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.
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 direct determination of various saturated hydroxy fatty acids (HFAs) in milk was developed for the first time. The method involves mild sample preparation conditions, avoids time-consuming derivatization procedures, and permits the simultaneous determination of 19 free HFAs in a single 10-min run. This method was validated and applied in 17 cow milk and 12 goat milk samples. This work revealed the existence of various previously unrecognized hydroxylated positional isomers of palmitic acid and stearic acid in both cow and goat milk, expanding our knowledge on the lipidome of milk. The most abundant free HFAs in cow milk were proven to be 7-hydroxystearic acid (7HSA) and 10-hydroxystearic acid (10HSA) (mean content values of 175.1 ± 3.4 µg/mL and 72.4 ± 6.1 µg/mL in fresh milk, respectively). The contents of 7HSA in cow milk seem to be substantially higher than those in goat milk.
In recent years, the development of light‐mediated methods for synthetic applications has attracted high interest, because such methods constitute alternative approaches for the production of valuable chemical products. We study herein a photochemical protocol for the synthesis of Weinreb amides and morpholine amides from carboxylic acids. Various carboxylic acids were directly coupled to N,O‐dimethylhydroxylamine, upon irradiation with either LED 370 nm or sunlight in the presence of 4‐dimethylaminopyridine and bromotrichloromethane, providing Weinreb amides in moderate to high yields. Similarly, morpholine amides were obtained in satisfactory to high yields under sunlight or LED 370 nm irradiation. Thus, the versatile building blocks Weinreb amides and morpholine amides may be efficiently synthesized directly from carboxylic acids by light‐mediated approaches, without the need of coupling reagents or pre‐activation of carboxylic acids.
The Cover Feature illustrates the photochemical conversion of carboxylic acids to Weinreb and morpholine amides. Sunlight or LED 370 nm irradiation mediates the direct coupling of carboxylic acids to N,O‐dimethylhydroxylamine or morpholine in the presence of 4‐dimethylaminopyridine and bromotrichloromethane, providing the corresponding amides in satisfactory to high yields. More information can be found in the Research Article by C. G. Kokotos, G. Kokotos et al.
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