Polystyrene-supported hydroxyproline: An insoluble, recyclable organocatalyst for the asymmetric aldol reaction in water

Article abstract of DOI:10.1021/ol061964j

4-Hhydroxyproline has been anchored to a polystyrene resin through click chemistry, and the resulting catalyst has been successfully applied to the direct aldol reaction in water. The high hydrophobicity of the resin and the presence of water are key to e

Full text of DOI:10.1021/ol061964j

ORGANIC
LETTERS
2
006
Vol. 8, No. 20
653-4655
Polystyrene-Supported Hydroxyproline:
An Insoluble, Recyclable Organocatalyst
for the Asymmetric Aldol Reaction in
Water
4
†
†
,†,‡
Daniel Font, Ciril Jimeno, and Miquel A. Peric a` s*
Institute of Chemical Research of Catalonia (ICIQ), AV. Pa ¨ı sos Catalans, 16. 43007
Tarragona, Spain, and Departament de Qu ´ı mica Org a` nica, UniVersitat de Barcelona
(UB), 08028 Barcelona, Spain
mapericas@iciq.es
Received August 8, 2006
ABSTRACT
4-Hhydroxyproline has been anchored to a polystyrene resin through click chemistry, and the resulting catalyst has been successfully applied
to the direct aldol reaction in water. The high hydrophobicity of the resin and the presence of water are key to ensuring high stereoselectivity,
whereas yield can be increased by using catalytic amounts of DiMePEG. This effect has been further demonstrated by the inefficiency of a
homogeneous, more polar analogue.
It has been recently shown1,2 that asymmetric direct aldol
reactions can be efficiently carried out in water as the sole
peptides supported on PEG-PS resins have led only to low
enantioselectivities.
1
0
3
solvent using as catalysts proline derivatives that contain
We thought that polystyrene (PS) could be a suitable
support for L-proline for this application, and that the high
hydrophobicity of the polymer chain could favor stereocon-
trol of the direct aldol reaction in water. Readily available
3-hydroxyproline was chosen as the monomer catalyst, since
it can be anchored to the polymer chain with minimal
4
large apolar groups and behave as aldolase mimics. From a
practical perspective, the use of water as the solvent for these
reactions is a very favorable characteristic, but it would be
even more desirable to be able to efficiently recycle and reuse
5
,6
the catalysts that perform the reaction in that media.
7
11
Following initial attempts to immobilize proline, excellent
results have been achieved using soluble poly(ethylene
glycol) (PEG), or mesoporous silica supported proline in
organic solvents. However, attempts to work in water with
perturbation of the catalytically active R-amino acid moiety.
8
9
(5) (a) Chiral Catalyst Immobilization and Recycling; De Vos, D. E.,
Vankelecom, I. F. J., Jacobs, P. A., Eds.; Wiley-VCH: Weinheim, 2000. (b)
Frenzel, T.; Solodenko, W.; Kirsching, A. Solid-Phase Bound Catalysts:
Properties and Applications, in Polymeric Materials in Organic Synthesis
and Catalysis; Buchmeiser, M. R., Ed.; Wiley-VCH: Weinheim, 2003.
(6) Benaglia, M.; Puglisi, A.; Cozzi, A. Chem. ReV. 2003, 103, 3401-
3429.
(7) (a) On polystyrene: Kondo, K.; Yamano, T.; Takemoto, K. Makro-
mol. Chem. 1985, 186, 1781-1785. (b) On silica: Sakthivel, K.; Notz,
W.; Bui, T.; Barbas, C. F., III. J. Am. Chem. Soc. 2001, 123, 5260-5267.
(8) (a) Benaglia, M.; Celentano, G.; Cozzi, F. AdV. Synth. Catal. 2001,
343, 171-173. (b) Benaglia, M.; Cinquini, M.; Cozzi, F.; Puglisis, A.;
Celentano, G. AdV. Synth. Catal. 2002, 344, 533-542.
†
ICIQ.
U.B.
‡
(
1) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.; Tanaka, F.;
Barbas, C. F., III. J. Am. Chem. Soc. 2006, 128, 734-735.
2) (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima,
(
T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958-961. (b) Hayashi, Y.;
Aratake, S.; Okano, T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2006, 45, early view (August 8, 2006).
(3) Dipeptide-catalyzed aldol reactions can be carried out in water/organic
solvent mixtures; see: Dziedzic, P.; Zou, W.; H a´ fren, J.; C o´ rdova, A. Org.
Biomol. Chem. 2006, 4, 38-40.
(9) Calder o´ n, F.; Fern a´ ndez, R.; S a´ nchez, F.; Fern a´ ndez-Mayoralas, A.
AdV. Synth. Catal. 2005, 347, 1395-1403.
(10) Akagawa, K.; Sakamoto, S.; Kudo, K. Tetrahedron Lett. 2005, 46,
8185-8187.
(
4) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39,
1
352-1375.
1
0.1021/ol061964j CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/29/2006

In this event, a novel strategy for the anchoring of the
catalyst, involving 1,3-dipolar cycloaddition12 of an azide-
substituted Merrifield resin with an O-propargyl hydroxy-
proline derivative was envisaged. With respect to common
Table 1. Solvent Effects on the Aldol Reaction of
Cyclohexanone with Benzaldehyde Catalyzed by Resin 1
N
S 2 anchoring, this strategy offers the advantages of being
compatible with the introduction of structural diversity on
the monomer and of increasing spatial separation between
the polymer backbone and the active site, while no negative
effects on reactivity or stereocontrol were expected from the
yielda
(%)
ee antic ee sync
entry
solvent
anti/synb
(%)
(%)
13
rather inert 1,2,3-triazole moiety.
14
1
2
3
4
5
6
7
8
9
water
DMF
26
90
30
48
28
95
90
73
55
<5
1
95:5
50:50
84:16
93:7
95:5
50:50
82:18
91:9
93:7
nd
96
44
92
96
96
84
91
95
96
nd
61
87
90
84
85
89
90
95
87
nd
Click-proline resin 1 was prepared uneventfully as shown
in Scheme 1 (see the Supporting Information for experi-
mental details).
d
DMF/water 94:6
DMF/water 71:29
DMF/water 50:50
d
DMSO
DMSO/water 94:6
DMSO/water 71:29
DMSO/water 50:50
neat
Scheme 1. Preparation of Polystyrene-Supported
Hydroxyproline
10
a
Isolated yield. b Determined by H NMR of the crude product.
c
d
Determined by HPLC using a chiral stationary phase. Synthesis grade.
that the reaction takes place at the interface between the
polymer and the aqueous phase.
In favor of a beneficial contribution of the polymer
backbone to the overall outcome of the reaction, when
monomer 2 (Figure 1) was tested in the reaction under the
Optimal conditions for the use of resin 1 were first
determined working on the aldol reaction of cyclohexanone
with benzaldehyde. Since resin swelling would likely be key
for catalysis, attention was paid to the determination of the
optimal composition in solvent-water mixtures for the
reaction (Table 1).
Very interestingly, the reaction worked nicely in water,
yielding the aldol product in high diastereoselectivity and
high ee for the major anti diastereomer (entry 1). On the
other hand, the diastereoselectivity was lost and ee for anti
diastereomers deteriorated when good resin-swelling solvents
such as DMF and DMSO (entries 2 and 10) were used in
the reaction. However, overall yield increased noticeably in
these reactions. Increasing the water content in these solvents
improved the diastereo- and enantioselectivities, but at the
expense of lower reactivity. Without solvent, the reaction
proceeded sluggishly (entry 10). Thus, water appears as the
optimal media for the reaction, and this strongly suggests
Figure 1. Monomer ligand 2.
conditions of entry 1, anti/syn ratio was reduced to 63:37,
and ee for the anti diastereomer was only 83%.
To improve the aldol yield, reaction time was increased
and a catalytic amount of water-soluble DiMePEG (MW
∼
2000) was added with the hope of facilitating difusion to
the resin.
The results are summarized in Table 2. Clearly, improved
15
yields can be obtained at shorter reaction times (compare
(
11) For examples of this strategy, see: (a) Vidal-Ferran, A.; Bampos,
N.; Moyano, A.; Peric a` s, M. A.; Riera, A.; Sanders, J. K. M. J. Org. Chem.
998, 63, 6309-6318. (b) Peric a` s, M. A.; Castellnou, D.; Rodr ´ı guez, I.;
Riera, A.; Sol a` , L. AdV. Synth. Catal. 2003, 345, 1305-1313. (c) Castellnou,
D.; Sol a` , L.; Jimeno, C.; Fraile, J. M.; Mayoral, J. A.; Riera, A.; Peric a` s,
M. A. J. Org. Chem. 2005, 70, 433-438. (d) Castellnou, D.; Fontes, M.;
Jimeno, C.; Font, D.; Sol a` , L.; Verdaguer, X.; Peric a` s, M. A. Tetrahedron
Table 2. DiMePEG Effect on the Aldol Reaction of
Cyclohexanone with Benzaldehyde Catalyzed by Resin 1
(10 mol % in Water)
1
additive
(10 mol %)
yielda
(%)
time
(h)
ee antic
entry
anti/synb
(%)
2
005, 61, 12111-12120.
12) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
001, 40, 2004-2021.
13) Click reactions for polymer functionalization: (a) Lutz, J.-F.; B o¨ rner,
H. G.; Weichenhan, K. Macromol. Rapid Commun. 2005, 26, 514-518.
b) Parrish, B.; Breitenkamp, R. B.; Emrick, T. J. Am. Chem. Soc. 2005,
(
2
1
2
3
4
a
none
DiMePEG
DiMePEG
67
46
75
70
84
18
60
60
95:5
95:5
96:4
92:8
95
96
96
91
(
(
d
DiMePEG
1
27, 7404-7410. (c) Helms, B.; Mynar, J. L.; Hawker, C. J.; Fr e´ chet, J.
Isolated yield. b Determined by H NMR of the crude product.
1
M. J. J. Am. Chem. Soc. 2004, 126, 15020-15021. (d) L o¨ ber, S.; Rodr ´ı guez-
c
d
Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753-1755.
Determined by HPLC using a chiral stationary phase. 5 mol % of 1 used.
(14) Patent pending.
4654
Org. Lett., Vol. 8, No. 20, 2006

allowed the isolation of the aldol in good yield, but with
somewhat diminished stereocontrol (entry 4).
Table 3. Asymmetric Aldol Reactions in Water Catalyzed by
Resin 1 (10 mol %) and DiMePEG
Next, a representative set of aldehydes and ketones was
examined under the optimized reaction conditions (10 mol
%
of 1, 10 mol % of DiMePEG, water, rt) to check the scope
of the catalyst (Table 3). Interestingly, aromatic aldehydes
reacted with cyclohexanone with diastereoselectivities higher
than those recorded for monomeric proline derivatives in
1
,2
water. Moreover, the ee for the major isomers practically
did not deteriorate with respect to those catalysts. In difficult
examples involving other ketones (entries 8-10), a similar
behavior was observed.
In addition to these characteristics, the robustness of resin
1
is noteworthy. Thus, after the reactions were quenched by
filtration, the resin was washed with AcOEt and simply dried
for reuse. No decrease in its performance was observed after
three uses of the same sample (see the Supporting Informa-
tion), and in fact, the results in Table 3 were obtained with
recycled samples of resin 1.
In summary, we have shown for the first time that click
chemistry is a most suitable strategy for immobilizing a
hydroxyproline derivative to a Merrifield resin for organo-
catalysis purposes, and we have shown that the resulting
catalyst promotes direct asymmetric aldol reactions in water
with similar or even better performance than their monomeric
counterparts.
Acknowledgment. We thank DGI-MCYT (Grant No.
CTQ2005-02193/BQU), DURSI (Grant No. 2005SGR225),
Consolider Ingenio 2010 (CSD2006-0003), and ICIQ Foun-
dation for financial support. C.J. is a Torres Quevedo
researcher.
Supporting Information Available: Experimental pro-
cedures and characterization of 1 and 2. Experimental
procedures for aldol reactions and HPLC data for aldol
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
Isolated yield. b Determined by H NMR of the crude product.
1
OL061964J
c
d
Determined by HPLC using a chiral stationary phase. 25 equiv of acetone
was used. Estimated by H NMR.
e
1
(15) For the use of DiMePEG as an additive in asymmetric catalysis,
see: (a) Rudolph, J.; Lormann, M.; Bolm, C.; Dahmen, S. AdV. Synth. Catal.
2
005, 347, 1361-1368. (b) Rudolph, J.; Hermanns, N.; Bolm, C. J. Org.
entries 1 and 3, and entry 2 with entry 1 in Table 1).
Reducing the amount of catalytic resin 1 to 5 mol % still
Chem. 2004, 69, 3997-4000. (c) Bolm, C.; Rudolph, J. J. Am. Chem. Soc.
2002, 124, 14850-14851.
Org. Lett., Vol. 8, No. 20, 2006
4655