Thiourea-catalyzed asymmetric conjugate addition of α-substituted cyanoacetates to maleimides

Article abstract of DOI:10.1016/j.tetasy.2012.11.009

Chiral isosteviol-derived tertiary amine-thiourea was proven to be effective in catalyzing the asymmetric conjugate addition between α-substituted cyanoacetate and maleimides. Diverse succinimides bearing vicinal quaternary-tertiary stereocenters were obt

Full text of DOI:10.1016/j.tetasy.2012.11.009

Tetrahedron: Asymmetry 24 (2013) 7–13
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Thiourea-catalyzed asymmetric conjugate addition of
cyanoacetates to maleimides
a-substituted
Zhi-wei Ma a, Ya Wu a,b, Bin Sun a, Hai-long Du a, Wei-min Shi a, Jing-chao Tao a,
⇑
a New Drug Research and Development Center, College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450052, PR China
b School of Pharmacy, Henan University of Traditional Chinese Medicine, Zhengzhou 450008, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 September 2012
Accepted 11 November 2012
Chiral isosteviol-derived tertiary amine-thiourea was proven to be effective in catalyzing the asymmetric
conjugate addition between
a-substituted cyanoacetate and maleimides. Diverse succinimides bearing
vicinal quaternary-tertiary stereocenters were obtained in excellent yields, excellent diastereoselectivi-
ties, and with good to high enantioselectivities. This catalytic system can be used efficiently in large-scale
reactions with the yields and stereoselectivities being maintained at the same level.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
essential third branch of asymmetric catalysis that complements
the fields of metal and enzyme catalysis.7 Over the past few years,
The chemistry of the construction of vicinal quaternary-tertiary
stereocenters has attracted more and more attention in recent
years because of their ubiquitous and important role in natural
products and pharmaceuticals.1 To date, numerous strategies have
been developed to produce adjacent quaternary and tertiary ste-
reocenters.2 Among these procedures, the catalytic enantioselec-
a series of thioureas have been designed, synthesized, and emerged
as efficient catalysts for various types of asymmetric reactions.8
Our novel designed chiral bifunctional amine-thioureas are highly
efficient and enantioselective in the application of asymmetric
Michael additions.9 Based on our previous work, and the concept
of bifunctional catalysis, we envisioned that the addition of
tive conjugate addition of
a-substituted cyanoacetates, prochiral
a-isocyanoacetates to maleimides could be realized in the
trisubstituted carbon nucleophiles, which contain two useful func-
tional groups of a nitrile and an ester, provides a generally applied
and feasible synthetic method.3
presence of our novel chiral tertiary amine thiourea catalysts. As
a part of our continuing interests in asymmetric synthesis,9,10 we
herein report the asymmetric Michael addition of
a-substituted
Substituted succinimides are valuable synthetic targets and
important structural scaffolds and precursors of biologically inter-
esting substances.4 The asymmetric Michael reaction of malei-
mides using an organocatalyst is one of the most practical
cyanoacetate to maleimides catalyzed by chiral tertiary amine
thioureas.
2. Results and discussion
synthetic procedures for effectively obtaining chiral a-substituted
succinimides. Many asymmetric Michael additions of maleimides
In our previous study, the novel chiral tertiary amine-thiourea
catalyst 1a/b (Fig. 1) exhibited excellent activity in the asymmetric
Michael addition between acetylacetone and nitroolefins.9c In or-
der to broaden the scope of the isosteviol-derived organocatalysts
and to improve the catalytic activities of the thioureas, we synthe-
sized compounds 1c and 1d (Fig. 1).
with a variety of nucleophiles promoted by organocatalysts have
been reported.5 However, reports using
a-substituted cyanoace-
tates as nucleophiles are rare. To the best of our knowledge, almost
at the same time, Yuan and Yan reported the organocatalytic con-
jugate addition of
a
-phenyl cyanoacetate onto maleimides.6 Both
used the Takemoto’s tertiary amine-thiourea catalyst, but the re-
sults were different. Therefore, it is highly desirable to develop
The catalytic performance of the catalysts was then evaluated in
the direct asymmetric Michael addition of
a-phenyl cyanoacetate
new catalytic asymmetric protocols using
tates and maleimides.
a-substituted cyanoace-
2a to N-phenylmaleimide 3a and the results are summarized in
Table 1. We found that each catalyst can efficiently catalyze this
conjugate addition with high yields and good diastereoselectivi-
ties, but only low to moderate enantioselectivites were obtained.
As expected, thioureas 1a and 1b exhibited a reversed sense of
asymmetric induction (Table 1, entries 1 and 2). However, only
20% ee was obtained when 1b was used as the catalyst. In addition,
when the tertiary amine moiety of the thiourea was changed from
Organocatalysis using small organic molecules has been estab-
lished as a highly selective and efficient method for a wide range of
reactions over the last decade and has been developed into an
⇑
Corresponding author. Tel./fax: +86 371 67767200.
E-mail address: jctao@zzu.edu.cn (J.-c. Tao).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.009

8
Z. Ma et al. / Tetrahedron: Asymmetry 24 (2013) 7–13
H
N
H
N
H
H
N
S
S
N
S
S
HN
N
HN
N
HN
N
HN
N
COOEt
COOEt
COOEt
COOEt
1a
1b
Figure 1. Novel chiral tertiary amine-thiourea catalysts.
1d
1c
Table 1
Comparison of the catalytic activities of thioureas for the model reactiona
O
O
O
O
Cat. 1 (10 mol%)
N
Ph
CN
N
Ph
EtO
EtO
CH2Cl2, rt, 5 h
Ph
2a
O
Ph CN
O
3a
4a
Entry
Catalyst
Yieldb (%)
drc
eec (%)
1
2
3
4
1a
1b
1c
1d
95
92
90
93
82/18
80/20
81/19
81/19
42
ꢀ20
35
39
a
Unless otherwise specified, all reactions were carried out using a-phenyl cyanoacetate 2a (0.10 mmol), N-phenylmaleimide 3a (0.12 mmol), and 10 mol % of catalyst in
1.0 mL of CH2Cl2 at room temperature.
b
Isolated yield.
Determined by chiral HPLC analysis.
c
a dimethyl group to a diethylamino group or a pyrrolidin-1-yl
group, no improvement in the enantioselectivity was obtained.
Thus, thiourea 1a was used for further studies.
A survey of solvents revealed that toluene was the most suitable
solvent (Table 2, entries 1–10). The reaction temperature was
found to be an essential factor for the diastereoselectivities and
Table 2
Optimization of the reaction conditionsa
O
O
O
O
Cat. 1a (X mol%)
CN
N
Ph
N
Ph
EtO
solvent, T, 5 h
EtO
Ph
2a
O
Ph CN
O
3a
4a
Entry
Solvent
X (mol %)
T (°C)
Yieldb (%)
drc
eec (%)
1
2
4
5
6
7
8
9
CH2Cl2
CHCl3
THF
10
10
10
10
10
10
10
10
10
10
10
10
10
5
rt
rt
rt
rt
rt
rt
rt
rt
rt
95
90
93
89
94
90
92
Trace
Trace
94
82/18
84/16
82/18
89/11
92/8
42
57
21
65
79
77
79
Ether
Toluene
Xylene
Mesitylene
H2O
91/9
90/10
d
d
—
—
—
—
10e
11
12
13
14
15
16f
Neat
d
d
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
0
92/8
94/6
97/3
96/4
96/4
97/3
82
87
93
77
87
92
ꢀ20
ꢀ30
ꢀ40
ꢀ30
ꢀ30
90
97
89
90
10
88
a
b
c
d
e
f
Unless otherwise specified, all reactions were carried out using
Isolated yield.
Determined by chiral HPLC analysis.
Not determined.
0.40 mmol of ethyl phenylcyanoacetate was used.
20 mg of 4 Å molecular sieves was used.
a-phenyl cyanoacetate 2a (0.10 mmol) and N-phenylmaleimide 3a (0.12 mmol) in 1.0 mL of solvent.

Z. Ma et al. / Tetrahedron: Asymmetry 24 (2013) 7–13
9
enantioselectivities of this reaction. The stereoselectivity gradually
increased when decreasing the reaction temperature from room
temperature to ꢀ30 °C (Table 2, entries 6, 11–13). However, when
the temperature was decreased further to ꢀ40 °C, both the yield
and the stereoselectivities decreased (Table 2, entry 14). In
addition, a decrease in the catalyst loading from 10% to 5% did
not affect the yield or the diastereoselectivity, but the enantiose-
lectivity was low (Table 2, entries 13 and 15). There was no
improvement when 4 Å molecular sieves were used as additive
(Table 2, entry 16).
tries 6 and 7). In addition, when the reaction was performed
with N-alkylmaleimides 3k, the yield and diastereoselectivity were
acceptable, but only as low as 20% ee was obtained (entry 11).
When using N-alkylmaleimides 3l as the Michael acceptor, the cor-
responding adduct was observed in only trace amounts (entry 12).
This further proved that the N-alkylmaleimides had a lower reac-
tivity than the N-arylmaleimides in this experimental protocol.
To expand upon the scope of this methodology, we subsequently
investigated the conjugate addition with various a-aryl cyanoace-
tates 2b–e to N-phenyl maleimide 3a (entries 13–16). In all cases,
the reactions proceeded smoothly to give the desired adducts in
excellent yields and with excellent diastereoselectivities and good
enantioselectivities. Variation of the ester moiety was then consid-
With the optimal reaction conditions in hand, a representative
selection of
a-substituted cyanoacetates and maleimides was
investigated to determine the scope of this Michael addition. As
Table 3
Substrate studies of the Michael addition promoted by 1aa
O
O
O
O
CN
R1O
N
R3
Cat. 1a (10 mol%)
R1O
R2
N
R3
Toluene, -30 o
C
O
CN
O
R2
2
3
4
c
Entry
R1
R2
R3
Time (h)
Product
Yieldb (%)
dr
eec (%)
1
2
3
4
5
6
7
8
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
H 2a
H 2a
H 2a
H 2a
H 2a
H 2a
H 2a
H 2a
H 2a
H 2a
H 2a
H 2a
CH3 2b
OCH3 2c
Cl 2d
Br 2e
H 2f
C6H5 3a
2
2
2
2
2
2
2
2
10
10
24
24
2
2
2
2
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
97
94
93
96
96
92
95
96
89
90
71
Trace
96
95
96
93
94
97/3
96/4
98/2
98/2
97/3
93/7
94/6
93/7
96/4
95/5
81/19
93
93
90
92
90
75
73
91
87
86
20
3-Br-C6H4 3b
4-Br-C6H4 3c
3-Cl-C6H4 3d
4-Cl-C6H4 3e
4-F-C6H4 3f
3-NO2-C6H4 3g
4-CH3-C6H4 3h
4-OCH3-C6H4 3i
1-Naphthyl 3j
Bn 3k
t-Bu 3l
C6H5 3a
C6H5 3a
C6H5 3a
C6H5 3a
C6H5 3a
9
10
11
12
13
14
15
16
17
d
d
—
—
95/5
92/8
97/3
93/7
91/9
85
84
77
80
84
a
Unless otherwise specified, all reactions were carried out using a-substituted cyanoacetate 2 (0.10 mmol), maleimide 3a–l (0.12 mmol), and Cat. 1a (10 mol %) in 1.0 mL
of toluene at ꢀ30 °C.
b
Isolated yield.
Determined by chiral HPLC analysis.
Not determined.
c
d
shown in Table 3, N-arylmaleimides 3b–i bearing a range of aryl
groups of varying electronic properties underwent efficient asym-
metric addition with a-phenyl cyanoacetate 2a, to give structurally
ered. Methyl cyanoacetate 2f reacted well with N-phenylmaleim-
ide 3a and gave the corresponding adducts with good results
(entries 17).
diverse succinimides 4b–i bearing vicinal quaternary-tertiary ste-
reocenters in excellent yields, excellent diastereoselectivities, and
with good to high enantioselectivities (entries 2–9). In the cases
of N-arylmaleimides 3f and 3g bearing strong electron-withdraw-
ing substituents, the enantioselectivities were slightly poor (en-
We further confirmed the synthetic utility of the catalytic ap-
proach by a gram-scale experiment. As can be seen from the results
summarized in Scheme 1, both the yield and stereoselectivities
were maintained at the same level for the large-scale reaction,
which offers a great possibility for industrial application.
O
O
O
O
Cat. 1a (10 mol%)
toluene, -30 oC, 3 h
N
Ph
CN
N
Ph
EtO
EtO
Ph
2a
5 mmol
O
Ph CN
O
3a
4a
1.71 g, 95%
1.2 eq.
dr: 97/3, ee: 90%
Scheme 1. Large-scale reaction.

10
Z. Ma et al. / Tetrahedron: Asymmetry 24 (2013) 7–13
Encouraged by these results, we also examined other electro-
4. Experimental
4.1. General
philes such as trans-b-nitrostyrene 5 and benzylideneacetone 7.
However, no reaction occured and so were not applicable in this
asymmetric conjugate addition (Scheme 2).
All reagents were obtained from commercial suppliers without
further purification. Commercial grade solvent was dried and puri-
NO2
O
NO2
EtO
Ph CN
O
5
6
Cat. 1a (10 mol%)
O
CN
EtO
Toluene, -30 o
C
O
O
Ph
2a
No reaction
EtO
Ph CN
7
8
Scheme 2. Conjugate addition of other electrophiles.
Although the precise reaction mechanism requires further
study, a possible transition state has been proposed based on the
stereoselectivities observed. In Figure 2, the thiourea moiety of
fied by standard procedures. Chemicals were used as received un-
less otherwise noted. Reagent grade solvents were redistilled prior
to use. 1H NMR and 13C NMR spectra were collected on a Bruker
DPX 400 NMR spectrometer with TMS as an internal reference. IR
spectra were determined on a Thermo Nicolet IR200 unit. High res-
olution mass spectra (HRMS) were obtained on a Waters Micro-
mass Q-Tof Micro™ instrument using the ESI technique.
Chromatography was performed on silica gel (200–300 mesh).
Melting points were determined using an aXT5 Apparatus and
are uncorrected. Optical rotations were determined on a Perkin El-
mer 341 polarimeter. Enantiomeric excess was determined by chi-
ral HPLC at room temperature using a Labtech 2006 pump
equipped with a Labtech UV600 ultra detector and with Chiral col-
umns (Chiralpak AD-H).
S
N
H
N
H
N
H
O
COOEt
Ph
N
O
OEt
Re-face attack
O
NC
4.2. General procedures for the preparation of catalysts 1
Ph
from Si-face
Compounds 1a and 1b are known compounds.9c Compounds 1c
and 1d were synthesized according to the similar procedure used
Figure 2. Proposed transition state.
9c,11
for 1a.
4.2.1. 1-(Ethyl ent-beyeran-19-oate-16-yl)-3-((1S,2S)-2-(diethyl
catalyst 1a interacts through double hydrogen bonding with the
maleimide, while the tertiary amine interacts with the OH of the
enolate through a single hydrogen bonding interaction. The attack
from the si-face of the enolate to the re-face of the maleimide gives
product 4a. Nevertheless, the precise catalytic mechanism still
requires further investigation.
amino)cyclohexyl) thiourea 1c
White solid; mp: 120–121 °C; ½a D20
ꢁ
¼ ꢀ34:9 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3, TMS): d 0.70 (s, 3H), 0.85 (dt, J = 13.2,
4.0 Hz, 1H), 0.95 (s, 3H), 0.96–1.10 (m, 6H), 1.15 (s, 4H), 1.24 (t,
J = 7.2 Hz, 5H), 1.34–1.41 (m, 12H), 1.53–1.82 (m, 9H), 1.90 (m,
4H), 2.14 (d, J = 13.6 Hz, 1H), 2.62 (m, 4H), 3.29 (s, 2H), 3.97–4.13
(m, 2H); 13C NMR (100 MHz, CHCl3): d 13.3, 14.1, 18.8, 21.7, 24.3,
28.9, 33.0, 38.0, 39.9, 41.5, 43.6, 55.7, 59.9, 63.9, 177.5, 182.0; IR
(KBr, cmꢀ1):
m 572, 1028, 1123, 1148, 1235, 1371, 1453, 1542,
3. Conclusion
1632, 1720, 2849, 2937, 3432; calcd for C33H58N3O2S [M+H]+:
560.4250, found 560.4248.
In conclusion, we have developed an organocatalytic asymmet-
ric conjugate addition of
a-substituted cyanoacetate to malei-
mides. The thiourea 1a was efficient for this transformation and
furnished structurally diverse succinimides bearing vicinal quater-
nary-tertiary stereocenters in excellent yields, excellent diastere-
oselectivities, and with good to high enantioselectivities. This
catalytic system can also be used efficiently in large-scale reactions
with the yield and stereoselectivity being maintained at the same
level, which offers a great possibility for industrial application. Fur-
ther investigation of these organocatalysts in other asymmetric
reactions as well as more detailed mechanistic study is currently
ongoing in our laboratory.
4.2.2. 1-(Ethyl ent-beyeran-19-oate-16-yl)-3-((1S,2S)-2-(pyrroli
din-1-yl)cyclohexyl) thiourea 1d
White solid; mp: 135–136 °C; ½a D20
ꢁ
¼ ꢀ24:0 (c 1.0, CHCl3); 1H
NMR (400 MHz, CDCl3, TMS): d 0.72 (s, 3H), 0.84 (dt, J = 13.2,
4.0 Hz, 1H), 0.95 (s, 3H), 0.97–1.07 (m, 4H), 1.15 (s, 3H), 1.24 (t,
J = 7.2 Hz, 4H), 1.31–1.47 (m, 9H), 1.58 (t, J = 10.8 Hz, 2H), 1.65–
1.72 (m, 3H), 1.74–1.84 (m, 3H), 1.92–2.07 (m, 7H), 2.14 (d,
J = 13.2 Hz, 2H), 2.35 (d, J = 12.4 Hz, 1H), 2.97 (s, 1H), 3.14 (s, 1H),
3.41 (t, J = 9.6 Hz, 2H), 3.65 (s, 1H), 3.99–4.12 (m, 2H), 4.48–4.58
(m, 2H), 7.18 (d, J = 7.2 Hz, 1H), 7.98 (d, J = 4.0 Hz, 1H); 13C NMR

Z. Ma et al. / Tetrahedron: Asymmetry 24 (2013) 7–13
11
(100 MHz, CHCl3): d 13.3, 14.1, 18.9, 21.7, 25.0, 28.9, 32.7, 38.0,
39.9, 41.5, 42.3, 55.0, 56.0, 57.1, 59.9, 62.3, 63.8, 77.3, 177.6,
182.7; IR (KBr, cmꢀ1):
753, 973, 1026, 1095, 1151, 1178, 1236,
1368, 1454, 1542, 1719, 2848, 2939, 3058, 3267; calcd for
33H56N3O2S [M+H]+: 558.4093, found 558.4091.
4.3.5. (R)-Ethyl 2-((S)-1-(4-chlorophenyl)-2,5-dioxopyrrolidin-
3-yl)-2-cyano-2-phenylacetate 4e6
m
½
a 2D0
ꢁ
¼ ꢀ54:0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.31 (t, J = 7.2 Hz, 3H), 2.53 (dd, J = 6.4, 18.4 Hz, 1H), 2.81 (dd,
J = 9.6, 18.4 Hz, 1H), 4.23–4.31 (m, 1H), 4.34–4.43 (m, 2H), 7.25–
7.29 (m, 2H), 7.42–7.51 (m, 5H), 7.62–7.65 (m, 2H); 13C NMR
(100 MHz, CHCl3): d 13.8, 31.6, 47.0, 55.5, 64.2, 115.9, 126.5,
127.8, 129.5, 129.8, 134.9, 165.9, 172.6, 173.8; HPLC analysis for
major diastereomer (Chiralpak AD-H column, i-propanol/hex-
ane = 70/30, flow rate = 0.5 mL/min, k = 254 nm): tmajor = 43.2 min,
C
4.3. Typical procedure for the Michael addition
The -phenyl cyanoacetate 2 (0.10 mmol) was added to a mix-
a
ture of catalyst 1a (10 mol %) and the corresponding maleimide 3
(0.12 mmol) in toluene (1.0 mL). The reaction mixture was stirred
tminor = 37.9 min.
at ꢀ30 °C for the required time. After the
a-phenyl cyanoacetate
was consumed as determined by TLC analysis, the reaction mixture
was subjected to thin layer chromatography on silica gel (ethyl
acetate/petroleum ether) to afford the pure Michael product.
4.3.6. (R)-Ethyl 2-cyano-2-((S)-1-(4-fluorophenyl)-2,5-dioxopyrr
olidin-3-yl)-2-phenylacetate 4f6
½
a 2D0
ꢁ
¼ ꢀ49:8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.31 (t, J = 7.2 Hz, 3H), 2.53 (dd, J = 6.4, 18.8 Hz, 1H), 2.81 (dd,
J = 9.6, 18.4 Hz, 1H), 4.23–4.43 (m, 3H), 7.13–7.18 (m, 2H), 7.28–
7.33 (m, 2H), 7.44–7.51 (m, 3H), 7.63–7.66 (m, 2H); 13C NMR
(100 MHz, CHCl3): d 13.8, 31.6, 46.9, 55.5, 64.2, 115.9, 116.3,
126.5, 128.4, 129.5, 129.8, 130.0, 131.2, 163.7, 166.0, 172.8,
174.0; HPLC analysis for major diastereomer (Chiralpak AD-H col-
4.3.1. (R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-
3-yl)-2-phenylacetate 4a6
½
a 2D0
ꢁ
¼ ꢀ51:4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.31 (t, J = 7.2 Hz, 3H), 2.53 (dd, J = 6.4, 18.4 Hz, 1H), 2.81 (dd,
J = 9.6, 18.8 Hz, 1H), 4.23–4.31 (m, 1H), 4.34–4.43 (m, 2H), 7.30–
7.32 (m, 2H), 7.39–7.50 (m, 5H), 7.64–7.67 (m, 2H); 13C NMR
(100 MHz, CHCl3): d 13.8, 31.7, 47.0, 55.5, 64.2, 115.9, 126.5,
126.6, 129.1, 129.3, 129.7, 129.9, 131.3, 166.0, 172.9, 174.0; HPLC
analysis for major diastereomer (Chiralpak AD-H column, i-propa-
umn,
i-propanol/hexane = 70/30,
flow
rate = 0.5 mL/min,
k = 254 nm): tmajor = 52.4 min, tminor = 45.9 min.
4.3.7. (R)-Ethyl 2-cyano-2-((S)-1-(3-nitrophenyl)-2,5-dioxopyrr
olidin-3-yl)-2-phenylacetate 4g6
nol/hexane = 70/30,
flow
rate = 0.5 mL/min,
k = 254 nm):
½ ꢁ
a 2D0
¼ ꢀ52:8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
tmajor = 61.6 min, tminor = 38.7 min.
1.32 (t, J = 7.2 Hz, 3H), 2.60 (dd, J = 6.4, 18.8 Hz, 1H), 2.88 (dd,
J = 9.6, 18.8 Hz, 1H), 4.25–4.44 (m, 3H), 7.45–7.52 (m, 3H), 7.62–
7.75 (m, 4H), 8.26–8.30 (m, 2H); 13C NMR (100 MHz, CHCl3): d
13.8, 31.7, 47.0, 55.4, 64.4, 115.9, 121.8, 123.6, 126.5, 129.6,
130.0, 130.1, 132.4, 148.5, 165.8, 172.0, 173.4; HPLC analysis for
major diastereomer (Chiralpak AD-H column, i-propanol/hex-
ane = 70/30, flow rate = 0.5 mL/min, k = 254 nm): tmajor = 43.7 min,
tminor = 52.7 min.
4.3.2. (R)-Ethyl 2-((S)-1-(3-bromophenyl)-2,5-dioxopyrrolidin-
3-yl)-2-cyano-2-phenylacetate 4b6
½
a 2D0
ꢁ
¼ ꢀ54:8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.32 (t, J = 7.2 Hz, 3H), 2.53 (dd, J = 6.4, 18.8 Hz, 1H), 2.81 (dd,
J = 9.6, 18.8 Hz, 1H), 4.24–4.32 (m, 1H), 4.35–4.43 (m, 2H), 7.26–
7.30 (m, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.46–7.51 (m, 4H), 7.54–7.56
(m, 1H), 7.63–7.65 (m, 2H); 13C NMR (100 MHz, CHCl3): d 13.8,
31.7, 47.0, 55.4, 64.3, 115.9, 122.6, 125.2, 126.5, 129.6, 129.8,
130.0, 130.5, 131.1, 132.2, 132.4, 165.9, 172.4, 173.6; HPLC analysis
for major diastereomer (Chiralpak AD-H column, i-propanol/hex-
ane = 70/30, flow rate = 0.5 mL/min, k = 254 nm): tmajor = 52.3 min,
4.3.8. (R)-Ethyl 2-cyano-2-((S)-2,5-dioxo-1-(p-tolyl)pyrrolidin-
3-yl)-2-phenylacetate 4h6
½
a 2D0
ꢁ
¼ ꢀ54:6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
tminor = 34.0 min.
1.31 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 2.53 (dd, J = 6.4, 18.8 Hz, 1H),
2.79 (dd, J = 9.6, 18.8 Hz, 1H), 4.23–4.31 (m, 1H), 4.34–4.42 (m,
2H), 7.17–7.28 (m, 4H), 7.43–7.50 (m, 3H), 7.64–7.66 (m, 2H);
13C NMR (100 MHz, CHCl3): d 13.8, 21.2, 31.6, 47.0, 55.5, 64.2,
115.9, 126.3, 126.5, 126.6, 128.6, 130.0, 139.2, 166.0, 173.0,
174.1; HPLC analysis for major diastereomer (Chiralpak AD-H col-
4.3.3. (R)-Ethyl 2-((S)-1-(4-bromophenyl)-2,5-dioxopyrrolidin-
3-yl)-2-cyano-2-phenylacetate 4c6
½
a 2D0
ꢁ
¼ ꢀ51:9 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.31 (t, J = 7.2 Hz, 3H), 2.53 (dd, J = 6.4, 18.8 Hz, 1H), 2.81 (dd,
J = 9.6, 18.8 Hz, 1H), 4.25–4.31 (m, 1H), 4.34–4.42 (m, 2H), 7.19–
7.23 (m, 2H), 7.45–7.51 (m, 3H), 7.58–7.65 (m, 4H); 13C NMR
(100 MHz, CHCl3): d 13.8, 31.7, 47.0, 55.5, 64.2, 115.9, 123.0,
126.5, 128.1, 129.8, 130.0, 130.2, 131.1, 132.5, 165.9, 172.5,
173.7; HPLC analysis for major diastereomer (Chiralpak AD-H
column, i-propanol/hexane = 70/30, flow rate = 0.5 mL/min,
k = 254 nm): tmajor = 41.6 min, tminor = 37.2 min.
umn,
i-propanol/hexane = 70/30,
flow
rate = 0.5 mL/min,
k = 254 nm): tmajor = 38.8 min, tminor = 24.7 min.
4.3.9. (R)-Ethyl 2-cyano-2-((S)-1-(4-methoxyphenyl)-2,5-dioxo
pyrrolidin-3-yl)-2-phenylacetate 4i6
½
a 2D0
ꢁ
¼ ꢀ50:6 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.31 (t, J = 7.2 Hz, 3H), 2.52 (dd, J = 6.4, 18.4 Hz, 1H), 2.80 (dd,
J = 9.6, 18.4 Hz, 1H), 3.82 (s, 3H), 4.25–4.41 (m, 3H), 6.96–7.00
(m, 2H), 7.20–7.24 (m, 2H), 7.43–7.50 (m, 3H), 7.64–7.66 (m,
2H); 13C NMR (100 MHz, CHCl3): d 13.8, 31.6, 46.9, 55.5, 64.2,
114.6, 115.9, 123.8, 126.5, 127.8, 129.7, 129.9, 131.3, 159.8,
166.0, 173.2, 174.2; HPLC analysis for major diastereomer (Chir-
4.3.4. (R)-Ethyl 2-((S)-1-(3-chlorophenyl)-2,5-dioxopyrrolidin-
3-yl)-2-cyano-2-phenylacetate 4d6
½
a 2D0
ꢁ
¼ ꢀ57:4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.32 (t, J = 7.2 Hz, 3H), 2.54 (dd, J = 6.4, 18.8 Hz, 1H), 2.82 (dd,
J = 9.6, 18.8 Hz, 1H), 4.24–4.32 (m, 1H), 4.35–4.43 (m, 2H), 7.23–
7.26 (m, 1H), 7.35–7.36 (m, 1H), 7.38–7.43 (m, 2H), 7.44–7.51
(m, 3H), 7.62–7.65 (m, 2H); 13C NMR (100 MHz, CHCl3): d 13.8,
31.7, 47.0, 55.4, 64.3, 115.9, 124.8, 126.5, 126.8, 129.3, 129.8,
130.0, 130.2, 131.1, 132.3, 134.9, 165.9, 172.4, 173.6; HPLC analysis
for major diastereomer (Chiralpak AD-H column, i-propanol/hex-
ane = 70/30, flow rate = 0.5 mL/min, k = 254 nm): tmajor = 41.1 min,
alpak
AD-H
column,
i-propanol/hexane = 70/30,
flow
rate = 0.5 mL/min, k = 254 nm): tmajor = 61.9 min, tminor = 46.1 min.
4.3.10. (R)-Ethyl 2-cyano-2-((S)-1-(naphthalen-1-yl)-2,5-dioxo
pyrrolidin-3-yl)-2-phenylacetate 4j
½
a 2D0
ꢁ
¼ ꢀ49:0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.33 (t, J = 7.2 Hz, 3H), 2.56 (dd, J = 6.4, 18.4 Hz, 1H), 2.84 (dd,
tminor = 29.3 min.
J = 9.6, 18.8 Hz, 1H), 4.25–4.39 (m, 3H), 7.13–7.20 (m, 2H), 7.24–

12
Z. Ma et al. / Tetrahedron: Asymmetry 24 (2013) 7–13
7.35 (m, 3H), 7.46–7.53 (m, 5H), 7.65–7.68 (m, 2H); 13C NMR
(100 MHz, CHCl3): d 13.8, 31.6, 46.9, 55.5, 64.2, 115.9, 126.5,
126.6, 128.4, 128.5, 129.5, 129.7, 129.8, 130.0, 131.2, 132.0,
166.0, 172.8, 174.0; HRMS (ESI) Calcd for C25H20N2NaO4 [M+Na]+:
435.1315, found: 435.1316; HPLC analysis for major diastereomer
(Chiralpak AD-H column, i-propanol/hexane = 70/30, flow
rate = 0.5 mL/min, k = 254 nm): tmajor = 43.6 min, tminor = 38.2 min.
4.3.16. (R)-Methyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-
3-yl)-2-phenylacetate 4q6
½
a 2D0
ꢁ
¼ ꢀ38:5 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
2.54 (dd, J = 6.4, 18.4 Hz, 1H), 2.82 (dd, J = 9.6, 18.8 Hz, 1H), 3.88
(s, 3H), 4.41 (dd, J = 6.4, 9.2 Hz, 1H), 7.03–7.32 (m, 2H), 7.40–7.51
(m, 6H), 7.64–7.67 (m, 2H); 13C NMR (100 MHz, CHCl3): d 31.6,
47.1, 54.6, 55.3, 115.9, 126.5, 129.1, 129.3, 129.8, 130.0, 131.1,
131.2, 166.6, 172.8, 174.0; HPLC analysis for major diastereomer
(Chiralpak AD-H column, i-propanol/hexane = 70/30, flow
rate = 0.5 mL/min, k = 254 nm): tmajor = 95.3 min, tminor = 47.0 min.
4.3.11. (R)-Ethyl 2-((S)-1-benzyl-2,5-dioxopyrrolidin-3-yl)-
2-cyano-2-phenylacetate 4k6
½
a 2D0
ꢁ
¼ ꢀ11:8 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.34 (t, J = 7.2 Hz, 3H), 2.38 (dd, J = 6.4, 18.4 Hz, 1H), 2.64 (dd,
J = 9.2, 18.4 Hz, 1H), 4.22–4.44 (m, 3H), 4.67–4.78 (m, 2H), 7.29–
7.48 (m, 8H), 7.60–7.62 (m, 2H); 13C NMR (100 MHz, CHCl3): d
13.7, 31.5, 42.8, 46.9, 55.0, 64.1, 115.8, 126.4, 128.6, 128.7, 129.8,
135.1, 166.0, 173.5, 174.5; HPLC analysis for major diastereomer
(Chiralpak AD-H column, i-propanol/hexane = 60/40, flow
rate = 0.1 mL/min, k = 254 nm): tmajor = 69.8 min, tminor = 72.9 min.
4.4. General procedure for large-scale Michael addition
The
a-phenyl cyanoacetate 2a (5.0 mmol) was added to a
mixture of catalyst 1a (10 mol%) and the corresponding N-phenyl-
maleimide 3a (6.0 mmol) in toluene (50 mL). The reaction mixture
was stirred at ꢀ30 °C for 3 h. After the maleimide was consumed as
determined by TLC analysis, the solvent was removed under
reduced pressure and the crude product was purified using column
chromatography eluting with ethyl acetate/petroleum ether. The
product was obtained as a white solid in 95% yield.
4.3.12. (R)-Methyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-
3-yl)-2-(p-tolyl)acetate 4m6
½
a 2D0
ꢁ
¼ ꢀ52:4 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.30 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 2.52 (dd, J = 6.4, 18.8 Hz, 1H),
2.81 (dd, J = 9.6, 18.4 Hz, 1H), 4.21–4.42 (m, 3H), 7.25–7.31 (m,
4H), 7.38–7.52 (m, 5H); 13C NMR (100 MHz, CHCl3): d 13.8, 21.1,
31.7, 46.9, 55.2, 64.1, 116.1, 126.4, 126.6, 128.3, 129.0, 129.3,
130.4, 140.1, 166.2, 173.1, 174.2; HPLC analysis for major diaste-
reomer (Chiralpak AD-H column, i-propanol/hexane = 70/30, flow
rate = 0.5 mL/min, k = 254 nm): tmajor = 50.0 min, tminor = 36.6 min.
Acknowledgments
We are grateful for the financial support of the National Natural
Science Foundation of China (NSFC 20772113, 51243004) and the
Doctoral Foundation of Henan University of Traditional Chinese
Medicine (No. BSJJ2009-41).
4.3.13. (R)-Methyl 2-cyano-2-((S)-2,5-dioxo-1-phenylpyrrolidin-
References
3-yl)-2-(4-methoxyphenyl)acetate 4n6
a 2D0
ꢁ
¼ ꢀ56:0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
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½
1.30 (t, J = 7.2 Hz, 3H), 2.53 (dd, J = 6.4, 18.4 Hz, 1H), 2.82 (dd,
J = 9.6, 18.4 Hz, 1H), 3.83 (s, 3H), 4.22–4.37 (m, 3H), 6.95–6.98
(m, 2H), 7.25–7.32 (m, 2H), 7.39–7.47 (m, 3H), 7.53–7.57 (m,
2H); 13C NMR (100 MHz, CHCl3): d 13.8, 31.7, 47.0, 54.9, 55.5,
64.1, 114.8, 115.0, 116.1, 123.0, 126.5, 126.6, 127.8, 128.0, 129.1,
129.2, 129.3, 131.3, 160.6, 166.3, 173.0, 174.1; HPLC analysis for
major diastereomer (Chiralpak AD-H column, i-propanol/hex-
ane = 70/30, flow rate = 0.5 mL/min, k = 254 nm): tmajor = 61.4 min,
tminor = 48.0 min.
4.3.14. (R)-Methyl 2-(4-chlorophenyl)-2-cyano-2-((S)-2,5-dioxo-
1-phenylpyrrolidin-3-yl)acetate 4o6
½
a 2D0
ꢁ
¼ ꢀ46:2 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.32 (t, J = 7.2 Hz, 3H), 2.52 (dd, J = 6.4, 18.4 Hz, 1H), 2.82 (dd,
J = 9.2, 18.4 Hz, 1H), 4.24–4.39 (m, 3H), 7.29–7.31 (m, 2H), 7.42–
7.50 (m, 5H), 7.58–7.61 (m, 2H); 13C NMR (100 MHz, CHCl3): d
13.8, 31.6, 47.0, 55.0, 64.4, 115.6, 126.5, 128.0, 129.2, 129.3,
136.4, 165.8, 172.6, 173.8; HPLC analysis for major diastereomer
(Chiralpak AD-H column, i-propanol/hexane = 70/30, flow
rate = 0.5 mL/min, k = 254 nm): tmajor = 51.0 min, tminor = 34.9 min.
4.3.15. (R)-Methyl 2-(4-bromophenyl)-2-cyano-2-((S)-2,5-dioxo-
1-phenylpyrrolidin-3-yl)acetate 4p6
½
a 2D0
ꢁ
¼ ꢀ49:0 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3, TMS): d
1.30 (t, J = 7.2 Hz, 3H), 2.50 (dd, J = 6.4, 18.4 Hz, 1H), 2.80 (dd,
J = 9.2, 18.4 Hz, 1H), 4.22–4.40 (m, 3H), 7.28–7.30 (m, 2H), 7.38–
7.53 (m, 5H), 7.56–7.60 (m, 2H); 13C NMR (100 MHz, CHCl3): d
13.8, 31.6, 46.8, 55.1, 64.4, 115.6, 124.5, 126.5, 128.2, 129.1,
129.3, 130.4, 131.2, 132.9, 165.7, 172.7, 173.9; HPLC analysis for
major diastereomer (Chiralpak AD-H column, i-propanol/hex-
ane = 70/30, flow rate = 0.5 mL/min, k = 254 nm): tmajor = 56.4 min,
tminor = 37.4 min.

Z. Ma et al. / Tetrahedron: Asymmetry 24 (2013) 7–13
13
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