Synthesis and Glycosidase Inhibition of Broussonetine M and Its Analogues

Abstract

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 ( 3) from the d-arabinose-derived cyclic nitrone 14. By a similar strategy, ent-broussonetine M ( ent-3 ) and six other stereoisomers have been synthesized, respectively, starting from l- arabino-nitrone ( ent-14 ), l- lyxo-nitrone ( ent-3- epi-14 ), and l- xylo-nitrone ( 2- epi-14 ) in five steps, in 26%–31% overall yield. The natural product broussonetine M ( 3) and 10’- epi-3 were potent inhibitors of β-glucosidase (IC ₅₀ = 6.3 μM and 0.8 μM, respectively) and β-galactosidase (IC ₅₀ = 2.3 μM and 0.2 μM, respectively); while their enantiomers, ent-3 and ent-10’- epi-3 , were selective and potent inhibitors of rice α-glucosidase (IC ₅₀ = 1.2 μM and 1.3 μM, respectively) and rat intestinal maltase (IC ₅₀ = 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.