Synthesis of (Z)-(2′R)-1-O-(2′-methoxynonadec-10′-enyl)- sn-glycerol, a new analog of bioactive ether lipids

Article abstract of DOI:10.1016/j.tet.2012.02.033

An unsaturated 2-methoxy-substituted 1-O-alkylglycerol, (Z)-(2′R)-1-O-(2′-methoxynonadec-10′-enyl)-sn-glycerol, a new analog of bioactive ether lipids, was synthesized from oleic acid and 2,3-isopropylidene-sn-glycerol. The two key steps of this synthesis were the conversion of oleyl aldehyde to a monounsaturated epoxide using Matteson's method followed by hydrolytic kinetic resolution and a nucleophilic epoxide opening by 2,3-isopropylidene-sn-glycerol in the presence of potassium tert-butoxide in anhydrous DMF, which appeared to be a good reagent for this purpose. Furthermore, the diol by-product of the HKR process was also easily converted back to the starting epoxide thus almost doubling the amount of target molecule.

Full text of DOI:10.1016/j.tet.2012.02.033

Tetrahedron 68 (2012) 2973e2983
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (Z)-(20R)-1-O-(20-methoxynonadec-100-enyl)-sn-glycerol, a new
analog of bioactive ether lipids
a
,
b
,
c
c
b,d,
*
ꢀ
ꢀ
Rene Pemha
, Dieudonne Emmanuel Pegnyemb , Paul Mosset
a
ꢀ
ꢀ ꢀ
Ecole Nationale Superieure de Chimie de Rennes, CNRS, UMR 6226, Avenue du General Leclerc, CS 50837, 35708 Rennes Cedex 7, France
b
c
ꢀ
ꢀ
Universite europeenne de Bretagne, Rennes, France
Departement de Chimie Organique, Faculte des Sciences, Universite de Yaounde I, BP 812 Yaounde, Cameroon
Universite de Rennes 1, Laboratoire SCR, CNRS, UMR 6226, Avenue du General Leclerc, 35042 Rennes Cedex, France
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
d
ꢀ
ꢀ ꢀ
a r t i c l e i n f o
a b s t r a c t
An unsaturated 2-methoxy-substituted 1-O-alkylglycerol, (Z)-(20R)-1-O-(20-methoxynonadec-100-enyl)-
Article history:
Received 19 May 2011
Received in revised form 29 January 2012
Accepted 14 February 2012
Available online 22 February 2012
sn-glycerol,
a new analog of bioactive ether lipids, was synthesized from oleic acid and 2,3-
isopropylidene-sn-glycerol. The two key steps of this synthesis were the conversion of oleyl aldehyde
to a monounsaturated epoxide using Matteson’s method followed by hydrolytic kinetic resolution and
a nucleophilic epoxide opening by 2,3-isopropylidene-sn-glycerol in the presence of potassium tert-
butoxide in anhydrous DMF, which appeared to be a good reagent for this purpose. Furthermore, the diol
by-product of the HKR process was also easily converted back to the starting epoxide thus almost
doubling the amount of target molecule.
Keywords:
Alkylglycerol
Methyl glyceryl ether
Isopropylideneglycerol
HKR
Ó 2012 Elsevier Ltd. All rights reserved.
Epoxide opening
1. Introduction
strengthening and wound healing. Later in the 20th century, bene-
ficial effects on health of SLO were attributed to 1-O-alkylglycerols,
Natural 1-O-alkylglycerols 1 are bioactive ether lipids, which are
present in various human cells but only in trace quantities. On the
contrary, the liver oil of some sharks species and of rat fish (elas-
mobranch fishes) are rich natural sources and for instance, shark
liver oil (SLO) contains 20e25% of 1-O-alkylglycerols as diesters 2
and phospholipids 3 but as a mixture of a few species varying by
length and unsaturation of the alkyl chain.1 It was established that
the alkyl chain is bound to the glycerol backbone at the sn-1 po-
sition thus leading to an S configuration at the asymmetric carbon.2
which were found to display several useful properties such as stim-
ulating hematopoiesis,3 lowering radiotherapy-induced injuries,4
reducing tumor growth,5 and improving vaccination efficiency.6,7
Biological testing has been done on natural sources, which are com-
plex mixtures and for which separation of individual components
would be tedious. To assess the biological activity of each individual
1-O-alkylglycerol, Legrand et al. recently reported the antitumor ac-
tivity (against lung cancer in mice) of each of the six prominent
components 4e9 of the natural mixture.8e10 These derivatives have
been obtained in pure form by total synthesis and it was observed
that the activity was strongly depending upon the saturation of the
alkyl chain. When this chain was saturated, corresponding 1-O-
alkylglycerols 4e7 exhibited little or no activity while it was mono-
unsaturated, a good antitumor activity has been observed for 8 and 9
thus indicating that the antitumor activity of the natural SLO mixture
was strongly related to its unsaturated components.
O
O
R2
O
R2
O
OH
O-
P
R1
O
OR
O
O
OR
HO
OR
+
Me3N
(S)
O
O
2
1
3
R: linear alkyl chain, saturated or monounsaturated
R1, R2 = linear alkyl chain from a fatty acid
OH
4-7: simple bond, n = 1,3,5,7
8,9: double bond, n = 5,7
n
O
OH
In traditional medicine of countries, which are strongly implied in
fishing such as Japan, Norway, and Iceland, SLO had been used for
In SLO from Greenland, were also identified small amounts
(2e4%) of 1-O-alkylglycerols with an additional methoxy group in
the 2-position (methyl glyceryl ethers: MGE) and containing
* Corresponding author. Tel./fax: þ33 2 23 23 69 78; e-mail address: paul.mos-
set.1@univ-rennes1.fr (P. Mosset).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.033

2974
R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
saturated and unsaturated alkyl chains from 14 to 22 carbon
OMe
OH
atoms.11e13 Among the four possible stereoisomers, Stallberg has
€
O
OH
established that the natural product had the 20R,2S configuration by
comparison of 1H NMR spectra and optical rotations with those of
each stereoisomer of 1-O-(20-methoxyhexadecyl)glycerol 10 pre-
pared by chemical synthesis.14 The most abundant MGE (20R,2S)-11
(2'R,2S)-13
was found to have 16 carbon atoms in the alkyl chain and a
D4
unsaturation.11 A higher homolog (20R,2S)-12 with a 18 carbon
atoms alkyl chain was also identified as well as the saturated de-
rivative (20R,2S)-10. MGE isolated from Greenland SLO was able to
inhibit tumor growth and metastasis formation and also to stim-
ulate the immunoreactivity in mice.15,16 Clearly, the presence of
a methoxy group is beneficial to the biological activity thus in-
ducing interest for the synthesis of this kind of valuable lipids.
Initially, a saturated MGE had been synthesized as a mixture of
stereoisomers in racemic form 1011,17 and then the stereoisomer
(20R,2S)-1014,18 in a stereocontrolled manner. Very recently, the
OH
O
O
O
(2'R,2R)-14
O
O
+
HO
O
synthesis of MGE (20R,2S)-11, with a
ported.19 For our part, we had observed the good antitumor prop-
erties of monounsaturated 1-O-alkylglycerols 8 (n-7, 9) and 9 (n-
9,
9).8e10 Therefore, it was expected that a MGE with a mono-
D4 unsaturation was re-
16
R-15
D
D
unsaturated alkyl chain could have an improved biological profile
by combining the favorable properties of the unsaturation and of
the methoxy group. As oleic acid was used as an affordable pre-
cursor in high purity (99%) for the synthesis of bioactive 9, we
became interested in a monounsaturated MGE that would equally
be synthesized from oleic acid, namely (20R,2S)-13 with also a n-9
CHO
17
(D10) double bond and for which we describe herein the total
synthesis.20
oleic acid
Scheme 1. Retrosynthetic analysis.
methylsulfate and 50% aqueous sodium hydroxide under phase-
transfer conditions23 did not afford any epoxide but only non-
polar by-products were formed probably due to a facile enoliza-
tion of the methylene group vicinal to the aldehyde. Moreover, it has
been reported later that reaction of an aliphatic aldehyde with
a sulfur ylide under phase-transfer conditions failed to give any
epoxide when there are two hydrogen atoms
a
to the aldehyde.24
Thereafter, we were able to react oleyl aldehyde 17 with samar-
ium and diiodomethane25 to obtain the iodohydrin 18, which was
easily converted to the epoxide rac-15 upon reaction with potassium
carbonate in methanol. Unfortunately, the overall yield of this
conversion was too low (17%). In fact, an efficient way to obtain the
epoxide rac-15 was the reaction of in situ generated (chloromethyl)
lithium by the method of Matteson:26 addition of methyllithium/
lithium bromide to a mixture of aldehyde and chloroiodomethane in
THF at low temperature (63% yield) (Scheme 2).
2. Results and discussion
Resolution of epoxide rac-15 could be done by hydrolytic kinetic
resolution (HKR). Initially, we have used Jacobsen’s method with
a (salen)cobalt(III) complex22 as a catalyst. After that to expedite the
reaction, we have been used another catalyst, a bimetallic (salen)
cobalt(II)eindium(III) complex developed by Geon-Joong Kim
et al.27 (Scheme 3). The latter method presented several advantages:
easier handling of the catalyst, faster reaction (overnight versus 3
days) and it was reported to afford a higher enantioselectivity
(generally well above 99%).27,28 The desired R enantiomer of 15 was
obtained by use of the R,R enantiomer of the catalyst. It was easily
separated by chromatography from the far more polar diol S-19.
HKR using Jacobsen’s method afforded 47% R-15 and 42% S-19. HKR
using the bimetallic complex afforded 50% R-15 and 48% S-19.
The nucleophilic opening of an epoxide by the primary alcohol
group of 2,3-isopropylidene-sn-glycerol 16 was first investigated by
the reaction of an analogous model epoxide, (R)-1,2-
The retrosynthetic analysis of (20R,2S)-13 indicates that the
molecule can be constructed via a regioselective opening of the
epoxide R-15 by the primary alcohol group of 2,3-isopropylidene-
sn-glycerol 16 leading to the secondary alcohol (20R,2R)-14, which
upon methylation followed by acetonide cleavage, would afford the
target (20R,2S)-13. Optically active epoxide R-15 would be obtained
by resolution of the racemic epoxide by Jacobsen’s method, which
is applicable to terminal epoxides.22 The unknown racemic epoxide
rac-15 would be obtained from oleyl aldehyde 17 by a one-carbon
homologation method such as reaction with a sulfur ylide for in-
stance (Scheme 1).
Oleyl aldehyde 17 was obtained by a classical two-step sequence.
Highly pure (99%) oleic acid was reduced to oleyl alcohol by Red-Al
in THFand this alcohol was oxidized by PCC in dichloromethane. The
attempted epoxidation of oleyl aldehyde with trimethylsulfonium

R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
2975
O
c
rac-15
OH
CHO
d
I
a, b
oleic acid
f
18
17
e
O
rac-15
Scheme 2. Synthesis of monounsaturated epoxide rac-15. Reagents and conditions: (a) Red-Al (1.7 equiv), THF, ca. 10 ꢀC to rt, until clear, 97%; (b) PCC (1.5 equiv), CH2Cl2, 1 h, rt, 75%;
(c) Me3SþMeSOꢁ4 , 50% aqueous NaOH, CH2Cl2; (d) Sm (2 equiv), CH2I2 (3 equiv), THF, 0 ꢀC, addition in 10 min then 20 min, 43%; (e) K2CO3 (1.4 equiv), MeOH, rt, 10 min, 39%; (f)
ClCH2I (2 equiv), MeLi$LiBr (1.5 equiv), THF, ꢁ80 ꢀC then rt, 17 h, 63%.
OH
O
OH
0.55 equiv H2
O
rac-15
+
cat*
S-19
R-15
t-Bu
t-Bu
H
H
N
N
O
O
N
Co
cat*:
O
Co
N
or
t-Bu
t-Bu
O
t-Bu
InCl3
OAc
t-Bu
t-Bu
t-Bu
(R,R)-salen Co(III)OAc
2
(R,R)-salen Co(II)-In(III)
Scheme 3. Resolution of epoxide 15 by HKR.
epoxyhexadecane 20. In the presence of sodium hydroxide29 and of
tetra-n-butylammonium bromide (1 equiv) in DMSO for 30 h at
45 ꢀC, the expected opened product 21 was obtained in 40% yield
along with a less polar by-product 22 (23%) arising from a sub-
sequent epoxide opening by the secondary alcohol 21 (Scheme 4).
expected product (20R,2R)-14 but instead by-product 23, which is
the unsaturated analog of 22 (Scheme 5).
Therefore we turned back to anhydrous conditions using so-
dium hydride in DMF. In fact, the reaction needed to be performed
above room temperature (35 ꢀC) with an appropriate dilution to
CH3(CH2)13
OH
O
O
O
O
O
NaOH
O
O
+
OH
CH3(CH2)13
O
O
CH3(CH2)13
+
CH3(CH2)13
HO
O
DMSO
n-Bu4NBr
21
20
22
16
Scheme 4. Model nucleophilic opening of (R)-1,2-epoxyhexadecane 20 by 2,3-isopropylidene-sn-glycerol 16.
Surprisingly, applying the previous conditions (KOH/n-Bu4NBr
cat. in DMSO at 35 ꢀC for 60 h) to unsaturated epoxide R-15 affor-
ded the corresponding diol 19 by hydrolysis30 with no evidence of
achieve after 2 days, a good conversion to the expected opened
product 14. Interestingly under these conditions, no by-product 23
resulting from a subsequent epoxide opening was observed
(2'R,2R)-14
OH
OH
O
OH
O
KOH
O
O
+
+
HO
O
O
O
DMSO
n-Bu NBr
16
R-15
19
23
Scheme 5. Unsuccessful initial attempt of synthesis of (20R,2R)-14.

2976
R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
although the yield was fair (only 35%, Scheme 6, step a). It is worthy
of note that alcohol (20R,2R)-14 was obtained as a single di-
astereoisomer with no trace of another isomer being detected by
NMR. This result is a very good indication that R-15 was obtained
with a high optical purity after HKR.
As it has been reported that the optical rotations of the four
diastereoisomers of the saturated MGE 10 were noticeably differ-
ent, those of the MGE (20R,2S)-13 were compared assuming that the
nature of the alkyl chain (insaturated or not) would not have
a noticeable influence on the order of magnitude. In a chlorinated
OH
O
O
O
O
d
a or b
R-15
(2'R,2R)-14
OMe
O
O
c
(2'R,2S)-13
(2'R,2R)-14
(2'R,2R)-24
Scheme 6. Conversion of epoxide R-15 to monounsaturated MGE (20R,2S)-13. Reagents and conditions: (a) NaH (5 equiv), 2,3-isopropylidene-sn-glycerol 16 (1.25 equiv), DMF, 0 ꢀ
C
then 2 days at 35 ꢀC, 35%; (b) KOt-Bu (2.21 equiv), 2,3-isopropylidene-sn-glycerol 16 (1.53 equiv), DMF, 5 ꢀC, 3 days, 40% (plus 25% recovered R-15); (c) KOH (6 equiv), n-Bu4NBr
(0.55 equiv), MeI (5 equiv), DMSO, 21 h, darkness, ca. 20 ꢀC, 87%; (d) p-TsOH$H2O (0.05 equiv), MeOH/H2O 10:1, 60 ꢀC, 3 h, 80%.
The secondary alcohol function could be methylated using
practical conditions such as iodomethane and potassium hydroxide
in DMSO in the presence of tetra-n-butylammonium bromide
affording methyl ether (20R,2R)-24 in 87% yield (Scheme 6, step c).
Easy acetonide cleavage under acid conditions (0.05 equiv p-tol-
uenesulfonic acid monohydrate in MeOH/H2O 10:1) afforded the
targeted monounsaturated MGE (20R,2S)-13 in 80% yield (Scheme 6,
step d).
solvent (chloroform or dichloromethane),31 the values for our
material and for the saturated analog (20R,2S)-10 were found to be
very close. This is in agreement with the 20R,2S stereochemistry of
(20R,2S)-13 (Table 2). In THF, the values are less close but of the
same order of magnitude and more importantly of opposite signs,
in agreement with literature data for 1-O-alkylglycerols.14
Table 2
All compounds gave spectroscopic properties (1H and 13C NMR
as well as correlation spectra) in full accordance with their struc-
ture. In particular for 1H NMR of the three last compounds of this
synthesis, the presence of the electronegative oxygen atom induces
the observation of eight protons at a lower field (from 3.3 to
4.3 ppm). Due to the proximity of the methoxy group to the ether
linkage, these eight protons could be distinguished and assigned.
Their chemical shifts and coupling constants are given in Table 1
and are in full agreement with those reported for analogous com-
Comparison of optical activity data for (20R,2S)-13 and (20R,2S)-10
Compound
(20R,2S)-13a
(20R,2S)-10
[a
]
ꢁ3.2 (c 1, CH2Cl2)
ꢁ2.6 (c 1.3, CHCl3)b
ꢁ3.0 (c 0.89, CHCl3)c
þ3.4 (c 5, THF)b
D
þ1.9 (c 1, THF)
a
b
c
Present study.
According to Ref. 14.
According to Ref. 19.
For each of the three last products of this synthesis, namely for
pounds with an unsaturation is another position (
D
D4 instead of
(20R,2R)-14, (20R,2R)-24, and (20R,2S)-13, 13C NMR in particular
showed one set of signals, which led us to think that these com-
pounds were obtained as single diastereoisomers as the reflect of
the high optical purity of R-15, which was obtained after HKR. To
make sure of this point and demonstrate that NMR is capable to
distinguish the other diasteroisomer (with an inverted configura-
tion at the 20 carbon), the three last steps were performed using
racemic epoxide rac-15 instead of R-15. But attempted reaction of
rac-15 with 2,3-isopropylidene-sn-glycerol 16 in the presence of
sodium hydride in anhydrous DMF did not afford any expected
product (Scheme 7, step a). This type of reaction was already dif-
ficult with R-15 likely due to the insolubility of sodium hydride,
which hampers the formation of the sodium alkoxide of 16. It came
10).19 Emphasis could be done on the geminal coupling constants.
For the methylene protons, which are vicinal to the ethereal oxy-
gen, they are about 10 Hz. In the acetonide unit, the geminal cou-
pling constants are lowered to 8.3 Hz by the cycle effect. As it could
be expected for the MGE (20R,2S)-13, this value is increased to
11.5 Hz due to the acyclic diol form.
Table 1
1H NMR parameters of protons, which are
a
to an oxygen atom
Compound
d
(ppm)
J (Hz)
0
0
0
0
0
0
0
0
0
0
0
H1
H2
H1
H2
H3
J1e1
J1e2
J1 e1
J1 e2
J2 e3
J3 e3
a
(20R,2R)-14
(20R,2R)-24
(20R,2S)-13b
3.33 and 3.53
3.48 and 3.52
3.48 and 3.57
3.79
3.31
3.33
3.56 and 3.56
3.49 and 3.57
3.54 and 3.61
4.28
4.27
3.86
3.74 and 4.06
3.76 and 4.06
3.63 and 3.70
9.7
10.3
10.5
3.0 and 8.1
4.2 and 5.9
3.5 and 6.0
?
5.2 and 5.5
5.4 and 5.8
3.8 and 6.3
6.4 and 6.5
6.3 and 6.4
3.9 and 5.2
8.3
8.3
11.5
10.0
10.2
a
Coupling constant was not seen since the two protons H1 are equivalent.
After exchange with D2O to suppress coupling with protons of hydroxyls (see Supplementary data).
b

R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
2977
a
OH
O
O
O
O
O
b
+
HO
O
16
rac-15
(2'R,2R)-14 + (2'S,2R)-14
1:1 mixture
OMe
OH
OMe
O
O
OH
O
O
d
c
(2'R,2R)-14 + (2'S,2R)-14
1:1 mixture
(2'R,2S)-13 + (2'S,2S)-13
(2'R,2R)-24 + (2'S,2R)-24
1:1 mixture
1:1 mixture
Scheme 7. Conversion of racemic epoxide R-15 to a 1:1 mixture of diastereoisomeric MGEs (20R,2S)-13 and (20S,2S)-13. Reagents and conditions: (a) NaH (5 equiv), 2,3-
isopropylidene-sn-glycerol 16 (1.25 equiv), DMF, 0 ꢀC then 35 ꢀC, 60 h, 0%; (b) KOt-Bu (2.5 equiv), 2,3-isopropylidene-sn-glycerol 16 (1.5 equiv), DMF, 5 ꢀC, 2.5 days, 50% (plus
23% recovered rac-15); (c) KOH (6 equiv), n-Bu4NBr (0.55 equiv), MeI (5 equiv), DMSO, 21 h, darkness, ca. 20 ꢀC, 87%; (d) p-TsOH$H2O (0.05 equiv), MeOH/H2O 10:1, 60 ꢀC, 3 h, 80%.
to the idea to use instead potassium tert-butoxide whose solubility
in DMF is quite good and which would be sufficiently basic to
generate potassium alkoxide of 16. To our delight, potassium tert-
butoxide efficiently mediated the reaction of rac-15 with 16
affording cleanly a 1:1 mixture of (20R,2R)-14 and (20S,2R)-14 in ca.
40% yield after 3 days at 5 ꢀC (the remaining was almost only
unreacted epoxide, Scheme 7, step b).32,33 Under the same condi-
tions, the reaction of R-15 with 16 also efficiently afforded (20R,2R)-
14 (Scheme 6, step b). Further reason of this success is that both
potassium tert-butoxide and tert-butanol, which is generated are
not sufficiently nucleophilic by themselves to open the epoxide. It is
noteworthy that for this 1:1 mixture, many carbons were clearly
distinguished by 13C NMR and even several protons by 1H NMR
(Scheme 8). Using the same reaction conditions as previously, the
secondary alcohol was methylated affording a 1:1 mixture of
(20R,2R)-24 and (20S,2R)-24 (Scheme 7, step c), which upon aceto-
nide cleavage gave a 1:1 mixture of (20R,2S)-13 and (20S,2S)-13
(Scheme 7, step d). In the same manner for these two products, the
two diasteroisomers were easily distinguishable by 1H and 13C
NMR. That confirmed the diastereoisomeric purity of (20R,2R)-14,
(20R,2R)-24, and (20R,2S)-13, which have been previously obtained
within of course the limit of detection of high field NMR (ca. 1e2%).
At this point, it also came in mind to assess the optical purity of
diol S-19, which is normally a by-product of the HKR process. The
intended solution was to convert it stereospecifically to epoxide R-
15 or S-15 followed by reaction with 2,3-isopropylidene-sn-glycerol
16 in order to get 14 whose diastereoisomeric purity would reveal
the enantiomeric purity of the epoxide 15 and hence that of the
OH
O
1H, 300.13 MHz, CDCl3, ref. TMS
O
O
1:1 mixture of diastereoisomers
4.40
4.30
4.20
4.10
4.00
3.90
3.80
(ppm)
3.70
3.60
3.50
3.40
3.30
OH
O
O
O
4.40
4.30
4.20
4.10
4.00
3.90
3.80
(ppm)
3.70
3.60
3.50
3.40
3.30
Scheme 8. Comparison of zoomed 1H NMR spectra for protons
a
to oxygen atoms of the 1:1 mixture of diastereoisomeric (20R,2R)-14 and (20S,2R)-14 (top) and (20S,2R)-14 (bottom,
made from diol S-19 and estimated to be of ca. 96% ee, vide supra).

2978
R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
starting diol 19. The primary alcohol function was easily selectively
protected as a benzoate using benzoyl cyanide and a catalytic
amount of triethylamine in dichloromethane yielding the mono-
benzoate S-25 in 76% yield (Scheme 9). The remaining secondary
alcohol function was activated by mesylation under classic condi-
tions affording mesylate S-26 in 97% yield. Treating S-26 by po-
tassium tert-butoxide in methanol cleaved the benzoate moiety
leaving an intermediate potassium alkoxide, which displaced the
nucleofugal mesylate with complete inversion of configuration
affording epoxide R-15 in 98% yield. Polarimetry confirmed the R
configuration of R-15, which was obtained by this process as it was
dextrorotatory like R-15 from HKR. In particular, it afforded an
optical rotation of þ9.2 in toluene compared with þ8.9 for the
epoxide from HKR.34 For a real assessment of its optical purity, it
was reacted with 2,3-isopropylidene-sn-glycerol 16 in the presence
of potassium tert-butoxide in anhydrous DMF. The alcohol (20R,2R)-
14, which was obtained contained a difficultly detectable amount of
ca. 2% (20S,2R)-14 (estimated by integration of protons at 3.31 and
3.33 ppm), which afforded ca. 96% ee for epoxide R-15 and starting
diol S-19.
through a column of a drying resin or by distilling over Na/ben-
zophenone. Anhydrous DMF over molecular sieves was used as
commercially supplied (Acros). Room temperature (rt) means
a temperature generally in the interval 15e20 ꢀC. Basic alumina,
which was used for column chromatographies was purchased from
Fluka. TLC plates were visualized by UV inspection followed by
staining with an acidic ethanolic solution of p-anisaldehyde or with
a solution of phosphomolybdic acid (5 g in 100 mL 95% ethanol). IR
spectra were measured as films between KBr plates for liquids or as
KBr disks for solids on a Thermo Nicolet Avatar 250 FTIR spec-
trometer. 1H NMR spectra (400.13 and 300.13 MHz) and 13C NMR
spectra (100.61 and 75.47 MHz) were recorded on Avance 400 and
300 Bruker spectrometers using TMS as an internal standard. Op-
tical rotations were measured using a Perkin Elmer 341 polarimeter
(concentration in g/100 mL). High-resolution mass spectra were
recorded using a MicrO-Tof-Q II spectrometer under electrospray
using methanol as solvent. Microanalyses were performed with
a CHNS analyzer. 2,3-Isopropylidene-sn-glycerol 16 (ꢂ95% pure)
was purchased from Alfa Aesar.
OH
OH
(S)
OCOPh
OH
a
S-25
S-19
OMs
(R)
O
OCOPh
c
b
S-25
S-26
R-15
Scheme 9. Conversion of HKR by-product, diol S-19 into epoxide R-15. Reagents and conditions: (a) PhCOCN (1.25 equiv), Et3N (0.4 equiv), CH2Cl2, 0 ꢀC, 40 min, 76%; (b) MsCl
(1.9 equiv), Et3N (2.5 equiv), CH2Cl2, ꢁ40 ꢀC to ꢁ10 ꢀC, 55 min, 97%; (c) KOt-Bu (1.96 equiv), MeOH, ca. 20 ꢀC, 40 min, 98%.
It is worth of note that by this easily performed three-step se-
quence, the diol of HKR process could be efficiently converted to
epoxide with the same configuration of the one, which is at first
produced and also with a good optical purity. The diol, which has
been otherwise regarded as a useless by-product is then valorised.
Additionally, it almost doubles the amount of optically active ep-
oxide, which is obtained by HKR.
4.2. Synthesis of oleyl alcohol
In a flamed-dried three-necked flask were introduced oleic acid
(20 g, 99% pure, 70.1 mmol) and anhydrous THF (175 mL). Under N2,
this solution was cooled to ca. 10 ꢀC by an ice/water bath and a ca.
3.4 M solution of Red-Al in toluene (35 mL, 1.7 equiv) was added
dropwise in ca. 80 min (using a syringe pump or manually if nec-
essary when the Red-Al is too viscous). Escape of hydrogen was
noticed when adding the first 0.5 equiv of Red-Al. The resulting
white suspension was left under moderate stirring. The progress of
the reduction was easy to follow with the gradual disappearance of
the white precipitate of carboxylate. The reduction was finished
when the reaction mixture became clear: after at least 4 h. It was
observed that the reaction time was longer when aged Red-Al was
used but the reaction was always complete after overnight. The
reaction was cooled by an ice/water bath and petroleum ether
(210 mL) was added. When the temperature had dropped to ca.
8 ꢀC, distilled water (ca. 0.5 mL) was added dropwise with caution
to destroy excess Red-Al (vigorous escape of hydrogen). A 10%
aqueous solution of citric acid was added (175 mL). Stirring at rt
was continued until the upper phase (organic), which was initially
turbid became clear (in ca. 30 min). The aqueous phase was
extracted with petroleum ether (4ꢃ100 mL). Combined organic
phases were dried (Na2SO4) and concentrated. To remove all sol-
vents (including toluene and 2-methoxyethanol arising from Red-
Al) with efficiency, the crude oily product was solidified by stand-
ing in a freezer. Then, it was put under high vacuum while slowly
warming up (thermal isolation). These operations were repeated
until boiling was no longer observed on the product during melting.
The crude product (19.07 g) was sufficiently pure oleyl alcohol for
the next reaction. Reaction on a smaller scale followed by purified
3. Conclusion
In summary, we developed a synthesis of a new unsaturated
methyl glyceryl ether, analog of known antitumor derivatives in
seven steps from oleic acid. A key intermediate was an unsaturated
fatty alkyl epoxide, which was suitably synthesized using Matte-
son’s method and efficiently resolved through HKR process. An-
other critical step was the nucleophilic opening of this epoxide by
2,3-isopropylidene-sn-glycerol. Potassium tert-butoxide was
showed to be a useful reagent for this reaction with excellent
chemoselectivity (primary alcohol of the reactant versus secondary
alcohol of the product) being observed in DMF. By an easy and ef-
ficient three-step sequence, the diol of an HKR process could be
converted to the epoxide with the same configuration than the
resolved one. That both valorise the diol and almost double the
amount of optically active epoxide, which was obtained by HKR.
4. Experimental
4.1. General
Moisture sensitive reactions were performed under nitrogen.
Anhydrous THF and diethyl ether were obtained by percolating

R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
2979
by chromatography on a column of silica gel afforded purified oleyl
alcohol in 97% yield. Rf 0.30 (petroleum ether/acetone 9:1). 1H NMR
silica gel afforded epoxide rac-15 as a colorless oil, which solidified
in the cold (23.8 mg, 39%). Rf 0.63 (petroleum ether/acetone 19:1).
(400 MHz, CDCl3):
d
¼5.40e5.30 (m, 2H, CH]CH), 3.64 (t, J¼6.7 Hz,
2H, CH2OH), 2.08e1.96 (m, 4H, CH2CH]CHCH2), 1.56 (tt, J¼7.2,
6.7 Hz, 2H, CH2CH2OH), 1.51e1.41 (br s, 1H, OH), 1.40e1.21 (m, 22H,
CH3(CH2)6CH2CH]CHCH2(CH2)5CH2CH2OH), 0.88 (pseudo t,
4.5.2. Using Matteson’s method. A solution of chloroiodomethane
(353 mg, 2 mmol, 2 equiv) and oleyl aldehyde 17 (266.5 mg,
1 mmol) in anhydrous THF (4 mL) was cooled to ꢁ80 ꢀC. Methyl-
lithium lithium bromide complex (2.2 M) in diethylether (0.7 mL,
1.5 equiv) was added dropwise. The mixture was allowed to warm
to rt and left 17 h at rt. Brine was added and epoxide rac-15
(colorless oil, 177 mg, 63%) was purified by chromatography on
basic alumina (2.5 g, 0/0.2% acetone in petroleum ether). Alter-
natively on a bigger scale (from 3 g oleyl aldehyde), the epoxide
was purified by chromatography on silica gel (15 g, 0.1% triethyl-
amine in petroleum ether). IR (film) nmax 3041, 3003, 2924, 2854,
J¼6.8 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d
¼129.97 and
129.83 (CH]CH), 63.07 (CH2OH), 32.80 (CH2), 31.92 (CH2), 29.78
(CH2), 29.76 (CH2), 29.54 (CH2), 29.52 (CH2), 29.43 (CH2), 29.34 (2
CH2), 29.25 (CH2), 27.22 (CH2), 27.20 (CH2), 25.75 (CH2), 22.70 (CH2),
14.14 (CH3).
4.3. Synthesis of oleyl aldehyde 17
2730, 1738, 1466, 1258, 723 cmꢁ1 1H NMR (400 MHz, CDCl3):
.
Pyridinium chlorochromate (485 mg, 1 mmol, 1.5 equiv) was
suspended in CH2Cl2 (3 mL) by stirring for 1 min. A solution of oleyl
alcohol (268.5 mg, 1 mmol) in CH2Cl2 (1 mL) was added rapidly.
Transfer was completed by CH2Cl2 (2ꢃ0.5 mL). After 1 h stirring at
rt under N2, tert-butyl methyl ether (10 mL) was added. The
resulting mixture was filtered over a short plug of silica gel with
rinsing of the silica gel by tert-butyl methyl ether. Concentration of
the filtrate and chromatography on silica gel afforded oleyl alde-
hyde as a colorless oil (201 mg, 75%). Rf 0.60 (petroleum ether/ac-
d
¼5.40e5.29 (m, 2H, CH]CH), 2.90 (dddd, J¼5.6, 5.3, 4.0, 2.7 Hz,
1H, CHeO), 2.75 (dd, J¼5.0, 4.0 Hz, 1H, CH2eO), 2.46 (dd, J¼5.0,
2.7 Hz, 1H, CH2eO), 2.07e1.96 (m, 4H, CH2CH]CHCH2), 1.56e1.49
(m, 2H), 1.50e1.40 (m, 2H), 1.40e1.19 (m, 20H), 0.88 (pseudo t,
J¼6.9 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3):
d
¼129.99 and
129.79 (CH]CH), 52.42 (CHeO), 47.15 (CH2eO), 32.50 (CH2), 31.92
(CH2), 29.78 (CH2), 29.73 (CH2), 29.54 (CH2), 29.46 (CH2), 29.43
(CH2), 29.33 (2 CH2), 29.19 (CH2), 27.22 (CH2), 27.18 (CH2), 25.98
(CH2), 22.70 (CH2), 14.13 (CH3).
etone 9:1). 1H NMR (400 MHz, CDCl3):
d
¼9.76 (t, J¼1.9 Hz, 1H,
CHO), 5.40e5.29 (m, 2H, CH]CH), 2.42 (ddd, J¼7.4, 7.3, 1.9 Hz, 2H,
CH2CHO), 2.08e1.94 (m, 4H, CH2CH]CHCH2), 1.69e1.57 (m, 2H,
4.6. Synthesis of (R,Z)-2-(heptadec-8-en-1-yl)oxirane R-15
CH2CH2CHO),
1.39e1.19
(m,
20H,
CH3(CH2)6CH2CH]
CHCH2(CH2)4CH2CH2CHO), 0.88 (pseudo t, J¼6.9 Hz, 3H, CH3). 13C
4.6.1. HKR of rac-15 using Jacobsen’s method. In a 10 mL flask, (R,R)-
(ꢁ)-N,N0-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamino-
cobalt(II) (37.8 mg, 0.062 mmol, 0.01 equiv) and toluene (0.37 mL)
NMR (100 MHz, CDCl3):
d¼202.92 (CHO), 130.06 and 129.71 (CH]
CH), 43.92 (CH2), 31.92 (CH2), 29.78 (CH2), 29.68 (CH2), 29.53 (CH2),
29.34 (CH2), 29.33 (CH2), 29.26 (CH2), 29.15 (CH2), 29.06 (CH2),
27.23 (CH2), 27.16 (CH2), 22.69 (CH2), 22.09 (CH2), 14.12 (CH3).
were introduced followed by acetic acid (7.5 mL, 0.13 mmol,
0.02 equiv). The mixture was stirred upon air exposure for 1 h. It was
concentrated and put under high vacuum to remove toluene and
acetic acid. The remaining brown oil was redissolved in anhydrous
diethyl ether (1.85 mL) and added to rac-15 (1.751 g, 6.24 mmol)
4.4. Synthesis of (Z)-1-iodononadec-10-en-2-ol 18
followed by distilled water (62
was purged under nitrogen, stoppered, and left under stirring for 3
days at rt. -Ascorbic acid (15 mg, 2 equiv versus catalyst) was added
and stirring was continued for 1 h. Dark brown catalyst was reduced
to red salenecobalt(II) complex, which is catalytically inactive.35,36
The mixture was taken up with ethyl acetate, dried (Na2SO4), and
concentrated. Chromatography on silica gel (9 g) afforded epoxide
R-15 (830 mg, 47%, eluted by 0.1% triethylamine in petroleum ether)
followed by diol S-19 (781 mg, 42%, eluted by 5/10% acetone in
petroleum ether).
mL, 3.44 mmol, 0.55 equiv). The flask
To freshly scraped samarium powder (using a lime and a sa-
marium ingot) (150 mg, 1 mmol, 2 equiv), was added via syringe in
10 min under stirring at 0 ꢀC, a solution of 17 (133.2 mg, 0.5 mmol),
diiodomethane (401.5 mg, 1.5 mmol, 3 equiv) in anhydrous THF
(3 mL). The gray samarium was consumed to leave a brown mixture
in 20 min. An aqueous solution of citric acid (500 mg in 4 mL) fol-
lowed by 1 N HCl was added. Extraction with ethyl acetate, washing
with aqueous sodium thiosulfate, drying over Na2SO4, concentra-
tion, and chromatography on silica gel (0/0.5% acetone in petro-
leum ether) afforded iodohydrin 18 as a colorless oil (87 mg, 43%).
Rf 0.24 (petroleum ether/acetone 9:1). 1H NMR (400 MHz, CDCl3):
L
4.6.2. Synthesis of bimetallic (salen)cobalt(II)eindium(III) complex.-
In an oven-dried flask, indium trichloride (91.6 mg, 0.414 mmol)
and anhydrous THF (3 mL) were introduced. Under stirring at
rt, indium trichloride was partially dissolved. A sufficient small
amount of distilled water (ca. 0.006 mL) was added to dissolve
completely and rapidly indium trichloride. (R,R)-(ꢁ)-N,N0-Bis(3,5-di-
tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) (500 mg,
0.828 mmol) was added in three portions. A fast change of color was
observed (from red to dark olive green and then to brown). The bi-
metallic complex precipitated. After 1 h good stirring at rt with the
flask left open in air, the resulting mixture was transferred to a sep-
arating funnel by means of dichloromethane. Water was added and
the separating funnel was vigorously shaked. After this washing with
water, the color changed from brown to dark olive green, which are
the respective colors of the bimetallic complex in THF and in
dichloromethane. The organic phase was withdrawn and rapidly
filtered over a short plug of silica gel (height: about 2 cm) with
rinsing of the silica gel by dichloromethane. The filtrate was con-
centrated and the remaining very fine olive green crystalline powder
d
¼5.40e5.29 (m, 2H, CH]CH), 3.51 (br ddddd, J¼6.8, 6.1, 6.1, 5.3,
3.5 Hz, 1H, CHOH), 3.39 (dd, J¼10.1, 3.5 Hz, 1H, CH2I), 3.23 (dd,
J¼10.1, 6.8 Hz, 1H, CH2I), 2.07e1.97 (m, 4H, CH2CH]CHCH2), 1.94
(br d, J¼5.3 Hz, 1H, OH), 1.57e1.51 (m, 2H, CH2CHOH), 1.40e1.19 (m,
22H, CH3(CH2)6CH2CH]CHCH2(CH2)5), 0.88 (pseudo t, J¼6.9 Hz,
3H, CH3). 13C NMR (100 MHz, CDCl3):
d¼130.00 and 129.77 (CH]
CH), 70.99 (CH), 36.61 (CH2), 31.91 (CH2), 29.77 (CH2), 29.72 (CH2),
29.53 (CH2), 29.43 (CH2), 29.40 (CH2), 29.33 (2 CH2), 29.19 (CH2),
27.22 (CH2), 27.18 (CH2), 25.68 (CH2), 22.70 (CH2), 16.87 (CH2I),
14.14 (CH3).
4.5. Synthesis of (Z)-2-(heptadec-8-en-1-yl)oxirane rac-15
4.5.1. Using 18. Potassium carbonate (42 mg, 0.303 mmol,
1.4 equiv) was added to a solution of iodohydrin 18 (88.4 mg,
0.216 mmol) in methanol (1.73 mL). After 10 min vigorous stirring,
15% aqueous NaCl (3.2 mL) was added. Extraction with petroleum
ether, drying (Na2SO4), concentration, and chromatography on

2980
R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
was put under vacuum to afford bimetallic (salen)cobalt(II)eindiu-
m(III) 2:1 complex (0.5413 g, 92%).
isopropylidene-sn-glycerol 16 (211 mg, 1.55 mmol, 1.5 equiv) in
DMF (0.33 mL) was added dropwise followed by DMF (2ꢃ0.2 mL) to
complete the transfer of 16. After 10 min stirring at 0 ꢀC, a solution
of epoxide R-15 (290 mg, 1.033 mmol) in DMF (0.4 mL) was added
to the resulting white suspension. Transfer of R-15 was completed
by rinsing with DMF (2ꢃ0.2 mL). This mixture was left under good
stirring at 30 ꢀC for 48 h. It was diluted with distilled water (5 mL)
and extracted with petroleum ether/ethyl acetate 4:1. After drying
(Na2SO4) and concentration, chromatography on basic alumina
(twice 3 g, 0/5% acetone in petroleum ether) afforded the oily
acetonide (20R,2R)-14 (148 mg, 35%). Rf 0.35 (petroleum ether/ac-
etone 9:1). IR (film) nmax 3458, 2925, 2854, 1466, 1458, 1379, 1370,
1257, 1214, 1098, 1057, 845, 723 cmꢁ1. 1H NMR (400 MHz, CDCl3):
4.6.3. HKR of rac-15 using a bimetallic (salen)cobalt(II)eindium(III)
complex. To a stirred mixture of rac-15 (3.847 g, 16 mmol) and bi-
metallic
0.048 mmol, 0.003 equiv) in anhydrous THF (8 mL), distilled water
(159 L, 8.8 mmol, 0.55 equiv) was added. The flask was purged
under nitrogen, stoppered, and left under stirring for 24 h at 25 ꢀC.
-Ascorbic acid (40 mg) was added and stirring was continued for
(salen)cobalt(II)eindium(III)
complex
(68.6 mg,
m
L
1 h (ascorbic acid presumably complexed InCl3 of the bimetallic
catalyst converting it to the red salenecobalt(II) complex).37 After
concentration of the resulting suspension (crystalline diol pre-
cipitated), chromatography on silica gel (13 g) afforded epoxide R-
15 (1.9247 g, 50%) followed by diol S-19 (1.965 g, 48%). After elution
of epoxide and before that of diol, elution with 1% and 2% acetone in
pentane afforded a small amount (19.2 mg) of a by-product, which
was identified as a chlorohydrin, (Z)-1-chlorononadec-10-en-2-ol
arising by opening of the epoxide by the chloride ions of the bi-
metallic catalyst.
d
¼5.40e5.29 (m, 2H, CH]CH), 4.28 (dddd, J¼6.5, 6.4, 5.5, 5.2 Hz,
1H), 4.06 (dd, J¼8.3, 6.5 Hz, 1H), 3.83e3.75 (m, 1H), 3.74 (dd, J¼8.3,
6.4 Hz, 1H), 3.56 (d, J¼5.4 Hz, 2H), 3.53 (dd, J¼9.7, 3.0 Hz, 1H), 3.33
(dd, J¼9.7, 8.1 Hz, 1H), 2.8e2.0 (br envelope, 1H, OH), 2.06e1.97 (m,
4H), 1.51e1.38 (m, 2H), 1.43 (q, J¼0.4 Hz, 3H, CH3), 1.37 (q, J¼0.4 Hz,
3H, CH3), 1.38e1.19 (m, 22H), 0.88 (pseudo t, J¼6.9 Hz, 3H). 13C NMR
(100 MHz, CDCl3):
d¼129.96 and 129.83 (CH]CH), 109.51 (CMe2),
Physical data for R-15: 1H and 13C NMR were identical to those of
76.20 (CH2), 74.72 (CHeO), 72.25 (CH2), 70.32 (CHOH), 66.57 (CH2),
33.02 (CH2), 31.92 (CH2), 29.78 (CH2), 29.76 (CH2), 29.66 (CH2),
29.53 (CH2), 29.47 (CH2), 29.33 (2 CH2), 29.25 (CH2), 27.22 (CH2),
27.20 (CH2), 26.73 (CeCH3), 25.52 (CH2), 25.38 (CeCH3), 22.69
20
20
20
20
20
rac-15. [
a
]
þ8.9, [
a
]
þ9.2, [
a]
þ10.4, [
a]
þ16.3, [
a]
D
578
546
436
365
þ22.3 (c 4.00, toluene).
20
20
20
4.6.3.1. Data of the chlorohydrin by-product, (Z)-1-
chlorononadec-10-en-2-ol. Rf 0.39 (petroleum ether/acetone 9:1).
(CH2), 14.13 (CH3). [
(c 3.03, CHCl3). [
a
]
20 ꢁ8.9, [
a
]
578 ꢁ9.4, [
a
]
546 ꢁ10.7, [ 436 ꢁ18.5
a
]
D
20
20
20
20
a
]
ꢁ7.5, [
a
]
ꢁ8.9, [
a
]
ꢁ9.9, [
a]
ꢁ16.2 (c
D
578
546
436
1H NMR (300 MHz, CDCl3):
d
¼5.42e5.28 (m, 2H, CH]CH),
1.40, acetone). HRMS (ESI) calcd for C25H48O4Na [MþNa]þ
3.87e3.74 (envelope, which centered at 3.80 ppm, 1H, CHOH), 3.64
(dd, J¼11.1, 3.2 Hz, 1H, CH2Cl), 3.48 (dd, J¼11.1, 7.2 Hz, 1H, CH2Cl),
2.25e2.08 (very br d, which centered at 2.14 ppm, J¼2.1 Hz, 1H,
OH), 2.08e1.92 (m, 4H, CH2CH]CHCH2), 1.60e1.17 (m, 24H), 0.88
435.3448, found 435.3449.
4.8.2. Using potassium tert-butoxide. In a flame-dried 25 mL two-
necked flask, potassium tert-butoxide (405 mg, 3.54 mmol,
2.21 equiv) was mostly dissolved in anhydrous DMF (3.2 mL) by
stirring under nitrogen for 5e10 min at rt. After cooling down to
0 ꢀC by an ice bath, 2,3-isopropylidene-sn-glycerol 16 (341.5 mg,
ꢂ95% pure, 2.45 mmol, 1.53 equiv) was added dropwise followed
by rinsing with anhydrous DMF (2ꢃ0.32 mL) to complete the
transfer of 16. A solution of epoxide R-15 (449 mg, 1.6 mmol) in
anhydrous DMF (0.5 mL) was then added dropwise. Transfer of R-15
was completed by rinsing with anhydrous DMF (2ꢃ0.4 mL). The
two necks of the reaction flask were well stoppered and this one
was left aside in a refrigerator at 5 ꢀC for 3 days. It was diluted with
distilled water plus little brine and extracted with pentane plus
ethyl acetate. Organic extracts were washed with little water and
dried (Na2SO4). After concentration, the residue was put at the
pump and chromatographied on florisil (60e100 mesh, 6 g). Ep-
oxide R-15 was eluted by 0/1% acetone in pentane (110.5 mg,
25%). Then, elution by 2/5% acetone in pentane afforded alcohol
(20R,2R)-14 as a colorless oil (264 mg, 40%), which solidified to give
a white crystallized solid on storage in a freezer. Mp: ꢁ0.5 ꢀC. It
contained a small amount of less polar by-product 23, which had
not been possible to separate by chromatography on florisil. On the
contrary, it had been possible to separate the by-product 23
(identical with the by-product of another reaction which is showed
in Scheme 5) by chromatography on basic alumina (8 g) and to
quantify it (9.5 mg, 2%). However, use of florisil was preferred as
some loss of (20R,2R)-14 was suspected after chromatography on
basic alumina.
(pseudo t, J¼6.7 Hz, 3H, CH3). 13C NMR (75 MHz, CDCl3):
¼130.01
d
(CH]CH), 129.78 (CH]CH), 71.46 (CHOH), 50.62 (CH2Cl), 34.23
(CH2), 31.92 (CH2), 29.78 (CH2), 29.73 (CH2), 29.53 (CH2), 29.48
(CH2), 29.40 (CH2), 29.33 (2 CH2), 29.20 (CH2), 27.23 (CH2), 27.18
(CH2), 25.53 (CH2), 22.70 (CH2), 14.13 (CH3).
4.7. Synthesis of (S,Z)-nonadec-10-ene-1,2-diol S-19
White crystals. Mp: 44 ꢀC (petroleum ether). Rf 0.05 (petroleum
ether/acetone 19:1). IR (KBr) nmax 3382 (br, OeH), 2998, 2955, 2924,
2918, 2849, 1468, 1081, 865, 721 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d¼5.41e5.29 (m, 2H, CH]CH), 3.74e3.67 (well resolved m after
exchange with D2O, 1H, CHOH), 3.65 (dd after exchange with D2O,
J¼11.0, 3.0 Hz, 1H, CH2OH), 3.42 (dd after exchange with D2O,
J¼11.0, 7.7 Hz, 1H, CH2OH), 2.07e1.96 (m, 4H, HeC9, 12), 2.18 (br s,
1H, OH), 2.09 (br s, 1H, OH), 1.51e1.38 (m, 3H, HeC3 and 1H of
HeC4), 1.39e1.19 (m, 21H, HeC5,6,7,12,13,14,15,16,17,18 and 1H of
HeC4), 0.88 (pseudo t, J¼6.9 Hz, 3H, HeC19). 13C NMR (100 MHz,
CDCl3):
d
¼129.99 and 129.80 (CH]CH), 72.33 (CH), 66.86 (CH2),
33.21 (CH2), 31.92 (CH2), 29.78 (CH2), 29.75 (CH2), 29.62 (CH2),
29.53 (CH2), 29.45 (CH2), 29.33 (2 CH2), 29.23 (CH2), 27.23 (CH2),
27.19 (CH2), 25.55 (CH2), 22.69 (CH2), 14.13 (CH3). [
23
23
a
]
ꢁ1.0, [
a]
D
578
23
23
23
ꢁ1.3, [
a
]
546 ꢁ3.4, [
a]
436 ꢁ4.9 (c 1.50, CH2Cl2). [
a]
23 ꢁ5.9, [
a
]
]
578 ꢁ6.6,
D
23
23
23
[
[
a
]
]
546 ꢁ7.4, [
a
]
a
436 ꢁ12.2, [
a
]
365 ꢁ17.7 (c 3.00, acetone). [
a
22.5 ꢁ7.1,
D
a
22.5 ꢁ8.2, [
]
22.5 ꢁ9.2, [
a
]
22.5 ꢁ14.8, [
a
]
22.5 ꢁ21.0 (c 1.00, acetone).
578
546
436
365
Anal. Calcd for C19H38O2: C, 76.45; H, 12.83. Found: C, 76.17;
H, 12.81.
4.8.2.1. Data of by-product 23. Rf 0.38 (pentane/acetone 9:1). 1H
4.8. Synthesis of (Z)-(20R)-1-O-(20-hydroxynonadec-100-enyl)-
2,3-O-isopropylidene-sn-glycerol (20R,2R)-14
NMR (300 MHz, CDCl3):
d
¼5.42e5.26 (m, 4H, CH]CH), 4.26 (dddd,
J¼6.4, 6.2, 5.6, 5.6 Hz, 1H), 4.06 (dd, J¼8.3, 6.4 Hz, 1H), 3.75 (dd,
J¼8.3, 6.2 Hz, 1H), 3.85e3.65 (m, 1H, CHOH), 3.62e3.43 (m, 6H),
3.35 (dd, J¼10.2, 7.7 Hz, 1H), 3.05e2.72 (br envelope, which topped
at 2.90 ppm [appeared in another sample as a br d at 2.88 ppm with
J¼3.0 Hz], 1H, OH), 2.10e1.94 (m, 8H), 1.42 (q, J¼0.6 Hz, 3H, CH3),
1.36 (q, J¼0.6 Hz, 3H, CH3), 1.54e1.17 (m, 48H), 0.88 (pseudo t,
4.8.1. Using sodium hydride. A 60% dispersion of sodium hydride in
mineral oil (210 mg, 5.2 mmol, 5 equiv) was washed three times
with petroleum ether under argon. Anhydrous DMF (4.85 mL) was
added and the mixture was cooled at 0 ꢀC. A solution of 2,3-

R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
2981
J¼6.7 Hz, 6H). 13C NMR (75 MHz, CDCl3):
d¼129.99 (1CH), 129.94
3.70 (dd after exchange with D2O, br dd at 3.71 ppm before ex-
change with D2O, J¼11.5, 3.9 Hz, 1H), 3.63 (dd after exchange with
D2O, 3.64 ppm before exchange with D2O, J¼11.5, 5.2 Hz, 1H), 3.61
(dd, J¼10.2, 3.8 Hz, 1H), 3.57 (dd, J¼10.5, 3.5 Hz, 1H), 3.54 (dd,
J¼10.2, 6.2 Hz, 1H), 3.48 (dd, J¼10.5, 6.0 Hz, 1H), 3.40 (s, 3H), 3.33
(dddd, J¼6.2, 6.1, 6.0, 3.5 Hz, 1H), 3.05 (envelope from 3.21 to
2.82 ppm, 1H, CHOH), 2.36 (envelope from 2.53 to 2.22 ppm, 1H,
CH2OH), 2.09e1.94 (m, 4H), 1.58e1.40 (m, 2H), 1.40e1.19 (m, 22H),
(1CH), 129.85 (1CH), 129.80 (1CH), 109.42 (1CMe2), 78.99 (1CH),
74.56 (1CH), 74.47 (1CH2), 74.43 (1CH2), 72.31 (1CH2), 70.19 (1CH),
66.79 (1CH2), 33.01 (1CH2), 31.93 (1CH2), 31.92 (2CH2), 29.78
(3CH2), 29.76 (2CH2), 29.73 (1CH2), 29.54 (2CH2), 29.52 (1CH2),
29.48 (1CH2), 29.33 (4CH2), 29.30 (1CH2), 29.26 (1CH2), 27.22
(3CH2), 27.20 (1CH2), 26.77 (CeCH3), 25.71 (1CH2), 25.54 (1CH2),
25.37 (CeCH3), 22.69 (2CH2), 14.13 (2CH3).
0.88 (pseudo t, J¼6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3):
¼129.99
d
4.9. Synthesis of (Z)-(20R)-1-O-(20-methoxynonadec-100-enyl)-
2,3-O-isopropylidene-sn-glycerol (20R,2R)-24
and 129.81 (CH]CH), 80.37 (CH), 73.62 (CH2), 73.40 (CH2), 70.58
(CH), 64.07 (CH2), 57.36 (CH3), 31.92 (CH2), 30.89 (CH2), 29.78
(2CH2), 29.76 (CH2), 29.53 (CH2), 29.49 (CH2), 29.33 (2CH2), 29.25
(CH2), 27.23 (CH2), 27.20 (CH2), 25.35 (CH2), 22.69 (CH2),14.13 (CH3).
To alcohol 14 (219.0 mg, 0.53 mmol) was added tetra-n-buty-
lammonium bromide (94 mg, 0.292 mmol, 0.55 equiv) and DMSO
(0.85 mL) followed after stirring by finely and freshly grounded
potassium hydroxide (210 mg, 3.18 mmol, 6 equiv, w85% KOH) and
20
20
20
20
[
a
]
20 ꢁ3.2; [
a
]
578 ꢁ3.8; [
a
]
546 ꢁ4.2; [
a
]
536 ꢁ6.8; [
a
]
365 ꢁ10.4 (c 1.00,
D
20
20
20
20
CH2Cl2). [
a
]
20 þ1.9; [
a
]
578 þ1.2; [
a
]
546 þ1.4; [
a
]
436 þ2.5; [ 365 þ3.5
a]
D
(c 1.00, THF). HRMS (ESI) calcd for C23H46O4Na [MþNa]þ
iodomethane (165
mL, 2.65 mmol, 5 equiv). The flask was purged
409.32883, found 409.3289.
under nitrogen and stoppered. It was dipped in an ultrasonic bath
while rotating by hand in order to finely divide potassium hy-
droxide, which required 1e2 min. It was wrapped with an alumi-
num foil for protection against light and left under stirring for 21 h
at rt (ca. 20 ꢀC). Distilled water was added and a little bit of sodium
thiosulfate. The resulting mixture was extracted four times with
pentane/ethyl acetate ca. 4:1 and each organic extract was washed
with a little bit of water. Drying (Na2SO4), concentration, and
chromatography on basic alumina (5 g, pentaneþ0.5% Et3N and
then pentaneþ1% acetone) afforded methyl ether (20R,2R)-24 as
a colorless oil (197.1 mg, 87%). Rf 0.62 (pentane/acetone 9:1). IR
(film) nmax 3004, 2925, 2855, 1466, 1458, 1379, 1370, 1256, 1214,
4.11. Synthesis of (Z)-(20R)-1-O-(20-hydroxynonadec-100-enyl)-
2,3-O-isopropylidene-sn-glycerolD(Z)-(20S)-1-O-(20-
hydroxynonadec-100-enyl)-2,3-O-isopropylidene-sn-glycerol
(20R,2R)-14D(20S,2R)-14
Using the same procedure as described for the synthesis of
(20R,2R)-14 (paragraph 4.8.2) with potassium tert-butoxide
(2.5 equiv), 2,3-isopropylidene-sn-glycerol 16 (1.5 equiv), and ep-
oxide rac-15 instead of R-15 in anhydrous DMF at 5 ꢀC for 2.5 days
afforded a 1:1 mixture of (20R,2R)-14 and (20S,2R)-14 (50% plus 23%
recovered rac-15). Rf 0.27 (pentane/acetone 9:1). Mp: ꢁ1.5 ꢀC. 1H
1098, 847, 723 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d¼5.40e5.30 (m,
NMR (300 MHz, CDCl3):
d¼5.41e5.28 (m, 2H, CH]CH), 4.298
2H, CH]CH), 4.27 (dddd, J¼6.4, 6.3, 5.6, 5.5 Hz, 1H), 4.06 (dd, J¼8.3,
6.4 Hz, 1H), 3.76 (dd, J¼8.3, 6.3 Hz, 1H), 3.57 (dd, J¼10.0, 5.4 Hz, 1H),
3.52 (dd, J¼10.3, 5.9 Hz, 1H), 3.49 (dd, J¼10.0, 5.8 Hz, 1H), 3.48 (dd,
J¼10.3, 4.2 Hz, 1H), 3.40 (s, 3H), 3.31 (dddd, J¼6.1, 5.9, 5.9, 4.2 Hz,
1H), 2.05e1.97 (m, 4H), 1.51e1.44 (m, 2H), 1.42 (q, J¼0.6 Hz, 3H,
CH3), 1.36 (q, J¼0.6 Hz, 3H, CH3), 1.40e1.20 (m, 22H), 0.88 (pseudo t,
(dddd, J¼6.5, 6.4, 5.9, 4.8, Hz, 0.5H, S,R), 4.286 (dddd, J¼6.5, 6.3, 5.5,
5.2, Hz, 0.5H, R,R), 4.064 (dd, J¼8.3, 6.5 Hz, 0.5H, S,R), 4.059 (dd,
J¼8.3, 6.5 Hz, 0.5H, R,R), 3.86e3.73 (m, 1H, CHOH), 3.741 (dd, J¼8.3,
6.4 Hz, 0.5H, R,R), 3.724 (dd, J¼8.3, 6.5 Hz, 0.5H, S,R), 3.589 (dd,
J¼10.2, 5.9 Hz, 0.5H, S,R), 3.559 (d, J¼5.4 Hz, 1H, R,R), 3.547 (dd,
J¼9.8, 3.0 Hz, 0.5H, S,R), 3.515 (dd, J¼10.2, 4.8 Hz, 0.5H, S,R), 3.534
(dd, J¼9.7, 3.0, Hz, 0.5H, R,R), 3.33 (dd, J¼9.7, 8.1 Hz, 0.5H, R,R), 3.31
(dd, J¼9.7, 8.2 Hz, 0.5H, S,R), 2.62e2.35 (br envelope, which topped
at 2.47 ppm, 1H, OH), 2.10e1.94 (m, 4H), 1.436 (q, J¼0.6 Hz, 1.5H,
CH3, S,R), 1.432 (q, J¼0.6 Hz, 1.5H, CH3, R,R), 1.371 (q, J¼0.6 Hz, 1.5H,
CH3, S,R), 1.368 (q, J¼0.6 Hz, 1.5H, CH3, R,R), 1.52e1.19 (m, 24H), 0.88
J¼6.9 Hz, 3H). 13C NMR (100 MHz, CDCl3):
¼129.96 and 129.84
d
(CH]CH), 109.35 (CMe2), 80.19 (CH), 74.69 (CHeO), 73.83 (CH2),
72.38 (CH2), 66.88 (CH2), 57.60 (CH3), 31.92 (CH2), 31.42 (CH2), 29.78
(2 CH2), 29.77 (CH2), 29.53 (CH2), 29.50 (CH2), 29.33 (2 CH2), 29.27
(CH2), 27.23 (CH2), 27.21 (CH2), 26.78 (CeCH3), 25.43 (CeCH3),
22
20
20
20
25.36 (CH2), 22.69 (CH2), 14.12 (CH3). [
a]
ꢁ6.8; [
a
a
]
]
ꢁ7.2; [
a
a
]
]
(pseudo t, J¼6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3):
¼129.96 (CH]
d
D
546
20
20
20
ꢁ8.2; [
a
]
]
ꢁ14.6; [
a
]
ꢁ23.7 (c 1.10, CHCl3). [
578 ꢁ5.8; [
CH), 129.83 (CH]CH), 109.58 (0.5 CMe2, S,R), 109.52 (0.5 CMe2, R,R),
76.22 (0.5 CH2, S,R), 76.20 (0.5 CH2, R,R), 74.78 (0.5 CHeO, S,R), 74.72
(0.5 CHeO, R,R), 72.34 (0.5 CH2, S,R), 72.24 (0.5 CH2, R,R), 70.32 (0.5
CHOH, R,R), 70.25 (0.5 CHOH, S,R), 66.56 (0.5 CH2, R,R), 66.48 (0.5
CH2, S,R), 33.01 (0.5 CH2, R,R), 32.93 (0.5 CH2, S,R), 31.91 (CH2), 29.78
(CH2), 29.76 (CH2), 29.66 (0.5 CH2, R,R), 29.65 (0.5 CH2, S,R), 29.53
(CH2), 29.46 (CH2), 29.33 (2 CH2), 29.25 (CH2), 27.22 (CH2), 27.20
(CH2), 26.72 (CeCH3), 25.52 (CH2), 25.38 (CeCH3), 22.69 (CH2),14.13
(CH3). Anal. Calcd for C25H48O4: C, 72.77; H, 11.72. Found: C, 73.34;
H, 11.70.
436
20
365
20
D
578
ꢁ7.3; [
a
ꢁ13.2; [ 436 ꢁ21.2 (c 0.86, acetone). HRMS (ESI) calcd
a]
546
for C26H50O4Na [MþNa]þ 449.36013, found 449.3601.
4.10. Synthesis of (Z)-(20R)-1-O-(20-methoxynonadec-100-
enyl)-sn-glycerol (20R,2S)-13
To acetonide (20R,2R)-24 (128 mg, 0.3 mmol) and methanol
(1.5 mL) were added p-toluenesulfonic acid monohydrate (4 mg,
0.02 mmol, 0.07 equiv) and distilled water (0.15 mL). The flask was
purged under nitrogen, stoppered, and dipped in a preheated bath
at 60 ꢀC. After 5 h at 60 ꢀC, sodium bicarbonate (6 mg, 0.071 mmol,
0.24 equiv) was added and stirring was continued for 1 h at 60 ꢀC.
Methanol and water were removed by concentration using a rotary
evaporator using sufficiently high vacuum. Chromatography of the
residue on basic alumina (3.15 g) first eluting impurities with
0/4% acetone in pentane and then with pentane/acetone 4:1
afforded alkylglycerol (20R,2S)-13 (93 mg, 80%) as a colorless oil,
which solidified giving a white solid after overnight storage in
a freezer. Mp: 21.5e23 ꢀC. Rf 0.09 (petroleum ether/acetone 9:1). IR
(film) nmax 3402, 2956, 2925, 2854, 1466, 1457, 1378, 1364, 1135,
4.12. Synthesis of (Z)-(20R)-1-O-(20-methoxynonadec-100-
enyl)-2,3-O-isopropylidene-sn-glycerolD(Z)-(20S)-1-O-(20-
methoxynonadec-100-enyl)-2,3-O-isopropylidene-sn-glycerol
(20R,2R)-24D(20S,2R)-24
The 1:1 mixture of (20R,2R)-14 and (20S,2R)-14 was methylated
using the same procedure as described for the synthesis of (20R,2R)-
14 (paragraph 4.9) affording a 1:1 mixture of (20R,2R)-24 and
(20S,2R)-24. Rf 0.62 (pentane/acetone 9:1). 1H NMR (300 MHz,
CDCl3):
d
¼5.41e5.28 (m, 2H, CH]CH), 4.28 (dddd, J¼6.4, 6.3, 5.6,
1118, 852, 722 cmꢁ1. 1H NMR (400 MHz, CDCl3):
2H, CH]CH), 3.86 (dddd after exchange with D2O, m centered at
3.87 ppm before exchange with D2O, J¼6.3, 5.2, 3.9, 3.8 Hz, 1H),
d
¼5.40e5.30 (m,
5.6 Hz, 0.5H, S,R), 4.27 (dddd, J¼6.4, 6.3, 5.6, 5.5 Hz, 0.5H, R,R), 4.06
(dd, J¼8.3, 6.4 Hz, 1H), 3.76 (dd, J¼8.3, 6.3 Hz, 0.5H, R,R), 3.75 (dd,
J¼8.3, 6.3 Hz, 0.5H, S,R), 3.570 (dd, J¼10.1, 5.4 Hz, 0.5H, R,R), 3.568

2982
R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
(dd, J¼9.8, 5.4 Hz, 0.5H, S,R), 3.525 (dd, J¼10.4, 5.8 Hz, 0.5H, R,R),
3.53e3.44 (m, 2.5H), 3.404 (s, 1.5H, OCH3, S,R), 3.401 (s, 1.5H, OCH3,
R,R), 3.321 (dddd, J¼6.0, 5.8, 5.8, 4.2 Hz, 0.5H, S,R), 3.315 (dddd,
J¼6.0, 5.9, 5.9, 4.2 Hz, 0.5H, R,R), 2.10e1.93 (m, 4H), 1.54e1.40 (m,
2H), 1.42 (br q, J¼0.6 Hz, 3H, CH3), 1.36 (q, J¼0.6 Hz, 3H, CH3),
1.40e1.20 (m, 22H), 0.88 (pseudo t, J¼6.7 Hz, 3H). 13C NMR
7.49e7.41 (m, 2H, H aromatic meta), 5.41e5.28 (m, 2H, CH]CH),
3.99 (dddd, J¼7.1, 6.5, 5.9, 3.1 Hz, 1H, CHOH), 4.40 (dd, J¼11.4,
3.1 Hz, 1H, CH2O), 4.23 (dd, J¼11.4, 7.1 Hz, 1H, CH2O), 2.28e2.0 (br
envelope centered at 2.13 ppm, 1H, OH), 2.09e1.92 (m, 4H),
1.62e1.45 (m, 3H),1.45e1.18 (m, 21H), 0.88 (pseudo t, J¼6.7 Hz, 3H).
13C NMR (75 MHz, CDCl3):
d¼166.76 (CO), 133.17 (CH aromatic
(75 MHz, CDCl3):
d
¼129.96 (CH]CH), 129.83 (CH]CH), 109.37 (0.5
para), 129.99 (CH]CH), 129.92 (C ipso aromatic), 129.80 (CH]CH),
129.67 (2 CH aromatic ortho), 128.44 (2 CH aromatic meta), 70.18
(CHOH), 69.25 (CH2O), 33.48 (CH2), 31.91 (CH2), 29.78 (CH2), 29.75
(CH2), 29.56 (CH2), 29.53 (CH2), 29.45 (CH2), 29.33 (2 CH2), 29.23
(CH2), 27.23 (CH2), 27.20 (CH2), 25.43 (CH2), 22.69 (CH2), 14.12
(CH3). Anal. Calcd for C26H42O3: C, 77.56; H, 10.51. Found: C, 77.69;
CMe2, S,R), 109.35 (0.5 CMe2, R,R), 80.19 (0.5 CHeOMe, R,R), 80.15
(0.5 CHeOMe, S,R), 74.74 (0.5 CHeO, S,R), 74.69 (0.5 CHeO, R,R),
73.99 (0.5 CH2, S,R), 73.82 (0.5 CH2, R,R), 72.46 (0.5 CH2, S,R), 72.37
(0.5 CH2, R,R), 66.89 (0.5 CH2, S,R), 66.87 (0.5 CH2, R,R), 57.63 (0.5
OCH3, S,R), 57.59 (0.5 OCH3, R,R), 31.92 (CH2), 31.41 (0.5 CH2, R,R),
31.34 (0.5 CH2, S,R), 29.78 (2 CH2), 29.77 (CH2), 29.54 (CH2), 29.50
(CH2), 29.33 (2 CH2), 29.27 (CH2), 27.22 (CH2), 27.21 (CH2), 26.782
(0.5CeCH3, S,R), 26.774 (0.5CeCH3, R,R), 25.43 (CeCH3), 25.38 (0.5
CH2, S,R), 25.36 (0.5 CH2, R,R), 22.69 (CH2), 14.13 (CH3).
22.5
22.5
22.5
22.5
22.5
365
22.5
436
22.5
546
H, 10.38. [
a
]
þ4.3; [
a
a
]
þ4.5; [
a
a
a
]
þ5.1; [
a]
a
þ8.8; [
a
a
a
]
]
]
D
578
546
436
þ14.0 (c 1.99, CH2Cl2). [
]
22.5 þ4.3; [
]
22.5 þ4.5; [
]
22.5 þ5.1; [
22.5
D
578
546
22.5
22.5
þ8.8; [
a
]
]
þ14.0 (c 2.00, CHCl3). [
]
ꢁ1.4; [
a]
ꢁ1.5; [
365
D
578
ꢁ1.7; [
a
22.5 ꢁ2.6; [
a]
22.5 ꢁ3.7 (c 2.01, acetone) (note the identity of
436
365
the optical rotation in CH2Cl2 and in CHCl3 as well as the reversal of
sign in acetone).
4.13. Synthesis of (Z)-(20R)-1-O-(20-methoxynonadec-100-
enyl)-sn-glycerol (20R,2S)-13D(Z)-(20S)-1-O-(20-
methoxynonadec-100-enyl)-sn-glycerol (20S,2S)-13
4.14.1. Data of the dibenzoate of S-19, (S,Z)-1,2-di(benzoyloxy)non-
adec-10-ene. Rf 0.66 (petroleum ether/acetone 9:1). 1H NMR
Using the same procedure as described for the synthesis of
(20R,2S)-13 (paragraph 4.10) with the 1:1 mixture of (20R,2R)-24 and
(20S,2R)-24 afforded a 1:1 mixture of (20R,2S)-13 and (20S,2S)-13. 1H
(400 MHz, CDCl3):
d
¼8.09e8.03 (m, 2H,
H aromatic ortho),
8.03e7.97 (m, 2H, H aromatic ortho), 7.56 (ddt, J¼8.1, 6.7, 1.4 Hz, 1H,
H aromatic para), 7.54 (ddt, J¼8.2, 6.6, 1.4 Hz, 1H, H aromatic para),
7.48e7.37 (m, 4H, H aromatic meta), 5.50 (dddd, J¼7.4, 6.6, 5.9,
3.5 Hz, 1H, CHOBz), 5.40e5.26 (m, 2H, CH]CH), 4.56 (dd, J¼11.9,
3.5 Hz,1H, CH2OBz), 4.47 (dd, J¼11.9, 6.6 Hz,1H, CH2OBz), 2.10e1.92
(m, 4H), 1.92e1.71 (m, 2H), 1.54e1.16 (m, 22H), 0.87 (pseudo t,
NMR (400 MHz, CDCl3):
d
¼5.40e5.29 (m, 2H, CH]CH), 3.91e3.83
(m, 1H, CHOH), 3.708 (dd, J¼11.4, 4.0 Hz, 0.5H), 3.705 (dd, J¼11.4,
3.9 Hz, 0.5H), 3.67e3.45 (m, 5H), 3.400 (s, 1.5H, OCH3, R,S), 3.398 (s,
1.5H, OCH3, S,S), 3.324 (dddd, J¼6.2, 6.1, 6.0, 3.5 Hz, 0.5H, CHOMe,
R,S), 3.323 (dddd, J¼6.1, 6.0, 5.5, 4.1 Hz, 0.5H, CHOMe, S,S), 3.10
(envelope from 3.27 to 2.85 ppm, 1H, CHOH), 2.45 (envelope from
2.70 to 2.22 ppm,1H, CH2OH), 2.09e1.95 (m, 4H),1.57e1.41 (m, 2H),
1.40e1.20 (m, 22H), 0.88 (pseudo t, J¼6.9 Hz, 3H). 13C NMR
J¼6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3):
¼166.33 (CO), 166.13
d
(CO), 133.06 (CH aromatic para), 133.00 (CH aromatic para), 130.23
(C ipso aromatic), 129.98 (CH]CH), 129.85 (C ipso aromatic), 129.76
(CH]CH), 129.68 (4 CH aromatic ortho), 128.38 (2 CH aromatic
meta), 128.37 (2 CH aromatic meta), 72.22 (CHOBz), 65.73 (CH2OBz),
31.91 (CH2), 30.99 (CH2), 29.77 (CH2), 29.71 (CH2), 29.53 (CH2),
29.42 (CH2), 29.34 (CH2), 29.32 (2 CH2), 29.18 (CH2), 27.22 (CH2),
27.18 (CH2), 25.20 (CH2), 22.69 (CH2), 14.12 (CH3).
(75 MHz, CDCl3):
d
¼129.98 (CH]CH), 129.80 (CH]CH), 80.36 (0.5
CHeO, R,S), 80.29 (0.5 CHeO, S,S), 73.55 (0.5 CH2, R,S), 73.39 (0.5
CH2, S,S), 73.34 (0.5 CH2, R,S), 73.22 (0.5 CH2, S,S), 70.61 (0.5 CHOH,
R,S), 70.51 (0.5 CHOH, S,S), 64.04 (0.5 CH2OH, R,S), 64.01 (0.5
CH2OH, S,S), 57.34 (0.5 OCH3, R,S), 57.29 (0.5 OCH3, S,S), 31.92 (CH2),
30.89 (0.5 CH2, R,S), 30.88 (0.5 CH2, S,S), 29.78 (2CH2), 29.76 (CH2),
29.53 (CH2), 29.49 (CH2), 29.33 (2CH2), 29.25 (CH2), 27.23 (CH2),
4.15. Synthesis of (S,Z)-1-benzoyloxy-2-
methanesulfonyloxynonadec-10-ene S-26
21
21
27.20 (CH2), 25.36 (CH2), 22.69 (CH2), 14.13 (CH3). [
a
]
þ2.5; [
a]
D
578
21
21
21
þ2.5; [
a
]
þ2.8; [
a]
436 þ4.4; [
a
]
þ6.6 (c 1.38, CH2Cl2).
To a cooled solution at ꢁ40 ꢀC under nitrogen of alcohol S-25
(728.6 mg, 1.81 mmol) and triethylamine (0.63 mL, 4.52 mmol,
2.5 equiv) in dichloromethane (7.25 mL, distilled over CaH2) was
added dropwise under stirring a solution of methanesulfonyl chlo-
ride (395 mg, 3.44 mmol, 1.9 equiv) in dichloromethane (1.15 mL).
Transfer of MsCl was completed by rinsing with dichloromethane
(2ꢃ0.15 mL). The cooling bath was allowed to warm up slowly. After
55 min, the temperature had risen to ꢁ10 ꢀC and a TLC control
showed that the reaction was complete (Rf of the mesylate¼0.60
with dichloromethane versus 0.34 for the starting alcohol). Distilled
water was added. After transferring into a separating funnel and
shaking, the organic phase was withdrawn. The remaining aqueous
phase was extracted three times with a small amount of dichloro-
methane. After drying over Na2SO4 and concentration, the remaining
oily yellow residue was subjected to a chromatography on silica gel
(21 g) eluting with dichloromethane. After long standing under high
vacuum while repeating several cycles of crystallizing by the cold
and slow melting (Dewar insulating), mesylate S-26 was obtained as
a slightly yellow oil (842.9 mg, 97%). Rf 0.60 (dichloromethane). Mp:
546
365
4.14. Synthesis of (S,Z)-1-benzoyloxynonadec-10-en-2-ol S-25
A solution of diol S-19 (913.1 mg, 3.06 mmol) and triethylamine
(0.17 mL, 1.22 mmol, 0.4 equiv) in dichloromethane (24.5 mL) was
cooled at 0 ꢀC under nitrogen. A solution of benzoyl cyanide
(528 mg, 3.82 mmol, 1.25 equiv, 95% pure) in dichloromethane
(1.84 mL) was then slowly added dropwise under stirring. Transfer
of PhCOCN was completed by rinsing with dichloromethane
(2ꢃ0.25 mL). After 40 min reaction at 0 ꢀC, methanol (0.155 mL)
was added. After 15 additional minutes at 0 ꢀC, distilled water
(30 mL) was added and the resulting mixture was well shaken in
a separating funnel. The organic phase was withdrawn and the
aqueous phase was extracted twice with dichloromethane. Com-
bined organic phases were dried (Na2SO4) and concentrated. The
residue was subjected to a flash-chromatography on silica gel
(25 g). It was transferred onto silica gel after dissolving in hot tol-
uene (0.6 mL) followed by rinsing with pentane. First, elution with
0/2% acetone in pentane removed the dibenzoate of S-19 (yellow
oil, 157 mg). Then, elution with 2/10% acetone in pentane afforded
a fraction containing a mixture of dibenzoate and monobenzoate
followed by the monobenzoate S-25 alone as a white crystallized
powder (937.8 mg, 76%). Mp: 49 ꢀC. Rf 0.35 (petroleum ether/ace-
8e8.5 ꢀC. 1H NMR (400 MHz, CDCl3):
d¼8.11e8.03 (m, 2H, H aro-
matic ortho), 7.59 (ddt, J¼8.2, 6.6, 1.4 Hz, 1H, H aromatic para),
7.51e7.42 (m, 2H, H aromatic meta), 5.41e5.28 (m, 2H, CH]CH), 5.02
(dddd, J¼7.2, 7.1, 5.9, 2.9 Hz,1H, CHOMs), 4.54 (dd, J¼12.4, 2.9 Hz, 1H,
CH2O), 4.39 (dd, J¼12.4, 7.1 Hz, 1H, CH2O), 3.03 (s, 3H, CH3 of OMs),
2.10e1.93 (m, 4H),1.91e1.67 (m, 2H),1.57e1.41 (m, 2H),1.41e1.18 (m,
20H), 0.88 (pseudo t, J¼6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3):
tone 9:1). 1H NMR (400 MHz, CDCl3):
matic ortho), 7.58 (ddt, J¼8.2, 6.7, 1.4 Hz, 1H, H aromatic para),
d¼8.09e8.02 (m, 2H, H aro-

R. Pemha et al. / Tetrahedron 68 (2012) 2973e2983
2983
3. Linman, J. W.; Long, M. J.; Korst, D. R.; Bethell, F. H. J. Lab. Clin. Med. 1959, 54,
335e343.
4. Brohult, A.; Brohult, J.; Brohult, S.; Joelsson, I. Acta Obst. Gynecol. Scand. 1977, 56,
441e448.
d
¼166.14 (CO),133.40 (CH aromatic para),130.04 (CH]CH),129.74 (2
CH aromatic ortho), 129.72 (CH]CH), 129.47 (C ipso aromatic),
128.56 (2 CH aromatic meta), 80.31 (CHOMs), 65.57 (CH2O), 38.80
(CH3 of OMs), 31.91 (CH2), 31.74 (CH2), 29.77 (CH2), 29.70 (CH2), 29.53
(CH2), 29.33 (CH2), 29.32 (CH2), 29.28 (CH2), 29.25 (CH2), 29.17 (CH2),
27.23 (CH2), 27.17 (CH2), 24.96 (CH2), 22.69 (CH2), 14.13 (CH3). Anal.
Calcd for C27H44O5S: C, 67.46; H, 9.23; S, 6.67. Found: C, 67.51; H,
5. Brohult, A.; Brohult, J.; Brohult, S. Acta Obstet. Gynecol. Scand. 1978, 57, 79e83.
6. Ngwenya, B. Z.; Foster, D. M. Proc. Soc. Exp. Biol. Med. 1991, 196, 69e75.
7. Brohult, A.; Brohult, J.; Brohult, S. Experientia 1972, 28, 954e955.
ꢀ
8. Deniau, A.-L.; Mosset, P.; Pedrono, F.; Mitre, R.; Le Bot, D.; Legrand, A. B. Mar.
Drugs 2010, 8, 2175e2184.
27
27
27
27
9.23; S, 6.33. [
a]
D
27 þ9.8; [
a
]
578 þ9.7; [
a
]
546 þ11.2; [
a
]
436 þ19.3; [
a]
9. Deniau, A.-L.; Le Bot, D.; Mosset, P.; Legrand, A. B. OCL 2010, 17, 236e237; http://
www.john-libbey-eurotext.fr/fr/revues/agro_biotech/ocl/e-docs/00/04/5E/2E/
article.phtml.
365
18
18
18
18
þ30.6 (c 1.90, CH2Cl2). [
a]
þ10.9; [
a]
þ11.6; [
a]
þ13.2; [
a
]
D
578
17.5
546
17.5
578
536
þ22.8; [a 18
]
þ36.0 (c 2.02, CHCl3). [
a
]
D
þ7.8; [
a
]
þ8.2; [a]
17.5
10. Deniau, A.-L.; Mosset, P.; Le Bot, D.; Legrand, A. B. Biochimie 2011, 93, 1e3.
546
þ9.2; [
a
]
173.565þ14.9; [a 17.5
365 þ22.5 (c 2.01, acetone).
]
€
11. Hallgren, B.; Stallberg, G. Acta Chem. Scand. 1967, 21, 1519e1529.
436
€
12. Hallgren, B.; Niklasson, A.; Stallberg, G.; Thorin, H. Acta Chem. Scand. Ser. B 1974,
28, 1029e1034.
€
13. Hallgren, B.; Niklasson, A.; Stallberg, G.; Thorin, H. Acta Chem. Scand. Ser. B.
4.16. Synthesis of (R,Z)-2-(heptadec-8-en-1-yl)oxirane R-15
1974, 28, 1035e1040.
€
14. Stallberg, G. A. M. Acta Chem. Scand. 1990, 44, 368e376.
€
15. Hallgren, B.; Stallberg, G.; Boeryd, B. Prog. Chem. Fats Other Lipids 1978,16, 45e58.
To a solution of mesylate S-26 (718.9 mg, 1.495 mmol) in meth-
anol (15 mL) was added under stirring potassium tert-butoxide
(329 mg, 2.93 mmol, 1.96 equiv). This reaction mixture was left
under stirring at rt. A gelatinous white precipitate rapidly appeared,
which was thereafter divided in ca. 20 min. A TLC control after
30 min showed that the reactionwas complete (Rf with pentaneþ4%
acetone¼0.65 for the epoxide and 0.50 for methyl benzoate, which
is formed at the same time). After 40 min, distilled water was added
and some brine. The resulting mixture was extracted with ethyl
acetateþpentane and then three times with pentane. After drying
over Na2SO4 and concentration, the remaining oily residue was
16. Hallgren, B. In Ether Lipids. Biochemical and Biomedical Aspects; Mangold, H. K.,
Paltauf, F., Eds.; Academic: London, 1983, Chapter 15.
17. Carballeira, N. M. Prog. Lipid Res. 2002, 41, 437e456 and reference cited therein.
18. Baig, M. H. A.; Baskaran, S.; Banerjee, S.; Trivedi, G. K. Tetrahedron 1995, 51,
4723e4732.
19. Magnusson, C. D.; Haraldsson, G. G. Tetrahedron: Asymmetry 2010, 21,
2841e2847.
20. In target (20R,2S)-13, the double bond is
D10 instead of D9 for oleic acid due to
homologation of oleyl aldehyde to epoxide 15. After the beginning of our study,
an efficient conversion of carboxylic acids to one-carbon degraded aldehydes
was reported.21 Moreover, this method had been applied to oleic acid affording
(Z)-heptadec-8-enal, which would replace oleyl aldehyde to give a one-carbon
lower homolog of (20R,2S)-13 where the double bond is
D9.
1) LDA
3) HCl aq.
2) O2
CHO
O
OH
oleic acid
OMe
OH
4) 50°C
(- CO2)
THF / HMPA
21. Akakabe, Y.; Nyuugaku, T. Biosci. Biotechnol. Biochem. 2007, 71, 1370e1371.
22. Schaus, S. E.; Brandes, B. D.; Larrow, J. F.; Tokunaga, M.; Hansen, K. B.; Gould, A.
E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124, 1307e1315.
23. Mosset, P.; Gree, R. Synth. Commun. 1985, 15, 749e757.
24. Kavanagh, S. A.; Piccinini, A.; Fleming, E. M.; Connon, S. J. Org. Biomol. Chem.
subjected to a short column chromatography on silica gel (3.5 g)
eluting with pentaneþ0.5% Et3N. After collecting the fractions and
concentration, methyl benzoate was removed by putting under high
vacuum for 2e3 h. Epoxide R-15 was obtained as a quite mobile
colorless oil (410.0 mg, 98%), which solidified to give a white crys-
tallized solid on storage in a freezer. It was estimated to have ca. 96%
ee as reaction with 2,3-isopropylidene-sn-glycerol afforded
ꢀ
2008, 6, 1339e1343.
25. Imamoto, T.; Takeyama, T.; Koto, H. Tetrahedron Lett. 1986, 27, 3243e3246.
26. Sadhu, K. M.; Matteson, D. S. Tetrahedron Lett. 1986, 27, 795e798.
27. Thakur, S. S.; Chen, S.-W.; Li, W.; Shin, C.-K.; Koo, Y.-M.; Kim, G.-J. Synth.
Commun. 2006, 36, 2371e2383.
28. However, bimetallic (salen)cobalt(II)eindium(III) complex had showed to be
less enantioselective after aging by several months storage in a freezer.
29. Potassium hydroxide gave the same result with nearly identical yields.
30. KOH in aqueous DMSO is known to promote epoxide hydrolysis: Berti, G.;
Macchia, B.; Macchia, F. Tetrahedron Lett. 1965, 6, 3421e3427.
18
18
(20R,2S)-13 with ca. 96% de. Mp: ꢁ10.5 ꢀC. [
a
]
þ4.7; [
a
a
]
]
þ4.8;
D
578
18.5
D
18
18
18
[
[
[
a
a
a
]
þ5.4; [
a
]
þ8.0; [
a
]
þ10.2 (c 2.12, CHCl3). [
þ5.7,
546
536
]
]
18.5 þ5.8, [
a]
18.5 þ6.4, [
a
]
183.655þ9.5; [
a
a
]
]
18.5 þ11.9 (c 2.10, acetone).
578
365
18
þ9.2; [
a
]
546þ9.4; [
a
]
436þ10.5; [
þ16.6; [
a]
365
þ23.4 (c
18
18
18
18
D
578
546
436
2.12, benzene). [
a
]
18.5 þ9.2; [
a
]
18.5 þ9.5; [
a
]
18.5 þ10.6; [
a]
18.5 þ16.7;
D
578
546
436
31. We observed in many instances that optical rotations are very close or equal in
chloroform and in dichloromethane, see the example of S-25.
[
a]
18.5 þ23.4 (c 2.10, toluene).
365
32. It was observed that upon repeated use of potassium tert-butoxide, conversion
gradually decreased to about 20% and more and more epoxide was recovered un-
reacted. This problem was obviously due to the highly hygroscopic character of
potassium tert-butoxide and that absorbed moisture destroyed t-BuOK by DMF
liberating dimethylamine. Handling t-BuOK in a glove-box would solve this problem.
33. Use of anhydrous NMP afforded similar results than that of anhydrous DMF.
On the other hand, use of anhydrous DMSO had resulted in a better con-
version but the reaction of R-15 with 16 was not selective and resulted in
a mixture of (20R,2R)-14, 23, and even of smaller amounts of other by-
products probably resulting of subsequent reaction of the secondary hy-
droxy group with the epoxide. The same absence of selectivity between
primary and secondary hydroxy groups was already observed for the reaction
of epoxide 20 with 16 in the presence of KOH or NaOH and n-Bu4NBr in
DMSO. Obviously, this could be explained by the enhancement of the nu-
cleophilic reactivity of the alcoholates
34. Optical rotation of epoxide from HKR was a little bit lower than that of epoxide,
which was made from diol. That could likely be due to a trace of salen ligand
arising from the decomposition of the catalyst ((R,R)-(ꢁ)-N,N0-bis(3,5-di-tert-
butylsalicylidene)-1,2-cyclohexanediamine), which is strongly levorotatory and
quite hard to remove completely from epoxide by chromatography
35. Hemberger, K. E.; Jasmin, S.; Kabir, H.; Larrow, J. F.; Morel, P. U.S. Patent Ap-
plication 20,030,088,114 A1, published on May 8, 2003.
Acknowledgements
Financial support from Agence Universitaire de la Francophonie
ꢀ
ꢀ
(AUF), Region Bretagne, CNRS (UMR 6226), and Universite de
Rennes 1 are gratefully acknowledged. We also thank CRMPO
ꢀ
(Centre Regional de Mesures Physiques de l’Ouest, Rennes, France)
for HRMS spectra and microanalyses.
Supplementary data
Supplementary data associated with this article including copies
of 1H and 13C NMR (1D and some 2D) spectra can be found in the
online version, at doi:10.1016/j.tet.2012.02.033. These data include
MOL files and InChiKeys of the most important compounds de-
scribed in this article.
36. Larrow, J. F.; Hemberger, K. E.; Jasmin, S.; Kabir, H.; Morel, P. Tetrahedron:
References and notes
Asymmetry 2003, 14, 3589e3592.
37. Without adding ascorbic acid, the bimetallic catalyst decomposed during
chromatography on silica gel leading to brown impurities, which were hard to
remove.
1. Bordier, C. G.; Sellier, N.; Foucault, A. P.; Le Goffic, F. Lipids 1996, 31, 521e528.
2. Baer, E.; Fisher, H. O. L. J. Biol. Chem. 1941, 140, 397e410.