Synthesis of monosaccharide-derived spirocyclic cyclopropylamines and their evaluation as glycosidase inhibitors

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. PdClequation image 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 PdClequation image, lowering the K_i value from 40 μM (PdClequation image) to 0.5 μM for a 1 : 1 mixture of PdClequation image and 1d. A similar effect is shown by cyclopropylamine, but not by several other amines.