Highly efficient enantioselective construction of bispirooxindoles containing three stereocenters through an organocatalytic cascade michael-cyclization reaction

Article abstract of DOI:10.1002/chem.201203221

Bispirooxindole derivatives containing three stereocenters, including two spiro quaternary centers, were synthesized in a high-yielding, atypically rapid, and stereocontrolled cascade Michael-cyclization reaction between methyleneindolinones and isothiocyanato oxindoles catalyzed by a bi- or multifunctional organocatalyst. Mild conditions were used to construct bispirooxindoles with excellent enantio- and diastereomeric purities within less than 1 min. Catalyst reconfiguration offered access to the opposite enantiomer. This exceptionally highly efficient procedure will allow diversity-oriented syntheses of this intriguing class of compounds with potential biological activities. Copyright

Full text of DOI:10.1002/chem.201203221

FULL PAPER
DOI: 10.1002/chem.201203221
Highly Efficient Enantioselective Construction of Bispirooxindoles
Containing Three Stereocenters through an Organocatalytic Cascade
Michael–Cyclization Reaction
Hao Wu,[a] Li-Li Zhang,[b] Zhi-Qing Tian,[a] Yao-Dong Huang,*[b] and Yong-Mei Wang*[a]
Abstract: Bispirooxindole derivatives
containing three stereocenters, includ-
ing two spiro quaternary centers, were
synthesized in a high-yielding, atypical-
ly rapid, and stereocontrolled cascade
Michael–cyclization reaction between
methyleneindolinones and isothiocya-
nato oxindoles catalyzed by a bi- or
multifunctional organocatalyst. Mild
conditions were used to construct bi-
AHCTUNGTRENNsGUN pirooxindoles with excellent enantio-
and diastereomeric purities within less
than 1 min. Catalyst reconfiguration of-
fered access to the opposite enantio-
ACHTUNGTRENUNmNG er. This exceptionally highly efficient
procedure will allow diversity-oriented
syntheses of this intriguing class of
compounds with potential biological
activities.
Keywords: asymmetric synthesis ·
cascade reactions · organocatalysis ·
spiro compounds · synthetic meth-
ods
Introduction
The structure complexity and well-defined three-dimension-
al architecture of natural molecules that act as the main
sources of templates are generally correlated with specificity
of drug action and potentially useful biological properties.[1]
This complexity and richness in stereogenic centers has in-
spired generations of synthetic chemists to design new enan-
tioselective strategies for assembling challenging target
structures and reproducing the structural diversity occurring
in natural molecules.[2]
The spirocyclic-oxindole scaffold defines the characteristic
structural core of a large family of alkaloid natural products
with strong bioactivity profiles and interesting structural
properties (Figure 1).[3] Motivated by the varied and signifi-
cant biological activities observed for this class of com-
pounds, many remarkable advances have been made on
enantioselective catalytic strategies for the construction of
spirooxindoles, especially applications to natural product
synthesis.[3a,4–6] For example, the groups of Wang and Bar-
Figure 1. Some biologically active compounds with the spirocyclic oxin-
dole core.
tion between a-isothiocyanato imides and methyleneindoli-
nones through dual activation by bifunctional organocata-
lysts, which provided excellent stereocontrol of the newly
formed spirocyclic oxindoles.[4j,s] In this context, however,
highly efficient methods for the enantioselective synthesis of
bispirooxindole derivatives, which are featured in a large
number of medicinal compounds, have been barely disclosed
due to the required challenging simultaneous creation of
multiple chiral centers including spiro quaternary ones in a
single step.[7] Given the demand for new methodologies for
the construction of bispirooxindole scaffolds, a simple and
efficient synthetic method for the densely functionalized
core scaffold with multiple stereogenic centers is highly de-
sirable.
ACHTUNGTRENNUNGbas III, respectively, reported an elegant asymmetric cascade
Michael–cyclization sequence or [3+2]-cycloaddition reac-
[a] H. Wu, Z.-Q. Tian, Prof. Y.-M. Wang
State Key Laboratory of Elemento-Organic Chemistry
Department of Chemistry, Nankai University
Tianjin 300071 (P.R. China)
Fax : (+86)22-23504439
E-mail: ymw@nankai.edu.cn
[b] L.-L. Zhang, Dr. Y.-D. Huang
Key Laboratory of Systems Bioengineering
School of Chemical Engineering and Technology, Tianjin University
Tianjin 300072 (P.R. China)
Recently, isothiocyanato oxindoles[4l,q,8] were used as effi-
cient Michael donors and methyleneindolinones[4h,5a–c,7a]
were used as highly reactive Michael acceptors. Encouraged
by these achievements and the excellent synthetic art of
E-mail: huangyaodong@tju.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203221.
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Table 1. Optimization of the organocatalytic cascade Michael–cyclization
reactions.[a]
Wang, Barbas III, and their respective co-workers, we envi-
sioned that bispirooxindole skeletons with multiple stereo-
centers, including two spiro quaternary centers,[2d,10] could
be constructed by a cascade Michael–cyclization[11] reaction
between rationally designed methyleneindolinones, 1, and 3-
isothiocyanato oxindoles, 2 (Scheme 1). However, three
Entry
Cat.
1
Solvent
t [min]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
I
II
III
IV
V
III
III
III
III
III
III
III
III
III
III
III
V
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
hexane
diethyl ether
THF
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
35
<1
<1
<1
<1
<1
<1
<1
93
95
97
92
98
89
94
90
91
96
97
95
86
98
97
97
98
96
95
95
74[g]
86[g]
89
85
74[g]
59
Scheme 1. Proposed strategy for the direct construction of bispirooxin-
doles through an organocatalytic cascade Michael–cyclization sequence.
PG: protecting group.
53
67
67
17
84
89
90
92
9
CH3CN
toluene
CHCl3
10
11
12
13[d]
14[e]
15[f]
16[e]
17[e]
18[e]
19[e]
20[e]
DCE
challenges are associated with the performance of this cas-
cade sequence in a single step: 1) the formation of a highly
sterically congested spirocyclic pyrrolidinyl ring with five
substituents; 2) the simultaneous creation of two chemical
bonds and three stereocenters including two spiro quarter-
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
90
78
94
VI
VII
VIII
18
ACHTUNGTRENNUNGnary centers in one step; and 3) the control of the diastereo-
88[g]
95[g]
and enantioselectivity of the products. Herein, we present
an exceptionally highly efficient strategy for the enantiose-
lective construction of bispirooxindoles containing three
stereocenters through a cascade Michael–cyclization reac-
tion between methyleneindolinones, 1, and isothiocyanato
oxindoles, 2. Under mild reaction conditions, all of the reac-
tions were completed in less than one minute and afforded
the bispirooxindole derivatives in almost quantitative yields
with excellent enantiomeric and diastereomeric purities (up
to 99% yield, up to >20:1 d.r., up to 99% ee) and signifi-
cant opportunities for structural diversification.
[a] Unless otherwise specified, all of the reactions were carried out by
using 1 (0.11 mmol, 1.1 equiv) and 2 (0.1 mmol, 1 equiv) with 10 mol%
of the catalyst in CH2Cl2 (1.0 mL) at room temperature. All of the dia-
stereomeric ratios were >20:1 d.r. and were determined by 1H NMR
spectroscopy of the crude mixture. DCE: 1,2-dichloroethane. [b] Yields
of the isolated diastereomeric mixture. [c] Major diastereoisomer deter-
mined by HPLC analysis. [d] The reaction was carried out at 08C.
[e] 15 mol% of catalyst was used. [f] 20 mol% of catalyst was used.
[g] The opposite configuration of product to that obtained under the opti-
mized reaction conditions.
Results and Discussion
In our initial investigation, several bi- or multifunctional or-
ganocatalysts (10 mol%) were screened to evaluate their
ability to promote the cascade reaction between meth
ACHUTGTNRENNUGylACTHNGUTREeNNUG ne-
ACHTUNGTRENNUNGindolinone 1a and 3-isothiocyanato oxindole 2a in dichloro-
methane at room temperature (Table 1, Scheme 2). Gratify-
ingly and surprisingly, all of the catalysts exhibited high ac-
tivity and the reaction finished, remarkably, in less than one
minute with high yields, high diastereoselectivities, and mod-
erate-to-high enantioselectivities (Table 1, entries 1–5). To
our delight, the quinine-derived bifunctional thiourea cata-
lyst III gave the desired bispirooxindole, 4a, with 97%
yield, >20:1 d.r., and 89% ee (Table 1, entry 3). Trifunction-
al catalyst V, designed by Barbas III and co-workers,[7a] only
afforded moderate enantioselectivity (Table 1, entry 5). No
significant improvement was achieved by changing solvents
or lowering the temperature, although comparable enantio-
selectivities were obtained with chloroform and DCE
Scheme 2. Bi- and multifunctional chiral organocatalysts studied.
(Table 1, entries 6–13). The best enantioselectivity was ob-
tained for product 4a if the catalyst loading was increased
to 15 mol% (Table 1, entry 14; 92% ee). On the basis that
the different carbonyl group would have additional interac-
tions with the catalyst, another methyleneinACTHNUTRGENNdGU olACHUTNGTRENiNNGU none, 1b,
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Cascade Formation of Bispirooxindoles Containing Three Stereocenters
FULL PAPER
with a ketone group was employed in further investigations.
Gratifyingly, in the presence of catalyst V, the reaction was
accomplished in less than one minute and gave the desired
product, 3a, in almost quantitative yield with excellent
enantioselectivity and diastereoselectivity (Table 1, entry 17;
98% yield, >20:1 d.r., 94% ee). Replacement of either the
R-diamine component of the catalyst with an S diamine
(catalyst VI) or of the quinine component with a quinACHTUNGRENNUiG AHCTNURTGEGdNNUN ine
(catalyst VII) did not lead to any improvement in enantiose-
lectivity (Table 1, entries 18 and 19). However, replacement
of both components, to generate catalyst VIII, afforded the
opposite enantiomer of the product with excellent stereo-
control, which suggests that both of the two chiral elements
of catalyst V played key roles in controlling the stereoselec-
tivity (Table 1, entry 20).
Our subsequent study probed the generality of our strat-
egy in synthesizing substituted bispirooxindoles by focusing
upon a variety of methyleneindolinones bearing different
ketone substituents, 1, and 3-isothiocyanato oxindoles, 2
(Scheme 3). All of the reactions catalyzed by catalyst V
were completed within less than one minute and afforded
high yields (93–99% yield), excellent diastereoselectivities
(>20:1 d.r.), and excellent enantioselectivities (90–99% ee).
Notably, minimal impact was observed on the efficiencies,
enantioselectivities, and diastereoselectivities, regardless of
the electronic nature, bulkiness, or positions of the substitu-
ents (Scheme 3, 3a–i, 3o–p). In addition to the phenyl
group, other aromatic groups with both electron-withdraw-
ing and electron-donating substituents, as well as heterocy-
clic analogues, were compatible under the optimized reac-
tion conditions and provided excellent stereoselectivities
(Scheme 3, 3j–m). Various N-protecting groups of the two
substrates with different electronic and steric parameters
were tolerated (Scheme 3, 3n and 3q).
Further exploration of the substrate scope was focused
upon methyleneindolinones bearing ester moieties, as sum-
marized in Scheme 4. Catalyst III promoted the cascade Mi-
chael–cyclization sequence in less than one minute, thereby
enabling access to a variety of bispirooxindole derivatives
with excellent yields, diastereomeric ratios, and optical puri-
ties (90–99% yield, > 20:1 d.r., 81–99% ee). There appears
to be significant tolerance towards electronic variations and
positions of the substituents, as well as different N-protect-
ing groups (Scheme 4, 4a–f, 4h–l). An increase in steric hin-
drance, introduced by a bulkier ester group, did not affect
the efficiency and diastereoselectivity, but it did decrease
the enantioselectivity (Scheme 4, 4g; 81% ee). The absolute
configurations of two bispirooxindoles with a ketone moiety
(3l) and an ester moiety (4l), respectively, were unambigu-
ously determined by X-ray crystallography (Figure 2 and 3).
Inspired by our successful work above, the opposite enan-
tiomers of the products were synthesized by employing the
catalyst VIII. The efficiency and stereocontrol of the reac-
tion were not affected relative to those for the reactions cat-
alyzed by catalyst V (Scheme 5). In support of the utility of
our strategy, there was no change in reactivity or stereose-
lectivity if the reaction was carried out on a gram scale
Scheme 3. Synthesis of bispirooxindoles with ketone moieties and three
contiguous stereocenters including two spiro quaternary centers. Unless
otherwise specified, the reaction was carried out with 1 (0.11 mmol), 2
(0.10 mmol), and catalyst V (0.015 mmol) in CH2Cl2 (1.0 mL) at room
temperature. 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 ee values were determined by chiral HPLC on a Chiralcel
column. Bn: benzyl.
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Y.-D. Huang, Y.-M. Wang et al.
Figure 2. X-ray crystal structure of compound (3S,4’S,5’S)-3l.
Scheme 4. Synthesis of bispirooxindoles with ester moieties and three
contiguous stereocenters including two spiro quaternary centers. Unless
otherwise specified, the reaction was carried out with 1 (0.11 mmol), 2
(0.10 mmol), and catalyst III (0.015 mmol) in CH2Cl2 (1.0 mL) at room
temperature. 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 ee values were determined by chiral HPLC on a Chiralcel
column. [a] Catalyst V was used to produce 4h.
Figure 3. X-ray crystal structure of compound (3S,4’S,5’S)-4l.
(Scheme 6). To further expand the potential of this reaction,
transformations of the products into other structurally di-
verse bispirooxindoles were performed. As illustrated in
Scheme 7, the g-thiolactam moiety of bispirooxindole 3b
was smoothly oxidized to form the g-lactam in 89% yield by
simple treatment with 30% aqueous hydrogen peroxide and
formic acid in CH2Cl2. In addition, the g-thiolactam moiety
of bispirooxindole 4k could be smoothly converted into a
methylated thiolactam (in 6k) according to the reported
procedure.[12] It is worth noting that no great changes took
place in the enantioselectivity during the above transforma-
tions.
In light of the dual-activation model proposed by Take-
moto and co-workers[13] and other recent studies,[4–6] we have
proposed two possible models to account for the stereo-
chemistry of the Michael–cyclization reaction (Scheme 8).
When catalyst V promoted the reaction between meth
ACHTUNGTRENNUNGylACHTUNGTRENNUNGene-
AHCTUNGTRENNUNG
two substrates were activated simultaneously by the catalyst
V, as shown in Scheme 8a. MS experiments[14] by mixing cat-
alyst V with 1b and 2a individually were investigated in
order to support this mechanism. Despite no obvious evi-
dence of interactions between catalyst V with 1b, a new spe-
cies was detected with the help of ESI-MS methods when
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Cascade Formation of Bispirooxindoles Containing Three Stereocenters
FULL PAPER
Figure 4. ESI-MS analysis indicating the peak of the new species in the
solution of catalyst V and substrate 2a.
Scheme 5. Synthesis of enantiomers (3R,4’R,5’R)-3a and (3R,4’R,5’R)-3l
by using catalyst VIII.
catalyst V was combined with 2a (Figure 4). This new spe-
cies was characterized by a base peak at m/z 854.3304 and
assigned as [V+2a]. This observation led us to propose a
strong interaction between catalyst V and 2a. Two further
control experiments were investigated for mechanistic stud-
ies. Employment of a methyleneindolinone attached directly
to a phenyl group with no ketone or ester moiety led to the
desired product in only 59% yield, 3:1 d.r., and 6% ee
(Scheme 9). In the absence of catalyst, the reaction was sig-
Scheme 6. Preparative-scale experiment.
Scheme 9. Control experiments for mechanism studies.
nificantly slower and required several hours to reach com-
pletion (Scheme 9). These poor results supported the impor-
tance of the hydrogen-bonding interaction between catalyst
V and 1b. The above findings
Scheme 7. Transformation of the products into other bispirooxindoles.
allow us to suggest our dual-ac-
tivation model: 2a interacts
with the tertiary amine of cata-
lyst V through multiple hydro-
gen bonds, which enhances the
electrophilicity of the reacting
carbon center. Concurrently,
the ketone moiety and the car-
bonyl group of the indolinone
in 1b coordinate to the primary
amine and thiourea moiety
through hydrogen-bonding in-
teractions that are crucial for
stereocontrol (Scheme 8a).
Scheme 8. a) Proposed activation mode of the reaction between a ketone-bearing methyleneindolinone and
isothiocyanato oxindole catalyzed by catalyst V. b) Proposed activation mode of the reaction between an ester-
bearing methyleneindolinone with isothiocyanato oxindole catalyzed by catalyst III.
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Y.-D. Huang, Y.-M. Wang et al.
crude product was purified by silica-gel chromatography to give the cor-
responding bispirocyclic oxindole derivative 4a: [a]2D5 = +125.8 (c=0.6,
CH2Cl2); HPLC: Chiralpak AD-H (hexane/iPrOH 80/20, flow rate
1 mLminÀ1, l=254 nm); tR (minor)=17.421 min, tR (major)=32.139 min;
When catalyst III was used for the reaction between methyl-
eneindolinone ester 1a and isothiocyanato oxindole 2a, the
electron-deficient methyleneindolinone was activated by hy-
drogen bonds involving the carbonyl group in the indolinone
and the thiourea moiety, while 2a was enolized and activat-
ed by the tertiary amine at the same time (Scheme 8b).
1
92% ee; H NMR (400 MHz, CDCl3): d=8.05 (s, 1H), 7.62 (d, J=7.4 Hz,
1H), 7.45 (t, J=7.6 Hz, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.21 (t, J=7.5 Hz,
1H), 7.12 (t, J=7.5 Hz, 1H), 6.94 (d, J=7.7 Hz, 2H), 4.92 (s, 1H), 3.52
(m, 2H), 3.33 (s, 3H), 3.31 (s, 3H), 0.53 ppm (t, J=7.1 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=201.43, 174.20, 173.95, 165.59, 144.99,
144.00, 130.99, 129.70, 128.66, 126.12, 125.15, 123.77, 123.25, 122.82,
109.06, 108.80, 70.40, 68.16, 60.79, 56.66, 27.32, 27.24, 13.15 ppm; HRMS
(ESI): m/z calcd for C23H21N3O4S+H [M+H]: 463.1326; found:
463.1323.
Conclusion
We have developed an exceptionally highly efficient strategy
for enantioselective construction of bispirocyclic oxindole
derivatives through a simple organocatalytic cascade Mi-
chael–cyclization reaction. Under mild reaction conditions,
all of the reactions catalyzed by bi- or multifunctional cin-
chona alkaloids finished in less than one minute, to provide
bispirooxindoles containing three contiguous chiral centers,
including two spiro quaternary stereocenters, in almost
quantitative yields and with excellent stereocontrol. Signifi-
cantly, catalyst reconfiguration offered access to the oppo-
site enantiomer. The power of this straightforward process is
highlighted by its extremely high efficiency in synthesizing
the bispirooxindole skeletons in such a short time in one
single operation, even if the experiment was performed on a
gram scale. We believe that these novel compounds based
on bispirocyclic oxindole skeletons will provide novel thera-
peutic agents and useful biological tools. The application of
this strategy to synthesize more promising candidates for
drug discovery and the biological evaluation of these com-
pounds are currently underway.
Acknowledgements
We are grateful for grants from the National Basic Research Program of
China (973 Program: 2010CB833300) and the State Key Laboratory of
Elemento-Organic Chemistry.
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Experimental Section
Typical experimental procedure for the catalytic asymmetric synthesis of
bispirooxindole with a ketone moiety (3a): Methyleneindolinone
a
ketone 1b (0.11 mmol, 1.1 equiv) and 3-isothiocyanato oxindole 2a
(0.10 mmol, 1.0 equiv) were added to a stirred solution of catalyst V
(15 mol%) in CH2Cl2 (1.0 mL) at room temperature. The reaction was
monitored by TLC. After complete consumption of 3-isothiocyanato ox-
indole 2a (usually less than 1 min; the dark red solution turned light
yellow), the crude product was purified by silica-gel chromatography to
give the corresponding bispirocyclic oxindole derivative 3a: [a]2D5 = +
274.0 (c=0.2, CH2Cl2); HPLC: Chiralpak AD-H (hexane/iPrOH 70/30,
flow rate 1 mLminÀ1, l=254 nm); tR (major)=20.915 min, tR (minor)=
23.269 min; 94% ee; 1H NMR (400 MHz, CDCl3): d=8.42 (s, 1H), 7.64
(d, J=7.1 Hz, 1H), 7.45 (d, J=7.3 Hz, 1H), 7.39 (m, 1H), 7.30 (m, 1H),
7.23 (m, 2H), 7.11 (m, 5H), 6.79 (d, J=7.8 Hz, 1H), 6.59 (d, J=7.7 Hz,
1H), 5.66 (s, 1H), 3.19 (s, 3H), 3.08 ppm (s, 3H); 13C NMR (101 MHz,
CDCl3): d=201.36, 194.15, 174.58, 174.25, 144.22, 143.09, 136.90, 132.73,
130.68, 129.61, 127.99, 127.64, 127.50, 126.40, 125.97, 124.82, 123.32,
123.00, 109.03, 108.56, 71.21, 68.89, 59.44, 27.12, 27.04 ppm; HRMS
(ESI): m/z calcd for C27H21N3O3S+H [M+H]: 468.1376; found:
468.1379.
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Typical experimental procedure for the catalytic asymmetric synthesis of
a bispirooxindole with an ester moiety (4a): Methyleneindolinone ester
1a (0.11 mmol, 1.1 equiv) and 3-isothiocyanato oxindole 2a (0.10 mmol,
1.0 equiv) were added to a stirred solution of catalyst III (15 mol%) in
CH2Cl2 (1.0 mL) at room temperature. The reaction was monitored by
TLC. After complete consumption of 3-isothiocyanato oxindole 2a (usu-
ally less than 1 min; the dark yellow solution turned light yellow), the
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Cascade Formation of Bispirooxindoles Containing Three Stereocenters
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[14] NMR experiments were also performed by mixing catalyst V with
the two substrates, respectively. However, no new chemical shift was
observed.
Received: September 10, 2012
Revised: November 8, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
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Y.-D. Huang, Y.-M. Wang et al.
Asymmetric Synthesis
H. Wu, L.-L. Zhang, Z.-Q. Tian,
Y.-D. Huang,* Y.-M. Wang* &&&& — &&&&
Highly Efficient Enantioselective
Construction of Bispirooxindoles
Containing Three Stereocenters
through an Organocatalytic Cascade
Michael–Cyclization Reaction
Cascade to complexity: Bispirooxin-
dole derivatives containing three
stereocontrolled cascade Michael–cy-
ACHTUNGTRENNUNG
stereo
quarter
in a high-yielding, atypically rapid, and
C
ACHTUNGTRENNUNG
G
doles catalyzed by a bi- or multifunc-
tional organocatalyst (see scheme).
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Chem. Eur. J. 0000, 00, 0 – 0
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These are not the final page numbers!