生物碱Minfiensine的全合成研究

发布时间：2018-03-10 07:10

本文选题：生物碱Minfiensine　切入点：[3+2]环加成反应　出处：《山东大学》2017年硕士论文　论文类型：学位论文

【摘要】：1989年,Massiot课题组首次从一种生长在非洲的植物Strychnos Minfiensis体内分离出了生物碱Minfiensine。虽然从发现并提取出生物碱Minfiensine距今已有将近三十年,但是迄今为止生物碱Minfiensine的生物合成途径仍然不清楚。然而,此类生物碱不仅生物活性好,而且化学结构也比较特殊,因此引起了有机合成化学家们的广泛关注。经过结构分析,我们认为生物碱Minfiensine可以看成是由吲哚、卤代酰胺及丁烯片段三部分构成。本论文的主要工作就是探索新的化学合成方法将三个片段组合起来合成生物碱Minfiensine。2016年,我们课题组报道了吲哚衍生物和卤代酰胺化合物的[3+2]环加成反应研究。随后,我们发现该研究可以用于构建生物碱Minfiensine的核心骨架结构。本论文以[3 + 2]环加成反应作为此全合成研究的基础,并在此基础上展开了生物碱Minfiensine的全合成研究。我们的全合成研究以廉价的苯肼作为起始原料,经过Fisher吲哚合成法合成吲哚片段。经过PMB保护基保护吲哚片段上的氮原子以后,与卤代酰胺化合物经过一步[3+2]环加成反应得到四元环骨架结构。此步反应也是我们整个全合成研究中的亮点。接下来,在催化量金属钌催化下,用金属锌铜切断四元环骨架化合物上的一个C-O键及两个C-C1键,然后经过一步还原消除和一步缩羰基保护基脱除反应得到四元环骨架中间体。拿到四元环骨架中间体以后,随即与丁烯基片段发生烃基化反应得到烯基碘代化合物。接着,在金属钯催化下完成分子内Heck环化反应以构建最后一个六元环。六元环构建成功后,用Comins'试剂将化合物上的酮羰基转化为三氟甲磺酸烯醇酯。最后,经过Stille偶联反应及保护基脱除反应等得到生物碱Minfiensine的消旋体。在此期间,我们也对[3+2]环加成反应进行了不对称合成研究,以期望可以找到合适的方法构建具有光学活性值的骨架结构。然后,基于该不对称合成方法构建具有光学活性值的核心四元环骨架结构。遗憾的是未能找到合适的配体合成不对称四元环骨架中间体。我们设计了全新的合成路线,成功连接了三个片段,并且以10步,26%的总收率成功完成了生物碱Minfiensine的全合成研究。相比于以前的全合成研究,我们的全合成研究不仅路线较短、总收率较高,而且反应原料廉价易得,条件温和,适合大量合成。
[Abstract]:In 1989, the Massiot team first isolated the alkaloid Minfiensine from Strychnos Minfiensis, a plant growing in Africa. Although it has been nearly 30 years since the discovery and extraction of the alkaloid Minfiensine, But the biosynthesis pathway of alkaloid Minfiensine is still unclear. However, this kind of alkaloids not only has good biological activity, but also has a special chemical structure, so it has attracted wide attention of organic synthetic chemists. We think that the alkaloid Minfiensine can be regarded as composed of indole, halogenated amides and butene fragments. The main work of this thesis is to explore a new chemical synthesis method to combine the three fragments to synthesize alkaloid Minfiensine.2016 year. Our group reported the [32] cycloaddition reaction of indole derivatives and halogenated amides. We found that this study can be used to construct the core skeleton structure of alkaloid Minfiensine. On this basis, the total synthesis of alkaloid Minfiensine was carried out. Our total synthesis was based on cheap phenylhydrazine as the starting material, and the indole fragment was synthesized by Fisher indole synthesis. After protecting the nitrogen atom in the indole fragment by PMB protection group, After one-step [32] cycloaddition reaction with halogenated amide compounds, the four-member ring skeleton structure was obtained. This step reaction is also a highlight in our whole synthesis. Then, under the catalysis of ruthenium, A C-O bond and two C-C1 bonds were cut off from the four-member ring skeleton compound by zinc and copper metal. After one-step reduction elimination and one-step carbonyl protection removal reaction, the four-member ring skeleton intermediate was obtained, and the four-member ring skeleton intermediate was obtained. The alkylation reaction with butenyl fragment was followed by the alkylation of alkyl iodide compounds. Then, the intramolecular Heck cyclization reaction was completed under the catalysis of palladium to construct the last six-member ring, and the six-member ring was successfully constructed. The ketone carbonyl group on the compound was converted to trifluoromethylsulfonate by comins' reagent. Finally, the racemates of alkaloid Minfiensine were obtained by Stille coupling reaction and protective group removal reaction. We have also studied the asymmetric synthesis of [32] cycloaddition reaction, which is expected to find a suitable method to construct the skeleton structure with optical activity. Based on the asymmetric synthesis method, the core quaternary ring skeleton structure with optical activity value was constructed. Unfortunately, it is not possible to find a suitable ligand to synthesize the asymmetric quadrilateral ring skeleton intermediate. We have designed a new synthesis route. The total synthesis of alkaloid Minfiensine was successfully completed with a total yield of 10 steps and 26%. Compared with the previous total synthesis studies, our total synthesis was not only shorter, but also higher in total yield. And the reaction raw material is cheap and easy to obtain, the condition is mild, suitable for a large number of synthesis.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O629.3

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