Project Summary/Abstract: The development of catalytic reactions to selectively transform ubiquitous functional groups to value-added products can enable the efficient synthesis of medicinally relevant molecules. The facile generation of classical reactive intermediates such as radicals, cations, and anions via photoredox catalysis and proton-coupled electron transfer (PCET) have shifted the way chemists construct complex molecules and enabled novel bond-forming logic. However, the application of these mild photocatalytic manifolds towards the generation of alkene-derived radical cation intermediates still relies on strongly oxidative conditions to facilitate alkene oxidation. The ambiphilic nature of alkene radical cation intermediates renders these species valuable synthetic linchpins capable of rapidly building molecular complexity and streamlining the development of pharmaceutically relevant molecules. The goal of the proposed research is the development of a novel synthetic platform for the photocatalytic formation of alkene radical cation intermediates from non-canonical alcohol starting materials. This proposal seeks to leverage the mechanistic insights gleaned from the intracellular formation of alkene radical cation intermediates in concert with the capabilities of excited state redox chemistry, to generate radical cations under synthetically advantageous conditions. The development of this methodology will address three fundamental limitations of radical cation chemistry: 1) the use of harsh oxidative conditions for alkene oxidation 2) the constraint of alkenes as radical cation progenitors and 3) the use of oxidatively labile reaction partners. The research strategy outlines a rigorous approach for establishing a mechanistically distinct method to access classical alkene-radical cations from non-canonical precursors, and the development of new synthetic methods outside the scope of conventional radical cation chemistries. In aim 1, we will leverage established principles of photoredox catalysis for the development of a reductive platform for the catalytic generation and subsequent functionalization of classical alkene radical cations intermediates from non-canonical halohydrin precursors. The reductive generation of alkene radical cations will initially be applied to the development of annulative carbofunctionalizations reactions. This reductive platform will then be expanded to enable formal access to non-classical vicinal di-cation reactivity which is inaccessible via conventional alkene radical cation chemistries. In aim 2, C–H PCET will be applied for the selective homolytic activation of strong C– H bonds of simple alcohols for the direct generation of alkene radical cation intermediates. PCET generated alkene radical cations will then be applied to the direct generation and functionalization of nucleotide-derived radical cations for the expedient synthesis of nucleotide analog libraries. This work will provide a novel and synthet...