手性α-羟基硅类化合物的合成研究

发布时间：2018-04-30 03:17

本文选题：硅替代新药研发 + 氮杂环卡宾　；参考：《山东大学》2017年硕士论文

【摘要】："硅替代"新药研发是指对现有药物结构进行硅修饰以获得具有有效生物活性的药物。硅元素与碳元素相比,它的亲脂性,电负性,原子大小以及共价键半径是不同的。这些差异使硅替代药物表现出优越的性质:1,硅替代药物里含有硅醇官能团,硅醇官能团与甲醇官能团相比,前者的氢键键能更加大,亲和力被加强,选择性被提高;2,硅替代药物具有更高的亲脂性,它们具有非常强的组织渗透能力,而且能明显增加药物的分布容积。它们还能提高表观油水分配系数,改善药物血脑屏障的通透性,从而进一步影响中枢神经系统活动,可以显著提高药物的疗效;3,硅替代药物的毒性低,从而提高了安全性。含硅类化合物的合成方法研究吸引越来越多人的注意,如何方便有效地合成硅类化合物成为研究人员亟待解决的问题。我们对醛与硅试剂的加成比较感兴趣,因为它们的产物为α-羟基硅烷,而含有羟基的α-羟基硅烷以及它们的衍生物已经被广泛应用在C-C键的构建和重排中。我们将三氮唑卡宾与[2.2]环仿进行结合,得到一类新颖的催化剂并且成功地应用在醛的硅基化反应里,得到一系列α-羟基硅烷产物。本论文包括以下几个方面:第一章,研究背景分别对硅替代新药研究、不对称硅基化反应研究、氮杂环卡宾(NHC)在不对称催化反应中的应用以及[2.2]PCP在不对称催化里的应用分别进行综述。第二章,目标配体的设计、合成和表征合成目标配体需要先合成两个原料,分别是基于面手性[2.2]环仿甲酰基肼盐以及手性氨基醇衍生的亚胺醚。一方面我们以对甲基苄基三甲基氯化铵为原料,通过消除聚合得到[2.2]PCP。然后进行溴代,高温转位。接着单亚胺化,酸解碱化。然后与Boc保护的L型脯氨酸反应,柱层析拆分,酸解碱化分别得到到RP/SP光学纯产物。然后重氮化,溴代。接着单腙化,甲酰化。然后经过Suzuik反应,酸解得到甲酰基肼盐。另一方面我们以L-苯甘氨醇为原料,经过酰胺化,关环以及甲基化得到亚胺醚。最后甲酰基肼盐与亚胺醚反应关环得到目标配体。第三章,目标配体(S,Sp)-4在醛的不对称硅基化反应中的应用我们以对氯苯甲醛作为模板底物,经过条件优化以及配体筛选,得到最优反应条件。在最优条件下,我们研究了各种芳香醛的不对称硅基化反应,得到一系列α-羟基硅产物。本论文的创新点:1,第一次合成出目标配体(R,Rp)-13;2,利用实验室里现有的配体库,研究了醛的不对称硅基化反应,开创了第一例无金属催化的醛的不对称硅基化反应。
[Abstract]:New drug R & D for silicon substitution refers to the modification of existing drug structures to obtain effective bioactive drugs. Compared with carbon, silicon has different lipophilicity, electronegativity, atomic size and covalent bond radius. These differences make silicon substitute drugs show superior properties: 1. Silicon substitute drugs contain silyl functional groups. Compared with methanol functional groups, the former has higher hydrogen bond energy and stronger affinity. The selectivity is improved and the silicon-substituted drugs have higher lipophilic properties. They have very strong tissue permeability and can obviously increase the distribution volume of the drugs. They can also improve the apparent distribution coefficient of oil and water, improve the permeability of the blood-brain barrier, and further affect the central nervous system activities. They can significantly improve the efficacy of the drug and the toxicity of silicon substitute drugs, thus improving the safety. More and more attention has been paid to the synthesis method of silicon-containing compounds. How to synthesize silicon compounds conveniently and effectively has become an urgent problem to be solved. We are interested in the addition of aldehydes and silicon reagents because their products are 伪 -hydroxysilane and their derivatives have been widely used in the construction and rearrangement of C-C bonds. A series of 伪 -hydroxysilane products were obtained by combining triazole carbene with [2.2] cycloform to obtain a new kind of catalyst and successfully applied to the silicylation of aldehydes. This paper includes the following aspects: chapter 1, the background of the research on silicon substitute new drugs, asymmetric silicylation reaction research, The applications of PCP in asymmetric catalysis and [2.2] PCP in asymmetric catalysis were reviewed. In chapter 2, the design, synthesis and characterization of the target ligands require the synthesis of two raw materials, one is based on [2.2] cycloimidyl hydrazide and the other is imide derived from chiral amino alcohol. On the one hand, we use p-methyl benzyl trimethylammonium chloride as raw material and get [2.2] PCPs by eliminating polymerization. Then brominate, high temperature transposition. Then monoimide, acidolysis and alkalination. Then, RP/SP optical pure products were obtained by reaction with L-type proline protected by Boc, separation by column chromatography and Alkalization of acidolysis. Then diazotization, bromination. Then monohydrazone, formylation. Then the formyl hydrazide salt was obtained by Suzuik reaction and acidolysis. On the other hand, we have amidation, ring closing and methylation of L-phenylglycinol as raw material to obtain imine ether. Finally, the target ligand was obtained by the reaction of formyl hydrazide with imine ether. In chapter 3, the application of the target ligand, SznSp-4, in the asymmetric silicylation of aldehydes, the optimal reaction conditions were obtained by using p-chlorobenzaldehyde as the template substrate, and the optimum conditions were obtained by optimizing the conditions and screening the ligand. Under the optimal conditions, asymmetric silicylation of aromatic aldehydes has been studied and a series of 伪 -hydroxysilicon products have been obtained. The innovation point of this thesis is: 1: 1, the target ligand RPN-13 / 2 was synthesized for the first time. Using the existing ligands in the laboratory, the asymmetric silicylation of aldehydes was studied, and the first non-metal-catalyzed asymmetric silicylation of aldehydes was initiated.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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