Synthesis of spirooxindoles via asymmetric 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2005.06.114

An efficient method was developed for the asymmetric synthesis of 2′-alkyl-4′aryl-1H-spiro[indole-3,3′-pyrrolidin]-2-ones, which are potential inhibitors of the p53-MDM2 interaction. Our X-ray crystallographic analysis revealed that this 1,3-dipolar cycloaddition proceeds with high stereoselectivity but differently from previously published results.

Full text of DOI:10.1016/j.tetlet.2005.06.114

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5949–5951
Synthesis of spirooxindoles via asymmetric
1,3-dipolar cycloaddition
Ke Ding,a Guoping Wang,a Jeffrey R. Deschamps,b
Damon A. Parrishb and Shaomeng Wanga,*
aDepartments of Internal Medicine and Medicinal Chemistry and Comprehensive Cancer Center, University of Michigan,
1500 East Medical Center Drive, Ann Arbor, MI 48109-0934, USA
bThe Laboratory for the Structure of Matter, Naval Research Laboratory, Washington, DC 20375, USA
Received 20 May 2005; revised 20 June 2005; accepted 21 June 2005
Available online 15 July 2005
Abstract—An efficient method was developed for the asymmetric synthesis of 20-alkyl-40aryl-1H-spiro[indole-3,30-pyrrolidin]-2-
ones, which are potential inhibitors of the p53–MDM2 interaction. Our X-ray crystallographic analysis revealed that this 1,3-
dipolar cycloaddition proceeds with high stereoselectivity but differently from previously published results.
Ó 2005 Elsevier Ltd. All rights reserved.
The spirooxindole system is the core structure of many
pharmacological agents and natural alkaloids.1–4 For
example, spirotryprostatin A (1), a natural product iso-
lated from the fermentation broth of Aspergillus fumi-
gatus, has been identified as a novel inhibitor of
microtubule assembly;4 and pteropodine (2) and isoptero-
podine (3) have been shown to modulate the function
of muscarinic and serotonin receptors.1 Recently, we
have designed compound 4 containing the spirooxindole
as the core structure as a potent non-peptide inhibitor of
the p53–MDM2 interaction5 (Fig. 1).
Me
O
O
H
HN
O
H
N
N
(S)
(S)
H
O
(S)
H
N
(S)
O
H
OMe
O
O
N
H
1
2
Spirotryprostatin A
Pteropodine
Me
O
N(CH )
3 2
O
1'
5'
H
N
NH
H
O
4'
H
Because of their remarkable biological activity, signifi-
cant effort has been devoted to the stereoselective syn-
thesis of substituted spirooxindole derivatives.6–22 For
example, Williams and co-workers have developed an
efficient asymmetric synthesis of 20,40,50-trisubstituted
spirooxindoles (8) using (5R,6S)-5,6-diphenylmorpho-
lin-2-one (7) as a chiral auxiliary (Scheme 1).19–22 They
have explored the reaction of active olefins with the
asymmetric 1,3-dipolar intermediates formed by alde-
hydes and the morpholinone (7) to achieve 40-carb-
alkoxyl-substituted 1H-spiro[indole-3,30-pyrrolidin]-2-ones
(8) (Scheme 1). To date, no synthesis of 20-alkyl-40-
Cl
3
2'
OMe
O
O
1
2
N
H
N
H
Cl
3
4
Isopteropodine
A potent inhibitor of
the p53-MDM2 interaction
Figure 1. Representatives of spirooxindole-containing compounds.
aryl-1H-spiro[indole-3,30-pyrrolidin]-2-ones has been re-
ported, which is the core structure of our designed inhibi-
tors of the p53–MDM2 interaction.5 Herein, we report
an asymmetric synthesis for this class of compounds.
Keywords: Spirooxindoles; Asymmetric 1,3-dipolar cycloaddition;
Inhibitors of the p53–MDM2 interaction.
First, the E-3-aryl-1,3-dihydro-indol-2-ones (11) were
synthesized by condensation of oxindoles 9 with differ-
ent aromatic aldehydes 10 under basic conditions either
*
Corresponding author. Tel.: +1 7346 150362; fax: +1 7346 479647;
e-mail: shaomeng@umich.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.114

5950
K. Ding et al. / Tetrahedron Letters 46 (2005) 5949–5951
RCHO
R1O2C
O
O
6
1'
N
1,3 dipolar
R1O2C
+
O
O
5'
4'
O
2'
3
N
R
O
2
H
N
H
1
N
H
5
7
8
Scheme 1. WilliamsÕ asymmetric 1,3-dipolar cycloaddition method for synthesis of substituted spirooxindoles.
Table 1. Preparation of E-3-aryl-1,3-dihydro-indol-2-ones
X-ray crystallographic analysis and was confirmed as
the E conformer (Fig. 2).
Ar
KF/Al O ,
2
3
The asymmetric 1,3-dipolar cycloaddition was carried
out by heating 11 with alkyl aldehydes 12 and
(5R,6S)-5,6-diphenylmorpholin-2-one (7) in toluene in
the presence of a dehydrating agent (Scheme 2). Com-
pounds 13 were obtained as the major products with
trace amount of other products observed by TLC. Com-
pounds 13 were partially purified by silica gel column
and were treated with 2 M dimethylamine in THF to
afford amides 15 in good overall yield (Table 2).
Microwave
R'
O
R'
O
ArCHO
+
N
H
or Piperazine,
MeOH, reflux
N
H
9
10
11
Compound
R0
H
Ar
Yield (%)
11a
11b
11c
11d
11f
11g
11h
11i
Phenyl
Phenyl
65a
60a
57a
70a
63a
80b
75b
60a
6-Br
6-CF3
6-Cl
6-F
Phenyl
Phenyl
Phenyl
In the previous studies,19–22 it was reported that com-
pounds 8 have the 20S,3S,40R,50R absolute stereochem-
istry starting from the (5R,6S)-5,6-diphenylmorpholin-
2-one 7 (Scheme 1). However, our X-ray crystallo-
graphic analysis of one important intermediate 14j
(Fig. 2) showed that the cycloaddition product 13 we ob-
tained using the same chiral auxiliary 7 (Scheme 2) has
the 20R,3S,40R,50R absolute configuration. The mecha-
nism of this unusual selectivity is not clear.
6-Cl
6-Cl
6-Cl
2-Pyridinyl
2-Thiophenyl
3-Methoxy-phenyl
a KF/Al2O3, microwave, 60W, 5 min.
b Piperazine, MeOH, reflux, 2–3 h.
in microwave23 or under refluxation in MeOH (Table
1).24 It was found that the latter condition gave better
yield (Table 1), although a small amount of Z-isomer
was observed. The crude products were used in a subse-
quent 1,3-dipolar cycloaddition without further purifica-
tion. Compound 11a was recrystallized from ethanol for
With the amides 14 in hand, removal of the chiral auxil-
iary by oxidization at 0 °C yielded the desired 20,40,50-tri-
substituted 1H-spiro[indole-3,30-pyrrolidin]-2-ones (15)
Figure 2. X-ray structures of compounds 11a, 14j and 15i.

K. Ding et al. / Tetrahedron Letters 46 (2005) 5949–5951
5951
H
O
RCHO
)
H
N(C
NH
(H3C)2N
2
3
O
Ph
Ph
Ar
Ph
Ph
O
12
O
O
Ar
Ar
N
O
O
Ph
Ph
Ar
N
b
c
R'
O
a
+
R
O
R
O
N
H
R
O
R'
N
H
R'
R'
N
H
N
H
N
H
14
15
11
7
13
0
0
0
˚
Scheme 2. Synthesis of 2 -alkyl-4 -aryl-1H-spiro[indole-3,3 -pyrrolidin]-2-one. Reagents and conditions: (a) toluene, 4 A molecular sieves, 70 °C, 5 h;
(b) 2 M dimeylamine in THF, 8–0h; (c) Pb(OAc) 4, MeOH–CH2Cl2, 0 °C.
Table 2. Summary of yield for intermediates 14 and the final target
compounds 15
4. Usui, T.; Kondoh, M.; Cui, C.-B.; Mayumi, T.; Osada, H.
Biochem. J. 1998, 333, 543.
5. Ding, K.; Lu, Y.; Nikolovska-Coleska, Z.; Qiu, S.; Ding
Y.; Gao, W.; Stuckey, J.; Krajewski, K.; Roller, P. P.,
Tomita, Y.; Parrish, D. A.; Deschamps, J. R.; Wang, S.
J. Am. Chem. Soc., in press.
6. Miyake, F. Y.; Yakushijin, K.; Horne, D. Org. Lett. 2004,
6, 711–713.
7. Takayama, H.; Fujiwara, R.; Kasai, Y.; Kitajima, M.;
Aimi, N. Org. Lett. 2003, 5, 2967–2970.
8. Lizos, D. E.; Murphy, J. A. Org. Biomol. Chem. 2003, 1,
117–122.
9. Dornyei, G.; Incze, M.; Kajtar-Peredy, M.; Szantay,
C. Coll. Czech. Chem. Commun. 2002, 67, 1669–1680.
10. Lerchner, A.; Carreira, E. M. J. Am. Chem. Soc. 2002,
124, 14826–14827.
Entry R0
Ar
R
14 15
(%) (%)
a
b
c
d
e
f
H
Phenyl
Phenyl
6-CF3 Phenyl
i-Butyl
i-Butyl
i-Butyl
i-Butyl
i-Butyl
7055
6-Br
75
75
68
73
62
59
60
58
6-Cl
6-F
Phenyl
Phenyl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
2-Pyridinyl 2,2-Dimethyl-propyl 6059
2-Thiophenyl 2,2-Dimethyl-propyl 65
3-MeO-phenyl 2,2-Dimethyl-propyl 75
g
h
i
63
65
Phenyl
Phenyl
Phenyl
2,2-Dimethyl-propyl 8063
j
2-Dimethyl-butyl
n-Propyl
78
77
60
59
k
11. Cochard, F.; Laronze, M.; Prost, E.; Nuzillard, J.-M.;
Auge, F.; Petermann, C.; Sigaut, P.; Sapi, J.; Laronze,
J.-Y. Eur. J. Org. Chem. 2002, 20, 3481–3490.
12. Selvakumar, N.; Azhagan, A. M.; Srinivas, D.; Krishna,
G. G. Tetrahedron Lett. 2002, 43, 9175–9178.
13. Wang, X. Z.; Cook, J. M. Org. Lett. 2002, 4, 4237–
4240.
14. Cravotto, G.; Giovenzana, G. B.; Pilati, T.; Sisti, M.;
Palmisano, G. J. Org. Chem. 2001, 66, 8447–8453.
15. Lizos, D.; Tripoli, R.; Murphy, J. A. Chem. Commun.
2001, 24, 2732–2733.
in 3–5 min. Higher temperature and/or longer reaction
time led to some byproducts. The structures of target
compounds 15 were determined by NMR and mass spec-
troscopy. The stereochemistry of the target compounds
was further confirmed by X-ray crystallographic analysis
of compound 15i (Fig. 2).
In summary, using asymmetric 1,3-dipolar cycloaddi-
tion as the key step, 20-alkyl-40aryl-1H-spiro[indole-
3,30-pyrrolidin]-2-ones were efficiently synthesized as a
novel class of inhibitors of the p53–MDM2 interaction.
Analysis of a key intermediate (14j) and one final prod-
uct (15i) by X-ray crystallography revealed that this 1,3-
dipolar cycloaddition showed different stereoselectivity
from that reported previously.19–21
16. Syam Kumar, U. K.; Ila, H.; Junjappa, H. Org. Lett. 2001,
3, 4193–4196.
17. Bagul, T. D.; Lakshmaiah, G.; Kawabata, T.; Fuji, K.
Org. Lett. 2002, 4, 249–251.
18. Edmondson, S. D.; Danishefsky, S. J. Angew. Chem., Int.
Ed. 1998, 37, 1138–1140.
19. Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000,
122, 5666–5667.
20. Onishi, T.; Sebahar, P. R.; Williams, R. M. Org. Lett.
2003, 5, 3135–3137.
21. Sebahar, P. R.; Williams, R. M. Heterocycles 2002, 58,
563–575.
References and notes
22. Overman, L. E.; Rosen, M. D. Angew. Chem., Int. Ed.
2000, 39, 4596–4599.
23. Villemin, D.; Martin, B. Synth. Commun. 1998, 28, 3201–
3208.
1. Kang, T.-H.; Matsumoto, K.; Murakami, Y.; Takayama,
H.; Kitajima, M.; Aimi, N.; Watanabe, H. Eur. J.
Pharmacol. 2002, 444, 39–45.
24. Andreani, A.; Rambaldi, M.; Locatelli, A.; Bossa, R.;
Galatulas, I.; NinciI, M. Eur. J. Med. Chem. 1990, 25,
187–190.
2. Ma, J.; Hecht, S. M. Chem. Commun. 2004, 10, 1190–1191.
3. Edmondson, S.; Danishefsky, S. J.; Sepp-lorenzinol, L.;
Rosen, N. J. Am. Chem. Soc. 1999, 121, 2147–2155.