Natural amino acid salt catalyzed aldol reactions of isatins with ketones: highly enantioselective construction of 3-alkyl-3-hydroxyindolin-2-ones

Article abstract of DOI:10.1016/j.tetasy.2015.07.008

Abstract The asymmetric synthesis of 3-alkyl-3-hydroxyindolin-2-ones via direct aldol reaction of isatin with ketones catalyzed by natural amino acid salts is described, in which the phenylalanine lithium salt was found to be the best catalyst. This strategy was then applied to a variety of isatin and ketone substrates and the corresponding aldol products were obtained in excellent yields (up to 97%) with good to excellent enantioselectivities (up to 90%).

Full text of DOI:10.1016/j.tetasy.2015.07.008

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Natural amino acid salt catalyzed aldol reactions of isatins
with ketones: highly enantioselective construction of
3-alkyl-3-hydroxyindolin-2-ones
a,
Gong Chen a, , Yuan Ju a, , Tao Yang a, Zicheng Li b, Wei Ang c, Zitai Sang a, Jie Liu a, , Youfu Luo
⇑
⇑
a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610041,
PR China
b School of Chemical Engineering, Sichuan University, Chengdu, Sichuan 610065, PR China
c Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, 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 synthesis of 3-alkyl-3-hydroxyindolin-2-ones via direct aldol reaction of isatin with
ketones catalyzed by natural amino acid salts is described, in which the phenylalanine lithium salt
was found to be the best catalyst. This strategy was then applied to a variety of isatin and ketone sub-
strates and the corresponding aldol products were obtained in excellent yields (up to 97%) with good
to excellent enantioselectivities (up to 90%).
Received 2 June 2015
Accepted 7 July 2015
Available online xxxx
Ó 2015 Published by Elsevier Ltd.
1. Introduction
used to directly catalyze asymmetric aldol reactions between isatin
derivatives and cyclic ketones under mild conditions.14 Despite the
3-Alkyl-3-hydroxyindolin-2-ones, key structural features of
many bioactive compounds,1 can be found in convolutamydines,2
celogentin K,3 TMC-95s,4 30-hydroxyglucoisatisin,5 diazonamide
A,6 dioxibrassinine7 as well as several other pharmaceutically
active compounds.8 Due to the fact that biologically active com-
pounds containing the 3-substituted-3-hydroxyoxindole moiety
are inherently asymmetric, many approaches have been developed
to construct the stereogenic center at the C-3 position.9 One of the
most straightforward approaches to 3-substituted-3-hydroxyin-
dolin-2-ones is the C–C bond formation of appropriate nucle-
ophiles to the isatin C-3 position. Among the most fundamental
and important measures for constructing carbon–carbon bonds
are the aldol reaction, and many efforts have been made in the
asymmetric synthesis of 3-alkyl-3-hydroxyindolin-2-ones by
employing this reaction.10 In 2005, the first enantioselective aldol
reaction of isatin with acetone was reported by Tomasini et al.
using a dipeptide-based organocatalyst.11 Later on, Zhao et al. suc-
cessfully developed a quinidine thiourea, which was used as the
organocatalyst in the asymmetric aldol reaction of inactivated
ketones and activated carbonyl compounds.12 Chen et al. reported
an example of carbohydrate-derived alcohols as organocatalysts in
enantioselective aldol reactions of isatins with ketones.13 Recently,
Nuclease p1, an enzyme from Penicillium citrinum, was successfully
above success, finding new catalysts with operation simplicity and
catalyst efficiency for the asymmetric synthesis of this structural
moiety still attracts considerable interest.
Over the past few decades, the catalytic performance of amino
acid metal salts, which take advantage of organocatalysis and
Lewis acid catalysis in asymmetric synthesis, has been intensively
studied. As pioneering works in this field, Yamaguchi et al. reported
that L-proline rubidium salt catalyzed the Michael addition of sim-
ple malonates to enones.15 Since then, as an ideal alternative to
organocatalysts and other metal based catalysts, the catalytic activ-
ity of amino acid metal salts has been demonstrated in many differ-
ent reactions.16 In 2005, Liu et al. reported an example of chiral
amino acid salts as a new type of catalyst, in which highly
enantioselective cyanosilylations of ketones were promoted by
L
-phenylglycine sodium salt.17 Not long ago, Kang described a
straightforward synthesis of Phaitanthrin A and its derivatives by
employing -phenylalanine potassium salt to catalyze this asym-
L
metric aldol reaction.18 Very recently, Chanda disclosed the utiliza-
tion of potassium salt of phenylalanine for the construction of
structurally valuable alkyl/aryl/hetaryl substituted and spirocyclic
3-hydroxyindanone frameworks.19 In continuation of our previous
efforts on asymmetric direct aldol reaction of functionalized
ketones catalyzed by amine organocatalysts based on bispidine,20
we herein investigate the possibility of adopting natural amino acid
salts as new agents to catalyze the synthesis of 3-alkyl-3-hydrox-
yindolin-2-ones via the direct aldol reactions of isatin and its
derivatives with ketones with high enantioselectivity.
⇑
Corresponding authors. Tel./fax: +86 28 85503817.
E-mail addresses: liujie2011@scu.edu.cn (J. Liu), luo_youfu@scu.edu.cn (Y. Luo).
These authors contributed equally to this work.
http://dx.doi.org/10.1016/j.tetasy.2015.07.008
0957-4166/Ó 2015 Published by Elsevier Ltd.
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2
G. Chen et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
catalyst at room temperature, the catalytic performance of these
2. Results and discussion
catalysts for asymmetric aldol reactions was evaluated and the
results are shown in Table 1. As evident from Table 1, the reaction
proceeded well with all 18 chiral amino acid salts; the most stud-
ied proline lithium salt 1a showed a good yield of 87% albeit with a
low ee value of 15% (Table 1, entry 1). The effects of either amino
acid or the cation species on the yield and ee values are summa-
rized in Table 1. For a specific type of amino acid, when the alkali
metal species was changed, we found that the lithium salt of the
amino acid usually led to a higher enantioselectivity of the product
than other two cation salts. Conversely, some sterically hindered
amino acid salts gave better results than others when they were
in the same type of alkali metal salt. Three different salts of previ-
ously reported phenylalanine all had relatively good catalytic
activities than others (Table 1, entries 10–12). Also, we found the
lithium salt 4a rather than the previously reported potassium salt
4c,18 that showed a higher activity in this template reaction, with
an ee value up to 49% (entry 10 vs 12) with a high yield of 95%.
Hence, the phenylalanine lithium salt 4a was chosen for further
investigation.
In a second step, we investigated the different ratios of the
mixed catalysts and catalysts loading, as well as the temperature
with the aim of improving the catalytic activity. Inspired by the
previous report that a mixed catalyst consisting of the salt of the
amino acid and its original amino acid can be more effective than
using these catalysts individually in the Michael addition of malo-
nates to enones,16e we examined the activity of catalysts prepared
with different ratios of phenylalanine and lithium hydroxide
(Table 2, entries 1–4). The results shows that catalyst 4a2
prepared in a ratio of phenylalanine/lithium hydroxide 1:0.9 was
Initially, the amino acid salts were synthesized employing a
simple reaction protocol described by Liu with some modifica-
tions.17 Accordingly, the corresponding amino acids were added
to the alkali metal hydroxide in methanol at 0 °C and stirring at
25 °C for 4 h. The solvent was then evaporated off at 25 °C in vac-
uum, and the salts were directly used without further purification.
The chemical structures of the amino acids and their salts are
shown in Scheme 1.
By setting up a template reaction with acetone 8a as the donor
substrate and isatin 7a as the acceptor using 20 mol % of the
O
O
O
(
S
)
( )
S
(
S
)
OM
OM
OM
NH2
NH2
NH
N
H
3a M = Li
1a
2a
M = Li
M = Li
2b M = Na
2c
3b M = Na
1b M = Na
1c M = K
3c
M = K
M = K
O
O
O
(
S
)
( )
S
(
S
)
OM
OM
OM
NH2
NH2
NH2
5a
5b
M = Li
M = Na
4a M = Li
6a M = Li
4b
4c
M = Na
M =K
6b M = Na
5c M = K
6c
M = K
Scheme 1. Various amino acid salts catalysts screened for aldol reaction.
Table 2
Effect of the reaction conditions for the enantioselective aldol reaction
Table 1
Enantioselective aldol reaction of isatin with acetone catalyzed by amino acid salts
O
O
HO
O
O
O
4a
HO
*
O
O
O
catalyst
*
N
H
N
H
O
O
N
H
N
H
8a
9a
7a
7a
8a
9a
Entrya
Catalyst
Time (h)
Yieldb (%)
eec (%) config.d
e
1
2
3
4
5
6
7
8
4a1
4a2
4a3
4a4
12
12
12
12
12
12
12
12
12
12
24
36
48
84
89
94
92
93
87
91
93
82
85
87
82
95
32
58
Racemic
56 (S)
48 (S)
41 (S)
57 (S)
56 (S)
56 (S)
53 (S)
46 (S)
32 (S)
21 (S)
15 (S)
16 (S)
21 (S)
Entrya
Catalyst
Yieldb (%)
eec (%) config.d
f
g
1
2
3
4
5
6
7
8
1a
1b
1c
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
6c
87
49
95
86
75
98
96
95
68
95
81
92
96
81
95
98
91
90
15 (S)
16 (S)
16 (S)
10 (S)
33 (S)
22 (S)
41 (S)
34 (S)
37 (S)
49 (S)
45 (S)
35 (S)
43 (S)
32 (S)
33 (S)
35 (S)
15 (S)
10 (S)
h
4a2 (30%)
4a2 (25%)
4a2 (20%)
4a2 (15%)
4a2 (10%)
4a2 (5%)
9
10
11
12
13
14
i
9
4a2
4a2
4a2
4a2
i
10
11
12
13
14
15
16
17
18
j
j
a
Unless specified otherwise, all the reactions were carried out with 0.1 mmol
(14.71 mg, 1 equiv) isatin 7a, 1 mL of acetone 8a, and 0.02 mmol catalyst 4a2
(20 mol %) at room temperature for 12 h.
Isolated yields after purification by flash column.
Determined by HPLC on CHIRALPAK AD-3 column after purification (eluent:
hexane/2-propanol = 80:20, 1.0 mL/min).
b
c
a
d
All the reactions were carried out with 0.1 mmol (14.71 mg, 1 equiv) isatin 7a,
1.0 mL of acetone 8a, and 0.02 mmol catalyst (20 mol %) at room temperature for
12 h.
Isolated yields after purification by flash column.
Determined by HPLC on CHIRALPAK AD-3 column after purification (eluent:
hexane/2-propanol = 80:20, 1.0 mL/min).
The absolute configuration was determined by comparison of the specific
rotation with that previously reported.11
e
The ratio of the catalyst is phenylalanine/lithium hydroxide 1:1.2.
The ratio of the catalyst is phenylalanine/lithium hydroxide 1:0.9.
The ratio of the catalyst is phenylalanine/lithium hydroxide 1:0.8.
The ratio of the catalyst is phenylalanine/lithium hydroxide 1:0.6.
Temperature at 0 °C.
Temperature at ꢀ20 °C.
b
f
c
g
h
d
i
The absolute configuration was determined by comparison of the specific
rotation with that previously reported.11
j
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G. Chen et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
Table 3
best catalyst loading. Then, we altered the temperature and
prolonged the reaction time. It seems that alteration of neither
the reaction time nor temperature could bring satisfying results
(Table 2, entries 11–14). On the contrary, they may hinder the
enantioselective synthesis of the product. So, 25 °C (rt) was
selected as the best reaction temperature.
In continuation of the screening studies, we conducted experi-
ments with different solvents to establish the optimal reaction
conditions of catalyst 4a2. As summarized in Table 3, seven differ-
ent polar and non-polar solvents were examined. Variation of the
reaction media had a significant effect on the reaction. When the
reaction was carried out in CH2Cl2, the enantioselectivity obtained
was higher than in CHCl3, xylene, PhOMe, PhMe, CH3CN or MTBE
(entry 1 vs entries 2–7), although its yield was lower compared
with PhOMe. Thus, as the optimal compromise between reactivity
and stereoselectivity, a mixture of CH2Cl2 and PhOMe was tested as
the reaction media, affording 9a in a relatively high yield while the
enantioselectivity was almost unchanged (Table 2, entry 8). Hence,
a mixture of CH2Cl2 and PhOMe was chosen as the best solvent
combination.
Thus, using the optimized conditions, the scope of this reaction
was studied and the results are reported in Table 4. With acetone
as the donor substrate, various substituted isatins were applied
in this reaction. The different N-substituted group of isatin 7
(either methyl or benzyl or PMB) had a positive effect on the ee
value of the corresponding product; the corresponding products
of N-methyl, N-benzyl and N-PMB-protected isatins 9b, 9c, and
9d were obtained in better yields and with higher ee (Table 4,
entries 2–4). This revealed that the steric modification at the N-1
position did have a positive influence on the reaction selectivity.
Conversely, isatin substrates bearing electron-withdrawing and
electron-donating groups had little influence on the results
(Table 4, entries 5–8). In general, electron-withdrawing substituted
analogues were superior to electron-donating substituted ana-
logues (Table 4, entries 5, 6 vs 8). In the case of 5-bromine isatin,
the reactivity is low due to the poor solubility in the cosolvents.
When compared with no substituent at the 5-position of isatin
7a, it seems that an electron-donating substituted group methyl
Optimization of the solvent for the enantioselective aldol reaction
O
O
HO
O
4a2 (20%)
*
O
O
r.t.
N
H
N
H
8a
9a
7a
Entrya
Solvents
Yieldb (%)
eec (%) config.d
1
2
3
4
5
6
7
8e
CH2Cl2
PhMe
79
35
48
49
86
53
60
86
71 (S)
67 (S)
69 (S)
65 (S)
61 (S)
49 (S)
54 (S)
70 (S)
CHCl3
xylene
PhOMe
CH3CN
MTBE
CH2Cl2/PhOMe
a
Unless specified otherwise, all the reactions were carried out with 0.1 mmol
(14.71 mg, 1 equiv) isatin 7a, 0.2 mL acetone 8a, and 0.02 mmol catalyst 4a2
(20 mol %) in 0.8 mL certain solvents at room temperature for 12 h.
b
Isolated yields after purification by flash column.
Determined by HPLC on CHIRALPAK AD-3 column after purification (eluent:
c
hexane/2-propanol = 80:20, 1.0 mL/min).
d
The absolute configuration was determined by comparison of the specific
rotation with that previously reported.11
e
0.4 mL of CH2Cl2 and 0.4 mL of PhOMe were used as cosolvents.
the most effective for this template reaction, with an ee value up to
56% without a loss of yield when compared with the original
catalyst 4a. However, if the lithium hydroxide was in excess at
all, the product would be formed in a racemic state (Table 2,
entry 1). The effect of different catalyst loading of 4a2 was tested
by altering the catalyst loading in a wide range from 5 mol % to
30 mol % (Table 2, entries 5–10). When the catalyst loading was
decreased from 30 mol % to 20 mol %, the ee value was almost
unchanged while the yield increased slowly from 87% to 93%. But
when the catalyst loading decreased down below to 15 mol %,
the ee value down to 53%, so we chose 20 mol % of 4a2 as the
Table 4
Substrate scope with various isatins and ketones
R4
O
O
R1
O
HO
R1
R3
4a2(20%)
O
*
R3
O
N
CH2Cl2/PhOMe, r.t.
N
R4
R2
R2
7a-h
8a-c
9a-l
Entrya
Product
R1
R2
R3
R4
Time
(h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
H
H
H
H
F
Cl
Br
Me
H
H
H
H
H
Me
Bn
PMB
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
12
12
12
16
16
22
48
48
16
24
12
24
86
91
90
87
89
97
nd
73
87
96
97
96
70
81
87
87
77
78
nd
66
79
80
83
90
9
–CH2CH2CH2–
–CH2CH2CH2–
–CH2CH2CH2CH2–
–CH2CH2CH2–
10
11
12
9j
9k
9l
Bn
Bn
PMB
a
Unless specified otherwise, all the reactions were carried out with 0.1 mmol isatin derivatives 7, 0.2 mL of ketone derivatives 8, and 0.02 mmol catalyst 4a2 (20 mol %) in
co-solvent of 0.4 mL of CH2Cl2 and 0.4 mL of PhOMe.
b
Isolated yields after purification by flash column.
Determined by HPLC on CHIRALPAK columns after purification.
c
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4
G. Chen et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
group at C-5 position may work against the catalyst efficiency
(Table 4, entry 8 vs 1). Cyclohexanone and cyclopentanone were
tested as donor substrates for their effects in this reaction. As
shown in Table 4, these substrates were also very efficient, afford-
ing the relevant adducts in excellent chemical yields and with rea-
sonable enantioselectivities. Along with previous results, the
reaction exhibits higher enantioselectivity when some sterically
hindered substrates were adopted (entries 10–12 vs entry 9).
AD-3 column (80:20 hexane/i-PrOH at 1 mL/min): tmaj = 11.6 min,
tmin = 15.0 min, k = 254 nm.
4.2.2. (S)-1-Methyl-3-(2-oxopropyl)-3-hydroxyindolin-2-one 9b
White solid, 91% yield, 81% ee. Mp: 155–157 °C; [
a
]
25 = ꢀ15.2 (c
D
2.4, MeOH); 1H NMR: d 7.28 (m, 2H), 6.98 (q, J = 8.0 Hz, J = 15.6 Hz,
2H), 6.06 (s, 1H), 3.37 (d, J = 6.4 Hz, 2H), 3.10 (s, 3H), 1.99 (s, 3H);
13C NMR: d 205.1, 176.5, 143.9, 130.9, 129.1, 123.2, 121.9, 108.2,
72.3, 50.4, 30.4, 25.8; MS (ESI): m/z 220 (M++1); The ee was deter-
mined by HPLC using Chiralpak AS-H column (80:20 hexane/i-
PrOH at 1 mL/min): tmaj = 26.6 min, tmin = 31.2 min, k = 254 nm.
3. Conclusion
In conclusion, we have demonstrated the successful application
of phenylalanine lithium salt as an effective novel catalyst for
highly enantioselective aldol reactions of acetone with isatin and
its derivatives. The advantage of these catalysts is that they are
easily prepared from inexpensive natural chiral amino acids. The
influence of different groups substituted on the isatin on the
enantioselectivity of the product of the aldol reaction was
primarily studied. Further investigations into the application of
these catalysts to other reactions and toward the synthesis of
active pharmaceutical motifs are currently underway in our
laboratory.
4.2.3. (S)-1-Benzyl-3-(2-oxopropyl)-3-hydroxyindolin-2-one 9c
Pale yellow solid, 90% yield, 87% ee; Mp: 161–163 °C;
[a]
25 = ꢀ16.4 (c 2.8, MeOH); 1H NMR: d 7.43 (d, J = 7.2 Hz, 1H),
D
7.33 (t, J = 7.2 Hz, 3H), 7.26 (t, J = 7.2 Hz, 1H), 7.17 (t, J = 7.6 Hz,
1H), 6.97 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H),
4.87 (q, J = 16.0 Hz, J = 20.0 Hz, 2H), 3.46 (d, J = 16.0 Hz, 1H), 3.19
(d, J = 16.0 Hz, 1H), 2.03 (s, 3H); 13C NMR: d 205.2, 176.7, 143.1,
136.3, 130.9, 129.0, 128.4, 127.2, 123.4, 122.0, 108.9, 72.3, 50.3,
42.6, 30.4; MS (ESI): m/z 296 (M++1); The ee was determined by
HPLC using Chiralpak AS-H column (80:20 hexane/i-PrOH at
1 mL/min): tmin = 14.7 min, tmaj = 16.5 min, k = 254 nm.
4. Experimental
4.2.4. (S)-1-(4-Methoxybenzyl)-3-(2-oxopropyl)-3-hydroxyindolin-
2-one 9d
25 = ꢀ16.3 (c
4.1. General methods
White solid, 87% yield, 87% ee. Mp: 114–116 °C; [
a]
D
3.7, MeOH); 1H NMR: d 7.36 (d, J = 8.4, 2H), 7.32 (d, J = 7.2, 1H), 7.17
(t, J = 7.6, 1H), 6.96 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 4.8 Hz, 2H), 6.76
(d, J = 7.6, 1H), 6.18 (s, 1H), 4.79 (q, J = 15.6 Hz, J = 37.6 Hz, 2H),
3.72 (s, 3H), 3.43 (d, J = 16.8 Hz, 1H), 3.16 (d, J = 17.2 Hz, 1H),
2.03 (s, 3H); 13C NMR: d 205.2, 176.6, 158.4, 143.1, 128.9, 128.6,
128.1, 121.9, 113.8, 109.0, 72.3, 55.0, 50.3, 42.1, 30.4; MS (ESI):
m/z 326 (M++1). The ee was determined by HPLC using Chiralpak
AS-H column (80:20 hexane/i-PrOH at 1 mL/min): tmaj = 13.6 min,
tmin = 14.1 min, k = 254 nm).
All solvents and reagents were of analytical reagents and used
without further purification. Crude products were purified by col-
umn chromatography on silica gel of 300–400 mesh. TLC analysis
was performed on Silica Gel 60, F254 plates, which were visualized
by UV at 254 nm. Chiral High-performance liquid chromatography
(HPLC) analyses were conducted with a Waters Alliance 2695
instrument, using a UV–visible light (Vis) Waters PDA 2998 detec-
tor and working at 254 nm. The chromatographic grade iso-
propanol and hexane were used as eluents. 1H NMR and 13C
NMR and 19F NMR spectra were recorded on a Bruker Avance
(Varian Unity Inova) 400 MHz spectrometer using TMS as internal
reference chemical shift in d, ppm. Solvent for NMR is DMSO-d6.
Low-resolution mass spectrometry (LR-MS) was carried out on an
AB/MDS Sciex 3200 QTRAP mass spectrometer (AB SCIEX, USA)
equipped with electro-spray ionization (ESI) source. Optical rota-
tions were measured on Anton Paar MCP 200 at k = 589 nm,
D = 1 dm. All aldol reactions were carried out under an atmosphere
of air in a closed system.
4.2.5. (S)-5-Fluoro-3-(2-oxopropyl)-3-hydroxyindolin-2-one 9e
Pale yellow solid, 89% yield, 77% ee. Mp: 183–185 °C;
[a]
25 = ꢀ17.0 (c 1.0, MeOH); 1H NMR: d 10.25 (s, 1H), 7.16 (dd,
D
J = 2.4, J = 8.4 Hz, 1H), 7.03–6.98 (m, 1H), 6.77 (dd, J = 4.0,
J = 8.4 Hz, 1H), 6.10 (s, 1H), 3.35 (d, J = 17.2 Hz, 1H), 3.05 (d,
J = 17.2 Hz, 1H), 2.02 (s, 3H); 13C NMR: d 205.2, 178.2, 158.3 (d,
J = 235.2 Hz), 139.2, 133.8 (d, J = 7.0 Hz), 115.5 (d, J = 23.4 Hz),
112.1 (d, J = 24.6 Hz), 110.6 (d, J = 8.3 Hz), 72.8, 50.0, 30.4; 19F
NMR: d ꢀ122.40; MS (ESI): m/z 224 (M++1). The ee was determined
by HPLC using Chiralpak AS-H column (80:20 hexane/i-PrOH at
1 mL/min): tmaj = 29.2 min, tmin = 36.3 min, k = 254 nm.
4.2. General procedure for the aldol reaction of isatins with
ketones
4.2.6. (S)-5-Chloro-3-(2-oxopropyl)-3-hydroxyindolin-2-one 9f
Pale yellow solid, 97% yield, 78% ee. Mp: 168–169 °C;
The organic salts were directly added to a stirred solution of isa-
tin 7 (0.10 mmol) and ketone 8 (1 mL or 0.2 mL) in the correspond-
ing solvent, then sealed and stirred for the corresponding time and
at the temperature given in Tables 1–4. The solvent was then
removed under reduced pressure and the mixture was purified
by flash chromatography on silica gel (PE and EA as eluents) to give
the desired aldol products.
[a]
25 = ꢀ22.0 (c 1.0, MeOH); 1H NMR: d 10.36 (s, 1H), 7.32 (d,
D
J = 2.0, 1H), 7.23 (d, J = 6.4, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6. 11 (s,
1H), 3.42 (d, J = 10.8 Hz, 1H), 3.07 (d, J = 17.2 Hz, 1H), 2.09 (s,
3H); 13C NMR: d 205.3, 177.8, 141.6, 133.7, 125.2, 124.0, 110.8,
72.6, 49.9, 30.3; MS (ESI): m/z 240 (M++1). The ee was determined
by using HPLC Chiralpak IA column (80:20 hexane/i-PrOH at
1 mL/min): tmaj = 11.1 min, tmin = 15.6 min, k = 254 nm.
4.2.1. (S)-3-(2-Oxopropyl)-3-hydroxyindolin-2-one 9a
Pale yellow solid, 86% yield, 70% ee. Mp: 167–169 °C;
D
4.2.7. 5-Bromo-3-(2-oxopropyl)-3-hydroxyindolin-2-one 9g
Compound 9g was not obtained due to the poor solubility of
5-bromine isatin in the cosolvents of CH2Cl2 and PhOMe.
[a
]
25 = ꢀ11.0 (c 1.0, MeOH); 1H NMR: d 10.23 (s, 1H), 7.24 (d,
J = 7.2 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.90 (t, J = 7.6 Hz, 1H), 6.77
(d, J = 7.6 Hz, 1H), 5.99 (s, 1H), 3.28 (d, J = 16.8 Hz, 1H), 3.05 (d,
J = 16.8 Hz, 1H), 1.99 (s, 3H); 13C NMR: d 205.2, 178.1, 142.5,
131.5, 128.9, 123.6, 121.2, 109.4, 72.6, 50.6, 30.5; MS (ESI): m/z
206 (M++1); The ee was determined by HPLC using Chiralpak
4.2.8. (S)-5-Methyl-3-(2-oxopropyl)-3-hydroxyindolin-2-one 9h
Pale yellow solid, 73% yield, 66% ee. Mp: 158–160 °C;
[a]
25 = ꢀ13.0 (c 1.0, MeOH); 1H NMR: d 10.12 (s, 1H), 7.06
D
Please cite this article in press as: Chen, G.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.008

G. Chen et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
5
(s, 1H), 6.98 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 5.94 (s, 1H),
Acknowledgements
3.24 (d, J = 16.8 Hz, 1H), 3.00 (d, J = 16.4 Hz, 1H), 2.23 (s, 3H), 2.01
(s, 3H); 13C NMR: d 205.2, 178.2, 140.0, 131.6, 129.9, 129.1, 124.3,
109.2, 72.7, 50.3, 30.5, 20.7; MS (ESI): m/z 220 (M++1). The ee was
determined by HPLC using Chiralpak IA column (80:20 hexane/i-
PrOH at 1 mL/min): tmaj = 11.5 min, tmin = 14.4 min, k = 254 nm.
Authors are thankful to Dr. Gu He and Dr. Yongmei Xie for their
valuable suggestions and support.
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[
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D
25 = ꢀ85.0 (c 1.0, MeOH); 1H NMR: d 10.33 (s, 1H), 7.36 (d,
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major diastereoisomer: tmaj = 29.5 min, tmin = 27.4 min, 79% ee;
minor diastereoisomer: tmaj = 20.9 min, tmin = 23.6 min, 52% ee,
k = 254 nm.
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25 = ꢀ75.0 (c
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6.98 (m, 1H), 6.78 (dd, J = 8.0 Hz, J = 38.4 Hz, 1H), 6.19 (d,
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PrOH at 0.8 mL/min): major diastereoisomer: tmaj = 29.9 min,
tmin = 35.3 min, 80% ee; minor diastereoisomer: tmaj = 41.6 min,
tmin = 32.7 min, 55% ee, k = 254 nm.
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4.2.11. 1-Benzyl-3-hydroxy-3-(2-oxocyclohexyl)indolin-2-one 9k
Pale white solid, 97% yield, 83% ee. Mp: 163–165 °C;
[
a]
D
25 = ꢀ42.0 (c 1.0, MeOH); 1H NMR: d 7.45 (d, J = 7.6 Hz, 2H),
7.28 (m, 4H), 7.18 (t, J = 14.8 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 6.72
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3.22 (dd, J = 4.4 Hz, J = 12.8 Hz, 1H), 2.23–1.44 (m, 8H), 13C NMR:
d 209.3, 177.3, 143.9, 136.4, 130.2, 128.6, 128.4, 127.7, 127.1,
124.6, 121.6, 108.9, 73.6, 57.6, 42.8, 41.3, 26.8, 26.6, 24.4. MS
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0.5 mL/min): major diastereoisomer: tmaj = 33.0 min, tmin = 25.7 min,
83% ee; minor diastereoisomer: tmaj = 42.7 min, tmin = 25.7 min,
52% ee, k = 254 nm.
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oxocyclopentyl)indolin-2-one 9l
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Brown solid, 96% yield, 90% ee. Mp: 118–120 °C; [
a]
25 = ꢀ51.0 (c
D
1.0, MeOH); 1H NMR: d 7.43–6.74 (m, 8H), 6.15 (d, J = 25.6, 1H),
4.77 (m, 2H), 3.72 (s, 3H), 2.96 (m, 1H), 2.77–1.64 (m, 6H), 13C
NMR: d 216.4, 176.8, 158.6, 143.4, 130.4, 128.7, 128.0, 124.4,
123.9, 122.3, 121.9, 113.8, 109.1, 74.6, 55.1, 53.9, 42.3, 25.0, 24.6,
19.6. MS (ESI): m/z 352 (M++1). The ee was determined by chiral
HPLC analysis using a ChiralCel OD-H column (90:10 hexane/i-
PrOH at 0.5 mL/min for 40 min, then up to 85:15 hexane/i-PrOH
in 50 min at 0.5 mL/min): major diastereoisomer: tmaj = 83.0 min,
tmin = 78.9 min, 90% ee; minor diastereoisomer: tmaj = 95.0 min,
tmin = 69.8 min, 65% ee, k = 254 nm.
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Tetrahedron Lett. 2015, 56, 981.
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S.; Hu, C. W. J. Am. Chem. Soc. 2008, 130, 5654.
Please cite this article in press as: Chen, G.; et al. Tetrahedron: Asymmetry (2015), http://dx.doi.org/10.1016/j.tetasy.2015.07.008