Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation

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 le...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2024-02, Vol.146 (8), p.5067-5073
Main Authors: Mao, Edna, Prieto Kullmer, Cesar N., Sakai, Holt A., MacMillan, David W. C.
Format: Article
Language:English
Subjects:
Alcohols - chemistry
Drug Discovery
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Summary: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.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.3c14460