UBC Theses and Dissertations
Studies directed towards a synthesis of resistomycin Kingston, John Francis
A possible route to the synthesis of resistomycin is outlined and the first steps in this are reported and discussed. Acetylation of the known compound 2-(3,5-dimethoxyphenyl)-2-methylpropionitri1e afforded 2-(4-acetyl-3,5-dimethoxyphenyl)-2-methylpropionitrile (22). Condensation of 22 with the dianion of methyl acetoacetate, followed by dehydration afforded an E,Z mixture of methyl 5-(4-1¹-cyano-1¹-methylethyl-2,6-dimethoxyphenyl)-3-oxo-hex-4-enoates (25). Several attempts to cyclise 25_ and a closely related model compound via their monoanions or their enol ethers or acetates were unsuccessful. In a model study related to the proposed synthesis of resistomycin the dianion of acetic acid was condensed with 2,4,6-trimethoxyacetophenone (94). Dehydration of the product yielded a mixture of 3-(2,4,6-trimethoxyphenyl)but-2 and 3-enoic acids (96 and 113). Attempts to acylate the methyl esters and acid chlorides of 96 and 113 with the enolate anion of 94 were unsuccessful. Several methods of generating the dianions of β-diketones and condensing them with hindered ketones such as 94, 22 and 2,6-dimethoxyacetophenone (39) were investigated. The synthesis of l-(2,4,6-trimethoxyphenyl)butane-1,3-dione (121) was accomplished by condensation of 94 with methyl acetate. One alternative to the dianion approach to the functiona-lisation of the γ carbon of β-diketones was examined. This involved the synthesis of 3-methyl-5-(2,4,6-trimethoxyphenyl)isoxazole (183) from 121. Attempts to functionalise the C-3 methyl group of 183 and its methyl fluorosulphonate salt were not successful. Condensation of the dianion of 40 with 94 afforded 5-hydroxy-l-phenyl-5-(2,4,6-trimethoxyphenyl)hexane-l,3-dione (158). This compound was dehydrated and in a novel reaction was cyclised, in the presence of hydrogen chloride, via loss of methanol, to 5,7-dimethoxy-2-hydroxy-4-methyl-l-naphthyl phenyl ketone (156). The dianion of 121 was reacted with ketones 39 and 22 and the products were dehydrated with boron trifluoride etherate. In these cases stannic chloride was required to effect cyclisation to 2-hydroxy-5-methoxy-4-methyl-l-naphthyl 2,4,6-trimethoxyphenyl ketone (217) and 2-(7-hydroxy-5-methyl-4-methoxy-8-2, ,4',6'-tri-methoxybenzoyl-2-naphthyl)-2-methylpropionitrile (27). Plans to convert 27 to resistomycin by additional cyclisations are discussed.
Item Citations and Data