Stereoselective Synthesis Of The Spiro [pyrrolidin-3,3'-oxindoles] Ring And Exploration Of The Synthesis Of Spirotryprostatin Analogs

3,3'-pyrrolidine indolone spiro ring is the core structure of many molecules with important biological activity,and it has a good application prospect in the research and development of new indole drugs.And spirotryprostatin is a natural product alkaloid with this spiro ring structure and has anticancer activity.Therefore,the study on the stereoselective synthesis of 3,3'-pyrrolidine indolone spiro ring and the alkaloid analogues is of great significance for the development of related drugs and the development of organic synthetic chemistry.This paper reviews the synthesis methods of Spirotryprostatin compounds,to summarize the experience,a series of studies on the synthesis of spirocyclic indole were carried out using metal salts catalyzed asymmetric Mannich reaction.And based on the structure of the spiro ring,the synthesis of the diketopiperazine skeleton was investigated.The effect of reaction conditions on the stereoselectivity of spiro ring construction and yield was investigated,such as the type of metal salt and ligand,the reaction solvent,the type and amount of base in the reaction,the amount of catalyst,the reaction temperature,and the ratio of aldehyde in the reaction.The factor shows,Zinc acetate and ligand 2,2'-diaminobiphenyl is relatively good catalyst;When base is added,the catalyst has excellent stereoselectivity in aprotic weak polar solvents?as dioxane?;The type of alkali is preferably inorganic alkali,with 0.5 equivalent of potassium carbonate as the best dosage;The best catalyst usage is 5%;The temperature is preferably 40?.The optimal amount of aldehyde is 3 times the equivalent of substrate.Under these conditions,?2'S,3R?-3,3'-pyrrolidine indolone spiro compounds can be synthesized selectively.To verify this method in the substrate expansion,after 16 kinds of substituent spiro compounds were successfully synthesized,it was found that the effect is good for the electron donating aromatic aldehyde?D.r.>94%,the highest yield can reach 89%?;When the same substituent is in different positions,the effects of para,meta and ortho positions are sequentially weakened;it also has good applicability to fatty aldehydes.The structure of the spiro ring product was characterized by ¹HNMR,¹³CNMR,COSY,NOESY,HR-MS,HPLC,and the relative spatial configuration of the spirocyclic products was verified..This method will provide a guiding basis for the efficient synthesis of indolinone spirocycles with specific configurations,and provide a more practical and efficient method for the high-throughput screening of spirocyclic skeleton small molecule drugs and subsequent full synthesis.In the preliminary exploration of the synthesis of analogues in this paper,it was found that among a series of representative amide condensation reagents,BOPCl has a good effect on the condensation of spiro compounds with a certain steric hindrance.