synthesis and evaluation of glycosidase inhibitory activity of octahydro-2H-pyrido[1,2-a]pyrimidine and octahydro-imidazo[1,2-a]pyridine bicyclic diazasugars

Abstract

An efficient chiron approach for the synthesis of bicyclic diazasugars 4a and 4b having both -CH₂OH and -OH functionality at the same carbon atom (C-6) is reported. Thus, easily available α-D-xylo-pentodialdo-1,4-furanose 5, obtained from D-glucose, on aldol-crossed Cannizzaro reaction followed by hydrogenolysis afforded 7. The regio-selective β- and α-sulfonylation of hydroxymethyl groups in 7 afforded 8a (β-sulfonylation) and 11 (α-sulfonylation) in good yields. The cleavage of the 1,2-acetonide functionality, individually in 8a and 11, followed by reaction with ethylenediamine gave in situ formation of sugar aminals that undergo concomitant nucleophilic displacement of the sulfonyloxy group, by amino functionality, to give hitherto unknown bicyclic diazasugars 4a and 4b, respectively. The inhibitory potency of the earlier reported bicyclic diazasugars 3a,b and 4a,b was evaluated against α- and β-glycosidases and they were found to be potent and specific against the β-glycosidases with IC₅₀ and K_i values in the micro molar range.