Lien vers Pubmed [PMID] – 26340432
J. Org. Chem. 2015 Sep;
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 multi-step synthesis of an important decasaccharide for vaccine development. We report the stepwise investigation, which led to an efficient chemical conversion of allyl alpha-D-glucopyranosyl-(1–>4)-alpha-L-rhamnopyranosyl-(1–>3)-2-deoxy-2-trichloroacetamido-beta-D-glucopyranoside, the product of site-specific enzymatic alpha-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 analogs of the disaccharide acceptor were synthesized and evaluated to reach a larger repertoire of O-glucosylation patterns encountered amongst S. flexneri type-specific polysaccharides. New insights on the potential and limitations of planned chemo-enzymatic pathways in oligosaccharide synthesis are provided.