©Copyright 2015 Mycah R. Uehling Gold-Catalyzed Asymmetric Synthesis of Cyclic Ethers and Copper-Catalyzed Hydrofunctionalization of Alkynes Mycah R. Uehling A dissertation submitted in partial fulfillment of the requirements for the degree of: Doctor of Philosophy University of Washington 2015 Reading Committee: Gojko Lalic, chair Forrest Michael Champak Chatterjee Program Authorized to Offer Degree: Department of Chemistry 2 University of Washington Abstract Gold-Catalyzed Asymmetric Synthesis of Cyclic Ethers and Copper-Catalyzed Hydrofunctionalization of Alkynes Mycah R. Uehling Chair of the Supervisory Committee: Professor Gojko Lalic Department of Chemistry Gold-catalyzed cyclization of enantioenriched trisubstituted allenols to form enantioenriched α- tetrasubstituted cyclic ethers has been developed. This structural motif can be found in many natural products that have useful biological properties. The cyclization reaction is compatible with multiple functional groups and can be used to prepare enantioenriched furans, pyrans, and chromans all containing an α-tetrasubstituted stereocenter. The reaction development, scope, and a preliminary mechanistic study are discussed. In addition, a method to synthesize the required enantioenriched trisubstituted allenols based on copper-catalyzed cross coupling of enantioenriched propargylic phosphates and organoboron reagents has been developed. This allows the overall sequence to be practical and convergent. Copper-catalyzed hydrobromination and hydroalkylation of alkynes have been developed. The reactions are compatible with many functional groups and can be used to prepare functionalized alkenes in high yield and as one regio- and diastereoisomer. The reaction development, scope, and preliminary mechanism studies are discussed for both reactions. The development of copper-catalyzed hydrobromination and hydroalkylation of alkynes demonstrates that copper-catalyzed 3 hydrofunctionalization of alkynes is a general approach to the synthesis of different types of functionalized alkenes. 4 Table Of Contents List of Abbreviations ................................................................................. 9 List of Figures .......................................................................................... 13 List of Schemes ....................................................................................... 14 List of Tables ........................................................................................... 15 Part 1: Asymmetric Synthesis of Cyclic Ethers Containing an α-Tetrasubstituted Stereocenter ............................................................... 18 Chapter 1: Copper-Catalyzed Asymmetric Synthesis of Trisubstituted Allenes ..................................................................................................... 19 1.1 Introduction ....................................................................................................................................... 19 1.2 Reaction Optimization ...................................................................................................................... 22 1.3 Scope ................................................................................................................................................. 24 1.4 Mechanism Studies ........................................................................................................................... 26 1.5 Conclusion ........................................................................................................................................ 32 1.6 Experimental ..................................................................................................................................... 33 1.6.1 General Information ................................................................................................................... 33 1.6.2 Materials .................................................................................................................................... 33 1.6.3 Synthesis of Propargylic Acohols .............................................................................................. 34 1.6.4 Chiral Resolution of Propargylic Alcohols ................................................................................ 34 1.6.5 Characterization Data for Propargylic Alchohols ...................................................................... 34 5 1.6.6 Synthesis of Propargylic Phosphates ......................................................................................... 36 1.6.7 Characterization Of Propargylic Phosphates ............................................................................. 36 1.6.8 Substitution of Propargylic Phosphates ..................................................................................... 38 1.6.9 Characterization of Allene Products .......................................................................................... 39 1.6.10 Determination of Absolute Stereochemistry ............................................................................ 46 1.6.11 Synthesis of Boronate .............................................................................................................. 47 1.6.12 Reaction Between Alkylborane And Various Alkali Metal Alkoxides ................................... 47 1.6.13 Reactivity Studies Using Borane or Borate Nucleophiles ....................................................... 47 1.6.14 Synthesis of ICyCuMe ............................................................................................................. 48 1.6.15 Stoichiometric Reaction Between ICyCuMe and Phosphate ................................................... 48 1.6.16 Catalytic Reaction Using ICyCuMe as the Catalyst ................................................................ 48 Chapter 1 References .............................................................................................................................. 49 Chapter 2: Catalytic Asymmetric Synthesis of Cyclic Ethers Containing an α-Tetrasubstituted Stereocenter .......................................................... 53 2.1 Introduction ....................................................................................................................................... 53 2.2 Reaction Optimization ...................................................................................................................... 56 2.3 Furan and Pyran Synthesis Scope ..................................................................................................... 59 2.4 Chroman Synthesis Optimization ..................................................................................................... 60 2.5 Chroman Synthesis Scope ................................................................................................................. 62 2.6 Mechanism of Ether Formation ........................................................................................................ 63 2.6.1 Mechanism of Furan and Pyran Formation ................................................................................ 63 2.6.2 Mechanism of Chroman Formation ........................................................................................... 66 2.7 Conclusions ....................................................................................................................................... 69 2.8 Experimental ..................................................................................................................................... 69 2.8.1 General ....................................................................................................................................... 69 2.8.2 Cyclization of Enantioenriched Hydroxy Allenes ..................................................................... 70 2.8.3 Cyclization of Enantioenriched Phenoxy Allenes ...................................................................... 77 2.8.4 Attempted Synthesis of Oxetanes and Oxepanes ....................................................................... 81 2.8.5 Investigation of Reaction Mechanism ........................................................................................ 82 Chapter 2 References .............................................................................................................................. 88 Part 2: Copper-Catalyzed Hydrofunctionalization of Alkynes ............... 91 6 Chapter 3: Catalytic Anti-Markovnikov Hydrobromination of Alkynes93 3.1 Introduction ....................................................................................................................................... 93 3.2 Reaction Development ...................................................................................................................... 94 3.2.1 Background Reaction 1: Formation of Bromoalkyne ................................................................ 99 3.2.2 Background Reaction 2: Alkyne Semireduction ...................................................................... 101 3.3 Optimized Reaction ........................................................................................................................ 102 3.4 Hydrobromination Scope ................................................................................................................ 103 3.4 Hydrobromination Mechanism ....................................................................................................... 107 3.5