Study On The Organocatalyzed Stereoselective Synthesis Of The Spiro [Pyrrolidin-3,3'-oxindoles] Ring

The spiro[pyrrolidin-3,3'-oxindoles]ring is characteristic of many natural or unnatural spirooxindolinyl compounds with very useful biological activities,especially the highly desirable anticancer activity,which is mainly reflected on inhibition of cell mitosis,induction of DNA cleavage,induction of apotosis in tumor cells,inhibition of microtubule polymerization etc.In the past twenty years,the synthesis of these compounds has attracted the interest of many experts and scholars.Based on the current research status of spirooxindole compounds,a series of studies have been carried out on the synthesis of the spiro[pyrrin-3,3'-oxindoles]ring via organocatalyzed asymmetric Mannich reaction in this thesis.In this thesis,the synthesis of spiro[pyrrolidin-3,3'-oxindoles]ring based on Mannich reaction was studied.The effects of reaction conditions?such as catalyst,solvent,stoichiometry,time and temperature?on the stereoselectivity and yield of the synthesis of spiro[pyrrolidin-3,3'-oxindoles]ring were investigated.The screening experiment of catalyst shows the best stereoselective catalyst is bifunctional Takemoto's catalyst in a series of common type hydrogen bond induced organic catalysts.The diastereoselectivity of this thiourea catalyst can reach more than 97%in the spirolization reaction in 1,4-dioxane.The study of steric configuration shows the configuration of main product catalyzed by Takemoto's catalyst is?3R,2'R,5'S?.Single factor experiments showed that the reaction stereoselectivity in polar solvents was low,but the yield was high,the reaction stereoselectivity was high in aprotic non-polar solvent,but the yield was low.The higher the temperature,the worse the selectivity,the higher the yield,50^oC was the best selective effect.The longer the reaction time,selectivity changed little,a slight increase in yield.The optimal reaction time was 48 h.Increasing the dosage of aldehyde can increase the reaction yield without affecting the stereoselectivity.Substituent effects showed that there was little relation between the substituent electronegativity of benzaldehyde and the reaction yield,but the steric resistance effect was closely related to the stereoselectivity and yield.The stereoselectivity of ortho and meta substituent was better than para substituents,the corresponding yield was better than meta and para substituents.In this thesis,the compounds were characterized by ¹H NMR,¹³C NMR,COSY,NOESY,LC-MS,HR-MS,HPLC,X-ray,and the absolute stereo configuration of spirooindole was established.