金催化的环化反应及其在Cephalotaxine和Cephalezomine H合成中的应用

发布时间：2018-03-18 21:39

本文选题：三尖杉类生物碱　切入点：烯酰胺　出处：《兰州大学》2017年博士论文　论文类型：学位论文

【摘要】：三尖杉类生物碱是从三尖杉科植物中分离出来的具有重要生物活性的天然产物。自上世纪七十年代三尖杉碱(Cephalotaxine)被分离鉴定以来,由于其独特的五元稠环结构及其酯碱(三尖杉酯碱和高三尖杉酯碱)的抗白血病活性,它们的化学合成一直都是有机化学家与药物化学家的重要研究内容。虽然到目前为止已有多篇关于它们的全合成报道,但是探索三尖杉类生物碱的新合成路线仍然是该研究领域的重要内容。本论文以Cephalotaxine和具有细胞毒性的Cephalezomine H为研究对象,针对其独特的“氮杂螺环结构”的高效构建,设计了关键的“金催化的[2+3]环化反应”,并在此基础上展开了相关方法学的研究和三尖杉类生物碱Cephalotaxine与Cephalezomine H的全合成。本论文主要分为以下三个部分:第一部分:简要介绍了三尖杉的分布与分类、三尖杉碱的分离与鉴定、三尖杉生物碱的结构与生物活性;基于对前人合成工作的回溯,从不同的合成策略重点介绍了三尖杉碱的全合成和形式全合成中的一些重要进展;简要介绍了Cephalezomine H的分离与结构鉴定、全合成进展;提出本论文的立题思想,并通过对三尖杉生物碱的反合成分析,确定了合成该类生物碱的关键反应。第二部分:我们对关键反应——“过渡金属催化的烯酰胺与炔丙醇羧酸酯的环化反应”做了具体的方法学分析和研究。首先,我们简要介绍了过渡金属催化的炔丙醇羧酸酯的反应;然后,我们通过对模板底物进行条件筛选确定了环化反应的标准条件,并对该反应的官能团适应性和应用范围进行了详细的探讨;最后,鉴于底物的考察结果,我们提出了该反应可能的反应机理。第三部分:我们在方法学研究的基础上,通过对三尖杉生物碱更具体的反合成分析,提出了第一代合成策略——通过分子内[2+3]环化反应构建三尖杉生物碱骨架结构,并探讨了该合成路线的可行性;第一代合成策略探索失败后,我们又提出了第二代合成策略——通过分子间[2+3]环化反应构建氮杂螺环结构,并通过Witkop光环化反应构建苯并七元环,实现了三尖杉类生物碱Cephalotaxine与Cephalezomine H的消旋全合成。
[Abstract]:Huperzine alkaloids are natural products with important biological activity isolated from Huperidae plants. Since -30s, Huperzine Cephalotaxine has been isolated and identified. Due to its unique pentacentric ring structure and its antileukemia activity of its ester alkaloids (harringtonine and homoharringtonine), Their chemical synthesis has been an important research topic for organic chemists and pharmaceutical chemists. However, exploring the new synthetic route of Huperzine alkaloids is still an important part of this research field. In this paper, Cephalotaxine and cytotoxic Cephalezomine H were used as the research objects, and the highly efficient construction of its unique "nitrogen heterocyclic structure" was studied. The key "gold catalyzed [23] cyclization reaction" was designed, and based on this, the related methodology and the total synthesis of Cephalotaxine and Cephalezomine H were studied. The thesis is divided into three parts: the first part:. This paper briefly introduces the distribution and classification of Acanthia tricuspidata. The isolation and identification of Huperzine, the structure and bioactivity of Huperzine, based on the retrospect of previous synthetic work, some important advances in the total synthesis and form synthesis of Huperzine were introduced from different synthesis strategies. This paper briefly introduces the separation, structure identification and total synthesis of Cephalezomine H, puts forward the idea of this paper, and analyzes the antisynthesis of Huperzine alkaloids. The key reactions for the synthesis of these alkaloids have been determined. Part two: we have made a specific methodological analysis and study on the key reactions "cyclization of allylamides and propargyl carboxylate catalyzed by transition metals". We briefly introduced the transition metal-catalyzed reaction of propargyl alcohol carboxylate, and then we determined the standard conditions for the cyclization reaction by screening the template substrate. Finally, in view of the results of the substrate investigation, we put forward the possible reaction mechanism of the reaction. Based on the more specific anti-synthesis analysis of Huperzine alkaloids, the first-generation synthesis strategy was proposed, which was to construct the skeleton structure of Huperzine alkaloids by intramolecular [23] cyclization reaction, and the feasibility of the synthesis route was discussed. After the failure of the first generation synthesis strategy, we put forward the second generation synthesis strategy, which is to construct the structure of the azapol ring by [23] cyclization reaction between molecules, and to construct the benzo seven member ring by the Witkop photocyclization reaction. The racemic synthesis of Huperzine alkaloids Cephalotaxine and Cephalezomine H was achieved.
【学位授予单位】：兰州大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：O629.3

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