Synthesis of 1‐ C ‐Glycoside‐Linked Lipid II Analogues Toward Bacterial Transglycosylase Inhibition

Preparation of Lipid II analogues containing an enzymatically uncleavable 1‐ C ‐glycoside linkage between the disaccharide moiety and the pyrophosphate‐ or pyrophosphonate‐lipid moiety is described. The synthesis of a common 1‐ C ‐vinyl disaccharide intermediate has been developed that allows easy preparation of both an elongated sugar‐phosphate bond and a sugar‐phosphonate moiety, which are coupled with the polyprenyl phosphate to give the desired molecules. Inhibition studies show how a subtle structural modification results in dramatically different potency toward bacterial transglycosylase (TGase), and the results identify Lipid II‐C‐O‐PP (IC 50 =25 μ M ) as a potential TGase inhibitor.