Stereochemistry of Linoleic Acid Esters of Hydroxy Linoleic Acids

Article abstract of DOI:10.1021/acs.orglett.9b03054

The syntheses of linoleic acid esters of hydroxy linoleic acids (LAHLAs) present in oat oil and human serum have been achieved, providing access to material for testing and the determination of the stereochemistry of the natural compounds. While 9- and 13-LAHLAs were found to be a mixture of enantiomers 15-LAHLA is generated in a single optical form in oat oil. The stereochemistry of 15-LAHLA in oat oil was found to be opposite to that reported for digalactosyldiacylglycerol that possesses an embedded 15-LAHLA.

Full text of DOI:10.1021/acs.orglett.9b03054

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereochemistry of Linoleic Acid Esters of Hydroxy Linoleic Acids
†
‡
‡
†
†
†
́
Huijing Wang, Matthew J. Kolar, Tina Chang, Jose Rizo, Srihari Konduri, Clare McNerlin,
Alan Saghatelian,‡ and Dionicio Siegel*,†
†Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego, 9500 Gilman Drive, La Jolla, California 92093-0934,
United States
‡Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La
Jolla, California 92037-1002, United States
S
* Supporting Information
ABSTRACT: The syntheses of linoleic acid esters of hydroxy linoleic acids
(LAHLAs) present in oat oil and human serum have been achieved, providing
access to material for testing and the determination of the stereochemistry of the
natural compounds. While 9- and 13-LAHLAs were found to be a mixture of
enantiomers 15-LAHLA is generated in a single optical form in oat oil. The
stereochemistry of 15-LAHLA in oat oil was found to be opposite to that reported for
digalactosyldiacylglycerol that possesses an embedded 15-LAHLA.
atty acid esters of hydroxy fatty acids (FAHFAs) are
oxidized and functionalized fatty acids that represent a
increasing interest in unsaturated FAHFAs with both the HFA
and FA bearing unsaturation as the compounds reported to
date have been characterized as having improved anti-
inflammatory activities relative to saturated FAHFAs. Docosa-
hexaenoic acid ester of 13-hydroxy linoleic acid (13-
DHAHLA) (Figure 1) has been shown to possess anti-
inflammatory and pro-resolving properties with greater
potency than 9-PAHSA.2b Similarly, linoleic acid ester of 13-
hydroxy linoleic acid (13-LAHLA) characterized from oat oil,
the predominant LAHLA isomer in human serum after oat oil
ingestion, and an endogenous lipid in mouse and human
adipose tissue were found to have enhanced anti-inflammatory
effects relative to 9-PAHSA.3 Comparison of the anti-
inflammatory effect of 13-LAHLA and 9-PAHSA on
suppression of LPS-stimulated cytokine expression in RAW
264.7 macrophages revealed that 13-LAHLA had a much
greater effect. Additionally, mRNA levels of iNOS and COX-2
in RAW 264.7 cells were also suppressed by 13-LAHLA when
cells were first stimulated with lipopolysaccharide (LPS).3
FAHFAs that originate from unsaturated fatty acids,
particularly in the HFA portion, have been studied to a lesser
extent than the saturated FAHFAs as a result of difficulties in
accessing material for testing through laboratory syntheses.
The synthesis of saturated FAHFAs has proven successful
using different strategies,1,2g,4 and enantioselective syntheses4c
have been achieved. The synthetic routes to saturated
derivatives benefit from less functional group incompatibility
F
new and growing class of signaling lipids. Following from the
first discovery of FAHFAs in 2014,1 these lipids have been
found in organisms ranging from plants to humans.1,2 In their
structurally simplest form, FAHFAs possess a saturated, mono-
oxygenated fatty acid bound through an ester linkage to a
saturated fatty acid. The most studied of the FAHFAs to date
has been the palmitic acid ester of 9-hydroxy stearic acid (9-
PAHSA) which has shown promising anti-inflammatory
activity, particularly in colitis and diabetic models of disease1,2
(Figure 1). In addition to 9-PAHSA, related structures have
been found with a remarkable diversity in the positioning of
the ester linkage, the lengths of the hydroxy fatty acid (HFA),
and composition of the fatty acid (FA), providing a structurally
diverse set of endogenous compounds that have yet to be
explored. Proceeding from the saturated FAHFAs, there is
Received: August 29, 2019
Figure 1. Structures of 9-PAHSA, 13-DHAHLA, and 13-LAHLA.
© XXXX American Chemical Society
A
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and more options for starting material selection. The syntheses
of 9-, 13-, and 15-LAHLAs were targeted, given the promising
effects seen in the previous studies of LAHLAs3 and the
connection of LAHLAs to previously characterized estolides5
(Figure 2). Both 9- and 13-LAHLA could be produced
LAHLAs are comprised of an ester-bound linoleic acid
connected to an HLA (Figure 2). Disconnection to reveal the
HLA components provided the subtarget for synthesis as the
combination of the unsaturated HLAs with the LA, and
selective ester hydrolysis of a terminal methyl ester over the
internal ester joining the HLA and LA was supported by
previous syntheses of saturated FAHFAs.4c,f These racemic
syntheses of the HLAs were achieved first, along with synthesis
of nonracemic LAHLA pending identification of enzymatically
formed, chiral LAHLAs. Two routes were developed for the
three HLA methyl esters 6, 7, and 8. For 9- and 13-LAHLA,
the HLAs 6 and 7 could be accessed in racemic form together
by selenium dioxide oxidation of the methyl ester of linoleic
acid 9 (Scheme 1).9 The synthesis of 15-HLA proved more
challenging and required eight steps and utilized Sonogashira
cross-coupling reaction and partial hydrogenation. While this
route was first achieved generating racemic material, the
translation to an enantioselective synthesis could be readily
achived.10
For our purposes, determining the stereochemistry of
natural LAHLAs and generating material for testing our
syntheses of 9-LAHLA and 13-LAHLA required the
preparation of large quantities of the intermediate methyl
esters of 9-HLA and 13-HLA. Synthetic efforts to prepare 9-
and 13-HLA (also known as 9- and 13-HODE)8 have been
reported. The concise approach employing a selenium dioxide-
mediated oxidation of the methyl ester of linoleic acid
(Scheme 1)9 was ideal as it proceeded in one step and
generated both methyl esters of 9-HLA and 13-HLA in a single
reaction. Key to the success of this reaction was our ability to
purify the products by silica gel column chromatography using
a stepwise gradient of mobile phases consisting of hexanes/
ethyl acetate to get the pure isomers 6 and 7, removing the
undesired E/E-isomers.9 Both of these compounds were
hydrolyzed to generate 9-HLA and 13-HLA and are used for
controls in testing anti-inflammatory effects.3 Steglich ester-
ification of the methyl esters of 9-HLA and 13-HLA (6 and 7)
with LA generated the methyl esters of 9- and 13-LAHLA (10
and 11). Selective hydrolysis of the methyl ester using LiOH·
H2O in turn generated 9-LAHLA (4) and 13-LAHLA (3) in
racemic form.
Figure 2. Structures of 9-, 13-, and 15-LAHLAs and the methyl esters
of the corresponding HLAs.
through an enzymatic process delivering a single enantiomer or
could be envisioned to arise through auto-oxidation of linoleic
acid. The isomer 15-LAHLA would likely require enzyme-
catalyzed oxidation to replace the homoallylic hydrogen with
oxygen.
Previously, the structure of a galactolipid digalactosyldiacyl-
glycerol (DGDG) found in oat oil possessed 15-LAHLA
embedded within the full structure.6 In addition to character-
izing the atomic connectivity, olefins as all cis, and the
positioning of the ester linkage at C-15 of linoleic acid, the
stereochemistry of the ester linkage of the 15-LAHLA was
determined to be R- through degradation studies and
comparison to N-(propionoxyacy)-L-phenylalanine methyl
ester derivatives of 3(R)- and 3(R,S)-hydroxy-hexanoic acid.7
Following from this, additional DGDGs were characterized
with multiple linked 15-HLAs (Figure 3).5b Alternatively, both
As shown in Scheme 2, the synthesis of 15-LAHLA
proceeded from alcohol 16, obtained by the regioselective
opening of epoxide 14 with THP-protected propargyl alcohol
15.10 Removal of the THP group of 16 with TsOH·H2O
generated diol 17. Selective conversion of the propargylic
alcohol to a bromine, in the presence of the secondary
homopropargylic alcohol, was achieved with triphenylphos-
phine and carbon tetrabromide, yielding bromine 18.11 The
Sonogashira coupling12 of bromine 18 and the known alkyne
1913 in the presence of CuI, NaI, and Cs2CO3 in DMF yielded
the skipped diyne 20. Partial hydrogenation of 20 with Brown’s
P-2 Ni catalyst in the presence of ethylene diamine14 afforded
the key intermediate, corresponding to the all-(Z)-diene of the
methyl ester of 15-HLA (8) in 85% yield. The reduction was
highly selective, and no over-reduced products or olefinic
isomers were observed. Subsequently, esterification of the
methyl ester of 15-HLA (8) with linoleic acid using a Steglich
esterification yielded the methyl ester of 15-LAHLA. Selective
hydrolysis of the methyl ester done over the LA ester
generated 15-LAHLA (5).
Figure 3. Structures of digalactosyldiacylglycerol (DGDG) found in
oat oil that possess embedded 15-LAHLA.
9-LAHLA and 13-LAHLA could be produced through
enzymatic processes or potentially auto-oxidation given the
previously characterized 9-HLA and 13-HLA also referred to as
9- and 13-HODE.8 With this as a starting point, racemic
syntheses were first developed to generate authentic standards
for comparison to isolated LAHLAs.
We have previously developed an LC-MS chiral separation
method for analyzing PAHSAs.4c Using a modified version of
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Scheme 1. Synthesis of 9-HLA, 13-HLA, and 9- and 13-LAHLAs from Methyl Linoleate
monitoring the following precursor-to-product ion transitions,
m/z 557.5 → 279.2 and m/z 557.5 → 295.2, which correspond
to the parent LAHLA to linoleic acid and hydroxy linoleic acid,
respectively. Analyzing the 15-LAHLA stereoisomers revealed
that the S-enantiomer elutes earlier than the R-enantiomer
(Supporting Information S1). This trend is consistent with our
previous studies analyzing PAHSA stereoisomers with the
same column4c and most likely holds true, with the earlier
peaks of rac-13- and rac-9-LAHLA being the S-enantiomer. Of
note, the smaller area under the curve of the R-15-LAHLA
compared to S-15-LAHLA is due to the addition of less of the
R-15-LAHLA stereoisomer.
Scheme 2. Synthesis of 15-HLA and 15-LAHLA
Oat oil contains 9-, 13-, and 15-LAHLA.3 Although 13-
LAHLA is the predominant isomer in human serum after
ingestion, 15-LAHLA was shown to be the most abundant
isomer in pure oat oil. In analyzing FAHFA-enriched oat oil
(Figure 4, bottom panel), we clearly see five peaks which
correspond to both enantiomers of 9- and 13-LAHLA and a
single S-15-LAHLA stereoisomer (for enantioselective syn-
thesis vida infra). Interestingly, this is opposite to that reported
for DGDGs from oat oil (Figure 3).
this method, we were able to achieve resolution of the 9-, 13-,
and 15-LAHLA stereoisomers (Figure 4). Specifically, LAHLA
resolution was achieved over 80 min using a Lux Cellulose-3
chiral column (3 μm, 250 × 4.5 mm, Phenomenex) with an
isocratic flow rate of 0.15 mL/min of 97:3 MeOH:H2O +
0.1% formic acid solution at 35 °C. Mass spectrometry settings
were as previously established.4c LAHLAs were analyzed using
multiple reaction monitoring in positive ionization mode,
While 9- and 13-LAHLA were racemic in oat oil, 15-LAHLA
was a single optical form; therefore, a synthesis of enantiopure
S-15-LAHLA (5-S) and R-15-LAHLA (5-R) was developed.
C
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presence of cuprous iodide to afford secondary alcohol 16-S.10
The relay of enantiopurity was determined by derivatization of
16-S as the Mosher ester15 with the diastereomeric ratio found
to be 99:1 (Supporting Information, SI). Starting from
secondary alcohol 16-S, enantiopure S-15-LAHLA (5-S) was
synthesized in an analogous manner with the racemic 15-
LAHLA (5). Similarly, R-15-LAHLA (5-R) was obtained
through the same ten-step sequence, substituting (S)-
(+)-epichlorohydrin as the starting material.
Recent studies have shown that naturally occurring 13-
LAHLA serves as a beneficial lipid with the ability to abrogate
inflammation by reducing interleukin 6 (IL-6) secretion upon
lipopolysaccharide (LPS) treatment.3 To assess the relative
anti-inflammatory potentials of the LAHLAs and enantiopure
R-15-LAHLA and S-15-LAHLA, the same in vitro assay was
used (Figure 5). LPS-stimulated RAW 264.7 cells were treated
Figure 5. Testing LAHLAs for anti-inflammatory activities.
Quantitation of IL-6 following a 20 h treatment of natural LAHLAs
and synthetic R-15-LAHLA and S-15-LAHLA in LPS-stimulated
RAW 264.7 cells. Dexamethasone was included as a positive control.
Data are means SEM with n = 3 per treatment at 25 μM. *p <
0.0001 versus DMSO by one-way ANOVA.
Figure 4. LC-MS chromatograms showing the retention times of S-
15-LAHLA and R-15-LAHLA (top panel), rac-13-LAHLA, rac-9-
LAHLA, a mixture of LAHLA standards, and LAHLAs in FAHFA-
enriched oat oil. Stereopure S-15-LAHLA and R-15-LAHLA were
combined (top panel).
This used the same strategy as the racemic synthesis starting
instead from nonracemic epichlorohydrin, proceeding through
either 16-S or 16-R (Scheme 3). The synthesis of S-15-LAHLA
(5-S) started with the regioselective ring opening of (R)-
(−)-epichlorohydrin with THP-protected propargyl alcohol
followed by epoxide formation to yield epoxide 22, which then
underwent a second epoxide opening reaction at the less
substituted position, using ethylmagnesium bromide in the
with either DMSO or select LAHLAs. Subsequent quantitation
of IL-6 following treatment determined the effectiveness of
these lipids in inhibiting inflammatory signaling. Consistent
with previous findings, individual treatments with 9-, 13-, or
15-LAHLA successfully reduced secretion of IL-6, further
supporting the anti-inflammatory characteristics of LAHLAs
(Figure 5). Among the natural lipids tested, 15-LAHLA was
the most potent lipid, potentiating more than 50% inhibition of
IL-6 secretion. Such differences in cytokine reduction highlight
that a structure−activity relationship in the LAHLA lipid
family exists and that the positioning of the ester linkage is
important. The stereochemistry of 15-LAHLA could also affect
the activity, and we observed that S-15-LAHLA inhibits IL-6
secretion more effectively than either R-15-LAHLA or the
racemic 15-LAHLA mixture alone. To ensure that the
reductions in IL-6 levels were not attributed to loss of cell
viability due to cytotoxicity, we measured the percentage of
viable cells post-treatment and found that cells remained viable
throughout the treatment (SI Figure S2).
Scheme 3. Synthesis of R/S-15-LAHLA
In summary, linoleic acid esters of hydroxy linoleic acids
(LAHLAs), a family of unsaturated FAHFAs, present in oat oil
and human serum, are anti-inflammatory lipids in which their
ability to mitigate proinflammatory signaling is dependent on
their chemical structures. Relative to saturated FAHFAs such
D
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Letter
as 9-PAHSA,3 13-LAHLA dose treatments demonstrated an
improved IC50 in IL-6 reduction, suggesting that unsaturated
FAHFAs may be more superior in suppressing acute
inflammation (SI Figures S3 and S4). The role of structural
chemistry and stereochemistry in LAHLA and how this shapes
the lipids’ ability to mediate acute inflammation were made
possible through synthesis. Three members of LAHLAs, 9-
LAHLA, 13-LAHLA, and15-LAHLA have been synthesized to
provide material for testing and analysis. In analyzing FAHFA-
enriched oat oil, 9- and 13-LAHLA are found to be naturally
racemic mixtures, while 15-LAHLA is generated as a single
optical form, S-15-LAHLA. Interestingly, the stereochemistry
of 15-LAHLA was found to be the opposite of that reported
for digalactosyldiacylglycerol that possessed embedded 15-
LAHLA. In addition, 15-LAHLA, specifically S-15-LAHLA,
demonstrated potent anti-inflammatory activities and warrants
further study of the new method of laboratory access through
synthesis.
Zhang, T. Y.; Xiao, H. M.; Feng, Y. Q. Anal. Chem. 2018, 90 (16),
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03054.
Experimental details and characterization of new
compounds (1H and 13C spectra) (PDF)
(5) (a) Hamberg, M.; Liepinsh, E.; Otting, G.; Griffiths, W. Lipids
1998, 33 (4), 355−363. (b) Moreau, R. A.; Doehlert, D. C.; Welti, R.;
Isaac, G.; Roth, M.; Tamura, P.; Nunez, A. Lipids 2008, 43 (6), 533−
48.
AUTHOR INFORMATION
■
(6) Moreau, R. A.; Doehlert, D. C.; Welti, R.; Isaac, G.; Roth, M.;
Tamura, P.; Nunez, A. Lipids 2008, 43, 533−548.
Corresponding Author
*E-mail: drsiegel@ucsd.edu (Dionicio Siegel).
ORCID
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732.
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Alan Saghatelian: 0000-0002-0427-563X
Dionicio Siegel: 0000-0003-4674-9554
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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