Organocatalytic stereocontrolled synthesis of 3,3′-pyrrolidinyl spirooxindoles by [3+2] annulation of isocyanoesters with methyleneindolinones

Article abstract of DOI:10.1039/c2cc30746d

A stereoselective [3+2] cycloaddition of isocyanoesters to methyleneindolinones catalyzed by a quinine-based thiourea-tertiary amine has been successfully developed. Just by tuning the protecting groups on substrates, a variety of optically enriched 3,3′-

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COMMUNICATION
Organocatalytic stereocontrolled synthesis of 3,30-pyrrolidinyl
spirooxindoles by [3+2] annulation of isocyanoesters with
methyleneindolinonesw
Liang-Liang Wang,ab Jian-Fei Bai,ab Lin Peng,a Liang-Wen Qi,ab Li-Na Jia,ab
Yun-Long Guo,ab Xi-Ya Luo,ab Xiao-Ying Xu*a and Li-Xin Wang*a
Received 2nd February 2012, Accepted 30th March 2012
DOI: 10.1039/c2cc30746d
A stereoselective [3+2] cycloaddition of isocyanoesters to
methyleneindolinones catalyzed by a quinine-based thiourea-
tertiary amine has been successfully developed. Just by tuning
the protecting groups on substrates, a variety of optically
enriched 3,30-pyrrolidinyl spirooxindole diastereomers could be
obtained in excellent enantioselectivities (up to 99% ee).
azomethine ylides to methyleneindolinones, generating 3,30-
pyrrolidinyl spirooxindoles with high level of enantio- and
diastereocontrol. Recently, Wang and Zhong7 also disclosed
an organocatalyzed Michael/cyclization sequence of isothio-
cyanate with methyleneindolinones, providing functionalized
hetero spirooxindoles with three adjacent chiral carbon centers.
Nevertheless, efficient catalytic stereoselective methods to access
such a motif with two quaternary stereocenters remain rare.
As a part of our persistent interest in the syntheses of optically
active spirooxindoles,8 herein, we wish to disclose the first
highly enantio- and diastereoselective [3+2] cycloaddition
involving a-substituted isocyanoesters9 and methyleneindolinones10
promoted by a thiourea-tertiary amine catalyst, affording
3,30-pyrrolidinyl spirooxindoles bearing congested multiple
stereogenic centers (Scheme 1).
3,30-Pyrrolidinyl spirooxindole scaffolds, extensively found in a
large number of natural alkaloids and bioactive molecules, can
serve as the core structural components for new pharmaceutical
candidates (Fig. 1).1 For instance, MI-147,2 a rationally designed
small molecule based on natural occurring Spirotryprostatin A,
functions as a specific, potent inhibitor of MDM2–p53 inter-
action, selectively inhibiting the growth of tumor cells. Spiro-
oxindole (ꢀ)-1a can directly inhibit tubulin polymerization in
cells, while its enantiomer (+)-1a or diastereomer 1b exhibits
no bioactivity.3 Therefore, in light of the principle of structure–
activity relationship for drug design,4 syntheses of structurally
diversified and stereocontrolled 3,30-pyrrolidinyl spirooxindoles
for bioactive evaluation are highly demanded. Due to their
appealing architectural complexity, chemists have developed
various approaches to establish the compound libraries of
3,30-pyrrolidinyl spirooxindole analogues.5 Waldmann et al.3
and Gong et al.,6 respectively, presented a Lewis and a
Brønsted acid catalyzed 1,3-dipolar cycloaddition reaction of
Diastereocontrolled synthesis in asymmetric catalysis is
regarded as one of the goals for structure-oriented synthesis.
To obtain diverse diastereomers, it is generally necessary to
modify catalysts11 or configuration of substrates.12 In this
study, we disclosed a novel method for stereocontrolled
syntheses of 3,30-pyrrolidinyl spirooxindole diastereomers just
by tuning the protecting groups on substrates without changing
the catalyst (Scheme 1).13
To initiate our study, N-phenylamide protected methylene-
indolinone 3a was selected to react with methyl a-phenyliso-
cyano acetate 4a catalyzed by the bifunctional thiourea-tertiary
amine 2a (Fig. 2) in DCM at room temperature (Table 1).
As expected, the cycloaddition proceeded smoothly and
afforded two diastereomers in moderate diastereoselectivity
(2.0 : 1 dr), good yield (70% overall yield) and enantiocontrol
Fig. 1 Natural products and unnaturally bioactive analogues.
a Key Laboratory of Asymmetric Synthesis and Chirotechnology of
Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, China.
E-mail: wlxioc@cioc.ac.cn, xuxy@cioc.ac.cn
b Graduate School of Chinese Academy of Sciences, Beijing, China
w Electronic supplementary information (ESI) available: Experimental
procedures, spectral data of new compounds, and crystallographic
data. CCDC 849672–849674. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2cc30746d
Scheme 1 Construction of 3,30-pyrrolidinyl spirooxindoles by [3+2]
cycloaddition of isocyanoesters to methyleneindolinones.
c
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Chem. Commun., 2012, 48, 5175–5177 5175

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Table 2 Generality of [3+2] reaction with N-phenyl amide protected
methyleneindolinonesa
Fig. 2 Catalysts screened in this study.
Table 1 Screening of reaction conditionsa
Entry 3/R1, R2
4
Time/h Yieldb (%) Drc(anti/syn) Eed (%)
1
2
3
4
5
6
7
8
3a/H, Et
4a 28
5a/60
5b/53
5c/61
5d/64
5e/61
5f/53
5g/50
5h/45
5i/41
5j/41
5k/50
5l/54
2.7 : 1
6.2 : 1
7.0 : 1
8.0 : 1
7.2 : 1
5.1 : 1
3.9 : 1
3.2 : 1
2.8 : 1
3.0 : 1
5.6 : 1
3.0 : 1
95
92
92
94
97
92
90
95
96
96
94
95
3b/5-F, Et 4a 22
3c/5-Cl, Et 4a 27
3d/5-Br, Et 4a 22
3e/5-Me, Et 4a 27
3f/6-Cl, Et 4a 27
3g/6-Br, Et 4a 27
3h/H, Bn
3i/H, tBu
3a/H, Et
Entry
2
Sol.
Time/h Yieldb (%) Drc (5a/5a0) Eed (%)
4a 23
4a 45
4b 27
9
1
2a CHCl3
2b CHCl3
2c CHCl3
2d CHCl3
2e CHCl3
2a DCM
2a Toluene 12
2a THF
2a CH3CN
2a DMF
2a DCM
2a CHCl3
12
17
17
17
4
70
64
63
62
72
61
63
50
58
70
71
82(52)g
2.0 : 1
1.3 : 1
1.6 : 1
1.8 : 1
1.1 : 1
2.2 : 1
1.1 : 1
1 : 1
1 : 3.1
1 : 4.2
3.9 : 1
3.1 : 1
78(72)
62(57)
65(72)
75(76)
47(65)
86(71)
81(82)
37(55)
8(8)
10
11
12
2e
3e
4
3d/5-Br, Et 4b 22
3e/5-Me, Et 4b 23
a
5e
6
7
8
Unless otherwise noted, the reaction was conducted with 0.2 mmol 3,
0.3 mmol 4 and 10 mol% 2a in the presence of 4 A MS (200 mg) in 1.0 mL
12
b
c
CHCl3 at ꢀ20 1C. Isolated yield of the pure anti-product. Ratio of
12
8
8
28
27
anti/syn diastereomers; determined by 1H NMR analysis of crude
d
products. Measured by chiral HPLC.
9
10e
11f
12f
18(45)
94(81)
95(87)
Notably, the formed cycloaddition products were highly
functionalized, along with an imine moiety which provided
convenience for further structural modification. As shown in
Scheme 2, product 5c was readily transformed to 3,30-pyrrolidinyl
spirooxindole 6 in good yield by transfer hydrogenation. After
removal of the N-phenylamide group in the presence of KOH
and silica gel in THF at 60 1C,10c spirooxindole 7 was obtained
without influence of the ester groups. Unexpectedly, when 5c was
treated with concentrated hydrochloric acid, decarbonylation
took place and furnished the chiral a-quaternary carbon amino
acid derivative 8. The absolute configurations of products 5a–l
were determined by X-ray analysis of compound 7.
a
Unless otherwise noted, the reaction was performed with 0.1 mmol 3a,
0.15 mmol 4a and 10 mol% catalyst 2 in 0.5 mL solvent at room
b
temperature. Total yield of two diastereomers after chromatography.
c
d
Determined by chiral HPLC. Measured by chiral HPLC; Ee value
e
of minor diastereomers in the parentheses. Contrary configuration.
f
g
At ꢀ20 1C and 4 A MS (100 mg). Isolated yield of the pure anti-
product is given in the parentheses.
(78% ee) (Table 1, entry 1). Encouraged by this result, we then
examined an array of bifunctional catalysts 2b–e and found that
quinine-based 2a was the optimal catalyst in terms of enantio- and
diastereoselectivity (Table 1, entry 1 vs. entries 2–5). After investi-
gation of various reaction parameters, the optimized conditions
were established to afford anti-5a in 52% yield (82% total yield),
95% ee and 3.1 : 1 dr in CHCl3 at ꢀ20 1C (Table 1, entry 12).
Under the optimized conditions, the scope of substrates was
evaluated, and the results are summarized in Table 2. A wide
range of methyleneindolinones with a phenylamide protecting
group were well tolerated and afforded the products in excellent
enantioselectivities (up to 97% ee). Substituents on the aromatic
ring of methyleneindolinones, regardless of the electronic nature
and substituted position, provided the desired products with
moderate to good yields and diastereoselectivities, and excellent
enantiocontrol (Table 2, entries 2–7). With the increase of steric
hindrance of the ester group on methyleneindolinone, the
reactivity and diastereocontrol were slightly decreased without
eroding enantioselectivity (Table 2, entry 9 vs. entry 8). Ethyl
a-phenylisocyano acetate 4b was also effective to deliver spiro-
oxindoles in excellent enantioselectivities (Table 2, entries 11
and 12), while a-alkyl such as methyl and benzyl substituted
isocyanoacetates were not available in this transformation
due to the decreased acidity of the a-hydrogen atoms in those
isocyanoesters (not shown in the table).
Interestingly, when evaluating the effect of N-protecting
groups on reactivity, we observed that N-tert-butoxycarbonyl
(N-Boc) protected methyleneindolinones reacted smoothly
with isocyanoacetates and provided spirooxindoles in a switched
diastereoselectivity as compared with N-phenylamide protected
methyleneindolinones (Table 3). Remarkably, in most cases,
optically pure (>99% ee) syn-products could be obtained when
phenylisocyano acetates 4a–b were employed, while a-alkyl such
as methyl and isopropyl substituted isocyanoacetates were
Scheme 2 Transformation of N-phenyl amide protected cycloadduct.
c
5176 Chem. Commun., 2012, 48, 5175–5177
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Table
3
Generality of [3+2] cycloaddition with Boc-protected
2 S. Yu, D. Qin, S. Shangary, J. Chen, G. Wang, K. Ding,
D. McEachern, S. Qiu, Z. Nikolovska-Coleska, R. Miller,
S. Kang, D. Yang and S. Wang, J. Med. Chem., 2009, 52,
7970.
methyleneindolinonesa
3 A. P. Antonchick, C. Gerding-Reimers, M. Catarinella, M. Schurmann,
H. Preut, S. Ziegler, D. Rauh and H. Waldmann, Nat. Chem.,
2010, 2, 735.
4 For selected reviews on Quantitative Structure–Activity Relation-
ships (QSAR): (a) A. Z. Dudek, T. Arodz and J. Galvez, Comb.
Chem. High Throughput Screening, 2006, 9, 213; (b) K. Creager and
T. H. Jordan, Drugs Future, 2002, 27, 577.
Entry 3/R1, R2
4
Time/h Yieldb (%) Drc (syn/anti) Eed (%)
5 For racemic or enantioselective syntheses of 3,30-pyrrolidinyl
spirooxindoles using chiral auxiliaries: ref. 1a and b.
1
2
3
3j/H, Et
3k/5-F, Et
3l/5-Cl, Et
4a 22
4a 22
4a 22
5m/53
5n/56
5o/58
5p/50
5q/50
5r/45
5s/53
5t/55
5u/58
5v/44
5w/50
5x/65
5y/62
3.0 : 1
4.9 : 1
4.5 : 1
3.9 : 1
2.0 : 1
2.3 : 1
4.1 : 1
4.0 : 1
3.5 : 1
2.4 : 1
1.9 : 1
4.4 : 1
5.1 : 1
99
>99
99
>99
98
6 X. H. Chen, Q. Wei, S. W. Luo, H. Xiao and L. Z. Gong, J. Am.
Chem. Soc., 2009, 131, 13819.
7 (a) Y. Cao, X. Jiang, L. Liu, F. Shen, F. Zhang and R. Wang,
Angew. Chem., Int. Ed., 2011, 50, 9124; (b) B. Tan, X. Zeng,
W. W. Y. Leong, Z. Shi, C. F. Barbas, III and G. Zhong,
Chem.–Eur. J., 2012, 18, 63.
8 (a) L. L. Wang, L. Peng, J. F. Bai, Q. C. Huang, X. Y. Xu and
L. X. Wang, Chem. Commun., 2010, 46, 8064; (b) L. L. Wang,
L. Peng, J. F. Bai, L. N. Jia, X. Y. Luo, Q. C. Huang, X. Y. Xu and
L. X. Wang, Chem. Commun., 2011, 47, 5593.
9 For review on isocyanide mediated reactions: (a) A. V. Gulevich,
A. G. Zhdanko, R. V. A. Orru and V. G. Nenajdenko, Chem. Rev.,
2010, 110, 5235. To date, there are only two examples regarding
asymmetric 1,3-dipolar cycloaddition of a-substituted isocyano-
esters to electron-deficient olefins with promising outcomes:
(b) C. Guo, M. X. Xue, M. K. Zhu and L. Z. Gong, Angew.
Chem., Int. Ed., 2008, 47, 3414; (c) J. Song, C. Guo, P. H. Chen,
J. Yu, S. W. Luo and L. Z. Gong, Chem.–Eur. J., 2011, 17,
7786. For asymmetric isocyanoacetate aldol: (d) F. Sladojevich,
A. Trabocchi, A. Guarna and D. J. Dixon, J. Am. Chem. Soc.,
2011, 133, 1710 and references therein; (e) M. X. Xue, C. Guo and
L. Z. Gong, Synlett, 2009, 2191.
4
3m/5-Br, Et 4a 22
3n/5-Me, Et 4a 23
3o/5-MeO, Et 4a 23
3p/6-Cl, Et
3q/6-Br, Et
3r/H, Me
3s/H, Bn
3t/H, tBu
3n/5-Me, Et 4b 23
3l/5-Cl, Et 4b 22
5e
6e
7
>99
98
4a 24
4a 22
4a 22
4a 42
4a 42
8
9
10
11
12
13
>99
>99
>99
>99
>99
97
a
Unless otherwise noted, the reaction was conducted with 0.2 mmol 3,
0.22 mmol 4 and 10 mol% 2a in the presence of 4 A MS (200 mg) in
b
1.0 mL CHCl3 at ꢀ20 1C. Isolated yield of the pure major isomer.
c
Ratio of syn/anti diastereomers; determined by 1H NMR analysis of
d
crude products. Measured by chiral HPLC. 0.3 mmol 4 used.
e
10 For selected recent examples using methyleneindolinones as
highly reactive Michael acceptors to construct spirooxindoles by
asymmetric organocatalysis: (a) B. Tan, N. R. Candeias and
C. F. Barbas III, Nat. Chem., 2011, 3, 473; (b) B. Tan,
G. Handez-Torres and C. F. Barbas III, J. Am. Chem. Soc.,
2011, 133, 12354; (c) B. Tan, N. R. Candeias and C. F. Barbas
III, J. Am. Chem. Soc., 2011, 133, 4672; (d) 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;
(e) G. Bencivenni, L. Y. Wu, A. Mazzanti, B. Giannichi,
F. Pesciaioli, M. P. Song, G. Bartoli and P. Melchiorre,
Angew. Chem., Int. Ed., 2009, 48, 7200; (f) F. Zhong, X. Han,
Y. Wang and Y. Lu, Angew. Chem., Int. Ed., 2011, 50, 7837;
(g) Q. Wei and L. Z. Gong, Org. Lett., 2010, 12, 1008; (h) K. Jiang,
Z. J. Jia, S. Chen, L. Wu and Y. C. Chen, Chem.–Eur. J., 2010,
16, 2852.
11 The endo or exo selectivity of [3+2] cycloadducts could be
switched via employing different metal catalysts: (a) T. Arai,
A. Mishiro, N. Yokoyama, K. Suzuki and H. Sato, J. Am. Chem.
Soc., 2010, 132, 5338; (b) X. X. Yan, Q. Peng, Y. Zhang, K. Zhang,
W. Hong, X. L. Hou and Y. D. Wu, Angew. Chem., Int. Ed., 2006,
45, 1979.
12 Two diastereomers can be obtained by using Z or E type of
alkenes with a single catalyst: (a) S. Cabrera, R. G. Arrayas and
J. C. Carretero, J. Am. Chem. Soc., 2005, 127, 16394; (b) J. M.
Longmire, B. Wang and X. Zhang, J. Am. Chem. Soc., 2002,
124, 13400.
Fig. 3 X-Ray crystal structure of 5p.
inactive in this reaction. The absolute configurations of
products 5m–y were assigned by X-ray analysis of 5p (Fig. 3).
In summary, we have developed a novel [3+2] cycloaddition of
isocyanoesters to methyleneindolinones and successfully obtained
various optically active 3,30-pyrrolidinyl spirooxindoles bearing
multiple adjacent stereocenters. Particularly, the controlled
synthesis of diastereomers could be achieved just by tuning the
protecting group. The detailed survey regarding the origin of a
protecting group induced diastereoselectivity switch is underway
in our lab (a plausible mechanism was proposed in ESIw).
Notes and references
1 For reviews: (a) C. V. Galliford and K. A. Scheidt, Angew. Chem.,
Int. Ed., 2007, 46, 8748; (b) C. Marti and E. M. Carreira, Eur. J.
Org. Chem., 2003, 2209For selected examples: (c) K. Ding, Y. Lu,
Z. Nikolovska-Coleska, S. Qiu, Y. Ding, W. Gao, J. Stuckey,
K. Krajewski, P. P. Roller, Y. Tomita, D. A. Parrish,
J. R. Deschamps and S. Wang, J. Am. Chem. Soc., 2005,
127, 10130; (d) S. Shangary, D. Qin, D. McEachern, M. Liu,
R. S. Miller, S. Qiu, Z. Nikolovska-Coleska, K. Ding, G. Wang,
J. Chen, D. Bernard, J. Zhang, Y. Lu, Q. Gu, R. B. Shah,
K. J. Pienta, X. Ling, S. Kang, M. Guo, Y. Sun, D. Yang and
S. Wang, Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 3933.
13 Recently, acidic additive inducing diastereo- and enantioselection
switch with a single catalyst was reported: (a) S. A. Moteki, J. Han,
S. Arimitsu, M. Akakura, K. Nakayama and K. Maruoka, Angew.
Chem., Int. Ed., 2012, 51, 1187; (b) X. Tian, C. Cassani, Y. Liu,
A. Moran, A. Urakawa, P. Galzerano, E. Arceo and
P. Melchiorre, J. Am. Chem. Soc., 2011, 133, 17934; (c) J. Gao,
S. Bai, Q. Gao, Y. Liu and Q. Yang, Chem. Commun., 2011,
47, 6716. For an example of substituted group leading to diastereo-
selectivity switch: (d) A. A. Desai and W. D. Wulff, J. Am. Chem.
Soc., 2010, 132, 13100.
c
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Chem. Commun., 2012, 48, 5175–5177 5177