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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‐, 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. [ABSTRACT FROM AUTHOR]

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Methods for regioselective N‐methylation and ‐alkylation of unsaturated heterocycles with "off the shelf" reagents are highly sought‐after. This reaction could drastically simplify synthesis of privileged bioactive molecules. Here we report engineered and natural methyltransferases for challenging N‐(m)ethylation of heterocycles, including benzimidazoles, benzotriazoles, imidazoles and indazoles. The reactions are performed through a cyclic enzyme cascade that consists of two methyltransferases using only iodoalkanes or methyl tosylate as simple reagents. This method enables the selective synthesis of important molecules that are otherwise difficult to access, proceeds with high regioselectivity (r.r. up to >99 %), yield (up to 99 %), on a preparative scale, and with nearly equimolar concentrations of simple starting materials. [ABSTRACT FROM AUTHOR]

A variant with three changes in the amino acid sequence was able to produce methylated derivatives of linear terpenoids with high selectivity by C-methylation of an unactivated alkene. Cover Picture: Methylation of Unactivated Alkenes with Engineered Methyltransferases To Generate Non-natural Terpenoids (Angew. Keywords: Alkene Methylation; Biocatalysis; Late-Stage Modification; Methyltransferase; Terpenoids EN Alkene Methylation Biocatalysis Late-Stage Modification Methyltransferase Terpenoids 1 1 1 06/20/23 20230626 NES 230626 B A methyltransferase b from the green alga I Chlamydomonas reinhardtii i was identified and engineered for late-stage modifications of the carbon skeleton of terpenes. [Extracted from the article]

A variant with three changes in the amino acid sequence was able to produce methylated derivatives of linear terpenoids with high selectivity by C-methylation of an unactivated alkene. A variant with three changes in the amino acid sequence was able to produce methylated derivatives of linear terpenoids with high selectivity by C-methylation of an unactivated alkene. Keywords: Alken-Methylierung; Biokatalyse; Diversifizierung; Methyltransferase; Terpenoide DE Alken-Methylierung Biokatalyse Diversifizierung Methyltransferase Terpenoide 1 1 1 06/20/23 20230626 NES 230626 B A methyltransferase b from the green alga I Chlamydomonas reinhardtii i was identified and engineered for late-stage modifications of the carbon skeleton of terpenes. [Extracted from the article]