Mild Strategies in the Direct Generation of Carbocation Intermediates from C(sp3)–H Bonds.

Worcester Polytechnic Institute, Worcester MA

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Abstract

Project Summary/Abstract The broad goal of the proposed research is to develop highly enabling and rapid chemical technologies for the synthesis of life-altering drug compounds. Our focus is in the area of C–H functionalization, a synthetic strategy that is well-established to expedite the discovery of bioactive small molecules. Since its conception, the majority of Csp3–H functionalization methods rely on open-shell mechanistic pathways via alkyl radicals or metal alkyl intermediates. To continue the advancement of C–H modification technologies, there is a critical need for new mechanistic designs. We hypothesize that polar (two- electron) mechanisms can be accessed in a C–H functionalization context to offer orthogonal reactivity to the current state-of-the-art methods. To this end, our central hypothesis is to design reaction platforms that can access carbocation intermediates directly from a Csp3–H bond. The design will bypass the need for pre-installed functional groups that are usually required to generate carbocations, thus streamlining the direct modification of late-stage drug leads and resulting in the rapid synthesis of compound libraries for high-throughput drug development. The innovative approach to convert Csp3–H bonds into highly reactive carbocations is via a stepwise dismantling process: first hydrogen atom abstraction at the desired bond followed by a radical-polar crossover, or oxidation of a carbon radical to its cationic equivalent. With the design of the mechanism executed with a photocatalytic platform, we envision the reaction to be mild and capable of engaging a broad scope. The five-year goal is to utilize the proposed strategy to target benzylic, aliphatic and a-halo C–H bonds and utilize the resulting carbocations to facilitate high value bond formations with abundant nucleophilic partners. The proposal is significant in that we will be investigating an underexplored reaction space that is ripe with new synthetic opportunities that have the potential to offer modularity in approach, simplicity of reagents, and complexity of products.