Diisobutylaluminium-promoted regioselective de-O-methylation of cyclodextrins: An expeditious entry to selectively modified cyclodextrins

Article abstract of DOI:10.1016/S0957-4166(01)00065-9

Substituted cyclodextrins carrying methyl groups on the primary rim undergo highly regioselective de-O-methylation in the presence of benzyl groups, using diisobutylaluminium. This gave access to AD or AB di-6-O-demethylated derivatives, which were fully

Full text of DOI:10.1016/S0957-4166(01)00065-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 517–523
Diisobutylaluminium-promoted regioselective de-O-methylation of
cyclodextrins: an expeditious entry to selectively modified
cyclodextrins
Wei Wang,a Alan J. Pearce,b Yongmin Zhanga and Pierre Sinay¨a,*
a
´
Ecole Normale Supe´rieure, De´partement de Chimie, associe´ au CNRS, 24 rue Lhomond, 75231 Paris Cedex 05, France
bSchool of Chemistry, University of Bristol, Bristol BS8 1TS, UK
Received 17 January 2001; accepted 9 February 2001
Abstract—Substituted cyclodextrins carrying methyl groups on the primary rim undergo highly regioselective de-O-methylation in
the presence of benzyl groups, using diisobutylaluminium. This gave access to AD or AB di-6-O-demethylated derivatives, which
were fully characterised by NMR, MS and chemical degradation using the hex-5-enose method. Direct functionalisation of these
derivatives, for example by glycosylation, makes this method an attractive procedure for the preparation of modified cyclodex-
trins. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Herein, we report the first regioselective de-O-methyl-
ation of CDs containing methyl groups at the primary
rim. This method is simple, remarkably regioselective
and synthetically convenient, and the cyclodextrin
obtained is selectively protected for direct further elabo-
ration. Furthermore, the benzyl protecting groups render
the CDs non-polar and the products can therefore be
readily purified by standard silica gel chromatography.
Selectively modified cyclodextrins (CDs) are in high
demand for applications ranging from supramolecular
building blocks to drug delivery systems.1–5 However,
despite several well-defined protocols, methods for the
synthesis of modified cyclodextrins are only slowly
responding to this demand and, furthermore, usually
involve tedious and laborious routes.6,7 An attractive
alternative is the regioselective deprotection of perfunc-
tionalised cyclodextrins. For example, we recently
reported8 that perbenzylated cyclodextrins such as 1
undergo regioselective de-O-benzylation at the primary
rim with DIBAL (diisobutylaluminium) to afford AD-
diols such as 2 in excellent yield (Scheme 1).
2. Results and discussion
When the known benzylated and AD-bis-methylated
a-cyclodextrin 38 was treated with excess DIBAL in
toluene at 50°C, we observed the preferential AD type
Scheme 1.
* Corresponding author. Fax: +33 1 44 32 33 97; e-mail: pierre.sinay@ens.fr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00065-9

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W. Wang et al. / Tetrahedron: Asymmetry 12 (2001) 517–523
Scheme 2.
O-demethylation reaction and the diol 2 was isolated in
42% purified yield. Minor O-debenzylation products
were also formed (about 15%), but were not analysed
further (Scheme 2).
The structure of 5 was identified as the AD-regioisomer
1
by H and 13C NMR, which clearly showed the pres-
ence of the expected twofold symmetry. This was fur-
ther confirmed by chemical degradation using the
hex-5-enose method12–15 in which the diol 5 was first
converted into bis iodide 6 by iodination according to
Garegg’s procedure16 and then fragmented with acti-
vated zinc, reduced with NaBH4 and finally acetylated.
Analysis of the product by FAB-MS identified a sole
fragment {m/z (%): 1147.4 (100) [M+Na+]} arising from
the AD-regioisomer and hence diol 5 was assigned
AD-regiochemistry (Scheme 4).
To the best of our knowledge this is the first example of
selective O-demethylation in the presence of a benzyl
ether. Furthermore, this de-O-alkylation reaction
occurs exclusively at the primary rim. We therefore
aimed to exploit these observations using other CDs
containing methyl groups at the primary rim and ben-
zyl groups at the secondary rim.
Thus, the known methylated a-cyclodextrin 49 was
conveniently prepared from 1 (67% from 1) by
acetolysis10,11 followed by de-O-acetylation with
NaOMe/MeOH and methylation using MeI/NaH in
DMF. Reaction of 4 with excess DIBAL in toluene at
55°C gave the C2-symmetric AD-diol 5 in 59% yield,
resulting from regioselective de-O-methylation at the
primary rim (Scheme 3). Mixtures of triols (25%) and
tetrols (6%) resulting from further de-O-methylation, as
identified by FAB-MS, were also isolated, but not
analysed further.
Due to its differential protection, compound 5 is an
attractive starting material for subsequent multiple syn-
thetic modifications. For example, it undergoes smooth
glycosylation with the thioglucosyl donor 717 to give the
protected glycoconjugate 8 in 85% yield (Scheme 5).
Modifiying the reaction conditions also allowed access
to products of mono de-O-methylation. Thus, when 4
was treated with 2 equivalents of DIBAL under more
dilute conditions, we isolated the mono-de-O-methyl-
ated product 9 in 30% yield, together with recovered
Scheme 3.
Scheme 4. Reagents and conditions: (i) I2, PPh3, Im, toluene, 70°C, 1 h, quant.; (ii) Zn, PrOH, H2O, reflux, 1 h (iii) NaBH4,
MeOH, H2O; (iv) Ac2O, pyridine.

W. Wang et al. / Tetrahedron: Asymmetry 12 (2001) 517–523
519
,
Scheme 5. Reagents and conditions: (i) 6 equiv. 7, NIS, TfOH, DCM, 4 A MS, −40 to −20°C, 1 h.
starting material 4 in 34% yield. Surprisingly, we also
isolated the AB-diol 10 in 27% yield, whilst only trace
amounts of the diol 5 and triols were recovered
(Scheme 6).
mixtures when treated with excess DIBAL (35 equiva-
lents) in toluene at 55°C. However, reaction with 7
equivalents of DIBAL under dilute conditions gave the
mono de-O-methylated product 14 in 40% yield
(Scheme 8). Compound 13 was recovered from the
reaction in 17% yield, and diols were also formed
(30%), but not analysed further.
The structure of diol 10 was again confirmed by conver-
sion to the corresponding bis iodide 11 and subsequent
hex-5-enose degradation as above. FAB-MS analysis of
the fragmentation products obtained {m/z (%): 1860.5
(15) [C108H124O26+Na+], 435.2 (100) [C24H28O6+Na+]}
confirmed the AB-regiochemistry (Scheme 7).
De-O-benzylation of 5 by catalytic hydrogenolysis fol-
lowed by purification of the product on Sephadex G-15
provided, after freeze-drying, the tetra-O-methyl-a-
cyclodextrin 15 in 97% yield (Scheme 9). Statistical
calculations indicate that several hundred positional
isomers are possible for a tetra-O-methyl-a-cyclodex-
trin, one of which is easily prepared by this method.
In contrast to a-CD, the methylated b-cyclodextrin 13,
prepared in 82% yield by methylation of heptakis(2,3-
di-O-benzyl)-b-cyclodextrin 12,5 gave complex product
Scheme 6.
Scheme 7.
Scheme 8. Reagents and conditions: (i) NaH, DMF, 0°C, 1 h, then MeI, 0°C to rt, 40 h; (ii) 0.1 M iBu2AlH (7 equiv.), toluene,
55°C, 20 min.

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W. Wang et al. / Tetrahedron: Asymmetry 12 (2001) 517–523
Scheme 9. Reagents and conditions: H2, Pd/C, EtOAc/MeOH (1/1), rt, 3 h.
3. Conclusion
(10 mL) was carefully added dropwise. The solidified
mixture was then filtered through Celite® in vacuo and
washed with hot EtOAc (30 mL). The filtrate was
combined, washed with water (3×10 mL), then the
organic phase was separated and dried with MgSO4.
After evaporation, the residue was purified by flash
column chromatography (CH2Cl2/acetone, 9/1–5/1) to
give 5 as an amorphous powder (73 mg, 59%): [h]D +28
(c 3.4, CHCl3); 1H NMR (CDCl3): l 7.06–7.40 (m,
60H, arom. H), 5.84 (d, 2H, J1,2=3.9 Hz, 2×H-1), 5.53,
4.96 (2d, 4H, J=10.3 Hz, 2×PhCH2), 5.26, 4.82 (2d,
4H, J=10.6 Hz, 2×PhCH2), 4.97, 4.80 (2d, 4H, J=11.8
Hz, 2×PhCH2), 4.82, 4.50 (2d, 4H, J=11.9 Hz, 2×
PhCH2), 4.66, 4.56 (2d, 4H, J=12.6 Hz, 2×PhCH2),
4.43, 4.38 (2d, 4H, J=12.6 Hz, 2×PhCH2), 4.65 (bs,
4H, 4×H-1), 4.25 (dd, 2H, J2,3=9.8 Hz, J3,4=7.7 Hz,
2×H-3), 3.60 (dd, 2H, J1,2=3.9 Hz, J2,3=9.8 Hz, 2×H-
2), 3.53 (dd, 2H, J1,2=3.5 Hz, J2,3=9.5 Hz, 2×H-2),
3.50 (dd, 2H, J1,2=3.3 Hz, J2,3=9.8 Hz, 2×H-2), 3.37,
3.35 (2s, 12H, 4×OMe); 13C NMR (CDCl3): l 139.24,
139.21, 139.15, 138.54, 138.17, 137.94 (12C, Ph),
128.37–126.16 (60C, arom. C), 98.7, 97.8, 97.4 (372C-
1), 81.8 (2C-3), 81.6 (2C-4), 81.4 (2C-4), 80.8 (2C-3),
80.5 (2C-3), 80.1 (2C-2), 79.1 (2C-2), 77.5 (2C-2), 76.5
(2PhCH2), 76.2 (2PhCH2), 73.9 (2PhCH2), 73.33
(2PhCH2), 73.31 (2PhCH2), 72.7 (2PhCH2), 72.6 (2C-
4), 72.0 (2C-6), 71.8 (2C-6), 60.6 (2C-6), 59.0 (2OMe),
58.9 (2OMe). MS: m/z 2132.4 (100%, M+Na+). Anal.
calcd for C124H140O30: C, 70.57; H, 6.69. Found: C,
70.51; H, 6.78%.
We have demonstrated that DIBAL-promoted de-O-
methylation of partially methylated cyclodextrins
occurs regioselectively, giving access to mono-6-O-
demethylated, AD or AB di-6-O-demethylated deriva-
tives, which are selectively protected for further
functionalisation. This simple method illustrates the use
of the de-O-alkylation strategy in the preparation of
selectively modified cyclodextrins. Extension of this
process to permethylated CDs, of interest due to their
enhanced water solubility compared to unprotected
CDs, is under investigation.
4. Experimental
4.1. General
Optical rotation measurements were obtained at 22°C
with a Perkin–Elmer Model 241 digital polarimeter,
using a 10 cm, 1 mL cell. Fast atom bombardment
mass spectra (FAB-MS) were obtained with a JMS-700
spectrometer using an m-nitrobenzyl alcohol (NBA)
matrix. Elemental analyses were performed by Service
de Microanalyse de l’Universite´ Pierre et Marie Curie, 4
1
Place Jussieu, 75005 Paris, France. H NMR spectra
were recorded with a Bruker DRX 400 spectrometer at
ambient temperature. Assignments were aided by
COSY experiments. 13C NMR spectra were recorded at
100.6 MHz with a Bruker DRX 400 spectrometer.
Assignments were aided by J-mod technique and pro-
ton–carbon correlation. Reactions were monitored by
thin-layer chromatography (TLC) on a precoated plate
of silica gel 60 F254 (layer thickness 0.2 mm; E. Merck,
Darmstadt, Germany) and detection by charring with
sulfuric acid. Flash column chromatography was per-
formed on silica gel 60 (230–400 mesh, E. Merck).
4.3. Hexakis(2,3-di-O-benzyl)-6A,6D-dideoxy-6A,6D-
diiodo)-6B,6C,6E,6F-tetra-O-methyl-a-cyclodextrin 6
Diol 5 (100 mg, 0.05 mmol), triphenylphosphine (80
mg, 0.31 mmol), imidazole (40 mg, 0.59 mmol) and I2
(76 mg, 0.3 mmol) were dissolved in anhydrous toluene
(10 mL), and the mixture was heated at 70°C for 1 h,
when TLC (cyclohexane/EtOAc, 2/1) showed that 5
was completely consumed. The mixture was concen-
trated and the residue purified by flash column chro-
matography (cyclohexane/EtOAc, 3/1) to give 6 as an
amorphous powder (110 mg, 100%): [h]D +21 (c 3.4,
CHCl3); 1H NMR (CDCl3): l 7.40–7.10 (m, 60H, arom.
H), 5.30, 4.96 (2d, 4H, J=11.1 Hz, 2×PhCH2), 5.22,
4.91 (2d, 4H, J=11.0 Hz, 2×PhCH2), 5.16 (d, 2H,
4.2. Hexakis(2,3-di-O-benzyl)-6B,6C,6E,6F-tetra-O-
methyl-a-cyclodextrin 5
Hexakis(2,3-di-O-benzyl)-6A,6B,6C,6D,6E,6F -hexa-O-
methyl-a-cyclodextrin 4 (125 mg, 0.058 mmol) was
dissolved in anhydrous toluene (16 mL), then DIBAL
(1.5 M, 1.2 mL, 31 equiv.) was added dropwise into the
stirred solution over 1 min at room temperature under
argon. The reaction mixture was stirred at 55–58°C for
1 h, when TLC (CHCl3/MeOH, 38/1) indicated a new
product (Rf 0.45) and disappearance of starting mate-
rial. The reaction mixture was cooled to 0°C, and water
J
1,2=3.15 Hz, 2×H-1), 5.14, 4.88 (2d, 4H, J=11.0 Hz,
2×PhCH2), 4.58, 4.46 (2d, 4H, J=12.6 Hz, 2×PhCH2),
4.56, 4.48 (2d, 4H, J=12.4 Hz, 2×PhCH2), 4.51, 4.47
(2d, 4H, J=12.7 Hz, 2×PhCH2), 3.39 (s, 6H, 2×OMe),
3.37 (s, 6H, 2×OMe); 13C NMR (CDCl3): l 139.4,

W. Wang et al. / Tetrahedron: Asymmetry 12 (2001) 517–523
521
139.3, 139.2, 138.3, 138.1, 138.1 (12C, Ph), 128.2–126.9
(60C, arom. C), 99.6, 99.4, 98.8 (3×2C-1), 75.6, 75.5,
75.3 (3×2PhCH2), 72.92, 72.92, 72.86 (3×2PhCH2),
71.6, 71.4 (C-6B,6C,6E,6F), 9.0 (C-6A,6D), 59.2, 59.1
(2×2OMe). MS: m/z 2352.7 (100%, M+Na+). Anal.
calcd for C124H138I2O28: C, 63.91; H, 5.97. Found: C,
63.93; H, 6.09%.
powder (54 mg, 30%): [h]D +15 (c 1.3, CHCl3); 1H
NMR (CDCl3): l 7.39–7.15 (m, 60H, arom. H), 5.70 (d,
1H, J1,2=3.7 Hz, H-1), 5.62 (d, 1H, J1,2=3.7 Hz, H-1),
5.53, 5.02 (2d, 2H, J=10.6 Hz, PhCH2), 5.45, 4.95 (2d,
2H, J=10.5 Hz, PhCH2), 5.28, 4.85 (2d, 2H, J=10.6
Hz, PhCH2), 5.21, 4.86 (2d, 2H, J=10.9 Hz, PhCH2),
4.98, 4.89 (2d, 2H, J=11.6 Hz, PhCH2), 4.92 (bs, 2H,
PhCH2), 4.78, 4.47 (2d, 2H, J=11.6 Hz, PhCH2), 4.77,
4.46 (2d, 2H, J=12.5 Hz, PhCH2), 4.63, 4.53 (2d, 2H,
J=12.6 Hz, PhCH2), 4.61, 4.52 (2d, 2H, J=12.7 Hz,
PhCH2), 4.56, 4.53 (2d, 2H, J=12.3 Hz, PhCH2), 4.40,
4.36 (2d, 2H, J=12.6 Hz, PhCH2), 3.38, 3.37, 3.36,
3.35, 3.30 (5s, 15H, 5×OMe); 13C NMR (CDCl3): l
139.5, 139.27, 139.25, 139.25, 139.22, 139.11, 138.6,
138.4, 138.3, 138.1, 138.0, 138.0 (12C, Ph), 128.3–126.3
(60C, arom. C), 99.1, 98.4, 98.3, 98.00, 97.97, 97.5
(6C-1), 76.3, 76.1, 75.85, 75.79, 74.4, 74.1, 73.3, 73.2,
73.14, 73.12, 72.8, 72.5 (12PhCH2), 71.78, 71.77, 71.77,
71.5, 71.2 (C-6B, 6C,6D,6E,6F), 60.6 (C-6A), 59.2, 59.0,
59.0, 58.93, 58.92 (5OMe). MS: m/z 2146.9 (100%,
M+Na+). Anal. calcd for C125H142O30: C, 70.67; H,
6.74. Found: C, 70.60; H, 6.76%.
4.4. 6A,6D-[Di-O-(2,3-di-O-benzoyl-4,6-O-benzylidene)-
b- -glucopyranosyl]-hexakis(2,3-di-O-benzyl)-
D
6B,6C,6E,6F-tetra-O-methyl-a-cyclodextrin 8
A mixture of 5 (41 mg, 0.02 mmol), phenyl 2,3-di-O-
benzoyl-4,6-O-benzylidene-1-thio-b-D-glucopyranoside
,
7 (70 mg, 0.12 mmol) and powdered 4 A molecular
sieves (100 mg) in dry CH2Cl2 (6 mL) was stirred at
room temperature for 30 min. N-Iodosuccinimide (81
mg, 0.36 mmol) was added at room temperature. The
reaction mixture was cooled to −60°C, and triflic acid
(5 mL, 0.06 mmol) was added dropwise. The reaction
mixture was stirred at −60°C for 1 h, neutralised with
Et3N and filtered through a layer of Celite®. The filtrate
was washed with aqueous thiosulfate, water and brine,
and then dried (MgSO4) and concentrated. The residue
was purified by flash column chromatography (eluent
gradient, cyclohexane/EtOAc, 4/1 to 3/1) to give 8 as
an amorphous powder (51 mg, 85%): [h]D +17 (c 2.2,
CHCl3); 1H NMR (CDCl3): l 8.00–7.10 (m, 90H, arom.
H), 5.83 (t, 2H, J2,3=J3,4=9.4 Hz, H-3%), 5.57 (dd, 2H,
Compound 10 was then eluted as an amorphous pow-
der (49 mg, 27%): Rf 0.48 for TLC (CHCl3/MeOH,
1
38/1); [h]D +24 (c 1.2, CHCl3); H NMR (CDCl3): l
7.40–7.10 (m, 60H, arom. H), 5.41 (d, 1H, J1,2=3.7 Hz,
H-1), 5.38, 4.90 (2d, 2H, J=10.6 Hz, PhCH2), 5.32,
4.90 (2d, 2H, J=10.6 Hz, PhCH2), 5.30, 4.97 (2d, 2H,
J=10.8 Hz, PhCH2), 5.31 (d, 1H, J1,2=3.8 Hz, H-1),
5.23, 4.97 (2d, 2H, J=10.8 Hz, PhCH2), 5.19 (d, 1H,
J1,2=7.8 Hz, J2,3=9.4 Hz, H-2%), 5.56 (s, 2H, 2×PhCH),
5.16, 4.78 (2d, 4H, J=11.2 Hz, 2×PhCH2), 5.14, 4.87
(2d, 4H, J=11.3 Hz, 2×PhCH2), 5.06, 4.85 (2d, 4H,
J=11.2 Hz, 2×PhCH2), 5.02 (d, 2H, J1,2=3.4 Hz, 2×H-
J
1,2=3.5 Hz, H-1), 5.12 (d, 1H, J1,2=3.5 Hz, H-1), 5.03,
4.88 (2d, 2H, J=11.4 Hz, PhCH2), 5.01, 4.92 (2d, 2H,
J=11.2 Hz, PhCH2), 4.75 (d, 1H, J1,2=3.4 Hz, H-1),
4.71 (d, 1H, J1,2=3.3 Hz, H-1), 4.70, 4.62 (2d, 2H,
J=12.2 Hz, PhCH2), 4.70, 4.54 (2d, 2H, J=12.5 Hz,
PhCH2), 4.69, 4.50 (2d, 2H, J=12.3 Hz, PhCH2), 4.63,
4.42 (2d, 2H, J=12.2 Hz, PhCH2), 4.61, 4.50 (2d, 2H,
J=12.3 Hz, PhCH2), 4.47, 4.41 (2d, 2H, J=12.6 Hz,
PhCH2), 3.40, 3.37, 3.36, 3.32 (4s, 12H, 4×OMe); 13C
NMR (CDCl3): l 139.4, 139.3, 139.21, 139.18, 139.09,
139.08, 138.5, 138.2, 138.14, 138.14, 138.12, 138.0 (12C,
Ph), 128.3–126.7 (60C, arom. C), 98.8, 98.6, 98.4, 97.9,
97.54, 97.49 (6C-1), 76.1, 76.1, 76.0, 75.3, 75.1, 75.1,
74.8, 73.24, 73.16, 73.04, 73.00, 73.00, 72.8, 72.2, 71.8,
71.5 (12PhCH2, C-6B,6C,6D,6E), 62.2, 61.3 (C-6A,6B),
59.12, 59.09, 59.02, 58.9 (4OMe). MS: m/z 2132.9
(100%, M+Na+). Anal. calcd for C124H140O30: C, 70.57;
H, 6.69. Found: C, 70.49; H, 6.89%.
1), 4.98 (d, 2H, J1,2=7.8 Hz, H-1%), 4.97 (d, 2H, J1,2
=
3.5 Hz, 2×H-1), 4.80 (d, 2H, J1,2=3.2 Hz, 2×H-1), 4.48,
4.39 (2d, 4H, J=12.6 Hz, 2×PhCH2), 4.42, 4.37 (2d,
4H, J=12.6 Hz, 2×PhCH2), 4.21, 3.92 (2d, 4H, J=12.7
Hz, 2×PhCH2), 4.01 (t, 2H, J3,4=J4,5=9.4 Hz, H-4%),
3.46, 3.39 (2s, 12H, 4×OMe), 3.13 (dd, 2H, J1,2=3.2
Hz, J2,3=9.9 Hz, 2×H-2); 13C NMR (CDCl3): l 165.6,
165.0 (2OꢀC, Bz), 139.4, 139.33, 139.26, 138.4, 138.24,
138.22, 136.7, 129.30, 129.00 (18C, Ph), 133.2–126.8
(90C, arom. C), 101.4 (2PhCH), 101.2 (2C, 2×C-1%),
99.8, 99.7, 99.1 (6C, C-1A-F), 75.9, 75.3, 75.2, 73.0, 72.7,
71.6 (12PhCH2), 72.3, 71.7, 68.4, 68.2 (8C-6), 59.0, 58.9
(4OMe). MS: m/z 3049.7 (100%, M+Na+). Anal. calcd
for C178H184O44: C, 70.62; H, 6.13. Found: C, 70.51; H,
6.20%.
4.5. Hexakis(2,3-di-O-benzyl)-6B,6C,6D,6E,6F-penta-O-
methyl-a-cyclodextrin 9 and hexakis(2,3-di-O-benzyl)-
6C,6D,6E,6F-tetra-O-methyl-a-cyclodextrin 10
4.6. Hexakis(2,3-di-O-benzyl)-6A,6B-dideoxy-6A,6B-
diiodo-6C,6D,6E,6F-tetra-O-methyl-a-cyclodextrin 11
To a stirred solution of 4 (180 mg, 0.084 mmol) in
anhydrous toluene (16 mL) was dropwise added
DIBAL (0.11 mL, 1.5 M in toluene, 2 equiv.) over 0.5
min at room temperature under argon. The stirring
mixture was heated to 55°C for 2 h under argon. The
reaction mixture was quenched and treated by the same
procedure as described for the preparation of 5. The
residue was purified by flash column chromatography
(eluent gradient, CH2Cl2/acetone, 9/1 to 6/1) to give the
mono-de-O-methylation product 9 as an amorphous
Compound 11 was prepared from 10 using the same
procedure as described for 6, and obtained as an amor-
phous powder (100%): [h]D +18 (c 1.4, CHCl3); 1H
NMR (CDCl3): l 7.31–7.17 (m, 60H, arom. H), 5.27 (d,
1H, J1,2=2.9 Hz, H-1), 5.24, 4.89 (2d, 2H, J=10.7 Hz,
PhCH2), 5.24, 4.90 (2d, 2H, J=10.5 Hz, PhCH2), 5.23,
4.94 (2d, 2H, J=10.8 Hz, PhCH2), 5.21, 4.92 (2d, 2H,
J=10.7 Hz, PhCH2), 5.16, 4.90 (2d, 2H, J=11.3 Hz,
PhCH2), 5.06, 4.87 (2d, 2H, J=11.0 Hz, PhCH2), 5.08
(d, 1H, J1,2=3.2 Hz, H-1), 5.07 (d, 1H, J1,2=3.7 Hz,

522
W. Wang et al. / Tetrahedron: Asymmetry 12 (2001) 517–523
H-1), 4.98 (d, 1H, J1,2=3.5 Hz, H-1), 4.97 (d, 2H,
1,2=3.4 Hz, 2×H-1), 4.68, 4.50 (2d, 2H, J=12.4 Hz,
7.30–7.19 (m, 70H, arom. H), 5.45 (d, 1H, J1,2=3.8 Hz,
H-1), 5.28 (d, 1H, J1,2=3.6 Hz, H-1), 5.22 (d, 1H,
J1,2=3.8 Hz, H-1), 4.96 (d, 1H, J1,2=3.4 Hz, H-1), 4.91
(d, 2H, J1,2=3.4 Hz, 2×H-1), 4.86 (d, 1H, J1,2=3.8 Hz,
H-1), 3.37, 3.35, 3.33, 3.33, 3.32, 3.31 (6s, 18H, 6×
OMe); 13C NMR (CDCl3): l 98.9, 98.77, 98.75, 98.6,
98.5, 98.1, 97.7 (7C-1), 61.18 (C-6A), 58.99, 58.96,
58.91, 58.90, 58.88, 58.84 (6OMe). MS: m/z 2503.2
(100%, M+Na+). Anal. calcd for C146H166O35: C, 70.68;
H, 6.74. Found: C, 70.52; H, 6.75%.
J
PhCH2), 4.58, 4.47 (2d, 2H, J=12.5 Hz, PhCH2), 4.56,
4.45 (2d, 2H, J=12.1 Hz, PhCH2), 4.53, 4.47 (2d, 2H,
J=12.5 Hz, PhCH2), 4.52, 4.41 (2d, 2H, J=12.6 Hz,
PhCH2), 4.48, 4.42 (2d, 2H, J=12.4 Hz, PhCH2), 3.38,
3.36, 3.35, 3.34 (4s, 12H, 4×OMe); 13C NMR (CDCl3):
l 139.5, 139.5, 139.38, 139.34, 139.07, 139.00, 138.4,
138.3, 138.28, 138.17, 138.12, 138.0 (12C, Ph), 128.3–
126.8 (60C, arom. C), 99.55, 99.50, 99.4, 98.9, 98.5, 98.4
(6C-1), 75.6, 75.6, 75.6, 75.34, 75.29, 75.2, 73.11, 73.08,
72.97, 72.88, 72.84, 72.84 (12PhCH2), 71.79, 71.76,
71.6, 71.3 (C-6C,6D,6E,6F), 9.7, 9.2 (C-6A,6B), 59.2,
59.08, 59.06, 59.06 (4OMe). MS: m/z 2352.7 (100%,
M+Na+). Anal. calcd for C124H138I2O28: C, 63.91; H,
5.97. Found: C, 63.94; H, 5.94%.
4.9. 6B,6C,6E,6F-Tetra-O-methyl-a-cyclodextrin 15
A solution of 5 (30 mg, 0.014 mmol) in EtOAc/MeOH
(1/1, 6 mL) was stirred in the presence of Pd/C (10%, 50
mg) at room temperature under H2 for 3 h, when TLC
(EtOAc/i-Propanol/H2O, 3/2/1) showed completion of
the reaction. The reaction mixture was filtered and the
filtrate was concentrated. The residue was purified on a
Sephadex G-15 column, using water as eluent. After
freeze-drying, compound 15 was obtained as a white
amorphous powder (14 mg, 97%): [h]D+105 (c 0.6,
4.7. Heptakis(2,3-di-O-benzyl-6-O-methyl)-b-cyclodex-
trin 13
Sodium hydride (60% dispersion in mineral oil, 1.1 g,
42 equiv.) was added portion-wise to a stirred solution
of heptakis(2,3-di-O-benzyl)-b-cyclodextrin 1210,11 (1.6
g, 0.66 mmol) in anhydrous DMF (100 mL) at 0°C.
The mixture was stirred for 1 h at 0°C, and methyl
iodide (1.46 mL) was added dropwise into the solution.
The reaction mixture was allowed to warm to room
temperature and stirred for 2 days, when TLC analysis
(CH2Cl2/acetone, 9/1) showed completion of the reac-
tion. The reaction mixture was cooled to 0°C and
methanol (2 mL) was added dropwise. The solvent was
evaporated in vacuo and the residue was diluted with
CH2Cl2 and filtered through a layer of Celite®. The
filtrate was diluted with CH2Cl2 and washed with
water. The organic phase was dried over MgSO4 and
concentrated. The residue was purified by flash column
chromatography (CH2Cl2/acetone, 9/1) to give 13 as a
1
MeOH); H NMR (D2O): l 5.03 (d, 2H, J1,2=3.7 Hz,
2×H-1), 5.02 (d, 2H, J1,2=3.7 Hz, 2×H-1), 5.01 (d, 2H,
J
1,2=3.4 Hz, 2×H-1), 3.38 (s, 12H, 4×OMe); 13C NMR
(D2O): l 101.80, 101.77, 101.62 (3×2C-1), 81.62, 81.59,
81.56, 73.60, 73.57, 72.35, 71.96, 71.03, 70.88 (ring C),
71.03, 70.98 (C-6B,6C,6E,6F), 60.70 (C-6A,6D), 58.80,
58.75 (4OMe). HRMS: m/z for C40H68O30: calcd,
1051.3693 (100%, M+Na+); found, 1051.3673 (100%,
M+Na+). Anal. calcd for C40H68O30·25 H2O: C, 32.48;
H, 8.04. Found: C, 32.63; H, 8.24%.
Acknowledgements
1
white foam (1.37 g, 82%): [h]D +20 (c 1.5, CHCl3); H
We would like to thank Mrs Ve´ronique Michon for
recording the NMR spectra, and Mrs Nicole Morin for
recording the mass spectra. We also thank the
NMR (CDCl3): l 7.30–7.10 (m, 70H, arom. H), 5.15,
4.86 (2d, 14H, J=11.0 Hz, 7×PhCH2), 5.13 (d, 7H,
J
1,2=3.6 Hz, 7×H-1), 4.59, 4.52 (2d, 14H, J=12.4 Hz,
European Community for a TMR Marie Curie
7×PhCH2), 4.11–4.05 (m, 7H, 7×H-3), 3.99–3.90 (m,
21H, 7×H-4, 7×H-5, 7×H-6a), 3.60–3.50 (m, 14H, 7×H-
2, 7×H-6b), 3.35 (s, 21H, 7×OMe); 13C NMR (CDCl3):
l 98.4 (7C-1), 80.9 (7C-3), 78.7 (7C-2), 78.2 (7C-4), 75.4
(7PhCH2), 72.9 (7PhCH2), 71.2 (7C-6), 71.0 (7C-5),
58.9 (7OMe). MS: m/z 2517.0 (100%, M+Na+). Anal.
calcd for C147H168O35: C, 70.77; H, 6.79. Found: C,
70.67; H, 6.84%.
Research Training Grant (No. ERBFMBICT983225)
to A.J.P.
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