POTENTIALLY MUTAGENIC, CHLORINE-SUBSTITUTED 2(5H)-FURANONES - STUDIES OF THEIR SYNTHESIS AND NMR PROPERTIES

The mutagen 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), 1, and seven analogues of it were synthesized from 4-(hydroxymethyl)-2(5H)-furanone, 2. This investigation was undertaken to learn if 2 would serve as a versatile starting point for the preparation of MX analogues required for structure/activity studies of genotoxicity. Compound 2 was treated with thionyl chloride-pyridine to develop the C-4 chloromethyl group. Oxidation of 2 with pyridinium chlorochromate to the aldehyde, followed by treatment of the latter with phosphorus pentachloride, developed the C-4 dichloromethyl group. Thereafter, when attachment of chlorine at C-3 was desired, the aluminum chloride promoted chlorine addition to the C-3-C-4 double bond followed by the triethylamine-promoted elimination of hydrogen chloride resulted in the required 3-chloro-4-(chloromethyl) or 4-(dichloromethyl)-5-desoxy analogues of MX. Hydroxylation at C-5 was achieved in two steps, involving first bromine substitution employing NBS under free radical conditions followed by metal ion assisted hydrolysis of the bromide in aqueous acetone. Special regard was paid to the characterization of MX and its analogues by assessing the values of 13C NMR chemical shift, the consistency of substitution effects, and the occurrence and magnitude of direct and long-range couplings in the spectra of these compounds. © 1990, American Chemical Society. All rights reserved.