Site-Selective Palladium-Catalyzed Oxidation of Glucose in Glycopeptides

Here we report a novel method of site-selective oxidation of glucose moieties on individual glycopeptides and on a mixture of tryptic glycopeptides. The organometallic catalyst [(neocuproine)PdOAc]₂OTf₂, that was previously shown to perform regioselective C3-oxidation of glucosides, was used in the scope of this work. The selectivity of the catalyst towards glucose and the sensitivity of specific amino acid residues to oxidation was explored by screening a select panel of glycopeptides in the oxidation reactions. We reveal that glucosylated peptides are more readily oxidized compared to galactosylated peptides, and Thr/Ser-oxidation is a concomitant side-reaction. The oxidation methodology was also applied to the complex mixture of tryptic glucopeptides that was generated from the fragment of Haemophilus influenzae adhesin glycoprotein. The resulting keto-group of the glucose was further transformed into an oxime functionality, which allows introduction of various groups of interest. The methodology outlined in this work will allow to perfrom late-stage modification of glucopeptides as well as selective oxidation and functionalization of tryptic glucopeptides for proteomics analysis.