Catalytic asymmetric michael addition/cyclization of isothiocyanato oxindoles: Highly efficient and versatile approach for the synthesis of 3,2′-pyrrolidinyl mono- and bi-spirooxindole frameworks

Article abstract of DOI:10.1002/chem.201204114

A-spiro-ing to greatness: The catalytic asymmetric Michael addition/cyclization of isothiocyanato oxindoles has been realized. This versatile approach provides an easy and highly efficient way to access not only the enantioselective synthesis of 3,2′-pyrrolidinyl spirooxindole frameworks, but also the construction of enatiomerically enriched bi-spirooxindoles containing three contiguous stereocenters and two spiro-quaternary centers (see scheme). Copyright

Full text of DOI:10.1002/chem.201204114

DOI: 10.1002/chem.201204114
Catalytic Asymmetric Michael Addition/Cyclization of Isothiocyanato
Oxindoles: Highly Efficient and Versatile Approach for the Synthesis of 3,2’-
Pyrrolidinyl Mono- and Bi-spirooxindole Frameworks
Yi-Ming Cao,[a] Fang-Fang Shen,[a] Fu-Ting Zhang,[a] and Rui Wang*[a, b]
The spirooxindole core is a privileged heterocyclic ring
system featured in a large number of natural or synthetic
compounds with diverse and important biological profiles. It
has therefore drawn tremendous interest from synthetic and
medicinal chemists.[1] Among the different types of the spi-
rooxindoles,[2] the pyrrolidinyl spirooxindole framework has
recently become one of the most important synthetic sub-
jects because of its significant medicinal relevance, and a
number of elegant works have been reported for its catalytic
asymmetric synthesis.[3] However, most of the synthetic tar-
gets are restricted to 3,3’-pyrrolidinyl spirooxindoles, and
the catalytic enantioselective synthesis approaches toward
the 3,2’-pyrrolidinyl spirooxindoles with a nitrogen atom ad-
jacent to the spiro-carbon atom[4] are very limited.
mainly confined to azomethine ylide cycloaddition of race-
mic or enantiopure reactants, and this limitation is a large
obstacle to medicinal chemistry research development of
these compounds.[6] So far only two methods, an azomethine
ylide cycloaddition and an N-heterocyclic carbene (NHC)-
catalyzed annulation, for the catalytic asymmetric construc-
tion of the 3,2’-pyrrolidinyl spirooxindole skeleton have
been reported by the groups of Gong and Chi, respectively,
and more efficient and accessible methodology towards
these synthetic targets is still highly in demand.[7] Herein, we
report the development of a new synthetic method for the
catalytic asymmetric construction of the 3,2’-pyrrolidinyl spi-
rooxindole framework with high efficiency. Moreover, as ox-
indole-based bi-spiro motifs have been found to be present
in many bioactive compounds, we also identified the validity
of this method for the synthesis of this architecture.[2j,l] Grat-
ifyingly, this method was excellent for the construction of a
series of complex bi-spirooxindole derivatives with three
contiguous stereocenters, including two spiro-quaternary
chiral carbon atoms (Scheme 1).
Compounds with the 3,2’-pyrrolidinyl spirooxindole
frameworkhave shown a wide spectrum of considerable bio-
activities, such as anti-microbial, anti-tumor, anti-inflamma-
tory, and acetylcholinesterase (AChE) inhibitory activities
(Figure 1).[5] Synthetic methods to access these motifs are
Figure 1. Bioactive compounds containing the 3,2’-pyrrolidinyl spirooxin-
dole framework.
[a] Y.-M. Cao, F.-F. Shen,+ F.-T. Zhang,+ Prof. Dr. R. Wang
Key Laboratory of Preclinical Study for New Drugs of
Gansu Province
State Key Laboratory of Applied Organic Chemistry
Institute of Biochemistry and Molecular Biology
School of Life Science, Lanzhou University
Lanzhou 730000 (P.R. China)
Scheme 1. Previous studies on the construction of the pyrrolidinyl spiro-
AHCTUNGTERGoNNUN xindole framework, and the cyclization reaction with isothiocyanato ox-
E-mail: wangrui@lzu.edu.cn
indole reported herein. EWG=electron-withdrawing group, PG=pro-
tecting group.
[b] Prof. Dr. R. Wang
State Key Laboratory of Chiroscience
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Kowloon, Hong Kong (P.R. China)
E-mail: bcrwang@polyu.edu.hk
Recently, a-isothiocyanato compounds were employed
not only for the synthesis of chiral b-hydroxy-a-amino acid
and a, b-diamino acid derivatives,[8] but also for the enatio-
selective construction of spirooxindoles.[3d,e,9] Very recently,
Shibasaki, Kanai, and co-workers developed an asymmetric
[+] These authors contributed equally to this work
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204114.
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Chem. Eur. J. 2013, 19, 1184 – 1188

COMMUNICATION
Table 1. Optimization of the reaction.[a]
Mannich-type reaction of isothiocyanato oxindoles for the
synthesis of the enantiopure imidazoline spirooxindole
framework that contains a nitrogen atom at the C3’ posi-
tion.[4a] However, the Michael-type reaction of isothiocyana-
to oxindoles has never been reported to our knowledge, al-
though it is a promising route for the construction of the
medicinally relevant 3,2’-pyrrolidinyl spirooxindole deriva-
tives. As part of our ongoing work on the development of
new methods for chiral spirooxindole synthesis with a-iso-
thiocyanato compounds,[3e,9a] we herein report the first cata-
lytic asymmetric Michael addition/cyclization reaction be-
tween isothiocyanato oxindoles and electron-deficient ole-
fins for construction of the 3,2’-pyrrolidinyl spirooxindole
framework.
On the basis of our recent success in asymmetric organo-
catalysis by using bifunctional thiourea catalysts,[10,11] we sur-
mised that this kind of organocatalyst would be suitable for
catalyzing the Micheal addition/cyclization in a double-acti-
vation manner. The initial investigation began with the reac-
tion between isothiocyanato oxindole 1a and the electron-
deficient olefin 2a in CH2Cl2 at room temperature in the
presence of a catalyst at a 15 mol% loading (Table 1). Sev-
eral cyclohexanediamine-derived bifunctional thiourea cata-
lysts were first screened. Although the catalysts L1–L3 gave
the desired product 3aa with excellent yield and diastereo-
selectivity, the enantioselective control was poor, indicating
that this type of structural scaffold is not suitable for the re-
action in terms of stereochemistry (Table 1, entries 1–3). We
then tested the cinchona alkaloid-derived thiourea bifunc-
tional catalysts (L4 and L5).[12] To our delight, compared to
L4, quinidine-derived catalyst L5, which contains a bulkier
dehydroabietic amine moiety and was developed in our
group, gave the product with a much higher enantioselevtivi-
ty (ee), as well as the same excellent yield and diastereose-
lectivity (d.r.; Table 1, entries 4–5). Further screening of the
solvents revealed that Et2O was better than other solvents
(Table 1, entries 6–8), and lowering the reaction temperature
to 08C resulted in a higher ee without obviously sacrificing
the reaction rate (89% ee, Table 1, entry 9). Variation of the
N-protecting group of the isothiocyanato oxindole had slight
effect on the enantioselectivity and the N-benzyl substrate
1b gave a higher ee (92% ee, Table 1, entry 10).
With the optimal reaction conditions established, the gen-
erality of the catalytic asymmetric cyclization reaction was
next investigated by using a series of electron-deficient ole-
fins 2 and isothiocyanato oxindoles (Table 2). Various olefin
derivatives with either electron-withdrawing or electron-do-
nating groups at the para-, meta-, or even sterically hindered
ortho-position on the aromatic ring were tolerated and gave
the corresponding cycloadducts in excellent chemical yield,
excellent diastereoselectivity, and good to excellent enantio-
selectivity (Table 2, 3ba–3bk). In addition, reactions with
substrates 2, which contain sterically hindered 1-naphthyl, as
well as various heteroaromatic rings also proceeded smooth-
ly to give the products with good results (except for 3bn,
which was only obtained with a moderate ee). Because the
oxindole–indole backbone is found in many medicinally
Entry
Cat.
Solvent
T
[8C]
Yield[b]
[%]
d.r.[c]
ee[d]
[%]
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L5
L5
L5
L5
L5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
PhMe
MeCN
Et2O
RT
RT
RT
RT
RT
RT
RT
RT
0
3aa, 90
3aa, 93
3aa, 85
3aa, 95
3aa, 92
3aa, 94
3aa, 94
3aa, 87
3aa, 95
3ba, 99
>20:1
>20:1
12:1
>20:1
>20:1
>20:1
>20:1
20:1
20
9
21
20
79
84
83
82
89
92
>20:1
>20:1
10
Et2O
0
[a] Unless otherwise specified, the reaction was performed on a 0.1 mmol
scale with 1 (1.0 equiv), 2 (1.1 equiv), and catalyst (15 mol%) in solvent
(1 mL) for 30 min. [b] Yield of isolated major diastereoisomer of product.
[c] Determined by 1H NMR spectroscopic analysis. [d] Determined by
HPLC analysis on a chiral stationary phase.
active compounds, an olefin substrate with an indole hetero-
cycle was also tested in this process and, gratifyingly, it gave
the products in 99% yield, >20:1 d.r., and 96% ee (Table 2,
entries 12–15). An aliphatic-substituted substrate also
proved to be amenable to this method, and the correspond-
ing product was obtained with an excellent result in terms
of yield and stereocontrol (Table 2, entry 16). In addition to
1b, both the electron-donating and -withdrawing substituted
isothiocyanato oxindoles gave the respective cycloadducts
with good results (Table 2, entries 18 and 19). The versatile
thiocarbonyl group of these products can be easily modified
by several different transformations, such as alkylation–
sulfur extrusion,[13] reductive desulfuration, oxidization,[3e]
and so on.
Encouraged by the successful synthesis of 3,2’-pyrrolidinyl
spirooxindole derivatives as described above, we attempted
to extend this approach for the construction of more com-
plex bi-spirooxindoles with three contiguous stereocenters,
including two spiro-quaternary chiral carbon atoms, that
also showed significant medical relevance. The model reac-
tion was performed between isothiocyanato oxindole and
Chem. Eur. J. 2013, 19, 1184 – 1188
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www.chemeurj.org
1185

R. Wang et al.
Table 2. Scope of the catalytic asymmetric synthesis of 3,2’-pyrrolidinyl
Table 3. Scope of the catalytic asymmetric synthesis of 3,2’-pyrrolidinyl
bi-spirooxindole derivatives with three contiguous stereocenters, includ-
ing two spiro-quaternary chiral carbons.[a]
spirooxindole derivatives.[a]
Entry
R3
1
Yield[b]
[%]
d.r.[c]
ee[d]
[%]
Entry
R4, R5, X
1
Yield[b]
[%]
d.r.[c]
ee[d]
[%]
1
2
3
4
5
6
7
8
9
10
11[e]
12
13
14
15[f]
16
17
18
19
Ph
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
1c
1d
3ba, 99
3bb, 99
3bc, 99
3bd, 97
3be, 96
3bf, 98
3bg, 91
3bh, 90
3bi, 90
3bj, 99
3bk, 92
3bl, 86
3bm, 88
3bn, 98
3bo, 99
3 bp, 94
3aa, 95
3ca, 99
3da, 90
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
92
92
93
93
92
89
94
93
93
90
93
89
89
78
96
92
89
92
90
4-F-C6H4
4-Cl-C6H4
2,4-diCl-C6H4
4-Br-C6H4
3-Br-C6H4
2-Br-C6H4
4-NO2-C6H4
4-MeO-C6H4
3-MeO-C6H4
2-Me-C6H4
1-naphthyl
2-thienyl
2-furyl
3-indolyl
ACHTUNGTRENNUNG(CH3)2CHCH2-
Ph
Ph
Ph
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
H, Et, NMe
5-F, Et, NMe
7-F, Et, NMe
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1a
1c
1d
5ba, 99
5bb, 98
5bc, 99
5bd, 99
5be, 95
5bf, 99
5bg, 92
5bh, 95
5bi, 96
5bj, 96
5bk, 93
5bl, 99
5bm, 93
5bn, 96
5bo, 94
5 bp, 95
5aa, 99
5ca, 95
5da, 94
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
13:1
97
95
93
92
86
98
93
93
95
94
96
91
92
86
94
90
94
95
95
5-Cl, Et, NMe
6-Cl, Et, NMe
7-Cl, Et, NMe
5-Br, Et, NMe
5-OCF3, Et, NMe
5-Me, Et, NMe
5-MeO, Et, NMe
5-Cl 7-Me, Et, NMe
H, Bn, NMe
13:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
H, tBu, NMe
H, Et, NBn
À
H, Et, N Allyl
H, Et, S
H, Et, NMe
H, Et, NMe
H, Et, NMe
[a] Unless otherwise specified, the reaction was performed on 0.1 mmol
scale with 1 (1.0 equiv), 2 (1.1 equiv), and catalyst L5 (15 mol%) in Et2O
(1 mL) in an ice bath for 30 min. [b] Yield of isolated major diaster-
eoisomer of product. [c] Determined by 1H NMR spectroscopic analysis.
[d] Determined by HPLC analysis on a chiral stationary phase. [e] The
reaction time was 1 h. [f] The reaction time was 4 h.
[a] Unless otherwise specified, the reaction was performed on 0.1 mmol
scale with 1 (1.0 equiv) 4 (1.1 equiv), and catalyst (15 mol%) in CH2Cl2
(2 mL). Compound 1 in 1 mL solvent was added to the reaction over
30 min. The reaction was complete after the addition of 1. [b] Yield of
isolated product as a mixture of diastereoisomers. [c] Determined by
1H NMR spectroscopic analysis. [d] Determined by HPLC analysis on a
chiral stationary phase.
methyleneindolinone, and the reoptimized conditions are
shown in Table 3. In contrast, the quinidine-derived thiourea
catalyst L4, which has a smaller steric moiety than L5 (see
the Scheme in Table 2), was superior for this process, pre-
sumably due to the fact that the smaller catalyst L4 was
more compatible for the catalyst–substrate transition state,
which has increasing steric hindrance when the bulkier elec-
tron-deficient olefin substrate 4 is used. Under the opti-
mized reaction conditions, a variety of bi-spirooxindoles
were synthesized and the results are summarized in Table 3.
Both electron-donating and electron-withdrawing substitu-
ents on methyleneindolinone at different positions on the ar-
omatic ring gave the corresponding products in excellent
yield, diastereoselectivity, and good to excellent enantiose-
lectivity (Table 3, entries 1–11). Steric tuning of either the
ester group or the nitrogen protecting group on 4 had little
effect on the yield and stereoselectivity of the reaction
(Table 3, entries 12–15). It is worth noting that when the ni-
trogen atom of methyleneindolinone was replaced by sulfur,
the reaction also proceeded smoothly, providing the product
5 bp with excellent results (Table 3, entries 16). Isothiocya-
nato oxindoles with different substituents are also tolerated
and gave the respective products in excellent yield, d.r., and
ee (Table 3, entries 17–19). The absolute configuration of
product 5aa was unambiguously determined by X-ray crys-
tallography.[14]
In summary, a highly efficient bifunctional thiourea-cata-
lyzed asymmetric Michael addition/cyclization reaction of
isothiocyanato oxindoles has been successfully developed.
This versatile process provides a promising approach not
only for the enantioselective construction of functionalized
3,2’-pyrrolidinyl spirooxindole derivatives (up to 99% yield,
>20:1 d.r., and 96% ee), but also for the synthesis of enan-
tiopure bi-spirooxindoles with three contiguous stereocen-
ters, including two spiro-quaternary chiral centers (up to
99% yield, >20:1 d.r., and 98% ee). The enantioselective
structurally diverse synthesis presented herein offers an un-
precedented platform for medicinal chemistry studies of
those biologically important 3,2’-pyrrolidinyl spirooxindoles,
as well as their bi-spirooxindole derivatives. Further studies
on expanding the application of this method and the biologi-
cal evaluation of these pyrrolidinyl spirooxindole derivatives
are in progress.
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Chem. Eur. J. 2013, 19, 1184 – 1188

Synthesis of 3,2’-Pyrrolidinyl Mono- and Bi-spirooxindole Frameworks
COMMUNICATION
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Experimental Section
General procedure: Catalyst L4 (0.015 mmol, 15 mol%) and 4a
(0.11 mmol, 1.1 equiv) were dissolved in CH2Cl2 (1 mL) in the ice bath.
A solution of 1b (0.10 mmol, 1.0 equiv) in CH2Cl2 (1 mL) was added to
the reaction over 30 min by a constant-flow pump. After the complete
addition of 1b, the mixture was purified by column chromatography on
silica gel to obtain desired product.
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Acknowledgements
We are grateful for grants from the National Natural Science Foundation
of China (nos. 20932003 and 90813012), the Key National S&T Program
“Major New Drug Development” of the Ministry of Science and Tech-
nology of China (2012ZX09504–001–003).
Keywords: asymmetric
synthesis
·
heterocycles
·
organocatalysis · oxindoles · spiro compounds · synthetic
methods
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Received: November 17, 2012
Published online: December 18, 2012
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Chem. Eur. J. 2013, 19, 1184 – 1188