Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst

Article abstract of DOI:10.1038/nchem.1039

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 o

Full text of DOI:10.1038/nchem.1039

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 diversity-
oriented syntheses of this intriguing class of compounds.
he biological activity and structural complexity found in envisioned that bispirooxindole skeletons with four stereocentres,
nature has stimulated generations of synthetic chemists to including three quaternary chiral carbons, could be constructed
T
design strategies for assembling challenging structures found by domino Michael–aldol reactions between rationally designed
in natural products1–5. Particularly intriguing is the spirocyclicoox- 3-substituted oxindoles (1) and methyleneindolinones (2) in reac-
indole scaffold, which features in a large number of natural6–8 and tions catalysed by cinchona alkaloids (Fig. 1c). Here, we present
unnatural compounds with important biological activities the first asymmetric catalytic domino process between 3-substituted
(Fig. 1a). Very recently, others have reported that a low nanomolar oxindoles and methyleneindolinones. Using a range of donors and
concentration of spiroindolone NITD609 kills the blood stages of acceptors, the reaction proceeded with extremely good stereocontrol
Plasmodium falciparum and Plasmodium vivax, indicating that to give bispirooxindole derivatives with high enantio and diastereo
this class of compounds has potential for the treatment of purity and significant opportunities for structural diversification.
malaria9. Motivated by the varied and significant biological activities
observed for this class of compounds, ‘diversity-oriented synthesis’ Results and discussion
(DOS) and structure-based design approaches have been developed The studies were initiated by evaluating the reaction between
to access analogues with the spirocyclic oxindole skeleton10,11
.
1-benzyl-3-(2-oxo-2-phenylethyl) indolin-2-one 1a and methylene-
The potential clinical significance of these enantiomerically pure indolinone 2a using quinine as the catalyst in dichloromethane at
backbones has led to a demand for efficient asymmetric synthetic room temperature. The reaction proceeded smoothly and afforded
methods. Significantly, within these structures are one or more the desired product in good yield with good diastereoselectivity,
asymmetric quaternary carbon atoms. In general, the construction but the enantioselectivity was moderate (Table 1, entry 1).
of a single asymmetric quaternary carbon is regarded as a challen- Hydroquinine amine II (Table 1, entry 2) and Deng’s catalysts
ging problem in organic synthesis12,13. Only a select few asymmetric (Table 1, entries 3 and 4) were poor catalysts for this domino
transformations, such as cycloaddition processes14–18 and the intra- process. Higher enantioselectivities (ꢀ90:10 e.r.) and diastereoselec-
molecular Heck reactions19, have been reported to provide reliable tivities (90:10 d.r.) were achieved with thiourea catalysts (Table 1,
approaches towards the construction of asymmetric quaternary entries 5 and 6), indicating that a tertiary amine and the thiourea
carbon centres. With bispirooxindoles, control of the stereo- moiety were important for control of the stereochemistry. Only
chemistry at each of the three quaternary chiral centres of the skel- slight improvements accompanied changes in solvents and decrease
eton is desired.
in temperature (Table 1, entries 7–10).
Organocatalytic20–23 enantioselective domino/cascade reac-
Attention was therefore turned to the catalyst design. In the pres-
tions24–28 are perceived as possible solutions to the synthesis of ence of strongly basic cinchona guanidine VII, the reaction was fast,
enantiomerically enriched spirooxindoles. Many organocatalytic giving almost quantitative yield and complete diastereoselectivity
reactions catalysed by cinchona alkaloid derivatives (Fig. 1b, (.99:1 d.r.) (Table 1, entry 11), although the reaction was not enantio-
I–VI) have been described in studies that were pioneered by Deng selective. Inspired by Melchiorre’s results that the binaphthyl primary
and others29–38. Recently, 3-substituted oxindoles were used as effi- amine and the thiourea hydrogen bond with the oxindole unit45, we
cient Michael donors and methyleneindolinones as highly reactive designed a trifunctional S-binaphthyl diamine catalyst VIII contain-
Michael acceptors39–47. Encouraged by these achievements, we ing a binaphthyl primary amine, a thiourea and a tertiary amine. In
1The Skaggs Institute for Chemical Biology and Departments of Chemistry and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines
2
´
Road, La Jolla, California 92037, USA, Faculdade de Farmacia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa.
e-mail: carlos@scripps.edu
*
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1039
ARTICLES
a
c
F
H
N
H
H
O
PG
N
HO
Cl
N
HO
H
N
O
OH
R1
N
O
H
R2
NHMe
MeN
H
NH
NO2
HN
MeO
O
NH
O
O
N
N
O
Cl
H
N
N
O
PG
H
O
Citrinadin B
Cyclopiamine B
Strychnofoline
NITD609
Bispirooxindoles
R4
b
Cinchona alkaloid
catalyst
R3
H
H
H
N
H
N
R2
F3C
N
F3C
N
N
N
N
R1O
OMe
S
S
R1
CF3
CF3
O
N
N
N
Aldol
Michael
NPG
I: R1 =Me; R2 =OH; R3 =H; R4 =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
V
VI
O
O
+
R2
N
PG
1
2
3-Substituted oxindoles Methyleneindolinones
NH2
R
N
N
N
H
H
N
H
H
N
N
N
N
N
N
OMe
OMe
S
S
MeO
N
N
N
VII
VIII: R=NH2; IX R=OH
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.
Ac
Ph
N
R
O
O
OH
20mol% catalyst
Solvent, rt, 24h
+
R
Ph
O
O
N
O
N
Ac
N
Bn
Bn
1a
2a: R=CO2Me,
2b: R=COPh
3a, 3b
Entry
Cat.
SM2
Solvent
Yield (%)*
d.r.†
e.r.‡
1
2
3
4
5
6
7
8
I
II
III
IV
V
VI
VI
VI
VI
VI
VII
VIII
IX
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
DCM
DCM
DCM
DCM
DCM
DCM
DCE
C6H5CN
C6H6
C6H6
DCM
DCM
DCM
DCM
C6H6
MeOH
DCE
78
65
83
67
84
81
91:9
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
80:20
83:17
64:36
92:8
80:20
82:18
93:7
92:8
88:12
.99:1
91:9
81
83
86
78
93
86
74
85
79
90
86
71
9
10§
11
12
13
14
15
16
17
18ꢁ
19
20}
90:10
91:9
X
VIII
VIII
VIII
VIII
VIII
VIII
89:11
94:6
90:10
88:12
96:4
96:4
DCM
DCM
DCM
86
87
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.
474
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1039
ARTICLES
Table 2 | Generality of the domino reactions for construction of bispirooxindoles.
Ac
N
R1
O
3
R
O
2
R
O
OH
R1
15mol% catalyst VIII
+
R2OC
3
DCM, rt, 24h
O
R
O
O
N
N
Ac
N
Bn
Bn
1a-i
2b-h
3b-m
Entry
R1
R2
R3
Yield (%)*
d.r.†
e.r.‡
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Cl-Ph
Ph
Ph
Ph
Ph
4-Cl-Ph
Ph
H
3b, 84
3c, 92
3d, 87
3e, 89
3f, 81
3g, 79
3h, 94
3i, 89
3j, 88
3k, 92
3l, 69
3m, 56
96:4
97:3
95:5
96:4
98:2
95:5
.99:1
96:4
.99:1
.99:1
95:5
97:3
97:3
97:3
97:3
95:5
98:2
97:3
98:2
98:2
98:2
91:9
97:3
5-F
5-Br
H
H
H
H
H
H
5-F
H
4-F-Ph
3-OMe-Ph
2-Furanyl
2-Thiophenyl
2-Thiophenyl
2-Thiophenyl
Ph
9
10
11§
12ꢁ
2-Me-Ph
Ph
Me
H
63:37
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
To further expand the potential of this transformation as a tool
gave rise to the desired product in high yield with good enantioselec- to obtain bispirooxindoles, we proceeded to investigate different
tivity (95:5 e.r.) and diastereoselectivity (Table 1, entry 12). Various protecting groups and removal of protecting groups (Fig. 4). The
solvents were evaluated, but no significant improvement was observed 4-bromobenzyl protecting group proved to be well tolerated by
(Table 1, entries 15–17). It is noteworthy that both d.r. and e.r. the reaction, providing for the efficient synthesis of 5. Use of carba-
dropped slightly when the temperature decreased (Table 1, entry mate protecting groups resulted in products with reduced optical
18). Replacement of the catalysts’ primary amine with a hydroxyl purity. The deprotection of 3b was achieved in quantitative yield
group (catalyst IX) or replacement of the S-diamine component of
the catalysts with an R-diamine (catalyst X) did not lead to more
R1
O
Ac
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 thenperformed the reactionwith a differentmethyleneindolinone,
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 sub-
strates and catalyst were crucial.
N
O
R4O
O
OH
R1
R3
20mol% catalyst VIII
R4O2C
R2
R2
+
R3
O
O
DCM, rt, 24h
N
N
O
Bn
Ac
N
Bn
Ac
N
Ac
N
Ac
N
O
OH
O
O
OH
OH
MeO2C
MeO2C
MeO2C
We explored the utility of this approach for the preparation of a
range of substituted bispirocyclic oxindoles containing three qua-
ternary chiral centres. Catalyst VIII promoted domino Michael–
aldol reactions of a variety of substituted oxindoles and methylene-
indolinone derivatives bearing various substituents in ketones and
in the oxindolinones (Table 2). Products were obtained in excel-
lent enantioselectivities (up to 98:2 e.r.) and diastereoselectivities
(up to .99:1 d.r.). Notably, minimal impact on efficiencies, enan-
tioselectivities 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 stereoselec-
tivities (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.
O
O
O
O
N
N
N
OMe
Bn
Bn
Bn
3a
3n
3o
78% yield,
91:9 d.r.,
95:5 e.r.
79% yield,
91:9 d.r.,
95:5 e.r.
86% yield,
93:7 d.r.,
96:4 e.r.
Ac
N
Ac
N
Ac
N
Cl
O
OH
O
OH
O
OH
MeO2C
MeO2C
MeO
EtO2C
O
O
O
N
N
N
Bn
Bn
Bn
3p
3q
3r
74% yield,
89:11 d.r.,
94:6 e.r.
77% yield,
88:12 d.r.,
96:4 e.r.
81% yield,
89:11 d.r.,
95:5 e.r.
From a DOS point of view it is interesting to provide methods to
access both enantiomers. Hence, we prepared and characterized cat-
alyst XI, in which the S-diamine component was kept and the tertiary Figure 2 | Further exploration of substrates involving methyleneindolinone
amine and the thioureaconfigurations were changed when compared esters. A wide variety of bispirooxindoles was obtained, regardless of the
with catalyst VIII. This novel catalyst allowed us to prepare the other electronic nature, bulkiness or positions of the substituents on the
enantiomer of the product with good stereocontrol (Fig. 3).
3-substituted oxindole substrate.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1039
ARTICLES
plan to expand the application of this multifunctional catalyst
in other asymmetric transformations and to investigate the bio-
logical 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 com-
pounds based on bispirocyclic oxindole skeletons, such as those
prepared here, will provide novel therapeutic agents and useful
biological tools.
NH2
N
H
H
Ac
N
N
N
OMe
Ph
S
O
OH
PhOC
O
XI
N
PhOC
Ph
20mol%
DCM, rt
O
O
+
O
N
N
N
Bn
1a
Ac
2b
Bn
76% yield,
94:6 d.r.,
5:95 e.r.
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.
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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 cata-
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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 impor-
tance 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 stereocon-
trol (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
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.1039
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Acknowledgements
The authors acknowledge the Skaggs Institute for Chemical Biology for funding. N.R.C.
ˆ
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thanks Fundac¸ao para a Ciencia e Tecnologia (SFRH/BPD/46589/2008) for financial
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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.
catalysts: asymmetric Michael and Mannich reactions of 3-aryloxindoles. Angew. Additional information
Chem. Int. Ed. 47, 4559–4561 (2009).
The authors declare no competing financial interests. Supplementary information and
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diastereoselective additions of oxindoles to nitroolefins: application to the formal
synthesis of (þ)-physostigmine. J. Am. Chem. Soc. 131, 8758–8759 (2009).
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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