Abstract
The glucose‐, mannose‐, and galactose‐derived spirocyclic cyclopropylammonium chlorides 1a–1d, 2a–2d and 3a–3d were prepared as potential glycosidase inhibitors. Cyclopropanation of the diazirine 5 with ethyl acrylate led in 71% yield to a 4 : 5 : 1 : 20 mixture of the ethyl cyclopropanecarboxylates 7a–7d, while the Cu‐catalysed cycloaddition of ethyl diazoacetate to the exo‐glycal 6 afforded 7a–7d (6 : 2 : 5 : 3) in 93–98% yield (Scheme 1). Saponification, Curtius degradation, and subsequent addition of BnOH or __t‐__BuOH led in 60–80% overall yield to the Z‐ or Boc‐carbamates 11a–11d and 12a–12d, respectively. Hydrogenolysis of 11a–11d afforded 1a–1d, while 12a–12d was debenzylated to 13a–13d prior to acidic cleavage of the N‐Boc group. The manno‐ and galacto‐isomers 2a–2d and 3a–3d, respectively, were similarly obtained in comparable yields (Schemes 2 and 4). Also prepared were the differentially protected __manno‐__configured esters 24a–24d; they are intermediates for the synthesis of analogous N‐acetylglucosamine‐derived cyclopropanes (Scheme 3).
The cyclopropylammonium chlorides 1a–1d, 2a–2d and 3a–3d are very weak inhibitors of several glycosidases (Tables 1 and 2). Traces of Pd compounds, however, generated upon catalytic debenzylation, proved to be strong inhibitors. PdCl$\rm{_{4}^{2-}}$ is, indeed, a reversible, micromolar inhibitor for the __β‐__glucosidases from C. saccharolyticum and sweet almonds (non‐competitive), the β‐galactosidases from bovine liver and from E. coli (both non‐competitive), the α‐galactosidase from Aspergillus niger (competitive), and an irreversible inhibitor of the α‐glucosidase from yeast and the α‐galactosidase from coffee beans. The cyclopropylamines derived from 1a–1d or 3a–3d significantly enhance the inhibition of the __β‐__glucosidase from C. saccharolyticum by PdCl$\rm{_{4}^{2-}}$, lowering the K~i~ value from 40 μM (PdCl$\rm{_{4}^{2-}}$) to 0.5 μM for a 1 : 1 mixture of PdCl$\rm{_{4}^{2-}}$ and 1d. A similar effect is shown by cyclopropylamine, but not by several other amines.