Strategies for Asymmetric Catalysis Utilizing Proton-Coupled Electron Transfer

Abstract

Radicals are often considered high energy and fleeting intermediates. Controlling the reactivity of these species remains an outstanding challenge in catalysis. This thesis is centered around the use of proton-coupled electron transfer (PCET) as a strategy to control selectivity in both bond forming and breaking processes involving high energy radical intermediates. PCET is an elementary step that describes the homolysis of an E−H bond through the simultaneous movement of a proton and electron to a structurally distinct base and oxidant, respectively. This enables the activation of strong E–H bonds, such as alcohols and amides for which no sufficient single hydrogen atom transfer (HAT) catalyst exists. In the first part of this thesis, PCET is utilized to develop an enantioselective hydroamination of alkenes by sulfonamides. The enantioselectivity observed in this reaction is a result of a key post-PCET hydrogen bonding interaction between the generated amidyl radical and resulting chiral conjugate acid. Catalyst design, scope studies, and preliminary mechanistic results will be described herein. While the first section of this thesis is dedicated to the use of PCET-generated radicals for enantioselective bond formation, the latter half of this work describes the utility of these radicals for destroying stereochemistry towards the development of a dynamic kinetic resolution of remote stereocenters and small molecule deracemization. In the former, racemization of a remote stereocenter, a traditionally challenging process, is facilitated by the generation of an amidyl radical via PCET and subsequent 1,5-HAT to generate an achiral radical intermediate. Finally, preliminary results for a light-driven deracemization protocol are reported, utilizing a thiyl radical HAT catalyst to generate a captodatively stabilized radical which then undergoes reduction and enantioselective protonation. These projects illustrate the use of PCET to generate high energy species which can then be utilized to facilitate challenging bond breaking and bond forming processes.