Synthesis of novel pyrazole-fused iminosugars from arabinose.

Azole-fused iminosugars have been used to achieve selective glycosidase inhibition by increasing the molecular planarity and modulating the electronic properties. However, pyrazole-fused iminosugars have been considerably less explored than their triazole- and imidazole-fused analogues. In this study, novel pyrazole-fused iminosugars were synthesised by leveraging the inherent stereochemical features of arabinose via an intramolecular 1,3-dipolar cycloaddition. The key reaction involves generating nitrilimines in situ from tetrazoles under microwave irradiation, which enables efficiently constructing a fused pyrazole framework. A series of stereochemically defined derivatives, including four stereoisomers, were successfully prepared. A structural analysis confirmed that pyrazole-containing iminosugars adopt a highly planar framework, enabling the intrinsic heteroatom orientation and electronic features to be assessed independently of the conformational effects. However, none of these compounds exhibited inhibitory activity against α- or β-glucosidases or β-galactosidase. A comparison with known imidazole- and triazole-fused analogues suggests that the azole electronic structure is a critical determinant of productive glycosidase recognition in iminosugar-based inhibitors. The systematic investigation of azole-fused iminosugars has been extended to the pyrazole series.