Enantioselective Mannich Reactions Of Acetaldehyde With Isatin Ketimines Catalyzed By Chiral Primary Amines And Its Synthetic Application

The 3-amino-2-oxindole cores bearing the quaternary carbon center extensively exists in many important natural products,synthetic biologically active or pharmaceutical compounds,such as AG-041R used for the treatment of gastric ulcers.Herein,the stereoselective synthesis of the promising cores is one of the most important topics in the asymmetrical organic synthesis.Focused on this topic,the dissertation mainly concerns the studies on the asymmetric Mannich reaction between acetaldehyde and isatin ketimines catalyzed by chiral amines,and its synthetical application.Meanwhile,a class of corresponding 3-amino-2-oxindole cores bearing the quaternary carbon center are achieved,even including the formal enantioselective synthesis of AG-041R and aza-spiro oxindoles.This dissertation consists of the following four chapters:Chapter 1:General research development and application of chiral amine catalysts,progress on organic catalytic asymmetric Mannich reactions of acetaldehyde,and progress on the asymmetric synthesis of AG-041R.Chapter 2:The highly enantioselective Mannich reactions between acetaldehyde and isatin ketimines were investigated,by using chiral amines as catalysts.After the careful screening of catalysts,additive acids,water,solvents,reaction concentration,and reaction temperature,the best remsult of the desired Mannich product?80%yield and 92%ee?was obtained under the presence of chiral amine?20 mol%?,TfOH?10mol%?,3-NO₂PhCOOH?20 mol%?,acetaldehyde?40%aqueous solution,10 equiv?in THF at 0?.Under the optimal reaction condition,a series of chiral3-amino-2-oxindole cores bearing the quaternary carbon center were afforded in62-81%yields with 86-94%ee values.Then,the utilities of enantioselective Mannich reaction were demonstrated to fulfill the formal asymmetric synthesis of AG-041R,and even the chiral construction of aza-spiro oxindoles.Chapter 3:Conclusion and outlook.Chapter 4:Introduction of the detail procedures of experiments.This charpter mainly refers to the general information,general procedures for the synthesis of substrates and catalysts,general procedures of the enantioselective Mannich reaction and the detail procedures for the formal asymmetric synthesis of AG-041R and the chiral construction of aza-spiro oxindoles.Finally,identification data of correspongding newly-synthezied products were analyzed and provided.