New Synthetic Methods Enabled by Excited-State Redox Chemistry

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Project Summary The work described in this proposal aims to develop novel synthetic methods enabled by excited-state redox events to address longstanding challenges in catalysis and synthetic organic chemistry. A primary focus of this proposal is the continued development of proton-coupled electron transfer (PCET) technologies in organic synthesis. In particular we focus on developing PCET-based methods for the catalytic functionalization of aliphatic C-C bonds, including redox-neutral isomerization reactions of cyclic alcohols to form linear carbonyl compounds, and novel methods for the catalytic ring-expansion and ring-contraction of carbocyclic alcohols. We also discuss efforts to develop a new class of chiral amide-based catalysts that can be activated by PCET to generate transient amidyls, which can then mediate enantioselective and site-selective functionalization of aliphatic C-H bonds. A second goal of this work is the development of out-of-equilibrium synthetic methods enabled by excited-state redox events. These technologies provide opportunities to use photon absorption events to drive reaction against a thermochemical gradient, but without requiring generation of excited state substrates. Importantly, these methods provide novel approaches to achieve non-Boltzmann product distributions and reaction outcomes that are not, by definition, possible to obtain using conventional ground- state methods. Applications to the development of light-driven deracemization reactions are presented. A third goal is to advance our efforts in developing photocatalytic methods for olefin hydroamination and hydroetherification. We propose to develop the first general catalytic protocol for intermolecular anti- Markovnikov hydroamination reactions between unactivated olefins with primary alkyl amines to yield secondary amine products, selectively, based on the chemistry of aminium radical cations. PCET-based methods for enantioselective hydroaminations with sulfonamides are also proposed, wherein the asymmetric induction is proposed to arise from direct non-covalent interactions between a chiral H-bond donor and a neutral N-centered radical intermediate. We also present plans to develop analogous intermolecular hydroetherification methods and their enantioselective variants. If successful, these efforts will provide valuable new reactions and concepts for the chemistry communities engaged in the discovery, synthesis, and manufacture of pharmaceuticals and other small-molecule probes of biological function, and thus create a significant benefit to human health.