Direct aroylation of β-cyclodextrin on the secondary hydroxyl face: A convenient equilibrium-dependent preparation of mono-3-aroyl-β-cyclodextrin via C2-O-aroyl to C3-O-aroyl group migration

Article abstract of DOI:10.1007/s00706-012-0749-x

A new and convenient method is presented for the preparation of mono-3-O-benzoyl-β-cyclodextrin by direct regioselective benzoylation of β-cyclodextrin using N-benzoylimidazole in carbonate buffer solution. This process involved equilibrium-dependent C2-O

Full text of DOI:10.1007/s00706-012-0749-x

Monatsh Chem (2012) 143:1719–1721
DOI 10.1007/s00706-012-0749-x
ORIGINAL PAPER
Direct aroylation of b-cyclodextrin on the secondary hydroxyl
face: a convenient equilibrium-dependent preparation of mono-3-
aroyl-b-cyclodextrin via C2-O-aroyl to C3-O-aroyl group
migration
•
Zhi-zhong Wang Qing Huang Shi-jie Wei
•
•
•
Lei Sun Jing Chen
Received: 2 August 2011 / Accepted: 3 March 2012 / Published online: 5 April 2012
Ó Springer-Verlag 2012
Abstract A new and convenient method is presented for
the preparation of mono-3-O-benzoyl-b-cyclodextrin by
direct regioselective benzoylation of b-cyclodextrin using
N-benzoylimidazole in carbonate buffer solution. This
process involved equilibrium-dependent C2-O-aroyl to
C3-O-aroyl group migration to improve the yield.
[5–11]. Since the more open secondary hydroxyl face of CDs
is stated to be catalytically very important [12–15], ben-
zoylations of this face are believed to produce valuable
derivatives for asymmetry catalysis. However only very few
reactions are known to introduce a single benzoyl group at
the secondary hydroxyl face of CDs, especially at the 3
position, presumably because hydroxyl groups at the 3
position are the most inaccessible and difficult to be modified
[16]. Hao et al. [17] benzoylated one of the C-3 hydroxyl
groups with benzoyl chloride in alkaline acetonitrile solu-
tion, but the isolated yield was relatively low (16 %). Herein,
we describe a new and convenient method for the preparation
of mono-3-O-benzoyl-b-CD by direct benzoylation of b-CD
using N-benzoylimidazole in a carbonate buffer solution, an
equilibrium process which involved C2-O-aroyl to C3-O-
aroyl group migration to improve the yield (Scheme 1).
Keywords Cyclodextrin ꢀ Benzoylation ꢀ Isomerization ꢀ
Equilibrium
Introduction
Cyclodextrins (CDs) are well-known macrocyclic oligo-
saccharides which have hollow truncated cone structures
capable of forming inclusion complexes with a variety of
organic molecules in aqueous solutions. They have
attracted widespread interest as hosts for building supra-
molecular structures, and their derivatives have evolved
into a versatile class of host molecules with applications in
enzyme mimics, molecular recognition, drug delivery, and
chiral discrimination, to mention a few [1–4].
Results and discussion
In previous work [18], we developed a simple and efficient
method for direct regioselective benzoylation of a single
C-2 hydroxyl group of b-CD, and found that its hydrolysis
occurred via benzoyl group migration, i.e., the C-3
hydroxyl group of b-CD attacked the carbonyl carbon of
the C2-O-benzoyl group. Therefore, mono-3-O-benzoyl-b-
CD can be prepared through isomerization of the corre-
sponding mono-C2-O-benzoyl isomer.
In recent years, selective benzoylation of the C-6 hydro-
xyl groups has been extensively studied, and the obtained
mono-6-O-benzoyl-b-CDs have been used as novel supra-
molecular photosensitizing hosts in photochirogenesis
Z. Wang (&) ꢀ Q. Huang ꢀ L. Sun ꢀ J. Chen
Engineering Research Center for Hui Medicine Modernization,
College of Pharmacy, Ningxia Medical University,
750004 Yinchuan, China
A mixture of b-CD, one molar equivalent of N-(p-
methylbenzoyl)imidazole, and carbonate buffer in DMF
was stirred at 60 °C for 2 h. The reaction regioselectively
generated mono-3-O-(p-methylbenzoyl)-b-CD (1), mono-
2-O-(p-methylbenzoyl)-b-CD, and multi-benzoates. The
mixture of mono-C2-O-benzoyl and mono-C3-O-benzoyl
isomers (1), isolated by a simple open reversed-phase
e-mail: wangzzsc@yahoo.com
S. Wei
Department of Pharmacy, Ningxia Medical University General
Hospital, 750004 Yinchuan, China
123

1720
Z. Wang et al.
Scheme 1
O
N
N
C
R
OH
OH
OH
OH
+
O
O
O
O
O
O
OH
O
O
O
HO
OH
HO
OH
HO
O
O
OH
6
6
O
CO32- Buffer
DMF, 60 °C
C
C
O
O
1, R = CH3
HO
OH
7
R
R
Isomerization
Lyophilization
2, R = CH3O
column chromatography, was purified by preparative
HPLC using 20 % aqueous MeOH as the eluent. The
fractions containing the mono-C2-O-benzoyl isomer were
concentrated under reduced pressure, dissolved in 20 %
aqueous MeOH, heated at 50 °C for 1 h until the equilib-
rium of isomerization was established, and then purified by
preparative HPLC. Through several isomerization and
purification cycles, the mono-C3-O-benzoyl isomer (1) was
obtained in good yield (39 %).
standard. The ESI–MS experiments were performed using a
ThermoQuest Finnigan LCQDECA system equipped with an
ESI source (ThermoQuest LC/MS Division, San Jose, CA,
USA). Carbonate buffer (0.2 M, pH 9.9) was prepared by
mixing equal volumes of 0.2 M sodium carbonate and
0.2 M sodium bicarbonate. N-Benzoylimidazole was pre-
pared according to a literature procedure [20]. All other
chemicals were of commercial grade and used without
further purification.
The structure of 1 was confirmed using ESI–MS and NMR
spectra. Its ESI–MS spectrum exhibited the molecular ion
[M ? Na]? at m/z = 1,275. 13C NMR spectroscopy is an
effective technique for the analysis of cyclic oligosaccha-
rides. Breslow [19] reported that aroylation of a hydroxyl
group of CDs usually leads to a downfield chemical shift of
the carbon carrying the hydroxyl (a carbon), but a small
upfield chemical shift of the b carbon and a still smaller shift
of the c carbon. In the 13C NMR spectra of 1, the peak at
d = 78.5 ppm (C-40) clearly indicates that the substituent is
at the 3 position of b-CD.
General experimental procedure
To a stirred solution of 2 g b-CD (1.76 mmol) with one molar
equiv. of N-benzoylimidazole in 60 cm3 DMF, 12 cm3 car-
bonate buffer (0.2 M, pH 9.9) was added. The reaction
mixture was heated at 60 °C for 2 h. Then the mixture was
neutralized with 1 N HCl, evaporated in vacuo to a volume of
ca. 5 cm3, and 300 cm3 of acetone was added to precipitate
cyclodextrin derivatives. The collected solid was isolated on
an open RP-18 column eluted with H2O/MeOH (10–30 %) to
give a mixture of mono-C2-O-benzoyl and mono-C3-O-
benzoyl isomers. The mixture was dissolved in 70 cm3 20 %
aqueous MeOH, heated at 50 °C for 1 h, and then purified by
preparative HPLC using 20 % aqueous MeOH as the eluent.
The fractions containing the mono-C2-O-benzoyl isomer
were evaporated in vacuo, dissolved in 30 cm3 20 % aqueous
MeOH, heated at 50 °C for 1 h, and purified by preparative
HPLC. The processes were carried out twice, and all the
fractions containing the mono-C3-O-benzoyl isomer were
combined and lyophilized to give the pure mono-C3-O-
benzoyl isomer.
Using N-(p-methoxybenzoyl)imidazole as an aroylating
reagent afforded 2 in 35 % yield.
In conclusion, mono-3-O-benzoyl-b-CD was prepared
by direct benzoylation of b-CD on the secondary hydroxyl
face using N-benzoylimidazole in carbonate buffer solution
in good yield. The process involved an isomerization
equilibrium, i.e., mono-2-O-benzoyl-b-CD was isomerized
to the corresponding mono-3-O-benzoyl-b-CD. This ben-
zoylation method can be highly useful for the preparation
of other benzoates of b-CD as macrocyclic host molecules.
Mono-3-O-(p-methylbenzoyl)-b-CD (1, C50H76O36)
Yield 0.87 g (39 %); ESI–MS: m/z = 1,275 ([M ? Na]?);
1H NMR (600 MHz, DMSO-d6): d = 2.35 (s, 3H),
3.20–3.74 (m, 39H), 3.77 (t, 1H), 3.86 (br, 1H),
4.33–4.58 (m, 7H), 4.70–4.87 (m, 6H), 4.92 (d, 1H), 5.35
(t, 2H), 5.50–5.90 (m, 12H), 7.26 (d, 2H), 7.84 (d, 2H)
ppm; 13C NMR (150 MHz, DMSO-d6): d = 21.5, 60.4,
71.8, 72.2, 72.8, 73.1, 73.5, 75.1, 78.5 (C-40), 81.7, 81.8,
82.0, 102.0, 102.2, 102.4, 128.9, 129.1, 129.9, 142.8,
166.1 ppm.
Experimental
Analytical and preparative HPLC column chromatogra-
phies were done using a Perkin-Elmer Series 200 HPLC
system with a UV–Vis detector. A Kromasil 100-10-C18
column (4.6 mm 9 250 mm) was used for the analytical
HPLC, and a Zorbax SB-C18 column (10 mm 9 250 mm)
was used for preparative HPLC. NMR spectra were recor-
ded on Bruker AM-600 spectrometer (1H 600 MHz and 13
C
150 MHz) in DMSO-d6 solutions with tetramethylsilane as
123

Direct aroylation of b-cyclodextrin on the secondary hydroxyl face
1721
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Mono-3-O-(p-methoxybenzoyl)-b-CD (2, C50H76O37)
Yield 0.79 g (35 %); ESI–MS: m/z = 1,291 ([M ? Na]?);
1H NMR (600 MHz, DMSO-d6): d = 3.20–3.75 (m, 39H),
3.76 (t, 1H), 3.82 (s, 3H), 3.89 (br, 1H), 4.38–4.61 (m, 7H),
4.74–4.87 (m, 6H), 4.94 (d, 1H), 5.34 (t, 1H), 5.39 (br, 1H),
5.48–6.08 (m, 12H), 7.00 (d, 2H), 7.91 (d, 2H) ppm; 13C
NMR (150 MHz, DMSO-d6): d = 55.8, 60.4, 71.5, 71.9,
72.2, 72.5, 72.8, 73.1, 73.4, 75.0, 78.6 (C-40), 81.8, 82.0,
82.1, 102.1, 102.3, 102.4, 113.9, 122.5, 131.9, 162.8,
165.8 ppm.
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Acknowledgments Financial support from the Natural Science
Foundation of Ningxia (No. NZ11110) is gratefully acknowledged.
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277:333
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