Studies towards the enantioselective synthesis of 5,6,8-trisubstituted amphibian indolizidine alkaloids via enaminone intermediates.
Investigations aimed at the enantioselective total synthesis of indolizidine 223A, a recently described 5,6,8-trisubstituted indolizidine alkaloid from a dendrobatid frog, are described. tert-Butyl (2R,3R)-3-amino-2-ethylhexanoate and its (2S,3R)-diastereomer, prepared in several steps from lithium N-benzyl-N-[(1R)-1-phenylethyl]amide and tert-butyl (2E)-hex-2-enoate by the Davies protocol, served as chiral building blocks from which two complementary suites of diastereomeric intermediates were made en route to pivotal tert-butyl 3-[2-(alkoxycarbonylmethylene)pyrrolidin-1-yl]-2-ethylhexanoate intermediates 20 and 21. Cyclisation of these enaminones, achieved by acid hydrolysis of the tert-butyl esters and activation of the liberated carboxylic acids as mixed anhydrides, afforded 6-ethyl-7-oxo-5-propyl-1,2,3,5,6,7-hexahydroindolizine-8-carboxylate esters 28 and 29. Several further transformations of these potential scaffolds for the synthesis of the target alkaloidal systems are also reported.
Michael
Joseph P
JP
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, P.O. Wits 2050, South Africa. jmichael@aurum.wits.ac.za
de Koning
Charles B
CB
van der Westhuyzen
Christiaan W
CW
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000663:Amphibians; D000818:Animals; D007212:Indolizines / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D013237:Stereoisomerism
C104548:6,8-diethyl-5-propylindolizidine; D000470:Alkaloids; D007212:Indolizines