Biocatalytic Fluoroalkylation Using Fluorinated <i>S</i>-Adenosyl-<scp>l</scp>-methionine Cofactors
Wenping Ding, Minqi Zhou, Huayu Li, Miao Li, Yanping Qiu, Yu Yin, Lifeng Pan, Wen‐Chao Yang, Yanan Du, Xingang Zhang, Zhijun Tang, Wen Liu
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 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%.