ARTICLES
PUBLISHED ONLINE: 8 MAY 2011 | DOI: 10.1038/NCHEM.1039
Construction of bispirooxindoles containing three
quaternary stereocentres in a cascade using a
single multifunctional organocatalyst
Bin Tan1, Nuno R. Candeias1,2 and Carlos F. Barbas III1 *
Single-step constructions of molecules with multiple quaternary carbon stereocentres are rare. The spirooxindole
structural motif is common to a range of bioactive compounds; however, asymmetric synthesis of this motif is complicated
due to the presence of multiple chiral centres. The development of organocatalytic cascade reactions has proven to be
valuable for the construction of several chiral centres in one step. Here, we describe a newly designed organocatalytic
asymmetric domino Michael–aldol reaction between 3-substituted oxindoles and methyleneindolinones that affords
complex bispirooxindoles. This reaction was catalysed by a novel multifunctional organocatalyst that contains tertiary and
primary amines and thiourea moieties to activate substrates simultaneously, providing extraordinary levels of stereocontrol
over four stereocentres, three of which are quaternary carbon stereocentres. This new methodology provides facile access
to a range of multisubstituted bispirocyclooxindole derivatives, and should be useful in medicinal chemistry and diversityoriented syntheses of this intriguing class of compounds.
T
he biological activity and structural complexity found in
nature has stimulated generations of synthetic chemists to
design strategies for assembling challenging structures found
in natural products1–5. Particularly intriguing is the spirocyclicooxindole scaffold, which features in a large number of natural6–8 and
unnatural compounds with important biological activities
(Fig. 1a). Very recently, others have reported that a low nanomolar
concentration of spiroindolone NITD609 kills the blood stages of
Plasmodium falciparum and Plasmodium vivax, indicating that
this class of compounds has potential for the treatment of
malaria9. Motivated by the varied and significant biological activities
observed for this class of compounds, ‘diversity-oriented synthesis’
(DOS) and structure-based design approaches have been developed
to access analogues with the spirocyclic oxindole skeleton10,11.
The potential clinical significance of these enantiomerically pure
backbones has led to a demand for efficient asymmetric synthetic
methods. Significantly, within these structures are one or more
asymmetric quaternary carbon atoms. In general, the construction
of a single asymmetric quaternary carbon is regarded as a challenging problem in organic synthesis12,13. Only a select few asymmetric
transformations, such as cycloaddition processes14–18 and the intramolecular Heck reactions19, have been reported to provide reliable
approaches towards the construction of asymmetric quaternary
carbon centres. With bispirooxindoles, control of the stereochemistry at each of the three quaternary chiral centres of the skeleton is desired.
Organocatalytic20–23 enantioselective domino/cascade reactions24–28 are perceived as possible solutions to the synthesis of
enantiomerically enriched spirooxindoles. Many organocatalytic
reactions catalysed by cinchona alkaloid derivatives (Fig. 1b,
I–VI) have been described in studies that were pioneered by Deng
and others29–38. Recently, 3-substituted oxindoles were used as efficient Michael donors and methyleneindolinones as highly reactive
Michael acceptors39–47. Encouraged by these achievements, we
envisioned that bispirooxindole skeletons with four stereocentres,
including three quaternary chiral carbons, could be constructed
by domino Michael–aldol reactions between rationally designed
3-substituted oxindoles (1) and methyleneindolinones (2) in reactions catalysed by cinchona alkaloids (Fig. 1c). Here, we present
the first asymmetric catalytic domino process between 3-substituted
oxindoles and methyleneindolinones. Using a range of donors and
acceptors, the reaction proceeded with extremely good stereocontrol
to give bispirooxindole derivatives with high enantio and diastereo
purity and significant opportunities for structural diversification.
Results and discussion
The studies were initiated by evaluating the reaction between
1-benzyl-3-(2-oxo-2-phenylethyl) indolin-2-one 1a and methyleneindolinone 2a using quinine as the catalyst in dichloromethane at
room temperature. The reaction proceeded smoothly and afforded
the desired product in good yield with good diastereoselectivity,
but the enantioselectivity was moderate (Table 1, entry 1).
Hydroquinine amine II (Table 1, entry 2) and Deng’s catalysts
(Table 1, entries 3 and 4) were poor catalysts for this domino
process. Higher enantioselectivities (90:10 e.r.) and diastereoselectivities (90:10 d.r.) were achieved with thiourea catalysts (Table 1,
entries 5 and 6), indicating that a tertiary amine and the thiourea
moiety were important for control of the stereochemistry. Only
slight improvements accompanied changes in solvents and decrease
in temperature (Table 1, entries 7–10).
Attention was therefore turned to the catalyst design. In the presence of strongly basic cinchona guanidine VII, the reaction was fast,
giving almost quantitative yield and complete diastereoselectivity
(.99:1 d.r.) (Table 1, entry 11), although the reaction was not enantioselective. Inspired by Melchiorre’s results that the binaphthyl primary
amine and the thiourea hydrogen bond with the oxindole unit45, we
designed a trifunctional S-binaphthyl diamine catalyst VIII containing a binaphthyl primary amine, a thiourea and a tertiary amine. In
1
The Skaggs Institute for Chemical Biology and Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines
Road, La Jolla, California 92037, USA, 2 Faculdade de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa.
* e-mail: carlos@scripps.edu
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ARTICLES
a
NATURE CHEMISTRY
H
H
N
HO
H
NHMe
N
H
O
O
O
N
H
NH
MeN
c
F
PG
N
R
NH
O
N
H
Strychnofoline
O
OH
2
HN
Cl
Cyclopiamine B
b
Cl
O
N
O
Citrinadin B
N
H
NO2
MeO
N
H
O
HO
DOI: 10.1038/NCHEM.1039
R1
O
N
PG
Bispirooxindoles
NITD609
R4
R2
R3
N
H
N
F3C
R1O
H
N
H
N
F3C
N
S
3
N
4
N
N
O
N
Aldol
Michael
O
+
NPG
O
R2
1
2
3-Substituted oxindoles Methyleneindolinones
NH2
H H
N N
N
H
N
N
OMe
S
OMe
N
N
N
VIII: R = NH2; IX R = OH
VII
R1
VI
S
MeO
OMe
N
PG
R
H
N
N
N
CF3
V
I: R = Me; R = OH; R = H; R = CH2 = CH
II: R1 = Me; R2 = H; R3 = NH2; R4 = CH3CH2
III: R1 = Ph; R2 = H; R3 = OH; R4 = CH2 = CH
IV: R1 = H; R2 = OBz; R3 = H; R4 = CH2 = CH
2
N
S
CF3
N
1
Cinchona alkaloid
catalyst
H
N
X
Figure 1 | Overview of spirooxindoles and a strategy for their preparation. a, Naturally occurring and biologically active spirooxindoles. b, Structures of
cinchona alkaloid derived organocatalysts. c, Proposed concept for direct construction of bispirooxindoles.
Table 1 | Optimization of organocatalytic domino Michael–Aldol reactions.
Ph
O
20 mol% catalyst
+
O
1a
Cat.
I
II
III
IV
V
VI
VI
VI
VI
VI
VII
VIII
IX
X
VIII
VIII
VIII
VIII
VIII
VIII
O
Solvent, rt, 24 h
N
Ac
N
Bn
Entry
1
2
3
4
5
6
7
8
9
10§
11
12
13
14
15
16
17
18
19
20}
Ac
N
R
Ph
O
N
Bn
3a, 3b
2a: R = CO2Me,
2b: R = COPh
SM2
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
R
O
OH
Solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCE
C6H5CN
C6H6
C6H6
DCM
DCM
DCM
DCM
C6H6
MeOH
DCE
DCM
DCM
DCM
Yield (%)*
78
65
83
67
84
81
81
83
86
78
93
86
74
85
79
90
86
71
86
87
d.r.†
91:9
80:20
83:17
64:36
92:8
80:20
82:18
93:7
92:8
88:12
.99:1
91:9
90:10
91:9
89:11
94:6
90:10
88:12
96:4
96:4
e.r.‡
40:60
70:30
58:42
51:49
12:88
90:10
91:9
79:21
92:8
91:9
50:50
95:5
86:14
90:10
93:7
52:48
95:5
91:9
97:3
97:3
Unless otherwise specified, all reactions were carried out using 3-substituted oxindole 1a (0.05 mmol, 1.0 equiv.) and methyleneindolinone 2a or 2b (0.075 mmol, 1.5 equiv.) with 20 mol% catalyst at room
temperature (22 8C). *Isolated yields of diastereomeric mixture. †Determined by crude 1H-NMR spectroscopy and chiral-phase HPLC. ‡Major diastereoisomer determined by chiral-phase HPLC analysis.
§
Reaction was conducted at 0 8C for 36 h. Reaction was conducted at 215 8C for 48 h. }15 mol% catalyst was used.
2
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NATURE CHEMISTRY
ARTICLES
DOI: 10.1038/NCHEM.1039
Table 2 | Generality of the domino reactions for construction of bispirooxindoles.
R1
O
2
R
O
+
O
O
1a-i
R1
Ph
Ph
Ph
Ph
4-F-Ph
3-OMe-Ph
2-Furanyl
2-Thiophenyl
2-Thiophenyl
2-Thiophenyl
Ph
Me
2
O
OH
R OC
DCM, rt, 24 h
R1
O
N
Ac
N
Bn
Entry
1
2
3
4
5
6
7
8
9
10
11§
12
15 mol% catalyst VIII
R3
Ac
N
R3
N
Bn
2b-h
3b-m
R2
Ph
Ph
Ph
4-Cl-Ph
Ph
Ph
Ph
Ph
4-Cl-Ph
Ph
2-Me-Ph
Ph
R3
H
5-F
5-Br
H
H
H
H
H
H
5-F
H
H
d.r.†
96:4
97:3
95:5
96:4
98:2
95:5
.99:1
96:4
.99:1
.99:1
95:5
63:37
Yield (%)*
3b, 84
3c, 92
3d, 87
3e, 89
3f, 81
3g, 79
3h, 94
3i, 89
3j, 88
3k, 92
3l, 69
3m, 56
e.r.‡
97:3
97:3
97:3
97:3
95:5
98:2
97:3
98:2
98:2
98:2
91:9
97:3
Unless otherwise specified, all reactions were carried out by using 3-substituted oxindole 1 (0.05 mmol, 1.0 equiv.) and methyleneindolinone 2 (0.075 mmol, 1.5 equiv.) with 15 mol% catalyst VIII at room
temperature (23 8C). *Yield of single diastereomer. †Determined by crude 1H-NMR spectroscopy and chiral-phase HPLC. ‡Determined by chiral-phase HPLC analysis. §The reaction required 48 h. The
reaction required only 12 h for completion, and the pure major diastereomer can be separated by column chromatography in 56% yield.
the presence of this new catalyst, the reaction proceeded smoothly and
gave rise to the desired product in high yield with good enantioselectivity (95:5 e.r.) and diastereoselectivity (Table 1, entry 12). Various
solvents were evaluated, but no significant improvement was observed
(Table 1, entries 15–17). It is noteworthy that both d.r. and e.r.
dropped slightly when the temperature decreased (Table 1, entry
18). Replacement of the catalysts’ primary amine with a hydroxyl
group (catalyst IX) or replacement of the S-diamine component of
the catalysts with an R-diamine (catalyst X) did not lead to more
efficient reaction, and enantioselectivities with these catalysts were
modest (Table 1, entries 13 and 14). These data suggest that the
primary amine in catalyst VIII plays a key role in this transformation.
We then performed the reaction with a different methyleneindolinone,
expecting that the added carbonyl group (2b) would have additional
interactions with the multifunctional catalyst. Products were obtained
with excellent diastereoselectivities and enantioselectivities (Table 1,
entries 19 and 20), demonstrating that interactions between the substrates and catalyst were crucial.
We explored the utility of this approach for the preparation of a
range of substituted bispirocyclic oxindoles containing three quaternary chiral centres. Catalyst VIII promoted domino Michael–
aldol reactions of a variety of substituted oxindoles and methyleneindolinone derivatives bearing various substituents in ketones and
in the oxindolinones (Table 2). Products were obtained in excellent enantioselectivities (up to 98:2 e.r.) and diastereoselectivities
(up to .99:1 d.r.). Notably, minimal impact on efficiencies, enantioselectivities and diastereoselectivities was observed, regardless
of the electronic nature, bulkiness or positions of the substituents.
In addition to aromatic groups, heterocyclic analogues were used
to acquire the bispirooxindole products with excellent stereoselectivities (Table 2, entries 7–10). Further exploration of the substrate
scope was focused on methyleneindolinone ester moieties. As
shown in Fig. 2, a wide variety of bispirooxindoles was obtained
in excellent yields and diastereo- and enantioselectivitites.
From a DOS point of view it is interesting to provide methods to
access both enantiomers. Hence, we prepared and characterized catalyst XI, in which the S-diamine component was kept and the tertiary
amine and the thiourea configurations were changed when compared
with catalyst VIII. This novel catalyst allowed us to prepare the other
enantiomer of the product with good stereocontrol (Fig. 3).
To further expand the potential of this transformation as a tool
to obtain bispirooxindoles, we proceeded to investigate different
protecting groups and removal of protecting groups (Fig. 4). The
4-bromobenzyl protecting group proved to be well tolerated by
the reaction, providing for the efficient synthesis of 5. Use of carbamate protecting groups resulted in products with reduced optical
purity. The deprotection of 3b was achieved in quantitative yield
R1
R3
20 mol% catalyst VIII
O + R3
R2
N
Bn
Ac
N
O
N
Ac
DCM, rt, 24 h
Ac
N
Ac
N
Ac
N
N
Bn
OMe
3o
86% yield,
93:7 d.r.,
96:4 e.r.
Ac
N
O
OH
MeO2C
MeO
O
OH
EtO2C
O
O
N
Bn
N
Bn
O
OH
O
O
3n
79% yield,
91:9 d.r.,
95:5 e.r.
O
OH
3p
74% yield,
89:11 d.r.,
94:6 e.r.
O
MeO2C
N
Bn
MeO2C
R1
R2
O
N
Bn
Ac
N
R O2C
O
OH
MeO2C
O
3a
78% yield,
91:9 d.r.,
95:5 e.r.
O
OH
4
N
Bn
O
OH
MeO2C
Cl
Ac
N
O
R4O
O
3q
77% yield,
88:12 d.r.,
96:4 e.r.
O
N
Bn
3r
81% yield,
89:11 d.r.,
95:5 e.r.
Figure 2 | Further exploration of substrates involving methyleneindolinone
esters. A wide variety of bispirooxindoles was obtained, regardless of the
electronic nature, bulkiness or positions of the substituents on the
3-substituted oxindole substrate.
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ARTICLES
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NH2
H H
N N
Ph
PhOC
O
XI
N
Bn
N
Ph
O
N
Bn
76% yield,
94:6 d.r.,
5:95 e.r.
2b
O
OH
PhOC
DCM, rt
N
Ac
1a
Ac
N
OMe
20 mol%
O
O+
plan to expand the application of this multifunctional catalyst
in other asymmetric transformations and to investigate the biological activity of the bispirocyclic compounds synthesized. These
studies highlight the growing potential of reaction and catalyst
design in organocatalysis. We believe that it is likely that novel compounds based on bispirocyclic oxindole skeletons, such as those
prepared here, will provide novel therapeutic agents and useful
biological tools.
N
S
3b
(1R,2R,3S,4R)
Received 4 February 2011; accepted 25 March 2011;
published online 8 May 2011
Figure 3 | Preparation of enantiomer (1R,2R,3S,4R )-3b. The 3b enantiomer
was prepared using catalyst XI; the S-diamine component was kept, and the
tertiary amine and thiourea configuration were changed compared with
catalyst VIII.
a
Me
Ph
O
O
O +
N
PG
Ac
N
PhOC
15 mol% catalyst VIII
N
Ac
2b
PG = 4-Br-Bn
4
b
Ac
N
O
O
OH
Ph
O
N
Bn
3b (97:3 e.r.)
PhOC
O
OH
Ph
N
PG
83% yield,
95:5 d.r.,
95:5 e.r.
5
H
N
HCl (conc.)
EtOH, 80 °C
2h
quantitative yield
References
O
DCM, rt, 24 h
O
OH
PhOC
Ph
O
N
Bn
6 (97:3 e.r.)
Figure 4 | Investigation of a different protecting group and deprotection of
bispirooxindole. a, Benzyl bromide as N-protecting group of 3-substituted
oxindole. b, Deprotection of N-acetyl bisspirooxindole.
with retention of stereochemistry by acidic ethanolysis at 80 8C
for 2 h.
According to the dual activation model proposed by Takemoto48,
Deng49 and theoretical calculations performed by Papai50, the two
substrates involved in the reaction are activated simultaneously by
the catalyst, as shown in Supplementary Fig. 7. The 3-substituted
oxindole presumably interacts with the thiourea moiety of the catalyst via multiple hydrogen bonds, enhancing the electrophilicity of
the reacting carbon centre. Concurrently, the ketone or ester
moiety of methyleneindolinone coordinates to the tertiary amine
group in an interaction crucial for stereocontrol. The poor results
of an experiment with a methyleneindolinone directly connected
to a phenyl group (no ketone or ester moiety) supports the importance of this hydrogen-bonding interaction (Supplementary Fig. 8).
The absolute configurations of 3e and 3p were determined by X-ray
analysis (Supplementary Fig. 9) and are in accordance with that
predicted by the catalytic model.
We have developed a highly efficient organocatalytic domino
Michael–aldol approach for the direct construction of bispirocyclic
oxindole derivatives containing four chiral centres, including three
quaternary carbon chiral centres. This straightforward process,
catalysed by a novel multifunctional cinchona alkaloid containing
a primary amine and axial chiral moiety, offers excellent stereocontrol (up to .99:1 d.r. and 98:2 e.r.), and makes use of simple starting
materials and mild conditions. Significantly, catalyst reconfiguration
provided access to the opposite enantiomer. In future studies we
4
DOI: 10.1038/NCHEM.1039
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Acknowledgements
The authors acknowledge the Skaggs Institute for Chemical Biology for funding. N.R.C.
thanks Fundação para a Ciência e Tecnologia (SFRH/BPD/46589/2008) for financial
support. The authors also thank A.L. Rheingold for X-ray crystallographic analysis.
Author contributions
B.T. and N.C. designed and carried out the chemical experiments. C.B. designed the
experiments and supervised the project. All authors discussed the results, contributed to
writing the manuscript, and commented on the manuscript.
Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://www.
nature.com/reprints/. Correspondence and requests for materials should be addressed to C.F.B.
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