The synthesis of 1,1'- glycosides is one of the most challenging glycosylation types which requires a control of stereochemistry on both the side of glycosyl donor and glycosyl acceptor. The literature reports cover mostly the synthesis of naturally occurring α,α-trehalose type disaccharides, whereas the assembly of a pseudo-trehalose type β,α-1,1′ linkage is scarcely studied and covers simply protected (benzylated or acetylated) glucoses. In an effort to develop novel TLR4- and/or caspase-4/11-spesific ligands we endeavoured the synthesis of zwitterionic glycolipids mimicking the Gram-negative bacterial endotoxin. Endotoxin mimetics were built up around β,α-1,1'-linked diglucosamine scaffold entailing eight orthogonal protecting groups which were subsequently sequentially substituted by diverse functional groups, e.g. phosphates, zwitterionic phosphodiesters and β-hydroxyalkanoyl lipid chains. Using non-reducing βGlcN(1↔1)αGlcN as scaffold was pivotal to achieve the desired biological outcome. Taking advantage of electronic and steric effects of multiple carefully selected orthogonal protecting groups we established efficient, scalable and fully stereoselective synthetic routes towards nonreducing β,α-1,1′-linked diglucosamines βGlcN(1↔1)αGlcN. Locking both glycosyl donor and glycosyl acceptor in 4C1 conformation by application of cyclic 4,6-O-protecting groups was advantageous for the unambiguous stereocontrol of β,α-1,1' glycosylation. Carbamate type neighbouring 2N-protecting groups favored the α-configuration of the GlcN-lactol acceptors. A “perfect match” between the reactivity of the glycosyl donor and the nucleophilicity of the lactol acceptor was achieved by cautious combination of “arming” and “disarming” protective groups.

En route to anti-inflammatory glycolipids: stereoselective synthesis of fully orthogonally protected β,α-1,1′ -diglucosamines

ACS Spring Meeting 2021

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