A convenient and economic method for the synthesis of mono-2-tosyl-β- cyclodextrin

Article abstract of DOI:10.1007/s00706-008-0884-6

A convenient and economic method for the regioselective synthesis of mono-2-tosyl-β-cyclodextrin was achieved by using the combination of N-tosylimidazole and carbonate buffer in DMF, the reaction does not require strict anhydrous or specific basic cataly

Full text of DOI:10.1007/s00706-008-0884-6

Monatsh Chem 139, 1109–1111 (2008)
DOI 10.1007/s00706-008-0884-6
Printed in The Netherlands
A convenient and economic method for the synthesis
of mono-2-tosyl-b-cyclodextrin
1
;2
1
1
Zhi-Zhong Wang , Guang-Yun He , Run-Hua Lu
1
Chinese Academy of Sciences, Chengdu Institute of Biology, Chengdu, China
Graduate University of Chinese Academy of Sciences, Beijing, China
2
Received 5 December 2007; Accepted 25 December 2007; Published online 19 June 2008
Springer-Verlag 2008
#
Abstract A convenient and economic method for the
regioselective synthesis of mono-2-tosyl-ꢀ-cyclodex-
trin was achieved by using the combination of N-tosy-
limidazole and carbonate buffer in DMF, the reaction
does not require strict anhydrous or specific basic
catalysts.
used intermediate for preparing other functional
groups, and whose synthesis is still difficult [3]. In
1982, Breslow and Ueno demonstrated the authenti-
cally successful sulfonylation of the C–2 OH of ꢀ-
CD by tosyl transfer from the m-nitrophenyl tosylate
bound in the CD cavity, although in only ca. 10%
yield [4]. In recent years, successful strategies were
developed, D’Souza and co-workers sulfonylated the
C–2 OH by deprotonation with NaH and subsequent
reaction with sulfonyl chloride or sulfonyltriazole
Keywords Cyclodextrins; Mono-2-tosyl-ꢀ-cyclodextrin; Re-
gioselective synthesis; Sulfonylimidazole.
[
5], this method needs the use of strong alkali as
Introduction
reactant. Teranishi et al. sulfonylated the C–2 OH
with N-sulfonylimidazole in DMF by utilizing mo-
lecular sieves as promoters [6], which took long time
for completion. Hua Yu et al. sulfonylated the C–2
OH with N-sulfonylimidazole in DMF by utilizing
Cs CO – an expensive catalyst [7]. Yields along
these routes are usually 20–30%. Herein, we report
a convenient and economic method for monosulfon-
ylation of ꢀ-CD at the 2-position.
Cyclodextrins (CDs) are well-known cyclic oligo-
saccharides consisting of six or more a-1,4-linked
D-glucopyranose units, which possess the secondary
C–2 and C–3 hydroxyls on their more open face
and the primary C–6 hydroxyls on the other face.
Cyclodextrins have been widely used as artificial
enzymes, sensors, drug delivery systems, and chiral
reagents [1], owing to their hydrophobic and opti-
cally active interior. Since the more open secondary
hydroxyl side of CDs is stated to be catalytically
very important [2], modifications of this face are
believed to produce valuable derivatives for catalysis,
enzyme mimic, and chiral discrimination, etc. Mono-
2
3
2
-tosyl-ꢀ-cyclodextrin (1, Scheme 1) is a widely
Correspondence: Run-Hua Lu, Chinese Academy of Sciences,
Chengdu Institute of Biology, Chengdu 610041, China.
E-mail: lurh@cib.ac.cn
Scheme 1

1
110
Z.-Z Wang et al.
Fig. 1 ESI (þ) mass spectra in the positive ion mode for (a) compound 1; (b) ESI (þ)-MS=MS of the ion of m=z ¼ 1311
Results and discussion
carbonate buffer solution in reasonable yield. The
reaction does not require strict anhydrous or specific
basic catalysts.
In our work, we found that simply mixing ꢀ-CD
with N-tosylimidazole in DMF did not result in
an obvious reaction when heated at 60 C for 4 h.
ꢀ
Carbonate buffer (pH 9.9) can efficiently promote
the reaction. The reaction is highly regioselective at
the 2-position, generating mainly monotosylate and a
little ditosylates.
Experimental
1
NMR spectra were recorded on a Bruker AM-600 ( H
13
6
a standard. The positive-ion ESI-MS experiments were
00 and C 150 MHz) in DMSO–d solutions with TMS as
6
n
DECA
The optimized conditions for the synthesis of
monotosylate are ꢀ-CD=N-sulfonylimidazole ¼ 1=1
performed using a ThermoQuest Finnigan LCQ
system
equipped with an ESI source (ThermoQuest LC=MS Division,
San Jose, CA, USA). N-Tosylimidazole was prepared accord-
ing to the method described in Ref. [8]. Carbonate buffer
3
(
6
mol=mol), ꢀ-CD=carbonate buffer ¼ 1=6 (g=cm ) at
ꢀ
0 C for 2 h. TLC demonstrated the formation of sig-
(
0
0.2M, pH 9.9) was prepared by mixing equal volumes of
.2 M sodium carbonate and 0.2M sodium bicarbonate. All
nificant amounts of multitosylates under higher tem-
perature and longer time.
The purity and structure were confirmed by TLC,
ESI-MS, and NMR spectra. TLC on silica gel using
other chemicals were of commercial grade without further
purification.
General experimental procedure
To a stirred solution of 2 g ꢀ-CD with one equiv of N-tosyl-
n-butanol:ethanol:H O¼5:4:3 (v=v) showed one spot
2
at R ¼ 0.5 for the product 1. In the positive ion
f
3
imidazole in 60cm DMF, 12cm of 0.2M carbonate buffer
3
mode ESI-MS (Fig. 1), two peaks were observed
at m=z ¼ 1139 and 1311 corresponding to the mono-
ꢀ
(pH 9.9) were added. The reaction mixture was heated at 60 C
for 2 h. Then the mixture was neutralized with 1 N HCL,
þ
3
evaporated in vacuo to a volume of ca. 5, and 300 cm acetone
tosylate of ꢀ-CD (M þ Na ). MS=MS conformed
that m=z ¼ 1139 ion was produced from m=z ¼ 1311
were added to precipitate cyclodextrin derivatives. The col-
lected solid was subjected to a RP-18 column eluted with
H O–MeOH; the eluent composition was gradually changed
1311 ion with the neutral loss of TsOH. Those data
indicated the product 1 was highly pure.
2
(MeOH–H O, 0–10–20–30%) until the pure product was
2
In conclusion, a convenient and economic method
for the synthesis of mono-2-tosyl-ꢀ-cyclodextrin was
developed, with the use of N-tosylimidazole in DMF-
eluted. The residue obtained after removal of the solvent
was triturated with acetone, filtered off, washed with acetone,
1
and dried. Thus, 0.56 g pure 1 were obtained (28%). H NMR

Synthesis of mono-2-tosyl-ꢀ-cyclodextrin
1111
(
600 MHz, DMSO–d ): ꢁ ¼ 2.40 (s, 3H), 3.23–3.80 (overlap-
Alderman SJ, Claridge TD, Anderson HL (2002) Angew
Chem Int Ed 41:1769; e) Hedges AR (1998) Chem Rev
98:2035; f) Uekama K, Hirayama F, Irie T (1998) Chem
Rev 98:2045
6
ping with HDO, m, 39H), 3.90 (t, 1H, J ¼ 8.3 Hz), 4.05 (dd, 1H,
J ¼ 10.0, 3.3 Hz), 4.16 (d, 1H, J ¼ 3.6Hz), 4.40–4.49 (m, 7H),
4
5
.83 (m, 7H), 5.62–5.73 (m, 10H), 5.76 (d, 1H, J ¼ 6.7 Hz),
.82 (d, 1H, J ¼ 6.2 Hz), 5.85 (d, 1H, J ¼ 6.2 Hz), 7.43 (d, 2H,
2. a) D’Souza VT, Bender ML (1987) Acc Chem Res
20:146; b) Vanetten RL, Sebastian JF, Clowes GA, Bender
ML (1967) J Am Chem Soc 89:3242
3. a) Yuan DQ, Tahara T, Chen WH, Okabe Y, Yang C, Yagi
Y, Nogami Y, Fukudome M, Fujita K (2003) J Org Chem
68:9456; b) Khan AR, Forgo P, Stine KJ, D’Souza VT
(1998) Chem Rev 98:1977
1
3
J ¼ 8.2 Hz), 7.84 (d, 2H, J ¼ 8.2 Hz) ppm; C NMR (150MHz,
DMSO–d ): ꢁ ¼ 21.6, 60.2, 60.4, 69.8, 72.1, 72.3, 72.5, 72.7,
6
7
1
2.8, 72.9, 73.3, 73.4, 80.1, 81.3, 81.9, 82.0, 82.1, 98.6, 102.2,
1
02.4, 102.5, 128.5, 130.2, 133.3, 145.3 ppm. H and C NMR
13
spectra were identical with the authentic mono-2-tosyl-ꢀ-cy-
clodextrin reported in Ref. [4].
4
5
. Ueno A, Breslow R (1982) Tetrahedron Lett 23:3451
. a) Rong D, D’Souza VT (1990) Tetrahedron Lett
Acknowledgements
3
Defaye (2003) J Carbohydr Res 338:451
. a) Teranishi K, Watanabe K, Hisamatsu M, Yamada T
(1998) J Carbohydr Chem 17:489; b) Teranishi K (2000)
1:4275; b) Law H, Baussanne I, Garc Fernandez JM,
Financial support from the Chinese Natural Science
Foundation (No. 20772120) is gratefully acknowledged.
6
Chem Commun 1255; c) Teranishi K (2000) Tetrahedron
Lett 41:7085; d) Teranishi K (2001) Tetrahedron Lett
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