Enantioselective synthesis of 3,3′-dihydropyrryl-spirooxindoles via an organocatalytic three-component reaction

Article abstract of DOI:10.1039/c2ob25629k

An organocatalytic three-component reaction of isatins, malononitrile and isocyanoacetates provided 3,3′-dihydropyrryl-spirooxindoles in excellent yields and enantioselectivities. The products could be readily converted to valuable 3,3′-pyrrolidinyl-spiro

Full text of DOI:10.1039/c2ob25629k

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PAPER
Enantioselective synthesis of 3,3′-dihydropyrryl-spirooxindoles via an
organocatalytic three-component reaction†
Wen-Tao Wei, Chun-Xia Chen, Rui-Jiong Lu, Jin-Jia Wang, Xue-Jing Zhang and Ming Yan*
Received 27th March 2012, Accepted 17th May 2012
DOI: 10.1039/c2ob25629k
An organocatalytic three-component reaction of isatins, malononitrile and isocyanoacetates provided
3,3′-dihydropyrryl-spirooxindoles in excellent yields and enantioselectivities. The products could be
readily converted to valuable 3,3′-pyrrolidinyl-spirooxindoles.
Introduction
The 3,3′-pyrrolidinyl-spirooxindole scaffold is the common core
of a large family of alkaloids and medicinally relevant com-
pounds.1 Many chiral 3,3′-pyrrolidinyl-spirooxindoles, such as
coerulescine, horsfiline, spirotryprostatins A and elacomine show
interesting biological activities (Scheme 1). Extensive efforts
have been made to develop efficient synthetic methods for these
compounds.2 In recent years, organocatalytic cascade reactions
have proven to be extremely useful for the synthesis of chiral
cyclic compounds.3 A number of excellent examples have been
reported for the preparation of chiral spirooxindoles via organo-
catalytic cascade reactions.4 Wang and co-workers reported the
Scheme 1 Representative examples of bioactive 3,3′-pyrrolidinyl-
spirooxindole natural products.
organocatalytic double Michael addition of α,β-unsaturated
ketones to isatylidene malononitriles. 3,3′-Cyclohexanyl-spiroox-
indoles were obtained in excellent yields and enantioselectivi-
ties.4e Lu and co-workers developed an highly enantioselective
[3 + 2] annulation of Morita–Baylis–Hillman adducts and isatyli-
dene malononitriles catalyzed by threonine-derived chiral phos-
phines. The reaction provided chiral 3,3′-cyclopentenyl-
spirooxindoles efficiently.4i Yuan and co-workers reported the
organocatalytic three-component reactions of isatins, malononi-
trile and 1,3-dicarbonyl compounds. A range of 3,3′-(4H-
pyranyl)-spirooxindoles were obtained in good yields and enan-
tioselectivities.4j Recently we also found that the cascade
Michael–Michael–oxa-Michael reaction of curcumins and isaty-
lidene malononitriles provided multicyclic spirooxindoles in
excellent yields.4k Isocyanoacetates are highly attractive nucleo-
philic reagents for a number of cascade reactions and multi-com-
ponent reactions.5 Their α-protons are readily removed by bases
to generate nucleophilic anions. The resulting reaction
intermediates are subsequently trapped by the isocyano groups to
provide cyclic products. Asymmetric organocatalytic cascade
reaction of isocyanoacetates with aldehydes,6 imines,7 α,β-un-
saturated ketones,8 nitroolefins9 and azodicarboxylates10 have
been developed. A variety of chiral nitrogen-containing hetero-
cyclic compounds were obtained in good yields and enantio-
selectivities. In this paper, we report an organocatalytic three-
component reaction of isatins, malononitrile and isocyanoacetates.
Dihydropyrryl-spirooxindoles could be prepared in excellent
yields and enantioselectivities.
Results and discussion
Initially we examined the reaction of isatylidene malononitrile
and methyl isocyanoacetate 3a in the presence of Takemoto’s
catalyst 4c (Scheme 2, eqn (1)). The reaction gave 3,3′-dihydro-
pyrryl-spirooxindoles 5a and 5a′ in excellent yields and enantio-
selectivities. Since isatylidene malononitriles are readily
generated from isatin and malononitrile, we further investigated
the three-component reaction of isatin 1a, malononitrile 2a
and isocyanoacetate 3a. To our delight, similar yield,
Institute of Drug Synthesis and Pharmaceutical Process, School of
Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006,
China. E-mail: yanming@mail.sysu.edu.cn; Fax: +86-20-39943049
†Electronic supplementary information (ESI) available: Including the
characterization data of the products and HPLC chromatograms. CCDC
859158. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob25629k
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Furthermore, the effect of the reaction solvents was examined.
Slightly better yields were observed for the reactions in toluene,
ethyl acetate, acetonitrile and methanol; however, lower enantio-
selectivities were obtained (Table 1, entries 7–10). The reactions
in several other solvents also provided inferior results (Table 1,
entries 11–14). Decreasing the reaction temperature is slightly
beneficial to the enantioselectivity, but an extended reaction time
was required (Table 1, entries 15–17). The enantioselectivity and
diastereoselectivity remained almost unchanged while the cata-
lyst loading was reduced from 10 to 1 mol%; however, longer
reaction time was necessary (Table 1, entries 18–20). The 2 mol
% catalyst loading was preferred in terms of good yield and
reasonable reaction time (Table 1, entry 19).
With the optimized reaction conditions in hand, the three-
component reaction of isatins 1a–1k, malononitrile 2a and iso-
cyanoacetate 3a were investigated. The results are summarized in
Table 2. The influence of the N-substitution of isatins was firstly
studied. The N-benzyl substituted isatin 1b gave a similar yield
and enantioselectivities to N-methyl substituted isatin 1a, but
better diastereoselectivity was obtained (Table 2, entry 2). When
the N-unsubstituted isatin 1c was used, a slight loss of enantio-
selectivity was observed (Table 2, entry 3). The introduction of
electron-withdrawing groups such as tert-butoxylcarbonyl and
acetyl completely inhibited the reaction (Table 2, entries 4 and
5). A variety of isatins with substitutions at the benzene ring
were also examined (Table 2, entries 6–11). The 4-halogen
substitutions led to lower yields and enantioselectivities
(Table 2, entries 6 and 7). The substitutions of halogen and
methoxyl at 5, 6 or 7-position increased the diastereoselec-
tivities, but slightly decreased the yields and enantioselectivities
(Table 2, entries 8–11).
Scheme 2 Organocatalytic reactions of isocyanoacetate 3a with isatyli-
dene malononitrile.
The relative and absolute configurations of the product 5g
were determined by X-ray diffraction analysis (Fig. 1).† The
configurations of other products were assigned analogously.11
The effect of α-substituents on the isocyanoacetates was also
studied (Scheme 4). α-Unsubstituted isocyanoacetate 3b pro-
vided the spirooxindole 5l in good yield, but with poor enantio-
selectivity. In addition, the 1,5-double bond of the dihydropyrrole
ring migrated to the 1,2-position. The p-methoxyl-phenyl and
p-chloro-phenyl substituted isocyanoacetates 3c and 3d gave the
products with good yields and excellent enantioselectivities. The
o-chloro-phenyl substituted isocyanoacetate 3e is unreactive,
probably due to the streric hindrance. The α-isopropyl isocyano-
acetate 3f and α-benzyl isocyanoacetate 3g are also unreactive
in the transformation. The results confirm that the α-aryl
substitution is crucial for achieving good reactivity and
enantioselectivity.
Scheme 3 Organocatalysts examined in the reaction.
enantioselectivities and diastereoselectivities were observed
(Scheme 2, eqn (2)). The result suggests that the formation of
isatylidene malononitrile is fast enough and the reaction can be
carried out in one pot.
Cinchona alkaloids 4a–4b and chiral tertiary amine-thioureas
4c–4f were examined as the organocatalysts in the three-com-
ponent reaction of isatin 1a, malononitrile 2a and isocyano-
acetate 3a (Scheme 3). The results are summarized in Table 1.
Quinine 4a provided the products 5a/5a′ in good yield and
moderate enantioselectivities (Table 1, entry 1). The 6′-demethyl
quinine 4b gave similar yield, but with lower enantioselectivities
(Table 1, entry 2). Takemoto’s catalyst 4c provided excellent
yield and enantioselectivities (Table 1, entry 3). More sterically
demanding catalysts 4d and 4e led to lower enantioselectivities
(Table 1, entries 4–5). Tertiary amine-thiourea 4f derived from
quinine was found to give the product 5a with the best enantio-
selectivity (Table 1, entry 6).
Several analogous nucleophiles of malononitrile including
methyl cyanoacetate, diethyl malonate, and ethyl nitroacetate
were examined in the one pot reaction with isatin 1a and iso-
cyanoacetate 3a, but no expected 3,3′-dihydropyrryl-spiro-
oxindole was obtained.
A plausible reaction mechanism is proposed (Scheme 5).4j
Initially the fast Knoevenagel condensation of isatin 1a and
malononitrile 2a affords isatylidene malononitrile. The deproto-
nation of methyl α-phenyl-isocyanoacetate 3a in the presence of
organocatalyst 4f generates the nucleophilic anion, which is
expected to form an ion pair with protonated 4f. In addition, the
H-bond interaction of 4f with isatylidene malononitrile increases
5246 | Org. Biomol. Chem., 2012, 10, 5245–5252
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Table 1 Catalyst screening and the optimization of reaction conditionsa
En
Cat. (mol%)
Solvent
T (°C)
Time (h)
Yieldb (%)
5a : 5a′c
eed (%)
1
2
3
4
5
6
7
8
4a (10)
4b (10)
4c (10)
4d (10)
4e (10)
4f (10)
4f (10)
4f (10)
4f (10)
4f (10)
4f (10)
4f (10)
4f (10)
4f (10)
4f (10)
4f (10)
4f (10)
4f (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
AcOEt
CH3CN
CH3OH
1,4-Dioxane
(CH2Cl)2
THF
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
2
5
3
1
3
2
1
2
8
1
4
20
20
1
80
82
90
85
83
89
93
94
95
93
90
90
73
84
92
88
83
92
92
85
84 : 16
75 : 25
80 : 20
80 : 20
67 : 33
80 : 20
78 : 22
80 : 20
73 : 27
80 : 20
78 : 22
78 : 22
86 : 14
75 : 15
78 : 22
78 : 22
80 : 20
78 : 22
78 : 22
80 : 20
56/35
0/12
95/96
88/90
92/95
97/94
93/95
93/93
78/72
0/13
92/94
95/95
93/92
96/92
97/95
98/95
99/96
97/94
97/94
97/94
9
10
11
12
13
14
15
16
17
18
19
20
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
4
−20
−40
RT
RT
RT
12
20
3
8
30
4f (2)
4f (1)
a The reactions were carried out with 1a (0.050 mmol), 2a (0.050 mmol) and 3a (0.055 mmol). b Combined yields of 5a and 5a′ after column
chromatography. c Determined by 1H NMR analysis of the crude reaction mixture. d Determined by chiral HPLC.
its electrophilic reactivity and also directs the attack of the
isocyanoacetate anion from the si-face of the double bond.
The resulting intermediate B undergoes the intramolecular
cycloaddition to give the products 5a/5a′. The π–π interaction of
isatylidene malononitrile with α-phenyl-isocyanoacetate anion
accounts for the preferential formation of 5a.
The product 5a was further treated with NaBH3CN.
Selective reduction of the imine group was achieved to give 3,3′-
pyrrolidinyl-spirooxindole 6a in excellent yield and enantio-
selectivity (Scheme 6).
Experimental
General
1a (32.2 mg, 0.200 mmol), 2a (13.2 mg, 0.200 mmol), 3a
(38.8 mg, 0.220 mmol), 4f (2.3 mg, 0.004 mmol) and dichloro-
methane (2 mL) in a flask were stirred at room temperature for
8 h. After evaporation of the solvent under vacuum, the residue
was separated by flash chromatography over silica gel to give 5a
and 5a′ (70.6 g, 92% yield) as white solids.
(2′S,3R)-Methyl-4′,4′-dicyano-1-methyl-2-oxo-2′-phenyl-2′,4′-
dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5a). The
product was obtained following the general procedure.
1
White solid. Mp 239–241 °C; H NMR (400 MHz, CDCl3) δ:
Conclusion
8.17 (s, 1H), 7.46–7.41 (m, 2H), 7.38–7.34 (m, 2H), 7.04 (d, J =
7.2 Hz, 2H), 6.97 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 7.7 Hz, 1H),
5.92 (d, J = 7.7 Hz, 1H), 3.76 (s, 3H), 3.31 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 173.48, 169.84, 152.75, 145.18, 131.19,
130.63, 130.18, 128.67, 127.98, 127.28, 122.47, 119.52, 109.77,
109.04, 108.79, 91.74, 64.31, 53.85, 51.23, 26.97; IR (KBr, thin
film) ν/cm−1: 2920, 2851, 1732, 1710, 1611, 1599, 1564, 1473,
1297, 1101, 1074, 577; HRMS (ESI) calcd for C22H16N4NaO3
(M + Na)+: 407.1115, found: 407.1114; [α]2D0 = 25.6 (c 1.0,
CHCl3); The enantiomeric excess was determined by HPLC
In conclusion, we have developed an organocatalytic three-
component reaction of isatins, malononitrile and α-aryl-isocya-
noacetates. The thiourea derived from quinine was identified
as the most efficient catalyst. A number of 3,3′-dihydropyrryl-
spirooxindoles were prepared in excellent yields and enantio-
selectivities. The products can be readily converted to valuable
3,3′-pyrrolidinyl-spirooxindoles via
a
selective reduction.
This new method is highly attractive for the synthesis of spiro-
oxindole derivatives in terms of the convenience and efficiency.
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Table 2 Organocatalytic three-component reaction of isatins 1a–1k, malononitrile 2a and isocyanoacetate 3aa
En
1
R1
R2
Time (h)
Yieldb (%)
5 : 5′c
eed (%)
1
2
1a
1b
1c
1d
1e
1f
1g
1h
1i
Me
PhCH2
H
CH3CO
Boc
Me
Me
Me
Me
Me
H
H
H
H
8
8
92, 5a/5a′
95, 5b/5b′
94, 5c/5c′
—
78 : 22
86 : 14
83 : 17
—
97/94
96/94
92/82
—
3
14
240
240
20
17
8
12
13
48
4e
5e
6
H
—
—
—
4-Cl
4-Br
5-Cl
7-Br
5-OCH3
6-OCH3
81, 5f/5f′
83, 5g/5g′
85, 5h/5h′
88, 5i/5i′
92, 5j/5j′
86, 5k/5k′
94 : 6
93 : 7
88 : 12
86 : 14
83 : 17
83 : 17
92/—
82/—
96/92
89/97
80/94
96/92
7
8
9
10
11
1j
1k
Me
a The reactions were carried out with 1a–1k (0.200 mmol), 2a (0.200 mmol), 3a (0.220 mmol) and 4f (0.004 mmol) in dichloromethane (2 mL) at
room temperature. b Combined yields of 5/5′ after column chromatography. c Determined by 1H NMR analysis of the crude reaction mixture.
d Determined by chiral HPLC. e No reaction.
Fig. 1 X-ray structure of 5g.
Scheme 5 Proposed reaction mechanism.
Scheme 4 Reaction of α-substituted isocyanoacetates with isatin 1a
and malononitrile 2a.
Scheme 6 Preparation of 3,3′-pyrrolidinyl-spirooxindole 6a.
5248 | Org. Biomol. Chem., 2012, 10, 5245–5252
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with Chiralpak AD column (hexane–iPrOH = 85/15, 0.8 mL
min−1, 208 nm), tR (major) = 34.4 min, tR (minor) = 55.7 min,
97% ee).
was obtained following the general procedure. White solid. Mp
109–111 °C; H NMR (400 MHz, CDCl3) δ: 8.17 (s, 1H), 8.03
1
(s, 1H), 7.45 (d, J = 6.3 Hz, 1H), 7.40–7.30 (m, 3H), 7.08 (d,
J = 7.3 Hz, 2H), 6.99 (d, J = 7.8 Hz, 1H), 6.81 (t, J = 7.7 Hz,
1H), 5.91 (d, J = 7.8 Hz, 1H), 3.78 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 175.46, 169.80, 153.04, 142.39, 131.17,
130.49, 130.23, 128.71, 128.18, 127.29, 122.39, 120.01, 110.95,
109.79, 108.62, 91.67, 64.84, 53.91, 51.37; IR (KBr, thin film)
ν/cm−1: 2957, 2925, 2852, 1780, 1735, 1620, 1599, 1472, 1398,
1297, 1197, 1077, 603; HRMS (ESI) calcd for C21H14N4NaO3
(M + Na)+: 393.0958, found: 393.0952; [α]2D0 = 61.7 (c 1.0,
CHCl3); The enantiomeric excess was determined by HPLC
with Chiralpak AD column (hexane–iPrOH = 85/15, 0.8 mL
min−1, 230 nm), tR (major) = 23.0 min, tR (minor) = 56.3 min,
92% ee).
(2′R,3R)-Methyl-4′,4′-dicyano-1-methyl-2-oxo-2′-phenyl-2′,4′-
dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5a′). The
product was obtained following the general procedure. White
1
solid. Mp 225–227 °C; H NMR (400 MHz, CDCl3) δ: 8.10
(s, 1H), 7.56 (t, J = 8.2 Hz, 2H), 7.28 (d, J = 7.0 Hz, 2H), 7.21
(t, J = 7.6 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 6.93 (d, J = 7.7 Hz,
1H), 3.81 (s, 3H), 2.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
170.17, 166.86, 154.18, 145.16, 135.02, 131.85, 128.89, 127.85,
126.64, 126.39, 123.74, 119.54, 110.49, 109.54, 109.27, 90.09,
53.46, 51.58, 29.68, 26.29; IR (KBr, thin film) ν/cm−1: 2925,
2030, 1728, 1613, 1461, 1386, 1243, 1157, 1082, 577; HRMS
(ESI) calcd for C22H16N4NaO3 (M + Na)+: 407.1115, found:
407.1115; [α]2D0 = 28.3 (c 1.0, CHCl3); The enantiomeric excess
was determined by HPLC with Chiralpak AD column (hexane–
iPrOH = 85/15, 0.8 mL min−1, 208 nm), tR (major) = 27.2 min,
tR (minor) = 36.6 min, 94% ee).
(2′R,3R)-Methyl-4′,4′-dicyano-2-oxo-2′-phenyl-2′,4′-dihydro-
spiro[indoline-3,3′-pyrrole]-2′-carboxylate (5c′). The product
was obtained following the general procedure. White solid.
1
Mp 185–187 °C; H NMR (400 MHz, CDCl3) δ: 8.09 (s, 1H),
7.56 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.47 (d, J =
6.7 Hz, 1H), 7.28–7.23 (m, 5H), 6.95 (d, J = 7.8 Hz, 1H), 3.82
(s, 3H); 13C NMR (100 MHz, CDCl3) δ: 172.16, 166.83,
153.94, 142.01, 135.01, 131.74, 128.95, 128.17, 126.73, 126.57,
123.74, 120.11, 111.29, 110.40, 109.32, 89.98, 66.19, 53.50,
51.97; IR (KBr, thin film) ν/cm−1: 2923, 2852, 1793, 1601,
1564, 1435, 1325, 1269, 1230, 1022, 577; HRMS (ESI) calcd
for C21H14NaN4O3 (M + Na)+: 393.0958, found: 393.0958;
[α]2D0 = 22.5 (c 1.0, CHCl3); The enantiomeric excess was deter-
mined by HPLC with Chiralpak OD column (hexane–iPrOH =
85/15, 0.8 mL min−1, 208 nm), tR (major) = 16.5 min,
tR (minor) = 14.5 min, 82% ee).
(2′S,3R)-Methyl-1-benzyl-4′,4′-dicyano-2-oxo-2′-phenyl-2′,4′-
dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5b). The
product was obtained following the general procedure. White
1
solid. Mp 196–198 °C; H NMR (400 MHz, CDCl3) δ: 8.20
(s, 1H), 7.45 (t, J = 8.2 Hz, 3H), 7.40–7.33 (m, 4H), 7.28 (dd,
J = 8.9, 7.8 Hz, 2H), 7.08 (d, J = 7.3 Hz, 2H), 6.83–6.76 (m,
2H), 5.91 (d, J = 7.7 Hz, 1H), 5.04 (d, J = 15.7 Hz, 1H), 4.93
(d, J = 15.7 Hz, 1H), 3.76 (s, 3H), 3.58 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 173.67, 169.76, 152.75, 144.44, 134.64,
131.02, 130.51, 130.19, 128.87, 128.65, 128.00, 127.96, 127.71,
127.34, 122.41, 119.50, 110.22, 109.92, 108.73, 91.72, 64.29,
53.85, 51.37, 44.90; IR (KBr, thin film) ν/cm−1: 3063, 2955,
1737, 1706, 1610, 1564, 1131, 1077, 576; HRMS (ESI) calcd
for C28H20N4NaO3 (M + Na)+: 483.1428, found: 483.1430;
[α]2D0 = 38.5 (c 1.0, CHCl3); The enantiomeric excess was deter-
mined by HPLC with Chiralpak AD column (hexane–iPrOH =
85/15, 0.8 mL min−1, 230 nm), tR (major) = 18.9 min, tR
(minor) = 62.8 min, 96% ee).
(2′S,3S)-Methyl-4-chloro-4′,4′-dicyano-1-methyl-2-oxo-2′-phenyl-
2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate (5f). The
product was obtained following the general procedure. White
1
solid. Mp 245–248 °C; H NMR (400 MHz, CDCl3) δ: 8.06 (s,
1H), 7.18 (t, J = 8.1 Hz, 2H), 7.11 (d, J = 7.2 Hz, 2H), 7.04 (s,
2H), 6.81 (d, J = 7.9 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 3.87 (s,
3H), 3.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.99,
166.14, 153.26, 145.03, 134.04, 132.65, 132.00, 128.58, 127.30,
126.99, 125.39, 122.60, 109.81, 107.83, 107.48, 93.28, 66.28,
53.64, 52.63, 27.73; IR (KBr, thin film) ν/cm−1: 3063, 2957,
1742, 1720, 1659, 1604, 1564, 1428, 1128, 1010, 596; HRMS
(ESI) calcd for C22H15N4NaO3Cl (M + Na)+: 441.0725, found:
441.0726; [α]2D0 = −155.5 (c 1.0, CHCl3); The enantiomeric
excess was determined by HPLC with Chiralpak AD column
(hexane–iPrOH = 85/15, 0.8 mL min−1, 254 nm), tR (major) =
40.1 min, tR (minor) = 29.1 min, 92% ee).
(2′R,3R)-Methyl-1-benzyl-4′,4′-dicyano-2-oxo-2′-phenyl-2′,4′-
dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5b′). The
product was obtained following the general procedure. White
1
solid. Mp 165–167 °C; H NMR (400 MHz, CDCl3) δ: 8.14 (s,
1H), 7.57 (d, J = 7.7 Hz, 1H), 7.46–7.40 (m, 1H), 7.31–7.27 (m,
1H), 7.25–7.21 (m, 4H), 7.21–7.15 (m, 4H), 7.00 (dd, J = 6.5,
2.9 Hz, 2H), 6.83 (d, J = 7.9 Hz, 1H), 4.51 (s, 2H), 3.81 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 170.49, 166.94, 154.16,
144.41, 134.90, 134.15, 131.74, 128.82, 128.64, 128.13, 127.95,
127.70, 126.81, 126.54, 123.73, 119.47, 110.60, 110.35, 109.48,
89.66, 65.96, 53.51, 52.08, 44.47; IR (KBr, thin film) ν/cm−1
:
(2′S,3S)-Methyl-4-bromo-4′,4′-dicyano-1-methyl-2-oxo-2′-phenyl-
2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate (5g). The
product was obtained following the general procedure. White
3057, 2928, 2032, 1728, 1612, 1456, 1386, 1259, 1163, 1076,
577; HRMS (ESI) calcd for C28H20N4NaO3 (M + Na)+:
483.1428, found: 483.1422; [α]2D0 = 40.0 (c 1.0, CHCl3); The
enantiomeric excess was determined by HPLC with Chiralpak
AD column (hexane–iPrOH = 85/15, 0.8 mL min−1, 230 nm), tR
(major) = 27.5 min, tR (minor) = 63.3 min, 94% ee).
1
solid. Mp 250–253 °C; H NMR (400 MHz, CDCl3) δ: 8.09 (s,
1H), 7.39–7.30 (m, 1H), 7.14–7.08 (m, 3H), 7.04 (s, 2H), 6.92
(d, J = 8.0 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 3.86 (s, 3H), 3.41
(s, 3H); 13C NMR (100 MHz, CDCl3) δ: 168.95, 166.38,
153.66, 145.41, 133.94, 131.95, 129.10, 128.58, 127.58, 126.95,
124.39, 121.66, 109.88, 108.04, 107.82, 93.45, 66.60, 53.67,
52.65, 27.70; IR (KBr, thin film) ν/cm−1: 3086, 2957, 1742,
(2′S,3R)-Methyl-4′,4′-dicyano-2-oxo-2′-phenyl-2′,4′-dihydro-
spiro[indoline-3,3′-pyrrole]-2′-carboxylate (5c). The product
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5245–5252 | 5249

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(2′R,3R)-Methyl-7-bromo-4′,4′-dicyano-1-methyl-2-oxo-2′-
phenyl-2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5i′). The product was obtained following the general procedure.
1721, 1659, 1601, 1564, 1459, 1243, 1008, 595; HRMS (ESI)
calcd for C22H15N4NaO3Br (M + Na)+: 485.0220, found:
485.0221; [α]2D0 = −203.8 (c 1.0, CHCl3); The enantiomeric
excess was determined by HPLC with Chiralpak AD column
(hexane–iPrOH = 85/15, 0.8 mL min−1, 254 nm), tR (major) =
46.3 min, tR (minor) = 30.9 min, 82% ee).
1
White solid. Mp 165–167 °C; H NMR (400 MHz, CDCl3) δ:
8.09 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 7.7 Hz, 1H),
7.32–7.24 (m, 3H), 7.14–7.09 (m, 3H), 3.79 (s, 3H), 3.17 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 170.77, 166.68, 154.08,
142.58, 137.56, 134.55, 129.08, 127.98, 126.68, 125.32, 124.53,
122.54, 110.21, 109.34, 103.38, 90.48, 65.29, 53.52, 51.63,
30.28; IR (KBr, thin film) ν/cm−1: 2921, 2851, 2361, 2025,
1729, 1601, 1459, 1361, 1162, 1076, 578; HRMS (ESI) calcd
for C22H15N4O3NaBr (M + Na)+: 485.0220, found: 485.0217;
[α]2D0 = 15.2 (c 1.0, CHCl3); The enantiomeric excess was
determined by HPLC with Chiralpak AD column (hexane–
iPrOH = 90/10, 0.8 mL min−1, 230 nm, tR (major) = 22.8 min,
tR (minor) = 15.4 min, 97% ee).
(2′S,3R)-Methyl-5-chloro-4′,4′-dicyano-2-oxo-2′-phenyl-2′,4′-
dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5h). The
product was obtained following the general procedure. White
1
solid. Mp 245–248 °C; H NMR (400 MHz, CDCl3) δ: 8.16 (s,
1H), 7.50 (d, J = 7.3 Hz, 1H), 7.43–7.38 (m, 3H), 7.03 (d, J =
6.9 Hz, 2H), 6.90 (d, J = 8.4 Hz, 1H), 5.76 (d, J = 1.8 Hz, 1H),
3.77 (s, 3H), 3.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
173.01, 169.71, 152.56, 143.69, 131.05, 130.53, 130.07, 128.80,
128.39, 127.98, 127.11, 121.07, 109.86, 109.51, 108.46, 92.08,
64.07, 53.96, 50.89, 27.08; IR (KBr, thin film) ν/cm−1: 2921,
2851, 1716, 1603, 1564, 1489, 1356, 1148, 579; HRMS (ESI)
calcd for C22H15N4NaO3Cl (M + Na)+: 441.0725, found:
441.0725; [α]2D0 = 76.6 (c 1.0, CHCl3); The enantiomeric excess
was determined by HPLC with Chiralpak AD column (hexane–
iPrOH = 85/15, 0.8 mL min−1, 230 nm), tR (major) = 46.2 min,
tR (minor) = 58.8 min, 96% ee).
(2′S,3R)-Methyl-4′,4′-dicyano-5-methoxy-1-methyl-2-oxo-2′-
phenyl-2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5j). The product was obtained following the general procedure.
1
White solid. Mp 240–242 °C; H NMR (400 MHz, CDCl3) δ:
8.18 (s, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.39 (t, J = 7.4 Hz, 2H),
7.08 (d, J = 7.0 Hz, 2H), 6.94 (dd, J = 8.6, 2.5 Hz, 1H), 6.87 (d,
J = 8.6 Hz, 1H), 5.50 (d, J = 2.4 Hz, 1H), 3.77 (s, 3H), 3.43 (s,
3H), 3.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 173.18,
169.75, 155.22, 152.75, 138.39, 130.59, 130.09, 128.71, 127.39,
120.32, 117.12, 113.90, 109.70, 109.56, 108.80, 91.69, 64.37,
55.45, 53.83, 51.29, 27.00; IR (KBr, thin film) ν/cm−1: 2920,
2851, 1717, 1602, 1564, 1500, 1386, 1206, 1076, 577; HRMS
(ESI) calcd for C23H18N4NaO4 (M + Na)+: 437.1220, found:
437.1216; [α]2D0 = 69.0 (c 1.0, CHCl3); The enantiomeric excess
was determined by HPLC with Chiralpak AD column (hexane–
iPrOH = 85/15, 0.8 mL min−1, 254 nm), tR (major) = 41.2 min,
tR (minor) = 64.6 min, 80% ee).
(2′R,3R)-Methyl-5-chloro-4′,4′-dicyano-2-oxo-2′-phenyl-2′,4′-
dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate (5h′). The
product was obtained following the general procedure. White
1
solid. Mp 129–131 °C; H NMR (400 MHz, CDCl3) δ: 8.08 (s,
1H), 7.59 (s, 1H), 7.54 (dd, J = 8.4, 1.9 Hz, 1H), 7.28 (s, 1H),
7.22 (t, J = 7.5 Hz, 2H), 7.11 (d, J = 7.2 Hz, 2H), 6.85 (d, J =
8.4 Hz, 1H), 3.82 (s, 3H), 2.81 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 169.78, 166.85, 154.06, 143.72, 134.69, 131.81,
129.28, 129.04, 127.94, 127.16, 126.58, 121.25, 110.21, 110.06,
109.21, 90.38, 65.55, 53.65, 51.44, 26.40; IR (KBr, thin film)
ν/cm−1: 2919, 2850, 1729, 1602, 1564, 1491, 1144, 577; HRMS
(ESI) calcd for C22H15N4NaO3Cl (M + Na)+: 441.0725, found:
441.0722; [α]2D0 = 23.3 (c 1.0, CHCl3); The enantiomeric excess
was determined by HPLC with Chiralpak AD column (hexane–
iPrOH = 85/15, 0.8 mL min−1, 254 nm), tR (major) = 26.2 min,
tR (minor) = 37.0 min, 92% ee).
(2′R,3R)-Methyl-4′,4′-dicyano-5-methoxy-1-methyl-2-oxo-2′-
phenyl-2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5j′). The product was obtained following the general procedure.
1
White solid. Mp 192–194 °C; H NMR (400 MHz, CDCl3) δ:
8.08 (s, 1H), 7.23–7.19 (m, 4H), 7.12 (d, J = 7.4 Hz, 2H), 7.06
(dd, J = 8.6, 2.4 Hz, 1H), 6.82 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H),
3.82 (s, 3H), 2.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ:
169.95, 166.91, 156.52, 154.25, 138.42, 135.13, 128.87, 127.83,
126.69, 120.66, 116.37, 113.87, 110.54, 109.64, 109.61, 90.32,
(2′S,3R)-Methyl-7-bromo-4′,4′-dicyano-1-methyl-2-oxo-2′-phenyl-
65.83, 55.94, 53.43, 51.73, 26.36; IR (KBr, thin film) ν/cm−1
:
2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5i). The
product was obtained following the general procedure. White
2921, 2850, 2025, 1722, 1600, 1497, 1468, 1364, 1293, 1169,
1076, 577; HRMS (ESI) calcd for C23H18N4NaO4 (M + Na)+:
437.1220, found: 437.1215; [α]2D0 = 21.3 (c 1.0, CHCl3); The
enantiomeric excess was determined by HPLC with Chiralpak
AD column (hexane–iPrOH = 85/15, 0.8 mL min−1, 254 nm),
tR (major) = 31.6 min, tR (minor) = 44.6 min, 94% ee).
1
solid. Mp 249–251 °C; H NMR (400 MHz, CDCl3) δ: 8.16 (s,
1H), 7.51 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H),
7.40–7.30 (m, 2H), 7.03 (d, J = 4.8 Hz, 2H), 6.65 (t, J = 7.9 Hz,
1H), 5.80 (d, J = 7.5 Hz, 1H), 3.77 (s, 3H), 3.68 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 174.15, 169.66, 152.58,
142.59, 136.91, 130.33, 130.30, 128.75, 127.27, 126.99, 123.27,
122.41, 109.52, 108.57, 103.09, 92.28, 63.55, 53.91, 51.37,
30.93; IR (KBr, thin film) ν/cm−1: 2925, 2030, 1720, 1605,
1451, 1373, 1270, 1160, 1086, 577; HRMS (ESI) calcd for
C22H15N4NaO3Br (M + Na)+: 485.0220, found: 485.0221;
[α]2D0 = 36.7 (c 1.0, CHCl3); The enantiomeric excess was deter-
mined by HPLC with Chiralpak AD column (hexane–iPrOH =
85/15, 0.8 mL min−1, 254 nm), tR (major) = 23.8 min, tR
(minor) = 34.4 min, 89% ee).
(2′S,3R)-Methyl-4′,4′-dicyano-6-methoxy-1-methyl-2-oxo-2′-
phenyl-2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5k). The product was obtained following the general procedure.
1
Red solid. Mp 95–97 °C; H NMR (400 MHz, CDCl3) δ: 8.15
(s, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.36 (t, J = 7.5 Hz, 2H), 7.06
(d, J = 7.7 Hz, 2H), 6.52 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 8.6,
2.2 Hz, 1H), 5.82 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H),
3.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 174.08, 169.85,
5250 | Org. Biomol. Chem., 2012, 10, 5245–5252
This journal is © The Royal Society of Chemistry 2012

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162.40, 152.86, 146.55, 130.71, 130.06, 128.91, 128.59, 127.24,
110.84, 109.88, 108.89, 106.43, 96.97, 91.22, 64.36, 55.57,
53.78, 51.18, 26.94; IR (KBr, thin film) ν/cm−1: 2957, 2919,
2850, 1763, 1720, 1627, 1598, 1510, 1378, 1146, 1098, 1039,
583; HRMS (ESI) calcd for C23H18N4NaO4 (M + Na)+:
437.1220, found: 437.1221; [α]2D0 = 49.3 (c 1.0, CHCl3); The
enantiomeric excess was determined by HPLC with Chiralpak
AD column (hexane–iPrOH = 85/15, 0.8 mL min−1, 208 nm),
tR (major) = 20.5 min, tR (minor) = 40.8 min, 96% ee).
Chiralpak AD column (hexane–iPrOH = 70/30, 0.8 mL min−1
,
230 nm), tR (major) = 22.9 min, tR (minor) = 44.3 min, 92% ee).
(2′R,3R)-methyl-4′,4′-dicyano-2′-(4-methoxyphenyl)-1-methyl-
2-oxo-2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate (5m′).
The product was obtained following the general procedure.
1
White solid. Mp 232–234 °C; H NMR (400 MHz, CDCl3) δ:
8.09 (s, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.29–7.25 (m, 1H),
7.04 (d, J = 7.1 Hz, 2H), 6.93 (d, J = 6.4 Hz, 1H), 6.74 (d, J =
7.3 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.87 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 170.19, 167.05, 159.81, 154.07, 145.09,
131.81, 127.94, 126.82, 126.27, 123.71, 119.62, 113.23, 110.51,
109.57, 109.27, 89.85, 65.76, 55.16, 53.43, 51.53, 26.41;
IR (KBr, thin film) ν/cm−1: 2922, 2849, 2025, 1730, 1639,
1613, 1512, 1493, 1372, 1254, 1177, 1098, 951, 543; HRMS
(ESI) calcd for C23H18N4NaO4 (M + Na)+: 437.1220, found:
437.1232; [α]2D0 = 87.5 (c 1.0, CHCl3); The enantiomeric excess
was determined by HPLC with Chiralpak AD column (hexane–
iPrOH = 80/20, 0.8 mL min−1, 230 nm), tR (major) = 26.1 min,
tR (minor) = 22.5 min, 89% ee).
(2′R,3R)-Methyl-4′,4′-dicyano-6-methoxy-1-methyl-2-oxo-2′-
phenyl-2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate
(5k′). The product was obtained following the general pro-
cedure. White solid. Mp 90–92 °C; 1H NMR (400 MHz, CDCl3)
δ: 8.08 (s, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.28 (d, J = 7.2 Hz,
1H), 7.21 (t, J = 7.3 Hz, 2H), 7.14 (d, J = 7.2 Hz, 2H), 6.73 (d,
J = 8.6 Hz, 1H), 6.46 (s, 1H), 3.91 (s, 3H), 3.80 (s, 3H), 2.79 (s,
3H); 13C NMR (100 MHz, CDCl3) δ: 170.77, 167.00, 162.86,
154.24, 146.61, 135.20, 128.79, 127.82, 127.50, 126.61, 110.76,
110.60, 109.68, 107.34, 97.39, 89.68, 65.93, 55.69, 53.38,
51.57, 26.26; IR (KBr, thin film) ν/cm−1: 2921, 2851, 1755,
1722, 1627, 1600, 1509, 1375, 1214, 1095, 582; HRMS (ESI)
Methyl-2′-(4-chlorophenyl)-4′,4′-dicyano-1-methyl-2-oxo-2′,4′-
dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate (5n/5n′). The
product was obtained as an inseparable mixture of 5n and 5n′
following the general procedure. White solid; 1H NMR
(400 MHz, CDCl3) δ, for 5n: 8.18 (s, 1H), 7.48–7.39 (m, 1H),
7.33 (d, J = 8.5 Hz, 2H), 7.04–6.89 (m, 4H), 6.07 (d, J = 7.7
Hz, 1H), 3.76 (s, 3H), 3.31 (s, 3H); for 5n′: 7.48–7.39 (m, 1H),
7.33 (d, J = 8.5 Hz, 2H), 7.04–6.89 (m, 4H), 6.14 (d, J = 7.8
Hz, 1H), 5.77 (d, J = 12.8 Hz, 1H), 3.71 (s, 3H), 3.36 (s, 3H);
13C NMR (100 MHz, CDCl3) δ: 176.89, 173.14, 169.61,
168.14, 165.55, 158.31, 153.27, 145.12, 144.34, 136.52, 136.29,
133.55, 131.40, 129.96, 129.43, 129.27, 128.84, 128.74, 127.79,
126.32, 123.85, 122.65, 122.64, 119.24, 115.64, 109.48, 109.26,
108.66, 108.62, 90.96, 78.03, 64.11, 62.26, 61.75, 54.01, 53.80,
51.17, 29.70, 27.01, 26.62; IR (KBr, thin film) ν/cm−1: 2921,
2920, 2851, 2050, 2025, 1726, 1634, 1629, 1615, 1546, 1469,
1384, 1357, 1215, 1163, 1075, 1015, 547, 523. HRMS (ESI)
calcd for C22H15ClN4NaO3 (M + Na)+: 441.0725, found:
441.0728; The enantiomeric excess was determined by HPLC
calcd for C23H18N4NaO4 (M
+
Na)+: 437.1220, found:
437.1215; [α]2D0 = 35.0 (c 1.0, CHCl3); The enantiomeric excess
was determined by HPLC with Chiralpak AD column (hexane–
iPrOH = 85/15, 0.8 mL min−1, 208 nm), tR (major) = 15.5 min,
tR (minor) = 17.7 min, 92% ee).
(R)-Ethyl-4′,4′-dicyano-1-methyl-2-oxo-4′,5′-dihydro-spiro-
[indoline-3,3′-pyrrole]-2′-carboxylate (5l). The product was
obtained following the general procedure. White solid. Mp
134–136 °C; 1H NMR (400 MHz, CDCl3) δ: 7.52 (t, J = 7.8 Hz,
1H), 7.40 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.01 (d,
J = 7.9 Hz, 1H), 5.11 (s, 2H), 4.20–4.09 (m, 2H), 3.33 (s, 3H),
1.14 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
168.63, 163.77, 158.81, 144.87, 131.84, 125.28, 123.82, 121.21,
112.77, 111.52, 109.54, 70.26, 69.65, 63.01, 43.04, 27.20,
13.64; IR (KBr, thin film) ν/cm−1: 2986, 1727, 1713, 1636,
1612, 1564, 1494, 1374, 1153, 1098, 574; HRMS (ESI) calcd
for C17H14N4NaO3 (M + Na)+: 345.0958, found: 345.0943;
[α]2D0 = 23.0 (c 1.0, CHCl3); The enantiomeric excess was deter-
mined by HPLC with Chiralpak AD column (hexane–iPrOH =
85/15, 0.8 mL min−1, 254 nm, tR (major) = 26.7 min, tR (minor)
= 22.4 min, 12% ee).
with Chiralpak AD column (hexane–iPrOH
=
80/20,
0.8 mL min−1, 230 nm), 5n: tR (major) = 26.6 min, tR (minor) =
40.7 min, 96% ee; 5n′: tR (major) = 19.4 min, tR (minor) =
17.4 min, 97% ee.
(2′S,3R)-Methyl-4′,4′-dicyano-1-methyl-2-oxo-2′-phenylspiro-
[indoline-3,3′-pyrrolidine]-2′-carboxylate (6a). 5a (38.4 mg,
0.100 mmol) was added into CH3CN (1 mL) and H2O (50 μL),
stirred for 10 min, then NaBH3CN (12.6 mg, 0.200 mmol) and
acetic acid (50 μL) were added and stirred for 2 h at room temp-
erature. After the evaporation of the solvent under vacuum,
extracted with EtOAc (5 mL) for three times. The mixture was
washed with NaOH (1 M) and brine. And the organic layer was
dried over anhydrous Na2SO4. After evaporation of the solvent
under vacuum, the residue was separated by flash chromato-
graphy over silica gel to give 7a as a white solid. Mp
(2′S,3R)-Methyl-4′,4′-dicyano-2′-(4-methoxyphenyl)-1-methyl-
2-oxo-2′,4′-dihydrospiro[indoline-3,3′-pyrrole]-2′-carboxylate (5m).
The product was obtained following the general procedure.
1
White solid. Mp 216–218 °C; H NMR (400 MHz, CDCl3) δ:
8.15 (s, 1H), 7.42 (t, J = 7.8 Hz, 1H), 6.99–6.94 (m, 3H),
6.90–6.51 (m, 3H), 6.04 (d, J = 7.7 Hz, 1H), 3.83 (s, 3H), 3.75
(s, 3H), 3.30 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 173.52,
170.00, 160.86, 152.44, 145.17, 131.11, 128.68, 128.07, 122.48,
122.20, 119.53, 113.92, 109.82, 109.01, 108.80, 91.33, 64.26,
55.37, 53.79, 51.00, 26.93; IR (KBr, thin film) ν/cm−1: 2918,
2835, 2025, 1718, 1637, 1614, 1512, 1494, 1374, 1260, 1162,
1068, 950, 542; HRMS (ESI) calcd for C23H18N4NaO4 (M +
Na)+: 437.1220, found: 437.1237; [α]D20 = 16.7 (c 1.0, CHCl3);
The enantiomeric excess was determined by HPLC with
1
162–164 °C; [α]2D0 = 37.5 (c 1.0, CHCl3); H NMR (400 MHz,
CDCl3) δ: 7.57 (d, J = 5.8 Hz, 2H), 7.40–7.32 (m, 2H), 7.27
(dd, J = 10.5, 4.3 Hz, 2H), 6.96 (d, J = 7.9 Hz, 1H), 6.82 (t, J =
7.7 Hz, 1H), 6.19 (d, J = 7.7 Hz, 1H), 4.57 (d, J = 1.0 Hz, 1H),
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 5245–5252 | 5251

View Online
4.04 (d, J = 1.0 Hz, 1H), 3.67 (s, 3H), 3.31 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ: 174.10, 171.41, 144.39, 135.99, 130.75,
129.19, 128.73, 128.62, 127.87, 122.46, 120.83, 113.54, 111.97,
108.68, 75.99, 63.83, 53.28, 44.02, 29.68, 26.77; IR (KBr, thin
film) ν/cm−1: 3395, 1741, 1712, 1611, 1564, 1493, 1472, 1376,
1242, 1098, 577; HRMS (ESI) calcd for C22H19N4O3 (M + H)+:
387.1452, found: 387.1450; The enantiomeric excess was
determined by HPLC with Chiralpak AD column (hexane–
iPrOH = 85/15, 0.8 mL min−1, 254 nm, tR (major) = 17.4 min,
tR (minor) = 19.2 min, 94% ee).
M. R. M. Hüttl, Angew. Chem., Int. Ed., 2007, 46, 1570; (e) G. Guillena,
D. J. Ramón and M. Yus, Tetrahedron: Asymmetry, 2007, 18, 693.
4 For the organocatalytic synthesis of spirooxindoles, see: (a) Y.-M. Cao,
X.-X. Jiang, L.-P. Liu, F.-F. Shen, F.-T. Zhang and R. Wang, Angew.
Chem., Int. Ed., 2011, 50, 9124; (b) B. Tan, N. R. Candeias and
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Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 20972195, 21172270) and Guangdong Engineering
Research Center of Chiral Drugs for the financial supports of
this study.
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11 CCDC-859158 contains the supplementary crystallographic data for this
paper.
5252 | Org. Biomol. Chem., 2012, 10, 5245–5252
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