Asymmetric quadruple aminocatalytic domino reactions to fused carbocycles incorporating a spirooxindole motif

Article abstract of DOI:10.1021/ol100857s

(Figure presented) The efficient assembly of hydroindane derivatives incorporating a spirooxindole motif was realized via a new three-component domino reaction of (E)-4-(1-methyl-2-oxoindolin-3-ylidene)-3-oxobutanoates and two molecules of α,β-unsaturated

Full text of DOI:10.1021/ol100857s

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2766-2769
Asymmetric Quadruple Aminocatalytic
Domino Reactions to Fused
Carbocycles Incorporating a
Spirooxindole Motif
Kun Jiang,† Zhi-Jun Jia,† Xiang Yin,† Li Wu,† and Ying-Chun Chen*,†,‡
Key Laboratory of Drug-Targeting and Drug DeliVery System of Education Ministry,
Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan
UniVersity, Chengdu 610041, China, and State Key Laboratory of Biotherapy, West
China Hospital, Sichuan UniVersity, Chengdu, China
ycchenhuaxi@yahoo.com.cn
Received April 15, 2010
ABSTRACT
The efficient assembly of hydroindane derivatives incorporating a spirooxindole motif was realized via a new three-component domino reaction
of (E)-4-(1-methyl-2-oxoindolin-3-ylidene)-3-oxobutanoates and two molecules of r,ꢀ-unsaturated aldehydes under quadruple iminium-enamine-
iminium-enamine catalysis. The complex products bearing six contiguous stereogenic centers were obtained in excellent stereoselectivities
(96->99% ee, >99% de).
The economic and effective concerns in organic synthesis
provoke increasing attention because of the current emphasis
on the development of green and sustainable chemistry.1 The
catalytic domino or cascade reactions would satisfy most of
the criteria for such purposes, and consequently, many efforts
have been devoted to this area.2 Over the past years, fruitful
results on asymmetric domino reactions have been presented
by the catalysis of environmentally benign small organic
molecules.3 Among them, the elegant combination of enam-
ine and iminium activation modes for carbonyl compounds
by amine catalysts provides a very attractive strategy for the
design of asymmetric domino sequences, from which a
diversity of multifunctional products, including variously
structured carbocycles and heterocycles, have been gener-
ated.4 Currently, the expansions to exemplify the power of
domino aminocatalysis are actively continuing.5 Neverthe-
less, the examples involving multiple catalytic modes, which
can allow rapid constructions of high levels of molecular
complexity and stereoselectivity, are still limited.6
† West China School of Pharmacy.
‡ West China Hospital.
(1) For a tutorial review, see: Newhouse, T.; Baran, P. S.; Hoffmann,
R. W. Chem. Soc. ReV. 2009, 38, 3010.
Recently, we have developed a highly stereoselective
domino Michael-Wittig reaction of (3-carboxy-2-oxopro-
pylidene)triphenylphosphoranes and R,ꢀ-unsaturated alde-
(2) For reviews, see: (a) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed.
2006, 45, 354. (b) Nicolaou, K. C.; Chen, J. S. Chem. Soc. ReV. 2009, 38,
2993. (c) Poulin, J.; Grise´-Bard, C. M.; Barriault, L. Chem. Soc. ReV. 2009,
38, 3092.
(3) For reviews, see: (a) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew.
Chem., Int. Ed. 2007, 46, 1570. (b) Alba, A.-N.; Companyo, X.; Viciano,
M.; Rios, R. Curr. Org. Chem. 2009, 13, 1432. (c) Grondal, C.; Jeanty,
M.; Enders, D. Nat. Chem. 2010, 2, 167.
(4) For reviews, see: (a) Yu, X.; Wang, W. Org. Biomol. Chem. 2008,
6, 2037. (b) Westermann, B.; Ayaz, M.; van Berkel, S. S. Angew. Chem.,
Int. Ed. 2010, 49, 846. (c) Also see references 3a-c.
10.1021/ol100857s  2010 American Chemical Society
Published on Web 05/19/2010

hydes to access chiral cyclohex-2-en-1-ones by using imi-
nium catalysis as the key stereocontrolling step.7 On the other
hand, we and Melchiorre et al. independently reported an
efficient three-component cascade reaction of aliphatic al-
dehydes, 3-olefinic oxindoles, and R,ꢀ-unsaturated aldehydes
to deliver spirooxindoles incorporating a six-membered cyclic
moiety by triple enamine-iminium-enamine catalysis.8,9
Based on these achievements, we were intrigued in the design
of a novel type of multifunctional synthons 2, 3-oxo-4-(2-
oxoindolin-3-ylidene)butanoates, which possess multiple
reactive sites and might successively perform as nucleo-
philes and electrophiles in a proper cascade process. We
envisaged that a three-component domino reaction of 2
and two molucules of R,ꢀ-unsaturated aldehydes might
be feasible by a quadruple iminium-enamine-iminium-
enamine catalysis of chiral secondary amine, such as
readily available R,R-diphenylprolinol O-TMS ether 1,10
as oultined in Scheme 1. Thus, densely substituted
hydroindane frameworks 3 incorporating an interesting
spirooxindole motif would be constructed with high
synthetic economy and effectiveness.11
Scheme 1
.
Proposed Quadruple Aminocatalytic Domino
Sequences to Fused Carbocycles
Inspired by these considerations, we initially investigated
the domino reaction of multifunctional substrate 2a and
excess crotonaldehyde (4 equiv) by the catalysis of 1a (20
mol %) and benzoic acid (BA) in toluene at ambient
temperature.12 To our gratification, 2a was consumed
smoothly, and the desired fused carbocycle 3a, bearing six
contiguous stereocenters, was isolated in 28% yield with
excellent stereoselectivity (Table 1, entry 1, >99% ee, >99%
(5) For selected recent examples, see: (a) Rueping, M.; Kuenkel, A.;
Tato, F.; Bats, J. W. Angew. Chem., Int. Ed. 2009, 48, 3699. (b) Albrecht,
L.; Richter, B.; Vila, C.; Krawczyk, H.; Jørgensen, K. A. Chem.sEur. J.
2009, 15, 3093. (c) McGarraugh, P. G.; Brenner, S. E. Org. Lett. 2009, 11,
5654. (d) Reyes, E.; Talavera, G.; Vicario, J. L.; Bad´ıa, D.; Carrillo, L.
Angew. Chem., Int. Ed. 2009, 48, 5701. (e) Wu, L.-Y.; Bencivenni, G.;
Mancinelli, M.; Mazzanti, A.; Bartoli, G.; Melchiorre, P. Angew. Chem.,
Int. Ed. 2009, 48, 7196. (f) Galzerano, P.; Pesciaioli, F.; Mazzanti, A.;
Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 7892. (g) Zu,
L.; Zhang, S.; Xie, H.; Wang, W. Org. Lett. 2009, 11, 1627. (h) Jiang, H.;
Elsner, P.; Jensen, K. L.; Falcicchio, A.; Marcos, V.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2009, 48, 6844. (i) Zhang, X.; Zhang, S.; Wang,
W. Angew. Chem., Int. Ed. 2010, 49, 1481. (j) Hong, L.; Sun, W.; Liu, C.;
Wang, L.; Wang, R. Chem.sEur. J. 2010, 16, 440. (k) Zhang, W.; Franze´n,
Table 1. Screening Studies of Domino Reaction of
Multifunctional 2 and Excess Crotonaldehydea
J. AdV. Synth. Catal. 2010, 352, 499
.
(6) For triple or quadruple aminocatalytic domino reactions, see: (a)
Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441,
861. (b) Carlone, A.; Cabrera, S.; Marigo, M.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2007, 46, 1101. (c) Hong, B.-C.; Nimje, R. Y.; Liao, J.-H.
Org. Biomol. Chem. 2009, 7, 3095. (d) Enders, D.; Jeanty, M.; Bats, J. W.
Synlett 2009, 3175. (e) Penon, O.; Carlone, A.; Mazzanti, A.; Locatelli,
M.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem.sEur. J. 2008, 14, 4788.
(f) Zhang, F.-L.; Xu, A.-W.; Gong, Y.-F.; Wei, M.-H.; Yang, X.-L.
Chem.sEur. J. 2009, 15, 6815. (g) Kotame, P.; Hong, B.-C.; Liao, J.-H.
Tetrahedron Lett. 2009, 50, 704. (h) Hong, B.-C.; Kotame, P.; Tsai, C.-
W.; Liao, J.-H. Org. Lett. 2010, 12, 776. (i) Enders, D.; Kru¨ll, R.; Bettray,
W. Synthesis 2010, 567. (j) Enders, D.; Wang, C.; Mukanova, M.; Greb,
entry solvent enal (equiv) additive time (h) yieldb (%) eec (%)
A. Chem. Commun. 2010, 46, 2447
(7) Liu, Y.-K.; Ma, C.; Jiang, K.; Liu, T.-Y.; Chen, Y.-C. Org. Lett.
2009, 11, 2848
.
1
2
3
4
5
6
7
8
9d
toluene
PhCF3
THF
4
BA
4
5
28
34
>99
>99
4
BA
.
4
BA
24
24
14
14
22
24
30
70
36
<10
<10
43
(8) (a) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.; Chen, Y.-C. Chem.sEur.
J. 2010, 16, 2852. (b) Bencivenni, G.; Wu, L.-Y.; Mazzanti, A.; Giannichi,
B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.; Melchiorre, P. Angew. Chem.,
DCM
DCE
4
BA
4
BA
>99
>99
>99
>99
>99
>99
>99
DCE
4
OFBA
AcOH
BA
34
Int. Ed. 2009, 48, 7200
.
DCE
4
44
(9) For other catalytic asymmetric reactions to construct chiral spirocyclic
oxindoles, see: (a) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem.
Soc. 2007, 129, 12396. (b) Hojo, D.; Noguchi, K.; Hirano, M.; Tanaka, K.
Angew. Chem., Int. Ed. 2008, 47, 5820. (c) Shintani, R.; Hayashi, S.-y.;
Murakami, M.; Takeda, M.; Hayashi, T. Org. Lett. 2009, 11, 3754. (d) Chen,
X.-H.; Wei, Q.; Luo, S.-W.; Xiao, H.; Gong, L.-Z. J. Am. Chem. Soc. 2009,
DCE
2.1 + 1
2.1 + 1
2.1 + 1
2.1 + 1
55
DCE
BA
60
10d,e DCE
BA
66
11d,e,f DCE
BA
66
a Unless otherwise noted, reactions were performed with 0.1 mmol of
2a, excess crotonaldehyde, 20 mol % of 1, and acid in 1.0 mL of solvent
at rt. b Yield of isolated 3. c Based on chiral HPLC analysis; >99% de. d In
2.0 mL of solvent. e 2b was used; yield for 3b. f At 35 °C.
131, 13819. (e) Wei, Q.; Gong, L.-Z. Org. Lett. 2010, 12, 1008
.
(10) Xu, L.-W.; Li, L.; Shi, Z.-H. AdV. Synth. Catal. 2010, 352, 243.
(11) For selected examples containing polyhydroindane structures, see:
(a) Rancitshomasm, A.; Zainne, I.; Untz-Dubini, R. Can. J. Chem. 1980,
58, 1810. (b) Srikrishna, A.; Vijaykumar, D. J. Chem. Soc., Perkin Trans.
1 1999, 1265. (c) Tori, M.; Makino, C.; Hisazumi, K.; Sono, M.; Nakashima,
K. Tetrahedron: Asymmetry 2001, 12, 301. (d) Hess, B. A., Jr. Org. Lett.
2003, 5, 165. (e) Sha, C.-K.; Liao, H,-W.; Cheng, P.-C.; Yen, S.-C. J. Org.
Chem. 2003, 68, 8704. (f) Maity, S.; Ghosh, S. Tetrahedron 2009, 65, 9202.
(g) Rahman, M. M.; Garvey, M.; Piddock, L. J. V.; Gibbons, S. Phytother.
Res. 2008, 22, 1356.
de), while a few unidentified byproducts were also observed.
Subsequently, some solvents were screened (entries 2-5),
and a slightly better yield was obtained in 1,2-dichloroethane
(DCE, entry 5). Similar data were afforded when benzoic
Org. Lett., Vol. 12, No. 12, 2010
2767

acid was replaced by o-fluorobenzoic acid (OFBA, entry 6)
or acetic acid (entry 7). We found that the yield could be
improved by adding crotonaldehyde in two potions and
diluting the reaction solution (entries 8 and 9). Moreover,
cleaner reaction was attained when 2b with a tert-butyl ester
group was applied (entry 10), even at higher reaction
temperature (entry 11).
Consequently, the substrate scope and limitations were
explored under the optimized reaction conditions. The results
were summarized in Table 2. For multifunctional substrate
Table 2. Substrate Scope and Limitationsa
Figure 1. X-ray structure of enantiopure 3h.
entry
2
R2
R3
time (h) yieldb (%) eec (%)
ployed. Product 3i possessing more functionalities was
isolated in outstanding stereoselectivity, albeit in low yield
(entry 8). The introduction of electron-donating substituent
to oxindole moiety provided slightly better outcomes in the
domino reaction (entries 9 and 10).13 On the other hand, we
hope to introduce more substitution diversity into the cyclic
products. After the domino Michael-Michael reaction of 2
and 1 equiv of a ꢀ-aryl-substituted enal was complete, from
which intermediate B, depicted in Scheme 1, would be
generated, excess crotonaldehyde was added to continue the
cascade Michael-aldol sequences. Such a tandem one-pot,
three-component reaction was successful, and better results
were obtained when substrate 2a was applied. The fused
carbocycles 3l-p were directly isolated in excellent stereo-
selectivities, while the yields were fair due to more possible
reaction pathways (entries 11-15).
1
2
3
4
5
6
7
8
9
2b Me
2b Ph
2b p-FPh
2b m-ClPh
2b o-BrPh
2b p-MeOPh p-MeOPh
2b 2-thienyl 2-thienyl
2b 1-propenyl 1-propenyl
2c Me
2d Ph
Me
Ph
36
24
24
21
20
19
40
41
48
11
31
68
70
68
72
3b, 66
3c, 73
3d, 91
3e, 81
3f, 84
3g, 78
3h, 93
3i, 30
3j, 69
3k, 97
3l, 40
3m, 47
3n, 45
3o, 32
3p, 30
>99
>99
>99
>99
>99
>99
>99d
>99
>99
>99
>99
96
p-FPh
m-ClPh
o-BrPh
Me
Ph
Me
Me
10
11e 2a Ph
12e 2a o-ClPh
13e 2a p-MeOPh Me
>99
>99
>99
14e 2a 2-thienyl
15e 2a Ph
Me
1-propenyl
a Unless otherwise noted, reactions were performed with 0.1 mmol of
2, 2.2-3.1 mmol of enal, 20 mol % of 1, and benzoic acid in 2.0 mL DCE
at 35 °C. See the Supporting Information for details. b Yield of isolated 3.
c Based on chiral HPLC analysis; >99% de. d The absolute configuration
of 3h was determined by X-ray crystallographic analysis (Figure 1). The
other products were assigned by analogy. e After the consumption of 2a
with a ꢀ-aryl-substituted enal (1.1 equiv, at rt, for 2 h), another enal (1.5
equiv) was added at 35 °C.
It was pleasing that the in situ generated intermediate B
could be also applied in a highly diastereoselective Michael
addition-Henry reaction with nitroolefins.8a As illustrated
Scheme 2. Synthetic Expansion of the Domino
Michael-Michael Intermediate
2b, a number of R,ꢀ-unsaturated aldehydes with a ꢀ-aryl
group, either bearing electron-withdrawing or electron-
donating substitutions, could be efficiently utilized. The
expected spirocyclic compounds 3c-g were obtained in good
to high yields and excellent stereoselectivities (entries 2-6).
The results were also remarkable for an enal with a heteroaryl
substitution (entry 7), and the structure of product 3h was
unambiguously determined by X-ray crystallographic analy-
sis (Figure 1). Interestingly, the regioselective Michael
addition could be realized when 2,4-hexadienal was em-
(12) For the synthesis of multifunctional substrates 2, see the Supporting
Information.
(13) Substrates 2 with electron-withdrawing groups on the oxindole motif
are unstable, and destruction occurs even at room temperature.
2768
Org. Lett., Vol. 12, No. 12, 2010

in Scheme 2, the one-pot, three-component tandem reaction
of substrate 2a, cinnamaldehyde, and ꢀ-nitrostyrene smoothly
afforded the fused and spiro carbocycle 4 with eight
contiguous chiral centers in an enantiopure form.
eight contiguous chiral centers has been assembled with
remarkable efficacy. Currently, more synthetic applications
and transformations are underway in our laboratory.
In conclusion, we have designed a new type of multifunc-
tional synthons, (E)-4-(1-methyl-2-oxoindolin-3-ylidene)-3-
oxobutanoates 2. They have been successfully applied in a
three-component, domino Michael-Michael-Michael-aldol
process with two molecules of R,ꢀ-unsaturated aldehydes
under quadruple iminium-enamine-iminium-enamine ca-
talysis. A spectrum of enantiomeric hydroindane derivatives,
bearing six contiguous stereocenters and a spirooxindole
motif, were delivered in a highly economic and effective
manner. Moreover, their one-pot, three-component tandem
reaction with R,ꢀ-unsaturated aldehydes and nitroolefins was
accessible, and a complex polycyclic framework with up to
Acknowledgment. We are grateful for the financial
support from the National Natural Science Foundation of
China (20972101), PCSIRTC (IRT0846), and the National
Basic Research Program of China (973 Program)
(2010CB833300).
Supporting Information Available: Experimental pro-
cedures, structural proofs, NMR spectra, HPLC chromato-
grams of the products, X-ray data of enantiopure 3h (CIF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100857S
Org. Lett., Vol. 12, No. 12, 2010
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