Biocatalytic Fluoroalkylation Using Fluorinated S-Adenosyl-l-methionine Cofactors

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 S -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%.