Synthesis Of Amino Acid And Cinchona Base Catalyst And Its Application In Asymmetric Mannich Reaction

Chiral ?-amino compounds are one of the most important organic compound.They are not only important in organic synthesis chemistry,but also have been paid attention in the field of pharmaceutical chemistry because of their potential physiological and pharmaceutical activities.Asymmeric Mannich reaction is one of the simple methods to construct chiral ?-amino compounds.In this thesis,we focus on the synthesis of bifunctional chiral organic catalysts and their application in asymmetric Mannich reaction.This thesis contains four chapters as following:1.We synthesized a series of bifunctional phase transfer catalysts derived from L-tert-leucine and successfully applied them to the Nitro-Mannich reaction of isatin derived ketimine with ?-arylnitromethane for the first time.The reaction has good universality.Different substituted ?-arylnitromethanes and N-Boc ketimines can provide the corresponding products in high yield(85-99% yield)with high enantioselectivity(83-95% ee)and diastereoselectivity(79:21-97:3).Mechanism control experiments show that urea structure and quaternary ammonium center play an important role in the activation of substrate and stereochemical control of reaction.Compared with previous studies,this work can effectively improve the reactivity and stereoselectivity of isatin derived ketimines containg subtstituents at C-6 and C-7positions.2.We successfully synthesized a new kind of bifunctional thiourea catalyst derived from hydroquinine as the skeleton and chiral amino alcohol as the hydrogen bond donor,and applied it to the reaction of long-chain nitroalkanes with isatin-derived ketimines.It was found that when the amino alcohol was l-phenylglycine,the addition product had high enantioselectivity(78 – 99% ee)and diastereoselectivity(66:34-99:1).Through the derivatization of the product and the gram reaction,the applicability and practicability of this reaction are proved.To our knowledge,this is the first example of exploring the stereoselectivity and diastereoselectivity of the asymmetric Nitro-Mannich reaction with long-chain nitroalkanes and obtaining satisfactory experimental results.3.A novel bifunctional catalyst was synthesized by introducing p-fluorophenyl into cinchona alkaloid derived thiourea.We have successfully synthesized a series of4-azaindoles with high enantioselectivity(69-95% ee)and high diastereoselectivity(60:40->99:1 dr)through the intramolecular asymmetric Mannich reaction catalyzed by this novel bifunctional chiral phase transfer catalyst derived from cinchona alkaloids.The derivatization of the product and the gram reaction prove that the reaction has applicability and practicality.4.We applied the bifunctional thiourea catalyst derived from cinchona alkaloids to catalyze the asymmetric oxa-Mannich reaction between isatin-derived ketimine with 3-chloro-1-propanol,and successfully synthesized a series of chiral chain N,O-ketal with high enantioselective(66-95% ee).On this basis,through intramolecular nucleophilic substitution and cyclization,a series of chiral1,3-oxazinones were synthesized,and the enantioselectivity could be maintained.