A Biocatalytic Platform for Synthesis of Chiral α- Trifluoromethylated Organoborons.

There are few biocatalytic transformations that produce fluorine-containing molecules prevalent in modern pharmaceuticals. To expand the scope of biocatalysis for organofluorine synthesis, we have developed an enzymatic platform for highly enantioselective carbene B-H bond insertion to yield versatile α- trifluoromethylated (α-CF ₃ ) organoborons, an important class of organofluorine molecules that contain stereogenic centers bearing both CF ₃ and boron groups. In contrast to current "carbene transferase" enzymes that use a limited set of simple diazo compounds as carbene precursors, this system based on Rhodothermus marinus cytochrome c ( Rma cyt c ) can accept a broad range of trifluorodiazo alkanes and deliver versatile chiral α-CF ₃ organoborons with total turnovers up to 2870 and enantiomeric ratios up to 98.5:1.5. Computational modeling reveals that this broad diazo scope is enabled by an active-site environment that directs the alkyl substituent on the heme CF ₃ -carbene intermediate toward the solvent-exposed face, thereby allowing the protein to accommodate diazo compounds with diverse structural features.
Competing Interests: The authors declare no competing financial interest.