Studies on the synthesis and biosynthesis of indole alkaloids
Creators: name: Fuller, George Bohn
Publisher: name: University of British Columbia
Year: 2010

description: 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&amp;,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.