Coupling Reactions of Anhydro-Aldose Tosylhydrazones with Boronic Acids.

A catalyst-free coupling reaction between O-peracetylated, O-perbenzoylated, O-permethylated, and O-permethoxymethylated 2,6-anhydro-aldose tosylhydrazones (C-(ß-d-glycopyranosyl)formaldehyde tosylhydrazones) and aromatic boronic acids is reported. The base-promoted reaction is operationally simple and exhibits a broad substrate scope. The main products in most of the transformations were open-chain 1-C-aryl-hept-1-enitol type compounds while the expected ß-d-glycopyranosylmethyl arenes (benzyl C-glycosides) were formed in subordinate yields only. A mechanistic rationale is provided to explain how a complex substrate may change the well-established course of the reaction.

Coupling of N-tosylhydrazones with tetrazoles: synthesis of 2-ß-D-glycopyranosylmethyl-5-substituted-2H-tetrazole type glycomimetics.

Coupling reactions of O-peracylated 2,6-anhydro-aldose tosylhydrazones (C-(ß-d-glycopyranosyl)formaldehyde tosylhydrazones) with tetrazoles were studied under metal-free conditions using thermic or microwave activation in the presence of different bases. The reactions proved highly regioselective and gave the corresponding, up-to-now unknown 2-ß-d-glycopyranosylmethyl-2H-tetrazoles in 7-67% yields. The method can be applied to get new types of disaccharide mimetics, 5-glycosyl-2-glycopyranosylmethyl-2H-tetrazoles, as well. Galectin binding studies with C-(ß-d-galactopyranosyl)formaldehyde tosylhydrazone and 2-(ß-d-galactopyranosylmethyl)-5-phenyl-2H-tetrazole revealed no significant inhibition of any of these lectins.

Pd-catalyzed coupling reactions of anhydro-aldose tosylhydrazones with aryl bromides to produce substituted exo-glycals.

Palladium-catalyzed cross-couplings of O-peracylated and O-permethylated 2,6-anhydro-aldose tosylhydrazones with aryl halides were studied under thermic conditions in the presence of LiOtBu and phosphine ligands. The reactions gave the corresponding aryl substituted exo-glycals as mixtures of diastereomers in 11-75% yields. The transformations represent a new access to these types of glycomimetic compounds. The double bond of some aryl substituted exo-glycals was saturated to give good yields of benzylic C-glycosyl derivatives.

Synthesis of 2-(ß-D-glucopyranosylamino)-5-substituted-1,3,4-oxadiazoles for inhibition of glycogen phosphorylase.

Aromatic aldehyde 4-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl)semicarbazones were synthesized by the addition of different hydrazones onto O-peracetylated ß-d-glucopyranosyl isocyanate. Oxidative transformations of these precursors gave O-protected 2-(ß-d-glucopyranosylamino)-5-substituted-1,3,4-oxadiazoles. Removal of the O-acetyl protecting groups under Zemplén conditions gave test compounds to show low micromolar inhibition against rabbit muscle glycogen phosphorylase b. Best inhibitors of these series were 4-(ß-d-glucopyranosyl)semicarbazones of 4-nitrobenzaldehyde (Ki=4.5µM), 2-naphthaldehyde (Ki=5.5µM) and 2-(ß-d-glucopyranosylamino)-5-(4-methylphenyl)-1,3,4-oxadiazole (Ki=12µM).