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Spin-Center Shift-Enabled Direct Enantioselective α-Benzylation of Aldehydes with Alcohols

Author:
Nacsa, Eric D., MacMillan, David W. C.
Source:
Journal of the American Chemical Society 2018 v.140 no.9 pp. 3322-3330
ISSN:
1520-5126
Subject:
DNA, alcohols, aldehydes, alkylation agents, biosynthesis, chemoselectivity, enamines, enantioselectivity, photocatalysts, redox reactions
Abstract:
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” (SCS) mechanism. Alcohols, however, remain underused as alkylating agents in synthetic chemistry due to their low reactivity in two-electron pathways. We report herein an enantioselective α-benzylation of aldehydes using alcohols as alkylating agents based on the mechanistic principle of spin-center shift. This strategy harnesses the dual activation modes of photoredox and organocatalysis, engaging the alcohol by SCS and capturing the resulting benzylic radical with a catalytically generated enamine. Mechanistic studies provide evidence for SCS as a key elementary step, identify the origins of competing reactions, and enable improvements in chemoselectivity by rational photocatalyst design.
Agid:
6038606