Synthesis of ³H‐labelled indicine N‐oxide

Abstract

SUMMARYIndicine E-oxide, an antitumor agent possessing an unusual type of potential alkylating capacity, was recently selected for clinical trial. Radioactive-labelled indicine E-oxide was sought for studies of its biological properties relating t o antitumor activity and toxicity. Available indicine E-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 l,Z-dehydro-?I3 -hydroxy-8a-pyrrolizidine-1-carboxylate followed by reduction of the methoxycarbonyl grouping with LiAl H4.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 E,"-dicyclohexylcarbodiirnide in the presence of 4-(dimethylamino)pyridine in toluene. Tritium-labelled indicine thus formed was then treated with g-chloroperoxybenzoic acid to give labelled indicine g-oxide. RESULTS AND DISCUSSIONThe basic synthetic steps used consisted of, first, the hydrolysis of indicine to its fundamental moieties ( -h a c h e l a n t h i c acid (111) and retronecine (IV), followed by introduction of a label into retronecine, and finally, the reassembly of constituents (111 and IV) to produce labelled indicine (see Scheme 1). The recombination was the k e y step in the task since methods for converting retronecine to [9- HI -retronecine are known (6,7) and, furthermore, the total synthesis of retronecine Syntheses of both retronecine and (-)-trachelanthic acid have been reported( 8 , lo), but their synthetic union to produce indicine has not heretofore been described. Other Ssubstituted monoesters of retronecine (and stereoisomeric heliotridine) have been prepared from the pyrrolizidine alcohol via t h e corresponding chloromethyl compound and the sodium salt of the appropriate acid (11-14).Reported examples utilize widely divergent isolation efforts; some products apparently were isolated readily, but the countercurrent distribution technique was used for others. Reported yields range from 13% (for 9-heliotrylretronecine) Thin-layer chromatography (TLC) used to monitor reactions and to examine products for homogeneity was done on Analtech precoated (250 pm) silica gel

Synthesis of pyrrolizidine alkaloids indicine, intermedine, lycopsamine, and analogs and their N-oxides. Potential antitumor agents

“…28, No. 6 689 Attempts to couple the isopropylidene derivatives of the necic acids 10-13 with retronecine according to the procedure of Piper et al,37 as previously mentioned, failed, in our hands, to give decent yields with use of toluene, chloroform, or ether as solvent integration in the absence or presence of DMAP. In the absence of DMAP, no coupling at all was observed.…”

Tritium-labelled alkaloids: Synthesis and applications

“…Monocrotaline was tritium labelled by the biosynthetic incorporation of [ 3 H]putrescine, and a similar strategy was used to prepare the pyrrolizidine alkaloid [ 3 H]jacobine . Useful pyrrolizidine intermediate retronecine ( 24 ) was tritiated by reacting a methyl ester precursor with lithium aluminum tritide, and it was then taken on to prepare [ 3 H]indicine N ‐oxide for oncology research . This same approach was also used to synthesize [ 3 H]disenecioyl retronecine .…”

“…125 Useful pyrrolizidine intermediate retronecine (24) was tritiated by reacting a methyl ester precursor with lithium aluminum tritide, and it was then taken on to prepare [ 3 H]indicine N-oxide for oncology research. 126 This same approach was also used to synthesize [ 3 H] disenecioyl retronecine. 127 An analogous strategy was also used to prepare [9-3 H]retronecine, but instead an aldehyde precursor with sodium borotritide was used.…”