An asymmetric approach toward chiral multicyclic spirooxindoles from isothiocyanato oxindoles and unsaturated pyrazolones by a chiral tertiary amine thiourea catalyst

Article abstract of DOI:10.1039/c3cc38386e

The first organocatalytic Michael-cyclization cascade reaction between isothiocyanato oxindoles and unsaturated pyrazolones has been developed. The multicyclic spiro[oxindole/thiobutyrolactam/pyrazolone] core structures containing three contiguous stereog

Full text of DOI:10.1039/c3cc38386e

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
An asymmetric approach toward chiral multicyclic
spirooxindoles from isothiocyanato oxindoles and
unsaturated pyrazolones by a chiral tertiary amine
thiourea catalyst†
Cite this: Chem. Commun., 2013,
49, 1657
Received 21st November 2012,
Accepted 7th January 2013
Qiao Chen,a Jinyan Liang,a Shoulei Wang,a Dong Wanga and Rui Wang*ab
DOI: 10.1039/c3cc38386e
www.rsc.org/chemcomm
The first organocatalytic Michael–cyclization cascade reaction for the asymmetric synthesis of a range of enantioenriched
between isothiocyanato oxindoles and unsaturated pyrazolones has spirooxindoles.4 Furthermore, Matsunaga and co-workers
been developed. The multicyclic spiro[oxindole/thiobutyrolactam/ demonstrated the utility of this attractive reactant in the
pyrazolone] core structures containing three contiguous stereogenic synthesis of a spiro[imidazolidine-4,30-oxindole] core through
centers, including two spiro quaternary centers, were prepared
with excellent diastereo- (up to >20 : 1) and enantioselectivities attracted considerable attention6 because of their wide range
a
Mannich-type reaction.5 Meanwhile, pyrazolones have
(up to 99% ee).
of biological properties such as antibacterial and antifungal
activities,7 antitumor property8 and anti-inflammatory effects.9
Spirocyclic structures are common in nature’s kingdom and Although various synthetic protocols have been achieved for the
have always been a challenge for synthetic organic chemists.1 construction of 4-substituted pyrazolones, there are few reports
Particularly heterocyclic spirooxindole subunits are featured in a concerning the synthesis of chiral pyrazolones with a quaternary
number of biologically, pharmaceutically, and medically active stereogenic center at the C-4 position. In addition, it has been
molecules (Fig. 1).2 As a consequence, many diverse methods to documented that the modification of the oxindole at the C-3
access structurally diverse heterocyclic spirooxindoles have position is crucial for the enhancement of the biological
been developed during the past few years.3 In spite of these activity.10 Thus, the combination of oxindole motifs with
remarkable advances, the asymmetric merge of this rigid spiro- pyrazolones for the formation of structurally diverse spiroox-
architecture with other heterocycles is rarely reported.
indoles is highly promising. However, no result has been
Recently, Yuan’s group synthesized a series of 3-isothio- reported in the literature for this fused spirocyclic motif. As
cyanato oxindoles and successfully used them as nucleophiles part of our ongoing research program toward the exploitation
of organocatalytic cascade reaction and our interest in seeking
an enantioselective approach toward the construction of spiro-
cyclic motifs,3f,m,r,s we will in this context present the first
organocatalytic asymmetric Michael–cyclization sequence of
3-isothiocyanato oxindoles and unsaturated pyrazolones with
bifunctional thiourea tertiary amines as catalysts, providing multi-
cyclic spiro[oxindole/thiobutyrolactam/pyrazolone] core structures
in high yields and excellent diastereo- and enantioselectivities.
Initially, we examined the model reaction between 3-iso-
thiocyanato-1-methylindolin-2-one 2a and unsaturated pyrazo-
lone 3a with several organocatalysts in dichloromethane at
room temperature for 12 hours (Table 1, entries 1–7). Considering
the yield, diastereoselectivity and enantioselectivity, the rosin-
derived tertiary amine thiourea catalyst 1a was optimal and
gave the desired product 4aa with 87% ee, 5 : 1 dr, and 98%
yield (entry 1). A survey of solvents indicated that a substantial
change of solvents has a significant effect on the diastereo- and
enantioselectivity (entries 8–11), and methyl tert-butyl ether
(MTBE) is the most suitable reaction medium. The enantio-
selectivity could be improved to >99% ee when the reaction was
Fig. 1 Some examples for biologically active important molecules containing a
heterocyclic spirooxindole framework.
a Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of
Basic Medical Sciences, State Key Laboratory of Applied Organic Chemistry and
Institute of Biochemistry and Molecular Biology, School of Life Sciences,
Lanzhou University, Lanzhou, 730000, China
b State Key Laboratory of Chiroscience, Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Kowloon,
Hong Kong, China. E-mail: wangrui@lzu.edu.cn
† Electronic supplementary information (ESI) available: Experimental details and
spectral data. CCDC 909596. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3cc38386e
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 1657--1659 1657

View Article Online
Communication
ChemComm
Table 1 Optimization of reaction conditionsa
Table 2 Investigation of substrate scopea
Entry
2
R2 (3)
4
Yieldb (%) drc
eed (%)
1
2
3
4
5
6
7
8
2a Ph(3a)
4aa
4ab
4ac
4ad
4ae
4af
4ag
4ah
4ai
96
93
93
95
90
90
96
81
87
87
86
85
96
72
96
14 : 1 >99
2a 2-MeOC6H4(3b)
2a 3-MeOC6H4(3c)
2a 4-MeOC6H4(3d)
2a 2-ClC6H4(3e)
2a 4-ClC6H4(3f)
2a 4-MeC6H4(3g)
2a 4-BrC6H4(3h)
2a 4-FC6H4(3i)
>20 : 1 >99
10 : 1 91
>20 : 1 >99
16 : 1
10 : 1
99
95
>20 : 1 >99
12 : 1
14 : 1
95
95
9
Entry
Cat.
Solvent
Yieldb (%)
drc
5 : 1
5 : 1
3 : 1
1 : 1
3 : 1
5 : 1
4 : 1
8 : 1
7 : 1
10 : 1
14 : 1
14 : 1
14 : 1
eec (%)
10
11
12
13
14
15
16
17
18
19
2a 3,4-Me2C6H3(3j) 4aj
19 : 1 >99
2a 2-Furyl (3k)
2a 2-Naphthyl (3l)
2b Ph (3a)
2b 2-ClC6H4(3e)
2b 4-ClC6H4(3f)
2b 3-ClC6H4(3m)
2c Ph (3a)
4ak
4al
4ba
4be
4bf
>20 : 1
12 : 1
96
92
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1a
1a
1a
1a
1a
1a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
THF
Et2O
MTBE
MTBE
MTBE
98
95
93
95
96
75
94
96
95
96
96
96
93
87
ꢀ82
ꢀ81
82
81
0
53
82
71
92
10 : 1 >99
8 : 1
8 : 1
5 : 1
91
90
80
98
4bm 82
4ca
4da
4an
86
88
82
13 : 1
2d Ph (3a)
2a Me2(3n)
>20 : 1 >99
>20 : 1 11
9
a
10
11
12d
13d,e
Reactions were performed with 2 (0.1 mmol), 3 (0.11 mmol), catalyst
b
93
>99
97
(0.01 mmol), and MTBE (1 mL) at 0 1C for 12–24 h. Isolated yields of 4.
c
d
Determined by 1H NMR. Determined by chiral HPLC.
a
Unless otherwise noted, the reactions were performed on a 0.1 mmol
the N-1 position did not affect the enantioselectivity (entry 13),
but the dr values of the products dropped slightly, especially
when there were other substituents on the aromatic ring of
the unsaturated pyrazolones (entries 13–16). Compared with
N-methyl and N-npropyl protected 3-isothiocyanato oxindole
(entries 1 and 17), this could be attributed to the increase of
the steric hindrance of the 3-isothiocyanato oxindole 2b. To
determine the effect of the substituents on the indole ring, we
tested 5-Me-substituted oxindole 2d. To our delight, it could
participate in the reaction with even better results: product 4da
was isolated in 88% yield, >20 : 1 dr and >99% ee. It is note-
worthy that the reaction reported herein could be performed in
a relatively large-scale without an obvious influence on the
enantioselectivity and reactivity even with a catalyst loading of
0.2 mol% (Scheme 1).
scale of 2a and 3a (1.1 equiv.), using 10 mol% of the catalyst in solvent
b
c
d
(1 mL) at rt. Isolated yield. Determined by chiral HPLC. The reac-
e
tion was carried out at 0 1C. 1 mol% catalyst was used.
conducted at 0 1C (entry 12). Additional experimentation
revealed that the catalyst loading could be lowered to 1 mol%
with only a slight effect on reaction efficiency (entry 13).
With the optimal reaction conditions in hand, the scope of
the reaction was investigated by varying the substituents on
both the unsaturated pyrazolones and the 3-isothiocyanato
oxindoles. Firstly, when 3-isothiocyanato oxindole 2a was used,
various unsaturated pyrazolones were tested and the results are
summarized in Table 2. Unsaturated pyrazolone derivatives
with both electron-donating and electron-withdrawing
substituents at different positions on the aromatic ring were
tolerated, affording their corresponding heterocyclic spiro-
oxindoles in high yields, good diastereoselectivities, and
excellent enantioselectivities (entries 1–10). Particularly, the
unsaturated heterocyclic pyrazolone could also be applied to
this asymmetric process, and provided the reaction product 4ak in
86% yield, >20 : 1 dr and 96% ee (entry 11). When a more sterically
hindered 2-naphthyl group was introduced into the pyrazolone,
remarkable enantioselectivity and good yield were still obtained
(entry 12). In addition, when an unsaturated pyrazolone bearing
two methyl groups was used, the reaction gave good yield, excellent
diastereoselectivity, but poor enantioselectivity (entry 19).
With the successful chiral construction of multicyclic spiro-
[oxindole/thiobutyrolactam/pyrazolone] skeletons above, we
turned our attention to the synthetic utility of the products
and the results are depicted in Scheme 2.11 The protection of
the NH group of 4ba was readily accomplished in two steps,
providing compound 5 with >20 : 1 dr, 86% yield and 99% ee.
Further exploration of the substrate scope was focused on
the 3-isothiocyanato oxindoles 2 (entries 13–18, Table 2). It was
found that 3-isothiocyanato oxindole 2 with a benzyl group at Scheme 1 A relatively large-scale reaction.
c
1658 Chem. Commun., 2013, 49, 1657--1659
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
G. Bartoli and G. Bencivenni, Chem. Soc. Rev., 2012, 41, 7247;
(i) N. R. Ball-Jones, J. J. Badillo and A. K. Franz, Org. Biomol. Chem.,
2012, 10, 5165.
3 For selected examples, see: (a) A. P. Antonchick, C. Gerding-Reimers,
M. Catarinella, M. Schurmann, H. Preut, S. Ziegler, D. Rauh and
H. Waldmann, Nat. Chem., 2010, 2, 735; (b) Q. Wei and L.-Z. Gong,
Org. Lett., 2010, 12, 1008; (c) K. Jiang, Z.-J. Jia, X. Yin, L. Wu and
Y.-C. Chen, Org. Lett., 2010, 12, 2766; (d) K. Jiang, Z.-J. Jia, S. Chen,
L. Wu and Y.-C. Chen, Chem.–Eur. J., 2010, 16, 2852; (e) A. Voituriez,
N. Pinto, M. Neel, P. Retailleau and A. Marinetti, Chem.–Eur. J., 2010,
16, 12541; ( f ) X. Jiang, Y. Cao, Y. Wang, L. Liu, F. Shen and R. Wang,
J. Am. Chem. Soc., 2010, 132, 15328; (g) B. Tan, N. R. Candeias and
C. F. Barbas III, Nat. Chem., 2011, 3, 473; (h) J. Peng, X. Huang,
L. Jiang, H.-L. Cui and Y.-C. Chen, Org. Lett., 2011, 13, 4584;
(i) B. Tan, N. R. Candeias and C. F. Barbas III, J. Am. Chem. Soc.,
2011, 133, 4672; ( j) Y.-B. Lan, H. Zhao, Z.-M. Liu, G.-G. Liu, J.-C. Tao
and X.-W. Wang, Org. Lett., 2011, 13, 4866; (k) Z.-J. Jia, H. Jiang,
J.-L. Li, B. Gschwend, Q.-Z. Li, X. Yin, J. Grouleff, Y.-C. Chen and
K. A. Jørgensen, J. Am. Chem. Soc., 2011, 133, 5053; (l) F. Zhong,
X. Han, Y. Wang and Y. Lu, Angew. Chem., Int. Ed., 2011, 50, 7837;
(m) Y. Cao, X. Jiang, L. Liu, F. Shen and R. Wang, Angew. Chem., Int.
Scheme 2 Transformations of the product 4ba to other chiral spiropyrazolone
frameworks.
Meanwhile, a direct approach to the construction of 6 from 4ba
would be achieved via a simple oxidant treatment with excellent
yield and enantioselectivity. In addition, compound 7, an
analogue of spirobrassinin (Fig. 1), could be acquired by a
straightforward methylation of 4ba without sacrificing either
yield or diastereoselectivity. The absolute configurations of the
products were determined by X-ray crystal structure analysis of
compound 7.12 On the basis of our experimental results and
recent studies,3m,4,13 a possible model to explain the stereo-
chemistry of the Michael–cyclization sequence was proposed.11
In conclusion, an efficient organocatalyzed asymmetric
Michael–cyclization sequence of isothiocyanato oxindoles with
various unsaturated pyrazolones has been developed. The
process provides multicyclic spiro[oxindole/thiobutyrolactam/
pyrazolone] core structures containing three contiguous stereo-
genic centers, including two spiro quaternary stereocenters,
with excellent diastereo- (up to >20 : 1) and enantioselectivities
(up to 99% ee). We believe that these fused heterocyclic
spirooxindoles will be promising candidates for chemical
biology and drug discovery.
´
Ed., 2011, 50, 9124; (n) B. Tan, G. Hernandez-Torres and C. F. Barbas
III, J. Am. Chem. Soc., 2011, 133, 12354; (o) Y.-K. Liu, M. Nappi,
E. Arceo, S. Vera and P. Melchiorre, J. Am. Chem. Soc., 2011,
133, 15212; (p) S.-W. Duan, Y. Li, Y.-Y. Liu, Y.-Q. Zou, D.-Q. Shi
and W.-J. Xiao, Chem. Commun., 2012, 48, 5160; (q) B. Tan, X. Zeng,
W. W. Y. Leong, Z. Shi, C. F. Barbas III and G. Zhong, Chem.–Eur. J.,
2012, 18, 63; (r) W. Sun, G. Zhu, C. Wu, L. Hong and R. Wang,
Chem.–Eur. J., 2012, 18, 6737; (s) W. Sun, G. Zhu, C. Wu, L. Hong and
R. Wang, Chem.–Eur. J., 2012, 18, 13959; (t) Y.-Y. Han, W.-Y.
Han, X. Hou, X.-M. Zhang and W.-C. Yuan, Org. Lett., 2012, 14,
4054.
4 W.-B. Chen, Z.-J. Wu, J. Hu, L.-F. Cun, X.-M. Zhang and W.-C. Yuan,
Org. Lett., 2011, 13, 2472.
5 S. Kato, T. Yoshino, M. Shibasaki, M. Kanai and S. Matsunaga,
Angew. Chem., Int. Ed., 2012, 51, 7007.
6 For selected examples see: (a) S. Gogoi, C.-G. Zhao and D. Ding, Org.
Lett., 2009, 11, 2249; (b) Y.-H. Liao, W.-B. Chen, Z.-J. Wu, X.-L. Du,
L.-F. Cun, X.-M. Zhang and W.-C. Yuan, Adv. Synth. Catal., 2010,
352, 827; (c) A.-N. R. Alba, A. Zea, G. Valero, T. Calbet, M. Font-
´
Bardıa, A. Mazzanti, A. Moyano and R. Rios, Eur. J. Org. Chem., 2011,
1318; (d) A. Zea, A.-N. R. Alba, A. Mazzanti, A. Moyano and R. Rios,
Org. Biomol. Chem., 2011, 9, 6519; (e) Z. Yang, Z. Wang, S. Bai, X. Liu,
L. Lin and X.-M. Feng, Org. Lett., 2011, 13, 596; ( f ) Z. Wang,
Z.-G. Yang, D.-H. Chen, X.-H. Liu, L.-L. Lin and X.-M. Feng, Angew.
Chem., Int. Ed., 2011, 50, 4928.
7 (a) E. Akbas and I. Berber, Eur. J. Med. Chem., 2005, 40, 401;
(b) D. Costa, A. P. Marques, R. L. Reis, J. L. F. C. Lima and
E. Fernandes, Free Radical Biol. Med., 2006, 40, 632;
(c) S. Bondock, R. Rabie, H. A. Etman and A. A. Fadda, Eur. J. Med.
Chem., 2008, 43, 2122; (d) K. Sujatha, G. Shanthi, N. P. Selvam,
S. Manoharan, P. T. Perumal and M. Rajendran, Bioorg. Med. Chem.
Lett., 2009, 19, 4501.
8 (a) S. A. F. Rostom, M. A. Shalaby and M. A. El-Demellawy, Eur. J.
Med. Chem., 2003, 38, 959; (b) J. S. Casas, E. E. Castellano, J. Ellena,
M. S. Garcia-Tasende, M. L. Peres-Paralle, A. Sanchez, A. Sanchez-
Gonzalez, J. Sordo and A. Touceda, J. Inorg. Biochem., 2008, 102, 33.
9 R. N. Brogden, Drugs, 1986, 32, 60.
We are grateful for the grants from the National Natural
Science Foundation of China (no. 20932003, 91213302,
21272102), the Key National S&T Program ‘‘Major New Drug
Development’’ of the Ministry of Science and Technology of
China (2012ZX09504001–003).
Notes and references
1 (a) M.-H. Chen, P. P. Pollard, A. A. Patchett, K. Cheng, L. Wei,
W. W.-S. Chan, B. Butler, T. M. Jacks and R. G. Smith, Bioorg. Med.
Chem. Lett., 1999, 9, 1261; (b) W. Francke and W. Kitching, Curr. Org.
Chem., 2001, 5, 233; (c) R. K. Behera, A. K. Behera, R. Pradhan, A. Pati
and M. Patra, Synth. Commun., 2006, 36, 3729; (d) S. Rosenberg and
´
R. Leino, Synthesis, 2009, 2651; (e) X. Companyo, A. Zea, A.-N. R.
10 (a) K. C. Joshi and P. Chand, Pharmazie, 1982, 37, 1; (b) J. F. M.
Da-Silva, S. J. Garden and A. C. Pinto, J. Braz. Chem. Soc., 2001,
12, 273; (c) A. H. Abdel-Rahman, E. M. Keshk, M. A. Hanna and
S. M. El-Bady, Bioorg. Med. Chem., 2004, 12, 2483; (d) S.-L. Zhu, S.-J. Ji
and Z. Yong, Tetrahedron, 2007, 63, 9365.
11 For details, see ESI†.
12 CCDC 909596†.
13 (a) S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc., 2007,
129, 15872; (b) S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc.,
2009, 131, 15358; (c) R. R. Knowles and E. N. Jacobsen, Proc. Natl.
Acad. Sci. U. S. A., 2010, 107, 20678.
Alba, A. Mazzanti, A. Moyano and R. Rios, Chem. Commun., 2010,
´
46, 6953; ( f ) C. Cassani, X. Tian, E. C. Escudero-Adan and
P. Melchiorre, Chem. Commun., 2011, 47, 233.
2 For recent reviews, see: (a) R. M. Williams and R. J. Cox, Acc. Chem.
Res., 2003, 36, 127; (b) C. Marti and E. M. Carreira, Eur. J. Org. Chem.,
2003, 2209; (c) H. Lin and S. J. Danishefsky, Angew. Chem., Int. Ed.,
2003, 42, 36; (d) C. V. Galliford and K. A. Scheidt, Angew. Chem., Int.
Ed., 2007, 46, 8748; (e) B. M. Trost and M. K. Brennan, Synthesis,
2009, 3003; ( f ) F. Zhou, Y.-L. Liu and J. Zhou, Adv. Synth. Catal.,
2010, 352, 1381; (g) J. J. Badillo, N. V. Hanhan and A. K. Franz,
Curr. Opin. Drug Discovery Dev., 2010, 13, 758; (h) R. Dalpozzo,
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 1657--1659 1659