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

Article abstract of DOI:10.1002/ejoc.201801881

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

Full text of DOI:10.1002/ejoc.201801881

DOI: 10.1002/ejoc.201801881
Full Paper
Asymmetric Synthesis
Asymmetric Synthesis of Saturated Hydroxy Fatty Acids and
Fatty Acid Esters of Hydroxy Fatty Acids
[a]
[a]
[a]
[a]
Olga G. Mountanea, Dimitris Limnios, Maroula G. Kokotou, Asimina Bourboula, and
George Kokotos*[
a]
Abstract: The recent discovery of a novel class of endogenous duction of the hydroxy group at different positions of the long
lipids, named Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs), chain by proper selection of the starting diol and the Grignard
that present antidiabetic and anti-inflammatory activities, has reagent. MacMillan's third generation imidazolidinone organo-
attracted the interest on hydroxy fatty acids (HFAs) and their catalyst has been employed for the epoxide formation, ensuring
derivatives. We present herein the development of a convenient products in high enantiomeric purity. Furthermore, an approach
and general methodology for the asymmetric synthesis of HFAs for the synthesis of deuterated HFAs and FAHFAs was devel-
and FAHFAs. The enantioselective organocatalytic synthesis of oped, leading to deuterated derivatives, which can be useful in
asymmetric terminal epoxides starting from monoprotected biological studies and in mass spectrometry studies as internal
α,ω-diols and their subsequent ring opening by a Grignard rea- standards.
gent are the key-steps for our methodology, allowing the intro-
Introduction
Bioactive lipids are essential cell components that play many
dynamic roles in signaling and in controlling a wide array of
[
1,2]
cellular activities.
The imbalance between lipid mediators
that regulate physiological conditions leads to a number of
pathophysiological conditions and diseases and as a conse-
quence, there is an increasing interest in emerging targets in
Figure 1. General structure of FAHFAs.
[
3]
lipid-based therapy. Lipidomics is a rapidly growing technol-
ogy that can be used in biomedical research to study disease
mechanisms and identify novel bioactive lipids.[4] Recently,
assisted LC–MS method for the comprehensive screening and
identification of FAHFAs in plant tissues was developed.
[
8]
lipidomics analysis of adipose tissue from mice engineered to
overexpress the glucose transporter GLUT4 (AG4OX mice) has
led to the discovery of a novel class of lipids that are highly
Palmitic acid esters of hydroxy stearic acids (PAHSAs) is one
of the most abundant families and PAHSA levels have been
found reduced in insulin-resistant people and highly correlated
[
5]
elevated in AG4OX adipose tissues. These lipids were named
Fatty Acid esters of Hydroxy Fatty Acids (FAHFAs) and contain
two acyl chains connected through an ester bond (Figure 1).
Several branched FAHFAs families have been identified, each
one consisting of multiple regioisomers, in which the hydroxy
group participating in the ester bond is at different positions
[
5]
with insulin sensitivity. The regioisomers of FAHFAs demon-
strate differential regulation and biological activity. 5- and 9-
PAHSA exhibit potent antidiabetic effects in vivo and enhance
glucose transport and insulin secretion in vitro, but only 9-
[
5,9]
PAHSA presents anti-inflammatory effects in dendritic cells.
Recently, both (R)- and (S)-9-PAHSA were synthesized starting
from commercially available enantiopure epichlorohydrin and
the (R)-enantiomer was identified as the predominant stereoiso-
mer that accumulates in adipose tissues from transgenic
(
(
e.g., 5- or 9-). A liquid chromatography-mass spectrometry
LC-MS) workflow for the measurement of FAHFAs in human
[
6]
and mouse tissues has been developed. Most recently, a faster
protocol for FAHFAs measurement in mouse tissues and human
plasma was reported, while a chemical isotope labeling-
[
10]
[
7]
mice. An efficient regiospecific synthesis of several branched
FAHFA has been described using terminal alkenes and alkynes
[
11]
as starting materials.
Most recently, a novel enantioselective
[
a] Laboratory of Organic Chemistry
Department of Chemistry,
National and Kapodistrian University of Athens,
Panepistimiopolis, Athens 15771, Greece
E-mail: gkokotos@chem.uoa.gr
URL: http://users.uoa.gr/~gkokotos/
synthesis of 9-PAHSA and 5-PAHSA using cross-metathesis was
[
12]
reported.
In contrast to previous reports, in this very recent
study no beneficial effects on glucose metabolism after acute
or repeated PAHSA treatment using cellular systems or mouse
[
12]
models of insulin resistance were observed.
However, other
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201801881.
[
13]
studies have demonstrated that PAHSAs activate GPR40,
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which is involved in their beneficial metabolic effects. In addi- plications in various fundamental organic transformations.[16]
tion, PAHSA treatment has been shown to regulate innate and Organocatalytic epoxidation employing such an organocatalyst
[
14]
adaptive immune responses and protect against colitis.
was the key-step in our synthetic approach to FAHFAs, followed
To investigate the biological roles that the members of this by epoxide opening with a Grignard reagent. The synthesis of
new class of lipids may play in humans, animals and plants, various 9-FAHFAs is depicted in Scheme 1.
synthetic methods providing various FAHFAs are needed. The
chemical diversity of FAHFAs superfamily (various families vary-
ing in the chain length, degree of unsaturation and position of
ester group) make their synthesis, as well as the synthesis of
their precursors hydroxy fatty acids (HFAs), very challenging.
The aim of the present work was the development of a conve-
nient general methodology for the asymmetric synthesis of
Monoprotected α,ω-diols, which are easily converted into
aldehydes, are ideal starting materials for our purposes. First,
benzyl protecting group was selected and monobenzyl-
[17]
protected 1,10-decanediol 1
was converted to aldehyde by
oxidation with pyridinium chlorochromate (Scheme 1). Among
the different enantioselective enamine-based chlorination
[18]
methodologies in literature, a modified procedure employing
[
15]
HFAs and FAHFAs. Organocatalysis,
a rapidly growing dy-
(
2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one trifluoro-
namic branch of asymmetric catalysis, has been employed as a
methodology for the induction of chirality and construction of
a single enantiomer. In addition to the asymmetric synthetic
methodology, we present our studies for the synthesis of
deuterated HFAs and FAHFAs, which may be useful as internal
standards in LC/MS studies.
acetate as the organocatalyst and 2,3,4,5,6,6-hexachlorocyclo-
hexa-2,4-dien-1-one as the chlorination agent was selected
for the chlorination of aldehyde 2. Subsequently, reduction by
[19]
NaBH , followed by treatment with KOH, led to the formation
4
of epoxide 3 in a one-pot procedure. In accordance with litera-
ture, this transformation afforded the (R)-epoxide in high enan-
tiomeric purity (93 % ee). Treatment with either hexylmagne-
sium bromide or octylmagnesium bromide provided a sixteen-
atom or eighteen-atom carbon chain, respectively, bearing a
Results and Discussion
Organocatalysis constitutes a powerful alternative for asymmet- hydroxy group at position-9 (compounds 4a,b). Any fatty chain
ric catalysis, offering new opportunities for the asymmetric syn- may be introduced by simply acylating the hydroxy group by a
[
15]
thesis of bioactive molecules.
Among the organocatalysts fatty acyl chloride. Palmitoyl and stearoyl chlorides were em-
developed, MacMillan's imidazolidinones stand out finding ap- ployed to obtain compounds 6a–c. Removal of the benzyl
Scheme 1. Synthesis of (S)-9-PAHPA, (S)-9-SAHPA, (S)-9-PAHSA, (S)-9-HPA and (S)-9-HSA. (a) PCC, CH
one trifluoroacetate (20 %), 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one, THF; ii. NaBH , EtOH; iii. KOH, EtOH, H
, Pd/C, EtOH; (g) Jones reagent, acetone; (h) LiOH, THF/H
2
Cl
2
; (b) i. (2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-
O; (c) C 13MgBr or C 17MgBr, CuI, dry
O.
4
2
6
H
8
H
THF; (d) CH
3
(CH
2
)14COCl or CH
3
(CH
2
)
16COCl, CH
2
Cl
2
; (e) AcCl, pyridine, CH
2
Cl
2
; (f) H
2
2
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group by hydrogenation, followed by Jones oxidation afforded long chain. As an example, the synthesis of FAHFAs substituted
the target FAHFAs: (S)-9-PAHPA (7a), (S)-9-SAHPA (7b), (S)-9- at position-5 is depicted in Scheme 2.
PAHSA (7c). 9-Hydroxy-palmitic acid (11a) and 9-hydroxy-stearic
Monoprotected benzyl 1,6-hexanediol 12 was converted by
acid (11b) were also synthesized (Scheme 1). Acetylation of similar procedures to alcohols 15a,b. Following reactions as de-
compounds 4a,b and similar reaction sequence (removal of scribed above, (S)-5-SAHPA (18a) and (S)-5-PAHSA (18b) were
benzyl group, oxidation and deprotection of acetyl group) pro- obtained.
vided (S)-9-HPA (11a) and (S)-9-HSA (11b) in high enantiomeric
Although benzyl protecting group worked well, it cannot be
purity. A general synthetic route to saturated fatty acids hydrox- applied in the case of unsaturated fatty chains. Thus, we ex-
ylated at position 6 or higher has been reported, however lead- plored the application of a silyl protecting group. Mono-TBDMS-
[
20]
[22]
ing to racemic products. Most recently, (R)-8-hydroxydo- protected 1,10-decanediol 19,
used as the starting material
decanoic acid and (S)-8-hydroxystearic acid have been synthe- for the synthesis of an oleyl derivative, was converted into the
sized through olefin cross-metathesis reactions starting from key-epoxide 21 (Scheme 3). Coupling of oleic acid with alcohol
[
21]
enantioenriched allylic alcohols.
22 was accomplished using mild conditions (water-soluble
The developed methodology permits the synthesis of vari- carbodiimide EDCI in the presence of DMAP) to overcome the
ous FAHFAs in high enantiomeric purity. Selection of the appro- possibility of affecting the silyl protecting group. Removal of
priate lengths of α,ω-diol and the Grignard reagent allows the the protecting group from 23 by treatment with TBAF, followed
introduction of the hydroxy functionality at any position of the by Jones oxidation, afforded (S)-9-OAHSA (25).
Scheme 2. Synthesis of (S)-5-SAHPA and (S)-5-PAHSA. (a) PCC, CH
,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one, THF; ii. NaBH , EtOH; iii. KOH, EtOH, H
CH (CH 14COCl, CH Cl ; (e) H , Pd/C, EtOH; (f) Jones reagent, acetone.
2
Cl
2
; (b) i. (2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one trifluoroacetate (20 %),
2
4
2
O; (c) C10 21MgBr or C12 25MgBr, CuI, dry THF; (d) CH (CH 16COCl or
H
H
3
2
)
3
2
)
2
2
2
Scheme 3. Synthesis of (S)-9-OAHSA. (a) PCC, CH
cyclohexa-2,4-dien-1-one, THF; ii. NaBH , EtOH; iii. KOH, EtOH, H
f) Jones reagent, acetone.
2
Cl
2
; (b) i. (2R,5S)-2-(tert-butyl)-3,5-dimethylimidazolidin-4-one trifluoroacetate (20 %), 2,3,4,5,6,6-hexachloro-
4
2
O; (c) C 17MgBr, CuI, dry THF; (d) oleic acid, EDCI·HCl, DMAP, Et N, CH Cl ; (e) TBAF, THF;
8
H
3
2
2
(
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As FAHFAs are of high biological and medical importance, we developed a method for the incorporation of a deuterium
their deuterated analogs may be useful in biological studies into the carbon atom carrying the hydroxy group. Our approach
and as internal standards for mass spectrometry studies. The to deuterated derivatives is shown in Scheme 4.
[
23]
recent approval by FDA of the first deuterated drug, signified
Aldehyde 2 was converted into α-dideuterated derivative 26
[
25]
a new era for research on deuterated bioactive compounds. by treatment with D O in the presence of triethylamine.
2
The replacement of a hydrogen atom by deuterium in The natural amino acid proline was used as the catalyst for α-
drug molecules may inhibit metabolic conversion to less active chlorination and N-chlorosuccinimide as the chlorinating agent.
or inactive molecules and/or may stabilize stereogenic centers Deuterated epoxide 27 was obtained in a one-pot procedure
[
24]
to stereomutation in enantiomers and diastereomers.
Thus, after reduction of α-chloro aldehyde with NaBH followed by
4
Scheme 4. Synthesis of 9-PAHPA-9-d and 9-HPA-9-d. (a) D
2
O, Et
3
N; (b) i. DL-proline, N-chlorosuccinimide, CH
2
Cl
2
; ii. NaBH
4
, EtOH; iii. KOH, EtOH, H
2
O;
(
c) C 13MgBr, CuI, dry THF; (d) CH (CH 14COCl, CH Cl ; (e) AcCl, pyridine, CH
6
H
3
2
)
2
2
2
Cl ; (f) H , Pd/C, EtOH; (g) Jones reagent, acetone; (h) LiOH, THF/H
2
2
2
O.
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).
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treatment with KOH. Using similar reactions with those previ- (250 × 4.6 mm ID) was used. The solvents used were HPLC grade
hexane and iPrOH. Purification by flash chromatography was per-
formed on Merck silica gel 60 (230–400 mesh).
teration in compounds 31 and 35 was determined using liquid Compounds 1,[17] 2,[26] 12,[27] 13,[27] 19,[22] 20[28] were prepared by
ously described, 9-(palmitoyloxy)hexadecanoic-9-d acid (31)
and 9-d-HPA (35) were obtained (Scheme 4). The degree of deu-
chromatography-high resolution mass spectrometry (LC/HRMS). known procedures and their spectroscopic data were identical with
those in literature.
An example of such a determination is depicted in Figure 2 for
compound 35. The extracted ion chromatograms for
General procedure for the synthesis of compounds 3, 14, 21: To
m/z 272.2341 (corresponding to deuterated derivative 35) and a round-bottomed flask containing (2R,5S)-2-(tert-butyl)-3,5-dimeth-
m/z 271.2279 (corresponding to non-deuterated analog of 35) ylimidazolidin-4-one trifluoroacetate (57 mg, 0.20 mmol, 20 %) in
are shown in Figure 2A and Figure 2B, while Figure 2C and THF (0.5 mL), 2,3,4,5,6,6-hexachlorocyclohexa-2,4-dien-1-one
(
5
381 mg, 1.10 mmol) was added and the solution was stirred for
min, before the aldehyde (1.00 mmol) was added. The reaction
Figure 2D present the corresponding mass spectra. The deuter-
ation degree of compound 35 was estimated to be 98.75 % (for
deuteration degree of compound 31, see supporting informa-
tion).
mixture was stirred for 20 min at room temperature. The resulting
mixture was cooled to 0 °C before NaBH (95 mg, 2.50 mmol) and
4
EtOH (1 mL) were added. After 10 minutes, 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 of water)
and EtOH (1.3 mL) was added and the resulting mixture was stirred
vigorously for 30 min. At this stage, water (20 mL) was added to
the mixture before it was extracted with Et O (3 × 20 mL), washed
with brine (1 × 20 mL), dried over Na SO , filtered and concentrated
under reduced pressure. Purification of the resulting crude product
by silica gel flash chromatography (petroleum ether:diethyl ether
Conclusions
In conclusion, we have developed a convenient asymmetric
synthesis of the highly important class of endogenous lipids
FAHFAs and the corresponding hydroxy fatty acids. Our meth-
odology employs as the key-steps the organocatalytic synthesis
2
2
4
of asymmetric terminal epoxides and the subsequent ring 8:2 or 7:3) afforded the desired epoxide.
opening by a Grignard reagent. Thus, it allows the introduction
(
R)-2-(8-(Benzyloxy)octyl)oxirane(3):[29] Prepared from 2 accord-
of the hydroxy group at different positions of the long chain by
proper selection of the starting diol and the Grignard reagent,
ing to the representative procedure, 3 was isolated as a colorless
oil, 73 % yield, (437 mg); H NMR (200 MHz, CDCl ) δ 7.40–7.28 (5H,
1
3
leading to various FAHFAs families. MacMillan's third generation m, ArH), 4.50 (2H, s, ArCH ), 3.46 (2H, t, J = 6.6 Hz, OCH ), 2.98–2.83
2
2
imidazolidinone organocatalyst has been employed for the ep- (1H, m, OCH), 2.75 (1H, t, J = 4.5 Hz, OCH), 2.46 (1H, dd, J = 5.0,
oxide formation ensuring products in high enantiomeric purity. 2.8 Hz, OCH), 1.64–1.26 (14H, m, 14 × CHH); 13C NMR (50 MHz,
CDCl ) δ 138.6, 128.3, 127.5, 127.4, 72.8, 70.4, 52.4, 47.1, 32.4, 29.7,
A silyl protecting group is compatible with unsaturated fatty
chains and its use permits the synthesis of FAHFAs containing
unsaturated acids, such as oleic acid. Finally, an approach for
the synthesis of deuterated HFAs and FAHFAs was developed,
leading to deuterated derivatives, which can be useful in bio-
logical studies and in mass spectrometry studies as internal
standards.
3
2
0
2
9.4, 29.3, 26.1, 25.9; [α] = +4.9 (c = 1.0, CH Cl ). For (S)-epoxide
D
2 2
2
5
[6]
+
+
[α] = –5.7 (c = 1, CHCl ); HRMS (ESI ): m/z calcd. for C H O :
D
3 17 27 2
+
2
62.2006; [M+H] found: 263.2005; HPLC analysis: 93 % ee, Daicel
Chiralpak OD-H, hexane/iPrOH (99.5:0.5), 0.7 mL/min, t = 31.1 (ma-
R
jor), t = 37.6 (minor).
R
(
R)-2-(4-(Benzyloxy)butyl)oxirane (14):[30] Prepared from 13 ac-
cording to the representative procedure, 14 was isolated as a color-
1
less oil, 65 % yield (344 mg); H NMR (200 MHz, CDCl ) δ 7.34–7.25
3
(
2
2
5H, m, ArH), 4.51 (2H, s, ArCH ), 3.49 (2H, t, J = 6.2 Hz, OCH ), 2.93–
.89 (1H, m, OCH), 2.77–2.72 (1H, m, OCH), 2.46 (1H, dd, J = 4.9,
.0 Hz, OCH), 1.76–1.48 (6H, m, 6 × CHH); 13C NMR (50 MHz, CDCl3)
2
2
Experimental Section
General information
δ 138.4, 128.2, 127.5, 127.4, 72.8, 70.0, 52.2, 47.0, 32.1, 29.4, 22.6;
[
Materials
2
0
26
α] = +4.5 (c = 1.0, CHCl ). For (S)-epoxide [α] = –5.3 (c = 1.4,
D
3
D
2
0
[7,8]
+
The reagents and solvents used in the present study were commer- CHCl
cially available products of Sigma-Aldrich, Fluka, Merck and Alfa
for C13
Aesar. Solvents were used as received or dried over molecular sieves 98 % ee, Daicel Chiralpak OD-H, hexane/iPrOH (99.8:0.2), 0.25 mL/
4 Å).
min (after 90 min flow was changed to 0.50 mL/min), t = 104.8
) and [α] = –5.1 (c = 2.3, CHCl
); HRMS (ESI ): m/z calcd.
H O : 207.1380; [M+H] found: 207.1378; HPLC analysis:
19 2
3
D
3
+
+
(
R
(
major), t = 118.9 (minor).
R
Instrumentation and methods
(
R)-tert-Butyldimethyl((8-(oxiran-2-yl)octyl)oxy)silane (21): Pre-
NMR spectra were obtained on a Mercury 200 MHz Varian instru-
pared from 20 according to the representative procedure, 21 was
isolated as a colorless oil, 67 % yield (300 mg); H NMR (200 MHz,
CDCl ) δ 3.58 (2H, t, J = 6.5 Hz, CH O), 2.92–2.81 (1H, m, OCH), 2.74–
2
ment in CDCl . The chemical shifts δ are reported in ppm relative
3
1
to residual solvent peaks. IR spectra were recorded as KBr disks with
a Perkin–Elmer Spectrum 100 FTIR instrument. HRMS spectra were
obtained on a Bruker Maxis Impact QTOF spectrometer or an AB
Sciex 4600 Triple TOF mass spectrometer. Melting points were
measured on a Buchi 530 apparatus. Optical rotations were meas-
ured using a Perkin-Elmer 343 polarimeter or an AA-65 series pola-
rimeter in a 10 cm cell at room temperature. HPLC analysis was
carried out on an Agilent 1100 Series with a DAD UV detector and
the peak intensities were measured in the UV range between 206
and 280 nm. A Daicel Chiralpak OD-H chromatography column
3
2
.70 (1H, m, OCH), 2.44 (1H, dd, J = 6.0, 1.8 Hz, OCH), 1.57–1.19
(
14H, m, 14 × CHH), 0.88 (9H, s, Hz, 3 × CH ), 0.03 (6H, s, 2 × CH );
3
3
1
3
C NMR (50 MHz, CDCl ) δ 63.2, 52.3, 47.1, 32.8, 32.5, 29.5, 29.4,
9.3, 26.0, 25.7, 18.3, –5.3; [α] = +1.6 (c = 0.5, CHCl ); HRMS (ESI ):
3
2
0
+
2
D
3
+
+
m/z calcd. for C H O SiNa : 309.2220; [M+Na] found: 309.2228.
16 34 2
2-(8-(Benzyloxy)octyl)oxirane-2-d (27): To a round-bottomed
flask containing DL-proline (227 mg, 1.97 mmol) in CH Cl (15 mL),
N-chlorosuccinimide (1.10 g, 7.90 mmol), 10-(benzyloxy)decanal-
2
2
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+
+
2
,2-d2 (520 mg, 1.97 mmol) were added consecutively. The reaction
(c = 1.0, CHCl ); HRMS (ESI ): m/z calcd. for C H O Na : 371.2921;
[M+Na] found: 371.2916.
3
25 44 2
+
mixture was stirred overnight at room temperature. The resulting
mixture was cooled to 0 °C before NaBH (300 mg, 7.90 mmol) and
4
(
S)-1-(Benzyloxy)octadecan-5-ol (15b): Prepared from 14 accord-
EtOH (1.3 mL) were added. After 10 min, the medium was warmed
to room temperature for 5 min before a freshly prepared solution
of aqueous KOH (4.50 g KOH diluted in 6.8 mL of distilled water)
and EtOH (3.3 mL) was added and the resulting mixture was stirred
vigorously for 30 min. At this stage, water (20 mL) was added to
ing to the representative procedure, 15b was isolated as a white
solid, m.p. 53–55 °C, 76 % yield (717 mg); H NMR (200 MHz, CDCl )
δ 7.35–7.19 (5H, m, ArH), 4.50 (2H, s, ArCH ), 3.65–3.53 (1H, m,
CHOH), 3.48 (2H, t, J = 6.3 Hz, OCH ), 1.78 (1H, s, ΟΗ), 1.68–1.44
1
3
2
2
(4H, m, 4 × CHH),1.41–1.07 (26H, m, 26 × CHH), 0.89 (3H, t, J =
the mixture before it was extracted with Et O (3 × 20 mL), washed
2
6
7
.4 Hz, CH3); 13C NMR (50 MHz, CDCl ) δ 138.5, 128.3, 127.6, 127.4,
3
with brine (1 × 50 mL), dried over Na SO , filtered and concentrated
2
4
2.8, 71.7, 70.2, 37.4, 37.1, 31.9, 29.6, 29.3, 25.6, 22.6, 22.3, 14.1;
under reduced pressure. Purification of the resulting crude product
by silica gel flash chromatography (petroleum ether:diethyl ether
2
0
+
+
[α] = +1.0 (c = 1.0, CHCl ); HRMS (ESI ): m/z calcd. for C H O :
D
3 25 45 2
+
3
77.3414; [M+H] found: 377.3413.
8
:2 or 7:3) afforded the desired epoxide as a colorless oil, 30 % yield
1
(136 mg); H NMR (200 MHz, CDCl ) δ 7.39–7.15 (5H, m, ArH), 4.50
3
(S)-1-((tert-Butyldimethylsilyl)oxy)octadecan-9-ol (22): Prepared
from 21 according to the representative procedure, 22 was isolated
as a colorless oil, 87 % yield (170 mg); H NMR (200 MHz, CDCl ) δ
3.59 (3H, m, CH O, CHO), 1.55–1.16 (31H, m, 30 × CHH, OH), 0.89
(
2H, s, ArCH ), 3.46 (2H, t, J = 6.6 Hz, OCH ), 2.73 (1H, d, J = 5.0 Hz,
2
2
OCH), 2.45 (1H, d, J = 5.0 Hz, OCH), 1.72–1.20 (14H, m, 14 × CHH);
1
3
13
C NMR (50 MHz, CDCl ) δ 138.5, 128.2, 127.5, 127.3, 72.7, 70.3,
3
2
5
1.9 (t, J = 26.3 Hz), 46.9, 32.2, 29.6, 29.4, 29.2, 26.0, 25.8; HRMS
13
(9H, s, 3 × CH ), 0.84–0.74 (3H, m, CH ), 0.04 (6H, s, 2 × CH );
C
3
3
3
+
+
+
(ESI ): m/z calcd. for C H DO Na : 286.1888; [M+Na] found:
17 25 2
NMR (50 MHz, CDCl ) δ 72.0, 63.3, 37.5, 32.9, 31.9, 29.7, 29.6, 29.4,
2
HRMS (ESI ): m/z calcd. for C H O Si : 401.3809; [M+H] found:
4
3
2
86.1895.
20
9.3, 26.0, 25.8, 25.6, 22.7, 14.1, –5.3; [α] = –1.5 (c = 1.0, CHCl );
D
3
+
+
+
General procedure for the synthesis of compounds 4a,b, 15a,b,
2, 28: To a flamed-dried flask containing copper(I) iodide (40 mg,
.20 mmol) under inert atmosphere, hexylmagnesium bromide (2 M
24 53 2
01.3803.
2
0
1
6-(Benzyloxy)hexadecan-8-d-8-ol (28): Prepared from 27 ac-
solution in diethyl ether, 2 mL, 2.00 mmol) was added. The mixture
was cooled to –40 °C and stirred for 10 min before the epoxide
cording to the representative procedure, 28 was isolated as a color-
less oil, 77 % yield (119 mg); H NMR (200 MHz, CDCl ) δ 7.35–7.26
1
3
(1.00 mmol) in dry THF (10 mL) was added dropwise. After the
(5H, m, ArH), 4.50 (2H, s, ArCH ), 3.46 (2H, t, J = 6.6 Hz, OCH ), 1.65–
2
2
addition, the mixture was left stirring at –40° C for 1 h and then
warmed to room temperature. Then, a saturated aqueous solution
1
.41 (3H, m, 2 × CHH, OH), 1.41–1.15 (24H, m, 24 × CHH), 0.89 (3H,
13
t, J = 6.4 Hz, CH3); C NMR (50 MHz, CDCl ) δ 138.6, 128.3, 127.6,
1
2
3
of NH Cl (10 mL) was added and the aqueous layer was extracted
4
27.4, 72.8, 71.4 (t, J = 21.4 Hz), 70.4, 37.3, 37.2, 31.8, 29.7, 29.6,
with Et O (3 × 20 mL). The organic phase was washed with brine
+
2
9.5, 29.4, 29.3, 29.2, 26.1, 25.7, 25.6, 22.6, 14.1; HRMS (ESI ): m/z
(
1 × 50 mL), dried over Na SO , filtered and concentrated under
+
+
2
4
calcd. for C H DO : 350.3164; [M+H] found: 350.3171.
23
40
2
reduced pressure. Flash silica chromatography (petroleum ether di-
ethyl ether 8:2 or 7:3) of the crude mixture resulted in the desired
alcohol.
General procedure for the synthesis of compounds 5a–c, 16a,b,
29: To a solution of secondary diol (1.00 mmol) in dry CH Cl
2
2
(
10 mL), palmitoyl chloride (412 mg, 1.50 mmol) or stearoyl chloride
(
S)-16-(Benzyloxy)hexadecan-8-ol (4a): Prepared from 3 accord-
(454 mg, 1.50 mmol) was added. The mixture was left stirring for
ing to the representative procedure, 4a was isolated as a white
solid, m.p. 39–41 °C, 76 % yield (102 mg); H NMR (200 MHz, CDCl )
δ 7.35–7.25 (5H, m, ArH), 4.50 (2H, s, ArCH ), 3.65–3.54 (1H, m,
CHOH), 3.46 (2H, t, J = 6.6 Hz, OCH ), 1.68–1.50 (3H, m, 2 × CHH,
1
16 h at room temperature. Then, the solvent was removed under
reduced pressure and the crude mixture was purified by flash chro-
matography (petroleum ether:diethyl ether 95:5) to afford the de-
sired ester.
3
2
2
13
OH), 1.48–1.15 (24H, m, 24 × CHH), 0.88 (3H, t, J = 6.3 Hz, CH3);
C
NMR (50 MHz, CDCl ) δ 138.6, 128.3, 127.6, 127.4, 72.8, 71.9, 70.4,
3
(S)-16-(Benzyloxy)hexadecan-8-yl palmitate (5a): Prepared from
3
1
7.5, 37.4, 31.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 26.1, 25.7, 25.6, 22.6,
4
a according to the representative procedure, 5a was isolated as a
2
0
+
4.1; [α]D = –1.1 (c = 1.0, CH Cl ); HRMS (ESI ): m/z calcd. for
1
2
2
colorless oil, 79 % yield; H NMR (200 MHz, CDCl ) δ 7.35–7.25 (5H,
3
+
+
C H O : 349.3101; [M+H] found: 349.3100.
23
41
2
m, ArH), 4.93–4.80 (1H, m, CHOC=O), 4.50 (2, s, ArCH ), 3.46 (2H, t,
2
J = 6.6 Hz, OCH ), 2.28 (2H, t, J = 7.4 Hz, CH C=O), 1.71–1.43 (8H,
(
S)-1-(Βenzyloxy)octadecan-9-ol (4b): Prepared from 3 according
2
2
m, 8 × CHH), 1.40–1.11 (44H, m, 44 × CHH), 0.87 (6H, t, J = 6.1 Hz,
to the representative procedure, 4b was isolated as a white solid,
m.p. 45–49 °C, 71 % yield (160 mg); H NMR (200 MHz, CDCl ) δ
7
3
1
13
1
2 × CH3); C NMR (50 Hz, CDCl ) δ 173.7, 138.6, 128.3, 127.6, 127.4,
3
3
7
2
4.0, 72.8, 70.4, 34.7, 34.1, 31.9, 31.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2,
.36–7.26 (5H, m, ArH), 4.50 (2H, s, ArCH ), 3.63–3.52 (1H, m, CHOH),
2
2
0
6.1, 25.3, 25.2, 22.7, 22.6, 14.1; [α] = +1.8 (c = 1.0, CH Cl ); HRMS
.46 (2H, t, J = 6.6 Hz, OCH ), 1.68–1.55 (3H, m, 2 × CHH, ΟΗ), 1.51–
D
2
2
+
2
+
+
13
(ESI ): m/z calcd. for C H O Na : 609.5217; [M+Na] found:
.15 (28H, m, 28 × CHH), 0.88 (3H, t, J = 6.3 Hz, CH3); C NMR
39 70 3
609.5234.
(50 MHz, CDCl ) δ 138.6, 128.3, 127.6, 127.4, 72.8, 71.9, 70.4, 37.4,
3
2
0
3
1.9, 29.7, 29.6, 29.5, 29.4, 29.3, 26.1, 25.6, 22.7, 14.1; [α] = +1.1
D
(S)-16-(Benzyloxy)hexadecan-8-yl stearate (5b): Prepared from
+
+
(c = 1.0, CH Cl ); HRMS (ESI ): m/z calcd. for C H O Na : 399.3234;
2 2 25 44 2
4
a according to the representative procedure, 5b was isolated as a
+
[
M+Na] found: 399.3233.
S)-1-(Benzyloxy)hexadecan-5-ol (15a): Prepared from 14 accord-
ing to the representative procedure, 15a was isolated as a white
1
colorless oil, 89 % yield (252 mg); H NMR (200 MHz, CDCl ) δ 7.34–
3
(
7.26 (5H, m, ArH), 4.93–4.78 (1H, m, CHOC=O), 4.50 (2H, s, ArCH2),
3.46 (2H, t, J = 6.6 Hz, OCH ), 2.28 (2H, t, J = 7.4 Hz, CH C=O), 1.68–
2
2
1
solid, m.p. 44–49 °C, 70 % yield (308 mg); H NMR (200 MHz, CDCl ) 1.49 (8H, m, 8 × CHH), 1.49–1.11 (48H, m, 48 × CHH), 0.88 (6H, t, J =
3
13
δ 7.35–7.26 (5H, m, ArH), 4.50 (2H, s, ArCH ), 3.65–3.54 (1H, m,
10.7 Hz, 2 × CH ); C NMR (50 MHz, CDCl ) δ 173.7, 138.6, 128.3,
2
3
3
CHOH), 3.48 (2H, t, J = 6.3 Hz, OCH ), 1.68–1.51 (3H, m, 2 × CHH,
127.6, 127.4, 74.0, 72.8, 70.5, 34.7, 34.1, 31.9, 31.8, 29.7, 29.5, 29.4,
2
13
20
OH), 1.51–1.06 (24H, m, 24 × CHH), 0.89 (3H, t, J = 5.9 Hz, CH3);
C
29.3, 29.2, 26.1, 25.3, 25.2, 22.7, 22.6, 14.1; [α] = –2.8 (c = 0.5,
D
+
+
+
NMR (50 MHz, CDCl ) δ 173.1, 138.4, 128.3, 127.6, 127.4, 72.8, 71.7, CHCl ); HRMS (ESI ): m/z calcd. for C H O Na : 637.5530; [M+Na]
3
3
41 74 3
2
0
7
0.2, 37.4, 37.1, 31.9, 29.6, 29.3, 25.6, 22.6, 22.3, 14.1; [α] = +1.5 found: 637.5525.
D
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13
(S)-1-(Benzyloxy)octadecan-9-yl palmitate (5c): Prepared from
(6H, s, 2 × CH ), 0.03 (6H, s, 2 × CH ); C NMR (50 MHz, CDCl ) δ
3 3 3
4
b according to the representative procedure, 5c was isolated as a
173.6, 129.9, 129.7, 74.0, 63.3, 34.7, 34.2, 32.9, 31.9, 29.8, 29.7, 29.5,
1
colorless oil, 87 % yield (225 mg); H NMR (200 MHz, CDCl ) δ 7.36– 29.4, 29.3, 29.2, 27.2, 26.0, 25.8, 25.3, 25.2, 22.7, 18.4, 14.1, –5.3;
3
2
0
+
7
3
1
.26 (5H, m, ArH), 4.93–4.81 (1H, m, CHOC=O), 4.50 (2H, s, ArCH2),
.46 (2H, t, J = 6.6 Hz, OCH ), 2.28 (2H, t, J = 7.4 Hz, CH C=O), 1.67–
.49 (10H, m, 10 × CHH), 1.49–1.15 (46H, m, 46 × CHH), 0.88 (6H, t,
[α]
= –0.4 (c = 1.0, CHCl ); HRMS (ESI ): m/z calcd. for
3
D
+
+
C H O SiNa : 687.6082; [M+Na] found: 687.6100.
2
2
42 84 3
13
General procedure for the synthesis of compounds 8a,b, 32: To
a flamed-dried flask containing the secondary alcohol (1.00 mmol),
dry dichloromethane (10 mL) was added and the mixture was left
stirring at 0 °C. Then, dry pyridine (0.12 mL, 1.50 mmol) followed
by acetyl chloride (0.14 mL, 2.00 mmol) were added. The resulting
mixture was warmed to room temperature and left stirring for 16 h.
J = 6.4 Hz, 2 × CH3); C NMR (50 MHz, CDCl ) δ 173.7, 138.6, 128.3,
3
1
2
27.6, 127.4, 74.0, 72.8, 70.5, 34.7, 34.1, 31.9, 29.7, 29.6, 29.5, 29.4,
9.3, 29.2, 26.1, 25.3, 25.2, 22.7, 14.1; [α] = +0.8 (c = 0.5, CHCl );
2
0
D
3
+
+
+
HRMS (ESI ): m/z calcd. for C H O Na : 637.5530; [M+Na] found:
4
1 74 3
6
37.5534.
S)-1-(Benzyloxy)hexadecan-5-yl stearate (16a): Prepared from
5a according to the representative procedure, 16a was isolated as
(
1
Then, a saturated aqueous solution of NH Cl (10 mL) was added
4
and the product was extracted with Et O (3 × 20 mL), dried over
2
1
a yellowish oil, 76 % yield (170 mg); H NMR (200 MHz, CDCl ) δ
3
Na SO , filtered and concentrated under reduced pressure. Flash
2
4
7
.35–7.26 (5H, m, ArH), 4.94–4.82 (1H, m, CHOC=O), 4.49 (2H, s,
silica chromatography of the crude mixture (petroleum ether:di-
ethyl ether 9:1) resulted in the desired acetyl protected product.
ArCH ), 3.46 (2H, t, J = 6.3 Hz, OCH ), 2.28 (2H, t, J = 7.4 Hz, CH C=
O), 1.65–1.52 (8H, m, 8 × CHH), 1.49–1.26 (48H, m, 48 × CHH), 0.88
2
2
2
1
3
(S)-16-(Βenzyloxy)hexadecan-8-yl acetate (8a): Prepared from 4a
(6H, t, J = 6.3 Hz, 2 × CH3); C NMR (50 MHz, CDCl ) δ 173.7, 138.5,
3
according to the representative procedure, 8a was isolated as a
1
2
1
28.3, 127.6, 127.4, 73.9, 72.83, 70.1, 34.7, 34.1, 33.9, 31.9, 29.7, 29.6,
9.5, 29.4, 29.3, 29.2, 25.3, 25.1, 22.7, 22.0, 14.1; [α] = +3.6 (c =
.0, CHCl ); HRMS (ESI ): m/z calcd. for C H O Na : 637.5530;
1
2
0
yellowish oil, 90 % yield (102 mg); H NMR (200 MHz, CDCl ) δ 7.36–
3
D
+
+
7.24 (5H, m, ArH), 4.92–4.79 (1H, m, CHOC=O), 4.50 (2H, s, ArCH2),
3
41 74 3
+
3.46 (2H, t, J = 6.6 Hz, OCH ), 2.04 (3H, s, CH C=O), 1.75–1.42 (6H,
2 3
[M+Na] found: 637.5542.
m, 6 × CHH), 1.41–1.18 (20H, m, 20 × CHH), 0.88 (3H, t, J = 5.6 Hz,
(S)-1-(Benzyloxy)octadecan-5-yl palmitate (16b): Prepared from
13
CH3); C NMR (50 MHz, CDCl ) δ 170.9, 138.6, 128.3, 127.6, 127.4,
3
1
5b according to the representative procedure, 16b was isolated
7
4.4, 72.8, 70.4, 34.1, 31.8, 29.7, 29.4, 29.2, 26.1, 25.3, 22.6, 21.3, 14.1;
1
as a colorless oil, 70 % yield (344 mg); H NMR (200 MHz, CDCl ) δ
20
+
3
[α]
= +1.6 (c = 0.5, CHCl ); HRMS (ESI ): m/z calcd. for
D
3
+
7
.35–7.26 (5H, m, ArH), 4.94–4.81 (1H, m, CHOC=O), 4.49 (2H, s,
+
C H O Na : 413.3026; [M+Na] found: 413.3039.
2
5 42 3
ArCH ), 3.46 (2H, t, J = 6.4 Hz, OCH ), 2.28 (2H, t, J = 7.4 Hz, CH C=
2
2
2
O), 1.65–1.49 (8H, m, 8 × CHH), 1.49–1.25 (48H, m, 48 × CHH), 0.88 (S)-1-(Benzyloxy)octadecan-9-yl acetate (8b): Prepared from 4b
1
3
(
6H, t, J = 6.4 Hz, 2 × CH3); C NMR (50 MHz, CDCl ) δ 173.7, 138.5, according to the representative procedure, 8b was isolated as a
3
1
1
2
1
28.3, 127.6, 127.5, 73.9, 72.8, 70.1, 34.7, 34.1, 33.9, 31.9, 29.7, 29.6, colorless oil, 90 % yield (330 mg); H NMR (200 MHz, CDCl ) δ 7.35–
9.5, 29.4, 29.3, 29.2, 25.3, 25.2, 22.7, 22.0, 14.1; [α] = +1.9 (c = 7.26 (5H, m, ArH), 4.92–4.80 (1H, m, CHOC=O), 4.50 (2H, s, ArCH2),
.0, CHCl ); HRMS (ESI ): m/z calcd. for C H O Na : 637.5530; 3.46 (2H, t, J = 6.1 Hz, OCH ), 2.03 (3H, s, CH C=O), 1.61–1.09 (30H,
3
2
0
D
+
+
3
41 74
3
2
3
+
13
[M+Na] found: 637.5525.
m, 30 × CHH), 0.88 (3H, t, J = 6.2 Hz, CH3); C NMR (50 MHz, CDCl3)
δ 170.9, 138.6, 128.3, 127.5, 127.4, 74.4, 72.8, 70.4, 34.1, 31.8, 29.7,
9.5, 29.4, 29.3, 26.1, 25.3, 22.6, 21.2, 14.1; [α] = +1.6 (c = 0.5,
1
2
6-(Benzyloxy)hexadecan-8-yl-8-d palmitate (29): Prepared from
8 according to the representative procedure, 29 was isolated as a
colorless oil, 82 % yield; H NMR (200 MHz, CDCl ) δ 7.38–7.23 (5H,
m, ArH), 4.50 (2, s, ArCH ), 3.46 (2H, t, J = 6.5 Hz, OCH ), 2.28 (2H, t,
2
0
2
D
+
+
+
1
CHCl ); HRMS (ESI ): m/z calcd. for C27H O Na : 441.3339; [M+Na]
3 46 3
3
found: 441.3349.
2
2
J = 7.3 Hz, CH C=O), 1.65–1.44 (8H, m, 8 × CHH), 1.44–1.10 (44H, m,
2
16-(Benzyloxy)hexadecan-8-yl-8-d acetate (32): Prepared from
1
3
4
4
×
C
H
H
)
,
0
.
8
8
(
6
H
,
t
,
J
=
5
.
9
H
z
,
2
×
C
H
)
;
C
N
M
R
(
5
0
H
z
,
C
D
C
l
)
3
3
31 according to the representative procedure, 32 was isolated as a
δ 173.6, 138.6, 128.3, 127.5, 127.4, 73.5 (t, J = 19.2 Hz), 72.8, 70.4,
1
colorless oil, 86 % yield (114 mg); H NMR (200 MHz, CDCl ) δ 7.35–
3
3
2
6
4.7, 34.0, 31.9, 31.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 26.1, 25.3,
7
.26 (5H, m, ArH), 4.50 (2H, s, ArCH ), 3.46 (2H, t, J = 6.5 Hz, OCH ),
2
2
+
+
5.1, 22.7, 22.6, 14.1, 14.0; HRMS (ESI ): m/z calcd. for C H DO Na :
3
9
69
3
2.03 (3H, s, CH C=O), 1.65–1.18 (26H, m, 26 × CHH), 0.88 (3H, t, J =
3
+
10.5280; [M+Na] found 610.5276.
13
6
1
2
4
.3 Hz, CH3); C NMR (50 MHz, CDCl ) δ 170.9, 138.6, 128.2, 127.5,
3
27.3, 73.9 (t, J = 21 Hz), 72.7, 70.4, 33.9, 31.7, 29.7, 29.4, 29.3, 29.1,
6.1, 25.2, 22.6, 21.2, 14.0; HRMS (ESI ): m/z calcd. for C H DO Na :
14.3089; [M+Na] found: 414.3090.
(
S)-1-((tert-Butyldimethylsilyl)oxy)octadecan-9-yl oleate (23): To
+
+
a solution of oleic acid (1.10 g, 4.00 mmol) in dry CH Cl (10 mL) at
25 41
3
2
2
+
0
°C, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride
(
767 mg, 4.00 mmol), triethylamine (0.55 mL, 4.00 mmol) and 4-
General procedure for the synthesis of compounds 6a–c, 9a,b,
dimethylaminopyridine (25 mg, 0.20 mmol) were added consecu-
tively. The mixture was left stirring at 0 °C for 10 min and then a
solution of alcohol 22 (1.00 mmol) in dry CH Cl (10 mL) was added.
After 16 h, whilst stirring the mixture was washed with a saturated
aqueous solution of NH Cl (20 mL), followed by a 5 % aqueous
1
1
7a,b, 30, 33: To a solution of mono-protected ester 5a–c, 8a,b,
6a,b, 29, 32 (1.00 mmol) in MeOH (10 mL), 10 % palladium on
2
2
activated charcoal was added. The reaction was left stirring under
hydrogen atmosphere for 16 h. Then, the resulting mixture was
filtered through a celite pad and the solvent was removed under
pressure to afford the desired alcohol without further purification.
4
solution of NaHCO (20 mL), a 5 % aqueous solution of citric acid
3
(20 mL), and a saturated NaCl solution (20 mL). The organic layers
were collected and dried with Na SO and the solvent was removed (S)-16-Hydroxyhexadecan-8-yl palmitate (6a): Prepared from 5a
2
4
under reduced pressure. The crude mixture was purified by flash
according to the representative procedure, 6a was isolated as a
1
silica chromatography (petroleum ether:diethyl ether 95:5) to afford colorless oil, 97 % yield; H NMR (200 MHz, CDCl ) δ 4.93–4.81 (1H,
3
the desired ester as a colorless oil, 80 % yield (213 mg); 1H NMR
200 MHz, CDCl ) δ 5.40–5.28 (2H, m, CH=CH), 4.91–4.80 (1H, m,
m, CHOC=O), 3.62 (2H, t, J = 6.4 Hz, CH OH), 2.27 (2H, t, J = 7.4 Hz,
2
(
CH C=O), 1.63–1.48 (11H, m, 10 × CHH, OH), 1.38–1.24 (42H, m,
3
2
1
3
CHOC=O), 3.59 (2H, t, J = 6.5 Hz, CH O), 2.27 (2H, t, J = 7.3 Hz,
42 × CHH), 0.86 (6H, t, J = 6.1 Hz, 2 × CH3); C NMR (50 Hz, CDCl3)
δ 173.8, 74.0, 63.0, 34.7, 34.1, 32.7, 31.9, 31.8, 29.7, 29.6, 29.5, 29.4,
29.3, 29.2, 25.6, 25.3, 25.2, 25.1, 22.7, 14.1; [α] = +3.8 (c = 1, MeOH);
2
CH C=O), 2.08–1.90 (4H, m, CHHCH=CH), 1.70–1.48 (10H, m,
2
2
0
1
0 × CHH), 1.40–1.12 (42H, m, 42 × CHH), 0.89 (9H, s, 3 × CH ), 0.84
3
D
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Full Paper
+
+
+
HRMS (ESI ): m/z calcd. for C H O Na : 519.4748; [M+Na] found:
16-Hydroxyhexadecan-8-yl-8-d palmitate (30): Prepared from 29
3
2 64 3
5
19.4750.
S)-16-Hydroxyhexadecan-8-yl stearate (6b): Prepared from 5b
according to the representative procedure, 6b was isolated as yel-
according to the representative procedure, 30 was isolated as a
1
colorless oil, 95 % yield; H NMR (200 MHz, CDCl ) δ 3.65–3.56 (2H,
3
(
m, CH OH), 2.25 (2H, t, J = 7.4 Hz, CH C=O), 1.69–1.47 (9H, m,
2
2
8
2
3
2
5
× CHH, OH), 1.40–1.10f (44H, m, 44 × CHH), 0.85 (6H, t, J = 5.7 Hz,
1
lowish oil, 88 % yield (191 mg); H NMR (200 MHz, CDCl ) δ 4.91–
4
J = 7.4 Hz, CH C=O), 1.63–1.42 (11H, m, 10 × CHH, OH), 1.42–1.16
3
13
× CH3); C NMR (50 Hz, CDCl ) δ 173.7, 73.6 (t, J = 19.2 Hz), 62.9,
3
.79 (1H, m, CHOC=O), 3.61 (2H, t, J = 6.5 Hz, CH OH), 2.26 (2H, t,
2
4.7, 34.0, 32.7, 31.9, 31.7, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1,
2
+
+
5.6, 25.2, 25.1, 22.7, 14.1; HRMS (ESI ): m/z calcd. for C H DO Na :
20.4810; [M+Na] found: 520.4815.
13
32 63
3
(46H, m, 46 × CHH), 0.86 (6H, t, J = 6.2 Hz, 2 × CH3); C NMR
+
(50 MHz, CDCl ) δ 173.7, 74.0, 63.0, 34.7, 34.1, 32.7, 31.9, 31.8, 29.7,
3
2
0
2
9.5, 29.4, 29.3, 29.2, 25.7, 25.3, 25.2, 22.7, 22.6, 14.1; [α] = +3.6 16-Hydroxyhexadecan-8-yl-8-d acetate (33): Prepared from 32
D
+ +
(c = 0.5, CHCl ); HRMS (ESI ): m/z calcd. for C H O Na : 547.5061;
according to the representative procedure, 33 was isolated as a
3
34 68 3
+
1
[M+Na] found: 547.5058.
yellowish low melting point solid, 89 % yield (80 mg); H NMR
(
200 MHz, CDCl ) δ 3.59 (2H, t, J = 6.5 Hz, CH OH), 2.01 (3H, s,
3
2
(
S)-1-Hydroxyoctadecan-9-yl palmitate (6c): Prepared from 5c ac-
CH C=O), 1.81 (1H, s, OH), 1.55–1.09 (26H, m, 26 × CHH), 0.84 (3H,
t, J = 5.9 Hz, CH ); C NMR (50 MHz, CDCl ) δ C NMR (50 MHz,
CDCl ) δ 171.0, 74.0 (t, J = 22.0 Hz), 62.8, 33.9, 32.6, 31.7, 29.7, 29.6,
2
3
cording to the representative procedure, 6c was isolated as a color-
less oil, 89 % yield (167 mg); H NMR (200 MHz, CDCl ) δ 4.92–4.80
13
13
1
3
3
3
3
(1H, m, CHOC=O), 3.62 (2H, t, J = 6.1 Hz, CH OH), 3.48 (1H, s, OH),
2
+
9.4, 29.3, 29.2, 29.1, 25.6, 25.2, 22.6, 21.2, 14.0; HRMS (ESI ): m/z
2
1
.27 (2H, t, J = 7.4 Hz, CH C=O), 1.65–1.48 (10H, m, 10 × CHH), 1.42–
2
+
+
13
calcd. for C18H35DO Na : 324.2619; [M+Na] found: 324.2619.
3
.08 (46H, m, 46 × CHH), 0.87 (6H, t, J = 5.5 Hz, 2 × CH3); C NMR
(
2
50 MHz, CDCl ) δ 173.7, 74.0, 63.0, 34.7, 34.1, 32.8, 31.9, 29.7, 29.5,
3
(S)-1-Hydroxyoctadecan-9-yl oleate (24): To a flamed-dried flask
containing (S)-1-((tert-butyldimethylsilyl)oxy)octadecan-9-yl oleate
(203 mg, 0.31 mmol) in dry THF (0.86 mL), tetra-N-butylammonium
fluoride (0.31 mL, 0.31 mmol) was added dropwise. The reaction
was left stirring for 1 h and then the solvent was removed under
reduced pressure. Flash chromatography on silica gel (petroleum
ether/ethyl acetate, 95:5) of the crude mixture provided the desired
2
0
9.4, 29.3, 29.2, 25.7, 25.3, 25.2, 22.7, 14.1; [α] = –2.2 (c = 0.5,
D
+
+
+
CHCl ); HRMS (ESI ): m/z calcd. for C H O Na : 547.5061; [M+Na]
found: 547.5064.
3
34 68 3
(
S)-16-Ηydroxyhexadecan-8-yl acetate (9a): Prepared from 8a ac-
cording to the representative procedure, 9a was isolated as a white
low melting point solid, 91 % yield (67 mg); H NMR (200 MHz,
CDCl ) δ 4.90–4.78 (1H, q, J = 6.1 Hz, CHOC=O), 3.61 (2H, t, J =
6
OH), 1.42–1.25 (20H, m, 20 × CHH), 0.86 (3H, t, J = 6.3 Hz, CH3);
NMR (50 MHz, CDCl ) δ 171.0, 74.4, 63.0, 34.1, 32.7, 31.7, 29.5, 29.4,
2
1
1
alcohol as a colorless oil, 80 % yield (152 mg); H NMR (200 MHz,
3
CDCl ) δ 5.36–5.28 (2H, m, CH=CH), 4.92–4.79 (2H, m, CHOC=O, OH),
.0 Hz, CH OH), 2.02 (3H, s, CH C=O), 1.57–1.48 (7H, m, 6 × CHH,
3
2
3
13
3.63 (2H, t, J = 6.5 Hz, CH OH), 2.27 (2H, t, J = 7.4 Hz, CH C=O),
C
2
2
2
.08–1.92 (4H, m, CHHCH=CH), 1.67–1.42 (10H, m, 10 × CHH), 1.40–
3
1
3
2
0
1.05 (42H, m, 42 × CHH), 0.87 (6H, t, J = 5.8 Hz, 2 × CH ); C NMR
(50 Hz, CDCl ) δ C NMR (50 MHz, CDCl ) 173.7, 130.0, 129.7, 74.0,
3 3
9.3, 29.2, 25.6, 25.3, 25.2, 22.6, 21.3, 14.0; [α] = +4.0 (c = 1.0,
3
D
13
+
+
+
CHCl ); HRMS (ESI ): m/z calcd. for C H O Na : 323.2557; [M+Na]
found: 323.2564.
3
18 36 3
6
2
3.0, 34.7, 34.1, 32.7, 31.9, 29.8, 29.7, 29.5, 29.4, 29.3, 29.2, 29.1, 27.2,
2
0
+
5.7, 25.3, 25.2, 22.7, 14.1; [α] = –0.5 (c = 1.0, CHCl ); HRMS (ESI ):
D
3
(
S)-1-Hydroxyoctadecan-9-yl acetate (9b): Prepared from 8b ac-
+
+
m/z calcd. for C H O Na : 573.5217; [M+Na] found: 573.5213.
36 70 3
cording to the representative procedure, 9b was isolated as a white
low melting point solid, 95 % yield (325 mg); H NMR (200 MHz,
CDCl ) δ 4.91–4.78 (1H, m, CHOC=O), 3.62 (2H, t, J = 6.5 Hz, CH OH),
2
1
1
General procedure for the synthesis of compounds 7a–c, 10a,b,
8a,b, 25, 31, 35: To a flask containing the appropriate alcohol
1 mmol), acetone (10 mL) was added and the mixture was left
stirring at 0 °C until full dissolution. Then, Jones reagent (2 M,
.5 mL, 3 mmol) was added dropwise at 0 °C and the reaction was
left stirring at 0 °C for 1 h. The mixture was left reach room tempera-
1
(
3
2
.03 (3H, s, CH C=O), 1.70 (1H, s, OH), 1.61–1.42 (8H, m, 8 × CHH),
3
13
.38–1.11 (22H, m, 22 × CHH), 0.87 (3H, t, J = 6.1 Hz, CH3); C NMR
1
(50 MHz, CDCl ) δ 171.0, 74.4, 63.0, 34.1, 32.7, 31.9, 29.5, 29.4, 29.3,
3
2
0
+
2
5.7, 25.3, 22.7, 21.3, 14.1; [α] = –1.4 (c = 0.5, CHCl ); HRMS (ESI ):
D
3
+
+
ture and a saturated solution of NaHSO (10 mL) was added. The
m/z calcd. for C H O Na : 351.2870; [M+Na] found: 351.288.
3
20 40 2
mixture was extracted with Et O (3 × 20 mL), washed with brine
2
(
S)-1-Hydroxyhexadecan-5-yl stearate (17a): Prepared from 16a
(
1 × 50 mL), dried over Na SO , filtered and concentrated under
2 4
according to the representative procedure, 17a was isolated as a
yellowish oil, 92 % yield (120 mg); H NMR (200 MHz, CDCl ) δ 4.94–
4
J = 7.5 Hz, CH C=O), 1.65–1.41 (9H, m, 8 × CHH, OH), 1.40–1.13 (48H,
m, 48 × CHH), 0.86 (6H, t, J = 5.9 Hz, 2 × CH3); C NMR (50 MHz,
CDCl ) δ 173.8, 73.8, 62.7, 34.7, 34.1, 33.9, 32.5, 31.9, 29.7, 29.6, 29.5,
2
reduced pressure. The residue was purified by flash chromatogra-
phy on silica gel (petroleum ether/diethyl ether) to afford the de-
sired fatty acids.
1
3
.81 (1H, m, CHOC=O), 3.61 (2H, t, J = 6.3 Hz, CH OH), 2.27 (2H, t,
2
2
1
3
(S)-9-(Palmitoyloxy)hexadecanoic acid (7a): Prepared from 6a ac-
cording to the representative procedure, 7a was isolated as a yel-
3
2
0
9.4, 29.3, 29.2, 25.3, 25.1, 22.7, 21.5, 14.1; [α] = –2.0 (c = 0.5, lowish oil, 94 % yield; Column elution system: petroleum ether/Et
O,
) δ 4.92–4.79 (1H, m, CHOC=O), 2.37–
CO), 1.61–1.42 (8H, m, 8 × CHH), 1.38–1.10 (42H,
2
D
2
+
+
+
1
MeOH); HRMS (ESI ): m/z calcd. for C H O Na : 547.5061; [M+Na]
found: 547.5075.
7:3; H NMR (200 MHz, CDCl
2.24 (4H, m, 2 × CH
3
3
4 68 3
13
m, 42 × CHH), 0.87 (6H, t, J = 6.1 Hz, 2 × CH3); C NMR (50 MHz,
(
S)-1-Hydroxyoctadecan-5-yl palmitate (17b): Prepared from 16b
CDCl ) δ 180.0, 173.8, 74.0, 34.7, 34.1, 34.0, 31.9, 31.8, 29.7, 29.5,
3
according to the representative procedure, 17b was isolated as a
2
9.4, 29.3, 29.2, 29.1, 28.9, 25.3, 25.2, 24.6, 22.7, 22.6, 14.1; IR (KBr):
yellowish low melting point solid, 89 % yield (173 mg); 1H NMR
–
1
20
ν˜ = 3400, 2923, 2853, 1732, 1712 cm ; [α] = –1.3 (c = 1, CH Cl );
D
2
2
(200 MHz, CDCl ) δ 4.94–4.81 (1H, m, CHOC=O), 3.63 (2H, t, J =
3
+
+
+
HRMS (ESI ): m/z calcd. for C H O Na : 533.4540; [M+Na] found:
32 62 4
6
1
.4 Hz, CH OH), 3.46 (1H, s, OH), 2.28 (2H, t, J = 7.4 Hz, CH C=O),
2 2
533.4540.
.59–1.46 (8H, m, 8 × CHH), 1.42–1.15 (48H, m, 48 × CHH), 0.87 (6H,
1
3
t, J = 6.4 Hz, 2 × CH3); C NMR (50 MHz, CDCl ) δ 173.8, 73.8, 62.8,
3
2
(S)-9-(Palmitoyloxy)octadecanoic acid (7b): Prepared from 6b ac-
cording to the representative procedure, 7b was isolated as a yel-
3
4.7, 34.1, 33.9, 32.5, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 25.3, 25.2,
2
0
+
2.7, 21.5, 14.1; [α] = +1.3 (c = 1.0, CHCl ); HRMS (ESI ): m/z calcd. lowish oil, 88 % yield (80 mg); Column elution system: petroleum
D
3
+
+
1
for C H O Na : 547.5061; [M+Na] found: 547.5066.
ether/Et O, 8:2; H NMR (200 MHz, CDCl ) δ 4.92–4.80 (1H, m,
34
68
3
2
3
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
8
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
CHOC=O), 2.37–2.24 (4H, m, 2 × CH CO), 1.61–1.43 (8H, m, 8 × CHH),
(S,Z)-9-(Oleoyloxy)octadecanoic acid (25): Prepared from 24 ac-
cording to the representative procedure, 25 was isolated as a color-
2
13
1
.43–1.11 (46H, m, 46 × CHH), 0.88 (6H, t, J = 5.6 Hz, 2 × CH3);
C
NMR (50 MHz, CDCl ) δ 180.0, 173.8, 74.0, 34.7, 34.1, 34.0, 31.9, 31.8,
less oil, 83 % yield (127 mg); Column elution system: PE/Et O, 6:4;
3
2
1
2
9.7, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0, 25.3, 25.2, 24.6, 22.7, 22.6, 14.1;
H NMR (200 MHz, CDCl ) δ 5.36–5.31 (2H, m, CH=CH), 4.91–4.78
3
–
1
20
=
IR (KBr): ν˜ = 3401, 2925, 2854, 1734, 1711 cm ; [α]
-0.7 (c = 1.0, (1H, m, CHOC=O), 2.37–2.24 (4H, m, CH C=O), 2.07–1.93 (4H, m,
D
2
–
–
–
CHCl ); HRMS (ESI ): m/z calcd. for C H O : 537.4888; [M – H]
CHHCH=CH), 1.69–1.49 (8H, m, 8 × CHH), 1.44–1.05 (42H, m,
42 × CHH), 0.87 (6H, t, J = 5.5 Hz, 2 × CH3); 13C NMR (50 MHz, CDCl3)
δ 179.7, 173.7, 130.0, 129.7, 74.0, 34.7, 34.1, 34.0, 31.9, 29.8, 29.7,
3
34 65 4
found: 537.4879.
S)-9-(Stearoyloxy)hexadecanoic acid(7c):[10] Prepared from 6c
(
2
9.5, 29.3, 29.2, 29.1, 29.0, 27.2, 25.3, 25.2, 24.6, 22.7, 14.1; IR (KBr):
according to the representative procedure, 7c was isolated as a yel-
–
1
20
ν˜ = 3401, 2925, 2854, 1734, 1711 cm ; [α] = –0.8 (c = 1.0, CHCl );
D
3
lowish oil, 87 % yield (120 mg); Column elution system: petroleum
–
–
–
1
HRMS (ESI ): m/z calcd. for C36
63.5038.
H O : 563.5045; [M – H] found:
67 4
ether/Et O, 7:3; H NMR (200 MHz, CDCl ) δ 4.91–4.80 (1H, m,
2
3
5
CHOC=O), 2.37–2.24 (4H, m, 2 × CH CO), 1.61–1.43 (8H, m, 8 × CHH),
2
13
1
.38–1.06 (46H, m, 46 × CHH), 0.87 (6H, t, J = 5.9 Hz, 2 × CH3);
C
9-(Palmitoyloxy)hexadecanoic-9-d acid (31): Prepared from 30
according to the representative procedure, 31 was isolated as a
white solid, m.p. 34–36 °C, 92 % yield; Column elution system: PE/
NMR (50 MHz, CDCl ) δ 179.8, 173.8, 74.0, 34.7, 34.1, 34.0, 31.9, 29.7,
3
2
9.5, 29.4, 29.3, 29.2, 29.1, 29.0, 25.3, 25.2, 24.6, 22.7, 14.1; IR (KBr):
–
1
20
ν = 3435, 2924, 2854, 1733, 1712 cm ; [α] = +1.6 (c = 0.5, CHCl ).
1
˜
D
3
Et O, 6:4; H NMR (200 MHz, CDCl ) δ 2.36–2.23 (4H, m, 2 × CH CO),
2
3
2
2
3
=
+
For (S)-9-(stearoyloxy)hexadecanoic acid [α]
0.1 (c = 1.0, CHCl3)
D
1.72–1.42 (8H, m, 8 × CHH), 1.40–1.16 (42H, m, 42 × CHH), 0.86 (6H,
10]
(
from –0.1160 to 0.3040);[
HRMS (ESI ): m/z calcd. for
13
t, J = 6.1 Hz, 2 × CH3); C NMR (50 MHz, CDCl ) δ 180.1, 173.8, 73.6
3
+
+
C H O Na : 561.4853; [M+Na] found: 561.4846.
34
66
4
(t, J = 20.0 Hz), 34.7, 34.0, 31.9, 31.8, 29.7, 29.6, 29.5, 29.3, 29.2, 29.1,
–
(
S)-9-Αcetoxyhexadecanoic acid (10a): Prepared from 9a accord-
28.9, 25.3, 25.2, 24.6, 22.7, 22.6, 14.1; ΗRMS (ESI ): m/z calcd. for
–
–
ing to the representative procedure, 10a was isolated as a colorless
C
32
H60DO
4
: 510.4638; [M – H] found: 510.4642.
oil, 86 % yield (59 mg), Column elution system: petroleum ether/
9
-Acetoxyhexadecanoic-9-d acid (34): Prepared from 33 accord-
1
Et O, 6:4 and 5:5. H NMR (200 MHz, CDCl ) δ 9.63 (1H, br s, COOH),
2
3
ing to the representative procedure, 34 was isolated as a colorless
oil, 73 % yield (50 mg); Column elution system: PE/Et O, 6:4; H NMR
4
.90–4.78 (1H, m, CHOC=O), 2.33 (2H, t, J = 7.4 Hz, CH COOH), 2.02
1
2
2
(
3H, s, CH C=O), 1.70–1.40 (6H, m, 6 × CHH), 1.38–1.13 (18H, m,
3
(200 MHz, CDCl ) δ 8.44 (1H, br s, COOH), 2.33 (2H, t, J = 7.4 Hz,
3
1
3
1
1
2
8 × CHH), 0.86 (3H, t, J = 5.8 Hz, CH3); C NMR (50 MHz, CDCl ) δ
3
CH COOH), 2.03 (3H, s, CH C=O), 1.68–1.40 (6H, m, 6 × CHH), 1.38–
2
3
79.9, 171.0, 74.4, 34.1, 34.0, 31.8, 29.5, 29.3, 29.2, 29.1, 28.9, 28.8,
13
1.11 (18H, m, 18 × CHH), 0.86 (3H, t, J = 5.8 Hz, CH3); C NMR
20
=
5.3, 25.2, 24.6, 22.6, 21.3, 14.1; [α]
-1.1 (c = 1.0, CHCl ); HRMS
D
3
(50 MHz, CDCl ) δ 179.8, 171.1, 74.0 (t, J = 22.3 Hz), 34.0, 33.0, 31.8,
3
–
–
–
(ESI ): m/z calcd. for C H O : 313.2384; [M – H] found: 313.2372.
+
1
8 33 4
29.5, 29.3, 29.2, 29.1, 28.9, 25.2, 24.6, 22.6, 21.3, 14.1; HRMS (ESI ):
+
+
+
HRMS (ESI ): m/z calcd. for C H O Na : 337.2349; [M+Na] found:
+
+
1
8 34 4
m/z calcd. for C H DO Na : 338.2412; [M+Na] found: 338.2411.
18
33
4
3
37.2351.
General procedure for the synthesis of compounds 11a,b, 35:
To a solution of the acetyl protected compound (1 mmol) in a mix-
ture of THF and H O (1:1, 5 mL), LiOH (96 mg, 4 mmol) was added
and the reaction mixture was left stirring at room temperature for
(S)-9-Acetoxyoctadecanoic acid (10b): Prepared from 9b accord-
ing to the representative procedure, 10b was isolated as a colorless
2
oil, 81 % yield (199 mg); Column elution system: petroleum ether/
1
Et O, 6:4 and 5:5; H NMR (200 MHz, CDCl ) δ 4.90–4.78 (1H, m,
2
3
16 h. After the addition of of HCl 1 N (10 mL) to pH 1, the mixture
CHOC=O), 2.34 (2H, t, J = 7.4 Hz, CH COOH), 2.03 (3H, s, CH C=O),
2
3
was extracted with Et O (3 × 10 mL), washed with brine (1 × 30 mL),
dried over Na SO , filtered and concentrated under reduced pres-
2 4
sure. Flash chromatography on silica gel of the crude mixture re-
sulted in the desired hydroxy fatty acids.
2
1
6
3
.63–1.50 (6H, m, 6 × CHH), 1.48–1.24 (22H, m, CHH) 0.87 (3H, t, J =
.3 Hz, CH3); 13C NMR (50 MHz, CDCl ) δ 179.8, 171.1, 74.4, 34.1,
3
4.0, 31.9, 29.5, 29.3, 29.1, 28.9, 25.3, 25.2, 24.6, 22.7, 21.3, 14.1;
2
0
=
+
+
[α]
-3.0 (c = 1.0, CHCl ); HRMS (ESI ): m/z calcd. for C H O Na :
D
3 20 38 3
+
(S)-9-Hydroxyhexadecanoic acid[31] (11a): Prepared from 10a ac-
cording to the representative procedure, 11a was isolated as a
white solid, m.p.60–62 °C, 63 % yield (33 mg); Column elution sys-
tem: petroleum ether/Et O, 2:8; H NMR (200 MHz, CDCl ) δ 6.63
(1H, br s, COOH), 3.63–3.52 (1H, m, CHOH), 2.33 (2H, t, J = 7.4 Hz,
CH COOH), 1.69–1.49 (3H, m, 2 × CHH, ΟΗ), 1.40–1.09 (22H, m,
3
65.2662; [M+Na] found: 365.2670.
(
S)-5-(Stearoyloxy)hexadecanoic acid (18a): Prepared from 17a
according to the representative procedure, 18a was isolated as a
1
yellowish oil, 88 % yield (109 mg); Column elution system: petro-
2
3
1
leum ether/Et O, 7:3 and 6:4; H NMR (200 MHz, CDCl ) δ 4.94–4.82
2
3
(
1H, m, CHOC=O), 2.39–2.24 (4H, m, 2 × CH CO), 1.74–1.42 (8H, m,
2
2
13
22 × CHH), 0.87 (3H, t, J = 6.0 Hz, CH3); C NMR (50 MHz, CDCl ) δ
8
2
3
1
× CHH), 1.42–1.06 (46H, m, 46 × CHH), 0.87 (6H, t, J = 6.1 Hz,
3
× CH3); 13C NMR (50 MHz, CDCl ) δ 179.5, 173.8, 73.3, 34.6, 34.0,
179.7, 72.1, 37.3, 37.2, 34.0, 31.8, 29.6, 29.4, 29.3, 29.2, 28.9, 25.6,
3
–1
2
5.5, 24.6, 22.6, 14.1; IR (KBr): ν˜ = 3306, 2923, 2850, 1703 cm ;
3.7, 33.4, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 25.3, 25.1, 22.7, 20.4,
20
+
+
–
1
20
=
[α] = –1.0 (c = 1.0, CHCl ); HRMS (ESI ): m/z calcd. for C H O Na :
4.1; IR (KBr): ν˜ = 3400, 2922, 2852, 1732 1712 cm ; [α]
-0.9
D
3 16 32 3
D
+
–
–
295.2244; [M+Na] found: 295.2255; HPLC analysis: 93 % ee, ob-
tained by derivatization of 9-hydroxy palmitic acid with L-phenyl-
alanine tert-butyl ester. Daicel Chiralpak OD-H, hexane/iPrOH
(c = 1.0, CHCl ); HRMS (ESI ): m/z calcd. for C H O : 537.4888;
3 34 65 4
–
[
M – H] found: 537.4777.
(
S)-5-(Palmitoyloxy)octadecanoic acid (18b): Prepared from 17b
(97.0:3.0), 0.5 mL/min flow, t = 104.8 (major), t = 118.9 (minor).
R R
according to the representative procedure, 18b was isolated as a
yellowish oil, 87 % yield (108 mg); Column elution system: PE/Et O,
(S)-9-Hydroxyoctadecanoic acid (11b):[31] Prepared from 10b ac-
2
1
6
:4; H NMR (200 MHz, CDCl ) δ 4.94–4.82 (1H, m, CHOC=O), 2.39– cording to the representative procedure, 11b was isolated as a
3
2
.24 (4H, m, 2 × CH CO), 1.67–1.48 (8H, m, 8 × CHH), 1.39–1.15 (46H,
white solid, m.p. 73–75 °C, 70 % yield (120 mg); Column elution
2
1
3
1
m, 46 × CHH), 0.87 (6H, t, J = 6.4 Hz, 2 × CH3); C NMR (50 MHz,
system: CH Cl /MeOH, 9:1; H NMR (200 MHz, CDCl ) δ 6.24 (1H, br
2
2
3
CDCl ) δ 179.5, 173.8, 73.3, 34.6, 34.0, 33.7, 33.3, 31.9, 29.7, 29.6, s, COOH), 3.65–3.52 (1H, m, CHOH), 2.33 (2H, t, J = 7.4 Hz,
3
2
2
9.5, 29.4, 29.3, 29.2, 25.3, 25.1, 22.7, 20.4, 14.1; IR (KBr): ν˜ = 3401, CH COOH), 1.65–1.55 (3H, m, 2 × CHH, OH), 1.50–1.18 (26H, m,
2
–
1
20
=
1
3
919, 2851, 1743, 1702 cm ; [α]
+1.8 (c = 1.0, CHCl ); HRMS 26 × CHH), 0.87 (3H, t, J = 6.2 Hz, CH3); C NMR (50 MHz, CDCl ) δ
3 3
D
–
–
–
(ESI ): m/z calcd. for C H O : 537.4888; [M – H] found: 537.4904. 179.5, 72.1, 37.4, 37.3, 34.0, 31.9, 29.7, 29.6, 29.4, 29.3, 29.2, 29.0,
34 65 4
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2
1
5.6, 25.5, 24.6, 22.7, 14.1; IR (KBr): ν˜ = 3413, 2924, 2851,
[2] T. Kimura, W. Jennings, R. M. Epand, Prog. Lipid Res. 2016, 62, 75–92.
[3] S. C. Tucker, K. V. Honn, Biochem. Pharmacol. 2013, 85, 673–688.
[4] T. Vihervaara, M. Suoniemi, R. Laaksonen, Drug Discovery Today 2014, 19,
–1
20
=
–
714 cm ; [α]
-11.2 (c = 0.5, CHCl ); HRMS (ESI ): m/z calcd. for
D
3
–
–
C H O : 299.2592; [M – H] found: 299.2553.
18 35 3
1
64–170.
9
-Hydroxyhexadecanoic-9-d acid (35): Prepared from 34 accord-
[5] M. M. Yore, I. Syed, P. M. Moraes-Vieira, T. Zhang, M. A. Herman, E. A.
Homan, R. T. Patel, J. Lee, S. Chen, O. D. Peroni, A. S. Dhaneshwar, A.
Hammarstedt, U. Smith, T. E. McGraw, A. Saghatelian, B. B. Kahn, Cell
2014, 159, 318–332.
ing to the representative procedure, 35 was isolated as a white
solid, m.p.60–62 °C, 62 % yield (27 mg); Column elution system:
petroleum ether/Et O, 5:5 and 2:8; H NMR (200 MHz, CDCl ) δ 5.28
1
2
3
[
6] T. Zhang, S. Chen, I. Syed, M. Ståhlman, M. J. Kolar, E. A. Homan, Q. Chu,
(1H, br s, COOH), 2.34 (2H, t, J = 7.2 Hz, CH COOH), 1.67–1.11 (25H,
2
1
3
U. Smith, J. Borén, B. B. Kahn, A. Saghatelian, Nat. Protoc. 2016, 11, 747–
m, 24 × CHH, OH), 0.88 (3H, t, J = 6.1 Hz, CH3); C NMR (50 MHz,
CDCl ) δ 179.6, 71.6 (t, J = 21.5 Hz), 37.2, 37.1, 34.0, 31.8, 29.6,
7
63.
3
[
7] M. J. Kolar, A. T. Nelson, T. Chang, M. E. Ertunc, M. P. Christy, L. Ohlsson,
2
9.4, 29.3, 29.2, 28.9, 25.6, 25.5, 24.6, 22.6, 14.1; Deuteration rate
M. Härröd, B. B. Kahn, D. Siegel, A. Saghatelian, Anal. Chem. 2018, 90,
–
[%] calculated using HRMS = 98.75 %; HRMS (ESI ): m/z calcd. for
5
358–5365.
[8] Q.-F. Zhu, J.-W. Yan, T.-Y. Zhang, H.-M. Xiao, Y.-Q. Feng, Anal. Chem. 2018,
0, 10056–10063.
9] P. M. Moraes-Vieira, A. Saghatelian, B. B. Kahn, Diabetes 2016, 65, 1808–
815.
–
–
C H DO : 272.2341; [M – H] found: 272.2339.
16
30
3
9
1
0-(Benzyloxy)decanal-2,2-d2 (26): A solution of 10-(benzyl-
[
oxy)decanal (262 mg, 1 mmol) in deuterium oxide (1 mL) and tri-
ethylamine (0.1 mL) was left stirring at 100 °C for 1 h. Then, HCl 1 N
1
[
[
10] A. T. Nelson, M. J. Kolar, Q. Chu, I. Syed, B. B. Kahn, A. Saghatelian, D.
Siegel, J. Am. Chem. Soc. 2017, 139, 4943–4947.
11] L. Balas, J. Bertrand-Michel, F. Viars, J. Faugere, C. Lefort, S. Caspar-Bau-
guil, D. Langin, T. Durand, Org. Biomol. Chem. 2016, 14, 9012–9020.
(1 mL) was added followed by extraction with Et O (3 × 2 mL). The
2
combined organic layers were washed with a saturated solution of
NaHCO3 (1 × 10 mL), dried over Na SO and the solvent was re-
2
4
moved under reduced pressure. The same procedure was repeated
twice to afford the 2,2-deuterated analogue. The aldehyde was iso-
lated as a colorless oil, which was used immediately for the next
[12] E. Pflimlin, M. Bielohuby, M. Korn, K. Breitschopf, M. Löhn, P. Wohlfart, A.
Konkar, M. Podeschwa, F. Bärenz, A. Pfenninger, U. Schwahn, T. Opatz, M.
Reimann, S. Petry, N. Tennagels, Cell Metab. 2018, 28, 217–227.
[13] I. Syed, J. Lee, P. M. Moraes-Vieira, C. J. Donaldson, A. Sontheimer, P. Aryal,
K. Wellenstein, M. J. Kolar, A. T. Nelson, D. Siegel, J. Mokrosinski, I. S.
Farooqi, J. J. Zhao, M. M. Yore, O. D. Peroni, A. Saghatelian, B. B. Kahn,
Cell Metab. 2018, 27, 419–427.
[14] J. Lee, P. M. Moraes-Vieira, A. Castoldi, P. Aryal, E. U. Yee, C. Vickers, O.
Parnas, C. J. Donaldson, A. Saghatelian, B. B. Kahn, J. Biol. Chem. 2016,
291, 22207–22217.
1
step without further purification. 88 % yield; H NMR (200 MHz,
CDCl ) δ 9.75 (1H, s, CHO), 7.35–7.25 (5H, m, ArH), 4.50 (2, s, ArCH ),
3
2
3
.46 (2H, t, J = 6.5 Hz, OCH ), 1.68–1.50 (4H, m, 4 × CHH), 1.41–1.21
2
13
(10H, m, 10 × CHH); C NMR (50 MHz, CDCl ) δ 203.1, 138.6, 128.2,
3
1
2
27.5, 127.4, 72.7, 70.4, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0, 26.1,
+
+
+
1.8; HRMS (ESI ): m/z calcd. for C H D O : 265.2131; [M + H]
17 25 2 2
found: 265.2128.
[15] For a book, see: P. I. Dalko (Eds.), Comprehensive Enantioselective Organo-
catalysis: Catalysts, Reactions, and Applications, Wiley-VCH, Weinheim,
Determination of deuteration degree
2013.
Samples of compounds 31 and 35 were analyzed by LC-HRMS/MS
using an AB Sciex 4600 Triple TOF combined with an Eksigent mi-
cro-LC and an autosampler. Electrospray ionization (ESI) – negative
[16] For reviews, see: a) D. W. C. MacMillan, Nature 2008, 455, 304–308; b) R.
Chawla, A. K. Singh, L. D. S. Yadav, RSC Adv. 2013, 3, 11385–11403.
[
[
17] T. Shioiri, N. Irako, Tetrahedron 2000, 56, 9129–9142.
18] a) M. P. Brochu, S. P. Brown, D. W. C. MacMillan, J. Am. Chem. Soc. 2004,
mode – was used for the MS experiments. Halo C18 2.7 μm, 90 Å,
1
26, 4108–4109; b) N. Halland, A. Braunton, S. Bachmann, M. Marigo,
2
0
.5 × 50 mm from Eksigent was used as a column and the mobile
K. A. Jørgensen, J. Am. Chem. Soc. 2004, 126, 4790–4791; c) M. Amatore,
T. D. Beeson, S. P. Brown, D. W. C. MacMillan, Angew. Chem. Int. Ed. 2009,
48, 5121–5124; Angew. Chem. 2009, 121, 5223.
phase consisted of a gradient (A: acetonitrile/0.01 % formic acid-2-
propanol 80:20 v/v; B: H O/0.01 % formic acid). The data acquisition
2
was carried out with MultiQuant from AB SCIEX (version 3.0). The %
deuteration degree was estimated as area of deuterated com-
pound/area of deuterated compound plus area of non deuterated
analog X100.
[19] N. Kaplaneris, C. Spyropoulos, M. G. Kokotou, C. G. Kokotos, Org. Lett.
2016, 18, 5800–5803.
[20] M. H. Kaspersen, L. Jenkins, J. Dunlop, G. Milligan, T. Ulven, Med. Chem.
Commun. 2017, 8, 1360–1365.
[
21] F. Asaro, S. Drioli, C. Forzato, P. Nitti, ChemistrySelect 2018, 3, 13372–
3376.
Conflict of interest
1
[
[
[
22] S. E. Tully, B. F. Cravatt, J. Am. Chem. Soc. 2010, 132, 3264–3265.
23] C. Schmidt, Nat. Biotechnol. 2017, 35, 493–494.
24] T. G. Gant, J. Med. Chem. 2014, 57, 3595–3611.
The authors declare no conflict of interest.
Acknowledgments
[25] X. Ariza, G. Asins, J. Garcia, F. G. Hegardt, K. Makowski, D. Serra, J. Velas-
coa, J. Labelled Compd. Radiopharm. 2010, 53, 556–558.
[26] A. Kondoh, A. Arlt, B. Gabor, A. Fürstner, Chem. Eur. J. 2013, 19, 7731–
7738.
The authors would like to thank the “Special Account for Re-
search Grants” of the National and Kapodistrian University of
Athens, Greece for its support (Grant 13300). O.G.M. would like
to thank the Eugenides Foundation for the “Alexandros Stavro-
poulos” fellowship.
[27] R. S. Narayan, B. Borhan, J. Org. Chem. 2006, 71, 1416–1429.
[28] E. Brehm, R. Breinbauer, Org. Biomol. Chem. 2013, 11, 4750–4750.
[29] G. Sabitha, G. Chandrashekhar, K. Yadagiri, J. S. Yadav, Tetrahedron Lett.
2010, 51, 3824–3826.
[
[
30] K. Matsumoto, K. Usuda, H. Okabe, M. Hashimoto, Y. Shimada, Tetrahe-
dron: Asymmetry 2013, 24, 108–115.
31] C. Ebert, F. Felluga, C. Forzato, M. Foscato, L. Gardossi, P. Nitti, G. Pitacco,
C. Boga, P. Caruana, G. Micheletti, N. Calonghi, L. Masotti, J. Mol. Catal. B
Keywords: Asymmetric synthesis · Fatty acids · Epoxides ·
Hydroxy fatty acids · Organocatalysis
2012, 83, 38–45.
[
1] For a book, see: G. Kokotos, A. Nicolaou (Eds.), Bioactive Lipids, The Oily
Press: Bridgewater, England, 2004.
Received: December 26, 2018
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Full Paper
Asymmetric Synthesis
O. G. Mountanea, D. Limnios,
M. G. Kokotou, A. Bourboula,
G. Kokotos* ....................................... 1–12
Asymmetric Synthesis of Saturated
Hydroxy Fatty Acids and Fatty Acid
Esters of Hydroxy Fatty Acids
Convenient enantioselective synthesis was developed, based on the organo-
of bioactive hydroxy fatty acids and catalytic synthesis of chiral epoxides.
fatty acid esters of hydroxy fatty acids
DOI: 10.1002/ejoc.201801881
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