Direct asymmetric hydrogenation of 2-oxo-4-arylbut-3-enoic acids

Article abstract of DOI:10.1021/jo101084t

A challenging direct asymmetric hydrogenation of (E)-2-oxo-4-arylbut-3- enoic acids to give 2-hydroxy-4-arylbutanoic acids (85.4-91.8% ee) was achieved with a Ru catalyst based on SunPhos as the chiral ligand. Further investigation of the reaction revealed that partial isomerization of 2-hydroxy-4-arylbutenoic acids was involved in the hydrogenation process. Employing the reaction conditions to the hydrogenation of 2-oxo-4-phenylbutanoic acid resulted in better enantioselectivity (91.8% ee) and efficiency (TON = 2000, TOF = 200 h^-1), which offers a useful method for the synthesis of a common intermediate for ACE inhibitors.

Full text of DOI:10.1021/jo101084t

pubs.acs.org/joc
optically active molecules.1 Metal-catalyzed asymmetric hy-
Direct Asymmetric Hydrogenation of
2-Oxo-4-arylbut-3-enoic Acids
drogenation of functionalized olefins or ketones has been
investigated extensively.2 However, asymmetric hydrogena-
tion of R-keto acids has rarely attracted attention,3 and
metal-catalyzed asymmetric hydrogenation of unsaturated
R-keto acids is not reported.4 To realize such a transforma-
tion, some issues should be taken into consideration: (i) the
competitive coordination of the substrate with the counter-
anion of the catalyst, which might cause deactivation of the
catalyst, thus leading to low enantioselectivity and/or reac-
tivity; (ii) the liberation of the product, the hydroxy acid,
which usually serves as a ligand, from the catalyst. Recently,
we have developed a convenient protocol for highly enantio-
selective preparation of ethyl 2-hydroxy-4-arylbutyrates,5
which can be employed in the synthesis of angiotensin-
converting enzyme (ACE) inhibitors6 by hydrogenation of
(E)-ethyl 2-oxo-4-arylbut-3-enoates. The hydrogenation
products, ethyl 2-hydroxy-4-arylbutyrate, are usually
liquids, and the enantiomeric purities can only be upgraded
by hydrolysis, acidification, and recrystallization. Further-
more, we have to prepare the hydrogenation substrates from
their corresponding acids by esterification. Therefore, it is
desirable to develop a direct method for the hydrogenation
Lvfeng Zhu,† Qinghua Meng,‡ Weizheng Fan,‡
Xiaomin Xie,‡ and Zhaoguo Zhang*,‡,§
†School of Chemical Engineering, Nanjing University of
Science & Technology, 200 Xiaolingwei, Nanjing 210094,
China, ‡School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, China, and §Shanghai Institute of Organic
Chemistry, 345 Lingling Road, Shanghai 200032, China
zhaoguo@sjtu.edu.cn
Received June 4, 2010
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ꢀ
€
A challenging direct asymmetric hydrogenation of (E)-2-
oxo-4-arylbut-3-enoic acids to give 2-hydroxy-4-arylbuta-
noic acids (85.4-91.8% ee) was achieved with a Ru catalyst
based on SunPhos as the chiral ligand. Further investiga-
tion of the reaction revealed that partial isomerization of
2-hydroxy-4-arylbutenoic acids was involved in the hydro-
genation process. Employing the reaction conditions to the
hydrogenation of 2-oxo-4-phenylbutanoic acid resulted in
better enantioselectivity (91.8% ee) and efficiency (TON =
2000,TOF =200h-1), which offers a useful method for the
synthesis of a common intermediate for ACE inhibitors.
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DOI: 10.1021/jo101084t
r
Published on Web 08/11/2010
J. Org. Chem. 2010, 75, 6027–6030 6027
2010 American Chemical Society

Zhu et al.
JOCNote
TABLE 1. Effects of Solvents, Pressure, and Temperaturea
TABLE 2. Effects of Additives and Catalystsa
entry
solvent
P/T/t (psi/°C/h)
product
ee (%)b
entry
additive
ee (%)b
1 M HCl aqc
1 M HCl aq
1 M HCl aqd
1 M HBF4 aq
1 M H3BO3 aq
1 M H2SO4 aq
1 M CSA aq
1 M HBr aq
1 M HI aq
86.8
87.1
85.9
78.4
82.2
84.4
87.4
89.2
86.6
73.8
66.8
65.0
85.0
82.3
86.0
88.5
48.0
84.0
84.8
68.7
1
2
3
4
5
6
7
8
9
EtOH
t-BuOH
i-Pr2O
dioxane
THF
THF
THF
THF
THF
400/90/20
400/90/20
400/90/20
400/90/20
400/90/20
400/70/20
400/90/10
400/110/20
200/90/20
800/90/20
400/90/20
5ac
2a
2a
2a
2a
64.2
58.2
69.4
82.6
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15f
16g
17h
18i
19j
20
87.1
2a (30)/3a(70) d
90.5/74.6
89.1/47.2
64.4
2a (97)/3a(3) d
2a
2a
2a
2a
86.6
85.8
10
11
THF
THF
CeCl3 6H2O
3
65.0 e
I2
none
aUnless otherwisely noted, all reactions were carried out with a
substrate (1 mmol) concentration of 0.20 M in a solvent for 20 h, 1 M
aq HCl as the additive, substrate/catalyst/additive=100/1/6, conver-
sion=100%. bDetermined by HPLC on a Chiralpak OD-H column after
H2Oe
1 M CeCl3 aq
1 M HBr aq
1 M HBr aq
1 M HBr aq
1 M HBr aq
1 M HBr aq
HBr (gas)
c
transferring acids to esters. The acid transferred to its corresponding
ester during the hydrogenation process. dThe numbers in parentheses refer
to a molar ratio of 2a/3a, which was determined by 1H NMR. eNo additive.
of R-keto acids. In this paper, we report an enantioselective
synthesis of 2-hydroxy-4-arylbutanoic acids by direct asym-
metric hydrogenation of their corresponding (E)-2-oxo-4-ar-
ylbut-3-enoic acids, which are prepared conveniently by
reaction of corresponding arylaldehydes and pyruvic acid.7
On the basis of our success in asymmetric hydrogenation
of ethyl 2-oxo-4-arylbut-3-enoates, we arbitrarily employ
[RuCl(benzene)(S)-SunPhos]Cl and catalytic amounts of
aqueous 1 M HCl as catalyst to test the hydrogenation of
2-oxo-4-phenylbutanoic acid across a range of solvents,
reaction temperatures, and hydrogen pressures (Table 1,
entries 1-10).
The purpose of the addition of HCl is to protonate the
product formed to achieve a quick leaving of the product
from the catalytic center and to use Cl- as the ligand to expel
the product from the catalyst. In fact, THF is the best solvent
investigated (Table 1, entry 5). At lower temperature or
shorter reaction time (Table 1, entries 6 and 7), 1a was also
hydrogenated with complete conversion to give a mixture of
2a and 3a, which revealed that rates of the hydrogenation of
the CdO bond and CdC bond are different, and the hydro-
genation of the CdO bond is much faster because we did not
detect any 2-oxo-4-phenylbutanoic acid during the hydro-
genation process. The fact that the enantiomeric excesses of
2a and 3a are not equal also implies that the hydrogenation
process is not a simple sequential hydrogenation of the CdO
double bond followed by hydrogenation of the CdC double
bond. Increasing the temperature improved the rate of
hydrogenation of the CdC bond (Table 1, entry 5 vs 6) but
decreased the enantioselectivities (Table 1, entry 5 vs 8). The
hydrogenation reaction is not sensitive to hydrogen pressure
(Table 1, entries 5, 9, and 10).
aUnless otherwisely noted, all reactions were carried out under 400 psi
of hydrogen with a substrate (1 mmol) concentration of 0.20 M in THF
for 20 h, substrate/catalyst/additive = 100/1/6, conversion = 100%.
bDetermined by HPLC on a Chiralpak OD-H column after transferring
acids to esters. c3% 1 M HCl aq. d12% 1 M HCl aq. e0.06 mL of H2O.
f Catalyst is [Ru(cymene)Cl(S)-Sunphos]Cl. gCatalyst is [Ru(benzene)-
Br(S)-Sunphos]Br. hCatalyst is [Ru(benzene)Cl(S)-Binap]Cl. iCatalyst is
[Ru(benzene)Cl(S)-C3-Tunephos]Cl. jCatalyst is [Ru(benzene)Cl(S)-
Segphos]Cl.
It has been reported that catalytic amounts of additives
play a crucial role in improving the reactivity and enantio-
selectivities in many asymmetric reactions,8 and it has also
been proven that HCl is a good additive in our preliminary
work; we then evaluated a number of other additives for the
asymmetric hydrogenation of 1a. As shown in Table 2,
among the tested aqueous solutions of Brønsted acids, it
seems that the proper counteranion was essential for achieving high
enantioselectivities (Table 2, entries 1-9), the addition of catalytic
amounts of 1 M aq HBr solution improved the enantiomeric excess
to 89.2%, which is better than that with 1 M aq HCl solution
(Table 2, entry 2 vs 8) and much better than that with 1 M aq HBF4
as additive (Table 2, entry 4 vs 8). To eliminate the possibility that
mixed counterions may have a complex effect on the enantio-
selectivity, [RuBr(benzene)(S)-SunPhos]Br was synthesized and
applied as catalyst, and essentially no enantiomeric excess improve-
ment was observed (Table 2, entry 8 vs 16), while [RuCl-
(cymene)(S)-SunPhos]Cl gave decreased ee (Table 2, entry 15).
^
(8) (a) Meng, Q.; Sun, Y.; Ratovelomanana-Vidal, V.; Genet, J. P.;
Zhang, Z. J. Org. Chem. 2008, 73, 3842. (b) Sun, Y.; Wan, X.; Wang, J.;
Meng, Q.; Zhang, H.; Jiang, L.; Zhang, Z. Org. Lett. 2005, 7, 5425. (c)
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Akiyama, T. Chem. Rev. 2007, 107, 5744. (d) Vogl, E. M.; Groger, H.;
Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 1570. (e) Spindler, F.; Blaser,
H.-U. Enantiomer 1999, 4, 557. (f ) Wang, C.; Xi, Z. Chem. Soc. Rev. 2007, 36,
1395. (g) Togni, A. Angew. Chem., Int. Ed. Engl. 1996, 35, 1475. (h) Xiao, D.;
Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425. (i) Wang, W.-B.; Lu, S.-M.;
Yang, P.-Y.; Han, X.-W; Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125, 10536.
( j) Chi, Y.; Zhou, Y.-G.; Zhang, X. J. Org. Chem. 2003, 68, 4120. (k)
Moessner, C.; Bolm, C. Angew. Chem., Int. Ed. 2005, 44, 7564. (l) Legault,
C. Y.; Charette, A. B. J. Am. Chem. Soc. 2005, 127, 8966. (m) Hou, G.-H.;
Xie, J.-H.; Wang, L.-X.; Zhou, Q.-L. J. Am. Chem. Soc. 2006, 128, 11774. (n)
Zhou, Y.-G. Acc. Chem. Res. 2007, 40, 1357.
(7) (a) Stecher, E. D.; Ryder, H. F. J. Am. Chem. Soc. 1952, 74, 4392. (b)
Audrain, H.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem.
2000, 65, 4487. (c) Srivastave, B. K.; Joharapurkar, A.; Raval, S.; Patel, J. Z.;
Soni, R.; Raval, P.; Gite, A.; Goswami, A.; Sadhwani, N.; Gandhi, N.; Patel,
H.; Mishra, B.; Solanki, M.; Pandey, B.; Jain, M. R.; Patel, P. R. J. Med.
Chem. 2007, 50, 5951. (d) Stecher, E. D.; Dunn, F.; Gelblum, E. J. Am. Chem.
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6028 J. Org. Chem. Vol. 75, No. 17, 2010

Zhu et al.
JOCNote
TABLE 3. Asymmetric Hydrogenation of 1 with [RuCl(benzene)(S)-
SunPhos]Cla
TABLE 4. Asymmetric Hydrogenation of 3a and 4aa
entry
substrate
C6H5 (1a)
4-Me-C6H4 (1b)
ee (%)b
configurationc
1
2
3
4
5
6
7
8
9
89.2
89.2
85.4
87.6
87.6
89.4
87.3
88.2
89.5
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
entry substrate
additive
time (h) ee (%)b (configurationc)
4-F-C6H4 (1c)
1
2
3
4
5
6
7
3a
3a
3a
4a
4a
4a
4a
1 M HCl aq
1 M HBr aq
1 M HI aq
1 M HCl aq
1 M HBr aq
1 M HI aq
20
20
20
5
5
5
10
13.0 (R)
21.2 (R)
23.0 (R)
89.3 (S)
4-Cl-C6H4 (1d)
4-Br-C6H4 (1e)
4-MeOC6H4 (1f)
3-Cl-C6H4 (1g)
91.8 (S)
91.4 (S)
2,4-Cl2-C6H3 (1h)
benzo[d][1,3]dioxol-5-yl (1i)
1 M HBr aq
90.1d/99.0e (S)
aAll reactions were carried out under 400 psi of hydrogen with a
substrate (1 mmol) concentration of 0.20 M in THF at 90 °C for 20 h;
substrate/catalyst/1 M HBr aq = 100/1/6, conversion = 100%. bValues
of corresponding esters 5. cThe configuration was determined to be S by
comparing the specific rotation with reported data.5
aUnless otherwisely noted, all reactions were carried out under 400 psi
of hydrogen with a substrate (1 mmol) concentration of 0.20 M in THF,
substrate/catalyst/additive = 100/1/6. bDetermined by HPLC on a
Chiralpak OD-H column after transferring acids to esters. cThe config-
uration was determined by comparing the specific rotation with reported
data. dSubstrate/catalyst = 2000/1 at 20 mmol scale. eEnantiomeric
excess value after upgrading.
Trace of pure water also plays an important role in promot-
ing the enantioselectivity (Table 2, entry 12 vs 13); it gives a
comparable result to that when 1 M aq HBr is used as
additive. To make it clear whether the acidic condition or
the aqueous condition is more important in achieving better
enantioselectivity,9 anhydrous HBr was employed as addi-
tive. To our surprise, the reaction gave much lower ee than
when water was used as additive (Table 2, entry 20). The
addition of water also improved hydrogenation rate, but the
combination of Brønsted acid and water is superior to either
of them in terms of reaction rate and enantioselectivity.
When Binap was used as ligand, the enantiomeric excess
dropped as low as 48.0% (Table 2, entry 17); C3-tunephos
and structurally related SegPhos gave similar results as
Sunphos, and products with 84.0 and 84.8% ee, respectively,
were obtained (Table 2, entries 18 and 19).
On the basis of these results, the optimized reaction
conditions were therefore set as follows: 1 mol % of [RuCl-
(benzene)(S)-SunPhos]Cl as the catalyst, 6 mol % of 1 M
aqueous HBr as the additive, THF as the solvent with a sub-
strate concentration of 0.2 M under 400 psi of H2 at 90 °C.
Under the optimized reaction conditions, a series of (E)-2-
oxo-4-arylbut-3-enoic acids were hydrogenated using [RuCl-
(benzene)(S)-SunPhos]Cl as catalyst (Table 3). Judging from
the results, although the influence is not remarkable, sub-
strates with electron-donating substituents gave better en-
antioselectivities than substrates with electron-withdrawing
substituents; steric factor of the aromatic ring seems to be not
important on the enantioselectivities.
of hydrochloric acid. The reaction time was intentionally set
short to detect the isomerized product and to analyze the
enantiomeric excess of the product and the unreacted start-
ing material. Both the starting material and the product are
nonracemic; unfortunately, we did not detect any isomer-
ized product, 2-oxo-4-phenylbutanoic acid.10 From the data
(Table 4, entries 1-3) obtained, the reaction is apparently
not a kinetic resolution reaction; otherwise, the enantiomeric
excess of the product will be 0 with complete conversion of
the starting material. These results imply that the hydro-
genation of 3a is not a purely direct hydrogenation reaction
of the CdC bond; isomerization of 3a to 4a is probably one
of the pathways, which is not rare in ruthenium-catalyzed
reactions.11 The results in Table 4 (entries 4-6) showed that
the reduction of 4a is much faster than those of 1a and 3a;
therefore, it is reasonable that we have not detected any 4a in
the hydrogenation of racemic 3a.
On the basis of the observed results, we proposed the
reaction pathways from 1a to 2a as follows (Scheme 1):
reduction of 1a to give 3a is a fast step, while the reduction of
3a to 2a is relatively slow but faster than the isomerization of
3a to 4a. Although we could not rule out the possibility of the
hydrogenation of the CdC bond prior to the hydrogenation
of the CdO bond in 2a,12 we believe that the reduction, if
there is any, should be very slow.
In conclusion, we have presented an effective strategy for
the conversion of inexpensive (E)-2-oxo-4-arylbut-3-enoic
To investigate whether the CdC double bond in 3a could
be isomerized into its corresponding saturated R-keto acid,
2-oxo-4-phenylbutanoic acid, before hydrogenation, some
control hydrogenation reactions were conducted under dif-
ferent reaction conditions, which provided further insight
into the reaction pathways. The results are summarized in
Table 4.
(10) If the hydrogenation was terminated after 5 h, the conversion is 25%.
The product 2a (S) was 35.4% ee, and the unreacted starting material 3a0 (R)
was 19.0% ee.
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Hydrogenation of racemic 3a was conducted with
[RuCl(benzene)(S)-SunPhos]Cl as catalyst in the presence
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€
(9) After reviewing our manuscript, one reviewer kindly suggested we do
more experiments to make it clear whether the counterion or the aqueous
reaction condition plays a more important role in achieving high enantio-
selectivity.
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J. A. J. Am. Chem. Soc. 2006, 128, 1360. ( j) Crochet, P.; Fernandez-Zumel,
M. A.; Gimeno, J.; Scheele, M. Organometallics 2006, 25, 4846.
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J. Org. Chem. Vol. 75, No. 17, 2010 6029

Zhu et al.
JOCNote
SCHEME 1. Reaction Pathways from 1a to 2a
to afford potassium 2-oxo-4-phenylbut-3-enoate as a yellow
solid (38.3 g, 89%).
A saturated solution of the salt at 40 °C was poured into a
rapidly stirred solution of hydrochloric acid (2 M), and the
resulting benzylidenepyruvic acid precipitated from water as a
hydrate. The hydrated product was dissolved in benzene after
azotropic removal of water with benzene, and product (1a) was
obtained (26.5 g, 84%) by cooling the benzene solution to room
temperature.
Typical Procedure for the Asymmetric Hydrogenation of 1:
[RuCl(benzene)(S)-SunPhos]Cl (40 mg, 0.04 mmol) was dis-
solved in degassed THF (20 mL) containing 1 M aq HBr
(240 μL), and then the solution was put into four vials equally.
To these vials were introduced (E)-2-oxo-4-arylbut-3-enoic acids
(1 mmol), and then the vials were taken into an autoclave. The
autoclave was purged three times with H2, and the pressure of
H2 was set to 400 psi. The autoclave was stirred under specified
reaction conditions. After being cooled to ambient temperature
and release of hydrogen, the autoclave was opened and the
solvent was evaporated. The residue was refluxed in EtOH with
a drop of concentrated sulfuric acid for 5 h, and the ester was
passed through a short pad of silica gel with petroleum ether and
ethyl acetate before the ee was determined by HPLC.
Procedure for the Improvement of Enantiomeric Purity. Hy-
drogenation reaction of 1a was run at 20 mmol scale. The
reaction solvent was evaporated under reduced pressure at
40 °C, and then the residue was dissolved in ethyl acetate
(20 mL) and washed with brine (5 mL ꢀ 3). After the organic
layer was separated and dried over MgSO4, the solvent was
evaporated to give the crude product which was recrystallized
from 1,2-dichloroethylene (20 mL) to give 2a (3.0 g, 85%) with
an enantiomeric purity of 99%.
acids directly into optically active 2-hydroxy-4-arylbutanoic
acids employing a homogeneous Ru-Sunphos catalyst.
Further investigation has proven that the hydrogenation
proceeds via three possible reaction pathways. The enantio-
meric excesses of 2-hydroxy-4-phenylbutanoic acids were
easily upgraded to 99% after a single recrystallization. This
reaction has indicated a potential procedure for the prepara-
tion of the useful intermediates for ACE inhibitors.
Experimental Section
General Procedure for the Preparation of (E)-2-Oxo-4-aryl-
but-3-enoic acid 1: To a stirred solution of benzaldehyde (21.2 g,
0.20 mol) in methanol (15 mL) was added pyruvic acid (17.2 g,
0.20 mmol) at 0 °C under nitrogen. A solution of KOH (16.8 g,
0.30 mmol) in methanol (60 mL) was added dropwise to keep
the reaction temperature below 15 °C; after the addition of 2/3 of
the alkali, the rest of the alkali was added in one portion before
precipitation of potassium pyruvate could occur. Then the ice
bath was removed, and the temperature of the reaction mixture
increased from 20 to 35-40 °C. The reaction mixture was stirred
at this temperature for 3 h and then cooled to 10 °C and
maintained at this temperature for 10 h. The solid precipitated
out was filtered on a Buchner funnel under suction and washed
with chilled methanol (75 mL) followed by diethyl ether (75 mL)
Acknowledgment. We thank the National Natural Science
Foundation of China, the Science and Technology Commis-
sion, and the Education Commission of Shanghai Munici-
pality for financial support.
(12) (a) Massonneau, V.; Le Maux, P.; Simonneaux, G. J. Organomet.
Chem. 1987, 327, 269. (b) Ohta, T.; Miyake, T.; Seido, N.; Kumobayashi, H.;
Takaya, H. J. Org. Chem. 1995, 60, 357. (c) Hilgraf, R.; Pfaltz, A. Adv. Synth.
Catal. 2005, 347, 61. (d) Jaekel, C.; Paciello, R. (BASF AG, Germany) PCT
Int. Appl. WO2006040096, 2006. (e) McIntosh, A. I.; Watson, D. J.; Burton,
J. W.; Lambert, R. M. J. Am. Chem. Soc. 2006, 128, 7329.
Supporting Information Available: NMR and HPLC data of
compounds 1, 2a, 3a, 4a, 5, and 6a. This material is available free
of charge via the Internet at http://pubs.acs.org.
6030 J. Org. Chem. Vol. 75, No. 17, 2010