Synthesis of Imidazolo‐Piperidinopentoses as Nagstatine Analogues

The syntheses of the four imidazolo‐piperidino‐pentoses 3−6 , which belong to the D ‐series, and of their L ‐enantiomers, ent ‐ 3 to ent ‐ 6 , are reported. Ascorbic acid and isoascorbic acid were converted over several steps into the L ‐ threo / L ‐ erythro ‐ and the D ‐ erythro / D ‐ threo ‐configured aldotetroses, respectively, which are the key building blocks for the eight target imidazolo‐pentoses cited above. Nucleophilic addition of a metallated imidazole to any one of these four aldotetroses gave the corresponding two diastereomeric adducts, intramolecular cyclisation of which provided the expected bicyclic target molecules, with some protection and deprotection steps being unavoidable prerequisites. The structures and configurations of all eight piperidinoses in Scheme 1 were determined unambiguously, by a combination of 1 H/ 13 C NMR spectroscopy, circular dichroism (CD) and [α] D values, in conjunction with single‐crystal X‐ray diffraction analyses of the L ‐ arabino and D ‐ lyxo azasugars ent ‐ 3 and 6 . Although lacking the hydroxymethylene group in the C(5) position, the overall structure of these eight stereomers strongly resembles that of the natural product nagstatine ( 1 ), a potent inhibitor of N ‐acetyl‐β‐ D ‐glucosaminidase. As a matter of fact, after examination of the inhibitory properties of these imidazolo‐piperidinoses against six commonly encountered glycosidases, we observe that the L ‐ arabino imidazolo‐sugar ent ‐ 3 is a potent inhibitor in this series, with K i = 1 μ M both with a β‐glucosidase and with a β‐galactosidase. The D ‐ ribo and D ‐ xylo stereomers 4 and 5 proved to be inhibitors of a β‐glucosidase of similar magnitude ( 4 : K i = 20 μ M ; 5: K i = 17 μ M ), the other stereomers being either modest to poor inhibitors, or showing no inhibition at all.