Applications Of Asymmetric Organocatalysis In The β-C-H Functionalization Of Aldehydes And The Synthesis Of Piperidino[1,2-α]indoline Derivatives

On the basis of the concepts of asymmetric organocatalysis and the contemporary organic synthesis in "Green Chemistry", the research project of "Methodological studies on C-H functionalization and cascade reactions based on asymmetric organocatalysis" has been selected in this thesis, and two parts of work "merging organocatalysis with transition metal catalysis and using O2as the oxidant for enantioselective P-C-H functionalization of aldehydes" and "organocatalytic asymmetric Michael-Michael cascade for the construction of highly functionalized N-fused piperidinoindoline derivatives" has been finished. This thesis is composed of three parts as follows:Chapter1:In the introduction section, we choose the fundamental concept of "Chirality" as the starting point and explained the demand of chiral drug in our daily life from the perspective of pharmacology. The development situation of asymmetric organocatalysis has also been illustrated. Combined with the theme of the contemporary organic synthesis in "Green Chemistry", we selected "Methodological studies on C-H functionalization and cascade reactions based on asymmetric organocatalysis" as the research project in this thesis. Then, we classified and summarized various cascade reactions based on asymmetric organocatalysis and retrospected the development course of this field with some classic examples. It can be concluded that developing new asymmetric cascade reactions for the quick construction of complex molecules with multiple chiral centers is still the theme of asymmetric organocatalysis. In addition, dual catalysis based on the asymmetric organocatalysis is also a hot topic in the field of asymmetric catalysis, and usage of organocatalytic dual catalysis to realize the internal integration of asymmetric organocatalysis and its cross-complementary with other areas will provide more room and new ideas for the extension of organocatalysis and the solution to some challenging problems (e.g., asymmetric C-H functionalization and controlled synthesis of diastereomers etc.) faced by current organic chemistry.Chapter2:Based on the review of the concept of C-H functionalization and its meaning, and the C-H functionalization based on asymmetric organocatalysis and Saegusa oxidation, we developed a chiral amine-Pd(OAc)2co-catalyzed Saegusa oxidation/Michael cascade reaction for enantioselective β-C-H functionalization of aldehydes. This method overcomes the "Oxidant Problem" existing in the field of enantioselective P-C-H functionalization of aldehydes and avoids the use of some stoichiometric oxidant (e.g., IBX and DDQ) by employing O2as an economical and green oxidant. The cascade reaction combines enamine activation with iminium activation via Saegusa oxidation and successfully achieves enantioselective β-C-H functionalization of aldehydes. This is the first use of Saegusa oxidant in the field of asymmetric catalysis. Also, this method is a successful example for solving challenging problems in organic chemistry by merging organocatalysis with transition metal catalysis.Chapter3:Based on the review of the piperidino[1,2-a]indoline scaffold and its major synthetic method, the asymmetric organocatalytic cascade reactions based on2-oxindole derivatives and research status of3-oxindole derivatives, and in view of the importance of piperidino[1,2-a]indoline scaffold in natural products and biologically active molecules and limited methods for its asymmetric catalytic synthesis, we successfully developed a new bifunctional thiourea catalyzed asymmetric Michael/Michael cascade reactions to construct complex polysubstituted piperidino[1,2-a]indoline derivatives containing four contiguous stereocenters (one chiral tetrasubstituted carbon center) on the basis of our previous work associated with3-oxindole chemistry. With regard to the indolin-3-one derivatives which need to be explored, it is the first successful example which applies indolin-3-one derivatives as the substrates in asymmetric cascade reactions to construct complex chiral molecules with good results. At the same time, it would be complementary to the well studied transformations of2-oxindoles chemistry.