APPROACHES TO MACROLIDE & IONOPHORE ANTIBIOTIC SYNTHESIS

这项建议的主要目标是实施新的 用于立体控制合成存在于细胞中的亚基的方法 非常重要的大环内酯类抗生素泰乐菌素和巨霉素B。 在开发这些路线的同时，我们还打算生产 离子载体抗生素的亚基，特别是离子霉素，我们建议 来合成石松生物碱luciduline。 这些目标被选中 为了说明我们开发的新方法的适用性， 实验室立体定向引入取代基到六和 七元碳环，利用强大的定向 连接到环上的过渡金属部分的作用。 这种方法 承诺是足够灵活的，以允许类似物的合成 天然产物，从而使疾病的潜在贡献 控制 所遵循的泰乐菌素和巨霉素B的方法使用 全新的合成原理 因此，合成键5， 7-二取代的环庚三烯是立体特异性方式， 环庚三烯铁络合物的手段，代表一个完全 这是一种前所未有的立体特异性官能化方法， 七元环。 产物环庚三烯的后续加工 将使用区域和立体特异性内酯化方法进行研究 最近开发的相关环己二烯基乙酸在我们的 laboratories. 环庚二烯基铁配合物的使用也具有相当大的价值 用于制备天然存在的大环内酯类的类似物，因为 关于取代基的性质有相当大的灵活性 从而给出了替换变量的方法 格局 放射性标记的碳13-和氘标记的合成 化合物也可以完成，这些将是非常有用的， 作用模式和代谢的体外和体内研究。

The major objective of this proposal is the implementation of new methodology for stereocontrolled synthesis of subunits found in the exceedingly important macrolide antibiotics tylosin and magnamycin B. Alongside the development of these routes we also intend to produce subunits for ionophore antibiotics, in particular ionomycin, and we propose to synthesize the Lycopodium alkaloid luciduline. These targets are chosen to illustrate the applicability of new methodology developed in our laboratory for stereospecific introduction of substituents onto six- and seven-membered carbocyclic rings which utilizes the powerful directing effect of a transition metal moiety attached to the ring. This approach promises to be sufficiently flexible to allow the synthesis of analogs of the natural products, thereby making a potential contribution to disease control. The approach to tylosin and magnamycin B which is to be followed uses entirely new synthetic principles. Thus, synthesis of a key 5, 7-disubstituted cycloheptadiene is a stereospecific manner is effected by means of a cycloheptadiene iron complex, representing an entirely unprecedented method for the stereospecific functionalisation of the seven-membered ring. Subsequent elaboration of the product cycloheptadiene will be investigated using a regio- and stereospecific lactonisation method recently developed on related cyclohexadienylacetic acids in our laboratories. The use of cycloheptadienyl iron complexes is also of considerable value for preparation of analogs of the naturally occurring macrolides, since there is considerable flexibility concerning the nature of substituents which are introduced, thereby giving methods for variation of substitution pattern. Synthesis of radiolabeled, carbon 13- and deuterium-labeled compounds can also be accomplished, and these would be extremely useful for in vitro and in vivo studies of mode of action and metabolism.