SYNTHETIC METHODOLOGY TOWARDS THE PREPARATION OF ANSAMYCIN ANTIBIOTICS

总对映选择性方法的开发 安沙霉素类抗生素利福霉素 S 和链霉素的合成 D、 hygrolide 类抗生素 bafilomycin A1 和 elaiophylin 是 本提案的长期目标。这些聚丙酸酯天然产物 表现出广泛的生物活性。近年来伟大的 对它们的研究和利用（以及一些半合成的 衍生物）作为治疗剂已被广泛证明 该领域正在产生科学文献。 更具体地说，我们提出了一种正式的全合成 利福霉素 S，以及聚丙酸酯单元的精制 链霉素 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， 其他研究小组对它们的合成表现出兴趣，并且 代表着不同的阐述的挑战 在其聚丙酸酯单元中发现的构型相同 方法论。 报道的这些目标的合成方法以及许多其他目标 聚丙酸酯系统，通常基于羟醛和相关的 化学。我们相信，利用环氧化物化学作为 这些系统的一般方法将受到 综合社区。我们的方法是一种反复的方法，并且基于 高烯丙醇的立体选择性环氧化 通过有机铝裂解后发生碘酰化反应 化学。通过这种方法，我们可以控制 甲基和羟基是聚丙酸酯的特征 单位。 不仅是本文中提出的所需化学转化 将完成广泛的研究。范围、限制、 关键反应的立体化学和机理意义 纳入本研究将进行审查。尽管我们的方法论将 原则上应适用于这些具体目标 适用于许多其他聚丙酸酯系统。

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.