Solvolysis of formylphenyl esters by a bifunctional peptide catalyst

Article abstract of DOI:10.1246/cl.151154

An artificial hydrolytic system using a formylphenyl ester and a bifunctional peptide catalyst was developed. Controlling the spatial positions of the two functional groups, the amino group of proline and the imidazole of histidine in the peptide, was important for the reaction efficiency of hydrolysis. The application of this system to kinetic resolution was shown to be plausible.

Full text of DOI:10.1246/cl.151154

CL-151154
Received: December 11, 2015 | Accepted: December 28, 2015 | Web Released: January 8, 2016
Solvolysis of Formylphenyl Esters by a Bifunctional Peptide Catalyst
Kengo Akagawa and Kazuaki Kudo*
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8505
(
E-mail: kkudo@iis.u-tokyo.ac.jp)
An artificial hydrolytic system using a formylphenyl ester
and a bifunctional peptide catalyst was developed. Controlling
the spatial positions of the two functional groups, the amino
group of proline and the imidazole of histidine in the peptide,
was important for the reaction efficiency of hydrolysis. The
application of this system to kinetic resolution was shown to be
plausible.
collaboratively. Because the imidazole group of histidine can
function as a nucleophile or a base for activating another
nucleophile such as water, this structural framework is expected
to be utilized in a hydrolytic system involving iminium formation
(Figure 2b). In this report, a novel strategy for solvolysis by a
peptide with two functional groups is demonstrated.
In the research for developing hydrolytic catalysts, 4-
nitrophenyl esters have been mainly used as substrates because
of high reactivity and UV­vis traceability. Instead, we employed
formyl-substituted phenyl ester 2, which potentially forms an
iminium ion with a secondary amino group of a peptide. A non-
catalyzed background reaction did not take place with substrate
2 (Table 1, Entry 1). In the presence of peptide catalyst 1,
hydrolysis proceeded with 38% conversion after 24 h. For the
participation of both the N-terminal amino group and the
Keywords: Artificial hydrolytic system
|
Bifunctional peptide catalyst
|
Formylphenyl ester
In living organisms, hydrolases play essential roles in
biological activity. Organic chemists have focused on the
efficiency and selectivity of hydrolases, and utilized them as
catalysts for organic syntheses. One of the most successful
examples is the application of lipases to the kinetic resolution of
1
racemic compounds. From the viewpoints of customizability
(a)
(b)
Tyr
Aib
Tyr
Aib
Tyr
Aib
and extendability, the development of a synthetic catalyst as an
alternate to natural hydrolases is desirable. The high capability
of hydrolases derives from the synergic action of multiple amino
acid side chains, which are properly arranged in a three-
dimensional space by folded polypeptides. A representative
hydrolytic system is the catalytic triad consisting of Ser, His,
His
His
His
D
-Pro
D
-Pro
H
D
-Pro
N
N
NH
N
N
N
N
N
N
or
H
HO
O
O
2
O N
R
R
O
O
2
and Asp. So far, much effort has been put into imitating such
Figure 2. Schematic illustration for the incorporation of two
functional groups: (a) capture of an enal substrate by the
addition of imidazole, and (b) proposed model for accelerating
hydrolysis.
3
­5
multifunctional systems with artificially designed catalysts.
However, the catalytic ability is much lower than those of
natural hydrolases. This might be because of the difficulty in
allocating each functional group at an ideal spatial position with
accuracy on the angstrom order. Rather than the attempt to
construct a structure similar to an enzymatic system, a different,
controlled hydrolytic system is necessary to develop a useful
synthetic catalyst.
Table 1. Evaluation of catalysts for hydrolysis of a 4-
formylphenyl ester
CHO
O
O
CHO
catalyst (0.2 equiv)
OH
+
O
THF/H O (2:1), 25 °C, 24 h
2
HO
Recently, we developed resin-supported bifunctional peptide
catalyst 1 containing an N-terminal prolyl group and histidine at
2
6
(QWU\ &DWDO\VW
&RQYHUVLRQꢀꢁ
the fifth residue (Figure 1). Utilizing the peptide bound to an
amphiphilic resin has two merits; the catalyst can be easily
prepared by well-established solid-phase peptide synthesis on
the resin, and can be used under aqueous conditions without
ꢂ
ꢃ
⎯
ꢋ
ꢄꢉ
ꢂꢆ
ꢄꢃ
ꢃꢃ
ꢃꢈ
ꢃꢈ
ꢂꢆ
ꢂꢇ
ꢂꢅ
Pro-
D
-Pro-Aib-Tyr-His-(Leu-Leu-Aib)2
-Pro-Aib-His-Tyr-(Leu-Leu-Aib)
-Pro-Aib-Tyr-His
-Pro-Aib-Ala-His-(Leu-Leu-Aib)2
(1)
(3)
7
regarding to the low solubility of the hydrophobic peptide. It
ꢄ
Pro-
D
2
was suggested that the catalyst had the ability to capture an enal
through the formation of an iminium intermediate at the N-
terminus followed by reversible Michael addition of the histidyl
ꢅ
Pro-
Pro-
Pro-
Pro-
D
6
side chain (Figure 2a). In the presence of a β-turn motif, D-Pro-
ꢆ
D
8
Aib (Aib: 2-aminoisobutyric acid), the two functional groups
ꢇ
D
-Pro-Aib-Phe-His-(Leu-Leu-Aib)
2
are considered to be allocated in appropriate positions to work
ꢈ
D
-Pro-Aib-Trp-His-(Leu-Leu-Aib)
-Pro-Aib-Trp-Trp-(Leu-Leu-Aib)2
2
Pro-
D
-Pro-Aib-Tyr-His-(Leu-Leu-Aib)2
(1)
ꢉ
Pro-
D
(4)
:
amphiphilic resin
ꢊ
LPLGD]ROH
ꢅ ꢌꢋꢍꢃꢎHTXLYꢏꢎꢐꢎLPLGD]ROHꢎꢌꢋꢍꢃꢎHTXLYꢏ
Figure 1. Resin-supported N-prolyl peptide with histidine at
the fifth residue.
ꢂꢋ
300 | Chem. Lett. 2016, 45, 300–302 | doi:10.1246/cl.151154
© 2016 The Chemical Society of Japan

imidazole of histidine, the position of the histidyl residue is
considered critical. When the amino acids at the fourth and
fifth positions were exchanged, the catalytic efficiency dropped
significantly (Table 1, Entry 3). In our previous study, it was
6 was opposite to the case with peptide 1. Peptide 4 showed a
similar tendency for selectivity (6: 3% ee with S major). These
data suggest that the different preference for the resolution with
peptide 1 is ascribed to the collaborative function of prolyl and
histidyl residues. Further investigation to improve the selectivity
is now under way in this group.
9
shown that the helical moiety, (Leu-Leu-Aib)2, played the role
1
0
of stabilizing an entire peptide structure in aqueous media.
Without this part, the reactivity of the catalyst somewhat
decreased compared to peptide 1 (Table 1, Entry 4). It was also
revealed that the fourth residue affected the catalytic efficiency
to some extent (Table 1, Entries 5 to 7), and the use of tyrosine
was optimum. In the case of peptide 4 without a histidyl residue,
the conversion was lower than that with histidine at the fifth
position (Table 1, Entry 8). It should be noted that the reaction
was catalyzed by an imidazole molecule (Table 1, Entry 9);
however, a simple mixture of imidazole and the prolyl peptide
did not enhance the reaction beyond the level of individual
activity (Table 1, Entry 10). This indicates that fixing the two
functional groups at appropriate positions is essential for this
multifunctional hydrolytic system, and the use of the peptide
with specific secondary structures is promising. To confirm the
importance of the interaction between the formyl group and
peptide, a control experiment using phenyl ester 5 without
a formyl substituent was conducted (Scheme 1). In this case,
only a slight difference in the reactivity was observed between
peptide catalyst 1 and imidazole.
In conclusion, an artificial hydrolytic system using a
formylphenyl ester and a bifunctional peptide catalyst was
developed. It was indicated that the appropriate allocation of the
terminal proline and histidine in a three-dimensional space is
important for efficiency of hydrolysis. A potential application of
the system is the kinetic resolution of the racemic carboxylic
acid ester. Although the selectivity was low, kinetic resolution
by methanolysis was found to be plausible. By changing the
structure of the formylphenyl group and redesigning the peptide
sequence, highly selective resolution is expected.
We thank Kanako Iwasaki for experimental assistance. This
work was supported by JSPS KAKENHI (No. 15K17851 to
K.A. and No. 15K05495 to K.K.), and MEXT KAKENHI
(No. 26105710 to K.K.).
Supporting Information is available on http://dx.doi.org/
10.1246/cl.151154.
This catalytic system could be applied to transesterification
when alcohol is used instead of water. Although the reaction
rate was lower than that of hydrolysis,11 good conversion was
achieved with methanol at higher temperatures after 48 h
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1
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63, 1721. e) M. Ahmed, T. Kelly, A. Ghanem, Tetrahedron
2012, 68, 6781.
(Scheme 2). The peptide-catalyzed hydrolysis or transesterifica-
tion is potentially applicable to the kinetic resolution of the ester
1
2,13
derived from a racemic carboxylic acid.
It was found that
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ee (Scheme 3). The use of peptide 3 resulted in a slightly lower
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2
3
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Scheme 1. Hydrolysis of a phenyl ester without a formyl
group.
CHO
O
O
1
(0.2 equiv
)
CHO
OMe
+
O
THF/MeOH (1:2)
4
HO
0% conversion
0 °C, 48 h
2
8
2
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presence of peptide 1.
4
5
O
O
O
1
(0.2 equiv)
+
O
O
OMe
THF/MeOH (1:2)
40 °C, 24 h
CHO
CHO
6 (11% ee, R major)
rac-6
74% conversion
(7% ee)
4
468. c) M. Kheirabadi, N. Çelebi-Ölçüm, M. F. L. Parker, Q.
7
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Scheme 3. Preliminary result for kinetic resolution of a
formylphenyl ester.
Chem. Lett. 2016, 45, 300–302 | doi:10.1246/cl.151154
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