Total Synthesis of Oxidized Phospholipids. 3. The (11E)-9-Hydroxy-13-oxotridec-11-enoate Ester of 2-Lysophosphatidylcholine

Article abstract of DOI:10.1021/jo000809u

A total synthesis of (11E)-9-hydroxy-13-oxotridec-11-enoate ester of 2-lysophosphatidylcholine (HOT-PC) was devised to facilitate identification of this oxidized phospholipid. A lactone, 8-(3-oxo-1H,6H-2-oxinyl)octanoic acid (1), believed to be generated through an intermediate (11E)-9-hydroxy-13-oxotridec-11-enoic acid (HOT), is produced upon autoxidation of linoleic acid. A synthesis of lactone 1 methyl ester was accomplished from HOT involving a novel trans-cis isomerization that is driven to completion by cyclization to a hemiacetal. An alternative route to this carbon skeleton was also acheived that provides the lactone 1 itself.

Full text of DOI:10.1021/jo000809u

6
660
J . Org. Chem. 2000, 65, 6660-6665
Tota l Syn th esis of Oxid ized P h osp h olip id s. 3. Th e
(
11E)-9-Hyd r oxy-13-oxotr id ec-11-en oa te Ester of
-Lysop h osp h a tid ylch olin e
2
Yijun Deng and Robert G. Salomon*
Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078
rgs@po.cwru.edu.
Received May 26, 2000
A total synthesis of (11E)-9-hydroxy-13-oxotridec-11-enoate ester of 2-lysophosphatidylcholine
(HOT-PC) was devised to facilitate identification of this oxidized phospholipid. A lactone, 8-(3-oxo-
1
1
H,6H-2-oxinyl)octanoic acid (1), believed to be generated through an intermediate (11E)-9-hydroxy-
3-oxotridec-11-enoic acid (HOT), is produced upon autoxidation of linoleic acid. A synthesis of
lactone 1 methyl ester was accomplished from HOT involving a novel trans-cis isomerization that
is driven to completion by cyclization to a hemiacetal. An alternative route to this carbon skeleton
was also acheived that provides the lactone 1 itself.
In tr od u ction
The study of lipid peroxidation is a rapidly growing
field in medicine and biology, spurred by increasing
evidence that lipid oxidation is involved in the patho-
genesis of many chronic diseases, e.g., atherosclerosis,
Alzheimer’s disease, Parkinson disease, stroke, and
1
aging. In vivo, most fatty acids are present as esters of
cholesterol or glycerol. Phospholipids, esters of glycerol-
3
-phosphate, are major components of biological mem-
branes and lipoproteins, circulating micellelike particles
solubilized with an outer shell of phospholipids. A vast
array of aldehydes are produced by oxidative cleavage
of polyunsaturated fatty acids and their phospholipid
derived carboxyalkylpyrrole protein modifications in
human blood proteins and oxidized low-density lipopro-
teins. Carboxyalkylpyrroles are formed by the reaction
of γ-hydroxy-R,â-unsaturated aldehydic esters of 2-lyso-
PC with the primary amino groups of protein lysyl
residues. For example, oxidative cleavage of linoleic acid-
PC ester (LA-PC) generates protein-based carboxyhep-
tylpyrroles by reaction of a 9-hydroxy-12-oxo-10-dode-
cenoic acid ester of lyso-PC (HODA-PC) with protein in
conjunction with ester hydrolysis (Scheme 1).
5
2
derivatives. Many alkanals and alkenals, some contain-
ing hydroxyl or epoxy groups, have been isolated and fully
characterized. Some covalently modify proteins, and this
may be important for their biological activities, e.g.,
malondialdehyde, 2(E)-4-hydroxy-2-nonenal and 2(E)-4-
hydroxy-2-hexenal. Less is known about aldehyde prod-
ucts of lipid peroxidation that remain esterified in
phospholipids. To foster progress in this area, we are
devising unambiguous chemical syntheses of oxidized
phospholipids.3 Recent studies showed that oxidative
cleavage of the arachidonic acid (AA) ester AA-PC of
Sch em e 1
2
-lyso-phosphatidylcholine (PC) generates a phospholipid
4
ester of 5-oxovaleric (OV) acid. OV-PC activates endo-
thelial cells to bind monocytes. This may facilitate entry
of monocytes into the vessel wall, an important event in
atherogenesis. Our chemical synthesis of OV-PC facili-
tated its structural and biological characterization.
Some of the aldehydes generated by oxidative cleavage
of phospholipids avidly bind covalently with proteins,
leading to protein modifications that may interfere with
biological functions. We previously identified lipid-
Very recently, the lactone 1 from (2Z)-5-hydroxy-2-
tridecenedioate was identified as a product from the
oxidative cleavage of LA. This lactone was postulated to
arrise from 9-hydroxy-13-oxo-11-tridecenoic (HOT) acid,
1
a δ-hydroxy-R,â-unsaturated aldehydic acid (Scheme 2).
*
To whom correspondence should be addressed. Telephone: 216-
To facilitate investigation of the formation of lactone 1
from LA and of various phospholipid derivatives from
oxidative fragmentation of LA-PC in vivo, we devised
total syntheses of lactone 1 and its putative precursor
phospholipid, HOT-PC (2).
3
68-2592. FAX: 216-368-3006.
(
1) Spiteller, G. Chem. Phys. Lipids 1998, 95, 105-62.
(2) Esterbauer, H.; Schaur, R. J .; Zollner, H. Free Radic. Biol. Med.
1
991, 11, 81-128.
(
3) , For previous papers in this series, see refs 4 and 6.
(4) Watson, A. D.; Leitinger, N.; Navab, M.; Faull, K. F.; Horkko,
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.
(5) Kaur, K.; Salomon, R. G.; O’Neil, J .; Hoff, H. F. Chem. Res.
Toxicol. 1997, 10, 1387-96.
1
0.1021/jo000809u CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/31/2000

Total Synthesis of Oxidized Phospholipids
J . Org. Chem., Vol. 65, No. 20, 2000 6661
Sch em e 2
Sch em e 5a
Sch em e 3
a
(a) PC, DCC, DMAP; (b) (1) AcOH/H2O, (2) Pb(OAc)4, -78 °C.
Sch em e 6a
Sch em e 4a
a
(a) n-BuLi, H2O; (b) Bu3SnH, AlBN; (c) CuCN, n-BuLi; (d)
HAl(i-C4H9)2; n-BuLi; (e) PPh3, I2; (f) TBDMSCl, DMAP, Et3N; (g)
DHP, PPTS.
8
etherate. The resulting secondary alcohol was protected
as a TBDMS ether 4 with TBDMSOTf and 2,6-lutidine
9
in quantitative yield. A controlled Lindlar hydrogenation
a
(
a) Ethyl vinyl ether, PPTS; (b) mCPBA; (c) BF3-Et2O, -78
of alkyne 4 provided cis-alkene 5. The acid 7Z was
prepared by PDC oxidation of the corresponding primary
alcohol 6.10
°
C; (d) TBDMSTf, 2,6-lutidine, -78 °C; (e) H2/Pd, quinoline; (f)
PPTS, MeOH; (g) PDC, DMF.
Resu lts a n d Discu ssion
Attempts to convert phospholipid derivative 8Z derived
from acid 7Z to HOT-PC through crotonaldehyde isomer-
ization failed to give the desired product. Rather, a cyclic
hemiacetal was produced (Scheme 5). Thus, interception
of the aldehyde with an internal nucleophile apparently
proceeded more rapidly than, and consequently prevented
the desired cis-trans isomerization.
Th e Syn th etic Design . The δ-hydroxy-R,â-unsatur-
ated aldehyde array in HOT-PC (2) is a vinylogous aldol
that was expected to be chemically sensitive. Therefore,
a primary consideration of our synthetic design was to
assemble a stable precursor from which HOT-PC could
be generated conveniently and efficiently. As in our
previous synthesis of HODA-PC,6 a 3,3-dimethyl-2,4-
dioxolanyl moiety was exploited as a latent aldehyde
A Tr a n s Isom er ic Ca r boxa ld eh yd ic Acid P r ecu r -
sor 7E. We reasoned that cyclization to an unreactive
hemiacetal could be avoided if the requisite E-alkenal
was generated from the trans isomer of 8Z. However,
several C-C connective routes, outlined in Scheme 6,
failed to deliver the target carbon skeleton with a trans
CdC bond. Hydrometalation of alkyne 10 provided trans
vinyl aluminum, tin, and copper nucleophiles. However,
neither vinylalanate 11 nor vinylcuprate 13 reacted with
epoxide 3 or iodide 17 to deliver trans alkenes of general
4
(
Scheme 3). Addition of an alkylnyl nucleophile to an
epoxide was chosen to provide the key carbon-carbon
bond forming step in a convergent assembly of the
requisite carbon skeleton.
A Cis Isom er ic Ca r boxa ld eh yd ic Acid P r ecu r sor
Z. Because cis-crotonaldehydes are converted rapidly
7
7
with a trace of acid to corresponding trans isomers, we
expected that 7Z (Scheme 4) could serve as a precursor
for HOT-PC. The carbon skeleton of HOT-PC was
assembled by the alkynylation of epoxide 3 with an
alkynyl borane reagent that was prepared in situ at -78
structure 14. Attempted reductions (LiAlH /diglyme/heat;
Red-Al/THF; Na/liquid NH ) of the alkyne 4 also failed
3
to deliver the desired trans alkene 14.
°
C in THF by the reaction of 4-ethynyl-2,2-dimethyl-1,3-
dioxolane with n-butyllithium and boron trifluoride
(
(
8) Yamguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394.
9) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 20, 399-402.
(6) Deng, Y.; Salomon, R. G. J . Org. Chem. 1998, 63, 7789-7794.
7) McGreer, D. E.; Page, B. D. Can. J . Chem. 1969, 47, 866-867.
(10) Corey, E. J .; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455-3458.
(

6
662 J . Org. Chem., Vol. 65, No. 20, 2000
Deng and Salomon
Sch em e 7a
Sch em e 8a
a
(a) AcOH/H2O, NaIO4; (b) NaClO2, NaH2PO4, 2-methyl-2-
butene; (c) t-BuOH/H2O, Et2AlCl, MeOH, UV 254 nm.
a
Sch em e 9a
(
h) Ph2S2 (0.5 equiv), benzene, sunlamp, 6 h; (i) PC, DCC,
DMAP; (j) (1) AcOH/H2O, (2) Pb(OAc)4, -78 °C.
Completion of the synthesis should be feasible if a cis-
trans isomerization of the CdC bond preceded, rather
than followed, generation of the aldehyde group. An
excellent route to the trans alkene 7E was ultimately
acheived by photochemical isomerization of 7Z. Of several
methods examined for the isomerization (including ther-
mal isomerization and photoisomerization, e.g., PhSH or
2 2 2
Ph S /AIBN/benzene/reflux; I
/benzene/sun lamp),1
1-13
the most effective was diphenyl disulfide catalyzed
photochemical isomerization. Compound 7Z in benzene
a
(
a) AcOH/H2O, NaIO4; (b) PDC, DMF.
was irradiated in the presence of Ph
a sun-lamp for 6 h to afford 7E (Z:E ) 4:96) in 95% yield
Scheme 7). Isomerization of alkene 5 under the same
2 2
S (0.5 equiv) with
Sch em e 10
(
reaction conditions gave a 1:1 (Z:E) mixture.
P r epar ation of th e Aldeh ydic P h osph olipid, HOT-
P C (2). The 2-lyso-phosphatidylcholine ester 8E, which
is a stable precursor of HOT-PC, was produced in 89%
yield by the reaction of acid 7E with 2-lyso-phosphati-
dylcholine in the presence of DCC and DMAP (Scheme
7
). Exposure of the ester 8E to aqueous acetic acid, which
hydrolytically removed the TBDMS and acetonide pro-
tecting groups, and subsequent treatment of the resulting
diol with lead tetraacetate in methylene chloride at -78
6
°C, delivered the target aldehyde HOT-PC in 90% yield.
A minor byproduct, presumably generated by cyclization
of the minor cis-crotonaldehyde isomeric intermediate,
was easily removed by reverse phase HPLC.
La cton e 1. Our first synthesis of the carbon skeleton
of lactone 1 was accomplished from the E alkenal HOT
because an appropriate nonalcoholic solvent could not be
found to accomplish isomerization without esterification.
An alternative approach, that generates a cis crotonal-
dehyde intermediate directly, was exploited to produce
lactone 1 (Scheme 9). Treatment of cis alkene 5 with
aqueous acetic acid and then oxidative cleavage of the
(18) through a novel trans-cis isomerization of a cro-
tonaldehyde intermediate that is driven to completion by
cyclization to a hemiacetal. This pathway is reminiscent
of that postulated for generation of lactone 1 during
autoxidation of linoleic acid. Exposure of acid 7E to
aqueous acetic acid and treatment of the resulting diol
corresponding diol with NaIO
1. The acetal 21 was then oxidized by PDC to deliver
lactone 1.
4
afforded the cyclic acetal
with NaIO
4
at room-temperature delivered the δ-hy-
2
droxy-R,â-unsaturated aldehydic acid HOT (18) (Scheme
6
8
). Selective oxidation of the aldehyde group of 18 with
NaClO produced the dicarboxylic acid 19 in excellent
2
4,15
Con clu sion
1
yield.
Lewis acid-catalyzed photochemical isomeriza-
tion16 of 19 to its cis isomer not only was accompanied
by cyclization to a δ-lactone, but also esterification
producing 20. Consequently, photochemical isomerization
of 19 did not provide an optimal route to the lactone 1
Oxidation of LA produces a complex array of aldehydes
by fragmentation of hydroperoxyoctadecadienoates, e.g.,
13-HPODE (22). A cascade of reactions was recently
1
proposed (Scheme 10) to accommodate the early forma-
tion of 13-oxotrideca-9,11-dienoic acid (23) and ultimate
generation of 9-oxononanoic acid (24) through Michael
addition of water to 23. The resulting HOT then gives
(
(
(
11) Moussebois, C.; Dale, J . J . Chem. Soc. (C) 1966, 260-264.
12) Sonnet, P. E. Tetrahedron 1980, 36, 557-604.
13) Henrick, C. A.; Willy, W. E.; Baum, J . W.; Baer, T. A.; Garcia,
2
4 through retro aldol fragmentation and lactone 1
B. A.; Mastre, T. A.; Chang, S. M. J . Org. Chem. 1975, 40, 1-7.
(
(
14) Dalcanale, E.; Montanari, F. J . Org. Chem. 1986, 51, 567-569.
15) Kokayashi, Y.; Nakno, M.; Kumar, G. B.; Kishihara, K. J . Org.
(16) Lewis, F. D.; Howard, D. K.; Barancyk, S. V.; Oxman, J . D. J .
Chem. 1998, 63, 7505-7515.
Am. Chem. Soc. 1986, 108, 3016-3023.

Total Synthesis of Oxidized Phospholipids
J . Org. Chem., Vol. 65, No. 20, 2000 6663
through further oxidation and lactonization. With the
completion of syntheses of HOT, HOT-PC, and lactone 1
reported above, as well as dienal 23 and the derived
phospholipid (to be reported elsewhere), all of the com-
pounds in the putative cascade as well as the correspond-
ing phospholipids are now readily available. The results
of ongoing studies to test the cascade hypothesis, to detect
the formation of the various oxidized phospholipids upon
oxidation of LA-PC, and determine their natural occur-
rence as well as to explore the biological activities of the
oxidized phospholipids will be reported in due course.
1 H), 3.83 (dd, J ) 7.7, 5.5 Hz, 1 H), 3.30-3.75 (5 H), 2.43 (dd,
J ) 16.7, 4.8,1.5 Hz, 1 H), 2.32 (ddt, J ) 16.7, 6.7, 2.0 Hz, 1
H), 1.4-1.6 (br, 2 H), 1.45 (s, 3 H), 1.34 (s, 3 H), 1.2-1.4 (1
1
3
0
H), 1.27 (d, J ) 5.2 Hz, 3 H), 1.17 (t, J ) 7.0 Hz, 3 H);
C
NMR (CDCl
3
, APT) δ 110.11 (C), 99.56 (CH), 83.10 (C), 79.92
), 69.96 (CH), 65.78, (CH), 65.54 (CH), 65.29
), 60.67 (CH ), 36.34 (CH ), 29.91 (CH ), 29.49 (CH ), 27.80
(
(
C), 70.14 (CH
CH
2
2
2
2
2
2
(CH ), 26.32 (CH ), 26.25 (CH ), 26.00 (CH ), 25.59 (CH ), 19.91
2
3
2
3
2
+
(CH
CH
41.2328, found 341.2320.
2-(E t h oxyet h oxy)-1-(3,3-d im et h yl-2,4-d ioxola n yl)-9-
1,1,2,2-tetr a m eth yl-1-sila p r op oxy)d od ec-11-yn e (4). To a
solution of the secondary alcohol (120 mg, 0.32 mmol) and 2,6-
lutidine (93 µL, 0.8 mmol, freshly distilled from CaH ) in CH
Cl (0.5 mL, 1 M of alcohol) was added TBDMSOTf (150 µL,
.64 mmol) at -78 °C. After being stirred for 40 min at -78
C, the reaction mixture was quenched by addition of saturated
NaHCO and diluted with ethyl ether, followed by extraction
3
), 15.35 (CH
3
); HRMS (EI) m/z calcd for C21
H
5
39
O
5
(M
-
+
3
) 355.2484, found 355.2489; calcd for C20
H
37
O
2 5
(M - C H )
3
1
(
Exp er im en ta l P r oced u r es
2
2
-
Gen er a l Meth od s. 1H NMR and 13C NMR spectra were
2
0
°
recorded at 300 and 75 MHz, respectively, and are reported
1
7
as described previously. High-resolution mass spectra, sol-
vent purification, and chromatography were performed as
3
and concentration. Flash chromatography on a silica gel
1
7
usual. All reactions conducted in an inert atmosphere were
in argon or N unless otherwise specified.
column (6% ethyl acetate in hexanes) gave 4 in a quantitative
2
1
yield. TLC (8% ethyl acetate in hexanes) R
(
f
) 0.29; H NMR
1
-(r-Eth oxyeth oxy)d ec-9-en e. Ethyl vinyl ether (9.2 g,
3
CDCl , 300 MHz) δ 4.68 (m, 1 H), 4.66(q, J ) 5.4 Hz, 1 H),
1
9
28 mmol) was added dropwise to an ice-cooled solution of
-decen-1-ol (10 g, 64 mmol) and PPTS (64 mg, 0.26 mmol) in
CH Cl (100 mL) under an argon atmosphere. The solution
2 2
4
6
1
3
.10 (dd, J ) 7.9, 6.2 Hz, 1 H), 3.3-3.9 (5 H), 2.32 (dd, J )
.2, 1.7, Hz 1 H), 1.4-1.6 (2 H), 1.45 (s, 3 H), 1.35 (s, 3 H),
.2-1.4 (10 H), 1.28 (d, J ) 5.4 Hz, 3 H), 1.18 (t, J ) 7.0 Hz,
1
8
was stirred for 1.5 h at room temperature and then poured
into a 1:1 mixture of hexanes and saturated aqueous NaHCO
H), 0.85 (s, 9 H), 0.03 (s, 6 H); HRMS (EI) m/z calcd for
3
+
C
26
H
49
O
5
Si (M - CH
3
) 469.3359, found 469.3349.
(
100 mL). The aqueous phase was extracted with hexane. The
cis-1-(Eth oxyeth oxy)-12-(3,3-d im eth yl-2,4-d ioxola n yl)-
-(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)d od ec-11-en e (5). To
a suspension of Lindlar catalyst (Pd/CaCO , 50 mg) and
4
combined organic extracts were dried (MgSO ), filtered, and
9
concentrated in vacuo. Flash chromatography on a silica gel
column afforded 1-(r-eth oxyeth oxy)d ec-9-en e (13.5 g, 92%).
3
1
synthetic quinoline (5 drops), after being evacuated and
flushed with hydrogen alternatively several times, was added
TLC (ethyl acetate/hexanes, 1:23) R
3
3
f
) 0.25; H NMR (CDCl
3
,
00 MHz) δ 5.65 (m, 1 H), 4.85-5.05 (2 H), 4.65 (m, 1 H), 3.30-
4
(630 mg, 1.3 mmol) in methanol (25 mL) via syringe. The
.70 (4 H), 2.02 (m, 2 H), 1.55 (2 H), 1.2-1.4 (10 H), 1.26 (d,
1
3
reaction was monitored by the uptake of hydrogen and was
stopped when the desired amount of hydrogen was consumed
J ) 5.2 Hz, 3 H), 1.17 (t, J ) 6.9 Hz, 3 H); C NMR (CDCl
3
,
7
2
5 MHz) δ 139.22, 114.14, 99.55, 65.30, 60.66, 33.82, 29.93,
(29.1 mL, 1 equiv) in about 1 h. The reaction mixture was
9.45, 29.10, 28.94, 26.72, 19.91, 15.35; HRMS (EI) m/z calcd
+
filtered, and the solvent was removed by rotary evaporation.
The crude product was dissolved in diethyl ether and washed
for C14
C
H
29
O
2
(MH ) 229.2170, found 229.2169; calcd for
+
13
H
1
25
O
2
(M - CH
3
) 213.1855, found 213.1855.
with saturated aqueous NH
phase was dried (MgSO ), concentrated, and purified by flash
4
Cl, water, and brine. The ether
-(8-(2-Oxir a n yl)octyloxy)-1-eth oxyeth a n e (3). To a so-
lution of 1-(R-ethoxyethoxy)dec-9-ene (3.6 g, 15.8 mmol) in CH
Cl (30 mL) was added m-chloroperbenzoic acid (2.3 g, 17.3
4
2
-
chromatography on a silica gel column (8% ethyl acetate in
hexanes) to afford 5 (672 mg, 94%). TLC (10% ethyl acetate
2
mmol, 85% pure) in small quantities with constant stirring at
room temperature. After the addition, the mixture was stirred
for 60 h at room temperature. The resulting mixture was
filtered, and the solvent was removed under reduced pressure.
1
in hexanes) R
1
f
) 0.28; H NMR (CDCl
3
, 300 MHz) δ 5.62 (m,
H), 5.44 (dd, J ) 10.5, 8.7 Hz, 1 H), 4.78 (dd, J ) 14.0, 8.0
Hz, 1 H), 4.64 (q, J ) 5.4 Hz, 1 H), 4.01 (dd, J ) 8.0, 6.0 Hz,
H), 3.2-3.7 (6 H), 2.22 (t, J ) 7.6 Hz, 2 H), 1.4-1.6 (2 H),
1
Flash chromatography on a silica gel column afforded 3 (2.4
1
1.39 (s, 3 H), 1.36 (s, 3 H), 1.27 (d, J ) 5.4 Hz, 3 H), 1.2-1.4
g, 70%); TLC (ethyl acetate/hexanes, 1:20) R
CDCl
f
) 0.26; H NMR
1
3
(
12 H), 1.17 (t, J ) 7.0 Hz, 3 H), 0.84 (s, 9 H), 0.01 (s, 6 H); C
(
3
, 300 MHz) δ 4.65 (q, J ) 5.4 Hz, 1 H), 3.32-3.68 (4
NMR (CDCl , 75 MHz, APT), δ 131.60, 131.22 (CH), 128.64,
3
H), 2.88 (m, 1 H), 2.72 (dd, J ) 4.9, 4.9 Hz, 1 H), 2.44(dd, J )
1
28.54 (CH), 109.07 (C), 99.55 (CH), 72.20, 72.14 (CH), 71.94,
4
3
.9, 2.7 Hz, 1 H), 1.28 (d, J ) 5.4 Hz, 3 H), 1.18 (t, J ) 7.1 Hz,
13
71.88 (CH), 69.46 (CH
2
), 65.30 (CH
), 29.93 (CH
), 26.27 (CH
), 18.13 (C), 15.36 (CH
2
), 60.66 (CH
), 29.73 (CH
), 25.92 (CH
), -4.52 (CH
Si (M - H) 485.3660, found
2
), 37.05 (CH
2
),
),
H). 1.2-1.6 (14 H); C NMR (CDCl
3
, 75 MHz, APT) δ 99.56
), 52.40 (CH), 47.14 (CH ), 32.51
), 29.40 (CH ), 26.26 (CH ), 25.98
); HRMS (EI) m/z calcd for
(M - H) 243.1957, found 243.1977; calcd for
3
2
6.79 (CH
9.47 (CH
2
), 35.63 (CH
), 26.81 (CH
2
2
2
), 29.61 (CH
2
(
(
(
CH), 65.29 (CH
CH
CH
2
), 60.69 (CH
), 29.52 (CH
), 19.92 (CH
2
2
), 29.92 (CH
2
2
2
2
2
3
2
3
), 25.39,25.27
); HRMS
2
(
CH
(EI) m/z calcd for C26
485.3636; calcd for C H O Si (M - CH ) 471.3495, found
2
), 19.91 (CH
3
3
3
2
3
), 15.36 (CH
3
+
+
H
54
O
5
C
C
14
H
H
27
O
O
3
+
+
(M - CH
3
) 229.1804, found 229.1801.
25 51
5
3
13
25
2
4
71.3490.
1
2-(Eth oxyeth oxy)-1-(3,3-dim eth yl-2,4-dioxolan yl)dodec-
-yn -4-ol. Under a nitrogen atmosphere, a solution of n-
butyllithium in hexane (0.52 mL of 1.6 M solution in hexanes,
.83 mmol) was added to a THF (1 mL) solution of alkyne 10
105 mg, 0.83 mmol) at -78 °C, and the mixture was stirred
1
cis-12-(3,3-Dim et h yl-2,4-d ioxola n yl)-9-(1,1,2,2-t et r a -
m eth yl-1-sila p r op oxy)d od ec-11-en -1-ol (6). A mixture of
ethoxyethyl ether 5 (540 mg, 1.11 mmol) and PPTS (28 mg,
0.11 mmol) in methanol (8 mL) was stirred for 4 h at room
temperature under argon. Then, the volatiles were removed
under reduced pressure. Saturated aqueous NaHCO was
3
added to the residue. The resulting mixture was extracted with
diethyl ether. The organic layer was washed with brine, dried
(MgSO ), and filtered. Solvent was removed under reduced
4
pressure, and the crude product was purified by flash chro-
matography on a silica gel column (20% ethyl acetate in
0
(
for 10 min. Then, boron trifluoride etherate (105 µL, 0.83
mmol) was added to the solution, and the stirring was
continued for another 10 min at -78 °C. A solution of epoxide
3
(120 mg, 0.5 mmol) in THF (1 mL) was added and after being
stirred for 30 min at -78 °C, the reaction mixture was
quenched by adding aqueous NaHCO . Flash chromatography
on a silica gel column provided the desired alcohol in 95% yield.
3
1
TLC (ethyl acetate/hexanes, 1:4) R
3
f
) 0.23; H NMR (CDCl
3
,
hexanes) to provide 6 (322 mg, 78%). TLC (25% ethyl acetate
1
00 MHz) δ 4.68 (m, 1 H), 4.64 (t, J ) 5.3 Hz, 1 H), 4.09 (m,
in hexanes) R
1
f
) 0.31; H NMR (CDCl
3
, 300 MHz) δ 5.64 (m,
H), 5.44 (m, 1 H), 4.77 (dd, J ) 14.7, 7.8 Hz, 1 H), 4.01 (dd,
J ) 8.0, 6.1, 1 H), 3.62 (m, 1 H), 3.58 (t, J ) 6.6 Hz, 3 H), 3.47
(dd, J ) 8.0, 8.0 Hz, 1 H), 2.22 (m, 2 H), 1.51 (m, 2 H), 1.38 (s,
3 H), 1.35 (s, 3 H), 1.1-1.4 (1 0H), 0.84 (s, 9 H), 0.01 (s, 6 H);
(
17) Miller, D. B.; Raychaudhuri, S. R.; Avasthi, K.; Lal, K.; Levison,
B.; Salomon, R. G. J . Org. Chem. 1990, 55, 3164-3175.
18) Schmid, C. R.; Bryant, J . D. Org. Synth. 1993, 72, 6-13.
(

6
664 J . Org. Chem., Vol. 65, No. 20, 2000
Deng and Salomon
13C NMR (CDCl
, 75 MHz, APT) δ 99.56 (CH), 65.29 (CH
),
),
),
was purified by flash chromatography on a silica gel column
3
2
2
3
6
2
1
0.69 (CH
9.52 (CH
5.36 (CH
2
), 52.40 (CH), 47.14 (CH
), 29.40 (CH ), 26.26 (CH
); HRMS (EI) m/z calcd for C23
Si (M - CH
2
), 32.51 (CH
2
), 29.92 (CH
(CHCl
a diastereomeric mixture of epimers at the allylic hydroxyl;
TLC (CHCl /MeOH/H O, 15:9:1) R
) 0.21; 1H NMR (300,
CDCl , 300 MHz) δ 9.49 (d, J ) 8.2 Hz, 1 H), 6.96 (dt, J )
3 2
/MeOH/H O, 15:9:1) to give HOT-P C (10 mg, 82%) as
2
2
2
), 25.98 (CH
2
), 19.92 (CH
+
3
H
46
O
4
Si (M ) 414.3165,
3
2
f
+
found 414. 3164; calcd for C22
found 399.2894, calcd for C23
found 396.3220.
H
43
O
4
3
) 399.2930
O) 396.3059
3
+
H
44
O
3
Si (M - H
2
15.6, 6.9 Hz, 1 H), 6.15 (dd, J ) 15.6, 8.2 Hz, 1 H), 5.18 (b, 1
H), 4.2-4.4 (3 H), 4.12(m, 1 H), 3.84-4.0 (2 H), 3.68-3.82 (3
H), 3.32 (s, 9 H), 2.45 (m, 2 H), 2.28(m, 2 H), 2.25 (t, J ) 7.7
Hz, 2 H),1.5-1.6 (4 H), 1.35-1.5 (2 H), 1.1-1.4 (32 H), 0.85
cis-12-(3,3-Dim et h yl-2,4-d ioxola n yl)-9-(1,1,2,2-t et r a -
m eth yl-1-sila p r op oxy)d od ec-11-en oic Acid (7Z). A solu-
tion of alcohol 6 (250 mg, 0.6 mmol) and pyridinium dichro-
mate (PDC) (1.35 g, 3.6 mmol) in DMF (5 mL) was stirred at
room temperature for 20 h, diluted with saturated aqueous
(
t, J ) 7.0 Hz, 3 H).HRMS (FAB, CsI/NaI/glycerol) m/z calcd
+
for C37H70NO11PCs (MCs ) 852.3791, found 852.3802.
4-(2,2-Dib r om ovin yl)-2,2-d im et h yl-1,3-d ioxola n e (9).
Triphenylphosphine (8.1 g, 30.9 mol) was slowly added to a
magnetically stirred solution of CBr (10.3 g, 31 mmol) in dry
4
NH
4
Cl (50 mL), and extracted with diethyl ether. The com-
and concentrated
bined ether phases were dried over MgSO
4
methylene chloride (100 mL). To the resulting orange solution,
zinc dust (2.1 g. 33 mmol) was added slowly at 0 °C (green to
light tan), and then the reaction mixture was stirred at room
temperature for 48 h. Glyceraldehyde acetonide (2.2 g, 16.9
mmol, freshly prepared from 1,2,5,6-di-O-isopropylidene-D-
1
8
2 2
mannitol ) in CH Cl (10 mL) was added dropwise to the above
mixture. After being stirred for 2 h, the reaction mixture was
transferred to a Erlenmeyer flask and extracted with pentane.
Solvent was removed on a rotary evaporator. Compound 9 (4.5
g, 94%) was obtained by distillation under reduced pressure
(55 °C, 30 mmHg). TLC (ethyl acetate/hexanes, 3:97) R
f
) 0.23;
, 300 MHz) δ 6.51 (d, J ) 7.6 Hz, 1 H), 4.70
ddd, J ) 10.2, 7.6 Hz, 1 H), 4.17 (ddd, J ) 10.2, 8.4, 6.5 Hz,
H), 3.66 (dd, J ) 8.4, 6.5 Hz, 1 H), 1.40 (s, 3 H), 1.36 (s, 3
1
H NMR (CDCl
3
(
1
1
3
H); C NMR (CDCl
3
, 75 MHz) δ 137.13 (CH), 110.01 (C), 92.61-
C), 76.17 (CH), 68.02 (CH ), 26.60 (CH ), 25.63(CH ).
-Eth yn yl-2,2-d im eth yl-1,3-d ioxola n e (10). A solution of
(7 g, 24.5 mmol) in 20 mL of dry THF at -78 °C under
(
2
3
3
4
9
nitrogen was treated with n-butyllithium in hexane (33.6 mL
of a 1.6 M solution in hexane, 53.8 mmol). After being stirred
for 1 h at -78 °C, the reaction mixture was warmed to 25 °C,
stirred for another 1 h, and then quenched with water. Extrac-
tion with pentane and distillation (85 °C, 110 mmHg) afforded
1
0 (2.7 g, 87%). TLC (ethyl acetate/hexanes, 5:95) R
f
) 0.27;
, 300 MHz) δ 4.69 (ddd, J ) 6.3, 6.3, 2.1 Hz,
H), 4.15 (dd, J ) 8.1, 6.3 Hz, 1 H), 3.93 (dd, J ) 8.1, 6.3 Hz,
1
H NMR (CDCl
1
3
1 H), 2.47 (d, J ) 1.8 Hz, 1 H), 1.48 (s, 3 H), 1.36 (s, 3 H).
1-(3,3-Dim eth yl(2,4-d ioxola n yl))-3,3-d ibu tyl-3-sta n n a -
h ep t -1-en e (12). Tri-n-butylstannane (770 mg, 2.64 mmol)
was added to a stirred mixture of 5-ethynyl-2,2-dimethyl-1,3-
dioxolane 10 (230 mg, 1.82 mmol) and azobis(isobutyronitrile)
19
(AIBN, 8 mg). The stirred solution was heated at 130 °C for
2 h and then cooled to room temperature. The residue was
purified by flash chromatography on silica gel (2% ethyl
acetate in hexanes R
mg, 70%). H NMR (CDCl , 300 MHz) δ 6.29 (d, J ) 12.6 Hz,
f
) 0.16) to afford tin compound 12 (530
1
3
1
H), 5.93 (dd, J ) 12.6, 4.5 Hz, 1 H), 4.45 (dd, J ) 9.3, 4.9
Hz, 1 H), 4.07 (dd, J ) 5.3, 4.1 Hz, 1 H), 3.58 (dd, J ) 5.3, 5.3
Hz, 1 H), 1.4-1.6 (6 H), 1.42 (s, 3 H), 1.37 (s, 3 H), 1.2-1.4 (6
1
3
H), 0.7-1.0 (15 H); C NMR (CDCl
3
, 75 MHz, APT) δ 145.23
), 29.06
), 13.70 (CH ), 9.48
Sn (M ) 418.1890,
(CH), 133.23 (CH), 109.30 (C), 80.04 (CH), 69.38 (CH
2
(
CH
2
), 27.27 (CH
); HRMS (EI) m/z calcd for C19H O
2
), 26.72 (CH
3
), 25.96 (CH
3
3
+
(CH
2
38
+
2
found 418.1847; calcd for C19
17.1803.
10-Iod od ececa n e-1,9-d iol (15). To a magnetically stirred
solution of iodine (150 mg, 0.58 mmol) in dry CH Cl (2 mL)
37 2
H O Sn (M - H) 417.1810 found
4
2
2
was added triphenylphosphine (153.5 mg, 0.58 mmol). The
brown solution turned immediately to a pale yellow color, and
then 1-(8-(2-oxiranyl)octyloxy)-1-ethoxyethane 3 (130 mg, 0.53
2 2
mmol) in CH Cl (1 mL) was added at room temperature. After
5
-10 min, the reaction mixture was poured into iced aqueous
3
NaHCO (5 mL). The aqueous phase was extracted with ethyl
ether. The combined organic layers were washed with 6%
NaS , water, and brine and then dried over MgSO . The
crude product was purified by flash chromatography on a silica
gel column (50% ethyl acetate in hexanes, TLC R ) 0.3) to
afford the product 15 (140 mg, 95%); H NMR (CDCl , 300
2
O
3
4
f
1
3
CH Cl (1 mL) in a dropwise manner at -78 °C under an argon
2
2
atmosphere. The reaction mixture was stirred for 10 min, the
solvent was removed via rotary evaporator, and the residue
(19) Roy, S. C.; Nagarajan, L.; Salomon, R. G. J . Org. Chem. 1999,
64, 1218-1224.

Total Synthesis of Oxidized Phospholipids
J . Org. Chem., Vol. 65, No. 20, 2000 6665
tion; H NMR (CD CO 300 MHz) δ 7.03 (dt, J ) 15.7, 7.3
1
MHz) δ 3.59 (t, J ) 6.6 Hz, 2 H), 3.47 (m, 1 H), 3.34 (dd, J )
3
)
2
,
1
0.2, 3.7 Hz, 1 H) 3.19 (dd, J ) 10.2, 6.7 Hz, 1 H), 1.4-1.6 (4
Hz, 1 H), 6.02 (dt, J ) 15.7, 1.44 Hz, 1 H), 3.72 (m, 1 H), 2.35
(m, 2 H), 2.29 (t, J ) 7.3 Hz, 2 H), 1.5-1.7 (2 H), 1.4-1.5 (4
1
3
H), 1.2-1.4 (10 H); C NMR (CDCl
6.60, 32.73, 29.46, 29.38, 29.32, 25.72, 25.65, 16.68.
-Iod o-10-(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)d eca n -2-
ol (16). To a solution of 10-iododececane-1,9-diol (175 mg, 0.58
mmol) and TBDMSCl (97 mg, 0.64 mmol) in CH Cl (3 mL)
were added DMAP (7 mg, 0.06 mmol) and Et N (70 mg, 0.7
mmol) at room temperature. The reaction mixture was stirred
under N overnight, washed with water, aqueous NH Cl, and
brine, and dried over MgSO . Flash chromatography on a silica
gel column (10% ethyl acetate in hexanes, R ) 0.35) afforded
, 300 MHz) δ 3.56 (t, J )
3
, 75 MHz) δ 70.96, 62.99,
1
3
3
3 2
H), 1.3-1.4 (6 H); C NMR (CO(CD ) , 75 MHz), δ 174.81
(
7
(
C
COOH), 167.57 (dCHCOOH), 147.80 (CHd). 123.75 (CHd),
0.70 (CHOH), 41.16 (CH ), 38.25 (CH ), 34.27 (CH ), 30.15
),25.74 (CH ); HRMS (EI) m/z calcd for
(M ) 258.1467, found 258.1460.
1
2
2
2
CH
2
), 26.41 (CH
O
22 5
2
2
2
2
+
13
H
3
Met h yl 8-(3-Oxo-1H ,6H -2-oxin yl)oct a n oa t e (20). Eth-
2
4
ylaluminum dichloride (0.016 mmol, 16 mL, 1 M solution in
hexane) was added to a solution of (2E)-5-hydroxytridec-2-
enedioic acid (19, 10 mg, 0.041 mmol) in MeOH (0.5 mL) under
an argon atmosphere. The resulting solution was transferred
to a small quartz tube and irradiated with 254 nm light in a
Rayonet photoreactor for 2-3 h. The irradiated solution was
quenched with water and extracted with ethyl acetate. The
4
f
1
1
6
3
6 (193 mg, 80%). H NMR (CDCl
3
.6 Hz, 2 H), 3.47 (m, 1 H), 3.36 (dd, J ) 10.2, 3.7 Hz, 1 H),
.20 (dd, J ) 10.2, 6.7 Hz, 1 H), 1.4-1.6 ((4 H), 1.2-1.3 (10
1
3
H), 0.86 (s, 9 H), 0.01 (s, 6 H); C NMR (CDCl
δ 71.01 (CH), 63.34 (CH ), 36.64 (CH
), 29.38 (CH ), 26.04 (CH
), 18.43 (C), 16.86 (CH ), -5.19 (CH
3
, 75 MHz, APT),
), 32.89 (CH ), 29.52
), 25.80 (CH ), 25.71
).
2
2
2
organic layer was dried over MgSO , concentrated, and
4
(
(
CH
CH
2
), 29.44 (CH
2
2
3
2
subjected to flash chromatography on silica gel with 50% ethyl
acetate in hexanes to provide the lactone methyl ester 20 (7
2
2
3
1
1
0-Iod o-9-(2-oxa n yloxy)-1-(1,1,2,2,-t et r a m et h yl-1-sila -
mg, 70%); H NMR (CDCl
3
, 300 MHz) δ 6.85 (dt, J ) 14.5, 5.6
p r op oxy)d eca n e (17). A small amount of pyridinium p-
toluenesulfonate (PPTS) (12 mg, 0.048 mmol) was added to a
solution of 16 (190 mg, 0.46 mmol) and dihydropyran (DHP)
Hz, 1 H), 6.00 (dt, J ) 14.5, 2.8 Hz, 1 H), 4.3-4.5 (m, 1 H),
3.65 (s, 3 H), 2.26-2.33 (m, 2 H), 2.28 (t, J ) 7.6 Hz, 2 H),
1
3
1.7-1.9 (m, 2 H), 1.5-1.7 (4 H), 1.2-1.4 (6 H); C NMR
(
58 mg, 0.69 mmol, freshly distilled) in 5 mL of dry methylene
(CDCl
3
, 75 MHz) δ 174.31, 164.62, 145.03, 121.51, 77.26, 51.52,
chloride. The resulting solution was stirred overnight at room
temperature, diluted and extracted with diethyl ether, and
washed with water and brine. The solvent was removed with
a rotary evaporator. The crude product was purified by flash
chromatography on a silica gel column (4% ethyl acetate in
34.88, 34.09, 29.45, 29.18, 29.11, 29.04, 24.91, 24.78; HRMS
+
(EI) m/z calcd for C14
H
22
O
4
(M ) 254.1518 found 254.1546; calcd
+
for C14
23 5
H O (MH ) 255.1597 found 255.1597.
2-(8-Hyd r oxyoctyl)-2H,3H,6H-oxin -6-ol (21). A solution
of the compound 5 (40 mg, 0.08 mmol) in acetic acid/water
(2:1, v/v, 1 mL) was stirred magnetically for 3.5 h at 40 °C,
and then sodium metaperiodate (26 mg, 0.12 mmol) was added
at room temperature. The resulting mixture was stirred at
room temperature for another 1.5 h, followed by removal of
the solvent under reduced pressure. The residue was extracted
with ethyl acetate. The extract was washed with water and
brine and dried over magnesium sulfate. The solvent was
removed under reduced pressure. The trace of acetic acid was
removed by azeotropic distillation with n-heptane (3 × 3 mL)
under high vacuum (0.1 mmHg). The crude product was
purified by flash chromatography on a silica gel column (50%
hexanes) to afford 17 (203 mg, 89%). TLC (6% ethyl acetate
1
in hexanes, R
f
) 0.5); H NMR (CDCl
3
, 300 MHz, four isomers)
δ 4.67 (dt, J ) 11.5, 4.1 Hz, 1 H), 3.89 (m, 1 H), 3.55 (t, J )
6
5
1
7
.6 Hz, 2 H), 3.47 (m, 1 H), 3.38 (m, 1 H), 3.28 (dd, J ) 10.4,
.8 Hz, 1 H), 3.18 (dd, J ) 10.4, 4.3 Hz, 1 H), 1.4-1.8 (8 H),
.2-1.3 (12 H), 0.85 (s, 9 H), 0.01 (s, 6 H); 13C NMR (CDCl
,
3
5 MHz, APT), δ 99.42 (CH), 96.78 (CH), 77.53 (CH), 73.92
(
(
(
(
(
CH), 63.33 (CH
2
), 62.95 (CH
), 31.00 (CH
), 25.81 (CH
2
), 62.66 (CH
2
), 35.46 (CH
2
2
2
), 34.36
), 25.41
), 25.04
CH
CH
CH
CH
2
2
2
3
), 32.90 (CH
), 26.03 (CH
), 19.65 (CH
2
3
2
), 29.53 (CH
), 25.47 (CH
2
), 29.48 (CH
2
), 25.25 (CH
2
2
), 18.41 (C), 12.15 (CH
); HRMS (EI) m/z calcd for C17
41.1281 found 441.1318.
2
), 10.64 (CH
2
), -5.20
+
H
34IO
3
Si (M - CMe )
3
ethyl acetate in hexanes, R
(
f
) 0.2) to afford cyclic acetal 21
18 mg, 93%); H NMR (CDCl , 300 MHz) δ 5.92-6.05 (m, 1
H), 5.55-5.75 (m, 1 H), 4.92 (m, 1 H), 3.75(m, 1 H), 3.61 (t, J
4
1
3
(
11E)-9-Hyd r oxy-13-oxotr id ec-11-en oic Acid (HOT, 18).
1
3
A solution of the compound 7E (40 mg, 0.093 mmol) in acetic
acid/water (2:1, v/v, 1 mL) was stirred magnetically for 3.5 h
at 40 °C, and then sodium metaperiodate (42 mg, 0.2 mmol)
was added at room temperature. The resulting mixture was
stirred for another 1.5 h at room temperature, followed by
removal of the solvent under reduced pressure. The residue
was extracted with ethyl acetate. The extract was washed with
water and brine and dried over magnesium sulfate. The
solvent was removed under reduced pressure. The trace of
acetic acid was removed by azeotropic distillation with n-
heptane (3 × 3 mL) under high vacuum (0.1 mmHg) to afford
) 6.5 Hz, 2 H), 1.92 (m, 2 H), 1.4-1.7 (4 H), 1.2-1.4 (8 H);
NMR (CDCl , 75 MHz) δ 129.11, 125.67, 94.78, 67.88, 66.30,
63.07, 35.59, 32.82, 30.82, 29.90, 29.64, 29.56, 29.45, 26.42,
C
3
+
25.64; HRMS (EI) m/z calcd for C13
20 3
H O (M ) 228.1725 found
228.1712.
8
-(3-Oxo-1H,6H-2-oxin yl)octa n oic Acid (1). A solution
of alcohol 21 (4 mg, 0.018 mmol) and pyridinium dichromate
PDC) (68 mg, 0.18 mmol) in DMF (0.3 mL) was stirred at room
temperature for 20 h, diluted with saturated aqueous NH Cl
1 mL), and extracted with ethyl acetate. The combined organic
(
4
(
4
phases were dried over MgSO and concentrated with a rotary
the title acid 18 (20 mg, 89%); TLC (ethyl acetate: hexanes:
evaporator. Flash chromatography on a silica gel column (55%
ethyl acetate in hexanes, TLC R ) 0.2) afforded racemic
lactone 1 (3.2 mg, 73%); H NMR (CDCl , 300 MHz) δ 6.86
dt, J ) 9.6, 3.8 Hz, 1 H), 6.50 (dt, J ) 9.6, 1.9 Hz, 1 H), 4.49
m, 1 H), 2.33 (t, 7.2 Hz, 2 H), 2.25-2.35 (m, 2 H), 1.5-1.7 (4
1
acetic acid ) 60:40:0.5, v/v/v, R
f
) 0.28); H NMR (CDCl
3
, 300
f
MHz) δ 9.49 (d, J ) 7.8 Hz, 1 H), 6.90 (dt, J ) 15.6, 7.1 Hz, 1
H), 6.16 (dd, J ) 15.6, 7.8 Hz, 1 H), 3.80 (m, 1 H), 2.50 (m, 2
H), 2.32 (t, J ) 7.4 Hz, 2 H), 1.55-1.60 (2 H), 1.40-1.50 (2
1
3
(
(
1
3
H), 1.20-1.40 (8 H); C NMR (CDCl
3
, 75 MHz), δ 194.12
CHO), 179.52 (COOH), 154.99 (CH ) ), 134.92 (CH ) ), 70.57
CHOH), 40.49 (CH ), 37.30 (CH ), 29.23 (CH ), 29.11 (CH ),
8.90 (CH ), 25.43 (CH ), 24.62 (CH ); HRMS (EI) m/z calcd
for C13 (M ) 242.1518 found 242.1520.
2E)-5-Hyd r oxytr id ec-2-en ed ioic Acid (19). To a mag-
+
H), 1.2-1.4 (8 H); HRMS (EI) m/z calcd for C13
2
H
20
O
4
(M )
(MH ) 241.1441
2
O) 222.1255 found
(
(
+
21 4
40.1362 found 240.1392; calcd for C13H O
2
2
2
2
+
found 241.1438; calcd for C13
22.1257.
H
18
O
3
(M - H
2
2
2
2
2
+
22 4
H O
(
Ack n ow led gm en t. We thank the National Institute
netically stirred solution of (11E)-9-hydroxy-13-oxotridec-11-
enoic acid (18, 20 mg, 0.08 mmol) in tert-butyl alcohol/water
of General Medical Sciences of the National Institutes
of Health for support of this research by grant GM21249
(to R.G.S.).
(
5:1, v/v, 1 mL) were added successively NaH
mmol), 2-methyl-2-butene (250 mL, 2 M solution in THF, 0.5
mmol), and NaClO (23 mg, 0.25 mmol). The resulting mixture
2 4
PO (17 mg, 0.12
2
was stirred for 2.5 h until the yellow solution turned colorless.
The solvent was removed under reduced pressure, and the
residue was extracted with ethyl acetate, washed with water
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
and brine, and dried over MgSO
4
. Removal of the solvent gave
the dicarboxylic acid 19 (20 mg, 95%) without further purifica-
J O000809U