DEVELOPMENT/PREPARATION OF ANSAMYCIN ANTIBIOTICS

描述(摘自应用)：大环内酯类和大环内酯类的合成 离子载体抗生素继续被视为一个非常活跃的领域 合成有机研究。这些目标分子的吸引力是 与它们广泛的生物和医药活动有关，以及 它们复杂的结构和立体生成中心的阵列。智能网的发展 阿萨霉素类抗生素合成的对映选择性方法学 利福霉素S和链霉菌素D，以及湿润内酯类抗生素巴菲罗星A1 和Elaiophylin，是这项提案的主要目标。这些产品的选择 靶分子是基于它们广泛的生物活性和 代表所发现的不同配置的精细化的挑战 在他们的聚丙酸酯单元中。近年来，人们对其研究产生了极大的兴趣 和利用(以及一些半合成的衍生物)作为治疗 越来越多的科学文献证明了代理人的存在 是在这个地区产生的。已报道的针对这些的合成方法 与许多其他聚丙酸酯体系一样，靶标通常是基于 羟醛及相关化学。申请者想要证明 环氧化物是一种可行的替代品，它们的使用可以合并到 通向这些非常重要目标的一般、灵活和立体选择性途径 化合物。他们的方法是简单和反复的，并基于 高烯丙醇的碘环化立体选择性环氧化 通过有机铝化学裂解后的反应。有了这个 方法学他们可以控制甲基和羟基的构型 表征聚丙酸酯单元的基团。不仅是想要的 这项研究中提出的化学转化将会实现。这个 关键字的范围、限制、立体化学和机械含义 我们将考察他们的反应。尽管该方法将应用于这些 具体目标，原则上应该适用于许多其他目标 聚丙酸酯体系，将为合成类似物打开大门， 可以提供增加或修改生物的机会 活跃性和治疗潜力。

Description (Adapted from Application): The synthesis of macrolide and ionophore antibiotics continues to be regarded as a very active area of synthetic organic research. The attractiveness of these target molecules is related to their broad range of biological and medicinal activity together with their complex structure and array of stereogenic centers. The development of an enantioselective methodology for the synthesis of the ansamycin antibiotics, rifamycin S and streptovaricin D, and the hygrolide antibiotics, bafilomycin A1 and elaiophylin, is the main goal of this proposal. The selection of these target molecules is based on their extensive biological activity and the challenge that represents the elaboration of the different configurations found in their polypropionate units. In recent years, a great interest in their study and utilization (and that of some semi-synthetic derivatives) as therapeutic agents has been evidenced by the extensive and increasing scientific literature being generated in this area. The reported synthetic approaches to these targets, as for many other polypropionate systems, have been usually based on aldol and related chemistry. The applicants would like to demonstrate that epoxides are a viable alternative and that their use can be incorporated into a general, flexible, and stereoselective route to these very important target compounds. Their approach is a simple and reiterative one, and is based on the stereoselective epoxidation of homoallylic alcohols by means of iodocyclization reactions, following their cleavage via organoaluminum chemistry. With this methodology they can control the configuration of the methyl and hydroxyl groups that characterize the polypropionate units. Not only the desired chemical transformations proposed in this study will be accomplished. The scope, limitations, stereochemistry, and mechanistic implications of the key reactions will be examined. Although the methodology will be applied to these specific targets, in principle, its should be applicable to many other polypropionate systems and will open the door for the synthesis of analogues, which can present opportunities for increased or modified of biological activity and therapeutic potential.