Synthesis and Glycosidase Inhibition of Broussonetine M and Its Analogues.

Cross-metathesis (CM) and Keck asymmetric allylation, which allows access to defined stereochemistry of a remote side chain hydroxyl group, are the key steps in a versatile synthesis of broussonetine M () from the d-arabinose-derived cyclic nitrone . By a similar strategy, -broussonetine M () and six other stereoisomers have been synthesized, respectively, starting from l--nitrone (), l--nitrone (), and l--nitrone () in five steps, in 26%-31% overall yield. The natural product broussonetine M () and were potent inhibitors of β-glucosidase (IC = 6.3 μM and 0.8 μM, respectively) and β-galactosidase (IC = 2.3 μM and 0.2 μM, respectively); while their enantiomers, and , were selective and potent inhibitors of rice α-glucosidase (IC = 1.2 μM and 1.3 μM, respectively) and rat intestinal maltase (IC = 0.29 μM and 18 μM, respectively). Both the configuration of the polyhydroxylated pyrrolidine ring and C-10' hydroxyl on the alkyl side chain affect the specificity and potency of glycosidase inhibition.