Design And Synthesis Of Novel Spiropyrrolidine Secondary Amine Catalysts And Asymmetric Construction Of Nitrogen Heterocycles

As a prevalent method for the current asymmetric catalysis,secondary amine organocatalysis has been widely used in the asymmetric construction of chiral nitrogen heterocycles and drugs with potential biologically activity during the past ten years.This dissertation mainly focuses on the design and synthesis of novel spiropyrrolidine secondary amine catalysts and secondary amine catalyzed novel cycloaddition reaction,providing efficient and rapid access to structurally diverse chiral nitrogen heterocycle compounds,including four aspects as fellows:1)design and synthesis of novel spiropyrrolidine secondary amine catalysts and its preliminary application;2)asymmetric construction of pyrazolone-pyridazinone compounds via[3+3]cycloaddition reaction catalyzed by chiral secondary amine;3)asymmetric construction of tetrahydrocarbazole derivatives via inverse-electron-demand Diels-Alder reaction catalyzed by chiral secondary amine;4)asymmetric construction of dihydrocarbazole derivatives via[4+2]cycloaddition reaction catalyzed by chiralsecondaryamine.In the first part,a series of novel chiral spiropyrrolidine secondary amine catalysts were designed and synthesized through a simple three-step transformation,based on the research of Cu-catalyzed asymmertic[3+2]cycloaddition of azomethine ylides to itaconic amide derivatives in our laboratory.The application of the catalysts was initially explored through the model reaction.Although it did not achieve the expected catalytic effect,it guided the direction of subsequent modification.In the second part,asymmetric[3+3]cycloaddition of isatin-cyclic azomethine imines with cinnamaldehyde derivatives via chiral secondary amine was described for the first time,affording the desired pyrazolone-pyridazinone compounds in high yields(53-91%),excellent enantioselectivities(86->99%ee)and moderate diastereoselectivities(1.1:1-3:1 dr).This method provides new opportunities for the enantioselective synthesis of polysubstituted pyrazolone-pyridazinone compounds.In the third part,a novel electron-deficient indole-dienes were devised,and an asymmetric inverse-electron-demand Diels-Alder reaction with enals catalyzed by secondary amine was developed.A variety of enantioenriched,multifunctionalized tetrahydrocarbazole derivatives were obtained in good yields(50-83%)with excellent stereoselectivities(10:1->20:1 dr,91-98%ee)through inverse-electron-demand Diels-Alder reaction for the first time.In addition,a novel electron-deficient pyrrole-dienes were also designed and synthesized,and the inverse-electron-demand Diels-Alder reaction of pyrrole-dienes with enals was explored initially,developing a novel route for the synthesis of chiral isoindole compounds.In the fourth part,asymmetric[4?2]cycloaddition reaction of 2-methyl-indolyl methylenemalononitriles with ?,?-unsaturated aldehydes was described,providing a straightforward access to structurally novel chiral dihydrocarbazoles as well as its analogous.Excellent enantioselectivities(94->99%ee)were obtained in the presence of chiral secondary amine catalytic systems.This process provides a practical way for subsequent application and derivatization of chiral dihydrocarbazole compounds in medicinal chemistry.