Improved Synthesis of Three Brominated Analogues of the Potent Environmental Mutagen 3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) Maia Lloveras, a Isabel Ramos, a Elies Molins b and Angel Messeguer a, * a Department of Biological Organic Chemistry, IIQAB (CSIC), J. Girona, 18, 08034 Barcelona, Spain b Institut de Cie Áncia de Materials de Barcelona (CSIC), Campus de la UAB, E. 08193 Bellaterra, Spain Received 20 January 2000; accepted 29 March 2000 Abstract ÐThe synthesis of three brominated analogues of the environmental mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)- furanone (MX), namely, 3-chloro-4-(bromochloromethyl)-5-hydroxy-2(5H)-furanone (BMX-1), 3-chloro-4-(dibromomethyl)-5-hydroxy- 2(5H)-furanone (BMX-2) and 3-bromo-4-(dibromomethyl)-5-hydroxy-2(5H)-furanone (BMX-3), by employing a simple procedure from a common precursor, is described. q 2000 Elsevier Science Ltd. All rights reserved. The occurrence of halogenated furanones in drinking water is a matter of concern due to the potential toxicity of these compounds. The most important representative of this family of toxins is 3-chloro-4-(dichloromethyl)-5-hydroxy- 2(5H)-furanone (MX, Scheme 1). This compound is a highly potent direct-acting mutagen in the Salmonella typhimurium assay. 1±3 The data available indicate that MX is originated from the reactions of chlorine with the humic substances not eliminated during the puri®cation of water. 4,5 It has been shown that MX induces DNA damage in mammalian cells in vitro 6±8 and in vivo, 9,10 and that the administration of this mutagen through drinking water caused cancer effects in rats. 11 More recently, adducts from the reaction of MX with nucleosides and calf thymus DNA have been identi®ed. 12,13 These ®ndings, together with the epidemiological studies showing a link between cancer in humans and consumption of chlorinated drinking water, suggest that MX should be considered as a health risk factor. 14,15 The chlorine disinfection of drinking water with high bromide content could also lead to the formation of bromi- nated hydroxyfuranones. These compounds may arise from the generation of hypobromous acid or bromine by the reaction of chlorine with bromide ion. Horth et al. described the formation of three bromohydroxyfuranones, namely BMX-1, BMX-2 and BMX-3 (Scheme 1) as result of the chlorination of water containing bromide ions; furthermore, mutagenic activities were reported for these compounds although their rigorous chemical characterization was not given. 4,16 Suzuki et al. reported the occurrence of BMX-1, BMX-2 and BMX-3, together with MX, in four different samples of Japanese chlorinated drinking water. 17 Finally, LaLonde and coworkers have recently published the synthesis and mutagenicity in the Ames Salmonella typhimurium TA-100 assay of two bromohydroxyfuranones, namely BMX-2 and BMX-3. 18 This work prompted us to report our results on these MX analogues. In the present contribution the synthesis of bromohydroxyfuranones BMX-1, BMX-2 and BMX-3 is reported. For BMX-1, this is the ®rst report on its synthesis and chemical characterization. The preparation of these bromohydroxy- furanones was accomplished by using a simple synthetic pathway starting from methyl 3-methylbut-2-enoate as common precursor. Tetrahedron 56 (2000) 3391±3397 Pergamon TETRAHEDRON 0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(00)00258-1 Keywords: mutagen; synthesis; bromofuranones; polybrominated compounds. * Corresponding author. Tel.: 139-93-4006121; fax: 134-93-2045904; e-mail: ampqob@iiqab.csic.es Scheme 1. Structure of MX and of its brominated analogues BMX-1, BMX-2 and BMX-3.