Progress in the synthesis of key intermediates of morphine by enzymatic enantioselective reduction of α, β - unsaturated imines

Morphine alkane is the skeleton structure of many bioactive natural products and drugs (such as dextromethorphan), which can be obtained by three steps of chemical reaction of 1-benzyloctahydroisoquinoline derivatives The synthesis methods of the intermediate include classical resolution method, asymmetric catalytic hydrogenation of transition metal and the de racemization of cyclohexylamine oxidase combined with boron amine However, these methods generally have the disadvantages of poor stereoselectivity, high production cost, poor atomic economy or serious environmental pollution The team of biocatalysis and green chemical industry led by Zhu dunming and Wu Qiqing, researchers of Tianjin Institute of industrial biotechnology, Chinese Academy of Sciences, has used imine reductase (ired) to enantioselectively reduce a series of α, β - unsaturated imines (1-benzylhexahydroisoquinoline derivatives) were successfully and effectively prepared corresponding 1-benzyloctahydroisoquinoline derivatives In this study, the imine reductase library was screened by using dextromethorphan precursor substrate It was found that two enzymes showed the highest and complementary stereoselectivity, the enantiomeric excess value reached 98% (s) and > 99% (R), and the catalytic efficiency was 5.4 × 10-2 and 24.1 × 10-2 S-1 mm-1, respectively On this basis, the laboratory scale preparation reaction was established, and the product separation yield was 74% and 80%, respectively After that, in the preparation of the derivatives with different substituents in the substituents and the substituents in the substituents, a more highly spatially adaptable enzyme was obtained, which could obtain high stereoselectivity and separation yield for all eight substrates Compared with the existing synthesis methods of this kind of compounds, it has significant competitive advantages The research work was supported by the National Natural Science Foundation of China (21778072), Tianjin Science and Technology Committee (15ptcysy00020 and 15ptgccx00060) Relevant research results have been published in the Journal of advanced synthesis & Catalysis recently, and selected as the hot topic of biocatalysis Yao Peiyuan, associate researcher of Tianjin Institute of technology and Xu zefei, graduate student, are the co first authors of the paper.