Fluorinated retinoic acids and their analogues. 3. Synthesis and biological activity of aromatic 6-fluoro analogues

Several analogues (15a--e) of methyl (E,E,Z,E)-3,7-dimethyl-6-fluoro-9-(4-methoxy-2,3,6-trimethylphenyl)nonatetraenoate (15f), which had been found to cause a marked regression of chemically induced skin papillomas in mice, were prepared. Two synthetically versatile methods leading to these derivatives are described. The key intermediate, ethyl (Z)-2-fluoro-3-methyl-4,4-dimethoxy-2-butenoate (8), was elaborated to the C10 aldehyde ester, methyl (2E,4E,6Z)-3-methyl-6-fluoro-7-formyl-2,4,6-octatrienoate (14a), which upon Wittig condensation with the aryl-phosphonium salts 13a--e gave the (2E,4E,6Z,8E)-3,7-dimethyl-6-fluoro-9-aryl-2,4,6,8-nonatetraenoates 15a--e. Alternatively, Wittig reaction of 8 and [(4-methoxy-2,3,6-trimethylphenyl)methyl]triphenylphosphonium chloride (13f) gave a mixture of (E/Z,E)-2-fluoro-3-methyl-5-(2,3,6-trimethyl-4-methoxyphenyl)-2,4-pentadienoates 17 and 18, which was converted to 15f. The biological activity of these analogues and the 1H and 19F NMR spectral properties of the intermediates and final products are discussed.