Optimized methods for preparation of 6I-(ω-sulfanyl-alkylenesulfanyl)-β-cyclodextrin derivatives

Article abstract of DOI:10.3762/bjoc.12.38

A general high-yielding method for the preparation of monosubstituted β-cyclodextrin derivatives which have attached a thiol group in position 6 is described. The thiol group is attached through linkers of different lengths and repeating units (ethylene glycol or methylene). The target compounds were characterized by IR, MS and NMR spectra. A simple method for their complete conversion to the corresponding disulfides as well as a method for the reduction of the disulfides back to the thiols is presented. Both, thiols and disulfides are derivatives usable for well-defined covalent attachment of cyclodextrin to gold or polydopamine-coated solid surfaces.

Full text of DOI:10.3762/bjoc.12.38

Optimized methods for preparation of 6I-(ω-sulfanyl-alkylene-
sulfanyl)-β-cyclodextrin derivatives
Eva Bednářová1, Simona Hybelbauerová2 and Jindřich Jindřich*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 349–352.
1Department of Organic Chemistry, Faculty of Science, Charles
doi:10.3762/bjoc.12.38
University in Prague, Hlavova 8, 128 43, Prague 2, Czech Republic,
Fax: +420 22195 1326 and 2Department of Teaching and Didactics of
Chemistry, Faculty of Science, Charles University in Prague, Hlavova
Received: 16 November 2015
Accepted: 09 February 2016
Published: 24 February 2016
8, 128 43, Prague 2, Czech Republic
Email:
This article is part of the Thematic Series "Superstructures with
cyclodextrins: Chemistry and applications III".
Jindřich Jindřich* - jindrich@natur.cuni.cz
*
Corresponding author
Guest Editor: E. Monflier
Keywords:
© 2016 Bednářová et al; licensee Beilstein-Institut.
cyclodextrins; disulfides; monosubstituted derivatives; thiols
License and terms: see end of document.
Abstract
A general high-yielding method for the preparation of monosubstituted β-cyclodextrin derivatives which have attached a thiol
group in position 6 is described. The thiol group is attached through linkers of different lengths and repeating units (ethylene glycol
or methylene). The target compounds were characterized by IR, MS and NMR spectra. A simple method for their complete conver-
sion to the corresponding disulfides as well as a method for the reduction of the disulfides back to the thiols is presented. Both,
thiols and disulfides are derivatives usable for well-defined covalent attachment of cyclodextrin to gold or polydopamine-coated
solid surfaces.
Introduction
Cyclodextrins (CDs) [1], cyclic oligomers of α-D-glucopyra- solubilizers and/or stabilizers in pharmaceutical, cosmetic,
nose, are used for their ability to form supramolecular inclusion agricultural and food industries [4]. These derivatives are
complexes with a wide range of guest molecules [2]. From the usually mixtures of randomly substituted CDs. On the other
native CDs (α-CD, β-CD, and γ-CD containing 6, 7, and 8 hand, CD derivatives which are well-defined chemical individ-
glucose units, respectively) the β-CD is studied the most due to uals are well suited for separation science [5], chemosensors [6]
its lowest price and the highest guest binding ability. A large or drug delivery [7] applications. These applications often
number of CD derivatives [3] which have been prepared up to involve a modification of solid surfaces by CDs. Among the
now can be divided into several groups according to their solid surfaces, to which CDs were attached, are sorbents for
intended use. The largest group is the one containing CD deriv- separation techniques or waste water treatment [8] or nanoparti-
atives with modified complexation properties, used mainly as cles [6].
349

Beilstein J. Org. Chem. 2016, 12, 349–352.
In our work, we focused on the preparation of sulfanyl-group- That is why a method to recover the thiols from the disulfides
containing CD derivatives – 6I-deoxy-6I-(ω-sulfanyl-alkylene- was also studied.
sulfanyl)-β-cyclodextrins (β-CD-S-X-SH) – which can be at-
tached to a gold surface [9,10] or a polydopamine-coated sur- Results and Discussion
face [11]. It has been already described that the surface cover- For the preparation of the starting compound for all syntheses –
age of self-assembled monolayers of CD derivatives on gold Ts-β-CD (1) – we recently described [17] a modification of one
depends substantially on the linker between the sulfanyl group of the commonly used method [18]. The modification consisted
and the CD. Derivatives with sulfanyl groups connected directly in the repeated recrystallization from 50% water–methanol
to the CD gave much lower surface coverage [12] than the de- which yielded a very pure product with no interfering impuri-
rivatives containing just one sulfanyl group connected by a ties (di- or tri-Ts-β-CD) or unreacted β-CD.
longer linker [13]. Therefore, we decided to prepare a series of
CD sulfanyl derivatives with different lengths of the linker The terminal sulfanyl groups were introduced to the oligo-
connecting the CD and the sulfanyl group. These derivatives are ethylene glycol linkers using standard chemical transformat-
needed for two projects which both will study the influence of ions (Scheme 1). Oligoethylene glycol ditosylates 2a–c [19]
the linker length on the properties of the whole system. The first were converted to S-acetyl dithiols 3a–c [20] and deacetylated
project will study the sensitivity of quartz crystal microbal- to the oligoethylene glycol dithiols 4a–c using a procedure
ances with a CD-modified gold sensor [14]; the second will published for similar thiols [21]. Compounds 4 can be easily
study photodynamic sensitizers included into CDs attached on oxidized to disulfides; therefore their preparation and purifica-
the surface of polydopamine-covered nanowires [15]. Synthe- tion must be performed under inert atmosphere.
ses of several sulfanyl group-containing CD derivatives suit-
able for this purpose were published. The first method [16] is Then we optimized methods for the preparation of β-CD-S-X-
using a direct substitution of 6I-O-(p-toluenesulfonyl)-β-CD SH derivatives (5a–g, Scheme 2) from Ts-β-CD for two types
with dithiols. We also intended to use this method, but the de- of compounds in which X is either a pure alkylene group
scribed procedure gives only yields around 20%. The second –(CH2)m– (m = 2, 3, 5, 8) or the oligoethylene glycol group
method [13] is using a disulfide of mercaptopropionic acid –CH2(CH2OCH2)nCH2– (n = 1, 2, 3). In addition, general high
which is coupled by an amide bond to two molecules of yielding methods for conversion of the prepared CD-thiols to
6
I-amino-β-CD to form a stable CD disulfide derivative. This CD disulfides (6a–g) by air oxidation and the CD disulfides
disulfide can be used directly for functionalization of a gold sur- back to CD-thiols by reduction with ethanethiol were de-
face, but its reduction to thiol was not described. In any case, veloped.
the amide-containing derivative might not be stable enough
under basic conditions needed for the polydopamine derivatiza- At first, we tried to reproduce the synthesis of the compound 5g
tion by the thiol. Besides, the common problem with the prepa- (Scheme 2) according to the published procedure [12]. Product
ration of this type of sulfanyl derivatives – formation of disul- 5g was detected in the reaction mixture by MS but to isolate it
fide byproducts – was not addressed in the literature at all. in a sufficient yield was difficult. The main byproduct was the
Therefore, we decided to develop more general procedures for corresponding disulfide 6g which is formed from 5g by air oxi-
the preparation of such CD derivatives and also a method for dation. Moreover, the obtained alkylene derivative 5g had a low
controlled preparation of corresponding disulfides, which are solubility in water and water/alcohol mixtures what represented
much more stable alternatives to the thiols for a longer storage. quite an obstacle for the intended use – derivatization of solid
Scheme 1: Synthesis of oligoethylene glycol dithiols.
350

Beilstein J. Org. Chem. 2016, 12, 349–352.
Scheme 2: Synthesis of β-cyclodextrinthiols and -disulfides.
surfaces by treatment with the water solution of the CD deriva- water) was used instead. This optimized procedure gave the
tive.
target compounds 5a–g in 60–90% yield, and the unreacted
dithiols could be easily recovered. Oxidation products of com-
Therefore, we decided also to prepare the derivatives contain- pounds 5a–g (disulfides 6a–g) are quite stable compounds and
ing the more hydrophilic and flexible oligoethylene glycol were prepared in quantitative yield just by bubbling air through
linker, which have been successfully applied in several studies the water/methanol solution of the thiol which was basified by
to position the CD units at a sufficient distance from the solid addition of aqueous ammonia. The disulfides 6 can be used, as
surface. These linkers also have the advantage, compared to the well as the thiols, for the attachment of the cyclodextrin cavity
aliphatic chain linkers, in a lower tendency to form an inclusion to a gold surface. So they can be used instead of the thiols in ap-
complex with β-CD [22], i.e., a suitable accessibility of the plications where well defined starting compounds are needed.
cavity should be kept, and further inclusion complexes could be On the other hand, for applications where only the thiol can be
formed with the guests.
used (like attachment to polydopamine-coated surfaces), and the
pure compound is often needed, the disulfide can be prepared in
Strict inert conditions are also required for the next synthetic larger amounts and used for a long term storage. The corre-
step – preparation of compounds 5. The air had to be removed sponding pure thiol can be then prepared when needed by a
from the reaction mixture by bubbling argon through the soni- simple one step high yielding procedure developed for com-
cated solution. The ideal solvent mixture for this reaction, pound 6e (Scheme 2), which does not require any chromato-
which dissolves both reactants, proved to be water/methanol 1:1 graphic separation and uses ethanethiol in basic solution as the
in which the reaction reached a complete conversion of the reducing agent. The separation of the thiol product consists just
starting Ts-β-CD in 20 h. The crucial step of the work-up was of its precipitation with acetone from the reaction mixture. This
the acidification of the basic reaction mixture and the extrac- separation method is very efficient and is used very often for
tion of the unreacted dithiols with chloroform. The prepared separation of monosubstituted CD derivatives. The same reac-
CD-thiols form disulfides very quickly under basic conditions tion conditions, as for compound 6e, were used for the reduc-
but are reasonably stable under neutral and acidic conditions. tion of all disulfides 6 on TLC scale. The TLC proved a conver-
Therefore, the final chromatographic separation could not be sion to the thiol for all of them. The only compound which was
done in the common elution mixture (propan-1-ol/water/ not completely converted under the given conditions was 6g,
ammonia) but the neutral solvent mixture (butan-1-ol/ethanol/ most probably due to its low solubility.
351

Beilstein J. Org. Chem. 2016, 12, 349–352.
1
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tion. The main problem – formation of the corresponding disul-
fides by air oxidation – could be suppressed substantially by
using an inert atmosphere and performing work-up under acidic
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stable disulfide byproducts can be obtained from the thiols in
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and the corresponding thiol can be prepared in one simple syn-
thetic step and isolated by precipitation.
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Supporting Information
Supporting Information File 1
General experimental procedures, instruments, materials.
Detailed experimental procedures and characterization data
for newly prepared compounds. 1H and 13C NMR spectra
of prepared compounds.
2
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J. Phys.: Condens. Matter 2012, 24, No. 164211.
doi:10.1088/0953-8984/24/16/164211
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Dargaville, T. R. Org. Lett. 2011, 13, 6006–6009.
doi:10.1021/ol202051y
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-12-38-S1.pdf]
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Polym. Adv. Technol. 1999, 10, 3–12.
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Acknowledgements
The work has been supported by Grant Agency of the Czech
Republic (project No. 13-01440S)
License and Terms
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