Authors
Jia-Yong Zhang, Pei-Jie Huang, Si-Yuan Chen, Cheng Luan, Qiang-Shuai Gu, Biao Wang, Yu-Feng Zhang, Chang-Jiang Yang, Ji-Jun Chen, Xin-Yuan Liu
Published in
Journal of the American Chemical Society. Jun 21, 2026. Epub Jun 21, 2026.
Abstract
Chiral tertiary alcohols are ubiquitous structural motifs in pharmaceutical agents and bioactive molecules, as well as versatile building blocks in organic synthesis, yet general catalytic enantioselective routes to these compounds remain limited. Direct transition-metal-catalyzed enantioconvergent C-O cross-coupling of racemic tertiary alkyl halides with water would provide an attractive entry to these structures, but this strategy remains largely unexplored because water can deactivate metal catalysts and presents a formidable challenge for enantiocontrol. Herein, we report a copper-catalyzed enantioconvergent O-alkylation of water with racemic α-tertiary haloamides through a radical-polar crossover pathway. Central to this process is the use of chiral anionic N,N,N-ligands, which promote the formation of coordinatively saturated Cu(III) intermediates that undergo enantioselective outer-sphere nucleophilic substitution by water, thereby enabling direct C(sp3)-O bond formation. This method provides practical and complementary access to a broad range of enantioenriched, sterically congested tertiary alcohols under mild conditions with good functional-group compatibility. The synthetic utility of this protocol is further demonstrated by the efficient preparation of diverse chiral tertiary alcohol building blocks and by concise syntheses of pharmaceutically relevant molecules, including sofpironium bromide and (S)-oxybutynin.
PMID:
42324756
Bibliographic data and abstract were imported from PubMed on 22 Jun 2026.
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