基于裂环马钱子碱的非天然生物碱的一步手性合成、改造及吲嗪类、二氢吲嗪类杂环化合物的构建

发布时间：2018-04-01 13:08

本文选题：裂环马钱子碱　切入点：一步法　出处：《浙江大学》2017年硕士论文

【摘要】：生物碱是一类广泛存在于自然界中具有重要活性的天然产物,其中萜类吲哚生物碱和异喹啉类生物碱具有重要生物活性,这两类生物碱具有一个共同的前体裂环马钱子碱。裂环马钱子碱在生物化学中具有很高的研究价值不仅是因为其乃是生物碱合成的重要前体物质,并因为富含多个反应官能团和多个手性中心,使其能作为反应原料合成具有复杂结构和复杂光学活性的化合物,为新结构新活性化合物的合成提供了基础。论文第二部分主要是非天然生物碱的合成,针对裂环马钱子碱的多个官能团的反应特性,以裂环马钱子碱为基础,与一分子具有双负电性的化合物苯二胺类,乙二胺类,羟氨类,乙醇胺类以及脯胺醇进行反应,通过一步法构建了具有立体选择性的五类共21个非天然生物碱,分别为苯丙咪唑类生物碱,[5,6,6]-四氢咪唑类生物碱,[5,5,6]-四氢异恶唑类生物碱,[5,6,6]-四氢恶唑类生物碱以及六氢吡咯并恶唑类生物碱。得到的五类生物碱具有单一的手性构型,以及多个反应活性位点,为后续继续改造提供了基础。此外,上述21个生物碱中,其中1个具有五元骈合的新结构母核,与喜树碱结构具有相似性,我们通过结构修饰得到更加稳定并且具有刚性结构的衍生物,希望通过后续的活性筛选和不断改造能得到具有良好生物活性的化合物。论文第三部分是类药性杂环化合物的构建,我们用简单、易得的原料通过"一锅法"快速构建19个二氢吲嗪和19个吲嗪类化合物。此方法以N-吡咯-2-甲醛衍生物和硝基乙烯苯衍生物为原料,采用简单,高效的方法合成了三取代的吲嗪衍生物,为吲嗪类药物中间体衍生物的合成提供了参考。
[Abstract]:Alkaloids are a class of natural products which have important activities in nature, among which terpenoids and isoquinoline alkaloids have important biological activities. These two kinds of alkaloids have a common precursor, cleft ring brucine, which is of great value in biochemistry not only because it is an important precursor in the synthesis of alkaloids, And because they are rich in many reaction functional groups and chiral centers, they can be used as raw materials to synthesize compounds with complex structure and complex optical activity. The second part is about the synthesis of non-natural alkaloids, which is based on the reaction characteristics of several functional groups of cleft ring brucine. In one step reaction with a molecule of di-negative compounds phenylenediamine, ethylenediamine, hydroxylamine, ethanolamine and proline, 21 non-natural alkaloids with stereoselectivity were obtained. These alkaloids are phenylpropylimidazole alkaloids, [5hloropyrroxazole alkaloids] -tetrahydroimidazole alkaloids, [5andioxazole alkaloids] -tetrahydrooxazole alkaloids, and hexahydropyrrolidone oxazole alkaloids. The five alkaloids obtained have a single chiral configuration. In addition, of the 21 alkaloids mentioned above, 1 has a new nuclear structure, which is similar to that of camptothecin. We get derivatives that are more stable and have rigid structures through structural modification. It is hoped that the compounds with good biological activity can be obtained by subsequent screening and continuous modification. The third part of this paper is about the construction of heterocyclic compounds, which we use simply. The easily obtained raw materials were quickly synthesized into 19 dihydroindapamide and 19 indapamide compounds by "one pot method". The method was simple, using N- pyrrole-2-formaldehyde derivatives and nitroethylbenzene derivatives as raw materials. Tri-substituted indapamide derivatives were synthesized by a high efficiency method, which provides a reference for the synthesis of indapamide derivatives.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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