New Applications of Proton-Coupled Electron Transfer in Synthesis

Abstract

Proton-coupled electron transfer (PCET) is a ubiquitous mechanism to access radical intermediates in nature. Key steps in biological redox processes, ranging from photosynthetic water oxidation to natural product biosynthesis, feature this kinetic coupling of electron transfers with proton motion. However, the deliberate use of concerted PCET in organic synthesis remains largely unexplored. The Knowles group is interested in the application of concerted PCET to catalysis with free radical intermediates to address several long-standing challenges in substrate activation and asymmetric catalysis. Herein, some of our efforts to apply PCET towards new bond-constructions in synthesis are described. First, a PCET-enabled method to homolyze strong O-H bonds and access alkoxy radicals catalytically under mild conditions is outlined. Based on this strategy, a protocol for catalytic and redox-neutral isomerization of cyclic alcohols to linear ketones was developed. Next, we describe work to use PCET as a platform to do asymmetric catalysis on neutral ketyl radicals. Ketyls formed in a reductive PCET event from ketones are remarkably strong hydrogen-bond donors and remain strongly associated to the conjugate base of the proton donor following a PCET event. When chiral proton donors are used, these successor H-bond complexes provide a basis for asymmetric induction in subsequent reactions of the ketyl radical. Specifically, this idea is highlighted by the development of an enantioselective catalytic protocol for the reductive coupling of ketones and hydrazones.

Finally, a mechanistic study on a photo-redox mediated indoline oxidation developed for large-scale synthesis towards Elbasvir is presented. Kinetic, electrochemical, and spectroscopic studies of this process indicates a radical chain mechanism of dehydrogenation involving selective hydrogen atom transfer from the substrate to an alkoxy radical.