摘要
本论文分为两部分：1)有机小分子催化剂的设计合成以及在不对称Michael加成反应和Aldol反应中的应用。2)PDK-1抑制剂的设计合成。
催化剂一直是有机合成中的热点,尤其是在List等人发现L-脯氨酸催化Aldol缩合反应后,有机小分子催化剂受到了极大的关注,近来发展迅速。目前,作为小分子的手性二胺化学的研究已成为不对称催化化学领域中一个十分活跃和引人注目的研究热点。本文第一部分首先报道了一种新的以环己二胺为母核的手性伯胺催化剂,并成功用于催化硝基烯烃与酮类的不对称Michael加成反应,首次报道了硝基苯乙烯与苯并环戊酮的不对称加成反应产物(dr=3：1,87% ee)。该反应底物具有普适性,并且以33-94%的产率和57-96% ee的对映选择性成功得到16个4-芳基-5-硝基-2-酮类的衍生物。其次是通过对催化剂和溶剂及反应条件的筛选,我们成功的发现了基于手性环己二胺的伯胺硫脲催化剂催化的马来酰亚胺与α取代醛的不对称Michael加成反应,之前Cordova等人报道了马来酰亚胺与丙醛等的不对称Michael加成反应,但对与α取代的醛反应效果却很差,我们的方法很好地解决了这个问题,并且该反应具有催化剂用量少、条件温和、产率高以及对映选择性好的特点。该反应底物具有普适性,得到了一批新型结构的手性化合物。在模型反应中,以0.5 mmo1%催化剂,反应70 h后得到的反应产物具有87%的产率和97% ee。所得产物的构型通过X-射线单晶衍射得到确证。再次是手性四氮唑催化剂催化靛红和醛的Aldol反应,通过条件的优化制备手性3-取代-3羟基-2-酮类吲哚生物碱,得到的化合物具有两个相邻的季碳中心,其中一个具有手性。此结构单元在很多的的天然产物及药物分子中都是核心的组成部分。实验发现模型反应得到的产物可以通过乙酸乙酯和石油醚重结晶提高其对映选择性,一次重结晶后可超过97%ee。
3-磷酸肌醇依赖性激酶-1(PDK-1)是蛋白激酶B的上游激酶,通过与3,4,5-三磷酸磷脂酰基醇作用激活相邻的PKB分子。同时,PDK-1被称为AGC激酶的掌管着,能够激活包含PKB在内的一系列的AGC激酶家族成员。PDK-1磷酸化这些激酶的保守区域T-loop区,使它们充分激活,从而调节细胞代谢,生长,扩散,生存,抗凋亡等诸多生理过程,但是过度激活却可能导致一些疾病的发生,所以必要的PDK-1抑制剂变得尤其重要。本文依据计算机辅助设计出的7个PDK-1抑制剂分子,设计了其合成路线,通过Suzuki偶联等反应构建其芳基-芳基全共轭结构,最终顺利合成了目标化合物,我们期望通过生物活性测试能够获得具有高选择性和高生物活性的PDK-1抑制剂,以达到治疗肿瘤的目的。
The whole thesis consists of two parts.1):design, synthesis and applications of novel organocatalysts in asymmetric Michael addition reactions and Aldol reactions. And 2):design, synthesis of the PDK-1 inhibitors.
Catalyst is always the focus of organic synthesis, especially, when List found that L-proline could catalyze the Aldol condensation reaction, much attention has been paid to small organic molecule catalyst. At present, studies and applications of chiral cyclohexane diamines as small molecule have been regarded as one of the hottest fields in catalytic asymmetric reactions. Initial of this paper we first reported a new chiral primary amine catalyst that the parent nucleus is the cyclohexane diamine, and successfully used in the Michael addition of ketones to nitroolefins, first reported the asymmetric addition reaction product of 1-indanone to nitrostyrene (dr=3:1,87% ee). The reaction substrates possessed catholicity, and we obtained sixteen 4-aryl-5-nitro-2-ones derivatives with 33-94% yield and 57-96% ee. Secondly, we successfully found the asymmetric Michael reaction of maleimide with a-substituted aldehyde that catalyzed by primary amine-thiourea bifunctional catalyst on account of chiral cyclohexane diamine after screening of catalysts, solvents and other reaction conditions. Priorly, Cordova and coworkers had reported this reaction, but the result of the a-substituted aldehyde was very bad, we overcame the problem smoothly, and the reaction possessed the features:low catalyst loading, mild conditions, high yields and enantioselectivities. Not only the reaction substrates possessed catholicity, but also we got a batch of new structure chiral compounds. In the model reaction with the presence of 0.5 mol% catalyst, we got the desired product with 87% yield and 97% ee after 70 h. The configuration of the product was confirmed with X-ray diffraction by a single crystal. Thirdly was the Aldol reaction of isatins with aldehydes catalyzed by (S)-pyrrolidine tetrazole, prepared the chiral two contiguous quaternary centered 3-substituted-2-hydroxyindol-2-ones indole alkaloids after screening the reaction conditions. This structure constituted a core unit of a number of natural products and pharmaceuticals. In the experiment, we found that the enantioselectivity of the product can be increased to more than 97% ee after one recrystallisation with the solvent of acetic ether and petroleum.
3-Phosphoinositide-dependent protein kinase-1 (PDK-1) is the upstream kinase of protein kinase B, which interacts with PtdIns (3,4,5) P3 and activates neighboring PKB. PDK-1 is also termed the master of AGC kinase. It activates many members of AGC kinase subfamily in addition to PKB. PDK-1 phosphorylates the conservative T-loop region of all these AGC members to gain their full activation, which subsequently adjust cellular metabolism, growth, proliferation, survival, anti-apoptosis and so on. But excessed activation can be lead to some diseases, so essential PDK-1 inhibitors become especially important. The thesis incorporated with computer-aided design, we designed seven PDK-1 inhibitors' synthetic routes and finally successfully synthetized the target compounds through Suzuki-coupling reaction and other reactions to build its aryl-aryl conjugation structures. With biological activity testing, we expect to obain high selectivity and high biological activity of PDK-1 inhibitors, in order to achieve the purpose of treatment of tumors.
引文
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