Linear polystyrene anchored l-proline, new recyclable organocatalysts for the aldol reaction in the presence of water

Article abstract of DOI:10.1016/j.tetasy.2007.10.032

Two l-proline-based linear polystyrene anchored catalysts 1a and 1b have been synthesized efficiently. The catalytic activities and stereoselectivity of these readily tunable and amphiphilic organocatalysts were evaluated in the direct asymmetric aldol re

Full text of DOI:10.1016/j.tetasy.2007.10.032

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2649–2656
Linear polystyrene anchored L-proline, new recyclable organocatalysts
for the aldol reaction in the presence of water
Yu-Xia Liu, Ya-Nan Sun, Hao-Han Tan, Wei Liu and Jing-Chao Tao*
Department of Chemistry, New Drug Research and Development Center, Zhengzhou University, Zhengzhou 450052, PR China
Received 7 September 2007; accepted 13 October 2007
Abstract—Two L-proline-based linear polystyrene anchored catalysts 1a and 1b have been synthesized efficiently. The catalytic activities
and stereoselectivity of these readily tunable and amphiphilic organocatalysts were evaluated in the direct asymmetric aldol reaction of
various aromatic aldehydes and ketones. By using 5 mol % of the catalysts, the corresponding products of the aldol reaction were
obtained in good yields (up to 94%) and with excellent anti diastereoselectivities (up to 96:4) and enantioselectivities (up to 96% ee)
in DMF in the presence of water. The yields of these reactions in a ketone/water mixture were lower than those in wet DMF (up to
76%). However, the stereoselectivity was comparable (up to 93:7 anti/syn ratio and 95% ee, respectively). In addition, catalysts 1a
and 1b could be recovered by a simple precipitation and filtration process. They could also be re-used for at least five times without obvi-
ous loss of catalytic efficiency.
ꢀ 2007 Published by Elsevier Ltd.
1. Introduction
organocatalysts not only secure the advantages of homo-
geneous process, easy characterization, high reactivity and
good enantioselectivity, but also allow simple product puri-
fication and catalyst recovery and recycling.
Asymmetric catalysis has witnessed a tremendous growth in
recent years. Since List et al. reported the direct aldol reac-
tion catalyzed by L-proline under a mild reaction condition
in 2000,1 asymmetric reaction catalyzed by organocatalysts
has received great attention.2 The direct asymmetric aldol
reaction (DAAR), one of the most powerful C–C bond
forming reactions, has been intensively studied in recent
years.3 The advantages of using an organocatalyst would
be higher if an efficient recovery and reuse of the catalyst
could be accomplished. From a practical point of view, it
would be desirable to have the catalyst immobilized so that
the product purification can be facilitated and the catalyst
recycled. Since Benaglia et al. utilized poly(ethylene gly-
col)-supported L-proline catalyzing asymmetric aldol con-
densations,4 much effort has been devoted to the recovery
of the L-proline-based organocatalysts.5 Different types of
polymers have been the subject of attention in connection
with organocatalysts recovery, for example, cross-linked
polystyrene anchored L-proline,5b–e mesoporous MCM-41
supported L-proline,5f and dendrimers supported L-pro-
line.5a,g Noto et al. recently utilized ionic liquids for the
recovery of organocatalysts.6 Soluble polymer-supported
The stereoselective reaction in water/aqueous media is
another important research area because water is an envi-
ronmentally safe media, which avoids the problems of pol-
lution that are inherent with organic solvents.7 Therefore,
reactions in aqueous media have received a great deal of
attention. Some organocatalysts for the direct aldol reac-
tion in water/aqueous media have been developed in recent
years.5f,8 However, the asymmetric aldol reaction in water
has proven to be very difficult although a small amount of
water is somewhat beneficial in some proline derivative
mediated aldol reactions. Hayashi,9a as well as our
group,9b has found that the long chain alkyl substituted
proline is capable of catalyzing the direct aldol reaction
in aqueous media with high diastereoselectivity and enantio-
selectivity. These findings induced our further interest in
exploring new classes of amphiphilic catalysts for the
C–C formation reactions.
Herein, we reported the synthesis of L-proline-based linear
polystyrene-supported catalysts 1a and 1b (Mw = ca. 5000)
with a flexible spacer. Their catalytic efficiency for the
asymmetric aldol reaction was evaluated in wet DMF
and ketone/water mixture. These catalysts are capable of
*
Corresponding author. Tel./fax: +86 371 67767200; e-mail: jctao@
zzu.edu.cn
0957-4166/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.10.032

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Y.-X. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2649–2656
catalyzing the direct aldol reaction in the presence of water
at high enantioselectivity (up to 96% and 93% ee,
respectively).
ity and stereoselectivity. Therefore, the reaction was
performed in DMF in the presence of different amounts
of water (entries 2–6). A comparative study was first per-
formed in DMF in the absence of water (entry 1). The re-
sults (entries 1–6) indicated that the activity and
stereoselectivity were all improved significantly and the
best ratio of DMF/H2O was 15:1. We presume that a pos-
sible interaction between water and the hydrophilic proline
moiety may increase the amphiphilic property of the cata-
lysts. Therefore, the hydrophilic catalytic moiety could stay
away from the hydrophobic main chains, and may interact
with the substrates more efficiently. The improvement of
the diastereoselectivity and enantioselectivity in the pres-
ence of small amounts of water may be attributed to the
participation of water in the transition state during the cat-
alytic aldol condensation. The results (entries 7–10) showed
that when a smaller excess of cyclohexanone was used, the
lower yields were obtained, although the diastereo- and
enantioselectivity were comparable. The temperature had
some effect on the reactivity but almost no effect on the
diastereo- and enantioselectivity (entries 4, 11 and 12).
Moreover, the performance of the recovered catalyst was
also evaluated after a simple separation from the reaction
mixture without any further treatment. It was seen that
the catalyst could be re-used at least five times without
an obvious decrease of anti/syn ratio and ee value;
although the reactivity decreased somewhat after using
four times (entries 13–17).
2. Results and discussion
2.1. Synthesis of the catalysts 1a and 1b
(2S,4S)-N-Cbz-4-aminoproline methyl ester 2 was easily
synthesized from the commercially available trans-4-hydro-
xy-L-proline with an overall yield of up to 72%.10
Compound 2 was reacted with succinic anhydride (or hexa-
nedioic acid) in anhydrous CH2Cl2 at room temperature to
give the compounds 3a and 3b. These compounds were
immobilized onto the linear aminomethyl polystyrene
(Mw = ca. 5000, f = 0.56 mmol/g) to give compounds 4a
and 4b (Scheme 1). The molecular weights of these poly-
mers were estimated by NMR spectroscopy according to
the terminal methyl group. The degree of substitution (f)
was determined by NMR spectroscopy according to the
methylene group (–CH2NH2). The deprotection of the pro-
line moiety was performed in refluxing 25% aq NaOH/
THF (v/v 10:30) for 6 h to remove the Cbz and methyl
groups simultaneously. The reaction mixture was treated
with 1 M HCl followed by treatment with Et3N/H2O
(2:98). The structures of the two catalysts were established
by IR, NMR spectroscopy and elemental analyses. Their
IR spectra showed two characteristic carbonyl absorptions
at around 1707 cmꢀ1 (–COOH) and 1675 cmꢀ1 (–CONH);
their NMR spectra showed signals of the proline back-
bone. The methylene signals of aminomethyl polystyrene
(3.75 ppm) shifted downfield (4.92 ppm). This approach
has been proven to be available to allow the synthesis of
polystyrene-supported L-proline possessing different linkers
and can be used for the immobilization of different organic
molecules.
To check the versatility of catalysts 1a and 1b, the reaction
between cyclohexanone and several other substituted benz-
aldehydes was investigated in DMF/H2O (15:1) at room
temperature. The results, as listed in Table 2, indicate that
the yields of the aldol reactions are good to excellent, which
are a little lower than those obtained with small molecule
L-proline derivatives in the presence of water. However,
the diastereoselectivities and the ee values are comparable
to those of the unsupported small molecule catalysts.8,9
In addition, the catalytic efficiency and selectivity observed
are comparable or better than those obtained with other
supported L-proline catalysts.5,6 The results also showed
that catalysts 1a and 1b have a similar catalytic efficiency.
When nitrobenzaldehydes were used as aldol acceptors,
o-nitrobenzaldehyde showed a lower activity than m- and
p-nitrobenzaldehyde, however, the diastereoselectivities
2.2. Aldol condensations
Initially, the catalytic effect of 1a was tested in the model
reaction of o-nitrobenzaldehyde with cyclohexanone in
the presence of 5 mol % catalyst. The results are shown in
Table 1. It was indicated in the literature11 that the pres-
ence of water promoted the catalytic reaction in both activ-
H
H2N
HO
N
O
O
O
CH2Cl2
n
O
O
COOCH3
or
COOCH3
N
N
or CH2Cl2/DCC
COOH
COOCH2Ph
COOCH2Ph
HOOC
3a-b
3a: n=2
3b: n=4
2
H
N
H
CH2NH
CH2NH
N
a) 25% aq. NaOH/THF
n
O
CH2Cl2/DCC
n
O
O
O
COOH
b) 1 M HCl
COOCH3
N
N
H
c) Et3N/H2O 2/98
COOCH2Ph
1a-b
1a: n=2
1b: n=4
4a-b
4a: n=2
4b: n=4
Scheme 1. Synthesis of linear polystyrene anchored catalysts 1a and 1b.

Y.-X. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2649–2656
2651
Table 1. The direct aldol reaction of o-nitrobenzaldehyde and cyclohexanone catalyzed by 1a in wet DMFa
O
O
NO2 OH
NO2
Cat. 5 mol%
24 h
CHO
Entry
Solvent
Cat
T (ꢁC)
Yieldb (%)
anti/sync
eec (anti) (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
DMF
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
30
rt
rt
rt
rt
rt
30
51
65
73
55
51
71
65
43
32
62
78
70
66
69
64
59
88:12
90:10
95:5
95:5
93:7
95:5
94:6
96:4
95:5
95:5
96:4
92:8
92:8
92:8
92:8
91:9
92:8
87
89
95
95
95
96
96d
94e
95f
96g
96
94
95
95
94
92
89
DMF/H2O (100:1)
DMF/H2O (30:1)
DMF/H2O (15:1)
DMF/H2O (10:1)
DMF/H2O (7.5:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
DMF/H2O (15:1)
Entry 4, cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
a The reaction of cyclohexanone (0.5 mL, 15.0 equiv to aldehyde), o-nitrobenzaldehyde (50 mg, 0.33 mmol) and 1a (0.016 mmol) was performed in wet
DMF (1.5 mL).
b Isolated yield after thin layer chromatography on silica gel.
c Determined by HPLC using a chiral column (Daicel OD-H).
d 10.0 equiv of cyclohexanone to aldehyde.
e 5.0 equiv of cyclohexanone to aldehyde.
f 1.5 equiv of cyclohexanone to aldehyde.
g 1.0 equiv of cyclohexanone to aldehyde.
and the ee values were comparable (entries 1–3 and 8–10).
When chlorobenzaldehydes were used as aldol acceptors,
there were no obvious differences among the three benz-
aldehydes not only in reactivity but also as the anti/syn
ratio and ee value (entries 4–6 and 11–13). m-Bromobenz-
aldehyde showed a similar activity and diastereoselectivity
to chlorobenzaldehydes but with much higher enantio-
selectivity (entries 7 and 14). Additionally, the nitrobenz-
aldehydes afforded higher reactivities, diastereo- and
enantioselectivities than the chlorobenzaldehydes.
Table 2. The aldol reaction of aromatic aldehydes with cyclohexanone
catalyzed by 1a–b in wet DMFa
O
O
OH
CHO
It has been shown that water can play a special role in the
catalyzed aldol reaction in aqueous (homogeneous) media.
The direct aldol reaction in water/aqueous media has been
developed in recent years.8 We also tested the catalytic
effect of 1a and 1b in a ketone/water mixture. Dickerson12
and Hayashi9a revealed that the reaction under these con-
ditions was not really performed in water. The results are
shown in Table 3. The reactions between cyclohexanone
and o-nitrobenzaldehyde were performed in the presence
of different amount of water. The reaction progressed very
slowly in the absence of water. Therefore, diastereo- and
enantioselectivity were not detected (entry 1). When differ-
ent amounts of water was added into the reaction mixture,
the reactivity was improved evidently. However, there were
no obvious differences in reactivity and stereoselectivity
among the different cyclohexanone/H2O ratios. Consider-
ing that cyclohexanone and water have an azeotropic point
at 1.5:1, we studied the catalytic effects of 1a and 1b in ke-
tone/water mixture (1.5:1 v/v). Although only moderate to
good yields were obtained, good to excellent diastereoselec-
tivities (entry 3, anti/syn ratio up to 93:7) and enantioselec-
tivities (entries 4 and 11, up to 95% ee) were observed.
Cat. 5 mol%
r.t 24 h
R
R
Entry
R
Cat
Yieldb (%)
anti/sync
eec (anti) (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
o-NO2
m-NO2
p-NO2
o-Cl
m-Cl
p-Cl
m-Br
o-NO2
m-NO2
p-NO2
o-Cl
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
73
82
91
72
68
77
46
76
85
94
73
69
76
78
95:5
92:8
91:9
87:13
86:14
86:14
89:11
93:7
92:8
92:8
90:10
83:17
84:16
90:10
95
95
94
86
87
90
96
92
93
91
88
84
86
94
m-Cl
p-Cl
m-Br
a The reaction of cyclohexanone (0.5 mL, 15.0 equiv to aldehyde), alde-
hyde (0.33 mmol) and 1 (0.016 mmol) was performed in DMF/H2O
(15:1, 1.5 mL).
b Isolated yield after thin layer chromatography on silica gel.
c Determined by HPLC using a chiral column (Daicel OD-H).

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Y.-X. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2649–2656
Table 3. The aldol reaction of aromatic aldehydes with cyclohexanone
catalyzed by 1a–b in ketone/water mixturea
lower yield was obtained with comparable enantioselectiv-
ity (entry 6).
O
O
OH
CHO
Cat. 5 mol%
r.t 24 h
3. Conclusions
R
R
In conclusion, a new type of amphiphilic and recyclable
catalysts 1a and 1b has been synthesized for the asymmetric
direct aldol reaction. The catalytic effect of these catalysts
for the aldol reaction was evaluated in wet DMF and a ke-
tone/water mixture. Good yields and high stereoselectivi-
ties (94% yield, 96:4 anti/syn ratio, 96% ee in wet DMF
and 76% yield, 93:7 anti/syn ratio, 95% ee in ketone/water
mixture) were obtained for the reactions of aromatic alde-
hydes with ketones. It was also found that water could play
a special role in improving the reactivity and stereoselectiv-
ity in the aldol reaction catalyzed by the linear polystyrene
anchored L-proline. Additionally, the polymer-supported
catalysts could be recovered and re-used giving virtually
unchanged stereoselectivity although slowly diminishing
yields were obtained after four cycles. These results expand
the scope of organic catalysts in the field of enantioselective
synthesis making the search for these reagents more
appealing.
Entry Solvent
R
Cat Yieldb anti/sync eec
(%)
(anti) (%)
1
2
3
4
5
None H2O
o-NO2 1a
<5
45
37
43
51
65
76
39
47
64
33
nd
90:10
93:7
92:8
92:8
90:10
91:9
90:10
86:14
87:13
88:12
nd
94
94
95
91
92
93
89
83
90
95
0.8 mL H2O o-NO2 1a
1.2 mL H2O o-NO2 1a
1.8 mL H2O o-NO2 1a
0.8 mL H2O o-NO2 1b
0.8 mL H2O m-NO2 1a
0.8 mL H2O p-NO2 1a
6
7
8
9
10
11
0.8 mL H2O o-Cl
0.8 mL H2O m-Cl
0.8 mL H2O p-Cl
0.8 mL H2O m-Br
1a
1a
1a
1a
a The reaction of cyclohexanone (1.2 mL), aldehyde (0.33 mmol) and 1
(0.016 mmol) was performed in ketone/water mixture.
b Isolated yield after thin layer chromatography on silica gel.
c Determined by HPLC using a chiral column (Daicel OD-H).
These results are comparable to the results observed in wet
DMF. Individually, when using p-nitro or p-chlorobenzal-
dehyde as an aldol acceptor, the yields of the aldol prod-
ucts were much higher than that of the corresponding o-
or m-isomers (entries 2 and 6–10).
4. Experimental
4.1. General
Cyclopentanone and acetone were finally explored as aldol
donors. The results are listed in Table 4. When cyclopenta-
none was taken as the aldol donor, moderate to good yields
were observed with moderate diastereoselectivities and
excellent enantioselectivities (entries 1 and 3) in wet
DMF. When the reaction was performed in ketone/water
mixture, lower catalytic activities were obtained without
any loss of stereoselectivity (entries 2 and 4). When acetone
was used as the aldol donor, only moderate yields and
good enantioselectivities were obtained (entries 5 and 7).
When a small amounts of water were added into the reac-
tion mixture of o-nitrobenzaldehyde and acetone, a much
All chemicals were used as received unless otherwise noted.
Reagent grade solvents were redistilled prior to use. All 1H
NMR spectra were collected on a Bruker DPX 400 NMR
spectrometer with TMS as an internal reference. FT-IR
spectra were determined on a Thermo Nicolet IR200 unit.
High resolution mass spectra (HR-MS) were obtained on a
Waters micromass Q-Tof MicroTM instrument using the ESI
technique. Chromatography was performed on silica gel
(200–300 mesh). Melting points were determined by a
XT5A apparatus and uncorrected. Optical rotations were
determined on a Perkin–Elmer 341 polarimeter. Element
analysis was determined on Flash EA1112. Enantiomeric
Table 4. The aldol reaction of o-nitrobenzaldehyde with cyclopentanone or acetone catalyzed by 1a–b
O
O
NO2 OH
NO2
Cat. 5 mol%
r.t 24 h
CHO
R1
R2
R1
R2
Entry
R1, R2
Solvent
Cat
Yieldd (%)
anti/syne
eee (anti) (%)
1
2
3
4
5
6
7
CH2, CH2
CH2, CH2
CH2, CH2
CH2, CH2
H, H
DMF/H2O (15:1)a
Ketone/waterb
DMF/H2O (15:1)a
Ketone/waterb
DMFc
DMF/H2O (100:1)c
DMFc
1a
1a
1b
1b
1a
1a
1b
55
42
86
47
61
40
72
75:25
75:25
70:30
80:20
94
93
92
92
78
76
76
H, H
H, H
a The reaction of cyclopentanone (0.5 mL), o-nitrobenzaldehyde (50 mg, 0.33 mmol) and 1 (0.016 mmol) was performed in DMF/H2O (15:1, 1.5 mL).
b The reaction of cyclopentanone (1.2 mL), o-nitrobenzaldehyde (50 mg, 0.33 mmol) and 1 (0.016 mmol) was performed in water (0.8 mL).
c The reaction of acetone (0.5 mL), o-nitrobenzaldehyde (50 mg, 0.33 mmol) and 1 (0.013 mmol) was performed in DMF (1.5 mL).
d Isolated yield after thin layer chromatography on silica gel.
e Determined by HPLC using a chiral column (Daicel OD-H).

Y.-X. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2649–2656
2653
excesses were measured by chiral HPLC at room tempera-
ture using JASCO PU-1580 pump equipped with JASCO
UV-1575 ultra detector (or Syltech 500 pump equipped
with a UV 500 version 4.1 ultra-violet detector) with
Chiralcel OD-H (4.6 mm · 250 mm) columns.
MS m/z: calcd for C20H26N2O7 (M+H)+ 407.1818, found
407.1819.
4.2.4. General procedure for the preparation of 4a and
4b. To a stirred mixture of 3 (1.1 mmol) and aminopoly-
styrene (0.5 g) in anhydrous CH2Cl2 (25 mL) was added
DCC (0.32 g, 1.5 mmol) and catalytic quantities of DMAP
at room temperature. After stirring for about 12 h, the
reaction mixture was filtered, and the filtrate was concen-
trated. The residue was washed with methanol
(15 mL · 3) to give white powder 4.
4.2. Preparation of the catalysts 1a and 1b
4.2.1. (2S,4S)-N-Cbz-4-aminoproline methyl ester 2.
Compound 2 was prepared from trans-4-hydroxy-L-proline
as reported in the literature10 with an overall yield of up to
20
72%. ½aꢁD ¼ ꢀ23:2 (c 1.18, EtOH); IR (KBr, cmꢀ1): 3374,
3386, 3033, 2952, 2886, 1747, 1704, 1498, 1418, 1356,
Compound 4a: IR (KBr, cmꢀ1): 3401, 3058, 3025, 2921,
2849, 1744, 1711, 1661, 1598, 1535, 1493, 1450, 1415,
1354, 1207, 1172, 757, 699; 1H NMR (CDCl3, ppm):
d = 1.22–1.68 (2.0H, br, PS–CH2–), 1.68–2.05 (1.2H, br,
PS–CH– and H-3), 2.05–2.17 (0.4H, m, NHC-
OCH2CH2CONH), 3.58–3.78 (0.5H, m, –OCH3 and H-
5), 4.42–4.49 (0.1H, m, H-2), 4.92 (0.3H, br, H-4 and PS–
CH2NH), 4.58 5.10–5.23 (0.2H, m, –OCH2Ph), 6.50–6.58
(2.0H, br, PS), 7.05–7.08 (3.0H, br, PS), 7.32–7.34 (0.5H,
m, –OCH2Ph).
1
1204, 1170, 1112, 769, 751, 699; H NMR (CDCl3, ppm):
d = 1.83–1.89 (1H, m, H-3), 2.42–2.48 (1H, m, H-3),
3.31–3.37 (1H, m, H-5), 3.56–3.57 (1H, m, H-5), 3.70–
3.79 (1H, m, H-4), 3.59 and 3.77 (3H, s, –OCH3), 4.33–
4.41 (1H, m, H-2), 5.02–5.20 (2H, m, –OCH2Ph), 7.28–
7.37 (5H, m, Ph); HR-MS m/z: calcd for C14H18N2O4
(M+H)+ 279.1345, found 279.1333.
4.2.2. (2S,4S)-1-Benzyloxycarbonyl-2-methoxycarbonyl-4-
(30-carboxyl-propanoyl)amino-pyrrolidine 3a. A solution
of compound 2 (0.56 g, 2.0 mmol) and succinic anhydride
(0.2 g, 2.0 mmol) in anhydrous CH2Cl2 (15 mL) was stirred
at room temperature for 2 h. The reaction mixture was
Compound 4b: IR (KBr, cmꢀ1): 3413, 3059, 3026, 2923,
2851, 1741, 1713, 1674, 1601, 1515, 1494, 1450, 1417,
1355, 1207, 1179, 758, 700; 1H NMR (CDCl3, ppm):
d = 1.13–1.65 (2.4H, br, PS–CH2– and –CH2CH2–), 1.65–
2.04 (1.3H, br, PS–CH– and H-3), 2.50 (0.4H, m, NHC-
OCH2, CH2CONH), 3.58–3.78 (0.5H, m, –OCH3 and
H-5), 4.32–4.60 (0.4H, m, H-2, H-4 and PS–CH2NH),
5.06–5.20 (0.2H, m, –OCH2Ph), 6.47–6.57 (2.0H, br, PS),
7.04–7.08 (3.0H, br, PS), 7.30–7.34 (0.5H, m, –OCH2Ph).
concentrated under reduced pressure. The residue was used
20
without any further purification. ½aꢁD ¼ ꢀ9:2 (c 1.50,
EtOH); IR (KBr, cmꢀ1): 3339, 3065, 3033, 2955, 1735,
1709, 1678, 1656, 1543, 1421, 1356, 1209, 1171, 770, 751,
1
699; H NMR (CDCl3, ppm): d = 1.99–2.02 (2H, m, H-
3), 2.43–2.48 (6H, m, H-3 and –CH2CONH–), 2.62–2.68
(4H, m, –CH2COOH), 3.60 and 3.79 (6H, s, –OCH3),
3.50–3.60 (2H, m, H-5), 3.67–3.71 (2H, m, H-5), 4.35–
4.42 (2H, m, H-2), 4.61–4.62 (2H, m, H-4), 5.02–5.20
(4H, m, –OCH2Ph), 7.28–7.36 (10H, m, Ph); 13C NMR
(CDCl3) d: 29.3, 30.7, 36.0, 48.0, 52.7, 53.1, 57.8, 67.5,
127.9, 128.1, 128.2, 128.5, 136.0, 154.4, 173.0, 175.5; HR-
MS m/z: calcd for C18H22N2O7 (M+H)+ 379.1505, found
379.1522.
4.2.5. General procedure for the preparation of 1a and
1b. Polymer 4 was dissolved in 20 mL of THF, after
which 7 mL of 25% NaOH aqueous solution was then
added. The reaction mixture was refluxed for 12 h and
acidified to pH <3 with 1 M hydrochloric acid. The
aqueous layer was extracted with CHCl3 (25 mL · 3). The
organic layer was washed with Et3N/H2O 2:98
(30 mL · 3), and then concentrated under reduced pres-
sure. The residue was washed with methanol (15 mL · 3)
to give white powder 1.
4.2.3. (2S,4S)-1-Benzyloxycarbonyl-2-methoxycarbonyl-4-
(50-carboxyl-valeryl)amino-pyrrolidine 3b. To a stirred
solution of compound 2 (0.56 g, 2.0 mmol) and hexa-
nedioic acid (0.28 g, 2.0 mmol) in anhydrous CH2Cl2
(15 mL) was added N,N-dicyclohexylcarbodiimine (DCC,
0.44 g, 2.1 mmol) and catalytic quanties of DMAP at room
temperature. After stirring for 6 h, the reaction mixture
was filtered, and the filtrate was concentrated. The residue
was purified by column chromatography on silica gel
Compound 1a: IR (KBr, cmꢀ1): 3405, 3336, 3059, 3026,
2923, 2851, 1707, 1662, 1602, 1538, 1516, 1494, 1450,
1419, 1358, 1208, 1027, 758, 700; 1H NMR (CDCl3,
ppm): d = 1.25–1.68 (2.0H, br, PS–CH2–), 1.68–2.10
(1.2H, br, PS–CH– and H-3), 2.05–2.43 (0.4H, m, NHC-
OCH2CH2CONH), 3.50 (0.2H, m, H-5), 4.40 (0.3H, m,
H-2 and PS–CH2NH), 5.0 (0.1H, m, H-4), 6.51–6.58
(2.0H, br, PS), 7.09 (3.0H, br, PS); Elemental Anal.: N,
2.3; C, 84.2; H, 7.6. Loading: 0.55 mmol/g.
(petroleum ether/ethyl acetate = 1:1, v/v) to give 0.36 g
20
(45%) of semi-solid product. ½aꢁD ¼ ꢀ13:8 (c 0.65, EtOH);
IR (KBr, cmꢀ1): 3374, 3065, 3033, 2951, 1747, 1709, 1672,
1653, 1543, 1420, 1356, 1208, 1170, 770, 751, 699; 1H NMR
(CDCl3, ppm): d = 1.64–1.66 (4H, m, –CH2CH2–), 1.95–
2.01 (1H, m, H-3), 2.45–2.48 (1H, m, H-3), 2.17–2.20
(2H, t, –CH2CONH–), 2.34–2.37 (2H, t, –CH2COOH),
3.59, 3.79 (3H, s, –O CH3), 3.48–3.69 (2H, m, H-5), 4.35–
4.42 (1H, m, H-2), 4.66 (1H, m, H-4), 5.03–5.21 (2H, m,
–OCH2Ph), 7.28–7.35 (5H, m, –Ph). 13C NMR (CDCl3)
d: 24.5, 25.3, 33.6, 35.6, 36.6, 48.0, 52.6, 53.3, 57.7, 67.5,
127.9, 128.1, 128.2, 128.5, 136.1, 154.3, 172.1, 174.6; HR-
Compound 1b: IR (KBr, cmꢀ1): 3399, 3059, 3026, 2924,
2852, 1711, 1656, 1603, 1538, 1516, 1494, 1450, 1420,
1358, 1207, 1073, 1028, 759, 700; 1H NMR (CDCl3,
ppm): d = 1.11–1.68 (2.0H, br, PS–CH2–), 1.68–2.41
(2.0H, br, PS–CH–, H-3 and NHCOCH2CH2CH2-
CH2CONH), 3.50 (0.2H, m, H-5), 4.0–5.0 (0.4H, m, H-2,
H-4 and PS–CH2NH), 6.51–6.59 (2.0H, br, PS), 7.06

2654
Y.-X. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2649–2656
(3.0H, br, PS); Elemental Anal.: N, 2.2; C, 84.5; H, 7.6.
Loading: 0.52 mmol/g.
8.22 (d, J = 8.4 Hz, 2H); anti-isomer: 1.36–1.44 (m, 1H),
1.51–1.73 (m, 3H), 1.83 (m, 1H), 2.10–2.15 (m, 1H),
2.33–2.46 (m, 1H), 2.50 (m, 1H), 2.57–2.63 (m, 1H), 3.80
(s, 1H), 4.90 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz,
2H), 7.22 (d, J = 8.4 Hz, 2H); HPLC (for anti-isomer):
Chiralcel OD-H, UV 254, i-PrOH/hexane = 5:95, flow rate
1.0 mL/min, tR 29 min (major), tR 45 min (minor).
4.2.6. Polystyrene. A solution of styrene (5.2 g, 5 mmol)
and AIBN (16 mg, 0.1 mmol) in anhydrous toluene
(15 mL) was stirred at 75 ꢁC in an argon atmosphere for
5 h. The reaction mixture was concentrated under reduced
pressure to give 4.1 g (80%) white powder product. IR
(KBr, cmꢀ1): 3441, 3059, 3026, 2922, 2850, 1601, 1492,
4.3.4.
2-(Hydroxyl(2-nitrophenyl)methyl)cyclohexanone.
1
1448, 1370, 1256, 1052, 843, 756, 698; H NMR (CDCl3,
1H NMR (CDCl3) d: syn-isomer: 1.53–1.87 (m, 5H), 2.10
(m, 1H), 2.42–2.47 (m, 2H), 2.90 (dd, J = 13.2, 4.8 Hz,
1H), 3.15 (s, 1H), 5.96 (d, J = 1.6 Hz, 1H), 7.46 (dt,
J = 0.8, 8.0 Hz, 1H), 7.66 (dt, J = 0.8, 8.0 Hz, 1H), 7.84
(dd, J = 8.0, 0.8 Hz, 1H), 8.02 (dd, J = 8.0, 0.8 Hz, 1H);
anti-isomer: 1.61–1.87 (m, 5H), 2.10 (m, 1H), 2.34–2.47
(m, 2H), 2.77 (m, 1H), 3.95 (s, 1H), 5.45 (d, J = 7.2 Hz,
1H), 7.44 (dt, J = 0.8, 8.0 Hz, 1H), 7.66 (dt, J = 0.8,
8.0 Hz, 1H), 7.78 (dd, J = 8.0, 0.8 Hz, 1H), 7.86 (dd,
J = 8.0, 0.8 Hz, 1H); HPLC (for anti-isomer): Chiralcel
OD-H, UV 254, i-PrOH/hexane = 5:95, flow rate
1.0 mL/min, tR 17 min (major), tR 21 min (minor).
ppm): d 0.90–0.95 (0.17H, m, terminal methyl), 1.09–1.16
(0.14H, m, terminal methyl), 1.26–1.54 (2.0H, br, –CH2–),
1.72–2.04 (1.1H, br, –CH–), 6.46–7.08 (5.0H, m, Ar-H).
4.2.7. Chloromethyl polystyrene. A mixture of polystyrene
(3 g), paraformaldehyde (3 g), trimethylchlorosilane
(2.8 mL) and tin tetrachloride (0.25 mL) in anhydrous
chloroform (30 mL) was stirred at 0 ꢁC for 0.5 h, and then
at room temperature for 2.5 h. The reaction mixture was
then filtered. The product was precipitated out by addition
of 30 mL of methanol into the filtrate. The precipitate was
filtered to give a white powder, which was washed with
methanol (15 mL · 3) and then dried in a vacuum shelf
dryer overnight to afford 2.8 g of a white powder. IR
(KBr, cmꢀ1): 3449, 3059, 3025, 2921, 2848, 1601, 1493,
4.3.5. 2-(Hydroxyl(2-chlorophenyl)methyl)cyclohexanone.
1H NMR (CDCl3) d: syn-isomer: 1.53–1.71 (m, 4H),
1.81–1.84 (m, 1H), 2.08 (m, 1H), 2.33–2.42 (m, 1H), 2.48
(m, 1H), 2.81 (m, 1H), 3.95 (s, 1H), 5.72 (d, J = 2.0 Hz,
1H), 7.20–7.34 (m, 3H), 7.56 (d, J = 8.0 Hz, 1H); anti-iso-
mer: 1.53–1.84 (m, 5H), 2.05–2.13 (m, 1H), 2.31–2.39 (m,
1H), 2.46–2.49 (m, 1H), 2.65–2.71 (m, 1H), 3.88 (s, 1H),
5.35 (d, J = 8.0 Hz, 1H), 7.20–7.34 (m, 3H), 7.56 (d,
J = 8.4 Hz, 1H); HPLC (for anti-isomer): Chiralcel OD-
H, UV 220, i-PrOH/hexane = 5:95, flow rate 1.0 mL/min,
tR 10 min (major), tR 13 min (minor).
1
1451, 1371, 1265, 1029, 840, 757, 699; H NMR (CDCl3,
ppm): d 0.89–0.93 (0.12H, m, terminal methyl), 1.09–1.13
(0.09H, m, terminal methyl), 1.22–1.54 (2.1H, br, –CH2–),
1.72–2.05 (1.2H, br, –CH–), 4.50 (0.18H, m, –CH2Cl),
6.45–7.08 (5.1H, br, Ar-H).
4.2.8. Aminomethyl polystyrene. Aminomethyl polysty-
rene was prepared from chloromethyl polystyrene as
reported in the literature.13 IR (KBr, cmꢀ1): 3385, 3059,
3025, 2921, 2848, 1601, 1493, 1451, 1372, 1068, 1028,
845, 757, 6998; 1H NMR (CDCl3, ppm): d 0.88–0.93
(0.12H, m, terminal methyl), 1.09–1.14 (0.09H, m, terminal
methyl), 1.26–1.5443 (2.0H, br, –CH2–), 1.85–2.46 (1.3H,
br, –CH–), 3.74–3.76 (0.19H, m, –CH2NH2), 6.51–7.24
(5.1H, br, Ar-H).
4.3.6. 2-(Hydroxyl(4-chlorophenyl)methyl)cyclohexanone.
1H NMR (CDCl3) d: syn-isomer: 1.42–2.11 (m, 6H),
2.32–2.45 (m, 2H), 2.53–2.56 (m, 1H), 3.05 (s, 1H), 5.36
(d, J = 2.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.32 (d,
J = 8.4 Hz, 2H); anti-isomer: 1.27–1.31 (m, 1H), 1.53–
1.82 (m, 4H), 2.07–2.11 (m, 1H), 2.35–2.56 (m, 3H), 4.76
(d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.32 (d,
J = 8.0 Hz, 2H); HPLC (for anti-isomer): Chiralcel OD-
H, UV 220, i-PrOH/hexane = 5:95, flow rate 1.0 mL/min,
tR 14 min (major), tR 22 min (minor).
4.3. General procedure for the aldol condensations
4.3.1. Reaction in wet DMF. To a stirred mixture of an
aldehyde (0.33 mmol), 1.5 mL of DMF (0.1 mL of water)
and 0.5 mL of the corresponding ketone was added cata-
lysts (0.016 mmol). The mixture was stirred for 24 h. The
catalyst was precipitated out by the addition of diethyl
ether and then filtered off. The filtrate was purified by thin
layer chromatography on a silica gel plate (petroleum
ether/ethyl acetate).
4.3.7.
2-(Hydroxyl(3-nitrophenyl)methyl)cyclohexanone.
1H NMR (CDCl3) d: syn-isomer: 1.48–2.10 (m, 6H),
2.33–2.48 (m, 2H), 2.62–2.66 (m, 1H), 3.16 (s, 1H), 5.48
(d, J = 2.0 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.66 (d,
J = 1.4 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.20 (d,
J = 8.0 Hz, 1H); anti-isomer: 1.33–2.10 (m, 6H), 2.32–
2.48 (m, 2H), 2.70 (m, 1H), 3.16 (s, 1H), 4.91 (d,
J = 8.4 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.68 (d,
J = 0.8 Hz, 1H), 8.15 (m, J = 8.0 Hz, 1H), 8.20 (d, J =
8.0 Hz, 1H); HPLC (for anti-isomer): Chiralcel OD-H,
UV 254, i-PrOH/hexane = 5:95, flow rate 1.0 mL/min, tR
24 min (major), tR 36 min (minor).
4.3.2. Reaction in ketone/water mixture. 0.33 mmol of an
aldehyde was added to a mixture of 1.2 mL of a ketone,
0.8 mL of water and 0.016 mmol of catalyst. After being
stirred at room temperature for 24 h, the mixture was trea-
ted as described above for the reaction in DMF.
4.3.3. 2-(Hydroxyl(4-nitrophenyl)methyl)cyclohexanone. 1H
NMR (CDCl3) d: syn-isomer: 1.50–1.88 (m, 5H), 2.09–2.15
(m, 1H), 2.37–2.52 (m, 2H), 2.62–2.66 (m, 1H), 3.10 (s,
1H), 5.49 (d, J = 1.6 Hz, 1H), 7.49 (d, J = 8.4 Hz, 2H),
4.3.8. 2-(Hydroxyl(3-chlorophenyl)methyl)cyclohexanone.
1H NMR (CDCl3) d: syn-isomer: 1.45–2.11 (m, 6H),
2.32–2.45 (m, 2H), 2.53–2.56 (m, 1H), 3.05 (s, 1H), 5.50
(d, J = 2.0 Hz, 1H), 7.21–7.30 (m, 3H, Ar), 7.37 (s, 1H,

Y.-X. Liu et al. / Tetrahedron: Asymmetry 18 (2007) 2649–2656
2655
3. (a) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev.
2004, 33, 65–75; (b) Alcaide, B.; Almendros, P. Eur. J. Org.
Chem. 2002, 1595–1601; (c) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138–5175; (d) Vidal-Ferran, A.;
Ar); anti-isomer: 1.31–2.08 (m, 6H), 2.30–2.45 (m, 3H),
4.80 (d, J = 8.8 Hz, 1H), 7.20–7.29 (m, 3H, Ar), 7.37 (s,
1H, Ar); HPLC (for anti-isomer): Chiralcel OD-H, UV
220, i-PrOH/hexane = 5:95, flow rate 1.0 mL/min, tR
13 min (major), tR 18 min (minor).
`
Bampos, N.; Moyano, A.; Pericas, M. A.; Riera, A.; Sanders,
`
J. K. M. J. Org. Chem. 1998, 63, 6309–6318; (e) Pericas, M.
´
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A.; Castellnou, D.; Rodrıguez, I.; Riera, A.; Sola, L. Adv.
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1H NMR (CDCl3) d: syn-isomer: 1.50–2.08 (m, 6H),
2.31–2.61 (m, 3H), 5.36 (d, J = 2.0 Hz, 1H), 7.20–7.23
(m, 2H), 7.39–7.50 (m, 2H); anti-isomer: 1.30–2.08 (m,
6H), 2.30–2.45 (m, 3H), 4.74 (d, J = 8.8 Hz, 1H), 7.20–
7.23 (m, 2H), 7.39–7.50 (m, 2H). HPLC (for anti-isomer):
Chiralcel OD-H, UV 220, i-PrOH/Hexane = 5:95, flow
rate 1.0 mL/min, tR 14 min (major), tR 19 min (minor).
`
Synth. Catal. 2003, 345, 1305–1313; (f) Castellnou, D.; Sola,
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`
`
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12120; (h) Shen, Z.-X.; Chen, W.-H.; Jiang, H.; Ding, Y.;
Luo, X.-Q.; Zhang, Y.-W. Chirality 2005, 17, 119–120; (i)
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Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004, 346,
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4.3.10. 2-(Hydroxyl(2-nitrophenyl)methyl) cyclopentanone.
1H NMR (CDCl3) d: syn-isomer: 1.70–1.78 (m, 2H), 2.03–
2.19 (m, 3H), 2.37 (dd, J = 8.0, 1.6 Hz, 1H), 2.60 (br, 1H),
2.74 (m, 1H), 5.92 (d, J = 2.4 Hz, 1H) 7.44 (td, J = 8.0,
0.8 Hz, 1H, Ar-H), 7.66 (t, J = 8.0 Hz, 1H, Ar-H), 7.89
(d, J = 8.0 Hz, 1H, Ar), 8.02 (d, J = 8.0 Hz, 1H, Ar-H);
anti-isomer: 1.70–2.03 (m, 4H), 2.19–2.38 (m, 2H), 2.68
(d, J = 7.6 Hz, 1H), 2.90 (br, 1H), 5.21 (d, J = 7.2 Hz,
1H), 7.44 (t, J = 8.0 Hz, 1H, Ar-H), 7.66 (t, J = 8.0 Hz,
1H, Ar-H), 7.89 (d, J = 8.0 Hz, 1H), 8.00 (dd, J = 8.0,
0.8 Hz, 1H); HPLC: syn-isomer: Chiralcel OD-H, UV
254, i-PrOH/Hexane = 5:95, flow rate 1.0 mL/min, tR
17 min (major), tR 13 min (minor); anti-isomer: Chiralcel
OD-H, UV 254, i-PrOH/hexane = 5:95, flow rate 1.0 mL/
min, tR 23 min (major), tR 26 min (minor).
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4-Hydroxyl-4-(20-nitrophenyl)-butan-2-one. 1H
NMR (CDCl3) d: 2.24 (s, 3H), 2.74 (dd, J = 17.8, 9.4 Hz,
1H), 3.13 (dd, J = 17.8, 1.8 Hz, 1H), 3.89 (s, 1H), 5.68
(dd, J = 9.4, 1.8 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.67
(t, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.96 (d,
J = 8.0 Hz, 1H); HPLC: Chiralcel OD-H, UV 254,
i-PrOH/hexane = 5:95, flow rate 1.0 mL/min, S-isomer,
tR 18 min, R-isomer, tR 21 min.
`
255–257; (e) Font, D.; Jimeno, C.; Pericas, M. A. Org. Lett.
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Acknowledgments
6. (a) Gruttadauria, M.; Riela, S.; Aprile, C.; Lo Meo, P.;
D’Anna, F.; Noto, R. Adv. Synth. Catal. 2006, 348, 82–92; (b)
Loh, T.-P.; Feng, L.-C.; Yang, H.-Y.; Yang, J.-Y. Tetrahedron
We are grateful for the financial support from the National
Natural Science Foundation of China (Grants 20372059).
We also thank Wei-Guo Zhu and Jian-Xun Kang for the
determination of NMR, Shao-Min Wang for HRMS,
and Zong-Pei Zhang for elemental analysis.
´
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Toma, S.; Solcaniova, E. Chem. Commun 2002, 2510–2511.
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