Noncovalently supported heterogeneous chiral amine catalysts for asymmetric direct aldol and Michael addition reactions

Article abstract of DOI:10.1002/chem.200701129

A new strategy for the immobilization of asymmetric organocatalysts by combining polystyrene (PS)/ sulfonic acids and chiral amines in situ through acid-base interactions is presented. The PS/sulfonic acids play a dual role as catalyst anchors and modulat

Full text of DOI:10.1002/chem.200701129

FULL PAPER
DOI: 10.1002/chem.200701129
Noncovalently Supported Heterogeneous Chiral Amine Catalysts for
Asymmetric Direct Aldol and Michael Addition Reactions
Sanzhong Luo,*[a] Jiuyuan Li,[a] Long Zhang,[b] Hui Xu,[a] and Jin-Pei Cheng*[b]
Abstract: A new strategy for the im-
mobilization of asymmetric organoca-
talysts by combining polystyrene (PS)/
sulfonic acids and chiral amines in situ
through acid–base interactions is pre-
sented. The PS/sulfonic acids play a
dual role as catalyst anchors and modu-
lators for activity and stereoselectivity.
Different types of polymeric sulfonic
acids were examined and 1% divinyl-
benzene (DVB) cross-linked PS/sulfon-
ic acid 1e with a medium loading of
sulfonic acid moieties was found to be
the optimal support. Furthermore, the
noncovalency of this system allows
combinatorial screening of optimal cat-
alysts for the targeted reactions. In this
regard, highly efficient and enantiose-
lective heterogeneous catalysts were
identified for the asymmetric direct
aldol and Michael addition reactions.
The catalysts could be easily recovered
by filtration and reused for six cycles
with similar stereoselectivity but slight-
ly decreased activity. Significantly, the
deactivated catalysts could be regener-
ated following an acidic washing/amine
recharging procedure.
Keywords: aldol reaction · hetero-
geneous catalysis · Michael addi-
tion · noncovalent immobilization ·
organocatalysis
Introduction
tions.[1] However, organocatalysis has also been considered
to be of low efficiency as a result of the high catalyst load-
ings and the difficulties in catalyst separation and recycling.
The heterogenization of organocatalysts may provide poten-
tial solutions to these challenges.[2] Indeed, this strategy has
been attempted for organocatalysts ever since their debut in
similar ways to the heterogenization of homogeneous transi-
tion-metal catalysts and enzymes.[2,3] In this regard, hetero-
genization is commonly achieved by covalent attachment to
solid supports such as PS, poly(ethylene glycol) (PEG), den-
drimers, and inorganic materials (Figure 1, I).[4] However,
the heterogeneous organocatalysts obtained in these cases
have the disadvantages that 1) the catalysts are less effective
than their nonsupported homogeneous counterparts; 2) as a
result of being less effective, high loading (both w/w% and
mol%) of the catalysts is normally employed to achieve rea-
sonable yields; and 3) multiple synthetic manipulations are
required to achieve the covalent immobilizations.
For the reason of practicality, the noncovalent immobili-
zation of homogeneous catalysts is highly desirable since
modifications of the parent catalysts are generally mini-
mized and the strategy is also quite facile and modular, thus
allowing fine-tuning of the support structure and the homo-
geneous catalyst and their combination.[5] Accordingly, non-
covalently supported organocatalysts have been developed
through physical adsorption (Figure 1, II)[6] and biphasic
technology (Figure 1, III).[7] Although high activities and ex-
Organocatalysis is increasingly recognized as the third im-
portant kind of asymmetric catalysis, thus complementing
the well-established asymmetric transition-metal and
enzyme catalysis processes.[1] Unlike transition-metal cata-
lysts, organocatalysts typically do not use metals, therefore
giving them greater potential in pharmaceutical processes in
which metal contaminations are problematic. Furthermore,
organocatalysts are also much cheaper and easier to handle
than their transition-metal and enzyme counterparts. These
properties have propelled the explosive development of or-
ganocatalysts for a wide variety of fundamental transforma-
[a] Prof. Dr. S. Luo, J. Li, H. Xu
Beijing National Laboratory for Molecular Sciences
Center for Chemical Biology
Institute of Chemistry and Graduate School
Chinese Academy of Sciences, Beijing, 100080 (China)
Fax: (+86)10-6255-4449
E-mail: luosz@iccas.ac.cn
[b] L. Zhang, Prof. Dr. J.-P. Cheng
Department of Chemistry and State Key Laboratory of Elemento-or-
ganic Chemistry
Nankai University, Tianjin, 300071 (China)
Fax: (+86)
E-mail: chengjp@mail.most.gov.cn
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2008, 14, 1273 – 1281
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1273

Results and Discussion
Design principle for the immobilization of chiral amines:
Chiral amines are a recent focus in research into organoca-
talysis because of their divergent nature, which results in the
formation of either nucleophilic enamines or electrophilic
imminium ions, and their structural modifiability to ease the
discovery of diversity-oriented catalysts.[11] The immobiliza-
tion of the chiral amine catalysts normally requires addition-
al manipulations with the original or newly installed func-
tional groups. These procedures are somewhat tedious and
also introduce marked perturbations to the original small
molecular skeletons, consequently leading to varied catalytic
outcomes.[2] The acid–base assembly of chiral amines has
proven to be one of the most efficient bifunctional enamine
catalysts.[12] The acids used in these cases were essential
units that dramatically impacted the catalytic activity and
stereoselectivity.[13] Taking advantage of this strategy, we de-
veloped a noncovalent immobilization strategy by utilizing
solid acids (Scheme 1). Besides their similar roles to homo-
geneous acids, the acidic units in the solid acids also serve as
anchors for the chiral amines, thus resulting in heterogene-
ous acid/chiral amine assemblies that may work as asymmet-
ric heterogeneous enamine-type organocatalysts. Although
the structure and acidity of the solid acids and the nature of
the chiral diamines are key issues that relate to the perfor-
mance of the obtained heterogeneous catalysts, the modular
and combinatorial features of the current strategy should
provide a great opportunity to find optimal catalysts for the
reactions studied.
Figure 1. Current immobilization strategies (I–III) for organocatalysts
and our noncovalent strategy (IV).
cellent enantioselectivities were achieved in some of these
examples,[8] the issue of catalyst recycling and reuse still re-
mains to be addressed. A noncovalent linkage of reasonable
strength should solve these problems.
Herein, we present a new strategy for noncovalent immo-
bilization through acid–base interactions (Figure 1, IV). Our
immobilization strategy employs readily available chiral dia-
mines and solid acids, such as PS/sulfonic acids. The immo-
bilization is simply carried out by mixing the two reagents
together without any pretreatment and additional modifica-
tion to the parent catalyst. The resultant acid–base linkage,
that is, electrostatic interaction through ion pairs, would suf-
fice for good recyclability and reusability as a result of the
reasonably high strength of the linkage. In fact, a similar
strategy of noncovalently attaching transition-metal catalysts
onto solid supports has been previously well explored with
good activity and reusability.[9] Recently, an acid–base strat-
egy was applied to immobilize ruthenium cross-metathesis
catalysts, thus leading to enhanced activity.[10] Our design
herein is distinct from these previous reports as a result of
the dual functions of the solid-acid supports: first, they act
as an anchor for the chiral diamines and second they act as
a critical modulator for the catalytic activity and stereoselec-
tivity (Scheme 1). We report herein the development of non-
covalently supported chiral amine catalysts as asymmetric
heterogeneous organocatalysts for asymmetric direct aldol
and Michael addition reactions.
Construction of heterogeneous chiral amine catalysts: We
started with PS as our selected solid support since PS is fre-
quently employed in solid-supported organic synthesis and
catalysis.[14] With commercially available PS (1% divinylben-
zene (DVB) cross-linked, 200–400 mesh), the corresponding
PS/sulfonic acids 1 were obtained by simple treatment with
chlorosulfonic acid (Scheme 2). The loading of the acid
units could be adjusted by using different quantities of
chlorosulfonic acid (Table 1). PS/sulfonic acids with hydro-
phobic groups and linear PS/sulfonic acids were prepared
using similar procedures.
Some representative chiral diamines are shown in
Scheme 3. To illustrate the synthesis of the supported cata-
lysts, chiral diamine 2d was selected as a model catalyst.
The PS/sulfonic acids were treated with approximately
1.2 equivalents of 2d in CH2Cl2, the reaction mixture was
then filtered and washed with CH2Cl2 and ethanol. The final
PS/sulfonic acid/2d hybrids are insoluble in most organic
solvents and readily obtained by filtration. An exception
was observed with PS/sulfonic acid 1 f, which has a high
loading of sulfonic acid (2.75 mmolgÀ1). In this case, the
high density of chiral amine 2d dramatically changed the
physical properties of the resultant hybrid solid, thus
making the filtration difficult and excluding its further appli-
cation in heterogeneous applications (see below). The con-
tent of 2d in the supported catalysts was determined by ele-
Scheme 1. Immobilization strategy through acid–base interactions.
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Chem. Eur. J. 2008, 14, 1273 – 1281

Asymmetric Catalysis of Aldol and Michael Addition Reactions
FULL PAPER
Scheme 2. Synthesis of PS/sulfonic acids and their chiral amine hybrids.
Table 1. Elemental analysis of the supported chiral amines.
was selected as a benchmark for testing our noncovalently
supported catalysts. The direct aldol reaction is one of the
most extensively explored organocatalytic enamine-based
transformations catalyzed by chiral amines.[15] Although a
number of solid-supported chiral amine catalysts have been
developed for these reactions, only a few of them have
shown good stereoselectivity under heterogeneous condi-
tions.[4n] The chiral amine 2d supported on PS/sulfonic acids
was submitted to the model reaction of cyclohexanone and
para-nitrobenzaldehyde. To our delight, the reaction pro-
ceeded smoothly in the presence of 10 mol% of supported
chiral amine 2d (Table 2). Both the activity and stereoselec-
tivity demonstrated clear dependence on the loading of 2d
on the polymer (Table 2). The
PS/sulfonic acids
Loading of SO3H
[mmolg]À1
Loading of
A
2d [mmolg]À1
calculated
determined
1a
1b
1c
1d
1e
1 f
3a
3b
3c
4
0.31
0.60
1.05
1.19
1.39
2.75
0.31
0.54
0.85
0.95
0.29
0.55
0.91
1.02
1.11
n.d.[a]
0.30
0.50
0.76
0.84
0.29
0.55
0.90
1.00
1.09
n.d.
0.30
0.50
0.75
0.90
[a] n.d.=not determined.
catalyst 1e/2d with a medium
loading of 1.09 mmolgÀ1 gave
the best enantioselectivity
(Table 2, entry 5). In contrast,
either a lower or higher load-
ing led to inferior results in
terms of activity and enantio-
selectivity (Table 2, entries 1–
4). The catalyst with a high
loading of 2.75 mmolgÀ1 was
totally
inactive
(Table 2,
entry 7). Other types of PS/sul-
fonic acids, such as 3 appended
Scheme 3. Library of selected chiral diamines.
with a long alkyl chain and
linear 4, gave poor results
mental analysis. The loading of 2d was in good agreement
with calculated data based on the loading of the sulfonic
acid (Table 1), except in the case of linear PS/sulfonic acid
4, in which a slightly higher loading than expected was ob-
served, probably because of the cross-linking between the
linear polymeric acids with the diamine 2d. These results
suggest that the active sites in the DVB cross-linked PS/sul-
fonic acids (1 and 3) were fully accessible.
(Table 2, entries 8–11). Notably, the catalysis of 1e/2d could
be significantly accelerated using much less solvent (Table 1,
entry 6 versus 5). Based on these results, PS/sulfonic acid 1e
was selected as our optimal support for further develop-
ment.
The solvent effect was briefly examined with 1e/2d as a
representative catalyst (Table 3). As is well known, the swel-
ling of a polymer resin has a significant influence on the cor-
responding supported catalyst.[14a] While the reactions
showed consistently high activities in all the solvents exam-
ined, there was an obvious solvent effect on the stereoselec-
Heterogeneous chiral amine catalysts for the asymmetric
direct aldol reaction: The asymmetric direct aldol reaction
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1275

S. Luo, J.-P. Cheng et al.
Table 2. The effect of catalyst loading in asymmetric direct aldol reac-
tions.
followed. For convenience, the supported chiral amine cata-
lysts were prepared in situ by simply mixing 1e and chiral
diamines 2 in 1:1 molar ratio. A quick screening identified
primary/tertiary diamines 2i and 2k as promising candidates.
We previously showed that this type of diamine combined
with a Brønsted acid was a highly effective enantioselective
catalyst for direct aldol reactions.[13f] In the presence of
10 mol% of 1e/2k, the product was obtained in 95% yield
with 95:5 d.r. and 94% ee over 19 h (Table 4, entry 8). The
Entry[a] Cat.
(10 mol%)
Loading
[mmolgÀ1
]
Yield
[%][b]
anti/syn[c] ee
[%][d] anti/syn
G
N
1
2
3
4
1a/2d
1b/2d
1c/2d
1d/2d
1e/2d
1e/2d
1 f/2d
3a/2d
3b/2d
3c/2d
4/2d
0.29
0.55
0.90
1.00
1.09
1.09
2.75
0.30
0.50
0.75
0.90
46
65
75
63
51
97
trace
54
59
89:11
86:14
81:19
84:16
84:16
80:20
n.d.
64:36
70:30
74:26
n.d.
55:78
55:53
40:58
46:51
62:83
75:63
n.d.
3:58
3:64
9:66
n.d.
5
Table 4. Screening of chiral amines 2.
6[e]
7[f]
8
9
10
11
44
trace
Entry[a]
Chiral
amine
t
Yield
[h][b]
anti/syn[c]
ee [%][d]
anti/syn
[h]
[a] Reactions
conditions:
aldehyde=0.25 mmol,
cyclohexanone=
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2h
2i
12
12
12
12
12
24
24
19
97
58
95
97
17
97
92
95
79:21
83:17
64:36
72:28
78:22
91:9
46:52
52:39
60:73
75:63
1.0 mmol, CH2Cl2 =500 mL. [b] Yield of the isolated products. [c] Deter-
mined by 1H NMR spectroscopic analysis. [d] Determined by chiral
HPLC. [e] The reaction was carried out in CH2Cl2 (100 mL) over 12 h.
[f] The catalyst was prepared in situ.
85:69
97:57[e]
94:80[e]
94:14[e]
2j
2k
90:10
95:5
Table 3. Solvent effect in asymmetric direct aldol reactions catalyzed by
1e/2d.
[a] Reactions
conditions:
aldehyde=0.25 mmol,
cyclohexanone=
1.0 mmol, CH2Cl2 =100 mL. [b] Yield of the isolated products. [c] Deter-
mined by 1H NMR spectroscopic analysis. [d] Determined by chiral
HPLC. [e] The products had a 1’S,2R configuration, which is opposite to
the products in the catalysis of 2a/2h (as shown above).
Entry[a]
Solvent
t [h]
Yield
[%][b]
anti/syn[c]
ee [%][d]
anti/syn
1
2
3
4
5
6
7
8
9
dioxane
toluene
methanol
THF12
CH2Cl2
CH3CN
ethyl acetate
CHCl3
12
12
12
98
94
97
78:22
80:20
62:38
54:62
80:20
84:16
76:24
83:17
79:21
80:20
50:60
59:66
41:56
reaction with 2i provided equally good results (Table 4,
entry 6) and these two chiral diamines were thus selected
for further investigation. To the best of our knowledge,
these represent the first examples of supported chiral pri-
mary amine catalysts.
95
79:21
12
12
12
12
12
6
97
95
98
97
97
97
75:63
55:65
40:42.
54:57
62:45
55:41
With the identified optimal catalysts, the major concerns
were then their recyclability, reusability, and applicability.
The supported catalysts 1e/2i and 1e/2k had shown that
they were suitable for a range of ketone donors and alde-
hyde acceptors (Table 5). In all the cases examined, the re-
actions demonstrated reasonably high activity and the prod-
ucts were afforded in up to 99% yield with 96:4 d.r. and
99% ee. Catalyst 1e/2k provided a better diastereoselectiv-
ity than catalyst 1e/2i in several cases (Table 5, entries 5, 7,
9, 11, and 13). The recyclability and reusability of catalyst
1e/2i was examined in the model reaction of cyclohexanone
and para-nitrobenzaldehyde (Table 6). On completion of the
reaction, the catalyst was simply filtered off and washed
with diethyl ether. The dried catalyst was then subjected to
the next run. The thus-recycled catalyst showed unchanged
activity and stereoselectivity in the first three rounds of
reuse. Decreased activity was observed in the subsequent
fourth and fifth rounds of reuse, but the stereoselectivity
was essentially maintained (Table 6, entries 4 and 5). Signifi-
cantly, the deactivated catalyst could be reactivated by
washing with HCl/dioxane and recharging with chiral dia-
mine 2i. The activity was recovered to the same level as the
H2O
neat
10
[a] Reactions
conditions:
aldehyde=0.25 mmol,
cyclohexanone=
1.0 mmol, solvent=100 mL. [b] Yield of the isolated products. [c] Deter-
mined by 1H NMR spectroscopic analysis. [d] Determined by chiral
HPLC.
tivity. The best enantioselectivity (75% ee for the major anti
isomer) was achieved in CH2Cl2 (Table 3, entry 5). A control
reaction was carried out in the presence of para-toluenesul-
fonic acid instead of the polymeric sulfonic acid 1e with an
enantiomeric excess of 54% ee being obtained for the major
anti isomer (anti/syn=74:26), thus highlighting the impor-
tance of the role of the polymeric acid on enantioselectivity.
To further improve the stereoselectivity, two strategies
were applicable: The first was to increase the acidity of the
polymeric acids; previous studies have shown that the com-
bination of stronger acids with chiral diamines, such as 2d,
give a better stereoselectivity.[13a,16] The second strategy was
to screen a library of chiral amines. Since libraries of chiral
amines were readily available to us, the latter strategy was
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Asymmetric Catalysis of Aldol and Michael Addition Reactions
FULL PAPER
Table 5. Applications of catalysts 1e/2i and 1e/2k in asymmetric direct aldol reactions.
tion of the catalyst (Figure 2).
This behavior suggests homo-
geneous catalysis arising from
the dissociated chiral amine
was insignificant and the reac-
tion mainly occurred under
heterogeneous conditions.
Entry[a]
R1, R2
R
Cat.
t [h]
Yield
[%][b]
anti/syn[c]
ee
[%][d]
1
4-NO2Ph
1e/2i
24
97
91:9
97
Heterogeneous chiral amine
catalysts for an asymmetric Mi-
chael reaction: The Michael re-
2
3
4
5
6
7
8
9
10
11
12
13
5
5
5
5
5
5
5
5
5
5
5
5
3-NO2Ph
2-NO2Ph
4-CF3Ph
4-CF3Ph
4-CNPh
4-CNPh
4-ClPh
4-ClPh
Ph
1e/2i
1e/2i
1e/2i
1e/2k
1e/2i
1e/2k
1e/2i
1e/2k
1e/2i
1e/2k
1e/2i
1e/2k
19
22
40
30
19
24
96
96
96
96
48
72
95
97
99
97
98
97
90
89
86
48
67
60
91:9
96:4
83:17
93:7
81:19
93:7
77:23
92:8
68:32
81:19
78:22
85:15
99
96
95
96
94
95
89
91
90
94
89
95
À
action is one of the basic C C
bond-forming reactions, and its
versatile utility in organic syn-
thesis has stimulated tremen-
dous research interest in the
development of asymmetric
Michael catalysts, especially
metal-free organocatalysts.[17]
To address the issue of catalyst
recycling and reuse, the use of
Ph
1-naph
1-naph
several
supported
chiral
14
2-NO2Ph
1e/2i
20
91
68:32
94
amines has been explored for
asymmetric Michael additions
to nitroolefins. Using biphasic
technology, recyclable chiral
amine catalysts supported by a
fluorous phase[7j,k] and dendri-
mers[4t] were developed for the
asymmetric Michael addition
of aldehydes to nitrostyrenes.
The catalysts offered high
enantioselectivity but limited
15
16
17
18
19
20
21
H, H (7)
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-CF3Ph
4-CNPh
3-BrPh
1e/2i
60
72
72
72
72
72
72
83
88
80
87
88
72
82
–
–
–
–
–
–
–
76
83
81
77
77
77
83
7
7
7
7
7
7
1e/2k
1e/2k
1e/2k
1e/2k
1e/2k
1e/2k
2-ClPh
[a] Reactions conditions: aldehyde=0.25 mmol, ketone=1.0 mmol, CH2Cl2 =100 mL; entries 15–21: reaction in
neat acetone (200 mL). [b] Yield of the isolated products. [c] Determined by 1H NMR spectroscopic analysis.
[d] Determined by chiral HPLC. 1-naph=1-naphthalene.
reusability.
PEG-supported
Table 6. Recycle and reuse of 1e/2i in the reaction of cyclohexanone
with para-nitrobenzaldehyde.
chiral amines were also tried for the Michael addition of ke-
tones, but showed poor stereoselectivity.[4e,18] Previously, we
developed functionalized chiral ionic liquids (FCILs) as new
types of recyclable and reusable small-molecular catalysts
Entry[a]
t
Yield
[%][b]
anti/syn[c]
ee [%][d]
anti/syn
[h]
1
2
3
4
24
24
26
34
48
24
97
97
98
95
53
92
91:9
97:57
97:60
97:66
98:67
96:20
89:26
89:11
88:12
92:8
92:8
86:14
5
6[e]
[a] Reactions
conditions:
aldehyde=0.25 mmol,
cyclohexanone=
1.0 mmol, CH2Cl2 =100 mL. [b] Yield of the isolated products. [c] Deter-
mined by 1H NMR spectroscopic analysis. [d] Determined by chiral
HPLC. [e] The catalyst was reactivated.
fresh catalyst; however, the enantioselectivity was decreased
slightly (Table 6, entry 6).
To probe the heterogeneous nature of the noncovalently
supported catalysts, the model reaction of cyclohexanone
and para-nitrobenzaldehyde was allowed to carry on until
approximately 50% conversion was reached. The catalyst
1e/2i was then filtered off. The reaction in the homogeneous
filtrate was monitored by 1H NMR spectroscopic analysis,
which showed less than 3% conversion over 24 h after filtra-
Figure 2. Reaction progress before and after filtration of the catalysts 1e/
2i.
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S. Luo, J.-P. Cheng et al.
for asymmetric Michael additions to nitroolefins.[8a] The
FCILs catalyzed the reaction in high yields and with excel-
lent stereoselectivity, could be recycled by precipitation with
diethyl ether and could be reused for four times. To further
enhance their recyclability, heterogeneous FCILs were pre-
pared by noncovalent immobilization through ion pairing
using a PS/sulfonic anion. Unfortunately, the heterogeneous
FCILs were nearly inactive for the catalysis of the same re-
action (Scheme 4).
Table 8. Screening of chiral amines 2 in the Michael addition reaction.
Entry[a]
Chiral
amine
t
Yield
[%][b]
syn/anti[c]
ee
[h]
[%][d]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
2g
2h
24
24
24
24
24
48
48
48
77
84
89
81
94
30
30
56
94:6
94:6
94:6
94:6
94:6
89:11
86:14
92:8
82
88
87
83
87
81
67
85
[a] Reaction conditions: nitrostyrene=0.25 mmol, cyclohexanone=
1.0 mmol, CH2Cl2 =100 mL. [b] Yield of the isolated products. [c] Deter-
mined by 1H NMR spectroscopic analysis. [d] Determined by chiral
HPLC.
Scheme 4. Heterogeneous FCIL-catalyzed asymmetric Michael addition.
amines such as 2i–2k were also examined but were found to
be ineffective for the catalysis of the Michael addition reac-
tions.
We then tested noncovalently supported chiral amine cat-
alysts in Michael addition reactions. To our delight, this type
of catalyst could effectively catalyze the Michael additions.
In the catalytic processes using 1e/2d, the reactions pro-
ceeded smoothly in organic solvents, but hardly occurred
under neat conditions (Table 7, entry 1). The reactions in
With the optimal catalyst 1e/2e, we investigated the het-
erogeneous catalysis of the Michael addition reaction of a
wide range of Michael donors and nitrostyrenes. The reac-
tion proceeded well with cyclohexanone. In all cases, the de-
sired Michael adducts were obtained in good diastereo- and
enantioselectivities (up to 96:4 d.r. and 90% ee, respective-
ly). Moreover, the reactions tolerated a variety of nitrostyr-
enes possessing either electron-withdrawing or -donating
substitutents and various substitution patterns (para-, meta-,
ortho-, and bis-). Cyclopentanone and acetone were also
tested under these conditions, but low yields and poor ste-
reoselectivity were obtained (Table 9, entries 13 and 14).
The heterogeneous catalyst 1e/2e also worked with alde-
hyde donors, such as isobutyraldehyde, thus affording 69%
yield and 83% ee in 36 hours.
To investigate the heterogeneous nature of the Michael
addition reactions, the supernatant of 1e/2e in the model re-
action (as shown in Table 10) at approximately 50% conver-
sion was monitored by 1H NMR spectroscopic analysis.
There was approximate 10% further conversion observed
over 10 h, thus suggesting the leaching of chiral amine 2e.
This leaching could be diminished by diluting the reaction
mixture with hexane or diethyl ether before filtration. Fol-
lowing this procedure, we found the catalyst could be reused
for six cycles, thus maintaining the same activity as the first
three cycles (Table 10). A significant decrease in activity
was only observed in the sixth cycle. At this stage, the cata-
lyst could be reactivated by washing with HCl/dioxane and
recharging with fresh 2e (Table 10, entry 7), again highlight-
ing the advantages of noncovalent immobilization.
Table 7. Solvent effect in asymmetric Michael addition reactions cata-
lyzed by 1e/2d.
Entry[a]
Solvent
Yield
[%][b]
syn/anti[c]
ee
[%][d]
1
2
3
4
5
6
7
8
neat
trace
81
85
–
–
83
85
toluene
methanol
THF77
CH2Cl2
CH3CN
ethyl acetate
CHCl3
94:6
91:9
78
96:4
93:7
94:6
95:5
93:7
67
74
66
73
84
80
85
84
[a] Reaction conditions: nitrostyrene=0.25 mmol, cyclohexanone=
1.0 mmol, solvent=100 mL. [b] Yield of the isolated products. [c] Deter-
mined by 1H NMR spectroscopic analysis. [d] Determined by chiral
HPLC.
methanol and toluene produced the best results in terms of
both activity and stereoselectivity (Table 7, entries 2 and 3).
Toluene was selected for further experiments to balance ac-
tivity and stereoselectivity. A small library of chiral amines
was then evaluated in the noncovalently supported catalytic
systems (Table 8), and chiral diamine 2e was found to be an
optimal choice (Table 8, entry 5). With 10 mol% of 1e/2e,
the product was obtained in 94% yield with 94:6 d.r. and
87% ee over 24 h. These results showed significant improve-
ment in activity relative to the nonsupported catalyst 2e
(20 mol% of 2d, 22 h, 93% yield).[17z] Finally, chiral primary
Conclusion
We have developed a new and very facile approach for the
development of heterogeneous asymmetric organocatalysts
1278
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1273 – 1281

Asymmetric Catalysis of Aldol and Michael Addition Reactions
FULL PAPER
Table 9. Applications of catalysts 1e/2e in asymmetric Michael addition reactions.
for combinatorial screening of
the desired heterogeneous
asymmetric organocatalysts for
the targeted reactions. In this
regard, 1e/2i and 1e/2e were
Entry[a]
R1, R2
Ar
Ph
t
Yield
[%][b]
syn/anti[c]
ee
[h]
[%][d]
identified from
a library of
readily available chiral amines
as the optimal catalysts for
asymmetric direct aldol and
Michael addition reactions, re-
1
24
94
94:6
87
2
3
4
5
6
7
8
9
5
5
5
5
5
5
5
5
5
5
5
4-MeOPh
1-naph
4-MePh
4-PhPh
24
24
30
30
20
8
97
97
91
88
56
80
95
77
96
70
78
94:6
95:5
95:5
96:4
94:6
96:4
95:5
95:5
95:5
93:7
94:6
82
89
89
80
88
88
84
90
89
68
87
spectively.
These
catalysts
demonstrated comparable or
even better activity and stereo-
selectivity than their nonsup-
ported homogeneous catalyst
counterparts.
The heterogeneous nature of
the noncovalently supported
catalysts facilitates easy recy-
cling of the catalysts through
filtration; furthermore, the cat-
alysts could be reused six times
with similar stereoselectivity,
although slightly decreased ac-
tivity. Significantly, the recy-
cled catalysts could be reacti-
vated following an acidic wash-
4-ClPh
4-NO2Ph
2-NO2Ph
3-NO2Ph
2-ClPh
piperal
2,4,-(MeO)2Ph
6
12
15
24
24
10
11
12
13
Ph
24
39
70:30
62
14
15
Me,H 7
isobutyraldehyde 8
Ph
Ph
36
36
21
69
–
–
20
83
[a] Reactions conditions: nitrostyrene=0.25 mmol, ketone=1.0 mmol, toluene=100 mL. [b] Yield of the isolat-
1
ed products. [c] Determined by H NMR spectroscopic analysis. [d] Determined by chiral HPLC.
ing/recharging
Overall, the noncovalency of
procedure.
Table 10. Recycle and reuse of 1e/2e in asymmetric Michael additions.
our heterogenization strategy enables simple catalyst prepa-
ration, combinatorial screening, and facile catalyst reuse and
reactivation. Since many kinds of solid acids, such as sulfo-
nated PSs, are commercially available, this strategy may
thus provide a new solution to the development of recovera-
ble and reusable asymmetric organocatalysts.[19] Ongoing in-
vestigations include the design of heterogeneous acids with
enhanced acidity,[16] applications to other organocatalytic
transformations, and the development of a flow catalytic
system.
Entry[a]
t
Yield
[%][b]
syn/anti[c]
ee
[h]
[%][d]
1
2
3
4
6
6
6
95
98
91
93
89
77
89
95:5
95:5
96:4
95:5
95:5
94:6
95:5
84
83
84
84
81
80
81
10
13
21
6
5
6
7 [e]
[a] Reaction conditions: nitrostyrene=0.25 mmol, ketone=1.0 mmol, tol-
uene=100 mL. [b] Yield of the isolated products. [c] Determined by
1H NMR spectroscopic analysis. [d] Determined by chiral HPLC. [e] The
catalyst was reactivated.
Experimental Section
General methods: Commercial reagents were used as received, unless
otherwise indicated. Visualization of the developed chromatograms was
performed by fluorescence quenching or staining with KMnO4 and para-
anisaldehyde. 1H and 13C NMR spectra were recorded in CDCl3 on a
300-MHz spectrometer at 258C and the chemical shifts are reported in
ppm from tetramethylsilane with the solvent resonance as the internal
standard. The IR spectra were recorded on a FT-IR instrument and are
reported in cmÀ1. HPLC analysis was performed using Chiralcel AD-H,
OD-H, AS-H, and OJ-H columns. The absolute configurations were de-
termined by correlation to reported results. Elemental analysis was ob-
tained from ThermoQuest. Polystyrene (1% DVB cross-linked) and
linear polystyrene (MW=25000) were commercial available (Acros).
Polystyrene appended with long alkyl chains was synthesized following a
reported procedure.[20]
through the complexation of PS/sulfonic acids and chiral
amines in situ through acid–base interactions. PS/sulfonic
acids were shown to not only act as the anchor for the cata-
lyst, but they also played critical roles in affecting the cata-
lytic activity and stereoselectivity. The structure and the
density of the sulfonic acid groups were found to have a
marked impact on the performance of the supported cata-
lysts. PS/sulfonic acid 1e with 1% DVB cross-linking and a
medium loading of sulfonic acid was identified as the opti-
mal support. Furthermore, the noncovalent feature allowed
Typical procedure for the synthesis of PS/sulfonic acid 1e: PS-supported
sulfonic acid was synthesized according to a reported procedure with
Chem. Eur. J. 2008, 14, 1273 – 1281
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1279

S. Luo, J.-P. Cheng et al.
minor modifications:[19] Chlorosulfonic acid (0.4 mL) was slowly added to
a suspension of PS (3.0 g, 1% DVB cross-linked, 200–400 mesh) in
CH2Cl2 (60 mL) at 08C, and the reaction mixture was stirred for 6 h.
THF/water (5:1, 60 mL) was added and after 1 h the resin was collected
on a glass filter, rinsed with water (3”50 mL), THF/water (5:1, 3”
50 mL), and dichloromethane (3”50 mL) and then dried under vacuum
to give resin 1e. From the result of elemental analysis (%) found: S 4.44;
result mixture was stirred for 5 min at room temperature. The solid cata-
lyst was separated and washed sequentially with methanol and ethyl
ether (3”5 mL). The obtained solid was resuspended in CH2Cl2 (0.5 mL)
and 2i (4.0 mg, 0.028 mmol) was added. The reaction mixture was then
stirred for 1 h. The solid was separated and washed with CH2Cl2 and di-
ethyl ether. After removing the residue solvent under vacuum, the solid
was used directly in the catalytic reactions.
thus, the sulfonic acid content was estimated to be 1.39 mmolgÀ1
.
Typical procedure for the synthesis of catalyst 1e/2d: PS/sulfonic acid 1e
(1.0 g, 1.39 mmol) was suspended in CH2Cl2 (20 mL) and the reaction
mixture was stirred for 15 min at room temperature. Chiral amine 2d
(280 mg, 1.8 mmol) was then added and the resultant mixture was stirred
for 2 h at room temperature. The catalyst was separated by filtration and
washed sequentially with CH2Cl2, ethanol, and CH2Cl2. The solid was
dried in vacuo at room temperature over night to give 1e/2d in quantita-
tive yield. Elemental analysis (%) found: N 3.05, equal to 1.09 mmolgÀ1
of 2d; IR (KBr): n˜ =3446, 3026, 2922, 2777, 2472, 1945, 1630, 1489, 1447,
Acknowledgements
This study was supported by the Natural Science Foundation of China
(NSFC 20421202, 20632060, and 20542007), the Ministry of Science and
Technology (MoST), and the Chinese Academy of Sciences.
1382, 1116, 835, 758, 696, 541 cmÀ1
.
The other catalysts were prepared using similar procedures.
[1] For selected reviews of organocatalysis, see: a) P. I. Dalko, L.
Moisan, Angew. Chem. 2004, 116, 5248–5286; Angew. Chem. Int.
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1390.
Catalyst 1e/2e: Elemental analysis (%) found: N 3.06, therefore the
loading of 2e was estimated to be 1.09 mmolgÀ1; IR (KBr): n˜ =3445,
3026, 2920, 1946, 1631, 1488, 1448, 1380, 1116, 834, 757, 696, 544 cmÀ1
.
Catalyst 1e/2i: Elemental analysis (%) found: N 3.08, therefore the load-
ing of 2i was estimated to be 1.10 mmolgÀ1. IR (KBr): n˜ =3442, 3027,
2921, 1947, 1634, 1488, 1449, 1380, 1164, 1116, 834, 756, 695, 537 cmÀ1
.
Catalyst 1e/2k: Elemental analysis (%) found: N 3.06, therefore the
loading of 2k was estimated to be 1.09 mmolgÀ1; IR (KBr): n˜ =3441,
3027, 2922, 1947, 1631, 1487, 1449, 1381, 1160, 1115, 834, 756, 696,
[3] For a monograph on supported asymmetric catalysts, see: a) Chiral
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538 cmÀ1
.
Typical procedure for the asymmetric direct aldol reaction: Catalyst 1e/
2i (22 mg, 0.025 mmol) was added to solution of cyclohexanone
a
(0.1 mL) in CH2Cl2 (0.1 mL). The heterogeneous solution was stirred for
10 min and then 4-nitrobenzaldehyde (38 mg, 0.25 mmol) was added. The
resulting mixture was stirred at room temperature until no 4-nitrobenzal-
dehyde could be detected. The catalyst was filtered and washed with di-
ethyl ether (3”5 mL). The catalyst could be directly used after removing
the residue volatile under vacuum. The organic portions were combined
and concentrated. The residue was purified by column chromatography
on silica gel to afford the desired product (61 mg, 97%). 1H NMR
(300 MHz, CDCl3): d=1.32–1.46 (1H, m), 1.46–1.76 (2H, m), 1.76–1.91
(1H, m), 2.04–2.19 (1H, m), 2.28–2.44 (1H, m), 2.44–2.72 (2H, m), 4.00–
4.16 (1H, d, J=3.0 Hz), 4.81–4.03 (1H, dd, J=3.0, 3.2 Hz, 8.3 Hz), 7.43–
7.67 (2H, m), 8.10–8.37 (2H, m) ppm; 13C NMR (CDCl3, 75 MHz): d=
24.7, 27.6, 30.7, 42.6, 57.1, 74.0, 123.5, 127.8, 147.6, 148.3, 214.6 ppm; the
enantiomeric excess was determined by HPLC on an AD-H column at
254 nm (2-propanol/hexane 20:80), 258C, 0.5 mLminÀ1
(major), tR =28.60 (minor).
All the aldol products in Table 5 are known products.[4r,13]
;
tR =22.44
Typical procedure for asymmetric Michael reaction: Catalysts 1e/2d
(22 mg, 0.025 mmol) were added to a solution of cyclohexanone (0.1 mL)
in toluene (0.1 mL). The heterogeneous mixture was stirred for 10 min
and b-nitrostyrene (37 mg, 0.25 mmol) was added. The resultant mixture
was stirred at room temperature until no b-nitrostyrene could be detect-
ed. Ethyl ether was then added to the reaction mixture. The product
layer was separated and the catalyst was washed with diethyl ether (3”
5 mL). The catalyst could be used directly after removing the residue vol-
atile under vacuum. The organic portions were combined and concentrat-
ed. The residue was purified by column chromatography on silica gel to
afford the desired product (58 mg, 94%). 1H NMR (300 MHz, CDCl3):
d=1.21–1.26 (1H, m), 1.16–1.74 (4H, m), 2.13–2.16 (1H, m), 2.37–2.47
(2H, m), 2.68–2.70 (1H, m), 3.72–3.79 (1H, m), 4.59–4.66 (1H, dd), 4.91–
4.96 (1H, dd), 7.15–7.35 (5H, m) ppm; the enantiomeric excess was de-
termined by HPLC with an AD-H column at 254 nm (2-propanol/hexane
10:90), 258C, 0.5 mLminÀ1; tR =20.86 (minor), tR =25.47 (major).
All the Michael adducts are known products.[17,21]
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catalyst (0.025 mmol) was treated with 1m HCl/dioxane (1 mL). The
1280
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1273 – 1281

Asymmetric Catalysis of Aldol and Michael Addition Reactions
FULL PAPER
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Received: July 23, 2007
Published online: November 15, 2007
Chem. Eur. J. 2008, 14, 1273 – 1281
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1281