Organocatalytic asymmetric conjugate addition of α-substituted cyanoacetates to maleimides

Article abstract of DOI:10.1016/j.tetasy.2011.04.009

The asymmetric conjugate addition of α-substituted cyanoacetates to N-substituted maleimides has been developed. A number of cinchona alkaloids and amine thioureas were evaluated as catalysts. Takemoto's catalyst was found to be the most efficient for the

Full text of DOI:10.1016/j.tetasy.2011.04.009

Tetrahedron: Asymmetry 22 (2011) 690–696
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalytic asymmetric conjugate addition of
cyanoacetates to maleimides
a-substituted
⇑
Jin-Jia Wang , Xue-Jiao Dong , Wen-Tao Wei, Ming Yan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric conjugate addition of a-substituted cyanoacetates to N-substituted maleimides has been
Received 4 March 2011
Accepted 4 April 2011
Available online 10 May 2011
developed. A number of cinchona alkaloids and amine thioureas were evaluated as catalysts. Takemoto’s
catalyst was found to be the most efficient for the transformation. Chiral succinimides with two adjacent
quaternary and tertiary stereogenic carbon centers were obtained in good yields, enantioselectivities, and
diastereoselectivities. The products were converted to chiral
enantioselectivity.
c
-lactams conveniently without a loss in the
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The enantioselective conjugate addition reaction with carbon
nucleophiles is one of the most efficient for the asymmetric forma-
tion of C–C bonds.1 In recent years, organocatalytic asymmetric
The reaction of a-phenyl cyanoacetate 1a and N-phenyl malei-
mide 2a was initially studied. A series of organocatalysts including
cinchona alkaloids 4a–4d and amine thioureas 4e–4h were evalu-
ated. The results are summarized in Table 1. The desired product
3a was obtained in excellent yields with cinchona alkaloids 4a–
4c, but the diastereoselectivities and the enantioselectivities were
unsatisfactory (Table 1, entries 1–3). 9-Benzyl-6-demethyl-quinine
4d gave an extremely low yield and almost racemic product (Ta-
ble 1, entry 4). We then turned our attention to bifunctional amine
thioureas 4e–4h. Improved enantioselectivity (77% ee) and moder-
ate diastereoselectivity (83:17) were obtained with Takemoto’s
catalyst 4e (Table 1, entry 5).17 Modified Takemoto’s catalyst 4f
provided lower enantioselectivity (Table 1, entry 6). Quinine and
cinchonine-derived thioureas 4g–4h also provided inferior enanti-
oselectivities and diastereoselectivities (Table 1, entries 7 and 8).
To determine the optimal reaction conditions with catalyst 4e,
we studied the effects of the reaction solvent, the temperature
and the catalyst loading. The results are listed in Table 2. Xylene
was found to be the best solvent in terms of enantioselectivity (Ta-
ble 2, entries 1–7). Decreasing the reaction temperature resulted in
a loss of enantioselectivity, although better diastereoselectivities
were achieved (Table 2, entries 8 and 9). Both the diastereoselec-
tivity and the enantioselectivity were improved slightly while
decreasing the catalyst loading from 10 to 1 mol % (Table 2, entries
6 and 10–12). Good enantioselectivity and yield were kept with
0.5 mol % catalyst loading, but the diastereoselectivity decreased
(Table 2, entry 13). Further study indicated that lowering the con-
centration of the substrates 1a and 2a did not provide favorable re-
sults (Table 2, entries 14 and 15).
conjugate addition has seen great progress.2,3
a,b-Unsaturated
aldehydes, ketones, imides and nitroolefins are mostly used as
Michael acceptors. Maleimides are also attractive Michael
acceptors, because the resulted enantioenriched succinimides are
valuable pharmacophores and synthetic intermediates.4,5 Organo-
catalytic conjugate additions of 1,3-dicarbonyl compounds,6 alde-
hydes,7 ketones,8 2-mercaptobenzaldehydes,9 dicyanoolefins,10
azlactones,11 3-substituted benzofuran-2(3H)-ones12, and oxin-
doles13 to maleimides have been reported to provide chiral succin-
imides in good enantioselectivities. On the other hand, the
asymmetric construction of quaternary stereocenters has been a
challenging area in organic synthesis.14
a-Substituted cyanoace-
tates are useful nucleophiles for the construction of stereogenic
quaternary carbon centers via the reaction with electrophilic
reagents.15 We speculate that the conjugate addition of
a-substi-
tuted cyanoacetate to maleimide is an efficient method to prepare
chiral succinimides with two adjacent quaternary and tertiary
stereogenic carbon centers.16 Herein we report the enantio-
selective conjugate addition of
a-substituted cyanoacetates to
maleimides catalyzed by organocatalysts. The reaction provided
functionalized succinimides with high levels of enantioselectivities
and diastereoselectivities. Furthermore the products could be con-
verted to chiral
purity.
c-lactams without any loss in the enantiomeric
The reaction of a series of
N-substituted maleimides 2 was investigated. The results are sum-
marized in Table 3. The reaction worked very well with N-aryl
a-substituted cyanoacetates 1 and
⇑
Corresponding author. Tel./fax: +86 20 39943049.
E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
These two authors contributed equally to this study.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.04.009

J.-J. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 690–696
691
Table 1
Table 2
Screening of organocatalystsa
Optimization of the reaction conditions with catalyst 4ea
O
Conv.b
(%)
drb
eec
(%)
EtO2C
Ph
CN
O
Entry
4e
(mol %)
Solvent
Time
(h)
Catalyst
CN
(10 mol%)
+
N
Ph
N
Ph
CH2Cl2, rt
1
2
3
4
5
6
7
10
10
10
10
10
10
10
10
10
5
2
1
0.5
1
1
CH2Cl2
CHCl3
Ether
3
3
3
3
3
3
3
5
8
3
4
7
12
12
36
>95
>95
>95
>95
>95
>95
>95
>95
83:17
83:17
91:9
86:14
89:11
90:10
87:13
90:10
93:7
90:10
90:10
93:7
89:11
91:9
77
75
75
34
83
85
81
83
81
85
85
87
86
86
85
Ph
CO2Et
O
O
1a
2a
3a
THF
Toluene
Xylene
Fluoro-benzene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
N
N
N
8d
9e
10
11
12
13
14g
15h
OH
OH
OH
H
H
H
>95
O
HO
>95 (99%)f
>95 (99%)f
>95 (99%)f
>95 (98%)f
>95 (99%)f
90 (86%)f
N
N
N
4a
4b
4c
CF3
CF3
90:10
N
S
a
OBn
S
Reactions were carried out with 1a (0.12 mmol), 2a (0.1 mmol) and the indi-
H
HO
cated amount of 4e in the solvent (0.5 mL) at room temperature.
N
H
N
H
CF3
N
H
N
CF3
b
Determined by 1H NMR analysis of the crude reaction mixture.
Determined by HPLC with a chiralpak AD-H column.
The reaction was conducted at 0 °C.
H
N
c
N
N
d
4f
4e
4d
e
The reaction was conducted at ꢀ40 °C.
f
The values in parentheses are isolated yields.
g
1 mL of xylene was used.
2 mL of xylene was used.
OMe
N
h
H
H
N
N
NH
NH
N
S
NH
S
NH
analysis (Fig. 1).18 The absolute configurations of the other prod-
ucts were assigned analogously.
F3C
CF3
A reaction transition state has been proposed to account for the
observed enantioselectivity and diastereoselectivity (Scheme 1).
Double hydrogen-bonding is generated between the thiourea
group of 4e with the maleimide.19 This interaction helps to activate
the maleimide toward the nucleophilic attack. The tertiary amine
F3C
CF3
4g
4h
b
Entry
Catalyst
Time (h)
Conv. (%)
drb
eec (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
3
3
3
>95
>95
>95
28
>95
>95
>95
>95
83:17
94:16
82:18
79:21
83:17
81:19
72:28
77:23
26
-27
30
group of 4e removes a proton from
a-phenyl-cyanoacetate. The
12
3
ꢁ0
resulting enolate ion forms a hydrogen bond with the ammonium
cation. The nucleophilic attack of an enolate ion from the re-face of
the maleimide gives product 3a.
77
3
3
3
45
68
ꢀ37
4g
4h
Chiral c-lactams serve as important structural motifs in many
biologically active products.20 The cyano group of product 3a could
a
Reactions were carried out with 1a (0.12 mmol), 2a (0.1 mmol) and catalyst
be reduced with NaBH4/CoCl2.21 The resulting amine underwent a
(0.01 mmol) in CH2Cl2 (0.5 mL) at room temperature.
Determined by 1H NMR analysis of the crude reaction mixture.
b
cascade lactamization in situ to give c-lactam 5 without a decrease
in the enantiomeric purity (Scheme 2).
c
Ee values of the major diastereomer, determined by HPLC with a chiralpak AD-
H column.
3. Conclusion
In conclusion, we have developed an organocatalytic asymmet-
ric conjugate addition of a-substituted cyanoacetates to N-substi-
tuted maleimides. Takemoto’s catalyst was identified as the best.
Chiral succinimides with two adjacent quaternary and tertiary ste-
reogenic carbon centers were obtained with good enantioselectiv-
ities and diastereoselectivities. The products could be conveniently
maleimides 2a–2j. In most cases, the products were obtained in
good yields and enantioselectivities. The substitution of electron-
withdrawing groups or electron-donating groups at N-phenyl did
not have a significant effect on the yield or enantioselectivity (Ta-
ble 3, entries 1–10). Maleimide 2k, N-ethyl maleimide 2l and N-
benzyl maleimide 2m showed significantly lower reactivity than
N-aryl maleimides. High catalyst loading and extended reaction
time were required. Products 3k–3m were obtained in good yields,
although with inferior diastereoselectivities and enantioselectivi-
ties (Table 3, entries 11–13). This indicates that the electron-
donating property of N-alkyl groups decreases the electrophilic
converted to chiral c-lactams.
4. Experimental
4.1. General Information
reactivity of maleimides.12 With regards to the
noacetates, -(4-methyl-phenyl)-cyanoacetate 1b provided better
enantioselectivity than -(4-MeO-phenyl)-cyanoacetate 1c and
-(4-bromo-phenyl)-cyanoacetates 1d (Table 3, entries 14–16).
Low yield, enantioselectivity, and diastereoselectivity were ob-
tained for -ethyl-cyanoacetate 1e (Table 3, entry 17).
a-substituted cya-
a
1H and 13C NMR spectra were recorded on a Bruker AVANCE 400
spectrometer. Chemical shifts of protons are reported in parts per
million downfield from tetramethylsilane (d = 0). Chemical shifts
of carbon are referenced to the central peak of the solvent (CDCl3,
d = 77.0). Peaks are labeled as singlet (s), doublet (d), triplet (t),
quartet (q), and multiplet (m). Optical rotations were measured
on a Perkin–Elmer 341 digital polarimeter. Melting points were
a
a
a
A single crystal of the product 3e was obtained. Its absolute
configuration was determined as (2R,3S) by X-ray diffraction

692
J.-J. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 690–696
Table 3
Asymmetric conjugate addition of cyanoacetates 1a–e to maleimides 2a–ka
O
EtO2C
R1
CN
O
CN
R2
4e (1 mol%)
xylene, rt
N
+
R2
N
R1
CO2Et
O
2a-k
O
1a-d
3a-3n
Entry
R1
R2
Time (h)
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 1a
Ph 2a
7
9
7
6
6
5
5
8
5
3a, 99
3b, 93
3c, 97
3d, 97
3e, 99
3f, 96
3g, 96
3h, 86
3i, 95
3j, 97
3k, 95
3l, 87
3m, 98
3n, 93
3o, 94
3p, 99
3q, 80
93:7
90:10
93:7
92:8
91:9
90:10
84:16
91:9
96:4
93:7
75:25
80:20
79:21
93:7
88:12
87:13
56:44
87
84
89
91
94
84
81
87
91
90
41
33
63
91
88
85
71
4-MeO-C6H4 2b
4-Me-C6H4 2c
4-Cl-C6H4 2d
4-Br-C6H4 2e
4-F-C6H4 2f
4-NO2-C6H4 2g
3-Me-C6H4 2h
3-Cl-C6H4 2i
3-Br-C6H4 2j
H 2k
C2H5 2l
PhCH2 2m
Ph 2a
Ph 2a
Ph 2a
9
10
7
11e
20
25
34
9
12
6
e
12
13e
14
Ph 1a
4-Me-C6H4 1b
4-MeO-C6H4 1c
4-Br-C6H4 1d
C2H5 1e
15
16
17e
Ph 2a
58
a
b
c
Reactions were carried out with 1a–e (0.12 mmol), 2a–m (0.1 mmol) and 4e (0.001 mmol) in xylene (0.5 mL) at room temperature.
Isolated yields.
Determined by 1H NMR analysis of the crude reaction mixture.
Determined by HPLC with a chiralpak AD-H or chiralcel OD-H column.
10 mol % catalyst 4e was used.
d
e
CF3
S
CF3
N
H
N
H
N
H
O
O
N
CN
O
O
Scheme 1. Proposed reaction transition state.
HN Ph
O
O
Figure 1. X-ray crystal structure of 3e.
CN
Ph
EtO2C
Ph
NaBH4/CoCl2.6H2O
N
O
Ph
CO2Et
HN
MeOH
O
measured on a WRS-2A melting point apparatus and are uncor-
rected. The high resolution mass spectroscopic data were obtained
with a Shimadzu LC–MS-IT-TOF spectrometer. Infrared (IR) spectra
were recorded on a Bruker Tensor 37 spectrophotometer. Data are
represented as follows: frequency of absorption (cmꢀ1), intensity
of absorption (s = strong, m = medium, w = weak). Enantiomeric
excesses were determined by HPLC using a Daicel Chiralpak AD-
H or Chiralcel OD-H column and eluting with a hexane/i-PrOH
solution. Purified products 3a–3q and 5 were used for the analysis.
Flash chromatography was performed over silica gel (230–400
mesh), purchased from Qingdao Haiyang Chemical Co., Ltd. Xylene
was purchased from Tianjin Fuyu Chemical Co., Ltd as a mixture of
three isomers. Commercially available reagents and analytical
grade solvents were used without further purification. Maleimides
were prepared according to reported procedures.22
3a
85% ee
5
58% yield, 84% ee
Scheme 2. Transformation of product 3a to
c
-lactam 5.
4.2. Typical procedure for asymmetric conjugate addition of
cyanoacetates to maleimides
A solution of a-phenyl cyanoacetates 1a (22.7 mg, 0.12 mmol),
maleimide 1b (17.3 mg, 0.10 mmol), catalyst 4e (0.42 mg,
0.001 mmol) in xylene (0.5 mL) was stirred at room temperature
for 7 h. After the solvent was evaporated under vacuum, the resi-
due was purified by flash column chromatography over silica gel
(petroleum ether/EtOAc = 3:1) to afford 3a as a white solid.

J.-J. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 690–696
693
4.3. Spectroscopic data of the products
tmajor = 13.43 min, tminor = 24.52 min, 91% ee; minor diastereomer:
tmajor = 21.32 min, tminor = 36.08 min, 26% ee.
4.3.1. (R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-
yl)-2-phenylacetate 3a
4.3.5. (R)-Ethyl 2-((S)-1-(4-bromophenyl)-2,5-dioxopyrrolidin-
White solid, mp 134–135 °C; ½a D20
ꢂ
¼ ꢀ28:6 (c 0.21, acetone); 1H
3-yl)-2-cyano-2-phenylacetate 3e
NMR (400 MHz, CDCl3): d 7.67–7.64 (m, 2H), 7.50–7.39 (m, 6H),
7.32–7.30 (m, 2H), 4.43–4.35 (m, 2H), 4.29–4.23 (m, 1H), 2.81
(dd, J = 18.4, 9.6 Hz, 1H), 2.54 (dd, J = 18.4, 6.4 Hz, 1H), 1.31 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 173.9, 172.8, 166.0,
131.2, 129.9, 129.7, 129.3, 129.2, 129.0, 126.5, 126.5, 115.8, 64.1,
55.4, 46.9, 31.6, 13.7; IR (KBr): 2249 (w), 1792 (w), 1750 (s),
1709 (s), 1597 (w), 1500 (m), 1452 (m); HRMS (ESI) calcd for
White solid, mp 157–159 °C; ½a D20
ꢂ
¼ ꢀ36:1 (c 0.38, acetone); 1H
NMR (400 MHz, CDCl3): d 7.65–7.55 (m, 4H), 7.49–7.49 (m, 3H),
7.21 (d, J = 8.8 Hz, 2H), 4.43–4.25 (m, 3H), 2.81 (dd, J = 18.8,
9.6 Hz, 1H), 2.52 (dd, J = 18.8, 6.4 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d 173.6, 172.5, 165.9, 132.4, 131.1,
130.2, 129.9, 129.7, 128.0, 126.4, 122.9, 115.8, 64.2, 55.4, 46.9,
31.6, 13.7; IR (KBr): 2250 (w), 1787 (w), 1747 (s), 1711 (s), 1587
(w), 1491 (m), 1447 (m); HRMS (ESI) calcd for C21H16N2O4Br
(MꢀH)ꢀ: 439.0293, found: 439.0299. The enantiomeric excess
was determined by HPLC with a Chiralcel OD-H column (hexane/
2-propanol = 80:20, k = 220 nm, 1.0 mL/min); major diastereomer:
tmajor = 14.23 min, tminor = 29.18 min, 94% ee; minor diastereomer:
tmajor = 22.95 min, tminor = 40.68 min, 20% ee.
C
21H17N2O4 (MꢀH)ꢀ: 361.1188, found: 361.1203. The enantio-
meric excess was determined by HPLC with a Chiralpak AD-H col-
umn (hexane/2-propanol = 60:40, k = 220 nm, 0.8 mL/min); major
diastereomer: tminor = 17.12 min, tmajor = 24.04 min, 87% ee; minor
diastereomer: tmajor = 9.82 min, tminor = 12.75 min, 13% ee.
4.3.2. (R)-Ethyl 2-cyano-2-((S)-1-(4-methoxyphenyl)-2,5-
4.3.6. (R)-Ethyl 2-cyano-2-((S)-1-(4-fluorophenyl)-2,5-
dioxopyrrolidin-3-yl)-2-phenylacetate 3f
dioxopyrrolidin-3-yl)-2-phenylacetate 3b
White solid, mp 136–138 °C; ½a D20
ꢂ
¼ ꢀ29:1 (c 0.20, acetone); 1H
White solid, mp 167–168 °C; ½a D20
ꢂ
¼ ꢀ27:9 (c 0.28, acetone); 1H
NMR (400 MHz, CDCl3): d 7.66–7.64 (m, 2H), 7.51–7.46 (m, 3H),
7.22 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 4.42 -4.23 (m, 3H),
3.82 (s, 3H), 2.79 (dd, J = 18.4, 9.6 Hz, 1H), 2.51 (dd, J = 18.4,
6.4 Hz, 1H), 1.31 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
174.2, 173.1, 166.0, 159.8, 131.2, 129.9, 129.7, 127.7, 126.5,
123.8, 115.9, 114.6, 64.1, 55.5, 46.9, 31.5, 13.7; IR (KBr): 2250
(w), 1787 (w), 1749 (s), 1706 (s), 1611 (w), 1514 (m), 1447 (m);
HRMS (ESI) calcd for C22H19N2O5 (MꢀH)ꢀ: 391.1294, found:
391.1298. The enantiomeric excess was determined by HPLC with
a Chiralpak AD-H column (hexane/2-propanol = 60:40, k = 220 nm,
0.8 mL/min); major diastereomer: tminor = 18.52 min, tma-
jor = 21.68 min, 84% ee; minor diastereomer: tmajor = 11.16 min, tmi-
nor = 14.98 min, 13% ee.
NMR (400 MHz, CDCl3): d 7.67–7.63 (m, 2H), 7.51–7.46 (m, 3H),
7.32–7.28 (m, 2H), 7.18–7.13 (m, 2H), 4.43–4.23 (m, 3H), 2.82
(dd, J = 18.4, 9.6 Hz, 1H), 2.53 (dd, J = 18.4, 6.4 Hz, 1H), 1.31 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 173.9, 172.8, 165.9,
1
3
162.4 (d, JC-F = 247 Hz), 131.1, 129.9, 129.7, 128.4 (d, JC-
4
2
F = 8 Hz), 127.1 (d, JC-F = 3 Hz), 126.4, 116.3 (d, JC-F = 22 Hz),
115.8, 64.2, 55.4, 46.8, 31.6, 13.7; IR (KBr): 2252 (w), 1790 (w),
1747 (s), 1710 (s), 1603 (w), 1512 (m), 1450 (m); HRMS (ESI) calcd
for C21H16N2O4F (MꢀH)ꢀ: 379.1094, found: 379.1087. The enantio-
meric excess was determined by HPLC with a Chiralpak AD-H col-
umn (hexane/2-propanol = 60:40, k = 220 nm, 0.8 mL/min); major
diastereomer: tminor = 19.35 min, tmajor = 20.68 min, 84% ee; minor
diastereomer: tmajor = 9.62 min, tminor = 13.55 min, 12% ee.
4.3.3. (R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-(p-tolyl)pyrrolidin-
4.3.7. (R)-Ethyl 2-cyano-2-((S)-1-(4-nitrophenyl)-2,5-
3-yl)-2-phenylacetate 3c
dioxopyrrolidin-3-yl)-2-phenylacetate 3g
White solid, mp 184–186 °C; ½a D20
ꢂ
¼ ꢀ31:0 (c 0.20, acetone); 1H
White solid, mp 144–145 °C; ½a D20
ꢂ
¼ ꢀ33:5 (c 0.20, acetone); 1H
NMR (400 MHz, CDCl3): d 7.66–7.64 (m, 2H), 7.50–7.46 (m, 3H),
7.27 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 4.41–4.35 (m, 2H),
4.28–4.24 (m, 1H), 2.79 (dd, J = 18.4, 9.6 Hz, 1H), 2.52 (dd,
J = 18.4, 6.4 Hz, 1H), 2.38 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 174.0, 173.0, 166.0, 139.2, 131.3, 129.9,
129.9, 129.7, 128.6, 126.5, 126.3, 115.8, 64.1, 55.4, 46.9, 31.6,
21.2, 13.7; IR (KBr): 2252 (w), 1788 (w), 1751 (s), 1706 (s), 1592
(w), 1514 (m), 1452 (m); HRMS (ESI) calcd for C22H19N2O4
(MꢀH)ꢀ: 375.1345, found: 375.1353. The enantiomeric excess
was determined by HPLC with a Chiralpak AD-H column (hex-
ane/2-propanol = 60:40, k = 220 nm, 0.8 mL/min); major diastereo-
mer: tminor = 14.63 min, tmajor = 19.98 min, 89% ee; minor
diastereomer: tmajor = 9.30 min, tminor = 11.00 min, 23% ee.
NMR (400 MHz, CDCl3): d 8.32 (d, J = 9.2 Hz, 2H), 7.65–7.63 (m,
2H), 7.59 (d, J = 9.2 Hz, 2H), 7.50–7.48 (m, 3H), 4.549–4.27 (m,
3H), 2.88 (dd, J = 18.4, 9.6 Hz, 1H), 2.58 (dd, J = 18.4, 6.4 Hz, 1H),
1.32 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 173.3, 172.0,
165.8, 147.3, 136.6, 130.9, 130.0, 129.8, 127.1, 126.4, 124.4,
115.8, 64.3, 55.4, 46.9, 31.6, 13.7; IR (KBr): 2252 (w), 1792 (w),
1752 (s), 1719 (s), 1595 (w), 1496 (s), 1451 (m); HRMS (ESI) calcd
for C21H16N3O6 (MꢀH)ꢀ: 406.1039, found: 406.1045. The enantio-
meric excess was determined by HPLC with a Chiralcel OD-H col-
umn (hexane/2-propanol = 60:40, k = 220 nm, 0.8 mL/min); major
diastereomer: tmajor = 18.00 min, tminor = 27.49 min, 81% ee; minor
diastereomer: tmajor = 36.20 min, tminor = 41.47 min, 14% ee.
4.3.8. (R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-(m-tolyl)pyrrolidin-
4.3.4. (R)-Ethyl 2-((S)-1-(4-chlorophenyl)-2,5-dioxopyrrolidin-
3-yl)-2-phenylacetate 3h
3-yl)-2-cyano-2-phenylacetate 3d
White solid, mp 92–93 °C, ½a D20
ꢂ
¼ ꢀ30:5 (c 0.21, acetone); 1H
White solid, mp 157–158 °C; ½a D20
ꢂ
¼ ꢀ38:0 (c 0.25, acetone); 1H
NMR (400 MHz, CDCl3): d 7.67–7.65 (m, 2H), 7.50–7.46 (m, 3H),
7.37–7.33 (m, 1H), 7.23–7.21 (m, 1H), 7.10–7.04 (m, 2H), 4.42–
4.22 (m, 3H), 2.80 (dd, J = 18.4, 9.6 Hz, 1H), 2.53 (dd, J = 18.4,
6.4 Hz, 1H), 2.38 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 174.0, 172.9, 165.9, 139.4, 131.2, 131.1,
129.9, 129.9, 129.7, 129.1, 127.1, 126.4, 123.6, 115.8, 64.1, 55.4,
46.9, 31.6, 21.3, 13.7; IR (KBr): 2250 (w), 1792 (w), 1753 (s),
1710 (s), 1611 (w), 1453 (m), 1451 (m); HRMS (ESI) calcd for
NMR (400 MHz, CDCl3): d 7.65–7.63 (m, 2H), 7.50–7.43 (m, 5H),
7.27 (d, J = 8.8 Hz, 2H), 4.43–4.23 (m, 3H), 2.81 (dd, J = 18.8,
9.6 Hz, 1H), 2.53 (dd, J = 18.8, 6.4 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): d 173.7, 172.5, 165.9, 134.9, 131.1,
129.9, 129.7, 129.6, 129.5, 127.7, 126.4, 115.8, 64.2, 55.4, 46.9,
31.6, 13.7; IR (KBr): 2251 (w), 1790 (w), 1749 (s), 1722 (s), 1495
(m), 1451 (m); HRMS (ESI) calcd for C21H16N2O4Cl (MꢀH)ꢀ:
395.0799, found: 395.0809. The enantiomeric excess was deter-
mined by HPLC with a Chiralcel OD-H column (hexane/2-propa-
nol = 80:20, k = 220 nm, 1.0 mL/min); major diastereomer:
C
22H19N2O4 (MꢀH)ꢀ: 375.1345, found: 375.1363. The enantio-
meric excess was determined by HPLC with a Chiralpak AD-H col-
umn (hexane/2-propanol = 60:40, k = 220 nm, 0.8 mL/min); major

694
J.-J. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 690–696
diastereomer: tminor = 15.02 min, tmajor = 22.33 min, 87% ee; minor
diastereomer: tmajor = 9.26 min, tminor = 10.73 min, 16% ee.
tmajor = 9.46 min, tminor = 10.90 min, 33% ee; minor diastereomer:
tmajor = 7.33 min, tminor = 10.12 min, 0% ee.
4.3.13. (R)-Ethyl 2-((S)-1-benzyl-2,5-dioxopyrrolidin-3-yl)-2-
cyano-2-phenylacetate 3m
4.3.9. (R)-Ethyl 2-((S)-1-(3-chlorophenyl)-2,5-dioxopyrrolidin-
3-yl)-2-cyano-2-phenylacetate 3i
Sticky oil, ½a 2D0
ꢂ
¼ ꢀ0:5 (c 0.21, acetone); 1H NMR (400 MHz,
White solid, mp 149–150 °C; ½a D20
ꢂ
¼ ꢀ38:9 (c 0.19, acetone); 1H
CDCl3): d 7.60–7.57 (m, 2H), 7.45–7.26 (m, 8H), 4.75–4.59 (m,
2H), 4.43–4.20 (m, 3H), 2.61 (dd, J = 18.4, 9.2 Hz, 1H), 2.36 (dd,
J = 18.4, 6.8 Hz, 1H), 1.32 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 174.4, 173.4, 166.0, 135.0, 131.3, 129.8, 129.6, 128.7,
128.6, 128.1, 126.3, 115.7, 64.0, 55.0, 46.9, 42.8, 31.4, 13.7; IR
(KBr): 2248 (w), 1785 (m), 1753 (s), 1718 (s), 1586 (w), 1497
NMR (400 MHz, CDCl3): d 7.65–7.63 (m, 2H), 7.49–7.46 (m, 3H),
7.41–7.36 (m, 3H), 7.25–7.23 (m, 1H), 4.43–4.24 (m, 3H), 2.82
(dd, J = 18.8, 9.6 Hz, 1H), 2.54 (dd, J = 18.8, 6.4 Hz, 1H), 1.32 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 173.6, 172.4, 165.9,
134.8, 132.2, 131.1, 130.2, 129.9, 129.7, 129.2, 126.7, 126.4,
124.7, 115.8, 64.2, 55.4, 46.9, 31.6, 13.7; IR (KBr): 2252 (w), 1792
(w), 1753 (s), 1711 (s), 1591 (w), 1476 (m), 1452 (m); HRMS
(ESI) calcd for C21H16N2O4Cl (MꢀH)ꢀ: 395.0799, found: 395.0809.
The enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (hexane/2-propanol = 60:40, k = 220 nm, 0.8 mL/
min); major diastereomer: tminor = 15.77 min, tmajor = 20.21 min,
91% ee; minor diastereomer: tmajor = 9.32 min, tminor = 11.24 min,
21% ee.
(m), 1453 (m); HRMS (ESI) calcd for
C
22H19N2O4 (MꢀH)ꢀ:
375.1345, found: 375.1344. The enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 80:20, k = 220 nm, 0.8 mL/min); major diastereomer
tmajor = 16.98 min, tminor = 18.61 min, 63% ee: minor diastereomer:
tmajor = 11.65 min, tminor = 14.20 min, 7% ee.
4.3.14. (R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-
yl)-2-(p-tolyl)acetate 3n
4.3.10. (R)-Ethyl 2-((S)-1-(3-bromophenyl)-2,5-dioxopyrrolidin-
White solid, mp 129–131 °C; ½a D20
ꢂ
¼ ꢀ36:0 (c 0.25, acetone); 1H
3-yl)-2-cyano-2-phenylacetate 3j
NMR (400 MHz, CDCl3): d 7.53–7.38 (m, 5H), 7.32–7.25 (m, 4H),
4.41–4.21 (m, 3H), 2.81 (dd, J = 18.4, 9.6 Hz, 1H), 2.53 (dd,
J = 18.8, 6.4 Hz, 1H), 2.38 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 174.0, 172.9, 166.1, 140.4, 131.2, 130.3,
129.2, 129.0, 128.2, 126.5, 126.3, 116.0, 64.0, 55.2, 46.9, 31.6,
21.0, 13.7; IR (KBr): 2250 (w), 1783 (w), 1751 (s), 1707 (s), 1594
White solid, mp 169–171 °C; ½a D20
ꢂ
¼ ꢀ34:4 (c 0.25, acetone); 1H
NMR (400 MHz, CDCl3): d 7.65–7.63 (m, 2H), 7.60–7.46 (m, 5H),
7.36–7.27 (m, 2H), 4.43–4.24 (m, 3H), 2.82 (dd, J = 18.8, 9.6 Hz,
1H), 2.54 (dd, J = 18.8, 6.4 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3): d 173.6, 172.4, 165.9, 132.3, 132.1, 131.0,
130.4, 129.9, 129.7, 129.5, 126.4, 125.2, 122.5, 115.8, 64.2, 55.4,
46.9, 31.6, 13.7; IR (KBr): 2254 (w), 1789 (w), 1753 (s), 1710 (s),
1591 (w), 1499 (m), 1451 (m); HRMS (ESI) calcd for C21H16N2O4Br
(MꢀH)ꢀ: 439.0293, found: 439.0299. The enantiomeric excess was
determined by HPLC with a Chiralpak AD-H column (hexane/2-
propanol = 60:40, k = 220 nm, 0.8 mL/min); major diastereomer:
tminor = 17.15 min, tmajor = 24.45 min, 90% ee; minor diastereomer:
tmajor = 10.33 min, tminor = 12.62 min, 18% ee.
(w), 1499 (m), 1452 (m); calcd for
C
22H19N2O4 (MꢀH)ꢀ:
375.1345, found: 375.1353. The enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 60:40, k = 220 nm, 0.8 mL/min); major diastereomer:
tminor = 13.48 min, tmajor = 17.81 min, 91% ee; minor diastereomer:
tmajor = 9.30 min, tminor = 10.65 min, 14% ee.
4.3.15. (R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-
yl)-2-(4-methoxyphenyl) acetate 3o
White solid, mp 145–146 °C, ½a D20
ꢂ
¼ ꢀ34:2 (c 0.26, acetone); 1
H
4.3.11. (R)-Ethyl 2-((S)-2,5-dioxopyrrolidin-3-yl)- 2-cyano-2-
phenylacetate 3k
NMR (400 MHz, CDCl3): d 7.56–7.53 (m, 2H), 7.49–7.38 (m, 3H),
7.32–7.23 (m, 2H), 6.98–6.94 (m, 2H), 4.39–4.22 (m, 3H), 3.83 (s,
3H), 2.82 (dd, J = 18.4, 9.6 Hz, 1H), 2.54 (dd, J = 18.6, 6.4 Hz, 1H),
1.30 (t, J = 7.2 Hz, 3H).; 13C NMR (100 MHz, CDCl3): d 174.0,
172.9, 166.2, 160.5, 131.2, 129.2, 129.0, 127.8, 126.5, 122.9,
116.0, 114.9, 64.0, 55.4, 54.8, 46.9, 31.6, 13.7; IR (KBr): 2250 (w),
1789 (w), 1750 (s), 1710 (s), 1611 (w), 1453 (m); HRMS (ESI) calcd
for C22H19N2O5 (MꢀH)ꢀ: 391.1294, found: 391.1296. The enantio-
meric excess was determined by HPLC with a Chiralpak AD-H col-
umn (hexane/2-propanol = 60:40, k = 220 nm, 0.8 ml/min); major
diastereomer: tminor = 16.24 min, tmajor = 20.00 min, 88% ee; minor
diastereomer: tmajor = 12.08 min, tminor = 14.20 min, 16% ee.
Colorless oil, ½a D20
ꢂ
¼ ꢀ2:3 (c 0.56, acetone); 1H NMR (400 MHz,
CDCl3): d 8.83 (s, 1H), 7.62–7.59 (m, 2H), 7.48–7.44 (m, 3H),
4.42–4.25 (m, 3H), 2.65 (dd, J = 18.4, 9.2 Hz, 1H), 2.42 (dd,
J = 18.4, 6.8 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 175.0, 173.9, 165.2, 131.2, 129.8, 129.6, 126.3, 115.7,
64.1, 54.9, 48.0, 32.6, 13.7; IR (KBr): 3251 (m), 2249 (w), 1789
(m), 1754 (s), 1704 (s), 1599 (m), 1494 (w), 1451 (m); HRMS
(ESI) calcd for C15H13N2O4 (MꢀH)ꢀ: 285.0875, found: 285.0877.
The enantiomeric excess was determined by HPLC with a Chiralpak
OD-H column (hexane/2-propanol = 80:20, k = 215 nm, 0.8 mL/
min); major diastereomer tmajor = 25.43 min, tminor = 28.27 min,
41% ee; minor diastereomer: tminor = 33.02 min, tmajor = 37.29 min,
21% ee.
4.3.16. (R)-Ethyl 2-(4-bromophenyl)-2-cyano-2-((S)-2,5-dioxo-
1-phenylpyrrolidin-3-yl)-acetate 3p
White solid, mp 166–167 °C; ½a D20
ꢂ
¼ ꢀ22:7 (c 0.63, acetone); 1H
4.3.12. (R)-Ethyl 2-((S)-1-ethyl-2,5-dioxopyrrolidin-3-yl)- 2-
cyano-2-phenylacetate 3l
NMR (400 MHz, CDCl3): d 7.61 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8 Hz,
2H), 7.49–7.40 (m, 3H), 7.31–7.24 (m, 2H), 4.40–4.25 (m, 3H), 2.81
(dd, J = 18.4, 9.2 Hz, 1H), 2.51 (dd, J = 18.4, 6.8 Hz, 1H), 1.31 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 173.7, 172.6, 165.6,
132.8, 131.1, 130.3, 129.3, 129.07, 128.1, 126.4, 124.5, 115.5,
64.4, 55.0, 46.8, 31.5, 13.7; IR (KBr): 2251 (w), 1789 (w), 1753
(s), 1711 (s), 1595 (w), 1498 (m), 1456 (m); HRMS (ESI) calcd for
Colorless oil, ½a D20
ꢂ
¼ ꢀ3:7 (c 0.46, acetone); 1H NMR (400 MHz,
CDCl3): d 7.62–7.44 (m, 5H), 4.44–4.24 (m, 2H), 4.21 (dd, J = 9.2,
6.4 Hz, 1H), 3.61 (q, J = 7.2 Hz, 2H), 2.63 (dd, J = 18.4, 9.2 Hz, 1H),
2.33 (dd, J = 18.4, 6.4 Hz, 1H), 1.33 (t, J = 7.2 Hz, 3H), 1.21 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d 174.6, 173.6, 166.0,
131.4, 129.8, 129.6, 126.4, 115.7, 64.0, 55.2, 46.7, 34.2, 31.4, 13.7,
12.9; IR (KBr): 2248 (w), 1780 (m), 1750 (s), 1716 (s), 1599 (m),
1494 (w), 1449 (m); HRMS (ESI) calcd for C17H17N2O4 (MꢀH)ꢀ:
313.1188, found: 313.1185; The enantiomeric excess was deter-
mined by HPLC with a Chiralpak AD-H column (hexane/2-propa-
nol = 70:30, k = 220 nm, 0.8 mL/min); major diastereomer
C
21H16N2O4Br (MꢀH)ꢀ: 439.0293, found: 439.0300. The enantio-
meric excess was determined by HPLC with a Chiralpak AD-H col-
umn (hexane/2-propanol = 60:40, k = 220 nm, 0.8 mL/min); major
diastereomer: tminor = 13.78 min, tmajor = 19.79 min, 85% ee; minor
diastereomer: tmajor = 10.76 min, tminor = 12.41 min, 14% ee.

J.-J. Wang et al. / Tetrahedron: Asymmetry 22 (2011) 690–696
695
Najera, C.; Ramon, D. J. Tetrahedron: Asymmetry 2007, 18, 2249; (e) Bertelsen,
S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
4.3.17. (S)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-
yl)butanoate 3q
3. For recent reviews of organocatalytic asymmetric conjugate additions, see: (a)
Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299; (b)
Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 11, 1701; (c) Chen, Y.-C. Synlett 2008,
1919; (d) Mukherjee, S.; Yang, J.-W.; Hoffman, S.; List, B. Chem. Rev. 2007, 107,
5471; (e) Pellissier, H. Tetrahedron 2007, 63, 9267; (f) Vicario, J. L.; Badía, D.;
Carrillo, L. Synthesis 2007, 2065.
Colorless oil, ½a D20
ꢂ
¼ ꢀ3:3 (c 0.21, acetone); 1H NMR (400 MHz,
CDCl3) signals corresponding to the major diastereomer: d 7.50–
7.45 (m, 3H), 7.30–7.29 (m, 2H), 4.39–4.31 (m, 2H), 3.49 (dd,
J = 9.6, 5.6 Hz, 1H), 3.07 (dd, J = 18.6, 9.6 Hz, 1H), 2.81 (dd,
J = 18.0, 5.6 Hz, 1H), 2.54–2.45 (m, 1H), 2.27–2.20 (m, 1H), 1.36
(t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H); signals corresponding to
the minor diastereomer: d 7.43–7.39 (m, 3H), 7.28–7.27 (m, 2H),
4.39–4.31 (m, 2H), 3.63 (dd, J = 9.6, 6.0 Hz, 1H), 3.14 (dd, J = 18.0,
9.6 Hz, 1H), 2.83 (dd, J = 18.0, 5.6 Hz, 1H), 2.15–2.04 (m, 2H), 1.36
(t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
signals corresponding to the major diastereomer: d 173.9, 173.0,
167.0, 131.3, 129.2, 129.0, 126.5, 116.6, 63.7, 51.6, 43.9, 32.4,
28.8, 14.0, 9.6; signals corresponding to the minor diastereomer:
d 173.7, 172.9, 167.2, 131.3, 129.2, 129.0, 126.4, 116.5, 63.6, 52.0,
44.8, 31.9, 29.6, 13.9, 9.5; IR (KBr): 2250 (w), 1784 (w), 1747 (s),
1709 (s), 1596 (w), 1500 (m), 1459 (m). calcd for C17H17N2O4
(MꢀH)ꢀ: 313.1188, found: 313.1199. The enantiomeric excess
was determined by HPLC with a Chiralpak AD-H column (hex-
ane/2-propanol = 60:40, k = 220 nm, 0.8 mL/min); major diastereo-
mer: tmajor = 10.54 min, tminor = 11.06 min, 71% ee; minor
diastereomer: tmajor = 8.91 min, tminor = 13.43 min, 2% ee.
4. For selected biological studies on chiral
a-substituted succinimides, see: (a)
Ahmed, S. Drug Des. Discovery 1996, 14, 77; (b) Curtin, M. L.; Garland, R. B.;
Heyman, H. R.; Frey, R. R.; Michaelidies, M. R.; Li, J.; Pease, L. J.; Glaser, K. B.;
Marcotte, P. A.; Davidsen, S. K. Bioorg. Med. Chem. Lett. 2002, 12, 2919.
5. For synthetic applications of chiral
a-substituted succinimides, see: (a)
Nguyen, T. M.; Nguyen, Q. V.; Youte, J.-J.; Lau, J.; Cheong, A.; Ho, Y. S.; Tan, B.
S. W.; Yoganathan, K.; Butler, M. S.; Chai, C. L. L. Tetrahedron 2010, 66, 9270; (b)
Duan, W.-L.; Imazaki, Y.; Shintani, R.; Hayashi, T. Tetrahedron 2007, 63, 8529;
(c) Ballini, R.; Bosica, G.; Cioci, G.; Fiorini, D.; Petrini, M. Tetrahedron 2003, 59,
3603.
6. (a) Bartoli, G.; Bosco, M.; Carlone, A.; Cavalli, A.; Locatelli, M.; Mazzanti, A.;
Ricci, P.; Sambri, L.; Melchiorre, P. Angew. Chem., Int. Ed. 2006, 45, 4966; (b)
Jiang, Z.-Y.; Pan, Y.-H.; Zhao, Y.-J.; Ma, T.; Lee, R.; Yang, Y.-Y.; Huang, K.-W.;
Wong, M. W.; Tan, C.-H. Angew. Chem., Int. Ed. 2009, 48, 3627; (c) Jiang, Z.-Y.;
Ye, W.-P.; Yang, Y.-Y.; Tan, C.-H. Adv. Synth. Catal. 2008, 350, 2345.
7. (a) Zhao, G.-L.; Xu, Y.-M.; Sunden, H.; Eriksson, L.; Sayah, M.; Cordova, A. Chem.
Commun. 2007, 734; (b) Xue, F.; Liu, L.; Zhang, S.-L.; Duan, W.-H.; Wang, W.
Chem. Eur. J. 2010, 16, 7979; (c) Yu, F.; Jin, Z.-C.; Huang, H.-C.; Ye, T.-T.; Liang,
X.-M.; Ye, J.-X. Org. Biomol. Chem. 2010, 8, 4767.
8. Yu, F.; Sun, X.-M.; Jin, Z.-C.; Wen, S.-G.; Liang, X.-M.; Ye, J.-X. Chem. Commun.
2010, 46, 4589.
9. Zu, L.-S.; Xie, H.-X.; Li, H.; Wang, J.; Jiang, W.; Wang, W. Adv. Synth. Catal. 2007,
349, 1882.
10. Lu, J.; Zhou, W.-J.; Liu, F.; Loh, T.-P. Adv. Synth. Catal. 2008, 350, 1796.
11. Alba, A.-N. R.; Valero, G.; Calbet, T.; Font-Bardia, M.; Moyano, A.; Rios, R. Chem.
Eur. J. 2010, 16, 9884.
12. Li, X.; Hu, S.-S.; Xi, Z.-G.; Zhang, L.; Luo, S.-Z.; Cheng, J.-P. J. Org. Chem. 2010, 75,
8697.
4.4. Preparation of (3R,4S)-ethyl 5-oxo-4-(2-oxo-2-(phenyl
amino)ethyl)-3-phenylpyrrolidine-3-carboxylate 5
A solution of CoCl2ꢃ6H2O (0.4 mmol) and 3a (0.1 mmol) in
MeOH (3 mL) was stirred under an ice-bath. NaBH4 (6.63 mmol)
was added in portions to give a black suspension. Once H2 evolu-
tion ceased, the reaction mixture was warmed to 25 °C and stirred
for additional 3 h. After the completion of the reaction, Na2-
SO4ꢃ10H2O (3 mmol) was added. The mixture was filtered, and
the filtrate was dried over anhydrous Na2SO4. After the evaporation
of the solvent under vacuum, the crude product was purified by
column chromatography over silica gel to afford 5 as a colorless
13. Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett.
2010, 12, 2896.
14. For the reviews on the asymmetric construction of quaternary stereocenters,
see: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363.
and references therein; (b) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003,
42, 1688; (c) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388;
(d) Bella, M.; Gasperi, T. Synthesis 2009, 1583; (e) Hawner, C.; Alexakis, A. Chem.
Commun. 2010, 46, 7295; (f) Trost, B. M.; Jiang, C. Synthesis 2006, 369; (g)
Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005, 347, 1473.
15. For applications of
a-substituted cyanoacetates, see: (a) Francesca, M.; Silvia,
S.; Francesca, D. V.; Lorenzo, T.; Marcello, T. Adv. Synth. Catal. 2009, 351, 1801;
(b) Francesca, M.; Silvia, S.; Francesca, D. V.; Lorenzo, T.; Marcello, T. Adv. Synth.
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oil. ½a 2D0
ꢂ
¼ ꢀ42:3 (c 0.30, acetone); 1H NMR (400 MHz, CDCl3): d
9.24 (br s, 1H), 7.52–7.50 (m, 2H), 7.40–7.28 (m, 5H), 7.30–7.21
(m, 2H), 7.08–7.04 (m, 1H), 6.13 (br s, 1H), 4.33–4.25 (m, 2H),
4.07 (d, J = 10.4 Hz, 1H), 3.91 (d, J = 10.4 Hz, 1H), 3.75 (dd, J = 9.2,
3.2 Hz, 1H), 2.35 (dd, J = 15.2, 3.2 Hz, 1H), 2.26 (dd, J = 15.2,
9.2 Hz, 1H), 1.27 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d
178.3, 172.8, 169.1, 138.4, 137.3, 129.1, 128.8, 128.2, 126.5,
123.8, 119.6, 62.2, 57.8, 49.5, 45.1, 35.9, 14.0; IR (KBr): 1739 (s),
1655 (s), 1598 (m), 1553 (m), 1499 (m), 1444 (m), 759 (m), 696
(m); HRMS (ESI) calcd for C21H16N2O4Br (MꢀH)ꢀ: 365.1501, found:
365.1501. The enantiomeric excess was determined by HPLC with
a Chiralpak AD-H column (hexane/2-propanol = 65:35, k = 254 nm,
0.8 mL/min); major diastereomer: tminor = 9.40 min, tmajor = 10.83 -
min, 84% ee.
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Acknowledgments
Financial support from the National Natural Science Foundation
of China (Nos. 20772160, 20972195), Ministry of Health of China
(No. 2009ZX09501-017), and Fundamental Research Funds for
the Central Universities are gratefully acknowledged.
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