Highly enantioselective construction of spiro[ 4H -pyran-3,3′- oxindoles] through a domino knoevenagel/Michael/Cyclization sequence catalyzed by cupreine

Article abstract of DOI:10.1021/ol1009224

(Figure Presented) The first enantioselective organocatalytic two- and three-component reactions via a domino Knoevenagel/Michael/cyclization sequence with cupreine as catalyst have been developed. A wide range of optically active spiro[4H-pyran-3,3′-oxindoles] were obtained in excellent yields (up to 99%) with good to excellent enantioselectivities (up to 97%) from simple and readily available starting materials under mild reaction conditions. These heterocyclic spirooxindoles will provide promising candidates for chemical biology and drug discovery.

Full text of DOI:10.1021/ol1009224

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3132-3135
Highly Enantioselective Construction of
Spiro[4H-pyran-3,3′-oxindoles] Through a
Domino Knoevenagel/Michael/Cyclization
Sequence Catalyzed by Cupreine
Wen-Bing Chen,†,‡ Zhi-Jun Wu,‡,§ Qing-Lan Pei,†,‡ Lin-Feng Cun,†
Xiao-Mei Zhang,† and Wei-Cheng Yuan*,†
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu
610041, China, Graduate School of Chinese Academy of Sciences, Beijing, China, and
Chengdu Institute of Biological, Chinese Academy of Sciences, Chengdu, China
yuanwc@cioc.ac.cn
Received April 21, 2010
ABSTRACT
The first enantioselective organocatalytic two- and three-component reactions via a domino Knoevenagel/Michael/cyclization sequence with
cupreine as catalyst have been developed. A wide range of optically active spiro[4H-pyran-3,3′-oxindoles] were obtained in excellent yields (up
to 99%) with good to excellent enantioselectivities (up to 97%) from simple and readily available starting materials under mild reaction conditions.
These heterocyclic spirooxindoles will provide promising candidates for chemical biology and drug discovery.
The heterocyclic spirooxindoles are attractive targets in
organic synthesis because of their highly pronounced bio-
logical activities as well as wide-ranging utility as synthetic
intermediates for alkaloids, drug candidates, and clinical
pharmaceuticals.1 Therefore, searching for efficient methods
for the synthesis of these compounds is interesting in organic
synthesis, and numerous impressive successes have been
recorded for the synthesis of diversely structured spirocyclic
oxindoles over the past years.2,3 However, the construction
of one unique spirocyclic oxindole, incorporating a 2-amino-
4H-pyran-3-carbonitrile ring at the C3 position of oxindole,
is still limited.4 To the best of our knowledge, no asymmetric
protocol to access optically active spiro[4H-pyran-3,3′-
oxindole] derivatives has yet been reported. In this context,
considering the broad biological activities of some spirocyclic
oxindoles containing a six-membered spirocyclic moiety at
the C3 position,5 we can envision that an efficient catalytic
(3) For recently selected examples, see: (a) Chen, X.-H.; Wei, Q.; Xiao,
H.; Luo, S.-W.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 13819. (b)
Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song,
M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7200.
(c) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem.-Eur. J. 2010,
16, 2852. (d) Wei, Q.; Gong, L.-Z. Org. Lett. 2010, 12, 1008. (e) Shintani,
R.; Hayashi, S.-y.; Murakami, M.; Takeda, M.; Hayashi, T. Org. Lett. 2009,
11, 3754. (f) Castaldi, M. P.; Troast, D. M.; Porco, J. A., Jr. Org. Lett.
† Chengdu Institute of Organic Chemistry.
‡ Graduate School of Chinese Academy of Sciences.
§ Chengdu Institute of Biological.
(1) (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127. (b)
Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748,
and references therein.
(2) For selected reviews, see: (a) Trost, B. M.; Jiang, C. Synthesis 2006,
369. (b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209
.
2009, 11, 3362.
10.1021/ol1009224  2010 American Chemical Society
Published on Web 06/14/2010

asymmetric tactic to access spiro[4H-pyran-3,3′-oxindole]
compounds is particularly promising as well as strongly
desired.
One of the desirable goals in organic chemistry is the
catalytic asymmetric assembly of simple and readily available
precursor molecules into stereochemically complex prod-
ucts.6 In addition, asymmetric organocatalysis has recently
emerged as a promising synthetic tool for the organic
synthesis.7 Therefore, as a continuation of our intense
research on asymmetric organocatalysis8a-c and the prepara-
tion of chiral oxindole derivatives,8d we have recently
become interested in the stereoselective construction of the
spiro[4H-pyran-3,3′-oxindole] motifs. Herein, we will report
the first asymmetric organocatalytic two- and three-compo-
nent reactions via a domino Knoevenagel/Michael/cyclization
sequence that provide a series of spiro[4H-pyran-3,3′-
oxindoles] in excellent yield (up to 99%) with good to
excellent ee values (up to 97% ee) from simple and readily
available starting materials.
Figure 1. Chiral organocatalysts tested in this study.
At the outset of the study, a variety of chiral organocata-
lysts cat. 1-10 (Figure 1) were tested in the selected reaction
of substrates 1c and 2a in 1,2-dichloroethane (DCE) at 0
°C, and the results are summarized in Table 1. As shown,
cupreine (CPN),9,10 quinine’s C6′-OH derivative, gave the
best results (92% yield, 85% ee) among these tested
organocatalysts (Table 1, entry 8 vs 1-7 and 9-10). Then,
with CPN as catalyst, the screening of the ratio of substrates
1c to 2a revealed that 5.0 equiv of 2a to 1c was the optimal
ratio (Table 1, entry 11).
Table 1. Screening of Different Chiral Organocatalysts and the
Ratio of Substrates 1c to 2aa
entry
cat.
1c:2a
time (h)
yield (%)b
ee (%)c
Afterward, during the investigation of the protecting
groups on the N1 of isatylidene malononitrile derivatives,
1
2
3
4
5
6
7
8
9
cat. 1
cat. 2
cat. 3
cat. 4
cat. 5
cat. 6
cat. 7
cat. 8
cat. 9
cat. 10
cat. 8
cat. 8
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:5
16
16
34
34
34
36
24
12
36
36
16
36
60
94
58
75
88
trace
trace
92
82
90
-2
0
-36
0
-3
nd
nd
85
7
54
86
84
(4) (a) Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. Tetrahedron 2007,
63, 2057. (b) Zhu, S.-L.; Ji, S.-J.; Zhang, Y. Tetrahedron 2007, 63, 9365.
(c) Gao, S.; Tsai, C. H.; Tseng, C.; Yao, C.-F. Tetrahedron 2008, 64, 9143.
(d) Elinson, M. N.; Ilovaisky, A. I.; Dorofeev, A. S.; Merkulova, V. M.;
Stepanov, N. O.; Miloserdov, F. M.; Ogibin, Y. N.; Nikishin, G. I.
Tetrahedron 2007, 63, 10543. (e) Fotouhi, L.; Heravi, M. M.; Fatehi, A.;
Bakhtiari, K. Tetrahedron Lett. 2007, 48, 5379. (f) Wang, L.-M.; Jiao, N.;
Qiu, J.; Yu, J.-J.; Liu, J.-Q.; Guo, F.-L.; Liu, Y. Tetrahedron 2010, 66,
339. (g) Shaabani, A.; Samadi, S.; Badri, Z.; Rahmati, A. Catal. Lett. 2005,
104, 39. (h) Shaabani, A.; Samadi, S.; Rahmati, A. Synth. Commun. 2007,
37, 491. (i) Abdolmohammadi, S.; Balalaie, S. Tetrahedron Lett. 2007, 48,
3299.
10
11
12
92
90
1:2
(5) For selected examples, see: (a) Fensome, A.; Adams, W. R.; Adams,
A. L.; Berrodin, T. J.; Cohen, J.; Huselton, C.; Illenberger, A.; Kern, J. C.;
Hudak, V. A.; Marella, M. A.; Melenski, E. G.; McComas, C. C.; Mugford,
C. A.; Slayden, O. D.; Yudt, M.; Zhang, Z.; Zhang, P.; Zhu, Y.; Winneker,
R. C.; Wrobel, J. E. J. Med. Chem. 2008, 51, 1861. (b) Fensome, A.; Bender,
R.; Cohen, J.; Collins, M. A.; Mackner, V. A.; Miller, L. L.; Ullrich, J. W.;
Winneker, R.; Wrobel, J.; Zhang, P.; Zhang, Z.; Zhu, Y. Bioorg. Med. Chem.
Lett. 2002, 12, 3487. (c) Bignan, G. C.; Battista, K.; Connolly, P. J.; Orsini,
M. J.; Liu, J.; Middleton, S. A.; Reitz, A. B. Bioorg. Med. Chem. Lett.
2005, 15, 5022. (d) Feldman, K. S.; Vidulova, D. B. Org. Lett. 2004, 6,
1869. (e) Kawasaki, T.; Ogawa, A.; Takashima, Y.; Sakamoto, M.
Tetrahedron Lett. 2003, 44, 1591.
a Reactions were performed on a 0.1 mmol scale in 1.0 mL of DCE at
0 °C. b Isolated yield. c Determined by HPLC.
methoxymethyl (MOM-) was superior to H-, Boc-, and Ac-
groups in light of the reactivity and enantioselectivity (Table
2, entries 1-4). Gratifyingly, a subsequent solvent screen
resulted in selection of conditions that significantly increased
the ee value without diminishing the yield (Table 2, entries
3 and 5-9). Further, adding 4 Å molecular sieves (MS) led
to fast reaction (14 h) and a slightly higher ee value of 95%
(Table 1, entry 10). Finally, 0 °C was found to be the most
suitable reaction temperature (Table 2, entries 10-12). In
summary, acetylacetone/isatylidene malononitriles (5/1),
(6) For selected reviews, see: (a) Tietze, L. F.; Evers, T. H.; To¨pken, E.
;Angew. Chem., Int. Ed. 2001, 40, 903. (b) Tietze, L. F.; Beifuss, U. Angew.
Chem., Int. Ed. 1993, 32, 131. (c) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(7) For selected reviews on asymmetric organocatalysis, see: (a)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (b)
Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int.
Ed. 2008, 47, 6138. (c) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007,
107, 5713. (d) Connon, S. J. Synlett 2009, 354.
(8) (a) Liao, Y.-H.; Zhang, H.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.;
Yuan, W.-C. Tetrahedron: Asymmetry 2009, 20, 2397. (b) Liao, Y.-H.;
Chen, W.-B.; Wu, Z.-J.; Du, X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-
C. AdV. Synth. Catal. 2010, 352, 827. (c) Zhang, H.; Cun, L.-F.; Zhang,
X.-M.; Yuan, W.-C. Lett. Org. Chem. 2010, 7, 219. (d) Chen, W.-B.; Du,
(9) For a representative review of cupreines and cupreidines as
bifunctional cinchona organocatalysts in asymmetric organocatalysis, see:
Marcelli, T.; van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed.
2006, 45, 7496.
X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2010, 66, 1441
.
Org. Lett., Vol. 12, No. 14, 2010
3133

CPN (10 mol %), and 4 Å MS in CH2Cl2 (DCM) at 0 °C
became our standard reaction conditions for the synthesis
of various spiro[4H-pyran-3,3′-oxindole] derivatives.
methyl 3-oxo-3-phenylpropanoate (2c) also gave the corre-
sponding product in 92% yield with 79% ee for 24 h (entry
17). We also observed that 1,3-cyclohexanediones 2d and
2e presented very high reaction activities, completing the
reactions in 30 and 15 min, respectively. However, very poor
enantioselectivities were obtained for 3u and 3v (entries 18
and 19).
Table 2. Optimization of Reaction Conditionsa
Table 3. Asymmetric Synthesis of
Spiro[4H-pyran-3,3′-oxindoles] with Two-Component Reactionsa
entry
1
solvent
time (h)
3/yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1c
1c
1c
1c
1c
1c
1c
1c
DCE
DCE
DCE
DCE
THF
DMF
toluene
CH2Cl2
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
28
48
20
60
36
14
13
18
18
14
24
14
3a/90
3b/trace
3c/92
3d/76
3c/91
3c/92
3c/94
3c/95
3c/93
3c/95
3c/94
3c/94
78
nd
86
55
6
-14
70
94
entry
1
2
3/yield (%)b
ee (%)c
95
55
10
11
12
95d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
R ) MOM
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2d
2e
3c/95
3e/97
3f/93
3g/95
3h/95
3i/95
3j/98
3k/96
3l/98
3m/94
3n/95
3o/87
3p/89
3q/95
3r/95
3s/92
3t/92
3u/95
3v/95
95d e
,
92d e
,
R ) MOM, 4-Cl
R ) MOM, 5-F
R ) MOM, 5-Cl
R ) MOM, 6-Cl
R ) MOM, 5-Br
R ) MOM, 6-Br
R ) MOM, 5-Me
R ) MOM, 5-OMe
R ) Me
92d f
,
96f
97f
94
a Unless noted, the reactions were carried out with 1 (0.1 mmol), 2a
(0.5 mmol), and CPN (0.01 mmol) in 1.0 mL of solvent at 0 °C. b Isolated
yield. c Determined by HPLC. d 4 Å MS (30 mg) was used. e -20 °C. f 25
°C.
97e g
,
95
93
96
95
94
94
72h
77h
82h
74i
77j
0k
The optimized protocol was then expanded to a variety
of isatylidene malononitrile derivatives 1 and 1,3-diones (2a,
2d-e) or ꢀ-oxo esters (2b-c). As shown in Table 3,
variation of the electronic properties of the substituents at
either C4 or C5 or C6 of N-MOM isatylidene malononitriles
was tolerable with excellent yields ranging from 93% to 98%
and enantioselectivities ranging from 92% to 97% ee (entries
2-9). It is worth noting that the reaction between 1c and 2a
proceeded cleanly for only 3 h and afforded the correspond-
ing spirocyclic oxindole product 3e in 97% yield with 92%
ee (entry 2). Electron-donating groups on the N1 of isatyl-
idene malononitrile also proved to be amenable to this
procedure with very high yields and ee values (entries
10-12). Additionally, another precursor 2b also reacted well
with different electron-types of N-MOM isatylidene mal-
ononitriles (entries 13-15) and N-Bn isatylidene malono-
nitrile (entry 16). In these cases, the desired spirooxindole
products were obtained smoothly in high yields (89-95%)
but with good enantioselectivities (72-82% ee), despite using
a large amount of solvent (entries 13-16).11 Moreover,
R ) Bn
R ) Allyl
R ) MOM
R ) MOM, 5-Cl
R ) MOM, 5-OMe
R ) Bn
R ) MOM
R ) MOM
R ) MOM
8l
a For reaction conditions, see Supporting Information. b Isolated yield.
c Determined by HPLC. d Run for 3 h. e In 6.0 mL of DCE.11 f In 6.0 mL
of DCM.11 g The absolute configuration of 3i was assigned as R configu-
ration by X-ray analysis (see Supporting Information), by inference, those
of all of the products of this reaction. h In 18.0 mL of DCM.11 i In 18.0 mL
of DCE.11 j Run for 24 h. k Run for 30 min. l Run for 15 min in 10 mL of
DCM.11
More importantly, under our optimal reaction conditions,
one-pot, three-component reactions among various isatins 4,
malononitrile (5), and 2a-c could proceed smoothly to
provide the desired products in excellent yields and good to
excellent enantioselectivities (Table 4, entries 1-14). More-
over, there appears to be significant tolerance toward
structural and electronic variations of isatins 4, to enable
access to a variety of complex spiro[4H-pyran-3,3′-oxindole]
derivatives. As to substrates 2d and 2e, results very similar
to the two-component reaction (Table 3, entries 18 and 19)
were obtained (Table 4, entries 15 and 16). All in all,
(10) For selected elegant examples of cupreines in asymmetric orga-
nocatalysis, see: (a) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem.
Soc. 2004, 126, 9906. (b) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.;
Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105.
(c) Li, H.; Song, J.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2005, 127, 8948.
(d) Wu, F.; Li, H.; Hong, R.; Deng, L. Angew. Chem., Int. Ed. 2006, 45,
947. (e) Wang, Y.; Liu, X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928.
(f) Wu, F.; Hong, R.; Khan, J.; Liu, X.; Deng, L. Angew. Chem., Int. Ed.
2006, 45, 4301.
3134
Org. Lett., Vol. 12, No. 14, 2010

compared with two-component reactions, hardly any delete-
rious effects on reactivity and enantioselectivity may be
observed in the one-pot, three-component reactions (Table
3 vs Table 4).
Scheme 1. Working Hypothesis for the Formation of Product 3
Table 4. Asymmetric Synthesis of Spiro[4H-pyran-3,3′-
oxindoles] with One-Pot, Three-Component Reactionsa
entry
4
2
3/yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
R ) MOM
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2d
2e
3c/93
3f/93
3g/95
3h/92
3j/95
95
R ) MOM, 5-F
R ) MOM, 5-Cl
R ) MOM, 6-Cl
R ) MOM, 6-Br
R ) MOM, 5-Me
R ) MOM, 5-OMe
R ) Me
R ) Bn
R ) Allyl
R ) MOM
R ) MOM, 5-Cl
R ) MOM, 5-OMe
R ) MOM
R ) MOM
R ) MOM
95d
95e
95
94
92
96
95
95
94
3k/90
3l/99
3m/94
3n/92
3o/85
3p/90
3q/95
3r/98
3t/90
3u/95
3v/96
72f
72f
80f
79g
5h
In summary, we have developed the first enantioselective
synthesis of spiro[4H-pyran-3,3′-oxindole] derivatives cata-
lyzed by readily available cupreine as the catalyst. This
catalytic system can be accommodated in the two-component
reaction for the formation of a spectrum of optically active
heterocyclic spirooxindoles in very high yields and enanti-
oselectivities. Moreover, the direct organocatalytic asym-
metric one-pot, three-component reaction through a domino
Knoevenagel/Michael/cyclization sequence for efficient con-
struction of spiro[4H-pyran-3,3′-oxindole] compounds has
also been successfully explored. These heterocyclic spiroox-
indole compounds will provide promising candidates for
chemical biology and drug discovery. More intense research
on the development of catalytic asymmetric approaches
applicable to the preparation of structure-diversified spiroox-
indole derivatives is underway in our laboratory.
7h i
,
a For reaction conditions, see Supporting Information. b Isolated yield.
c Determined by HPLC. d In 6.0 mL of DCM.11 e In 6.0 mL of DCE.11 f In
18.0 mL of DCM.11 g Run for 24 h. h Run for 2 h. i In 10 mL of DCM.11
Although the exact mechanism awaits further study, we
suggest Scheme 1 as a working hypothesis. The isatin 4 first
condenses with malononitrile (5) to afford 1 through fast
Knoevenagel condensation. Subsequently, we propose that
the Michael addition of 2 to 1 catalyzed by CPN proceeds
via transition-state TS1 to generate TS2. TS2 and TS3
coexist as a keto-enol tautomerism equilibrium in the
reaction system. Then, the intramolecular cycloaddition,
involving the CN group activated by the phenolic OH as
the electrophile, occurs via TS3 to form TS4. Finally,
molecular tautomerization leads to the formation of the
desired product spiro[4H-pyran-3,3′-oxindole] derivatives 3
and concurrently releases catalyst CPN back into the catalytic
cycle. As shown by transition-state models TS1-4 illustrated
in Scheme 1, the stereochemical outcome of this asymmetric
cascade reaction catalyzed by CPN results from a network
of hydrogen-bonding interactions among the sequence Michael
addition, keto-enol tautomerization, cyclization, and tau-
tomerization sequence steps.
Acknowledgment. We are grateful for financial support
from the NSFC (No. 20802074) and the National Basic
Research Program of China (973 Program) (2010CB833300).
Supporting Information Available: Experimental pro-
cedures, spectral data, X-ray crystal structure, and a CIF.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(11) The reaction was performed under diluted conditions to improve
the enantioselectivity.
OL1009224
Org. Lett., Vol. 12, No. 14, 2010
3135