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 β‐glycosidase inhibitors. The intramolecular Diels–Alder reaction of the masked o‐benzoquinone generated from 2‐(allyloxy)phenol (6) gave the α‐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 β‐mannosidase (IC50 > 10 mM), Caldocellum saccharolyticum β‐glucosidase (IC50 > 10 mM), sweet almond β‐glucosidase (IC50 > 10 mM), yeast α‐glucosidase (5: IC50 > 10 mM; 19: IC50 = 1.2 mM), and Jack bean α‐mannosidase (no inhibition detected).