Diisobuty laluminium hydride (DIBAL-H) promoted secondary rim regioselective demethylations of permethylated β-cyclodextrin: A mechanistic proposal

Article abstract of DOI:10.1002/ejoc.200901230

Diisobutylaluminiurn hydride (DIBAL-H) promotes secondary rim regioselective bis-de-O-methylation at the 2^A- and 3 ^B-positions of permethylated β-cyclodextrin, This result contrasts with the selective bis-de-O-benzylation of perbenzylated cyclodextrins in which regioselective deprotection occurs at the primary rim. To gain an insight into the mechanism of this remarkable contrasting behavior, the two corresponding permethylated cyclodextrins with an alcohol function at either the 2- or 3-position were synthesized. The cyclodextrin with the alcohol at the 3-position reacts with DIBAL-H to afford the 2^A,3^B-diol whereas the cyclodextrin with the alcohol at the 2-position is unreactive. This observation allows us to propose a mechanism for the demethylation reaction that involves for each demethylation step two molecules of aluminium, reagent, in accord with the previous hypothesis on the debenzylation reaction. The second demethylation step appears to be faster than the first, the coordination of aluminium now being an intramolecular process.

Full text of DOI:10.1002/ejoc.200901230

FULL PAPER
DOI: 10.1002/ejoc.200901230
Diisobutylaluminium Hydride (DIBAL-H) Promoted Secondary Rim
Regioselective Demethylations of Permethylated β-Cyclodextrin: A Mechanistic
Proposal
Sulong Xiao,[a,b] Ming Yang,[a] Pierre Sinaÿ,[b] Yves Blériot,[b] Matthieu Sollogoub,*[b] and
Yongmin Zhang*[b]
Keywords: Cyclodextrins / Dealkylation / Reaction mechanisms / Regioselectivity / Protecting groups
Diisobutylaluminium hydride (DIBAL-H) promotes second-
ary rim regioselective bis-de-O-methylation at the 2A- and
cyclodextrin with the alcohol at the 3-position reacts with
DIBAL-H to afford the 2A,3B-diol whereas the cyclodextrin
3B-positions of permethylated β-cyclodextrin. This result con- with the alcohol at the 2-position is unreactive. This observa-
trasts with the selective bis-de-O-benzylation of perbenzyl- tion allows us to propose a mechanism for the demethylation
ated cyclodextrins in which regioselective deprotection oc- reaction that involves for each demethylation step two mo-
curs at the primary rim. To gain an insight into the mecha- lecules of aluminium reagent, in accord with the previous
nism of this remarkable contrasting behavior, the two corre-
sponding permethylated cyclodextrins with an alcohol func-
tion at either the 2- or 3-position were synthesized. The
hypothesis on the debenzylation reaction. The second de-
methylation step appears to be faster than the first, the coor-
dination of aluminium now being an intramolecular process.
cessfully applied to benzylated sugars and CDs,[4,5] allowing
access to polyhetero-functionalized CDs containing two,
three or even four different functionalities[5–7] (Scheme 1).
This approach allowed us to synthesize complex CD dimers
used as supramolecular cross-linkers of biopolymers.[8] In
all these syntheses, the last step is always the removal of the
remaining benzyl groups. Use of permethylated CDs would
suppress this step and, more interestingly, would allow
modulation of the affinity and solubility of the CDs and
thus avoid the drawbacks associated with the presence of
free OH groups in applications such as catalysis. We report
herein a full account of our work on the demethylation re-
action of permethylated CDs.
Introduction
Cyclodextrins (CDs) are involved in a wide spectrum of
applications due to their ability to form water-soluble in-
clusion complexes with hydrophobic molecules.[1] Simple
modifications of CDs, for example, by per-O-methylation,
alter their chemophysical properties, including their solubil-
ity both in water and in organic solvents,[3] as well as the
stability of their inclusion complexes. The efficient synthesis
of methylated CDs bearing specifically located hydroxy
groups is of considerable interest for their further modifica-
tion and is a stimulating chemical challenge.[1,2] Up to now,
selectively modified poly-O-methylated CDs have usually
been synthesized[3] by temporary regioselective protection
of specific hydroxy groups of the native CD followed by
permethylation of the remaining hydroxy groups and final
removal of the protecting groups to unmask the required
hydroxy functions.
Results and Discussion
We submitted per-O-methylated β-CD 4 to the action of
DIBAL-H and observed demethylation reactions leading to
a mixture of compounds. Careful optimization of the reac-
tion conditions was necessary to drag the reaction towards
a major product and we have been able to delineate three
sets of conditions to access three different CDs, 5, 6 and 7,
as major products. Note, CDs 5, 6 and 7 are modified on
the secondary rim in a regioselective manner, a rather diffi-
cult task to achieve.[9–11] The optimized results are summa-
rized in Scheme 2 and Table 1.
From the opposite point of view, we have developed over
the years an approach that involves the deprotection of pro-
tected CDs. The methodology uses diisobutylaluminium hy-
dride (DIBAL-H) as a dealkylating agent and has been suc-
[a] State Key Laboratory of Natural and Biomimetic Drugs,
School of Pharmaceutical Sciences, Peking University Health
Science Center,
100083 Beijing, P. R. China
[b] UPMC Univ. Paris 06, Institut Parisien de Chimie Moléculaire
(UMR CNRS 7201), FR2769, C. 181,
When permethylated CD 4 was treated with 9 equiv. of a
0.2  solution of DIBAL-H in toluene for 18 h at 0 °C, diol
5[12,13] was obtained as the main compound in 56% yield,
a result of double de-O-methylation on the secondary rim
4 place Jussieu, 75005 Paris, France
E-mail: matthieu.sollogoub@upmc.fr
yongmin.zhang@upmc.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901230.
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Eur. J. Org. Chem. 2010, 1510–1516

Regioselective Demethylations of Permethylated β-Cyclodextrin
Scheme 1. The de-O-benzylation reactions of per-O-benzylated β-CD by DIBAL-H.
Scheme 2. Major product profile of the de-O-methylation reactions of per-O-methylated β-CD with DIBAL-H.
Table 1. Yields of the major products and reaction conditions of
the de-O-methylation reactions of per-O-methylated β-CD with
DIBAL-H.
Such a finding may be explained either by a concerted
double demethylation or by a stepwise process in which the
second dealkylation would be faster than the first. To this
end, we synthesized both alcohols 8 and 13 to study their
reactivity towards DIBAL-H. Diol 5 was selectively methyl-
ated at the 2-position in the presence of NaH and MeI to
give CD 8 as the major product (70% yield).[16] The struc-
ture of CD 8 was confirmed by its acetylation to compound
9, the NMR spectrum of which displays a deshielded trip-
let, clearly indicating the acetylation of 3-OH. The synthesis
of alcohol 13 with a free OH at the 2-position required a
roundabout approach due to the selectivity of the alkylation
reaction in favor of the 2-position. Benzylation of CD 5, as
expected, afforded alcohol 10 as the major product (87%).
In this case also, acetylation of the remaining OH to 11
confirmed it to be the correct regioisomer, as indicated by
the appearance of a deshielded triplet in the NMR spec-
trum. Further methylation of alcohol 10 afforded CD 12 in
89% yield, which was debenzylated to give the desired CD
13 in 96% yield. Further acetylation of 13 induced the ap-
pearance of a deshielded double doublet in the NMR spec-
trum of 14, which confirms the presence of a free 2-OH in
CD 13 (Scheme 3).
Entry Conc. of DIBAL-H
[molL–1]
Equiv. of
DIBAL-H [°C] [h]
T
t
Yield [%]
5
6
7
1
2
3
0.2
0.8
0.4
9
50
50
0
r.t.
r.t.
18
3
28
56
51
45
of two contiguous sugar units at the 2A- and 3B-positions.
Treatment of 4 with 50 equiv. of DIBAL-H (0.8 ) for 3 h
at room temperature gave tetrol 6[14] as the major product
in 51% yield. If left for a prolonged period of time but at a
lower DIBAL-H concentration (0.4 ), the reaction led to
hexol 7[15] as the major compound (45% yield). These re-
markable results appear to be in sharp contrast to the case
of benzylated CDs in which debenzylation occurs on the
primary rim of the CD and on two diametrically opposed
sugar rings. Furthermore, we showed that such a bis-deben-
zylation reaction was a stepwise process because we could
isolate alcohol 2 and resubmit it to the action of DIBAL-
H to obtain diol 1[5–7] (Scheme 1). In the case of permethyl-
ated CDs, and in spite of our efforts, we were unable to
isolate a mono-alcohol on the secondary rim, which sug-
gests a subtly different mechanism.
Both 2-hydroxy-CD 13 and 3-hydroxy-CD 8 were then
allowed to react with DIBAL-H. Although CD 8 afforded
the 2A,3B-dihydroxy-CD 5, CD 13 did not react at all even
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S. Xiao, M. Yang, P. Sinaÿ, Y. Blériot, M. Sollogoub, Y. Zhang
FULL PAPER
Scheme 3. Synthetic routes to the mono-functionalized methylated β-CDs 8 and 13.[3,13]
Scheme 4. Only 3-hydroxy-CD 8 affords diol 5 upon action of DIBAL-H.
after prolonged reaction times. Remarkably, demethylation
of CD 8 to diol 5 took place at a much faster rate than the
double dealkylation of permethylated CD 4 to afford the
same diol 5 (Scheme 4). This result indicates that the double
2A,3B-demethylation reaction is a stepwise mechanism, the
first dealkylation occurring at the 3B-position followed by
a faster demethylation at the 2A-position of the adjacent
sugar.
Scheme 5. Proposed general mechanism for the debenzylation reac-
tion.[5]
We previously proposed a mechanism for the de-O-benz-
ylation reaction involving two molecules of the aluminium
Based on these results, we would like to propose a plaus-
reagent.[5] We also observed that two oxygen atoms were ible mechanism for the remarkable bis-demethylation of the
necessary for the reaction to occur. As illustrated in secondary rim of permethylated β-CD. The first step must
Scheme 5, with benzylated cyclohexanediol as a model, the be the chelation of an aluminium species by two proximal
first aluminium molecule is chelated by the two oxygen and easily accessible oxygen atoms on the secondary rim. It
atoms and the second coordinates to the less hindered oxy- has been shown that an acetal regioselectively forms be-
gen of the two to form 16. In this situation, one aluminium tween O-2A and O-3B on an unprotected secondary rim of
plays the role of the Lewis acid and activates the C–O bond a CD.[11] Hence, we propose that it is also O-2A and O-3B
whereas the other is activated and can deliver its hydride that preferentially chelate aluminium to form species 19.
leading to dealkylation to give 17. It is the combination of Such chelation on the secondary rim is precluded with per-
the two that allows the dealkylation process. However, fur- benzylated β-CD due to the steric congestion caused by the
ther debenzylation was never observed in such systems and benzyl residues. The second aluminium reagent required for
alcohol 18 is inert to the action of DIBAL-H.
dealkylation would then select the less hindered O-3 oxygen
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Eur. J. Org. Chem. 2010, 1510–1516

Regioselective Demethylations of Permethylated β-Cyclodextrin
Scheme 6. Proposed mechanism for the formation of 2A,3B-diol 5 from per-O-methylated β-CD 4.
of the chelate, which points away from the cavity of the benzylated β-CD is certainly due to the ease of access to
CD, to form complex 20. Dealkylation then occurs at the appropriate dioxygenated “tweezers”, O-5A/O-6A in the
3-position to give 21. If this first transformation is indeed case of hindered benzylated β-CD and O-2A/O-3B in the
the rate-limiting step, the second dealkylation must be case of unhindered β-CD 4. In the latter case, a third oxy-
faster. This is the reason why we suppose that the alumin- gen is situated in the vicinity and allows a second demethyl-
ium atom already in place and coordinated to the O-2 to ation to rapidly occur after the first one, which is not pos-
be dealkylated plays an essential role. Furthermore, the in- sible in the case of the benzylation reaction.
terglycosidic oxygen atom is perfectly situated to participate
in a second coordination to yield the required chelate 22;
this reactive chelate is also formed by the reaction of
DIBAL-H with alcohol 8. This intramolecular coordination
probably accounts for the increased rate of this step. Re-
duction then proceeds via complex 23 to afford diol 5 after
Experimental Section
General: Optical rotations were measured at 20Ϯ2 °C with a digital
polarimeter by using a 10 cm, 1 mL cell. High-resolution mass
spectrometry (HRMS) was carried out with a spectrometer in the
positive ESI mode. NMR spectra were recorded with a spectrome-
hydrolysis (Scheme 6). Duplication and triplication of this
mechanism, directed by the steric hindrance of the alumin-
ium adducts, leads to the formation of tetrol 6 and hexol 7,
just as the conversion of alcohol 2 to diol 1 occurs by a
duplication of the primary rim de-O-benzylation mecha-
nism directed by the crowding induced by the aluminium
species attached to the first debenzylation site.[5]
ter at ambient temperature. 1H NMR chemical shifts are referenced
to residual protic solvent (CDCl3; δH = 7.28 ppm). 13C NMR
chemical shifts are referenced to the solvent signal (δC = 77.00 ppm
for the central line of CDCl3). Assignments were aided by the CO-
SY,J-mod technique and HMQC. Reactions were monitored by
thin-layer chromatography (TLC) on precoated silica gel 60 F254
plates (layer thickness 0.2 mm) and detected by charring with a
10% solution of sulfuric acid in ethanol. Flash column chromatog-
raphy was performed on silica gel 60 (230–400 mesh). Solvents were
freshly distilled from Na/benzophenone (THF, toluene), or P2O5
(CH2Cl2). Diisobutylaluminium was purchased from Aldrich as a
1.5  solution in toluene.
Conclusions
The action of DIBAL-H on permethylated CD 4 allows
a one-step easy access to regioselectively modified di-, tetra-
and hexa-functionalized CDs 5, 6 and 7, respectively, which
are suitable for further transformations.[17] The striking re-
2A,3B-Dihydroxy-per-O-methyl-β-cyclodextrin (5): A 1.5  solution
of DIBAL-H in toluene (2.52 mmol, 9 equiv., 1.7 mL) was added to
activity difference between permethylated β-CD 4 and per- a solution of heptakis-2,3,6-tri-O-methyl-β-cyclodextrin 4 (400 mg,
Eur. J. Org. Chem. 2010, 1510–1516
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S. Xiao, M. Yang, P. Sinaÿ, Y. Blériot, M. Sollogoub, Y. Zhang
FULL PAPER
0.28 mmol) in anhydrous toluene (10.9 mL) at 0 °C under nitrogen.
The reaction mixture was stirred at 0 °C for 18 h under nitrogen.
Aqueous HCl (1 ) was carefully added dropwise and the mixture
was stirred vigorously at room temperature for 10 min. The toluene
phase was separated and the aqueous layer was extracted with ethyl
acetate (3ϫ10 mL). The combined organic layers were washed
with brine, dried with MgSO4, filtered and the solvent removed in
vacuo. The residue was subjected to flash chromatography (eluent:
CH2Cl2/CH3OH = 40:1–35:1) to give 220 mg (56%) of 5. Rf = 0.2
(dichloromethane/methanol = 15:1). [α]D = +154 (c = 1.0, CHCl3).
MS (FAB): m/z = 1423.7 [M + Na]+. 1H NMR (400 MHz, CDCl3):
δ = 3.14 (m, 6 H, 6ϫ2-H), 3.35 [s, 12 H, 4ϫOCH3 (C-6)], 3.36 [s,
9 H, 3ϫOCH3 (C-6)], 3.45 [s, 9 H, 3ϫOCH3 (C-3)], 3.46 [s, 3 H,
(1 ), the toluene phase was separated and the aqueous phase was
concentrated to a quarter of the original volume. The residue was
extracted with ethyl acetate (50 mL) and the combined organic
phases wer washed with brine, dried with MgSO4 and the solvents
evaporated to dryness. The resultant solid was subjected to silica
gel chromatography, eluting with CH2Cl2/MeOH (94:6, v/v), to give
85 mg (yield 45%) of 7. Rf = 0.14 (CH2Cl2/MeOH, 91:9). [α]D
=
+157 (c = 1.0, CHCl3) {ref.[15] [α]D = +156.7 (c = 1.0, CHCl3)}.
1
MS (FAB): m/z = 1367 [M + Na]+. H NMR (400 MHz, CDCl3):
δ = 3.12–3.93 (m, 97 H), 4.94–4.95, (m, 3ϫ1-H), 5.03 (d, J =
3.3 Hz, 1-H), 5.06 (d, J = 3.4 Hz, 2ϫ1-H), 5.09 (d, J = 3.4 Hz, 1-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 57.94, 58.09, 58.18,
58.20, 58.75, 58.77, 58.79, 58.90, 60.95, 61.07, 61.64, 61.95
OCH3 (C-3)], 3.47 [s, 6 H, 2ϫOCH3 (C-3)], 3.54 (dd, J1,2 = 3.5, (15ϫOCH3), 70.21, 70.28, 71.20, 71.45, 71.51, 71.55, 71.60 (7ϫC-
J2,3 = 9.6 Hz, 1 H, 2A-H), 3.57 [s, 3 H, OCH3 (C-2)], 3.58 [s, 3 H, 5), 70.64, 70.93, 71.10, 71.20 (7ϫC-6), 73.03, 73.19, 73.23, 81.09,
OCH3 (C-2)], 3.59 [s, 3 H, OCH3 (C-2)], 3.60 [s, 3 H, OCH3 (C- 81.13, 81.20, 81.28, 81.40, 81.45, 81.56, 81.84, 82.05, 82.30, 82.74
2)], 3.61 [s, 3 H, OCH3 (C-2)], 3.69 [s, 3 H, OCH3 (C-2)], 3.40–3.90
(m, 34 H, 6ϫ3-H, 7ϫ4-H, 7ϫ5-H, 14ϫ6-H), 3.94 (t, J2,3 = J3,4
= 9.4 Hz, 1 H, 3B-H), 4.07 (d, 1 H, OH), 4.37 (s, 1 H, OH), 4.95
(d, J1,2 = 3.6 Hz, 1 H, 1A-H), 5.05 (d, J1,2 = 3.2 Hz, 2 H, 2ϫ1-H),
5.07 (d, J1,2 = 3.9 Hz, 1 H, 1-H), 5.09 (d, J1,2 = 2.9 Hz, 2 H, 2ϫ1-
H), 5.10 (d, J1,2 = 3.2 Hz, 1 H, 1B-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 58.32, 58.34, 58.44, 58.50, 58.69, 58.92, 58.95, 58.98,
59.04 [13 C, 6ϫOCH3 (C-2), 7ϫOCH3 (C-6)], 61.30, 61.36, 61.38,
61.41, 61.55, 62.15 [6 C, 6ϫOCH3 (C-3)], 70.43, 70.83, 70.91,
70.99, 71.68 (7ϫC-5), 71.22, 71.31, 71.37, 71.40, 71.54 (7ϫC-6),
71.79 (C-3B), 73.50 (C-2A), 80.06, 80.39, 81.00, 81.03, 81.36, 81.43,
81.64, 81.67, 81.80, 81.93, 82.07, 82.26, 82.43, 82.97 (19 C, 6ϫC-
2, 6ϫC-3, 7ϫC-4), 98.72, 98.97, 98.99, 99.36, 99.48 (6 C, 6ϫC-
1), 102.03 (C-1A) ppm. C61H108O35 (1401.49): calcd. C 52.28, H
7.77; found C 52.09, H 7.81.
(7ϫC-2, 7ϫC-3, 7ϫC-4), 99.38, 99.61, 99.68, 99.73, 101.94,
102.12, 102.20 (7ϫC-1) ppm. C57H100O35 (1345.38)·2H2O: calcd.
C 49.56, H 7.59; found C 49.26, H 7.46.
3B-Hydroxy-per-O-methyl-β-cyclodextrin (8):[13] NaH (60%, 2.8 mg,
0.071 mmol, 1 equiv.) was added to a solution of 5 (100 mg,
0.071 mmol) in anhydrous THF (10 mL) at 0 °C under nitrogen.
After stirring at 0 °C for 1 h, CH3I (0.071 mmol, 1.0 equiv., 4.4 µL)
was added. The reaction mixture was stirred at 0 °C for 6 h and
then kept at room temperature for another 12 h under nitrogen.
CH3OH was added dropwise to quench the reaction and the sol-
vent was removed in vacuo. The residue was dissolved in CH2Cl2,
washed with brine, dried with MgSO4, filtered and the solvent re-
moved in vacuo. The residue was subjected to flash chromatog-
raphy (eluent: CH2Cl2/EtOAc/CH3OH = 2:8:0.6) to give 71 mg
(70%) of 8 as a white foam. [α]D = +136 (c = 1.0, CHCl3) {ref.[13]
[α]D = +157 (c = 0.96, CHCl3)}. The analytical data of 8 are in
agreement with those reported previously.[13]
2A,3B,2E,3D-Tetrahydroxy-per-O-methyl-β-cyclodextrin
(6):[14]
DIBAL-H (35.1 mmol, 50 equiv., 1.5  in toluene, 23.4 mL) was
added to a stirred solution of permethylated CD 4 (1.0 g, 0.7 mmol)
in anhydrous toluene (20 mL) at room temperature under argon.
The reaction mixture was stirred at this temperature for 3 h. The
solution was cooled to 0 °C, quenched with aqueous HCl (1 ) and
the mixture was stirred vigorously at room temperature for 30 min.
The toluene phase was collected and the aqueous phase extracted
with ethyl acetate (3ϫ50 mL). The combined organic phases were
washed with brine, dried with MgSO4 and the solvent removed in
vacuo. Purification of the crude product by silica gel chromatog-
raphy, eluting with 96:4 dichloromethane/methanol, afforded
492 mg (51%) of 6 as a colourless foam. [α]D = +152 (c = 1.3,
CHCl3) {ref.[14] [α]D = +152 (c = 1.3, CHCl3)}. MS (FAB): m/z =
3B-O-Acetyl-per-O-methyl-β-cyclodextrin (9):[13] DMAP (3.2 mg,
0.026 mmol, 1 equiv.) and Ac2O (1 mL) were added to a solution
of 8 (37 mg, 0.026 mmol) in dry pyridine (2 mL) at room tempera-
ture. The reaction mixture was stirred for 18 h under nitrogen. The
solvent was removed in vacuo. The residue was subjected to flash
chromatography (eluent: cyclohexane/acetone = 2:1) to give 36 mg
(95%) of 9 as a white foam. Rf = 0.2 (cyclohexane/acetone = 3:2).
[α]D = +140 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
2.15 (s, 3 H, CH3CO), 3.12 (dd, J1,2 = 3.1, J2,3 = 9.6 Hz, 1 H, 2-
H), 3.16–3.21 (m, 5 H, 5ϫ2-H), 3.30 (dd, J1,2 = 3.7, J2,3 = 10.3 Hz,
1 H, 2B-H), 3.39–3.42 [m, 21 H, 7ϫOCH3 (C-6)], 3.43 (m, 1 H, 3-
H), 3.48, 3.49, 3.50, 3.51, 3.52, 3.53 [m, 21 H, 7ϫOCH3 (C-2)],
3.61, 3.63, 3.65, 3.66, 3.67, 3.68 [s, 18 H, 6ϫOCH3 (C-3)], 3.46–
3.68 (m, 17 H, 5ϫ3-H, 5ϫ4-H, 7ϫ6a-H), 3.75 (m, 1 H, 4B-H),
3.71–3.96 (m, 13 H, 7ϫ5-H, 6ϫ6b-H), 4.05 (dd, J5,6b = 2.4, J6a,6b
= 10.6 Hz, 1 H, 6b-H), 4.98 (d, J1,2 = 3.0 Hz, 1 H, 1-H), 5.08 (d,
J1,2 = 3.5 Hz, 1 H, 1-H), 5.12–5.14 (m, 4 H, 4ϫ1-H), 5.30 (d, J1,2
= 3.7 Hz, 1 H, 1B-H), 5.41 (dd, J2,3 = 10.3, J3,4 = 9.0 Hz, 1 H, 3B-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.32 (1 C, CH3CO),
58.13, 58.22, 58.34, 58.52, 58.63, 58.86, 58.90, 58.94, 59.07, 59.26
[14 C, 7ϫOCH3 (C-2), 7ϫOCH3 (C-6)], 60.98, 61.45, 61.47, 61.62,
61.72, 61.79 [6 C, 6ϫOCH3 (C-3)], 70.45, 71.18, 71.38, 71.52, 71.89
1
1395.6 [M + Na]+. MS (CI): m/z = 1390.7 [M + NH4]+. H NMR
(500 MHz, [D6]DMSO): δ = 3.61, 3.64, 3.95 (7 H, 7ϫ2-H), 3.85,
3.88, 3.90, 4.30, 4.31 (7 H, 7ϫ3-H), 3.96, 3.97, 3.98, 4.01, 4.02 (7
H, 7ϫ4-H), 4.27, 4.29, 4.32, 4.34, 4.35 (7 H, 7ϫ5-H), 5.36, 5.37,
5.60, 5.61, 5.62 (7 H, 7ϫ1-H), 6.23, 6.25, 6.47, 6.50 (4 H,
4ϫOH) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 74.61, 74.80,
74.82, 75.16, 75.22, 75.52, 75.55 (7ϫC-5), 75.56, 75.58, 85.73,
85.79, 87.41, 87.54 (7ϫC-3); 77.05, 77.24, 85.48, 85.79, 85.80
(7ϫC-2), 84.11, 84.23, 84.30, 84.74, 84.86, 85.54, 85.56 (7ϫC-4),
102.4, 102.5, 103.0, 105.6, 105.7 (7ϫC-1) ppm. C59H104O35·2H2O
(1373.43): calcd. C 50.27, H 7.72; found C 50.28, H 7.77.
2A,3B,2E,3D,2F,3G-Hexahydroxy-per-O-methyl-β-cyclodextrin: (7):[15] (7 C, 7ϫC-6), 70.50, 70.79, 70.87, 70.96, 71.23 (7 C, 7ϫC-5), 71.32
DIBAL-H (7 mmol, 50 equiv., 1.5  in toluene, 4.67 mL) was
added to a solution of heptakis-2,3,6-tri-O-methyl-β-cyclodextrin
(200 mg, 0.14 mmol) in anhydrous toluene (12 mL). The reaction
mixture was stirred at room temperature for 28 h under argon. Af-
ter quenching the reaction by adding an aqueous solution of HCl
(C-3B), 78.66 (C-4B), 79.21, 79.80, 80.48, 80.53, 80.56, 80.80, 81.16,
81.27, 81.52, 81.62, 81.68, 81.76, 81.94, 82.18, 82.24, 82.42, 82.55
(19 C, 7ϫC-2, 6ϫC-3, 6ϫC-4), 98.63, 98.71, 98.90, 99.00, 99.29,
99.51, 99.61 (7 C, 7ϫC-1), 170.45 (CH3CO) ppm. HRMS: calcd.
for C64H112O36 [M + Na]+ 1479.6831; found 1479.6826.
1514
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Eur. J. Org. Chem. 2010, 1510–1516

Regioselective Demethylations of Permethylated β-Cyclodextrin
2A-O-Benzyl-3B-hydroxy-per-O-methyl-β-cyclodextrin (10): NaH
(60%, 2.8 mg, 0.071 mmol, 1.0 equiv.) was added to a solution of
5 (100 mg, 0.071 mmol) in anhydrous THF (10 mL) at 0 °C under
nitrogen. After stirring the reaction mixture at 0 °C for 1 h, BnBr
(0.071 mmol, 1.0 equiv., 8.6 µL) was added. The reaction mixture
was stirred at 0 °C for 6 h and then kept at room temperature for
12 h under nitrogen. CH3OH was added dropwise to quench the
reaction and the solvent removed in vacuo. The residue was dis-
solved in CH2Cl2, washed with brine, dried with MgSO4, filtered
and the solvent removed. The residue was subjected to flash
chromatography (eluent: CH2Cl2/EtOAc/CH3OH = 2:8:0.4) to give
93 mg (87%) of 10 as a white foam. Rf = 0.3 (CH2Cl2/EtOAc/
CH3OH = 5:5:1). [α]D = +132 (c = 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 3.16–3.20 (m, 5 H, 5ϫ2-H), 3.27 (dd, J1,2
= 3.5, J2,3 = 10.1 Hz, 1 H, 2B-H), 3.33 [3 H, 1ϫOCH3 (C-6)], 3.36
[3 H, 1ϫOCH3 (C-6)], 3.39 [m, 17 H, 7ϫOCH3 (C-6), 2A-H], 3.46
(m, 1 H, 4B-H), 3.50, 3.51, 3.56 [18 H, 6ϫOCH3 (C-2)], 3.63, 3.65
[15 H, 5ϫOCH3 (C-3)], 3.70 [3 H, 1ϫOCH3 (C-3)], 3.47–3.70 (m,
19 H, 6ϫ3-H, 6ϫ4-H, 7ϫ6a-H), 3.79–3.88 (m, 14 H, 7ϫ5-H,
128.28, 128.34 138.49 (6 C, arom-C), 170.63 (CH3CO) ppm.
HRMS: calcd. for C70H116O36 [M + Na]+ 1555.7144; found
1555.7139.
2A-O-Benzyl-per-O-methyl-β-cyclodextrin (12):[3] NaH (60%,
2.8 mg, 0.071 mmol, 1 equiv.) was added to a solution of 10
(106 mg, 0.071 mmol) in anhydrous THF (10 mL) at 0 °C under
nitrogen. After stirring at 0 °C for 1 h, CH3I (0.071 mmol,
1.0 equiv., 4.4 µL) was added. The reaction mixture was stirred at
0 °C for 6 h and then kept at room temperature for another 12 h
under nitrogen. CH3OH was added dropwise to quench the reac-
tion and the solvent was removed in vacuo. The residue was dis-
solved with CH2Cl2, washed with brine, dried with MgSO4, filtered
and the solvent removed in vacuo. The residue was subjected to
flash chromatography (eluent: cyclohexane/acetone = 5:2) to give
95 mg (89%) of 12 as a white foam. [α]D = +126 (c = 0.8, CHCl3).
Its NMR spectroscopic data are in agreement with those published
earlier.[3]
2A-Hydroxy-per-O-methyl-β-cyclodextrin (13):[3,13] Pd/C (10%,
135 mg, 0.13 mmol, 1.0 equiv.) was added to a solution of 12
(192.8 mg, 0.13 mmol) in methanol (10 mL). The suspension was
purged three times with nitrogen and then subjected to a flow of
hydrogen. The reaction mixture was stirred at room temperature
for 16 h. The suspension was filtered through a pad of Celite, which
was then washed with CH3OH (3ϫ4 mL). The combined filtrate
was concentrated to dryness. The residue was subjected to flash
chromatography (eluent: cyclohexane/acetone = 2:1) to give 174 mg
(96%) of 13 as a white foam. Rf = 0.3 (cyclohexane/acetone = 1:1).
[α]D = +143 (c = 1.0, CHCl3) {ref.[13] [α]D = +160.6 (c = 1.57,
CHCl3)}. Its NMR spectroscopic data are in agreement with those
reported previously.[13]
7ϫ6b-H), 3.99 (t, J2,3 = J3,4 = 10.1 Hz, 1 H, 3B-H), 4.62 (d, J1,2
=
3.7 Hz, 1 H, 1A-H), 4.72 (d, Jgem = 12.5 Hz, 1 H, PhCH2), 4.89 (d,
Jgem = 12.5 Hz, 1 H, PhCH2), 5.05 (d, J1,2 = 3.5 Hz, 1 H, 1-H),
5.09–5.13 (m, 5 H, 4ϫ1-H, 3B-OH), 5.15 (d, J1,2 = 3.5 Hz, 1 H,
1B-H), 7.29–7.36 (m, 3 H, arom-H), 7.40–7.42 (m, 2 H, arom-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 58.40, 58.42, 58.44,
58.46, 58.52, 58.59, 58.80, 58.88, 58.90, 58.92 [13 C, 6ϫOCH3 (C-
2), 7ϫOCH3 (C-6)], 61.34, 61.35, 61.41, 61.46, 61.56, 61.86 [6 C,
6ϫOCH3 (C-3)], 70.01, 70.84, 70.91, 70.93, 70.97, 71.26 (7 C,
7ϫC-6), 70.81, 71.03, 71.31, 71.40 (7 C, 7ϫC-5), 71.70 (C-3B),
73.87 (PhCH2), 78.84 (C-2A), 80.22, 80.10, 80.82, 81.20, 81.28,
81.40, 81.52, 81.65, 81.73, 82.00, 82.04, 82.07, 82.24, 82.34, 82.62,
83.21 (19 C, 6ϫC-2, 6ϫC-3, 7ϫC-4), 98.73, 98.87, 98.99, 99.38,
99.69, 99.81 (6 C, 6ϫC-1), 101.47 (C-1A), 128.20, 128.48, 128.83,
137.12 (6 C, arom-C) ppm. HRMS: calcd. for C68H114O35 [M +
Na]+ 1513.7038; found 1513.7033.
2A-O-Acetyl-per-O-methyl-β-cyclodextrin (14):[13] DMAP (4.8 mg,
0.039 mmol, 1 equiv.) and Ac2O (1.5 mL) were added to a solution
of 13 (55 mg, 0.039 mmol) in dry pyridine (3 mL) at room tempera-
ture. The reaction mixture was stirred for 16 h under nitrogen. The
solvent was removed in vacuo and the residue subjected to flash
chromatography (eluent: cyclohexane/acetone = 2:1) to give 56 mg
(99%) of 14 as a white foam. Rf = 0.25 (cyclohexane/acetone =
2A-O-Benzyl-3B-O-acetyl-per-O-methyl-β-cyclodextrin (11): DMAP
(3.2 mg, 0.026 mmol, 1 equiv.) and Ac2O (1 mL) were added to a
solution of 10 (38 mg, 0.026 mmol) in dry pyridine (2 mL) at room
temperature. The reaction mixture was stirred for 18 h under nitro-
gen. The solvent was removed in vacuo and the residue was sub-
jected to flash chromatography (eluent: CH2Cl2/CH3OH = 40:1) to
give 32 mg (80%) of 11 as a white foam. Rf = 0.3 (CH2Cl2/CH3OH
= 10:1). [α]D = +136 (c = 1.0, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.94 (s, 3 H, CH3CO), 3.17–3.22 (m, 5 H, 5ϫ2-H),
3.30 (dd, J1,2 = 3.3, J2,3 = 9.6 Hz, 1 H, 2-H), 3.38 (dd, J1,2 = 3.9,
J2,3 = 9.4 Hz, 1 H, 2B-H), 3.35, 3.37, 3.40 [21 H, 7ϫOCH3 (C-6)],
3.49, 3.50, 3.51, 3.52, 3.53 [18 H, 6ϫOCH3 (C-2)], 3.62, 3.65, 3.67,
3.68 [18 H, 6ϫOCH3 (C-3)], 3.47–3.72 (m, 19 H, 6ϫ3-H, 6ϫ4-
H, 7ϫ6a-H), 3.79 (m, 1 H, 4B-H), 3.77–3.99 (m, 14 H, 7ϫ5-H,
1
1:1). [α]D = +164 (c = 1.0, CHCl3). H NMR (400 MHz, CDCl3):
δ = 2.16 (s, 3 H, CH3CO), 3.14 (dd, J1,2 = 3.5, J2,3 = 9.4 Hz, 1 H,
2-H), 3.18–3.21 (m, 5 H, 5ϫ2-H), 3.37–3.39 [m, 21 H, 7ϫOCH3
(C-6)], 3.50, 3.51, 3.52 [m, 18 H, 6ϫOCH3 (C-2)], 3.61, 3.63, 3.64,
3.65, 3.66, [m, 21 H, 7ϫOCH3 (C-3)], 3.47–3.70 (m, 20 H, 6ϫ3-
H, 7ϫ4-H, 7ϫ6a-H), 3.72 (m, 1 H, 3A-H), 3.74–3.90 (m, 14 H,
7ϫ5-H, 7ϫ6b-H), 4.65 (dd, J1,2 = 3.5, J2,3 = 9.6 Hz, 1 H, 2A-H),
5.11–5.17 (m, 6 H, 6ϫ1-H), 5.18 (m, 1 H, 1A-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 20.95 (CH3CO), 58.31, 58.39, 58.48, 58.52,
58.71, 58.74, 58.90, 58.96 [13 C, 6ϫOCH3 (C-2), 7ϫOCH3 (C-6)],
61.13, 61.19, 61.25, 61.28, 61.42, 61.49, 61.52 [7 C, 7ϫOCH3 (C-
3)], 70.79, 70.85, 70.90, 71.00, 71.13 (7 C, 7ϫC-5), 71.26, 71.31,
71.41, 71.52, 71.55, 71.61 (7 C, 7ϫC-6), 74.09 (C-2A), 79.90, 79.97,
80.02, 80.17, 80.20, 80.31, 80.37, 80.44, 81.43, 81.63, 81.72, 81.75,
81.79, 81.83, 81.94, 82.03, 82.18 (19 C, 6ϫC-2, 7ϫC-3, 7ϫC-4),
98.07 (C-1A), 98.79, 98.87, 99.00, 99.10 (6 C, 6ϫC-1), 170.76
7ϫ6b-H), 4.63 (d, Jgem = 12.3 Hz, 1 H, PhCH2), 4.72 (d, J1,2
=
3.3 Hz, 1 H, 1-H), 4.76 (d, Jgem = 12.3 Hz, 1 H, PhCH2), 5.08–5.15
(m, 5 H, 5ϫ1-H), 5.34 (d, J1,2 = 3.9 Hz, 1 H, 1B-H), 5.41 (pseudo-
t, J2,3 = J3,4 = 9.4 Hz, 1 H, 3B-H), 7.31–7.33 (m, 1 H, arom-H),
7.35–7.38 (m, 2 H, arom-H), 7.42–7.44 (m, 2 H, arom-H) ppm. 13
C
(CH3CO) ppm. HRMS: calcd. for C64H112O36 [M
+
Na]+
NMR (100 MHz, CDCl3): δ = 21.17 (1 C, CH3CO), 58.06, 58.28,
58.33, 58.50, 58.58, 58.62, 58.78, 58.89, 58.92, 58.95, 59.07, 59.38,
60.83 [13 C, 6ϫOCH3 (C-2), 7ϫOCH3 (C-6)], 61.41, 61.44, 61.46,
61.61, 61.77, 61.81 [6 C, 6ϫOCH3 (C-3)], 70.27, 71.11, 71.27,
71.38, 71.41, 71.52, 71.98 (7 C, 7ϫC-6), 70.40, 70.78, 70.81, 70.93,
70.96, 71.15 (7 C, 7ϫC-5), 73.56 (PhCH2), 78.17 (C-4B), 78.74,
79.83, 80.31, 80.64, 80.67, 80.78, 81.23, 81.56, 81.64, 81.76, 81.82,
81.89, 82.06, 82.19, 82.24, 82.45 (20 C, 7ϫC-2, 7ϫC-3, 6ϫC-4),
1479.6831; found 1479.6826.
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of compounds 5–14.
Acknowledgments
Financial support of this study from the Centre National de la
98.71, 98.92, 98.96, 99.10, 99.41, 99.58, 99.74 (7 C, 7ϫC-1), 127.86, Recherche Scientifique (CNRS) is gratefully acknowledged. The
Eur. J. Org. Chem. 2010, 1510–1516
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1515

S. Xiao, M. Yang, P. Sinaÿ, Y. Blériot, M. Sollogoub, Y. Zhang
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Received: October 28, 2009
Published Online: February 1, 2010
1516
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1510–1516