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Paper | Special issue | Vol 79, No. 1, 2009, pp.935-953
Published online, 9th December, 2008
DOI: 10.3987/COM-08-S(D)68
Formal Synthesis of (5R,8R,8aS)-Indolizidine 209I via Enaminones Incorporating Weinreb Amides

Charles B. de Koning, Joseph P. Michael,* and Darren L. Riley

*School of Chemistry, University of the Witwatersrand, Private Bag 3, PO WITS
2050, South Africa


A formal enantioselective synthesis of the amphibian alkaloid (5R,8R,8aS)-(–)-indolizidine 209I (6) is reported. Control of the absolute stereochemistry at C-5 resulted from application of the Davies procedure, which entails stereoselective conjugate addition of (R)-(+)-N-benzyl-1-phenylethylamine to tert-butyl (E)-hex-2-enoate. The resulting chiral adduct 26 was converted in eight steps into a pivotal enaminone incorporating a Weinreb amide, the inherent nucleophilicity of which was exploited in a cyclisation that yielded the key bicyclic intermediate (5R)-N-methoxy- N-methyl-5-propyl-1,2,3,5,6,7-hexahydroindolizine- 8-carboxamide (38). Stereoselective catalytic hydrogenation of the alkene bond, reaction of the Weinreb amide with ethylmagnesium bromide, and epimerisation of the resulting ketone completed the formal synthesis of the target alkaloid.