Azafagomine hydrazones: An argument against a flat transition state in glycoside cleavage

Two hydrazones, (3R,4R,5R)-4,5-dihydroxy-3-hydroxymethyl-2,3,4,5-tetrahydropyridazine (2) and (4R,5R)-4,5- dihydroxy-6-hydroxymethyl-2,3,4,5-tetrahydropyridazine (3), were obtained in good yield from oxidation of 1-azafagomine (1). Both 2 and 3 have the half-chair conformations commonly believed to be important in good transition state analogues and an almost identical molecular composition to the strong glucosidase inhibitor 1. Yet 2 and 3 are very poor glucosidase inhibitors, which suggests that the half-chair geometry is far less important for a transition state analogue than its ability to accept protons.