Study On Asymmetric Carbon-carbon Bond Formation In The Presence Of Novel Chiral Catalyst

Catalytic asymmetric carbon–carbon bond formation is one of the most active research areas in organic synthesis. This thesis was focused on the study of catalytic asymmetric carbon–carbon bond formation via two kinds of reactions: asymmetric Michael addition and enantioselective addition of diethylzinc (Et2Zn) to aldehydes. In addition, we reported direct ester condensation from carboxylic acids and alcohols catalyzed by TiCl4.Ⅰ. Investigation on asymmetric Michael addition in the presence of (R)-tetrahydrothiazo-2-thione-4-carboxylic acid [(R)-TTCA] potass salt synthesized from L-cysteine hydrochloride1. Asymmetric Michael addition of cyclohexanone, cyclopentanone or cyclooctanone with acrylonitrile in the presence of (R)-TTCA·K Our first effort was to investigate the optimum conditions for asymmetric additions reaction. The addition of cyclohexanone with acrylonitrile was chosen as the standard reaction to investigate the optimum conditions.We further studied the addition of cyclopentanone and cyclooctanone with acrylonitrile under the optimum conditions and obtained optically active (+)-2-cyanoethyl cyclohexanone, (+)-2-cyanoethyl cyclopentanone and (+)-2-cyanoethyl cyclooctanone. To the best our knowledge, (+)-2-cyanoethyl cyclopentanone and (+)-2-cyanoethyl cyclooctanone have not been described in the literature previously.2. Asymmetric Michael addition of cyclohexanone, cyclopentanone or cyclooctanone with methyl acrylate in the presence of (R)-TTCA·K The catalytic capability of (R)-TTCA·K was further tested in the asymmetric Michael addition of cyclohexanone, cyclopentanone or cyclooctanone with methyl acrylate. Three optically active compounds were obtained. In addition methyl-3-(2′-oxocyclopentyl)-propionate and methyl-3-(2′-oxocyclooctyl)-propionate have not been described in the literature previously.3. Hydrolysis of 5 and determining its enantiomeric excess (S)-(+)-2-oxocyclohexanepropionic acid ([α] 2D0 = + 15.46 (c 0.2 CHCl3))was obtained by resolution of racemic 2-oxocyclohexanepropionic acid with (-)-quinine. Hydrolysis of 5 afforded optically active (S)-(-)-2-oxocyclohexanepropionic acid ([α] 2D0 = - 2.95 (c 2.9 CHCl3)). Enantiomeric excess of 5 (e.e. 19 %) was determining by comparison of the optical rotation value of (S)-(-)-2-oxocyclohexanepropionic acid ([α]2D0 = -2.95 ( c 2.9 CHCl3)) with (S)-(+)-2-oxocyclohexanepropionic acid ([α]2D0 = + 15.46 (c 0.2 CHCl3).4. Esterification of (S)-(-)-2-oxocyclohexanepropionic acid Direct ester condensation of (S)-(-)-2-oxocyclohexanepropionic acid and alcohols catalyzed by Fe2(SO4)3·XH2O afforded corresponding optically active (S)-3-(2′-oxocyclohexyl)propionates. This experiment results proved (S)-(-)-2-oxocyclohexanepropionic or (S)-3-(2′-oxocyclohexyl) propionates did not racemize in the presence of Fe2(SO4)3·XH2O.5. Based on these experiment findings, a possible mechanism was proposed.Ⅱ. Synthesis ofβ-amino alcohols and their application in catalytic asymmetric addition of diethylzinc to aldehydesEight novel chiral ligands were synthesized from (R)-TTCA. Those ligands have not been described in the literature previously and were characterized by IR, 1H NMR and Ms spectra.1. Synthesis of chiral intermediates c1-c4 from (R)-TTCAThe compound c1-c4 can be obtained by treating compound a with alkyl bromide in alkaline condition. This method has not been described in the literature previously.2. Synthesis of chiral ligands d1-d3 from chiral intermediates c1 And the compound c1 could be transformed to chiral ligands d1-d3 by treatment with RMgBr, thus compound d1-d3 as new catalysts was obtained in moderate yield.3. Synthesis of chiral ligands h1-h4 from chiral intermediates c1-c4 (R)-4-(2-alkylthio-4,5-dihydrothiazol) methanol h1-h4 was obtained by reduction of c1-c3 with sodium borohydride in methanol.4. Synthesis of chiral ligands i from chiral intermediates b (R)-4-(hydroxymethyl)thiazolidine-2-thione was obtained by reduction of b with sodium borohydride in methanol.5. Enantioselective addition of diethylzinc (Et2Zn) to aldehyde catalyzed by d1-d3,h1-h4or i. The optimum amount of chiral catalysts was proved to be 5 mol% relative to aldehyde and the best solvents for the reaction was hexane. Under these condition, chiral ligand d1-d3,h1-h4 or i was used to catalyze the addition of diethylzinc to various aldehydes including ortho-, meta- substituted benzaldehydes and aliphatic aldehydes. The optical active second alcohols were obtained with high chemical and optical yield.6. Based on our experimental findings and other groups work, a possible mechanism was proposed.Ⅲ. Esterification and selective esterification in the presence of TiCl4 We obtained ethyl-(R)-tetrahydrothiazo-2-thione-4-carboxylate by accident from (R)-TTCA and ethanol in the presence of TiCl4. Further investigation showed this esterification method applied to many substrates. Furthermore, for the substantial differences of reaction rate of esterification of each substrate, this simple esterification method had high chemoselectivity. For example, this esterification had high chemoselectivity for primary alcohol in the presence of secondary alcohols and for nonconjugated acids in the presence of conjugated or aromatic acids.1. The esterification of (R)-tetrahydrothiazo-2-thione-4-carboxylic acid and alcohols was successfully catalyzed by TiCl4This experiment results proved all the optical active compounds maintained their original configuration and did not racemize in the presence of TiCl4.2. Selective esterification of primary alcohols in the presence of secondary alcohols3. Selective esterification of nonconjugated acids in the presence of conjugated or aromatic acids...