Two novel racemic synthetic approaches to LTB4 and LTB3 methyl esters

Article abstract of DOI:10.1039/b108847e

The formal racemic synthesis of LTB₄ and LTB₃ methyl esters 1 and 2 is reported by introducing in a one step-procedure the E,E,Z-conjugated trienic system provided by (1E,3E,5Z)-1,6-dibromohexa-1,3,5-triene 3 and (1E,3E,5Z)-1-bromo-7,7-diethoxyhepta-1,3,5-triene 4, respectively, as building blocks.

Full text of DOI:10.1039/b108847e

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Two novel racemic synthetic approaches to LTB4 and
LTB3 methyl esters
Christine Gauthier, Dominique Castet, Yvan Ramondenc and Gérard Plé*
1
4 (Scheme 1), following
Université de Rouen, IRCOF, UMR 6014, F-76821 Mont Saint Aignan, France.
E-mail: Gerard.Ple@univ-rouen.fr; Fax: 33-2/35522971; Tel: 33-2/35522448
Received (in Cambridge, UK) 2nd October 2001, Accepted 21st November 2001
First published as an Advance Article on the web 18th December 2001
The formal racemic synthesis of LTB4 and LTB3 methyl esters 1 and 2 is reported by introducing in a one
step-procedure the E,E,Z-conjugated trienic system provided by (1E,3E,5Z)-1,6-dibromohexa-1,3,5-triene 3
and (1E,3E,5Z)-1-bromo-7,7-diethoxyhepta-1,3,5-triene 4, respectively, as building blocks.
7,7-diethoxyhepta-1,3,5-triene11
Introduction
methodologies successfully developed in our group.10a,11
One observes that, as in the target leukotrienes, the trienic
E,E,Z-conjugated system already exists in compounds 3 and 4;
hence, they could be a priori seen as building blocks able to give
access to the title methyl esters 1 and 2.
Leukotriene B4 (LTB4) (Fig. 1), an important metabolite
of arachidonic acid,1 biosynthesised via the 5-lipoxygenase
pathway,2 is one of the most potent inducers of chemotaxis,
chemokinesis, aggregation and degranulation of leukocytes.
Important roles in allergic,3a inflammatory4 and immunological
reaction5 have been attributed to LTB4. On the other hand,
following an analogous 5-lipoxygenase pathway, eicosa-5,8,11-
trienoic acid is metabolised in vivo into LTB3.6 The latter has
also been reported to possess biological activities, similar to
LTB4.7
To the best of our knowledge, the syntheses of LTB4
and LTB3 by a stereocontrolled introduction of the E,E,Z
conjugated trienic unit, in a one step procedure, have not been
reported so far.
Results and discussion
Two synthetic strategies were imagined, based mainly on the
ability of the proposed starting materials 310a,12 and 411 to
afford lithio derivatives by stereocontrolled halogen–metal
exchange reactions and subsequent treatment with an
appropriate aldehyde.
Synthesis from (1E,3E,5Z )-1,6-dibromohexa-1,3,5-triene 3
The 1E,3E,5Z-isomer of 1,6-dibromohexa-1,3,5-triene 3 has
been previously prepared by us,10a exploiting a Wittig reaction
performed on (2E,4E)-5-bromopenta-2,4-dienal10 5.
Fig. 1
Moreover, we have previously demonstrated that the two
bromine atoms linked at C-1, C-6 significantly exhibit different
reactivity when 3 is involved in a halogen–metal exchange reac-
tion10a or in a palladium-catalyzed cross-coupling process.13
This behaviour was considered of crucial importance since
simple retrosynthetic disconnection revealed the availability of
LTB4 and LTB3 from a 1E,3E,5Z-hexatriene dianion equivalent
in reaction with two different aldehydes. Thus, the synthetic
approaches to LTB4 and LTB3 methyl esters 1 and 2 were
attempted as two successive selective bromine–lithium exchange
reactions, followed by quenching of the reaction mixture with
the required aldehyde (Scheme 2).
As a result of their physiological importance and limited
availability from biological sources, a number of synthetic
8
8d,8h,9
routes to LTB4 and to LTB3
have been described in the
literature.
Herein, we report two new synthetic approaches to LTB4 and
LTB3 as their methyl esters 1 and 2 based on the great reactivity
and versatility of our reagent (2E,4E)-5-bromopenta-2,4-dienal
5 (Scheme 1).10 Thus, as summarised in Scheme 1, it can be
Indeed, a first bromine–lithium exchange reaction on pure
1E,3E,5Z-isomer 3, by treatment with tert-butyllithium in
diethyl ether at Ϫ75 ЊC, occurred with high selectivity on the
bromine atom of the E double bond. The condensation with
(3Z)-non-3-enal 6a (synthetic approach to LTB4 methyl esters
1) or nonanal 6b (synthetic approach to LTB3 methyl esters 2),
afforded the desired monosubstituted compounds 7a and 7b in
large excess over the side products 8a, 9a and 8b, 9b, respect-
ively. After optimisation of the reaction conditions and column
chromatography, the expected monobrominated derivatives 7a
and 7b and the by-products 8a, 9a and 8b, 9b were isolated pure
in the molar proportions 7a : 8a : 9a 65 : 8 : 10 and 7b : 8b : 9b
Scheme 1
successfully used to yield diastereomerically pure (1E,3E,5Z)-
1,6-dibromohexa-1,3,5-triene10a 3 and (1E,3E,5Z)-1-bromo-
DOI: 10.1039/b108847e
J. Chem. Soc., Perkin Trans. 1, 2002, 191–196
This journal is © The Royal Society of Chemistry 2002
191

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Scheme 2 Reagents and conditions: i, ButLi, Et2O, Ϫ75 ЊC, 90 min; (3Z)-non-3-enal 6a or nonanal 6b, 0 ЊC, 90 min.
Scheme 3 Reagents and conditions: i, ButLi, Et2O, Ϫ75 ЊC, 90 min; methyl 4-formylbutanoate 10, 0 ЊC, 60 min.
56 : 10 : 10 (Scheme 2) and fully characterised. Discrimination
between pure diastereomeric bromohydrins 7a vs. 8a and 7b vs.
8b and stereochemical analyses of all new compounds 7–9 were
procedure from the readily available (1E,3E,5Z)-1,6-dibromo-
hexa-1,3,5-triene 3.
1
made by using H NMR spectroscopy. The stereochemistry of
Synthesis via (1E,3E,5Z )-bromo-7,7-diethoxyhepta-1,3,5-triene
the trienic system of compounds 7–9 has been determined from
the J values of the different double bonds (for example,
compound 7a: J1,2 = 7.1; J3,4 = 13.5 and J5,6 = 13.8 Hz). All
compounds 7–9 were obtained from the starting material 3 with
total retention of configuration.
Finally, we note that (3Z)-non-3-enal 6a was prepared
in 91% yield by oxidation of the corresponding commer-
cially available (3Z)-non-3-en-1-ol by using the Dess–Martin
procedure.14
Keeping in mind that the bromohydrins 7a,b are useful
intermediates in the syntheses of LTB4 and LTB3 methyl esters 1
and 2, respectively, the next step of the chemistry was straight-
forward. Thus, a second bromine–lithium exchange reaction
was performed on pure isolated 7a,b followed by quenching
with methyl-4-formylbutanoate15 10 (Scheme 3).
4
In this second synthetic strategy, the starting material was
(2E,4E)-5-bromopenta-2,4-dienal10 5 (Schemes 1 and 4). As the
chemistry depicted in Scheme 4 suggests, the crucial step should
be the Wittig homologation of aldehyde 5 promoted by the
diethyl acetal of 13. Then, in order to prepare the diethoxy
derivative 4, the early stage of our research was inspired by the
work of Bestmann16 concerning the diastereoselective synthesis
of α,β-unsaturated aldehydes with high Z stereocontrol. How-
ever, in order to optimise the formation of 4, we had to modify
Bestmann’s experimental protocol16 (Scheme 4).
The LTB4 methyl esters 1 (as a non-separable diastereomeric
mixture) were obtained and isolated in analytical purity after
column chromatography in 51% yield (with respect to 7a, over-
all yield 33% vs. starting material 3). We mention, however, the
occurrence of the side acetylenic product 11, in 25% yield (from
7a), presumably as the result of the dehydrobromination of 7a
promoted by the ButLi. This compound 11 has been isolated
pure and fully analyzed.
Similar methodology carried out with 7b afforded the LTB3
methyl esters 2 (as a non-separable diastereomeric mixture) in
60% yield (overall yield 34% with respect to 3).
The isolated pure LTB4 and LTB3 methyl esters 1 and 2 have
been fully characterised using classical methods.
Scheme 4 Reagents and conditions: i, EtBr, reflux, 2 days; ii, 5, EtONa,
THF, Ϫ10 ЊC, reflux, 12 h.
Surprisingly, we note that attempts at condensing directly the
aldehyde 5 with the diethyl acetal of 13 (prepared from 12 and
EtONa) failed since non-reproducible results were obtained. To
ensure the accurate formation of 4, we had to introduce the
In our opinion, the above results reveal a simple and con-
venient route towards LTB4 and LTB3 precursors in a two-step
192
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non-enolisable aldehyde 5 to the reaction mixture containing
the phosphonium salt 12 prior to EtONa. The addition of the
latter generated in situ the diethyl acetal of 13, which condensed
with 5, as soon as it had formed. Thus, the aldehyde 5 added to
the phosphonium enol ether salt 12 (available from the Trippett
and Walker17 phosphorylide reagent 13), followed by sodium
etharolate (EtONa), afforded the new ω-bromo conjugated
trienic diethyl acetal 4 in 70% yield (with respect to 5). The
total 1E,3E,5Z stereochemistry of the latter, seen as the key
intermediate, was revealed by means of 1H NMR spectroscopy.
Next, according to a bromine–lithium exchange reaction
(treatment with ButLi in Et2O at Ϫ75 ЊC) performed on pure
isolated compound 4 followed by quenching with (3Z)-non-3-
enal 6a or nonanal 6b, the desired hydroxytrienic diethyl acetals
14a,b were obtained in 76 and 78% yield (from 4), after
column chromatographic purification, with total retention of
configuration (Scheme 5).
Scheme 6 Reagents and conditions: i, Li(CH2)3C(OMe)3, Et2O, 0 ЊC,
120 min.
Hydrolysis of 14a,b under mild acidic conditions yielded the
corresponding crude aldehydes 15a,b in (almost) quantitative
yield (Scheme 5). The unstable compounds 15a,b (isomerisation
into the corresponding conjugated aldehydes with an all E
configuration) have been used as crude product.
Bruker AM 400 MHz with Aspect 3000 calculator. CDCl3 or
C6D6 was used as solvent. No SiMe4 was added; rather, shifts
were referenced to the solvent line (chemical shifts δ in ppm and
coupling constants J in Hz). Mass spectra were performed
on an ATI-Unicam Automass apparatus, fitted (or not) with a
GC-mass coupling (high-resolution J&W column, 30 m, 0.25
mm ID, flow rate: 1.2 mL minϪ1), or on a JEOL JMS AX-500
spectrometer. Analytical TLC was performed on Kieselgel 60F-
254–0.25 mm plates and developed with UV (250 nm) or phos-
phomolybdic acid. Products were purified by silica gel column
chromatography (SDS Company, 230–400 mesh). All reactions
were carried out under dry Ar. Microanalyses were carried
out in IRCOF Microanalysis Laboratory of Rouen. Melting
points were measured on a Reichert-Jung microscope appar-
atus. Solvents were purified according to standard procedures.
Finally, an ω-butanoate homologation was performed on the
aldehyde 15b by using trimethyl 4-lithioorthobutanoate,18 to
afford the LTB3 methyl esters 2 in 52% yield (from 15b) after
mild acidic hydrolysis (Scheme 6).
A similar procedure was previously reported by Taylor8k for
the synthesis of LTB4 methyl esters 1 by condensation of the
same reagent with a silylated trienic aldehyde analogous to our
precursor 15a.
Conclusions
In conclusion, we have succeeded in developing two new formal
synthetic approaches to LTB4 and LTB3 methyl esters 1 and 2
by introduction of the conjugated trenic system in a one-step
E,E,Z-stereocontrolled pathway.
(1Z,3E,5E,9Z )-1-Bromo-7-hydroxy-pentadeca-1,3,5,9-tetraene
7a
From (1E,3E,5Z)-1,6-dibromohexa-1,3,5-triene 3 the LTB4
and LTB3 methyl esters 1 and 2 were obtained in two steps (in
33 and 34% overall yield respectively, vs. 3) and from (2E,4E)-5-
bromopenta-2,4-dienal 5 via the new reagent (1E,3E,5Z)-1-
bromo-7,7-diethoxyhepta-1,3,5-triene 4, the LTB3 methyl esters
2 were obtained in four steps (overall yield 28% vs. 5).
These new processes should be easily applicable to the syn-
thesis of a wide variety of structural analogs. The synthesis
with stereocontrol of the hydroxyallylic chiral centres is under
investigation.
To a solution of (1E,3E,5Z)-1,6-dibromohexa-1,3,5-triene10a,b
3 (0.240 g, 1.00 mmol) in dry Et2O (4 mL), cooled to Ϫ75 ЊC,
under argon was added a solution of ButLi (1.07 mL of a 1.7 M
solution in pentane; 1.80 mmol) slowly with a syringe. The
reaction mixture was stirred for 90 min and a solution of
(3Z)-non-3-enal8j 6a (0.140 g, 1.00 mmol) in dry Et2O (1 mL)
was introduced. The reaction mixture was warmed to 0 ЊC and
was stirred for 90 min before treatment with water (2 mL). After
extraction with Et2O (3 × 30 mL), the organic layer was dried
(MgSO4) and concentrated. By silica gel column chromato-
graphy [pentane–Et2O (80 : 20 v/v)] we isolated and identified
the expected monosubstituted compound 7a (0.195 g, 65%)
as a yellow oil, compound 8a (0.025 g, 8%, yellow oil) and
compound 9a (0.035 g, 10%, yellow oil).
Experimental
General
IR spectra were recorded on a Perkin-Elmer 16 PC FT-IR spec-
trometer for samples as thin films. NMR spectra were recorded
on a Bruker AC 200 MHz, Bruker Avance DPX 300 MHz, or
Compound 7a. νmax/cmϪ1 3114, 3050, 2976, 1630, 1487, 1047
and 688; δH(300 MHz; C6D6) 0.86 (3H, t, J 6.7, 15-H3), 1.15–
Scheme 5 Reagents and conditions: i, ButLi, Et2, Ϫ75 ЊC, 90 min; (3Z)-non-3-enal 6a or nonanal 6b, 0 ЊC, 2h; ii, PTSA, acetone, water, 0 ЊC, 45 min.
J. Chem. Soc., Perkin Trans. 1, 2002, 191–196
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1.35 (6H, m, 12–14-H2), 2.00 (2H, m, 11-H2), 2.28 (2H, m,
8-H2), 4.00 (1H, q, J 6.4 and 7.0, 7-H), 5.30–5.45 (2H, m, 9-H
and 10-H), 5.60 (1H, dd, J 6.4 and 13.8, 6-H), 5.80 (1H, d, J 7.1,
1-H), 6.10 (2H, m, 4-H and 5-H), 6.25 (1H, dd, J 7.1 and 10.4,
2-H) and 6.60 (1H, dd, J 10.4 and 13.5, 3-H); δC(75 MHz; C6D6)
14.62 (C-15), 23.26 (C-14), 28.06 (C-11), 29.97 (C-12), 32.11
(C-13), 35.87 (C-8), 72.07 (C-7), 108.42 (C-1), 124.90 (C-9),
128.14 (C-3), 132.80 (C-4), 133.23 (C-2), 135.03 (C-10), 135.18
(C-5) and 139.07 (C-6) (Found: C, 60.38; H, 7.59. C15H23BrO
requires C, 60.21; H, 7.75%).
67.71 (C-7), 110.00 (C-1), 128.53 (C-5), 132.45 (C-4), 136.46
(C-6), 137.40 (C-2) and 139.57 (C-3); m/z (CI, CH4) 331–329
(Mϩ ϩ 29, 6%), 303–301 (Mϩ ϩ 1, 1), 285–283 (9), 221 (10), 203
(18) and 174 (100) (Found: C, 59.57; H, 8.41. C15H25BrO
requires C, 59.80; H, 8.36%).
(10E,12E,14Z )-9,16-Dihydroxytetraeicosa-10,12,14-triene
9b. νmax/cmϪ1 3328, 2954, 1680, 1650, 1464, 1056 and 994;
δH(300 MHz; C6D6) 0.80 (6H, m, 1-H3 and 24-H3), 1.00–1.20
(24H, m, 2–7-H2 and 18–23-H2), 1.25 (2H, m, 8-H2), 1.40 (2H,
m, 17-H2), 4.05 (1H, m, 9-H), 4.55 (1H, m, 16-H), 5.45 (1H, t,
J 9.8, 15-H), 5.65 (1H, dd, J 6.3 and 14.5, 10-H), 6.00 (1H,
t, J 11.2, 14-H), 6.15 (1H, dd, J 10.8 and 14.0, 12-H), 6.25
(1H, dd, J 10.7 and 14.2, 11-H) and 6.55 (1H, dd, J 11.8 and
13.7, 13-H); δC(75 MHz; C6D6) 14.53 (C-1 and C-24), 22.95,
23.25, 26.03, 29.42, 30.62, 32.44 (C-2–7 and C-18–23), 30.24
(C-8), 30.96 (C-17), 68.25 (C-16), 72.64 (C-9), 128.50 (C-13),
129.81 (C-14), 130.23 (C-11), 134.36 (C-12), 135.55 (C-15)
and 138.55 (C-10); m/z (EI) 364 (Mϩ, 1%), 346 (M Ϫ H2O3), 328
(M Ϫ 2H2O3), 141 (74), 95 (34) and 57 (100); m/z (CI, CH4) 347
(Mϩ ϩ 1 Ϫ H2O, 100%).
(1E,3E,5Z,9Z )-1-Bromo-7-hydroxypentadeca-1,3,5,9-tetraene
8a. νmax/cmϪ1 3134, 3060, 2985, 1630, 1055 and 670; δH(300
MHz; C6D6) 0.80 (3H, t, J 6.7, 15-H), 1.10–1.40 (6H, m, 12–14-
H2), 2.00 (2H, m, 11-H2), 2.40 (2H, m, 8-H2), 4.40 (1H, m, 7-H),
5.30–5.50 (4H, m, 5–6-H and 9–10-H), 5.62 (1H, m, 3-H), 5.78
(1H, d, J 13.6, 1-H), 6.30 (1H, dd, J 11.7 and 15.1, 4-H) and
6.52 (1H, dd, J 10.9 and 13.6, 2-H); δC(75 MHz; C6D6) 14.23
(C-15), 21.00 (C-14), 27.72 (C-11), 28.64 (C-12), 31.89 (C-13),
35.66 (C-8), 67.93 (C-7), 109.65 (C-1), 124.79 (C-9), 128.88
(C-5), 129.07 (C-4), 131.23 (C-2), 135.38 (C-10), 135.90 (C-3)
and 137.72 (C-6) (Found: C, 60.38; H, 7.59. C15H23BrO requires
C, 60.21; H, 7.75%).
Methyl (6Z,8E,10E,14Z )-5,12-dihydroxyeicosa-6,8,10,14-
tetraenoate 1: LTB4 methyl esters
(6Z,10E,12E,14Z,18Z )-9,16-Dihydroxytetraeicosa-6,10,12,
14,18-pentane 9a. νmax/cmϪ1 3346, 2920, 1654, 1466 and 1032;
δH(300 MHz; C6D6) 0.88 (6H, m, 1-H3 and 24-H3), 1.15–1.34
(12H, m, 2–4-H2, 21–23-H2), 2.00 (4H, m, 5-H2 and 20-H2),
2.30 (4H, m, 8-H2 and 17-H2), 4.10 (1H, m, 9-H), 4.53 (1H, m,
16-H), 5.36–5.60 (5H, m, 6–7-H, 15-H and 18–19-H), 5.67 (1H,
dd, J 5.9 and 15.0, 10-H), 6.02 (1H, t, J 11.5, 14-H), 6.14 (1H,
dd, J 10.8 and 14.7, 12-H), 6.31 (1H, dd, J 10.8 and 15.0, 11-H)
and 6.55 (1H, dd, J 11.5 and 14.7, 13-H); δC(75 MHz; C6D6)
14.46 (C-1 and C-24), 23.12, 29.86, 31.99 (C-2–4 and C-21–23),
27.94 (C-5 or C-20), 27.96 (C-20 or C-5), 36.07 (C-17 or C-8),
36.19 (C-8 or C-17), 68.15 (C-16), 72.20 (C-9), 125.25, 125.28,
133.25, 133.36, 134.73 (C-6–7, C-15 and C-18–19) 128.31
(C-13), 130.03 (C-14), 130.42 (C-11), 134.38 (C-12) and 137.70
(C-10); m/z (CI, CH4) 389 (Mϩ ϩ 29.1 %), 361 (Mϩ ϩ 1, 3), 343
(100), 325 (32), 249 (80), 231 (60), 189 (60), 137 (23) and 69 (28).
Under argon, a solution of ButLi (1.80 mL of a 1.79 M solution
in pentane; 2.80 mmol) was added to a solution of compound
7a (0.22 g, 1.00 mmol) in dry Et2O (3 mL), cooled to Ϫ75 ЊC.
The reaction mixture was stirred for 90 min and a solution of
methyl 4-formylbutanoate15 10 (0.10 g, 1.00 mmol) in dry Et2O
(2 mL) was introduced. The reaction mixture was warmed to
0 ЊC and stirred for 60 min before treatment with water (2 mL).
After extraction with Et2O (3 × 30 mL), the organic layer was
dried (MgSO4) and concentrated. By silica gel column chrom-
atography [CH2Cl2–EtOAc (80 : 20 v/v)] we isolated and identi-
fied the LTB4 methyl esters 1 (0.13 g, 51%) as a yellow oil, and
the acetylenic derivative 11 (0.06 g, 25%, yellow oil).
Compound 1: LTB4 methyl esters. νmax/cmϪ1 3423, 2980, 1755,
1642, 1487, 1084 and 968; δH(300 MHz; CDCl3) 0.87 (3H, t,
J 6.6, 20-H3), 1.21–1.37 (6H, m, 17–19-H2), 1.50–1.75 (6H, m,
3-H2, 4-H2, and 2 × OH), 2.02 (2H, m, 16-H2), 2.33 (4H, m,
2-H2 and 13-H2), 3.65 (3H, s, OCH3), 4.20 (1H, m, 12-H), 4.55
(1H, m, 5-H), 5.35 (2H, m, 6-H and 14-H), 5.56 (1H, m, 15-H),
5.75 (1H, dd, J 6.0 and 14.7, 11-H), 6.06 (1H, t, J 11.3, 7-H),
6.15–6.35 (2H, m, 9-H and 10-H) and 6.47 (1H, dd, J 11.7 and
13.5, 8-H); δC(75 MHz; CDCl3) 13.94 (C-20), 20.34 (C-3), 22.44
(C-19), 27.31 (C-16), 29.16 (C-17), 31.39 (C-18), 33.69 (C-2),
35.20 (C-13), 36.60 (C-4), 51.46 (OCH3), 67.46 (C-5), 71.74
(C-12), 123.91 (C-14), 127.32 (C-8), 130.08 (C-7 and C-10),
133.51 (C-6), 133.84 (C-9), 133.94 (C-15), 136.69 (C-11) and
173.94 (C-1); m/z (EI) 333 (Mϩ Ϫ OH, 7%), 315 (10, M Ϫ H2O
Ϫ OH), 301 (9), 221 (12), 189 (14), 131 (25), 99 (68) and 61 (100)
(Found: C, 71.74; H, 9.92. C21H34O4 requires C, 71.96; H,
9.78%).
(1Z,3E,5E )-1-Bromo-7-hydroxypentadeca-1,3,5-triene 7b
According to the procedure described for preparation of
compound 7a, from (1E,3E,5Z)-1,6-dibromo-1,3,5-triene10a,b
3 (0.240 g, 1.00 mmol) and using a solution of nonanal 6b
(0.140 g, 1.00 mmol) in dry Et2O (1 mL) we isolated and identi-
fied, after silica gel column chromatography [pentane–Et2O
(80 : 20 v/v)], compound 7b (0.170 g, 56%) as a yellow solid,
compound 8b (0.030 g, 10%, yellow oil) and compound 9b
(0.035 g, 10%, yellow oil).
Compound 7b. Mp 32–33 ЊC; νmax/cmϪ1 3184, 3060, 2968,
1650, 1465, 1060 and 680; δH(300 MHz; C6D6) 0.90 (3H, t, J 6.8,
15-H3), 1.20–1.40 (12H, m, 9–14-H2), 1.42 (2H, m, 8-H2), 3.86
(2H, m, 7-H2), 5.63 (1H, dd, J 6.4 and 14.4, 6-H), 5.79 (1H, d,
J 7.1, 1-H), 6.10 (2H, m, 4-H and 5-H), 6.26 (1H, dd, J 6.8 and
10.4, 2-H) and 6.61 (1H, dd, J 10.5 and 14.0, 3-H); δC(75 MHz;
C6D6) 14.33 (C-15), 19.61, 23.05, 25.73, 29.98, 31.93 (C-9–14),
37.58 (C-8), 72.25 (C-7), 108.28 (C-1), 128.85 (C-3), 129.60
(C-4), 132.75 (C-2), 136.34 (C-5) and 139.88 (C-6) (Found: C,
59.64; H, 8.22. C15H25BrO requires C, 59.80; H, 8.36%).
Methyl (8E,10E,14Z)-5,12-dihydroxyeicosa-8,10,14-trien-6-
ynoate 11. νmax/cmϪ1 3490, 3012, 2954, 2851, 1738, 1456, 1030
and 986; δH(300 MHz; CDCl3) 0.82 (3H, t, J 6.5, 20-H3), 1.20–
1.40 (6H, m, 17–19-H2), 1.70–1.80 (4H, m, 3-H2 and 4-H2), 2.00
(2H, m, 16-H2), 2.20–2.36 (4H, m, 2-H2 and 13-H2), 3.62 (3H, s,
OCH3), 4.17 (1H, m, 12-H), 4.50 (1H, m, 5-H), 5.30 (1H, m,
15-H), 5.50–5.62 (2H, m, 8-H and 14-H), 5.78 (1H, dd, J 6.0
and 15.2, 11-H), 6.24 (1H, dd, J 10.8 and 15.2, 10-H) and 6.51
(1H, dd, J 10.8 and 15.5, 9-H); δC(75 MHz; CDCl3) 14.02
(C-20), 20.53 (C-3), 22.51 (C-19), 27.37 (C-16), 29.22 (C-17),
31.45 (C-18), 33.52 (C-2), 35.19 (C-13), 36.97 (C-4), 51.58
(OCH3), 62.41 (C-5), 71.52 (C-12), 84.05 (C-6), 92.28 (C-7),
110.60 (C-8), 123.81 (C-14 or C-15), 129.13 (C-10), 134.06
(C-15 or C-14), 138.29 (C-11), 141.39 (C-9), and 173.93 (C-1);
(1E,3E,5Z )1-Bromo-7-hydroxypentadeca-1,3,5-triene
8b.
νmax/cmϪ1 3204, 2922, 1686, 1640, 1466, 1090 and 990; δH(400
MHz; C6D6) 0.90 (3H, t, J 6.8, 15-H3), 1.20–1.40 (12H, m, 9–14-
H2), 1.45 (2H, m, 8-H2), 4.30 (2H, m, 7-H2), 5.43 (1H, m, 6-H),
5.68 (1H, dd, J 11.5 and 15.4, 3-H), 5.91 (1H, d, J 13.5, 1-H),
6.32 (1H, dd, J 11.6 and 14.9, 4-H), 6.54 (1H, dd, J 11.2 and
13.5, 2-H) and 6.61 (1H, m, 5-H); δC(100 MHz; C6D6) 14.01
(C-15), 22.75, 25.47, 29.38, 29.69, 31.90 (C-9–14), 37.66 (C-8),
194
J. Chem. Soc., Perkin Trans. 1, 2002, 191–196

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m/z (CI, CH4) 377 (Mϩ ϩ 29, 13%), 349 (Mϩ ϩ 1, 8), 331 (100),
313 (38), 299 (84), 219 (50) and 177 (23) (Found: C, 72.54; H,
9.12. C21H32O4 requires C, 72.38; H, 9.26%).
3.60 (2H, m, OCH2CH3), 4.07 (1H, q, J 6.0, 8-H), 5.37 (1H, d,
J 5.9, 1-H), 5.47 (2H, m, 10-H and 11-H), 5.59 (1H, dd, J 5.9
and 11.1, 2-H), 5.68 (1H, dd, J 6.0 and 15.1, 7-H), 6.08 (1H, dd,
J 11.1 and 11.8, 3-H), 6.12 (1H, dd, J 10.9 and 14.8, 5-H), 6.28
(1H, dd, J 10.8 and 15.1, 6-H) and 6.73 (1H, dd, J 11.8 and
14.7, 4-H); δC(100 MHz; C6D6) 13.91 (C-16), 15.21 (OCH2-
CH3), 22.58 (C-15), 27.41 (C-12), 29.32 (C-13), 31.47 (C-14),
35.53 (C-9), 59.85 (OCH2CH3), 71.31 (C-8), 97.93 (C-1), 124.87
(C-10), 127.86 (C-4), 128.88 (C-2), 129.73 (C-6), 131.64 (C-3),
132.62 (C-11), 134.78 (C-5) and 137.84 (C-7); m/z (EI) 322 (Mϩ,
3%), 277 (100), 259 (7), 233 (9), 211 (68), 181 (90), 155 (21), 138
(74), 110 (92), 92 (81) and 51 (70) (Found: C, 74.63; H, 10.66.
C20H34O3 requires C, 74.49; H, 10.63%).
Methyl (6Z,8E,10E )-5,12-dihydroxyeicosa-6,8,10-trienoate 2:
LTB3 methyl esters
In the same manner as described for the preparation of the
LTB4 methyl esters 1, from (1Z,3E,5E)-1-bromo-7-hydroxy-
pentadeca-1,3,5-triene 7b we isolated and identified, after silica
gel column chromatography [CH2Cl2–EtOAc (80 : 20 v/v)], the
LTB3 methyl esters 2 (0.14 g, 60%) as a colourless oil.
δmaxϪcmϪ1 3436, 2924, 1742, 1634, 1442, 1074 and 998; δH(400
MHz; CDCl3) 0.82 (3H, t, J 6.3, 20-H3), 1.15–1.70 (20H, m,
3-H2, 4-H2, 13–19-H and 2 × OH), 2.30 (2H, t, J 7.3, 2-H2), 3.61
(3H, s, OCH3), 4.10 (1H, q, J 6.5, 12-H), 4.53 (1H, m, 5-H), 5.36
(1H, t, J 10.3, 6-H), 5.70 (1H, dd, J 6.2 and 15.0, 11-H), 6.02
(1H, t, J 11.3, 7-H), 6.20 (2H, m, 9-H and 10-H) and 6.43 (1H,
dd, J 10.9 and 15.0, 8-H); δC(100 MHz; CDCl3) 14.02 (C-20),
20.74, 22.59, 25.34, 29.20, 29.48, 29.51, 30.26, 31.81 and 37.28
(C-3, C-4 and C-13–19), 33.77 (C-2), 51.44 (OCH3), 67.45
(C-12), 72.21 (C-5), 127.29 (C-10 or C-9), 129.98 (C-8 and C-10
or C-9), 133.72 (C-7), 134.02 (C-6), 137.69 (C-11) and 173.94
(C-1); m/z (EI) 334 (Mϩ Ϫ H2O, 2%), 303 (2), 219 (5), 161 (12),
129 (94) and 91 (100) (Found: C, 71.69; H, 10.08. C21H36O4
requires C, 71.59; H, 10.23%).
(2Z,4E,6E,)-1,1-Diethoxyhexadeca-2,4,6-trien-8-ol 14b
According to the procedure described for the preparation of
compound 14a, from (1E,3E,5Z)-1-bromo-7,7- diethoxyhepta-
1,3,5-triene 4 (0.38 g, 1.46 mmol) and a solution of nonanal 6b
(4.00 g) in dry Et2O (1 mL) we isolated and identified, after
silica gel column chromatography [pentane–Et2O 80 : 20 (v/v)],
compound 14b (0.37 g, 78%) as a yellow oil, νmax/cmϪ1 3463,
2926, 1642, 1465, 1355, 1142 and 980; δH(400 MHz, C6D6) 0.90
(3H, t, J 6.9, 16-H3), 1.12 (6H, t, J 7.1, 2 × OCH2CH3), 1.41
(14H, m, 9–15-H2), 2.54 (1H, s, OH), 3.43 (2H, m, OCH2CH3),
3.57 (2H, m, OCH2CH3), 4.06 (1H, q, J 6.3, 8-H), 5.39 (1H, d,
J 5.9, 1-H), 5.60 (1H, dd, J 5.9 and 11.1, 2-H), 5.70 (1H, dd,
J 6.4 and 14.8, 7-H), 6.10 (1H, dd, J 11.0 and 11.9, 3-H), 6.13
(1H, dd, J 10.9 and 14.7, 5-H), 6.28 (1H, dd, J 10.7 and 14.9,
6-H) and 6.75 (1H, dd, J 11.8 and 14.5, 4-H); δC(100 MHz,
C6D6) 14.32 (C-16), 15.54 (OCH2CH3), 23.03, 25.85, 29.70,
30.00, 30.06, 32.24, 37.76 (C-9–15), 60.11 (OCH2CH3), 72.33
(C-8), 98.22 (C-1), 128.09 (C-4), 129.18 (C-2), 129.88 (C-6),
132.00 (C-3), 135.19 (C-5) and 139.03 (C-7); m/z (EI) 324 (Mϩ,
2%), 307 (10), 279 (46), 261 (10), 227 (11), 197 (6), 141 (10), 103
(100) and 85 (15) (Found: C, 74.18; H, 11.61. C20H36O3 requires
C, 74.03; H, 11.18%).
(1E,3E,5Z )-1-Bromo-7,7-diethoxyhepta-1,3,5-triene 4
Under argon,
a solution of (2E,4E)-5-bromopenta-2,4-
dienal10a,b 5 (0.15 g, 0.93 mmol) in dry THF (4 mL) was added
to a solution of (2-ethoxyvinyl)triphenylphosphonium brom-
ide16 12 (0.96 g, 2.33 mmol) in dry THF (30 mL), at room
temperature. To the solution cooled to Ϫ10 ЊC, were added
EtONa (0.30 g, 4.41 mmol) and EtOH (0.25 mL). The reaction
mixture was allowed to warm to room temperature and then
was heated at reflux for 12 h, filtered on Celite, and concen-
trated. After silica gel column chromatography [light petroleum
(distilled 50–65 ЊC)–Et2O (70 : 30 v/v)] we isolated and identi-
fied compound 4 (0.17 g, 70%) as a yellow oil, νmax/cmϪ1 3062,
2974, 1608, 1562, 1322, 1118 and 992; δH(400 MHz; C6D6) 1.10
(6H, t, J 7.0, 2 × CH3), 3.40 (2H, m, OCH2CH3), 3.57 (2H, m,
OCH2CH3), 5.30 (1H, d, J 5.8, 7-H), 5.62 (1H, dd, J 11.5 and
14.8, 3-H), 5.66 (1H, dd, J 5.8 and 10.8, 6-H), 5.87 (1H, d,
J 13.6, 1-H), 5.88 (1H, t, J 11.2, 5-H), 6.49 (1H, dd, J 11.4 and
13.8, 4-H) and 6.54 (1H, dd, J 12.0 and 13.6, 2-H); δC(100 MHz;
C6D6) 15.54 (CH3), 60.11 (OCH2CH3), 98.07 (C-7), 110.20
(C-1), 129.05 (C-4), 130.82 (C-6), 131.22 (C-2), 132.06 (C-5)
and 137.64 (C-3); m/z (EI) 260–262 (Mϩ, 7%), 215–217 (21), 181
(6), 159 (5), 136 (28), 107 (29) and 79 (100) (Found: C, 50.59; H,
6.56. C11H17BrO2 requires C, 50.72; H, 6.65%).
(2Z,4E,6E,10Z )-8-Hydroxyhexadeca-2,4,6,10-tetraenal 15a
At 0 ЊC, aq. toluene-p-sulfonic acid (0.25 g in 2mL) was added
to (2Z,4E,6E,10Z)-1,1-diethoxyhexadeca-2,4,6,10-tetraen-8-ol
14a (0.19 g, 0.59 mmol) in acetone (10 mL). The mixture was
stirred for 45 min, washed with saturated aq. NaHCO3 (10 mL),
and extracted with Et2O (3 × 10 mL). Evaporation of the dried
(MgSO4) solution gave crude compound 15a (0.14 g, 95%) as a
yellow oil, νmax/cmϪ1 3423, 2945, 2820, 1672, 1451, 1124 and
990; δH(400 MHz; C6D6) 0.87 (3H, t, J 6.5, 16-H3), 1.23–1.45
(7H, m, 13–15-H2 and OH), 2.02 (2H, m, 12-H2), 2.30 (2H, m,
9-H2), 4.06 (1H, q, J 6.0, 8-H), 5.53 (2H, m, 10-H and 11-H),
5.69 (1H, dd, J 7.4 and 11.0, 2-H), 6.09 (1H, dd, J 11.0 and 14.5,
5-H), 6.07 (2H, m, 6-H and 7-H), 6.35 (1H, t, J 11.3, 3-H), 6.82
(1H, dd, J 11.3 and 14.4, 4-H) and 9.92 (1H, d, J 7.3, 1-H);
δC(100 MHz; C6D6) 14.05 (C-16), 17.43 (C-15), 22.27 (C-12),
24.16 (C-13), 26.32 (C-14), 30.25 (C-9), 66.05 (C-8), 122.53
(C-10), 124.56 (C-2), 127.27 (C-7 or C-6), 128.06 (C-7 or C-6),
136.10 (C-11), 136.60 (C-5), 140.37 (C-3), 145.21 (C-4) and
186.93 (C-1).
(2Z,4E,6E,10Z )-1,1-Diethoxyhexadeca-2,4,6,10-tetraen-8-ol
14a
Under argon, a solution of But Li (0.6 mL of a 1.7 m solution in
pentane; 1.02 mmol) was added to a solution of compound 4
(0.15 g, 0.58 mmol) in dry Et2O (2 mL), cooled to Ϫ75 ЊC. The
reaction mixture was stirred for 90 min and a solution of (3Z)-
non-3-enal8j 6a (0.20 g, 1.43 mmol) in dry Et2O (2 mL) was
introduced. The reaction mixture was stirred for 2 h and then
warmed to 0 ЊC, before treatment with water (3 mL). After
extraction with Et2O (3 × 10 mL), the organic layer was dried
(MgSO4) and concentrated. By silica gel column chromato-
graphy [light petroleum (distilled 50–65 ЊC)–Et2O 50 : 50 (v/v)]
we have isolated and identified the compound 14a (0.14 g, 76%)
as a yellow oil. νmax/cmϪ1 3428, 2956, 1628, 1456, 1330, 1126 and
999; δH(400 MHz; C6D6) 0.85 (3H, t, J 7.1, 16-H3), 1.10 (6H, t,
J 7.0, 2 × OCH2CH3), 1.24 (7H, m, 13–15-H2 and OH), 1.98
(2H, m, 12-H2), 2.28 (2H, m, 9-H2), 3.42 (2H, m, OCH2CH3),
(2Z,4E,6E )-8-Hydroxyhexadeca-2,4,6-trienal 15b
In the same manner as described for the preparation of 15a,
from (2Z,4E,6E)-1,1-diethoxyhexadeca-2,4,6-trien-8-ol 14b
(0.27 g, 0.84 mmol) we isolated and identified crude (2Z,4E,
6E)-8-hydroxyhexadeca-2,4,6-trien 15b (0.21 g, 100%) as a
yellow oil, νmax/cmϪ1 3408, 2924, 2854, 1668, 1462, 1134 and
1010; δH(200 MHz; C6D6) 0.90 (3H, t, J 6.2, 16-H3), 1.26 (15H,
m, 9–15-H2 and OH), 3.92 (1H, m, 8-H), 5.61 (1H, dd, J 6.7
and 10.8, 2-H), 5.65 (1H, dd, J 11.2 and 13.8, 5-H), 6.07 (2H, m,
6-H and 7-H), 6.29 (1H, t, J 11.2, 3-H), 6.81 (1H, dd, J 11.2 and
14.2, 4-H) and 9.95 (1H, d, J 7.1, 1-H); δC(50 MHz; C6D6) 14.28
J. Chem. Soc., Perkin Trans. 1, 2002, 191–196
195

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141.64 (C-5), 142.95 (C-3), 145.77 (C-4) and 189.22 (C-1).
Methyl (6Z,8E,10E )-5,12-dihydroxyeicosa-6,8,10-trienoate 2:
LTB3 methyl esters
8 (a) E. J. Corey, A. Marfat, G. Goto and F. Brion, J. Am. Chem. Soc.,
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Under argon, a solution of ButLi (4 mL of a 1.67 M solution
in pentane; 6.68 mmol) was added to a solution of methyl
4-bromoorthobutanoate18 (0.84 g, 3.70 mmol) in dry Et2O (10
mL), cooled to Ϫ75 ЊC. The reaction mixture was stirred for
90 min and a solution of compound 15b (0.23 g, 0.93 mmol) in
dry Et2O (5 mL) was introduced. The reaction mixture was
warmed to 0 ЊC and stirred for 2 h, before treatment with aq.
CH3COOH (5% w/v; 5 mL) and was then washed with water
(5 mL). After extraction with Et2O (3 × 20 mL), the organic
layer was dried (MgSO4) and concentrated. By silica gel column
chromatography [pentane–Et2O 30 : 70 (v/v)] we isolated and
identified the LTB3 methyl esters 2 (0.17 g, 52%) as a colourless
oil. The analyses of LTB3 methyl esters 2 were identical with
those previously described in the case of the sample obtained
from 7b in the first manner.
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