Next Article in Journal
Pharmacokinetics and Tissue Distribution of a Novel Bis-Chelated Gold(I) Diphosphine Compound, Bis(2,3-bis(tert-butylmethylphosphino)Quinoxaline)Aurate(I), in Rats
Previous Article in Journal
The Blossoming of Technology for the Analysis of Complex Aroma Bouquets—A Review on Flavour and Odorant Multidimensional and Comprehensive Gas Chromatography Applications
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 24
Issue 11
10.3390/molecules24112081
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

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

by
Asimina Bourboula
,
Dimitris Limnios
,
Maroula G. Kokotou
,
Olga G. Mountanea
and
George Kokotos
*
Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece
*
Author to whom correspondence should be addressed.
Molecules 2019, 24(11), 2081; https://doi.org/10.3390/molecules24112081
Submission received: 17 March 2019 / Revised: 27 May 2019 / Accepted: 27 May 2019 / Published: 31 May 2019
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

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.

Graphical Abstract

1. Introduction

Saturated and unsaturated fatty acids (FAs), as well as hydroxy fatty acids (HFAs) are components of biomolecules and have been shown to exert cellular effects through G protein–coupled receptors named free fatty acid receptors (FFA1–FFA4) and hydroxycarboxylic acid receptors (HCA1–HCA3) [1]. A recent study has shown that the G protein-coupled receptor 84 (GPR84) is activated by 2-hydroxy or 3-hydroxy medium chain fatty acids more effectively than by their non-hydroxylated counterparts [2]. 3-Hydroxy fatty acids are produced in mitochondria by β-oxidation [3] and are constituents of inflammatory lipopolysaccharides [4]. The determination of 3-hydroxy fatty acids in plasma or tissue cultures provides diagnostic information regarding medium/short-chain mitochondrial L-3 hydroxyacyl coenzyme A dehydrogenases (M/SCHAD) deficiency [5]. Recently, a method for the quantitative profiling of 3-hydroxy fatty acids as environmental markers of endotoxin in occupational and environmental samples has been developed, using liquid chromatography coupled to tandem mass spectrometry [6].
Several methods for the synthesis of 3-hydroxy acids are known in the literature. For example, these hydroxy acids may be synthesized by the reduction of β-keto esters, while the choice of the reducing agent may lead either to racemic or to chiral products [7,8]. An efficient synthesis of 3-hydroxy carboxylic acids employs an aldol-type reaction of unmasked iodoacetic acid with carbonyl compounds promoted by samarium iodide [9]. Another approach based on the Reformatsky reaction has been applied for the synthesis of medium chain β-hydroxy esters [10]. Recently, the synthesis of 3-hydroxylauric acid by γ-alkylation of doubly deprotonated ethyl acetoacetate followed by reduction of the β-keto moiety and ester hydrolysis has been reported [11]. 3-Hydroxy fatty acids may be also synthesized via the opening of chiral long chain terminal epoxides by Me3SiCN in the presence of TBAF, followed by hydrolysis of the resulting nitriles [12]. Another approach employs the ring opening of chiral 2-(2-benzyloxyethyl)-oxirane by a long chain alkylmagnesium bromide, followed by functional group transformations to give 3-hydroxy fatty acids [13]. The aim of the present study was the development of a convenient general methodology for the asymmetric synthesis of 3-hydroxy fatty acids. An organocatalytic step using an imidazolidinone catalyst was employed for the induction of chirality. In addition, a synthetic route to deuterated 3-hydroxy fatty acids is presented. The synthesis of 4-hydroxy fatty acids was also studied and applied to the synthesis of a fatty acid ester of a 4-hydroxy fatty acid.

2. Results and Discussion

Organocatalysis has been recognized as a powerful methodology in asymmetric catalysis, complementing metal catalysis and biocatalysis and offering new opportunities for the enantioselective synthesis of biomolecules [14]. The organocatalytic formation of epoxides was selected as the key-step of our asymmetric method, employing MacMillan’s imidazolidinone catalyst, which has found a wide range of applications [15]. A number of different enantioselective methodologies for the α-chlorination of aldehydes have been reported in literature, and the enantiomeric excess of the product depends on the catalyst, the chlorination agent and the reaction conditions [16,17,18,19,20]. For the chlorination of long chain aldehydes, we selected a modified procedure employing (2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one trifluoroacetate as the organo-catalyst and 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one as the chlorination agent [21].
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). A different strategy, employing ozonolysis and subsequent oxidation of the hydroxy alkenes, was followed to obtain the final 3-hydroxy fatty acids or 4-hydroxy fatty acid derivatives.
As depicted in Scheme 1, applying the selected protocol, commercially available long chain aldehydes 1a–d were chlorinated and subsequent reduction by NaBH4, followed by treatment with KOH, led in a one-pot procedure to the formation of terminal chiral epoxides 2a–d in good yields and high enantiomeric purity. Treatment of these epoxides with vinylmagnesium bromide resulted in the ring opening and afforded 4-hydroxy terminal alkenes 3a–d in high yields. The target compounds 4a–d, were obtained through ozonolysis of the alkene, followed by a Pinnick oxidation (Scheme 1).
3-Hydroxy fatty acids are of high biological importance and thus, their deuterated analogs could be useful in biology and in mass spectrometry as internal standards. When a hydrogen atom of a bioactive compound is replaced by deuterium, the deuterated derivative may present altered metabolic stability [23].
Recently the FDA has approved the first deuterated drug [24], signifying a new era for research on deuterated bioactive compounds. Thus, we developed a method for the incorporation of a deuterium at the 3-position on the carbon atom carrying the hydroxy group. Our approach for the synthesis of deuterated 3-hydroxy palmitic acid is shown in Scheme 2. Deuterated epoxide 6 was obtained in low yield. Apparently the replacement of the deuterium by chlorine occurs in lower yield in comparison to the replacement of hydrogen.
First, pentadecanal 1c was converted into the corresponding α,α-dideuterated derivative 5 by treatment with D2O in the presence of triethylamine [25]. Organocatalytic α-chlorination of 5, followed by reduction with NaBH4 and subsequent treatment with KOH, afforded in a one-pot procedure the deuterated epoxide 6. For the α-chlorination, d,l-proline used as the catalyst and N-chlorosuccinimide as the chlorinating agent, since deuterated derivatives used as internal standards in mass spectrometry studies are not needed to be chiral compounds. Then, using similar reactions with those previously described, the deuterated hydroxy alkene 7 was obtained and converted into product 8 (Scheme 2). The degree of deuteration in compound 8 was determined using liquid chromatography-high resolution mass spectrometry (LC/HRMS) as depicted in Figure 2. The extracted ion chromatograms for m/z 272.2341 (corresponding to deuterated derivative 8) and m/z 271.2279 (corresponding to non-deuterated analog of 8) are shown in Figure 2A,B, while Figure 2C,D present the corresponding mass spectra. The deuteration degree of compound 8 was estimated to be 95.8%.
To extend our studies and in an effort to synthesize 4-hydroxy fatty acids derivatives, a similar procedure was explored. As presented in Scheme 3, the ring opening of epoxides 2b and 10 was carried out by treatment with allylmagnesium bromide to afford 5-hydroxy terminal alkenes 11a,b in high yields. Ozonolysis of these compounds, followed by treatment with PPh3 led to a mixture of lactols 12a,b and lactones 13a,b. Jones oxidation of such mixtures resulted in full conversion to lactones 13a,b. Both lactones are naturally occurring products found either in insects or in food stuff [26,27,28].
To avoid lactonization, the hydroxyl functionality of 5-hydroxy terminal alkenes has to be derivatized. Such a synthesis leading to biologically relevant 4-(palmitoyloxy)octadecanoic acid (4-PAHSA) is shown in Scheme 4. Fatty acid esters of hydroxy fatty acids (FAHFAs) have been recently identified as a novel class of endogenous lipids that present antidiabetic and/or anti-inflammatory properties [29,30,31]. Various families of FAHFAs varying in the chain length and the position of the ester group (5-, 9-, etc.) have been reported and synthetic routes to FAHFAs and HFAs, where the hydroxyl is at a position higher to 5-, have been developed [22,32,33]. FAHFAs containing the ester group at the 4-position have not yet reported and thus, we decided to synthesize such a derivative. Epoxide 15 was synthesized using d,l-proline as the catalyst and N-chlorosuccinimide for the α-chlorination step, followed by reduction with NaBH4 and treatment with KOH. Treatment of 15 with allylmagnesium bromide afforded hydroxy alkene 16 in high yield, which was coupled with palmitic acid, using N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) as the coupling agent in the presence of 4-(dimethylamino)pyridine (DMAP). Ozonolysis of 17, followed by a Pinnick oxidation, as previously described, gave 4-PAHSA 18.

3. Experimental Section

3.1. General Information

All reactions were monitored by analytical thin-layer chromatography (TLC) using plates precoated with silica gel (0.2 mm, 60 Å pore size) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by exposure to ultraviolet light (UV) and then stained with 12-molybdophosphoric acid hydrate in EtOH followed by brief heating on a hot plate.
1H-NMR spectra were recorded in CDCl3 at 200 MHz (Mercury, Varian, Darmstadt, Germany). Data were reported as follows: chemical shifts in ppm from TMS with the solvent resonance as the internal standard (CDCl3, δ 7.26 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal), coupling constants (Hz) and integration. Proton-decoupled carbon nuclear magnetic resonance spectra (13C-NMR) were recorded at 50 MHz. Chemical shifts were expressed in parts per million (ppm, δ scale) downfield from TMS and are referenced to the carbon resonances of the solvent (CDCl3, δ 77.0). High-resolution mass spectra (HRMS) were recorded on a Maxis Impact QTOF (Bruker, Bremen, Germany) and a 4600 Triple TOF (AB Sciex, Singapore). Optical rotations ([α]D20) were measured on an AA-65 series (Optical Activity Ltd., Bury, UK) polarimeter and melting points (m.p.) were measured on a Buchi 530 apparatus (Buchi, Flawil, Switzerland).
Enantiomeric excesses of 4a–d were determined by chiral LC/HRMS analysis using a Chiralpak AD-RH column and acetonitrile/H2O (95:5) containing 0.1% formic acid as the mobile phase (flow rate 0.3 mL/min). Extracted ion chromatograms for the determination of enantiomeric excesses of 4a–d are presented in the Supplementary Materials.

3.2. Synthesis and Characterization

3.2.1. General Procedure for the Synthesis of Chiral Epoxides 2a–d, 10

To a solution of (2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one trifluoroacetate (57 mg, 0.20 mmol) in THF (0.5 mL), 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one (331 mg, 1.10 mmol) was added and the solution was stirred for 5 min, before the aldehyde (1.00 mmol) was added. The reaction mixture was stirred for 30 min at room temperature and was cooled to 0 °C, before EtOH (0.6 mL) and NaBH4 (121 mg, 3.20 mmol) were added. After 10 min, the medium was warmed to room temperature for 5 min, before a freshly prepared solution of aqueous KOH (1.70 g KOH diluted in 2.7 mL water) and EtOH (1.3 mL) were added and the resulting mixture was stirred vigorously for 30 min. Then, water (1 × 20 mL) was added to the mixture before it was extracted with Et2O (3 × 10 mL), washed with brine (1 × 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the resulting residue by silica gel chromatography (petroleum ether 40–60 °C/diethyl ether, 9:1 or 8:2) afforded the title compounds.
(R)-2-Nonyloxirane (2a). Colorless oil, 129 mg, yield: 76%; Rf value: (pet. ether:diethyl ether = 9:1) 0.42; [α]D20 −5.80 (c 1.0, CHCl3), [ref. [18], for S-enantiomer: [α]D20 +6.34 (c 1.0, CHCl3)]; 1H-NMR (CDCl3) δ 2.85–2.76 (m, 1H, OCH), 2.64 (dd, J = 5.0, 4.1 Hz, 1H, OCHH), 2.36 (dd, J = 5.1, 2.7 Hz, 1H, OCHH), 1.64–0.98 (m, 16H, 8 × CH2), 0.81 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 52.0, 46.7, 32.4, 31.7, 29.4, 29.3, 29.2, 25.8, 22.5, 13.9.
(R)-2-Dodecyloxirane (2b). Colorless oil, 174 mg, yield 82%; Rf value: (pet. ether:diethyl ether = 9:1) 0.37; [α]D20 +4.70 (c 1.0, CHCl3), [ref. [34], [α]D20 +4.30 (c 1.42, CHCl3)]; 1H-NMR (CDCl3) δ 2.92–2.84 (m, 1H, OCH), 2.72 (dd, J = 5.0, 4.0 Hz, 1H, OCHH), 2.44 (dd, J = 5.1, 2.7 Hz, 1H, OCHH), 1.57–1.16 (m, 22H, 11 × CH2), 0.86 (t, J = 6.2 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 52.5, 47.2, 32.7, 32.1, 29.8, 29.7, 29.6, 26.2, 22.9, 14.3.
(R)-2-Tridecyloxirane (2c). Colorless oil, 179 mg, yield 79%; Rf value: (pet. ether:diethyl ether = 9:1) 0.31; [α]D20 +5.70 (c 0.5 CHCl3), [ref. [35], [α]D20 +6.54 (c 1.0, CHCl3)]; 1H-NMR (CDCl3) δ 2.79–2.70 (m, 1H, OCH), 2.57 (dd, J = 5.9, 4.0 Hz, 1H, OCHH), 2.29 (dd, J = 5.1, 2.7 Hz, 1H, OCHH), 1.48–1.05 (m, 24H, 12 × CH2), 0.77 (t, J = 5.4 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 51.8, 46.5, 32.4, 31.7, 29.5, 29.4, 29.3, 29.2, 25.8, 22.5, 13.8.
(R)-2-Pentadecyloxirane (2d). Colorless oil, 211 mg, yield 83%; Rf value: (pet. ether:diethyl ether = 8:2) 0.37; [α]D20 +5.00 (c 1.0, CHCl3), [ref. [36], [α]D20 +5.43 (c 1.4, CHCl3)]; 1H-NMR (CDCl3) δ 2.89–2.80 (m, 1H, OCH), 2.67 (dd, J = 5.0, 4.0 Hz, 1H, OCHH), 2.39 (dd, J = 5.1, 2.7 Hz, 1H, OCHH), 1.53–1.11 (m, 28H, 14 × CH2), 0.83 (t, J = 5.4 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 52.1, 46.8, 32.4, 31.9, 29.6, 29.5, 29.4, 29.3, 25.9, 22.6, 14.0.
(R)-2-Octyloxirane (10). Colorless oil, 117 mg, yield 75%; Rf value: (pet. ether:diethyl ether = 9:1) 0.35; [α]D20 +8.00 (c 1.0, CHCl3) [ref. [37], for S-enantiomer: [α]D20 −8.20 (c 1.03, CHCl3)]; 1H-NMR (CDCl3) δ 2.89–2.80 (m, 1H, OCH), 2.68 (dd, J = 5.0, 4.0 Hz, 1H, OCHH), 2.40 (dd, J = 5.1, 2.7 Hz, 1H, OCHH), 1.53–1.11 (m, 14H, 7 × CH2), 0.83 (t, J = 6.4 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 52.2, 46.9, 32.4, 31.7, 29.4, 29.3, 29.1, 25.9, 22.5, 13.9.

3.2.2. General Procedure for the Synthesis of Racemic Epoxides 6, 15

To a solution of 5 or 14 (1.00 mmol) in CH2Cl2 (5 mL), d,l-proline (115 mg, 0.10 mmol) and N-chlorosuccinimide (174 mg, 1.30 mmol) were added and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was cooled to 0 °C, before NaBH4 (121 mg, 3.20 mmol) and EtOH (1 mL) were added. After 10 min, the medium was warmed to room temperature for 5 min before a freshly prepared solution of aqueous KOH (2.25 g KOH diluted in 3.4 mL distilled water) and EtOH (1.7 mL) were added and the resulting mixture was stirred vigorously for 30 min. At this stage, water (10 mL) was added to the mixture before it was extracted with Et2O (1 × 10 mL), saturated aqueous solution of NH4Cl (1 × 10 mL) and brine (1 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The resulting residue purified by column chromatography (petroleum ether 40–60 °C/diethyl ether, 9:1 or 8:2).
2-Tridecyloxirane-2-d (6). Colorless oil, 80 mg, yield 35%; Rf value: (pet. ether:diethyl ether = 8:2) 0.48; 1H-NMR (CDCl3) δ 2.68 (d, J = 5.0 Hz, 1H, OCHH), 2.40 (d, J = 5.0 Hz, 1H, OCHH), 1.53–1.03 (m, 24H, 12 × CH2), 0.84 (t, J = 6.2 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 51.8 (t, J = 25.0 Hz, OCD), 46.8, 32.3, 31.9, 29.6, 29.5, 29.4, 29.3, 25.9, 22.6, 14.0; HRMS (ESI) exact mass calculated for [M + Na]+ (C15H29DONa+) requires m/z 250.2252, found m/z 250.2249.
2-Tetradecyloxirane (15). Colorless oil, 195 mg, yield 81%; Rf value: (pet. ether:diethyl ether = 9:1) 0.41; 1H-NMR (CDCl3) δ 2.87–2.79 (m, 1H, OCH), 2.66 (dd, J = 5.1, 4.0 Hz, 1H, OCHH), 2.38 (dd, J = 6.0, 2.0 Hz, 1H, OCHH), 1.58–0.98 (m, 26H, 13 × CH2), 0.83 (t, J = 6.4 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 52.1, 46.8, 32.4, 31.8, 29.6, 29.5, 29.4, 29.3, 25.9, 22.6, 13.9 [38].

3.2.3. General Procedure for the Synthesis of 4-Hydroxy Terminal Alkenes 3a–d, 7

To a flame-dried round flask, degassed and under argon atmosphere, copper(I) iodide (38 mg, 0.20 mmol) and vinylmagnesium bromide (1M solution in THF, 2.0 mL, 2.00 mmol) were added and cooled to −78 °C. Then, a solution of the epoxide (1.00 mmol) in anhydrous THF (5 mL) was added dropwise and the reaction mixture was left stirring at −78 °C overnight. The reaction mixture was allowed to warm to room temperature and after treatment with a saturated aqueous solution of NH4Cl (1 × 5 mL) was extracted with Et2O (3 × 10 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the resulting residue by silica gel chromatography (petroleum ether 40–60 °C/diethyl ether, 9:1 or 8:2) afforded the desired compounds.
(R)-Tridec-1-en-4-ol (3a). Colorless oil, 169 mg, yield 85%; Rf value: (pet. ether:diethyl ether = 8:2) 0.48; [α]D20 −6.70 (c 1.0, CHCl3) [ref. [39], [α]D20 −7.50 (c 1.0, CHCl3)]; 1H-NMR (CDCl3) δ 5.87–5.68 (m, 1H, =CH), 5.15–5.04 (m, 2H, =CH2), 3.66–3.54 (m, 1H, CHOH), 2.32–2.02 (m, 3H, CH2CH, OH), 1.49–1.09 (m, 16H, 8 × CH2), 0.84 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 134.9, 117.7, 70.6, 41.8, 36.7, 31.8, 29.6, 29.5, 29.3, 25.6, 22.6, 14.0; HRMS (ESI) exact mass calculated for [M + Na]+ (C13H26ONa+) requires m/z 221.1876, found m/z 221.1875.
Hexadec-1-en-4-ol (3b). Colorless oil, 195 mg, yield 81%; Rf value (pet. ether/diethyl ether 9:1) 0.52; [α]D20 −5.00 (c 1.0, CHCl3) [ref. [40], [α]D20 −5.50 (c 1.0, CHCl3)]; 1H-NMR (CDCl3) δ 5.92–5.71 (m, 1H, =CH), 5.17–5.06 (m, 2H, =CH2), 3.67–3.51 (m, 1H, CHOH), 2.34–2.01 (m, 2H, CH2CH), 1.83 (s, 1H, OH), 1.48–0.96 (m, 22H, 11 × CH2), 0.86 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 134.9, 117.8, 70.6, 41.9, 36.8, 31.9, 29.6, 29.3, 25.6, 22.6, 14.0; HRMS (ESI) exact mass calculated for [M + Na]+ (C16H32ONa+) requires m/z 263.2345, found m/z 263.2340 [41].
(R)-Heptadec-1-en-4-ol (3c). Colorless oil, 211 mg, yield 83%; Rf value (pet. ether:diethyl ether = 9:1) 0.46; [α]D20 + 4.00 (c 1.0, CHCl3), [ref. [35], [α]D20 +4.92 (c 1.0, CHCl3)]; 1H-NMR (CDCl3) δ 5.90–5.70 (m, 1H, =CH), 5.12–5.05 (m, 2H, =CH2), 3.68–3.53 (m, 1H, CHOH), 2.32–2.02 (m, 3H, CH2CH, OH), 1.49–1.10 (m, 24H, 12 × CH2), 0.85 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 134.9, 117.7, 70.6, 41.9, 36.7, 31.9, 29.6, 29.3, 25.6, 22.6, 14.0; HRMS (ESI) exact mass calculated for [M + Na]+ (C17H34ONa+) requires m/z 277.2502, found m/z 277.2503.
(R)-Nonadec-1-en-4-ol (3d). White solid, 220 mg, m.p.: 50–52 °C (ref. [42], 44–45 °C), yield 79%; Rf value (pet. ether:diethyl ether = 8:2) 0.57; [α]D20 −17.0 (c 0.50, CHCl3), [ref. [43], [α]D20 −18.33 (c 0.36, CHCl3)]; 1H-NMR (CDCl3) δ 5.90–5.69 (m, 1H, =CH), 5.12–5.04 (m, 2H, =CH2), 3.64–3.53 (m, 1H, CHOH), 2.32–2.03 (m, 3H, CH2CH, OH), 1.41–1.09 (m, 28H, 14 × CH2), 0.85 (t, J = 5.8 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 138.6, 114.6, 71.3, 37.4, 36.4, 31.9, 30.0, 29.7, 29.3, 25.6, 22.6, 14.0; HRMS (ESI) exact mass calculated for [M + Na]+ (C19H38ONa+) requires m/z 305.2815, found m/z 305.2811.
Heptadec-1-en-4-d-4-ol (7). Colorless oil, 194 mg, yield 76%; Rf value (pet. ether:diethyl ether = 7:3) 0.52; 1H-NMR (CDCl3) δ 5.91–5.70 (m, 1H, =CH), 5.13–5.05 (m, 2H, =CH2), 2.31–1.99 (m, 3H, CH2CH, OH), 1.41–1.14 (m, 24H, 12 × CH2), 0.85 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 134.9, 117.8, 70.1 (t, J = 20 Hz), 41.7, 36.6, 31.9, 29.6, 29.3, 25.6, 22.6, 14.0; HRMS (ESI) exact mass calculated for [M + Na]+ (C17H33DONa+) requires m/z 278.2565, found m/z 278.2566.

3.2.4. General Procedure for the Synthesis of 5-Hydroxy Terminal Alkenes 11a,b, 16

To a flame-dried round flask, degassed and under argon atmosphere, copper(I) iodide (38 mg, 0.20 mmol) and allylmagnesium bromide (1M solution in THF, 2.0 mL, 2.00 mmol) were added and cooled to −40 °C. Then, a solution of the epoxide (1.00 mmol) in anhydrous THF (5 mL) was added dropwise and the reaction mixture was left stirring at −40 °C for 2 h. The reaction mixture was allowed to warm to room temperature and after treatment with a saturated aqueous solution of NH4Cl (5 mL) was extracted with Et2O (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the resulting residue by silica gel chromatography (petroleum ether 40–60 °C/diethyl ether, 9:1 or 8:2) afforded the desired products.
(R)-Tridec-1-en-5-ol (11a). Colorless oil, 151 mg, yield 76%; Rf value (pet. ether:diethyl ether = 9:1) 0.59; [α]D20 +2.30 (c 0.9, MeOH), [ref. [37], [α]D20 +2.40 (c 0.86, MeOH)]; 1H-NMR (CDCl3) δ 5.92–5.72 (m, 1H, =CH), 5.06–4.92 (m, 2H, =CH2), 3.63–3.55 (m, 1H, CHOH), 2.25–2.04 (m, 2H, CH2CH=), 1.94 (s, 1H, OH), 1.55–1.15 (m, 16H, 8 × CH2), 0.86 (t, J = 6.4 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 138.6, 114.6, 71.4, 37.4, 36.4, 30.0, 29.7, 29.6, 29.2, 25.6, 25.5, 22.6, 22.4, 14.1.
(R)-Heptadec-1-en-5-ol (11b). Colorless oil, 193 mg, yield 76%; Rf value (pet. ether:diethyl ether = 9:1) 0.61; [α]D20 + 0.80 (c 0.5, CHCl3); 1H-NMR (CDCl3) δ 5.94–5.74 (m, 1H, =CH), 5.09–4.93 (m, 2H, =CH2), 3.67–3.55 (m, 1H, CHOH), 2.31–2.00 (m, 2H, CH2CH=), 1.58–1.15 (m, 25H, 12 × CH2, OH), 0.87 (t, J = 6.0 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 138.6, 114.6, 71.4, 37.5, 36.4, 31.9, 31.7, 30.1, 29.6, 29.3, 25.6, 22.7, 14.1 [44].
Nonadec-1-en-5-ol (16). Colorless oil, 223 mg, yield 79%; Rf value (pet. ether:diethyl ether = 9:1) 0.53; 1H-NMR (CDCl3) δ 5.92–5.72 (m, 1H, =CH), 5.07–4.91 (m, 2H, =CH2), 3.64–3.53 (m, 1H, CHOH), 2.26–2.04 (m, 2H, CH2CH=), 1.88 (s, 1H, OH), 1.57–1.24 (m, 28H, 14 × CH2), 0.86 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 138.6, 114.6, 71.3, 37.4, 36.4, 33.2, 33.1, 31.9, 30.0, 29.7, 29.5, 29.3, 25.6, 22.6, 14.0 [45].

3.2.5. General Procedure for the Synthesis of 3-Hydroxy Fatty Acids 4a–d, 8

Ozone was passed through a solution of 3a–d or 7 (1.00 mmol) in a mixture of CH2Cl2 (4.5 mL) and pyridine (0.5 mL) at −78 °C. Once the reaction solution had a persistent blue color, was Ar passed through until the solution was discolored, then dimethylsulfide (0.4 mL, 14.0 mmol) was added at 0 °C and the reaction mixture was left stirring for 1 to 2 h. After concentration under reduced pressure, the residue was oxidized to the desired 3-hydroxy fatty acid as described below.
To a round-bottomed flask containing the aldehyde (1.00 mmol), MeCN (10 mL), t-BuOH (2 mL), distilled H2O (0.5 mL), 2-methylbut-2-ene (0.5 mL), NaH2PO4 (48 mg, 0.40 mmol), aqueous solution of NaClO2 (154 mg NaClO2 diluted in 1 mL water) were added at 0 °C. The reaction mixture was left stirring for 2 h and then was quenched by the addition of Na2SO3 (101 mg, 0.80 mmol). After acidification to pH 1 by the addition of a solution of 1N HCl, the reaction mixture was extracted with Et2O (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (CH2Cl2/MeOH 9:1 containing 10% CH3COOH) and recrystallized with hexane.
(R)-3-Hydroxydodecanoic acid (4a). White solid, 76 mg, m.p.: 63–64 °C (ref. [46], 67–68 °C), yield 35%; Rf value (dichloromethane:methanol = 9:1) 0.37; [α]D20 −15.80 (c 1.0, CHCl3), [ref. [47], [α]D20 −16.90 (c 1.0, CHCl3)]; 1H-NMR (CDCl3) δ 7.47 (s, 1H, COOH), 4.00 (s, 1H, CHOH), 2.55–2.34 (m, 2H, CH2COOH), 1.43–1.24 (m, 16H, 8 × CH2), 0.85 (t, J = 5.7 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 177.3, 68.2, 41.2, 36.4, 31.8, 29.6, 29.5, 29.3, 25.4, 22.6, 14.0; HRMS (ESI) exact mass calculated for [M − H]− (C12H23O3−) requires m/z 215.1653, found m/z 215.1634; LC-HRMS analysis: 95% ee, Chiralpak AD-RH, acetonitrile/H2O (95:5) formic acid 0.1%, 0.3 mL/min, tR = 9.3 (minor), tR = 9.9 (major).
(R)-3-Hydroxypentadecanoic acid (4b). White solid, 119 mg, m.p.: 82–83 °C (ref. [48], 86–87 °C), yield 46%; Rf value (dichloromethane:methanol = 9:1) 0.29; [α]D20 −14.00 (c 1.0, CHCl3), [ref. [49], [α]D20 −15.00 (c 1.0, CHCl3)]; 1H-NMR (CDCl3) δ 4.06–3.97 (m, 1H, CHOH), 2.63–2.46 (m, 2H, CH2COOH), 1.57–1.01 (m, 22H, 11 × CH2), 0.85 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 177.4, 68.0, 41.0, 36.5, 31.9, 29.6, 29.6, 29.5, 29.4, 25.4, 22.7, 14.1; HRMS (ESI) exact mass calculated for [M − H]− (C15H29O3−) requires m/z 257.2122, found m/z 257.2110; LC-HRMS analysis: 91% ee, Chiralpak AD-RH, acetonitrile/H2O (95:5) formic acid 0.1%, 0.3 mL/min, tR = 12.7 (minor), tR = 14.7 (major).
(R)-3-Hydroxyhexadecanoic acid (4c). White solid, 106 mg, m.p.: 80–81 °C (ref. [50], 83–84 °C), yield 39%; Rf value (dichloromethane:methanol = 9:1) 0.32; [α]D20 −13.00 (c 2.0, CHCl3), [ref. [13], [α]D20 −12.60 (c 2.08, CHCl3)]; 1H-NMR (CDCl3) δ 4.02 (s, 1H, CHOH), 2.61–2.31 (m, 3H, CH2COOH, OH), 1.66–1.11 (m, 24H, 12 × CH2), 0.87 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 177.9, 68.0, 41.0, 36.4, 31.9, 29.7, 29.6, 29.5, 29.4, 29.2, 25.4, 22.7, 14.1; HRMS (ESI) exact mass calculated for [M − H]− (C16H31O3−) requires m/z 271.2279, found m/z 271.2274; LC-HRMS analysis: 89% ee, Chiralpak AD-RH, acetonitrile/H2O (95:5) formic acid 0.1%, 0.3 mL/min, tR = 14.7 (minor), tR = 17.8 (major).
(R)-3-Hydroxyoctadecanoic acid (4d). White solid, 129 mg, m.p.: 82–84 °C (ref. [51], 88–90 °C), yield 43%; Rf value (dichloromethane:methanol = 9:1) 0.27; [α]D20 −16.00 (c 1.0, CHCl3), [ref. [8], [α]D20 −15.80 (c 1.0, CHCl3)]; 1H-NMR (CDCl3) δ 4.06–4.01 (m, 1H, CHOH), 2.62–2.39 (m, 3H, CH2COOH, OH), 1.65–1.17 (m, 28H, 14 × CH2), 0.87 (t, J = 6.4 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 177.3, 68.0, 41.0, 36.5, 31.9, 29.7, 29.6, 29.5, 29.4, 25.4, 22.7, 14.1; HRMS (ESI) exact mass calculated for [M − H]− (C18H35O3−) requires m/z 299.2592, found m/z 299.2572; LC-HRMS analysis: 92% ee, Chiralpak AD-RH, acetonitrile/H2O (95:5) formic acid 0.1%, 0.3 mL/min, tR = 21.0 (minor), tR = 26.5 (major).
3-Hydroxyhexadecanoic-3-d acid (8). White solid, 104 mg, m.p.: 80–82 °C, yield 38%; Rf value (pet. ether:diethyl ether = 7:3) 0.27; 1H-NMR (CDCl3) δ 2.58 (d, J = 16.0 Hz, 1H, CHHCOOH), 2.45 (d, J = 16.0 Hz, 1H, CHHCOOH), 2.03 (s, 1H, OH), 1.48–1.10 (m, 24H, 12 × CH2), 0.88 (t, J = 6.0 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 177.3, 40.8, 36.4, 31.9, 29.7, 29.6, 29.5, 29.4, 25.4, 22.7, 14.1; HRMS (ESI) exact mass calculated for [M − H]− (C16H30DO3−) requires m/z 272.2341, found m/z 272.2331.

3.2.6. General Procedure for the Synthesis of Lactones 13a,b

Ozone passed through a solution of 11a,b (1.00 mmol) in CH2Cl2 (10 mL) at −78 °C. Once the reaction solution had a persisted blue color, O2 passed through for 5 min and then Ar, until the solution was discolored. The reaction mixture was allowed to warm to room temperature and then, PPh3 (262 mg, 1.00 mmol) was added and left stirring overnight. The solution was concentrated in vacuo and the resulting residue was purified by column chromatography (petroleum ether 40–60 °C/diethyl ether, 8:2 or 7:3). Thus, a mixture of lactol/lactone was obtained, which was fully oxidized to the desired lactone as described below.
To a solution of lactol/lactone (1.00 mmol) in acetone (10 mL) Jones solution 2 M (1.5 mL, 3.00 mmol) was added dropwise at 0 °C and the reaction mixture was left stirring for 1 h. Then, the reaction mixture was quenched by the addition of a saturated aqueous solution of NaHSO3 (10 mL) and extracted with Et2O (3 × 10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (petroleum ether 40–60 °C/diethyl ether, 7:3 or 6:4).
(R)-5-Octyldihydrofuran-2(3H)-one (13a). Colorless oil, 182 mg, yield 92%; Rf value (pet. ether:diethyl ether = 7:3) 0.62; [α]D20 + 42.80 (c 1.0, MeOH) [ref. [37], for S-enantiomer: [α]D20 −43.10 (c 1.01, MeOH)]; 1H-NMR (CDCl3) δ 4.52–4.39 (m, 1H, CH), 2.54–2.46 (m, 2H, CH2CO), 2.37–2.21 (m, 1H, CHHCH), 1.89–1.23 (m, 15H, 7 × CH2, CHHCH), 0.84 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 177.4, 81.0, 35.5, 31.7, 29.3, 29.2, 29.1, 28.8, 27.9, 25.1, 22.6, 14.0.
(R)-5-Dodecyldihydrofuran-2(3H)-one (13b). White solid, 226 mg, m.p.: 35–36 °C (ref. [52], 38–39 °C), yield 89%; Rf value (pet. ether:diethyl ether = 7:3) 0.56; [α]D20 +7.60 (c 1.0, CHCl3); 1H-NMR (CDCl3) δ 4.56–4.39 (m, 1H, CH), 2.56–2.44 (m, 2H, CH2CO), 2.38–2.22 (m, 1H, CHHCH), 1.93–1.56 (m, 3H, CH2, CHHCH), 1.59–1.24 (m, 20H, 10 × CH2), 0.86 (t, J = 6.3 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 177.3, 81.0, 35.5, 31.9, 29.6, 29.5, 29.4, 29.3, 28.8, 28.0, 25.2, 22.6, 14.1.

3.2.7. Nonadec-1-en-5-yl Palmitate (17)

To a solution of palmitic acid (1.0 g, 4.00 mmol) in dry CH2Cl2 (15 mL), EDC (770 mg, 4.00 mmol), Et3N (0.6 mL, 4.00 mmol) and 4-DMAP (24 mg, 0.20 mmol) were added at 0 °C and the reaction mixture was left stirring for 10 min. Then, a solution of alcohol 16 (300 mg, 1.00 mmol) in dry CH2Cl2 (10 mL) was added and the mixture was left stirring at room temperature overnight. The reaction mixture was washed sequentially with a saturated aqueous solution of NH4Cl (10 mL), an aqueous solution of 10% NaHCO3 (10 mL), an aqueous solution of 10% citric acid (10 mL) and brine (15 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and the product was purified by column chromatography (pet.ether 40–60 °C/ EtOAc 95:5). White solid; 458 mg, m.p.: 105–107 °C, yield 88%; Rf value (pet. ether:EtOAc = 95:5) 0.44; 1H-NMR (CDCl3) δ 5.88–5.70 (m, 1H, =CH), 5.05–4.83 (m, 3H, =CH2, CHCOO), 2.27 (t, J = 7.4 Hz, 2H, CH2COO), 2.10–2.00 (m, 2H, CH2CH=), 1.71–1.25 (m, 54H, 27 × CH2), 0.87 (t, J = 6.4 Hz, 6H, 2 × CH3); 13C-NMR (CDCl3) δ 173.5, 137.9, 114.8, 73.4, 34.7, 34.1, 33.4, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 25.3, 25.1, 22.7, 14.1; HRMS (ESI) exact mass calculated for [M + Na]+ (C35H68O2Na+) requires m/z 543.5112, found m/z 543.5101.

3.2.8. 4-(Palmitoyloxy)octadecanoic acid (18)

Ozone was passed through a solution of compound 17 (521 mg, 1.00 mmol) in a mixture of CH2Cl2 (4.5 mL) and pyridine (0.5 mL) at −78 °C. Once the reaction solution had a persistent blue color, Ar was passed through until the solution was discolored, then dimethylsulfide (0.4 mL, 14.0 mmol) was added at 0 °C and the reaction mixture was left stirring for 1 to 2 h. Then, after concentration under reduced pressure, the residue was oxidized by a Pinnick oxidation. The desired product was obtained after purification by column chromatography (pet. ether 40–60 °C/EtOAc 8:2). White solid, 210 mg, m.p.: 129–131 °C, yield 39%; Rf value (dichloromethane:methanol = 9:1) 0.34; 1H-NMR (CDCl3) δ 4.91 (s, 1H, CH), 2.41–2.24 (m, 4H, 2 × CH2COO), 1.95–1.78 (m, 4H, 2 × CH2), 1.64–1.25 (m, 50H, 25 × CH2), 0.87 (t, J = 5.9 Hz, 6H, 2 × CH3); 13C-NMR (CDCl3) δ 178.5, 173.7, 72.9, 34.5, 34.1, 31.9, 30.0, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 28.9, 25.2, 25.1, 22.7, 14.1; HRMS (ESI) exact mass calculated for [M − H]− (C34H65O4−) requires m/z 537.4888, found m/z 537.4887.

3.2.9. 2,2-d2-Pentadecanal (5)

To a flame-dried round-bottom flask under argon atmosphere, pentadecanal (226 mg, 1.00 mmol), D2O (1 mL) and triethylamine (0.01 mL, 0.10 mmol) were added and the mixture was left stirring in an oil bath at 100 °C for 1 h. Then, the mixture was allowed to warm to room temperature and after the addition of an aqueous solution of 1 N HCl, it was extracted with Et2O (2 × 10 mL). The organic layers were washed successively with an aqueous solution of 10% NaHCO3 (10 mL) and brine (10 mL) and then collected, dried over Na2SO4 and concentrated in vacuo. The aldehyde was immediately used for the next step without further purification. Colorless oil, 185 mg, yield 81%; Rf value (pet. ether:diethyl ether = 9:1) 0.37; 1H-NMR (CDCl3) δ 9.59 (s, 1H, CHO), 1.46–1.06 (m, 24H, 12 × CH2), 0.75 (t, J = 6.2 Hz, 3H, CH3); 13C-NMR (CDCl3) δ 201.9, 43.6–42.1 (m, CD2) 31.7, 29.5, 29.4, 29.3, 29.2, 28.9, 22.5, 21.7, 13.8.

4. Conclusions

In conclusion, we have developed a convenient enantioselective synthesis of biologically important 3-hydroxy fatty acids. Our methodology employs as the key-step the organocatalytic synthesis of chiral terminal epoxides using MacMillan’s third generation imidazolidinone organocatalyst thus ensuring high enantiomeric purity. The subsequent ring opening by vinylmagnesium bromide, followed by ozonolysis and oxidation leads to the target products. An approach for the synthesis of deuterated 3-hydroxy fatty acids is demonstrated, leading to deuterated derivatives, which can be useful in biological studies and in mass spectrometry studies as internal standards. Furthermore, a similar procedure using allylmagnesium bromide for the opening of epoxides leads to fatty γ-lactones and allows the synthesis of fatty acid asters of 4-hydroxy fatty acids.

Supplementary Materials

Supplementary Materials are available online.

Author Contributions

G.K. conceived and designed the experiments; A.M., D.L. and O.G.M. synthesized and characterized the compounds; M.G.K. performed the mass spectrometry studies; A.M. and G.K. wrote the paper.

Funding

We would like to thank the Special Account for Research Grants of the National and Kapodistrian University of Athens for the financial support (Grant 13300). M. G. Kokotou’s Post-Doctoral Research was implemented under IKY scholarship funded by the “Supporting Post-Doctoral Researchers” Action of the Operational Programme “Human Resources Development, Education and Lifelong Learning” with priority axes 6,8,9 and co-funded by the European Social Fund (ESF) and Greek National Resources.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Offermanns, S. Free fatty acid (FFA) and hydroxy carboxylic acid (HCA) receptors. Annu. Rev. Pharmacol. Toxicol. 2014, 54, 407–434. [Google Scholar] [CrossRef] [PubMed]
  2. Suzuki, M.; Takaishi, S.; Nagasaki, M.; Onozawa, Y.; Iino, I.; Maeda, H.; Komai, T.; Oda, T. Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor. J. Biol. Chem. 2013, 288, 10684–10691. [Google Scholar] [CrossRef] [PubMed]
  3. Jin, S.-J.; Hoppel, C.L.; Tserng, K.-Y. Incomplete fatty acid oxidation. The production and epimerization of 3-hydroxy fatty acids. J. Biol. Chem. 1992, 267, 119–125. [Google Scholar] [PubMed]
  4. Raetz, C.R.; Whitfield, C. Lipopolysaccharide endotoxins. Annu. Rev. Biochem. 2002, 71, 635–700. [Google Scholar] [CrossRef]
  5. Jones, P.M.; Bennett, M.J. Clinical applications of 3-hydroxy fatty acid analysis by gas chromatography–mass spectrometry. Biochim. Biophys. Acta 2011, 1811, 657–662. [Google Scholar] [CrossRef]
  6. Uhlig, S.; Negård, M.; Heldal, K.K.; Straumfors, A.; Madsø, L.; Bakke, B.; Eduard, W. Profiling of 3-hydroxy fatty acids as environmental markers of endotoxin using liquid chromatography coupled to tandem mass spectrometry. J. Chromatogr. A 2016, 1434, 119–126. [Google Scholar] [CrossRef]
  7. Oikawa, Y.; Sugano, K.; Yonemitsu, O. Meldrum’s acid in organic synthesis. 2. A general and versatile synthesis of α-keto esters. J. Org. Chem. 1978, 43, 2087–2088. [Google Scholar] [CrossRef]
  8. Ratovelomanana-Vidal, V.; Girard, C.; Touati, R.; Tranchier, J.P.; Ben Hassine, B.; Genêt, J.P. Enantioselective hydrogenation of α-keto esters using chiral diphosphine-ruthenium complexes: Optimization for academic and industrial purposes and synthetic applications. Adv. Synth. Catal. 2003, 345, 261–274. [Google Scholar] [CrossRef]
  9. Concellon, J.M.; Concellon, C. Aldol-type reactions of unmasked iodoacetic acid with carbonyl compounds promoted by samarium diiodide: Efficient synthesis of carboxylic 3-hydroxyacids and their derivatives. J. Org. Chem. 2006, 71, 4428–4432. [Google Scholar] [CrossRef]
  10. Sailer, M.; Dubicki, K.I.; Sorensen, J.L. The synthesis of medium-chain-length β-hydroxy esters via the Reformatsky reaction. Synthesis 2015, 47, 79–82. [Google Scholar]
  11. Kaspersen, M.H.; Jenkins, L.; Dunlop, J.; Milligan, G.; Ulven, T. Succinct synthesis of saturated hydroxy fatty acids and in vitro evaluation of all hydroxylauric acids at FFA1, FFA4 and GPR84. Med. Chem. Comm. 2017, 8, 1360–1365. [Google Scholar] [CrossRef] [PubMed]
  12. Guaragna, A.; De Nisco, M.; Pedatella, S.; Palumbo, G. Studies towards lipid A: A synthetic strategy for the enantioselective preparation of 3-hydroxy fatty acids. Tetrahedron: Asymmetry 2006, 17, 2839–2841. [Google Scholar] [CrossRef]
  13. Jakob, B.; Voss, G.; Gerlach, H. Synthesis of (S)- and (R)-3-hydroxyhexadecanoic acid. Tetrahedron: Asymmetry 1996, 7, 3255–3262. [Google Scholar] [CrossRef]
  14. Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications; Dalko, P.I. (Ed.) Wiley-VCH: Weinheim, Germany, 2013. [Google Scholar]
  15. MacMillan, D.W.C. The advent and development of organocatalysis. Nature 2008, 455, 304–308. [Google Scholar] [CrossRef]
  16. Brochu, M.P.; Brown, S.P.; MacMillan, D.W.C. Direct and enantioselective organocatalytic α-chlorination of aldehydes. J. Am. Chem. Soc. 2004, 126, 4108–4109. [Google Scholar] [CrossRef]
  17. Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K.A. Direct organocatalytic asymmetric α-chlorination of aldehydes. J. Am. Chem. Soc. 2004, 126, 4790–4791. [Google Scholar] [CrossRef]
  18. Amatore, M.; Beeson, T.D.; Brown, S.P.; MacMillan, D.W.C. Enantioselective linchpin catalysis by SOMO catalysis: An approach to the asymmetric alpha-chlorination of aldehydes and terminal epoxide formation. Angew. Chem. Int. Ed. 2009, 48, 5121–5124. [Google Scholar] [CrossRef] [PubMed]
  19. Kang, B.; Britton, R. A general method for the synthesis of nonracemic trans-epoxides: Concise syntheses of trans-epoxide-containing insect sex pheromones. Org. Lett. 2007, 24, 5083–5086. [Google Scholar] [CrossRef]
  20. Wang, L.; Cai, C.; Curran, D.P.; Zhang, W. Enantioselective α-chlorination of aldehydes with recyclable fluorous (S)-pyrrolidine–thiourea bifunctional organocatalyst. Synlett 2010, 433–436. [Google Scholar] [CrossRef]
  21. Kaplaneris, N.; Spyropoulos, C.; Kokotou, M.G.; Kokotos, C.G. Enantioselective organocatalytic synthesis of 2-oxopiperazines from aldehydes: Identification of the elusive epoxy lactone intermediate. Org. Lett. 2016, 18, 5800–5803. [Google Scholar] [CrossRef]
  22. Mountanea, O.G.; Limnios, D.; Kokotou, M.G.; Bourboula, A.; Kokotos, G. Asymmetric synthesis of saturated hydroxy fatty acids and fatty acid esters of hydroxy fatty acids. Eur. J. Org. Chem. 2019, 2019, 2010–2019. [Google Scholar] [CrossRef]
  23. Gant, T.G. Using deuterium in drug discovery: Leaving the label in the drug. J. Med. Chem. 2014, 57, 3595–3611. [Google Scholar] [CrossRef]
  24. Schmidt, C. First deuterated drug approved. Nat. Biotechnol. 2017, 35, 493–494. [Google Scholar] [CrossRef] [PubMed]
  25. Ariza, X.; Asins, G.; Garcia, J.; Hegardt, F.G.; Makowski, K.; Serra, D.; Velascoa, J. Preparation of α-labeled aldehydes by base-catalyzed exchange reactions. J. Label. Compd. Radiopharm. 2010, 53, 556–558. [Google Scholar] [CrossRef]
  26. Solladié, G.; Matloubi-Moghadam, F. Asymmetric synthesis of five- and six-membered lactones from chiral sulfoxides: Application to the asymmetric synthesis of insect pheromones, (R)-(+)-delta-n-hexadecanolactone and (R)-(+)-gamma-n-dodecanolactone. J. Org. Chem. 1982, 47, 91–94. [Google Scholar] [CrossRef]
  27. Wheeler, J.W.; Happ, G.M.; Araujo, J.; Pasteels, J.M. γ-Dodecalactone from rove beetles. Tetrahedron Lett. 1972, 46, 4635–4638. [Google Scholar] [CrossRef]
  28. Bittencourt, M.L.F.; Ribeiro, P.R.; Franco, R.L.P.; Hilhorst, H.W.M.; De Castro, R.D.; Fernandez, L.G. Metabolite profiling, antioxidant and antibacterial activities of Brazilian propolis: Use of correlation and multivariate analyses to identify potential bioactive compounds. Food Res. Int. 2015, 76, 449–457. [Google Scholar] [CrossRef] [Green Version]
  29. Yore, M.M.; Syed, I.; Moraes-Vieira, P.M.; Zhang, T.; Herman, M.A.; Homan, E.A.; Patel, R.T.; Lee, J.; Chen, S.; Peroni, O.D.; et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 2014, 159, 318–332. [Google Scholar] [CrossRef]
  30. Moraes-Vieira1, P.M.; Saghatelian, A.; Kahn, B.B. GLUT4 Expression in adipocytes regulates de novo lipogenesis and levels of a novel class of lipids with antidiabetic and anti-inflammatory effects. Diabetes 2016, 65, 1808–1815. [Google Scholar] [CrossRef]
  31. Kuda, M.; Brezinova, M.; Rombaldova, B.; Slavikova, M.; Posta, P.; Beier, P.; Janovska, J.; Veleba, J.; Kopecky, J., Jr.; Kudova, E.; et al. Docosahexaenoic acid-derived fatty acid esters of hydroxy fatty acids (FAHFAs) with anti-inflammatory properties. Diabetes 2016, 65, 2580–2590. [Google Scholar] [CrossRef]
  32. Nelson, A.T.; Kolar, M.J.; Chu, Q.; Syed, I.; Kahn, B.B.; Saghatelian, A.; Siegel, D. Stereochemistry of endogenous palmitic acid ester of 9-hydroxystearic acid and relevance of absolute configuration to regulation. J. Am. Chem. Soc. 2017, 139, 4943–4947. [Google Scholar] [CrossRef] [PubMed]
  33. Pflimlin, E.; Bielohuby, M.; Korn, M.; Breitschopf, K.; Löhn, M.; Wohlfart, P.; Konkar, A.; Podeschwa, M.; Bärenz, F.; Pfenninger, A.; et al. Acute and repeated treatment with 5-PAHSA or 9-PAHSA isomers does not improve glucose control in mice. Cell Metab. 2018, 28, 217–227. [Google Scholar] [CrossRef] [PubMed]
  34. Savle, P.S.; Lamoreaux, M.J.; Berry, J.F.; Gandour, R.D. A convenient resolution of long-chain alkyl epoxides with Jacobsen’s salen(Co)III(OAc) catalysts. Tetrahedron: Asymmetry 1998, 11, 1843–1846. [Google Scholar] [CrossRef]
  35. Harbindu, A.; Kumar, P. Synthesis of aculeatins A and B via iterative hydrolytic kinetic resolution. Synthesis 2010, 1479–1484. [Google Scholar]
  36. Hubieki, M.P.; Gandour, R.D.; Ashendel, C.L. Synthesis of optically pure cyclic lipoidal ammonium salts and evaluation of inhibition of protein kinase C. J. Org. Chem. 1996, 61, 9379–9384. [Google Scholar] [CrossRef]
  37. Matsumoto, K.; Usuda, K.; Okabe, H.; Hashimoto, M.; Shimada, Y. Synthesis of optically active heterocyclic compounds via deracemization of 1,2-diol monotosylate derivatives bearing a long aliphatic chain by a combination of enzymatic hydrolysis with Mitsunobu inversion. Tetrahedron: Asymmetry 2013, 24, 108–115. [Google Scholar] [CrossRef]
  38. Jacoby, C.; Braekman, J.-C.; Daloze, D. Asymmetric synthesis of (2R)- and (2S)- 2-iodohexadecanal, natural inhibitors of the thyroid gland metabolism. Tetrahedron 1996, 52, 10473–10484. [Google Scholar] [CrossRef]
  39. Kumar, S.C.; Sreedhar, E.; Venkateswar, R.; Suresh, B.; Rao, J.M. A simple and efficient enantioselective route to 2, 6-disubstituted piperidines: Synthesis of (2R, 6S)-isosolenopsin A and (2S, 6R)-isosolenopsin. Tetrahedron: Asymmetry 2009, 20, 1160–1163. [Google Scholar] [CrossRef]
  40. Boga, C.; Drioli, S.; Forzato, C.; Micheletti, G.; Nitti, P.; Prati, F. An easy route to enantiomerically enriched 7- and 8-hydroxy-stearic acids by olefin-metathesis-based approach. Synlett 2016, 27, 1354–1358. [Google Scholar]
  41. Wetzel, I.; Krauss, J.; Bracher, F. Enantiodivergent chemoenzymatic synthesis of (S)- and (R)-(Z)-9-dodecyl-4,5,8,9-tetrahydro-3H-oxonin-2-one as analogues of topsentolides. Lett. Org. Chem. 2012, 9, 169–174. [Google Scholar] [CrossRef]
  42. Padhi, B.; Reddy, G.S.; Mohapatra, D.K. Total synthesis of tetraketide and cryptorigidifoliol I via a sequential allylation strategy. J. Nat. Prod. 2016, 79, 2788–2796. [Google Scholar] [CrossRef] [PubMed]
  43. Perez, F.; Waldeck, A.R.; Krische, M.J. Total synthesis of cryptocaryol A via enantioselective iridium catalyzed alcohol C-H allylation. Angew. Chem. Int. Ed. 2016, 55, 5049–5052. [Google Scholar] [CrossRef]
  44. Tremblay, A.E.; Whittle, E.; Buist, P.H.; Shanklin, J. Stereochemistry of Δ4 dehydrogenation catalyzed by an ivy (Hedera helix) Δ9 desaturase homolog. Org. Biom. Chem. 2007, 5, 1270–1275. [Google Scholar] [CrossRef]
  45. Kumar, P.; Pandey, M.; Gupta, P.; Dhavale, D.D. Organocatalytic stereoselective synthesis of passifloricin A. Org. Biom. Chem. 2012, 10, 1820–1825. [Google Scholar] [CrossRef]
  46. Hardy, P.M.; Aubrey Prout, R.; Rydon, H.N. Polypeptides. Part XXIV. Synthesis of isariic acid. J. Chem. Soc. Perkin Trans. 1 1974, 796. [Google Scholar] [CrossRef]
  47. Pirrung, M.C.; Zhang, F.; Ambadi, S.; Rao, Y.G. Total synthesis of fellutamides, lipopeptide proteasome inhibitors. More sustainable peptide bond formation. Org. Biomol. Chem. 2016, 14, 8367–8375. [Google Scholar] [CrossRef] [Green Version]
  48. Lammek, B. Resolution of racemic 3-hydroxypentadecanoic acid into its enantiomers and determination of their absolute configuration. Roczn. Chem. 1976, 50, 997. [Google Scholar] [CrossRef]
  49. Skogh, M. The higher normal chain DL-beta-hydroxy acids-synthesis and investigation of the crystal behavior of 17 homologous acids with 8 to 24 carbon atoms. Acta Chem. Scand. 1952, 6, 809–817. [Google Scholar] [CrossRef]
  50. Ansari, A.A.; Osman, S.M. Reaction of hydrogen bromide with diols of long chain α,β-unsaturated acids. J. Am. Oil Chem. Soc. 1976, 53, 118–121. [Google Scholar] [CrossRef]
  51. Negelmann, L.; Pisch, S.; Bornscheuer, U.; Schmid, R.D. Properties of unusual phospholipids. III: Synthesis, monolayer investigations and DSC studies of hydroxy octadeca(e)noic acids and diacylglycerophosphocholines derived therefrom. Chem. Phys. Lipids 1997, 90, 117–134. [Google Scholar] [CrossRef]
  52. Goossen, L.J.; Ohlmann, D.M.; Dierker, M. Silver triflate-catalysed synthesis of γ-lactones from fatty acids. Green Chem. 2010, 12, 197–200. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds are available from the authors.
Molecules 24 02081 g001 550
Figure 1. Previous work for the synthesis of 9-hydroxy fatty acids [22] (left) and current design plan for the synthesis of 3-hydroxy fatty acids or 4-hydroxy fatty acid derivatives (right).
Figure 1. Previous work for the synthesis of 9-hydroxy fatty acids [22] (left) and current design plan for the synthesis of 3-hydroxy fatty acids or 4-hydroxy fatty acid derivatives (right).
Molecules 24 02081 g001
Molecules 24 02081 sch001 550
Scheme 1. Reagents and conditions: (a) 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one, (2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one trifluoroacetate (20%), THF, r.t., 15 min, (b) NaBH4, EtOH, 0 °C, 30 min, (c) KOH/EtOH/H2O, r.t., 15 min, (d) vinylmagnesium bromide 1M, CuI, dry THF, −78 °C, overnight, (e) O3, CH2Cl2/pyridine 9:1, −78 °C, (f) i. Ar, 5 min, ii. Me2S, 0 °C, 1 h, (g) i. MeCN, t-BuOH, H2O, 2-methylbut-2-ene, NaH2PO4, NaClO2/H2O, r.t., 2 h, ii. Na2SO3.
Scheme 1. Reagents and conditions: (a) 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one, (2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one trifluoroacetate (20%), THF, r.t., 15 min, (b) NaBH4, EtOH, 0 °C, 30 min, (c) KOH/EtOH/H2O, r.t., 15 min, (d) vinylmagnesium bromide 1M, CuI, dry THF, −78 °C, overnight, (e) O3, CH2Cl2/pyridine 9:1, −78 °C, (f) i. Ar, 5 min, ii. Me2S, 0 °C, 1 h, (g) i. MeCN, t-BuOH, H2O, 2-methylbut-2-ene, NaH2PO4, NaClO2/H2O, r.t., 2 h, ii. Na2SO3.
Molecules 24 02081 sch001
Molecules 24 02081 sch002 550
Scheme 2. Reagents and conditions: (a) D2O, Et3N, 100 °C, 1 h, (b) N-chlorosuccinimide, d,l-proline, CH2Cl2, r.t., overnight, (c) NaBH4, EtOH, 0 °C, 15 min, (d) KOH/EtOH/H2O, r.t., 30 min, (e) vinylmagnesium bromide 1M, CuI, dry THF, −78 °C, overnight, (f) O3, CH2Cl2/pyridine 9:1, −78 °C, (g) i. Ar, 5 min, ii. Me2S, 0 °C, 1 h, (h) i. MeCN, t-BuOH, H2O, 2-methylbut-2-ene, NaH2PO4, NaClO2/H2O, r.t., 2 h, ii. Na2SO3.
Scheme 2. Reagents and conditions: (a) D2O, Et3N, 100 °C, 1 h, (b) N-chlorosuccinimide, d,l-proline, CH2Cl2, r.t., overnight, (c) NaBH4, EtOH, 0 °C, 15 min, (d) KOH/EtOH/H2O, r.t., 30 min, (e) vinylmagnesium bromide 1M, CuI, dry THF, −78 °C, overnight, (f) O3, CH2Cl2/pyridine 9:1, −78 °C, (g) i. Ar, 5 min, ii. Me2S, 0 °C, 1 h, (h) i. MeCN, t-BuOH, H2O, 2-methylbut-2-ene, NaH2PO4, NaClO2/H2O, r.t., 2 h, ii. Na2SO3.
Molecules 24 02081 sch002
Molecules 24 02081 g002 550
Figure 2. Extracted ion chromatograms for m/z 272.2341 (A) and m/z 271.2279 (B) and their corresponding mass spectra (C) and (D).
Figure 2. Extracted ion chromatograms for m/z 272.2341 (A) and m/z 271.2279 (B) and their corresponding mass spectra (C) and (D).
Molecules 24 02081 g002
Molecules 24 02081 sch003 550
Scheme 3. Reagents and conditions: (a) 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one, (2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one trifluoroacetate (20%), THF, r.t., 15 min, (b) NaBH4, EtOH, 0 °C, 30 min, (c) KOH/EtOH/H2O, r.t., 15 min, (d) allylmagnesium bromide 1M, CuI, dry THF, −40 °C, 1 h, (e) O3, CH2Cl2, −78 °C, (f) i. O2, 5 min., ii. Ar, 5 min, (g) PPh3, dry CH2Cl2, r.t., overnight, (h) Jones oxidation.
Scheme 3. Reagents and conditions: (a) 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one, (2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one trifluoroacetate (20%), THF, r.t., 15 min, (b) NaBH4, EtOH, 0 °C, 30 min, (c) KOH/EtOH/H2O, r.t., 15 min, (d) allylmagnesium bromide 1M, CuI, dry THF, −40 °C, 1 h, (e) O3, CH2Cl2, −78 °C, (f) i. O2, 5 min., ii. Ar, 5 min, (g) PPh3, dry CH2Cl2, r.t., overnight, (h) Jones oxidation.
Molecules 24 02081 sch003
Molecules 24 02081 sch004 550
Scheme 4. Reagents and conditions: (a) N-chlorosuccinimide, d,l-proline, CH2Cl2, r.t., overnight, (b) NaBH4, EtOH, 0 °C, 15 min, (c) KOH/EtOH/H2O, r.t., 30 min, (d) allylmagnesium bromide 1M, CuI, dry THF, −40 °C, 1 h, (e) CH3(CH2)14COOH, EDC, Et3N, 4-DMAP, dry CH2Cl2, r.t., overnight, (f) O3, CH2Cl2/pyridine 9:1, −78 °C, (g) i. Ar, ii. Me2S, 0 °C, 1 h, (h) i. MeCN, t-BuOH, H2O, 2-methylbut-2-ene, NaH2PO4, NaClO2/H2O, r.t., 2 h, ii. Na2SO3.
Scheme 4. Reagents and conditions: (a) N-chlorosuccinimide, d,l-proline, CH2Cl2, r.t., overnight, (b) NaBH4, EtOH, 0 °C, 15 min, (c) KOH/EtOH/H2O, r.t., 30 min, (d) allylmagnesium bromide 1M, CuI, dry THF, −40 °C, 1 h, (e) CH3(CH2)14COOH, EDC, Et3N, 4-DMAP, dry CH2Cl2, r.t., overnight, (f) O3, CH2Cl2/pyridine 9:1, −78 °C, (g) i. Ar, ii. Me2S, 0 °C, 1 h, (h) i. MeCN, t-BuOH, H2O, 2-methylbut-2-ene, NaH2PO4, NaClO2/H2O, r.t., 2 h, ii. Na2SO3.
Molecules 24 02081 sch004

Share and Cite

MDPI and ACS Style

Bourboula, A.; Limnios, D.; Kokotou, M.G.; Mountanea, O.G.; Kokotos, G. Enantioselective Organocatalysis-Based Synthesis of 3-Hydroxy Fatty Acids and Fatty γ-Lactones. Molecules 2019, 24, 2081. https://doi.org/10.3390/molecules24112081

AMA Style

Bourboula A, Limnios D, Kokotou MG, Mountanea OG, Kokotos G. Enantioselective Organocatalysis-Based Synthesis of 3-Hydroxy Fatty Acids and Fatty γ-Lactones. Molecules. 2019; 24(11):2081. https://doi.org/10.3390/molecules24112081

Chicago/Turabian Style

Bourboula, Asimina, Dimitris Limnios, Maroula G. Kokotou, Olga G. Mountanea, and George Kokotos. 2019. "Enantioselective Organocatalysis-Based Synthesis of 3-Hydroxy Fatty Acids and Fatty γ-Lactones" Molecules 24, no. 11: 2081. https://doi.org/10.3390/molecules24112081

Article Metrics

Back to TopTop