Stereoselective Synthesis of 3‐Deoxy‐4‐ S ‐(1→4)‐Thiodisaccharides and Their Inhibitory Activities Towards β‐Glycoside Hydrolases

The sulfur linkage of β‐(1→4)‐thiodisaccharides was constructed with excellent diastereoselectivity by Michael addition of 2,3,4,6‐tetra‐ O ‐acetyl‐1‐thio‐β‐ D ‐galactose ( 2 ) or its β‐ D ‐glucose isomer ( 3 ) to sugar‐derived (2 S , 6 S )‐6‐acetoxymethyl‐2‐(2‐propyloxy)‐2 H ‐pyran‐3(6 H )‐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 Galβ(1→4)Gal, proved to be a competitive inhibitor of the β‐galactosidase from E. coli ( K i = 0.16 m M ). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)