In Search of Glycogen Phosphorylase Inhibitors: 5‐Substituted 3‐ C ‐Glucopyranosyl‐1,2,4‐oxadiazoles from β‐ D ‐Glucopyranosyl Cyanides upon Cyclization of O ‐Acylamidoxime Intermediates

Upon treatment with hydroxylamine‐, benzyl‐ and benzoyl‐protected β‐ D ‐glucopyranosyl cyanides efficiently afforded the corresponding amidoximes. They reacted by O ‐acylation in the presence of carboxylic acids or acyl chlorides to provide benzyl‐ and benzoyl‐protected O ‐acylamidoximes. The latter were isolated and fully characterized. Thermal cyclization of O ‐acylamidoximes yielded the corresponding 5‐substituted 3‐ C ‐β‐ D ‐glucopyranosyl‐1,2,4‐oxadiazoles, either in a “one‐pot” procedure (benzylated series), or in two steps (benzoylated series). The twelve 5‐substituted 1,2,4‐oxadiazoles obtained upon debenzoylation were assayed against glycogen phosphorylase (GP). 3‐ C ‐(β‐ D ‐Glucopyranosyl)‐5‐(2‐naphthyl)‐1,2,4‐oxadiazole was the best inhibitor of rabbit muscle glycogen phosphorylase b ( K i = 38.4 ±3.0 μ M ). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)