Core structure-based design of organocatalytic [3+2]-cycloaddition reactions: Highly efficient and stereocontrolled syntheses of 3,3′-pyrrolidonyl spirooxindoles

Article abstract of DOI:10.1002/chem.201103449

Extraordinary levels of stereocontrol were achieved in an efficient organocatalytic asymmetric [3+2]-cycloaddition reaction between an α-isothiocyanato imide and various methyleneindolinones. Simple precursors were used for the rapid construction of spiro

Full text of DOI:10.1002/chem.201103449

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DOI: 10.1002/chem.201103449
Core Structure-Based Design of Organocatalytic [3+2]-Cycloaddition
Reactions: Highly Efficient and Stereocontrolled Syntheses of 3,3’-
Pyrrolidonyl Spirooxindoles
Bin Tan,[a, b] Xiaofei Zeng,[b, c] Wendy Wen Yi Leong,[b, c] Zugui Shi,[b, c]
Carlos F. Barbas, III,*[a] and Guofu Zhong*[b, c]
A spirocyclic oxindole core is the structural centerpiece of
a wide variety of natural and synthetic compounds that ex-
hibit diverse biological activities.[1] Consequently, ap-
proaches towards the efficient asymmetric synthesis of these
molecules have received considerable attention.[2,3] As part
of a program to address this family of molecules with orga-
nocatalysis, we have recently reported strategies based on
oxindoles that provide rapid access to bispirooxindoles,[3a]
spirocyclopenteneoxindoles,[3b] and carbazolespirooxindo-
les.[3c] While these approaches have met with some success,
these efforts do not address the 3,3’-pyrrolidonyl spirooxin-
dole motif[4] common to many bioactive molecules from this
family of molecules (Scheme 1). Thus, an enantioselective
catalytic approach for the direct construction of 3,3’-pyrroli-
donyl spirooxindole skeletons is a significant unmet chal-
lenge.
To address this challenge, we sought to design an organo-
catalytic[5] domino reaction[6] that would ideally involve the
reaction of two simple and readily accessible starting materi-
als. Given the recent success of a-isothiocyanato derivatives
as nucleophiles in organocatalytic aldol and Mannich reac-
tions,[7] we envisioned that [3+2]-cycloaddition reactions be-
Scheme 1. Examples of natural and synthetic bioactive compounds con-
taining a 3,3’-pyrrolidonyl spirooxindole structural motif.
tween a-isothiocyanato imides and methyleneindolinones
would yield the desired 3,3’-pyrrolidonyl spirooxindole skel-
etons in
a highly stereoselective transformation (see
Scheme 3). Given the pioneering studies of Deng and co-
workers on cinchona alkaloid catalysis[8] and our own find-
ings that this class of catalysts works efficiently in oxindole-
based reactions,[3a,9] we focused our attention on this class of
organocatalysts (Scheme 2). Herein, we present organocata-
lytic asymmetric [3+2]-cycloaddition reactions between iso-
thiocyanato imide and methyleneindolinones that provide
3,3’-pyrrolidonyl spirooxindoles in good yields with high dia-
stereo- and enantio-purity.[10]
We initiated our studies by evaluating the reaction be-
tween isothiocyanato imide 1a and methyleneindolinone 2a
using quinine as the catalyst in dichloromethane at room
temperature (Scheme 3). We found that the reaction pro-
ceeded smoothly and afforded the desired product in high
yield, albeit with poor diastereoselectivity (3:2).[11] Although
high enantioselectivities (up to 97% ee) were attained with
the thiourea catalysts of Scheme 2, the diastereoselectivities
were consistently poor despite optimization studies with re-
[a] Dr. B. Tan, Prof. Dr. C. F. Barbas, III
The Skaggs Institute for Chemical Biology and the
Departments of Chemistry and Molecular Biology
The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax : (+1)858-784-2583
E-mail: carlos@scripps.edu
[b] Dr. B. Tan, X. Zeng, W. W. Y. Leong, Z. Shi, Prof. Dr. G. Zhong
College of Materials, Chemistry and Chemical Engineering
Hangzhou Normal University, Hangzhou 310036 (P. R. China)
E-mail: zgf@hznu.edu.cn
[c] X. Zeng, W. W. Y. Leong, Z. Shi, Prof. Dr. G. Zhong
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371 (Singapore)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103449.
Chem. Eur. J. 2012, 18, 63 – 67
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63

Scheme 4. Key strategy for improvement of diastereoselectivity.
Table 1. Screen of reaction conditions.[a]
Entry
Catalyst
Solvent
Yield [%][b]
d.r.[c]
10:1
ee [%][d]
1
2
I
II
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
Et2O
71
91
94
94
93
91
83
87
93
5
97
97
97
97
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
3[e]
4
III
IV
V
VI
IV
IV
IV
5
6
7
À92
98
8
95
97
9[f]
CH2Cl2
[a] Unless otherwise specified, all reactions were carried out using a-iso-
thiocyanato imide 1b (0.1 mmol, 1 equiv) and methyleneindolinone 2a
(0.1 mmol, 1 equiv) with 10 mol% of catalyst at 238C. [b] Isolated yields.
Scheme 2. Structures of cinchona alkaloid derived organocatalysts stud-
ied.
1
[c] Determined by H NMR spectroscopy and chiral-phase HPLC. [d] de-
termined by chiral-phase HPLC analysis. [e] Reaction took 16 h to com-
plete. [f] Reaction was conducted at 08C for 18 h.
spect to solvent, catalyst, and temperature (see the Support-
ing Information).
reaction and provided largely
diastereo- and enantiopure
product (Table 1, entries 2–9).
Of note is our newly designed
catalyst III (see Scheme 2),[3a]
which does not include a strong
electron-withdrawing
group
(CF3). This catalyst was as effi-
cient as those containing the
Scheme 3. Initial test of [3+2]-cycloaddition reaction catalyzed by quinine.
CF3 group despite a predicted
weaker acidity of its thiourea
To solve this problem, we turned our attention towards
modification of isothiocyanato imide 1a with the aim of in-
creasing its potential to hydrogen bond with our catalysts by
providing it with another acceptor site that might aid in ste-
reochemically fixing the reactive enolate and consequently
guiding the stereochemical outcome of the reaction. We
were inspired to attempt this based on a report by Sibi and
Itoh in which it was shown that the 3,5-dimethyl pyrazole
template plays a crucial role in providing H-bond acceptor
sites with a thiourea catalyst in an organocatalytic Michael
reaction.[12] We therefore designed the novel isothiocyanato
imide 1b to react with 2a using quinine I as the catalyst
with the expectation of improved diastereoselectivity
(Scheme 4). Indeed, the [3+2]-cycloaddition reaction pro-
ceeded smoothly and provided the desired product with vir-
tually complete diastereoselectivity. As noted in Table 1, the
thiourea functionality within the catalyst is the key for this
group (Table 1, entry 3). Solvent screening showed that the
reaction was efficient in many solvents. Furthermore, use of
the quinidine thiourea derivative VI as catalyst provided
access to the opposite enantiomer of our products with ex-
cellent chemical and optical yields (Table 1, entry 6).
In our exploratory effort, this new methodology provided
access to a range of multi-substituted spirocyclic oxindole
derivatives and served as an expedient approach for the
preparation of a range of substituted spirocyclo oxindoles
containing three chiral centers in excellent enantiomeric ex-
cesses (91–98% ee) and almost complete diastereoselectivi-
ties (>25:1 d.r. in all cases) (Scheme 5). The IV-promoted
[3+2]-cycloaddition reaction proceeded with a variety of
methyleneindolinone derivatives bearing various substitu-
ents at the carbon–carbon double bond such as esters and
ketones. Notably, minimal impact on efficiencies, enantiose-
lectivities, and diastereoselectivities were observed regard-
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Chem. Eur. J. 2012, 18, 63 – 67

3,3’-Pyrrolidonyl Spirooxindoles
COMMUNICATION
less of the electronic nature and
bulkiness of the substituents
(Scheme 5, 3g–3k). The current
system does have limitations:
Phenyl-substituted
methyle-
neindolinone was virtually un-
reactive, while the cyano(CN)-
substituted
methyleneindoli-
none provided product with low
diastereoselectivity.
Further exploration of the
substrate scope was focused on
the
indolinone
moiety
(Scheme 6). Substituents with a
range of electronic properties
were tolerated, and product
yields ranged from 86% to
95% with excellent stereoselec-
tivities (91–98% ee; >25:1
d.r.). The presence of chlorine
or fluorine on the indolinone
moiety is important for phar-
macological activity for some
molecules of this type.[13]
Our findings together with
the dual activation model pro-
posed by Takemoto and co-
workers,[14] and the theoretical
calculation studies by Papai[15a]
and Zhong[15b] and their co-
workers, allow us to suggest
that the two substrates involved
in the reaction are activated si-
multaneously by the catalyst as
shown in Scheme 7. The acetyl-
protecting group is crucial to
high enantioselectivity, as seen
from the low enantioselectivity
(55% ee) obtained when a tert-
butoxycarbonyl (Boc) protect-
Scheme 5. Generality of organocatalytic [3+2]-cycloaddition reactions.
ing
group
was
utilized
(Scheme 8). The absolute con-
figurations of 3b and 3g deter-
mined by X-ray analysis (see
Figure 1[16] and the Supporting
Information, respectively) are
in accordance with that predict-
ed by the catalytic model.
While we introduced the pyr-
azole group into the isothiocya-
nato imide to facilitate stereo-
chemical control, the pyrozole
group provides other advantag-
es to our approach. Its intrinsic
reactivity can be exploited in
subsequent reactions that serve
to further diversify our prod-
Scheme 6. Further exploration of the effects of indolinone substituents.
Chem. Eur. J. 2012, 18, 63 – 67
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www.chemeurj.org
65

C. F. Barbas III, G. Zhong et al.
al diversity of the products, some transformations into other
spirooxindoles were investigated (Scheme 9). In support of
the utility of our reaction, when the reaction was carried out
on a gram scale, there was no change in reactivity or stereo-
selectivity (Scheme 10).
In summary, we have developed an efficient organocata-
lytic [3+2]-cycloaddition reaction for the direct construction
the 3,3’-pyrrolidonyl spirooxindole motif common to many
bioactive molecules through the rational design of a-isothio-
cyanato imides as dienophiles. Stereochemically complex
products were obtained in excellent chemical and optical
yield allowing us to set three contiguous stereocenters, in-
Scheme 7. Proposed mode of activation of substrates.
ucts, since the pyrazole moiety
can be easily displaced by nu-
cleophiles such as alcohols and
amines. Furthermore, the thio-
lactam can be converted into
the corresponding lactam, de-
sulfurized, or subjected to
Scheme 10. Preparative-scale experiment.
cluding one all-carbon spiro
quaternary center, in the prod-
ucts. This straightforward pro-
cess makes use of simple start-
ing materials and proceeds
under mild conditions and will
be useful in medicinal chemis-
try and diversity-oriented syn-
thesis.
Scheme 8. Control experiment in support of mechanism.
Acknowledgements
Research support from Hangzhou Normal University in China, the Min-
istry of Education in Singapore (ARC12/07, no. T206B3225) and the
Skaggs Institute for Chemical Biology is gratefully acknowledged. We
also thank Dr. Yongxin Li for the X-ray crystallographic analysis.
Keywords: 3,3’-pyrrolidonyl spirooxindoles · cycloaddition ·
methyleneindolinones · organocatalysis · spiro compounds
Figure 1. X-ray crystal structure of compound 3b.[16]
sulfur contraction to obtain fully substituted spiropyrrolidine
oxindole derivatives.[17] To further demonstrate the structur-
Scheme 9. Transformation of the pyrazole functionality.
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3,3’-Pyrrolidonyl Spirooxindoles
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Received: November 2, 2011
Published online: December 9, 2011
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