I. Synthesis of C4-Modified Tetracyclines II. Aldolizations of Pseudoephenamine Glycinamide and Applications Toward the Synthesis of Monocyclic Beta-Lactam Antibiotics

Part one of this thesis describes the production of C4-modified tetracycline derivatives. Our synthetic strategy originally targeted SF2575, a C4-oxygenated tetracycline analog with antiproliferative properties, but was later amended to target antibacterial C4-oxygentaed minocycline analogs. The C4-modified tetracyclines were accessed utilizing a strategy based on the Myers' platform to 6-deoxytetracyclines (Michael--Claisen cyclization between AB enone 71 and D-ring phenyl esters 44 or 84) in addition to the 4th generation route to tetracycline key AB enone (Michael--Claisen cyclization between B-ring enone 8 and isoxazole 21). The crucial enabling step along this route was the C4-epimerization of Boc bis-carbonate 82 to Boc bis-carbonate 83. Five C4-modified tetracyclines were synthesized and their antibiotic properties were assessed.;Part two of this thesis describes the development of a new chiral glycine equivalent for aldol reactions, pseudoephenamine glycinamide ((R,R )-179), and an application of this methodology toward the production of C4-disubstituted monocyclic beta-lactam antibiotics. Asymmetric aldolization of pseudoephenamine glycinamide with aldehydes and ketones produces syn-beta-hydroxy-alpha-amino amides 180 with high diastereoselectivities and without the use of protecting groups. These aldol adducts can be transformed into enantiomerically enriched alcohols, ketones, and carboxylates, many of which enable powerfully simplified syntheses of various antibiotics. Utilization of the newly developed methodology enabled access to beta,beta'-disubstituted-beta-hydroxy-alpha-amino acids. Elaboration of these substrates provided novel C4-disubstitued monobactam analogs, an underrepresented class of beta-lactam antibiotics. Four C4-disubstituted monocyclic beta-lactam antibiotic candidates were synthesized and their antibiotic activities were assessed.