Synthesis and Reactivity of Dihalofuranones

Abstract

Background: Halogenated furanones have been found to act as potent quorum sensing inhibitors in several bacterial species. It is believed that dihalofuranones covalently bind to the LuxS enzyme, which is necessary for autoinducer-2 synthesis. In addition to their antimicrobial activity, halogenated furanones also possess anti-cancer, antioxidant, and depigmentation properties. However, traditional routes to these compounds are low-yielding and capricious. Objective: This study aimed at investigating higher-yielding preparations of gem-dihalofuranones and comparing their reactivity using Suzuki chemistry. Methods: Ramirez dibromoolefination of maleic anhydride was optimised using a variety of conditions. A similar route was investigated for the preparation of bromofluorofuranones and dichlorofuranones. The conversion of a dichlorofuranone to the corresponding iodofuranone derivatives using microwave-assisted Finkelstein chemistry was also studied. Lastly, the reactivity of the different dihalofuranones was compared by Pd-mediated coupling with phenylboronic acid. Results: A higher-yielding, concise synthesis of dibromofuranones was developed using a modified Ramirez reaction. Additionally, a telescoped preparation of dichlorofuranone proved higher yielding than previous approaches. Bromine- and iodine-substituted dihalofuranones proved more reactive than their chlorine-substituted analogues. Conclusion: Higher yielding routes to bromine-, fluorine-, chlorine- and iodine-containing dihalofuranones were successfully developed. Suzuki couplings of gem-dihalofuranones were found to proceed with high stereoselectivity.