Study On The Synthesis Of Chiral Spirooxindoles Catalyzed By Squaramides

The structural unit of chiral spirooxindoles compounds widely present in the natural products,and many of them are with high biological activities.Given the potential medicinal value of such compounds,the development of new synthetic methods for constructing chiral spirooxindoles is of great importance.Because of the strong nucleophilic ability,the reaction with 3-isothiocyanate oxindole as raw material has become a hotspot.In order to study the applications of 3-isothiocyanate indolinone in the synthesis of spirooxindole compounds,the following aspects of the reaction was explored.First,the Michael addition/cyclization cascade reaction of 1-benzyl-3-isothiocyanato oxindole with N-phenylmaleimide was investigated.Based on the screen of catalyst,solvent,temperature and catalyst loading,the optimum reaction conditions were determined as using 5 mol% of catalyst at 0 ?C for 24 h,with dichloromethane as solvent.Then the substrate scope was investigated,the corresponding products were obtained with excellent yield with excellent stereoselectivity(up to 99% yield,> 99: 1 dr,90% ee).The configurations of the target products were assigned as(2R,3R,4S)according to single crystal X-ray diffraction analysis.According to the experimental conditions and previous literature,we propose a possible mechanism for this reaction.In order to further study the reaction,the reaction product was further derivatized,and the corresponding product was obtained in 93% yield with high stereoselectivity(87: 13 dr,85% ee).Then the synthesis of a spirooxindole with three spirocyclics through 3-isothiocyanate indolinone and benzylidene succinimide was studied.The screening of reaction conditions was conducted,and best result was obtained when the reaction was performed with 20 mol% of catalyst in dichloromethane at room temperature.The stereoselectivity was high(up to 91: 9 dr,99% ee),however the yield was relatively low.Finally,the Michael addition/cyclization reaction bewteen chalcone and 3-isothiocyanate indolinone was invesgated.By screening conditions,the reaction was carried out in dichloromethane at-20 ?C for 12 h.The desired spirooxindole was obtained in 99% yield with >99: dr and 97% ee.