Biomimetic asymmetric Michael addition reactions in water catalyzed by amino-containing β-cyclodextrin derivatives

Article abstract of DOI:10.1016/S1872-2067(15)61122-6

Nine β-cyclodextrin derivatives containing an amino group were synthesized via nucleophilic substitution from mono(6-O-p-tolylsulfonyl)-β-cyclodextrin and used in asymmetric biomimetic Michael addition reactions in water at room temperature. The mechanism responsible for the moderate activity and enantioselectivity of the β-cyclodextrin derivatives was explored using nuclear magnetic resonance spectroscopy, namely 2D ¹H rotating-frame overhauser effect spectroscopy (ROESY), ultraviolet absorption spectroscopy, and quantum chemical calculations, which provide a useful technique for investigating the formation of inclusion complexes. The effects of the pH of the reaction medium, the β-cyclodextrin derivative dosage, the structure of the modifying amino group, and various substrates on the yield and enantioselectivity were investigated. The results indicated that these factors had an important effect on the enantiomeric excess (ee) in the reaction system. Experiments using a competitor for inclusion complex formation showed that a hydrophobic cavity is necessary for enantioselective Michael addition. A comparison of the reactions using 4-nitro-β-nitrostyrene and 2-nitro-β-nitrostyrene showed that steric hindrance improved the enantioselectivity. This was verified by the optimized geometries obtained from quantum chemical calculations. An ee of 71% was obtained in the asymmetric Michael addition of cyclohexanone and 2-nitro-β-nitrostyrene, using (S)-2-aminomethylpyrrolidine-modified β-CD as the catalyst, in an aqueous buffer solution, i.e., CH₃COONa-HCl (pH 7.5).

Full text of DOI:10.1016/S1872-2067(15)61122-6

Chinese Journal of Catalysis 37 (2016) 1227–1234
a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / c h n j c
Article
Biomimetic asymmetric Michael addition reactions in water
catalyzed by amino‐containing β‐cyclodextrin derivatives
Qingying Zhu a, Haimin Shen b, Zhujin Yang a, Hongbing Ji a,*
a School of Chemistry and Chemical Engineering, Sun Yat‐sen University, Guangzhou 510275, Guangdong, China
b College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Nine β‐cyclodextrin derivatives containing an amino group were synthesized via nucleophilic sub‐
stitution from mono(6‐O‐p‐tolylsulfonyl)‐β‐cyclodextrin and used in asymmetric biomimetic Mi‐
chael addition reactions in water at room temperature. The mechanism responsible for the moder‐
ate activity and enantioselectivity of the β‐cyclodextrin derivatives was explored using nuclear
magnetic resonance spectroscopy, namely 2D 1H rotating‐frame overhauser effect spectroscopy
(ROESY), ultraviolet absorption spectroscopy, and quantum chemical calculations, which provide a
useful technique for investigating the formation of inclusion complexes. The effects of the pH of the
reaction medium, the β‐cyclodextrin derivative dosage, the structure of the modifying amino group,
and various substrates on the yield and enantioselectivity were investigated. The results indicated
that these factors had an important effect on the enantiomeric excess (ee) in the reaction system.
Experiments using a competitor for inclusion complex formation showed that a hydrophobic cavity
Received 11 March 2016
Accepted 24 April 2016
Published 5 August 2016
Keywords:
β‐Cyclodextrin
Modification
Enantioselective Michael addition
Quantum chemistry calculation
is necessary for enantioselective Michael addition.
A comparison of the reactions using
4‐nitro‐β‐nitrostyrene and 2‐nitro‐β‐nitrostyrene showed that steric hindrance improved the enan‐
tioselectivity. This was verified by the optimized geometries obtained from quantum chemical cal‐
culations. An ee of 71% was obtained in the asymmetric Michael addition of cyclohexanone and
2‐nitro‐β‐nitrostyrene, using (S)‐2‐aminomethylpyrrolidine‐modified β‐CD as the catalyst, in an
aqueous buffer solution, i.e., CH3COONa‐HCl (pH 7.5).
© 2016, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
1. Introduction
additions are therefore important. The use of small organic
molecules as catalysts in asymmetric Michael additions [3] is
Enantioselective Michael addition is an asymmetric C–C
bond‐forming strategy for single‐step generation of multiple
stereogenic centers [1]. Excellent conversions and enantio‐
meric excesses (ee) have been achieved in asymmetric synthe‐
ses using metal catalysts such as Cu, Ca, Ni, Co, and Rh [2].
However, the use of metal catalysts in the pharmaceutical in‐
dustry is restricted to avoid the presence of trace heavy metals
in products. Metal‐free catalysts for enantioselective Michael
growing because of their low price, and high stability, efficien‐
cy, and selectivity; examples are primary amines [4], pyrroli‐
dine derivatives [5], (thio)ureas [6], chiral squaramides [7],
binaphthols [8], quinines [9], chiral phosphines [10], ionic liq‐
uids [11], and peptides [12]. However, green reactions that use
non‐toxic and harmless solvents need to be developed. Water is
a safe, economical, and environmentally benign solvent, there‐
fore there has been increasing interest in asymmetric organic
* Corresponding author. Tel: +86‐20‐84113658; Fax: +86‐20‐84113654; E‐mail: jihb@mail.sysu.edu.cn
This work was supported by the National Natural Science Foundation of China (21425627, 21376279).
DOI: 10.1016/S1872‐2067(15)61122‐6 | http://www.sciencedirect.com/science/journal/18722067 | Chin. J. Catal., Vol. 37, No. 8, August 2016

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Qingying Zhu et al. / Chinese Journal of Catalysis 37 (2016) 1227–1234
reactions in neat aqueous media [13]. Cyclodextrins (CDs) and
their derivatives in aqueous systems have been extensively
studied as enzyme mimics [14], which can significantly in‐
crease the reaction rates and enantioselectivities of various
organic transformations.
β‐CD is
a cyclic polysaccharide consisting of seven
d‐glucopyranoside units. It has a hydrophilic outer surface and
a hydrophobic inner cavity, which can induce chiral recognition
through complex formation with substrates, similar to the ac‐
tion of enzymes, via non‐covalent bonds in water [15]. β‐CD
modification with catalytic or reactive groups such as catalytic
sites or enzyme binding sites could improve its binding ability
and enantioselectivity compared with the hydroxyl‐containing
parent CD [16]. The construction of an asymmetric catalytic
center to enable asymmetric reactions to be performed using
CDs is the main target in CD catalysis. In recent years, many
asymmetric reactions such as reduction [17], oxidation [18],
epoxidation [19], aldol reactions [20], Henry reactions [21], and
transamination [22] catalyzed by modified CDs have given ac‐
ceptable yields and poor to high enantioselectivities. The enan‐
tioselectivity is greatly influenced by the structure of the modi‐
fying group, solvent, and temperature. Michael additions of
nitromethane and thiols to chalcones in water, catalyzed by
per‐6‐amino‐β‐cyclodextrin, are highly efficient [23] and
achieved 68.5% ee; only 30% ee was achieved with the unmod‐
ified β‐CD using 2‐cyclohexenone and octyl maleate with ben‐
zenethiol [24].
Scheme 1. Supramolecular amino catalysts CD‐1 to CD‐9.
or D2O. Tetramethylsilane was used as the internal standard
(0.00 ppm) in CDCl3 and DMSO‐d6, and H2O was used as the
internal standard (4.79 ppm) in D2O. The ee was determined by
high‐performance liquid chromatography (HPLC) using a Shi‐
madzu LC‐20AT chromatography system equipped with an
ultraviolet (UV)‐visible detector and a Chiralcel AS‐H or OD‐H
column, with n‐hexane and isopropyl alcohol as the eluents.
The absolute configuration was determined using HPLC by
comparison of the elution sequences of the enantiomers with
those of authentic samples and those reported in Ref. [4].
Quantum chemical calculations were performed at the PM3 and
B3LYP/6‐31G(d) levels using the GAUSSIAN 09 program.
In our previous studies, use of an (S)‐2‐aminomethylpyr‐
rolidine‐modified β‐CD (CD‐1) as a chiral base catalyst signifi‐
cantly enhanced the stereoselectivity in asymmetric aldol reac‐
tions, achieving 94% ee [25]. It would be useful to know
whether this asymmetric catalytic effect could also be obtained
in Michael additions with CD‐1 in water. To the best of our
knowledge, there are few reports focusing on the asymmetric
Michael addition of cyclohexanones to nitroolefins catalyzed by
modified CDs in water. Catalysts CD‐1 and CD‐2 were tested in
Michael additions, and CD‐3 to CD‐9 (Scheme 1) were prepared
under identical conditions and used for comparison.
2.2. Typical procedure for synthesis of CD‐1 to CD‐9
CD‐1 to CD‐9 were synthesized according to the procedure
reported in Ref. [18]; a representative synthesis is shown in
Scheme 2. Nucleophilic substitution of mono(6‐O‐p‐tol‐
ylsulfonyl)‐β‐CD (6.4459 g, 5 mmol) with the corresponding
amine (25 mmol) was performed by reaction in anhydrous
dimethylformamide (DMF) at 80 °C in a nitrogen atmosphere
for 24.0 h, followed by cooling to room temperature.
(S)‐Prolinamide and (R)‐prolinamide were reduced with LiAlH4
to (S)‐2‐aminomethylpyrrolidine and (R)‐2‐aminomethylpyr‐
rolidine.
2. Experimental
CD‐1: yield 32.5%; [α]D25 +138.27 (c 0.2006, H2O); mp > 240
°C (decomp.); 1H NMR (400 MHz, D2O): δ (ppm) 5.14–4.99 (m,
7H), 3.97–3.68 (m, 24H), 3.61–3.30 (m, 15H), 3.11–3.00 (m,
3H), 2.78–2.37 (m, 5H), 1.92–1.43 (m, 5H);13C NMR (400 MHz,
DMSO‐d6): δ (ppm) 164.9, 161.2, 102.0–101.3 (m), 84.1, 84.0,
81.6–80.9 (m), 72.8–71.8 (m), 66.0, 63.3, 59.6, 56.3–55.0 (m),
44.4, 27.4, 27.1, 23.3, 23.0; MS (ESI): m/z 1246 [M + CH3CH2]+,
1218 [M + H]+.
2.1. Materials and methods
β‐CD (99%) was purchased from the Shanghai Boao Biolog‐
ical Technology Co., Ltd, China. (S)‐Prolinamide, (R)‐pro‐
linamide, piperazidine, 4‐aminopiperidine, 1,2‐diaminopro‐
pane (racemic), N,N'‐dimethyl‐1,2‐ethanediamine, N,N'‐dime‐
thyl‐1,3‐propanediamine, and 4‐nitro‐β‐nitrostyrene (purity
98% in all cases) were purchased from the Sahn Chemical
Technology Co., Ltd, China. p‐Toluenesulfonyl chloride, LiAlH4,
and 1,3‐diaminopropane were purchased from Aladdin. Eth‐
ylenediamine and other common reagents were analytical
grade. n‐Hexane and isopropyl alcohol were chromatograph‐
ically pure grade. All reagents were used as received without
further purification, unless otherwise noted.
CD‐2: yield 24.2%; [α]2D5 +143.01 (c 0.2017, DMF); mp > 250
°C (decomp.); 1H NMR (400 MHz, D2O): δ (ppm) 5.03–4.93 (m,
Nuclear magnetic resonance (NMR) spectra were recorded,
using a Bruker Avance III 400 spectrometer, in CDCl3, DMSO‐d6,
Scheme 2. Representative synthesis of supramolecular amino catalysts.

Qingying Zhu et al. / Chinese Journal of Catalysis 37 (2016) 1227–1234
1229
7H), 3.90–3.68 (m, 23H), 3.56–3.29 (m, 15H), 3.05–2.53 (m,
[M + H2]+, 1177 [M + H]+.
7H), 2.26–2.13 (m, 1H), 1.95–1.36 (m, 6H);13C NMR (400 MHz,
DMSO‐d6): δ (ppm) 165.6, 161.3, 101.8–101.5 (m), 84.1, 84.0,
81.5–80.8 (m), 72.8–71.7 (m), 69.2, 62.1, 59.7–59.1 (m), 53.9,
53.7, 42.7, 27.0, 22.5; MS (ESI): m/z 1246 [M + CH3CH2]+, 1218
[M + H]+.
2.3. Typical procedure for asymmetric Michael reaction
Aqueous CH3COONa‐HCl buffer solution (1 mL, 0.5 mol/L)
and cyclohexanone (0.2 mL, 2 mmol) were added to a stirred
solution of CD‐1 (0.0487 g, 0.04 mmol) and 4‐nitro‐β‐nitrosty‐
rene (0.0388 g, 0.20 mmol). The solution was stirred at 25 °C
for 96.0 h and then extracted with ethyl acetate (3 × 2 mL). The
combined organic phases were dried over anhydrous Na2SO4
and the solvent was evaporated under reduced pressure to give
the crude product, which was purified by column chromatog‐
raphy over silica gel. The yield and ee were determined using
HPLC.
CD‐3: yield 54.3%; [α]D25 +141.22 (c 0.2010, H2O); mp > 250
°C (decomp.); 1H NMR (400 MHz, D2O): δ (ppm) 5.02–4.95 (m,
7H), 3.96–3.72 (m, 26H), 3.57–3.28 (m, 14H), 3.09–2.52 (m,
6H), 2.30–1.72 (m, 4H), 1.45–1.23 (m, 2H);13C NMR (400 MHz,
DMSO‐d6): δ (ppm) 109.2, 101.9–101.2 (m), 83.6, 81.4–81.0
(m), 72.8–71.7 (m), 70.1, 59.6, 57.5, 53.3, 52.3, 47.8, 34.7, 34.5;
MS (ESI): m/z 1220 [M + H2]+, 1218 [M + H]+.
CD‐4: yield 64.9%; [α]D25 +146.54 (c 0.2023, H2O); mp > 250
°C (decomp.); 1H NMR (400 MHz, D2O): δ (ppm) 5.01–4.93 (m,
7H), 3.97–3.74 (m, 26H), 3.58–3.28 (m, 16H), 2.81–2.72 (m,
4H), 2.56–2.48 (m, 4H);13C NMR (400 MHz, DMSO‐d6): δ (ppm)
102.1–101.5 (m), 83.8, 81.7–81.3 (m), 73.1–72.0 (m), 70.3,
70.0, 59.9, 58.4, 57.6, 54.7, 54.3, 53.1, 45.3, 44.9; MS (ESI): m/z
1205 [M + H2]+, 1203 [M + H]+.
2.4. Preparation of CD‐1 inclusion complex of
4‐nitro‐β‐nitrostyrene
A mixture of CD‐1 (0.6085 g, 0.5 mmol) and 4‐nitro‐β‐ni‐
trostyrene (0.0970 g, 0.5 mmol) in deionized water (10 mL)
was stirred at 50 °C for 2 h, i.e., until the solution was clear. The
solution was cooled at 5 °C for 24 h and filtered to give a light
yellow precipitate. The precipitate was washed with hexane to
remove free 4‐nitro‐β‐nitrostyrene. The inclusion complex was
dried under vacuum at 50 °C for 24 h.
CD‐5: yield 30.1%; [α]D25 +148.67 (c 0.2074, H2O); mp > 240
°C (decomp.); 1H NMR (400 MHz, D2O): δ (ppm) 5.06–4.98 (m,
7H), 3.97–3.77 (m, 26H), 3.61–3.51 (m, 14H), 3.43 (t, 1H), 2.92
(t, 1H), 2.68–2.47 (m, 4H), 2.30(s, 3H), 2.23 (s, 3H); 13C NMR
(400 MHz, DMSO‐d6): δ (ppm) 102.1–101.6 (m), 84.2, 81.6–81.1
(m), 73.2–71.9 (m), 70.2, 59.8, 58.3, 56.9, 48.8, 42.7, 35.7, 29.2;
MS (ESI): m/z 1207 [M + H2]+, 1206 [M + H]+.
2.5. Quantum chemical calculations
CD‐6: yield 46.6%; [α]D25 +149.87 (c 0.2105, H2O); mp > 240
°C (decomp.); 1H NMR (400 MHz, D2O): δ (ppm) 5.13–5.03 (m,
7H), 4.01–3.79 (m, 26H), 3.70–3.53 (m, 14H), 3.60–3.38 (m,
Quantum chemical calculations were performed using the
GAUSSIAN 09 program to investigate the energies and struc‐
tures of CD‐1 and 4‐nitro‐β‐nitrostyrene. The initial β‐CD
structure was constructed using information available in Ref.
[26]. The modifying amino groups and the guest molecule
4‐nitro‐β‐nitrostyrene were constructed using ChemBioOffice
3D Ultra (Version 12.0, Cambridge Software) and were fully
optimized using the PM3 and B3LYP/6‐31G(d) methods, with‐
out any symmetric restrictions. The optimized amino groups
were attached to C‐6 of β‐CD and the modified β‐CDs were op‐
timized using PM3. In the coordinate system, the glycosidic
oxygen atoms of β‐CD were placed in the XY plane and their
center was defined as the origin. The C‐2 and C‐3 hydroxyls
were placed on the negative Z axis. The guest molecule, i.e.,
4‐nitro‐β‐nitrostyrene, was located with three virtual atoms in
the coordinates, two in the XY plane, and one on the Z axis. The
carbon atom linked to the nitro group in the benzene ring of
4‐nitro‐β‐nitrostyrene was the labeled atom. The inclusion
complexes were optimized based on the PM3 calculation to
obtain the optimized energies, and the output files were used
as the input files for optimization at the ONIOM level
(B3LYP/6‐31G(d):PM3). The binding energy (BE) was calcu‐
lated as BE = E[C]ONIOM  E[H]PM3  E[G]B3LYP/6‐31G(d), where
E[C]ONIOM is the optimized energy of the inclusion complex ob‐
tained using the ONIOM (B3LYP/6‐31G(d):PM3) method,
E[H]PM3 is the optimized energy of the modified CD obtained
using PM3, and E[G]B3LYP/6‐31G(d) is the optimized energy of the
guest molecule, i.e., 4‐nitro‐β‐nitrostyrene, obtained using
B3LYP/6‐31G(d).
1H), 3.15–2.95 (m, 2H), 2.89–2.42 (m, 4H), 1.07 (d, 3H); 13
C
NMR (400 MHz, DMSO‐d6): δ (ppm) 101.7–101.4 (m), 83.1,
81.1, 72.6–71.6 (m), 70.4–69.7 (m), 59.5, 57.1, 57.0, 54.2, 54.0,
49.2–49.1 (m), 46.8, 46.4, 45.8, 45.6, 20.85, 17.8, 17.6; MS (ESI):
m/z 1193 [M + H2]+, 1192 [M + H]+.
CD‐7: yield 30.1%; [α]D25 +146.52 (c 0.2081, H2O); mp > 240
°C (decomp.); 1H NMR (400 MHz, D2O): δ (ppm) 5.07–4.97 (m,
7H), 3.98–3.76 (m, 26H), 3.62–3.50 (m, 14H), 3.43 (t, 1H), 2.92
(d, 1H), 2.64–2.38 (m, 4H), 2.40 (s, 3H), 2.22 (s, 3H), 1.65–1.58
(m, 2H); 13C NMR (400 MHz, DMSO‐d6): δ (ppm) 102.2–101.5
(m), 84.1, 81.5–81.1 (m), 79.1, 73.2–71.8 (m), 70.2,
59.9–59.6(m), 58.0, 56.2, 49.6, 42.9, 35.8, 26.6; MS (ESI): m/z
1221 [M + H2]+, 1220 [M + H]+.
CD‐8: yield 50.6%; [α]D25 +156.72 (c 0.2064, H2O); mp > 240
°C (decomp.); 1H NMR (400 MHz, D2O): δ (ppm) 5.01–4.92 (m,
7H), 3.88–3.74 (m, 26H), 3.56–3.45 (m, 14H), 3.32 (t, 1H), 2.94
(d, 1H), 2.70–2.49 (m, 5H), 1.58–1.51 (m, 2H); 13C NMR (400
MHz, DMSO‐d6): δ (ppm) 101.8, 101.4, 83.6, 81.1, 80.8,
73.0–72.9 (m), 72.0–71.7 (m), 70.3, 60.2–60.1 (m), 49.4, 46.4,
38.5, 37.9, 32.5, 30.8; MS (ESI): m/z 1193 [M + H2]+, 1192[M +
H]+.
CD‐9: yield 52.4%; [α]D25 +148.15 (c 0.2036, H2O); mp > 240
°C (decomp.); 1H NMR (400 MHz, D2O): δ (ppm) 5.02–5.00 (m,
7H), 3.93–3.79 (m, 26H), 3.60–3.49 (m, 14H), 3.38 (t, 1H),
3.01–2.98 (m, 1H), 2.77–2.58 (m, 7H);13C NMR (400 MHz, D2O):
δ (ppm) 101.8, 100.5, 83.6, 81.1, 80.9, 73.1–73.0 (m), 72.0–72.0
(m), 71.8, 70.4, 60.2, 50.7, 49.3, 42.2, 39.7; MS (ESI): m/z 1178

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Qingying Zhu et al. / Chinese Journal of Catalysis 37 (2016) 1227–1234
3. Results and discussion
Table 2
Effect of modifying group structure on enantioselectivity in asymmetric
Michael reactions.
3.1. Optimization of asymmetric Michael addition conditions
Entry
CDs
Yield a (%)
syn/anti a
82/18
76/24
99/1
81/19
71/29
77/23
73/27
74/26
87/13
ee a (%)
61/97
41/93
34/37
16/63
5/77
1/96
4/100
4/98
1
2
3
4
5
6
7
8
9
CD‐1
CD‐2
CD‐3
CD‐4
CD‐5
CD‐6
CD‐7
CD‐8
CD‐9
46
17
7.5
6.2
6.1
44
33
49
96
The diamine‐catalyzed Michael addition is pKa dependent;
therefore, the effect of pH on the enantioselectivity of the
asymmetric Michael addition catalyzed by CD‐1 was studied in
detail. The effect of pH on the catalytic activity and enantiose‐
lectivity in the asymmetric Michael addition catalyzed by CD‐1,
assuming an intermolecular enaminetransition state, is shown
in Table 1. When the pH of the CH3COONa‐HCl buffer solution
was kept at 6.0 or lower, both the amino group in the pyrroli‐
dine and the secondary amine linked to C‐6 were protonated,
therefore the active catalytic center became inactive (Table 1,
entries 1–5), and no catalytic activity was observed. When the
pH was increased from 6.5 to 7.5, the ee increased from 42%
(Table 1, entry 6) to 61% (Table 1, entry 8), and the yield in‐
creased from 13% to 46%, because protonation of the second‐
ary amine became weaker, and both amino groups were able to
catalyze the Michael addition with moderate enantioselectivity
and yield.
1/98
Reaction conditions: modified CDs 0.04 mmol, 4‐nitro‐β‐nitrostyrene
0.20 mmol, cyclohexanone 2 mmol, solvent (pH 7.5, 0.5 mol/L
CH3COONa‐HCl) 2 mL, 25 °C, 96.0 h.
a Determined by HPLC analysis with a Chiralcel OD‐H column. The ab‐
solute configurations of the Michael products were determined by
comparison of the eluting sequence of the enantiomers with the au‐
thentic sample and Ref. [27].
β‐CDs modified with various diamines were investigated at pH
7.5; the results are shown in Table 2. The CD‐9‐catalyzed Mi‐
chael addition gave a good yield 96% (Table 2, entry 9) but
poor ee. The enantioselectivity did not improve when the eth‐
ylenediamine group in CD‐9 was substituted with one methyl
group (CD‐6) or two methyl groups (CD‐5), and the reaction
yields decreased to 44% (Table 2, entry 6) and 6% (Table 2,
entry 5), respectively. The same substituent effect was ob‐
served with the 1,3‐propanediamine‐based catalysts CD‐8 and
CD‐7; the reaction yield decreased from 49% (Table 2, entry 8)
to 33% (Table 2, entry 7). Catalysts containing a tertiary amino
group, i.e., CD‐4 and CD‐5, and a bifunctional secondary amine,
i.e., CD‐3, were inert and gave low yields. These 6‐monosubsi‐
tuted β‐CD derivatives would mainly exist in self‐included con‐
formations in pure water solutions, as shown by previous
studies, therefore the reaction rates decreased [20]. The dif‐
ference between CD‐1 and CD‐2 was the absolute configuration
of the appended modifying group; CD‐1 showed better catalytic
efficiency and enantioselectivity (61% ee vs 41% ee) than did
CD‐2. Quantum chemical calculations showed that their opti‐
mum conformations were different [25], because the secondary
amine in the pyrrolidine ring cannot be included in the hydro‐
phobic cavity of CD‐2, giving racemic products. The structure
and absolute configuration of the modifying group in the β‐CD
therefore plays a decisive role in the catalytic activity and in
inducing enantioselectivity in the asymmetric Michael addition.
The enantioselectivity of conjugate addition in amine or‐
ganocatalysis is induced and controlled through three routes,
i.e., (1) formation of an enamine or imine; (2) non‐covalent
interactions such as hydrogen bonding; and (3) steric hin‐
drance. Catalysis using the modified β‐CDs CD‐1 to CD‐9 could
therefore be improved by considering these factors.
When CD‐1 dosage was decreased to half, the yield was
halved (Table 1, entry 10), but the ee remained almost the
same. This shows that in water the effect of the pH on the enan‐
tioselectivity was greater than that of the catalyst dosage. There
is an optimum pKa for the amines to be effective, which in the
present case was 7.5.
3.2. Asymmetric Michael additions with various modified β‐CDs
On the basis of the initial experiments, the reactions using
Table 1
Effect of pH on enantioselectivity in asymmetric Michael reactions cat‐
alyzed by CD‐1.
NO
2
O
Catalyst
(20 mol%)
NO
2
O
+
o
H O, 25
2
C
NO
2
O N
2
Entry
1
2
pH
Yield b (%)
Trace
Trace
Trace
Trace
Trace
13
syn/anti b
N.D.
N.D.
ee b (%)
N.D.
N.D.
4.0
4.5
5.0
5.5
6.0
6.5
7.0
7.5
8.0
7.5
3
4
5
6
7
8
N.D.
N.D.
N.D.
82/18
70/30
82/18
56/44
95/5
N.D.
N.D.
N.D.
42/94
56/90
61/97
61/87
59/100
21
46
9
10a
46
23
Reaction conditions: CD‐1 0.04 mmol, 4‐nitro‐β‐nitrostyrene 0.20 mmol,
cyclohexanone 2 mmol, solvent (0.5 mol/L CH3COONa‐HCl) 2 mL, 25 °C,
96.0 h.
a CD‐1 0.02 mmol. b Determined by HPLC analysis with a Chiralcel OD‐H
column. The absolute configurations of the Michael addition products
were determined by comparison of the eluting sequence of the enan‐
tiomers with the authentic sample and Ref. [27].
3.3. CD‐1‐catalyzed asymmetric Michael additions of various
substrates
The CD‐1‐catalyzed asymmetric Michael additions of cyclo‐
hexanone to a variety of conjugated nitroolefins were investi‐
N.D.: Not determined.

Qingying Zhu et al. / Chinese Journal of Catalysis 37 (2016) 1227–1234
1231
stituent effect was observed in the cases of Table 3, entry 3
(50% ee) and entry 4 (68% ee).
Table 3
CD‐1‐catalyzed asymmetric Michael reactions of various substrates.
The yield and optical yield decreased from 46% and 61%
(Table 3, entry 2) to 12% and 46% (Table 3, entry 10), respec‐
tively, when 2‐adamantanone (0.2 equiv. relative to 4‐nitro‐β‐
nitrostyrene) was added to the reaction system. 2‐Adaman‐
tanone immediately forms a 1:1 inclusion complex with β‐CD
and can be used as a competitive inhibitor in the formation of
inclusion complex, resulting in inhibition of the catalytic pro‐
cess, i.e., the hydrophobic cavity is necessary in the present
asymmetric Michael addition.
Entry
1
2
3
4
5
6
7
R
Yield b (%)
syn/anti b
97/3
82/18
79/21
91/9
99/1
93/7
57/43
83/17
85/15
69/31
ee b (%)
71/—
61/97
50/—
68/35
61/—
50/87
34/82
43/17
46/9
2‐NO2C6H4
4‐NO2C6H4
4‐ClC6H4
2‐ClC6H4
4‐MeC6H4
C6H5
4‐OCH3C6H4
1‐naph
2‐naph
47
46
36
51
57
12
24
41
37
12
3.4. Mechanistic studies
8
9
10a
β‐CD can form inclusion complexes with guest molecules,
and the formation of inclusion complexes is important in the
induction of enantioselectivity. In this study, inclusion com‐
plexes between modified β‐CDs and 4‐nitro‐β‐nitrostyrene
were prepared by stirring mixtures of CD‐1 to CD‐9 and
4‐nitro‐β‐nitrostyrene in water; the complexes were charac‐
terized using 1H rotating‐frame overhauser effect spectroscopy
(ROESY), UV spectroscopy, and quantum chemical calculations.
The 1H ROESY results for the inclusion complex between CD‐1
and 4‐nitro‐β‐nitrostyrene is shown as an example in Fig. 2.
The clear correlation peaks between the H atoms located in the
phenyl ring of 4‐nitro‐β‐nitrostyrene and H‐3 and H‐5 in the
cavity of the parent β‐CD indicate formation of an inclusion
complex between CD‐1 and 4‐nitro‐β‐nitrostyrene. No correla‐
tion peaks between the H atoms located in the phenyl ring of
4‐nitro‐β‐nitrostyrene and H‐2 and H‐4 outside the parent
β‐CD are observed. These results show that in the inclusion
complex of CD‐1 and 4‐nitro‐β‐nitrostyrene, the phenyl ring is
almost entirely situated in the cavity of the parent β‐CD.
4‐NO2C6H4
46/83
Reaction conditions: modified CDs 0.04 mmol, nitroolefin 0.20 mmol,
cyclohexanone 2 mmol, solvent (pH 7.5, 0.5 mol/L CH3COONa‐HCl) 2
mL, 25 °C, 96.0 h.
a 2‐Adamantanone 0.04 mmol was added.
b Determined by HPLC analysis with a Chiralcel AS‐H column and a
Chiralcel OD‐H column. The absolute configurations of the Michael
products were determined by comparison of the eluting sequence of
the enantiomers with the authentic sample and Refs. [27–29].
gated. Additions of cyclohexanone to substituted nitroolefins
containing both electron‐withdrawing and electron‐donating
groups were studied; the results are shown in Table 3. In most
cases, the corresponding Michael adducts were obtained with
moderate diastereoselectivity and enantioselectivity, suggest‐
ing that electronic factors slightly influenced the enantioselec‐
tivity. The highest ee, i.e., 71%, was obtained with 2‐nitro‐β‐
nitrostyrene (Table 3, entry 1); the value for 4‐nitro‐β‐ni‐
trostyrene was 61% (Table 3, entry 2). The observed enanti‐
oselectivity can be rationalized based on quantum chemical
calculations. The side views of the optimized geometries of the
inclusion complexes between the two substrates and CD‐1
were visualized, as shown in Fig. 1. The active site of the double
bond in 4‐nitro‐β‐nitrostyrene was deep inside the cavity of
CD‐1 (Fig. 1(b)), but the active site of 2‐nitro‐β‐nitrostyrene
remained outside the narrow rim of CD‐1 (Fig. 1(a)); this is
attributed to the ortho substituent making the binary complex
more crowded. Steric hindrance might therefore improve en‐
antioselection and give higher ee values. The same ortho sub‐
Fig. 3 shows that the UV absorbance changed when
4‐nitro‐β‐nitrostyrene was treated with solutions of the CD
catalysts; for example, the absorbance decreased when CD‐1
was added to a dilute solution of 4‐nitro‐β‐nitrostyrene in wa‐
ter and DMF, suggesting formation of a complex between CD‐1
and 4‐nitro‐β‐nitrostyrene.
H atoms belong to 4-nitro-β-nitrostyrene
active site
active site
(a)
(b)
ΔE = −644.05 kJ/mol
ΔE = −648.31 kJ/mol
δ (ppm)
Fig. 1. Side views of optimized geometries of inclusion complexes be‐
tween CD‐1 and 2‐nitro‐β‐nitrostyrene (a) and 4‐nitro‐β‐nitrostyrene
(b), obtained at ONIOM level (B3LYP/6‐31G(d):PM3).
Fig. 2. 1H ROESY results for CD‐1 and 4‐nitro‐β‐nitrostyrene in D2O at
25 °C.

1232
Qingying Zhu et al. / Chinese Journal of Catalysis 37 (2016) 1227–1234
active site
G
2.0
1.8
1.6
1.4
1.2
1.0
0.8
0.6
G+CD-1
G+CD-5
G+CD-6
G+CD-7
active site
(a)
(b)
Fig. 4. Two proposed models of binding between CD‐9 and
4‐nitro‐β‐nitrostyrene.
290
300 310 320
330 340
350 360
Wavelength (nm)
Fig. 3. Effect of β‐CD derivatives CD‐1, and CD‐5 to CD‐7 on UV absorb‐
ance of 4‐nitro‐β‐nitrostyrene. G: 4‐nitro‐β‐nitrostyrene 0.10 mmol/L;
β‐CD derivatives 0.10 mmol/L; solvent DMF/water 3/1 (v/v), 20 °C.
The inclusion complex was investigated in greater detail by
determining the BEs of the inclusion complexes between the
modified β‐CDs and 4‐nitro‐β‐nitrostyrene using quantum
chemical calculations at the ONIOM (B3LYP/6‐31G(d):PM3)
level to verify the intramolecular interactions (Table 4). The
negative BE indicates that formation of an inclusion complex is
thermodynamically favorable and spontaneous; two models of
the inclusion complex are shown in Fig. 4. In model (a), the
catalytic center is next to the active site and intramolecular
catalysis would occur, giving a chiral product. In model (b), the
catalytic center is beyond the active site and intermolecular
catalysis would occur, giving an achiral product. However, the
difference between the BEs for models (a) and (b) is just below
15 kJ/mol, a low energy barrier, for each modified β‐CD. The
difference between the BEs of models (a) and (b) can therefore
be ignored, and both are involved in the asymmetric Michael
addition. When intramolecular catalysis is dominant, a better
ee is achieved. The probabilities of Michael addition of
β‐nitrostyrene to cyclohexanone are nearly the same for mod‐
els (a) and (b), and a moderate enantioselectivity (50% ee, Ta‐
ble 3, entry 6) was achieved. Increased steric hindrance of the
nitroolefin increased the enantioselectivity to some extent.
These results suggest that the mechanism of Michael addi‐
tion is similar to that suggested by Xu and co‐workers [30].
Scheme 3. Suggested mechanism of asymmetric Michael addition cata‐
lyzed by CD‐1.
When primary or secondary chiral amines are used as organo‐
catalysts, the reaction proceeds via an enamine pathway. A
plausible mechanism is as follows (Scheme 3). The initial step is
formation of a chiral enamine 1 between CD‐1 and cyclohexa‐
none. Michael addition, the C–C bond‐forming step, between 1
and 4‐nitro‐β‐nitrostyrene occurs, leading to formation of the
corresponding product via transition state 2. The product is
released and escapes from the cavity and CD‐1 is regenerated
for use in subsequent catalytic cycles.
4. Conclusions
Nine β‐CD derivatives containing amino‐groups were used
in asymmetric Michael additions in water. The (S)‐2‐ami‐
nomethylpyrrolidine‐modified β‐CD (CD‐1) gave the best per‐
formance, with 71% ee being obtained. The structure of the
modifying group, pH, and steric hindrance between the sub‐
strate and the modified β‐CD played important roles in induc‐
ing enantioselectivity in the asymmetric Michael addition.
Quantum chemical calculations were effective in investigating
the enantioselectivities of Michael additions using various β‐CD
derivatives. Studies of the use of CD‐1 in other asymmetric re‐
actions are in progress.
Table 4
Binding energies (BEs) of CD‐1 to CD‐9 with 4‐nitro‐β‐nitrostyrene in
two models.
∆BE a (kJ/mol)
1.55
Entry
CDs
BEa (kJ/mol)
BEb (kJ/mol)
1
2
3
4
5
6
7
8
9
CD‐1
CD‐2
CD‐3
CD‐4
CD‐5
CD‐6
CD‐7
CD‐8
CD‐9
648.31
649.97
649.86
647.68
650.60
658.66
652.19
648.18
649.50
649.86
641.83
651.46
652.07
650.72
643.85
648.70
645.08
651.51
8.14
1.60
4.39
0.12
14.81
3.49
3.10
2.01
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a ∆BE = BEa  BEb.

Qingying Zhu et al. / Chinese Journal of Catalysis 37 (2016) 1227–1234
1233
Graphical Abstract
Chin. J. Catal., 2016, 37: 1227–1234 doi: 10.1016/S1872‐2067(15)61122‐6
Biomimetic asymmetric Michael addition reactions in water
catalyzed by amino‐containing β‐cyclodextrin derivatives
NO2
NO2
HN
Qingying Zhu, Haimin Shen, Zhujin Yang, Hongbing Ji *
Sun Yat‐sen University; Zhejiang University of Technology
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