Studies on the biosynthesis, degradation and synthesis of olivacine-ellipticine type indole alkaloids
Creators: name: Grierson, David Scott
Publisher: name: University of British Columbia
Year: 2010

description: 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).