【作者】 安雅洁；

【导师】 陶京朝；

【作者基本信息】 郑州大学 ， 药物化学， 2011， 博士

【摘要】 近年来,利用有机小分子作手性催化剂的不对称合成研究成为不对称催化研究的热点。本文以廉价易得的天然异斯特维醇和氨基酸为主要原料,通过简单的缩合反应,设计合成了一系列两亲型手性催化剂——异斯特维醇-氨基酸衍生物,并考察了其在水相/有机相直接不对称Aldol反应、不对称α-胺氧化反应和直接不对称Mannich反应中的催化性能。设计合成了两亲型脯氨酰胺类催化剂,并考察了其在直接不对称Aldol反应和不对称Biginelli反应中的催化性能,取得一系列有应用价值的研究结果。1.新型两亲手性异斯特维醇-氨基酸衍生物的设计合成1)以廉价易得的天然异斯特维醇和反式-4-羟基-L-脯氨酸为原料,不经保护-脱保护过程,经一锅两步反应,高收率的合成了具有两亲性能的手性催化剂异斯特维醇-脯氨酸衍生物5,然后经还原反应,立体选择性地得到化合物7。通过1H NMR,13C NMR, IR和HR-MS对新化合物的结构和构型进行了表征。2)以异斯特维醇和开链氨基酸为原料,不经保护-脱保护步骤,合成了四种具有两亲性能的手性催化剂异斯特维醇-氨基酸衍生物10-13,并通过1H NMR, 13C NMR, IR和HR-MS对其结构和构型进行了表征。2.异斯特维醇-脯氨酸衍生物在催化直接不对称Aldol反应中的应用研究了催化剂5和7在有机相和水相中模拟Ⅰ类醛缩酶对分子间直接不对称Aldol反应的催化活性和立体选择性。发现此类两亲型催化剂在水相中的催化效果明显比在有机相中好,并且催化剂5的催化活性优于催化剂7。在水相室温反应条件下,催化剂5仅以1 mol%的催化剂用量,即可高效催化环己酮与芳香醛的直接不对称Aldol反应,并表现出优异的立体选择性(dr值>99：1,ee值高达99%)；该类催化剂对环戊酮和丙酮也具有较好的对映选择性,分别得到了高达98%和90%的ee值。在有机相中,催化剂5可以有效的催化以丙酮为给体的反应,在5 tmo1%的催化剂用量下,即可在6-9小时内完成反应,并获得高达94%的ee值；同时对以环己酮和环戊酮为给体的反应,也分别获得了98%和94%的ee值。探讨了以异斯特维醇-脯氨酸衍生物作为催化剂,水相中的直接不对称Aldol反应的催化机理。研究结果表明,异斯特维醇疏水性刚性骨架与L-脯氨酸的亲水性结构的合理组合,使得该两亲型催化剂可以在水表面有效的与反应底物聚集,形成笼状不对称有机微环境,其催化中心与反应底物通过自组装形成优势过渡态,从而实现高效高立体选择性地模拟酶催化直接不对称Aldol反应。3.异斯特维醇-脯氨酸衍生物在催化不对称α-胺氧化反应中的应用以异斯特维醇-脯氨酸衍生物5和7为催化剂,考察了水相体系中醛、酮与取代亚硝基苯的不对称α-胺氧化反应。发现催化剂7对此类反应的催化活性明显优于催化剂5,室温下数分钟内即可完成催化反应,并且取得了很好的反应收率和ee值；发现化合物7的催化活性和立体选择性对反应介质的pH值比较敏感,特别是对醛的反应,随着pH值的增加,反应时间逐渐降低,对映选择性逐渐增加。在pH为9.1的磷酸缓冲液中,醛、酮的不对称α-胺氧化反应均获得了最佳的反应收率和ee值。通过对水相中的不对称α-胺氧化反应机理的探讨,我们认为在L-脯氨酸的4-位引入大的手性疏水性基团,催化剂的作用机制保持不变,得到的仍是以R构型为主的氧端加成产物。同时,两亲型催化剂更易在含磷酸盐的水相表面通过氢键作用与反应底物聚集,使反应在自组装的不对称有机微环境中进行,从而大大提高了催化剂的活性和反应的立体选择性。4.异斯特维醇-氨基酸衍生物在催化直接不对称Mannich反应中的应用考察了两亲型催化剂异斯特维醇-氨基酸衍生物在有机相和水相中对直接不对称Mannich反应的催化活性和立体选择性。发现水相体系中,L-脯氨酸衍生的催化剂7具有优异的催化性能。特别是对环己酮,硝基苯甲醛与非强给电子基团取代的苯胺(如甲基苯胺,苯胺和卤代苯胺)之间的反应,ee值高达99%。有机相体系中,L-脯氨酸衍生物7可以在较低的催化剂用量(5 mol%)下,在4-18小时内,得到了以syn构型为主的加成产物(dr值和ee值高达99：1和99%)；而L-苏氨酸衍生物13则在较短的反应时间内(3-12小时),得到了以anti构型为主的加成产物(dr值高达97：3,ee值高达99%)。通过比较各种催化剂对直接不对称Mannich反应的催化结果,我们认为异斯特维醇特殊的不对称刚性骨架与L-脯氨酸的刚性吡咯烷结构具有更好的适配性,表现在L-脯氨酸衍生物的催化活性和立体选择性明显优于非环状氨基酸衍生物。对L-脯氨酸衍生物7在水相体系中催化直接不对称Mannich反应的机理进行了探讨,认为催化剂的活性中心仍是氨基酸的氨基和羧基双活性中心。催化剂在水分子表面利用疏水作用,有效的与反应底物聚集,使反应在笼状手性微环境中进行,进而高效高立体选择性的得到syn-Mannich反应产物。5.两亲型脯氨酰胺类手性催化剂的设计合成及其不对称催化性能的探讨1)本实验室前期工作表明,脯氨酰胺酚型手性催化剂在催化直接不对称Aldol反应中表现出优异的催化活性和立体选择性。其中催化剂14和15带有大位阻基团及可提供氢键的极性基团,根据催化剂的结构特点,我们考察了其在催化不对称Biginelli反应中的应用,发现催化剂吡咯烷上的羟基对反应影响不大,两种催化剂得到相似的催化结果。其中,催化剂14在以四氢吠喃作溶剂时,对硝基苯甲酸作添加剂,或以二氯甲烷作溶剂,加入对氯苯甲酸作添加剂时,表现出较好的催化活性,但立体选择性较差。2)设计合成了两种由异斯特维醇和脯氨酸组合构建的新型两亲型脯氨酰胺类手性催化剂23和24,并通过1H NMR、13C NMR、IR和HR-MS对其结构进行了表征。考察了催化剂23和24对直接不对称Aldol反应的催化活性和立体选择性,发现该类催化剂对以环己酮为给体的反应,可以得到较好的立体选择性。但是对于以丙酮或苯乙酮为给体的Aldol反应,几乎没有选择性。更多还原

【Abstract】 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%).更多还原