Studies on the synthesis and biosynthesis of indole alkaloids
Creators: name: Lewis, Norman G.
Publisher: name: University of British Columbia
Year: 2010

description: Part I of this thesis describes the more recent investigations towards the elucidation of the biosynthetic pathways leading to the formation of a class of indole alkaloids found in Aspidosperma vargasii. In this respect, the in vivo role of tryptophan (lb) and stemmadenine (63) were studied but the incorporation levels obtained were not conducive with the active intermediacy of either (lb) or (63) in the biosynthesis of the alkaloids uleine (103), guatambuine (104) or 9-methoxy-olivacine (111). Conditions for the growth of Aspidosperma australe, A. pyricollum and A. vargasii tissue cultures are also reported. Part II discusses the more recent studies towards the synthesis of stemmadenine (63) with radioactive labels at the required positions in the molecule. The studies initially involved conversion of strychnine (5) to 2β, 16α-cur-19-en-17-ol (143) by a previously described sequence of reactions. Conditions for the efficient conversion to the known 2β-cur-19-en-l7-al (145) were developed but subsequent conversion to stemmadenine (63) was not accomplished. The conversion of (143) to des-carbomethoxystemmadenine (128) is reported. Further studies towards the synthesis of stemmadenine (6 3) were initiated from methyl-2β,16α-cur-19-en-17-oate (133). The ester (133), derived from strychnine (5) in overall low yield via Wieland-Gumlich aldehyde (129) was an important intermediate in the synthesis of epistemmadenine (138). A more efficient synthesis of (133) was developed from Wieland-Gumlich aldoxime (130). Ester (133) was efficiently converted to (-) akuammicine (64) by treatment with lead tetra-acetate and these recent conditions have been successfully applied in the total synthesis of vindoline (11). Akuammicine (64) was converted to deshydroxymethylstemmadenine (122). Attempts to convert (122) or Na-carbomethoxydeshydroxymethylstemmadenine (175) to stemmadenine (63) were unsuccessful. These failures prompted alkylation studies with the model system, 1-carbomethoxy-1,2,3,4-tetrahydrocarbazole (156) prepared from tetrahydrocarbazole (155) via a three step synthesis. The N-carbomethoxy derivative (170) of (156) was treated with formaldehyde in the presence of potassium hydride and gave the required 1-carbomethoxy-1-hydroxymethyl-1,2,3,4-tetrahydrocarbazole (157) in good yield. Further alkylation studies with 18β-carbomethoxycleavamine (72) and the corresponding Na-carbomethoxy (180) and Na-methyl (183) derivatives were unsuccessful. Indeed, it appears that introduction of the hydroxymethyl group in the more complex systems cannot be accomplished using this strategy. Part III of this thesis investigated the role of catharanthi: Nb-oxide (205) as a possible precursor for the in vivo formation of the medicinally important dimeric alkaloid vincristine (201) in Catharanthus roseus. In these studies the chemistry of catharanthine (12) was appropriately developed in order that radioactive labels at (1) the aromatic positions C₁₁-C₁₄ (2) C-19 (3) C-18 and (4) C-22 could be introduced. (Ar³H) catharanthine-Nb-oxide (205) was administered to C. roseus and the alkaloid vincristine (201) isolated by cold dilution. The incorporation levels obtained do not give substantial in vivo support for the intermediacy of (205) in the biosynthesis of (201). Part IV of this thesis discusses the formation of important intermediates in the recent investigations towards the synthesis of the anti-tumour alkaloids ellipticine (106) and olivacine (105) . In this respect the synthesis of indol-2-y1-1-(4' pyridyl)-ethanol (239) was carried out. Hydrogenolysis of (239) with H₂/Pd/C afforded indol-2-y1-1-(4' pyridyl)-ethane (240). Treatment of (239) with acetic acid in pyridine gave the required indol-2-y1-1-(4' pyridyl)-ethene (241). With the chemistry developed for the formation of derivatives (239-241) further studies for the introduction of the N'-methyl group and the C-3 side chain ((CH₃) ₂N CH₂) were executed to give derivatives (246) and (247). The tetrahydropyridine derivative (248) was obtained by sodium borohydride reduction of (246). The cyclisation of (24 8) to the pyridocarbazole derivative (235) was not attempted. However the conditions necessary for the cyclisation have been reported for the synthesis of the close related alkaloid ellipticine (106). Further cyclisation studies using the corresponding dihydropyridine derivatives of (246) and (247) are currently under investigation.