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Synthetic Uses of S-Nitrosothiols in Organic Chemistry

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SYNTHETIC USES OF S-NITROSOTHIOLS IN ORGANIC CHEMISTRY By TYLER DAVID BIGGS A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY WASHINGTON STATE UNIVERSITY Department of Chemistry MAY 2017 © Copyright by TYLER DAVID BIGGS, 2017 All Rights Reserved © Copyright by TYLER DAVID BIGGS, 2017 All Rights Reserved To the Faculty of Washington State University: The members of the Committee appointed to examine the dissertation of TYLER DAVID BIGGS find it satisfactory and recommend that it be accepted. Ming Xian, Ph.D., Chair Cliff E. Berkman, Ph.D. Aurora Clark, Ph.D. Jeffery Jones, Ph.D. ii ACKNOWLEDGMENT I would like to thank Dr. Ming Xian for his supervision, help, and guidance over the course of my Ph.D. study. His challenges and questions kept me on track, and forced me to constantly reevaluate myself critically. I would also like to thank Dr. Ronald for helping to kindle my interest and passion in chemistry. I would like to thank my committee members for sharing their time and knowl- edge. I would also like to thank the Washington State University Chemistry depart- ment for the resources and equipment provided, and those in the front office who keep things running. Finally I would like to thank my fellow students who have supported me. Ryan Joseph, for his help and enthusiasm in chemistry and LATEX. Nelmi Devarie, for talks of cooking and science. Laksiri, Hua Wang, and Chung-Min Park for their help in training me in the basics. Most importantly are my family and friends, with out their support I would have never started this journey, or have a place to go up on finishing it, without their help and commitment. iii SYNTHETIC USES OF S-NITROSOTHIOLS IN ORGANIC CHEMISTRY Abstract by Tyler David Biggs, Ph.D. Washington State University May 2017 Chair: Ming Xian S-Nitrosothiols have risen to prominence since their identification as an impor- tant post-translational modification of cysteine residues. The full range of chem- istry and biological implications of this motif are under exploration. Direct chem- ical reactions of S-nitrosothiols should reveal clues into their biological effects, and produce new synthetic tools for the construction of sulfur and nitrogen con- taining compounds. Here several explorations into synthetic applications of S-Nitrosothiols are ex- plored. The relevant background literature is reviewed. Then a phosphine medi- ated reductive ligation of aldehydes and S-Nitrosothiols is discussed. Followed the development of a proline-based phosphine reagent and its reactivity with S-nitrosothiols is explored. iv TABLE OF CONTENTS Page ACKNOWLEDGMENTS . iii ABSTRACT . iv A REVIEW OF S-NITROSOTHIOLS . .1 1.1 Introduction................................1 1.1.1 Historical Context.........................1 1.1.2 Chemical Background......................2 1.1.3 Biological Significance......................3 1.2 Properties of S-Nitrosothiols.......................4 1.2.1 Structure and Electronic Nature of S-Nitrosothiols......5 1.2.2 Isomerization of S-Nitrosothiols.................6 1.3 Spectra...................................7 1.3.1 Infrared and Raman Spectra...................7 1.3.2 UV-Vis Spectra...........................8 1.4 S-Nitrosation................................8 1.4.1 Direct Reaction of Thiols with Nitric Oxide..........8 1.4.2 Nitrosation by Nitrite in Acidic Media............. 10 1.4.3 Nitrosation by Alkyl Nitrites................... 10 1.4.4 Transnitrosation.......................... 11 1.5 Decomposition............................... 12 1.5.1 Homolytic & Heterolytic Cleavage of the S-N Bond...... 13 1.5.2 Rates of Decomposition of S-Nitrosothiols........... 14 v 1.5.3 Metal-based SNO Decomposition................ 15 1.6 Reactions of S-Nitrosothiols....................... 16 1.6.1 Bioorthogonal Reactions of SNO................ 16 1.6.2 Reactions with Phosphines.................... 16 1.6.3 Light Induced Reactions..................... 28 1.6.4 Reactions with Sulfenic Acids.................. 29 1.6.5 Reactions with Carbanions.................... 30 1.6.6 Miscellaneous Reactions..................... 31 CONJUGATION OF S-NITROSOTHIOLS WITH ALDEHYDES . 34 2.1 Introduction................................ 34 2.1.1 Hypothesis............................. 34 2.2 Results and Discussion.......................... 35 2.2.1 Experimental Plan........................ 35 2.2.2 Preparation of Starting Materials................ 36 2.2.3 Condition Screen......................... 37 2.2.4 Intramolecular Substrate Screen................. 38 2.2.5 Intermolecular Substrate Screen................. 38 2.2.6 Application - Synthesis of Benzoisothiazole.......... 41 2.3 Conclusion................................. 43 2.A Appendix.................................. 43 2.A.1 Methods.............................. 43 PROLINE BASED PHOSPHORAMIDITE REDUCTIVE LIGATION REAGENTS 49 3.1 Introduction................................ 49 3.1.1 Rationale for S-N bond Formation Methodology Development 50 3.2 Results and Discussion.......................... 52 3.2.1 Experimental Plan........................ 52 3.2.2 Reaction Screening........................ 53 3.2.3 Removal of the Phosphine Oxide Moiety............ 55 vi 3.2.4 Use as a Nitroxyl trap....................... 55 3.3 Conclusion................................. 58 3.A Appendix.................................. 58 3.A.1 Methods.............................. 58 3.A.2 Preparation of S-Nitrosothiols.................. 60 3.A.3 General Reductive Ligation Procedure............. 60 3.A.4 Deprotection of the Diphenylphosphoryl Group....... 64 BIBLIOGRAPHY . 78 vii LIST OF TABLES Page 1.1 Bond lengths and angles of selected S-nitrosothiols..........5 1.2 Characteristic IR bands of SNO.....................7 1.3 Characteristic UV/Vis bands S-nitrosothiols...............8 1.4 Rates of nitrosation of the thiolate anion................ 11 1.5 Rates of transnitrosation by SNAP.................... 12 1.6 Half-life values of selected SNO compounds............... 15 1.7 Thioether formation from SNO..................... 31 1.8 Generation of polysulfides from copper (II) halides.......... 32 2.1 Solvent screen for the intramolecular phosphine mediated conjugation. 38 2.2 Substrate screen of the intramolecular conjugation.......... 39 2.3 Aldehyde substrates amenable to the conjugation............ 41 3.1 Substrate screen of the proline-based phosphoramidate coupling.. 56 viii LIST OF FIGURES Page 1.1 Seminal nitrosation of phenyl mercaptan................2 1.2 Resonance description of S-Nitrosothiols................5 1.3 The cis-trans isomerization of t-butyl-S-nitrosothiol..........7 1.4 Mechanism of the Staudinger Reaction.................. 18 1.5 Radical TrSNO addition to olefins.................... 29 2.1 General form of the aldehyde & SNO coupling............. 34 2.2 Benzoisothiazole containing pharmaceuticals.............. 42 3.1 General form of the proline based phosphoramidite coupling..... 49 3.2 S-N linkages in pharmaceuticals..................... 50 ix LIST OF SCHEMES Page 1.1 Glutathione and cysteine SNO......................4 1.2 Synthesis of a stable S-nitrosothiol iridium complex..........6 1.3 Formation of a thio-azaylide........................ 17 1.4 Trapping of a nitrene derived from TrSNO................ 17 1.5 Proposed nitrene mechanism pathway A................. 18 1.6 Proposed 3-membered ring mechanism pathways B1 & B2...... 19 1.7 Fast reductive ligation........................... 19 1.8 Mechanism of the reductive ligation................... 20 1.9 Traceless ligations using phosphine esters/thioesters.......... 20 1.10 Mechanism of the traceless ligation.................... 21 1.11 Formation of thioimidates from phosphine thioesters......... 22 1.12 One-step reductive disulfide formation................. 22 1.13 One-step disulfide formation from SNO................ 23 1.14 SNO labeling with the traceless ligation reagent............ 24 1.15 One-pot thioether formation....................... 24 1.16 Mechanism of the one-pot thioether formation............ 25 1.17 Bis-ligation of primary SNO....................... 26 1.18 Dehydroalanine formation........................ 26 1.19 Determination of the intra-molecular elimination........... 27 1.20 A water soluble phosphine........................ 27 1.21 One-pot formation of benzoisothiazoles................. 28 1.22 Synthesis of α-tritylthio oximes..................... 29 x 1.23 Dimerization of allyl SNO compounds................. 29 1.24 Thiosulfonates from sulfenic acids and S-nitrosothiols......... 30 1.25 Cross-reactivity profile of SNO and sulfenic acids........... 30 1.26 Asymmetrical disulfide formation from SNO.............. 31 1.27 Amines converted to their corresponding aryl halides......... 32 1.28 Yields of 2-aryl-1-haloethanes...................... 33 2.1 Inspiration for aldehyde conjugation from our previous work.... 35 2.2 Proposed mechanism of an intramolecular conjugation of an alde- hyde and SNO................................ 36 2.3 Synthesis of 2-(diphenylphosphaneyl) benzaldehyde......... 37 2.4 Benzaldehyde fails to couple with TrSNO................ 40 2.5 Cinnamaldehyde successfully undergoes the intermolecular conjuga- tion...................................... 40 2.6 One-pot synthesis of benzoisothiazole.................. 43 3.1 Phosphine based reductive ligation.................... 52 3.2 General form of the proline-based ligation............... 53 3.3 Preparation of the proline-phosphoramidate - esterification...... 53 3.4 Preparation of the proline-phosphoramidate - phosphoramidite
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