Catalytic Asymmetric Synthesis Of Chiral Polycyclic Indoles And Chiral Amines

Chiral heterocyclic compounds and chiral amines are wildly found in natural products and biologically active molecules.Thus,development of efficient methods for the highly stereoselective synthesis of these compounds has always been important research.This dissertation focused on the efficient enantioselective synthesis of structurally important chiral polycyclic indoles,chiral?-gem-diaryl substituted ketimines,?,?-disubstituted chiral allylic amines,chiral 1,3-diamines,chiral?,?-disubstituted?-amino acids via transition-metal and chiral ligand complex catalytic strategies.1.Construction of chiral tricyclic indoles through a rhodium-catalyzed asymmetric arylation protocolPolycyclic indoles constitute an important class of fused heterocycles,among them,2,3-dihydro-1H-pyrrolo[1,2-a]indoles and-cyclopenta[b]indoles are especially attractive due to their vital roles in medicinal chemistry.We have developed a highly effective rhodium/diene catalytic system for the asymmetric 1,4-addition of arylboronic acids to?,?-unsaturated N1/C3-free 2-indolyl acrylates to afford the corresponding arylation products in high yields with excellent enantioselectivities.The method was applicable to benzofuran and benzothiophene derived acrylates as well as 3-indolyl acrylates.By taking advantage of the nucleophilic character of indole N1/C3 positions and the ester functionality,the synthetic utility of the arylation products in the flexible construction of four different indole-based tricyclic motifs through site-selective intramolecular cyclization was demonstrated.2.Synthesis of chiral?-gem-diaryl substituted ketimines and?,?-disubstituted chiral allylic amines through ligand-controlled site-selective reactionsRhodium-catalyzed asymmetric addition of organoboron reagents to electron-deficient olefins,imines,and carbonyl constitutes an important and powerful method for the construction of C-C bonds.?,?-Unsaturated imines represent an intriguing class of substrates,as they might be subjected to 1,4-addition and 1,2-addition simultaneously.We have developed a site-selective rhodium-catalyzed asymmetric 1,4-/1,2-addition of arylboronic acids to?,?-unsaturated cyclic ketimines through a ligand-controlled strategy.C₁-symmetric chiral diene and branched chiral sulfur-olefin were utilized to afford 1,4-and 1,2-adducts,respectively,which enabled efficient synthesis of various chiral?-gem-diaryl substituted ketimines and?,?-disubstituted chiral allylic amines in a highly regio-and enantioselective manner.Further product transformation provided easy access to various quaternary carbon-containing chiral amines and amino acid derivatives bearing multifunctional groups.We explored the bioactivity of the afforded products and found that the 1,4-adducts showed anti-tumor activity in human non-small cell lung cancer cells vitro experiment.We did more structural transformation and the best IC₅₀ of cell is 300 nM.More mechanism studies are underway.3.Construction of chiral 1,3-diamines through rhodium-catalyzed asymmetric arylation of cyclic N-sulfonyl aldiminesChiral 1,3-diamines constitute ubiquitous structural scaffolds in natural products,bioactive compounds as well as chiral ligands and catalysts.They have been widely used in the field of medicinal chemistry and organic synthesis.Our group has succeeded in efficient asymmetric addition to 1,2,5-thiadiazolidine 1,1-dioxide type cyclic ketimines,which are useful for the synthesis of highly enantioenriched 1,2-diamines.In considering the construction of 1,3-diamine framework,we incorporated one more carbon in the heterocyclic system,designed 1,2,6-thiadiazinane 1,1-dioxide type cyclic imines as substrates and applied them to rhodium/chiral sulfur-olefin-catalyzed 1,2-addition of arylboronic acids.By taking advantage of the active enamine and the chiral influence of carbon center,a series of valuable chiral 1,3-diamines with different substituents can be efficiently achieved in a highly enantioenriched way.4.Synthesis of?-tertiary chiral amino acid derivatives through aymmetric arylation of cyclic N-sulfonyl?-ketimino esters?-Tertiary chiral amino acids are common structure motifs in diverse bioactive compounds.We newly designed a kind of six-membered cyclic N-sulfonyl?-ketimino esters substrates,and explored the asymmetric 1,2-addition through rhodium and palladium catalyst.The catalyst system has a wide range of substrate scope,and the enantioselectivity of the products was up to 99.9%.After hydrogenation reduction,ring-opening and esterification,we could easily afford the five-membered lactam,which is the chiral fragment analogue of selective TNF-?-convertase enzyme inhibitor BMS-561392.