Studies On The Synthesis Of Chiral Isoquinoline Compounds With Potential Medicinal Value

The isoquinoline structure skeleton is widely present in natural products such as traditional Chinese medicine and many drug molecules.Traditionally,tetrahydropalmatine have long been used to treat gastric and duodenal ulcers,dysmenorrhoea,rheumatism and cardiac arrhythmia disease.A large number of isoquinoline alkaloids,such as berberine,are widely used in clinical treatments such as anti-tumor,anti-inflammatory,anti-cardiocerebrovascular diseases,etc.Therefore,it is very important to explore green,economical and efficient synthetic methods for the construction of chiral isoquinoline compounds.At present,the construction method of isoquinoline structure skeleton is becoming more and more mature,but the problems can be listed as follows: the synthetic route is complicated,the starting material is expensive,the yield is lower,and the stereoselectivity is difficult to control.In this context,this article aims to develop a method for the synthesis of chiral isoquinoline compounds based on dipolar cycloaddition reactions catalyzed by small organic molecules.For the synthesis of chiral isoquinoline skeleton,the design is to activate phenylacetic acid in situ and react with organic catalyst to form acyl ion intermediate.Then,the enolamine induced by deprotonation is added to the isoquinoline dipolar imine to obtain isoquinolinopyrazole compounds with stereocenter.Through condition screening,under the activation of p-toluenesulfonyl chloride and N,N-diisopropylethylamine,using chiral isothiourea(BTM)as the catalyst,the reaction system showed excellent catalytic effect.The reaction can obtain the target compound with higher yield and excellent enantioselectivity,the product yield is basically higher than 80%,and the ee value is higher than 95%.The system can construct CC bond and CN bond at the same time by the "one-pot method".The reaction conditions are mild and easy to operate.Using cheap and easily available simple acid to replace the raw materials such as unsaturated aldehydes and unsaturated nitriles,which reduces the reaction cost.In addition,based on the dipolar cycloaddition reaction accompanied by dearomatization,we chose the imine that is easier to add.The target compound obtained by using the above catalytic system maintains the advantages of high yield and high stereoselectivity.The product yield is between 70% and 90%,and the ee value is higher than 90%.From the analysis of the results,we can speculate that this system is suitable for a wide range of substrates,and has the potential to become a universal method for constructing isoquinoline structure skeletons.In summary,a new method for the cyclization of isoquinoline dipolar imine and phenylacetic acid catalyzed by chiral isothiourea was developed in this paper,and 31 isoquinoline pyrazole compounds with various structures were obtained.When synthesizing individual compounds by this method,there is still a problem that the reaction rate and stereoselectivity cannot be taken into consideration,and it is expected that the problem will be solved by screening the reaction temperaturein the future.The cost of the reaction is low,and the operation is simple.It is especially suitable for the reaction of different dipolar imines with simple acids.It has strong innovation and great significance for the construction of chiral isoquinoline skeletons.We have made a preliminary assessment of the activity of these compounds.These compounds have certain anti-inflammatory activities,and more in-depth activity evaluation remains to be studied.