Direct Bioisostere Replacement Enabled by Metallaphotoredox Deoxydifluoromethylation.

Autor: Mao E; Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States., Prieto Kullmer CN; Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States., Sakai HA; Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States., MacMillan DWC; Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, United States.
Jazyk: angličtina
Zdroj: Journal of the American Chemical Society [J Am Chem Soc] 2024 Feb 28; Vol. 146 (8), pp. 5067-5073. Date of Electronic Publication: 2024 Feb 16.
DOI: 10.1021/jacs.3c14460
Abstrakt: 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(sp 3 )-CF 2 H bond formation. The utility of this method is showcased in a variety of complex alcohols and drug compounds.
Databáze: MEDLINE
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