DE NOVO SYNTHESIS OF A LEGIONAMINIC ACID BUILDING BLOCK

Nosocomial infections, also known as hospital-acquired infections, are a major threat particularly to immunocompromised patients. The Centers for Disease Control and Prevention estimate that 1.7 million nosocomial infections each year account for 99,000 deaths in the United States alone,^[1] thus rendering them a major cause of death in the Western world.^[2] Gram-negative bacteria account for about 40% of all nosocomial infections. Legionella pneumophila and Pseudomonas aeruginosa are both Gram-negative bacteria that cause hospital-acquired pneumonia. Syntheses of the respective antigenic surface oligosaccharides are crucial to explore biological interactions, structure‑activity relationships, and eventually, for the development of powerful drug candidates and vaccines. The O‑antigens of L. pneumophila and P. aeruginosa consist of the uncommon legionaminic acid monosaccharides. The latter are members of the family of sialic acids, but although structurally related to sialic acid, they are exclusively found in bacterial glycomes.^[3]

Herein, we present the chemical synthesis of a structurally complex monosaccharide ‑ legionaminic acid ‑ using a de novo strategy. The approach relies on an ex‑chiral-pool strategy starting from cheap and commercially available amino acids, featuring a multi-component and an organometallic addition reaction. A flexible and concise synthesis of the target was devised. This synthetic strategy of the legionaminic acid building block opens new possibility towards the assembly of bacterial oligosaccharides and thereby paves the way to the development of both potential carbohydrate-vaccine candidates and biological probes.