Studies related to the biosynthesis of indole alkaloids
Creators: name: Sood, Rattan Sagar
Publisher: name: University of British Columbia
Year: 2011

description: The Strychnos skeleton (e.g. preakuammicine, 56) has been postulated in the literature to rearrange to Aspidosperma (e.g. vindoline, 5) and Iboga (e.g. catharanthine, 6) bases via the intervention of Δ⁴‧²¹ -dehydrosecodine (76). Part A of the thesis describes the syntheses and biosynthetic evaluation of two close relatives, 16,17-dihydrosecodin-17-ol (90) and secodine (107), of the fugitive acrylic ester (76). In the synthetic sequence, condensation of 3-ethylpyridine with 2-carboethoxy-3-(3-chloroethyl)-indole (80) followed by the reduction of the resulting pyridinium chloride (82) gave N[β-{3-(2-hydroxymethylene)-indolyl}-ethyl]-3'-ethyl-3'-piperideine (84). The benzoate ester (85) of alcohol (84) was treated with potassium cyanide to afford N-[β-{3-(2-cyanomethylene)-indolyl}-ethyl]-3'-ethyl-3'-piperideine (86). This latter compound upon treatment with methanol and hydrogen chloride gas gave N- [β-{3- (2-carbomethoxymethylene)-indolyl}-ethyl]-3’-ethyl-3'-piperideine (88). Formylation of the ester (88) with methyl formate followed by reduction of the resulting enol (89) gave 16,17-dihydro-secodin -17-61 (90). Feeding of [¹⁴C00CH₃]-16,17-dihydrosecodin-17-ol (90) into Vinca minor L. revealed no significant activity into the isolated alkaloids. The substance in fact appeared to be a toxic component with marked deterioration of the plant occurring within 24 hours. In another investigation, synthetic 16,17-dihydrosecodin-17-ol (90) was dehydrated to secodine (107). Feeding of [ar- ³H]-secondine (107) into Vinca minor L. showed low but positive incorporation into vincamine (72) and minovine (73). "Blank" experiments revealed that after the maximum period required for the plant to absorb a solution of the labelled compound, 61% remained as monomer (107) while 32% had been converted to the dimers (presecamine and secamine). In conclusion this study while providing some preliminary information on the later stages of indole alkaloid biosynthesis has also created an entry into more sophisticated biosynthetic experiments. This situation will hopefully lead to a better understanding of the manner in which this large family of natural products is synthesized in the living plant. In Part B of the thesis some preliminary studies leading to the biosynthesis of vincamine (ebumamine family) are described. The intermediacy of a tetracyclic pyruvic ester (12) was invoked by Wenkert several years ago to rationalise the rearrangement of Aspido-sperma skeleton to vincamine (2) . To confirm this speculation a short synthesis of a close relative (i.e., 24) of the postulated precursor was contemplated. In the synthetic sequence reaction of tryptophyl bromide (18), produced by the action of phosphorus tribromide on tryptophol (17), with 3-acetylpyridine ethylene ketal (16) gave N-[β-(3-indolyl)-ethyl]-3'-acetylpyridinium ethylene ketal bromide (19). The pyridinium bromide (19) on catalytic reduction and acid hydrolysis furnished N-[β-(3-indolyl)-ethyl]-3'-acetylpiperidine (21). Alkylation of the ketone (21) using trityl sodium and allyl bromide gave N-[β-(3-indolyl)-ethyl]-3'-allyl-3'-acetylpiperidine (22). Osmylation of the allylic double bond in (22) did not give the desired diol (23). Tentative assignment is given in structure (34) to the polar compound obtained in this manner.