TY - JOUR
T1 - Spin-Center Shift-Enabled Direct Enantioselective α-Benzylation of Aldehydes with Alcohols
AU - Nacsa, Eric D.
AU - MacMillan, David W.C.
N1 - Funding Information:
Financial support was provided by the NIHGMS (R01 GM-103558-05) and kind gifts were from Merck, Abbvie, BMS, and Janssen. E.D.N. acknowledges the NIH for a postdoctoral fellowship (F32 GM119362-01A1).
Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/3/7
Y1 - 2018/3/7
N2 - 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.
AB - 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.
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U2 - 10.1021/jacs.7b12768
DO - 10.1021/jacs.7b12768
M3 - Article
C2 - 29400958
AN - SCOPUS:85043264213
SN - 0002-7863
VL - 140
SP - 3322
EP - 3330
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
IS - 9
ER -