Studies towards the enantioselective synthesis of 5,6,8-trisubstituted amphibian indolizidine alkaloids via enaminone intermediates

Abstract

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.