SYNTHETIC METHODOLOGY TOWARDS THE PREPARATION OF ANSAMYCIN ANTIBIOTICS

全对映体选择性方法学的发展 阿霉素类抗生素利福霉素、S和链球菌的合成 D，湿润内酯类抗生素巴菲罗星A1和伊莱普林为 这项提议的长期目标。这些聚丙酸酯天然产物 展示了广泛的生物活性。近年来，一个很大的问题 对它们的研究和利用感兴趣(以及一些半合成的 衍生品)作为治疗剂已经被广泛的 在这一领域产生了科学文献。 更具体地说，我们正在提议一个正式的全合成 利福霉素S及其聚丙酸酯基团的阐述 链霉素D、巴菲尔霉素A1和伊莱普林 环氧乙烷化学的利用。这些目标选择 分子是基于它们显著的生物活性，伟大的 其他研究小组对它们的合成表现出兴趣，以及 挑战，代表着不同的 在其聚丙酸酯单元中发现的构型 方法论。 报道的针对这些目标的合成方法，以及许多其他目标 聚丙酸酯体系，通常是基于羟醛和相关的 化学反应。我们认为，利用环氧化物化学作为一种 这些系统的一般方法将受到 人工合成社区。我们的方法是一种反复的方法，并基于 高烯丙醇的立体选择性环氧化 通过有机铝裂解后的碘甲基化反应 化学反应。使用此方法，我们可以控制 聚丙酸酯的甲基和羟基 单位。 不仅在这篇文章中提出了所需的化学转化 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 将对这项研究中包括的内容进行审查。尽管我们的方法论 原则上应适用于这些特定的目标 适用于许多其他聚丙酸酯体系。

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.