Polymerization of L-proline functionalized styrene and its catalytic performance as a supported organocatalyst for direct enantioselective aldol reaction

Article abstract of DOI:10.1016/j.tetasy.2016.06.014

As an alternative approach to the graft modification of polymers to fabricate polymer-supported chiral organocatalysts in a bottom-up fashion, L-prolinamide functionalized polymers were prepared by general solution homopolymerization or copolymerization of L-proline functionalized styrene monomer in the presence of 1,4-divinylbenzene as the crosslinking agent. The catalytic performance of the as-prepared heterogeneous catalysts towards the direct enantioselective aldol reaction of ketones with a series of aromatic aldehydes was explored. Our findings indicate that the as-prepared heterogeneous catalysts can afford relevant aldol addition products with good yields (up to 96%), high diastereoselectivities (up to 8:92 dr) and excellent enantiomeric excess (up to 96%); they also exhibit good recyclability, retaining high yield and rate as well as good selectivity after several cycles.

Full text of DOI:10.1016/j.tetasy.2016.06.014

Tetrahedron: Asymmetry 27 (2016) 740–746
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Polymerization of L-proline functionalized styrene and its catalytic
performance as a supported organocatalyst for direct
enantioselective aldol reaction
a
b
b
b
b
a,b,
⇑
Guozhang Guo , Yufeng Wu , Xiaowei Zhao , Jing Wang , Lei Zhang , Yuanchen Cui
a
Engineering Research Center for Nanomaterials, Henan University, Kaifeng 475000, China
College of Chemistry and Chemical Engineering, Henan University, Kaifeng 475000, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
As an alternative approach to the graft modification of polymers to fabricate polymer-supported chiral
organocatalysts in a bottom-up fashion, -prolinamide functionalized polymers were prepared by general
solution homopolymerization or copolymerization of -proline functionalized styrene monomer in the
presence of 1,4-divinylbenzene as the crosslinking agent. The catalytic performance of the as-prepared
heterogeneous catalysts towards the direct enantioselective aldol reaction of ketones with a series of aro-
matic aldehydes was explored. Our findings indicate that the as-prepared heterogeneous catalysts can
afford relevant aldol addition products with good yields (up to 96%), high diastereoselectivities (up to
Received 15 April 2016
Accepted 5 June 2016
Available online 4 July 2016
L
L
8
:92 dr) and excellent enantiomeric excess (up to 96%); they also exhibit good recyclability, retaining
high yield and rate as well as good selectivity after several cycles.
Ó 2016 Elsevier Ltd. All rights reserved.
1
. Introduction
can only provide the target products with a low grafting ratio.11
The low grafting ratio, undoubtedly, will further affect the catalytic
performance of polymer-supported heterogeneous catalysts.
Therefore, it remains a challenge to develop new polymer-sup-
ported organocatalysts, with good control of catalyst loading and
simple work-up and purification.
Direct enantioselective aldol reactions involving a non-acti-
vated ketone as the nucleophile, are an effective and straightfor-
ward route to provide C–C backbones. This reaction has been
extensively used in the synthesis of a variety of natural products
and non-natural drug molecules.1
,2
12
In recent years, Pericàs et al. and Gruttadauria et al. have
Amongst
a
wide range of efficient chiral homogeneous
reported the synthesis of cross-linked polystyrene anchored pro-
organocatalysts for the direct enantioselective aldol reaction, L-
line and especially good results have been obtained. Hansen et al.13
proline and its derivatives3 have attracted great attention from
,4
have explored the incorporation of several L-proline functionalized
chemists since they are water and air tolerant and exhibit high effi-
monomers into polymers to substitute for grafting a chiral
line molecule onto polymer scaffolds directly, and a range of
L
-pro-
-pro-
5
,6
ciency. However, the application of
L-proline and its derivatives
L
as organocatalysts is often limited by the difficulty of separating
line functionalized methacrylate monomers and several L-proline
them from the reaction system. To facilitate the recyclability of
proline and its derivatives as organocatalysts, many researchers
have made great efforts to immobilize L-proline with various poly-
L
7
-
functionalized styrenic as well as methacrylic copolymer beads
were synthesized. The as-prepared functional polymers showed
good activities and high stereoselectivities as well as good recycla-
bility. These researchers and more recently others have provided
a novel bottom-up fashion for synthesizing supported proline-
derived chiral organocatalysts with good control of the catalyst
loading and simple work-up.
1
4
mer scaffolds via grafting modification reactions. The resultant
polymer-supported heterogeneous catalysts8 have many unique
advantages such as easy purification, potential recyclability,
enhanced catalytic activity and the absence of an organic sol-
,9
1
0,15
vent.
Unfortunately, polymer molecular chains are often sus-
Bearing those perspectives in mind, we chose styrenic
namide as the highly active and stereoselective monomer to syn-
thesise the -proline functionalized polymers via general
L-proli-
ceptive to curling and twinning, which means that due to the
embedding of the functional group, grafting modification reaction
L
a
solution polymerization, hoping to explore a straightforward pro-
cess for synthesizing new, robust, efficient and recyclable
organocatalysts. In addition, according to the urgent need for a
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetasy.2016.06.014
957-4166/Ó 2016 Elsevier Ltd. All rights reserved.
0

G. Guo et al. / Tetrahedron: Asymmetry 27 (2016) 740–746
741
more environmentally responsible chemistry,10,15 we tried to
adopt ethanol as the solvent in the solution polymerization. Herein
2
with SOCl to give the target product acyl chloride 2. Secondly, the
acyl chloride 2 was modified by p-aminostyrene in the presence of
we report the synthesis of
L
-proline functionalized polymers and
pyridine as the acid binding agent, and the resultant product was
the application of these novel functional polymers as supported
organocatalysts for a typical direct enantioselective aldol reaction
between ketones and a series of aromatic aldehydes at room tem-
perature. The recyclability of the aforementioned catalysts was
also evaluated in the mixed solvent system with petroleum
ether/water.
further modified via one deprotection reaction to yield L-proline
functionalized styrene monomer 3. Finally, monomer 3 was initi-
ated by azodiisobutyronitrile (AIBN) to homopolymerize and yield
the functional polymer Cat.I or copolymerize with 1,4-divinylben-
zene to give the cross-linked Cat.II.
For the evaluation of the catalytic properties of the synthesized
L-proline functionalized polymers Cat.I and Cat.II, the representa-
tive aldol reaction between 4-nitrobenzaldehyde and cyclohex-
anone served as a model reaction. Table 1 summarizes the effects
of catalyst dosage on the aqueous aldol reaction. It can be seen that
high selectivity (87–95% ee) and high activity (up to 95% yield)
were achieved in the tested range of catalyst dosage. When
2
. Results and discussion
Schemes 1 and 2 depict the procedures for preparing Cat.I and
Cat.II, where three major steps are involved. Firstly, N-9-fluorenyl-
methyloxy-carbonyl protected L-proline (Fmoc-L-Pro) was reacted
1
)
H
2
N
C
H
CH
2
1
) Fmoc-Osu, THF
) SOCl , DCM
COOH
N
COCl
N
N
H
CONH
C
H
CH2
2
2
2) diethylamine, DCM, 24h, r.t.
H
Fmoc
1
2
3
Scheme 1. The preparation of L-proline functionalized styrene monomer 3.
CH
3 2
CH OH
AlBN, 62 o
C
CONH
CH CH2
N
H
Cat.I
H
C
N
H
CONH
C
H
CH
2
CH
2
CH
2
CH
3
N
C
H
C
H
2 2
CH CH CH
O
3 2
CH CH OH, 1,4-divinylbenzene
AlBN, 62 o
HN
C
N
C
H
O
Cat.II
HN
Scheme 2. The polymerization of functionalized monomer 3 to afford Cat.I and Cat.II.
Table 1
Effect of catalyst dosage on the aldol reaction between p-nitrobenzaldehyde and cyclohexanone in a water medium
a
O
O
OH
OHC
Cat.(X mol%)
2
+
H O, r.t.
NO2
NO2
Entry
Catalyst
Mol %
Time (h)
Yieldb (%)
drc (syn/anti)
eec (%; anti)
1
2
3
4
5
6
7
8
Cat.I
Cat.I
Cat.I
Cat.I
Cat.II
Cat.II
Cat.II
Cat.II
5
10
15
20
5
10
15
20
24
24
15
15
24
24
15
15
81
94
89
96
72
87
91
92
20:80
19:81
20:80
23:77
29:71
26:74
28:72
25:75
89
95
95
94
87
95
92
94
a
b
c
Reaction was carried out using 4-nitrobenzaldehyde (1 equiv, 1.98 ꢀ 10 mol) and cyclohexanone (10 equiv, 1.98 ꢀ 10ꢁ3 mol) in 0.5 mL of H
ꢁ4
2
O.
Isolated yield.
Determined by chiral-phase HPLC analysis (Chiralpak AD-H).

7
42
G. Guo et al. / Tetrahedron: Asymmetry 27 (2016) 740–746
Table 2
Screening solvents for the organocatalytic enantioselective aldol reaction between p-nitrobenzaldehyde and cyclohexanonea
O
O
OH
OHC
Cat.(10 mol%)
solvent, r.t.
+
NO2
NO2
Entry
Catalyst
Solvent (mL)
Time (h)
Yieldb (%)
drc (syn/anti)
eec (%; anti)
1
2
3
4
5
6
7
8
9
Cat.I
Cat.II
Cat.I
Cat.II
Cat.I
Cat.II
Cat.I
Cat.II
Cat.I
Cat.II
Cat.I
Cat.II
Cat.I
Cat.II
Cat.I
Cat.II
H
H
H
H
H
H
2
2
2
2
2
2
O (0.01)
O (0.01)
O (0.20)
O (0.20)
O (0.50)
O (0.50)
24
24
24
24
24
24
48
48
48
48
48
48
48
48
48
48
86
81
89
91
90
82
76
63
76
79
91
89
72
62
59
71
21:79
28:72
22:78
30:70
19:81
26:74
31:69
23:77
19:81
31:69
27:73
26:74
29:71
25:75
30:70
27:73
90
91
94
92
95
92
88
57
90
89
90
86
61
69
76
66
Neat
Neat
Petroleum ether
Petroleum ether
Hexane
Hexane
CH
CH
10
11
12
13
14
15
16
3
CN
CN
3
Dimethylformamide (DMF)
Dimethylformamide (DMF)
a
Reaction was carried out with p-nitrobenzaldehyde (1 equiv, 0.030 g, 1.985 ꢀ 10ꢁ4 mol) and cyclohexanone (10 equiv, 0.2 mL, 1.985 ꢀ 10ꢁ3 mol) in 0.5 mL undistilled
solvent.
b
Isolated yield.
c
Determined by chiral-phase HPLC analysis (Chiralpak AD-H).
1
0 mol % of catalyst was used, the best overall results were
organocatalysts, and an increased reaction time of 48 h was
required in the less polar solvents (Table 2, entries 13–16). More-
over, high yields and ee values were obtained in non-polar organic
solvents (Table 2, entries 9–12); and Cat.I and Cat.II exhibit
decreased enantioselectivities in association with low yields under
neat reaction conditions (Table 2, entries 7–8).
Furthermore, as shown in Table 2, the enantioselectivity of Cat.I
and Cat.II depends greatly on the volume of water (entries 1–6).
The ee values and yields rise significantly when increasing the
water volume from 0.01 mL to 0.20 mL (Table 2, entries 1–4).
When a large amount of water (0.50 mL) is employed, the relevant
aldol products were obtained with good yields and near perfect ee
values (Table 2, entries 5 and 6). According to these findings, in the
presence of trace water, we speculate that the as-synthesized
amphiphilic polymers could provide a hydrophobic microenviron-
ment for the substrates and catalytic sites capable of efficiently
catalyzing the aldol reaction between cyclohexanone and 4-
obtained after 24 h of reaction (Table 1, entries 2 and 6, 94–87%
yield and 95% ee). When the catalyst dosage was fixed at 5 mol
%
1
, the yields and ee values decreased significantly (Table 1, entries
and 5). Moreover, when the reaction time was decreased to 15 h,
an increased amount (15 –20 mol %) of the catalyst did not signif-
icantly change the diastereoselectivities but decreased the ee val-
ues. Thus the optimal catalyst dosage of either Cat.I or Cat.II is
suggested to be 10 mol %.
Table 2 presents the catalytic activity of the synthesized poly-
mer-supported organocatalysts for the above-mentioned aldol
reaction in various solvent systems at 10 mol % catalyst dosage. It
can be seen that the catalysts possess the best reactivities and
stereoselectivities in the presence of 0.5 mL of water, and the reac-
tion can be completed in only 24 h (Table 2, entries 5 and 6). How-
ever, less polar solvents are unfavorable for the catalytic efficiency
and stereoselectivities of the as-synthesized polymer-supported
Table 3
Yield, final diastereomeric ratio (dr) and enantiomeric excess (ee) with 10 mol % as-synthesized catalysts in the mixed solvent system of petroleum ether/H
Oa
2
O
O
OH
OHC
Cat.(10 mol%)
r.t.
NO2
+
NO2
Entry
Catalyst
% Water in petroleum ether
Time (h)
Yieldb (%)
drc (syn/anti)
eec (%; anti)
1
2
3
4
5
6
7
8
Cat.I
Cat.I
Cat.I
Cat.I
Cat.II
Cat.II
Cat.II
Cat.II
0
5
7.5
10
0
5
7.5
10
48
24
24
24
48
24
24
24
61
81
93
87
72
81
89
92
19:81
18:82
16:84
24:76
31:69
27:73
26:74
29:71
90
90
96
92
89
92
94
93
a
Reaction was carried out with 4-nitrobenzaldehyde (1 equiv, 0.030 g, 1.985 ꢀ 10ꢁ4 mol) and cyclohexanone (10 equiv, 0.2 mL, 1.985 ꢀ 10ꢁ3 mol) under 10 mol % catalyst
dosage in undistilled mixed solvent.
b
Isolated yield.
c
Determined by chiral-phase HPLC analysis (Chiralpak AD-H).

G. Guo et al. / Tetrahedron: Asymmetry 27 (2016) 740–746
743
nitrobenzaldehyde to produce the product with excellent enantios-
electivity (ee). The volume of the water medium, however, should
be below 0.5 mL, because above this volume level, the catalysts
tend to precipitate from the solution, due to the presence of a
hydrophobic group in the as-synthesized polymer-supported
catalysts.
To further investigate the potential of the synthesized polymer-
supported organocatalysts, we also explored the effects of the
2
mixed solvent system of petroleum ether/H O in different ratios
(Table 4, entry 10). To broaden the scope of the methodology, we
also adopted polymer-supported catalysts to catalyze the direct
enantioselective aldol reaction between cyclopentanone and ben-
zaldehyde. We found that the aldol products were obtained with
moderate yields and good stereoselectivity (Table 4, entries 13–
14). In the presence of hydrophilic acetone as the donor, the aldol
reaction furnished b-hydroxy carbonyl aldol products in medium
ee values, but the yields were too low (41–52%) (Table 4, entries
15–16).
for the selected aldol reactions. The relevant results are summa-
rized in Table 3. It can be seen that increasing the water content
in petroleum ether to 7.5% (volume fraction) led to excellent yields
and high ee values (Table 3, entries 3 and 7). When the water con-
tent in petroleum ether was fixed at 10 vol %, slightly decreased
stereo- and enantioselectivities were obtained. Particularly, when
petroleum ether alone was used as the reaction solvent, the corre-
sponding aldol products were obtained with low yield and enan-
tioselectivity, while the reaction time increased to 48 h (Table 3,
entries 1 and 5). In combination with the results shown in Tables
Table 5 shows the recovery and recycling of the synthesized
catalysts towards the aldol reaction between cyclohexane and 4-
nitrobenzaldehyde in a mixed solvent of petroleum ether/water
(volume ratio: 92.5/7.5). It can be seen that the polymer-supported
Cat.I retains almost unchanged reactivity and selectivity after
three cycles. The cross-linked Cat.II exhibits better recyclability
than Cat.I., i.e., Cat.II retains high selectivity and a slightly
decreased yield after five consecutive cycles, which indicates that
Table 5
1
and 2, the optimized catalyst dosage and solvent system for
the title aldol reaction are suggested as 10 mol % and petroleum
ether/H O (volume ratio: 92.5/7.5).
Recyclability of polymer-supported catalysts under the optimized conditionsa
2
O
O
OH
OHC
+
The reactions of various aromatic aldehydes with cyclohex-
anone (cyclopentanone, and acetone) were studied under the opti-
Cat.(10 mol%)
r.t. 48h
NO2
mized conditions [10 mol % of catalyst in petroleum ether/H
2
O
NO2
(
volume ratio: 92.5/7.5)]. The results are summarized in Table 4.
Entry
Catalyst
Yieldb (%)
drc (syn/anti)
eec (%; anti)
It can be seen that a wide range of aromatic aldehydes can effec-
tively participate in the aldol reactions. With regards to some ben-
zaldehydes with electron-withdrawing substituents, the reaction
was completed with good selectivity (anti/syn ratio and ee) and
high yield; in particular, 2,4-dinitrobenzaldehyde and 4-nitroben-
zaldehyde can provide relatively high selectivity and yield (Table 4,
entries 1 and 3, 8/92 to 15/85 syn/anti ratio and 86–94% ee). In con-
trast, longer reaction times (72 h) were required for aromatic alde-
hydes containing an electron-donating group to provide medium
diastereoselectivities and poor yields, but the enantioselectivities
retain high (Table 4, entries 11–12). Moreover, the high diastereos-
electivity was achieved with the participation of neutral aldehyde
1
2
3
4
5
6
7
8
Cat.I (cycle 1)
Cat.I (cycle 2)
Cat.I (cycle 3)
Cat.II (cycle 1)
Cat.II (cycle 2)
Cat.II (cycle 3)
Cat.II (cycle 4)
Cat.II (cycle 5)
93
94
87
91
95
89
90
84
19:81
21:79
25:75
26:74
29:71
30:70
23:77
28:72
95
94
92
95
92
92
94
93
a
Reaction performed at 0.2 mmol scale of aldehyde and 10 equiv of cyclohex-
anone in petroleum ether/water (volume ratio: 92.5/7.5) after 48 h.
b
Isolated yield.
c
Determined by chiral-phase HPLC analysis (Chiralpak AD-H).
Table 4
a
Asymmetric Aldol reactions catalyzed by polymer-supported catalysts
O
O
OH
OHC
Cat.(10 mol%)
r.t.
R
R
+
n
n
Entry
R
Catalyst
Time (h)
Yieldb (%)
drc (syn/anti)
eec (%; anti)
1
2
3
4
5
6
7
8
9
2,4-Dinitro
2,4-Dinitro
Cat.I
Cat.II
Cat.I
Cat.II
Cat.I
Cat.II
Cat.I
Cat.I
Cat.I
Cat.I
Cat.I
Cat.I
Cat.I
Cat.I
Cat.I
Cat.I
48
48
48
48
48
48
48
72
72
72
72
72
48
48
60
60
89
79
92
90
85
87
73
52
63
69
58
45
72
76
41
52
8:92
12:88
15:85
27:73
11:89
14:86
10:90
25:75
24:76
17:83
32:68
43:57
39:61
31:69
—
86
80
94
92
80
79
84
69
64
76
83
84
69
88
67
65
4-NO
4-NO
3-NO
3-NO
2-NO
4-CN
4-F
2
2
2
2
2
1
1
1
1
1
1
1
0
1
2
3
4
5
6
4-H
4-CH
4-OCH
3
3
d
d
e
e
4-NO
2-NO
4-NO
3-NO
2
2
2
2
—
a
b
c
Reaction performed at 0.2 mmol scale of aromatic aldehyde and 10 equiv of ketone in the presence of petroleum ether/water (volume ratio: 92.5/7.5).
Isolated yield.
Determined by chiral-phase HPLC analysis (Chiralpak AD-H).
Cyclopentanone was used as the nucleophile.
Acetone was used as the nucleophile.
d
e

7
44
G. Guo et al. / Tetrahedron: Asymmetry 27 (2016) 740–746
the cross-linked Cat.II is superior to Cat.I in terms of the applica-
tion in engineering.
1H), 7.34–7.25 (m, 1H), 4.51–4.42 (m, 1H), 4.25–4.28 (d, 1H),
3.40 (s, 1H), 3.51 (m, 2H), 2.02–1.98 (m, 2H), 1.86 (m, 2H). 13
NMR (100 MHz, CDCl ): 177.12, 175.50, 155.67, 153.48, 141.43,
C
3
1
4
42.60, 126.62, 126.13, 123.89, 118.92, 66.80, 66.52, 58.26, 57.42,
6.12, 45.63, 29.92, 28.34, 23.30, 22.31.
3
. Conclusions
Two -proline functionalized polymer catalysts have been suc-
L
4
.2.2. Synthesis of functionalized monomer 3
cessfully prepared via a general solution polymerization in a bot-
tom-up fashion, and the catalytic performance of the as-prepared
polymer-supported organocatalysts for the aldol condensation
reaction between ketones and aromatic aldehydes has been care-
fully evaluated. Our results indicate that the catalysts can catalyze
the aldol reaction at rt in the presence of various solvent systems.
Yields of up to 96%, anti/syn ratios of up to 8:92, and enantiomeric
excesses of up to 96% were achieved when the aldol reaction was
carried out in a mixed solvent of petroleum ether/water with a vol-
ume ratio of 92.5:7.5. The as-synthesized polymer-supported cata-
lysts can be recovered and reused for several consecutive cycles
while their reactivity and selectivity remained almost unchanged;
the cross-linked Cat.II exhibited better recyclability than Cat.I. We
have hopefully provided a novel method towards the development
of new supports for chiral heterogeneous organocatalysts. Further
Fmoc-L-Pro (1.49 g, 4.42 mmol) was dissolved with CH
3 mL) in a flask. To the resultant solution was slowly added
mL of SOCl at 37 °C with 15 min of stirring. The mixture was
2 2
Cl
(
1
2
stirred at 37 °C for 1.5 h to afford acyl chloride 2. Next, p-aminos-
tyrene was dissolved in pyridine and added to acyl chloride 2 in
3
resultant N-Fmoc was deprotected prior to polymerization with
diethylamine with stirring overnight to give the functionalized
monomer 3. The product was characterized by FTIR and 1H NMR.
0 min while the temperature was kept under 25 °C for 6 h. The
ꢁ1 1
FTIR (m = 3246, 2965, 1671, 1621, 1517, 1424, 988, 903 cm ). H
NMR (400 MHz, CDCl ): 9.82–9.80 (s, H), 7.52–7.46 (d, 2H), 7.36–
.28 (d = 2H), 6.63–6.58 (dd, 1H), 5.10–5.58 (m, 2H), 3.82–3.89
m, 1H), 2.98–3.16 (m, 2H), 2.94–2.96(m, 1H), 1.95–2.11 (m, 2H),
3
7
(
1
.72–1.74 (m, 2H).
work is intended to extend L-proline functionalized polymer cata-
lysts for other asymmetric reactions and to reveal reaction mecha-
nisms as well.
4
.2.3. Synthesis of catalysts I–II
L
-Proline functionalized monomer 3 (1.42 g, 6.6 mmol) was dis-
solved in 3 mL of CH CH OH and sequentially mixed with 1,4-
divinylbenzene (10%, 0.142 g, 1.091 mmol) and AIBN (2%, 0.028 g,
.173 mmol). The resultant mixture was stirred at 62 °C for 12 h
3
2
4
4
. Experimental
0
to allow for polymerization to yield a white powder precipitate.
At the end of the polymerization, the crude product was washed
sequentially with ethanol, acetone and water. The target product,
cross-linked copolymer Cat.II was dried in vacuum oven until the
.1. General
Raw material 4-aminostyrene containing a small amount of
quinone stabilizer was purchased from J&K Technology Company
Ltd (Beijing, China) and used without further purification. The
other chemicals were provided by various commercial suppliers
and were used as-received.
Thin-layer chromatograph (TLC) analysis was performed with
pre-coated silica gel GF254 plates. Infrared spectra were recorded
with an Avatar360 Fourier transform infrared spectrometer (FTIR;
Nicolet, Thermo Scientific, Pittsburgh, PA). Nuclear magnetic reso-
weight remained constant. L-Proline functionalized homopolymer
Cat.I was prepared in the same manner, except that crosslinking
agent 1,4-DIVINYLBENZENE was not added. The products were
characterized by means of Fourier transformation infrared (FTIR)
spectrometry. The final target products Cat.I and Cat.II were used
as novel catalysts for direct enantioselective aldol reactions. Gel
permeation chromatograph (GPC) analysis showed that Cat.I has
4
a weight-average molecular weight (Mw) of 1.42 ꢀ 10 and PDI
nance (NMR) spectra were obtained from Bruker Avance 400 M
system, and the chemical shifts of 1H NMR spectra were reported
value of 1.81. Proline loading of I-II was determined, by elemental
analysis to be 2.10 and 2.01 mmol/g, respectively.
in relation to tetramethyl silane (d = 0). Thermal degradation
behavior of the as-synthesized polymer-supported catalysts were
analyzed by means of thermo gravimetric analyzer (TGA/
SDTA851e, Mettler Toledo, Switzerland) at a heating rate of 10 °-
4
.3. Recyclability of the as-synthesized polymer-supported
catalysts
ꢁ1
C min
from 25 °C to 700 °C in nitrogen atmosphere. Column
Upon completion of the reaction between cyclohexanone and
chromatograph was conducted to purify the aldol products; and
the stereoselectivity was determined by a chiral high performance
liquid chromatograph (HPLC) with Daicel Chiralpak AD-H chiral
columns.
the aromatic aldehyde, the catalyst was separated by centrifuging
and washed with dichloromethane, followed by drying under 45 °C
in an oven for 24 h. As-recovered catalysts can be reused directly
without further purification.
4
.2. General procedure for the preparation of chiral
4
.4. General procedure for the aldol reaction
organocatalysts
Substituted aromatic aldehyde (0.2 mmol) was added to cyclo-
4
.2.1. Synthesis of N-Fmoc-
-Proline (1.5 g) was dissolved in 30 mL of aqueous Na
mass fraction:10%) under stirring and mixed with 4.5 g of N-(9-
L-proline, 2
hexanone with stirring at room temperature. Into the resultant
mixture were sequentially added a certain amount of catalyst
and solvent. The resultant reaction system was stirred at room
temperature for a certain period of time and monitored by TLC
L
2 3
CO
(
fluorenylmethoxycarbonyloxy)succinimide (Fmoc-Osu) dissolved
in THF (30 mL). After 48 h, water (40 mL) was added and the mix-
ture extracted with ether (5 ꢀ 30 mL). The pH value of the aqueous
phase was adjusted to 2–3 with aqueous HCl and extracted with
ethyl acetate (5 ꢀ 30 mL), while the organic layer containing the
(
ethyl acetate/petroleum ether = 1:2 (volume ratio)). The crude
products were extracted with ethyl acetate (4 ꢀ 1 mL) once the
reaction was completed, then the organic layers were dried (Na
SO ), vacuum filtered, concentrated and evaporated under reduced
2
-
4
2 4
target product was dried overnight with Na SO . Subsequently,
pressure. The crude products were purified by column chro-
matograph (eluted with ethyl acetate/petroleum ether (volume
ratio: 10:20) to yield desired aldol products.
the ethyl acetate was removed by decompression-evaporation to
obtain 2.7 g of a white solid powder. 1H NMR (400 MHz, CDCl
3
):
.68 (s, 1H), 7.75–7.73 (m, 1H), 7.60–7.57 (m, 1H), 7.42–7.36 (m,
9

G. Guo et al. / Tetrahedron: Asymmetry 27 (2016) 740–746
745
4
ne
.4.1. (S)-2-[(R)-Hydroxy(4-nitrophenyl)methyl] cyclohexano-
(major) and 33.28 min; 1H NMR (300 MHz, CDCl
5H), 1.91–2.21 (m, 1H), 2.26–2.49 (m,3H), 3.01–3.20 (br s, 1H),
3.88–3.92 (br s, 1H), 4.70–4.73 (d, J = 9 Hz, 1H), 5.29 (s, 1H),
6.96–7.00 (m, 2H), 7.20–7.23 (br s, 2H).
3
):1.41–1.87 (m,
5
c,8b
20
D 3
White powder; mp 129–130 °C; [a] = +12.8 (c 1.85, CHCl ).
Enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (n-hexane/isopropanol, volume ratio 92:8), flow rate
1
2
.0 mL/min, k = 268 nm;
9.86 min, t
(syn) = 22.99 min and 26.25 min (major); 1H NMR
): 8.20–8.24 (m, 2H), 7.48–7.54 (m, 2H), 4.90 (d,
J = 8.1 Hz, 1H), 4.09 (s, 1H), 2.32–2.64 (m, 3H), 2.08–2.16 (m, 1H),
t
R
(anti) = 40.25 min (major) and
.4.7. (S)-2-[(R)-Hydroxy(phenyl)methyl] cyclohexanone14a
Enantiomericexcess was determined by HPLC with a Chiralpak
4
R
(
300 MHz, CDCl
3
AS-H column (n-hexane/isopropanol = 95:5), flow rate 0.5 mL/
min, k = 221 nm; t (anti) = 40.79 min (major) and 43.94 min, t (-
syn) = 29.19 min and 37.08 min (major); NMR (300 MHz,
R
R
1
.82–1.86 (m, 1H), 1.35–1.73 (m, 4H).
1
H
CDCl3): d 1.40–1.22 (m,1H), 1.72–1.50 (m, 3H), 1.87–1.73 (m,
1H), 2.16–2.03 (m, 1H), 2.34 (td, J = 12.3, 5.4 Hz, 1H), 2.55–2.44
(m, 1H), 2.70–2.56 (m,1H), 4.00(m, 1H), 4.80 (d, J = 9.0 Hz, 1H),
7.39–7.28 (m, 5H).
4
ne
.4.2. (S)-2-[(R)-Hydroxy(2,4-nitrophenyl)methyl] cyclohexano-
5
c,8b
Yellow oil. Enantiomeric excess was determined by HPLC with a
Chiralpak AD-H column (n-hexane/isopropanol, volume ratio
9
3
2:8), flow rate 1.0 mL/min, k = 254 nm; t
9.37 min (major), t (syn) = 24.60 min and 32.95 min (major);
): 8.74–8.75 (d, J = 2.3 Hz, 1H), 8.45–8.49
d, J = 8.7 Hz, J = 2.4 Hz, 1H), 8.06–8.08 (d, J = 8.7 Hz, 1H), 6.05–
.06 (d, J = 1.9 Hz, 1H), 5.51–5.53 (br s, 1H), 2.73–2.77 (m, 1H),
.44–2.47 (m, 1H), 2.11–2.33 (m, 1H), 2.04–2.14 (m, 1H), 1.82–
.88 (m, 1H), 1.79–1.82 (m, 1H), 1.69–1.79 (m, 1H), 1.61–1.68
R
(anti) = 44.06 min and
.4.8. (2S,10R)-2-(Hydroxy-(4-tolyl)methyl) cyclohexanone1e
Enantiomericexcess was determined by HPLC with a Chiralpak
4
1
R
H
NMR (400 MHz, CDCl
(
6
2
1
3
AD-H column (n-hexane/isopropanol = 90:10), flow rate 0.5 mL/
min, k = 221 nm; t = 32.8 min (anti, major), t = 44.5 min (anti,
NMR(300 MHz, CDCl3): 7.18 (dd, 4H, J = 17.1,
.4 Hz), 4.75 (dd, 1H, J = 9.0, 2.7 Hz), 3.91 (d, 1H, J = 2.7 Hz), 2.66–
R
R
1
minor).
H
d
8
2
2
3
.54 (m, 1H), 2.51–2.43 (m, 1H), 2.35 (td, 1H, J = 13.2, 6.0 Hz),
.34 (s, 3H), 2.14–2.03(m, 1H), 1.82–1.72 (m, 1H), 1.70–1.50 (m,
H), 1.38–1.18 (m, 1H).
(
m, 1H).
4
ne
.4.3. (S)-2-[(R)-Hydroxy(2-nitrophenyl)methyl] cyclohexano-
5
c,8b
4
ne
.4.9. 2-[Hydroxyl(4-methoxyphenyl)-methyl] cyclohexano-
24
Yellow powder; mp 116–118 °C; [
a]
D
= +19.8 (c 1.60, CHCl
3
).
5c,8b
Enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (n-hexane/isopropanol, volume ratio 92:8), flow rate
White powder; mp 74–76 °C; [Daicel Chiralpak AD-H column,
n-hexane/isopropanol = 92: 8, flow rate 1.0 mL/min, k = 218 nm;
(anti) = 36.54 min and 29.20 min, t (syn) = 25.25 min (major)
and 21.15 min]; H NMR (300 MHz, CDCl ) d: 1.19–1.33 (m, 1H),
.48–1.81 (m, 4H), 2.05–2.13 (m, 1H), 2.31–2.64 (m, 3H), 3.80 (s,
1
.0 mL/min, k = 209 nm;
t
R
(anti) = 24.05 min and 22.53 min
t
R
R
1
(
(
(
major); H NMR (300 MHz, CDCl ): 7.84 (d, J = 7.8 Hz, 1H), 7.77
d, J = 7.8 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.40–7.46 (m, 1H), 5.44
d, J = 7.2 Hz, 1H), 4.11 (br, 1H), 2.73–2.81 (m, 1H), 2.29–2.48 (m,
3
1
3
1
3
7
H), 3.92 (s, 1H), 4.74 (d, J = 8.7 Hz, 1H), 6.86–6.90 (m, 2H), 7.22–
.26 (m, 2H).
2
H), 2.04–2.14 (m, 1H), 1.55–1.86 (m, 5H).
4
ne
.4.4. (S)-2-[(R)-Hydroxy(3-nitrophenyl)methyl] cyclohexano-
5
c,8b
4.4.10. (S)-2-[(R)-hydroxyl(4-nitrophenyl)methyl] cyclopentan-
5
c
24
one
Light yellow powder; mp 88–90 °C; [
CHCl ). Enantiomeric excess was determined by HPLC with a Chi-
ralpak AD-H column (n-hexane/isopropanol = 90:10), 1.0 mL/min,
k = 254 nm; t (anti) = 23.94 min (major) and 23.06 min, t (syn)
13.95 min and 18.04 min (major); H NMR (300 MHz, CDCl ): d
D 3
White powder; mp 69–71 °C; [a] = +32.5 (c 1.35, CHCl ).
2
2
a]
D
= ꢁ30.6 (c 0.56,
Enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (n-hexane/isopropanol, volume ratio 92:8), flow rate
3
1
.0 mL/min, k = 263 nm;
major), (syn) = 23.10 min (major) and 22.08 min;
300 MHz, CDCl ): 8.15–8.22 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.53
t, J = 7.8 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.14 (d, J = 2.4 Hz, 1H),
R
t (anti) = 33.94 min and 26.05 min
1
R
R
(
(
(
t
R
H NMR
1
=
8
2
3
3
.20–8.24 (m, 2H), 7.51–7.56 (m, 2H), 4.78–5.43 (m, 1H), 1.52–
.62 (m, 7H).
2
1
.58–2.67 (m, 1H), 2.32–2.54 (m, 2H), 2.09–2.16 (m, 1H), 1.82–
.86 (m, 1H), 1.36–1.71 (m, 4H).
4
one
.4.11. (S)-2-[(R)-Hydroxyl(2-nitrophenyl)methyl] cyclopentan-
5
c
4
ne
.4.5. (S)-2-[(R)-Hydroxy(4-cyanophenyl)methyl] cyclohexano-
5
c,8b
Enantiomeric excess was determined by HPLC with a Chiralpak
AS-H column (n-hexane/IPA, volume ratio 95:5), flow rate 1.0 mL/
22
D 3
White powder; mp 82–83 °C; [a] = +23.3 (c 1.55, CHCl ).
min, k = 225 nm; t
syn) = 22.75 and 36.83 min (major); H NMR (CDCl
R
(anti) = 28.22 min (major) and 31.09 min, t
R
(-
Enantiomeric excess was determined by HPLC with a Chiralpak
AD-H column (n-hexane/isopropanol, volume ratio 92:8), flow rate
1
3
, 300 MHz) d:
7
5
.78 ꢂ 7.81 (m, 2H), 7.59 ꢂ 7.72 (m, 1H), 7.38 ꢂ 7.57 (m, 1H),
.89 ꢂ 5.90 (d, J = 3 Hz, 1H), 5.41 ꢂ 5.44 (d, J = 8.4 Hz, 1H), 4.50
1
3
.0 mL/min, k = 267 nm;
1.98 min, t
(syn) = 23.20 min and 27.33 min (major); 1H NMR
): 7.65 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H),
.84 (d, J = 8.4 Hz, 1H), 4.07 (s, 1H), 2.47–2.62 (m, 2H), 2.31–2.41
m, 1H), 2.08–2.15 (m, 1H), 1.81–1.83 (m, 1H), 1.49–1.73 (m,
R
t (anti) = 40.88 min (major) and
R
(
(
2
1
br s, 1H), 2.65 ꢂ 2.85 (m, 1H), 2.26 ꢂ 2.60 (m, 2H), 1.95 ꢂ 2.26
(
300 MHz, CDCl
3
13
m, 2H), 1.69 ꢂ 1.8 (m, 2H); C NMR (CDCl
3
, 300 MHz): d 20.1,
0.4, 22.8, 26.5, 38.6, 54.7, 55.3, 66.4, 69.0, 123.9, 124.4, 127.9,
28.5, 128.6, 128.9, 133.1, 133.3, 138.6, 146.9, 219.1.
4
(
3
H), 1.32–1.41 (m, 1H).
0
2d,5d
4
ne
.4.6. (S)-2-[(R)-Hydroxy(4-fluorophenyl)methyl] cyclohexano-
4.4.12. 4-Hydroxyl-4-(4 -nitrophenyl)-butan-2-one
5
c,8b
[Daicel Chiralpak AS-H column, n-hexane/isopropanol = 70:30,
flow rate 1.0 mL/min, flow rate 1.0 mL/min, k = 254 nm; t (anti)
= 15.39 min and 12.08 min(major)]; H NMR (300 MHz, CDCl ) d:
2
2
[a]
D
= +27.5 (c 0.35, CHCl
3
). Enantiomeric excess was deter-
R
1
mined by HPLC with a Chiralpak AD-H column (n-hexane/iso-
3
propanol, volume ratio 90:10), flow rate 0.3 mL/min; k = 208 nm;
2.21 (s, 3H), 2.80–2.85 (m,2H), 3.56 (br s, 1H), 5.20–5.30 (m, 1H),
t
R
(anti) = 49.15 min and 44.19 min (major), t
R
(syn) = 29.38 min
7.52 (d, J = 7.0 Hz, 2H), 8.20 (d, J = 7.0 Hz, 2H).

7
46
G. Guo et al. / Tetrahedron: Asymmetry 27 (2016) 740–746
0
2d,5d
4
.4.13. 4-Hydroxyl-4-(3 -nitrophenyl)-butan-2-one
[
8. (a) Ding, K. J.; Uozomi, F. J. K. Handbook of Asymmetric Heterogeneous Catalysts;
Wiley-VCH: Weinheim, 2008; (b)Recoverable and Recyclable Catalysts; Benaglia,
M., Ed.; John Wiley and Sons Ltd., 2009; (c) Haraguchi, N.; Itsuno, S. Polymeric
Chiral Catalyst Design and Chiral Polymer Synthesis; John Wiley & Sons, 2011; (d)
Itsuno, S.; Parvez, M. M.; Haraguchi, N. Polym. Chem. 2011, 2, 1942–1949; (e) Li,
J.; Yang, G. X.; Qin, Y. Y.; Yang, X. R.; Cui, Y. C. Tetrahedron: Asymmetry 2011, 22,
Daicel Chiralpak AS-H column, n-hexane/isopropanol = 70:30,
flow rate 1.0 mL/min, k = 254 nm; t = 11.37 min and 9.74 min(ma-
jor)]; H NMR (300 MHz, CDCl3) d: 2.23 (s, 3H), 2.82 (m, 2H), 3.50
br s, 1H), 5.15–5.27 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.71 (d,
R
1
(
613–618; (f) KochetKov, S. V.; Kucherenko, A. S.; Kryshtal, G. V.; Zhdankina, G.
J = 7.5 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.24 (s, 1H).
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(a) Hong, G. J.; Yong, Q. S.; Li, Q. M.; Wang, Y.-Z.; Zang, Y.; Peng, J.-J. Chem.
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