School of Chemical Engineering and Technology, Hebei University of Technology, No. 8 Guangrong Road, Hongqiao District, Tianjin, 300130, China.
Department of Chemistry, University of Manchester, Manchester Institute of Biotechnology, 131 Princess Street, Manchester, M1 7DN, UK.
Angew Chem Int Ed Engl. 2022 May 16;61(21):e202202264. doi: 10.1002/anie.202202264. Epub 2022 Mar 23.
The direct asymmetric reductive amination of heteroaryl ketones has been a long-standing synthetic challenge. Here we report the engineering of an amine dehydrogenase (AmDH) from Jeotgalicoccus aerolatus for the asymmetric synthesis of chiral α-(hetero)aryl primary amines in excellent conversions (up to 99 %) and enantioselectivities (up to 99 % ee). The best AmDH variant (Ja-AmDH-M3 ) exhibited high activity and specificity toward alkyl (hetero)aryl ketones, even for those bearing a bulky alkyl chain. An efficient directed evolution approach based on molecular docking was implemented to enlarge the active pocket with a more hydrophobic entrance, which is responsible for the high activity. The Ja-AmDH-M3 was also used for preparative-scale synthesis of pharmaceutically relevant amines and a key intermediate of chiral pincer ligands, which highlighted its practical application in synthetic chemistry.
芳基酮的直接不对称还原胺化一直是一个长期存在的合成挑战。在这里，我们报告了来自 Aerolatus 的胺脱氢酶 (AmDH) 的工程改造，用于在手性 α-(杂)芳基伯胺的不对称合成中，具有极好的转化率 (高达 99%) 和对映选择性 (高达 99%ee)。最佳的 AmDH 变体 (Ja-AmDH-M3) 对烷基 (杂)芳基酮表现出高活性和特异性，即使是那些带有大体积烷基链的酮。实施了一种基于分子对接的高效定向进化方法，以扩大活性口袋，使其具有更疏水的入口，这是高活性的原因。Ja-AmDH-M3 还用于制药相关胺和手性钳配体关键中间体的制备规模合成，突出了其在合成化学中的实际应用。
