具有重要生理活性海洋天然产物Apratoxin E的合成研究

发布时间：2018-08-09 18:30

【摘要】：大多数海洋天然产物都具有广泛的生理活性,环肽酯作为一类重要的天然产物,表现出优异的生理活性。对海洋环肽类天然产物的研究是当前天然产物研究的热点之一。然而,大多数海洋天然产物由于分离困难而限制了其进一步的研究。通过全合成的方法对海洋环肽类天然产物进行研究,可以克服这一弊端。而且,结构多样性合成可以作为发现先导化合物重要手段。本论文工作包括以下两个部分:第一部分内容为:具有抗癌活性的海洋天然产物Apratoxin E的合成及构型确证。1.以皂苷降解过程中产生的工业废水提取物内酯163为手性源,经过(R)-CBS诱导的不对称还原以dr=88:12构筑手性羟基。最终经10步反应,以19%的总收率完成了Apratoxin E合成所需关键片段161的合成。2.通过分子间烯烃复分解反应以高选择性构筑所需反式双键,最后在C6-N处以HATU为缩合剂以19%的收率完成大环环合,实现了Apratoxin E的合成。3.通过对对接关环策略的优化,在C27-N以FDPP为缩合剂进行大环环合,最终以43%的收率实现大环环合,提高了Apratoxin E的合成效率。4.通过对30-epi-Apratoxin E的合成,完成了Apratoxin E的结构确证。第二部分内容为:羟乙基二肽电子等排体的多样性合成工艺研究。1.以谷氨酸为原料,通过不对称烷基化,经10步反应,以6.5%的总收率完成了亚胺315的合成。2.完成了羟乙基二肽电子等排体关键中间体317的多样性合成。得到了6个C-6位不同取代的化合物317a-f的十克级产物。
[Abstract]:Most marine natural products have a wide range of physiological activities, cyclic peptide esters as a class of important natural products, showing excellent physiological activity. The research of marine cyclic peptides is one of the hot spots in the research of natural products. However, most marine natural products have limited their further research due to the difficulty of separation. This drawback can be overcome by studying the natural products of marine cyclic peptides by the method of total synthesis. Moreover, the synthesis of structural diversity can be used as an important means of finding lead compounds. The work of this thesis includes the following two parts: the first part is: synthesis and configuration confirmation of marine natural product Apratoxin E with anticancer activity. The chiral hydroxyl group (dr=88:12) was constructed by asymmetric reduction induced by (R)-CBS using lactone 163, an industrial wastewater extract produced during the degradation of saponins, as a chiral source. Finally, the key fragment 161 for Apratoxin E synthesis was synthesized with a total yield of 19% through a 10-step reaction. The necessary trans-double bonds were constructed by the cross-molecular olefin double decomposition reaction. Finally, the macrocyclic cyclization of Apratoxin E was achieved with 19% yield at C6-N with HATU as the condensation agent, and the synthesis of Apratoxin E was realized. By optimizing the closing ring strategy, macrocyclic cyclization was carried out at C27-N with FDPP as the condensation agent, and the macrocyclic cyclization was finally achieved in 43% yield, and the synthesis efficiency of Apratoxin E was improved by .4. The structure of Apratoxin E was confirmed by the synthesis of 30-epi-Apratoxin E. In the second part, the synthesis process of hydroxyethyl dipeptide was studied. Through asymmetric alkylation with glutamic acid as raw material, the synthesis of imide 315 was completed in a total yield of 6.5% after 10 steps of reaction. The diversity synthesis of the key intermediate 317 of hydroxyethyl dipeptide was completed. Six C-6 disubstituted compounds, 317a-f, were obtained in 10 g order.
【学位授予单位】：西北农林科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O629

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