Studies On Chiral Imidazolethione Catalyst In Asymmetic Reactions And Synthesis Of Steroids

Organocatalysis has become a popular asymmetric catalytic technology with the advantages of mild reaction conditions,metal-free,the good stereoselectivity and atomic economy.Meanwhile,the design,synthesis of organocatalyst and the new catalytic mechanism get continuous development.Based on the superiority of thioamide on stereoselectivity and the wide applications of imidazolidone,a series of imidazolethione catalysts were designed and synthesized in this thesis.The catalytic activities in different activation mechanism were investigated and the application in synthesis of chiral drugs was carried out.1.Five common activation mechanisms including enamine,iminium,SOMO,hydrogen-bonding and phase-transfer catalysis were reviewed and summarized.The representative catalysts and asymmetric reaction were illustrated.2.The imidazolethione catalysts were applied to the“asymmetric a-oxyamination of aldehydes”reaction and the catalytic activity in enamine or SOMO mechanism were examined.A one-pot reaction system including oxidation of primary alcohols,followed by the asymmetric a-oxyamination of aldehydes,and then the reduction were developed.The corresponding products were obtained in good yields with high to excellent enantioselectivities,which solved the problems that low yields in one-pot reaction and relatively low stereoselectivity in short-chain aliphatic substrates.3.The reaction mechanism of the imidazolethione catalyzed a-oxyamination of aldehydes reaction was investigated by ESI-MS.The key enamine intermediate and Cu（II）-TEMPO complex were detected and structurally characterized by ESI-MS/MS,which proved the synergistic catalytic mechanism of asymmetric a-oxyamination of aldehydes reaction for the first time.4.The imidazolethione catalysts were applied to the“asymmetric Diels-Alder reaction”and the catalytic activity in iminium mechanism were evaluated.Both exo-and endo-isomers were obtained in high yields with good to excellent enantioselectivities.Stereoselective rDA reaction during the catalytic cycle was confirmed by deracemization experiments.The Endo and S-selectivity were verified by stability comparative experiments with DFT calculations,which could account for the low ee values in Diels-Alder reaction when using CH₃CN-H₂O as reaction medium.5.A preliminary attempt with using imidazolethione catalysts to synthesize steroid was performed.The enal and dione substrates were synthesized and steroid ring was constructed by one-step asymmetric Diels-Alder reaction.The ee value was better than 99%.This successful result promoted the applications of imidazolethione catalysts in the sythesis of other chiral drugs.