An efficient synthesis of unsymmetrical optically active phosphatidyl glycerol

Full text of DOI:10.1021/jo981653p

648
J . Org. Chem. 1999, 64, 648-651
Sch em e 1
An Efficien t Syn th esis of Un sym m etr ica l
Op tica lly Active P h osp h a tid yl Glycer ol
Kazuo Murakami, Erich J . Molitor, and Hung-wen Liu*
Department of Chemistry, University of Minnesota,
Minneapolis, Minnesota 55455
Received August 14, 1998
The availability of optically active phospholipids con-
taining unsymmetrical fatty acids of defined regiochem-
istry has become increasingly important for the research
of enzymes involved in signal transduction and mem-
brane biochemistry. An eminent example of an enzyme
1
using phospholipids as substrates is phospholipase A2
which catalyzes the hydrolysis of phosphatidyl cholines
at the sn-2 position to generate a variety of proinflam-
matory lipid mediators, such as prostaglandins,2 leuko-
trienes,3 and platelet activating factors.4 Another notable
example is cyclopropane fatty acid synthase, which
catalyzes the transfer of a methylene bridge, derived from
the methyl group of S-adenosylmethionine, to the cis
double bond of an unsaturated fatty acid chain at the
sn-2 position of a phosphatidyl glycerol (PG) substrate
to form a cyclopropane ring.5 The unique structure of the
resultant cyclopropane-containing phospholipid has been
postulated to contribute to the drug resistance and
survival of mycobacteria in the hostile intracellular
environment of macrophages by the formation of an
impermeable asymmetric lipid bilayer.6
In support of our ongoing research to study cyclopro-
pane fatty acid synthase, it has been necessary for us to
prepare a series of PGs with various oleic acid derivatives
at the sn-2 position as enzyme substrates and/or mecha-
nistic probes. The most general strategy to prepare PGs
begins with acylation of the R-isomer of isopropylidene
glycerol (1), which is commercially available and can be
synthesized,7 if necessary, from ascorbic acid,8 L-manni-
tol,9 L-arabinose,10 or L-erythrulose.11 Removal of the
acetonide protecting group of 1-acyl-isopropylidene glyc-
erol followed by protection of the primary alcohol with
the trityl or other bulky protecting group gives 1-acyl-3-
protected glycerol (2) (Scheme 1). Acylation with the same
or a different fatty acid yields 1,2-diacyl-3-protected
glycerol, which, after removal of the protecting group,
affords 1,2-diacylglycerol (3). The phosphoglycerol head-
group is then installed by a three-step reaction series
involving treatment of 3 with phosphorus oxychloride and
triethylamine, with 1 and triethylamine, and with metha-
nol in sequence.7 The synthesis is completed by depro-
tection of the methyl ester and acetonide group. This
method, although quite commonly used, has a few notable
drawbacks including multiple protection and deprotection
steps and the use of easily hydrolyzable and corrosive
phosphorus oxychloride as the phosphorylating reagent.
The most serious problem with this synthesis is the high
likelihood of acyl migration during acid-catalyzed depro-
tection of the acetonide group. To minimize the above
complications, we have developed an efficient and con-
venient alternate strategy to make this type of molecule.
Herein we report the versatility of this method as
exemplified by the synthesis of 1-lauroyl-2-oleoyl-sn-
glycero-3-[phospho-1-glycerol] (4).
* To whom correspondence should be addressed. Tel: (612)-625-
5356. Fax: (612)-626-7541. E-mail: liu@chem.umn.edu.
(1) J ain, M. K.; Gelb, M. H.; Rogers, J .; Berg, O. G. Methods
Enzymol. 1995, 249, 567.
(2) Willis, A. L. Handbook of Eicosanoids: Prostaglandins and
Related Lipids; CRC Press, Inc.: Boca Raton, 1987.
(3) Piper, P. J . The Leukotrienes Their Biological Significance; Raven
Press: New York, 1986.
(4) Snyder, F. Platelet-Activating Factor and Related Lipid Media-
tors; Plenum Press: New York, 1987.
(5) (a) Wang, A.-Y.; Grogan, D. W.; Cronan, J . E. Biochemistry 1992,
31, 11020. (b) Grogan, D. W.; Cronan, J . E. J . Bacteriol. 1984, 158,
286. (c) Buist, P. H.; MacLean, D. B. Can. J . Chem. 1981, 59, 828. (d)
Cronan, J . E.; Reed, R.; Taylor, F. R.; J ackson, M. B. J . Bacteriol. 1979,
138, 118. (e) Taylor, F. R.; Cronan, J . E. Biochemistry 1979, 18, 3292.
(f) Cronan, J . E.; Nunn, W. D.; Batchelor, J . G. Biochim. Biophys. Acta
1974, 348, 63. (g) Polacheck, J . W.; Tropp, B. E.; Law, J . H. J . Biol.
Chem. 1966, 241, 3362.
(6) George, K. M.; Yuan, Y.; Sherman, D. R.; Barry, C. E., III. J .
Biol. Chem. 1995, 270, 27292.
(7) For reviews on phospholipid synthesis see the following: (a)
Paltauf, F.; Hermetter, A. Prog. Lipid Res. 1994, 33, 239. (b) Eibl, H.
Chem. Phys. Lipids 1980, 26, 405.
(8) J ung, M. E.; Shaw, T. J . J . Am. Chem. Soc. 1980, 102, 6304.
(9) (a) Eibl, H. Chem. Phys. Lipids 1981, 28, 1. (b) Hirth, G.;
Walther, W. Helv. Chim. Acta 1985, 68, 1863.
(10) Kodali, D. R. J . Lipid Res. 1987, 28, 464.
(11) DeWilde, H.; DeClero, P.; Vandewalle, M. Tetrahedron Lett.
1987, 28, 4757.
The starting material, 2,5-dibenzyl-D-mannitol (5), was
prepared from D-mannitol by a known procedure consist-
ing of 1,3-4,6-dibenzylidenylation of D-mannitol, benzyl
protection of the 2,5-hydroxyls, and acid hydrolysis of the
10.1021/jo981653p CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/05/1999

Notes
J . Org. Chem., Vol. 64, No. 2, 1999 649
Sch em e 2
lauroyl-sn-glycerol-3-[phospho-1-isopropylideneglycer-
ol] methyl ester (8) bearing the fully assembled phos-
phatidylglycerolheadgroup.With the1-acyland3-phosphoryl
portions of the molecule attached, the benzyl protecting
group was removed to expose the sn-2 hydroxyl for
further derivatization. Acylation at the sn-2 position of
2-hydroxy-1-lauroyl-sn-glycero-3-[phospho-1-isopropy-
lideneglycerol] methyl ester (9) with oleic acid was
accomplished under standard coupling conditions with
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro-
chloride (EDCI) and DMAP to give 1-lauroyl-2-oleoyl-sn-
glycero-3-[phospho-1-isopropylideneglycerol] methyl ester
(10) in satisfactory yield. Deprotection of the methyl ester
and the glycerol acetonide, in sequence, using sodium
iodide in 2-butanone14 and trifluoroacetic acid (TFA),
respectively, afforded target phospholipid 4. The overall
yield of 4 from 5 through this 10-step synthesis was
nearly 19%.
In summary, the route to make phosphatidyl glycerol
derivatives outlined here offers several advantages over
the common strategy used for the preparation of this
class of compounds. First, and quite importantly, is that
this synthesis eliminates the possibility of the acyl
migration which is a problem in the alternative synthesis
beginning with isopropylidene glycerol. Second, our
synthesis, beginning with readily available D-mannitol,
generates two equivalents of the glycerol backbone from
each mannitol equivalent. Third, acylation of the two
primary hydroxyls of 5 prior to the diol cleavage step
eliminates at least two protection and deprotection steps
required in most previous syntheses in which 5 was used
as a starting material for phospholipid synthesis.7 Instal-
lation of the polar headgroup has also been made easy
in this work by using phosphoramidite chemistry15
instead of phosphorus oxychloride, which is more difficult
to handle. Compared to the traditional scheme where the
sn-2 acylation is performed with five reaction steps
remaining, this sequence performs the acylation in the
third to the last step of the synthesis with only two
deprotections remaining. Efficient incorporation of the
sn-2 fatty acid is important to our study of cyclopropane
fatty acid (CFA) synthase since the enzymatic transfor-
mation occurs on the sn-2 fatty acid of the substrate.
These fatty acid analogues are themselves products of
multiple-step syntheses, and hence it is critical to carry
out the sn-2 acylation near the end of the synthesis to
most effectively utilize these valuable fatty acid deriva-
tives. This general and efficient route presented herein
could be applied to the synthesis of similar compounds
such as phosphatidyl choline, phosphatidyl ethanolamine,
cardiolipins,16 and platelet activating factors.
benzylidene groups.12 Acylation of both primary hy-
droxyls of 5 to give 2,5-dibenzyl-1,6-dilauroyl-D-mannitol
(6) was accomplished using lauric acid chloride and
(dimethylamino)pyridine (DMAP) (Scheme 2). The de-
sired alcohol, 2-benzyl-1-lauroyl-sn-glycerol (7), was iso-
lated in 64% yield after NaBH3CN reduction of the
nascent aldehyde generated directly from periodate
cleavage.13
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected. El-
emental analysis was carried out by National Chemical Consult-
ing, Inc. (Tenafly, NJ ). 1H, 13C, and 31P NMR spectra were
recorded at 300, 75, and 121 MHz, respectively, and all chemical
shifts are in hertz (Hz). Flash chromatography was performed
in columns of various diameters with Lagand Chemical (230-
400 mesh) silica gel by elution with the specified solvents. Thin-
layer chromatography (TLC) was carried out on Merck silica gel
60 F254 plates and developed with the appropriate solvents. The
With compound 7 in hand, phosphorylation was con-
veniently and efficiently carried out using tetrazole and
methyl tetraisopropylphosphorodiamidite. The diisopro-
pylphosphoramidite product generated in situ was treated
with (R)-isopropylidene glycerol and another equivalent
of tetrazole followed by m-CPBA to give 2-benzyl-1-
(12) Massing, U.; Eibl, H. Chem. Phys. Lipids 1995, 76, 211.
(13) A (Nishio, Y.; Murata, M.; Achiwa, K. Tetrahedron Lett. 1988,
29, 5173, Shimizu, C.; Ohta, N.; Achiwa, K. Chem. Pharm. Bull. 1990,
38, 3347.) It is worth mentioning that the optical rotation ([R]D) of 7
prepared in our current work is more than twice the value reported in
this reference.
(14) McMillen, D, A.; Volwerk, J . J .; Ohishi, J .; Erion, M.; Keana,
J . F. W.; J ost, P. C.; Griffith, O. H. Biochemistry 1986, 25, 182.
(15) He´bert, N.; J ust, G. J . Chem. Soc., Chem. Commun. 1990, 1497.
(16) Ioannou, P.; Golding, B. T. Prog. Lipid Res. 1979, 17, 279.

650 J . Org. Chem., Vol. 64, No. 2, 1999
Notes
TLC spots were visualized with either UV light or by heating
plates previously stained with a solution of phosphomolybdic acid
(7% ethanolic solution). All chemicals were products of Aldrich
(Milwaukee, WI) except for isopropylidene glycerol which was
from Oakwood (West Columbia, SC). The drying agent used in
the routine workup was anhydrous magnesium sulfate. Solvents
were of analytical-reagent grade or of the highest quality
commercially available. Dichloromethane was purified by pas-
sage through a column of activated alumina. Compounds 8-10
were isolated as 1:1 mixtures of diastereomers based on 31P
NMR. No attempt was made to assign the 13C NMR peaks for
diastereotopic carbons which have different chemical shifts.
2,5-Diben zyl-D-m a n n itol (5). Compound 5 was prepared
from D-mannitol by known procedures with minor modifica-
tions.12 The [R]24D -7.8 (c 0.48, ethanol) compared well with the
literature value.12
acetate in hexanes) Rf ) 0.31; 1H NMR (300 MHz, CDCl3) δ
7.34-7.24 (5 H, m), 4.64 (2 H, s), 4.31-4.22 (2 H, m), 4.20-4.08
(3 H, m), 4.06-3.95 (3 H, m), 3.84-3.70 (2 H, m), 3.75, 3.72 (total
3 H, each d, J H-P ) 1.8), 2.28 (2 H, t, J ) 7.5), 1.58 (2 H, m)
1.38 (3 H, s), 1.32 (3 H, s), 1.23 (16 H, bs), 0.85 (3 H, t, J ) 6.8);
13C NMR (75.4 MHz, CDCl3) δ 173.4, 137.6, 128.4, 127.9, 127.8,
109.9, 75.1, 75.0, 74.0, 73.9, 72.2, 67.7, 67.6, 66.4, 66.3, 66.0,
62.3, 54.59, 54.52, 34.1, 31.9, 29.6, 29.4, 29.3, 29.2, 29.1, 26.7,
25.2, 24.8, 22.6, 14.1 (a mixture of diastereomers); 31P NMR
(121.4 MHz, CDCl3) δ 0.7; high-resolution FABMS m/z calcd for
C
29H50O9P (M + H+) 573.3194, found 573.3173.
2-Hyd r oxy-1-la u r oyl-sn -glycer o-3-[p h osp h o-1-isop r op yl-
id en eglycer ol] Meth yl Ester (9). A solution of 8 (400 mg,
0.698 mmol) in ethyl acetate (25 mL) and methanol (5 mL)
containing Pd on charcoal (Pd/C, 70 mg) was stirred under H2
at room temperature for 4 h. The Pd/C was removed by filtration
through Celite, and the filtrate was concentrated to give a clear
oil 9 which consisted of a 1:1 mixture of diastereomers (336 mg,
2,5-Diben zyl-1,6-d ila u r oyl-D-m a n n itol (6). To a stirred
solution of 2,5-dibenzyl-D-mannitol 5 (1.0 g, 2.76 mmol) and
(dimethylamino)pyridine (DMAP, 0.775 g, 6.35 mmol) in DMF
(16 mL) cooled to 5 °C was added lauroyl chloride (1.21 g, 5.52
mmol) dropwise under argon. The reaction was stirred at 5 °C
for 45 min, quenched by the addition of water, and extracted
with ethyl acetate (3 × 35 mL). The combined extracts were
washed with brine, dried, and concentrated. Purification by
silica-gel column chromatography (20% then 33% ethyl acetate
in hexanes) gave 6 as a white solid (1.3 g, 65%): mp 49 °C
1
quantitative): TLC (33% CHCl3 in ethyl acetate) Rf ) 0.19; H
NMR (300 MHz, CDCl3) δ 4.31 (1 H, m), 4.18-4.00 (8 H, m),
3.79 (1 H, m), 3.80, 3.72 (total 3 H, each d, J H-P ) 0.6), 2.31 (2
H, t, J ) 7.7), 1.59 (2 H, m), 1.41 (3 H, s), 1.33 (3 H, s), 1.22 (16
H, bs), 0.85 (3 H, t, J ) 6.8); 13C NMR (75.4 MHz, CDCl3) δ
173.6, 109.88, 109.86, 74.0, 73.98, 73.91, 73.88, 68.8, 68.7, 68.2,
68.1, 67.8, 67.78, 67.71, 65.7, 64.1, 54.6, 54.5, 33.9, 31.8, 29.5,
29.3, 29.2, 29.1, 29.0, 26.5, 25.1, 24.7, 22.5, 14.0 (a mixture of
diastereomers); 31P NMR (121.4 MHz, CDCl3) δ -0.01, -0.06.
1-La u r oyl-2-oleoyl-sn -glycer o-3-[p h osp h o-1-isop r op yl-
id en eglycer ol] Meth yl Ester (10). To a solution of 9 (100 mg,
0.207 mmol) and oleic acid (87 mg, 0.308 mmol) in methylene
chloride (1 mL), cooled to -6 °C under argon, was added
dropwise over 110 min a solution of EDCI‚HCl (48 mg, 0.25
mmol) and DMAP (30.5 mg, 0.25 mmol) in methylene chloride
(hexanes); [R]24 -15.9 (c 0.56, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.35-7.25 (m, 10 H), 4.71 (2 H, d, J ) 11.6), 4.52 (2 H,
d, J ) 11.6), 4.46 (2 H, dd, J ) 12.2, 3.3), 4.25 (2 H, dd, J )
12.2, 4.7), 3.88 (2 H, d, J ) 7.2), 3.72 (2 H, m), 2.31 (2 H, t, J )
7.7), 1.60 (2 H, m), 1.24 (16 H, bs), and 0.88 (3 H, t, J ) 6.8); 13
C
NMR (75.4 MHz, CDCl3) δ 174.1, 137.7, 128.5, 128.1, 128.17,
78.0, 72.8, 68.7, 62.8, 34.3, 31.9, 29.7, 29.5, 29.4, 29.3, 29.2, 25.0,
22.7, and 14.2. Anal. Calcd for C44H70O8: C, 72.69; H, 9.70.
Found: C, 72.83; H, 9.88.
o
as the temperature was increased to 10 C. After being stirred
for an additional 19 h at room temperature, the reaction was
quenched with water and extracted with chloroform (3 × 10 mL).
The combined organic extracts were dried and concentrated.
Chromatography on silica gel (stepwise elution with 25%, 33%,
and then 50% ethyl acetate in hexanes) yielded 10 as a clear
colorless oil consisting of a 1:1 mixture of diastereomers (131
mg, 85%): TLC (33% CHCl3 in ethyl acetate) Rf ) 0.71; 1H NMR
(300 MHz, CDCl3) δ 5.33 (2 H, m), 5.23 (1 H, m), 4.35-4.28 (2
H, m), 4.21-4.12 (3 H, m), 4.10-4.00 (3 H, m), 3.84-3.78 (1 H,
m), 3.79, 3.75 (total 3 H, each d, J ) 2.1), 2.32 (2 H, t, J ) 7.5),
2.29 (2 H, t, J ) 7.5), 2.00 (4 H, m), 1.60 (4 H, m), 1.42 (3 H, s),
1.35 (3 H, s), 1.32-1.20 (34 H, m), 0.87 (6 H, m); 13C NMR (75.4
MHz, CDCl3) δ 173.2, 172.8, 130.0, 129.6, 109.9, 74.0, 73.9, 69.4,
69.3, 67.84, 67.80, 66.0, 65.5, 61.6, 54.64, 54.56, 34.1, 34.0, 31.9,
29.77, 29.72, 29.6, 29.5, 29.4, 29.3, 29.28, 29.21, 29.1, 29.0, 27.2,
27.1, 26.2, 25.3, 24.8, 22.6, 14.1 (a mixture of diastereomers);
31P NMR (121.4 MHz, CDCl3) δ 0.58, 0.53.
2-Ben zyl-1-la u r oyl-sn -glycer ol (7). To a stirred solution of
6 (2.48 g, 3.41 mmol) in methylene chloride (125 mL), 95%
ethanol (50 mL), and saturated aqueous NaHCO3 (2.5 mL) was
added NaIO4 (2.325 g, 10.87 mmol), and the resulting solution
was then stirred at room temperature for 2.5 h. The reaction
mixture was dried and concentrated, and the resulting residue
was dissolved in methanol (25 mL). To this solution was added
NaBH3CN (975 mg, 15.5 mmol, in water (2.5 mL)), followed by
acetic acid (3 mL), and then the solution was stirred at room
temperature for 1.5 h. The reaction was quenched with saturated
NaHCO3 and extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried, and concentrated.
Chromatography on silica gel (stepwise elution with 5%, 10%,
20%, and then 33% ethyl acetate in hexanes) yielded 7 as a
colorless oil (1.60 g, 64%): TLC (33% ethyl acetate in hexanes)
Rf ) 0.47; [R]25 -15.6 (c 1.17, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.36-7.26 (5 H, m), 4.62 (1 H, d, J ) 11.7), 4.55 (1 H,
d, J ) 11.7), 4.18 (1 H, dd, J ) 24.6, 11.7), 4.17 (1 H, dd, J )
24.6, 11.7), 3.64-3.55 (3 H, m), 3.03 (1 H, bs), 2.26 (2 H, t, J )
7.7), 1.57 (2 H, m), 1.24 (16 H, bs), 0.87 (3 H, t, J ) 6.6); 13C
NMR (75.4 MHz, CDCl3) δ 173.8, 137.8, 128.5, 127.9, 127.8, 77.2,
72.1, 62.7, 62.0, 34.2, 31.9, 29.6 (2 C), 29.4, 29.3, 29.2, 29.1, 24.9,
22.7, 14.1; high-resolution MS m/z calcd for C22H40NO4 (M +
NH4+) 382.2957, found 382.2964.
2-Ben zyl-1-la u r oyl-sn -glycer o-3-[p h osp h o-1-isop r op yl-
id en eglycer ol] Meth yl Ester (8). To a solution of 7 (4.0 g, 10.9
mmol) and methyltetraisopropylphosphorodiamidite (4.03 g,
15.36 mmol) in methylene chloride (90 mL) cooled to 0 °C was
added 1H-tetrazole (1.38 g, 19.75 mmol). The resulting mixture
was stirred at 0 °C for 2 h. To this solution were added
isopropylidene glycerol (2.55 g, 19.3 mmol) and additional
tetrazole (1.38 g, 19.75 mmol), and the stirring was continued
at 0 °C for another 2 h. The reaction was cooled to -20 °C,
treated with m-CPBA (4.35 g, 25.2 mmol), and stirred from -20
to 0 °C over 0.5 h. To this solution were added Na2SO3 (1.6 g,
12.6 mmol) and saturated NaHCO3, and the resulting mixture
was stirred for 45 min as it warmed from 0 °C to room
temperature. The reaction mixture was extracted with chloro-
form, dried, and concentrated. Chromatography on silica gel
(stepwise elution with 10%, 20%, 33%, and then 50% ethyl
acetate in hexanes) yielded 8 as a clear yellow oil consisting of
a 1:1 mixture of diastereomers (4.7 g, 75%): TLC (33% ethyl
1-La u r oyl-2-oleoyl-sn -glycer o-3-[p h osp h o-1-glycer ol] (4).
To a solution of 10 (95 mg, 0.127 mmol) in 2-butanone (3.5 mL)
was added NaI (124 mg, 0.824 mmol). The reaction was stirred
as it was heated to 75 °C for 1 h. The solvent was removed under
vacuum to give
a yellow residue which was dissolved in
chloroform/methanol (5:1). The resulting solution was washed
with 10% aqueous HCl followed by brine. The combined aqueous
solutions were extracted with chloroform/methanol (5:1) three
times. The combined organic extracts were dried (Na2SO4) and
concentrated. The resulting residue was taken up in CH2Cl2/
TFA/MeOH (6:3:1) (6 mL) and stirred at room temperature for
1.5 h. The solvent was removed by vacuum, and residual TFA
was removed by coevaporation with toluene. Chromatography
on silica gel (stepwise elution with 0, 9%, and 17% methanol in
chloroform) yielded a light yellow powder (66 mg, 73%): TLC
(chloroform/ethyl acetate/methanol/acetic acid, 2:2:1:1) Rf ) 0.50;
[R]23 +1.75 (c 0.214, CHCl3); 1H NMR (300 MHz, CD3OD) δ
D
5.34 (2 H, m), 5.22 (1 H, m), 4.43 (1 H, dd, J ) 12.0, 3.0), 4.18
(1 H, dd, J ) 12.0, 6.6), 4.00 (2 H, m, J ) 5.4), 3.90 (2 H, m),
3.77 (1 H, m, J ) 4.8), 3.60 (2 H, m), 2.34 (2 H, t, J ) 7.2), 2.32
(2 H, t, J ) 7.2), 2.03 (4 H, m), 1.60 (4 H, m), 1.35-1.25 (36 H,
bs), 0.90 (6 H, m); 13C NMR (75.4 MHz, CDCl3) δ 172.4, 172.1,
129.4, 129.3, 70.9 (d, J C-P ) 6.4), 70.1 (d, J C-P ) 7.8), 66.1, 62.8,
62.5, 62.3, 33.5, 33.4, 31.30, 31.27, 29.1-28.3 (14 Cs), 26.60,
26.56, 24.4, 24.3, 22.1, 13.8; 31P NMR (121.4 MHz, CD3OD/
CDCl3) δ -2.47.

Notes
Ack n ow led gm en t. This work is supported by Na-
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Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 6 and 7 and 1H, 13C, and 31P NMR
spectra of compounds 8-10 and 4 (16 pages). This material is
J O981653P