SYNTHESIS OF BETA-LACTAMS FROM HYDROXAMIC ACIDS

β-内酰胺类抗生素是使用和研究最广泛的 抗生素。然而，对结构化修改的搜索，尚未 生物活性，β-内酰胺类是细菌所必需的 产生抗生素的β-内酰胺酶的研究进展 效果不佳。几个化合物的最新发现和结构解析 新型单环和双环β-内酰胺类化合物 结构与通常的青霉素有很大的不同 头孢菌素类药物可能有用。而β-内酰胺的合成已经 从几乎所有可以想到的方式来看，没有一种方法是完全 与现在需要的结构多样性相比较 考虑过了。羟基甲酸酯介导的N-C4键封闭 提案提供了前所未有的简单性和多功能性 光学活性β-内酰胺类药物的合成。实验上的简单性 该方法可以概括为几乎所有的β-羟基 羧酸A可以在一步内转化为相应的 异羟甲酸酯B，然后可以直接环化到取代的 N-羟基β-内酰胺C。N-羟基内酰胺是唯一的，用途广泛的。 (化学和生物方面)。它们可以用来准备小说 含抗生素的N-杂原子，还原为N-未取代 β-内酰胺类，适合精制，或直接用于 通过N-杂原子裂解构建其他取代体系(for 一种新的杂原子诱导的[1，2]-阴离子重排将提供 双环β-内酰胺类药物的新路线)。N-C4环化过程还 促进含β-羟基氨基酸多肽的直接转化 对于β-内酰胺类药物来说，这是一个具有相当大的概念兴趣的过程 综合效用。描述的所有方法都与 合成该化合物所需的外周功能和手性 需要多种经典和新型单环和双环β-内酰胺类药物 进行深入的结构活性研究。

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.