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

We report the synthesis of seven-membered iminosugars derived from a 3-acetamido-4,5,6-trihydroxyazepane scaffold and their evaluation as inhibitors of functionally related -acetylhexosaminidases including human -GlcNAcase (OGA), human lysosomal β-hexosaminidase (HexAB), and 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 -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.

Synthesis and chelation study of a fluoroionophore and a glycopeptide based on an aza crown iminosugar structure.

Capitalizing on a recently reported iminosugar-based aza-crown (ISAC) accessed by a double Staudinger azaWittig coupling reaction, we have expanded the structural diversity of this new family of sweet cyclam analogs. Replacement of the two secondary amines linking the iminosugar units by two amide bonds obtained a cyclodimerization by with BOP and DIPEA led to a macrocycle that did not demonstrate efficient Zn chelation unlike the parent ISAC. Introduction of two pyrene moieties on the secondary amines of the parent ISAC yielded a new fluoroionophore that selectively binds Hg in methanol.

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.

N- and C-alkylation of seven-membered iminosugars generates potent glucocerebrosidase inhibitors and F508del-CFTR correctors.

The glycosidase inhibitory properties of synthetic C-alkyl and N-alkyl six-membered iminosugars have been extensively studied leading to therapeutic candidates. The related seven-membered iminocyclitols have been less examined despite the report of promising structures. Using an in house ring enlargement/C-alkylation as well as cross-metathesis methodologies as the key steps, we have undertaken the synthesis and biological evaluation of a library of fourteen 2C- and eight N-alkyl tetrahydroxylated azepanes starting from an easily available glucopyranose-derived azidolactol.

Access to L- and D-iminosugar C-glycosides from a D-gluco-derived 6-azidolactol exploiting a ring isomerization/alkylation strategy.

A flexible synthetic access to six-membered L- and D-iminosugar C-glycosides is reported starting from the easily available 6-azido-6-deoxy-2,3,4-tri-O-benzyl-D-glucopyranose precursor. This methodology involves a highly diastereoselective tandem ring enlargement/alkylation and a stereocontrolled ring contraction. It allows an efficient synthesis of iminosugar C-glycosides displaying structural diversity at both C-1 and C-6.