Chiral amine-polyoxometalate hybrids as recoverable asymmetric enamine catalysts under neat and aqueous conditions

Article abstract of DOI:10.1002/ejoc.200800915

Solid acid-chiral amine hybrids have been synthesized and explored as recyclable and reusable enamine-type asymmetric catalysts. Simple chiral amine-polyoxometalate (CA-POM) hybrids were identified as the optimal catalysts to promote a range of enamine-ba

Full text of DOI:10.1002/ejoc.200800915

FULL PAPER
DOI: 10.1002/ejoc.200800915
Chiral Amine–Polyoxometalate Hybrids as Recoverable Asymmetric Enamine
Catalysts under Neat and Aqueous Conditions
Jiuyuan Li,[a] Shenshen Hu,[a] Sanzhong Luo,*[a] and Jin-Pei Cheng*[b]
Keywords: Polyoxometalates / Amines / Organocatalysis / Immobilization / Biphasic catalysis
Solid acid–chiral amine hybrids have been synthesized and
fast reactions and high stereoselectivities. Under both condi-
explored as recyclable and reusable enamine-type asymmet- tions, the CA–POM hybrid catalysts could be easily recycled
ric catalysts. Simple chiral amine–polyoxometalate (CA–
POM) hybrids were identified as the optimal catalysts to pro-
mote a range of enamine-based transformations with high
activity and excellent stereoselectivity under either neat or
aqueous conditions. A catalyst loading as low as 0.33 mol-%
(1 mol-% loading of chiral amine) was sufficient to achieve
and reused up to seven times with essentially unchanged
stereoselectivity, although diminished activity was observed
upon extensive reuse, especially under aqueous conditions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
with low loadings (Ͻ5 mol-%) are highly desirable. In spite
of the tremendous efforts dedicated to exploring chiral
amine catalysis in water, examples of highly active aqueous
catalysts, for example, with a loading as low as 1 mol-%,
are quite limited.[7] In this context, reusable chiral amine
catalysts in water have been much less explored. Several
polymer-supported chiral amine catalysts have been re-
ported to work favorably in aqueous conditions,[8] but the
immobilized catalysts generally demonstrated inferior ac-
tivity to their homogeneous counterparts and catalyst load-
ings in the range of 10–30 mol-% were frequently employed.
To the best of our knowledge, a highly active, reusable chi-
ral amine catalyst that can be used with a loading as low as
1 mol-% in water has not been reported.
Acid–base assembly of chiral amines has proved to be
one of the most efficient bifunctional enamine catalysts.[9]
The acids used in these examples were essential units that
dramatically impacted the catalytic activity and stereoselec-
tivity. Taking advantage of the acid–base principle, we de-
veloped a noncovalent immobilization strategy for chiral
amines by utilizing solid acids.[5q] Inspection of a range of
solid acids including some polymeric Brønsted acids re-
vealed that polyoxometalates serve as a promising type of
solid acid. As is well known, polyoxometalates (POMs)
have been applied as catalysts or catalyst supports due to
their intrinsic properties such as high acidity, favorable re-
dox potentials, and large framework.[10] However, asymmet-
ric catalysis utilizing POMs has remained largely unex-
plored.[11] During our studies, we found that chiral amine–
POM hybrids acted as highly efficient and recoverable
asymmetric enamine catalysts. Catalyst loadings as low as
1 mol-% were achieved under both neat and aqueous condi-
tions. Herein, we report the full details of these studies.[12]
Introduction
Besides transition-metal catalysts and enzymes, organo-
catalysts are increasingly recognized as the third most im-
portant class of asymmetric catalysts for chiral synthesis.[1]
However, organocatalysts are generally of low efficiency as
a result of the high catalyst loading and the difficulties in
catalyst separation and recycling. Accordingly, immobiliza-
tion of these small molcular catalysts has attracted exten-
sive research activities in order to address the above chal-
lenges ever since the renaissance of organocatalysts.[2] In
this regard, various immobilizing strategies, including at-
taching the catalysts to supports,[3] adsorbing them onto
solid surfaces,[4] and the so-called biphasic technology,[5]
have been extensively explored. Though good stereoselec-
tivity was achieved in many cases,[2c] a large amount of sup-
ported organocatalysts in terms of both weight and molar
ration are still required to achieve reasonable yields due to
their reduced activity upon immobilization. A new strategy
that overcomes the above shortcomings is therefore highly
desirable.
Aqueous-phase asymmetric catalysis has attracted inten-
sive research interest due to the favorable features of water
as an inexpensive, safe, and environmentally benign me-
dium.[6] In terms of both atomic economy and green syn-
thesis, chiral amine catalysts that work actively in water
[a] Beijing National Laboratory for Molecular Sciences (BNLMS),
Centre for Chemical Biology, Institute of Chemistry, Chinese
Academy of Sciences,
Beijing 100190, China
Fax: +86-10-82613774
E-mail: luosz@iccas.ac.cn
[b] Department of Chemistry and State Key Laboratory of Ele-
mento-organic Chemistry, Nankai University,
Tianjin 300071, China
132
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 132–140

Chiral Amine–Polyoxometalate Hybrids as Recoverable Asymmetric Catalysts
general, the hybrid solids, for example 1d–2a, have biphasic
Results and Discussions
characteristics and are soluble in polar organic solvents
such as acetone, NMP, DMF, and DMSO, but they insolu-
ble in less-polar solvents like hexane, toluene, and ethyl
ether. These properties, together with their easy prepara-
tions, are sufficient for practical applications in biphasic
asymmetric organocatalysis. Interestingly, all the CA–POM
hybrids are well dispersed in water as a milk-like solution
(Figure 1c), and optical microscopy shows uniform micelle-
like aggregates with 0.4 µm mean diameter (Figure 1a). This
surfactant-like property would make the CA–POM hybrids
potential asymmetric catalysts in water as usually observed
with many other surfactant-type catalysts.[14]
Design and Synthesis of CA–POM Hybrid Catalysts
Our design is based on the well-applied “acid–base”
strategy in organocatalysis by utilizing the intrinsic high
acidity of POMs and the proven catalytic capability of chi-
ral amines (Scheme 1). Because both amines and POMs are
readily available, the noncovalent features of the current
strategy thus allow for combinatorial screening of the cata-
lysts for the target reaction by simply switching the chiral
amine and the POM and their combinations. In addition,
organic modifications of POM have been well applied to
tune their physical properties and/or structure diversity[13]
and POM-type surfactants have been developed by using
this approach.[13h] Hydrophobic CA–POM hybrids that
work preferentially in aqueous media may therefore be
evolved by organic modification of POM with chiral
amines.
Evaluation of CA–POM Hybrid Catalysts
The CA–POM hybrid catalysts were next tested in a typi-
cal direct aldol reaction.[15] The screening results of the
model reaction between acetone or cyclohexanone and p-
nitrobenzaldehyde are listed in Table 1. All the CA–POM
hybrid catalysts could catalyze the asymmetric reaction
smoothly. In general, stronger acids gave better results in
terms of both activity and enantioselectivity. Following this
trend, H3PW12O40, the most acidic POM, provided the best
results. With H3PW12O40 as the selected solid acid, a variety
of chiral diamines were then tested, and hybrid 1d–2a was
identified as the optimal catalyst for the reaction of acetone
(Table 1, entry 10). To our delight, the loading of the cata-
lyst could be reduced to less than 0.33 mol-%, while still
maintaining good activity and selectivity (Table 1, entry 11;
24 h, 87% yield, 91%ee). In comparison to nonsupported
catalyst 1d–TfOH (Table 1, entry 12), less dehydration
product was detected with 1d–2a and the only byproduct
was the bis(aldol) adduct in this case. These results high-
light the synergistic effect by combining chiral amine and
Scheme 1. Strategy for the construction of CA–POM hybrid cata-
lysts.
The CA–POM hybrids were prepared by slow addition POM.
of a POM acid into a solution of the chiral amine in dry
Encouraged by the results above and bearing in mind
THF. After removal of the solvent, the resulting powders the unique surfactant-like features of CA–POM hybrids in
were washed with ethyl ether and dried under vacuum. water, we next examined the use of CA–POM hybrids as
NMR and IR spectroscopic studies and elemental analysis reusable catalysts in water. However, the reaction did not
confirmed that the compositions of the hybrid compounds work well with the aldol reaction of acetone (Table 1, en-
were consistent with the structures shown in Scheme 1. In tries 6 and 7), and both activity and selectivity were signifi-
Figure 1. Laser scanning confocal microscopy images of (a) freshly prepared hybrid catalyst 1d–2a in water and (b) catalyst 1d–2a in
water after its sixth reuse. Picture (c) refers to fresh 1d–2a in water.
Eur. J. Org. Chem. 2009, 132–140
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
133

J. Li, S. Hu, S. Luo, J.-P Cheng
FULL PAPER
Table 1. Screening of chiral amine hybrid catalysts in a direct aldol reaction.
Entry
Cat. (X/3)
Conditions[a]
Time [h]
Yield [%][b]
anti/syn[c]
ee [%][d]
1
2
3
4
1a–2a (10)
1a–2b (10)
1a–2c (10)
1a–2d (10)
1a–2e (10)
1e–2a (10)
1d–2f (10)
1b–2a (5)
1c–2a (5)
1d–2a (5)
1d–2a (1)
1d–TfOH (1)
1a–2a (5)
1b–2a (5)
1c–2a (5)
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
B
B
B
10
15
15
15
19
24
24
15
12
7
24
24
12
12
10
4
10
16
7
16
4
5
5
87
78
78
79
84
21
27
87
86
86
87
78
92
90
96
97
88
89
95
57
95
96
91
98
87
–
–
–
–
–
–
–
–
–
90
86
89
84
75
19
32
86
90
92
91
91
97
95
96
97
96
85
62
53
96
97
97
97
97
5
6[e]
7[e]
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25[f]
–
–
–
87:13
84:16
88:12
89:11
86:14
82:18
78:22
72:28
87:13
86:14
85:15
90:10
90:10
1d–2a (5)
1e–2a (5)
1d–TfOH (5)
1d–DBSA (5)
1d–PTSA (5)
1d–2c (5)
1d–2f (5)
1d–2g (5)
1d–2a (1)
1d–2a (1)
12
24
[a] Unless otherwise stated, A: acetone as aldol donor, aldehyde (0.5 mmol) in neat acetone (0.5 mL); B: cyclohexanone as donor, p-
nitrobenzaldehyde (0.5 mmol) and cyclohexanone (1 mmol) in H2O (0.5 mL). [b] Isolated yields. [c] Determined by 1H NMR spectroscopy.
[d] Determined by chiral HPLC. [e] Aldehyde (0.5 mmol) with acetone (0.2 mL) in H2O (0.4 mL). [f] Cyclohexanone (1 equiv.) was used.
DBSA: p-dodecylbenzenesulfonic acid; PTSA: p-toluenesulfonic acid.
cantly reduced under aqueous condition. Subsequent ex- the necessary hydrophobic environment for efficient cataly-
periments indicated that the reaction of cyclic ketones such sis in water.
as cyclohexanone proceeded very well, a reason partially
The CA–POM hybrid catalysis in water was further opti-
ascribed to the hydrophobicity of cyclic ketone donors as mized in terms of different chiral amines. Hybrid 1d–2a
previously reported.[7p,7s] Cyclohexanone was therefore se- turned out to be the optimal catalyst (Table 1, entry 16).
lected for further screening. An initial test of a typical Both smaller chiral amines such as 1a, 1b, and 1c and a
Brønsted acid, such as TfOH, suggested that acidity would larger surfactant-type chiral amine such as 1e demonstrated
be a key factor influencing the stereoselectivity and that inferior activities (Table 1, entries 13–15 and 17). Remark-
more acidic compounds would lead to better stereoselec- ably, the loading of catalyst 1d–2a could be reduced to
tivity in water (Table 1, entries 18 and 20). In addition, sur- 0.33 mol-% while still maintaining high activity and excel-
factant Brønsted acids, such as DBSA, gave better results lent stereoselectivity (Table 1, entry 24). Under these condi-
than p-toluenesulfonic acid (Table 1, entries 19 and 20). On tions, the reaction with the use of a stoichiometric amount
the basis of these observations, surfactant POMs such as 2f of cyclohexanone still gave reasonably good results (Table 1,
and 2g and the nonmodified POMs were then tested in the entry 25). In comparison, the same reaction under neat con-
model reaction in water. Quite interestingly, the reactions ditions required a large excess of donors. These results also
with simple CA–POM hybrids such as 1d–2a and 1d–2c stand in contrast to the same reaction in less-polar organic
gave excellent yields and stereoselectivities (Table 1, en- solvents such as CH2Cl2, diethyl ether, THF, and so on,
tries 16 and 21), whereas surfactant-type POMs 2f and 2g wherein CA–POM catalysts were hardly dissolved and vir-
did not provide additional benefits for catalysis (Table 1, tually inactive. CA–POM hybrid 1d–2a gave optimal results
entries 22 and 23). These results suggest that a simple POM in the model reactions under both neat and aqueous condi-
in concert with a chiral amine like 1d is sufficient to provide tions, which was therefore selected for further studies.
134
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 132–140

Chiral Amine–Polyoxometalate Hybrids as Recoverable Asymmetric Catalysts
Recycling and Reusing of Catalyst
ing the residue organic solvent, the recovered catalyst could
be reused seven times while maintaining high enantio-
selectivity, but with a slightly reduced activity (Table 2).
However, the formation of a bis(aldol) byproduct increased
in the recycling experiments.
Under aqueous conditions, catalyst 1d–2a could also be
easily recycled and reused and no problems of emulsion
The recyclability and reusability of the CA–POM hybrid
catalysts were next evaluated. Under neat conditions, cata-
lyst 1d–2a could be recovered from the homogeneous reac-
tion system by precipitation with diethyl ether. After remov-
Table 2. Reusability of catalyst 1d–2a under neat conditions.
Table 3. Reusability of catalyst 1d–2a under aqueous conditions.
Run[a]
Time
[h]
Aldol product
yield[b] [%]
Bis(aldol)
product yield[b]
[%]
ee[c]
[%]
Run[a]
Time [h]
Yield[b] [%]
anti/syn[c]
ee[d] [%]
1
2
3
4
5
6
7
24
24
24
26
30
30
30
87
82
78
70
70
67
60
7
91
92
91
92
91
92
92
10
16
16
20
18
17
1
2
3
4
5
6
10
18
24
30
36
40
88
85
80
79
71
66
87:13
85:15
85:15
86:14
83:17
84:16
98
97
95
92
94
93
[a] Reaction of aldehyde (0.5 mmol) in neat ketone (0.5 mL).
[b] Isolated yield. [c] The ee value of aldol product determined by
HPLC.
[a] Reaction of aldehyde (0.5 mmol) with ketone (1 mmol) in water
(0.5 mL). [b] Isolated yield. [c] Determined by 1H NMR spec-
troscopy. [d] Determined by HPLC.
Table 4. POM–CA hybrid catalyst 1d–2a or 1c–2a catalyzed direct aldol reactions under neat condition.
Entry[a]
R1, R2
R3
Time [h]
Yield[b] [%]
anti/syn[c]
ee[d] [%]
1
2
3
4
5
6
7
8
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
Me, H
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-ClC6H4
2-ClC6H4
3-BrC6H4
2-BrC6H4
Ph
4-MeOC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-ClC6H4
3-BrC6H4
Ph
24
24
22
48
48
96
72
90
72
144
144
16
19
24
30
30
96
75
96
6
87 (78)[e]
86 (73)
82 (78)
86 (80)
90 (77)
73 (64)
91 (84)
88 (46)
92 (87)
37 (14)
11
–
–
–
–
–
–
–
–
–
91 (91)[e]
89 (90)
91 (86)
91 (91)
90 (90)
88 (90)
92 (87)
90 (90)
90 (89)
90 (89)
87
9
Me, H
Me, H
Me, H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24[f]
–
–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)4–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
Me, Me
99 (99)[e]
94
87:13 (80:20)[e]
83:17
87:13
86:14
90:10
88:12
88:12
87:13
77:23
71:29
67:33
75:25
90:10[g]
–
99 (97)[e]
Ͼ99
98
97
Ͼ99
98
98
96
95
95
90
92
99
94
95
64
51
86
90
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-NO2C6H4
6
8
19
19
88
91
94
59[g]
98[g]
40[h]
90
94[h]
98
25[f]
H[i]
4-NO2C6H4
72
–
[a] Reaction of aldehyde (0.5 mmol) in neat ketone (10–20 equiv.), catalyst (0.33 mol-%; equal to 1 mol-% chiral amine); 1d–2a was used
1
for acyclic ketone donors (entries 1–11) and 1c–2a for cyclic ketone donors (entries 2–23). [b] Isolated yield. [c] Determined by H NMR
spectroscopy. [d] Determined by HPLC. [e] Data in parentheses refer to that obtained by nonsupported catalyst 1c–TfOH. [f] Catalyst
1d–2a (1.67 mol-%; equal to 5 mol-% chiral amine) was used. [g] Data for the branched product. [h] Data for the linear product. [i] Isobu-
tyraldehyde was used as the aldol donor.
Eur. J. Org. Chem. 2009, 132–140
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
135

J. Li, S. Hu, S. Luo, J.-P Cheng
FULL PAPER
were encountered in all the cases examined. In practice, cat- homogeneous solutions were generally observed. In the
alyst 1d–2a was directly used for next run after simply ex- cases of cyclic ketones, the reaction catalyzed by catalyst
tracting the product with a minimum amount of diethyl 1c–2a gave better results in terms of selectivity despite a
ether. As demonstrated in Table 3, the catalyst could be re- lower activity than that with catalyst 1d–2a. All the donors
used six times with similar stereoselectivity but reduced ac- tested worked very well, and the desired products were ob-
tivity, likely due to the slow aggregations of POM hybrid tained with excellent yields and enantioselectivities (up to
for extending reuse as shown by microscopy (Figure 1b). 99% yield and Ͼ99%ee), which demonstrates the wide
Nonetheless, catalyst 1d–2a, to the best of our knowledge, scope of the CA–POM catalyst in asymmetric direct aldol
still represents the first reusable enamine catalyst that works reactions.
efficiently with 0.33 mol-% loading in water. A turnover fre-
With identified catalyst 1d–2a, we also examined the
quency of ca. 25 h–1 was achieved in the catalysis of 1d–2a scopes of reactions with a variety of aldol donors and ac-
in water.
ceptors under aqueous conditions. In general, the reactions
were carried out with two equivalents of donor in the pres-
ence of 0.33 mol-% of hybrid 1d–2a. As shown in Table 5,
both cyclopentanone and cyclohexanone work with a range
of aromatic aldehydes bearing either electron-donating or
CA–POM-Catalyzed Direct Asymmetric Aldol Reactions
under Neat and Aqueous Conditions: Substrate Scope
With optimal catalyst 1d–2a, a series of aldehyde ac- electron-withdrawing groups in water. The reactions af-
cepters and aldol donors were then examined under neat forded mainly the anti aldol products with high yields and
conditions. In the presence of catalyst 1d–2a (0.33 mol-%), excellent enantioselectivities. For comparison, the same re-
various aromatic aldehydes reacted with acetone to afford actions with nonsupported catalyst 1d–TfOH under neat
the desired product with low-to-high yield and high conditions have also been examined, showing considerably
enantioselectivity. The results obtained from the same reac- lower activities and stereoselectivities (Table 5, entries 2 and
tion with the use of the nonsupported catalyst are listed in 12). Furthermore, the diastereoselectivity was significantly
Table 4 for comparison. Catalyst 1d–2a performed better in improved relative to that obtained under neat conditions.
nearly all the cases tested, which proves the synergistic ef-
Notably, the reaction of cyclopentanone afforded high
fect of the POM supports. Other aldol donors including anti selectivity in all the cases examined, whereas many
cyclic ketones, linear ketones, and aldehydes were also ex- other secondary amine catalysts just gave low anti selectiv-
amined with the CA–POM catalyst. Homogeneous or semi- ity or syn selectivity.[16] Aliphatic aldehydes such as cyclo-
Table 5. CA–POM hybrid 1d–2a-catalyzed direct aldol reaction in water.
Entry[a]
1
2
3
4
5
6
7
X
R1, R2
R3
Time [h]
Yield[b] [%]
anti/syn[c]
ee[d] [%]
1
1
1
1
1
1
5
5
5
5
5
5
5
1
1
1
1
1
5
5
5
5
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
H, H
4-NO2C6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-ClC6H4
8
6
10
8
90 (8)[f]
79 (17)[f]
88 (7)[f]
84 (13)[f]
83 (10)[f]
73
86
29
45
27
86
89
36
98
97
91
69
73
86:14
82:18
87:13
72:28
87:13
83:17
86:14
49:51
99:1
85:15
79:21
47:53
87:13
90:10
90:10
92:8
97
94
98
97
96
97
96
84 (18)
95
93
94
85
95
97
98
98
97
98
[e]
14
18
36
48
48
48
48
48
48
12
12
12
12
12
24
30
48
48
8
9
1-naph
cyclohexal
4-MeOC6H4
3-BrC6H4
3-BrC6H4
4-MeC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-CNC6H4
4-CF3C6H4
4-ClC6H4
10
11
12[e]
13
14
15
16
17
18
19
20
21[g]
22[g]
91:9
89:11
87:13
88:12
–
82:18
–
77
31
98
94
Ph
4-NO2C6H4
4-NO2C6H4
41
29
H, CH3
38[h]
21[i]
41[h]
23[i]
[a] Unless otherwise stated, reaction of aldehyde (0.5 mmol) with aldol donor (1 mmol) in water (0.5 mL). [b] Isolated yield. [c] Determined
1
by H NMR spectroscopy. [d] Determined by HPLC. [e] The reaction with 1d–TfOH as the catalyst under neat condition. [f] Bis(aldol)
adduct isolated. [g] Aldol donor (4 equiv.) was used. [h] Data for the branch product. [i] Data for the linear product.
136
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 132–140

Chiral Amine–Polyoxometalate Hybrids as Recoverable Asymmetric Catalysts
Table 6. CA–POM hybrid catalyst 1d–2c catalyzed Michael addition reactions.
Entry
Catalyst
R
Conditions[a]
Time [h]
Yield[b] [%]
syn/anti[c]
ee [%][d]
1
2
3
4
5
6
7
8
1c–2a
1d–2a
1d–2a
1d–2c
1d–2c
1d–2c
1d–2c
1d–2c
1d–2c
1d–2c
1d–2c
1d–2c
1d–2c
1d–2c
1d–2c
1d–2c
Ph
Ph
Ph
Ph
A
A
B
A
B
A
B
A
B
A
A
B
A
B
A
A
48
48
48
40
48
40
48
40
30
40
40
48
28
24
28
24
41
37
47
94
96
86
99
83
98
97
95
79
95
89
91
96
92:8
93:7
92:8
94:6
95:5
93:7
95:5
93:7
94:6
95:5
94:6
93:7
92:8
96:4
94:6
95:5
84
85
83
85
87
86
88
89
87
86
80
86
87
86
89
86
Ph
4-MeC6H4
4-MeC6H4
2-ClC6H4
2-ClC6H4
4-MeOC6H4
1-naph
9
10
11
12
13
14
15
16
1-naph
4-NO2C6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
[a] Conditions A: Reaction of nitrostyrene (0.5 mmol) in neat cyclohexanone (0.5 mL), catalyst (5 mol-%, based on chiral amine used);
Conditions B: Reaction of nitrostyrene (0.5 mmol) with cyclohexanone (4 equiv.) in water (0.5 mL). [b] Isolated yield. [c] Determined by
1H NMR spectroscopy. [d] Determined by HPLC.
hexanecarboxylaldehyde also applied under the present conditions. Under neat conditions, biphasic catalysis was
conditions to afford the desired aldol product with excellent achieved to afford the desired product in high yield and
anti diastereoselectivity and enantioselectivity (Table 5, en- enantioselectivity with a catalyst loading of 0.33 mol-%.
try 9; 99:1 anti/syn, 95%ee). Other aldol donors such as Under aqueous conditions, the same catalyst forms micelle-
acetone and 2-butanone were also examined in the current like aggregates that serve as hydrophobic reaction sites, a
reactions but with lower yields and enantioselectivities unique feature likely to arise from the large framework of
(Table 5, entries 21 and 22), suggesting the hydrophobicity the POM anions. Excellent yields and stereoselectivities
of aldol donors is critical for effective reactions in the pres- were again achieved with a catalyst loading as low as
ent catalytic reaction in water.
0.33 mol-% in pure water. In addition, the hybrid catalysts
could be recycled and directly reused up to seven times with
unchanged stereoselectivity but with a slightly lower ac-
tivity. The hybrid catalysts can also be applied to other en-
amine-based reactions, for example, the Michael addition
to nitrostyrenes, with high activity and stereoselectivity.
Michael Addition Reaction Under Neat and Aqueous
Conditions
To further demonstrate the potential of the current im-
mobilization strategy, CA–POM hybrid catalysts were
tested in another important C–C bond-formation reaction:
the Michael addition reaction.[17] A quick screening indi-
cated that 1d–2c was the optimal catalyst, and the reaction
in the presence of 5 mol-% of 1d–2c proceeded smoothly to
afford the desired products with high yield and selectivity
under both neat and aqueous conditions (Table 6, entries 4
and 5). CA–POM hybrid 1d–2c showed significantly im-
proved activity over the corresponding nonsupported chiral
diamine catalyst.[17q] In the presence of 5 mol-% of 1d–2c,
the reaction gave equally good activity and selectivity under
neat or aqueous conditions. Notably, much less cyclohexa-
none was used under aqueous conditions, showing the ad-
vantage of the aqueous system.
Experimental Section
General Method: Commercial reagents were used as received, unless
1
otherwise indicated. H NMR and 13C NMR were recorded with
a Bruker AMX-300 instrument, as noted, and are internally refer-
enced to residual protic solvent signals. Chemical shifts are re-
ported in ppm from tetramethylsilane with the solvent resonance
as the internal standard. Elemental analysis was obtained from
ThermoQuest (Flash 1112Ea, ITALY). IR spectra were obtained
with a Jasco FT/IR-480 Plus instrument; HPLC analysis was per-
formed by using Chiralcel AD-H, OD-H, AS-H, and OJ-H col-
umns. Absolute configurations were determined by correlation to
literature reported results.
Representative Procedure for the Preparation of CA–POM Hybrid
1d–2a: Chiral amine 1d (910 mg, 5.0 mmol) was dissolved in dry
THF (20 mL) in a 50-mL round-bottomed flask under an atmo-
sphere of argon. H3PW12O40 (4.98 g, 1.67 mmol) was then added
slowly, and the resulting mixture was stirred for 1 h. The volatiles
Conclusions
We developed highly efficient and reusable CA–POM hy-
brid catalysts for aldol reactions under neat and aqueous were then removed under vacuum. The obtained solid was washed
Eur. J. Org. Chem. 2009, 132–140
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
137

J. Li, S. Hu, S. Luo, J.-P Cheng
FULL PAPER
extensively with ether and dried under vacuum at 40 °C to give
quantitatively hybrid catalyst (5.89 g) 1d–2a as a pale-yellow pow-
der. 1H NMR (300 MHz, [D6]DMSO): δ = 1.16–1.28 and 1.70–
FC on silica gel to afford the pure product. The recovered catalyst
(Ͼ98%) can be directly used after removing the volatiles residue
under vacuum. All the Michael addition products are known com-
1.82 [m, 2 H, (R2)N-CH2], 1.50–1.63 [br., 10 H, 4-CH2 and C- pounds.[5o,5p,5s]
(CH2)4-C], 2.31–2.45 (m, 2 H, 3-CH2), 2.56–2.62 (m, 4 H, CH2-N-
General Procedure for the Michael Addition Reactions under Aque-
CH2), 2.70–2.74 and 2.80–2.83 (m, 2 H, 5-CH2), 2.98–3.08 (m, 1
H, N-CH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 24.7, 26.6,
28.0, 29.7, 45.61, 55.2, 56.4, 62.9 ppm. 31P NMR (400 MHz, ace-
ous Conditions: To a mixture of cyclohexanone (0.2 mL) in water
(0.5 mL) was added catalyst 1d–2c (0.00625 mmol). The solution
was vigorously stirred for 10 min and the corresponding nitrosty-
rene (0.5 mmol) was then added. The resulting mixture was stirred
at room temperature for 24–48 h. Ethyl ether was added to extract
the product. The product layer was separated, and the catalyst in
water was extracted with ether (3ϫ). The combined organic layer
was concentrated. The residue was purified by FC on silica gel to
afford the pure product. The catalyst (Ͼ98% recovery yield) in
water can be directly used after removing the organic residue by
heating to 40 °C. All the Michael addition products are known
compounds.[5o,5p,5s]
tone): δ = –14.240 ppm. IR (KBr): ν = 811, 895, 982, 1621, 1081,
˜
2945, 3445 cm–1. C33H69N6O40PW12 (3426.97): calcd. C 11.55, H
2.01, N 2.45; found C 11.54, H 2.29, N 2.75.
Other hybrid catalysts were prepared by using a similar procedure.
Catalyst 1c–2a: 1H NMR (300 MHz, [D6]DMSO): δ = 1.42–1.52
(m, 2 H, CH2), 1.55–1.67 [m, 4 H, CH2-C(H2)-CH2], 1.76–1.83 (m,
2 H, 4-CH2), 1.89–2.01 and 2.04–2.18 [m, 2 H, (R2)N-CH2], 2.56–
2.78 (br., 4 H, CH2NCH2), 3.14–3.27 (m, 2 H, 3-CH2), 3.60–3.68
(m, 2 H, 5-CH2), 3.72–3.85 (m, 1 H, N-CH) ppm. 13C NMR
(75 MHz, [D6]DMSO): δ = 23.06, 24.88, 25.09, 28.04, 44.90, 53.80,
55.89, 66.98 ppm. 31P NMR (400 MHz, cyclohexanone): δ =
Acknowledgments
–14.770 ppm. IR (KBr): ν = 810, 892, 978, 1082, 1627, 2934,
˜
3449 cm–1. C30H63N6O40PW12 (3384.54): calcd. C 10.63, H 1.86, N
2.48; found C 9.97, H 2.03, N 2.46.
This work is supported by the Natural Science Foundation of
China (NSFC 20421202, 20632060, 20542007), the Ministry of Sci-
ence and Technology (MoST) of China, and the Chinese Academy
of Sciences.
Catalyst 1d–2c: 1H NMR (300 MHz, [D6]DMSO): δ = 1.46–1.74
[br., 10 H, 4-CH2 and C-(CH2)4-C], 1.85–2.01 [m, 2 H, (R2)N-
CH2], 2.02–2.14 (m, 1 H, NH), 2.60–2.85 (m, 6 H, 4-CH2 and CH2-
N-CH2), 3.11–3.27 (m, 2 H, 5-CH2), 3.59–3.75 (m, 1 H, N-CH)
ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 23.2, 26.4, 27.1, 27.8,
[1] For selected reviews on organocatalysis, see: a) P. I. Dalko, L.
Moisan, Angew. Chem. 2004, 116, 5248–5286; Angew. Chem.
Int. Ed. 2004, 43, 5138–5175; b) A. Berkessel, H. Groger, Asym-
metric Organocatalysis, Wiley-VCH, Weinheim, 2005; c) J.
Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719–724; d) B.
List, Chem. Commun. 2006, 819–824; e) G. Lelais, D. W. C.
MacMillan, Aldrichimica Acta 2006, 39, 79–87; f) Chem. Rev.
2007, 107, issue 12, special issue on organocatalysis.
[2] For reviews, see: a) M. Benaglia, A. Puglisi, F. Cozzi, Chem.
Rev. 2003, 103, 3401–3429; b) M. Benaglia, New J. Chem. 2006,
30, 1525–1533; c) F. Cozzi, Adv. Synth. Catal. 2006, 348, 1367–
1390; d) M. Gruttadauria, F. Giacalone, R. Noto, Chem. Soc.
Rev. 2008, 37, 1666–1688.
[3] For recent examples, see: a) R. Annunziata, M. Benaglia, F.
Cozzi, G. Tocco, Org. Lett. 2000, 2, 1737–1739; b) M. Benaglia,
G. Celentano, F. Cozzi, Adv. Synth. Catal. 2001, 343, 171–173;
c) M. Benaglia, G. Celentano, M. Cinquini, A. Puglisi, F.
Cozzi, Adv. Synth. Catal. 2002, 344, 149–152; d) M. Benaglia,
M. Cinquini, F. Cozzi, A. Puglisi, G. Celentano, Adv. Synth.
Catal. 2002, 344, 533–542; e) M. Benaglia, M. Cinquini, F.
Cozzi, A. Puglisi, G. Celentano, J. Mol. Catal. A 2003, 204,
157–163; f) G. Pozzi, M. Cavazzini, S. Quici, M. Benaglia, G.
Dell’Anna, Org. Lett. 2004, 6, 441–443; g) A. Puglisi, M. Bena-
glia, M. Cinquini, F. Cozzi, G. Celentano, Eur. J. Org. Chem.
2004, 567–573; h) S. A. Selkala, P. M. Pihko, A. M. P. Kos-
kinen, Adv. Synth. Catal. 2002, 344, 941–945; i) C. Ogawa, M.
Sugiura, S. Kobayashi, Chem. Commun. 2003, 192–193; j) H. S.
Kim, Y. M. Song, J. S. Choi, J. W. Yang, H. Han, Tetrahedron
2004, 60, 12051–12057; k) M. R. M. Andreae, A. P. Davis, Tet-
rahedron: Asymmetry 2005, 16, 2487–2492; l) K. Akagawa, S.
Sakamoto, K. Kudo, Tetrahedron Lett. 2005, 46, 8185–8187;
m) J. D. Revell, D. Gantenbein, P. Krattiger, H. Wennemers,
Biopolymers 2006, 84, 105–113; n) D. Font, C. Jimeno, M. A.
Pericàs, Org. Lett. 2006, 8, 4653–4655; o) Y. Zhang, L. Zhao,
S. S. Lee, J. Y. Ying, Adv. Synth. Catal. 2006, 348, 2027–2032;
p) F. Giacalone, M. Gruttadauria, A. M. Marculescu, R. Noto,
Tetrahedron Lett. 2007, 48, 255–259; q) L. Gu, Y. Wu, Y.
Zhang, G. Zhao, J. Mol. Catal. A 2007, 263, 186–194; r) Y.
Wu, Y. Zhang, M. Yu, G. Zhao, S. Wang, Org. Lett. 2006, 8,
4417–4420; s) X. Liu, Y. Li, G. Wang, Z. Chai, Y. Wu, G. Zhao,
44.8, 54.7, 57.1, 57.8 ppm. IR (KBr): ν = 795, 883, 972, 1621, 1014,
˜
2928, 3441 cm–1. C33H70N6O40SiW12 (3424.71): calcd. C 14.6, H
2.55, N 3.10; found C 13.9, H 2.44, N 3.19.
General Procedure for the Aldol Reactions under Neat Conditions:
To a given anhydrous ketone (10–20 equiv.) was added the corre-
sponding catalyst (0.00167 mmol). The obtained homogeneous
solution was stirred for 10 min and the corresponding aldehyde
(0.5 mmol) was then added. The resulting mixture was stirred at
room temperature for 16–96 h. Ethyl ether was added to precipitate
the catalyst. The product layer was separated, and the catalyst was
washed with ether (3ϫ). The combined organic layer was concen-
trated. The residue was purified by flash chromatography (FC) on
silica gel to afford the pure product. The recovered catalyst (Ͼ98%)
can be directly used after removing the volatile residues under vac-
uum. All the aldol products are known compounds.[5r,5s,16]
General Procedure for the Aldol Reactions under Aqueous Condition:
To a given ketone (2 equiv.) in water (0.5 mL) was added catalyst
1d–2a (0.00167 mmol). The solution was stirred vigorously for
10 min and then the corresponding aldehyde (0.5 mmol) was
added. The resulting mixture was stirred at room temperature for
16–48 h. Ethyl ether was added to extract the product. The com-
bined organic layer was concentrated. The residue was purified by
FC on silica gel to afford the pure product. The catalyst in water
(Ͼ98% recovery yield) can be directly used after removing the or-
ganic residue by heating to 40 °C. All the aldol products are known
compounds.[5q,5r,5s,16]
General Procedure for the Michael Addition Reactions under Neat
Conditions: To cyclohexanone (0.4 mL) was added catalyst 1d–2c
(0.00625 mmol). The semihomogeneous solution was stirred for
10 min and nitrostyrene (0.5 mmol) was then added. The resulting
mixture was stirred at room temperature for 24–48 h. Ethyl ether
was then added to precipitate the catalyst. The product layer was
separated, and the catalyst was washed with ether (3ϫ). The com-
bined organic layer was concentrated. The residue was purified by
138
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 132–140

Chiral Amine–Polyoxometalate Hybrids as Recoverable Asymmetric Catalysts
Tetrahedron: Asymmetry 2006, 17, 750–755; t) Y. Li, X. Liu, G.
Zhao, Tetrahedron: Asymmetry 2006, 17, 2034–2039.
H. Gotoh, T. Urushima, M. Shoji, Angew. Chem. 2006, 118,
972–975; Angew. Chem. Int. Ed. 2006, 45, 958–961; q) X. Chen,
S. Luo, Z. Tang, L. Cun, A. Mi, Y. Jiang, L. Gong, Chem. Eur.
J. 2007, 13, 689–701; r) Hayashi, S. Aratake, T. Itoh, T. Okano,
T. Sumiya, M. Shoji, Chem. Commun. 2007, 957–959; s) N.
Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka,
C. F. Barbas III, J. Am. Chem. Soc. 2006, 128, 734–735; t) N.
Mase, K. Watanabe, H. Yoda, K. Takabe, F. Tanaka, C. F.
Barbas III, J. Am. Chem. Soc. 2006, 128, 4966–4967; u) Y. Hay-
ashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya, M. Shoji,
Angew. Chem. 2006, 118, 5653–5656; Angew. Chem. Int. Ed.
2006, 45, 5527–5530; v) C. Palomo, A. Landa, A. Mielgo, M.
Oiarbide, Á. Puente, S. Vera, Angew. Chem. 2007, 119, 8583–
8587; Angew. Chem. Int. Ed. 2007, 46, 8431–8435; w) S.-L. Zhu,
S.-Y. Yu, D.-W. Ma, Angew. Chem. 2008, 120, 555–558; Angew.
Chem. Int. Ed. 2008, 47, 545–548; x) J. Huang, X. Zhang, D. W.
Armstrong, Angew. Chem. 2007, 119, 9231–9235; Angew.
Chem. Int. Ed. 2007, 46, 9073–9076; y) V. Maya, M. Raj, V. K.
Singh, Org. Lett. 2007, 9, 2593–2595.
[4] For recent examples, see: a) M. Gruttadauria, S. Riela, C. Apr-
ile, P. Lo Meo, F. D’Anna, R. Noto, Adv. Synth. Catal. 2006,
348, 82–92; b) Z. An, W. H. Zhang, H. M. Shi, J. He, J. Catal.
2006, 241, 319–327; c) M. Gruttadauria, S. Riela, P. L. Meo,
F. D’Anna, R. Noto, Tetrahedron Lett. 2004, 45, 6113–6115.
[5] For recent examples, see: a) P. Kotrusz, I. Kmentova, B. Gotov,
ˇ
S. Toma, E. Solèániová, Chem. Coummun. 2002, 2510–2511; b)
T.-P. Loh, L.-C. Feng, H.-Y. Yang, J.-Y. Yang, Tetrahedron
Lett. 2002, 43, 8741–8743; c) N. S. Chowdari, D. B. Ramach-
ary, C. F. Barbas III, Synlett 2003, 1906–1909; d) P. Kotrusz,
ˇ
S. Toma, H.-G. Schmalz, A. Adler, Eur. J. Org. Chem. 2004,
1577–1583; e) H. M. Guo, L. F. Cun, L. Z. Gong, A. Q. Mi,
Y. Z. Jiang, Chem. Commun. 2005, 1450–1452; f) P. Kotrusz, S.
Alemayehu, T. Toma, H. G. Schmalz, A. Adler, Eur. J. Org.
Chem. 2005, 4904–4911; g) A. Córdova, Tetrahedron Lett.
2004, 45, 3949–3952; h) M. S. Rasalkar, M. K. Potdar, S. S.
Mohile, M. M. Salunkhe, J. Mol. Catal. A 2005, 235, 267–270;
i) R. T. Dere, R. R. Pal, P. S. Patil, M. M. Salunkhe, Tetrahe-
dron Lett. 2003, 44, 5351–5353; j) H. M. Guo, H. Y. Niu, M. X.
Xue, Q. X. Guo, L. F. Cun, A. Q. Mi, Y. Z. Jiang, J. J. Wang,
Green Chem. 2006, 8, 682–684; k) L. Zu, J. Wang, H. Li, W.
Wang, Org. Lett. 2006, 8, 3077–3079; l) L. Zu, H. Li, J. Wang,
X. Yu, W. Wang, Tetrahedron Lett. 2006, 47, 5131–5134; m)
Y. Abe, T. Hirakawa, S. Nakajima, N. Okano, S. Hayase, S.
Kawatsura, Y. Hirose, T. Itoh, Adv. Synth. Catal. 2008, 350,
1954–1958; n) J. Shah, H. Blumenthal, Z. Yacob, J. Liebscher,
Adv. Synth. Catal. 2008, 350, 1267–1270; o) S. Luo, X. Mi, L.
Zhang, S. Liu, H. Xu, J.-P. Cheng, Angew. Chem. 2006, 118,
3165–3169; Angew. Chem. Int. Ed. 2006, 45, 3093–3097; p) S.
Luo, X. Mi, L. Zhang, S. Liu, H. Xu, J.-P. Cheng, Tetrahedron
2007, 63, 1923–1930; q) S. Luo, J. Li, L. Zhang, H. Xu, J.-P.
Cheng, Chem. Eur. J. 2008, 14, 1273–1278; r) L. Zhang, S. Luo,
X. Mi, S. Liu, Y. Qiao, J.-P. Cheng, Org. Biomol. Chem. 2008,
6, 567–576; s) S. Luo, L. Zhang, X. Mi, Y. Qiao, J.-P. Cheng,
J. Org. Chem. 2007, 72, 9350–9352; t) W. S. Miao, T. H. Chan,
Adv. Synth. Catal. 2006, 348, 1711–1718; u) L. Zu, H. Xie, H.
Li, J. Wang, W. Wang, Org. Lett. 2008, 10, 1211–1214.
[8]
[9]
For examples, see: a) Y. Wu, Y. Zhang, M. Yu, G. Zhao, S.
Wang, Org. Lett. 2006, 8, 4417–4420; b) D. Font, C. Jimeno,
M. A. Pericàs, Org. Lett. 2006, 8, 4653–4655; c) D. Font, S.
Sayalero, A. Bastero, C. Jimeno, M. A. Pericàs, Org. Lett. 2008,
10, 337–340; d) L. Zu, H. Xie, H. Li, J. Wang, W. Wang, Org.
Lett. 2008, 10, 1211–1214.
For a review, see: a) S. Saito, H. Yamamoto, Acc. Chem. Res.
2004, 37, 570–579; for examples, see: b) M. Nakadai, S. Saito,
H. Yamamoto, Tetrahedron 2002, 58, 8167–8177; c) T. Ishii, S.
Fujioka, Y. Sekiguchi, H. Kotsuki, J. Am. Chem. Soc. 2004,
126, 9558–9559; d) N. Mase, K. Watanabe, H. Yoda, K. Tak-
abe, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128,
4966–4967; e) N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Tak-
abe, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128,
734–735; f) S. V. Pansare, K. Pandya, J. Am. Chem. Soc. 2006,
128, 9624–9625; g) D. Gryko, M. Zimnicka, R. Lipin´ski, J.
Org. Chem. 2007, 72, 964–970; h) S. Luo, H. Xu, J. Li, L.
Zhang, J.-P. Cheng, J. Am. Chem. Soc. 2007, 129, 3073–3074;
i) S. Luo, H. Xu, J. Li, L. Zhang, X. Mi, X. Zheng, J.-P. Cheng,
Tetrahedron 2007, 63, 11307–11314; j) S. Luo, H. Xu, L. Zhang,
J. Li, J.-P. Cheng, Org. Lett. 2008, 10, 653–656; k) S. Luo, H.
Xu, L. Chen, J.-P. Cheng, Org. Lett. 2008, 10, 1775–1778.
[6] For reviews on organic reactions in aqueous media, see: a) P. A.
Grieco (Ed.), Organic Synthesis in Water, Blackie A & P, Lon-
don, 1998; b) U. M. Lindström, Chem. Rev. 2002, 102, 2751–
2772; c) S. Kobayashi, K. Manabe, Acc. Chem. Res. 2002, 35,
209–217; d) C.-J. Li, Chem. Rev. 2005, 105, 3095–3165 and ref-
erences cited therein.
[10]
[11]
Chem. Rev. 1998, 98, issue 1 (thematic issue).
a) C. Boglio, G. Lemière, B. Hasenknopf, S. Thorimbert, E.
Lacôte, M. Malacria, Angew. Chem. 2006, 118, 3402–3405; An-
gew. Chem. Int. Ed. 2006, 45, 3324–3327; b) R. Augustine, S.
Tanielyan, S. Anderson, H. Yang, Chem. Commun. 1999, 1257–
1258; c) R. L. Augustine, P. G. N. Mahata, C. Reyes, S. K. Tan-
ielyan, J. Mol. Catal. A 2004, 216, 189–197.
[7] For discussions on aqueous organocatalysis, see: a) A. P. Bro-
gan, T. J. Dickerson, K. D. Janda, Angew. Chem. 2006, 118,
8278–8280; Angew. Chem. Int. Ed. 2006, 45, 8100–8102; b) Y.
Hayashi, Angew. Chem. 2006, 118, 8281–8282; Angew. Chem.
Int. Ed. 2006, 45, 8103–8104; c) D. G. Blackmond, A. Arm-
strong, V. Coombe, A. Wells, Angew. Chem. 2007, 119, 3872–
3874; Angew. Chem. Int. Ed. 2007, 46, 3798–3800; d) S. Na-
rayan, J. Muldoon, M. G. Finn, W. Fokin, H. C. Kolb, K. B.
Sharpless, Angew. Chem. 2005, 117, 3339–3343; Angew. Chem.
Int. Ed. 2005, 44, 3275–3279; e) J. Mlynarski, J. Paradowska,
Chem. Soc. Rev. 2008, 37, 1502–1511; for recent examples of
asymmetric aminocatalysis in aqueous media, see: f) K. Sakthi-
vel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem. Soc. 2001,
123, 5260–5267; g) A. Córdova, W. Notz, C. F. Barbas III,
Chem. Commun. 2002, 3024–3025; h) W. Zhang, M. Marigo,
K. A. Jørgensen, Org. Biomol. Chem. 2005, 3, 3883–3885; i) Y.-
S. Wu, W.-Y. Shao, C.-Q. Zheng, Z.-L. Huang, J. Cai, Q.-Y.
Deng, Helv. Chim. Acta 2004, 87, 1377–1384; j) S. S. Chimni,
D. Mahajan, V. V. S. Babu, Tetrahedron Lett. 2005, 46, 5617–
5619; k) Ramachary, N. S. Chowdari, C. F. Barbas III, Tetrahe-
dron Lett. 2002, 43, 6743–6746; l) L. Zu, J. Wang, H. Li, W.
Wang, Org. Lett. 2006, 8, 3077–3079; m) S. S. Chimni, D. Ma-
hajan, Tetrahedron: Asymmetry 2006, 17, 2108–2119; n) G. Gu-
illena, M. Hita, C. Najera, Tetrahedron: Asymmetry 2006, 17,
1493–1497; o) Z. Jiang, Z. Liang, X. Wu, Y. Lu, Chem. Com-
mun. 2006, 2801–2803; p) Y. Hayashi, T. Sumiya, J. Takahashi,
[12]
[13]
For a preliminary communication, see: S. Luo, J. Li, H. Xu, L.
Zhang, J.-P. Cheng, Org. Lett. 2007, 9, 3675–3678.
For recent examples, see: a) C. Ritchie, E. M. Burkholder, D.
Long, D. Adam, P. Kögerler, L. Cronin, Chem. Commun. 2007,
468–470; b) A. Haimov, H. Cohen, R. Neumann, J. Am. Chem.
Soc. 2004, 126, 11762–11763; c) M. V. Vasylyev, R. Neumann,
J. Am. Chem. Soc. 2004, 126, 884–890; d) H. Zeng, G. R. New-
kome, C. L. Hill, Angew. Chem. 2000, 112, 1841–1844; Angew.
Chem. Int. Ed. 2000, 39, 1772–1774; e) S. Bareyt, S. Piligkos,
B. Hasenknopf, P. Gouzerh, E. Lacôte, S. Thorimbert, M. Mal-
acria, J. Am. Chem. Soc. 2005, 127, 6788–6794; f) H. Yamam-
oto, H. Suzuki, Y. M. A. Yamada, H. Tabata, H. Takahashi, S.
Ikegami, Angew. Chem. 2005, 117, 4612–4614; Angew. Chem.
Int. Ed. 2005, 44, 4536–4538; g) S. Bareyt, S. Piligkos, B.
Hasenknopf, P. Gouzerh, E. Lacôte, S. Thorimbert, M. Malac-
ria, Angew. Chem. 2003, 115, 3526–3528; Angew. Chem. Int.
Ed. 2003, 42, 3404–3406; h) H. Li, H. Sun, W. Qi, M. Xu, L.
Wu, Angew. Chem. 2007, 119, 1322–1325; Angew. Chem. Int.
Ed. 2007, 46, 1300–1303 and references cited therein; i) I. Bar-
Nahum, R. Neumann, Chem. Commun. 2003, 2690–2691; j) I.
Bar-Nahum, A. M. Khenkin, R. Neumann, J. Am. Chem. Soc.
2004, 126, 10236–10237.
Eur. J. Org. Chem. 2009, 132–140
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
139

J. Li, S. Hu, S. Luo, J.-P Cheng
FULL PAPER
[14] For examples, see: a) N. Mase, K. Watanabe, H. Yoda, K. Tak-
abe, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006, 128,
4966–4967; b) S. Luo, H. Xu, J. Li, L. Zhang, X. Mi, X. Zheng,
J.-P. Cheng, Tetrahedron 2007, 63, 11307–11314; c) S. Luo, X.
Mi, S. Liu, H. Xu, J.-P. Cheng, Chem. Commun. 2006, 3687–
3689.
[15] For reviews on direct aldol reactions, see: a) R. Mahrwald
(Ed.), Modern Aldol Additions, Wiley-VCH, Weinheim, 2004;
b) C. Palomo, M. Oiarbide, J. M. GarcVa, Chem. Eur. J. 2002,
8, 36–44; c) T. D. Machajewski, C.-H. Wong, Angew. Chem.
2000, 112, 1406–1430; Angew. Chem. Int. Ed. 2000, 39, 1352–
1374.
[16] For example of aldol reaction of cyclopentanone, see: a) K.
Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem. Soc.
2001, 123, 5260–5267; b) Z. Tang, Z.-H. Yang, X.-H. Chen,
L.-F. Cun, A. Q. Mi, Y.-Z. Jiang, L.-Z. Gong, J. Am. Chem.
Soc. 2005, 127, 9285–9289; c) J.-R. Chen, X.-Y. Li, X.-N. X,
W.-J. Xiao, J. Org. Chem. 2006, 71, 8198–8208; d) N. Mase, Y.
Nakai, N. Ohara, K. Tanaka, C. F. Barbas III, J. Am. Chem.
Soc. 2006, 128, 734–735; e) L. Gu, M. Yu, X. Wu, Y. Zhang,
G. Zhao, Adv. Synth. Catal. 2006, 348, 2223–2228.
Chem. 2002, 1877–1894; for examples, see: c) B. List, P. Pojar-
liew, J. H. Maritn, Org. Lett. 2001, 3, 2423–2425; d) D. Enders,
A. Seki, Synlett 2002, 26–28; e) J. M. Betancort, C. F.
Barbas III, Org. Lett. 2001, 3, 3737–3740; f) A. J. A. Cobb,
D. A. Longbottom, D. M. Shaw, S. V. Ley, Chem. Commun.
2004, 1808–1809; g) A. Alexakis, O. Andrey, Org. Lett. 2002,
4, 3611–3614; h) W. Wang, J. Wang, H. Li, Angew. Chem. 2005,
117, 5991–5996; Angew. Chem. Int. Ed. 2005, 44, 1369–1374; i)
J. Wang, H. Li, B. Lou, L. Zu, H. Guo, W. Wang, Chem. Eur.
J. 2006, 12, 4321–4332; j) C.-L. Cao, M.-C. Ye, X.-L. Sun, Y.
Tang, Org. Lett. 2006, 8, 2901–2904; k) Y. Xu, W. Zou, H.
Sunden, I. Ibrahem, A. Córdova, Adv. Synth. Catal. 2006, 348,
418–424; l) S. B. Tsogoeva, S. Wei, Chem. Commun. 2006,
1451–1453; m) H. Huang, E. N. Jacobsen, J. Am. Chem. Soc.
2006, 128, 7170–7171; n) N. Mase, K. Watanabe, H. Yoda, K.
Takabe, F. Tanaka, C. F. Barbas III, J. Am. Chem. Soc. 2006,
128, 4966–4967; o) D. Enders, M. R. M. Huttl, C. Grondal, G.
Raabe, Nature 2006, 441, 861–863; p) Y. Hayashi, H. Gotoh,
T. Hayashi, M. Shoji, Angew. Chem. 2005, 117, 3170–3175; An-
gew. Chem. Int. Ed. 2005, 44, 4212–4215; q) J. M. Betancort,
K. Sakthivel, R. Thayumanava, F. Tanaka, C. F. Barbas III,
Synthesis 2004, 1509–1521.
[17] For reviews on asymmetric Michael addition reactions, see: a)
S. Sulzer-Mosse, A. Alexakis, Chem. Commun. 2007, 3123–
3135; b) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org.
Received: September 17, 2008
Published Online: November 21, 2008
140
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 132–140