Repurposing trifluoromethyl copper (III) complexes for difluoromethylation of saccharides and complex alcohols.

Dai, Shuolu; Xie, Chuhong; Long, Shan; Luo, Min; Chen, Chen; Li, Tingting; Lv, Wen-Xin; Chi, Yonggui Robin · Nat Commun · 2026

basic_science · Level V

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Abstract

Grushin's reagent, (bpy)Cu(CF<sub>3</sub>)<sub>3</sub>, is a well-known trifluoromethylation agent, but its potential as a difluorocarbene source has remained largely unexplored. Here, we present a photo- and acid-mediated strategy that repurposes Grushin's reagent as an efficient difluorocarbene precursor for the difluoromethylation of diverse alcohols, including complex primary, secondary, and tertiary alcohols bearing multiple polar functional groups. This method exhibits broad functional group compatibility and has been successfully applied to the late-stage modification of complex natural products and bioactive molecules. A notable achievement is the regioselective difluoromethylation of saccharides and polyols, a challenging transformation enabled by Me<sub>2</sub>SnCl<sub>2</sub>, which serves a dual role as a hydroxyl activator and an in situ source of hydrogen chloride. Antifungal activity evaluation reveals that compounds 3c and 3n possess good efficacy, highlighting their potential as promising leads for antifungal development.