Thesis (M. Phil.)--University of Hong Kong, 1988.

Thesis (Ph.D)---University of Adelaide, Dept. of Organic Chemistry, 1962. / Typewritten.

Thesis (Ph. D.)--University of Hong Kong, 1992.

Thesis (Ph. D.)--University of Hong Kong, 1995. / Includes bibliographical references (leaf 251-258).

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

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

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published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

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