Selective Biocatalytic N‐Methylation of Unsaturated Heterocycles

• Published in: Angewandte Chemie International Edition Vol. 61; no. 48; pp. e202213056 - n/a
• Main Authors: Ospina, Felipe, Schülke, Kai H., Soler, Jordi, Klein, Alina, Prosenc, Benjamin, Garcia‐Borràs, Marc, Hammer, Stephan C.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 25.11.2022; John Wiley and Sons Inc
• Edition: International ed. in English
• Subjects: Alkylation; Benzimidazoles; Biocatalysis; Chemical synthesis; Communication; Communications; Heterocycles; Imidazole; Imidazoles; Methylation; Methyltransferase; Methyltransferases - metabolism; Reagents; Regioselectivity; SAM Recycling; Heterocycles; Biocatalysis; SAM Recycling; Alkylation; Methyltransferase
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202213056

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. N‐Methylated and ‐alkylated unsaturated heterocycles are privileged scaffolds in pharmaceuticals that are often tedious to synthesize. Now, promiscuous and engineered enzymes can be used to access such molecules through alkylation with high regioselectivity, high yield and on a preparative scale using simple starting materials.