Organocatalytic asymmetric formal [4 + 2] cycloaddition for the synthesis of spiro[4-eyelohexanone-1,3′-oxindoline] derivatives in high optical purity

Article abstract of DOI:10.1021/ol100020v

Chemical Equetion Presentation A bifunctional organocatalytic asymmetric formal [4 + 2] cycloaddition reaction of Nazarov reagents and methyleneindolinones afforded spiro[4-cyclohexanone-1,3′-oxindoline] derivatives with excellent enantioselectivity (up to 98% ee).

Full text of DOI:10.1021/ol100020v

ORGANIC
LETTERS
2010
Vol. 12, No. 5
1008-1011
Organocatalytic Asymmetric Formal
[4 + 2] Cycloaddition for the Synthesis of
Spiro[4-cyclohexanone-1,3′-oxindoline]
Derivatives in High Optical Purity
Qiang Wei and Liu-Zhu Gong*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of
Chemistry, UniVersity of Science and Technology of China, Hefei 230026, China
gonglz@ustc.edu.cn
Received January 4, 2010
ABSTRACT
A bifunctional organocatalytic asymmetric formal [4 + 2] cycloaddition reaction of Nazarov reagents and methyleneindolinones afforded
spiro[4-cyclohexanone-1,3′-oxindoline] derivatives with excellent enantioselectivity (up to 98% ee).
The spiro[4-cyclohexane-1,3′-oxindoline] structural motif is
commonly present in a number of natural products as
exemplified by gelsemium and marcfortine alkaloids.1,2 It
also comprises a core component of various biologically
active compounds.3 Recently, they have been found serving
as antagonists of MDM2 interactions and hence hold great
potential to be selective and potent anticancer agents.4 In
the past several years, significant advances have been
achieved on the development of synthetic methods to access
spirooxindole derivatives with a concomitant creation of an
all-carbon quaternary stereogenic center in an enantioselec-
tive manner.5 Overman pioneered an asymmetric intramo-
lecular Heck reaction rendering the synthesis of spiro[pyr-
rolidin-3,3′-oxindole] derivatives with high enantiomeric
purity.6 Trost developed an elegant asymmetric alkylation
reaction of an oxindole enolate enabling a concise synthesis
of horsfiline.7 Recently, Barbas and Melchiorre independently
reported organocatalytic conjugate addition reactions of
3-substituted oxindoles to electronically deficient olefins
creating an all-carbon stereogenic center with high levels of
stereochemical control.8 Chen and co-workers presented a
(5) For reviews, see: (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209. (b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363. (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (d)
Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46, 8748.
(6) (a) Ashimori, A.; Overman, L. E. J. Org. Chem. 1992, 57, 4571. (b)
Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc.
1998, 120, 6477. (c) Matsuura, T.; Overman, L. E.; Poon, D. J. J. Am.
Chem. Soc. 1998, 120, 6500. (d) Overman, L. E.; Rosen, M. D. Angew.
Chem., Int. Ed. 2000, 39, 4596. (e) Dounay, A. B.; Hatanaka, K.; Kodanko,
J. J.; Oestreich, M.; Overman, L. E.; Pfeifer, L. A.; Weiss, M. M. J. Am.
Chem. Soc. 2003, 125, 6261.
(1) (a) Saxton, J. E. Nat. Prod. Rep. 1992, 9, 393. (b) Takayama, H.;
Sakai, S.-J. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New
York, 1997; Vol. 49, pp 1-78.
(2) (a) Polousky, J.; Merrien, M.-A.; Prange´, T.; Pascard, C.; Moreau,
S. J. Chem. Soc., Chem. Commun. 1980, 601. (b) Prange´, T.; Billion, M.-
A.; Vuilhorgne, M.; Pascard, C.; Polonsky, J.; Moreau, S. Tetrahedron Lett.
1981, 22, 1977. (c) Yamazaki, M.; Okuyama, E.; Kobayashi, M.; Inoue,
H. Tetrahedron Lett. 1981, 22, 135
.
(3) (a) Fensome, A.; Koko, M.; Wrobel, J.; Zhang, P.; Zhang, Z.; Cohen,
J.; Lundeen, S.; Rudnick, K.; Zhu, Y.; Winneker, R. Bioorg. Med. Chem.
Lett. 2003, 13, 1317. (b) Venkatesan, H.; Davis, M. C.; Altas, Y.; Snyder,
J. P.; Liotta, D. C. J. Org. Chem. 2001, 66, 3653. (c) Mah, S. C.; Hofbauer,
K. G. Drugs of the Future 1987, 12, 1055.
(7) (a) Trost, B. M.; Cramer, N.; Bernsmann, H. J. Am. Chem. Soc.
2007, 129, 3086. (b) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am.
Chem. Soc. 2007, 129, 12396.
(8) (a) Bui, T.; Syed, S.; Barbas, C. F., III. J. Am. Chem. Soc. 2009,
131, 8758. (b) Galzerano, P.; Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.;
Giannichi, B.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem.sEur. J. 2009,
15, 7846.
(4) Liu, J.-J.; Zhang, Z. (Hoffmann-LaRoche AG), PCT Int. Appl.
WO2008/055812, 2008.
10.1021/ol100020v  2010 American Chemical Society
Published on Web 02/04/2010

Mannich reaction of 3-substituted oxindoles to imines,
yielding oxindole derivatives with high enanioselectivity.9
Very recently, we disclosed a Brønsted acid catalyzed 1,3-
dipolar addition of azomethine ylide to methyleneindolino-
nes, leading to a structurally diverse synthesis of optically
active spiro[pyrrolidin-3,3′-oxindole] derivatives.10 In sharp
contrast to the well-established approaches to access spiro-
[pyrrolidin-3,3′-oxindole] derivatives,5 however, so far only
a single asymmetric catalytic entry currently available to
spiro[4-cyclohexanone-1,3′-oxindoline] was very recently
disclosed by Melchiorre and co-workers, consisting of an
enamine-catalyzed cyclization reaction of enones with me-
thyleneindolinones.11 As our continuous efforts on seeking
efficient enantioselective approach toward the construction
of spirooxindole motif,10 we will herein report a formal
[4 + 2] cycloaddition reaction, providing spiro[4-cyclohex-
anone-1,3′-oxindoline] derivatives in excellent enantioselec-
tivity.
anone-1,3′-oxindoline]. In principal, chiral BH-LB bifunc-
tional organocatalyst14 will afford an enantioselective cascade
cyclization reaction.
Initially, we chose Takemoto type catalysts (Figure 1) to
promote a model reaction of Nazarov reagent 1a with (E)-
Figure 1. Organocatalysts evaluated in this study.
Nazarov reagents of type 1 possess a nucleophilic acidic
carbon and an electronically poor C-C double bond,12
allowing for design of a cascade procedure to build up an
all-carbon ring system by the use of organocatalysts.13 Our
initial idea for the catalytic synthesis of spiro[4-cyclohex-
anone-1,3′-oxindoline] including double conjugate addition
reactions cascade is shown in Scheme 1. The reaction is
1-acetyl-3-benzylideneindolinone (2a) for the validation of
our hypothesis because these catalysts possess Brønsted
acidic and Lewis basic functionalities and have shown unique
ability in catalyzing conjugate addition reactions.15 Indeed,
the reaction proceeded smoothly in the presence of 10 mol
% of the catalysts under the assistance of 4 Å molecular
sieves. In general, both the reaction conversion and stereo-
selectivity relied apparently on the electronic feature of the
aryl substituent on the thiourea moiety. As can be seen from
the reaction with 4a-e, the catalysts with highly electroni-
cally poor aryl group basically delivered higher enantiose-
lectivity and yields than those bearing electronically neutral
substituents (entries 1-3 vs 4-5), indicating that the more
acidic thiourea proton renders the reaction cleaner and more
Scheme 1. General Strategy for the Cyclization of
Methyleneindolinones with Nazarov Reagents by Bifunctional
Catalysts
Table 1. Evaluation of Organocatalystsa
entry
4
time (days)
yield (%)b
drc
ee (%)d
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
3
3
3
5
2
3
3
7
7
3
3
5
7
5
78
91
91
56
56
87
89
6
17
90
90
25
14
60
95/5
95/5
94/6
95/5
85/15
95/5
95/5
90/10
88/12
95/5
95/5
95/5
92/8
97/3
75
85
84
71
58
70
77
67
70
91
91
80
49
94
believed to commence with one conjugate addition of a
Nazarov reagent to a methyleneindolinone, followed by the
other conjugate addition of the carbon anion generated from
the former conjugate addition, yielding a spiro[4-cyclohex-
(9) Tian, X.; Jiang, K.; Peng, J.; Du, W.; Chen, Y.-C. Org. Lett. 2008,
10, 3583.
9
(10) Chen, X.-H.; Wei, Q.; Xiao, H.; Luo, S.-W.; Gong, L.-Z. J. Am.
Chem. Soc. 2009, 131, 13819.
10
11
12
13
14
(11) 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.
(12) Nazarov, I. N.; Zavyalov, S. I. J. General Chem. USSR 1953, 23,
1793.
(13) For enantioselective organocatalytic reactions of Nazarov reagents,
see: (a) Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004, 45,
9185. (b) Cabrera, S.; Alema´n, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2007, 47, 121. (c) Zhu, M.-K.; Wei, Q.; Gong,
L.-Z. AdV. Synth. Catal. 2008, 350, 1281.
a Reaction was performed in 0.1 mmol scale in DCM (0.5 mL) with 4
Å MS (100 mg) and the ratio of 2a/1a is 1:2. b Isolated yield. c Measured
by HNMR. d Determined by HPLC.
1
Org. Lett., Vol. 12, No. 5, 2010
1009

stereoseletive by engaging in the activation of either reaction
component through hydrogen bonding interactions, as dem-
onstrated in previous reports.14,15 Finely tuning the substitu-
ent of the Lewis basic tertiary amine moiety did not provide
further improvement in the catalytic activity and stereose-
lectivity (entries 6-9). Interestingly, a significant enhance-
ment in the stereoselectivity was achieved by the use of urea
surrogates as catalysts (entries 10 and 11). 1,2-Diphenyle-
thane-1,2-diamine derived bifunctional catalysts showed less
catalytic activity (entries 12-14), although 4n afforded the
highest levels of enantioselectivity (entry 14). In terms of
the reaction conversion and stereoselectivity, 4j and 4k
turned out to be the optimal catalysts (entries 10 and 11).
However, 4j is easier and cheaper to be prepared than 4k.
Thus, we chose 4j as the catalyst for further investigations.
Then, we optimized the reaction conditions (Table 2). The
reaction proceeded slower in toluene than dichloromethane
yleneindolinones (Table 3). A wide range of 3-aryl meth-
yleneindolinones were examined to react with Nazarov
Table 3. Generality for 3-Substituted Methyleneindolinonesa
yield
(%)b
entry
3
R1
R2
drc
ee (%)d
1
2
3
4
5
6
7
8
9
10
3b Ph
3c Ph
3d Ph
3e Ph
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-MeO2CC6H4
3-ClC6H4
2-ClC6H4
3,4-Cl2C6H3
Ph
2-naphthyl
COOEt
COOBn
COOtBu
Pr
80
76
91
89
95
98
66
91
86
90
80
80
93
91
94
89
78
86
97
91
29
98:2
96:4
92:8
92:8
90:10
93:7
95:5
89:11
96:4
95:5
94:6
94:6
94:6
99:1
99:1
97:3
95:5
96:4
95:5
96:4
99:1
93
94
91
91
95
91
90
88
95
93
96
97
97
90
93
90
94
93
93
93
93
3f
Ph
3g Ph
3h Ph
Table 2. Optimization of Reaction Conditionsa
3i
3j
Ph
Ph
3k Ph
11e 3l
Ph
12e 3m Ph
13e 3n Ph
14
15
16
17
18
19
20
3o Ph
3p Ph
3q Pr
ratio
time
i-Bu
Ph
entry of 2a/1a (days) temp (°C) yield (%)b drc ee (%)d
3r 4-OMeC6H4 Ph
1
2
3
4
5
6
7
8
9
1/2
1/2
1/2
1/2
1/1.2
1/1.5
1.2/1
1.5/1
2/1
3
3
3
4
3
3
3
3
3
20
20
10
0
10
10
10
10
10
70
90
90
71
54
67
73
73
83
99/1
95/5
96/4
96/4
95/5
95/5
95/5
95/5
95/5
90e
91
94
96
92
93
90
91
91
3t
4-MeC6H4
Ph
Ph
3u 4-BrC6H4
3v 4-NO2C6H4 Ph
COOEt
21e 3w OMe
a Reaction was performed in 0.2 mmol scale in DCM (1 mL) with 4 Å
MS (200 mg) at 10 °C and the ratio of 2/1 is 1:2. The reaction was performed
for 2-7 days. b Isolated yield. c Measured by 1HNMR. d Determined by
HPLC. e Reaction was conducted at -30 °C.
a Reaction was performed in 0.1 mmol scale in DCM (0.5 mL) with 4
Å MS (100 mg). b Isolated yield. c Measured by 1HNMR. d Determined by
HPLC. e In toluene.
reagent 1a (entries 1-10). Basically, the reaction proceeded
smoothly to give desired product in high yields. The
electronic feature of aryl substituent has little effect on the
enantioselectivity. As a result, monosubstituted benzalde-
hydes engaged in the cyclization reactions with excellent
enantioselectivity ranging from 90 to 94% ee (entries 1-7).
On the contrary, the diastereoselection was to some degree
sensitive to electronic property of the substituent and
benefited from the electron donating feature. For example,
very high diastereomeric ratio of 98/2 was observed for (E)-
1-acetyl-3-(4-methoxybenzylidene)indolinone, whereas (E)-
methyl 4-((1-acetyl-2-oxoindolin-3-ylidene)methyl)benzoate
only gave 90/10 dr (entry 1 vs 5). Interestingly, the methyl-
eneindolinones having a much electron-deficient carbon-
carbon double bond are much more reactive toward the
Nazarov reagent and thus achieved clean cyclization reactions
at -30 °C with high enantioselectivity (96-97% ee, entries
11-13). More significantly, 3-alkyl methyleneindolinones
could be accommodated in the reaction in high yields and
with excellent enantioselectivity (entries 14 and 15). More-
over, the current cyclization reaction was also operative for
but afforded comparable stereoselectivity (entries 1 and 2).
Lowering the temperature led to a higher enantioselectivity
(entries 2-4) but suffered from an eroded yield as demon-
strated by a reaction conducted at 0 °C (entry 4). By tuning
the stoichiometry of 2a to 1a we found that the use of 2
equiv of Nazarov reagent was necessary to ensure a cleaner
reaction because decreasing the amount of 1a led to a lower
conversion (entries 3, 5, and 6). Although excess amounts
of 2a gave good yields, the enantioselectivity was sacrificed
slightly (entries 7-9).
Having the optimized reaction conditions, we explored the
generality of the protocol for different 3-substituted meth-
(14) For reviews, see: (a) Doyle, A.-G.; Jacobsen, E. N. Chem. ReV.
2007, 107, 5713. (b) Akiyama, A.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal.
2006, 348, 999.
(15) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672. (b) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int.
Ed. 2005, 44, 4032. (c) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am.
Chem. Soc. 2006, 128, 9413. For an account, see: (d) Miyabe, H.; Takemoto,
Y. Bull. Chem. Soc. Jpn. 2008, 81, 785.
1010
Org. Lett., Vol. 12, No. 5, 2010

a variety of Nazarov reagents, including alkyl, aryl and
methoxy substituted ones, providing high stereoselectivity
(entries 16-21), but an incomplete reaction was found for
the 3-methoxy methyleneindolinone (entry 21).
Scheme 2. Synthesis of a
Spiro[cyclohexane-1,3′-indoline]-2′,4-dione
The capability of the reaction conditions in tolerating the
substituent on the indolinone moiety of methyleneindolinones
was finally investigated. As shown in Figure 2, the substitu-
hydroxide solution in a solvent mixture of THF and water
readily accomplished a deprotection reaction to give 6. The
hydrogenation of 6 on Pd/C to remove the benzyl group and
followed by a decarboxylation reaction with triethylamine
provided 8 in 71% overall yield and 95% ee.
In summary, we have disclosed a highly enantioselective
formal [4 + 2] cycloaddition reaction between methylenein-
dolinones and Nazarov Reagents catalyzed by Brønsted acid-
Lewis base binfunctional organocatalysts. This reaction is
accomplished via sequential double Michael addition reac-
tions in which the bifunctional chiral catalyst activates each
reaction component by hydrogen bonding interactions. This
protocol holds great potential in the synthesis of biologically
active spiro[cyclohexane-1,3′-indoline]-2′,4-dione derivatives
in high enantiomeric purity.
Figure 2. Generality for Substituent at the indolinone moiety. The
reaction was performed in 0.2 mmol scale in DCM (1 mL) with 4
Å MS (200 mg) at 10 °C and the ratio of 2a/1a is 1:2. Isolated
1
yield. The dr was measured by HNMR. The ee was determined
by HPLC. The reaction was performed for 2-4 days. The reactions
producing 5c and 5e were conducted at -20 °C.
tion at indolinone moiety with halogen was well tolerable
in high yields and with high levels of stereochemical control.
Importantly, the configuration of 5c was assigned as 1R,2S,6S
on the basis of the X-ray crystallography.16
To demonstrate the synthetic utility of the current reaction,
a straightforward synthesis of spiro[cyclohexane-1,3′-indo-
line]-2′,4-dione derivatives, which have found applications
in the discovery of antitumor agents, was established
(Scheme 2).4 The treatment of 5e (97% ee) with a lithium
Acknowledgment. We are grateful for financial support
fromNSFC(20732006),MOST(973program2010CB833300),
Ministry of Education, and CAS.
Supporting Information Available: Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) CCDC 740395. See the Supporting Information for details.
OL100020V
Org. Lett., Vol. 12, No. 5, 2010
1011