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Fusidic acid is a translation inhibitor with activity against major Gram-positive bacterial pathogens such as S. aureus. However, its activity against Gram-negatives is poor based on an inability to access its cytoplasmic target in these organisms. Opportunities for functionalization of the fusidic acid scaffold to enhance activity against Gram-negative pathogens have not been explored. Using an activity-guided synthetic strategy, the tolerance of the tetracyclic natural product to derivatization at the A- and C-rings and its carboxylic acid side chain was explored with the goal of enhancing its activity spectrum and pharmacological properties. All side-chain carboxylic acid esters were inactive. Oxidation of the C-ring alcohol and oxime were not tolerated either. A number of esters of the A-ring alcohol retained modest activity against Gram-positive bacteria and were informative for future activity-guided studies. For the A-ring esters, differences in antibacterial activity relative to inhibitory activity in a ribosome in vitro translation assay suggested the possibility of a pro-druglike effect for the fusidic acid pyrazine-2-carboxylate. This study furthers the understanding of the activity of the fusidic acid scaffold against Gram-positive bacteria. These results suggest promise for future modification of the A-ring alcohol of fusidic acid in the advancement of its antibiotic properties. 

The ability to recognize hidden symmetry in a highly asymmetric world is a key factor in how we view and understand the world around us. Despite the fact that it is an intrinsic property of the natural world, we have an innate ability to find hidden symmetry in asymmetric objects. The inherent asymmetry of the natural world is a fundamental property built into its chemical building blocks (e.g., proteins, carbohydrates, etc.). This review highlights the role of asymmetry in the structure of the carbohydrates and how these stereochemical complexities present synthetic challenges. This survey starts with an overview of the role synthetic chemistry plays in the discovery of carbohydrates and their 3D structure. This review then introduces various de novo asymmetric synthetic approaches that have been developed for the synthesis of carbohydrates and, in particular, oligosaccharides. The two most successful strategies for oligosaccharide synthesis rely on diastereoselective palladium-catalyzed glycosylation. The first uses an Achmatowicz reaction to asymmetrically prepare pyranose building blocks along with a substrate-controlled Pd-glycosylation. The other strategy couples a ligand-controlled Pd-glycosylation with a ring-closing metathesis for oligosaccharide assembly.