Stereoselective synthesis of spirooxindoles by palladium-catalyzed decarboxylative cyclization of γ-methylidene-β-valerolactones with isatins

Article abstract of DOI:10.1021/ol901348f

Image Presented A new synthetic method of spirooxindole derivatives has been developed by way of a palladium-catalyzed decarboxylative cyclization of γ-methylidene-β-valerolactones with isatins. By employing a newly prepared phosphoramidite ligand, the re

Full text of DOI:10.1021/ol901348f

ORGANIC
LETTERS
2009
Vol. 11, No. 16
3754-3756
Stereoselective Synthesis of
Spirooxindoles by Palladium-Catalyzed
Decarboxylative Cyclization of
γ-Methylidene-δ-valerolactones with
Isatins
Ryo Shintani,* Shin-ya Hayashi, Masataka Murakami, Momotaro Takeda, and
Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity,
Sakyo, Kyoto 606-8502, Japan
shintani@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
Received June 22, 2009
ABSTRACT
A new synthetic method of spirooxindole derivatives has been developed by way of a palladium-catalyzed decarboxylative cyclization of
γ-methylidene-δ-valerolactones with isatins. By employing a newly prepared phosphoramidite ligand, the reaction proceeds smoothly with
excellent diastereoselectivity. Preliminary results of its application to asymmetric catalysis using a chiral phosphoramidite ligand are also
described.
Spirooxindoles are a class of compounds that can be found
in many natural products and biologically active compounds,1
and the development of synthetic methods for these com-
pounds, including the ones with new substitution patterns,
is therefore of high importance in organic chemistry.
Although several efficient methods are available in the
literature,2,3 those with high stereoselectivity are still limited.3
In this context, here we describe the development of a highly
diastereoselective synthesis of spirooxindoles through pal-
ladium-catalyzed decarboxylative cyclization of γ-meth-
ylidene-δ-valerolactones4 with isatins, including some pre-
liminary results of its application to asymmetric catalysis.
Initially, we conducted a reaction of γ-methylidene-δ-
valerolactone 1a with N-methylisatin (2a) in the presence
of 5 mol % of palladium catalyst in THF at 40 °C to examine
(3) For examples: (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel,
D. R.; Carreira, E. M. Angew. Chem., Int. Ed. 1999, 38, 3186. (b)
Malinakova, H. C.; Liebeskind, L. S. Org. Lett. 2000, 2, 4083. (c) Lo,
M. M.-C.; Neumann, C. S.; Nagayama, S.; Peristein, E. O.; Schreiber, S. L.
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J. Org. Chem. 2006, 71, 2587. (e) Hojo, D.; Noguchi, K.; Hirano, M.;
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(1) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007, 46,
8748. and the references therein.
(4) (a) Shintani, R.; Murakami, M.; Hayashi, T. J. Am. Chem. Soc. 2007,
129, 12356. (b) Shintani, R.; Park, S.; Hayashi, T. J. Am. Chem. Soc. 2007,
129, 14866. (c) Shintani, R.; Park, S.; Shirozu, F.; Murakami, M.; Hayashi,
T. J. Am. Chem. Soc. 2008, 130, 16174. (d) Shintani, R.; Murakami, M.;
Hayashi, T. Org. Lett. 2009, 11, 457. (e) Park, S.; Shintani, R.; Hayashi, T.
Chem. Lett. 2009, 38, 204.
(2) For a review, see: (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem.
2003, 2209. For recent examples, see: (b) Hilton, S. T.; Ho, T. C. T.;
Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639. (c) Zhu, S.-L.; Ji, S.-J.;
Zhang, Y. Tetrahedron 2007, 63, 9365
.
10.1021/ol901348f CCC: $40.75
Published on Web 07/28/2009
 2009 American Chemical Society

the effect of several known ligands (Table 1, entries 1-4).
Among those tested, the reaction was best catalyzed by the
Table 2. Palladium-Catalyzed Decarboxylative [4 + 2]
Cyclization of γ-Methylidene-δ-valerolactone 1b with Carbonyl
Compounds 2a
Table 1. Palladium-Catalyzed Decarboxylative [4 + 2]
Cyclization of γ-Methylidene-δ-valerolactones 1 with
N-Methylisatin (2a)
entry
1
ligand
PPh3
P(Oi-Pr)3
dppf
4a
4b
4b
4b
4b
4b
4b
4b
4b
product
yield (%)a
drb
1
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
3aa
3aa
3aa
3aa
3aa
3ba
3ca
3da
3ea
3fa
77c
82c
86c
94c
98c
96
73/27
77/23
77/23
80/20
90/10
97/3
95/5
97/3
>99/1
97/3
98/2
2
3d
4
5
6
7
8
84e
94
9
70e
93
10
11
12
a Conditions: 1b (0.21 mmol), 2 (0.20 mmol), PdCp(η3-C3H5) (5 mol
%), 4b (10 mol %), THF (1.0 mL), 40 °C, 3 h. b Combined isolated yield
of two diastereomers. c Determined by 1H NMR of the crude material.
d Ligand 4a was used.
1g
1h
3ga
3ha
96
76e
95/5
a Combined isolated yield of two diastereomers unless otherwise noted.
b Determined by 1H NMR of the crude material. c Determined by 1H NMR
against internal standard (o-xylene). d 5 mol % of ligand was used. e Isolated
yield of the major diastereomer.
similar efficiency (dr g 95/5; entries 3-6). The relative
configuration of 3bf (entry 5) was determined by X-ray
crystallographic analysis as shown in Figure 1. The same
use of phosphoramidite 4a,5 giving spirooxindole 3aa in 94%
yield with dr ) 80/20 (entry 4). We subsequently found that
the diastereoselectivity of 3aa could be improved to 90/10
by using newly prepared phosphoramidite 4b having a
bis(diphenylmethyl)amino group on phosphorus (entry 5).
By changing the ester group of 1a from methyl to tert-butyl
(1b), the diastereoselectivity was further improved to 97/3
with ligand 4b (entry 6). Under these conditions, various
R-(hetero)aryl-γ-methylidene-δ-valerolactones 1 efficiently
undergo decarboxylative cyclization with 2a in high yield
with excellent diastereoselectivity (dr g 95/5; entries 7-11).
R-Alkyl lactones can also be successfully employed by
adjusting the ester group to phenyl (entry 12) instead of
methyl or tert-butyl, which results in less than 30% yield
under otherwise the same conditions.
In addition to N-methylisatin (2a), N-benzyl- and N-
methoxymethylisatins can be employed in the reaction with
lactone 1b as well, giving the corresponding spirooxindoles
in high yield with excellent diastereoselectivity (dr g 95/5;
Table 2, entries 1 and 2). Isatins having various substituents
on the benzene ring also undergo the present reaction with
Figure 1. X-ray crystal structure of the major diastereomer of 3bf.
mode of catalysis can be extended to other activated ketones.
Thus, acenaphthenequinone (2h) and diethyl ketomalonate
(5) Dura´n, J.; Moise´s, G.; Castedo, L.; Mascarenjas, J. L. Org. Lett. 2005,
7, 5693.
Org. Lett., Vol. 11, No. 16, 2009
3755

(2i) can be successfully used in the reaction with 1b to give
the decarboxylative cyclization products in high yield (entries
7 and 8).
A proposed catalytic cycle of the reaction of 1b with 2a
is illustrated in Figure 2. Thus, oxidative addition of the allyl
tivity (dr ) 88/12 to 92/8, major 80-87% ee; eq 2). The
use of lactone 1b having a tert-butyl ester does improve the
diastereoselectivity, but the enantioselectivity becomes some-
what lower under these conditions (dr ) 95/5, 73% ee).
In summary, we have developed a palladium-catalyzed
decarboxylative cyclization of γ-methylidene-δ-valerolac-
tones with isatins to generate spirooxindoles under mild
conditions. We have also described our preliminary results
toward the development of an asymmetric variant. Future
studies will focus on further improvement of the reaction
conditions to achieve more efficient asymmetric catalysis.
Figure 2. Proposed catalytic cycle for the palladium-catalyzed
decarboxylative cyclization of 1b with 2a.
ester moiety of 1b to palladium(0), followed by decarboxy-
lation,6,7 gives 1,4-zwitterionic species A. The anionic carbon
of A then attacks the electrophilic carbon atom of 2a to give
intermediate B, which undergoes a ring closure through a
nucleophilic attack of the oxygen atom to the π-allylpalla-
dium moiety, leading to the formation of 3ba along with
regeneration of palladium(0).
Spirooxindoles obtained by the present catalysis can be
further derivatized to more complex structures. For example,
treatment of compound 3ba with LiAlH4 in THF readily
provides tetracyclic compound 5 with an N,O-acetal func-
tionality in high yield (eq 1).
Acknowledgment. Support has been provided in part by
a Grant-in-Aid for Scientific Research (S) (19105002), the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan, the Global COE Program “Integrated Materials
Science” on Kyoto University, and in part by the Sumitomo
Foundation.
Supporting Information Available: Experimental pro-
cedures and compound characterization data and X-ray data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL901348F
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We have also begun to explore the development of
asymmetric variant of this catalytic process to control the
relative and absolute stereochemistry of the two contiguous
quaternary stereocenters. By employing chiral phosphora-
midite 68 as a ligand, the reaction of lactone 1a or 1i with
isatin 2a or 2c proceeds smoothly at 0 °C to give the
corresponding spirooxindoles 3 with promising stereoselec-
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