Asymmetric Synthesis Of Optically Active Indoles And Other Azaarenes Bearing Chiral Quaternary Centers

This thesis aimed to develop novel efficient catalytic asymmetric synthetic approaches to biologically active compounds, particularly, azaarenes (nitrogen-containing aromatic heterocycles) with high optically purity. With the metal complexes of chiral bis(oxazoline) (BOX) ligands, the asymmetric synthesis of chiral indole derivatives were studied. As well, a variety of structural novel and synthetic versatile azaarene-containing compounds bearing all-carbon quaternary stereocenters were obtained in high yields with excellent enantioselectivities.First, we successfully realized the first copper-catalyzed enantioselective conjugate addition of indoles to β-substituted unsaturated acyl phosphonates by using a BOX Lla-Cu(OTf)2 complex, yielding a series of 1H-indole-3-carboxylic acid derivatives. The reaction features high efficiency, cheap catalyst and broad generality. In the case of β-alkyl-substituted unsaturated acyl phosphonates, BOX Lla-Cu(OTf)2 complex was one of the best catalysts. In addition, the 3-indolyl adducts can be transformated to tryptamine intermediates.Second, a cascade sequence involving Friedel-Crafts alkylation of 3-methyl indoles with β,γ-unsaturated a-ketoester followed by N-hemiacetalization were realized using a BOX Ll-Cu(OTf)2 complex. A series of pyrrolo[1,2-a]indole products with two chiral centers were obtained in high yields (85～95%) with both high diastereoselectivities (up to 98:2 d.r.) and enantioselectivities (up to 98% ee) under mild conditions. These results are almost comparable to those have been achieved in this asymmetric reaction catalyzed by Inda-Box ligand reported by Xiao’s group.Third, the first highly enantioselective Michael addition of 2-acetyl azaarenes to a-substituted-β-nitroacrylates catalyzed by BOX L2a-Ni(acac)2 complex under mild conditions is explored, providing various chiral azaarene-containing derivatives bearing all-carbon quaternary stereocenters (up to>99% ee), The resulting adducts could be transformed to β2,2 -amino esters, pyrrolines, succinates, y-lactones and y-lactams etc.. These results provided a novel and effective strategy to optical compounds with one chiral quarternary carbon, providing novel methodologies for the development of drugs and materials. This asymmetric reaction displays some significant advantages: a). Mild conditions, high enantioselectivity and yield; b). Broader substrate scope; c). Versatile transformations to some compounds bearing chiral all-carbon quaternary centers.