Synthesis of 5-Azacastanospermine, a Conformationally Restricted Azafagomine Analogue

The 5‐aza‐6‐deoxy analogue of castanospermine (±)‐5 a and its 1‐epimer (±)‐5 b was synthesized. The synthesis started from the known compound 5‐benzyloxy‐7‐hydroxyhepta‐1,3‐diene, which was protected and subjected to Diels–Alder reaction with 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione to give two epimeric adducts. One of these was transformed through epoxidation, acetolysis, a series of side‐chain transformations that converted it into a terminally protected aldehyde, deprotection, and hydrogenolysis/reductive amination into 5 a. By a similar set of reactions the other adduct epimer was converted into 5 b. The castanospermine analogue 5 a was a weaker inhibitor of almond β‐glucosidase and rice α‐glucosidase than castanospermine (2) or 1‐azafagomine (4), but was considerably more potent than its epimer 5 b. This suggests that these enzymes have a strong preference for binding substrates or azasugars with the 6‐OH in an axial conformation. Castanospermine, an azasugar inhibitor with antiviral activity, is a transition‐state analogue of glycoside cleavage, mimicking charge development at the ring oxygen of glucose. In this paper we report the synthesis and evaluation of two castanospermine analogues (shown here) that mimic the charge development not only on the ring oxygen but also on the anomeric carbon.