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Pure Appl. Chem., 2012, Vol. 84, No. 1, pp. 11-21

Published online 2011-11-19

Synthesis of lipid A and inner-core lipopolysaccharide (LPS) ligands containing 4‑amino-4-deoxy-L-arabinose units

Alla Zamyatina, Ralph Hollaus, Markus Blaukopf and Paul Kosma*

Department of Chemistry, University of Natural Resources and Life Sciences, A‑1190 Vienna, Austria

Abstract: Attachment of 4-amino-4-deoxy-L-arabinose (Ara4N) to phosphates or sugar hydroxyl groups of lipopolysaccharide (LPS) contributes to bacterial resistance against common antibiotics. For a detailed study of antigenic properties and binding interactions, Ara4N‑containing inner-core ligands related to Burkholderia and Proteus LPS have been synthesized in good yields. Glycosylation at position 8 of allyl glycosides of oct-2-ulosonic acids (Ko, Kdo) has been accomplished using an N-phenyltrifluoroacetimidate 4-azido-4-deoxy-L-arabinosyl glycosyl donor followed by azide reduction and global deprotection. The β-L-Ara4N-(1 → 8)-α-Kdo disaccharide was further extended into the branched β-L-Ara4N-(1 → 8)[α-Kdo-(2 → 4)]-α-Kdo trisaccharide via a regioselective glycosylation of a protected triol intermediate. Synthesis of Ara4N-modified lipid A part structure occurring in the LPS of Burkholderia, Pseudomonas, and Klebsiellla strains was accomplished using the H‑phosphonate approach. The stereocontrolled assembly of the phosphodiester linkage connecting glycosidic centers of two aminosugars was elaborated employing an anomeric H‑phosphonate of cyclic silyl-ether protected 4-azido-4-deoxy-β-L-arabinose, which was coupled to the hemiacetal of the lipid A GlcN-disaccharide backbone. Conditions for global deprotection, which warrant the integrity of “double anomeric” phosphodiester linkage, were successfully developed. Introduction of thiol-terminated spacer at the synthetic ligands allows both coupling to bovine serum albumin (BSA) and immobilization on gold nanoparticles as well as generation of glycoarrays.