First total synthesis of (+)-broussonetine W: glycosidase inhibition of natural product & analogs

The first total synthesis of (+)-broussonetine W ( 4 ), a naturally-occurring pyrrolidine iminosugar isolated from the traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic route starting from the readily available d -arabinose derived cyclic nitrone 10 in 11 steps and 31% overall yield, with regioselective installation of the α,β-unsaturated ketone functional group by the elimination of HBr from α-bromoketone as the key step. A number of analogs of (+)-broussonetine W ( 4 ) with variable side chain length, different polyhydroxylated pyrrolidine core configurations or saturated cyclohexanones have also been prepared to explore the glycosidase inhibition and the preliminary structure-activity relationship of this intriguing class of compounds. Glycosidase inhibition studies identified the natural product (+)-broussonetine W ( 4 ) as a selective and potent inhibitor of β-galactosidase (IC 50 = 0.03 μM), while its enantiomer was a selective and potent inhibitor of α-glucosidase (IC 50 = 0.047 μM). It was found that the configuration of the polyhydroxylated pyrrolidine ring played a key role on their glycosidase inhibitory activities. The length of side chain and α,β-unsaturated ketone functional group also exhibited some effect on their glycosidase inhibition. Broussonetine W and its 11 analogues have been first synthesized from cyclic nitrones and assayed as potential gycosidase inhibitors.