CHIRALITY 21:492496 (2009)

Aldol Reaction Catalyzed by a Hydrophilic Catalyst in Aqueous

Micelle as an Enzyme Mimic System
HEFENG ZHANG,1 WENSHAN ZHAO,1 JUN ZOU,1 YI LIU,1 RUNTAO LI,2 AND YUANCHEN CUI1,3*
1
College of Chemistry and Chemical Engineering, Henan University, Kaifeng, Peoples Republic of China
2
School of Pharmaceutical Sciences, Peking University, Beijing, Peoples Republic of China
3
Institute of Natural Products and Medicinal Chemistry, Henan University, Kaifeng, Peoples Republic of China

ABSTRACT
Chitosan-supported L-proline complex was synthesized and applied as a
catalyst for the direct asymmetric aldol reaction in various organic solvents and water as
well. It was found that the novel synthesized catalyst was able to efciently catalyze the
aldol reaction in various media. The catalytic capacity and stereoselectivity of the catalyst were obviously improved with the introduction of aqueous micelle, possibly because
the micelle functioned as a hydrophobic pocket, like the hydrophobic portion in
enzymes. Moreover, the present synthetic catalyst showed performance similar to that
of enzymes and could be used as a model of enzyme catalysis to help better understand
C 2008 Wiley-Liss, Inc.
the mystic mechanism of enzymes. Chirality 21:492496, 2009. V
KEY WORDS: hydrophilic catalyst; direct asymmetric aldol reaction; aqueous micelle;
enzyme mimic

INTRODUCTION

Although L-proline was found to be an efcient catalyst

for intramolecular aldol reaction early in 1970s,14 no unprecedented development has been realized in the organocatalysis of aldol reaction until the intermolecular aldol
reaction catalyzed by L-proline was reported by List et al.
in 2000.5 From then on, many proline derivatives have
been developed and found to be powerful organocatalysts
for various reactions.610 The mechanism of proline and its
derivatives as organocatalysts was proposed to be similar
to that of an enamine intermediate5,11 taking part in the
reactions catalyzed by aldolase enzymes of Class I, while
proline and its derivatives were considered to be the smallest enzymes.12 L-proline together with many of its derivatives has been found to efciently catalyze aldol reaction
with good yields and high enantioselectivities in organic
solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF).610 However, L-proline is unable
to catalyze aldol reaction in water, though water as the
best solvent for enzymes can facilitate optimization of the
performance of enzymes,13,14 and few progress has been
seen in the research of the aldol reactions in water, not to
mention poor understanding of the mechanism therein.15,16
Fortunately, enzymes as ideal catalysts in water have high
activity and seteroselectivity, and it had been supposed
that the reactions catalyzed by enzymes occurred in the
hydrophobic portion of the enzymes, like a pocket in the
three-dimensional congures.1720 Also, a natural polysaccharide grafted with L-proline via a peptide bond was supposed to be suitable model for studying the special performance of enzymes.
As a natural polycationic polymer made from alkaline Ndeacetylation of inexpensive and degradable chitin,21 chiC 2008 Wiley-Liss, Inc.
V

tosan was used in our previous work to support palladium

complex and found to have special performance for Heck
reaction in water.22 Enlightened and encouraged by that
nding, we synthesized chitosan-supported L-proline and
applied it to catalyze the direct asymmetric aldol reaction
of p-nitrobenzaldehyde and ketone in various organic solvents and water as well in the present research. This article reports our research results in those aspects.

MATERIALS AND METHODS

All the reagents and solvents were purchased from

commercial suppliers and used without further purication. Thin layer chromatograph (TLC) analysis was performed on GF254 silica gel plates. Infrared spectrometric
analysis was performed on an Avatar360 Fourier transformation infrared spectrometer. Nuclear magnetic resonance (NMR) spectra were recorded using a Bruker
AVANCE400M facility, and the chemical shifts of 1H NMR
spectra were measured using tetramethyl silane (d 5 0) as
the reference. The melting points were measured with an
X-6 melting point apparatus and were uncorrected. Highperformance liquid chromatograph (HPLC) analysis was
performed on an Agilent 1100 facility equipped with diode
Additional Supporting Information may be found in the online version of
this article.
Contract grant sponsor: Opening Fund of Henan University of China
*Correspondence to: Yuanchen Cui, College of Chemistry and Chemical
Engineering, Henan University, Kaifeng 475001, Peoples Republic of China.
E-mail: yccui@henu.edu.cn
Received for publication 28 December 2007; Accepted 20 May 2008
DOI: 10.1002/chir.20621
Published online 24 July 2008 in Wiley InterScience
(www.interscience.wiley.com).

493

AQUEOUS MICELLE AS AN ENZYME MIMIC SYSTEM

Scheme 1. Synthesis of the novel catalyst.

array ultraviolet (UV) detector and Daicel Chiralpak AD or

AS column.
Chitosan-supported L-proline complex with a graft ratio
of 2 mmol/g was synthesized by grafting L-proline onto
the chitosan molecules (Scheme 1). The complex was
then investigated as a heterogeneous catalyst for direct
asymmetric aldol reaction in various organic solvents and
water as well.

RESULTS AND DISCUSSION

To our expectation, the novel catalyst was found to have

good catalyzing performance for the direct aldol reaction
of p-nitrobenzaldehyde and ketone (Scheme 2) in various
media (Table 1). Namely, it gave a yield of 66 and 44%,
with an e.e value of 78 and 74%, respectively, in the organic solvents such as tetrahydrofuran and ethanol
(Entries 3 and 4). However, it showed a much smaller
enantioselectivity in the organic solvents such as cyclohexanone, DMF, DMSO, and N-methyl-2-pyrrolidone (NMP).
At the same time, although p-nitrobenzaldehyde and ketone as the reagents are insoluble in water, the chitosansupported L-proline complex as the catalyst for the direct
aldol reaction of these two compounds was found to be more
efcient in water than in the organic solvents (Entry 7).
The special performance of the synthesized complex
catalyst in water was supposed to be attributed to the
hydrophilicity of chitosan. Namely, in the presence of
abundant amino and hydroxyl groups, a hydrogen-bonded
network was formed in both chitosan and catalyst, leading
to partial crystallization and embedding the catalytic centers. When the direct aldol reaction was carried out in the
organic solvents, it would be hard for the solvent and

Scheme 2. Aldol reaction of substituted benzaldehyde and cyclohexanone catalyzed by the novel catalyst.

reagents to reach the inner of the catalyst, and it would

also be hard for the catalytic center and aldehyde reagent
to form enamine. Subsequently, low yields were obtained
for the direct aldol reaction catalyzed by the novel catalyst
in the organic solvents. Contrary to the above, when water
TABLE 1. Aldol reaction catalyzed by the novel catalyst in
different solventsa
Entry
1
2
3
4
5
6
7
8e
9e
10e
11f
12f
13f

Solvent

Time
/d

Yieldb
/%

e.ec/%
(anti)

d.rd
(anti/syn)/%

Cyclohexanone
DMF
THF
EtOH
DMSO
NMP
H2O
DMF 1 H2O
THF 1 H2O
DMSO 1 H2O
H2O
DMF
Wet DMF

10
10
10
10
10
5
3
3
3
3
0.2
3
1

32
61
66
44
53
19
50
99
77
33
95
20
95

28
38
78
74
57
58
72
54
46
52
36
23
40

55:45
77:23
69:31
59:41
71:29
59:41
75:25
82:18
72:28
76:24

The reaction was carried out on the conditions: p-nitrobenzaldehyde 0.4

mmol, catalyst 15% mmol based on the proline, solvent 4 ml, r.t.
b
Isolated yields.
c
The e.e value was determined by HPLC.
d
The d.r value was determined by 1H NMR.
e
The ratio of organic solvent to water(V) is 3:1.
f
Acetone was used replace of cyclohexanone.

Scheme 3. Activation of the catalyst by water.

Chirality DOI 10.1002/chir

494

ZHANG ET AL.

TABLE 2. Aldol reactions carried out in aqueous micellea

Entry
1
2
3
4
5
6e
7f
8
9
10
11
12g
13
14
15h
16h

Surfactant

Time/d

Yieldb/%

e.ec/% (anti)

d.rd (anti/syn)/%

p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
p-NO2
m-NO2
m-NO2
m-NO2
m-NO2
p-NO2
p-NO2

SLS
H2O1Span-40
H2O1Span-80
Tween-80
Tween-20
Tween-20
Tween-20
PEG-400
PEG400-benzene
Glycerol
Span-40
Tween-20
Span-80
PEG-400
Tween-20
SLS

1
3
3
3
3
3
3
3
3
3
3
2
2
3
1
1

78
99
99
60
85
78
80
34
30
20
64
77
99
92
70
90

75
78
61
85
92
87
90
63
63
60
83
90
50
60
64
57

75:25
75:25
67:33
89:11
90:10
89:11
89:11
75:25
80:20
83:17
90:10
88:12
67:33
75:25

The reaction was carried out on the conditions: aldehyde 0.4 mmol, ketone 2 mmol, catalyst 15% mmol based on the proline, solvent 4 ml, r.t.
Isolated yields
The e.e value was determined by HPLC.
d
The d.r value was determined by 1H NMR.
e
The second run.
f
The third run.
g
The reaction was carried at 08C.
h
Acetone was used replace of cyclohexanone.
b
c

was used as the solvent, the intramolecular hydrogenbonded network in the catalyst would be broken and
replaced by the intermolecular one formed with water,
allowing well swelling and unfolding of the large molecule
chain of the catalyst. This implies that it would be much
easier for abundant catalytic center (Scheme 3) and enamine intermediate of the catalytic center and reagent to
form when the direct aldol reaction was conducted in
water. Therefore, in combination with the supposition that
water is a cocatalyst as evidenced by density functional calculations and kinetic isotope effect studies,13 it can be
rationally inferred that the better performance of the synthesized catalyst in the presence of water should be attributed to the swelling and unfolding of the large molecule

chain of the catalyst, changing of the hydrogen-bonded

network, and the cocatalysis of water. Since water can be
considered as an activating reagent for the synthesized
catalyst, it was added into the direct aldol reaction system
catalyzed by the synthetic catalyst in various organic solvents, aiming at accelerating the reaction. As being
expected, it was found that water did efciently accelerate
the direct aldol reactions carried out in the organic solvents (Entries 813).
It is known that the reaction catalyzed by enzymes in
water preferentially occurs at the hydrophobic portion of
the enzymes with complex congure, while the catalyst
can be well swelled in water and catalyze the reaction
with high yields and moderate enantioselectivities in the

Scheme 4. Reaction catalyzed by the catalyst in aqueous micelle and the proposed transition state.
Chirality DOI 10.1002/chir

495

AQUEOUS MICELLE AS AN ENZYME MIMIC SYSTEM

Scheme 5. Aldol reaction of substituted benzaldehyde and cyclohexanone catalyzed by the novel catalyst.

presence of abundant hydroxyl and amino groups. Compared to the enzyme catalysis, however, the hydrophobic
pocket formed in the present system would be less efcient. In other words, it could be feasible to improve the
performance of the synthesized catalyst by introducing a
hydrophobic portion in the catalytic system. Thus aqueous micelle was used for such a purpose (Table 2).

TABLE 3. The aldol reaction of different aldehydes carried out in Tween-20 aqueous micellea
Time/d

Yieldb/%

e.e.c/% (anti)

d.rd (anti/syn)/%

85

92

90:10

42

80

94:6

77

91

87:13

86

45

85:15

61

64

75:25

95

60

25:75

52

41

75:25

80

64

65

65

Entry

Product

The reaction was carried out on the conditions: aldehyde 0.4 mmol, ketone 2 mmol, catalyst 15 mol%, solvent 4 ml, r.t.
Isolated yields.
c
The e.e value was determined by HPLC.
d
The d.r value was determined by 1H NMR.
b

Chirality DOI 10.1002/chir

496

ZHANG ET AL.

Interestingly, with the introduction of the aqueous micelle, both the catalytic activity and enantioselectivity of
the catalyst were improved in some cases. Namely, in
the aqueous micelle of anionic surfactant sodium lauryl
sulfate (SLS, Entry 1), the catalytic activity was greatly
improved, and a yield of 78% was obtained in 24 h. In
particular, in the aqueous micelle of nonionic surfactant
Tween 20 (Entry 5), both the enantioselectivity and steroselectivity were improved, and a yield of 85% with an
e.e value of 92% and a d.r (anti/syn) ratio of 90:10 was
obtained. Besides, the catalytic activity and stereoselectivity were retained when the system was reused for two
times (Entries 6 and 7).
In the aqueous micelle, the catalyst would be well swelled
and readily adsorbed onto the hydrophilic hydroxyl and
amino groups of chitosan and the grafted catalytic center of
prolimade. At the same time, the micelle could act as a
hydrophobic pocket, allowing the reactants to be dissolved
and the reaction to be catalyzed. Scheme 4 shows the proposed mechanism for the synthesized catalyst. In the enamine intermediate, it was proposed that the hydroxyl hydrogen in chitosan, instead of the imide hydrogen in prolinamide, functioned to form hydrogen bond with aldehyde,
providing the seteroselectivities of the products.23
The present enzyme mimic system have been used to
various aldehydes (Scheme 5, Table 3). It was found that
the reaction of various aldehydes and cyclohexanone
could be efciently catalyzed by the present enzyme
mimic system. The products obtained from p-nitrobenzaldehyde and m-nitrobenzaldehyde showed the highest
enantioselectivities (Entries 1 and 3). Namely, their e.e values are as high as 92 and 91%, and their d.r (anti/syn)
ratios are as much as 90:10 and 87:13, respectively. Moreover, the highest stereoselectivity of 94:6 was obtained
from the reaction of o-nitrobenzaldehyde and cyclohexanone (Entry 2).
CONCLUSIONS

Direct asymmetric aldol reaction in various media could

be efciently catalyzed by the novel catalyst. The best catalytic performance was obtained in aqueous micelle, possibly because the micelle might have special function, like
the hydrophobic pocket in enzymes. The present enzyme
mimic system containing natural amylase, asymmetric center, and aqueous micelle could be used as a model of
enzyme catalysis and help to better reveal the mystic
mechnism of enzymes.
ACKNOWLEDGMENTS

We are grateful for the nancial support from open fund

of Henan University. See supporting information for more
experimental details and data.

Chirality DOI 10.1002/chir

LITERATURE CITED
1. Zoltan GH, David RP. German Patent DE 2,102,623, 1971.
2. Zoltan GH, David RP. Asymmetric synthesis of bicyclic intermediates
of natural product chemistry. J Org Chem 1974;39:16151621.
3. Ulrich E, Gerhard S, Rudolf W. German Patent DE 2,014,757, 1971.
4. Ulrich E, Gerhard S, Rudolf W. New type of asymmetric cyclization to
optically active steroid CD partial structures. Angew Chem Int Ed
1971;10:496497.
5. Benjamin L, Richard AL, Carlos FB III. Proline-catalyzed direct asymmetric aldol reactions. J Am Chem Soc 2000;122:23952396.
6. Benjamin L. Proline-catalyzed asymmetric reactions. Tetrahedron 2002;
58:55735590.
7. Benjamin L. Asymmetric aminocatalysis. Syn Lett 2001;16751685.
8. Benito A, Pedro A. The direct catalytic asymmetric cross-aldol reaction of Aldehydes. Angew Chem Int Ed 2003;42:858860.
9. Benjamin L. Enamine catalysis is a powerful strategy for the catalytic
generation and use of carbanion equivalents. Acc Chem Res 2004;
37:548557.
10. Wolfgang N, Fujie T, Carlos FB III. Enamine-based organocatalysis
with proline and diamines: the development of direct catalytic asymmetric Aldol, Mannich, Michael, and Diels-Alder reactions. Acc Chem
Res 2004;37:580591.
11. Kandasamy S, Wolfgang N, Tommy B, Carlos FB III. Amino acid catalyzed direct asymmetric aldol reactions: a bioorganic approach to catalytic asymmetric carbon-carbon bond-forming reactions. J Am Chem
Soc 2001;123:52605297.
12. Mohammad M, Eric NJ. The simplest enzyme. Science 2002;
298:19041905.
13. Tobin JD, Kim DJ. Aqueous aldol catalysis by a nicotine metabolite.
J Am Chem Soc 2002;124:32203221.
14. Ramachary DB, Naidu SC, Carlos FB III. Amine-catalyzed direct self
DielsAlder reactions of a,b-unsaturated ketones in water: synthesis
of pro-chiral cyclohexanones. Tetrahedron Lett 2002;43:67436746.
15. Lindstro
m UM. Stereoselective organic reactions in water. Chem Rev
2002;102:27512772.
16. Shu
K, Yuichiro M, Satoshi N, Kei M. Catalytic asymmetric aldol reactions in water using a chiral Lewis acid-surfactant-combined catalyst.
Green Chem 1999;1:175177.
17. Ronald B, Steven DD. Biomimetic reactions catalyzed by cyclodextrins and their derivatives. Chem Rev 1998;98:19972011.
18. Junmin H, Xiaotong Z, Daniel W. Armstrong. Highly efcient asymmetric direct stoichiometric aldol reactions on/in water. Angew Chem
2007;119:92319235.
19. Armando C, Weibiao Z, Pawel D, Ismail I, Efraim R, Yongmei X.
Direct asymmetric intermolecular aldol reactions catalyzed by amino
acids and small peptides. Chem Eur J 2006;12:53835386.
20. Pawel D, Weibiao Z, Jonas H, Armando C. The small peptide-catalyzed
direct asymmetric aldol reaction in water. Org Biomol Chem 2006;
4:3840.
21. Majeti NV, Ravi K, Riccardo M, Corrado M, Hitoshi S, Abraham JD.
Chitosan chemistry and pharmaceutical perspectives. Chem Rev
2004;104:60176084.
22. Hefeng Z, Lei Z, Yuanchen C. Synthesis of chitosan microsphere-resin
supported palladium complex and its catalytic properties for MizorokiHeck reaction. React Funct Polym 2007;67:322328.
23. Ayumi T, Hiroshi T, Masaya K, Takashi F, Tomoya M. Novel enantiocontrol system with aminoacyl derivatives of glucoside as enaminebased organocatalysts for aldol reaction in aqueous media. Tetrahedron Lett 2007;48:52135217.