Synthesis of LewisX-O-Core-1 threonine: A building block for O-linked LewisX glycopeptides

Lewis^X (Le^X) is a branched trisaccharide Galβ1→4(Fucα1→3)GlcNAc that is expressed on many cell surface glycoproteins and plays critical roles in innate and adaptive immune responses. However, efficient synthesis of glycopeptides bearing Le^X remains a major limitation for structure-function studies of the Le^X determinant. Here we report a total synthesis of a Le^X pentasaccharide 1 using a regioselective 1-benzenesulfinyl piperidine/triflic anhydride promoted [3 + 2] glycosylation. The presence of an Fmoc-threonine amino acid facilitates incorporation of the pentasaccharide in solid phase peptide synthesis, providing a route to diverse O-linked Le^X glycopeptides. The described approach is broadly applicable to the synthesis of a variety of complex glycopeptides containing O-linked Le^X or sialyl Lewis^X (sLe^X).