DEVELOPMENT/PREPARATION OF ANSAMYCIN ANTIBIOTICS

说明（摘自《应用》）：大环内酯的合成， 离子载体抗生素仍然被认为是一个非常活跃的领域， 有机合成研究这些目标分子的吸引力是 与其广泛的生物和医药活性有关， 它们复杂的结构和立体中心的排列。制定一项 合成安莎霉素抗生素的对映选择性方法， 利福霉素S和静脉曲张链菌素D，以及乙内酰类抗生素巴弗洛霉素A1 和依莱叶林是该提议的主要目标。选择这些 靶分子是基于它们广泛的生物活性， 这是一个挑战，代表了不同的配置的详细说明， 在它们的聚丙酸酯单元中。近年来，对他们的研究产生了极大的兴趣 和利用（和一些半合成衍生物）作为治疗剂 广泛和不断增加的科学文献证明了 在这一领域产生。报道的合成方法，这些 与许多其它聚丙酸酯体系一样，目标通常基于 羟醛和相关化学。申请人希望证明 环氧化物是一种可行的替代品，并且它们的使用可以并入到 通用、灵活和立体选择性的路线，这些非常重要的目标 化合物.他们的方法是一种简单而重复的方法，它是基于 高烯丙醇的碘环化立体选择性环氧化 反应，然后通过有机铝化学裂解。与此 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 本研究中提出的化学转化将得以实现。的 范围，限制，立体化学，和关键的机械含义 将检查反应。虽然该方法将适用于这些 具体目标，原则上应适用于许多其他 聚丙酸酯系统，并将打开合成类似物的大门， 这可能会增加或改变生物学上的 活性和治疗潜力。

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.