作者:       管玉翠
论文题目:   抗肿瘤活性复杂天然大环内酯24-Demethylbafilomycin C1的全合成研究
学位：      博士
年份：      2007
摘要：      复杂天然产物的全合成是有机化学中一个非常重要的领域，它不断地推动新的方法学和合成策略的发展。天然产物24-Demethylbafilomycin C1 是B类Plecomacrolide 家族中一个新型的具有抗菌、抗肿瘤活性的大环内酯抗生素。本论文的内容就是研究这个复杂分子的全合成 。           

                        第一章主要介绍了Plecomacrolide 家族各类化合物的结构特征、活性以及已经报道的四种合成Bafilomycin A1 的策略和路线。Bafilomycin A1与24-Demethylbafilomycin C1 的结构非常类似，都含有一个16 元环的四烯内酯，属于B 类Plecomacrolide。我们提出了一条新颖的全合成路线，采用Diene-ene闭环烯烃复分解反应来构建16 元环内酯骨架。

                        第二章主要论述了我们合成24-Demethylbafilomycin C1 片断C13-C25的路线。此片断共有8 个手性中心，我们采用了关键的aldol 反应连接手性醛和手性乙基酮小片断。我们的实验证明了C22 位甲基的立体化学对aldol 反应的选择性影响巨大。醛片断的合成从手性原料出发，利用了不对称Takai 甲氧基烯丙基化反应。乙基酮片断的合成充分利用了不对称催化氢化、分子内诱导的反式烷基化、Sharpless 不对称环氧化、区域选择性环氧开环等高度立体选择性的反应来建立所需手性中心。

                        第三章系统地介绍了我们对Diene-Ene RCM 反应在Bafilomycin 类大环四烯内酯合成应用中的探索。我们通过模型反应考察了催化剂、反应温度、取代基、分子内双键的位置等对RCM 反应的影响，提出了一条新颖的合成16元环四烯内酯的路线：aldol 反应-Diene-ene RCM-b-消除。

                        实验部分罗列了具体操作步骤和新化合物的表征数据以及引用文献。总之，我们对“Diene-ene RCM”策略的探索和实现片断C13-C25 的不对称合成为天然产物24-Demethylbafilomycin C1 及其系列物的全合成奠定了基础。

关键词：   全合成、24-Demethylbafilomycin C1、aldol 反应、Diene-Ene RCM、16 元环四烯内酯

Author:             Yucui GUAN
Title:                 Study toward Total Synthesis of Complex Antitumor Plecomacrolide 24-Demethylbafilomycin C1
Degree:            PhD
Year:                2007
Abstract:          Total synthesis of complex natural products, which often facilitates new discovery and development in synthetic methodologies and strategies, is a very important field in organic chemistry. This thesis focuses on studies toward total synthesis of 24-demethylbafilomycin C1, a new member of the Class B plecomacrolide antibiotics, exhibiting strong cytotoxicity against tumor cell lines.

                        Chapter One outlines the structures and biologic activities of the plecomacrolides, and the reported total syntheses of Bafilomycin A1, a representative structure of the Class B sub-group, which shares a common 16-membered ring macrolactone with our synthetic target. Introduction of our novel retro-synthetic strategy is followed, featuring a “1,3-diene-ene RCM” protocol for formation of the macrocycle.

                        Chapter Two describes our efficient synthesis of C13-C25 fragment of 24-demthylbafilomycin C1. It possesses 8 chiral centers, which are assembled through enantioselective ketone hydrogenation, b-hydroxy-directed anti-a-alkylation, Sharpless asymmetric epoxidation, Takai’s g-methoxyallylation, and substrate-controlled aldol reaction.

                        Chapter Three presents our results on a systematic investigation of “1,3-diene-ene RCM” toward the 16-membered macrolactone ring. The effort enables construction of a model macrolactone possessing the tetra-ene functionality via a sequence of methoxyacetate aldol reaction→1,3-diene-ene RCM→b-elimination.

                        The experimental section summarizes all reaction procedures with full compound characterization data. It is followed by cited references. In conclusion, establishment of the “1,3-diene-ene RCM” protocol toward the macrolactone and access to the C13-C25 fragment lay down the foundation for total synthesis of 24-demethylbafilomycin C1.

Keywords:       aldol reaction, 24-demethylbafilomycin C1, diene-ene RCM, 16-membered tetraenoic macrolactone, total synthesis