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

Year: 2018

Type: article

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.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.7b12768

Authors: Eric D. Nacsa, David W. C. MacMillan

Institution: Princeton University

Language: English

Topic: Radical Photochemical Reactions

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funders: National Institutes of Health, National Institute of General Medical Sciences

Awards: Alcohols as Latent Alkylating Agents Using Photoredox Organocatalysis, G1660036133, Combining Nickel and Photoredox Catalysis, G5537962391