Total synthesis of (5Z,8Z,11Z,14Z)-18- and 19-oxoeicosa-5,8,11,14-tetraenoic acids

Article abstract of DOI:10.1016/S0040-4020(02)01029-3

18-oxo-ETE was synthesized via the corresponding tetraacetylenic precursor, which was prepared by cross-coupling of three key synthons: methyl 5-hexynoate, the bisfunctional C₇-C₁₃ fragment - 7-bromo-2,5-heptadiyne-1-ol and rac-3-(be

Full text of DOI:10.1016/S0040-4020(02)01029-3

Tetrahedron 58 (2002) 8483–8487
Total synthesis of (5Z,8Z,11Z,14Z)-18- and
19-oxoeicosa-5,8,11,14-tetraenoic acids
Stepan G. Romanov,a Igor V. Ivanov,a,b Nataliya V. Groza,a Hartmut Kuhnb
and Galina I. Myagkovaa
,
*
aM. V. Lomonosov State Academy of Fine Chemical Technology, Pr. Vernadskogo 86, 119571 Moscow, Russian Federation
´
Institute of Biochemistry, University Clinics Charite, Humboldt University, Hessische Str. 3-4, D-10115 Berlin, Germany
b
Received 17 June 2002; revised 14 August 2002; accepted 16 August 2002
Abstract—18-oxo-ETE was synthesized via the corresponding tetraacetylenic precursor, which was prepared by cross-coupling of three key
synthons: methyl 5-hexynoate, the bisfunctional C7–C13 fragment—7-bromo-2,5-heptadiyne-1-ol and rac-3-(benzoyloxy)hept-6-yn. The
carbonyl function was introduced at the last synthesis step. 19-oxo-ETE was synthesized by coupling of acid anhydride, prepared from
monomethyl ester of (5Z,8Z,11Z,14Z)-nonadeca-5,8,11,14-tetraen-1,19-dioic acid, either with lithium dimethylcuprate or methylcuprate in a
one-step procedure. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
function was introduced at the last synthesis step. rac-1-
Chloropentan-3-ol (1) (bp 73.5–748C), obtained from
commercially available 1-chloro-3-pentanone by reduction
with NaBH4, was converted to the corresponding iodide 2
by the reaction with NaI in acetone. Alkylation of acetylene
3 with 2 (n-BuLi, THF/HMPA) afforded rac-7-(trimethyl-
silyl)hept-6-yn-3-ol (4). Finaly, benzoyl ester formation and
acetylene deprotection resulted in rac-3-(benzoyloxy)hept-
6-yn (5) in an overall yield 53%. Cross-coupling of 5 with
bromoalcohol 6 under copper(I) catalysis6 afforded skipped
triacetylenic alcohol 7 in 74% yield. Subsequent displace-
ment of hydroxyl group with bromine using PPh3/CBr4 as
reactant followed by final cross-coupling of bromide 8 with
methyl 5-hexynoate (9) resulted in methyl ester of rac-18-
(benzoyloxy)eicosa-5,8,11,14-tetraynoate (10). Stereo-
specific hydrogenation of the skipped-triple bonds of 10
with Lindlar’s catalyst and quinoline in benzene gave rise to
the tetraenoate 11. Since methanolysis of benzoate 11 did
not proceed at high yield we deprotected the functional
groups with NaOH in MeOH–H2O solution to yield 12 in
82%. After the free acid 12 was methylated with
diazomethane, the OH-group was oxidized by PCC.
Subsequent hydrolysis of the ketoester afforded desirable
(5Z,8Z,11Z,14Z)-18-oxoeicosa-5,8,11,14-tetraenoic acid
(13) in 75% yield.
Eicosanoids, such as prostaglandins1,2 and leukotrienes,2 are
lipid mediators, which have been implicated in a variety of
physiological and patho-physiological events in mammals.
The biosynthesis of these compounds has been studied for
many years but still its mechanism is not completely
understood. As reported previously, polyenoic fatty acids
oxygenated in hydrophobic part of the carbon backbone
constitute valuable tools for mechanistic investigation of
eicosanoids biosynthesis.3,4 As a part of our studies on the
metabolic fate of oxygenated fatty acids we worked out a
convergent procedure for preparation of (5Z,8Z,11Z,14Z)-
18- and 19-oxoeicosa-5,8,11,14-tetraenoic acids (18- and
19-oxo-ETEs), which are suitable tools for mechanistic
studies on eicosanoid biosynthesis.
2. Results and discussion
2.1. Preparation of 18-oxo-ETE (13)
Our strategy to synthesize 18-oxo-ETE is based on the
preparation of a tetraacetylenic precursor, which could be
easily obtained by cross-coupling of three building blocks:
commercially available methyl 5-hexynoate (9), the bis-
functional C7–C13 fragment—7-bromo-2,5-heptadiyne-1-
ol5 (6) and substituted alkynol 5 (Scheme 1). The carbonyl
2.2. Preparation of 19-oxo-ETE (15)
Total synthesis of 19-oxo-ETE has previously been
described,7 but this procedure required 14,15-epoxy-AA8,9
which is not commercially available. Monomethyl ester of
(5Z,8Z,11Z,14Z)-nonadeca-5,8,11,14-tetraen-1,19-dioic
acid10 (14) has been reported to be a useful precursor for the
Keywords: eicosanoids; keto fatty acids; coupling reactions; copper and
compounds.
*
Corresponding author. Tel.: þ49-30-2093-7539; fax: þ49-30-450-
528905; e-mail: hartmut.kuehn@charite.de
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01029-3

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S. G. Romanov et al. / Tetrahedron 58 (2002) 8483–8487
Scheme 1. (a) NaI, acetone, 758C, 15 h; (b) TMSCuCH (3), n-BuLi, THF, HMPA, 2208C, 5 h; (c) BzCl, Py, benzene, rt, 10 h then n-Bu4NF, THF, rt, 2 h;
(d) 6, CuI, NaI, K2CO3, DMF, rt, 12 h; (e) CBr4, PPh3, CH2Cl2, rt, 1 h; (f) 9, CuI, NaI, K2CO3, DMF, rt; (g) H2/Lindlar’s catalyst, quinoline, benzene, 108C; (h)
NaOH, MeOH/H2O, rt; (i) CH2N2 then PCC, CH2Cl2, rt; (j) LiOH, MeOH/H2O, rt.
synthesis of arachidonic acid analogues modified in
v-terminal part of the carbon backbone. In this study we
used this compound for a one-step preparation of 19-oxo-
ETE (15) (Scheme 2). Lithium dimethylcuprate is known to
react with acid chlorides under mild conditions to afford
coupling products in good yields.11 Following this strategy
we observed, that beside the desired 19-oxo-ETE (15)
substantial amounts (35%) of methyl (5Z,8Z,11Z,14Z)-19-
hydroxy-19-methyleicosa-5,8,11,14-tetraenoate (17) were
formed. Even when the molar acid chloride: Me2CuLi-ratio
was decreased to 1:1 similar results were obtained and a part
of 17 was not reduced. A possible reason for a side product
formation may be alkylation of acyl moiety of 15 with a
second equivalent of organocuprate (MeCu) formed in the
reaction with Me2CuLi. When we used equimolar amount of
the less reactive MeCu a single product (15) was formed
with a satisfactory yield.
3. Conclusions
In conclusion, we have described herein a convergent
synthetic approach, which allows the preparation of (v-n)-
oxo-ETEs in a fast and economic way. This strategy does
further provide the possibility to prepare a variety of novel
eicosanoid related compounds.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded either on a Brucker
MSL 200 or Brucker MSL 300 spectrophotometer in CDCl3
as solvent. Chemical shifts are referenced to tetramethyl-
silane as an internal standard for 1H NMR or to the
Scheme 2. (a) (COCl)2, CH2Cl2, 108C; (b) Cul, MeLi, Et2O, 2788C, 20 min; (c) LiOH, MeOH/H2O, rt.

S. G. Romanov et al. / Tetrahedron 58 (2002) 8483–8487
8485
deuterium lock signal of CDCl3 (d 13C¼77.19 ppm). IR
spectra were recorded on Shimadzu IR-435. HPLC analysis
was carried out on a Shimadzu LC-10Avp liquid chromato-
graph connected to SPD-10Advp UV detector. RP-HPLC
analysis was performed on a Nucleosil C18-column;
250£4 mm, 5 mm particle size (Machery–Nagel, Du¨ren,
Germany) with different solvent systems: MeOH/H2O
(95:5, by volume) and a flow rate of 1 mL/min were used
for analysis of compound 11. MeOH/H2O/Ac (85:15:0.1, by
volume) and a flow rate of 1 mL/min were used for other
compounds. Preparative HPLC was carried out on a
Lichrospher 100 RP18 column; 250£22.5 mm, 10 mm
particle size (Knauer, Berlin, Germany) with MeOH/H2O/
AcOH (95:5, by volume) and a flow rate of 10 mL/min. For
EIMS analysis a Shimadzu GC–MS QP-2000 system was
used with an ion source temperature of 1808C and an
electron energy of 70 eV. High resolution mass spectra were
recorded either on a MAT 711 mass spectrometer (Finigan
MAT) or VG Autospec instrument. Column chromato-
graphy was carried out on Silica Gel 60 (Merck, Darmstadt,
Germany particle size ranging from 70 to 230 mesh). For
thin-layer chromatography we employed precasted Silica
Gel 60 F254 sheets (Merck, Darmstadt, Germany). THF was
freshly distilled from sodium/benzophenone ketyl, and
HMPA was dried over CaH2. All solvents and reagents
used were of extra pure grade and purchased from Merck,
Aldrich or Across (Germany). MeLi and n-butyllithium
(Merck) was titrated as described by Watson and Eastman.12
Prior to use all glassware and syringes were dried at 1408C
overnight and all reactions were carried out under
atmosphere of dry argon.
(neat)/cm21
: 3600–3200 (OH), 2240 (CuC), 1115
(C–O), 1245, 840 (Si(CH3)3). 1H NMR (200 MHz,
CDCl3) d 3.64 (m, 1H, 3-CH), 2.34 (t, 2H, J¼6.8 Hz,
5-CH2), 1.50–1.68 (m, 4H, 2- and 4-CH2), 0.92 (t, 3H,
J¼6.8 Hz, CH), 0.12 (s, 9H, Si(CH3)3). 13C NMR (50 MHz,
CDCl3) d 107.41, 85.39, 72.74, 35.70, 30.26, 16.70, 9.86,
0.23 (3C). Anal. calcd for C10H20OSi: C, 65.15; H, 10.94.
Found: C, 65.25; H, 11.05.
4.1.3. rac-3-(Benzoyloxy)hept-6-yn (5). A solution of BzCl
(0.98 g, 6.99 mmol) in benzene (15 mL) was added to a
solution of 4 (0.99 g, 5.38 mmol) in benzene (30 mL) and
pyridine (15 mL). The mixture was stirred for 10 h at rt, then
acidified with H2SO4 (1 M, 50 mL). Reaction products were
extracted with Et2O (2£50 mL) and the extracts were
concentrated under reduced pressure. The residue was
filtrated through a silica gel column (hexane/Et2O, 4:1). The
product which showed an Rf¼0.59 in silica gel thin layer
chromatography (hexane/Et2O, 1:1) was dissolved in THF
(50 mL) and the silyl group was removed by addition of
n-Bu4NF (2.37 g, 7.53 mmol) for 2 h at rt. The mixture was
quenched with H2O (100 mL), organic layer was separated
and lipophilic products were extracted from the water phase
with Et2O (2£40 mL). The combined organic layers were
washed with satd aq. NaCl (70 mL), dried over Na2SO4 and
concentrated under vacuum. Silica gel chromatography
using gradient elution with hexane/Et2O (from 1 to 10%
Et2O) gave pure 5 as a colorless oil in a yield 1.09 g (95%).
TLC: Rf¼0.57 (hexane/Et2O, 1:1). IR (neat)/cm21: 3272
1
(CuC), 1725 (CvO), 1273 (C–O), 710 (Ph). H NMR
(200 MHz, CDCl3) d 8.05 (m, 2H, o-Bz), 7.41 (m, 3H,
(mþp)-Bz), 5.16 (m, 1H, 3-CH), 2.25 (m, 2H, 5-CH2), 1.91
(m, 3H, 4-CH2 and 7-CH), 1.68 (m, 2H, 2-CH2), 0.95 (t, 3H,
J¼6.8 Hz, CH3). 13C NMR (50 MHz, CDCl3) d 166.33,
132.88, 131.01, 129.76 (2C), 128.47 (2C), 83.67, 75.18,
68.82, 32.95, 27.18, 15.13, 9.54. Anal. calcd for C14H16O2:
C, 77.75; H, 7.46. Found: C, 77.70; H, 7.59.
4.1.1. rac-1-Iodo-pentan-3-ol (2). A mixture of chloride 1
(3.81 g, 31.6 mmol) and NaI (14.22 g, 98.4 mmol) in dry
acetone (55 mL) was stirred for 15 h at 758C. After the
standard work up procedure final filtration of the raw
product over silica gel (hexane/Et2O, 1:1) afforded pure 2 in
a yield 94% (6.76 g). TLC: Rf¼0.39 (hexane/Et2O, 1:1). IR
1
(neat)/cm21: 3470 (OH), 590 (C–I). H NMR (200 MHz,
4.1.4. rac-12-(Benzoyloxy)tetradeca-2,5,8-triyn-1-ol (7).
To a suspension of previously dried salts CuI (1.35 g,
7.10 mmol), NaI (1.06 g, 7.10 mmol) and K2CO3 (0.74 g,
5.32 mmol) in DMF (25 mL) were added bromide 6 (0.66 g,
3.55 mmol) and acetylene 5 (0.78 g, 3.60 mmol) under
argon atmosphere. After stirring for 12 h at rt, the reaction
mixture was quenched with satd aq. NH4Cl (100 mL) and
the products were extracted with Et2O (4£100 mL). The
combined organic extracts were washed with satd aq. NaCl
(2£50 mL), dried over Na2SO4 and the solvent was
evaporated under reduced pressure. The residue was
purified by silica gel flash chromatography (hexane/Et2O,
1:2) to afford acetylene alcohol 7. Overall yield of pure 7
0.85 g (74%). TLC: Rf¼0.31 (hexane/Et2O, 1:2). IR
(neat)/cm21: 3600–3200 (OH), 2240, 2170 (CuC), 1725
(CvO), 1115 (C–O), 709 (Ph). 1H NMR (200 MHz,
CDCl3) d 7.98 (m, 2H, o-Bz), 7.39 (m, 3H, (mþp)-Bz),
5.11 (m, 1H, 12-CH), 4.21 (m, 2H, 1-CH2), 3.14 (m, 2H,
4-CH2), 3.03 (m, 2H, 7-CH2), 2.23 (m, 2H, 10-CH2), 1.88
(m, 2H, 11-CH2), 1.70 (m, 2H, 13-CH2), 0.92 (t, 3H,
J¼6.8 Hz, CH3). 13C NMR (50 MHz, CDCl3) d 166.47,
132.92, 130.93, 129.76 (2C), 128.47 (2C), 80.18, 80.03,
79.07, 75.40 (2C), 74.45, 74.04, 51.29, 32.95, 27.14, 15.38,
9.98, 9.83, 9.57. Anal. calcd for C21H22O3: C, 78.23; H,
6.88. Found: C, 78.01; H, 6.97.
CDCl3) d 3.58 (m, 1H, 3-CH), 3.27 (t, 2H, J¼6.8 Hz,
1-CH2), 1.80–1.95 (m, 2H, 2-CH2), 1.45 (m, 2H, 4-CH2),
0.89 (t, 3H, J¼6.8 Hz, CH3). 13C NMR (50 MHz, CDCl3) d
73.22, 40.66, 30.15, 9.79, 2.84. Anal. calcd for C5H11IO: C,
28.06; H, 5.18. Found: C, 28.01; H, 5.24.
4.1.2. rac-7-(Trimethylsilyl)hept-6-yn-3-ol (4). A 150 mL
two-necked round-bottomed flask equipped with a rubber
septum and magnetic stirring bar was filled with dry Ar.
Then a solution of ethynyltrimethylsilane (3) (3.07 g,
30.9 mmol) in THF (50 mL) was placed in it and cooled
to 2788C. After n-BuLi (16 mL, 1.6 M in hexane) was
added the mixture was allowed to warm to 2358C for
35 min. Finally, a solution of 2 (2.21 g, 10.3 mmol) in THF
(15 mL) and HMPA (10 mL) was added and the reaction
mixture was stirred for 5 h at 2208C and then additionally
for 1 h at rt. The reaction was quenched with satd aq. NH4Cl
(100 mL) and acidified with HCl (1 M) to pH 5.0. The
organic products were extracted with Et2O (2£100 mL).
The combined extracts were washed with satd aq. NaCl and
dried over Na2SO4. The solvents were evaporated under
vacuum and the reaction products were purified by silica gel
column chromatography (hexane/Et2O, 3:1) to yield 1.12 g
(59%) pure 4. TLC: Rf¼0.41 (hexane/Et2O, 1:1). IR

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S. G. Romanov et al. / Tetrahedron 58 (2002) 8483–8487
1
4.1.5. rac-1-3-(Benzoyloxy)-14-bromotetradeca-6,9,12-
triyne (8). To solution of alcohol (700 mg,
HPLC: Rt¼6.69 min. H NMR (200 MHz, CDCl3) d 8.01
a
7
(m, 2H, o-Bz), 7.40 (m, 3H, (mþp)-Bz), 5.25–5.50 (m, 8H,
CHvCH), 5.08 (m, 1H, 18-CH2), 3.62 (s, 3H, OCH3), 2.75
(m, 6H, 7-, 10- and 13-CH2), 2.28 (t, 2H, J¼7.1 Hz, 2-CH2),
2.09 (m, 4H, 4- and 16-CH2), 1.68 (m, 6H, 3-,17- and 19-
CH2), 0.93 (t, 3H, J¼6.8 Hz, CH3). 13C NMR (50 MHz,
CDCl3) d 173.93, 166.43, 132.76, 131.22, 129.71 (2C),
129.42, 129.09 (2C), 128.68, 128.43 (6C), 75.87, 51.39,
33.86, 33.64, 27.28, 26.79 (3C), 25.81, 25.00, 23.49, 9.64.
MS (EI) m/z 316 (2.74) [Mþ2BzCOO], 287 (1.25)
[Mþ2BzCOO–C2H5], 260 (2.66) [Mþ2BzCOO–C4H9].
Anal. calcd for C28H38O4: C, 76.68; H, 8.73. Found: C,
76.54; H, 8.67.
2.17 mmol) and CBr4 (1025 mg, 3.24 mmol) in CH2Cl2
(30 mL) was added a solution of PPh3 (849 mg, 3.24 mmol)
in CH2Cl2 (15 mL) at 108C. The reaction mixture was
stirred for 1 h at rt, quenched with MeOH (2 mL) and
volatile components were removed under vacuum. Column
chromatography on silica gel (hexane/Et2O, 1:1) afforded
pure 8. Yield 735 mg (88%). TLC: Rf¼0.51 (hexane/Et2O,
1:1). IR (neat)/cm21: 2240 (CuC), 1740, 1725 (CvO),
1115 (C–O), 710 (Ph). 1H NMR (200 MHz, CDCl3) d 7.99
(m, 2H, o-Bz), 7.40 (m, 3H, (mþp)-Bz), 5.10 (m, 1H,
3-CH), 3.86 (t, 2H, J¼2.1 Hz, 14-CH2), 3.18 (m, 2H,
8-CH2), 3.02 (m, 2H, 11-CH2), 2.24 (m, 2H, 5-CH2), 1.85
(m, 2H, 4-CH2), 1.69 (m, 2H, 2-CH2), 0.92 (t, 3H,
J¼6.8 Hz, CH3). 13C NMR (50 MHz, CDCl3) d 166.36,
132.88, 131.08, 129.76 (2C), 128.47 (2C), 81.65, 80.10,
75.84, 75.40 (2C), 74.41, 73.49, 39.06, 27.18, 22.77, 15.42,
10.23, 9.87, 9.57. Anal. calcd for C21H21BrO2: C, 65.46; H,
5.49. Found: C, 65.24; H, 5.40.
4.1.8. rac-(5Z,8Z,11Z,14Z)-18-Hydroxyeicosa-5,8,11,14-
tetraenoic acid (12). An aqueous solution (15 mL) of
NaOH (129 mg, 3.22 mmol) was added to a solution of 11
(200 mg, 0.46 mmol) in methanol (40 mL) under argon
atmosphere. The resulting mixture was stirred overnight at
rt. After the reaction was completed, methanol was removed
by evaporation under reduced pressure, the residue was
carefully acidified to pH 4.5 using dilute HCl (1 M) and the
lipophilic products were extracted with Et2O (3£40 mL).
Combined organic extracts were dried over Na2SO4 and
concentrated in vacuum. The crude residue was purified by
silical gel column chromatography (hexane/Et2O, 1:3) to
give pure 12 (121 mg, 82%). TLC: Rf¼0.31 (hexane/Et2O,
1:3). RP-HPLC: Rt¼6.05 min. 1H NMR (200 MHz, CDCl3)
d 5.25–5.40 (m, 8H, CHvCH), 3.55 (m, 1H, 18-CH2),
2.65–2.71 (m, 6H, 7-, 10- and 13-CH2), 2.28 (t, 2H,
J¼7.1 Hz, 2-CH2), 2.04 (m, 4H, 4- and 16-CH2), 1.67 (m,
2H, 3-CH2), 1.45 (m, 4H, 17- and 19-CH2), 0.88 (t, 3H,
J¼6.8 Hz, CH3). 13C NMR (50 MHz, CDCl3) d 178.44,
129.89, 129.16, 128.97, 128.46, 128.31 (2C), 128.24 (2C),
73.22, 36.78, 33.49, 30.22, 26.65 (3C), 25.80, 24.74, 23.67,
9.85. MS (EI) m/z 320 (0.55) [Mþ], 302 (1.02) [Mþ2H2O],
273 (1.64) [Mþ2H2O–C2H5]. HRMS calcd for C20H32O3
[Mþ]: 320.2351. Found 320.2364.
4.1.6. Methyl rac-18-(benzoyloxy)eicosa-5,8,11,14-tetra-
ynoate (10). In an Ar filled previously dried round-
bottomed flask equipped with magnetic stirrer anhydrous
K2CO3 (350 mg, 2.53 mmol), NaI (507 mg, 3.38 mmol) and
CuI (644 mg, 3.38 mmol) were suspended in DMF (15 mL).
Methyl 5-hexynoate (9) (213 mg, 1.69 mmol) was added at
once to the suspension followed by bromide 8 (650 mg,
1.69 mmol). The reaction mixture was vigorously stirred
overnight at rt, then quenched with satd aq. NH4Cl
(200 mL). The lipophilic products were extracted with
Et2O (4£100 mL). The combined organic extracts were
washed with satd aq. NaCl (2£150 mL). After drying over
Na2SO4 the ethereal solution was concentrated in vacuum.
The crude residue was purified by silica gel flash
chromatography (hexane/Et2O, 3:1) under Ar to give pure
10 as yellow oil; yield: 545 mg (75%). TLC: Rf¼0.39
(hexane/Et2O, 1:1). IR (neat)/cm21 2240 (CuC), 1740,
1
1725 (CvO), 1115 (C–O), 710 (Ph). H NMR (200 MHz,
CDCl3) d 7.95 (m, 2H, o-Bz), 7.40 (m, 3H, (mþp)-Bz), 5.05
(m, 1H, 18-CH), 3.56 (s, 3H, OCH3), 3.01 (m, 6H, 7-, 10-
and 13-CH2), 2.31 (t, 2H, J¼7.1 Hz, 2-CH2), 2.12 (m, 4H, 4-
and 16-CH2), 1.71–1.90 (m, 6H, 3-, 17- and 19-CH2), 0.85
(t, 3H, J¼6.8 Hz, CH3). 13C NMR (50 MHz, CDCl3) d
173.33, 166.05, 132.61, 130.69, 129.44 (2C), 128.19 (2C),
79.68, 79.39, 77.95, 75.09, 74.90, 74.76, 74.21 (2C), 74.09,
51.27, 32.78, 32.71, 26.86, 23.85, 18.12, 15.11, 9.59 (3C),
9.33. Anal. calcd for C28H30O4: C, 78.11; H, 7.02. Found:
77.87; H, 7.15.
4.1.9. (5Z,8Z,11Z,14Z)-18-Oxoeicosa-5,8,11,14-tetra-
enoic acid (13). The acid 12 (38.2 mg, 0.119 mmol)
dissolved in Et2O (25 mL) was methylated with a
diazomethane. Et2O was removed, and the residue was
dissolved in CH2Cl2 (4 mL). Then a suspension of PCC
(102.4 mg, 0.476 mmol) in CH2Cl2 (8 mL) was added. After
the reaction mixture was stirred for 2 h at rt, Et2O (25 mL)
was added and the resulting mixture was filtrated over silica
gel. Then solvent was removed and the residue was
dissolved in MeOH (30 mL). Finally, a solution of LiOH
(65 mg, 1.593 mmol) in H2O (10 mL) was added and the
mixture was left to stir overnight at rt. After the reaction was
completed, methanol was removed by evaporation under
reduced pressure, the residue was acidified to pH 4 using
dilute HCl (1 M) and organic products were extracted with
Et2O (3£40 mL). Combined organic extracts were dried
over Na2SO4, concentrated in vacuum and the crude residue
was purified by silica gel column chromatography
(hexane/Et2O, 1:2) to give pure 13 (28.4 mg, 75%). TLC:
4.1.7. Methyl rac-(5Z,8Z,11Z,14Z)-18-(benzoyloxy)-
eicosa-5,8,11,14-tetraenoate (11).
A
suspension of
Lindlar’s catalyst (500 mg) in dry benzene (15 mL) was
saturated with H2 in a 100 mL Erlenmeyer flask at rt and
cooled to 108C. Then a solution of 10 (400 mg, 0.93 mmol)
in benzene (35 mL) and quinoline (0.5 mL) were added to
the catalyst under a stream of Ar. After the Ar was
exchanged with H2 the reaction mixture was stirred for 1 h
at 108C, filtered, washed with HCl (2 M, 2£30 mL). The
solvent was evaporated and the residue was filtered over
silica gel (hexane/Et2O, 2:1) and purified by preparative RP-
HPLC (solvent system MeOH/H2O, 95:5) to yield 293 mg
(72%) pure 11. TLC: Rf¼0.52 (hexane/Et2O, 1:1). RP-
1
Rf¼0.36 (hexane/Et2O, 1:3). RP-HPLC: Rt¼6.20 min. H
NMR (200 MHz, CDCl3) d 5.25–5.45 (m, 8H, CHvCH),
2.81 (m, 6H, 7-,10- and 13-CH2), 2.25–2.45 (m, 8H, 2-, 16-,
17-, and 19-CH2), 2.07 (m, 2H, 4-CH2), 1.68 (m, 2H,
3-CH2), 1.03 (t, 3H, J¼6.8 Hz, CH3). 13C NMR (50 MHz,

S. G. Romanov et al. / Tetrahedron 58 (2002) 8483–8487
8487
CDCl3) d 211.52, 179.51, 129.13, 129.07, 128.92, 128.50,
128.34, 128.32, 128.27, 128.23, 42.17, 36.18, 33.49, 26.58,
25.75 (2C), 25.70, 24.63, 21.86, 7.91. FAB HRMS calcd for
C20H30O3Na [MþNa]þ: 341.2087. Found: 341.2080.
pH 4 using dilute HCl (1 M) and organic products were
extracted with Et2O (3£40 mL). Combined organic extracts
were dried over Na2SO4, concentrated in vacuum and the
crude residue was purified by silica gel column chromato-
graphy (hexane/Et2O, 1:2) to give pure 16 (92 mg, 91%).
TLC: Rf¼0.35 (hexane/Et2O, 1:3). RP-HPLC: Rt¼6.20 min.
1H NMR (200 MHz, CDCl3) d 5.30–5.50 (m, 8H,
CHvCH), 5.10 (m, 1H, 18-CH2), 2.72 (m, 6H, 7-, 10-
and 13-CH2), 2.35 (t, 2H, J¼7.1 Hz, 2-CH2), 2.24 (t, 2H,
J¼7.5 Hz, 18-CH2), 2.05 (m, 7H, 4-,16-CH2 and 20-CH3),
1.60 (m, 4H, 3- and 17-CH2). 13C NMR (50 MHz, CDCl3) d
208.05, 178.87, 129.27, 128.95 (2C), 128.79, 128.31 (2C),
128.25 (2C), 42.98, 33.50, 29.72, 26.65 (2C), 25.77 (3C),
24.86, 23.79. FAB HRMS calcd for C20H30O3Na
[MþNa]þ: 341.2087. Found: 341.2090.
4.1.10. Methyl (5Z,8Z,11Z,14Z)-19-oxoeicosa-5,8,11,14-
tetraenoate (15). Method A. To a cooled (2788C)
suspension of CuI (237 mg, 1.24 mmol) in Et2O (20 mL)
MeLi (1.78 mL, 2.49 mmol) was added. The mixture was
allowed to warm (2258C) until grayish solution resulted.
After about 5 min at 2258C the temperature was lowered to
2788C. A precooled ethereal solution (5 mL) of acid
chloride, prepared from ester 14 (396 mg, 1.18 mmol),
was injected. The resulting mixture was stirred for 20 min at
-788C, quenched with satd aq. NH4Cl (100 mL) and organic
products were extracted with Et2O (2£60 mL). The
combined organic extracts were washed with satd aq.
NaCl, dried over Na2SO4 and concentrated under vacuum.
TLC analysis of the crude residue revealed two products
formed: 15 with Rf¼0.53 (hexane/Et2O, 1:3) and 17 with
Rf¼0.33 (hexane/Et2O, 1:3) which were separated by
column chromatography on silica gel. Yield of 15:
180 mg (46%); 17: 146 mg (35%). Analytical data for 15:
Acknowledgements
This work was supported in part by the Russian Foundation
for Basic Research (02-03-33138), by DAAD (fellowship
for I. I.) and by Deutsche Forschungsgemeinschaft (Ku
961/7-1). The authors wish to thank Deutsche Akademische
Austauschdienst (DAAD) for providing an HPLC system to
I. I. at the Lomonosov State Academy of Fine Chemical
Technology. Part of this work was carried out by I. I. during
a working stay at the Humboldt University.
1
RP-HPLC: Rt¼8.91 min. H NMR (200 MHz, CDCl3) d
5.27–5.50 (m, 8H, CHvCH), 3.57 (s, 3H, OCH3), 2.74 (m,
6H, 7-, 10- and 13-CH2), 2.35 (t, 2H, J¼7.1 Hz, 2-CH2),
2.23 (t, 2H, J¼7.5 Hz, 18-CH2), 2.04 (m, 7H, 4-,16-CH2 and
20-CH3), 1.59 (m, 4H, 3- and 17-CH2). 13C NMR (50 MHz,
CDCl3) d 208.14, 173.78, 129.27, 129.01, 128.94, 128.79,
128.35 (2C), 128.20 (2C), 51.28, 43.01, 33.49, 29.70, 26.65
(2C), 25.73 (3C), 24.89, 23.75. FAB HRMS calcd for
C21H32O3Na [MþNa]þ: 355.2249. Found: 355.2248.
Analytical data for 17: RP-HPLC: Rt¼10.82 min. 1H
NMR (200 MHz, CDCl3) d 5.25–5.40 (m, 8H, CHvCH),
3.61 (s, 3H, OCH3), 2.77 (m, 6H, 7-, 10- and 13-CH2), 2.27
(t, 2H, J¼7.1 Hz, 2-CH2), 2.04 (m, 4H, 4- and 16-CH2), 1.65
(m, 2H, 3-CH2), 1.42 (m, 4H, 17- and 18-CH2), 1.15 (s, 6H,
CH3). 13C NMR (50 MHz, CDCl3) d 173.99, 130.19, 129.05
(2C), 128.61, 128.35 (2C), 128.13 (2C), 70.87, 51.42, 43.71,
33.60, 29.37 (2C), 27.79, 26.73, 25.81 (3C), 24.96, 24.52.
FAB HRMS calcd for C22H36O3Na [MþNa]þ: 371.2557.
Found: 371.2561. Method B. Compound 15 was prepared by
the procedure analogous to Method A using CuI (237 mg,
1.24 mmol), MeLi (0.89 mL, 1.24 mmol) and acid chloride,
prepared from ester 14 (410 mg, 1.24 mmol). Yield of 15:
243 mg (62%).
References
1. McGettigan, P.; Henry, D. Curr. Pharm. Des. 2000, 6, 1693.
2. Bulger, E. M.; Maier, R. V. Crit. Care Med. 2000, 28, 27.
3. Ivanov, I. V.; Schwarz, K.; Holzhutter, H.; Myagkova, G. I.;
Kuhn, H. Biochem. J. 1998, 336, 345.
4. Walther, M.; Ivanov, I. V.; Myagkova, G. I.; Kuhn, H. Chem.
Biol. 2001, 8, 779.
5. Ivanov, I. V.; Romanov, S. G.; Groza, N. V.; Nigam, S.; Kuhn,
H.; Myagkova, G. I. Bioorg. Med. Chem. 2002, 10, 2335.
6. Lapitskaya, M. A.; Vasiljeva, L. L.; Pivnitsky, K. K. Synthesis
1993, 65.
7. Manna, S.; Falck, R. J.; Chacos, N.; Capdevila, J. Tetrahedron
Lett. 1983, 24, 33.
8. Corey, E. J.; Niwa, H.; Falck, J. R. J. Am. Chem. Soc. 1979,
101, 1586.
4.1.11. (5Z,8Z,11Z,14Z)-19-Oxoeicosa-5,8,11,14-tetra-
enoic acid (16). An aqueous solution (20 mL) of LiOH
(60 mg, 2.52 mmol) was added to a solution of 15 (105 mg,
0.32 mmol) in MeOH (45 mL) under Ar atmosphere. The
resulting mixture was stirred overnight at rt. After the
reaction was completed, MeOH was removed by evapor-
ation under reduced pressure, the residue was acidified to
9. Ennis, M. D.; Baze, M. E. Tetrahedron Lett. 1986, 27, 6031.
10. Ivanov, I. V.; Groza, N. V.; Romanov, S. G.; Kuhn, H.;
Myagkova, G. I. Synthesis 2000, 691.
11. Posner, G. H.; Whitten, C. E.; McFarland, P. E. J. Am. Chem.
Soc. 1972, 94, 5106.
12. Watson, S. C.; Eastman, J. F. J. Organomet. Chem. 1967, 9,
165.