Total Synthesis of γ-Hydroxy-α,β-Unsaturated Aldehydic Esters of Cholesterol and 2-Lysophosphatidylcholine

Article abstract of DOI:10.1021/jo980861e

Free radical-induced oxidation of polyunsaturated fatty esters in low-density lipoproteins (LDLs) generates 2-lysophosphatidylcholine (PC) and cholesterol esters of γ-hydroxy-α,β-unsaturated aldehydic acids that covalently modify LDL protein, and protein adducts of the corresponding acids are found in human blood. The chemistry and structures of these compounds resemble those of (E)-4-hydroxy-2-nonenal (HNE), previously considered the most cytotoxic aldehyde released during peroxidation of linoleate and arachidonate esters. The present report details total syntheses of 2-lyso-PC and cholesteryl esters of (E)-9-hydroxy-12-oxododec-10-enoic and (E)-5-hydroxy-8-oxooct-6-enoic acid that presumably are derived in vivo from linoleate and arachidonate esters, respectively. The syntheses depend on the use of a 3,3-dimethyl-2,4-dioxolanyl moiety as a latent aldehyde from which the chemically sensitive γ-hydroxy-α,β-unsaturated aldehyde array can be generated in the final step. For the cholesteryl esters, generation of the aldehyde group by oxidative cleavage of a vicinal diol could be accomplished in very good yields with periodate. However, for esters of 2-lyso-PC, the target aldehydes were not obtained upon treatment of vicinal diol precursors with periodate owing to a novel oxidative cleavage of the γ-hydroxy-α,β-unsaturated aldehydes by periodate. Fortunately, treatment of the vicinal diol precursors with Pb(OAc)4 at -80 deg C delivered good yields (82-85 percent) of the desired phospholipid aldehydes.

Full text of DOI:10.1021/jo980861e

J . Org. Chem. 1998, 63, 7789-7794
7789
Tota l Syn th esis of γ-Hyd r oxy-r,â-Un sa tu r a ted Ald eh yd ic Ester s of
Ch olester ol a n d 2-Lysop h osp h a tid ylch olin e
Yijun Deng and Robert G. Salomon*
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078
Received May 7, 1998
Free radical-induced oxidation of polyunsaturated fatty esters in low-density lipoproteins (LDLs)
generates 2-lysophosphatidylcholine (PC) and cholesterol esters of γ-hydroxy-R,â-unsaturated
aldehydic acids that covalently modify LDL protein, and protein adducts of the corresponding acids
are found in human blood. The chemistry and structures of these compounds resemble those of
(E)-4-hydroxy-2-nonenal (HNE), previously considered the most cytotoxic aldehyde released during
peroxidation of linoleate and arachidonate esters. The present report details total syntheses of
2
6
-lyso-PC and cholesteryl esters of (E)-9-hydroxy-12-oxododec-10-enoic and (E)-5-hydroxy-8-oxooct-
-enoic acid that presumably are derived in vivo from linoleate and arachidonate esters, respectively.
The syntheses depend on the use of a 3,3-dimethyl-2,4-dioxolanyl moiety as a latent aldehyde from
which the chemically sensitive γ-hydroxy-R,â-unsaturated aldehyde array can be generated in the
final step. For the cholesteryl esters, generation of the aldehyde group by oxidative cleavage of a
vicinal diol could be accomplished in very good yields with periodate. However, for esters of 2-lyso-
PC, the target aldehydes were not obtained upon treatment of vicinal diol precursors with periodate
owing to a novel oxidative cleavage of the γ-hydroxy-R,â-unsaturated aldehydes by periodate.
Fortunately, treatment of the vicinal diol precursors with Pb(OAc) at -80 °C delivered good yields
4
(82-85%) of the desired phospholipid aldehydes.
In tr od u ction
may also contribute to atherogenesis. Thus, recognition
of the resulting protein modifications by macrophage
The most abundant polyunsaturated fatty acids (PU-
FAs) in human low-density lipoprotein (LDL) are arachi-
donic acid (AA), linoleic acid (LA), and docosahexenoic
acid, whose mean levels are 1100, 153, and 29 mol/mol
LDL in healthy donors.1 These PUFAs are present
mainly as esters in phospholipid, cholesteryl ester, and
triglyceride components of LDL. Aldehydes generated
by oxidative cleavage of PUFA esters are the subject of
intense study because their formation is a key event in
pathological processes known collectively as oxidative
stress,2 and because some of the aldehydes are biologi-
cally active (vide infra). A subset of these aldehydes
remain esterified to cholesterol, glycerol, or lysophos-
phatidylcholine (PC).4 For example, the 5-oxovaleric acid
ester of 2-lyso-PC (OV-PC) is generated in LDL by an
oxidative cleavage of the AA ester of 2-lyso-PC. OV-PC
scavenger receptors leads to endocytosis of the oxidized
9-11
(ox) LDL
and accumulation of LDL components, such
as cholesteryl esters which aggregate into droplets that
resemble foam. The resulting bloated macrophages,
called “foam cells”, are progenitors of atherosclerotic
12
plaques. Nonenzymatic, free radical-induced oxidative
cleavage of both AA and LA esters in LDL generates (E)-
4
-hydroxy-2-nonenal (HNE), a γ-hydroxy-R,â-unsaturated
aldehyde. HNE forms protein adducts that include
-pentylpyrrole derivatives (HNE-pyrrole) which incor-
porate the ꢀ-amino group of protein lysyl residues (Scheme
2
,3
13
1
).
14
Studies with LDL containing 2-[1- C]-arachidonyl PC
show that, unlike HNE, a major fraction of the lipid-
derived products that become bound to protein as a
consequence of LDL oxidation retain the carbonyl carbon
5
activates endothelial cells to bind monocytes and, con-
of their fatty ester precursor.8 Recently, we found
sequently, may promote atherogenesis by fostering entry
of monocytes into the vessel wall.
immunological evidence for the generation of protein-
bound 2-(ω-carboxyalkyl)pyrroles (CAPs) during free
radical-induced oxidative modification of LDL, and we
Covalent modification of LDL by reactions of lipid-
derived electrophiles with protein-based nucleophiles6
-8
14
found CAP immunoreactivity in human blood plasma.
In analogy with the chemistry of HNE, we postulated
that CAPs are formed by reactions of γ-hydroxy-R,â-
*
To whom correspondence should be addressed: Telephone: 216-
68-2592. Fax: 216-368-3006. E-mail: rgs@po.cwru.edu.
1) Esterbauer, H.; Ramos, P. Rev. Physiol. Biochem. Pharmacol.
3
(
1
995, 127, 31-64.
(8) Steinbrecher, U. P. J . Biol. Chem. 1987, 262, 3603-3608.
(9) Hoppe, G.; Subbanagounder, G.; O’Neil, J .; Salomon, R. G.; Hoff,
H. F. Biochim. Biophys. Acta 1997, 1344, 1-5.
(
(
(
2) Camhi, S. L.; Lee, P.; Choi, A. M. New Horiz. 1995, 3, 170-82.
3) Davies, K. J . Biochem. Soc. Symp. 1995, 61, 1-31.
4) Kamido, H.; Kuksis, A.; Marai, L.; Myher, J . J . Lipids 1993, 28,
(10) Hoff, H. F.; Whitaker, T. E.; O’Neil, J . J . Biol. Chem. 1992,
267, 602-609.
3
31-6.
(5) Watson, A. D.; Leitinger, N.; Navab, M.; Faull, K. F.; Horkko,
(11) Haberland, M. E.; Fogelman, A. M.; Edwards, P. A. Proc. Natl.
Acad. Sci. U.S.A. 1992, 79, 1712-1716.
(12) Berliner, J . A.; Heinecke, J . W. Free Radical Biol. Med. 1996,
20, 707-727.
(13) Sayre, L. M.; Sha, W.; Zu, G.; Kaur, K.; Nadkarni, D.; Subbna-
gounder, G.; Salomon, R. G. Chem. Res. Toxicol. 1996, 9, 1194-1201.
(14) Kaur, K.; Salomon, R. G.; O’Neil, J .; Hoff, H. F. Chem. Res.
Toxicol. 1997, 10, 1387-1396.
S.; Witztum, J . L.; Palinski, W.; Schwenke, D.; Salomon, R. G.; Sha,
W.; Subbanagounder, G.; Fogelman, A. M.; Berliner, J . A. J . Biol.
Chem. 1997, 272, 13597-607.
(6) Esterbauer, H.; J u¨ rgens, G.; Quehenberger, O.; Koller, E. J . Lipid
Res. 1987, 28, 495-509.
7) Esterbauer, H.; Gebicki, J .; Puhl, H.; J u¨ rgens, G. Free Radical
Biol. Med. 1992, 13, 341-390.
(
1
0.1021/jo980861e CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/07/1998

7
790 J . Org. Chem., Vol. 63, No. 22, 1998
Deng and Salomon
Sch em e 1
Sch em e 2
Sch em e 3
Sch em e 4
Sch em e 5
unsaturated aldehydic esters with the ꢀ-amino group of
lysyl residues in LDL protein. Thus, oxidative cleavage
of AA and LA esters can give 5-hydroxy-8-oxooct-6-enoic
acid (HOOA) and 9-hydroxy-12-oxododec-10-enoic acid
(HODA) esters respectively (Scheme 2). To facilitate
investigations on the chemistry and biology of HOOA and
HODA derivatives, we now report total syntheses of their
cholesterol and 2-lyso-PC esters.
Resu lts a n d Discu ssion
Syn th etic Design . A synthetic strategy was adopted
that exploits a 3,3-dimethyl-2,4-dioxolanyl moiety in a
common intermediate 1 as a latent aldehyde (Scheme
1
5
3
).
Because the carboxyalkyl group in the target is
introduced as a unit in a Grignard reagent precursor 2,
this convergent approach should be applicable to total
syntheses of the entire family of γ-hydroxy-R,â-unsatur-
ated carboxaldehydic esters that are derivable from
PUFA esters.
Syn th esis of Com m on In ter m ed ia te 1. A common
intermediate 1 for the γ-hydroxy-R,â-unsaturated alde-
hyde portion of the target carboxaldehydic esters was
assembled from D-mannitol as outlined in Scheme 4.
D-Glyceraldehyde acetonide is readily available from
D-mannitol by oxidative cleavage of an intermediate bis-
Syn th esis of La ten t Ca r boxa ld eh yd ic Acid s 6.
The carbon skeletons of the latent carboxyaldehydic acids
6
a ,b were assembled by 1,2-addition of a Grignard
reagent from the TBDMS ethers of 4-iodobutanol and
-bromooctanol, respectively (Scheme 5). That the Grig-
nard additions produce the allylic stereocenter in adducts
8
acetonide).16 Wittig olefination with triphenylphospho-
(
1
3
1
7,18
3 nonstereoselectively is especially evident from C NMR
spectra that show pairs of peaks of nearly equal intensity
for several carbons in each of these secondary alcohols.
The nonenzymatic, free radical-induced oxidations of
PUFAs in vivo are also expected generate an allylic
hydroxyl nonstereoselectively to produce esters of racemic
HOOA and HODA. The secondary allylic alcohols 3 were
protected as THP ethers 4 from which the primary
ranylidene acetaldehyde provides 1 in good yield.
(15) Miller, D. B.; Raychaudhuri, S. R.; Avasthi, K.; Lal, K.; Levison,
B.; Salomon, R. G. J . Org. Chem. 1990, 55, 3164-3175.
(
(
(
16) Coffen, D. L. Org. Synth. 1993, 72, 6-13.
17) Trippett, S.; Walker, D. M. J . Chem. Soc. 1961, 1266-1272.
18) Katsuki, T.; Lee, A. W. M.; Ma, P.; Martin, V. S.; Masamune,
S.; Sharpless, K. B.; Tuddenham, D.; Walker, F. J . J . Org. Chem. 1982,
7, 1373-1378.
4

γ-Hydroxy-R,â-Unsaturated Core Aldehydes
J . Org. Chem., Vol. 63, No. 22, 1998 7791
Sch em e 6
Sch em e 7
alcohols 5 were obtained upon desilylation with fluoride.
Oxidation of these primary alcohols with PDC delivered
the target latent carboxyaldehydic acids 6a ,b in 80% and
6
3% overall yields, respectively, in four steps. The
starting 4-iodobutanol TBDMS ether is readily available
in excellent yield (94%) in a single step from tetrahydro-
furan by treatment with NaI and (TBDMS)Cl.1 A more
lengthy procedure afforded the requisite TBDMS ether
of 8-bromooctanol. Thus, reaction of the sodium mono
alkoxide from 1,8-octanediol with (TBDMS)Cl provides
a mono TBDMS ether20 in 69% yield after column
chromatographic purification. Conversion of the remain-
ing hydroxyl into a bromide was then accomplished in
and treatment of the resulting diol with lead tetraacetate
in methylene chloride in the presence of a suspension of
sodium carbonate at room temperature (22% yield of 9b
from 8b). The yield was improved to 37% when the
oxidative cleavage was conducted at 0 °C and was
improved further (82%) by performing the oxidative
cleavage at -80 °C.
9
Owing to its reactive electrophilic γ-hydroxy-R,â-
unsaturated aldehyde functional array, HNE readily
forms covalent adducts with protein-based nucleophiles.
2
1
8
1% yield by treatment with DEAD, Ph
3 2
P, and ZnBr .
Ch olester yl Ester s. The γ-hydroxy-R,â-unsaturated
aldehyde array is chemically sensitive, e.g. rearranging
readily to generate furan derivatives.22 Therefore, it is
important to store the target carboxaldehydic esters as
chemically stable precursors. The cholesterol esters 7,
obtained from the acids 6 in 92-96% yields, are excellent
stable precursors that can be transformed readily into
the corresponding aldehydes. Thus, a convenient one-
pot hydrolysis of the THP and acetonide protecting
groups and periodate cleavage of a vicinal diol intermedi-
ate delivers aldehydes 8 in 85-90% yield (Scheme 6).
P h osp h olip id s. In view of the successful one-pot
generation of analogous cholesterol esters outlined above
and our effective use of this chemistry for a synthesis of
radiolabeled HNE,23 synthesis of phospholipid γ-hydroxy-
R,â-unsaturated aldehydes 10 from esters 9 of 2-lyso-PC
with the acids 6 proved unexpectedly elusive. Thus,
exposure of the esters 9 to aqueous acetic acid and
periodate failed to give any of the desired γ-hydroxy-R,â-
unsaturated carboxaldehydic esters 10. Rather, shorter
chain aldehydes 12 were produced, presumably by Michael
addition of periodate to the target R,â-unsaturated alde-
hydes 10 and oxidative fragmentation of intermediate
periodate esters 11 (Scheme 7). Some of the target
aldehyde was obtained upon hydrolytic removal of the
THP and acetonide protecting groups with aqueous acetic
acid, followed by evaporation of the aqueous acetic acid
2
4-27
This results, inter alia, in the inactivation of enzymes
and is undoubtedly the chemical basis for the view that
HNE is the “most cytotoxic aldehyde” released during
peroxidation of AA and LA esters.28 The succinct total
syntheses detailed above provide ready access to authen-
tic samples of carboxaldehydic esters that incorporate the
same reactive γ-hydroxy-R,â-unsaturated aldehyde func-
tional array as that in HNE. Studies on the biological
activities and biologically important chemistry of these
lipid oxidation products are now feasible.
Exp er im en ta l P r oced u r es
Gen er a l Meth od s. 1H NMR and 13C NMR spectra were
recorded at 300 and 75 MHz, respectively, and are reported
15
as described previously. High-resolution mass spectroscopy,
solvent purification, and chromatography was performed as
usual.15 All reactions conducted in an inert atmosphere were
in argon unless otherwise specified.
4-Iodo-1-(1,1,2,2-tetr am eth yl-1-silapr opoxy)bu tan e. This
1
9
1
iodide was prepared as described previously. The H NMR
spectrum agreed with that reported.19 The C NMR (75 MHz,
13
APT, CDCl
3
) showed δ 61.99 (CH
2
), 46.59 (CH
), 7.17 (C), and -5.28 (CH
2
), 33.57 (CH
).
2
),
3
0.23 (CH ), 25.97(CH
2
3
3
(24) Schaur, R. J .; Zollner, H.; Esterbauer, H. Biological effects of
aldehydes with particular attention to 4-hydroxynonenal and malonal-
dehyde; CRC Press: Boca Raton, FL, 1991; Vol. 3, pp 141-163.
(25) Ferrali, M.; Fulceri, R.; Benedetti, A.; Comporti, M. Res.
Commun. Chem. Path. Pharm. 1980, 30, 99-112.
(26) Siems, W. G.; Hapner, S. J .; Kuijk, F. J . v. Free Radical Biol.
Med. 1996, 20, 215-223.
(
19) Sodeoka, M.; Yamada, H.; Shibasaki, M. J . Am. Chem. Soc.
990, 112, 4906-4911.
20) McDougal, P. G.; Rico, J . G.; Oh, Y.-I.; Condon, B. D. J . Org.
1
(
Chem. 1986, 51, 3388-3390.
(
(
21) Mitsunobu, O. Synthesis 1981, 1, 1-28.
(27) Uchida, K.; Stadtman, E. R. J . Biol. Chem. 1993, 268, 6388-
6693.
22) Sayre, L. M.; Arora, P. K.; Iyer, R. S.; Salomon, R. G. Chem.
Res. Toxicol. 1993, 6, 19-22.
(28) Esterbauer, H.; Schaur, R. J .; Zollner, H. Free Radical Biol.
Med. 1991, 11, 81-128.
(
23) Deng, Y.; Salomon, R. G. J . Org. Chem. 1998, 63, 3504-3507.

7
792 J . Org. Chem., Vol. 63, No. 22, 1998
Deng and Salomon
8
-(1,1,2,2-Tet r a m et h yl-1-sila p r op oxy)oct a n -1-ol. So-
stirrer and condenser under an argon atmosphere at room
temperature. A few drops of a solution of 8-bromo-1-(1,1,2,2-
tetramethyl-1-silapropoxy)octane (2.0 g, 6.2 mmol) in dry THF
(2 mL) were added. After formation of the Grignard reagent
commenced, another 30 mL of dried THF were added followed
by dropwise addition of the remaining bromide. The reaction
mixture was stirred overnight and then chilled to 0 °C,
followed by slow addition of 4,5-(isopropylidenedioxy)-2-pen-
tenal (1, 450 mg, 2.88 mmol). After the mixture was stirred
dium hydride (900 mg, 37.5 mmol) was suspended in THF (50
mL) after being washed with hexanes. 1,8-Octanediol (5 g,
4.2 mmol) was added to the suspension at room temperature,
and the mixture was stirred for 20 h. (TBDMS)Cl (5.2 g, 34.5
mmol) was then added, and vigorous stirring was continued
for 4 h. After filtration, the solvent was removed on a rotary
evaporator. Flash chromatography of the residue with 15%
ethyl acetate in hexanes gave the title monosilyl ether (6.1 g,
9%); TLC (ethyl acetate/hexanes, 3:17) R
CDCl
2
0
3
1
6
(
1
f
) 0.31; H NMR
4
for another 30 min, saturated aqueous NH Cl was added, and
3
) δ 3.62 (t, J ) 6.6 Hz, 2 H), 3.57 (t, J ) 6.6 Hz, 2 H),
the resulting mixture was extracted with diethyl ether and
dried with magnesium sulfate. The solvent was removed with
a rotary evaporator. The residue was flash chromatographed
on a silica gel column (20% ethyl acetate in hexanes) to give
1
3
.4-1.6 (4 H), 1.25-1.35 (8 H), 0.89 (s, 9 H), 0.02 (s, 6 H);
) 63.32 (CH ), 62.92 (CH ), 32.83 (CH
), 32.77 (CH ), 29.42 (CH ), 26.0 (CH ), 25.74 (CH
8.38 (C), -5.25 (CH ). HRMS (EI) (m/z) calcd for C10
) 203.1467, found 203.1468.
-B r o m o -1-(1,1,2,2-t e t r a m e t h y l-1-s ila p r o p o x y )o c -
ta n e. To a magnetically stirred solution of 8-(1,1,2,2-tetram-
ethyl-1-silapropoxy)octan-1-ol (62.5 mg, 0.24 mmol) and Ph
C
NMR (APT, CDCl
3
2
2
2
),
),
3
1
(
2.78 (CH
2
2
2
3
2
3
H
23
O
2
Si
3b (950 mg, 82%, based on 1): TLC (ethyl acetate/hexanes,
+
1
M
- CMe
3
1:4): R
f
) 0.23; H NMR (CDCl
3
) δ 5.81 (dd, J ) 15.3 Hz, 5.9
8
Hz, 1 H), 5.64 (m, 1 H), 4.49 (dd, J ) 13.8 Hz, 7.4 Hz, 1 H),
4.00-4.15 (2 H), 3.57 (t, J ) 6.5 Hz, 2 H), 3.57 (dd. J ) 6.5
Hz, 6.7 Hz, 1 H), 1.4-1.6 (6 H), 1.40 (s, 3 H), 1.35 (s, 3 H),
3
P
(54
2
1
13
(
189 mg, 0.72 mmol) in THF (3 mL) under argon, ZnBr
2
1.18-1.30 (8 H), 0.89 (s, 9 H), 0.02 (s, 6 H); C NMR (APT,
mg, 0.24 mmol) in THF (2.5 mL) was added. After the solution
was stirred for 10 min, diethyl azodicarboxylate (DEAD, 167
mg, 0.96 mmol) in THF (1 mL) was added dropwise with a
syringe. The resulting mixture was stirred at room temper-
ature for another 40 min. The solution was filtered and the
solvent removed with a rotary evaporator. The crude product
was purified by flash chromatography on a silica gel column
with 1.5% ethyl acetate in hexanes to afford the title bromide
3
CDCl , 3bS + 3bR) δ 137.50, 137.42 (CH), 127.79, 127.72 (CH),
109.37 (-C-), 76.62, 76.58 (CH), 72.07, 71.95 (CH), 69.49
(CH ), 63.33 (CH ), 37.17, 37.06 (CH ), 32.88 (CH ), 29.56,
29.50 (CH ), 29.39 (CH ), 26.71 (CH ), 26.02 (CH ), 25.93 (CH ),
25.80 (CH ), 25.41 (CH ), 25.35 (CH ), 18.41 (-C-), -5.22
(CH ); HRMS (EI) (m/z) calcd for (C21
2
2
2
2
2
2
3
3
3
2
2
2
+
3
H
H
41
O
4
Si) (M - Me)
3
+
385.2774, found 385.2772, calcd for C22
382.2902, found 382.2897.
42
O
2
Si (M - H O)
(
63 mg, 81%): TLC (ethyl acetate/hexanes, 1:24) R
f
) 0.30;
1-(5-(2-Oxan yloxy)-7-(3,3-dim eth yl-2,4-dioxolan yl)h ept-
6-en yloxy)-1,1,2,2-tetr a m eth yl-1-sila p r op a n e (4a ). Pyri-
dinium p-toluenesulfonate (PPTS, 11 mg, 0.044 mmol) was
added to a solution of alcohol 3a (150 mg, 0.44 mmol) and
dihydropyran (55 mg, 0.65 mmol, freshly distilled) in dry
methylene chloride (4 mL).30 The resulting solution was
stirred overnight at room temperature and then diluted with
water and extracted with diethyl ether and washed with brine.
Solvent was removed with a rotary evaporator. The crude
product was purified by flash chromatography on a silica gel
column (8% EtOAc in hexanes) to afford the THP ether 4a
1
H NMR (CDCl
3
) δ 3.57 (t, J ) 6.4 Hz, 2 H), 3.38 (t, J ) 6.8
Hz, 2 H), 2.83 (m, 2 H), 1.35-1.55 (4 H), 1.2-1.4 (6 H), 0.89
1
3
(s, 9 H), 0.02 (s, 6 H); C NMR (APT, CDCl
3
) δ 63.20 (CH
2
2
),
),
3
2
3.92 (CH
5.97 (CH
2
), 32.80 (CH
2
), 29.21 (CH
2
), 28.74 (CH ), 28.10 (CH
2
3
), 25.69 (CH
2
), 18.35 (C), -5.27 (CH
3
); HRMS (EI)
) 265.0610, found
+
(m/z) calcd for C10
H
22BrOSi (M - CMe
3
2
65.0620.
1
-(3,3-Dim eth yl-2,4-d ioxola n yl)-7-(1,1,2,2-tetr a m eth yl-
1
-sila p r op oxy)h ep t-1-en -3-ol (3a ). Magnesium turnings
(926 mg, 38.1 mmol) and dry diethyl ether (3.0 mL) were
placed in a 200 mL, flame dried, three-necked flask with a
mechanical stirrer and condenser under an argon atmosphere
at room temperature. A few drops of a solution of 4-iodo-1-
(180 mg, 97%). TLC (ethyl acetate/hexanes, 2:23): R
f
) 0.25;
1
H NMR (CDCl
3
) δ 5.50-5.86 (m, 2 H), 4.55-4.68 (m, 1 H),
4.45-4.55 (m, 1 H), 4.0-4.12 (m, 2 H), 3.82 (m, 1 H), 3.56 (m,
(1,1,2,2-tetramethyl-1-silapropoxy)butane (4.0 g, 12.7 mmol)
3 H), 3.45 (m, 1 H), 1.3-1.9 (12 H), 1.40 (s, 3 H), 1.37 (s, 3 H),
in dry diethyl ether (2 mL) were added. After formation of
the Grignard reagent began, another 45 mL of dry diethyl
ether was added, the remaining iodide was then added
dropwise, and the reaction mixture was then stirred overnight.
After chilling of the mixture to 0 °C, (4,5-(isopropylidenedioxy)-
41 5
0.86 (s, 9 H), 0.02 (s, 6 H); HRMS (EI) (m/z) calcd for C22H O -
+
3
Si (M - CH ) 414.2719, found 414.2734.
1-(9-(2-Oxa n yloxy)-11-(3,3-d im eth yl-2,4-d ioxola n yl)u n -
d ec-10-en yloxy)-1,1,2,2-t et r a m et h yl-1-sila p r op a n e (4b ).
This THP ether was prepared similarly to 4a using PPTS (25.0
mg, 0.1 mmol) alcohol 3b (460 mg, 1.15 mmol) and dihydro-
pyran (145.3 mg, 1.73 mmol, freshly distilled) in dry methylene
chloride (15 mL). The crude product was purified by flash
chromatography on a silica gel column (10% ethyl acetate in
hexanes) to afford the THP ether 4b (450 mg, 98%). TLC
1
7,18,29
2
-pentenal
After being stirred for another 30 min, the reaction was
quenched by addition of saturated aqueous NH Cl, extracted
(1, 700 mg, 4.5 mmol) was added dropwise.
4
with diethyl ether, and the extract dried with magnesium
sulfate. The solvent was removed with a rotary evaporator.
The residue was flash chromatographed on a silica gel column
1
(ethyl acetate/hexanes, 3:22): R ) 0.31; H NMR (CDCl ) δ
f
3
(
30% ethyl acetate in hexanes) to give 3a (1.5 g, 97%, based
5.55-5.88 (m, 2 H), 4.56-4.68 (m, 1 H), 4.50 (m, 1 H), 4.00-
4.12 (2 H), 3.84 (m, 1 H), 3.57 (t, J ) 6.6 Hz, 2 H), 3.55 (m, 1
H), 3.45 (m, 1 H), 1.4-1.9 (12H), 1.40 (s, 3 H), 1.37 (s, 3 H),
1.15-1.35 (8 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 0.87 (s, 9 H), 0.02
1
on 1): TLC (ethyl acetate/hexanes, 3:7) R
(
1
f
) 0.25; H NMR
CDCl3, 3a S + 3a R) δ 5.81 (ddd, J ) 15.4 Hz, 5.8 Hz, 2.7 Hz,
H), 5.648, 5.644 (ddd, J ) 15.4 Hz, 6.9 Hz, 3.3 Hz, 1 H), 4.49
+
(
dd, J ) 6.8 Hz, 7.5 Hz, 1 H), 4.12 (m, 1 H), 4.075, 4.082 (td,
(s, 6 H); HRMS (EI) (m/z) calcd for C H O Si (M - CH )
2
6
49
5
3
+
J ) 8.1 Hz, 6.2 Hz, 1 H), 3.5-3.65 (3 H), 1.4-1.6 (12 H), 1.39
469.3349, found 469.3374, calcd for C H O Si (M - CMe3)
2
3
43
5
(
(
s, 3 H), 1.35 (s, 3 H), 0.89 (s, 9 H), 0.02 (s, 6 H); 13C NMR
APT, CDCl ) δ 137.39 (CH), 127.84, 127.65 (CH, two diaster-
),
), 26.00
), 18.38 (C), -5.25 (CH );
) 329.2144,
427.2880, found 427.2889.
3
5-(2-Oxa n yloxy)-7-(3,3-d im eth yl-2,4-d ioxola n yl)h ep t-6-
eomers), 109.39 (C), 76.58 (CH), 71.96, 71.75 (CH), 69.44 (CH
3.07 (CH ), 36.82, 36.70 (CH ), 32.58 (CH ), 26.69 (CH
CH ), 25.91 (CH ), 21.74, 21.67 (CH
3
2
en -1-ol (5a ). n-Bu NF (0.55 mL, 1 M in THF) was added
4
6
(
2
2
2
3
dropwise to a stirred solution of the silyl ether 4a (78 mg, 0.82
mmol) at room temperature.31 The resulting mixture was
stirred overnight, and then 2.0 mL of water was added. The
resulting mixture was extracted with diethyl ether (3 × 10
3
3
2
+
HRMS (EI) (m/z) calcd for C17
H
33
O
4
Si (M - CH
3
found 329.2163.
1
-(3,3-Dim eth yl-2,4-d ioxola n yl)-11-(1,1,2,2-tetr a m eth yl-
-sila p r op oxy)u n d ec-1-en -3-ol (3b). Magnesium turnings
301 mg, 12.4 mmol) and dry THF (10 mL) were placed in a
00 mL, flame-dried, three-necked flask with a mechanical
mL), washed with brine, and dried (MgSO ), and solvents were
4
1
(
2
removed with a rotary evaporator. The resulting residue was
flash chromatographed on a silica gel column (40% ethyl
(
30) Miyashita, N.; Yoshikosh, A.; Grieco, P. A. J . Org. Chem. 1977,
(
29) Schmid, C. R.; Bryant, J . D.; Dowlatzedah, M.; Phillips, J . L.;
Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S. J . Org. Chem.
991, 56, 4056-4058.
42, 3772-3774.
(31) Kobayashi, Y.; Shimazaki, T.; Taguchi, H.; Sato, F. J . Org.
Chem. 1990, 55, 5324-5335.
1

γ-Hydroxy-R,â-Unsaturated Core Aldehydes
J . Org. Chem., Vol. 63, No. 22, 1998 7793
acetate in hexanes) to afford the primary alcohol 5a (55 mg,
prepared similarly to 7a using a mixture of the acid 6b (18.5
mg, 0.048 mmol), cholesterol (12.4 mg, 0.032 mmol), DCC (20.0
1
9
(
(
6%): TLC (ethyl acetate/hexanes, 3:7) R
CDCl
m, 2 H), 3.80 (m, 1 H), 3.48-3.64 (m, 3 H), 3.42 (m, 1 H),
.3-1.9 (12 H), 1.39 (s, 3 H), 1.35 (s, 3 H); HRMS (EI) (m/z)
f
) 0.17; H NMR
3
) δ 5.50-5.85 (m, 2 H), 4.42-4.66 (m, 2 H), 3.88-4.14
mg, 0.096 mmol), and DMAP (5 mg, 0.04 mmol) in dry CH
2
-
Cl (1.0 mL). The crude product was purified by flash
2
1
chromatography on a silica gel column (12% ethyl acetate in
+
calcd for C16
-(2-Oxan yloxy)-11-(3,3-dim eth yl-2,4-dioxolan yl)u n dec-
0-en -1-ol (5b). This primary alcohol was prepared similarly
to 5a using n-Bu NF (2.3 mL, 1 M in THF) and the silyl ether
b (440 mg, 0.91 mmol) in THF (2 mL) at room temperature.
H
27
O
5
(M - CH
3
) 299.1854, found 299.1866.
hexanes) to afford the ester 7b (22 mg, 92%): TLC (ethyl
1
9
acetate/hexanes, 3:17): R
f
) 0.32; H NMR (CDCl
3
) δ 5.5-
1
5.86 (m, 2 H), 5.35 (bd, J ) 4.0 Hz, 1 H), 4.55-4.70 (m, 2 H),
4.48 (m, 1H), 4.06 (m, 2 H), 3.83 (m, 1H), 3.55 (m, 1 H), 3.45
(m, 1 H), 2.23 (t, J ) 7.6 Hz, 2 H), 2.26 (d, J ) 7.6 Hz, 2H),
0.8-2.2 (43 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 0.99 (s, 3 H), 0.89
(d, J ) 6.5 Hz, 3 H), 0.840 (d, J ) 6.6 Hz, 3 H), 0.836 (d, J )
6.7 Hz, 3 H), 0.65 (s, 3 H).
4
4
The crude product was flash chromatographed on a silica gel
column (40% ethyl acetate in hexanes) to give primary alcohol
5
b (320 mg, 95%): TLC (ethyl acetate/hexanes, 2:3) R
f
) 0.26;
) δ 5.50-5.85 (m, 2 H), 4.64 (m, 1 H), 4.50 (m,
H), 4.06 (dd, J ) 8.1 Hz, 6.3 Hz, 1 H), 4.06 (m. 1 H), 3.84
m, 1 H), 3.61 (t, J ) 6.6 Hz, 2 H), 3.55 (m, 1 H), 3.45 (m, 1 H),
.4-1.9 (12 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.15-1.35 (8 H);
1
H NMR (CDCl
1
(
1
HRMS (EI) (m/z) calcd for C20
found 355.2466, calcd for C16
found 269.2107.
3
Ch olester yl 5-Hyd r oxy-8-oxooct-6-en oa te (8a ). A solu-
tion of 7a (21.0 mg, 0.03 mmol) in acetic acid/water (2:1, v/v,
15
1
.2 mL) was stirred for 4 h at 40 °C, and then sodium
metaperiodate (9.7 mg, 0.045 mmol) was added. After being
stirred another 1.5 h at room temperature, the solution was
neutralized by the portionwise addition of saturated aqueous
sodium bicarbonate and then extracted with diethyl ether. The
ether phase was dried over MgSO , and solvents were removed
4
with a rotary evaporator. The residue was flash chromato-
graphed on a silica gel column (25% ethyl acetate in hexanes)
+
H
35
O
3
5
(M - CH ) 355.2484,
(M+ - C
H O ) 269.2117,
5 9 2
3
H
29
O
5
-(2-Oxa n yloxy)-7-(3,3-d im eth yl-2,4-d ioxola n yl)h ep t-6-
en oic Acid (6a ). A solution of alcohol 5a (44 mg, 0.14 mmol)
and pyridinium dichromate (PDC, 316 mg, 0.84 mmol) in DMF
3
2
(
0.5 mL) was stirred for 20 h at room temperature and then
to provide aldehyde 8a (13.8 mg, 85%): TLC (ethyl acetate/
diluted with aqueous acetic acid to pH ) 4 and extracted with
1
hexanes, 2:3): R
f
) 0.26; H NMR (CDCl
3
) δ 9.57 (d, J ) 7.75
diethyl ether (3 × 10 mL). The combined ether extracts were
Hz, 1 H), 6.79 (dd, J ) 15.6 Hz, 4.5 Hz, 1 H), 6.30 (ddd, J )
5.6 Hz, 6.6 Hz, 1.5 Hz, 1 H), 5.35 (bd, J ) 4.3 Hz, 1 H), 4.59
4
dried over MgSO and concentrated with a rotary evaporator.
1
(
9
6
(
Flash chromatography on a silica gel column (55% ethyl
m, 1 H), 4.43 (m, 1H), 2.34 (t, J ) 6.4 Hz, 2 H) 2.30 (dd, J )
acetate in hexanes) afforded the acid 6a (40.7 mg, 88.5%): TLC
.7 Hz, 7.8 Hz, 2 H), 0.8-2.2 (30 H), 0.99 (s, 3 H), 0.89 (d, J )
1
(
5
4
ethyl acetate/hexanes, 11:9) R
f
) 0.26; H NMR (CDCl
3
) δ
13
.5 Hz, 3 H), 0.84 (d, J ) 6.5 Hz, 6 H), 0.65 (s, 3 H); C NMR
.50-5.86 (m, 2 H), 4.55-4.68 (m,1 H), 4.49 (m, 1H), 3.88-
.18 (m, 2 H), 3.82 (m, 1 H), 3.55 (m, 1 H), 3.45 (m, 1 H), 2.35
3
APT, CDCl ) δ 193.43 (CHO), 173.01 (CdO), 158.35 (CH),
1
5
3
3
2
1
39.54 (C), 130.91 (CH), 122.82 (CH), 74.27 (CH), 70.52 (CH),
6.71 (-), 56.17 (-), 50.05 (+), 42.35 (+), 39.75 (+), 39.55 (+),
8.17 (+), 37.00 (+), 36.63 (+), 36.22 (+), 35.83 (-), 35.72 (+),
4.03 (+), 31.95 (+), 31.88 (-), 28.27 (+), 28.05 (-), 27.85 (+),
4.32 (+), 23.87 (+), 22.86 (-), 22.61 (-), 21.07 (+), 20.42 (+),
(
2t, J ) 6.6 Hz, 7.5 Hz, 2H), 1.4-1.8 (10 H), 1.40 (s, 3 H), 1.36
+
(s, 3 H); HRMS (EI) m/z 328.1886 (M ) calcd for C17
H
28
O
6
found
+
3
3
28.1895, calcd for C16
13.1650.
H
24
O
6
(M - CH
3
) 313.1647, found
9
-(2-Oxan yloxy)-11-(3,3-dim eth yl-2,4-dioxolan yl)u n dec-
9.35 (-), 18.76 (-), 11.90 (-); HRMS (EI) (m/z) calcd for
1
0-en oic Acid (6b). This carboxylic acid was prepared
+
C
35
H
54
O
5
(M - H
2
O) 522.4071, found 522.4099.
similarly to 6a using a solution of alcohol 5b (271 mg, 0.73
mmol) and PDC (1.65 g, 4.38 mmol) in DMF (4 mL). Flash
chromatography of the crude product on silica gel column (50%
Ch olest er yl 9-Hyd r oxy-12-oxod od ec-10-en oa t e (8b ).
This aldehyde was prepared similarly to 8a using a solution
of 7b (20 mg, 0.0265 mmol) in acetic acid/water (2:1, v/v, 1.2
mL) and sodium metaperiodate (8.5 mg, 0.040 mmol). The
crude product was flash chromatographed (20% ethyl acetate
ethyl acetate in hexanes) afforded the acid 6b (320 mg, 82%):
1
TLC (ethyl acetate/hexanes, 1:1) R
f
) 0.28; H NMR (CDCl
3
)
δ 5.50-5.88 (m, 2 H), 4.62 (m, 1 H), 4.49 (m, 1H), 4.0-4.1 (2
in hexanes) to afford the aldehyde 8b (14 mg, 90%): TLC (ethyl
H), 3.83 (m, 1 H), 3.54 (m, 1 H), 3.44 (m, 1 H), 2.35 (t, J ) 7.4
1
acetate/hexanes, 1:4) R
f
) 0.21; H NMR (CDCl
3
) δ 9.57 (d, J
Hz, 2H), 1.4-1.9 (10 H), 1.39 (s, 3 H), 1.36 (s, 3 H), 1.15-1.35
+
) 7.8 Hz, 1 H), 6.80 (dd, J ) 15.6 Hz, 4.51 Hz, 1 H), 6.29 (ddd,
J ) 15.6 Hz, 7.7 Hz, 1.7 Hz, 1 H), 5.35 (d, J ) 4.3 Hz, 1 H),
4.59 (m, 1 H), 4.41 (m, 1H), 2.27 (t, J ) 7.8 Hz, 2 H) 2.26 (dd,
J ) 15.0 Hz, 7.4 Hz, 2 H), 0.8-2.2 (38 H), 0.99 (s, 3 H), 0.89
(8 H); HRMS (EI) (m/z) calcd for C21
H
36
O
6
(M ) 384.2512, found
(M+ - Me) 369.2277, found
3
3
2
84.2465, calcd for C20
69.2235, and calcd for C16
65.1802, found 265.1806.
H
33
O
6
+
H
25
O
3
(M - C
5
H
9
O
2
2
- H O)
(
d, J ) 6.5 Hz, 3 H), 0.84 (d, J ) 5.6 Hz, 6 H), 0.65 (s, 3 H);
Ch olester yl 5-(2-Oxa n yloxy)-7-(3,3-d im eth yl-2,4-d iox-
ola n yl)h ep t-6-en oa te (7a ). Dicyclohexylcarbodiimide (DCC)
114 mg, 0.54 mmol) and N,N-dimethylaminopyridine (DMAP,
6 mg, 0.21 mmol) were added to a solution of the acid 6a (88.0
mg, 0.27 mmol) and cholesterol (69.5 mg, 0.18 mmol) in dry
1
3
C NMR (APT, CDCl ) δ 193.50 (CHO), 173.31 (-CO-),
3
1
7
58.80 (CH), 139.73 (C), 130.74 (CH), 122.67 (CH), 73.79 (CH),
1.11 (CH), 56.72 (-), 56.17 (-), 50.05 (+), 42.34 (+), 39.76
(
2
(
+), 39.55 (+), 38.20 (+), 37.03 (+), 36.64 (+), 36.51 (+), 36.21
3
3
(+), 35.83 (-), 34.66 (+), 31.95 (+), 31.89 (-), 29.20 (+), 29.09
2 2
CH Cl (2.0 mL). The resulting mixture was stirred at room
(
(
(
(
+), 28.97 (+), 28.26 (+), 28.05 (-), 27.85 (+),25.12 (+), 24.96
temperature for 48 h. The solution was then filtered, and
solvent was removed with a rotary evaporator. The residue
was purified by flash chromatography on a silica gel column
+), 24.32 (+), 23.86 (+), 22.86 (-), 22.60 (-), 21.07 (+), 19.36
-), 18.75 (-), 11.89 (-); HRMS (EI) (m/z) calcd for C39
M
62 3
H O
+
- H
2
O) 578.4651, found 578.4705.
(
9
12% ethyl acetate in hexanes) to afford the ester 7a (120 mg,
1
6%): TLC (ethyl acetate/hexanes, 3:22) R
f
) 0.22; H NMR
P h osp h olip id 9a . Dicyclohexylcarbodiimide (DCC, 101
(
(
(
CDCl
3
) δ 5.54-5.89 (m, 2 H), 5.37 (bd, J ) 4.5 Hz, 1 H), 4.67
mg, 0.49 mmol) and N,N-dimethylaminopyridine (DMAP) (26
mg, 0.21 mmol) were added to a solution of the acid 6a (107
mg, 0.32 mmol) and L-R-lysophosphatidylcholine (104 mg, 0.21
m, 1 H), 4.61 (m, 1H), 4.52 (td, J ) 6.6 Hz, 7.4 Hz, 1 H), 4.10
m, 2 H), 3.85 (m, 1 H), 3.58 (m, 1 H), 3.47 (m, 1 H), 2.30 (4
mmol) in dry CHCl
3
(5 mL).33 The resulting mixture was
H), 0.8-2.2 (35 H), 1.42 (s, 3 H), 1.39 (s, 3 H), 1.02 (s, 3 H),
0
.92 (d, J ) 6.6 Hz, 3 H), 0.87 (d, J ) 6.6 Hz, 6 H), 0.68 (s, 3
stirred for 48 h at room temperature. The solution was
filtered, and the solvent was removed by rotary evaporation.
+
H); HRMS (EI) (m/z) calcd for C43
found 681.5119, and calcd for C39
95.4726, found 595.4737.
Ch olester yl 9-(2-Oxa n yloxy)-11-(3,3-d im eth yl-2,4-d iox-
ola n yl)u n d ec-10-en oa te (7b). This carboxylic ester was
H
69
O
6
(M - CH
3
) 681.5094,
+
H
63
O
4
(M - C
5
H
9
O
2
)
Flash chromatography of the residue (CHCl
3
/MeOH/H
/MeOH/
) δ 5.5-5.85 (m, 2
2
O, 30:
5
19:1) gave phospholipid 9a (210 mg, 82%): TLC (CHCl
3
1
H
2
O, 30:19:1) R
f
) 0.16; H NMR (CDCl
3
H), 5.18 (m, 1 H), 4.5-4.65 (m, 1 H), 4.48 (td, J ) 6.8 Hz, 6.4
Hz, 1 H), 4.15-4.42 (m, 3 H), 4.0-4.1 (3 H), 3.92 (m, 2 H),
3
2
.65-3.85 (3 H), 3.55 (m, 1 H), 3.43 (m, 1 H), 3.35 (s, 9 H),
.24 (t, J ) 7.6 Hz, 2 H), 2.27 (m, 2 H), 1.4-1.9 (12 H), 1.39 (s,
(
(
32) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 5, 399-402.
33) Heber, N.; Beck, A.; Lennox, R. B.; J ust, G. J . Org. Chem. 1992,
5
7, 1777-1783.
3H), 1.35 (s, 3H), 1.22 (24H), 0.85 (t, J ) 6.8 Hz, 3 H); HRMS

7
794 J . Org. Chem., Vol. 63, No. 22, 1998
Deng and Salomon
(
FAB, CsI/NaI/glycerol) (m/z) calcd for C41
H
76NO12PCs (MCs+)
3.30 (s, 9 H), 2.36 (m, 2 H), 2.26 (t, J ) 6.2 Hz), 1.5-1.9 (6 H),
9
38.4155, found 938.4154.
P h osp h olip id 9b. This phospholipid was prepared simi-
larly to 9a using the acid 6b (74 mg, 0.19 mmol), L-R-
lysophosphatidylcholine (47 mg, 0.095 mmol), dry CHCl (2
1.22 (24 H), 0.85 (t, J ) 6.4 Hz); 13C NMR (APT, CDCl
) δ
3
194.18 (CHO), 173.56 (-CO-), 173.15 (-CO-), 161.06 (CH),
130.52 (CH), 70.79 (CH), 70.31 (CH), 66.40 (CH
2
), 62.56 (CH
2
2
2
),
),
),
3
59.41 (CH
29.73 (CH
2
), 59.32 (CH
), 29.55 (CH
2
), 54.51 (CH
), 29.37 (CH
3
), 34.10 (CH
), 29.19 (CH
2
), 31.95 (CH
2
), 24.90 (CH
mL),DCC (60 mg, 0.29 mmol), and DMAP (12 mg, 0.095 mmol).
Flash chromatography of the crude product on a silica gel
2
2
2
3
14.14 (CH ).
column (CHCl
TLC (CHCl /MeOH/H
δ 5.5-5.85 (m, 2 H), 5.17 (m, 1 H),4.54-4.67 (m, 1 H), 4.48
m, 1 H), 4.18-4.42 (3 H), 3.96-4.14 (3 H), 3.92 (3 H), 3.72-
.98 (3 H), 3.53 (m, 1 H), 3.43 (m, 1 H), 3.35 (s, 9 H), 2.25 (4
H), 1.4-1.9 (13 H), 1.39 (s, 3 H), 1.37 (s, 3H), 1.22 (33 H), 0.85
t, J ) 6.4 Hz, 3 H); HRMS (FAB, CsI/NaI/Gly) (m/z) calcd for
3
/MeOH/H
2
O, 30:19:1) gave 9b (78 mg, 95%):
P h osp h olip id Ald eh yd e (10b). This aldehyde was pre-
pared similarly to 10a using a solution of the compound 9b
1
3
2
O, 30:19:1) R
f
3
) 0.28; H NMR (CDCl )
(
28 mg, 0.032 mmol) in acetic acid/water (2:1, v/v, 1.5 mL)
followed by treating a solution of the vicinal diol intermediate
in dry methylene chloride (1.2 mL) with Na CO (6.8 mg, 0.064
mmol) and then Pb(OAc) (15.5 mg, 0.035 mmol) in dry CH
Cl (1 mL). The crude product was flash chromatographed
on a silica gel column (CHCl /MeOH/H O, 15:9:1) to give the
phospholipid aldehyde 10b (19.2 mg, 85%): TLC (CHCl
(
3
2
3
4
2
-
(
C
2
+
45
H
84NO12PCs (MCs ) 994.4781, found 994.4773.
3
2
Hyd r olysis a n d P er iod a te Oxid a tion of 9b. Treatment
3
/
of a solution of 9b in acetic acid/water (2:1, v/v), and sodium
metaperiodate as described for 7b above, did not deliver the
expected γ-hydroxy-R,â-unsaturated aldehyde 10b. Rather,
1
MeOH/H
2
O, 15:9:1) R
f
) 0.18; H NMR (300 MHz, CDCl ) δ
3
9
6
4
.53 (d, J ) 8.0 Hz, 1 H), 6.86 (dd, J ) 15.5 Hz, 4.1 Hz, 1 H),
.28 (ddd, J ) 15.5 Hz, 8.1 Hz, 1.3 Hz, 1 H), 5.19 (m, 1 H),
.37 (m, 1 H), 4.32 (dd, J ) 12.1 Hz, 3.2 Hz, 1 H), 4.27 (m, 2
1
-palmitoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine (12,
n ) 7) was obtained (75-80%): HRMS (FAB, CsI/NaI/Gly) (m/
H), 4.11 (dd, J ) 12.0 Hz, 7.3 Hz, 1 H), 3.92 (dd, J ) 6.1 Hz,
6
+
9
z) calcd for C33H64NO PCs (MCs ) 782.3368, found 782.3391.
.0 Hz, 2 H), 3.76 (m, 2 H), 3.32 (s, 9 H), 2.28 (m, 2 H), 2.25 (t,
1
The H NMR spectrum of the phospholipid was identical with
J ) 7.5 Hz, 2 H), 1.45-1.70 (7 H), 1.3-1.5 (12 H), 1.22 (19 H),
5
that reported previously for 12 (n ) 7).
13
0
(
(
6
3
.85 (t, J ) 6.5 Hz); C NMR (300 MHz, APT, CDCl ) δ 194.21
3
P h osp h olip id Ald eh yd e 10a . A solution of the compound
CHO), 173.62 (-CO-), 173.32 (-CO-), 161.77 (CH), 130.21
CH), 70.74, 70.65 (CH), 70.16, 70.11 (CH), 66.53, 66.48, (CH
9
a (22 mg, 0.027 mmol) in acetic acid/water (2:1, v/v, 1.2 mL)
2
),
),
was stirred magnetically for 4 h at 40 °C, and then the solvent
was removed with a rotary evaporator. Traces of residual
HOAc were removed by azeotropic distillation with n-heptane
3.56, (CH
6.40, (CH
2
), 62.89 (CH
), 34.16 (CH
2
), 59.28, 59.23 (CH
2
), 54.54 (CH
3
2
2
), 31.96 (CH ), 29.96 (CH
2
2
), 29.74
(
(
(
CH
CH
CH
2
), 29.65 (CH
2
), 28.19 (CH
3
).
2
), 29.39 (CH
), 24.93 (CH
2
2
), 29.20 (CH
), 24.72 (CH
2
2
), 28.77 (CH
), 22.73 (CH
2
), 28.56
), 14.16
(
2 × 1 mL) under high vacuum. Dry methylene chloride (1
mL) and Na CO (5.7 mg, 0.054 mmol) were added to the
residue. The solution was stirred magnetically at -78 °C
under argon. Pb(OAc) (13.3 mg, 0.03 mmol) in dry methylene
2
2
2
3
4
3
4
Ack n ow led gm en t. We thank the National Insti-
tutes of the Health for support of this research by
Grants GM21249 and HL53315.
chloride (1 mL) was added dropwise with a syringe. The
resulting solution was stirred for 10 min, and then the solvent
was removed by rotary evaporation and the residue was flash
chromatographed on a silica gel column (CHCl
3 2
/MeOH/H O,
1
5:9:1) to give phospholipid aldehyde 10a (14.3 mg, 82%): TLC
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
1
(
(
(
CHCl
3
/MeOH/H
2
O, 15:9:1) R
f
) 0.17; H NMR (CDCl ) δ 9.53
3
spectra of all new compounds (26 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from ACS; see any current masthead page for ordering
information.
d, J ) 7.7 Hz, 1 H), 6.85 (dd, J ) 15.3 Hz, 3.7 Hz, 1 H), 6.28
dd, J ) 15.3 Hz, 8.2 Hz, 1 H), 5.22 (m, 1 H), 4.37 (m, 1 H),
4
.1-4.35 (4 H), 3.99 (m, 1 H), 3.91 (m, 1 H), 3.75 (m, 2 H),
(34) Corey, E. J .; Marfat, A.; Goto, G.; Brion, F. J . Am. Chem. Soc.
1
980, 102, 7984-7985.
J O980861E