Oxidation of thiols promoted by PhSeZnCl

Article abstract of DOI:10.1016/j.tetlet.2011.11.025

The ability of PhSeZnCl 1 to catalyze the oxidation of thiols to disulfides has been evaluated and correlated to a catalytic GPx-like activity. The first evidence that vinyl phenylselenides can promote the oxidation of thiols reducing hydrogen peroxide through the formation of a selenoxide intermediate is also reported.

Full text of DOI:10.1016/j.tetlet.2011.11.025

Tetrahedron Letters 53 (2012) 232–234
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Tetrahedron Letters
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Oxidation of thiols promoted by PhSeZnCl
Caterina Tidei a, Marta Piroddi b, Francesco Galli b, Claudio Santi a,
⇑
a Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06134 Perugia, Italy
b Dipartimento di Medicina, Interna Università di Perugia, Via del Giochetto, 06134 Perugia, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The ability of PhSeZnCl 1 to catalyze the oxidation of thiols to disulfides has been evaluated and corre-
lated to a catalytic GPx-like activity. The first evidence that vinyl phenylselenides can promote the oxi-
dation of thiols reducing hydrogen peroxide through the formation of a selenoxide intermediate is also
reported.
Received 3 October 2011
Revised 27 October 2011
Accepted 4 November 2011
Available online 10 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Selenolate
GPx mimetics
Thiols
Peroxide
Oxidation
Selenium containing compounds have been recently investi-
gated as efficient and promising catalysts in electrophilic reactions,
coordination chemistry and oxygen transfer processes.1
GPx-like activity with that of other selenium containing
compounds.
From a synthetic point of view the oxidation of thiols to disul-
fides has important applications in the preparation of biomolecules
as well as ligands and it has recently received considerable atten-
tion by several research groups.10–13 This reaction plays an impor-
tant role in redox signaling and in structural and functional
regulations of proteins. A preliminary evaluation has been carried
out starting from a series of thiols 2a–g and using stoichiometric
or catalytic amount of PhSeZnCl at room temperature in D2O or
THF under aerobic conditions. The results, summarized in Table 1,
clearly indicate that the reaction strongly depends on the nature of
the substrate. Cysteine (2a) and homocysteine (2b) resulted to be
completely unreactive under the above mentioned conditions
and after 48 h the starting material can be quantitatively recov-
ered. On the contrary glutathione (GSH) 2c slowly reacted with a
stoichiometric amount of PhSeZnCl and was completely converted
into 3c in 30 h (using a 10% of 1, after 168 h the conversion was
lower than 10%). We also verified that in the absence of 1, GSH is
not subjected to spontaneous oxidation when exposed to air
(Fig. 1). Better results were obtained starting from dithiotreitol
(DTT) 2d, a non physiological thiol. In this case, even using a
Selenium is a biologically relevant element involved in some re-
dox regulating enzymes such as the glutathione peroxidase (GPx)
and thioredoxin reductase (TRx).2 Small size organoselenium
derivatives can be used to develop GPx mimetic molecules.3 Even
if various oxidation states of selenium have been observed within
proteins, at physiological pH the selenol moiety, that represents
the catalytic site of GPx, is fully dissociated conferring to the sele-
nium atom strong nucleophilicity toward peroxide substrates.4
Selenolates are usually very unstable and reactive species but, a
–SeH group participates to the catalytic triad of the enzyme being
stabilized by hydrogen bonds to tryptophan and glutamine
residues.4
We recently reported the synthesis of PhSeZnCl5 (1) as the first
example of air-stable selenolate, easily available through oxidative
zinc insertion starting from the commercially available PhSeCl. In
‘on water’ conditions,6 it is an excellent nucleophilic reagent, and
it has been used for several synthetic purposes such as nucleophilic
substitution at sp3 and sp2 carbon,5,7 ring-opening reaction of
epoxides,5 and aziridines8 as well as Michael-type addition reac-
tions.9 Considering that the oxidation state of selenium in 1 is
the same as in the catalytic site of the enzyme, we investigated
the reactivity of PhSeZnCl toward thiols in the presence of air or
peroxides as stoichiometric oxidants (Scheme 1) comparing its
PhSeZnCl
1
RSH
(RS)2
oxidant
2
3
⇑
Corresponding author. Tel.: +39 075 585 5112; fax: +39 075 585 5116.
E-mail address: santi@unipg.it (C. Santi).
Scheme 1. Oxidation of thiols promoted by 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.025

C. Tidei et al. / Tetrahedron Letters 53 (2012) 232–234
233
Table 1
Oxidation of thiols 2a–g in presence of PhSeZnCla
40
Thiol 2
NH2
HS
%1
Solvent Time (h) Yield %
30
20
10
0
OH
a
100 D2O
48
48
—
—
O
NH2
OH
b
HS
100 D2O
O
HS
O
O
O
H
N
168
30
10 D2O
100 D2O
<10
100
c
N
H
OH
HO
HS
O
NH2
OH
0
2
4
6
8
10
120
48
100
100
10 D2O
100
SH
SH
d
e
Time (h)
D2O
OH
Figure 2. Oxidation of GSH in the presence of: TBHP (d), H2O2 (j) H2O2 and 1 (10%)
(N).
100 THF
100 THF
48
48
22b
N
than those effected under aerobic conditions and the oxidation
rate, in the case of hydrogen peroxide, is accelerated by the pres-
ence of a catalytic amount of PhSeZnCl, suggesting a GPx-like
mechanism. The GSH/GSSG ratio has been measured by the inte-
gration of the corresponding proton NMR signals.
f
36b,c
SH
SH
10 THF
100 THF
120
48
60b
82b
g
In order to better evaluate this GPx-like activity, the oxidation
of 2d was performed in D2O and followed by 1H NMR spectroscopy
modifying the procedure previously reported by Iwaoka and co-
workers.14 Resonances at d = 2.58 and 3.64 ppm relative to 2d
(DTTred) decreased with respect to the increasing intensity of the
signals centered at d = 2.85, 3.04 e 3.55 ppm relative to 3d (DTTox).
Figure 3 shows the comparison between the results obtained using
a
Conditions: Reaction carried out under aerobic conditions thiol concentration
0,04 M, stirring speed 800 rpm, 23 °C.
b
The yield is referred to the isolated product after chromatographic purification.
(PhSe)2 and PhSZnCl were obtained as side products.
c
40
35
30
25
20
15
10
5
L-selenocystine, PhSeZnCl, and diphenyl diselenide, as catalysts
(10%), respectively. The time required to convert DTTred into DTTox
H2O2
H2O
Cat
D O
2
OH
HO
HO
SH
S
S
HS
0
OH
2d
0
5
10
15
20
25
30
3d
Time (h)
16
14
12
10
8
Figure 1. Oxidation of GSH under aerobic conditions without catalysts (d), in the
presence of a stoichiometric amount of PhSeZnCl (N).
catalytic amount (10%) of PhSeZnCl, disulfide 3d was quantita-
tively obtained in 120 h.
The oxidation of the thiols 2a–d was performed at room temper-
ature in D2O and monitored directly by 1H NMR. The yields reported
in Table 1 are referred to the conversion observed from the NMR
spectra and, in all the cases, were confirmed after the workup.
Starting from non water soluble thiols 2e–g the reactions were
carried out in THF and the corresponding disulfides 3e–g were
purified by flash chromatography on silica gel column. The yields
were moderate for the aromatic compounds 2e and 2f and good
in the case of the benzyl derivative 2g for which catalytic condi-
tions afforded 60% of 3g in 120 h.
6
4
2
0
-2
-50
0
50 100 150 200 250 300 350 400
Time (sec)
The oxidation of GSH has been further investigated in the pres-
ence of hydrogen peroxide and TBHP as terminal oxidants. As
shown in Figure 2, the reactions promoted by peroxides are faster
Figure 3. Comparison of the catalytic activity for the oxidation of DTT: without
catalysts (j), (PhSe)2 [1,4⁄10À3N] (d), PhSeZnCl [1,4⁄10À3N] (N),
(L-Sec)2
[1,4⁄10À3N] (ꢀ).

234
C. Tidei et al. / Tetrahedron Letters 53 (2012) 232–234
O
PhSeZnCl H2O
H2O2
Ph
SePh
Ph
SePh
1
7
6
H2O
PhSeH Zn(OH)Cl
(T50 = 144 sec)
(T50 = 176 sec)
Scheme 3. Vinyl selenides 6, 7 and the corresponding T50 = time required to
convert DTTrid into DTTox by 50%.
PhSe
O
4
ZnCl
+H2O
-H2O
selenides. Biological assays will be performed to demonstrate the
effective correlation between the proposed catalytic mechanism
and an actual GPx-like activity at the cellular levels.
Zn(OH)Cl
PhSeOH
G-SH
G-SS-G
Acknowledgments
PhSeSG
ZnCl
G-SH
Financial support from Fondazione Cassa di Risparmio di
Perugia, Ricerca di Base 2010 – progetto 2010.011.0415, M.I.U.R.
H2O
5
Scheme 2. Proposed mechanism for GPx-like activity of 1.
(Ministero Italiano Università
e Ricerca), National Projects
PRIN2007 (Progetto di Ricerca d’Interesse Nazionale), Consorzio
CINMPIS, Bari (Consorzio Interuniversitario Nazionale di Metodol-
ogie e Processi Innovativi di Sintesi) are gratefully acknowledged.
by 50% (T50) can be conveniently used to compare GPx-like activ-
ities of different organoselenium compounds.
It is interesting to observe that 1 showed T50 (128 s) higher
References and notes
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L-Sec)2
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1.9 Two selected examples (6 and 7) are reported in Scheme 3. Also
in these cases the GPx-like activity has been evaluated comparing
the corresponding T50 for the oxidation of DTT in D2O at 23 °C in
the presence of 1 equiv of H2O2 and 10% of catalyst [1,4⁄10À3N].
77Se-NMR investigations demonstrate that, in the case of these
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correlation between structure and catalytic activity of vinyl