The development of metal-mediated methodologies for the syntheses of monocyclic and bicyclic oxamazins

beta-Lactam antibiotics are arguably the most important discovery in the history of modern medicine. Because of these small molecules, minor infections are no longer necessarily considered a death sentence. However, in recent years, the prevalence of resistance to these life-saving compounds has dramatically increased. One way to combat resistance is to generate both new antibiotic compounds and new synthetic strategies to make these chemical entities. Oxamazins, heteroatom-activated beta-Lactams, have demonstrated activity similar to traditional beta-Lactams, and thus are of interest. Herein, we report different strategies for the syntheses of bicyclic and monocyclic oxamazins.;In chapter 1, a broad overview of beta-Lactam antibiotics will be given including the discovery of these life-saving compounds and their historical syntheses. Several synthetic strategies for the closure of the beta-Lactam ring and subsequent elaboration will be discussed. The rapidly growing concern of bacterial resistance development and the means by which bacteria maintain their resistance will also be presented.;In chapter 2, initial studies incorporating Pd (0) methodology will be discussed. In an attempt to take advantage of pi-allyl chemistry, several acyclic substrates were generated to test the utility of pi-allyl chemistry for the formation of monocyclic and bicyclic oxamazins. The syntheses of the substrates and the challenges associated with the Pd (0) chemistry are discussed. Additionally, an interesting new route to cephalosporins through the use of Pd(0) chemistry will be proposed. Finally, a new synthetic strategy for the rapid access of carbocyclic nucleosides utilizing the protocols discussed in this chapter will be hypothesized.;In chapter 3, ring-closing olefin metathesis will be introduced and the utility of this versatile chemistry for the synthesis of the bicyclic oxamazin core will be explored. The core backbone of bicyclic oxamazins were synthesized and used in intramolecular ring-closing olefin metathesis reactions. The results of those studies will be presented. Finally, the potential of this chemistry to generate fully realized antibiotics will be discussed.;In chapter 4, the incorporation of peripheral C-3 acylamine and ionizable group functionalization on the bicyclic oxamazin core generated from the use of ring-closing olefin metathesis will be presented. The synthesis of the fully functionalized bicyclic oxamazin was addressed through three pathways. The first focused on the generation two subunits: and amino acid and an aminooxy acid ester. Two other strategies employing later stage synthetic intermediates as scaffolds for further functionalization were also explored. Compounds generated through these pathways were tested for their biological activity and those data are presented as well.