Synthesis of Nucleotide Diphosphate Uronic Acids via the Coupling of Activated Nucleotides with Uronic Acid-1-phosphates

The stereoselective synthesis of nucleotide diphosphate (NDP) uronic acids from simple sugar precursors, including d-gluco-, d-galacto-, and d-mannopyranoside derivatives, is described. Key to this convergent synthesis is the coupling of unprotected uronic acid 1-phosphate with a nucleotide phosphorimidazolide to directly form the NDP-uronic acid, of which 11 derivatives were prepared. The coupling is compatible with the carboxylic acid functionality present in uronic acid-1-phosphates, with conversions of >95% and isolated yields typically above 60%. Key features of this work include (i) stereoselective synthesis of α-d-phosphoglycosides from perbenzylated α- and β-d-thioglycosides, (ii) selective and mild oxidation of galactose-, glucose-, and mannose-1-phosphates to the corresponding uronic acid-1-phosphate, and (iii) mild coupling conditions to directly provide nucleotide diphosphate uronic acids from unprotected uronic acid-1-phosphates and nucleotide phosphorimidazolides. This chemistry is currently in use to develop inhibitors of key enzymes involved in antibiotic resistance.