Highly enantioselective Michael additions of α-cyanoacetate with chalcones catalyzed by bifunctional cinchona-derived thiourea organocatalyst

Article abstract of DOI:10.1016/j.tetasy.2007.02.016

The conjugate addition of ethyl α-cyanoacetate with chalcones has been developed. In the presence of cinchona alkaloid-derived thiourea organocatalyst 1i (10 mol %), ethyl α-cyanoacetate could react with various chalcones to afford Michael adducts with hi

Full text of DOI:10.1016/j.tetasy.2007.02.016

Tetrahedron: Asymmetry 18 (2007) 455–463
Highly enantioselective Michael additions of a-cyanoacetate
with chalcones catalyzed by bifunctional cinchona-derived
thiourea organocatalyst
a,b
a,
a,b
a,b
a
a,
*
*
Chun-ling Gu, Li Liu, Yong Sui, Jun-Lin Zhao, Dong Wang and Yong-Jun Chen
a
Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China
b
Graduate School of Chinese Academy of Sciences, Beijing 100049, China
Received 22 December 2006; accepted 16 February 2007
Abstract—The conjugate addition of ethyl a-cyanoacetate with chalcones has been developed. In the presence of cinchona alkaloid-
derived thiourea organocatalyst 1i (10 mol %), ethyl a-cyanoacetate could react with various chalcones to afford Michael adducts with
high yields (80–92%) and enantioselectivities (83–95% ee).
ꢀ
2007 Elsevier Ltd. All rights reserved.
1
. Introduction
highly enantioselective Michael addition of a-cyanoacetate
with a bidentate substrate, a,b-unsaturated imines cata-
lyzed by thiourea-type organocatalyst. Herein, we report
a catalytic and highly enantioselective addition reaction of
a-cyanoacetate with monodentate Michael acceptors, chal-
cone derivatives, in the presence of a bifunctional thiourea
organocatalyst derived from hydroquinine. (Fig. 1).
1
1
The Michael addition of carbon nucleophiles to electron-
deficient alkenes is one of the most powerful tools for
carbon–carbon bond formation. Considerable efforts have
been directed toward the development of catalytic asym-
1
metric versions of this process. 1,3-Dicarbonyl com-
pounds and their equivalents have been widely used as C-
2
nucleophiles in the Michael addition. Among them, a-cya-
noacetates, which contain the two useful functional groups
of nitrile and ester, have received considerable attention.
The enantioselective addition of a-cyanoacetates to enones
could be catalyzed by chiral ligand–metal complexes, such
2
. Results and discussion
Initially, four natural cinchona alkaloids 1a–d were used in
the asymmetric Michael addition of ethyl a-cyanoacetates
with chalcone 3a. As shown in Table 1, for catalysts
1a–c very low yields and ee values were obtained (entries
–3). In the case of quinine 1d, a relatively high enantio-
selectivity (72% ee) was reached, but the yield of 4a was still
low (28%, entry 4). Subsequently, modified cinchona alka-
loids 1e–h based on quinine 1d were used in the reaction of
2 with 3a. When 9-OH was capped by Bn, the catalytic
3
4
5
as Rh, Pd or salen-Al, and applied in the synthesis of b-
2
amino acids, as well as in the further total syntheses of par-
5
b
5a
oxetine and quinine. Recently highly enantioselective
Michael addition of various C-nucleophiles were achieved
1
6
–8
by using organocatalysts.
Suitable organocatalysts
included proline-derived reagents, pyrrolidine-derived
compounds, cinchona alkaloids, thiourea–amine, and
9
cinchona-derived thiourea compounds. Cinchona alka-
ability of the resulting Q-Obn 1f dropped noticeably (entry
). Although 6 -OH quinine alkaloids proved to be efficient
catalysts in the conjugate addition of a-cyanoacetates with
loids demonstrated prominent bifunctional catalytic abili-
ties, most of the time, for both nucleophiles and
electrophiles as hydrogen-bond acceptors and donors,
0
6
1
0
other type of Michael acceptors such as vinyl sulfone or
respectively.
More recently, Takemoto reported the
8
b–e
0
acrylonitrile,
6 -OH catalysts 1e and 1g for the reaction
of 2 with 3a provided low yields and poor ee, or in some
cases did not work at all (entries 5 and 7). Catalyst 1h,
the reduction product of 1d, provided a good yield (78%)
with 72% ee of syn- and anti-4a (entry 8).
*
0
Corresponding authors. Tel.: +86 10 62554614; fax: +86 10 62554449
L.L.); e-mail: lliu@iccas.ac.cn
(
957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.02.016

456
C. Gu et al. / Tetrahedron: Asymmetry 18 (2007) 455–463
H
H
H
yield of 4a (82%) with high enantioselectivity (entry 9).
Although the diastereomeric ratio (syn/anti) of the product
mixture 4a was moderate (61:39), the enantioselectivities of
each diastereomer were the same (87%). Cinchona alka-
loids 1a–i, except for 1b, afforded 4a in the same antipodes.
N
N
N
HO
HO
R O
2
H
H
H
R
R
1
R O
N
N
N
The reaction conditions were optimized under catalysis
with 1i. It was found that toluene was a better solvent than
THF, and that the reaction in CH Cl and CH CN affor-
1
a
C
R=H
1c CD R=H
1e Q-OH
R
1
2
=H, R =H
1
1
f
Q-OBn R =Me, R =Bn
1
b QD R=OMe
1d
Q
R=OMe
1
2
2
2
3
g Q-OH-OBn
R
1
=H, R
2
=Bn
ded low yield and ees (Table 2, entries 1–4). The reaction
temperature has an impact on the reaction speed, but a lim-
ited effect on the enantioselectivity (entries 4–7). Consider-
ing the reaction time and selectivity, toluene as a solvent, at
room temperature, and 10 mol % catalyst loading were
chosen as the general reaction conditions.
H
N
H
CF
3
H
N
N
N
H
HO
H
MeO
S
MeO
CF
3
N
N
1i
DHQ-T
CF
a
1
h DHQ
Table 2. Reaction conditions for the Michael addition of 2 with 3a
3
b
CF3
Entry Solvent Temperature Time Yield (%) ee of syn/
c
d
S
(ꢁC)
(h)
(syn/anti)
anti-4a (%)
S
1
2
3
4
5
6
7
8
9
THF
rt
rt
72
72
72
80 (63/37) 81/82
40 (62/38) 79/80
30 (64/36) 60/60
82 (61/39) 87/87
30 (62/38) 84/85
84 (63/37) 88/89
90 (60/40) 85/84
86 (63/37) 89/89
83 (62/38) 86/86
F
3
C
N
H
N
F
3
C
N
H
N
H
H
N
CH
CH
2
Cl
CN rt
2
OH
3
1
k
Toluene rt
72
1
j
Toluene ꢀ45
144
144
60
144
72
Figure 1. Three types of organocatalysts.
Toluene
0
Toluene 60
Toluene rt
Xylene
e
a
Table 1. Catalytic asymmetric reactions of 2 with 3a
rt
a
b
c
catalyst
1
EtO
2
C
CN
Catalyst: 1i (10 mol %).
O
O
10 mol%
NC
CO
2
Et
+
Isolated yield.
Determined by H NMR.
Ph
Ph
toluene, rt
Ph
Ph
1
2
d
e
3
a
4a
Determined by chiral HPLC analysis.
% Catalyst was used.
5
a
b
Entry
Catalyst
Time
(
Yield (%)
(syn/anti)
ee of syn/
anti-4a (%)
c
d
h)
The addition of ethyl a-cyanoacetate 2 to various chalcones
a–p catalyzed by 1i was proved to be remarkably general
e
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
36
36
36
36
36
36
36
72
72
36
72
<5 (n.d.)
0
3
<10 (65/35)
<5 (61/39)
28 (62/38)
46/46
39/39
72/72
33/33
12/12
—
72/72
87/87
0
(
Scheme 1, Table 3). Although electron-donating or elec-
0
tron-withdrawing substituents at the 4 -position of the
Ar group decrease or promote the reaction rate (entries
1
e
<5 (n.d.)
e
<5 (n.d.)
8, 9 vs 5 and entries 6, 7 vs 5), both had very limited effect
f
0
2
1g
1h
1i
—
on the enantioselectivity. Conversely, 4 -Cl of the Ar
78 (63/37)
82 (61/39)
60 (60/40)
36 (63/37)
group not only increased the activities of chalcones, but
also benefited for the enantioselectivities (entries 1–4 vs
g
1
1
0
1
1j
1k
2
5
–9). When Ar was a heteroaromatic substituent, the reac-
5/5
tion of chalcones 3j–p gave high yields and ees with shorter
a
b
c
d
e
f
Catalyst loading: 10 mol %.
Yield of isolated product.
Determined by H NMR.
Determined by chiral HPLC.
Not determined.
No reaction occurred.
reaction time, probably due to an additional coordination
of 2 -hetero atom of Ar causing 3j–p to be bidentate
substrates.
0
2
1
Ar1
*
O
O
g
With 0.5 equiv Et
3
N.
cat. 1i (10 mol %)
EtO C
2
NC
CO Et
+
Ar1
Ar2
Ar2
2
toluene, rt
*
CN
It was noted that a combination of a thiourea moiety and
tert-amino group could offer an efficient catalytic ability for
the Michael addition. Unfortunately, the use of thiourea
organocatalysts 1j and 1k in the reaction of 2 with 3a only
afforded very poor enantioselectivities of 4a (entries 10 and
2
3a-p
4a-p
Scheme 1.
The absolute configuration of syn-4k was deduced to be
(2S,3S) by X-ray crystallography analysis (Fig. 2). In order
to determine the absolute configuration of the major
isomer of anti-4k, decarboxylation of the mixture of
syn- and anti-4k (1.2:1) proceeded smoothly to provide
1
1). To obtain higher yield and enantioselectivity, further
modification for the cinchona catalyst was performed.
We were pleased to find that a bifunctional thiourea organo-
5
c
1
2
catalyst derived from hydroquinine 1i resulted in a good

C. Gu et al. / Tetrahedron: Asymmetry 18 (2007) 455–463
457
a
Table 3. Asymmetric Michael reactions of 2 with 3a–p
b
c
d
Entry
Chalcone
Time (h)
Product
Yield (%) (syn/anti)
ee of syn/anti (%)
3
a
O
4
a
CN
CN
1
144
84 (63/37)
88/89
EtO C
2
O
O
4
b
3
3
b
O
EtO C
2
2
72
88 (64/36)
88/88
Cl
Cl
CN
4
c
c
O
EtO C
2
O
3
144
82 (60/40)
88/89
H C
3
CH3
4
d
CN
3
d
e
O
EtO C
2
4
5
144
O
82 (59/41)
88 (62/38)
83/83
92/94
MeO
OMe
4
4
e
f
Cl
Cl
CN
3
O
EtO C
72
2
O
O
Cl
CN
3
3
3
f
O
EtO C
2
6
7
24
24
92 (60/40)
89/86
88/88
O N
Cl
2
NO2
4
4
g
h
Cl
Cl
CN
g
h
O
EtO C
2
O
O
89 (63/37)
Cl
Cl
Cl
CN
O
EtO C
2
8
120
93 (60/40)
91/91
H C
3
Cl
CH3
CN
4
i
Cl
3i
O
EtO C
2
9
96
O
84 (59/41)
88/88
MeO
Cl
OMe
(
continued on next page)

458
C. Gu et al. / Tetrahedron: Asymmetry 18 (2007) 455–463
Table 3 (continued)
Entry Chalcone
b
c
d
Time (h)
24
Product
Yield (%) (syn/anti)
ee of syn/anti (%)
3j
O
4j
CN
CN
10
95 (67/33)
93/92
EtO C
O
O
2
O
O
O
4
k
3k
O
EtO C
2
e f
11
36
91 (62/38)
93/93 (>99/— )
O
Cl
Br
Cl
CN
4
4
4
l
3
l
O
O
O
O
EtO C
2
O
O
O
12
13
14
24
48
24
90 (63/37)
89 (60/40)
94 (61/39)
94/93
93/93
O
Br
CN
m
3
m
O
EtO C
2
O
H C
3
CH3
CN
n
3
n
O
EtO C
2
f
93/93 (99/99)
O
MeO
OMe
4
o
p
CN
3
o
p
O
EtO C
S
N
f
2
1
1
5
6
30
20
92 (61/39)
80 (60/40)
87/87 (93/93)
O
O
S
4
CN
3
O
EtO C
2
94/95
N
Cl
Cl
a
b
c
d
e
f
Catalyst: 1i (10 mol %); reaction temperature: room temperature.
Isolated yield.
Determined by H NMR.
1
Determined by chiral HPLC.
Not determined.
After recrystallization.
3
8
-(4-chlorophenyl)-5-(furan-2-yl)-5-oxopentanenitrile 5 in
5% yield with 93% ee (Scheme 2). Similarly starting from
The proposed transition state of the reaction is shown in
Figure 3. The enolization of a-cyanoacetate is catalyzed
by the tertiary amine group in the quinoline moiety of 1i.
As a bifunctional catalyst 1i could also coordinate with
the carbonyl group of chalcones through hydrogen-
bonding interaction of thiourea moiety. The attack of
a-cyanoacetate enolate to the chalcone from the Si face
of the double bond of the chalcone molecule is controlled
syn-4k, product 5 was obtained with the same enantio-
selectivity (93% ee) and configuration. No racemization
was observed during the course of decarboxylation. The
C3 configuration of anti-4k can be deduced as (S) by the
C3 (S)-configuration of syn-4k, while the absolute config-
uration of anti-4k should be assigned as (2R,3S).
1
3

C. Gu et al. / Tetrahedron: Asymmetry 18 (2007) 455–463
459
acid precursors and building blocks in organic synthesis.
Further investigation in improving the diastereoselectivity
and deriving the Michael products into useful compounds
is currently in process.
4. Experimental
4.1. General
IR spectra were recorded on a BrukerTensor 27 infra-red
1
13
spectrometer. H and C NMR spectra were measured
on a Bruker AV-300 spectrometer in CDCl with tetra-
3
methylsilane as an internal standard. Mass spectra were re-
corded on a GCT-MS Micromass spectrometer. Elemental
analyses were performed on a Carlo Flash 1112 Element
Analysis instrument. Melting points were measured by a
Beijing-Tike X-4 apparatus and are uncorrected. Optical
rotations were measured on a Perkin Elmer 3411C instru-
ment (589 nm). The X-ray crystal structures were measured
on Rigaku R-axis RAPID IP. Common reagents and mate-
Figure 2. ORTEP presentation of (2S,3S)-4k.
CN
EtO C
O
NC
O
2
O
O
DMSO/H
2
O=5:1,
o
1
10 C, 24 h
rials were purchased from commercial sources and purified
Cl
Cl
12e
before used. According to the reported procedure,
1i
¼
2
0
25
D
was synthesized, ½aꢁ ¼ ꢀ120:0 (c 0.5, CHCl ) lit. ½aꢁ
4
k,
5, 85%
93% ee
93% ee
D
3
syn
syn
/
/
anti = 1.2:1
anti = 18:1
ꢀ
124:6 (c 0.5, CHCl ).
3
Scheme 2.
4.2. Typical procedure for conjugate addition reaction of
ethyl a-cyanoacetate with chalcones
by multi-point hydrogen-bond interaction, leading to excel-
lent C3-(S)-stereoselectivities. The coordination of a-cya-
noacetate enolate with the basic quinuclidine nitrogen
atom of catalyst 1i could adopt two possible modes I or
II (Fig. 3). The difference between I and II is probably
not large enough to reach high C-2 stereoselectivity, result-
ing in poor diastereoselectivities of the Michael addition
products. However, poorly selective protonation of the
transient enol intermediate after Michael addition may also
lead to low diastereoselectivities. Chelation of the carbonyl
group of the chalcone molecule with the thiourea moiety
provides excellent stereocontrol in the reaction involving
a monodentate carbonyl compound.
To a solution of ethyl a-cyanoacetate 2 (15 lL, 0.15 mmol)
and trans-chalcone 3a (20.8 mg, 0.1 mmol) in toluene
(0.2 mL), catalyst 1i (6 mg, 0.01 mmol) was added at room
temperature. The reaction was monitored by TLC. After 3a
disappeared, the reaction mixture was concentrated in vac-
uum. The residue was purified by flash chromatography on
silica gel (eluent: petroleum ether/ethyl acetate = 6:1) to
1
4
give 4a as a colorless oil (26.7 mg, 82%).
4
.2.1. Ethyl 2-cyano-5-oxo-3,5-diphenylpentanoate 4a.
A
1
colorless oil in 82% yield. H NMR (300 MHz, CDCl ):
3
d = 7.98–7.95 (m, 2H), 7.59–7.55 (m, 1H), 7.50–7.25 (m,
7H), 4.37 (d, J = 5.5 Hz, 1H), 4.22–4.06 (m, 3H), 3.91 (d,
J = 5.1 Hz, 1H), 3.77–3.45 (m, 2H), 1.22, 1.11 (2t,
J = 7.1 Hz, 3H). The ratio of the syn- to anti-isomer
(62:38) was determined by the proton absorptions at 4.37
*
*
*
N
H
*
N
H
S
S
13
*
N
N
and 3.91; C NMR (75 MHz, CDCl ): d = 197.1(196.6) ,
3
O
N
O
Ar
N
H
Ar
N
HN
165.1(164.9), 139.3(138.4), 136.5(136.3), 133.7(133.5),
H RO
O
H
OR
129.0(128.9),
128.8(128.7),
128.2(127.7),
128.1,
1
4
15.7(115.6), 77.1, 63.0(62.7), 44.2(43.3), 41.6(40.6),
0.8(40.1), 13.8. ( The data in parentheses are diastereo-
Si attack
O
Si attack
*
Ar2
Ar1
Ar2
Ar1
meric peak.) IR (film): m = 2250, 1743, 1685, 1596, 1580,
ꢀ
1
1496, 1449, 1252, 1210 cm . Ees were determined by
I
II
HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
70:30, flow rate = 0.3 mL/min, 5 ꢁC): for anti-isomer:
Figure 3.
t
= 39.9 min and t
= 45.7 min, 87% ee; for syn-iso-
major
minor
3. Conclusions
mer: tminor = 36.8 min and tmajor = 63.4 min, 87% ee.
In the presence of a cinchona-derived bifunctional thiourea
catalyst, the Michael addition of a-cyanoacetates to chal-
cones had been developed. The reaction proceeds in high
enantioselectivity (83–95% ee) and good to excellent yields
4.2.2. Ethyl 3-(4-chlorophenyl)-2-cyano-5-oxo-5-phenylpent-
anoate 4b. A colorless oil in 88% yield was obtained by
flash chromatography on silica gel (elution gradient: ethyl
1
acetate/petroleum ether = 1:10–1:8). H NMR (300 MHz,
(
80–95%). The Michael adducts provide versatile b-amino
CDCl ): d = 7.97–7.94 (m, 2H), 7.60–7.57 (m, 1H), 7.50–
3

460
C. Gu et al. / Tetrahedron: Asymmetry 18 (2007) 455–463
7
4
2
.46 (m, 2H), 7.38–7.26 (m, 4H), 4.32 (d, J = 5.4 Hz, 1H),
.22–4.08 (m, 3H), 3.88 (d, J = 5.2 Hz, 1H), 3.72–3.46 (m,
H), 1.22, 1.15 (2t, J = 7.1 Hz, 3H). The ratio of the syn- to
CDCl ): d = 7.92–7.87 (m, 2H), 7.45–7.26 (m, 7H), 4.33
(d, J = 5.6 Hz, 1H), 4.21–4.04 (m, 3H), 3.90 (d,
3
J = 5.1 Hz, 1H), 3.72–3.46 (m, 2H), 1.22, 1.10 (2t,
J = 7.1 Hz, 3H). The ratio of the syn- to anti-isomer
(62:38) was determined by the proton absorptions at
anti-isomer (64:36) was determined by the proton absorp-
tions at d = 4.32 and 3.88. C NMR (75 MHz, CDCl3):
d = 196.8(196.3), 164.9(164.7), 137.7(136.9), 136.3(136.1),
1
1
1
1
HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH = 70:30,
flow rate = 0.3 mL/min, 5 ꢁC): for syn-isomer: t
4
1
3
1
3
d = 4.33 and 3.90.
d = 195.9(195.4), 165.1(164.9), 140.2(140.0), 139.1(138.2),
134.7(134.6), 129.5, 129.1(129.0), 129.0(128.9),
C
NMR (75 MHz, CDCl3):
34.2, 133.9(133.6), 129.5, 129.2, 129.0, 128.8, 128.8,
28.0, 115.4, 63.1(62.8), 43.9(43.2), 41.5(40.2), 40.4(39.5),
3.9; IR (film): m = 2250, 1743, 1685, 1597, 1580, 1494,
128.3(128.2), 128.0(127.6), 115.7(115.6), 77.1, 63.0(62.7),
44.1(43.2), 41.6(40.6), 40.79(40.1), 13.8. IR (film):
m = 2250, 1743, 1685, 1590, 1571, 1496, 1455, 1252,
ꢀ
1
448, 1254, 1211, 1015 cm . Ees were determined by
ꢀ1
=
1209 cm . Ees were determined by HPLC (Daicel Chir-
alpak AS-H, hexane/i-PrOH = 70:30, flow rate = 0.4 mL/
min, 5 ꢁC): for syn-isomer: tminor = 37.0 min and
minor
3.0 min and t
= 65.6 min, 88% ee; for anti-isomer:
major
tminor = 40.4 min and tmajor = 73.6 min, 88% ee.
tmajor = 58.9 min, 92% ee; for anti-isomer: t
and tmajor = 46.1 min, 94% ee.
= 39.9 min
minor
4
4
.2.3. Ethyl 2-cyano-5-oxo-5-phenyl-3-p-tolylpentanoate
c. A colorless oil in 82% yield was obtained by flash
chromatography on silica gel (elution gradient: ethyl ace-
tate/petroleum ether = 1:10–1:8). H NMR (300 MHz,
1
4.2.6. Ethyl 5-(4-chlorophenyl)-2-cyano-3-(4-nitrophenyl)-5-
oxo-pentanoate 4f. A colorless oil in 92% yield was
CDCl ): d = 7.98–7.93 (m, 2H), 7.59–7.56 (m, 1H), 7.50–
3
obtained by flash chromatography on silica gel (elution
7
(
.45 (m, 2H), 7.31–7.24 (m, 2H), 7.16–7.13 (m, 2H), 4.33
d, J = 5.5 Hz, 1H), 4.19–4.08 (m, 3H), 3.89 (d,
J = 5.1 Hz, 1H), 3.70–3.42 (m, 2H), 2.31 (s, 3H), 1.23,
.14 (2t, J = 7.1 Hz, 3H). The ratio of the syn- to anti-
isomer (60:40) was determined by the proton absorptions
1
gradient: ethyl acetate/petroleum ether = 1:10–1:8).
H
NMR (300 MHz, CDCl ): d = 8.23–8.19 (m, 2H), 7.92–
3
7
(
.86 (m, 2H), 7.64–7.56 (m, 2H), 7.8–7.44 (m, 2H), 4.36
d, J = 5.4 Hz, 1H), 4.32–4.10 (m, 3H), 3.94 (d, J =
5.2 Hz, 1H), 3.74–3.51 (m, 2H), 1.25, 1.17 (2t, J = 7.1 Hz,
H). The ratio of the syn- to anti-isomer (60:40) was deter-
1
1
3
at d = 4.33 and 3.89.
C NMR (75 MHz, CDCl3):
3
d = 197.2(196.7), 165.2(165.0), 138.0(137.8), 136.5(136.3),
13
mined by the proton absorptions at d = 4.36 and 3.94.
C
1
1
4
1
35.3, 133.7(133.5), 129.6, 129.5, 128.8, 128.7, 128.0,
27.9, 127.5, 115.7, 77.1, 62.9(62.6), 44.3(43.4), 41.7(40.4),
0.5(39.8), 21.1, 13.8. IR (film): m = 2249, 1743, 1684,
NMR (75 MHz, CDCl ): d = 195.0(194.7), 164.5(164.3),
3
1
47.7(147.6), 146.4(145.5), 140.6(140.5), 134.2(134.2),
129.5, 129.3(129.3), 129.2(128.9), 124.2(124.0), 115.1,
7.1, 63.5(63.2), 43.3(42.7), 41.2(40.2), 40.2(39.6), 13.9.
ꢀ
1
597, 1580, 1515, 1448, 1252, 1209 cm . Ees were deter-
7
mined by HPLC (Daicel Chiralpak AD-H, hexane/
IR (film): m = 2250, 1743, 1686, 1590, 1571, 1522, 1490,
i-PrOH = 70:30, flow rate = 0.3 mL/min, 5 ꢁC): syn-isomer:
ꢀ1
1
348, 1251, 1211 cm . HRMS (FAB) m/z calcd for
t
= 43.0 min and t
= 55.7 min, 88% ee; for anti-
minor
major
C H ClN O (M+H): 401.0904, found 401.0895. Ees
2
0
17
2
5
isomer: tminor = 38.9 min and tmajor = 66.9 min, 89% ee.
were determined by HPLC (Daicel Chiralpak AD-H,
hexane/i-PrOH = 70:30, flow rate = 0.3 mL/min, 5 ꢁC):
4
.2.4. Ethyl 2-cyano-3-(4-methoxyphenyl)-5-oxo-5-phenyl-
for syn-isomer: t
= 134.1 min and t
= 205.8 min,
major
minor
pentanoate 4d. A yellowish oil in 82% yield was obtained
by flash chromatography on silica gel (elution gradient:
ethyl acetate/petroleum ether = 1:10–1:8).
89% ee; for anti-isomer: tminor = 128.9 min and
1
tmajor = 243.2 min, 86% ee.
H
NMR
(
300 MHz, CDCl ): d = 7.98–7.95 (m, 2H), 7.59–7.55 (m,
3
1
2
H), 7.50–7.45 (m, 2H), 7.35–7.26 (m, 2H), 6.88–6.85 (m,
H), 4.31 (d, J = 5.4 Hz, 1H), 4.19–4.09 (m, 3H), 3.88 (d,
4.2.7. Ethyl 3,5-bis(4-chlorophenyl)-2-cyano-5-oxo-pentan-
oate 4g. A colorless oil in 89% yield was obtained by flash
chromatography on silica gel (elution gradient: ethyl ace-
J = 5.2 Hz, 1H), 3.78 (s, 3H), 3.730–3.45 (m, 2H), 1.21,
.14 (2t, J = 7.1 Hz, 3H). The ratio of the syn- to anti-iso-
mer (59:41) was determined by the proton absorptions at
1
1
tate/petroleum ether = 1:8–1:6). H NMR (300 MHz,
CDCl ): d = 7.93–7.88 (m, 2H), 7.49–7.44 (m, 2H), 7.40–
3
1
3
d = 4.31 and 3.88.
d = 197.2(196.7), 165.2(165.0), 159.4(159.3), 133.7(133.4),
C
NMR (75 MHz, CDCl3):
7.33 (m, 4H), 4.32 (d, J = 5.5 Hz, 1H), 4.25–4.10 (m,
3H), 3.89 (d, J = 5.2 Hz, 1H), 3.70–3.45 (m, 2H), 1.25,
1.17 (2t, J = 7.1 Hz, 3H). The ratio of the syn- to anti-iso-
mer (63:37) was determined by the proton absorptions at
1
1
4
1
30.4, 129.2, 128.8, 128.7, 128.0, 115.8(115.7),
14.3(114.2), 62.9(62.6), 55.2, 44.3(43.6), 41.8(40.2),
0.7(39.4), 13.9. IR (film): m = 2250, 1742, 1684, 1596,
581, 1515, 1448, 1252, 1210 cm . Ees were determined
HPLC (Daicel Chiralpak AD-H, hexane/
i-PrOH = 70:30, flow rate = 0.3 mL/min, 5 ꢁC): for syn-iso-
mer: t = 38.6 min and t = 65.1 min, 83% ee; for
1
3
d = 4.32 and 3.89.
C
NMR (75 MHz, CDCl3):
ꢀ1
d = 195.5(195.1), 164.8(164.6), 140.4, 137.6(136.7), 134.6/
134.5, 134.3(134.1), 129.4, 129.2, 129.2, 129.1, 129.1,
115.3, 63.1(62.8), 43.8(43.0), 41.5(40.1), 40.5(39.4), 13.8.
IR (film): m = 2250, 1742, 1685, 1590, 1572, 1492, 1445,
by
minor
major
ꢀ1
anti-isomer: tminor = 35.7 min and tmajor = 82.1 min, 83%
1251, 1209, 1092, 828 cm . HRMS (FAB): m/z calcd for
ee.
C H Cl NO (M+H): 390.0664, found 390.0659. Ees
2
0
18
2
3
were determined by HPLC (Daicel Chiralpak AD-H, hex-
4
.2.5. Ethyl 5-(4-chlorophenyl)-2-cyano-5-oxo-3-phenylpent-
ane/i-PrOH = 70:30, flow rate = 0.3 mL/min, 5 ꢁC): for
anoate 4e. A colorless oil in 88% yield was obtained by
syn-isomer: t
= 52.5 min and t
= 77.8 min, 88%
major
minor
flash chromatography on silica gel (elution gradient: ethyl
acetate/petroleum ether = 1:10–1:8). H NMR (300 MHz,
ee; for anti-isomer: tminor = 56.7 min, tmajor = 115.4 min,
88% ee.
1

C. Gu et al. / Tetrahedron: Asymmetry 18 (2007) 455–463
461
4
.2.8. Ethyl 5-(4-chlorophenyl)-2-cyano-5-oxo-3-p-tolylpent-
312.1233. Ees were determined by HPLC (Daicel Chir-
anoate 4h. A colorless oil in 93% yield was obtained by
alpak AD-H, hexane/i-PrOH = 70:30, flow rate =
flash chromatography on silica gel (elution gradient: ethyl
acetate/petroleum ether = 1:8–1:6). H NMR (300 MHz,
0.3 mL/min, 5 ꢁC): for syn-isomer: t
= 39.2 min and
minor
1
t
= 47.9 min, 93% ee; for anti-isomer: t
= 35.9 min
major
minor
CDCl ): d = 7.91–7.86 (m, 2H), 7.45–7.41 (m, 2H), 7.29–
and tmajor = 58.6 min, 92% ee.
3
7
1
3
.22 (m, 2H), 7.15–7.12 (m, 2H), 4.30 (d, J = 5.9 Hz,
H), 4.20–4.06 (m, 3H), 3.88 (d, J = 5.2 Hz, 1H), 3.69–
.44 (m, 2H), 2.31 (s, 3H), 1.13, 1.05 (2t, J = 7.1 Hz, 3H).
4.2.11. Ethyl 3-(4-chlorophenyl)-2-cyano-5-(furan-2-yl)-5-
oxo-pentanoate 4k. A white solid in 91% yield was obt-
ained by flash chromatography on silica gel (elution gradi-
The ratio of the syn- to anti-isomer (62:38) was determined
1
3
1
by the proton absorptions at d = 4.30 and 3.88. C NMR
75 MHz, CDCl3): d = 196.0(195.5), 165.1(165.0),
40.2(139.9), 138.0(137.8), 136.1(135.2), 134.8(134.7),
29.7, 129.5, 129.5, 129.1(129.0), 127.9(127.5),
ent: ethyl acetate/petroleum ether = 1:6–1:4). H NMR
(
(300 MHz, CDCl ): d = 7.51–7.48 (m, 1H), 7.27–7.13 (m,
3
1
1
1
4
1
5H), 6.46–6.44 (m, 1H), 4.15 (d, J = 5.5 Hz, 1H), 4.12–
3.97 (m, 3H), 3.78 (d, J = 5.5 Hz, 1H), 3.45–3.28 (m,
2H), 1.12, 1.05 (2t, J = 7.1 Hz, 3H). The ratio of the syn-
to anti-isomer (67:33) was determined by the proton
15.7(115.6), 77.1, 63.0(62.6), 44.2(43.4), 41.7/40.6,
0.4(39.8), 21.0, 13.8. IR (film): m = 2250, 1743, 1686,
590, 1572, 1489, 1446, 1252, 1207, 818 cm . HRMS
ꢀ
1
13
absorptions at d = 4.15 and 3.78. C NMR (75 MHz,
(
FAB): m/z calcd for C H ClNO (M+H): 370.1210,
CDCl3): d = 185.6(185.3), 164.7(164.6), 152.2(152.2),
147.0(146.7), 137.7(136.5), 134.2(134.0), 129.5(129.2),
129.1(129.0), 117.9(117.6), 115.6(115.5), 112.6(112.5),
63.1(62.8), 43.8(43.2), 41.2(40.2), 40.0(39.3), 13.8. IR (film):
2
1
21
3
found 370.1207. Ees were determined by HPLC (Daicel
Chiralpak AD-H, hexane/i-PrOH = 70:30, flow rate =
0
t
.3 mL/min, 5 ꢁC): for syn-isomer: t
= 54.5 min and
= 68.4 min, 91% ee; for anti-isomer: tminor = 48.3 min
minor
ꢀ1
m = 2252, 1743, 1673, 1569, 1493, 1468, 1255, 1015 cm
HRMS (FAB): m/z calcd for C H ClNO (M+H):
.
major
and tmajor = 100.0 min, 91% ee.
18
17
4
3
46.0846, found 346.0843. Ees were determined by HPLC
(Daicel Chiralpak AS-H, hexane/i-PrOH = 70:30, flow
rate = 0.5 mL/min, 10 ꢁC): for syn-isomer: t = 39.6
4
.2.9. Ethyl 5-(4-chlorophenyl)-2-cyano-3-(4-methoxyphen-
yl)-5-oxo-pentanoate 4i. A colorless oil in 84% yield
was obtained by flash chromatography on silica gel (elution
gradient: ethyl acetate/petroleum ether = 1:8–1:6).
minor
min and t
= 58.7 min, 93% ee; for anti-isomer:
major
1
H
tminor = 45.9 min and tmajor = 50.5 min, 93% ee. The crystal
NMR (300 MHz, CDCl ): d = 7.92–7.86 (m, 2H), 7.46–
(syn-4k, mp: 94–96 ꢁC) used for the X-ray study had the
3
3
7
.42 (m, 2H), 7.34–7.26 (m, 2H), 6.89–6.84 (m, 2H), 4.29
d, J = 5.2 Hz, 1H), 4.22–4.06 (m, 3H), 3.87 (d,
J = 5.2 Hz, 1H), 3.78 (s, 3H), 3.68–3.44 (m, 2H), 1.22,
.14 (2t, J = 7.1 Hz, 3H). The ratio of syn- to anti-isomer
59:41) was determined by the proton absorptions at
dimensions
0.75 · 0.26 · 0.15 mm .
Crystal
data:
(
C H ClNO , Mr = 345.77; monoclinic; space group,
18 16 4
˚
˚
˚
P2(1), a = 7.0340(14) A, b = 10.199(2) A, c = 11.881(2) A,
3
3
˚
1
V = 850.2(3) A , Z = 2, D
= 1.351 g/cm , F0 = 3449,
calcd
˚
(
k = 0.71073 A. Final R indices [I > 2r(I)] R = 0.0489,
1
1
3
d = 4.29 and 3.87.
C
NMR (75 MHz, CDCl3):
wR = 0.1222, absolute structure parameter 0.06(9).
2
d = 196.0(195.5), 165.1(164.9), 159.5(159.3), 140.2(140.0),
CCDC No. 638112.
1
1
4
1
34.6, 131.0(130.1), 129.5, 129.1(129.1), 129.0(128.7),
15.6, 114.4(114.2), 63.0(62.7), 44.2(43.5), 41.8(40.7),
0.2(39.4), 13.8. IR (film): m = 2250, 1742, 1685, 1590,
4.2.12. Ethyl 3-(4-bromophenyl)-2-cyano-5-(furan-2-yl)-5-
oxo-pentanoate 4l. A white solid in 90% yield was obt-
ained by flash chromatography on silica gel (elution gradi-
ꢀ
1
572, 1492, 1445, 1251, 1209, 829 cm . HRMS (FAB):
1
m/z calcd for C H ClNO (M+H): 386.1159, found
ent: ethyl acetate/petroleum ether = 1:6–1:4). H NMR
2
1
21
4
3
86.1152. Ees were determined by HPLC (Daicel
(300 MHz, CDCl ): d = 7.60–7.58 (m, 1H), 7.42–7.47 (m,
3
Chiralpak AD-H, hexane/i-PrOH = 70:30, flow rate =
2H), 7.30–7.19 (m, 3H), 6.56–6.52 (m, 1H), 4.26 (d,
J = 5.5 Hz, 1H), 4.19–4.07 (m, 3H), 3.89 (d, J = 5.5 Hz,
1H), 3.53–3.42 (m, 2H), 1.22, 1.14 (2t, J = 7.1 Hz, 3H).
The ratio of syn- to anti-isomer (67:33) was determined
0
.3 mL/min, 5 ꢁC): for syn-isomer: t
= 74.0 min and
minor
t
= 100.0 min, 88% ee; for anti-isomer: t
= 68.5
major
minor
min and tmajor = 176.1 min, 88% ee.
1
3
by the proton absorptions at d = 4.15 and 3.78.
C
4
.2.10. Ethyl 2-cyano-5-(furan-2-yl)-5-oxo-3-phenylpentan-
NMR (75 MHz, CDCl ): d = 185.6(185.2), 164.7(164.6),
3
oate 4j. A white solid in 95% yield was obtained by flash
152.2(152.1), 147.0(146.8), 137.9(137.1), 132(131.9),
129.8(129.5), 122.3(122.1), 117.9(117.9), 115.4(115.3),
112.6(112.6), 63.1(62.9), 43.8(43.2), 41.2(40.1), 40.0(39.3),
chromatography on silica gel (elution gradient: ethyl ace-
1
tate/petroleum ether = 1:6–1:4). H NMR (300 MHz,
ꢀ
1
CDCl ): d = 7.60–7.59 (m, 1H), 7.41–7.23 (m, 6H), 6.56–
13.8. IR (KBr): m = 2907, 2252, 1738, 1760 cm . HRMS
(EI): m/z calcd for C H BrNO : 389.0263, found
3
6.54 (m, 1H), 4.28 (d, J = 5.6 Hz, 1H), 4.21–4.02 (m,
3H), 3.88 (d, J = 5.4 Hz, 1H), 3.60–3.38 (m, 2H), 1.12,
1.02 (2t, J = 7.1 Hz, 3H). The ratio of the syn- to anti-iso-
1
8
17
4
389.0267. Ees were determined by HPLC (Daicel Chir-
alpak OD-H, hexane/i-PrOH = 70:30, flow rate =
mer (67:33) was determined by the proton absorptions at
0.5 mL/min, 7 ꢁC): for syn-isomer: t
major
= 30.0 min and
minor
1
3
d = 4.28 and 3.88.
d = 186.0(185.6), 165.0(164.8), 152.3, 146.9(146.6),
C
NMR (75 MHz, CDCl3):
t
= 31.3 min, 94% ee; for anti-isomer: t
= 36.0 min
minor
and tmajor = 39.8 min, 93% ee.
1
1
4
38.9(138.1), 128.9(128.8), 128.2(128.1), 128.0(127.7),
17.8(117.4), 115.6(115.5), 112.5(112.4), 63.0(62.6),
4.1(43.4), 41.3(40.6), 40.4(40.0), 13.8. IR (film):
4.2.13. Ethyl 2-cyano-5-(furan-2-yl)-5-oxo-3-p-tolylpentan-
oate 4m. A white solid in 89% yield was obtained by flash
chromatography on silica gel (elution gradient: ethyl ace-
ꢀ
1
m = 2248, 1741, 1664, 1276, 1037 cm . HRMS (FAB):
m/z calcd for C H NO (M+H): 312.1236, found
1
tate/petroleum ether = 1:6–1:4). H NMR (300 MHz,
1
8
18
4

462
C. Gu et al. / Tetrahedron: Asymmetry 18 (2007) 455–463
CDCl ): d = 7.51–7.48 (m, 1H), 7.20–7.03 (m, 5H), 6.47–
4.2.16. Ethyl 3-(4-chlorophenyl)-2-cyano-5-oxo-5-(pyridin-2-
yl)pentanoate 4p. A white solid in 80% yield was obtained
3
6.45 (m, 1H), 4.17 (d, J = 5.6 Hz, 1H), 4.13–3.95 (m,
3H), 3.78 (d, J = 5.4 Hz, 1H), 3.48–3.27 (m, 2H), 2.22 (s,
3H), 1.13, 1.05 (2t, J = 7.1 Hz, 3H). The ratio of the syn-
by flash chromatography on silica gel (elution gradient:
1
ethyl acetate/petroleum ether = 1:6–1:4).
H
NMR
to anti-isomer (60:40) was determined by the proton
absorptions at d = 4.17 and 3.78. C NMR (75 MHz,
CDCl3): d = 186.1(185.6), 165.0(164.9), 152.4(152.3),
(300 MHz, CDCl ): d = 8.71–8.69 (m, 1H), 8.03–7.95 (m,
3
1
3
1H), 7.88–7.79 (m, 1H), 7.54–7.48 (m, 1H), 7.41–7.28 (m,
4H), 4.28 (d, J = 5.5 Hz, 1H), 4.23–4.08 (m, 3H), 4.00–
3.75 (m, 2H), 1.25, 1.18 (2t, J = 7.1 Hz, 3H). The ratio of
the syn- to anti-isomer (60:40) was determined by the pro-
1
1
6
46.8(146.6), 138.0(137.8), 135.9(135.0), 129.6(129.5),
27.9(127.5), 117.7(117.4), 115.6(115.5), 112.5(112.4),
2.9(62.6), 44.3(43.5), 41.4(40.4), 40.3(39.6), 21.0, 13.8.
1
3
ton absorptions at d = 4.28 and 3.87. C NMR (75 MHz,
IR (film): m = 2250, 1739, 1669, 1564, 1415, 1467, 1249,
CDCl ): d = 198.7/198.2, 164.9, 152.6(152.5), 149.1(149.1),
3
ꢀ
1
1
037 cm . HRMS (FAB): m/z calcd for C H NO
137.7,
137.0(136.9),
134.0(133.8),
129.6(129.3),
1
9
20
4
(
M+H): 326.1392, found 326.1386. Ees were determined
129.0(128.9), 127.7(127.6), 121.8, 115.6, 63.0(62.8),
by HPLC (Daicel Chiralpak OD-H, hexane/i-PrOH =
44.1(43.4), 40.8(39.8), 40.4(39.7), 13.9. IR (film): m =
ꢀ1
7
0:30, flow rate = 0.5 mL/min, 5 ꢁC): for syn-isomer:
= 36.3 min and t = 48.3 min, 93% ee; for anti-
2250, 1744, 1700, 1584, 1493, 1464, 1266, 1093, 739 cm
.
t
HRMS (FAB) m/z calcd for C H ClN O (M+H):
minor
major
19 18
2
3
isomer: tminor = 39.2 min and tmajor = 44.4 min, 93% ee.
357.1006, found 357.1000. Ees were determined by HPLC
Daicel Chiralpak AS-H, hexane/i-PrOH = 70:30, flow
(
4
.2.14. Ethyl 2-cyano-5-(furan-2-yl)-3-(4-methoxyphenyl)-5-
rate = 0.3 mL/min, 10 ꢁC): for syn-isomer: tminor =
33.8 min and tmajor = 42.3 min, 94% ee; for anti-isomer:
tminor = 45.8 min and tmajor = 55.4 min, 95% ee.
oxo-pentanoate 4n. A white solid in 94% yield was obt-
ained by flash chromatography on silica gel (elution gradi-
ent: ethyl acetate/petroleum ether = 1:6–1:4). H NMR
1
(
300 MHz, CDCl ): d = 7.50–7.47(m, 1H), 7.23–7.13 (m,
4.3. (S)-3-(4-Chlorophenyl)-5-(furan-2-yl)-5-oxopentane-
nitrile 5
3
3
H), 6.78–6.73 (m, 3H) 6.46–6.44 (m, 1H), 4.13 (d,
J = 5.4 Hz, 1H), 4.09–3.95 (m, 3H), 3.77 (d, J = 5.4 Hz,
H), 3.43–3.19 (m, 2H), 1.12, 1.05 (2t, J = 7.1 Hz, 3H).
The ratio of the syn- to anti-isomer (61:39) was determined
1
A mixture of syn- and anti-4k (34.5 mg, 0.1 mol) was dis-
solved in dimethylsulfoxide/water (5:1, 2 mL), followed
by stirring at 110 ꢁC for 24 h. After cooling to room tem-
perature, 20% aqueous lithium bromide solution (5 mL)
was added, and the reaction mixture was extracted with
dichloromethane (5 · 10 mL). The combined organic ex-
tracts were washed twice with 20% lithium bromide solu-
tion (2 · 10 mL), dried over sodium sulfate, and
concentrated. The residue was purified by flash chromato-
graphy on silica gel (eluent: ethyl acetate/petroleum
ether = 1:4–1:3), yielding a viscous colorless oil 5 (23 mg,
1
3
by the proton absorptions at d = 4.17 and 3.78. C NMR
75 MHz, CDCl3): d = 186.1(185.7), 165.0(164.9),
59.4.4(159.3), 152.4(152.3), 146.9(146.6), 130.8(130.0),
29.2(128.8), 117.8(117.5), 115.6, 114.3(114.2),
(
1
1
1
2
1
2.5(112.4), 62.9(62.6), 44.3(43.5), 41.4(40.4), 40.3(39.6),
1.0, 13.8. IR (film): m = 2250, 1742, 1673, 1612, 1569,
ꢀ1
514, 1467, 1254, 1031 cm . Elemental Anal. Calcd for
C H NO : C, 60.60; H, 5.65; N, 4.11. Found: C, 60.49;
H, 5.64; N, 4.14. Ees were determined by HPLC (Daicel
Chiralpak AS-H, hexane/i-PrOH = 70:30, flow rate =
0
1
9
19
5
2
0
1
85% yield with 93% ee). ½aꢁ ¼ þ28:0 (c 0.85, CHCl ). H
D
3
.5 mL/min, 25 ꢁC): for syn-isomer: tminor = 40.1 min and
NMR (300 MHz, CDCl ): d = 7.59 (d, J = 1.0 Hz, 1H),
3
t
= 53.8 min, 93% ee; for anti-isomer: t = 44.2 min
8.34–7.21 (m, 5H), 6.56, 6.54 (dd, J = 1.7, 3.6 Hz, 1H),
major
minor
and tmajor = 112.4 min, 93% ee.
3.76–3.67 (m, 1H), 3.41–3.26 (m, 2H), 2.79–2.73 (m, 2H).
1
3
C NMR (75 MHz, CDCl ): d = 186.0, 152.3, 146.8,
3
4
.2.15. Ethyl 2-cyano-5-oxo-3-phenyl-5-(thiophen-2-yl)pent-
139.3, 133.6, 129.2, 128.6, 117.8, 117.7, 42.3, 36.1, 24.3.
ꢀ1
anoate 4o. A white solid in 92% yield was obtained by
flash chromatography on silica gel (elution gradient: ethyl
acetate/petroleum ether = 1:6–1:4). H NMR (300 MHz,
IR (film): m = 2247, 1673 cm . HRMS (EI): m/z calcd
for C H ClNO : 273.0557, found 273.0559. Ee was deter-
1
5
12
2
1
mined by HPLC analysis (Daicel chiralcel AD-H, hexane/
i-propanol = 70:30, 0.6 mL/min, 25 ꢁC): t = 12.0 min
CDCl ): d = 7.79–7.77 (m, 1H), 7.69–7.67 (m, 1H), 7.40–
3
minor
7.26 (m, 5H), 7.15–7.14 (m, 1H), 4.32 (d, J = 5.5 Hz,
1H), 4.21–4.03 (m, 3H), 3.90 (d, J = 5.2 Hz, 1H), 3.69–
3.42 (m, 2H), 1.20, 1.08 (2t, J = 7.1 Hz, 3H). The ratio of
and t
= 17.1 min.
major
Acknowledgment
the syn- to anti-isomer (61:39) was determined by the pro-
ton absorptions at d = 4.32 and 3.90. C NMR (75 MHz,
CDCl3): d = 189.9(189.3), 165.0(164.8), 143.6(143.4),
1
3
We thank the National Natural Science Foundation of
China and the Chinese Academy of Sciences for financial
support.
1
1
4
39.0(138.1), 134.5(134.2), 132.5(132.3), 129.0(128.9),
28.3, 128.2(128.1), 128.0(127.7), 115.6(115.5), 63.0(62.7),
4.0(43.3), 42.2(41.0), 41.2(40.3), 13.8. IR (film):
m = 2251, 1744, 1661, 1519, 1496, 1455, 1416, 1256, 1214,
ꢀ
1
References
1
027 cm . HRMS (FAB): m/z calcd for C H NO S
18 18 3
(
M+H): 328.1007, found 328.1004. Ees were determined
1
. For reviews, see: (a) Tomioka, K.; Nagaoka, Y.; Yamaguchi,
M. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol.
3, Chapters 31.1 and 31.2; (b) Krause, N.; Hoffmann-R o¨ der,
A. Synthesis 2001, 171–196; (c) Sibi, M. P.; Manyem, S.
by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =
7
t
0:30, flow rate = 0.3 mL/min, 5 ꢁC): for syn-isomer:
= 43.0 min and t = 52.4 min, 87% ee; for anti-
minor
major
isomer: tminor = 38.6 min and tmajor = 58.0 min, 87% ee.

C. Gu et al. / Tetrahedron: Asymmetry 18 (2007) 455–463
463
Tetrahedron 2000, 56, 8033–8061; (d) Christoffers, J.; Baro, A.
Angew. Chem., Int. Ed. 2003, 42, 1688–1690.
8. For selected examples, cyanoacetates: (a) Wu, F.; Hong, R.;
Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int. Ed. 2006, 45,
4301–4305; (b) Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.;
Wu, Y.; Ding, L.-S.; Chen, Y.-C. Org. Biomol. Chem. 2006, 4,
2097–2099; (c) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem.
Soc. 2006, 128, 3928–3930; (d) Li, H.; Song, J.; Liu, X.; Deng,
L. J. Am. Chem. Soc. 2005, 127, 8948–8949; (e) Wang, B.-M.;
Wu, F.-H.; Wang, Y.; Liu, X.-F.; Deng, L. J. Am. Chem. Soc.
2007, 129, 768–769.
2
. (a) Perlmutter, P. Conjugate Addition Reaction in Organic
Synthesis; Pergamon: Oxford, 1992; (b) Ballini, R.; Bosica, G.;
Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105, 933.
. (a) Motoyama, Y.; Koga, Y.; Kobayashi, K.; Aoki, K.;
Nishiyama, H. Chem. Eur. J. 2002, 8, 2968–2975; (b) Inagaki,
K.; Nozaki, K.; Takaya, M. Synlett 1997, 119–120; (c)
Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron 1994,
3
5
0, 4439–4454; (d) Sawamura, M.; Hamashima, H.; Ito, Y.
9. Reviews: (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed.
2004, 43, 5138–5175; (b) Taylor, M. S.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2006, 45, 1520–1543; (c) Special issue
on organocatalysis: Houk, K. N., List, B., Eds.; Acc. Chem.
Res. 2004, 37, 487–631.
10. Tian, S.-K.; Chen, Y.; Hang, J.; Tang, L.; McDaid, P.; Deng,
L. Acc. Chem. Res. 2004, 37, 621–631.
11. Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2006, 128, 9413–9419.
12. For Michael addition: (a) Vakulya, B.; Varga, S.; Csampai,
A.; Soos, T. Org. Lett. 2005, 7, 1967–1969; (b) Wang, J.; Li,
H.; Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am.
Chem. Soc. 2006, 128, 12652–12653; (c) Tillman, A. L.; Ye, J.;
Dixon, D. J. Chem. Commun. 2006, 1191–1193; (d) Ye, J.;
Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481–4483;
(e) McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed.
2005, 44, 6367–6370; (f) Li, B.-J.; Jiang, L.; Liu, M.; Chen,
Y.-C.; Ding, L. S.; Wu, Y. Synlett 2005, 603–606; For
Mannich reaction: (g) Song, J.; Wang, Y.; Deng, L. J. Am.
Chem. Soc. 2006, 128, 6048–6049; (h) Marcelli, T.; van der
Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem., Int. Ed. 2006, 45, 929–931; (i) Bernardi, L.; Fini, F.;
Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron 2006, 62,
375–380; For Friedel–Craft reaction: (j) Yang, Y.-Q.; Song,
J.; Hong, R.; Li, H.-M.; Deng, L. J. Am. Chem. Soc. 2006,
128, 8156–8157.
J. Am. Chem. Soc. 1992, 114, 8295–8296.
4
5
. Takenaka, K.; Uozumi, Y. Org. Lett. 2004, 6, 1833–1835.
. (a) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 706–707; (b) Taylor, M. S.; Jacobsen,
E. N. J. Am. Chem. Soc. 2003, 125, 11204–11205; (c) Taylor,
M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N.
J. Am. Chem. Soc. 2005, 127, 1313–1317.
6
. For selected examples, 1,3-diketones: (a) Wang, J.; Li, H.;
Duan, W.-H.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4713–
4
716; Malonate esters: (b) Okino, T.; Hoashi, Y.; Takemoto,
Y. J. Am. Chem. Soc. 2003, 125, 12672–12673; (c) Brandau,
S.; Landa, A.; Franzen, J.; Marigo, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 4305–4309; (d) Okino, T.;
Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119–125; (e) Li, H.; Wang, Y.; Tang,
L.; Deng, L. J. Am. Chem. Soc. 2004, 126, 9906–9907; (f)
Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2003, 42, 661–665; b-Ketoesters: (g) Berkessel, A.;
Cleemann, F.; Mukherjee, S. Angew. Chem., Int. Ed. 2006, 45,
9
47–950; (h) Li, H.-M.; Tang, L.; Wu, F.-H.; Liu, X.-F.; Guo,
C.-Y.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005,
4, 105–108.
4
7
. For selected examples, Nitroesters: (a) Prieto, A.; Halland,
N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897–3900; 1,3-
Dinitriles: (b) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew.
Chem., Int. Ed. 2005, 44, 4032–4035; Nitroalkanes: (c)
Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975–2978; (d)
Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257–4259; (e)
Wang, J.; Li, H.; Zu, L.-S.; Jiang, W.; Wang, W. Adv. Synth.
Catal. 2006, 348, 2047–2050.
13. Two distinct reaction pathways were discussed: Hamza, A.;
Schubert, G.; Soo’s, T.; Papai, I. J. Am. Chem. Soc. 2006,
128, 13151–13160.
14. El-Sadany, S. K.; Sharaf, S. M.; Darwish, A. I.; Youssef, A.
A. Indian J. Chem., Sect. B 1991, 30, 567–573.