Highly enantioselective hydrogenation of 2-oxo-4-arybutanoic acids to 2-hydroxy-4-arylbutanoic acids

Article abstract of DOI:10.1016/j.tet.2011.06.071

The Ru-catalyzed asymmetric hydrogenation of 2-oxo-4-arybutanoic acids to afford 2-hydroxy-4-arybutanoic acids was accomplished by employing SunPhos as chiral ligand and 1 M aq HBr as additive. The high enantioselectivities (88.4%-92.6% ee) and efficiency (TON=10,000, TOF=300 h^-1) make this method efficient for the synthesis of an important intermediate, (R)-2-hydroxy-4-phenylbutanoic acid, for ACE inhibitors.

Full text of DOI:10.1016/j.tet.2011.06.071

Tetrahedron 67 (2011) 6186e6190
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly enantioselective hydrogenation of 2-oxo-4-arybutanoic acids
to 2-hydroxy-4-arylbutanoic acids
,
b
b
b
b,c,
*
Lufeng Zhu a, Houhe Chen a , Qinghua Meng , Weizheng Fan , Xiaomin Xie , Zhaoguo Zhang
*
a School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiaolingwei, Nanjing 210094, China
b School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
c Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 May 2011
Received in revised form 16 June 2011
Accepted 21 June 2011
Available online 28 June 2011
The Ru-catalyzed asymmetric hydrogenation of 2-oxo-4-arybutanoic acids to afford 2-hydroxy-4-
arybutanoic acids was accomplished by employing SunPhos as chiral ligand and 1 M aq HBr as addi-
tive. The high enantioselectivities (88.4%e92.6% ee) and efficiency (TON¼10,000, TOF¼300 hꢀ1) make
this method efficient for the synthesis of an important intermediate, (R)-2-hydroxy-4-phenylbutanoic
acid, for ACE inhibitors.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric hydrogenation
a
-Keto acid
Ruthenium
SunPhos
Additive
1. Introduction
dihydrocinchonidine (DHCD) to give the product with up to 88% ee,
on 100e200 g scale with 50e60% yield and >99% ee of the final
The optically pure
a
-hydroxy acids and their derivatives are
product, but the repeatability and future hydrogenation of the
carbonyl group to methylene group with Pd/C make the method
less attractive (Scheme 1);7 Rh complexes (AMPP,8 BoPhoz9) and Ru
complexes (MandyPhos,10 TaniaPhos,10 PQ-Phos,11,12b TunePhos12
and etc.13) were applied as catalysts in the asymmetric hydroge-
nation of ethyl 2-oxo-4-phenylbutanoate, fair to excellent enan-
important chiral structural units, which have been used as a con-
venient building block in organic synthesis of a wide variety of
natural products and biologically active molecules.1 For instance,
ethyl (R)-2-hydroxy-4-phenylbutyrate is an intermediate of a vari-
ety of commercially angiotensin-converting enzyme (ACE) in-
hibitors, such as benazepril, cilazapril and delapril hydrochloride.2
Some synthetic routes to ethyl (R)-2-hydroxy-4-phenylbutyrate
have been developed, including classical kinetic resolution of
chemical or enzyme,3 catalytic enantioselective reduction of its
prochiral precursor 2-oxo-4-phenylbutanoic acid or its ethyl ester
by microbe and enzyme,4 multistep asymmetric synthesis5 and
heterogeneous asymmetric hydrogenation.6 Among these strate-
tioselectivities were obtained, however, a-keto esters are unstable
substrates for asymmetric hydrogenation, which makes it difficult
to repeat even under delicately optimized reaction conditions.7a,14
O
OH
O
OH
DHCD/Pt/Al2O3
toluene, H2
OEt
OEt
OEt
Ph
Ph
Ph
gies, asymmetric hydrogenation of the corresponding
a
-keto acid
O
O
yield: 98%; ee: 88%
and its derivatives to give enantiomerically pure ethyl (R)-2-
hydroxy-4-phenylbutyrate is most practical and powerful.1
recrystalli-
zation
Recently, some significant progresses have been achieved in the
synthesis of optically pure 2-hydroxy-4-phenylbutanoic acid and
its ester by transition metal-catalyzed asymmetric hydrogenation.
Hydrogenation of ethyl 2-hydroxy-4-oxo-4-phenyl-2-butenoate
with heterogeneous platinum/Al2O3 catalyst modified with
OH
O
OH
5% Pd/C
EtOH/HCl, H2
OEt
Ph
O
O
overall yield: 50-60%
yield: 65%; ee: >99%
ee: >99%
* Corresponding authors. Tel./fax: þ86 021 5474 8925 (Z.Z.); tel.: þ86 025 8431
5523 (H.C.); e-mail addresses: chhh42792@yahoo.com.cn (H. Chen), zhaoguo@
sjtu.edu.cn (Z. Zhang).
Scheme 1. DHCD/Pt/Al2O3 catalyzed asymmetric hydrogenation of ethyl 2-hydroxy-4-
oxo-4-phenyl-2-butenoate.7
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.071

L. Zhu et al. / Tetrahedron 67 (2011) 6186e6190
6187
To solve this problem, we chose (E)-ethyl 2-oxo-4-phenylbut-3-
enoate as the hydrogenation substrate and Ru-SunPhos complex as
catalyst, an excellent enantioselectivity (up to 94% ee, TON up to
2000) was obtained. Both catalytic efficiency and repeatability
were improved, however, hydrolysis and recrystallization of the
resulting acid were still needed to upgrade the enantiomeric purity
of the product (Scheme 2).15
catalyst, however, addition of pure water gave even poorer ee
(entry 11 vs entry 1). Addition of other aqueous Brønsted acid
showed negligible effect on enantioselectivity (entries 12e17).
To examine the ligand effects, (S)-SunPhos, (R)-L5, (R)-L6 and
three commercially available chiral bidentate phosphines, (S)-
Binap, (S)-C3-TunePhos and (S)-SegPhos (Fig. 1) were screened
under the same reaction conditions (Table 2). The catalyst was
O
OH
OH
Ru-SunPhos
OEt
LiOH
hydrolysis
OEt
OH
Ph
Ph
Ph
Ph
EtOH, H2
O
O
O
ee: 94%
ee: 94%
recrystalli-
zation
OH
OH
OEt
EtOH
OH
Ph
esterification
O
O
overall yield: 77%
ee: 99%
yield: 81%; ee: 99%
Scheme 2. Asymmetric hydrogenation of ethyl 2-oxo-4-phenylbut-3-enoate with Ru-SunPhos catalyst.15
Table 1
Therefore, we have designed a direct conversion of (E)-2-oxo-4-
phenylbut-3-enoic acid to corresponding optically pure saturated
The effects of pressure, temperature and additivea
O
OH
hydroxyl acid by asymmetric hydrogenation. Although
a-keto acids
OH
catalyst, H2
additive
OH
and -hydroxy acids usually serve as ligands, which compete with
a
Ph
Ph
O
the counter anion of the catalyst and affect the enantioselectivity
and/or reactivity of catalyst,16 with the help of a Brønsted acid as
additive, we succeeded in hydrogenating two unsaturations in the
substrates and obtained hydroxy acids with good enantioselectiv-
ities.17 Further investigation indicated that the hydrogenation did
not proceed via a sequential hydrogenation of C]O and C]C
O
1a
2a
O
cat. = [RuCl (benzene)(S)-SunPhos]Cl
O
O
PPh2
PPh2
O
double bonds, and the reduction of a-keto acids proceeded even
(S)-SunPhos
faster. Therefore, an extensive investigation of asymmetric hydro-
genation of 2-oxo-4-arylbutanoic acids was conducted.
Entry
Additive
Press (psi)
Temp (ꢁC)
Time (h)
eeb (%)
1
2
3
4
5
6
7
8
None
None
None
None
None
I2
HBr (gas)
1 M HCl aq
1 M HI aq
1 M HBr aq
H2O
1 M CF3CO2H aq
1 M CF3SO3H aq
1 M H3BO3 aq
1 M H2SO4 aq
1 M CSA aq
1 M HBF4 aq
400
400
400
200
600
400
400
400
400
400
400
400
400
400
400
400
400
70
90
110
70
70
70
70
70
70
70
70
70
70
70
70
70
70
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
87.8
81.4
73.8
83.0
83.8
81.6
76.5c
89.4
89.6
92.2
84.5d
85.8
89.2
86.2
86.2
88.2
88.9
2. Results and discussion
We first chose 2-oxo-4-phenylbutanoic acid 1a as the substrate,
employ [RuCl(benzene)(S)-SunPhos]Cl as catalyst, THF as solvent to
examine the effects of the reaction temperature and H2 pressure.
The representative results are summarized in Table 1 (entries 1e5).
The influence of temperature is dramatic, when the reaction was
run at temperature lower than 50 ꢁC, no reaction was observed;
when the reaction was conducted at a temperature higher than
70 ꢁC, the reaction rate was improved at a cost of scarifying enan-
tioselectivity. H2 pressure also impact a slight effect on the enan-
tioselectivity (Table 1, entries 1 vs 4, 5), finally, the reaction
condition was set at a H2 pressure of 400 psi and reaction tem-
perature of 70 ꢁC.
In the hydrogenation of 2-oxo-4-aryl-3-butenoic acids, we
employed aqueous solutions of Brønsted acids and Lewis acids as
additives and found that not only enantioselectivities but also
catalytic efficiency were improved,17 we screened a number of
commonly-used aqueous solutions of Brønsted as additives ac-
cordingly in the asymmetric hydrogenation of 2-oxo-4-
phenylbutanoic acid, the results were also summarized in Table 1
(entries 6e17).
9
10
11
12
13
14
15
16
17
a
Unless otherwisely noted, all reactions were carried out with a substrate
in solvent for 20 h, substrate/catalyst/
(1 mmol) concentration of 0.20
M
a
additive¼200/1/12, conversion: >99%.
b
ee values were determined by HPLC on a Chiralpak OD-H column after trans-
ferring acid 2a to ester 3a.
c
HBr (6 mol %) gas in solvent.
H2O (60 mL).
d
prepared similarly from [Ru(benzene)Cl2]2 and a diphosphine li-
gand by refluxing them in degassed EtOH/DCM, the results were
summarized in Table 2. Unfortunately, of the ligands investigated,
none gave better enantioselectivity. When structurally similar li-
gands were employed, such as (S)-C3-TunePhos, (S)-SegPhos, (R)-L5
and (R)-L6, similar ees have been observed (Table 2, entries 1e4);
when Binap was applied as ligand, the enantioselectivity dropped
as low as 45.6% (Table 2, entry 5).
Addition of anhydrous hydrohalogenic acid (anhydrous HI was
generated in situ with I2 and hydrogen) resulted decrease of
enantioselectivity (entries 6, 7); aqueous hydrohalogenic acid im-
proved the enantioselectivity, and the ee was increased to 92.2%
with catalytic amount of 1 M aq HBr. It implies that water plays an
important role in affecting the enantioselectivity and activity of

6188
L. Zhu et al. / Tetrahedron 67 (2011) 6186e6190
Although the substitution pattern of the aryl did not impact a re-
O
markable influence (88.4e92.6% ee), the substrates with electron-
donating substituents generally gave a little better enantiose-
lectivities (Table 3, entries 5e10 vs entries 2e4). It is worth noting
that when the substrate to catalyst ratio was increased to 10,000,
the asymmetric hydrogenation complete in 30 h with neglectable
enantioselectivity decrease (Table 3, entry 11).
O
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
PPh2
H2C
3
O
O
(S)-C3-TunePhos
(S)-SegPhos
(S)-Binap
As was reported in our previous publications,15,17 the resulted
acids can be easily upgraded to >99.0% ee by simple re-
crystallization, and this method provides a most direct and efficient
way up to now in asymmetric hydrogenation reactions to make
optically pure ethyl 2-hydroxy-4-phenylbutanoate.
O
O
O
O
O
PPh2
PPh2
PAr2
PAr2
O
O
O
L5, Ar = 4-MeC6H4-
, Ar = 4-OMe-3,5-(CH3)2C6H2-
3. Conclusion
(R)-L
(S)-SunPhos
L6
In conclusion, we have presented an effective strategy for the
conversion of inexpensive 2-oxo-4-arylbutanoic acids directly into
optically active 2-hydroxy-4-arylbutanoic acids by asymmetric
hydrogenation. And up to 92.6% ee has been achieved with
[RuCl(benzene)(S)-SunPhos]Cl as the catalyst and 1 M aq HBr as the
additive. The ee of 2-hydroxy-4-phenylbutanoic acid was easily
upgraded to 99% after a single recrystallization. The application of
this procedure for the large scale preparation of ethyl 2-hydroxy-4-
phenylbutanoate is in progress.
Fig. 1. Struture of chiral bidentate ligands.
Table 2
Catalytic asymmetric hydrogenation of 1a with [RuCl(benzene)L]Cla
Entry
Ligand
eeb (%)
Configc
1
2
3
4
5
6
(S)-C3-TunePhos
(S)-SegPhos
(R)-L5
(R)-L6
(S)-Binap
84.2
85.8
86.7
89.0
45.6
92.2
(S)
(S)
(R)
(R)
(S)
(S)
(S)-SunPhos
a
Unless otherwisely noted, all reactions were carried out with a substrate
(1 mmol) concentration of 0.20 M in a solvent for 12 h, 1 M HBr aq as the additive,
substrate/catalyst/additive¼200/1/12, conversion: >99%.
4. Experimental section
b
ee values were determined by HPLC on a Chiralpak OD-H column after trans-
ferring acid 2a to ester 3a.
The configuration was determined to be S or R by comparing the specific rota-
tion with reported data.
4.1. General procedure for the preparation of 2-oxo-4-
arylbutanoic acids 1
c
2-Oxo-4-arylbutanoic acids were synthesized according to the
literatures.18
Based on the results, the optimized reaction conditions were
therefore set as the following: 1.0 mmol 1 as substrate, 0.5 mol % of
[RuCl(benzene)(S)-SunPhos]Cl as the catalyst, 6 mol % of 1 M aq HBr
as the additive, THF as the solvent with a substrate concentration of
0.2 M under 400 psi of H2 at 70 ꢁC.
Under the optimized reaction conditions, a variety of 2-oxo-4-
arylbutanoic acids were examined for the hydrogenation reaction
with [RuCl(benzene)(S)-SunPhos]Cl as the catalyst (Table 3).
4.1.1. Compound 1a. 1H NMR (400 MHz, CDCl3)
d 7.30e7.18 (m, 5H),
3.23 (t, J¼7.6 Hz, 2H), 2.95 (t, J¼7.2 Hz, 2H). 13C NMR (100 MHz,
CDCl3)
d 195.6, 161.8, 140.2, 128.9, 128.6, 126.6, 40.4, 29.0.
4.1.2. Compound 1b. 1H NMR (400 MHz, CDCl3)
d 7.26e7.18 (m, 2H),
7.08e6.99 (m, 2H), 3.27 (t, J¼7.2 Hz, 2H), 3.00 (t, J¼7.1 Hz, 2H). 13C
Table 3
NMR (101 MHz, CDCl3)
J¼4.5 Hz), 128.6 (d, J¼7.7 Hz), 126.6 (d, J¼15.8 Hz), 124.3 (d,
J¼5.2 Hz), 115.5 (d, J¼21.9 Hz), 38.2, 22.9 (d, J¼3.5 Hz).
d
194.5, 161.4 (d, J¼209.2 Hz),160.0,130.8 (d,
Asymmetric hydrogenation of 1 with [RuCl(benzene)(S)-SunPhos]Cla
O
OH
OH
catalyst, H2
1M HBr aq
OH
Ar
Ar
4.1.3. Compound 1c. 1H NMR (400 MHz, CDCl3)
d 7.21e7.24 (m, 1H),
O
O
6.99e6.90 (m, 3H), 3.30 (t, J¼7.5 Hz, 2H), 2.99 (t, J¼7.6 Hz, 2H). 13C
1
2
NMR (100 MHz, CDCl3)
(d, J¼7.2 Hz), 130.2 (d, J¼8.3 Hz), 124.1 (d, J¼7.5 Hz), 115.5 (d,
J¼21.1 Hz), 113.7 (d, J¼24.3 Hz), 39.1, 28.7 (d, J¼1.7 Hz).
d
194.5, 163.0 (d, J¼244.1 Hz), 160.2, 142.2
Entry
Substrate
eeb (%)
Configc
1
2
3
4
5
6
7
8
C6H5 (1a)
92.2
88.4
89.2
89.9
92.6
90.8
92.6
91.9
92.0
92.4
91.6d
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
2-FeC6H4 (1b)
3-FeC6H4 (1c)
4-FeC6H4 (1d)
4-CleC6H4 (1e)
4-BreC6H4 (1f)
2,4-Cl2eC6H3 (1g)
4-MeeC6H4 (1h)
4-MeOC6H4 (1i)
4.1.4. Compound 1d. 1H NMR (400 MHz, CDCl3)
d 7.18e7.15 (m, 2H),
7.00e6.96 (m, 2H), 3.27 (t, J¼7.4 Hz, 2H), 2.96 (t, J¼7.4 Hz, 2H). 13C
NMR (100 MHz, CDCl3)
d
194.4,161.8 (d, J¼208.4 Hz),160.4,135.3 (d,
J¼4.0 Hz),129.9 (d, J¼8.8 Hz), 115.5 (d, J¼10.7 Hz), 39.7, 28.2. HRMS:
calculated for C10H9FO3 (MꢀH)þ: 195.0457, found: 195.0471.
9
10
11
Benzo[d][1,3]dioxol-5-yl (1j)
C6H5 (1a)
4.1.5. Compound 1e. 1H NMR (400 MHz, CDCl3)
d 7.28e7.25 (m,
a
2H), 7.15e7.13 (m, 2H), 3.28 (t, J¼7.3 Hz, 2H), 2.96 (t, J¼7.3 Hz, 2H).
All reactions were carried out under 400 psi of hydrogen with a substrate
(1 mmol) concentration of 0.20 M in THF at 70 ꢁC for 20 h. Substrate/catalyst/1 M
HBr aq¼200/1/12, conversion: >99%.
13C NMR (100 MHz, CDCl3)
39.3, 28.3.
d 194.5, 160.3, 138.1, 132.4, 129.8, 128.9,
b
ee values of corresponding esters 3.
c
The configuration was determined to be S by comparing the specific rotation
4.1.6. Compound 1f. 1H NMR (400 MHz, CDCl3)
d 7.43e7.41 (m, 2H),
with reported data.
7.16e6.82 (m, 2H), 3.29 (t, J¼7.4 Hz, 2H), 2.97 (t, J¼7.4 Hz, 2H). 13C
d
The reaction was run at substrate/catalyst¼10,000, substrate: 20 mmol, con-
version: >99%.
NMR (101 MHz, CDCl3) d 194.7, 160.9, 138.8, 131.8, 130.2, 120.4, 39.6,

L. Zhu et al. / Tetrahedron 67 (2011) 6186e6190
6189
28.4. HRMS: calculated for C10H9BrO3 (MꢀH)þ: 254.9657, found:
(100 MHz, DMSO)
130.2 (d, J¼7.2 Hz), 115.1 (d, J¼21.0 Hz), 69.0, 35.9, 30.2.
d
175.9, 160.8 (d, J¼239.7 Hz), 137.7 (d, J¼2.8 Hz),
254.9661.
4.1.7. Compound 1g. 1H NMR (400 MHz, CDCl3)
d
7.38e7.20 (m,
4.2.5. Compound 2e. 1H NMR (400 MHz, DMSO)
d 7.35e7.32 (m,
3H), 3.30 (t, J¼7.4 Hz, 2H), 3.06 (t, J¼7.3 Hz, 2H). 13C NMR (100 MHz,
2H), 7.25e7.21 (m, 2H), 3.90 (dd, J¼8.4, 4.2 Hz, 1H), 2.66 (t, J¼7.9 Hz,
CDCl3)
d 194.3, 159.9, 135.8, 134.7, 133.3, 131.6, 129.6, 127.45, 37.5,
2H), 1.95e1.79 (m, 1H), 1.78e1.74 (m, 1H). 13C NMR (100 MHz,
26.6. HRMS: calculated for C10H8Cl2O3 (MꢀH)þ: 244.9772, found:
DMSO)
d 175.8, 140.6, 130.5, 130.3, 120.3, 68.9, 35.6, 30.3.
244.9767.
4.2.6. Compound 2f. 1H NMR (400 MHz, DMSO)
d
7.48e7.45 (m,
4.1.8. Compound 1h. 1H NMR (400 MHz, CDCl3)
d
7.09 (m, 4H), 3.25
2H), 7.19e7.17 (m, 2H), 3.90 (dd, J¼8.4, 4.1 Hz, 1H), 2.64 (t,
(t, J¼7.4 Hz, 2H), 2.94 (t, J¼7.4 Hz, 2H), 2.31 (s, 3H). 13C NMR
J¼7.9 Hz, 2H), 1.95e1.86 (m, 1H), 1.83e1.74 (m, 1H). 13C NMR
(100 MHz, CDCl3)
28.6, 21.0.
d
195.4, 161.4, 136.9, 136.0, 129.3, 128.26, 40.2,
(100 MHz, DMSO) d 176.4, 141.6, 131.8, 131.3, 119.5, 69.5, 36.2, 30.9.
HRMS: calculated for C10H11BrO3 (MꢀH)þ: 256.9813, found:
256.9819.
4.1.9. Compound 1i. 1H NMR (400 MHz, CDCl3)
d 7.13e7.11 (m, 2H),
6.85e6.82 (m, 2H), 3.79 (s, 3H), 3.25 (t, J¼7.4 Hz, 2H), 2.93 (t,
4.2.7. Compound 2g. 1H NMR (400 MHz, DMSO)
d
7.56 (d, J¼1.0 Hz,
J¼7.4 Hz, 2H). 13C NMR (100 MHz, CDCl3)
d
194.7, 160.8, 158.0, 132.0,
1H), 7.37 (t, J¼4.9 Hz, 2H), 3.96 (dd, J¼8.2, 4.2 Hz, 1H), 2.77 (t,
129.4, 114.1, 55.4, 39.9, 28.1.
J¼8.0 Hz, 2H), 1.95e1.88 (m, 1H), 1.83e1.74 (m, 1H). 13C NMR
(100 MHz, DMSO) d 175.6,138.1,133.9,131.9,131.5,128.7,127.4, 69.0,
4.1.10. Compound 1j. 1H NMR (400 MHz, CDCl3)
3H), 5.93 (s, 2H), 3.24 (dd, J¼9.1, 5.7 Hz, 2H), 2.91 (t, J¼7.3 Hz, 2H).
13C NMR (100 MHz, CDCl3)
194.8, 160.2, 147.8, 146.2, 133.5, 121.3,
d
6.74e6.65 (m,
33.7, 28.4. HRMS: calculated for C10H10Cl2O3 (MꢀH)þ: 246.9929,
found: 246.9920.
d
108.9, 108.5, 101.0, 39.7, 28.8. HRMS: calculated for C11H10O5
4.2.8. Compound 2h. 1H NMR (400 MHz, DMSO)
d 7.08e7.00 (m,
(MꢀH)þ: 221.0450, found: 221.0444.
4H), 3.88 (dd, J¼8.4, 4.1 Hz, 1H), 2.60 (t, J¼7.9 Hz, 2H), 2.24 (s, 3H),
1.91e1.82 (m, 1H), 1.79e1.70 (m, 1H). 13C NMR (100 MHz, DMSO)
d
175.9, 138.5, 134.7, 1289.0, 128.3, 69.0, 36.0, 30.6, 20.7.
4.2. Typical procedure for the asymmetric hydrogenation of 1
4.2.9. Compound 2i. 1H NMR (400 MHz, DMSO)
d
7.12 (d, J¼8.6 Hz,
The catalyst [RuCl(benzene)(S)-SunPhos]Cl (40 mg, 0.04 mmol)
was dissolved in degassed THF (40 mL) containing 1 M of aq HBr
2H), 6.84 (dd, J¼9.1, 2.5 Hz, 2H), 3.90 (dd, J¼8.3, 4.1 Hz, 1H), 3.72 (s,
3H), 2.60 (t, J¼7.8 Hz, 2H), 1.91e1.83 (m, 1H), 1.89e1.71 (m, 1H). 13C
(480
mL), and then the solution was put into eight vials equally. To
NMR (100 MHz, DMSO) d 176.0, 147.3, 145.4, 135.4, 121.2, 108.9,
these vials 2-oxo-4-arylbutanoic acids 1 (1 mmol) were introduced,
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 condi-
tions. After being cooled to ambient temperature and release of
hydrogen, the autoclave was opened and the solvent was evapo-
rated. The residue 2 were refluxed in EtOH with a drop of con-
centrated sulfuric acid for 5 h, and the corresponding esters were
passed through a short pad of silica gel with petroleum ether and
ethyl acetate before the ees were determined by HPLC.
108.2, 100.7, 69.0, 36.1, 30.7.
4.2.10. Compound 2j. 1H NMR (400 MHz, DMSO)
d
6.77 (dd, J¼14.3,
4.6 Hz, 2H), 6.65 (dd, J¼7.9, 1.6 Hz, 1H), 5.96 (s, 2H), 3.94e3.83 (m,
1H), 2.66e2.53 (m, 2H), 1.94e1.81 (m, 1H), 1.82e1.66 (m, 1H). 13C
NMR (100 MHz, DMSO)
d 176.0, 147.3, 145.4, 135.4, 121.2, 108.9,
108.2, 100.7, 69.0, 36.1, 30.7. HRMS: calculated for C11H12O5
(MꢀH)þ: 223.0606, found: 223.0606.
4.3. Procedure for the improvement of enantiomeric purity
4.2.1. Compound 2a. 1H NMR (400 MHz, CDCl3)
d 7.31e7.18 (m, 5H),
Hydrogenation 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 (50 mL) and
washed with brine (20 mLꢂ3). After the organic layer was sepa-
rated 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, 83%) with enantio-
meric purity of 99%.
4.27 (dd, J¼4.0, 8.0 Hz,1H), 2.80 (t, J¼8.0 Hz, 2H), 2.23e2.14 (m,1H),
2.05e1.97 (m, 1H). 13C NMR (100 MHz, CDCl3)
d 178.0, 140.9, 128.8,
128.7, 126.4, 69.7, 35.9, 31.2.
4.2.2. Compound 2b. 1H NMR (400 MHz, DMSO)
d 7.26e7.16 (m,
2H), 7.07e6.99 (m, 2H), 4.27 (dd, J¼4.0, 8.0 Hz,1H), 2.84 (t, J¼8.0 Hz,
2H), 2.20e2.16 (m, 1H), 2.05e1.98 (m, 1H). 13C NMR (100 MHz,
DMSO)
d
175.8, 160.7 (d, J¼241.4 Hz), 130.9 (d, J¼5.2 Hz), 128.2 (d,
J¼16.2 Hz), 128.1 (d, J¼4.1H), 124.5 (d, J¼3.6 Hz), 115.2 (d,
J¼20.9 Hz), 69.2, 35.5, 24.4 (d, J¼3.1 Hz). HRMS: calculated for
C10H11FO3 (MꢀH)þ: 197.0603, found: 197.0606.
Acknowledgements
We thank the National Natural Science Foundation of China, the
Science and Technology Commission, and the Education Commis-
sion of Shanghai Municipality for financial support.
4.2.3. Compound 2c. 1H NMR (400 MHz, DMSO)
d 7.35e7.30 (m,
1H), 7.05e6.98 (m, 3H), 3.91 (dd, J¼8.4, 4.1 Hz, 1H), 2.69 (t, J¼7.9 Hz,
2H), 1.95e1.89 (m, 1H), 1.85e1.77 (m, 1H). 13C NMR (100 MHz,
DMSO)
d
175.8, 162.3 (d, J¼242.5 Hz), 144.6 (d, J¼7.2 Hz), 130.2 (d,
J¼8.3 Hz), 124.5 (d, J¼1.9H), 115.1 (d, J¼20.7 Hz), 112.7 (d,
J¼20.8 Hz), 68.9, 35.5, 30.4 (d, J¼62.9 Hz). HRMS: calculated for
C10H11FO3 (MꢀH)þ: 197.0603, found: 197.0601.
Supplementary data
Copies of 1H NMR and 13C NMR spectra of all substrates and
hydrogenation products, and copies of HPLC data of the corre-
sponding chiral esters.
4.2.4. Compound 2d. 1H NMR (400 MHz, DMSO)
d 7.26e7.21 (m,
J¼8.0, 6.4 Hz, 2H), 7.13e7.08 (m, 2H), 3.91 (dd, J¼8.4, 4.1 Hz, 1H),
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.06.071.
2.65 (t, J¼7.9 Hz, 2H), 1.94e1.86 (m, 1H), 1.83e1.76 (m, 1H). 13C NMR

6190
L. Zhu et al. / Tetrahedron 67 (2011) 6186e6190
121, 4920e4921; (c) Exner, C.; Pfaltz, A.; Studer, M.; Blaser, H.-U. Adv. Synth.
Catal. 2003, 345, 1253e1260; (d) Li, X.; Li, C. Catal. Lett. 2001, 77, 251e254; (e)
Szori, K.; Sutyinszki, M.; Felfoldi, K.; Bartok, M. Appl. Catal., A 2002, 237,
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