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Title Studies Toward the Synthesis of Exiguaquinol

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Author Schwarzwalder, Gregg Martin

Publication Date 2015

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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

Gregg Martin Schwarzwalder

Dissertation Committee: Professor Christopher D. Vanderwal, Chair Professor Elizabeth R. Jarvo Professor Sergey V. Pronin

2015

DEDICATION

To my parents, siblings, Erica, the Ross family, and Casey

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

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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

LIST OF FIGURES

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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

LIST OF TABLES

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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

LIST OF SCHEMES

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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

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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

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Scheme 2.24. Potential mechanisms of hemiaminal epimerization 59

Scheme 2.25. Examples of hemiaminal epimerizations 60

Scheme 2.26. Overview of the exiguaquinol core synthesis 64

Scheme 3.1. Retrosynthetic plan for exiguaquinol synthesis 96

Scheme 3.2. Classes of o-quinodimethane precursors 97

Scheme 3.3. Synthesis of benzocyclobutene 3.24 by Wallace 98

Scheme 3.4. o-Quinodimethane Diels–Alder cycloaddition by Keay and coworkers 99

Scheme 3.5. Synthesis of benzocyclobutene 3.36 and cycloaddition attempts 100

Scheme 3.6. o-Xylylene and cheletropic extrusion methods for accessing naphthaldehyde 3.8 101

Scheme 3.7. Overview of our naphthoic acid strategy 102

Scheme 3.8. Efforts to access naphthoate ester 3.49 from 3.45 103

Scheme 3.9. Synthesis of simplified naphthaldehyde 3.54 103

Scheme 3.10. Overview of the iododesilylation strategy 104

Scheme 3.11. Iododesilylation strategy to access 3.43 105

Scheme 3.12. Overview of vinyl quinone strategy for the synthesis of 3.43 105

Scheme 3.13. Prior examples of vinyl quinone Diels–Alder reactions 106

Scheme 3.14. Efforts to perform a vinyl quinone Diels–Alder reaction 107

Scheme 3.15. Our plan to access 3.78 via [4+2]/cheletropic extrusion 107

Scheme 3.16. Our ultimately successful route to synthesize naphthaldehyde 3.78 108

Scheme 3.17. Ideas for incorporating the N-alkyl substituent 110

Scheme 3.18. Exploring various N-alkyl substituents 111

Scheme 3.19. Examples of radical translocation reactions and our proposed reaction 112

Scheme 3.20. Substrate synthesis and attempts at radical translocation 113

Scheme 3.21. Examples of lactam functionalizations and our imide reduction and unsuccessful alkylation attempts 115

Scheme 3.22. Aldol reactions requiring BF3·OEt2 to proceed 116

Scheme 3.23. Silyl protection and sulfide oxidation 118

Scheme 3.24. Rationale for stereochemical inversion in the [1,3]-rearrangement 120

Scheme 3.25. Leighton's example of a [1,3]-rearrangement and our observed [1,3]- rearrangement 120

Scheme 3.26. Selenoxide and sulfilimine eliminations in organic synthesis 121

Scheme 3.27. Initial hit for reductive Heck cyclization 122

Scheme 3.28. Deprotection, oxidation, and oxidative cleavage of pentacycle 3.157 125

Scheme 3.29. Two possible pathways for accessing sulfonate 3.165 126

Scheme 3.30. Sulfonic acid installation on model and desired substrates via the alkyl bromide 127

Scheme 3.31. Sulfonic acid installation on model and desired substrates via Mitsunobu reaction 128

Scheme 3.32. Proposed mechanism of two-step hemiaminal epimerization 132

Scheme 3.33. Two parallel pathways for the synthesis of model system 3.178 133

Scheme 3.34. Deprotection of dimethoxynaphthalene substrates 134

Scheme 3.35. Examples of sulfations using chlorosulfonic acid 135

Scheme 3.36. Examples of sulfate installation using DCC/H2SO4 and the mechanism of this transformation 136

Scheme 3.37. Examples of phenolic sulfations on complex molecules using SO3·amine adducts 138

Scheme 3.38. Example of a dihydroxynaphthalene monosulfation by Prudhomme 139

Scheme 3.39. Monosulfation examples in the syntheses of symbioimine (3.214) 141

Scheme 3.40. Hypothesis for regioselective sulfation of dihydroxynaphthalenes 142

Scheme 3.41. Strategies for introducing a protected sulfate group 147

Scheme 3.42. Protected sulfates in total synthesis 148

Scheme 3.43. Two possible mechanisms for quinone formation 150

Scheme 3.44. Protected sulfation of pentacyclic exiguaquinol substrate 3.180 151

Scheme 3.45. Desymmetrization of meso-imides by the Simpkins group 154

Scheme 3.46. Summary of our progress toward exiguaquinol 157

ACKNOWLEDGMENTS

First and foremost, I would like to thank my advisor, Professor Chris Vanderwal, for his mentorship and unconditional support throughout my graduate school career. Even as an undergraduate, I knew that I wanted to work in his lab and Chris graciously accepted me into his group as a summer student preceding my first year of graduate studies. Since then, his encouragement and unwavering optimism have motivated me to tackle some very challenging problems. I would also like to thank my dissertation committee members, Professor Liz Jarvo and Professor Sergey Pronin, for taking the time to read this dissertation and attend my defense. Professors Liz Jarvo, Scott Rychnovsky, Suzanne Blum, Ken Shea, and Christopher Schwarz served on my orals committee and their help throughout the process was greatly appreciated. In addition, I must thank Professors Zhibin Guan and Richard Chamberlin for reviewing my second year report. Lastly, I have to extend my gratitude to Professor Larry Overman for helpful discussions about my research project and other chemistry topics during our joint group meetings. Before coming to UC Irvine, I was fortunate to learn from some outstanding mentors, in both an academic and an industrial setting, whose encouragement led me to pursue my Ph.D. in chemistry. I would like to thank Dr. Christopher Cooper for hiring me as his summer intern at Genzyme and for showing me how chemistry research is conducted in the pharmaceutical industry. I would also like to thank my undergraduate research advisor, Professor Jon Njardarson, for allowing me to join his research group for two years at Cornell. Lastly, I must thank my graduate student mentor from the Njardarson group, Dr. Daniel Mack, for teaching me how to conduct research in an academic environment. For the past five and a half years, the Vanderwal group has been an amazing place to work. The lab dynamic fosters creativity, learning, and hard-work—much of which can be attributed to the highly motivated lab members. In particular, I would like to thank Dr. Karl Bedke, Dr. Grant Shibuya, Professor Dave Martin, Dr. Sarah Steinhardt, Dr. Theo Michels, Dr. Evan Horn, Dr. Peter Mai, Dr. Anne Szklarski, Dr. Jon Lam, Dr. Sam Tartakoff, and Professor Won-jin Chung for their mentorship while I was a young, impressionable graduate student. Also, I must thank Dr. Joey Carlson, Dmitriy Uchenik, Carl Vogel, Philipp Roosen, Mary Beth Daub, Zef Konst, Alex White, Brian Atwood, Alex Karns, Sharon Michalak, Bryan Ellis, and Florian de Nanteuil for being fantastic coworkers in more recent times. I have to thank my family for their continued support throughout my graduate career. Although I moved across the country to attend UC Irvine, my parents, sisters, and brother have been supportive whenever I needed someone to talk to. I am also grateful to my in-laws, the Ross family, for including me in their family while I’ve lived in California. I would also like to thank my adorable cat, Casey, who has kept me company while I wrote the bulk of this dissertation. Most importantly, I must thank my amazing wife Erica, who has stuck with me throughout this grueling process of graduate school. She is always so supportive of me and I appreciate all the sacrifices she has made while I put real life on hold to attend graduate school. I love her unconditionally and I can’t wait to see where life after graduate school will take us.

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CURRICULUM VITAE Gregg Martin Schwarzwalder

1102 Natural Sciences II University of California – Irvine Irvine, CA 92697-2025 Email: [email protected]

Education University of California – Irvine, CA 2010–2015 Ph.D. in Chemistry

Cornell University, Ithaca, NY 2006–2010 B.A. in Chemistry, Magna Cum Laude

Research Experience Graduate Student Researcher, NIH Predoctoral Fellow 2010–2015 University of California – Irvine, CA Advisor: Professor Christopher Vanderwal  Studies toward the synthesis of exiguaquinol.  Developed a 14 step synthesis of the tetracyclic core of exiguaquinol.

Undergraduate Researcher 2008–2010 Cornell University, Ithaca, NY Advisor: Professor Jon Njardarson  Developed a copper-mediated ring expansion methodology for the synthesis of substituted dihydropyrans from vinyl oxetane precursors.

Synthetic Organic Chemistry Intern, Chemical Process Development 2008 Genzyme Corporation, Waltham, MA Advisor: Dr. Christopher Cooper  Prepared several compounds to be used for a fragment based drug discovery program.  Synthesized Ki16425, a patented LPA receptor antagonist.

Honors & Awards University of California – Irvine UCI Chemistry Department Safety Award 2015 AbbVie Scholar 2014 Ruth L. Kirschstein NIH Predoctoral Fellowship (F31-CA180568) 2013–2015

Cornell University Merck Index Award 2010 Gerald A. Hill and Kathleen Holmes Hill Fellowship 2009 School of Arts & Sciences Dean’s List 2006, 2008–2010

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Publications Schwarzwalder, G. M.; Steinhardt, S. E.; Pham, H. V.; Houk, K. N.; Vanderwal, C. D. “Synthesis of the Tetracyclic Core of Exiguaquinol” Org. Lett. 2013, 15, 6014–6017.

Guo, B.; Schwarzwalder, G.; Njardarson, J. T. “Catalytic Ring Expansion of Vinyl Oxetanes: Asymmetric Synthesis of Dihydropyrans Using Chiral Counterion Catalysis” Angew. Chem. Int. Ed. 2012, 51, 5675–5678.

Presentations Schwarzwalder, G. M.; Steinhardt, S. E.; Pham, H. V.; Houk, K. N.; Vanderwal, C. D. “Progress Toward the Synthesis of Exiguaquinol.” 248th ACS National Meeting & Exposition; 2014 Aug 10–14; San Francisco, CA.

Schwarzwalder, G. M.; Steinhardt, S. E.; Pham, H. V.; Houk, K. N.; Vanderwal, C. D. “Progress Toward the Synthesis of Exiguaquinol” (Poster). AbbVie Scholars Symposium; 2014 Jul 31; North Chicago, IL.

Schwarzwalder, G. M.; Steinhardt, S. E.; Pham, H. V.; Houk, K. N.; Vanderwal, C. D. “Progress Toward the Synthesis of Exiguaquinol” (Poster). ACS Division of Organic Chemistry Graduate Research Symposium; 2014 Jul 24–27; Irvine, CA.

Schwarzwalder, G.; Steinhardt, S. E.; Vanderwal, C. D. “Progress Towards the Total Synthesis of Exiguaquinol.” Graduate Student and Post-doc Colloquium; 2012 Jun 8; Irvine, CA.

Steinhardt, S. E.; Schwarzwalder, G.; Suh, J.; Vanderwal, C. D. “Progress Towards the Total Synthesis of Exiguaquinol.” 241st ACS National Meeting & Exposition; 2011 Mar 27–31; Anaheim, CA.

Schwarzwalder, G.; Cooper, C. “The Synthesis of Ki16425.” Genzyme Summer Intern Research Symposium; 2008 Jul 29; Waltham, MA.

Teaching Experience University of California – Irvine Discussion Leader / Teaching Assistant Organic Synthesis (Graduate level) Winter 2013 Organic Chemistry I (Undergraduate level) Fall 2011

Laboratory Instructor / Teaching Assistant Advanced Organic Synthesis Lab (Undergraduate level) Spring 2012 General Chemistry Lab III (Undergraduate level) Spring 2011 Organic Chemistry Lab II (Undergraduate level) Winter 2011 Organic Chemistry Lab I (Undergraduate level) Fall 2010

Affiliations American Chemical Society 2012–Present Alpha Epsilon Pi 2007–2010

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ABSTRACT OF THE DISSERTATION

Studies Toward the Synthesis of Exiguaquinol

Gregg Martin Schwarzwalder

Doctor of Philosophy in Chemistry

University of California, Irvine, 2015

Professor Christopher D. Vanderwal, Chair

This dissertation describes our efforts to develop a total synthesis of the biologically

active marine natural product exiguaquinol. Chapter 1 focuses on the isolation and structure

elucidation of exiguaquinol, its biological significance as a Helicobacter pylori MurI inhibitor,

and its proposed biogenesis from halenaquinol sulfate. In addition, synthetic efforts yielding

related furanosteroid natural products halenaquinone and xestoquinone are discussed.

Chapter 2 details our synthesis of the tetracyclic core scaffold of exiguaquinol. While

several functional groups were omitted in this endeavor, this model system was targeted in order

to test the feasibility of our proposed strategy. Through a desymmetrizing aldol reaction, a

thermal sulfoxide elimination, and a 5-exo reductive Heck cyclization, the tetracyclic core was

prepared in 14 steps from commercially available starting materials. In the end, an unexpected

stereochemical outcome involving the N-acyl hemiaminal was uncovered, which could be

explained through a favorable internal hydrogen bonding arrangement between the alcohol and

the C9 ketone. This phenomenon was simulated computationally by the Houk group for further

understanding.

In Chapter 3, our efforts to apply this strategy to the first total synthesis of exiguaquinol

are disclosed. After preparing the necessary naphthaldehyde, the pentacyclic framework was

assembled using the strategy developed previously for the tetracyclic core. Although we were

able to access exiguaquinol des-sulfate, the final regioselective sulfation was ultimately

unsuccessful. Further studies regarding the regioselective installation of sulfate groups will be

necessary to provide exiguaquinol.

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CHAPTER 1:

INTRODUCTION TO EXIGUAQUINOL

1.1: Introduction

Exiguaquinol (1.1), a novel pentacyclic hydroquinone natural product, was isolated from

an Australian sponge in 2008 by Quinn and coworkers (Figure 1.1). In an in vitro assay,

exiguaquinol exhibited moderate activity against the H. pylori glutamate racemase enzyme. This

unique biological activity, coupled with its complex and unprecedented structure, inspired us to

develop a chemical synthesis of 1.1. The following chapter focuses on the isolation and

biological activity of 1.1, its postulated biosynthesis from halenaquinol sulfate (1.2), and several

synthetic studies towards related compounds.

Figure 1.1. Structure and numbering of exiguaquinol (1.1) and halenaquinol sulfate (1.2).

1.2: Isolation and Structure Determination of Exiguaquinol

The isolation and characterization of exiguaquinol was reported in 2008 by the Quinn

group (Griffith University).1 In an NADH fluorescence high-throughput screening assay of forty thousand plant and marine organism extracts, those from the Australian sponge Neopetrosia exigua exhibited activity for H. pylori MurI inhibition. The methanolic extract of the sponge was found to inhibit the H. pylori MurI enzyme at 0.25 mg dry wt/mL. The active component was identified from the extracts by bioassay-guided fractionation, leading to the isolation of a novel pentacyclic hydroquinone, exiguaquinol (1.1), as an orange powder.

The chemical formula of exiguaquinol was determined by high-resolution electrospray

mass spectrometry in negative ion mode. The major signal at m/z = 276.5189 indicated a doubly

2– 1 charged molecular ion [M – 2H] with a chemical formula of C22H21NO12S2.

The chemical structure was elucidated by a combination of techniques, including IR and

NMR spectroscopy. The infrared spectrum displayed diagnostic bands at 3448, 1685, 1206, and

1048 cm-1, indicating the presence of a hydroxyl group, a ketone, and a sulfonate.1 The 1H NMR spectrum in d6-DMSO showed a methyl singlet at δ1.67 ppm and nine additional protons

between δ1.74 and δ3.47 ppm. In addition, one moderately deshielded proton appeared at δ5.51

ppm and six downfield signals, located between δ6.83 and δ10.34 ppm, indicated the presence of

aromatic and hydroxyl-attached protons. The 13C NMR spectrum displayed 22 carbon

resonances: two ketones (δ202.7 and δ206.7 ppm), one amide (δ170.8 ppm), ten unsaturated

carbons, and eight aliphatic carbons, one of which appears at δ80.9 ppm and is likely bound to a

heteroatom. This information, taken in conjunction with the thirteen degrees of unsaturation in

the molecular formula, suggested the presence of three carbonyls, a naphthalene ring, and three

additional rings in exiguaquinol. Comparison of the NMR spectra and mass spectrometry data

with that of halenaquinol sulfate (1.2) indeed showed some similarities, which indicated a structural resemblance between the two natural products (Figure 1.1). Lastly, the COSY and

HMBC data were interpreted to determine the connectivity of exiguaquinol.1

The relative stereochemical relationship between the four stereogenic centers in

exiguaquinol (1.1) was determined by ROESY experiments (Figure 1.2). Correlations were observed between the hemiaminal hydroxyl group proton and the C20 methyl protons, suggesting that these groups were located on the same face of the molecule. In addition, the hemiaminal C2 proton and the adjacent C3 proton had a strong ROESY correlation, which

implied that they are situated on the same side of the molecule and most likely on the opposite

face as the aforementioned C20 methyl and hemiaminal hydroxyl groups.1

Figure 1.2. ROESY correlations between exiguaquinol protons.

The Quinn group was unable to determine the absolute configuration of exiguaquinol

owing to the limited quantity of material isolated. However, they deduced that the absolute

configuration of the C7 quaternary center in 1.1 should be consistent with that of halenaquinol

sulfate (1.2), its postulated biosynthetic precursor (Figure 1.1). The absolute stereochemistry of

halenaquinol was predicted through CD spectroscopy by Harada and coworkers in 1985 and later

confirmed through total synthesis in 1988.2,3 Therefore, the remaining stereogenic centers in 1.1

were inferred from their relative stereochemical relationship to the C7 quaternary center.

1.3: H. pylori MurI Enzyme and AstraZeneca's Selective Inhibitors

The MurI enzyme, a glutamate racemase responsible for the interconversion of L- and D-

glutamate, has become a target of biological interest over the past 25 years. Its vital role in cell

wall peptidoglycan biosynthesis has led to considerable research in the area of antibiotic drug

discovery,4 spurring the identification of glutamate racemase enzymes from a variety of gram-

positive4 and gram-negative bacteria.4–7 In general, the structural features of bacterial MurI are

not conserved among different species, and these disparities can likely be exploited for the

development of species-selective antibiotics.4 Therefore, synthetic and biological studies on

exiguaquinol (1.1), the first natural product reported to inhibit the Helicobacter pylori MurI

enzyme, could lead to novel therapeutic agents for the selective treatment of H. pylori infection.

Helicobacter pylori infection is the most common bacterial infection worldwide; over

50% of the world’s population harbors H. pylori in their gastrointestinal tract and nearly all

experience coexisting gastritis or ulcers.8 H. pylori-induced gastritis is the highest singular risk factor for the development of stomach cancer, the second leading cause of cancer-associated death globally, with an attributable risk of approximately 75%.8,9 Current treatment for H. pylori

infection most often involves a "triple therapy" (a proton pump inhibitor, amoxicillin, and

clarithromycin) and is only effective for approximately 70–80% of patients.10 These broad-

spectrum remedies are also plagued by several issues including low selectivity and antibiotic

resistance.11 Therefore, new therapeutics with high H. pylori selectivity need to be identified and

further developed to prevent unwanted effects on the gut microbiome.12

As part of an AstraZeneca program designed to develop selective MurI inhibitors,

Lundqvist and Fisher investigated the biophysical and kinetic similarities and differences

involved in glutamate racemase activity among several different species of bacteria.4 They

identified three distinguishable isoforms of bacterial MurI, varying mainly in their quaternary

structure. Most MurI isozymes displayed a dimeric oligomerization state in solution; however, E. coli MurI was the only exception, adopting a monomeric aggregation state in solution.4 Of the

dimeric forms of MurI, two distinct arrangements were identified. Most gram-positive bacterial

MurI formed tail–tail homodimers or heterodimers, with active sites occupying distal positions

and located far away from each other. In contrast, H. pylori MurI was observed to form a head–

head dimer, with active sites located in close proximity and shielded from the solvent and

exterior. Each dimer is comprised of two monomeric subunits, each containing an active site for

glutamate racemization. Furthermore, each monomer subunit is comprised of two distinct

domains in which the active site is located at the interface between the two domains. Domain A

(N-terminus) contains the amino acid residues responsible for deprotonation of D-glutamate and

domain B (C-terminus) contains residues for the deprotonation of L-glutamate. In order for

catalysis to occur, a coordinated hinge movement between domains must occur to create an open

form and accept glutamate into the active site.4

Computational studies have been performed to elucidate the mechanism of glutamate

racemization in H. pylori MurI.13 Based on the crystal structure, MD simulations and QM/MM

calculations were used to determine the residues likely involved in the four-step inversion

sequence of L-glutamate in the active site (Scheme 1.1). First, Asp7 deprotonates Cys70 to form a thiolate, which is located in close proximity to the α-position of L-glutamate (1.3). The Cys70 thiolate deprotonates glutamate, generating the achiral enolate with reorganization of nearby residues (1.5). On the opposite face of the active site, Cys181 delivers a proton to the glutamate

enolate thereby inverting the stereochemistry of the substrate (1.6). Lastly, a protonated His183

quenches the Cys181 thiolate anion (1.7) and D-glutamate (1.8) is released.

Scheme 1.1. Simplified mechanism of glutamate racemization.

His183 Asp7 His183 Asp7 O HN O HN O O O O N HO O N O2C CO2 H H H H H NH3 S H3N SH S H3N SH O O 1.3: L-Glu O O Cys70 Cys181 Cys70 Cys181

1.4 1.5

His183 His183 Asp7 Asp7 O HN O HN O O O2C CO2 HO O N HO O N H H H NH3 H SH H3N S SH H3N S O O 1.8: D-Glu O O Cys70 Cys181 Cys70 Cys181 1.7 1.6

After discovering H. pylori MurI as a unique target for selective antibiotic treatment, a group at AstraZeneca developed a high-throughput screening assay to identify small-molecule inhibitors from their compound database (385,861 compounds).4 The first round of screening uncovered pyrazolopyrimidinedione 1.9 as a promising lead compound for structure-activity relationship (SAR) studies (Figure 1.3). 1.9 was particularly amenable to structural diversification and displayed MurI inhibition in vitro, as well as with intact H. pylori cells at low micromolar concentration (IC50 = 1.4 μM). Interestingly, kinetic studies revealed 1.9 to be a

noncompetitive allosteric inhibitor of MurI, binding to a cryptic site removed from the active

site. Analogue synthesis and evaluation led to identification of 1.10 as a low nanomolar inhibitor

of MurI (IC50 = 26 nM); unfortunately, 1.10 displayed poor bioavailability and low water

solubility in mouse models.11 More polar functionality was incorporated on analogues to

improve oral bioavailability, and sulfoxide 1.11 was identified as a potent inhibitor in vivo (IC50

= 37 nM) with 60% bioavailability. Incubation studies with microsomes showed that sulfoxide

1.11 was converted to the corresponding sulfone, which functions as the active inhibitor of H.

pylori MurI in vivo (Figure 1.3). Further modifications to improve pharmacokinetic properties led to the discovery of imidazole-containing pyrazolopyrimidinedione 1.12.14 Unfortunately,

1.12 was essentially ineffective at eradicating H. pylori in a murine infection model compared to

both positive and negative controls, despite dosing at 4×MIC.14

Figure 1.3. Pyrazolopyrimidinedione inhibitors of H. pylori MurI.

Inhibition of D-glutamate production by pyrazolopyrimidinedione 1.9 has been shown to exhibit profound effects on peptidoglycan production. In peptidoglycan biosynthesis (Scheme

1.2), residues are sequentially appended to UDP-N-acetyl muramic acid (UDP-MurNAc) by a series of enzymes.15,16 After incorporation of L-alanine by MurC, a D-glutamate residue (formed

by MurI glutamate racemase activity) is added by the MurD enzyme to form 1.15. Next, MurE

appends a diaminopimelic acid (mDap) residue to the growing peptidoglycan chain. Lastly, two

D-alanine residues are added by the MurF enzyme to form 1.17, a UDP-MurNAc-pentapeptide

that is the final cytoplasmic peptidoglycan precursor before extra-cellular transport.15 In this

sequence, inhibition of MurI by a pyrazolopyrimidinedione leads to a stoppage of peptidoglycan

biosynthesis at the MurD stage. As a result, a reduction in MurD–F products is observed and a

build-up of UDP-MurNAc-(L)-Ala (1.14) occurs.15 This result has been confirmed by HPLC

analysis of H. pylori cell lysates after treatment with inhibitor 1.12—a large accumulation of

UDP-MurNAc-(L)-Ala is observed with none of the pentapeptide present.15

Scheme 1.2. Cytoplasmic steps of the peptidoglycan biosynthetic pathway.

UDP-MurNAc 1.13 L-Ala MurC

UDP-MurNAc-(L)-Ala 1.14 MurI L-Glu D-Glu MurD

UDP-MurNAc-(L)-Ala-(D)-Glu 1.15

mDap MurE

UDP-MurNAc-(L)-Ala-(D)-Glu-mDap 1.16

D-Ala-D-Ala MurF

UDP-MurNAc-(L)-Ala-(D)-Glu-mDap-(D)-Ala-(D)-Ala 1.17

peptidoglycan

The in vivo inhibition of H. pylori MurI by pyrazolopyrimidinedione 1.12 was confirmed

by two additional experiments. In a MurI-overexpressing strain of H. pylori, de Jonge and

coworkers observed that the MIC for 1.12 (4 μg/mL) was increased approximately 8-fold

compared to that of the wild type strain (0.5 μg/mL).15 This result demonstrates that an increase

in MurI abundance leads to a decrease in bacterial growth inhibition, implicating MurI as the

most likely target of 1.12. In addition, the cell morphology of wild type H. pylori was observed

upon treatment with compound 1.12. After a few hours at 2×MIC, the cells lost their typical

spiral shape and became transparent cocci. This observation is also seen when H. pylori is treated with amoxicillin, another peptidoglycan biosynthesis inhibitor, suggesting peptidoglycan biosynthesis is disrupted by 1.12 through MurI inhibition.15

Due to their low solubility and high plasma protein binding properties, the

pyrazolopyrimidinedione compounds (1.9–1.12) were unable to succeed in animal efficacy

experiments. Therefore, the pyridodiazepine amines (1.18–1.19) emerged as a new class of lead

targets, identified through additional high-throughput screening efforts in the AstraZeneca

12 database (Figure 1.4). Benzodiazepine amine 1.18 (IC50 = 1.7 μM and MIC = 0.5 μg/mL) was

the first lead compound for MurI inhibition, showing selectivity for H. pylori MurI over other bacterial isozymes. SAR studies on the benzodiazepine amines demonstrated that incorporation of a pyridine ring in place of the fused-benzene ring significantly improved solubility without affecting potency. In addition, these scaffolds exhibited moderately reduced plasma protein binding, compared to the previous classes of inhibitors. Thus, compounds resembling 1.19 became promising lead targets for anti-H. pylori oral therapeutics.

Figure 1.4. Benzodiazepine amine inhibitors of H. pylori MurI.

An X-ray co-crystal structure of 1.19, MurI, and D-glutamate revealed a bridging water

molecule connecting the pyridine nitrogen atom in 1.19 to an active site bound D-glutamate

through a network of hydrogen bonds.12 As observed with the pyrazolopyrimidinedione inhibitors (1.9–1.12), the co-crystal structure of 1.19 illustrated a non-competitive binding

interaction at the domain interface only when substrate was bound. Interestingly, the allosteric

inhibitor binding sites filled by these two classes of compounds are unique and situated at

different positions on the domain interface.12

Unfortunately, neither the pyrazolopyrimidinedione nor the pyridodiazepine amine classes of H. pylori inhibitors have shown enough promising data to translate into a successful clinical candidate. Initially plagued by pharmacokinetic problems (i.e. poor solubility, low

bioavailability, high plasma protein binding, etc.), SAR studies led to marked improvements, as

equipotent analogues with better pharmacokinetic profiles were identified. However, these

compounds with improved biophysical properties were not effective in vivo. Therefore, before

advancing into the clinic, significant research must be performed to determine the cause of

bacterial insusceptibility to these inhibitors, and whether the H. pylori MurI enzyme is a viable

target for oral antibiotic drug development.

1.4: Exiguaquinol’s Biological Properties

After its bioassay-guided isolation and characterization in 2008, exiguaquinol (1.1) was

evaluated for its H. pylori MurI binding properties. Weak MurI inhibition was observed in the D- glutamate assay, despite D-glutamate being the natural MurI substrate (IC50 = 361 μM). In the D-

serine-O-sulfate assay, in which D-serine-O-sulfate is used as D-glutamate analogue, the Quinn

1 group observed an approximately 80-fold improvement in enzyme inhibition (IC50 = 4.4 μM).

This discrepancy likely arises from differences in intermolecular forces: the D-glutamate carboxylate appears to engage in a hydrogen bond with A-domain MurI residues Tyr39–Gly40, and the aliphatic D-glutamate side chain forms a hydrophobic interaction with Val146 in the B- domain. This combination of interactions across both domains effectively tightens the domain interface and hinders larger molecules from binding. In contrast, the authors believe that when

D-serine-O-sulfate binds to the active site, the interactions with the larger sulfate group produce a more loosely fastened domain interface, thereby allowing larger molecules, such as exiguaquinol (1.1), to bind the allosteric site more readily.1

The Quinn group also performed computational docking studies with exiguaquinol using

the enzyme-substrate complex that was previously obtained by co-crystalization with

pyrazolopyrimidinedione 1.9.1 Using GOLD, a computational docking program, they found that

exiguaquinol likely binds to the same allosteric site as pyrazolopyrimidinedione 1.9 (Figure

1.5a). The Quinn group also identified hydrogen bonding interactions between exiguaquinol and

side chain nitrogen atoms of Trp252, Arg247, and Trp244. Hydrogen bonds were also observed

between the hemiaminal alcohol and the backbone of Glu150. In addition, a π-stacking

interaction is observed between Trp252 and the naphthalene moiety on exiguaquinol in an

analogous manner to the co-crystal structure of pyrazolopyrimidinedione 1.9.1 Figure 1.5b

illustrates this interaction between Trp252 and the heteroaromatic scaffold of 1.9.

Figure 1.5. MurI binding interactions of (a) exiguaquinol (1.1) and (b) pyrazolopyrimidinedione 1.9.

(a)π-stacking (b)

Lys17 Me HO Trp252 OSO hydrophobic NH2 3 hydrophobic pocket H Me pocket N Val10 O N H π-stacking N O Me N Me O Me MeN NH2 Arg247 O N Me Trp252 Me H NH O Val10 N N O S H H H O O O N Phe13 H H Phe13 H N O Trp244 H O N HN Ser152 Glu150 1.20 1.21

Lastly, Quinn and coworkers compared the binding orientation of AstraZeneca inhibitor

1.9 (blue) with docked exiguaquinol (1.1) (green) (Figure 1.5). Immediately apparent was that the naphthyl moiety on 1.9 was directed towards a hydrophobic pocket which remained unfilled by exiguaquinol. The authors hypothesized that structural modification of exiguaquinol to include a hydrophobic group to fill the aforementioned pocket could produce a more potent H. pylori MurI inhibitor.1 Therefore, we believed a chemical synthesis was justified in order to

produce unnatural analogues of exiguaquinol (1.1) with more potent biological properties.

1.5: Proposed Biosynthesis of Exiguaquinol

The Quinn group proposed a biosynthesis of exiguaquinol (1.1) starting from a

structurally similar natural product, halenaquinol sulfate (1.2) (Scheme 1.3). First, an oxidative

ring opening of the furan group in 1.2 is proposed, generating tetracarbonyl intermediate 1.23. A

molecule of taurine (1.24) can then condense with the aldehyde and cyclize onto the nearby ketone, forming hemiaminal 1.26. Finally, the tertiary alcohol can undergo a semi-pinacol ring contraction to afford the fused 5-6-5 ring system present in 1.1.1

Scheme 1.3. Quinn's postulated biogenesis of exiguaquinol (1.1) from halenaquinol sulfate (1.2).

Besides exiguaquinol, other halenaquinol-derived natural products have been isolated that contain the addition of a taurine moiety (Figure 1.6). In 1988, a regioisomeric mixture of hypotaurine adducts of both xestoquinone and halenaquinone, named adociaquinone A–B (1.27–

1.28) and ketoadociaquinone A–B (1.29–1.30) respectively, were isolated from a South Pacific marine sponge, Adocia sp.17 Semi-syntheses from xestoquinone (1.31) and halenaquinone (1.34)

were performed in order to confirm their structural assignment, while also supporting the likely

biosyntheses of adociaquinones and ketoadociaquinones from their respective natural product

precursors.17,18

Figure 1.6. Structures of xestoquinone- and halenaquinone-derived natural products.

According to reports by Harada and Kitagawa, the unprotected dihydroxynaphthalene

groups of xestoquinol (1.32) and halenaquinol (1.35) are unstable to air, moisture, and light, and

they readily oxidize back to the corresponding naphthoquinones (Figure 1.6).3,19 Therefore, we hypothesized that the sulfated alcohols in xestoquinol sulfate (1.33), halenaquinol sulfate (1.2), and exiguaquinol (1.1) could serve as protecting groups for the hydroquinone forms of the natural products. With the proper sulfatase enzyme, 1.33, 1.2, and 1.1 could likely be converted to the unprotected dihydroxynaphthalene analogue, which will spontaneously oxidize to the naphthoquinone under ambient conditions; this form might be responsible for the observed bioactivity of this family of natural products.

1.6: Previous Syntheses of Related Furanosteroid Natural Products

The furanosteroid class of natural products contains a structurally diverse array of

compounds, including wortmannin (1.36), viridin (1.37), halenaquinol/xestoquinol sulfate (1.33

and 1.2), and others (Figure 1.7). The halenaquinone and xestoquinone derivatives contain the

most relevant structural features pertaining to exiguaquinol (1.1) and possess antibiotic,20 cardiotonic,21 cytotoxic,22 antifungal,22 and protein tyrosine kinase inhibitory activity.23 To date, there have been four syntheses of halenaquinone or halenaquinol (three asymmetric) and four syntheses of xestoquinone or xestoquinol (two asymmetric). In addition, several approaches have been reported to access the core structural features of halenaquinone and xestoquinone. The following sections will highlight the synthetic efforts towards both the halenaquinone and xestoquinone classes of natural products.

Figure 1.7. Structure of several furanosteroid natural products and exiguaquinol.

1.6.1: Harada’s Syntheses of Halenaquinol, Xestoquinol, and Adociaquinones A & B

The first total syntheses of (+)-halenaquinone and (+)-halenaquinol were performed by

Harada group in 1988 (Scheme 1.4).3 Using their π-electron SCF-CI-dipole velocity MO method

to calculate the CD spectrum,2 they were able to predict the natural configuration of the C6

methyl quaternary stereogenic center to be (S), and then complete the first enantioselective

syntheses of halenaquinone and halenaquinol (Scheme 1.4). This was accomplished in 15 steps

in the longest linear sequence for halenaquinone and one additional transformation to access

halenaquinol. Both feature a benzocyclobutene ring-opening/o-quinodimethane Diels–Alder

cycloaddition to stitch together the molecule.

Starting from (8aR)-(–)-Wieland–Miescher ketone (1.38), the Harada group accessed

enone 1.39 in nine steps (Scheme 1.4). Dienophile 1.39 underwent an o-quinodimethane Diels–

Alder cycloaddition with benzocyclobutene 1.40 upon heating to temperatures above 200 °C to generate 1.41 in 33% yield. DDQ was used to aromatize 1.41 to the corresponding naphthalene, which was then treated with O2 and tBuOK in tBuOH to provide diosphenol 1.42 in 90% yield.

In order to forge the furan ring, the Harada group developed a modified Pfitzner–Moffatt

oxidation protocol that utilized DCC, DMSO and trifluroacetic acid.3,24 After ketal deprotection, the 1,3-diol was oxidized to the β-ketoaldehyde and undergoes spontaneous cyclization to reveal furan 1.43. Finally, pentacycle 1.43 can be converted to halenaquinone (1.34) by oxidative deprotection with CAN; subsequent reduction with sodium dithionite affords halenaquinol

(1.36). Due to the high instability of 1.36 to light, air, and heat, the final reduction to halenaquinol was performed in a dark room. With synthetic samples of enantiopure halenaquinone and halenaquinol, the Harada group was able to verify that the CD spectrum of the synthetic sample matched the one calculated by their SCF-CI-DV MO method, indicating that the enantiomer synthesized was identical to the one isolated by Kitagawa.2,3

Scheme 1.4. Synthesis of halenaquinol by the Harada group.

Me Me

OO Me Me O OO 200–215 °C H 1. DDQ, PhH (89%) 9steps MeO PhH H Me H 2. KOtBu Me (33%) O (32%) OMe H tBuOH, O Me MeO 2 O (90%) O 1.40 1.38: (8aR)-(–)-Wieland– 1.39 Miescher ketone OMe 1.41 O O O Me Me

OO O Na2S2O4 O CAN, H2O O 6 H2O, Me2CO MeOH 1. 60% AcOH (aq) Me Me Me OH O (quant.) O (45%) O 2. DMSO, DCC TFA, pyr, PhH Me HO O MeO (48%, 2 steps) O MeO OH O OMe 1.36: halenaquinol 1.34: halenaquinone 1.43 OMe 1.42

Using a nearly identical route, Harada and coworkers were able to complete a synthesis

of xestoquinone (1.31)25 and adociaquinones A and B (1.27–1.28)18 starting from enone 1.44

(Scheme 1.5). Overall, Harada’s syntheses provided halenaquinone in 15 steps and 2% overall

yield from 1.38 and xestoquinone in 17 steps and 1% overall yield from 1.38.

Scheme 1.5. Synthesis of xestoquinone and adociaquinones A and B by the Harada group.

1.6.2: Kanematsu’s Synthesis of Xestoquinone

In 1991, the Kanematsu group published the second synthesis of xestoquinone based on a

furan ring transfer strategy developed previously in their lab (Scheme 1.6).26,27 This reaction

rearranges a furfuryl ether (1.45) into a dihydroisobenzofuran (1.48) by a base-mediated isomerization to the allene (1.46) followed by an intramolecular Diels–Alder/ring-opening

cascade (Scheme 1.6). Other furfuryl ethers, bearing alkyl substituents on the furan or linker,

were found to participate in this transformation, affording substituted dihydroisobenzofurans in

excellent yields.26

Scheme 1.6. Mechanism of Kanematsu’s Furan Ring Transfer methodology.

tBuOK H [4+2] tBuOH, 83 °C OtBu O O O O O O O HO (98%) · 1.45 1.46 1.47 1.48

Starting with furfuryl alcohol (1.49), a four-step sequence involving furan ring transfer produced 1.50,28 which can engage methyl acrylate in a conjugate addition followed by regioselective methylation to afford 1.51 (Scheme 1.7). The ketone in 1.51 was reduced via the tosylhydrazone and the methyl ester was saponified and cyclized to 1.53 through a Friedel–

Crafts acylation. Oxidation of the cyclohexanone provided enone 1.54, which served as the dienophile in the subsequent Cr-mediated o-quinodimethane Diels–Alder reaction between 1.54

and 1.55. To complete their formal synthesis of xestoquinone, the Diels–Alder adduct was

aromatized to generate 1.56, which can be converted to xestoquinone (1.31) by oxidation with

CAN.25

Scheme 1.7. Formal synthesis of (±)-xestoquinone by the Kanematsu group.

The Kanematsu synthesis furnished xestoquinone in 14 steps from furfuryl alcohol with an overall yield of 0.8%. The key transformations included a furan ring transfer reaction and an o-quinodimethane Diels–Alder cycloaddition originating from the Cr-mediated reductive metallation of an o-bis(bromomethyl) arene.

1.6.3: Keay’s Synthesis of the Xestoquinone

The Keay group disclosed an asymmetric formal synthesis of xestoquinone in 1996 that took advantage of a Pd-catalyzed polyene cyclization to assemble the pentacyclic scaffold

(Scheme 1.8).29,30 This work constituted the third synthesis of xestoquinone and the second

asymmetric synthesis. Their strategy relied on joining two key fragments: one containing the

furan and another bearing the naphthalene.

The synthesis of the furan portion began with the two-step silylation of furan-3-methanol

(1.57) to provide 1.58.30 Hydroxyl-directed borylation and Suzuki cross-coupling afforded 1.59,

which underwent oxidation and olefination to yield the desired furan fragment 1.60 (Scheme

1.8).

The naphthalene segment was prepared in 11 steps from 2,5-dimethoxybenzoic acid

(1.61). According to the procedure developed by Wallace, 1.61 can be transformed into 1,3,6- trimethoxybenzocyclobutene (1.62) in seven steps and 49% yield utilizing a [2+2] cycloaddition of an in situ generated benzyne.31 Under thermal conditions, 1.62 can fragment to the o- quinodimethane and undergo a Diels–Alder reaction with ethyl 3-bromopropiolate (1.63) to generate 1.64.32 With three additional steps, 1.64 was converted into acid chloride 1.65 (Scheme

1.8).

Scheme 1.8. Synthesis of xestoquinone by the Keay group.

The two key building blocks (1.60 and 1.65) were united in 54% yield by lithiation of the

furan and addition into the naphthoyl chloride to afford 1.66 (Scheme 1.8). Formation of aryl

triflate 1.67 followed by their pivotal asymmetric polyene cyclization with catalytic Pd2(dba)3 and (S)-BINAP produced pentacycle 1.68 in 82% yield over two steps and up to 68% ee. Finally,

1.68 was hydrogenated and demethylated to provide xestoquinone (1.31).25

In their synthesis of xestoquinone, the Keay group demonstrated the importance of Pd- catalysis in asymmetric total synthesis. Although the syntheses of their two key fragments (1.60 and 1.65) were fairly lengthy, the steps following their unification rapidly produced xestoquinone (1.31). Overall, the Keay group’s enantioselective synthesis afforded xestoquinone in 17 steps (longest linear) and 4% overall yield.

1.6.4: Shibasaki’s Synthesis of Halenaquinone

In 1996, Shibasaki and coworkers disclosed the second total synthesis and the first catalytic asymmetric synthesis of halenaquinone (Schemes 1.9–1.10). Their synthetic strategy revolved around the naphthalene portion of the molecule while the remaining three rings were annulated sequentially. The enantiodetermining Suzuki cross-coupling/Heck cyclization step proved successful and this reaction constituted the first example of this type of cascade.

Scheme 1.9. Synthesis of naphthalene 1.72 by the Shibasaki group.

The synthesis of the tricyclic aromatic fragment began with a five-step protocol to access

naphthalene 1.70 from commercially available tetralone 1.69 (Scheme 1.9). Double triflation of

1.70 followed by the remarkable one-pot Suzuki cross-coupling/asymmetric Heck cascade using

Pd(OAc)2 and (S)-BINAP directly provided 1.72 in 85% ee, although in low yield. Alternative

stepwise pathways were investigated to afford 1.72 with improved yields.

With the tetrahydroanthracene intact, tricycle 1.72 was converted to the primary alkyl

triflate and treated with acyl anion equivalent 1.74 to afford propargyl ketone 1.75 after collapse

of the cyanohydrin intermediate (Scheme 1.10). Following protection of the ynone, α-oxidation

of the ketone was accomplished under Harada's conditions3 to give 1.77, and Cu-mediated

iodination using I2 and CuSO4·5H2O provided 1.78 in 97% yield. Finally, Pd-catalyzed furan

formation under dilute conditions forged the fused pentacyclic scaffold of halenaquinol (1.43).

Desilylation with TBAF and naphthoquinol demethylation following Harada's protocol3 yielded halenaquinone (1.34).

Scheme 1.10. Synthesis of halenaquinone by the Shibasaki group.

O TBDPSO HO H

1. Tf2O, pyr 1. HO(CH2)3OH 1. TBAF, AcOH 2. LDA, 1.74; p-TsOH·H O (98%) Me Me 2 2. NaBH4,MeOH then NaF Me 2. nBuLi, TIPSCl (98%)

MeO (93%, 2 steps) MeO 3. DDQ (96%) (68%, 2 steps) MeO

OMe OMe OMe 1.72 1.73 1.75

O O O TIPS O TIPS O TIPS I 1. Pd2(dba)3·CHCl3 1. CuSO4·5H2O O2, tBuOK K2CO3,DMF(72%) OH NaI (97%) OH tBuOH Me Me Me 2. TBAF, AcOH (83%) O 2. p-TsOH (98%) O (79%) O MeO MeO MeO

OMe OMe OMe O 1.78 O 1.77 1.76

O O OTMS Me Me ref. 3 TIPS O O CN MeO O 1.74

OMe O 1.43 1.34: halenaquinone

Although the Shibasaki synthesis accessed halenaquinone in the greatest number of steps

(18 longest linear steps using their most direct route, 1% overall yield), it constituted the first

catalytic asymmetric synthesis of halenaquinone. Key features included their Pd-catalyzed

Suzuki cross-coupling/Heck reaction cascade and the metal-mediated iodination/furan formation

sequence.

1.6.5: Rodrigo’s Syntheses of Halenaquinone and Xestoquinone

In 2001, the Rodrigo group disclosed a short formal synthesis of racemic halenaquinone

in which they rapidly assemble the ABC tricycle using an intramolecular Diels–Alder

cycloaddition that was previously developed in their lab (Scheme 1.11).33–35 Afterwards, the

naphthalene portion was appended through the use of an isobenzofuran cycloaddition.

Diene 1.80 was prepared from propargyl alcohol in four steps and subjected to the

Rodrigo group's optimal conditions for o-benzoquinone monoketalization/IMDA with

methylguaiacol 1.79 and PIFA (Scheme 1.11). Adducts 1.81 and 1.82 were obtained as an

inseparable mixture; however, heating this mixture to reflux in 1,2,4-trimethylbenzene converted

1.81 into 1.82 by means of a Cope rearrangement, and 1.82 was obtained in 36% overall yield.

Treatment of enone 1.82 with dimethoxyisobenzofuran 1.83 afforded pentacycle 1.84 in high

yield. Naphthalene 1.85 was formed after base-mediated aromatization and acid-mediated

elimination of the ketal. To complete their formal synthesis, 1.85 was aromatized to the furan

with p-chloranil and the vinyl sulfide was converted into ketone 1.43 by heating with TiCl4 in wet acetic acid. 1.43 can be transformed into halenaquinone using the previously disclosed methods.3 This short sequence provided 1.43 in eight steps from 1.79 and with roughly 4%

overall yield.

Scheme 1.11. Synthesis of halenaquinone by the Rodrigo group.

Prior to their synthesis of halenaquinol, the Rodrigo group completed a formal synthesis of xestoquinone using a similar strategy (Scheme 1.12). In this case, their dienol fragment (1.86) was lacking the thiophenyl ether group and required a late-stage hydrogenation of the cyclohexene to afford xestoquinone (1.31). Similarly, this route provided 1.31 in eight steps and

7% overall yield from 1.79. Following their synthesis, several methoxy-substituted congeners of xestoquinone were synthesized to validate their proposed structures.36

Scheme 1.12. Synthesis of xestoquinone by the Rodrigo group.

1.6.6: Trauner’s Synthesis of Halenaquinone

To showcase their methodology involving the inverse-electron-demand Diels–Alder reaction of vinyl quinones,37,38 the Trauner group developed a concise asymmetric total synthesis of (–)-halenaquinone (Scheme 1.13).39 First, 3,4-diiodofuran (1.89) and aldehyde 1.90 were

combined to access enantioenriched alcohol 1.91 in three steps. Silyl protection followed by

regioselective formylation of the lithiated furan afforded aldehyde 1.92 without any lithium-

halogen exchange byproducts. Next, a diastereoselective 6-exo Heck reaction using Pd(OAc)2 and TBAB closed the cyclohexane ring in 1.93 (dr = 7:1). Nucleophilic addition of the stannate of 1.94 to aldehyde 1.93 produced an inconsequential mixture of carbinol diastereomers (1.95) in high yield. Next, deprotection and Ley–Griffith oxidation of both secondary alcohols yielded cinnamyl ketone 1.96, which was oxidized to vinyl quinone 1.97 with AgO and HNO3. The desired inverse-electron-demand Diels–Alder cycloaddition was conducted under high pressure and aromatized with MnO2 to afford halenaquinone (1.34). Alternatively, the pressurization step can be avoided by treating ketone 1.96 with AgO/HNO3 then DDQ, although a substantial

sacrifice in yield is observed (not shown).39

Scheme 1.13. Synthesis of (–)-halenaquinone by the Trauner group.

The Trauner group accomplished their asymmetric synthesis of the unnatural enantiomer of halenaquinone in 12 linear steps and 8% overall yield from diiodofuran 1.89. The route

features a diastereoselective intramolecular Heck cyclization and a Diels–Alder cycloaddition of

a vinyl-substituted benzoquinone to assemble the furanosteroid pentacyclic scaffold.

1.6.7: Wipf’s Synthesis of Thiohalenaquinone

The furanodecalin scaffold is believed to play a significant role in the biological activity

of the furanosteroids.40 However, as a potent electrophile, this moiety is likely responsible for its

poor target specificity and in vivo toxicity.41,42 In order to probe the biological significance of the

furanodecalin present in halenaquinone (1.34), the Wipf group synthesized thiohalenaquinone

(1.108), an analogue containing a thiophene ring in place of the typical furan (Scheme 1.14).

They reasoned that the reduced strain energy due to the longer C–S bonds in the thiophene and

the increased resonance stabilization energy should make thiohalenaquinone less prone to

nucleophilic addition compared to halenaquinone, thus making the sulfur-variant a more

selective inhibitor for its target enzymes.41 Their synthetic strategy initially revolved around

functionalization of the thiophene ring. The naphthalene portion was installed via an o- quinodimethane Diels–Alder reaction and the carbon framework was assembled with a Heck reaction followed by a late-stage RCM.

Conversion of 3,4-dibromothiophene (1.98) into 1.99 was accomplished through a five- step protocol to yield an inconsequential mixture of alkene isomers (E:Z = 2:1) which was carried through the majority of their synthesis (Scheme 1.14). Next, hydroxyl-directed silylation of the thiophene 2-position followed by silyl protection of the primary alcohol provided 1.100.

The remaining unsubstituted thiophene position was formylated and alkynylated to yield 1.101.

Oxidation to the propargyl ketone and bromination of the terminal alkyne provided dienophile

1.102. Treatment of 1.102 with benzocyclobutene 1.103 at 220 °C afforded aryl bromide 1.104, which was then subjected to a Pd-catalyzed 6-exo Heck reaction under microwave irradiation to

forge the cyclohexanone ring of 1.105 in 10% yield over four steps. In order to form the final 6- membered ring, the protected alcohol was converted to the aldehyde and allylated with

allyltributyltin and BF3·OEt2 to give 1.106. Ru-catalyzed isomerization to the internal olefin and

RCM with Hoveyda–Grubbs catalyst produced pentacycle 1.107 in 56% yield over the two steps.

Interestingly, RCM of the vinylated compound (not shown) proceeded in poor yield; fortunately, their allylation/isomerization sequence was shown to work significantly better. Finally, the synthesis of thiohalenaquinone was completed in three steps by Dess–Martin oxidation, conjugate reduction, and CAN oxidation to unveil the naphthoquinone in 1.108. In the end, the

Wipf synthesis of thiohalenaquinone was accomplished in 22 linear steps and 0.4% overall yield and utilized a convergent Diels–Alder–Heck sequence to assemble the majority of the carbon framework of 1.108.

Scheme 1.14. Synthesis of thiohalenaquinone by the Wipf group.

1. nBuLi; then OH OTBS OTBS TMSCl, Et3N TMS TMS Br Br 2. Citric acid, MeOH 1. nBuLi; DMF 5steps (76%, 2 steps) 2. HCCMgBr S S S Me Me Me S 3. TBSCl, imidazole (85%, 2 steps) 1.98 (90%) OH Me Me 1.99 1.100 Me (E:Z = 2:1) 1.101 OTBS OMe OTBS MeO TMS TMS OTBS TMS Pd(PPh ) ,Et N Me 1. MnO S 3 4 3 S OMe 2 NMP, 210 °C 1.103 S 2. NBS, AgNO3 Me Me MeO O (10%, 4 steps) Me O 4ÅMS,K2CO3 o-DCB, 220 °C O MeO Me Br Br OMe OMe 1.102 1.105 OH OH 1.104 O 1. TBAF 1. DMP (87%) 2. MnO2 S 1. (CO)RuHCl(Ph3P)3 S 2. Stryker's reagent S (80%, 2 steps) Me 2. HG-II 140 °C (53%) Me O Me 3. Allyltributyltin (56%, 2 steps) O 3. CAN, MeCN MeO O BF3·OEt2 (95%) MeO H2O (66%) O

OMe OMe 1.106 O 1.107 (d.r. = 6:1) 1.108

1.6.8: Crews’s Syntheses of Halenaquinone and Xestoquinone Analogues

During their studies on the protein tyrosine kinase activity associated with various

furanosteroids and naphthalene-derived structures, the Crews group synthesized some complex

halenaquinone and xestoquinone analogues (1.109–1.111) (Figure 1.8).43 The structures most relevant for our synthetic endeavors towards exiguaquinol include those in which the furan is replaced with a benzene ring (1.109–1.110) or those lacking the fused aromatic ring altogether

(1.111). While no yields are reported throughout their syntheses, enough of each analogue was

isolated for biological evaluation. Their unique synthetic strategy appears to take inspiration

from the work of Harada and Kanematsu.3,27

Figure 1.8. Furanosteroid analogues targeted by the Crews group.

O O

Me Me Me O O O O O O

O O O 1.109 1.110 1.111

Beginning with ethyl levulinate (1.112), tricycle 1.114 was prepared in two steps

according to a modified procedure by Dutt and coworkers (Scheme 1.15).44 1.114 was then oxidized to enone 1.115 and treated with PCC to obtain diketone 1.116. Heating 1.116 in the

presence of sulfone 1.117 effected a cheletropic extrusion and o-quinodimethane Diels–Alder

with the enone to provide pentacycle 1.118. Finally, aromatization to the naphthalene was

accomplished with DDQ and oxidative demethylation with CAN led to halenaquinone analogue

1.109, containing a fused benzene ring in place of the furan. Similarly, a synthesis of benzofused

xestoquinone analogue (1.110) was carried out using 1.115 as the dienophile (Scheme 1.15).

Scheme 1.15. Syntheses benzofused halenaquinone and xestoquinone analogues 1.109 and 1.110 by Crews.

The synthesis of the tetracyclic analogue 1.111, lacking the furan ring, began from ketal-

protected Wieland–Miescher ketone (1.119) (Scheme 1.16). 1.119 was converted into decalin

1.120 in three steps followed by a Shapiro elimination to access bicycle 1.121. Next, Swern

oxidation of the secondary alcohol followed by allylic oxidation with CrO3 provided diketone

1.122. This intermediate was heated with sulfone 1.117 to form tetracycle 1.123. Lastly,

aromatization with DDQ followed by oxidation with CAN gave halenaquinone analogue 1.111,

in which the fused aromatic moiety is omitted. After conducting inhibition assays, each analogue

exhibited diminished activity towards protein tyrosine kinase inhibition (IC50 = 27 μM for 1.109,

9 μM for 1.110, and 10 μM for 1.111) compared to halenaquinone and halenaquinol (IC50 = 1.5

and 0.6 μM, respectively).43

Scheme 1.16. Synthesis of halenaquinone analogue 1.111 lacking the furan ring by the Crews group.

1.6.9: Nemoto’s Synthesis of the Halenaquinone Core

In 2001, the Nemoto group detailed their strategy for accessing the tetracyclic core of halenaquinone (1.130) (Scheme 1.17).45,46 They planned to access a fused tetracycle resembling

halenaquinol through an intramolecular o-quinodimethane Diels–Alder cycloaddition to rapidly

assemble the molecule.

Scheme 1.17. Synthesis of halenaquinone core 1.130 by the Nemoto group.

Furan-3-carbonyl chloride (1.124) was converted into 1.125 in three steps47 and the resulting alcohol was brominated and subsequently displaced by the nitrile anion of 1.126.

Benzocyclobutene 1.127 was heated to reflux in o-dichlorobenzene to unveil the o- quinodimethane, which underwent facile intramolecular cycloaddition with the furan to afford

1.128. Only the endo product was formed, owing to the secondary orbital overlap stabilization

between the electron-rich furan and the electron-poor dienophile in the endo transition state

(1.131) (Figure 1.9).46 Formation of the phenylselenide followed by oxidation and elimination

provided dihydrofuran 1.129. Finally, treatment with acid generated furan 1.130 with loss of

methanol (Scheme 1.17).

Figure 1.9. Endo and exo transition states for Nemoto’s IMDA.

The halenaquinone core synthesis by the Nemoto group provided tetracycle 1.130 in nine

steps and 8% overall yield from 1.124. Although their target still lacks a ketone and an additional

aryl ring, it remains a unique and concise strategy in the halenaquinone synthesis literature.

1.6.10: Ahn’s Synthesis of the Xestoquinone Core

In 2003, the Ahn group published a racemic synthesis of the tetracyclic core of

xestoquinone (1.144) (Scheme 1.18).48 Their approach focused on the early formation of the

quaternary center and postponed construction of the fused ring scaffold until a later stage. Using

a [4+2] cycloaddition of propargyl aldehyde 1.140, the 6,5-ring system was assembled in a single

step, although with poor conversion.

Starting from 3-butyn-1-ol (1.133), alkyl iodide 1.134 was produced in five steps and

alkylated ethyl 2-phenylpropionate (1.135) in 88% yield (Scheme 1.18). Reduction to aldehyde

1.137 followed by Corey–Fuchs reaction provided diyne 1.138. Next, the terminal alkyne was

acylated with methyl chloroformate and the propargyl MOM ether was deprotected and oxidized

with Dess–Martin periodinane to yield 1.140. Upon heating in toluene, 1.140 underwent the

intended cascade, involving a tetradehydro-hetero-Diels–Alder reaction followed by a ring

rearrangement and hydride shift, to provide 1.143 (Scheme 1.18).48 Although this reaction

proceeded in only 5% yield, enough 1.143 was isolated to evaluate the final step. Methyl ester

1.143 was treated with BBr3 to effect a one-pot demethylation/Friedel–Crafts acylation to afford

the tetracyclic core of xestoquinone (1.144) in 42% yield.

Scheme 1.18. Synthesis of the xestoquinone core by the Ahn group.

The Ahn synthesis provided the tetracyclic core of xestoquinone (1.144) in 15 linear steps

and 0.3% overall yield. While they demonstrated that their thermal cascade can yield furan

1.143, significant optimization of this step must be performed to increase the efficiency of the

Ahn group’s overall approach.

1.7: Goals for the Synthesis of Exiguaquinol and Analogues

Exiguaquinol (1.1) contains several features that distinguish it from halenaquinol sulfate

(1.2). Most notably, exiguaquinol contains a rearranged pentacyclic carbon skeleton that lacks the furan moiety present in the furanosteroid framework. Taking inspiration from the syntheses

of halenaquinone and xestoquinone derivatives, we aimed to develop an efficient and modular

approach to synthesize exiguaquinol (1.1) in its natural enantiomeric form. Once completed, we

intended to obtain a co-crystal structure of 1.1 in the MurI inhibitor binding pocket, which would

permit the rational identification of more potent structural analogues by computational methods.

Using a modular approach towards 1.1 would facilitate the preparation of several structural analogues for biological evaluation.

The structure of exiguaquinol presents several key synthetic challenges that warranted investigation before embarking on our total synthesis. Specifically, we wanted to evaluate our strategy for constructing the fused tricyclic scaffold, which features four contiguous stereogenic centers, the two vicinal quaternary centers, and the N-acyl hemiaminal (Figure 1.10). In order to accomplish this task, we decided to first target a tetracyclic model system (1.145) with the stipulation that a synthesis of 1.145 must also, in principle, be amenable to exiguaquinol (1.1) and analogues (Figure 1.10). In designing this “tetracyclic core” (1.145), we purposely omitted the polar, anionic sulfate and sulfonate groups to simplify handling and characterization of the compounds produced. After completing a successful synthesis of 1.145, we planned to assess the introduction of the sulfonate and aryl sulfate moieties in a total synthesis of 1.1.

Figure 1.10. Exiguaquinol and its tetracyclic core.

O H OH SO 3 O OH N H O NMe Me O O Me O

O SO 3 OH

1.1: exiguaquinol 1.145: tetracyclic core of exiguaquinol

After accomplishing the first synthesis of exiguaquinol, we aimed to begin a

collaboration to better understand its biological profile. As discussed in Section 1.4, the Quinn

group’s computational docking studies of exiguaquinol in the H. pylori MurI enzyme suggested

the binding orientation depicted in Figure 1.5. Comparison with inhibitor 1.9 indicated that a

more potent analogue may arise from filling a hydrophobic pocket surrounding to the molecule.

Therefore, a co-crystal structure validating this binding orientation would direct our synthetic

efforts towards analogues such as 1.146–1.147, which contain nonpolar groups that protrude into

this hydrophobic environment (Figure 1.11).

Additionally, we intended to synthesize hydrogen bonding probes including 1.148, which

replace the sulfonate with a different hydrogen bond acceptor (Figure 1.11). Owing to its

comparatively large size, exiguaquinol binds MurI poorly when the natural substrate, D-

glutamate, is bound. Therefore, smaller variants of exiguaquinol, such as 1.149, would be

worthwhile to test in the binding assay.

Figure 1.11. Structural analogues of exiguaquinol for biological evaluation.

Based on precedent from the previous syntheses of furanosteroid natural products, we

devised a novel strategy to access exiguaquinol. In the following chapters, our efforts towards

the syntheses of exiguaquinol’s tetracyclic core (1.145) (Chapter 2) and exiguaquinol (1.1)

(Chapter 3) are described.

1.8: Notes and References

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CHAPTER 2:

SYNTHESIS OF THE TETRACYCLIC CORE OF EXIGUAQUINOL

2.1: Introduction

Exiguaquinol (2.1) possesses several complex structural features that make it a challenging synthetic target. It contains five fused rings, four contiguous stereocenters, an aryl sulfate, and an embedded taurine moiety (Figure 2.1).1 The aryl sulfate is prone to decomposition

and the vicinal quaternary centers create a congested space in the molecule, so careful choice of

strategy would be required.2,3 To address these challenges, we aimed to first develop a synthesis

of the tetracyclic core (2.2) as a model system and later apply our route toward the natural

product, as well as structural analogues. We chose 2.2 as our target because it contains all of the

stereogenic centers in the natural product. Tetracycle 2.2 also omits both the polar, anionic

sulfonate and aryl sulfate functional groups (highlighted in red), simplifying the handling of the

material. Therefore, we set out to synthesize the tetracyclic core of exiguaquinol (2.2) with the requirement that our route must be applicable to the total synthesis of exiguaquinol (2.1) and

structural analogues.

Figure 2.1. Structure of exiguaquinol (2.1) and its tetracyclic core model system (2.2).

2.2: Retrosynthetic Analysis

Our retrosynthetic analysis of 2.2 began with a few functional group manipulations followed by disconnection of the C7–C15 bond to form intermediate 2.4 (Scheme 2.1). We

envisioned forming the C-ring with a 5-exo-trig radical or metal-catalyzed cyclization of the aryl

halide onto the proximal C7–C16 alkene in 2.4. The exocyclic olefins in intermediate 2.4 could

be constructed through an oxidation and thermal sulfoxide elimination sequence of bis(thioether)

2.5. The bicyclic scaffold was projected to arise from a Diels–Alder reaction between diene 2.6

and highly activated dienophile 2.7, which we intended to prepare from a Morita–Baylis–

Hillman reaction between N-methylmaleimide (2.8) and a 2-halobenzaldehyde (2.9).

Scheme 2.1. Synthetic plan to access exiguaquinol's tetracycle core (2.2).

2.3: Synthetic Efforts Toward an Acylmaleimide Diels–Alder Strategy

Fellow graduate student Dr. Sarah Steinhardt and I demonstrated that the bis(phenylsulfide) diene 2.6 can be synthesized on a multi-gram scale in three steps from inexpensive starting materials (Scheme 2.2).4 First, a pinacol homocoupling of acrolein yields a

mixture of (±)- and meso-divinyl glycols (2.11), which are used directly in the next step.5

Although this diastereomeric mixture of glycols is commercially available, it was found to be more economical to synthesize it from acrolein. Next, bromination with cuprous chloride and hydrobromic acid generated dibromodiene 2.12 in good yields.6 Lastly, nucleophilic

displacement of the bromides with sodium thiophenolate led to bis(phenylsulfide) diene 2.6.7

Scheme 2.2. Synthesis of bis(phenylsulfide) diene 2.6.

The synthesis of the dienophile began with a Morita–Baylis–Hillman reaction between 2- bromobenzaldehyde (2.13) and N-methylmaleimide (2.8) to afford benzylic alcohol 2.14

(Scheme 2.3).8 This reaction proved highly irreproducible and frequently resulted in

polymerization of the starting materials; however, enough of the Morita–Baylis–Hillman adduct

(2.14) was obtained to evaluate its use in subsequent steps. Unfortunately, we quickly realized

that oxidation of 2.14 to ketone 2.15 was problematic, likely because of the highly electrophilic

nature of 2.15 at ambient temperature (Scheme 2.3).9 When subjected to Swern oxidation,

chloride adduct 2.16 was isolated as the only identifiable product resulting from conjugate

addition of chloride anion to the electrophilic maleimide. Attempts to isolate ketone 2.15 using

other oxidation conditions resulted in complete decomposition of the starting material. Our

difficulties obtaining ketone 2.15 are likely attributable to its susceptibility to hydration upon

exposure to moisture.

Scheme 2.3. Attempted synthesis of 2.15 using a Morita–Baylis–Hillman reaction.

Br O Br OH Br O DABCO O oxidation O CHO PhOH, 70 °C conditions NMe NMe NMe (40%) (see below) O 2.14O 2.15 O 2.13 2.8 Br OH Oxidations tried: O -Swern -PCC -Parikh–Doering -MnO 2 NMe -Pfitzner–Moffatt -TPAP/NMO -Jones -Dess–Martin Periodinane Cl 2.16 O

Because isolation of 2.15 proved unsuccessful, trapping the highly activated dienophile in

situ with a Diels–Alder cycloaddition was attempted. This strategy was shown to be effective in

a similar case by Durrant and Thomas in which they make use of both cyclopentadiene and

(E,E)-2,4-hexadiene in an in situ Diels–Alder cycloaddition.9 Using a procedure adapted from

the literature, phenylselenide 2.18 was prepared in two steps and treated with mCPBA to

generate 2.19 in situ. Unfortunately, none of the desired cycloadduct (2.20) was observed when

excess bis(phenylsulfide) diene 2.6 was added to the reaction mixture, with and without heating

(Scheme 2.4). As reported in the literature, cyclopentadiene successfully underwent in situ

cycloaddition with maleimide 2.19 at –78 °C to produce 2.21.9 This result indicates that the

bis(phenylsulfide) diene (2.6) is insufficiently reactive in the cycloaddition reaction, most likely

due to its moderately electron-rich properties and its preference for the s-trans diene conformation.

Scheme 2.4. Synthesis of highly activated dienophile 2.19 and Diels–Alder trapping.

To circumvent these problems, other dienophiles were investigated in the Diels–Alder reaction with diene 2.6 (Schemes 2.5 and 2.6).10,11 We envisioned that a more stable maleimide

with a functional handle (2.22) could be used to intercept the desired bicycle, albeit with one or

two additional linear steps (Scheme 2.5).

Scheme 2.5. Diels–Alder cycloaddition strategy using less labile dienophiles.

Therefore, maleimide 2.14 was first evaluated for its ability to undergo the Diels–Alder

reaction with 2.6 (Scheme 2.6). In principle, a diastereoselective Diels–Alder reaction at this stage could provide enantioenriched 2.25 based on the absolute configuration of the secondary alcohol in 2.14. Afterwards, oxidation of the benzylic alcohol would provide bicycle 2.24.

However, both thermal and Lewis acidic conditions (using SnCl4, Et2AlCl, BF3·OEt2, Sc(OTf)3, or ZnBr2) were shown to be ineffective at uniting diene 2.6 and maleimide 2.14 in a [4+2]

cycloaddition (Scheme 2.6). Next, we turned our attention to 2-bromo-N-methylmaleimide (2.26)

as a functionalized dienophile. The product of the Diels–Alder cycloaddition would contain an α-

bromocarbonyl, which could be used in a Reformatsky reaction to append the acyl group.

Unfortunately, no desired product was obtained under Lewis acidic conditions (using Et2AlCl,

BF3·OEt2, or CBS-catalyst/AlBr3) and a 2.2:1 mixture of endo/exo diastereomers was obtained

under thermal conditions (Scheme 2.6).

Scheme 2.6. Attempted Diels–Alder cycloadditions using substituted maleimides.

2.4: Second Generation Retrosynthetic Analysis

After encountering reactivity and diastereoselectivity issues in the substituted maleimide

strategy, a new synthetic plan was devised that attempted to circumvent these early stage

problems. We anticipated that using N-methylmaleimide in the Diels–Alder reaction would lead to an achiral meso product (2.31) with high endo/exo selectivity, which could be further

functionalized through a desymmetrizing aldol addition or Claisen condensation to generate 2.29

(Scheme 2.7). Additionally, the desymmetrization of meso bicycle 2.31 may be performed enantioselectively with a chiral base to access the core of exiguaquinol as a single enantiomer.

Scheme 2.7. Revised synthetic plan to access exiguaquinol's tetracycle core (2.2).

Previous work by the Simpkins group has demonstrated that asymmetric Claisen and

aldol reactions proceed with high yield and enantioselectivity on similar meso bicyclic imides

(Scheme 2.8).12–15 Using chiral lithium amide base 2.33, an asymmetric deprotonation can be

used to differentiate the two pairs of α-protons leading to a single enantiomer of Claisen or aldol

products (2.34 and 2.36, respectively). Our efforts towards enantioselective desymmetrization en

route to exiguaquinol are discussed in Section 3.6.

Scheme 2.8. Enantioselective Claisen and aldol reactions discovered by the Simpkins group.

2.5: Synthesis of the Tetracyclic Core of Exiguaquinol

2.5.1: Diels–Alder Cycloaddition and Aldol Reaction

When heated to reflux in toluene, N-methylmaleimide (2.8) readily underwent the

thermal Diels–Alder reaction with 2.6 to exclusively afford the endo-cycloadduct (2.37) in

excellent yield (Scheme 2.9). However, fellow graduate student Dr. Sarah Steinhardt showed that

all attempts to acylate, alkylate, or deuterate the C-2 α-position of Diels–Alder adduct 2.37 led to

recovery of starting material, suggesting that enolization of the bicyclic imide was not occurring

to any appreciable extent.4 It was hypothesized that the rigid, boat-shaped conformation9 of the molecule was inhibiting enolate formation by positioning the methylene thioether groups in close

proximity to the acidic α-protons, effectively shielding them from deprotonation (Scheme 2.9).

We reasoned that reduction of the cyclohexene double bond in 2.37 should allow the molecule to

adopt a more flexible chair-like conformation, facilitating enolization of the C2 α-position for

further functionalization (Scheme 2.10).

Scheme 2.9. Successful cycloaddition and attempted functionalizations of 2.37.

After testing many catalysts and conditions for alkene hydrogenation, Dr. Sarah

Steinhardt found that PtO2 in acetonitrile under 500 psi of H2 (g) efficiently yielded desired saturated bicycle 2.41.4 When performing this reduction on a larger scale in a high-pressure reactor, the addition of THF as a co-solvent improved the solubility of 2.37 and allowed for increased material throughput.

Scheme 2.10. Functionalization of the reduced bicyclic imide (2.38).

Preliminary efforts showed that deuterium incorporation and alkylation with activated

electrophiles were successful after generating the presumed dienolate of 2.41 with excess LDA.4

Unfortunately, Claisen condensation with methyl 2-bromobenzoate proved unsuccessful after several attempts. However, we were pleased to find that the aldol reaction of 2.41 with 2- bromobenzaldehyde (2.13) led to the desired product (2.42) as a single diastereomer in 40% yield on small scale (Table 2.1, entry 1). Formation of the zincate enolate with Et2Zn and DMPU

did not seem to have a significant effect on the yield (entry 2). The addition of anhydrous LiCl

seemed to improve the reproducibility of the reaction, but did not seem to enhance the isolated

yield (entry 3).14 It has been shown by Collum and coworkers that the addition of LiCl can serve

to accelerate the rate of deprotonation in enolate formation, likely by affecting the aggregation

state of LDA in solution.16,17 Interestingly, the isolated yield tended to increase with scale

suggesting that the reaction may be highly sensitive to trace quantities of adventitious moisture

or air (entries 4–5). When only one equivalent of LDA was used, the aldol reaction did not

occur; instead, bicyclic maleimide 2.45 and benzyl alcohol 2.46 were observed (entry 6). This

observation suggests the presence of a redox decomposition pathway which likely arises through

a mechanism similar to the Cannizzaro reaction.18 Furthermore, Dr. Sarah Steinhardt also

isolated this product by quenching the dienolate with I2, an observation that supports the facile

oxidation of the enolate to the maleimide in the presence of an oxidant.19 This byproduct was not

investigated further; however its ability to serve as a conjugate-acceptor could be explored en

route to the core of exiguaquinol. Lastly, the same conditions can be used with 2-

iodobenzaldehyde as the electrophile to produce 2.44 in 74% yield on gram scale (entry 7).

Table 2.1. Optimization of the aldol reaction.

2.5.2: Sulfoxide Elimination and Closure of the C-Ring

With aldol product 2.42 in hand, we proceeded to install the exocyclic alkenes through

sulfoxide elimination. Oxidation of 2.42 to the bis(sulfoxide) occured readily with

iodosobenzene, but high temperature conditions resulted in the desired thermal elimination of the

sulfoxides along with undesired retro-aldol fragmentation.4 To mitigate this unwanted reactivity,

the alcohol was oxidized to the corresponding ketone (2.43) with Dess–Martin periodinane,

leaving the thioethers untouched (Scheme 2.11). Next, the phenylsulfides were oxidized to reveal

a mixture of four bis(sulfoxide) diastereomers, which were subsequently eliminated under

thermal conditions to provide diene 2.44.4,20 A brief optimization of the thermal elimination

showed that heating to 180 °C in xylenes afforded the highest yield of desired product 2.44.

Unfortunately, Dr. Sarah Steinhardt found that treatment of aryl bromide 2.44 with AIBN and Bu3SnH in refluxing benzene furnished 6-endo cyclization product 2.45 exclusively, with no

trace of the desired 5-exo isomer (Scheme 2.11). This result was surprising at first because 5-exo cyclizations are known to be kinetically faster than the competing 6-endo pathway; however, this observation turned out to be fairly well-precedented.21,22

Scheme 2.11. Elaboration of aldol product 2.42 and 6-endo cyclization performed by Dr. Sarah Steinhardt.

Ishibashi and coworkers found that aryl halide 2.46 will undergo a net 6-endo radical cyclization under the same reaction conditions.21 Probing the mechanism, they found that the 5-

exo product can be observed at very high concentrations of Bu3SnH. This implies that 2.51 arises

from an initial 5-exo cyclization to form 2.48, followed by a neophyl rearrangement to form

intermediate 2.51 (Scheme 2.12). This rearrangement occurs when the highly reactive methyl

radical intermediate 2.48 is able to dearomatize the phenyl ring through a 3-exo cyclopropanation

to generate a cyclohexadienyl radical (2.49). Intermediate 2.49 can then fragment either of two

ways to restore aromaticity; pathway a (blue) regenerates unstable methyl radical (2.48), while

the alternative pathway b (green) creates a cyclohexene ring and a more stable tertiary radical

(2.50). After hydrogen atom abstraction from Bu3SnH, pathway b forms the net 6-endo

cyclization product (2.51). Unfortunately, we were unable to observe desired 5-exo product

under any additional radical conditions attempted.

Scheme 2.12. Net 6-endo radical cyclization through neophyl rearrangement mechanism proposed by Ishibashi.

We hypothesized that the presence of an sp2 center at the C9 position was hampering the

desired cyclization by causing additional angular strain during cyclization. If the ketone were

replaced with the corresponding alcohol, the sp3 center would impart less angular strain and may

allow the cyclization to proceed.

With this idea in mind, a substrate bearing an aliphatic C9 position and was targeted

(Scheme 2.13). Due to the propensity of aldolate 2.42 to undergo retro-aldol decomposition

when heated, the free alcohol was protected as the triethylsilyl ether. Oxidation of this protected

compound with mCPBA at –78 °C afforded a mixture of four sulfoxide diastereomers (2.52),

which were used without separation.

Scheme 2.13. Synthesis of diene 2.53.

Various conditions were surveyed to identify a suitable procedure for thermal sulfoxide

elimination (Table 2.2). Heating 2.52 in xylenes between 120 °C and 180 °C in the microwave

led to decomposition. We considered that the acidic sulfenic acid byproduct (PhSOH) could be

facilitating decomposition of the substrate, so an excess of an amine base was added to buffer the

reaction. Using triethylamine, the reaction proceeded at 180 °C to provide desired alkene product

2.53 with variable yields. Heating 2.52 to 180 °C or 190 °C in o-dichlorobenzene (o-DCB) led to

low conversion, but raising the temperature to 210 °C facilitated higher conversion to the desired alkene product (2.53) with greater reproducibility.

Table 2.2. Optimization of the sulfoxide elimination.

Straightforward access to 2.53, containing a C9 sp3 carbon, permitted evaluation of this

substrate in the cyclization step. Initially, reductive radical cyclization conditions were evaluated

using AIBN and Bu3SnH with the hope that the more flexible C9 geometry would permit

formation of the 5-exo regioisomer. Again, the overall 6-endo cyclization, resulting from a

presumed neophyl rearrangement, could not be overcome and 2.54 was the only observed

product (Scheme 2.14).21,22 When triethylborane was used as the radical initiator at room

temperature in THF, similar results were observed.

Scheme 2.14. Reductive radical cyclization of aryl bromide 2.53.

Although this result was unproductive for the synthesis of exiguaquinol, the six-

membered ring isomers could serve as interesting analogues to test against the H. pylori MurI. In

addition, the tetracyclic scaffold formed by the 6-endo cyclization (2.54) permitted assignment of

the relative stereochemistry at the benzylic stereocenter based on NOESY correlations between

the C-ring protons (Scheme 2.14).

With the emergence of the field of photoredox catalysis,23–26 many mild, tin-free radical

generation conditions have been developed to form C–C bonds. With the limited success

observed with tin hydride conditions, we were interested to see whether photoredox generation

of the same aryl radical could switch our selectivity in favor of 5-exo cyclization. We were

particularly inspired by the work of Professor Corey Stephenson (Boston University) in which he

is able to perform a reductive radical cyclization on aryl iodide substrates, such as 2.55, to

generate the 5-exo product 2.56 in good yield using catalytic fac-Ir(ppy)3 and visible light

(Scheme 2.15).27 Therefore, a sample of aryl iodide 2.69 was sent to Professor Stephenson's lab

to be tested under these conditions. Unfortunately, graduate student John Nguyen did not observe

any desired product despite full consumption of starting material; instead, the photoredox

conditions appeared to reduce the succinimide portion of 2.53.

Scheme 2.15. Stephenson's photoredox 5-exo cyclization.

Our limited success with reductive radical cyclization approaches forced us to survey a

parallel method for forming the C7–C15 bond—an intramolecular reductive Heck cyclization of

the aryl bromide and the pendant olefin. Substrate 2.53 is particularly apt to undergo the desired

5-exo palladium-catalyzed cyclization to place the large palladium species at the less substituted

carbon atom of the alkene (Scheme 2.16). Additionally, the Pd–C bond and the alkene in

intermediate 2.57 can align in a parallel orientation to favor the 5-exo cyclization pathway.28

Once the palladium hydride species 2.59 is formed, reductive elimination will occur to afford

2.60. Indeed, 5-exo Heck cyclizations onto terminal alkenes are well precedented, as shown by the work of Larock, Grigg, Banerjee, and others (Scheme 2.16).29–31 Based on these examples,

we aimed to apply this chemistry to access tetracycle 2.60.

Scheme 2.16. Proposed catalytic cycle for reductive Heck reaction and examples.

As depicted in Scheme 2.16, Banerjee and coworkers have shown that a similar exocyclic olefin substrate (2.65), en route to several taiwaniaquinone and dichroanal natural products, will undergo an aryl 5-exo reductive Heck cyclization using Pd(PPh3)4 and sodium formate in DMF

to yield a [6-5-6] fused ring system (2.66).31 After subjecting 2.53 to these conditions for two

days at 95–100 °C, a new product bearing the tetracyclic carbon framework resulting from a 5-

exo reductive Heck reaction was observed. Unfortunately, isomerization of the C4 exocyclic

alkene had also occurred to generate 2.67 (Scheme 2.17).

Scheme 2.17. Initial success for 5-exo reductive Heck cyclization.

Me H O O Pd(PPh3)4, HCO2Na NMe DMF, 95–100 °C NMe

OSiEt3 O (54%) Me O OSiEt3 Br

2.67 2.53 Since the isomerization was suspected to be facilitated by the elevated temperature, a

reductive Heck reaction was attempted at room temperature. However, no reaction took place

and mostly starting material was recovered. After testing several other palladium catalysts and

ligands, no reactivity was observed at ambient temperature and alkene migration took place upon

heating. While we were unable to improve upon this result, it demonstrated that a successful

reductive Heck cyclization must be performed at ambient temperature to preclude olefin

isomerization.

With the goal of improving conversion in the Heck reaction without increasing the

reaction temperature, we decided to employ aryl iodide 2.69 instead of bromide 2.53 in the

reductive Heck reaction. Owing to the weaker C–I bond, oxidative addition by palladium is

significantly faster for aryl iodides compared to other aryl electrophiles. Therefore, aryl iodide

2.69 was synthesized in a similar fashion as shown previously (Scheme 2.18). Protection of the

iodide-containing aldol adduct (2.44) as the triethylsilyl ether and oxidation of the sulfides

afforded bis(sulfoxide) 2.68 as a mixture of four diastereomers. Thermal pericyclic elimination

generated cyclization precursor 2.69 upon microwave irradiation.

Scheme 2.18. Synthesis of diene 2.69 containing an aryl iodide.

Initial efforts to perform the desired reductive Heck cyclization focused on using

Pd(PPh3)4 as the catalyst. However, when 2.69 was treated with Pd(PPh3)4 at 0 °C, no reaction

took place, and decomposition was observed when warmed above 35 °C. We reasoned that a

more electron-rich phosphine ligand might accelerate the oxidative addition relative to other

decomposition pathways. Therefore, aryl iodide 2.69 was treated with sodium formate, and a

catalytic amount of Pd(OAc)2 and PCy3 in DMF. To our delight, the desired 5-exo tetracycle

(2.70) was formed as the major product in 33% yield with no observable olefin migration after

14 h at room temperature (Table 2.3, entry 1). To improve upon this result, alternative conditions were evaluated for increased efficiency in the desired transformation (Table 2.3).

Substituting PdCl2 or Pd2(dba)3 for Pd(OAc)2 as the precatalyst led to diminished yields of the tetracycle (entry 2–3). Additionally, using Pd(DPE-Phos)Cl2 and Pd(dppf)Cl2 precatalysts did

not produce 2.70 to an appreciable extent (entries 4–5). Low conversion to desired product was

also observed when BINAP and JohnPhos were used in conjunction with Pd(OAc)2 (entries 6–

7); however, a significant increase in conversion was seen in the presence of the CyJohnPhos

ligand (entry 8). Furthermore, the best result was observed when Pd(PtBu3)2 was used as the

catalyst (entry 9). The interesting trend in reaction conversion may be explained by comparing

the Tolman cone angles32 of some of the monodentate phosphine ligands (Table 2.3): JohnPhos

displays the largest cone angle of all the ligands tested and resulted in low conversion, while

PCy3 had the smallest cone angle and afforded moderate levels of conversion. The success of

Pd(PtBu3)2, among many other factors, may be partially attributable to having the ideal Tolman

cone angle for the reductive Heck transformation on our particular substrate.

Table 2.3. Optimization of the reduction Heck cyclization and Tolman cone angles.

O H H O Pd, Ligand NMe NMe PtBu2 PCy2 HCO2Na, DMF OSiEt3 O 18 h, rt Me O OSiEt3 I JohnPhos CyJohnPhos 2.69 2.70 a Entry CatalystLigand Conversion Tolman Ligand Cone Angle ( ) 1 Pd(OAc)2 PCy3 33% JohnPhos 246° 2 PdCl2 PCy3 25% CyJohnPhos 226° 3 Pd2(dba)3 PCy3 17% P(o-tol) 194° 4 Pd(DPE-Phos)Cl2 - <5% 3 PtBu3 182° 5 Pd(dppf)Cl2 - <5% PCy3 170° 6 Pd(OAc)2 BINAP 22% PtBu2Me 161° 7 Pd(OAc) JohnPhos 10% 2 PiPr3 160°

8 Pd(OAc)2 CyJohnPhos 45% PPh3 145° PnBu 132° 9 Pd(PtBu3)2 - 71% 3 aBased on 1H-NMRcomparisontorecoveredSM.

Aside from the Tolman cone angle, additional factors point to Pd(PtBu3)2 as the optimal

catalyst for the desired reaction. Its highly electron-rich nature leads to a facile oxidative addition

process33 and therefore, higher conversion compared to other phosphine ligands. In addition, the

mono-ligated Pd(0) species contains open coordination sites to permit association of the alkene

and hydride ligands.33 Lastly, the bulky ligands accelerate reductive elimination of the

alkylpalladium hydride intermediate and release the final product. For these reasons, many

groups including Fu, Feringa, Denmark, Lautens, and many others have found Pd(PtBu3)2 to be

32–39 the optimal catalyst in palladium-catalyzed transformations. After identifying Pd(PtBu3)2 as

a competent catalyst for the reductive Heck reaction, no additional metal-ligand combinations

were explored.

This exciting result showed that we could install the desired C–C bond through an

intramolecular reductive Heck reaction on the silyl protected substrate. However, we realized

that a successful cyclization of substrate 2.72, bearing a ketone in the C9 position, would lead to

the core of exiguaquinol in fewer steps and avoid the protection/deprotection sequence.

Therefore, ketone 2.72 was synthesized according to the aforementioned procedure (Scheme

2.19).4 Oxidation of aldol product 2.44 with Dess–Martin periodinane yielded ketone 2.71 and

oxidation of the phenylsulfides to the sulfoxides afforded a mixture of diastereomers, which were

converted to cyclization precursor 2.72 upon microwave irradiation at 180 °C in xylenes.20

Scheme 2.19. Synthesis of ketone 2.72 for evaluation of the reductive Heck.

Various palladium sources and ligands were evaluated to effect the desired 5-exo

reductive Heck cyclization on the C9 ketone substrate (Table 2.4). Using triarylphosphines such

as PPh3 or (R)-BINAP, no cyclization was detected and alkene isomerization or decomposition

occurred (entries 1–3). Alkene isomerization even occurred at 0 °C under these conditions (entry

2). When more electron-rich phosphines (dppe or PCy3) were employed, 5-exo cyclization was observed, accompanied by olefin migration (entries 4–6). A brief solvent screen indicated that

DMF was only solvent in which cyclization took place (entries 7–9). Lastly, the use of Pd(0) precatalysts, including Pd2(MeO-dba)3 or the previously successful Pd(PtBu3)2, yielded the

isomerized tetracycle 2.74 exclusively (entries 10–11).

Table 2.4. Attempted reductive Heck cyclizations on ketone 2.72.

Based on our optimization of conditions, a successful 5-exo reductive Heck cyclization to

afford 2.3 was never realized for ketone 2.72 owing to the unstoppable alkene isomerization. We

believe the isomerization could be occurring through either of two possible mechanisms. First,

the high temperature reaction conditions could facilitate addition of the palladium hydride

species across the C4–C17 alkene, and β-hydride elimination toward the C3 proton would lead to

isomerization to the more thermodynamically stable and undesired alkene (Scheme 2.20).40–42

Alternatively, sodium formate could also promote this isomerization through a base-catalyzed pathway (Scheme 2.20).43 To gain insight into this undesired reactivity, a control reaction was

performed in which 2.72 was heated to 55 °C with sodium formate in DMF. Complete alkene

isomerization occurred in the absence of catalyst, suggesting Pd is likely not responsible for this

undesired outcome and elevated temperatures may be a contributing factor. To further

distinguish between the two potential pathways, a deuterium incorporation study using

Pd(PtBu3)2 and DCO2Na could be performed. If deuterium incorporation is observed, this

outcome would support the Pd–H(D) mechanism (Pathway 1); alternatively, if no deuterium labeling occurs, the base-mediated mechanism (Pathway 2) would appear more plausible. At present, more experimental evidence is needed before we can conclusively determine the mechanism of this undesired reactivity.

Scheme 2.20. Mechanistic proposals for alkene isomerization.

Pathway 1: H(D) (D)H L Pd H O n O O LnPd H (D)H NMe LnPd–H(D) NMe NMe

O O O O O LnPd–H O I I I

2.75 2.76 2.77

Pathway 2: B H H O B–H O O base NMe NMe NMe

O O O O O base O I I I

2.78 2.79 2.73

Furthermore, it is unclear as to why 2.72 is more prone to alkene migration than 2.69. It

is possible that the bulky silyl protecting group in 2.69 rests in close proximity to the C3 α-

proton and blocks the C3 proton from deprotonation, whereas no such blocking group exists in

2.72. However, further studies would be needed to test this hypothesis.

2.5.3: Hemiaminal Formation

Since a successful reductive Heck cyclization was achieved with substrate 2.69, we

decided to further evaluate our synthetic plan using this material (Scheme 2.21). Following

cyclization, we sought to form ketone 2.3 through deprotection and oxidation. Initial attempts to

deprotect using TBAF or hydrofluoric acid yielded olefin isomerization products. When subjected to oxidative deprotection conditions using IBX in DMSO and water,44 a mixture of

protected, deprotected and oxidized products were obtained. Adding 1 M acetic acid facilitated

deprotection in the presence of IBX and led to full conversion to ketone 2.3.

Next, we hoped to take advantage of the inherent steric crowding in 2.3 to reduce the

least hindered carbonyl in the presence of two others (Scheme 2.21). However, all attempted

reduction conditions resulted in decomposition, isomerization, or over-reduction. Using LiBH4 or NaBH4, reduction of both the benzylic ketone and the undesired imide carbonyl was

exclusively observed, yielding diol 2.80. This unexpected product was isolated as a single

diastereomer and most likely results from initial reduction of the benzylic ketone, followed by a

directed intramolecular hydride delivery from the resulting alkoxyborohydride.

Scheme 2.21. Attempts to elaborate 2.70 into the core of exiguaquinol.

To avoid reduction of the indanone carbonyl, reduction was attempted on tetracycle 2.70

(Scheme 2.21). Recovery of starting material was observed using either LiBH4 or NaBH4, and

decomposition occurred with L-selectride. When treated with DIBAL-H in toluene, reduction

predominantly took place at the undesired imide carbonyl to afford 2.81 as the major product.

This product is the result of hydride delivery to the convex face of the molecule. In addition,

both diastereomers of the desired hemiaminal regioisomer (2.82) were isolated as minor

components.

Surprisingly, reduction of bicyclic imide 2.69 with LiBH4 generated a single regioisomer

and diastereomer of the N-acyl hemiaminal. NOESY correlations from the hemiaminal methine proton suggested that the epimer formed by reduction was inconsistent with the natural configuration. These suspicions were later confirmed by single crystal X-ray diffraction, which placed the alcohol on the convex face of the molecule (Scheme 2.22).

Two possible rationales can be used to explain this observation: first, the hydride nucleophile could be delivered exclusively from the concave face of the bicyclic imide.

Approaching from the concave (top) face would avoid unfavorable steric interactions with the aryl ring and bulky silyl protecting group, directly yielding the observed product (Scheme 2.22).

Furthermore, reduction from convex (bottom) face would create torsional strain in the transition state, thereby disfavoring this desired diastereomer. The second explanation for the high selectivity in the reduction could be attributed to post-reduction equilibration. We originally hypothesized that a hydride reduction would come from the convex face to generate the desired epimer as the kinetically preferred product. If equilibration is possible under the reaction

conditions, epimerization to the thermodynamically preferred product (2.84) will occur. An internal hydrogen bond between the hemiaminal alcoholic proton and the silyl-protected alcohol may serve to stabilize the unnatural configuration, leading to its thermodynamic favorability

(Scheme 2.22). Currently, we are unable to definitively rule out either pathway; however, we have not been able to observe the desired hemiaminal as a reaction intermediate using this substrate.

Scheme 2.22. Rationale for stereoselectivity in the LiBH4 reduction of imide 2.69.

2.5.4: Completion of the Exiguaquinol Core

While this hydride reduction was highly selective for the undesired epimer, we reasoned

that exiguaquinol likely exists in the thermodynamically preferred configuration, which should

be attainable late-stage, either spontaneously or through reagent-controlled epimerization.

Therefore, hemiaminal 2.84 was subjected to the previously optimized reductive Heck conditions

(Scheme 2.23) to provide tetracycle 2.85 uneventfully. Although the one-pot deprotection/oxidation using IBX, DMSO,44 and AcOH led to decomposition, a two-step

deprotection and oxidation protocol using TBAF followed by MnO2 afforded ketone 2.86 in good yield. Finally, ozonolysis of the exocyclic olefin cleanly generated ketone 2.87 after a reductive quench (Scheme 2.23).

Scheme 2.23. Final steps of the exiguaquinol core synthesis.

At this stage, NOESY correlations and single crystal X-ray diffraction of 2.87 still indicated the presence of the unnatural hemiaminal configuration. Closer inspection of the crystal structure revealed a hydrogen bond between the hemiaminal hydroxyl group and the indanone carbonyl at the C9 position (Scheme 2.23, highlighted in green). Despite isolation of the undesired epimer, we still expected a thermodynamic preference for the (R)-configured

hemiaminal if the thermodynamic profile of our model system closely mimicked that of

exiguaquinol. Therefore, we set out to invert the stereochemistry to the "natural" configuration at

this center. We hypothesized that epimerization should be possible under either acidic or basic

conditions via different mechanisms. In the presence of acid, protonation and loss of water can

occur to form an N-acyliminium ion, which can hydrate from the opposite face to yield the other epimer (Scheme 2.24). With base, the hemiaminal can be deprotonated and opened to the aldehyde, which can rotate and cyclize to the opposite epimer (Scheme 2.24).

Scheme 2.24. Potential mechanisms of hemiaminal epimerization.

Several examples of hemiaminal epimerizations under both acidic and alkaline conditions

have been reported in the literature (Scheme 2.25). In his synthesis of the amathaspiramides,

Fukuyama was able to successfully convert amathaspiramide C (2.92) into amathaspiramide F

(2.93) with Cs2CO3, illustrating the kinetic stability of N-acyl hemiaminals and their propensity

to equilibrate to the thermodynamic configuration with mild base.45 Additionally, Koizumi

showed that the N-acyl hemiaminal resulting from convex face imide reduction (2.94) can be epimerized to the opposite configuration (2.95) by treatment with either EtONa/EtOH or catalytic HCl.46 Similar phenomena were seen by de Kimpe,47 Matsuki,48 and Speckamp49 in the

course of their respective studies. Serendipitously, Nicolaou and Baran discovered that their N-

acyl hemiaminal intermediate en route to the CP molecules was converted to its opposite

50 diastereomer when treated with Ac2O and Et3N.

Scheme 2.25. Examples of hemiaminal epimerizations.

Despite the wealth of epimerization examples, none involved a β-hydroxyketone such as

in 2.87. We expected that elimination of the alcohol to provide vinylogous imide 2.100 could be problematic, but epimerizations were conducted on 2.87 nonetheless (Table 2.5). Subjection of

2.87 to basic conditions resulted in either rapid decomposition or elimination to the vinylogous

imide, as suspected (entries 1–2). Treatment with p-TsOH produced a complex mixture of multiple hemiaminal-containing compounds; however none of the products could be isolated and characterized (entry 3). Under mildly Lewis acidic conditions, only starting material was

recovered (entry 4). Disruption of any intramolecular hydrogen bonds by silylation with TESOTf

cleanly produced the siloxyaminal as expected without any epimerization (entry 5). At this stage,

further evaluation of epimerization conditions was thwarted by our limited supply of 2.87, and

unfortunately we were never able to successfully convert 2.87 to 2.2.

The difficulties encountered with this epimerization initially forced us to question the

stereochemical assignment of exiguaquinol; however, the ROESY data1 and the calculated 13C

and 1H NMR chemical shifts were more consistent with the proposed hemiaminal epimer.51

Therefore, we set out to determine the cause of this stereochemical inconsistency through computational modeling.

Table 2.5. Attempts to epimerize the hemiaminal configuration.

O O O O H OH H OH H OSiEt3

NMe NMe NMe NMe O conditions O O O Me O Me O Me O Me O

2.87 2.2 2.100 2.101 Entry Conditions Result

1 NaOH (cat), THF/H2O Decomposition 2Cs2CO3 (10 mol %), MeCN, rt 2.87 + 2.100 3 p-TsOH (cat), THF/H2O Complex mixture 4MgSO4,CH2Cl2 2.87 5 TESOTf, Et3N, CH2Cl2 2.101 (>99%)

2.6: Ground State Energy Calculations of Hemiaminal Epimers

Despite its close structural resemblance to exiguaquinol (2.1), synthetic tetracycle 2.87

appears to exist preferentially as the opposite hemiaminal conformer at C2. Since the

configuration at this center is likely under thermodynamic control, we suspected that the omitted

sulfonate or extended aromatic ring may play more of a pivotal role in epimer configuration than

initially expected. However, before synthesizing complex substrates to test these new

hypotheses, we first elected to evaluate our ideas computationally.

In collaboration with Professor Ken Houk (UCLA) and graduate student Hung Pham

(UCLA), many hydrogen-bonding conformations were modeled computationally in order to determine the lowest energy ground-state orientation for each epimer of the tetracycle and natural product. Consistent with our experimental observations, gas phase ground-state calculations on both epimeric states of the tetracyclic core revealed that the "unnatural" (S)-

epimer of the core (2.87) is more thermodynamically stable by 4.6 kcal/mol than the (R)-epimer

corresponding to the natural product configuration (2.2). As shown in Figure 2.2, the energy-

minimized conformation of 2.87, as determined computationally, is stabilized by a 1.96 Å

internal hydrogen bond between the hemiaminal hydroxyl group and the C9 indanone carbonyl.

Alternative hydrogen-bonding arrangements procured higher ground-state energy values and

likely do not contribute to the thermodynamic stability of 2.87. In addition, the energy-

minimized conformation of 2.2, also shown in Figure 2.2, benefits from a 2.17 Å internal

hydrogen bond between the hemiaminal hydroxyl group and the C4 ketone. However, the greater

distance between the hydrogen bond donor and acceptor, coupled with the poorer orbital

alignment between the two groups (O–H–O angle), contribute to the higher energy ground-state

of the (R)-epimer (2.2) and favor 2.87 thermodynamically.

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.

Unsurprisingly, ground-state calculations performed on the hemiaminal epimers of the natural product indicated that the lowest energy conformer of the natural (R)-epimer (2.1) was thermodynamically preferred over the most stable conformer of the (S)-epimer (2.102) by 2.3 kcal/mol. In both cases, the hemiaminal hydroxyl group is involved in an eight-membered ring hydrogen-bonding interaction with the sulfonate anion, presumably to partially offset the discrete

negative charge of the sulfonate. Upon initial inspection, the hydrogen bond distances appear

comparable at 1.71 Å and 1.72 Å, suggesting that a tighter hydrogen bond for one epimer is not

likely the predominant thermodynamic driving force. Instead, the preference for the natural

configuration can be plausibly explained by the anomeric stabilization present in the (R)-isomer

(2.1) that cannot be achieved by the (S)-epimer (2.102). Specifically, there appears to be better

orbital overlap between the amide π-system and the C–O σ* orbital in 2.1, thus leading to an overall lower-energy ground-state and a thermodynamic preference for 2.1 (Figure 2.2).

Alternative ground-state conformations containing hydrogen bonds to the C4 or C9 carbonyls were calculated, however, each was at least 7.5 kcal/mol higher in energy than the sulfonate- bound conformers of exiguaquinol.

Although these calculations explain our experimental observations, the fact that they were performed in the gas phase in the absence of solvent could detract from their chemical significance. It is possible that solvation and hydrogen-bonding to polar solvents may have a dramatic effect on the stability of each epimer, particularly for those of the natural product.

Regardless, the NMR studies performed on exiguaquinol by the Quinn group demonstrated that

1 only the (R)-configuration of the hemiaminal (2.1) was present in wet d6-DMSO.

2.7: Conclusions

We were able to successfully gain access to a tetracyclic model system resembling the

natural product exiguaquinol through a short sequence of 13 steps from commercially available starting materials (Scheme 2.26). These efforts validated our synthetic route, demonstrating that the key C–C bonds can be installed through a Diels–Alder cycloaddition, an aldol reaction, and a

5-exo reductive Heck cyclization.

Scheme 2.26. Overview of the exiguaquinol core synthesis.

Although our synthetic efforts yielded the C2 epimer of our original target, we now understand more about the thermodynamic preferences of the targeted N-acyl hemiaminals.

Knowing that natural exiguaquinol exists as the thermodynamically favored R-epimer, it is reasonable to propose a synthesis of exiguaquinol and epimerize, if necessary, to the natural configuration when the sulfonate group is present. This allowed us to confidently embark on a total synthesis of exiguaquinol (2.1) containing fully functionalized fragments.

2.8: Experimental Procedures

General Experimental. All reactions were carried out under an inert atmosphere of argon in

oven-dried or flame-dried glassware using Teflon® coated magnetic stir bars. Commercial reagents were used as received unless otherwise noted. Microwave reactions were performed in a

CEM Discover Microwave or an Anton Parr Monowave 300 Microwave. Reactions were

monitored by thin-layer chromatography (TLC) performed on 250 μm Dynamic Adsorbents or

60 Å EMD Millipore glass-backed TLC plates impregnated with a fluorescent dye using UV

light as a visualizing agent and KMnO4/NaOH, p-anisaldehyde or ceric ammonium molybdate and heat as developing stains. Flash chromatography was performed on Dynamic Adsorbents

(230–400 mesh) or EMD (0.040–0.063 mm) silica gel. NMR spectra were recorded on a Bruker

400, 500, or 600 MHz spectrometer and calibrated using residual non-deuterated solvent as an

internal reference. NMR spectra were obtained at 25 °C unless otherwise noted. Chemical shifts

are reported in ppm; the following abbreviations were used to explain multiplicities: s=singlet,

d=doublet, t=triplet, q=quartet, m=multiplet, br=broad signal. Coupling constants are reported in

hertz (Hz). FT-IR spectra were recorded on a Perkin-Elmer Spectrum RX1 or a Varian 640

spectrometer. High resolution mass spectra (HRMS) were recorded on a Waters LCT Premier

spectrometer using ESI-TOF (electrospray ionization-time of flight) unless otherwise noted.

Melting points (Mp) are uncorrected and were measured on a Mel-Temp II melting point

apparatus.

dl/meso-Hexa-1,5-diene-3,4-diol (2.11). To a biphasic mixture of THF (188 mL) and saturated

aqueous NH4Cl (113 mL) was added acrolein (5.00 mL, 74.8 mmol) and zinc powder (10.13 g,

154.9 mmol). The aqueous layer had become orange after 2 h and the reaction mixture was

filtered through a pad of Celite and the layers were separated. The aqueous layer was extracted

with CH2Cl2 (2 x 20 mL) and the combined organic layers were dried over MgSO4, filtered and

concentrated in vacuo to yield 2.11 as an inseparable mixture of dl- and meso-diols (2.54 g, 22.3

mmol, 60%). The crude yellow oil was used without purification.

1H and 13C NMR spectra were in complete accordance with those previously reported.5

Br 2.12

(2E,4E)-1,6-dibromohexa-2,4-diene (2.12). To a mixture of 2.11 (2.54 g, 22.3 mmol) and 48%

w/w aqueous hydrobromic acid (19 mL) was added CuCl (0.22 g, 2.2 mmol). The reaction

mixture turned dark purple and was heated to 50 °C. After 30 min, the reaction mixture was

filtered through a Buchner funnel and the dark solid was rinsed with water (5 x 20 mL). The crude product was recrystallized with hexanes to yield 2.12 as a yellow solid (1.45 g, 6.04 mmol,

27%).

1H and 13C NMR spectra were in complete accordance with those previously reported.6

PhS

PhS 2.6

(2E,4E)-1,6-bis(phenylthio)hexa-2,4-diene (2.6). To a solution of thiophenol (0.34 mL, 3.3

mmol) in THF (8 mL) was added 60 % NaH in mineral oil (0.179 g, 4.47 mmol) in one portion.

Gas was evolved and the reaction mixture became a cloudy suspension. After 10 min, a solution

of 2.12 (0.358 g, 1.49 mmol) in THF (7 mL) was added dropwise. After 2 h, the reaction mixture

was quenched with water and extracted with EtOAc (3 x 15 mL), and the combined organic

extracts were washed with brine (1 x 15 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield a faintly peach-colored solid, which was recrystallized with hexanes to afford 2.6 as a white solid (0.44 g, 1.5 mmol, 99%).

1 Mp = 102–104 °C; H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 7.3 Hz, 4H), 7.27 (t, J = 7.5, 4H),

7.19 (t, J = 7.1 Hz, 2H), 6.09–5.98 (m, 2H), 5.71–5.59 (m, 2H), 3.55 (d, J = 7.0 Hz, 4H); 13C

NMR (125 MHz, CDCl3) δ 136.0, 132.4, 130.3, 129.0, 128.7, 126.6, 36.8; IR (thin film) ν 3050,

-1 + 2910, 1435, 984, 896, 732, 692 cm ; HRMS (EI) m / z calcd for C18H18S2 (M) 298.0850, found

298.0853.

Br OH O

NMe

O 2.14

Alcohol 2.14. To a mixture of N-methylmaleimide (0.150 g, 1.35 mmol), DABCO (0.045 g, 0.41

mmol), and phenol (0.127 g, 1.35 mmol), was added 2-bromobenzaldehyde (0.19 mL, 1.6

mmol). The reaction mixture was heated to 70 °C and was orange after 30 min. After 1 h, the

purple reaction mixture was cooled to room temperature and dissolved in EtOAc (30 mL), and

washed with 1M HCl (1 x 20 mL), water (1 x 15 mL) and brine (1 x 15 mL). The combined aqueous layer was extracted with EtOAc (1 x 15 mL) and the combined organic layer was dried over MgSO4, filtered and concentrated in vacuo to yield a peach-colored oil. The oil was purified

by column chromatography (SiO2, 28:72 EtOAc:hexanes) to yield 2.14 as a colorless oil (0.16 g,

0.54 mmol, 40%).

1 H NMR (500 MHz, CDCl3) δ 7.62–7.53 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.8 Hz,

1H), 6.22 (d, J = 0.9 Hz, 1H), 6.08 (s, 1H), 3.43 (br s, 1H), 2.99 (s, 3H); 13C NMR (125 MHz,

CDCl3) δ 171.2, 170.2, 148.2, 138.4, 133.2, 130.4, 128.6, 128.3, 128.0, 122.6, 68.3, 24.0; IR

(thin film) ν 3317, 1702, 1441, 1388, 1024, 754 cm-1; HRMS (ESI) m / z calcd for

+ C13H14BrNO4Na (M + Na + CH3OH) 350.0004, found 350.0000.

endo-Bromocycloadduct 2.27 and exo-Bromocycloadduct 2.28. A solution of 2.6 (0.020 g,

0.067 mmol) and 3-bromo-N-methylmaleimide (0.013 g, 0.067 mmol) in toluene (1.4 mL) was sparged with Ar (g) and heated to reflux. After 14 h, the reaction was cooled to room temperature and concentrated to yield a brown oil, which was purified by column chromatography (SiO2, 20:80 EtOAc:hexanes) to yield an inseparable mixture of 2.27 and 2.28

as a colorless oil (0.0049 g, 0.010 mmol, 15%, endo/exo = 2.2:1).

endo-2.27: 7.45–7.06 (m, 10H), 6.27 (s, 2H), 4.36 (d, J = 13.1 Hz, 1H), 4.07–3.96 (m, 2H), 3.17

(d, J = 16.7 Hz, 1H), 3.03–2.94 (m, 2H), 2.92 (s, 3H), 2.48 (dd, J = 16.7, 9.3 Hz, 1H). exo-2.28: 7.45–7.06 (m, 10H), 6.37 (s, 2H), 4.58 (d, J = 13.7 Hz, 1H), 4.07–3.96 (m, 1H), 3.48

(d, J = 8.4 Hz, 1H), 3.17 (d, J = 16.7 Hz, 1H), 3.02 (s, 3H), 2.96–2.93 (m, 1H), 2.77 (dd, J =

13.0, 3.8 Hz, 1H), 1.97 (t, J = 12.1 Hz, 1H).

PhS H O

NMe

H O PhS 2.37

Cycloadduct 2.37. To a solution of 2.6 (0.552 g, 1.85 mmol) in toluene (19 mL) was added N-

methylmaleimide (2.8) (0.205 g, 1.85 mmol). A reflux condenser was added and the reaction

mixture was heated to reflux for 40 h. The reaction was cooled to room temperature and the

solvent was removed in vacuo to yield 2.37 as a white solid (0.708 g, 1.73 mmol, 94%). The

crude solid was used without purification.

1 Mp = 139–140 °C; H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 7.3 Hz, 4H), 7.28 (t, J = 7.6 Hz,

4H), 7.20 (t, J = 7.3 Hz, 2H), 5.88 (s, 2H), 3.60 (dd, J = 13.4, 6.9 Hz, 2H), 3.37–3.28 (m, 4H),

13 2.90 (s, 3H), 2.40 (s, 2H); C NMR (125 MHz, CDCl3) δ 177.4, 135.8, 132.3, 130.0, 129.3,

126.6, 43.7, 36.6, 35.2, 24.9; IR (thin film) ν 3053, 2926, 1769, 1694, 1582, 1480, 1438, 1383,

-1 + 1288, 740, 691 cm ; HRMS (ESI) m / z calcd for C23H23NO2S2Na (M + Na) 432.1068, found

432.1060.

PhS H O

NMe

H O PhS 2.41

Saturated Bicycle 2.41. To a solution of 2.37 (0.524 g, 1.28 mmol) in THF (12 mL) inside a

glass cylindrical vessel was added PtO2 (0.023 g, 0.10 mmol). The reaction mixture was sealed

inside a bomb reactor and pressurized to 1200 psi with H2 gas, and left to stir overnight. After 12

h, the reaction mixture was filtered through a pad of silica gel and the silica gel was rinsed with

CH2Cl2. The organic solution was concentrated in vacuo to yield a gray oil, which was purified

by column chromatography (SiO2, 20:80 EtOAc:hexanes) to afford 2.41 as a white solid (0.46 g,

1.1 mmol, 88%).

1 Mp = 98–100 °C; H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 8.0 Hz, 4H), 7.28 (t, J = 7.7 Hz,

4H), 7.19 (t, J = 7.3 Hz, 2H), 3.45 (dd, J = 13.4, 7.6 Hz, 2H), 3.30 (br s, 2H), 3.03 (dd, J = 13.4,

7.1 Hz, 2H), 2.99 (s, 3H), 2.10 (br s, 2H), 1.96–1.88 (m, 2H), 1.30–1.17 (m, 2H); 13C NMR (125

MHz, CDCl3) δ 178.2, 136.5, 129.6, 129.2, 126.4, 42.7, 36.7, 32.9, 24.8, 23.8; IR (thin film) ν

-1 2930, 1767, 1694, 1436, 1284, 739, 691 cm ; HRMS (ESI) m / z calcd for C23H25NO2S2Na (M +

Na)+ 434.1224, found 434.1218.

PhS H O

NMe

O PhS OH Br

2.42

Aldol Adduct 2.42. To a solution of anhydrous lithium chloride (0.309g, 7.30 mmol), and

diisopropylamine (0.85 mL, 6.1 mmol), in THF (25 mL) at –78 °C was added a solution of

nBuLi in hexanes (2.59 mL, 2.44 M, 6.32 mmol). The reaction mixture was stirred for 30 min

and a solution of 2.41 (1.00 g, 2.43 mmol) in THF (15 mL) was added over 5 min. The red-

orange mixture was stirred for 15 min. A solution of 2-bromobenzaldehyde (0.85 mL, 7.3 mmol)

in THF (10 mL) was added slowly over 5 min and the yellow mixture was warmed to –40 °C.

The temperature was maintained between –40 °C and –20 °C and the mixture was stirred for 2 h.

The reaction mixture was quenched with an aqueous NH4Cl solution (30 mL) and the aqueous

layer was extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over

MgSO4, filtered and concentrated in vacuo. The crude yellow oil was purified by column

chromatography (SiO2, 15:85 – 30:70 EtOAc:hexanes) to afford 2.42 as a yellow oil (1.2 g, 2.0

mmol, 84%).

1 H NMR (500 MHz, CDCl3) δ 7.49 (t, J = 9.0 Hz, 2H), 7.33–7.17 (m, 10H), 7.02 (t, J = 7.6 Hz,

1H), 6.73 (t, J = 7.5 Hz, 1H), 5.87 (d, J = 4.4 Hz, 1H), 3.88 (dd, J = 12.7, 1.7 Hz, 1H), 3.86 (d, J

= 3.0 Hz, 1H), 3.65 (dd, J = 13.7, 8.9 Hz, 1H), 3.17 (dd, J = 13.7, 5.4 Hz, 1H), 3.03 (s, 3H), 2.65

(d, J = 4.4 Hz, 1H), 2.60 (t, J = 12.1 Hz, 1H), 2.11–2.04 (m, 1H), 1.80–1.68 (m, 2H), 1.66 (t, J =

13 11.9 Hz, 1H), 1.43–1.31 (m, 1H), 1.07–0.99 (m, 1H); C NMR (125 MHz, CDCl3) δ 179.3,

178.5, 138.1, 137.1, 137.0, 133.5, 130.3, 129.44, 129.36, 129.3, 129.1, 128.4, 128.1, 126.2,

125.8, 124.2, 71.9, 58.5, 41.9, 37.0, 36.6, 36.2, 32.5, 25.1, 24.7, 23.9; IR (thin film) ν 3440,

-1 2936, 1766, 1690 1438, 738, 691 cm ; HRMS (ESI) m / z calcd for C30H30BrNO3S2Na (M +

Na)+ 618.0748, found 618.0728.

PhS H O

NMe

O PhS OH I

2.44

Aldol Adduct 2.44 To a solution of anhydrous lithium chloride (0.062 g, 1.5 mmol) and

diisopropylamine (0.17 mL, 1.2 mmol) in THF (5 mL) at –78 °C was added a solution of nBuLi

in hexanes (0.49 mL, 2.56 M, 1.3 mmol). The reaction mixture was stirred for 30 min and a

solution of 2.41 (0.200 g, 0.486 mmol) in THF (3 mL) was added. The red-orange mixture was

stirred for 15 min. A solution of 2-iodobenzaldehyde (0.338 g, 1.46 mmol) in THF (2 mL) was

added over 5 min and the yellow reaction mixture was warmed to –40 °C. The temperature was

maintained between –40 °C and –20 °C and the mixture was stirred for 1 h. The light pink

reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and the aqueous layer

was extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude yellow oil was purified by column chromatography (SiO2, 15:85 – 20:80 EtOAc:hexanes) to afford 2.44 as a yellow oil (0.24 g,

0.37 mmol, 76%).

1 H NMR (500 MHz, CDCl3) δ 7.79 (dd, J = 7.9, 1.1 Hz, 1H), 7.37 (dd, J = 7.8, 1.0 Hz, 1H), 7.30

(d, J = 4.4 Hz, 4H), 7.24–7.17 (m, 5H), 7.13 (t, J = 6.8 Hz, 1H), 6.87 (td, J = 7.6, 1.6 Hz, 1H),

6.73 (t, J = 7.5 Hz, 1H), 5.66 (d, J = 4.6 Hz, 1H), 3.86 (dd, J = 12.9, 2.0 Hz, 1H), 3.83 (d, J = 3.8

Hz, 1H), 3.66 (dd, J = 13.8, 9.1 Hz, 1H), 3.20 (dd, J = 13.8, 5.9 Hz, 1H), 3.04 (s, 3H), 2.65 (d, J

= 4.8 Hz, 1H), 2.64 (t, J = 12.0 Hz, 1H), 2.13–2.04 (m, 1H), 1.94–1.85 (m, 1H), 1.83–1.73 (m,

1H), 1.66 (t, J = 12.0 Hz, 1H), 1.37 (q, J = 12.0 Hz, 1H), 1.13–1.01 (m, 1H); 13C NMR (125

MHz, CDCl3) δ 179.3, 178.2, 141.0, 140.4, 136.8, 136.5, 130.6, 129.23, 129.18, 129.1, 128.9,

128.4, 128.2, 126.0, 125.7, 100.5, 77.6, 58.3, 42.2, 36.54, 36.49, 36.0, 32.7, 24.9, 24.4, 23.7; IR

(thin film) ν 3370, 3055, 2932, 1765, 1692, 1438, 1291, 738, 690 cm-1; HRMS (ESI) m / z calcd

+ for C30H30INO3S2Na (M + Na) 666.0610, found 666.0596.

Maleimide 2.45. To a solution of 2.41 (0.020 g, 0.049 mmol) in THF (0.44 mL) at –78 °C was

added a solution of LDA in THF (0.058 mL, 1.0 M, 0.058 mmol), and the reaction mixture

turned yellow then red. After stirring for 30 min, 2-bromobenzaldehyde (0.01 mL, 0.09 mmol)

was added and the reaction mixture became yellow, and was warmed to –40 °C. The temperature

was maintained between –40 °C and –20 °C for 1 h. The reaction mixture was quenched with

water (5 mL) and the aqueous layer was extracted with EtOAc (3 x 5 mL). The combined

organic extracts were dried over MgSO4, filtered and concentrated in vacuo to yield a yellow oil,

which was purified by column chromatography (SiO2, 10:90 EtOAc:hexanes) to afford 2.45 as a

yellow solid (0.004 g, 0.01 mmol, 20%).

1 H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 7.7 Hz, 4H), 7.30 (t, J = 7.6 Hz, 4H), 7.19 (t, J = 7.3

Hz, 2H), 3.56 (dd, J = 13.4, 2.7 Hz, 2H), 3.03 (dd, J = 13.4, 9.3 Hz, 2H), 2.90 (s, 3H), 2.88–2.81

13 (m, 2H), 2.02–1.93 (m, 2H), 1.83–1.74 (m, 2H); C NMR (125 MHz, CDCl3) δ 170.4, 143.8,

135.8, 129.6, 129.2, 126.4, 35.9, 31.9, 23.8, 23.6; IR (thin film) ν 2920, 2850, 1767, 1698, 1439,

-1 + 1383, 990, 739, 691 cm ; HRMS (ESI) m / z calcd for C23H23NO2S2Na (M + Na) 432.1068,

found 432.1064.

PhS H O

NMe

O PhS OSiEt3 Br

2.103

Silyl Protected Alcohol 2.103. To a solution of 2.42 (0.100 g, 0.168 mmol) in CH2Cl2 (6 mL) was added Et3N (0.07 mL, 0.5 mmol) followed by TESOTf (0.11 mL, 0.503 mmol). After 30

min, water (10 mL) was added and the aqueous layer was extracted with CH2Cl2 (2 x 10 mL).

The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to yield a colorless oil, which was purified by column chromatography (SiO2, 5:95 EtOAc:hexanes) to afford 2.103 as a colorless oil (0.09 g, 0.1 mmol, 73%).

1 H NMR (500 MHz, CDCl3) δ 7.47 (dd, J = 12.0, 8.0 Hz, 2H), 7.31–7.26 (m, 6H), 7.23 (t, J =

7.6 Hz, 2H), 7.21–7.17 (m, 1H), 7.14 (t, J = 7.3 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 6.63 (t, J = 7.6

Hz, 1H), 5.85 (s, 1H), 4.10 (br s, 1H), 3.99 (dd, J = 12.5, 1.7 Hz, 1H), 3.72 (dd, J = 13.8, 9.0 Hz,

1H), 3.16 (dd, J = 13.8, 4.9 Hz, 1H), 3.00 (s, 3H), 2.57 (t, J = 12.0 Hz, 1H), 2.09–2.00 (m, 1H),

1.75–1.64 (m, 2H), 1.45–1.30 (m, 2H), 1.00–0.90 (m, 1H), 0.75 (t, J = 8.0 Hz, 9H), 0.49–0.34

13 (m, 6H); C NMR (125 MHz, CDCl3) δ 179.1, 178.8, 138.6, 137.30, 137.29, 133.3, 130.11,

130.06, 129.4, 129.3, 129.0, 128.0, 127.9, 126.0, 125.7, 123.8, 72.3, 59.7, 41.4, 37.3, 36.3, 35.9,

32.8, 24.87, 24.86, 24.2, 6.7, 4.7; IR (thin film) ν 2952, 1769, 1698, 1435, 1290, 1088, 737, 690

-1 + cm ; HRMS (ESI) m / z calcd for C36H44BrNO3S2SiNa (M + Na) 732.1613, found 732.1610.

O PhS H O

NMe

O PhS OSiEt3 Br O

2.52

Bis(sulfoxide) 2.52. To a solution of 2.103 (0.029 g, 0.041 mmol) in CH2Cl2 (0.5 mL) at –78 °C

was added a solution of mCPBA (0.015 g, 0.085 mmol) in CH2Cl2 (0.5 mL). After 2 h, a 10 %

w/v Na2SO3 solution (5 mL) was added and the aqueous layer was extracted with CH2Cl2 (2 x 10 mL). The combined organic extracts were washed with water (1 x 10 mL) and brine (1 x 10 mL), and the organic phase was dried over MgSO4, filtered and concentrated in vacuo to yield 2.52 as

a white solid (0.027 g, 0.036 mmol, 30%). Compound 2.52 was isolated as a complex mixture of

four sulfoxide diastereomers and used without purification.

1H NMR and 13C NMR spectra were complicated by the existence of sulfoxide diastereomers; IR

(thin film) ν 2952, 2875, 1769, 1698, 1435, 1292, 1086, 1044, 747 cm-1; HRMS (ESI) m / z calcd

+ for C36H44BrNO5S2SiNa (M + Na) 764.1511, found 764.1528.

H O

NMe

O OSiEt3 Br

2.53

Diene 2.53. To a solution of 2.52 (10 mg, 0.013 mmol) in xylenes (1 mL) was added Et3N (0.02 mL, 0.1 mmol) and the reaction mixture was sealed in a microwave tube. The reaction mixture

was heated by microwave irradiation to 180 °C for 1 h. The brown solution was concentrated in

vacuo and the remaining brown residue was purified by column chromatography (SiO2, 5:95 –

10:90 EtOAc:hexanes) to yield 2.53 as a colorless oil (4 mg, 0.008 mmol, 58%).

1 H NMR (500 MHz, CDCl3) δ 7.51 (dd, J = 7.8, 1.5 Hz, 1H), 7.45 (dd, J = 8.0, 1.0 Hz, 1H), 7.21

(t, J = 7.4 Hz, 1H), 7.10 (td, J = 7.9, 1.7 Hz, 1H), 5.97 (s, 1H), 5.65 (s, 1H), 5.14 (s, 1H), 5.10 (t,

J = 1.6 Hz, 1H), 5.06 (d, J = 1.7 Hz, 1H), 4.37 (s, 1H), 3.03 (s, 3H), 2.13–2.07 (m, 1H), 1.99 (dt,

J = 13.9, 3.3 Hz, 1H), 1.81 (t, J = 14.0 Hz, 1H), 0.82–0.74 (m, 10H), 0.56–0.41 (m, 6H); 13C

NMR (125 MHz, CDCl3) δ 178.2, 176.8, 140.2, 139.8, 138.2, 132.9, 131.2, 129.9, 127.1, 123.6,

117.9, 116.4, 73.3, 59.7, 48.1, 33.7, 32.9, 25.7, 6.7, 4.7; IR (thin film) ν 2952, 1776, 1706, 1434,

-1 + 1380, 1080, 1009, 732 cm ; HRMS (ESI) m / z calcd for C24H32BrNO3SiNa (M + Na)

512.1232, found 512.1215.

H O

NMe OSiEt3 H O

2.54

6-endo Tetracycle 2.54. To a refluxing solution of 2.53 (2 mg, 0.004 mmol) in benzene (1 mL)

was added a solution of AIBN (0.3 mg, 0.002 mmol) and Bu3SnH (0.002 mL, 0.008 mmol) in benzene (0.2 mL). After 8 h, the reaction mixture was concentrated in vacuo to yield a colorless oil, which was purified by column chromatography (SiO2, 5:95 EtOAc:hexanes) to afford 2.54 as

a colorless oil (0.001 g, 0.003 mmol, 85%).

1 H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 7.4 Hz, 1H), 7.22 (t, 7.3 Hz, 1H), 7.18 (t, J = 7.3 Hz,

1H), 7.05 (d, J = 7.0 Hz, 1H), 5.14 (s, 1H), 4.64 (s, 1H), 4.59 (s, 1H), 3.24 (s, 1H), 3.06 (dd, J =

16.0, 9.6 Hz, 1H), 3.05 (s, 3H), 2.83 (dq, J = 9.1, 4.5 Hz, 1H), 2.60 (dd, J = 16.1, 4.0 Hz, 1H),

2.12 (t, J = 7.1 Hz, 2H), 1.63–1.57 (m, 1H), 1.50–1.42 (m, 1H), 0.94 (t, J = 7.9 Hz, 9H), 0.74–

13 0.58 (m, 6H); C NMR (125 MHz, CDCl3) δ 182.3, 178.2, 138.9, 138.0, 136.6, 127.5, 127.4,

126.1, 124.5, 115.2, 72.9, 56.0, 47.9, 33.5, 32.4, 27.6, 26.0, 25.6, 7.0, 5.1; IR (thin film) ν 2918,

-1 1774, 1703, 1433, 1288, 1008, 779, 742 cm ; HRMS (ESI) m / z calcd for C24H33NO3SiNa (M +

Na)+ 434.2127, found 434.2134.

Me O

NMe

OSiEt3 Me O

2.67

Epimerized 5-exo Tetracycle 2.67. To a dry test tube with a stirbar was added 2.53 (0.0018 g,

0.0037 mmol), Pd(PPh3)4 (0.0004 g, 0.0004 mmol), and sodium formate (0.0002 g, 0.004 mmol) under Ar (g). The mixture was evacuated and backfilled with Ar (g) and DMF (1 mL) was added. The reaction mixture was heated to 100 °C for 39 h. The brown solution was cooled to

® room temperature and filtered through Celite . H2O (5 mL) was added and the suspension was

extracted with 10% EtOAc/hexanes (3 x 5 mL). The organic phases were combined, dried over

MgSO4, filtered, and concentrated to yield a brown oil, which was purified by column

chromatography (SiO2, 5:95 EtOAc:hexanes) to afford 2.67 as a colorless residue (0.80 g, 0.0019

mmol, 54%).

1 H NMR (500 MHz, CDCl3) δ 7.35 (t, J = 7.3 Hz, 1H), 7.31–7.20 (m, 3H), 4.98 (s, 1H), 2.98 (s,

3H), 2.33 (s, 3H), 2.32–2.26 (m, 1H), 2.23–2.12 (m, 2H), 1.60–1.57 (m, 1H), 1.25 (s, 3H), 0.89

(t, J = 8.0 Hz, 9H), 0.56 (q, J = 8.0 Hz, 6H); Insufficient sample present to obtain a 13C NMR

+ spectrum; LRMS (ESI) m / z calcd for C24H33NO3SiNa (M + Na) 434.2127, found 434.20.

Silyl Protected Alcohol 2.104. To a solution of 2.44 (0.332 g, 0.516 mmol) in CH2Cl2 (18 mL)

was added Et3N (0.22 mL, 1.6 mmol) followed by TESOTf (0.35 mL, 1.6 mmol). After 30 min,

water (20 mL) was added and the aqueous layer was extracted with CH2Cl2 (2 x 20 mL). The

combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to yield a

colorless oil, which was purified by column chromatography (SiO2, 10:90 EtOAc:hexanes) to

afford 2.104 as a colorless oil (0.30 g, 0.40 mmol, 77%).

1 H NMR (500 MHz, CDCl3) δ 7.76 (dd, J = 7.9, 1.1 Hz, 1H), 7.41 (dd, J = 7.9, 1.4 Hz, 1H),

7.34–7.29 (m, 4H), 7.29–7.26 (m, 2H), 7.21 (t, J = 7.6 Hz, 3H), 7.13 (t, J = 7.3 Hz, 1H), 6.82 (td,

J = 7.6, 1.6 Hz, 1H), 6.64 (t, J = 7.6 Hz, 1H), 5.65 (s, 1H), 4.14 (d, J = 3.5 Hz, 1H), 4.04 (dd, J =

12.5, 1.7 Hz, 1H), 3.75 (dd, J = 13.8, 9.5 Hz, 1H), 3.18 (dd, J = 13.8, 5.3 Hz, 1H), 3.00 (s, 3H),

2.56 (t, J = 11.9 Hz, 1H), 2.06–1.96 (m, 1H), 1.84–1.74 (m, 1H), 1.74–1.64 (m, 1H), 1.43–1.30

(m, 2H), 1.04–0.96 (m, 1H), 0.75 (t, J = 7.9 Hz, 9H), 0.51–0.36 (m, 6H); 13C NMR (125 MHz,

CDCl3) δ 179.1, 178.9, 141.7, 140.4, 137.3, 137.2, 130.5, 129.6, 129.34, 129.30, 129.0, 128.8,

128.0, 126.0, 125.7, 100.0, 60.2, 53.6, 41.4, 37.5, 36.1, 36.0, 33.1, 24.9, 24.8, 24.4, 6.7, 4.9; IR

(thin film) ν 2950, 2874, 1769, 1698, 1436, 1084, 1008, 737 cm-1; HRMS (ESI) m / z calcd for

+ C36H44INO3S2SiNa (M + Na) 780.1475, found 780.1472.

Bis(sulfoxide) 2.68. To a solution of 2.104 (0.302 g, 0.399 mmol) in CH2Cl2 (4 mL) at –78 °C

was added a solution of mCPBA (0.145 g, 0.840 mmol) in CH2Cl2 (4 mL). After 2 h, a 10 % w/v

Na2SO3 solution (15 mL) was added and the aqueous layer was extracted with CH2Cl2 (2 x 15 mL). The combined organic extracts were washed with water (1 x 15 mL) and brine (1 x 15 mL), and the organic phase was dried over MgSO4, filtered and concentrated in vacuo to yield 2.68 as

a white solid (0.285 g, 0.361, 90%). Compound 2.68 was isolated as a complex mixture of four

sulfoxide diastereomers and used without purification.

1H NMR and 13C NMR spectra were complicated by the existence of sulfoxide diastereomers; IR

(thin film) ν 3057, 2953, 2874, 1769, 1698, 1442, 1292, 1086, 1043, 732 cm-1; HRMS (ESI) m /

+ z calcd for C36H44INO5S2SiNa (M + Na) 812.1373, found 812.1380.

H O

NMe

O OSiEt3 I

2.69

Diene 2.69. To a solution of crude 2.68 (0.037 g, 0.047 mmol) in o-dichlorobenzene (1 mL) was added Et3N (0.06 mL, 0.5 mmol) and the reaction mixture was sealed in a microwave tube. The

reaction mixture was heated by microwave irradiation to 210 °C for 2 h. The brown solution was

concentrated in vacuo with heating and the remaining brown residue was purified by column chromatography (SiO2, 5:95 EtOAc:hexanes) to yield 2.69 as a colorless oil (0.01 g, 0.02 mmol,

50%).

1 H NMR (500 MHz, CDCl3) δ 7.75 (dd, J = 7.9, 0.7 Hz, 1H), 7.46 (dd, J = 7.8, 1.4 Hz, 1H), 7.24

(t, J = 7.5 Hz, 1H), 6.93 (td, J = 7.6, 1.5 Hz, 1H), 5.79 (s, 1H), 5.70 (s, 1H), 5.14 (s, 1H), 5.11 (s,

1H), 5.08 (s, 1H), 4.38 (s, 1H), 3.03 (s, 3H), 2.10 (dt, J = 13.6, 3.1 Hz, 1H), 1.96 (dt, J =13.7, 3.4

Hz, 1H), 1.80 (t, J = 14.0, 1H), 0.79 (t, J = 8.0 Hz, 9H), 0.75–0.69 (m, 1H), 0.57–0.42 (m, 6H);

13 C NMR (125 MHz, CDCl3) δ 178.2, 176.8, 142.7, 140.2, 139.9, 137.9, 130.7, 130.2, 127.9,

118.8, 116.5, 100.1, 77.2, 59.9, 48.1, 33.7, 33.0, 25.7, 6.8, 4.9; IR (thin film) ν 2951, 2874, 1775,

-1 + 1706, 1433, 1380, 1079, 1010, 729 cm ; HRMS (ESI) m / z calcd for C24H33NO3SiNa (M + Na)

560.1094, found 560.1071.

H O

NMe

OSiEt3 Me O

2.70

5-exo Tetracycle 2.70. To a heterogeneous mixture of 2.69 (0.025 g, 0.047 mmol), sodium

formate (0.005 g, 0.07 mmol), tricyclohexylphosphine (0.010 g, 0.035 mmol), and palladium (II)

acetate (0.003 g, 0.01 mmol) was added DMF (6 mL). After 72 h, the brown reaction mixture

was passed through a pad of Celite® and water (10 mL) and 10:90 EtOAc:hexanes (10 mL) were

added. The aqueous phase was extracted with 10:90 EtOAc:hexanes (3 x 10 mL) and the

combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to yield a

yellow oil, which was purified by column chromatography (SiO2, 5:95 EtOAc:hexanes) to afford

2.70 as a colorless oil (0.006 g, 0.02 mmol, 33%).

1 H NMR (500 MHz, CDCl3) δ 7.31–7.19 (m, 3H), 7.02 (d, J = 6.2 Hz, 1H), 5.84 (s, 1H), 4.73 (s,

1H), 4.71 (s, 1H), 3.89 (s, 1H), 3.06 (s, 3H), 2.40 (ddd, J = 16.2, 7.3, 2.1 Hz, 1H), 2.23–2.10 (m,

1H), 2.06 (ddd, J = 14.6, 7.2, 2.2, 1H), 1.61 (ddd, J = 14.7, 11.1, 7.3 Hz, 1H), 1.25 (s, 3H), 0.96

13 (t, J = 8.0 Hz, 9H), 0.74–0.61 (m, 6H); C NMR (125 MHz, CDCl3) δ 178.5, 177.6, 145.3,

142.5, 138.0, 128.5, 127.6, 123.9, 122.1, 116.4, 76.6, 66.0, 48.3, 47.9, 31.5, 27.4, 26.3, 25.2, 7.0,

5.1; IR (thin film) ν 2878, 1776, 1704, 1434, 1378, 1125, 1005, 842, 748 cm-1; HRMS (ESI) m /

+ z calcd for C24H33NO3SiNa (M + Na) 434.2127, found 434.2133.

Ketone 2.71. To a slurry of Dess–Martin periodinane (0.294 g, 0.693 mmol) in CH2Cl2 (10 mL) at –78 °C was added a solution of 2.44 (0.138 g, 0.214 mmol) in CH2Cl2 (4 mL). After 5 h,

aqueous solutions of Na2S2O3 (10 mL) and NaHCO3 (5 mL) were added and the aqueous phase

was extracted with CH2Cl2 (2 x 10 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to yield 2.71 as a white solid, which was used without purification (0.152 g, >100%).

1 H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.7 Hz, 4H), 7.31–7.26 (m,

4H), 7.25–7.16 (m, 3H), 7.12 (d, J = 7.7, 1.4 Hz, 1H), 7.08 (td, J = 7.7, 1.6 Hz, 1H), 3.61 (d, J =

3.9 Hz, 1H), 3.57–3.49 (m, 1H), 3.45 (dd, J = 13.7, 7.5 Hz, 1H), 3.22 (dd, J = 13.7, 7.4 Hz, 1H),

3.00 (s, 3H), 2.70–2.60 (m, 2H), 2.28–2.18 (m, 2H), 2.04–1.95 (m, 1H), 1.43–1.32 (m, 1H),

13 1.15–1.03 (m, 1H); C NMR (125 MHz, CDCl3) δ 200.5, 176.6, 174.8, 143.5, 140.6, 136.0,

135.8, 131.8, 130.6, 129.9, 129.3, 129.2, 128.1, 126.8, 126.6, 126.4, 93.0, 65.4, 47.6, 37.6, 36.8,

36.0, 32.6, 25.4, 23.9, 22.8; IR (thin film) ν 2928, 1771, 1698, 1582, 1436, 1286, 738, 691 cm-1;

+ HRMS (ESI) m / z calcd for C30H28INO3S2Na (M + Na) 664.0453, found 664.0433.

O PhS H O

NMe

O PhS O I O

2.105

Bis(sulfoxide) 2.105. To a solution of 2.71 (0.152 g, 0.236 mmol) in CH2Cl2 (2 mL) at –78 °C

was added a solution of mCPBA (0.086 g, 0.498 mmol) in CH2Cl2 (2 mL). After 2 h, a 10 % w/v

Na2SO3 solution (5 mL) was added and the aqueous layer was extracted with CH2Cl2 (2 x 5 mL).

The combined organic extracts were washed with water (1 x 5 mL) and brine (1 x 5 mL), and the organic phase was dried over MgSO4, filtered and concentrated in vacuo to yield 2.105 as a

white solid (0.122 g, 0.181 mmol, 78%). Compound 2.105 was isolated as a complex mixture of

four sulfoxide diastereomers and used without purification.

1H NMR and 13C NMR spectra were complicated by the existence of sulfoxide diastereomers; IR

(thin film) ν 2929, 1773, 1702, 1582, 1436, 1286, 738, 691 cm-1; HRMS (ESI) m / z calcd for

+ C30H28INO5S2Na (M + Na) 696.0352, found 696.0350.

Diene 2.72. A solution of 2.105 (0.092 g, 0.14 mmol) in xylenes (3 mL) was sealed in a

microwave tube. The reaction mixture was heated by microwave irradiation to 180 °C for 1 h.

The brown solution was concentrated in vacuo and the remaining brown residue was purified by

column chromatography (SiO2, 5:95 – 10:90 EtOAc:hexanes) to yield 2.72 as a white solid

(0.019 g, 0.045 mmol, 33%).

1 H NMR (500 MHz, CDCl3) δ 7.85 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 7.7, 1.4 Hz, 1H), 7.37 (t, J

= 7.5 Hz, 1H), 7.12 (td, J = 7.9, 1.5 Hz, 1H), 5.37 (s, 1H), 5.26 (s, 1H), 5.21 (s, 1H), 5.18 (s, 1H),

4.38 (s, 1H), 3.06 (s, 3H), 2.54–2.48 (m, 1H), 2.40–2.34 (m, 1H), 2.21–2.05 (m, 2H); 13C NMR

(125 MHz, CDCl3) δ 199.8, 174.8, 174.0, 142.9, 140.2, 139.9, 137.2, 131.5, 128.3, 127.3, 118.0,

117.8, 91.7, 54.2, 34.0, 33.4, 29.9, 25.9; IR (thin film) ν 2926, 1779, 1708, 1430, 1377, 1010,

-1 + 815, 760 cm ; HRMS (ESI) m / z calcd for C18H16INO3Na (M + Na) 444.0073, found 444.0073.

Epimerized Diene 2.73 and Epimerized 5-exo Tetracycle 2.74. To a heterogeneous mixture of

2.72 (0.9 mg, 0.002 mmol), sodium formate (0.2 mg, 0.003 mmol), tricyclohexylphosphine (0.2

mg, 0.0006 mmol), and palladium(II) acetate (0.1 mg, 0.0004 mmol) was added DMF (1 mL).

After 24 h, the reaction mixture was passed through a pad of Celite® and water (3 mL) and 10:90

EtOAc:hexanes (3 mL) were added. The aqueous phase was extracted with 10:90

EtOAc:hexanes (3 x 3 mL) and the combined organic extracts were dried over MgSO4, filtered

and concentrated in vacuo to yield a yellow oil, which was purified by column chromatography

(SiO2, 7:93 – 10:90 EtOAc:hexanes) to afford 2.73 and 2.74 as a colorless residues (<1 mg each).

1 2.73: H NMR (600 MHz, CDCl3) δ 7.85 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.34 (t, J

= 7.7 Hz, 1H), 7.10 (t, J = 8.0 Hz, 1H), 5.70 (s, 1H), 5.22 (s, 1H), 3.01 (s, 3H), 2.60–2.52 (m,

1H), 2.47–2.40 (m, 1H), 2.40–2.33 (m, 1H), 2.33–2.28 (m, 1H), 2.31 (s, 3H); Insufficient sample

present to obtain a 13C NMR spectrum; IR (thin film) ν 2917, 2848, 1756, 1698, 1428, 1374,

-1 + 1269, 1017, 760 cm ; HRMS (ESI) m / z calcd for C18H16INO3Na (M + Na) 444.0073, found

444.0074.

1 2.74: H NMR (600 MHz, CDCl3) δ 7.73 (dd, J = 13.0, 7.1 Hz, 2H), 7.59 (d, J = 7.8 Hz, 1H),

7.43 (t, J = 7.5 Hz, 1H), 3.08 (s, 3H), 2.36 (s, 3H), 1.98–1.91 (m, 2H), 1.69–1.64 (m, 2H), 1.62

(s, 3H); Insufficient sample present to obtain a 13C NMR spectrum; IR (thin film) ν 2917, 2849,

-1 1758, 1697, 1464, 1376, 1281, 1010, 769 cm ; HRMS (ESI) m / z calcd for C18H17NO3Na (M +

Na)+ 318.1106, found 318.1104.

H O

NMe O Me O

2.3

Ketone 2.3. To a solution of 2.70 (0.013 g, 0.032 mmol) in DMSO (3.2 mL) was added IBX

(0.089 g, 0.318 mmol) and acetic acid (0.63 mL, 1.0 M) at room temperature. After 16 h, the

reaction mixture was partitioned between H2O (10 mL) and Et2O (10 mL) and the aqueous layer

was further extracted with Et2O (1 x 10 mL). The combined organic extracts were dried over

MgSO4, filtered and concentrated in vacuo to yield a colorless oil, which was purified by column

chromatography (SiO2, 20:80 EtOAc:hexanes) to afford 2.3 as a colorless oil (0.007 g, 0.025

mmol, 79%).

1 H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 7.5 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.49 (d, J = 7.6

Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 5.15 (s, 2H), 4.09 (s, 1H), 3.02 (s, 3H), 2.37–2.27 (m, 2H),

13 1.95 (dt, J = 14.0, 4.0 Hz, 1H), 1.50 (s, 3H), 1.38–1.30 (m, 1H); C NMR (125 MHz, CDCl3) δ

200.1, 176.2, 174.8, 161.9, 137.1, 136.4, 133.4, 128.5, 125.1, 123.3, 116.6, 67.6, 49.0, 44.9, 41.3,

28.6, 25.6, 19.8; IR (thin film) ν 2933, 1778, 1718, 1699, 1604, 1288, 1008, 767 cm-1; HRMS

+ (ESI) m / z calcd for C18H17NO3Na (M + Na) 318.1106, found 318.1100.

H O

NMe OH Me OH

2.80

Diol 2.80. To a solution of 2.3 (0.007 g, 0.025 mmol) in THF (2.0 mL) was added a solution of

LiBH4 in THF (0.03 mL, 2.0 M) at room temperature. After 3 h, the reaction mixture was

quenched with an aqueous solution of NH4Cl (5 mL) and extracted with 10:90 EtOAc:hexanes (2

x 5 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated in

vacuo to yield a white solid, which was purified by column chromatography (SiO2, 90:10

EtOAc:hexanes) to afford 2.80 as a white solid (0.002 g, 0.008 mmol, 32%).

1 H NMR (500 MHz, CDCl3) δ 7.40 (appar t, J = 7.3 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 7.23 (d, J

= 7.7 Hz, 1H), 5.41 (d, J = 11.8 Hz, 1H), 4.98 (s, 1H), 4.93 (s, 1H), 4.44 (d, J = 4.3 Hz, 1H), 3.07

(s, 3H), 2.40–2.32 (m, 2H), 2.26 (dt, J = 13.0, 3.1 Hz, 1H), 2.12 (d, J = 11.8 Hz, 1H), 1.98 (td, J

= 14.0, 3.8 Hz, 1H), 1.80 (d, J = 4.8 Hz, 1H), 1.74 (td, J = 13.5, 3.8 Hz, 1H), 1.53 (s, 3H); 13C

NMR (125 MHz, CDCl3) δ 174.3, 151.0, 147.0, 141.0, 130.2, 128.0, 126.3, 122.2, 109.5, 88.2,

81.9, 58.7, 51.9, 47.4, 37.4, 31.8, 29.4, 27.8; IR (thin film) ν 3366, 2928, 2857, 1672, 1479,

-1 + 1030, 907, 762 cm ; HRMS (ESI) m / z calcd for C18H21NO3Na (M + Na) 322.1419, found

322.1424.

H OH

NMe

O OSiEt3 I

2.84

Hemiaminal 2.84. To a solution of 2.69 (0.300 g, 0.558 mmol) in THF (55 mL) was added a

solution of LiBH4 in THF (1.67 mL, 2.0 M, 3.347 mmol). The colorless reaction mixture was left

to stir at room temperature for 5 days. The reaction mixture was quenched with an aqueous

NH4Cl solution (50 mL) and water (10 mL) and extracted with 50% EtOAc in hexanes (3 x 20

mL). The organic extracts were combined, dried with MgSO4, filtered, and concentrated to yield

2.84 as a white solid (0.283 g, 0.525 mmol, 94%).

1 Mp = 148–151 °C; H NMR (500 MHz, CDCl3) δ 7.73 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 7.7, 1.4

Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.89 (td, J = 7.8, 1.5 Hz, 1H), 5.65 (s, 1H), 5.64 (s, 1H), 5.03

(s, 1H), 5.00 (s, 1H), 4.86 (s, 1H), 4.67 (dd, J = 8.8, 6.0 Hz, 1H), 3.45 (d, J = 6.0, 1H), 2.88 (s,

3H), 2.29 (d, J = 8.8 Hz, 1H), 2.12–2.04 (m, 1H), 2.00–1.92 (m, 1H), 1.92–1.85 (m, 1H), 0.82 (t,

13 J = 7.9 Hz, 9H), 0.77–0.71 (m, 1H), 0.61–0.41 (m, 6H); C NMR (125 MHz, CDCl3) δ 173.1,

144.0, 143.7, 139.7, 139.6, 131.2, 129.7, 127.6, 118.4, 113.2, 100.0, 85.3, 77.6, 59.8, 50.6, 33.4,

32.8, 27.1, 6.9, 4.9; IR (thin film) ν 3362, 2951, 2874, 1666, 1462, 1398, 1078, 1009, 729 cm-1;

+ HRMS (ESI) m / z calcd for C24H34INO3SiNa (M + Na) 562.1251, found 562.1250.

5-exo Tetracycle 2.85. To a mixture of 2.84 (0.283 g, 0.525 mmol), Pd(PtBu3)2 (0.080 g, 0.158

mmol) and HCO2Na (0.046 g, 0.683 mmol) was added DMF (60 mL). The brown reaction

mixture was stirred for 16 h at room temperature, and was filtered through a plug of Celite® and rinsed with 20% EtOAc in hexanes. The organic filtrate was washed with water (20 mL) and brine (20 mL) and the aqueous layer was extracted with 20% EtOAc in hexanes (5 x 20 mL).

The combined organic extracts were washed with brine (20 mL), dried with MgSO4, filtered, and

concentrated to yield the tetracycle as a brown oil, which was purified by column

chromatography (SiO2, 15:85 – 30:70 EtOAc:hexanes) to afford 2.85 as a white solid (0.158 g,

0.382 mmol, 73%).

1 Mp = 181–183 °C; H NMR (500 MHz, CDCl3) δ 7.25–7.18 (m, 3H), 7.04–7.00 (m, 1H), 5.55 (s,

1H), 4.91 (dd, J = 8.8, 5.3 Hz, 1H), 4.75 (s, 1H), 4.65 (s, 1H), 3.00 (d, J = 5.3 Hz, 1H), 2.89 (s,

3H), 2.47 (d, J = 8.8 Hz, 1H), 2.38–2.29 (m, 1H), 2.24–2.16 (m, 1H), 2.06–1.98 (m, 1H), 1.64

(ddd, J = 14.6, 9.2, 6.1 Hz, 1H), 1.25 (s, 3H), 0.97 (t, J = 8.1 Hz, 9H), 0.69 (q, J = 8.1 Hz, 6H);

13 C NMR (125 MHz, CDCl3) δ 174.0, 147.6, 143.1, 142.2, 128.3, 127.1, 124.1, 122.0, 112.8,

85.9, 78.0, 64.6, 51.2, 47.3, 34.7, 27.2, 26.7, 25.3, 7.1, 5.3; IR (thin film) ν 3210, 2957, 2876,

1653, 1460, 1396, 1348, 1206, 1123, 1101, 1005, 914, 845, 750 cm-1; HRMS (ESI) m / z calcd

+ for C24H35NO3SiNa (M + Na) 436.2284, found 436.2291.

H OH

NMe OH Me O

2.106

Diol 2.106. To a solution of 2.85 (0.010 g, 0.024 mmol) in THF (5 mL) was added a solution of

TBAF in THF (0.03 mL, 1.0 M, 0.029 mmol). After 5 h, brine (30 mL) and water (10 mL) were

added followed by 50% EtOAc in hexanes (20 mL). The aqueous layer was extracted with 50%

EtOAc in hexanes (2 x 20 mL) and EtOAc (20 mL), and the organic extracts were washed with

brine (20 mL). The organic layer was dried with MgSO4, filtered, and concentrated to yield a

white solid, which was purified by column chromatography (SiO2, 80:20 EtOAc:hexanes) to

afford 2.106 as a white solid (0.0061 g, 0.020 mmol, 85%).

1 Mp = 178–182 °C; H NMR (400 MHz, (CD3)2CO) δ 7.30 (d, J = 7.2 Hz, 1H), 7.21 (t, J = 7.4

Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 5.32 (d, J = 5.9 Hz, 1H), 5.27 (d, J =

7.6 Hz, 1H), 4.98 (dd, J = 7.5, 6.4 Hz, 1H), 4.76 (s, 1H), 4.61 (s, 1H), 4.48 (d, J = 5.9 Hz, 1H),

3.20 (d, J = 6.2 Hz, 1H), 2.78 (s, 3H), 2.45–2.35 (m, 1H), 2.18 (ddd, J = 14.9, 6.4, 6.2 Hz, 1H),

1.91 (ddd, J = 13.8, 8.6, 5.2, 1H), 1.71 (ddd, J = 13.3, 7.2, 5.5 Hz, 1H), 1.20 (s, 3H); 13C NMR

(125 MHz, (CD3)2CO) δ 174.5, 150.2, 144.7, 144.1, 128.7, 127.4, 125.1, 122.6, 112.2, 85.6,

77.9, 63.8, 51.5, 47.8, 37.3, 27.4, 26.1, 24.1; IR (thin film) ν 3227, 2920, 2853, 1651, 1456,

-1 + 1395, 1344, 1092, 1053, 997, 754 cm ; HRMS (ESI) m / z calcd for C18H21NO3Na (M + Na)

322.1419, found 322.1424.

H OH

NMe O Me O

2.86

Ketone 2.86. To a solution of 2.106 (0.005 g, 0.017 mmol) in THF (2.5 mL) was added MnO2

(0.050 g, 10 mass equiv.). The brown slurry was stirred for 4 h at room temperature and was filtered through a plug of silica gel to remove residual solids by rinsing with CH2Cl2 and EtOAc.

The colorless filtrate was dried with MgSO4, filtered, and concentrated to yield a white solid,

which was purified by column chromatography (SiO2, 60:40 EtOAc:hexanes) to afford 2.86 as a

white solid (0.0035 g, 0.012 mmol, 71%).

1 Mp = 194–198 °C; H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 7.7 Hz, 1H), 7.69 (td, J = 7.6, 1.0

Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 5.20 (d, J = 12.0 Hz, 1H), 5.07 (s,

1H), 4.96 (s, 1H), 4.90 (d, J = 12.1 Hz, 1H), 3.04 (s, 1H), 2.94 (s, 3H), 2.55–2.41 (m, 2H), 1.85

(ddd, J = 14.1, 6.4, 2.1 Hz, 1H), 1.53 (s, 3H), 1.39 (ddd, J = 13.4, 12.1, 8.4 Hz, 1H); 13C NMR

(125 MHz, CDCl3) δ 205.3, 169.0, 164.4, 140.8, 136.7, 133.0, 128.2, 125.2, 123.5, 111.2, 84.1,

70.0, 48.7, 44.2, 39.9, 28.9, 27.7, 18.5; IR (thin film) ν 3381, 2926, 2851, 1713, 1674, 1605,

-1 + 1470, 1435, 1292, 1098, 916, 764 cm ; HRMS (ESI) m / z calcd for C18H19NO3Na (M + Na)

320.1263, found 320.1258.

O H OH

NMe O Me O

2.87

Dione 2.87. Ozone was bubbled into a stirring solution of 2.86 (0.0027 g, 0.009 mmol) in

CH2Cl2 (5 mL) at –78 °C. After 0.5 h, the reaction mixture was a deep blue color and Me2S (0.18 mL) was added (to quench). The colorless solution was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was poured into water (5 mL) and the organic layer was washed with brine (10 mL). The aqueous layer was extracted with 50% EtOAc in hexanes (3 x

10 mL) and washed with brine (10 mL). The combined organic extracts were dried with MgSO4, filtered, and concentrated to yield a white solid, which was purified by column chromatography

(SiO2, 40:60 EtOAc:hexanes) to afford 2.87 as a white solid (0.0018 g, 0.006 mmol, 67%).

1 Mp = 164–166 °C; H NMR (500 MHz, CDCl3) δ 7.82 (d, J = 7.7 Hz, 1H), 7.76 (t, J = 7.6 Hz,

1H), 7.56 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 5.60 (d, J = 13.0 Hz, 1H), 4.53 (d, J =

13.0 Hz, 1H), 3.15 (s, 1H), 2.92 (s, 3H), 2.57 (ddd, J = 19.3, 13.0, 6.6 Hz, 1H), 2.48 (ddd, J =

19.1, 7.1, 1.2 Hz, 1H), 2.03 (ddd, J = 14.2, 6.2, 1.0 Hz, 1H), 1.88 (td, J = 13.5, 7.1 Hz, 1H), 1.55

13 (s, 3H); C NMR (125 MHz, CDCl3) δ 205.6, 204.8, 167.6, 163.5, 137.3, 132.3, 128.8, 125.5,

123.6, 81.5, 69.3, 54.8, 43.2, 38.5, 34.9, 27.8, 17.8; IR (thin film) ν 3418, 2922, 2864, 1717,

1686, 1603, 1470, 1437, 1271, 1240, 1055, 1032, 1009, 762, 737 cm-1; HRMS (ESI) m / z calcd

+ for C17H17NO4Na (M + Na) 322.1055, found 322.1047.

O H OSiEt3

NMe O Me O

2.101

Silyloxyaminal 2.101. To a solution of 2.87 (0.005 g, 0.017 mmol) in CH2Cl2 (1 mL) was added

triethylamine (0.003 mL, 0.018 mmol). TESOTf (0.004 mL, 0.018 mmol) was added at 0 °C and

the reaction was stirred at that temperature for 3 h. H2O (5 mL) and CH2Cl2 (5 mL) were added

and the organic layer was separated, washed with H2O (5 mL) and brine (5 mL), dried with

MgSO4, filtered and concentrated to yield a yellow residue, which was purified by column

chromatography (SiO2, 15:85 – 20:80 EtOAc:hexanes) to afford 2.101 as a white residue (0.007

g, 0.017 mmol, >99%).

1 H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.50 (d, J = 7.6

Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 5.71 (d, J = 1.1 Hz, 1H), 3.24 (s, 1H), 2.80 (s, 3H), 2.51 (ddd, J

= 19.2, 12.5, 6.5 Hz, 1H), 2.43 (ddd, J = 19.2, 7.0, 2.2 Hz, 1H), 1.93 (ddd, J = 14.3, 6.3, 2.3 Hz,

1H), 1.76 (td, J = 13.2, 7.2 Hz, 1H), 1.44 (s, 3H), 1.05 (t, J = 8.0 Hz, 9H), 0.75 (q, J = 8.0 Hz,

13 6H); C NMR (125 MHz, CDCl3) δ 207.5, 200.7, 168.2, 161.1, 135.9, 133.6, 128.4, 125.0,

123.0, 83.2, 69.7, 54.9, 43.7, 38.4, 34.9, 27.5, 17.3, 7.0, 5.0; IR (thin film) ν 2953, 2874, 1713,

1695, 1603, 1396, 1241, 1084, 1064, 1003, 823, 747 cm-1; HRMS (ESI) m / z calcd for

+ C23H31NO4SiNa (M + Na) 436.1920, found 436.1908.

2.9: Notes and References

(1) de Almeida Leone, P.; Carroll, A. R.; Towerzey, L.; King, G.; McArdle, B. M.; Kern, G.; Fisher, S.; Hooper, J. N. A.; Quinn, R. J. Org. Lett. 2008, 10, 2585–2588.

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(4) Work performed with fellow graduate student, Dr. Sarah Steinhardt.

(5) Trost, B. M.; Aponick, A. J. Am. Chem. Soc. 2006, 128, 3931–3933.

(6) Schneider, G.; Horvath, T.; Sohar, P. Carbohydr. Res. 1977, 56, 43–52.

(7) Kauffmann, T.; Gaydoul, K.-R. Tetrahedron Lett. 1985, 26, 4067–4070.

(8) Karthikeyan, K.; Perumal, P. T. Synlett 2009, 2366–2370.

(9) Durrant, M. L.; Thomas, E. J. J. Chem. Soc., Perkin Trans. 1 1984, 901–904.

(10) Tedaldi, L. M.; Smith, M. E. B.; Nathani, R. I.; Baker, J. R. Chem. Commun. 2009, 6583–6585.

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(13) Gill, C. D.; Greenhalgh, D. A.; Simpkins, N. S. Tetrahedron 2003, 59, 9213–9230.

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(15) Prestly, M. R.; Simpkins, N. S. Angew. Chem. Int. Ed. 2012, 51, 12068–12071.

(16) Singh, K. J.; Hoepker, A. C.; Collum, D. B. J. Am. Chem. Soc. 2008, 130, 18008–18017.

(17) Gupta, L.; Hoepker, A. C.; Singh, K. J.; Collum, D. B. J. Org. Chem. 2009, 74, 2231–2233.

(18) Phonchaiya, S.; Panijpan, B.; Rajviroongit, S.; Wright, T.; Blanchfield, J. T. J. Chem. Educ. 2009, 86, 85– 86.

(19) Hine, J.; Brader, Jr., W. H. J. Am. Chem. Soc. 1955, 77, 361–364.

(20) Trost, B. M.; Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887–4902.

(21) Ishibashi, H.; Kobayashi, T.; Nakashima, S.; Tamura, O. J. Org. Chem. 2000, 65, 9022–9027.

(22) Pal, S.; Mukhopadhyaya, J. K.; Ghatak, U. R. J. Org. Chem. 1994, 59, 2687–2694.

(23) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102–113.

(24) Xi, Y.; Yi, H.; Lei, A. Org. Biomol. Chem. 2013, 11, 2387–2403.

(25) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322–5363.

(26) Koike, T.; Akita, M. Inorg. Chem. Front. 2014, 1, 562–576.

(27) Nguyen, J. D.; D’Amato, E. M.; Narayanam, J. M. R.; Stephenson, C. R. J. Nat. Chem. 2012, 4, 854–859.

(28) Link, J. T. In Organic Reactions; 2002; Vol. 60, pp 157–213, 523–547.

(29) Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 28, 5291–5294.

(30) Burns, B.; Grigg, R.; Ratananukul, P.; Sridharan, V.; Stevenson, P.; Worakun, T. Tetrahedron Lett. 1988, 29, 4329–4332.

(31) Banerjee, M.; Mukhopadhyay, R.; Achari, B.; Banerjee, A. K. J. Org. Chem. 2006, 71, 2787–2796.

(32) Rousseaux, S.; Davi, M.; Sofack-Kreutzer, J.; Pierre, C.; Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin, O. J. Am. Chem. Soc. 2010, 132, 10706–10716.

(33) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555–1564.

(34) Littke, A. F.; Fu, G. C. Org. Synth. 2005, 81, 63–76.

(35) Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 2719–2724.

(36) Giannerini, M.; Fañanás-Mastral, M.; Feringa, B. L. Nat. Chem. 2013, 5, 667–672.

(37) Denmark, S. E.; Smith, R. C.; Chang, W.-T. T.; Muhuhi, J. M. J. Am. Chem. Soc. 2009, 131, 3104–3118.

(38) Petrone, D. A.; Malik, H. A.; Clemenceau, A.; Lautens, M. Org. Lett. 2012, 14, 4806–4809.

(39) He, L.-Y. Synlett 2015, 26, 851–852.

(40) Sen, A.; Lai, T.-W. Inorg. Chem. 1981, 20, 4036–4038.

(41) Wu, X.; Zhou, J. (Steve). Chem. Commun. 2013, 49, 4794.

(42) Wu, X.; Lu, Y.; Hirao, H.; Zhou, J. Chem. Eur. J. 2013, 19, 6014–6020.

(43) Hartung, C. G.; Köhler, K.; Beller, M. Org. Lett. 1999, 1, 709–711.

(44) Wu, Y.; Huang, J.-H.; Shen, X.; Hu, Q.; Tang, C.-J.; Li, L. Org. Lett. 2002, 4, 2141–2144.

(45) Chiyoda, K.; Shimokawa, J.; Fukuyama, T. Angew. Chem. Int. Ed. 2012, 51, 2505–2508.

(46) Arai, Y.; Matsui, M.; Fujii, A.; Kontani, T.; Ohno, T.; Koizumi, T.; Shiro, M. J. Chem. Soc., Perkin Trans. 1 1994, 25–39.

(47) Van Brabandt, W.; De Kimpe, N. J. Org. Chem. 2005, 70, 3369–3374.

(48) Matsuki, K.; Inoue, H.; Ishida, A.; Takeda, M.; Nakagawa, M.; Hino, T. Chem. Pharm. Bull. 1994, 42, 9–18.

(49) Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W. N. Tetrahedron 1978, 34, 179–187.

(50) Nicolaou, K. C.; Baran, P. S.; Jautelat, R.; He, Y.; Fong, K. C.; Choi, H.-S.; Yoon, W. H.; Zhong, Y.-L. Angew. Chem. Int. Ed. 1999, 38, 549–552.

(51) NMR chemical shift calculations performed by Dr. Warren Hehre (Wavefunction, Inc).

CHAPTER 3:

PROGRESS TOWARD THE SYNTHESIS OF EXIGUAQUINOL

3.1: Introduction

After completing a synthesis of the tetracyclic core of exiguaquinol (3.1),1 we sought to

apply the acquired knowledge to a total synthesis of exiguaquinol (3.2). Despite the structural

resemblance between 3.1 and 3.2, many significant challenges remained unaddressed at the onset

of this stage of the synthesis, including: (1) formation of the desired hemiaminal epimer, (2)

incorporation of the taurine fragment, and (3) the regioselective installation of the aryl sulfate

(Figure 3.1). The reaction conditions and order of events required careful planning to ensure

functional group compatibility while maintaining step economy and chemical efficiency.

Following completion of the total synthesis of exiguaquinol, protein-ligand cocrystallization will

be performed to learn about exiguaquinol's MurI binding properties. This data will facilitate our

SAR studies to identify more potent H. pylori MurI inhibitors.

Figure 3.1. Comparison of exiguaquinol (3.2) and its tetracyclic core (3.1).

3.2: Retrosynthetic Analysis

Our retrosynthetic strategy began by disconnection of the dihydroxynaphthalene

monosulfate in 3.2 to a more manageable dimethoxynaphthalene precursor (3.3) (Scheme 3.1).

We envisioned introducing the remaining sulfonic acid group in 3.3 through either of two

distinct methods: (1) direct displacement of an alkyl halide with sulfite anion or (2) installation

of a low valent sulfur nucleophile and subsequent oxidation. Regardless, both pathways can arise

from a common intermediate (3.6). Based on the Houk lab's calculations, epimerization of the

hemiaminal should be possible after the sulfonic acid is introduced, owing to the hydrogen bond

formed between the C2 hemiaminal and the sulfonic acid (See Section 2.6).

In a similar fashion to our successful tetracyclic core synthesis (Chapter 2), we planned to disconnect the cyclopentanone through an intramolecular 5-exo reductive Heck reaction to

produce 3.7, which we hoped to access by a convergent aldol reaction between bicycle 3.9 and naphthaldehyde 3.8. Bicycle 3.9 could be synthesized by combining diene 3.12, maleimide

(3.11), and alkyl bromide 3.10 in a Diels–Alder cycloaddition and imide N-alkylation sequence.

Scheme 3.1. Retrosynthetic plan for exiguaquinol synthesis.

3.3: Strategies to Access an Appropriately Substituted Naphthaldehyde

The early part of our exiguaquinol synthesis hinged on an aldol reaction between a

bicyclic imide (3.9) and a naphthaldehyde (3.8). However, before the union of these fragments

could be evaluated, a scalable and efficient route to naphthaldehyde 3.8 was needed. Although

substituted naphthalenes may appear to be simple targets, synthesizing highly substituted

aromatics efficiently can be quite challenging. Consequently, many strategies were evaluated

before arriving at a successful route to 3.8.

3.3.1: o-Quinodimethane Diels–Alder Strategy

o-Quinodimethanes (3.17) are highly reactive dienes that have been utilized in organic

synthesis over the past 60 years (Scheme 3.2).2–4 In almost all cases, they serve as competent

Diels–Alder dienes to generate the corresponding benzannulated structures. The restoration of aromaticity serves as a key thermodynamic driving force and the locked s-cis conformation facilitates rapid C–C bond formation with a low kinetic barrier.

Owing to their highly reactive nature, o-quinodimethanes are typically formed in situ and

require generation from a suitable precursor (Scheme 3.2). Such compounds include

benzocyclobutenes (3.13), substituted o-xylene (3.14) or o-tolualdehyde (3.15) derivatives, or

dihydroisobenzothiophene dioxides and other cheletropic extrusion precursors (3.16).

Throughout the course of our research, each of these classes was evaluated in a Diels–Alder

cycloaddition towards accessing naphthaldehyde 3.8.

Scheme 3.2. Classes of o-quinodimethane precursors.

The most commonly used o-quinodimethane precursors are the benzocyclobutenes,

owing to their facile 4π electrocyclic ring opening under thermal conditions.5–12 In order to

obtain the desired dimethoxynaphthalene through cycloaddition and aromatization,

trimethoxybenzocyclobutene 3.24 could be prepared in 4–6 steps according to the Wallace

group's procedure (Scheme 3.3).6,7,11 Beginning with 2,5-dimethoxybenzoic acid (3.19), nitration followed by reduction yields aniline 3.20 in good yields. Next, benzyne formation and trapping with either vinyl acetate or 1,1-dichloroethylene affords benzocyclobutenes 3.21 or 3.22 in moderate yield, respectively. 3.21 can be converted to trimethoxybenzocyclobutene 3.24 by

deprotection of the acetate group and methylation of the alcohol. 3.22 can be treated with acid to

afford a ketone, which upon reduction and methylation, affords 3.24 through an overall higher

yielding route. Alternatively, 1-halo-2,5-dimethoxybenzene (3.25) can be used to access 3.24.

Treatment of 3.25 with NaNH2 and a ketene acetal afforded benzocyclobutene 3.26 in low to moderate yields via a presumed benzyne intermediate. The resulting ketal can be deprotected with acid, reduced, and methylated to produce trimethoxybenzocyclobutene 3.24 in the shortest number of steps, albeit with a lower overall yield.

Scheme 3.3. Synthesis of benzocyclobutene 3.24 by Wallace.

In their synthesis of xestoquinone, the Keay group utilized acyl chloride 3.29 to introduce

the naphthalene portion of the molecule (Scheme 3.4).13 They successfully united

trimethoxybenzocyclobutene 3.24 and ethyl bromopropiolate 3.27 through an o-quinodimethane

Diels–Alder reaction by heating to reflux in toluene with 4 Å molecular sieves. Furthermore,

Keay showed that 3.24 can be engaged in an o-quinodimethane Diels–Alder cycloaddition with

other dienophiles to form substituted naphthalenes.11

Scheme 3.4. o-Quinodimethane Diels–Alder cycloaddition by Keay and coworkers.

Although these strategies using key intermediate 3.24 appear suitable for our synthesis of exiguaquinol, several drawbacks prevented us from adopting this chemistry for our purposes. We were plagued by low yields in the nitration and nitro reduction steps (Scheme 3.3), leading us to

investigate alternative benzyne formation conditions. After subjecting 1-halo-2,5-

dimethoxybenzenes to NaNH2 and a [2+2] partner (ethyl vinyl ether or 2-methylene-1,3-

dioxolane), no benzocyclobutene was observed.7 In addition, benzyne formation followed by trapping with the lithium enolate of acetaldehyde was unsuccessful after several attempts.10,12

These obstacles drove us to seek alternative methods for benzocyclobutene formation.

Taking inspiration from the literature, we hoped to utilize an o-trimethylsilylaryl triflate in our synthesis of a suitable benzocyclobutenol derivative (Scheme 3.5). Starting from 2,5- dimethoxybenzaldehyde, a Dakin oxidation followed by protection as the THP acetal provided

3.32 in good yield.14,15 Ortho-lithiation and quenching with TMSCl provided arylsilane 3.33 with

deprotection of the THP group during an acidic workup.15 Lastly, triflation with triflic anhydride

afforded the o-trimethylsilyl aryl triflate benzyne precursor (3.34). When CsF was used to unveil

the benzyne in ethyl vinyl ether, only starting material was recovered, suggesting that CsF was not soluble under these conditions. Fortunately, switching to TBAF procured the desired 1- ethoxy-3,6-dimethoxybenzocyclobutene (3.36) in 46% yield.

Scheme 3.5. Synthesis of benzocyclobutene 3.36 and cycloaddition attempts.

Based on our prior work toward the tetracyclic model system of exiguaquinol (3.1)

(Chapter 2), we anticipated that an aryl iodide would be necessary to participate in the reductive

Heck reaction. Therefore, cycloadditions were attempted using ethyl 3-iodopropiolate (3.37).

However, subjection of benzocyclobutene 3.36 to Keay's optimized conditions using 3.37 as the dienophile primarily led to recovery of starting material. Further optimization would be necessary to determine conditions for effectively converting 3.36 and 3.37 into naphthalene 3.38.

Due to the inefficiencies of this route, we shifted our attention to alternative ways of accessing naphthaldehyde 3.8 using o-quinodimethane chemistry.

The second method for accessing o-quinodimethanes involves the reduction of an o-

bis(halomethyl) arene (Scheme 3.6). To apply this chemistry to our desired reaction, a synthesis

of dibromide 3.40 was required. Beginning with commercially available 2,3-

dimethylhydroquinone (3.39), methylation and radical bromination provided o-quinodimethane

precursor 3.40. Unfortunately, treatment of 3.40 and 3.37 with CrCl2 or NaI at elevated

100

temperatures resulted in decomposition; in this case, we reasoned that the alkynyl iodide was the most probable liability in the presence of a reductant because o-quinodimethane Diels–Alder reactions using 3.40 have been reported to proceed with excellent efficiency.16–28

Scheme 3.6. o-Xylylene and cheletropic extrusion methods for accessing naphthaldehyde 3.8.

OH OMe OMe 1. KOH, MeI I CO2Et Me CO2Et DMSO (84%) Br 3.37 Br Me 2. NBS, (BzO)2 I CrCl2 or NaI CCl4 (51%) OH OMe OMe 3.41 3.40 3.39 OMe

1. Na2S·9H2O I CO2Et EtOH (29%) 3.37 SO2 2. mCPBA OMe CH2Cl2 (25%) 3.42

With dibromide 3.40 in hand, we investigated the formation of the o-quinodimethane

from a cheletropic extrusion of SO2 (Scheme 3.6). This strategy has been used in complex molecule synthesis by Nicolaou,29 Crews,16 Silva,30–32 and many others.33–35 Displacement of the

bromides with Na2S followed by oxidation to the sulfone with mCPBA afforded

dihydrobenzothiophene dioxide 3.42. Cycloadditions with iodopropiolate 3.37 were attempted

under thermal conditions in o-dichlorobenzene or toluene with both microwave and conventional

heating; however, we never observed any desired product under these conditions. Decomposition

or evaporation of the dienophile was likely occurring faster than cheletropic extrusion and

cycloaddition.

Although many examples in the literature demonstrate successful photo-induced

cycloadditions of tolualdehydes,36–44 we did not evaluate these conditions because the substrate

we needed would be difficult to prepare and would be derived from the expensive starting

material 2,3-dimethylhydroquinone. These factors, coupled with the difficulties in our previously described endeavors, drove us to abandon the o-quinodimethane approach to synthesizing naphthaldehyde 3.8 in favor of a more attractive strategy.

101

3.3.2: 3,5-Dihydroxy-2-naphthoic Acid Strategy

After experiencing difficulties synthesizing the desired naphthalene framework, we

turned our attention to a strategy based on functionalizing a commercially available and

affordable naphthalene, 3,5-dihydroxy-2-naphthoic acid (3.45). Previous work by Kozlowski and

others has shown that 3.45 can be esterified and oxidized to naphthoquinone 3.46 through

transition metal-catalyzed processes.45–47 With all the oxidation in place, several functional group manipulations remained to be evaluated; most notably, we intended to convert the C3 phenol into

48–52 53,54 an aryl halide through an organometallic reaction or SNAr displacement of an aryl triflate

(Scheme 3.7). Although an aryl triflate could conceivably participate in the planned reductive

Heck reaction, we discovered that aryl triflates are prone to decomposition in the convergent

aldol step; therefore, conversion to the aryl halide was necessary.

Scheme 3.7. Overview of our naphthoic acid strategy.

Beginning with naphthoquinone 3.46,45 triflation of the C3 phenol produced aryl triflate

3.47 irreproducibly, owing to competitive decomposition of the product upon workup (Scheme

3.8). Nevertheless, 3.47 can be reduced to the dihydroxynaphthalene and methylated to afford

3.48. Unfortunately, attempts to transform this material and 3.47 to the aryl iodide using either

Hayashi's ruthenium-catalyzed halogenation reaction or direct SNAr displacement did not yield

any of the desired products.50 Additionally, conversion of 3.48 to the aldehyde, a stronger

electron-withdrawing group, produced similarly disappointing iodination results.

102

Scheme 3.8. Efforts to access naphthoate ester 3.49 from 3.45.

Therefore, a two-step protocol for halogenation was investigated on a simplified substrate bearing only one methoxy group (3.51) (Scheme 3.9): eventually, we found that borylation using bis(pinacolato)diboron and Pd(PPh3)4 followed by iododeborylation under Hartwig's conditions

gave aryl iodide 3.52 in low yield with significant amounts of protodeborylation side product

3.53 (3.52:3.53 = 1:1.8). In an effort to limit side product formation, alternative conditions were

evaluated. It was found that by reducing the equivalents of water in the reaction and utilizing

DMF as the solvent, a 4:1 ratio (3.52:3.53) favoring the aryl iodide could be achieved.

Invariably, this transformation suffered from reproducibility issues on scale, which significantly

limited material throughput. Nevertheless, aryl iodide 3.52 was reduced with DIBAL-H and

oxidized with MnO2 to afford naphthaldehyde 3.54.

Scheme 3.9. Synthesis of simplified naphthaldehyde 3.54.

1. H SO ,MeOH CO2H 2 4 CO2Me Tf2O, Et3N CO2Me reflux (quant.) CH2Cl2, –78 °C OH OH OTf 2. K2CO3,MeI (96%) OH 3.45Me2CO (33%) OMe 3.50OMe 3.51

CO Me 1. Pd(PPh ) ,B(pin) CHO 2 3 4 2 2 1. DIBAL-H, THF NaOAc, dioxane, 90 °C R I 2. MnO2,CH2Cl2 2. CuI, phen, KI, DMF OMe OMe (79%, 2 steps) (29%, 2 steps) 3.54 3.52: R = I 3.53: R = H

While this route provided access to naphthaldehyde 3.54, several key issues prevented its

103

application in our total synthesis. First of all, the triflation of 3.46 gave variable outcomes and

often resulted in total decomposition for several reaction batches. In addition, the two-step

iodination sequence was plagued by poor reproducibility, low yields, and protodeborylation as

major problems that could not be overcome. With only limited quantities of 3.54 attainable from

each batch, a more scalable and reproducible route to 3.8 was required for our total synthesis of

exiguaquinol.

3.3.3: Cycloaddition/Iododesilylation Strategy

Due to our limited success with previous routes, we decided to target a different

disconnection to access the desired naphthaldehyde. In particular, we noticed that the 1,4-

dimethoxyarene ring could be installed from a Diels–Alder cycloaddition between benzoquinone

and a suitable diene. In this case, a diene bearing a vinylsilane and an aldehyde precursor (3.57) was targeted with the intent of a late-stage iododesilylation.

Scheme 3.10. Overview of the iododesilylation strategy.

We hoped to prepare diene 3.57 in one step using an enyne metathesis of propargyl alcohol 3.58 with ethylene. We were pleased to discover that this reaction proceeds efficiently

under 200–400 psi of ethylene gas using 5 mol % of Grubbs II catalyst. Interestingly, we were

unable to find any other reports of an intermolecular enyne cross-methathesis reaction of a

silylated alkyne in the literature;55 evaluation of the scope and limitations of this transformation

could afford a useful method for preparing vinyl- or arylsilanes.

104

Scheme 3.11. Iododesilylation strategy to access 3.43.

Diene 3.57 was then heated with 10 equivalents of benzoquinone to provide

naphthoquinone 3.59 in 54% yield. Excess benzoquinone is required in order to oxidize the

cycloadduct to naphthoquinone 3.59; otherwise, the isolated yield is greatly diminished.

Oxidation of 3.59 to the aldehyde followed by reduction and methylation of the quinone afforded

naphthaldehyde 3.60. Unfortunately, attempts to iododesilylate silanes 3.57, 3.59 or 3.60 with

ICl, chloramine-T/NaI, NIS, or I2 did not provide the desired product. When treating 3.60 with

ICl, iododesilylation of the arylsilane seemed to occur along with iodination of the electron-rich aryl ring. To circumvent over-halogenation, we attempted to utilize the adjacent alcohol in a

Brook rearrangement/iodination sequence on silane 3.60. Following the procedures of Smith,

3.60 was treated with nBuLi/CuI/DMPU to affect a 1,4-Brook rearrangement followed by quenching with an electrophilic iodine source;56 however, none of the desired iodide was ever

observed under these and related conditions.57

3.3.4: Other Strategies

Scheme 3.12. Overview of vinyl quinone strategy for the synthesis of 3.43.

OMe O OMe X CHO [4+2] CO2R CO2R or I I 3.63 OMe O OMe 3.43 3.61 3.62

Hydroxynaphthalenes have been synthesized through additional strategies, including

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those beginning with styrenes or vinyl quinones. The Noland and Trauner groups, among few others, have utilized this strategy for accessing hydroxylated naphthalenes through the Diels–

Alder disconnection pictured in Scheme 3.12.58–61 Using nitrovinyl quinones as inverse-electron-

demand Diels–Alder dienes, Noland demonstrated that these unconventional substrates

participate in a cycloaddition reaction with electron-rich dienophiles (Scheme 3.13). Featured in

their total synthesis of halenaquinone, the Trauner group utilized a late-stage intramolecular

vinyl quinone Diels–Alder to assemble the naphthyl portion of the molecule.60

Scheme 3.13. Prior examples of vinyl quinone Diels–Alder reactions.

We attempted to apply this strategy towards naphthaldehyde 3.8 by first preparing 3.69

and 3.71 through a Horner–Wadsworth–Emmons olefination (Scheme 3.14). Oxidation to

quinone 3.71 was performed with Oxone® and a catalytic amount of 4-iodophenoxyacetic acid

following Yakura's protocol.62 Unfortunately, subjection of either 3.69 or 3.71 to thermal or

Lewis acidic cycloaddition conditions in the presence of dienophiles 3.72–3.75 never produced any of the desired annulation products. Instead, recovery of starting materials, decomposition, or dimerization of the vinyl quinone occurred preferentially, depending on the conditions; therefore,

we shifted our efforts away from this strategy.

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Scheme 3.14. Efforts to perform a vinyl quinone Diels–Alder reaction.

I O OMe OMe O (EtO)2P CO2Et CHO CO2Et O CO2H CO2Et 3.68 3.70 Dienophiles:

NaH, THF TFE/H2O, Oxone (95%) (99%) 3.72: TMS OMe OMe 3.69 O 3.71 3.31 3.73: OEt 3.72–3.75 3.72–3.75 OMe 3.74: SiMe3 Br OMe OH 3.75: SiMe CO2Et CO2Et 3

R R OMe 3.76 OH 3.77

3.3.5: Thiophene Dioxide Diels–Alder Strategy

Related to the disconnection used in the cycloaddition/iododesilylation strategy (Section

3.3.3), a synthesis of naphthaldehyde 3.78 could take advantage of a Diels–Alder/cheletropic extrusion cascade with benzoquinone to forge the requisite C–C bonds (Scheme 3.15). This reactivity has been exploited by many groups while employing a variety of heterocycles, including pyrones,63–68 furans,69–74 cyclopentadienones,75 and thiophene dioxides76–79. This transformation is favored enthalpically by the formation of an aryl ring with greater aromatic stabilization and entropically by the extrusion of a gas. When benzoquinone is used as the electrophile in excess, the product is obtained in the naphthoquinone oxidation state.

Scheme 3.15. Our plan to access 3.78 via [4+2]/cheletropic extrusion.

When applying this concept to our synthesis of naphthaldehyde 3.78, consideration must

be taken with regards to installation of the aldehyde and halide functional handles (Scheme

3.16). Originally, we intended to incorporate the formyl group prior to aromatic ring annulation.

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Beginning with 3,4-dibromothiophene (3.80), lithium-halogen exchange and formylation provided aldehyde 3.81 in excellent yield. Because 3.81 was impervious to thiophene oxidation under a multitude of conditions, the aldehyde was reduced with NaBH4. We suspected that the

electron-withdrawing aldehyde functionality deactivated the thiophene ring towards oxidation.

Although Rozen and coworkers have shown that HOF·MeCN, an extremely strong oxidant, is

capable of converting many electron-poor thiophenes into the corresponding thiophene dioxides,

these conditions were not investigated as we were never able to obtain gaseous fluorine.80

Nevertheless, oxidation to thiophene dioxide 3.82 was possible using trifluoroperacetic acid after aldehyde 3.81 was reduced. Cycloaddition of this material with excess benzoquinone yielded the naphthoquinone and oxidation with PCC afforded aldehyde 3.83. Conversion of the naphthoquinone to the dimethoxynaphthalene was met with decomposition, likely owing to the presence of a reactive aldehyde group; therefore, we decided to postpone installation of the aldehyde until the last step in our sequence.

Scheme 3.16. Our ultimately successful route to synthesize naphthaldehyde 3.78.

Fortunately, 3,4-dibromothiophene undergoes facile oxidation to the sulfone when treated with excess trifluoroperacetic acid (Scheme 3.16).81 A report by Vance and Williams showed that 3,4-dibromothiophene-S,S-dioxide will undergo a [4+2] cycloaddition and cheletropic extrusion with excess benzoquinone to afford naphthoquinone 3.84 in modest yield with no

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observable dimerization.76 When an equimolar amount or small excess of benzoquinone was

used, a significant amount of double cyclization was seen, resulting in formation of

tetrabromoanthraquinone; this undesired pathway was avoided by using 10 or more equivalents

of benzoquinone in the reaction. Reduction and methylation of naphthoquinone 3.84 afforded dimethoxynaphthalene 3.85 with high efficiency.82 Initially, metal-halogen exchange using

iPrMgCl·LiCl followed by a DMF quench did not produce any desired product (3.78).83–85

However, a literature report by Tamborski and coworkers demonstrated that 1,2-dihaloarenes can be formylated without the formation of benzyne intermediates at temperatures below –90 °C.86

Gratifyingly, this procedure translated well to our system and yielded naphthaldehyde 3.78 in quantitative yield.

Although this synthetic plan suffered from a poor-yielding Diels–Alder cycloaddition, it permitted access to naphthaldehyde 3.78 in only five steps (the shortest linear sequence investigated). Compared to the previous approaches, this route minimizes the number of unnecessary redox manipulations, thereby increasing step economy and overall efficiency. Over several iterations, we were able to demonstrate the scalability and reliability of this strategy, and decided to employ it in our synthesis of exiguaquinol. While there was no guarantee that aryl bromide 3.78 would participate in the desired reductive Heck reaction, we suspected that the analogous aryl iodide (3.43) could be prepared from 3,4-diiodothiophene if necessary.

3.4: Synthesis of the Pentacyclic Framework of Exiguaquinol

Our development of a simple and scalable route to naphthaldehyde 3.78 provided access to the aryl portion of exiguaquinol, which contained the proper functionality for connection to the remainder of the molecule. A nucleophile can engage the aromatic aldehyde in an aldol reaction to connect the two fragments and the aryl bromide can close the C-ring via an

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intramolecular Heck reaction. Before the two groups can be united, the synthesis of a suitable

bicyclic imide partner, containing useful functionality on the succinimide nitrogen, must be

established.

3.4.1: Substitution of the Succinimide Nitrogen

The bicyclic imide fragment, corresponding to the A- and B-rings of exiguaquinol, was

prepared in a similar manner to that of our tetracyclic core synthesis (Scheme 2.9). However, we

now needed to incorporate functionality that could be converted to the sulfonic acid at a later

stage. Initially, we intended to attach a sulfonate ester via the conjugate addition of a

deprotonated succinimide (Scheme 3.17). This strategy would allow us to unveil the polar

sulfonic acid by deprotection or hydrolysis when ready.87,88 Various conjugate acceptors bearing

sulfonate esters (3.87) were explored with 3.86; however, all reactions were thwarted by low

conversion or undesired reactivity. When methyl vinylsulfonate was used as the electrophile,

methylation of succinimide 3.86 was observed exclusively.

Scheme 3.17. Ideas for incorporating the N-alkyl substituent.

Alternatively, the succinimide could be alkylated with functionality that can be displaced by a sulfur atom towards the end of our synthesis (Scheme 3.17). We planned to postpone the introduction of this sulfur group until after the cyclization in order to avoid catalyst inhibition in the reductive Heck reaction, because sulfides and other sulfur-containing functional groups have

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been shown to poison Pd catalysts.89–92 Four different alkyl bromides were investigated in the

alkylation with 3.86 (Scheme 3.18), one bearing a sulfonic acid: sodium 2-bromoethanesulfonate

(3.92), 1-bromo-2-chloroethane (3.93), 1,2-dibromoethane (3.94), and TBS-protected 2-

bromoethanol (3.95). Likely owing to solubility issues related to the sulfonate group, reaction

with 3.92 did not produce any of the desired product. However, alkyl bromides 3.93–3.95

successfully alkylated 3.86 to provide 3.97–3.99 and alkene reduction to produce 3.101–3.103

respectively in high yield. When K2CO3, nBuLi, or LDA were used in the alkylation with 3.95

(R = OTBS), complete epimerization to 3.100 was seen; fortunately, switching to KOtBu afforded bicycle 3.99 with trace epimerization. Unsurprisingly, 3.101 and 3.102 decomposed

upon subjection to aldol conditions, likely owing to the labile alkyl halides. The presence of

1 alkene peaks in the crude H NMR spectrum suggested that E2 elimination had occurred, among

other undesired pathways. While 3.103 did not productively undergo the intended aldol reaction at first, recovery of starting material from attempted reactions indicated its stability to strongly

basic conditions. Therefore, bicycle 3.103 was chosen as the best candidate with which to

evaluate the desired aldol reaction.

Scheme 3.18. Exploring various N-alkyl substituents.

In addition to these strategies, an idea to access the alkyl sulfonate involving radical

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translocation was explored. This strategy takes advantage of a weak O–X bond to form an O-

centered radical, which can functionalize the position five atoms away (Scheme 3.19).

Originally, Barton had shown that this type of reaction takes place with nitrite esters (3.104)

under photochemical conditions to a form γ-hydroxy oxime (3.105) (Scheme 3.19).93 More recently, the Suárez and Čeković groups have shown that this transformation can proceed with hypoiodites94,95 and sulfenate esters96–99 on rigid or flexible systems (Scheme 3.19). The intermediate radical can also be trapped by methyl vinyl ketone and other electrophiles (Scheme

3.19).99 We hoped to employ this remote functionalization to install the sulfonate moiety located

on the taurine sidechain of exiguaquinol. Using N-ethyl hemiaminal 3.111, hypoiodite or

sulfenate ester formation and photolysis would form O-centered radical 3.112, which could

abstract the primary N-ethyl hydrogen atom. The expected product (3.114), bearing an iodide or a sulfide, can be converted to the sulfonate at a later stage. This strategy would enable us to carry

an inert N-ethyl group through the majority of our synthesis and remotely activate it when ready.

Scheme 3.19. Examples of radical translocation reactions and our proposed reaction.

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To evaluate this strategy, a bicyclic model system was synthesized and used (Scheme

3.20). Diels–Alder cycloaddition between maleimide (3.11) and butadiene sulfone (3.115)

afforded a bicyclic imide and alkene reduction produced 3.116. Alkylation with bromoethane

followed by reduction with NaBH4 provided hemiaminal 3.117 as a single diastereomer, which

100 was assigned based on comparison to the literature. Unfortunately, subjecting 3.117 to I2,

PhI(OAc)2, and photolysis did not provide the desired remote functionalization product and

simple oxidation back to the imide took place. During sulfenate ester photolysis, the starting

hemiaminal was consumed under tin-free conditions; however, the phenylsulfide was not

incorporated in the product. Additionally, all attempts to isolate the sulfenate ester for exposure

to (Bu3Sn)2 were unsuccessful. Although this ambitious strategy was ultimately unsuccessful, it

could have been a practical method for sulfonic acid incorporation.

Scheme 3.20. Substrate synthesis and attempts at radical translocation.

I ,PhI(OAc) O 1. PhMe, reflux O 1. NaH, EtBr OH H 2 2 OH H H CH Cl ,h ;or H (74%) DMSO (93%) 2 2 X SO2 NH NH N N 2. H2,PtO2 2. NaBH4,MeOH H H PhSCl, base H 3.115 O MeCN (93%) O rt O O then (Bu Sn) ,h 3.11 3.116 3.117 3 2 3.118: X = I 3.119: X = SPh

3.4.2: Aldol Reaction

With access to both bicyclic imide 3.103 and aryl aldehyde 3.78, we took inspiration from our tetracyclic core synthesis and set out to unite these fragments in an aldol reaction

(Table 3.1). However, enolization of 3.103 with LDA followed by the addition of 3.78 furnished recovered starting materials and decomposition products, both with and without LiCl (entry 1).

When the same conditions were employed using 2-iodobenzaldehyde as the electrophile (instead of 3.78), the aldol adduct (3.121) was obtained in 23% yield (unoptimized), suggesting that enolization of the bicyclic imide was not problematic (entry 2). Additionally, quenching the dienolate of 3.103 with d4-methanol led to full deuterium incorporation at the ring juncture. As

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suspected, the electron-rich naphthaldehyde (3.78) appeared to be responsible for the decreased reactivity in the aldol reaction, and we aimed to devise a solution to this obstacle.

Table 3.1. Initial attempts at aldol reactions.

Attempted aldol reactions using titanium, boron, or zinc enolates never produced any desired product. Mukaiyama aldol conditions with the in situ formed bis(siloxy)pyrrole were also tried, but with no success.101 When 3-bromothiophene-4-carboxaldehyde (3.81) was employed as

the electrophile, only trace conversion to product 3.122 was seen after exposure to the lithium

enolate of 3.103—a result consistent with the poor reactivity of electron-rich aldehydes (Table

3.1, entry 3). Replacing the electrophile with formaldehyde afforded the primary alcohol in 22%

yield and 1.3:1 diastereomeric ratio, along with a small amount of double addition (entry 4).

Because formaldehyde is a fairly small electrophile, it can approach from either the top or

bottom face of the imide enolate with little steric clashing, giving rise to the poor

diastereoselectivity observed. Utilizing Mander's reagent provided the double Claisen

condensation adduct (3.124) as the major product in 33% yield (entry 5).

Considering that an imide enolate is less nucleophilic than an amide enolate, we were

interested to see whether an aldol reaction could proceed using a 2-pyrrolidinone derivative

(Scheme 3.21). Reduction of 3.103 with DIBAL-H yielded the hemiaminal; however, silylation

or methylation of the free alcohol led to complex mixtures. The Meyers group has shown that

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bicyclic lactams such as 3.125 undergo facile alkylations or Claisen condensations and we anticipated that this reactivity could translate to our desired aldol reaction (Scheme 3.21).102–106

Although the diastereoselectivity for alkylation typically ranges from poor to modest, we expected that the Zimmerman–Traxler transition state and additional substitution in our system should enhance the diastereocontrol. When 3.129 was treated with acid (p-TsOH or TFA) to effect deprotection and cyclization, unsaturated lactam 3.132 was the only product formed, presumably through dehydration and alkene isomerization. Finally, lactam 3.125 was synthesized according to the literature precedent107,108 and subjected to aldol and Claisen

conditions with 3.78, benzoyl chloride, or Mander's reagent; unfortunately, the corresponding

aldol or Claisen adduct was never observed in our hands. From these experiments, it appeared

that increasing the reactivity of the nucleophile was not a viable solution.

Scheme 3.21. Examples of lactam functionalizations and our imide reduction and unsuccessful alkylation attempts.

Meyers (1994): Sen (2011): H O H O H O LiHMDS H O LiHMDS BnBr MeOC(O)Cl N N N Ph N Ph Ph Ph MeO Ph (72%) (95%) H O O O O O 3.125 3.126: (endo/exo = 3:1) 3.127 3.128: (endo/exo = 1:1)

PhS PhS PhS PhS PhS HO H O DIBAL-H H OH H OR H O OTBS PhMe, –78 °C OTBS OTBS N N N or N N

H O H O H O H O O PhS PhS PhS PhS PhS 3.103 3.129 3.130 3.131 3.132

In attempts to increase the electrophilicity of 3.78, we investigated the use of Lewis acids in the aldol reaction. Interestingly, one report by the Rubio and García Ruano groups describes a versatile method for the aldol reaction of imides with ketones and poorly reactive aldehydes

109 using BF3·OEt2 (Scheme 3.22). In particular, they showed that by premixing m-

methoxybenzaldehyde with BF3·OEt2, aldolization occurs at –78 °C with the premade lithium

enolate of N-Boc lactam 3.133 in 61% yield. Applying the procedure of Rubio and García Ruano

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to our substrates, we were pleased to find that the desired product (3.136) was obtained as the

major component and as a single diastereomer. However, we feared that premixing of aldehyde

3.78 and BF3·OEt2 was resulting in accelerated decomposition of the aldehyde prior to the aldol

reaction. After experimentation, we discovered that premixing 3.78 and BF3·OEt2 was unnecessary and the desired reaction proceeds cleanly after the sequential addition of aldehyde

3.78 followed by BF3·OEt2 to the prepared lithium mono-enolate of 3.103. Increasing the scale

of this transformation led to a slight boost in the isolated yield. Other Lewis acids, including

TESOTf and La(OTf)3, were tested, although none gave better results than with BF3·OEt2. This

example constitutes one of the few lithium aldol reactions in which a Lewis acid is needed in

order to proceed.

Scheme 3.22. Aldol reactions requiring BF3·OEt2 to proceed.

The high diastereoselectivity in this reaction may derive from the chair-like transition structure formed between 3.78 and the enolate of 3.103 (Figure 3.2). Placing the naphthalene ring in the axial position avoids pronounced steric interactions with the substituents on the cyclohexyl ring and affords diastereomer 3.136 preferentially. Alternatively, the exogenous

Lewis acid may promote the aldol reaction through an open transition state. Although the configuration of the C9 alcohol is irrelevant for our synthesis, the complete diastereocontrol

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provides insight into the reactive aldol conformation and simplifies the characterization of the

product.

Figure 3.2. Possible reactive chair confirmation for highly diastereoselective aldol.

This aldol procedure is a significant improvement over that used in our core synthesis.

Most notably, only 1.1 equivalents of aldehyde and 1.2 equivalents of lithium amide base are needed in this transformation, whereas 2.5 equivalents of both aldehyde and base were required in the former case. In addition, the reaction can be kept at –78 °C and does not require warming to –40 °C. By combining our two complex fragments, this example serves as a testament to the versatility of the aldol reaction in organic synthesis.

3.4.3: Sulfoxide Elimination

From our synthesis of the core of exiguaquinol, we learned that the aldolate product required protection in order to survive the sulfoxide elimination. Therefore, 3.136 was protected uneventfully as triethylsilyl ether 3.137 (Scheme 3.23). Treatment of 3.137 with mCPBA at –78

°C yielded a mixture of sulfoxides and over-oxidized sulfone products. This result was surprising because no over-oxidation products were ever observed with the model system. Nevertheless, we quickly found that H2O2 (30% in H2O) in a mixture of CH2Cl2 and trifluoroethanol can oxidize

the sulfides to provide 3.138 without any detectable sulfone formation.110,111

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Scheme 3.23. Silyl protection and sulfide oxidation.

Microwave-assisted sulfoxide elimination was met with inconsistent results, depending on the scale and batch of material (Table 3.2). The reactions were typically messy and the yields of 3.139 varied from poor to moderate. Heating at 140 °C or below did not initiate any elimination under a variety of conditions (entries 1–4). When heated above 200 °C with Et3N,

naphthaldehyde 3.78 was detected in the crude 1H NMR, indicating desilylation and retro-aldol

fragmentation was occurring to an appreciable extent (entry 5). In addition, the elevated

temperatures frequently resulted in the formation of a rearrangement side product (3.140) in

significant quantities. Irradiation at 190 °C for 30 min resulted in a 2.5:1 ratio of desired product

(3.139) to rearranged product (3.140) (entry 6) and extended heating led to higher levels of 3.140

(entries 7–8). Unsurprisingly, elevated temperatures also produced a greater proportion of 3.140,

typically resulting in diminished isolated yields (entries 9–11).

Conventional heating using an oil bath led to more consistent sulfoxide elimination

results, potentially because of more accurate control over the reaction temperature. As expected,

lower temperatures (160 °C) suppressed formation of 3.140 but led to a substantial amount of

mono-elimination products (entries 12–15). Fortunately, the sulfoxide resulting from mono-

elimination could be isolated and resubjected to the reaction conditions to afford additional

3.139. Lastly, despite heating under conventional methods, exposure to 180 °C for 14 h produced

the lowest ratio of 3.139:3.140 to date, illustrating the importance of both time and temperature

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in this fastidious reaction (entry 16).

Table 3.2. Conditions investigated for sulfoxide elimination.

PhS Me O O O H H OTBS OTBS OTBS N N N

conditions O O O OSiEt3 PhS OSiEt3 OSiEt3 Br Br Br MeO O MeO MeO

OMe OMe OMe 3.138 3.139 3.140 Entry Conditions Resulta

1 iPr2NEt, o-DCB, 140 °C (µwave), 4 h No reaction

2Et3N, PhMe, 140 °C No reaction

3 P(OMe)3, Xylenes, 135 °C No reaction 4 Xylenes, 135 °C, 40 h No reaction

5Et3N, o-DCB, 240 °C (µwave), 20 min 3.139, Retro-aldol, decomp.

6 iPr2NEt, o-DCB, 190 °C (µwave), 30 min 3.139:3.140 = 2.5:1; (54%)

7 iPr2NEt, o-DCB, 190 °C (µwave), 1 h 3.139:3.140= 1.2:1; (45%)

8 iPr2NEt, o-DCB, 190 °C (µwave), 2 h 3.139:3.140 = 1.7:1; (45%)

9 iPr2NEt, o-DCB, 220 °C (µwave), 30 min 3.139:3.140 = 1.4:1; (46%) b 10 iPr2NEt, o-DCB, 220 °C (µwave), 30 min 3.139:3.140 = 0.7:1; (30%)

11 iPr2NEt, o-DCB, 225 °C (µwave), 40 min 3.139:3.140 = 1.0:1; (26%)

12 iPr2NEt, o-DCB, 160 °C, 5 h 3.139 + mono-sulfoxides; (56%)

13 iPr2NEt, o-DCB, 160 °C, 9 h 3.139 + mono-sulfoxides; (46%)

14 iPr2NEt, o-DCB, 160 °C, 14 h 3.139 + mono-sulfoxides; (50%) b 15 iPr2NEt, o-DCB, 160 °C, 14 h 3.139 + mono-sulfoxides; (44%)

16 iPr2NEt, o-DCB, 180 °C, 14 h 3.139:3.140 = 0.5:1; (17%) aYields in parentheses represent isolated yield of 3.139. bRepeated run.

We believe the undesired product (3.140) may arise from either of two possible

pathways: (1) a retro-Mukaiyama aldol reaction followed by a vinylogous Mukaiyama aldol

reaction (not shown) or (2) a sigmatropic [1,3]-rearrangement and alkene isomerization under the

high temperature reaction conditions. Although sigmatropic [1,3]-rearrangements usually require

an antarafacial geometry and are therefore typically forbidden, it is possible for carbon atoms to

undergo a suprafacial [1,3]-shift using the smaller lobe of an sp3 orbital, resulting in net

inversion of the sp3 center (Scheme 3.24).

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Scheme 3.24. Rationale for stereochemical inversion in the [1,3]-rearrangement.

In their synthesis of the cyclocitrinol core, the Leighton group attempted to perform a Cope

rearrangement on 3.144 and serendipitously discovered a similar suprafacial [1,3]-rearrangement

of a strained C–C bond to form 3.147 (Scheme 3.25).112–114 After performing some computational analysis, Leighton and coworkers found that this rearrangement is facilitated by a weakened and polarized C–C bond in 3.144 (indicated in red) that is in alignment with the

neighboring olefin. In our case, the C–C bond in 3.139 (indicated in red) is similarly polarized

and can adopt a conformation in which [1,3]-rearrangement is possible. Therefore, a congruent

mechanism seems to rationalize the observed product (3.140) most plausibly. In order to confirm

this mechanism, a thermal [1,3]-rearrangement should be performed using a single enantiomer of

Scheme 3.25. Leighton's example of a [1,3]-rearrangement and our observed [1,3]-rearrangement.

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3.139 to identify whether stereochemical inversion is occurring at the C9 position.

Although we were able to inhibit side product formation, we were never able to obtain

high yields of 3.139. We reasoned that if elimination could occur at lower temperatures through

a selenoxide or sulfilimine elimination, cleaner reactivity and improved yields may be possible.

Indeed, many selenoxide115–119 and sulfilimine120–125 eliminations have been shown to proceed under very mild conditions with excellent yields (Scheme 3.26). Unfortunately, we encountered difficulties displacing the two bromides in the dibromodiene with phenylselenide groups and were unable to pursue this idea further. Alternatively, oxidation to the sulfilimine was evaluated on 3.137 using various conditions with chloramine-T. Despite exposure to elevated temperatures

and various additives, mostly starting material was recovered in each case with trace amounts of

sulfoxide. Further experimentation with other nitrogen-transfer reagents is needed in order to

harness the utility of sulfilimines.

Scheme 3.26. Selenoxide and sulfilimine eliminations in organic synthesis.

Selenoxide: Marshall (1982): Kuehne (1996): SePh I I OTBS OTBS H2O2 mCPBA, CH2Cl2 N N CH2Cl2,rt Me –75 °C; then PPh ,–30°C 3 Me O (74%) O SePh N (62%) N H H O O CO Me 2 CO2Me 3.149 3.150 3.151 3.152 Sulfilimine: Ortiz (2015): OBz Chloramine-T OBz OBz O AcOH (0.1 equiv.) O nBuOH O O NH MeCN, 20 °C O NH 95 °C O NH N O N O N O (87%, 2 steps) S Me S NTs Me Me Ar Ar 3.155 3.153 3.154

3.4.4: Pentacycle Formation

The sulfoxide elimination product (3.139) was treated with several reductants to determine the most suitable criteria for imide reduction. When DIBAL-H was used, a

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regioisomeric mixture of hemiaminals, resulting from reduction at either the C1 or C2 position,

was isolated from the crude reaction mixture. Alternatively, reduction using LiBH4 afforded a

single regioisomer and diastereomer of the hemiaminal (3.156) (Scheme 3.27). Consistent with

the tetracyclic core synthesis, the configuration of the C2 hemiaminal was epimeric to that of

exiguaquinol;1 however, 3.156 was taken forth with the plan to perform a late-stage

epimerization after installation of the sulfonic acid moiety. Whether this single stereoisomer is

the kinetic product or if it arises from epimerization to the thermodynamically favored

configuration still remains unclear.

Scheme 3.27. Initial hit for reductive Heck cyclization.

Initially, when Pd(PtBu3)2 and sodium formate were employed in the intramolecular

reductive Heck reaction of 3.156, successful cyclization was observed in up to 71% yield

(Scheme 3.27). This result was particularly exciting because it demonstrated the utility of an aryl

bromide in our reductive Heck reaction. Unfortunately, this transformation was plagued by

inconsistent levels of conversion, ranging from a single catalyst turnover to full conversion

(Table 3.3, entry 1), and we decided that a brief survey of Pd catalysts, ligands, and conditions

was warranted. Heating at elevated temperatures led to full consumption of starting material but

only 13% isolated yield of product (entry 2). Surprisingly, the major component of this reaction

was ketone 3.158, arising from deprotection and oxidation of the C9 alcohol. Regardless of how

it is formed under reductive conditions, 3.158 can still be utilized in our synthesis by conversion

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to late-stage compounds (vide infra). The addition of tetrabutylammonium salts has proven

necessary for some Heck reactions and we tested its utility in our case.126,127 Although the use of

Bu4NBr suppressed ketone formation, it had a pronounced inhibitory effect on the catalytic

efficiency (entry 3). Moreover, the use of Ag2CO3 was detrimental to the reaction and did not provide any of the desired pentacycle (entry 4). This result was somewhat perplexing because

Overman has demonstrated that silver(I) additives tend to facilitate Heck reactions through formation a cationic Pd species which contains a free coordination site for alkene binding.128–130

Table 3.3. Survey of reductive Heck conditions for pentacycle formation.

H OH H OH OTBS OTBS N N conditions OSiEt3 O Me O OSiEt3 Br MeO MeO OMe

OMe 3.157 3.156 Catalyst Loading Entry Conditions Resulta (mol %) b 1Pd(PtBu3)2, HCO2Na, DMF, rt30–50 30–100% Conversion (Up to 71% yield) OH 2Pd(PtBu3)2, HCO2Na, DMF, 50 °C30 100% Conversion H 3.157: (13%) OTBS 3.158: (29%) N O 3Pd(PtBu3)2, HCO2Na, Bu4NBr, DMF, 70 °C30 50% Conversion Me O 4Pd(PtBu3)2, HCO2Na, Ag2CO3, DMF, rt20 No Reaction

5Pd[P(o-tol)3]2, HCO2Na, Et3N, DMF, 40 °C20 No Reaction MeO 6Pd2(dba)3,PtBu3, HCO2Na, dioxane, 40 °C 20 No Reaction OMe 7Pd(OAc)2,PCy3, HCO2Na,DMF,rt20 3.156anddecomp. 3.158 8 Pd(MeCN)2Cl2, HCO2H, PMP, DMF, 65 °C20 No Reaction 9Pd2(dba)3,[tBu3PH]BF4, HCO2Na 20 No Reaction Cy2NMe, DMF, 60 °C OH 10 Pd(PtBu3)2,[tBu3PH]BF4, HCO2Na, DMF, 55 °C30 100% Conversion H (71%) OTBS N 11 Pd(PtBu3)2,[tBu3PH]BF4, HCO2Na, DMF, 65 °C20 100% Conversion 3.157: (14%) OH 3.158: (5%) Me O 3.159: (60%)

12 Pd(PtBu3)2,[tBu3PH]BF4, HCO2Na,DMF,40°C 20 91% Conversion MeO (640 mg scale) (80%) OMe 13 Pd(PtBu3)2,[tBu3PH]BF4, HCO2Na,DMF,35°C 20 91% Conversion (850 mg scale) (86%) 3.159 aIsolated yield of 3.157 in parentheses unless indicated. bIrreproducible results.

Various other precatalysts, ligands, and additives were investigated to identify a better set

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of conditions to access pentacycle 3.157, but each failed to effect the desired Heck reaction

(entries 5–9).127,131–133 Intrigued by a report from the Fu group that utilized phosphonium tetrafluoroborate salts as air-stable precursors to phosphine ligands, we tested whether or not the presence of this additive would have an effect on our desired reaction. To our delight, an equimolar ratio of Pd(PtBu3)2 to [tBu3PH]BF4 resulted in full conversion to 3.157 with 71%

isolated yield (entry 10). When heated to 65 °C in the presence of 20 mol% catalyst, aryl

bromide 3.156 was fully consumed and the product lacking the triethylsilyl protecting group

(3.159) was isolated in 60% yield (entry 11). In order to prevent deprotection and other decomposition pathways, the reaction was performed at 35–40 °C and nearly full conversion was achieved, resulting in 80% yield and 86% yield respectively (entries 12–13). It is worth noting that these reactions were performed on over half a gram of 3.156 using only 20 mol% Pd catalyst. While we have not tried lowering the catalyst loading below 20 mol%, it would be worth investigating whether or not these optimized conditions would still provide 3.157 in good yields at lower Pd loadings.

The exact reason for the enhanced catalytic efficiency with [tBu3PH]BF4 remains unknown to us; however, we hypothesized that it is likely due to increase in the lifetime of the

134,135 active catalyst, Pd(PtBu3). While the presence of excess PtBu3 would be expected to favor

the inactive bis(phosphine) complex by Le Châtelier's Principle, the addition of its conjugate

acid may actually promote ligand dissociation to the active state. Alternatively, the added

[tBu3PH]BF4 may provide a “reservoir” of phosphine ligand, which becomes necessary when the

PtBu3 is oxidized to tBu3P=O. Mechanistic studies with added phosphonium salt are needed to

conclusively determine the cause of this enhanced reactivity.

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Scheme 3.28. Deprotection, oxidation, and oxidative cleavage of pentacycle 3.157.

Access to pentacycle 3.157 allowed us to investigate conditions for its deprotection and

oxidation (Scheme 3.28). We found that treatment with TBAF in THF led to rapid

decomposition, but deprotection under heterogeneous conditions using cesium fluoride in

acetonitrile slowly afforded triol 3.160 in modest yield. Next, manganese-based oxidants were

evaluated in the selective oxidation of the C9 benzylic alcohol. When subjected to MnO2 or

BaMnO4, little to no reactivity was detected. However, DDQ in dioxane oxidized the C9 position

selectively while leaving the remaining functionality untouched (Scheme 3.28).136 Interestingly, the X-ray crystal structure of 3.161 depicted the primary alcohol and the hemiaminal engaging in a seven-membered-ring hydrogen bond (Figure 3.3, shown in green).

Figure 3.3. Internal hydrogen bond observed in X-ray crystal structure of 3.161.

Next, we set out to unveil the C4 ketone. As anticipated, ozonolysis uncontrollably

oxidized 3.161 to a complex mixture at –78 °C. The electron-rich extended aromatic ring is susceptible to ozonolysis and undergoes oxidative cleavage, as evidenced by the loss of resonances attributed to the naphthalene protons in the NMR spectrum of the crude reaction

125

mixture. Although aromatic rings are typically stable towards ozonolysis, examples of electron-

rich aromatics undergoing oxidative degradation have been reported in the literature many times,

most notably by the Woodward group in their synthesis of strychnine.137 Therefore, a

dihydroxylation/diol cleavage sequence was employed as a milder alternative. Under Johnson–

Lemieux conditions (OsO4 and NaIO4 in a single pot), 3.161 was converted into ketone 3.162

138 with very poor yields (5–38%). Switching to Upjohn conditions (OsO4/NMO and NaIO4 in

two steps) produced ketone 3.162 cleanly and with improved isolated yields (Scheme 3.28).139

The presence of the intermediate diol was confirmed by 1H NMR and ESI mass spectrometry.

3.4.5: Sulfonic Acid Installation

With 3.162 in hand, we focused our attention on converting the primary alcohol into the

sulfonic acid on the taurine sidechain. In most cases, this transformation is accomplished by

either conversion of the alcohol into a leaving group followed by displacement with sodium

sulfite (Pathway A) or Mitsunobu reaction with a sulfur-based nucleophile then oxidation

(Pathway B) (Scheme 3.29). Before testing these conditions on our precious material, simplified

model systems were prepared.

Scheme 3.29. Two possible pathways for accessing sulfonate 3.165.

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We selected 3.102 as our model substrate for alkyl halide displacement, because we had

shown that it can be synthesized easily from imide 3.86 (Scheme 3.18). After several sulfonation

attempts using Na2SO3 in polar solvents, we were able to isolate sulfonic acid 3.166 in 17% yield

after heating in a dioxane/water mixture for 14 h (Scheme 3.30). The major byproducts isolated

from these displacement reactions included unreacted 3.102 and the primary alcohol resulting

from hydroxide displacement of the alkyl bromide. Although we were unable to improve the

yield of 3.166, we had proven that the desired reaction can take place on the model system.

Scheme 3.30. Sulfonic acid installation on model and desired substrates via the alkyl bromide.

Intending to evaluate the sulfonation reaction on the fully functionalized scaffold, the primary alcohol in 3.162 was converted into a leaving group (Scheme 3.30). At first, 3.162 was treated under Appel (PPh3 and CBr4 or I2) and mesylation conditions, only to witness

decomposition and elimination of the hemiaminal. Fortunately, a modified set of bromination

conditions, disclosed by Iranpoor and coworkers and utilizing PPh3, DDQ, and Bu4NBr, provided alkyl bromide 3.167 efficiently.140,141 After subjecting 3.167 to sodium sulfite in hot

aqueous dioxane, the desired sulfonic acid was never observed, despite incorporation of

sulfonate groups in the mass spectra. Instead, we believe the sulfite nucleophile preferentially

reacts with the hemiaminal hydroxyl group under these conditions because the C2 hemiaminal

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proton resonance at δ5.5 ppm is absent in the crude 1H NMR spectrum. Due to our inability to

control this undesired reactivity, sulfonic acid installation was tested via the Mitsunobu route.

The simplified model system for thioester oxidation (3.168) was prepared by acetylation

of decanethiol and exposure to several oxidants to effect a one-pot thioester hydrolysis and

sulfide oxidation. Treatment with NaIO4 returned unreacted starting material, but mCPBA and

142 methyltrioxorhenium(VII) with H2O2 successfully transformed 3.168 into decanesulfonic acid.

Therefore, we set out to evaluate these conditions on our complex exiguaquinol substrate.

Scheme 3.31. Sulfonic acid installation on model and desired substrates via Mitsunobu reaction.

To gain access to the thioester, a Mitsunobu reaction was carried out on 3.162 using

thioacetic acid. The reliability of this reaction was improved by preforming the PPh3/DIAD complex and transferring the betaine into the reaction mixture.143,144 Extremely high yields were

achieved with this procedure to provide useful quantities of 3.170.

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Table 3.4. Oxidation conditions tested on thioester 3.170.

O O H OH H OH SAc SO3Na N N O oxidants O Me O Me O

MeO MeO OMe OMe

3.170 3.165 Entry Conditions Result

1 Oxone, MeOH/H2O, rt Decomposition

2 Oxone, THF, Bu4NOH, H2O Decomposition

3 NaOCl, TEMPO, KBr, NaHCO3 (aq), MeCN Decomposition

4O2,h (254 nm), Li2CO3, MeOH Decomposition

5DMDO,Me2CO/CH2Cl2, 0 °C Decomposition

6CH3ReO3,H2O2, MeCN, rt Decomposition

7H2O2, AcOH Decomposition

8H2O2, AcOH, 60 °C Decomposition 9 Oxone, KOAc, AcOH Decomposition

10 Urea H2O2, TFAA, MeCN, 0 °C to rt Decomposition 11 mCPBA, THF/H2O, 0°C to rt 3.165: (31–53%)

A comprehensive examination of oxidants was then performed on 3.170 (Table 3.4).

® 145–147 148 149 Milder conditions using Oxone , TEMPO/NaOCl, O2 with UV light, or DMDO in

acetone150 were tested first, but these all resulted in eventual decomposition of thioacetate 3.170

(entries 1–5). Although it worked for our model substrate, methyltrioxorhenium(VII) and H2O2 also decomposed 3.170 (entry 6). Methyltrioxorhenium(VII) has been shown to be a competent catalyst for Baeyer–Villiger oxidations and 3.170 may be particularly susceptible to this undesired pathway because it contains two ketones.151,152 The majority of thioester oxidations

that can be found in the literature use reactive peracids to accomplish this task.153–158 However,

in-situ generated peracetic acid led to rapid decomposition of thioester 3.170 (entries 7–9).

Unsurprisingly, trifluoroperacetic acid also degraded thioester 3.170 (entry 10). The

disappearance of the yellow color in conjunction with peracid oxidation suggests that these

reagents are not only reacting with the thioester but also with the naphthyl portion of the

molecule. Taking inspiration from a report by the Keck group in which mCPBA is used to

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oxidatively cleave a t-butyl thioester, we found that mCPBA is capable of cleanly converting

thioester 3.170 into sulfonic acid 3.165 in modest yield.159 While we were unable to dramatically

improve the efficiency of this transformation, enough material could be synthesized to evaluate

the final steps of our synthesis.

3.4.6: Hemiaminal Epimerization

Calculations performed by Dr. Hung Pham in the Houk group suggested that a synthesis

of sulfonate 3.165 should permit epimerization to the (R)-configured hemiaminal.1 At this stage,

the natural (R)-configuration is more thermodynamically preferred owing to anomeric

stabilization in the energy minimized conformation (where the polar sulfonate group is in a

hydrogen bond with the C2 hemiaminal hydroxyl proton). Therefore, experiments were

conducted to invert the hemiaminal to its natural configuration (Table 3.5).

We focused our attention on epimerization of 3.165, despite our expectation that E1cb elimination of the hemiaminal would be a major competing pathway. Employing Fukuyama's conditions160 (See Scheme 2.25), incomplete conversion to the (R)-epimer (3.3) was observed

along with significant amounts of decomposition or elimination (entries 1–2). Concerned that

elimination was facilitated by reversible proton transfer in the presence of Cs2CO3, deprotonation was performed using sodium hydride or potassium t-butoxide in polar aprotic solvent (entries 3–

4). Interestingly, 3.165 was very cleanly converted to a new aldehyde-containing compound, which was assigned structure 3.172 (Table 3.5). Anticipating that 3.172 could be cyclized back to the hemiaminal in an overall two-step inversion, 3.172 was treated with scandium triflate, resulting in isolation of the elimination product (3.171) most likely through the intermediacy of a hemiaminal (entry 5). We were pleased to find that hemiaminal 3.3 could be isolated without elimination when a suspension of silica gel and methanol was used (entry 6). Remarkably, 3.3 is

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the only epimer observed from the ring closure, thus validating the ground state computational

hypotheses proposed by the Houk group at the outset of our synthetic endeavor! The epimer

formed was confirmed by NOE analysis and comparison of the NMR spectra to that of the

natural product.

Table 3.5. Hemiaminal epimerization attempts.

The most plausible mechanism for the two-step hemiaminal epimerization is shown in

Scheme 3.32. Treatment of 3.165 with strong base results in deprotonation of the hemiaminal alcohol to form the alkoxide, which can open to reveal a β-ketoaldehyde and tautomerize to aldehyde 3.172. Although this tautomer was unexpected, there are several instances of similar tautomerizations taking place in related systems.161–163 In our case, we have observed the

presence of this aldehyde tautomer (3.172) by crude 1H NMR; however, 3.172 is unstable to

chromatographic isolation and partially cyclizes to 3.3. Complete conversion to 3.3 is achieved

with mild acid by tautomerization back to the β-ketoaldehyde followed by ring closure.

Tautomerization is believed to occur prior to ring closure to prevent formation of a strained

alkene intermediate. A successful synthesis of 3.3 permitted us to investigate the final sulfation

step en route to exiguaquinol.

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Scheme 3.32. Proposed mechanism of two-step hemiaminal epimerization.

3.5: Studies Toward Regioselective Sulfation

Sulfated alcohols are a common structural motif among marine natural products.164

However, owing to their high degree of polarity and water solubility, the isolation and handling of sulfated compounds can be significantly more complicated than typical organic molecules. In addition, many sulfated compounds are prone to hydrolysis under acidic or basic conditions. For these reasons, the sulfation of an alcohol is usually postponed until the end of a synthesis to prevent complications.165 For our synthesis of exiguaquinol, we envisioned our demanding

regioselective dihydroxynaphthalene monosulfation would require significant optimization or

possibly even the development of a new methodology; therefore, a model system for sulfate

installation was synthesized to reduce the amount of precious material used in this process.

Our original plan to access model system 3.178 began with the nucleophilic addition of isopropenyl Grignard reagent to naphthaldehyde 3.78 followed by a low-yielding 5-endo Heck cyclization to form cyclopentanone 3.175.166 Next, the α-position was methylated with NaOtBu

and MeI to form naphthalene 3.176 in 29% yield.167 Alternatively, a more efficient route to 3.176

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commenced with the addition of t-butyl Grignard reagent to naphthaldehyde 3.78 and oxidation

to ketone 3.177 using PCC. The cyclopentanone ring was forged in remarkably high yield by a

Pd-catalyzed C–H activation reaction adapted from the Fagnou group.168 3.176 was treated with

CAN followed by sodium dithionite to afford dihydroxynaphthalene 3.178.

Scheme 3.33. Two parallel pathways for the synthesis of model system 3.178.

To evaluate the sulfate installation on fully functionalized exiguaquinol substrates, three

late-stage compounds were demethylated to unveil the dihydroxynaphthalene (Scheme 3.34).

Treatment of thioester 3.170 with CAN provided naphthoquinone 3.179 in excellent yield and

reduction with sodium dithionite yielded unstable dihydroxynaphthalene 3.180,169 which was

used immediately in the sulfation attempts without purification. The demethylation reactions of

3.165 and 3.3 were complicated by aqueous miscibility issues and resulted in complete

decomposition of the quinone intermediate when concentrated in the presence of CAN.

Therefore, reductive quenching with sodium dithionite enabled a one-pot oxidation/reduction

protocol and permitted observation of 3.181 and 3.182 (Scheme 3.34). Unfortunately, 3.181 and

3.182 were also highly unstable and were used in the sulfation attempts without further

purification.169

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Scheme 3.34. Deprotection of dimethoxynaphthalene substrates.

O O O H OH H OH H OH SAc SAc SAc N N N O CAN O Na2S2O4 (aq) O Me O MeCN/H2O Me O Et2O, THF Me O

(87%) (50%)

MeO O HO OMe O OH

3.170 3.179 3.180

O O H OH H OH SO3Na SO3Na N N CAN O O MeCN/H2O; Me O Me O then Na2S2O4

(43%) MeO HO OMe OH

3.165 3.181 O O H OH H OH SO3Na SO3Na N N CAN O O MeCN/H2O; Me O Me O then Na2S2O4

(75%) MeO HO OMe OH 3.3 3.182

With access to several dihydroxynaphthalene substrates, conditions were explored to

effect their monosulfation. The conventional reagent-based approaches for installing a sulfate

group include the use of four main categories of compounds: (1) sulfuric acid derivatives, (2)

DCC/H2SO4, (3) sulfur trioxide-amine complexes, and (4) chlorosulfonate esters with a cleavable protecting group. Each reagent class was considered in our synthesis of the monosulfate.

3.5.1: Sulfuric Acid Derivatives

Sulfuric acid derivatives, such as chlorosulfonic acid or sulfamic acid, are highly reactive sulfating reagents, capable of sulfating most free amines or alcohols.170,171 Because of its

reactivity, chlorosulfonic acid frequently yields sulfated products in moderate to poor yields and

is often reserved for sulfation of molecules containing limited amounts of additional

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functionality to preclude decomposition.171 Nevertheless, chlorosulfonic acid has been used in

many examples, including by the Vanderwal group in the synthesis of the chlorosulfolipid

malhamensilipin A (3.184) (Scheme 3.35).172 In this example, chlorosulfonic acid is used to

deprotect the primary TBS group and sulfate both the primary and secondary alcohols.

Chlorosulfonic acid is also capable of sulfating phenolic alcohols, as shown by the precedent

from the Lattuada and Botting groups (Scheme 3.35).173,174 We were skeptical about whether our complex exiguaquinol substrates could survive exposure to chlorosulfonic acid owing to the multitude of potential acid-mediated side reactions. Additionally, we anticipated difficulty achieving regiocontrol with such a highly reactive reagent; therefore alternative methods for sulfation were investigated instead.

Scheme 3.35. Examples of sulfations using chlorosulfonic acid.

3.5.2: DCC/H2SO4 Sulfation

In 1969, the Mumma group disclosed a versatile method for sulfate formation using a

mixture of DCC and sulfuric acid in DMF.175 Although their standard "dilute" conditions (0.08

M in nucleophile) were not sufficient for the sulfation of phenols, "concentrated" conditions (0.8

M in nucleophile) were capable of forming the sulfate esters of phenol, α-naphthol, and β-

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naphthol. Scheme 3.36 shows an example of this selectivity phenomenon as it relates to the

syntheses of 17β-estradiol-17-sulfate (3.190) and estrone sulfate (3.192).176 The mechanism of

sulfate formation is believed to involve the initial activation of H2SO4 by addition to DCC

(3.193) followed by alcohol addition and ejection of dicyclohexylurea (3.198) (Scheme 3.36).

Despite being a very practical method, the use of DCC/H2SO4 has not been widely adopted in

chemical synthesis and the majority of examples of this methodology originate from the Mumma

group’s seminal work.

Scheme 3.36. Examples of sulfate installation using DCC/H2SO4 and the mechanism of this transformation.

When treated with DCC and 2.2 equivalents of H2SO4, 3.178 was converted mostly to

disulfate 3.199 (Table 3.6, entry 1). When reducing the amount of H2SO4 to 1.0 equivalents, a

nearly equimolar ratio of monosulfates and disulfate was observed (entry 2). Surprisingly, under

these conditions, there appears to be a slight preference for the desired regioisomer (3.200) of

monosulfate compared to the undesired isomer (3.201) of our model system! Hoping to improve

the ratio of 3.200 to 3.201, the reaction was cooled further to –40 °C (entry 3). Unfortunately,

while the formation of disulfate 3.199 was suppressed, a nearly 1:1 mixture of monosulfates was observed in the crude reaction mixture.

136

Table 3.6. DCC/H2SO4 sulfation.

Although these results appeared promising for application to exiguaquinol, we were

afraid that the preferential reactivity towards aliphatic alcohols may decompose the hemiaminal.

Nevertheless, 3.181 was treated with to DCC and H2SO4 at 0 °C (entry 4). Unfortunately,

decomposition occurred and no sulfated products were observed.

3.5.3: SO3∙Amine Complexes

Owing to their strongly acidic properties, the previous methods are often not conducive to sulfation of sensitive substrates. Thus, stable adducts of sulfur trioxide with amines have been used preferentially to prevent acid-mediated side reactions. Many are commercially available solids which demonstrate a range of sulfating capability (SO3·NEt3 ≈ SO3·NMe3 < SO3·pyridine

< SO3·DMF). Nucleophilic alcohols are readily sulfated by adducts containing stronger bases

(SO3·NR3) while weaker nucleophiles, including phenols, usually require stronger sulfation

171 reagents (SO3·pyridine or SO3·DMF). With more reactive SO3·amine adducts, the sulfation of

phenols often occurs at room temperature or with moderate heating; however, at higher

temperatures (above 100 °C), sulfonation of the aromatic ring takes place.177

Because of the inherent versatility of these milder reagents, SO3·amine complexes have

been used extensively in organic synthesis, particularly in the sulfation of phenolic alcohols

(Scheme 3.37). In their synthesis of adociasulfate 1 (3.203), Overman demonstrated that

137

SO3·pyridine can be used to disulfate hydroquinone 3.202 in the penultimate step of their

synthesis.178 Shortly afterwards, the Kobayashi group disulfated hydroquinone 3.204 as the final

179 step in their synthesis of the terpenoid natural product akaterpin (3.205) using SO3·pyridine.

Intriguingly, they found that monosulfated products were inadvertently observed when the sulfation was performed on a truncated model system at room temperature.180

Scheme 3.37. Examples of phenolic sulfations on complex molecules using SO3·amine adducts.

In addition, several groups have explored the chemical and biological effects of sulfation

by converting natural products into sulfated analogues (Scheme 3.37). For example, Breslow was

able to convert 6-ketoestrone (3.206) into its sulfated derivative by treatment with SO3·pyridine

138

181 at 55 °C to explore the diastereoselectivity of ketone reduction. Additionally, SO3·DMF was

used by the Faulkner group to sulfate the free phenols of lamellarin α (3.208).182 While attempting to obtain a mixture of monosulfates by titrating 3.208 with SO3·DMF, Faulkner and

coworkers noticed that only disulfate 3.209 was formed in low yield. They surmised that

sulfation of the first phenol activates the molecule for further sulfation, possibly through

182 complexation of SO3·DMF with the previously formed sulfate.

Often, achieving high regiocontrol in the sulfation of phenols can prove very challenging.

However, there are several interesting examples of monosulfate formation of phenols using

SO3·amine complexes in the literature (Schemes 3.38 and 3.39). Prudhomme showed that

dihydroxynaphthalene 3.210 can be monosulfated with SO3·pyridine with high selectivity for the

product depicted (3.211).183 Although no explanation for regioselectivity is provided, an internal

hydrogen bond between the imide carbonyl and the proximal phenolic alcohol is likely

responsible for precluding sulfation at this position.

Scheme 3.38. Example of a dihydroxynaphthalene monosulfation by Prudhomme.

Some fantastic examples of monosulfate formation in the context of complex molecule

synthesis comes from the work on the symbioimine natural products (Scheme 3.39). Both

symbioimine (3.214) and neosymbioimine (3.217) contain a 1,3-dihydroxybenzene monosulfate

moiety and three groups have targeted this challenge with different strategies. The first total

synthesis was conducted by Maier in 2006 and culminated in a disulfation with SO3·pyridine at

elevated temperature followed by an acid-mediated desulfation using p-TsOH to afford racemic

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3.214 in high yield.184 Quickly thereafter, they followed up with a synthesis of (+)-

neosymbioimine (3.217) using a fairly similar disulfation-desulfation strategy, although a

methanol and water mixture was sufficient for disulfate degradation.185 While acidic conditions

usually result in complete sulfate decomposition, 3.214 appears to be a special substrate

predisposed to monosulfate formation owing to the zwitterionic stabilization between the

ammonium salt and the aryl sulfate. Concurrently, the Snider group published the second

racemic total synthesis of symbioimine (3.214) in which they treated diol 3.212 with 10

equivalents of SO3·DMF at room temperature in a mixture of DMF and pyridine to afford 53%

of the desired product (3.214) along with 25% of the disulfate byproduct (3.218).186 Even though

disulfate formation could not be fully suppressed, this example shows that a stronger sulfating

agent at lower temperatures can be used for monosulfation. Lastly, the Thomson group disclosed

the first enantioselective synthesis of (+)-symbioimine just one year later.187 Sulfation of 3.212

was accomplished in a single step using SO3·pyridine at room temperature over 24 h, although in

fairly low isolated yield.

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Scheme 3.39. Monosulfation examples in the syntheses of symbioimine (3.214).

Maier (2006): OH OSO3 OH Me Me Me N SO ·pyr HN p-TsOH, H2O HN H 3 H H pyr, 70 °C dioxane, rt OH OSO3 OSO3 H H H (74%, 2 steps) H H H 3.212 3.213 3.214: (±)-symbioimine

Maier (2007): OH OSO3 OH Me Me Me N SO ·pyr HN HN H 3 H MeOH/H2O H pyr, 60 °C 36 °C OH OSO3 OSO3 H H H Me Me (79%, 2 steps) Me H H H Me Me Me 3.215 3.216 3.217: (+)-neosymbioimine

Snider (2006): OH OH OSO3 Me Me Me N SO ·DMF, DMF/ HN HN H 3 H H pyr, Na2SO4,rt OH OSO3 OSO3 H H H

H H H 3.212 3.214: (±)-symbioimine (53%) 3.218 (25%) Thomson (2007): OH OH Me Me N HN H H SO3·pyr, pyr OH OSO3 H H (27%) H H 3.212 3.214: (+)-symbioimine

Despite the numerous chemical syntheses of exiguaquinol relatives (See Section 1.6), there have been no reports of any halenaquinol (3.219) or xestoquinol (3.220) derivatives undergoing monosulfation to its natural sulfated form (Scheme 3.40)! This gap in the literature is likely due to undesirable reactivity, arising from poor regiocontrol of monosulfation, competitive oxidation to the naphthoquinone, and disulfation. For our synthesis, we hypothesized that the electron-withdrawing properties of the C9 ketone should electronically differentiate the two aromatic alcohols and sulfation will occur preferentially on the more electron-rich alcohol to provide the desired regioisomer (3.2) (Scheme 3.40). Therefore, this idea was first investigated with our tricyclic model system (3.178).

141

Scheme 3.40. Hypothesis for regioselective sulfation of dihydroxynaphthalenes.

The many successful examples of phenolic sulfations involving SO3·amine complexes

drove us to spend the majority of our effort on this strategy (Table 3.7). We began by treating

model system (3.178) with SO3·pyridine in pyridine at room temperature but no reactivity was

observed (entry 1). However, heating this reaction mixture led to decomposition of the

dihydroxynaphthalene (entry 2). Attempting to deprotonate the dihydroxynaphthalene with NaH

prior to sulfation resulted in formation of the naphthoquinone (3.224) as the major product (entry

3). We were pleased to find that SO3·pyridine in MeCN at 40 °C effected monosulfation of 3.178

in a 1.2:1.0 ratio of 3.200 to 3.201 without any observable disulfated product (entry 4)!188 The observed regioselectivity slightly favored the desired sulfate, suggesting our hypothesis for selectivity is less significant than originally anticipated. While this still appeared promising, we were unfortunately unable to reproduce these results under the same conditions (entry 5).

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Table 3.7. Sulfation of model system 3.178.

We next investigated the use of SO3·DMF in our desired monosulfation. A brief survey

of solvents was performed to determine the optimal choice for this transformation (entries 6–10).

No reactivity was observed in DMF (entry 6) and when MeCN was used, loss of 3.178 was

observed by TLC; however, 3.178 was reisolated upon aqueous workup. The use of nitromethane provided a mixture of monosulfated and disulfated products, along with significant amounts of decomposition. No conversion was observed with an ionic liquid solvent, and a solvent mixture of MeCN and pyridine produced a complex mixture. In order to monitor the reaction progress by

NMR, the sulfation was performed in d3-MeCN and full conversion to the disulfate was observed

with no noticeable decomposition (entry 11). Only complex mixtures were obtained following

aqueous NaHCO3 workup. To mitigate this problem, TBAI was added as a phase transfer reagent

(entry 12). While this plan worked successfully to produce 3.223, salt metathesis to exchange the

143

tetrabutylammonium counterion for an alkali metal ion did not proceed. Instead, we found that

quenching with aqueous Na2CO3 permitted isolation of disulfate 3.199 without the need for chromatography, and scaling up provided 3.199 in 63% yield (entries 13–14). Lastly, when only one equivalent of SO3·DMF was added, a 1.6:1.3:1.0 mixture of 3.200:3.201:3.199 was formed

(entry 15).

SO3·amine complexes were then evaluated for their ability to sulfate our complex

exiguaquinol substrates (Table 3.8). First, the hemiaminal epimer (3.181) was treated with

SO3·DMF in CD3CN to monitor the reaction progress (entry 1); however, decomposition was observed by 1H NMR under these conditions and with pyridine/DMF as solvent (entry 2). To

simplify handling of the starting material, thioester 3.180 was substituted in our attempted

sulfations. When SO3·DMF was added to 3.180 in CD3CN or MeCN, decomposition was again

observed and no hemiaminal was present in the 1H NMR spectrum (entries 3–4). Hoping to prevent decomposition of 3.180, SO3·DMF was replaced with SO3·pyridine, a milder sulfating reagent. Unfortunately, complex mixtures of polar compounds were also obtained under each of the conditions employed (entries 5–8). Although the reaction mixtures were fairly complex, the presence of aryl signals between δ6.8 ppm and δ7.7 ppm suggested the possibility of monosulfation; however, we were unable to isolate the monosulfate by chromatography and no mass corresponding to the desired product was observed by ESI-MS. The sulfation was also tested on the natural epimer (3.182) using SO3·pyridine in pyridine. These conditions resulted in

a complex mixture of products without the formation of exiguaquinol (entry 9). When carried out

1 in d5-pyridine, no sulfation was observed and the aromatic H NMR signals around δ7 ppm

vanished. Based on literature precedence and ESI-MS data, the products formed appear to be

zwitterionic oxy-d5-pyridinium adducts (3.228 and 3.229), arising from addition of solvent into

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189 an oxidized naphthalene (entry 10). While we were disappointed that SO3·amine complexes

did not result in a successful sulfation to form exiguaquinol, a more comprehensive evaluation of

this class of sulfating reagents and reaction conditions could potentially provide the necessary

recipe for accessing exiguaquinol.

Table 3.8. Sulfation attempts on complex exiguaquinol substrates.

3.5.4: Protected Chlorosulfonate Esters

The state-of-the-art approach to sulfate installation involves the formation of a sulfate

diester from a chlorosulfonate ester that is cleavable at a later stage. This reagent amounts to a

protecting group for the sulfated compound because it permits the protected substrate to survive

harsh reaction conditions and undergo standard purification methods.171 Therefore, unlike the

previous methods, the introduction of a sulfate diester need not be performed at the very end of

the sequence because the protected products are less polar and exhibit greater functional group

tolerance.

The first example of this protection strategy was disclosed by Perlin in 1981 and utilized

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phenyl chlorosulfonate in the sulfation of carbohydrates (Scheme 3.41).190 Although it was

useful for protected carbohydrate substrates (3.230), the harsh deprotection conditions

diminished the overall utility of this strategy, as deprotection involved complete hydrogenation

of the phenyl protecting group to the cyclohexyl group then hydrogenolysis with PtO2 under 37 psi of H2 gas. In 2004, the Taylor group found the trichloroethyl group to be an effective protecting group for phenolic sulfates because it can be cleaved under milder conditions using Zn or Pd/C and ammonium formate (Scheme 3.41).165 They proved this method to be competent in

the sulfation of estrone derivative 3.233, which was then difluorinated and deprotected to

provide aryl sulfate 3.236 in high yield. A modification of this methodology using the

trichloroethyl sulfonylimidazolium triflate salt was applied to the sulfation of carbohydrates (not

shown).191 This reagent was preferred because it contained a good leaving group that was poorly

nucleophilic, which enabled the successful O- or N-sulfation and deprotection of various carbohydrates in moderate to excellent yields. Most recently, a sulfate protecting group strategy using isobutyl or neopentyl chlorosulfonate was developed by Widlanski and coworkers as an alternative method that avoids reductive deprotection conditions.192 They showcased its

efficiency using estrone (3.237) and several carbohydrates as substrates. Despite these few

advances in the field of masked sulfates, no single strategy is generally applicable to every

substrate and significant room for improvement exists for both the sulfation and deprotection

steps.

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Scheme 3.41. Strategies for introducing a protected sulfate group.

Perlin (1981): Me Me Me Me Me Me O O O H NaH, THF H H2 (37 psi), PtO2 H O O O O K CO ,EtOH/HO; O O O PhOSO2Cl O 2 3 2 O Me Me Me then DOWEX Na+ O Me (75%) O Me O Me HO H PhO3SO H ion-exchange resin NaO3SO H 3.230 3.231 3.232 Taylor (2004): Me O Me O Me O Cl3CCH2OSO2Cl DAST H Et3N, DMAP, THF H CH2Cl2 H OHC OHC HF2C O O O O H H (97%) H H (91%) H H S S HO Cl3C O O Cl3C O O 3.233 3.234 3.235 Me O 10% Pd/C H HCO NH ,MeOH HF2C 2 4 H H (86%) H4NO3SO 3.236 Widlanski (2006): O O O Me NaHMDS, THF, –15 °C; Me Me NaSCN, Et3N i H then BuOSO2Cl H Me2CO, 55 °C H O O H H H H (96%) H H (82%) Me S HO O O NaO3SO 3.237Me 3.238 3.239

Even though there are many benefits to this strategy, protected sulfate esters have only been used in a few total syntheses. In 2005 and 2006, Fürstner disclosed syntheses of dictyodendrins B, C, and E, a family of telomerase inhibiting alkaloids, which featured Taylor's trichloroethyl protecting group strategy (Scheme 3.42).193,194 In their synthesis, the sulfation of

3.240 proceeds in 92% yield to generate sulfate diester 3.241, which is treated with boron

trichloride and TBAI to demethylate the remaining methoxy groups. Lastly, the trichloroethyl

group is removed with Zn and ammonium formate to provide dictyodendrin B (3.242) as the ammonium salt. The endgame sulfation strategies for the dictyodendrin C and E syntheses (not shown) were similar to the dictyodendrin B example. In addition, Tokuyama's 2010 synthesis of dictyodendrins A and B relied on nearly the same endgame sulfation/deprotection strategy (not shown).195 In 2011, Iwao disclosed a synthesis of lamellarin α 20-sulfate (3.245) analogues

(Scheme 3.42).196 Using the trichloroethyl protecting group strategy, excellent yields were

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obtained for sulfate diester installation, MOM deprotection, and sulfate deprotection to provide lamellarin α 20-sulfate (3.245). It is worthwhile to note that the trichloroethyl sulfate diester remains completely intact even after exposure to concentrated HCl in MeOH/CH2Cl2. Finally, the Mikula group published a synthesis of zearalenone-14-sulfate (3.249) utilizing the sulfonylimidazolium triflate reagent (Scheme 3.42).197,198 They found that when using 3.247

instead of the chlorosulfonate ester, sulfation of a model system provided the monosulfate

preferentially over the disulfate (not shown). Unfortunately, application of this strategy to

zearalenone (3.346) gave a nearly 1:1 mixture of monosulfate and disulfate esters, with the

monosulfate (3.248) being isolated in 43% yield. Deprotection with Zn and ammonium formate

yielded the ammonium salt of zearalenone-14-sulfate (3.249) in 95% yield.

Scheme 3.42. Protected sulfates in total synthesis.

The protected sulfate strategy was initially applied to our tricyclic model system (Table

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3.9). At first, a variety of bases were evaluated in conjunction with trichloroethyl chlorosulfonate

to identify the most suitable amine for our transformation. Using Et3N/DMAP, pyridine,

imidazole, or Hünig's base all yielded the quinone byproduct (3.224) (entries 1–5). When no base

was employed with DMF as solvent, no reactivity was observed (entry 6). However, when 2

equivalents of chlorosulfonate and 5 equivalents of DABCO were used, a nearly 1:1 mixture of

3.250:3.224 was produced (entry 7). Adding more equivalents of chlorosulfonate led to a higher

ratio of 3.250:3.224, ultimately resulting in an isolated yield of 3.250 in up to 60% (entries 8–9).

Alternative solvents, such as MeCN were explored (entry 10); however, THF remained the most

effective choice for the desired transformation. Other sulfation reagents, including trimethylsilyl

chlorosulfonate and 3.247, were briefly tested but resulted in recovered starting material or

quinone formation, respectively (entries 11–12).

Table 3.9. Protected sulfation of model system 3.178.

OH O OR1 O O O Me conditions Me Me Me Me Me

OH OR2 O 3.178 3.224 3.250: R1 =R2 =SO3CH2CCl3 Entry Conditions Result

1Cl3CCH2OSO2Cl, Et3N, DMAP, THF, 0 °C 3.224

2Cl3CCH2OSO2Cl, Et3N, DMAP (cat.), THF, rt 3.224

3Cl3CCH2OSO2Cl, pyr, THF, rt 3.224

4Cl3CCH2OSO2Cl, Imidazole, THF 3.224 5Cl3CCH2OSO2Cl, iPr2NEt, THF 3.224 6Cl3CCH2OSO2Cl,DMF,rt 3.178

7Cl3CCH2OSO2Cl (2 equiv.), DABCO, THF, rt 3.250:3.224 = 1:1

8Cl3CCH2OSO2Cl (3 equiv.), DABCO, THF, rt 3.250:3.224 = 2.4:1 (43%)

9Cl3CCH2OSO2Cl (4 equiv.), DABCO, THF, rt 3.250 (60%) 10 Cl3CCH2OSO2Cl (1 equiv.), DABCO, MeCN 3.224

11 Me3SiOSO2Cl, DABCO, THF, rt 3.178 12 3.247, THF, rt 3.224

Quinone 3.224 seems to be the most common byproduct arising from this class of reagents. It is plausible that the chlorosulfonate can serve as a "Cl+" source to effectively oxidize

the dihydroxynaphthalene to the naphthoquinone in the presence of base (Scheme 3.43). One

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method to circumvent this problem would be to use the fluorosulfate derivative, as this class of

sulfonyl halides has been shown by Sharpless and Finn to be significantly less prone to redox

reactivity.199 While we were unable to obtain any sulfuryl fluoride (Vikane®) starting material, we believe it would be worthwhile to investigate this reagent in our desired sulfate installation in the future. Alternatively, it is possible that the protected monosulfate undergoes rapid oxidation in the presence of base, which would explain our failure to observe it under all conditions tested.

Regardless of the mechanism, it appeared that disulfation was the only way to incorporate any protected sulfates on our model system.

Scheme 3.43. Two possible mechanisms for quinone formation.

The successful set of conditions was then applied to the sulfate diester formation of thioester 3.180 and a 1.6:1.0 ratio of quinone 3.179 to protected disulfate 3.253 was observed.

Unfortunately, decomposition occurred upon deprotection and none of the unmasked disulfate product was observed in the 1H NMR spectrum. Although no monosulfates were produced, this

method appears to be the most promising route for accessing exiguaquinol. Further

experimentation with other protecting groups (i.e. iBu or neopentyl) and bases is needed to

identify suitable conditions for monosulfation that precludes quinone formation. In addition, a

protocol for unmasking the sulfate group in complex exiguaquinol substrates needs to be

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developed.

Scheme 3.44. Protected sulfation of pentacyclic exiguaquinol substrate 3.180.

3.5.5: Enzymatic Sulfation

Sulfated molecules are fairly common motifs in nature and have been studied extensively to understand their biological function and biogenesis. The sulfation of organic molecules is believed to occur in living organisms for three main purposes: (1) to increase propensity for excretion or elimination of toxic compounds, (2) to elicit a particular biological response, and (3) to regulate the release or concentration of a bioactive congener.171 The sulfation of alcohols is an

enzymatically-controlled process in which sulfotransferase enzymes transport a sulfonate group

– (SO3 ) from a donor molecule, usually 3’-phosphoadenosine-5’-phosphosulfate (PAPS) or p-

nitrophenyl sulfate (p-NPS), to the specific alcoholic substrate.200 The Wong group has

demonstrated that sulfotransferase activity can be performed with catalytic quantities of PAPS

when a sacrificial sulfonate donor is included.201,202 In contrast, sulfatase enzymes are

responsible for cleaving the O–S bond to remove a sulfonate group. Both types of enzymes have

been discovered for aliphatic and aryl sulfates, and some work has been done using these

enzymes in an ex-vivo setting for chemoenzymatic transformations.203–207

We chose to try the aryl sulfotransferase enzyme from Haliangium ochraecum (HocAST) with our system because the García-Junceda group discovered it to be fairly promiscuous towards phenolic substrates (Table 3.10).207 Additionally, this PAPS-independent

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sulfotransferase relies on p-NPS and was demonstrated to sulfate phenols and phosphates

selectively over aliphatic alcohols. Substrates 3.254–3.268 were tested by García-Junceda (Table

3.10) and they found that HocAST was most active towards 4,4'-biphenol (3.260), possibly due

to the symmetry of the molecule. Perhaps most intriguing to us was their observation that both

monosulfated and disulfated catechol were observed by ESI-MS when catechol (3.255) was

treated with HocAST and p-NPS in aqueous buffer. This information encouraged us to

investigate chemoenzymatic sulfation for the final step of our exiguaquinol synthesis.

Table 3.10. Substrate specificity evaluation performed on HocAST by the García-Junceda group.207

Professor García-Junceda supplied us with a sample of the plasmid containing the

HocAST gene, which was recombinantly expressed from E. coli cells with assistance from our collaborator, Jake Milligan in Professor Sheryl Tsai's lab. After FPLC purification and cleavage of the 6xHis-tag, we tested chemoenzymatic sulfations on three small molecule acceptors: hydroquinone (3.269), catechol (3.255), and 1,4-dihydroxynaphthalene (3.270) (Figure 3.4).

Each phenolic acceptor was evaluated at 4 °C, 23 °C, and 37 °C to determine the optimal

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temperature for enzyme activity. Unfortunately, despite repeated experimentation, we were

unable to conclusively identify any sulfated or disulfated products by ESI-MS using Professor

García-Junceda's methods. With no evidence of sulfation in our model systems, it remained

inconclusive that our complex exiguaquinol substrate would undergo successful reactivity;

therefore, efforts were focused on more traditional sulfation methods.

Figure 3.4. Phenolic substrates tested for HocAST activity.

In the end, we were unable to selectively form the final monosulfate with any of the

strategies evaluated. Although many more conditions remain to be tested, it is not surprising that

decomposition is facile, as exemplified by the highly light-, air-, and heat-sensitive nature of

known related pentacyclic dihydroxynaphthalenes.169,208

3.6: Entry into Enantioselective Synthesis: Aldol Desymmetrization

As discussed earlier, we envisioned that our strategy targeting exiguaquinol would be amenable to an asymmetric synthesis at the desymmetrizing aldol stage. This challenging transformation first requires the use of a chiral base to enantioselectively deprotonate meso- bicyclic imide 3.103 and an achiral Lewis acid to effect aldolization with naphthaldehyde 3.78.

Most of the literature on desymmetrizing enolate chemistry utilizes chiral lithium amide bases

with cyclic ketones,209–214 but several examples by Simpkins employ imides. Scheme 3.45 illustrates a few relevant instances of desymmetrizing alkylations, Claisen condensations, and

aldol reactions performed by the Simpkins group with cyclic imides. At first, Simpkins used α-

phenylethylamine-derived monoamine base 3.272 for the enantioselective deprotonation and C-

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silylation of 3.271 and similar bicyclic succinimides.215 Later, they discovered that α-

phenylethylamine-derived diamine base 3.275 is optimal for the desymmetrizing enolization of prochiral imides 3.274 and 3.277.216,217 As expected, the enolates can engage with a variety of

electrophiles including alkyl halides, Mander's reagent, or benzaldehyde. Using this strategy, the

Simpkins group completed an asymmetric synthesis of the proposed structure of jamtine

(3.279).217 Lastly, glutarimides can be engaged in an aldol reaction with benzaldehyde using the

dilithiated diamine base 3.281.218 Although they obtained poor levels of diastereoselectivity (dr =

1:1), a high enantiomeric excess was observed for aldol adduct 3.282.

Scheme 3.45. Desymmetrization of meso-imides by the Simpkins group.

Me Me

O O H Ph N Ph Me3Si Li NPh 3.272 NPh LiCl, Me3SiCl H H O –100 °C O 3.271 (65%, 93% ee) 3.273

Ph Ph Me Me O O H NLi HN Me Ph Ph NBn 3.275 NBn THF, –78 °C; H H O then MeI O 3.274 (62%, >98% ee) 3.276 Ph Ph Me Me MeO O Ar NLi HN O Ar H MeO2C N Ph 3.275 Ph MeO H N N MeO2C THF, –78 °C; then MeO CCN H O 2 H O (85%, 95–98% ee) 3.277 3.278 3.279: (+)-jamtine (Ar = 3,4-(MeO)2C6H3) Ph Ph Me Me OH O NLi LiN Ph O Ph 3.281 Ph H F NBn F NBn THF, –78 °C; 3.280O then PhCHO 3.282 O (75%, 97% ee, dr = 1:1)

Inspired by the work of Simpkins, we initially attempted to apply chiral base technology

to our synthesis of exiguaquinol's tetracyclic core (Table 3.11). Employing the monolithiated α-

phenylethylamine-derived diamine base (3.286), no productive reactivity was observed when the

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reaction was maintained at –78 °C or when warmed to ambient temperature (entries 1–2). In one

instance, trace amounts of the aldol adduct were obtained in 47% ee after warming to room

temperature (entry 3). Hoping to promote enolization, the dilithiated diamine base 3.286·Li was

explored; however, destruction of the bicyclic imide substrate took place (entry 4). The cause for

diminished reactivity with diamine base 3.286 compared to that of Simpkins likely derives from

the substitution at the β-position of our bicyclic imide (–CH2SPh groups). The additional steric strain involved in deprotonation presumably raises the barrier for enolization and requires increased temperatures to proceed. Finally, a smaller chiral monoamine base (3.287) was evaluated in our aldol reaction and similarly, no conversion was detected at –78 °C (entry 5).

When warmed to room temperature, a minute quantity of aldol product 3.285 was isolated and

found to be completely racemic, indicating that no discrimination of enantiotopic α-protons was

taking place during enolization (entry 6).

With this information, we turned our attention to the elaborated substrates for our

exiguaquinol synthesis. As expected, no reactivity was observed when 3.103 was deprotonated

with monolithiated chiral diamine base 3.286 and maintained at –78 °C (entry 7). To our delight,

allowing the deprotonation step to warm from –78 °C to 0 °C procured aldol adduct 3.136 in

56% yield, albeit with only 18% ee (entry 8). Repetition of these conditions with gradual warming to 0 °C resulted in a similar isolated yield and a two-fold increase in enantioselectivity

(entry 9). Attempting to further increase the enantioselectivity, the reaction was warmed to –45

°C; unfortunately, no conversion to 3.136 was observed (entry 10). Lastly, only decomposition

was seen when monoamine base 3.287 was investigated for enantioinduction in this aldol step

(entry 11). While this array of reaction conditions is far from exhaustive, our example with 37% ee is a promising initial result for this transformation. Further optimization studies involving

155

other chiral bases and temperatures should be carried out to improve the yield and enantiomeric

purity of 3.136.

Table 3.11. Asymmetric aldol reactions performed on model system and elaborated system.

PhS Ph Ph PhS H O Me Me H O NLi HN CHO conditions NMe Ph 3.286 Ph NMe Me Me I O H O PhS OH 3.284 I Ph N Ph PhS 3.283 Li 3.285 3.287

PhS O PhS H OMe OTBS H O CHO N OTBS conditions N O Br H PhS OH O Br OMe MeO PhS 3.103 3.78 3.136 OMe Entry Substrate Conditions Yield (%) % ee 1 3.283 3.286, THF, –78 °C No rxn – 2 3.283 3.286 THF, –78 °C to rt No rxn – 3 3.283 3.286, THF, –78 °C to rt <10 47 4 3.283 3.286·Li, THF, –78 °C Decomp – 5 3.283 3.287, THF, –78 °C No rxn – 6 3.283 3.287, THF, –78 °C to rt <10 0

7 3.103 3.286 THF, –78 °C; BF3 OEt3 No rxn –

8 3.103 3.286, THF, –78 to 0 °C; BF3 OEt3 56 18

9 3.103 3.286, THF, –78 to 0 °C; BF3 OEt3 46 37

10 3.103 3.286, THF, –78 to –45 °C; BF3 OEt3 No rxn – 11 3.103 3.287, THF, –78 °C; BF3 OEt3 Decomp –

3.7: Future Directions and Conclusions

Future efforts towards the synthesis of exiguaquinol should focus on improving two key

reactions: the sulfoxide elimination and the monosulfate formation. The development of a

successful sulfilimine or selenoxide elimination would likely afford improved yields and abolish

this step as the “bottleneck” in our synthesis.

The monosulfation of complex exiguaquinol intermediates will most likely be achieved

using the chlorosulfonate ester strategy. Future work using trichloroethyl chlorosulfonate or

similar reagents should be carried out on substrate 3.182. If disulfation occurs preferentially over

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monosulfation, it would be worthwhile to evaluate conditions for the hydrolysis of a single

sulfate group to generate exiguaquinol.

Scheme 3.46. Summary of our progress toward exiguaquinol.

Applying the knowledge gained from our synthesis of exiguaquinol's tetracyclic core

(3.1), we developed an 18-step synthesis of exiguaquinol des-sulfate (3.175) (Scheme 3.46). We discovered that naphthaldehyde 3.78 could be accessed in five steps from 3,4-dibromothiophene and can undergo aldolization with bicyclic imide 3.103. Furthermore, a reductive Heck cyclization forges the pentacyclic scaffold of exiguaquinol (3.152) and a Mitsunobu/oxidation sequence was developed to install the sulfonic acid group. Lastly, a late-stage hemiaminal

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epimerization was realized, which provided access to the natural configuration of exiguaquinol

(3.3). While attempts to regioselectively install the final sulfate were ultimately unsuccessful, we

remain optimistic that the proper set of conditions can be identified through further

experimentation.

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3.8: Experimental Procedures:

General Experimental. All reactions were carried out under an inert atmosphere of argon in oven-

dried or flame-dried glassware using Teflon® coated magnetic stir bars. Commercial reagents were

used as received unless otherwise noted. Microwave reactions were performed in a CEM Discover

Microwave or an Anton Parr Monowave 300 Microwave. Reactions were monitored by thin-layer

chromatography (TLC) performed on 60 Å EMD Millipore glass-backed TLC plates impregnated

with a fluorescent dye using UV light as a visualizing agent and KMnO4/NaOH, p-anisaldehyde

or ceric ammonium molybdate and heat as developing stains. Flash chromatography was

performed on EMD (0.040–0.063 mm) silica gel. NMR spectra were recorded on a Bruker 400,

500, or 600 MHz spectrometer and calibrated using residual non-deuterated solvent as an internal reference. NMR spectra were obtained at 25 °C unless otherwise noted. Chemical shifts are reported in ppm; the following abbreviations were used to explain multiplicities: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad signal. Coupling constants are reported in hertz (Hz). FT-IR spectra were recorded on a Perkin-Elmer Spectrum RX1 or a Varian 640 spectrometer. High resolution mass spectra (HRMS) were recorded on a Waters LCT Premier spectrometer using ESI-TOF (electrospray ionization-time of flight) unless otherwise noted.

Melting points (Mp) are uncorrected and were measured on a Mel-Temp II melting point apparatus.

3,6-Dimethoxy-2-(trimethylsilyl)phenol (3.33). To a solution of TMEDA (0.03 mL, 0.18 mmol)

159

in Et2O (2 mL) at room temperature was added a solution of nBuLi in hexane (0.08 mL, 0.018 mmol). 3.32 (0.020 g, 0.084 mmol) was added and the reaction mixture was warmed to 40 °C.

After 0.5 h, the cloudy suspension was cooled to 0 °C and TMSCl (0.04 mL, 0.34 mmol) was

added dropwise. The reaction was warmed to room temperature, stirred for 1 h, and quenched with

1M HCl (10 mL). The aqueous phase was extracted with 1:1 EtOAc/pentane (2 x 10 mL) and the

combined organic phases were dried over MgSO4, filtered, and concentrated to yield an oil, which

was purified by column chromatography (SiO2, 2:98 – 5:95 EtOAc:pentane) to afford 3.33 as a colorless oil (0.0096 g, 0.042 mmol, 51%).

1 H NMR (500 MHz, CDCl3) δ 6.78 (d, J = 8.6 Hz, 1H), 6.29 (d, J = 8.6 Hz, 1H), 5.92 (s, 1H), 3.83

13 (s, 3H), 3.71 (s, 3H), 0.32 (s, 9H); C NMR (125 MHz, CDCl3) δ 159.3, 151.2, 141.1, 112.7,

+ 112.0, 100.9, 56.7, 55.7, 1.3; LRMS (ESI) m / z calcd for C11H18O3SiNa (M + Na) 249.0917,

found 249.19.

3,6-Dimethoxy-2-(trimethylsilyl)phenyl triflate (3.34). To a solution of 3.33 (0.065 g, 0.28

mmol) in CH2Cl2 (7 mL) was added Et3N (0.08 mL, 0.57 mmol). At –78 °C, Tf2O (0.07 mL, 0.40

mmol) was added. After stirring for 1 h, the reaction mixture was quenched with saturated aqueous

NH4Cl (10 mL), warmed to room temperature, and extracted with EtOAc (3 x 20 mL). The

combined organic phases were dried over MgSO4, filtered, and concentrated to yield an oil, which

was purified by column chromatography (SiO2, 5:95 EtOAc:pentane) to afford 3.34 as a colorless

oil (0.0681 g, 0.190 mmol, 66%).

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1 H NMR (600 MHz, CDCl3) δ 6.95 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.77

13 (s, 3H), 0.37 (s, 9H); C NMR (125 MHz, CDCl3) δ 158.3, 145.3, 142.8, 124.1, 119.1 (q, J =

321.3 Hz), 114.3, 110.1, 56.3, 56.0, 0.9.

Benzocyclobutene 3.36. To a solution of 3.34 (0.049 g, 0.14 mmol) in ethyl vinyl ether (10 mL)

was added a solution of TBAF in THF (0.21 mL, 0.21 mmol). The reaction mixture was stirred at

room temperature for 1 h and H2O (10 mL) was added. The organic phase was dried over MgSO4, filtered and concentrated to yield an oil, which was purified by column chromatography (SiO2,

5:95 EtOAc:pentane) to afford 3.36 as a colorless oil (0.013 g, 0.062 mmol, 46%).

1 H NMR (500 MHz, CDCl3) δ 6.71 (d, J = 8.8 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1H), 5.10 (d, J = 4.1

Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 3.74–3.60 (m, 2H), 3.52 (dd, J = 13.6, 4.3 Hz, 1H), 3.20 (d, J

13 = 13.6 Hz, 1H), 1.27 (t, J = 7.0 Hz, 3H); C NMR (125 MHz, CDCl3) δ 148.9, 148.7, 131.2, 127.4,

116.5, 114.3, 75.9, 63.9, 56.8, 56.7, 37.9, 15.6; HRMS (ESI) m / z calcd for C12H16O3Na (M +

Na)+ 231.0997, found 231.1005.

Naphthoquinone 3.47. To a solution of 3.46 (0.0954 g, 0.411 mmol) in CH2Cl2 (10 mL) was

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added Et3N (1.14 mL, 8.22 mmol). After cooling to –78 °C, Tf2O (0.083 mL, 0.49 mmol) was

added dropwise and the reaction mixture was stirred for 1 h at this temperature, before being

warmed to 0 °C and stirring for 3 h. NaHCO3 (20 mL) was added and the aqueous phase was extracted with EtOAc (2 x 15 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to yield an oil, which was purified by column chromatography (SiO2, 10:90 –

20:80 EtOAc:hexanes) to afford 3.47 as a colorless oil (0.0573 g, 0.157 mmol, 40%).

1 13 H NMR (600 MHz, CDCl3) δ 8.77 (s, 1H), 7.97 (s, 1H), 7.11 (s, 2H), 4.03 (s, 3H); C NMR (150

MHz, CDCl3) δ 182.62, 182.56, 162.9, 151.6, 139.4, 139.1, 136.0, 132.1, 131.1, 129.5, 121.1,

118.9 (q, J = 319 Hz), 53.6; IR (thin film) ν 2958, 1736, 1679, 1432, 1218, 1136 cm-1; LRMS

– (ESI) m / z calcd for C26H13F6O14S2 (2M – H) 726.9651, found 726.91.

Naphthoate 3.48. To a solution of 3.47 (0.050 g, 0.14 mmol) in Et2O (10 mL) was added a solution of Na2S2O4 (0.358 g, 2.06 mmol) in H2O (10 mL). The biphasic mixture was mixed with a pipette

every 10 min for 1 h. The aqueous phase was extracted with Et2O (2 x 15 mL), dried over MgSO4, filtered, and concentrated to yield a residue, which was immediately dissolved in DMF (4 mL). To this solution was added K2CO3 (0.057 g, 0.41 mmol), 18-crown-6 (0.0007 g, 0.003 mmol), and

MeI (0.19 mL, 3.02 mmol). The reaction mixture was heated to 85 °C for 14 h and cooled to room

temperature. H2O (15 mL) was added and the reaction mixture was extracted with CH2Cl2 (3 x 15

mL). The combined organic phases were washed with saturated aqueous NH4Cl (1 x 15 mL), H2O

(1 x 15 mL), and brine (1 x 15 mL), dried over MgSO4, filtered, and concentrated to yield an oil,

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which was which was purified by column chromatography (SiO2, 15:85 EtOAc:hexanes) to afford

3.48 as a brown oil (0.020 g, 0.051 mmol, 37%).

1 H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.08 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4

13 Hz, 1H), 4.01 (s, 3H), 3.98 (s, 3H), 3.97 (s, 3H); C NMR (125 MHz, CDCl3) δ 164.7, 150.1,

148.9, 145.4, 129.4, 128.2, 124.5, 121.6, 119.0 (q, J = 320 Hz), 116.1, 107.6, 105.5, 56.1, 56.0,

52.8; IR (thin film) ν 2954, 1729, 1426, 1278, 1211, 1140 cm-1; LRMS (ESI) m / z calcd for

+ C15H13F3O7SNa (M + Na) 417.0226, found 417.00.

Aryl Triflate 3.51. To a solution of 3.50 (0.49 g, 2.11 mmol) in CH2Cl2 (50 mL) was added Et3N

(5.88 mL, 42.2 mmol). The reaction mixture was cooled to –78 °C and Tf2O (0.39 mL, 2.32 mmol)

was added. After 0.5 h, the reaction was quenched with saturated NaHCO3 (20 mL). The organic phase was washed with water (20 mL) and brine (20 mL), dried over MgSO4, filtered, and

concentrated to yield a blue solid, which was purified by column chromatography (SiO2, 15:85

EtOAc:hexanes) to afford 3.51 as a white solid (0.74 g, 2.04 mmol, 96%).

1 H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 8.14 (s, 1H), 7.57–7.50 (m, 2H), 6.99 (dd, J = 5.5, 3.0

13 Hz, 1H), 4.03 (s, 3H), 4.02 (s, 3H); C NMR (125 MHz, CDCl3) δ 164.5, 155.1, 144.4, 134.3,

132.4, 128.5, 127.2, 122.4, 120.9, 118.9 (q, J = 321 Hz), 116.2, 107.3, 55.8, 52.8; IR (thin film) ν

2957, 1727, 1505, 1422, 1214, 1142, 794, 610; HRMS (ESI) m / z calcd for C14H11F3O6SNa (M

+ Na)+ 387.0126, found 387.0127.

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Aryl Iodide 3.52. To a solution of 3.51 (9.88 g, 27.12 mmol) in dioxane (400 mL) was added

NaOAc (6067 g, 81.36 mmol), B2(pin)2 (13.77 g, 54.24 mmol), and Pd(PPh3)4 (3.13 g, 2.71 mmol).

The reaction mixture was heated to 90 °C for 5 h. After cooling to room temperature, hexanes (400

mL) were added and the reaction mixture was filtered through SiO2, rinsing with 1:1

CH2Cl2/hexanes. The filtrate was concentrated and the crude residue was purified by column

chromatography (SiO2, 40:60 – 60:40 CH2Cl2:hexanes) to afford the boronic ester with excess

B2(pin)2. The crude boronic ester was immediately dissolved in dry DMF (550 mL) and potassium

iodide (10.48 g, 63.13 mmol), cuprous iodide (0.87 g, 4.59 mmol), and 1,10-phenanthroline (1.14

g, 6.31 mmol) were added. After 20 min, H2O (0.22 mL) was added and the reaction mixture was

heated to 85 °C for 36 h. After cooling to room temperature, H2O (800 mL) and Et2O (500 mL)

were added, followed by 1M HCl (500 mL). The phases were separated and the aqueous phase

was extracted with Et2O (3 x 200 mL), washed with H2O (2 x 100 mL) then brine (100 mL). The organic phase was dried over MgSO4, filtered, concentrated, and purified by column

chromatography (SiO2, 0:100 – 15:85 EtOAc:hexanes) to afford 3.52 as a white solid (2.72 g, 7.95

mmol, 29% over 2 steps).

1 H NMR (500 MHz, CDCl3) δ 8.89 (s, 1H), 8.28 (s, 1H), 7.48–7.39 (m, 2H), 6.90 (d, J = 7.3 Hz,

13 1H), 4.00 (s, 3H), 3.98 (s, 3H); C NMR (125 MHz, CDCl3) δ 167.2, 154.2, 135.5, 132.7, 131.9,

131.2, 127.9, 127.7, 120.7, 106.5, 87.8, 55.8, 52.7; IR (thin film) ν 2949, 1731, 1574, 1455, 1273,

+ 1204, 1113, 791; HRMS (ESI) m / z calcd for C13H11O3INa (M + Na) 364.9651, found 364.9650.

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3-Iodo-5-methoxy-2-naphthaldehyde (3.54). To a solution of 3.52 (0.30 g, 0.88 mmol) in THF

(15 mL) at room temperature was added DIBAL-H (0.66 mL, 4.22 mmol) dropwise. After 1 h, 1M

HCl (10 mL) was added carefully. The aqueous phase was extracted with Et2O (3 x 15 mL) and

the combined organic extracts were combined, washed with brine (10 mL), dried over MgSO4, filtered, and concentrated to yield a white solid, which was dissolved in CH2Cl2 (50 mL). MnO2

(2.5 g, 10 mass equiv.) was added and the suspension was stirred at room temperature for 2 h and filtered through a plug of SiO2, rinsing with CH2Cl2. The filtrate was concentrated to yield an

orange solid, which was purified by column chromatography (SiO2, 5:95 – 15:85 EtOAc:hexanes)

to afford 3.54 as an orange solid (0.22 g, 0.70 mmol, 79% over 2 steps).

1 H NMR (600 MHz, CDCl3) δ 10.24 (s, 1H), 8.83 (s, 1H), 8.32 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H),

13 7.47 (t, J = 7.8 Hz, 1H), 6.94 (dd, J = 7.3, 0.7 Hz, 1H), 4.01 (s, 3H); C NMR (125 MHz, CDCl3)

δ 196.0, 154.3, 134.9, 133.1, 131.8, 131.6, 129.6, 128.0, 121.9, 107.5, 92.2, 55.9; IR (thin film) ν

2838, 1680, 1578, 1452, 1268, 1105, 996, 879, 786, 732; HRMS (CI) m / z calcd for C12H13O2NI

+ (M + NH4) 329.9991, found 329.9984.

Diene 3.57. To a flame-dried vial equipped with a stirbar was added Grubbs’ II catalyst (0.066 g,

0.08 mmol) under Ar (g). A solution of TMS-propargyl alcohol (0.200 g, 1.56 mmol) in CH2Cl2

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(8 mL) was added and the reaction mixture was sealed in a bomb reactor. The vessel was filled to

200 psi and evacuated four times with ethylene, then filled and sealed at 200 psi. The reaction mixture was left to stir at room temperature for 36 h then depressurized and filtered through a plug of SiO2. The black solution was concentrated to yield 3.57 as a black oil (0.231 g, 1.48 mmol,

95%) that was used without further purification.

1 H NMR (500 MHz, CDCl3) δ 5.74 (d, J = 2.2 Hz, 1H), 5.49 (d, J = 1.9 Hz, 1H), 5.14 (s, 1H), 4.96

13 (s, 1H), 4.21 (s, 2H), 0.15 (s, 9H); C NMR (125 MHz, CDCl3) δ 150.8, 150.4, 126.6, 111.3, 65.4,

-0.7; IR (thin film) ν 3352, 2956, 1989, 1632, 1408, 1249, 1048, 839; HRMS (ESI) m / z calcd for

+ C8H16OSiNa (M + Na) 179.0868, found 179.0868.

Naphthoquinone 3.59. To a solution of 3.57 (0.017 g, 0.107 mmol) in toluene (2 mL) in a

microwave vial was added p-benzoquinone (0.115 g, 1.07 mmol). The reaction mixture was heated

to 125 °C for 500 min in a microwave reactor (300 W) with a 30 min ramp time. The black reaction

mixture was filtered and concentrated to yield a crude black solid, which was purified by column

chromatography (SiO2, 10:90 – 20:80 EtOAc:pentane) to afford 3.59 as a yellow solid (0.015 g,

0.058 mmol, 54%).

1 H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 8.19 (s, 1H), 6.96 (s, 2H), 4.91 (d, J = 3.7 Hz, 2H),

13 1.89 (br s, 1H), 0.41 (s, 9H); C NMR (125 MHz, CDCl3) δ 185.6, 185.5, 153.0, 146.1, 138.9,

138.8, 133.0, 132.4, 129.6, 124.1, 64.9, 0.2; IR (thin film) ν 3507, 2957, 1667, 1586, 1313, 1252,

– 1053, 838; HRMS (ESI) m / z calcd for C14H15O3Si (M – H) 259.0790, found 259.0789.

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Naphthoquinone Carbaldehyde 3.288. To a solution of 3.59 (0.020 g, 0.075 mmol) in CH2Cl2

(2 mL) was added PCC (0.032 g, 0.150 mmol). The reaction mixture was stirred at room temperature for 12 h and the solvent was removed carefully. The residue was washed with 50%

EtOAc/pentane (3 x 10 mL) and filtered through a plug of SiO2. The filtrate was dried with MgSO4, filtered, and concentrated to yield 3.288 as a yellow solid (0.0150 g, 0.058 mmol, 78%).

1 H NMR (500 MHz, CDCl3) δ 10.30 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 7.07 (d, J = 10.3 Hz, 1H),

13 7.05 (d, J = 10.3 Hz, 1H), 0.42 (s, 9H); C NMR (125 MHz, CDCl3) δ 192.5, 185.0, 184.5, 150.4,

144.9, 139.11, 139.09, 134.0, 132.9, 132.6, 130.2, 0.0; IR (thin film) ν 2957, 1715, 1672, 1291,

1244, 841.

Naphthaldehyde 3.60. To a test tube containing 3.288 (0.0150 g, 0.058 mmol) in Et2O (6 mL)

was added a solution of Na2S2O4 (0.151 g, 0.870 mmol) in H2O (6 mL). The biphasic mixture was

agitated by pipette every 10 min for 1 h. The organic phase was separated, dried with MgSO4, filtered, and concentrated to yield a yellow oil. The crude yellow oil was dissolved in acetone (2 mL) and K2CO3 (0.024 g, 0.174 mmol) and CH3I (0.08 mL, 1.276 mmol) were added. The reaction

mixture was heated to 60 °C overnight then diluted with EtOAc (10 mL) and washed with saturated

aqueous NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL). The organic phase was dried with

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MgSO4, filtered, concentrated, and purified by column chromatography (SiO2, 7:93

EtOAc:pentane) to afford 3.60 as a yellow-green solid (0.0075 g, 0.026 mmol, 45%).

1 H NMR (500 MHz, CDCl3) δ 10.19 (s, 1H), 8.72 (s, 1H), 8.54 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H),

13 6.80 (d, J = 8.4 Hz, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 0.40 (s, 9H); C NMR (125 MHz, CDCl3) δ

194.1, 150.2, 149.6, 138.4, 136.5, 131.4, 130.7, 127.6, 125.8, 107.3, 105.1, 56.1, 56.0, 0.3; IR (thin

film) ν 2924, 2853, 1685, 1462, 1242, 1184, 1098, 840; HRMS (ESI) m / z calcd for C16H20O3SiNa

(M + Na)+ 311.1079, found 311.1071.

3-Bromo-4-(hydroxymethyl)thiophene 1,1-dioxide (3.82). To neat trifluoroacetic anhydride (13 mL, 95.1 mmol) was added 30 % aqueous hydrogen peroxide solution (5.83 mL, 51.4 mmol) at 0

°C slowly. After 5 minutes, a solution of the thiophene (1.24 g, 6.42 mmol) in CH2Cl2 (120 mL)

was added and the reaction was allowed to warm to room temperature. After stirring for 3 h,

saturated aqueous NaHCO3 was added slowly and the organic phase was separated. MeOH was

added and the organic phase was washed with brine (1 x 100 mL), dried with MgSO4, filtered, and

concentrated. The residue was purified by column chromatography (SiO2, 30:70 EtOAc:hexanes)

to afford 3.82 as a colorless oil (0.38 g, 1.69 mmol, 26%).

1 H NMR (500 MHz, CDCl3) δ 6.85 (d, J = 2.5 Hz, 1H), 6.57 (dd, J = 4.8, 2.3 Hz, 1H), 4.52 (d, J

13 = 1.9 Hz, 2H), 2.12 (br s, 1H); C NMR (125 MHz, CDCl3) δ 144.6, 131.2, 126.2, 125.5, 60.4; IR

(thin film) ν 3400, 2918, 2851, 1726, 1309, 1137; LRMS (APCI) m / z calcd for C5H6BrO3S (M +

H)+ 224.9221, found 225.0.

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Naphthoquinone 3.289. A solution of 3.82 (0.38 g, 1.69 mmol) and p-benzoquinone (1.82 g, 16.9 mmol) in toluene (150 mL) was heated to reflux for 48 h. The reaction mixture was cooled to room temperature and concentrated. Water was added to the residue and the aqueous phase was extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts were dried with MgSO4, filtered, and

concentrated. The residue was purified by column chromatography (SiO2, 20:80 EtOAc:hexanes)

to afford 3.289 (0.195 g, 0.73 mmol, 43%).

1 H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 11.0 Hz, 2H), 6.99 (dd, J = 13.9, 10.3, 2H), 4.86 (d, J

13 = 5.5 Hz, 2H), 2.11 (t, J = 6.0 Hz, 1H); C NMR (125 MHz, CDCl3) δ 184.6, 184.0, 146.7, 139.1,

138.6, 131.9, 131.0, 130.8, 128.6, 126.2, 64.7; IR (thin film) ν 3320, 2920, 1516, 1472, 1245, 1098,

+ 830; LRMS (APCI) m / z calcd for C11H8BrO3 (M + H) 266.9657, found 267.1.

Naphthoquinone Carbaldehyde 3.83. To a solution of 3.289 (0.036 g, 0.135 mmol) in CH2Cl2

(2 mL) was added pyridinium chlorochromate (0.038 g, 0.18 mmol). The solution was left to stir overnight then concentrated. The residue was washed with 1:1 EtOAc:Hexanes (4 x 10 mL), filtered through a short plug of SiO2 and concentrated to yield 3.83 as a faintly yellow solid (0.0311 g, 0.117 mmol, 87%).

169

1 H NMR (500 MHz, CDCl3) δ 10.45 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.07 (dd, J = 14.9, 10.4

13 Hz, 2H); C NMR (125 MHz, CDCl3) δ 190.3, 183.31, 183.29, 139.6, 138.8, 137.2, 135.3, 132.5,

132.3, 131.2, 128.8; IR (thin film) ν 2921, 1696, 1672, 1588, 1321, 1297, 849; LRMS (APCI) m /

+ z calcd for C11H6BrO3 (M + H) 264.9495, found 265.1.

6,7-Dibromo-1,4-dimethoxynaphthalene (3.85). To a solution of 3.84 (6.04 g, 19.1 mmol) in

Et2O (250 mL) was added an aqueous solution of Na2S2O4 (250 mL, 0.764 M, 191 mmol). The

biphasic mixture was stirred at a high rate for 2 h full consumption of starting material was

observed by TLC. The layers were separated and the aqueous phase was extracted with Et2O (2 x

50 mL). The combined organic phases were dried with MgSO4, filtered and concentrated to yield

a faintly blue solid. The crude naphthoquinol was immediately dissolved in DMF (300 mL) and

K2CO3 (25.36 g, 183.5 mmol), 18–crown–6 (0.101 g, 0.38 mmol) and CH3I (4.76 mL, 76.5 mmol)

were added. The reaction mixture was heated to 95 °C for 12 h and allowed to cool to room

temperature. The purple reaction mixture was filtered to remove solids and H2O (200 mL) was

added. The aqueous phase was extracted with 1:1 EtOAc/hexanes (4 x 150 mL) and the combined

organic phases were washed with H2O (100 mL) and brine (100 mL), dried with MgSO4, filtered, and concentrated. The brown residue was purified by column chromatography (SiO2, 0:100 –

10:90 EtOAc:hexanes) to afford 3.85 as a white solid (5.34 g, 15.4 mmol, 81%).

1 13 H NMR (600 MHz, CDCl3) δ 8.47 (s, 2H), 6.70 (s, 2H), 3.94 (s, 6H); C NMR (125 MHz, CDCl3)

δ 148.5, 127.1, 126.1, 122.4, 104.6, 55.9; IR (thin film) ν 2036, 1625, 1574, 1410, 1317, 1262,

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-1 + 1115, 1088, 883, 801 cm ; HRMS (CI) m / z calcd for C12H10O2Br2 (M) 343.9048, found

343.9037.

3-Bromo-5,8-dimethoxy-2-naphthaldehyde (3.78). A solution of 3.85 (0.687 g, 1.99 mmol) in

dry Et2O (25 mL) and THF (25 mL) was cooled to –98 °C (MeOH/Liq. N2) and nBuLi in hexanes

(2.42 M, 0.98 mL, 2.38 mmol) was added down the wall of the flask to keep the temperature below

–90 °C. After stirring for 20 min, DMF was added and the reaction mixture was allowed to warm to room temperature. After 1 h, H2O (20 mL) was added and the aqueous phase was extracted with

1:1 EtOAc/Hexanes (2 x 25 mL). The organic extracts were washed with brine (15 mL), dried with

MgSO4, filtered, and concentrated. The yellow residue was purified by column chromatography

(SiO2, 5:95 EtOAc:hexanes) to afford 3.78 as a yellow solid (0.56 g, 1.90 mmol, 96%).

1 Mp = 156–160 °C; H NMR (500 MHz, CDCl3) δ 10.48 (s, 1H), 8.82 (s, 1H), 8.47 (s, 1H), 6.86

(d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 3.96 (s, 3H); 13C NMR (125 MHz,

CDCl3) δ 192.3, 151.0, 148.3, 130.3, 129.7, 127.2, 126.9, 124.8, 121.3, 107.9, 104.6, 56.0, 55.9;

IR (thin film) ν 2930, 1685, 1653, 1618, 1575, 1465, 1325, 1265, 1110, 1087, 800 cm-1; HRMS

+ (CI) m / z calcd for C13H12O3Br (M + H) 294.9970, found 294.9982.

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Succinimide 3.86. To a stirring solution of 3.12 (6.26 g, 21.0 mmol) in toluene (300 mL) was

added maleimide (1.94 g, 19.9 mmol). A reflux condenser was added and the reaction was heated to reflux. After 16 h, the solution was cooled to room temperature and concentrated. The crude oil was purified by column chromatography (SiO2, 0:100 – 10:90 EtOAc:PhMe) to afford 3.86 as a

white solid (7.10 g, 18.0 mmol, 90%).

1 H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 7.36 (d, J = 8.3 Hz, 4H), 7.28 (t, J = 7.7 Hz, 4H), 7.19

(t, J = 7.6 Hz, 2H), 5.92 (s, 2H), 3.55 (dd, J = 13.3, 6.7 Hz, 2H), 3.30 (dd, J = 13.3, 9.2 Hz, 2H),

13 3.28 (s, 2H), 2.36 (s, 2H); C NMR (125 MHz, CDCl3) δ 177.9, 135.7, 132.3, 129.9, 129.2, 126.6,

44.9, 36.5, 35.0; IR (thin film) ν 3237, 3057, 1775, 1701, 1582, 1352, 1184, 737 cm-1; HRMS

+ (ESI) m / z calcd for C22H21NO2S2Na (M + Na) 418.0912, found 418.0897.

Alkyl Chloride 3.97. To a stirring suspension of NaH (0.031 g, 0.78 mmol, 60% in mineral oil)

in DMSO (10 mL) was added a solution of 3.86 (0.100 g, 0.253 mmol) in DMSO (10 mL). After

15 min, 1-bromo-2-chloroethane (0.065 mL, 0.78 mmol) was added and stirred for 14 h. H2O (50

mL) was added and the reaction mixture was extracted with Et2O (2 x 30 mL). The combined

organic phases were dried over MgSO4, filtered, and concentrated to yield 3.97 as an oil (0.0938

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g, 0.205 mmol, 81%).

1 H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 7.7 Hz, 4H), 7.28 (t, J = 7.6 Hz, 4H), 7.20 (t, J = 7.4

Hz, 2H), 5.90 (s, 2H), 3.61 (t, J = 6.2 Hz, 2H), 3.59 (dd, J = 13.4, 7.1 Hz, 2H), 3.36–3.34 (m, 2H),

13 3.33 (dd, J = 13.4, 8.8 Hz, 2H), 2.42 (s, 2H); C NMR (125 MHz, CDCl3) δ 176.9, 135.7, 132.2,

129.9, 129.2, 126.6, 43.5, 40.11, 40.08, 36.5, 35.1; IR (thin film) ν 2924, 2853, 1700, 1399, 739

-1 + cm ; LRMS (ESI) m / z calcd for C24H24ClNO2S2Na (M + Na) 480.0835, found 479.76.

Alkyl Bromide 3.98. To a solution of 3.86 (0.10 g, 0.25 mmol) in DMF (4 mL) was added K2CO3

(0.175 g, 1.26 mmol). After 0.5 h, 1,2-dibromoethane (0.04 mL, 0.51 mmol) was added and the reaction mixture was heated to 50 °C for 2 h. The solution was cooled to room temperature, quenched by addition of sat. aq. NH4Cl (5 mL) and H2O (5 mL), and extracted with 1:1

EtOAc/hexanes (3 x 10 mL). The organic phases were combined, washed with H2O (5 mL) and

brine (5 mL), dried with MgSO4, filtered and concentrated. The crude oil was purified by column

chromatography (SiO2, 8:92 – 20:80 EtOAc:hexanes) to afford 3.98 as an oil (0.0993 g, 0.198 mmol, 78%).

1 H NMR (500 MHz, CDCl3) δ 7.37 (d, J = 8.0 Hz, 4H), 7.28 (t, J = 7.7 Hz, 4H), 7.20 (t, J = 7.3

Hz, 2H), 5.91 (s, 2H), 3.85 (t, J = 6.4 Hz, 2H), 3.59 (dd, J = 13.5, 7.0 Hz, 2H), 3.45 (t, J = 6.4 Hz,

13 2H), 3.37–3.29 (m, 4H), 2.42 (s, 2H); C NMR (125 MHz, CDCl3) δ 176.9, 135.7, 132.3, 129.9,

129.3, 126.6, 43.6, 40.1, 36.5, 35.1, 27.5; IR (thin film) ν 3055, 2924, 1771, 1695, 1582, 1399,

-1 + 740 cm ; LRMS (ESI) m / z calcd for C24H25BrNO2S2Na (M + H) 502.0505, found 502.03.

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Silyloxy Bicycle 3.99. To a solution of 3.86 (16.00 g, 40.4 mmol) in DMF (640 mL) was added

solid tBuOK (5.45 g, 48.5 mmol). After 20 min, 3.95 (10.4 mL, 48.5 mmol) was added and the

reaction mixture was allowed to stir at room temperature for 16 h. The reaction was quenched by

addition of sat. aq. NH4Cl (500 mL) and H2O (500 mL) and extracted with 1:1 EtOAc:hexanes (4

x 200 mL). The organic phases were combined, washed with H2O (250 mL) and brine (250 mL), dried with MgSO4, filtered and concentrated to yield a crude oil, which was purified by column

chromatography (SiO2, 0:100 – 15:85 EtOAc:hexanes) to afford 3.99 as a colorless oil (17.45 g,

31.5 mmol, 78%).

1 H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 7.7 Hz, 4H), 7.28 (t, J = 7.6 Hz, 4H), 7.20 (t, J = 7.3

Hz, 2H), 5.88 (s, 2H), 3.66 (t, J = 6.0 Hz, 2H), 3.60 (dd, J = 13.4, 6.8 Hz, 2H), 3.56 (t, J = 5.9 Hz,

2H), 3.32 (dd, J = 13.4, 9.0 Hz, 2H), 3.28 (dd, J = 4.1, 2.0 Hz, 2H), 2.40 (s, 2H), 0.86 (s, 9H), 0.02

13 (s, 6H); C NMR (125 MHz, CDCl3) δ 177.1, 135.8, 132.2, 129.9, 129.2, 126.5, 59.3, 43.6, 41.1,

36.5, 35.2, 26.0, 18.3, –5.2; IR (thin film) ν 2928, 1769, 1698, 1583, 1399, 1110, 837, 738 cm-1;

+ HRMS (ESI) m / z calcd for C30H39NO3S2SiNa (M + Na) 576.2039, found 576.2031.

Epimerized Bicycle 3.100. To a solution of 3.86 (2.88 g, 7.28 mmol) in DMSO (40 mL) was

174

added 60% NaH in mineral oil (0.35 g, 8.74 mmol). After 0.5 h, 3.95 (3.12 mL, 14.56 mmol) was added and the reaction mixture was stirred at room temperature. After 14 h, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2 x 50 mL). The

combined organic extracts were washed with brine (25 mL), dried over MgSO4, filtered, and

concentrated to yield a yellow oil, which was purified by column chromatography (SiO2, 5:95 –

15:85 EtOAc:hexanes) to afford 3.100 as a yellow oil.

1 H NMR (500 MHz, CDCl3) δ 7.41 (d, J = 7.6 Hz, 4H), 7.28 (t, J = 7.6 Hz, 4H), 7.18 (t, J = 7.4

Hz, 2H), 5.93 (s, 2H), 3.71 (t, J = 5.9 Hz, 2H), 3.63 (t, J = 5.9 Hz, 2H), 3.59 (dd, J = 13.1, 4.7 Hz,

2H), 3.10 (dd, J = 13.1, 7.7 Hz, 2H), 2.95 (dd, J = 5.1, 1.8 Hz, 2H), 2.52 (d, J = 4.4 Hz, 2H), 0.83

13 (s, 9H), 0.00 (s, 6H); C NMR (125 MHz, CDCl3) δ 178.7, 135.8, 130.5, 129.7, 129.2, 126.5,

59.2, 42.8, 40.9, 38.5, 34.8, 26.0, 18.3, -5.25; IR (thin film) ν 3058, 2928, 2856, 1772, 1702, 1583,

+ 1438, 1398, 1110, 836, 740, 691; HRMS (ESI) m / z calcd for C30H39NO3S2SiNa (M + Na)

576.2039, found 576.2019.

Alkyl Chloride 3.101. To a glass vessel was added a solution of 3.97 (0.094 g, 0.20 mmol) in THF

(1 mL) and MeCN (4 mL). PtO2 (0.005 g, 0.02 mmol) was added and the vessel containing the reaction mixture was sealed in a bomb reactor, filled with H2 and evacuated (2 x 600 psi) and sealed at 600 psi of H2. After 5 d, the reaction mixture was diluted with 1:1 CH2Cl2/hexanes (10 mL) and filtered through a plug of SiO2. The SiO2 was rinsed with 1:1 CH2Cl2/hexanes (10 mL)

and the filtrate was dried with MgSO4, filtered and concentrated to yield a gray oil, which was

175 purified by column chromatography (SiO2, 10:90 EtOAc:hexanes) to afford 3.101 as a colorless oil (0.0831 g, 0.18 mmol, 88%).

1 H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 7.7 Hz, 4H), 7.28 (t, J = 7.3 Hz, 4H), 7.18 (t, J = 7.3

Hz, 2H), 3.87 (t, J = 5.6 Hz, 2H), 3.74 (t, J = 5.6 Hz, 2H), 3.43 (dd, J = 13.5, 8.0 Hz, 2H), 3.34 (s,

2H), 3.01 (dd, J = 13.5, 6.9 Hz, 2H), 2.10 (s, 2H), 1.91 (d, J = 7.8 Hz, 2H), 1.39–1.28 (m, 2H); 13C

NMR (125 MHz, CDCl3) δ 177.8, 136.4, 129.6, 129.2, 126.4, 42.5, 40.5, 40.2, 36.7, 32.9, 23.8; IR

(thin film) ν 3055, 2928, 1769, 1702, 1582, 1398, 1160, 739 cm-1; LRMS (ESI) m / z calcd for

+ C24H26ClNO2S2Na (M + Na) 482.0991, found 482.09.

Alkyl Bromide 3.102. To a glass vessel was added a solution of 3.98 (0.037 g, 0.074 mmol) in

THF (0.5 mL) and MeCN (2 mL). PtO2 (0.002 g, 0.007 mmol) was added and the vessel containing the reaction mixture was sealed in a bomb reactor, filled with H2 and evacuated (2 x 550 psi) and sealed at 550 psi of H2. After 14 h, the reaction mixture was diluted with 1:1 CH2Cl2/hexanes (10 mL) and filtered through a plug of SiO2. The SiO2 was rinsed with 1:1 CH2Cl2/hexanes (10 mL) and the filtrate was dried with MgSO4, filtered and concentrated to yield a gray oil, which was purified by column chromatography (SiO2, 15:85 EtOAc:hexanes) to afford 3.102 as a colorless oil (0.029 g, 0.057 mmol, 78%).

1 H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 7.5 Hz, 4H), 7.28 (t, J = 7.4 Hz, 4H), 7.19 (t, J = 7.4

Hz, 2H), 3.95 (t, J = 6.1 Hz, 2H), 3.59 (t, J = 6.1 Hz, 2H), 3.43 (dd, J = 13.5, 7.5 Hz, 2H), 3.34 (s,

2H), 3.02 (dd, J = 13.5, 7.1 Hz, 2H), 2.11 (s, 2H), 1.97–1.86 (m, 2H), 1.42–1.30 (m, 2H); 13C NMR

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(125 MHz, CDCl3) δ 177.8, 136.4, 129.6, 129.2, 126.4, 42.5, 40.2, 36.7, 32.9, 28.0, 23.8; IR (thin

film) ν 3055, 2928, 1769, 1697, 1582, 1479, 1398, 740 cm-1; LRMS (ESI) m / z calcd for

+ C24H26BrNO2S2Na (M + Na) 526.0487, found 526.05.

Silyloxy Bicycle 3.103. To a glass vessel was added a solution of 3.99 (4.39 g, 7.93 mmol) in THF

(40 mL) and MeCN (100 mL). PtO2 (0.090 g, 0.40 mmol) was added and the vessel containing the

reaction mixture was sealed in a bomb reactor, filled with H2 and evacuated (2 x 300 psi) and sealed at 300 psi of H2. After 17 h, the reaction mixture was diluted with 1:1 CH2Cl2/hexanes (200

mL) and filtered through a plug of SiO2. The SiO2 was rinsed with 1:1 CH2Cl2/hexanes (100 mL)

and the filtrate was dried with MgSO4, filtered and concentrated to yield 3.103 as a colorless oil

(4.30 g, 7.74 mmol, 98%), which was used without further purification.

1 H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 7.5 Hz, 4H), 7.27 (t, J = 7.5 Hz, 4H), 7.18 (t, J = 7.3

Hz, 2H), 3.76 (t, J = 5.6 Hz, 2H), 3.64 (t, J = 5.6 Hz, 2H), 3.44 (dd, J = 13.5, 7.6 Hz, 2H), 3.27 (s,

2H), 3.01 (dd, J = 13.5, 7.1 Hz, 2H), 2.08 (s, 2H), 1.93–1.81 (m, 2H), 1.36–1.24 (m, 2H), 0.86 (s,

13 9H), 0.04 (s, 6H); C NMR (125 MHz, CDCl3) δ 178.0, 136.5, 129.5, 129.2, 126.3, 59.5, 42.6,

41.1, 36.7, 32.8, 26.0, 23.7, 18.4, 5.2; IR (thin film) ν 2929, 1768, 1698, 1583, 1398, 1106, 836,

-1 + 738 cm ; HRMS (ESI) m / z calcd for C30H41NO3S2SiNa (M + Na) 578.2195, found 578.2209.

177

Hemiaminal 3.129. To a solution of 3.103 (0.020 g, 0.036 mmol) in toluene (2 mL) at –78 °C was

added DIBAL-H (0.01 mL, 0.043 mmol). The reaction mixture was stirred for 1 h and MeOH (0.5

mL) was added followed by 4M HCl (1 mL). The organic phase was filtered through a plug of

SiO2 and concentrated to yield an oil, which was purified by column chromatography (SiO2, 15:85

– 20:80 EtOAc:hexanes) to afford 3.129 as a colorless oil (0.015 g, 0.027 mmol, 75%).

1 H NMR (500 MHz, CDCl3) δ 7.37–7.22 (m, 8H), 7.18 (t, J = 7.1 Hz, 1H), 7.11 (t, J = 7.1 Hz,

1H), 5.14 (d, J = 5.2 Hz, 1H), 5.03 (s, 1H), 4.15 (d, J = 14.5 Hz, 1H), 3.79–3.64 (m, 2H), 3.35 (q,

J = 12.4 Hz, 2H), 3.16 (dd, J = 13.0, 5.7 Hz, 1H), 2.99 (d, J = 13.8 Hz, 1H), 2.92 (t, J = 12.4 Hz,

1H), 2.70 (t, J = 8.3 Hz, 1H), 2.67–2.60 (m, 1H), 1.98–1.87 (m, 1H), 1.68 (q, J = 13.1 Hz, 1H),

1.50–1.40 (m, 1H), 1.35–1.27 (m, 1H), 0.91 (s, 9H), 0.12 (d, J = 6.3 Hz, 6H); 13C NMR (125 MHz,

CDCl3) δ 176.7, 136.85, 136.79, 129.2, 129.13, 129.08, 128.1, 126.0, 125.4, 85.1, 62.8, 45.8, 44.5,

37.3, 36.5, 36.0, 32.0, 31.4, 26.5, 26.0, 23.8, 18.4, –5.28 (d, J = 5.4 Hz); IR (thin film) ν 3363,

-1 + 2928, 1672, 1582, 1439, 1088, 739 cm ; LRMS (ESI) m / z calcd for C30H43NO3S2SiNa (M + Na)

580.2351, found 580.24.

Lactam 3.132. To a solution of 3.129 (0.0036 g, 0.006 mmol) in toluene (0.2 mL) was added p-

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TsOH·H2O (0.0001 g, 0.0006 mmol). The reaction was stirred at room temperature for 2 h, quenched with NaHCO3 (0.2 mL), and extracted with 1:1 EtOAc:hexanes (1 x 2 mL). The organic

phase was dried over MgSO4, filtered, and concentrated to yield 3.132 as a white residue.

1 H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 7.7 Hz, 2H), 7.38–7.27 (m, 6H), 7.23 (tt, J = 7.2, 1.4

Hz, 1H), 7.14 (tt, J = 7.4, 1.1 Hz, 1H), 4.49 (t, J = 5.2 Hz, 2H), 4.13 (d, J = 18.8 Hz, 1H), 3.90 (d,

J = 18.8 Hz, 1H), 3.83 (ddd, J = 15.3, 5.5, 4.5 Hz, 1H), 3.73 (ddd, J = 15.3, 6.1, 4.6 Hz, 1H), 3.65

(d, J = 10.6 Hz, 1H), 3.06 (dd, J = 6.5, 1.9 Hz, 2H), 2.80–2.72 (m, 2H), 2.69–2.60 (m, 1H), 2.13–

13 2.01 (m, 1H), 1.90–1.82 (m, 2H), 1.75–1.66 (m, 2H); C NMR (125 MHz, CDCl3) δ 171.2, 153.8,

136.5, 135.8, 134.6, 129.8, 129.4, 129.1, 128.5, 126.8, 125.7, 67.1, 53.7, 40.9, 38.3, 35.5, 34.8,

30.9, 25.6, 24.3; IR (thin film) ν 3349, 2925, 1777, 1699, 1672, 1440, 1172, 742, 691 cm-1; HRMS

+ (ESI) m / z calcd for C24H27NO2S2Na (M + Na) 448.1381, found 448.1367.

Alcohol 3.136. To a solution of 3.103 (1.00 g, 1.80 mmol) in THF (30 mL) at –78 °C was added

a 1.0 M solution of LiHMDS in THF (2.34 mL, 2.34 mmol) and the reaction mixture was allowed

to warm to room temperature. After stirring for 0.5 h, the reaction was cooled to –78 °C and a

solution of 3.78 (0.584 g, 1.98 mmol) in THF (30 mL) was added via syringe. After 15 min,

BF3·OEt2 (0.33 mL, 2.70 mmol) was added and left to stir for 1 h. The reaction mixture was

quenched with sat. aq. NH4Cl (30 mL) and the phases were separated. The aqueous phase was

179

extracted with EtOAc (2 x 25 mL) and the combined organic phases were dried over MgSO4, filtered and concentrated to yield an orange residue, which was purified by column chromatography (SiO2, 5:95 – 25:75 EtOAc:hexanes) to afford 3.136 as a white foam (1.31 g, 1.54

mmol, 77 %).

1 H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 8.37 (s, 1H), 7.21–7.17 (m, 2H), 7.17–7.13 (m, 2H),

7.13–7.02 (m, 6H), 6.74 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 5.97 (d, J = 4.5 Hz, 1H),

3.98 (s, 3H), 3.87 (d, J = 12.6 Hz, 1H), 3.84 (s, 3H), 3.82–3.76 (m, 2H), 3.73–3.66 (m, 3H), 3.48–

3.34 (m, 2H), 2.76–2.67 (m, 2H), 2.08 (t, J = 11.8 Hz, 1H), 1.84–1.66 (m, 3H), 1.37–1.27 (m, 1H),

13 1.23–1.13 (m, 1H), 0.85 (s, 9H), 0.03 (s, 6H); C NMR (125 MHz, CDCl3) δ 179.3, 178.2, 149.4,

148.3, 137.3, 136.9, 135.3, 129.4, 128.84, 128.79, 128.7, 127.2, 126.8, 125.9, 125.6, 125.2, 122.8,

122.0, 105.2, 104.0, 72.1, 59.6, 58.3, 55.9, 55.7, 44.2, 41.3, 37.2, 36.8, 36.3, 32.9, 26.0, 23.8, 23.4,

18.4, -5.27 (d, J = 4.6 Hz, 3C); IR (thin film) ν 3457, 2934, 1768, 1694, 1584, 1106, 738 cm-1;

+ HRMS (ESI) m / z calcd for C43H52BrNO6S2SiNa (M + Na) 872.2086, found 872.2090.

Silyl Protected Alcohol 3.137. To a stirring solution of 3.136 (12.75 g, 14.98 mmol) and Et3N

(4.18 mL, 30.0 mmol) in CH2Cl2 (900 mL) at 0 °C was added TESOTf (5.08 mL, 22.5 mmol). The

reaction mixture was stirred for 0.5 h at this temperature, and warmed to room temperature. After

stirring for 6 h, the reaction mixture was quenched with sat. aq. NaHCO3 (500 mL) and the phases

180

were separated. The aqueous phase was extracted with CH2Cl2 (2 x 250 mL) and the combined

organic phase was washed with brine (200 mL), dried over MgSO4, filtered, and concentrated to

yield a crude yellow oil, which was purified by column chromatography (SiO2, 0:100 – 15:85

EtOAc:hexanes) to afford 3.137 as a faintly yellow oil (13.68 g, 14.17 mmol, 95%).

1 H NMR (500 MHz, CDCl3) δ 8.412 (s, 1H), 8.418 (s, 1H), 7.28–7.24 (m, 2H), 7.19 (t, J = 7.6 Hz,

2H), 7.15–7.10 (m, 3H), 7.08–7.01 (m, 3H), 6.74 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.4 Hz, 1H),

6.00 (s, 1H), 4.02 (dd, J = 12.2, 1.3 Hz, 1H), 3.98 (s, 3H), 3.94 (d, J = 2.9 Hz, 1H), 3.81 (s, 3H),

3.80–3.76 (m, 2H), 3.72–3.62 (m, 2H), 3.54 (dd, J = 12.1, 10.2 Hz, 1H), 3.46 (dd, J = 12.2, 5.2

Hz, 1H), 2.62 (t, J = 11.8 Hz, 1H), 1.99 (t, J = 12.5 Hz, 1H), 1.71–1.58 (m, 1H), 1.55–1.47 (m,

1H), 1.44 (t, J = 12.3 Hz, 1H), 1.28 (q, J = 12.1 Hz, 1H), 1.17–1.07 (m, 1H), 0.85 (s, 9H), 0.76 (t,

13 J = 8.0 Hz, 9H), 0.50–0.36 (m, 6H), 0.02 (d, J = 3.8 Hz, 6H); C NMR (125 MHz, CDCl3) δ

179.0, 178.4, 149.5, 148.3, 137.53, 137.46, 136.0, 129.4, 128.9, 128.7, 128.3, 127.2, 126.5, 125.9,

125.4, 125.1, 123.5, 121.8, 105.0, 103.7, 71.8, 59.8, 59.5, 55.9, 55.6, 43.8, 41.1, 37.5, 37.0, 35.8,

32.9, 26.0, 23.7, 23.6, 18.4, 6.7, 4.7, -5.3; IR (thin film) ν 2953, 2876, 1768, 1698, 1585, 1461,

-1 + 1106, 1090, 835, 738 cm ; HRMS (ESI) m / z calcd for C49H66BrNO6S2Si2Na (M + Na) 986.2951,

found 986.2953.

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Bis(sulfoxide) 3.138. To a 0 °C solution of 3.137 (2.38 g, 2.47 mmol), dissolved in a 1:1 mixture

of trifluoroethanol/CH2Cl2 (136 mL), was added 30% aqueous H2O2 (1.93 mL, 24.7 mmol). The

reaction mixture was warmed to room temperature, stirred for 14 h, and quenched with 10% aq.

Na2SO3 (50 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2 x 100 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated. The

crude residue was loaded onto a SiO2 plug and rinsed with 30:70 EtOAc:hexanes to remove

nonpolar impurities, and subsequently flushed with EtOAc to afford 3.138 as a white foam upon

concentration (2.28 g, 2.29 mmol, 93%).

1H NMR and 13C NMR spectra were complicated by the existence of sulfoxide diastereomers.

+ HRMS (ESI) m / z calcd for C49H66BrNO8S2Si2Na (M + Na) 1018.2850, found 1018.2858.

Diene 3.139. To a solution of 3.138 (0.64 g, 0.64 mmol) in o-dichlorobenzene (32 mL) was added

182

iPrNEt (0.41 mL, 3.21 mmol). The reaction was heated to 160 °C for 9 h, then cooled to room

temperature and washed with saturated aquous NaHCO3 (15 mL). The aqueous phase was

extracted with CH2Cl2 (2 x 15 mL) and the combined organic phase was dried over MgSO4, filtered, and concentrated to yield an oil, which was purified by column chromatography (SiO2,

5:95 – 10:90 EtOAc:hexanes) to afford 3.139 as a colorless oil (0.220 g, 0.30 mmol, 46%).

1 H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 8.31 (s, 1H), 6.69 (s, J = 8.3 Hz, 1H), 6.66 (d, J = 8.3

Hz, 1H), 6.07 (s, 1H), 5.70 (s, 1H), 5.18 (s, 1H), 5.06 (s, 1H), 4.93 (s, 1H), 4.54 (s, 1H), 3.94 (s,

3H), 3.93 (s, 3H), 3.77–3.67 (m, 4H), 1.97–1.88 (m, 2H), 1.73 (t, J = 12.9 Hz, 1H), 0.86 (s, 9H),

0.80 (t, J = 7.9 Hz, 9H), 0.71–0.61 (m, 1H), 0.55–0.38 (m, 6H), 0.03 (s, 6H); 13C NMR (125 MHz,

CDCl3) δ 178.1, 176.9, 149.8, 148.2, 139.5, 138.2, 136.8, 127.0, 125.6, 125.5, 124.8, 121.7, 118.2,

116.6, 104.4, 103.5, 73.3, 59.7, 59.3, 55.78, 55.75, 48.1, 41.4, 34.0, 32.7, 26.0, 18.3, 6.7, 4.8, -5.31

(d, J = 2.4 Hz) ; IR (thin film) ν 2953, 2877, 1777, 1708, 1588, 1462, 1268, 1107, 1090, 837 cm-1;

+ HRMS (ESI) m / z calcd for C37H54BrNO6Si2Na (M + Na) 766.2571, found 766.2571.

Rearranged Diene 3.140. To a solution of 3.138 (10.23 g, 10.23 mmol) in o-dichlorobenzene (550

mL) was added iPr2NEt (8.93 mL, 51.29 mmol). The reaction mixture was sparged with Ar (g)

and heated to 180 °C for 14 h. The reaction mixture was cooled to room temperature, washed with

183

saturated aqueous NaHCO3 (500 mL), and the organic phase was concentrated in vacuo with

heating to yield a brown oil (3.139:3.140 = 0.5:1). The crude mixture was purified by column

chromatography (SiO2, 0:100 – 15:85 EtOAc:hexanes) to afford 3.140 as a colorless oil (1.31 g,

1.76 mmol, 17%).

1 H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 8.35 (s, 1H), 6.67 (s, 2H), 5.52 (dd, J = 7.2, 4.8 Hz,

1H), 3.94 (s, 3H), 3.93 (s, 3H), 3.69–3.59 (m, 4H), 3.54 (dd, J = 12.4, 7.5 Hz, 1H), 2.87 (dd, J =

12.5, 4.8 Hz, 1H), 2.49–2.29 (m, 4H), 2.28 (s, 3H), 0.87–0.81 (m, 18H), 0.57–0.45 (m, 6H), 0.01

13 (d, J = 1.2 Hz, 6H); C NMR (125 MHz, CDCl3) δ 166.7, 165.8, 149.7, 148.4, 144.6, 143.5, 141.2,

126.7, 125.5, 125.4, 122.3, 122.2, 120.4, 120.2, 104.0, 103.6, 72.7, 59.7, 55.84, 55.81, 42.0, 39.6,

30.9, 29.7, 25.9, 18.9, 18.3, 6.8, 4.9, -5.3; IR (thin film) ν 2952, 1748, 1703, 1587, 1384, 1264,

+ 1106, 836; HRMS (ESI) m / z calcd for C37H54BrNO6Si2Na (M + Na) 766.2565, found 766.2557.

Hemiaminal 3.156. To a solution of 3.139 (0.22 g, 0.30 mmol) in THF (7 mL) at room temperature

was added a 2M solution of LiBH4 in THF (0.30 mL, 0.59 mmol). A small amount of MeOH (0.1 mL) was added and the reaction was left to stir for 1 d. Saturated aqueous NH4Cl (10 mL) was

added and the reaction mixture was extracted with 1:1 EtOAc:hexanes (3 x 10 mL). The combined

organic phase was dried over MgSO4, filtered, and concentrated to yield a crude residue, which

was purified by column chromatography (SiO2, 20:80 EtOAc:hexanes) to afford 3.156 as a white

184

foam (0.204 g, 0.27 mmol, 92%).

1 H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 8.29 (s, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.64 (d, J = 8.4

Hz, 1H), 5.92 (s, 1H), 5.56 (s, 1H), 5.13 (s, 1H), 4.99 (s, 1H), 4.84 (dd, J = 6.3, 5.2 Hz, 1H), 4.69

(s, 1H), 3.99 (d, J = 5.3 Hz, 1H), 3.930 (s, 3H), 3.926 (s, 3H), 3.81–3.75 (m, 2H), 3.74–3.67 (m,

2H), 3.39 (dt, J = 14.3, 5.1 Hz, 1H), 1.95–1.81 (m, 3H), 0.91 (s, 9H), 0.83 (t, J = 7.9 Hz, 9H),

13 0.58–0.40 (m, 6H), 0.10 (d, J = 6.0 Hz, 6H); C NMR (125 MHz, CDCl3) δ 173.4, 150.0, 148.2,

142.6, 140.6, 138.1, 126.8, 126.3, 125.1, 124.8, 122.2, 117.2, 113.9, 104.1, 103.2, 84.2, 73.7, 62.6,

60.0, 55.8, 55.7, 49.6, 43.8, 33.8, 32.7, 26.0, 18.4, 6.8, 4.9, –5.33 (d, J = 2.8 Hz); IR (thin film) ν

3380 (br), 2951, 2876, 1668, 1588, 1460, 1266, 1108, 1091, 836 cm-1; HRMS (ESI) m / z calcd for

+ C37H56BrNO6Si2Na (M + Na) 768.2727, found 768.2714.

Pentacycle 3.157. To a mixture of Pd(PtBu3)2 (0.116 g, 0.227 mmol), [tBu3PH]BF4 (0.066 g, 0.227 mmol), and HCO2Na (0.155 g, 2.28 mmol) at room temperature was added a solution of 3.156

(0.85 g, 1.14 mmol) in DMF (30 mL). The suspension was evacuated and backfilled with Ar (g)

(3x) and heated to 35 °C for 16 h. The reaction was cooled to room temperature, quenched with

H2O (50 mL), and extracted with Et2O (3 x 30 mL). The combined organic phase was dried over

MgSO4, filtered, and concentrated to yield a residue, which was purified by column

chromatography (SiO2, 10:90 – 30:70 EtOAc:hexanes) to afford 3.157 as a white solid (0.65 g,

185

0.97 mmol, 86%).

1 Mp = 178–180 °C; H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.81 (s, 1H), 6.64 (d, J = 8.4 Hz,

1H), 6.62 (d, J = 8.4 Hz, 1H), 5.64 (s, 1H), 5.12 (t, J = 5.8 Hz, 1H), 4.74 (s, 1H), 4.55 (s, 1H),

3.944 (s, 3H), 3.937 (s, 3H), 3.89 (d, J = 5.8 Hz, 1H), 3.84–3.74 (m, 2H), 3.60 (ddd, J = 14.3, 5.6,

3.0 Hz, 1H), 3.50 (ddd, J = 14.3, 6.5, 3.0 Hz, 1H), 3.15 (d, J = 5.9 Hz, 1H), 2.44–2.35 (m, 1H),

2.33–2.24 (m, 1H), 2.15 (dt, J = 14.2, 6.2 Hz, 1H), 1.76 (dt, J = 14.3, 7.3 Hz, 1H), 1.32 (s, 3H),

13 0.99 (t, J = 7.9 Hz, 9H), 0.92 (s, 9H), 0.77–0.70 (m, 6H), 0.11 (s, 6H); C NMR (125 MHz, CDCl3)

δ 174.2, 150.1, 149.6, 146.7, 142.2, 141.7, 126.9, 126.3, 117.2, 114.5, 113.4, 102.9, 102.7,

84.8, 77.5, 64.7, 62.4, 56.0, 55.8, 50.7, 47.1, 43.1, 27.0, 26.0, 25.5, 18.4, 7.1, 5.2, -5.3; IR (thin film) ν 3407, 2954, 2876, 1659, 1612, 1460, 1262, 1112, 835, 795 cm-1; HRMS (ESI) m / z calcd

+ for C37H57NO6Si2Na (M + Na) 690.3622, found 690.3627.

Ketone 3.158. To a mixture of Pd(PtBu3)2 (0.013 g, 0.025 mmol) and HCO2Na (0.017 g, 0.25

mmol) at room temperature was added a solution of 3.156 (0.094 g, 0.126 mmol) in DMF (13 mL).

The suspension was evacuated and backfilled with Ar (g) (3x) and heated to 50 °C for 2 d. The

reaction was cooled to room temperature, quenched with H2O (15 mL), and extracted with Et2O

(3 x 10 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated to

yield a residue, which was purified by column chromatography (SiO2, 10:90 – 20:80

186

EtOAc:hexanes) to afford 3.157 (0.011 g, 0.016 mmol, 13%) and 3.158 (0.020 g, 0.036 mmol,

29%).

1 H NMR (500 MHz, CDCl3) δ 8.76 (s, 1H), 8.23 (s, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 8.3

Hz, 1H), 5.37 (dd, J = 10.1, 3.1 Hz, 1H), 5.14 (s, 1H), 5.02 (s, 1H), 4.74 (d, J = 10.0 Hz, 1H), 3.98

(s, 3H), 3.95 (s, 3H), 3.81 (ddd, J = 10.3, 5.7, 4.2 Hz, 1H), 3.73 (ddd, J = 10.9, 7.1, 4.0 Hz, 1H),

3.53 (ddd, J = 14.3, 5.7, 4.0 Hz, 1H), 3.47 (ddd, J = 14.3, 7.0, 4.0 Hz, 1H), 2.46 (td, J = 13.8, 5.7

Hz, 1H), 2.37 (dd, J = 15.5, 6.0 Hz, 1H), 1.93 (ddd, J = 14.0, 5.8, 2.5 Hz, 1H), 1.64 (s, 3H), 1.45–

13 1.36 (m, 1H), 0.92 (s, 9H), 0.09 (d, J = 11.6 Hz, 6H); C NMR (125 MHz, CDCl3) δ 204.6, 169.9,

156.5, 151.7, 149.3, 141.0, 131.1, 130.9, 126.2, 121.2, 115.9, 112.6, 107.0, 103.4, 83.8, 69.9, 62.0,

56.07, 56.06, 49.9, 44.2, 43.1, 41.1, 28.9, 26.1, 19.5, 18.5, –5.2 (d, J = 4.2 Hz); IR (thin film) ν

-1 3390, 2928, 1686, 1462, 1265, 1100, 836 cm ; LRMS (ESI) m / z calcd for C31H41NO6SiNa (M +

Na)+ 574.2595, found 574.21.

H OH OTBS N OH Me O

MeO OMe

3.159

Diol 3.159. To a mixture of Pd(PtBu3)2 (0.028 g, 0.055 mmol), [tBu3PH]BF4 (0.016 g, 0.055

mmol), and HCO2Na (0.037 g, 0.55 mmol) at room temperature was added a solution of 3.156

(0.204 g, 0.273 mmol) in DMF (8 mL). The suspension was evacuated and backfilled with Ar (g)

(3x) and heated to 65 °C for 16 h. The reaction was cooled to room temperature, quenched with

H2O (10 mL), and extracted with Et2O (3 x 10 mL). The combined organic phase was dried over

187

MgSO4, filtered, and concentrated to yield a residue, which was purified by column

chromatography (SiO2, 10:90 – 20:80 EtOAc:hexanes) to afford 3.157 (0.025 g, 0.037 mmol, 14%)

and 3.158 (0.007 g, 0.013 mmol, 5%). The column was flushed with EtOAc to afford 3.159 as the

major component (0.090 g, 0.163 mmol, 60%).

1 H NMR (500 MHz, CDCl3) δ 8.23 (s, 1H), 7.88 (s, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 8.3

Hz, 1H), 5.55 (s, 1H), 5.19–5.15 (m, 1H), 4.87 (s, 1H), 4.73 (s, 1H), 4.30 (d, J = 4.5 Hz, 1H), 3.95

(s, 3H), 3.94 (s, 3H), 3.83 (ddd, J = 10.5, 7.5, 2.8 Hz, 1H), 3.76 (ddd, J = 10.7, 5.6, 3.2 Hz, 1H),

3.73–3.69 (m, 1H), 3.66 (ddd, J = 14.4, 5.6, 2.8 Hz, 1H), 3.45 (ddd, J = 14.4, 7.4, 3.0 Hz, 1H),

3.17 (d, J = 5.1 Hz, 1H), 2.45–2.37 (m, 1H), 2.33 (dt, J = 15.8, 6.2 Hz, 1H), 2.00 (ddd, J = 14.2,

8.2, 6.1 Hz, 1H), 1.85 (dt, J = 13.3, 6.5 Hz, 1H), 1.39 (s, 3H), 0.93 (s, 9H), 0.12 (s, 6H).

Triol 3.160. To a scintillation vial was added a solution of 3.157 (0.024 g, 0.036 mmol) dissolved in a 4:1 mixture of MeCN/THF (5 mL). Solid CsF (0.027 g, 0.18 mmol) was added and the reaction mixture was left to stir at room temperature for 18 h. The reaction was quenched with H2O (3 mL) and brine (3 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated to yield a yellow solid, which was purified by column

chromatography (SiO2, 0:100 – 10:90 MeOH:CH2Cl2) to afford 3.160 as a white solid (0.011 g,

0.025 mmol, 70%).

188

1 Mp = 178–185 °C; H NMR (500 MHz, CDCl3) δ 8.19 (s, 1H), 7.86 (s, 1H), 6.67 (d, J = 8.3 Hz,

1H), 6.64 (d, J = 8.3 Hz, 1H), 5.72 (s, 1H), 5.09 (d, J = 4.2 Hz, 1H), 4.81 (s, 1H), 4.65 (s, 1H),

4.50 (br s, 1H), 3.95 (s, 3H), 3.93 (s, 3H), 3.90–3.79 (m, 4H), 3.43–3.33 (m, 1H), 3.14 (d, J = 4.8

Hz, 1H), 2.44–2.35 (m, 1H), 2.34–2.24 (m, 1H), 2.13 (dt, J = 14.2, 5.8 Hz, 1H), 1.80 (ddd, J =

13 14.7, 9.2, 6.1 Hz, 1H), 1.39 (s, 3H); C NMR (125 MHz, CDCl3) δ 176.0, 150.0, 149.5, 145.9,

141.5, 140.8, 127.1, 126.4, 117.2, 114.7, 113.4, 103.2, 102.8, 85.9, 77.1, 64.5, 61.7, 55.82, 55.79,

50.1, 47.6, 44.5, 34.5, 27.2, 26.2; IR (thin film) ν 3363, 2925, 2853, 1668, 1610, 1460, 1336, 1263,

-1 + 1084, 907, 730 cm ; HRMS (ESI) m / z calcd for C25H29NO6Na (M + Na) 462.1893, found

462.1885.

Ketone 3.161. To a solution of 3.160 (0.19 g, 0.43 mmol) in 1,4-dioxane (11 mL) was added DDQ

(0.29 g, 1.30 mmol). The reaction mixture was stirred at room temperature for 16 h and H2O (5 mL) and saturated aqueous NaHCO3 (5 mL) were added. The reaction mixture was extracted with

CH2Cl2 (3 x 10 mL) and the combined organic phase was dried over MgSO4, filtered, and concentrated to yield a yellow residue, which was purified by column chromatography (SiO2, 4:96

– 8:92 MeOH:CH2Cl2) to afford 3.161 as a yellow solid (0.180 g, 0.411 mmol, 95%).

1 Mp = 194–200 °C; H NMR (500 MHz, CDCl3) δ 8.78 (s, 1H), 8.25 (s, 1H), 6.85 (d, J = 8.4 Hz,

1H), 6.70 (d, J = 8.4 Hz, 1H), 5.63 (d, J = 11.4 Hz, 1H), 5.33 (dd, J = 11.4, 0.8 Hz, 1H), 5.09 (s,

189

1H), 5.00 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.82 (ddd, J = 14.5, 4.1, 3.2), 3.75–3.68 (m, 2H), 3.51

(dd, J = 6.5, 5.9 Hz, 1H), 3.37–3.30 (m, 1H), 3.15 (s, 1H), 2.54 (ddd, J = 16.1, 11.9, 6.9 Hz, 1H),

2.46 (dd, J = 16.1, 7.8 Hz, 1H), 1.92 (dd, J = 14.0, 6.9 Hz, 1H), 1.65 (s, 3H), 1.47 (td, J = 12.9,

13 8.0, 1H); C NMR (125 MHz, CDCl3) δ 205.5, 169.8, 156.8, 151.6, 149.2, 140.6, 131.1, 130.3,

126.1, 121.8, 116.1, 111.4, 107.3, 103.5, 83.7, 70.3, 61.8, 56.02, 56.00, 49.0, 45.7, 44.2, 40.0, 28.8,

19.1; IR (thin film) ν 3376, 2928, 2852, 1717, 1670, 1626, 1463, 1340, 1266, 1084, 722 cm-1;

+ HRMS (ESI) m / z calcd for C25H27NO6Na (M + Na) 460.1736, found 460.1739.

Cyclohexanone 3.162. To a solution of 3.161 (0.040 g, 0.091 mmol) in a mixture of acetone (4 mL) and H2O (0.7 mL) was added NMO·H2O (0.023 g, 0.174 mmol) and 4% aqueous osmium

tetroxide (0.01 mL, 0.002 mmol). The reaction mixture was stirred at room temperature for 14 h

and quenched by stirring with saturated aqueous Na2S2O3 solution for 0.5 h. The acetone was

removed in vacuo and the aqueous phase was extracted with 30:70 MeOH:CH2Cl2 (3 x 10 mL).

The combined organic phase was dried with MgSO4, filtered, and concentrated to yield a yellow

solid, which was immediately dissolved in a 2:1 MeOH:H2O (4.2 mL). To this solution was added

NaIO4 (0.094 g, 0.439 mmol) and the white suspension was stirred at room temperature for 1 h.

H2O (5 mL) was added and the aqueous phase was extracted with EtOAc (3 x 5 mL). The combined organic phase was dried over MgSO4, filtered, and concentrated to yield a yellow residue, which

190

was purified by column chromatography (SiO2, 8:92 MeOH:CH2Cl2) to afford 3.162 as a yellow

solid (0.0368 g, 0.084 mmol, 92%).

1 Mp = 179–182 °C; H NMR (500 MHz, CDCl3) δ 8.83 (s, 1H), 8.31 (s, 1H), 6.90 (d, J = 8.4 Hz,

1H), 6.74 (d, J = 8.4 Hz, 1H), 5.70 (d, J = 12.4 Hz, 1H), 5.23 (d, J = 12.4 Hz, 1H), 4.00 (s, 3H),

3.98 (s, 3H), 3.78–3.68 (m, 3H), 3.42–3.32 (m, 2H), 3.29 (s, 1H), 2.63 (ddd, J = 19.1, 12.5, 6.8

Hz, 1H), 2.51 (dd, J = 19.1, 6.9 Hz, 1H), 2.12 (dd, J = 14.2, 6.8 Hz, 1H), 2.00 (td, J = 12.9, 7.4,

13 1H), 1.65 (s, 3H); C NMR (125 MHz, CDCl3) δ 206.0, 204.9, 168.4, 155.8, 151.6, 149.2,

131.3, 129.3, 126.3, 122.3, 116.4, 110.1, 107.8, 103.9, 81.1, 70.0, 61.5, 56.04, 56.03, 54.9, 46.0,

43.2, 38.9, 35.1, 18.3; IR (thin film) ν 3400, 2934, 1716, 1686, 1624, 1605, 1340, 1267, 1192,

-1 + 1080, 724 cm ; HRMS (ESI) m / z calcd for C24H25NO7Na (M + Na) 462.1529, found 462.1534.

Sulfonic Acid 3.166. To a suspension of 3.102 (0.10 g, 0.20 mmol) in 1:1 H2O:1,4-dioxane (2

mL) was added Na2SO3 (0.10 g, 0.79 mmol). The reaction mixture was heated to 80 °C for 16 h and cooled to room temperature. The reaction mixture was concentrated and dissolved in H2O (5

mL). The aqueous solution was extracted with EtOAc (1 x 5 mL), acidified with 4M HCl until

acidic, and extracted with EtOAc (2 x 5 mL). The combined organic phases were dried over

MgSO4, filtered, and concentrated to yield a white solid, which was purified by column

chromatography (SiO2, 10:90 MeOH:CH2Cl2) to afford 3.166 (0.017 g, 0.034 mmol, 17%).

1 H NMR (500 MHz, d6-DMSO) δ 7.35–7.26 (m, 8H), 7.17 (t, J = 6.8 Hz, 2H), 3.69–3.61 (m, 2H),

191

3.36–3.32 (m,2H), 3.29 (s, 2H), 3.01 (dd, J = 13.6, 7.1 Hz, 2H), 2.66–2.59 (m, 2H), 2.02 (s, 2H),

13 1.85–1.73 (m, 2H), 1.15–1.06 (m, 2H); C NMR (125 MHz, d6-DMSO) δ 177.7, 136.3, 129.1,

128.1, 125.6, 48.1, 41.7, 35.3, 35.0, 31.8, 23.1; IR (thin film) ν 3441, 2924, 1694, 1582, 1404,

-1 – 1192, 1050, 740, 691 cm ; HRMS (ESI) m / z calcd for C24H26NO5S3 (M – H) 504.0973, found

504.0980.

O H OH Br N O Me O

MeO OMe

3.167

Alkyl Bromide 3.167. A 0.16 M stock solution of betaine was prepared by adding PPh3 (0.103 g,

0.39 mmol) to a solution of DDQ (0.090 g, 0.39 mmol) in CH2Cl2 (2.5 mL). After 0.5 h, the

solution had become a yellow suspension and Bu4NBr (0.127g, 0.39 mmol) was added. A portion

of the 0.16 M betaine stock solution (0.21 mL, 0.034 mmol) was added to a stirring solution of

3.162 (0.0097 g, 0.022 mmol) in CH2Cl2 (1.0 mL) and the reaction mixture was stirred at room

temperature for 14 h. H2O (2 mL) was added and the phases were separated. The aqueous phase

was extracted with CH2Cl2 (2 x 3 mL) and the combined organic phase was dried over MgSO4, filtered, and concentrated to yield a yellow oil, which was purified by column chromatography

(SiO2, 45:55 EtOAc:hexanes) to afford 3.167 as a yellow oil (0.0060 g, 0.012 mmol, 55%).

1 H NMR (500 MHz, CDCl3) δ 8.82 (s, 1H), 8.31 (s, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 8.4

Hz, 1H), 5.77 (s, 1H), 4.72 (d, J = 9.2 Hz, 1H), 4.00 (s, 3H), 3.98 (s, 3H), 3.80 (td, J = 14.3, 7.2

Hz, 1H), 3.71 (ddd, J = 14.2, 7.2, 6.4, 1H), 3.57–3.45 (m, 2H), 3.21 (s, 1H), 2.63 (ddd, J = 19.2,

192

13.0, 6.7 Hz, 1H), 2.49 (dd, J = 19.1, 6.9 Hz, 1H), 2.10 (dd, J = 14.3, 6.6 Hz, 1H), 1.96 (td, 13.5,

13 7.0 Hz, 1H), 1.66 (s, 3H); C NMR (125 MHz, CDCl3) δ 205.2, 204.8, 168.1, 156.0, 151.6, 149.2,

131.3, 129.4, 126.3, 122.2, 116.4, 107.7, 103.8, 80.4, 69.8, 56.04, 56.03, 54.9, 43.1, 42.8, 38.7,

35.0, 28.3, 18.3; IR (thin film) ν 3410, 2930, 1718, 1689, 1624, 1605, 1340, 1267, 1191, 723 cm-

1 + ; HRMS (ESI) m / z calcd for C24H24BrNO6Na (M + Na) 524.0685, found 524.0699.

Thioester 3.170. A 0.27 M stock solution of betaine was prepared by adding DIAD (0.32 mL,

1.62 mmol) to a solution of PPh3 (0.42 g, 1.60 mmol) in THF (5.68 mL) at 0 °C. The mixture was

allowed to warm to room temperature and became a milky white suspension. A portion of the 0.27

M betaine stock solution (2.67 mL, 0.720 mmol) was transferred via syringe to a stirring solution

of 3.162 (0.0633 g, 0.144 mmol) and thioacetic acid (0.05 mL, 0.720 mmol) in THF (6 mL) at 0

°C. The reaction mixture was allowed to warm to room temperature, stirred for 0.5 h, and quenched

with saturated aqueous NH4Cl solution (10 mL). The aqueous phase was extracted with Et2O (3 x

10 mL) and the combined organic phase was dried over MgSO4, filtered, and concentrated to yield

a yellow oil, which was purified by column chromatography (SiO2, 30:70 – 50:50 EtOAc:hexanes)

to afford 3.170 as a yellow solid (0.071 g, 0.143 mmol, 99%).

1 Mp = 152–156 °C; H NMR (500 MHz, CDCl3) δ 8.81 (s, 1H), 8.30 (s, 1H), 6.89 (d, J = 8.4 Hz,

1H), 6.73 (d, J = 8.4 Hz, 1H), 5.75 (d, J = 12.9 Hz, 1H), 4.66 (d, J = 12.9 Hz, 1H), 4.00 (s, 3H),

193

3.98 (s, 3H), 3.63 (dt, J = 14.0, 6.6 Hz, 1H), 3.48 (dt, J = 14.0, 6.6 Hz, 1H), 3.21 (dt, 13.7, 6.8 Hz,

1H), 3.19 (s, 1H), 3.04 (dt, J = 13.7, 6.8 Hz, 1H), 2.62 (ddd, J = 19.4, 13.0, 6.8 Hz, 1H), 2.48 (dd,

J = 19.2, 6.8 Hz, 1H), 2.34 (s, 3H), 2.09 (dd, J = 14.2, 6.6 Hz, 1H), 1.95 (td, J = 13.5, 7.0 Hz, 1H),

13 1.67 (s, 3H); C NMR (125 MHz, CDCl3) δ 205.4, 204.9, 195.2, 168.1, 156.1, 151.6, 149.2, 131.3,

129.5, 126.3, 122.1, 116.4, 107.6, 103.8, 80.5, 69.8, 56.04, 56.02, 55.0, 43.1, 40.4, 38.8, 35.0, 30.7,

27.5, 18.3; IR (thin film) ν 3416, 2925, 2852, 1715, 1690, 1624, 1340, 1267, 1192, 724 cm-1;

+ HRMS (ESI) m / z calcd for C26H27NO7SNa (M + Na) 520.1406, found 520.1398.

Sulfonate 3.165. To a solution of 3.170 (0.0446 g, 0.090 mmol) in 4:1 THF/H2O (3 mL) at 0 °C

was added mCPBA (0.077 g, 0.448 mmol). The reaction mixture was warmed to room temperature,

stirred for 18 h, diluted with H2O (3 mL), and passed through a plug (RP-C18 SiO2, 20:80

MeCN:H2O). The fractions containing product were combined and 10% aq. Na2SO3 (5 mL) was

added. The solution was concentrated under a stream of air to yield a yellow residue, which was

purified by column chromatography (RP-C18 SiO2, 20:80 MeCN:H2O) and concentrated under a

stream of air to afford 3.165 as a yellow solid (0.0228 g, 0.043 mmol, 49%).

1 H NMR (500 MHz, d6-DMSO) δ 8.45 (s, 1H), 8.25 (s, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.95 (d, J =

8.5 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 5.47 (dd, J = 7.6, 4.6 Hz, 1H), 3.969 (s, 3H), 3.966 (s, 3H),

3.55 (ddd, J = 14.0, 10.7, 5.2 Hz, 1H), 3.31–3.27 (m, 1H), 3.26 (d, J = 4.4 Hz, 1H), 2.77–2.69 (m,

194

1H), 2.69–2.62 (m, 1H), 2.18 (dt, J = 17.0, 4.4 Hz, 1H), 2.08 (dt, J = 13.7, 4.4 Hz, 1H), 1.74–1.68

13 (m, 1H), 1.56 (s, 3H); C NMR (125 MHz, d6-DMSO) δ 206.8, 202.0, 168.1, 154.9, 150.4, 148.4,

131.1, 129.5, 124.9, 118.6, 115.6, 107.6, 104.4, 80.8, 69.3, 56.0, 55.8, 54.7, 48.4, 43.6, 38.4, 36.3,

35.0, 18.6; IR (thin film) ν 3419, 3230, 2933, 1716, 1685, 1625, 1457, 1267, 1187, 1045 cm-1;

+ HRMS (ESI) m / z calcd for C24H24NO9SNa2 (M + Na) 548.0967, found 548.0980.

Sulfonate 3.3. To a solution of 3.165 (0.0121 g, 0.023 mmol) in DMF (1.5 mL) was added solid

KOtBu (0.013 g, 0.115 mmol) at room temperature. The reaction mixture was left to stir for 2 h.

H2O (1 mL) was added and the reaction mixture was concentrated to dryness under a stream of

air. The residue (containing 3.172) was dissolved in wet MeOH (2 mL) and SiO2 (0.040 g) was

added. The slurry was left to stir at room temperature for 16 h, diluted with MeCN (2.5 mL), and

filtered through a plug of Celite. The filtrate was concentrated under a stream of air, purified by

column chromatography (RP-C18 SiO2, 20:80 – 50:50 MeCN:H2O), and concentrated under a stream of air to afford 3.3 as a yellow solid (0.0073 g, 0.014 mmol, 60%).

1 H NMR (500 MHz, d6-DMSO) δ 8.45 (s, 1H), 8.29 (s, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.94 (d, J =

8.5 Hz, 1H), 5.53 (d, J = 6.1 Hz, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.51 (d, J = 6.5 Hz, 1H), 3.49–

3.42 (m, 2H), 2.71 (ddd, J = 13.2, 8.7, 6.6 Hz, 1H), 2.60 (ddd, J = 13.2, 8.5, 6.0 Hz, 1H), 2.47–

2.39 (m, 1H), 2.24–2.15 (m, 1H), 2.03–1.92 (m, 1H), 1.80–1.73 (m, 1H), 1.71 (s, 3H); 13C NMR

195

(125 MHz, d6-DMSO) δ 206.4, 202.5, 170.6, 154.9, 150.4, 148.4, 131.5, 129.7, 124.9, 118.5,

115.8, 107.6, 104.4, 81.2, 67.2, 56.0, 55.9, 50.6, 49.6, 43.4, 38.6, 37.9, 37.6, 19.9; IR (thin film) ν

-1 3439, 2937, 1717, 1686, 1625, 1266, 1190, 1048 cm ; HRMS (ESI) m / z calcd for C24H24NO9S

(M – Na)– 502.1172, found 502.1189.

Naphthyl Alcohol 3.290. To a 0.23 M solution of isopropenylmagnesium bromide in THF (1.85

mL, 0.424 mmol) at 0 °C was added dropwise a solution of 3.78 (0.050 g, 0.169 mmol) in THF (1

mL). After 15 min, saturated aqueous NH4Cl (5 mL) was added and the reaction mixture was

extracted with 1:1 EtOAc:hexanes (2 x 10 mL). The combined organic phases were dried over

MgSO4, filtered, and concentrated to yield 3.290 as a faintly yellow solid (0.057 g, 0.169 mmol,

100%).

1 H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 8.32 (s, 1H), 6.69 (s, 2H), 5.63 (s, 1H), 5.16 (s, 1H),

13 5.06 (s, 1H), 3.94 (s, 6H), 1.75 (s, 3H); C NMR (125 MHz, CDCl3) δ 149.6, 148.4, 145.6, 138.3,

126.8, 126.2, 125.3, 121.8, 121.7, 113.2, 104.4, 103.8, 76.4, 55.9, 55.8, 19.4; IR (thin film) ν 3368,

-1 + 2937, 1587, 1461, 1265, 1106, 723 cm ; LRMS (ESI) m / z calcd for C16H17BrO3Na (M + Na)

359.0260, found 359.01.

196

Cyclopentenone 3.175. To a mixture of Pd(OAc)2 (0.002 g, 0.007 mmol), (+)-cinchonine (0.004

g, 0.014 mmol), and NaHCO3 (0.013 g, 0.152 mmol) was added a solution of 3.290 (0.0465 g,

0.138 mmol) in DMF (5 mL). The reaction mixture was heated to 130 °C for 45 min and cooled

to room temperature. H2O (5 mL) was added and the aqueous phase was extracted with Et2O (3 x

5 mL). The combined organic phases were washed with H2O (5 mL), dried over MgSO4, filtered, and concentrated to yield an orange oil, which was purified by column chromatography (SiO2,

15:85 – 20:80 EtOAc:hexanes) to afford 3.175 (0.015 g, 0.059 mmol, 43%).

1 H NMR (600 MHz, CDCl3) δ 8.72 (s, 1H), 8.23 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 8.3

Hz, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.57 (dd, J = 16.7, 8.3 Hz, 1H), 2.89 (dd, J = 16.7, 4.8 Hz, 1H),

13 2.86–2.78 (m, 1H), 1.36 (d, J = 7.4 Hz, 3H); C NMR (125 MHz, CDCl3) δ 210.0, 151.5, 149.1,

146.9, 134.0, 130.4, 126.0, 119.5, 118.9, 106.1, 102.9, 56.0, 55.9, 43.0, 34.9, 16.5.

Dimethylcyclopentenone 3.176.

From 3.175: To a solution of 3.175 (0.0085 g, 0.033 mmol) in THF (0.5 mL) at 0 °C was added

NaOtBu (0.007 g, 0.073 mmol). After stirring for 20 min, MeI (0.01 mL, 0.113 mmol) was added

and the reaction was warmed to room temperature for 40 h. Saturated aqueous NH4Cl (2 mL) was

197

added and the reaction mixture was extracted with EtOAc (3 x 5 mL). The combined organic

phases were dried over MgSO4, filtered, and concentrated to yield an oil, which was purified by column chromatography (SiO2, 10:90 – 20:80 EtOAc:hexanes) to afford 3.176 (0.0026 g, 0.010

mmol, 29%).

From 3.177: To a flask was added PCy3·HBF4 (0.040 g, 0.108 mmol), Pd(OAc)2 (0.012 g, 0.054

mmol), Cs2CO3 (0.39 g, 1.19 mmol), and pivalic acid (0.033 g, 0.32 mmol). A solution of 3.177

(0.38 g, 1.08 mmol) in mesitylene (6.5 mL) was added to the mixture of solids and Ar (g) was

bubbled through the suspension for 10 min. The reaction mixture was heated to 140 °C. After 24

h, the reaction mixture was diluted with EtOAc (10 mL), filtered, and concentrated to yield 3.176

as a yellow residue (0.300 g, 1.1 mmol, 100%).

1 H NMR (500 MHz, CDCl3) δ 8.73 (s, 1H), 8.22 (s, 1H), 6.80 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 8.3

13 Hz, 1H), 3.98 (s, 3H), 3.97 (s, 3H), 3.15 (s, 2H), 1.28 (s, 6H); C NMR (125 MHz, CDCl3) δ

211.9, 151.5, 149.1, 145.7, 133.1, 130.5, 126.1, 120.1, 119.0, 106.1, 102.9, 56.0, 55.9, 46.5, 42.8,

25.5; IR (thin film) ν 2957, 1712, 1628, 1464, 1266, 1155, 1077 cm-1; HRMS (ESI) m / z calcd for

+ C17H18O3Na (M + Na) 293.1154, found 293.1157.

Naphthyl Alcohol 3.291. To a solution of 3.78 (0.020 g, 0.068 mmol) in THF (0.5 mL) at 0 °C

was added a 2.0 M solution of tBuMgCl in THF (0.06 mL, 0.12 mmol). The reaction mixture was warmed to room temperature and stirred for 14 h. Saturated aqueous NH4Cl (5 mL) was added and

the reaction mixture was extracted with EtOAc (3 x 5 mL), dried over MgSO4, filtered and

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concentrated to yield a red residue, which was purified by column chromatography (SiO2, 15:85

EtOAc:hexanes) to afford 3.291 as a yellow oil (0.0145 g, 0.041 mmol, 60%).

1 H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 8.35 (s, 1H), 6.68 (s, 2H), 5.16 (d, J = 3.4 Hz, 1H),

13 3.94 (s, 6H), 1.95 (d, J = 3.4 Hz, 1H), 1.04 (s, 9H); C NMR (125 MHz, CDCl3) δ 149.6, 148.4,

139.1, 126.6, 125.7, 125.1, 122.94, 122.88, 104.2, 103.6, 79.2, 55.8 (2), 37.2, 26.1; IR (thin film)

-1 ν 3517, 2953, 1586, 1460, 1265, 1105, 802, 721 cm ; HRMS (ESI) m / z calcd for C17H21BrO3Na

(M + Na)+ 375.0572, found 375.0562.

OMe O Me Me Me Br OMe 3.177

t-Butyl Ketone 3.177. To a solution of 3.291 (0.0122 g, 0.034 mmol) in CH2Cl2 (0.5 mL) was

added PCC (0.015 g, 0.070 mmol). After 4 h, H2O was added and the reaction mixture was

extracted with CH2Cl2 (3 x 5 mL). The combined organic phases were washed with brine (2 mL),

dried over MgSO4, filtered through a plug of SiO2, and concentrated to yield a faintly yellow oil,

which was purified by column chromatography (SiO2, 15:85 EtOAc:hexanes) to afford 3.177 as a colorless oil (0.0095 g, 0.027 mmol, 79%).

1 H NMR (500 MHz, CDCl3) δ 8.43 (s, 1H), 7.96 (s, 1H), 6.73 (d, J = 1.2 Hz, 2H), 3.94 (s, 3H),

13 3.93 (s, 3H), 1.33 (s, 9H); C NMR (125 MHz, CDCl3) δ 212.4, 149.6, 148.4, 139.8, 127.0, 126.4,

124.2, 119.8, 115.8, 105.1, 104.4, 55.93, 55.87, 45.3, 27.4; IR (thin film) ν 2966, 1697, 1580, 1460,

-1 + 1317, 1270, 1106 cm ; HRMS (ESI) m / z calcd for C17H19BrO3Na (M + Na) 373.0415, found

373.0417.

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Naphthoquinone 3.224. To a solution of 3.176 (0.005 g, 0.018 mmol) in 2:1 MeCN:H2O (1.5 mL)

at 0 °C was added a solution of CAN (0.030 g, 0.055 mmol) in H2O (0.1 mL). The reaction mixture

was warmed to room temperature, stirred for 0.5 h, and extracted with CHCl3 (3 x 5 mL). The

combined organic extracts were washed with brine (5 mL), dried over MgSO4, filtered, and

concentrated to yield 3.224 as a yellow oil, which was used without further purification (0.0034 g,

0.014 mmol, 77%).

1 H NMR (500 MHz, CDCl3) δ 8.48 (s, 1H), 8.17 (s, 1H), 7.05 (s, 2H), 3.14 (s, 2H), 1.28 (s, 6H);

13 C NMR (125 MHz, CDCl3) δ 210.0, 184.8, 184.1, 156.9, 139.5, 139.4, 138.9, 136.1, 131.9,

125.2, 123.6, 46.4, 43.4, 25.3; IR (thin film) ν 2964, 1721, 1672, 1603, 1326, 1124, 845 cm-1;

+ HRMS (ESI) m / z calcd for C15H12O3Na (M + Na) 263.0684, found 263.0675.

OH O Me Me

OH 3.178

Dihydroxynaphthalene 3.178. To a solution of 3.224 (0.0098 g, 0.041 mmol) in Et2O (0.5 mL)

was added a solution of Na2S2O4 (0.106 g, 0.611 mmol) in H2O (0.5 mL). The biphasic mixture

was stirred for 1 h and the phases were separated. The aqueous phase was extracted with Et2O (2

x 2 mL) and the combined organic phases were washed with brine (2 mL), dried over MgSO4, filtered, and concentrated to yield 3.178 as a yellow solid, which was used without further

200

purification (0.010 g, 0.041 mmol, 100%).

1 H NMR (500 MHz, CD3CN) δ 8.46 (s, 1H), 8.14 (d, J = 0.7 Hz, 1H), 7.31 (s, 1H), 7.18 (s, 1H),

6.82 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H)¸ 3.16 (s, 2H), 1.22 (s, 6H); 13C NMR (125 MHz,

CD3CN) δ 212.2, 148.6, 146.2, 145.9, 133.5, 130.2, 125.8, 120.0, 119.7, 111.7, 108.5, 46.9, 42.8,

25.4; IR (thin film) ν 3305, 2925, 1695, 1626, 1283, 1147, 753 cm-1; HRMS (ESI) m / z calcd for

+ C15H14O3Na (M + Na) 265.0841, found 265.0846.

Naphthoquinone 3.179. To a solution of 3.170 (0.0093 g, 0.019 mmol) in 7:1 MeCN:H2O (0.8 mL) at 0 °C was added a solution of CAN (0.041 g, 0.074 mmol) in 1:1 MeCN:H2O (0.4 mL). The

solution was warmed to room temperature and stirred for 1 h. H2O (2 mL) was added and the

reaction mixture was extracted with CHCl3 (3 x 2 mL) and washed with brine (2 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated to yield 3.179 as a

yellow solid (0.0076 g, 0.016 mmol, 87%), which was used without further purification.

1 H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H), 8.29 (s, 1H), 7.11 (s, 2H), 5.75 (d, J = 12.9 Hz, 1H),

4.21 (d, J = 12.9 Hz, 1H), 3.62 (dt, J = 14.2, 6.5 Hz, 1H), 3.46 (dt, J = 14.2, 6.8 Hz, 1H), 3.21 (dt,

J = 13.9, 6.8 Hz, 1H), 3.17 (s, 1H), 3.00 (dt, J = 13.9, 6.4 Hz, 1H), 2.63 (ddd, J = 19.3, 12.9, 6.5

Hz, 1H), 2.52 (dd, J = 19.3, 7.0 Hz, 1H), 2.34 (s, 3H), 2.11 (dd, J = 14.1, 6.5 Hz, 1H), 1.86 (td, J

13 = 13.6, 7.0 Hz, 1H), 1.64 (s, 3H); C NMR (125 MHz, CDCl3) δ 204.0, 203.9, 195.3, 184.3, 183.5,

201

167.2, 167.1, 139.6, 139.2, 137.5, 136.1, 132.5, 124.6, 122.2, 80.7, 69.7, 54.7, 44.0, 40.6, 38.1,

34.6, 30.8, 27.4, 17.7; IR (thin film) ν 3333, 2928, 1695, 1675, 1605, 1418, 1240, 1191, 732 cm-1;

+ HRMS (ESI) m / z calcd for C24H21NO7SNa (M + Na) 490.0937, found 490.0945.

Dihydroxynaphthalene 3.180. To a solution of 3.179 (0.002 g, 0.004 mmol) in 1:1 Et2O:THF

(0.6 mL) at room temperature was added a solution of Na2S2O4 (0.007 g, 0.042 mmol) in H2O (0.3

mL). The reaction mixture was stirred for 1 h and the phases were separated. The aqueous phase

was extracted with Et2O (2 x 2 mL) and the combined organic phases were washed with brine (1

x 1 mL), dried over MgSO4, filtered, and concentrated to yield 3.180 as a yellow residue (0.001 g,

0.002 mmol, 50%). 3.180 is unstable and decomposes rapidly upon standing.

1 H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H), 7.85 (s, 1H), 6.22 (d, J = 7.6 Hz, 1H), 6.18 (d, J = 7.6

Hz, 1H), 5.81 (d, J = 11.2 Hz, 1H), 4.75 (s, 1H), 3.82–3.70 (m, 1H), 3.58 (dt, J = 14.1, 6.6 Hz,

1H), 3.31 (dt, J = 13.8, 6.6 Hz, 1H), 3.18–3.05 (m, 2H), 2.62–2.51 (m, 1H), 2.43–2.35 (m,1H),

13 2.39 (s, 3H), 1.96–1.81 (m, 2H), 1.69 (s, 3H); C NMR (125 MHz, CDCl3) δ 205.19, 205.18,

204.2, 170.1, 153.9, 147.2, 144.7, 129.3, 128.0, 124.3, 122.9, 116.6, 112.9, 108.8, 81.0, 70.4, 54.7,

+ 42.9, 40.7, 39.0, 34.9, 30.8, 27.3, 18.0; HRMS (ESI) m / z calcd for C24H23NO7SNa (M + Na)

492.1093, found 492.1088.

202

Dihydroxynaphthalene 3.181. To a solution of 3.165 (0.0005 g, 0.001 mmol) in 2:1 d3-

MeCN:D2O (1.05 mL) at 0 °C was added a solution of CAN (0.0015 g, 0.003 mmol) in D2O (0.1 mL). The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was cooled to 0 °C and a solution of sodium dithionite (0.0016 g, 0.009 mmol) in D2O

(0.2 mL) was added. The resulting suspension was warmed to room temperature, stirred for 2 h,

filtered, and concentrated to yield a yellow solid, which was triturated with MeOH and filtered to

afford 3.181 as a yellow residue (0.0002 g, 0.0004 mmol, 43%). 3.181 is unstable and decomposes

rapidly upon standing.

1 H NMR (500 MHz, CD3CN) δ 8.57 (s, 1H), 8.22 (s, 1H), 8.11 (s, 2H), 7.62 (s, 1H), 6.91 (d, J =

8.1 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.62 (t, J = 2.4 Hz, 1H), 3.67–3.58 (m, 1H), 3.53–3.45 (m,

1H), 3.32 (t, J = 2.8 Hz, 1H), 3.03–2.95 (m, 1H), 2.95–2.87 (m, 1H), 2.56 (ddd, J = 18.7, 12.3, 5.7

Hz, 1H), 2.35 (d, J = 18.7 Hz, 1H), 2.06–1.99 (m, 2H), 1.53 (s, 3H); LRMS (ESI) m / z calcd for

– C22H20NO9S (M – Na) 474.0859, found 474.08.

203

O H OH SO3Na N O Me O

HO OH

3.182

Dihydroxynaphthalene 3.182. To a solution of 3.3 (0.0025 g, 0.0047 mmol) in 2:1 MeCN:H2O

(0.4 mL) at 0 °C was added a solution of CAN (0.0077 g, 0.014 mmol) in H2O (0.1 mL). The

reaction mixture was warmed to room temperature and stirred for 1 h. A solution of sodium

dithionite (0.0049 g, 0.028 mmol) in H2O (0.1 mL) was added at room temperature and the

suspension was stirred for 1 h. The crude reaction mixture was filtered through a plug of RP-C18

SiO2, flushing with 1:3 MeCN:H2O, and concentrated to afford 3.182 as an orange solid (0.0018

g, 0.0036 mmol, 75%). 3.182 is unstable and decomposes rapidly upon standing.

1 H NMR (500 MHz, d6-DMSO) δ 9.81 (s, 1H), 9.66 (s, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.16 (d, J

= 4.4 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.1 Hz, 1H), 5.52 (dd, J = 6.3, 4.5 Hz, 1H),

3.53–3.42 (m, 3H), 2.76–2.66 (m, 1H), 2.60 (ddd, J = 13.3, 8.7, 5.8 Hz, 1H), 2.43 (dt, J = 12.9, 3.6

Hz, 1H), 2.24–2.14 (m, 1H), 2.02–1.93 (m, 1H), 1.76 (t, J = 12.5 Hz, 1H), 1.70 (s, 3H); IR (thin

-1 film) ν 3431, 2921, 1715, 1672, 1606, 1192, 1048 cm ; HRMS (ESI) m / z calcd for C22H20NO9S

(M – Na)– 474.0859, found 474.0844.

Disulfate 3.199. To a solution of 3.178 (0.010 g, 0.041 mmol) in acetonitrile (0.7 mL) was added

204

SO3·DMF complex (0.031 g, 0.206 mmol) at room temperature. After 1 h, saturated aqueous

Na2CO3 (1 mL) was added and the mixture was concentrated in vacuo. The residue was dissolved

in 1:1 MeOH:CH2Cl2 and purified by column chromatography (SiO2, 10:2:0.5 – 10:4:0.5

CH2Cl2:MeOH:NH4OH) to afford 3.199 as a brown residue (0.0115 g, 0.026 mmol, 63%).

1 H NMR (500 MHz, d4-MeOH) δ 8.72 (s, 1H), 8.35 (d, J = 0.9 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H),

13 7.56 (d, J = 8.4 Hz, 1H), 3.22 (s, 2H), 1.27 (s, 6H); C NMR (125 MHz, d4-MeOH) δ 213.9, 148.7,

147.0, 146.4, 134.4, 134.1, 129.4, 121.6, 121.4, 120.8, 117.6, 47.5, 43.3, 25.6; IR (thin film) ν

3498, 3155, 3049, 1705, 1631, 1459, 1408, 1242, 1027, 827 cm-1; HRMS (ESI) m / z calcd for

– C15H13O9S2 (M – 2Na + H) 401.0001, found 401.0011.

OH O OH O OSO3Na O Me Me Me Me Me Me

OH OSO3Na OH 3.178 3.200 3.201

Monosulfates 3.200 and 3.201. To a solution of 3.178 (0.0046 g, 0.019 mmol) in MeCN (0.2 mL)

was added SO3·pyr (0.026 g, 0.164 mmol). The reaction mixture was heated to 40 °C for 14 h and

cooled to room temperature. H2O (1 mL) was added and the reaction mixture was concentrated to

yield a brown residue, which was purified by column chromatography (SiO2, 10:90 – 20:80

MeOH:EtOAc) to afford a 1:1 mixture of 3.200 and 3.201 as a yellow residue (0.002 g, 0.006

mmol, 31%).

1 3.200: H NMR (400 MHz, d6-DMSO) δ 8.43 (s, 1H), 8.12 (s, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.82

(d, J = 1.9 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 3.15 (s, 2H), 1.18 (s, 6H).

1 3.201: H NMR (400 MHz, d6-DMSO) δ 8.43 (s, 1H), 8.15 (s, 1H), 7.22 (d, J = 8.2 Hz, 1H), 6.89

(d, J = 8.2 Hz, 1H), 6.64 (d, J = 1.8 Hz, 1H), 3.15 (s, 2H), 1.18 (s, 6H).

205

Protected Disulfate 3.250. To a solution of 3.178 (0.004 g, 0.016 mmol) in THF (0.5 mL) was

trichloroethyl chlorosulfonate (0.016 g, 0.066 mmol) followed by DABCO (0.009 g, 0.082 mmol)

at room temperature. The reaction mixture was stirred for 2 h and quenched with H2O (0.5 mL).

The phases were separated and the aqueous phase was extracted with EtOAc (1 x 2 mL). The

combined organic phases were washed with brine (1 mL), dried over MgSO4, filtered, and

concentrated to yield a yellow oil, which was purified by column chromatography (SiO2, 10:90

EtOAc:hexanes) to afford 3.250 as a colorless oil (0.0066 g, 0.010 mmol, 60%).

1 H NMR (500 MHz, CDCl3) δ 8.66 (s, 1H), 8.23 (d, J = 0.8 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.65

(d, J = 8.5 Hz, 1H), 4.93 (s, 2H), 4.92 (s, 2H), 3.24 (s, 2H), 1.31 (s, 6H); 13C NMR (125 MHz,

CDCl3) δ 210.4, 148.4, 146.9, 144.7, 135.8, 131.3, 127.2, 119.5, 119.45, 119.43, 116.6, 92.3, 92.2,

80.9, 80.8, 46.8, 42.7, 25.4; IR (thin film) ν 2961, 1720, 1637, 1420, 1196, 1132, 997, 865, 724

-1 + cm ; HRMS (ESI) m / z calcd for C19H16Cl6O9S2Na (M + Na) 684.8265, found 684.8274.

206

Protected Disulfate 3.253. To a solution of 3.179 (0.0022 g, 0.005 mmol) in 1:1 Et2O:THF (0.6

mL) was added a solution of Na2S2O4 (0.008 g, 0.047 mmol) in H2O (0.3 mL). The reaction

mixture was stirred for 1 h and extracted with Et2O (3 x 3 mL). The combined organic phases were

dried over MgSO4, filtered, and concentrated to yield 3.180, which was immediately dissolved in

THF (0.3 mL). Trichloroethyl chlorosulfonate (0.003 g, 0.012 mmol) was added followed by

DABCO (0.0013 g, 0.012 mmol). After 3 h, H2O (1 mL) was added and the reaction mixture was

extracted with Et2O (3 x 3 mL). The combined organic phases were dried over MgSO4, filtered,

and concentrated to yield a 1.6:1 mixture of 3.179:3.253.

1 H NMR (600 MHz, CDCl3) δ 8.75 (d, J = 0.7 Hz, 1H), 8.30 (d, J = 0.7 Hz, 1H), 7.82 (d, J = 8.5

Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 5.78 (d, J = 13.0 Hz, 1H), 4.94 (s, 2H), 4.91 (s, 2H), 4.26 (d, J

= 13.0 Hz, 1H), 3.62 (dt, J = 14.0, 6.5 Hz, 1H), 3.49 (t, J = 6.7 Hz, 1H), 3.25–3.18 (m, 2H), 3.03

(dt, J = 13.8, 6.5 Hz, 1H), 2.67–2.62 (m, 1H), 2.54 (dd, J = 18.9, 7.0 Hz, 1H), 2.35 (s, 3H), 2.13

(dd, J = 14.5, 6.5 Hz, 1H), 2.01–1.92 (m, 1H), 1.71 (s, 3H); LRMS (ESI) m / z calcd for

+ C28H25NO13S3Cl6Na (M + Na) 911.8517, found 911.87.

207

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APPENDIX A: NMR and Chiral HPLC Data

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3 NMe Br O O OSiEt H 2.52 O O PhS PhS

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3 NMe Br O O OSiEt H 2.52 O O PhS PhS

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O NMe O O 2.74 Me Me

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O NMe O O H 2.3 Me

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O NMe O O H 2.3 Me

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OH NMe OH O H 2.106 Me

276

OH NMe OH O H 2.106 Me

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OEt 3.36 OMe OMe

288

OEt 3.36 OMe OMe

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Me 2 CO OTf 3.51 OMe

294

Me 2 CO OTf 3.51 OMe

295

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301

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OTBS 3 OSiEt OMe N OH O H 3.157 Me MeO

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OTBS O N OMe OH O H 3.158 Me MeO

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OTBS O N OMe OH O H 3.158 Me MeO

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OTBS OH N OMe OH O H 3.159 Me MeO

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OH OH N OMe OH O H 3.160 Me MeO

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OH OH N OMe OH O H 3.160 Me MeO

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APPENDIX B: X-ray Crystallographic Data

398

Crystal data and structure refinement for 2.84. Identification code cdv19 (Greg Schwarzwalder)

Empirical formula C24 H34 I N O3 Si Formula weight 539.51 Temperature 88(2) K Wavelength 0.71073 Å Crystal system Monoclinic

Space group P21 Unit cell dimensions a = 12.4043(4) Å = 90°. b = 11.4302(4) Å = 92.4761(4)°. c = 17.7674(6) Å  = 90°. Volume 2516.77(15) Å3 Z 4 Density (calculated) 1.424 Mg/m3 Absorption coefficient 1.344 mm-1 F(000) 1104 Crystal color colorless Crystal size 0.265 x 0.207 x 0.112 mm3 Theta range for data collection 1.643 to 28.924° Index ranges -16 ≤ h ≤ 16, -15 ≤ k ≤ 15, -23 ≤ l ≤ 23 Reflections collected 30446 Independent reflections 12174 [R(int) = 0.0158] Completeness to theta = 25.500° 100.0 % Absorption correction Numerical Max. and min. transmission 0.9101 and 0.7781 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 12174 / 1 / 550 Goodness-of-fit on F2 1.041 Final R indices [I>2sigma(I) = 11769 data] R1 = 0.0219, wR2 = 0.0545 R indices (all data, 0.74Å) R1 = 0.0231, wR2 = 0.0551 Absolute structure parameter 0.226(11) Largest diff. peak and hole 1.055 and -0.346 e.Å-3

399

Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 2.84. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______I(1) 3198(1) 10133(1) 8566(1) 24(1) Si(1) 4915(1) 8718(1) 6231(1) 20(1) O(1) 8842(2) 11034(2) 6766(1) 25(1) O(2) 5310(2) 12005(2) 6757(1) 21(1) O(3) 5772(2) 9230(2) 6901(1) 16(1) N(1) 7162(2) 12001(3) 6822(2) 22(1) C(1) 6187(3) 11667(3) 7037(2) 16(1) C(2) 8062(3) 11460(3) 7242(2) 19(1) C(3) 7525(2) 10438(3) 7649(2) 15(1) C(4) 8143(2) 10128(4) 8373(2) 18(1) C(5) 7915(3) 10867(3) 9049(2) 20(1) C(6) 6704(3) 10992(3) 9146(2) 20(1) C(7) 6164(2) 11501(3) 8438(2) 16(1) C(8) 6329(2) 10826(3) 7707(2) 14(1) C(9) 5481(2) 9832(3) 7565(2) 14(1) C(10) 5384(3) 8986(3) 8212(2) 16(1) C(11) 4536(3) 9004(3) 8715(2) 18(1) C(12) 4534(3) 8261(3) 9333(2) 22(1) C(13) 5366(3) 7464(3) 9459(2) 24(1) C(14) 6185(3) 7387(3) 8956(2) 21(1) C(15) 6182(3) 8133(3) 8339(2) 19(1) C(16) 5631(3) 12513(3) 8459(2) 22(1) C(17) 8877(3) 9283(4) 8399(2) 27(1) C(18) 7326(3) 12903(4) 6261(2) 36(1) C(19) 3066(3) 9488(4) 5380(2) 32(1) C(20) 3729(3) 9715(3) 6123(2) 30(1) C(21) 6165(3) 9910(4) 5168(2) 36(1) C(22) 5676(3) 8712(3) 5352(2) 25(1) C(23) 5318(3) 6281(3) 6577(2) 36(1) C(24) 4450(3) 7221(3) 6484(2) 32(1) I(2) 1744(1) 9432(1) 1340(1) 22(1)

400

Si(2) -47(1) 11339(1) 3587(1) 18(1) O(4) -3772(2) 8705(2) 3303(1) 25(1) O(5) -174(2) 7958(2) 3269(1) 19(1) O(6) -841(2) 10688(2) 2937(1) 17(1) N(2) -2011(2) 7920(2) 3308(1) 18(1) C(25) -1081(3) 8221(3) 3008(2) 15(1) C(26) -2976(2) 8278(3) 2853(2) 17(1) C(27) -2526(2) 9272(3) 2368(2) 15(1) C(28) -3194(2) 9469(4) 1654(2) 19(1) C(29) -3004(3) 8661(3) 1004(2) 20(1) C(30) -1789(3) 8548(3) 880(2) 20(1) C(31) -1200(3) 8131(3) 1597(2) 17(1) C(32) -1318(2) 8924(3) 2284(2) 14(1) C(33) -508(2) 9967(3) 2336(2) 15(1) C(34) -409(3) 10709(3) 1632(2) 16(1) C(35) 442(2) 10609(3) 1151(2) 17(1) C(36) 502(3) 11321(3) 511(2) 20(1) C(37) -296(3) 12146(3) 360(2) 22(1) C(38) -1138(3) 12271(3) 838(2) 21(1) C(39) -1193(3) 11562(3) 1466(2) 18(1) C(40) -712(3) 7095(3) 1629(2) 21(1) C(41) -3928(3) 10313(3) 1603(2) 26(1) C(42) -2056(3) 7173(3) 3966(2) 26(1) C(43) -883(3) 13644(3) 3255(2) 36(1) C(44) -822(3) 12657(3) 3853(2) 27(1) C(45) -879(3) 10107(4) 4830(2) 39(1) C(46) 162(3) 10358(3) 4422(2) 28(1) C(47) 1932(3) 12572(4) 3670(2) 32(1) C(48) 1271(3) 11713(3) 3178(2) 24(1) ______

401

Bond lengths [Å] and angles [°] for 2.84. ______I(1)-C(11) 2.109(3) Si(1)-O(3) 1.668(2) Si(1)-C(22) 1.860(3) Si(1)-C(20) 1.863(3) Si(1)-C(24) 1.867(4) O(1)-C(2) 1.399(4) O(2)-C(1) 1.238(4) O(3)-C(9) 1.426(3) N(1)-C(1) 1.340(4) N(1)-C(18) 1.453(4) N(1)-C(2) 1.454(4) C(1)-C(8) 1.535(4) C(2)-C(3) 1.540(4) C(3)-C(4) 1.510(4) C(3)-C(8) 1.556(4) C(4)-C(17) 1.327(5) C(4)-C(5) 1.506(5) C(5)-C(6) 1.525(5) C(6)-C(7) 1.515(4) C(7)-C(16) 1.334(5) C(7)-C(8) 1.532(4) C(8)-C(9) 1.562(4) C(9)-C(10) 1.511(4) C(10)-C(15) 1.400(5) C(10)-C(11) 1.410(4) C(11)-C(12) 1.388(4) C(12)-C(13) 1.387(5) C(13)-C(14) 1.385(5) C(14)-C(15) 1.388(4) C(19)-C(20) 1.548(4) C(21)-C(22) 1.539(6) C(23)-C(24) 1.525(6) I(2)-C(35) 2.118(3) Si(2)-O(6) 1.661(2)

402

Si(2)-C(44) 1.859(3) Si(2)-C(48) 1.867(3) Si(2)-C(46) 1.869(3) O(4)-C(26) 1.385(4) O(5)-C(25) 1.235(4) O(6)-C(33) 1.423(3) N(2)-C(25) 1.336(4) N(2)-C(42) 1.451(4) N(2)-C(26) 1.473(4) C(25)-C(32) 1.534(4) C(26)-C(27) 1.545(4) C(27)-C(28) 1.502(4) C(27)-C(32) 1.563(4) C(28)-C(41) 1.327(5) C(28)-C(29) 1.505(5) C(29)-C(30) 1.537(5) C(30)-C(31) 1.519(4) C(31)-C(40) 1.330(5) C(31)-C(32) 1.532(4) C(32)-C(33) 1.559(4) C(33)-C(34) 1.520(4) C(34)-C(35) 1.392(4) C(34)-C(39) 1.400(5) C(35)-C(36) 1.402(4) C(36)-C(37) 1.385(5) C(37)-C(38) 1.382(5) C(38)-C(39) 1.383(4) C(43)-C(44) 1.549(5) C(45)-C(46) 1.535(5) C(47)-C(48) 1.530(5)

O(3)-Si(1)-C(22) 105.62(13) O(3)-Si(1)-C(20) 109.56(13) C(22)-Si(1)-C(20) 110.07(16) O(3)-Si(1)-C(24) 110.10(14) C(22)-Si(1)-C(24) 111.85(17)

403

C(20)-Si(1)-C(24) 109.56(17) C(9)-O(3)-Si(1) 125.69(18) C(1)-N(1)-C(18) 123.5(3) C(1)-N(1)-C(2) 114.5(3) C(18)-N(1)-C(2) 121.8(3) O(2)-C(1)-N(1) 125.8(3) O(2)-C(1)-C(8) 125.3(3) N(1)-C(1)-C(8) 109.0(3) O(1)-C(2)-N(1) 111.9(3) O(1)-C(2)-C(3) 110.1(3) N(1)-C(2)-C(3) 103.0(2) C(4)-C(3)-C(2) 111.4(3) C(4)-C(3)-C(8) 117.4(2) C(2)-C(3)-C(8) 104.4(2) C(17)-C(4)-C(5) 122.2(3) C(17)-C(4)-C(3) 121.6(3) C(5)-C(4)-C(3) 116.2(3) C(4)-C(5)-C(6) 111.2(3) C(7)-C(6)-C(5) 110.2(3) C(16)-C(7)-C(6) 120.7(3) C(16)-C(7)-C(8) 123.1(3) C(6)-C(7)-C(8) 116.1(3) C(7)-C(8)-C(1) 109.1(3) C(7)-C(8)-C(3) 111.3(2) C(1)-C(8)-C(3) 101.8(2) C(7)-C(8)-C(9) 113.0(2) C(1)-C(8)-C(9) 106.0(2) C(3)-C(8)-C(9) 114.8(3) O(3)-C(9)-C(10) 110.7(2) O(3)-C(9)-C(8) 107.0(2) C(10)-C(9)-C(8) 114.7(2) C(15)-C(10)-C(11) 116.8(3) C(15)-C(10)-C(9) 119.2(3) C(11)-C(10)-C(9) 124.0(3) C(12)-C(11)-C(10) 121.2(3) C(12)-C(11)-I(1) 116.5(2)

404

C(10)-C(11)-I(1) 122.3(2) C(13)-C(12)-C(11) 120.2(3) C(14)-C(13)-C(12) 120.0(3) C(13)-C(14)-C(15) 119.5(3) C(14)-C(15)-C(10) 122.2(3) C(19)-C(20)-Si(1) 111.9(2) C(21)-C(22)-Si(1) 113.2(2) C(23)-C(24)-Si(1) 116.6(3) O(6)-Si(2)-C(44) 104.07(14) O(6)-Si(2)-C(48) 109.52(13) C(44)-Si(2)-C(48) 112.60(16) O(6)-Si(2)-C(46) 109.97(14) C(44)-Si(2)-C(46) 109.85(16) C(48)-Si(2)-C(46) 110.62(16) C(33)-O(6)-Si(2) 126.79(19) C(25)-N(2)-C(42) 122.5(3) C(25)-N(2)-C(26) 113.9(3) C(42)-N(2)-C(26) 123.1(3) O(5)-C(25)-N(2) 125.1(3) O(5)-C(25)-C(32) 125.5(3) N(2)-C(25)-C(32) 109.4(3) O(4)-C(26)-N(2) 111.4(3) O(4)-C(26)-C(27) 110.3(3) N(2)-C(26)-C(27) 101.9(2) C(28)-C(27)-C(26) 112.5(3) C(28)-C(27)-C(32) 117.0(2) C(26)-C(27)-C(32) 103.7(2) C(41)-C(28)-C(27) 121.2(3) C(41)-C(28)-C(29) 121.6(3) C(27)-C(28)-C(29) 117.2(3) C(28)-C(29)-C(30) 110.4(3) C(31)-C(30)-C(29) 110.1(3) C(40)-C(31)-C(30) 121.1(3) C(40)-C(31)-C(32) 123.5(3) C(30)-C(31)-C(32) 115.1(3) C(31)-C(32)-C(25) 109.7(3)

405

C(31)-C(32)-C(33) 114.5(2) C(25)-C(32)-C(33) 104.6(2) C(31)-C(32)-C(27) 110.6(2) C(25)-C(32)-C(27) 101.7(2) C(33)-C(32)-C(27) 114.7(2) O(6)-C(33)-C(34) 109.3(3) O(6)-C(33)-C(32) 106.3(2) C(34)-C(33)-C(32) 116.9(2) C(35)-C(34)-C(39) 117.7(3) C(35)-C(34)-C(33) 123.4(3) C(39)-C(34)-C(33) 118.8(3) C(34)-C(35)-C(36) 121.3(3) C(34)-C(35)-I(2) 123.2(2) C(36)-C(35)-I(2) 115.5(2) C(37)-C(36)-C(35) 119.3(3) C(38)-C(37)-C(36) 120.2(3) C(37)-C(38)-C(39) 120.0(3) C(38)-C(39)-C(34) 121.4(3) C(43)-C(44)-Si(2) 115.2(2) C(45)-C(46)-Si(2) 113.3(3) C(47)-C(48)-Si(2) 112.4(2) ______

406

Anisotropic displacement parameters (Å2x 103) for 2.84. The anisotropic displacement factor exponent takes the form: -22[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______I(1) 20(1) 24(1) 27(1) 3(1) 9(1) 1(1) Si(1) 17(1) 27(1) 16(1) -7(1) 0(1) 1(1) O(1) 21(1) 26(1) 29(1) -4(1) 8(1) -2(1) O(2) 18(1) 23(1) 21(1) 4(1) 0(1) 6(1) O(3) 16(1) 21(1) 12(1) -3(1) 1(1) 1(1) N(1) 16(1) 26(2) 23(1) 11(1) 4(1) 1(1) C(1) 20(2) 17(2) 13(1) 2(1) 2(1) 3(1) C(2) 17(1) 23(2) 18(1) 3(1) 3(1) 3(1) C(3) 13(1) 14(2) 17(1) 2(1) -1(1) 1(1) C(4) 15(1) 18(1) 21(1) 6(2) -2(1) -2(1) C(5) 23(2) 18(2) 19(2) 1(1) -7(1) -3(1) C(6) 25(2) 21(2) 14(1) -2(1) -1(1) 0(1) C(7) 14(2) 20(2) 16(1) -1(1) 3(1) -1(1) C(8) 13(1) 14(1) 14(1) 2(1) 1(1) 1(1) C(9) 14(1) 16(1) 12(1) -1(1) 1(1) 1(1) C(10) 17(1) 15(1) 15(1) -2(1) 1(1) -2(1) C(11) 19(2) 16(1) 19(1) -2(1) 0(1) -3(1) C(12) 25(2) 23(2) 17(1) -2(1) 3(1) -8(1) C(13) 32(2) 19(2) 19(2) 2(1) -6(1) -8(1) C(14) 23(2) 17(2) 23(2) 1(1) -6(1) -1(1) C(15) 21(2) 16(2) 19(1) 0(1) -1(1) -2(1) C(16) 23(2) 21(2) 23(2) -6(1) 3(1) 3(1) C(17) 24(2) 24(2) 31(2) 4(2) -2(1) 4(2) C(18) 28(2) 42(2) 37(2) 27(2) 6(2) 5(2) C(19) 24(2) 47(2) 25(2) -17(2) -8(1) 9(2) C(20) 21(2) 44(2) 24(2) -16(1) -7(1) 8(1) C(21) 37(2) 47(2) 23(2) -2(2) 8(1) -1(2) C(22) 26(2) 35(2) 16(1) -4(1) -1(1) 6(2) C(23) 41(2) 26(2) 42(2) -7(2) 6(2) -10(2) C(24) 28(2) 35(2) 32(2) -10(2) 5(2) -10(2) I(2) 21(1) 20(1) 26(1) 2(1) 8(1) 0(1)

407

Si(2) 16(1) 21(1) 17(1) -5(1) 1(1) -2(1) O(4) 21(1) 26(1) 28(1) -2(1) 8(1) -4(1) O(5) 18(1) 19(1) 19(1) -1(1) -2(1) 3(1) O(6) 16(1) 19(1) 15(1) -4(1) 1(1) -2(1) N(2) 17(1) 20(1) 17(1) 6(1) -1(1) 0(1) C(25) 16(1) 14(1) 15(1) -2(1) 2(1) 0(1) C(26) 12(1) 18(1) 19(1) 2(1) 2(1) -1(1) C(27) 13(1) 14(2) 18(1) 0(1) 1(1) 1(1) C(28) 19(1) 17(2) 21(1) -1(2) -1(1) -6(2) C(29) 20(2) 21(2) 17(1) 1(1) -6(1) -2(1) C(30) 25(2) 20(2) 14(1) -1(1) 1(1) -2(1) C(31) 18(2) 18(2) 15(1) 0(1) 2(1) -5(1) C(32) 14(1) 14(1) 14(1) -1(1) 2(1) -1(1) C(33) 14(1) 17(1) 13(1) -2(1) 1(1) -2(1) C(34) 21(2) 15(1) 14(1) 1(1) -2(1) -6(1) C(35) 18(1) 16(1) 18(1) -2(1) 0(1) -3(1) C(36) 23(2) 24(2) 15(1) -1(1) 2(1) -9(1) C(37) 27(2) 22(2) 18(2) 4(1) -1(1) -7(1) C(38) 22(2) 18(2) 22(2) 3(1) -5(1) -3(1) C(39) 18(2) 19(2) 18(1) -2(1) 1(1) -1(1) C(40) 22(2) 23(2) 17(1) -4(1) -1(1) 1(1) C(41) 24(2) 26(2) 26(2) 2(1) -5(1) 5(2) C(42) 28(2) 29(2) 22(2) 10(1) 4(1) -2(1) C(43) 38(2) 26(2) 45(2) -2(2) 5(2) 10(2) C(44) 23(2) 26(2) 31(2) -8(1) 4(1) -1(1) C(45) 50(2) 42(2) 27(2) 6(2) 9(2) 0(2) C(46) 33(2) 33(2) 18(2) 2(1) -5(1) -2(1) C(47) 24(2) 40(2) 32(2) -8(2) 4(1) -11(2) C(48) 19(2) 28(2) 26(2) -5(1) 2(1) -3(1) ______

408

Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for 2.84. ______x y z U(eq) ______

H(1) 9332 11535 6727 38 H(2A) 8393 12024 7615 23 H(3A) 7537 9740 7310 18 H(5A) 8238 11652 8989 24 H(5B) 8253 10503 9507 24 H(6A) 6389 10217 9250 24 H(6B) 6576 11511 9579 24 H(9A) 4760 10204 7462 17 H(12A) 3962 8298 9671 26 H(13A) 5373 6972 9889 28 H(14A) 6746 6828 9033 25 H(15A) 6739 8063 7991 22 H(16A) 5588 12924 8922 27 H(16B) 5296 12824 8012 27 H(17A) 9279 9128 8856 32 H(17B) 9001 8833 7962 32 H(18A) 6624 13201 6072 53 H(18B) 7714 12571 5843 53 H(18C) 7748 13544 6491 53 H(19A) 2408 9962 5370 48 H(19B) 2873 8658 5346 48 H(19C) 3498 9700 4951 48 H(20A) 3260 9603 6554 36 H(20B) 3983 10536 6132 36 H(21A) 6473 9881 4670 53 H(21B) 6733 10104 5548 53 H(21C) 5600 10510 5170 53 H(22A) 6263 8128 5402 31 H(22B) 5185 8468 4926 31 H(23A) 4977 5520 6655 54

409

H(23B) 5797 6469 7014 54 H(23C) 5738 6251 6123 54 H(24A) 4070 7276 6962 38 H(24B) 3916 6958 6090 38 H(4) -4104 8143 3490 37 H(26A) -3255 7619 2530 20 H(27A) -2540 10010 2670 18 H(29A) -3376 8969 542 24 H(29B) -3307 7879 1110 24 H(30A) -1673 7984 468 23 H(30B) -1498 9316 730 23 H(33A) 222 9647 2479 18 H(36A) 1084 11237 185 24 H(37A) -264 12628 -75 27 H(38A) -1679 12844 735 25 H(39A) -1776 11656 1790 22 H(40A) -729 6602 1198 25 H(40B) -347 6848 2083 25 H(41A) -4039 10806 2023 31 H(41B) -4343 10423 1146 31 H(42A) -1453 7360 4320 40 H(42B) -2007 6352 3811 40 H(42C) -2739 7301 4210 40 H(43A) -1341 14278 3430 55 H(43B) -1191 13332 2779 55 H(43C) -156 13945 3178 55 H(44A) -1566 12414 3960 32 H(44B) -489 12980 4326 32 H(45A) -719 9583 5257 59 H(45B) -1406 9735 4480 59 H(45C) -1176 10843 5013 59 H(46A) 471 9607 4255 34 H(46B) 693 10724 4781 34 H(47A) 2623 12723 3442 48 H(47B) 2062 12236 4173 48 H(47C) 1533 13308 3711 48

410

H(48A) 1693 10987 3117 29 H(48B) 1135 12060 2672 29 ______

411

Torsion angles [°] for 2.84. ______C(22)-Si(1)-O(3)-C(9) 152.8(2) C(20)-Si(1)-O(3)-C(9) 34.3(3) C(24)-Si(1)-O(3)-C(9) -86.3(3) C(18)-N(1)-C(1)-O(2) 5.6(5) C(2)-N(1)-C(1)-O(2) -179.5(3) C(18)-N(1)-C(1)-C(8) -172.4(3) C(2)-N(1)-C(1)-C(8) 2.5(4) C(1)-N(1)-C(2)-O(1) 132.9(3) C(18)-N(1)-C(2)-O(1) -52.1(4) C(1)-N(1)-C(2)-C(3) 14.6(4) C(18)-N(1)-C(2)-C(3) -170.4(3) O(1)-C(2)-C(3)-C(4) 88.0(3) N(1)-C(2)-C(3)-C(4) -152.5(3) O(1)-C(2)-C(3)-C(8) -144.4(2) N(1)-C(2)-C(3)-C(8) -24.9(3) C(2)-C(3)-C(4)-C(17) -94.9(4) C(8)-C(3)-C(4)-C(17) 144.9(3) C(2)-C(3)-C(4)-C(5) 82.3(3) C(8)-C(3)-C(4)-C(5) -37.9(4) C(17)-C(4)-C(5)-C(6) -134.1(3) C(3)-C(4)-C(5)-C(6) 48.7(4) C(4)-C(5)-C(6)-C(7) -56.7(4) C(5)-C(6)-C(7)-C(16) -119.7(3) C(5)-C(6)-C(7)-C(8) 56.7(4) C(16)-C(7)-C(8)-C(1) 20.8(4) C(6)-C(7)-C(8)-C(1) -155.5(3) C(16)-C(7)-C(8)-C(3) 132.3(3) C(6)-C(7)-C(8)-C(3) -44.0(4) C(16)-C(7)-C(8)-C(9) -96.9(4) C(6)-C(7)-C(8)-C(9) 86.8(3) O(2)-C(1)-C(8)-C(7) -78.5(4) N(1)-C(1)-C(8)-C(7) 99.5(3) O(2)-C(1)-C(8)-C(3) 163.8(3) N(1)-C(1)-C(8)-C(3) -18.2(3)

412

O(2)-C(1)-C(8)-C(9) 43.4(4) N(1)-C(1)-C(8)-C(9) -138.6(3) C(4)-C(3)-C(8)-C(7) 33.6(4) C(2)-C(3)-C(8)-C(7) -90.2(3) C(4)-C(3)-C(8)-C(1) 149.8(3) C(2)-C(3)-C(8)-C(1) 26.0(3) C(4)-C(3)-C(8)-C(9) -96.2(3) C(2)-C(3)-C(8)-C(9) 140.0(2) Si(1)-O(3)-C(9)-C(10) 93.2(3) Si(1)-O(3)-C(9)-C(8) -141.1(2) C(7)-C(8)-C(9)-O(3) -176.1(2) C(1)-C(8)-C(9)-O(3) 64.5(3) C(3)-C(8)-C(9)-O(3) -47.1(3) C(7)-C(8)-C(9)-C(10) -53.0(3) C(1)-C(8)-C(9)-C(10) -172.4(3) C(3)-C(8)-C(9)-C(10) 76.0(3) O(3)-C(9)-C(10)-C(15) 45.0(4) C(8)-C(9)-C(10)-C(15) -76.1(3) O(3)-C(9)-C(10)-C(11) -135.9(3) C(8)-C(9)-C(10)-C(11) 102.9(3) C(15)-C(10)-C(11)-C(12) 4.0(4) C(9)-C(10)-C(11)-C(12) -175.0(3) C(15)-C(10)-C(11)-I(1) -175.0(2) C(9)-C(10)-C(11)-I(1) 5.9(4) C(10)-C(11)-C(12)-C(13) -1.2(5) I(1)-C(11)-C(12)-C(13) 177.9(2) C(11)-C(12)-C(13)-C(14) -1.7(5) C(12)-C(13)-C(14)-C(15) 1.7(5) C(13)-C(14)-C(15)-C(10) 1.3(5) C(11)-C(10)-C(15)-C(14) -4.1(5) C(9)-C(10)-C(15)-C(14) 175.0(3) O(3)-Si(1)-C(20)-C(19) 164.4(3) C(22)-Si(1)-C(20)-C(19) 48.7(3) C(24)-Si(1)-C(20)-C(19) -74.7(3) O(3)-Si(1)-C(22)-C(21) -54.6(3) C(20)-Si(1)-C(22)-C(21) 63.5(3)

413

C(24)-Si(1)-C(22)-C(21) -174.4(3) O(3)-Si(1)-C(24)-C(23) -60.8(3) C(22)-Si(1)-C(24)-C(23) 56.4(3) C(20)-Si(1)-C(24)-C(23) 178.7(3) C(44)-Si(2)-O(6)-C(33) 151.7(3) C(48)-Si(2)-O(6)-C(33) 31.1(3) C(46)-Si(2)-O(6)-C(33) -90.6(3) C(42)-N(2)-C(25)-O(5) -3.9(5) C(26)-N(2)-C(25)-O(5) -175.9(3) C(42)-N(2)-C(25)-C(32) 175.2(3) C(26)-N(2)-C(25)-C(32) 3.1(4) C(25)-N(2)-C(26)-O(4) -138.8(3) C(42)-N(2)-C(26)-O(4) 49.2(4) C(25)-N(2)-C(26)-C(27) -21.3(3) C(42)-N(2)-C(26)-C(27) 166.7(3) O(4)-C(26)-C(27)-C(28) -84.8(3) N(2)-C(26)-C(27)-C(28) 156.9(3) O(4)-C(26)-C(27)-C(32) 147.9(2) N(2)-C(26)-C(27)-C(32) 29.6(3) C(26)-C(27)-C(28)-C(41) 98.1(4) C(32)-C(27)-C(28)-C(41) -142.1(3) C(26)-C(27)-C(28)-C(29) -81.2(3) C(32)-C(27)-C(28)-C(29) 38.6(4) C(41)-C(28)-C(29)-C(30) 132.8(3) C(27)-C(28)-C(29)-C(30) -47.9(4) C(28)-C(29)-C(30)-C(31) 56.5(4) C(29)-C(30)-C(31)-C(40) 114.8(4) C(29)-C(30)-C(31)-C(32) -59.0(4) C(40)-C(31)-C(32)-C(25) -15.1(4) C(30)-C(31)-C(32)-C(25) 158.5(3) C(40)-C(31)-C(32)-C(33) 102.1(4) C(30)-C(31)-C(32)-C(33) -84.4(3) C(40)-C(31)-C(32)-C(27) -126.5(3) C(30)-C(31)-C(32)-C(27) 47.0(4) O(5)-C(25)-C(32)-C(31) 78.1(4) N(2)-C(25)-C(32)-C(31) -100.9(3)

414

O(5)-C(25)-C(32)-C(33) -45.1(4) N(2)-C(25)-C(32)-C(33) 135.8(3) O(5)-C(25)-C(32)-C(27) -164.7(3) N(2)-C(25)-C(32)-C(27) 16.2(3) C(28)-C(27)-C(32)-C(31) -35.9(4) C(26)-C(27)-C(32)-C(31) 88.5(3) C(28)-C(27)-C(32)-C(25) -152.3(3) C(26)-C(27)-C(32)-C(25) -28.0(3) C(28)-C(27)-C(32)-C(33) 95.4(3) C(26)-C(27)-C(32)-C(33) -140.2(2) Si(2)-O(6)-C(33)-C(34) -94.4(3) Si(2)-O(6)-C(33)-C(32) 138.6(2) C(31)-C(32)-C(33)-O(6) 171.7(2) C(25)-C(32)-C(33)-O(6) -68.2(3) C(27)-C(32)-C(33)-O(6) 42.3(3) C(31)-C(32)-C(33)-C(34) 49.4(4) C(25)-C(32)-C(33)-C(34) 169.5(3) C(27)-C(32)-C(33)-C(34) -80.0(3) O(6)-C(33)-C(34)-C(35) 137.2(3) C(32)-C(33)-C(34)-C(35) -102.1(3) O(6)-C(33)-C(34)-C(39) -40.9(4) C(32)-C(33)-C(34)-C(39) 79.8(4) C(39)-C(34)-C(35)-C(36) -1.3(5) C(33)-C(34)-C(35)-C(36) -179.5(3) C(39)-C(34)-C(35)-I(2) 176.8(2) C(33)-C(34)-C(35)-I(2) -1.3(4) C(34)-C(35)-C(36)-C(37) 0.6(5) I(2)-C(35)-C(36)-C(37) -177.7(2) C(35)-C(36)-C(37)-C(38) 0.4(5) C(36)-C(37)-C(38)-C(39) -0.7(5) C(37)-C(38)-C(39)-C(34) 0.0(5) C(35)-C(34)-C(39)-C(38) 1.1(5) C(33)-C(34)-C(39)-C(38) 179.3(3) O(6)-Si(2)-C(44)-C(43) -72.4(3) C(48)-Si(2)-C(44)-C(43) 46.1(3) C(46)-Si(2)-C(44)-C(43) 169.9(3)

415

O(6)-Si(2)-C(46)-C(45) -64.2(3) C(44)-Si(2)-C(46)-C(45) 49.8(3) C(48)-Si(2)-C(46)-C(45) 174.7(3) O(6)-Si(2)-C(48)-C(47) 165.8(2) C(44)-Si(2)-C(48)-C(47) 50.5(3) C(46)-Si(2)-C(48)-C(47) -72.8(3) ______

416

Hydrogen bonds for 2.84 [Å and °]. ______D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ______O(1)-H(1)...O(5)#1 0.84 1.93 2.753(3) 165.1 C(2)-H(2A)...I(2)#1 1.00 3.33 4.230(3) 150.9 C(3)-H(3A)...O(3) 1.00 2.35 2.856(4) 110.3 C(9)-H(9A)...I(1) 1.00 2.82 3.426(3) 119.8 O(4)-H(4)...O(2)#2 0.84 2.02 2.722(3) 141.2 C(27)-H(27A)...O(6) 1.00 2.28 2.797(4) 111.1 C(33)-H(33A)...I(2) 1.00 2.84 3.426(3) 118.2 ______Symmetry transformations used to generate equivalent atoms: #1 -x+1,y+1/2,-z+1 #2 -x,y-1/2,-z+1

417

Crystal data and structure refinement for 2.87. Identification code cdv20 (Greg Schwarzwalder)

Empirical formula C17 H17 N O4 Formula weight 299.31 Temperature 143(2) K Wavelength 0.71073 Å Crystal system Monoclinic

Space group P21/n Unit cell dimensions a = 6.486(3) Å = 90°. b = 7.921(3) Å = 90.113(5)°. c = 27.059(11) Å  = 90°. Volume 1390.2(10) Å3 Z 4 Density (calculated) 1.430 Mg/m3 Absorption coefficient 0.102 mm-1 F(000) 632 Crystal color colorless Crystal size 0.150 x 0.120 x 0.110 mm3 Theta range for data collection 0.752 to 25.346° Index ranges -7 ≤ h ≤ 7, -9 ≤ k ≤ 9, -32 ≤ l ≤ 32 Reflections collected 13828 Independent reflections 2551 [R(int) = 0.0977] Completeness to theta = 25.346° 100.0 % Absorption correction Numerical Max. and min. transmission 0.8620 and 0.7470 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2551 / 0 / 202 Goodness-of-fit on F2 1.019 Final R indices [I>2sigma(I) = 1897 data] R1 = 0.0524, wR2 = 0.1103 R indices (all data, 0.83Å) R1 = 0.0787, wR2 = 0.1213 Largest diff. peak and hole 0.272 and -0.286 e.Å-3

418

Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 2.87. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______O(1) -2355(4) 4313(3) 17(1) 36(1) O(2) -908(4) 79(2) 668(1) 26(1) O(3) 3881(3) 3434(3) 1183(1) 21(1) O(4) -481(4) 1089(3) 1678(1) 27(1) N(1) 1841(4) 2036(3) 630(1) 19(1) C(1) 2178(5) 3096(4) 1008(1) 18(1) C(2) -315(5) 1712(4) 520(1) 22(1) C(3) -1422(5) 3125(4) 796(1) 18(1) C(4) -2131(5) 4542(4) 455(1) 20(1) C(5) -2628(5) 6195(4) 697(1) 21(1) C(6) -2235(5) 6206(4) 1252(1) 20(1) C(7) -62(5) 5550(4) 1386(1) 19(1) C(8) 89(5) 3689(4) 1207(1) 18(1) C(9) -204(5) 2614(4) 1681(1) 22(1) C(10) -58(5) 3738(4) 2106(1) 21(1) C(11) -54(5) 3330(5) 2606(1) 28(1) C(12) 77(5) 4628(4) 2942(1) 28(1) C(13) 190(5) 6294(4) 2782(1) 27(1) C(14) 182(5) 6691(4) 2289(1) 25(1) C(15) 67(5) 5396(4) 1944(1) 22(1) C(16) 1608(5) 6743(4) 1188(1) 22(1) C(17) 3490(5) 1071(4) 404(1) 28(1) ______

419

Bond lengths [Å] and angles [°] for 2.87. ______O(1)-C(4) 1.208(4) O(2)-C(2) 1.408(4) O(3)-C(1) 1.231(4) O(4)-C(9) 1.221(4) N(1)-C(1) 1.339(4) N(1)-C(17) 1.452(4) N(1)-C(2) 1.453(4) C(1)-C(8) 1.533(5) C(2)-C(3) 1.525(4) C(3)-C(4) 1.522(4) C(3)-C(8) 1.547(4) C(4)-C(5) 1.499(4) C(5)-C(6) 1.525(4) C(6)-C(7) 1.544(4) C(7)-C(15) 1.516(4) C(7)-C(16) 1.535(4) C(7)-C(8) 1.555(4) C(8)-C(9) 1.550(4) C(9)-C(10) 1.458(4) C(10)-C(15) 1.387(4) C(10)-C(11) 1.390(4) C(11)-C(12) 1.377(5) C(12)-C(13) 1.391(5) C(13)-C(14) 1.372(4) C(14)-C(15) 1.389(4)

C(1)-N(1)-C(17) 122.2(3) C(1)-N(1)-C(2) 115.0(3) C(17)-N(1)-C(2) 122.0(3) O(3)-C(1)-N(1) 125.1(3) O(3)-C(1)-C(8) 126.2(3) N(1)-C(1)-C(8) 108.5(3) O(2)-C(2)-N(1) 111.6(3) O(2)-C(2)-C(3) 114.0(3)

420

N(1)-C(2)-C(3) 102.9(2) C(4)-C(3)-C(2) 112.8(3) C(4)-C(3)-C(8) 114.4(2) C(2)-C(3)-C(8) 105.4(2) O(1)-C(4)-C(5) 122.2(3) O(1)-C(4)-C(3) 121.3(3) C(5)-C(4)-C(3) 116.5(3) C(4)-C(5)-C(6) 113.5(3) C(5)-C(6)-C(7) 112.3(3) C(15)-C(7)-C(16) 111.0(3) C(15)-C(7)-C(6) 108.0(3) C(16)-C(7)-C(6) 110.8(3) C(15)-C(7)-C(8) 103.3(2) C(16)-C(7)-C(8) 115.5(3) C(6)-C(7)-C(8) 107.7(3) C(1)-C(8)-C(3) 102.6(2) C(1)-C(8)-C(9) 103.4(2) C(3)-C(8)-C(9) 111.0(3) C(1)-C(8)-C(7) 117.2(3) C(3)-C(8)-C(7) 117.2(3) C(9)-C(8)-C(7) 104.8(2) O(4)-C(9)-C(10) 128.2(3) O(4)-C(9)-C(8) 123.8(3) C(10)-C(9)-C(8) 108.0(3) C(15)-C(10)-C(11) 121.9(3) C(15)-C(10)-C(9) 109.4(3) C(11)-C(10)-C(9) 128.7(3) C(12)-C(11)-C(10) 118.1(3) C(11)-C(12)-C(13) 120.4(3) C(14)-C(13)-C(12) 121.4(3) C(13)-C(14)-C(15) 119.0(3) C(10)-C(15)-C(14) 119.3(3) C(10)-C(15)-C(7) 112.8(3) C(14)-C(15)-C(7) 127.8(3) ______

421

Anisotropic displacement parameters (Å2x 103) for 2.87. The anisotropic displacement factor exponent takes the form: -22[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______O(1) 51(2) 33(1) 24(1) -2(1) -6(1) 12(1) O(2) 32(1) 12(1) 36(1) -1(1) -3(1) -3(1) O(3) 16(1) 21(1) 27(1) -1(1) -2(1) 0(1) O(4) 30(1) 20(1) 31(1) 1(1) 2(1) 1(1) N(1) 18(2) 18(1) 22(2) -5(1) -1(1) 3(1) C(1) 19(2) 15(2) 21(2) 5(1) 3(1) 0(1) C(2) 17(2) 20(2) 29(2) -3(1) -1(2) -2(1) C(3) 17(2) 15(2) 24(2) -1(1) -2(1) -1(1) C(4) 18(2) 18(2) 24(2) 1(1) 2(2) -3(1) C(5) 18(2) 14(2) 31(2) 1(1) -2(2) 2(1) C(6) 18(2) 18(2) 23(2) -2(1) 0(1) 1(1) C(7) 19(2) 18(2) 21(2) -4(1) 0(2) 0(2) C(8) 19(2) 16(2) 19(2) 0(1) -1(2) -1(1) C(9) 14(2) 21(2) 29(2) 3(2) 3(2) -1(1) C(10) 13(2) 28(2) 24(2) 2(2) 1(2) 2(2) C(11) 24(2) 35(2) 24(2) 5(2) 1(2) 1(2) C(12) 26(2) 36(2) 21(2) 1(2) 0(2) 2(2) C(13) 23(2) 36(2) 23(2) -11(2) 2(2) -1(2) C(14) 22(2) 24(2) 28(2) -5(1) -1(2) -2(2) C(15) 15(2) 26(2) 23(2) 0(2) 0(2) -2(2) C(16) 19(2) 18(2) 28(2) -2(1) -2(1) -1(1) C(17) 23(2) 25(2) 36(2) -9(2) -1(2) 10(2) ______

422

Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for 2.87. ______x y z U(eq) ______

H(2) -908 23 978 40 H(2B) -556 1843 157 26 H(3A) -2669 2632 958 22 H(5A) -4097 6465 635 25 H(5B) -1787 7092 541 25 H(6A) -3281 5492 1417 23 H(6B) -2393 7372 1378 23 H(11A) -140 2188 2711 33 H(12A) 91 4384 3286 33 H(13A) 275 7175 3020 33 H(14A) 254 7835 2185 30 H(16A) 1354 7889 1311 33 H(16B) 1573 6743 826 33 H(16C) 2965 6359 1302 33 H(17C) 4578 1841 293 42 H(17D) 2946 445 120 42 H(17A) 4060 276 645 42 ______

423

Torsion angles [°] for 2.87. ______C(17)-N(1)-C(1)-O(3) 4.1(5) C(2)-N(1)-C(1)-O(3) 174.3(3) C(17)-N(1)-C(1)-C(8) -171.4(3) C(2)-N(1)-C(1)-C(8) -1.2(4) C(1)-N(1)-C(2)-O(2) -107.1(3) C(17)-N(1)-C(2)-O(2) 63.1(4) C(1)-N(1)-C(2)-C(3) 15.5(4) C(17)-N(1)-C(2)-C(3) -174.3(3) O(2)-C(2)-C(3)-C(4) -136.3(3) N(1)-C(2)-C(3)-C(4) 102.7(3) O(2)-C(2)-C(3)-C(8) 98.2(3) N(1)-C(2)-C(3)-C(8) -22.8(3) C(2)-C(3)-C(4)-O(1) 21.2(4) C(8)-C(3)-C(4)-O(1) 141.6(3) C(2)-C(3)-C(4)-C(5) -161.7(3) C(8)-C(3)-C(4)-C(5) -41.3(4) O(1)-C(4)-C(5)-C(6) 179.9(3) C(3)-C(4)-C(5)-C(6) 2.8(4) C(4)-C(5)-C(6)-C(7) 50.4(4) C(5)-C(6)-C(7)-C(15) -172.7(2) C(5)-C(6)-C(7)-C(16) 65.5(3) C(5)-C(6)-C(7)-C(8) -61.7(3) O(3)-C(1)-C(8)-C(3) 171.2(3) N(1)-C(1)-C(8)-C(3) -13.4(3) O(3)-C(1)-C(8)-C(9) -73.4(4) N(1)-C(1)-C(8)-C(9) 102.1(3) O(3)-C(1)-C(8)-C(7) 41.3(4) N(1)-C(1)-C(8)-C(7) -143.3(3) C(4)-C(3)-C(8)-C(1) -102.3(3) C(2)-C(3)-C(8)-C(1) 22.1(3) C(4)-C(3)-C(8)-C(9) 147.8(3) C(2)-C(3)-C(8)-C(9) -87.7(3) C(4)-C(3)-C(8)-C(7) 27.5(4) C(2)-C(3)-C(8)-C(7) 152.0(3)

424

C(15)-C(7)-C(8)-C(1) -101.5(3) C(16)-C(7)-C(8)-C(1) 19.9(4) C(6)-C(7)-C(8)-C(1) 144.3(3) C(15)-C(7)-C(8)-C(3) 135.9(3) C(16)-C(7)-C(8)-C(3) -102.7(3) C(6)-C(7)-C(8)-C(3) 21.7(3) C(15)-C(7)-C(8)-C(9) 12.4(3) C(16)-C(7)-C(8)-C(9) 133.8(3) C(6)-C(7)-C(8)-C(9) -101.8(3) C(1)-C(8)-C(9)-O(4) -67.9(4) C(3)-C(8)-C(9)-O(4) 41.4(4) C(7)-C(8)-C(9)-O(4) 168.8(3) C(1)-C(8)-C(9)-C(10) 111.4(3) C(3)-C(8)-C(9)-C(10) -139.3(3) C(7)-C(8)-C(9)-C(10) -11.9(3) O(4)-C(9)-C(10)-C(15) -174.4(3) C(8)-C(9)-C(10)-C(15) 6.4(4) O(4)-C(9)-C(10)-C(11) 5.0(6) C(8)-C(9)-C(10)-C(11) -174.2(3) C(15)-C(10)-C(11)-C(12) 0.0(5) C(9)-C(10)-C(11)-C(12) -179.3(3) C(10)-C(11)-C(12)-C(13) 0.4(5) C(11)-C(12)-C(13)-C(14) -0.2(5) C(12)-C(13)-C(14)-C(15) -0.3(5) C(11)-C(10)-C(15)-C(14) -0.6(5) C(9)-C(10)-C(15)-C(14) 178.9(3) C(11)-C(10)-C(15)-C(7) -177.3(3) C(9)-C(10)-C(15)-C(7) 2.1(4) C(13)-C(14)-C(15)-C(10) 0.7(5) C(13)-C(14)-C(15)-C(7) 176.9(3) C(16)-C(7)-C(15)-C(10) -133.8(3) C(6)-C(7)-C(15)-C(10) 104.4(3) C(8)-C(7)-C(15)-C(10) -9.5(4) C(16)-C(7)-C(15)-C(14) 49.7(5) C(6)-C(7)-C(15)-C(14) -72.0(4) C(8)-C(7)-C(15)-C(14) 174.1(3)

425

______

426

Hydrogen bonds for 2.87 [Å and °]. ______D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ______O(2)-H(2)...O(4) 0.84 2.09 2.860(3) 151.9 C(3)-H(3A)...O(3)#1 1.00 2.41 3.233(4) 139.6 C(5)-H(5B)...O(2)#2 0.99 2.46 3.274(4) 139.4 C(17)-H(17D)...O(2)#3 0.98 2.54 3.467(4) 158.0 ______Symmetry transformations used to generate equivalent atoms: #1 x-1,y,z #2 x,y+1,z #3 -x,-y,-z

427

Crystal data and structure refinement for 3.161. Identification code cdv32 (Greg Schwarzwalder)

Empirical formula C25 H27 N O6 Formula weight 437.47 Temperature 133(2) K Wavelength 0.71073 Å Crystal system Orthorhombic

Space group Pca21 Unit cell dimensions a = 14.9079(12) Å = 90°. b = 13.4611(11) Å = 90°. c = 11.006(9) Å  = 90°. Volume 2208.6(18) Å3 Z 4 Density (calculated) 1.316 Mg/m3 Absorption coefficient 0.094 mm-1 F(000) 928 Crystal color yellow Crystal size 0.412 x 0.194 x 0.144 mm3 Theta range for data collection 1.513 to 27.088° Index ranges 0 ≤ h ≤ 19, 0 ≤ k ≤ 17, 0 ≤ l ≤ 14 Reflections collected 2571 Independent reflections 2571 Completeness to theta = 25.500° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.8621 and 0.7865 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2571 / 1 / 398 Goodness-of-fit on F2 1.043 Final R indices [I>2sigma(I) = 2222 data] R1 = 0.0366, wR2 = 0.0721 R indices (all data, 0.78Å) R1 = 0.0507, wR2 = 0.0781 Largest diff. peak and hole 0.218 and -0.181 e.Å-3

428

Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for 3.161. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______x y z U(eq) ______O(1) 8905(1) -1035(1) 4680(2) 22(1) O(2) 8027(1) -2384(2) 3045(2) 34(1) O(3) 7908(1) 651(1) 1504(2) 20(1) O(4) 10293(1) 1103(1) 1917(2) 20(1) O(5) 7258(1) 5327(1) 874(2) 27(1) O(6) 10091(1) 3707(2) -1701(2) 28(1) N(1) 8040(1) -129(2) 3341(2) 17(1) C(1) 8245(1) 567(2) 2514(2) 16(1) C(2) 8553(2) -74(2) 4455(2) 18(1) C(3) 9296(1) 696(2) 4160(2) 16(1) C(4) 9584(2) 1309(2) 5236(2) 19(1) C(5) 8993(2) 2183(2) 5531(2) 22(1) C(6) 8888(2) 2840(2) 4406(2) 20(1) C(7) 8409(2) 2294(2) 3356(2) 17(1) C(8) 8917(1) 1291(2) 3088(2) 15(1) C(9) 9606(1) 1569(2) 2118(2) 16(1) C(10) 9282(1) 2468(2) 1514(2) 17(1) C(11) 9574(2) 2884(2) 442(2) 18(1) C(12) 9136(2) 3731(2) -6(2) 19(1) C(13) 9401(2) 4178(2) -1130(3) 22(1) C(14) 8956(2) 4996(2) -1550(3) 26(1) C(15) 8225(2) 5403(2) -894(3) 26(1) C(16) 7954(2) 4985(2) 174(2) 22(1) C(17) 8394(2) 4132(2) 652(2) 17(1) C(18) 8113(2) 3684(2) 1756(2) 17(1) C(19) 8554(1) 2863(2) 2178(2) 16(1) C(20) 7410(2) 2168(2) 3655(3) 19(1) C(21) 7252(2) -776(2) 3207(3) 22(1) C(22) 7442(2) -1698(2) 2467(3) 25(1) C(23) 10330(2) 1106(2) 5843(3) 28(1) C(24) 6820(2) 6210(3) 472(3) 39(1)

429

C(25) 10463(2) 4188(3) -2742(3) 36(1) ______

430

Bond lengths [Å] and angles [°] for 3.161. ______O(1)-C(2) 1.419(3) O(2)-C(22) 1.420(3) O(3)-C(1) 1.225(3) O(4)-C(9) 1.222(3) O(5)-C(16) 1.371(3) O(5)-C(24) 1.428(3) O(6)-C(13) 1.362(3) O(6)-C(25) 1.428(3) N(1)-C(1) 1.342(3) N(1)-C(2) 1.447(3) N(1)-C(21) 1.469(3) C(1)-C(8) 1.534(3) C(2)-C(3) 1.550(3) C(3)-C(4) 1.506(4) C(3)-C(8) 1.533(3) C(4)-C(23) 1.326(4) C(4)-C(5) 1.506(4) C(5)-C(6) 1.529(4) C(6)-C(7) 1.545(4) C(7)-C(19) 1.521(4) C(7)-C(20) 1.534(3) C(7)-C(8) 1.577(3) C(8)-C(9) 1.528(3) C(9)-C(10) 1.463(3) C(10)-C(11) 1.377(4) C(10)-C(19) 1.413(3) C(11)-C(12) 1.404(4) C(12)-C(17) 1.428(3) C(12)-C(13) 1.432(4) C(13)-C(14) 1.366(4) C(14)-C(15) 1.416(4) C(15)-C(16) 1.364(4) C(16)-C(17) 1.425(4) C(17)-C(18) 1.420(4)

431

C(18)-C(19) 1.367(3) C(21)-C(22) 1.510(4)

C(16)-O(5)-C(24) 116.8(2) C(13)-O(6)-C(25) 116.9(2) C(1)-N(1)-C(2) 114.7(2) C(1)-N(1)-C(21) 121.8(2) C(2)-N(1)-C(21) 122.6(2) O(3)-C(1)-N(1) 125.9(2) O(3)-C(1)-C(8) 125.7(2) N(1)-C(1)-C(8) 108.2(2) O(1)-C(2)-N(1) 107.2(2) O(1)-C(2)-C(3) 112.50(18) N(1)-C(2)-C(3) 103.6(2) C(4)-C(3)-C(8) 115.1(2) C(4)-C(3)-C(2) 113.9(2) C(8)-C(3)-C(2) 104.28(18) C(23)-C(4)-C(5) 122.9(3) C(23)-C(4)-C(3) 121.5(3) C(5)-C(4)-C(3) 115.5(2) C(4)-C(5)-C(6) 109.7(2) C(5)-C(6)-C(7) 112.2(2) C(19)-C(7)-C(20) 112.12(19) C(19)-C(7)-C(6) 109.4(2) C(20)-C(7)-C(6) 109.9(2) C(19)-C(7)-C(8) 101.76(19) C(20)-C(7)-C(8) 114.3(2) C(6)-C(7)-C(8) 108.96(19) C(9)-C(8)-C(3) 114.68(18) C(9)-C(8)-C(1) 107.9(2) C(3)-C(8)-C(1) 103.06(19) C(9)-C(8)-C(7) 104.09(19) C(3)-C(8)-C(7) 118.8(2) C(1)-C(8)-C(7) 107.92(18) O(4)-C(9)-C(10) 128.3(2) O(4)-C(9)-C(8) 124.4(2)

432

C(10)-C(9)-C(8) 107.38(19) C(11)-C(10)-C(19) 122.3(2) C(11)-C(10)-C(9) 128.4(2) C(19)-C(10)-C(9) 109.3(2) C(10)-C(11)-C(12) 118.9(2) C(11)-C(12)-C(17) 119.3(2) C(11)-C(12)-C(13) 121.1(2) C(17)-C(12)-C(13) 119.6(2) O(6)-C(13)-C(14) 125.9(3) O(6)-C(13)-C(12) 114.3(2) C(14)-C(13)-C(12) 119.8(2) C(13)-C(14)-C(15) 120.8(3) C(16)-C(15)-C(14) 120.5(3) C(15)-C(16)-O(5) 124.8(2) C(15)-C(16)-C(17) 120.9(2) O(5)-C(16)-C(17) 114.3(2) C(18)-C(17)-C(16) 121.5(2) C(18)-C(17)-C(12) 120.2(2) C(16)-C(17)-C(12) 118.3(2) C(19)-C(18)-C(17) 119.4(2) C(18)-C(19)-C(10) 119.9(2) C(18)-C(19)-C(7) 128.9(2) C(10)-C(19)-C(7) 111.1(2) N(1)-C(21)-C(22) 113.1(2) O(2)-C(22)-C(21) 114.1(2) ______

433

Anisotropic displacement parameters (Å2x 103) for 3.161. The anisotropic displacement factor exponent takes the form: -22[ h2 a*2U11 + ... + 2 h k a* b* U12 ] ______U11 U22 U33 U23 U13 U12 ______O(1) 28(1) 18(1) 19(1) 4(1) -5(1) 2(1) O(2) 38(1) 24(1) 41(1) 1(1) -12(1) 0(1) O(3) 21(1) 23(1) 17(1) 1(1) -4(1) 2(1) O(4) 16(1) 26(1) 19(1) 2(1) 2(1) 5(1) O(5) 32(1) 24(1) 26(1) 8(1) 1(1) 11(1) O(6) 28(1) 32(1) 24(1) 10(1) 10(1) -2(1) N(1) 16(1) 18(1) 16(1) 3(1) -3(1) -1(1) C(1) 14(1) 20(1) 16(1) 0(1) 1(1) 4(1) C(2) 19(1) 19(1) 15(1) -1(1) -1(1) 1(1) C(3) 14(1) 20(1) 14(1) 2(1) -1(1) 0(1) C(4) 22(1) 24(1) 13(1) 3(1) -1(1) -4(1) C(5) 29(1) 24(1) 14(1) -4(1) -2(1) -1(1) C(6) 25(1) 20(1) 17(1) -2(1) 1(1) 2(1) C(7) 18(1) 17(1) 17(1) 3(1) 1(1) 4(1) C(8) 16(1) 16(1) 13(1) 1(1) 1(1) 1(1) C(9) 16(1) 20(1) 12(1) -2(1) -1(1) -2(1) C(10) 16(1) 18(1) 16(1) 0(1) -2(1) -1(1) C(11) 15(1) 23(1) 17(1) 2(1) -1(1) -5(1) C(12) 18(1) 21(1) 17(1) 1(1) -3(1) -7(1) C(13) 23(1) 25(1) 20(1) 4(1) -1(1) -6(1) C(14) 32(1) 27(2) 20(1) 9(1) -2(1) -8(1) C(15) 32(1) 19(1) 26(2) 4(1) -6(1) 0(1) C(16) 23(1) 19(1) 23(1) 2(1) -4(1) -2(1) C(17) 18(1) 17(1) 17(1) 1(1) -4(1) -4(1) C(18) 17(1) 19(1) 16(1) -1(1) -1(1) -2(1) C(19) 16(1) 18(1) 15(1) 0(1) -1(1) -2(1) C(20) 18(1) 23(1) 18(1) 1(1) 4(1) 6(1) C(21) 17(1) 26(1) 24(1) 2(1) 0(1) -5(1) C(22) 25(1) 23(1) 27(2) 3(1) -6(1) -4(1) C(23) 29(1) 31(2) 25(2) 3(1) -9(1) -3(1) C(24) 48(2) 35(2) 33(2) 10(2) 3(2) 18(2)

434

C(25) 37(2) 40(2) 30(2) 12(2) 10(2) -5(2) ______

435

Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for 3.161. ______x y z U(eq) ______

H(1) 9120(20) -1060(30) 5410(40) 56(12) H(2) 8410(20) -2020(30) 3450(40) 60(12) H(2A) 8189(17) 140(20) 5180(30) 24(7) H(3A) 9811(14) 279(17) 3880(20) 11(6) H(5A) 8385(18) 1960(20) 5770(30) 20(7) H(5B) 9255(18) 2580(20) 6220(30) 30(8) H(6A) 9504(18) 3040(20) 4090(30) 25(7) H(6B) 8542(17) 3440(20) 4580(30) 21(7) H(11A) 10076(17) 2590(20) 40(30) 18(7) H(14A) 9102(16) 5284(19) -2300(30) 14(7) H(15A) 7940(20) 5990(20) -1170(30) 41(9) H(18A) 7600(20) 3940(20) 2160(30) 32(8) H(20A) 7109(14) 1879(18) 2980(20) 8(6) H(20B) 7139(14) 2823(18) 3740(20) 9(6) H(20C) 7336(17) 1730(20) 4380(30) 25(7) H(21A) 7069(16) -960(20) 4030(30) 19(7) H(21B) 6766(17) -350(20) 2840(30) 20(7) H(22A) 7670(17) -1475(19) 1680(30) 19(7) H(22B) 6855(16) -2072(19) 2330(20) 16(7) H(23A) 10513(19) 1520(20) 6550(30) 32(8) H(23B) 10687(18) 540(20) 5600(30) 27(8) H(24A) 6340(20) 6350(30) 1110(40) 54(11) H(24B) 7280(20) 6780(30) 360(40) 53(11) H(24C) 6590(20) 6050(30) -340(30) 39(9) H(25A) 10980(20) 3780(20) -2930(30) 33(8) H(25B) 10629(18) 4870(30) -2490(30) 38(9) H(25C) 10010(20) 4220(20) -3360(30) 43(10) ______

436

Torsion angles [°] for 3.161. ______C(2)-N(1)-C(1)-O(3) 178.7(2) C(21)-N(1)-C(1)-O(3) -11.5(4) C(2)-N(1)-C(1)-C(8) -6.0(3) C(21)-N(1)-C(1)-C(8) 163.9(2) C(1)-N(1)-C(2)-O(1) -129.2(2) C(21)-N(1)-C(2)-O(1) 61.1(3) C(1)-N(1)-C(2)-C(3) -10.0(3) C(21)-N(1)-C(2)-C(3) -179.7(2) O(1)-C(2)-C(3)-C(4) -97.0(2) N(1)-C(2)-C(3)-C(4) 147.6(2) O(1)-C(2)-C(3)-C(8) 136.8(2) N(1)-C(2)-C(3)-C(8) 21.3(2) C(8)-C(3)-C(4)-C(23) -139.0(2) C(2)-C(3)-C(4)-C(23) 100.6(3) C(8)-C(3)-C(4)-C(5) 38.4(3) C(2)-C(3)-C(4)-C(5) -81.9(3) C(23)-C(4)-C(5)-C(6) 122.9(3) C(3)-C(4)-C(5)-C(6) -54.5(3) C(4)-C(5)-C(6)-C(7) 63.5(3) C(5)-C(6)-C(7)-C(19) -164.4(2) C(5)-C(6)-C(7)-C(20) 72.1(3) C(5)-C(6)-C(7)-C(8) -53.9(3) C(4)-C(3)-C(8)-C(9) 93.2(2) C(2)-C(3)-C(8)-C(9) -141.3(2) C(4)-C(3)-C(8)-C(1) -149.83(19) C(2)-C(3)-C(8)-C(1) -24.4(2) C(4)-C(3)-C(8)-C(7) -30.7(3) C(2)-C(3)-C(8)-C(7) 94.8(2) O(3)-C(1)-C(8)-C(9) -43.6(3) N(1)-C(1)-C(8)-C(9) 141.0(2) O(3)-C(1)-C(8)-C(3) -165.3(2) N(1)-C(1)-C(8)-C(3) 19.3(2) O(3)-C(1)-C(8)-C(7) 68.3(3) N(1)-C(1)-C(8)-C(7) -107.1(2)

437

C(19)-C(7)-C(8)-C(9) 24.5(2) C(20)-C(7)-C(8)-C(9) 145.6(2) C(6)-C(7)-C(8)-C(9) -91.0(2) C(19)-C(7)-C(8)-C(3) 153.46(19) C(20)-C(7)-C(8)-C(3) -85.5(3) C(6)-C(7)-C(8)-C(3) 38.0(3) C(19)-C(7)-C(8)-C(1) -89.9(2) C(20)-C(7)-C(8)-C(1) 31.2(3) C(6)-C(7)-C(8)-C(1) 154.6(2) C(3)-C(8)-C(9)-O(4) 26.1(3) C(1)-C(8)-C(9)-O(4) -88.0(3) C(7)-C(8)-C(9)-O(4) 157.5(2) C(3)-C(8)-C(9)-C(10) -153.9(2) C(1)-C(8)-C(9)-C(10) 92.0(2) C(7)-C(8)-C(9)-C(10) -22.5(2) O(4)-C(9)-C(10)-C(11) 14.0(4) C(8)-C(9)-C(10)-C(11) -166.0(2) O(4)-C(9)-C(10)-C(19) -168.9(2) C(8)-C(9)-C(10)-C(19) 11.1(3) C(19)-C(10)-C(11)-C(12) 0.2(4) C(9)-C(10)-C(11)-C(12) 177.0(2) C(10)-C(11)-C(12)-C(17) -0.8(3) C(10)-C(11)-C(12)-C(13) -178.6(2) C(25)-O(6)-C(13)-C(14) 9.3(4) C(25)-O(6)-C(13)-C(12) -172.0(2) C(11)-C(12)-C(13)-O(6) 0.5(3) C(17)-C(12)-C(13)-O(6) -177.3(2) C(11)-C(12)-C(13)-C(14) 179.3(2) C(17)-C(12)-C(13)-C(14) 1.5(4) O(6)-C(13)-C(14)-C(15) 177.8(2) C(12)-C(13)-C(14)-C(15) -0.8(4) C(13)-C(14)-C(15)-C(16) 0.1(4) C(14)-C(15)-C(16)-O(5) 179.7(2) C(14)-C(15)-C(16)-C(17) -0.2(4) C(24)-O(5)-C(16)-C(15) -2.9(4) C(24)-O(5)-C(16)-C(17) 177.0(3)

438

C(15)-C(16)-C(17)-C(18) -179.3(2) O(5)-C(16)-C(17)-C(18) 0.8(3) C(15)-C(16)-C(17)-C(12) 0.8(4) O(5)-C(16)-C(17)-C(12) -179.1(2) C(11)-C(12)-C(17)-C(18) 0.9(3) C(13)-C(12)-C(17)-C(18) 178.7(2) C(11)-C(12)-C(17)-C(16) -179.3(2) C(13)-C(12)-C(17)-C(16) -1.5(3) C(16)-C(17)-C(18)-C(19) 179.8(2) C(12)-C(17)-C(18)-C(19) -0.4(3) C(17)-C(18)-C(19)-C(10) -0.2(3) C(17)-C(18)-C(19)-C(7) 176.4(2) C(11)-C(10)-C(19)-C(18) 0.3(4) C(9)-C(10)-C(19)-C(18) -177.1(2) C(11)-C(10)-C(19)-C(7) -176.9(2) C(9)-C(10)-C(19)-C(7) 5.8(3) C(20)-C(7)-C(19)-C(18) 41.3(4) C(6)-C(7)-C(19)-C(18) -80.9(3) C(8)-C(7)-C(19)-C(18) 163.9(2) C(20)-C(7)-C(19)-C(10) -141.8(2) C(6)-C(7)-C(19)-C(10) 95.9(2) C(8)-C(7)-C(19)-C(10) -19.3(2) C(1)-N(1)-C(21)-C(22) 86.9(3) C(2)-N(1)-C(21)-C(22) -104.1(3) N(1)-C(21)-C(22)-O(2) 68.4(3) ______

439

Hydrogen bonds for 3.161 [Å and °]. ______D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ______O(1)-H(1)...O(4)#1 0.86(4) 1.88(4) 2.738(3) 174(4) O(2)-H(2)...O(1) 0.87(4) 2.04(4) 2.871(3) 161(3) O(2)-H(2)...N(1) 0.87(4) 2.61(4) 3.052(3) 113(3) C(2)-H(2A)...O(3)#2 1.01(3) 2.30(3) 3.284(3) 166(2) C(21)-H(21B)...O(4)#3 1.01(3) 2.62(3) 3.277(3) 122.5(19) C(25)-H(25A)...O(2)#4 0.97(3) 2.62(3) 3.423(4) 140(3) ______Symmetry transformations used to generate equivalent atoms: #1 -x+2,-y,z+1/2 #2 -x+3/2,y,z+1/2 #3 x-1/2,-y,z #4 -x+2,-y,z-1/2

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