Chemo-enzymatic strategies hold great potential for the development of stereo- and regioselective syntheses of structurally defined bioactive
oligosaccharides. Herein, we illustrate the potential of the appropriate combination of a planned chemo-enzymatic pathway and an engineered
biocatalyst for the multistep synthesis of an important decasaccharide for
vaccine development. We report the stepwise investigation, which led to an efficient chemical conversion of allyl α-d-glucopyranosyl-(1→4)-α-l-rhamnopyranosyl-(1→3)-2-deoxy-2-trichloroacetamido-β-d-glucopyranoside, the product of site-specific enzymatic α-d-glucosylation of a lightly protected non-natural
disaccharide acceptor, into a pentasaccharide building block suitable for chain elongation at both ends. Successful differentiation between
hydroxyl groups features the selective acylation of primary
alcohols and acetalation of a cis-vicinal diol, followed by a controlled per-O-benzylation step. Moreover, we describe the successful use of the pentasaccharide intermediate in the [5 + 5] synthesis of an aminoethyl aglycon-equipped decasaccharide, corresponding to a dimer of the basic repeating unit from the
O-specific polysaccharide of Shigella flexneri 2a, a major cause of
bacillary dysentery. Four analogues of the
disaccharide acceptor were synthesized and evaluated to reach a larger repertoire of O-glucosylation patterns encountered among S. flexneri type-specific
polysaccharides. New insights on the potential and limitations of planned chemo-enzymatic pathways in
oligosaccharide synthesis are provided.