Structural variation of the 3-acetamido-4,5,6-trihydroxyazepane iminosugar through epimerization and C-alkylation leads to low micromolar HexAB and NagZ inhibitors.

We report the synthesis of seven-membered iminosugars derived from a 3S-acetamido-4R,5R,6S-trihydroxyazepane scaffold and their evaluation as inhibitors of functionally related exo-N-acetylhexosaminidases including human O-GlcNAcase (OGA), human lysosomal ß-hexosaminidase (HexAB), and Escherichia coli NagZ. Capitalizing on the flexibility of azepanes and the active site tolerances of hexosaminidases, we explore the effects of epimerization of stereocenters at C-3, C-5 and C-6 and C-alkylation at the C-2 or C-7 positions. Accordingly, epimerization at C-6 (L-ido) and at C-5 (D-galacto) led to selective HexAB inhibitors whereas introduction of a propyl group at C-7 on the C-3 epimer furnished a potent NagZ inhibitor.

Lewis acid-catalysed nucleophilic opening of a bicyclic hemiaminal followed by ring contraction: Access to functionalized L-idonojirimycin derivatives.

The Lewis acid-catalyzed nucleophilic opening of a D-gluco-configured bicyclic hemiaminal has been examined. Several Lewis acids and silylated nucleophiles have been screened allowing the introduction of acetophenone, phosphonate or nitrile at the pseudoanomeric position in satisfactory yields and high 1,2 trans stereoselectivities. Their skeletal rearrangement triggered by the N-benzyl anchimeric assistance provided the corresponding L-ido-configured piperidines displaying various functional groups at C-6 position in good yield.

γ-Aminoalcohol rearrangement applied to pentahydroxylated azepanes provides pyrrolidines epimeric to homoDMDP.

A series of pentahydroxylated pyrrolidines, displaying five contiguous stereogenic centres and epimeric to α-glucosidase inhibitor homoDMDP, have been synthesized. The key step involves a γ-aminoalcohol rearrangement applied to polyhydroxylated azepanes. These five-membered iminosugars demonstrate micromolar inhibition of glycosidases.