Design And Synthesis Of Novel Chiral Thiazoline Catalysts And Study On Their Applications In Asymmetric Catalysis

Due to the wide use of chiral compounds in many research fields, especially inmedicinal and materials science, widespread attention has been draw to the synthesis ofchiral compounds recently. Asymmetric organocatalysis has become one of the mostactive and attractive branch in modern synthetic chemistry. It is also regarded as animportant means and an attractive strategy for the construction of chiral compounds,especially natural products. Therefore, numerous efforts have been made to develop neweffective chiral catalysts in asymmetric catalysiesis. Among various chiral catalysts,proline and its derivatives have been widely developed as a class of catalysts inasymmetric synthesis. Despite these results, there are only a few examples where chiralthiazoline-catalysts have been employed. Therefore, it is challenging and meaningful inthe development of efficient new chiral catalyst containing thiazoline moieties forasymmetric transformations. We fixed our attention on employing serises of novelcatalysts containing thiazoline and demonstrated their catalytic activities in differentasymmetric reaction. The innovative research results achieved are as follows:(1) Several novel chiral thiazoline primary and tertiary alcohols were simplysynthesized from commercially available L-cysteine in three steps and high yield. Theseligands were subsequently applied to the asymmetric addition of diethylzinc (Et2Zn) tovarious aldehydes. The configuration of the products could be tunable by simplemodification of the structures of thiazoline ligands. The products with S configurationwere obtained when the thiazoline-containing tertiary alcohol ligands were used ascatalysts. The primary alcohol induced corresponding products with R configuration in68%ee, which was a higher value relative to other N-O ligands possessing a primaryalcohol unit in the literatures. Furthermore, a plausible transition state model wasproposed given to explain the observed enantioselectivities. (2) Several novel chiral tridentate ligands containing thiazoline were simply synthesizedfrom commercially available L-cysteine in high yield. These ligands were prepared by thereaction of chiral thiazoline, cinchona alkali, benzimidazole, chiral amino alcohol, and8-aminoquinolines, respectively. These ligands were subsequently applied to theasymmetric Henry reaction of nitromethane and various aldehydes. We found that thestructures of thiazoline ligands significantly affected the conversion and enantioselectivity.The study shown that the optimal catalyst for this reaction was locked on ligands7, whichwas formed from chiral thiazoline with the chiral amino alcohol. At-20°C, with10mol%of ligand7complexed with CuCl, in ethanol, the product was obtained with Sconfiguration, and stereoselectity up to98%ee.(3) Several novel chiral bifunctional L-thiazoline-amide derivatives were simplysynthesized from commercially available L-cysteine in high yield. These catalysts weresubsequently applied to the direct enantioselective aldol reactions of various aldehydes,which had been unprecedented in the literatures. The products with anti configurationwere obtained in97%ee and99%dr when the L-thiazoline-amide derivatives were used.A plausible transition state model was proposed to explain the observedenantioselectivities.(4) Several novel chiral bifunctional L-thiazoline-thiourea derivatives were simplysynthesized from commercially available L-cysteine in high yield. These catalysts weresubsequently applied to the enantioselective Michael addition of acetylacetone toβ-nitrostyrenes, which had been rarely reported in the literatures. The products with Sconfiguration were obtained in97%ee when the L-thiazoline-thiourea derivatives wereused. A plausible transition state model was proposed to explain the observedenantioselectivities.(5) As one type of important natural compounds, the synthesis and biologicalproperties of Chromene derivative have been widely known. However, to date, theasymmetric catalytic approaches to construct these heterocycles in enantiomerically pureform are still rare, especially for the2-amino-4H-chromenes. In this work, we present aprocess for the synthesis of optically active2-amino-4H-chromenes through an organocatalytic Knoevenagel/Michael/cyclization sequence (cascade reactions) by usingbifunctional L-thiazoline-thiourea derivatives as catalysts. The product was obtained withstereoselectity85%ee.