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.
