Organocatalytic synthesis of spiro[pyrrolidin-3,3′-oxindoles] with high enantiopurity and structural diversity

Article abstract of DOI:10.1021/ja905302f

The privileged spiro[pyrrolidin-3,3′-oxindole] derivatives exhibit important biological activities. An enantioselective organocatalytic approach to the rapid synthesis of spiro[pyrrolidin-3,3′-oxindole] derivatives with high enantiopurity and structural d

Full text of DOI:10.1021/ja905302f

Published on Web 09/09/2009
Organocatalytic Synthesis of Spiro[pyrrolidin-3,3′-oxindoles]
with High Enantiopurity and Structural Diversity
Xiao-Hua Chen,†,‡ Qiang Wei,† Shi-Wei Luo,† Han Xiao,† and Liu-Zhu Gong*,†
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, UniVersity of Science and Technology of China, Hefei, 230026, China, and Chengdu
Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China
Received June 30, 2009; E-mail: gonglz@ustc.edu.cn
Abstract: The privileged spiro[pyrrolidin-3,3′-oxindole] derivatives exhibit important biological activities. An
enantioselective organocatalytic approach to the rapid synthesis of spiro[pyrrolidin-3,3′-oxindole] derivatives
with high enantiopurity and structural diversity is described. The asymmetric catalytic three-component
1,3-dipolar cycloaddition of a broad range of methyleneindolinones with aldehydes and amino esters in
the presence of chiral phosphoric acid provides spirooxindole derivatives in high yield with unusual
regiochemistry and excellent stereoselectivities (up to 98% ee) under mild conditions. The straightforward
construction of spirooxindole skeletons with high stereo- and regioselectivity suggests a new avenue to
medicinal chemistry and diversity-oriented synthesis. Theoretical calculations disclosed that both the
azomethine ylide and the methyleneindolinone are hydrogen-bonded with the phosphoric acid, which
accounted for the high enantio- and regioselectivity and indicated that the unusual regioselectivity results
from the stabilization stemming from the favorable π-π stacking interaction between the oxo-indole ring
and the conjugated esters.
Introduction
The significance of these heterocyclic motifs has led to a
demand for efficient synthetic methods, particularly those
producing enantiomerically pure spiro[pyrrolidin-3,3′-oxin-
doles]. Numerous elegant transformations have been devel-
oped for the construction of these structural skeletons,2 which
usually employ either enantiopure starting materials or
multistep reactions to construct the optically active spiroox-
indole skeletons. Williams reported another approach to
access the optically pure spiro[pyrrolidin-3,3′-oxindoles] in
the synthesis of spirotryprostatin B.7 This chiral auxiliary-
induced three-component 1,3-dipolar cycloaddition reaction
of methyleneindolinones 1 with azomethine ylides proved
to be an attractive synthetic method, regiospecifically provid-
ing spiro[pyrrolidin-3,3′-oxindole] derivatives of type 4
(Scheme 1).4,6,7 Although these were elegant and creative
strategies toward the construction of spirooxindole architec-
ture, the directly catalytic asymmetric approach to access
optically pure spiro[pyrrolidin-3,3′-oxindoles] has met with
little success.8 Consequently, an enantioselective catalytic
method for the direct construction of spirooxindole skeletons
The spiro[pyrrolidin-3,3′-oxindole] ring system constitutes
the core structural element found in a large family of natural
alkaloids and unnatural compounds exhibiting important
biological activities as exemplified by those shown in Figure
1.1,2 For example, the spirotryprostatins A and B were
isolated from the fermentation broth of Aspergillus fumigatus
and have been shown to completely inhibit the G2/M
progression of cell division in mammalian tsFT210 cells.3
The significant biological activity and recent synthetic
advances of these natural products have encouraged the
development of biologically promising analogues that are
often more efficacious and selective than the original natural
products,4-6 as exemplified by MI-219,4 a potent, highly
selective, and orally active inhibitor of the interaction between
the tumor suppressor p53 and the E3 ubiquitin ligase MDM2.
The privileged spirooxindole skeletons have high potential
as core elements for the development of related compounds
leading to medicinal agents.2a
† University of Science and Technology of China.
‡ Chengdu Institute of Organic Chemistry.
(1) Bindra, J. S. The Alkaloids, Vol. 14; Manske, R. H. F., Ed.; Academic
Press: New York, 1973; pp 84.
(2) For reviews. (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int.
Ed. 2007, 46, 8748. (b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209.
(7) (a) Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122,
5666. (b) Onishi, T.; Sebahar, P. R.; Williams, R. M. Org. Lett. 2003,
5, 3135.
(8) (a) Catalytic synthesis of spiro[pyrrolidin-3,3′-oxindoles] includes
asymmetric intramolecular Heck reaction; see: Overman, L. E.; Rosen,
M. D. Angew. Chem., Int. Ed. 2000, 39, 4596. (b) Pd-catalyzed
asymmetric alkylation of an oxindole enolate in a synthesis of
horsfiline; see: Trost, B. M.; Brennan, M. K. Org. Lett. 2006, 8, 2027.
For very recent organocatalytic conjugate additions of oxindoles to
electronically poor olefins for the generation of all-carbon quaternary
stereogenic center, see: (c) Bui, T.; Syed, S.; Barbas, C. F. J. Am.
Chem. Soc. 2009, 131, 8758. (d) Galzerano, P.; Bencivenni, G.;
Pesciaioli, F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.;
Melchiorre, P. Chem.sEur. J. 2009, 15, 7846.
(3) (a) Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651.
(b) Cui, C. B.; Kakeya, H.; Osada, H. J. Antibiot. 1996, 49, 832.
(4) (a) Ding, K.; et al. J. Am. Chem. Soc. 2005, 127, 10130. (b) Ding, K.;
et al. J. Med. Chem. 2006, 49, 3432. (c) Shangary, S.; et al. Proc.
Natl. Acad. Sci. U.S.A. 2008, 105, 3933.
(5) Edmondson, S.; Danishefsky, S. J.; Sepp.-Lorenzino, L.; Rosen, N.
J. Am. Chem. Soc. 1999, 121, 2147.
(6) Lo, M. M.-C.; Neumann, C. S.; Nagayama, S.; Perlstein, E. O.;
Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077.
9
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J. AM. CHEM. SOC. 2009, 131, 13819–13825 13819

A R T I C L E S
Chen et al.
Figure 1. Biologically important molecules containing spiro[pyrrolidin-3,3′-oxindole].
Scheme 1. 1,3-Dipolar Cycloaddition Reactions for Synthesis of Spiro[pyrrolidin-3,3′-oxindole] Derivatives
in one pot is highly desirable with respect to synthetic
efficiency and atom economy.
compounds11 for stereoselective transformations. We have
recently reported the chiral phosphoric acid catalyzed 1,3-dipolar
addition reactions providing five-membered heterocycles.12
Encouraged by these achievements, we proposed 1,3-dipolar
cycloaddition reactions between azomethine ylides and meth-
yleneindolinones catalyzed by chiral phosphoric acid to construct
the spirooxindole skeleton with concomitant generation of
stereogenic centers in high levels of stereoselectivity (Scheme
1). However, several challenges are associated with the directly
catalytic asymmetric construction of the spirooxindole structure
in one cycloaddition step. First, it was more difficult to control
the regioselectivity at the C3 and C4, as two sites of regio-
chemistry may result from this type of cycloaddition according
to previous reports.13 Moreover, a unique spiro quaternary
stereogenic center at C3 site is created, which, in having six
substituents on the pyrrolidine ring, is more sterically congested
Recently, chiral phosphoric acids have been widely used as
organocatalysts in the activation of imines9,10 and carbonyl
(9) For reviews: (a) Akiyama, T. Chem. ReV 2007, 107, 5744. (b) Doyle,
A. G.; Jacobsen, E. N. Chem. ReV. 2007, 107, 5713. (c) Terada, M.
Chem. Commun. 2008, 4097. For leading references, see: (d) Uraguchi,
D.; Terada, M. J. Am. Chem. Soc. 2004, 126, 5356. (e) Akiyama, T.;
Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem., Int. Ed. 2004, 43,
1566. For recent examples, see: (f) Wang, X.-W.; List, B. Angew.
Chem., Int. Ed. 2008, 47, 1119. (g) Cheng, X.; Goddard, R.; Buth,
G.; List, B. Angew. Chem., Int. Ed. 2008, 47, 5079. (h) Cheon, C. H.;
Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246. (i) Jiao, P.;
Nakashima, D.; Yamamoto, H. Angew. Chem., Int. Ed. 2008, 47, 2411.
(j) Rueping, M.; Antonchick, A. P. Angew. Chem., Int. Ed. 2008, 47,
5836. (k) Hu, W.-H.; Xu, X.-F.; Zhou, J.; Liu, W.-J.; Huang, H.-X.;
Hu, J.; Yang, L.-P.; Gong, L.-Z. J. Am. Chem. Soc. 2008, 130, 7782.
(l) Sickert, M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631.
(m) Kang, Q.; Zheng, X.-J.; You, S.-L. Chem.sEur. J. 2008, 14, 3539.
(n) Xu, S.; Wang, Z.; Zhang, X.; Zhang, X.-M.; Ding, K.-L. Angew.
Chem., Int. Ed. 2008, 47, 2840. (o) Guo, Q.-S.; Du, D.-M.; Xu, J.-X.
Angew. Chem., Int. Ed. 2008, 47, 759. (p) Li, G.-L.; Fronczek, F. R.;
Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216. (q) Sorimachi, K.;
Terada, M. J. Am. Chem. Soc. 2008, 130, 14452. (r) Enders, D.; Narine,
A. A.; Toulgoat, F.; Bisschops, T. Angew. Chem., Int. Ed. 2008, 47,
5661. (s) Terada, M.; Tanaka, H.; Sorimachi, K. J. Am. Chem. Soc.
2009, 131, 3430. (t) Rueping, M.; Antonchick, A. P.; Sugiono, E.;
Grenader, K. Angew. Chem., Int. Ed. 2009, 48, 908. (u) Liu, H.;
Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc.
2009, 131, 4598.
(11) Chiral phosphoric acids used in the activation of carbonyl compounds;
see: (a) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128,
9626. (b) Rueping, M.; Ieawsuwan, W.; Antonchick, A. P.; Nacht-
sheim, B. J. Angew. Chem., Int. Ed. 2007, 46, 2097. (c) Rueping, M.;
Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem., Int. Ed.
2008, 47, 593. (d) Terada, M.; Soga, K.; Momiyama, N. Angew. Chem.,
Int. Ed. 2008, 47, 4122. (e) Zeng, M.; Kang, Q.; He, Q.-L.; You, S.-
L. AdV. Synth. Catal. 2008, 350, 2169. (f) Akiyama, T.; Katoh, T.;
Mori, K. Angew. Chem., Int. Ed. 2009, 48, 4226.
(12) (a) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am. Chem. Soc. 2008,
130, 5652. (b) Liu, W.-J.; Chen, X.-H.; Gong, L.-Z. Org. Lett. 2008,
10, 5357.
(10) Theoretical study on bifunctional chiral Brønsted acid catalyzed
asymmetric transformations; see: (a) Simo´n, L.; Goodman, J. M. J. Am.
Chem. Soc. 2008, 130, 8741. (b) Simo´n, L.; Goodman, J. M. J.
Am. Chem. Soc. 2009, 131, 4070. (c) Yamanaka, M.; Hirata, T. J.
Org. Chem. 2009, 74, 3266.
(13) (a) Nyerges, M.; Gajdics, L.; Szollosy, A.; Toke, L. Synlett 1999, 111.
(b) Fejes, I.; Toke, L.; Nyerges, M.; Pak, C. S. Tetrahedron 2000, 56,
639.
9
13820 J. AM. CHEM. SOC. VOL. 131, NO. 38, 2009

Synthesis of Spiro[pyrrolidin-3,3′-oxindoles]
A R T I C L E S
Figure 2. Computed natural bond orbital (NBO) charges of 1a and a dipole by B3LYP/6-31G* method.
as compared to chiral auxiliary-induced dipolar addition
reactions.4,7 Nonetheless, it is a greater challenge to control the
high diastereoselectivity, in consideration of the simultaneous
creation of two quaternary centers at the pyrrolidine ring.14 In
addition, it has been unclear whether the chiral Brønsted acid
activated the azomethine ylide alone to control the stereochem-
istry or whether both substrates were required to achieve high
asymmetric induction.10,11 Herein, we report the first asymmetric
catalytic 1,3-dipolar cycloaddition between an azomethine ylide
and methyleneindolinones with concomitant creation of two
adjacent quaternary stereogenic centers14 for the rapid synthesis
of spiro[pyrrolidin-3,3′-oxindole] derivatives with high enan-
tiopurity and structural diversity. The highly stereoselective
construction of spirooxindole skeletons with unusual regiose-
lectivity suggests a new avenue of great importance to medicinal
chemistry and diversity-oriented synthesis.6,15 In addition,
theoretical calculations on the transition states have been carried
out to explain the unusual regioselectivity and high enantiose-
lectivity.
produced the desired compounds in a high yield (eq 1).
Interestingly, the regiochemistry is independent of the electron
distribution over two carbon atoms of the C-C double bond of
(E)-3-benzylideneindolinone. The calculations show that in the
(E)-3-benzylideneindolinone 1a the carbon bonded to phenyl
is more electronically poor than the other one and in azomethine
ylide, formed from 4-nitrobenzaldehyde and diethyl aminoma-
lonate, the carbon next to the two esters is negatively charged
(Figure 2); therefore 4a should be dominantly formed according
to the regulations obtained from previous reports on the 1,3-
dipolar addition of azomethine ylides to unsymmetrical elec-
tronically poor olefins.16,18 However, we observed a major
product 5a, implying that the regiochemistry is not directed by
the electronic effect but by some other factors. Notably, this
finding is quite unusual because a very limited number of
intermolecular 1,3-dipolar addition reactions have been reported
with the regioselectivity opposite to that directed by the
electronic effect.19 Moreover, the chemistry represents thus far
the sole enantioselective catalytic cycloaddition involving
methyleneindolinone dipolarophiles to straightforwardly access
the optically active spiro[pyrrolidin-3,3′-oxindole] derivatives.
Screening of the BINOL-derived phosphoric acids 6 revealed
that the presence of either highly sterically congested or less
bulky substituents on the catalysts were deleterious to the
enantioselectivity (Table 1, entries 1-5). 3,3′-ꢀ-Naphthyl
phosphoric acid 6f was found to effect the most enantioselective
cycloaddition (entry 6, >93/7 rr, 93% ee). However, in our
earlier studies, the bis-phosphoric acid, which delivered a high
ee in the 1,3-dipolar cycloaddition of azomethine ylides to
maleates,12a exhibited poor stereoselectivity (93% yield, 2% ee).
A survey of solvents revealed that dichloromethane was most
suitable for the reaction. Lowering the reaction temperature did
not enhance the enantioselectivity (entry 12), while conducting
the reaction at room temperature provided the best results (entry
13).
Results and Discussion
1,3-Dipolar Cycloaddition Reaction To Construct
Spirooxindole Skeletons. We initially believed that the asym-
metric catalytic 1,3-dipolar cycloaddition reaction of methyl-
eneindolinones 1 with azomethine ylides would be an elusive
objective because no catalysts have been reported to effect this
reaction although numerous asymmetric catalytic procedures for
1,3-dipolar cycloaddition reaction have been described.16,17 In
consideration of the above-mentioned challenges, we selected
(E)-1-acetyl-3-benzylideneindolinone (1a) as a dipolarophile on
the supposition that the acetyl group on the nitrogen atom would
enhance the polarizability of the dipolarophile and contribute
to the high regioselectivity. Moreover, the acetyl group on the
nitrogen atom served to reduce the energy of the lowest
unoccupied molecular orbital (LUMO) of the dipolarophiles and
consequently increased the reactivity of the methyleneindoli-
none.
With the optimal conditions in hand, we investigated the
generality for the scope of aldehydes (Table 2). In the asym-
metric catalytic 1,3-dipolar addition, a wide range of aromatic
and aliphatic aldehydes were tolerated and provided high yields
(14) For an excellent review on the importance and challenge in the catalytic
synthesis of all-carbon stereogenic centers, see: Douglas, C. J.;
Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5363.
(15) For an excellent review on the importance of diversity-oriented organic
synthesis in drug discovery, see: Schreiber, S. L. Science 2000, 287,
1964.
(16) For reviews: (a) Coldham, I.; Hufton, R. Chem. ReV. 2005, 105, 2765.
(b) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. ReV. 2006, 106,
4484. (c) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
(17) For organocatalytic 1,3-dipolar addition reactions, also see: (a) Vicario,
J. L.; Reboredo, S.; Bad˙ıa, D.; Carrillo, L. Angew. Chem., Int. Ed.
2007, 46, 5168. (b) Ibrahem, I.; Rios, R.; Vesely, J.; Cordova, A.
Tetrahedron. Lett. 2007, 48, 6252. (c) Liu, Y.-K.; Liu, H.; Du, W.;
Yue, L.; Chen, Y.-C. Chem.sEur. J. 2008, 14, 9873.
Indeed, (E)-3-benzylideneindolinone (1b), usually used as a
dipolarophile in chiral auxiliary-induced dipolar addition
reactions,4,6 showed low reactivity, providing moderate regi-
oselectivity and accompanying other isomers, while (E)-1-acetyl-
3-benzylideneindolinone (1a) reacted with 4-nitrobenzaldehyde
and diethyl aminomalonate (3a) under the catalysis of phos-
phoric acid 6a in dichloromethane at 25 °C smoothly and
(18) For discussion on regioselectivity of 1,3-dipolar addition reactions,
see: (a) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem.
Soc. 1973, 95, 7301, and refs 16a, 16b.
(19) Barr, D. A.; Grigg, R.; Sridharan, V. Tetrahedron Lett. 1989, 30, 4727.
9
J. AM. CHEM. SOC. VOL. 131, NO. 38, 2009 13821

A R T I C L E S
Chen et al.
Table 1. Optimization of Reaction Conditionsa
Table 3. Asymmetric Cycloaddition Reactions of Substituted
Methyleneindolinones Catalyzed by 6fa
entry
7
2
R1
rrc
yield (%)b
ee (%)d
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
7a
2a
2a
2a
2a
2t
4-CNC6H4
4-MeO2CC6H4
4-BrC6H4
4-FC6H4
4-ClC6H4
4-MeOC6H4
4-MeC6H4
2-FC6H4
2-ClC6H4
3-ClC6H4
3,4-Cl2C6H4
2-naphthyl
1-naphthyl
2-furanyl
(E)-PhCHdCH
i-Bu
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
95/5
83/17
89/11
80/20
>99/1
>99/1
>99/1
>99/1
95
93
97
91
94
96
92
97
95
93
91
90
92
74
82
94
94
88
94
89
94
91
92
91
93
92
92
90
81
86
90
90
92
98
93
90
89
83
82
92
93
88
entry
catalyst (6)
solvent
temp (°C)
yield (%)b
rrc
ee (%)d
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6f
6f
6f
6f
6f
6f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
(CH2Cl)2
PhCH3
THF
0
0
0
0
0
0
0
0
0
89
85
90
95
89
91
79
73
40
83
77
94
94
95/5
95/5
99/1
95/5
99/1
97/3
99/1
97/3
99/1
99/1
99/1
95/5
>99/1
22
40
5
2
0
93
83
78
83
84
-4
90
93e
9
10
11
12
13
14
15
16
17
18
19
20
21
9
10
11
12
13
0
0
CH2Cl2
CH2Cl2
-10
25
n-Pr
a The reaction was carried out on a 0.2 mmol scale with 3 Å MS
(300 mg) at 0 °C for 72 h, and the ratio of 1a/2a/3a was 2.0/1.2/1.0.
b Isolated yield. c The rr refers to the regiomeric ratio of 5a/4a and was
4-MeC6H4
4-ClC6H4
4-FC6H4
2t
2t
2u
7t
7u
determined by H NMR. d The ee was determined by HPLC. e The ratio
1
3-ClC6H4
of 1a/2a/3a was 1.2/1.2/1.0, and the reaction time was 24 h.
f Benzaldehyde was used as a reaction component.
a The reaction was carried out on a 0.2 mmol scale with 3 Å MS
(300 mg) for 24-96 h, the ratio of 1/2/3a was 1.2/1.2/1. b Isolated
yields. c The rr refers to the regiomeric ratio and was determined by 1H
NMR. d The ee was determined by HPLC.
Table 2. Scope of Aldehydes and Amino Estersa
and regioselectivities. The electronically deficient benzaldehydes
afforded higher stereoselectivity than the electronically rich and
neutral derivatives (entries 1-13 vs 14-16), but the electroni-
cally rich benzaldehydes gave lower regioselectivity (entries 15
and 16). Significantly, aliphatic aldehydes, including linear
enolizable variants such as n-butyraldehyde and n-pentanal, were
good reaction partners to give the desired products in good to
high yields and with excellent regio- and enantioselectivity
(>99/1 rr, 86-93% ee, entries 17-20). R-Arylglycine methyl
esters could also undergo the cycloaddition with 4-nitrobenzal-
dehyde and (E)-1-acetyl-3-benzylideneindolinone (1a) to re-
giospecifically give rise to spiro[pyrrolidin-3,3′-oxindoles] 5v-x
bearing two adjacent quaternary stereogenic centers (entries
21-23). These outcomes are particularly significant in view of
the challenges in the construction of quaternary stereogenic
centers.14
Further exploration of the substrate scope was focused on
methyleneindolinone derivatives bearing various substituents at
the carbon-carbon double bond (Table 3). The protocol was
applicable to either aromatic, aliphatic, or vinyl substituted
eneindolinones. For benzylideneindolinone derivatives, variation
at the para-substituent of the benzylidene moiety had little effect
on the enantioselectivity (entries 1-7). In contrast, ortho-
substituents of benzylideneindolinones were deleterious to the
stereoselectivity. Thus, 1-acetyl-3-(2-fluorobenzylidene)indoli-
none and 1-acetyl-3-(2-chlorobenzylidene)indolinone gave 81%
and 86% ee, respectively (entries 8-9), lower than those of
their structural analogues (entries 1-7, 10, and 11). Naphthal-
enylmethyleneindolinones participated in the cycloaddition
reactions to give the products with up to 98% ee (entries
12-13). 1-Acetyl-3-(2-furanylmethylene)indolinone afforded
entry
R (2)
R2 (3)
5
yield (%)b
rrc
ee (%)d
1
2
3
4
5
6
7
8
9
3-NO2C6H4 (2b)
2-NO2C6H4 (2c)
4-CNC6H4 (2d)
3-CNC6H4 (2e)
4-BrC6H4 (2f)
2-BrC6H4 (2g)
4-ClC6H4 (2h)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
5b
5c
5d
5e
5f
5g
5h
5i
96
91
93
91
96
89
97
97
94
93
96
97
93
87
95
86
71
59
89
90
85
80
90
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
>99/1
98/2
93
92
91
91
87
90
88
98
94
90
90
89
89
85
82
81
91
86
93
92
2,4-(NO2)2C6H3 (2i) CO2Et (3a)
2,3-Cl2C6H3 (2j)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
5j
10 3,4-Cl2C6H3 (2k)
11 2-Cl-4-FC6H3 (2l)
12 3-F-4ClC6H3 (2m) CO2Et (3a)
13 2-F-3-ClC6H3 (2n) CO2Et (3a)
5k
5 L
5m
5n
5o
5p
5q
5r
5s
>99/1
>99/1
95/5
14 Ph (2o)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
CO2Et (3a)
Ph (3b)
15 4-MeC6H4 (2p)
16 4-MeOC6H4 (2q)
17 n-Pr (2r)
18 n-Bu (2s)
19 i-Bu (2t)
20 t-BuCH2 (2u)
21 4-NO2C6H4 (2a)
22 4-NO2C6H4 (2a)
23 4-NO2C6H4 (2a)
87/13
>99/1
>99/1
>99/1
>99/1
5t
5u
5v
>99/1 82e
>99/1 85e
>99/1 84e
4-ClC6H4 (3c) 5w
4-FC6H4 (3d) 5x
a The reaction was carried out on a 0.2 mmol scale with 3 Å MS
(300 mg) for 24-96 h, the ratio of 1a/2/3a was 1.2/1.2/1. b Isolated
yields. c The rr refers to the regiomeric ratio of 5/4 and was determined
by 1H NMR. d The ee was determined by HPLC. e The reaction with 3
(Arylglycine methyl ester) in the presence of 20 mol % 6f at 35 °C,
giving >95/5 exo/endo, with a ratio of 1a/2a/3 of 2/1.2/1.
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Synthesis of Spiro[pyrrolidin-3,3′-oxindoles]
A R T I C L E S
Table 4. Generality of Asymmetric Cycloaddition Reactions for the Indolinone Moiety of Methyleneindolinonesa
a The reaction was carried out on a 0.2 mmol scale with 3 Å MS (300 mg) for 24-96 h, giving regiospecific products; the ratio of 1/2/3a was 1.2/
1.2/1. b Isolated yields. c The ee was determined by HPLC.
93% ee (entry 14). 1-Acetyl-3-((E)-3-phenylallylidene)indoli-
none and two species of 1-acetyl-3-(alkyl)indolinones underwent
clean cycloaddition reactions with good enantioselectivities, but
the regioselectivity was comparably lower (entries 15-17). In
addition to aromatic aldehydes, the less reactive aliphatic
aldehydes were also good reaction components for methyl-
eneindolinone derivatives. Thus, a number of benzylidenein-
dolinones reacted with 3-methylbutanal and 3,3-dimethylbutanal
in high yields and enantioselectivities (entries 18-21).
The generality of the reaction condition for the substituents
on the indolinone moiety of the methyleneindolinones was also
investigated (Table 4). Variation of the electronic properties of
the substituents at either C5 or C6 of methyleneindolinones was
tolerable with high yields ranging from 86% to 95% and
enantioselectivities ranging from 91% to 93% ee (entries 1-8).
The cycloaddition reactions with methyleneindolinones substi-
tuted at both C5 and C6 proceeded cleanly to afford spiro[py-
rrolidin-3,3′-oxindoles] in good yields and stereoselectivities
(entries 9-12). The presence of chlorine or fluorine at either
C5 or C6 of the spiro derivatives is very important for
pharmacological activity.4 Thus, these spiro[pyrrolidin-3,3′-
oxindole] derivatives will provide promising candidates for
chemical biology and drug discovery. The relative and absolute
configurations of 8d were assigned by the X-ray analysis (see
Supporting Information).
Theoretical Study of the Transition Structures and
Mechanism Considerations. We performed theoretical calcula-
tions on the transition state to explain the unusual regioselectivity
and high enantioselectivity observed in these reactions.20 As
shown in Figure 3, the best transition structure for the three-
component 1,3-dipolar cycloaddition reaction is TS-1, wherein both
the methyleneindolinone and the azomethine ylide are hydrogen-
bonded with the hydroxyl proton and phosphoryl oxygen of the
catalyst, which serve respectively as Brønsted acid and Lewis base
to activate the two substrates simultaneously.10,11 The hydroxyl
group appears to be a better hydrogen-bond donor as indicated
(20) All calculations were performed with the Gaussian 03 program.
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J. AM. CHEM. SOC. VOL. 131, NO. 38, 2009 13823

A R T I C L E S
Chen et al.
Figure 3. Located transition state structures and relative energies expressed in terms of enthalpy and of free energy in parentheses via B3LYP/6-31G*
calculations (distances in angstrom and energies in kcal/mol). Most H atoms are removed for clarity.
by the shorter hydrogen bond in all cases. TS-1, which leads to
the formation of the major product observed experimentally, is
found to be more stable than TS-2, which corresponds to the
minor product with regioselectivity opposite to the major
product, presumably due to the stabilization stemming from the
favorable π-π stacking interaction between the oxo-indole ring
and the conjugated esters in TS-1 (the distance between the oxo-
indole ring and the conjugated esters is only ∼3.0 Å).21 TS-3,
which leads to the formation of the enantiomer of the major
product, is considerably less stable than TS-1 in energy.
Moreover, in TS-3 the distance of PdO· · ·Hs(N) is as much
as 4.745 Å, unable to allow the formation of a hydrogen bond
for the activation of the azomethine ylide; therefore the
azomethine ylide is less activated than that in TS-1, resulting
in a slower 1,3-dipolar addition to generate the minor enantiomer.
regioselectivity observed experimentally, we proposed that two
zwitterionic azomethine ylide resonance forms might exist in
the present 1,3-dipolar cycloaddition reactions and be respon-
sible for the regioselectivity of the cycloaddition reaction of
azomethine ylide with unsymmetrical dipolarophiles.
The two zwitterionic resonance forms IIa and IIb were
confirmed by the theoretical calculations (Figure 3). As indicated
by the located transition state structures in TS-1, the C4-C5
bond is formed earlier than the C2-C3 bond, as the distance
of C4-C5 is shorter than that of C2-C3 by ∼0.86 Å. In TS-3,
the C4-C5 bond is also formed in the initial stage of the
reaction. In the transition states TS-1 and TS-3, the azomethine
ylide served as the zwitterionic resonance form IIb, reacting
with methyleneindolinones to afford spiro[pyrrolidin-3,3′-ox-
As reported previously in the relevant reactions, the azome-
thine ylide can present as two zwitterionic resonance forms IIa
and IIb.22 On the basis of the DFT calculations and the
(21) (a) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books; Sausalito, CA, 2005. (b)
Demeshko, S.; Dechert, S.; Meyer, F. J. Am. Chem. Soc. 2004, 126,
4508. (c) The aromatic stacking interaction between the aryl groups
to fix the geometry in chiral phosphoric acid catalysis; see: Yamanaka,
M.; Itoh, J.; Fuchibe, K.; Akiyama, T. J. Am. Chem. Soc. 2007, 129,
6756.
(22) (a) The proposed zwitterionic resonance forms are similar to the
principal resonance forms of the carbanion intermediate in transami-
nation reactions; see: Martell, A. E. Acc. Chem. Res. 1989, 22, 115.
(b) For the zwitterionic resonance forms of azomethine ylides, also
see: 16a, 16b.
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13824 J. AM. CHEM. SOC. VOL. 131, NO. 38, 2009

Synthesis of Spiro[pyrrolidin-3,3′-oxindoles]
A R T I C L E S
Scheme 2. Proposed Mechanism for the Regiospecific 1,3-Dipolar Reaction of Methyleneindolinones with Azomethine Ylides under the
Catalysis of the Chiral Brønsted Acid
Conclusion
indole] derivatives of type 5 (Scheme 2). However, in TS-2,
the distance of the forming C2-C4 bond is shorter than C3-C5
by ∼0.65 Å, indicating that the C2-C4 bond is formed earlier
than the latter, with the azomethine ylide serving as zwitterionic
resonance form IIa, giving the opposite regiomer of type 4.
Although the azomethine ylide form IIb in TS-1 is not usually
proposed in 1,3-dipolar cycloaddition reactions,7 TS-1 is favored
due to its lower enthalpy of ∼1.47 kcal mol-1 compared to TS-2
(Figure 3).
In summary, we have reported an unprecedented asymmetric
catalytic three-component 1,3-dipolar cycloaddition of a broad
range of methyleneindolinones with aldehydes and amino esters
by using a phosphoric acid as the chiral catalyst. This reaction
is so far the sole catalytic synthesis of spiro[pyrrolidin-3,3′-
oxindole] derivatives with high enantioselectivity and structural
diversity. This new, straightforward protocol for rapid construc-
tion of the privileged spirooxindole architecture has great
usefulness in medicinal chemistry and diversity-oriented
synthesis2a,4,6 and, thus, may lead to further development of
related compounds as potential medicinal agents. Theoretical
calculations disclosed that both the azomethine ylide and the
methyleneindolinone are hydrogen-bonded with the phosphoric
acid, which accounted for the high enantio- and regioselectivity
and indicated that the unusual regioselectivity results from the
stabilization stemming from the favorable π-π stacking interac-
tion between the oxo-indole ring and the conjugated esters. We
will next focus on the evaluation of the biological activity of
the molecules obtained from this method.
The proposed mechanism for the reaction course of this
cycloaddition reaction is summarized in Scheme 2. The 1,3-
dipolar cycloaddition reaction started with a condensation of
the aldehyde with amino esters, to give an imine 9. The chiral
phosphoric acid and the imino ester are able to form a chiral
azomethine ylide IIIa, which principally undergoes a 1,2-
prototropic process to form IIIb (Scheme 2).23 Either the chiral
azomethine ylide IIIa or IIIb reacts with the methyleneindoli-
none (1) to generate an intermediate IV, wherein the hydroxyl
proton and the phosphoryl oxygen of the chiral phosphoric acid
would form double hydrogen bonding interactions with the
methyleneindolinone and the azomethine ylide dipole, respec-
tively.10,11 The resulting reaction intermediate IV undergoes a
1,3-dipolar cycloaddition reaction, regiospecifically yielding
spiro[pyrrolidin-3,3′-oxindole] derivatives 5 via the transition
state Va (Scheme 2), as suggested by DFT calculation. In
contrast, the minor regiomer 4 was given by the reaction via
the energetically less favored transition state Vb.
Acknowledgment. We are grateful for financial support from
NSFC (20732006), MOST (973 program 2009CB825300), Ministry
of Education, and CAS. We also thank Dr. Zhenyu Li for his early
calculation on the electron density of 1a.
Supporting Information Available: Experimental details and
characterization of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(23) Grigg, R. Chem. Soc. ReV. 1987, 16, 89.
JA905302F
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J. AM. CHEM. SOC. VOL. 131, NO. 38, 2009 13825