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Synthesis of Inhibitors of Steroid Sulfatase and Towards the Synthesis of a Chiral Electrophilic Fluorinating Reagent Synthesis of Inhibitors of Steroid Sulfatase and Towards the Synthesis of a Chiral Electrophilic Fluorinating Reagent By Yong Liu A thesis presented to the University of Waterloo in fulfillment of the thesis requirement for the degree of Doctor of Philosophy in Chemistry Waterloo, Ontario, Canada, 2006 ©Yong Liu 2006 AUTHOR'S DECLARATION FOR ELECTRONIC SUBMISSION OF A THESIS I hereby declare that I am the sole author of this thesis. This is a true copy of the thesis, including any required final revisions, as accepted by my examiners. I understand that my thesis may be made electronically available to the public. ii Abstract Steroid sulfatase (STS) catalyzes the desulfation of sulfated steroids such as estrone sulfate to the corresponding steroid such as estrone. Inhibitors of STS are believed to have potential for treating estrogen-dependent breast cancer. A new class of potential irreversible suicide inhibitors of STS, based on aryl sulfates bearing a monofluoromethyl or difluoromethyl group ortho to the sulfate group, was synthesized. Key to the success of these syntheses was the use of new sulfation methodology recently developed in the Taylor group. A new and efficient route to 4-formyl estrone, a time-dependent, irreversible STS inhibitor, is also reported. Several new classes of potential, reversible STS inhibitors were synthesized. These compounds are analogs of known STS substrates in which the sulfate group is replaced with an α,α -difluoromethylenesulfonamide group, a boronic acid group or a sulfinic acid group. We also report the synthesis of estrone sulfate analogs that bear a carboxylate moiety at the 17-position and a sulfate surrogate at the 3-position. It is anticipated that these compounds will inhibit STS by interacting with Arg98 which lies at the periphery of the active site. Key to the success of this synthesis was the use of the t-butyl group as a protecting group for the 2-position of estrone. Finally, our preliminary investigations into the synthesis of a new class of chiral electrophilic fluorinating agents are presented. These reagents are based on a chiral binaphthyl sulfonimide scaffold and are expected to be capable of performing enantioselective electrophilic fluorinations. Such reagents may be useful in synthesizing organofluorines of biological significance including STS inhibitors. iii Acknowledgements I would like to thank my supervisor, Professor Scott D. Taylor. It has been such a pleasure to work with him and I have learned so much from him during my entire research project in the past four and half years. I really appreciate him for spending so much time helping me out with research problems. I also thank my advisory committee, Professor Michael J. Chong, Professor Gary Dimitrienko and Professor William Tam for their valuable guidance and generous help during the past few years. I have benefited a lot by taking Professor Tam’s, Professor Chong’s and Professor Fillion’s courses. I would like to thank all former and present members of the Taylor group, which include Farzad, Bryan, Chenguo, Wallach, Mehdi, Vanessa, Laura, Zena, Munawar and Ahmed M. and Ahmed D. They have been so helpful to me. I acknowledge Richard for mass spectra and Jan for NMR help. I also acknowledge all of the people on the third floor of C2 and ESC. I am very lucky to meet so many friendly people here. Finally, I want to express my special acknowledgement to my wife Fang, who has been supporting me with love, encouragement and dedication. iv To my wife Fang and my parents who have given me so much… v Table of Contents Title i Declaration ii Abstract iii Acknowledgements iv Table of Contents vi List of Tables ix List of Figures x List of Abbreviations xi Chapter 1. Inhibitors of Steroid Sulfatase 1 1.1. Introduction: Steroid Sulfatase and Breast Cancer 1 1.2. Steroid Sulfatase – Structure and Mechanism 2 1.3. Inhibitors of STS 5 1.4. Objective and Overview 8 1.5. References 10 Chapter 2. Irreversible Inhibitors of STS: Synthesis of Estrogens Modified at the 2- and 4-Positions 12 2.1. Introduction 12 2.2. Results and Discussion 16 2.2.1. Synthesis of 2-Formyl Estrone 16 2.2.2. Synthesis of Compounds 2.4-2.11 24 2.2.3. New Approaches to the Synthesis of 2.13 32 2.2.4. Synthesis of Other A-Ring Modified E1 and E2 Derivatives 51 2.3. Summary and Future work 56 2.4. Experimental 58 vi 2.4.1. General 58 2.4.2. Syntheses 59 2.5. References 108 Chapter 3. Synthesis of Steroidal and Non-Steroidal Compounds Bearing Sulfate Surrogates 112 3.1. Introduction 112 3.1.1. Reversible Inhibitors of STS Bearing Sulfate Surrogates 112 3.1.2. The α, α-Difluoromethylenesulfonamide Group as a Sulfate Surrogate 113 3.1.3. Boronic Acids as STS Inhibitors 115 3.1.4. Sulfinic Acids as STS Inhibitors 116 3.1.5. Enhancing the Potency of STS inhibitors by Iintroducing Anionic Groups at the 17-Position. 117 3.1.6. Objectives 118 3.2. Results and Discussion 118 3.2.1. Synthesis of α, α-Difluoromethylenesulfonamides 118 3.2.2. Synthesis of Boronic Acids 126 3.2.3. Synthesis of Sulfinic Acids 133 3.2.4. Synthesis of Steroids Modified at the 17-Position with a Carboxylic Acid Group 136 3.2.5. Preliminary Results from Inhibition Studies 140 3.2.6. Future Work 145 3.3. Experimental 148 3.3.1. General 148 3.3.2. Syntheses 149 3.4. References 198 Chapter 4. Towards the Synthesis of a Chiral Electrophilic Fluorinating Agent 202 vii 4.1. Introduction and Background 202 4.1.1. Enantioselective Fluorination 202 4.1.2. Enantioselective Fluorination Using Chiral Electrophilic Fluorinating Agents 203 4.1.3. Enantioselective Fluorination Using Transition-Metal Catalysts 205 4.1.4. Enantioselective Fluorination Using Chiral Organocatalysts 207 4.1.5. Chiral Halogenating Agents Based on Chiral Binaphthyl Scaffolds 208 4.1.6. Objectives 212 4.2. Results and Discussion 212 4.3. Summary and Future Work 220 4.4. Experimental 221 4.4.1. General 221 4.4.2. Syntheses 223 4.5. References 238 viii List of Tables Table 2.1 Synthesis of 2.14 by Direct Formylation of E1 21 Table 2.2 Synthesis of 2.13 by Reduction of the Nitrile Group in Compound 2.52 Using Raney Ni 33 Table 2.3 Formylation of 2.70 under Different Conditions 47 Table 3.1 STS Inhibitors in which the Sulfate Group of Estrone Sulfate is Replaced With an O-, N-, or S-Linked Sulfate Surrogate 112 Table 4.1 Enantioselective EF of β-Keto Esters Using Selectfluor and Catalyst 4.17 205 Table 4.2 An Enantioselective Mannich Reaction Catalyzed by Chiral Brønsted Acids 4.38a-d 211 ix List of Figures Figure 1.1 Structures of Norethindrone, Estrone and Estradiol 1 Figure 1.2 Ribbon Structure of STS (Courtesy of D. Ghosh) 4 Figure 1.3 Active Site of STS (Courtesy of D. Ghosh) 5 Figure 1.4 Structures of Sulfamate Inhibitors 1.1-1.4 6 Figure 1.5 Structures of Reversible Inhibitors 1.5-1.8 7 Figure 2.1 Proposed Suicide Inhibitors of STS 13 Figure 2.2 Structure of 4-Formylestrone 16 Figure 2.3 Structure of 2,4-Diformyl Estrone (2.87) 55 Figure 3.1 Structures of EMATE, Estrone Sulfate (E1S) and Selected Analogs 113 Figure 3.2 A Potential Approach to Rationally Designed STS Inhibitors 117 Figure 3.3 Structures of Target Sulfonamides 118 Figure 3.4 Structures of Target Boronic Acids 127 Figure 3.5 Structures of Target Sulfinic Acids 133 Figure 3.6 Structures of Target Steroids Modified at the 17-Position 137 Figure 3.7 Crystal Structure of Compound 3.53 Bound to STS (Courtesy of D. Ghosh) 142 Figure 4.1 Structures of Chiral Monofluoromethylenephosphonic Acids 4.1 and 4.2 202 Figure 4.2 Chiral N-F Reagents Prepared by Davis et al. and Takeuchi and Coworkers 204 Figure 4.3 Structure of Ligand 4.22 207 Figure 4.4 Structure of Chiral N-F Reagent 4.28 209 Figure 4.5 Structures of Compounds of Type 4.40 and 4.41 212 Figure 4.6 Structures of Compounds 4.42 and 4.43 213 Figure 4.7 Structures of Byproduct 4.54 215 Figure 4.8 Racemic S-Aryl Thiocarbamate 4.60 216 Figure 4.9 Structure of the Proposed Four-Center Transition State/Intermediate for the NKR 221 x List of Abbreviations 2-FE1 2-formylestrone 4-FE1 4-formylestrone Ac acetyl AIBN 2,2′-azo-bis(isobutyronitrile) All allyl aq aqueous Ar aryl Arg arginine Asn asparagine Asp aspartic acid ARS aryl sulfatase ARSA aryl sulfatase A BINOL 2,2′-dihydroxy-1,1′-binaphthalene Bn benzyl br broad Bu butyl CA cinchona alkaloids conc concentrated cacld calculated cat catalyst CHO Chinese Hamster Ovary compd compound COUMATE coumarin sulfamate CTH catalytic transfer hydrogenation d doublet DAST diethylaminosulfur trifluoride xi DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DIBAL diisobutylaluminium hydride DFMS difluoromethylenesulfonamide DMAP 4-(N,N-dimethylamino)pyridine DMB 2,4-dimethoxybenzyl DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide E+ electrophile E1 estrone E1S estrone sulfate E2 estradiol EAS electrophilic aromatic substitution EMATE estrone sulfamate eq or equiv equivalent(s) ether diethyl ether EF electrophilic fluorination ESI electrospray ionization Et ethyl fGly formyl glycine Gln glutamine F-C Friedel-Crafts h hour His histidine HMPA hexamethylphosphoric amide HRMS high resolution mass spectrometry HMT hexamethyltetramine xii HTS high throughput screening Hz Hertz i iso IC50 concentration of an inhibitor that is required for 50% inhibition of catalytic activity IR infrared spectroscopy J spin coupling constant Ki equilibrium dissociation constant of the enzyme-inhibitor complex LRMS low resolution mass spectrometry Lys lysine m multiplet M molar mCPBA meta-chloroperbenzoic acid Me methyl mesylate methanesulfonate min minute mL millilitre Ms methanesulfonyl mmol millimole mol mole MOM methoxymethyl mp melting point MUS 4-methylumbelliferyl-6-O-sulfate m/z mass/charge N normal NaHMDS sodium hexamethyldisilazane NBA N-bromoacetamide xiii NBS N-bromosuccinimide NCS N-chlorosuccinimide NFSi N-fluorobenzenesulfonimide NKR Newman-Kwart rearrangement nM nanomolar NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance Nu nucleophile PCC pyridinium chlorochromate Ph phenyl pM picomolar PMB para-methoxybenzyl Pr propyl PTP1B protein tyrosine phosphatase 1B PTSA para-toluenesulfonic acid q quartet quint quintet R alkyl group rt.
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