手性方酰胺催化的不对称Michael加成反应研究

发布时间：2018-03-19 23:31

  本文选题：手性方酰胺　切入点：不对称催化　出处：《武汉理工大学》2014年硕士论文　论文类型：学位论文

【摘要】：不对称合成是指使用手性物质为诱导前手性化合物为原料立体选择性反应构建一个或者多个手心中心分子的过程，，它是代替拆分法获得手性化合物的另一种途径。这种不对称合成方法只需要非常少量的手性催化剂就能产生大量的手性产物，并且具有高效性和高立体选择对映性，在合成手性化合物中应用广泛，前景广阔。 过去十几年里，使用有机小分子作为催化剂在不对称反应中发展十分迅猛，已经成为了不对称催化领域的一个新的研究热点。其中，手性方酰胺类催化剂在手性硫脲催化剂的基础上经过近年来的研究发展，成为了极为有效的不对称合成手性分子的新型大类催化剂，是目前研究的热点之一。 本文以金鸡纳碱、1,2-环己二胺、三氟甲基苯胺和2,3-二甲氧基-3-环丁烯-1,2-二酮为原料合成了三种不同结构类型的手性催化剂6、18、4。以金鸡纳碱为起始经羟基转化为胺基合成中间体34，三氟甲基苯胺与2,3-二甲氧基-3-环丁烯-1,2-二酮合成催化剂中间体36，再中间体34与中间体36合成具有金鸡纳碱衍生的手性方酰胺催化剂6；以(1S,2S)-1,2-环己二胺为底物与中间体36合成催化剂37，再经胺的甲基化等到催化剂18；以(1S,2S)-1,2-环己二胺此为底物与戊二醛缩合，醋酸硼氢化钠还原合成（1S,2S）-2-哌啶-1-环己胺，其与中间体36亲核性取代合成手性催化剂4。 论文对催化剂中间体36的合成工艺中投料顺序、反应温度和反应物料的配比等进行了研究，优化了反应条件使收率提高约30%。论文对合成中间体36工艺中溶剂、温度、物料的配比进行优化，得到了最佳反应时间，反应时间缩短了一半。在脂肪胺的亲核性取代中，对反应溶剂、时间、温度、底物的配比进行了研究，得到催化剂6、18、4合成的最佳反应条件。 在2-羟基萘醌与1,2-二氰基-2-苯基乙烯的不对称Michael加成反应中，研究了三种不同的手性催化剂的催化效果；相比较而言，几种手性方酰胺类催化剂之间的对映选择性差别不大。其中，以手性方酰胺催化剂6a的催化效果最好，其对应选择性为25.5%。 在以手性方酰胺催化剂6a为催化剂对2-羟基萘醌与1,2-二氰基-2-（取代）苯基乙烯进行了不对称催化，以二氯甲烷为溶剂，催化剂量为20%mol，0℃下反应24小时，反应的收率为34.8%～65.6%，反应的对映选择性为13.4%～25.5%。实验研究发现，底物1,2-二氰基-2-苯基乙烯上的苯环不同的取代基团（给电子、吸电子、空间位阻）几乎不影响反应的立体选择性。
[Abstract]:Asymmetric synthesis refers to the process of constructing one or more chiral center molecules using chiral substances as the inducer of stereoselective reactions of chiral compounds as raw materials. It is another way to obtain chiral compounds instead of resolution, which requires a very small amount of chiral catalysts to produce a large number of chiral products, with high efficiency and stereoselective enantioselectivity. It is widely used in the synthesis of chiral compounds and has a broad prospect. In the past decade, the use of small organic molecules as catalysts in asymmetric reactions has developed rapidly, and has become a new research hotspot in the field of asymmetric catalysis. On the basis of chiral thiourea catalysts, chiral butylamides have become a new type of catalysts for asymmetric synthesis of chiral molecules, and have become one of the hot spots in recent years. In this paper, a new method was developed for the determination of cinchona alkaloid and 2-cyclohexanediamine. Trifluoromethyl aniline and 2o 3-dimethoxy-3-cyclobutene-2-diketone were used as raw materials to synthesize three kinds of chiral catalysts, 6 / 18 ~ (18) O ~ (4) ~ (4). The intermediates 34, trifluoromethylaniline and 2H ~ (3-) were synthesized by hydroxyl conversion from cinchona base. Synthesis of dimethoxy-3-cyclobutene-2-diketone catalyst intermediate 36, intermediate 34 and intermediate 36 synthesis of chiral galactamide catalyst 6 derived from cinnabine. The catalyst 18 was then methylated by amines, and the substrate was condensed with glutaraldehyde. Sodium borohydride acetic acid was reduced to a chiral catalyst for synthesis of ~ (1) S ~ (2 +) S ~ (2) -piperidine ~ (-1) -cyclohexylamine, which was substituted for 36 nucleophilic intermediates. In this paper, the feeding order, reaction temperature and reaction material ratio of catalyst intermediate 36 were studied. The yield of catalyst intermediate 36 was increased by about 30% by optimizing the reaction conditions. The optimum reaction time was obtained, and the reaction time was shortened by half. In the nucleophilic substitution of aliphatic amine, the reaction solvent, time, temperature and the ratio of substrate were studied. The optimum reaction conditions for the synthesis of catalyst 6 ~ (18) O _ (4) were obtained. In the asymmetric Michael addition reaction of 2-hydroxy-naphthoquinone with 1-dicyano-2-phenylethylene, the catalytic effects of three different chiral catalysts were studied. There was little difference in enantioselectivity between several chiral sulfamide catalysts, among which, the chiral sulfamide catalyst 6a had the best catalytic effect, and the corresponding selectivity was 25.5%. Asymmetric catalytic reaction of 2-hydroxy-naphthoquinone with 1-tri-2-dicyano-2-phenylene was carried out using chiral calcite catalyst 6a as catalyst. The reaction was carried out in dichloromethane as solvent at 20 mol / 0 鈩

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