Dynamic kinetic resolution of β′-keto-β-amino esters using Ru-DTBM-Sunphos catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1016/j.tet.2013.05.136

A convenient method for the enantioselective synthesis of β′-hydroxy-β-amino esters was developed through intensive investigations of the reaction conditions. Dichloromethane (DCM)/2,2,2- trifluoroethanol (TFE) and 1,2-dichloroethane (DCE)/TFE combination

Full text of DOI:10.1016/j.tet.2013.05.136

Tetrahedron 69 (2013) 7152e7156
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Tetrahedron
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Dynamic kinetic resolution of b b-amino esters using
0-keto-
RueDTBMeSunphos catalyzed asymmetric hydrogenation
Xiaoming Li a, Xiaoming Tao a, Xin Ma a, Wanfang Li a, Mengmeng Zhao a, Xiaomin Xie a,
,
a,
*
Tahar Ayad b, Virginie Ratovelomanana-Vidal b , Zhaoguo Zhang
*
a School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
b ENSCP Chimie ParisTech, Laboratoire Charles Friedel (LCF), 75005 Paris, France
a r t i c l e i n f o
a b s t r a c t
A convenient method for the enantioselective synthesis of b b-amino esters was developed
0-hydroxy-
Article history:
Received 24 April 2013
Received in revised form 29 May 2013
Accepted 31 May 2013
Available online 11 June 2013
through intensive investigations of the reaction conditions. Dichloromethane (DCM)/2,2,2-trifluoro-
ethanol (TFE) and 1,2-dichloroethane (DCE)/TFE combinations were found to be the appropriate co-
solvents for the reaction. In this mixed solvent system, [Ru(cymene)Cl2]2eSunphos exhibited un-
usually higher activity and selectivity than the corresponding [Ru(cymene)I2]2eSunphos. In situ gener-
ated catalyst could be used for this transformation. Asymmetric hydrogenation of a series of
amino esters derivatives using RueSunphos complexes via dynamic kinetic resolution led to the corre-
sponding
0-hydroxy-
-amino esters with ee up to 99.6% and de up to 98.8% (S/C¼1000).
Ó 2013 Elsevier Ltd. All rights reserved.
b b-
0-keto-
Keywords:
Asymmetric hydrogenation
Dynamic kinetic resolution
Carbapenem
b
b
O
O
OH
O
1. Introduction
H2
OMe
NHBz
1a
OMe
NHBz
sy n-2a
Ru-(R)-BINAP
Enantiomerically pure
for the asymmetric synthesis of biologically active compounds.1
More specifically, -amino acids play a crucial role in
0-hydroxy-
b-amino acids are useful building blocks
k
fast
b
b
k
k
fast / kslow=15
the syntheses of carbapenem derivatives and other types of b-lac-
k
inv
tams.2 Chemical1,3 and enzymatic approaches1,4 have been de-
veloped to perform the enantio- and diastereo-selective
inv / kslow =92
preparation of
b
0-hydroxy-
b
-amino acids from the corresponding
O
O
OH
O
H2
b
0-keto-
b
-amino acids. Among them, the Takasago’s industrial
OMe
OMe
NHBz
anti-2a
production of 4-acetoxyazetidin-2-one has been successfully ach-
ieved through the asymmetric hydrogenation of racemic 2-
Ru-(R)-BINAP
NHBz
ent-1a
k
slow
substituted
b-ketoesters using dynamic kinetic resolution (DKR,
Scheme 1),5 which was first reported by Noyori et al.6
Scheme 1. Asymmetric hydrogenation of 1 in DCM via DKR process.
Takaya and co-workers7 further investigated the factors con-
trolling the activity and stereoselectivity by using a variety of
dihaloeRu(arene)eBinap complexes as catalysts. They found that
the stereochemical outcome of the reaction strongly depended on
both the nature of halide counter anions of the catalyst
(Iꢀ>Brꢀ>Clꢀ), and the nature of the aryl substituents at the phos-
phorus atom. Particularly, the nature of the substituents on the
phenyl rings of the phosphorus of the Binap-type ligands plays
a crucial role in the reaction. A combination of [Ru(cymene)I2]2 and
(R)-3,5-t-Bu2-Binap gives syn-2a in 99% ee and 98% de. These
results inspired other groups to improve the efficiency and selec-
tivity of new catalytic systems. The catalytic properties of several
ligands, such as Segphos,8 Bitiop,9 and Diophep10 and the use of
different counter anions11 have been evaluated for this trans-
formation. However, most of the reported catalytic methods used
the expensive [Ru(cymene)I2]2 and required careful manipulations.
Our group has focused on the studies of asymmetric hydrogenation
and developed a series of effective methods for the enantioselective
reduction of
a- and b-ketoesters, b-ketosulfones, and poly-
functionalized ketones.12 We report herein the application of
DTBMeSunphos for the enantioselective synthesis of b b-
0-hydroxy-
* Corresponding authors. E-mail address: zhaoguo@sjtu.edu.cn (Z. Zhang).
amino acids via DKR process.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.136

X. Li et al. / Tetrahedron 69 (2013) 7152e7156
7153
2. Results and discussion
Taking into account that the temperature plays a crucial role in
the stereochemical outcome of the hydrogenation (Table 2), com-
pound 2 was prepared with a slightly better ee and de by lowering
the reaction temperature to 60 ꢁC, albeit with a lower conversion
(entry 1) although higher temperature up to 110 ꢁC (Table 2, entries
3e4) led to a roughly 10% decreased diastereoselectivity down to
80.3%, thus 70 ꢁC was chosen as the preferred temperature.
Ethyl 2-(benzamidomethyl)-3-oxobutanoate 1b was chosen as
the model substrate and [Ru(cymene)Cl2]2e(S)-Sunphos was set as
the catalyst to investigate the dynamic kinetic resolution reaction.
Given that large kfast/kslow and kinv/kslow are crucial parameters for
the success of this reaction, solvent, temperature, catalyst and the
factors affecting the reaction rate must be carefully considered.
Because significant solvent effects have been observed in Noyori’s
protocol,6 preliminary studies using the RueSunphos catalytic
system began with a solvent screen (Table 1). When using single
solvents, no desirable ee and de could be obtained. Although al-
cohols exhibited high enantioselectivities, none of them led to good
diastereoselectivities (Table 1, entries 1e4). 2,2,2-Trifluoroethanol
(TFE),13 which is more acidic than methanol and ethanol gave
better de up to 83.2% but lower ee up to 92.9% compare to MeOH or
EtOH (entries 1, 2 vs 5). As for aprotic solvents, DCM and 1,2-DCE
afforded good ee and much better syn/anti diastereoselectivity
than the corresponding alcohols (entries 9e10). Noyori et al. re-
ported that the reaction could be carried out in a mixed solvent of
DCM/MeOH.6 Consequently, several experiments using either DCM
or DCE and alcohols as co-solvents were conducted (entries
12e23). No remarkable enhancement was made using DCM/MeOH,
DCM/EtOH or DCE/EtOH although a significant improvement was
obtained using DCM/TFE with 98.9% ee and 95/5 syn/anti diaster-
eoselectivity using a volumetric ratio of DCM/TFE¼3/1 (entry 18). A
co-solvent of DCE/TFE¼3/1 showed comparable result (entry 23).
Moreover, the enantioselectivity decreased when the ratio of DCM/
TFE changed from 3/1 to 1/7 (entries 18e22). Therefore, the co-
solvent of DCM/TFE¼3/1 was selected to perform the
hydrogenation.
Table 2
Optimization of reaction temperaturea
O
O
OH
O
H2
OEt
NHBz
OEt
NHBz
Ru-(S)-Sunphos
1b
2b
Entry
Temperature (ꢁC)
Conversion (%)
ee (2R,3S, %)
de (%)
1
2
3
4
60
70
90
79.7
100
100
99.3
98.9
98.6
98.7
91.5
90.0
81.5
80.3
110
100
a
Catalyst¼[Ru(cymene)Cl2]2e(S)-Sunphos (preformed), S/C¼100, c¼0.25 M, sol-
vent: DCM/TFE¼3/1, P¼50 bar, t¼20 h, ee and de were determined by HPLC.
The reaction was not influenced by the hydrogen pressure, and
similar ee and de of the products were obtained when the hydrogen
pressure varied from 10 to 70 bar. Therefore, the optimized con-
dition of hydrogenation using [Ru(cymene)Cl2]2e(S)-Sunphos as
catalyst was set as: 70 ꢁC, 50 bar of H2, in a 0.25 M solution of
a mixed solvent of DCM/TFE¼3/1 (v/v). Under these conditions, an
extensive number of Ru-complexes bearing diphosphine ligands
were tested (Table 3). In all cases, the reaction proceeded smoothly
to give the desired product 2b with good to excellent enantio- and
diastereo-selectivity. Atropisomeric diphosphine ligands, such as
Binap,14 Segphos,8 Synphos,15 MeO-Biphep,16 and C3-Tunephos17
led to high enantioselectivities up to 98.7% and diaster-
eoselectivities up to 90.2% (Table 3, entries 1e5, preformed
Table 1
Solvent screena
O
O
OH
O
H2
OEt
NHBz
OEt
NHBz
Table 3
Ru-(S)-Sunphos
Asymmetric hydrogenation of 1b with Ru(II) complexes
O
O
OH
O
1b
2b
H2
*
*
OEt
OEt
Entry
Solvent
Conversion (%)
ee (2R,3S, %)
de (%)
Ru-Ligands
1
2
3
4
MeOH
100
100
100
100
100
27.7
60.8
51.2
100
100
89.6
100
100
100
100
100
100
100
100
100
100
100
100
98.3
98.7
95.1
61.9
92.9
76.3
44.5
72.8
98.7
97.9
66.0
99.4
98.0
99.4
94.5
98.8
97.9
98.9
96.9
95.2
95.5
93.3
99.2
23.2
19.8
28.2
33.6
83.2
ꢀ74.8
ꢀ8.2
ꢀ80.4
73.8
73.2
37.8
61.6
62.2
60.0
82.4
84.6
86.0
90.0
83.6
84.8
84.6
82.6
88.6
NHBz
1b
NHBz
2b
EtOH
n-PrOH
i-PrOH
O
L1: (S)-Sunphos, Ar=phenyl
L2: (S)-Me-Sunphos, Ar=4-Me-phenyl
L3: (S)-Xyl-Sunphos, Ar=3,5-Me -phenyl
O
O
5
TFE
PAr2
PAr2
6b
7b
8b
9
Toluene
2
L4: (R)-DMM-Sunphos, Ar=3,5-Me -4-MeO-phenyl
2
EtOAc
L5: (S)-DTBM-Sunphos, Ar=3,5-t-Bu -4-MeO-phenyl
2
O
THF
DCM
Entry
Ligand
Conversion (%)
ee (%)
de (%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1,2-DCE
1,4-Dioxane
DCM/MeOH¼7/1
DCM/EtOH¼7/1
1,2-DCE/EtOH¼7/1
DCM/TFE¼9/1
DCM/TFE¼7/1
DCM/TFE¼5/1
DCM/TFE¼3/1
DCM/TFE¼1/1
DCM/TFE¼1/3
DCM/TFE¼1/5
DCM/TFE¼1/7
1,2-DCE/TFE¼3/1
1
2
3
4
5
6
7
8
(R)-Binap
(S)-Segphos
(R)-Synphos
(S)-MeO-Biphep
100
100
100
100
100
100
100
100
100
100
100
100
100
90.5
98.1 (2S,3R)
98.2 (2R,3S)
92.4 (2S,3R)
98.7 (2R,3S)
98.7 (2R,3S)
98.9 (2R,3S)
96.7 (2R,3S)
97.3 (2R,3S)
98.1 (2S,3R)
99.3 (2R,3S)
99.0 (2R,3S)
98.7 (2R,3S)
99.2 (2R,3S)
95.9 (2R,3S)
87.2
84.2
87.4
87.8
90.2
90.0
89.7
89.5
92.3
99.4
90.5
97.5
90.7
88.0
(S)-C3-Tunephos
L1
L2
L3
L4
L5
L1
L5
L1
L1
9
10
11a
12a
13b
14c
a
Catalyst¼[Ru(cymene)Cl2]2e(S)-Sunphos (preformed), S/C¼100, c¼0.25 M,
P¼50 bar, T¼70 ꢁC, t¼20 h, ee and de were determined by HPLC, the absolute
configuration was determined by comparison with Ref. [9]. de¼[(syn-2b)ꢀ(anti-
2b)]/[(syn-2b)þ(anti-2b)].
a
Catalysts were in situ formed. [Ru(cymene)Cl2]2 and ligands were added to-
gether with substrates and used directly for hydrogenation.
b
[Ru(benzene)Cl2]2.
[Ru(cymene)I2]2.
b
c
(2R,3S)-2b was not the major product.

7154
X. Li et al. / Tetrahedron 69 (2013) 7152e7156
catalysts). Better results were obtained in term of enantioselectiv-
ities with the Sunphos family of ligands L4 and L5 demonstrating
that the in situ generated chiral ruthenium catalysts could be effi-
ciently used for such hydrogenation reaction. Substituent effects
were investigated by changing the nature of the substituents on the
phenyl rings of the phosphorus of the Sunphos ligands. (S)-Me-
Sunphos L2 (entry 7) (S)-xyl-Sunphos L3 (entry 8) and (S)-DMM-
Sunphos L4 (entry 9) led to similar results both in enantio- and
diastereo-selectivities. Pleasingly, better results were obtained with
bulkier DTBMeSunphos L5 leading to 2b with an excellent enantio-
and diastereo-facial discrimination up to 99.3% ee and 99.4% de
(entry 10). To the best of our knowledge, such level of enantio- and
diastereo-selectivity has never been attained for such process using
in situ generated RueCl complexes. Comparable results were ob-
tained when performing the hydrogenation reaction of 1b by
mixing [Ru(cymene)Cl2]2, Ligands L1 or L5, substrate 1b and DCM/
TFE¼3/1 (entries 6, 10 vs entries 11, 12). [Ru(cymene)Cl2]2 and
[Ru(benzene)Cl2]2 gave similar results regarding the stereochemi-
cal outcome of the reaction (entry 6 vs entry 13). Surprisingly,
[Ru(cymene)I2]2 was not efficient compare to [Ru(cymene)Cl2]2
(entry 6 vs entries 14) resulting in a lower selectivity and slower
reaction rate, the conversion being not complete under 50 bar of
hydrogen pressure after 20 h (entry 14).
which is in agreement with Maheswaran and co-worker’s report.11b
They found that hydrogenation of 1a with Ru(H)(p-cymene)((R)-
DTBMeSegphos)(SbF6) as catalyst afforded 2a in 94% ee and 90% de
in EtOH while no product could be obtained in a co-solvent of DCM/
MeOH. Therefore, halogen ions remain to be the appropriate
counter anions in such mixed solvent systems. Bases have been
widely used to accelerate the racemization between enantiomers.5,
which may led in this case to a higher kinv/kslow. However, the use of
K2CO3, NEt3 or DBU gave complete conversions albeit with low
selectivities (entries 14e16). We had previously demonstrated that
CaCO3 was advantageous to neutralize HCl generated during
hydrogenation.12g However, no significant effect of CaCO3 was
found in the hydrogenation reaction (entry 17). Addition of 0.5% (v/
v) of water led to an excellent ee up to 99% with a decreased de of
86.2% (entry 18).
Following these careful investigations, the S/C ratio was changed
from 100 to 1000 and the hydrogenation reaction was carried out
with preformed Ru-(S)-DTBMeSunphos in DCE/TFE (3/1) under
70 bar of H2. Pleasingly, Reactions of 1a and 1b could be accom-
plished with a complete conversion within 72 h, giving, re-
spectively, 2a in 96.6% ee, 98.4% de and 2b in 99.6% ee, 98.8% de.
However, hydrogenation of 1b under the same reaction conditions
with the in situ prepared catalyst at S/C¼1000 gave 2b in 87.5%
conversion, 98.3% ee and 96.3% de, suggesting higher substrate/
diphosphine loading might inhibit the formation of active catalytic
species. Finally, we evaluated the scope of this hydrogenation re-
action and demonstrated that this dynamic kinetic resolution using
the RueDTBMeSunphos catalytic system could be successfully
Acids have been reported to promote the hydrogenation of
functionalized ketones.7b,12d,18 Particularly, Lewis acids could im-
prove the diastereoselectivity in similar reactions.19 Recently,
Ackermann20 disclosed the positive effect of carboxylic acids or
carboxylates as additives in ruthenium-catalyzed reactions. Thus,
a series of additives were tested and the results are illustrated in
Table 4. None of these acids was effective in the reaction (Table 4,
entries 1e8). On the contrary, the presence of Lewis acids (entries
4e6) enhanced the transesterification between substrates and
TFE.21 Carboxylic acids and phenols did not improve the selectivity
extended to other
b
0-keto-
-amino esters 2c, 2d, 3 and 4 with excellent
b-amino esters leading to the corre-
sponding
b
0-hydroxy-
b
enantioselectivities up to 99.9% and diastereoselectivities up to
98.1% using our experimental conditions (Scheme 2).
t
(entries 7e10) either. As for counter anions, AcOK and BuONa led
to a dramatic decrease in the enantio- and diastereo-selectivity
(entries 11, 12). No conversion was observed using AgBF4 (entry 13),
Table 4
Additives screena
O
O
OH
O
H2
OEt
NHBz
OEt
NHBz
Ru-(S)-Sunphos
additives
Scheme 2. Substrate scope of the RueDTBMeSunphos catalytic system.
1b
2b
Entry
1b
2
3
4
5
6
7
8
Additives
Conversion (%)
ee (2R,3S, %)
de (%)
3. Conclusion
HCl
I2
HBF4
LiCl
100
99.3
94.8
100
100
100
100
100
100
100
92.5
32.7
ND
99.8
100
84.3
66.1
57.4
84.5
76.9
70.0
86.2
87.2
87.4
87.5
ꢀ2.6
ꢀ88.2
d
In conclusion, a convenient and practical method for the
96.6
98.0
89.8
95.6
97.3
96.8
98.3
98.9
ꢀ1.8
73.1
d
enantio- and diastereo-selective synthesis of b b-amino
0-hydroxy-
acids has been developed using the in situ generated [Ru(cymene)
Cl2]2eSunphos as catalyst. We demonstrated that [Ru(cymene)Cl2]2
associated to atropisomeric diphosphines in DCM/TFE and DCE/TFE
combinations of solvent was more efficient than the corresponding
[Ru(cymene)I2]2 in DCM/MeOH and DCM/EtOH for common
diphosphine ligands. These unusual experimental conditions have
ZnCl2
CeCl3$7H2O
PhCOOH
tBuCOOH
Phenol
2,6-t-Bu2-Phenol
AcOK
9
10
11
12
13
14
15
16
17
18c
been applied to the synthesis of a series of enantioenriched b0
hydroxy- -amino acids with high level of enantio- and diastereo-
-
tBuONa
AgBF4
K2CO3
NEt3
DBU
CaCO3
H2O
b
100
100
100
100
100
ꢀ11.0
66.2
11.2
98.1
99.0
39.9
52.8
0.2
88.5
86.2
selectivites.
4. Experimental section
4.1. General
a
Catalyst¼[Ru(cymene)Cl2]2e(S)-Sunphos (preformed), S/C¼100, c¼0.25 M, sol-
vent: DCM/TFE¼3/1, T¼70 ꢁC, P¼50 bar, t¼20 h, additives/catalyst¼10/1 (exception:
AgBF4/catalyst¼1/1), all additives were added together with substrates, ee and de
were determined by HPLC.
All reactions were carried out under an atmosphere of nitrogen
using standard Schlenk techniques or in a nitrogen-filled glovebox,
unless otherwise noted. 1H NMR spectra were recorded at 400 MHz,
b
1 M in DCM.
0.5% v/v.
c

X. Li et al. / Tetrahedron 69 (2013) 7152e7156
7155
with TMS as internal standard. 13C NMR spectra were obtained at
100 MHz and referenced to the central peak of 77.0 ppm for CDCl3.
Coupling constants (J) are reported in Hertz and refer to apparent
peak multiplications. Flash column chromatography was per-
formed on silica gel (300e400 mesh). Commercially available re-
agents were used throughout without further purification other
than those detailed below. The solvents used in catalyst preparation
and hydrogenation reactions were pretreated and degassed by lit-
erature methods.22 Compound 1a and 1b were synthesized
according to the literature.23
14.3. [
a
]
20 ꢀ46.7 (c 1.0, CHCl3, 99.3% ee, 99.4% de). HPLC: (Chiralcel
D
AD-H column, hexane/i-PrOH: 85/15, 0.5 mL/min, 230 nm, 30 ꢁC)
t1¼14.1 min, t2¼15.4 min (major), t3¼17.6 min, t4¼18.4 min.
4.3.5. (2R,3S)-2,2,2-Trifluoroethyl 2-(benzamidomethyl)-3-
hydroxybutanoate (2c).6a,6c 1H NMR (400 MHz, CDCl3)
d 7.79e7.74
(m, 2H), 7.56e7.50 (m, 1H), 7.48e7.41 (m, 2H), 6.81 (s, 1H),
4.64e4.43 (m, 2H), 4.31e4.14 (m, 2H), 4.08e3.93 (m, 1H),
3.65e3.53 (m, 1H), 2.76e2.64 (m, 1H), 1.30e1.28 (m, 3H). 13C NMR
(101 MHz, CDCl3)
d 171.9, 169.1, 133.6, 132.1, 128.8, 127.1, 122.9 (q,
JFC¼277.7 Hz), 65.6, 60.4 (q, JFC¼36.6 Hz), 52.8, 38.0, 21.0. 19F NMR
4.2. Typical procedure for the asymmetric hydrogenation
(376 MHz, CDCl3)
d
ꢀ74.1 (t, J¼8.4 Hz). HRMS (QTOF-ESI) calcd for
C14H17NO4F3, (MþH): 320.1110, found: 320.1108. [
a
]
D
20 ꢀ40.1 (c 1.0,
To a 25 mL Schlenk tube were added [Ru(cymene)Cl2]2 (12 mg,
0.02 mmol) and (S)-SunPhos (30 mg, 0.045 mmol). The tube was
vacuumed and purged with nitrogen three times before addition of
freshly distilled and degassed EtOH/CH2Cl2 (2 mL/2 mL). The
resulting mixture was heated at 50 ꢁC for 1.5 h and then cooled to
room temperature. The solvent was removed under vacuum to give
the catalyst. The catalyst was dissolved in a mixture of degassed DCM
and TFE (12 mL/4 mL) and then the solution was equally put into
eight vials, in which compound 1b (132 mg, 0.5 mmol) was pre-
introduced, and then the vials were taken into an autoclave. The
autoclave was purged three times with H2 and stirred under specified
reaction conditions. After being cooled to ambient temperature and
release of the hydrogen, the autoclave was opened and the solvent
was evaporated. The ee was determined by HPLC after passing the
samples through a short pad of silica gel with pure ethyl acetate.
CHCl3, 95.5% ee, 98.1% de). HPLC: (Chiralcel AD-H column, hexane/i-
PrOH: 92/08, 0.6 mL/min, 230 nm, 30 ꢁC) t1¼19.9 min, t2¼21.3 min,
t3¼25.1 min, t4¼28.5 min.
4.3.6. (2R,3S)-Isopropyl 2-(benzamidomethyl)-3-hydroxybutanoate
(2d).6a,6c 1H NMR (400 MHz, CDCl3)
d 7.82e7.74 (m, 2H),
7.55e7.38 (m, 3H), 7.04 (s, 1H), 5.07e5.01 (m, 1H), 4.20e3.88 (m,
3H), 3.65e3.51 (m, 1H), 2.62e2.48 (m, 1H), 1.30e1.21 (m, 9H). 13C
NMR (101 MHz, CDCl3) d 173.5, 168.8, 133.8, 131.9, 128.8, 127.1, 68.7,
65.7, 52.8, 38.0, 21.9, 20.8. HRMS (QTOF-ESI) calcd for C15H21NO4
(MþH): 280.1549, found: 280.1571. [
a
]
20 þ27.4 (c 1.0, MeOH, 99.9%
D
ee, 82.0% de). HPLC: (Chiralcel OD-H column, hexane/i-PrOH: 90/10,
0.5 mL/min, 230 nm, 30 ꢁC) t1¼14.3 min, t2¼15.3 min (major),
t3¼16.3 min, t4¼17.0 min.
4.3.7. (2S,3S)-Ethyl 2-(benzamidomethyl)-3-hydroxy-3-
4.3. The hydrogenation with in situ prepared catalyst
phenylpropanoate (3).4c 1H NMR (400 MHz, CDCl3)
d 7.78e7.70
(m, 2H), 7.53e7.46 (m, 1H), 7.42e7.40 (m, 2H), 7.36e7.21 (m, 5H),
7.09 (s, 1H), 4.96e4.94 (m, 1H), 4.50e4.49 (m, 1H), 4.15e3.88 (m,
3H), 3.65e3.61 (m, 1H), 2.99e2.95 (m, 1H), 0.99 (t, J¼7.1 Hz, 3H). 13C
To a 50 mL Schlenk tube were added [Ru(cymene)Cl2]2 (6 mg,
0.01 mmol), (S)-SunPhos (15 mg, 0.022 mmol), and compound 1b
(526 mg, 2 mmol). The tube was vacuumed and purged with ni-
trogen three times before addition of freshly distilled and degassed
DCM and TFE (6 mL/2 mL). The resulting solution was taken into an
autoclave. The autoclave was purged three times with H2 and
stirred under specified reaction conditions.
NMR (101 MHz, CDCl3) d 173.1, 168.5, 141.1, 133.9, 131.8, 128.7, 128.5,
20
127.9, 127.1, 126.3, 60.9, 52.9, 38.1, 13.9. [
a]
ꢀ12.6 (c 1.0, CHCl3,
D
95.4% ee, 97.8% de). HPLC: (Chiralcel IA-3 column, hexane/i-PrOH:
85/15, 0.5 mL/min, 230 nm, 25 ꢁC) t1¼20.9 min, t2¼22.2 min,
t3¼27.5 min, t4¼33.5 min.
4.3.1. Methyl 2-(benzamidomethyl)-3-oxobutanoate (1a).23 1H NMR
4.3.8. (2R,3S)-Ethyl 3-hydroxy-2-((4-methylbenzamido)methyl)bu-
(400 MHz, CDCl3)
d
7.76e7.69 (m, 2H), 7.53e7.46 (m, 1H), 7.45e7.38
tanoate (4).6a,6c 1H NMR (400 MHz, CDCl3)
d 7.69e7.63 (m, 2H),
(m, 2H), 6.79 (s,1H), 4.00e3.82 (m, 3H), 3.77 (s, 3H), 2.33 (s, 3H). 13C
7.24e7.17 (m, 2H), 7.01 (s, 1H), 4.24e4.04 (m, 3H), 3.97e3.95 (m,
1H), 3.56e3.54 (m, 1H), 2.58e2.56 (m, 1H), 2.37 (s, 3H), 1.30e1.21
NMR (101 MHz, CDCl3)
58.3, 52.9, 37.8, 30.1.
d 202.6, 169.2, 167.7, 134.0, 131.8, 128.7, 127.1,
(m, 6H). 13C NMR (101 MHz, CDCl3)
d 173.9, 168.8, 142.4, 130.9,
129.4, 127.1, 65.6, 61.0, 52.8, 37.9, 21.6, 20.9, 14.3. HRMS (QTOF-ESI)
4.3.2. (2R,3S)-Methyl 2-(benzamidomethyl)-3-hydroxybutanoate
(1b).6a,7b 1H NMR (400 MHz, CDCl3)
7.80e7.75 (m, 2H),
7.54e7.49 (m, 1H), 7.46e7.44 (m, 2H), 6.96 (s, 1H), 4.18e4.11 (m,
2H), 4.01e3.98 (m, 1H), 3.73 (s, 3H), 3.60e3.55 (m, 1H), 2.64e2.60
calcd for C15H21NO4 (MþH): 280.1549, found: 280.1576. [
a
]
20 þ23.6
D
d
(c 1.0, MeOH, 97.8% ee, 97.2% de). HPLC: (Chiralcel AD-H column,
hexane/i-PrOH: 85/15, 0.5 mL/min, 230 nm, 30 ꢁC) t1¼20.0 min,
t2¼21.5 min (major), t3¼25.2 min, t4¼28.8 min.
(m, 1H), 1.26 (d, J¼6.3 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 168.9,
ꢀ45.3 (c 1.0,
20
132.0, 128.8, 127.2, 65.6, 52.7, 52.1, 38.0, 20.9. [
a
]
D
Acknowledgements
CHCl3, 96.6% ee, 98.4% de). HPLC: (Chiralcel AD-H column, hexane/
i-PrOH: 85/15, 0.5 mL/min, 230 nm, 30 ꢁC) t1¼15.1 min, t2¼16.1 min
(major), t3¼17.4 min, t4¼18.8 min.
We thank the National Natural Science Foundation of China for
financial support.
4.3.3. Ethyl 2-(benzamidomethyl)-3-oxobutanoate (2a).9 1H NMR
(400 MHz, CDCl3) d 7.77e7.68 (m, 2H), 7.52e7.45 (m, 1H), 7.45e7.37
Supplementary data
(m, 2H), 6.84 (s, 1H), 4.27e4.13 (m, 2H), 4.01e3.81 (m, 3H), 2.32 (s,
Copies of 1H NMR and 13C NMR spectra of compounds 1e4
are available in Supplementary data. Supplementary data related
to this article can be found at http://dx.doi.org/10.1016/j.tet.
2013.05.136.
3H), 1.27 (t, J¼7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d 202.8, 168.7,
167.7, 134.0, 131.8, 128.7, 127.0, 62.0, 58.5, 37.8, 30.1, 14.2.
4.3.4. (2R,3S)-Ethyl 2-(benzamidomethyl)-3-hydroxybutanoate
(2b).9 1H NMR (400 MHz, CDCl3)
d 7.87e7.66 (m, 2H), 7.57e7.30
References and notes
(m, 3H), 7.10 (s, 1H), 4.42e3.88 (m, 5H), 3.61e3.56 (m, 1H),
2.60e2.56 (m, 1H), 1.36e1.14 (m, 6H). 13C NMR (101 MHz, CDCl3)
1. Juaristi, E.; Soloshonok, V. A. Enantioselective Synthesis of b-Amino Acids, 2nd
d
173.8, 168.8, 133.8, 131.9, 128.7, 127.1, 65.8, 61.1, 52.7, 38.0, 20.9,
ed.; Wiley-VCH: New York, NY, 1997.

7156
X. Li et al. / Tetrahedron 69 (2013) 7152e7156
2. (a) Berks, A. H. Tetrahedron 1996, 52, 331e375; (b) Bruggink, A. Synthesis of
b
-
12. (a) Sun, Y.; Wan, X.; Guo, M.; Wang, D.; Dong, X.; Pan, Y.; Zhang, Z. Tetrahedron:
Asymmetry 2004, 15, 2185e2188; (b) Meng, Q.; Zhu, L.; Zhang, Z. J. Org. Chem.
2008, 73, 7209e7212; (c) Zhu, L.; Meng, Q.; Fan, W.; Xie, X.; Zhang, Z. J. Org.
Chem. 2010, 75, 6027e6030; (d) Li, W.; Ma, X.; Fan, W.; Tao, X.; Li, X.; Xie, X.;
Zhang, Z. Org. Lett. 2011, 13, 3876e3879; (e) Ma, X.; Li, W.; Li, X.; Tao, X.; Fan,
W.; Xie, X.; Ayad, T.; Ratovelomanana-Vidal, V.; Zhang, Z. Chem. Commun. 2012,
5352e5354; (f) Tao, X.; Li, W.; Ma, X.; Li, X.; Fan, W.; Xie, X.; Ayad, T.; Rato-
velomanana-Vidal, V.; Zhang, Z. J. Org. Chem. 2012, 77, 612e616; (g) Fan, W.; Li,
W.; Ma, X.; Tao, X.; Li, X.; Xie, X.; Yao, Y.; Zhang, Z. Chem. Commun. 2012,
4247e4249.
13. (a) Teunissen, H. T.; Elsevier, C. J. Chem. Commun. 1998, 1367e1368; (b) Milani,
B.; Corso, G.; Mestroni, G.; Carfagna, C.; Formica, M.; Seraglia, R. Organometallics
2000, 19, 3435e3441; (c) Wang, D.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G. Chem.
Rev. 2012, 112, 2557e2590.
Lactam Antibiotics; Kluwer: Dordrecht, The Netherlands, 2001; (c) Palomo, C.;
Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Synlett 2001, 1813e1826.
3. Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991e8035.
4. For reviews, see: (a) Lelais, G.; Seebach, D. Biopolymers 2004, 76, 206e243 For
recent examples, see: (b) Gandolfi, R.; Cesarotti, E.; Molinari, F.; Romano, D.;
Rimoldi, I. Tetrahedron: Asymmetry 2009, 20, 411e414; (c) Rimoldi, I.; Cesarotti,
E.; Zerla, D.; Molinari, F.; Albanese, D.; Castellano, C.; Gandolfi, R. Tetrahedron:
Asymmetry 2011, 22, 597e602.
5. For selected reviews, see: (a) Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem.
Soc. Jpn. 1995, 68, 36e56; (b) Shimizu, H.; Nagasaki, I.; Matsumura, K.; Sayo, N.;
Saito, T. Acc. Chem. Res. 2007, 40, 1385e1393; (c) Stecher, H.; Faber, K. Synthesis
1997, 1e16; (d) Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475e1490; (e)
Caddick, S.; Jenkins, K. Chem. Soc. Rev. 1996, 447e456; (f) Pellissier, H. Tetra-
hedron 2003, 59, 8291e8327 For mathematical studies of DKR see: (g) Kita-
mura, M.; Tokunaga, M.; Noyori, R. J. Am. Chem. Soc. 1993, 115, 144e152; (h)
Kitamura, M.; Tokunaga, M.; Noyori, R. Tetrahedron 1993, 49, 1853e1860; (i)
Andraos, J. J. Phys. Chem. A 2003, 107, 2374e2387.
6. (a) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.; Takaya, H.;
Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumobayashi, H. J. Am. Chem.
Soc. 1989, 111, 9134e9135; (b) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23,
345e350; (c) Sayo, R.; Saito, T.; Okeda, Y.; Nagashima, H.; Kumobayashi, H. U.S.
Patent US 4,981,992, 1991.
14. Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.; Souchi, T.; Noyori, R. J.
Am. Chem. Soc. 1980, 102, 7932e7934.
15. (a) Duprat de Paule, S.; Champion, N.; Ratovelomanana-Vidal, V.; Genet, J.-P.;
Dellis, P. French Patent 2830254, 2001, WO Patent 03029259, 2003. (b) Duprat
de Paule, S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.;
Dellis, P. Eur. J. Org. Chem. 2003, 1931e1941; (c) Duprat de Paule, S.; Jeulin, S.;
Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.; Deschaux, G.; Dellis, P.
Org. Process Res. Dev. 2003, 7, 399e406.
16. Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricher, J.; Lalonde, M.;
€
7. (a) Mashima, K.; Matsumura, Y.; Kusano, K.; Kumobayashi, H.; Sayo, N.; Hori, Y.;
Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Chem. Soc., Chem. Commun. 1991,
609e610; (b) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.-I.; Nozaki, K.;
Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.; Takaya, H. J. Org.
Chem. 1994, 59, 3064e3076.
Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure Appl. Chem. 1996, 68,
131e138.
17. Zhang, Z.; Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem. 2000, 65,
6223e6226.
18. King, S. A.; Thompson, A. S.; King, A. O.; Verhoeven, T. R. J. Org. Chem. 1992, 57,
6689e6691.
8. Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumobayashi,
H. Adv. Synth. Catal. 2001, 343, 264e267.
9. Benincori, T.; Cesarotti, E.; Piccolo, O.; Sannicolo, F. J. Org. Chem. 2000, 65,
2043e2047.
10. Cesarotti, E.; Abbiati, G.; Rossi, E.; Spalluto, P.; Rimoldi, I. Tetrahedron: Asym-
metry 2008, 19, 1654e1659.
19. Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K. Tetrahedron 1993, 49,
11169e11182.
20. Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12,
5032e5035.
21. Otera, J. Chem. Rev. 1993, 93, 1449e1470.
11. (a) Lei, A.; He, M.; Zhang, X. J. Am. Chem. Soc. 2003, 125, 11472e11473; (b) Sa-
tyanarayana, P.; Maheswaran, H.; Kantama, M. L.; Chawla, H. P. S. Catal. Sci.
Technol. 2012, 2, 2508e2511.
22. Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory Chemicals, 4th ed.;
Butterworth-Heinemann: Oxford, Boston, MA, 1996.
23. Chao, M.; Hao, A.; Wang, H. Org. Process Res. Dev. 2009, 13, 645e646.