This article is part of a series on Indolizidines and quinolizidines: natural products and beyond, edited by Prof Joseph P Michael, University of Witwatersrand.

Full Research Paper

Analogues of amphibian alkaloids: total synthesis of (5R,8S,8aS)-(-)-8-methyl-5-pentyloctahydroindolizine (8-epi-indolizidine 209B) and [(1S,4R,9aS)-(-)-4-pentyloctahydro-2H-quinolizin-1-yl]methanol

Joseph P Michael, Claudia Accone, Charles B de Koning and Christiaan W van der Westhuyzen

Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050, South Africa

Beilstein Journal of Organic Chemistry 2008, 4:5doi:10.1186/1860-5397-4-5

Published:	18 January 2008

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Abstract

Background

Prior work from these laboratories has centred on the development of enaminones as versatile intermediates for the synthesis of alkaloids and other nitrogen-containing heterocycles. In this paper we describe the enantioselective synthesis of indolizidine and quinolizidine analogues of bicyclic amphibian alkaloids via pyrrolidinylidene- and piperidinylidene-containing enaminones.

Results

Our previously reported synthesis of racemic 8-epi-indolizidine 209B has been extended to the laevorotatory enantiomer, (-)-9. Attempts to adapt the synthetic route in order to obtain quinolizidine analogues revealed that a key piperidinylidene-containing enaminone intermediate (+)-28 was less tractable than its pyrrolidinylidene counterpart, thereby necessitating modifications that included timing changes and additional protection-deprotection steps. A successful synthesis of [(1S,4R,9aS)-4-pentyloctahydro-2H-quinolizin-1-yl]methanol (-)-41 from the chiral amine tert-butyl (3R)-3-{benzyl [(1R)-1-phenylethyl]amino}octanoate (+)-14 was achieved in 14 steps and an overall yield of 20.4%.

Conclusion

The methodology reported in this article was successfully applied to the enantioselective synthesis of the title compounds. It paves the way for the total synthesis of a range of cis-5,8-disubstituted indolizidines and cis-1,4-disubstituted quinolizidines, as well as the naturally occurring trans-disubstituted alkaloids.

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