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.