天然产物紫杉醇6/8/6骨架的合成研究

SYNTHETIC STUDY TOWARD THE 6/8/6 CORE SKELETON OF TAXOL

周毅飞

11849104

硕士

生物工程领域工程

李闯创

2020-06-01

2020-07-20

哈尔滨工业大学

深圳

作为对天然产物研究和利用的关键环节， 活性天然产物的全合成一直是有机化学的重要分支领域之一。本文所研究的紫杉醇是紫杉烷类二萜天然产物中最具代表性的一种，其复杂的分子结构和引人瞩目的生物活性长期以来一直是化学家、生物学家和医学家的研究热点。紫杉醇具有良好的抗肿瘤活性， 已在临床上广泛用于卵巢癌、乳腺癌和部分肺癌的治疗，是目前已知对卵巢癌和乳腺癌疗效最好的天然抗癌药物之一。紫杉醇的分子结构复杂，拥有一个[6/8/6]三环核心骨架，同时分子内八元环和桥头双键的存在导致了其分子环张力较大，多达十一个手性中心和较高的氧化态也大幅提高了紫杉醇的全合成难度。因其重要的生物活性以及极具合成挑战性的分子结构，紫杉醇自发现起就引起了众多科学家的研究兴趣。本论文对当前已有的紫杉醇的全合成、形式合成研究工作以及工业生产方法进行了简要总结，同时还汇总了其他一些紫杉醇家族化合物的合成研究进展。 本文希望借鉴当前已有的各类研究工作， 探索出一条高效、 简洁的合成路线来实现对紫杉醇[6/8/6]核心骨架的合成。本篇论文的合成工作采用了汇聚式合成策略，分别合成各个前体片段并利用锂卤交换反应将各个片段连接，再通过分子内Diels-Alder 反应完成紫杉醇核心骨架的构建， 达到了较高的合成效率。 同时，本文将尝试通过对分子内 Diels-Alder 反应前体分子结构的设计， 来实现紫杉醇核心骨架的手性控制。本论文已经完成了设计路线中各个前体片段的合成，并利用锂卤交换反应将各个前体进行连接， 最后经过筛选找到合适的反应条件，利用分子内 Diels-Alder反应得到了含有紫杉醇[6/8/6]核心骨架的分子， 所得的分子骨架构型和天然产物一致，为接下来实现对紫杉醇的全合成研究打下了坚实的基础。

As one of the key steps of the research and exploitation of natural products, total synthesis of bioactive natural products has been one of the most important fields of organic chemistry for a long time. Taxol, which is studied in this dissertation, is a notable member of the bioactive taxane diterpenoid family. Due to its complicated structure and impressive biological activities, chemists and biologists have paid a lot of concern on it since its first discovering. Taxol showed great antitumor bioactivities and has been used in the clinical treatment of many kinds of cancers, especially ovarian carcinoma, breast cancer for decades. Taxol is structured with a complicated and distinctive [6/8/6] tricyclic ring system, which is gifted with a high tension due to its eight-membered-ring and bridge-head double bond. The molecule has overall eleven chiral centers including three quaternary carbon chiral centers, which also makes a large contribution to the difficulty of the total synthesis of taxol. Because of its impressive biological activities and highly challenging molecular structure, taxol has been a research focus of many scientists for several decades.This paper includes a brief conclusion of the total synthesis, formal synthesis and industrial producting ways of taxol, as well as the synthetic research of other taxane family molecules. Based on the summary of precedent researches, we hope to developa concise synthetic route with high efficiency to obtain the [6/8/6] core skeleton of taxol. The whole plan is to utilize the convergent synthesis strategy to construct the core skeleton of the natural product through intramolecular Diels-Alder reaction,which is promising to increase the efficiency of the synthesis of taxol. Meanwhile, we desire to acquire the right chirality of the taxol core skeleton by feasible molecular design.In this study, we have already prepared the synthetic precursors and connected them with coupling reactions, intramolecular Diels-Alder reaction is applied for the synthesis of the core skeleton of taxol, of which the chirality is the same as the naturaltaxol molecules, making a solid foundation for our challenge to the total synthesis of taxol.

天然产物 紫杉醇 全合成 汇聚式合成 分子内 Diels-Alder 反应

natural product taxol total synthesis convergent synthesis intramolecular Diels-Alder reaction

中文

联合培养

南方科技大学

周毅飞. 天然产物紫杉醇6/8/6骨架的合成研究[D]. 深圳. 哈尔滨工业大学,2020.