Syntheses of 4,6’-thioether-linked pseudodisaccharides as hydrolytically stable glycomimetics

MARÍA LAURA UHRIG; LÁSZLÓ SZILÁGYI; OSCAR VARELA; KATALIN E. KOVER

Erzurum – Turkía

Conferencia; International Conference on Organic Chemistry; 2007

Faculty of Arts and Sciences, Department of Chemistry, Atatürk University

Here we report on the syntheses of various thiodisaccharide mimics in which the monosaccharide units are linked via non-glycosidic carbons; a rare kind of di(oligo)saccharidic structures.  Essentially, these syntheses involve Michael-type addition of primary sugar thiols to unsaturated monosaccharide derivatives. As an example, 6-deoxy-6-thio-glucopyranoside 1 reacts with a,b-unsaturated pyranose-2-uloside 2, under mild conditions, to furnish the thioether-linked pseudodisaccharide  derivative 3. The addition proceeds with high diastereoselectivity due to preferential attack of the thiol 1 to the face of the enone 2 opposite to the axial anomeric substituent. Reduction of the carbonyl function of uloside 3 afforded thioether-linked pseudodisaccharides 4a and 4b in a ratio of 2:1. Following deprotection of the base-sensitive acyl groups, mild acid hydrolysis of the glycosidic isopropyl substituent resulted, unexpectedly, in the formation of 1,6-anhydro derivatives, such as 5. Opening of the 1,6-anhydro  ring was achieved by acetolysis with Ac2O–TFA. Several analogous derivatives have been synthesized. The free thiopseudodisaccharides are promising candidates for inhibition of glycosidase enzymes since their interglycosidic linkages, unlike those of O-glycosides, are not hydrolyzable. Enzyme inhibition studies are in progress.