Syntheses of some sulfur-containing polyunsaturated fatty acids as potential lipoxygenase inhibitors

Article abstract of DOI:10.1080/00397910701575053

Starting from (all-Z)-eicosa-5,8,11,14,17-pentaenoic acid (EPA) and (all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), several polyunsaturated fatty acids, containing a sulfur atom either in the chain or in a thiophene ring, have been synthesized as potential inhibitors of lipoxygenases. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701575053

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Syntheses of Some Sulfur‐Containing
Polyunsaturated Fatty Acids as Potential
Lipoxygenase Inhibitors
a
b
b
Solveig Flock , Anne Kristin Holmeide & Lars Skattebøl
a
Department of Chemistry, Biotechnology and Food Science , Norwegian
University of Life Sciences , Aas, Norway
b
Department of Chemistry , University of Oslo , Oslo, Norway
Published online: 19 Nov 2007.
To cite this article: Solveig Flock , Anne Kristin Holmeide & Lars Skattebøl (2007) Syntheses of
Some Sulfur‐Containing Polyunsaturated Fatty Acids as Potential Lipoxygenase Inhibitors, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:22,
4005-4015, DOI: 10.1080/00397910701575053
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Synthetic Communications , 37: 4005–4015, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701575053
Syntheses of Some Sulfur-Containing
Polyunsaturated Fatty Acids as Potential
Lipoxygenase Inhibitors
Solveig Flock
Department of Chemistry, Biotechnology and Food Science, Norwegian
University of Life Sciences, Aas, Norway
Anne Kristin Holmeide and Lars Skattebøl
Department of Chemistry, University of Oslo, Oslo, Norway
Abstract: Starting from (all-Z)-eicosa-5,8,11,14,17-pentaenoic acid (EPA) and
(
all-Z)-4,7,10,13,16,19-docosahexaenoic acid (DHA), several polyunsaturated fatty
acids, containing a sulfur atom either in the chain or in a thiophene ring, have been
synthesized as potential inhibitors of lipoxygenases.
Keywords: polyunsaturated fatty acids, sulfur-containing fatty acids, 5-lipoxygenase,
dicyclohexylborane
INTRODUCTION
Leukotrienes are final products from the oxidation of arachidonic acid, a poly-
unsaturated v-6 fatty acid. It is well established that leukotrienes, particularly
LTB , are important mediators of widespread inflammatory diseases as
4
[1]
bronchial asthma, rheumatoid arthritis, gout, and psoriasis. Consequently, it
is not surprising that considerable research effort has been targeted at the devel-
[2]
opment of drugs that inhibit the formation of leukotrienes. Among the
primary targets are inhibitors of 5-lipoxygenase (5-LO), an enzyme that starts
the cascade of oxidation steps leading to a number of structurally different
Received in the U.K. August 22, 2007
Address correspondence to Solveig Flock, Department of Chemistry, Biotechnol-
ogy and Food Science, Norwegian University of Life Sciences, P. O. Box 5003,
N-1432, Aas, Norway. E-mail: solveig.flock@umb.no
4
005

4
006
S. Flock, A. K. Holmeide, and L. Skattebøl
leukotrienes. The same oxidative enzymes also convert the v-3 polyunsaturated
acid eicosapentaenoic acid (1, EPA) into the corresponding leukotrienes, which
diverge structurally from those derived from arachidonic acid only by an
additional Z-double bond. However, the biological properties of these leuko-
trienes differ from those derived from arachidonic acid in several respects, par-
ticularly by not being such strong mediators of inflammation. The competition
with arachidonic acid for 5-LO may explain why EPA acts as a weak inhibitor
[3,4]
of this enzyme and consequently its ant-iinflammatory properties.
The initial reaction of 5-LO with either arachidonic acid or EPA seems to
[5]
be hydrogen abstraction at carbon-7. Corey et al. substituted the methylene
group at this position in arachidonic acid with sulfur, and the resulting
[6]
compound 2 possessed inhibitory activity for 5-LO. Later, Hanko et al. syn-
thesized and tested for 5-LO inhibition several analogs of arachidonic acid
containing a sulfur atom at the 5-position. Structure–activity studies concluded
that the sulfur atom should preferably be attached to a conjugated diene moiety
as in compound 3, the most active 5-LO inhibitor of those tested (Fig. 1).
We have prepared several analogs of EPA and docosahexaenoic acid (4,
[7,8]
DHA) that incorporate a sulfur atom at different positions in the molecules.
Some of these compounds have shown interesting biological activity, particu-
[
9,10]
larly as inhibitors of the enzymes cPLA and COX-2.
Considering the
available biological data, it seemed interesting to prepare the vinyl sulfides
and 6 and the thiophene derivatives 7 and 8 as potential lipoxygenase inhibi-
2
5
tors. The present article describes our synthetic effort toward this goal starting
from EPA and DHA (Fig. 2).
RESULTS AND DISCUSSION
We expected to obtain the vinyl sulfides 5 and 6 by selective reduction of the
corresponding acetylenic esters 9 and 10. The syntheses are outlined in
Scheme 1. The aldehydes 11 and 12, which were available in 75% overall
[7]
yields by oxidative degradation of EPA and DHA, respectively, were
Figure 1. Structures of the natural PUFAs eicosapentaenoic acid (EPA) and docosa-
hexaenoic acid (DHA) and two previously synthesized sulfur-containing analogues of
arachidonic acid.

Polyunsaturated Fatty Acids
4007
Figure 2. Structures of some sulfur-containing v-3 PUFAs.
converted to the corresponding acetylenic derivatives 13 and 14 by treatment
of the respective gem. dibromoolefin with methylithium.
[11]
In a one-pot
reaction, the lithium derivative of 13 was subjected to elemental sulfur and
ethyl 4-iodobutanoate, furnishing the ester 9 in 40% yield. A similar
reaction sequence transformed the acetylene 14 with sulfur and methyl bro-
moacetate into the ester 10 in 67% yield. Finally, selective reduction of the
acetylenic bond of each of the esters should have provided the target
compounds. However, several hydrogenation methods were tried without
success. Only when the reduction was carried out with dicyclohexylborane
[
12]
in THF
were the esters 5 and 6 were present in the reaction products, but
we were unable to separate them from other components of the reaction
mixtures.
The synthetic strategy to the thiophene derivatives 7 and 8 also involved
as the last step the selective reduction of the corresponding acetylenic
Scheme 1. Reagents and conditions: (i) CBr
iii) (a) BuLi, S , 278–208C; (b) ethyl 4-iodobutanoate, 0–208C; (iv) (a) BuLi, S
78–208C; (b) methyl bromoacetate 0–208C.
4 3 2 2
, Ph P, Zn, CH Cl ; (ii) MeLi, 2788C;
(
8
8
,
2

4
008
S. Flock, A. K. Holmeide, and L. Skattebøl
derivatives, which we anticipated to obtain by Pd(0)-catalyzed coupling of a
[13]
3-halothiophene derivative with the appropriate polyenyne (Scheme 2).
With respect to the functionality at the 2-position of the thiophene ring, it
could either be introduced after the coupling reaction or be present in the
halothiophene derivative. Initially we opted for the first alternative,
rendering the synthesis of the thiophene derivative 15 as our first objective.
The Pd(0)-catalyzed coupling of 3-bromothiophene with the tetraenyne 13
proceeded as expected, furnishing the thiophene derivative 15 in 58% yield.
In the subsequent reaction with alkylithium, a selective hydrogen–lithium
exchange at the 5-position of the thiophene ring was not achieved; the
reaction of 15 with butylithium at 2788C followed by quenching with solid
carbon dioxide and acidification gave a mixture of acids in a disappointingly
poor yield. The result was equally unsatisfactory when the lithium derivative
was quenched with 2-(2-bromoethyl)-1,3-dioxolane, en route to the ester 8.
Hence, we abandoned this approach in preference for coupling the
acetylene with an appropriately substituted bromothiophene derivative.
Methyl 4-bromothiophene-2-carboxylate was prepared from 2,4-dibromothio-
[14]
phene according to the literature, but the Pd(0)-catalyzed coupling with the
acetylene 13 was not satisfactory. On the other hand, coupling of the ethylene
acetal of commercially available 4-bromo-2-thiophenecarboxaldehyde (16)
with the acetylene proceeded smoothly to give compound 17 in 94% yield.
Subsequent hydrolysis to the aldehyde 18 followed by silver nitrate
oxidation furnished the acid 19 in 80% overall yield. Methyl 3-(4-bromo-2-
thienyl)propanoate (20), prepared from the corresponding commercially
available acrylic acid derivative by esterification and Rh-catalyzed hydrogen-
ation, underwent Pd(0)-catalyzed coupling with the acetylene 13 to give the
Scheme 2. Reagents and conditions: (i) 13, MeLi, Pd(0), 2788C; (ii) HCO
iii) Ag O; (iv) dicyclohexenylborane-Me S.
2 2
H, H O;
(
d
2

Polyunsaturated Fatty Acids
4009
thienyl ester 21 in 93% yield. It now remained to reduce selectively the triple
bond to a Z-double bond, but again this transformation caused problems. To
find satisfactory conditions, compound 15 was used as model substrate.
Although several methods gave none or very little of the expected product,
reaction of this compound with the dicyclohexylborane–dimethylsulfide
[
12]
complex in THF
afforded the all-Z polyene 22 in 50% yield. However,
when this procedure was applied to the ester 21, the thiophene derivative 8
was obtained in a disappointing 20% yield.
The biological testing of the polyunsaturated fatty acid derivatives is in
progress, and the results will be reported elsewhere in due course.
EXPERIMENTAL
The NMR spectra were recorded in CDCl with a Varian Gemini 200 instru-
3
ment, a Bruker Avance DPX 200 instrument, a Bruker Avance DPX 300
instrument, or a Bruker Avance DRX 500 instrument. IR spectra were
obtained with a Perkin-Elmer 1310 infrared spectrophotometer or a Nicolet
Magna-IR 550 spectrometer. Mass spectra were recorded at 70 eV with a
Fisons VG Pro spectrometer.
Dichloromethane and acetonitrile were dried by distillation over
calcium hydride. Methanol was dried over magnesium. 3-Bromothiophene,
4
-bromothiophene-2-carboxaldehyde, methyl (E)-3-(4-bromo-2-thienyl)acry-
late, ethyl 4-iodobutanoate, and 2-(2-bromoethyl)-1,3-dioxalane were obtained
commercially.
(all-Z)-4,7,10,13-hexadecatetraen-1-yne (13)
A mixture of zinc powder (2.40 g, 37 mmol), Ph P (9.69 g, 37 mmol), and
3
CBr (12.26 g, 37 mmol) in CH Cl (100 ml) was stirred at rt for 40 h. A
4
2
2
[
7]
solution of the aldehyde 11 (4.0 g, 18 mmol) in CH Cl (20 ml) was
2
2
added. After stirring for 1 h at rt, the mixture was filtered and the solvent
partially evaporated under reduced pressure. The residue was filtered
through a plug of silica gel (hexane as eluent) to give the dibromide
(6.58 g, 96%) as an oil. d (200 MHz) 0.98 (t, J 7.5 Hz, 3H), 2.06 (m, 2H),
H
2
1
1
.6–3.0 (m, 8H), 5.2–5.6 (m, 8H), 6.35 (t, J 7.2 Hz, 1H); dC (50 MHz)
4.8 (CH ), 21.1, 26.1, 26.2, 26.3, 31.8 (CH ), 89.2 (CBr ), 123.6, 126.4,
3
2
2
26.9, 127.1 (CH), 128.1 (2 ꢀ CH), 129.7, 131.4, 135.9 (3 ꢀ CH 55 ). MeLi
(
(
10 ml, 1.6 M, 16 mmol) was added to a stirred solution of the dibromide
5.0 g, 13 mmol) in dry ether (60 ml) at 2788C. After 1 h, water was added,
and the mixture extracted with ether. The combined organic extracts were
dried (MgSO ) and concentrated under reduced pressure. The residue was
4
purified by flash chromatography (SiO , hexane) to give the acetylene 13
2
2
1
(
2.44 g, 85%) as an oil. nmax (film)/cm 3268, 2985, 2935, 2100, 1632,

4
010
S. Flock, A. K. Holmeide, and L. Skattebøl
1420; dH (200 MHz) 0.96 (t, J 7.5 Hz, 3H), 1.96 (t, J 2.7 Hz, 1H), 2.06
(
m, 2H), 2.7–2.9 (m, 6H), 2.9-3.0 (m, 2H), 5.2–5.6 (m, 8H); d (50 MHz)
C
1
4.7 (CH ), 17.3, 20.9 (CH ), 25.9 (2 ꢀ CH ), 26.1 (CH ), 68.2 (CH), 82.4
3
2
2
2
(
C), 123.6, 126.5, 126.8, 127.2, 128.1, 128.2, 129.6, 131.5 (CH); m/z (EI):
þ þ
14 (M , 0.2%), 117, 91, 79 (100). (HRMS: found: M 214.1703. C H
16 22
2
requires 214.1722).
(
all-Z)-4,7,10,13,16-nonadecapentaen-1-yne (14)
[7]
Reaction of the aldehyde 12 by the procedure described for 13 gave the
2
1
acetylene 14 as an oil in 78% yield. nmax (film)/cm 3285, 3000, 2950,
2120, 1645, 1430; dH (200 MHz) 0.96 (t, J 7.5 Hz, 3H), 1.96 (t, J 2.7 Hz,
1H), 2.06 (m, 2H), 2.7–2.9 (m, 8H), 2.9–3.0 (m, 2H), 5.3–5.5 (m, 10H);
dC (75 MHz) 14.3 (CH ), 16.9, 20.6 (CH ), 25.5 (2 ꢀ CH ), 25.6
3
2
2
(
2 ꢀ CH ), 68.1 (CH), 82.5 (C), 124.1, 127.0, 127.4, 127.8, 127.9, 128.4,
2
þ
1
28.6, 128.7, 130.1, 132.0 (CH); m/z (EI) 254 (M , 15%), 117, 91, 79
þ
(
100). (HRMS found: M 254.2022. C H requires 254.2035).
9 26
1
Acetylenic Sulfides: General Procedure
n-BuLi (1 equiv.) was added to a solution of the acetylene (1 equiv.) in dry
ether (0.3 mmol/ml) at 2788C. The mixture was stirred at this temperature
for 30 min before addition of elemental sulphur (1.3 equiv.). The reaction
mixture was slowly warmed to rt and stirred for 1 h. Then the halide was
added to the mixture at 08C. After stirring for 30 min at 08C and 2 h at
room temperature, the mixture was poured into water and the phases
separated. The aq. phase was extracted with ether. The combined ether
extract was washed with brine and water and then dried (MgSO ). Evaporation
4
of solvents under reduced pressure followed by flash chromatography of the
residue on silica gel (95:5 hexane/EtOAc) gave the pure product.
Ethyl (all-Z)-5-thia-9,12,15,18-heneicosapentaen-6-ynoate (9)
This was obtained as an oil in 40% yield by reaction of the acetylene 13 with
sulfur and ethyl 4-iodobutanoate according to the general procedure. n
max
2
1
(
film)/cm 2990, 2950, 1730, 1200; d (300 MHz) 0.95 (t, J 7.5 Hz, 3H),
H
1
7
2
.24 (t, J 7.1 Hz, 3H), 2.03 (m, 4H), 2.45 (t, J 7.3 Hz, 2H), 2.70 (t, J
.0 Hz, 2H), 2.8–2.9 (m, 6H), 3.06 (d, J 4.9 Hz, 2H), 4.11 (q, J 7.1 Hz,
H), 5.3–5.5 (m, 8H); dC (75 MHz) 14.2, 14.3 (CH ), 18.6, 20.6, 24.4
3
(
CH ), 25.5 (2 ꢀ CH ), 25.6, 32.4, 34.5 (CH ), 60.4 (OCH ), 68.0, 92.1 (C),
2
2
2
2
1
24.2, 126.9, 127.4, 127.7, 128.7, 128.8, 129.7, 132.1 (CH) 172.9 (C 55 O)

Polyunsaturated Fatty Acids
4011
þ
þ
m/z (EI) 360 (M , 2.2%), 245, 87 (100). (HRMS found: M 360.2115.
C H O S requires 360.2123).
2
2 32 2
Methyl (all-Z)-3-thia-7,10,13,16,19-docosapentaen-4-ynoate (10)
This was obtained as an oil in 43% yield by reaction of the acetylene 14 with
sulfur and methyl bromoacetate according to the general procedure. n
max
2
film)/cm 2990, 2940, 1730, 1430, 1270; d (300 MHz) 0.95 (t, J 7.5 Hz,
1
(
H
3
3
2
H), 2.04 (m, 2H), 2.7–2.9 (m, 8H), 3.05 (d, J 5.5 Hz, 2H), 3.43 (s, 2H),
.72 (s, 3H), 5.3–5.5 (m, 10H); d (75 MHz) 14.2 (CH ), 18.5, 20.5 (CH ),
C
3
2
5.5 (2 ꢀ CH ), 25.6 (2 ꢀ CH ), 37.2 (CH ), 52.6 (OCH ), 66.7, 93.8
2
2
2
3
(
2 ꢀ C), 123.9, 126.9, 127.3, 127.7, 127.8, 128.3, 128.5, 128.6, 129.9,
þ
1
31.9 (CH), 168.9 (C 55 O); m/z (EI) 358 (M , 1.78%), 299, 285, 91 (100).
þ
(HRMS found: M 2 59 299.1830; C H S requires 299.1833. Found
M 2 73 285.1676; C H S requires 285.1677).
2
0 27
þ
1
9 25
(all-Z)-1-(3-thienyl)-4,7,10,13-hexadecatetraen-1-yne (15)
A mixture of the acetylene 13 (1.2 g, 5.6 mmol), 3-bromothiophene (0.92 g,
5
.6 mmol), 10% Pd-C (0.24 g), CuI (41 mg, 0.22 mmol), Ph P (230 mg,
3
0
reflux for 40 h, while the reaction was monitored by gas chromatography
.88 mmol), and Et N (15 ml) in dry acetonitrile (7.5 ml) was heated under
3
w
(
GC). After cooling, the reaction mixture was filtered through Celite , and
solvents were evaporated. The residue was purified by flash-chromatography
21
(
hexane) to give the thiophene 15 (0.96 g, 58%) as an oil. nmax(film)/cm
2
2
7
1
1
2
983, 2938, 2905, 1378, 1260, 1140; d (200 MHz): 0.96 (t, J 7.5 Hz, 3H),
H
.06 (m, 2H), 2.6–3.0 (m, 6H), 3.15 (d, J 4.1 Hz, 2H), 5.2–5.6 (m, 8H), 7.1–
.2 (m, 1H), 7.2–7.3 (m, 1H), 7.4–7.5 (m, 1H); d (50 MHz): 14.3 (CH ),
C
3
7.8, 20.6, 25.5 (CH ), 25.6 (2 ꢀ CH ), 75.5, 87.5, 122.6 (C), 124.3, 124.9,
2
2
26.9, 127.4, 127.6, 127.7, 128.5, 128.6, 129.8, 129.9, 132.0 (CH); m/z (EI):
96 (M , 1.5%), 227, 108, 91, 79 (100). (HRMS found: M 296.1586.
þ
þ
C H S requires 296.1599).
20 24
(all-Z)-4-(4,7,10,13-hexadecatetraen-1-ynyl)-2-(1,3-dioxolanyl)
thiophene (17)
[15]
A mixture of the acetylene 13 (1.0 g, 4.67 mmol), the thienyl acetal 16
(440 mg, 1.87 mmol), 10% Pd-C (200 mg), CuI (40 mg), Ph P (250 mg),
3
and triethylamine (25 ml) in dry acetonitrile (15 ml) was heated under
reflux for 75 h while monitoring the reaction by GC. After cooling to rt, the
w
reaction mixture was filtered through Celite , and solvents evaporated.
Flashchromatography of the residue (9:1 hexane/CH Cl ) recovered
2
2

4
012
S. Flock, A. K. Holmeide, and L. Skattebøl
unreacted acetylene (450 mg), and further elution (9:1 hexane/EtOAc) gave
2
1
compound 17 (650 mg, 94%) as an oil. nmax(film)/cm 3012, 2940, 2962,
1438, 1231, 1155; d (300 MHz): 0.96 (t, 3H, J 7.5 Hz), 2.06 (m, 2H), 2.7–
H
2.9 (m, 6H), 3.13 (d, J 5.5 Hz, 2H), 3.9–4.1 (m, 4H), 5.3–5.6 (m, 8H), 6.02
(
s, 1H), 7.09 (m, 1H), 7.31 (m, 1H); d (75 MHz): 14.2 (CH ), 17.7, 20.5
C 3
(
CH ), 25.5 (3 ꢀ CH ), 65.1 (2 ꢀ CH O), 75.3, 87.2 (C), 99.7 (O-C-O),
2
2
2
1
1
9
22.3 (C), 124.2, 126.9, 127.3, 127.7, 128.5, 128.6 (CH), 128.8 (2 ꢀ CH),
þ
29.8, 131.9 (CH), 141.5 (C); m/z (EI): 368 (M , 7.1%), 299, 182, 108,
þ
1, 79 (100), (HRMS found: M 368.1825. C H O S requires 368.1810).
23 28 2
(all-Z)-4-(4,7,10,13-hexadecatetraen-1-ynyl)thiophene-2-
carboxaldehyde (18)
Aqueous formic acid (80%, 10 ml) was added to a solution of the acetal 17
510 mg, 1.4 mmol) in dioxane (15 ml). The solution was stirred for 1 h at
(
rt. Water was added, and the mixture was extracted with ether. The extract
was washed with saturated aq. NaHCO and dried (MgSO ). Evaporation of
solvents followed by flash chromatography (95:5 hexane/EtOAc) gave the
3
4
2
1
aldehyde 18 (400 mg, 90%) as an oil. nmax(film)/cm 3020, 2985, 2943,
682, 1446, 1238, 1163; dH (200 MHz): 0.94 (t, J 7.5 Hz, 3H), 2.04
1
(
m, 2 H), 2.7–2.9 (m, 6H), 3.15 (d, J 4.8 Hz, 2H), 5.2–5.6 (m, 8H), 7.67
s, 2H), 9.83 (d, J 0.7 Hz, 1H); d (50 MHz): 14.2 (CH ), 17.7, 20.5, 25.4
(
C
3
(
CH ), 25.5 (2 ꢀ CH ), 74.0, 89.0 (C), 123.6 (CH), 124.3 (C), 126.8, 127.2,
2
2
1
27.6, 128.6, 128.7, 130.2, 132.0, 136.5, 138.5 (CH), 143.1 (C), 182.4
þ
(
C 55 O); m/z (EI): 324 (M , 3.2%), 307, 295, 187, 115, 108, 91, 79 (100).
þ
(
HRMS found: M 324.1567. C H OS requires 324.1548).
21 24
(all-Z)-4-(4,7,10,13-hexadecatetraen-1-ynyl)thiophene-2-carboxylic
Acid (19)
To a vigorously stirred solution of NaOH (150 mg, 3.8 mmol) in water (3 ml),
a solution of AgNO (330 mg, 1.9 mmol) in water (3 ml) was added. The
3
mixture was cooled in an ice bath before a solution of the aldehyde 18
(
310 mg, 0.96 mmol) in dioxane (2 ml) was added. After stirring for
0 min, water and ether were added. The organic phase was separated, and
the water phase was acidified with 5% aq. HCl and extracted with ether.
2
The extract was dried (MgSO ) and concentrated under reduced pressure to
4
2
1
give the acid 19 (290 mg, 89%) as an oil. nmax(film)/cm 3028, 2981,
1
2
688, 1455, 1276; d (200 MHz): 0.96 (t, J 7.5 Hz, 3H), 2.06 (m, 2H), 2.7–
H
.8 (m, 6H), 3.16 (d, J 4.8 Hz, 2H), 5.2–5.9 (m, 8H), 7.58 (m, 1H), 7.81
(
m, 1H), 11.7 (br s, 1H); d (50 MHz): 14.9 (CH ), 18.4, 21.1 (CH ), 26.1
C 3 2
(
3 ꢀ CH ), 74.3, 88.5 (C), 123.3 (CH), 123.5 (C), 126.3, 126.7, 127.1,
2
1
28.1, 128.2, 129.6, 131.4 (CH), 131.7 (C), 135.0, 136.8 (CH), 182.4

Polyunsaturated Fatty Acids
4013
þ
(
C 55 O); m/z (EI): 340 (M , 0.6%), 307, 283, 115, 108, 91, 79 (100), (HRMS
þ
found: M 340.1518. C H O S requires 340.1497).
21 24 2
Methyl 3-(4-Bromo-2-thienyl)-propanoate (20)
To a solution of 3-(4-bromo-2-thienyl)-propenoic acid (2.50 g, 10.7 mmol) in
methanol/benzene (1:1, 80 ml), conc. H SO (1 ml) was added, and the
2
4
mixture was heated under reflux for 4 h. The mixture was washed successively
with saturated aq. NaHCO and brine, then dried (MgSO ), and the solvents
3
4
were evaporated under reduced pressure. The crude ester was dissolved in
benzene (60 ml) and hydrogenated on a Parr apparatus using (Ph P) RhCl
3
3
(0.5 g) as catalyst. After 10 and 20 h, additional amounts of catalyst (0.5 g)
were added, and ethanol (10 ml) was added as well. After 30 h, the mixture
w
was filtered through Celite , and the solvents were evaporated under
reduced pressure. Purification of the residue by flash chromatography (8:2
2
1
hexane/EtOAc) gave the ester 20 (1.75 g, 66%) as an oil. nmax(film)/cm
2
7
3
915, 1739, 1427, 1171; dH (300 MHz) 2.63 (t, J 7.5 Hz, 2H), 3.08 (t, J
.5 Hz, 2H), 3.66 (s, 3H), 6.71 (m, 1H), 6.99 (m, 1H); d (75 MHz) 25.3,
C
5.6 (CH ), 52.1 (OCH ), 109.8 (C), 121.6, 128.2 (CH 55 ), 145.3 (C), 173.5
2
3
þ
(
(
C 55 O); m/z (EI): 250/248 (M , 50.6/55.8%), 190/188, 177/175, 43
100). (HRMS: found: M 247.9495. C H BrO S requires 247.9506).
8
þ
9
2
Methyl 3-[4-(all-Z-4,7,10,13,16-hexadecapentaenyl)-2-
thienyl]propanoate (21)
Reaction of the acetylene 13 with the bromide 20 was carried out as described
1
2
for compound 17 to give the ester 21 in 93% yield, as an oil. nmax(film)/cm
3
3
3
010, 2955, 2925, 1733, 1434, 1195, 1170; d (200 MHz): 0.95 (t, J 7.5 Hz,
H
H), 2.06 (m, 2H), 2.63 (t, J 7.3 Hz, 2H), 2.7–3.0 (m, 6H), 3.0–3.2 (m, 4H),
.67 (s, 3H), 5.2–5.6 m, 8H), 6.77 (m, 1H), 7.13 (m, 1H); d (50 MHz): 14.3
C
(
CH ), 17.8, 20.6, 25.1 (CH ), 26.0 (3 ꢀ CH ), 35.5 (CH ), 51.7 (CH O), 75.7,
3
2
2
2
3
8
1
5
6.9, 121.7 (C), 123.8, 125.6, 126.3 (CH), 126.8 (2 ꢀ CH), 127.1, 127.9,
þ
28.0, 129.1, 131.3 (CH), 141.8 (C), 171.4 (C 55 O); m/z (EI): 382 (M ,
.4%), 313, 199, 187, 91, 79, 73 (100). (HRMS found: M 382.1951.
þ
C H O S requires 382.1967).
24 30 2
(all-Z)-1-(3-thienyl)-4,7,10,13,16-hexadecapentaene (22)
Cyclohexene (0.18 ml, 1.77 mmol) was added dropwise to an ice-cooled
solution of borane-dimethylsulfide complex (8 M; 0.10 ml, 0.77 mmol) in
dry THF (4.0 ml). The resulting mixture was left stirring at rt for 2 h and
cooled to 08C before a solution of 15 (100 mg, 0.34 mmol) in dry THF
(1.0 ml) was added. The mixture was allowed to reach rt during 1 h and

4
014
S. Flock, A. K. Holmeide, and L. Skattebøl
stirred for an additional 2 h. Acetic acid (0.5 ml) was then added dropwise,
and the resulting mixture was left stirring overnight. The mixture was
cooled to 08C, and aq. NaOH (2 M, 5.0 ml) was slowly added followed by
dropwise addition of 50% aq. H O (0.30 ml). The mixture was extracted
2
2
with ether. The extract was washed with water and brine and then dried
MgSO ). Solvents were evaporated under reduced pressure, and the residue
(
4
was purified by flash chromatography (9:1 hexane/EtOAc) to give the all-Z
2
1
polyene 22 (50 mg, 50%), as an oil. nmax(film)/cm 2933, 2922, 1436,
1
3
161; d (200 MHz): 0.95 (t, J 7.5 Hz, 3H), 2.05 (m, 2H), 2.7–2.9 (m, 6H),
H
.0–3.2 (m, 2H), 5.2–5.7 (m, 9H), 6.26 (dt, J 1.7, 11.4 Hz, 1H), 7.0–7.2
(
m, 2H), 7.2–7.3 (m, 1H); d (50 MHz): 14.7 (CH ), 20.9, 25.6, 25.7, 25.8,
C 3
2
1
2
6.1 (CH ), 121.0, 125.3, 126.0, 126.5, 126.6, 127.5 (CH), 127.6 (2 ꢀ CH),
2
þ
28.0, 128.2, 128.5, 129.3, 131.5 (CH), 137.9 (C). (HRMS found: M
98.1751. C H S requires 298.1755).
2
0 26
Methyl 3-[4-(all-Z-4,7,10,13,16-hexadecapentaenyl)-2-
thienyl]propanoate (8)
Cyclohexene (0.38 ml, 3.71 mmol) was added dropwise to an ice-cooled
solution of borane–dimethylsulfide complex (8 M; 0.24 ml, 1.84 mmol) in
dry THF (4.0 ml). The resulting mixture was left stirring at rt for 2 h and
cooled to 08C before a solution of the ester 21 (500 mg, 1.31 mmol) in dry
THF (2.0 ml) was added. The mixture was allowed to reach rt over 1 h and
stirred for an additional 2.5 h. AcOH (1.06 ml) was then added dropwise,
and the resulting mixture was left stirring overnight. The mixture was
cooled to 08C, and aq. NaOH (2.0 M, 7.2 ml) was added slowly, followed
by dropwise addition of 30% aq. H O (0.70 ml). The mixture was
2
2
extracted with ether. The extract was washed with water and brine and then
dried (MgSO ). Solvents were evaporated under reduced pressure, and the
4
residue was purified by flash chromatography (9:1 hexane/EtOAc) to give
the ester 8 (100 mg, 20%) as an oil. d (200 MHz): 0.95 (t, J 7.5 Hz, 3H),
H
2
3
1
2
1
1
1
.05 (m, 2H), 2.67 (t, J 7.5 Hz, 2H), 2.6–2.9 (m, 6H), 3.0–3.2 (m, 4H),
.67 (s, 3H), 5.2–5.6 (m, 9H), 6.26 (dt, J 1.5, 11.4 Hz, 1H), 6.80 (d, J
.0 Hz, 1H), 6.94 (s, 1H); d (50 MHz): 14.7 (CH ), 20.9, 25.6, 25.8, 25.9,
C
3
6.1, 27.7, 30.0 (CH ), 51.9 (OCH ), 120.9, 123.3, 126.0, 126.6 (CH),
2
3
27.5 (2 ꢀ CH), 127.6, 128.0, 128.2, 128.5, 129.3, 131.7 (CH), 137.9,
þ
42.2 (C), 172.1 (C 55 O); m/z (EI): 384 (M , 35.2%), 313, 183, 147, 135,
08, 91, 79. (HRMS found: M 384.2109. C H O S requires 384.2123).
þ
2
4 32 2
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1