Study On Biocatalytic Synthesis Of 6,7-dimethoxy Tetrahydroisoquinoline

The 1-aryl substituted tetrahydroisoquinoline(THIQs)molecular scaffolds are an important class of structural units,Generally,it can be divided into simple isoquinolines,benzyl isoquinolines,original berberine,morphine and other more than 20 species,which are widely found in natural alkaloids and synthetic analogues,and have excellent biological activity and medicinal value.Some tetrahydroisoquinoline alkaloids such as berberine(berberine hydrochloride)and solifenacin have been used in the treatment of bladder hyperactivity.At present,the synthesis methods of tetrahydroisoquinoline mainly include small molecule catalysis,metal catalysis and kinetic resolution.However,due to the harsh reaction conditions,expensive metal ligands,poor three-dimensional selectivity,environmental friendliness and low optical purity,their application in industrial production is limited.Enzymatic catalytic asymmetric reduction of imine substrates to prepare chiral amine compounds,with high efficiency,environmental friendliness and high economic efficiency,has attracted more and more attention from academia and industry.IREDs in this study are NADPH-dependent oxidoreductase capable of reducing imine substrates to chiral amines,which have an obvious effect in synthesis of cyclic chiral amines,superior to kinetic resolution and desorption.However,due to the large steric hindrance and poor flexibility of 1-aryl substituted dihydroisoquinoline,asymmetric catalytic reduction by imine reductase is faced with great challenges.Five literature have been synthesized in this research reported of imine reduction substrate.Based on the 100 imine reduction enzyme libraries constructed in the earlier stage,the catalytic efficiency,enzyme activity,kinetic data and stereoselectivity were screened,the imine reductase that catalyzes the reduction of cyclic imide substrates with large steric hindrance was successfully found.Through molecular docking simulation and analysis of protein sequences,the activity of pocket near key amino acid mutations,modified imide reductase activity and stereoselectivity were better than that of the wild strains,for subsequent imine reductase research provides an important tool.The enzyme library was successfully applied to the asymmetric catalytic synthesis of 1-aryl-isoquinolines with large steric hindrance and the 6,7-dimethoxysubstituted-1-aryl-isoquinolines with greater steric hindrance,providing a more efficient and environmentally friendly strategy for the synthesis of such important drug intermediates.