轴手性醌类化合物不对称合成的研究

ORGANOCATALYTIC ASYMMETRIC CONSTRUCTION OF AXIALLY CHIRAL ARYL O-NAPHTHOQUINONES DERIVATIVES

朱帅

11649171

硕士

化学工程

谭斌

2018

2018.7.10

哈尔滨工业大学

深圳

本论文的主要研究内容为通过有机催化不对称合成的方法，构建轴手性醌类化合物，然后考察底物普适性并拓展其部分应用。醌类化合物广泛存在于天然产物中，是一类重要的生物活性分子和药物活性分子。 邻位醌类化合物不稳定，所以自然存在的醌类化合物大多为对位醌化合物。醌类化合物作为一类重要的氧化剂可以参与一系列氧化反应中。此外醌类化合物具有重要的药用价值，在许多药物中也含有对位醌和邻位醌骨架。同时醌类化合物在生物体内作为辅酶因子参与一系列生化反应，可以参与生物体的酶催化氧化进程，所以在生物仿生方面醌类化合物也具有重要应用前景。大量研究表明，不同构型的手性分子具有不同的催化活性和生理活性，其药效和药物代谢动力学方面也具有巨大差异。因此，单一构型的轴手性化合物的合成方法开发对天然产物全合成、药物分子设计以及手性材料等方面的研究具有重要意义。目前为止，高对映选择性地合成轴手性醌类化合物的方法尚未有任何报道。基于醌类和轴手性骨架的重要性，我们认为轴手性醌类化合物在药物和模拟仿生方面具有重要前景，因此本文研究了轴手性醌类化合物的不对称合成方法及衍生应用。为了构筑轴手性醌类化合物，本论文建立了一种以手性磷酸为催化剂，通过醌类化合物与不 同亲核试剂反应生成轴手性醌类化合物的简便方法。本论文以 2-萘酚和 2-萘胺及其衍生物为不同的亲核试剂，与邻醌进行反应，通过加入过量的醌对第一步中间体进行氧化从而生成醌类化合物。本论文首先筛选了不同骨架的手性磷酸，确定了反应的最优催化剂，然后又对反应溶剂、反应温度、反应浓度和催化剂用量等变量进行了细致考察，最终确定了反应的最优条件。然后考察了具有不同取代基的醌类底物在最优条件下的普适性，发现基团兼容性较好，论文中共合成了40个不同取代基的轴手性邻醌类化合物，产物 ee值都接近 99%。然后在此基础上进行了产物的衍生 化应用，进一步构建了吡嗪、轴手性非天然氨基酸衍生物和螺手性化合物等不同分子。

This thesis is mainly focused on organocatalytic asymmetric construction of axi-ally chiral aryl o-quinones derivatives and their applications.Quinone derivatives are ubiquitous in natural products and have remarkable bio-activity and drug activity. Structurally speaking, quinones could be classified to o-qui-none and p-quinone. Due to its unstable structure, o-quinone is uncommon in nature. Quinones are important redox-active organic molecules that have applications in di-verse redox processes, including in the manufacture of industrial chemicals, in oxida-tion reactions for organic synthesis and so on. Many pharmaceutical molecule contains o-quinone and p-quinone constructure. Except for widespread in pharmaceutical mol-ecules, quinones also play important role as cofactors in the enzymatic oxidation of organic substrates. Several families of “quinoenzymes” are known.A large number of studies have shown that the two enantiomers of axial chiral molecules have different catalytic activity and physiological activity, and their phar-macokinetics and pharmacokinetics are also very different. Therefore, the synthetic method of single configuration of axial chiral compounds is of great significance for the development of natural product synthesis, drug molecular design and chiral mate-rials. So far, there have been no reports on the methods of high enantioselective syn-thesis of chiral quinones. Based on the importance of quinones and chiral axis skeleton, we believe that the axis of chiral quinone compounds is vital in drug and biosynthesis. This dissertation explores the synthesis of axially chiral quinone compounds.In order to construct axially chiral quinone compounds, we successfully devel-oped a new method. We used chiral phosphoric acid as catalyst to promote the reaction of quinone compounds and different nucleophilic reagents. In this dissertation, we use 2-naphthol and 2-naphthylamine and there derivatives as different nucleophilic reagent to react with different kinds of quinones. By adding excessive quinone oxidation, the intermediate in the first step was oxidized by excessive quinone.We first screened dif-ferent skeleton of chiral ligands phosphate to determine the optimum catalyst reaction, and then the reaction solvent, reaction temperature, reaction concentration. With the optimized conditions in hand, we next set out to explore the substrate scope of this reaction with different nucleophiles. Overall, all the 40 tested substrates gave the de-sired products in good yields with excellent stereocontrol. Finally, we exploit the cat-alytic and synthetic applications of our axially chiral quinones.

醌 轴手性 手性磷酸 不对称催化

Quinone Axial chirality Chiral phosphoric acid Asymmetric synthesis

中文

联合培养

南方科技大学

朱帅. 轴手性醌类化合物不对称合成的研究[D]. 深圳. 哈尔滨工业大学,2018.