DEUTERIODESILYLATION: A MILD AND SELECTIVE METHOD FOR THE SITE- SPECIFIC INCORPORATION OF DEUTERIUM INTO DRUG CANDIDATES AND PHARMACEUTICAL STRUCTURES Kimberly N. Voronin A Thesis Submitted to the University of North Carolina Wilmington in Partial Fulfillment of the Requirements for the Degree of Master of Science Department of Chemistry and Biochemistry University of North Carolina Wilmington 2012 Approved by Advisory Committee Chris V. Galliford Pamela J. Seaton John A. Tyrell Chair Accepted by Dean, Graduate School TABLE OF CONTENTS ABSTRACT ................................................................................................................................... vi ACKNOWLEDGEMENTS .......................................................................................................... vii DEDICATION ............................................................................................................................... ix LIST OF TABLES .......................................................................................................................... x LIST OF FIGURES ...................................................................................................................... xi LIST OF ABBREVIATIONS ...................................................................................................... xiii LIST OF SCHEMES .....................................................................................................................xv CHAPTER 1: INTRODUCTION ....................................................................................................1 Background ......................................................................................................................................1 History of Deuterium ...........................................................................................................2 Kinetic Isotope Effects (KIEs ..............................................................................................4 Primary Kinetic Isotope Effect ............................................................................................6 Secondary Kinetic Isotope Effect ........................................................................................7 Zero Kinetic Isotope Effect ..................................................................................................8 Solvent Effects .....................................................................................................................9 Stable Isotope/Radiolabeling ...........................................................................................................9 Motivation For Use of Deuterium in Pharmaceutical Structures ...................................................11 Methods for Incorporation of Deuterium .......................................................................................14 Addition to Alkynes or Alkenes ........................................................................................15 Reduction of Carbonyl Compounds...................................................................................16 Reduction of Carbon-Halogen Bonds ................................................................................19 ii Protic Exchange Reactions ................................................................................................19 H/D Exchange with D2O Compounds ...............................................................................20 Acid-Catalyzed Exchange Methods ...................................................................................21 Base-Catalyzed Exchange Methods ...................................................................................25 Homogeneous Catalysis of H/D Exchange ....................................................................................27 Iridium Catalyzed-Exchange .............................................................................................28 Platinum Catalyzed-Exchange ...........................................................................................32 Rhodium Catalyzed-Exchange...........................................................................................32 Ruthenium Catalyzed-Exchange ........................................................................................34 Heterogeneous Catalysis of H/D Exchange ...................................................................................35 Palladium Catalyzed-Exchange .........................................................................................37 Platinum Catalyzed-Exchange ...........................................................................................38 Nickel Catalyzed-Exchange ...............................................................................................40 Protiodesilylation for Hydrogen Incorporation and the Proposed Research .........................................................................................................................40 Proposed Research .............................................................................................................40 Survey of Literature Precedent for Protiodesilylation .......................................................42 Organosilanes .................................................................................................................................45 Methods for the Preparation of Organosilicon Compounds ..........................................................45 Synthesis of Alkylsilanes ...................................................................................................47 Synthesis of Alkenylsilanes ...............................................................................................48 Synthesis of Alkynylsilanes ...............................................................................................49 Synthesis of Allylsilanes ....................................................................................................50 Overview of Organosilane Chemistry ...........................................................................................51 iii Silicon -Effect ..................................................................................................................53 Stabilization of -Silyl Anions ..........................................................................................55 Silicon Groups as Latent Anions .......................................................................................56 Reactions of Organosilanes ............................................................................................................57 Peterson Olefination Reaction ...........................................................................................57 Tamao-Fleming Oxidation .................................................................................................58 Hosomi-Sakurai Reaction ..................................................................................................59 Hiyama Coupling Reaction ................................................................................................60 Brook Rearrangement ........................................................................................................61 Epoxidation-Hydrolysis of Vinylsilanes ............................................................................62 Chemistry of Hypervalent Silicates ...............................................................................................63 Nucleophilic Substitution...................................................................................................63 Activation by Lewis Base: Hydride Donor ........................................................................66 Activation Driven by Strain Release Acidity.....................................................................68 Hypervalent Silicates as Lewis Acid Catalysts ..................................................................69 Stereoselective Reactions...............................................................................................................69 Lewis-Base-Catalyzed Allylation Reaction .......................................................................69 Hypervalent Silicates for Hydride Transfer .......................................................................71 Denmark’s Bisphosphoramide Catalyst .............................................................................72 CHAPTER 2: RESULTS AND DISCUSSION .............................................................................75 Selection of a Model Substrate ......................................................................................................75 Survey of Reaction Conditions Using a Model Substrates ............................................................70 Choice of Fluoride Source and Reaction Conditions .....................................................................80 iv Comparison of Protio-and Deuteriodesilylation Kinetics ..............................................................81 Scope of Reaction ..........................................................................................................................83 3 Attempted Deuteration of C(sp )-SiR3 Substrates .........................................................................86 Tritiodesilylation ............................................................................................................................89 CHAPTER 3: CONCLUSION