Polystyrene-supported proline and prolinamide. Versatile heterogeneous organocatalysts both for asymmetric aldol reaction in water and α-selenenylation of aldehydes

Article abstract of DOI:10.1016/j.tetlet.2006.11.040

A simple and efficient synthesis of polystyrene-supported proline and prolinamide has been carried out. Polystyrene-supported proline has been used as organocatalyst in the asymmetric aldol reaction between cyclohexanone and substituted benzaldehydes in w

Full text of DOI:10.1016/j.tetlet.2006.11.040

Tetrahedron Letters 48 (2007) 255–259
Polystyrene-supported proline and prolinamide.
Versatile heterogeneous organocatalysts both for asymmetric
aldol reaction in water and a-selenenylation of aldehydes
Francesco Giacalone, Michelangelo Gruttadauria,* Adriana Mossuto Marculescu
and Renato Noto
`
`
Dipartimento di Chimica Organica ‘E. Paterno’, Universita di Palermo, Viale delle Scienze, Parco d’Orleans,
Pad. 17, I-90128 Palermo, Italy
Received 6 October 2006; revised 2 November 2006; accepted 8 November 2006
Available online 28 November 2006
Abstract—A simple and efficient synthesis of polystyrene-supported proline and prolinamide has been carried out. Polystyrene-sup-
ported proline has been used as organocatalyst in the asymmetric aldol reaction between cyclohexanone and substituted benzalde-
hydes in water without any additive. High yields, diastereoselectivities and ee values have been observed. The versatility of this resin
was demonstrated in the a-selenenylation of aldehydes. Both proline and prolinamide resins gave high yields. Recycling studies
showed that the proline resin gave better results than prolinamide resin.
Ó 2006 Elsevier Ltd. All rights reserved.
In the last years organocatalysis has emerged as a pow-
erful methodology.1 The development of small organic
molecules which do not contain a metal atom as useful
catalysts for enantioselective reactions is attracting
much interest. The advantage of using an organocatalyst
can be higher if an efficient recovery and reuse of the
catalyst can be carried out.2 From an economical point
of view this aspect is important since in several cases
organocatalysts are used up to 30 mol %, but also in
order to avoid wastes, so improving the greenness of
the process.
used as a catalyst in the reaction between cyclohexanone
and p-nitrobenzaldehyde in water, using a-cyclodextrin
as an additive, with interesting results.7 Very recently,
a paper dealing with asymmetric aldol reaction in water
using a polystyrene-supported proline appeared.8 The
L-proline was anchored to a polystyrene resin through
a 1,2,3-triazole moiety. This catalyst was used for the
aldol reaction in water giving high stereoselectivities,
whereas yields were increased by using a 10 mol % of
DiMePEG as an additive. A debate is now open as to
whether some of these reactions really are ‘all wet’.9
In addition to these aspects, a very recent development
has been the use of water as solvent for organocatalytic
asymmetric reactions. Indeed, water is a desirable sol-
vent in terms of safety, cost and environmental con-
cerns. Excellent results for the aldol reaction in water
have been obtained using a diamine, derived from pyr-
rolidine, containing a large apolar group in the presence
of an additive (TFA),3 or proline derivatives containing
a large apolar group too4 or protonated prolinamide
derivatives.5 Good results have been observed using
tryptophan in water.6 Also a simple dipeptide has been
Our efforts have been devoted to the recycling studies of
the organocatalyst. Such investigations have led us to
interesting achievements. We prepared an ionic liquid-
modified silica gel in which the L-proline is supported
as useful and recyclable catalyst for aldol reaction be-
tween acetone and several aldehydes.10 Our approach
has advantages in terms of yields, enantiomeric excess
values and recyclability. Moreover, since the proline
was supported by adsorption, the spent catalyst was
easily regenerated and reused. However, this aspect re-
presents a disadvantage too. Indeed, the use of a solvent
more polar than acetone can cause the desorption of the
proline from the surface support. Then we started a
study to overcome this inconvenience. In order to reach
this goal we carried out the covalent immobilization of
*
Corresponding author. Tel.: +39 091 596919; fax: +39 091 596825;
e-mail: mgrutt@unipa.it
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.040

256
F. Giacalone et al. / Tetrahedron Letters 48 (2007) 255–259
L-proline. Recently, covalently immobilization of L-pro-
line has been carried out on soluble poly(ethyleneglycol)
(PEG)11 or mesoporous silica.12 Such proline-modified
materials gave good results for the asymmetric aldol
reaction in organic solvents.
line possessing different linkers and can be used for the
immobilization of different organic molecules.
First we carried out a reaction between acetone and
benzaldehyde at room temperature using a 30 mol %
of catalyst. We checked the reaction after 2 h. Both con-
version (30%) and ee value (61%) were not good.
Our first aim was the preparation of a L-proline-modi-
fied material that can be used for the asymmetric aldol
reaction in more polar solvents than acetone and even
in water. Moreover, since proline is able to catalyze
many reactions, we decided to use the same material
to investigate the a-selenenylation of aldehydes cata-
lyzed by proline or prolinamide.13 Indeed, stereoselec-
tive synthesis using organoselenium compounds is
another area of interest in our laboratory.14
Then we turned our attention to the reaction using water
as the sole solvent, since the insoluble apolar polystyrene
resin may act as artificial aldolase.8 We investigated the
reaction between cyclohexanone and several substituted
benzaldehydes.15 The results are reported in Table 1. We
were delighted to find that the catalyst works well in
water.
To reach our goals we decided to immobilize the L-pro-
line on a polystyrene resin. The polystyrene support was
chosen in order to have an insoluble catalytic material
that can be easily recovered. Moreover, since polystyr-
ene may be regarded as a large apolar substituent, this
material may be useful for asymmetric aldol reaction
in water.
Yields are quite good whichever was the aldehyde. Reac-
tion times are ranging from 22 to 90 h. Diastereoselec-
tivities were high, comparable4a or even better3 than
those obtained with proline derivatives in water. Also
ee values were comparable. We also carried out the reac-
tion with p-nitrobenzaldehyde using DiMePEG as the
additive.8 In our case both anti/syn ratio and ee value
were identical to those obtained without additive, but
the isolated yield was lower (55%). The crucial role
played by water was evident when the reaction was car-
ried out under neat conditions (Table 1, entry 9). We
hypothesize that the hydrophilic proline moiety lies in
the interface (resin/H2O). This facilitates the formation
of a hydrophobic core on the inner surface of the resin.
Such microenvironment promotes the aldol reaction
with a high stereoselectivity.17
Commercially available trans-N-Boc-4-hydroxy-L-pro-
line was used for proline immobilization since its hydr-
oxyl group can be easily functionalized. As support we
have chosen the commercially available mercaptomethyl
polymer-bound (1% cross-linked with DVB, spherical
beads, particle size 100–200 mesh, 2.5 mmol/g loading).
The anchorage of L-proline was accomplished in two
steps accordingly to Scheme 1: (a) synthesis of styrene
derivative 1 of hydroxy-L-proline; (b) radical reaction
between the polystyrene and 1 followed by the deprotec-
tion of proline moiety. The removal of tert-butoxy-
carbonyl group was carried out with TFA/CH2Cl2 20/
80 followed by treatment with Et3N/MeOH 2/98.
The performance of the resin was also checked using it
several times. The reactions were quenched by filtration.
After each cycle the resin was washed with EtOAc and
acetone then dried. The resin was used four times using
p-cyanobenzaldehyde. Each cycle gave reproducible
This procedure gave the polystyrene-supported L-pro-
line in a high yield and in a very simple way (proline
loading ca. 1.5 mmol/g, determined by elemental analy-
sis and weight gain). Moreover, this approach is flexible,
allowing the synthesis of polystyrene-supported L-pro-
Table 1. The catalytic asymmetric aldol reaction in water catalyzed by
polystyrene-supported proline 2
O
O
OH
O
OH
O
R
+
2 (10% mol)
H2O, r.t.
R
R
Cl
HO
4
5
O
COOH
Boc
COOH
Time [h] Conv.a [%] anti/synb eec [%]
N
Entry
R
NaH, 18C6
THF, Δ, 80%
N
Boc
1
1
2
3
4
5
6
7
8
9e
H
Br
60
90
22
48
71
85
85
74
98
79
65
62
<5
95/5
96/4
95/5
96/4
92/8
96/4
95/5
95/5
nd
93
96d
90
94
98
98
98
98
nd
1.
NO2
CF3
CN cycle 1 22
Cycle 2
Cycle 3
Cycle 4
CN
SH
AIBN, Toluene
2. TFA, CH2Cl2
MeOH/Et3N 98:2
22
22
22
22
S
O
a Yields >98% (based on conversion).
b Determined by the 1H NMR of the crude product.
c Determined by HPLC using a chiral column (Daicel AS-H).
d Determined by optical rotation (see Ref. 16).
e Reaction carried out without water.
COOH
N
H
2
Scheme 1. Synthesis of polystyrene-supported proline.

F. Giacalone et al. / Tetrahedron Letters 48 (2007) 255–259
257
anti/syn ratio and ee values. However, a decrease in con-
version was observed.
was used in the reaction with 3-methylbutanal. Three
cycles were carried out. Each cycle gave a high isolated
yield. Excellent yields were observed using hexanal. In
this case four cycles were performed.
In order to check the versatility of the resin, we used it
in the a-selenenylation of aldehydes by reaction with
N-(phenylseleno)-phthalimide (NPSP).18 In our first at-
tempt we used resin 2 (30% mol) and decanal in dichloro-
methane. The reaction was quenched by filtration with
EtOAc after 1 h (see Table 2). We were pleased to find
a very clean reaction and an interesting isolated yield
(65%). The resin was dried for a few minutes then reused
in a second cycle using the same aldehyde. In the second
cycle the reaction time was 2.5 h. In this case the yield
was higher (85%). We decided to carry out reactions
using a 30 mol % of resin 2 for 2.5 h. Fresh resin 2
Finally, we used 3-phenylpropanal, also in this case a
high yield was obtained. Even if proline is able to cata-
lyze the a-selenenylation of aldehydes in good yields, it
has been reported that prolinamide is more efficient.13
For this reason we decided to prepare the L-prolin-
amide-supported resin 7. The synthesis was straightfor-
ward (see Scheme 2). The resin was obtained starting
from the trans-N-Boc-4-hydroxy-L-proline in three steps
(prolinamide loading 2.5 mmol/g). The prolinamide
derivative 6 was easily prepared by reaction of com-
pound 1 with ammonium hydrogen bicarbonate, pyr-
idine and Boc2O in MeCN.19 Selenenylation of hexanal
was carried out for 2.5 h using a 10 mol % of resin 7
instead of 30% of resin 2. The yield was excellent.
The reaction was also carried out using less amount of
resin for different times (Table 3, entries 2–4).
Table 2. The catalytic a-selenenylation of aldehydes catalyzed by
polystyrene-supported proline 2 (30% mol)
SePh
N-PSP (30% mol)
O
O
Time [h]
1
R
CH Cl , r.t.
R
2
2
Entry
1
Product
Conv.a [%]
65
Again, after 2.5 h, but using a 5% mol of catalyst 7, an
excellent yield was obtained. Resin 7 was used in the
reaction with other aldehydes (Table 3, entries 5–7) giv-
ing high yields. As for catalyst 2, hexanal was used as
substrate for recycling studies. Resin 7 was used four
times. However, in this case resin 7 gave the a-phenyl-
selenoaldehyde with a decreased conversion after four
cycles. The ee values of a-phenylselenoaldehydes
obtained were low as those observed under homo-
geneous conditions.13
SePh
C8H17
cycle 1
SePh
C8H17
cycle 2
O
O
2
3
4
5
2.5
2.5
2.5
2.5
85
88
90
89
SePh
O
O
O
In conclusion we have reported the straightforward syn-
thesis of the polystyrene-supported proline and polystyr-
ene-supported prolinamide. It has been showed that the
proline resin is a useful catalyst both in the aldol reac-
tion in water as the sole solvent without any additive
and in the a-selenenylation of aldehydes. Moreover,
the proline resin is recyclable and reusable at least for
four cycles with excellent results especially in the case
of the a-selenenylation of aldehydes. As observed under
homogeneous conditions, even the prolinamide-sup-
ported resin is more efficient than the corresponding
cycle 1
SePh
cycle 2
SePh
cycle 3
SePh
O
O
O
6
7
2.5
2.5
2.5
2.5
2.5
96
97
97
97
85
C4H9
cycle 1
SePh
C4H9
Boc2O, py
O
cycle 2
NH4HCO3
O
O
SePh
1
6
MeCN, r.t.
80%
C
O
N
8
C
NH2
C4H9
N
Boc
OH
cycle 3
Boc
1.
SePh
SH
AIBN, Toluene
O
O
9
C4H9
2. TFA, CH2Cl2
MeOH/Et3N 98:2
cycle 4
O
SePh
S
O
C
NH2
10
N
7
H
a Yields >98% (based on conversion).
Scheme 2. Synthesis of polystyrene-supported prolinamide.

258
F. Giacalone et al. / Tetrahedron Letters 48 (2007) 255–259
Table 3. The catalytic a-selenenylation of aldehydes catalyzed by
polystyrene-supported prolinamide 7
References and notes
Conv.a [%]
´
1. (a) Guillena, G.; Ramon, D. J. Tetrahedron: Asymmetry
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Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103,
3401–3429.
SePh
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O
O
1
2
10
5
2.5 h
98
SePh
C4H9
5 min 52
SePh
C4H9
O
3
5
1 h
63
3. Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc. 2006,
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958–961; (b) Hayashi, Y.; Aratake, S.; Okano, T.;
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SePh
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O
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4
5
6
5
5
5
2.5 h
2.5 h
2.5 h
96
84
86
SePh
C8H17
SePh
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SePh
SePh
´
´
7. Dziedzic, P.; Zou, W.; Hafren, J.; Cordova, A. Org.
7
8
5
5
5
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O
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O
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Celentano, G. Adv. Synth. Catal. 2002, 344, 533–542.
C4H9
cycle 2
SePh
C4H9
cycle 3
9
SePh
C4H9
cycle 4
a Yields >98% (based on conversion).
´
´
´
´
12. Calderon, F.; Fernandez, R.; Sanchez, F.; Fernandez-
Mayoralas, A. Adv. Synth. Catal. 2005, 347, 1395–1403.
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10
proline resin. The former catalyst showed a diminished
activity in subsequent runs. These data represent the
first examples of heterogeneous catalytic a-selenenyl-
ation of aldehydes.
Further investigations are in progress with different sub-
strates in order to study the scope and limitation of this
methodology.
Acknowledgments
Financial support from the University of Palermo
(Funds for selected topics) and Italian MIUR within
National Project ‘Non-aromatic heterocyclic in stereo-
controlled processes’ is gratefully acknowledged.
15. Typical procedure for aldol reaction: To a mixture of the
corresponding benzaldehyde (0.5 mmol) and cyclohexa-
none (2.5 mmol) in distilled water (0.18 ml), catalyst 2 was
added (0.05 mmol) and the reaction mixture was stirred at
rt for the time indicated in Table 1. The reaction was
quenched by adding ethyl acetate and, upon filtration, the
catalyst was washed thoroughly with ethyl acetate,
acetone and ethyl ether. The organic layers were collected
and, after evaporation of solvents, the crude product was
purified by chromatography (petroleum ether/ethyl
acetate).
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2006.
11.040.

F. Giacalone et al. / Tetrahedron Letters 48 (2007) 255–259
259
16. Wadamoto, M.; Ozasa, N.; Yanagisawa, A.; Yamamoto,
H. J. Org. Chem. 2003, 68, 5593–5601.
17. Lindstro¨m, U. M.; Andersson, F. Angew. Chem., Int. Ed.
2006, 45, 548–551.
CH2Cl2 (3.0 ml), catalyst 2 or 7 was added (0.15 mmol or
0.025 mmol, respectively) and the reaction mixture was
stirred at rt for 2.5 h. A usual work-up gave the
corresponding a-phenylselenoaldehydes.
18. Typical procedure for a-selenenylation of aldehydes: To a
mixture of the corresponding aldehyde (0.5 mmol) and N-
(phenylseleno)-phthalimide (0.6 mmol) in freshly distilled
19. Momiyama, N.; Torii, H.; Saito, S.; Yamamoto, H. Proc.
Nat. Acad. Sci. 2004, 101, 5374–5378.