期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 61, 期 48, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202213056
关键词
Alkylation; Biocatalysis; Heterocycles; Methyltransferase; SAM Recycling
资金
- Deutsche Forschungsgemeinschaft [HA 7668/2-1]
- Deutsche Bundesstiftung Umwelt [20020/690]
- Spanish MICINN (Ministerio de Ciencia e Innovacion) [PID2019-111300GA-I00]
- Ramon y Cajal program [RYC2020-028628-I]
- Spanish MIU (Ministerio de Universidades) predoctoral FPU fellowship [FPU18/02380]
- Projekt DEAL
This study reports a new method for regioselective N-methylation of unsaturated heterocycles. By using two methyltransferases and simple reagents, important molecules with biological activities can be synthesized efficiently.
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.
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