Biocatalytic Fluoroalkylation Using Fluorinated <i>S</i>-Adenosyl-<scp>l</scp>-methionine Cofactors

Abstract

Modification of organic molecules with fluorine functionalities offers a critical approach to develop new pharmaceuticals. Here, we report a multienzyme strategy for biocatalytic fluoroalkylation using <i>S</i>-adenosyl-l-methionine (SAM)-dependent methyltransferases (MTs) and fluorinated SAM cofactors prepared from ATP and fluorinated l-methionine analogues by an engineered human methionine adenosyltransferase hMAT2A^I322A. This work introduces the first example of biocatalytic 3,3-difluoroallylation. Importantly, this strategy can be applied to late-stage site-selective fluoroalkylation of complex molecule vancomycin with conversions up to 99%.