From transient sulfenic acids toward peculiar sulfurated molecules

Article abstract of DOI:10.1080/10426507.2016.1252373

Sulfenic acids (R-SOH) frequently act as reactive intermediates in biological and synthetic chemistry. Among the numerous examples that Nature offers to our knowledge, cysteine-derived sulfenic acids are recognized as key intermediates in signal transduct

Full text of DOI:10.1080/10426507.2016.1252373

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From Transient Sulfenic Acids towards Peculiar Sulfurated Molecules
Anna Barattucci, Paola Bonaccorsi*
Dipartimento di Scienze Chimiche Biologiche Farmaceutiche ed Ambientali, Università degli
Studi di Messina, Messina, Italy
*Corresponding author Email: pbonaccorsi@unime.it
Abstract
Sulfenic acids (R-SOH) frequently act as reactive intermediates in biological and synthetic
chemistry. Among the numerous examples that Nature offers to our knowledge, cysteine-derived
sulfenic acids are recognized as key intermediates in signal transduction, transcriptional
regulation events, and oxidative stress response. They also play catalytic and structural roles in
enzymes. Furthermore, the sulfenic function is involved in the biosynthesis of thiosulfinates that
give the characteristic odor and flavor to the Allium species and in the lachrymatory process of
cut onion. On the other hand, the electronic nature of their S--O bond and its involvement in
various, often stereospecific, reactions have prompted many applications of sulfenic acids in
organic synthesis, such as their use as key intermediates in the preparation of peculiar sulfurated
molecules. This paper aims at summarizing recent contributions on the generation and use of
transient sulfenic acids in the stereocontrolled synthesis of sulfoxides and disulfides. These
substrates offer a wide range of synthetic opportunities such as the synthesis of sulfinyl dienes to
be involved in stereoselective DA reactions, the preparation of libraries of bioactive sulfurated
molecules, the synthesis of unsymmetrical disulfides and tripodal sulfoxides and disulfides.
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GRAPHICAL ABSTRACT
Keywords
Sulfenic acids, Vinyl sulfoxides, Unsymmetrical disulfides, Thiacyclophanes,
Thiaglycoconjugates
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INTRODUCTION
Sulfenic acids are usually very reactive intermediates. In a proteic environment, they can
be considered as the oxidation products of Cysteine thiols. With the oxidation number of zero in
sulfenic acids, sulfur shows its unique ability to function as both a nucleophile and electrophile.
This dual nature is illustrated by the formation of thiosulfinates, where the reaction is favored by
inter-molecular hydrogen bonding. Sulfenic acids have an acidic pK ranging from 5 to 12 in
dependence of their structure.1 In general, it is difficult to have an exact measure of their acidity
since their anhydrides, the thiosulfinates, are more stable than their precursors, the sulfenic acids.
This sulfurated species play relevant roles in a variety of chemical and biochemical
reactions. Significant cellular processes such as signal transduction, oxidative stress response
transcriptional regulation involve the sulfenic function embedded in several protein skeletons.
The sulfenic function is also involved in the biosynthesis of thiosulfinates that give the
characteristic odor and flavor to the Allium species and in the lachrymation process when a onion
is cut.2 A vast majority of literature on sulfenic acids is concerned with their biological role and
most of the publications have been devoted to the synthesis of chemical probes for the detection
of the transient cysteine sulfenic acids (CysSOH) in proteins.3
Stable sulfenic acids, that resemble some of the protein sulfenic residues have been
synthesized and accurately studied, allowing significant improvements in the studies on the
biological role of CysSOH.4 There is a number of papers on the use in cross-coupling reactions
of sulfenate anions,5 which can be in turn generated from sulfenic acids.6
The key step in the generation of transient sulfenic acids is the thermolysis of sulfinyl
precursors that must possess an acidic H atom in the beta carbon. To enhance the mobility of the
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H and, hence, to lower the thermolysis temperature electron-withdrawing groups linked to the
beta C atom are needed and/or sterically demanding groups on the alfa C atom.7 The sulfinyl
precursors of sulfenic acids are prepared in two steps starting from thiols that are reacted with
electron-deficient alkenes to obtain the corresponding sulfides that are oxidized, in a controlled
manner, to sulfoxides. These sulfoxides usually are prepared and immediately used for the
generation.8
RESULTS AND DISCUSSION
The Alkyne/sulfenic acid reaction proceeds with a concerted mechanism. It is a
regioselective reaction: the sulfur adds to the most electrophilic C atom of a substituted triple
bond. It is a stereospecific, syn-addition that affords vinylsulfoxides with a known
stereochemistry at the double bond. A new stereogenic centre at the sulfoxide sulfur is formed. If
no chiral elements are present in the starting products, a racemic mixture is obtained. With chiral
groups attached to the sulfenic function, the addition affords epimeric mixtures of sulfoxides.
These epimeric mixtures are generally separable by column chromatography and enantiopure
vinyl sulfoxides can be obtained by this way.
Inspired by the Allium chemistry, we decided to use L-Cysteine as starting thiol for the
generation of the enantiomerically pure L-Cysteine sulfenic acid 1 (Scheme 1) that we involved
in the synthesis of enantiomerically pure nor-allin 2 or in the synthesis of diastereomeric sulfinyl
dienes 3 which were separated and the major diastereisomer 3a was involved in a Diels-Alder
cycloadditon with N-methyl-maleimide (NMM).9 We then used the Cysteine sulfoxide residue,
possessing a further mobile H, of the major cycloadduct 4 in the generation of a new sulfenic
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function, which we reacted again with the triple bond of the 1,4-dimethyl ester of 2-butynedioic
acid 5. Although we lose the Cysteine residue, this could represent a way to construct sulfoxides
with not accessible functionalities.
We also decided to generate anomeric sulfenic acids from sugar units. 1-Thio-alfa-D-
glucopyranose and its anomer were used in the synthesis of sulfinyl precursors 6 and 7 (Scheme
2) that were thermolyzed at different temperatures to generate the anomeric glucosylsulfenic
acids 8 and 9.10 We prepared thioglucoconjugates by reacting the glucosulfenic acid 9 with a
glucosyl unsaturated acceptor. Reflux in DCM (40°C), no acid or basic conditions, led to
compounds 10 with unaltered configuration at the anomeric carbon atom.
Condensation with thiols to give disulfides is also a typical reaction of sulfenic acids and
we have used it to developed a methodology which allows the synthesis of unsymmetrical
disulfides in good yields and just three steps of procedure (Scheme 3).11 By this methodology we
prepared a collection of dithioglycoconjugates, with the disulfide bond linking two sugar units
with different spacers, some of which showed apoptotic properties towards cancer cells.
dithiogalactoconjugate 11 gave the best results.12
We prepared thiacyclophanes (thiaCPs) from bis-sulfinyl precursors 12 and 13, as shown
in Scheme 4, by adopting diluted conditions for the generation of the transient species in DCM
at reflux and in the presence of an equivalent molar quantity of diethynylbenzenes. The
stereochemical outcome of these reactions was quite unexpected since, in both cases, when p-
diethynylbenzene was used as trapper of the sulfenic functions a complete stereoselectivity was
observed towards the meso compound, whereas with m-diethynylbenzene a 1:1 diastereoisomeric
mixture of the meso and the racemate was obtained.13 Recently, we have described an approach
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to new dithiaCP S,S-dioxides showing both planar and central chirality.14 We have chosen a
different precursor to generate the sulfenic functions and the thermolysis was conducted at 83°C.
We isolated intermediates such as 14 and 15 (Figure 1), still possessing a sulfinyl
function on one of the two arms.
Therefore, we had to observe that the formation of thiaCPs is a stepwise process, in these
conditions. The cyclization reaction proceeds in four distinct steps: i) formation of a first sulfenic
acid function, ii) addition to the triple bond, to give a vinyl sulfoxide-containing intermediate, iii)
generation of the second sulfenic acid function, iv) cyclization via intramolecular addition to the
second triple bond of the diethynylbenzene to generate the second vinyl sulfoxide bridging unit.
These open intermediates 14 and 15 gave us the possibility to study the stereochemical results
obtained in the synthesis of these macrocycles. Computational calculations suggest that the
exclusive formation of the meso thiaCPs in the reaction with p-diethynylbenzene takes place
under kinetic control.15
The synthesis of thiaCPs with a “cylindrical” structure appeared also interesting because
of their cage-like form. Syn-addition of the trisulfinyl precursor 16 to the triple bonds of an
equimolecular quantity of 1,3,5-triethynylbenzene led to the formation of the thiaCPs 17 as
diastereomeric mixture in about 1:1 ratio, respectively, of the cage possessing a C3 axis of
symmetry, and the cage with not C3 symmetry (Scheme 5).13 They were not completely
separable by column chromatography and for this reason were converted into the sulfonyl
derivative 18 by oxidation with m-CPBA.
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A synthetic procedure, to prepare sulfurated tripodal molecules from 1,3,5-
triethylbenzene, was also performed and is shown in Scheme 6. The best conditions for the
generation of the sulfenic functions and their syn-addition onto the 2-ethynylpyridine16 or their
condensation to different thiols,17 such as benzenethiol, have been found in dioxane at its
refluxing temperature of 101°C. The tripodal compound 18 was a mixture of C3 and not C3
diastereisomers which were easily separated by column chromatography. The C3 symmetric
tripodal diastereoisomer of 1, with the two coordinating nitrogen and sulfur atoms in the correct
relative position, was reacted with square planar platinum(II) complexes, in toluene at rt,
allowing the formation of a new class of tripodal bidentate ligands.16
CONCLUSIONS
In conclusion, we have described the synthesis of peculiar sulfurated molecules via
sulfenic acid generation and reaction with suitably substituted triple bonds or thiols. The choose
of the proper sulfenyl precursor is of dramatic importance for the outcome of the overall process
and the obtainment of the desired final products. The use of such molecules can space in many
chemical fields. Sulfinyl and disulfide derivatives containing the natural occurring residues of
cysteine, galactose, glucose have shown biological potentiality. Tripodal trivinylsulfoxides have
opened the way for their application in coordination chemistry. In thiacyclophanes the presence
of elements of chirality appears as a promising feature in their use as organocatalysts and
tripodal disulfides offer the opportunity to develop new functionalized nanoparticles.
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Figure 1 Intermediates in the synthesis of thiaCPs
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Scheme 1 Reactivity of L-Cysteine sulfenic acid 1 with suitably substituted triple bonds
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Scheme 2 From 1-thioglucopyranoses to diglucoconjugates via sulfenic acids
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Scheme 3 Procedure for the synthesis of unsymmetrical disulfides via sulfenic acids
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Scheme 4 Synthesis of thiacyclophanes via sulfenic acids
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Scheme 5 Synthesis of cylindral thiacyclophanes via sulfenic acids
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Scheme 6 Synthesis of tripodal sulfurated molecules via sulfenic acid
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