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Topics in natural product synthesis and biosynthesis

University of British Columbia

In Part I of this thesis is described the syntheses of radiolabelled ∝-bisabolene, monocyclofarnesol and farnesol-10 ,11-epoxide, and the evaluation of their role as precursors of the mould metabolite trichothecin. ∝-Bisabolene was prepared by dehydration of radiolabelled ∝-bisabolol, which itself was prepared by the action of ¹⁴C-methyl magnesium iodide on 2-methyl-6-keto-6-(4'-methylcyclohex-3'-enyl)-hex-2-ene. This ketone was prepared in a modified Grignard reaction from 5-bromo-2-methyl-pent-2-ene, (obtained from cyclopropyl methyl ketone by treatment with methyl magnesium iodide followed by reaction of the intermediate 2-cyclopropylpropan-2-ol with 48% hydrogen bromide) and 4-methylcyclohex-3-ene carboxylic acid (prepared in a Diels Alder reaction between acrylic acid, or its methyl ester, and isoprene). Monocyclofarnesol was prepared from β-ionone by reduction of the central double bond to dihydro- β-ionone followed by a modified Wittig reaction with radiolabelled trimethyl phosphono- acetate, prepared from trimethyl phosphite and 1- ¹⁴C-methyl bromoacetate. Farnesol-10,11-epoxide was prepared from geraniol by formation of geranyl bromide which was condensed with ethyl acetoacetate. Hydrolysis and decarboxylation then gave geranyl acetone which was treated in the same way as dihydro- -ionone to give ¹⁴C-labelled farnesol. Treatment of farnesol with N- bromosuccinimide in aqueous glyme followed by base catalysed ring closure gave ¹⁴C-labelled farnesol-10,11-epoxide. The mechanisms whereby these compounds could be converted to trichothecin are described and the relevance, to contemporary reports, of their non-incorporation into trichothecin is discussed. In Part II is described an attempted synthesis of ∝-cuparenone from 5-acetoxy-6-methyl-2-p-tolylhepta-1,5-diene. Reaction of p-tolualdehyde with 5-bromo-2-methylpent-2-ene gave 6-keto-2-methyl-6-p-tolylhex-2-ene . Protection of the ketone as a ketal followed by hydroboration of the double bond and acetylation of the resulting alcohol, gave, after deketalisation and Wittig reaction, 5-acetoxy-6-methyl-2-p-tolylhept -1-ene. Hydrolysis of the acetate and oxidation gave 6-methyl-2-p-tolylhept-l-ene 5-one which gave 5-acetoxy-6-methyl-2-p-tolylhepta-1,5-diene on treatment with isopropenyl acetate and p-toluenesulpfionic acid. This enol acetate could not be converted to ∝-cuparenone. In Part III is described the photochemistry of triacetic acid lactone methyl ether. Photolysis of this compound in methanol solution gave 6,6-dimethoxy-4-methyl-2-pyrone which on treatment with water gave cis - β -carbomethyoxymethylcrotonic acid. The mechanism for this process is discussed.

Text

2011-03-17

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http://hdl.handle.net/2429/32548

Chemistry

University of British Columbia

Graduate