Asymmetric Synthesis of Saturated Hydroxy Fatty Acids and Fatty Acid Esters of Hydroxy Fatty Acids

Abstract

The recent discovery of a novel class of endogenous lipids, named Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs), that present antidiabetic and anti‐inflammatory activities, has attracted the interest on hydroxy fatty acids (HFAs) and their derivatives. We present herein the development of a convenient and general methodology for the asymmetric synthesis of HFAs and FAHFAs. The enantioselective organocatalytic synthesis of asymmetric terminal epoxides starting from monoprotected α,ω‐diols and their subsequent ring opening by a Grignard reagent are the key‐steps for our methodology, allowing the introduction of the hydroxy group at different positions of the long chain by proper selection of the starting diol and the Grignard reagent. MacMillan's third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, an approach for the synthesis of deuterated HFAs and FAHFAs was developed, leading to deuterated derivatives, which can be useful in biological studies and in mass spectrometry studies as internal standards.

Enantioselective Organocatalysis-Based Synthesis of 3-Hydroxy Fatty Acids and Fatty γ-Lactones

“…We have recently presented the synthesis of 9-hydroxy fatty acids starting from monoprotected diols and employing organocatalytic α-chlorination, epoxide formation and ring opening by an alkylmagnesium bromide (Figure 1, left). Through a multistep procedure (acetylation, debenzylation, oxidation, deacetylation), 9-hydroxy fatty acids were obtained [22]. In the current work, we started from commercially available long chain aldehydes and through an organocatalytic α-chlorination, chiral terminal epoxides were synthesized, which were then opened either by vinylmagnesium bromide or by allylmagnesium bromide (Figure 1, right).…”

Analytical Methods for the Determination of Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) in Biological Samples, Plants and Foods

“…Samples of the major FAHFAs are commercially available by various companies. In addition, methodologies for their synthesis, either in racemic or chiral form, have been developed [2,[8][9][10][11]. During the last five years, a tremendous effort has been devoted to the development of analytical methods for the detection and quantitation of FAHFAs in biological samples as well as in plants and foods.…”

“…Samples of the major FAHFAs are commercially available by various companies. In addition, methodologies for their synthesis, either in racemic or chiral form, have been developed [ 2 , 8 , 9 , 10 , 11 ].…”

A Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of Free Hydroxy Fatty Acids in Cow and Goat Milk

“…The method developed herein allowed us to study for the first time the existence of various hydroxylated positional isomers of palmitic acid and stearic acid in milk and to expand our knowledge on the lipidome of milk. Having on hand a variety of HFAs that previously synthesized by us [26,27], we were able to demonstrate that two families of previously unrecognized HFAs are The method developed herein allowed us to study for the first time the existence of various hydroxylated positional isomers of palmitic acid and stearic acid in milk and to expand our knowledge on the lipidome of milk. Having on hand a variety of HFAs that previously synthesized by us [26,27], we were able to demonstrate that two families of previously unrecognized HFAs are present in milk, HPAs and HSAs, each one consisting of various members carrying the hydroxyl functionality at different chain positions.…”