Catalytic asymmetric construction of spirocyclopentaneoxindoles by a combined Ru-catalyzed cross-metathesis/double michael addition sequence

Article abstract of DOI:10.1021/ol202624f

Biologically important and synthetically challenging spirocyclopentaneoxindoles with four contiguous stereocenters including one spiroquaternary stereocenter have been constructed in good yields (72-87%) with excellent diastereoselectivity (16:1→30:1 dr)

Full text of DOI:10.1021/ol202624f

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6200–6203
Catalytic Asymmetric Construction of
Spirocyclopentaneoxindoles by a
Combined Ru-Catalyzed Cross-Metathesis/
Double Michael Addition Sequence
Ying-Mei Li, Xiang Li, Fang-Zhi Peng, Ze-Qian Li, Shou-Tao Wu, Zhong-Wen Sun,
Hong-Bin Zhang, and Zhi-Hui Shao*
Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education,
School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
zhihui_shao@hotmail.com
Received September 29, 2011
ABSTRACT
Biologically important and synthetically challenging spirocyclopentaneoxindoles with four contiguous stereocenters including one spiro-
quaternary stereocenter have been constructed in good yields (72ꢀ87%) with excellent diastereoselectivity (16:1f30:1 dr) and enantioselectivity
(93f99% ee) by a combined Ru-catalyzed cross-metathesis/organocatalyzed asymmetric double-Michael addition sequence.
The spirocyclic oxindole scaffold is featured in a large
number of natural products and medicinally relevant com-
pounds.1ꢀ5 Thus, considerable efforts have been devoted
toward the development of enantioselective methods to
construct these spiroheterocyclic systems. Remarkable
advances have been made on the enantioselective synthesis
of pyrrolidinylspirooxindole compounds and analogues1
as well as six-membered spirocyclic oxindole deriva-
tives.2 Quite recently, enantioselective syntheses of spiro-
cyclic 2-oxindoles bearing a cyclopentene motif have also
been developed via tertiary phosphine- or amine-catalyzed
(1) For reviews, see: (a) Trost, B. M.; Brennan, M. K. Synthesis 2009,
3003. (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 8748. (c) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
For selected recent examples, see:(d) Chen, X.; Wei, Q.; Luo, S.; Xiao,
H.; Gong, L. J. Am. Chem. Soc. 2009, 131, 13819. (e) Cheng, M.; Wang,
H.; Gong, L. Org. Lett. 2011, 13, 2418. (f) Jiang, X.; Cao, Y.; Wang, Y.;
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2472.
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Wu, L.; Chen, Y. Org. Lett. 2010, 12, 2766. (b) Jiang, K.; Jia, Z.; Chen,
S.; Wu, L.; Chen, Y. Chem.;Eur. J. 2010, 16, 2852. (c) Wei, Q.; Gong, L.
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r
10.1021/ol202624f
Published on Web 11/01/2011
2011 American Chemical Society

[3 þ 2] cycloaddition reactions.3 In contrast, the direct
catalytic asymmetric construction of the spirocyclopenta-
neoxindole scaffold has remained an important challenge.
The 3-spirocyclopentane-2-oxindoles represent an im-
portant class of substructures that are widely encountered
in a number of biologically active natural alkaloids4 (Figure1)
and drug candidates.5 However, the catalytic enantioselec-
tive synthesis of these molecules remain a daunting task.
Generally, their asymmetric syntheses rely on chiral sub-
strate-controlled methods.4bꢀd To the best of our knowl-
edge, so far there are only two general reports concerning
the catalytic enantioselective construction of spirocyclo-
pentaneoxindole scaffolds. Trost and co-workers reported
an elegant Pd-catalyzed asymmetric [3 þ 2] cycloaddition
of methyleneindolinones for the synthesis of spiro-
cyclopentaneoxindoles.6 During the course of our cur-
rent work, Barbas and co-workers represented the only
example of organocatalytic highly enantioselective
synthesis of spirocyclopentaneoxindoles through cas-
cade Michaelꢀaldol reaction of activated methyleneindo-
linones.7 This impressive cascade process led to bispiro-
cyclic oxindole derivatives containing three quaternary
stereocenters.
organocatalytic asymmetric method to construct spirocy-
clopentaneoxindole scaffold with novel structural and
stereochemical diversity. We envisioned that the densely
substituted 3-spirocyclopentane-2-oxindole skeletons 3
could be constructed through organocatalytic cascade
double Michael addition reactions8 between rationally
designed new type of Michael donorꢀacceptor synthons
2, bifunctional oxindoles,9 and nitroolefins 310 (Scheme 1).
The bifunctional oxindoles 2 might be achieved through
Ru-catalyzed cross-metathesis of easily available 3-allylox-
indoles 1.
Recently, we have developed a new class of bifunctional
thioureacatalystsbearingcentraland axial chiralelements,
which showed good performance in the catalytic asym-
metric addition of 1,3-dicarbonyl compounds to nitro-
olefins.11 Interestingly, we have found that this class of
bifunctional thiourea catalysts could highly effectively
catalyze designed cascade double-Michael addition with
excellent diastereo- and enantioselectivity. As part of our
interest in developing new catalysts for novel catalytic
asymmetric reactions,12 herein we report new results in
the catalytic asymmetric construction of spirocyclopenta-
neoxindole scaffold.
Scheme 1. Strategy for Catalytic Asymmetric Construction of
Spirocyclopentaneoxindole Scaffold
We initiated our studies by evaluating the model
reaction involving a Ru-catalyzed cross-metathesis of
Figure 1. Representative natural products containing the spiro-
cyclopentaneoxindole scaffold.
(9) For a recent review on catalytic asymmetric routes to 3,3-
disubstituted oxindoles, see: (a) Zhou, F.; Liu, Y.; Zhou, J. Adv. Synth.
Catal. 2010, 352, 1381. For selected examples of asymmetric reactions
with 3-prochiral oxindoles, see: (b) Duan, S.; An, J.; Chen, J.; Xiao, W.
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Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
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In view of their biological and pharmacological poten-
tials as well as the challenges associated with their catalytic
asymmetric syntheses, the development of a new strategy
for the direct catalytic asymmetric synthesis of structurally
diverse spirocyclopentaneoxindoles is highly desirable. In
this context, we were intrigued in the development a new
(6) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc.
2007, 129, 12396.
(7) Tan, B.; Candeias, N. R.; Barbas, C. F., III. Nat. Chem. 2011, 3,
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W. Nat. Commun. 2011, 2, 211.
(8) For recent examples of organocatalytic asymmetric cascade
double Michael addition, see: (a) Wang, X.; An, J.; Zhang, X.; Tan,
F.; Chen, J.; Xiao, W. Org. Lett. 2011, 13, 808. (b) Wang, X.; Hua, Q.;
Cheng, Y.; An, X.; Yang, Q.; Chen, J.; Xiao, W. Angew. Chem., Int. Ed.
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Org. Lett., Vol. 13, No. 23, 2011
6201

3-allyloxindole 1a followed by an organocatalytic asym-
metric double-Michael addition. Gratifyingly, the desired
cross-metathesis reaction proceeded smoothly to afford
the bifunctional oxindole 2a in the presence of Zhan-1B
catalyst (5 mol %) in dichloromethane.13 With our bifunc-
tional thiourea catalyst 4a bearing central and axial chiral
elements,11 the expected asymmetric double Michael addi-
tion product 3a was obtained in excellent stereoselectivity
(25:1 dr, 99% ee) (Table 1, entry 1). To examine the effect
of catalyst structure on the diastereo- and enantioselec-
tivity, a series of other types of organocatalysts were also
investigated (Figure 2). The cinchona alkaloid 4cꢀe14aꢀd
(entries 3ꢀ5) and R-amino acid-derived thiourea catalysts
4g14e,f (entry 7) afforded unsatisfactory results. The bifunc-
tional primary amine catalyst 4f8f was also less effective
(entry 6). Takemoto’s catalyst 4h15 and Barbas’s bulky
catalyst 4i9c proved to be promising (entries 8 and 13).
These results indicated that the diamine scaffolds of the
catalysts had a significant impact on both diastereo- and
enantioselectivity, and notably the axial chiral binaphthyl
moiety of our catalysts played an important role in the
stereocontrol of the current reaction.
Figure 2. Catalysts evaluated in this study.
With the optimal reaction conditions established, the
generality of the sequential catalytic asymmetric process
was evaluated (Table 2). The desired sequential reactions
proceeded smoothly to afford a variety of multifunctiona-
lized spirocyclopentaneoxindoles containing the versatile
nitro and ester groups in good yields with excellent diaster-
eo- and enantioselectivity. Thereactions tolerated different
substituents in aromatic nitroolefins. The heteroaromatic
nitroolefin was also a suitable substrate for the cascade
process (entry 8). Notably, the reactions also worked well
for the aliphatic nitroolefin (entries 10 and 11). The reac-
tion with a β,β-disubstituted nitroolefin (E)-(1-nitroprop-
1-en-2-yl)benzene did not occur. The substituted oxindole
was also tested, giving the desired products in 82ꢀ84%
yield with 25:1f30:1 dr and >99% ee values (entries 9 and
10). The relative and absolute configurations of the se-
quential reaction products were assigned on the basis of
X-ray crystal structural analysis of the product of 3i
(Figure 3; see the Supporting Information).
Table 1. Screening Studies of Ru-Catalyzed Cross-Metathesis/
Organocatalyzed Michael/Michael Additiona
entry
cat.
solvent
yieldb (%)
drc
eed (%)
1
2
4a
4b
4c
4d
4e
4f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
86
80
70
78
82
72
80
83
91
90
84
90
82
25:1
10:1
6:1
99
ꢀ84
3
3
4
6:1
68
5
5:1
60
6
2.5:1
50:1
10:1
10:1
6:1
60
7
4g
4h
4h
4h
4h
4h
4i
41
8
ꢀ88
ꢀ84
ꢀ88
ꢀ82
ꢀ28
ꢀ90
9
10
11
12
13
toluene
m-xylene
THF
7:1
15:1
15:1
CH2Cl2
To demonstrate the synthetic utility of this sequential
process further, the reaction product 3a was transformed
into an interesting tetracyclic molecule 5 possessing indo-
line,16 pyrrolidin-2-one,17 fused [5,5] bicyclic lactams18,
a All double Michael reactions were performed with oxindole 2a (0.1
mmol) with nitrostyrene (1.1 equiv) in the presence of 10 mol % of
organocatalyst 4 in 0.5 mL of solvent at room temperature. b Isolated
yields. c Determined by 1H NMR analysis of the crude reaction mixture.
d The ee of the major diastereoisomer was determined by HPLC analysis
using a chiral stationary phase.
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(13) The reaction between 1a and 1-phenylprop-2-en-1-one gave the
cross-metathesis product 2a0 in very low yield.
(14) (a) Li, B.; Jiang, L.; Liu, M.; Chen, Y.; Ding, L.; Wu, Y. Synlett
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2005, 603. (b) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett.
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6202
Org. Lett., Vol. 13, No. 23, 2011

and spirocyclic components by reduction with NaBH4/
NiCl2 6H2O (eq 1). Because of the wide presence of these
3
key moieties in numerous biologically active molecules, this
would make the tetracyclic molecule 5 an attractive candi-
date for drug discovery.
Table 2. Ru-Catalyzed Cross-Metathesis/Organocatalyzed
Asymmetric Michael/Michael Addition Sequencea
entry
R1, R2 (3)
H, Ph (3a)
yieldb (%)
drc
eed (%)
1
2
86
72
73
76
75
78
75
87
82
84
87
25:1
25:1
30:1
25:1
30:1
25:1
25:1
16:1
25:1
>30:1
>30:1
99
99
H, 4-BrC6H4 (3b)
H, 4-CF3C6H4 (3c)
H, 3-CF3C6H4 (3d)
H, 4-ClC6H4 (3e)
H, 4-MeOC6H4 (3f)
H, 4-MeC6H4 (3g)
H, 2-furyl (3h)
3
>99
96
Figure 3. X-ray structure of 3i.
4
5
94
challenging spirocyclopentaneoxindoles with four contiguous
stereocenters including one spiroquaternary stereocenter
in good yields (72ꢀ87%) with excellent diastereoselectivity
(16:1f30:1 dr) and enantioselectivity (93f99% ee). The
multifunctional spirocyclopentaneoxindole molecules that
are generated in the current catalytic asymmetric reaction
are poised for use in medicinal chemistry and transforma-
tion into a variety of other potential candidates for drug
discovery.
6
99
7
93
8
94
9
5-MeO, Ph (3i)
>99
>99
97
10
11
5-MeO, n-C7H15 (3j)
H, n-C7H15 (3k)
a The double Michael reactions were performed with 2 (0.1 mmol)
and nitroolefins (1.1 equiv) in the presence of 10 mol % of organoca-
talyst 4a in 0.5 mL of solvent. b Isolated yields. c Determined by 1H NMR
analysis. d The ee of major diastereoisomer determined by HPLC
analysis using a chiral stationary phase.
Acknowledgment. We gratefully acknowledge financial
support from the NSFC (20962023, 21162034) and the
Program for New Century Excellent Talents in University
(NCET-10-0907).
In summary, through the design of a new type of
Michael donorꢀacceptor oxindole synthon and the use
of our recently developed bifunctional thiourea catalysts
bearing central and axial chiral elements, we have devel-
oped a combined Ru-catalyzed cross-metathesis/organo-
catalyzed asymmetric double-Michael addition sequence19
to construct biologically important and synthetically
Supporting Information Available. Representative ex-
perimental procedure, compound characterization data,
copies of spectra, and proposed reaction mechanism. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38, 2745.
Org. Lett., Vol. 13, No. 23, 2011
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