and chromatography to ease reaction workup and product
isolation.4
less hydrophilic supporting electrolyte, and found that a
1:1 (v/v) mixture of THF and MeOH was effective for both
the supporting electrolyte and the hydrophobic support.
We then prepared a model peptide (1) for oxidative
disulfide bond formation using a hydrophobic-tag-assisted
method (Scheme S2, Supporting Information). In contrast
to chemical oxidation by iodine, however, anodic oxida-
tion of the peptide (1) gave no cyclized product (2) and the
starting material was recovered quantitatively even after
the application of a large excess of current (Scheme 1).
In addition to macromolecules, several small hydropho-
bic molecules simply based on long alkyl chains have been
proposed as soluble supports, particularly in the synthesis
of oligosaccharides and peptides.5 In this context, we have
developed soluble-support-assisted liquid-phase techni-
ques using hydrophobic benzyl alcohols,6 leading to ver-
satile preparation of bioactive peptides.7 Using this tech-
nique, excellent precipitation yields were realized through
simple dilution of the reaction mixtures with poor solvent.
Described herein is the application of soluble-support-
assisted strategies to electrochemical reactions using oxi-
dative disulfide bond formation as a model.
The present work began with the construction of elec-
trolyte solutions applicable to hydrophobic-support-as-
sisted techniques (Figure 1). We investigated numerous
compositions of electrolyte solutions, using Et4NClO4 as a
Figure 1. Structures of the hydrophobic tags (HO-TAGa, HO-
TAGb) used in this work.
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Scheme 1. Oxidative Disulfide Bond Formation using Iodine or
Anode as Oxidant
With this result in hand, we then tested other tetraethyl
ammonium salts as supporting electrolytes (Table 1).
Although Et4NI was also found to be ineffective, anodic
disulfide bond formation took place efficiently in the
presence of Et4NBr or Et4NBF4. Although the bromide
anion is known to function as an electron transfer med-
iator, the mediated mechanism can be proposed when
Et4NBr is used (Scheme 2), this should also be proved by
electrochemical analysis. For this reason, we carried out
cyclic voltammetry measurements to illustrate a clear-cut
reaction pathway (Figure 2). However, when Et4NBr was
used as a supporting electrolyte (0.10 M), the oxidation
current of bromide anion was observed dominantly at 0.73
V vs Ag/AgCl and higher potentials because of its high
concentration (Figure S1, Supporting Information). On
the other hand, the voltammogram of Et4NBr as a sub-
strate (1.0 mM) was recorded using Et4NBF4 as a support-
ing electrolyte (0.10 M) to show reversible redox property
(black line in Figure 2), which changed significantly by the
addition of the peptide (1) (1.0 mM) (red line in Figure 2).
The oxidized species of the bromide anion generated
through the electron transfer at the surface of the anode
was reduced by the peptide (1) to regenerate the bromide
anion, leading to the increased oxidative current and the
decreased reductive current. In addition to such mediated
mechanism, a direct electron transfer pathway might also
be possible when Et4NBF4 was used. It should also be
noted that the reaction mixture was simply diluted with
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