APPROACHES TO MACROLIDE & IONOPHORE ANTIBIOTIC SYNTHESIS

大环内酯的研究方法

• 批准号: 3280720
• 负责人: ANTHONY J PEARSON
• 金额: $ 10.18万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-04-01 至 1987-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3280720
• 关键词: drug design /synthesis /production; ionophores; macrolide antibiotics

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.

该提案的主要目标是实施新的 立体控制合成亚基的方法 极为重要的大环内酯类抗生素泰乐菌素和麦霉素B。 除了开发这些路线外，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 合成石松生物碱luciduline。 这些目标被选定 说明我们开发的新方法的适用性 将取代基立体定向引入到六位和六位上的实验室 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。 这种做法 有望足够灵活以允许合成类似物 天然产物，从而对疾病有潜在贡献 控制。 泰乐菌素和麦格霉素 B 的后续使用方法 全新的合成原理。 因此，合成了密钥5， 7-二取代环庚二烯是通过立体定向方式实现的 环庚二烯铁络合物的意思，代表了完全 前所未有的立体特异性功能化方法 七元环。 产品环庚二烯的后续精制 将使用区域和立体特异性内酯化方法进行研究 最近在我们的相关环己二烯基乙酸上开发 实验室。 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 引入这些，从而给出了替代变化的方法 图案。 放射性标记、碳 13 和氘标记的合成 也可以实现化合物，这些对于 作用模式和代谢的体外和体内研究。