A biomimetic S_H2 cross-coupling mechanism for quaternary sp³-carbon formation.

Abstract

Bimolecular homolytic substitution (S_H2) is an open-shell mechanism that is implicated across a host of biochemical alkylation pathways. Surprisingly, however, this radical substitution manifold has not been generally deployed as a design element in synthetic C–C bond formation. We found that the S_H2 mechanism can be leveraged to enable a biomimetic sp³-sp³ cross-coupling platform that furnishes quaternary sp³-carbon centers, a long-standing challenge in organic molecule construction. This heteroselective radical-radical coupling uses the capacity of iron porphyrin to readily distinguish between the S_H2 bond-forming roles of open-shell primary and tertiary carbons, combined with photocatalysis to generate both radical classes simultaneously from widely abundant functional groups. Mechanistic studies confirm the intermediacy of a primary alkyl–Fe(III) species prior to coupling and provide evidence for the S_H2 displacement pathway in the critical quaternary sp³-carbon bond formation step.