Scaffold-inspired enantioselective synthesis of biologically important spiro[pyrrolidin-3,2'-oxindoles] with structural diversity through catalytic isatin-derived 1,3-dipolar cycloadditions

Article abstract of DOI:10.1002/chem.201200358

Catalytic asymmetric construction of the biologically important spiro[pyrrolidin-3,2'-oxindole] scaffold with contiguous quaternary stereogenic centers in excellent stereoselectivities (up to >99:1 d.r., 98 % ee) has been established by using an organocat

Full text of DOI:10.1002/chem.201200358

FULL PAPER
DOI: 10.1002/chem.201200358
Scaffold-Inspired Enantioselective Synthesis of Biologically Important
Spiro[pyrrolidin-3,2’-oxindoles] with Structural Diversity through Catalytic
Isatin-Derived 1,3-Dipolar Cycloadditions
Feng Shi,[a] Zhong-Lin Tao,[b] Shi-Wei Luo,*[b] Shu-Jiang Tu,[a] and Liu-Zhu Gong*[b]
Abstract: Catalytic asymmetric con-
struction of the biologically important
spiro[pyrrolidin-3,2’-oxindole] scaffold
with contiguous quaternary stereogenic
centers in excellent stereoselectivities
(up to >99:1 d.r., 98% ee) has been es-
tablished by using an organocatalytic
1,3-dipolar cycloaddition of isatin-
based azomethine ylides. This protocol
represents the first example of catalytic
asymmetric 1,3-dipolar cycloadditions
involving azomethine ylides generated
in situ from unsymmetrical cyclic ke-
tones. In addition, theoretical calcula-
tions were performed on the transition
state of the reaction to understand the
stereochemistry. Preliminary bioassays
with these spiro[pyrrolidin-3,2’-oxin-
dole] revealed that several compounds
showed moderate cytotoxicity to
SW116 cells.
Keywords: cycloaddition
·
asym-
metric synthesis · multicomponent
reactions · organocatalysis · spiro
compounds
Introduction
The spiro[pyrrolidin-3,2’-oxindole] core is a privileged het-
erocyclic ring system that is featured in a large family of me-
ACHTUNGTRENNUNG
dicinally relevant compounds exhibiting a wide spectrum of
important bioactivities such as antitumor,[1] antidiabetic,[2]
antimycobacterial,[3] antimicrobial,[4] antitubercular,[5] and
acetylcholinesterase-inhibitory[6] activities. Particularly, as
exemplified in Figure 1, compounds of type I, II, and III
showed potent antimycobacterial,[3b] antimicrobial,[4c] and
antitubercular[5b] activities, respectively.
Figure 1. Some biologically important compounds containing the spiro-
AHCTUNGTRENGN[UN pyrrolidin-3,2’-oxindole] core.
The significant medicinal relevance of such a structural ar-
chitecture has led to great demand for efficient synthetic
methods, especially those producing enantiomerically pure
spiro[pyrrolidin-3,2’-oxindole] derivatives. However, the es-
tablished synthetic approaches are either racemic or require
enantiopure starting materials,[3c,4b,c,7] and no catalytic asym-
metric approaches have been available to access optically
pure spiro[pyrrolidin-3, 2’-oxindole] compounds.[8] As a con-
sequence, the catalytic enantioselective construction of this
structurally rigid architecture containing quaternary stereo-
centers has remained a formidable challenge and is highly
desirable.
In the past decades, elegant developments have been de-
scribed in the field of catalytic asymmetric 1,3-dipolar cyclo-
additions of azomethine ylides to electron-deficient olefins
by using either chiral metal-based catalysts[9] or organocata-
lysts [Eq. (1)].[10] The azomethine ylides that participate in
these reactions are mostly generated from aldehydes. In
contrast, ketones have rarely been applied to 1,3-dipolar cy-
cloadditions as azomethine ylide precursors, presumably due
to the low reactivity inherent in both the ketone and the re-
sultant azomethine ylide. So far, catalytic asymmetric 1,3-di-
polar cycloaddition reactions involving ketone-based azome-
thine ylides have occasionally been used in a limited
number of metal-catalyzed transformations[11] and in one or-
ganocatalytic variant.[10d] However, none of these protocols
employed unsymmetrical cyclic ketones [Eq. (2)]. Neverthe-
less, the application of 1,3-dipolar cycloaddition reactions
with ketones, in particular unsymmetrical cyclic ketones,
would enable structurally diverse syntheses of spiro-pyrroli-
dines with concomitant creation of quaternary stereogenic
centers and hence holds great synthetic promise.
[a] F. Shi, Prof. S.-J. Tu
School of Chemistry and Chemical Engineering
Xuzhou Normal University
Xuzhou, 221116 (P.R. China)
[b] Z.-L. Tao, S.-W. Luo, Prof. L.-Z. Gong
Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (P.R. China)
Fax : (+86)551-3606266
E-mail: gonglz@ustc.edu.cn
luosw@ustc.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200358.
Chem. Eur. J. 2012, 00, 0 – 0
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Table 1. Screening of catalyst and optimization of conditions.[a]
Herein, we report the catalytic asymmetric construction
of a biologically important spiro[pyrrolidin-3,2’-oxindole]
scaffold with multiple contiguous stereogenic centers includ-
ing one or two quaternary chiral centers by using an organo-
catalytic 1,3-dipolar cycloaddition reaction with isatins as
azomethine precursors, which gives excellent stereoselectiv-
ity (up to >99:1 diastereomeric ratio (d.r.) and 98% enan-
tiomeric excess (ee))
Entry
4
Catalyst
Solvent
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
4aaa
4aaa
4aaa
4aaa
4aaa
4aaa
4aaa
4aaa
4aaa
4baa
4baa
4baa
4baa
4baa
4baa
4baa
4baa
4baa
4baa
5a
5b
5c
5d
5e
5 f
5g
5h
6
6
6
6
6
6
6
6
6
6
6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
87
87
78
86
73
88
59
92
54
78
12
45
16
26
23
87
59
85
88
10
25
13
5
18
25
1
Results and Discussion
31
90
93
9
10
11
12
13
14
15
16
17
18
19
Catalytic asymmetric synthesis of spiro[pyrrolidin-3,2’-oxin-
dole] derivatives: The 1,3-dipolar cycloaddition of electron-
deficient olefins with the azomethine ylide generated from
isatin provides a straightforward entry to the spiro[pyrroli-
din-3,2’-oxindole] scaffold (Scheme 1).
5
CHCl3
(ClCH2)2
92
93
91
CH2Cl2
toluene
toluene
toluene
toluene
toluene
77[d]
92[e]
91[f]
91[g]
93[h]
[a] Reagents and conditions (0.1 mmol scale): solvent (1 mL), 3 ꢁ MS
(100 mg), 36 h, ratio of 1/2a/3a 1.2:1:5. [b] Isolated product yield and
a single diastereomer was observed unless indicated otherwise. [c] The ee
value was determined by HPLC analysis. [d] Performed at 08C. [e] Per-
formed at 408C. [f] The ratio of 1b/2a/3a was 1.2:1:10. [g] By using 5 ꢁ
MS (100 mg). [h] In the presence of 15 mol% 6.
Scheme 1. Strategy used for the construction of the spiro[pyrrolidin-3,2’-
oxindole] scaffold with a chiral Brønsted acid catalyst.
We have recently established a series of enantioselective
1,3-dipolar cycloaddition reactions between electron-defi-
cient olefins and azomethine ylides formed from aldehydes
using chiral phosphoric acids[12] as catalysts in which a chiral
Brønsted acid bonded dipole is involved.[13] Encouraged by
these successes and in view of the synthetic importance of
developing an enantioselective version of the 1,3-dipolar cy-
cloaddition reaction involving azomethine ylides generated
from unsymmetrical cyclic ketones, we envisioned that keti-
mine-based azomethine ylides could also be activated by the
chiral Brønsted acid to undergo enantioselective 1,3-dipolar
cycloadditions, leading to the production of the spiro[pyrro-
lidin-3, 2’-oxindole] skeleton with multiple stereogenic cen-
ters.
room temperature in the presence of 10 mol% chiral phos-
phoric acids 5 or 6 (Table 1). The results revealed that bi-
sphosphoric acid (Bis-PA) 6 was much superior to other
phosphoric acids 5, delivering 90% ee (Table 1, entries 1–8
vs. 9). Interestingly, the reaction with 1-benzylisatin (1b)
proceeded more efficiently in a higher yield of 78% and
enantioselectivity of 93% ee under similar conditions
(Table 1, entry 10). Thus, this substrate was subsequently
employed to optimize the conditions. A survey of solvents
revealed that toluene was
a suitable reaction media
(Table 1, entries 10–14). Changes to the reaction tempera-
ture did not enhance the enantioselectivity (Table 1, en-
tries 10 vs. 15 and 16). In addition, tuning other reaction pa-
rameters such as substrate ratio and molecular sieves did
not deliver higher ee values (Table 1, entries 10 vs. 17 and
18). Finally, the presence of 15 mol% 6 was found to facili-
tate the reaction, delivering a higher yield while maintaining
the enantioselectivity (Table 1, entry 19 vs. 10).
Optimization of reaction conditions: Our study began with
the reaction of 1-methylisatin (1a) and diethyl 2-amino-
ACHTUNGTRENNUNGmalonate (2a) with dimethyl maleate (3a) in toluene at
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Synthesis of Spiro[pyrrolidin-3,2’-oxindoles]
FULL PAPER
Table 3. Influence of the substituent at the phenyl moiety of isatins 1 on
Scope of isatins: With the optimal conditions in hand, the
generality of the reaction for isatins 1 was then explored
with the reactions of diethyl 2-aminomalonate (2a) and di-
methyl maleate (3a). Initially, the effect of N-substituents of
isatins 1 on the reaction was investigated. As shown in
Table 2, this protocol is amenable to a wide range of isatins
with different types of N-substituents, including alkyl, aryl,
and benzyl groups, and the products were obtained with
high enantioselectivities (up to 94% ee). Generally, N-
benzyl substituted isatin gave higher stereoselectivity than
N-alkyl or N-phenyl derivatives (Table 2, entry 2 vs. 1, 3,
and 4). For N-benzylisatin derivatives, variation of the sub-
stituent on the benzyl moiety had little effect on the enan-
tioselectivity (Table 2, entries 5–9). However, linear N-alkyl
substituted isatins delivered higher enantioselectivity than
the branched and cyclic analogues (Table 2, entry 10 vs. 11
and 12).
the reaction.[a]
Entry
4
R1
3
Yield
[%][b]
d.r.[c]
ee
[%][d]
1
2
3
4
5
6
7
8
4maa
4naa
4oaa
4paa
4qaa
4raa
4saa
4taa
4bab
4qab
4rab
4sab
4rba
5-F (1m)
5-Me (1n)
6-F (1o)
6-Me (1p)
6-Br (1q)
7-Br (1r)
7-CF3 (1s)
5,6-F2 (1t)
H (1b)
6-Br (1q)
7-Br (1r)
7-CF3 (1s)
7-Br (1r)
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3b
3b
3a
90
95
82
84
63
89
90
86
84
52
77
86
72
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
83
87
89
94
94
96
96
91
9
81[e]
89[e]
83[e]
88[e]
98[f]
10
11
12
13
Table 2. Effect of N-substituents of isatins 1 on the reaction.[a]
[a] Reagents and conditions (carried out with 2a in 0.1 mmol scale): tolu-
ene (1 mL), 3 ꢁ MS (100 mg), 36 h, 1/2a/3 was 1.2:1:5. [b] Isolated prod-
uct yield. [c] The d.r. was determined by 1H NMR spectroscopic analysis.
[d] The ee value was determined by HPLC analysis. [e] The reaction time
was 48 h. [f] Compound 2b was used as a reaction component and in the
presence of 6 (25 mol%) and the reaction time was 96 h.
Entry
4
R
Yield
[%][b]
d.r.[c]
ee
[%][d]
1
2
3
4
5
6
7
8
4aaa
4baa
4caa
4daa
4eaa
4 faa
4gaa
4haa
4iaa
4jaa
4kaa
4laa
Me (1a)
Bn (1b)
Ph (1c)
9-Anthracenyl-CH2ACTHNGUTER(NNUG 1d)
p-tBuC6H4CH
p-BrC6H4CH2 (1 f)
o-BrC6H4CH2A(1g)
p-FC6H4CH2A(1h)
C6F5CH2 (1i)
n-Hexyl (1j)
iPr (1k)
77
88
90
48
70
91
62
78
94
86
89
91
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
93
93
Therefore, this reaction tolerated various isatins to afford
spiro[pyrrolidin-3,2’-oxindole] compounds with high enan-
tioselectivities and excellent diastereoselectivities. In addi-
tion to dimethyl maleate (3a), the use of diethyl maleate
(3b) as a 1,3-dipolarophile provided high enantioselectivities
ranging from 81 to 89% ee and excellent diastereoselectivi-
ties of more than 99:1 d.r. (Table 3, entries 9–12), although
the ee values of the spiro[pyrrolidin-3, 2’-oxindole] deriva-
tives synthesized from diethyl maleate (3b) were not as high
as their counterparts from the reactions with dimethyl male-
ate (3a). Importantly, spiro[pyrrolidin-3,2’-oxindole] 4aaa
could be obtained as a single crystal in more than 99% ee
after recrystallization; the X-ray analysis of which revealed
that the absolute configuration was (2’S,3’R,4’S)
(Figure 2).[14] The configurations of other spiro[pyrrolidin-
3,2’-oxindole] derivatives generated from maleates were as-
signed by analogy.
80[e]
88[e]
94
2ACHTUNGERTN(NUNG 1e)
92
92
92
92
92
86
86
G
G
9
10
11
12
cyclopentyl (1l)
[a] Reagents and conditions (0.1 mmol scale): toluene (1 mL), 3 ꢁ MS
(100 mg), 36 h, 1/2a/3a ratio 1.2:1:5. [b] Isolated yield. [c] The d.r. was
determined by 1H NMR spectroscopic analysis. [d] The ee value was de-
termined by HPLC analysis. [e] In the presence of 6 (10 mol%).
The influence of the substituent at the phenyl moiety of
isatins 1 on the reaction was then studied (Table 3). Gener-
ally, the introduction of an electronically different substitu-
ent at C5, C6, or C7 of the isatin was tolerated, with high
enantioselectivities ranging from 81 to 98% ee. The position
of the substituent appeared to exert some influence on the
stereoselectivity. Broadly, the C6-substituted isatins provid-
ed higher ee values than C5-substituted derivatives (Table 3,
entry 3 vs. 1 and entry 4 vs. 2), whereas no remarkable dif-
ference in the enantioselectivity was observed between the
C7- and C6-substituted isatins (Table 3, entry 5 vs. 6). In ad-
dition, C5,C6 disubstituted isatins also participated in the re-
action with 91% ee (Table 3, entry 8). It is noteworthy that
d.r. values of more than 99:1 were obtained in all cases.
Figure 2. X-ray structure of spiro[pyrrolidin-3,2’-oxindole] 4aaa.
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L.-Z. Gong, S.-W. Luo et al.
Scope of 1,3-dipolarophiles: Although fumarates represent
challenging dipolarophiles compared with maleates in the
asymmetric 1,3-dipolar cycloaddition,[13d] a variety of isatins
were accommodated in the 1,3-dipolar cycloaddition with di-
methyl fumarate (3c) under similar reaction conditions. The
presence of 25 mol% of catalyst 6 enabled the generation of
spiro[pyrrolidin-3,2’-oxindole] compounds 4bac–wac with
high diastereomeric ratios (30:1 to >99:1 d.r.) and excellent
enantioselectivity ranging from 88 to 96% ee (Table 4, en-
tries 1–6). The absolute configuration of spiro[pyrrolidin-
produce spiro[pyrrolidin-3, 2’-oxindole] compounds 4bad–
wad with high enantioselectivities of up to 97% ee and ex-
cellent diastereoselectivities of more than 99:1 d.r. (Table 4,
entries 7–11). The use of dimethyl 2-aminomalonate (2b) as
a reaction component also provided excellent stereochemi-
cal outcomes (Table 4, entries 12 and 13).
Importantly, the use of methyl 2-phenylacrylate (3e) as
a reaction component to participate in the 1,3-dipolar cyclo-
addition allowed the creation of spiro[pyrrolidin-3,2’-oxin-
dole] derivatives possessing two contiguous quaternary
chiral centers, one of which is an all-carbon stereogenic
center. However, when the previously optimized conditions
for maleates were applied to the reaction involving 3e, spi-
ro[pyrrolidin-3,2’-oxindole] 4bae was obtained in an unsatis-
factory enantioselectivity (82% ee, Table 5, entry 1). Thus,
the reaction conditions were reoptimized. Screening of the
Table 4. The use of dimethyl fumarate (3c) and methyl acrylate (3d) as
1,3-dipolarophiles for the synthesis of spiro[pyrrolidin-3,2’-oxindoles].[a]
Table 5. Optimization of reaction conditions for the reactions using
methyl 2-phenylacrylate 3e as 1,3-dipolarophile.[a]
Entry
4
R/R1
3
Yield d.r.[c]
[%][b]
ee
[%][d]
1
2
3
4
5
6
7
8
4bac Bn/H (1b)
4qac Bn/6-Br (1q)
3c 71
3c 41
3c 63
3c 71
3c 70
40:1
>99:1
>99:1
30:1
30:1
40:1
>99:1
>99:1
>99:1
>99:1
>99:1
88
93
95
96
94
92
87
93
94
94
97
4rac
Bn/7-Br (1r)
4uac p-tBuC6H4CH2/6-Br (1u)
4vac p-tBuC6H4CH2/7-Br (1v)
4wac p-tBuC6H4CH2/7-CF3 (1w) 3c 76
4bad Bn/H (1b)
4qad Bn/6-Br (1q)
4rad Bn/7-Br (1r)
4vad p-tBuC6H4CH2/7-Br (1v)
4wad p-tBuC6H4CH2/7-CF3 (1w) 3d 92
Entry
x
T
[8C]
Solvent
Yield
[%][b]
ee
[mol%]
[%][c]
3d 91
3d 44
3d 83
3d 86
1
2
3
4
5
6
7
8
15
15
15
15
20
25
25
25
RT
RT
RT
RT
RT
RT
40
toluene
CH2Cl2
CHCl3
AHCTUNTGREG(NNUN ClCH2)2
CHCl3
CHCl3
CHCl3
CHCl3/toluene=1:1 v/v
64
27
31
35
38
46
51
51
82
90
89
74
91
90
88
93
9
10
11
12
13
4rbc
Bn/7-Br (1r)
3c 46
3d 72
>99:1 96[e]
>99:1 96[e]
4rbd Bn/7-Br (1r)
RT
[a] Reagents and conditions (carried out with 2a on 0.1 mmol scale): tol-
uene (1 mL), 3 ꢁ MS (100 mg), 60 h, 1/2a/3 ratio 1.2:1:5. [b] Isolated
product yield. [c] The d.r. was determined by 1H NMR spectroscopic
analysis. [d] The ee value was determined by HPLC analysis. [e] Com-
pound 2b was used as a reaction component and the reaction time was
96 h.
[a] Reagents and conditions (0.1 mmol scale): solvent (1 mL), 3 ꢁ MS
(100 mg), 72 h, 1b/2a/3e ratio 1.2:1:5. [b] Isolated product yield and
a single diastereomer was observed unless indicated otherwise. [c] The ee
value was determined by HPLC analysis.
solvents revealed that chloroform or dichloromethane were
more suitable media for the reaction in terms of stereoselec-
tivity; use of these solvents led to higher enantiomeric ex-
cesses than those obtained in toluene, however, lower yields
were observed (Table 5, entries 2 and 3 vs. 1). The fine-
tuning of catalyst loading and reaction temperature revealed
that the presence of 25 mol% of catalyst 6 could give high
enantioselectivity and reasonable yield in chloroform at
room temperature (Table 5, entry 6). Although a slightly im-
proved yield was observed at elevated temperature, this was
at the expense of reduced enantioselectivity (Table 5,
entry 7). Finally, using a solvent mixture of chloroform and
toluene with 1:1 ratio allowed the reaction to proceed in
51% yield with an excellent enantioselectivity of 93% ee
(Table 5, entry 8).
3,2’-oxindole] 4bac was assigned as (2’S,3’R,4’R) by X-ray
crystallographic analysis (Figure 3).[14] The stereochemistry
of the other products were assigned by analogy. Moreover,
the 1,3-dipolar cycloaddition of methyl acrylate (3d) also
proceeded smoothly under similar reaction conditions to
Under the reoptimized reaction conditions, a variety of
isatins were examined in the 1,3-dipolar cycloaddition re-
Figure 3. X-ray structure of spiro[pyrrolidin-3,2’-oxindole] 4bac.
ACHTUNGTRENaNUGN ction with methyl 2-phenylacrylate (3e). The protocol
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Synthesis of Spiro[pyrrolidin-3,2’-oxindoles]
FULL PAPER
Table 6. The use of methyl 2-phenylacrylate (3e) as a 1,3-dipolarophile
for the synthesis of spiro[pyrrolidin-3,2’-oxindoles] with two contiguous
quaternary chiral centers.[a]
Entry
4
R/R1
Yield
[%][b]
d.r.[c]
ee
[%][d]
1
2
3
4
5
6
4bae
4rae
4uae
4vae
4wae
4rbe
Bn/H (1b)
Bn/7-Br (1r)
p-tBuC6H4CH2/6-Br (1u)
p-tBuC6H4CH2/7-Br (1v)
p-tBuC6H4CH2/7-CF3 (1w)
Bn/7-Br (1r)
51
52
53
51
57
41
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
93
93
97
Figure 4. X-ray structure of spiro[pyrrolidin-3,2’-oxindole] 4bae.
95
95
isatin-derived 1,3-dipolar cycloaddition reaction. The bis-
phosphoric acid (Bis-PA) is proposed to activate the dipolar-
ophile by forming two hydrogen bonds between its two hy-
droxyl groups and the two ester carbonyls of maleate and,
simultaneously, to activate the dipole by another hydrogen
95[e]
[a] Reagents and conditions (carried out with 2a in 0.1 mmol scale): tolu-
ene/CHCl3 (1:1 v/v, 1 mL), 3 ꢁ MS (100 mg), 72 h, 1/2a/3e ratio 1.2:1:5.
[b] Isolated product yield. [c] The d.r. was determined by 1H NMR spec-
troscopic analysis. [d] The ee value was determined by HPLC analysis.
[e] Compound 2b was used as a reaction component and the reaction
time was 96 h.
À
bond between its P=O and the N H of the azomethine
ylide, as illustrated in Model-BiAct. The other way to accel-
erate this cycloaddition is described as Model-MoAct, in
which only one hydrogen bond between the catalyst and the
dipolarophile was formed, making the dipolarophile more
electronically deficient. Another hydrogen bond between
two phosphoric acids may shift the proton between the two
phosphate groups to adjust the acidity and basicity of the
two phosphoric acids to activate the dipole and dipolaro-
phile more effectively. The dipole of isatin azomethine ylide
showed high generality for isatin substrates, and provided
spiro[pyrrolidin-3,2’-oxindole] derivatives possessing two
contiguous quaternary chiral centers in good yields and with
excellent stereoselectivities ranging from 93 to 97% ee and
more than 99:1 d.r. in all cases (Table 6).
The absolute configuration of spiro[pyrrolidin-3,2’-oxin-
dole] 4bae was unambiguously
determined to be (2’R,3’S) by
X-ray analysis on a single crys-
tal, which was obtained in more
than 99% ee after recrystalliza-
tion (Figure 4).[14] The configu-
rations of other spiro[pyrroli-
din-3,2’-oxindole]
derivatives
generated from acrylates were
assigned by analogy.
To understand the observed
stereochemistry, theoretical cal-
culations were performed on
the transition state (TS) of this
isatin-derived 1,3-dipolar cyclo-
addition by using the hybrid
density
functional
theory
(DFT) method[15] combined
with the 6-31G(d) basis set,[16]
as implemented in the Gaussi-
an03 program.[17] Based on our
theoretical studies on enantio-
selective 1,3-dipolar cycloaddi-
tions between electron-deficient
olefins and azomethine ylide di-
poles,[13d] TS models were pro-
posed as shown in Scheme 2 for
this catalytic enantioselective Scheme 2. Proposed transition state models for the 1,3-dipolar cycloaddition reaction.
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L.-Z. Gong, S.-W. Luo et al.
may take two orientations, one is the C=O of isatin cis to
À
the N H and the second is trans, as shown as Up or Down
in the present models, respectively. To save computational
resources, the naphthyl moieties in the catalyst were re-
placed with phenyl groups and the ethyl esters in the sub-
À
strate with methyl esters. Furthermore, N Me was used to
À
replace all N R groups (Scheme 2).
The located TS structures for the catalytic cycloaddition
between maleate and isatin-derived azomethine ylide are
shown in Figure 5. The calculated results indicated that the
dipole of isatin-derived azomethine ylide, the key intermedi-
ate, should take an orientation with the C=O of isatin trans
À
to the N H (Model-Down). In all cases, the TSs with the
Up orientation of C=O of isatin was predicted to be less
stable than those with C=O Down by about 10 kcalmolÀ1,
probably due to electronic repulsion between the oxygen
atoms on C=O and P=O. The repulsive interaction between
the C=O and phosphoric oxygen atom may contribute to
the clear destabilization in TSs with the Up orientation of
C=O.
The located TS structure Model-BiAct-Down-1 represents
the most stable TS located, which corresponds to the main
product 4aaa observed experimentally. Model-BiAct-Down-
2, corresponding to the enantiomer of the main product,
was predicted to be less stable than Model-BiAct-Down-
1 by about 4 kcalmolÀ1. This difference between these two
TSs may come from the distinct interaction between the
phosphate and the ester group of the dipole. The basic
oxygen atom of the ester was slightly removed from the
oxygen atom of the phosphate and closer to the positively
charged phosphorus atom in Model-BiAct-Down-1, result-
ing in a favorable ion pair. In contrast, in Model-BiAct-
Down-2, the basic oxygen atom of the ester was close to the
oxygen atom of the phosphate and far from the positively
charged phosphorus atom, resulting in an electronically re-
pulsive interaction. This distinguished ion pair interaction
may lead to the high stereoselectivity observed. The Model-
MoAct-Down with the single hydrogen-bond activation
model was predicted to be less favored by about 6 kcal
molÀ1.
À
The hydrogen bond distance between the P=O and H N
is predicted to be 5.68 ꢁ in Model-MoAct-Down-1, which
corresponds to the main product 4aaa. The hydrogen bond
between the two phosphoric acids may make the framework
of the catalyst too compact to allow access to the relatively
bulky substrates, including both maleates and isatin-derived
azomethine ylides. In contrast, the electron-rich carbon of
the 1,3-dipole attacking the a-carbon of activated maleate,
as in Model-MoAct-Down-2, corresponding to the enantio-
mer of main product, was also predicted to be less favored
by approximately 6 kcalmolÀ1, due to the mismatched polar-
ity and repulsive interaction between the two ester groups
of maleate and the dipole. Most likely, the two hydrogen-
bond activation model of Model-BiAct-Down has a more
flexible framework that enables its active site to open for
Figure 5. B3LYP/6-31G* optimized transition state structures of the 1,3-
dipole cycloaddition reaction of maleate with isatin-derived azomethine
ylide and partial crucial bond length parameters (ꢁ). The relative ener-
gies in enthalpy (first value) and Gibbs free energy (second value) are
shown in parentheses.
bulky substrates, such as ma
thine ylides.
ACHTUNGTRNElNUNG eates and isatin-derived azome-
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Synthesis of Spiro[pyrrolidin-3,2’-oxindoles]
FULL PAPER
For the 1,3-dipolar cycloaddition with acrylate or fuma-
rate as dipolarophile, the TSs should principally adopt
Model-MoAct rather than Model-BiAct as shown in
Scheme 2, because only one hydrogen bond between the
ester group of dipolarophile and the phosphoric acid group
of catalyst is formed. The located TS structures are shown in
Figure 6. Similar to the case with maleate, the TSs with the
Up orientation of the C=O of isatin was predicted to be less
stable than that with C=O Down. However, the difference
between the two orientations of Up and Down was predict-
ed to be smaller than that in maleate, because the repulsive
interaction between the ester group of the dipolarophile and
the dipole was reduced both in acrylate, with only one ester
group, and fumarate, with the ester group trans to the C=O
of the isatin. The most stable TS located for acrylate was
Model-MoAct-DownA-1 and for fumarate the Model-
MoAct-DownF-1 turned out to be most stable, both of
which correspond to the main products observed experimen-
tally. In both MoAct-DownA-1 and Model-MoAct-DownF-
1, nucleophilic attack of the electron-rich carbon of the 1,3-
dipole to the b-carbon of the activated ester group clearly
against the colon carcinoma cell line SW116.[18] The prelimi-
nary bioassay revealed compounds 4raa, 4uac, and 4taa to
À
occurs early with a C C distance of approximately 2.1 ꢁ,
À
compared to the other forming C C bond distance of ap-
proximately 2.7 and 2.6 ꢁ for acrylate and fumarate, respec-
tively. An alternative way to perform the 1,3-dipolar addi-
tion was for the electron-rich carbon of the 1,3-dipole to
attack the a-carbon of the activated ester group, as shown in
TS MoAct-DownA-2 and Model-MoAct-DownF-2, with
À
a forming C C bond distance of 2.1–2.4 ꢁ; these were eval-
uated to be less stable than MoAct-DownA-1 by approxi-
mately 5 kcalmolÀ1 and then Model-MoAct-DownF-1 by ap-
proximately 2 kcalmolÀ1 in Gibbs free energy, respectively.
The mismatched polarity should contribute to this higher ac-
tivation barrier and, because the fumarate seems less mis-
matched, this results in less difference. The calculated TS
structures indicated that this 1,3-dipolar cycloaddition pro-
cess may still proceed through a concerted pathway, but
À
with one C C bond formed earlier than the second in the
TS to afford the cycloadducts. These TS structures were
quite similar to those of other related 1,3-dipolar cycloaddi-
tion reactions.[13d] Whereas 2-phenylacrylate was used as the
dipolarophile, similar computed results were obtained to
those involving acrylate. The located TS structures are
shown in Figure 7.
The theoretical studies on the TS models implied that the
bisphosphoric acid catalysts with a flexible linkage between
the two acid groups make it much easier to recruit bulky
substrates and act as a bifunctional catalyst. The dipole and
dipolarophile were simultaneously activated by the bisphos-
phoric acid in this 1,3-dipolar cycloaddition. The differing
ion pair interactions between the catalyst and substrates,
and either matched or mismatched nucleophilic attack be-
tween the activated dipole and dipolarophile resulted in the
high stereoselectivity.
Figure 6. B3LYP/6-31G* optimized transition state structures of isatin-de-
rived azomethine ylide with acrylate or fumarate; partial crucial bond
length parameters (ꢁ). The relative energies in enthalpy (first value and
Gibbs free energy (second value) are shown in parentheses.
Finally, to identify the bioactivity of these new com-
pounds, a number of spiro[pyrrolidin-3, 2’-oxindole] deriva-
tives 4 were selected for in vitro testing of their cytotoxicity
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L.-Z. Gong, S.-W. Luo et al.
that the dipole and dipolarophile were simultaneously acti-
vated by the bisphosphoric acid in this 1,3-dipolar cycloaddi-
tion. The molecular modeling computations on the TS struc-
tures suggest that the C=O of isatin should adopt an orienta-
À
tion trans to the H N in the 1,3-dipole to reduce the repul-
sive interaction between the C=O and phosphoric oxygen
atom in the TS. For maleate, the two hydrogen-bond-activa-
tion model of Model-BiAct-Down with a more flexible
framework is better than the single hydrogen-bond model of
Model-MoAct-Down because it allows its active site to open
up enough to recruit relatively bulky substrates such as mal-
eates and isatin-derived azomethine ylides. However, when
fumarate, acrylate, or 2-phenylacrylate is the dipolarophile,
the TSs should principally take the single hydrogen-bond
model of Model-MoAct rather than the two hydrogen-bond
model of Model-BiAct. The ion pair interaction between
the catalyst and substrates, and either matched or mis-
matched nucleophilic attack between the activated dipole
and dipolarophile contributed to the high stereoselectivity
of this 1,3-dipolar cycloaddition reaction.
Experimental Section
Typical experimental procedure for the catalytic asymmetric synthesis of
spiro[pyrrolidin-3,2’-oxindole] 4aaa: A solution of isatin 1a (0.12 mmol),
amino-ester 2a (0.1 mmol), catalyst 6 (0.015 mmol), and 3 ꢁ molecular
sieves (100 mg) in toluene (0.5 mL) was stirred for 15 min. Dipolarophile
3a (0.5 mmol) and toluene (0.5 mL) were then added sequentially. After
stirring at RT for 36 h, the reaction mixture was filtered to remove mo-
lecular sieves and the solid powder was washed with ethyl acetate. The
resulting solution was concentrated under reduced pressure to give a resi-
due, which was purified by flash column chromatography on silica gel to
afford pure product 4aaa.
Figure 7. B3LYP/6-31G* optimized transition state structures of isatin-de-
rived azomethine ylide with 2-phenylacrylate; partial crucial bond length
parameters (ꢁ). The relative energies in enthalpy (first value) and Gibbs
free energy (second value) are shown in parentheses.
(2’S,3’R,4’S)-5’,5’-Diethyl 3’,4’-dimethyl 1-methyl-2-oxospiro[indoline-3,2’-
pyrrolidine]-3’,4’,5’,5’-tetracarboxylate (4aaa): Purified by flash column
chromatography (petroleum ether/ethyl acetate=6:1 then 5:1); reaction
have moderate cytotoxicity to SW116 cells, with an inhibi-
tion rate of 28.4, 27.6, and 23.6%, respectively, at a concen-
tration of 50 mgmLÀ1. The results suggest that the spiro[pyr-
rolidin-3,2’-oxindole] derivatives 4 may have potential in
medicinal applications if these compounds are subjected to
molecular modulation and further biological studies.
time=36 h; yield: 77%; >99:1 d.r.; white solid; m.p. 111–1138C; [a]D20
=
À42.4 (c 0.71, CHCl3); ee: 93% determined by HPLC (Daicel Chirapak
OD-H; hexane/isopropanol=80:20; flow rate 1.0 mLminÀ1; T=308C;
254 nm): tR =11.306 (major), 13.123 min (minor); 1H NMR (CDCl3,
400 MHz): d=7.61 (d, J=7.6 Hz, 1H; ArH), 7.33–7.27 (m, 1H; ArH),
7.07–7.00 (m, 1H; ArH), 6.77 (d, J=7.8 Hz, 1H; ArH), 4.66 (d, J=
7.9 Hz, 1H; CH), 4.42–4.24 (m, 4H; 2 ꢂCH2), 3.96–3.90 (m, 2H; CH and
NH), 3.79 (s, 3H; CH3), 3.23 (s, 3H; CH3), 3.16 (s, 3H; CH3), 1.31 (t, J=
7.1 Hz, 3H; CH3), 1.28 ppm (t, J=7.1 Hz, 3H; CH3); 13C NMR (CDCl3,
100 MHz): d=178.1, 171.5, 169.3, 168.5, 167.9, 144.2, 130.1, 127.2, 125.6,
123.1, 107.8, 76.3, 69.5, 62.8, 62.6, 54.8, 52.2, 51.7, 51.1, 26.4, 14.0 ppm; IR
(KBr): n˜ =3346, 2986, 2952, 1740, 1612, 1473, 1436, 1369, 1217, 1026,
756 cmÀ1; FTMS (ESI): m/z calcd. for C22H26N2O9 +H+: 463.1711 [M+
H]; found: 463.1711.
Conclusion
We have established a catalytic, enantioselective route to
the biologically important spiro[pyrrolidin-3,2’-oxindole]
scaffold with multiple contiguous stereogenic centers includ-
ing one or two quaternary chiral centers in excellent stereo-
selectivities (up to >99:1 d.r. and 98% ee). Importantly, this
transformation represents the first example of a catalytic,
asymmetric 1,3-dipolar cycloaddition reaction involving azo-
methine ylides generated in situ from unsymmetrical cyclic
ketones, and provides an unprecedented platform for the
preparation of spiro-architectures with concomitant creation
of multiple stereogenic centers. The theoretical calculations
performed on the transition states of the reaction revealed
Typical experimental procedure for the catalytic asymmetric synthesis of
spiro[pyrrolidin-3,2’-oxindole] 4bae with two contiguous quaternary
chiral centers: A solution of isatin 1b (0.12 mmol), amino ester 2a
(0.1 mmol), catalyst 6 (0.025 mmol), and 3 ꢁ molecular sieves (100 mg)
in a solvent mixture of toluene and CHCl3 (1:1 v/v, 0.5 mL) was stirred
for 15 min. The dipolarophile 3e (0.5 mmol) and further solvent mixture
of toluene and CHCl3 (1:1 v/v, 0.5 mL) were added sequentially. After
stirring at RT for 72 h, the reaction mixture was filtered to remove mo-
lecular sieves and the solid powder was washed with ethyl acetate. The
resulting solution was concentrated under reduced pressure to give a resi-
due, which was purified by flash column chromatography on silica gel to
afford pure product 4bae.
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Synthesis of Spiro[pyrrolidin-3,2’-oxindoles]
FULL PAPER
A
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3,2’-pyrrolidine]-3’,5’,5’-tricarboxylate (4bae): Purified by flash column
chromatography (petroleum ether/ethyl acetate=6:1 then 5:1); reaction
time=72 h; yield: 51%; >99:1 d.r.; white solid; m.p. 134–1358C; [a]D20
2.4 (c 0.572, CHCl3); ee: 93% determined by HPLC (Daicel Chirapak
OD-H; hexane/isopropanol=90:10; flow rate 1.0 mLminÀ1; T=308C;
254 nm): tR =9.391 (minor), 11.311 min (major); 1H NMR (CDCl3,
400 MHz): d=7.39 (dd, J1 =7.6 Hz, J2 =0.9 Hz, 1H; ArH), 7.27 (dd, J1 =
7.8 Hz, J2 =1.2 Hz, 1H; ArH), 7.22–7.14 (m, 4H; ArH), 7.10–7.04 (m,
3H; ArH), 7.01–6.95 (m, 2H; ArH), 6.87–6.79 (m, 2H; ArH), 6.68 (d,
J=7.7 Hz, 1H; ArH), 4.86 (d, J=15.5 Hz, 1H; CH), 4.40–4.33 (m, 3H;
CH and CH2), 4.33–4.27 (m, 2H; CH2), 4.20 (d, J=15.5 Hz, 1H; CH),
3.95 (s, 1H; NH), 3.61 (s, 3H; CH3), 3.51 (d, J=13.7 Hz, 1H; CH), 1.36
(t, J=7.1 Hz, 3H; CH3), 1.29 ppm (t, J=7.1 Hz, 3H; CH3); 13C NMR
(CDCl3, 100 MHz): d=175.9, 172.8, 170.8, 170.4, 144.4, 130.3, 128.5,
128.2, 127.7, 127.6, 127.5, 127.4, 125.7, 122.6, 109.3, 74.3, 71.9, 62.7, 62.5,
62.4, 52.4, 44.0, 40.2, 14.2, 14.1 ppm; IR (KBr): n˜ =3546, 3336, 2982, 2926,
1736, 1610, 1467, 1364, 1268, 1232, 1097, 755, 699 cmÀ1; FTMS (ESI): m/z
calcd for C32H32N2O7 +H+: 557.2282 [M+H]; found: 557.2282.
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[14] CCDC-845939 (4aaa), CCDC-848672 (4bac), and CCDC-845940
(4bae) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_-
request/cif. See the Supporting Information for details.
[15] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652..
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We are grateful for financial support from MOST (973 project
2009CB82530), Ministry of Education and NSFC (20732006, 21002083,
21072181).
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L.-Z. Gong, S.-W. Luo et al.
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[18] Details of the procedure used to bioscreen 4 is provided in the Sup-
porting Information.
Received: February 2, 2012
Published online: && &&, 2012
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Synthesis of Spiro[pyrrolidin-3,2’-oxindoles]
FULL PAPER
Asymmetric Synthesis
F. Shi, Z.-L. Tao, S.-W. Luo,* S.-J. Tu,
L.-Z. Gong* .................. &&&& — &&&&
Scaffold-Inspired Enantioselective
Synthesis of Biologically Important
Spiro[pyrrolidin-3,2’-oxindoles] with
Structural Diversity through Catalytic
Isatin-Derived 1,3-Dipolar Cycloaddi-
tions
The organocatalytic approach: The
first catalytic asymmetric construction
of a spiro[pyrrolidin-3,2’-oxindole]
scaffold with contiguous quaternary
stereogenic centers in excellent stereo-
selectivities has been established (see
scheme). This protocol represents the
first example of catalytic asymmetric
1,3-dipolar cycloadditions involving
azomethine ylides generated in situ
from unsymmetrical cyclic ketones.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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