Total synthesis of the lipoxygenase substrates (5Z,8Z,11Z,14Z)-nonadeca- 5,8,11,14-tetraene-1,19-dioic acid and (5Z,8Z,11Z,14Z)-20,20- dimethylheneicosa-5,8,11,14-tetraenoic acid

Article abstract of DOI:10.1055/s-2000-6400

For mechanistic studies on the lipoxygenase reaction, the special substrate fatty acids (5Z,8Z,11Z,14Z)-nonadeca-5,8,11,14-tetraene-1,19-dioic and (5Z,8Z,11Z,14Z)-20,20-dimethylheneicosa-5,8,11,14-tetraenoic acids were synthesized. The synthetic scheme involves a joint route for the formation of (5Z,8Z,11Z,14Z)-nonadeca-5,8,11,14-tetraene-1,19-dioic acid, which is based on the polyacetylenic approach. Regioselective reduction of the ω-carboxylic group to the primary alcohol, exchange of an OH-group to corresponding iodine and subsequent coupling with low-order organocuprates (t-Bu₂CuLi) resulted in the formation of (5Z,8Z,11Z,14Z)-20,20-dimethylheneicosa-5,8,11,14- tetraenoic acid with an overall yield of 11%.

Full text of DOI:10.1055/s-2000-6400

PAPER
691
Total Synthesis of the Lipoxygenase Substrates (5Z,8Z,11Z,14Z)-Nonadeca-
5,8,11,14-tetraene-1,19-dioic Acid and (5Z,8Z,11Z,14Z)-20,20-
Dimethylheneicosa-5,8,11,14-tetraenoic Acid
Igor V. Ivanov,*a,b Nataliya V. Groza,a Stepan G. Romanov,a Hartmut Kühn,b Galina I. Myagkovaa
aM.V. Lomonosov State Academy of Fine Chemical Technology, 117571 Moscow, Russian Federation
Fax+70954348711
bInstitute of Biochemistry, University Clinics Charité, Humboldt University, 10115 Berlin, Germany
Received 30 September 1999; revised 21 January 2000
available 4-chlorobut-2-yn-1-ol (1)7 and 2-propyne-1-ol
(2) under copper(I) catalysis.8 This reaction afforded the
diacetylenic diol 3 in 70% yield (Scheme). Subsequent
displacement of both hydroxy groups with bromine using
Abstract: For mechanistic studies on the lipoxygenase reaction, the
special substrate fatty acids (5Z,8Z,11Z,14Z)-nonadeca-5,8,11,14-
tetraene-1,19-dioic and (5Z,8Z,11Z,14Z)-20,20-dimethylheneicosa-
5,8,11,14-tetraenoic acids were synthesized. The synthetic scheme
involves a joint route for the formation of (5Z,8Z,11Z,14Z)-nonade- PPh3/CBr4 as a reagent gave the bispropargilicbromide 4
ca-5,8,11,14-tetraene-1,19-dioic acid, which is based on the poly-
acetylenic approach. Regioselective reduction of the w-carboxylic
group to the primary alcohol, exchange of an OH-group to corre-
presence CuI, NaI and K2CO3 afforded the dimethyl ester
sponding iodine and subsequent coupling with low-order organocu-
prates (t-Bu2CuLi) resulted in the formation of (5Z,8Z,11Z,14Z)-
in 72% yield. Cross-coupling of 4 with 2 equivalents of
commercially available methyl 5-hexynoate (5) in the
of nonadeca-5,8,11,14-tetrayne-1,19-dioic acid 6 in ~80%
yield. Hydrogenation of the tetraynoate 6 in dry benzene
with Lindlar’s catalyst in the presence of quinoline gave
the dimethylester of (5Z,8Z,11Z,14Z)-nonadeca-
5,8,11,14-tetraene-1,19-dioic acid 7 in 83% yield. The
crude dimethylester 7 contained about 7% of UV-absorb-
ing impurities as indicated by analytical RP-HPLC
(MeOH/H2O, 85:15, by vol.). These impurities were re-
moved by preparative RP-HPLC and the dimethylester 7
was hydrolyzed in the presence of LiOH to form the free
dicarboxylic acid 8. This acid was monomethylated by
treatment with stoichiometric amounts of diazomethane
and the resulting monomethylester was purified by col-
umn chromatography on silica gel. In principle, methyl
esters can be reduced to primary alcohols with a large mo-
lar excess of NaBH4.9 However, all attempts failed to re-
duce preparative amounts of our tetraenedioic acid
monomethyl ester. Therefore the non-methylated carbox-
ylic group was derivatized with oxalyl chloride and the re-
sulting chloroanhydride was reduced to the primary
alcohol 9 in 56% yield. The w-hydroxy fatty acid methyl-
ester was then converted to the corresponding w-chloride
10 and subsequently to the iodide 11.
20,20-dimethylheneicosa-5,8,11,14-tetraenoic acid with an overall
yield of 11%.
Key words: polyunsaturated fatty acids, cross-coupling reaction,
copper(I) catalysis, Gilman cuprates, lipoxygenase
The products of oxidative metabolism of polyenoic fatty
acids via lipoxygenase and/or cyclooxygenase pathway1,2
are of biological importance. Lipoxygenase products such
as leukotrienes and lipoxins constitute important media-
tors of anaphylactic disorders3 and have also been impli-
cated in inflammation,3 cell differentiation2 and athero-
genesis.2 Polyenoic fatty acids, which are modified at the
w-terminus are useful tools for mechanistic studies on the
LOX reaction.4 Such studies may lead to the development
of powerful LOX inhibitors, which constitute potential
anti-asthmatic and anti-inflammatory drugs.5
Here we report the total synthesis of novel w-modified
polyenoic fatty acids which can be used to investigate the
mechanism of oxidative fatty acid metabolism of mam-
malian cells. The aim of our study was to develop a diver-
gent synthetic approach, which allows the preparation of
different arachidonic acid analogs bearing either hydro-
philic (carboxy-, hydroxy-) or bulky hydrophobic substit-
uents at the w-terminus in the frame of a single synthetic
scheme. This approach should be flexible enough to allow
variations in the type of the w-substituent.
Although unactivated tosylates are more suitable for sub-
stitution reactions with Gilman cuprates (R2CuLi)10,11
than halides (I, Br) our attempts to prepare fatty acid 12
from the corresponding tosylate were not successful. This
was probably due to the limited stability of the polyenoic
tosylates and/or their low reactivity. Thus, sequential
preparation of the halides (Scheme) was used as a method
of choice. The complete substitution of chlorine by iodine,
which was carried out with NaI in anhydrous acetone,
took about 20 hours as indicated by repeated RP-HPLC
analysis.
Wittig olefination traditionally used for the preparation of
linear, cis-skipped polyenes usually leads to formation of
coupling products containing 10-20% of Z,E-isomers. In
contrast, preparation of olefins from acetylenic precursors
via stereoselective hydrogenation on Lindlar’s catalyst
gives Z,Z-products in high yield and with high geometric
purity.6 Based on the polyacetylenic approach our syn-
thetic scheme started with cross-coupling of the easily
The final step of the synthetic procedure, the incorpora-
tion of t-Bu group at the w-terminus of the fatty acid, was
carried out by coupling the iodide 11 with t-Bu2CuLi, pre
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692
I. V. Ivanov et al.
PAPER
NaI (6.28 g, 41.90 mmol) and K2CO3 (4.33 g, 31.42 mmol) in DMF
(25 mL) under a stream of Ar. The mixture was stirred overnight at
30 °C, the reaction was then quenched with sat. NH4Cl (400 mL)
and the lipophilic products were extracted with Et2O (5 ¥ 60 mL).
The combined organic extracts were washed with sat. NaCl
(2 ¥ 100 mL), dried (Na2SO4) and the solvent was evaporated under
vacuum. The residue was purified on silica gel (hexane/EtOAc, 1:7)
to give 3, yield: 1.83 g (70%), mp 58-59 °C.
IR (neat): n = 3040 (OH), 2240 (C∫C) cm-1.
1H NMR (200 MHz, CD3OD): d = 3.32 (m, 2H, 4-CH2), 4.20 (t, 4H,
J = 2.5 Hz, 1-CH2, 7-CH2).
13C NMR (75 MHz, CD3OD): d = 10.76, 64.73 (2C), 79.44 (2C),
80.78 (2C).
Anal. Calcd for C7H8O2: C, 67.73; H, 6.49. Found: C, 67.56; H,
6.71.
1,7-Dibromohepta-2,5-diyne (4)
A solution of PPh3 (8.31 g, 7.21 mmol) in dry CH2Cl2 (50 mL) was
added dropwise over 30 min to a stirred solution of the diol 3 (1.79
g, 14.42 mmol) and CBr4 (10.53g, 31.71 mmol) in CH2Cl2 (20 mL)
and DMF (6 mL) at 0 °C. This mixture was then stirred for 1 h at 0-
10 °C and the reaction was quenched with MeOH (5 mL). The sol-
vents were evaporated under reduced pressure and the residue was
purified by chromatography on silica gel using a linear solvent gra-
dient (hexane-hexane/Et2O, 1:1) to give 4, yield: 2.59 g (72%).
Scheme
IR (neat): n = 2240, 2170 (C∫C), 600 (CH2Br) cm-1.
1H NMR (200 MHz, CDCl3): d = 3.27 (m, 2H, 4-CH2), 3.87 (t, 4H,
pared from one equivalent of CuI and two equivalents of
t-BuLi in THF/HMPA (hexamethylphosphoramide). Af-
ter HPLC purification of the final product, an 85% yield
of the last synthetic step was calculated.
J = 3.0 Hz, 1-CH2, 7-CH2).
13C NMR (75 MHz, CDCl3): d = 10.56, 14.45 (2C), 76.27 (2C),
80.47 (2C).
Anal. Calcd for C7H6Br2: C, 33.64; H, 2.42. Found: C, 33.89; H,
2.65.
1H and 13C NMR spectra were recorded either on a Bruker MSL 200
MHz or on a Bruker MSL 300 MHz spectrometer in CDCl3. Chem-
ical shifts are relative to TMS as an internal standard for 1H NMR
or to the deuterium lock signal of CDCl3 (d 13C = 77.24 ppm) and
that of CD3OD (d 13C = 49.50 ppm). IR spectra were recorded on
Shimadzu IR-435. RP-HPLC analysis was carried out on a Shimad-
zu LC-10Avp liquid chromatograph connected to SPD-10Advp UV
detector. Fatty acid analysis was performed on a Nucleosil C18-col-
umn; 150 ¥ 4 mm, 5 mm particle size (Machery-Nagel, Düren, Ger-
many). A solvent system of MeOH/H2O/AcOH (85:15:0.1) and a
flow rate of 1mL/min were used for all compounds except for the
final synthesised product 12. For this product, a solvent system of
MeOH/CH3CN/H2O (47.5:47.5:5) and a flow rate of 1.2 mL/min
were employed. Preparative purification was carried out on a Li-
chrospher 100 RP18 column, 250 ¥ 22.5 mm, 10 mm particle size
(Knauer, Berlin, Germany). For EIMS analysis a Shimadzu GC-MS
QP-2000 system was used with an ion source temperature of 180 °C
and an electron energy of 70 eV. For thin-layer chromatography we
employed precoated silica gel 60 F254 sheets (Merck, Darmstadt,
Germany). Column chromatography was carried out on silica gel
60.; 70-230 mesh (Merck, Darmstadt, Germany). THF was freshly
distilled from sodium/benzophenone ketyl, and HMPA was dried
over CaH2. All other solvents used were of extra pure grade and pur-
chased from Merck or Aldrich (Germany). t-Butyllithium was titrat-
ed as described by Watson.12 Prior to use, all glassware and syringes
were dried at 140 °C overnight and all reactions were carried out
under Ar atm.
Nonadeca-5,8,11,14-tetrayne-1,19-dioic Acid Dimethyl Ester (6)
In a dry Ar filled round-bottomed flask equipped with a magnetic
stirrer, anhyd K2CO3 (3.44 g, 24.9 mmol), NaI (4.99 g, 33.2 mmol)
and CuI (6.34 g, 33.2 mmol) were suspended in DMF (25 mL).
Methyl 5-hexynoate (5) (2.20 g, 17.47 mmol) and the dibromide 4
(2.08 g, 8.32 mmol) were added, and the mixture was vigorously
stirred overnight at r.t. The reaction was quenched with sat. NH4Cl
(200 mL). The lipophilic products were extracted with Et2O
(4 ¥ 100 mL) and the combined organic layers were washed with
sat. NaCl (2 ¥ 150 mL). After drying (Na2SO4), the ethereal
solution was concentrated under vacuum. The residue was purified
by chromatography on silica gel (hexane/Et2O, 1:2) under Ar to
give pure 6, yield: 2.27g (80%).
TLC: Rf = 0.51 (hexane/Et2O, 1:4, with 1% AcOH).
IR (neat): n = 2170 (C∫C), 1740 (C = O) cm-1.
1H NMR (200 MHz, CDCl3): d = 1.79 (m, 4H, 3-CH2, 17-CH2),
2.22 (tt, 4H, J = 6.8, 2.2 Hz, 4-CH2, 16-CH2), 2.42 (t, 4H, J = 7.0
Hz, 2-CH2, 18-CH2), 3.12 (m, 6H, 7-CH2, 10-CH2, 13-CH2), 3.66 (s,
6H, OCH3).
13C NMR (75 MHz, CDCl3): d = 9.72 (3C), 18.21 (2C), 23.94(2C),
32.88 (2C), 51.44 (2C), 74.26 (2C), 74.85 (2C), 75.03 (2C), 79.52
(2C), 174.91(2C).
Anal. Calcd for C21H24O4: C, 74.09; H, 7.11. Found: C, 73.95; H,
7.33.
(5Z,8Z,11Z,14Z)-Nonadeca-5,8,11,14-tetraene-1,19-dioic Acid
Dimethyl Ester (7)
To a 250 mL Erlenmeyer flask containing Lindlar's catalyst (1.60
g), dry benzene (40 mL) was added. The mixture was saturated with
Hepta-2,5-diyne-1,7-diol (3)
The chloride 1 (2.18 g, 20.95 mmol) (bp 50 °C/0.5 mbar, nD
1.4980) and 2-propyn-1-ol (2) (1.64 g, 29.28 mmol) were added to
a suspension of the previously dried salts; CuI (7.98 g, 41.90 mmol),
20
Synthesis 2000, No. 5, 691–694 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Total Synthesis of the Lipoxygenase Substrates
693
H2 at r.t. and cooled to 10 °C, and a solution of 6 (1.01 g, 2.94
mmol) in benzene (40 mL) and quinoline (1.5 mL) were added un-
der a stream of Ar. After the Ar was exchanged with H2, the reaction
mixture was stirred for 1 h at 10 °C. H2 uptake was measured with
a gas burette. The reaction mixture was filtered, washed with HCl
(2 M, 2 ¥ 50 mL) and the solvent was evaporated. The crude residue
was purified by preparative RP-HPLC (MeOH/H2O, 9:1) to yield
0.83 g (81%) of pure 7.
(10 mL), the solution was acidified with HCl (1 M) to pH 5.0 and
the lipophilic products were extracted with Et2O (3 ¥ 30 mL). The
combined organic extracts were washed with H2O (40 mL) and
dried (Na2SO4). After evaporation of the solvents, the resulting yel-
low oil was subjected to column chromatography on silica gel (hex-
ane/Et2O, 1:3). Purified compound 9 was obtained in a yield of 282
mg (56.5%).
Analytical RP-HPLC: tR = 3.65 min.
Analytical RP-HPLC: tR = 4.57 min.
TLC: Rf = 0.34 (hexane/Et2O, 1:4, with 1% AcOH).
TLC: Rf = 0.64 (hexane/Et2O, 1:4, with 1% AcOH).
IR (neat): n = 3030, 1670 (CH=CH), 1740 (C=O) cm-1.
1H NMR (200 MHz, CDCl3): d = 1.70 (m, 4H, 3-CH2, 17-CH2),
2.09 (m, 4H, 4-CH2, 16-CH2), 2.32 (t, 4H, J = 7.0 Hz, 2-CH2, 18-
CH2), 2.80 (m, 6H, 7-CH2, 10-CH2, 13-CH2), 3.67 (s, 6H, OCH3),
5.35-5.45 (m, 8H, CH=CH).
13C NMR (75 MHz, CDCl3): d = 24.60 (2C), 25.80 (3C), 26.55
(2C), 33.56 (2C), 51.42 (2C), 128.28 (2C), 128.39 (2C), 128.95
(2C), 129.13 (2C), 174.04 (2C).
IR (neat): n = 3600-3200 (OH), 3030, 1670 (CH=CH), 1740 (C=O)
cm-1.
1H NMR (200 MHz, CDCl3): d = 1.45-1.75 (m, 6H, 3-CH2, 17-
CH2, 18-CH2), 2.09 (m, 4H, 4-CH2, 16-CH2), 2.32 (t, 2H, J = 7.0
Hz, 2-CH2), 2.79 (m, 6H, 7-CH2, 10-CH2, 13-CH2), 3.62 (t, 2H,
J = 6.4 Hz, 19-CH2), 3.64 (s, 3H, OCH3), 5.30-5.40 (m, 8H,
CH=CH).
13C NMR (75 MHz, CDCl3): d = 24.89, 25.74 (3C), 25.92, 26.69,
27.06, 32.47, 33.53, 51.43, 62.79, 128.10 (2C), 128.32 (2C),
128.54, 128.98 (2C), 130.05, 174.04.
MS (EI): m/z = 348 (M+).
MS (EI): m/z (%) = 320 (M+, 7.2), 261 (M+-COOCH3, 5.7).
Anal. Calcd for C21H32O4: C, 72.38; H, 9.25. Found: C, 72.18; H,
9.47.
Anal. Calcd for C20H32O3: C, 74.96; H, 10.06. Found: C, 75.12; H,
9.87.
(5Z,8Z,11Z,14Z)-Nonadeca-5,8,11,14-tetraene-1,19-dioic Acid
(8)
(5Z,8Z,11Z,14Z)-19-Chlorononadeca-5,8,11,14-tetraenoic Acid
(10)
An aq solution of LiOH (1.8 M, 20 mL) was added to a solution of
the diester 7 (820 mg, 2.35 mmol) in MeOH (80 mL) under Ar and
the mixture was stirred at r.t. for 8 h. After the reaction was com-
plete, MeOH was removed by evaporation, the pH was adjusted
carefully to 5.0 using HCl (1 M) and the lipophilic compounds were
extracted with Et2O (3 ¥ 40 mL). The combined organic extracts
were dried (Na2SO4), concentrated under reduced pressure, and the
product was purified by chromatography on silica gel (hexane/Et2O,
1:3), yield: 670 mg (89%).
To a solution of ester 9 (200 mg, 0.62 mmol) in CCl4 (3 mL), a so-
lution of PPh3 (245 mg, 0.93 mmol) in CH2Cl2 (4 mL) was added at
r.t. After the reaction mixture was stirred for 24 h, the solvent was
removed under reduced pressure. Column chromatography on silica
gel (hexane/Et2O, 1:1) gave 199 mg of a product with Rf = 0.57
(hexane/Et2O, 1:2). This compound was >99% pure as indicated by
RP-HPLC. Subsequent saponification was carried out by a proce-
dure analogous to that used for the preparation of acid 8. Final col-
umn chromatography on silica gel (hexane/Et2O, 1:2) afforded pure
10 in a yield of 181 mg (90%).
TLC: Rf = 0.23 (hexane/Et2O, 1:4, with 1% AcOH).
IR (neat): n = 3030, 1670 (CH=CH), 1705 (C=O) cm-1.
1H NMR (200 MHz, CDCl3): d = 1.70 (m, 4H, 3-CH2, 17-CH2),
2.10 (m, 4H, 4-CH2, 16-CH2), 2.35 (t, 4H, J = 7.0 Hz, 2-CH2, 18-
CH2), 2.80 (m, 6H, 7-CH2, 10-CH2, 13-CH2), 5.35-5.45 (m, 8H,
CH=CH).
Analytical RP-HPLC: tR = 2.47 min.
TLC: Rf = 0.38 (hexane/Et2O, 1:2, with 1% AcOH).
IR (neat): n = 3030, 1670 (CH=CH), 1705 (C=O), 720, 640 (C-Cl)
cm-1.
13C NMR (75 MHz, CDCl3): d = 24.60 (2C), 25.81 (3C), 26.55
(2C), 33.46 (2C), 128.28 (2C), 128.39 (2C), 128.94 (2C), 129.31
(2C), 180.21 (2C).
MS (EI): m/z (%) = 320 (M+, 30), 302 (M+-H2O, 12.6), 284 (M+-
2H2O, 9.8).
1H NMR (200 MHz, CDCl3): d = 1.45-1.70 (m, 6H, 3-CH2, 17-
CH2, 18-CH2), 2.10 (m, 4H, 4-CH2, 16-CH2), 2.35 (t, 2H, J = 7.0
Hz, 2-CH2), 2.80 (m, 6H, 7-CH2, 10-CH2, 13-CH2), 3.51 (t, 2H,
J = 6.5 Hz, 19-CH2), 5.30-5.40 (m, 8H, CH=CH).
13C NMR (75 MHz, CDCl3): d = 24.78, 25.89 (3C), 26.70 (2C),
27.07, 32.42, 33.62, 45.02, 128.44 (2C), 128.54 (2C), 128.69,
129.03, 129.29, 129.69, 179.86.
Anal. Calcd for C19H28O4: C, 71.22; H, 8.81. Found: C, 71.48; H,
8.51.
MS (EI): m/z = 324 (M+).
(5Z,8Z,11Z,14Z)-19-Hydroxynonadeca-5,8,11,14-tetraenoic
Acid Methyl Ester (9)
Anal. Calcd for C19H29O2Cl: C, 70.24; H, 8.99. Found: C, 70.47; H,
9.01.
The dicarboxylic acid 8 (500 mg, 1.56 mmol) dissolved in Et2O (4
mL) was methylated with a small molar excess of diazomethane
(1.60 mmol). Et2O was removed by evaporation in a stream of Ar
and the residue was purified by column chromatography on silica
gel (hexane/Et2O, 1:2). Fractions containing the product, Rf = 0.40
(hexane/Et2O, 1:4 with 1% AcOH), were pooled, the solvent was re-
moved under vacuum and the residue was redissolved in CH2Cl2 (4
mL). To this solution cooled to 0-10 °C, a 10-fold molar excess of
oxalyl chloride (0.54 mL, 6.24 mmol) was added in one portion and
the mixture was stirred for 0.5 h at 10 °C. After the volatile compo-
nents had been removed under vacuum, a suspension of NaBH4
(100 mg, 2.65 mmol) in CH3CN (6 mL) was added and the mixture
was stirred for 3 h at r.t. The reaction was quenched with ice-water
(5Z,8Z,11Z,14Z)-19-Iodononadeca-5,8,11,14-tetraenoic Acid
(11)
A mixture of acid 10 (150 mg, 0.46 mmol) and NaI (207 mg, 1.38
mmol) in dry acetone (4 mL) was stirred at 65 °C for 20 h. After ac-
etone was evaporated, the residue was redissolved in Et2O (60 mL),
the resulting mixture was washed with H2O (2 ¥ 40 mL) and the or-
ganic layer was dried (Na2SO4). After evaporation of the solvent,
under reduced pressure, the crude residue was purified on silica gel
(hexane/Et2O, 1:1) to yield 11 as a colorless oil, which was analyzed
to be >98% pure by RP-HPLC, yield: 170 mg (89%).
Analytical RP-HPLC: tR = 2.95 min.
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694
I. V. Ivanov et al.
PAPER
IR (neat): n = 3030, 1670 (CH=CH), 1705 (C=O), 570 (C-I) cm-1.
Anal. Calcd for C23H38O2: C, 79.71; H, 11.05. Found: C, 79.54; H,
10.89.
1H NMR (200 MHz, CDCl3): d = 1.47 (m, 2H, 18-CH2), 1.75 (m,
4H, 3-CH2, 17-CH2), 2.10 (m, 4H, 4-CH2, 16-CH2), 2.35 (t, 2H,
J = 7.0 Hz, 2-CH2), 2.79 (m, 6H, 7-CH2, 10-CH2, 13-CH2), 3.17 (t,
2H, J = 6.5 Hz, 19-CH2), 5.30-5.40 (m, 8H, CH=CH).
Acknowledgement
This work was supported in part by the Deutsche Forschungsge-
meinschaft (Ku 961-2-3). The authors wish to thank the Deutscher
Akademischer Austauschdienst for providing an HPLC system to I.
I. at the Lomonosov State Academy of Fine Chemical Technology.
13C NMR (75 MHz, CDCl3): d = 6.60, 24.79, 25.89 (3C), 26.34,
26.74, 30.64, 33.32, 33.61, 128.32, 128.40(2C), 128.51(2C),
128.69, 129.02, 129.28, 179.59.
MS (EI): m/z (%) = 416 (M+, 4.9), 289 (M+-I, 38).
Anal. Calcd for C19H29O2I: C, 54.81; H, 7.02. Found: C, 55.01; H,
7.27.
References
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(5Z,8Z,11Z,14Z)-20,20-Dimethylheneicosa-5,8,11,14-tetraenoic
Acid (12)
To a cooled (-78 °C) suspension of CuI (175 mg, 0.92 mmol) in
THF/HMPA (8 mL and 3 mL, respectively) t-BuLi (1.26 mL, 1.84
mmol) was added with a syringe. The mixture was stirred for 45 min
at -75 °C until a dark, nearly homogenous solution was formed. Af-
ter addition of a solution of acid 11 (154 mg, 0.37 mmol) in THF (2
mL), the resulting mixture was warmed to -45 °C and stirred for 1
h. Afterwards the sample was poured into a separatory funnel con-
taining sat. NH4Cl, acidified with HCl (1 M) to pH 5.0, and the or-
ganic products were extracted with Et2O (2 ¥ 50 mL). The
combined organic extracts were washed with sat. NaCl, dried
(Na2SO4), and concentrated under vacuum. The crude residue was
purified by preparative RP-HPLC (MeOH/CH3CN/H2O,
47.5:47.5:5) to give pure 12, yield: 109 mg (85%).
(3) Samuelsson, B.; Dahlen, S. E.; Lindgren, J. A.; Rouzer, C. A.;
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Analytical RP-HPLC: tR = 2.49 min.
TLC: Rf = 0.36 (hexane/Et2O, 1:1, with 1% AcOH).
IR (neat): n = 3030, 1670 (CH=CH), 1705 (C=O), 1390 cm-1.
1H NMR (200 MHz, CDCl3): d = 0.84 (s, 9H, C(CH3)3), 1.25-1.35
(m, 6H, 17-CH2, 18-CH2, 19-CH2), 1.70 (m, 2H, 3-CH2), 2.08 (m,
4H, 4-CH2, 16-CH2), 2.35 (t, 2H, J = 7.0 Hz, 2-CH2), 2.79 (m, 6H,
7-CH2, 10-CH2, 13-CH2), 5.30-5.40 (m, 8H, CH=CH)
13C NMR (75 MHz, CDCl3): d = 24.49, 24.75, 24.85(3C), 26.69,
27.50, 29.53(3C), 30.48, 30.81, 33.60, 44.37, 127.80, 128.09,
128.32, 128.50, 128.83, 128.94, 129.31, 130.67, 179.70.
MS (EI): m/z (%) = 346 (M+, 19), 331 (M+-CH3, 5.8).
Article Identifier:
1437-210X,E;2000,0,05,0691,0694,ftx,en;Z06799SS.pdf
Synthesis 2000, No. 5, 691–694 ISSN 0039-7881 © Thieme Stuttgart · New York