Enzymatic Trifluoropropylation by a Trifluoropropyl S-Adenosylmethionine Analogue

Abstract

The trifluoropropyl group is valuable in medicinal chemistry for enhancing drug stability and bioavailability. Selective trifluoropropylation is a challenge. Here, we developed an enzymatic approach using a trifluoropropyl Sadenosylmethionine analog (TP-SAM) and methyltransferases. Directed evolution of a halide methyltransferase (AclHMT) yielded a variant (W41L) that synthesizes TP-SAM from trifluoropropyl iodide and S-adenosylhomocysteine. Enzyme cascades comprising AclHMT (W41L) and engineered N-, C-, O-, and S-methyltransferases catalyze the selective trifluoropropylation of diverse substrates under mild conditions. This engineered biocatalytic system provides a versatile platform for synthesizing trifluoropropyl-containing bioactive molecules.