Studies related to the synthesis and biosynthesis of indole alkaloids
Creators: name: Hanssen, Harald Wilhelm
Publisher: name: University of British Columbia
Year: 2010

description: In Part I, a modified synthesis of radio-labelled secodine (68) and its incorporation into vindoline (7) is described. In a model study, for the synthesis of side-chain labelled 3-ethylpyridine (74), [2-² H]-(3'-pyridyl)-ethane was achieved from the correspondingly labelled 3-acetylpyridine by desulphurization of the intermediate thioketal (93). In a second study, [1- ³H]-(3'-pyridyl)- ethane was synthesized by treating 3-acetylpyridine with sodium borohydride-³H. The resulting alcohol (95) was acetylated, and hydrogenolysis achieved the desired product. The ester alcohol (74) was coupled to [1- ³H]-(3'-pyridyl)-ethane and the resulting pyridinum salt (90) was reduced to the corresponding piperdeine ester (80) in a "one-pot" synthesis. The conversion of (80) to [19-³H]-secodine was achieved by a known procedure. In two experiments, [19-³H, ¹⁴C0₂CH₃]-secodine (68)(³H/¹³C ratios = 3.00 and 1.54) was administered to Catharanthus roseus plants. The vindoline (7) which was isolated was shown to have been biosynthesized from the entire secodine molecule (³H/¹³C = 3.31 and 1.35 respectively). In Part II, a degradation scheme designed to achieve the isolation of the N-methyl group of uleine (1) is described as well as preliminary results from an investigation into the biosynthesis of uleine (1) and olivacine (4). Variously radio-labelled forms of tryptophan (15), anthranilic acid and secodine (18) were administered to Aspidosperma pyricollum root segments and whole plants. The uleine (1) which was isolated was found to be inactive in all experiments. Variously radio-labelled forms of tryptophan (15), anthranilic acid and secodine (18) as well as ¹⁴CH₃-methionine (30) was administered to Aspidosperma australe plants. Uleine (1) and olivacine (4) was isolated. The only incorporation that could be demonstrated was that of ¹⁴CH₃ methionine (30) into uleine (1) to the extent of 0.168% and 0.147%. The isolation of the N-methyl group from (1) showed that it contained 97% and 98% of the activity. In Part III, the attempted synthesis of compounds of the preakuammicine- and stemmadenine-series is described. A new method for the C-18 deoxygenation of curan derivatives using Birch reduction conditions was achieved. Also, a modification of the Oppenauer oxidation of the curenol (36) to achieve improved yields of the aldehyde (37) and nor-fluorocurarine (39) was developed. The introduction of a carbomethoxy group into the C-16 position of the curan aldehyde derivatives (44) and (50) using a base and methylchloroformate was unsuccessful. Also, the introduction of cyanide into position C-16 of the indole alcohol (52) or indole acetate (57) via the corresponding chloroindolenines was unsuccessful. The synthesis of product (60), which is believed to be identical with preakuammicine aldehyde (7), was achieved. This material could not be converted into akuammicine (5) or stemmadenine (4). Only the dehydrated indolenine (72) could be obtained. The ring-opening reaction of the corresponding thioacetal derivative (73) yielded the decarboxylated indole thioacetals (75) and (76).