Synthesis Of Five-Membered Nitrogen-Containing Hetercycles By 1,3-Dipolar Cycloaddition With Isocyanoacetates

Nitrogen-containing hetercycles exist as core skeletons in many natural products,drug molecules and organic synthetic intermediates.Most of them exhibit biological activities.Studies on the synthetic methods for these compounds are of great significance for the development of medicine,pesticide,materials and chemical industry.Isocyanoacetate is one of most important isocyanides.Due to its acidic ?-CH fragment,it is easy to form 1,3-dipoles by deprotonation under alkaline conditions to participate in the reaction.The 1,3-dipolar cycloaddition reaction between isocyanoacetates and various dipoles is an important way to synthesize nitrogen-containing heterocyclic compounds.The first part of the thesis is about the asymmetric synthesis of hetero-substituted pyrrolidine derivatives.With the combination of cinchona-derived aminophosphine precatalyst and Ag(I)employed as a binary catalyst system,the 1,3-dipolar cycloadditions of isocyanoacetates with ?-sulfur,-nitrogen and-oxygen substituted methyl acrylate were realized.The isolated pyrroline derivatives can be converted into the corresponding pyrrolidines in quantitative yields by simple reduction without erosion of enantiopurities.According to this method,one or two quaternary centers were constructed in one step,and a series of hetero-containing pyrrolidine derivatives were obtained with high yields and excellent enantioselectivities(up to 99% yield and 99% ee).The second part of the thesis is about the asymmetric synthesis of spiropyrrolidine derivatives.The 1,3-dipolar cycloaddition reaction of ?-substituted isocyanoacetates with aurones was successfully realized with the aid of chiral silver(I)complexes at 0 oC,accessing a number of spiropyrrolidine derivatives in excellent yields and stereoselectivities(up to 99% yield,>20:1 dr,and 97% ee).Nevertheless,the scope with respect to ?-unsubstituted isocyanoacetates with aurones resulted in a significant reduction of yield due to the formation of 2,3,4-three substituted pyrroles through the ring opening/aromatization sequence.However,the asymmetric cycloaddition could also be achieved by lowering the reaction temperature,affording the corresponding spiropyrrolidines with good yield.The third part of the thesis is about the transition-metal-free catalytic synthesis of polysubstituted pyrrole derivatives.At present,the pyrrole synthesis involving isocyanides is mostly catalyzed by heavy metal catalysts such as silver,copper and rhodium,and some reactions also need to be carried out at high temperature,which greatly limit the application of this kind of reaction.In this work,a Na OH catalyzed method to produce polypyrrole through a cyclization/ring opening/isomerization sequence has been developed.This reaction is economical and environmentally friendly without the involvement of metal catalysts.Owing to the operational simplicity,synthetic efficiency,atom economy,mild reaction conditions,and wide substrate scope,the 1,3-dipolar cycloadditons with isocyanoacetatrs to synthesize five membered nitrogen-containing heterocyclic compounds would provide an important support for the synthesis,structural modification and drug discovery of these compounds.