Unsymmetrical target disulfides from transient sulfenic acids

Article abstract of DOI:10.1080/10426507.2010.506901

In accordance with our research interests devoted to the development of synthetic procedures involving sulfenic acids as intermediates, their condensation with various thiols has been exploited as an easy and versatile methodology to obtain unsymmetrical disulfides. Even if this reaction is well known, to the best of our knowledge it has never been used before as a methodology to synthesize unsymmetrical disulfides. The mild generation of mono-, di-, and tri-sulfenic acids from different sulfoxide precursors, depending on the required reaction conditions, allows the presence of even base/acid-sensitive and thermolabile functional groups and the synthesis, in excellent yields, of various kinds of unsymmetrical disulfides, some of which carry typical moieties of natural substances. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.506901

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Phosphorus, Sulfur, and Silicon and the
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Unsymmetrical Target Disulfides from
Transient Sulfenic Acids
Professor Maria Chiara Aversa a , Dr Anna Barattucci a , Dr Gianluca
Battaglia a & Professor Paola Bonaccorsi a
a Dipartimento di Chimica Organica e Biologica , Università degli
Studi di Messina , Messina, Italy
To cite this article: Professor Maria Chiara Aversa , Dr Anna Barattucci , Dr Gianluca Battaglia
& Professor Paola Bonaccorsi (2011) Unsymmetrical Target Disulfides from Transient Sulfenic
Acids, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:5, 1220-1224, DOI:
10.1080/10426507.2010.506901
To link to this article: http://dx.doi.org/10.1080/10426507.2010.506901
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Phosphorus, Sulfur, and Silicon, 186:1220–1224, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.506901
UNSYMMETRICAL TARGET DISULFIDES FROM
TRANSIENT SULFENIC ACIDS
Maria C. Aversa, Anna Barattucci, Gianluca Battaglia,
and Paola Bonaccorsi
Dipartimento di Chimica Organica e Biologica, Universita` degli Studi di Messina,
Messina, Italy
Abstract In accordance with our research interests devoted to the development of synthetic
procedures involving sulfenic acids as intermediates, their condensation with various thiols
has been exploited as an easy and versatile methodology to obtain unsymmetrical disulfides.
Even if this reaction is well known, to the best of our knowledge it has never been used before
as a methodology to synthesize unsymmetrical disulfides. The mild generation of mono-, di-,
and tri-sulfenic acids from different sulfoxide precursors, depending on the required reaction
conditions, allows the presence of even base/acid-sensitive and thermolabile functional groups
and the synthesis, in excellent yields, of various kinds of unsymmetrical disulfides, some of
which carry typical moieties of natural substances.
Keywords Condensation; disulfides; sulfenic acids; thiols
INTRODUCTION
It is generally assumed that the biological function of the cysteine thiol moiety
depends, to a large extent, on the oxidation of the SH group to the cystine disulfide bridge,
through the generation of the cysteine sulfenic acid.1 A sulfenic acid intermediate is also
formed in the enzymatic reactions involving the methionine sulfoxide reductases, repair
enzymes that reduce methionine sulfoxide oxidized by reactive oxygen or nitrogen species.2
The biological role that sulfenic acids play appears significant not only in oxidative stress
response but in several other cellular processes.
Indeed, sulfenic acids cannot be considered casual intermediates in synthetic pro-
cesses and their transient nature has been used with cleverness in the synthesis of sulfur-
containing molecules3 or in the removal of a sulfinyl moiety to obtain compounds not easily
accessible by different procedures.4 Sulfenic acid additions/eliminations are stereospecific,
and highly stereoselective processes are sometimes observed in the formation of a sulfur
stereogenic center of the sulfoxide moiety generated from the sulfenic one; both these
Received 1 June 2010; accepted 5 July 2010.
This work was supported by the Ministero dell’Istruzione, dell’Universita` e della Ricerca, and the Universita`
degli Studi di Messina, Italy (PRIN 2008).
Address correspondence to Paola Bonaccorsi, Dipartimento di Chimica Organica e Biologica, Univer-
sita` degli Studi di Messina, Viale Ferdinando Stagno d’Alcontres 31, 98166 Messina, Italy. E-mail: pbonac-
corsi@unime.it
1220

UNSYMMETRICAL DISULFIDES FROM SULFENIC ACIDS
1221
characteristics allow the stereo-controlled formation of molecules with definite structural
features.
The β-elimination of sulfenic acids from suitable sulfoxides can be regarded as one of
the best ways for their generation and involvement in intra- or intermolecular syn-addition
to unsaturated compounds or in coupling reactions with other sulfurated molecules, as well
as one of the best ways for the extrusion of a sulfinyl moiety. Several applications of both
of these synthetic aspects of the sulfenic acid chemistry have been reported in the recent
literature.5
As part of a research program centered on the development of synthetic procedures
involving sulfenic acids as intermediates,6 we forecast that the condensation reaction of in
situ generated sulfenic acids with thiols could represent an efficient procedure to obtain
unsymmetrical disulfides. Although this reaction has been previously reported for trapping
transient sulfenic acids and recognizing their involvement in some organic processes,7 it has
never been regarded as a general methodology for the synthesis of disulfides. In this article
we describe the controlled generation of the sulfenyl moiety from suitable precursors and
the development of the sulfenic acid/thiol condensation for the construction of the disulfide
bridge between two different structural skeletons.
In particular, we are now developing libraries of molecules containing at least two
small sugar units, linked by spacers of different lengths and flexibility, as pro-apoptotic
inducers, taking into account the pivotal role of apoptosis regulation in both the controlled
expansion and removal of immune cells and cancer progression and therapy.8 Because the
control of molecular architecture and sugar residue distance can play a significant role in
the enhancement of cytotoxic activity, the introduction into the molecular skeleton of the
disulfide bond, present in many biological systems and hydrolysis resistant, can provide a
basis for the development of a new series of biologically active glycoconjugates.
RESULTS AND DISCUSSION
Our synthetic strategy for the formation of the disulfide bridge has already been
described.9 The desired products can be obtained by a three-step procedure, starting from
a thiol to prepare the suitable sulfoxide precursor of the corresponding sulfenic acid in two
steps and concluding the process with the condensation of the in situ generated sulfenic
acid with a thiol—different from the one acting as a starting product toward the sulfenic
acid—to obtain unsymmetrical disulfides (Scheme 1).
Scheme 1
The generation of the sulfenic acid is achieved by β-syn-elimination, through the
thermolysis of a sulfoxide bearing at least a mobile hydrogen in β-position to the sulfinyl
group.6
The methodology offers the possibility of reacting even structurally complex thiols,
such as 2, giving access to unconventional disulfides such as compound 3, showing a
tripodal skeleton (Scheme 2). The tripodal disulfide 3 has been prepared starting from 1,3,5-
triethylbenzene (1) to obtain thiol 2, following literature procedures.10 Thiol 2 underwent

1222
M. C. AVERSA ET AL.
the three steps procedure mentioned above, and compound 3 was obtained in 55% total
yield.11
Scheme 2
Compound 3 has been synthesized as a model for the development of a small library
of tripodal molecules. The use of the 1,3,5-trisubstituted-2,4,6-triethylbenzene scaffold in
supramolecular chemistry has emerged rapidly. Several receptor molecules for cationic
and anionic guests have been designed by placing various conformationally controlled
binding groups around the benzene platform. The presence of the disulfide bonds lends
characteristics of flexibility and the possibility of reversible formation and cleavage of the
S-S bond to these molecules, promoting their use not only in molecular recognition12 but
also in material science.13
Thiols are used either as starting compounds to synthesize sulfenic acid precursors or
as sulfenic acid acceptors, which allows a wide modulation of the procedure, as exemplified
in Scheme 3. Starting from thiol 6 we have synthesized disulfide 109 running through two
different routes (a and b), and the results obtained deserve some comments. Sulfoxides 511
and 11 are suitable precursors of transient sulfenic acids 7 and 8, respectively. They show a
different alkane sulfinyl moiety involved in the β-syn-elimination: the mobile hydrogen in
the β-position to the sulfinyl group in sulfoxide 11 allows the generation of sulfenic acid 8 at
40◦C (refluxing CH2Cl2), because of the two electron-withdrawing ester functions attached
to the same carbon atom and the two methyl groups in the α-position to the sulfur atom.
Sulfoxide 11 was prepared starting from thiol 9, through a controlled oxidation of sulfide
12,6g and must be handled with caution because it easily undergoes spontaneous β-syn-
elimination, leading to undesirable mixtures of self-condensation products of glucosulfenic
acid 8. Therefore, freshly prepared sulfoxide 11 was thermolyzed in refluxing CH2Cl2 in
the presence of the bis-thiol 6 (11/6 molar ratio 5:1) to give compound 10 in 50% yield.
The quite low yield of compound 10, obtained following this approach (a1 to a3),9
was overcome using the bis-sulfenic acid 7 as intermediate. Compound 6 was considered
as a suitable starting product for the synthesis of sulfoxide 5 (b1 to b2), precursor of the
bis-sulfenic acid 7 to be generated in situ in the presence of thiol 9 (b3). In our experience,
the presence of a methoxycarbonylethyl residue involved in the β-syn-elimination allows
the thermolysis of sulfoxide 5 to occur at 83◦C (refluxing ClCH2CH2Cl). The expertise
gained in the choice and preparation of sulfenic acid precursors6 directed us toward the use
of sulfoxide 5, which, contrary to sulfoxide 11, can be kept on the bench without any trace
of decomposition and easily purified by column chromatography, thus raising its reactivity
as generator of the corresponding sulfenic acid 7 (Scheme 3). The thermolysis of sulfoxide
5 in the presence of thiol 9 led to the obtainment of compound 10 in 85% yield, a result

UNSYMMETRICAL DISULFIDES FROM SULFENIC ACIDS
1223
Scheme 3
comparable with others achieved using this methodology for the formation of the disulfide
link.9 The bio-potentialities of bis-disulfide 10 and its deprotected analogue are under study.
CONCLUSIONS
In conclusion, we have described an easy synthetic approach to unsymmetrical disul-
fides. It is a general procedure that allows the preparation of even structurally complex
disulfides, in mild conditions and good yields. The generation of mono-, di-, or tri-sulfenic
acids, from suitable sulfinyl precursors, in the presence of various kinds of thiols, as applied
for the synthesis of compounds 3 and 10, illustrates the versatility of our procedure.
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