Stereoselective Synthesis of 3-Deoxy-4-S-(1-4)-Thiodisaccharides and their Inhibitory Activities towards beta-Glycoside hydrolases

MARÍA LAURA UHRIG; VERÓNICA ELENA MANZANO; OSCAR VARELA

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY

Wiley-VCH, Verlag GmbH and Co, KGaA

Año: 2006 vol. 2006 p. 162 - 168

1434-193X

The sulfur linkage of b-(1-4)-thiodisaccharides was constructed with excellent diastereoselectivity by Michael addition of 2,3,4,6-tetra-O-acetyl-1-thio-b-D-galactose (2) or its b-D-glucose isomer (3) to sugar-derived (2S, 6S)-6-acetoxymethyl-2-(2-propyloxy)-2H-pyran-3(6H)-one (1). These reactions led to the per-O-acetyl glycosides of 3-deoxy-4-S-glycopyranosyl-4-thiohexopyranosid-2-ulose (4 and 5, respectively). Similar conjugated addition to the enone 1 of the isothiouronium salts 6 or 7, precursors in the synthesis of 2 or 3, also afforded the thiodisaccharides 4 or 5, respectively, with exclusive formation of the isomer that has an R configuration for the C-4 stereocenter of the reducing-end. The carbonyl function of 4 and 5 was reduced, and the resulting products were O-deacetylated to give the free 4-S(1-4)-thiodisaccharides 10, 11, 14, and 15, which have a deoxy functionality adjacent to the thio group. These compounds were tested as inhibitors of glycoside hydrolases. Thus 11, the 3-deoxy-4-thiomimetic of Galb(1-4)Gal, proved to be a competitive inhibitor of the b-galactosidase from E. coli (Ki = 0.16 mM).