A facile synthesis of novel cyclodextrin derivatives incorporating one beta-(1,4)-glucosidic bond and their unique inclusion ability.

Article abstract of DOI:10.1039/b309261e

Novel cyclodextrin derivatives incorporating one (1,4)-glucosidic bond are easily synthesized in three steps from permethylated alpha- and beta-cyclodextrins, and such host molecules show inclusion selectivity for sodium m-nitrobenzoate over the corresponding p-isomer, in contrast to the cases of the parent permethylated alpha- and beta-cyclodextrins.

Full text of DOI:10.1039/b309261e

A facile synthesis of novel cyclodextrin derivatives incorporating one
b-(1,4)-glucosidic bond and their unique inclusion ability†
Toshiyuki Kida, Akira Kikuzawa, Yohji Nakatsuji and Mitsuru Akashi*
Department of Molecular Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka,
Suita, Osaka 565-0871, Japan. E-mail: akashi@chem.eng.osaka-u.ac.jp; Fax: +81-6-6879-7359;
Tel: +81-6-6879-7356
Received (in Cambridge, UK) 6th August 2003, Accepted 24th October 2003
First published as an Advance Article on the web 10th November 2003
Novel cyclodextrin derivatives incorporating one b-
1,4)-glucosidic bond are easily synthesized in three steps
from permethylated a- and b-cyclodextrins, and such host
molecules show inclusion selectivity for sodium m-ni-
trobenzoate over the corresponding p-isomer, in contrast to
the cases of the parent permethylated a- and b-cyclodex-
trins.
1 by cleavage of one a-(1,4)-glucosidic bond, the reaction of the
C-1 hydroxyl group on acyclic maltooligosaccharide deriva-
tives 2 with trichloroacetonitrile, and the intramolecular
glucosidation of the resulting trichloroacetimidates 3. Recently,
we developed an efficient method for the selective cleavage of
one glucosidic bond of permethylated a-CD 1a by treatment
(
with 30% aq. HClO
4
at room temperature.3h This method was
also successfully applied to the cleavage of one glucosidic bond
Cyclodextrins (CDs) are a class of cyclic oligosaccharides
of the permethylated b-CD 1b to give the desired maltoheptaose
1
consisting of several a-(1,4)-linked
D
-glucopyranose units and
derivative in 75% isolated yield. H NMR spectra in CDCl
3
have a hydrophobic cavity into which a guest molecule of
appropriate size and shape is incorporated in aqueous media.
Much effort has been devoted to the chemical modification of
CDs in order to improve and control their inclusion ability.1
Most of such work, however, has been limited to the
modification of the hydroxyl groups on the upper and/or lower
rims of CDs.2 Recently, the modification of the CD ring
skeleton as another methodology has attracted increasing
show that 2a and 2b are obtained as 55 : 45 and 65 : 35 mixtures
of the a- and b-anomers, respectively. Reactions of 2a and 2b
2 3 2 2
with trichloroacetonitrile in the presence of Cs CO in CH Cl
9
at room temperature almost quantitatively afforded the corre-
sponding trichloroacetimidates 3a and 3b, respectively. Under
such reaction conditions, the C-4 hydroxyl groups on the
terminal glucose units in 2a and 2b did not react with
trichloroacetonitrile, possibly due to the larger steric hindrance.
Without further purification of these trichloroacetimidates, the
3
attention, because such modification is believed to cause a
more significant change in the cavity size and/or shape of CDs,
thus altering more remarkably the original inclusion ability and
selectivity, compared with the modification of the CD hydroxyl
groups. Conversion of the a-(1,4)-glucosidic bonds of CDs into
BF
3
·OEt
2
-promoted intramolecular glucosidation in the pres-
Cl at room
ence of powdered molecular sieves 4A in CH
2
2
temperature10 was carried out to give the desired cyclic
compounds 4a and 4b bearing one b-(1,4)-glucosidic bond in
14% and 18% yields, respectively. Here the corresponding
permethylated CDs 1a and 1b were also isolated as by-products
in 4% and 5% yields, respectively. The separation of 4a and 4b
from the corresponding a/b anomeric mixtures was success-
4
other types of interglucosidic linkages, such as b-(1,3)- and b-
5
(
1,6)-glucosidic bonds, is one of the most effective methods to
3e
modify the CD ring skeleton. These synthetic processes,
however, have required considerably more reaction steps in
comparison with the modification of the CD hydroxyl groups.
For example, Ogawa et al. reported the synthesis of an
interesting cyclodextrin analog consisting of one a-(1,6)-gluco-
sidic bond and five a-(1,4)-glucosidic bonds, but the synthetic
approach required more than 15 reaction steps from
-maltose.6
D
Although these CD derivatives with different interglucosidic
linkages are expected to show unique complexation behavior,
the binding ability of such host molecules has not yet been
described except for the case of b-(1,6)-linked cycloglucote-
traose peracetate which exhibits metal cation-binding ability.7
Therefore, the development of an alternative methodology for
facile synthesis of CD derivatives incorporating different
interglucosidic bonds from that of the native CDs and the
elucidation of their binding properties are strongly desired. In
this communication, we report a facile synthesis of novel CD
derivatives incorporating one b-(1,4)-glucosidic bond and their
unique inclusion ability toward m- and p-nitrobenzoates.
The skeleton-modified CD derivatives 4a and 4b, in which
one a-(1,4)-glucosidic bond of permethylated a- and b-CDs is
replaced by a b-(1,4)-glucosidic bond, were chosen as the target
molecules. Scheme 1 shows the synthetic route to 4a and 4b.
According to the previously reported method, a- and b-CDs
were converted into the corresponding permethylated deriva-
8
tives 1a and 1b, respectively. Conversion of one a-(1,4)-gluco-
sidic bond into a b-(1,4)-glucosidic bond was carried out in
three reaction steps: the ring-opening of the permethylated CD
1
†
Electronic supplementary information (ESI) available: H NMR spectra
of 4a and 4b; NMR chemical shifts of the carbohydrate protons of 4a and
b; HPLC chromatograms of 4a and 4b. See http://www.rsc.org/suppdata/
4
cc/b3/b309261e/
Scheme 1
3
020
CHEM. COMMUN., 2003, 3020–3021
This journal is © The Royal Society of Chemistry 2003

fully carried out by reversed-phase column chromatography
with acetonitrile as an eluent. The use of trimethylsilyl triflate
into a b-(1,4)-glucosidic bond causes a reversal of the original
inclusion selectivity. To the best of our knowledge, this is the
first example of CD derivatives exhibiting clear inclusion
selectivity for m-substituted benzoate over the corresponding p-
isomer.
In conclusion, we have successfully developed a facile
synthetic route to novel CD derivatives incorporating one b-
(1,4)-glucosidic bond and demonstrated that such CD deriva-
tives show different inclusion ability and selectivity from those
of the parent permethylated a- and b-CDs. Work on elucidation
of the structures of the CD derivatives and their complexes with
MNB and PNB is now in progress in our laboratory.
This work was supported by a Grant-in-Aid for Scientific
Research (No. 14750668) from the Japan Society of Promotion
of Science.
3 2
(TMSOTf) instead of BF ·OEt in these cycloglucosidations
somewhat lowered the yields of 4a and 4b to 7% and 10%
yields, respectively. The structures of these CD derivatives were
confirmed by NMR and mass spectra.‡ Intense molecular ion
signals at m/z 1248 (M+Na) and 1452 (M+Na) were observed in
1
MALDI-TOF mass spectra of 4a and 4b, respectively. In the H
NMR spectrum of 4a, the anomeric proton signals were
observed in the range of 4.5 to 5.7 ppm. Among them, a signal
present at 4.56 ppm as a doublet can be assigned to the anomeric
proton with b-
1,2 = 7.7 Hz). In the case of 4b, the anomeric protons were
clearly separated into seven signals and the one at 4.70 ppm (J1,2
-configuration.
D-configuration by the larger coupling constant
(J
=
7.0 Hz) is assigned to the proton with b-
D
These NMR results suggest that both 4a and 4b have
unsymmetrical structures, in contrast to the cases of the
permethylated a- and b-CDs.
Notes and references
1
‡
Spectroscopic data for 4a: mp 88–90 °C; H NMR (400 MHz, CDCl
3
)
We determined the stability constants of the complexes of
d 5.62 (d, 1H, J = 3.3 Hz), 5.08 (m, 2H), 5.04 (d, 1H, J = 3.3 Hz), 5.02 (d,
these host molecules 4a and 4b with sodium m-nitrobenzoate
1
6
3
H, J = 3.3 Hz), 4.56 (d, 1H, J = 7.7 Hz), 4.15 (m, 1H), 3.44–3.91 (m,
5H), 3.37–3.40 (m, 15H), 3.33 (s, 3H), 3.25 (m, 1H), 3.15–3.18 (m, 4H),
.09 (t, 1H, J = 8 Hz); MALDI-TOF m/z: 1248 [M+Na] , 1264 [M+K] ;
1
(
MNB) and sodium p-nitrobenzoate (PNB) by the H NMR
titration method in D
2
O including 132 mM NaOD and 50 mM
+
+
KCl (Table 1). The upfield shift of the signals of the anomeric
protons of these host molecules was observed upon addition of
the m- and p-isomers of sodium nitrobenzoate, suggesting that
the aromatic parts of these guest molecules are incorporated into
the cavity of 4a and 4b. The inclusion ability of host 4a toward
both guest molecules was lower than that of the parent
permethylated a-CD 1a. On the other hand, host 4b exhibited
higher inclusion ability toward the m-isomer than the parent
permethylated b-CD 1b, while these hosts showed almost the
same inclusion ability toward the p-isomer. There was little
difference in the inclusion ability toward either guest between
Anal. Calcd for C54
7.64%.
For 4b: mp 92–94 °C; H NMR (400 MHz, CDCl
Hz), 5.33 (d, 1H, J = 3.7 Hz), 5.28 (d, 1H, J = 3.3 Hz), 5.23 (d, 1H, J =
H
96
O
30: C, 52.93; H, 7.90. Found: C, 52.74; H,
1
3
) d 5.63 (d, 1H, J = 3.7
3
.7 Hz), 5.09 (d, 1H, J = 3.3 Hz), 5.06 (d, 1H, J = 3.3 Hz), 4.70 (d, 1H, J
=
7.0 Hz), 4.01 (m, 1H), 3.40–3.95 (m, 75H), 3.31–3.39 (m, 22H),
3
.16–3.28 (m, 6H), 3.10 (t, 1H, J = 7.3 Hz); MALDI-TOF m/z: 1452
+
+
[M+Na] , 1468 [M+K] ; Anal. Calcd for C63
112
H O35: C, 52.93; H, 7.90.
Found: C, 52.58; H, 7.56%.
1 (a) G. Wenz, Angew. Chem., Int. Ed. Engl., 1994, 33, 803; (b) J. Szejtli
and T. Osa, Comprehensive Supramolecular Chemistry, Vol. 3 (Eds.: J.
L. Atwood, J. E. D. Davies, D. D. MacNicol, F. Vögtle and J.-M. Lehn),
Pergamon, Oxford, 1996.
4
a and 4b, in contrast to the cases of 1a and 1b where the former
host formed a more stable complex with either guest than the
latter. These results clearly indicate that the hosts 4a and 4b
possess different cavity shapes from those of the corresponding
permethylated CDs. Interestingly, hosts 4a and 4b showed
2
(a) A. P. Croft and R. A. Bartsch, Tetrahedron, 1983, 39, 1417; (b) C.
J. Easton and S. F. Lincoln, Chem. Soc. Rev., 1996, 25, 163; (c) A. R.
Khan, P. Forgo, K. J. Stine and V. T. D’Souza, Chem. Rev., 1998, 98,
1
977; (d) R. Breslow and S. D. Dong, Chem. Rev., 1998, 98, 1997.
inclusion selectivity for the m-isomer over the p-isomer (KMNB
/
3 (a) A. Gadelle and J. Defaye, Angew. Chem., Int. Ed. Engl., 1991, 30,
78; (b) P. R. Ashton, P. Ellwood, I. Staton and J. F. Stoddart, Angew.
Chem., Int. Ed. Engl., 1991, 30, 80; (c) R. Bürli and A. Vasella, Angew.
Chem., Int. Ed. Engl., 1997, 36, 1852; (d) J. C. Morales, D. Zurita and
S. Penadés, J. Org. Chem., 1998, 63, 9212; (e) G. Gattuso, S. A.
Nepogodiev and J. F. Stoddart, Chem. Rev., 1998, 98, 1919; (f) B.
Hoffmann, D. Zanini, I. Ripoche, R. Bürli and A. Vasella, Helv. Chim.
Acta, 2001, 84, 1862; (g) B. Hoffmann, B. Bernet and A. Vasella, Helv.
Chim. Acta, 2002, 85, 265; (h) T. Kida, T. Michinobu, W. Zhang, Y.
Nakatsuji and I. Ikeda, Chem. Commun., 2002, 1596.
K
PNB = 1.8 ± 0.5 for 4a, KMNB/KPNB = 1.8 ± 0.6 for 4b), in
contrast to the cases of the permethylated CDs with the p-isomer
selectivity (KPNB/KMNB = 2.1 ± 0.4 for 1a, KPNB/KMNB = 2.6
±
1.0 for 1b). This finding demonstrates that the conversion of
one a-(1,4)-glucosidic bond of permethylated a- and b-CDs
21
Table 1 Stability constants (M ) of complexes of CD derivatives 4a and
a
a
b
4
2
b with MNB and PNB in D O at 25 °C
4
P. M. Collins and M. H. Ali, Tetrahedron Lett., 1990, 31, 4517.
Guest
MNB
5 G. Excoffier, M. Paillet and M. Vignon, Carbohydr. Res., 1985, 135,
C10.
6 Y. Takahashi and T. Ogawa, Carbohydr. Res., 1987, 169, 127.
Host
PNB
28 ± 2
23 ± 2
410 ± 20
21 ± 4
7
(a) G. Bonas, C. Bosso and M. R. Vignon, J. Inclusion Phenom., 1989,
7, 637; (b) G. Bonas and M. R. Vignon, J. Biomol. Struct. Dyn., 1991,
8, 781.
4a
4b
1a
1b
50 ± 10
40 ± 10
200 ± 30
9 ± 2
8 J. Boger, R. J. Corcoran and J.-M. Lehn, Helv. Chim. Acta, 1978, 61,
2190.
a
b
9 D. Becker and N. Galili, Carbohydr. Res., 1993, 248, 129.
10 R. R. Schmidt and J. Michel, Angew. Chem., Int. Ed. Engl., 1980, 19,
MNB
=
sodium m-nitrobenzoate; PNB
=
sodium p-nitrobenzoate.
Including 132 mM NaOD and 50 mM KCl.
7
31.
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