不对称Michael加成反应合成多取代四氢呋喃环及其在新药研发中的应用

发布时间：2018-07-12 18:07

本文选题：半缩醛 + 多取代四氢呋喃环　；参考：《苏州大学》2014年硕士论文

【摘要】：含氧脂肪杂环是一类广泛存在于各种天然产物和已上市药物中的化学结构，其在生物、医药、农药等领域都具有重要的应用价值。特别值得一提的是，DNA结构中的脱氧核糖核酸单元的四氢呋喃核心也是一种含氧脂肪杂环，这样的结构也存在于核苷类药物中，广泛应用于抗肿瘤和抗病毒等。有机催化的不对称Michael加成反应是一类构建C-C键、C-N键、C-O键等的重要方法，具有对环境污染小、稳定性好、价格便宜、绿色环保且可一步合成多个手性中心等优点。本论文报道的是利用2-羟基四氢呋喃这样一种半缩醛结构化合物在有机催化剂的作用下与各种亲电底物反应得到一系列的四氢呋喃多取代衍生物，这样可以制得高对映异构体纯度的化合物。同样对天然产物的全合成及药物的发现也具有重要意义。本论文第一部分对含有四氢呋喃环的天然产物及化学药物进行了综述，并对合成四氢呋喃环结构的研究方法进行了简要概述，并介绍了催化剂二苯基脯氨醇三甲基硅醚催化的不对称Michael加成反应的研究进展。本论文第二部分对2-羟基四氢呋喃和硝基烯的高效不对称Michael加成反应进行了详细研究，得到的手性3-取代半缩醛产物进一步进行结构修饰得到了一系列文拉法辛类似物，测试其抗抑郁活性发现，其中三个化合物的活性接近于文拉法辛。本论文第三部分对2-羟基四氢呋喃与其他亲电底物的不对称反应进行了广泛的初步研究，这些亲电底物包括邻羟基硝基苯乙烯、醌、马来酰亚胺等，证明了半缩醛在各类亲电底物中的广泛应用性。
[Abstract]:Oxygenated aliphatic heterocycles are a class of chemical structures which are widely used in various natural products and listed drugs. They have important application value in biology, medicine, pesticide and so on. It is especially worth mentioning that the tetrahydrofuran core of DNA unit in DNA structure is also an oxygen-containing fatty heterocycle which is also present in nucleoside drugs and is widely used in anti-tumor and anti-virus. Organic catalyzed asymmetric Michael addition reaction is an important method to construct C-C bond C-N bond and C-O bond. It has the advantages of low environmental pollution, good stability, low price, green environment and the ability to synthesize many chiral centers in one step. In this paper, a series of tetrahydrofuran polysubstituted derivatives were synthesized by the reaction of 2-hydroxytetrahydrofuran with various electrophilic substrates under the action of organic catalyst. In this way, a compound with high enantiomer purity can be prepared. It is also of great significance to the synthesis of natural products and the discovery of drugs. In the first part of this thesis, the natural products and chemical drugs containing tetrahydrofuran ring are reviewed, and the research methods for the synthesis of tetrahydrofuran ring structure are briefly summarized. The research progress of asymmetric Michael addition catalyzed by diphenyl proline trimethylsilyl ether was also introduced. In the second part of this thesis, the highly efficient asymmetric Michael addition reaction between 2-hydroxytetrahydrofuran and nitroene was studied in detail. The chiral 3-substituted semi-acetals were further modified to obtain a series of venlafaxine analogues. The antidepressant activity of three of the compounds was similar to that of venlafaxine. In the third part of this thesis, the asymmetric reactions of 2-hydroxytetrahydrofuran with other electrophilic substrates, such as o-hydroxynitrobenzene, quinone, maleimide, were studied. It is proved that hemiacetal is widely used in various electrophilic substrates.
【学位授予单位】：苏州大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

【参考文献】