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

Abstract

Terpenoids are built from isoprene building blocks and have 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. Herein 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-, sesquiand diterpenoids to produce C 11 , C 16 and C 21 derivatives. Preparative conversion and product isolation reveals that this biocatalyst performs CÀ 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.

A Career in Catalysis: Bernhard Hauer

“…They developed a novel biocatalyst that allows C-methylation of alkenes into mono-, sesqui-, and diterpenes, such as farnesol, geranylgeraniol, homofarnesol, and geranylacetone, with up to 94% conversion. 88 Future efforts will focus on the modification of terpenes beyond methylation. In this respect, they will draw inspiration from their own work.…”

“…More recently, Bernhard’s group has expanded the chemical space of terpenes by generating non-natural terpenes through engineered C -methyltransferases. They developed a novel biocatalyst that allows C -methylation of alkenes into mono-, sesqui-, and diterpenes, such as farnesol, geranylgeraniol, homofarnesol, and geranylacetone, with up to 94% conversion . Future efforts will focus on the modification of terpenes beyond methylation.…”