Enantioselective Synthesis Of Spirooxindoles

Chiral 3,3'-pyrrolidinyl spirooxindoles are a very special class of heterocycles,which are the basic structure skeleton of many alkaloids and biologically active molecules.These molecules have drawn an attention to organic chemists and medicinal chemists due to their unique chemical architecture and promising biological activities.Therefore,it's of significance to develop new methodologies for the efficient asymmetric synthesis of these compounds.Recently,the cyclization of methyleneindolinones has emerged as a powerful tool to construct indole-fused heterocyclic compounds or spirooxindoles.Cycloaddition reaction has been widely used in the synthesis of cyclic compounds,and 1,3-dipole cycloaddition reaction is an important method for the synthesis of five-membered heterocycles.In these studies,enolates,such as 1,2-dipole enolates,1,3-dipole enolates or 1,4-dipole enolates were briefly generated as reaction intermediates for the cyclization reaction.In particular,isocyanoacetates were introduced as 1,3-dipole enolate intermediates in the synthesis of five-membered heterocycles.To synthesize biologically active alkaloids containing chiral 3,3'-pyrrolidinyl spirooxindoles,it is necessary to further explore the synthesis of such spiro structures and develop more efficient synthetic methods.Herein,we report a highly enantioselective formal [3+2] cycloaddition reaction of ?-unsubstituted and ?-alkyl isocyanoacetates with less active methyleneindolinones catalyzed by a chiral silver(I)complex derived from the Lewis acid silver oxide and Br?nsted base quinine derivative to construct the basic skeleton of chiral 3,3'-pyrrolidinyl spirooxindoles.Thus we have developed the first formal [3+2] cycloaddition reaction of ?-unsubstituted and ?-alkyl isocyanoacetates with less active protecting-group free methyleneindolinones under mild reaction conditions,in which methyleneindolinones as Michael acceptors reacted with ?-unsubstituted and ?-alkyl isocyanoacetates as 1,3-dipole enolate intermediates to synthesize the basic skeleton of chiral 3,3'-pyrrolidinyl spirooxindoles.A variety of optically enriched 3,3'-pyrrolidinyl spirooxindoles were obtained in excellent yields,diastereoselectivties and enantioselectivities(up to 99% yield,> 20:1 dr and 99% ee).In this study,11 methyleneindolinones and 5 isocyanoacetates substrates were prepared,and 17 desired compounds with chiral 3,3'-pyrrolidinyl spirooxindoles were synthesized under established optimal reaction conditions.The structures of the target molecules were characterized and verified by nuclear magnetic resonance spectroscopy(NOE,~1H NMR and ~13C NMR),high resolution mass spectrum(HRMS),high performance liquid chromatography(HPLC)and/or X-ray crystallographic analysis.The high efficiency of this process,coupled with operational simplicity,makes it a simple and effective method for the synthesis of alkaloids containing chiral 3,3'-pyrrolidinyl spirooxindole moiteties.