Direct and convenient access to mono 3-hydroxy per-O-methylated α-cyclodextrin

Article abstract of DOI:10.1016/j.tetlet.2004.06.003

A direct way to reach mono 3-hydroxy per-O-methylated α-cyclodextrin by de-O-methylation with phenylthiotrimethylsilane is reported. This compound is fully characterized by NMR spectroscopy and liquid chromatography with mass spectroscopy coupling.

Full text of DOI:10.1016/j.tetlet.2004.06.003

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5853–5856
Direct and convenient access to mono 3-hydroxy per-O-methylated
a-cyclodextrin
Thomas Chaise, Eric Bourgeaux, Pascal Cardinael* and J. C. Combret
Laboratoire de chromatographie, Universitꢀe de Rouen, UPRES-EA 2659, Sciences et Mꢀethodes Sꢀeparatives, IRCOF,
76821 Mont Saint Aignan Cedex, France
Received 14 April 2004; revised 27 May 2004; accepted 1 June 2004
Available online 19 June 2004
Abstract—A direct way to reach mono 3-hydroxy per-O-methylated a-cyclodextrin by de-O-methylation with phenylthiotrimeth-
ylsilane is reported. This compound is fully characterized by NMR spectroscopy and liquid chromatography with mass spectroscopy
coupling.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Cyclodextrins (CD) and their derivatives are successfully
used in various chiral chromatographic techniques1–4 for
enantiomers separation: their unique structural and
physical properties allow general use as chiral selectors.
Moreover, coupling several hydroxyl groups’ modifica-
tions lead to derivative compounds with specific physi-
cal, chemical, and/or binding properties, covering a wide
range of applications.1e;5 Nevertheless, modification of
only one hydroxyl group among 21 (for b-CD for
example) or modification of just one glucopyranose unit
is still a difficult task6 since the potentiality of other
hydroxyl groups to react and form by-products.
In order to complete this first set of asymmetric CD
derivatives, this procedure has been investigated to the
preparation of asymmetric b-CD derivatives. In this
context, the unexpected behavior of the per-O-methyl-
ated a-CD met during the first step of the methodology
quoted above, for example, the a-CD’s ring opening is
described.
As previously reported by Sakairi et al.,8 ‘thiolyze’ is an
interesting method to selectively cleave one interglu-
cosidic bond. The reaction was performed by action of
the ‘Hannessian’s reagent’,10 namely phenylthiotri-
methylsilane (PhSTMS) (4 equiv), on the per-O-methyl-
ated CD in presence of zinc bromide (4 equiv) in 1,2-
dichloroethane at room temperature during five days.
This reaction was perfectly reproducible for the b-CD,7
and purification of the mixture by chromatography on
silica gel offered ring opening product as an anomeric
mixture having an a:b ratio of 1:1 (determined by re-
verse phase high performance liquid chromatography
with mass spectroscopy detection (RP-HPLC–MS) and
1H NMR analysis), with a satisfactory yield of 38%.
Recently, a general way to access asymmetric c-CD
derivatives from the permethylated b-CD was developed
in our lab.7 This methodology inspired by Sakairi et al.8
consists in a three-step process: ring opening of the
permethylated b-CD, chain elongation with correctly
modified monosaccharide derivatives and, finally, mac-
rocyclization to obtain desired products. So, the inser-
tion of
a
single glucopyranose unit differently
substituted allows the lost of the pseudo eightfold axis
symmetry of the asymmetric c-CD thus obtained. These
compounds are currently studied in our lab as chiral
selectors for gas chromatography (GC).9
This procedure was repeated for the thiolyze of the per-
O-methylated a-CD (Scheme 1) and the reaction was
monitored by TLC. After five days, TLC showed dif-
ferent spots with almost the same chromatographic
behavior with no ultra violet (UV) absorption at 254 nm
and one spot with UV absorption, which had a lower
retention factor (RF) than the others. RP-HPLC-evap-
orated light scattered detector (ELSD) and RP-HPLC–
MS analyses of the reaction mixture after washings
Keywords: a-Cyclodextrin; Phenylthiotrimethylsilane; de-O-Methyl-
ation; 2I–VI, 3II–VI, 6I–VI-Heptadeca-O-methylcyclomaltohexaose.
* Corresponding author. Tel.: +33-2-35-52-24-12; fax: +33-2-35-52-29-
59; e-mail: pascal.cardinael@univ-rouen.fr
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.003

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T. Chaise et al. / Tetrahedron Letters 45 (2004) 5853–5856
Scheme 1. de-O-Methylation of per-O-methylated a-cyclodextrin.
showed the presence of five compounds: Unchanged 1,
opening product 2, and three isomeric mono hydroxy
per-O-methylated a-CD, among them only product 3
methylation of cyclodextrins using iodotrimethylsilane
were not described in the literature.
has been isolated. Per-O-methylated a-CD
1
In order to ascertain the position of the free hydroxyl
group of the compound 3, O-methylation with 13CH3I
was performed. So, the 13C NMR spectra permits to
attribute unambiguously the free hydroxyl group on the
3-O-hydroxy group position for compound 3 (Fig. 1).
Furthermore, in the 57–63 ppm zoomed area of com-
pound 3 13C NMR spectra, it appears very clearly five
different signals corresponding to the five methyl groups
located at the 3-O-hydroxy group positions (Fig. 1).14
This particular behavior met during this reaction is not
so surprising, since several authors6a;15 already reported
‘reactivity discriminations’. This de-O-methylation
(m=z ¼ 1248:0 [M+Naþ]; rt ¼ 19.8 min; no UV k ¼
254 nm detection), mono hydroxy per-O-methylated a-
CD 300 (m=z ¼ 1234:0 [M+Naþ]; rt ¼ 15.52 min; no UV
k ¼ 254 nm detection), mono hydroxy per-O-methylated
a-CD 30 (m=z ¼ 1234:0 [M+Naþ]; rt ¼ 14.55 min; no UV
k ¼ 254 nm detection), mono hydroxy per-O-methylated
a-CD 3 (m=z ¼ 1234:0 [M+Naþ]; rt ¼ 12.74 min; no UV
k ¼ 254 nm detection), and opening product
2
(m=z ¼ 1358:5 [M+Naþ]; rt ¼ 6.9 min; UV k ¼ 254 nm
detection). Purification using toluene/acetone mixture
on silica gel gave compound 1 and 2 as major products,
compound 3 was in smaller quantity. Using HPLC
analysis comparison, compounds 3 and 300 were respec-
tively, identified as mono 3-hydroxy per-O-methylated
a-cyclodextrin11 and mono 6-hydroxy per-O-methylated
a-cyclodextrin.12 Compound 30 appeared to be mono 2-
hydroxy per-O-methylated a-cyclodextrin. To improve
the reaction yield, other catalysts were used (ZnI2,
TfOTMS, Tf2O) to reach about 15–25%. Yield of 3
depending of the catalyst used but classical use of
complements de-O-methylation performed with DIBAL
12
reported by Sinay and co-workers, which allow
€
access to only mono 6-hydroxy per-O-methylated
a-cyclodextrin and dihydroxy per-O-methylated
a-cyclodextrin.
In conclusion, the fully characterized mono 3-hydroxy
per-O-methylated a-CD can be obtained in a one step
synthesis with a moderate yield of 25%. This method
seems to be quite an easy way versus others synthe-
sis,6c;11;16 which classically use the ‘sledgehammer’
method.
ꢁ
molecular sieves 4 A support formation of 2.
Moreover, a classical de-O-methylation using iodotri-
methylsilane in chloroform13 was performed (1.3 equiv
of TMS-I are added to permethylated a-cyclodextrin in
Isomeric mono hydroxy compounds are currently
studied in our laboratory as chiral selector for chiral
GC.
ꢁ
chloroform (c ¼ 0:04 M) with molecular sieves 4 A un-
der nitrogen atmosphere. The mixture is stirred during
6 h at room temp. When TLC shows two spots, the
reaction mixture is stopped with 4 equiv of methanol.
After diluting with diethyl ether, washing by NaHSO3,
NaHCO3, and NaCl saturated solutions, solvents are
evaporated. Purification is then performed using tolu-
ene/acetone on silica gel). The surprising result leads to
mono 3-hydroxy per-O-methylated a-cyclodextrin (13%)
and mono 2-hydroxy per-O-methylated a-cyclodextrin
(3%, determined by HPLC). To our knowledge, de-O-
Typical procedure: Preparation of mono 3-hydroxy per-
O-methylated a-cyclodextrin 3.
Per-O-methylated a-CD was prepared following the
Schurig procedure.17
Solvents were preliminary distilled and per-O-methyl-
ated a-CD was dry under vaccum at 90 ꢁC.

T. Chaise et al. / Tetrahedron Letters 45 (2004) 5853–5856
5855
Figure 1. Portion of 13C NMR spectra of per-O-methylated a-cyclodextrin.
In a round bottom flask, 3 g (2.45 mmol) of hexakis
(2,3,6-tri-O-methyl)-a-cyclodextrin are dissolved in
60 mL of 1,2-dichloroethane under nitrogen atmo-
sphere. To the stirred mixture, 3.12 g (4 equiv,
9.79 mmol) of zinc iodide and 1.86 mL (4 equiv,
9.83 mmol, 1.79 g) of phenylthiotrimethylsilane were
added and the reaction was performed during five days.
Reaction mixture was poured into 300 mL ice-water and
extracted twice with 200 mL of 1,2-dichloroethane. To
the combined extracts was then added 4:1 (v/v) metha-
nol–triethylamine. The mixture was stirred at room
temperature for 5 h and then concentrated under re-
duced pressure. Residue was diluted with 1,2-dichloro-
ethane and then washed twice with a solution of
NaHCO3 satd, twice with brine, dried under magnesium
sulfate, and evaporated to obtain a slightly yellow syrup.
After chromatography using toluene/acetone (4:1) on
silica gel, 2I–VI, 3II–VI, 6I–VI-heptadeca-O-methylcyclo-
maltohexaose was obtained (740 mg, 25%).
RP-HPLC–MS: CH3OH/H2O (4:1); column HYPER-
SILꢂ C18, 25 cm · 2.1 cm · 5 lm; flow ¼ 0.25 mL/min;
rt ¼ 12.74 min; m=z ¼ 1234:01 [M+Na]þ([C53H94O30+
25
Na]þ requires 1233.57). ½aꢀ +117.2 (c 1.0 in CHCl3).
D
Anal. Calcd for C53H94O30: C, 52.55; H, 7.82. Found: C,
52.54; H, 7.96.
1H NMR: (d ppm; 300 MHz; CDCl3): 3.10 (dd, 6H,
3
3
6 · C2–H, JH2;H3 ¼ 9:70 Hz, JH2;H1 ¼ 3:60 Hz), 3.32 (s,
18H, 6 · O–CH3), 3.40–3.62 (m, –O–CH3, Cn–H), 5.05
(m, 6H, 6 · C1–H).
13C NMR (d ppm; 75 MHz; CDCl3): 55.9, 57.1, 57.2,
57.6, 58.1, 58.3, 58.4, 58.4, 58.5, 61.0, 61.1, 61.2, 61.3,

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T. Chaise et al. / Tetrahedron Letters 45 (2004) 5853–5856
6. (a) D’Souza, V. T.; Stine, K. J.; Forgo, P.; Raufkhan, A.
Chem. Rev. 1998, 98, 1977–1996; (b) D’Souza, V. T.;
Forgo, P.; Zhu, H.; Tian, S. J. Org. Chem. 2000, 65, 2624–
2630; (c) Cousin, H.; Cardinael, P.; Oulyadi, H.; Pan-
necoucke, X.; Combret, J. C. Tetrahedron: Asymmetry
2001, 12, 81–88.
61.5, 70.4, 70.5, 70.5, 70.6, 70.7, 71.1, 71.2, 78.9, 79.2,
80.1, 80.3, 80.3, 81.6, 81.7, 81.9, 82.0, 82.1, 82.1, 82.2,
99.1, 99.3, 99.6, 99.6, 99.7, 99.7.
References and notes
7. Bourgeaux, E.; Combret, J. C. Tetrahedron: Asymmetry
2000, 11, 4189–4205.
1. (a) Kobor, F.; Angermund, K.; Schomburg, G. J. High
Resolut. Chromatogr. 1993, 16, 299–309; (b) Bicchi, C.;
D’Amato, A.; Manzin, V. J. Chromatogr. A 1994, 66, 137–
147; (c) Jaques, K.; Buda, W. M.; Venema, A.; Sandra, P.
J. Chromatogr. A 1994, 666, 131–136; (d) Schurig, V. J.
Chromatogr. A 2001, 906, 275–299; (e) Chem. Rev. 1998,
98, 1743–2076.
8. (a) Sakairi, N.; Wang, L. X.; Kuzuhara, H. J. Chem. Soc.,
Chem. Commun. 1991, 289–290; (b) Sakairi, N.; Kuzu-
hara, H. Carbohydr. Res. 1996, 280, 139–143.
9. Bourgeaux, E. Ph.D. Thesis, University of Rouen, 2000.
10. Hanessian, S.; Guindon, Y. Carbohydr. Res. 1980, 86, C3–
C6.
11. Cousin, H. Ph.D. Thesis, University of Rouen, 2002.
€
12. (a) Du Roizel, B.; Baltaze, J. P.; Sinay, P. Tetrahedron
Lett. 2002, 43, 2371–2373; (b) Lecourt, T.; Mallet, J. M.;
2. (a) Gazdag, M.; Szepesi, G.; Huszar, L. J. Chromatogr.
1988, 436, 31–38; (b) Pullen, R. H.; Brennan, J. J.;
Patonay, G. J. Chromatogr. A 1995, 691, 187–193.
€
Sinay, P. Carbohydr. Res. 2003, 338, 2417–2419; (c) Wang,
W.; Pearce, A. J.; Zhang, Y.; Sinay, P. Tetrahedron:
€
€
3. (a) Lindner, W.; Bohs, B.; Seidel, V. J. Chromatogr. A
1995, 697, 549–560; (b) Yanagawa, M.; Terabe, S.;
Tanaka, Y. J. High Resolut. Chromatogr. 1996, 19, 421–
443.
Asymmetry 2001, 12, 517–523.
13. Jung, M. E.; Lyster, M. A. J. Org. Chem. 1977, 42(23),
3761–3764.
4. (a) Armstrong, D. W.; Zukowski, J. J. Chromatogr. A
1994, 666, 445–448; (b) Armstrong, D. W.; Tang, Y.;
Ward, T.; Nichols, M. Anal. Chem. 1993, 65, 1114–1117;
14. Botsi, A.; Yannakopoulou, K.; Hadjoudis, E.; Perly, B.
Magn. Reson. Chem. 1996, 34, 419.
15. D’Souza, V. T.; Forgo, P.; Tian, S. Tetrahedron Lett.
1996, 37, 8309–8312, and references cited therein.
16. Nakanishi, N.; Saeki, M.; Koizumi, K. J. Carbohydr.
Chem. 1994, 13, 923–933.
€
(c) Dittmann, H.; Scharwachter, K.; Konig, W. Carbo-
hydr. Res. 2000, 324, 75–96.
€
5. (a) Croft, A. P.; Bartsch, R. A. Tetrahedron 1983, 39,
€
1417–1474; (b) Konig, W. A. Gas Chrom. Enantio. Sep.
With Modif. Cyclodextrins; Huthig: Heidelberg, 1992.
17. Nowotny, H. P.; Schmalzing, D.; Wistuba, D.; Schurig, V.
J. High Resolut. Chromatogr. 1989, 12, 383.
€