An organocatalytic cascade strategy for the enantioselective construction of spirocyclopentane bioxindoles containing three contiguous stereocenters and two spiro quaternary centers

Article abstract of DOI:10.1002/chem.201200478

A rapid and efficient organocatalytic cascade sequence for the direct construction of spirocyclopentane bioxindoles has been carried out by using a chiral squaramide catalyst in the presence of a base. This process constitutes a powerful approach to the preparation of biologically important bispirooxindoles in high enantioselectivities (see scheme). Copyright

Full text of DOI:10.1002/chem.201200478

COMMUNICATION
DOI: 10.1002/chem.201200478
An Organocatalytic Cascade Strategy for the Enantioselective Construction
of Spirocyclopentane Bioxindoles Containing Three Contiguous
Stereocenters and Two Spiro Quaternary Centers
Wangsheng Sun, Gongming Zhu, Chongyang Wu, Liang Hong,* and Rui Wang*[a]
Spirocyclic oxindoles are structural motifs frequently
found in many natural products and biologically active mol-
ecules.[1] Among them, the 3,3’-pyrrolidonyl spirooxindole
unites are well known for their bioactivity profiles, thus re-
markable advances have been made on the enantioselective
synthesis of this fused heterocyclic system.[2] However, spiro-
cyclic oxindoles with carbocyclic five- or six-membered rings
are also important substructures that are widely present in
numerous bioactive natural products[3] (Figure 1). To our
lytic asymmetric approach to access optically pure cyclopen-
tane spirocyclic oxindoles has met with little success[6] Con-
sequently, it is highly desirable to develop an effective cata-
lytic system for the direct construction of carbocyclic spi-
rooxindole skeletons with respect to synthetic efficiency.
On the other hand, bi-indole, indole-oxindole, or bioxin-
dole scaffolds are featured in a large number of medicinally
compounds. Remarkable advances have been made recently
on the enantioselective synthesis of bi-indole and indole-ox-
indole backbones, mainly based on catalytic asymmetric cy-
cloaddition or cascade strategies.[7] However, the construc-
tion of spirocyclic bioxindoles is regarded as a challenging
problem due to the simultaneous creation of multiple chiral
centers and spiro quaternary centers.[8] Quite recently, Bar-
bas III and co-workers represented the only elegant example
of organocatalytic highly enantioselective synthesis of spiro-
cyclopentane bioxindoles through cascade Michael-Aldol re-
action of activated methyleneindolinones.[7c]
Recently, chiral squaramides have been demonstrated as
a novel type of good hydrogen-bonding donors in organoca-
talysis and successfully applied in various asymmetric reac-
tions. Based on the inherent resemblances and differences
with their urea/thiourea counterparts, squaramides may
offer complementarity or even superiority in respect to reac-
tivity and stereoinduction.[9] However, they are far from
being well investigated as efficient organocatalysts and their
further studies are in great demand.
We have recently reported some reactions using methyle-
neindolinones or oxindoles for the construction of chiral spi-
rocyclic oxindole derivatives with quaternary centers.[10] En-
couraged by these achievements, we envisioned that spirocy-
clopentane bioxindole skeletons with three contiguous ste-
reocenters, including two spiro quaternary centers, might be
constructed by cascade[11] Michael-alkylation[12] sequence be-
tween methyleneindolinones 1 and rationally designed 3-
substituted oxindoles 2 (Scheme 1). However, several chal-
lenges are associated with this cascade sequence in one
single operation: 1) the poisoning of the catalyst by the gen-
erated HBr, 2) the formation of highly sterically congested
spirocyclopentane having five substituents, 3) the control of
diastereo- and enantioselectivity, in consideration of the si-
multaneous creation of three quaternary centers, including
two spiro quaternary centers at the cyclopentane.
Figure 1. Representative natural products containing carbocyclic spiroox-
indole skeletons.
surprise, despite the syntheses of spirocyclohexane oxindoles
have been well documented,[4] efficient methods for the
enantioselective synthesis of spirocyclopentane oxindoles
have been barely disclosed. Quite recently, the tertiary phos-
phine catalyzed [3+2] cycloaddition reactions have been de-
veloped for the synthesis of spirocyclopentane oxindoles.[5]
Although these elegant and creative strategies toward the
construction of carbocyclic spirooxindoles, the directly cata-
[a] W. Sun, G. Zhu, C. Wu, L. Hong, Prof. Dr. R. Wang
Key Laboratory of Preclinical Study
for New Drugs of Gansu Province
School of Basic Medical Science
Institute of Biochemistry and Molecular Biology
School of Life Sciences, Lanzhou University
Lanzhou, 730000 (P.R. China)
Fax : (+86)931-891-2567
E-mail: hongl@lzu.edu.cn
wangrui@lzu.edu.cn
The feasibility of this proposed cascade reaction was first
evaluated between the methyleneindolinone 1a and 3-sub-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200478.
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good yield, though the enantioselectivity was yet satisfactory
(Table 1, entries 2 and 3). Encouraged by these results, we
then examined several bifunctional thiourea catalysts. The
results showed that Takemotoꢁs catalyst III[13] served best to
the reaction (Table 1, entries 3–6). Subsequent screening of
solvents displayed that the reaction media had a significant
effect on the reaction (Table 1, entries 5 and 7-10), and
CH2Cl2 gave the best result (Table 1, entry 8). A survey of
bases revealed that K2CO3 was the optimal one (Figure 2;
Table 1, entries 8 and 11–14).
Scheme 1. Molecular complexity from just two simple substrates in an or-
ganocatalytic cascade Michael-alkylation sequence.
stituted oxindole 2a by a bifunctional thiourea catalyst I de-
rived from quinine. Pleasingly, the reaction proceeded
smoothly to afford the desired product 3a in good yield
albeit with four diastereomers (Table 1, entry 1). Consider-
ing that the protecting group on the substrates might greatly
affect the diastereoselectivity via interaction with the multi-
functional catalyst, we modified the substrates and found
that the reaction between Boc protected 1b and benzyl pro-
tected 2b could give much better diastereoselectivity in
Table 1. Optimization of the reaction.[a]
Figure 2. Screened catalysts.
With these results in hand, it was realized that we could
do better to further optimize the reaction. We therefore
turned our attention toward the use of chiral 1,2-diaminocy-
clohexane derived squaramides as the H-bonding motif.
Gratifyingly, the chiral squaramide catalyst VI, which struc-
turally resembled the analogous Takamotoꢁs thiourea cata-
lyst, catalyzed the reaction in 97% yield, d.r. of 12.9:2:1 and
93% ee (Table 1, entry 16). When the catalyst loading was
reduced to 10 mol%, the same excellent results were ob-
tained (Table 1, entry 17). It is noteworthy that both diaste-
reoselectivity and enantioselectivity dropped slightly when
the catalyst loading decreased to 1 mol% (Table 1,
entry 18). Thus catalyst VI at a 10 mol% loading was select-
ed for further studies in terms of efficiency. Furthermore,
Lowering the reaction temperature to 08C has a greatly neg-
ative effect on both yield and diastereoselectivity (Table 1,
entry 19).
The generality of this cascade process was next investigat-
ed by using various methyleneindolinones (Scheme 2). Most
of the reactions evaluated were completed within 24 h with
good yields (70–98%) and enantioselectivities (90–96% ee).
Notably, minimal impact on efficiencies, enantioselectivities
and diastereoselectivities was observed, regardless of the
electronic nature, bulkiness or positions of the substitution
patterns on the methyleneindolinone 1 (3c–3m). Further ex-
ploration of the substrate scope was focused on the N-pro-
tecting groups of the 3-substituted oxindoles. They both
gave the corresponding compounds in good yields and enan-
tioselectivities (3n–3o).[14] Although this cascade sequence
proceeded with moderate control over the relative configu-
Entry Cat. Solvent Base
Yield [%][b] d.r.[c]
ee [%][d]
n.d.[e]
43
17
60
1
2
3
4
5
6
7
8
I
I
I
II
tol
tol
tol
tol
tol
tol
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
3a, 85
3b, 87
3c, 86
3c, 90
3c, 92
3c, 78
3c, 72
3c, 94
3c, 89
3c, 91
3c, 95
3c, 93
1:1:1:1
1.5:1:1
10:2:1
2:1:1
3:1:1
0:1:1
2:1:1
4:1:1
2:1:1
3:1:1
III
IV
III
III
III
III
III
III
III
III
V
65
n.d.[e]
48
THF
CH2Cl2 Na2CO3
CHCl3
DCE
CH2Cl2 K2CO3
CH2Cl2 KHCO3
86
73
85
89
83
81
55
9
Na2CO3
Na2CO3
10
11
12
13
14
15
16
17[f]
18[g]
19[f,h]
5.2:1:1
4.5:1:1
5:1:1
CH2Cl2 NaHCO3 3c, 54
CH2Cl2 Cs2CO3
CH2Cl2 K2CO3
CH2Cl2 K2CO3
CH2Cl2 K2CO3
CH2Cl2 K2CO3
CH2Cl2 K2CO3
3c, 76
3c, 92
3c, 94
3c, 95
3c, 90
3c, 65
2:1:1
10.7:1.8:1 89
12.9:2:1 93
13.7:2.1:1 94
13.4:5.6:1 90
2:1:1
VI
VI
VI
VI
n.d.[e]
[a] Unless otherwise specified, the reaction was carried out with
1 (0.12 mmol), 2 (0.10 mmol), catalyst (0.02 mmol) and base (0.10 mmol)
in solvent (1.0 mL) at room temperature for 24 h. [b] Sum of diastereo-
isomers. [c] Determined by 1H NMR spectroscopy of the crude mixture.
[d] Determined by chiral HPLC on a Chiralcel IA column. [e] Not deter-
mined. [f] 10 mol% of catalyst was used. [g] 1 mol% of catalyst was
used. [h] The reaction was performed at 08C.
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Enantioselective Construction of Spirocyclopentane Bioxindoles
COMMUNICATION
To assume a possible mechanism for this reaction, we did
some MS and NMR experiments by mixing catalyst VI with
methyleneindolinone 1b and 3-substituted oxindole 2b. In
1H and 13C NMR experiments, no obvious evidence of cata-
lyst VI interactions with methyleneindolinone 1b was found,
but a new species was detected with the help of MS (ESI)
methods. As shown in Figure 3a, this new species was char-
acterized by a base peak at m/z 767.2833 and assigned as
VI+1b. This observation led us to propose a strong interac-
tion between the catalyst VI and 1b.
Furthermore, strong interactions between the catalyst VI
1
and the 3-substituted oxindole 2b were observed in the H
and 13C NMR spectra, and a new structure was formed (Fig-
ure 3b). When compared with that of 2b, this structure was
identified as the enol form of 2b. The same phenomenon
was observed when mixing 2b with Et3N, indicating that the
tertiary amine of the catalyst VI could activated substrate
2b by its enolization. Furthermore, the poor reactivity ob-
tained in the reaction with catalyst containing a free NH or
OH group indicated that the tertiary amine of the catalyst
VI was essential (Figure 3c). On the basis of these data, we
hypothesized that it was the tertiary amine of the catalyst
that activated substrate 2b.
Our above findings allow us to suggest that the two sub-
strates involved in the reaction are activated simultaneously
by the catalyst as shown in Figure 3d.[9c–g]
In summary, we have developed a highly rapid and effi-
cient organocatalytic cascade sequence for the direct con-
struction of spirocyclopentane bioxindoles. This process, effi-
ciently catalyzed by a chiral squaramide in the presence of
a base, serves as a powerful approach to the preparation of
biologically important bispirooxindoles in high enantioselec-
tivities. Remarkably, the power of the cascade process is
fueled by its high efficiency of the production of two new
À
C C bonds, three contiguous stereocenters, including two
spiro quaternary centers in one single operation, which oth-
erwise is difficult to achieve by traditional strategies. We be-
lieve that these bispirooxindoles prepared here will provide
promising candidates for chemical biology and drug discov-
ery. The biological evaluation of these compounds is cur-
rently underway in our laboratory.
Scheme 2. Synthesis of spirocyclopentane bioxindoles with three contigu-
ous stereocenters, including two spiro quaternary centers. Unless other-
Experimental Section
wise specified, the reaction was carried out with
1 (0.12 mmol), 2
(0.10 mmol), catalyst VI (0.01 mmol) and K2CO3 (0.10 mmol) in CH2Cl2
(1.0 mL) at room temperature for 24 h. The reported yields are of the
sum of the diastereoisomers. The d.r. values were determined by
1H NMR spectroscopy of the crude mixture, the values in brackets refer
to the percentage of the major product. The ee values were determined
by chiral HPLC on a Chiralcel column.
Methyleneindolinone 1 (0.12 mmol, 1.2 equiv), 3-substituted oxindole 2
(0.10 mmol, 1.0 equiv), and K2CO3 (0.10 mmol, 1.0 equiv) were added to
a stirred solution of catalyst VI (10 mol%) in CH2Cl2 (1.0 mL). The reac-
tion was vigorously stirred at room temperature for 24 h. Next, the crude
product was purified by silica-gel chromatography to give the corre-
sponding spirocyclopentane bioxindole derivatives 3.
ration, the possibility to easily isolate the diastereoisomers
by column chromatography testifies to the synthetic utility
of the process. The absolute configuration of the stereogenic
centers of compound 3l was unambiguously determined by
X-ray crystallographic analysis.[15]
Acknowledgements
We gratefully acknowledge the financial support from NSFC (20932003,
90813012) and the National S&T Major Project of China
(2012ZX09504001–003).
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R. Wang et al.
Keywords: cascade reactions
·
methyleneindolinone
·
organocatalysis · spiro compounds · squaramides
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Enantioselective Construction of Spirocyclopentane Bioxindoles
COMMUNICATION
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Received: February 14, 2012
Published online: && &&, 2012
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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R. Wang et al.
Cascade Reactions
W. Sun, G. Zhu, C. Wu, L. Hong,*
R. Wang* ...................... &&&& — &&&&
An Organocatalytic Cascade Strategy
for the Enantioselective Construction
of Spirocyclopentane Bioxindoles
Containing Three Contiguous Stereo-
centers and Two Spiro Quaternary
Centers
A rapid and efficient organocatalytic
cascade sequence for the direct con-
struction of spirocyclopentane bioxin-
doles has been carried out by using
a chiral squaramide catalyst in the
presence of a base. This process consti-
tutes a powerful approach to the prep-
aration of biologically important bis-
pirooxindoles in high enantioselectivi-
ties (see scheme).
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!