Construction Of Nitrogenous Bioactive Molecular Skeletons Via Multicomponent Reactions

The skeletons of nitrogenous bioactive molecules, especially chiral nitrogenous heterocyclicstructural skeletons are prevalent in many natural products and artificial pharmaceuticals. Moreover,these skeletons constitute key intermediates with widespread application in organic synthesis. Therefore,it is urgent to develop facile and efficient methods to synthesize such skeletons, while catalyticasymmetric multicomponent reactions serve as a type of concise and effective approach to build upchiral heterocyclic scaffolds. In this dissertation, we focused on chiral phosphoric acid-catalyzedasymmetric multicomponent reactions to efficiently construct chiral skeletons of nitrogenous bioactivemolecules. To this end, we have carried out a series of research work, which are briefly described asfollows.Firstly, we have established electron-deficient alkyne-involved catalytic asymmetricthree-component1,3-dipolar cycloadditions, which provide novel2,5-dihydropyrrole derivatives withpotential bioactivities in perfect enantioselectivities of up to>99%ee. And we have found severalbioactive compounds through the preliminary evaluation on the cyctotoxicity of these chiral2,5-dihydropyrroles. This approach not only represents the first example of catalytic asymmetric1,3-dipolar cycloaddition involving carbon-carbon triple bond dipolarophiles, but also provides a facilemethod to access chiral2,5-dihydropyrrole architecture.Secondly, we have developed isatin-involved catalytic asymmetric three-component1,3-dipolarcycloadditions, which construct biologically important spiro[pyrrolidin-3,2′-oxindole] scaffold withcontiguous quaternary stereogenic centers in excellent stereoselectivities (up to>99:1dr,98%ee). Thisprotocol represents the first example of catalytic asymmetric1,3-dipolar cycloadditions involvingazomethine ylides generated in situ from unsymmetrical cyclic ketones, providing a new way tosynthesize spiro-scaffolds with multiple stereogenic centers.Thirdly, we have developed an organocatalytic asymmetric three-component Povarov reactioninvolving2-hydroxystyrenes to access structurally diverse cis-disubstituted chiral tetrahydroquinolinesin high stereoselectivities of up to>99:1dr and97%ee. Besides, this protocol also provides an easyaccess to tetrahydroquinolines with chiral quaternary stereocenters upon using α-alkyl2-hydroxystyrenes as substrates.Finally, we have developed microwave-assisted multicomponent reactions and tandem reactions toachieve substrate-controlled chemoselective synthesis of5,6,7-triarylpyrido[2,3-d]pyrimidin-4-ones,efficient synthesis of3-aminohexahydrocoumarins, and diversity-oriented synthesis of dipeptide mimetic compounds embedded with bioactive molecular skeletons. These approaches have advantagesof wide substrate scope, high chemoselectivity and diastereoselectivity, atom economy, short reactiontime, high yield and easy operation. The bioassay on their in vitro cytotoxicity has disclosed severalcompounds possessing significant cytotoxicity.