苯醌安莎霉素类天然产物的全合成探索（Ⅱ）

发布时间：2018-02-03 06:56

本文关键词： 苯醌安莎霉素 Herbimycin A 热休克蛋白90抑制剂不对称合成　出处：《北京协和医学院》2014年硕士论文　论文类型：学位论文

【摘要】：本论文介绍了一条兼具实用性与经济性的苯醌安沙霉素类天然产物的通用合成路线。以Sharpless不对称双羟化反应、Katuski不对称环氧化反应为关键步骤,构建了苯醌安莎霉素类天然产物C8-C15部分的通用合成砌块。利用Weinreb-CBS策略引入芳香片段,并构建C15位手性中心。以市售手性源物质为原料,经7步简单的化学反应合成了C1-C7片段。随后,通过5步反应实现了目标分子的后期组装工作；其中,借助于二甲基锌介导的亲核加成反应,立体选择性地完成了片段连接。最终,经19步线性步骤成功地完成了HerbimycinA的全合成,总收率为4.2%。另一方面,凭借Weinreb-去羰基化策略,经9步反应,构建了GeldanamycinC11-C21片段,总收率为24%。证明了此路线系一条苯醌安沙霉素类天然产物的通用合成路线。以上合成路线以催化的不对称反应代替了昂贵且敏感的手性试剂及原料；同时,避免了因使用手性辅基而带来的官能团转化步骤。此外,在后期阶段引入芳环部分,实现了该类化合物的汇聚性合成。简捷的骨架构建方法和灵活的手性中心建立策略,使我们有能力开展关于苯醌安莎霉素类化合物的构效关系研究以及结构改造工作。
[Abstract]:This paper introduces a general synthetic route of benzoquinone anamycin natural products which is both practical and economical. The key step is Sharpless asymmetric double hydroxylation reaction and Katuski asymmetric epoxidation reaction. The general synthetic block of natural product of benzoquinone Ansanamycin C 8-C 15 was constructed and aromatic fragments were introduced by Weinreb-CBS strategy. The C _ 1-C _ 7 fragment was synthesized by a simple chemical reaction of seven steps, and the target molecule was assembled at a later stage by a five-step reaction, and the chiral center of C _ (15) was constructed. The chiral material was used as the raw material and the C _ 1-C _ 7 fragment was synthesized by a simple chemical reaction in 7 steps. The fragment ligation was accomplished stereoselective by dimethylzinc-mediated nucleophilic addition reaction. Finally, the complete synthesis of HerbimycinA was successfully completed through 19 step linear steps. The total yield was 4.2. On the other hand, the GeldanamycinC11-C21 fragment was constructed by 9 steps with Weinreb-decarbonylation strategy. The total yield is 24. It is proved that this route is a general synthetic route for the natural products of benzoquinone ansarcomycin. The above synthetic route replaces the expensive and sensitive chiral reagents and raw materials with catalytic asymmetric reactions. At the same time, the step of functional group transformation caused by the use of chiral cogroups is avoided. In addition, the aromatic ring is introduced at a later stage. The convergent synthesis of this kind of compounds, simple skeleton construction method and flexible chiral center establishment strategy have been realized. It enables us to study the structure-activity relationship and structural modification of benzoquinone Ansanamycin compounds.
【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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