SYNTHESIS OF BETA-LACTAMS FROM HYDROXAMIC ACIDS

由异羟肟酸合成 β-内酰胺

• 批准号: 3274315
• 负责人: MARVIN J MILLER
• 金额: $ 14.85万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-07-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3274315
• 关键词: acyl group; alkyl group; beta lactam antibiotic; cyclization; drug design /synthesis /production; drug screening /evaluation; enzyme inhibitors; hydroxamate

The Beta-lactam antibiotics are the most widely used and studied antibiotics. However, the search for structurally modified, yet biologically active, Beta-lactams is made necessary by the bacterial development of Beta-lactamase enzymes which render the antibiotics ineffective. The recent discovery and structural elucidation of several novel monocyclic and bicyclic Beta-lactams suggests that compounds whose structures differ considerably from the usual penicillins and cephalosporins may be useful. While Beta-lactam synthesis has been approached from nearly every conceivable way, no methods are completely comparative with the structural diversity which now needs to be considered. The hydroxamate mediated N-C4 bond closure described in this proposal provides approaches of unprecedented ease and versatility for the synthesis of optically active Beta-lactams. The experimental simplicity of the method can be summarized by the fact that nearly any Beta-hydroxy carboxylic acid A can be converted in one step to the corresponding hydroxamate B which can then be cyclized directly to the substituted N-hydroxy Beta-lactam C. The N-hydroxylactams are unique and versatile (chemically and biologically). They can be used to prepare novel N-heteroatom containing antibiotics, reduced to give N-unsubstituted Beta-lactams suitable for elaboration, or utilized directly for the construction of other substituted systems by N-heteroatom cleavage (for example a novel heteroatom induced [1,2]-anionic rearrangement will provide new routes to bicyclic Beta-lactams). The N-C4 cyclization procedure also promotes direct conversion of Beta-hydroxy containing amino acid peptides to Beta-lactams, a process of considerable conceptual interest and synthetic utility. All the methods described are compatible with the peripheral functionality and chirality needed for the synthesis of the variety of classical and novel monocyclic and bicyclic Beta-lactams needed for thorough structure - activity studies.

β-内酰胺类抗生素是应用和研究最广泛的抗生素 抗生素 然而，对结构改变的研究， 具有生物活性的β-内酰胺是细菌生长所必需的 β-内酰胺酶的发展，使抗生素 无效。 最近发现和结构鉴定了几个 新的单环和双环β-内酰胺表明， 结构与通常的青霉素有很大不同， 头孢菌素可能是有用的。 虽然β-内酰胺的合成一直是 从几乎所有可以想象的方式接近，没有方法是完全 与现在需要的结构多样性相比， 考虑了 本文中描述的异羟肟酸盐介导的N-C4键闭合 建议提供了前所未有的方便和多功能的方法， 光学活性β-内酰胺的合成。 实验的简单性 该方法可以概括为几乎任何β-羟基 羧酸A可以在一个步骤中转化为相应的 异羟肟酸酯B，然后可将其直接环化为取代的 N-羟基β-内酰胺C. N-羟基内酰胺类药物是独一无二的，用途广泛 （化学和生物学）。 它们可以用来准备小说 含N-杂原子的抗生素，还原得到N-未取代的 适合精制或直接用于 通过N-杂原子裂解构建其它取代的体系（例如， 实施例新的杂原子诱导的[1，2]-阴离子重排将提供 双环β-内酰胺的新路线）。 N-C4环化程序还 促进含β-羟基氨基酸肽的直接转化 β-内酰胺，一个相当大的概念感兴趣的过程， 综合效用 所有描述的方法都与 外围官能度和手性的合成所需的 需要多种经典和新型单环和双环β-内酰胺 进行彻底的结构活性研究。