Ortho- and para-(difluoromethyl)aryl-β-d-glucosides: A new class of enzyme-activated irreversible inhibitors of β-glucosidases

New ortho- and para-(difluoromethyl)aryl-β-d-glucosides were stereoselectively prepared in three steps from 1-bromo-2,3,4,6-tetraacetyl glucose, using an appropriate ortho- or para-hydroxybenzaldehyde derivative. The fluorine atoms were introduced by reacting the soformed ortho- or para-O-glucosyl benzaldehyde derivatives with DAST. Title compounds are potent time-dependent irreversible inhibitors of almond β-glucosidase. The inactivation is explained by the enzyme-catalyzed hydrolysis of the glucosidic linkage, releasing an ortho- or para-(difluoromethyl)phenol. The ortho- and para-(difluoromethyl)phenols are assumed to rapidly form fluorinated quinone methides which alkylate a nucleophilic residue of the enzyme active site.