Highly enantioselective construction of polycyclic spirooxindoles by organocatalytic 1,3-dipolar cycloaddition of 2-cyclohexenone catalyzed by proline-sulfonamide

Article abstract of DOI:10.1002/ejoc.201402953

The enantioselective 1,3-dipolar cycloaddition of 2-cyclohexene-1-one and azomethine ylides generated in situ from isatins and amino esters was developed by employing prolinosulfonamides as the catalyst. Consequently, novel polycyclic spirooxindole scaffolds with three contiguous stereocenters were prepared in high yield (up to 95%) with excellent diastereo- (>20:1dr) and enantioselectivity (up to 99%ee). The highly enantioselective construction of polycyclic spirooxindoles through 1,3-dipolar cycloaddition of cyclohexenone with azomethine ylides is achieved by employing prolinosulfonamides as the catalyst. This catalytic system essentially benefits from iminium activation and hydrogen-bonding formation induced by the prolinosulfonamides. Copyright

Full text of DOI:10.1002/ejoc.201402953

Job/Unit: O42953
/KAP1
Date: 11-08-14 11:22:57
Pages: 6
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402953
Highly Enantioselective Construction of Polycyclic Spirooxindoles by
Organocatalytic 1,3-Dipolar Cycloaddition of 2-Cyclohexenone Catalyzed by
Proline-Sulfonamide
Jun-An Xiao,[a][‡] Qi Liu,[a][‡] Ji-Wei Ren,[a] Jian Liu,[a] Rich G. Carter,[b]
Xiao-Qing Chen,[a] and Hua Yang*[a]
Keywords: Organocatalysis / Cycloaddition / Spiro compounds / Alkaloids / Nitrogen heterocycles
The enantioselective 1,3-dipolar cycloaddition of 2-cyclo-
hexene-1-one and azomethine ylides generated in situ from
isatins and amino esters was developed by employing
prolinosulfonamides as the catalyst. Consequently, novel
polycyclic spirooxindole scaffolds with three contiguous
stereocenters were prepared in high yield (up to 95%) with
excellent diastereo- (Ͼ20:1dr) and enantioselectivity (up to
99%ee).
1,3-dipolar cycloaddition strategy to enantioselectively pre-
pare spiro(pyrrolidin-3,2Ј-oxindole)s. Notably, only linear
dipolarophiles were used in the asymmetric synthesis of the
spiro(pyrrolidin-3,2Ј-oxindole) core and pyrrolidine deriva-
tives.[3,7] A review of the literature revealed that the catalytic
asymmetric 1,3-dipolar cycloaddition of azomethine ylides
with cyclic dipolarophiles, especially cyclic α-enones show-
ing comparatively lower reactivity toward this type of reac-
tion, has been rarely explored.[8] Thus, it would be highly
desirable to explore 1,3-dipolar cycloadditions by using cy-
clic enones to provide facile access to novel polycyclic spiro-
oxindole ring systems (as shown in Scheme 1).
On the other hand, enones and enals activated by lower-
ing the LUMO through the formation of iminium interme-
diates with chiral amine organocatalysts have proven to be
highly reactive toward azomethine ylides with high stereo-
selectivity.[9] Usually, this protocol is limited to enal and
linear enone dipolarophiles, which can easily form iminium
species with amines. In 2007, Chen and co-workers reported
elegant work on the organocatalytic enantioselective 1,3-
dipolar cycloaddition of cyclohexenone with azomethine
imines catalyzed by 9-amino-9-deoxyepicinchona alka-
loids.[10] Unfortunately, research on organocatalytic 1,3-di-
polar cycloaddition reactions by using cyclic enones has re-
mained dormant since then.
Introduction
Natural alkaloids and relevant compounds featuring the
spiro(pyrrolidin-3,2Ј-oxindole) ring system have proven to
possess interesting biological activities, including anti-in-
flammatory, antidiabetic, antitumor, antitubercular, and
acetylcholinesterase (AChE) inhibitory activities.[1] Driven
by thorough investigation of the biological activities of
these compounds, much attention over the last decades has
been directed to the development of structurally diversified
and stereocontrolled methodologies to access these spiroox-
indoles.[2] In particular, the 1,3-dipolar cycloaddition of
azomethine ylides to electron-deficient alkenes has been
found to be a versatile and atom-economic pathway to pre-
pare the spiro(pyrrolidin-3,2Ј-oxindole) scaffold.[3] How-
ever, to date the catalytic asymmetric synthesis of spiro(pyr-
rolidin-3,2Ј-oxindole)s still poses a challenge, as most of the
established approaches either provide racemic products or
employ enantiopure starting materials.[4]
In recent years, organocatalysis has emerged as a versa-
tile tool for asymmetric synthesis.[5] In 2012, Gong and co-
workers described the first organocatalytic asymmetric
method to construct spiro(pyrrolidin-3,2Ј-oxindole)s
through 1,3-dipolar cycloaddition of N-acetyl-2-oxoindol-
in-3-ylidenes and in situ formed azomethine ylides.[6] Sub-
sequently, Xu[3a] and Tu[3b] employed the organocatalytic
In our previous work, proline p-dodecylphenylsulfon-
amide (Hua Cat®) was successfully employed to catalyze
the [4+2] cycloaddition of cyclohexenone through HOMO
activation.[11] Our continued interest in this area prompted
us to investigate this catalytic system in 1,3-dipolar cycload-
ditions of cyclohexenone with azomethine ylides facilitated
by LUMO activation of cyclohexenone. Herein, we report
the organocatalyzed asymmetric 1,3-dipolar cycloaddition
of cyclic enones with azomethine ylides to construct novel
polycyclic spiro(pyrrolidin-3,2Ј-oxindole) scaffolds.
[a] College of Chemistry and Chemical Engineering, Central South
University,
Changsha 410083, P. R. China
E-mail: hyangchem@csu.edu.cn
http://www.csuchem.cn
[b] Department of Chemistry, Oregon State University,
Corvallis, Oregon 97331, USA
E-mail: rich.carter@oregonstate.edu
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402953.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O42953
/KAP1
Date: 11-08-14 11:22:57
Pages: 6
H. Yang et al.
SHORT COMMUNICATION
Scheme 1. Construction of spiro(pyrrolidin-3,2Ј-oxindole)s through organocatalytic 1,3-dipolar cycloaddition.
sluggish reaction and a decrease in the chemical yield and
enantioselectivity (Table 1, entry 12). Subsequently, the
effect of the molar ratio of the reactants was studied. It was
found that a 1:1.2:1.5 molar ratio of 1a/2/3a gave the
best chemical yield and enantioselectivity (Table 1, en-
try 17). Next, the efficiency of different solvents was also
tested. Dichloromethane was found to be the best for this
transformation, although α,α,α-trifluorotoluene also signif-
icantly facilitated the reaction and provided both an excel-
lent chemical yield and enantioselectivity (see Table foot-
note).
Having established the optimal conditions, the scope of
this 1,3-dipolar cycloaddition was investigated (as shown in
Table 2). For 5- or 6-substituted isatins, the reaction pro-
ceeded well and moderate to good yields with excellent
enantioselectivity were usually achieved to afford corre-
sponding cycloadducts 4a–g. However, the employment of
7-chloroisatin (4h) significantly decreased the enantio-
selectivity (83%ee) and the diastereoselectivity (7.7:1). Pre-
sumably, this could be explained by the presence of the
chlorine atom at the C7 position of isatin, which sterically
hinders the N–H isatin moiety and hence interferes with the
formation of a hydrogen bond with the catalyst. Moreover,
different aminomalonic acid diesters such as dimethyl
aminomalonate and diisopropyl aminomalonate also showed
good reactivity toward this 1,3-dipolar cycloaddition (see
products 4i–o). Surprisingly, the employment of cyclo-
pentenone and cycloheptenone in this reaction did not af-
ford the corresponding cycloadduct. Finally, the absolute
configuration of 4j was unequivocally established by X-ray
crystallographic analysis of a single crystal.[12]
Results and Discussion
Initially, in the presence of triethylamine (10 mol-%),
proline p-methylphenylsulfonamide (5a) was found to
smoothly catalyze the three-component 1,3-cycloaddition
by using isatin (1a), 2-cyclohexenone (2), and diethyl
aminomalonate (3a) in a ratio of 1a/2/3a = 1:1.5:1.5. To our
delight, excellent diastereo- (Ͼ 20:1) and enantioselectivity
(94%ee), albeit with moderate chemical yield (67%), were
obtained (Table 1, entry 1). Encouraged by this result, vari-
ous proline sulfonamide catalysts were screened, and 5d
gave the optimum yield and enantioselectivity (Table 1, en-
tries 2–4). Interestingly, bifunctional catalyst 6 bearing both
secondary amine and tertiary amine motifs was therefore
designed and synthesized by the direct coupling between N-
Boc-proline (Boc = tert-butoxycarbonyl) and 1-benzylpiper-
azine followed by deprotection of the Boc protecting group.
Presumably, it can activate 2-cyclohexenone and azo-
methine ylide simultaneously. Indeed, this catalyst afforded
relatively higher yield without adding any additive. Un-
satisfyingly, poor ee values were observed with or without
additive (Table 1, entries 5 and 6). Noticeably, upon using
pyrrolidine as the catalyst, only the hemiaminal was
formed. No desired product was observed by using 2,2,6,6-
tetramethylpiperidine as the catalyst (Table 1, entries 7 and
8). In addition, different additives were also screened for
this reaction. It was found that the additive had a signifi-
cant effect on this reaction. The addition of acetic acid af-
forded the racemic product in decreased chemical yield. 1,4-
Diazobicyclo[2.2.2]octane (DABCO) was less efficient than
triethylamine in this reaction (Table 1, entries 9 and 10).
Furthermore, this reaction was performed without any ad-
We next turned our attention to examine the reactivities
ditive, and only a moderate yield and poor ee (12%) were of N-protected isatins in this reaction. However, to our sur-
observed (Table 1, entry 11). Intriguingly, an increase in the prise, the enantioselectivities were severely eroded upon
amount of triethylamine (20 mol-%) led to an extremely using N-methyl- or N-benzylisatin (Scheme 2), although the
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42953
/KAP1
Date: 11-08-14 11:22:57
Pages: 6
Highly Enantioselective Construction of Polycyclic Spirooxindoles
Table 1. Optimization of the 1,3-dipolar cycloaddition reaction.[a]
Table 2. Scope of the 1,3-dipolar cycloaddition.[a]
Entry
Catalyst Additive (mol-%) Time [h] Yield [%][b] ee [%][c]
1[d]
5a
5b
5c
5d
6
6
7
8
5d
5d
5d
5d
5d
5d
5d
5d
5d
5d
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
–
Et3N (10)
Et3N (10)
AcOH (10)
DABCO (10)
–
Et3N (20)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (10)
Et3N (5)
36
48
60
36
60
48
48
48
48
60
60
72
48
48
48
48
36
48
67
54
44
68
30
86
trace
–
49
38
51
21
35
50
49
58
90
57
94
85
70
96
4
2[d]
3[d]
4[d]
5[d]
6[d]
17
n.d.
n.d.
rac
82
12
83
87
86
90
89
96
89
7[d]
8[d]
9[d]
10[d]
11[d]
12[d]
13[e]
14[f]
15[g]
16[h]
17[i,j]
18[i]
[a] Unless otherwise noted, the reaction was performed on
0.2 mmol scale in CH2Cl2 (4 mL) at r.t. with a 1:1.2:1.5 molar ratio
of 1a/2/3a and catalyst (20 mol-%). [b] Yield of isolated product.
[c] Determined by HPLC on a chiral stationary phase; n.d.: not
determined. [d] 1a/2/3a = 1:1.5:1.5. [e] 1a/2/3a = 1:1:1. [f] 1a/2/3a =
1:1.5:1.2. [g] 1a/2/3a = 1:1.2:2. [h] 1a/2/3a = 1:1.5:1. [i] 1a/2/3a =
1:1.2:1.5. [j] TFT = α,α,α-trifluorotoluene. Other solvents were also
evaluated in this reaction. (MeOH, 36 h, 70% yield, –28%ee; tolu-
ene, 36 h, 90% yield, 87%ee; 1,2-dichloroethane, 48 h, 86% yield,
94%ee; CHCl3, 60 h, 82% yield, 93%ee; α,α,α-trifluorotoluene,
12 h, 91% yield, 94%ee).
chemical yields were maintained. These results suggest that
the N–H isatin moiety has a sizeable influence on the
stereoselectivity and might be involved in the stereocontrol
of this reaction. However, the exact catalytic mechanism
still needs further investigation.
To further expand the synthetic utility of this cycload-
dition reaction, the reduction and decarboxylation reac-
tions of the corresponding spirooxindoles were performed
(Scheme 3). A simple protocol of sodium borohydride in
methanol successfully afforded corresponding alcohol 11 as
[a] Unless otherwise noted, the reaction was performed on
0.2 mmol scale in CH2Cl2 (4 mL) at r.t. with a 1:1.2:1.5 molar ratio
of 1/2/3. [b] Determined by 1H NMR spectroscopy. [c] Yield of iso-
lated product. [d] Determined by HPLC on a chiral stationary
phase.
a single isomer in 86% yield with 96%ee. On the other step process, including monohydrolysis of the diester fol-
hand, the decarboxylated product was obtained by a two- lowed by decarboxylation. As a result, a mixture of
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O42953
/KAP1
Date: 11-08-14 11:22:57
Pages: 6
H. Yang et al.
SHORT COMMUNICATION
by readily available proline p-dodecylphenylsulfonamide
was developed. The products were obtained in high yields
with excellent stereoselectivities (up to 99%ee, Ͼ20:1dr).
This catalytic system could effectively activate cyclohex-
enone and enable the formation of hydrogen bonding be-
tween the catalyst and the dipole. This should significantly
broaden the synthetic application of cyclic enones in enan-
tioselective 1,3-cycloaddition reactions and afford facile ac-
cess to novel polycyclic spirooxindole ring systems, which
could provide new opportunities for medicinal chemistry
and drug discovery.
Scheme 2. 1,3-Dipolar cycloaddition of N-protected isatins.
exo/endo isomers (70:30) was obtained. No apparent ero-
sion of enantioselectivity occurred and 91 and 95%ee were
observed, respectively. Presumably, the exo isomer would
be thermodynamically favorable. More interestingly,
ibophyllidine-like compounds 14a–c were synthesized in
moderate yields with high enantiopurity through Fischer
indole synthesis.[13] These resulting polycyclic structures
bear both indole and isatin motifs, and they therefore might
possess interesting biological activities.
Experimental Section
Typical Procedure for the Asymmetric Synthesis of Polycyclic Spiro-
oxindole 4a: Isatin (1a, 0.20 mmol), aminomalonate diester (3a;
0.30 mmol, 1.5 equiv.), 2-cyclohexane-1-one (2; 23.0 mg,
0.24 mmol, 1.2 equiv.), and the catalyst (20 mol-%) were dissolved
in the solvent (2 mL), which was followed by the addition triethyl-
amine (2.00 mg, 10 mol-%). Upon completion of the reaction
(monitored by TLC), the organic solvent was removed in vacuo.
Then, the residue was purified by flash chromatography to yield
spirooxindole 4a as a white solid (72.0 mg, yield 90%, Ͼ20:1dr,
96%ee), m.p. 230–231 °C. [α]2D0 = +17.6 (c = 0.3, CHCl3). 1H NMR
(400 MHz, [D6]DMSO): δ = 10.24 (s, 1 H), 7.34 (d, J = 7.2 Hz, 1
H), 7.17 (t, J = 7.2 Hz, 1 H), 6.95 (t, J = 7.4 Hz, 1 H), 6.72 (d, J
= 7.6 Hz, 1 H), 4.08–4.28 (m, 4 H), 3.92 (s, 1 H), 3.30–3.34 (m, 2
H), 1.19–2.11 (m, 2 H), 1.64–1.81 (m, 4 H), 1.18–1.23 (m, 6 H)
ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 207.9, 181.5, 170.1,
169.1, 143.0, 129.9, 129.7, 126.3, 121.6, 110.1, 76.7, 70.4, 62.0, 61.5,
59.5, 45.1, 40.1, 22.9, 22.5, 14.5, 14.3 ppm. IR (KBr): ν = 3302,
˜
2936, 1725, 1619, 1245, 1187, 1028, 851, 759 cm–1. HRMS (TOF-
ES+): calcd. for C21H24N2O6Na [M + Na]+ 423.1532; found
423.1519. HPLC (CHIRALCEL OD-H, 30% isopropanol/hexanes,
0.8 mLmin–1, λ = 254 nm): tR = 14.3 (minor), 19.9 min (major).
Typical Procedure for the Preparation of Indolospirooxindole 14a:
Phenylhydrazine (13; 43.3 mg, 0.4 mmol, 2 equiv.) was added to a
solution of polycyclic spirooxindole 4a (0.2 mmol) in acetic acid
(2 mL). The mixture was then heated at reflux for 2 h and then
cooled to r.t. Acetic acid was removed under reduced pressure. The
residue was dissolved in EtOAc (10 mL) and washed with a satu-
rated aqueous solution of NaHCO3 (2ϫ 30 mL). The aqueous
phase was back extracted with EtOAc (2ϫ 5 mL). The combined
organic phase was dried and concentrated under reduced pressure.
The crude mixture was purified by silica gel column chromatog-
raphy to give indolospirooxindole 14a as a white solid (59.6 mg,
yield 63%, Ͼ20:1dr, 99%ee), m.p. Ͼ300 °C. [α]2D0 = +155.7 (c =
1
0.5, CHCl3). H NMR (400 MHz, [D6]DMSO): δ = 10.17 (s, 1 H),
10.13 (s, 1 H), 7.29–7.31 (m, 1 H), 6.93–6.97 (m, 2 H), 6.85–6.91
(m, 2 H), 6.69–6.84 (m, 2 H), 6.52 (t, J = 7.2 Hz, 1 H), 4.15–4.31
(m, 4 H), 3.99 (d, J = 6.4 Hz, 1 H), 3.81 (s, 1 H), 2.63–2.94 (m, 2
H), 1.84–2.00 (m, 2 H), 1.22–1.26 (m, 6 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 181.53, 170.3, 169.3, 142.9, 136.9,
131.3, 130.6, 128.7, 126.4, 125.6, 125.6, 121.4, 120.8, 118.0, 111.2,
109.6, 109.5, 75.8, 69.9, 61.8, 61.4, 44.5, 43.8, 22.3, 19.6, 14.5,
Scheme 3. Transformation of the spirooxindole compounds.
14.3 ppm. IR (KBr): ν = 3387 (br.), 2979, 1732, 1620, 1469, 1248,
˜
Conclusions
1108, 860, 746 cm–1. HRMS (TOF-ES+): calcd. for C27H27N3O5Na
[M + Na]+ 496.1848; found 496.1839. HPLC (CHIRALCEL OD-
H, 25% isopropanol/hexanes, 1.0 mLmin–1, λ = 254 nm): tR = 26.4
In summary, the enantioselective 1,3-dipolar cycload-
dition of cyclohexenone with azomethine ylides generated
in situ from isatins and aminomalonate diesters catalyzed (minor), 29.1 min (major).
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42953
/KAP1
Date: 11-08-14 11:22:57
Pages: 6
Highly Enantioselective Construction of Polycyclic Spirooxindoles
Org. Lett. 2014, 16, 544–547; c) K. Albertshofer, B. Tan, C. F.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures; NMR spectral and analytical data
for 4a–o, 6, 10a, 10b, 11, 12, and 14a–c; and HPLC chromatograms
for 4a–o, 10a, 10b, 11, 12, and 14a–c.
Barbas, Org. Lett. 2012, 14, 1834–1837; d) I. C. Y. L. Mat-
tia Silvi, Angew. Chem. Int. Ed. 2013, 52, 10780–10783; Angew.
Chem. 2013, 125, 10980–10983; e) H. Guo, H. Liu, F. Zhu, R.
Na, H. Jiang, Y. Wu, L. Zhang, Z. Li, H. Yu, B. Wang, Y.
Xiao, X. Hu, M. Wang, Angew. Chem. Int. Ed. 2013, 52,
12641–12645; Angew. Chem. 2013, 125, 12873–12877; f) B. Tan,
G. Hernández-Torres, C. F. Barbas, J. Am. Chem. Soc. 2011,
133, 12354–12357; g) C. F. Nising, U. K. Ohnemüller, S. Bräse,
Angew. Chem. Int. Ed. 2006, 45, 307–309; Angew. Chem. 2006,
118, 313–315; h) X. Feng, Z. Zhou, C. Ma, X. Yin, R. Li, L.
Dong, Y. Chen, Angew. Chem. Int. Ed. 2013, 52, 14173–14176;
Angew. Chem. 2013, 125, 14423–14426; i) G. Pandey, P.
Banerjee, R. Kumar, V. G. Puranik, Org. Lett. 2005, 7, 3713–
3716.
Acknowledgments
Financial support from the National Natural Science Foundation
of China (NSFC) (grant numbers 21175155, 21276282, 21376270),
Hunan Provincial Science
& Technology Department (grant
number 2012WK2007), and from the Central South University is
gratefully acknowledged.
[6]
[7]
F. Shi, Z. Tao, S. Luo, S. Tu, L. Gong, Chem. Eur. J. 2012, 18,
6885–6894.
[1] a) A. S. Girgis, Eur. J. Med. Chem. 2009, 44, 91–100; b) R.
Murugan, S. Anbazhagan, S. Sriman Narayanan, Eur. J. Med.
Chem. 2009, 44, 3272–3279; c) R. S. Kumar, S. M. Rajesh, S.
Perumal, D. Banerjee, P. Yogeeswari, D. Sriram, Eur. J. Med.
Chem. 2010, 45, 411–422; d) R. R. Kumar, S. Perumal, P. Sen-
thilkumar, P. Yogeeswari, D. Sriram, J. Med. Chem. 2008, 51,
5731–5735; e) A. Thangamani, Eur. J. Med. Chem. 2010, 45,
6120–6126; f) G. Periyasami, R. Raghunathan, G. Surendiran,
N. Mathivanan, Bioorg. Med. Chem. Lett. 2008, 18, 2342–2345;
g) P. Prasanna, K. Balamurugan, S. Perumal, P. Yogeeswari, D.
Sriram, Eur. J. Med. Chem. 2010, 45, 5653–5661; h) Y. Arun,
K. Saranraj, C. Balachandran, P. T. Perumal, Eur. J. Med.
Chem. 2014, 74, 50–64; i) M. A. Ali, R. Ismail, T. S. Choon,
Y. K. Yoon, A. C. Wei, S. Pandian, R. S. Kumar, H. Osman,
E. Manogaran, Bioorg. Med. Chem. Lett. 2010, 20, 7064–7066;
j) Y. Zhao, L. Liu, W. Sun, J. Lu, D. McEachern, X. Li, S. Yu,
D. Bernard, P. Ochsenbein, V. Ferey, J. Carry, J. R. Deschamps,
D. Sun, S. Wang, J. Am. Chem. Soc. 2013, 135, 7223–7234.
[2] For reviews, see: a) K. V. Gothelf, K. A. Jørgensen, Chem. Rev.
1998, 98, 863–910; b) G. Pandey, P. Banerjee, S. R. Gadre,
Chem. Rev. 2006, 106, 4484–4517; c) L. M. Stanley, M. P. Sibi,
Chem. Rev. 2008, 108, 2887–2902; d) I. Coldham, R. Hufton,
Chem. Rev. 2005, 105, 2765–2810; e) G. S. Singh, Z. Y. Desta,
Chem. Rev. 2012, 112, 6104–6155; f) D. Cheng, Y. Ishihara, B.
Tan, C. F. Barbas III, ACS Catal. 2014, 4, 743–762; g) M. Han,
J. Jia, W. Wang, Tetrahedron Lett. 2014, 55, 784–794; h)
S. L. D. S. Zheng Wang, Chem. Eur. J. 2013, 19, 6739–6745.
[3] For previous reports on the synthesis of spirooxindole, see: a)
L. Tian, X. Hu, Y. Li, P. Xu, Chem. Commun. 2013, 49, 7213–
7215; b) F. Shi, R. Zhu, X. Liang, S. Tu, Adv. Synth. Catal.
2013, 355, 2447–2458; c) X. Chen, Q. Wei, S. Luo, H. Xiao, L.
Gong, J. Am. Chem. Soc. 2009, 131, 13819–13825.
[4] a) D. Du, Y. Jiang, Q. Xu, M. Shi, Adv. Synth. Catal. 2013,
355, 2249–2256; b) L. Wang, J. Bai, L. Peng, L. Qi, L. Jia, Y.
Guo, X. Luo, X. Xu, L. Wang, Chem. Commun. 2012, 48,
5175–5177; c) C. E. Puerto Galvis, V. V. Kouznetsov, Org. Bio-
mol. Chem. 2013, 11, 7372–7386; d) Y. Kia, H. Osman, R. S.
Kumar, V. Murugaiyah, A. Basiri, S. Perumal, I. A. Razak, Bi-
oorg. Med. Chem. Lett. 2013, 23, 2979–2983; e) J.
Naga Siva Rao, R. Raghunathan, Tetrahedron Lett. 2013, 54,
6568–6573; f) S. N. Singh, S. Regati, A. K. Paul, M. Layek, S.
Jayaprakash, K. V. Reddy, G. S. Deora, S. Mukherjee, M. Pal,
Tetrahedron Lett. 2013, 54, 5448–5452; g) Y. Kia, H. Osman,
R. S. Kumar, A. Basiri, V. Murugaiyah, Bioorg. Med. Chem.
2014, 22, 1318–1328; h) S. Lanka, S. Thennarasu, P. T. Per-
umal, Tetrahedron Lett. 2014, 55, 2585–2588; i) Y. Kia, H. Os-
man, R. S. Kumar, V. Murugaiyah, A. Basiri, S. Perumal, H. A.
Wahab, C. S. Bing, Bioorg. Med. Chem. 2013, 21, 1696–1707.
[5] For selected recent reviews on asymmetric organocatalysis, see:
a) J. Li, T. Liu, Y. Chen, Acc. Chem. Res. 2012, 45, 1491–1500;
b) W. Sun, L. Hong, G. Zhu, Z. Wang, X. Wei, J. Ni, R. Wang,
For selected examples on the synthesis of spirooxindole and
pyrrolidine derivatives, see: a) B. Tan, N. R. Candeias, C. F.
Barbas, Nat. Chem. 2011, 3, 473–477; b) T. Liu, Z. He, Q. Li,
H. Tao, C. Wang, Adv. Synth. Catal. 2011, 353, 1713–1719; c)
X. Li, L. Stuart, C. Chen, J. Am. Chem. Soc. 2003, 125, 10174–
10175; d) J. Hernández-Toribio, S. Padilla, J. Adrio, J. C. Carre-
tero, Angew. Chem. Int. Ed. 2012, 51, 8854–8858; Angew. Chem.
2012, 124, 8984–8988; e) C. Guo, J. Song, L. Gong, Org. Lett.
2013, 15, 2676–2679; f) L. M. Castelló, C. Nájera, J. M. San-
sano, O. Larrañaga, A. D. Cózar, F. P. Cossío, Org. Lett. 2013,
15, 2902–2905; g) Q. Li, T. Liu, L. Wei, X. Zhou, H. Tao, C.
Wang, Chem. Commun. 2013, 49, 9642–9644; h) P. Yuvaraj,
B. S. R. Reddy, Tetrahedron Lett. 2014, 55, 806–810; i) A. P.
Antonchick, H. Schuster, H. Bruss, M. Schürmann, H. Preut,
D. Rauh, H. Waldmann, Tetrahedron 2011, 67, 10195–10202;
j) X. Chen, W. Zhang, L. Z. Gong, J. Am. Chem. Soc. 2008,
130, 5652–5653; k) C. Wang, X. Chen, S. Zhou, L. Z. Gong,
Chem. Commun. 2010, 46, 1275–1277; l) T. Liu, Z. Xue, H.
Tao, C. J. Wang, Org. Biomol. Chem. 2011, 9, 1980–1986.
a) C. Zhang, S. Yu, X. Hu, D. Wang, Z. Zheng, Org. Lett.
2010, 12, 5542–5545; b) S. Mutti, C. Daubié, F. Decalogne, R.
Fournier, P. Rossi, Tetrahedron Lett. 1996, 37, 3125–3128; c) Z.
He, T. Liu, H. Tao, C. Wang, Org. Lett. 2012, 14, 6230–6233;
d) I. Oura, K. Shimizu, K. Ogata, S. Fukuzawa, Org. Lett.
2010, 12, 1752–1755; e) G. Bhaskar, Y. Arun, C. Balachandran,
C. Saikumar, P. T. Perumal, Eur. J. Med. Chem. 2012, 51, 79–
91.
[8]
[9]
a) J. L. Vicario, S. Reboredo, D. Badía, L. Carrillo, Angew.
Chem. Int. Ed. 2007, 46, 5168–5170; Angew. Chem. 2007, 119,
5260–5262; b) W. Chen, X. Yuan, R. Li, W. Du, Y. Wu, L.
Ding, Y. Chen, Adv. Synth. Catal. 2006, 348, 1818–1822.
[10] W. Chen, W. Du, Y. Duan, Y. Wu, S. Yang, Y. Chen, Angew.
Chem. Int. Ed. 2007, 46, 7667–7670; Angew. Chem. 2007, 119,
7811–7814.
[11] H. Yang, R. G. Carter, J. Org. Chem. 2009, 74, 5151–5156.
[12] CCDC-996984 (for rac-4m) and -996985 (for enantiopure 4j)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[13] For the application of the Fischer indole Synthesis see: a) L.
Kötzner, M. J. Webber, A. Martínez, C. De Fusco, B. List, An-
gew. Chem. Int. Ed. 2014, 53, 1–5; b) H. Huang, K. Zhu, W.
Wu, Z. Jin, J. Ye, Chem. Commun. 2012, 48, 461–463; c) C. Li,
J. Chen, G. Fu, D. Liu, Y. Liu, W. Zhang, Tetrahedron 2013,
69, 6839–6844; d) M. López-Iglesias, E. Busto, V. Gotor, V.
Gotor-Fernández, J. Org. Chem. 2012, 77, 8049–8055.
Received: July 20, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42953
/KAP1
Date: 11-08-14 11:22:57
Pages: 6
H. Yang et al.
SHORT COMMUNICATION
Spirooxindoles
J.-A. Xiao, Q. Liu, J.-W. Ren, J. Liu,
R. G. Carter, X.-Q. Chen,
H. Yang* .......................................... 1–6
Highly Enantioselective Construction of
Polycyclic Spirooxindoles by Organocata-
lytic 1,3-Dipolar Cycloaddition of 2-Cyclo-
hexenone Catalyzed by Proline-Sulfon-
amide
The highly enantioselective construction of
polycyclic spirooxindoles through 1,3-di-
polar cycloaddition of cyclohexenone with
azomethine ylides is achieved by employing
prolinosulfonamides as the catalyst. This
catalytic system essentially benefits from
iminium activation and hydrogen-bonding
formation induced by the prolinosulfon-
amides.
Keywords: Organocatalysis
dition / Spiro compounds / Alkaloids /
Nitrogen heterocycles
/
Cycload-
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0