Nature routinely engages alcohols as leaving groups, as DNA biosynthesis relies on the removal of water from ribonucleoside diphosphates by a radical-mediated ‘spin-center shift’ mechanism. Alcohols, however, remain underused as alkylating agents in synthetic chemistry due to their low reactivity in two-electron pathways. This talk describes an enantioselective alpha-benzylation of aldehydes using alcohols as alkylating agents based on the mechanistic principle of spin-center shift. Our strategy harnesses the dual activation modes of photoredox and organocatalysis, engaging the alcohol by spin-center shift and capturing the resulting benzylic radical with a catalytically-generated enamine. Mechanistic studies provide evidence for spin-center shift as a key elementary step, identify the origins of competing reactions, and enable improvements in chemoselectivity by rational photocatalyst design.

Spin-center shift-enabled direct enantioselective alpha-benzylation of aldehydes with alcohols

255th National Meeting (2018)

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