Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation

Edna Mao; Cesar N. Prieto Kullmer; Holt A. Sakai; David W.C. MacMillan

doi:10.1021/jacs.3c14460

Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation

Edna Mao, Cesar N. Prieto Kullmer, Holt A. Sakai, David W.C. MacMillan

Princeton University

Research output: Contribution to journal › Article › peer-review

Abstract

The replacement of a functional group with its corresponding bioisostere is a widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties of candidates while maintaining potency. However, the incorporation of bioisosteres typically requires lengthy de novo resynthesis of potential candidates, which represents a bottleneck in their broader evaluation. An alternative would be to directly convert a functional group into its corresponding bioisostere at a late stage. Herein, we report the realization of this approach through the conversion of aliphatic alcohols into the corresponding difluoromethylated analogues via the merger of benzoxazolium-mediated deoxygenation and copper-mediated C(sp³)-CF₂H bond formation. The utility of this method is showcased in a variety of complex alcohols and drug compounds.

Original language	American English
Pages (from-to)	5067-5073
Number of pages	7
Journal	Journal of the American Chemical Society
Volume	146
Issue number	8
DOIs	https://doi.org/10.1021/jacs.3c14460
State	Published - Feb 28 2024

ASJC Scopus subject areas

General Chemistry
Biochemistry
Catalysis
Colloid and Surface Chemistry

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abstract = "The replacement of a functional group with its corresponding bioisostere is a widely employed tactic during drug discovery campaigns that allows medicinal chemists to improve the ADME properties of candidates while maintaining potency. However, the incorporation of bioisosteres typically requires lengthy de novo resynthesis of potential candidates, which represents a bottleneck in their broader evaluation. An alternative would be to directly convert a functional group into its corresponding bioisostere at a late stage. Herein, we report the realization of this approach through the conversion of aliphatic alcohols into the corresponding difluoromethylated analogues via the merger of benzoxazolium-mediated deoxygenation and copper-mediated C(sp3)-CF2H bond formation. The utility of this method is showcased in a variety of complex alcohols and drug compounds.",

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Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation

Abstract

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