Biocatalytic Strategy for the Highly Stereoselective Synthesis of CHF₂ -Containing Trisubstituted Cyclopropanes.

ABSTRACT: The difluoromethyl (CHF₂ ) group has attracted significant attention in drug discovery and development efforts, owing to its ability to serve as fluorinated bioisostere of methyl, hydroxyl, and thiol groups. Herein, we report an efficient biocatalytic method for the highly diastereo- and enantioselective synthesis of CHF₂ -containing trisubstituted cyclopropanes. Using engineered myoglobin catalysts, a broad range of α-difluoromethyl alkenes are cyclopropanated in the presence of ethyl diazoacetate to give CHF₂ -containing cyclopropanes in high yield (up to >99 %, up to 3000 TON) and with excellent stereoselectivity (up to >99 % de and ee). Enantiodivergent selectivity and extension of the method to the stereoselective cyclopropanation of mono- and trifluoromethylated olefins was also achieved. This methodology represents a powerful strategy for the stereoselective synthesis of high-value fluorinated building blocks for medicinal chemistry, as exemplified by the formal total synthesis of a CHF₂ isostere of a TRPV1 inhibitor.

SUBMITTER: Carminati DM 

PROVIDER: S-EPMC7969403 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature