Novel Lincosamide Antibiotics Containing an Azepane Amino Acid Moiety

Abstract

Clindamycin is the only member of the lincosamide class of antibiotics currently used in the clinic. It is used to treat Gram-positive infections, including infections caused by methicillin-resistant S. aureus (MRSA). However, its medical use has decreased since it was first introduced in the clinic in 1970 because of 3 major reasons: 1) it can promote C. difficile infections, which can lead to life-threatening colitis, 2) its spectrum of activity covers only Gram-positive pathogens, and 3) the levels of antibacterial resistance are rising. To address these shortcomings, the Myers laboratory started a research program that focuses on the development of fully synthetic, next-generation lincosamide antibiotics. Ten years before us, Vicuron, a pharmaceutical company, had a medicinal chemistry program for lincosamides, and one of their most important findings was that analogs containing an azepane amino acid moiety are active against the Gram-negative pathogen H. influenzae. Using this discovery as a starting point, my doctoral research focused on designing and synthesizing lincosamide analogs containing azepane amino acid derivatives, with the goal of expanding the spectrum of activity of lincosamides to include Gram-negative pathogens. Three synthetic routes for the construction of azepane derivatives are presented in this dissertation. The first route starts from the commercially available amino acid, L-allylglycine (2.1), and employs an ene-yne metathesis reaction as key step, which leaves a two-carbon handle used for further diversification (2.15). The second route also starts from L-allylglycine but targets a vinylsilane (4.4) and a triflate (4.6) as diversifiable intermediates in order to rigidify the analogs. The third route starts from a different commercially available amino acid derivative (4.19), used in an alternative strategy to access a more rigid azepane scaffold. These three routes allowed me to synthesize 115 analogs. Many of them show antibacterial activity and several of them show potency against the Gram-negative pathogens E. coli, K. pneumoniae and H. influenzae, thus achieving the goal set at the beginning of this project.