Application Of Quinine And Amino Acid Derived Catalysts In Asymmetric Michael Addition And Mannich Reaction

In recent years,organocatalysis has been widely applied in a variety of asymmetric catalytic reactions.Among them,asymmetric Michael addition cyclization is one of the most important synthetic strategies to construct chiral heterocyclic compounds with potential pharmaceutical activity.Asymmetric Mannich reaction is the most direct method to construct chiral β-amino compounds.These compounds have important applications in organic synthetic chemistry,and have attracted much attention in the field of pharmacy.Based on this,organocatalytic asymmetric Michael addition cyclization and asymmetric Mannich reaction were studied to explore the asymmetric synthesis of chiral spiro(indole-3,4’-pyran)-2-ones and α,β-diamino acid derivatives.The specific research content of this thesis is as follows:1.A series of chiral bifunctional squaramide catalysts derived from cinchona alkaloids were synthesized and successfully applied to the asymmetric Michael addition of isatin-derived malononitrile olefins with 1,3-indanedione.The optimal reaction conditions were determined by optimizing the catalyst,solvent,temperature,additive and substrate equivalent.The optimal reaction conditions were as follows: 10 mol%catalyst loading,tetrahydrofuran as reaction solvent,5(?) molecular sieve as additive,reaction temperature 45℃,reaction time 4 hours.Under the optimal reaction conditions,a series of spiro(indole-3,4’-pyran)-2-ones were synthesized by using a series of isatinderived malononitriles with different substituents.The results show that the asymmetric reaction has high yield(up to 95%)and good enantioselectivity(up to 82%).The chiral configuration of the product was determined as R by single crystal X-ray diffraction.The gram-scale reaction and the derivatization of the addition product prove the applicability of the asymmetric reaction.Based on the stereochemistry of the reaction product,a possible transition state model for the asymmetric catalytic reaction was proposed.2.A series of bifunctional chiral urea phase transfer catalysts derived from L-tert leucine were synthesized and successfully applied to the asymmetric Mannich reaction of isatin-derived ketimines with glycine schiff bases.The optimal reaction conditions were determined by optimizing the catalyst,solvent,temperature,additive and substrate equivalent.The optimal reaction conditions were as follows: 10 mol% catalyst loading,ether as reaction solvent,and reaction temperature of-40℃.Under the optimal reaction conditions,a series of isatin-derived ketimines and glycine schiff bases with different substituents were used to synthesize chiral α,β-diamino acid precursors.The results show that the asymmetric reaction has the advantages of high yield(> 96%),good enantioselectivity and diastereoselectivity(up to 96% ee and 95:5 dr).The application of the asymmetric catalytic reaction was proved by gram-scale reaction.