A simple and efficient method for direct acylation of acetals with long alkyl-chain carboxylic acid anhydrides

Article abstract of DOI:10.1016/S0040-4020(00)00924-8

We have developed an efficient and simple method for direct transformation of acetals to carboxylic acid esters. The method consists of treatment of acetals with carboxylic anhydrides in the presence of boron trifluoride etherate as a catalyst and affords the corresponding ester derivatives in high yields with retention of configuration in the alcohol moiety. Some mechanistic aspects of this synthetically useful transformation are also discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00924-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9697±9703
A Simple and Ef®cient Method for Direct Acylation of Acetals
with Long Alkyl-Chain Carboxylic Acid Anhydrides
b,c,
Stephan D. Stamatova, and Jacek Stawinski
*
*
aDepartment of Chemical Technology, University of Plovdiv, 24 Tsar Assen St., Plovdiv 4000, Bulgaria
bDepartment of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
cInstitute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland
Received 24 July 2000; revised 13 September 2000; accepted 28 September 2000
AbstractÐWe have developed an ef®cient and simple method for direct transformation of acetals to carboxylic acid esters. The method
consists of treatment of acetals with carboxylic anhydrides in the presence of boron tri¯uoride etherate as a catalyst and affords the
corresponding ester derivatives in high yields with retention of con®guration in the alcohol moiety. Some mechanistic aspects of this
synthetically useful transformation are also discussed. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
triacylglycerols, and various phospholipids, where
extensive side-reactions (e.g. acyl and phosphoryl migra-
tion, formation of cyclic systems, racemization, etc) often
occur after exposing the free hydroxyl groups of the
glycerol backbone.4±6,10,13±16 To overcome these dif®culties,
various attempts have been made to prepare the correspond-
ing carboxylic esters via a one-pot acylolytic cleavage of
acetals. For this purpose, the following reagent systems
have been proposed: mixtures of acetic anhydride±sul-
phuric acid,17 tri¯uoroacetic anhydride±acetic acid,12
tri¯uoroacetic anhydrideÐa fatty acid (also in combination
with BF3´OEt2),18 carboxylic acids±p-toluenesulfonic acid19
and acid chlorides in conjunction with ZnCl2.19,20 All these
methods, although useful in general context, suffer from
various disadvantages, e.g. incompatibility with substrates
containing acid-sensitive groups, low to moderate yields
(35±68%) of the desired compounds, extended reaction
time (1±3 days), and often harsh reaction conditions.18±20
One should also note that in most instances these methods
were evaluated only on racemic substrates with limited
structural variations, and thus scope and stereochemical
courses of the reactions involved remain obscure.
Due to its reactivity towards various electrophilic reagents,
a hydroxyl function usually has to be protected in long
preparative schemes. Although a vast array of protecting
groups are available for this purpose,1 acetals of various
degrees of stability are still the most common derivatives
that are used in protection±deprotection protocols in carbo-
hydrate, nucleic acid, steroid, and lipid chemistry.1±7
Since acyl groups in polyhydroxylic systems have a
tendency to undergo facile migration and cleavage,8,9
acetals are often used as a transient protection that enables
subsequent introduction of an ester functionality at the end
of a synthesis. Due to this, deprotection conditions for
acetals have to be carefully chosen to preserve the integrity
of a molecular framework of synthesised products. The
moderate to strong acidic conditions required for deprotec-
tion of acetals are known to provoke often undesirable
molecular rearrangements, elimination processes or other
side-reactions.4±6,10±12 Consequently, the respective poly-
hydroxylic intermediates obtained after the removal of an
acetal-protecting group have to be separated from the
accompanying by-products. This is not always an easy
task and adversely affects the total yield of the synthesis.
In this paper we describe an ef®cient method for stereo-
selective acylation of acetal-protected hydroxyl functions
with long alkyl-chain carboxylic acid anhydrides, in
which the replacement of the acetal moiety by the acyl
function is mediated by catalytic amounts of BF3´OEt2 to
give the target esters in practically quantitative yields under
mild reaction conditions.
These problems are probably most acute in the synthesis of
lipids and their conjugates as it is apparent from repeatedly
reported complications in the synthesis of chiral mono-, di-,
Keywords: acetals; carboxylic acid esters; boron tri¯uoride.
* Corresponding authors. Department of Organic Chemistry, Arrhenius
Laboratory, Stockholm University, S-106 91 Stockholm, Sweden; e-mail:
js@organ.su.se; Tel.: 1359-32-261-536; fax: 1359-32-635-046; e-mail:
sstov@argon.acad.bg
Results and Discussion
The purpose of our studies was to investigate the reaction of
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00924-8

9698
S. D. Stamatov, J. Stawinski / Tetrahedron 56 (2000) 9697±9703
acetals with carboxylic anhydrides mediated by BF3´OEt2
for direct preparation of carboxylic acid esters without
prior deprotection of the acetal functionality. From a large
array of different types of acetals we chose those with differ-
ent structural features and which are most interesting as
substrates for designing lipophilic acyl bioconjugates
based on glycerol and glycerophospholipids.3±6,21±23 As
typical representatives we selected three types of acetals:
isopropylidene, benzylidene and tetrahydropyranyl deriva-
tives. These included 2,2-dimethoxypropane (1a), benzalde-
hyde dimethylacetal (1b), 2-O-hexadecyl-1,3-benzylidene
optimised runs were isolated and their structure and purity
1
were con®rmed by H and 13C NMR spectroscopy (see the
Experimental).
Best results were obtained when acetals (1a±h) were
allowed to react with carboxylic anhydrides (2a±c,
1 equiv. per alcohol moiety) in the presence of boron
tri¯uoride etherate (,0.2 equiv. per alcohol moiety) in
aprotic solvents (e.g. CH2Cl2, CHCl3) with moderate heat-
ing (,40±608C). Under these conditions the expected ester
derivatives 3a±k were produced within 4±6 h in con-
sistently excellent isolated yields (.90%).24 When the
reactions were carried out on enantiomerically pure
substrates (e.g. glycerol derivatives 1d±g and cholesteryl
derivative 1h), the optical rotation of the isolated products
indicated that the transformation occurred with complete
retention of con®guration at the chiral centre in the corre-
sponding alcohol moiety.
glycerol
(1c),
1-O-hexadecyl-2,3-isopropylidene-sn-
glycerol (1d), 1,2-isopropylidene-3-(20,20,20-trichloroethoxy)-
carbonyl-sn-glycerol (1e), 3-O-benzyl-1,2-isopropylidene-
sn-glycerol (1f), 1,2-isopropylidene-sn-glycero-3-O-p-
toluenesulfonate (1g), and cholesteryl-3-O-tetrahydro-2H-
pyran (1h) (see Chart 1). The choice of oleic (2a), stearic
(2b) and palmitic (2c) anhydrides as acylating agents in
these studies was justi®ed by the biological importance of
these fatty acids and the synthetic interest they represent
as lipid constituents with a different chain length and a
different degree of unsaturation.
In these reactions the catalytic effect of BF3´OEt2 is most
likely due to Lewis acid properties of the catalyst, which
exhibited a maximum activity when ca. 0.2 equiv. of
BF3´OEt2 per alcohol moiety were used. In the acylation
of typical substrates 1c, 1d and 1h, BF3´OEt2 exerted only
negligible catalytic effect when used in less than 0.1 equiv./
alcohol moiety, as judged from the exceedingly slow forma-
tion of the acylated products 3 (.5 days at ,608C). The rate
The reactions were investigated under various experimental
conditions by changing solvents and varying amounts of the
reactants and the catalyst (BF3´OEt2). Progress of the acyl-
ation was monitored by TLC analysis and the products from
Chart 1.

S. D. Stamatov, J. Stawinski / Tetrahedron 56 (2000) 9697±9703
9699
Scheme 1.
of esteri®cation was sharply increased in a very narrow
range of the concentration of the catalyst (0.1±0.2 equiv.)
and then showed a certain tendency to decreasing when the
amount of BF3´OEt2 exceeded 0.25 equiv. per alcohol
moiety. This dependency on the concentration of boron
tri¯uoride, is most likely due to involvement of the catalyst
in complex equilibria systems resulting from its co-ordina-
tion to various nucleophilic centres in substrates, products
and intermediates. It is worth noting, however, that acetals 1
(e.g. 1c, 1d and 1h) and carboxylic anhydride 2a±c, when
treated separately in deuterated chloroform with equimolar
amounts of BF3´OEt2, remained completely unchanged
clearly indicated the formation of free fatty acids during the
course of the reaction.
In the acylation of glycerol derivatives 1c±g with
carboxylic anhydrides 2 we observed that the starting
acetals disappeared within a few minutes upon addition of
BF3´OEt2 with little formation of the ®nal products 3.
Instead, TLC analysis revealed formation of polar inter-
mediates (one or two spots with Rf values ca 0.2±0.4;
System B) that gradually underwent conversion to the corre-
sponding ®nal products 3. Since the observed intermediates
had chromatographic mobility identical to those of the refer-
ence mono-deacylated compounds derived from products of
type 3 (structures not shown) we assumed that these were
artefacts and arose via hydrolysis on TLC plates of some
other reactive species initially present in the reaction
mixtures.
1
within 24 h at rt, as judged from the H- and 13C NMR
spectra of the corresponding reaction mixtures.
As to a possible mechanism for the replacement of an acetal
group by an acyl group under the investigated reaction
conditions, some additional observations are pertinent.
Although acetals 1a±g in the presence of BF3´OEt2 required
at least 1 equiv. of carboxylic anhydride 2 per alcohol
moiety for the reaction to go to completion,25 the TLC
analysis and 13C NMR spectra did not reveal any formation
of the corresponding fatty acids, but instead, partially
unreacted anhydrides 2 were still present at the end of the
reaction (TLC and 13C NMR analyses).26 Only for the tetra-
hydropyranyl derivative 1h, both TLC and 13C NMR data
The above ®ndings permitted us to propose a tentative
mechanism for a BF3´OEt2-catalysed direct acylation of
acetals with carboxylic anhydrides (Schemes 1 and 2).
According to the mechanism in Scheme 1, the reaction
commences with a BF3´OEt2-assisted transfer of the ®rst
acyl group to an alcohol moiety of an acetal. The cleavage
of the latter and the formation of oxocarbenium ion (inter-
mediate A) can occur simultaneously or may involve the
Lewis acid-mediated generation of an acylium ion from
the carboxylic anhydride followed by reaction with the
acetal. This transformation is apparently fast and may
explain the observed rapid disappearance of the starting
material upon addition of BF3´OEt2 to the reaction mixtures.
The oxocarbenium ion may co-ordinate the carboxylate
formed and collapses to intermediate B, which reaction
with another molecule of the anhydride is apparently the
rate determining step of the whole transformation.
For glycerol derivatives, transfer of the second acyl group
could, in principle, occur as an intramolecular reaction of
intermediate B, but this is probably not the case on two
counts. First, an intramolecular acyl transfer would require
a four-membered cyclic transition state and this, probably, is
not kinetically favoured. Second, the reaction should be
relatively insensitive to the concentration of the carboxylic
Scheme 2.

9700
S. D. Stamatov, J. Stawinski / Tetrahedron 56 (2000) 9697±9703
anhydride used and would require only 0.5 equiv. of 2 per
alcohol moiety for the completion. Since these possibilities
disagree with the experimental data, a more likely pathway
for collapsing of intermediate B into product C probably is
an intermolecular reaction of B with 2, which ultimately
regenerates equimolar amounts of the carboxylic anhydride.
Since none of the reaction steps in Scheme 1 involve the
C±O bond scission of an alcohol moiety, the proposed
mechanism predicts retention of con®guration in the alcohol
unit.
v); System D, n-hexane±CH2Cl2 (80:20, v/v). Progress of
the reactions was monitored by analytical thin-layer
chromatography (TLC) on pre-coated glass plates of silica
gel 60 F254 (Merck) using the same solvent systems as for
CC. The spots were visualised using the commercially
available 3.5% molybdatophosphoric acid spray reagent
(Merck) or 50% sulphuric followed by heating at 1408C.
1H and 13C NMR spectra were recorded on a Varian
400 MHz machine and chemical shifts are reported in
ppm relative to TMS. The assignment of proton and carbon
resonances of 3a±k was done on the basis of known or
expected chemical shifts in conjunction with 1H±1H,
1H±13C, and DEPT correlated NMR spectroscopy. Infrared
(IR) spectra were recorded on a Perkin±Elmer FT-IR 1750
spectrometer and positions of the absorption bands are
reported in cm21. Optical rotations were measured on a
Perkin±Elmer 241 digital polarimeter. The melting points
were determined on a Ko¯er melting point apparatus and are
uncorrected.
A similar tentative mechanism, consistent with experi-
mental data, can also be proposed for the conversion of
tetrahydropyranylated derivative 1h to the corresponding
ester 3k (Scheme 2).
In this instance, the transfer of an acyl group leads directly
to product 3k or may involve the initial generation of an
acylium ion from the carboxylic anhydride mediated by
BF3´OEt2. The observed formation of free fatty acids during
the course of this reaction can probably occur either by a
direct abstraction of proton from the oxocarbenium ion or
may involve an acylacetal as an intermediate.27
General procedure for direct acylation of acetals 1
To a solution of acetal 1 (0.20 mmol) and carboxylic acid
anhydride 2 (0.50 mmol) in alcohol-free chloroform
(10 mL), was added boron tri¯uoride etherate (0.014 g;
0.10 mmol) and the reaction mixture was re¯uxed
(,618C) with stirring under nitrogen for 4 h. After cooling
to room temperature, triethylamine (0.101 g, 1.00 mmol)
was added and the mixture was stirred for 30 min. To
remove BF3´OEt2, the reaction mixture was passed through
an aluminium oxide pad (15 g; weakly acidic, type 506 C
from Fluka) and the support was washed with ethyl acetate
(3£50 mL). Fractions containing crude product 3 were
combined, the solvents removed under reduced pressure,
and the residue was chromatographed on a silica gel column
using solvent systems A±D.
In summary, direct acylation of acetals 1 with carboxylic
anhydrides 2 in the presence of BF3´OEt2 represents a
general protocol that secures synthesis of the corresponding
carboxylic esters 3 in consistently high yields and with
retention of con®guration in the alcohol moiety. The main
advantages of the method are: (i) high ef®ciency and mild
reaction conditions, (ii) the method makes use of commer-
cially available reactants and is easy to scale-up, (iii) it
alleviates problems of deprotection of an acetal function
prior to acylation, and thus minimises the possibility of
occurrence of side reactions due to generation of free
hydroxyl functions.
Experimental
Methyl oleate 3a. Obtained from benzaldehyde dimethyl-
acetal (1b; 0.030 g; 0.20 mmol), oleic anhydride (2a;
0.273 g; 0.50 mmol) and boron tri¯uoride etherate
(0.014 g; 0.10 mmol). CC system A. Yield:0.109 g (93%,
colourless oil); Rf (system B)ˆ0.60. Anal. Calcd for
C19H36O2 (296.50): C, 76.96; H, 12.26. Found: C, 76.74;
1,2-Isopropylidene-3-(20,20,20-trichloroethoxy)carbonyl-sn-
glycerol, 1-O-hexadecyl-2,3-isopropylidene-sn-glycerol, 2-
O-hexadecyl-1,3-benzylidene glycerol, and cholesteryl-3-
O-tetrahydro-2H-pyran were synthesised according to
published procedures.28±32 The reference samples of acetals
3c, 3d, and 3i were prepared via acylation of the correspond-
ing glycerol derivatives (i.e. 2-O-hexadecyglycerol, 1-O-
hexadecyl-sn-glycerol, and 3-O-p-toluenesulfonyl-sn-
glycerol, respectively) with the corresponding fatty acids
in the presence of dicyclohexylcarbodiimide,33 and their
melting points or speci®c rotation were identical to those
of compounds synthesised via a direct acylation protocol
(see below). All other reagents were commercial grade
(Fluka, Lancaster, Merck, Sigma) with purity .98% and
were used as provided without further puri®cation. Solvents
were dried and distilled prior to use according to standard
protocols.34
1
H, 12.38. H NMR dH (in ppm, CDCl3) 0.88 (t, Jˆ6.7 Hz,
CH3, 3H); 1.24±1.38 (m, (CH2)4; (CH2)6; 20H); 1.56±1.66
(m, CH2CH2CO, 2H); 1.94±2.06 (m, CH2CHv, 4H); 2.30
(t, Jˆ7.3 Hz, CH2CO, 2H); 5.30±5.39 (m, CHv, 2H):
oleoyl fragment; 3.66 (m, CH3, 3H): methyl fragment. 13C
NMR dC (in ppm, CDCl3) 14.50 (18-CH3); 23.06 (C-17);
25.33 (C-3); 27.53, 27.59 (C-11, C-8); 29.46±30.14 (C-4±
C-7, C-12±C-15); 32.27 (C-16); 34.45 (C-2); 129.86,
130.11 (C-9, C-10) 174.27 (C-1): oleoyl fragment; 51.71
(CH3): methyl fragment. IR (®lm) n 3004 (CHv); 1745
(CvO); 1171 cm21 (C±O±C).
Methyl stearate 3b. Obtained from 2,2-dimethoxypropane
(1a; 0.021 g; 0.20 mmol), stearic anhydride (2b; 0.275 g;
0.50 mmol) and boron tri¯uoride etherate (0.014 g;
0.10 mmol). CC system D. Yield: 0.108 g (90%, white crys-
tals); mpˆ46.7±48.38C (from system D, identical to that of
a commercial sample from Fluka); Rf (system B)ˆ0.61.
Anal. Calcd for C19H38O2 (298.51): C, 76.45; H, 12.83.
Column chromatography (CC) was carried out on silica gel
60 (70±230 mesh ASTM, Merck) using the following
mobile phases: System A, n-hexane±ethyl acetate (95:5,
v/v); System B, n-hexane±ethyl acetate (90:10, v/v);
System C, n-hexane±toluene±ethyl acetate (70:20:10, v/v/

S. D. Stamatov, J. Stawinski / Tetrahedron 56 (2000) 9697±9703
9701
1
Found: C, 76.53; H, 12.80. H NMR dH (in ppm, CDCl3)
0.88, CHCl3). Anal. Calcd for C42H73O7Cl3 (796.50): C,
63.33; H, 9.26; Found: C, 63.50; H, 9.20. H NMR dH (in
1
0.87 (t, Jˆ6.6 Hz, CH3, 3H); 1.22±1.34 (m, (CH2)14; 28H);
1.56±1.66 (m, CH2CH2CO, 2H); 2.30 (t, Jˆ7.7 Hz, CH2CO,
2H): stearoyl fragment; 3.66 (m, CH3, 3H): methyl frag-
ment. 13C NMR dC (in ppm, CDCl3) 14.51 (18-CH3);
23.07 (C-17); 25.35 (C-3); 29.53±30.06 (C-4±C-15);
32.29 (C-16); 34.48 (C-2); 174.33 (C-1): stearoyl fragment;
51.71 (CH3): methyl fragment. IR (KBr) n 1742 (CvO);
1177 cm21 (C±O±C).
ppm, CDCl3) 0.88 (t, Jˆ6.6 Hz, CH3, 6H); 1.22±1.38 (m,
(CH2)4; (CH2)6; 40H); 1.56±1.66 (m, CH2CH2CO, 4H);
1.94±2.06 (m, CH2CHv, 8H); 2.31 (sxt, Jˆ3.3 Hz,
CH2CO, 4H); 4.18 (dd, Jˆ5.9, 5.5 Hz, CH2CHCHaHbO-
C(O)O, 1H); 4.34 (m, CH2CHCH2OC(O)O, 2H); 4.44 (dd,
Jˆ4.0, 4.0 Hz, CH2CHCHaHbOC(O)O, 1H); 4.77 (m,
CH2CCl3, 2H); 5.27±5.39 (m, CHv, CH2CHCH2, 5H).
13C NMR dC (in ppm, CDCl3) 14.53 (18-CH3); 23.08
(C-17); 25.20, 25.22 (C-3, both acyl chains); 27.56, 27.61
(C-11, C-8); 29.40±30.14 (C-4±C-7, C-12±C-15); 32.27
(C-16); 34.36, 34.48 (C-2, both acyl chains); 129.83,
130.16 (C-9, C-10) 172.83, 173.19 (C-1, both acyl chains):
oleoyl fragment; 62.00, 66.98 (C-1, C-3); 68.76 (C-2):
glycerol fragment; 77.25 (C-2): 20,20,20-trichloroethylcarbo-
nyl fragment. IR (®lm) n 3005 (CHv); 1747 (CvO,
O(O)CvO); 1164 (C±O±C); 727 cm21 (C±Cl).
2-O-Hexadecyl-1,3-distearoyl glycerol 3c. Obtained from
2-O-hexadecyl-1,3-benzylidene glycerol (1c; 0.081 g;
0.20 mmol), stearic anhydride (2b; 0.275 g; 0.50 mmol)
and boron tri¯uoride etherate (0.014 g; 0.10 mmol). CC
system C. Yield: 0.153 g (90%, white crystals);
mpˆ54.5±56.38C (from system C); Rf (system B)ˆ0.71.
Anal. Calcd for C55H108O5 (849.63): C, 77.75; H, 12.84.
1
Found: C, 77.85; H, 12.77. H NMR dH (in ppm, CDCl3)
0.87 (t, Jˆ6.6 Hz, CH3, 9H); 1.22±1.34 (m, (CH2)14;
(CH2)13, 82H); 1.51±1.67 (m, CH2CH2CO, CH2CH2O,
6H); 2.32 (t, Jˆ7.7 Hz, CH2CO, 4H); 3.54 (t, Jˆ6.2 Hz,
CH2OCH2(CH2)14, 2H); 3.67 (p, Jˆ5.5 Hz, CHO(CH2)15,
1H); 4.11, 4.18 (dd, Jˆ5.9, 5.5 Hz, Jˆ4.8, 4.8 Hz,
CH2CHCH2, 4H). 13C NMR dC (in ppm, CDCl3) 14.53
(18-CH3); 23.09 (C-17); 25.32 (C-3); 29.54±30.06 (C-4±
C-15); 32.31 (C-16); 34.57 (C-2); 173.6 (C-1): stearoyl
fragment; 14.53 (16-CH3); 23.09±30.30 (C-3±C-15);
32.31 (C-2); 70.96 (C-1): hexadecyl fragment; 63.36 (C-1,
C-3); 75.45 (C-2): glycerol fragment. IR (KBr) n 1743
(CvO); 1179 (C±O±C); 1118 cm21 (C±O±Cether).
1,2-Distearoyl-sn-glycero-3-O-20,20,20-trichloroethylcar-
bonate 3f. Obtained from 1,2-isopropylidene-sn-glycero-3-
O-20,20,20-trichloroethylcarbonate (1e; 0.062 g; 0.20
mmol), stearic anhydride (2b; 0.275 g; 0.50 mmol) and
boron tri¯uoride etherate (0.014 g; 0.10 mmol) in CH2Cl2.
Stirred and re¯uxed (,408C) for 6 h under nitrogen. CC
system B. Yield: 0.152 g (95%, white crystals);
mpˆ55.2±56.48C (from system C); Lit. 36: mpˆ54±558C;
Rf (system B)ˆ0.70; [a]2D0ˆ21.69 (c, 2.20, CHCl3); Lit.35:
[a]2D5ˆ21.70 (c, 1.050, CHCl3). Anal. Calcd for
C42H77O71Cl3 (800.54): C, 63.01; H, 9.71; Found: C, 63.07;
H, 9.63. H NMR dH (in ppm, CDCl3) 0.88 (t, Jˆ6.6 Hz,
CH3, 6H); 1.22±1.32 (m, (CH2)14; 56H); 1.56±1.66 (m,
CH2CH2CO, 4H); 2.32 (sxt, Jˆ3.3 Hz, CH2CO, 4H); 4.18
(dd, Jˆ5.5, 5.9 Hz, CH2CHCHaHbOC(O)O, 1H); 4.35 (m,
CH2CHCH2OC(O)O, 2H); 4.44 (dd, Jˆ4.0, 4.0 Hz,
CH2CHCHaHbOC(O)O, 1H); 4.77 (m, CH2CCl3, 2H); 5.30
(m, CH2CHCH2, 1H). 13C NMR dC (in ppm, CDCl3) 14.54
(18-CH3); 23.09 (C-17); 25.22, 25.24 (C-3, both acyl
chains); 29.45±30.08 (C-4±C-15); 32.31 (C-16); 34.40,
34.51 (C-2, both acyl chains); 172.9, 173.2 (C-1, both
acyl chains): stearoyl fragment; 62.01, 66.98 (C-1, C-3);
68.75 (C-2): glycerol fragment; 77.25 (C-2): 20,20,20-
1-O-Hexadecyl-2, 3-dipalmitoyl-sn-glycerol 3d. Obtained
from 1-O-hexadecyl-2,3-isopropylidene-sn-glycerol (1d;
0.071 g; 0.20 mmol), palmitic anhydride (2c; 0.247 g;
0.50 mmol) and boron tri¯uoride etherate (0.014 g;
0.10 mmol). CC system C. Yield: 0.150 g (95%, white
crystals); mpˆ47.9±48.08C (from system C); Rf (system
B)ˆ0.73; [a]2D0ˆ24.2 (c, 2.02, CHCl3). Anal. Calcd for
C51H100O5 (793.51): C, 77.19; H, 12.73; Found: C, 77.01;
H, 12.80. 1H NMR dH (in ppm, CDCl3) (t, Jˆ6.6 Hz, CH3,
9H); 1.22±1.34 (m, (CH2)12; (CH2)13, 74H); 1.50±1.66 (m,
CH2CH2CO, CH2CH2O, 6H); 2.30 (q, Jˆ7.3 Hz, CH2CO,
4H); 3.42 (m, CH2OCH2(CH2)14, 2H); 3.53 (m,
CH2CHCH2OCH2(CH2)14, 2H); 4.15, 4.33 (dd, Jˆ6.6,
6.2 Hz, Jˆ3.7, 3.7 Hz, CH2CHCH2, 1H, 1H). 5.19 (m,
CH2CHCH2, 1H). 13C NMR dC (in ppm, CDCl3) 14.54
(16-CH3); 23.09 (C-15); 25.31, 25.38 (C-3, both acyl
chains); 29.54±30.09 (C-4±C-13); 32.31 (C-14); 34.53,
34.73 (C-2, both acyl chains); 173.2, 173.5 (C-1, both
acyl chains): palmitoyl fragment; 14.54 (16-CH3); 23.09±
30.09 (C-3±C-15); 32.31 (C-2); 69.23 (C-1): hexadecyl
fragment; 63.08, 72.03 (C-1, C-3); 70.35 (C-2): glycerol
fragment. IR (KBr) n 1732 (CvO); 1184 (C±O±C);
1105 cm21 (C±O±Cether).
trichloro±ethylcarbonyl fragment. IR (KBr)
n
1770
(O(O)CvO) 1732 (CvO); 1156 (C±O±C); 728 cm21
(C±Cl).
3-O-Benzyl-1,2-dioleoyl-sn-glycerol 3g. Obtained from
3-O-benzyl-1,2-isopropy-lidene-sn-glycerol (1f; 0.044 g;
0.20 mmol), oleic anhydride (2a; 0.273 g; 0.50 mmol) and
boron tri¯uoride etherate (0.014 g; 0.10 mmol). CC system
B. Yield: 0.126 g (89%, colourless oil); Rf (system B)ˆ0.65;
[a]2D0ˆ15.94 (c, 2.02, CHCl3); Lit.37: [a]Dˆ16.20 (c, 10.0,
CHCl3). Anal. Calcd for C46H78O5 (711.24): C, 77.68; H,
1
11.08; Found: C, 77.75; H, 11.15. H NMR dH (in ppm,
CDCl3) 0.86 (t, Jˆ6.6 Hz, CH3, 6H); 1.20±1.38 (m,
(CH2)4; (CH2)6; 40H); 1.57±1.66 (m, CH2CH2CO, 4H);
1.96±2.05 (m, CH2CHv, 8H); 2.30 (m, CH2CO, 4H);
3.58 (d, Jˆ5.1 Hz, CH2CHCH2OCH2C6H5, 2H); 4.18 (dd,
Jˆ6.4, 6.4 Hz, CH2CHCHaHbOCH2C6H5, 1H); 4.34 (dd,
Jˆ3.7, 3.7 Hz, CH2CHCHaHbOCH2C6H5, 1H); 4.54 (m,
CH2C6H5, 2H); 5.24 (m, CH2CHCH2, 1H); 5.34 (m,
CHv, 4H); 7.31 (m, CH2C6H5, 5H). 13C NMR dC (in
ppm, CDCl3) 14.58 (18-CH3); 23.12 (C-17); 25.27, 25.35
1,2-Dioleoyl-sn-glycero-3-O-20,20,20-trichloroethylcarbon-
ate 3e. Obtained from 1,2-isopropylidene-sn-glycero-3-O-
20,20,20-trichloroethyl±carbonate (1e; 0.062 g; 0.20 mmol),
oleic anhydride (2a; 0.273 g; 0.50 mmol), and boron
tri¯uoride etherate (0.014 g; 0.10 mmol) in CH2Cl2. Stirred
and re¯uxed (,408C) for 6 h under nitrogen. CC system B.
Yield: 0.148 g (92%, colourless oil); Rf (system B)ˆ0.66;
[a]2D0ˆ21.42 (c, 1.54, CHCl3); Lit. 35: [a]2D5ˆ21.40 (c,

9702
S. D. Stamatov, J. Stawinski / Tetrahedron 56 (2000) 9697±9703
(C-3, both acyl chains); 27.58, 27.62 (C-11, C-8); 29.47±
30.17 (C-4±C-7, C-12±C-15); 32.31 (C-16); 34.47, 34.69
(C-2, both acyl chains); 129.9, 130.2 (C-9, C-10)
173.17, 173.5 (C-1, both acyl chains): oleoyl fragment;
62.96, 68.51 (C-1, C-3); 70.27 (C-2): glycerol fragment;
73.58 (C-7); 127.8, 127.9, 128.6 (C-2±C-6); 137.8 (C-
1): benzyl fragment. IR (®lm) n 3004 (CHv); 1742
(CvO); 1497 (CvCaryl); 1168 (C±O±C); 1115 cm21
(C±O±Cether).
1,2-Distearoyl-sn-glycero-3-O-p-toluenesulfonate
3j.
Obtained from 1,2-isopropylidene-sn-glycero-3-O-p-toluene-
sulfonate (1g; 0.057 g; 0.20 mmol), stearic anhydride (2b;
0.275 g; 0.50 mmol) and boron tri¯uoride etherate (0.014 g;
0.10 mmol). CC system C. Yield: 0.144 g (93%, white crys-
tals); mpˆ73.5±74.68C (from system C); Lit.14: mpˆ73.0±
75.08C; Rf (system B)ˆ0.60; [a]2D0ˆ15.18 (c, 0.675,
CHCl3±CH3OH, 1:1); Lit.14: [a]2D5ˆ15.50 (c, 0.545,
CHCl3±CH3OH, 1:1). Anal. Calcd for C46H82O7S
(779.34): C, 70.89; H, 10.63; S, 4.11. Found: C, 70.71; H,
10.69; S, 4.09. 1H NMR dH (in ppm, CDCl3) 0.88 (t,
Jˆ7.0 Hz, CH3, 6H); 1.20±1.34 (m, (CH2)14; 56H); 1.54
(m, CH2CH2CO, 4H); 2.25 (m, CH2CO, 4H); 2.45 (s,
CH3C6H4, 3H); 4.08±4.20 (m, CH2CHCHaHbO-
S(O)2C6H4CH3, CH2CHCH2OS(O)2C6H4CH3, 3H); 4.24
(dd, Jˆ4.4, 4.8 Hz, CH2CHCHaHbOS(O)2C6H4CH3, 1H);
5.16 (p, Jˆ4.8 Hz, CH2CHCH2, 1H); 7.34±7.80 (dd,
Jˆ8.1, 8.4 Hz, CH3C6H4, 4H). 13C NMR dC (in ppm,
CDCl3) 14.54 (18-CH3); 23.09 (C-17); 25.14, 25.19 (C-3,
both acyl chains); 29.44±30.09 (C-4±C-15); 32.31 (C-16);
34.32, 34.40 (C-2, both acyl chains); 172.71, 173.10 (C-1,
both acyl chains): stearoyl fragment; 61.67, 67.58 (C-1,
C-3); 68.56 (C-2): glycerol fragment; 22.07 (7-CH3);
128.13, 130.07 (C-2, C-3, C-5, C-6); 132.76 (C-1); 145.21
(C-4): tosyl fragment. IR (KBr) n 1738 (CvO);.1598
(CvCaryl); 1368, 1192, 1174 cm21 (SO2).
3-O-Benzyl-1,2-distearoyl-sn-glycerol 3h. Obtained from
3-O-benzyl-1,2-isopropylidene-sn-glycerol (1f; 0.044 g;
0.20 mmol), stearic anhydride (2b; 0.275 g; 0.50 mmol)
and boron tri¯uoride etherate (0.014 g; 0.10 mmol). CC
system C. Yield: 0.130 g (92%, white crystals);
mpˆ50.2±50.68C (from system C); Lit.38: mpˆ50.5±
51.08C; Rf (system B)ˆ0.68; [a]2D0ˆ15.80 (c, 1.50,
CHCl3); Lit.38 [a]Dˆ16.10 (c, 7.48, CHCl3). Anal. Calcd
for C46H82O5 (715.28): C, 77.24; H, 11.58; Found: C, 77.05;
1
H, 11.62. H NMR dH (in ppm, CDCl3) 0.88 (t, Jˆ6.6 Hz,
CH3, 6H); 1.20±1.36 (m, (CH2)14; 56H); 1.54±1.68 (m,
CH2CH2CO, 4H); 2.30 (m, CH2CO, 4H); 3.58 (d,
Jˆ5.1 Hz, CH2CHCH2OCH2C6H5, 2H); 4.18 (dd, Jˆ6.2,
6.6 Hz, CH2CHCHaHbOCH2C6H5, 1H); 4.34 (dd, Jˆ3.7,
4.0 Hz, CH2CHCHaHbOCH2C6H5, 1H); 4.54 (m,
CH2C6H5, 2H); 5.24 (m, CH2CHCH2, 1H); 7.31 (m,
CH2C6H5, 5H). 13C NMR dC (in ppm, CDCl3) 14.52
(18-CH3); 23.09 (C-17); 25.28, 25.36 (C-3, both acyl
chains); 29.48±30.08 (C-4±C-15); 32.31 (C-16); 34.50,
34.71 (C-2, both acyl chains); 173.12, 173.42 (C-1, both
acyl chains): stearoyl fragment; 62.96, 68.57 (C-1, C-3);
70.30 (C-2): glycerol fragment; 73.59 (C-7); 127.8, 127.9,
128.6 (C-2±C-6); 137.9 (C-1): benzyl fragment. IR (KBr) n
1734 (CvO); 1473 (CvCaryl); 1178 (C±O±C); 1112 cm21
(C±O±Cether).
Cholesteryl stearate 3k. Obtained from cholesteryl-3-O-
tetrahydro-2H-pyran (1h; 0.094 g; 0.20 mmol), stearic
anhydride (2b; 0.138 g; 0.25 mmol) and boron tri¯uoride
etherate (0.007 g; 0.05 mmol). CC system D. Yield of 3k:
0.124 g (95%, white crystals); mpˆ80.2±81.38C (from
system D); Rf (system D)ˆ0.40; [a]2D0ˆ223.6 (c, 3.41,
CHCl3) (the same as of a commercially available sample
from Fluka). Anal. Calcd for C45H80O2 (653.25): C, 82.73;
H, 12.37. Found: C, 82.89; H, 12.28. 1H NMR dH (in ppm,
CDCl3) 0.68 (s, 18-CH3, 3H); 4.61 (m, C-3, 1H); 5.37 (m,
C-6, 1H): cholesteryl fragment; 0.87 (CH3); 1.25 ((CH2)14);
2.30 (CH2CO): stearoyl fragment (overlapping with signals
from cholesteryl fragment). 13C NMR dC (in ppm, CDCl3)
12.28 (18-CH3); 19.12 (C-21); 19.73 (C-19); 21.43 (C-11);
22.96 (C-26); 23.22 (C-27); 73.94 (C-3); 122.72 (C-6);
139.84 (C-5): cholesteryl fragment; 14.54 (18-CH3); 23.09
(C-17); 25.47 (C-3); 29.50±30.09 (C-4±C-15); 32.28
(C-16); 35.10 (C-2); 173.4 (C-1): stearoyl fragment IR
(KBr) n 1741 (CvO); 1178 cm21 (C±O±C).
1,2-Dioleoyl-sn-glycero-3-O-p-toluenesulfonate 3i. Obtained
from 1,2-isopropylidene-sn-glycero-3-O-p-toluenesulfonate
(1g; 0.057 g; 0.20 mmol), oleic anhydride (2a; 0.273 g;
0.50 mmol) and boron tri¯uoride etherate (0.014 g;
0.10 mmol) in CH2Cl2. Stirred and re¯uxed (,408C) for
5 h under nitrogen. Yield: 0.139 g (90%, colourless oil);
Rf (system B)ˆ0.53; [a]2D0ˆ15.20 (c, 0.635, CHCl3±
CH3OH, 1:1). Anal. Calcd for C46H78O7S (775.30): C,
71.26; H, 10.16; S, 4.13. Found: C, 71.35; H, 10.10; S,
1
4.21. H NMR dH (in ppm, CDCl3) 0.87 (t, Jˆ7.0 Hz,
CH3, 6H); 1.20±1.37 (m, (CH2)4; (CH2)6; 40H); 1.57 (m,
CH2CH2CO, 4H); 2.0 (m, CH2CHv, 8H); 2.30 (m, CH2CO,
4H); 2.45 (s, CH3C6H4, 3H); 4.08±4.20 (m, CH2CHCHaH-
2C6H4CH3, CH2CHCH2OS(O)2C6H4CH3, 3H); 4.24
Acknowledgements
b
OS(O)
(dd, Jˆ4.8, 4.8 Hz, CH2CHCHaHbOS(O)2C6H4CH3, 1H);
5.15 (p, Jˆ4.8 Hz, CH2CHCH2, 1H); 5.34 (m, CHv, 4H);
7.34±7.80 (dd, Jˆ8.1, 8.4 Hz, CH3C6H4, 4H). 13C NMR dC
(in ppm, CDCl3) 14.53 (18-CH3); 23.07 (C-17); 25.12, 25.17
(C-3, both acyl chains); 27.56, 27.61 (C-11, C-8); 29.41±
30.14 (C-4±C-7, C-12±C-15); 32.27 (C-16); 34.29, 34.37
(C-2, both acyl chains); 130.07, 130.17 (C-9, C-10) 172.68,
173.07 (C-1, both acyl chains): oleoyl fragment; 61.67,
67.57 (C-1, C-3); 68.57 (C-2): glycerol fragment; 22.06
(7-CH3); 128.1, 129.8 (C-2, C-3, C-5, C-6); 132.8 (C-1);
145.2 (C-4): tosyl fragment. IR (®lm) n 3004 (CHv);
1747 (CvO);.1599 (CvCaryl); 1373, 1191, 1179 cm21
(SO2).
We are indebted to Professor Per J. Garegg for his interest in
this work. Financial support from the Swedish Institute, the
Swedish Natural Science Research Council and the
Swedish Foundation for Strategic Research, is gratefully
acknowledged.
References
1. Green, T. W. Protective Groups in Organic Synthesis, 2nd ed.;
Wiley: New York, 1991.
2. Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 1994.

S. D. Stamatov, J. Stawinski / Tetrahedron 56 (2000) 9697±9703
9703
3. Wurl, M.; Enterling, D.; Kunze, H. Chem. Phys. Lipids 1985,
37, 307±315.
23. Schmidt, R. R. Pure Appl. Chem. 1998, 70, 397±402.
24. The reactions can also be effected at room temperature but this
usually requires extended reaction time (overnight or longer).
25. When anhydrides 2 were used in a lower proportion, part of the
starting material remained either unreacted or underwent some
decomposition, regardless of the amount of boron tri¯uoride
etherate (up to 0.50 equiv./alcohol moiety) present in the reaction
mixture.
4. Kodali, D. R. J. Lipid Res. 1987, 28, 464±469.
5. Brachwitz, H.; Franke, P.; Hintsche, R.; Langen, P.; Schildt, J.
Chem. Phys. Lipids 1984, 36, 137±152.
6. Massing, U.; Eibl, H. Chem. Phys. Lipids 1994, 69, 105±120.
7. Lloyd, W.; Reese, C. B.; Song, Q. L.; Vandersteen, A. M.;
Visintin, C.; Zhang, P. Z. J. Chem. Soc., Perkin Trans. 1 2000,
165±176.
26. The carbonyl and the adjacent methylene carbons in free fatty
acids, the corresponding carboxylic anhydrides, and in fatty acid
esters, have distinctive chemical shifts permitting their assignment
to the appropriate species. For example, for ester 3c, anhydride 2b,
and for stearic acid, these chemical shifts in CDCl3 are: 173.8 and
34.8 ppm; 169.6 and 35.7 ppm; 180.1 and 34.3 ppm; respectively.
27. One can also envisage a one-step synchronous mechanism for
this reaction.
8. Predvoditelev, D. A.; Smirnova, L. I.; Smirnov, M. B.;
Nifantyev, E. E. Dokl. Akad. Nauk SSSR 1981, 256, 402±406.
9. Xia, J.; Hui, Y.-Z. Tetrahedron: Asymmetry 1997, 8, 3131±
3142.
10. Nyilas, A. Chem. Phys. Lipids 1997, 87, 171±174.
11. Chandrasekhar, S.; Sarkar, S. Tetrahedron Lett. 1998, 39,
2401±2404.
12. Bourne, E. J.; Burdon, J.; Tatlow, J. C. J. Chem. Soc. 1959,
1864±1870.
28. Lands, W. E. M.; Zschocke, A. J. Lipid Res. 1965, 6, 324±325.
29. Mattson, F. H.; Volpenhein, R. A. J. Lipid. Res. 1962, 3, 281±
296.
13. Sonnet, P. E. Chem. Phys. Lipids 1991, 58, 35±39.
14. Ali, S.; Bittman, R. J. Org. Chem. 1988, 53, 5547±5549.
15. Lok, C. M. Chem. Phys. Lipids 1978, 22, 323±337.
16. Lapidot, Y.; Barzilay, I.; Hajdu, J. Chem. Phys. Lipids 1969, 3,
125±134.
30. Surles, J. R.; Wykle, R. L.; O'Flaherty, J. T.; Salzer, W. L.;
Thomas, M. J.; Snyder, F.; Piantadosi, C. J. Med. Chem. 1985, 28,
73±78.
31. Tsushima, S.; Yoshioka, Y.; Tanida, S.; Nomura, H.; Nojima,
S.; Hozumi, M. Chem. Pharm. Bull. 1982, 30, 3260±3270.
32. Neilson, T.; Werstiuk, E. S. Can. J. Chem. 1971, 49, 493±499.
33. Radhakrishnan, R.; Robson, R. J.; Takagaki, Y.; Khorana,
H. G. Methods Enzymol. 1981, 72, 408±433.
17. Haskins, W. T.; Hann, R. M.; Hudson, C. S. J. Am. Chem. Soc.
1942, 64, 132±136.
18. Gras, J.-L.; Bonfanti, J.-F. Synlett 1999, 1835±1837.
19. Nifantyev, E. E.; Predvoditelev, D. A.; Fursenko, I. V.;
Smirnova, L. I. Synthesis 1982, 132±134.
34. Puri®cation of Laboratory Chemicals, Perrin, D. D., Armar-
ego, W. L. F., Eds.; Pergamon: New York, 1988.
35. Pfeiffer, F. R.; Miao, C. K.; Weisbach, J. A. J. Org. Chem.
1970, 35, 221±224.
20. Nifantev, E. E.; Predvoditelev, D. A. Russ. Chem. Rev. 1997,
66, 43±52.
21. Piantadosi, C.; Marasco, C. J.; Morris-Natschke, S. L.; Meyer,
K. L.; Gumus, F.; Surles, J. R.; Ishaq, K. S.; Kucera, L. S.; Iyer, N.;
Wallen, C. A.; Piantadosi, S.; Modest, E. J. J. Med. Chem. 1991,
34, 1408±1414.
36. Rakhit, S.; Bagli, J. F.; Deghenghi, R. Can. J. Chem. 1969, 47,
2906±2910.
37. Baer, E.; Buchnea, D. J. Biol. Chem. 1958, 230, 447±456.
38. Sowden, J. C.; Fischer, H. O. L. J. Am. Chem. Soc. 1941, 63,
3244±3248.
22. Berti, D.; Baglioni, P.; Bonaccio, S.; BarsacchiBo, G.; Luisi,
P. L. J. Phys. Chem. B 1998, 102, 303±308.