苯安莎霉素类天然产物的全合成探索（Ⅰ）

发布时间：2018-06-19 04:27

本文选题：Hsp90抑制剂 + Reblastatin　；参考：《北京协和医学院》2014年硕士论文

【摘要】：Hsp90是一类能够促进蛋白质正确折叠,并在应激条件下防止蛋白质变性以及细胞凋亡的分子伴侣,它在癌细胞中高度表达,促进癌症的发生与发展。抑制Hsp90的功能,可促使癌基因泛素化并降解,达到治疗癌症的目的。 Geldanamycin和Reblastatin等苯安莎霉素类天然产物及其结构修饰物能够竞争性抑制Hsp90的N端ATP结合位点,表现出良好的Hsp90抑制活性。本论文总结前人的研究基础,设计了一条经济高效的路线完成了对Reblastatin的全合成,并对Geldanamycin的合成进行了探索。具体分为以下几点：1.Geldanamycin的合成探索尝试通过Evans辅基诱导的烷基化反应构建C11-C20片段以及经Julia烯化和环氧开环引入C8-C10片段失败,最终探索了一条以Y-丁内酯诱导的不对称烷基化、将酯基彻底还原为甲基以及手性丙二烯诱导的不对称炔丙基化等为关键反应的路线完成了Geldanamycin的C8-C20片段的克级制备。虽在片段连接中出现了脱溴还原的现象以及关环反应中出现了脱MOM的情况,但提出了此问题的解决方法,为后续的全合成工作打下了基础。 2.Iteblastatin的全合成45mg first batch 经γ-丁内酯诱导的不对称烷基化、将酯基彻底还原为甲基、手性丙二烯诱导的不对称炔丙基化以及Zr/Zn介导的还原偶联等关键反应完成Reblastatin的全合成,优化了手性丙二烯的合成方法及Panek的组装策略。3.经HWE、Sharpless不对称双羟化以及Pd/C氢化的方法完成了Herbimycin A全合成中关键中间体γ-丁内酯的制备。
[Abstract]:Hsp90 is a kind of molecular chaperones which can promote the correct folding of proteins and prevent protein degeneration and apoptosis under stress. Hsp90 is highly expressed in cancer cells and promotes the occurrence and development of cancer. Inhibiting the function of Hsp90 can promote the Ubiquification and degradation of oncogene and achieve the purpose of cancer treatment. The natural products of benzamicin such as Geldanamycin and Reblastatin and their structural modifiers can competitively inhibit the N-terminal ATP binding sites of Hsp90. It showed good inhibitory activity of Hsp90. In this paper, we summarized the previous research basis, designed an economical and efficient route to complete the total synthesis of Reblastatin, and explored the synthesis of Geldanamycin. Geldanamycin synthesis attempts to construct C11-C20 fragment by Evans cogroup induced alkylation reaction, and failed to introduce C8-C10 fragment through Julia alkenation and epoxide ring opening. Finally, a key reaction route of asymmetric alkylation induced by Y- butyrolactone, complete reduction of ester group to methyl and asymmetric allylation induced by chiral allene was explored to prepare the C8-C20 fragment of Geldanamycin. Although the debromination reduction occurred in the fragment connection and the de-MOM occurred in the closed ring reaction, the solution to this problem was put forward. 2. The complete synthesis of Iteblastatin was induced by asymmetric alkylation of 纬 -butyrolactone, and the ester group was completely reduced to methyl. The synthesis of Reblastatin was completed by asymmetric allylation induced by chiral allylene and reduction coupling mediated by Zr / Zn. The synthesis method of chiral allylene and the assembly strategy of Panek were optimized. The synthesis of the key intermediate 纬 -butyrolactone in the total synthesis of Herbimycin A was completed by using the method of asymmetric double hydroxylation and PD / C hydrogenation.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

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