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

Abstract

3-Hydroxy fatty acids have attracted the interest of researchers, since some of them may interact with free fatty acid receptors more effectively than their non-hydroxylated counterparts and their determination in plasma provides diagnostic information regarding mitochondrial deficiency. We present here the development of a convenient and general methodology for the asymmetric synthesis of 3-hydroxy fatty acids. The enantioselective organocatalytic synthesis of terminal epoxides, starting from long chain aldehydes, is the key-step of our methodology, followed by ring opening with vinylmagnesium bromide. Ozonolysis and subsequent oxidation leads to the target products. MacMillan’s third generation imidazolidinone organocatalyst has been employed for the epoxide formation, ensuring products in high enantiomeric purity. Furthermore, a route for the incorporation of deuterium on the carbon atom carrying the hydroxy group was developed allowing the synthesis of deuterated derivatives, which may be useful in biological studies and in mass spectrometry studies. In addition, the synthesis of fatty γ-lactones, corresponding to 4-hydroxy fatty acids, was also explored.

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 present in milk, HPAs and HSAs, each one consisting of various members carrying the hydroxyl functionality at different chain positions.…”

“…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.…”

“…2HPA and 2HSA were commercially available from Cayman Chemical (Michigan, USA), and 16HPA from Sigma-Aldrich (Darmstadt, Germany). 3HCA, 3HLA, 3HMA, 3HPDA, 3HPA, and 3HSA were synthesized as previously described, and their analytical data were in accordance with the literature [ 27 ]. 9HPA, 9HSA, 11HPA, and 12HSA were synthesized as previously described, and their analytical data were in accordance with the literature [ 26 ].…”

“…For example, 9-hydroxystearic acid (9HSA) has been shown to inhibit cell growth in human colon cancer, targeting histone deacetylase−1 [ 24 ], and to mediate the switch from proliferation to differentiation in retinal progenitor cells [ 25 ]. We have recently developed methods for the synthesis of various SHFAs, including both 9-hydroxy and 3-hydroxy FAs [ 26 , 27 ].…”

Potential physio-pathological effects of branched fatty acid esters of hydroxy fatty acids

“…The configuration of the chiral center was shown [18] to be of great importance for the rate of their biosynthesis and ester linkage hydrolysis (see section V). Thus, for the last three years, organic chemists focused their efforts on stereocontrolled multistep strategies, providing several enantio-pure or enantio-enriched FAHFAs, using (R)-and (S)-chiral pools [epichlorohydrin epimers [18,19]; (S)-glycidol [20]; (R)-glyceraldehyde [21]; D-glucose derivatives [22e24] or asymmetric enantioselective reactions (asymmetric Jorgensen epoxidation [25,26]; asymmetric allylations [27,28]; lipase-catalyzed transesterification [29]; asymmetric hydrogenation [30], respectively. Both (R)-and (S)-enantiomers were detected in vivo [18,31].…”