Copper(?)-Catalyzed Asymmetric Intermolecular [3+2] Cycloaddition Reaction Of ?-substituted Iminoesters With Trisubstituted Trifluoromethyl Alkenes

Pyrrolidine compounds as core structural motifs were found in an array of natural products,pharmaceuticals and catalysts.The most powerful and straightforward synthetic method for the construction of pyrrolidine ring was the transition-metalcatalyzed asymmetric 1,3-dipolar [3+2]-cycloaddition of iminoesters with electrondeficient alkenes.The physical,chemical,and biological properties of organic molecules may be significantly modified by introduction of trifluoromethyl groups,therefore many pharmaceuticals contain trifluoromethyl group.However,there are few methods for the synthesis of these compounds.Therefore,the development of efficient methods for the synthesis of chiral pyrrolidines containing trifluoromethylated allcarbon quaternary stereocenters is currently the focus in organic chemistry.Based on the traditional methods for the synthesis of chiral pyrrolidine compounds,this thesis focus on the [3+2] cycloadditions of trisubstituted trifluoromethyl olefinic substrates,and after screening of the catalysts and conditions,we have successfully obtained chiral pyrrolidines with trifluoromethyl all-carbon quaternary stereocenters.Part I: Enantioselective Regiodivergent Synthesis of Chiral Pyrrolidines with Two Quaternary Stereocenters via Ligand-Controlled Copper(?)-Catalyzed Asymmetric 1,3-Dipolar Cycloadditions?-Substituted iminoester and ?-trifluoromethyl ?,?-disubstituted enones were screened as the substrates.Chiral pyrrolidines with two adjacent(aza)quaternary stereocenters including a CF3 all-carbon quaternary stereocenter were obtained.Interestingly,another pyrrolidines which with two skipped(aza)quaternary stereocenters could be also obtained by subtle change the chiral ligand.In the context of the [3+2] cycloaddition of iminoesters,no any example describing ligand-controlled enantioselective regiodivergent reactions has been reported thus far.We delivered the first example on enantioselective regiodivergent synthesis of two different chiral products from identical staring materials.The salient features of this cycloaddition include outstanding functional group tolerance,atom-economy,high regioselectivity(> 20:1 rr),diastereoselectivity(> 20:1 dr)and enantioselectivity(> 99% ee),promising scalability and allows for synthetic transformations to valuable compounds.Through kinetic experiments and DFT calculations,the reaction mechanism was rationalized.This strategy has a novel concept and opens up new ideas for the traditional [3+2] reactions,it also provides a new direction for the comprehensive utilization of the azomethionine ylide.Part II: Copper(?)-Catalyzed Asymmetric [3+2]-Cycloaddition of a-Substituted iminoesters with a-Trifluoromethyl a,b-Unsaturated EstersAlthough the transition metal catalyzed [3+2] asymmetric cycloaddition reaction of azomethine ylide with olefins has been reported a lot,while few reports have been reported on the synthesis of pyrrolidine compounds with polytetrasubstituted chiral stereocenters.After examined a series of reaction conditions,we successfully overcomed the low reactivity and sterically congested of the trisubstituted olefins and ?-substituted iminoesters.We reported an example of Cu(I)-catalyzed intermolecular [3+2] cycloaddition reaction of a-substituted iminoesters with a-trifluoromethyl a,bunsaturated esters.This novel reaction provided a facile access to pyrrolidines with two skipped(aza)quaternary stereocenters including a CF3 all-carbon quaternary stereocenter.A broad substrate scope was observed and high yields(up to 94%)with excellent diastereoselectivity(up to > 20:1 dr)and enantioselectivity(up to 98% ee).This work enriches the exampes of transition metal-catalyzed reactions of azomethine ylide with deficient olefines construction pyrrolidine compounds containing(aza)quaternary stereocenters at C2 and C4 positions.