Design, Synthesis, and Study of Lincosamide Antibiotics Containing a Bicyclic Amino Acid Moiety

Abstract

The lincosamide class has a small but important place in the armament of current antibiotics. Clindamycin, a semi-synthetic derivative of the natural product lincomycin, was first approved for clinical use in 1970 and has found continuous utility against Gram-positive bacterial infections, including Streptococci and methicillin-resistant S. aureus (MRSA). However, clinical usage of clindamycin is limited by its narrow spectrum of activity, increasingly prevalent antibacterial resistance, and its documented propensity to promote secondary C. difficile infections. To address these concerns, a fully synthetic, convergent approach to the development of next-generation lincosamide antibiotics was begun, with the hope of discovering a new candidate for the treatment of bacterial infections. Prior work on the lincosamide project established bicyclic amino acids as a novel scaffold with promising antibacterial activity. These bicyclic amino acid scaffolds relied on a β-hydroxy-γ-allyl proline derivative (1.16) as a key synthetic intermediate. This dissertation presents a novel chiral pool strategy to the synthesis of 1.16, starting with the naturally occurring amino acid trans-γ-hydroxyproline (2.1). This chiral pool route enabled the preparation of 1.16 from 2.1 in 5 steps on multigram-scale, reducing the longest linear sequence from 11 steps to 5 steps while also enabling late-stage diversification at the γ-position. This dissertation also describes a variety of chemical methods for diversification and exploration of the bicyclic scaffold 1.18 with the goal of improving its antibacterial activity. First, a pyrrolidinooxazepane scaffold (3.6) was synthesized through an ozonolysis–reductive amination sequence, enabling direct substitution on the amine functionality. Next, a vinyl triflate was formed on the pyrrolidinooxepine to establish a powerful handle for diversification. The vinyl triflate (4.2a) could be substituted through either palladium- or iron-catalyzed cross-coupling reactions to access a wide range of aryl and alkyl substituents. Through transformations of the vinyl triflate, structure–activity relationships around the bicycle were developed and refined. Many of these substituted bicyclic derivatives demonstrate superior antibacterial activity to clindamycin, and several of them show significant efficacy against clindamycin-resistant bacterial strains. The lincosamide analog FSA-513018b has emerged as a promising lead compound with excellent in vitro activity against multiple drug-resistant clinical isolates.