Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

Lipid II is an essential glycolipid found in bacteria. Accessing this valuable cell wall precursor is important both for studying cell wall synthesis and for studying/identifying novel antimicrobial compounds. Herein we describe optimizations to the modular chemical synthesis of lipid II and unnatural analogues. In particular, the glycosylation step, a critical step in the formation of the central disaccharide unit (GlcNAc-MurNAc), was optimized. This was achieved by employing the use of glycosyl donors with diverse leaving groups. The key advantage of this approach lies in its adaptability, allowing for the generation of a wide array of analogues through the incorporation of alternative building blocks at different stages of synthesis.