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Selective Biocatalytic N-Methylation of Unsaturated Heterocycles.

ABSTRACT: 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.

SUBMITTER: Ospina F

PROVIDER: S-EPMC9827881 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Selective Biocatalytic N-Methylation of Unsaturated Heterocycles.

Ospina Felipe F Schülke Kai H KH Soler Jordi J Klein Alina A Prosenc Benjamin B Garcia-Borràs Marc M Hammer Stephan C SC

Angewandte Chemie (International ed. in English) 20221026 48

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 ...[more]

PMID: 36202763

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