Syntheses of polymerizable monoacylglycerols and 1,2-diacyl-sn-glycerols

Article abstract of DOI:10.1021/jo960010b

The first chemical syntheses of polymerizable monoacylglycerol and 1,2-diacyl-sn-glycerol are reported. The monodienoylglycerol is obtained in 80% yield from 1,2-O-isopropylidene-sn-glycerol and dienoyl fatty acid. The dienoic acid is accessible in 60% yield from the base-catalyzed hydrolysis of dienoyl ester, which is synthesized from the Wittig-Horner reaction of aldehyde and trimethyl 4-phosphonocrotonate. The acylation is carried out in the presence of 4-(dimethylamino)pyridine and dicyclohexylcarbodiimide. The use of excess protected glycerol relative to fatty acid affords the acylated product in high yield. The final step is the deprotection of isopropylidene group using dilute HCl solution. The 1,2-diacyl-sn-glycerol is synthesized by acylation of 3-(4-methoxybenzyl)-sn-glycerol with dienoyl fatty acid in the presence of 4-(dimethylamino)pyridine and dicyclohexylcarbodiimide. The removal of the 4-methoxybenzyl group by dimethylboron bromide catalyzed hydrolysis is especially useful in the synthesis of polymerizable lipids because the deprotection proceeds without any apparent effect on the dienoyl polymerizable group and without detectable isomerization of 1,2-diacylglycerol to 1,3-diacylglycerol. The overall yield for the synthesis of the polymerizable 1,2-diacyl-sn-glycerol from the dienoyl fatty acid is ca. 50%.

Full text of DOI:10.1021/jo960010b

J . Org. Chem. 1996, 61, 5911-5915
5911
Syn th eses of P olym er iza ble Mon oa cylglycer ols a n d
1
,2-Dia cyl-sn -glycer ols
Warunee Srisiri, Henry G. Lamparski, and David F. O’Brien*
C. S. Marvel Laboratories, Department of Chemistry, The University of Arizona,
Tucson, Arizona 85721-0048
Received J anuary 2, 1996 (Revised Manuscript Received J une 14, 1996X)
The first chemical syntheses of polymerizable monoacylglycerol and 1,2-diacyl-sn-glycerol are
reported. The monodienoylglycerol is obtained in 80% yield from 1,2-O-isopropylidene-sn-glycerol
and dienoyl fatty acid. The dienoic acid is accessible in 60% yield from the base-catalyzed hydrolysis
of dienoyl ester, which is synthesized from the Wittig-Horner reaction of aldehyde and trimethyl
4
-phosphonocrotonate. The acylation is carried out in the presence of 4-(dimethylamino)pyridine
and dicyclohexylcarbodiimide. The use of excess protected glycerol relative to fatty acid affords
the acylated product in high yield. The final step is the deprotection of isopropylidene group using
dilute HCl solution. The 1,2-diacyl-sn-glycerol is synthesized by acylation of 3-(4-methoxybenzyl)-
sn-glycerol with dienoyl fatty acid in the presence of 4-(dimethylamino)pyridine and dicyclohexyl-
carbodiimide. The removal of the 4-methoxybenzyl group by dimethylboron bromide catalyzed
hydrolysis is especially useful in the synthesis of polymerizable lipids because the deprotection
proceeds without any apparent effect on the dienoyl polymerizable group and without detectable
isomerization of 1,2-diacylglycerol to 1,3-diacylglycerol. The overall yield for the synthesis of the
polymerizable 1,2-diacyl-sn-glycerol from the dienoyl fatty acid is ca. 50%.
In tr od u ction
Q
II phase belonging to the Pn3m space group (at ca. 60
°
C). Redox-initiated radical polymerization of these lipids
During the past decade the polymerization of pre-
formed lipid assemblies has been successfully utilized to
modify the chemical and physical properties of two-
dimensional lamellar assemblies, e.g., monolayer, mul-
stabilized this QII phase in a manner that permitted it
to exist at temperatures as low as ca. 0 °C. This strategy
for the stabilization of nonlamellar phases relies on the
design of suitable polymerizable lipids, which upon
hydration form nonlamellar assemblies. The nonlamellar
phase is then fixed by cross-linking polymerization.
8
1
tilayer, and bilayer vesicles. A variety of lipids contain-
ing polymerizable groups such as diacetylene, dienoyl,
sorbyl, vinyl, styryl, and acryloyl have been designed and
synthesized.2
,3
In order to demonstrate the generality of this approach,
we have designed other classes of polymerizable lipids
that are likely to form nonlamellar phases. The forma-
At certain conditions of concentration,
temperature, and pressure, biological and synthetic lipids
can form hydrated nonlamellar assemblies such as
inverted cubic (QII) and inverted hexagonal (HII) phases.
It has been proposed that some of these nonlamellar lipid
tion of nonlamellar phases from monoacylglcerols (MAG)
is well documented.9
-11
The phase behavior of mono-
structures may be important in biological process.4
-6
acylglycerols alone or mixed with other lipids, e.g.,
diacylglycerols, dioleoylPC, has been extensively inves-
tigated and utilized as a model membrane system for the
Various QII phases have been reported to exist between
the lamellar and the HII phases.4,5 Several inverted cubic
physicochemical investigation of lipid structures and
phases are possible, and those which are bicontinuous
with respect to the polar (aqueous) and nonpolar (lipid)
regions can be considered as organic zeolites. The
potential use of these lipid assemblies depends at least
in part on the prospects for stabilization of their non-
lamellar architecture in order to expand their useful
temperature and concentration range. Recently, we
prepared a polymerizable phosphatidylethanolamine (PE)
and a phosphatidylcholine (PC) in order to stabilize a
bicontinuous cubic phase.7 A 3:1 molar mixture of a
monodienoylphosphatidylethanolamine (mono-DenPE)
and bis-dienoylphosphatidylcholine (bis-DenPC) form a
dynamics.9
-12
The temperature-composition phase dia-
grams of various monoacylglycerols in water have been
constructed on the basis of data from X-ray diffraction.
9
-11
In addition to lamellar phases, these hydrated lipids form
various QII phases, e.g., monoolein at room temperature
forms a QII phase with Ia3d symmetry at 25-33 wt %
water, whereas at higher water content the phase with
Pn3m symmetry is favored.9
On the basis of the literature precedents, we designed
a monoacylglycerol with a polymerizable group incorpo-
rated into the acyl chain. Such a reactive monoacylg-
lycerol may have the polymerizable moiety located either
at a position near the lipid backbone or at the hydropho-
bic chain end. We have prepared lipids with dienoyl
groups at either position. When the polymerizable diene
X
Abstract published in Advance ACS Abstracts, August 1, 1996.
(
1) O'Brien, D. F. Trends Polym. Sci. 1994, 2, 183-188.
(2) O'Brien, D. F.; Ramaswami, V. Encyclopedia of Polymer Science
and Engineering, 2nd ed.; Wiley: New York, 1989; pp 108-135.
(3) (a) Ringsdorf, H.; Schlarb, B.; Venzmer, J . Angew. Chem., Int.
Ed. Engl. 1988, 27, 113-158. (b) Singh, A.; Schnur, J . M. Polymerizable
Phospholipids. In Phospholipids Handbook; Cevc, G., Ed.; Marcel
Dekker: New York, 1993; pp 233-291.
(8) Lee, Y.-S.; Yang, J .; Sisson, T. M.; Frankel, D. A.; Gleeson, J .
T.; Aksay, E.; Keller, S. L.; Gruner, S. M.; O'Brien, D. F. J . Am. Chem.
Soc. 1995, 117, 5573-5578.
(
4) Lindblom, G.; Rilfors, L. Biochim. Biophys. Acta 1989, 988, 221-
2
56.
(9) Hyde, S.; Andersson, S.; Ericsson, B.; Larsson, K. Z. Kristallogr.
1984, 168, 213-219.
(
5) Seddon, J . M. Biochim. Biophys. Acta 1990, 1031, 1-69.
(
6) Tate, M. W.; Eikenberry, E. F.; Turner, D. C.; Shyamsunder, E.;
(10) Briggs, J .; Caffrey, M. Biophys. J . 1994, 66, 573-587.
(11) Briggs, J .; Caffrey, M. Biophys. J . 1994, 67, 1594-1602.
(12) Nilsson, A.; Holmgren, A.; Lindblom, G. Biochemistry 1991, 30,
2126-2133.
Gruner, S. M. Chem. Phys. Lipids 1991, 57, 147-164.
7) Lee, Y.-S.; Srisiri, W.; Devanathan, S.; O'Brien, D. F. Submitted
for publication.
(
S0022-3263(96)00010-2 CCC: $12.00 © 1996 American Chemical Society

5
912 J . Org. Chem., Vol. 61, No. 17, 1996
Srisiri et al.
Sch em e 1a
is conjugated to the acyl carbonyl, the formation of the
polymer does not directly affect the motions of the
hydrophobic lipid tail. Polymerization of the diene-
substituted lipids can be accomplished with the aid of
either thermal or redox initiators or by direct photo-
1
3,14
polymerization.
Recently Martin et al.15 reported general methods for
the synthesis of various glycerophospholipids starting
from 1,2-diacyl-sn-glycerol, which was treated with alkyl
dichlorophosphite in the presence of alcohol and then
oxidized and deprotected to yield the desired phospholipid
derivatives. Diacylglycerols (DAGs) are second mes-
sengers produced in the receptor-mediated hydrolysis of
inositol phospholipids.16 They play important roles in
signal transduction of a variety of extracellular mes-
sengers taking place at the cell surface through activation
of protein kinase C.17 Diacylglycerols are also known to
induce a variety of structural changes in membranes,
1
8
including alternation of membrane curvature, lateral
phase separation,19 the formation of ripple phase, the
20
2
1
promotion of membrane fusion, and the production of
nonlamellar phases.22 Here we describe a convenient
synthetic route to polymerizable 1,2-diacyl-sn-glycerols.
In addition to inducing structural changes, this polymer-
izable DAG could also serve as a cross-linking reagent
for polymerizable MAGs to stabilize lipid assemblies.
Stabilized cubic phases are expected to be useful models
for the investigation of bicontinuous cubic phases, drug
or reagent carriers, and the organic analogs of zeolite.
In addition, by adaptation of Martin et al.15 procedures,
polymerizable 1,2-diacyl-sn-glycerols are a good starting
point for the preparation of a variety of other polymer-
izable lipids.
a
(
a) NaH, THF; (b) trimethyl 4-phosphonocrotonate; (c) 85%
KOH, MeOH; (d) urea inclusion.
In this paper, we describe the total synthesis of the
polymerizable mono(2,4-(E,E)-tetradecadienoyl)glycerol
(1) and 1,2-bis[(2,4-(E,E)-tetradecadienoyl)-sn-glycerol (2).
A study of the effect of polymerization on the phase
behavior of these lipids will be described elsewhere.
Resu lts a n d Discu ssion
The polymerizable monoacylglycerol synthesized was
3
-(2,4-(E,E)-tetradecadienoyl)-sn-glycerol (1). It was ob-
that the methyl ester 3 was composed of ca. 80% (E,E)-
isomer and ca. 20% (E,Z)-isomer. The multiplet peaks
at 7.55-7.68 ppm are characteristic of the vinyl proton
of the (E,Z)-isomer, while the multiplet peaks at 7.29-
tained from the acylation of 1,2-O-isopropylidene-sn-
glycerol with 2,4-(E,E)-tetradecadienoic acid (4a ). The
dienoic acid 4a was accessible in two steps in 60% yield
from commercially available decanal (Scheme 1). The
Wittig-Horner reaction of decanal and trimethyl 4-phos-
phonocrotonate2 in THF gave methyl 2,4-tetradecadi-
7
.40 ppm are due to the vinyl proton of the (E,E)-isomer.
This corresponds well with the previously observed
3
proton NMR spectra of (E,E)- and (E,Z)-16-methyl-2,4-
1
enoate (3) in 75% yield. The H NMR spectrum indicated
octadecadienoic acids.7 The separation of (E,E)- and
(
E,Z)-isomers was accomplished after the esters were
(
13) Tsuchida, E.; Hasegawa, E.; Kimura, N.; Hatashita, M.; Makino,
E. Macromolecules 1992, 25, 207-212.
14) Lamparski, H. G.; O'Brien, D. F. Macromolecules 1995, 28,
786-1794.
15) Martin, S. F.; J osey, J . A.; Wong, Y.-L.; Dean, D. W. J . Org.
Chem. 1994, 59, 4805-4820.
16) Majerus, P. W.; Connolly, T. M.; Deckmyn, H.; Ross, T. E.; Ishii,
converted to the corresponding acids, since some isomer-
ization of the carbon-carbon double bonds may take
place during the hydrolysis process. The hydrolysis of
the methyl dienoate 3 was catalyzed by 1.5 molar equiv
of KOH in methanol24 at reflux for 4-5 h. The reaction
was followed by TLC using hexane/ethyl acetate (97/3)
as the mobile phase. Alternative methods to hydrolyze
these methyl esters by acidic (formic acid) or neutral
(iodotrimethylsilane)25 procedures were less satisfactory.
Urea is known for its ability to form a crystalline
(
1
(
(
H.; Bansal,U.S.; Wilson, D. B. Science 1986, 234, 1519-1526.
(
17) Berridge, M. J . Annu. Rev. Biochem. 1987, 56, 159-193.
(18) Ohki, T.; Sekiya, T.; Yamauchi, T.; Nozawa, T. Biochim.
Biophys. Acta 1982, 693, 341-350.
19) Ortiz, A.; Villalain, J .; Gomez-Fernandez, J . C. Biochemistry
988, 27, 9030-9036.
20) Lopez-Garcia, F.; Villalain, J .; Gomez-Fernandez, J . C.; Quinn,
P. J . Biophys. J . 1995, 68, 558-566.
21) Siegel, D. P.; Banschbach, J .; Alford, D.; Ellens, H.; Lis, L. J .;
Quinn, P. J .; Yeagle, P. L.; Bentz, J . Biochemistry 1989, 28, 3703-9.
22) Siegel, D. P.; Banschbach, J .; Yeagle, P. L. Biochemistry 1989,
8, 5010-5019.
23) Dorn, K.; Klingbiel, R. T.; Specht, D. P.; Tyminiski, P. N.;
Ringsdorf, H.; O'Brien, D. F. J . Am. Chem. Soc. 1984, 106, 1627-1633.
(
1
(
2
6,27
inclusion complex with certain compounds.
hydrogen-bonded urea molecules in methanol orient in
The
(
(
2
(24) Allen, C. F.; Kalm, K. J . Org. Synth. 1963, 4, 608-611.
(25) J ung, M. E.; Lyster, M. A. J . Am. Chem. Soc. 1977, 99, 968-
969.
(

Syntheses of Polymerizable Acylglycerols
J . Org. Chem., Vol. 61, No. 17, 1996 5913
Sch em e 2a
a helical crystal lattice in such a way as to leave a narrow
cylindrical channel with the diameter of 5.3 Å. Com-
pounds with a small cross-section diameter can reside
in these clathrate channels. Straight-chain normal al-
kanes having seven or more carbon atoms such as
n-hexadecane form complexes with urea, but bulky,
branched-chain hydrocarbons such as 2,2,4-trimethyl-
pentane do not. The single-crystal X-ray diffraction
shows that the guest molecule hydrocarbon was not
bonded to the host urea, but merely trapped in the
channel.28 This urea inclusion complexation has also
been utilized for the separation of oleic acid from linoleic
acid,29 because the two cis double bonds at the 9- and
1
2-positions in linoleic acid render it too bulky to lie
inside the clathrate channel. We utilized urea inclusion
complexation to separate the (E,E)-dienoic acid from its
(E,Z)-isomer. The optimum ratio of the host urea to the
guest dienoic acid was predetermined to be 14. The
mixed-isomer dienoic acid sample was added to a metha-
nolic solution of urea. The more linear (E,E)-dienoic acid
formed an inclusion complex with the urea and precipi-
tated. The bent (E,Z)-isomer apparently did not fit in
the urea clathrate channel and stayed in the solution.
Upon filtration and then extraction of the inclusion
complex with ether, the recovered dienoic acid was
exclusively the (E,E)-isomer. The characteristic vinyl
proton of (E,Z)-isomer at 7.55-7.68 ppm was not ob-
1
served in the H NMR spectrum.
a
(
a) 1 equiv of DCC, 1 equiv of DMAP, CHCl3, rt; (b) 1 N HCl,
The acylation of 1,2-O-isopropylidene-sn-glycerol with
dienoic acid 4a using DCC and DMAP in chloroform gave
the protected monodienoylglycerol 5 (Scheme 2). The
amount of protected glycerol and acid 4a employed is
quite crucial to the yield of the product. When equimolar
amounts of the protected glycerol and acid 4a were used,
the product 5 was obtained in ca. 40% yield along with
acid anhydride and acid-DCC complex side products.
However, the yield could be increased to 96% based on
dienoic acid when excess protected glycerol (1.5 molar
equiv) was employed. The deprotection of the isopropy-
lidene group proceeded in high yield upon treating 5 with
a 1 N HCl solution in methanol at rt. The monodienoyl-
glycerol 1 was obtained as a white solid in 80% yield after
purification by column chromatography. The purity of
this polymerizable lipid was confirmed by elemental
MeOH, rt, 2 h.
or by hydrolysis using dimethylboron bromide at 10 °C.
However deprotection via hydrogenation will affect the
dienoyl group. The deprotection of benzyl ether with
dimethylboron bromide usually does not proceed com-
pletely and sometimes affords the deprotected product
in only low yield. Another possibility is 2,2,2-trichloro-
ethoxycarbonate (Troc) which can readily be removed by
activated zinc,3
1,32
which does not interfer with the
polymerizable dienoyl group. However the acylation of
the Troc-protected glycerol also liberated 2,2,2-trichlo-
roethanol leading to several side reactions. Recently,
Hebert et al. reported the synthesis of an unusual
macrocyclic and bolaform phosphatidylcholine using 3-(4-
methoxybenzyl)-sn-glycerol as the starting material and
a new reagent for the removal of the 4-methoxybenzyl
ether (PMB) protecting group.33 The subsequent acid-
catalyzed hydrolysis of the electron-rich PMB using
dimethylboron bromide proceeded rapidly at low tem-
perature (-78 °C), giving the deprotected product in high
yield. In our synthesis of the polymerizable 1,2-bis-
1
analysis and H NMR. It was further characterized by
UV/vis spectroscopy. Lipid 1 in water shows a λmax at
4
2
cm).
56 nm with an extinction coefficient of 1.24 × 10 L/(mol
The successful synthesis of 1,2-bis[2,4-(E,E)-tetradeca-
dienoyl]-sn-glycerol depends on effectiveness of C3 hy-
droxy group protection in the glycerol (Scheme 3). The
requirements for this protecting group are (1) stability
during the acylation step, (2) ready removal without
affecting the polymerizable dienoyl group, and (3) depro-
tection under nonbasic conditions in order to avoid acyl
chain migrations leading to the formation of the 1,3-
diacylglycerol. Several groups have reported the use of
(
dienoyl)-sn-glycerol 2, we found that PMB was an
effective hydroxyl protecting group which could be re-
moved without isomerization of the desired 1,2-diacyl-
glycerol.
1
,2-Bis[2,4-(E,E)-tetradecadienoyl]-sn-glycerol (2) was
synthesized by acylation of 3-(4-methoxybenzyl)-sn-
glycerol with (E,E)-dienoyl fatty acid 4a (Scheme 3). 3-(4-
Methoxybenzyl)-sn-glycerol (7)33 was obtained in two
steps starting from 1,2-O-isopropylidene-sn-glycerol.
3
-O-benzyl-sn-glycerol derivatives as intermediates in the
3
0
synthesis of various phospholipids and diacylglycerols.
Benzyl ethers can be removed by catalytic hydrogenation
(
30) Kadali, D. R.; Tereyak, A.; Fahey, D. A.; Small, D. M. Chem.
(
26) Fetterly, L. C. Non-Stoichiometric Compounds; Mandelcorn, L.,
Ed.; Academic Press: New York, 1965; Chapter 8.
27) (a) Farina, N. Inclusion Compounds; Atword, J . L., et al., Eds.;
Academic Press: New York, 1984; Vol. 2, p 69. (b) Reference 27a, Vol.
, p 297.
Phys. Lipids 1990, 52, 163-175.
(31) Pfeiffer, F. R.; Cohen, S. R.; Weisbach, J . A. J . Org. Chem. 1969,
34, 2795-2796.
(
(32) Pfeiffer, F. R.; Miao, C. K.; Weisbach, J . A. J . Org. Chem. 1970,
35, 221-224.
3
(
(
28) Smith, A. E. Acta. Crystallogr. 1952, 5, 224.
29) (a) Fieser, L. F. J . Chem. Educ. 1963, 457; (b) 1965, 42, 408.
(33) Hebert, N.; Beck, A.; Lennox, R. B.; J ust, G. J . Org. Chem. 1992,
57, 1777-1783.

5
914 J . Org. Chem., Vol. 61, No. 17, 1996
Srisiri et al.
Sch em e 3a
a
(a) NaH, THF; (b) 4-methoxybenzyl chloride; (c) 1 N HCl, MeOH; (d) 3, DMAP, DCC, CHCl3; (e) Me2BBr, -78 °C, CH2Cl2.
Treating the protected glycerol with NaH base in DMF
solvent and then trapping the anion with 4-methoxy-
benzyl chloride gave 1,2-O-isopropylidene-3-(4-methoxy-
benzyl)-sn-glycerol (6). The use of DMF facilitates this
nucleophilic substitution. The isopropylidene protecting
group was then easily removed in dilute HCl solution,
to give white solid 3-(4-methoxybenzyl)-sn-glycerol (7) in
quantitative yield. The acylation of protected glycerol 7
with 2,4-(E,E)-dienoyl fatty acid 4a in the presence of
coupling reagent DCC and DMAP again proceeded in
high yield when an excess amount of protected glycerol
relative to the fatty acid was used. The final step was
the removal of PMB group on the protected glycerol 8.
The PMB group was removed by treating it with excess
Con clu sion s
In summary, the polymerizable monodienoylglycerol 1
and 1,2-bis(dienoyl)-sn-glycerol 2 were designed and
synthesized for the future studies of the polymerization
of hydrated lipid-water phases. The synthesis utilized
for monodiacylglycerol 1 is straightforward, giving the
lipid in four steps in ca. 50% yield. The choice of
protecting group for hydroxy group on C3 of glycerol
backbone was crucial for the successful synthesis of 1,2-
bis(dienoyl)-sn-glycerol 2. 4-Methoxybenzyl ether is an
excellent choice for this protecting group since the
deprotection via Me
BBr-catalyzed hydrolysis at -78 °C
2
proceeded without affecting with the polymerizable di-
enoyl group or isomerization of 1,2-diacylglycerol to 1,3-
diacylglycerol. A phase investigation of these lipids and
their mixtures as well as their polymerization behavior
will be reported in due course.
2 2
dimethylboron bromide in dry CH Cl at -78 °C for 15
min. The reaction was quenched by diluting with ether
and washing with water until the aqueous extracts were
neutral. 1,2-Bis[2,4-(E,E)-tetradecadienoyl)-sn-glycerol
Exp er im en ta l Section
(2) was obtained in 80% yield after purification by column
chromatography. The purity of the product was deter-
mined by thin layer chromatography and H NMR
spectroscopy. The solvent system of toluene, chloroform,
and methanol (85:15:5) is useful for the separation of 1,2-
diacylglycerol and 1,3-diacylglycerol. TLC of the isolated
Gen er a l P r oced u r e. Decanal, 2,2,2-trichloroethylchloro-
formate, and (S)-(+)-2,2-dimethyl-1,3-dioxalane-4-methanol
were obtained from Aldrich Chemical Corp. Trimethyl
1
4
-phosphonocrotonate was purchased from Lancaster Synthe-
sis Inc. THF was distilled from sodium benzophenone ketyl,
and chloroform was distilled from CaH . Compounds contain-
2
product in this solvent system showed only one spot with
ing UV-sensitive group were handled under yellow light. The
reactions were monitored by TLC visualized by UV lamp.
NMR spectra were recorded on a 250 MHz magnetic resonance
spectrometer in chloroform-d with TMS as an internal refer-
ence. Melting points were measured and corrected. Elemental
analyses were performed by Desert Analytics, Tucson, AZ.
FAB-MS was performed by Nebraska Center of Mass Spec-
trometer, NE. High-resolution mass spectroscopy was per-
formed by Mass Spectroscopy Facility, The University of
Arizona.
Meth yl 2,4-Tetr a d eca d ien oa te (3). Hexane (30 mL) was
added into the flask containing 1.6 g (45 mmol) of NaH (60%
in mineral oil) under argon. The mixture was stirred for 5
min, and the hexane was removed under vacuum. Dry THF
(100 mL) was transferred into the flask under argon, and the
solution of trimethyl 4-phosphonocrotonate (8.0 g, 38 mmol)
in 200 mL of THF was then added dropwise at 0 °C. After 1
h, the solution of decanal (5.0 g, 32 mmol) in 200 mL of THF
was added slowly at 0 °C. The reaction was allowed to warm
up to rt and monitored by TLC using hexane/EtOAc (97/3) as
the mobile phase. After the reaction was completed, excess
NaH was killed by slow addition of cold water to the reaction.
After evaporation of THF, the residue was diluted by diethyl
1
a R
f
value of 0.24.34 The H NMR spectrum of the product
showed distinctive multiplet peaks at chemical shifts of
.10-5.00 ppm that are characteristic of the proton at
5
the C2 position on glycerol backbone of 1,2-diacylglycerol.
The characteristic multiplet peaks at chemical shifts of
4
.10-4.00 ppm for the proton at the C2 position of 1,3-
3
4
1
diacylglycerol was not observed. The TLC and H NMR
data show that deprotection of PMB group by Lewis acid
catalyzed hydrolysis proceeds without detectable isomer-
ization of the 1,2-diacylglycerol. In contrast attempted
deprotection of the PMB group via DDQ oxidation under
nearly neutral conditions at room temperature35 took
place slowly and afforded product 2 in only low yield
along with its 1,3-isomer.
(
34) Ponpipom, M. M.; Bugianesi, R. L. J . Lipid Res. 1980, 21, 336-
3
39.
(
35) Quindon, Y.; Yoakim, C.; Morton, H. E. J . Org. Chem. 1984,
2
9, 3912-3920.

Syntheses of Polymerizable Acylglycerols
J . Org. Chem., Vol. 61, No. 17, 1996 5915
ether and extracted with water and brine. The organic layer
was dried with anhydrous MgSO and concentrated. The
4
product was purified by column chromatography using hexane/
A solution of 1,2-O-isopropylideneglycerol (2 g, 15 mmol) in
anhydrous DMF was added dropwise to a suspension of NaH
(1 g, 60% dispersion in mineral oil, 25 mmol) in 100 mL of
DMF. The reaction mixture was refluxed for 30 min, and
4-methoxybenzyl chloride (2.37 g, 15 mmol) was added in two
portions. The reaction was followed by TLC using hexane/
EtOAc (3/1) as the mobile phase. As soon as the 4-methoxy-
benzyl chloride was totally consumed, the reaction mixture was
allowed to cool to rt, and water was added slowly to quench
the excess NaH. The reaction mixture was then concentrated.
The residue was dissolved in ether and extracted many times
with water and brine. The organic layers were combined, dried
EtOAc (97/3) to give methyl ester 2 in 75% yield. IR (NaCl):
926, 1718, 1647 cm-1
.
1
2
3
H NMR (CDCl ): 7.68-7.55 ((E,Z)-
isomer, m, 1H) and 7.40-7.29 ((E,E)-isomer, dd, J ) 15.18,
1
1
0
0.01 Hz, 1H), 6.10-6.05 (m, 2H), 5.75-5.68 (d, J ) 15.18 Hz,
H), 3.67 (s, 3H), 2.10-2.04 (m, 2H), 1.33-1.09 (br, 14H),
.83-0.78 (t, J ) 5.05 Hz, 3H) ppm. Anal. Calcd: C, 75.63;
H, 10.92. Found: C, 75.30; H, 11.19.
,4-Tetr a d eca d ien oic Acid (4). A methanolic solution of
methyl ester 3 (5.0 g, 200 mmol in 100 mL) was treated with
.5 molar equiv of an 85% aqueous solution of KOH. The
mixture was refluxed gently until the ester disappeared (about
h) as determined by TLC using hexane/ethyl acetate (97/3)
2
1
with anhydrous MgSO
was purified by column chromatography using hexane/EtOAc
4
, and concentrated. The crude product
-
1
5
(3/1) as the eluent (90% yield). IR (NaCl): 2988, 1612 cm .
1
as the mobile phase. The methanolic solution was concen-
trated and then diluted with ether. After the solution was
acidified to pH 3 with dilute HCl solution, it was extracted
many times with water. The organic layer was dried with
anhydrous MgSO
4
and then concentrated, affording the crude
dienoic acid 4.
3
H NMR (CDCl ): 7.27-7.24 (d, J ) 8.71 Hz, 2H), 6.89-6.86
(d, J ) 8.71 Hz, 2H), 4.50-4.49 (d, J ) 3.73 Hz, 2H), 4.31-
4.25 (m, 1H), 4.07-4.01 (m, 1H), 3.79 (s, 3H), 3.75-3.68 (m,
1H), 3.55-3.40 (m, 2H), 1.42 (s, 3H), 1.36 (s, 3H) ppm.
33
3
-(4-Meth oxyben zyl)-sn -glycer ol (7). A dilute solution
of 1 N HCl was added into the solution of compound 6 in
methanol solvent, and the reaction was stirred for 2 h. After
extraction with ether and removal of solvent, the residue was
purified by column chromatography using hexane/EtOAc (3/
2
,4-(E,E)-Tetr a d eca d ien oic Acid (4a ). A well-stirred
solution of urea (6.0 g, 100 mmol) in methanol (100 mL) was
treated with a solution of acid 4 (2.7 g, 12 mmol) in methanol
(100 mL). The solution was then kept at 0 °C overnight. The
1
) as the eluent. The product was obtained in quantitative
crystalline needles were filtered, washed many times with
methanol, and then dried under vacuum. These crystals were
dissolved in ether and washed several times with dilute HCl
solution and water. The organic layer was combined and dried
with anhydrous MgSO
4
. After concentration, the crude acid
was purified by recrystallization from hexane at -30 °C, giving
the dienoic acid 4a as colorless needles in 80% yield. IR
-1
1
yield as a white solid. IR (NaCl): 3426, 1605 cm
.
H NMR
(
8
3
3
CDCl ): 7.27-7.24 (d, J ) 8.71 Hz, 2H), 6.91-6.87 (d, J )
.71 Hz, 2H), 4.49 (s, 2H), 3.49-3.89 (m, 1H), 3.81 (s, 3H),
.76-3.49 (m, 4H) ppm.
1
,2-Bis[(E,E)-2,4-tetr adecadien oyl]-3-(4-m eth oxyben zyl)-
sn -glycer ol (8). 4-Methoxybenzyl-protected glycerol 7 (0.3 g,
.4 mmol), acid 4a (0.4 g, 1.8 mmol), and DMAP (0.2 g, 1.8
mmol) were dissolved in 20 mL of chloroform, and then 0.4 g
41.8 mmol) of DCC in 10 mL of chloroform was added. After
1
-
1
1
(
(
(
3
NaCl): 3429, 2922, 1684 cm . H NMR (CDCl ): 7.40-7.29
dd, J ) 15.28, 10.26 Hz, 1H), 6.21-6.18 (m, 2H), 5.81-5.75
d, J ) 15.28 Hz, 1H), 2.22-2.14 (m, 2H), 1.43-1.21 (br, 14H),
(
the solution was stirred at rt overnight, the urea was filtered
and the filtrate was concentrated. The crude product was
0
.91-0.85 (t, J ) 6.50 Hz, 3H) ppm. Anal. Calcd: C, 75.00;
H, 14.29. Found: C, 75.30; H, 14.42.
,2-O-Isop r op ylid en e-3-(2,4-(E,E)-t et r a d eca d ien oyl)-
purified by column chromatography using hexane/EtOAc (9/
1
1
1
) to give the protected glyceride 5 in 50% yield. H NMR
sn -glycer ol (5). (S)-(+)-2,2-Dimethyl-1,3-dioxalane-4-metha-
nol (0.7 g, 4.8 mmol), acid 4a (0.9 g, 4.0 mmol), and DMAP
3
(CDCl ): 7.19-7.15 (m, 4H), 6.81-6.77 (d, J ) 8.69 Hz, 2H),
6
5
2
.10-6.05 (m, 4H), 5.76-5.65 (dd, J ) 12.65, 15.20, 2H), 5.25-
.23 (m, 1H), 4.42-4.40 (d, J ) 13.62 Hz, 2H), 4.31-4.25 (m,
H), 3.72 (s, 3H), 3.55-3.53 (d, J ) 5.14 Hz, 2H), 2.13-2.05
(0.5 g, 4.0 mmol) were dissolved in 20 mL of chloroform, and
then 0.8 g (4.0 mmol) of DCC in 10 mL of chloroform was
added. After the solution was stirred at rt overnight, the urea
was filtered and the filtrate was concentrated. The crude
product was purified by column chromatography using hexane/
(
m, 4H), 1.61-1.19 (b, 28H), 0.83-0.78 (t, J ) 6.53 Hz, 6H)
ppm.
1,2-Bis[(E,E)-2,4-tetr a d eca d ien oyl]-sn -glycer ol (2). A
1
EtOAc (9/1), to give the protected glyceride 5 in 96% yield. H
the solution of the protected glycerol 8 (0.1g, 0.16 mmol) in
dry dichloromethane at -78 °C was treated with dimethyl-
boron bromide (0.05 mL, 0.51 mmol) by addition through a
syringe under argon. The reaction mixture was stirred for 15
min while the dry-ice bath was removed. The reaction was
then diluted with ether and quenched with water slowly. The
organic layer was washed many times with water until the
aqueous part was neutral. After evaporation of the solvent,
NMR (CDCl
5
2
3
): 7.31-7.21 (m, 1H), 6.14-6.11 (m, 2H), 5.82-
.67 (d, J ) 15.29 Hz, 1H), 4.35-4.04 (m, 5H), 2.17-2.09 (m,
H), 1.41 (s, 6H), 1.39-1.23 (br, 14H), 0.87-0.82 (t, J ) 6.85
Hz, 3H) ppm. Anal. Calcd: C, 71.00; H, 10.06. Found: C,
1.36; H, 9.91.
-(2,4-(E,E)-Tetr a d eca d ien oyl)-sn -glycer ol (1). A solu-
7
3
tion of protected glyceride 4 (1.3 g) in 20 mL of methanol was
treated with 5 mL of a 1 N HCl solution. The solution was
stirred at rt for 2 h and then diluted with 50 mL of ether. The
ether solution was washed with saturated NaHCO
After being dried with anhydrous MgSO , the organic layer
the crude 1,2-bis(dienoyl)-sn-glycerol 2 was purified by column
1
chromatography using hexane/EtOAc (1/1) (80% yield).
NMR (CDCl
H
3
and brine.
3
): 7.35-7.23 (m, 2H), 6.18-6.15 (m, 4H), 5.84-
4
5
2
1
.76 (m, 2H), 5.19-5.15 (m, 1H), 4.62-4.37 (d, J ) 5.08 Hz,
H), 3.81-3.77 (m, 2H), 2.48 (b, 1H), 2.20-2.13 (m, 4H), 1.45-
.27 (b, 28H), 0.91-0.85 (t, J ) 6.52 Hz, 6H) ppm. FAB-MS:
was concentrated. The crude product was purified by column
chromatography using hexane/EtOAc (1/1), affording the
monoacylglycerol 1 as a white solid in 81% yield. Mp: 50-51
+
+
-
1
1
calcd 504 (M ), 224 (fatty acid), found 504 (M ), 224 (fatty
acid). High-resolution-MS: found 505 (M + 1), 487 (M - OH),
2
°
C. IR (NaCl): 3279, 2920, 1705 cm
.
H NMR (CDCl
3
):
+
7
.25-7.19 (m, 1H), 6.13-6.09 (m, 2H), 5.77-5.71 (d, J ) 15.27
81 (487 - tetradecadienoyl), 207 (fatty acid-OH).
Hz, 1H), 4.21-4.13 (m, 2H), 3.91-3.88 (m, 1H), 3.67-3.51 (m,
2
0
2
H), 2.23 (br, 2H), 2.12-2.07 (m, 2H), 1.36-1.20 (br, 14H),
+
.84-0.79 (t, J ) 6.85 Hz, 3H) ppm. FAB-MS: calcd 298 (M ),
Ack n ow led gm en t. The authors thank the National
Science Foundation for support of this research.
+
07 (fatty acid-OH) found 298 (M ), 207 (fatty acid-OH). High-
resolution-MS found.: 299 (M+1), 207 (fatty acid-OH).
1
,2-O-Isopr opyliden e-3-(4-m eth oxyben zyl)glycer ol (6).33
J O960010B