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

  • Author(s): Huang, Xiongyi
  • Garcia-Borràs, Marc
  • Miao, Kun
  • Kan, SB Jennifer
  • Zutshi, Arjun
  • Houk, KN
  • Arnold, Frances H
  • et al.
Abstract

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-CF3) organoborons, an important class of organofluorine molecules that contain stereogenic centers bearing both CF3 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-CF3 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 CF3-carbene intermediate toward the solvent-exposed face, thereby allowing the protein to accommodate diazo compounds with diverse structural features.

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