The first asymmetric synthesis of a 4-aryl-substituted 5-carboxy-3,4-dihydropyridin-2-one derivative

Article abstract of DOI:10.1016/j.tetlet.2010.01.049

A simple and practical route for the asymmetric synthesis of (S)-4-(4-fluorophenyl)-1,4,5,6-tetrahydro-6-oxo-3-pyridinecarboxylic acid (1) is presented. The procedure comprises catalytic desymmetrization of a meso-anhydride using a chiral thiourea organocatalyst, followed by selective formylation and cyclization.

Full text of DOI:10.1016/j.tetlet.2010.01.049

Tetrahedron Letters 51 (2010) 1554–1557
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Tetrahedron Letters
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The first asymmetric synthesis of a 4-aryl-substituted
5-carboxy-3,4-dihydropyridin-2-one derivative
*
Xiaojun Huang , Jiang Zhu, Scott Broadbent
Chemical Synthesis, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and practical route for the asymmetric synthesis of (S)-4-(4-fluorophenyl)-1,4,5,6-tetrahydro-6-
oxo-3-pyridinecarboxylic acid (1) is presented. The procedure comprises catalytic desymmetrization of a
meso-anhydride using a chiral thiourea organocatalyst, followed by selective formylation and cyclization.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 24 December 2009
Revised 12 January 2010
Accepted 14 January 2010
Available online 20 January 2010
1. Introduction
condensation of 3 with diethyl malonate, followed by decarboxyl-
ation to a give better (84%) overall yield.3 Dehydration to the anhy-
The synthesis of (S)-4-(4-fluorophenyl)-1,4,5,6-tetrahydro-6-
oxo-3-pyridinecarboxylic acid (1, Fig. 1) attracted our attention be-
cause a number of compounds derived from this core structure
showed very promising biological activities in models of rheuma-
toid arthritis and chronic inflammatory pain. This type of 4-aryl-
substituted 5-carboxy-3,4-dihydropyridin-2-one structure has
not often been described in the literature. A racemic synthesis
involving selective 1,4-addition of Grignard reagents to 6-chloron-
icotinic acid derivatives has been disclosed.1 The enantiomers of 1
could be separated by chiral chromatography, however this is not
desirable for large-scale preparation. To the best of our knowledge,
there is no literature precedent for the asymmetric synthesis of
this type of dihydropyridinone structure. In order to satisfy our
need for multi-kilogram amounts of acid 1, an enantioselective
synthesis was envisioned.
We disclose herein our studies on the first practical asymmetric
synthesis of 1. We focused on the set of retrosynthetic disconnec-
tions as shown in Scheme 1. The selective formylation and cycliza-
tion of the monoester of 3-arylglutaric acids should give the
desired dihydropyridinone core. The chiral monoester of 3-arylglu-
taric acids can be synthesized by the asymmetric methanolysis of
3-arylglutaric anhydrides, the latter readily available from the
corresponding benzaldehydes.
dride was performed equally well using any of the following
conditions: (a) acetyl chloride under reflux;2a,b (b) trifluoroacetic
anhydride, THF, 55 °C;2c and (c) acetic anhydride, toluene under re-
flux.2d Acetic anhydride in toluene was used for large-scale work
because of its low cost.
The enantioselective synthesis of mono acid 7 from anhydride 5
was investigated extensively. Literature precedent suggested that
desymmetrization of prochiral anhydride 5 to set the absolute ste-
reo-chemistry of the stereogenic center would be best accom-
plished by enantioselective alcoholysis. We first investigated the
enzymatic desymmetrization with methanol using NovozymÒ
435.2a About 4% conversion was observed after 5 days and the
enantiomeric excess was only ꢀ14% in favor of the undesired (S)
enantiomer. Methanolysis of anhydride 5 was also investigated
using a stoichiometric amount of quinine, in toluene.4 Moderate
ee was observed at low temperatures: 48% at ꢁ40 °C, 58% at
ꢁ45 °C, 67% at ꢁ55 °C.
The most promising lead came from a reported enantioselective
desymmetrization of meso-anhydrides by a bifunctional thiourea-
based organocatalyst (6), whereby Connon and co-workers demon-
F
2. Results and discussion
4-(4-Fluorophenyl)-glutaric anhydride (5) was readily available
from 4-fluorobenzaldehyde (3) following slightly modified litera-
ture procedures (Scheme 2). The condensation of 3 with ethyl ace-
toacetate, followed by decarbonylation, gave diacid 4 in 60–65%
yield over three steps.2 Preparation of 4 was also achieved by
CO2H
O
N
H
1
* Corresponding author. Tel.: +1 650 704 6432.
E-mail address: xiaojun.huang5@gmail.com (X. Huang).
Figure 1. Structure of compound 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.049

X. Huang et al. / Tetrahedron Letters 51 (2010) 1554–1557
1555
Ar
O
Ar
O
Ar
O
O
O
cyclization
NH4OAc
OMe
OH
HO
OMe
O
N
H
O
N
H
H
selective
formylation
Ar
Ar
O
O
desymmetrization
HO
OMe
O
O
O
Scheme 1. Retrosynthetic analysis.
F
a wide range of solvents of differing polarity (entries 1–14). The
reactions were usually very clean and no byproducts were ob-
served using organocatalyst 6. Level of polarity was very important
to achieving good conversion and enantioselectivity. Low conver-
sion was observed if the solvent was too polar (entries 2–5), pre-
sumably because of catalyst solvation. Less polar solvents usually
gave full conversion (entries 6–14), but the enantioselectivity
was poor when the polarity of the solvents was too low (entries
6 and 7). Ethers proved to be the best solvents. Both THF (entry
11) and 2-methyl-THF (entry 14) gave 100% conversion and the
best observed ee (80%). 2-Methyl-THF was chosen for further stud-
ies since it gave a faster reaction rate—full conversion was achieved
in 4.5 h, compared to 89% conversion in THF over the same period.
The product enantioselectivity was slightly increased at lower
reaction concentrations (entries 14–17). For practical reasons, forty
volumes of 2-methyl-THF were chosen for large-scale studies. The
use of 5, 10, or 20 equiv of methanol led to the same enantioselec-
tivity (entries 14, 18, and 19), but the reaction rate was slower
when less methanol was used. Catalyst loading was also screened
(entries 20–22). Lower catalyst loading resulted in lower ee and
slower reaction. The enantioselectivity reached the maximum ob-
served value when 2 mol % of 6 was used.
F
F
a,b
f
or c, d, e
HO2C
CO2H
CHO
O
O
O
3
4
5
Scheme 2. Reagents and conditions: (a) ethyl acetoacetate, piperidine, rt, 3 d; (b)
25% sodium methoxide in methanol, water, ethanol, 80–90 °C, 3 h, 60–65% yield
from 3; (c) diethyl malonate, piperidine, toluene, reflux, 2.5 h; (d) diethyl malonate,
sodium ethoxide, ethanol, 0 °C, 15 min; (e) concd hydrochloric acid under reflux,
8 h, 84% from 3; and (f) acetic anhydride, toluene under reflux, 80–90% yield.
strated the successful asymmetric methanolysis of succinic anhy-
dride derivatives and glutaric anhydrides.5 The results of our preli-
minary investigations to test this method are outlined in Table 1.
As a starting point, the methanolysis of the meso-anhydride 5
was carried out using 10 equiv of methanol, 2 mol % of 6, in 40 vol-
umes of methyl t-butyl ether (MTBE) at ambient temperature (en-
try 1). Full conversion was achieved after 24 h, and 73% ee was
observed for the crude product. We then studied this reaction with
Having identified a readily available organocatalyst and reac-
tion conditions (10 equiv methanol, 2 mol % 6, 40 vol 2-Me-THF)
Table 1
Initial catalyst screening and optimization of the asymmetric methanolysis of anhydride 5a
Entry
Cat. (mol %)
Solvent
Solvent vol
x (equiv)
t (h)
Conv (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14b
15
16
17
18
19
20
21
22
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
1
0.5
MTBE
DMSO
NMP
DMF
MeCN
PhMe
CH2Cl2
EtOAc
Diethyl carbonate
Et2O
THF
Dioxane
i-Pr2O
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
2-Me-THF
40
40
40
40
40
40
40
40
40
40
40
40
40
40
20
80
800
40
40
40
40
40
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
24
24
24
24
24
24
24
24
24
24
24
24
24
24 (4.5)
24
24
24
100
24
17
30
78
73
6
36
29
51
47
49
70
61
70
80
77
62
80
75
82
88
80
80
80
79
77
100
100
100
100
100
100
100
100
100
100
100
100
98
4.5
4.5
4.5
4.5
4.5
20
10
10
10
100
100
86
83
a
6, methanol (x equiv), solvent, rt.
Achieved full conversion after 4.5 h.
b

1556
X. Huang et al. / Tetrahedron Letters 51 (2010) 1554–1557
F
F
F
CO2Me
a
b
c
HO2C
CO2Me
H
5
HO2C
CO2Me
O
N
H
O
7
8
2
OMe
N
CF3
NH
N
S
N
CF3
H
6
Scheme 3. Reagents and conditions: (a) 10 equiv methanol, 2 mol % 6, 2-Me-THF, rt, overnight, 80% ee; then treatment with toluene/hexane, 96% ee; (b) LDA, methyl formate,
THF, ꢁ45 °C; and (c) ammonium acetate, acetic acid, 80 °C, overnight, 48% overall yield (three steps).
F
F
conducive to clean asymmetric anhydride desymmetrization at
room temperature, attention now turned to enhancement of the
enantiomeric purity of monoacid 7. The goal was to improve the
ee from 80% to >95%. Attempts to make solid amine salts of 7 using
triethylamine, Hünig’s base, t-butyldimethylamine, tributylamine,
and pyridine were unsuccessful, as were attempts to make sodium
or lithium salts using sodium methoxide or n-butyllithium. Some
solids were collected but there were some byproducts, including
diacid 4 as the major one. It was finally found that treatment of
crude 7 with a toluene/hexane mixture (8 vol/4 vol) caused solid
7 to precipitate in near-racemic form (<10% ee). The enantiomeric
excess of monoacid 7 in the mother liquor was enriched to >95%.
The ee in the mother liquor could be further increased to >98%
by running at lower temperatures, but the ee of the solid also
increased. It is noteworthy that both the 2-Me-THF solvent and
catalyst 6 can be recovered and re-used to effect this transforma-
tion with the same outcome.
With the chiral monoacid (R)-7 of desired enantiomeric excess
available, the next step was the selective formylation to make
intermediate 8. Very few examples have been reported for the
selective alkylation or acetylation of glutaric acid monoester deriv-
atives. In fact, the only procedure found in the literature used
2.2 equiv of LDA in HMPA/THF at ꢁ78 °C for the C-methylation of
glutaric acid monoester derivatives.6 When methyl iodide was
used as the alkylating agent, the product was isolated in 60–93%
yield. The formylation of esters is well known in the literature.7
However, no examples utilizing an ester/acid longer than four car-
bons similar to 7 are known. When the same conditions used in the
methylation were used for the selective formylation of monoacid 7
with methyl formate, we were delighted to find that the desired
product was formed in about 70% conversion. Since we targeted
multi-kilogram preparations of acid 1 in our pilot plant, the elim-
ination of HMPA was necessary. It was found that the reaction
did not require the presence of HMPA. The reaction achieved best
conversion (85–90%) with 2.5 equiv of LDA (2.2, 2.5, 3, and 4 equiv
were tested). Moreover, it worked at ꢁ45 °C, a temperature that
can easily be achieved in our pilot plant. It is noteworthy that
the addition of 7 to LDA was preferred for the deprotonation step,
because the reaction mixture is physically easier to agitate, and
better conversion was achieved. The cyclization of 8 with ammo-
CO2H
CO2Me
a, b
O
N
H
O
N
H
1
2
Scheme 4. Reagents and conditions: (a) 1.5 N aqueous lithium hydroxide, meth-
anol, rt, overnight; and (b) 1 N hydrochloric acid, 86% yield.
nium acetate in the presence of acetic acid smoothly gave product
2 in good overall yield (48%, three steps) and >95% ee (Scheme 3).8
The hydrolysis of 2 by the action of lithium hydroxide in water/
methanol afforded acid 1 in 86% isolated yield after acidification
(Scheme 4).9 Sodium hydroxide was also tried for this transforma-
tion but it led to some ring-opening byproducts.
In conclusion, we have demonstrated the first asymmetric syn-
thesis of 1, which represents a novel class of 5-carboxy-3,4-dihy-
dropyridin-2-one structures. The chiral center was set by the
desymmetrization of anhydride 5 with thiourea-based chiral cata-
lyst 6, and the enantiomeric excess of 7 was improved from 80% to
>95% by treatment with toluene/hexane. Selective formylation and
cyclization were key reactions to achieving the dihydropyridinone
core. The whole process is amenable to a large-scale synthesis.
Acknowledgments
We thank Dr Pankaj Rege and Charles Dvorak for helpful sug-
gestions, Frida Dobrouskin and Tim Lane for analytical support,
and Drs. Gary Cooper, Andrew Briggs, and Kieran Durkin for review
of the manuscript.
References and notes
1. Hoffmann-Emery, F.; Hilpert, H.; Scalone, M.; Waldmeier, P. J. Org. Chem. 2006,
71, 2000–2008. and references therein.

X. Huang et al. / Tetrahedron Letters 51 (2010) 1554–1557
1557
2. (a) Fryszkowska, A.; Komar, M.; Koszelewski, D.; Ostaszewski, R. Tetrahedron:
Asymmetry 2005, 16, 2475–2485; (b) Liu, L. T.; Hong, P.-C.; Huang, H.-L.; Chen,
S.-F.; Wang, C.-L. J.; Wen, Y.-S. Tetrahedron: Asymmetry 2001, 12, 419–426; (c)
Poldy, J.; Peakall, R.; Barrow, R. A. Tetrahedron Lett. 2008, 49, 2446–2449; (d)
Theisen, P. D.; Heathcock, C. H. J. Org. Chem. 1993, 58, 142–146.
3. (a) Guzman, A.; Romero, M.; Maddox, M. L.; Muchowski, J. M. J. Org. Chem. 1990,
55, 5793–5797; (b) Leonardi, A.; Barlocco, D.; Montesano, F.; Cignarella, G.;
Motta, G.; Testa, R.; Poggesi, E.; Seeber, M.; De Benedetti, P. G.; Fanelli, F. J. Med.
Chem. 2004, 47, 1900–1918.
4. (a) Keen, S. P.; Cowden, C. J.; Bishop, B. C.; Brands, K. M. J.; Davies, A. J.; Dolling,
U. H.; Lieberman, D. R.; Stewart, G. W. J. Org. Chem. 2005, 70, 1771–1779; (b)
Bolm, C.; Gerlach, A.; Dinter, C. L. Synlett 1999, 195–196; (c) Bolm, C.; Schiffers,
I.; Dinter, C. L.; Gerlach, A. J. Org. Chem. 2000, 65, 6984–6991.
5. Peschiulli, A.; Gun’ko, Y.; Connon, S. J. J. Org. Chem. 2008, 73, 2454–2457. and
references therein.
(ca. 0.38 mol) in THF was added over 30 min (T < ꢁ45 °C). After 40 min at ꢁ45 to
ꢁ55 °C, methyl formate (65.2 mL, 1.06 mol) was added. The mixture was slowly
warmed to ꢁ20 °C over 1 h, and then stirred at ꢁ20 °C for 1 h. The mixture was
slowly quenched with 3 N HCl (800 mL, final pH = 0.15) and EtOAc (0.8 L) was
added. The organic layer was separated, washed with brine (0.8 L) and
concentrated to give a thick oil (8).
To this thick oil (crude 8), AcOH (326 mL, 5.70 mol) and NH4OAc (87.9 g,
1.14 mol) were added and the mixture was warmed to 80 °C. After overnight at
80 °C, the mixture was cooled to ambient temperature and water (0.825 L) was
added very slowly over 3 h. After 2 h at ambient temperature, the mixture was
slowly cooled to 0 °C and stirred for another 3 h. The cooled mixture was filtered
and washed with water (70 mL) and cold toluene (70 mL, 0 °C). The solid was
dried overnight (60 °C) under reduced pressure to give product 2 (57.7 g, 48%
yield over three steps, 96% ee) as an off-white solid: mp 176–178 °C; ½a D20
ꢂ
182.6;
HPLC assay >99%; IR (KBr):
m 3274, 2954, 1688, 1648, 1602, 1508, 1473, 1440,
6. Brandt, J. D.; Moeller, K. D. Heterocycles 2006, 67, 621–628.
1351, 1304, 1222, 1204, 1176, 1099, 839 cmꢁ1 1H NMR (300 MHz, CDCl3) d 2.71
;
7. (a) Huang, N.; Jiang, T.; Wang, T.; Soukri, M.; Ganorkar, R.; Deker, B.; Léger, J.-M.;
Madalengoitia, J.; Kuehne, M. E. Tetrahedron 2008, 64, 9850–9856; (b) Reddy, C.
P.; Tanimoto, S. Synthesis 1987, 575–577. and references therein.
(d, J = 16.58 Hz, 1H) 3.00 (dd, J = 16.58, 8.29 Hz, 1H) 3.71 (s, 3H) 4.18 (d,
J = 7.16 Hz, 1H) 6.90–7.05 (m, 2H) 7.13–7.24 (m, 2H) 7.48 (d, J = 5.65 Hz, 1H)
7.93 (br s, 1H); 13C NMR (75.4 MHz, CDCl3) d 35.8, 38.1, 51.8, 111.0, 115.6, 115.9,
128.2, 128.3, 135.4, 137.1, 137.2, 160.3, 163.6, 166.3, 170.5; Anal. Calcd for
C13H12FNO3: C, 62.65; H, 4.85; N, 5.62. Found: C, 62.78; H, 4.77; N, 5.64.
9. (S)-4-(4-Fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylic acid (1):
Aqueous lithium hydroxide solution (803 mL, 1.5 M, 1.2 mol) was added to
methyl ester 2 (100.0 g, 0.402 mol) in MeOH (500 mL) at ambient temperature.
The reaction achieved full conversion overnight. The mixture was slowly
acidified with 2 L of 1 N aqueous HCl solution (24–33 °C). The mixture was
slowly cooled to 0 °C and stirred for 2 h. The cooled mixture was filtered. The
solid was washed with water and dried at 70 °C under reduced pressure to give
8. (S)-4-(4-Fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-3-carboxylic acid methyl
ester (2): To a 5 L flask equipped with an overhead stirrer, anhydride 5 (100.0 g,
0.481 mol) and catalyst 6 (4.81 g, 0.00962 mol) were charged under nitrogen. 2-
Me-THF (4.0 L) was added, followed by methanol (195 mL, 4.81 mol) at ambient
temperature. The mixture was stirred overnight. The reaction achieved full
conversion with 80% ee for the crude product. The mixture was concentrated
under reduced pressure (23–45 °C). Toluene (1.0 L) was added, followed by
hexane (0.5 L). The mixture was stirred overnight at ambient temperature, then
12 °C for 2 h. The mixture was filtered to give a solid (23 g, 6% ee). The filtrate
(96% ee) was extracted with saturated aqueous NaHCO3 (two times, 1 L then
0.5 L). The organic layer was concentrated to give the recovered catalyst 6 for re-
use. The combined aqueous layer was acidified with concd HCl (180 mL, final pH
= 0.36) and the mixture was extracted with toluene (2 L). The organic extract
was washed with brine (1 L) and concentrated under reduced pressure. The
residue (7, 96% ee) was used in the next step without further purification.
To a solution of diisopropylamine (134 mL, 0.950 mol) in THF (548 mL) at ꢁ10 to
10 °C was added n-BuLi (380 mL, 2.5 M in hexane, 0.95 mol) over 20 min. After
15 min at 0 °C, the mixture was cooled to ꢁ55 °C. To this LDA solution, crude 7
acid 1 (81.2 g, 86% yield, 96% ee) as a white solid: mp 209–212 °C; ½a D20
ꢂ
278.3;
HPLC assay 100%; IR (KBr):
m 3254, 2944, 1690, 1647, 1559, 1509, 1482, 1373,
1283, 1214, 1194, 1170, 1101, 831 cmꢁ1 1H NMR (300 MHz, DMSO-d6) d 2.39
;
(d, J = 16.58 Hz, 1H) 3.00 (dd, J = 16.58, 8.29 Hz, 1H) 4.03 (d, J = 7.16 Hz, 1H)
7.01–7.27 (m, 4H) 7.36 (d, J = 5.27 Hz, 1H) 9.88 (d, J = 5.65 Hz, 1H) 12.07 (br s,
1H); 13C NMR (75.4 MHz, DMSO-d6) d 35.3, 38.4, 109.4, 115.3, 115.5, 128.4,
128.5, 136.8, 138.6, 159.5, 162.7, 167.2, 169.4; Anal. Calcd for C12H10FNO3: C,
61.28; H, 4.29; N, 5.95. Found: C, 61.05; H, 4.21; N, 6.03.