclic Framework of Exiguaquinol 109 3.4.1 Substitution of the Succinimide Nitrogen 110 3.4.2 Aldol Reaction 113 3.4.3 Sulfoxide Elimination 117 3.4.4 Pentacycle Formation 121 3.4.5 Sulfonic Acid Installation 126 3.4.6 Hemiaminal Epimerization 129 3.5 Studies Toward Regioselective Sulfation 132 3.5.1 Sulfuric Acid Derivatives 134 3.5.2 DCC and H2SO4 Sulfation 135 3.5.3 SO3·Amine Complexes 137 3.5.4 Protected Chlorosulfonate Esters 145 3.5.5 Enzymatic Sulfation 151 3.6 Entry into Enantioselective Synthesis: Aldol Desymmetrization 153 3.7 Future Directions and Conclusions 156 3.8 Experimental Procedures 159 3.9 Notes and References 208 APPENDIX A: NMR and Chiral HPLC Data 223 APPENDIX B: X-ray Crystallographic Data 398 iv LIST OF FIGURES Page Figure 1.1. Structure and numbering of exiguaquinol (1.1) and halenaquinol sulfate (1.2) 1 Figure 1.2. ROESY correlations between exiguaquinol protons 3 Figure 1.3. Pyrazolopyrimidinedione inhibitors of H. pylori MurI 6 Figure 1.4. Benzodiazepine amine inhibitors of H. pylori MurI 9 Figure 1.5. MurI binding interactions of (a) exiguaquinol (1.1) and (b) pyrazolopyrimidinedione 1.9 11 Figure 1.6. Structures of xestoquinone- and halenaquinone-derived natural products 13 Figure 1.7. Structure of several furanosteroid natural products and exiguaquinol 14 Figure 1.8. Furanosteroid analogues targeted by the Crews group 26 Figure 1.9. Endo and exo transition states for Nemoto’s IMDA 29 Figure 1.10. Exiguaquinol and its tetracyclic core 31 Figure 1.11. Structural analogues of exiguaquinol for biological evaluation 32 Figure 2.1. Structure of exiguaquinol (2.1) and its tetracyclic core model system (2.2) 36 Figure 2.2. Computed relative free energies of the hemiaminal epimers of the tetracyclic “core” (2.87 and 2.2) and exiguaquinol (2.102 and 2.1). Calculations performed at the B3LYP/6-31G(d) level of theory in the gas phase 62 Figure 3.1. Comparison of exiguaquinol (3.2) and its tetracyclic core (3.1) 95 Figure 3.2. Reactive confirmation for highly diastereoselective aldol 117 Figure 3.3. Internal hydrogen bond observed in X-ray crystal structure of 3.161 125 Figure 3.4. Phenolic substrates tested for HocAST activity 153 v LIST OF TABLES Page Table 2.1. Optimization of the aldol reaction 44 Table 2.2. Optimization of the sulfoxide elimination 47 Table 2.3. Optimization of the reduction Heck cyclization and Tolman cone angles 52 Table 2.4. Attempted reductive Heck cyclizations on ketone 2.72 54 Table 2.5. Attempts to epimerize the hemiaminal configuration 61 Table 3.1. Initial attempts at aldol reactions 114 Table 3.2. Conditions investigated for sulfoxide elimination 119 Table 3.3. Survey of reductive Heck conditions for pentacycle formation 123 Table 3.4. Oxidation conditions tested on thioester 3.170 129 Table 3.5. Hemiaminal epimerization attempts 131 Table 3.6. DCC/H2SO4 sulfation 137 Table 3.7. Sulfation of model system 3.178 143 Table 3.8. Sulfation attempts on complex exiguaquinol substrates 145 Table 3.9. Protected sulfation of model system 3.178 149 Table 3.10. Substrate specificity evaluation performed on HocAST by the García- Junceda group 152 Table 3.11. Asymmetric aldol reactions performed on model system and elaborated system 156 vi LIST OF SCHEMES Page Scheme 1.1. Simplified mechanism of glutamate racemization 5 Scheme 1.2. Cytoplasmic steps of the peptidoglycan biosynthetic pathway 8 Scheme 1.3. Quinn's postulated biogenesis of exiguaquinol (1.1) from halenaquinol sulfate (1.2) 12 Scheme 1.4. Synthesis of halenaquinol by the Harada group 15 Scheme 1.5. Synthesis of xestoquinone and adociaquinones A and B by the Harada group 16 Scheme 1.6. Mechanism of Kanematsu’s Furan Ring Transfer methodology 16 Scheme 1.7. Formal synthesis of xestoquinone by the Kanematsu group 17 Scheme 1.8. Synthesis of xestoquinone by the Keay group 18 Scheme 1.9. Synthesis of naphthalene 1.72 by the Shibasaki group 19 Scheme 1.10. Synthesis of halenaquinone by the Shibasaki group 20 Scheme 1.11. Synthesis of halenaquinone by the Rodrigo group 22 Scheme 1.12. Synthesis of xestoquinone by the Rodrigo group 22 Scheme 1.13. Synthesis of (–)-halenaquinone by the Trauner group 23 Scheme 1.14. Synthesis of thiohalenaquinone by the Wipf group 25 Scheme 1.15. Syntheses benzofused halenaquinone and xestoquinone analogues 1.109 and 1.110 by Crews 27 Scheme 1.16. Synthesis of halenaquinone analogue 1.111 lacking the furan ring by the Crews group 28 Scheme 1.17. Synthesis of halenaquinone core 1.130 by the Nemoto group 28 Scheme 1.18. Synthesis of the xestoquinone core by the Ahn group 30 Scheme 2.1. Synthetic plan to access exiguaquinol's tetracycle core (2.2) 37 vii Scheme 2.2. Synthesis of bis(phenylsulfide) diene 2.6 38 Scheme 2.3. Attempted synthesis of 2.15 using a Morita–Baylis–Hillman reaction 38 Scheme 2.4. Synthesis of highly activated dienophile 2.19 and Diels–Alder trapping 39 Scheme 2.5. Diels–Alder cycloaddition strategy using less labile dienophiles 40 Scheme 2.6. Attempted Diels–Alder cycloadditions using substituted maleimides 40 Scheme 2.7. Revised synthetic plan to access exiguaquinol's tetracycle core (2.2) 41 Scheme 2.8. Enantioselective Claisen and aldol reactions discovered by the Simpkins group 42 Scheme 2.9. Successful cycloaddition and attempted functionalizations of 2.37 42 Scheme 2.10. Functionalization of the reduced bicyclic imide (2.38) 43 Scheme 2.11. Elaboration of aldol product 2.42 and 6-endo cyclization performed by Dr. Sarah Steinhardt 45 Scheme 2.12. Net 6-endo radical cyclization through neophyl rearrangement mechanism proposed by Ishibashi 46 Scheme 2.13. Synthesis of diene 2.53 46 Scheme 2.14. Reductive radical cyclization of aryl bromide 2.53 48 Scheme 2.15. Stephenson's photoredox 5-exo cyclization 48 Scheme 2.16. Proposed catalytic cycle for reductive Heck reaction and examples 49 Scheme 2.17. Initial success for 5-exo reductive Heck cyclization 50 Scheme 2.18. Synthesis of diene 2.69 containing an aryl iodide 51 Scheme 2.19. Synthesis of ketone 2.72 for evaluation of the reductive Heck 53 Scheme 2.20. Mechanistic proposals for alkene isomerization 55 Scheme 2.21. Attempts to elaborate 2.70 into the core of exiguaquinol 56 Scheme 2.22. Rationale for stereoselectivity in the LiBH4 reduction of imide 2.69 57 Scheme 2.23. Final steps of the exiguaquinol core synthesis 58 viii Scheme 2.24. Potential mechanisms of hemiaminal epimerization 59 Scheme 2.25. Examples of hemiaminal epimerizations 60 Scheme 2.26.