Synthesis Of Isosteviol-Amino Acid Conjugates And Their Application In The Catalytic Asymmetric C-X Bond Formation

The small molecular organocatalysts have been received great attention for C-C and C-X bonding formation in asymmetric synthesis in the presence of water. In this dissertation, the simple amphiphilic isosteviol-amino acid conjugates have been developed by the condensation of Isosteviol with amino acids without protected groups, and the catalytic effects of those catalysts on the direct asymmetric Aldol reaction,α-aminoxylation reactions and the direct asymmetric Mannich reaction have been investigated. Additionally, the prolinamides have been synthesized and their catalytic activities and stereoselectivities were also evaluated by the direct asymmetric Aldol reaction and the asymmetric Biginelli reaction.1. Synthesis of novel amphiphilic isosteviol- amino acid conjugates1) Two novel amphiphilic isosteviol-proline conjugates 5 and 7 were synthesized by the condensation of Isosteviol with trans-4-Hydroxy-L-proline according to the following procedure. The structures of these catalysts were fully characterized by IR, 1H NMR,13C NMR, and HR-MS.2) Four novel amphiphilic isosteviol-amino acid conjugates 10-13 were synthesized through condensation of Isosteviol with acyclic amino acids. Their chemical structures were characterized by IR,1H NMR, 13C NMR and HR-MS. 2. The application of amphiphilic isosteviol-proline conjugates in asymmetric direct Aldol reaction.The catalytic effects of 5 and 7 on the asymmetric direct Aldol reaction were evaluated both in organic solvents and aqueous phase. The catalytic activity of catalyst 5 was higher than that of 7. And the catalyst 5 afforded anti configuration products of cyclohexanone with excellent stereoselectivities when using 1 mol% catalysts loading in the presence of water. The catalyst also showed good performance on cyclopentane and acetone (ee up to 98% and 94%, respectively).The reactions proceeded smoothly in neat ketone with 5 mol% catalysts loading. The R-configuration products were obtained with 94% ee value using acetone as reaction donor within 6-9 h. And the anti-Aldol products were also obtained with up to 98% and 94% ee using cyclohexanone and cyclopentanone as donor respectively.The catalytic mechanism in aqueous phase was investigated. Combination of hydrophobic Isosteviol and hydrophilic L-proline, the catalyst effective assembled the reactants in the surface of water through hydrophobic interactions and sequester the transition state from water. Therefore, the reaction proceeded efficiently in the aggregated chiral microenvironment which afforded the Aldol products with high stereoselectivity.3. The application of amphiphilic isosteviol-proline conjugates in asymmetricα-aminoxylation reaction.The asymmetricα-aminoxylation reactions of aldehyde/ketone and nitrosobenzene have been investigated using isosteviol-proline conjugates 5 and 7 as organocatalalysts in the presence of water. The reactions were completed in several minutes using 7 as catalyst with good yields and excellent enantioselectivities. At pH 9.1, the amphiphilic catalyst 7 showed a pH responsive ability in phosphate buffer solution, which facilitated the excellent O-selectivity reactions.The catalytic mechanism ofα-aminoxylation reactions was also investigated. The amphiphilic catalyst molecules remained the catalytic active center of L-proline and could effective assembles the reactants in the surface of phosphate buffer solution through hydrophobic interactions. Therefore, the reaction proceeded efficiently in the aggregated chiral microenvironment afford the R configurationα-aminoxylation products with high stereoselectivity.4. The application of amphiphilic isosteviol-amino acid conjugates in asymmetric direct mannich reaction.The catalytic effects of catalysts 10-13 on the asymmetric direct Mannich reaction were evaluated in organic solvents and in aqueous phase respectively. The L-proline derivative 7 showed better performance than others in the presence of water. We obtained the excellent enantioselectivities using 10 mol% 7 as orgnocatalyst with cyclohexanone as donor. When the reaction proceeded in organic solvent, the L-proline derivative 7 afforded the syn-products in excellent dr and ee values with 5 mol% catalysts loading in 4-18 h, and the L- threonine derivative 13 afforded the anti-products in 97:3 dr and 99% ee values with 10 mol% catalysts loading in 3-12 h.The catalytic mechanism in aqueous phase was investigated. The catalyst 7 remained the catalytic active center of L-proline; the introducing of hydrophobic Isosteviol made the reaction proceeded efficiently in an aggregated chiral microenvironment which afforded the syn mannich products.5. Synthesis of prolinamides and their application in asymmetric C-C bond formation.1) The prolinamides 14 and 15 were synthesized and used as organocatalysts in asymmetric Biginelli reaction. It is found that the catalyst 14 showed good activities when using THF or CH2Cl2 as solvent with acid additives. However, the enantioselectivities were unsatisfactory. 2) Two novel prolinamides 23 and 24 were designed and synthesized with Isosteviol and L-proline. Their chemical structures were characterized by IR,1H NMR, 13C NMR and HR-MS.The catalytic effects of catalysts on the asymmetric Aldol reaction of ketones were evalued. The good stereoselectivity was obtained when using cyclohexanone as donor (dr up to 90:10 and ee up to 90%).