Enantioselective aldol reaction between isatins and cyclohexanone catalyzed by amino acid sulphonamides

Article abstract of DOI:10.1002/chir.22433

Sulphonamides derived from primary α-amino acid were successfully applied to catalyze the aldol reaction between isatin and cyclohexanone under neat conditions. More interestingly, molecular sieves, as privileged additives, were found to play a vital role in achieving high enantioselectivity. Consequently, high yields (up to 99%) along with good enantioselectivities (up to 92% ee) and diastereoselectivities (up to 95:5 dr) were obtained. In addition, this reaction was also conveniently scaled up, demonstrating the applicability of this protocol.

Full text of DOI:10.1002/chir.22433

CHIRALITY (2015)
Enantioselective Aldol Reaction Between Isatins and Cyclohexanone
Catalyzed by Amino Acid Sulphonamides
JUN WANG,1 QI LIU,1 QING HAO,1 YANHUA SUN,1 YIMING LUO,1 AND HUA YANG1,2
*
1College of Chemistry and Chemical Engineering, Central South University, Changsha, P.R. China
2Collaborative Innovation Center of Resource-conserving & Environment-friendly Society and Ecological Civilization, Changsha, P.R. China
ABSTRACT
Sulphonamides derived from primary α-amino acid were successfully applied
to catalyze the aldol reaction between isatin and cyclohexanone under neat conditions. More
interestingly, molecular sieves, as privileged additives, were found to play a vital role in
achieving high enantioselectivity. Consequently, high yields (up to 99%) along with good
enantioselectivities (up to 92% ee) and diastereoselectivities (up to 95:5 dr) were obtained. In
addition, this reaction was also conveniently scaled up, demonstrating the applicability of this
protocol. Chirality 00:000-000, 2015. © 2015 Wiley Periodicals, Inc.
KEY WORDS: organocatalysis; neat conditions; asymmetric synthesis; molecular sieves;
3-cycloalkanone-3-hydroxy-2-oxindole
3-Substituted-3-hydroxy-2-oxindoles are an important class
of structure motifs in numerous natural products and biologi-
cally active compounds, which thus have been widely studied
in the field of medicinal chemistry.1–6 Due to their interesting
biological profiles including anticonvulsant activity, 3-alkyl-3-
hydroxy-2-oxindoles hold great promise for medicinal studies
and therefore have attracted growing interest for synthetic
chemists in recent years.7–9 Apparently, considering their in-
trinsic chiral character, the direct organocatalytic aldol reac-
tion between isatin and the carbonyl compound has proved
to be the most straightforward and concise route to install this
structure with the desired absolute configuration.10–12 In 2005,
Tomasini and colleagues successfully employed dipeptide-
based organocatalysts to realize the first enantioselective
aldol reaction of isatin with acetone.13 Since then, intensive
efforts have been devoted to develop a more efficient
organocatalytic system, aiming to achieve satisfactory
stereocontrol. In recent years, specific attention has focused
on the asymmetric synthesis of 3-cycloalkanone-3-hydroxy-2-
oxindole, owing to its promising anticonvulsant activity. Singh
and coworkers reported their elegant work on the first
enantioselective synthesis of 3-cycloalkanone-3-hydroxy-2-
oxindole, which was catalyzed by primary-tertiary diamine-
Brønsted acid.14 Subsequently, several research groups re-
ported encouraging results to enantioselectively prepare this
compound.15–22
On the other hand, in consideration of practicability, it
is highly desirable to develop effective organocatalysts
derived from readily available natural chiral feedstock. In
our previous work we designed and conveniently synthesized
a series of primary α-amino acid sulphonamides, which dem-
onstrated enhanced solubility profiles in regular organic sol-
vents and showed satisfactory catalytic performance in the
enantioselective synthesis of 2-aryl-2,3-dihydro-4-quinolones
via an intramolecular Mannich reaction.23 Thus, our contin-
ued research interest prompted us to further investigate the
versatility of the catalytic activities for various asymmetric
transformations. Herein we report an enantioselective aldol
reaction of cyclohexanone with isatin catalyzed by primary
α-amino acid sulphonamides under neat conditions. More
important, molecular sieves, possessing advantages such as
environmentally benign properties, easy separation, and low
© 2015 Wiley Periodicals, Inc.
cost, were found to be crucial to the stereocontrol in this
protocol.
MATERIALS AND METHODS
Materials
Unless otherwise noted, all reagents were acquired at high commercial
quality and used without purification. All reactions were monitored by
thin-layer chromatography (TLC) and products were purified by flash
chromatography on silica gel (200–300 mesh). All reported nuclear mag-
netic resonance (NMR) spectra were collected on a Bruker (Billerica,
MA) Avance 400 spectrometer. Chemical shifts in ppm relative to either
tetramethylsilane (TMS) or the residual solvent as an internal standard,
integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet,
dd = double-doublet, m = multiplet, and br = broad), coupling constants
(Hz), and assignment. Infrared (IR) spectra were recorded on a Nicolet
NEXUS 670 FT-IR spectrophotometer. Enantiomeric excesses (ee) and
diastereoselectivities were determined by high-performance liquid chro-
matography (HPLC) using Chiralcel OJ-H, AD-H and OD-H column using
n-Hexane/i-PrOH as a mobile phase. Catalysts 1a-1d were prepared
according to the reported procedures.23
Substrate Synthesis
General procedure for the synthesis of 1e and 1f. Under a dry
argon atmosphere, to a stirred ice-cold solution of Cbz-serine (2.39 g,
10.0 mmol) in DMF (8 mL) was added tert-butyldimethylchlorosilane
(1.81 g, 12.0 mmol) and imidazole (1.91 g, 28.0 mmol) sequentially. The
resulting mixture was stirred at 0°C for 1 h, warmed to room tempera-
ture, and then stirred for 24 h. The mixture was diluted with EtOAc
(50 mL) and stirred for 15 min before being partitioned between EtOAc
(150 mL) and aq. HCl (1 N, 40 mL). The organic layer was washed with
saturated brine (2 x 50 mL) and dried over Na2SO4. The extract was con-
centrated in vacuo and the crude product (colorless oil) was used for the
next step without further purification. The crude product was added into a
solution of substituted benzenesulfonamide (11.0 mmol), DMAP (0.37 g,
3.0 mmol), and EDCI (2.30 g, 12.0 mmol) in dichloromethane (50 mL)
Contract grant sponsor: National Natural Science Foundation of China; Con-
tract grant numbers: 21376270.21276282.
Contract grant sponsor: Hunan Provincial Science & Technology Department;
Contract grant number: 2012WK2007.
*Correspondence to: H. Yang, College of Chemistry and Chemical Engineer-
ing, Central South University, Changsha 410083, P.R. China. E-mail:
hyangchem@csu.edu.cn
Received for publication 4 November 2014; Accepted 16 January 2015
DOI: 10.1002/chir.22433
Published online in Wiley Online Library
(wileyonlinelibrary.com).

WANG ET AL.
under a dry argon atmosphere. After 24 h the reaction mixture was acid- (S)-5-Bromo-3-hydroxy-3-((R)-2-oxocyclohexyl)indolin-2-one,
ified to pH = 3 with aq. HCl (3 N, 40 mL). Next, the solvent was removed
in vacuo. The residue was redissolved in EtOAc (100 mL), washed with
half-saturated brine (4 x 50 mL), and dried over Na2SO4. The solution
was concentrated to give the crude product (light yellow oil). Then the
residue was dissolved in MeOH (30 mL) and 10% Pd/C (0.50 g) was
added to it. The reaction mixture was allowed to react under a hydrogen
atmosphere overnight before it was filtered and concentrated in vacuo.
The resulting residue was purified through flash column chromatography
on silica gel (CH2Cl2/MeOH = 39:1-9:1) to provide the corresponding
sulfonamide 1e or 1f.
4d22
. White solid, mp: 226–228°C; Catalyzed by 1a: 50.0 mg, 77% yield;
[α]2D5 = -16.3 (c = 0.1, MeOH); syn/anti = 86:14; 67% ee of syn- diastereomer;
HPLC analysis: Diacel Chiralcel AD-H, n-Hexane/i-PrOH = 85/15, flow rate
= 1 mL/min, λ = 254 nm, retention time: 20.3 min (major) and 27.8 min (mi-
nor); 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.36 (dd, J = 8.0, 2.0
Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.01 (s, 1H),
3.09 (dd, J = 12.4, 4.4 Hz, 1H), 2.55-2.60 (m, 1H), 2.29-2.34 (m, 1H), 1.92-
2.05 (m, 3H), 1.66-1.79 (m, 2H), 1.48-1.56 (m, 1H).
(S)-6-Chloro-3-hydroxy-3-((R)-2-oxocyclohexyl)indolin-2-one,
4e18
. White solid, mp: 206–208°C; Catalyzed by 1a: 47.4 mg, 85% yield;
[α]2D5 = -29.8 (c = 0.2, MeOH); syn/anti = 79:21; 84% ee of syn- diastereomer;
HPLC analysis: Diacel Chiralcel OD-H, n-Hexane/i-PrOH = 95/5, flow rate
= 1.0 mL/min, λ = 260 nm, retention time: 46.4 min (major) and 43.6 min
(minor); 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.21 (d, J = 8.0
Hz, 1H), 6.88-6.91 (m, 1H), 6.80 (d, J = 1.6 Hz, 1H), 5.94 (s, 1H), 3.09 (dd,
J = 12.8, 4.8 Hz, 1H), 2.55-2.60 (m, 1H), 2.29-3.37 (m, 1H), 1.91-2.04 (m,
3H), 1.63-1.81 (m, 2H), 1.41-1.51 (m, 1H).
O-(tert-Butyldimethylsiloxy)-N-4-dodecylbenzenesulfonyl-L-serine
amide, 1e. White powder (2.48 g, yield 47%); [α]2D5 = +34.0 (c = 0.5,
MeOH); mp: 156–158°C; IR (KBr disc) v 3445, 2927, 1638, 1503, 1258,
1089, 844, 779 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J = 8.0
Hz, 2H), 7.68 (br s, 2H), 7.15 (d, J = 8.0 Hz, 2H), 3.81-3.88 (m, 2H), 3.45
(t, J = 4.0 Hz, 2H), 1.49-1.60 (m, 4H), 1.02-1.21 (m, 15H), 0.78-0.88 (m,
15H), 0.02 (s, 3H), -0.01 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
170.1, 148.5, 143.5, 127.4, 127.0, 63.0, 57.1, 45.4, 45.1, 36.7, 31.7, 29.5,
29.1, 27.5, 27.1, 26.3, 22.5, 20.6, 18.5, 14.4, 12.5, 5.1; HRMS (TOF-ES+)
m/z: [M+Na]+ calcd for C27H50N2O4SSiNa 549.3158, found 549.3138.
(S)-7-Chloro-3-hydroxy-3-((R)-2-oxocyclohexyl)indolin-2-one,
4f. Whitesolid,mp:195–197°C;Catalyzedby1a:51.9mg,93%yield;[α]D25
=
-33.1(c=0.1,MeOH);syn/anti=86:14;72%eeofsyn-diastereomer;HPLCanal-
ysis:DiacelChiralcelAD-H,n-Hexane/i-PrOH=92/8,flowrate=1.0mL/min,
λ = 260 nm, retention time: 53.5 min (major) and 45.6 min (minor); IR (KBr
disc) v 3425, 2944, 1729, 1619, 1473, 1088, 791, 735 cm-1; 1H NMR (400
MHz, DMSO-d6) δ 10.62 (s, 1H), 7.19-7.26 (m, 2H), 6.90 (t, J = 8.0 Hz, 1H),
6.03 (s, 1H), 3.12 (dd, J = 12.8, 4.8 Hz, 1H), 2.58-2.61 (m, 1H), 2.31-3.39 (m,
1H), 1.42-2.06 (m, 6H); 13C NMR (100 MHz, DMSO-d6) δ 209.7, 179.1,
141.5, 133.3, 129.1, 123.8, 122.7, 114.2, 74.9, 57.9, 41.9, 27.1, 24.9; HRMS
(TOF-ES+) m/z: [M+Na]+ calcd for C14H14NO3ClNa 302.0560, found
302.0562.
O-(tert-Butyldimethylsiloxy)-N-2,4,6-tris-(methylbenzene)sulfonyl-
L-serine amide, 1f. White powder (2.04 g, yield 51%); [α]2D5 = +27.4 (c =
0.5, MeOH); mp: 214–216°C; IR (KBr disc) v 3447, 2959, 1636, 1501,
1259, 1084, 841, 729, 662 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.68
(br s, 2H), 6.78 (s, 2H), 3.97 (dd, J = 10.8, 3.6 Hz, 1H), 3.70 (dd, J = 10.4,
3.6 Hz, 1H), 3.43-3.46 (m, 1H), 2.59 (s, 6 H), 2.18 (s, 3H), 0.86 (s, 9H),
0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 170.1,
140.3, 138.8, 138.4, 130.6, 63.1, 57.2, 26.3, 23.0, 20.8, 18.6, -5.0, -5.1; HRMS
(TOF-ES+) m/z: [M+H]+ calcd for C18H33N2O4SSi 401.1930, found
401.1911.
(S)-6-Bromo-3-hydroxy-3-((R)-2-oxocyclohexyl)indolin-2-one,
4g18
. White solid, mp: 222–224°C; Catalyzed by 1a: 51.0 mg, 79% yield;
General procedure for the synthesis of 4a-4q. To a stirred solution
of catalyst 1a (10.8 mg, 0.04 mmol) in cyclohexanone 3 (1 mL) was
added isatins (0.2 mmol) and the powder of 4 Å molecular sieves (4 Å
MS, 0.2 g) sequentially at room temperature. The resulting mixture was
stirred at room temperature for 18 h and filtered to achieve a clear solu-
tion, which was directly purified through flash column chromatography
on silica gel (PE: EtOAc = 3:2) to afford the corresponding product.
1
[α]2D5 = -41.2 (c = 0.1, MeOH); H NMR (400 MHz, DMSO-d6) δ 10.37 (s,
1H), 7.16 (d, J = 8.0 Hz, 1H), 7.04 (dd, J = 8.0, 2.0 Hz, 1H), 6.94 (d, J = 1.6
Hz, 1H), 5.96 (s, 1H), 3.09 (dd, J = 12.8, 4.8 Hz, 1H), 2.55-2.60 (m, 1H),
2.30-2.38 (m, 1H), 1.91-2.05 (m, 3H), 1.67-1.85 (m, 2H), 1.43-1.53 (m, 1H).
(S)-3-Hydroxy-5-methyl-3-((R)-2-oxocyclohexyl)indolin-2-one,
4h22
. White solid, mp: 202–204°C; Catalyzed by 1a: 38.8 mg, 75% yield;
1
[α]2D5 = -34.3 (c = 0.2, MeOH); H NMR (400 MHz, DMSO-d6) δ 10.08 (s,
1H), 7.04 (s, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 5.76 (s,
1H), 3.06 (dd, J = 13.2, 4.8 Hz, 1H), 2.51-2.60 (m, 4H), 2.28-2.36 (m, 1H),
1.80-2.05 (m, 4H), 1.63-1.72 (m, 1H), 1.44-1.55 (m, 1H).
(S)-3-Hydroxy-3-((R)-2-oxocyclohexyl)indolin-2-one, 4a22
. White
solid, mp: 188–190°C; Catalyzed by 1a: 48.5 mg, 99% yield; [α]2D5 = -32.9
(c = 0.2, MeOH); syn/anti = 95:5; 92% ee of syn- diastereomer; HPLC anal-
ysis: Diacel Chiralcel OJ-H, n-Hexane/i-PrOH = 80/20, flow rate = 1.0
mL/min, λ = 254 nm, retention time: 15.5 min (major) and 12.2 min (mi-
nor); 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 7.15-7.23 (m, 2H),
6.78-6.88 (m, 2H), 5.82 (s, 1H), 3.08 (dd, J = 13.2, 5.2 Hz, 1H), 2.57-2.62
(m, 1H), 2.28-2.36 (m, 1H), 1.79-2.05 (m, 4H), 1.63-1.72 (m, 1H), 1.41-
1.53 (m, 1H).
(S)-3-Hydroxy-1-methyl-3-((R)-2-oxocyclohexyl)indolin-2-one,
4i22
. White solid, mp: 158–160°C; Catalyzed by 1a: 47.3 mg, 91% yield;
[α]2D5 = -47.8 (c = 0.2, MeOH); syn/anti = 98:2; 91% ee of syn- diastereomer;
HPLC analysis: Diacel Chiralcel OJ-H, n-Hexane/i-PrOH = 80/20, flow
rate = 1.0 mL/min, λ = 254 nm, retention time: 14.4 min (major) and
13.5 min (minor); 1H NMR (400 MHz, DMSO-d6) δ 7.26-7.30 (m, 2H),
6.93-6.98 (m, 2H), 5.91 (s, 1H), 3.09-3.16 (m, 4H), 2.59-2.64 (m, 1H),
2.27-2.35 (m, 1H), 1.67-2.02 (m, 5H), 1.41-1.51 (m, 1H).
(S)-5-Fluoro-3-hydroxy-3-((R)-2-oxocyclohexyl)indolin-2-one,
4b22
. White solid, mp: 206–208°C; Catalyzed by 1a: 50.3 mg, 96% yield;
[α]2D5 = -23.9 (c = 0.2, MeOH); syn/anti = 91:9; 82% ee of syn- diastereomer;
HPLC analysis: Diacel Chiralcel AD-H, n-Hexane/i-PrOH = 92/8, flow rate =
1.0 mL/min, λ = 254 nm, retention time: 53.6 min (major) and 62.5 min
(minor); 1H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 6.98-7.07 (m, 2H),
6.76-6.79 (m, 1H), 5.98 (s, 1H), 3.09 (dd, J = 13.2, 4.8 Hz, 1H), 2.55-2.60 (m,
1H), 2.29-2.38 (m, 1H), 1.63-2.06 (m, 5H), 1.44-1.56 (m, 1H).
(S)-1-Benzyl-3-hydroxy-3-((R)-2-oxocyclohexyl)indolin-2-one,
4j22
. White solid, mp: 194–196°C; Catalyzed by 1a: 62.1 mg, 93% yield;
[α]2D5 = -32.4 (c = 0.1, MeOH); syn/anti = 93:7; 82% ee of syn- diastereomer;
HPLC analysis: Diacel Chiralcel OJ-H, n-Hexane/i-PrOH = 80/20, flow
rate = 1.0 mL/min, λ = 254 nm, retention time: 14.5 min (major) and 12.3
min (minor); 1H NMR (400 MHz, DMSO-d6) δ 7.44-7.46 (m, 2H), 7.24-
7.35 (m, 4H), 7.15-7.19 (m, 1H), 6.91-6.95 (m, 1H), 6.73 (d, J = 7.6 Hz,
1H), 6.03 (s, 1H), 4.79-4.92 (m, 2H), 3.21-3.25 (m, 1H), 2.64-2.68 (m, 1H),
2.33-2.41 (m, 1H), 1.85-2.08 (m, 4H), 1.70-1.73 (m, 1H), 1.44-1.54 (m, 1H).
(S)-5-Chloro-3-hydroxy-3-((R)-2-oxocyclohexyl)indolin-2-one,
4c6h
. White solid, mp: 225–227°C; Catalyzed by 1a: 53.5 mg, 96% yield;
[α]2D5 = -27.8 (c = 0.2, MeOH); syn/anti = 95:5; 77% ee of syn- diastereomer;
HPLC analysis: Diacel Chiralcel AD-H, n-Hexane/i-PrOH = 85/15, flow
rate = 1.0 mL/min, λ = 254 nm, retention time: 20.7 min (major) and 26.6
min (minor); 1H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 7.20-7.25
(m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.02 (s, 1H), 3.11 (dd, J = 12.8, 4.8 Hz,
1H), 2.57-2.61 (m, 1H), 2.30-2.38 (m, 1H), 1.47-2.06 (m, 6H).
(S)-5-Fluoro-3-hydroxy-1-methyl-3-((R)-2-oxocyclohexyl)indolin-2-
one, 4k. White solid, mp: 165–167°C; Catalyzed by 1a: 54.4 mg, 98%
yield; [α]2D5 = -40.5 (c = 0.2, MeOH); syn/anti = 92:8; 78% ee of syn- diaste-
reomer; HPLC analysis: Diacel Chiralcel OJ-H, n-Hexane/i-PrOH = 97/3,
Chirality DOI 10.1002/chir

ALDOL REACTION BETWEEN ISATINS AND CYCLOHEXANONE
flow rate = 1.0 mL/min, λ = 254 nm, retention time: 39.9 min (major) and
PrOH = 80/20, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 18.8
min (major) and 15.1 min (minor); 1H NMR (400 MHz, DMSO-d6) δ
10.21 (s, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.15-7.19 (m, 1H), 6.90 (t, J = 7.6
Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 5.97 (s, 1H), 3.27 (d, J = 16.4 Hz, 1H),
3.00 (d, J = 16.8 Hz, 1H), 2.00 (s, 3H).
48.6 min (minor); IR (KBr disc) v 3266, 2942, 1701, 1619, 1498, 1378,
1
1092, 883, 665 cm-1; H NMR (400 MHz, DMSO-d6) δ 7.11-7.16 (m, 2H),
6.97-7.00 (m, 1H), 6.07 (s, 1H), 3.10-3.18 (m, 4H), 2.57-2.62 (m, 1H),
2.28-2.37 (m, 1H), 1.63-2.04 (m, 5H), 1.43-1.55 (m, 1H); 13C NMR (100
MHz, DMSO-d6) δ 209.6, 177.4, 159.6, 157.3, 141.5 (d, JC-F = 1.4 Hz),
132.3 (d, JC-F = 7.6 Hz), 115.1 (d, JC-F = 22.8 Hz), 113.0 (d, JC-F = 24.8
Hz), 109.3 (d, JC-F = 8.1 Hz), 74.2, 58.1, 41.9, 27.1, 27.0, 26.5, 24.9; HRMS
(TOF-ES+) m/z: [M+Na]+ calcd for C15H16N O3FNa 300.1012, found
300.1022.
(S)-3-Hydroxy-3-((R)-2-oxocyclopentyl)indolin-2-one, 4p22
. White
solid, mp: 180–182°C; Catalyzed by 1a: 36.0 mg, 78% yield; [α]2D5 = -20.4
(c = 0.1, MeOH); syn/anti = 62:38; 13% ee of syn- diastereomer; HPLC anal-
ysis: Diacel Chiralcel AD-H, n-Hexane/i-PrOH = 90/10, flow rate = 1.0
mL/min, λ = 254 nm, retention time: 37.1 min (major) and 33.8 min
(minor); 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.37 (d, J = 7.6 Hz,
1H), 7.19 (td, J = 8.0, 0.8 Hz, 1H), 6.88-6.92 (m, 1H), 6.77 (d, J = 7.6 Hz,
1H), 5.99 (s, 1H), 2.86-2.91 (m, 1H), 2.18-2.27 (m, 1H), 2.08-2.16 (m,
2H), 1.89-1.96 (m, 1H), 1.68-1.85 (m, 2H).
(S)-5-Chloro-3-hydroxy-1-methyl-3-((R)-2-oxocyclohexyl)indolin-2-
one, 4l18
. White solid, mp: 179–180°C; Catalyzed by 1a: 54.6 mg, 93%
yield; [α]2D5 = -29.6 (c = 0.1, MeOH); syn/anti = 78:22; 83% ee of syn- diaste-
reomer; HPLC analysis: Diacel Chiralcel AD-H, n-Hexane/i-PrOH = 95/5,
flow rate = 1.0 mL/min, λ = 254 nm, retention time: 54.0 min (major) and
50.5 min (minor); IR (KBr disc) v 3312, 2938, 2867, 1704, 1611, 1493,
(S)-3-Hhydroxy-3-((R)-2-oxocycloheptyl)indolin-2-one, 4q22
. White
solid, mp: 178–180°C; Catalyzed by 1a: 36.3 mg, 70% yield; [α]2D5 = -19.8
(c = 0.5, CHCl3); syn/anti = 79:21; 31% ee of syn- diastereomer; HPLC analy-
sis: Diacel Chiralcel AD-H, n-Hexane/i-PrOH = 92/8, flow rate = 1.0
mL/min, λ = 254 nm, retention time: 57.9 min (major) and 73.5 min (mi-
1370, 1092, 821, 649 cm-1; H NMR (400 MHz, DMSO-d6) δ 7.36 (dd, J =
1
8.0, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.10
(s, 1H), 3.10-3.19 (m, 4H), 2.59-2.62 (m, 1H), 2.29-2.38 (m, 1H), 1.65-
2.04 (m, 5H), 1.46-1.57 (m, 1H).
1
nor); H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 7.24 (d, J = 7.6 Hz,
(S)-5-Bromo- 3-hydroxy-1-methyl-3-((R)-2-oxocyclohexyl)indolin-
2-one, 4m. White solid, mp: 173–175°C; Catalyzed by 1a: 66.4 mg,
99% yield; [α]2D5 = -36.3 (c = 0.2, MeOH); syn/anti = 92:8; 80% ee of syn- di-
astereomer; HPLC analysis: Diacel Chiralcel OD-H, n-Hexane/i-PrOH =
95/5, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 31.8 min (major)
and 26.9 min (minor); IR (KBr disc) v 3335, 2938, 1704, 1607, 1364, 1114,
1059, 819 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (dd, J = 8.4, 2.0 Hz,
1H), 7.34 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.10 (s, 1H), 3.13-3.18
(m, 1H), 3.08 (s, 3H), 2.58-2.62 (m, 1H), 2.28-2.37 (m, 1H), 1.92-2.03 (m,
3H), 1.64-1.83 (m, 2H), 1.45-1.56 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 209.8, 177.1, 144.7, 133.0, 131.9, 127.6, 113.8, 110.7, 74.0,
58.2, 41.9, 27.2, 27.1, 26.5, 24.8; HRMS (TOF-ES+) m/z: [M+Na]+ calcd
for C15H16NO3BrNa 360.0211, found 360.0198.
1H), 7.13-7.19 (m, 1H), 6.86-6.92 (m, 1H), 6.73-6.78 (m, 1H), 5.97 (s, 1H),
3.10 (dd, J = 11.6, 2.8 Hz, 1H), 2.41-2.46 (m, 1H), 2.14-2.28 (m, 2H), 1.99-
2.02 (m, 1H), 1.80-1.89 (m, 1H), 1.62-1.76 (m, 1H), 1.24-1.51 (m, 3H).
(S)-3-Hhydroxy-3-((R)-2-oxopentan-2-yl)indolin-2-one, 4r24
. White
solid, mp: 103–105°C; Catalyzed by 1a: 14.9 mg, 23% yield; [α]2D5 = -21.3 (c =
0.5, MeOH); syn/anti = 76:24; 27% ee of syn- diastereomer; HPLC analysis:
Diacel Chiralcel OJ-H, n-Hexane/i-PrOH = 80/20, flow rate = 1.0 mL/min, λ
= 254 nm, retention time: 14.2 min (major) and 16.5 min (minor); 1H NMR
(400 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.18-7.26 (m, 2H), 6.91-6.95 (m, 1H),
6.77 (d, J = 7.6 Hz, 1H), 6.73-6.78 (m, 1H), 3.13 (dd, J = 14.4, 7.2 Hz, 1H),
2.40-2.55 (m, 2H), 1.17 (d, J = 7.2 Hz, 3H), 0.77-0.81 (m, 3H).
RESULTS AND DISCUSSION
(S)-6-Bromo-3-hydroxy-1-methyl-3-((R)-2-oxocyclohexyl)indolin-2-
one, 4n. White solid, mp: 126–128°C; Catalyzed by 1a: 63.7 mg, 95%
yield; [α]2D5 = -41.1 (c = 0.2, MeOH); syn/anti = 89:11; 87% ee of syn- diaste-
reomer; HPLC analysis: Diacel Chiralcel OJ-H, n-Hexane/i-PrOH =
90/10, flow rate = 1.0 mL/min, λ = 254 nm, retention time: 13.2 min
(major) and 19.0 min (minor); IR (KBr disc) v 3423, 2947, 1707, 1606, 1440,
1373, 1106, 967, 818 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 7.24 (d, J =
2.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.12 (dd, J = 8.0, 2.0 Hz, 1H), 6.10
(s, 1H), 3.09-3.16 (m, 4H), 2.57-2.61 (m, 1H), 2.27-2.36 (m, 1H), 1.90-
2.01 (m, 3H), 1.63-1.81 (m, 2H), 1.39-1.50 (m, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 209.7, 177.5, 147.1, 129.9, 126.6, 124.5, 122.3, 111.9, 73.7,
58.2, 41.8, 27.2, 27.1, 26.5, 24.8; HRMS (TOF-ES+) m/z: [M+H]+ calcd
for C15H17NO3Br 338.0392, found 338.0394.
A series of primary α-amino acid-derived sulfonamides were
readily synthesized via the direct coupling of Cbz-protected
amino acids with sulphonamides followed by deprotection,
which were subjected to the subsequent investigation on cata-
lytic activities for the aldol reaction of cyclohexanone and
isatin (Scheme 1).
Initially, we examined the aldol reaction of isatin 2 with cy-
clohexanone 3 under neat conditions to evaluate the catalytic
activities of 1a–f at room temperature. The results are shown
in Table 1. It was found that the catalytic activities of these six
catalysts varied significantly. To our delight, alanine-derived
sulfonamide catalysts 1a and 1b furnished the desired aldol
products in excellent yields and good diastereoselectivities
(entries 1 and 2). But 1a can afford a relatively higher ee
value. Compared with catalysts 1a and 1b, phenylalanine
(S)-3-Hydroxy-3-(2-oxopropyl)indolin-2-one, 4o19
. White solid,
mp: 176–178°C; Catalyzed by 1a: 36.5 mg, 89% yield; [α]2D5 = -17.3 (c =
0.1, MeOH); 26% ee; HPLC analysis: Diacel Chiralcel OJ-H, n-Hexane/i-
Scheme 1. Primary amino acid-derived sulfonamides screened for the Aldol reaction.
Chirality DOI 10.1002/chir

WANG ET AL.
TABLE 1. Optimization of asymmetric synthesis of 3-
cycloalkanone-3-hydroxy-2-oxindolea
and 1f can deliver products in good yields (91% and 92%), their
enantioselectivities and diastereoselectivities are frustrating
(entries 5 and 6). Overall, 1a was found to be the superior cat-
alyst for this reaction under neat conditions, in terms of yield
(99%), enantioselectivity (46% ee), and diastereoselectivity
(79:21). In order to evaluate the efficacy of neat conditions for
this catalytic system, several regular organic solvents were also
examined (entries 7–9). All the reactions were performed in the
presence of 20 mol% catalyst 1a at room temperature. With
CH2Cl2 as the solvent, the reaction proceeded smoothly with
good yield (93%), but poor stereoselectivity (12% ee) (entry 7).
Using toluene also gave unsatisfactory stereoselectivity, albeit
with excellent yield (99%) (entry 8). Then more polar solvents
were tested and it was found that enantiomeric excess was dra-
matically eroded to 1% in DMF (entry 9). As a result, the neat
conditions would be employed due to its incomparable perfor-
mance in this reaction.
Yieldb
(%)
eec,d (%)
(syn/anti)
drc
(syn/anti)
Entry
Catalyst
Solvent
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1a
1a
1a
neat
neat
neat
neat
neat
95
97
89
79
91
92
93
99
96
46/72
22/39
21/52
17/35
30/35
11/25
12/24
20/57
1/37
79:21
74:26
73:27
61:39
67:33
53:47
58:42
53:47
54:46
In this context, various additives for this aldol reaction
were also tested to improve stereoselectivity and
diastereoselectivity, and the results are summarized in
Table 2. The addition of water (3.0 equiv) can accelerate
this reaction and afford an excellent yield (98%) along
with the slightly dropped stereoselectivity in a shorter time
(entry 1). The reactions performed in the presence of cate-
chol or triethylamine afforded aldol adduct 4a with close
enantioselectivities (43% ee and 41% ee) and diastereomeric ra-
tio (75:25 and 72:28 dr), respectively (entries 2 and 3). Sur-
prisingly, when 0.1 g of 4 Å molecular sieves (MS) without
activation was added into the reaction, enantioselectivity
(86% ee) and diastereomeric ratio (91:9) were significantly
improved, albeit with moderate yield obtained (85%) (entry 4).
Furthermore, additional studies on the amount of molecular
sieves indicated that 0.2 g of 4 Å molecular sieves was
the best choice, giving the desired aldol product 3-
cycloalkanone-3-hydroxy-2-oxindole in 99% yield, 92% ee,
and 95:5 dr (entry 5). A large amount of molecular sieves
neat
e
CH2Cl2
Toluenee
DMFe
aReaction conditions: isatin 2 (0.2 mmol), cyclohexanone 3 (1 mL), catalysts 1
(0.04 mmol), room temperature (25°C) and reaction time (24 h).
bYield of a mixture of syn and anti products.
cDetermined by chiral HPLC.
dAbsolute configuration of the major syn diastereoisomer was determined by
1H NMR spectroscopy comparing with literature data.14
e1 mL of solvent used.
sulfonamide catalysts 1c and 1d showed lower catalytic activ-
ities in terms of yield (89% and 79%) and enantioselectivity
(21% ee and 17% ee), respectively. This might be attributed
to the reason that the water molecules cluster involved in
the stereoselective process is transmitting chiral information
in a less efficient way with this catalyst. Although catalysts 1e
TABLE 2. Screening of additive for the reactiona
Entry
Additive
T
Time (h)
Yieldb (%)
eec,d (%) (syn)
drc (syn/anti)
1
2
3
4
5
6
7
8
9
H2O (3.0 equiv)
Catechol(3.0equiv)
Et3N (3.0 equiv)
4 Å MS (0.1 g)e
4 Å MS (0.2 g)e
4 Å MS (0.3 g)e
4 Å MS (0.4 g)e
4 Å MS (0.2 g)e
4 Å MS (0.2 g)f
25°C
25°C
25°C
25°C
25°C
25°C
25°C
0°C
18
18
18
24
18
22
24
72
12
98
99
95
85
99
81
67
41
99
34
43
41
86
92
80
72
51
24
77:23
75:25
72:28
91:9
95:5
82:18
69:31
53:47
81:19
25°C
aReaction conditions: isatin 2 (0.2 mmol), cyclohexanone 3 (1 mL), catalyst 1a (0.04 mmol), additive, room temperature (25°C).
bYield of a mixture of syn and anti products.
cDetermined by chiral HPLC.
1
dAbsolute configuration of the major syn diastereoisomer was determined by H NMR spectroscopy comparing with literature data.14
ePulverized without activation.
fPulverized after activation at 120°C for 4 h.
Chirality DOI 10.1002/chir

ALDOL REACTION BETWEEN ISATINS AND CYCLOHEXANONE
inthe reaction would be detrimental to chemical yield,
good yields, ee could not be identified due to the inseparability
of two enantiomers on chiral HPLC. Interestingly, N-
methylisatin reacted smoothly to give 4i in high yield and ee,
along with excellent dr. Similarly, using N-benzylisatin also
afforded 4j in high yield, but moderate ee and dr. Subse-
quently, N-methylisatins with various substitution patterns
were evaluated. Excellent yield and moderate to good ee and
dr were generally observed (entries 10–13). Different ketones
including acetone, cyclopentanone, and cycloheptanone
were also tested to react with isatin, providing products
4p–4q in good yields along with significantly dropped
enantioselectivities and diastereoselectivities. 3-Pentanone
provides product 4r in poor yield and enantioselectivity.
In order to test the feasibility and reliability of this protocol,
the aldol reaction of isatin 2 with cyclohexanone 3 was scaled
up to 2 mmol, which was conducted in a 12-mL reaction vial as
shown in Scheme 2. At the same time, the catalyst loading
was reduced to 10 mol% with the addition of molecular sieves
(1.0 g). Satisfyingly, good chemical yield and dr were also
achieved, albeit with a slightly dropped ee.
Based on the experimental results and effect of molecular
sieves, a plausible reaction mode is proposed in Figure 1.
Initially, cyclohexanone reacted with sulphonamide 1a to
furnish the corresponding enamine. The hydrogen-bonding
between N-H of sulphonamide and isatin would enforce an
Re face attack of enamine to the carbonyl group of isatin,
resulting in the corresponding absolute configuration. It is
worth noting that water might possibly mediate the hydrogen
bonding formation between the N atom of enamine and car-
bonyl group of isatin. In this way, the facial selectivity of this
process was obviously strengthened due to the existence of
multiple hydrogen-bondings.
enantioselectivity, and diastereoselectivity (entries 6 and 7).
Then, aiming to achieve higher enantioselectivity, the reac-
tion was conducted at 0°C. Unfortunately, the reaction
results were even worse (entry 8). Interestingly, if 4 Å molec-
ular sieves were preactivated before use, excellent yield
(99%) was obtained in a shorter reaction duration (10 h).
However, enantioselectivity was severely eroded to 24% ee
and diastereoselectivity also dropped (entry 9). These results
suggested that water might participate in the reaction path-
way and offer assistance in achieving high enantioselectivity.
Consequently, the activated molecular sieves could effec-
tively remove the trace amount of water in the reaction sys-
tem, resulting in the lowered ee. The molecular sieves may
play a role in controlling the amount of water. Therefore,
the presence of an exact amount of molecular sieves had
a beneficial effect on the reaction and this result may be
found in the organocatalyzed processes where water partici-
pates.24–26 As a result, the optimized reaction conditions
were finalized as this: isatin 2 (1.0 equiv, 0.2 mmol) with cy-
clohexanone 3 (1 mL) under neat conditions in the presence
of catalyst 1a (20 mol%) and 4 Å molecular sieve (0.2 g) with-
out preactivation at room temperature.
Next, the substrate scope of the reaction was studied
and the results are illustrated in Table 3. 5-Fluoro and 5-
chloroisatin gave the corresponding aldol products in high
yields and good ee and dr (entries 1 and 2). Lower yield and
enantioselectivity as well as diastereoselectivity were ob-
served by employing 6-bromoisatin (entry 3). 6-Chloroisatin
and 7-chloroisatin could provide 4e and 4f in 84% and 93%
yield, respectively, with moderate dr and good ee (entries 4
and 5). Unfortunately, although 4g and 4h were obtained in
TABLE 3. Substrate scope for the asymmetric synthesis of 3-substituted-3-hydroxy-2-oxindolea
Entry
R1 R2 R3, R4
Product
Time (h)
Yieldb (%)
eec (%) (syn)
drc (syn/anti)
1
2
3
4
5
6
7
8
5-F H -(CH2)3-
5-Cl H -(CH2)3-
5-Br H -(CH2)3-
6-Cl H -(CH2)3-
7-Cl H -(CH2)3-
6-Br H -(CH2)3-
5-Me H -(CH2)3-
H -Me -(CH2)3-
H -Bn -(CH2)3-
5-F -Me -(CH2)3-
5-Cl -Me -(CH2)3-
5-Br -Me -(CH2)3-
6-Br -Me -(CH2)3-
H H H, H
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
18
18
22
18
18
22
30
18
18
18
18
18
18
18
48
24
24
96
96
77
84
93
79
75
91
93
98
93
99
95
89
32
78
70
82
77
67
84
72
ND
ND
91
82
78
83
80
87
26
27
13
31
91:9
95:5
86:14
79:21
86:14
—
—
98:2
93:7
92:8
78:22
92:8
89:11
—
9
10
11
12
13
14
15
16
17
H HCH3,CH3
H H -(CH2)2-
H H -(CH2)4-
76:24
62:38
79:21
aReaction conditions: isatin 2 (0.2 mmol), cyclohexanone 3 (1 mL), catalysts 1a (0.04 mmol), 4 Å MS (0.2 g), room temperature (25°C).
bYield of a mixture of syn and anti products.
cDetermined by chiral HPLC.
Chirality DOI 10.1002/chir

WANG ET AL.
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good yields (up to 99%) as well as moderate to good
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Chirality DOI 10.1002/chir