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.
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%.


CONCLUSIONS
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.
Michael
Joseph P
JP
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits 2050, South Africa. joseph.michael@wits.ac.za
Accone
Claudia
C
de Koning
Charles B
CB
van der Westhuyzen
Christiaan W
CW