Faculty of Chemistry, Organic Chemistry and Biocatalysis, Bielefeld University, Universitätsstraße 25, 33615, Bielefeld, Germany.
Institut de Química Computacional i Catàlisi (IQCC) and Departament de Química, Universitat de Girona, Carrer Maria Aurèlia Capmany 69, Girona, 17003, Catalonia, Spain.
Angew Chem Int Ed Engl. 2022 Nov 25;61(48):e202213056. doi: 10.1002/anie.202213056. Epub 2022 Oct 26.
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.
方法对具有“现成”试剂的不饱和杂环进行区域选择性 N-甲基化和烷基化是备受追捧的。该反应可以极大地简化具有优势生物活性分子的合成。在这里，我们报告了用于挑战性杂环 N-（m）甲基化的工程化和天然甲基转移酶，包括苯并咪唑、苯并三唑、咪唑和吲唑。这些反应通过一个循环酶级联反应进行，该反应由两个甲基转移酶组成，仅使用碘代烷烃或甲基对甲苯磺酸盐作为简单试剂。该方法能够选择性合成其他方法难以获得的重要分子，具有高区域选择性（r.r. 高达>99%）、产率（高达 99%）、在制备规模上，并使用近乎等摩尔浓度的简单起始原料。
