Methylation of Unactivated Alkenes with Engineered Methyltransferases To Generate Non‐natural Terpenoids

numerous biological functions. Selective late-stage modification of their carbon scaffold has the potential to optimize or transform their biological activities. However, the synthesis of terpenoids with a non-natural carbon scaffold is often a challenging endeavor because of the complexity of these molecules. Here we report the identification and engineering of S-adenosyl-l-methionine-dependent sterol methyltransferases for selective C‑methylation of linear terpenoids. The engineered enzyme catalyzes selective methylation of unactivated alkenes in mono-, sesqui- and diterpenoids to produce C11, C16 and C21 derivatives. Preparative conversion and product isolation reveals that this biocatalyst performs C‑C bond formation with high chemo‑ and regioselectivity. The alkene methylation most likely proceeds via a carbocation intermediate and regioselective deprotonation. This method opens new avenues for modifying the carbon scaffold of alkenes in general and terpenoids in particular.