SYNTHESIS OF BETA-LACTAMS FROM HYDROXAMIC ACIDS

由异羟肟酸合成 β-内酰胺

• 批准号: 3274310
• 负责人: MARVIN J MILLER
• 金额: $ 12.03万
• 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 1989-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3274310
• 关键词: acyl group; alkyl group; beta lactam antibiotic; cyclization; drug design /synthesis /production; drug screening /evaluation; 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 -内酰胺类抗生素的应用和研究最为广泛