Abstract
Indicine N‐oxide, an antitumor agent possessing an unusual type of potential alkylating capacity, was recently selected for clinical trial. Radioactive‐labelled indicine N‐oxide was sought for studies of its biological properties relating to antitumor activity and toxicity. Available indicine N‐oxide was reduced to indicine, and the alkaloid ester was hydrolyzed to its component compounds, retronecine and (−)‐trachelanthic acid. The radioactive label was then introduced into the hydroxymethyl grouping of retronecine by a previously reported procedure involving oxidation of retronecine to methyl 1,2‐dehydro‐7β‐hydroxy‐8α‐pyrrolizidine‐1‐carboxylate followed by reduction of the methoxycarbonyl grouping with LiAl^3^H~4~. Recombination of the alcohol and the carboxylic acid, a heretofore challenging problem in syntheses of pyrrolizidine alkaloid esters, was achieved using an adaptation of the mild esterification procedure recently reported by Hassner and Alexanian. By this method, indicine was obtained following reaction of retronecine, the isopropylidene derivative of (−)‐trachelanthic acid, and N,N′‐dicyclohexylcarbodiimide in the presence of 4‐(dimethylamino)pyridine in toluene. Tritium‐labelled indicine thus formed was then treated with m‐chloroperoxybenzoic acid to give labelled indicine N‐oxide.