Applications Of Organic Catalysts Derived From Quinine And Amino Acids In The Mannich Reaction Of Oxa And Aza

Chiral N,O-or N,N’-ketals are important components of many bioactive drug molecules.Therefore,the development of a simple and efficient method for the synthesis of chiral N,O-,N,N’-ketals has become one of the research focuses.It is well known that the asymmetric addition of alcohols or amines to imines derived from aldehydes and ketones is the most direct and simple method for the synthesis of chiral N,O-or N,N’-acetals(ketals).In this thesis,we synthesized a series of bifunctional catalysts from quinine and amino acids,and successfully applied them to the asymmetric addition alcohols and amines to ketone derived imines.The specific work is as follows:(1)A series of bifunctional chiral catalysts derived from quinine as the basic framework have been successfully used in the asymmetric oxa-Mannich reaction of trifluoroacetophenone-derived imines and aliphatic alcohols.Through screening,the optimal reaction conditions were determined as follows: 5 mol% quinine derived squaramide as catalyst,1:1 mixture of methanol and isopropyl ether as solvent,and-30℃,4? molecular sieve as additive.Under the optimal conditions,a series of chiral N,O-ketals were synthesized by expanding the substrates.The yields of the correspondding products were 90-94% and the ee values were 54-92%.The results of gram order reaction showed that the enantioselectivity and yield of the product did not decrease significantly.(2)A series of bifunctional chiral urea catalysts were synthesized from L-tert-Leucine by derivatization,and they were successfully applied to the asymmetric aza-Mannich reaction of arylamines with isatin-derived ketimines.Through the screening of solvent,temperature,catalyst and its loading,the optimal reaction conditions were determined as-20℃,MTBE as solvent and 15 mol% catalyst loading.Under the optimal conditions,a series of chiral 3-substituted 3-amino-2-oxoindole derivatives with N,N′-ketal structure were synthesized by expanding the reaction substrates.The yields of the corresponding products were 90-99%,and the ee values were 50-93%.The results of gram order reaction show that the enantioselectivity can be maintained.According to the chiral configuration of the products,a possible transition state model was proposed.