Stable S-Adenosylmethionine Analogue for Enzymatic Fluoromethylation

Fluorine is an important atom in medicinal chemistry and agrochemistry, and the fluoromethyl group, an isostere for various functional groups, can improve the metabolic stability and biological activity of compounds. However, enzymes that introduce fluorine and fluorine-containing groups are rare, and performing selective fluoromethylation remains a great challenge in organic chemistry. Biocatalytic fluoromethylation is severely limited by the instability of fluoro S-adenosylmethionine (SAM). Here, we designed and synthesized a stable fluoro SAM analogue, fluoro decarboxyl SAM (F-dcSAM). The F-dcSAM analogue is stable and can be accepted by many O-, S-, and N-methyltransferases, transferring fluoromethyl groups to their substrate. F-dcSAM and methyltransferases were applied to fluoromethylate various compounds, including several bioactive natural products, with high chemo- and regioselectivity. Kinetics studies showed that compared to SAM, F-dcSAM is an analogous or even better substrate for the methyltransferases NtCOMT and DnrK. We further showed that F-dcSAM can be readily prepared enzymatically by halide methyltransferase (HMT) from decarboxyl S-adenosyl-l-homocysteine (dcSAH) and CH2FI. The enzyme cascade reaction involving HMT and methyltransferases can transfer the CH2F group from CH2FI to substrates efficiently with multiple turnovers. Therefore, F-dcSAM can be directly used for enzymatic fluoromethylation or generated in situ through the coupled activities of HMT and methyltransferases. Our results suggest that F-dcSAM is a general abiological cofactor of methyltransferases for late-stage enzymatic fluoromethylation and facilitates the preparation of fluoro analogues of drug molecules. In addition, F-dcSAM is a stable nonaromatic sulfonium ion compound that serves as a fluoromethyl donor, which provides new opportunities for the development of novel CH2F reagents.