Stereoselective synthesis of two highly potent 5-oxo-ETE receptor antagonists

Article abstract of DOI:10.1016/j.tetlet.2015.10.097

Enantioselective synthesis of highly potent 5-oxo-ETE receptor antagonists 5a and 6a with a high level of enantiomeric purity is described. The main feature of this work is the simple and efficient synthesis of the bi-functionalized 3-(S)-methyl-pentanedi

Full text of DOI:10.1016/j.tetlet.2015.10.097

Tetrahedron Letters 56 (2015) 6896–6899
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of two highly potent 5-oxo-ETE receptor
antagonists
a
a
a
b
b
Chintam Nagendra Reddy , Qiuji Ye , Shishir Chourey , Sylvie Gravel , William S. Powell ,
Joshua Rokach
a
a,
⇑
Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 West University Boulevard, Melbourne, FL 32901, USA
Meakins-Christie Laboratories, Centre for Translational Biology, McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantioselective synthesis of highly potent 5-oxo-ETE receptor antagonists 5a and 6a with a high level of
enantiomeric purity is described. The main feature of this work is the simple and efficient synthesis of the
bi-functionalized 3-(S)-methyl-pentanedioic acid monomethyl ester (24) with the enantiomeric ratio of
S/R:98.4/1.6. We investigated the asymmetric conjugate addition of MeMgBr to 5-Benzyloxy-pent-2-
enoic acid methyl ester (23) catalyzed by the CuBr/(S)-Tol-BINAP system, and optimized the reaction con-
ditions toward regioselectivity and high enantioselectivity.
Received 27 October 2015
Accepted 28 October 2015
Available online 2 November 2015
Keywords:
5
-Oxo-ETE
Ó 2015 Published by Elsevier Ltd.
Eosinophils
Conjugate addition
(S)-Tol-BINAP
Introduction
(PLE) to obtain the chiral synthon 8,5,6 which gave an enantiomeric
ratio of R/S:90/10. This synthon was used for the synthesis of both
5
-Oxo-ETE is the most powerful chemoattractant for human
the R and S enantiomers as shown in Scheme 1. A limitation of this
method is that the enantiomeric ratio is only ꢀ90/10 (S/R) for both
5a and 6a. Furthermore, this procedure is not well suited for the
larger scale synthesis of the active antagonists 5a and 6a, which
we require for further in vivo evaluation.
1
eosinophils among lipid mediators and could potentially play an
important role in the infiltration of these cells into the lungs in
asthma. It is formed by oxidation of the 5-lipoxygenase (5-LO) pro-
duct 5S-hydroxy-6,8,11,14-eicosatetraenoic acid (5S-HETE) by 5-
hydroxyeicosanoid dehydrogenase (5-HEDH) (Fig. 1).
Various other syntheses of the chiral C5-synthon have also been
The actions of 5-oxo-ETE are mediated by the selective
Gi-protein coupled OXE receptor (OXE-R).2 To prevent allergen-
induced eosinophil accumulation in the lungs we have synthesized
two potent and selective OXE-R antagonists, 5 and 6.3 An essen-
tial component of both antagonists is the 3-methyl-5-oxovalerate
side chain, which contains one asymmetric center. Even minor
alterations of this side chain result in major losses in antagonist
potency.
reported, all using 3-methyl glutaric anhydride as a starting mate-
7–13
rial.
In the present approach (Scheme 2) we elected to use an
inexpensive commercial catalyst for the construction of an asym-
,4
metric center. We settled for (S)-Tol-BINAP for the enantioselective
conjugate addition of MeMgBr to an
a
,b-unsaturated ester.14 We
decided to explore this method for our purpose, which required a
C5-bifunctional synthon with one end to be attached to the indole
and the other bearing the carboxylic acid group.
Chiral HPLC isolation of the enantiomers of the racemic 5 and 6
revealed that the utmost activity resides on only one of the
enantiomers for both the compounds.3 We synthesized both the
enantiomers to identify the active isomer, and found that the
Here, we report the development of the conjugate addition of
MeMgBr to the
a,b-unsaturated ester 23 to obtain the chiral syn-
thon 24 with a high level of enantioselectivity, and its application
in the synthesis of the highly potent OXE-R antagonists 5a and 6a.
(
S)-isomer is over 300 times more potent than the (R)-isomer in
4
both the series (Fig. 2).
Results and discussion
Our previous synthesis of the enantiomers of 5 and 6 (5a, 5b, 6a,
and 6b) commenced with the stereoselective hydrolysis of a sym-
metrical dimethyl ester of glutaric acid 7 using pig liver esterase
We first synthesized the precursor of 24, the
a,b-unsaturated
ester 23 from commercial 1,3-propandiol 20 (Scheme 2). One end
of the symmetrical diol 20 was selectively protected with the
benzyl group to obtain 21. The PCC oxidation of the free alcohol
⇑
Corresponding author. Tel.: +1 321 674 7329; fax: +1 321 674 7743.
E-mail address: jrokach@fit.edu (J. Rokach).
http://dx.doi.org/10.1016/j.tetlet.2015.10.097
040-4039/Ó 2015 Published by Elsevier Ltd.
0

C. Nagendra Reddy et al. / Tetrahedron Letters 56 (2015) 6896–6899
6897
CO H
2
5
-LO
CO H
Peroxidase
CO H
5-HEDH
NADP+
CO H
2
OXE
Eosinophil
2
2
OOH
OH
O
Receptor
chemotaxis in
lungs
2
4
1
3
5
S-HPETE
5
-Oxo-ETE
OXE-R
Antagonist
AA
5
-HETE
Figure 1. Biochemical formation of 5-oxo-ETE from AA.
O
CO2H
N
Cl
Cl
CO H
2
O
N
5
6
(
IC50, 28 nM)
(IC50, 28 nM)
Chiral resolution
O
O
CO2H
CO H
2
Cl
(
S)
N
(R)
Cl
(R)
Cl
N
Cl
(
S)
CO H
6a
CO H
6b
2
2
N
N
O
O
5a
5b
(
IC50, 7 nM)
(
IC50, 6 nM)
(IC50, 2700 nM)
(IC50, 2200 nM)
Figure 2. Chiral resolution of the racemic lead compounds 5 and 6.5
O
Cl
Cl
O
CO2H
CO2Me
CO2Me
N
Cl
Cl
(R)
1
0
d
N
c
N
11
5b
O
O
O
O
O
O
a
b
HO
OCH3
O
Cl
OCH3
H3CO
OCH3
8
9
7
N
H
12
f
Si
g
OH
Cl
N
N
(R)
e
Cl
1
4
CO2H
O
O
O
O
O
OH
13
6b
(
S)
h
Si
Si
O
O
O
1
5
16
i
O
O
O
CO2H
l
O
O
j
k
m
Si
Cl
(S)
Cl
O
Si
(S)
N
O
O
Cl
N
N
N
10 Cl
O
12
Cl
Si
CO2H
5a
18
17
O
O
19
6a
Scheme 1. Synthesis of the enantiomers of 5 and 6 (5a, 5b, 6a, and 6b).5 Reagents and conditions: (a) PLE, KH
CH Cl , rt, 3 h, 90%; (c) Me AlCl, CH Cl , rt, 1 h, 89.5%; (d) LiOH, i-PrOH/H O (4:1), rt, 24 h, 89%; (e) t-BuOK, CH Cl
DMAP, CH Cl , rt, 10 h, 90%; (h) LiOH, i-PrOH/H O (4:1), rt, 7 h, 60%; (i) (COCl) , cat. DMF, CH Cl , rt, 3 h, 89%; (j) 12, t-BuOK, CH
.5 h, 80%; (l) 10, Me AlCl, CH Cl , 0 °C–rt,1 h, 25%; (m) LiOH, i-PrOH/H O (4:1), rt, 24 h, 85%.
PO
buffer, À78 to 0 °C, 20 h, 89.6%; (b) (COCl)
, cat. DMF,
2
4
2
2
2
2
2
2
2
2
2
, 0 °C–rt, 7 h, 60%; (f) 6 N HCl, THF, reflux, 7 h, 60%; (g) DCC,
Cl , 0 °C–rt, 6 h, 60%; (k) TiCl , CH Cl , 0 °C–rt,
2
2
2
2
2
2
2
2
4
2
2
0
2
2
2
2
2
1 gave the aldehyde 22. This was followed by a stabilized Wittig
along with 50% of the side product 30 (Entry 4). Chiral HPLC anal-
ysis of 24 obtained from this reaction showed the enantiomeric
ratio as S/R:83.3/16.7. Similar results in terms of the enantioselec-
tivity (S/R:84.3/15.7) and yield (50%) for 24 were obtained with
4.5 mol % (S)-Tol-BINAP, 3 mol % CuBr, and 3.2 equiv MeMgBr
(Entry 5). Further lowering the amount of CuBr improved the enan-
tiomeric ratio dramatically, affording S/R:97.5/2.5 with 2.5 mol %
(Entry 6) and S/R:98.4/1.6 with 2 mol % (Entry 7), (Scheme 2).
The reaction is highly reproducible, and we routinely obtain the
desired product 24 with the enantioselectivity of 98–99%.
14
reaction to afford 23 in a high yield (90%).
Our next step, the addition of MeMgBr to the
a,b-unsaturated
ester 23 to get the bis-functionalized chiral synthon 24 (Scheme 3),
was a crucial step since it would dictate the enantiomeric purity of
the intermediates and final compounds. We investigated this reac-
tion in detail by varying the reaction conditions as summarized in
Table 1.
We first performed this reaction (Scheme 3) following condi-
tions reported in the literature15, using 5 equiv of MeMgBr,
2
mol % CuI and 3 mol % (S)-Tol-BINAP at À20 °C, but only the
Next, we removed the benzyl group of 24 using 10% Pd/C in
EtOH, but obtained mainly the side product 6-membered methyl
lactone 32 (Scheme 4). However, changing the solvent for the
undesired b-methyl substituted methyl ketone 30 and the b-
methyl substituted dimethyl alcohol 31 were obtained (Table 1,
Entry 1). Repeating the reaction with identical reagent ratios at a
lower temperature (À78 °C), afforded principally the ketone 30,
but not the desired product 24 (Entry 2). Reduction of the amount
of MeMgBr (3.2 equiv) at À20 °C, still didn’t yield the desired pro-
duct 24 (Entry 3). Eventually, we chose to modify the catalytic sys-
tem ((S)-Tol-BINAP and CuX) by using CuBr16 instead of CuI, which
gave better results.
1
7
debenzylation reaction to EtOAc:EtOH (4:1) afforded the desired
product 25 in 85% yield (Step e, Scheme 2). The free primary alco-
1
8
hol 25 was then subjected to the PDC oxidation to furnish the
carboxylic acid 26, which was then converted to the corresponding
acid chloride 27 using (COCl)
ther, the Friedel–crafts acylation of the 5-chloro-2-hexyl indole
derivative 10 with the acyl chloride 27 using Me AlCl as Lewis acid
2
and a catalytic amount of DMF. Fur-
2
The combination of 6 mol % (S)-Tol-BINAP, 4 mol % CuBr and
.2 equiv MeMgBr afforded the desired product 24 in 50% yield
afforded the acylated product 28 in 95% yield. Basic hydrolysis of
the methyl ester 28 then furnished 5a, the S-enantiomer of 5.
3

6
898
C. Nagendra Reddy et al. / Tetrahedron Letters 56 (2015) 6896–6899
Chiral HPLC of 24
24
Racemate
S
S
R
R
3
4
5
6
3
4
5
6
Time (min)
Scheme 2. Novel synthesis of 5a and 6a. Reagents and conditions: (a) NaH, BnBr, THF:DMF (1:1), 0 °C–rt, 2 h, 70%; (b) PCC, CH
, rt, 6 h; (f) PDC, DMF, rt, 12 h, 85% over two steps; (g)
O (4:1), rt, 24 h, 85%. (j) 12, t-BuOK, CH Cl , 0 °C–rt, 7 h, 65%; (k) BBr , CH Cl
2 2 3 2
Cl , 0 °C–rt, 3 h, 70%; (c) PPh @CHACO Me,
THF, reflux, 3 h, 90%; (d) MeMgBr, CuBr, (S)-Tol-BINAP, t-BuOMe, À20 °C, 2 h, 50%; (e) 10% Pd/C, EtOAc/EtOH (4:1), H
2
(
COCl)
2
, cat. DMF, CH
2
Cl
2
, rt, 3 h; (h) 10, Me
2
AlCl, CH
2
Cl
2
, 0 °C–rt,1 h, 95%; (i) LiOH, i-PrOHn/H
2
2
2
3
2
2
,
0
°C–rt, 30 min, 80%.
O
1) MeMgBr
O
O
OH
+
+
BnO
OMe
BnO
OMe
BnO
BnO
CuX, (S)-Tol-BINAP
t-BuOMe, temp, 2 h
23
24
30
31
2
) MeOH/NH4Cl
Scheme 3. Enantioselective conjugate addition of MeMgBr to (E)-5-Benzyloxy-pent-2-enoic acid methyl ester 23.
Table 1
Optimization of the reaction conditions for the conjugate addition of MeMgBr to 23
Entry #
(S)-Tol-BINAP (mol %)
CuX
MeMgBr (equiv)
Temperature (°C)
24:30:31
S/R for 24a
Yield for 24b (%)
1
2
3
4
5
6
7
3
3
3
6
4.5
4.5
4.5
(X = I) 2 mol %
(X = I) 2 mol %
(X = I) 2 mol %
(X = Br) 4 mol %
(X = Br) 3 mol %
(X = Br) 2.5 mol %
(X = Br) 2 mol %
5
5
À20
À78
À20
À20
À20
À20
À20
0:50:50
0:90:10
0:50:50
50:50:0
50:50:0
50:50:0
50:50:0
—
—
—
—
—
—
50
50
50
50
3.2
3.2
3.2
3.2
3.2
83.3/16.7
84.3/15.7
97.5/2.5
98.4/1.6
a
S/R ratio was calculated using chiral HPLC by comparison with the racemic compound.
Isolated yield.
b
The N-acylation of the 6-chloro-2-hexyl indole derivative 12 using
t-BuOK as a base afforded 29, and the acidic hydrolysis of the
2 2
(Fig. 3B), so they were converted with CH N to their methyl esters,
which were well separated from one another (Fig. 3C). In this way
the chiral purity of the S-enantiomer was found to be 96.5%.
We knew from previous experience that in the deuteration of
double or triple bonds using Pd/C there is some scrambling of
19
methyl ester 29 using BBr
3
afforded 6a, the S-enantiomer of 6.
5
Chiral HPLC analysis of the final compound 6a showed 98.5% of
the S-enantiomer (Fig. 3A). In the case of 5a, we were unable to
completely separate the two enantiomers as their free acids
2
0
the deuterium. We therefore paid careful attention to the enantio
analysis of the final indole derivatives 5a and 6a. We found that
prolongation of the hydrogenolysis time diminishes chiral purity
by as much as 3–4%. Since this is an important issue for us, we opti-
mized the various conditions of the reaction to try to improve the
enantioselectivity. In particular, we reduced the time of the hydro-
genation and stopped the reaction just prior to completion, with
O
1
0% Pd/C, H2,
O
EtOH, rt, 6 h
O
BnO
OMe
24
3
2
ꢀ5% of the starting benzyl derivative remaining. This allowed us
Scheme 4. Formation of (S)-4-Methyl-tetrahydro-pyran-2-one (32).

C. Nagendra Reddy et al. / Tetrahedron Letters 56 (2015) 6896–6899
6899
Research (W. S. P.; MOP-6254 and PP2-133388) and AmorChem,
Montreal, Canada. The Meakins-Christie Laboratories – MUHC-RI
are supported in part by a Center grant from Le Fond de la
Recherche en Santé du Québec as well as by the J. T. Costello
Memorial Research Fund. J. R. wishes to acknowledge the National
Science Foundation for the Bruker 400 MHz (Grant Number
CHE-03-42251) NMR instrument.
6a
A
5a
B
5a-Me
C
S
S
S
Supplementary data
Supplementary data (experimental procedures, characteriza-
1
13
R
tion data, and copies of H NMR spectra and C NMR spectra)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2015.10.097.
R
R
30 35 40 45
9
12
15
21 24 27 30
References and notes
Time (min)
Time (min)
1
2
3
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Acknowledgments
This work was supported by the American Asthma Foundation
(
J. R.; Award Number 12-0049), the Canadian Institutes of Health