Enhanced activity and stereoselectivity of polystyrene-supported prolinebased organic catalysts for direct asymmetric aldol reaction in water

Article abstract of DOI:10.1002/ejoc.200900829

Several polystyrene-supported proline dipeptides and a prolinamide derivative were prepared by thiol-ene coupling. These materials were used as catalysts for the direct asymmetric aldol reaction in water, and results compared with unsupported catalysts in

Full text of DOI:10.1002/ejoc.200900829

FULL PAPER
DOI: 10.1002/ejoc.200900829
Enhanced Activity and Stereoselectivity of Polystyrene-Supported Proline-
Based Organic Catalysts for Direct Asymmetric Aldol Reaction in Water
Michelangelo Gruttadauria,*[a] Anna Maria Pia Salvo,[a] Francesco Giacalone,[a]
Paola Agrigento,[a] and Renato Noto[a]
Keywords: Peptides / Organocatalysis / Amino acids / Supported catalysts / Solid-phase synthesis
Several polystyrene-supported proline dipeptides and a pro-
linamide derivative were prepared by thiol–ene coupling.
These materials were used as catalysts for the direct asym-
metric aldol reaction in water, and results compared with un-
supported catalysts in water. Such an approach gave more
active or stereoselective catalysts compared to the unsup-
ported compounds, showing that our immobilization pro-
cedure may be useful to develop catalytic materials with en-
hanced performance. Moreover, these catalysts can be reco-
vered and reused for at least nine times without loss of ac-
tivity or can be easily regenerated when their activity has
decreased.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
tages such as safety and economy. Since several years many
researchers have examined the use of catalysts based on
amino acids for asymmetric reactions in water.[6] Looking
at the proline-catalyzed aldol reactions, it could be seen that
immobilized proline on highly hydrophobic supports, such
as a polystyrene backbone, furnished excellent results in
terms of yield and stereoselectivity if compared to native
proline under aqueous conditions.[7] These are not trivial
examples of how immobilization can give more active and
selective catalysts. Moreover, as stated before, immobiliza-
tion on insoluble supports allows recovery and recycling of
organic catalysts, thus counterbalancing the higher cost of
the immobilization procedure. In this context, we have re-
ported that supported prolinamides 1 and 2 (Figure 1) gave
excellent results[8] compared to the unsupported catalysts,
although used in higher quantities (10 mol-%) compared to
the unsupported catalysts (down to 0.5 mol-%).[9] Indeed,
we obtained high stereoselectivities without the need of per-
forming the reaction at low temperature (–40 °C in CHCl3,
and –5/–10 °C in brine).[9]
Introduction
Immobilization and recycling of asymmetric catalysts is
of current interest and many efforts have been devoted both
to organic catalysts and metal-based catalysts.[1] Polymeric
materials are widely used in organic synthesis and cataly-
sis.[2] During the last years we have been involved in re-
search regarding immobilization and recycling of organic
catalysts such as proline and proline derivatives[3] and their
use under aqueous conditions.[4] Indeed, water plays an im-
portant role both when used with nonsupported or sup-
ported catalysts. One of the most important challenges with
catalyst immobilization is to retain the activity and stereo-
selectivity of the immobilized catalysts. Usually, perform-
ances similar to homogeneous catalysts can be reached, but
sometimes lower activity and stereoselectivity are observed
in the first cycle or after a few cycles.[1] Moreover, another
important aspect of immobilized catalysts is the separation,
which should be achieved by a simple operation such as
filtration. For these reasons, immobilization of organic cat-
alysts on insoluble supports can give very useful catalytic
materials to be used in highly stereoselective transforma-
tions such as the aldol reaction, one of the most powerful
carbon–carbon bond-forming reactions.[5] Even if the mere
use of water does not make a reaction “green” because of
the necessity of disposal or clean up of the aqueous waste,
its use can result in higher activities of catalysts and more
stereoselective transformations, in addition to other advan-
[a] Dipartimento di Chimica Organica “E. Paternò”, Università di
Palermo,
Viale delle Scienze s/n, Ed. 17, 90128 Palermo, Italy
Fax: +39-091-566825
E-mail: mgrutt@unipa.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900829.
Figure 1. Supported prolinamides 1 and 2.
Eur. J. Org. Chem. 2009, 5437–5444
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Gruttadauria et al.
FULL PAPER
Encouraged by these results we wondered if our immobi-
lization procedure would provide more active and stereose-
lective catalysts. The synthetic strategy we are currently
using is very simple and relies on a thiol–ene coupling
(TEC) reaction between a preformed commercially avail-
able mercaptomethyl–polystyrene resin and an organic cata-
lyst bearing a styrene linker. The importance of the TEC
reaction as a click process for materials and bioorganic
chemistry has been recently highlighted.[10]
Results and Discussion
Supported catalysts were prepared as outlined in
Scheme 1. First, the styrene derivative of N-Boc-protected
trans-4-hydroxy--proline 4 was prepared.[7b] This com-
pound was used as a starting material for generating molec-
ular diversity (Figure 3). Indeed, compound 4 can be used
to obtain polystyrene-supported proline, prolinamides, and
proline-based dipeptides through immobilization on a pre-
formed resin (Figure 3, routes a–d) or could be used as a
monomer for the synthesis of functionalized polystyrene
resins (Figure 3, route e). Very recently, this approach was
developed by using other 4-substituted-hydroxy -proline
derivatives as monomers.[20,21] In the present work a series
of dipeptides 5a–h was obtained by reaction with the proper
amino ester in the presence of triethylamine and ethyl chlo-
roformate in dichloromethane. In the same way, prolinam-
ide 7 was also prepared. In our case we anchored styrene
derivatives 5a–h and 7 on a preformed polystyrene resin.
Immobilization was carried out by using the thiol–ene cou-
pling reaction between a mercaptomethyl polymer-bound
(1% cross-linked with DVB, spherical beads, particle size
100–200 mesh, 2.5 mmolg–1 loading) and the styrene deriv-
ative of protected dipeptides 5a–h.
Then, we looked at the literature, searching for some or-
ganic catalysts that need additives or low temperatures to
reach a good yield and level of stereoselectivity in order to
investigate if the corresponding supported catalysts may be
more active and/or stereoselective. We focused our attention
on small peptide-[11] and prolinamide-based[12] organocata-
lysts for aldol reactions carried out in the presence of
water.[13,14] Several small peptides have also been immobi-
lized on insoluble supports such as polystyrene or silica in
order to get easily recyclable catalytic materials.[15] In con-
trast, simple polystyrene-supported prolinamides have been
very scarcely investigated.[7a,8a] Recently, few examples have
regarded the use of prolinamide dendrons.[16] Among the
unsupported organocatalysts, it has been reported that sev-
eral -proline-based dipeptides have been used in the aldol
reaction between cyclohexanone and several aromatic alde-
hydes; the dipeptide -Pro--Trp was the most promising
(Figure 2).[17,18] Extensive studies on reaction conditions
showed that the presence of a base and a surfactant was
essential for the success of the reaction. Usually, NMM/
SDS or DABCO/PEG400 were employed as additive, and
the reactions were carried out in water at 0 °C. Our idea was
that immobilization may avoid the use of such additives.
In order to expand this investigation, and considering that
polystyrene-supported prolinamides have not been exten-
sively investigated, we also studied prolinamide 3 (Figure 2)
as catalyst for the aldol reaction in water. Also, in this case,
we compared such catalyst with the corresponding sup-
ported catalyst, immobilized by using our procedure. Re-
cently, prolinamide 3 was tested as a catalyst for the aldol
reaction between cyclohexanone and 4-nitrobenzaldehyde
under solvent-free conditions.[19]
Figure 2. -Pro--Trp and prolinamide 3.
Scheme 1. Synthesis of supported dipeptides 6a–h and prolinamide
8. Reagents and conditions: (i) 4-vinylbenzyl chloride, NaH, 18-
crown-6, THF, 50 °C, 80%; (ii) ethyl chloroformate, triethylamine,
RNH2, CH2Cl2, 0 °C to r.t., overnight; (iii) mercaptomethyl poly-
mer-bound, AIBN, toluene, 110 °C, 24 h; (iv) LiOH, THF/H2O,
r.t., 24 h; (v) trifluoroacetic acid, CH2Cl2, r.t., 24 h then THF/Et3N,
98:2. See Table 1 for R1 and R2.
Here we report the results obtained in the aldol reaction
performed in water as a reaction medium in the presence of
several polystyrene-supported proline derivatives. The main
aim of this research was to show that immobilization may
Usually, 3 equivalents of compound 5 were employed,
furnish more highly active and/or stereoselective catalysts but the excess amount was easily recovered after the reac-
compared to the unsupported catalysts.
tion.[22] Deprotection of the ester group was carried out by
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Polystyrene-Supported Proline-Based Organic Catalysts
served by us and an explanation was given.[7b,8a] Also, the
presence of the free carboxylic acid group plays an impor-
tant role. For instance, when catalysts were obtained after
mild deprotection with a slight excess amount of LiOH, the
aldol products were obtained with lower optical purity with
respect to when we deprotected the ester group with a large
excess of LiOH. As an example, catalysts 6g and 6h, not
fully hydrolyzed, gave the aldol product in 54 and 66%ee,
respectively (Table 2, Entries 23 and 26). When the catalysts
were fully hydrolyzed, the ee values increased up to 65 and
80%, respectively. Such a result showed that the excess
amount of LiOH was needed to fully hydrolyze the ester
function and also that the COOH group plays a role in the
stereochemical outcome of the reaction, even in the immo-
bilized catalysts.
Table 2. Screening of catalysts 6a–h (20 mol-%) in the direct asym-
metric aldol reaction between cyclohexanone and 4-nitrobenzalde-
hyde in the presence of water and recycling studies.[a]
Figure 3. Different routes for proline-based organocatalysts immo-
bilization.
treatment with an excess amount of LiOH in THF/H2O.
Removal of the tert-butoxycarbonyl group was carried out
with TFA/CH2Cl2 (20:80), followed by treatment with
Et3N/THF (2:98). Following this procedure, catalysts 6a–h
were prepared (Table 1). Dipeptide loadings, determined by
weight gain, were found to be ca. 0.7–1 mmolg–1; catalyst
6f had the highest loading (1.38 mmolg–1). Compound 8
was also prepared (0.92 mmolg–1) by using the same strat-
egy.
Entry Catalyst Cycle Solvent
Conv. Yield[b] anti/syn[c] ee[d]
[%]
[%]
[%]
1
6a
6a
6a
6a
6b
6b
6b
6c
6c
6c
6d
6d
6d
6d
6d
6e
6e
6e
6e
6f
1
4
1
2
1
4
1
1
4
1
1
2
3
4
1
1
4
1
2
1
4
1
1
1
4
1
1
4
H2O
H2O
Ͼ99
Ͼ99
45
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
–
95
94
41
97
96
96
93
98
96
–
81:19
82:18
84:16
68:32
83:17
83:17
79:21
83:17
83:17
–
66
64
70
58
72
71
54
94
76
–
2
3
4
5
CHCl3
DMSO
H2O
6
H2O
Table 1. Catalysts 6a–h used in this work.
7
8
CHCl3
H2O
9
H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23[e]
24
25
26[e]
27
28
CHCl3
H2O
H2O
H2O
H2O
CHCl3
H2O
H2O
CHCl3
DMSO
H2O
H2O
CHCl3
H2O
H2O
H2O
H2O
H2O
H2O
99
94
95
95
95
nd
98
98
33
97
97
97
–
83:17
86:14
85:15
86:14
77:23
84:16
84:16
83:17
73:27
91:9
78
90
85
93
nd
75
84
60
78
86
85
–
Ͼ99
Ͼ99
Ͼ99
5
Ͼ99
Ͼ99
39
Ͼ99
Ͼ99
Ͼ99
–
6f
6f
91:9
–
6g
6g
6g
6h
6h
6h
Ͼ99
98
99
Ͼ99
95
98
96
94
94
95
89
92
83:17
82:18
84:16
83:17
87:13
85:15
54
65
52
66
80
74
[a] Reaction conditions: cyclohexanone (260 µL, 2.5 mmol), alde-
hyde (0.5 mmol), catalyst (0.1 mmol), H2O (200 µL) at room tem-
perature. [b] Isolated yield. [c] Determined by 1H NMR spectro-
scopic analysis of the crude product. [d] Diastereoisomer (anti) de-
termined by HPLC by using a chiral column. [e] Catalyst contain-
With catalytic materials 6a–h in hand we started our in- ing ester function not fully hydrolyzed.
vestigation by carrying out the reaction between cyclohexa-
none and 4-nitrobenzaldehyde. First we checked the role of
In order to test the recyclability of our catalytic materi-
water. When catalysts 6a–h were used under neat conditions als, recycling studies were carried out even when ee values
no reaction took place. Such results were previously ob- were not high. Catalyst 6a gave reproducible results after
Eur. J. Org. Chem. 2009, 5437–5444
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. Gruttadauria et al.
FULL PAPER
four cycles when employed in water: quantitative yields and used in organic solvent gave a decreased enantioselectivity
about 4:1 diastereomeric ratio were observed, but the ee when the -Phe unit was used. On the contrary, our sup-
values were not high (Table 2, Entries 1 and 2). Similar ported catalyst gave better performances with the -Phe
stereoselectivities were obtained in CHCl3, but the conver- configuration.
sion was lower (Table 2, Entry 3), whereas a quantitative
In Table 3 we reported data obtained by using catalyst 6f
yield but a lower stereoselectivity was obtained in DMSO along with the recycling investigation performed with the
(Table 2, Entry 4). These preliminary data seem to indicate same catalyst. With the only exception of the reaction per-
the superior outcome given by water. Also, catalyst 6b was formed with the use of cyclopentanone, which gave the al-
successfully used for four cycles with unchanged results and dol product with low stereoselectivity (Table 3, Entry 5), in
a slightly better enantioselectivity compared to 6a (Table 2, all other cases yields from moderate to high, high diastereo-
Entries 5 and 6). With this catalyst a quantitative conver- selectivity (Ͼ90:10), and good to high enantioselectivity
sion was observed in CHCl3, but the stereoselectivity was were obtained. Moreover, it is worthy to note that this ma-
not good (Table 2, Entry 7). High enantioselectivity was ob- terial was used up to nine times. In the last run, we carried
served with catalyst 6c; however, after four cycles, although out again the reaction with 4-bromobenzaldehyde, repro-
the yield was still quantitative, a decreased ee value was ducing the result obtained in the sixth cycle. A comparison
obtained, whereas the diastereomeric ratio was unaffected with several data obtained by using dipeptide -Pro--Trp
(Table 2, Entries 8 and 9). No reaction took place in CHCl3 in the presence of base/surfactant at 0 °C under homogen-
(Table 2, Entry 10). Catalyst 6d gave also quantitative con- eous conditions[17] showed comparable stereoselectivities
version after four cycles with unchanged diastereoselectiv- (Table 3, Entries 1, 4, and 7).
ity, whereas the ee values ranged from 78 to 95% randomly
(Table 2, Entries 11–14). Also, in this case, CHCl3 gave a
Table 3. Direct asymmetric aldol reaction between cyclohexanone
or cyclopentanone and aldehydes in the presence of water catalyzed
poor conversion. Catalyst 6e showed a similar behaviour
compared to that of 6a. Again, water gave better results
in terms of conversion and stereoselectivity with respect to
CHCl3 and DMSO and a small increase in enantio-
selectivity was observed after four cycles (Table 2, En-
tries 16 and 17). Catalyst 6f behaved differently, giving en-
hanced diastereoselectivity and reproducible ee values after
four cycles (Table 2, Entries 20 and 21), whereas no reaction
was observed in CHCl3. Catalysts 6g gave low enantio-
selectivity, which decreased after four cycles (Table 2, En-
tries 24 and 25). Catalyst 6h, having opposite configuration
at carbon atom α to the phenylglycine unit, gave higher
enantioselectivity even after four cycles (Table 2, Entries 27
and 28). These data showed that water was a better reaction
medium compared to DMSO, which gave lower stereoselec-
tivities, and to CHCl3, which gave low yields in many cases.
Our catalytic systems were much more reactive compared
to the unsupported dipeptides,[17] as we did not need to use
additives such as a combination of base and surfactant. For
instance, a comparison with the catalyst -Pro--Phe[18]
showed that our catalytic system was much more reactive
and stereoselective when used in water, whereas in DMSO
a decreased ee value was observed. On the whole, better
performances were obtained with -phenylalanine deriva-
tive 6f. -Tryptophan derivative 6d, which gave good per-
formances under homogeneous condition,[17] gave good,
but irreproducible, results. Then, we decided to perform ad-
ditional experiments, employing different aldehydes with
catalyst 6f. Interestingly, by comparing the data from
by resin 6f (20 mol-%) and recycling studies.[a]
Entry Cycle
Compound
Conv.
[%]
Yield[b] anti/syn[c] ee[d]
[%]
[%]
1
1
n = 1; R = 4-CN
Ͼ99
98
94[e]
91
93:7
93:7[e]
94:6
93:7
94:6
86
85[e]
99
2
3
4
2
3
4
n = 1; R = 4-CF3
n = 1; R = 4-Cl
n = 1; R = 3-NO2
94
83
84
79
81
87
81
89[e]
94
90:10[e] 80[e]
5
6
7
5
6
7
n = 0; R = 4-CF3
n = 1; R = 4-Br
n = 1; R = 2-NO2
97
69
95
50:50
91:9
64
87
63
91
97:3
90
88[e]
34
Ͼ99:1[e]
93:7
89[e]
90
8
9
8
9
n = 1; R = 3-
OCH3
n = 1; R = 4-Br
40
69
65
92:8
87
[a] Reaction conditions: ketone (2.5 mmol), aldehyde (0.5 mmol),
catalyst (0.1 mmol), H2O (200 µL) at room temperature. [b] Iso-
lated yield. [c] Determined by 1H NMR spectroscopic analysis of
the crude product. [d] Diastereoisomer (anti) determined by HPLC
by using a chiral column. [e] Data from ref.[17] with the use of -
Pro--Trp.
Because good results were obtained with the use of cata-
Table 2 we can argue that both the nature of the R group lyst 6f, which has the  configuration in the phenylalanine
at the α-carbon and the configuration at the same carbon moiety, we wondered if also an inversion of configuration
atom play a role in the stereochemical outcome of the reac- at C-4 of the -proline unit may have a role in the stereo-
tion, but the key role is played by the C-α configuration of chemical outcome of the reaction.[25] In order to study this
the proline unit. Such role has been recently reported in role, we prepared catalyst 9 and checked it in the aldol reac-
proline-based dipeptides amides as catalysts for aldol reac- tion (Figure 4). Although diastereoselectivities were high
tions in CHCl3.[23] Sulfonamides of -Pro--Phe and -Pro- (94:6 anti/syn), the ee values were lower than the supported
-Phe[24] and dipeptides -Pro--Phe and -Pro--Phe[18] trans-4-hydroxy--proline.[7b] Because of this deleterious ef-
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Polystyrene-Supported Proline-Based Organic Catalysts
fect caused by the C-4 configuration, we decided that the unsupported catalyst 3. The reaction carried out with the
synthesis of supported dipeptides based on the cis-4-hy- use of resin 8 in 20 mol-% under neat conditions was, as
droxy--proline was, in this case, useless.
expected, unsuccessful (Table 5, Entry 4). By maintaining
the same catalyst loading, we checked the reaction in the
presence of different amounts of water (Table 5, Entries 5
and 6). No appreciable differences were observed. This cata-
lyst was used for a further three cycles with unchanged re-
sults (Table 5, Entries 7–9). Similar results were obtained
when resin 8 was used in lower amount (10 mol-%); how-
ever, in the third and fourth cycle a decreased conversion
was observed (Table 5, Entries 11 and 12). The diminished
activity could be ascribed to the formation of the corre-
sponding imidazolidinone.[8b] In order to regenerate resin 8,
it was treated with formic acid at room temperature for
2.5 h.[27] After this treatment the catalytic activity was re-
stored (Table 5, Entry 13). It is interesting to note that pro-
line-based dipeptides were used up to nine cycles without
the need for regeneration. This result could be ascribed to
the higher acidity of these catalysts compared to that of 8.
Supported catalyst 8 was more stereoselective with respect
to 3 used under solvent-free conditions.[19]
Figure 4. Polystyrene-supported cis-4-hydroxy--proline 9 and ee
values of aldol products obtained by using 9.
Then, we turned our attention to prolinamide 3. Because
this compound was not investigated for the aldol reaction
in water, we carried out several reactions. First, we per-
formed the reaction between cyclohexanone and 4-ni-
trobenzaldehyde by using the same conditions as those used
for the dipeptides (aldehyde/cyclohexanone, 5:1; H2O
200 µL) and by using only 5 mol-% of catalyst 3. The con-
version was good; however, the ee value was poor (Table 4,
Entry 1). Increasing the amount of catalyst resulted in an
even lower ee value (Table 4, Entries 2 and 3). Reactions
carried out under neat conditions[26] or in chloroform gave
also poor enantioselectivity (Table 4, Entries 4 and 5). The
minor syn diastereoisomer gave a slightly better enantio-
selectivity. A comparison with the literature datum showed
that water and CHCl3 had a detrimental effect on the stere-
oselectivity of the reaction.[19] After these preliminary data,
we carried out several reactions by using supported catalyst
8.
Table 5. Direct asymmetric aldol reaction between cyclohexanone
and 4-nitrobenzaldehydes in the presence of water catalyzed by
resin 8.[a]
Entry Cycle Cat. loading H2O
Conv.
[%]
Yield[b] anti/syn[c] ee[d]
[mol-%]
[µL]
[%]
[%]
1
2
3
4
5
6
7
8
1
1
1
1
2
1
2
3
4
2
3
4
5
1
5
200
200
200
0
96
Ͼ99
Ͼ99
–
93
98
98
–
87:13
86:14
84:16
–
79
78
76
–
Table 4. Direct asymmetric aldol reaction between cyclohexanone
and 4-nitrobenzaldehydes in the presence of water catalyzed by pro-
linamide 3.[a]
10
20
20
20
20
20
20
20
10
10
10
10
20
9[e]
96
92
97
98
97
93
89
70
78
94
–
82:18
83:17
86:14
86:14
87:13
89:11
88:12
88:12
85:15
–
71
72
79
83
81
82
83
86
82
–
300
200
200
200
200
200
200
200
200
Ͼ99
Ͼ99
Ͼ99
97
94
73
85
97
Ͻ5
9
10
11
12
13[f]
14[g]
Entry Catalyst loading
[mol-%]
H2O
[µL]
Conv.[b] anti/syn[c] ee[d] anti ee[d] syn
[%]
[%]
[%]
1
2
3
5
10
20
20
20
200
200
200
0
85
99
Ͼ99
99
81:19
78:22
78:22
65:35
72:28
22
15
10
32
24
52
48
37
47
49
[a] Reaction conditions: cyclohexanone (260 µL, 2.5 mmol), alde-
hyde (0.5 mmol), catalyst, H2O at room temperature. [b] Isolated
yield. [c] Determined by 1H NMR spectroscopic analysis of the
crude product. [d] Diastereoisomer (anti) determined by HPLC by
using a chiral column. [e] 1 equiv. [f] After regeneration with
HCOOH. [g] CHCl3 as solvent.
4
5[e]
200
80
[a] Reaction conditions: cyclohexanone (260 µL, 2.5 mmol), alde-
hyde (0.5 mmol), catalyst, H2O at room temperature. [b] Yield at
Ն95% conversion. [c] Determined by 1H NMR spectroscopic
analysis of the crude product. [d] Determined by HPLC by using a
chiral column. [e] CHCl3 as solvent.
These data showed that unsupported prolinamide 3 was
not a good catalyst for the asymmetric aldol reaction and
it was sensitive to the amount of water with respect to the
When resin 8 was employed in 5–20 mol-% with water we amount of catalyst. Immobilization of catalyst 3 on a poly-
obtained a high yield and good enantioselectivity (Table 5, styrene backbone resulted in a strong increase in enantio-
Entries 1–3). It is worthy to note that, in each case, the selectivity. Moreover, the optical purity of the anti com-
enantioselectivity was much higher than that observed with pound was independent from the water/catalyst ratio. In or-
Eur. J. Org. Chem. 2009, 5437–5444
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M. Gruttadauria et al.
FULL PAPER
Table 6. Direct asymmetric aldol reaction between cyclohexanone and aldehydes in the presence of water catalyzed by resin 8 or prolinam-
ide 3.[a]
Entry
R
Cycle
8
3
Conv.[b] [%]
anti/syn[c]
ee[d] [%]
Conv.[b] [%]
anti/syn[c]
ee[d] [%]
1
2
3
4
5
4-CN
4-Br
2-NO2
3-NO2
3-NO2
2
3
4
98
60
98
31
99
81:19
89:11
84:16
82:18
81:19
81
78
78
75
75
99
62
99
99
56:44
79:21
68:32
72:28
41
38
42
12
5
6[e]
[a] Reaction conditions: cyclohexanone (260 µL, 2.5 mmol), aldehyde (0.5 mmol), catalyst (20 mol-%), H2O (200 µL) at room temperature.
1
[b] Yield at Ն95% conversion. [c] Determined by H NMR spectroscopic analysis of the crude product. [d] Diastereoisomer (anti) deter-
mined by HPLC by using a chiral column. [e] After regeneration with HCOOH.
der to test resin 8 with other substrates, we carried out a least six times without loss of stereoselectivity. Moreover,
set of reactions with four different aldehydes. Again, resin as soon as decreased activity is observed after several cycles,
8 appeared much more stereoselective than catalyst 3. As a the activity of such catalytic materials can easily be restored
matter of fact, the ee values increased from 12–42 to 75– by simple treatment with formic acid.
81% without the use of additives (Table 6). A decreased
In conclusion, we showed that immobilization of the
conversion was observed with resin 8 in the fifth cycle. proper organic catalyst, such as dipeptides or prolinamides,
Treatment with HCOOH fully restored its activity without may afford more active and/or stereoselective organic cata-
affecting the stereoselectivity (Table 6, Entry 5). The higher lysts when employed in water as reaction medium compared
stereoselectivity obtained with resin 8 could be attributed to to the corresponding unsupported catalysts, although the
the higher hydrophobicity of the catalyst. The polystyrene ee values of the aldol products are not excellent. Particu-
backbone plays two roles: it enables the recovery and acts larly, the data collected for polystyrene-supported prolin-
as a large apolar substituent, as in nonsupported proline amides in this work and in our previous work[8] indicate
derivatives carrying large apolar substituents in the C-4 po- that their immobilization furnishes catalytic materials with
sition.[25,28]
comparable or better activity than those observed for un-
supported catalysts in water. Studies are in progress to fur-
ther develop and optimize this procedure, not only for the
aldol reaction, but for other reactions as well.
Conclusions
The strategy based on TEC reaction is a very simple pro-
cedure that allows the preparation of a wide range of useful
materials that can be successfully used in water as reaction
medium. This approach can be applied to a variety of styr-
ene derivatives of organic catalysts. In this context, styr-
ene–proline derivative 4 proved its potential as a starting
material for molecular diversity. Supported proline-based
Experimental Section
General Procedures: NMR spectra were recorded with a Bruker
300 MHz spectrometer in CDCl3 as solvent. FTIR spectra were
recorded with a Shimadzu FTIR 8300 infrared spectrophotometer.
Carbon and nitrogen contents were determined by combustion
dipeptides showed enhanced activity compared to the un- analysis with a Fisons EA 1108 elemental analyzer. Optical rota-
tions were measured in chloroform with a Jasco P1010 polarimeter.
Chiral HPLC analyses were performed with a Shimadzu LC-10AD
apparatus equipped with a SPD-M10A UV detector and Daicel
columns (OD-H, AD-H, AS-H, 4.6 mmϫ250 mm) with hexane/
isopropyl alcohol as the eluent. Aldol products are known com-
pounds and showed spectroscopic and analytical data in agreement
with their structures.[8a,9b,12o] The anti/syn ratios were determined
by analysis of the 1H NMR spectra of the crude reaction mixtures;
ee values were determined by HPLC chromatograms of the crude
reaction mixtures.[8a,9b,12o]
supported catalysts. Indeed, thanks to the hydrophobic
backbone, there is no need for additives such as a combina-
tion of base and surfactant. Moreover, good to high yields
and stereoselectivities were obtained working at room tem-
perature without the need for lower temperatures. The cata-
lysts can easily be reused over several cycles (so far up to
nine). Furthermore, the proline C-4 configuration and the
C-α configuration of the second amino acid played a role
in determining the ee value of the aldol adducts but did not
determine the configuration of the final products.
Typical Procedure for the Synthesis of Compounds 5a–h and 7: Tri-
ethylamine (344 µL, 2.44 mmol) was slowly added to a solution of
acid 5 (0.85 g, 2.44 mmol) in CH2Cl2 (9 mL) at 0 °C. Ethyl chloro-
formate (238 µL, 2.44 mmol) was added dropwise, and the solution
was stirred at the same temperature for 15 min. Then, the proper
Supported prolinamide 8 is much more stereoselective
than unsupported prolinamide 3. Resin 8 provides a power-
ful increase in enantioselectivity and a good increase in dia-
stereoselectivity, its use is less dependent on the amount of
water. Again, this resin can be recovered and reused for at amino ester or (1S,2R)-(–)-cis-1-amino-2-indanol (2.44 mmol) was
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Eur. J. Org. Chem. 2009, 5437–5444

Polystyrene-Supported Proline-Based Organic Catalysts
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ethyl acetate, 3:1–2:1).
Typical Procedure for the Synthesis of Polystyrene-Supported Dipep-
[3]
[4]
[5]
[6]
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tides 6a–h and
L-Prolinamide 8: (Mercaptomethyl)–polystyrene
(286 mg, 0.72 mmol) was added to a degassed solution of styrene
derivative 5a–h or 7 (2.15 mmol) and AIBN (7.5 mg, 2 mol-%) in
toluene (17 mL). The mixture was stirred at 110 °C overnight under
an atmosphere of argon. After cooling to room temperature, the
resin was filtered and washed with dichloromethane. A yellow resin
was obtained. From the weight increase the amount of monomer
that was covalently attached to the resin was calculated. The
dichloromethane solution was evaporated under reduced pressure
to recover the unreacted styrene derivative, which was then purified
by column chromatography (recovery 90%). The resin was sus-
pended in THF and an aqueous solution of LiOH (5 ). Typical
amounts were, for 4.13 mmol of anchored catalyst, THF (19 mL)
and LiOH (13.8 mL). The suspension was stirred for 24 h. After
this time, the resin was filtered under vacuum, and it was then
washed with an aqueous solution of HCl (1 ), water, methanol,
and dichloromethane. The resin was dried for a few minutes then
suspended in dichloromethane (4 mL) and CF3COOH (1 mL) and
stirred overnight. The resin was filtered and washed with dichloro-
methane, triethylamine in THF (2%, v/v), water, methanol, and
dichloromethane. The resin was dried for a few minutes at 60 °C.
The weight difference corresponds to the amount of Boc removed,
which was identical to the amount of available proline. In the case
of resin 8, only treatment with TFA was carried out.
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was added to a mixture of the corresponding aldehyde (0.5 mmol)
and ketone (2.5 mmol) in distilled water (0.20 mL). The reaction
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1
checked by H NMR spectroscopy and HPLC, and then purified
by chromatography (petroleum ether/ethyl acetate).
Procedure for Catalyst Regeneration: Catalyst 8 was placed in a
round-bottomed flask and HCOOH was added (usually 200 µL for
100 mg of catalyst). The mixture was agitated for 2.5 h, then fil-
tered and washed with water, aqueous NaHCO3, water, MeOH,
and diethyl ether. Finally, the product was dried for a few minutes
at 60 °C.
Supporting Information (see also the footnote on the first page of
1
this article): Compound characterization and copies of the IR, H
NMR, and 13C NMR spectra of compounds 5a–h and 7.
Acknowledgments
Financial support from the University of Palermo (Funds for se-
lected topics) is gratefully acknowledged.
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Published Online: September 21, 2009
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Eur. J. Org. Chem. 2009, 5437–5444