Design and Synthesis of Lincosamide Antibiotics bearing Bicyclic Southern Halves

Abstract

Lincomycin, the first member of the lincosamides, was isolated by Upjohn company in 1963. The lincosamides can be separated at the amide bond into 2 halves: the northern aminooctose sugar and the southern amino acid. Clindamycin, a semi-synthetic derivative of lincomycin, received clinical approval in 1970 for the treatment of Staphylococcal and Streptococcal infections. However, clindamycin has high propensity to cause secondary C. difficile infections, resulting in diarrhoea and life-threatening colitis. In addition, clindamycin's spectrum of activity is restricted to gram-positive pathogens. Till today, clindamycin remains the only lincosamide antibiotic on the market. In 2013, the Myers group started the lincosamide project with the aim of discovering new, fully synthetic antibiotics that addressed the key limitations of clindamycin in clinical medicine. Earlier work on the lincosamides established a novel oxepanoprolinamide southern half as a scaffold with good antibacterial activity. Employing the same concepts of rigidification and preorganization into its preferred binding conformation, this dissertation presents the design and synthesis of novel bicyclic piperidine and bicyclic azepane scaffolds. This culminated in the discovery of a trans-7,6 bicyclic azepane (3.79) which exhibits good antibacterial activity. Prior work in the north employed the same concept of preorganization and a 10-membered macrocyclic north was found to further improve antibacterial activity, exhibiting efficacy against multidrug-resistant bacterial strains. It was envisioned that adding a trifluoromethyl group adjacent to the sulfur atom would improve its metabolic stability due to stereoelectronic effects. This dissertation outlines the synthesis and bioactivity of a trifluoromethyl substituted northern half (4.12).