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Biocatalytic Strategy for the Highly Stereoselective Synthesis of CHF 2 ‐Containing Trisubstituted Cyclopropanes
Author(s) -
Carminati Daniela M.,
Decaens Jonathan,
CouveBonnaire Samuel,
Jubault Philippe,
Fasan Rudi
Publication year - 2021
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202015895
Subject(s) - stereoselectivity , cyclopropanation , chemistry , isostere , enantioselective synthesis , ethyl diazoacetate , combinatorial chemistry , total synthesis , organic chemistry , stereochemistry , catalysis
The difluoromethyl (CHF 2 ) 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 CHF 2 ‐containing trisubstituted cyclopropanes. Using engineered myoglobin catalysts, a broad range of α‐difluoromethyl alkenes are cyclopropanated in the presence of ethyl diazoacetate to give CHF 2 ‐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 CHF 2 isostere of a TRPV1 inhibitor.