New Synthetic Methods Enabled by Excited-State Redox Chemistry

Princeton University, Princeton NJ

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Abstract

Project Summary The work described in this proposal aims to develop novel synthetic methods that address longstanding challenges in organic synthesis and catalysis. A primary goal of this work is the development of non-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 light-driven deracemization of ketones and asymmetric contra- thermodynamic olefin isomerizations are presented. An additional focus is the continued development of proton- coupled electron transfer (PCET) technologies for use in organic synthesis. In particular we present a new PCET- based method for the redox-neutral cleavage of aliphatic C-C bonds in amino alcohols. The resulting amino- carbonyl complexes can be directly converted in situ to valuable ring-expanded cyclic amines or lactams. Analogous methods are presented for the conversion of cyclic 1,2 diols into cyclic ethers and lactones. We also propose to develop an improved and general PCET-based protocol for the anti-Markovnikov hydroamination of unfunctionalized olefins with sulfonamides, which accommodates a much wider scope of amine derivatives than our previous methodology. We will also develop PCET-enabled transformations of hydrazones, including Wolf- Kishner type deoxygenations under neutral conditions at room temperature and the ring-contraction reactions of cyclic pyrazolines to form cyclopropanes and other small-ring products. Lastly, we will expand the scope of our PCET-based methods for the nucleophilic aromatic substitution reactions of phenol via transient phenoxyl radical intermediates with respect to both the nucleophilic and electrophilic components. If successful, these efforts will provide valuable new transformations and reactivity 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.