Asymmetric Synthesis Of Chiral Tetrahydroisoquinoline Alkaloids

Chinese medicines such as Corydalis,Rhizoma Coptidis and Stephania tetrandra,all contain chiral tetrahydroisoquinoline alkaloid compounds,which play an important role in the clinical treatment of pain relief and anti-inflammatory diseases.In order to meet the needs of new drug research and the study of active ingredients of natural products,the preparation of chiral tetrahydroisoquinolines has attracted great attentions,especially the catalytic asymmetric hydrogenation synthesis methods with high efficiency,simple substrate preparation and environmentally friendliness.Although great progress has been made in the preparation of chiral tetrahydroisoquinolines by asymmetric hydrogenation,there is still a lack of catalytic systems that are truly used in the synthesis of natural products and structural modification.This condition may caused by（1）The complicacy of the main effect components in natural products and traditional Chinese medicine are challenging for asymmetric hydrogenation,and the current research is mostly focused on the structure with less sterically hindered（alkyl,phenyl,etc.）substituents;（2）Isoquinoline substrates are basic and the coordination ability of nitrogen atoms is relatively strong,which often deactivates the catalyst and cannot obtain high catalytic activity and high enantioselectivity.In order to more accurately apply asymmetric hydrogenation technology to the synthesis and structural modification of active ingredients of traditional Chinese medicines and natural products,this article has carried out two parts of work:（1）Synthesis of chiral 1-hydrosterically substituted tetrahydroisoquinoline alkaloids;Chiral 1-substituted tetrahydroisoquinoline,as the backbone of the dominant class of drugs,is an important building block for many traditional Chinese medicine effect molecules,natural products,and chemical drugs.Most of the existing catalytic systems are only suitable for alkyl substituents（methyl,ethyl）and aryl substituents with less steric hindrance at the C1 position,and for substrates with greater steric hindrance（tert-butyl,tert-amyl and adamantyl,etc.）have not been reported.In this study,27 1-large hindered（tert-butyl,tert-amyl,adamantyl,etc.）substituted dihydroisoquinolines were synthesized specifically,and Ir/^t-Bu-ax-Joisphos complexes were used as a catalyst（1.0 mol%）,40%HBr aq.（0.1 eq.）as an additive,the asymmetric catalytic hydrogenation reaction of the above substrate was conducted at 50°C and50 atm H₂,and 27（S）-1-Substituted tetrahydroisoquinoline derivatives were obtained（85%-95%yield,74%-99%ee）.At the same time,this catalytic system was applied to the synthesis of tetracyclic alkaloid（S）-dimethylxylopinine（85%yield,96%ee）which is the derivative of（S）-xylopinine.Developed a new way in the field of high-efficiency synthesis and structure modification of Chinese medicine effect components.（2）Synthesis of chiral 3-substituted tetrahydroisoquinolines alkaloidsGreat application prospects of pharmacy were founded by the study of Chiral 3-substituted tetrahydroisoquinolines.Unlike 1-substituted tetrahydroisoquinolines,chiral 3-substituted tetrahydroisoquinolines have a single preparation method.Due to the basicity and the strong coordination ability of the nitrogen atom in the structure,the preparation of chiral 3-substituted tetrahydroisoquinolines through the asymmetric hydrogenation reaction of 3-substituted isoquinoline salts is very challenging,and the lack of preparation method severely restricts the pharmaceutical research of such framework compounds.This study designed and synthesized19 3-arylisoquinolines,using 3-arylisoquinoline hydrochloride as the substrate,and using the bromine bridged dinuclear cation complex formed by Ph-ax-Josiphos and metal iridium as the catalyst.With acetone as the solvent,under 30℃and 20 atm hydrogen conditions,19 chiral3-aryltetrahydroisoquinoline derivatives were successfully synthesized with yields（88%-96%）and enantioselectivity（68%-97%ee）.At the same time,3-phenylisoquinoline was hydrogenated on a gram scale,with a separation yield of 93%and an enantioselectivity of 96%ee.This study expands the library of chiral 3-aryltetrahydroisoquinolines and provides an important technical reference for the in-depth study of the effective components of traditional Chinese medicines containing such compounds.