Study On The Synthesis Of Chiral Spirooxindoles Catalyzed By Squaramides

Chiral spirooxindole is a common molecular skeleton that constitutes a natural product or a drug,therefore most of the chiral spirooxindole compounds have high biological activity and are also a hotspot in asymmetric synthesis.Because the molecular skeleton of these compounds has good application in the pharmaceuticals,it is the direction that scientists devote to construct the chiral spirooxindole compounds in a simple and efficient way.Due to the active nucleophilic ability of 3-hydroxyoxindole,it is an important synthetic route to synthesize chiral spirooxindoles by asymmetric tandem reaction with this compound as substrate.The application and reactivity of 3-hydroxyoxindole in the synthesis of spirooxindole compounds were investigated from the following two aspects.The Michael addition/cyclization tandem reaction between 3-hydroxyoxindole and?,?-unsaturated succinimide was studied.Initially,some Michael receptors were screened to obtain the best unsaturated amide with the reaction of3-hydroxyoxindole,which was used as template reaction.The optimum conditions for the reaction were determined by the catalyst type,solvent,temperature and catalyst loading:10 mol%squaramide catalyst was reacted in dichloromethane for 48 h at–10 ~oC.Subsequently the generality of this reaction was studied.Most of the reactions were obtained in high yield with excellent stereoselectivity(up to 89%yield,>95:5 dr,99%ee).The configurations of the target products were assigned as(2S,3R)according to single crystal X-ray diffraction analysis.According to the reaction results and the published literature,the possible reaction mechanism was proposed.In order to further explore the proposed reaction mechanism,two control experiments were performed to provide evidences.Then the Michael addition/cyclization of 3-hydroxyoxindole with benzylidene malononitrile for synthesis of spirooxindole derivatives was investigated.The reaction conditions were evaluated,and finally get the best reaction conditions:the reaction was carried out in dichloromethane using 5 mol%squaramide catalyst at–10°C.Although the reaction has an excellent yield(up to 99%),but the stereoselectivity of the product is undesirable.