Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotine

doi:10.1073/pnas.0401322101

Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotine

Max-Planck-Institut für Kohlenforschung, D-45470 Mülheim/Ruhr, Germany

Edited by Kyriacos C. Nicolaou, The Scripps Research Institute, La Jolla, CA (received for review February 25, 2004)

Abstract

A concise and efficient total synthesis of the spermidine alkaloid (-)-isooncinotine (1) incorporating a 22-membered lactam ring is outlined. The approach is largely catalysis-based, involving a selective iron-catalyzed alkyl–aryl cross-coupling reaction of a difunctionalized pyridine substrate, a heterogeneous asymmetric hydrogenation step to set the chiral center of the target, and a highly integrated ring-closing metathesis/hydrogenation sequence to forge the saturated macrocyclic edifice in a single operation.

Footnotes

↵ * To whom correspondence should be addressed at: Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim/Ruhr, Germany. E-mail: fuerstner{at}mpi-muelheim.mpg.de.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: THF, tetrahydrofuran; HMPA, hexamethylphosphoramide; DMF, dimethylformamide; EI, electron impact; HRMS, high-resolution MS; ee, enantiomeric excess; RCM, ring-closing metathesis.
↵ † For example, compounds 2 and 3 are inseparable by chromatography (6). A pure sample of 2 was obtained only after 3 was transformed into 1 by base-induced ring expansion.
↵ ‡ Slow addition of the Grignard reagent over 30 min is essential, resulting in the exclusive formation of the monosubstitution product, whereas more rapid addition affords product mixtures.