μ-Waves avoid large excesses of diisobutylaluminium-hydride (DIBAL-H) in the debenzylation of perbenzylated α-cyclodextrin

Article abstract of DOI:10.1016/j.tetlet.2009.12.037

Regioselective double deprotection of cyclodextrins using diisobutylaluminium-hydride (DIBAL-H) has become an important tool in functional cyclodextrin synthesis. When conventionally heated a very large excess of reagent is necessary for the reaction to happen, when μ-waves irradiation is employed the quantity of DIBAL-H can be lowered down to 5 equiv. Reaction with a smaller quantity of DIBAL-H never achieved complete double debenzylation. These results also sustain the mechanistic hypothesis according to which a minimum of two aluminium atoms are necessary for each debenzylation to occur.

Full text of DOI:10.1016/j.tetlet.2009.12.037

Tetrahedron Letters 51 (2010) 1254–1256
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
l
-Waves avoid large excesses of diisobutylaluminium-hydride (DIBAL-H)
in the debenzylation of perbenzylated
a-cyclodextrin
*
Elena Zaborova, Yves Blériot, Matthieu Sollogoub
UPMC Univ Paris 06, Institut Parisien de Chimie Moléculaire (UMR CNRS 7201), FR629, 4 Place Jussieu 75005 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselective double deprotection of cyclodextrins using diisobutylaluminium-hydride (DIBAL-H) has
become an important tool in functional cyclodextrin synthesis. When conventionally heated a very large
Received 12 November 2009
Revised 2 December 2009
Accepted 8 December 2009
Available online 16 December 2009
excess of reagent is necessary for the reaction to happen, when
l-waves irradiation is employed the
quantity of DIBAL-H can be lowered down to 5 equiv. Reaction with a smaller quantity of DIBAL-H never
achieved complete double debenzylation. These results also sustain the mechanistic hypothesis accord-
ing to which a minimum of two aluminium atoms are necessary for each debenzylation to occur.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Cyclodextrin
Microwaves
Deprotection
Cyclodextrins (CDs) are naturally occurring water-soluble con-
cave molecules possessing a hydrophobic cavity, and made of six
enzymes,4 cyclic oligomers of CDs,5 amphiphilic CDs,6 or CD-
vesicules.7
glucopyranosidic units linked in an
a
-1,4 fashion. Due to their high
This CD deprotection reaction is based on a regioselective deb-
enzylation reaction first discovered while working on mono- and
disaccharides and which required a large excess of aluminium re-
agent,8 relative to the number of oxygen atoms present in the
starting material. For example, debenzylation of a monosaccharide
required 5 equiv of aluminium reagent whereas 10 equiv were
needed for a disaccharide, in both cases only a single debenzylation
occurred (Scheme 1). Logically, when extended to CDs this reaction
consumed an even larger excess of reagent, up to 120 equiv, which
is a drawback for scale up. We rapidly experienced the importance
of the concentration of reagent, and optimized the reaction condi-
tions using 30 equiv of a 1 M solution of DIBAL-H allowing the con-
version of perbenzylated CD 1 into diol 2 in 85% yield3 (Scheme 1).
Attempts to further decrease the amount of reagent failed
mainly due to reproducibility problems, which prompted us to ex-
symmetry and to the close reactivity of all hydroxyl groups, selec-
tive functionalization of CDs is an intensively studied and challeng-
ing domain, but only a limited number of functionalization
methods has been accessed so far. Functionalization of a cyclic
structure formed of identical subunits must overcome two chal-
lenges: (1) the control of the number of identical functionalities
introduced, (2) the control of the positions where the modifications
are taking place. Functionalization of all OHs or all OH-2s, OH-3s,
or OH-6s individually is feasible upon small reactivity differences,
and monofunctionalization can be performed by controlling the
amount of reagents. A more complex task consists in modifying
two precise positions. Two strategies have been developed to
tackle this problem: the first one is based on the use of sterically
hindered reagents,1 and the second one consists in capping the
CD with bifunctional reagents.2 Most of the available protocols
describing the preparation of CD derivatives suffer many limita-
tions, including low yields, poor regioselectivity, and long reaction
times; furthermore the resulting CD derivatives generally require
time-consuming chromatographic purifications. For some time
now, we have developed an original strategy relying on an efficient
regioselective deprotection reaction of perbenzylated CDs, giving
access to CDs bearing two or three new functionalities on their pri-
mary rim.3 This method is now classically employed for the syn-
thesis of complex molecules such as, for example, artificial
plore l-waves activation to overcome this limitation. According to
our proposed reaction mechanism,3 two DIBAL-H molecules are
necessary to operate one debenzylation reaction. Four equivalents
should be therefore sufficient to achieve the double debenzylation
on perbenzylated cyclodextrins, however this assumption was dif-
ficult to sustain considering the large excess of reagent employed.
(Scheme 2) Reaching the minimum DIBAL-H hence also becomes
an important argument in support of the proposed mechanism.3
Hence, perbenzylated CD 1 was exposed to DIBAL-H in toluene
and subjected to
l-waves irradiation, screening various tempera-
tures, reagent concentrations and reaction times.9 The kinetics of
the reaction were monitored by NMR following specific signals of
each product: a doublet at d 5.13 ppm (6 Â H-1) for starting perb-
enzylated CD 1, a doublet at d 5.77 ppm (2 Â H-1) for diol 2, and a
* Corresponding author. Tel.: +33 (0) 1 44 27 61 63.
E-mail address: matthieu.sollogoub@upmc.fr (M. Sollogoub).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.037

E. Zaborova et al. / Tetrahedron Letters 51 (2010) 1254–1256
OBn
1255
OBn
iBu3Al (5 eq)
O
O
BnO
BnO
BnO
BnO
50°C, 3 h
98%
BnO
OH
OMe
OMe
OBn
OBn
O
O
BnO
BnO
BnO
BnO
iBu3Al (10 eq)
OBn
OBn
BnO
BnO
O
O
50°C, 3 d
74%
O
O
BnO
BnO
OH
OMe
BnO
OMe
BnO
BnO
BnO
BnO
BnO
HO
O
O
OBn
O
O
OH
O
O
OBn
OBn
OBn
OBn
DIBAL-H (30 eq, 1M)
O
O
O
O
50°C, 2h
85%
O
O
O
O
O
O
BnO
BnO
BnO
OBn
BnO
OBn
OBn
BnO
OBn
BnO
BnO
BnO
OBn
OBn
1
2
Scheme 1. Debenzylation reactions using isobutylaluminium reagents.
BnO
BnO
O
BnO
O
BnO
O
OBn
O
OH
O
OBn
O
OH
O
OBn
OBn
OBn
OBn
DIBAL-H
O
O
O
O
O
O
O
O
O
BnO
BnO
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn OBn OBn
1
2
2 x DIBAL-H
Al
OBn
OBn
OBn
OBn
BnO
Al
Al
H
OBn
Al
O
O
OBn
O
O
O
Al
H
H
OBn
OBn
OBn
OBn
H
Al
2 x DIBAL-H
O
O
H
O
O
O
O
O
O
O
O
O
O
BnO
BnO
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
Scheme 2. Proposed debenzylation reaction mechanism involving two molecules of aluminium reagent.
doublet at d 5.55 ppm (1ÂCHPh) for monol 3, to assess the ratio of
CD derivatives in the reaction mixture. The results are summarised
in Table 1.
and more concentrated reagent (1.5 M instead of 1 M) only a small
quantity of diol is formed probably because only 2.5 equiv of DI-
BAL-H are present. In order to reduce the proportion of 2 in the
mixture, dilution of the aluminium reagent to a 0.5 M solution to
slow down the second step was achieved but at least 5 equiv of DI-
BAL-H were needed to observe some conversion (see entries 7 and
8). Therefore upon treatment of CD 1 with 5 equiv of a 0.5 M solu-
tion of DIBAL-H at 130 °C (entries 13–15) or 150 °C (entries 16–20)
the highest ratio in favour of monol 3 was reached after 30 min and
5 min respectively but always in the presence of diol 2.
As a conclusion, we have an easy and fast access to a CD bearing
two functionalities on its primary rim using a reduced amount of
5 equiv of DIBAL-H. Beside this practical optimization, which is
crucial for further scaling up of the reaction, this work also pro-
vides an additional proof sustaining our mechanism proposal in
which two aluminium atoms are involved and necessary for the
reaction to occur.3 Another advantage of our methodology is re-
lated to the relevant choice of benzyl protecting groups, which al-
lows the use of modern efficient chemical reactions in apolar
solvents and standard silica gel flash chromatography. Multistep
syntheses of CD-based structures with a high degree of complexity
are now possible in large scale using the DIBAL-H deprotection un-
To reach the theoretical minimum amount of aluminium re-
agent, we used 5 equiv, keeping a slight excess, and observed that
much higher temperatures than the ones attained with the oil bath
were necessary to obtain decent conversions (Table 1, entries 1–6).
The most efficient conditions were as follows: 5 equiv of a 1 M
solution of DIBAL-H at 150 °C for 30 min gave a reproducible and
complete conversion of perbenzylated CD 1 into diol 2 with neither
traces of starting material nor monol intermediate 2, but as in all
cases accompanied by some overdebenzylation products detected
by TLC (entry 6). These conditions were applied to convert 6 g of
material and the CD diol was isolated in 64% yield.10 We next re-
duced the quantities of aluminium reagent to 2.5 equiv, hoping
that we could obtain monol 2 exclusively. However, these condi-
tions resulted in a dramatic decrease of reaction kinetics, requiring
an increase of the reagent concentration as well as longer reaction
times to observe significant conversions (entries 7–12). Monol 3
was obtained in a satisfactory 65% yield, but was always contami-
nated with diol 2, supporting a faster second debenzylation mech-
anism (entry 12). However, when comparing entries 6 and 12, even
if the latter uses longer reaction times (60 min instead of 30 min)
der l-waves irradiation.

1256
E. Zaborova et al. / Tetrahedron Letters 51 (2010) 1254–1256
Table 1
Ratios of products 1, 2 and 3 obtained in the l-waves-assisted debenzylation reaction
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
O
O
O
O
HO
O
BnO
O
OBn
OBn
O
O
OH
O
O
OH
O
O
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Entry
O
O
BnO
BnO
O
O
BnO
OBn
BnO
OBn
OBn
BnO
OBn
BnO
BnO
BnO
BnO
OBn
BnO
OBn
OBn
BnO
OBn
BnO
OBn BnO
OBn BnO
BnO
BnO
OBn
OBn
Equiv
M
T (°C)
t (min)
1,%
2,%
3,%
1
2
3
4
5
6
5
5
5
5
5
5
1
1
1
1
1
1
60
80
100
150
150
150
60
60
60
15
20
30
51
7
0
0
0
11
48
72
84
91
38
45
28
16
9
0
100
0
7
8
9
10
11
12
2,5
2,5
2,5
2,5
2,5
2,5
0,5
0,5
1
1
1,5
1,5
150
150
150
150
150
150
30
60
30
60
30
60
95
94
88
86
82
22
0
0
0
0
0
5
6
12
14
18
65
13
13
14
15
5
5
5
0,5
0,5
0,5
130
130
130
5
15
30
21
15
13
20
24
29
59
61
58
16
17
18
19
20
5
5
5
5
5
0,5
0,5
0,5
0,5
0,5
150
150
150
150
150
0,5
1
5
15
30
30
26
18
13
12
10
12
18
24
27
60
62
65
63
61
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Acknowledgement
The authors thank Cyclolab (Hungary) for generous supply of
cyclodextrin.
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9. General procedure for
cyclodextrine 1 was sealed in the
Then toluene and DIBAL-H were added at rt. The reaction mixture was heated
under
-waves, then poured on ice. HCl (1 mol LÀ1 in water) and EtOAc were
l
-waves-assisted debenzylation: Perbenzylated
a-
l
-wave vial and purged with nitrogen.
l
added and the solution was stirred during one hour. The aqueous layer was
extracted with EtOAc. The combined organic layers were dried over MgSO4,
filtered, and concentrated under vacuum. The ratio of perbenzylated
cyclodextrine 1, diol 2 and monol 3 was determined by 1H NMR.
10. Optimized procedure for diol
(6.0 g, 2.3 mmol) was sealed in the
nitrogen. Then toluene (3.9 mL) and DIBAL-H (7.7 mL, 11.6 mmol) were
3
synthesis: Perbenzylated
a-cyclodextrine 1
l-wave vial and purged with
added at rt. The reaction mixture was heated at 150 °C under
l-waves
for 30 min, then poured on ice. HCl (15 mL, 1 mol LÀ1 in water) and
EtOAc (20 mL) were added and the solution was stirred during 1 h. The
aqueous layer was extracted with EtOAc (3 Â 20 mL). The combined
organic layers were dried over MgSO4, filtered, and concentrated under
vacuum. After purification by silica gel chromatography (Cy/EtOAc, 4:1),
4. Rousseau, C.; Christensen, B.; Pedersen, T. E.; Bols, M. Org. Biomol. Chem. 2004,
2, 3476–3482; Rousseau, C.; Christensen, B.; Bols, M. Eur. J. Org. Chem. 2005,
diol
2 (3.6 g, 64%) was obtained as a white foam.