SYNTHETIC METHODOLOGY TOWARDS THE PREPARATION OF ANSAMYCIN ANTIBIOTICS

全反式异构体对映体选择性方法学的发展 安莎霉素类抗生素利福霉素S和静脉曲张链菌素的合成 而乙内酰抗生素巴弗洛霉素A1和elaiophylin是 这是该提案的长期目标。这些聚丙酸天然产物 显示出广泛的生物活性。近年来， 对它们研究和利用（以及一些半合成 衍生物）作为治疗剂已经被广泛的 科学文献在这个领域产生。 更具体地说，我们建议正式全面综合 利福霉素S，以及 链静脉霉素D、巴弗洛霉素A1和elaiophylin，基于 环氧乙烷化学的利用。这些目标的选择 分子是基于其显着的生物活性，伟大的 其他研究小组对它们的综合表现出兴趣， 这是一个挑战，代表着不同的 在其聚丙酸酯单元中发现的相同构型 方法论 报告的这些目标的综合方法，以及许多其他目标， 聚丙酸酯体系，通常基于羟醛和相关的 化学.我们认为，利用环氧化学作为一种 这些系统的一般方法将受到 合成社区我们的方法是一个迭代的，是基于 高烯丙醇的立体选择性环氧化， 碘环化反应后，它们通过有机铝裂解 化学.通过这种方法，我们可以控制 聚丙酸酯的特征甲基和羟基 单位 不仅在此提出的所需的化学转化， 将完成广泛的研究。范围、限制、 立体化学和关键反应的机理含义 本研究中所包含的内容将被研究。尽管我们的方法论 原则上应适用于这些具体目标， 适用于许多其它聚丙酸酯体系。

The development of an enantioselective methodology for the total synthesis of the ansamycin antibiotics rifamycin S and streptovaricin D, and the hygrolide antibiotics bafilomycin A1 and elaiophylin is the long term goal of this proposal. These polypropionate natural products exhibit a broad range of biological activity. In recent years a great interest in their study and utilization (and that of some semisynthetic derivatives) as therapeutic agents has been evidenced by the extensive scientific literature being generated in this area. More specifically, we are proposing a formal total synthesis of rifamycin S, and the elaboration of the polypropionate units of streptovaricin D, bafilomycin A1 and elaiophylin, based on the utilization of oxirane chemistry. The selection of these target molecules is based on their notable biological activity, the great interest in their synthesis shown by other research groups, and the challenge that represents the elaboration of the different configurations found in their polypropionate units by the same methodology. The reported synthetic approaches to these targets, as for many other polypropionate systems, have been usually based on aldol and related chemistry. We believed that the utilization of epoxide chemistry as a general approach to these systems will be well received by the synthetic community. Our approach is a reiterative one and is based on the stereoselective epoxidation of homoallylic alcohols by means of iodocylisation reactions followed their cleavage via organoaluminium chemistry. With this methodology we can control the configuration of the methyl and hydroxyl groups which characterize the polypropionate units. Not only the desired chemical transformations proposed in this extensive study will be accomplished. The scope, limitations, stereochemistry and mechanistic implications of the key reactions included in this study will be examined. Although our methodology will be applied to these specific targets in principle its should be applicable to many other polypropionate systems.