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.
Campbell
Erica L
EL
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Zuhl
Andrea M
AM
Liu
Christopher M
CM
Boger
Dale L
DL
D030009:Aspidosperma / Q000737:chemistry; D003500:Cyclization; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D013237:Stereoisomerism
C549511:1-acetylaspidoalbidine; D026121:Indole Alkaloids; C549510:fendleridine