Asymmetric cross aldol addition of isatins with α,β-unsaturated ketones catalyzed by a bifunctional Br?nsted acid-Br?nsted base organocatalyst

Article abstract of DOI:10.1016/j.tet.2012.03.042

The asymmetric cross-aldol reaction of isatins with α,β- unsaturated ketones has been developed under catalysis by a Cinchona alkaloid-derivated bifunctional Br?nsted acid-Br?nsted base catalyst, affording the aldol adducts in moderate to good yields (18-98%) with moderate to good enantioselectivities (30-97%). The noncovalent organo-catalyzed asymmetric cross-aldol reaction displays a broad substrate scope and wide functional-group tolerability, albeit the electronic and steric properties of both reaction partners have considerable and regular effects on the reactivity and stereocontrol.

Full text of DOI:10.1016/j.tet.2012.03.042

Tetrahedron 68 (2012) 3843e3850
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Asymmetric cross aldol addition of isatins with a,b-unsaturated ketones catalyzed
by a bifunctional Brønsted acideBrønsted base organocatalyst
Guo-Gui Liu a, Hua Zhao b, Yu-Bao Lan b, Bin Wu a, Xiao-Fei Huang a, Jian Chen a, Jing-Chao Tao b,
,
Xing-Wang Wang a
*
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
b Department of Chemistry, Zhengzhou University, Zhengzhou 450001, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The asymmetric cross-aldol reaction of isatins with a,b-unsaturated ketones has been developed under
Received 23 December 2011
Received in revised form 6 March 2012
Accepted 13 March 2012
catalysis by a Cinchona alkaloid-derivated bifunctional Brønsted acideBrønsted base catalyst, affording
the aldol adducts in moderate to good yields (18e98%) with moderate to good enantioselectivities
(30e97%). The noncovalent organo-catalyzed asymmetric cross-aldol reaction displays a broad substrate
scope and wide functional-group tolerability, albeit the electronic and steric properties of both reaction
partners have considerable and regular effects on the reactivity and stereocontrol.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 17 March 2012
Keywords:
3-Hydroxyindolin-2-one
Benzylideneacetone
Thiourea
Cross aldol
1. Introduction
of the oxindole greatly affects the biological and pharmacological
activities of those compounds.3a
The asymmetric intermolecular cross-aldol reactions between
aldehydes and aldehydes or aldehydes and ketones have been
proved important access to carbonecarbon formation, which has
been extensively explored for construction of chiral
b-hydroxy al-
dehydes or
b
-hydroxy ketones in organically synthetic chemistry.1
In contrast, enantioselective intermolecular cross-aldol reaction
between ketones, which produces 3-substituted-3-hydroxy ke-
tones with quaternary stereogenic centres, is much more deman-
ded and challenged.2
The 3-hydroxyindolin-2-one structural cores with quaternary
stereogenic centres are widely existed in natural products, phar-
maceuticals, agrochemicals, indole alkaloids and synthetic indole
derivatives.3 Moreover, these natural products containing 3-
hydroxyindolin-2-one cores display invaluable biological and
pharmacological activity,4 such as convolutamydines AeE,5a
donaxaridine,5b dioxibrassinine,5c maremycins AeD,5d diazo-
namide A,5e leptosin D,5f spiro-isoxazolidynyl oxindole,5g witin-
dolinone C,5h madindoline A and B,5i,j and CPC-1,5k and efavirenz
mimics5l (selected structures see Scheme 1). In addition, recent
structureeactivity relationship studies have shown that the qua-
ternary configuration of the C3 hydroxyl group and the substituent
Scheme 1. Selected 3-hydroxyindolin-2-one structures in natural products.
As convolutamydine A shows the potent inhibitory activity to-
wards the differentiation of HL-60 human promyelocytic leukaemia
cells, the construction of stereocontrolled tetrasubstituted 3-
hydroxyindolin-2-one motifs has attracted great interests of the
chemists.6 Particularly, the methods for enantioselective synthesis
* Corresponding author. Tel./fax: þ86 512 65880378; e-mail address: wangxw@
suda.edu.cn (X.-W. Wang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.042

3844
G.-G. Liu et al. / Tetrahedron 68 (2012) 3843e3850
of convolutamydine became very prevalent in the presence of
organocatalyst. In 2006, Tomasini7 and co-workers pioneerly
reported the cross-aldol reaction of isatins with acetone by using
dipeptide organocatalyst derived from D-proline and L-b-homo-
phenylgricine. Xiao,8 Malkov, Bella and Kocovsky, Nakamura and
Toru10 independently reported enantioselective cross-aldol re-
action of isatins with acetone catalyzed by primary or secondary
amine catalysts. Recently, Zhao disclosed that quinidine thiourea as
a new noncovalent catalyst could efficiently catalyzed the cross-
aldol reaction of isatins with unactivated ketones in THF at ꢀ5 ꢁC
for 3e6 days, which provided the 3-alkyl-3-hydroxyindolin-2-ones
in high yields with high enantioselectivities.11 Although the enan-
tioselective cross-aldol reaction between isatins and ketones has
been extensively studied, few examples of the corresponding aldol
ꢀ
ꢁ 9
reactions of various
found in the literature.
The aldol addition of
aryl-3-hydroxyindolin-3-one with an additional enone moiety, to
provide a chance for further elaboration of the products (Scheme
a
,
b
-unsaturated ketones with isatins were
a,b
-unsaturated ketone to isatin leads to 3-
Scheme 3. Catalysts screened for the cross-aldol reaction of isatins with
saturated ketones.
a
,
b-un-
2). In addition, the obvious difficulty in using
tones as a nucleophile is arising from the inherent multiple re-
activity that involve ketone, -carbon (electrophilic sites) and
a,b-unsaturated ke-
Table 1
b
Catalyst screening and reaction conditions optimizationa
active methylene unit (nucleophilic site). In order to selectively
achieve targeted cross aldol-type reaction chemoselective activa-
tion of the carbonyl in isatin should be a key point. In virtue of
limited examples reported by Zhao, herein, we investigate the
O
Ph
O
Ph
or
HO
O
HO
O
cat.(20 mol%)
rt, 24-120 h
O
O
+
O
Ph
N
N
N
H
H
H
asymmetric cross-aldol reaction between a,b-unsaturated ketones
3a'
3a
1a
2a
and isatins in the presence of thiourea-modified Cinchona alkaloids
as bifunctional Brønsted acideBrønsted base catalysts, which pro-
vides enantiomerically enriched 3-hydroxy-3-(2-oxo-4-arylbut-3-
en-1-yl) indolin-2-ones in moderate to high yields (up to 98%)
and moderate to good enantioselectivities (up to 97% ee). Both
enantiomers of the 3-hydroxyindolin-3-one adducts can be pre-
pared by using two epimers of the quinidine-derived thiourea
catalysts. An investigation of the electronic and steric effect on the
stereochemical outcome is also detailed.
Entry Cat.
Solv.
Ratio (1a/2a) Time (h) Yieldb (%) eec (%)
1d
2d
3d
4d
5d
6
I
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Toluene
DCM
Et2O
n-Hexane
EtOH
Dioxane
1:1
1:1
1:1
1:1
1:1
1:2
1:2
1:1
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
24
24
120
48
24
24
48
48
48
48
48
48
48
48
48
48
NR
NR
Trace
70
46
51
82
75
78
34
52
58
56
35
68
69
d
IþTFA
d
II
d
III
IV
IV
IV
V
63
75
79
80
60
71
31
33
47
38
45
47
76
7
8d
9
V
10
11
12
13
14
15
16
VI
IV
IV
IV
IV
IV
IV
a
Unless otherwise indicated, all reactions were carried out with isatin 1a
(0.10 mmol), benzylideneacetone 2a (0.20 mmol) and the catalyst (0.04 mmol,
20 mol %) in the specified solvent (1.0 mL) at room temperature.
b
Yield of the isolated product after column chromatography.
Determined by HPLC analysis. Absolute configuration of IV for R enantiomer and
c
V for S enantiomer were determined according to the literature reported.11,14
d
Carried out with isatin 1a (0.20 mmol) and 2a (0.20 mmol).
Scheme 2. Further elaboration of 3-hydroxy-3-(2-oxo-4-arylbut-3-enyl)indolin-2-one
product.
catalyst unilaterally activates the benzylideneacetone 2a to form an
enamine intermediate. Then, we turned our attention to other
chiral Brønsted acideBrønsted base bifunctional catalysts. The
Cinchona alkaloid derived bifunctional catalyst II was found to be
ineffective for the reaction, affording essentially only trace amount
of the desired products after prolonged reaction times (5 days,
entry 3). Pleasingly, the reaction proceeded smoothly in the pres-
ence of 20 mol % Takemoto thiourea catalyst III to afford the desired
aldol product 3a in 70% yield with 63% ee after 48 h (entry 4).13
Subsequently, the quinidine-derived thiourea catalyst IV and its
pseudo-enantiomer V were investigated for this transformation,
which furnished the desired product with improvement in both
yields and enantioselectivities (IV: 82% yield and 80% ee; V: 78%
yield and 71% ee, respectively) after 48 h of reaction time, while the
reactant’s molar ratio of 1a/2a¼1:2 was employed (entry 7 vs
Initially, several common organocatalysts (Scheme 3) bearing
a quinuclidine and/or a thiourea moiety,12 were examined for the
catalysis of the cross-aldol reaction of isatin 1a as an acceptor and
(E)-4-phenylbut-3-en-2-one 2a as a donor with a catalyst loading
of 20 mol % in THF at ambient temperature. The results of the
screening and optimizations are shown in Table 1. At the beginning,
we examined the reaction substrates of isatin 1a with the benzy-
lideneacetone 2a with the molar ratio of 1:1 in the presence of
20 mol % of quinidine-derived primary amine or combination with
40 mol % of trifluoro acetic acid (TFA) as Brønsted acid additives. No
expected cross aldol adducts were observed after direct de-
termination by TLC (entries 1 and 2). This indicated that it is im-
possible for the cross-aldol reaction in which the primary amine

G.-G. Liu et al. / Tetrahedron 68 (2012) 3843e3850
3845
entries 5 and 6; entry 9 vs entry 8). Furthermore, the C60eOH
Cinchona alkaloid derivative bearing a C9eOBn group VI was also
tested for this reaction, which gave the inferior results in terms of
both reactivity and enantioselectivity (entry 10). Furthermore,
several common solvents were screened for this reaction in the
presence of 20 mol % of quinidine-derived thiourea catalysts IV. The
results demonstrated that THF was still the optimal reaction media
for this transformation (entry 7 vs entries 11e16). Finally, Cinchona
alkaloid derived thioureas IV and V were proved to be effective
catalysts for this reaction, which suggest that basic quinuclidine
backbone and acidic thiourea motif co-activate both benzylide-
neacetone 2a and isatin 1a in this transformation.
2a gave the desired products 3dej and 3d0ej0 with varying levels of
yields (18e93%) and moderate to high enantiomeric ratios (30e81%
ees) (entries 7e20). In addition, the N-Me and N-Bnprotected isatins
1k and 1l were also tested under otherwise identical conditions, and
the N-Bn protected isatins 1l displayed better reactivities and
enantioselectivities than those of 1k in this aldol transformation
(entries 23 and 24 vs entries 21 and 22). On the other hand, com-
pared the catalytic results of 3a0el0 with that of 3ael, it is evident
that the quinidine derived thiourea IV generally was a more effec-
tive catalyst than its pseudo-enantiomer V, thought 4-Br and 4-Cl
substituted isatins 1b or 1c furnished the expected aldol adducts
with slight better enantioselectivities under the catalysis by V (93%
ee and 86% ee vs 88% ee and 83% ee).
Having found the obvious regulation that the cross-aldol re-
actions of 4-Br and 4-Cl substituted isatins 1b or 1c with the ben-
zylideneacetone 2a showed distinctly better reactivities and
enantioselectivities than those of the other position substituted
isatin derivatives, we further investigated the cross-aldol reaction of
4-chloroisatin 1c with various of a,b-unsaturated ketones 2beo in
the presence of 20 mol % of Cinchona alkaloid derived thiourea cat-
alysts IV and V in THF at room temperature. As shown in Table 3, all
With the optimized reaction conditions established, the gener-
ality and limitation of the protocol was investigated for the asym-
metric cross-aldol reaction of isatin derivatives 1ael and
a,b-
unsaturated ketone 2a, which catalyzed by 20 mol % of Cinchona
alkaloid derived thiourea catalysts IV and V in THF at room tem-
perature, respectively. The representative results are summarized in
Table 2. Generally, these results indicated that the electronic prop-
erty and steric hindrance have a great effect on the reactivity and
enantioselectivity of the cross-aldol reaction. Gratefully, when
substituents (eBr, eCl) on 4-position of isatin backbones 1b or 1c
were employed for the aldol reactions catalyzed by IV and V, re-
spectively, which progressed very well and provided the desired
products in increased yields (80e94%) with improved enantiose-
lectivities (83e93% ees) relative to those of the other isatin de-
the aldol reactions between a,b-unsaturated ketones 2beo and 4-
chloroisatin 1c proceeded smoothly, affording the corresponding
aldol adducts 3aaenn and 3aa0enn0 in good to excellent yields
(85e98% yields) with good to excellent enantiomeric excesses
(70e97% ees). For the benzylideneacetone derivatives 2bel, the
electron-donating groups (eOMe, eMe, eiPr) and the electron-
withdrawing groups (eCl, eF, eBr, eCF3) on different position of
the phenyl ring demonstrated great effect on enantioselectivities
rivatives (entries 3e6 vs entries
1 and 2, 7e24). To our
disappointment, for the substrates 1dej bearing different sub-
stituents (eF, eCl, eBr, eCF3, eMe) on 5-, 6- and 7-positions of isatin
backbones, the cross-aldol reactions with the benzylideneacetone
Table 3
Cross-aldol reaction of isatin derivative 1c and a,b
-unsaturated ketones 2beoa
O
Ar
O
Ar
Cl
O
Table 2
Cl
Cl
HO
HO
O
cat. IV or V
(20 mol%)
Cross-aldol reaction of isatins 1ael and
a
,b
-unsaturated ketone 2aa
O
or
O
O
+
Ar
N
H
O
Ph
THF, rt, 48h
O
Ph
N
N
H
3aa-nn
H
3aa'-nn'
HO
O
HO
O
1c
2a-n
cat. IV or V
(20 mol%)
R
O
R
O
R
O
Ph
or
+
N
R
N
R
THF, rt, 48h
N
R
Entry
Cat.
Sub. (Ar)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
o-MeOC6H4 (2b)
o-MeOC6H4 (2b)
o-FC6H4 (2c)
3aa/92
3aa0/94
3bb/98
3bb0/96
3cc/90
3cc0/92
3dd/98
3dd0/96
3ee/87
3ee0/85
3ff/90
þ87
ꢀ83
þ82
ꢀ86
þ76
ꢀ73
þ81
ꢀ74
þ85
ꢀ87
þ89
ꢀ85
þ88
ꢀ79
þ83
ꢀ70
þ86
ꢀ83
þ85
ꢀ94
þ63
ꢀ71
þ85
ꢀ87
þ93
ꢀ92
þ91
ꢀ97
1a-l
2a
3a-l
3a'-l'
Entry
Cat.
Sub. (R1, R2)
Yieldb (%)
eec (%)
o-FC6H4 (2c)
1
2
3
4
5
6
7
8
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
IV
V
R1¼H, R2¼H (1a)
3a/82
3a0/78
3b/94
3b0/88
3c/88
3c0/80
3d/93
3d0/72
3e/89
3e0/74
3f/89
þ80
ꢀ71
þ88
ꢀ93
þ83
ꢀ86
þ77
ꢀ75
þ79
ꢀ55
þ81
ꢀ63
þ63
ꢀ59
þ75
ꢀ53
þ76
ꢀ30
þ73
ꢀ75
þ62
ꢀ47
þ72
ꢀ67
o-ClC6H4 (2d)
o-ClC6H4 (2d)
m-ClC6H4 (2e)
m-ClC6H4 (2e)
p-MeOC6H4 (2f)
p-MeOC6H4 (2f)
p-iPrC6H4 (2g)
p-iPrC6H4 (2g)
p-MeC6H4 (2h)
p-MeC6H4 (2h)
p-FC6H4 (2i)
R1¼H, R2¼H (1a)
R1¼4-Br, R2¼H (1b)
R1¼4-Br, R2¼H (1b)
R1¼4-Cl, R2¼H (1c)
R1¼4-Cl, R2¼H (1c)
R1¼5-Cl, R2¼H (1d)
R1¼5-Cl, R2¼H (1d)
R1¼5-F, R2¼H (1e)
R1¼5-F, R2¼H (1e)
R1¼5-Br, R2¼H (1f)
R1¼5-Br, R2¼H (1f)
R1¼5-Me, R2¼H (1g)
R1¼5-Me, R2¼H (1g)
R1¼6-Br, R2¼H (1h)
R1¼6-Br, R2¼H (1h)
R1¼7-CF3, R2¼H (1i)
R1¼7-CF3, R2¼H (1i)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
3ff0/87
3gg/94
3gg0/97
3hh/97
3hh0/98
3ii/92
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
3f0/77
3g/67
3g0/47
3h/90
3h0/68
3i/37
p-FC6H4 (2i)
p-ClC6H4 (2j)
p-ClC6H4 (2j)
p-BrC6H4 (2k)
p-BrC6H4 (2k)
p-CF3C6H4 (2l)
p-CF3C6H4 (2l)
2-Thienyl (2m)
2-Thienyl (2m)
2-Furyl (2n)
3ii0/94
3jj/93
3jj0/93
3kk/93
3kk0/92
3ll/95
3i0/18
3j/89
R1¼5,6-2F, R2¼H (1j)
R1¼5,6-2F, R2¼H (1j)
R1¼H, R2¼Me (1k)
R1¼H, R2¼Me (1k)
R1¼H, R2¼CH2Ph (1l)
R1¼H, R2¼CH2Ph (1l)
3j0/74
3k/32
3k0/34
3l/95
3ll0/96
3mm/98
3mm0/97
3nn/96
3nn0/95
2-Furyl (2n)
1-Naphthyl (2o)
1-Naphthyl (2o)
3l0/78
a
a
Unless otherwise indicated, all reactions were carried out with isatin 1aen
(0.10 mmol), benzylideneacetone 2a(0.2 mmol) and the catalyst (0.04 mmol,
Unless otherwise indicated, all reactions were carried out with isatin
-unsaturated ketones (0.2 mmol) and the catalyst (0.04 mmol,
(0.10 mmol),
a
,
b
20 mol %) in THF (1.0 mL) at room temperature for 48 h.
20 mol %) in THF (1.0 mL) at room temperature for 48 h.
b
b
Yield of the isolated product after column chromatography.
Yield of the isolated product after column chromatography.
c
c
Determined by HPLC analysis.
Determined by HPLC analysis.

3846
G.-G. Liu et al. / Tetrahedron 68 (2012) 3843e3850
(from 63% ee up to 94% ee), albeit with a slight variation in the re-
activity as evidenced by the yields of the corresponding aldol ad-
ducts 3aae3kk and 3aa0e3kk0 (87e98% yields) (entries 1e22).
q¼quartet, m¼multiplet), coupling constants (J) and assignment.
Data for 13C NMR are reported in terms of chemical shift (
, ppm).
d
Liquid chromatographyemass spectrometry (LCeMS) for all the
compounds were determined with ESI resource. High performance
liquid chromatography (HPLC) analysis was performed on an Agi-
lent Technologies 1200 Series instrument equipped with a quater-
nary pump, using a Daicel Chiralcel OD-H Column (250ꢂ4.6 mm)
and Daicel Chiralcel OJ-H Column (250ꢂ4.6 mm). UV absorption
was monitored at 210e280 nm. Optical rotations were measured
Intriguingly, we found that the
a,b-unsaturated ketones 2meo
bearing heteroaromatic or fused aromatic rings were more suitable
substrates for this catalytic aldol reaction in the presence of the
catalysts IV or V, furnishing the desired products 3llenn and
3ll0enn0 in 95e98% yields with 85e97% ees (entries 23e28). From
Tables 2 and 3, it could be observed that cinchona alkaloid derived
thiourea IV and its pseudo-enantiomer V gave apparently different
catalytic results for the cross-aldol reactions of either isatins 1ael
with the benzylideneacetone 2a or the benzylideneacetone de-
rivatives 2bel with 4-chloroisatin 1c (Table 2, entries 1e24 and
Table 3, entries 1e22). However, thiourea catalysts IV and V herein
almost did not show any catalytic difference for the cross-aldol re-
actions of 2meo with 1c in terms of both the reactivities and
enantioselectivities (Table 2, entries 23e28).
on an Autopol IV polarimeter, and [
a
]
values are reported in
D
10ꢀ1 dg cm2 ꢀ1; concentration (c) is reported in g/100 mL. Com-
g
mercial grade reagents and solvents were used without further
purification; otherwise, where necessary, they were purified as
recommended. Chiral organocatalyst was prepared according to
reported methods.
4.2. General procedure for the cross aldol addition
In the light of Zhao’s creative noncovalent catalysis mechanism
for the aldol reaction of unactivated ketones and activated carbonyl
compounds11 and the catalyst screening results discussed above in
Table 1, we envision that the (E)-4-arylbut-3-en-2-ones is depro-
tonated by the tertiary amine in the quinuclidine backbone to form
active enolates. The isatins could be activated and orientated
through hydrogen bonding between the isatin carbonyl groups and
In an ordinary vial equipped with a Teflon-coated stir bar,
thiourea IV or V (0.04 mmol, 11.89 mg, 20 mol %) was dissolved in
1.0 mL of THF. Then the corresponding isatins 1 (0.1 mmol,
1.0 equiv) was added, followed by the addition of a,b-unsaturated
ketones 2 (0.2 mmol, 2.0 equiv). The vial was capped with a rubber
stopper and the mixture was stirred at room temperature for the
time given in the tables. The crude mixture was then purified by
flash column chromatography silica gel, using hexane/ethylacetate
2:1 as the eluent. Solvent was removed in vacuo to give the desired
products.
the thiourea motifs. The co-activation of both a,b-unsaturated ke-
tones and isatins by the bifunctional Brønsted acideBrønsted base
catalyst is attributable to working for the cross-aldol reaction to the
corresponding aldol adducts. In addition, the catalytic results in
Tables 2 and 3 show that the steric hindrance at position 4 on
isatins plays a positive role for enantioface discrimination in tran-
sition state. This catalytic regulation has also been found and pro-
posed by Zhao group in their genius publication.11
4.3. Spectroscopic data for part of products
4.3.1. (R)-3-Hydroxy-3-((E)-2-oxo-4-phenylbut-3-enyl)indolin-2-
one (3a). White solid, 82% yield and 80% ee. 1H NMR (400 MHz,
2. Results and discussion
DMSO-d6)
d
¼10.27 (s, 1H), 7.67e7.64 (m, 2H), 7.54 (d, J¼16.3 Hz,
1H), 7.42e7.40 (m, 3H), 7.28 (d, J¼7.4 Hz, 1H), 7.16 (t, J¼7.7 Hz, 1H),
6.88 (t, J¼7.5 Hz, 1H), 6.80 (d, J¼7.7 Hz, 1H), 6.76 (d, J¼16.3 Hz, 1H),
6.09 (s, 1H), 3.67 (d, J¼16.4 Hz, 1H), 3.25 (d, J¼16.4 Hz, 1H). 13C NMR
See Scheme 3, Tables 1, 2 and 3.
3. Conclusions
(100 MHz, DMSO-d6)
d
¼201.60, 183.59, 147.99, 147.92, 139.58,
136.80, 135.88, 134.28, 133.78, 133.28, 131.66, 129.10, 126.51, 114.75,
In summary, we have developed the asymmetric cross-aldol
78.46, 53.01. ½a D25
þ67.0 (c 1.1, MeOH). The ee was determined by
ꢃ
reaction of isatins with
a
,b
-unsaturated ketones catalyzed by
HPLC analysis on a Daicel Chiralpak OJ-H column: hexane/i-PrOH
a Cinchona alkaloid-derivated bifunctional Brønsted acideBrønsted
base catalyst, to afford the aldol adducts in moderate to good yields
(18e98%) with moderate to good enantioselectivities (30e97%).
Both enantiomers of the 3-hydroxyindolin-3-one adducts can be
prepared by using two epimers of the quinidine-derived thiourea
catalysts. The noncovalent organo-catalyzed asymmetric trans-
formation displays a broad substrate scope and wide functional-
group tolerability, albeit the electronic and steric properties of
both reaction partners have a great and regular effect on the re-
activity and stereocontrol. Considering the resulting 3-
hydroxyindolin-2-ones with an additional enone moiety as useful
chiral building blocks for the synthetic utility, further investigations
of the enantioselective epoxidation or cyclization of the Aldol ad-
ducts are undergoing in our laboratory.
80:20 flow rate
1
ml/min,
l
¼210 nm: major enantiomer:
tR¼32.81 min; minor enantiomer: tR¼37.66 min. ESIeMS: m/z
[MþH]þ calcd for C18H16NO3: 294.1126; found: 293.1052.
4.3.2. (R)-4-Bromo-3-hydroxy-3-((E)-2-oxo-4-phenylbut-3-enyl)in-
dolin-2-one (3b). White solid, 94% yield and 88% ee. 1H NMR
(300 MHz, acetone-d6)
d
¼9.43 (s, 1H), 7.55e7.52 (m, 2H), 7.48 (d,
J¼16.3 Hz,1H), 7.30e7.28 (m, 3H), 7.02e6.97 (m, 1H), 6.93e6.90 (m,
1H), 6.77 (d, J¼7.5 Hz, 1H), 6.65 (d, J¼16.3 Hz,1H), 5.14 (d, J¼17.5 Hz,
1H), 4.14 (d, J¼17.1 Hz, 1H), 3.36 (d, J¼17.1 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6)
d¼196.88, 178.14, 145.91, 143.71, 134.81,
131.55, 131.33, 129.85, 129.62, 129.22, 126.45, 125.74, 118.99, 109.61,
75.14, 46.42. ½a D25
þ35.3 (c 1.3, MeOH). The ee was determined by
ꢃ
HPLC analysis on a Daicel Chiralpak OJ-H column: hexane/i-PrOH
75:25 flow rate
1
ml/min,
l
¼280 nm: major enantiomer:
4. Experimental section
4.1. General
tR¼23.22 min; minor enantiomer: tR¼14.95 min. ESIeMS: m/z
[MþH]þ calcd for C18H15BrNO3: 372.023; found: 372.024.
4.3.3. (R)-4-Chloro-3-hydroxy-3-((E)-2-oxo-4-phenylbut-3-enyl)in-
1H (400 MHz) and 13C (100 MHz) spectra were recorded in
dolin-2-one (3c). White solid, 88% yield and 83% ee. 1H NMR
DMSO-d6 on Varian Inova-400 NMR spectrometer. Chemical shifts
(300 MHz, acetone-d6)
d
¼9.37 (s, 1H), 7.52e7.44 (m, 3H), 7.29e7.23
(d
ppm) are relative to the resonance of the deuterated solvent as
the internal standard (DMSO-d6, 2.50 ppm for proton NMR,
39.51 ppm for carbon NMR). 1H NMR data are reported as follows:
chemical shift
ppm), multiplicity (s¼singlet, d¼doublet,
(m, 5H), 6.76e6.72 (m, 1H), 6.66 (d, J¼16.3 Hz, 1H), 5.24 (s, 1H), 3.62
d
(d, J¼17.0 Hz, 1H), 3.30 (d, J¼17.0 Hz, 1H). 13C NMR (100 MHz,
d
DMSO-d6)
d
¼196.97, 178.94, 145.66, 143.67, 134.84, 131.34, 130.48,
(d
,
129.61, 129.17, 128.18, 126.78, 122.69, 109.16, 99.88, 73.58, 48.06.

G.-G. Liu et al. / Tetrahedron 68 (2012) 3843e3850
3847
½
a 2D5
on a Daicel Chiralpak OD-H column: hexane/i-PrOH 75:25 flow rate
ꢃ
þ67.8 (c 1.2, MeOH). The ee was determined by HPLC analysis
J¼16.3 Hz, 1H), 7.42e7.40 (m, 2H), 7.24 (d, J¼7.8 Hz, 1H), 7.08 (dd,
J¼7.9 Hz, 1.7 Hz, 1H), 6.96 (d, J¼1.5 Hz, 1H), 6.76 (d, J¼16.3 Hz, 1H),
6.20 (s, 1H), 3.72 (d, J¼16.9 Hz, 1H), 3.31 (d, J¼16.9 Hz, 1H). 13C NMR
1 ml/min,
l
¼210 nm: major enantiomer: tR¼13.85 min; minor
enantiomer: tR¼11.03 min. ESIeMS: m/z [MþH]þ calcd for
(100 MHz, DMSO-d6)
d¼197.9,179.70,146.09,144.48,135.77,132.54,
C18H15ClNO3: 328.0735; found: 328.0742.
132.21, 130.53, 130.07, 127.69, 127.12, 125.36, 123.17, 113.85, 74.28,
49.06. ½a 2D5
þ81.2 (c 0.9, MeOH). The ee was determined by HPLC
ꢃ
4.3.4. (R)-5-Chloro-3-hydroxy-3-((E)-2-oxo-4-phenylbut-3-enyl)in-
analysis on a Daicel Chiralpak OD-H column: hexane/i-PrOH 75:25
dolin-2-one (3d). White solid, 93% yield and 77% ee. 1H NMR
flow rate 1 ml/min,
l
¼210 nm: major enantiomer: tR¼13.45 min;
(300 MHz, acetone-d6)
d
¼9.46 (s, 1H), 7.88e7.65 (m, 2H), 7.61 (d,
minor enantiomer: tR¼17.88 min. ESIeMS: m/z [MþH]þ calcd for
J¼16.4 Hz, 1H), 7.43e7.40 (m, 4H), 7.23 (dd, J¼8.3, 2.1 Hz, 1H), 6.91
(d, J¼8.3 Hz, 1H), 6.80 (d, J¼16.3 Hz, 1H), 5.29 (s, 1H), 3.76 (d,
J¼16.9 Hz, 1H), 3.43 (d, J¼16.9 Hz, 1H). 13C NMR (100 MHz, DMSO-
C18H15BrNO3: 372.023; found: 372.024.
4.3.9. (R)-7-(Trifluoromethyl)-3-hydroxy-3-((E)-2-oxo-4-phenylbut-
3-enyl)indolin-2-one (3i). White solid, 37% yield and 76% ee. 1H
d6)
d
¼197.02, 178.65, 143.54, 142.34, 134.88, 134.40, 131.29, 129.62,
129.37, 129.15, 126.81, 125.87, 124.72, 111.50, 73.78, 48.12. ½a D25
ꢃ
NMR (300 MHz, acetone-d6)
d
¼9.54 (s, 1H), 7.59e7.49 (m, 3H), 7.47
þ32.7 (c 1.3, MeOH). The ee was determined by HPLC analysis on
(d, J¼16.3 Hz, 1H), 7.40e7.32 (m, 1H), 7.32e7.19 (m, 3H), 6.99 (t,
J¼7.4 Hz,1H), 6.65 (d, J¼16.3 Hz,1H), 3.68 (d, J¼17.2 Hz,1H), 3.37 (d,
a Daicel Chiralpak OJ-H column: hexane/i-PrOH 75:25 flow rate
1 ml/min,
l
¼210 nm: major enantiomer: tR¼29.99 min; minor
J¼17.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
¼197.01, 179.35,
d
enantiomer: tR¼44.39 min. ESIeMS: m/z [MþH]þ calcd for
143.71, 141.05, 134.85, 134.35, 131.32, 129.92, 129.62, 129.30, 129.17,
C18H15ClNO3: 328.0735; found: 328.0739.
128.06, 126.59, 125.90, 125.73, 122.04, 122.00, 72.26, 48.28. ½a D25
ꢃ
þ66.9 (c 0.9, MeOH). The ee was determined by HPLC analysis on
a Daicel Chiralpak OJ-H column: hexane/i-PrOH 75:25 flow rate
4.3.5. (R)-5-Fluoro-3-hydroxy-3-((E)-2-oxo-4-phenylbut-3-enyl)in-
dolin-2-one (3e). White solid, 79% yield and 78% ee. 1H NMR
1 ml/min,
l
¼280 nm: major enantiomer: tR¼21.15 min; minor en-
(400 MHz, DMSO-d6)
d
¼10.29 (s, 1H), 7.68e7.66 (m, 2H), 7.55 (d,
antiomer: tR¼25.01 min. ESIeMS: m/z [MþH]þ calcd for
J¼16.3 Hz, 1H), 7.43e7.41 (m, 3H), 7.20 (dd, J¼8.2, 2.7 Hz, 1H),
7.01e6.93 (m, 1H), 6.79e6.76 (m, 1H), 6.76 (d, J¼16.3 Hz, 1H), 6.20
(s, 1H), 3.70 (d, J¼16.7 Hz, 1H), 3.28 (d, J¼16.7 Hz, 1H). 13C NMR
C19H15F3NO3: 362.100; found: 362.1013.
4.3.10. (R)-5,6-Difluoro-3-hydroxy-3-((E)-2-oxo-4-phenylbut-3-
enyl)indolin-2-one (3j). White solid, 89% yield and 73% ee. 1H NMR
(100 MHz, DMSO-d6)
d
¼196.94, 178.90, 159.64, 157.29, 143.47,
139.52, 134.89, 134.05, 133.97, 131.29, 129.62, 129.13, 126.88, 115.79,
(300 MHz, acetone-d6)
d
¼9.34 (s, 1H), 7.55e7.52 (m, 2H), 7.47 (d,
115.54, 112.48, 112.16, 110.77, 110.68, 74.00, 48.14. ½a D25
ꢃ
þ71.4 (c 0.5,
J¼16.4 Hz, 1H), 7.30e7.23 (m, 4H), 6.76e6.70 (m, 1H), 6.66 (d,
MeOH). The ee was determined by HPLC analysis on a Daicel
J¼16.3 Hz, 1H), 5.21 (s, 1H), 3.62 (d, J¼17.0 Hz, 1H), 3.36e3.17 (d,
Chiralpak OJ-H column: hexane/i-PrOH 70:30 flow rate 1 ml/min,
J¼17.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
¼197.91, 179.86,
d
l
¼254 nm: major enantiomer: tR¼20.94 min; minor enantiomer:
152.62, 152.48, 150.19, 150.05, 147.79, 147.67, 145.45, 145.30, 144.51,
141.11, 140.99, 135.76, 132.20, 130.53, 130.85, 130.06, 129.30, 129.24,
127.67, 115.29, 115.22, 115.09, 115.00, 100.92, 100.70, 74.51, 48.96.
tR¼32.68 min. ESIeMS: m/z [MþH]þ calcd for C18H15FNO3: 312.103;
found: 312.1038.
½
a 2D5
ꢃ
þ73.4 (c 1.2, MeOH). The ee was determined by HPLC analysis
4.3.6. (R)-5-Bromo-3-hydroxy-3-((E)-2-oxo-4-phenylbut-3-enyl)in-
on a Daicel Chiralpak OJ-H column: hexane/i-PrOH 75:25 flow rate
dolin-2-one (3f). White solid, 89% yield and 81% ee. 1H NMR
1 ml/min,
l
¼210 nm: major enantiomer: tR¼19.60 min; minor
(400 MHz, DMSO-d6)
d
¼10.43 (s, 1H), 7.67 (m, 2H), 7.56 (d,
enantiomer: tR¼22.44 min. ESIeMS: m/z [MþH]þ calcd for
J¼16.3 Hz, 1H), 7.50 (d, J¼2.0 Hz, 1H), 7.43e7.41 (m, 3H), 7.34 (dd,
J¼8.2, 2.2 Hz, 1H), 6.78 (s, 1H), 6.75 (d, J¼9.0 Hz, 1H), 6.22 (s, 1H),
3.76 (d, J¼16.8 Hz, 1H), 3.31 (d, J¼16.8 Hz, 1H). 13C NMR (100 MHz,
C18H14F2NO3: 330.0936; found: 330.0956.
4.3.11. (R)-3-Hydroxy-1-methyl-3-((E)-2-oxo-4-phenylbut-3-enyl)
DMSO-d6)
d
¼197.02, 178.50, 143.51, 142.76, 134.88, 134.80, 132.18,
indolin-2-one (3k). White solid, 32% yield and 62% ee. 1H NMR
131.28, 129.60, 129.15, 127.34, 126.81, 113.57, 112.06, 73.73, 48.10.
a 2D5
þ18.1 (c 1.1, MeOH) The ee was determined by HPLC analysis
on a Daicel Chiralpak OJ-H column: hexane/i-PrOH 70:30 flow rate
(400 MHz, DMSO-d6)
d
¼7.66e7.64 (m, 2H), 7.53 (d, J¼16.3 Hz, 1H),
½
ꢃ
7.45e7.38 (m, 3H), 7.33 (d, J¼7.2 Hz, 1H), 7.26 (t, J¼7.7 Hz, 1H), 6.96
(t, J¼7.4 Hz, 2H), 6.74 (d, J¼16.3 Hz, 1H), 6.45e5.74 (m, 1H), 3.72 (d,
J¼16.7 Hz, 1H), 3.30 (d, J¼16.7 Hz, 1H), 3.14e3.08 (m, 3H). 13C NMR
1 ml/min,
l
¼254 nm: major enantiomer: tR¼25.50 min; minor
enantiomer: tR¼31.26 min. ESIeMS: m/z [MþH]þ calcd for
(100 MHz, DMSO-d6)
d¼197.76, 178.18, 145.73, 144.28, 135.79,
C18H15BrNO3: 372.023; found: 372.023.
132.42, 132.20, 130.74,130.53, 130.04,127.68,124.85, 123.46,109.79,
74.34, 49.60, 27.50. ½a D25
þ65.1 (c 0.8, MeOH). The ee was de-
ꢃ
4.3.7. (R)-3-Hydroxy-5-methyl-3-((E)-2-oxo-4-phenylbut-3-enyl)in-
termined by HPLC analysis on a Daicel Chiralpak OJ-H column:
dolin-2-one (3g). White solid, 67% yield and 63% ee. 1H NMR
hexane/i-PrOH 75:25 flow rate 1 ml/min,
l
¼230 nm: major enan-
(300 MHz, acetone-d6)
d
¼9.08 (s, 1H), 7.56e7.48 (m, 2H), 7.44 (d,
tiomer: tR¼18.82 min; minor enantiomer: tR¼17.01 min. ESIeMS:
J¼16.3 Hz, 1H), 7.34e7.21 (m, 3H), 7.04 (s, 1H), 6.86 (d, J¼7.7 Hz,1H),
6.66 (d, J¼16.3 Hz, 1H), 6.64 (d, J¼7.7 Hz, 1H), 4.98 (s, 1H), 3.48 (d,
J¼16.3 Hz, 1H), 3.19 (d, J¼16.3 Hz, 1H), 2.09 (s, 3H). 13C NMR
m/z [MþH]þ calcd for C19H18NO3: 308.1281; found: 308.1283.
4.3.12. (R)-1-Benzyl-3-hydroxy-3-((E)-2-oxo-4-phenylbut-3-enyl)in-
(100 MHz, DMSO-d6)
d
¼196.90, 178.92, 143.19, 140.84, 134.94,
dolin-2-one (3l). White solid, 95% yield and 72% ee. 1H NMR
132.21, 131.22, 130.56, 129.77, 129.60, 129.11, 127.01, 125.14, 109.82,
(300 MHz, acetone-d6)
d
¼7.55e7.52 (m, 2H), 7.49 (d, J¼16.2 Hz, 1H),
73.88, 48.43, 21.32. ½a D25
ꢃ
þ35.3 (c 0.8, MeOH). The ee was de-
7.36 (d, J¼6.9 Hz, 2H), 7.30e7.25 (m, 4H), 7.21e7.19 (m, 3H), 7.02 (t,
J¼7.2 Hz, 1H), 6.82 (t, J¼7.5 Hz, 1H), 6.66 (d, J¼16.3 Hz, 1H), 6.61 (d,
J¼7.9 Hz, 1H), 4.81 (q, J¼15.9 Hz, 2H), 3.68(d, J¼16.6 Hz, 1H), 3.36(d,
termined by HPLC analysis on a Daicel Chiralpak OJ-H column:
hexane/i-PrOH 75:25 flow rate 1 ml/min,
l
¼280 nm: major enan-
tiomer: tR¼17.0 min; minor enantiomer: tR¼27.68 min. ESIeMS: m/
J¼16.6 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
¼197.91, 178.38,
d
z [MþH]þ calcd for C19H18NO3: 308.1281; found: 308.1283.
144.84, 144.83, 144.52, 137.94, 135.82, 132.47, 132.20, 130.05, 128.78,
127.78, 125.07, 123.58, 110.52, 74.44, 49.29, 44.36. ½a D25
þ57.4 (c 1.3,
ꢃ
4.3.8. (R)-6-Bromo-3-hydroxy-3-((E)-2-oxo-4-phenylbut-3-enyl)in-
MeOH). The ee was determined by HPLC analysis on a Daicel
dolin-2-one (3h). White solid, 90% yield and 75% ee. 1H NMR
Chiralpak OJ-H column: hexane/i-PrOH 75:25 flow rate 1 ml/min,
(400 MHz, DMSO-d6)
d
¼10.45 (s, 1H), 7.67e7.65 (m, 2H), 7.56 (d,
l¼230 nm: major enantiomer: tR¼29.09 min; minor enantiomer:

3848
G.-G. Liu et al. / Tetrahedron 68 (2012) 3843e3850
tR¼26.46 min. ESIeMS: m/z [MþH]þ calcd for C25H22NO3:
2H), 7.53 (d, J¼16.2 Hz, 1H), 7.17 (t, J¼8.0 Hz, 1H), 6.97(d, J¼8.7 Hz,
2H), 6.85 (d, J¼8.7 Hz, 1H), 6.76 (d, J¼7.7 Hz, 1H), 6.62 (d, J¼16.3 Hz,
1H), 6.21 (s, 1H), 4.01 (d, J¼17.0 Hz 1H), 3.79 (s, 3H), 3.32 (d,
384.1594; found: 384.1607.
4.3.13. (R)-4-Chloro-3-hydroxy-3-((E)-4-(2-methoxyphenyl)-2-
oxobut-3-enyl)indolin-2-one (3aa). Pale yellow solid, 92% yield and
J¼17.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
¼196.04, 177.54,
d
161.38, 145.04, 143.04, 130.70, 130.49, 129.83, 127.63, 126.71, 123.54,
87% ee. 1H NMR (400 MHz, DMSO-d6)
d
¼10.52 (s, 1H), 7.72 (d,
122.03,114.48, 108.50, 73.93, 55.39, 45.80. ½a D25
þ80.9 (c 0.34,
ꢃ
J¼16.3 Hz, 1H), 7.64 (d, J¼8.0 Hz, 1H), 7.41 (m, 1H), 7.18 (t, J¼8.0 Hz,
1H), 7.06 (d, J¼8.3 Hz, 1H), 6.98 (t, J¼7.6 Hz, 1H), 6.86 (d, J¼8.1 Hz,
1H), 6.80 (d, J¼16.5 Hz, 1H), 6.77 (d, J¼8.5 Hz, 1H), 6.25 (s, 1H), 3.97
(d, J¼16.9 Hz, 1H), 3.84 (s, 3H), 3.33 (d, J¼16.9 Hz, 1H). 13C NMR
MeOH). The ee was determined by HPLC analysis on a Daicel
Chiralpak OJ-H column: hexane/i-PrOH 70:30 flow rate 1 ml/min,
l
¼210 nm: major enantiomer: tR¼12.61 min; minor enantiomer:
tR¼15.79 min. ESIeMS: m/z [MþH]þ calcd for C19H17ClNO4:
(100 MHz, DMSO-d6)
d
¼197.72, 179.01, 159.73, 146.53, 138.97,
358.0841; found: 358.0851.
133.97, 132.28, 131.40, 130.12, 129.04, 127.32, 123.83, 123.61, 122.32,
113.38, 110.08, 75.43, 57.26, 47.79. ½a D25
ꢃ
þ87.8 (c 1.0, MeOH). The ee
4.3.18. (R)-4-Chloro-3-hydroxy-3-((E)-4-(4-isopropylphenyl)-2-
oxobut-3-enyl)indolin-2-one (3ff). White solid, 90% yield and 89%
was determined by HPLC analysis on a Daicel Chiralpak OD-H col-
umn: hexane/i-PrOH 75:25 flow rate 1 ml/min,
l
¼210 nm: major
ee. 1H NMR (400 MHz, DMSO-d6)
d
¼10.51 (s, 1H), 7.60 (d, J¼8.2 Hz,
enantiomer: tR¼12.7 0 min; minor enantiomer: tR¼15.62 min.
ESIeMS: m/z [MþH]þ calcd for C19H17ClNO4: 358.041; found:
358.0855.
2H), 7.55 (d, J¼16.3 Hz, 1H), 7.29 (d, J¼8.2 Hz, 2H), 7.18 (t, J¼8.0 Hz,
1H), 6.86 (d, J¼8.2 Hz, 1H), 6.77 (d, J¼7.7 Hz, 1H), 6.71 (d, J¼16.3 Hz,
1H), 6.23 (s, 1H), 3.99 (d, J¼15.1 Hz, 1H), 3.34 (d, J¼15.1 Hz, 1H)
2.94e2.87 (m, 1H), 1.19 (d, J¼6.9 Hz, 6H). 13C NMR (100 MHz,
4.3.14. (R)-4-Chloro-3-((E)-4-(2-fluorophenyl)-2-oxobut-3-enyl)-3-
hydroxyindolin-2-one (3bb). Pale yellow solid, 98% yield and 82%
DMSO-d6)
d
¼201.82, 183.09, 157.12, 150.62, 148.70, 137.46, 136.32,
135.43, 134.32, 133.15, 132.55, 130.56, 127.63, 114.11, 79.48, 39.02,
a 25
ee. 1H NMR (400 MHz, DMSO-d6)
d
¼10.55 (s, 1H), 7.80 (t, J¼7.8 Hz,
29.21. ½ ꢃD þ84.2 (c 1.0, MeOH). The ee was determined by HPLC
1H), 7.57 (d, J¼16.4 Hz, 1H), 7.52e7.46 (m, 1H), 7.27 (dd, J¼16.1,
8.4 Hz, 2H), 7.20 (t, J¼8.0 Hz, 1H), 6.88 (d, J¼16.2 Hz, 1H), 6.88e6.87
(m, 1H), 6.28 (s, 1H), 4.01 (d, J¼17.1 Hz, 1H), 3.39 (d, J¼17.1 Hz, 1H).
analysis on a Daicel Chiralpak OJ-H column: hexane/i-PrOH 70:30
flow rate 1 ml/min,
l
¼210 nm: major enantiomer: tR¼10.83 min;
minor enantiomer: tR¼13.72 min. ESIeMS: m/z [MþH]þ calcd for
13C NMR (100 MHz, DMSO-d6)
d
¼201.70, 182.99, 167.68, 165.18,
C21H20ClNO3: 370.1204; found: 370.1194.
150.56, 144.8, 140.06, 138.36, 136.46, 136.27, 135.48, 135.01, 134.88,
133.47, 133.02, 130.59, 127.75, 127.64, 127.45, 127.34, 114.19, 79.45,
4.3.19. (R)-4-Chloro-3-hydroxy-3-((E)-2-oxo-4-p-tolylbut-3-enyl)in-
51.92. ½a 2D5
ꢃ
þ85.4 (c 0.85, MeOH). The ee was determined by HPLC
dolin-2-one (3gg). White solid, 94% yield and 88% ee. 1H NMR
analysis on a Daicel Chiralpak OJ-H column: hexane/i-PrOH 70:30
(400 MHz, DMSO-d6)
d
¼10.51 (s, 1H), 7.57 (d, J¼8.0 Hz, 2H), 7.54 (d,
flow rate 1 ml/min,
l
¼254 nm: major enantiomer: tR¼15.00 min;
J¼16.4 Hz, 1H), 7.23 (d, J¼8.0 Hz, 2H), 7.18 (t, J¼8.0 Hz, 1H), 6.86 (d,
J¼8.0 Hz, 1H), 6.77 (d, J¼7.6 Hz, 1H), 6.71 (d, J¼16.4 Hz, 1H), 6.23 (s,
1H), 4.03 (d, J¼17.1 Hz, 1H), 3.35 (d, J¼17.1 Hz, 1H), 2.32 (s, 3H). 13C
minor enantiomer: tR¼8.79 min. ESIeMS: m/z [MþH]þ calcd for
C18H14ClFNO3: 346.0663; found: 346.0643.
NMR (100 MHz, DMSO-d6)
d¼201.80, 183.10, 150.62, 148.67, 146.39,
4.3.15. (R)-4-Chloro-3-((E)-4-(2-chlorophenyl)-2-oxobut-3-enyl)-3-
137.03, 136.20, 135.30, 135.10, 134.20, 133.18, 130.45, 127.68, 114.09,
hydroxyindolin-2-one (3cc). White solid, 90% yield and 76% ee. 1H
79.49, 51.48, 26.71. ½a D25
þ101.62 (c 0.4, MeOH). The ee was de-
ꢃ
NMR (400 MHz, DMSO-d6)
d
¼10.55 (s, 1H), 7.87 (dd, J¼7.7, 1.3 Hz,
termined by HPLC analysis on a Daicel Chiralpak OJ-H column:
1H), 7.73 (d, J¼16.1 Hz, 1H), 7.53 (dd, J¼7.9, 0.9 Hz, 1H), 7.46e7.37
(m, 1H), 7.39 (t, J¼7.2 Hz, 1H), 7.20 (t, J¼8.0 Hz, 1H), 6.91 (d,
J¼16.2 Hz, 1H), 6.87 (d, J¼8.4 Hz, 1H), 6.79 (d, J¼7.6 Hz, 1H), 6.29 (s,
1H), 4.00 (d, J¼17.2 Hz, 1H), 3.39 (d, J¼17.3 Hz, 1H). 13C NMR
hexane/i-PrOH 60:40 flow rate 1 ml/min,
l
¼210 nm: major enan-
tiomer: tR¼17.08 min; minor enantiomer: tR¼7.98 min. ESIeMS: m/
z [MþH]þ calcd for C19H17ClNO3: 342.0891; found: 342.0886.
(100 MHz, DMSO-d6)
d
¼195.98, 177.39, 144.98, 137.22, 134.22,
4.3.20. (R)-4-Chloro-3-((E)-4-(4-fluorophenyl)-2-oxobut-3-enyl)-3-
hydroxyindolin-2-one (3hh). White solid, 97% yield and 83% ee. 1H
132.13, 131.77, 130.84, 130.09, 129.87, 128.24, 128.11, 127.82, 127.38,
122.14, 108.61, 73.79, 46.61. ½a D25
ꢃ
þ72.3 (c 0.7, MeOH). The ee was
NMR (400 MHz, DMSO-d6)
d
¼10.52 (s, 1H), 7.76 (dd, J¼8.7, 5.6 Hz,
determined by HPLC analysis on a Daicel Chiralpak OJ-H column:
2H), 7.60 (d, J¼16.3 Hz, 1H), 7.26 (t, J¼8.8 Hz, 2H), 7.19 (t, J¼8.0 Hz,
1H), 6.86 (dd, J¼8.2, 0.6 Hz, 1H), 6.78 (dd, J¼7.6, 0.4 Hz, 1H), 6.74 (d,
J¼16.3 Hz, 1H), 6.25 (s, 1H), 4.05 (d, J¼17.2 Hz, 1H), 3.37 (d,
hexane/i-PrOH 85:15 flow rate 1 ml/min,
l
¼254 nm: major enan-
tiomer: tR¼24.93 min; minor enantiomer: tR¼22.50 min. ESIeMS:
m/z [MþH]þ calcd for C18H13Cl2NO3: 362.0345; found: 362.0351.
J¼17.2 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
¼201.84, 183.08,
d
170.26, 167.79, 150.62, 147.46, 136.44, 136.23, 135.44, 133.15, 131.34,
4.3.16. (R)-4-Chloro-3-((E)-4-(3-chlorophenyl)-2-oxobut-3-enyl)-3-
127.70, 121.62, 114.15, 79.47, 51.47. ½a D25
þ85.4 (c 0.85, MeOH). The
ꢃ
hydroxyindolin-2-one (3dd). White solid, 98% yield and 81% ee. 1H
ee was determined by HPLC analysis on a Daicel Chiralpak OJ-H
NMR (400 MHz, DMSO-d6)
d
¼10.53 (s, 1H), 7.80 (s, 1H), 7.65 (d,
column: hexane/i-PrOH 70:30 flow rate 1 ml/min,
l
¼210 nm:
J¼7.2 Hz, 1H), 7.56 (d, J¼16.3 Hz, 1H), 7.49e7.42 (m, 2H), 7.19 (t,
J¼8.0 Hz, 1H), 6.87 (d, J¼16.2 Hz, 1H), 6.86 (d, J¼8.2 Hz, 1H), 6.78 (d,
J¼7.8 Hz, 1H), 6.26 (s, 1H), 4.05 (d, J¼17.9 Hz, 1H), 3.38 (d, J¼17.9 Hz,
major enantiomer: tR¼22.00 min; minor enantiomer:
tR¼10.61 min. ESIeMS: m/z [MþH]þ calcd for C18H14ClFNO3:
346.0663; found: 346.0646.
1H). 13C NMR (100 MHz, DMSO-d6)
d¼201.90, 183.05, 150.62, 146.90,
142.10, 139.37, 136.34, 135.81, 135.43, 133.70, 133.58, 133.10, 132.80,
4.3.21. (R)-4-Chloro-3-((E)-4-(4-chlorophenyl)-2-oxobut-3-enyl)-3-
hydroxyindolin-2-one (3ii). Pale yellow solid, 92% yield and 86% ee.
127.72, 127.61, 114.11, 79.41, 51.67. ½a D25
ꢃ
þ82.7 (c 0.6, MeOH). The ee
was determined by HPLC analysis on a Daicel Chiralpak OJ-H column:
1H NMR (400 MHz, DMSO-d6)
d
¼10.52 (s, 1H), 7.71 (d, J¼8.5 Hz,
hexane/i-PrOH 70:30 flow rate 1 ml/min,
l¼254 nm: major enan-
2H), 7.57 (d, J¼16.3 Hz, 1H), 7.47 (d, J¼8.5 Hz, 2H), 7.18 (t, J¼8.0 Hz,
1H), 6.86 (d, J¼8.2 Hz, 1H), 6.79 (d, J¼16.6 Hz, 1H), 6.77 (d, J¼7.1 Hz,
1H), 6.25 (s, 1H), 4.04 (d, J¼17.2 Hz, 1H), 3.36 (d, J¼17.2 Hz, 1H). 13C
tiomer: tR¼15.63 min; minor enantiomer: tR¼7.81 min. ESIeMS: m/z
[MþH]þ calcd for C18H13Cl2NO3: 362.0345; found: 362.0347.
NMR (100 MHz, DMSO-d6)
d
¼196.30, 177.47, 145.02, 141.66, 135.20,
4.3.17. (R)-4-Chloro-3-hydroxy-3-((E)-4-(4-methoxyphenyl)-2-
133.18, 130.74, 130.29, 129.84, 129.04, 127.52, 126.47, 122.08, 108.55,
oxobut-3-enyl)indolin-2-one (3ee). White solid, 87% yield and 85%
73.85, 45.97. ½a D25
þ82.7 (c 0.6, MeOH). The ee was determined by
ꢃ
ee. 1H NMR (400 MHz, DMSO-d6)
d¼10.49 (s, 1H), 7.63 (d, J¼8.7 Hz,
HPLC analysis on a Daicel Chiralpak OJ-H column: hexane/i-PrOH

G.-G. Liu et al. / Tetrahedron 68 (2012) 3843e3850
3849
70:30 flow rate
1
ml/min,
l
¼210 nm: major enantiomer:
1H), 7.91 (d, J¼7.2 Hz, 1H), 7.62e7.53 (m, 3H), 7.20 (t, J¼8.0 Hz, 1H),
6.88 (d, J¼8.2 Hz, 1H), 6.85 (d, J¼15.8 Hz, 1H), 6.80 (d, J¼7.7 Hz, 1H),
6.30 (s, 1H), 4.15 (d, J¼17.1 Hz, 1H), 3.52 (d, J¼17.1 Hz, 1H). 13C NMR
tR¼36.09 min; minor enantiomer: tR¼12.65 min. ESIeMS: m/z
[MþH]þ calcd for C18H13Cl2NO3: 362.0345; found: 362.0349.
(100 MHz, DMSO-d6)
d
¼196.29, 177.55, 145.02, 139.22, 133.34,
4.3.22. (R)-3-((E)-4-(4-Bromophenyl)-2-oxobut-3-enyl)-4-chloro-3-
131.05, 131.01, 130.89, 130.82, 130.75, 129.95, 128.75, 128.35, 127.62,
hydroxyindolin-2-one (3jj). Pale yellow solid, 93% yield and 85% ee.
127.19, 126.39, 125.73, 125.42, 123.26, 122.14, 116.29, 108.59, 74.02,
25
1H NMR (400 MHz, DMSO-d6)
d
¼10.51 (s, 1H), 7.65e7.59 (m, 4H),
46.16. [
a
]
þ87.4 (c 0.3, MeOH). The ee was determined by HPLC
D
7.55 (d, J¼16.3 Hz, 1H), 7.18 (t, J¼8.0 Hz, 1H), 6.85 (d, J¼8.3 Hz, 1H),
6.79 (d, J¼16.3 Hz, 1H), 6.76 (d, J¼7.5 Hz, 1H), 6.24 (s, 1H), 4.03 (d,
J¼17.2 Hz, 1H), 3.36 (d, J¼17.2 Hz, 1H). 13C NMR (100 MHz, DMSO-
analysis on a Daicel Chiralpak OJ-H column: hexane/i-PrOH 70:30
flow rate 1 ml/min,
l
¼210 nm: major enantiomer: tR¼25.56 min;
minor enantiomer: tR¼14.77 min. ESIeMS: m/z [MþH]þ calcd for
d6)
d
¼196.31, 177.46, 145.02, 141.75, 133.53, 131.97, 130.76, 130.49,
C22H17ClNO3: 378.0891; found: 378.0881.
129.83, 127.52, 126.51, 124.95, 122.07, 108.54, 73.84, 45.96. ½a D25
ꢃ
þ62.7 (c 1.1, MeOH). The ee was determined by HPLC analysis on
Acknowledgements
a Daicel Chiralpak OJ-H column: hexane/i-PrOH 50:50 flow rate
1 ml/min,
l
¼210 nm: major enantiomer: tR¼21.86 min; minor en-
We are grateful for financial support of the National Natural
Science Foundation of China (21072145), Foundation for the Author
of National Excellent Doctoral Dissertation of PR China (200931)
and Natural Science Foundation of Jiangsu Province of China
(BK2009115). This project was funded by the Priority Academic
Program Development of Jiangsu Higher Education Institutions
(PAPD).
antiomer: tR¼8.68 min. ESIeMS: m/z [MþH]þ calcd for
C18H13BrClNO3: 405.984; found: 405.9838.
4.3.23. (R)-4-Chloro-3-((E)-4-(4-(trifluoromethyl)phenyl)-2-oxobut-
3-enyl)-3-hydroxyindolin-2-one (3kk). White solid, 93% yield and
63% ee. 1H NMR (400 MHz, DMSO-d6)
d¼10.54 (s, 1H), 7.90 (d,
J¼8.1 Hz, 2H), 7.77 (d, J¼8.3 Hz, 2H), 7.65 (d, J¼16.4 Hz, 1H), 7.18 (t,
J¼7.9 Hz, 1H), 6.90 (d, J¼16.4 Hz, 1H), 6.86 (d, J¼8.1 Hz, 1H), 6.77 (d,
J¼7.6 Hz, 1H), 6.26 (s, 1H), 4.06 (d, J¼17.3 Hz, 1H) 3.44(d, J¼17.3 Hz,
Supplementary data
1H). 13C NMR (100 MHz, DMSO-d6)
d¼201.69, 182.71, 150.29, 146.41,
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.042.
143.59, 136.09, 136.04, 135.42, 134.46, 133.48, 132.75, 131.07, 127.37,
113.84, 79.09, 51.38. ½a D25
þ47.2 (c 0.8, MeOH). The ee was de-
ꢃ
termined by HPLC analysis on a Daicel Chiralpak OD-H column:
References and notes
hexane/i-PrOH 75:25 flow rate 1 ml/min,
l¼210 nm: major enan-
tiomer: tR¼15.45 min; minor enantiomer: tR¼12.81 min. ESIeMS:
1. For reviews and books on aldol reaction, see: (a) Mukaiyama, T. Org. React.1982, 28,
203e331; (b) Evans, D. A. Aldrichimica Acta 1982,15, 23e32; (c) Heathcock, C. H. In;
Trost, B. M., Fleming, I., Heathcock, C. H., Eds. Comprehensive Organic Synthesis;
Pergamon: Oxford, 1991; Vol. 2, p 133; (d) Machajewski, T. D.; Wong, C.-H. Angew.
Chem., Int. Ed. 2000, 39, 1352e1375; (e) . ; Mahrwald, R., Ed. ; Wiley-VCH GmbH
KGaA: Weinheim, 2004; Vols.1 and 2; (f) List, B. Acc. Chem. Res. 2004, 37, 548e557;
(g)Notz, W.;Tanaka, F.;Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580e591;(h) Dalko,
P. I.; Moisan, L. Angew. Chem. 2004,116, 5248e5286; Angew. Chem., Int. Ed. 2004, 43,
5138e5175; (i) Dalko, P. I.; Moisan, L. Enantioselective Organocatalysis; Wiley-VCH:
Weinheim, 2007; (j) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471e5569 Selected pioneering publications; (k) List, B.; Lerner, R. A.;
Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122, 2395e2396; (l) Notz, W.; List, B. J. Am.
Chem. Soc. 2000,122, 7386e7387; (m) Sakthivel, K.; Notz,W.;Bui, T.;Barbas, C. F., III.
J. Am. Chem. Soc. 2001, 123, 5260e5267; (n) MacMillan, D. W. C.; Northrup, A. B. J.
Am. Chem. Soc. 2002, 124, 6798e6799; (o) Tang, Z.; Jiang, F.; Yu, L.-T.; Cui, X.; Gong,
L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am. Chem. Soc. 2003, 125, 5262e5263; (p)
Tang, Z.; Yang, Z.-H.; Chen, X.-H.; Cun, L.-F.; Mi, A.-Q.; Jiang, Y.-Z.; Gong, L.-Z. J. Am.
Chem. Soc. 2005, 127, 9285e9289.
m/z [MþH]þ calcd for C19H14ClF3NO3: 396.0609; found: 396.062.
4.3.24. (R)-4-Chloro-3-hydroxy-3-((E)-2-oxo-4-(thiophen-2-yl)but-
3-enyl)indolin-2-one (3ll). Pale yellow solid, 95% yield and 85% ee.
1H NMR (400 MHz, DMSO-d6)
d¼10.54 (s, 1H), 7.75 (d, J¼15.8 Hz,
1H), 7.74 (d, J¼5.1 Hz, 1H), 7.77e7.73 (m, 1H), 7.53 (d, J¼3.5 Hz, 1H),
7.19 (d, J¼8.0 Hz,1H), 7.17e7.13 (m,1H), 6.90e6.83 (m,1H), 6.77 (dd,
J¼7.7, 0.6 Hz, 1H), 6.43 (d, J¼16.0 Hz, 1H), 6.25 (s, 1H), 3.96 (d,
J¼16.9 Hz, 1H), 3.31 (d, J¼16.9 Hz, 1H). 13C NMR (100 MHz, DMSO-
d6)
d
¼201.20, 183.05, 150.55, 144.72, 141.48, 138.51, 136.33, 136.04,
135.44, 134.34, 133.09, 129.68, 127.66, 114.14, 79.50, 51.42. ½a D25
ꢃ
þ90.09 (c 1.1, MeOH). The ee was determined by HPLC analysis on
a Daicel Chiralpak OJ-H column: hexane/i-PrOH 60:40 flow rate
2. For selected publications: (a) Adachi, S.; Harada, T. Eur. J. Org. Chem. 2009,
3661e3671; (b) Zheng, C.-W.; Wu, Y.-Y.; Wang, X.-S.; Zhao, G. Adv. Synth. Catal.
2008, 350, 2690e2694; (c) Wang, F.; Xiong, Y.; Liu, X.-H.; Feng, X.-M. Adv. Synth.
Catal. 2007, 349, 2665e2668; (d) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc. 2006,
128, 7442e7443; (e) Wang, Y.-J.; Shen, Z.-X.; Ding, J.; Zhang, Y.-W. Chin. J. Chem.
2007, 27, 235e239.
3. For reviews of oxindole alkaloids, see: (a) Peddibhotla, S. Curr. Bioact. Compd.
2009, 5, 20e38; (b) Galliford, C. V.; Scheidt, K. A. Angew. Chem. 2007, 119,
8902e8912; Angew. Chem., Int. Ed. 2007, 46, 8748e8758; (c) Marti, C.; Carreira,
E. M. Eur. J. Org. Chem. 2003, 2209e2219; (d) Lin, H.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2003, 42, 36e51; (e) Trost, B. M.; Brennan, M. K. Synthesis 2009,
3003e3025; (f) Zhou, F.; Liu, Y.-L.; Zhou, J. Adv. Synth. Catal. 2010, 352,
1381e1407.
1 ml/min,
l
¼210 nm: major enantiomer: tR¼12.17 min; minor en-
antiomer: tR¼8.18 min. ESIeMS: m/z [MþH]þ calcd for
C16H12ClNO3S: 334.0299; found: 334.0294.
4.3.25. (R)-4-Chloro-3-((E)-4-(furan-2-yl)-2-oxobut-3-enyl)-3-
hydro xyindolin-2-one (3mm). White solid, 98% yield and 93% ee.
1H NMR (300 MHz, DMSO-d6)
d
¼10.48 (s, 1H), 7.84 (s, 1H), 7.37 (d,
J¼15.9 Hz, 1H), 7.16 (t, J¼7.9 Hz, 1H), 6.95 (d, J¼3.1 Hz, 1H), 6.84 (d,
J¼8.1 Hz, 1H), 6.74 (d, J¼7.7 Hz, 1H), 6.66e6.60 (m, 1H), 6.44 (d,
J¼15.8 Hz, 1H), 6.21 (s, 1H), 3.92 (d, J¼16.9 Hz, 1H), 3.29 (d,
J¼16.9 Hz, 1H). 13C NMR (100 MHz, DMSO-d6)
¼195.60, 177.45,
d
4. For examples, see: (a) Raunak; Kumar, V.; Mukherjee, S.; Poonam; Prasad, A. K.;
€
Olsen, C. E.; Schaffer, S. J. C.; Sharma, S. K.; Watterson, A. C.; Errington, W.;
150.34, 146.37, 144.96, 130.75, 129.87, 129.54, 127.49, 122.40, 122.08,
Parmar, V. S. Tetrahedron 2005, 61, 5687e5697; (b) Hewawasam, P.; Erway, M.;
Moon, S. L.; Knipe, J.; Weiner, H.; Boissard, C. G.; Post-Munson, D. J.; Gao, Q.;
Huang, S.; Gribkoff, V. K.; Meanwell, N. A. J. Med. Chem. 2002, 45, 1487e1499.
5. Selected examples of natural products that possess 3-substituted 3-hydroxy-
oxindole substructures, see: (a) Zhang, H.-P.; Kamano, Y.; Ichihara, Y.; Kizu, H.;
Komiyama, K.; Itokawa, H.; Pettit, G. R. Tetrahedron 1995, 51, 5523e5528; (b)
Khuzhaev, V. U.; Zhalolov, I.; Turguniv, K. K.; Tashkhodzhaev, B.; Levkovich, M.
G.; Aripova, S. F.; Shashkov, A. S. Chem. Nat. Compd. 2004, 40, 269e272; (c)
117.24,113.09, 108.53, 73.91, 45.90. ½a D25
þ99.7 (c 0.9, MeOH). The ee
ꢃ
was determined by HPLC analysis on a Daicel Chiralpak OJ-H col-
umn: hexane/i-PrOH 70:30 flow rate 1 ml/min,
l¼210 nm: major
enantiomer: tR¼16.19 min; minor enantiomer: tR¼13.37 min.
ESIeMS: m/z [MþH]þ calcd for C16H13ClNO4: 318.0528; found:
318.0527.
ꢁ
Suchy, M.; Kutschy, P.; Monde, K.; Goto, H.; Harada, N.; Takasugi, M.; Dzurilla,
ꢁ
M.; Balentova, E. J. Org. Chem. 2001, 66, 3940e3947; (d) Tang, Y. Q.; Sattler, I.;
Thiericke, R.; Grabley, S.; Feng, X.-Z. Eur. J. Org. Chem. 2001, 261e267; (e) Nic-
olaou, K. C.; Rao, P. B.; Hao, J.-L.; Reddy, M. V.; Rassias, G.; Huang, X.-H.; Chen,
D. Y. K.; Snyder, S. A. Angew. Chem. 2003, 115, pp 1795e1800; Angew. Chem., Int.
Ed. 2003, 42, 1753e1758; (f) Takahashi, C.; Numata, A.; Ito, Y.; Matsumura, E.;
Araki, H.; Iwaki, H.; Kushida, K. J. Chem. Soc., Perkin Trans. 11994, 1859e1864; (g)
4.3.26. (R)-4-Chloro-3-hydroxy-3-((E)-4-(naphthalen-1-yl)-2-
oxobut-3-enyl)indolin-2-one (3nn). White solid, 96% yield and 91%
ee. 1H NMR (400 MHz, DMSO-d6)
1H), 8.27 (d, J¼8.2 Hz, 1H), 8.02 (d, J¼8.2 Hz, 1H), 7.98 (d, J¼8.1 Hz,
d
¼10.57 (s,1H), 8.36 (d, J¼16.0 Hz,

3850
G.-G. Liu et al. / Tetrahedron 68 (2012) 3843e3850
9. Malkov, A. V.; Kabeshov, M. A.; Bella, M.; Kysilka, O.; Malyshev, D. A.;
Sharma, V.; Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2006, 128, 9137e9143;
ꢁꢀ
ꢁ
ꢀ
ꢁ
(h) Jimenez, J. I.; Huber, U.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod. 1999, 62,
569e572; (i) Hayashi, M.; Rho, M. C.; Enomoto, A.; Fukami, A.; Kim, Y. P.; Ki-
kuchi, Y.; Sunazuka, T.; Hirose, T.; Komiyama, K.; Omura, S. Proc. Natl. Acad. Sci.
U.S.A. 2002, 99, 14728e14733; (j) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett.
2009, 11, 3854e3857; (k) Kitajima, M.; Mori, I.; Arai, K.; Kogure, N.; Takayama,
H. Tetrahedron Lett. 2006, 47, 3199e3202; (l) Boechat, N.; Kover, W. B.; Bongertz,
V.; Bastos, M. M.; Romeiro, N. C.; Azavedo, M. L. G.; Wollinger, W. Med. Chem.
2007, 3, 533e542.
6. For selected publications: (a) Cravotto, G.; Giovenzana, G. B.; Palmisano, G.;
Penoni, A.; Pilati, T.; Sisti, M.; Stazi, F. Tetrahedron: Asymmetry 2006, 17,
3070e3074; (b) Nakamura, T.; Shirokawa, S. I.; Hosokawa, S.; Nakazaki, A.;
Kobayashi, S. Org. Lett. 2006, 8, 677e679; (c) Jnaneshwar, G. K.; Deshpande, V.
H. J. Chem. Res., Synop. 1999, 10, 632e633; (d) Jnaneshwar, G. K.; Bedekar, A. V.;
Pluhackova, K.; Kocovsky, P. Org. Lett. 2007, 9, 5473e5476.
10. Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.; Shibata, N.; Toru, T. Chem.
dEur. J. 2008, 14, 8079e8081.
11. Guo, Q.-S.; Bhanushali, M.; Zhao, C.-G. Angew. Chem. 2010, 122, 9650e9654;
Angew. Chem., Int. Ed. 2010, 49, 9460e9464.
12. The selected publications for the thiourea-based organo-catalysis: (a) Sigman,
M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901e4902; (b) Schreiner, P. R.;
Wittkopp, A. Org. Lett. 2002, 4, 217e220; (c) Sohtome, Y.; Hashimoto, Y.; Na-
gasawa, K. Adv. Synth. Catal. 2005, 347, 1643e1648; (d) Wang, J.; Li, H.; Yu, X.-H.;
Zu, L.-S.; Wang, W. Org. Lett. 2005, 7, 4293e4296; (e) Cao, C.-L.; Ye, M.-C.; Sun,
X.-L.; Tang, Y. Org. Lett. 2006, 8, 2901e2904; (f) Wu, B.; Liu, G.-G.; Li, M.-Q.;
Zhang, Y.; Zhang, S.-Y.; Qiu, J.-R.; Xu, X.-P.; Ji, S.-J.; Wang, X.-W. Chem. Commun.
2011, 3992e3994.
Deshpande, V. H. Synth. Com
ˇ
mun. 1999, 29, 3627e3633.
13. (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672e12673;
(b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.-N.; Takemoto, Y. J. Am. Chem. Soc.
2005, 127, 119e125; (c) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2006, 128, 9413e9419.
7. Luppi, G.; Monari, M.; Correa, R. J.; Violante, F. de. A.; Pinto, A. C.; Kaptein, B.;
Broxterman, Q. B.; Garden, S. J.; Tomasini, C. Tetrahedron 2006, 62,
12017e12024.
8. Chen, J.-R.; Liu, X.-P.; Zhu, X.-Y.; Li, L.; Qiao, Y.-F.; Zhang, J.-M.; Xiao, W.-J. Tet-
rahedron 2007, 63, 10437e10444.
14. Beccalli, E. M.; Marchesini, A.; Pilati, T. J. Chem. Soc., Perkin Trans. 1 1994,
579e587.