Organocatalytic conjugate additions of acetylacetone to 3-ylideneoxindoles: A direct access to highly enantioenriched oxindole derivatives

Article abstract of DOI:10.1055/s-0030-1260463

A highly enantioselective organocatalytic conjugate addition of acetylacetone to 3-ylideneoxindoles is described. This method provides polysubstituted oxindoles in good to excellent enantioselectivities and high isolated yields. Georg Thieme Verlag Stuttg

Full text of DOI:10.1055/s-0030-1260463

PAPER
1847
Organocatalytic Conjugate Additions of Acetylacetone to 3-Ylideneoxindoles:
A Direct Access to Highly Enantioenriched Oxindole Derivatives
Synthesis of
H
h
ighly Enanti
u
oenriche
d
O
-
xindole
D
W
erivatives en Duan, Hai-Hua Lu, Fu-Gen Zhang, Jun Xuan, Jia-Rong Chen, Wen-Jing Xiao*
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, P. R. of China
Fax +86(27)67862041; E-mail: wxiao@mail.ccnu.edu.cn
Received 15 March 2011
bond-forming reactions, provide a very straightforward
Abstract: A highly enantioselective organocatalytic conjugate ad-
approach to access polysubstituted oxindole derivatives.
dition of acetylacetone to 3-ylideneoxindoles is described. This
In this context, however, a functionalized oxindole has
method provides polysubstituted oxindoles in good to excellent
been utilized as the Michael donor in most cases.13 As part
enantioselectivities and high isolated yields.
of our ongoing investigation on organocatalytic enantio-
Key words: organocatalysis, bifunctional activation, oxindole,
conjugate addition, 3-ylideneoxindole
selective conjugate addition reactions,14 we describe here-
in an alternative route to construct polysubstituted
oxindoles by using 3-ylideneoxindoles as the Michael ac-
ceptor. Not only is this methodology attractive for the
The oxindole scaffold has been recognized as a prominent
preparation of enantioenriched oxindole derivatives, but it
and privileged structural motif found in various kinds of
also exhibits great enatioselectivities for both diastereo-
natural products and synthetic intermediates, displaying a
isomers (up to >99% ee) in excellent isolated yields.
wide range of biological activities.1,2 For example, spiro-
Initially, the reaction of ethyl (E)-2-(2-oxoindolin-3-
ylidene)acetate (7¢, R = H) and acetylacetone (8) was ex-
amined in the presence of natural cinchona alkaloids 1 and
2 (Figure 2). Only poor stereoselectivities were obtained,
although the reaction gave the product 9¢ (R = H) in high
efficiency (Table 1, entries 1, 2). To our delight, bifunc-
tional organocatalyst 3 successfully gave the desired con-
jugate adduct in 93% yield and 89% and 84% ee for both
enantiomers, respectively (Table 1, entry 3). Other thio-
urea-containing bifuctional catalysts 4–6 (Figure 2) were
also examined in this asymmetric conjugate reaction, but
no further advance in stereoselectivities was achieved
(Table 1, entries 4–6). Better results can be obtained with
the nitrogen atom being protected by benzyl or methyl
group (Table 1, entries 8, 9). A subsequent solvent screen-
ing showed that the conjugate reaction could proceed
tryprostatin A, isolated from Aspergillu fumigates, has
shown antimitotic activity.3 Furthermore, the oxindole
moiety can be converted to indoline derivatives under
operationally simple conditions. These compounds, like
flustramines A and B, have been found to exhibit both
skeletal and smooth muscle relaxant activities (Figure 1).4
N
O
Br
O
N
N
N
Me
H
O
N
MeO
H
spirotryprostatin A
flustramine A
Br
N
N
N
H
H
N
Me
OH
N
N
CF3
H
H
R
H
R
S
CF3
flustramine B
N
N
1 R = H
2 R = OMe
3 R = H
4 R = OMe
Figure 1 Examples of biologically active oxindoles and derivatives
S
Ph
Ph
As oxindoles play an important role in medicinal chemis-
try, the development of new strategies for the construction
of enantioenriched oxindoles has been one of the focuses
in chemical synthesis.5–12 Among them, conjugate addi-
tions, recognized as one of the most fundamental C–C
CF3
N
N
H
H
O
N
HN
S
Me
CF3
Me
S
O
N
N
H
H
N
6
Me
Me
5
SYNTHESIS 2011, No. 12, pp 1847–1852
x
x.
x
x
.
2
0
1
1
Advanced online publication: 13.05.2011
DOI: 10.1055/s-0030-1260463; Art ID: C00611SS
© Georg Thieme Verlag Stuttgart · New York
Figure 2 Organocatalysts used in asymmetric conjugate addition
reaction of 3-ylideneoxindoles

1848
S.-W. Duan et al.
PAPER
optimal catalyst in the subsequent experiments. The ex-
amination of the additives showed that there was little im-
pact on the diastereoselectivities in the presence of
different kinds of additives (entries 6–8). Excellent enan-
tioselectivities and yields could be obtained in all cases.
Table 1 Screening Study for Asymmetric Conjugate Addition with
3-Ylideneoxindoles 7¢a
EtO2C
O
O
O
N
Table 2 Effect of Various Additives on the Stereoselectivity of the
Conjugate Addition Reaction to 7aa
R
7′
catalyst (10 mol%)
solvent, 0.5 M, r.t.
CO2Et
*
PrO2C
+
O
O
O
N
R
9′
O
O
O
8
N
Me
7a
Entry
R
Cat.
Solvent
Time Yield drc
ee
(h)
(%)b
90
83
93
81
91
83
98
95
92
85
93
88
(%)c
CO2Pr
catalyst (10 mol%)
+
toluene
additive
r.t.
1
2
H
1
2
3
4
5
6
5
5
5
5
5
5
Et2O
8
64:36
63:37
60:40
58:42
59:41
67:33
60:40
66:34
69:31
65:35
64:36
60:40
6, 8
O
N
O
O
Me
H
Et2O
29
7
4, 10
9a
8
3
H
Et2O
89, 84
80, 80
78, 93
82, 79
88, 84
88, 89
95, 95
94, 94
93, 93
98, 98
Entry Concn Cat. Additive
Yield drc
(%)b
ee
(%)c
4
H
Et2O
6
of 7a (M)
(equiv)
5
H
Et2O
6
1
2
3
4
5
6
7
8
1
5
5
5
5
3
3
3
3
none
98
96
95
97
98
98
96
64:36
70:30
>99, 98
6
H
toluene
toluene
toluene
toluene
THF
10
2
0.5
none
>99, 98
7
H
0.25
0.1
none
72:28
71:29
73:27
72:28
70:30
70:30
>99, 98
8
Bn
Me
Me
Me
Me
2
none
>99, 98
9
2
0.1
none
>99, >99
>99, >99
>99, >99
>99, >99
10
11
12
3
0.1
H2O (1.0)
NH4OAc (1.0)
H2O
1
0.1
acac
1
0.1
PhCO2H (0.05) 97
a A mixture of 7¢ (0.25 mmol), catalyst 1–6 (0.025 mmol), and acetyl-
acetone (8; 0.75 mmol, 75 mL) in solvent was stirred at r.t.
b Isolated yield.
a A mixture of 7a, catalyst 3 or 5 (0.025 mmol), and acetylacetone (8;
0.75 mmol, 75 mL) in toluene (2.5 mL) was stirred at r.t.
b Isolated yield.
c Determined by chiral HPLC analysis.
c Determined by chiral HPLC analysis.
smoothly in the presence of a variety of reaction media
(Table 1, entries 9–12). It was found that toluene was su-
perior to other solvents in terms of the stereoselectivity
and reaction efficiency (Table 1, entry 9). Notably, we
found that water was also suitable for this asymmetric
procedure (Table 1, entry 11).
The substrate scope of the enantioselective conjugate ad-
dition reaction was investigated under the optimized con-
ditions. The reactions between acetylacetone (8) and 3-
ylideneoxindoles 7 of different substitution patterns pro-
ceeded in 43:57 to 83:17 dr, and most of the diastereoiso-
mers were generated in more than 90% ee (Table 3,
entries 1–9). For both electron-rich (Table 3, entry 5) and
electron-poor oxindoles (Table 3, entries 2–4 and 6–9),
the corresponding products could be obtained in high
enantiomeric excess and always in excellent yields. The
reactions were completed fast with little effect from the
substituent group at C5–C7 positions. Furthermore, the
nucleophile scope can be extended to nitromethane
(Table 3, entry 10).
Further optimization of the reaction conditions was car-
ried out by changing the ester group on the 3-ylideneoxin-
dole, including methyl ester, n-propyl ester, benzyl ester,
n-butyl, and tert-butyl ester. The reaction appears quite
general with respect to the nature of the ester group. Pre-
liminary studies revealed that a slight improvement was
achieved when n-propyl was introduced as the ester group
(see Supporting Information for details).
Experiments to probe the concentration of propyl (E)-2-
(2-oxoindolin-3-ylidene)acetate (7a) showed that lower
concentration could slightly improve distereoselectivity
without influence on the yields and ee (Table 2, entries 1–
4). As catalyst 3 gave better results at low concentration
than catalyst 5 (Table 2, entry 5 vs 4), 3 was chosen as the
In conclusion, we have developed an asymmetric Michael
addition reaction of 3-ylideneoxindoles and acetylacetone
by means of readily accessible bifunctional organocata-
lyst. The reaction exhibits excellent enantioselectivities
and provides an efficient synthesis of enantiomerically
enriched polysubstituted oxindoles under benign condi-
Synthesis 2011, No. 12, 1847–1852 © Thieme Stuttgart · New York

PAPER
Synthesis of Highly Enantioenriched Oxindole Derivatives
1849
tromethane adduct] to give the corresponding conjugate adduct 9
(Table 3).
Table 3 Scope of the Asymmetric Conjugate Addition Reaction
with 3-Ylideneoxindoles 7a
PrO2C
Propyl 3-Acetyl-2-(1-methyl-2-oxoindolin-3-yl)-4-oxopen-
tanoate (9a)
4
5
R
6
Yield: 97%; light yellow oil; >99%, >99% ee; 73:27 dr. HPLC:
Chiralpak AD-H column; detected at 254 nm; hexane–i-PrOH
O
O
O
7
N
(90:10); flow:
1
mL/min; tR1 (major) = 26.87 min, tR1
Me
4
5
(minor) = 33.32 min; tR2 (major) = 39.34 min, tR2 (minor) = 44.43
min.
7
R
3 (10 mol%), toluene
CO2Pr
+
6
r.t. or –60 °C
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.49) = 7.27–7.31
(m, 3 H, major + minor), 7.02–7.08 (m, 1.5 H, major + minor),
6.80–6.82 (m, 1.5 H, major + minor), 4.79 (d, J = 12 Hz, 1 H, ma-
jor), 4.47 (d, J = 12 Hz, 1 H, minor), 4.28 (dd, J = 12, 6 Hz, 1 H, mi-
nor), 4.07 (dd, J = 12, 6 Hz, 1 H, major), 3.81 (t, J = 6 Hz, 2 H,
major), 3.68–3.76 (m, 2 H, minor), 3.66 (d, J = 6 Hz, 1 H, major),
3.37 (s, 1 H, minor), 3.22 (s, 3 H, minor), 3.18 (s, 3 H, major), 2.35
(s, 3 H, major), 2.30 (s, 3 H, major), 2.24 (s, 3 H, major), 2.20 (s, 3
H, minor), 1.26–1.39 (m, 3 H, major + minor), 0.72–0.75 (m, 4.5 H,
major + minor).
13C NMR (150 MHz, CDCl3): d (major + minor) = 202.1, 201.9,
201.9, 201.5, 175.2, 174.9, 171.1, 170.2, 144.3, 144.0, 128.7, 128.4,
125.6, 124.9, 124.3, 124.2, 122.3, 122.3, 108.0, 107.9, 69.1, 66.8,
66.7, 66.2, 45.8, 45.2, 44.5, 43.8, 30.3, 29.7, 26.2, 25.9, 21.3, 10.0.
7
O
O
N
O
Me
9
8
Entry
R
Time (h) Yield (%)b
drc
ee (%)c
>99, >99
>99, 93
>99, 91
>99, >99
95, 92
1d
2
H
3
2
9a
9b
9c
9d
9e
9f
97
98
95
96
98
98
97
95
94
90
73:27
81:19
83:17
80:20
43:57
80:20
78:22
72:28
75:25
52:48
5-F
3
5-Br
5-CF3
5-Me
6-Cl
6-Br
7-F
8
4
2
5d
6
8
HRMS (EI+): m/z [M+] calcd for C19H23NO5: 345.1576; found:
345.1573.
84
35
3
>99, >99
>99, >99
>99, 90
>99, 84
96, 96
7
9g
9h
9i
Propyl 3-Acetyl-2-(5-fluoro-1-methyl-2-oxoindolin-3-yl)-4-oxo-
pentanoate (9b)
Yield: 98%; light yellow oil; >99%, 93% ee; 81:19 dr. HPLC:
Chiralpak OD-H column; detected at 254 nm; hexane–i-PrOH
(80:20); flow: 1 mL/min; tR1 (minor) = 8.76 min, tR1 (major) = 10.23
min; tR2 (minor) = 11.76 min, tR2 (major) = 15.70 min.
8
9
5-Cl, 6-Br
H
3
10d,e
15
9j
a A mixture of 7 (0.25 mmol), 3 (0.025 mmol), and acetylacetone (8;
1.5 mmol, 0.15 mL) in toluene (2.5 mL) was stirred at –60 °C, unless
otherwise noted.
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.57) = 7.06–7.10
(m, 1.6 H, major + minor), 6.99–7.02 (m, 1.6 H, major + minor),
6.73–6.75 (m, 1.6 H, major + minor), 4.84 (d, J = 12 Hz, 1 H, ma-
jor), 4.46 (d, J = 12 Hz, 1 H, minor), 4.23 (d, J = 12 Hz, 1 H, minor),
4.03 (d, J = 12 Hz, 1 H, major), 3.74–3.83 (m, 3.2 H, major + mi-
nor), 3.65 (s, 1 H, major), 3.39 (s, 1 H, minor), 3.21 (s, 3 H, minor),
3.17 (s, 3 H, major), 2.36 (s, 3 H, minor), 2.35 (s, 3 H, major), 2.28
(s, 3 H, major), 2.23 (s, 3 H, minor), 1.30–1.41 (m, 3.4 H, major +
minor), 0.75 (t, J = 6 Hz, 4.7 H, major + minor).
13C NMR (150 MHz, CDCl3): d (major + minor) = 201.9, 201.9,
201.8, 201.3, 174.8, 174.6, 170.8, 170.0, 159.7, 159.4, 158.1, 157.8,
140.3, 140.0, 129.2, 127.5, 127.4, 126.5, 114.9, 114.8, 114.6, 114.5,
112.7, 112.6, 112.4, 112.3, 108.4, 108.3, 108.3, 68.6, 67.0, 66.8,
66.1, 45.5, 45.1, 44.7, 44.0, 30.4, 30.3, 29.8, 27.8, 26.3, 26.1, 21.3,
9.9.
b Isolated yield.
c Determined by chiral HPLC analysis.
d Reaction was carried out at r.t.
e Nitromethane (6 equiv) was used as the nucleophile.
tions. Further application of the current methodology for
the synthesis of more complex heterocyclic systems is un-
derway in our laboratory.
1
Unless otherwise indicated, H NMR spectra were obtained on a
Bruker Avance 600 spectrometer operating at 600 MHz, with TMS
as an internal standard. J values are given in Hz. 13C NMR spectra
were obtained on a Bruker Avance 600 spectrometer operating at
150 MHz. Enantiomeric excess values were determined using
HPLC (see individual compounds for details) with a UV detector at
254 nm. All solvents were purified by standard procedures prior to
use. See the Supporting Information for the detailed preparation and
NMR spectra of the 3-ylideneoxindoles.
HRMS (EI+): m/z [M+] calcd for C19H22FNO5: 363.1482; found:
363.1492.
Propyl 3-Acetyl-2-(5-bromo-1-methyl-2-oxoindolin-3-yl)-
4-oxopentanoate (9c)
Yield: 95%; semi-solid; >99%, 91% ee; 83:17 dr. HPLC: Chiralpak
OD-H column; detected at 254 nm; hexane–i-PrOH (80:20); flow:
1 mL/min; tR1 (minor) = 10.39 min, tR1 (major) = 11.55 min; tR2
(minor) = 14.19 min, tR2 (major) = 18.85 min.
Conjugate Additions of 3-Ylideneoxindoles and Acetylacetone;
General Procedure
To a mixture of 3-ylideneoxindole 7 (0.25 mmol), catalyst 3 (0.025
mmol, 14.1 mg) in toluene (2.5 mL) was added acetylacetone (8; 1.5
mmol, 0.15 mL) or nitromethane (1.5 mmol, 81 mL) at r.t. or –60 °C.
The resulting solution was stirred at a constant temperature until the
reaction was found to be complete by TLC analysis. The crude
product was purified by silica gel chromatography [petroleum ether
(bp 60–90 °C)–EtOAc, 2:1 for acetylacetone adducts or 5:1 for ni-
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.25) = 7.32–7.59
(m, 2.5 H, major + minor), 6.69–6.81 (m, 1.3 H, major + minor),
4.86 (d, J = 12 Hz, 1 H, major), 4.44 (dd, J = 12, 6 Hz, 1 H, minor),
4.02 (dd, J = 12, 6 Hz, 1 H, major), 3.73–3.81 (m, 2.5 H, major +
minor), 3.64 (s, 1 H, major), 3.40 (s, 1 H, minor), 3.31 (s, 1 H, mi-
nor), 3.20 (s, 3 H, minor), 3.16 (s, 3 H, major), 2.36 (s, 3 H, minor),
2.35 (s, 3 H, major), 2.29 (s, 3 H, major), 2.22 (s, 3 H, minor), 1.31–
Synthesis 2011, No. 12, 1847–1852 © Thieme Stuttgart · New York

1850
S.-W. Duan et al.
PAPER
1.40 (m, 2.5 H, major + minor), 0.76 (t, J = 9 Hz, 3 H, major), 0.57–
0.66 (m, 3 H, minor).
13C NMR (150 MHz, CDCl3): d (major + minor) = 201.9, 201.8,
201.2, 174.6, 170.8, 143.1, 131.1, 128.0, 127.2, 114.9, 109.3, 67.0,
66.9, 66.2, 45.6, 45.1, 44.4, 43.6, 30.5, 29.8, 26.1, 21.4, 10.0.
J = 12 Hz, 1 H, major), 7.00 (d, J = 6 Hz, 1 H, minor), 4.80 (d,
J = 12 Hz, 1 H, major), 4.44 (d, J = 6 Hz, 1 H, minor), 4.24 (dd,
J = 12, 6 Hz, 1 H, minor), 4.03 (dd, J = 12, 6 Hz, 1 H, major), 3.83
(t, J = 6 Hz, 2 H, major), 3.70–3.78 (m, 2 H, minor), 3.63 (d, J = 6
Hz, 1 H, major), 3.35 (d, J = 6 Hz, 1 H, minor), 3.20 (s, 3 H, minor),
3.15 (s, 3 H, major), 2.35 (s, 3 H, minor), 2.34 (s, 3 H, major), 2.26
(s, 3 H, major), 2.21 (s, 3 H, minor), 1.32–1.41 (m, 2.9 H, major +
minor), 0.75 (t, J = 9 Hz, 4.5 H, major + minor).
Anal. Calcd for C19H22BrNO5: C, 53.79; H, 5.23; N, 3.30. Found: C,
53.19; H, 5.57; N, 3.24.
13C NMR (150 MHz, CDCl3): d (major + minor) = 202.0, 201.8,
201.8, 201.3, 175.2, 174.9, 170.8, 170.0, 145.6, 145.2, 134.5, 134.1,
125.2, 125.1, 124.2, 123.3, 122.1, 122.1, 108.7, 108.6, 68.8, 67.0,
66.9, 66.1, 62.9, 45.6, 45.1, 44.1, 43.4, 30.4, 30.2, 29.8, 27.8, 26.3,
26.1, 21.4, 10.0.
Propyl 3-Acetyl-2-[1-methyl-2-oxo-5-(trifluoromethoxy)indo-
lin-3-yl]-4-oxopentanoate (9d)
Yield: 96%; light yellow oil; >99%, >99% ee; 80:20 dr. HPLC:
Chiralpak OD-H column; detected at 254 nm; hexane–i-PrOH
(80:20); flow: 1 mL/min; tR1 (minor) = 7.54 min, tR1 (major) = 8.56
min; tR2 (minor) = 11.78 min, tR2 (major) = 19.00 min.
HRMS (EI+): m/z [M+] calcd for C19H22ClNO5: 379.1187; found:
379.1194.
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.30) = 7.18–7.24
(m, 2.6 H, major + minor), 6.80–6.82 (m, 1.3 H, major + minor),
4.87 (d, J = 12 Hz, 1 H, major), 4.43 (d, J = 12 Hz, 1 H, minor), 4.21
(dd, J = 12, 6 Hz, 1 H, minor), 4.04 (dd, J = 12, 6 Hz, 1 H, major),
3.78–3.82 (m, 2.6 H, major + minor), 3.68 (s, 1 H, major), 3.48 (s,
1 H, minor), 3.23 (s, 3 H, minor), 3.19 (s, 3 H, major), 2.36 (s, 3.9
H, major + minor), 2.29 (s, 3 H, major), 2.20 (s, 3 H, minor), 1.33–
1.37 (m, 2.6 H, major + minor), 0.71–0.77 (m, 3.9 H, major + mi-
nor).
Propyl 3-Acetyl-2-(6-bromo-1-methyl-2-oxoindolin-3-yl)-
4-oxopentanoate (9g)
Yield: 97%; light yellow oil; >99%, >99% ee; 78:22 dr. HPLC:
Chiralpak OD-H column; detected at 254 nm; hexane–i-PrOH
(85:15); flow:
1
mL/min; tR1 (minor) = 15.06 min, tR1
(major) = 17.13 min; tR2 (minor) = 20.33 min, tR2 (major) = 27.41
min.
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.33) = 7.13–7.21
(m, 2.7 H, major + minor), 6.95 (s, 1.3 H, major + minor), 4.80 (d,
J = 12 Hz, 1 H, major), 4.43 (d, J = 12 Hz, 1 H, minor), 4.23 (dd,
J = 12, 6 Hz, 1 H, minor), 4.03 (dd, J = 12, 6 Hz, 1 H, major), 3.71–
3.83 (m, 2.6 H, major + minor), 3.60 (s, 1 H, major), 3.32 (s, 1 H,
minor), 3.20 (s, 3 H, minor), 3.16 (s, 3 H, major), 2.34 (s, 4 H, major
+ minor), 2.26 (s, 3 H, major), 2.21 (s, 3 H, minor), 1.31–1.42 (m,
2.7 H, major + minor), 0.75 (t, J = 9 Hz, 4 H, major + minor).
13C NMR (150 MHz, CDCl3): d (major + minor) = 201.9, 201.8,
201.2, 175.0, 174.7, 170.8, 170.0, 144.4, 144.2, 143.1, 142.8, 127.5,
126.7, 121.9, 121.6, 118.6, 118.3, 108.3, 108.3, 68.6, 67.1, 66.9,
66.1, 45.5, 45.2, 44.7, 43.9, 30.6, 30.3, 29.9, 27.9, 26.4, 26.1, 21.3,
9.8.
HRMS (EI+): m/z [M+] calcd for C20H22F3NO6: 429.1399; found:
429.1395.
13C NMR (150 MHz, CDCl3): d (major + minor) = 202.0, 201.8,
201.3, 191.2, 175.1, 174.8, 170.8, 170.0, 145.7, 145.4, 125.6, 125.4,
125.1, 124.8, 123.9, 122.3, 121.9, 111.4, 68.9, 67.0, 66.9, 66.1,
45.6, 45.1, 44.2, 43.5, 30.5, 30.3, 29.8, 27.8, 26.3, 26.1, 21.4, 10.0.
HRMS (EI+): m/z [M+] calcd for C19H22BrNO5: 423.0681; found:
423.0681.
Propyl 3-Acetyl-2-(1,5-dimethyl-2-oxoindolin-3-yl)-4-oxopen-
tanoate (9e)
Yield: 98%; light yellow oil; 95%, 92% ee; 43:57 dr. HPLC: Chiral-
pak AS-H column; detected at 254 nm; hexane–i-PrOH (80:20);
flow: 1 mL/min; tR1 (minor) = 7.57 min, tR1 (major) = 9.51 min; tR2
(minor) = 11.91 min, tR2 (major) = 21.31 min.
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.39) = 7.08–7.13
(t, 2.8 H, major + minor), 6.68–6.70 (m, 1.4 H, major + minor), 4.81
(d, J = 12 Hz, 1 H, major), 4.47 (d, J = 12 Hz, 1 H, minor), 4.26 (dd,
J = 12, 6 Hz, 1 H, minor), 4.04 (dd, J = 12, 6 Hz, 1 H, major), 3.78–
3.85 (m, 2 H, major), 3.68–3.76 (m, 2 H, minor), 3.61 (d, J = 6 Hz,
1 H, major), 3.32 (d, J = 6 Hz, 1 H, minor), 3.20 (s, 3 H, minor),
3.15 (s, 3 H, major), 2.35 (s, 3 H, minor), 2.34 (s, 3 H, major), 2.33
(s, 3 H, minor), 2.31 (s, 3 H, major), 2.25 (s, 3 H, major), 2.20 (s, 3
H, minor), 1.26–1.39 (m, 3.8 H, major + minor), 0.72–0.76 (m, 4.2
H, major + minor).
13C NMR (150 MHz, CDCl3): d (major + minor) = 202.2, 202.0,
201.9, 201.5, 175.1, 174.8, 171.1, 170.2, 141.9, 141.6, 131.9, 131.8,
128.9, 128.5, 125.7, 125.0, 124.9, 107.7, 107.6, 95.1, 69.2, 66.8,
66.7, 66.3, 62.9, 45.8, 45.3, 44.6, 43.9, 30.4, 30.2, 29.7, 27.6, 26.2,
25.9, 21.4, 20.9, 10.0.
Propyl 3-Acetyl-2-(7-fluoro-1-methyl-2-oxoindolin-3-yl)-4-oxo-
pentanoate (9h)
Yield: 95%; light yellow oil; >99%, 90% ee; 72:28 dr. HPLC:
Chiralpak OD-H column; detected at 254 nm; hexane–i-PrOH
(80:20); flow: 1 mL/min; tR1 (minor) = 7.75 min, tR1 (major) = 9.71
min; tR2 (minor) = 11.86 min, tR2 (major) = 14.59 min.
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.40) = 7.06–7.11
(m, 1.4 H, major + minor), 6.97–7.03 (m, 2.8 H, major + minor),
4.86 (d, J = 12 Hz, 1 H, major), 4.45 (d, J = 12 Hz, 1 H, minor), 4.27
(dd, J = 12, 6 Hz, 1 H, minor), 4.04 (dd, J = 12, 6 Hz, 1 H, major),
3.72–3.85 (m, 2.8 H, major + minor), 3.66 (s, 1 H, major), 3.43 (s,
3 H, minor), 3.39 (s, 3 H, major), 2.35 (s, 4.1 H, major + minor),
2.28 (s, 3 H, major), 2.22 (s, 3 H, minor), 1.32–1.40 (m, 2.8 H, ma-
jor + minor), 0.73–0.78 (m, 4.2 H, major + minor).
13C NMR (150 MHz, CDCl3): d (major + minor) = 202.1, 201.8,
201.3, 174.9, 174.6, 170.8, 170.0, 148.2, 146.5, 130.7, 130.7, 128.8,
122.9, 122.9, 119.9, 116.3, 116.2, 69.0, 67.0, 66.9, 66.2, 45.9, 45.4,
44.7, 43.9, 30.6, 30.3, 29.8, 28.5, 28.4, 27.7, 21.4, 10.0.
HRMS (EI+): m/z [M+] calcd for C20H25NO5: 359.1733; found:
359.1734.
Propyl 3-Acetyl-2-(6-chloro-1-methyl-2-oxoindolin-3-yl)-4-oxo-
pentanoate (9f)
HRMS (EI+): m/z [M+] calcd for C19H22FNO5: 363.1482; found:
Yield: 98%; light yellow oil; >99%, >99% ee; 80:20 dr. HPLC:
Chiralpak OD-H column; detected at 254 nm; hexane–i-PrOH
363.1475.
(85:15); flow:
1
mL/min; tR1 (minor) = 12.82 min, tR1
Propyl 3-Acetyl-2-(6-bromo-5-chloro-1-methyl-2-oxoindolin-3-
yl)-4-oxopentanoate (9i)
(major) = 14.99 min; tR2 (minor) = 18.45 min, tR2 (major) = 25.53
min.
Yield: 94%; semi-solid; >99%, 84% ee; 75:25 dr. HPLC: Chiralpak
OD-H column; detected at 254 nm; hexane–i-PrOH (80:20); flow:
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.49) = 7.23 (d,
J = 12 Hz, 1 H, major), 7.20 (d, J = 12 Hz, 1 H, minor), 7.04 (d,
Synthesis 2011, No. 12, 1847–1852 © Thieme Stuttgart · New York

PAPER
Synthesis of Highly Enantioenriched Oxindole Derivatives
1851
1 mL/min; tR1 (minor) = 15.10 min, tR1 (major) = 17.00 min; tR2
Cook, J. M. Org. Lett. 2002, 4, 4237. (g) Bagul, T. D.;
(minor) = 22.20 min, tR2 (major) = 31.37 min.
Lakshmaiah, G.; Kawabata, T.; Fuji, K. Org. Lett. 2002, 4,
249. (h) Malinakova, H. C.; Liebeskind, L. S. Org. Lett.
2000, 2, 4083.
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.31) = 7.41 (s, 1
H, major), 7.36 (s, 1 H, minor), 7.06 (d, 1.3 H, major + minor), 4.84
(d, J = 12.0 Hz, 1 H, major), 4.43 (d, J = 12.0 Hz, 1 H, minor), 4.19
(dd, J = 12.0, 6 Hz, 1 H, minor), 4.01 (dd, J = 12.0, 6 Hz, 1 H, ma-
jor), 3.78–3.84 (m, 2.7 H, major + minor), 3.60 (d, J = 6 Hz, 1 H,
major), 3.37 (d, J = 6 Hz, 1 H, minor), 3.19 (s, 3 H, minor), 3.15 (s,
3 H, major), 2.36 (s, 4 H, major + minor), 2.30 (s, 3 H, major), 2.23
(s, 3 H, minor), 1.35–1.43 (m, 2.7 H, major + minor), 0.75–0.79 (m,
4 H, major + minor).
13C NMR (150 MHz, CDCl3): d (major + minor) = 201.9, 201.8,
201.1, 191.2, 174.6, 174.3, 170.6, 169.8, 143.9, 143.6, 127.7, 127.6,
126.9, 126.0, 126.0, 125.6, 122.2, 121.8, 112.8, 68.4, 67.2, 67.0,
66.1, 45.4, 44.9, 44.2, 43.4, 30.5, 30.3, 29.8, 27.9, 26.4, 26.2, 21.4,
10.0.
(2) For selected examples, see: (a) Ding, K.; Lu, Y.-P.;
Nikolovska-Coleska, Z.; Qiu, S.; Ding, Y. S.; Gao, W.;
Stuckey, J.; Krajewski, K.; Roller, P. P.; Tomita, Y.; Parrish,
D. A.; Deschamps, J. R.; Wang, S.-M. J. Am. Chem. Soc.
2005, 127, 10130. (b) Hewawasam, P.; Erway, M.; Moon, S.
L.; Knipe, J.; Weiner, H.; Boissard, C. G.; Post-Munson, D.
J.; Gao, Q.; Huang, S.; Gribkoff, V. K.; Meanwell, N. A.
J. Med. Chem. 2002, 45, 1487. (c) Tokunaga, T.; Hume, W.
E.; Umezome, T.; Okazaki, K.; Ueki, Y.; Kumagai, K.;
Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.;
Nagata, R. J. Med. Chem. 2001, 44, 4641.
(3) (a) Edmondson, S. D.; Danishefsky, S. J. Angew. Chem. Int.
Ed. 1998, 37, 1138. (b) Cui, C.-B.; Kakeya, H.; Osada, H.
Tetrahedron 1997, 53, 59. (c) Cui, C.-B.; Kakeya, H.;
Osada, H. Tetrahedron 1996, 52, 12651.
(4) (a) Carle, J. S.; Christophersen, C. J. Org. Chem. 1980, 45,
1586. (b) Carle, J. S.; Christophersen, C. J. Am. Chem. Soc.
1979, 101, 4012.
(5) For asymmetric Heck reactions, see: (a) Dounay, A. B.;
Overman, L. E. Chem. Rev. 2003, 103, 2945. For selected
examples, see: (b) Ruck, R. T.; Huffman, M. A.; Kim, M.
M.; Shevlin, M.; Kandur, W. V.; Davies, I. W. Angew.
Chem. Int. Ed. 2008, 47, 4711. (c) Dounay, A. B.;
Hatanaka, K.; Kodanko, J. J.; Oestreich, M.; Overman, L. E.;
Pfeifer, L. A.; Weiss, M. M. J. Am. Chem. Soc. 2003, 125,
6261.
(6) For selected asymmetric aldol reactions, see: (a) Hanhan,
N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.; Franz, A.
K. Angew. Chem. Int. Ed. 2010, 49, 744. (b) Ellis, J. M.;
Overman, L. E.; Tanner, H. R.; Wang, J. J. Org. Chem. 2008,
73, 9151. (c) Chen, J.-R.; Liu, X.-P.; Zhu, X.-Y.; Li, L.;
Qiao, Y.-F.; Zhang, J.-M.; Xiao, W.-J. Tetrahedron 2007,
63, 10437. (d) Ogawa, S.; Shibata, N.; Inagaki, J.;
Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem. Int. Ed.
2007, 46, 8666.
HRMS (EI+): m/z [M+] calcd for C19H21BrClNO5: 457.0292; found:
457.0298.
Propyl 2-(1-Methyl-2-oxoindolin-3-yl)-3-nitropropanoate (9j)
Yield: 90%; light yellow oil; 96%, 96% ee; 52:48 dr. HPLC: Chiral-
pak AD-H column; detected at 254 nm; hexane–i-PrOH (70:30);
flow: 1 mL/min; tR1 (major) = 7.11 min, tR1 (minor) = 8.88 min; tR2
(major) = 8.36 min, tR2 (minor) = 9.46 min.
1H NMR (600 MHz, CDCl3): d (major/minor = 1:0.85) = 7.34 (t,
J = 9 Hz, 1.9 H, major + minor), 7.23 (d, J = 6 Hz, 1 H, minor), 7.16
(d, J = 6 Hz, 1 H, major), 7.06–7.09 (m, 1.9 H, major + minor), 6.87
(d, J = 6 Hz, 1.8 H, major + minor), 4.94 (dd, J = 18, 12 Hz, 1 H,
minor), 4.72 (dd, J = 12, 12 Hz, 1 H, major), 4.36–4.42 (m, 1.9 H,
major + minor), 4.00–4.14 (m, 5.7 H, major + minor), 3.89–3.92 (m,
1.9 H, major + minor), 3.22 (s, 3 H, major), 3.22 (s, 3 H, minor),
1.52–1.62 (m, 3.7 H, major + minor), 0.84–0.89 (m, 5.7 H, major +
minor).
13C NMR (150 MHz, CDCl3): d (major + minor) = 174.3, 174.1,
169.8, 169.2, 144.3, 144.1, 129.2, 129.0, 124.3, 124.1, 123.9, 123.8,
122.8, 108.4, 72.2, 71.9, 67.5, 67.4, 44.5, 43.3, 43.0, 26.3, 26.2,
21.6, 21.5, 10.1.
(7) For selected asymmetric alkylation reactions, see: (a) Trost,
B. M.; Zhang, Y. Chem. Eur. J. 2011, 17, 2916. (b) Vyas,
D. J.; Fröhlich, R.; Oestreich, M. J. Org. Chem. 2010, 75,
6720. (c) Ma, S.; Han, X.-Q.; Krishnan, S.; Virgil, S. C.;
Stoltz, B. M. Angew. Chem. Int. Ed. 2009, 48, 8037.
(d) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2007, 129,
14548. (e) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006,
128, 4590. (f) Trost, B. M.; Frederiksen, M. U. Angew.
Chem. Int. Ed. 2004, 43, 308.
HRMS (EI+): m/z [M+] calcd for C15H18N2O5: 306.1216; found:
306.1218.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
(8) For selected asymmetric hydroxylation reaction, see:
(a) Sano, D.; Nagata, K.; Itoh, T. Org. Lett. 2008, 10, 1593.
(b) Ishimaru, T.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru,
T.; Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488.
(9) For selected asymmetric ring-expansion reactions, see:
(a) Meyers, C.; Carreira, E. M. Angew. Chem. Int. Ed. 2003,
42, 694. (b) Lerchner, A.; Carreira, E. M. J. Am. Chem. Soc.
2002, 124, 14826. (c) Alper, P. B.; Meyers, C.; Lerchner,
A.; Siegel, D. R.; Carreira, E. M. Angew. Chem. Int. Ed.
1999, 38, 3186.
(10) For selected asymmetric 1,4- and 1,2-addition reactions,
see: (a) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Cun, L.-F.;
Zhang, X.-M. Org. Lett. 2010, 12, 2896. (b) Li, X.; Zhang,
B.; Xi, Z.-G.; Luo, S.-Z.; Cheng, J.-P. Adv. Synth. Catal.
2010, 352, 416. (c) He, R.-J.; Shirakawa, S.; Maruoka, K.
J. Am. Chem. Soc. 2009, 131, 16620. (d) Bui, T.; Syed, S.;
Barbas, C. F. J. Am. Chem. Soc. 2009, 131, 8758. (e) Kato,
Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9168. (f) Lai,
We are grateful to the National Science Foundation of China (NO.
20872043, 21072069, and 21002036), the National Basic Research
Program of China (2011CB808600), and the Program for Chang-
jiang Scholars and Innovation Research Team in University
(IRT0953) for support of this research.
References
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Synthesis 2011, No. 12, 1847–1852 © Thieme Stuttgart · New York

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H.-S.; Huang, Z.-Y.; Wu, Q.; Qin, Y. J. Org. Chem. 2009,
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W.; Xiao, W.-J. Org. Lett. 2010, 12, 5636. (d) Chen, J.-R.;
Cao, Y.-J.; Zou, Y.-Q.; Tan, F.; Fu, L.; Zhu, X.-Y.; Xiao,
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Wang, X.-F.; Yao, C.-J.; Zhang, J.-M.; Wu, H.; Xiao, W.-J.
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Synthesis 2011, No. 12, 1847–1852 © Thieme Stuttgart · New York