Concise Synthesis of Hydroxy β-Methyl Fatty Acid Ethyl Esters

Abstract

Hydroxy β-methyl fatty acid ethyl esters bearing different carbon chain lengths and varying hydroxyl group positions were successfully synthesized from symmetric diols. These fatty acid derivatives are useful intermediates of chemical probes for metabolic analyses of fatty acid.Key words β-methyl fatty acid; chemical synthesis; Johnson-Claisen rearrangement; hydroxy fatty acid Fatty acids are hydrocarbon compounds that contain various lengths of saturated carbon chains, unsaturated carbon chains, and substituted carbon chains. Fatty acids and their derivatives (including phospholipids and glycerolipids) are widely distributed in living organism and have various roles as structural and metabolic substrates.1) More specifically, methyl-substituted fatty acids are widespread in both prokaryotic and eukaryotic cells. For example, phytanic acid (1) (Fig. 1), a tetramethyl-substituted fatty acid derived from phytol, is substituted at the β-position by one of the four methyl groups.2) Although fatty acids are generally metabolized by β-oxidation, the presence of a methyl group on the β-position inhibits β-oxidation, and so metabolism via α-oxidation dominates. In terms of their biological influence, the accumulation of methyl-substituted fatty acids can cause a neurotic disorder known as Refsum disease. This disease results from a deficiency in peroxisomal α-oxidation enzymes, and manifests an accumulation of 1.3) The suppression of β-oxidation by a methyl group can also be employed for molecular imaging, as probe molecules can accumulate in the target tissue. ) for myocardial imaging. Based on this importance of hydroxy β-methyl fatty acids as valuable chemical probes in metabolic analyses, we herein report the concise synthesis of hydroxy β-methyl fatty acid ethyl esters bearing different carbon chain lengths and varying hydroxyl group positions. Results and DiscussionThe synthesis of β-methylated fatty acid derivatives was carried out from the symmetric diols 1,6-hexanediol (5a) and 1,12-dodecandiol (5b) (see Chart 1). Initially, a single hydroxyl group from each diol was converted into the corresponding benzyl ether under basic conditions to give 6a and b in moderate yields, while the remaining hydroxyl group was efficiently converted to an aldehyde by a (2,2,6,6-tetramethylpiperidin-1-yl) oxyl (TEMPO)-mediated oxidation reaction. 8)The resulting aldehydes (7a, b) were then converted to allylic alcohols in good yields using propenylmagnesium bromide at −60°C, and the resulting allylic alcohols (8a, b) were heated under reflux in the presence of triethyl orthoacetate and catalytic amounts of pivalic acid to give the β-methylated γ, δ-unsaturated ethyl esters. 9) Finally, the γ, δ-unsaturated ethyl esters were reduced and the benzyl ether groups were removed under hydrogenation conditions to yield the desired ω-1-hydroxy-β-methyl fatty acids (9a, b) in good yields.Subsequently, the corresponding ω-7-hydroxy-β-methyl fatty acids were synthesized from alcohols 9a and b, as depicted in Chart 2. This was achieved throug...