Synthesis of regioselectively and uniformly modified maltoheptaose derivatives from cyclomaltoheptaose precursors

Article abstract of DOI:10.1016/j.carres.2005.01.021

Heptadeoxy-6^I-VII-halo, -azido, and hepta-6^I-VII S-hepta(N-Boc-2-amino)ethyl-6^I-VII-heptathiomaltoheptaose derivatives were prepared by acetolysis of the corresponding per-C-6-modified β-cyclodextrin derivatives. The rapid

Full text of DOI:10.1016/j.carres.2005.01.021

Carbohydrate
RESEARCH
Carbohydrate Research 340 (2005) 1225–1231
Note
Synthesis of regioselectively and uniformly modified
maltoheptaose derivatives from cyclomaltoheptaose precursors
David Lesur, Abdoulaye Gassama, Vincent Moreau,
Serge Pilard and Florence Djeda¨ıni-Pilard*
´
Laboratoire des Glucides FRE 2779, Universite Picardie Jules Verne, 33 rue St-Leu, F-80039 Amiens, France
Received 25 August 2004; received in revised form 21 January 2005; accepted 22 January 2005
Abstract—Heptadeoxy-6I–VII-halo, -azido, and hepta-6I–VII S-hepta(N-Boc-2-amino)ethyl-6I–VII-heptathiomaltoheptaose deriva-
tives were prepared by acetolysis of the corresponding per-C-6-modified b-cyclodextrin derivatives. The rapid and convenient struc-
tural characterisation of all of the modified oligosaccharides by ESIMS is described.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Keywords: Acetolysis; Cyclodextrins; 6I–VII-Heptadeoxyhalomaltoheptaose derivatives; 6I–VII-Heptaazidodeoxymaltoheptaose derivatives; 6I–VII-S-
Heptacysteaminylmaltoheptaose derivatives
Since natural and modified oligosaccharides have found
increasing interest in cosmetic and pharmaceutical
applications, the need for modified homologous oligo-
saccharides by more convenient and efficient routes
has evolved. Up to now however, there has been rela-
tively few published work to reflect such demand due
to: (i) the difficulty of achieving good regioselectivity
by chemical modification of linear oligosaccharides; (ii)
the extreme difficulty of accessing to pure homologous
linear oligosaccharides on a large scale.
Thus, the cost of obtaining the higher maltooligosac-
charides of dp 6 and 7 is prohibitive on a gram scale and
those of dp 8 are not yet commercially available. More-
over, their chemical synthesis is not suitable for operat-
ing at a preparative scale. Nevertheless, their acetylated
and benzoylated derivatives can be obtained readily
from cyclomaltooligosaccharides (a-, b-, and c-cyclo-
dextrins, a-, b- and c-CDs), respectively. The H2SO4-
catalysed acetolysis of per-O-acetylated a-, b- and
c-CDs has been reported by Farkas et al.1 and Sakairi
et al.2 They obtained fully acetylated maltohexaose, -hep-
taose and -octaose derivatives in about 45% yield. Simi-
larly, Sakairi et al.3 used acetolysis of a single glycosidic
bond of per-O-benzoylated a-, b- and c-CDs to afford
comparable yields of the corresponding linear deriva-
tives. Recently, this procedure has been improved by
Hoffmann et al.4 and per-O-acetylated maltohexaose
was obtained from a-CD in 95% yield using 70%
HClO4. The concept has been extended to the acetolysis
of permethylated a-CD by Kida et al.5 by the use of 30%
HClO4 resulting in the maltohexaose derivative in 31%
yield.
Previously reported chemical modifications of such
maltooligosaccharides have been carried out mainly at
the anomeric position1,2,4,6–8 or at the terminal non-
reducing end through a 4,6-O-benzylidene acetal inter-
mediate.1–4,9 To our knowledge, selective modification
at primary hydroxyl groups of maltooligosaccharides
has not yet been reported. Synthesis of regioselectively
and uniformly halogenated oligosaccharides can lead
to potentially interesting compounds in only few steps.
Since the selective halogenation of primary hydroxyl
groups of CDs is now well established,10–16 we have cho-
sen to use halogenated CDs as starting materials to
explore routes to regioselectively derivatised maltooli-
gosaccharides by acetolysis of appropriate CDs. Hepta-
kis(2,3-di-O-acyl-6-bromo-6-deoxy)-b-CDs10 were selec-
ted for this study since the subsequent linear products
would be suitably substituted for further chemical
*
Corresponding author. Tel./fax: +33
florence.pilard@sc.u-picardie.fr
3 22 82 75 62; e-mail:
0008-6215/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2005.01.021

1226
D. Lesur et al. / Carbohydrate Research 340 (2005) 1225–1231
modification. We report therein an approach to homo-
logous series of regioselectively C-6 derivatised maltooli-
gosaccharides in high purity and yield.
the previously unknown heptakis(2,3-di-O-benzoyl-6-
bromo-6-deoxy)-b-CD, 12, each in 90% overall yield.
It is worth of note that the use of benzoyl chloride,
which is cheaper than the corresponding bromide, gives
heptakis(2,3-di-O-benzoyl-6-chloro-6-deoxy)-b-CD as
the exclusive product under the present conditions.
Our initial attempts to acetolyse heptakis(2,3-di-O-
acyl-6-bromo-6-deoxy)-b-CDs 11 and 12 employed ace-
tic anhydride and sulfuric acid as catalyst. Both 11 and
12 proved to be more resistant to acid catalysed ring
opening than their per-O-esterified analogues. In con-
trast, halogenated maltoheptaose per-esters were shown
to be more susceptible to acetolysis when subjected to
longer reaction times, thus resulting in maltooligosac-
charides of dp 5 and 6. The optimum reaction condi-
tions (Scheme 2) found for the acetolysis of 11 and 12
gave 1I,2I–VII,3I–VII,4VII-hexadeca-O-acetyl-6I–VII-hep-
tabromo-6I–VII-heptadeoxy-a-maltoheptaose (13) and
In our initial experiments, the known acetolysis proce-
dures for a-, b- and c-CDs were repeated (Scheme 1).
Per-O-benzoylated a-, b- and c-CD17 1, 2 and 3 were re-
acted with Ac2O–H2SO4 according to Ref. 3. In our
hands, the expected di-O-acetylated maltohexaose, -hep-
taose and -octaose derivatives 4, 5 and 6 were obtained
in high yield (82%, 76% and 70%, respectively). The
unreacted CDs and the corresponding maltooligosac-
charide products were readily separated by flash
chromatography.
Hoffmann et al. procedure,4 which has only been de-
scribed for a-CD, was used for the acetolysis of both
hexakis(2,3,6-tri-O-acetyl)-a-CD 7 and heptakis(2,3,6-
tri-O-acetyl)-b-CD 8. Unfortunately, we were not able
to reproduce the high yields reported with the conse-
quence that the corresponding acetylated maltohexaose
9 and -heptaose 10 derivatives were only obtained in
60% and 35% yields, respectively. Nevertheless, both
Sakairi et al.3 and Hoffmann et al.4 methods were
explored to open the macrocycle in heptakis(2,3-di-O-
acyl-6-bromo-6-deoxy)-b-CD.
1I,4VII-di-O-acetyl-2I–VII,3I–VII-tetradeca-O-benzoyl-6I–VII
-
heptabromo-6I–VII-heptadeoxy-a-maltoheptaose (14) in
16% and 32% yields, respectively. For these two hepta-
bromo compounds, a good agreement was found in
ESIMS between the experimental isotopic patterns of
the [M+Na]+ ions and those predicted by theoretical
means.
Heptakis(2,3-di-O-acetyl-6-bromo-6-deoxy)-b-CD 1110
and heptakis(2,3-di-O-benzoyl-6-bromo-6-deoxy)-b-CD
12 were each prepared in two steps from native b-CD.
The primary hydroxyl groups of b-CD were first haloge-
nated using the in situ generation of bromodimethyl-
iminium bromide (Vilsmeier reagent) via the triphen-
ylphosphine–bromine system in DMFaccording to
lit.11 The resulting heptakis(6-bromo-6-deoxy)-b-CD
was esterified in the presence of acetic anhydride and
benzoyl bromide, respectively, to afford the desired hep-
takis(2,3-di-O-acetyl-6-bromo-6-deoxy)-b-CD, 1110 and
As has already been observed for the fully esterified
CDs 1–3, the unchanged halo-CDs 11 and 12 could be
recovered in 78% and 58% yields showing that no degra-
dation occurred despite the harsh reaction conditions
used. It should be pointed out that the use of harsher
conditions or longer reaction times lead to a depolymeri-
sation of the acyclic product rather than an increase of
the amount of opened CDs. At this stage of the synthe-
sis, compounds 13 and 14 could not be obtained with
very high purity. Even after purification by means of
OR
O
Br
O
O
RO
OR
RO
O
O
RO
Br
O
RO
RO
O
RO
O
n
RO
RO
6
R =
OBz OAc
n = 5
n = 6
n = 7
1
2
3
7
8
i
11 R = Ac
i or ii
12 R = Bz
OR
O
OR
O
AcO
RO
Br
O
AcO
RO
Br
RO
OR
O
RO
O
O
RO
RO
Br
O
O
RO
RO
O
RO
n
RO
O
RO
OAc
5
RO
OAc
R =
OBz OAc
13 R = Ac
14 R = Bz
n = 4
n = 5
n = 6
4
5
6
9
10
Scheme 2. Reagents and conditions (yields): (i) 97:3 Ac2O–H2SO4,
57 ꢁC, 28 h (16% of 13) or 96:4 Ac2O–H2SO4, 57 ꢁC, 30 h (32% of 14);
(ii) Ac2O, 4.6 equiv HClO4, 0 ꢁC, 20 h then 36 ꢁC, 20 h (30% of 14).
Scheme 1. Reagents and conditions (yields): (i) 49:1 Ac2O–H2SO4, 50–
60 ꢁC, 30–40 h, 70–82%.

D. Lesur et al. / Carbohydrate Research 340 (2005) 1225–1231
1227
silica gel column chromatography, some traces of the
corresponding maltohexaose derivative could be
observed by mass spectrometry.
tathio-a-maltoheptaose (19) from the contaminating
maltohexaose derivative proved unsuccessful. However,
an alternative was found to give the desired product 19
in high purity from the precursor 15 in 89% yield. More-
over, it should be pointed out that the use of Na2CO3
instead of NaH to generate the thiolate ion from
2-(Boc-amino)ethanethiol allowed to avoid the partial
O-deacetylation of the product and formation of malto-
oligosaccharides of lower dp.
Optimisation of the Hoffmann et al.4 methodology
was applied to cleave heptakis(2,3-di-O-acetyl-6-bro-
mo-6-deoxy)-b-CD, 11. It was found that a higher reac-
tion temperature was required (40 ꢁC vs 23 ꢁC) to obtain
the desired maltoheptaose derivative 13 in an optimum
yield of 30%, but this was achieved at the expense of a
lower purity. In this case, a certain amount of the corre-
sponding maltohexaose and also maltopentaose deriva-
tives could be observed by mass spectrometry.
The modest yields obtained for the macrocycle open-
ing of heptakis(2,3-di-O-acyl-6-bromo-6-deoxy)-b-CDs
11 and 12 (Scheme 2) prompted us to modify our strat-
egy by reversing the order of the latter two steps of the
sequence Ôbromination–acetolysis–substitutionÕ thus per-
forming acetolysis as the last step. Thus, heptakis(2,3-di-
O-benzoyl-6-bromo-6-deoxy)-b-CD (12) was allowed to
react with sodium azide in DMFto give heptakis(6-azi-
do-2,3-di-O-benzoyl-6-deoxy)-b-CD (20) in 90% yield.
Acetolysis of 20 was performed according to Sakairi
et al.3 (49:1 Ac2O–H2SO4) to afford 1I,4VII-di-O-acetyl-
With the key acyclic maltooligosaccharides 13 and 14
in hand, nucleophilic substitution of the bromide groups
was examined. As depicted in Scheme 3, these were eas-
ily substituted sequentially, by iodide, azide and 2-(Boc-
amino)ethanethiolate to afford, accordingly, 15–19 in
yields ranging from 70% to 90%. Interestingly, all of
the compounds, 1I,2I–VII,3I–VII,4VII-hexadeca-O-acetyl-
6I–VII-heptadeoxy-6I–VII-heptaiodo-a-maltoheptaose (15),
1I,4VII-di-O-acetyl-2I–VII,3I–VII-tetradeca-O-benzoyl-6I–VII
-
6I–VII-heptaazido-2I–VII,3I–VII-tetradeca-O-benzoyl-6I–VII
-
heptadeoxy-6I–VII-heptaiodo-a-maltoheptaose (16), 1I,
2I–VII,3I–VII,4VII-hexadeca-O-acetyl-6I–VII-heptaazido-
6I–VII-heptadeoxy-a-maltoheptaose (17) and 1I,4VII-di-
O-acetyl-6I–VII-heptaazido-2I–VII,3I–VII-tetradeca-O-benz-
oyl-6I–VII-heptadeoxy-a-maltoheptaose (18), could be
readily separated from the contaminating maltohexaose
derivatives by flash chromatography. In contrast, similar
attempts to remove 1I,2I–VII,3I–VII,4VII-hexadeca-O-
acetyl-6I–VII-S-[hepta-(N-Boc-2-amino)ethyl]-6I–VII-hep-
heptadeoxy-a-maltoheptaose 18 in 30% yield and in
high purity. Once again, an esterified per-(6-substi-
tuted-6-deoxy)-b-CD proved to be the more resistant
to macrocycle opening in acidic conditions than its cor-
responding fully esterified analogue (Scheme 4).
All of the maltooligosaccharides obtained were fully
characterised by mass spectrometry. Accurate mass
measurements were obtained on the [M+Na]+ ions of
the products at a resolution of 10,000, using appropriate
I
O
AcO
RO
I
O
RO
i
I
O
RO
O
RO
O
RO
5
RO
OAc
OAc
O
15 R = Ac
16 R = Bz
Br
N3
O
O
AcO
RO
AcO
RO
Br
N3
O
O
RO
RO
O
Br
N3
ii
O
RO
RO
O
O
RO
RO
O
O
iv
RO
RO
5
5
RO
RO
OAc
17 R = Ac
18 R = Bz
13 R = Ac
14 R = Bz
NHBoc
NHBoc
S
NHBoc
O
AcO
AcO
S
O
AcO
S
iii
O
AcO
AcO
O
AcO
5
AcO
OAc
19
Scheme 3. Reagents and conditions (yields): (i) NaI, butanone, 90 ꢁC, 12 h, 72% of 15, 83% of 16; (ii) LiN3 (20% in water), DMF, 48 h, rt, 91% of 17,
91% of 18; (iii) 2-(Boc-amino)ethanethiol, Na2CO3, DMF , N, rt, 4 days, 70%; (iv) 2-(Boc-amino)ethanethiol, Na2CO3, DMF, N2, rt, 48 h, 89%.
2

1228
D. Lesur et al. / Carbohydrate Research 340 (2005) 1225–1231
´
de lÕUniversite de Champagne-Ardennes in Reims,
Br
O
France. Preparative HPLC was carried out with a
Waters Prep LC 4000 System chromatograph fitted with
an evaporative light scattering detector PL-ELS 1000
(Polymer Laboratories) and a Prevail C-18 column
(5l, 22 · 250 mm). Thin-layer chromatography was per-
formed on E. Merck glass plates silica gel sheets (Silica
Gel F254) followed by charring with vanilin. Column
chromatography was performed on Kieselgel (E. Merck
230–400 mesh). Stepwise control of the reaction and
structure elucidation of the final products has been read-
ily achieved using mass spectrometry ESI-MS in the po-
sitive ion mode and high resolution (HR) along with the
tandem mass spectrometric (MS/MS) capabilities of a
quadrupole orthogonal time-of-flight mass spectrometer
(Q-TOF).18 High-resolution electrospray mass spectra
in the positive ion mode were obtained on Waters-
Micromass Q-TOF Ultima Global hybrid quadrupole/
time-of-flight instrument, equipped with a pneumati-
cally assisted electrospray (Z-spray) ion source
(Waters-Micromass, Manchester, UK). The source and
solvation temperatures were kept at 80 and 150 ꢁC,
respectively. Nitrogen was used as the drying and nebuli-
sing gas at flow rates of 350 and 50 L/h, respectively.
The capillary voltage was 3.5 kV, the cone voltage
100 V and the RFlens1 energy was optimised for each
sample (50–200 V). For collision-induced dissociation
(CID) experiments, argon was used as collision gas at
an indicated analyser pressure of 5 · 10À5 Torr and the
collision energy was set to 80 V. For accurate mass mea-
surements, an internal lock mass correction, using
appropriate cluster ions of sodium iodide [(NaI)n+Na]+
was applied. The mass range was typically 50–4450 amu
and spectra were recorded at 4 s/scan in the profile mode
at a resolution of 10,000 (FWMH). Data acquisition
and processing were performed with MassLynx 4.0
software. Samples of maltooligosaccharides derivatives
were dissolved (0.01 mg mLÀ1) in 1:1 MeOH–water
and the solns directly introduced (5 lL mnÀ1) through
an integrated syringe pump into the electrospray
source.
O
BzO
Br
BzO
O
O
BzO
BzO
6
12
i
N3
O
O
BzO
N3
BzO
O
O
BzO
BzO
6
20
ii
N3
O
AcO
BzO
N3
O
BzO
N3
O
BzO
O
BzO
O
BzO
5
BzO
OAc
18
Scheme 4. Reagents and conditions (yields): (i) NaN3, DMF, 100 ꢁC,
24 h, 90%; (ii) 49:1 Ac2O–H2SO4, 55 ꢁC, 30 h, 30%.
cluster ions of sodium iodide [(NaI)n+Na]+ as the inter-
nal lock mass.
We have opened the way to novel C-6 modified malto-
oligosaccharides in excellent yield and high purity and
shown that nucleophilic substitution of bromide groups
can be easily performed leading in very few steps to
potentially interesting linear oligosaccharides. Indeed
the synthesis of regioselectively and uniformly modified
oligosaccharide derivatives such anionic, cationic or
amphiphilic oligosaccharides is in progress in our
laboratory.
1. Experimental
1.1. General methods
1.2. 1I,4VI-Di-O-acetyl-2I–VI,3I–VI,6I–VI-octadeca-O-benz-
oyl-a-maltohexaose (4)
Optical rotations were measured with a JASCO DIP-370
digital polarimeter, using a sodium lamp (k = 589 nm) at
20 ꢁC. All NMR experiments were performed at
300.13 MHz using a Bruker DMX300 spectrometer
equipped with a Z-gradient unit for pulsed-field gradient
spectroscopy. Me4Si was used as an external standard
and calibration was performed using the signal of the
residual protons or of the carbon of the solvents as a
secondary reference. Measurements were performed at
300 K with careful temperature regulation. The length
of the 90ꢁ pulse was approximately 7 ls. 1D NMR data
spectra were collected using 16K data points. Elemental
analysis were performed at the Service de Microanalyse
Hexakis(2,3,6-tri-O-benzoyl)cyclomaltohexaose17 1 (2 g,
0.7 mmol) was dried at 60 ꢁC for 2 h under diminished
pressure and dissolved in 49:1 Ac2O–H2SO4 (20 mL).
The mixture was stirred at 60 ꢁC for 30 h, cooled,
quenched by the addition of pyridine (4 mL), concen-
trated under diminished pressure and then co-evapo-
rated with toluene (·3). The residue was subjected to
silica gel column chromatography (15:1 toluene–EtOAc)
affording unreacted 1 (0.3 g, 15%) and the diacetate 4
(1.7 g, 82%): [a]D +89 (c 2.5, EtOAc); lit.3 [a]D +76 (c
0.26, CHCl3). 13C NMR identical with lit.3

D. Lesur et al. / Carbohydrate Research 340 (2005) 1225–1231
1229
1.3. 1I,4VII-Di-O-acetyl-2I–VII,3I–VII,6I–VII-heneicosa-O-
benzoyl-a-maltoheptaose (5)
55%) and the diacetate 10 (0.7 g, 35%): [a]D +121 (c 1.33,
EtOAc); 13C NMR (75 MHz, CDCl3): d 170.64, 170.36,
169.85, 169.55, 169.45 (OCOCH3), 95.62 (C-1II–VII),
88.78 (C-1I), 73.03, 72.15, 71.64, 70.37, 69.96, 69.70,
69.27, 68.85, 68.35, 67.81 (C-2I–VII, C-3I–VII, C-4I–
VII, C-5I–VII), 62.20, 61.25 (C-6I–VII), 20.83, 20.54
(OCOCH3); ESI-HRMS: m/z 2141.6113 ([M+Na]+),
(C88H118NaO59 requires 2141.6131).
Heptakis(2,3,6-tri-O-benzoyl)cyclomaltoheptaose17
2
(9 g, 2.71 mmol) in 49:1 Ac2O–H2SO4 (34 mL) was
heated at 55 ꢁC for 42 h. Workup as described for the
preparation of 4, gave unreacted 2 (1.5 g, 17%) and
the diacetate 5 (7 g, 76%) as an amorphous solid: [a]D
+79 (c 2.3, EtOAc); lit.3 [a]D +67 (c 0.47, CHCl3). 13C
NMR identical with lit.3
1.7. Heptakis(2,3-di-O-acetyl-6-bromo-6-deoxy)cyclo-
maltoheptaose (11)
1.4. 1I,4VIII-Di-O-acetyl-2I–VIII,3I–VIII,6I–VIII-tetracosa-
O-benzoyl-a-maltooctaose (6)
Heptakis(6-bromo-6-deoxy)cyclomaltoheptaose15 (8 g,
5.07 mmol) was dissolved in pyridine (100 mL) and
Ac2O (30.5 mL, 325 mmol) was added. The mixture
was stirred for 48 h, quenched with MeOH at 0 ꢁC
and evaporated under diminished pressure. The residue
was subjected to silica gel column chromatography (4:1
EtOAc–hexane) to afford 11 (10.5 g, 96%): [a]D +79.0 (c
2.3, EtOAc); lit.10 [a]D +98 (c 1.6, CHCl3). 13C NMR
identical with lit.10
Octakis(2,3,6-tri-O-benzoyl)cyclomaltooctaose17 3 (2.9 g,
0.77 mmol) was treated with 49:1 Ac2O–H2SO4 (50 mL)
at 50 ꢁC for 35 h. The workup was as described for the
preparation of 7, which gave unreacted 3 (0.5 g, 17%)
and the diacetate 6 (2.13 g, 70%) as an amorphous solid:
[a]D +75 (c 5.95, EtOAc); lit.3 [a]D +72 (c 0.19, CHCl3).
13C NMR identical with lit.3
1.5. 1I,2I–VI,3I–VI,4VI,6I–VI-Eicosa-O-acetyl-a-maltohexa-
ose (9)
1.8. Heptakis(2,3-di-O-benzoyl-6-bromo-6-deoxy)-
cyclomaltoheptaose (12)
Under N2 and with vigorous stirring, compound 7 (1 g,
0.56 mmol) was dissolved in Ac2O (30 mL) at room tem-
perature. The soln was cooled to 0 ꢁC and 70% HClO4
(0.4 mL, 2.57 mmol) was added. The soln was stirred
for 20 h, and allowed to warm to room temperature.
After 2 h at rt, the soln was cooled to 0 ꢁC and neutra-
lised by the addition of a 10% aq NaHCO3 soln (24 mL).
The mixture was concentrated to 1/4 of its original vol-
ume (15 mL) under diminished pressure. The remaining
soln was diluted with EtOAc and washed with water.
The aq layer was extracted with EtOAc. The residue
was subjected to silica gel column chromatography
(4:1 EtOAc–hexane) to afford unreacted 7 (0.3 g, 30%)
and the diacetate 9 (0.63 g, 60%): [a]D +107 (c 1.85,
EtOAc); 13C NMR (75 MHz, CDCl3): d 170.61,
170.31, 169.80, 169.49, 168.94 (OCOCH3), 95.59 (C-
1II–VII), 88.75 (C-1I), 73.04, 72.12, 71.53, 70.33,
69.93, 69.69, 68.83, 68.32, 67.77 (C-2I–VII, C-3I–VII,
C-4I–VII, C-5I–VII), 62.17, 61.22 (C-6I–VII), 20.79,
To a soln of dried heptakis(6-bromo-6-deoxy)cyclomal-
toheptaose15 (8.33 g, 5,28 mmol) in pyridine (100 mL)
was added dropwise benzoyl bromide (22 mL,
222 mmol) at 0 ꢁC. The mixture was stirred at room
temperature for 16 h, quenched with MeOH at 0 ꢁC
and concentrated under diminished pressure. The resi-
due was subjected to silica gel column chromatography
(2:3 EtOAc–hexane), to give the per-benzoyl derivative
12 (15.8 g, 99%): [a]D +72 (c 5.4, EtOAc); 13C NMR
(75 MHz, CDCl3):
d 166.41, 164.85 (OCOC6H5),
133.06, 132.86, 130.17, 128.27, 128.11 (OCOC6H5),
97.53 (C-1I–VII), 79.47 (C-4I–VII), 71.87, 71.29, 71.07
(C-2I–VII, C-3-I–VII, C-4I–VII), 34.21 (C-6I–VII);
ESI-HRMS: m/z 3055.1339 ([M+Na]+), (C140H119
-
79Br381Br4NaO42 requires 3055.1275). Anal. Calcd for
140H119Br7O42: C, 55.44; H, 3.95. Found: C, 55.40;
H, 3.87.
C
1.9. 1I,2I–VII,3I–VII,4VII-Hexadeca-O-acetyl-6I–VII-hep-
tabromo-6I–VII-heptadeoxy-a-maltoheptaose (13)
20.50 (OCOCH3); ESI-HRMS: m/z
1853.5332
([M+Na]+), (C76H102NaO51 requires 1853.5286).
Heptakis(2,3-di-O-acetyl-6-bromo-6-deoxy)cyclomalto-
heptaose 11 (9 g, 0.41 mmol) was dried at 60 ꢁC for 24 h
under diminished pressure and dissolved in 97:3 Ac2O–
H2SO4 (20 mL). The mixture was stirred at 57 ꢁC for
28 h, cooled, and the reaction mixture was quenched
by the addition of pyridine (4 mL). The soln was evapo-
rated under diminished pressure. The residue was sub-
jected to silica gel column chromatography (3:2
EtOAc–hexane then EtOAc) to afford unchanged 11
(7 g, 78%) and 13 (1.5 g, 16%): [a]D +115 (c 0.5, EtOAc);
1.6. 1I,2I–VII,3I–VII,4VII,6I–VII-Tricosa-O-acetyl-a-malto-
heptaose (10)
Under N2 and with vigorous stirring, 8 (2 g, 0.99 mmol)
was dissolved in Ac2O (54 mL) at room temperature.
The soln was cooled to 0 ꢁC and 70% HClO4 (0.7 mL,
4.56 mmol) was added. The soln was stirred for 20 h,
and allowed to warm to rt. The workup was as described
for the preparation of 9, which gave unreacted 8 (1.1 g,

1230
D. Lesur et al. / Carbohydrate Research 340 (2005) 1225–1231
13C NMR (75 MHz, CDCl3): d 170.48, 170.05, 169.83,
169.68, 169.25, 168.92 (OCOCH3), 95.45, 95.27 (C-1II–
VII), 88.94 (C-1I), 73.55, 73.43, 71.95, 71.50, 71.38,
71.18, 70.33, 69.99, 69.63, 69.04, 68.82, 68.56 (C-2I–
VII, C-3I–VII, C-4I–VII, C-5I–VII), 34.42, 34.06,
33.67 (C-6I–VII), 20.89, 20.56, 20.47 (OCOCH3), ESI-
MS: m/z 2288.9446 ([M+Na]+), (C74H9779Br381Br4NaO45
requires 2288.9401). Anal. Calcd for C74H97Br7O45: C,
39.23; H, 4.31. Found: C, 39.33; H, 4.17.
1.12. 1I,4VII-Di-O-acetyl-2I–VII,3I–VII-tetradeca-O-benz-
oyl-6I–VII-heptadeoxy-6I–VII-heptaiodo-a-maltoheptaose
(16)
To a soln of 14 (0.33 g, 0.10 mmol) in butanone (40 mL)
was added NaI (1.1 g, 7.4 mmol). The reaction mixture
was stirred at 90 ꢁC for 12 h, then concentrated under
diminished pressure. The residue was purified by flash
chromatography (2:3 then 1:1 EtOAc–hexane), to afford
16 (0.3 g, 83%): [a]D +59 (c 0.5, EtOAc); 13C NMR
1.10. 1I,4VII-Di-O-acetyl-2I–VII,3I–VII-tetradeca-O-benz-
oyl-6I–VII-heptabromo-6I–VII-heptadeoxy-a-maltohepta-
ose (14)
(75 MHz, CDCl3): d 169.13 (OCOCH3), 165.67,
165.32, 165.05, 164.71 (OCOC6H5), 133.03, 129.80,
129.59, 129.41, 128.73, 128.32, 127.88, 127.74
(OCOC6H5), 97.03, 96.54, 96.21, 95.87 (C-1II–VII),
88.88 (C-1I), 72.25, 71.14, 70.78, 70.49, 69.51, 68.80,
68.39 (C-2I–VII, C-3I–VII, C-4I–VII, C-5I–VII), 20.95,
20.60 (OCOCH3), 10.38, 10.06, 9.61, 8.72, 5.50 (C-6I–
VII); ESI-HRMS: m/z 3485.0750 ([M+Na]+),
(C144H125I7NaO45 requires 3485.0704). Anal. Calcd for
The b-cyclodextrin derivative 12 (6 g, 1.97 mmol) was
dried at 60 ꢁC for 24 h under diminished pressure and
dissolved in 28:1 Ac2O–H2SO4 (20 mL). The mixture
was stirred at 57 ꢁC for 30 h, cooled, quenched by the
addition of pyridine (4 mL) and evaporated under
diminished pressure. The residue was subjected to silica
gel column chromatography (20:1 then 10:1 toluene–
EtOAc) to afford unchanged 12 (3.5 g, 58%) and 14
(2 g, 32%): [a]D +51 (c 1.135, EtOAc); 13C NMR
C144H125I7O45: C, 49.93; H, 3.64. Found: C, 50.75; H,
3.72.
1.13. 1I,2I–VII,3I–VII,4VII-Hexadeca-O-acetyl-6I–VII-hep-
taazido-6I–VII-heptadeoxy-a-maltoheptaose (17)
(75 MHz, CDCl3):
d 169.25, 168.92 (OCOCH3),
165.47, 164.85, 164.65, 164.32, 164.00 (OCOC6H5),
133.14, 132.72, 132.11, 131.91, 129.63, 129.37, 129.23,
129.04, 128.64, 128.28, 127.93, 127.67, 127.58, 127.47,
127.32, 127.16 (OCOC6H5), 96.57, 96.19, 95.56 (C-1II–
VII), 88.88 (C-1I), 78.53, 73.78, 73.51, 71.08, 70.94,
70.35, 70.14, 69.32, 68.88, 68.57 (C-2I–VII,C-3I–VII,
C-4I–VII, C-5I–VII), 34.39, 33.26, 31.38 (C-6I–VII),
20.47, 20.13 (OCOCH3), ESI-HRMS: m/z 3157.1848
To a soln of 13 (0.25 g, 0.11 mmol) in DMF(10 mL) was
added a LiN3 (0.2 mL, 4.64 mmol, 20% in water). The
reaction mixture was stirred at room temperature for
48 h and concentrated under diminished pressure. The
residue was purified by flash chromatography (1:1 then
3:2 EtOAc–hexane), to afford 17 (0.2 g, 91%): [a]D
+154 (c 0.85, EtOAc); 13C NMR (75 MHz, CDCl3): d
170.23, 169.71, 169.63, 169.45, 169.15, 168.65
(OCOCH3), 95.14, 94.90 (C-1II–VII), 88.60 (C-1I),
71.83, 71.43, 71.29, 70.38, 69.91, 69.53, 69.14, 68.86
(C-2I–VII, C-3I–VII, C-4I–VII, C-5I–VII), 50.82, 51.50
(C-6I–VII), 20.66, 20.31, 20.18 (OCOCH3); ESI-HRMS:
m/z 2022.5773 ([M+Na]+), (C74H97N21NaO45 requires
2022.5845). Anal. Calcd for C74H97N21O45: C, 44.42;
H, 4.89; N, 14.7. Found: C, 44.80; H, 4.84; N, 12.99.
([M+Na]+),
(C144H12579Br381Br4NaO45
requires
3157.1769). Anal. Calcd for C144H125Br7O45: C, 55.17;
H, 4.02. Found: C, 54.99; H, 3.95.
1.11. 1I,2I–VII,3I–VII,4VII-Hexadeca-O-acetyl-6I–VII-hep-
tadeoxy-6I–VII-heptaiodo-a-maltoheptaose (15)
To a soln of 13 (0.4 g, 0.18 mmol) in butanone (40 mL)
was added NaI (1.85 g, 12.4 mmol). The reaction mix-
ture was stirred at 90 ꢁC for 12 h. The solvent was
removed by concentration under diminished pressure
and the residue was purified by flash chromatography
(1:1 then 3:2 EtOAc–hexane), to afford 15 (0.33 g,
72%): [a]D +85 (c 0.65, EtOAc); 13C NMR (75 MHz,
CDCl3): d 170.84, 170.74, 170.15, 169.69, 169.31
(OCOCH3), 95.86, 95.65 (C-1II–VII), 89.16 (C-1I),
77.09, 76.97, 76.87, 72.65, 72.13, 71.50, 71.42, 71.27,
71.10, 70.69, 70.08, 69.55, 69.42, 69.32, 69.20, 68.81,
68.57 (C-2I–VII, C-3I–VII, C-4I–VII, C-5I–VII), 21.39,
21.28, 21.10, 20.92, 20,79 (OCOCH3), 9.99, 9.19, 8.68,
1.14. 1I,4VII-Di-O-acetyl-6I–VII-heptaazido-2I–VII,3I–VII
-
tetradeca-O-benzoyl-6I–VII-heptadeoxy-a-maltoheptaose
(18)
Method a: Compound 20 (5 g, 1.8 mmol) was dried at
60 ꢁC for 24 h under diminished pressure and dissolved
in 49:1 Ac2O–H2SO4 (17.6 mL). The reaction mixture
was stirred at 55 ꢁC for 30 h, cooled, quenched by the
addition of pyridine (4 mL) and concentrated under
diminished pressure. The residue was subjected to silica
gel column chromatography (20:1 then 10:1 toluene–
EtOAc) giving unreacted 20 (3.3 g, 66%) and compound
18 (1.5 g, 30%).
5.57
(C-6I–VII);
ESI-HRMS:
m/z
2616.8428
([M+Na]+), (C74H97I7NaO45 requires 2616.8513). Anal.
Calcd for C74H97I7O45: C, 34.25; H, 3.77. Found: C,
34.83; H, 3.83.
Method b: Compound 14 (0.25 g, 0.08 mmol) was dis-
solved in DMF(10 mL). To this soln was added LiN
3

D. Lesur et al. / Carbohydrate Research 340 (2005) 1225–1231
1231
(0.15 mL, 3.35 mmol, 20% in water) and the reaction
mixture was stirred at room temperature for 48 h. After
concentration under diminished pressure, the residue
was subjected to silica gel column chromatography
(3:2 EtOAc–hexane) to afford 18 (0.21 g, 91%): [a]D
+114 (c 2.25, EtOAc); 13C NMR (75 MHz, CDCl3): d
169.34, 168.89 (OCOCH3), 165.72, 165.16, 164.80
(OCOC6H5), 133.18, 133.05, 132.59, 132.36, 129.84,
129.72, 129.60, 129.40, 128.96, 128.61, 128.34, 128.11,
128.03, 127.80, (OCOC6H5), 97.05, 96.23, 95.99 (C-
1II–VII) 88.97 (C-1I), 77.38, 71.98, 71.90, 71.76, 71.05,
70.75, 70.50, 69.78, 69.07 (C-2I–VII, C-3I–VII, C-4I–
VII, C-5I–VII), 51.83, 51.33, 51.10 (C-6I–VII), 21.37,
20.88, 20.53 (OCOCH3); ESI-HRMS: m/z 2890.8115
([M+Na]+), (C144H125N21NaO45 requires 2890.8036).
Anal. Calcd for C144H125N21O45: C, 60.27; H, 4.39; N,
10.25. Found: C, 60.32; H, 4.58; N, 9.23.
165.94, 164.52 (OCOC6H5), 132.63, 132.38, 129.71,
129.15, 128.11, 127.82, 127.66 (OCOC6H5), 97.04
(C-1I–VII), 77.35 (C-4I–VII), 71.39, 71.15, 71.04
(C-2I–VII, C-3I–VII, C-5I–VII), 51.81 (C-6I–VII);
ESI-HRMS: m/z 2788.7708 ([M+Na]+), (C140H119N21-
NaO42 requires 2788.7719). Anal. Calcd for
C140H119N21O45: C, 60.76; H, 4.33; N, 10.63. Found:
C, 59.85; H, 4.15; N, 10.13.
Acknowledgements
We are greatly indebted to G. Mackenzie for his interest
and for his indispensable help in the preparation of the
manuscript. This work was supported by the Conseil
Regional de Picardie under the scientific ÔAlternatives
´ ´
VegetalesÕ program. D.L. is grateful to the Conseil
Regional de Picardie for a doctoral fellowship.
1.15. 1I,2I–VII,3I–VII,4VII-Hexadeca-O-acetyl-6I–VII-S-
[hepta-(tert-butoxycarbonyl-2-amino)ethyl]-6I–VII hepta-
thio-a-maltoheptaose (19)
References
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(15 mL) was stirred for 30 min. Then 15 (1 g, 0.38 mmol)
was added and the mixture stirred under N2 at 40 ꢁC for
48 h. After concentration under diminished pressure, the
residue was subjected to silica gel column chromatogra-
phy (3:2 then 7:3 EtOAc–hexane) to afford 19 (1 g, 89%):
[a]D +98 (c 0.8, EtOAc); 13C NMR (75 MHz, CDCl3): d
170.46, 169.72 (OCOCH3), 155.76 (CONH), 95.73,
95.25 (C-1II–VII), 88.70 (C-1I), 79.04 (C(CH3)3),
73.87, 72.11, 71.61, 70.83, 70.51, 70.03, 69.80, 69.16
(C-2-I–VII, C-3I–VII, C-4I–VII, C-5I–VII), 39.81
(SCH2CH2NH), 33.93, 33.56, 32.85 (C-6I–VII,
SCH2CH2NH), 28.33 (C(CH3)3), 20.82, 20.60, 20.46
(OCOCH3); ESI-HRMS: m/z 2961.0513 ([M+Na]+),
(C123H195N7NaO59S7 requires 2961.0416). Anal. Calcd
for C123H195N7O59: C, 50.25; H, 6.68; N, 3.33. Found:
C, 49.19; H, 6.90; N, 3.19.
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1.16. Heptakis(6-azido-2,3-di-O-benzoyl-6-deoxy)-
cyclomaltoheptaose (20)
Compound 12 (5 g, 1.65 mmol) was dissolved in DMF
(25 mL). Then NaN3 (3 g, 46 mmol) was added. The
mixture was stirred vigorously for 24 h at 100 ꢁC, then
concentrated under diminished pressure. The crude
product was precipitated by addition of 10:1 MeOH–
water, filtered, washed with water, and dried. Hepta-
kis(6-azido-2,3-di-O-benzoyl-6-deoxy)cyclomaltohepta-
ose 20 (4.1 g, 90%) was isolated as a white powder: [a]D
+134 (c 1.2, EtOAc); 13C NMR (75 MHz, CDCl3): d
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