Convenient approach for the synthesis of ONO-LB-457, a potent leukotriene B4 receptor antagonist

Article abstract of DOI:10.1016/j.tet.2020.131740

This study reports a new approach for the synthesis of 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-(5E)-hexen-1-yloxy]phenoxy]pentanoic acid V (ONO-LB-457), previously described by Konno and col. and which is considered a highly potent and orally active

Full text of DOI:10.1016/j.tet.2020.131740

Tetrahedron 77 (2021) 131740
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convenient approach for the synthesis of ONO-LB-457, a potent
leukotriene B4 receptor antagonist
,
,
,
, *
Salha Hamri a d, Jabrane Jouha a c, Asmaa Oumessaoud a b, M.D. Pujol b
,
Mostafa Khouili a , Gerald Guillaumet
Laboratoire de Chimie Organique & Analytique, Universite Sultan Moulay Slimane, Faculte des Sciences et Techniques, BP 523, 23000, Beni-Mellal,
,
**
c, ***
ꢀ
a
ꢀ
ꢀ
ꢀ
Morocco
b
ꢁ
ꢁ
Laboratori Química Farmaceutica, Facultat de Farmacia, 08028, Barcelona, Universitat de Barcelona, Spain
c
ꢀ
ꢀ
ꢀ
Institut de Chimie Organique et Analytique, Universite D’Orleans, UMR-CNRS 7311, BP 6759, Rue de Chartres, 45067, Orleans, Cedex 2, France
Laboratoire de Chimie Organique, Organometallique et Valorisation des Substances Naturelles, Faculte des Sciences, Universite Ibn Zohr, BP 8106, Cite
d
ꢀ
ꢀ
ꢀ
ꢀ
Dakhla, Agadir, 80000, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
This study reports a new approach for the synthesis of 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-
(5E)-hexen-1-yloxy]phenoxy]pentanoic acid V (ONO-LB-457), previously described by Konno and col.
and which is considered a highly potent and orally active LTB4 receptor antagonist. This compound acts
as an inhibitor of aggregation and chemotaxis, in addition to LTB4-induced human neutrophil
degranulation.
Received 4 September 2020
Received in revised form
23 October 2020
Accepted 31 October 2020
Available online 17 November 2020
In this work, the preparation of ONO-LB-457 was proposed through a convergent synthesis focused on
the preparation of two fragments. First, the preparation of 5-hydroxychroman-2-one (4) from 2,6-
dimethoxybenzaldehyde and malonic acid, involving a Knoevenagel reaction, followed by a reduction
of the olefin and intramolecular cyclization catalyzed by Lewis acid (tribromide) was achieved with an
overall yield of 57%. Second, preparation of (E)-6-(4-methoxyphenyl)hex-5-en-1-yl-methanesulfonate
(18) from 5-bromovaleric acid (15) involving a Wittig reaction. The desired compound V (ONO-LB-457)
was obtained by nucleophilic substitution of (E)-6-(4-methoxyphenyl)hex-5-en-1-yl-methanesulfonate
(18) with the ring-opened phenolic diester 14 followed by hydrolysis, in seven steps with an overall yield
of about 11%.
Keywords:
5-Hydroxychroman-2-one
5-Bromovaleric acid
Knoevenagel
Wittig reaction
Leukotriene B4
ONO-LB-457
Inflammatory
© 2020 Elsevier Ltd. All rights reserved.
1. Introduction
(cytokines) that cannot be eliminated or inhibited sufficiently
quickly [7e9]. These cytokines, by following the steps of acute or
Inflammation is a defense reaction of living beings to injury or
excessive or abnormal cell stimulation.
chronic inflammation, can lead to the synthesis of inhibitors or
activators that have a feedback effect on the inflammatory process.
In 1980, the team of Samuelsson described a group of mediators
of inflammation called leukotrienes (LT) [10e12]. Recently, research
was conducted on one of these inflammation mediators, namely,
the leukotriene LTB4, which is a potent activator and chemotactic
for leukocytes. It is involved in many allergic and inflammatory
diseases, such as allergic pulmonary inflammation, mycobacterial
infections and tuberculosis susceptibility [13].
It can result from trauma, burns, radiation or penetration of
external pathogens (viruses, bacteria, parasites, antigens) or self-
antigens (molecules inducing autoimmune antibodies) [1e6]. In
the latter case, the organism is attacked by its own immune system.
An inflammatory immune response involves cells participating in
the immune response (reactive T lymphocytes, helper, suppressor
and T4, T8 cells) but also the production of cellular mediators
This powerful pro-inflammatory lipid derived from arachidonic
acid via the action 5-lipoxygenase and an activator of leukocytes,
particularly granulocytes and T cells, is mediated by two G-coupled
protein receptors, BLT1 and BLT2, high- and low-affinity receptors,
respectively (Fig. 1) [14].
* Corresponding author.
** Corresponding author.
*** Corresponding author.
Previous works describe the role of LTB4 in the development of
E-mail address: mdpujol@ub.edu (M.D. Pujol).
https://doi.org/10.1016/j.tet.2020.131740
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

S. Hamri, J. Jouha, A. Oumessaoud et al.
Tetrahedron 77 (2021) 131740
Fig. 2. Structures of antagonists of LTB4 receptors described in the literature as mol-
ecules that have entered clinical trials [19].
Fig. 1. Biosynthetic pathway of leukotrienes (LTs). PLA2: phospholipase A2; FLAP: five-
lipoxygenase activating protein; 5-LO: 5-lipoxygenase; GSH: glutathione.
airway hyper-responsiveness, severe asthma and exacerbation of
asthma [15e18].
Several studies have demonstrated that leukotrienes (LT), either
cysteinyl LT (CysLT) or LTB4, are important lipid mediators in the
pathophysiology of asthma phenotypes. They identified at least two
receptor subtypes for CysLTs-CysLT1 and CysLT2.
Several antagonists of LTB4 receptors, with various biological
activities, have been reported in the literature [19e26]. Among
these compounds was SC-41930 an LTB4 antagonist with multiple
biological activities (IC50 ¼ 300 nM). Goodnow et al. (see Fig. 2)
cited other compounds such as BIIL-284, which inhibit the action of
LTB4 on BLT1 and/or BLT2 [19].
All these compounds have entered clinical trials for various in-
dications, such as inflammatory diseases and cancers.
According to a structure-activity study carried out using the
conformers of leukotriene B4, joining the carbon atoms C7 and C9 of
the conformer (A) into an aromatic ring system led to the discovery
Fig. 3. Chart 1: Possible conformers of LTB4/Chart 2: Partial stiffening of conformers A
and B.
of benzene analog I (IC50 ¼ >1.0
mM) (Fig. 3) [27].
The compound I showed a high affinity for rat neutrophil LTB4
receptors, but a low affinity for human neutrophils. Further in-
vestigations showed that replacing the aliphatic unit of C-4 to C-9
by an aromatic ring (conformer B) leads to the compound II, which
the aromatic ring of compound (II) in the meta position relative to
the propionic acid chain and replacing the allyl alcohol group by
para-methoxystyrene provides compound (III) which is a potent
LTB4 receptor antagonist (IC50 ¼ 0.09
mM).
is
a
potent antagonist of human neutrophil LTB4 receptors
M).
The grafting of the side chain in the ortho propionic part, rather
than meta, yields the derivative ortho IV (ONO-LB-448), whose
activity is six times greater than that of III.
(IC50 ¼ 0.18
m
Structural analogues of leukotriene B4 have very interesting
pharmacological properties, and are the target of a series of syn-
thetic approaches.
Unfortunately, in vivo, and administered orally, compound III
has an extremely short duration of action, whereas the carboxylic
The introduction of a side chain carrying an amide function on
2

S. Hamri, J. Jouha, A. Oumessaoud et al.
Tetrahedron 77 (2021) 131740
acid V (ONO-LB-457) has an activity comparable to that of com-
pound IV (ONO-LB-448), with sustainable action in vivo, and it is
the most promising compound of the entire series (Fig. 4).
In this report, we describe the synthesis of analogue V (ONO-LB-
457) that has a strong affinity to the LTB4 receptor.
This compound can be considered a lead as an antagonist of the
LTB4 receptor. New structural modifications should allow opti-
mizing its anti-inflammatory capacity.
2. Results and Discussion
The synthesis of ONO-LB-457 in eight steps from 1,3-
cyclohexanedione and ethyl acrylate was described, though
without analytical details, in the patent by Konno et al. (Scheme 1)
[20].
This sequence involves a Michael reaction and aromatization of
the enol-acetate derivative, followed by a cyclization reaction,
thereby providing a 5-hydroxy-chroman-2-one intermediate (4).
Therefore, a simple nucleophilic attack of the phenoxide moiety
on the mesylate derivative leads to the formation of (E)-5-((6-(4-
methoxyphenyl) hex-5-en-1-yl)oxy)chroman-2-one (5), then the
opening of the heterocyclic system gives the O-substituted phenol
ester derivative at the C-6 position of the aromatic ring, (E)-ethyl 3-
(2-hydroxy-6-((6-(4)methoxyphenyl)hex-5-en-1-yl) oxy)phenyl)
propanoate (6).
Scheme 1. Previous work: synthesis of compound
Konno’s group from 1,3-cyclohexane-dione [20].
V (ONO-LB-457) reported by
This intermediate 6 undergoes a second substitution, this time,
with the ethyl 5-bromovalerate motif, giving ONO-LB-457, as
described in the patent after a last saponification step (Scheme 1).
Another strategy for the synthesis of 5-hydroxychroman-2-one
(4) from 1,3-cyclohexanodione (1) and ethyl acrylate, in three steps
with an overall yield of 41%, was reported in 2013 by Sharma’s team
[28] (Scheme 2).
In order to fine-tune the synthesis of the LTB4 receptor antag-
onists, we initially focused on the preparation of the ONO-LB-457
itself, required as a reference for the desired biological tests.
At first, an attempt was made to reproduce the synthesis
described by Konno et al. starting from 1,3-cyclohexanedione [20a]
with the aim of obtaining compound V: ONO-LB-457. However, the
first step of adding cyclohexanedione to ethyl acrylate led to a
mixture of the expected ester and the diester product of the double
Michael addition. Starting with small amounts of cyclohexanone,
the use of NaH as a base offers better results than sodium ethoxide,
but on a multigram scale, a crude reaction difficult to purify was
obtained.
Scheme 2. Preparation of chroman-2-one 4 according to the methodology described
in the literature by Sharma et al. [28].
Subsequently, the aromatization stage of the cyclohexanedione
with a mixture of acid and acetic anhydride [20a], with iodine and
methanol [28a] or with copper chloride in a basic medium [27b]
leads to the expected substituted benzene with yields lower than
40%, yields based on products purified by column chromatography.
It should be noted that in its synthesis Konno et al. they do not
describe the yields of their work [20a] or they indicate the yields of
the compounds without purification by chromatography [27b].
In view of the drawbacks found in these preliminary tests, our
objective focused on the preparation of V: ONO-LB-457 with an
alternative synthesis. The strategy described below was focused
primarily on optimizing the preparation of the 5-hydroxychroman-
2-one 4, starting this time from the commercial compound, 2,6-
dimethoxy-benzaldehyde (11) (see Scheme 3).
The first stage of this synthesis requires the condensation of the
aldehyde 11 with the malonic acid by applying the Doebner-
modified methodology of the Knoevenagel reaction [29e32].
This reaction was conducted in pyridine in presence of catalytic
amount of piperidine (Scheme 4).
The 2,6-methoxycinnamic acid (10), was recently described in a
study carried out by a Chinese team on a traditional herbal of local
origin [33].
Catalytic hydrogenation of the double bond of acid 10 was car-
ried out in the presence of palladium, in acetic acid. The 3-(1,3-
dimethoxybenzen-2-yl)propanoic acid (12) was thus isolated in
82% yield. This reaction was followed by cleavage of the methoxy
Fig. 4. Structural leukotriene B4 analogues.
3

S. Hamri, J. Jouha, A. Oumessaoud et al.
Tetrahedron 77 (2021) 131740
Scheme 6. Synthesis of phenolic diester 14 from 5-hydroxychroman-2-one (4).
Despite this disappointing result, we continued our work by
preparing the trisubstituted homocycle. Ring opening by an attack
at C-2 was not followed by re-cyclization products, as it often is in
the monocyclic series. Ring-opened products were therefore iso-
lated. The opening of the lactone 13 carried out in ethanol at reflux
in the presence of concentrated sulfuric acid, led to the phenolic
diester 14 with 82% of yield (Scheme 6).
Scheme 3. This work: Retrosynthesis of ONO-LB-457 compound prepared from 2,6-
dimethoxybenzaldehyde.
To complete the synthesis of V, the preparation of the inter-
mediate compound (E)-6-(4-methoxyphenyl)hex-5-en-1-yl meth-
anesulfonate (18) was carried out. This compound was obtained in
three steps from 5-bromovaleric acid (15), using the Wittig reaction
conditions in the key step of this sequence (Scheme 7).
The reaction of 5-bromovaleric acid (15) with triphenylphos-
phine gives phosphonium salt, which subsequently allows the
Wittig reaction on anisaldehyde in the presence of LiHMDS [34].
Subsequently, the majority product of the derivative (E)-6-(4-
methoxyphenyl)hex-5-enoic acid (16) was obtained, with a yield
of 62%, and the analytical data is in accordance with the work
carried out by the group of Maryanoff (Scheme 7). [35, 36].
(E)-6-(4-Methoxyphenyl)hex-5-en-1-ol (17) was prepared from
the corresponding carboxylic acid by reduction with lithium
aluminum hydride in tetrahydrofuran. While the mesylate 18 was
obtained directly from the alcohol, (E)-6-(4-methoxyphenyl)hex-5-
en-1-ol (17) applying classical conditions (Scheme 8). Finally,
compound 19 was prepared as indicated in Scheme 8.
The substitution of mesylate (E)-6-(4-methoxyphenyl)hex-5-
en-1-yl methanesulfonate (18), with ethyl 5-(2-(3-ethoxy-3-
oxopropyl)-3-hydroxyphenoxy)-pentanoate (14) previously pre-
pared, in the presence of sodium hydride afforded 19 with an
average yield of 50%.
In this case, 30% of the starting product 14 was recovered, and
was used for a new synthesis of compound 19. The hydrolysis of the
ester derivative 19 in a basic solution of 10% NaOH in EtOH afforded
the desired product V (ONO-LB-457) with 80% yield.
Scheme 4. Preparation of 10.
groups by the action of boron tribromide, leading to an intra-
molecular cyclization reaction to form the desired 5-
hydroxychroman-2-one 4 with 76% yield (Scheme 5). The overall
yield for the preparation of 4 from aldehyde 11 was 57%, much
higher than the described methods of which we are aware.
We subsequently followed the best conditions for the prepara-
tion of ethyl 5-((2-oxochroman-5-yl)oxy)pentanoate (13). A few
preliminary tests of the nucleophilic substitution reaction of ethyl
5-bromovalerate with the 5-hydroxychroman-2-one 4 were carried
out in the presence of potassium carbonate in refluxing acetone.
This proved unsuccessful, with yields below 20%.
The nucleophilic substitution reaction was accomplished,
however, preparing the phenoxide with sodium hydride (NaH) in
N,N-dimethylformamide with 55% of yield of the purified product.
With both pathways, either potassium carbonate (K2CO3) or so-
dium hydride (NaH) as base, we recovered part of the unreacted
starting substrate. In the best case, 41% of the starting material was
recovered with sodium hydride, or 64% when carbonate was used
(Scheme 6).
An increase in the number of NaH equivalents gave only sec-
ondary products, which are due to the presence of the acidic proton
at alpha carbonyl position of 5-hydroxychroman-2-one 4, in addi-
tion to the products of unidentified degradations.
Scheme 7. Synthesis of (E)-6-(4-methoxyphenyl)hex-5-en-1-yl methanesulfonate (18)
from 5-bromovaleric acid (15).
Scheme 5. Preparation of 5-hydroxychroman-2-one 4.
4

S. Hamri, J. Jouha, A. Oumessaoud et al.
Tetrahedron 77 (2021) 131740
aqueous HCl to pH ¼ 2 until crystal appeared. The crystal was
filtered, washed with water and dried. Yield: 92%; mp: 152e154 ꢀC [
literature: mp: 154e156 ꢀC [28]; mp: 151e153 ꢀC [29]; IR (cm-1):
3269 (OH), 1702 (C]O), 1091 (CeO); 1H NMR (CDCl3 þ D2O)
d
(ppm), 8.10 (d, J ¼ 16.1 Hz, 1H), 7.13 (t, 1H, J ¼ 8.3 Hz), 6.80 (d,
J ¼ 16.1 Hz, 1H), 6.60 (d, 2H, J ¼ 8.3 Hz), 3.85 (s, 6H); HRM:
ESI(ꢁ)(M ꢁ 1) cald for C11H11O4, 207.0657, found, 207.0660
[29e32].
4.2.2. 3-(2,6-Dimethoxyphenyl)propanoic acid (12)
To a solution of the corresponding previously obtained acid 10
(4.26 g, 20.4 mmol) in acetic acid (70 mL) was added 10% Pd/C
(2.12 g). The reaction mixture was stirred under hydrogen atmo-
sphere until the complete consumption of the starting material
(4 h). The mixture was filtered through Celite and evaporation of
the solvent in vacuo provided a crude residue, which was purified
by chromatography on silica gel using (MeOH/CH2Cl2, 6/94) to
afford compound 12 as a white solid. Yield: 82%; mp: 109e111 ꢀC;
IR (cmꢁ1): 3772-2556 (OH), 1696 (C]O); 1H NMR (DMSO þ D2O)
Scheme 8. Synthesis of V (ONO-LB-457) from ethyl 5-(2-(3-ethoxy-3-oxopropyl)-3-
hydroxyphenoxy)pentanoate.
3. Conclusion
The results obtained in the attempts to reproduce the synthetic
route used by Konno et al. for the preparation of the ONO-LB-457
compound have led us to apply alternative routes.
d
(ppm),7.13 (t, 1H, J ¼ 8.3 Hz), 6.60 (d, 2H, J ¼ 8.3 Hz), 3.75 (s, 6H),
2.79 (t, 2H, J ¼ 8.0 Hz), 2.27 (t, 2H, J ¼ 8.0 Hz); HRM: ESI(ꢁ)(M ꢁ 1)
Knoevenagel condensation between aldehyde and malonic acid,
followed by double reduction and subsequent deprotection and
cyclization, have allowed the chroman-2-one 4 to be achieved with
an overall yield of 57%. It has also been shown that the Wittig re-
action allows the mesylated key intermediate 18 to achieve an
overall yield of 44% from 5-bromovaleric acid in three steps.
The preparation of ONO-LB-457, which is a leukotriene B4 re-
ceptor antagonist, has been achieved by a convergent synthesis
different from that previously described by other authors for the
same compound. The number of stages has been reduced and the
overall yields turns out to be higher.
cald for C11H13O4, 209.0814, found, 209.0821.
4.2.3. 3,4-Dihydro-5-hydroxychromen-2-one (4)
Under nitrogen atmosphere, boron tribromide (2.24 mL;
23.75 mmol, 2.5 eq.) was slowly added to a solution of the corre-
sponding acid 12 (2 g, 9.5 mmol) in (150 mL) anhydrous CH2Cl2. The
reaction mixture was stirred at room temperature for 1 h and
poured onto iced water. The aqueous layer was extracted three
times with CH2Cl2, and the combined organic layers were dried
over MgSO4, filtered, and concentrated in vacuo. The residue was
purified by chromatography on silica gel using a CH2Cl2 to afford
the desired product 4 as a white solid. Yield 76%; mp: 170e172 ꢀC;
IR (cmꢁ1): 3261 (OH), 1723 (C]O); 1H NMR (CDCl3 þ D2O)
4. Experimental
d
(ppm),7.10 (t, 1H, J ¼ 8.2 Hz), 6.67 (d, 1H, J ¼ 8.2 Hz), 6.57 (d, 1H,
4.1. General experimental
J ¼ 8.2), 3.00 (t, 2H, J ¼ 7.5 Hz), 2.78 (t, 2H, J ¼ 7.5 Hz). 13C NMR
(CDCl3 þ D2O)
d (ppm), 17.6, 29.0, 107.1, 109.4, 129.5, 152.6, 157.1,
All reagents were purchased from commercial suppliers and
were used without further purification. The reactions were moni-
tored by thin-layer chromatography (TLC) analysis using silica gel
(60 F254) plates. Compounds were visualized by UV irradiation at
256 or 365 nm. Flash column chromatography was performed on
silica gel 60 (230e400 mesh, 0.040e0.063 mm). Melting points
(mp [ꢀC]) were taken on samples in open capillary tubes. Infrared
spectra of compounds were recorded with a Thermo Scientific
Nicolet iS10 instrument. 1H NMR spectra were recorded with a
Bruker spectrometer at 400 MHz. Chemical shifts are given in parts
per million (ppm) from tetramethylsilane (TMS) as internal stan-
dard in CDCl3, and the residual peak of DMSO in [D6] DMSO. The
following abbreviations are used for the 1H NMR spectra multi-
plicities: br. s: broad singlet, s: singlet, d: doublet, t: triplet, q:
quartet, qt: quintuplet, m: multiplet. Coupling constants (J) are
reported in Hertz [Hz]. High Resolution Mass Spectrometry data
(HRMS) were adquired using a LC/MSD-TOF analyser in methanol
or acetonitrile.
171.2; HRM: ESI(þ)(Mþ1) cald for C9H9O3, 165.0552, found,
165.0559.
4.3. Synthesis of phenolic diester 14
4.3.1. Ethyl 5-(3,4-dihydro-2-oxo-2H-chromen-5-yloxy)pentanoate
(13)
Sodium hydride (80% w/w, 0.11 g, 3.67 mmol) was added portion
wise to a stirred solution of 5-hydroxychroman-2-one (4) (0.55 g,
3.3 mmol) in dry DMF (10 mL). The solution was stirred under ni-
trogen atmosphere at room temperature for 20 min and a solution
of ethyl 5-bromovalerate (0.64 mL, 4.0 mmol) in dry DMF (1 mL)
was added dropwise. The resulting mixture was stirred for 1 h at
60 ꢀC, then poured onto iced water and the solution was slowly
acidified by addition of aqueous (1 N) HCl. The aqueous layer was
extracted three times with AcOEt, and the combined organic layers
were dried over MgSO4, filtered, checked with TLC plate and
concentrated in vacuo. The resulting residue was purified by silica
gel chromatography using a mixture (AcOEt/EP, 30/70) to separate
the starting material (41%) of the desired compound 13 as a white
solid. Yield 55%; mp: 57e59 ꢀC; IR (Nujol) (cmꢁ1): 1765 and 1721
4.2. Synthesis of the 3,4-dihydro-5-hydroxy-chromen-2-one 4
4.2.1. (E)-3-(2,6-Dimethoxyphenyl)acrylic acid (10)
To a solution of 2,5-dimethoxy-benzaldehyde (3.4 g, 20.0 mmol)
in 15 mL of pyridine, piperidine (0.4 mL) and the malonic acid
(4.26 g, 41.0 mmol) was added. The reaction mixture was stirred at
85 ꢀC for 1 h, and 3 h at 110 ꢀC. The solid residue was solubilized in
160 mL of water. The solution was slowly acidified by addition of
(C]O); 1H NMR (CDCl3)
d
(ppm) 7.17 (t, 1H, J ¼ 8.2 Hz), 6.68 (d, 1H,
J ¼ 8.2 Hz), 6.63 (d, 1H, J ¼ 8.2 Hz), 4.14 (q, 2H, J ¼ 7.2 Hz), 4.00 (m,
2H), 2.98 (t, 2H, J ¼ 7.6 Hz), 2.75 (t, 2H, J ¼ 7.6 Hz), 2.38 (m, 2H), 1.85
(m, 4H), 1.26 (t, 3H, J ¼ 7.2 Hz); HRM: ESI(þ)(Mþ1) cald for
C
16H21O5, 293.1389, found, 293.1392.
5

S. Hamri, J. Jouha, A. Oumessaoud et al.
Tetrahedron 77 (2021) 131740
4.3.2. Ethyl 5-[2(3-ethoxy-3-oxopropyl)-3-hydroxyphenoxy]
pentanoate (14)
2.22 (q, 2H, J ¼ 7.1 Hz), 1.69e1.46 (m, 4H); HRM: ESI(þ)(Mþ1) cald
for C13H18O2, 206.1307, found, 206.1310.
To a solution of ester 13 (0.542 g, 1.86 mmol) in ethanol (15 mL),
4 mL of sulfuric acid was slowly added while stirring. The reaction
mixture was stirred at 60 ꢀC for 4 h, and then partitioned between
AcOEt and water. The aqueous layer was extracted three times with
AcOEt. The combined organic layers were washed with water and
brine, dried over MgSO4, and concentrated in vacuo. The solid
residue was purified by chromatography on silica gel using (Ether/
CH2Cl2, 1/99) to afford the desired product 14 as a solid. Yield 82%;
mp: 67e68 ꢀC; IR (cmꢁ1): 3376 (OH),1731 and 1713 (C]O); 1H NMR
4.4.3. (E)-6(4-methoxyphenyl)-5-hexenyl methane sulfonate (18)
At 0 ꢀC, mesyl chloride (0.8 mL, 10.33 mmol) was added drop-
wise to a stirred solution of the alcohol 17 (1.66 g, 8.05 mmol) in
CH2Cl2 (60 mL) and (4.7 mL). The solution was stirred under ni-
trogen atmosphere at 0 ꢀC for 1 h and was hydrolyzed with water.
The aqueous phase was extracted with CH2Cl2. The combined
organic layers were dried with MgSO4, the solvent was evaporated,
and the crude product was purified by chromatography on silica gel
using a mixture (AcOEt/EP, 46/54) to afford the desired product 18
as crystallizing oil. Yield 94%; mp ¼ 32e33 ꢀC; IR (cmꢁ1): 2983 (CH),
(CDCl3 þ D2O) (ppm),7.06 (t,1H, J ¼ 8.1 Hz), (d,1H, J ¼ 8.1 Hz), 6.42
d
(d, 1H, J ¼ 8.1 Hz), 4.14 (m, 4H), 3.95 (m, 2H), 2.90 (t, 2H, J ¼ 6.6 Hz),
2.70 (t, 2H, J ¼ 6.6 Hz), 2.39 (m, 2H), 1.83 (m, 4H), 1.25 (m, 6H);
HRM: ESI(þ)(Mþ1) cald for C18H27O6, 339.1808, found, 339.1807.
1605 (C]C); 1H NMR (CDCl3)
d
(ppm), 7.27 (d, 2H, J ¼ 8.7 Hz), 6.83
(d, 2H, J ¼ 8.7 Hz), 6.35 (d, 1H, J ¼ 15.8 Hz), 6.09e5.96 (m, 1H), 4.25
(t, 2H, J ¼ 6.5 Hz), 3.80 (s, 3H), 3.00 (s, 3H), 2.25 (q, 2H, J ¼ 7.3 Hz),
1.81 (q, 2H, J ¼ 7.3 Hz), 1.59 (q, 2H, J ¼ 7.5 Hz); HRM: ESI(þ)(Mþ1)
cald for C14H20O4S, 284.1082, found, 284.1087.
4.4. Synthesis of (E)-6-(4-methoxyphenyl)hex-5-en-1-yl
methanesulfonate (18)
4.4.1. (E)-6-(4-Methoxyphenyl)hex-5-enoic acid (16)
4.5. Synthesis of V (ONO-LB-457) from phenolic diester 14
The phosphonium salt, (4-carboxybutyl)triphenyl phosphonium
bromide was previously prepared from 5-bromovaleric acid (15)
and triphenylphosphine according to the following procedure: In a
250 mL flask equipped with a refrigerant containing 10.0 g of 5-
bromovaleric acid 15 (1 eq, 55.2 mmol), 16.0 g of triphenylphos-
phine (1.1 eq., 61.0 mmol) and 150 mL of xylene were added. The
mixture was heated at reflux for 2 h with stirring. After cooling the
mixture to room temperature, the white precipitate formed was
filtered on sintered glass and washed with acetone. After drying,
15.92 g of (4-carboxybutyl)triphenyl-phosphonium bromide were
recovered as a white solid with 65% yield.
4.5.1. Ethyl 5-(2-(3-ethoxy-3-oxopropyl)-3-{[(E)-6(4-
methoxyphenyl)-5-hexenyl]oxy}-phenoxy)penta neate (19)
Sodium hydride (0.173 g, 3.23 mmol) was added portionwise to
a stirred solution of phenol 14 (0.79 g, 2.43 mmol) in dry DMF
(16 mL). The solution was stirred under nitrogen atmosphere at
room temperature for 15 min and a solution of the mesylate 18
(0.55 g, 1.94 mmol) in dry DMF (4 mL) was added dropwise. The
resulting mixture was stirred for 2 h at 60 ꢀC, then poured onto iced
water and the solution was slowly acidified by addition of aqueous
(1 N) HCl. The aqueous layer was extracted three times with AcOEt,
and the combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by chroma-
tography on silica gel using a (CH2Cl2) to afford the desired product
19 as a colorless oil. Yield 50%; IR (cmꢁ1): 1738 (C]O), 1650 (C]C);
Thereafter, to
a stirred solution of hexamethyldisilazane
(12.23 mL, 58.0 mmol) in anhydrous THF (60 mL) under nitrogen, n-
butyllithium (1.6 in hexane, 33.75 mL, 54 mmol) was added at 0 ꢀC.
After 30 min at 0 ꢀC, a solution of (4-carboxybutyl)triphenylphos-
phonium bromide (9 g, 20.31 mmol) in anhydrous THF (100 mL)
was added via cannula slowly. The solution was vigorously stirred
for 30 min, and a solution of anisaldehyde (3 mL, 24.72 mmol) was
added. The resulting mixture was stirred for 2 h and subsequently
quenched with water (160 mL). The homogeneous solution was
acidified to pH ¼ 2 with an aqueous solution of sulfuric acid. The
aqueous layer was extracted with AcOEt, and the combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by chromatography on silica gel using a
mixture (AcOEt/EP/AcOH, 90/9/1) to afford the desired product 16
as a solid. Yield 62%; mp: ¼ 76e78 ꢀC; IR (cmꢁ1): 3730-2500 (OH),
1H NMR (CDCl3)
d
(ppm), 7.27 (d, 2H, J ¼ 8.8 Hz), 7.07 (t, 1H,
J ¼ 8.1 Hz), 6.82 (d, 2H, J ¼ 8.8 Hz), 6.48 (m, 2H), 6.35 (d, 1H,
J ¼ 15.4 Hz), 6.14e6.01 (m, 1H), 4.09 (m, 4H), 3.96 (m, 4H), 3.79 (s,
3H), 3.02 (t, 2H, J ¼ 8.1 Hz), 2.49 (t, 2H, J ¼ 8.1 Hz), 2.38 (m, 2H), 2.25
(q, 2H, J ¼ 7.3 Hz), 1.83 (m, 6H), 1.66 (q, 2H, J ¼ 7.4 Hz), 1.23 (m, 6H);
HRM: ESI(þ)(Mþ1) cald for C31H43O7, 527.3009, found, 527.3011.
4.5.2. 5-(2-(2-Carboxyethyl)-4-meyhoxy-3-{[(E)-6-(4-methoxy-
phenyl)-5-hexenyl]-oxy}-phenoxy)-pentanoic acid (V) (ONO-LB-
457)
To a solution of ester 19 (0.62 g, 1.17 mmol) in ethanol (40 mL),
10% the potassium hydroxide (0.7 g, 17.57 mmol/in 14 mL water)
was slowly added. The reaction mixture was stirred for 24 h min at
room temperature and was hydrolyzed with water. The aqueous
phase was extracted with CH2Cl2. The combined organic layers
were washed with water and brine, dried over MgSO4, and
concentrated in vacuo. The solid residue was purified by chroma-
tography on silica gel using a mixture (MeOH/CH2Cl2, 10/90) to
1709 (C]O), 1611 (C]C); 1H NMR (CDCl3 þ D2O)
d (ppm), 7.26 (d,
2H, J ¼ 8.7 Hz), 6.83 (d, 2H, J ¼ 8.7 Hz), 6.35 (d, 1H, J ¼ 15.7 Hz),
6.10e5.96 (m, 1H), 3.08 (s, 3H), 2.41 (t, 2H, J ¼ 7.4 Hz), 2.26 (q, 2H,
J ¼ 7.4 Hz), 1.81 (q, 2H, J ¼ 7.4 Hz).
4.4.2. (E)-6(4-methoxyphenyl)-5-hexen-1-ol (17)
Lithium aluminum hydride (2 g, 52.7 mmol) in anhydrous THF
(100 mL) was added portion wise at 0 ꢀC to a stirred solution of acid
16 (2.79 g, 12.68 mmol) in 100 mL of THF. The solution was stirred
under nitrogen atmosphere at 25 ꢀC for 4 h and poured onto iced
water. Solution of KOH (3 M, 2 mL) and 6.75 mL water were added
and the reaction mixture was stirred for 1 h. The resulting sus-
pension was filtered. The filtrate was dried over MgSO4; the solvent
was removed in vacuo. The residue was purified by chromatog-
raphy on silica gel using a mixture (AcOEt/EP, 50/50) to afford the
desired product 17 as a white solid. Yield 75%; mp ¼ 57e60 ꢀC; IR
(cmꢁ1): 3614-3102 (OH), 1606 (C]C); 1H NMR (CDCl3 þ D2O)
afford the desired product
V as white crystals. Yield 80%;
mp ¼ 146e148 ꢀC; IR (cmꢁ1): 3640-3000 (OH), 1712 (C]O). 1H
NMR (CDCl3þ D2O)
d
(ppm), 7.24 (d, 2H, J ¼ 8.8 Hz), 7.00 (t, 1H,
J ¼ 8.1 Hz), 6.80 (d, 2H, J ¼ 8.8 Hz), 6.43 (d, 1H, J ¼ 8.1 Hz), 6.37 (d,
1H, J ¼ 8.1 Hz), 6.30 (d, 1H, J ¼ 15.4 Hz), 6.02 (m, 1H), 3.94e3.78 (m,
4H), 3.76 (s, 3H), 2.97 (m, 2H), 2.45 (m, 2H), 2.33 (m, 2H), 2.19 (q,
2H, J ¼ 7.3 Hz), 1.90e1.63 (m, 6H), 1.56 (m, 2H); SM (IC/NH3): m/
z ¼ 470 (M); 471 (Mþ1).
Declaration of competing interest
d
(ppm), 7.26 (d, 2H, J ¼ 8.7 Hz), 6.83 (d, 2H, J ¼ 8.7 Hz), 6.34 (d, 1H,
J ¼ 15.7 Hz), 6.13e6.00 (m, 1H), 3.79 (s, 3H), 3.68 (t, 2H, J ¼ 6.4 Hz),
The authors declare that they have no known competing
6

S. Hamri, J. Jouha, A. Oumessaoud et al.
Tetrahedron 77 (2021) 131740
X. Wei, Y.L. Li, J. O’Neil, R. Marcano, K. Pozzani, T. Molinaro, J. Santiago,
L. Singer, M. Hargaden, D. Moore, A.R. Catala, L.C.F. Chao, G. Hermann,
R. Venkat, H. Mancebo, L.M. Renzetti, J. Med. Chem. 53 (2010) 3502e3516.
[20] a) M. Konno, T. Nakae, N. Hamanaka, Eur. Pat. Appl. 115 (1991) 28892j,
0405116B1, Ono Pharmaceutical Co., Ltd. (January 02, 1991); Chem. Abstr.;
b) M. Konno, T. Nakae, S. Sakuyama, Y. Odagaki, H. Nakai, N. Hamanaka,
Bioorg. Med. Chem. 5 (1997) 1649e1674.
[21] M. Konno, S. Sakuyama, T. Nakae, N. Hamanaka, T. Miyamoto, A. Kawasaki,
Leukotriene Res. 21A (1991) 411e414.
[22] S.W. Djuric, P.W. Collins, P.H. Jones, R.L. Shone, B.S. Tsai, D.J. Fretland,
G.M. Butchko, D. Villani-Price, R.H. Keith, J.M. Zemaitis, L. Metcalf, R.F. Bauer,
J. Med. Chem. 32 (1989) 1145e1147.
financial interest or potential relationships that could have
appeared to influence the work reported in this paper.
Acknowledgements
This work was supported by ICOA (Institut de Chimie Organique
et Analytique), University of Orleans (France).
Appendix A. Supplementary data
[23] A.H. Lin, J. Morris, D.G. Wishka, R.R. Gorman, Ann. N. Y. Acad. Sci. 524 (1988)
196e200.
[24] K. Kashikawa, N. Tateishi, T. Maruyama, R. Seo, M. Toda, T. Miyamoto, Pros-
taglandins 44 (1992) 261e275.
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131740.
[25] B.S. Tsai, R.H. Keith, D. Villani-Price, J.F. Kachur, D.C. Yang, S.W. Djuric, S. Yu,
J. Pharmacol. Exp. Therapeut. 268 (1994) 1499e1505.
[26] F.-C. Huang, W.-K. Chan, J.D. Warus, M.M. Morrissette, K.J. Moriarty,
M.N. Chang, J.J. Travis, L.S. Mitchell, G.W. Nuss, C.A. Sutherland, J. Med. Chem.
35 (1992) 4253e4255.
[27] (a) M. Konno, T. Nakae, S. Sakuyama, K. Nishizaki, Y. Odagaki, H. Nakai,
N. Hamanaka, Bioorg. Med. Chem. 5 (1997) 1621e1647;
(b) M. Konno, T. Nakae, S. Sakuyama, K. Imaki, H. Nakai, N. Hamanaka, Synlett
(1997) 1472e1474.
[28] (a) D. Sharma, C.B. Reddy, A.K. Shil, R.P. Saroach, P. Das, Mol. Divers. 17 (2013)
651e659;
References
[1] P. Borgeat, B. Samuelsson, Proc. Natl. Acad. Sci. U.S.A. 76 (1979) 3213e3217.
[2] R.J. Smith, S.S. Iden, B.J. Bowman, Inflammation 8 (1984) 365e384.
[3] M.J.H. Smith, A.W. Ford-Hutchinson, M.A. Bray, J. Pharm. Pharmacol. 32 (1980)
517e518.
[4] N.D. Kim, A.D. Luster, Sci. World J. 7 (2007) 1307e1328.
[5] A. Sala, G. Folco, R.C. Murphy, Pharmacol. Rep. 62 (2010) 503e510.
[6] G. Folco, R.C. Murphy, Pharmacol. Rev. 58 (2006) 375e388.
[7] D.M. Tobin, F.J. Roca, S.F. Oh, R. McFarland, T.W. Vickery, J.P. Ray, D.C. Ko,
Y. Zou, N.D. Bang, T.T. Chau, J.C. Vary, T.R. Hawn, S.J. Dunstan, J.J. Farrar,
G.E. Thwaites, M.C. King, C.N. Serhan, L. Ramakrishnan, Cell 148 (2012)
434e446.
(b) D. Sharma, A.K. Shil, B. Singh, P. Das, Synlett 23 (2012) 1199e1204;
(c) 21. P. Das, D. Sharma, B. Singh (2011). WO/2011/117881. (d) D. Sharma,
Bandna, C.B. Reddy, S. Kumar, A.K. Shil, N.R. Guha, P. Das, RSC Adv. 3 (2013)
10335e10340;
(e) J.M. Kim, K.Y. Lee, J.N. Kim, Bull. Kor. Chem. Soc. 24 (2003) 1057e1058,
https://doi.org/10.5012/bkcs.2003.24.8.1057;
[8] C.N. Serhan, Annu. Rev. Immunol. 25 (2007) 101e137.
[9] J.M. Dayer, S. Demczuk, Springer Semin. Immunopathol. 7 (1984) 387e413.
[10] B. Samuelsson, S. Hammarstrom, R.C. Murphy, P. Borgeat, Allergy 35 (1980)
€
(f) L. Zuo, S. Yao, W. Wang, W. Duan, Tetrahedron Lett. 49 (2008) 4054e4056.
D.L. Terrian, T. Mohammad, H. Morrison, J. Org. Chem. 60 (1995) 1981-1984.
[29] H.A. Shah, R.C. Shah, J. Chem. Soc. (1938) 1832e1833.
[30] M. Tanaka, O. Oota, H. Hiramatsu, K. Fujiwara, Bull. Chem. Soc. Jpn. 61 (1988)
2473e2479.
375e381.
[11] B. Samuelsson, Angew. Chem. Int. Ed. 21 (1982) 902e910.
[12] P. Sirois, S. Roy, P. Borgeat, S. Picard, P. Vallerand, Prostag. Leukotr. Med. 8
(1982) 157e170.
[13] A. Bafica, C.A. Scanga, C. Serhan, F. Machado, S. White, A. Sher, J. Aliberti, J. Clin.
Invest. 115 (2005) 1601e1606.
[14] K.A. Lundeen, B. Sun, L. Karlsson, A.M. Fourie, J. Immunol. 177 (2006)
3439e3447.
[15] T.S. Hallstrand, W.R. Henderson Jr., Curr. Opin. Allergy Clin. Immunol. 10
(2010) 60e66.
ꢀ
[31] O.B. Berryman, A.C. Sather, A. Lledo, J. Rebek Jr., Angew Chem. Int. Ed. Engl. 50
(2011) 9400e9403.
[32] Y. Bai, X. He, Y. Bai, Y. Sun, Z. Zhao, X. Chen, B. Li, J. Xie, Y. Li, P. Jia, X. Meng,
Y. Zhao, Y. Ding, C. Xiao, S. Wang, J. Yu, S. Liao, Y. Zhang, Z. Zhu, Q. Zhang,
Y. Zhao, F. Qin, Y. Zhang, X. Wei, M. Zeng, J. Liang, Y. Cuan, G. Shan, T.-P. Fan,
B. Wu, X. Zheng, Eur. J. Med. Chem. 183 (2019) 111650e111677.
[33] D.M. Gapinski, B.E. Mallet, L.L. Froelich, W.T. Jackson, J. Med. Chem. 33 (1990)
2798e2807.
[34] B.E. Maryanoff, B.A. Duhl-Emswiler, Tetrahedron Lett. 22 (1981) 4185e4188.
[35] B.E. Maryanoff, A.B. Reitz, B.A. Duhl-Emswiler, Tetrahedron Lett. 24 (1983)
2477e2480.
[16] P. Montuschi, Pharmaceuticals 3 (2010) 1792e1811.
[17] P. Montuschi, A. Sala, S.-E. Dahlen, G. Folco, Drug Discov. Today 12 (2007)
ꢀ
404e412.
[18] S.E. Dahlen, Eur. J. Pharmacol. 533 (2006) 40e56.
[19] R.A. Goodnow Jr., A. Hicks, A. Sidduri, A. Kowalczyk, R. Dominique, Q. Qiao,
J.P. Lou, P. Gillespie, N. Fotouhi, J. Tilley, N. Cohen, S. Choudhry, G. Cavallo,
S.A. Tannu, J.D. Ventre, D. Lavelle, N.S. Tare, H. Oh, M. Lamb, G. Kurylko,
R. Hamid, M.B. Wright, A. Pamidimukkala, T. Egan, U. Gubler, A.F. Hoffman,
[36] B.E. Maryanoff, A.B. Reitz, B.A. Duhl-Emswiler, J. Am. Chem. Soc. 107 (1985)
217e226.
7