RCEES OpenIR  > 中国科学院环境生物技术重点实验室
海洋天然产物Leiodolide A的全合成研究
Alternative TitleStudies Towards the Total Synthesis of Leiodolide A
Thesis Advisor杜宇国
Degree Grantor中国科学院研究生院
Place of Conferral北京
Degree Discipline有机化学
Keyword海洋天然产物 全合成 Leiodolide a 手性源途径 Total Synthesis 碳水化合物 Leiodolide a Marine Natural Products Chiron
Other Abstract      海洋天然产物开发是目前资源最丰富、保存最完整、最具有新药开发潜力的新领域,全合成则是解决此类天然产物来源需求的首要途径。天然产物Leiodolide A是从深海海绵中提取得到的具有抗肿瘤活性的大环内酯,本论文主要涉及糖类化合物作为手性源对该复杂分子的全合成以及合成方法学研究等内容。全文共分五章:
      第一章 综述了2000年以来由糖类化合物作为手性原料合成复杂海洋天然产物或衍生物的研究进展,同时也简要介绍了在这些合成工作中发展的一些常见合成策略和优秀方法学。
      第二章 介绍了leiodolides类化合物的分离、鉴定、生物背景以及文献已报道的合成工作。本工作设计了Leiodolide A的逆合成分析路线,将其拆分成C1-C10、C11-C17、C22-C31三个片段,以期采用汇聚式的合成策略完成目标分子的合成, 并以L-阿拉伯糖醇为手性源完成了手性砌块C11-C17的构建。
      第三章 通过Evans aldol反应、Stille偶联等关键反应以线性步骤7步完成了噁唑片段C1-C10的构建。同时,也利用Vinylogous aldol反应完成了该片段外消旋体的合成,线性步骤和总产率都有较高优化。发展了一种利用B-Alkyl Suzuki-Miyaura 偶联来构建2-alkyl-oxazole的方法学,并首次发现了2, 4-二碘代噁唑的2位选择性B-Alkyl Suzuki反应。
      第四章 发展了一种在碘代乙烯基存在下,利用P2-Ni氢化将炔键还原成顺式双键的方法学,并通过该方法完成了Leiodolide A的片段C22-C31的合成。
      第五章 详细阐述了三个片段的组装摸索。通过B-Alkyl Suzuki-Miyaura 偶联成功将片段C1-C10和C11-C17连接起来,并尝试利用Nozaki-Hiyama-Kishi反应和卤锂交换的策略来完成与片段C22-C31的对接,但实验结果不理想。目前已经对路线进行了适当调整,正在探索中。;       Natural products exist in a wide range of organism derived from marine source, which often exhibit extensive biological activities. This dissertation deals with the new synthetic methodologies research and study towards the synthesis of Leiodolide A, a complex marine natural product, exhibiting significant cytotoxic activity. Five chapters are included in the thesis:
      Chapter one reviewed total synthesis of marine natural products using carbohydrate as chiron since 2000. Several efficient strategies and methodologies developed in this area were introduced.
      Chapter two outlined the structures、biological activities and recent synthetic research of leiodolides. A convergent synthetic strategy of Leiodolide A was proposed in this thesis work, dissecting the target molecule into three subunits C1-C10、C11-C17、C22-C31. The fragment C11-C17 was finished from L-Arabitiol in 11 steps.
      Chapter three described the synthesis of fragment C1-C10 using Evans aldol reaction and Stille coupling as key steps. And then a more efficient synthesis of racemic fragment C1-C10 was developed via Vinylogous aldol reaction. In addition, an efficient synthesis towards 2-alkyl substituted oxazoles has been achieved through Suzuki cross-coupling reaction.
      Chapter four established a rapid and efficient cis-reduction of alkyne bond in the presence of a vinyl iodide. And then a stereoselective synthesis of fragment C22-C31 was constructed using this new methodology.
      Chapter five elaborated the coupling research between the three fragments above. Fragment C1-C10 and C11-C17 were successfully connected via Suzuki coupling, but the connection with fragment C22-C31 was unsatisfactory. However, modified synthetic route is established and new explorations are in progress.
Document Type学位论文
Recommended Citation
GB/T 7714
张幸. 海洋天然产物Leiodolide A的全合成研究[D]. 北京. 中国科学院研究生院,2014.
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