Clockwise-counterclockwise differentiation on the upper rim of a monofunctional γ-cyclodextrin: Efficient topological control in the syntheses of capped cyclodextrins

Article abstract of DOI:10.1039/b612437b

Intramolecular condensation of 6^A-(N-dansyl-l-cysteine)-γ- cyclodextrin occurred only at 6^B-OH of the many OH groups to afford the corresponding lactone with an exo-topology. The Royal Society of Chemistry.

Full text of DOI:10.1039/b612437b

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Clockwise–counterclockwise differentiation on the upper rim of a
monofunctional c-cyclodextrin: efficient topological control in the
syntheses of capped cyclodextrins
Hua Yu,ab De-Qi Yuan,*a Yuji Makino,a Makoto Fukudome,a Ru-Gang Xieb and Kahee Fujita*a
Received (in Cambridge, UK) 30th August 2006, Accepted 25th September 2006
First published as an Advance Article on the web 12th October 2006
DOI: 10.1039/b612437b
Intramolecular condensation of 6A-(N-dansyl-L-cysteine)-
ethanedithiol generated two pairs (endo- and exo-, with the
c-cyclodextrin occurred only at 6B-OH of the many OH groups
pyridoxamino group located near the A or B glucose unit) of
6A,6B-capped CDs, and the rigid exo-pair displayed much higher
to afford the corresponding lactone with an exo-topology.
selectivity than the endo-pair or the flexibly suspended analog in
the transamination reaction of pyruvic acids.4 Although such
Cyclodextrins (CDs) are frequently employed as the guest-binding
elements to develop artificial receptors, supramolecular catalysts,
drug carriers, and so forth.1 With the aim of improving their
existing features as well as creating novel functions, profound
investigations on the modification of CDs have been carried out.2
The functionalities are usually connected to the CD rims via
flexible spacers. However, such functional CDs can adopt many
conformations, most of which do not favor cooperation between
the functionality and the CD cavity or even prevent the functional
CDs from performing with the desired selectivity. The capping
technique in which one organic segment links two glucose units on
the same rim,3 and it was proved efficient in controlling the
geometry of functional groups above the cavity entrance.4
Reaction of 6A,6B-diiodo-b-CD with pyridoxamine-bearing
restriction of the geometry proved efficient in inducing selectivity,
it was not addressed further because of the lack of selective
methods to access the desired geometry. Herein we describe the
first example of topologically controlled syntheses of capped CDs.
c-CD was subjected to tosylation of one 6-OH (Scheme 1),
subsequent substitution with L-cysteine and final reaction with
dansyl chloride to afford 6A-(N-dansyl-L-cysteine)-c-CD (3).
Condensation in DMF gave the corresponding lactone 4 in 53%
yield.{ The TOF-MS spectrum of 4 displayed the expected pseudo-
molecular ions at m/z 1637 (M + Na) and 1653 (M + K). Its
structure and purity were confirmed by NMR (Fig. 1). The
aromatic protons resonated as 4 doublets and one triplet at d 8.53
(d, 1H), 8.29 (d, 2H), 8.13 (d, 1H), 7.32 (d, 1H) and d 7.64 (t, 2H),
respectively. The cysteine segment demonstrated 3 doublets of
doublets at d 3.90 (1H, a-H), 2.79 (1H) and 2.66 (1H, b-H) while
the two geminal protons of S-substituted 6A appeared at d 2.53 (t,
1H), 3.11 (overlapped, 1H). Another pair of geminal protons were
observed at d 4.33 (d, 1H) and 4.03 (overlapped with HDO), much
larger than the chemical shifts of normal 6-Hs. Such a downfield
aDepartment of Molecular Medicinal Sciences, Graduate School of
Biomedical Sciences, Nagasaki University, Bunkyo-machi 1-14,
Nagasaki 852-8521, Japan. E-mail: deqiyuan@nagasaki-u.ac.jp;
fujita@nagasaki-u.ac.jp
bSchool of Chemistry, Sichuan University, Chengdu 610064, Sichuan,
China
Scheme 1
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 5057–5059 | 5057

View Article Online
Fig. 1 1H and 13C NMR spectra of lactone 4 in DMSO-d6/D2O (6 : 1).
shift is indicative of the esterification of that glucose unit.
Consistent with the acylation, a reasonable downfield shift of that
methylene carbon (at d 64.5) was confirmed. The clear one-to-one
nuclei–signal correlations in the 13C NMR spectrum relating the
substituents and modified methylene groups strongly suggested
that lactone 4 is a pure compound rather than a mixture of
regio-isomers.
should be rigid enough to fix the distance between the two sulfonyl
groups, otherwise all possible regio-isomers form with poor
selectivity as in the case of benzophenone 3,39-di(sulfonyl
chloride).5 Even more interesting is that, in addition to the spatial
differentiation, the flexible cysteine moiety can also differentiate
hydroxyl groups in a clockwise–counterclockwise relationship, and
thus ensures an efficient control of the topology of the product
(high endo-/exo-selectivity). The bulky dansyl group is supposed to
display an important role in controlling the regio-selectivity.
Considering the short length of the cysteine moiety, one of the
OH groups adjacent to the cysteine moiety should be most
The above result is somewhat astonishing since the cysteine
moiety is quite flexible and seven primary hydroxyl groups may
compete in the esterification. Arene di(sulfonyl chloride)s are
frequently used to cap CDs at two specific positions, but they
Scheme 2
5058 | Chem. Commun., 2006, 5057–5059
This journal is ß The Royal Society of Chemistry 2006

View Article Online
In conclusion, we have described for the first time how a
functionality at the primary rim of a CD, even one as flexible as
a cysteine moiety, may differentiate hydroxyl groups of the CD in
a clockwise–counterclockwise relationship, and thus afford the
possibility of building a specific topology on the CD rim in a
controlled manner.
Notes and references
{ Compound 2 (1.44 g) and Na2CO3 (0.33 g) were dissolved in water
(15 ml), and an acetonitrile solution (15 ml) containing 0.53 g dansyl
chloride was added. After being stirred at rt for 3 h, the reaction mixture
was adjusted to pH 3 and added to acetone. The precipitates were collected
and chromatographed on a reversed phase Lobar column to afford
compound 3 (1.17 g, 70%). TOF-MS, m/z 1655 (M + Na); 1H NMR
(DMSO-d6), d 8.43 (d, 1H), 8.24 (d, 1H), 8.18 (d, 1H), 7.58 (t, 2H), 7.23 (d,
1H), 5.90–5.73 (m, 18H), 4.88–4.50 (m, 17H), 3.72–3.21 (m, overlapped
with HDO), 2.88–2.80 (m, 9H), 2.57 (dd, 1H) ppm; 13C NMR (DMSO-d6),
d 170.9, 151.1, 136.3, 129.1, 128.9, 127.6, 123.2, 119.2, 114.8, 102.1, 101.7,
101.5, 101.2, 84.2, 81.3, 81.2, 80.9, 80.8, 80.7, 72.9, 72.8, 72.6, 72.4, 72.3,
72.2, 72.0, 71.9, 60.0, 59.9, 59.7, 45.0, 37.3, 33.7 ppm.
Compound 3 (100 mg), DCC (110 mg), and 1-hydroxybenzotriazole
(66 mg) were dissolved in DMF (2 ml), and the resulting solution was
stirred overnight at rt. The reaction mixture was then added to acetone and
the precipitates were collected and chromatographed on a reversed phase
Lobar column to afford lactone 4 (52 mg, 53%). TOF-MS, m/z 1637 (M +
Na) and 1653 (M + K); NMR, Fig. 1.
Fig. 2 HPLC chromatograms of lactone 4 (top), mixture of 7 and 8
(middle), and lactone 4 + mixture of 7 and 8 (bottom). A Cosmosil packed
5C18-AR-II column (4.6 6 150 mm) and a gradient elution of 5–60%
aqueous acetonitrile at a flow rate of 0.8 ml min21 were applied.
susceptible to esterification. Unfortunately, NMR experiments
failed to afford useful information for the identification of that
OH. To solve this problem, we developed another method to
synthesize (N-dansyl cysteine)-capped c-CDs from bifunctional
CDs whose regio-chemistry is unambiguously determined. The 6A-
(N-dansyl-L-cysteine)-6B or H-tosyl-c-CDs 5 and 6,6 stable enough
in aqueous solution, readily underwent intramolecular substitution
in DMF, generating the exo- and endo-topologies, respectively
(Scheme 2). Just stirring 5 in DMF at rt overnight ensured a
complete substitution of tosylate by carboxylate group and the
lactone 7 was isolated in 55% yield.{ The counterclockwise regio-
isomer 6 is less reactive, and its conversion to the corresponding
lactone 8 was realized by an overnight heating of the DMF
solution at 70 uC.
The intramolecular displacement reactions of 5 and 6 were carried out
simply by stirring the bifunctional c-CDs overnight in DMF at rt (for 5) or
at 70 uC (for 6). Work-up of the reaction mixtures by a procedure similar to
that described for lactone 4 afforded lactones 7 and 8 in 55% and 60%
yields, respectively. Lactone 7: TOF-MS and NMR spectra are identical to
those of lactone 4. Lactone 7: TOF-MS, m/z 1637 (M + Na) and 1653 (M
+ K); 13C NMR (DMSO-d6), d 169.7, 150.9, 135.6, 129.4, 128.7, 128.1,
127.6, 123.2, 119.1, 114.8, 102.0, 101.9, 101.7, 101.5, 101.4, 101.1, 100.3,
99.8, 85.5, 81.5, 80.7, 80.5, 80.2, 80.1, 79.4, 79.2, 75.8, 73.9, 73.1, 72.8, 72.7,
72.6, 72.5, 72.4, 72.2, 72.1, 72.0, 71.9, 71.8, 71.7, 71.5, 67.3, 64.0, 60.1, 60.0,
59.6, 59.5, 59.3, 55.5, 44.9, 35.0, 31.8 ppm.
1 W. B. Motherwell, M. J. Bingham and Y. Six, Tetrahedron, 2001, 57,
4663–4686; R. Breslow and S. D. Dong, Chem. Rev., 1998, 98,
1997–2011; A. R. Hedges, Chem. Rev., 1998, 98, 2035–2044;
K. Uekama, F. Hirayama and T. Irie, Chem. Rev., 1998, 98, 2045–2076.
2 D.-Q. Yuan, T. Tahara, W.-H. Chen, Y. Okabe, C. Yang, Y. Yagi,
Y. Nogami, M. Fukudome and K. Fujita, J. Org. Chem., 2003, 68,
9456–9466; A. R. Kahn, P. Forgo, K. J. Stine and V. T. D’Souza, Chem.
Rev., 1998, 98, 1977–1996.
3 I. Tabushi, K. Shimokawa, N. Shimizu, H. Shirakata and K. Fujita,
J. Am. Chem. Soc., 1976, 98, 7855–7856; I. Tabushi, Y. Kuroda,
K. Yokota and L. C. Yuan, J. Am. Chem. Soc., 1981, 103, 711–712;
I. Tabushi, K. Yamamura and T. Nabeshima, J. Am. Chem. Soc., 1984,
106, 5267–5270; I. Tabushi, T. Nabeshima, K. Fujita, A. Matsunaga and
T. Imoto, J. Org. Chem., 1985, 50, 2638–2643; D.-Q. Yuan, T. Yamada
and K. Fujita, Chem. Commun., 2001, 2706–2707. For a recent review on
capped cyclodextrins, see: E. Engeldinger, D. Armspach and D. Matt,
Chem. Rev., 2003, 103, 4147–4173.
Lactones 7 and 8 show the pseudomolecular ions at m/z 1637
(M + Na) and 1653 (M + K) in the TOF-MS spectra. Their NMR
spectra are different from each other but very similar. Both the 1H
and 13C NMR spectra of
7 are superimposable on the
corresponding spectra of 4, indicating that the intramolecular
condensation of 3 occurred at 6B-OH and generated the exo-
topology with a very high selectivity. This assignment was further
confirmed by HPLC analysis.
Due to the topological effect, the two lactones also behave quite
differently on the reversed phase HPLC column. The exo-lactone 7
eluted much slower than the endo-lactone 8, affording the
possibility of making an unambiguous identification of the lactone
4 by HPLC. As shown in Fig. 2, lactone 4 displayed a single peak
at Rf = ca. 16 min, and this peak was superimposed on the one
with longer retention time of the mixture of lactones 7 and 8,
suggesting that lactones 4 and 7 are identical. This result is
consistent with that obtained by NMR spectral analyses and
confirmed the structural assignment of lactone 4.
4 R. Breslow, J. W. Canary, M. Varney, S. T. Waddell and D. Yang, J. Am.
Chem. Soc., 1990, 112, 5212–5219.
5 In the reaction of c-CD with benzophenone 3,39-di(sulfonyl chloride), the
AB-, AC-, and AD-capped c-CDs were isolated in a ratio of ca. 1/2/1.
K. Fujita, K. Koga, M. Fukudomome and D.-Q. Yuan, to be published.
6 Y. Yu, Y. Makino, M. Fukudome, R.-G. Xie, D.-Q. Yuan and K. Fujita,
to be published. Compounds 5 and 6 were prepared from 6A,6B-ditosyl-
c-CD by treatment with equimolar L-cysteine and then dansyl chloride.
Their regio-chemistry was unambiguously determined by enzymatic
conversion of 5 and 6 to the corresponding linear trioses and subsequent
sequence determination of the trioses by NMR and PSD-MS.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 5057–5059 | 5059