TY - JOUR
T1 - Alcohols as Alkylating Agents
T2 - Photoredox-Catalyzed Conjugate Alkylation via In Situ Deoxygenation
AU - Wang, Johnny Z.
AU - Sakai, Holt A.
AU - MacMillan, David W.C.
N1 - Funding Information:
The authors are grateful for financial support provided by the National Institute of General Medical Sciences (NIGMS), the NIH (under award no. R35GM134897‐03), the Princeton Catalysis Initiative, and kind gifts from Merck, Janssen, BMS, Genentech, Celgene and Pfizer. J.Z.W. acknowledges Princeton University for a first‐year fellowship. We thank Prof. Dr. Zhe Dong, Nathan Dow, and John F. Hoskin for helpful discussions.
Publisher Copyright:
© 2022 Wiley-VCH GmbH.
PY - 2022/8/26
Y1 - 2022/8/26
N2 - The rapid exploration of sp3-enriched chemical space is facilitated by fragment-coupling technologies that utilize simple and abundant alkyl precursors, among which alcohols are a highly desirable, commercially accessible, and synthetically versatile class of substrate. Herein, we describe an operationally convenient, N-heterocyclic carbene (NHC)-mediated deoxygenative Giese-type addition of alcohol-derived alkyl radicals to electron-deficient alkenes under mild photocatalytic conditions. The fragment coupling accommodates a broad range of primary, secondary, and tertiary alcohol partners, as well as structurally varied Michael acceptors containing traditionally reactive sites, such as electrophilic or oxidizable moieties. We demonstrate the late-stage diversification of densely functionalized molecular architectures, including drugs and biomolecules, and we further telescope our protocol with metallaphotoredox cross-coupling for step-economic access to sp3-rich complexity.
AB - The rapid exploration of sp3-enriched chemical space is facilitated by fragment-coupling technologies that utilize simple and abundant alkyl precursors, among which alcohols are a highly desirable, commercially accessible, and synthetically versatile class of substrate. Herein, we describe an operationally convenient, N-heterocyclic carbene (NHC)-mediated deoxygenative Giese-type addition of alcohol-derived alkyl radicals to electron-deficient alkenes under mild photocatalytic conditions. The fragment coupling accommodates a broad range of primary, secondary, and tertiary alcohol partners, as well as structurally varied Michael acceptors containing traditionally reactive sites, such as electrophilic or oxidizable moieties. We demonstrate the late-stage diversification of densely functionalized molecular architectures, including drugs and biomolecules, and we further telescope our protocol with metallaphotoredox cross-coupling for step-economic access to sp3-rich complexity.
KW - Alcohols
KW - Conjugate Addition
KW - Deoxygenation
KW - Photoredox
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U2 - 10.1002/anie.202207150
DO - 10.1002/anie.202207150
M3 - Article
C2 - 35727296
AN - SCOPUS:85134416774
VL - 61
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1433-7851
IS - 35
M1 - e202207150
ER -