Direct asymmetric aldol reaction in aqueous media using polymer-supported peptide

Article abstract of DOI:10.1016/j.tetlet.2005.09.113

PEG-PS resin-supported tripeptide/zinc chloride catalyst system has been developed for use in the direct asymmetric aldol reaction of acetone with aldehydes in aqueous media. The peptide catalyst could be separated from the reaction mixture by filtration,

Full text of DOI:10.1016/j.tetlet.2005.09.113

Tetrahedron
Letters
Tetrahedron Letters46 (2005) 8185–8187
Direct asymmetric aldol reaction in aqueous media
using polymer-supported peptide
Kengo Akagawa, Seiji Sakamoto and Kazuaki Kudo*
Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505, Japan
Received 28 July 2005; revised 15 September 2005; accepted 20 September 2005
Available online 6 October 2005
Abstract—PEG-PS resin-supported tripeptide/zinc chloride catalyst system has been developed for use in the direct asymmetric
aldol reaction of acetone with aldehydes in aqueous media. The peptide catalyst could be separated from the reaction mixture
by filtration, and was reusable at least five times without significant change in its activity and selectivity.
Ó 2005 Elsevier Ltd. All rights reserved.
7
The direct asymmetric aldol reaction (DAAR) is one of
the most powerful C–C bond forming reactions and has
been intensively studied in recent years. In 2000, List
96%ee in the presence of 10–20 mol % catalyst. In this
reaction, the weight-based amount of catalyst is some-
times comparable to that of the substrate aldehyde,
because the catalyst has much higher molecular weight
than the substrate. Particularly in such a case, it is highly
desirable that the catalyst be recovered and reused.
However, recyclability wasnot mentioned in that report.
In thispaper, we report a DAAR under aqueouscondi-
tionscatalyzed by recyclable N-terminal prolyl peptides
immobilized on a polymer solid.
1
et al. reported that proline catalyzesthe intermolecular
DAAR under mild conditions, and proposed the reac-
tion mechanism to be class I aldolase-like, that is, to
2
involve the enamine intermediate. Subsequently, a
number of proline-related compoundshave been pre-
pared and applied asthe cataly st for the DAAR, aiming
3
,4
at improving the catalytic performance.
In most
cases, the reactions are carried out in organic solvents,
and the addition of a small amount of water is known
to bring about an acceleration of the reaction to some
For the solid support, we chose polyethyleneglycol
grafted on cross-linked polystyrene (PEG-PS) resin.
PEG-PS is widely used in solid-phase peptide synthesis
(SPPS), and isknown to be compatible with a variety
of solvents, including water, by virtue of its amphiphilic
5
extent. However, excess water sometimes causes a
3
severe decrease in the enantioselectivity. The DAAR cat-
alyzed by prolines in aqueous media is of special interest
because it is directly relevant to the class I aldolase-cat-
alyzed reactions under physiological conditions, hence
the reaction ispotentially applicable in chemical biol-
ogy. There are several studies on the direct aldol reac-
tion under such conditions. Following earlier reports
9
nature. Immobilized peptide catalysts were prepared on
a terminally aminated PEG-PS (loading = 0.20 mmol/g)
1
0,11
resin by the standard Fmoc SPPS procedure.
This
resin-bound catalyst is advantageous particularly when
the peptidesare hydrophobic; the re si n rendersthe pep-
tides so luble in water due to the hydrophilic PEG chain
and preventsthe aggregation/ se dimentation of the pep-
tides. As a result, the resin-supported peptide can be
used in a high concentration.
6
on proline-catalyzed non-enantioselective reactions,
there appeared a couple of paperson the DAAR cata-
7
,8
lyzed by proline-related compounds. Among them,
the reaction catalyzed by Pro-(Phe) –OMe (n = 3 or 4)
n
showed marked enantioselectivity; the DAAR of
hydroxyacetone and aldehydesproceeded with up to
The reaction of p-nitrobenzaldehyde with acetone was
performed as an initial test of the peptide catalyst (Table
1
). Although a simple prolyl resin showed catalytic
activity, enantioselectivity was low (entry 1). The selec-
tivity was somewhat increased by incorporating one or
two Phe residue(s) between the prolyl group and the
resin (entries 2 and 3). Further insertion of Phe did not
Keywords: Peptide catalyst; Direct asymmetric aldol reaction; Solid
support; Aqueous conditions; Catalyst reuse.
*
Corresponding author. Tel.: +81 3 5452 6357; fax: +81 3 5452
359; e-mail: kkudo@iis.u-tokyo.ac.jp
6
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.113

8186
K. Akagawa et al. / Tetrahedron Letters 46 (2005) 8185–8187
Table 1.
a
b
c
d
Entry
Catalyst
Yield (%)
ee (%)
absconfig
1
2
3
4
5
85
78
12
27
R
R
R
S
e
e
e
100(100)
34(64)
26
81
e
90(66)
33(73)
S
a
The symbol
Isolated yield.
denotesamino group terminated PEG-PS re si n.
b
c
Determined by chiral HPLC analysis using Chiralcel OJ.
Absolute configuration of the major product.
Values in parentheses were those obtained under the following conditions: in acetone/H
d
e
2 2
O/THF = 1/1/1 at 0 °C in the presence of 20 mol % ZnCl .
show any improvement. When the residues were substi-
tuted from Phe to other amino acids, such as Leu, Val,
or Trp, only lower selectivity was observed. When
D-Pro-Phe-Phe was used as a catalyst, a reversal of
enantioselectivity was observed, but the degree of the
selectivity was lower than that with the corresponding
L-Prolyl catalyst (entry 4). This means that the residue
next to the prolyl group has some influence on the selec-
tivity. After screening with several amino acids at that
position, D-Pro-Tyr-Phe was found to show a good result
Table 2. Aldol reactionsbetween acetone and aldehydeswith
a
catalyst
b
c
Entry Aldehyde
1
Time (h) Yield (%)
ee (%)
d
18
24
30
89
84
2
3
83
76
(
entry 5). Then we optimized the reaction conditionsfor
e
d
50(91)
72
enantioselectivity. The best result was obtained when
the reaction wasperformed in acetone/H 2O/THF =
1
:1:1 (v/v/v) at 0 °C using 20 mol % of both the peptide
1
2
d
catalyst and ZnCl (entries 3, 5 in parentheses). For
4
5
30
20
93
74
2
the reaction in entry 5, the elongation of the reaction
time from 6 to 20 h brought about the increase in the
chemical yield from 66% to the quantitative yield with-
out any significant loss of enantioselectivity (73%ee to
100
71
7
1%ee). It should be noted that DarbreÕsgroup has
6
7
8
9
(first reuse of cat.)
(second reuse of cat.) 20
(third reuse of cat.)
(fourth reuse of cat.) 20
20
99
92
96
96
73
75
74
71
reported a DAAR under aqueousconditionscatalyzed
by zinc–proline complex. They found that the catalyst
8
20
prepared from L-proline preferentially gave the product
aldol having (S)-configuration in the same reaction as
the one we tested above. Such a mode of enantioselectiv-
ity is in disagreement with our results. This implies that
the role of Zn(II) ion in our system is quite different
from that of DarbreÕsgroup.
a
The reaction wascarried out in acetone/H O/THF = 1/1//1 at 0 °C
in the presence of 20 mol % ZnCl
Isolated yield.
Determined by chiral HPLC analysis using Chiralcel OJ unless
otherwise noted.
Determined by chiral GC analysis using Chrompack Chirasil-
Dex-CB.
2
2
.
b
c
d
e
Next, the scope of the substrate was examined (Table
2
1
3
). The aromatic aldehydeshaving an electron-with-
Yield based on the recovered starting aldehyde is shown in
parentheses.
drawing substituent gave the corresponding adducts in
high yield with modest to good enantioselectivity. In
contrast, the resin-bound peptide did not catalyze the
reaction of p-anisaldehyde, which has an electron-donat-
ing methoxy group.
tageous because the products can be easily separated
from the reaction mixture by simple filtration and wash-
ing. It wasfound that the immobilized peptide catalyst
could be repeatedly used at least five times without large
loss of yield or selectivity (Table 2, entries5–9). The
reaction using recycled catalyst proceeded even in the
A major drawback of the proline(-derivative)-catalyzed
aldol reaction isitslow efficiency, and asmuch as10–
4
0 mol %, typically 20 mol %, of catalyst is needed. In
order to indirectly overcome thisproblem, multiple use
of the catalyst has been investigated.14,15 From the view-
point of recycling, the solid-supported catalyst is advan-
absence of ZnCl , but the efficiency and selectivity were
2
slightly lower. Basically, adding ZnCl to each cycle
2
resulted in a better outcome.

K. Akagawa et al. / Tetrahedron Letters 46 (2005) 8185–8187
8187
In conclusion, we have developed a reusable resin-
immobilized tripeptide catalyst for the DAAR of ace-
tone and aldehydesin aqueousmedia. Further ts udies
on the peptide catalyst bound to the solid support are
8. Darbre, T.; Machuqueiro, M. Chem. Commun. 2003, 1090–
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now under investigation in this laboratory.
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