Towards the Biosynthesis of Mollisin

Finnie, Alistair Andrew (1989) Towards the Biosynthesis of Mollisin. PhD thesis, University of Glasgow.

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Mollisin, a unique dichloroacetylnapthoquinone metabolite of the fungus Mollisia caesia is of polyketide origin. The biosynthesis of mollisin is proposed to proceed either through the condensation of two polyketide precursors or through the condensation of a single octaketide chain by means of a phenanthrenoid intermediate. M. caesia was incubated with sodium [2-2H3, 1-13C] acetate. Subsequent isolation of mollisin and examination by NMR spectroscopy has shown that acetate was incorporated. Close examination of 13C and spectra provided evidence that biosynthesis may proceed via the octaketide route. A postulated biosynthetic intermediate is 1,5,7,10-tetrahydroxy-3-methylphenanthrene. A synthetic route to its 1,5,7-trimethyl ether has been developed which utilises the condensation of a 3,5-dimethoxyphenylacetonitrile anion with a benzoate ester. The enol acetate of the resulting 3-ketonitrile undergoes photocyclisation to give a 10-acetoxy-9-cyanophenanthrene. Photolysis of the corresponding methyl enol ether failed to give cyclised product. It was found that the condensation product of the phenylacetonitrile with methyl 2-methoxy-4-methylbenzoate gave a mixture of 5,7-dimethoxy- and 1,5,7-trimethoxy-phenanthrenes upon photoylsis of the enol acetate. These result from non-oxidative and oxidative reaction pathways respectively, the former involving loss of methanol. In contrast the enol acetate of the condensation product of a 2,6-dimethoxy-4-methylbenzoate upon photolysis gave the 10-acetoxy-9-cyano-1,5,7-trimethoxyphenanthrene as the sole product - the oxidative mechanism being precluded. Hydrolysis of the nitrile functionality of this material proved impossible even under forced conditions. This proved similarly so for the corresponding 10-hydroxy- and 10-methoxy-phenanthrenes prepared from this compound. On attempting to prepare the aldehyde by reaction of the nitrile with Raney nickel in formic acid, a novel reductive decyanation was observed to furnish the hydroxytrimethoxyphenanthrene. Mechanistically, this degradation is proposed to proceed either via a Birch-type process or via a series of hydrogenation and elimination steps. Complete demethylation of 10-hydroxy-1,5,7-trimethoxy-3-methylphenanthrene using standard techniques was not found to be possible. Attempts to adapt this synthetic route to provide 4-substituted phenanthrenes were unsuccessful. Condensation of 3,5-dimethoxyphenylacetonitrile with a 2,5-dimethoxybenzoate ester followed by photolysis of the enol acetate of the resulting ketone gave exclusively the 2-methoxyphenanthrene through non-oxidative methanol loss. No 1,4-dimethoxyphenanthrene was obtained. A series of methyl 2,3,6-trimethoxybenzoates was prepared. However, condensation with the phenylacetonitrile was not possible because of steric hindrance of the ester moeity. Bromination of 10-acetoxy-9-cyano-1,5,7-trimethoxy-3-methylphenanthrene has been found to be reversible and temperature dependant. The 2-bromo, 6-bromo, 2,6-dibromo, and 4,6-dibromophenanthrenes can be formed depending upon the reaction conditions. On prolonged reaction, a thermodynamic equilibrium mixture is formed. The structure of these bromophenanthrenes was elucidated by 200 MHz proton NMR spectroscopy.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Organic chemistry
Date of Award: 1989
Depositing User: Enlighten Team
Unique ID: glathesis:1989-77921
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 30 Jan 2020 15:48
Last Modified: 30 Jan 2020 15:48

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