Studies On Asymmetric Reactions Of Nitrogen-Containing Functional Group-Modified Pyrazolones And Oxindoles

Aza-quarternary carbon centers of pyrazolone and oxindole skeletons are the structural characteristics of many drug lead compounds and active natural products.Therefore,the diverse derivatization of these two pharmacophore heterocyclic structures has important value in organic synthesis and drug development.In recent years,a series of novel aza-quarternary carbon centers of pyrazolone and oxindole with potential biological activity have been reported by organic asymmetric catalytic strategies.However,in terms of the structural diversity of the target products and the effectiveness of the synthesis methods,the development of efficient and asymmetric methods to construct the stereochemically complex pyrazolone and oxindole motifs bearing aza-quarternary carbon centers remains a challenge.Therefore,the methodological study on the stereoselective synthesis of pyrazolone and oxindole derivatives containing azaquarternary carbon centers has important academic significance and potential application value.In this dissertation,a series of new methods for the efficient construction of novel azaquarternary carbon centers of pyrazolone and oxindole structures have been developed,and the following results have been obtained:(1)A new method has been developed for the efficient construction of the dispiro[pyrazolone-pyrrolidinethione-oxindole]structures bearing three continuous stereogenic centers.In the presence of quinine-derived squaramide catalyst,the asymmetric Michael addition/cyclization cascade reaction between 4-isothiocyanato pyrazolone and 3-alkylidene oxindole was carried out.A series of dispiro[pyrazolone-pyrrolidinethione-xindole]core structures bearing three contiguous stereogenic centers were synthesized with high stereoselectivity of up to 99%ee and more than 20:1 dr value.The results of cytotoxic activity evaluation showed that the target product 3ma exhibited high anticancer activity against MCF7.(2)A new method has been established to construct multi-nitrogen-containing spiro[pyrazolone-triazole]skeletons.In this method,4-isothiocyanato pyrazolones as bulding blocks for synthesis of triazoles were involved in[3+2]annulation with azodicarboxylates.In presence of bisquinine catalyst,a series of multi-nitrogen-containing spiropyrazolones were obtained with high enantioselectivity of up to 97%ee.(3)The asymmetric Michael addition reaction of 3-aminooxindoles to nitroolefins catalyzed by tartrate-based chiral guanidine was optimized.By screening the tartrate-derived chiral guanidine catalysts,it was found that the chiral guanidine catalyst with L-1phenylethylamine fragment exhibited excellent asymmetric catalytic performance for the above reactions.A series of chiral oxindole structures containing aza-quarternary carbon centers were constructed with high stereoselectivities.The stereoselectivity was up to 98%ee and more than 20:1 dr value.(4)A new method for the synthesis of spiro[thiazolethione-4,3’-oxindole]containing axially chiral styrenes has been developed.In the presence of quinine-derived squaramide catalyst,asymmetric parallel resolution of spiro[thiazolethione-4,3’-oxindole]was achieved via nucleophilic addition to 1-arylacetenyl-2-naphthols.The diastereoisomers of novel aminospiroxindoles bearing axially chiral styrenes were synthesized in excellent stereoselectivities.The stereoselectivity of the products was 94%,96%ee and more than 20:1 dr value,respectively.(5)A new method for constructing the chiral spiro[pyrrolidine-2,3’-oxindole]containing all-carbon seven-membered bridged biaryls has been developed.By using biaryl aldehydes and aminooxindole hydrochlorides as substrates,the chiral spiro[pyrrolidine-2,3’-oxindole]scaffolds bearing bridged biaryl axises were selectively synthesized in different catalytic systems through intramolecular[3+2]cycloaddition reactions.One of the diastereoisomer showed up to 96%ee and more than 16:1 dr.