Synthesis and Inhibitory Properties of 2-Acetamido-2-Deoxynojirimycin (2-Acetamido-5-amino-2,5-dideoxy-D-glucopyranose, 1) and 2-Acetamido-1,2-dideoxynojirimycin (2-Acetamido-1,5-imino-1,2,5-trideoxy-D-Glucitol, 2)

Abstract

The title compounds were synthesized from N-acetyl--glucosamine by a 10-step route which featured oxidation at C-5 of a suitably protected 2-acetamido-2-deoxy--glucofuranoside. Reduction of its 5-oxime with Raney nickel gave the -gluco epimer with ∼ 90% stereoselectivity. Problems encountered in the preparation of 1 during cleavage of its precursor glycoside were circumvented by the use of trifluoromethane-sulfonic acid.

N-Acetylglucosaminidases of fungal, plant, molluscan, and mammalian origin were inhibited by 1 and 2 in the nano- to micromolar range with 1 inhibiting > 100-fold better than 2. The inhibition equilibrium with 1 was approached on a time-scale of minutes with all enzymes tested. Comparison with N-acetyl--glucosamine showed that replacement of the pyranose oxygen by nitrogen resulted in an up to 10⁶-fold enhancement of the binding constants. N-Acetylglucosaminidases thus resemble the majority of other glycoside hydrolases. The enzymes from Aspergillus niger and Helix pomatia presented an exception in that their inhibition by 2 was only slightly better than by N-acetyl--glucosamine.