The synthesis of novel, biologically active isoflavone analogues

Abstract

This thesis explores the synthesis of novel isoflavone analogues, with a particular focus on isoflavonoid compounds that are substituted at C2 or C4. Isoflavylium salts were prepared via the treatment of isoflavenes with tritylium hexafluorophosphate or thallium trifluoroacetate. The reactivity of these salts towards nucleophiles was exploited to generate a diverse series of 2-substituted isoflavenes. Isoflavylium salts reacted readily with alkylzinc reagents, primary and secondary amines, thiols, indoles and α-methyl ketones. Some of the isoflavenes generated in this manner were reduced to the corresponding isoflavans. 2-Substituted isoflavenes were also synthesised via an alternative route. 2-Substituted isoflavones were prepared via the cyclisation of deoxybenzoins with symmetrical anhydrides or acyl chlorides. Reduction of the 2-substituted isoflavones to the corresponding isoflavanols, followed by acid-catalysed dehydration afforded 2- substituted isoflavenes. 2-Substitituted isoflavones were also partially reduced to the corresponding isoflavanones, which can serve as precursors to the synthesis of 4- substituted isoflavonoid compounds. Isoflavene epoxides were also explored as potential precursors to 4-substituted isoflavonoid species. Novel epoxides were prepared via the oxidation of isoflavenes with meta-chloroperbenzoic acid. This reaction was found to generate meta- chlorobenzoate ester side products. These esters were converted to the corresponding epoxides via treatment with acid. The biological activity of 2-substitued isoflavenes was also investigated. A number of the analogues synthesised as part of this project exhibited promising anti-cancer activity.