Synthesis of selenocystine derivatives from cystine by applying the transformation reaction from disulfides to diselenides

Article abstract of DOI:10.1016/j.tetlet.2006.03.177

A stepwise conversion of a disulfide (SS) to a diselenide (SeSe) bond through the corresponding iodide intermediate was implemented and was applied to the synthesis of selenocystamine and l-selenocystine derivatives from cystamine and l-cystine, respectively, in moderate yields.

Full text of DOI:10.1016/j.tetlet.2006.03.177

Tetrahedron Letters 47 (2006) 3861–3863
Synthesis of selenocystine derivatives from cystine by applying
the transformation reaction from disulfides to diselenides
Michio Iwaoka,* Chie Haraki, Ryuta Ooka, Masahiro Miyamoto, Ai Sugiyama,
Yumiko Kohara and Noriyoshi Isozumi
Department of Chemistry, School of Science, Tokai University, Kitakaname, Hiratsuka-shi, Kanagawa 259-1292, Japan
Received 17 February 2006; revised 26 March 2006; accepted 29 March 2006
Available online 27 April 2006
Abstract—A stepwise conversion of a disulfide (SS) to a diselenide (SeSe) bond through the corresponding iodide intermediate was
implemented and was applied to the synthesis of selenocystamine and L-selenocystine derivatives from cystamine and L-cystine,
respectively, in moderate yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
We present here a novel chemical procedure to convert a
disulfide (SS) bond to the heavier analog, that is, a
diselenide (SeSe) bond, through the iodide intermediate.
The reaction was successfully applied to the synthesis
of selenocystamine and L-selenocystine ([L-Sec]2), an
oxidized dimer of L-Sec, derivatives starting from cyst-
amine and L-cystine ([L-Cys]2), respectively, in moderate
yields. Our strategy will open the possibility for post-
modification of the Cys residues in a polypeptide chain
to Sec residues.
Selenocysteine (Sec)1 is an interesting amino acid not
only because it is a structural and chemical analog to
cysteine (Cys), a common amino acid in living systems,
but also because it has characteristic features as the
active sites of several enzymes,2 and as the 21st amino
acid genetically coded in DNA.3 Some efficient organic
methodologies were developed for the synthesis of Sec
derivatives starting from such compounds as serine,4
b-chloroalanine,5 and glycine.6 However, no practical
method to directly transform Cys to Sec derivatives
has been reported.
2. Results and discussion
Recently, point mutation of Cys to Sec in a polypeptide
chain, that is, the replacement of the sulfur atoms of the
Cys residues to selenium atoms, has attracted interest
from a view point of oxidative refolding of proteins7
as well as protein structure determination.8 In the
previous strategies, the Sec residues were incorporated
into a polypeptide chain by chemical modification of
the serine residues in natural enzymes9 or by cysteine
auxotrophic expression in the presence of Sec.8,10 Native
chemical ligation of polypeptides between the C-termi-
nal thioester and the N-terminal Sec residue was also
developed recently.11
Conversion of a C–S bond to a C–Se bond is not an easy
task. The bond dissociation energy of the C–S linkage in
diethyl sulfide (69.7 kcal/mol) is larger than that of the
C–Se linkage in diethyl selenide (59.9 kcal/mol),12
suggesting that the SN2-type direct conversion by use
of a selenide (HSeꢀ) or diselenide ðSe22ꢀÞ anion would
be difficult. However, this energetic disadvantage was
recently overcome by Kreif et al. by the activation of
the C–S linkage to the diphenyl sulfonium salt.13 We
employed an alternative pathway, which goes through
the iodide intermediate (Scheme 1),14 by exploiting the
reaction of triphenylphosphine–iodine complex (PPh3ÆI2)
reported by Oae and Togo.15
.
1) 2NaHSe
2) O2
PPh3 I2
Keywords: Selenocystine; Selenocystamine; Diselenides; Disulfides;
Iodination.
RSSR
Scheme 1.
2 RI
RSeSeR
DMAP
*
Corresponding author. Tel.: +81 463581211; fax: +81 463502094;
e-mail: miwaoka@tokai.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.177

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M. Iwaoka et al. / Tetrahedron Letters 47 (2006) 3861–3863
Table 1 summarizes the results of the transformation
reactions from various disulfides to the corresponding
diselenides. In the sequential reactions, the iodide
intermediates were not isolated because the purification
process usually caused significant loss due to instability
or volatility.
55% for 4c, which were protected with Z and Fmoc
groups, respectively.
In the case of [L-Cys]2, protection of the both amino and
carboxyl groups was required. Disulfides 5a and 5b were
synthesized from [L-Cys]2 by the reaction with ZCl or
FmocCl, respectively, in 1 M NaOH, followed by the
esterification in ethanol in the presence of concentrated
H2SO4. The obtained compounds were then successfully
transformed to the corresponding [L-Sec]2 derivatives
(6a and 6b, respectively) in moderate yields. Stereochemi-
stry of the Ca atoms was retained through the transfor-
mation reaction because 6a and 6b showed similar
Cotton effects in the CD spectra to 5a and 5b, respec-
tively, and also because they were not contaminated
with the diastereomeric isomers in the NMR spectra.
Deprotection of 6a by hydrolysis in 1 M NaOH–DMF
at 40 °C followed by the treatment in HBr–acetic acid
at room temperature, afforded [L-Sec]2 in 62% yield.
The total yield of [L-Sec]2 was 34% from unprotected
[L-Cys]2 through 5a and 6a.
We first applied the methodology to simple dialkyl disul-
fides. When di(n-butyl) disulfide (1a) was reacted with
PPh3ÆI2 complex in the presence of 4-dimethylamino-
pyridine (DMAP) as base, n-butyl iodide was obtained
as a single product. Successive treatment of the iodide
with the selenide ion (HSeꢀ), generated in methanol
from selenium and sodium borohydride (NaBH4),16
and air oxygen afforded di(n-butyl) diselenide (2a) in
20% overall yield. Although the yield was low due to
volatility of the iodide and the diselenide, the reaction
proceeded clean, yielding the diselenide as an only
selenium-containing product. Similarly, di(s-butyl)
disulfide (1b) was transformed to the corresponding
diselenide (2b) in a modest yield. However, when di-
(t-butyl) disulfide (1c) was applied to this transforma-
tion process, the corresponding iodide was not obtained.
Thus, the methodology was applicable only for primary
and secondary alkyl disulfides. As for the iodination
mechanism, the iodide would be formed through the
nucleophilic attack of an Iꢀ ion at the carbon center
of the C–S bond that may be activated with Ph3P+–I
cation.17
The transformation reaction from disulfides to diselen-
ides reported here is useful not only for simple primary
and secondary alkyl disulfides, but also for cysta-
mine and cystine derivatives, which have amide,
urethane and ester functional groups. This suggests that
the protocol would be extended to the chemical conver-
sion of Cys to Sec residues in a polypeptide chain and a
protein.
The methodology was subsequently applied to cyst-
amine derivatives (3a–c). The attempt to directly trans-
form cystamine to selenocystamine was unsuccessful.
Therefore, the amino groups were protected with
benzoyl (Bz), benzyloxycarbonyl (Z) or 9-fluorenyl-
methoxycarbonyl (Fmoc) group. The latter two are
commonly used protecting groups for amino acids and
would be easily removed after the transformation to
diselenides. When 3a was employed through the
transformation process from disulfides to diselenides,
N,N0-dibenzoylselenocystamine (4a) was obtained in
32% yield. The yield was increased to 66% for 4b and
Acknowledgements
This work was supported by Grant-in-Aid for Scien-
tific Research (B) (No. 16350092) from the Ministry
of Education, Culture, Sports, Science and Technol-
ogy of Japan; Fellowship to Researchers from the
Association for the Progress of New Chemistry of
Japan; and Research and Study Program of Tokai
University Educational System General Research
Organization.
Table 1. Transformation reactions from disulfides to diselenidesa
Reactants
Products
Yieldsb (%)
S
1a
1b
Se
2a
2b
20
23
2
2
S
Se
2
2
c
1c
—
S
2
3a (X = Bz)
3b (X = Z)
3c (X = Fmoc)
4a (X = Bz)
4b (X = Z)
4c (X = Fmoc)
32
66
55
XHN
XHN
XHN
S
S
Se
Se
2
2
XHN
5a (X = Z)
5b (X = Fmoc)
6a (X = Z)
6b (X = Fmoc)
66
75
CO2Et
CO2Et
2
2
a Reaction conditions from disulfides to iodides were RSSR–PPh3–I2–DMAP = 1:3:2:2 refluxed in benzene for 2 h. Reaction conditions from iodides
to diselenides were NaHSe (2.5 equiv with respect to RSSR) in methanol at ꢀ4 °C for 16 h.
b Overall yields of isolated diselenides.
c t-Butyl iodide was not obtained.

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3863
1331–1334; (c) Quaderer, R.; Sewing, A.; Hilvert, D. Helv.
Chim. Acta 2001, 84, 1197–1206.
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1
as a pale yellow solid in 75% yield; H NMR (500 MHz,
CDCl3): d 7.76 (4H, d, J = 7.4 Hz), 7.59 (4H, m), 7.39 (4H,
t, J = 7.4 Hz), 7.32 (4H, t, J = 7.4 Hz), 5.76 (2H, d,
J = 7.2 Hz), 4.69 (2H, m), 4.40 (4H, m), 4.23 (6H, m),
3.6–3.0 (4H, m), 1.29 (6H, t, J = 7.1 Hz); 13C NMR
(CDCl3): d 170.5, 155.7, 143.8, 143.7, 141.3, 127.8, 127.1,
125.1, 120.0, 67.2, 62.1, 54.4, 47.1, 32.3, 14.2; 77Se NMR
(CDCl3): d 298.1. Anal Calcd for C40H40N2O8Se2: C,
57.56; H, 4.83; N, 3.36. Found: C, 57.44; H, 4.74; N, 3.49.
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