Beta-replacement reaction of serine-O-carbonate derivatives with thiols catalyzed by a pyridoxal model having an ionophore side-chain.

Article abstract of DOI:10.1039/b206061b

Serine-O-carbonate derivatives, including peptides having a serine-O-carbonate residue at the N-terminal position, are catalytically transformed into S-substituted cysteine derivatives employing the pyridoxal model having an ionophore function in the pres

Full text of DOI:10.1039/b206061b

b-Replacement reaction of serine-O-carbonate derivatives with thiols
catalyzed by a pyridoxal model having an ionophore side-chain
Kazuyuki Miyashita, Hidenobu Murafuji, Hiroshi Iwaki, Eito Yoshioka and Takeshi Imanishi*
Graduate School of Pharmaceutical Sciences, Osaka University, 1–6 Yamadaoka, Suita, Osaka 565-0871,
Japan. E-mail: imanishi@phs.osaka-u-ac.jp
Received (in Cambridge, UK) 25th June 2002, Accepted 17th July 2002
First published as an Advance Article on the web 30th July 2002
Serine-O-carbonate derivatives, including peptides having a
serine-O-carbonate residue at the N-terminal position, are
catalytically transformed into S-substituted cysteine deriva-
tives employing the pyridoxal model having an ionophore
desired product 5 was not obtained, and only a complex mixture
was formed. As this appears to be due to the acid formed by the
elimination, we eventually employed serine-O-carbonate 3c,
which forms carbon dioxide and methanol as the elimination
products. The reaction of 4c was found to smoothly take place
as expected, to give the aldimine 5 in almost quantitative yield.
However, acidic hydrolysis of the aldimine 5 resulted in only
poor yield (ca. 10%) (Scheme 1).
+
function in the presence of Li ; this is the first artificial
model mimicking cystathionine b-synthase.
b-Replacement reaction of the serine hydroxy group with a
nucleophile, which is catalyzed by a pyridoxal-dependent
enzyme, is an important reaction for biosynthesis of amino acids
in biological systems (Fig. 1). Cystathionine b-synthase (CBS)
and tryptophan synthase are typical examples of such biological
reactions, in which the nucleophiles are homocysteine and
tryptophan, respectively. From the viewpoint of synthetic
organic chemistry, this reaction appears to be useful for the
synthesis of various b-modified amino acids. Although some
examples mimicking tryptophan synthase have been re-
ported,1 there is no example mimicking CBS. CBS is a
biologically very important enzyme, which catalyzes b-replace-
ment reaction of a serine hydroxy group with the thiol group of
homocysteine to produce cystathionine.3 Deficiency of this
,2
4
enzyme is known to cause homocystinuria. Here we describe
biomimetic transformation of serine derivatives into S-substi-
tuted cysteine derivatives employing pyridoxal models 1a and
1
b (Fig. 2).
In previous papers, we have reported pyridoxal model
compound 1a having an ethoxyethoxy group at the C-3 position,
a characteristic feature of which is that the aldimine is
Scheme 1 Stoichiometric b-replacement reaction.
+
5
specifically activated by Li . At first, we examined the reaction
of aldimine 4a prepared from the pyridoxal derivative 1a and
serine benzyl ester 3a using thiophenol in the presence of
lithium perchlorate. However, no reaction took place, and the
starting aldimine 4a was recovered. In order to increase the
eliminating ability of the hydroxy group, we next employed
aldimine 4b which was obtained from serine O-benzoate or O-
acetate 3b and 1a. In this case, 4b disappeared quickly, but the
Expecting an imine-exchange reaction between the aldimine
and serine-O-carbonate 3c, we examined the reaction
5
employing a catalytic amount of 1a as shown in Fig. 3, and the
results are summarized in Table 1.† The reaction proceeded in
the presence of only 1% mol of 1a (run 1). In this case, the yield
based on the starting serine-O-carbonate 3c was 76% and that
based on 1a was 7600%, which means that one molecule of 1a
can convert ca. 76 molecules of 3c into the cysteine derivative
6
1
a. The reaction rate was improved by increasing the amount of
a (runs 2 and 3). However, the best yield based on 3c was
obtained when 5% mol of 1a was employed (run 2). Regardless
of the substituents on the benzene ring, other aromatic thiols
also reacted, giving rise to S-aryl cysteines 6b–d (runs 4–6).
However, the reactions with alkanethiols required longer
reaction time to complete, and the yields were lower than those
with aromatic thiols (runs 7–10). We next examined the reaction
with the pyridoxal model 1b having an imidazole moiety,‡
expecting activation of the elimination of the O-carbonate
moiety and/or activation of the nucleophile. Consequently, the
reactions with alkanethiols proceeded smoothly, and the yields
were improved (runs 7–10 vs. runs 11–14).
Fig. 1 b-Replacement reaction of Ser.
Fig. 2 Structures of pyridoxal model compounds.
Fig. 3 Catalytic b-replacement reaction of 3c with thiols.
1
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CHEM. COMMUN., 2002, 1922–1923
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Table 1 Catalytic b-replacement reaction of 3c to S-substituted cysteines 6a
Run
PL (mol%)
LiClO
4
(mol%)
RSH
Time/h
Product
Yield based on 3c
Yield based on 1
1
2
3
4
5
6
7
8
9
0
1
2
3
4
1a (1)
1a (5)
1a (10)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1b (5)
1b (5)
1b (5)
1b (5)
1
5
10
5
5
5
5
5
5
5
Ph
Ph
Ph
4-MeC
38
5
2
5
5
6a
6a
6a
6b
6c
6d
6e
6f
6g
6h
6e
6f
76
93
87
86
90
92
61
41
30
28
84
80
49
60
7600
1860
870
1720
1800
1840
1220
820
600
560
1680
1600
980
6
H
4
4-MeOC
6
H
4
4-O
Bn
Et
HO(CH
HS(CH
Bn
Et
HO(CH
HS(CH
2
6
NC H
4
3
19
22
72
25
19
22
72
25
)
2 3
b
1
1
1
1
1
a
)
2 3
5
5
5
5
)
2 3
6g
6h
b
)
2 3
1200
Although optically active L
-serine-O-carbonate was employed as a starting material, the products 6a–h were obtained as a racemic form. b Dithiol (0.6 eq.)
was employed and the both thiol groups were alkylated.
A possible reaction mechanism of the present catalytic
reaction is proposed in Fig. 5. The first step would involve
formation of the aldimine 4c from 1 and 3c. As the reaction did
+
+
not proceed without Li , chelation of Li plays a crucial role in
the reaction and appears to restrict the conformation of the
+
5
imino-ester moiety as shown by 4c–Li , which would
consequently activate the elimination of the carbonate group to
form unsaturated species 7. Michael addition of a thiol, which
would be activated by the imidazole moiety in the case of 1b,§
Fig. 4 Catalytic b-replacement reaction of 7 with thiols.
Table 2 Catalytic b-replacement reaction of Ser amide and peptides
+
would take place to afford cysteine aldimine 5–Li . Eventually,
Yield
(%)
+
+
transimination of 5–Li with 3c is thought to give 4c–Li and
the cysteine derivative 6, forming a catalytic cycle.
Run Compd. 7
X
RSH
Producta
In conclusion, an efficient and catalytic conversion of the
serine-O-carbonate ester to various S-substituted cysteine
derivatives was achieved in one pot by employing pyridoxal
derivatives 1a and b, which is the first example mimicking
CBS. Further applications of this reaction system to other
nucleophiles than thiols and to a chiral system are also in
progress in our laboratory.
1
2
3
4
5
6
a
a
b
c
d
b
b
Bn
Bn
Bn
Bn
Bn
Ph
Et
8a
8b
8c
8d
9
81
76
70
68
81
70
L
L
L
L
L
-Ala-OBn
-Val-OBn
-Ala- -Ala-OBn
-Ala-OBn
-Ala-OBn
L
10
Products 8b–d were obtained as a mixture of diastereomers based on the
cysteine residue.
This work was financially supported by a SUNBOR Grant.
Notes and references
Encouraged by the result described above, we applied the
†
We studied the effect of the solvent, and found that, although the reaction
proceeded in other solvents, MeCN was the most effective.
Pyridoxal model compound 1b was synthesized by esterification of a
reaction to peptides having a serine-O-carbonate residue at the
6
N-terminal position (Fig. 4), and the results are summarized in
‡
Table 2. Although longer reaction time (ca. 100 h) was required,
serine amide 7a was converted into cysteine amide 8a (run 1).
Dipeptides 7b, c and tripeptide 7d were also transformed into
the corresponding peptides bearing S-benzylcysteine at the N-
terminal position (runs 2–4). Phenyl and ethyl mercaptans also
reacted with 7b to give 9 and 10, respectively (runs 5 and 6).
pyridoxal derivative with N-tosylimidazole-4-propanoic acid, details of
which will be reported in a full article.
§ We disclosed that the imidazole moiety does not activate the elimination
of the carbonate, but activates the addition procedure, details of which will
be described in a full article.
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1
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1
1
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6
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Fig. 5 Proposed reaction mechanism.
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