Enantioselective Total Syntheses of (+)-Castanospermine, (+)-6-Epicastanospermine, (+)-Australine, and (+)-3-Epiaustraline

The total syntheses of the potent glycosidase inhibitors castanospermine ((+)-1), 6-epicastanospermine ((+)-2), australine ((+)-3), and 3-epiaustraline ((+)-4) are described. The syntheses of indolizidine alkaloids (+)-1 and (+)-2 were accomplished in eight steps and in 18% and 24% overall yields from 2,5-dihydrofuran while the pyrrolizidine alkaloids (+)-3 and (+)-4 were obtained in a nine-step sequence in 17% and 22% overall yields from the same starting material. These four natural products are derived from a single common intermediate, nitroso acetal (−)-31, which is created in the key step by the asymmetric tandem [4 + 2]/[3 + 2] cycloaddition between silaketal nitro olefin 18 and chiral vinyl ether (+)-23. The ability to access both 5,5- and 5,6-fused bicyclic systems was a result of a successful in situ N-alkylation strategy during the hydrogenolysis of four highly functionalized nitroso acetals. A novel silaketal tether provided exceptional levels of diastereocontrol and the ideal combination of protection and functional-group placement for the tandem nitroalkene cycloaddition process.