Mono-6-(O-2,4,6-triisopropylbenzenesulfonyl)-γ-cyclodextrin, a novel intermediate for the synthesis of mono-functionalised γ-cyclodextrins

Article abstract of DOI:10.1016/S0040-4039(01)01934-7

A reaction between γ-cyclodextrin (γ-CD) and 2,4,6-triisopropylbenzenesulfonyl chloride in pyridine gave mono-6-(O-2,4,6-triisopropylbenzenesulfonyl)-γ-cyclodextrin in good yield (～69%) and high purity (>98%). In contrast to other sulfonylations of γ-CD, this reaction did not give di- or tri-substituted side products and is thus useful for preparing pure mono-substituted γ-CD derivatives.

Full text of DOI:10.1016/S0040-4039(01)01934-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8897–8899
Mono-6-(O-2,4,6-triisopropylbenzenesulfonyl)-g-cyclodextrin,
a novel intermediate for the synthesis of mono-functionalised
g-cyclodextrins
Ronald Palin,* Simon J. A. Grove, Alan B. Prosser and Ming-Qiang Zhang
Department of Medicinal Chemistry, Organon Laboratories Ltd., Newhouse ML1 5SH, Scotland, UK
Received 13 July 2001; revised 1 October 2001; accepted 12 October 2001
Abstract—A reaction between g-cyclodextrin (g-CD) and 2,4,6-triisopropylbenzenesulfonyl chloride in pyridine gave mono-6-(O-
2,4,6-triisopropylbenzenesulfonyl)-g-cyclodextrin in good yield (ꢀ69%) and high purity (>98%). In contrast to other sulfonyla-
tions of g-CD, this reaction did not give di- or tri-substituted side products and is thus useful for preparing pure mono-substituted
g-CD derivatives. © 2001 Elsevier Science Ltd. All rights reserved.
Cyclodextrins (CDs) have found wide utility in recent
years in such fields as drug formulation,1 waste man-
agement,2 chromatographic supports3 and artificial
enzymes.4 In order to expand these areas of industrial
applications, the synthesis of functionalised CDs on a
preparative scale is necessary. The purity of CDs is
often one of the key factors for success, especially in the
area of pharmaceutical applications.1 Despite a consid-
erable amount of synthetic effort,5 several obstacles
remain for selective CD derivatisation in an industrial
scale with high purity. Firstly, only mono- and per-sub-
stitutions are feasible, and secondly, the yields are
usually very low and purification requires tedious chro-
matographic work. Therefore, chemically modified CDs
are expensive and at present only statistical mixtures
are commercially available.
one of the C(6) hydroxyls converted into a suitable
leaving group such as sulfonate or halide6–9 (Scheme 1).
Reaction of a- or b-CD with p-toluenesulfonyl chloride
in pyridine gives mixtures of mono-, di- and tri-adducts
arising from polysulfonation of the primary face.10
Extensive chromatography and crystallisation are nec-
essary to yield the desired monotosylates with low
yields (20–30%). It has been reported6 that pyridine
forms a pyridinium complex with the CD cavity and
directs the reaction to the 6-position whereas in DMF
sulfonation occurs on both faces of the CD. The bigger
cavity size of g-CD causes polysubstitution when
reacted with p-toluenesulfonyl chloride.11 Although
mono-6-(2-naphthalenesulfonyl)-g-CD is useful for
selective C(6) mono-substitution, purification of this
compound is not always easy, e.g. ion-exchange12 or
reverse phase HPLC.13 We have experienced di- and
tri-adduct formation when preparing mono-6-(2-naph-
Mono-6-functionalised CDs are often prepared by
nucleophilic displacement of an intermediate having
Scheme 1.
Keywords: g-cyclodextrins; mono-substitution; sulfonation.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01934-7

8898
R. Palin et al. / Tetrahedron Letters 42 (2001) 8897–8899
thalenesulfonyl)-g-CD according to literature proce-
dures. Purification has been attempted using charcoal
columns and crystallisation without success, which has
prompted our efforts to find a more convenient route to
the C(6) mono substituted g-CDs.
The other sulfonyl chlorides used presented various
problems. 4-(Chlorosulfonyl)benzoic acid (entry 6) for
example substituted both the primary and secondary
faces of g-CD. ‘3,6-anhydro’ formation also occurs,
derived from one of the 3-hydroxyls displacing the C(6)
sulfonate. Although some of the desired C(6) mono-
derivative was formed, it was not possible to purify it
using the amine based Sephadex DEAE-A25 resin chro-
matography. When dansyl chloride (entry 5) was the
substrate some mono-derivative formed but purification
proved fruitless with either the acid based Sephadex
CM-25 or Dianion HP-20 resin chromatography. 2,5-
Dinitrobenzenesulfonyl chloride (entry 4) provided no
mono-substituted material and mesitylene chloride
(entry 3) afforded a mixture of mono- and di-adducts
inseparable after crystallisation.
Here we report a convenient preparation of highly pure
mono-6-(O-2,4,6-triisopropylbenzenesulfonyl)-g-CD14
in good yield. Several other arenesulfonylations were
also investigated for comparison. The selection of these
substrates is based on their potential for easy purifica-
tion, e.g. a handle for ion-exchange chromatography,
crystallisation, etc.
The results are shown in Table 1 for the six different
arenesulfonylations investigated. It is interesting to note
that reaction with 2-naphthalenesulfonyl chloride (entry
2) yielded considerable amount of di-substituted g-CD
even with reduced reaction times. The longer reaction
times resulted in polysubstituted derivatives. Crystalli-
sation of this mixture from water gave no pure mono-
derivative.
Reaction of g-CD with the sterically more hindered
2,4,6-triisopropylbenzenesulfonyl chloride (entry 1)
efficiently produced the C(6) mono-derivative in good
yield. In fact the only side product detected is the
corresponding sulfonic acid, arising from the hydrolysis
Table 1. Sulfonation of g-CD

R. Palin et al. / Tetrahedron Letters 42 (2001) 8897–8899
8899
of the excess starting sulfonyl chloride on work-up. The
C(6) mono sulfonate is conveniently separated from
any impurities by treating with resin bound carbonate
or crystallisation from water in high purity (>98%).
This mono-derivative has been displaced with common
nucleophiles such as azide15 and thiophenol providing
evidence that it is a suitable synthon for C(6) mono-
functionalisation of g-CD. Considering that the impu-
rity present in this sample is the corresponding sulfonic
acid, which is easily removed, we believe that this
method provides the most convenient route to the C(6)
mono-substituted g-CD to date.
12. Uekama, K.; Minami, K.; Hirayama, F. J. Med. Chem.
1997, 40, 2755–2761.
13. Fujita, K.; Tahara, T.; Imoto, T.; Koga, T. Chem. Lett.
1988, 1329–1332.
14. Mono-6-(O-2,4,6-triisopropylbenzenesulfonyl)-k-CD. To a
dry round-bottomed flask was added pyridine (300 ml),
followed by g-CD (5.0 g, 3.85 mmol). After stirring for 30
min at room temperature under nitrogen, dissolution
occurred. 2,4,6-Triisopropylbenzenesulfonyl chloride (3.5
g, 11.56 mmol) was added and stirred for 24 h. The
mixture was evaporated to low volume and acetone (500
ml) added. The resulting precipitate was filtered and dried
at 60°C under vacuum to leave 5.0 g of crude product
(LC–MS taken at this point). 1.0 g of crude material was
dissolved in DMF (10 ml) and stirred with resin-bound
carbonate at room temperature for 24 h. The resin was
filtered and the solution evaporated to low volume. Ace-
tone (100 ml) was added and the resultant solid filtered
and dried at 60°C under vacuum to leave mono-6-(O-
2,4,6-triisopropylbenzenesulfonyl)-g-CD (834 mg, 69%)
Acknowledgements
The authors would like to thank their colleagues in the
Department of Analytical Chemistry, Organon Labora-
tories Ltd., for the measurement of LC–MS and vari-
ous analyses.
1
as a white solid. H NMR (D2O)/DMSO) l 7.36 (2H, s,
Ar-H), 5.42 (1H, s, OH), 5.18–5.00 (8H, m, CyD H-1),
4.40–4.32 (1H, m, CH2OSO2Ar), 4.22–4.09 (2H, m,
CH2OSO2Ar+CyD H-5), 4.23–3.45 (47H, m, CyD 2, 3, 4,
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