Asymmetric Synthesis Of Polysubstitutedγ-Nitroketones And Tetrahydrothiophenes Via Bifunctional Organocatalysis

Since the seminal work pioneered by List, MacMillan and Jacobsen groups, organocatalysis has become the third pillar in the realm of asymmetric catalysis. Over the past decade, fruitful achievements have been reached concerning the development of new activation modes, new catalysts, novel reaction design and catalysis-based natural products synthesis. As a continuing program to our group’s study in organocatalyzed efficient and green transformations toward functionalized molecules, this thesis mainly centered on the following four chapters involving binfunctional organocatalzyed generation of complex molecules such as polysubstituted y-nitroketones and tetrahydrothiophenes.Chapter1:This chapter firstly introduced the superior abilitiy of bifunctional organocatalysis toward improving synthetic efficiency and enhancing selectivities via synergetic activation of both reaction partners. Then the recent advances in the field of bifunctional organocatalyzed asymmetric synthesis over the past decade were described from the standpoint of active sites, with an emphasis on bifunctional Bronsted base-Bronsted acid and Lewis base-Bronsted acid bifunctional organocatalysis. Additionally, the advent and development in the field of bifunctional Lewis base-Lewis acid organocatalysis also was presented.Chapter2:This chapter firstly described the recent advances of primary amine-catalyzed asymmetric transformations involving sterically hindered carbonyl compounds and the organocatalyzed asymmetric synthesis of functionalized y-nitro carbonyl compounds, respectively. Then we presented a cinchona alkaloid-derived tertiary-primary diamine promoted cross-Michael addition of a-Me-β-nitroalkene to simple a, β-unsaturated enones for the synthesis of chiral functionalized y-nitroketones incorporating a terminal alkene moiety, whereby effectively combining nucleophilic activation of tertiary amine toward nitroalkene and iminium ion activation of primary amine toward enone. The products containing transformable nitro, carbonyl and terminal alkene group could be potentially applied to library synthesis of y-amino acid, nitrogen-containing heterocycles and other valuable molecules. Chapter3:This chapter firstly presented the recent progress on organcatalyzed asymmetric synthesis of polysubstituted tetrahydrothiophenes and bifunctional Bronsted base-Bronsted acid catalyst-promoted cascade reaction, respectively. Next we described a bifunctional squaramide catalyzed sulfa-Michael/aldol cascade reaction for the direct assembly of chiral trisubstituted tetrahydrothiophenes starting from commercially available2,5-dihydroxy-1,4-dithiane (dimer of mercaptoacetaldehyde) and chalcones. Notably, relatively inert chalcone derivatives were exploited as reaction partners for the first time in such type of cascade transformations. The chemistry features moderate to high yields, high diastereo-and enantiocontrol, relatively low catalyst loading and remarkable temperature effect upon the reaction efficiency, providing a direct, pratical, efficient and green access to chiral functionalized tetrahydrothiophenes.Chapter4:This chapter firstly described recent achievements for the asymmetric synthesis of functionalized molecules containing a trifluoromethyl group. Next we presented our efforts toward the development of a bifunctional squaramide catalyzed sulfa-Michael/aldol cascade reaction between1,4-dithiane-2,5-diol (dimer of mercaptoacetaldehyde) and β-aryl-p-trifluoromethylated enones for the synthesis of the trisubstituted tetrahydrothiophenes with a trifluoromethylated quaternary stereocenter. Pleasingly, this chemistry could be extended to enones activated by other electron-withdrawing group for the generation of chiral quaternary carbons.