Synthesis and desaturation of monofluorinated fatty acids1

Abstract

A series of monofluoro C₁₆ and C₁₈ fatty acids have been synthesized and used as mechanistic probes for fatty acid desaturation. Only fluoroolefinic products are obtained when these compounds are processed by an in vivo Saccharomyces cerevisiae ω⁹ desaturating system as determined by ¹H-decoupled ¹⁹F NMR and GC–MS analysis. No evidence for fluorohydrin formation has been found when either methyl (R,S)-9- or 10-fluoropalmitate (stearate) 3a,b and 5a,b was incubated with the ω⁹ desaturase. On desaturation α- and β-fluorine substituent effects (k_H/k_F) of magnitude 6.2 and 2.4, respectively, have been measured by direct competition experiments between 3a and 3b and between methyl 16-fluoropalmitate 3c and 3b. These results do not support the involvement of discrete hydroxylated and carbocationic intermediates in fatty acid desaturation. Substantial apparent steric effects have been observed for monofluorostearoyl substrates 5c–f bearing a fluorine distal from the site of initial oxidation. In the case of (R,S)-methyl 12-fluorostearate 5f, we show that both enantiomers are desaturated at comparable rates.