Synthesis of 2-azabicyclo[3.2.2]nonane-derived monosaccharide mimics and their evaluation as glycosidase inhibitors

The racemic 2-azabicyclo[3.2.2]nonanes 5 and 18 were synthesized and tested as P-glycosidase inhibitors. The intramolecular Diels-Alder reaction of the masked o-benzoquinone generated from 2-(allyloxy)phenol (6) gave the a-keto acetal 7 which was reduced with SMI2 to the hydroxy ketone 8. Dihydroxylation, isopropylidenation (-> 12), and Beckmann rearrangement provided lactam 15. N-Benzylation of this lactam, reduction to the amine 17, and deprotection provided the amino triol 19 which was debenzylated to the secondary amine 5. Both 5 and 19 proved weak inhibitors of snail beta-mannosidase (IC50 > 10 mm), Caldocellum saccliarolyticum beta-glucosidase (IC50 > 10 mm), sweet almond P-glucosidase (IC50 > 10 mm), yeast alpha-glucosidase (5: IC50 > 10 mm; 19: IC50 > 1.2 mm), and Jack bean alpha-mannosidase (no inhibition detected).