The 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 gluco-, galacto-, and mannopyranoside derivatives, is described. Key to this convergent synthesis is the coupling of a uronic acid 1-phosphate with a nucleotide monophosphate activated as the phosphorimidazolide to form the NDP-uronic acid, of which 10 derivatives were prepared. The coupling is compatible with the carboxylic acid functionality present in uronic acid-1-phosphates with conversions above 95% and isolated yields typically above 60%. Key features of this work include (i) stereoselective synthesis of ⍺-phosphoglycosides from perbenzylated ⍺- and β-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.