Regioselective synthesis of methylated β-cyclodextrins leaving hydroxy groups

Article abstract of DOI:10.1016/S0040-4039(00)02276-0

A series of methylated β-cyclodextrins (CDs) regioselectively leaving one or two hydroxy groups were prepared, and fluorescence spectroscopic measurements showed that they have unique binding characteristics against 2-p-toluidinylnaphthalene-6-sulfonate as a guest molecule in aqueous solution.

Full text of DOI:10.1016/S0040-4039(00)02276-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1531–1533
Regioselective synthesis of methylated b-cyclodextrins leaving
hydroxy groups
Koji Matsuoka,* Yoko Shiraishi, Daiyo Terunuma and Hiroyoshi Kuzuhara
Department of Functional Materials Science, Faculty of Engineering, Saitama University, Urawa, Saitama 338-8570, Japan
Received 4 October 2000; revised 4 December 2000; accepted 8 December 2000
Abstract—A series of methylated b-cyclodextrins (CDs) regioselectively leaving one or two hydroxy groups were prepared, and
fluorescence spectroscopic measurements showed that they have unique binding characteristics against 2-p-toluidinylnaphthalene-
6-sulfonate as a guest molecule in aqueous solution. © 2001 Elsevier Science Ltd. All rights reserved.
In developing an enzyme mimic, attractive molecules as
starting materials are cyclodextrins (CDs), which are
cyclic oligosaccharides composed of a(1“4) glucosyl
residues.1 CDs are known to function as host molecules
making inclusion complexes with hydrophobic guest
compounds in aqueous solution.2 Although CDs have a
number of hydrophilic functional groups, such as pri-
mary and secondary hydroxy groups, CDs, particularly
b-CD, have low solubility in water.3 Furthermore, the
b-CD inclusion complexes have much lower solubility
in water. In order to enhance the solubility of b-CD in
an aqueous medium, totally and partially methylated
b-CD derivatives have been synthesized.4 Hitherto,
regioselective modifications of the specific hydroxy
groups in b-CD by methylation leaving one or two
hydroxy groups for future manipulating functions have
not been accomplished. Successful protection of two
hydroxy groups of a primary face by an interglycosidic
bridge of sulfonamide was first reported by Tabushi et
al.5 We recently reported the successful protection of
two hydroxy groups of a secondary face with benzyli-
dene acetal after protection of primary hydroxy groups
by pivaloyl esters.6 This communication describes a
novel method for the synthesis of partially methylated
b-CDs in a regiospecific manner and their binding
properties with 2-p-toluidinylnaphthalene-6-sulfonate
(TNS) as determined by examination of fluorescence
spectra of the inclusion complexes in aqueous solution.
Heptakis 6-pivaloate 1 and the inter glycosidic benzyli-
dene derivative 2 were prepared according to the
method previously reported.6a Since direct benzylation
of 2 has been successfully demonstrated using a combi-
nation of NaH and BnBr in DMF,6b direct methylation
for 2 was firstly examined under similar conditions.
Unfortunately, 3 was obtained in only 18% yield.
Therefore, we focused our attention on a two-step
procedure (i.e. de-O-pivaloylation in a Zemple´n man-
ner and then usual methylation). Thus, de-O-pivaloyla-
tion of 2 in methanol in the presence of excess sodium
methoxide at 50°C gave the 31,22-benzylidene deriva-
tive, which was further transformed by methyl iodide in
the presence of NaH in DMSO to give per-methylated
benzylidene derivative 3 in 89.0% yield; 1H NMR
(CDCl3) l: 5.93 (s, 1H, CHPh).
When transformation of 1 into 2 was performed with
an excess amount of a,a-dimethoxytoluene (12 equiv.
mol.) followed by treatment of multi-benzylidenated
products using 0.1 M of CSA in 1:1 CHCl3–MeOH at
0°C, an unexpected compound 4 was formed with 2
having the same Rf (0.55, 4:1 CHCl3–MeOH) on TLC
as judged by the results of 1H NMR spectra of the
mixture. Since these compounds could not be sepa-
rated, further manipulation of the mixture was per-
formed. Thus, de-O-pivaloylation followed by
methylation of the mixture was carried out in the same
manner as that described above to afford a still-insepa-
rable mixture of 3 and 5; Rf (0.57, 10:1 CHCl3–MeOH);
1H NMR (CDCl3) l: 5.93 (s, 2/3H, CHPh), 5.86 (s,
1/3H, CHPh) (Scheme 1).
Keywords: cyclodextrins; methylations; regiospecificity; inclusion;
host compounds.
For the preparation of monoalcohol at the C-3 posi-
tion, a reductive ring-opening reaction of the benzyli-
* Corresponding author. Tel./fax: +81-48-858-3099; e-mail: koji@
fms.saitama-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02276-0

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K. Matsuoka et al. / Tetrahedron Letters 42 (2001) 1531–1533
dene derivative of 3 proceeded smoothly and regioselec-
tively in the presence of LAH and AlCl3 to give 6,
having a mono hydroxy group at the C-22 position and
a benzyl group at the C-31 position; [h]2D0 +141.7° (c
1.07, CHCl3). When BH3·NMe3 was used as the reduc-
ing reagent, the reaction did not proceed. In order to
elucidate the structure of 6, the remaining hydroxy
group was acetylated to afford mono-2-O-acetete 7 in
Since the acetal mixture of 3 and 5 could be regarded as
the precursors of mono- and di-hydroxy derivatives,
acid hydrolysis of the mixture was attempted, and two
separate mixtures were obtained. These mixtures were
purified by silica gel chromatography, giving 21-
monoalcohol 11 in 71% yield; [h]1D7 +160.6° (c 1.57,
1
CHCl3); H NMR (CDCl3) l: 4.36 (d, 1H, J2,OH 11.2
Hz, OH-21) and 31,22-diol 13 in 28% yield; [h]2D4 +160.8°
(c 1.28, CHCl3). The structures of 11 and 13 were
determined from 1H NMR after acetylation of the
remaining hydroxyl groups, 21-acetate 12; 1H NMR
(CDCl3) l: 5.17 (d, 1H, J1,2 3.6 Hz, H-11), 4.65 (dd, 1H,
J2,3 10.1 Hz, H-21), 2.16 (s, 3H, OAc) and 31,22-diac-
1
quantitative yield; H NMR (CDCl3) l: 4.68 (dd, 1H,
J1,2 3.5 Hz and J2,3 9.7 Hz, H-22), 1.71 (s, 3H, OAc).
Protection of the free hydroxy group of 6 was carried
out in the usual way to afford per-methylated 8 in 98%
1
yield; [h]2D0 +151.6° (c 1.09, CHCl3); H NMR (CDCl3)
1
l: 5.09 (d, 1H, Jgem 10.6 Hz, CHa-Ph), 4.81 (d, 1H,
CHb-Ph). Final deprotection of the benzyl group in 8
by hydrogenolysis gave mono-3-hydroxy derivative 9 in
91% yield; [h]2D0 +156.7° (c 0.96, CHCl3); 1H NMR
(CDCl3) l: 5.19 (s, 1H, OH-31), 3.97 (t, 1H, J 9.4 Hz,
H-31), which was further transformed into the acetate
etate 14; H NMR (CDCl3) l: 5.42 (t, 1H, J3,4 9.7 Hz,
H-31), 5.31 (d, 1H, J1,2 3.5 Hz, H-11), 5.06 (d, 1H, J1,2
3.3 Hz, H-12), 4.68 (dd, 1H, J2,3 10.1 Hz, H-22), 3.25
(dd, 1H, J2,3 10.3 Hz, H-21), 2.21 (s 3H, OAc), 2.16 (s,
3H, OAc) (Scheme 2).
1
10; H NMR (CDCl3) l: 5.39 (t, 1H, J3,4 9.5 Hz, H-31),
Since the preparation of methylated b-CD having
regioselective hydroxyl groups had been accomplished,
we turned our attention to evaluation of the alcoholic
5.28 (d, 1H, J1,2 3.6 Hz, H-11), 3.73 (t, 1H, H-41), 3.28
(dd, 1H, J2,3 10.4 Hz, H-21), 2.13 (s, 3H, OAc).
Scheme 1. Reagents and conditions: (i) a,a-dimethoxytoluene (6 molar excess), CSA, DMF, 60°C, reduced pressure; (ii)
a,a-dimethoxytoluene (12 molar excess), CSA, DMF, 60°C, reduced pressure; (iii) NaOMe, MeOH, 50°C, then NaH, MeI,
DMSO, rt.
Scheme 2. Reagents and conditions: (i) LAH, AlCl3, THF, 0°C“rt; (ii) 80% aq. AcOH, 90°C; (iii) Ac2O, pyridine; (iv) NaH, MeI,
THF, rt; (v) H2, Pd(OH)2, MeOH, rt.

K. Matsuoka et al. / Tetrahedron Letters 42 (2001) 1531–1533
1533
6>2-monoalcohol 11>31,22-diol 13>3-monoalcohol 9>
per-methylated b-CD>b-CD itself. This result suggested
that an alcohol in the chiral products is capable of
interacting with hydrophilic functional groups in other
chiral guest compounds through hydrogen bonds.
In conclusion, we have reported the successful synthesis
of a series of partially methylated b-CD derivatives
leaving regulated hydroxy groups and the inclusion
properties against TNS in water. These regularly
methylated b-CDs are potential intermediates for con-
structing new types of artificial enzymes.
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