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

1999-03-23T00:00:00Z (GMT) by Scott E. Denmark Esther A. Martinborough
The total syntheses of the potent glycosidase inhibitors castanospermine ((+)-<b>1</b>), 6-epicastanospermine ((+)-<b>2</b>), australine ((+)-<b>3</b>), and 3-epiaustraline ((+)-<b>4</b>) are described. The syntheses of indolizidine alkaloids (+)-<b>1</b> and (+)-<b>2</b> were accomplished in eight steps and in 18% and 24% overall yields from 2,5-dihydrofuran while the pyrrolizidine alkaloids (+)-<b>3</b> and (+)-<b>4</b> 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 (−)-<b>31</b>, which is created in the key step by the asymmetric tandem [4 + 2]/[3 + 2] cycloaddition between silaketal nitro olefin <b>18</b> and chiral vinyl ether (+)-<b>23</b>. 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.