Part A of this thesis provides a resume1 of the synthesis of various radioactively labelled forms of secodine C76) and provides an evaluation of these compounds, as well as some radioactively labelled forms of tryptophan C25), as precursors in the Biosynthesis of apparicine (81), uleine C83), guatam-buine (90) , and olivacine (88) in Aspidosperma australe. Only apparicine (81) could be shown to incorporate these precursors to a significant extent. Degradation of apparicine (81) from Aspidosperma pyricollum provided evidence for the intact incorporation of the secodine system. Part B discusses the synthesis of 16-epi-stemmadenine (161), which provides an entry into the stemmadenine system with, radioactive labels at key positions in the molecule. The synthesis involved the degradation of strychnine (29) to Wieland-Gumlich aldehyde (130) by a previously established sequence of reactions. Initial conversion of Wieland-Gumlich aldehyde to nor^fluorocurarine (134) succeeded by a previously described route, although some study was necessary for determining the conditions by which the Oppenauer oxidation of 2B,16a-cur-19-en-17-ol (137) could selectively yield either 23,16a-cur-19-en-17-al (133) or nor-fluorocurarine (134). When nor-fluoro-curarine (134) could not be converted to the desired stemmadenine system, Wieland^GxunlictL aldehyde was converted to methyl 18-hydroxy^2&,16a-cur-19-en-17^oate (156) by a previously established procedure. Conversion of this compound to methyl 2 6/, 16a-cur-19- en-17-^oate 0.571 was accomplished by successive treatment with, hydrogen bromide and zinc in acetic acid. The ester 157 was converted to its- N Ca I *s£ o rmy-1 derivative 158 by reaction with methyl formate and sodium hydride. Treatment of this product with dry formaldehyde and sodium hydride in dimethyl sulfoxide led to the formation of the unexpected but nevertheless useful tetrahydrooxazine derivative 159. Hydrolysis of the tetrahydrooxazine moiety was accomplished with methanolic hydrogen chloride, resulting in the isolation of 2g,16g-carbo-methoxy-cur-19-en-17-ol (160) . Oxidation of compound 160 with lead tetraacetate followed immediately by treatment with sodium borohydride in methanolic acetic acid provided 16-epi-stemmaden-ine C161). Hydride reduction of the C-16 ester function in 161 and authentic stemmadenine (6a) led to the same diol 175 thereby providing the required interrelationship between the synthetic and natural compounds. This sequence also established the previously unknown configuration of stemmadenine (6a) about C-16 and provided an obvious pathway for the synthesis of stemmadenine via the saturated aldehyde 133. Also discussed in Part B is the lead tetraacetate oxidation of the ester 157 to akuammicine (66), representing the first total synthesis of that compound. Part C discusses the synthesis of 16-epi-stemmadenine (161) labelled with tritium in the aromatic ring. Simultaneous 3 administration of this material and stemmadenine-Car- H) (6a) to separate portions of A., pyricolluro root sections established that, while the latter was incorporated into apparicine (81), no incorporation could be detected in the. case of the former. / Science, Faculty of / Chemistry, Department of / Graduate

The first part of this thesis describes the synthesis of 3,4- functionalized cleavamine templates bearing a C₁₈- carbomethoxy group. Thus hydroboration of 18β-carbomethoxycleavamine (29) produced two epimeric alcohols; 18α- and 18β -carbomethoxydihydrocleavamin -3 -ol (56 and 57). These compounds could be interconverted by using boron trifluoride etherate in benzene. One of these compounds (56) could be oxidized to the corresponding C₃ ketone which is a key intermediate for future work. The second part describes the research in the area of the so-called dimerization reaction. The generality of a procedure which had been used before was tested. When the chloroindolenine of 4(3-dihydrocleavamine and 18-carbomethoxy-43-dihydrocleavamine were each treated with vindoline in 1.5% methanolic hydrogen chloride,good yields of dimeric products were obtained. These materials have been shown by X-ray to be epimeric at C₁₈, to the natural dimers vincristine (VCR) and vinblastine (VLB). When these conditions were applied to the chloro- indolenines of 18β -carbomethoxycleavamine arid the 18α - and 18β -carbomethoxy-cleavaminols (56 and 57),good yields of dimers did not result. A detailed study, which has illuminated the mechanism of this reaction, was thus undertaken. As a result of this study, an improved procedure for the dimerization of such sensitive cleavamine templates was discovered. The insight gained from this study has permitted changes in the reaction conditions which have resulted in the isolation of two dimeric products from a single dimerization reaction. Previously, only one dimer had resulted from such reactions stereoselectively. Several new and exciting other approaches to the coupling of the indole and dihydroindole portions have been explored. Some of these have uncovered novel and useful avenues for eventually achieving the synthesis of the natural dimers such as VLB, VCR leurosine and leurosidine. / Science, Faculty of / Chemistry, Department of / Graduate

Part I of this thesis describes the isolation of representatives of a class of indole alkaloids, lacking the 3-Ƃ-ethylamino side chain, from two plant sources Aspidospema australe, and Aspidosperna vargasii. A preliminary investigation of the biosynthesis of several of these compounds was conducted in Aspidosperca vargasii. From crude extracts of Aspicosperma australe the pyridocarbazole alkaloids olivacine (16) and guatambuine (25) were isolated. From Aspidosperra vargasii uleine (18), apparicine (19), desmethyluleine (85 ) and the pyridocarbazoles 9-methoxyolivacine (82) and guatanbuine (25) were isolated. Aromatic tritium labelled tryptophan (27) and stemoadenine (13) were shown to be incorporated into 9-methoxyolivacine (82) and tryptophan (27) was also incorporated into guatanbuine (25) in Aspidosperma vargasii. Neither precursor was incorporated into uleine (18). In part II a degradation scheme was developed for the isolation of the C-l methyl, C-2 methyl(N-methyl) and C-3 methylene groups of the "D" ring of the olivacine (16) and ellipticine (17) systems. Both ellipticine (17) and olivacine (16) were converted to their N-methyl tetrahydro derivatives guatambuine (25) and N-methyltetrahydroellipticine (26) via formation of the methiodide salts of 16 and 17 followed by reduction with sodium borohydride. Compounds 25 and 26 were converted to their corresponding methiodides 86 and 95 and reacted under Hofmann reaction conditions. Olefins 88 and 97 were obtained from guatambuine methiodide (86) and olefin 102 was obtained from 95. Olefins 88 and 102 were reacted with ozone and the formaldehyde produced was isolated as the bisdimedone derivative. The C-2 vinyl compound 97 was elaborated into the C-3 vinyl compound 112 by hydrogenation of 97 to 103, formation of the methiodide 111 and reaction of 111 with sodium hydride in dimethylformamide. The methiodides 86 and 95 were also ring opened to 89 and 107 by reaction with lithium aluminum hydride. These compounds were in turn converted to their methiodides 90 and 108 and reacted with potassium t-butoxide in t-butanol. The trimethylamine produced during the reactions was isolated as the tetramethyl-ammonium iodide salt. The efficiency of the N-methyl group isolation was determined by degrading (N-¹⁴C methyl)-guatambuine methiodide (86) and N-methyl-tetrahydroellipticine methiodide (95) via the lithium aluminum hydride ring-opening sequence. Guatambuine (25) was also ring-opened to a C-3 vinyl derivative 125 by reaction with acetic anhydride and sodium acetate. Part III was concerned with the synthesis of olivacine (16). Two approaches were developed; in sequence A the reaction of tryptophyl bromide (207) with methylacetoacetate (205) gave 3-carbomethoxy-5-(3-indolyl)-2- pentanone (204). Cyclization of 204 led to an equal mixture of 1-methyl-2-carbomethoxycarbazole (134) and 1-methyl-2-carbomethoxy-1,2,3,4-tetrahydrocarbazole (209) formed by disproportionation of the initially fomed 208. Dehydrogenation of the mixture of 134 and 209 over Pd/C gave 134. The carbazole ester 134 was also obtained directly from 204 by cyclization in the presence of chloranil as the hydrogen acceptor. Compound 134 was reduced to the alcohol 157 with lithium aluminum hydride and the alcohol 157 was oxidized to the aldehyde 152 with Jones reagent. The aldehyde 152 was converted to olivacine (16) and guatamabuine (25) by a known procedure. In sequence B., when 9-benzyltetrahydrocarbazole (217) was reacted under Vilsmeier-Haack conditions 1-methyl-3-formyl-9-benzylcarbazole (219) was forced. Compound 219 was elaborated to the aminoacetal 224 by two routes; condensation with aminoacetaldehyde diethylacetal (171) led to the imine acetal 221 which was alkylated with methylmagnesium chloride to give 224. Alternatively 219 was alkylated to give the α-hydroxyethyl carbazole 222 which was converted to its corresponding acetate 223. The acetate group was displaced by aminoace-taldehyde diethylacetal (171) to give 224. The cyclization of 224 to 6-benzo-olivacine (225) followed by debenzylation to olivacine (16) was not attempted, however the conditions necessary for the cyclization have been worked out for the synthesis of the closely related molecule, ellipticine (17). / Science, Faculty of / Chemistry, Department of / Graduate

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. / Science, Faculty of / Chemistry, Department of / Unknown

No description available.

This thesis describes the application of the Sonogashira coupling reaction to access a variety of 5-and 7-azaindoles derivatives. The background chapter paints a picture about the importance of indole-containing compounds and azaindole-containing compounds. In this first chapter, discovery, synthesis, properties and reactivity of indole and azaindoles were explained.

No description available.

Les spirooxindoles se retrouvent fréquemment dans les produits naturels et les composés biologiquement actifs. Certains principes actifs pharmaceutiques contenant un motif spirooxindole ont également été décrits, stimulant un grand intérêt pour la construction et la modification de ce squelette. Cependant, peu de travaux ont été réalisés pour remplacer le carbonyle en position 2 par un autre groupe fonctionnel d’intérêt. Basées sur l’expertise reconnue de notre équipe en désaromatisation d’indoles par umpolung et l’importance des fonctions CF₃ et PO(OR)₂ nous avons entrepris la synthèse de 3,3-spiroindolines substitueés en position 2 par un trifluoromethyl ou un phosphonate. Nous avons ainsi généré des radicaux trifluoromethyl ou phosphonyl par oxydation respective de trifluoromethyl sulfinate de sodium et de phosphites. Les espèces radicalaires obtenues peuvent ensuite s’additionner sur la position 2 des indoles et effectuer la désaromatisation d’indoles. / Spirooxindoles are frequently found in natural products and biologically active compounds. Certain pharmaceutical active ingredients containing a spirooxindole motif have also been described, stimulating great interest in the construction and modification of this structures. However, not a lot of work has been done to replace the carbonyl in position 2 with another functional group of interest. Based on the recognized expertise of our team in deflation of indoles by umpolung and the importance of CF₃ and PO(OR)₂ functions, we have undertaken the synthesis of 3,3-spiroindolines substituted in position 2 by a trifluoromethyl or a phosphonate . We have thus generated trifluoromethyl or phosphonyl radicals by respective oxidation of sodium trifluoromethyl sulfinate and phosphites. The radical species obtained can then be added to the position 2 of the indoles and perform the dearomatization of indoles.

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Ecology and Biodiversity / Master / Master of Philosophy