Research For The Asymmetric Organocatalytic Construction Of 3,3'-pyrrolidinyl-dispirooxindoles

ObJective:Spirooxidation of indole skeleton is a very special skeleton structure,but also a very important skeleton structure,because it exists in many natural products and bioactive compounds,has important medicinal value,showing good anti-cancer anti-fungal anti-virus and other biological activity,it has become one of the most attractive synthetic targets.Organic fluorine compounds are widely used in chemistry,biology,medicine,materials science and other disciplines,in the field of pharmaceutical chemistry,the introduction of fluorine atoms into biologically active molecules can effectively enhance the affinity,lipophilicity,metabolic stability,bioavailability and other properties.Taking into account the importance of containing fluorine atoms and spirooxoindole skeletons,it is considered necessary to develop such compounds containing both fluorine atoms and spirooxoindole skeletons which is believed that such structures will contribute to the study of active pharmaceutical ingredients and human health.However,there are few methods for synthesizing these complex spirooxindoles therefore,the development of rapid,high selectivity,high efficiency and environment-friendly method for the synthesis of drug molecules has important practical significance.Methods:?1?The azomethine ylide compounds containing a trifluoromethyl group is obtained by condensation of trifluoroethylamine and isatin.?2?The methylindolone compounds.are synthesized by ethyl?triphenylphosphoranylidene?acetateand and isatin.?3?The organocatalysts were applied to 1,3-dipolar cycloaddition reactions of azomethine ylide and methylindolones at room temperature.the types and equivalents of the catalysts,the effects of the reaction solvent on the yield,reactivity and enantioselectivity were examined in turn and the optimal reaction conditions were obtained.?4?Based on the optimum reaction conditions,the application range of the substrates azomethine ylide and methylindolone was extended to obtain a series of spirooxoindole compounds containing fluorine atom.Results:The optimal reaction conditions were obtained:Catalyst VIII?5mol%?,temperature is room temperature,the solution was chloroform?1.0ml?,azomethine ylide was 1.0 eq,the methylindolone was 1.5 eq.A series of spirooxoindole compounds with potentially important bioactivity containing fluorine atoms have been constructed with highly efficient stereoselectivity according to the optimal reaction conditions,the reaction leads to the formation of four contiguous stereogenic centers,including two adjacent spiro quaternary stereocenters.The yield was 84%-99%,diastereomeric and enantioselective selectivity are as high as>20:1 dr and>99%ee.The effects of steric hindrance and electron effect on the reaction substrate were studied,the utility of this reaction was also explored,the reaction was subjected to gram scale amplification and showed that the reaction could be carried out on a gram scale without significant yield,diastereoselectivity and reduced enantioselectivity.The absolute structure of the product was determined,and the chiral center was confirmed to be?2'R,3'R,4'S,5'S?.Conclusion:In this paper,the azomethine ylide and methylindolone were used to the asymmetric racemic[3+2]cycloaddition reaction in the presence of the squaramide catalyst to efficiently introduce the CF₃ group into the highly functionalized 3,3'-pyrrolidinyl-dispirooxindoles.Under the mild conditions,higher reaction activity and stereoselectivity control were achieved,which could be a promising candidate for the study of chemical biology and drug active ingredients.Asymmetric catalysis is an effective method for the construction of spirooxindole compounds,significant progress has been made in the past few years,highly reactive and stereoselective synthesis of important active spirooxindole compounds under asymmetric conditions can be achieved by asymmetric catalysis,due to its simple,mild and environmentally friendly reaction conditions are destined to be a strong concern over the next period of time,however,in many cases,the amount of catalyst is very large and the range of application of the substrate is limited,which means that it has a lot of room for development in the future.