硫叶立德与手性磷酸的合成及其在构筑螺环体系中的应用

发布时间：2018-05-05 11:34

本文选题：螺环化合物 + 硫叶立德　；参考：《成都学院》2017年硕士论文

【摘要】：螺环骨架是药用化合物中非常重要的一类结构骨架。由于其高效的药用价值,螺环骨架也一直是有机化学中的研究热点。本文通过硫叶立德和BINOL手性磷酸,成功的合成了螺环环丙烷产物,和N-杂螺环产物,为螺环化合物的研究和发展提供了有力的参考借鉴。本文的第一章对环丙烷的研究进展进行了系统的综述,包括环丙烷的理化特性、药用价值、参与的主要化学反应和主要构建方法等。环丙烷对药物体内代谢的影响主要包括增加整体结构的稳定、延缓化合物的氧化代谢,以及改变药物的亲脂性等。目前,多种含有环丙烷骨架的化合物已作为安全有效的药物进入了临床使用,包括抗癌药物Lenvatinib,抗HCV药物Boceprevir和Ledipasvir等。从结构上分析,环丙烷的C-C键与烯烃的C=C具有相类似的反应活性,在催化剂的作用下能够发生开环反应,生成1,3-两性离子中间体,进而与亲核试剂或者亲电试剂发生反应构建各类杂环体系。目前,已报道的环丙烷的构建方法主要是Simmons-Smith反应、过渡金属催化的成环丙烷反应,以及Michael-initiated关环反应。本文的第二章报道了一种基于硫叶立德构建螺环环丙烷骨架的方法。该实验以稳定的硫叶立德和缺电子环烯酮为底物,合成了一系列螺环环丙烷产物。该实验具有反应活性高、高产率和高非对映选择性等优势,同时反应条件温和,操作简便。并且通过手性诱导的方式,合成了具有对映选择性的螺环环丙烷产物,该手性系列产物的反应同样具有高产率。本文的第三章论述了BINOL手性磷酸的合成及应用。对制备手性BINOL磷酸的工艺路线进行了简单的优化,得到了一条高效、简便的合成路线。使用所制备的BINOL磷酸催化剂实现了缺电子环烯酮和吖内酯衍生物的[2+3]成环反应,得到了系列N-杂五元螺环产物。该反应不但具有高产率,同时具有很高的立体选择性。
[Abstract]:Snail cytoskeleton is one of the most important structural skeletons in medicinal compounds. Because of its efficient medicinal value, snail skeleton has been a hot spot in organic chemistry. In this paper, the products of spirocyclic propane and N-heterospira were successfully synthesized by using sulfurylide and BINOL chiral phosphoric acid, which provides a useful reference for the research and development of spirocyclic compounds. In the first chapter, the research progress of cyclopropane is reviewed systematically, including the physicochemical properties, medicinal value, main chemical reactions and construction methods of cyclopropane. The effects of cyclopropane on drug metabolism mainly include increasing the stability of the whole structure, delaying the oxidative metabolism of compounds, and changing the lipophilicity of the drug. At present, many kinds of compounds containing cypropane skeleton have been used as safe and effective drugs, including the anticancer drugs Lenvatinib, HCV drugs Boceprevir and Ledipasvir and so on. The structure analysis shows that the C-C bond of cyclopropane has a similar activity to that of alkenes, and the ring opening reaction can take place under the action of catalyst to form an intermediate of 1 ~ (3) -amphoteric ion. Furthermore, various heterocyclic systems were constructed by reaction with nucleophilic reagents or electrophilic reagents. At present, the construction methods of cyclopropane are mainly Simmons-Smith reaction, transition metal catalyzed cyclopropane reaction and Michael-initiated ring closing reaction. In the second chapter, a method of constructing the framework of spirocyclic propane based on Sulphur is reported. In this experiment, a series of spirocyclic propane products were synthesized by using stable ylide and electron-deficient cycloketene as substrates. The experiment has the advantages of high reaction activity, high yield and high enantioselectivity. The reaction conditions are mild and the operation is simple. The enantioselective products of spirocyclic propane were synthesized by chiral inducement. The reaction of the chiral series was also of high yield. In chapter 3, the synthesis and application of BINOL chiral phosphoric acid are discussed. A simple and simple synthetic route of chiral BINOL phosphoric acid was obtained. Using the prepared BINOL phosphoric acid catalyst, the [23] ring formation reaction of electron-deficient cyclienone and acridine derivatives was carried out, and a series of N-hetero-pentagonal spiroring products were obtained. This reaction not only has high yield, but also has high stereoselectivity.
【学位授予单位】：成都学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914.5

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