Synthesis and evaluation of calystegine B-2 analogues as glycosidase inhibitors

A practical synthesis of polyhydroxylated 6-oxa-nor-tropanes incorporating the essential structural features of calystegine B-2 from 5-deoxy-5-thioure ido and 5-ureido-L-idofuranose precursors is presented. The methodology rel ies on the ability of pseudoamide-type nitrogen atoms (thiourea, urea, and carbamate) to undergo nucleophilic addition to the masked aldehyde group of the monosaccharide. The generated hemiaminal functionality may further und ergo in situ intramolecular glycosidation to give the bicyclic aminoacetal compounds, the whole process being favored by the anomeric effect. A series of derivatives bearing different substituents at nitrogen has been prepare d and screened against several glycosidases in comparison with xylonojirimy cin-type piperidine analogues. Interestingly, strong and highly specific in hibition of bovine liver beta -glucosidase was observed for 6-oxacalystegin e B-2 analogues incorporating aromatic pseudoaglyconic groups. On the basis of these data, a 1-azasugar inhibition mode is proposed for this family of glycomimetics.