Synthesis and Glycosidase Inhibition Studies of 5-Methyl-Substituted Tetrahydroxyindolizidines and -pyrrolizidines Related to Natural Hyacinthacines B

The synthesis of three tetrahydroxyindolizidines and one tetrahydroxypyrrolizidine related to natural hyacinthacines B and their biological evaluation as glycosidase inhibitors is reported. The target molecules were obtained through highly stereoselective cycloadditions between sugriched allylic and homoallylic alcohols. This allowed the installation of a methyl group at C5 – a common feature of many natural hyacinthacines – with high control over the stereoselectivity. The new compounds inhibit amyloglucosidase from Aspergillus niger and β-glucosidase from almonds. Compound 1 is a competitive inhibitor of amyloglucosidase and shows a fair selectivity towards this enzyme. The presence of C5-Me substitution in indolizidines 2 and 3 slightly diminishes the inhibitory activity towards amyloglucosidase whereas it improves the inhibitory properties towards β-glucosidase.