Total Synthesis of the Glycoside Antibiotic Paulomycin A

Paulomycin A is a structurally distinctive glycoside antibiotic that displays potent activity against Gram-positive pathogens, yet its intrinsic chemical instability and high structural complexity have long prevented both drug development and synthetic exploration. Here, we describe the first total synthesis of paulomycin A, accomplished through a sequence of highly selective transformations tailored to its unusual reactivity profile. Key features of the synthesis include an aryl C-glycosylation via Wan glycosylation that provides efficient access to aniline-containing aryl C-glycosides, solvent-controlled anomeric stereocontrol in a gold-catalyzed Yu O-glycosylation, and a late-stage site-selective esterification/[3,3]-sigmatropic rearrangement used to install the pharmacologically essential paulic acid fragment.