Synthesis of fluorinated benzophenones and phenylcoumarins.

Abstract

The aim of this project was to develop methods for the preparation of fluorine analogues of natural products. The incorporation of fluorine into bioactive organic compounds enhances bioactivity and the replacement of either a hydrogen atom or oxygen atom with fluorine atom is sterically favoured since their atomic sizes are similar. Three classes of fluorine-containing compounds were synthesized, i.e. prenylated benzophenones, geranylated benzophenones and 4-phenylcoumarins. Prenylated benzophenones are compounds with interesting activities such as anticancer, anti-inflammation, anti-HIV, cholesterol regulatory, cytotoxic and antimicrobial activity. Fluorine-containing prenylated benzophenones were prepared by an improved synthetic route which includes the application of Friedel-Crafts acylation and electrophilic aromatic substitution reactions. The analogues of benzophenones that were synthesized in this study include monoprenylated, diprenylated, triprenylated and tetraprenylated benzophenones with a fluorine substituent in either the ortho-, meta- or para-position of the benzene ring. Among the analogues of benzophenones synthesized were (3-fluorophenyl)[2,4,6-trihydroxy-3-(3-methyl-2-butenyl)phenyl]methanone (monoprenylated), (3-fluorophenyl)[2,4,6-trihydroxy-3,5-bis(3-methyl-2-butenyl)phenyl]methanone (diprenylated), (3-fluorophenyl)[2,4,6-tris(3-methylbut-2-enyloxy)phenyl]methanone (triprenylated) and (3-fluorophenyl)[2-hydroxy-3,5-bis(3-methylbut-2-enyl)-4,6-bis(3-methylbut-2-enyloxy)phenyl]methanone (tetraprenylated). Similar types of 4-fluoro analogues of benzophenones were synthesized which includes C- and O-prenylated benzophenones. Geranylated benzophenones were also synthesized in this study including monogeranylated, digeranylated, trigeranylated and tetrageranylated benzophenones. The prenylation reaction of a 2-fluorobenzophenone using prenyl bromide and DBU was not successful, but when K₂CO₃ was used instead of DBU, the reaction was successful. Coumarins belong to a class of phenolic compounds characterized by a benzene ring fused to a pyrone ring. Many coumarins exhibit biological activities such as antibacterial, anti-inflammatory, anti-oxidant, anticoagulant, anti-tumour, hepatoprotective, anti-carcinogenic, anti-viral and anti-thrombotic activities. In this study, fluorinated 4-phenylcoumarins (fluorine-substituted neoflavones) were synthesized by the Pechmann reaction. Fluorine-substituted 4-aryl β-ketoesters were successfully synthesized by a newly developed method and subjected to Pechmann reactions using resorcinol and phloroglucinol as starting materials to form 7-hydroxyneoflavones and 5,7-dihydroxyneoflavones, respectively. Some of the synthesized fluorinated prenylated benzophenones and fluorinated neoflavones were assayed for HIV activity at a concentration of 10 μg.mL⁻¹ but did not show any activity at this concentration.