Catalytic asymmetric alkylation of α-cyanocarboxylates and acetoacetates using a phase-transfer catalyst

Article abstract of DOI:10.1016/j.tetasy.2009.10.018

The catalytic asymmetric alkylation of α-cyanocarboxylates and acetoacetates with an alkyl halide was performed under phase-transfer conditions to afford compounds which have a chiral quaternary carbon with up to 97% and 94% ee, respectively. As applicati

Full text of DOI:10.1016/j.tetasy.2009.10.018

Tetrahedron: Asymmetry 20 (2009) 2530–2536
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Catalytic asymmetric alkylation of
using a phase-transfer catalyst
a-cyanocarboxylates and acetoacetates
*
Kazuhiro Nagata, Daisuke Sano, Yu Shimizu, Michiko Miyazaki, Takuya Kanemitsu, Takashi Itoh
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic asymmetric alkylation of
a
-cyanocarboxylates and acetoacetates with an alkyl halide was
Received 1 September 2009
Accepted 14 October 2009
Available online 22 November 2009
performed under phase-transfer conditions to afford compounds which have a chiral quaternary carbon
with up to 97% and 94% ee, respectively. As applications of this method, chiral 2-oxindole derivatives and
a b-lactam derivative were synthesized.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
not proceed without PTC. Thus we carried out the screening of chi-
ral catalysts in the system (Table 1). Among the chiral phase-trans-
The stereoselective formation of a chiral carbon with all-carbon
substituents is important, because a number of naturally occurring
bioactive compounds and pharmaceuticals have a chiral quater-
nary carbon.1 In order to create an all-carbon quaternary center
stereoselectively, an asymmetric C–C bond-forming reaction needs
to be developed. Although asymmetric alkylation is thought to be a
useful and straightforward method for achieving this purpose, the
steric repulsion between the carbon substituents makes the reac-
tion difficult and challenging. Since a Merck research group
reported the alkylation of phenylindanone derivative under
phase-transfer conditions,2 development of chiral phase-transfer
catalysts (PTC) and the reactions using them has been studied
extensively. As a result, several examples of alkylation, which af-
ford an all-carbon quaternary center, have been reported3 but
the most commonly studied are the asymmetric alkylations of pro-
tected glycine derivatives.4 In order to develop a general method
for the synthesis of the compounds that have an all-carbon quater-
nary center, we chose substrates with an acidic methane to form a
carbanion under phase-transfer conditions. It was found that the
fer catalysts, such as cinchonidine-derived catalysts 1a–c,2,6
binaphthyl derivative 2a,7 and tartrate-derived bis-ammonium salt
3,8 catalyst 2a gave a higher ee and faster reaction rate. In the
phase-transfer alkylation using catalyst 2a, the reaction rate and
ee were improved further (32% ee) by using Cs2CO3 as a base in
ether solvent. Other solvents such as toluene, CH2Cl2, CHCl3, and
AcOEt were also investigated, but the results were inferior to the
reaction using diethyl ether as a solvent. Thus we next examined
the influence of the ester group on the selectivity (Table 2). The
reaction was carried out using 5 mol % of catalyst 2a and benzyl
bromide (1.2 equiv) in ether/satd Cs2CO3 aqueous solution at room
temperature. The result was that bulky ester groups tended to give
high enantioselectivity, the ee went up to 73% when t-butyl or
diisopropylmethyl ester was employed. With these results, we
next investigated the influence of the base on the selectivity and
the yield using 2-cyanopropanoic acid t-butyl ester as a substrate
(Table 3). Since the substrate with a t-butyl ester was more reluc-
tant to hydrolysis, a base stronger than Cs2CO3 was tested. The re-
sults showed that KOH and CsOH increased the reaction rate and
gave higher enantioselectivity. By using a solid base, it became
possible to lower the reaction temperature. When the reaction
was run at ꢀ60 °C, 93% ee and an acceptable reaction rate were ob-
tained even in the presence of 1 mol % of the catalyst (entry 5).
Next the reaction with various alkyl halides was investigated (Ta-
ble 4). Alkyl halides with a functional group were also revealed to
react in high yields with high enantioselectivities. It was also found
that the products with an opposite configuration were obtained by
substitution reaction of
with an alkyl halide proceeded stereoselectively in the presence
of a chiral PTC. Herein, we report these results in detail.
a
-cyanocarboxylates5 and acetoacetates
2. Results and discussion
Prior to asymmetric alkylation, commercially available ethyl 2-
cyanopropanoate was tested for the reaction with benzyl bromide
in satd Na2CO2 aqueous solution/toluene using achiral tetrabutyl-
ammonium iodide as a PTC. It was found that ethyl 2-benzyl-2-
cyanopropanoate was obtained in 70% yield, but the reaction did
changing the order of introduction of alkyl substituent at the a-po-
sition of cyanoacetate (entries 3 and 9). Binaphthyl-derived spiro
quaternary ammonium salt 2b was found to enhance enantioselec-
tivity further. The absolute configurations of compounds 5d and 6
were determined by derivatization to the corresponding
disubstituted- -cyanoacetic acids and comparison of the specific
rotations with the literature values.9
a,a-
a
* Corresponding author.
E-mail address: itoh-t@pharm.showa-u.ac.jp (T. Itoh).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.10.018

K. Nagata et al. / Tetrahedron: Asymmetry 20 (2009) 2530–2536
2531
Table 1
Catalyst screening for the phase-transfer asymmetric benzylation of 4
H
Ar
Br -
Me
Me
NC
Cl -
Bn
O
BnBr,
cat.
+
N
(1.2 equiv)
H
(5 mol%)
OEt
+
H
OEt
N
NC
HO
aq.Na2CO3/toluene=1/6
5
Ar
O
4
Ar
quant.
2a:
N
Ar = 3,4,5-trifluorophenyl
2b: Ar = 3,5-trifluoromethylphenyl
1a:
Ar = phenyl
1b: Ar = 9-anthracenyl
1c: Ar = 4-(trifluoromethyl)benzyl
Me
-
2BF4
Ar
N
+
+
N
O
Ar
Ar
O
Ar
Me
3: Ar = 4-methylphenyl
Cat.
Time (d)
%ee
1a
1b
1c
2a
3
7
12
12
4
12
16
17
28
3
12
chiral quaternary center at the 3-position have received increasing
attention due to their unique biological activities and their poten-
tial as intermediates to synthesize bioactive natural products.10
Thus we chose 2-bromophenylcyanoacetate 12 as a substrate,
and investigated the allylation. In Table 5, the base and tempera-
ture effects on the yield and ee are shown. The reaction did not
proceed at ꢀ60 °C, while the ee did not increase under ꢀ10 °C.
When Et2O solvent was used in the reaction, reaction rate and ee
decreased. In order to determine the absolute configuration of 13
and to confirm the availability of the chiral adduct, compound 13
was transformed to b-lactam 16 whose specific rotation was re-
ported (Scheme 1).11 After reduction of the allyl and bromo groups
with HCO2NH4 catalyzed by Pd/C, the cyano group was reduced
with NaBH4 in the presence of CoCl212 and the subsequent protec-
tion of the thus-produced amino group with CbzCl afforded com-
pound 15. Next, b-lactam 16 was synthesized by the subsequent
removal of both the t-butyl and CBz groups followed by intramo-
lecular condensation with dipyridyl disulfide13 and PPh3 in 90%
yield from 15.14 By comparing the specific rotation of 16 thus ob-
tained with that of the reported one, the absolute configuration
of 16 was determined to be (R). Therefore compound 13 was found
to have an (R)-configuration. Next, conversion of 13 to oxindoles
was investigated (Scheme 2). Treatment of 13 with TFA followed
by amidation of the resulting carboxylic acid with benzyl amine
gave 17 in 88% yield. The copper-mediated intramolecular aryl
amination15 of 17 afforded 3,3-disubstituted chiral oxindole 18 in
quantitative yield. The cyano group of 18 was shown to convert
Table 2
Effect of ester group on the enantioselectivity
Me
Me
NC
Bn
O
BnBr (1.2 equiv),
2a (5 mol%)
OR
NC
OR
aq.Cs2CO3 /Et2O, rt
O
quant
5a-e
4a-e
Entry
Compound
R
Time (d)
%ee of 5
1
2
3
4
5
4a
4b
4c
4d
4e
Et
Me
i-Pr
t-Bu
–CH(iPr)2
1.5
1
1.5
7
32
15
51
73
73
7
Table 3
Effect of base on the phase-transfer benzylation of 4d in the presence of 2a
Me
Me
NC
5d
Bn
BnBr (1.2 equiv),
base /Et2O
2a (5 mol%)
Ot-Bu
Ot-Bu
NC
O
O
4d
Entry
Base
Temp (°C)
Time (h)
Yield (%)
ee of 5d (%)
a
1
2
3
aq Cs2CO3
Cs2CO3
KOH
CsOH
CsOH
rt
168
48
2
Quant
37
99
73
73
87
89
93
ꢀ40
ꢀ40
ꢀ40
ꢀ60
to
peroxide.16
We then investigated the chiral phase-transfer-catalyzed alkyl-
a carboxyl group by treatment with alkaline hydrogen
4
2
Quant
98
5b
72
ation of acetoacetates. Also in this case, catalysts 2a and 2b gave
higher enantioselectivity than cinchonidine-derived catalysts 1a–
c (Table 6). In the reaction of entry 5, changing the base from
KOH to CsOH gave almost the same result (y. 93%, 63% ee). Thus,
further optimization of the reaction was carried out using KOH
as a base (Table 7), and the results showed that the less polar sol-
a
A saturated aqueous solution was used.
1 mol % of 2a was used.
b
As an application of the present method, we next carried out the
synthesis of 3,3-disubstituted 2-oxindoles. 2-Oxindoles bearing a

2532
K. Nagata et al. / Tetrahedron: Asymmetry 20 (2009) 2530–2536
Table 4
Catalytic enantioselective phase-transfer alkylation of 4 with various alkyl halides
R2X
(1.2 equiv)
catalyst
(1 mol%)
R1
R2
O
R1
NC
5d, 6-11
,
Ot-Bu
Ot-Bu
NC
Et2O, CsOH (5 equiv)
-60oC
O
4
Entry
R1
R2X
Cat.
Time (h)
Yield (%)
Product
%ee (config.)
1
2
3
4
5
6
7
8
9
10
11
12
13
Me
Me
Me
Me
Me
Me
Me
Me
Allyl
Allyl
Allyl
Allyl
Allyl
BnBr
BnBr
CH2@CHCH2I
CH2@CHCH2I
2-(Bromomethyl)pyridine
ICH2CO2Et
ICH2CO2Et
BrCH2CO2tBu
MeI
BnBr
BnBr
ICH2CO2Et
ICH2CO2Et
2a
2b
2a
2b
2a
2a
2b
2a
2a
2a
2b
2a
2b
72
72
72
72
72
96
96
96
120
72
72
96
96
98
96
5d
5d
6
6
7
8
8
9
6
10
10
11
11
93(R)
97(R)
89(R)
92(R)
70
76
85
92
67(S)
91
Quant
90
Quant
Quant
97
Quant
81
Quant
Quant
Quant
Quant
>99
80
90
vent tended to give higher ee (entries 1–8). When the reaction was
run at ꢀ60 °C in mesitylene containing 10% toluene which was
added to lower the freezing point of mesitylene, the ee value was
improved to 94% (entry 14). Based on these results, the reactions
with other electrophiles were examined (Table 8).
Although mesitylene containing 10% toluene gave the best re-
sult in the case of benzylation, the solvent was not always suited
for the other alkylations. When allyl iodide was subjected to the
reaction using the solvent, starting material was recovered due
to the reaction of allyl iodide with mesitylene (entry 4).17 In the
case of the reaction with allyl iodide and/or ethyl iodoacetate,
Et2O gave better results than mesitylene/toluene = 9/1(entries 6
and 8). The absolute configuration of 21a was determined as fol-
lows (Scheme 3); since the specific rotation of ethyl ester deriva-
tive 23 was reported,18 ethyl ester 22 was subjected to the
present reaction. As a result, compound 23 with an (R)-configura-
tion was obtained with 66% ee. Product 23 was then converted to
Table 5
Phase-transfer allylation of 12 catalyzed by 2b
Br
2b (5 mol%)
Br
I
+
Ot-Bu
base (5 equiv) / toluene
Ot-Bu
NC
NC
(2 equiv)
O
O
12
13
Entry
Base
Temp (°C)
Time
Yield (%)
ee (%)
1
2
3
KOH
CsOH
rt
rt
rt
2 h
2 h
7 d
1 d
1 d
7 d
Quant
Quant
7
Quant
Quant
0
85
87
89
93
93
—
Cs2CO3
CsOH
CsOH
CsOH
4
ꢀ10
ꢀ10
ꢀ60
5a
6
a
1 mol % of catalyst was used.
1) TFA, rt, 3 h
Br
NC
Br
2) BnNH2, EDC-HCl (2 equiv)
HOAt (2 equiv)
Bn
NH
Ot-Bu
10% Pd/C (10 mol%)
NC
y. 88%
Br
O
O
Ot-Bu
Ot-Bu
sat. HCO2NH4 aq
EtOH, rt
Ot-Bu
0oC
rt
NC
NC
13
17
13
O
O
y. 99%
14
93% ee
CN
CuI (2 equiv)
CsOAc (4 equiv)
1) CoCl2 (2 equiv), NaBH4 (10 equiv)
1.0M NH3 in EtOH, rt
O
N
DMSO, 70oC, 10 h
CbzHN
CH2Ph
quant. 93% ee
2) CbzCl , Na2CO3 , H2O, rt
O
18
y. 48% in 2 steps
15
O
1) TFA, rt
2) 10% Pd/C (10 mol%)
MeOH, under H2, rt
K2CO3 (2 equiv)
30% H2O2 aq (10 equiv)
OH
O
rac-18
O
N
DMSO, rt
3) PPh3, (PyS)2, CH3CN, 60°C
y. 90% in 3 steps
CH2Ph
NH
y. 93%
[α]D25 = +56.9
(c 2.00, CHCl3)
16
19
Scheme 1. Synthesis of b-lactam 16.
Scheme 2. Synthesis of 2-oxindole derivatives.

K. Nagata et al. / Tetrahedron: Asymmetry 20 (2009) 2530–2536
2533
Table 6
purchased from commercial suppliers. Al CsOH used was anhy-
drous salt. Moisture-sensitive reactions were carried out under
an atmosphere of Ar. 1H and 13C NMR spectra ware recorded on
a 500 MHz (125 MHz for 13C) or a 400 MHz (100 MHz for 13C) spec-
trometer. All melting points were uncorrected.
Phase-transfer benzylation of 20 catalyzed by 1a–2b
Me
Me
O
Bn
O
BnBr (1.2 equiv),
PTC (5 mol%)
Et2O,
Ot-Bu
Ot-Bu
KOH solid (2 equiv),
rt, 3 h
O
O
4.2. General procedure for the asymmetric phase-transfer
alkylation of a-cyanocarboxylates
20
21
Entry
PTC
Yield (%)
ee of 21 (%)
A solution of tert-butyl 2-cyanopropanoate or tert-butyl 2-
cyanopent-4-enoate (0.1 mmol) in Et2O (2.4 ml) was cooled at
ꢀ60 °C. The PTC (2a or 2b) (0.001 mmol), alkyl halide (0.12 mmol),
and CsOH (75 mg, 0.5 mmol) were added to the solution. The reac-
tion mixture was vigorously stirred for the time indicated in Table 4
and then diluted with Et2O. The organic layer was washed with
H2O and brine, dried over MgSO4, and the solvents were removed
by evaporation. The residue was chromatographed on silica gel
(AcOEt/hexane) to give the corresponding 2-cyanocarboxylate.
1
2
3
4
5
1a
1b
1c
2a
2b
62
66
76
60
92
0
6
8
38
64
the t-butyl ester 21a. The absolute configuration of 21a prepared
from 20 was determined by comparison of the retention time of
chiral HPLC analysis with that of 21a prepared from 23. The other
products 21b and 21c were assigned to be (R) based on the
assumption that the same stereocontrol had occurred.
4.3. (R)-tert-Butyl 2-cyano-2-methyl-3-phenylpropanoate 5d
Colorless oil; ½a D25
ꢁ
¼ ꢀ14:7 (c 2.00, CHCl3) (97% ee); 1H NMR
(CDCl3) d 1.42 (9H, s), 1.57 (3H, s), 2.98–3.01 (1H, d, J = 13.7 Hz),
3.17–3.21 (1H, d, J = 13.4 Hz), 7.30–7.33(5H, m); 13C NMR (CDCl3)
d 24.1, 28.4, 44.3, 46.7, 83.1, 121.9, 128.5, 129.2, 130.9, 135.2,
169.2; HR-FAB MS: calcd for C15H20NO2 [M+H]+: 246.1493, found:
246.1494. The ee was determined by HPLC analysis (Daicel CHI-
RALCEL OJ, 2-propanol/hexane = 1:400).
2b (2 mol%)
CsOH (5 equiv)
O
O
O
O
BnBr (2.4 equiv)
R
Et
Et
O
O
Et2O, -30oC, quant.
Bn
[α]25D +41.7
(c 1.33, CHCl3)
23
22
4.4. (R)-tert-Butyl 2-cyano-2-methylpent-4-enoate 6
O
O
Et
Colorless oil; ½a D25
ꢁ
¼ þ2:2 (c 1.67, CHCl3) (92% ee); 1H NMR
O
(CDCl3) d 1.50 (9H, s), 1.54 (3H, s), 2.47 (1H, dd, J = 13.8, 7.4 Hz),
2.64 (1H, dd, J = 13.8, 7.2 Hz), 5.22–5.26 (2H, m), 5.82 (1H, m);
13C NMR (CDCl3) d 22.7, 27.8, 42.1, 44.2, 83.9, 120.0, 120.7, 130.9,
167.8; HR-FAB MS: calcd for C11H18NO2 [M+H]+: 196.1407, found:
196.1321. The ee was determined by HPLC analysis (Daicel CHI-
RALCEL OJ-H, 2-propanol/hexane = 1:400).
Bn
Ti(OCHMe2)4
t-BuONa, BuOH
80oC
22
[
]
-58.2 (92% ee)
lit.18b
α
D
(CHCl3)
2b (5 mol%)
KOH (2 equiv)
BnBr (1.2 equiv)
O
O
O
O
4.5. tert-Butyl 2-cyano-2-methyl-3-pyridin-2-ylpropanoate 7
t-Bu
(R)
t-Bu
O
O
Colorless oil; ½a D25
ꢁ
¼ þ8:4 (c 3.45, CH2Cl2) (92% ee); 1H NMR
10% toluene
in mesitylene
-60oC
Bn
21a
(CDCl3) d 1.48 (9H, s) 1.65 (3H, s), 3.21 (1H, d, J = 14.6 Hz), 3.45
(1H, d, J = 14.6 Hz), 7.19 (1H, ddd, J = 7.6, 4.8, 1.2 Hz), 7.27 (1H,
m), 7.64 (1H, td, J = 7.6, 2.0 Hz), 8.54 (1H, ddd, J = 4.9, 2.1,
0.8 Hz); 13C NMR (CDCl3) d 23.6, 27.7, 44.3, 44.9, 83.6, 120.3,
122.3, 123.8, 136.4, 149.1, 155.2, 168.0; HR-FAB MS: calcd for
C14H19N2O2 [M+H]+: 247.1440, found: 247.1449. The ee was deter-
mined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-propanol/
hexane = 1:4).
20
Scheme 3. Determination of the absolute configuration of 21a.
3. Conclusion
In conclusion, we have performed the catalytic asymmetric
alkylation of
a-cyanocarboxylates and acetoacetates using PTC,
and it was demonstrated that synthetic cyanocarboxylates with a
chiral quaternary carbon center were converted to an oxindole
and a b-lactam derivative. The present method is straightforward
in constructing an all-carbon quaternary center and is thought to
provide facile access to the more complex compounds which have
such a stereocenter. Further application of this method to the
synthesis of bioactive natural products is now under investigation.
4.6. 1-tert-Butyl 4-ethyl 2-cyano-2-methylbutanedioate 8
Colorless oil; ½a D25
ꢁ
¼ þ15:6 (c 2.00, CHCl3) (85% ee); 1H NMR
(CDCl3) d 1.28 (3H, t, J = 7.2 Hz), 1.52 (9H, s), 1.63 (3H, s), 2.77 (1H,
d, J = 17.1 Hz), 2.98 (1H, d, J = 17.1 Hz), 4.20 (2H, q, J = 7.1 Hz); 13C
NMR (CDCl3) d 14.1, 23.7, 27.7, 41.2, 41.6, 61.4, 84.1, 120.0, 167.4,
168.7; HR-FAB MS: calcd for C12H20NO4 [M+H]+: 242.1332, found:
242.1411. The ee was determined by HPLC analysis (Daicel CHIRAL-
CEL OJ-H, 2-propanol/hexane = 1:200).
4. Experimental
4.1. General
4.7. Di-tert-butyl 2-cyano-2-methylbutanedioate 9
Colorless oil; ½a D25
ꢁ
¼ þ19:3 (c 7.50, CHCl3) (92% ee); 1H NMR
Unless otherwise specified, reagents were purchased from com-
mercial suppliers and used without further purification. Dehy-
drated toluene, DMSO, THF, CH2Cl2, EtOH, and MeOH were
(CDCl3) d 1.47 (9H, s), 1.51 (9H, s), 1.60 (3H, s), 2.69 (1H, d,
J = 16.8 Hz), 2.89 (1H, d, J = 16.8 Hz); 13C NMR (CDCl3) d 23.7,

2534
K. Nagata et al. / Tetrahedron: Asymmetry 20 (2009) 2530–2536
Table 7
Phase-transfer benzylation of 20 catalyzed by 2b in various solvents
Me
Me
O
Bn
O
BnBr (1.2 equiv),
2b (5 mol%)
solvent
Ot-Bu
Ot-Bu
KOH solid (2 equiv),
O
O
20
21
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)
ee of 21 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Et2O
TBME
THF
rt
rt
rt
rt
rt
rt
rt
rt
ꢀ60
ꢀ60
ꢀ30
ꢀ40
ꢀ50
ꢀ60
3
3
3
3
3
3
3
3
72
72
72
72
72
72
92
32
85
85
92
80
90
Quant
75
56
64
53
28
9
CH2Cl2
CH3CN
Toluene
Xylene
Mesitylene
Et2O
Toluene
Xylene
10% Toluene in xylene
Mesitylene
0
68
71
69
64
74
84
85
82
94
95
84
75
85
10% Toluene in mesitylene
Table 8
Phase-transfer alkylation of 20 catalyzed by 2b
Me
Me
O
R
R-X (1.2 equiv),
2b
Ot-Bu
Ot-Bu
base, solvent, -60oC
O
O
O
20
21a: R = CH2Ph
21b: R = CH2CH=CH2
21c: R = CH2CO2Et
Entry
R–X
Solvent
2b (mol %)
Base
Time (h)
Yield (%)
ee of 21 (%)
1
2
3
Mesitylene/toluene = 9/1
Et2O
Et2O
5
5
1
KOH
KOH
CsOH
72
72
72
85
75
89
94
64
80
BnBr
4
5
6
Mesitylene/toluene = 9/1
Et2O
Et2O
5
5
1
KOH
KOH
CsOH
72
72
72
0
65
84
—
68
78
CH2@CHCH2I
7
8
ICH2CO2Et
Mesitylene/toluene = 9/1
Et2O
5
1
KOH
CsOH
96
72
70
100
23
80
27.7, 28.0, 41.4, 42.6, 82.3, 83.9, 120.0, 167.5, 167.8; HR-FAB MS:
calcd for C14H24NO4 [M+H]+: 270.1694, found: 270.1709. The ee
was determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-
propanol/hexane = 1:800).
J = 13.7, 7.3 Hz), 2.62 (1H, dd, J = 13.9, 7.3 Hz), 2.72 (1H, d,
J = 17.1 Hz), 2.96 (1H, d, J = 16.8 Hz), 4.16 (2H, q, J = 7.3 Hz), 5.20–
5.26 (2H, m), 5.80 (1H, m); 13C NMR (CDCl3) d 14.1, 27.7, 40.0,
41.2, 45.9, 61.4, 84.3, 118.5, 121.3, 130.0, 166.6, 168.7; HR-FAB
MS: calcd for C14H22NO4 [M+H]+: 268.1560, found: 268.1545. The
ee was determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-
propanol/hexane = 1:100).
4.8. tert-Butyl 2-benzyl-2-cyanopent-4-enoate 10
Colorless oil; ½a D25
ꢁ
¼ ꢀ18:1 (c 1.74, CHCl3) (99% ee); 1H NMR
(CDCl3) d 1.29 (9H, s), 2.47 (1H, dd, J = 13.6, 6.8 Hz), 2.63 (1H, dd,
J = 13.7, 7.8 Hz), 2.96 (1H, d, J = 13.4 Hz), 3.09 (1H, d, J = 13.4 Hz),
5.17–5.21 (2H, m), 5.78 (1H, m) 7.19–7.30 (5H, m); 13C NMR
(CDCl3) d 27.7, 41.7, 42.5, 84.2, 119.0, 120.8, 127.7, 128.4, 130.1,
130.7, 134.3, 166.9; HR-FAB MS: calcd for C17H22NO2 [M+H]+:
272.1621, found: 272.1662. The ee was determined by HPLC anal-
ysis (Daicel CHIRALCEL OD, 2-propanol/hexane = 1:800).
4.10. tert-Butyl (2-bromophenyl)cyanoacetate 12
To a stirred solution of 2-bromophenylacetonitrile (4.02 ml,
30 mmol) in DMF (100 ml) was added NaH (60% in oil) (1.32 g,
33 mmol) slowly at 0 °C. After 5 min di-tert-butyl dicarbonate
(10.3 ml, 45 mmol) was added, and the solution was stirred for
6 h at room temperature in Ar atmosphere. Then water was added
and the mixture was extracted with CH2Cl2. The combined organic
layer was washed with brine and dried over MgSO4. After the sol-
vent was removed by evaporation, the residue was chromato-
graphed on silica gel (AcOEt/hexane = 1/16) to give 12 (8.8 g) in
99% yield. Colorless oil: 1H NMR (CDCl3) d 1.48 (9H, s), 5.13 (1H,
4.9. 1-tert-Butyl 4-ethyl 2-cyano-2-prop-2-en-1-ylbutanedioate 11
Colorless oil; ½a D25
ꢁ
¼ þ13:9 (c 2.38, CHCl3) (90% ee); 1H NMR
(CDCl3) d 1.25 (3H, t, J = 7.1 Hz), 1.48 (9H, s), 2.50 (1H, dd,

K. Nagata et al. / Tetrahedron: Asymmetry 20 (2009) 2530–2536
2535
s), 7.26 (1H, dt, J = 1.5, 8.0 Hz), 7.40 (1H, dt, J = 1.0, 7.6 Hz), 7.57–
7.63 (2H, m); 13C NMR (CDCl3) d 27.7, 44.4, 85.0, 115.5, 123.9,
128.3, 129.9, 130.6, 130.7, 133.4, 162.8; HR-FAB MS: calcd for
C13H15BrNO2 [M+H]+: 296.0286, found 296.0283.
s), 7.22–7.33 (10H, m); 13C NMR (CDCl3) d 14.8, 17.9, 27.9, 36.9,
45.9, 55.5, 66.4, 81.5, 126.5, 126.9, 128.0, 128.0, 128.4, 128.5,
136.6, 140.9, 156.3, 173.9; HR-FAB MS: calcd for C24H32NO4
[M+H]+: 398.2331, found: 398.2308.
4.11. (R)-tert-Butyl 2-(2-bromophenyl)-2-cyanopent-4-enoate 13
4.14. (R)-3-Phenyl-3-propylazetidin-2-one 16
To a solution of 12 (29.6 mg, 0.1 mmol) in toluene (2.4 ml)
cooled at ꢀ10 °C were added PTC 2b (1.1 mg, 0.001 mmol) and allyl
Compound 15 (397 mg, 1.0 mmol) was dissolved in TFA (5 ml),
and the solution was stirred for 12 h at room temperature. The
reaction mixture was evaporated, and the residue was dissolved
in MeOH (5 ml). Then, 10% Pd/C (106 mg, 0.10 mmol) was added
to the solution and stirred for 1 d under H2 atmosphere. The reac-
tion mixture was filtered through a pad of Celite, and the filtrate
was evaporated. Then MeCN (20 ml) was added, and PPh3(315 mg,
1.2 mmol) and 2,2’-dipyridyl disulufide (264 mg, 1.2 mmol) were
added to the solution. The reaction mixture was stirred for 4d at
60 °C under an Ar atmosphere. After being diluted with H2O, the
solution was extracted with CH2Cl2. The combined organic layer
was washed with brine and dried over MgSO4. After the solvent
was removed by evaporation, the residue was chromatographed
on silica gel (AcOEt/hexane = 1/4?1/2?1/0) to give 16 (170 mg)
iodide (18 ll, 0.2 mmol), then CsOH (75 mg, 0.5 mmol) was added
to the solution. The reaction mixture was stirred vigorously for 1d
and diluted with H2O. The mixture was extracted with CH2Cl2 and
the combined organic layer was washed with brine and dried over
MgSO4. After the solvent was removed by evaporation, the residue
was chromatographed on silica gel (AcOEt/hexane = 1/16) to give
13 in quantitative yield. Colorless oil; ½a D25
¼ ꢀ9:2 (c 2.00, CHCl3)
ꢁ
(93% ee); 1H NMR (CDCl3) d 1.48 (9H, s), 3.11 (1H, dd, J = 7.6,
14.0 Hz), 3.27 (1H, dd, J = 6.8, 14.0 Hz), 5.19–5.26 (2H, m), 5.78
(1H, m), 7.24 (1H, dt, J = 1.6, 7.6 Hz), 7.37 (1H, dt, J = 1.2, 8.0 Hz),
7.55 (1H, dd, J = 1.4, 8.0 Hz), 7.64 (1H, dd, J = 1.6, 8.0 Hz); 13C
NMR (CDCl3) d 27.6, 39.7, 54.8, 84.7, 117.7, 120.7, 122.8, 127.7,
129.6, 130.1, 130.8, 133.9, 134.7, 165.2; HR-FAB MS: calcd for
C16H19O2NBr [M+H]+: 336.0630, found: 336.0584. The ee was
determined by HPLC analysis (Daicel CHIRALCEL OJ-H, 2-propanol/
hexane = 1:100).
in 90% yield. Colorless oil: ½a D25
¼ þ56:9 (c 2.00, CHCl3) (93% ee),
ꢁ
1H NMR (CDCl3) d 0.89 (3H, t, J = 7.6 Hz), 1.28 (1H, m), 1.44 (1H,
m), 1.95 (2H, m), 3.50 (1H, d, J = 5.6 Hz), 3.59 (1H, d, J = 4.8 Hz),
5.76 (1H, br s), 7.26 (1H, m), 7.33–7.36 (2H, m), 7.40–7.43 (2H,
m), 13C NMR (CDCl3) d 14.2, 18.3, 39.9, 48.4, 64.7, 126.6, 127.0,
128.4, 140.0, 172.2; HR-FAB MS: calcd for C12H16NO [M+H]+:
190.1232, found: 190.1223.
4.12. tert-Butyl 2-cyano-2-phenylpentanoate 14
To a solution of 13 (3.36 g, 10 mmol) in EtOH (25 ml) were
added 10% Pd/C (1.06 g) and satd HCO2NH4 aq (25 ml) under Ar
atmosphere. The solution was stirred for 1 d at room temperature,
and then filtered through a pad of Celite. The filtrate was evapo-
rated to remove EtOH, and the remaining aqueous layer was ex-
tracted with CH2Cl2. The combined organic layer was washed
with brine and dried over MgSO4. After the solvent was removed
by evaporation, the residue was chromatographed on silica gel
(AcOEt/hexane = 1/6) to give 14 (2.57 g) in 99% yield. Colorless
oil: 1H NMR (CDCl3) d 0.97 (3H, t, J = 7.3 Hz), 1.39–1.52 (11H, m),
2.03 (1H, m), 2.31 (1H, m), 7.36–7.41 (3H, m), 7.53 (2H, d,
J = 7.3 Hz); 13C NMR (CDCl3) d 13.8, 18.9, 27.6, 40.0, 55.0, 84.1,
118.9, 125.9, 128.5, 129.0, 135.2, 166.5; HR-FAB MS: calcd for
C16H22NO2 [M+H]+: 260.1651, found: 260.1659.
4.15. (R)-N-Benzyl-2-(2-bromophenyl)-2-cyanopent-4-
enamide 17
Compound 13 (34 mg, 0.1 mmol) was dissolved in TFA (1.0 ml)
and stirred at room temperature for 12 h under an Ar atmosphere.
The TFA was then removed by evaporation and CH2Cl2 (1.0 ml) was
added. The solution was cooled to 0 °C and EDCꢂHCl (38 mg,
0.2 mmol), 1-hydroxy-7-azabenzotriazole (27 mg, 0.2 mmol), and
BnNH2 (16 ll, 0.15 mmol) were added. The reaction mixture was
stirred overnight at room temperature under an Ar atmosphere.
After the addition of H2O, the mixture was extracted with CH2Cl2.
The organic layer was washed with brine, dried over MgSO4, and
the solvents were removed by evaporation. The residue was chro-
matographed on silica gel (AcOEt/hexane = 1/4) to give compound
4.13. tert-Butyl 2-(benzyloxycarbonylaminomethyl)-2-
phenylpentanoate 15
17 in 88% yield. Mp 124 °C (CH2Cl2); ½a D25
¼ ꢀ21:9 (c 3.07, CHCl3)
ꢁ
(93% ee); 1H NMR (CDCl3) d 3.19–3.30 (2H, m), 4.44 (1H, dd,
J = 5.1, 14.8 Hz), 4.54 (1H, dd, J = 6.0, 14.8 Hz), 5.19–5.27 (2H, m),
5.75 (1H, m), 6.13 (1H, br s), 7.24–7.34 (6H, m), 7.39 (1H, t,
J = 7.6 Hz), 7.61 (1H, d, J = 7.6 Hz), 7.66 (1H, d, J = 8.0 Hz); 13C
NMR (CDCl3) d 39.6, 44.8, 54.6, 118.4, 121.2, 123.0, 127.9, 128.1,
128.8, 130.3, 130.7, 130.7, 133.2, 135.3, 136.8, 165.3; HR-FAB
MS: calcd for C19H18ON2Br [M+H]+: 369.0619, found: 369.0592;
Anal. Calcd for C19H17ON2Br: C, 61.80; H, 4.64; N, 7.59. Found: C,
61.78; H, 4.54; N, 7.48. The ee was determined by HPLC analysis
(Daicel CHIRALCEL OJ-H, 2-propanol/hexane = 1:20).
To a solution of 14 (2.57 g, 10 mmol) in EtOH (25 ml) was
added 2.0 M NH3 in EtOH (25 ml). Then a mixture of NaBH4
(3.75 g, 100 mmol) and CoCl2 (2.57 g, 20 mmol) was added slowly
to the solution. The reaction mixture was stirred for 1d at room
temperature and quenched with 1 M aq HCl. After the precipitate
was removed by filtration, the filtrate was evaporated off. Then
AcOEt was added to the residue and extracted with 1 M aq HCl.
The combined aqueous layer was neutralized with NaHCO3 and
extracted with AcOEt. The combined organic layer was washed
with brine and dried over MgSO4. After the solvent was removed
by evaporation, H2O (20 ml), Na2CO3 (2.07 g, 20 mmol), and CbzCl
(0.88 ml, 6.2 mmol) were added and the solution was stirred for
1 d at room temperature. The reaction mixture was extracted
with CH2Cl2 and the combined organic layer was washed with
brine and dried over MgSO4. After the solvent was removed by
evaporation, the residue was chromatographed on silica gel
(AcOEt/hexane = 1/10?1/8) to give 15 (1.91 g) in 48% yield. Col-
orless oil: 1H NMR (CDCl3) d 0.92 (3H, t, J = 7.1 Hz), 1.26–1.27
(2H, m), 1.42 (9H, s), 1.89–1.95 (2H, m), 3.62 (1H, dd, J = 4.6,
13.9 Hz), 3.82 (1H, dd, J = 7.8, 13.7 Hz), 4.89 (1H, br s), 5.28 (2H,
4.16. (R)-1-Benzyl-3-cyano-3-(prop-2-en-1-yl)-1,3-
dihydroindol-2-one 18
To a solution of compound 17 (44 mg, 0.11 mmol) in DMSO
(1.1 ml) were added CuI (42 mg, 0.2 mmol) and CsOAc (106 mg,
0.5 mmol). The mixture was stirred for 10 h at 70 °C under an Ar
atmosphere. After the addition of Et2O, the organic layer was washed
with H2O and brine, and dried over MgSO4. The solvent was removed
by evaporation and the residue was chromatographed on silica gel
(AcOEt/hexane = 1/7) to give the compound 18 in quantitative yield.
Mp 122 °C (CH2Cl2); ½a D25
ꢁ
¼ þ27:3 (c 5.81, CHCl3) (93% ee); 1H NMR

2536
K. Nagata et al. / Tetrahedron: Asymmetry 20 (2009) 2530–2536
(CDCl3) d 2.83 (1H, dd, J = 8.4, 13.6 Hz), 3.05 (1H, dd, J = 6.4, 13.2 Hz),
4.81 (1H, d, J = 15.6 Hz), 5.02 (1H, d, J = 15.6 Hz), 5.18–5.22 (2H, m),
5.65 (1H, m), 6.78 (1H, d, J = 7.6 Hz), 7.11 (1H, t, J = 7.6 Hz), 7.26–7.33
(6H, m), 7.41 (1H, d, J = 7.2 Hz); 13C NMR (CDCl3) d 41.1, 44.6, 46.4,
110.1, 116.7, 122.2, 123.6, 124.5, 124.7, 127.4, 128.1, 128.9, 129.0,
130.3, 134.7, 142.2, 170.1; HR-FAB MS: calcd for C19H17ON2
[M+H]+: 289.1351, found: 289.1337; Anal. Calcd for C19H16ON2: C,
79.14; H, 5.59; N, 9.72. Found: C, 79.02; H, 5.52; N, 9.75. The ee
was determined by HPLC analysis (Daicel CHIRALCEL IA, 2-propa-
nol/hexane = 1:10).
(1H, d, J = 16.4 Hz), 4.11 (2H, J = 7.2 Hz); 13C NMR (CDCl3) d 13.7,
19.6, 25.7, 27.3, 39.5, 57.7, 60.2, 81.7, 170.3, 170.5, 204.4; HR-
FAB MS: calcd for C13H23O5 [M+H]+: 259.1467, found: 259.1531.
The ee was determined by HPLC analysis (Daicel CHIRALCEL IA,
AcOEt/hexane = 1:25).
Acknowledgments
This work was supported in part by Grants-in-Aid for Scientific
Research and the High-Technology Research Center Project from
the Ministry of Education, Culture, Sports, Science and Technology,
Japan.
4.17. 3-Allyl-1-benzyl-2-oxo-2,3-dihydro-1H-indole-3-
carboxylic acid 19
To a solution of 18 (290 mg, 1.0 mmol) in DMSO (10 ml) were
added K2CO3 (280 mg, 2.0 mmol) and 30% aq H2O2 (1.02 ml,
10 mmol) at 0 °C. The solution was stirred for 1 d at room temper-
ature, then diluted with H2O, and extracted with CH2Cl2. The or-
ganic layer was washed with brine, dried over MgSO4, and the
solvents were removed by evaporation. The residue was chromato-
graphed on silica gel (AcOEt/hexane = 1/1) to give the compound
19 (286 mg) in 93% yield.
References
1. For reviews, see: (a) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005, 347, 1473–
1481; (b) Peterson, E. A.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
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10146; (e) Christoffer, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688–1690; (f)
Christoffer, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591–4597; (g) Bella,
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2. Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446–
447.
Mp 199–200 °C (AcOEt); 1H NMR (CDCl3) d 2.88 (1H, dd, J = 13.4,
8.0 Hz), 2.97 (1H, dd, J = 13.4, 6.3 Hz), 4.84 (1H, d, J = 15.6 Hz),
4.94–5.07 (3H, m), 5.45 (1H, m), 6.73 (1H, d, J = 7.8 Hz), 7.09 (1H,
m), 7.19 (1H, dt, J = 7.6, 1.2 Hz), 7.22–7.31 (5H, m), 7.70 (1H, m);
13C NMR (CDCl3) d 43.3, 44.2, 58.8, 109.1, 119.9, 123.3, 126.7,
127.4, 127.9, 128.6, 128.9, 131.1, 135.5, 142.1, 169.3, 176.5; HR-
FAB MS: calcd for C19H18NO3 [M+H]+: 308.1287, found: 308.1284.
3. (a) Bella, M.; Kobbelgaard, S.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 3670–
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K. Angew. Chem., Int. Ed. 2003, 42, 3796–3798; (c) Manabe, K. Tetrahedron Lett.
1998, 39, 5807–5810; (d) Park, E. J.; Kim, M. H.; Kim, D. Y. J. Org. Chem. 2004, 69,
6897–6899; (e) Nerinckx, W.; Vandewalle, M. Tetrahedron: Asymmetry 1990, 1,
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5017; (i) Nibbs, A. E.; Baize, A.-L.; Herter, R. M.; Scheidt, K. A. Org. Lett. 2009, 11,
4010–4013.
4.18. General procedure for the asymmetric phase-transfer
alkylation of acetoacetates
4. For reviews, see: (a) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222–
4266; (b) O’Donnel, M. J. Acc. Chem. Res. 2004, 37, 506–517; (c) Maruoka, K.;
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5228–5229; (b) Ooi, T.; Taniguchi, M.; Kameda, M.; Maruoka, K. Angew. Chem.,
Int. Ed. 2002, 41, 4542–4544.
8. Ohshima, T.; Shibuguchi, T.; Fukuta, Y.; Shibasaki, M. Tetrahedron 2004, 60,
7743–7754.
9. (a) Badorrey, R.; Cativiela, C.; Díaz-de-Villegas, M. D.; Gálves, J. A. Tetrahedron:
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Villegas, M. D.; Gálves, J. A.; Lepeña, Y. Tetrahedron: Asymmetry 1997, 8, 311–
317.
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4555–4558.
A solution of tert-butyl 2-methyl-3-oxobutanoate (0.1 mmol) in
Et2O or 10% toluene in mesitylene (2.4 ml) was cooled at ꢀ60 °C.
Next, PTC 2b (0.001 mmol), alkyl halide (0.12 mmol), and then
base (0.4 mmol) were added to the solution. The reaction mixture
was vigorously stirred for the time indicated in Table 7 and
quenched with 1 M aq HCl. After the solution was diluted with
AcOEt, organic layer was washed with H2O and brine, and dried
over MgSO4. The solvents were removed by evaporation and the
residue was chromatographed on silica gel (AcOEt/hexane) to give
the corresponding 2-substituted acetoacetates.
4.19. tert-Butyl 2-benzyl-2-methyl-3-oxobutanoate 21a
Colorless oil: 1H NMR (CDCl3) d 1.17 (3H, s), 1.37 (9H, s), 2.10 (3H,
s), 2.98 (1H, d, J = 14 Hz) 3.15 (1H, d, J = 13.6 Hz), 7.04–7.19 (5H, m);
13C NMR (CDCl3) d 19.1, 26.4, 27.8, 40.2, 61.3, 82.0, 126.7, 128.1,
130.3, 136.7, 171.5, 205.5; HR-FAB MS: calcd for C16H23O3 [M+H]+:
263.1569, found: 263.1637. The ee was determined by HPLC analysis
(Daicel CHIRALCEL IA, AcOEt/hexane = 1:11).
13. Kobayashi, S.; Iimori, T.; Izawa, T.; Ohno, M. J. Am. Chem. Soc. 1981, 103, 2406–
2408.
14. Hydrogenation of the cyano group by the reported method11 using
rhodium on alumina in 1% ammonia in EtOH did not take place and
resulted in the recovery of 14. The direct conversion of the b-amino
ester, which was obtained by reduction of cyano group, to the b-lactam
failed.
4.20. tert-Butyl 2-acetyl-2-methylpent-4-enoate 21b
Colorless oil: 1H NMR (CDCl3) d 1.23 (3H, s), 1.41 (9H, s), 2.11 (3H,
s), 2.39–2.45 (1H, m), 2.52–2.58 (1H, m), 5.03–5.04 (2H, m), 5.56–
5.66 (1H, m); 13C NMR (CDCl3) d 19.2, 26.5, 28.2, 39.6, 60.3, 82.2,
119.1, 133.2, 171.9, 205.7; HR-FAB MS: calcd for C12H21O3 [M+H]+:
213.1412, found: 213.1475. The ee was determined by HPLC analysis
(Daicel CHIRALCEL AD-H, 2-propanol/hexane = 1:500).
15. Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2003,
125, 6630–6631.
16. When hydrolysis was carried out with H2SO4 in 1,4-dioxane/H2O, carboxylic
acid 19 was obtained in 60% yield.
17. When a mixture of mesitylene and allyl iodide was stirred for 1 day at rt, many
TLC spots were observed and allyl iodide was not detected by measurement
with 1H NMR.
18. (a) Tanaka, M.; Oba, M.; Tamai, K.; Suemune, H. J. Org. Chem. 2001, 66, 2667–
2673; (b) Tomioka, K.; Ando, K.; Takemasa, I.; Koga, K. J. Am. Chem. Soc. 1984,
106, 2718–2719.
4.21. 1-tert-Butyl 4-ethyl 2-acetyl-2-methylbutanedioate 21c
Colorless oil: 1H NMR (CDCl3) d 1.25 (3H, t, J = 7.2 Hz), 1.461
(9H, s), 1.455 (3H, s), 2.24 (3H, s), 2.81 (1H, d, J = 16.8 Hz), 2.87