Total Synthesis of (+)-Fendleridine (Aspidoalbidine) and (+)-1-Acetylaspidoalbidine

A total synthesis of the Aspidosperma alkaloids (+)-fendleridine and (+)-1-acetylaspidoalbidine is detailed, providing access to both enantiomers of the natural products and establishing their absolute configuration. Central to the synthetic approach is a powerful intramolecular [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole in which the pentacyclic skeleton and all the stereochemistry of the natural products are assembled in a reaction that forms three rings, four C-C bonds, and five stereogenic centers including three contiguous quaternary centers, and introduces the correct oxidation state at C19 in a single synthetic operation. The final tetrahydrofuran bridge is subsequently installed in one step, enlisting an intramolecular alcohol addition to an iminium ion generated by nitrogen-assisted opening of the cycloadduct oxido bridge, with a modification that permits release of useful functionality (a ketone) at the cleavage termini.