Synthesis of oligosaccharide dendrimers

Article abstract of DOI:10.1002/(SICI)1521-3765(19980710)4:7<1244::AID-CHEM1244>3.0.CO;2-8

Two β-D-glucopyranoside-based dendrimers, one incorporating three tetra- and the other three heptasaccharide wedges attached to a central trisfunctionalized nonsaccharide core component, have been synthesized. Branching at designated saccharide units of t

Full text of DOI:10.1002/(SICI)1521-3765(19980710)4:7<1244::AID-CHEM1244>3.0.CO;2-8

FULL PAPER
Synthesis of Oligosaccharide Dendrimers**
Barbara Colonna, Valerie D. Harding, Sergey A. Nepogodiev, Françisco M. Raymo, Neil
Spencer, and J. Fraser Stoddart*
Abstract: Two
b-d-glucopyranoside-
tive primary amino groups at their focal
points located at the termini of spacer
arms connected to the reducing glucose
residues. Amide bond formation be-
tween these amino groups and appro-
priate core components carrying three
carboxylic acid functions afforded two
dendrimers incorporating a total of 12
and 21 monosaccharide units when the
tetra- and the heptasaccharide wedges
were employed, respectively. These
nanosized highly branched macromole-
cules possess molecular diameters of 5 ±
6 nm and molecular weights of 6195 and
10008 Daltons for the 12-mer and 21-
mer, respectively. The wedges and den-
drimers were characterized and the
intersaccharide connectivity elucidated
by extensive mono- and bidimensional
1H and 13C NMR spectroscopic inves-
tigations. In addition, LSIMS and MAL-
DI-TOFMS investigations were also
performed and revealed molecular ion
peaks generally as H, Na, or K adducts
for all oligosaccharides.
based dendrimers, one incorporating
three tetra- and the other three hepta-
saccharide wedges attached to a central
trisfunctionalized nonsaccharide core
component, have been synthesized.
Branching at designated saccharide
units of the tetra- and of the heptasac-
charide wedges arises from (1 !2)/
(1 !3)/(1 !6) and from (1 !3)/(1 !6)
intersaccharide linkages, respectively,
with the 1,2-trans configuration at all
anomeric centers. Both oligosaccharide
wedges were constructed by stepwise
glycosylation strategies and have reac-
Keywords: carbohydrates
drimers glycosylations
structures ´ oligosaccharides
´
den-
nano-
´
´
blocks for the construction of carbohydrate-containing den-
dritic moleculesÐso-called glycodendrimers[2]Ðgiving rise to
new kinds of glycoconjugate derivatives and polysaccharide
mimics. Indeed, the syntheses and the evaluations of the
biological activities of a number of carbohydrate-coated
dendrimers, in which sugar residues are attached to the
termini of noncarbohydrate dendritic skeleton, has been
accomplished by Roy[3] and Lindhorst,[4] as well as by
ourselves.[5] This research activity is directed at developing
the concept of the multivalent or cluster effect[6] exhibited by
multiantennary saccharides in some particular carbohydrate ±
protein interactions. However, it is not unreasonable to
speculate that the range of possible applications for carbohy-
drate-containing dendrimers could be much more extensive.
Saccharides can also be considered as suitable building blocks
for controlling various characteristics of dendrimers, such as
their sizes, shapes, topologies, flexibilities, and surface proper-
ties, and are likely to confer biocompatibility upon the
molecules. For example, given certain combinations of sizes
and structures for particular generations, carbohydrate den-
drimers could possess internal void volumes similar to the
cavities present in cyclodextrins[7] or to the channels formed in
some polysaccharides,[8] and hence be capable of solubilizing
hydrophobic organic molecules in aqueous media. Recently,
we have described two different approaches to the production
of dendrimers coated with carbohydrates on their exterior
Introduction
The iterative assembly of monodisperse, highly branched,
polyfunctionalized macromolecules in the form of so-called
dendrimers[1] that relies upon the use of strictly abiotic
synthetic methods has recently assumed considerable impor-
tance. One of the reasons for this development is that these
synthetic dendrimers can be created in many different forms
with precise molecular structures comparable, in their sizes
and shapes, to biomolecules. On account of their multi-
functionalities, saccharides can be utilized easily as building
[*] Prof. J. F. Stoddart,[‡] Dr. S. Nepogodiev, Dr. F. M. Raymo,[‡]
Dr. N. Spencer, B. Colonna[‡]
School of Chemistry, University of Birmingham
Edgbaston, Birmingham B15 2TT (UK)
Dr. V. D. Harding
Central Research, Pfizer Ltd.
Sandwich, Kent CT13 9NJ (UK)
Fax : (‡ 44)1304-616221
‡
[ ] Current address:
Department of Chemistry and Biochemistry
University of California at Los Angeles
405 Hilgard Avenue, Los Angeles, CA 90095-1569 (USA)
Fax : (‡ 1)310-206-1843
E-mail: stoddart@chem.ucla.edu
[**] Part 7 of the series Synthetic Carbohydrate Dendrimers: for Part 6,
see ref. [5].
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1244±1254
surfacesÐnamely, a convergent[9] and a divergent[10] one.
Here, we report on a synthetic strategy for assembling
carbohydrate dendrimers based on a combination of branched
oligosaccharides as dendritic components and noncarbohy-
drate units as trivalent cores. From the numerous possible
structures of branched oligosaccharides, we have chosen one
based on b-d-glucopyranose residues with (1 !3) and (1 !6)
glycosidic linkages. Our synthetic efforts for preparing
branched glucans were inspired by the well-documented
syntheses of both linear (1 !6)-linked[11] and (1 !3)-linked[12]
b-d-gluco-oligosaccharides, as well as of (1 !3)/(1 !6)-
branched[13] b-d-gluco-oligosaccharides.
glycosylation route, starting from its monosaccharide compo-
nents. The use of two different leaving groups X and Y which
exhibit different reactivities in coupling reactions allows us to
carry out the direct glycosylation by the trisaccharide without
having to evoke additional steps for the activation of its
reactive anomeric center.[14]
The synthetic route commences with the synthesis of the
disaccharide derivative 3, which was obtained by regioselec-
tive coupling of the diol 1[13b] with the trichloroacetimidate
2[13b, 15] under conditions previously developed by van
Boom[13b] involving catalysis by TMSOTf at 208C in CH2Cl2
(Scheme 2). Benzoylation of 3 gave the fully protected
Results and Discussion
Synthesis: The synthesis of carbohydrate dendrimers requires
the preparation of two types of building blocks, namely 1) a
branched oligosaccharide bearing a spacer arm with, at its
terminus, a reactive group which can couple efficiently to 2) a
trivalent core component. Thus, our first synthetic target was
a functionalized heptasaccharide containing a 6-aminohexyl
aglycone and appropriate protecting groups. The retrosyn-
thetic analysis of such a heptasaccharide derivative is outlined
in Scheme 1. This scheme relies on an approach which
involves glycosylations at positions 3 and 6 of a monosac-
charide glucosyl acceptor with a 3,6-branched glucotriosyl
donor. In turn, the latter can be constructed by a similar
Scheme 2. Synthesis of the trisaccharide 7. Reagents and conditions:
a) TMSOTf/CH2Cl2, mol. sieves 4 Š, 208C, 1 h, 63%; b) BzCl/C5H5N,
238C, 24 h, 98%; c) 90% CF3CO2H/CH2Cl2, 238C, 10 min, 80%;
d) AgOTf/mol. sieves 4 Š/CH2Cl2, 30 to 58C, 1 h, 79%.
derivative 4,[13b] which was treated with 90% CF3CO2H in
CH2Cl2 in order to remove the benzylidene group, affording a
new glucosyl acceptor, the diol 5. On account of the much
higher reactivity of the primary hydroxyl group in 5, it was
possible to carry out 6-O-glucosylation with total regioselec-
tivity. This reaction was carried out between 5 and a slight
excess of the glucosyl bromide 6[16] in the presence of AgOTf
as a promoter and molecular sieves 4 Š as an acid scavenger,
resulting in the formation of only one glycosylation product,
the trisaccharide derivative 7 in 79% yield. In the presence of
a base such as collidine, the yield of the glycoside 7 was much
lower as a result of a competing reaction leading to the
formation of a considerable amount of the corresponding
orthoester.
Assuming that we might exploit the different reactivities of
the 2-OH and 3-OH groups of 4,6-O-benzylidene glucosides
in glycosylation reactions, we have identified the glucosyl
acceptor 11 (Scheme 3), similar to the glucosyl acceptor 1. The
monosaccharide residue of the glycosyl acceptor 11 represents
the focal portion of the target dendritic heptasaccharide. Thus,
it should contain a spacer arm, which was introduced when the
glucosyl bromide 6 was coupled with N-benzyloxycarbonyl-
Scheme 1. Retrosynthetic scheme for the assembly of the 3,6-branched
glucoheptaoside, outlining the order of the glycosylation steps, without
specifying the nature of the protecting groups and their precise positions.
Chem. Eur. J. 1998, 4, No. 7
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J. F. Stoddart et al.
FULL PAPER
subjected to condensation with the glycosyl donor 7 under the
same conditions as those used for the glycosylation of 11, but
at a lower temperature (08C). These conditions allowed us to
accomplish the coupling with an excellent 6-O-regioselectiv-
ity, affording the heptasaccharide 15 in the modest yield of
28%. Notably, only very small amounts of self-condensation
products of 7 were detected in both reactions (Scheme 4)
when this compound was used as a glycosyl donor despite the
presence of a free 4-OH group in the molecule. Removal of
the Z-protecting group from 15 by conventional hydrogenol-
ysis led to the free amine 16, which could act as a dendron in
the subsequent assembly of a carbohydrate dendrimer.
Scheme 3. Synthesis of the spacer-armed glucopyranoside 12. Reagents
and conditions: a) HgBr2/Hg(CN)2, mol. sieves 4 Š, 238C, 12 h, 69%;
b) NaOMe/MeOH, 238C, 5 h, 100%; c) PhCH(OMe)2/10-camphorsulfonic
acid/DMF, 508C, 5 Torr, 4 h, 90%; d) BzCl/Bu4NI/K2CO3/CH2Cl2, 258C,
3 days, 58%.
In addition to the synthesis of the heptasaccharide 16, other
branched oligoglucoside dendrons have been prepared.
Although the iodonium-ion-promoted (NIS/TfOH in CH2Cl2
at 258C) monoglycosylation of the diol 11 with the perben-
zoylated thioglycoside 17 was completely unsuccessful, the
same reaction carried out with two molar equivalents of the
donor 17, gave the trisaccharide 18 (Scheme 5) in 55% yield as
aminohexanol[17] (8) under standard Helferich conditions
(HgBr2/Hg(CN)2 in CH2Cl2) to give the b-glucoside 9 in
69% yield. Debenzoylation of 9 (MeONa in MeOH) afforded
quantitatively the tetraol 10, which was converted into the 4,6-
O-benzylidene acetal 11 in 90% yield by the treatment of 10
with PhCH(OMe)2 in the presence of a catalytic amount of
(‡)-camphorsulfonic acid.
In order to investigate the possibility of carrying out
regioselective 3-O-glycosylation of the diol 11 with thioglyco-
side donors, we employed a monosaccharide analogue of the
triglycosyl donor 7, namely, ethyl 2,3,4,6-tetra-O-benzoyl-1-
thio-b-d-glucopyranoside.[18] The reaction was carried out in
the presence of the NIS/TfOH catalytic system.[19] However,
no regioselectivity was observed in this case and the isolation
of individual products of the glycosylation was not easy.
Therefore, selective protection of the 2-OH group in 11 was
necessary. This protection was achieved by partial benzoyla-
tion of 11 under phase-transfer conditions[20] (BzCl/Bu4NI/
K2CO3 in CH2Cl2) which affords the monobenzoate 12 in 58%
yield. Glycosylation of this compound with the thioglucotrio-
side 7, promoted by NIS/TfOH in CH2Cl2 at room temper-
ature, afforded the tetrasaccharide derivative 13 in 39% yield
(Scheme 4). Debenzylidenation (90% CF3CO2H in CH2Cl2)
of 13 gave the diol 14 (61% yield), which was once again
Scheme 5. Synthesis of the tetrasaccharide wedge 21. Reagents and
conditions: a) TfOH/NIS, 238C, 10 min, 55%; b) 90% CF3CO2H/CH2Cl2,
238C, 10 min, 96%; c) TfOH/NIS, 238C, 10 min, 30%; d) H2, 10% Pd/C,
EtOH/CH2Cl2, 358C, 4 h.
the major product. Debenzylidenation of 18 (90% CF3CO2H
in CH2Cl2) afforded the diol 19, which was glycosylated yet
again with the glycosyl donor 17 catalyzed by NIS/TfOH. On
this occasion, the reaction proved to be 6-O-regioselective as
expected, leading to the tetrasaccharide derivative 20. Indeed,
no glycosylation of the unreactive 4-OH group was observed.
The synthesis of the dendron 21 was completed with the
deprotection of the amino group, as described above in the
preparation of the amine 16. Both amines 16 and 21 were used
directly in the final steps to form dendrimers without further
purification.
The target dendrimers containing glucooligosaccharide
wedges were synthesized by employing the approach previ-
ously elaborated[9] for the construction of some carbohydrate-
coated dendrimers. This approach involves the creation of
three amide bonds between a tricarboxylic acid core and
Scheme 4. Synthesis of the heptasaccharide wedge 16. Reagents and
conditions: a) TfOH/NIS, 238C, 5 min, 39%; b) 90% CF3CO2H/CH2Cl2,
238C, 10 min, 61%; c) TfOH/NIS, 0 to 238C, 1 h, 28%; d) H2, 10% Pd/C,
MeOH/CH2Cl2, 358C, 18 h, 20%.
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Chem. Eur. J. 1998, 4, No. 7

Oligosaccharide Dendrimers
1244±1254
saccharide dendrons bearing free amino groups. Thus, the
condensation of 3.3 molar equivalents of the tetrasaccharide
derivative 21 with benzene tricarbonyl trichloride (22) gave
the dendrimer 23 (Scheme 6) incorporating 12 b-d-glucopyr-
anosidic residues in 20% yield after the purification by
column chromatography on sili-
ca gel.
In contrast, no trace of the
dendrimer incorporating the tri-
substituted core was detected
when the heptasaccharide deriv-
ative 16 was treated with the
trisacid chloride 22. In order to
encourage the formation of a
three-directional dendrimer in
this case, the extended core
24[9a] had to be employed
(Scheme 7). The reaction of the
bulky heptasaccharide dendron
16 with 24 used the standard
coupling methodology,[21] involv-
ing the use of DCC/HOBT. The
pure dendrimer 25 was isolated
in a yield of 8% after extensive
purification by gel permeation
chromatography performed with
THF as the eluant. This purifica-
tion procedure allowed us to
separate 25 from substantial
amounts of 1) a compound in-
corporating two wedges attached
to the core component, 2) the
starting heptasaccharide wedge
16, and 3) low molecular weight
side-products and reagents (Fig-
ure 1).
Figure 1. GPC traces of a) the
crude reaction mixture and of
b) the pure 21-mer dendrimer
25 after its isolation from the
reaction mixture. Peaks I, II,
and III correspond to tri- (25)
and disubstituted core mole-
cules and the starting hepta-
saccharide 16, respectively.
Peaks IV and V correspond
to unidentified low molecular
weight compounds. GPC was
performed in THF on a Phe-
nogel (500 Š) semiprepara-
tive column (30 Â 7.8 mm) at-
tached to a Gilson 714 HPLC
system.
Scheme 6. Synthesis of the oligosaccharide dendrimer 23. Reagents and
conditions: a) CH2Cl2/Et3N, 238C,6 h, 20%.
Scheme 7. Synthesis of the oligosaccharide dendrimer 25. Reagents and conditions: DCC/HOBT/ CH2Cl2/DMF, 238C,14 days, 8%.
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J. F. Stoddart et al.
FULL PAPER
Mass spectrometry: For all the compounds reported in this
paper, the mass spectra produced by the liquid secondary ion
(LSI) and the matrix-assisted laser-desorption ionization/
time-of-flight (MALDI-TOF) mass spectrometric techniques
show large peaks for molecular ions, generally as H, Na, or K
adducts. In many cases, the molecular ion is the base peak in
the spectrum, indicating the high stability of these macro-
molecules under the conditions used for mass spectrometry.
The calculated and observed masses of the various saccharide
derivatives are listed in Table 1. The MALDI-TOF technique
was also employed to analyze the reaction mixtures in order
to monitor the progress of the glycosylations. The spectra
produced are dominated by H, Na, and K adducts and are
largely devoid of fragmentation.
frame Overhauser enhancement spectroscopy (ROESY)[25]
were employed successfully.
In the case of trisaccharide 7, complete assignment of all the
peaks in the spectra was achieved after the analysis of dqf-
COSY and NOESY experiments. The dqf-COSY spectrum
(Figure 2a) enabled the identification of the chemical shifts of
the ring protons in each of the three different d-glucopyr-
anosidic residues. Intersaccharide connectivities were con-
firmed (Figure 2b) by a NOESY experiment. Clear cross-
Table 1. Mass spectrometric data[a] of the oligosaccharides 3 ± 7, 9 ± 16, and
18 ± 21, and of the dendrimers 23 and 25.
Com- Molecular
pound formula
Molecular weight
calcd observed
Technique
3
4
5
7
C49H46O14S
C56H50O15S
C49H46O15S
C83H72O24S
C48H47O12N
C20H31O8N
C27H35O8N
C34H39O9N
C115H105O33N
890
994
906
1484
829
413
911 [M‡Na]
MALDI-TOF[b,c]
LSIMS
LSIMS
LSIMS
LSIMS
LSIMS
LSIMS
MALDI-TOF[b,c]
LSIMS
1017 [M‡Na]
929 [M‡Na]
1507 [M‡Na]
829 [M]
9
10
11
12
13
14
15
16
18
19
20
21
23
25
414 [M‡H]
501
605
524 [M‡Na]
627 [M‡Na]
2051 [M‡Na]
1963 [M‡Na]
3387 [M‡Na]
3252 [M‡Na]
1681 [M‡Na]
1592 [M‡Na]
2172 [M‡Na]
2039 [M‡Na]
6230 [M‡Na]
10042 [M‡Na]
2027
1939
3361
3227
1657
1569
2147
2013
6195
10008
C
108H101O33N
LSIMS
LSIMS
C189H167O57N
C181H161O55N
C95H87O26N
MALDI-TOF[c,d]
MALDI-TOF[b,c]
MALDI-TOF[b,c]
LSIMS
C88H83O26N
C122H109O35N
C114H103O33N
C351H309O102N3
C558H492O171N6
MALDI-TOF[b,c]
MALDI-TOF[c,d]
MALDI-TOF[c,e]
[a] The masses given are the centroids of the isotopic distributions.
[b] Gentisic acid was employed as the matrix. [c] Insulin (MW 5734),
gramicidin (MW1142), or lysozyme
C (MW 14305) were used for
calibration. [d] trans-3-Indoleacrylic acid was employed as the matrix.
[e] Retinoic acid was employed as the matrix.
1H NMR spectroscopy: 1H NMR spectroscopic investigations
were indispensable to the characterization of the oligosac-
charides. The unambiguous assignments of the signals in the
1H NMR spectra were achieved by means of a variety of two-
dimensional NMR spectroscopic methods. Correlation spec-
troscopy experiments (COSY 45) were sufficient to assign the
resonances for all the disaccharides. For systems with larger
numbers of monosaccharide residues, however, the complex-
ity of the spectra increases rapidly, since the protons of the
glucosidic units all resonate characteristically in narrow
regions of the spectra. Hence, for the medium to high
molecular weight saccharides, further, more sophisticated
experiments were needed to delineate fully the spin systems
of the individual monosaccharide residues. To this end, a
combination of double-quantum-filtered correlation spectro-
scopy (dqf-COSY),[22] two-dimensional nuclear Overhauser
enhancement spectroscopy (NOESY),[23] homonuclear Hart-
mann ± Hahn spectroscopy (HOHAHA)[24] and rotating-
Figure 2. Saccharide region of the 2D-transformed data matrix from
experiments (400 MHz, CDCl3 288C) conducted on the trisaccharide 7:
a) dqf-COSY experiment with the complete assignment of the glucopyr-
anosidic protons of 7 indicated, and b) NOESY experiment (tm ˆ 400 ms),
with the intersaccharide connectivities highlighted. The glucopyranose
residues of 7 are marked A, B, C as illustrated in Table 2.
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Oligosaccharide Dendrimers
1244±1254
peaks, indicating magnetization transfer between the anome-
ric proton of the B unit and the H-3 proton of A, and between
the anomeric proton of C and the H-6 proton of the same A
residue confirm that the three d-glucopyranose rings are
linked in a B(1 !3)A and C(1 !6)A fashion. The overall
structure of the trisaccharide can thus be fully established.
The values observed for the vicinal coupling constants
between the protons on H-1 and H-2 associated with the
the six glycosidic linkages, as these were considered the most
relevant in relation to a complete structural analysis. Studies
of the dqf-COSY and HOHAHA spectra and, in particular, a
1H/13C gradient selected heteronuclear multiple quantum
correlation (HMQC)[26] experiment (Figure 4b), enabled the
assignment of all of the anomeric protons, as well as of the H-3
and H-6 protons of the internal d-glucopyranosidic residues.
The anomeric protons of the four residues located at the
3
residues A, B, and CÐthat is, J1,2 > 8 HzÐconfirm 1,2-trans
configurations at all the newly-formed intersaccharide link-
ages.
The dqf-COSY spectrum (Figure 3a) was insufficient to
allow a complete assignment of the intraresidue connectivities
of the tetrasaccharide 21 to be made. An additional HOHA-
HA experiment (Figure 3b) was necessary in order to isolate
Figure 4. Saccharide region of the 2D-transformed data matrices from
experiments conducted on the heptasaccharide 15 (400 MHz, 100 MHz,
CDCl3, 288C). a) A ROESYexperiment (spin-lock field 2 kHz) illustrating
the intersaccharide connectivities. b) The anomeric region (w1) of the
1
gradient-selected HMQC revealing the seven H/13C anomeric connectiv-
ities.
periphery of the heptasaccharide (i.e., those bearing four
benzoyl protecting groups) could be readily distinguished
from those of the partially deprotected internal monobenzoy-
lated bisglycosylated residues and from the one at the
reducing end by considerations of their relative chemical
shifts. Specifically, all the protons on the fully protected
peripheral monosaccharide residues are expected to resonate
at lower field with respect to those on the internal residues.
Unlike previous examples, NOESY experiments performed
using a number of mixing intervals (300 ± 900 ms) proved
ineffective at defining the interresidue connectivities in this
instance. Numerous antiphase cross peaks, arising as a result
of zero quantum coherence between J coupled pairs, were
observed in the matrix, even at very extended mixing times.
Thus, the unambiguous distinction of the expected in-phase
cross-peaks arising from dipolar coupled pairs (i.e., nOe) was
not possible. In this case, the use of a different experimentÐ
namely a ROESY experiment (Figure 4a)Ðwas necessary to
establish the connectivities across the glycosidic linkages. The
Figure 3. Saccharide region of the 2D-transformed data matrices from
experiments (400 MHz, CDCl3, 288C) conducted on the tetrasaccharide 20.
a) dqf-COSY experiment illustrating the spin system for the residue D,
along with the anomeric protons of the residues A, B, and C. b) A fragment
of the data from the HOHAHA experiment (tm ˆ 150 ms) centered on the
anomeric proton of residue D. The mode of the A/B/C/D assignment of the
d-glucopyranose residues in 20 is as illustrated in Table 2.
the contributing individual spin systems for the four d-
glucopyranosidic residues. The dqf-COSY spectrum could
then be used to delineate the coupled pairs of vicinal and
geminal protons within each residue. The intraresidue con-
nectivities were thus established by a joint analysis following
both experiments. Interresidue connectivities could be deci-
phered unambiguously by analysis of the NOESY experiment
confirming the B(1 !2)A/C(1 !3)A/D(1 !6)A connections.
1
In the case of the final heptasaccharide 16, the H NMR
spectrum is exceptionally complex. Experiments were con-
ducted in an effort to distinguish the protons associated with
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J. F. Stoddart et al.
FULL PAPER
Table 2. Chemical shifts (d values) and coupling constants (J in Hz) of the glucopyranosidic protons in the 1H NMR spectra (CDCl3, 25 8C) of compounds
3 ± 5, 7, 9, 12, 14, and 18 ± 20. The individual d-glucopyranose residues in the frameworks of the oligosaccharides are identified below.
Compound Residue
H-1 (J1,2
)
H-2 (J2,3
)
H-3 (J3,4
)
H-4 (J4,5
)
H-5
H-6a (J5,6a
)
H-6b (J5,6b, J6a,6b)
3
4
5
7
A
B
A
B
A
B
A
B
C
4.36d (10.0)
5.19d (7.5)
4.56d (10.0)
5.02d (8.0)
4.46d (10.0)
4.92d (8.0)
4.26d (10.0)
4.84d (8.0)
5.02d (8.0)
4.84d (8.0)
4.62d (8.0)
4.30d (8.0)
4.47d (8.0)
4.66d (8.0)
5.20d (8.0)
4.39d (8.0)
4.86d (8.0)
4.75d (8.0)
4.27d (7.5)
4.64d (8.0)
4.52d (8.0)
4.06d (8.0)
4.62d (8.0)
4.50d (8.0)
5.00d (8.0)
3.36 ± 3.54m
5.50pt (7.5)
5.35dd (9.0)
5.46dd (9.5)
5.20dd (9.0)
5.52dd (10.0)
4.99dd (9.0)
5.52dd (10.0)
5.59dd (10.0)
5.55dd (9.5)
5.19dd (10.0)
4.93dd (10.0)
5.00dd (10.0)
5.39dd (10.0)
5.57dd (10.0)
3.95dd (9.0)
5.44dd (9.0)
5.58dd (9.0)
3.64dd (9.0)
5.38 ± 5.59m
5.38 ± 5.59m
3.50 ± 3.56m
5.38 ± 5.47m
5.53dd (10.0)
5.55dd (10.0)
3.86pt (9.0)
5.91dd (10.0)
4.22pt (9.0)
5.70pt (9.5)
3.87pt (9.0)
5.82pt (10.0)
3.72pt (9.0)
5.80pt (10.0)
5.91pt (10.0)
5.93pt (9.5)
4.02dpt (10.0)
3.55 ± 3.63m
3.55 ± 3.63m
5.66pt (10.0)
5.94pt (10.0)
3.60pt (9.0)
5.80pt (9.0)
5.82pt (9.0)
3.55pt (9.0)
5.64pt (10.0)
5.80pt (10.0)
3.45pt (9.0)
5.63pt (10.0)
5.79pt (10.0)
5.88pt (10.0)
3.70pt (9.0)
5.69pt (10.0)
3.91pt (9.0)
5.59pt (9.5)
3.73pt (9.0)
5.58pt (10.0)
3.54pt (9.0)
5.55pt (10.0)
5.70pt (10.0)
5.70pt (9.5)
3.64pt (10.0)
3.55 ± 3.63m
3.43pt (10.0)
5.52pt (10.0)
5.71pt (10.0)
3.80pt (9.0)
5.45 ± 5.53m
5.45 ± 5.53m
3.47pt (9.0)
5.38 ± 5.59m
5.38 ± 5.59m
3.24 ± 3.28m
5.38 ± 5.47m
5.38 ± 5.47m
5.69pt (10.0)
3.36 ± 6.54m
3.89 ± 3.97m
3.55 ± 3.60m
3.79 ± 3.87m
3.39 ± 3.47m
4.20 ± 4.28m
3.40 ± 3.48m
4.19 ± 4.24m
4.10 ± 4.18m
4.12 ± 4.21m
3.48 ± 3.54m
3.32 ± 3.38m
3.55 ± 3.63m
4.07 ± 4.13m
4.19 ± 4.25m
3.43 ± 3.53m
2.66 ± 2.82m
3.25 ± 3.35m
3.09 ± 3.25m
2.39 ± 2.49m
2.65 ± 2.75m
3.67 ± 3.74m
2.46 ± 2.52m
2.69 ± 2.75m
4.09 ± 4.18m
3.66 ± 3.83m
4.26 ± 4.33m
3.79 ± 3.87m
4.27dd (4.0)
3.79dd (6.0)
4.40dd (6.5)
4.29 ± 4.40m
4.29 ± 4.40m
4.48dd (6.0)
4.51dd (5.0)
3.82pt (10.0)
3.77 ± 3.98m
3.77 ± 3.98m
4.29 ± 4.35m
4.48 ± 4.52m
3.65 ± 3.76m
4.16 ± 4.36m
4.16 ± 4.36m
3.66 ± 3.76m
4.09 ± 4.25m
4.09 ± 4.25m
3.24 ± 3.28m
4.09 ± 4.18m
4.09 ± 4.18m
4.47dd (5.0)
4.26 ± 4.33m
4.48dd (3.5, 12.0)
4.38dd (4.5, 11.0)
4.48dd (4.0, 12.0)
3.97dd (3.5, 12.0)
4.80dd (3.5, 12.5)
3.82dd (6.5, 12.0)
4.79dd (3.0, 12.5)
4.65dd (4.0, 12.0)
4.65dd (3.0, 12.0)
4.38dd (5.0, 10.0)
3.77 ± 3.98m
4.19 ± 4.25m
4.69 ± 4.75m
4.69 ± 4.75m
3.65 ± 3.76m
4.16 ± 4.36m
4.16 ± 4.36m
3.87dd (3.5, 12.0)
4.09 ± 4.25m
4.39dd (2.5, 12.5)
4.22 ± 4.28m
9
12
14
A
B
C
D
A
B
C
A
B
C
A
B
C
D
18
19
20
4.22 ± 4.28m
4.37dd (3.5, 12.5)
4.64dd (3.5, 12.0)
assignment of the protons of the d-glucopyranosidic residues
of a number of key intermediate compounds is presented in
Tables 2 and 3.
minimization. The resulting structures were subjected to
simulated annealing employing the AMBER* forcefield,[28]
the generalized Born surface-area solvation model[29] for
CHCl3, and the Polak ± Ribiere conjugate gradient algo-
rithm[30] to afford the global minima shown in Figures 5 and
6. The approximate maximum radius (the maximum distance
measured between the ring centroid of the core and the
surface of the dendrimer) correspond to 25 and 28 Š for 23
Table 3. Chemical shifts (d values) and coupling constants (J in Hz) of the
1
anomeric protons in the H NMR spectrum (400 MHz, CDCl3, 258C) of the
heptasaccharide 15.
A
B
C
D
E
F
G
H-1
J1,2
3.89
9.0
4.29
8.0
4.34
8.0
4.61
8.0
4.81
8.0
4.98
8.0
5.05
8.0
Molecular modeling: In order to visualize the three-dimen-
sional structures associated with the 12-mer and the 21-mer
dendrimers 23 and 25, respectively, a computational inves-
tigation was carried out on these highly branched molecules.
They were constructed within the input mode of Macro-
model5.0[27] and their geometries were optimized by energy
Figure 5. Computer-generated space-filling representation of the global
minimum found for the 12-mer dendrimer 23.
1250
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0947-6539/98/0407-1250 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 7

Oligosaccharide Dendrimers
1244±1254
zotriazole, N-iodosuccinimide, trifluoromethanesulfonic acid, and trime-
thylsilyl trifluoromethanesulfonate are indicated by the acronyms DBU,
DCC, HOBT, NIS, TfOH, and TMSOTf, respectively. The benzoyl and
benzyloxycarbonyl groups are identified by the abbreviations Bz and Z,
respectively. Yields refer to chromatographically pure products. Thin-layer
chromatography (TLC) was carried out on aluminum sheets coated with
silica gel 60 (Merck 5554). Column chromatography and medium-pressure
liquid chromatography were performed on silica gel 60 (Merck, 40 ± 63 nm)
and (Merck, 15 ± 40 nm), respectively. Gel permeation chromatography
(GPC) was carried out on a Phenogel semipreparative column (500 Š,
300 Â 7.80 mm, Phenomenex, England) attached to a Gilson 714 high-
performance liquid chromatographic system in THF (GPC grade, Fisons)
using
a variable UV detector set at 260 nm. Melting points were
determined on an Electrothermal 9200 melting point apparatus. Micro-
analyses were performed by the University of North London Micro-
analytical Services. LSIMS were recorded on
a VG ZabSpec mass
spectrometer equipped with a cesium ion source using m-nitrobenzyl
alcohol containing a trace amount of NaOAc. For accurate mass measure-
ments using high-resolution LSIMS (HRLSIMS), the instrument was
operated at a resolution of ca. 6000 by narrow-range voltage scanning along
with polyethylene glycol or CsI as reference compounds. MALDI-TOF MS
was performed on a Kratos Kompact MALDI-III instrument, with either
gentisic acid, trans-3-indoleacrylic acid, or retinoic acid as matrices. Optical
rotation measurements were measured at 238C on a Perkin ± Elmer 457
polarimeter. 1H NMR spectra were recorded on either a Bruker AC300
(300 MHz) or a Bruker AMX400 (400 MHz) spectrometer. 13C NMR
spectra were recorded on either a Bruker AC300 (75.5 MHz) spectrometer
or a Bruker AMX400 (100.6 MHz) spectrometer. All NMR experiments
were carried out in CDCl3 solution (with the exception of compound 10
which was analyzed in D2O solution), at room temperature with the
residual CHCl3 (or HOD in the case of 10) as an internal standard. All 2D
experiments were recorded with the sample nonspinning. NMR spectro-
scopic data processing was carried out on a Bruker ASPECT station 1
offline processing facility with standard UXNMR software. HOHAHA[24]
spectra were obtained by means of a MLEV-17 sequence for isotropic
mixing and in-phase sensitive mode using time-proportional phase
Figure 6. Computer-generated space-filling representation of the global
minimum found for the 21-mer dendrimer 25.
and 25, respectively. Larger differences are observed in the
2
total molecular van der Waals surfaces (6143 and 9845 Š for
23 and 25, respectively), as well as in the molecular volumes
3
(4537 and 7270 Š for 23 and 25, respectively).
Conclusion
The syntheses of 23 and 25, representatives of a new class of
carbohydrate-containing dendritic molecule, have been real-
ized. The distinctive feature of this class of glycodendrimers is
that it incorporates branched oligosaccharides as dendritic
components (dendrons) into their structures. In the case of the
dendrimer 23, such dendrons are exemplified by the glucote-
traoside having glycosidic linkages at positions 2, 3, and 6 of
the branching residue. The larger dendrimer 25 contains three
heptasaccharide dendrons composed of glucopyranose resi-
dues, interconnected by b-(1 !3)- and b-(1 !6)-glycosidic
bonds. The principles involved in assembling these carbohy-
drate dendrimers are similar to those reported earlier[9] for the
construction of glycodendrimers possessing monosacharide
units only on their peripheries. This approach involves the
attachment of three dendrons to a central core component as
the final step in the synthesis. The oligosaccharide dendrons
were obtained using a combination of various glycosylation
techniques in a stepwise manner. In the case of the con-
struction of the branched heptasaccharide components of the
larger dendrimer, a convergent scheme utilizing trisaccharide
building blocks and repetitive 3-O- and 6-O-glycosylation has
been developed. Further extensions of this general synthetic
approach for constructing much more complex glycoden-
drimers are possible.
incrementation (TPPI).
A 10 kHz spin-lock was used and 438 ± 512
increments of 2 K data points were acquired. dqf-COSY,[22] ROESY,[25]
and NOESY[23] spectra were obtained with similar spectral widths and
digitization to those described above for the HOHAHA experiments. For
NOESY experiments, a range of mixing times covering 300 ± 900 ms was
explored. For ROESY, a CW spin-lock field of 2 kHz was used and
512 increments of 2 K data points were acquired. The chemical shift values
are expressed as d values and the coupling constant values (J) are in Hertz.
The following abbreviations are used for the signal multiplicities or
characteristics: s, singlet; d, doublet; dd, double doublet; t, triplet; pt,
pseudotriplet; dpt, double pseudotriplet; m, multiplet; br, broad.
Ethyl 2-O-benzoyl-3-O-(2,3,4,6-tetra-O-benzoyl-b-d-glucopyranosyl)-1-
thio-b-d-glucopyranoside (5): A solution of 4 (1.40 g, 1.4 mmol) in CH2Cl2
(100 mL) was treated with 90% aqueous CF3CO2H (13 mL) at room
temperature (RT) for 10 min, after which time TLC analysis (SiO2:PhMe/
EtOAc 3:2) showed the reaction to be complete. The solution was then
washed with saturated aqueous NaHCO3 (3 Â 100 mL) and H2O (3 Â
100 mL), dried, and concentrated. The residue was purified by column
chromatography (SiO2:PhMe/EtOAc, 7:3) to give the title compound 5
(1.00 g, 80%). M.p. 215 ± 2168C; [a]D
ˆ
5.5 (c ˆ 1 in CHCl3); LSIMS: m/
z ˆ 929 [M‡Na] ; 1H NMR (CDCl3, 258C): d ˆ 1.13 (t, 3H, J ˆ 7.5 Hz),
2.55 ± 2.69 (m, 2H), 3.39 ± 3.47 (m, 1H), 3.73 (pt, 1H, J ˆ 9.0 Hz), 3.79 (dd,
1H, J ˆ 6.0, 12.0 Hz), 3.87 (pt, 1H, J ˆ 9.0 Hz), 3.97 (dd, 1H, J ˆ 3.5,
12.0 Hz), 4.20 ± 4.28 (m, 1H), 4.40 (dd, 1H, J ˆ 6.5, 12.5 Hz), 4.46 (d, 1H,
J ˆ 10.0 Hz), 4.80 (dd, 1H, J ˆ 3.5, 12.5 Hz), 4.92 (d, 1H, J ˆ 8.0 Hz), 5.20
(dd, 1H, J ˆ 9.0, 10.0 Hz), 5.52 (dd, 1H, J ˆ 8.0, 10.0 Hz), 5.58 (pt, 1H, J ˆ
10.0), 5.82 (pt, 1H, J ˆ 10.0 Hz), 7.18 ± 8.18 (m, 25H); 13C NMR (CDCl3,
258C): d ˆ 14.7, 23.9, 62.8, 63.1, 69.4, 69.8, 70.8, 71.6, 72.6, 72.7, 80.1, 83.7,
86.8, 101.8, 128.1 ± 133.7, 164.5, 165.0, 165.1, 165.7, 166.2; C49H46O15S: calcd
C 64.89, H 5.11, S 3.53; found C 64.95, H 5.13.
‡
Experimental Section
Ethyl 2-O-benzoyl-3,6-di-O-(2,3,4,6-tetra-O-benzoyl-b-d-glucopyranosyl)-
1-thio-b-d-glucopyranoside (7): A solution of AgOTf (390 mg, 1.50 mmol)
in freshly distilled PhMe (30 mL) was added dropwise over 30 min to a
stirred mixture of the diol 5 (980 mg, 1.10 mmol), 2,3,4,6-O-tetrabenzoyl-a-
d-glucopyranosyl bromide[16] (6; 990 mg, 1.50 mmol) and ground 4 Š
General methods: Chemicals were purchased from Aldrich and used as
received. Solvents were dried according to literature procedures.[31] 1,8-
Diazabicyclo[5.4.0]undec-7-ene, dicyclohexylcarbodiimide, 1-hydroxyben-
Chem. Eur. J. 1998, 4, No. 7
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0947-6539/98/0407-1251 $ 17.50+.25/0
1251

J. F. Stoddart et al.
FULL PAPER
molecular sieves (2 g) in dry CH2Cl2 (50 mL) under Ar at 308C. After
30 min, another portion of AgOTf (390 mg, 1.50 mmol) in PhMe (30 mL)
was added, following the same procedure. The temperature was then
allowed to rise to 58C over 1 h and the reaction mixture was neutralized
with C5H5N and filtered through Celiteꢁ. The residue was washed with
CH2Cl2 (50 mL) and the combined filtrates were washed with 10% aqueous
Na2S2O3 (2 Â 100 mL), H2O (1 Â 100 mL), H2SO4 (1m, 2 Â 100 mL), and
aqueous NaHCO3 (2 Â 100mL). The organic solution was dried and
concentrated to give a residue which was subjected to medium-pressure
liquid chromatography (SiO2:PhMe/EtOAc, 95:5 to 9:1) to afforded 7
258C): d ˆ 1.29 ± 1.70 (brm, 8H), 2.87 (s, 1H), 2.98 (s, 1H), 3.12 ± 3.24 (m,
2H), 3.40 ± 3.57 (m, 4H), 3.74 ± 3.82 (m, 2H), 3.85 ± 3.92 (m, 1H), 4.32 (dd,
1H, J ˆ 5.0, 11.0 Hz), 4.37 (d, 1H, J ˆ 8.0 Hz), 4.78 (brs, 1H), 5.09 (s, 2H),
5.51 (s, 1H), 7.25 ± 7.55 (m, 10H); 13C NMR (CDCl3, 258C): d ˆ 25.4, 26.2,
29.3, 29.7, 40.7, 66.4, 66.7, 68.7, 70.3, 73.2, 74.6, 80.6, 101.9, 103.2, 126.3 ±
129.3, 136.8, 137.0, 156.0; C27H35O8N: calcd C 64.66, H 7.03, N 2.79; found C
64.52, H 7.17, N 2.62.
6-Benzyloxycarbonylaminohexyl 2-O-benzoyl-4,6-O-benzylidene-b-d-glu-
copyranoside (12): n-Bu4NI (550 mg, 1.5 mmol) and dry K2CO3 (690 mg,
5.00 mmol) were added to a stirred solution of the diol 11 (503 mg,
1.00 mmol) in dry CH2Cl2 (6 mL), followed by slow addition of a solution of
benzoyl chloride (140 mL, 1.20 mmol) in dry CH2Cl2 (1 mL). The mixture
was stirred for 3 days at 258C and diluted with CH2Cl2 (55 mL) before the
precepitate was removed by filtration and the solution was washed with
H2O (5 Â 25 mL), dried, and concentrated. Subjecting the residue to
medium-pressure liquid chromatography (SiO2:PhMe/EtOAc, 7:3) gave 12
‡
(1.27 g, 79%). [a]D ˆ ‡1 (c ˆ 2 in CHCl3); LSIMS: m/z ˆ 1507 [M‡Na] ;
1H NMR (CDCl3, 258C): d ˆ 0.96 (t, 3H, J ˆ 7.5 Hz), 2.20 ± 2.39 (m, 2H),
3.40 ± 3.48 (m, 1H), 3.54 (pt, 1H, J ˆ 9.0 Hz), 3.72 (pt, 1H, J ˆ 9.0 Hz), 3.82
(dd, 1H, J ˆ 6.5, 12.0 Hz), 4.10 ± 4.18 (m, 1H), 4.19 ± 4.24 (m, 1H), 4.26 (d,
1H, J ˆ 10.0 Hz), 4.29 ± 4.40 (m, 2H), 4.48 (dd, 1H, J ˆ 6.0, 12.0 Hz), 4.65
(dd, 1H, J ˆ 4.0, 12.0 Hz), 4.79 (dd, 1H, J ˆ 3.0, 12.5 Hz), 4.84 (d, 1H, J ˆ
8.0 Hz), 4.99 (dd, 1H, J ˆ 9.0, 10.0 Hz), 5.02 (d, 1H, J ˆ 8.0 Hz), 5.52 (dd,
1H, J ˆ 8.0, 10.0 Hz), 5.55 (pt, 1H, J ˆ 10.0 Hz), 5.59 (dd, 1H, J ˆ 8.0,
10.0 Hz), 5.70 (pt, 1H, J ˆ 10.0 Hz), 5.80 (pt, 1H, J ˆ 10.0 Hz), 5.91
(pt, 1H, J ˆ 10.0 Hz), 7.06 ± 8.15 (m, 45H); 13C NMR (CDCl3, 258C): d ˆ
14.4, 23.3, 62.6, 62.9, 68.5, 69.0, 69.3, 70.4, 71.3, 71.8, 72.0, 72.4, 72.5,
72.9, 79.7, 83.1, 86.7, 101.5, 128.0 ± 133.5, 164.2, 164.8, 164.9, 165.4,
165.5, 165.7, 166.0; C83H72O24S: calcd C 67.11, H 4.89, S 2.16; found C
67.19, H 4.93.
(351 mg, 58%). [a]D
ˆ
28 (c ˆ 0.6 in CHCl3); MALDI-TOF: m/z ˆ 627
[M‡Na] , 642 [M‡K] ; 1H NMR (CDCl3, 258C): d ˆ 1.02 ± 1.23 (brm,
6H), 1.36 ± 1.57 (m, 2H), 2.92 ± 3.00 (m, 2H), 3.11 (d, 1H, J ˆ 3.5 Hz), 3.42 ±
3.48 (m, 1H), 3.49 ± 3.52 (m, 1H), 3.64 (pt, 1H, J ˆ 10.0 Hz), 3.82 (pt, 1H,
J ˆ 10.0 Hz), 3.84 ± 3.91 (m, 1H), 4.02 (dpt, 1H, J ˆ 3.5, 10.0 Hz), 4.38 (dd,
1H, J ˆ 5.0, 10.0 Hz), 4.62 (d, 1H, J ˆ 8.0 Hz), 4.71 (brs, 1H), 5.07 (s, 2H),
5.19 (dd, 1H, J ˆ 8.0, 10.0 Hz), 5.29 (s, 1H), 7.25 ± 8.10 (m, 15H); 13C NMR
(CDCl3, 258C): d ˆ 25.5, 26.2, 29.3, 29.7, 40.9, 66.3, 66.6, 68.7, 70.2, 72.3,
74.9, 81.0, 101.7, 101.9, 126.4 ± 133.3, 136.7, 137.0, 156.4, 165.8; C34H39NO9:
calcd C 67.42, H 6.49, N 2.31; found C 67.43, H 6.49, N 2.17.
‡
‡
6-Benzyloxycarbonylaminohexyl 2,3,4,6-tetra-O-benzoyl-b-d-glucopyra-
noside (9): A solution of 8 (3.36 g, 13.4 mmol), HgBr2 (2.60 g, 7.20 mmol),
Hg(CN)2 (3.40 g, 13.5 mmol), and ground 4 Š molecular sieves (20 g) in dry
CH2Cl2 (50 mL) was stirred for 2 h at RT under N2. Next, a solution of the
glycosyl bromide 6 (9.20 g, 13.9 mmol) in dry CH2Cl2 (40 mL) was added
dropwise over 30 min and the mixture was stirred for a further 12 h until
TLC analysis (SiO2:hexane/EtOAc, 3:2) showed an almost complete
conversion of the starting bromide 6 to products. The mixture was filtered
through a layer of Celite and the residue was washed with CH2Cl2
(100 mL). The washings were combined with the filtrate. The solution
was then washed with 10% aqueous NaBr (3 Â 100 mL) and H2O (3 Â
100 mL), dried and concentrated. Column chromatography (SiO2:hexane/
6-Benzyloxycarbonylaminohexyl 2-O-benzoyl-4,6-O-benzylidene-3-O-[2-
O-benzoyl-3,6-di-O-(2,3,4,6-tetra-O-benzoyl-b-d-gluco-pyranosyl)-b-d-gl-
ucopyranosyl]-b-d-glucopyranoside (13): A catalytic amount of TfOH
(7 mL, 0.07 mmol) was added very slowly to a stirred mixture of 12 (112 mg,
0.18 mmol), 7 (316 mg, 0.20 mmol) and NIS (90 mg, 0.4 mmol) in dry
CH2Cl2 (20 mL) under an atmosphere of N2 at RT. After 5 min, the reaction
mixture was neutralized with C5H5N, diluted with CH2Cl2 (50 mL), and
washed with 10% aqueous NaS2O3 (2 Â 50 mL), aqueous NaHCO3 (2 Â
50 mL), and H2O (1 Â 50 mL) before the organic layer was dried and
concentrated. Medium-pressure liquid chromatography (SiO2:PhMe/
EtOAc, 4:1) of the residue gave the title compound 9 (7.60 g, 69%). [a]D
ˆ
EtOAc, 7:1) of the residue afforded the pure tetrasaccharide 13 (135 mg,
‡15 (c ˆ 1 in CHCl3); LSIMS: m/z ˆ 829 [M] , 852 [M‡Na] ; 1H NMR
(CDCl3, 258C): d ˆ 1.05 ± 1.38 (brm, 6H), 1.40 ± 1.61 (brm, 2H), 2.95 ± 3.06
(brm, 2H), 3.47 ± 3.58 (m, 1H), 3.86 ± 3.96 (m, 1H), 4.12 ± 4.21 (m, 1H),
4.51 (dd, 1H, J ˆ 5.0, 12.0 Hz), 4.65 (dd, 1H, J ˆ 3.0, 12.0 Hz), 4.84 (d, 1H,
J ˆ 8.0 Hz), 5.10 (s, 2H), 5.55 (dd, 1H, J ˆ 8.0, 9.5 Hz), 5.70 (pt, 1H, J ˆ
9.5 Hz), 5.93 (pt, 1H, J ˆ 9.5 Hz), 7.21 ± 8.07 (m, 25H); 13C NMR (CDCl3,
258C): d ˆ 25.5, 26.2, 29.2, 29.7, 40.9, 63.2, 66.5, 69.9, 70.2, 72.0, 72.2, 73.0,
101.3, 128.1 ± 133.5, 165.1, 165.2, 165.9, 166.2; C48H47O12N: calcd C 69.47, H
5.71, N 1.69; found C 69.83, H 5.52, N 1.59.
‡
‡
‡
39%). [a]D
ˆ
2 (c ˆ 1 in CHCl3); LSIMS: m/z ˆ 2051 [M‡Na] ; 1H NMR
(CDCl3, 258C): d ˆ 0.96 ± 1.48 (m, 8H), 2.91 ± 3.04 (m, 2H), 3.25 ± 3.32 (m,
1H), 3.38 ± 3.58 (m, 5H), 3.69 ± 4.02 (m, 8H), 4.05 ± 4.13 (m, 1H), 4.20 ± 4.32
(m, 2H), 4.28 (d, 1H, J ˆ 10.0 Hz), 4.48 ± 4.55 (m, 1H), 4.56 (d, 1H, J ˆ
8.0 Hz), 4.62 (d, 1H, J ˆ 8.0 Hz), 4.72 ± 4.80 (m, 2H), 5.08 (s, 2H), 5.12 (d,
1H, J ˆ 9.0 Hz), 5.36 (pt, 1H, J ˆ 10.0 Hz), 5.39 ± 5.47 (m, 1H), 5.51 (pt, 1H,
J ˆ 10.0 Hz), 5.63 (s, 1H), 5.64 (pt, 1H, J ˆ 10.0 Hz), 5.70 (pt, 1H, 10.0 Hz),
5.84 (pt, 1H, 10.0 Hz), 7.01 ± 8.12 (m, 60H); 13C NMR (CDCl3, 258C): d ˆ
25.2, 25.3, 25.9, 29.3, 40.6, 61.6, 62.2, 66.2, 66.4, 67.8, 68.4, 68.6, 68.7, 69.0,
69.7, 71.0, 71.1, 72.0, 72.3 72.9, 73.5, 76.3, 77.0, 79.1, 85.4, 100.2, 100.3, 100.7,
101.4, 125.6 ± 137.2, 163.6, 163.8, 164.4, 164.7, 164.8, 165.1, 165.4, 165.8,
6-Benzyloxycarbonylaminohexyl b-d-glucopyranoside (10): A solution of
the protected glucoside 9 (5.47 g, 6.60 mmol) in dry MeOH (50 mL) was
treated with NaOMe (1m) in MeOH (0.2 mmol) at RT until TLC
(SiO2:hexane/EtOAc, 3:2) showed that the reaction was complete (5 h).
‡
165.9; HRLSIMS: calcd for C115H105NNaO33 [M‡Na] 2050.6467, observed
m/z ˆ 2050.6488.
‡
The mixture was neutralized with Amberlyst 15 (H form), filtered and
6-Benzyloxycarbonylaminohexyl 2-O-benzoyl-3-O-[2-O-benzoyl-3,6-di-O-
(2,3,4,6-tetra-O-benzoyl-b-d-glucopyranosyl)-b-d-gluco-pyranosyl]-b-d-gl-
concentrated to give compound 10 as a white solid (2.73 g, 100%). M.p.
‡
110 ± 1128C; [a]D
ˆ
11 (c ˆ 1 in H2O); LSIMS: m/z ˆ 414 [M‡H] , 436
ucopyranoside (14):
A solution of the tetrasaccharide 13 (161 mg,
[M‡Na] ; 1H NMR (D2O, 258C): d ˆ 0.95 ± 1.50 (brm, 8H), 2.75 ± 2.95
(brm, 2H), 3.16 ± 3.48 (m, 5H), 3.50 (s, 2H), 3.62 ± 3.84 (m, 3H), 4.26 (d,
1H, J ˆ 8.0 Hz), 6.91 ± 7.10 (m, 5H); 13C NMR (D2O, 258C): d ˆ 27.7, 28.8,
31.7, 32.0, 43.3, 54.6, 63.5, 68.8, 72.2, 72.8, 75.8, 78.5, 105.1, 130.3, 130.9,
‡
0.08 mmol) in dry CH2Cl2 (5 mL) was treated with 90% aqueous CF3CO2H
(0.5 mL) at RT. After 10 min, TLC monitoring (SiO2:PhMe/EtOAc, 1:1)
showed that the reaction had almost gone to completion. The mixture was
diluted with CH2Cl2 (40 mL) and then washed with aqueous NaHCO3 (3 Â
30 mL), and H2O (2 Â 30 mL), after which the organic layer was dried and
concentrated to give a crude product, which was subjected to medium-
pressure liquid chromatography (SiO2:PhMe/EtOAc, 7:3 to 1:1), affording
the title compound 14 (93 mg, 61%). [a]D ˆ 9 (c ˆ 2 in CHCl3); LSIMS: m/
‡
131.9, 139.3, 159.9; HRLSIMS: calcd for C20H31NNaO8 [M‡Na] 436.1947,
observed m/z ˆ 436.1948.
6-Benzyloxycarbonylaminohexyl 4,6-O-benzylidene-b-d-glucopyranoside
(11): A catalytic amount of 10-camphorsulfonic acid was added to a
solution of the deprotected glucoside 10 (2.40 g, 5.8 mmol) and
PhCH(OMe)2 (1.2 mL, 7.7 mmol) in dry DMF (20 mL) and the mixture
was stirred under reduced pressure ( ꢀ 5 Torr) for 4 h at 508C until no trace
of the starting material was detected by TLC (SiO2:PhMe/EtOAc, 1:1). The
reaction mixture was then neutralized with Et3N and solvent was removed
by evaporation in vacuo. The residue was dissolved in EtOAc (150 mL) and
washed with aqueous NaHCO3 (3 Â 100 mL) and H2O (2 Â 100 mL), and
the organic layer was dried and concentrated. Column chromatography
‡
z ˆ 1963 [M ‡ Na] ; 1H NMR (CDCl3, 258C): d ˆ 0.94 ± 1.37 (m, 8H), 1.80
(brs, 1H), 2.50 (brs, 1H), 2.89 ± 2.96 (m, 2H), 3.22 ± 3.30 (m, 1H), 3.32 ±
3.38 (m, 1H), 3.43 (pt, 1H, J ˆ 10.0 Hz), 3.55 ± 3.63 (m, 4H), 3.70 ± 3.76 (m,
1H), 3.77 ± 3.98 (m, 3H), 4.07 ± 4.13 (m, 1H), 4.19 ± 4.25 (m, 2H), 4.30 (d,
1H, J ˆ 8.0 Hz), 4.29 ± 4.35 (m, 1H), 4.47 (d, 1H, J ˆ 8.0 Hz), 4.48 ± 4.52 (m,
1H), 4.60 (brs, 1H), 4.66 (d, 1H, J ˆ 8.0 Hz), 4.69 ± 4.75 (m, 2H), 4.93 (dd,
1H, J ˆ 8.0, 10.0 Hz), 5.00 (dd, 1H, J ˆ 8.0, 10.0 Hz), 5.07 (s, 2H), 5.20 (d,
1H, J ˆ 8.0 Hz), 5.39 (dd, 1H, J ˆ 8.0, 10.0 Hz), 5.52 (pt, 1H, J ˆ 10.0 Hz),
5.57 (dd, 1H, J ˆ 8.0, 10.0 Hz), 5.66 (pt, 1H, J ˆ 10 Hz), 5.71 (pt, 1H, J ˆ
10.0 Hz), 5.94 (pt, 1H, J ˆ 10.0 Hz), 6.95 ± 8.09 (m, 55H); 13C NMR
(SiO2:PhMe/EtOAc, 1:1) of the residue gave compound 11 (2.60 g, 90%).
‡
[a]D
ˆ
30 (c ˆ 1, CHCl3); LSIMS: m/z ˆ 524 [M‡Na] ; 1H NMR (CDCl3,
1252
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0947-6539/98/0407-1252 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 7

Oligosaccharide Dendrimers
1244±1254
(CDCl3, 258C): d ˆ 25.3, 26.0, 29.0, 29.4, 40.7, 62.5, 62.7, 66.4, 68.9, 69.1, 69.4,
10 min, the reaction mixture was neutralized with C5H5N, diluted with
CH2Cl2 (20 mL) and worked up according to the procedure already
described for 13. Purification of the crude product by medium-pressure
liquid chromatography (SiO2:PhMe/EtOAc, 9:1 ± 85:15) gave the tetrasac-
charide 20 (135 mg, 30%). [a]D ˆ ‡43 (c ˆ 1 in CHCl3); LSIMS: m/z ˆ
71.2, 71.8, 72.2, 72.4, 72.8, 75.6, 84.1, 84.9, 101.2, 128.0 ± 133.4, 163.7, 163.9,
‡
164.8, 165.1, 165.5, 166.0; HRLSIMS: calcd for C108H101NNaO33 [M‡Na]
1962.6154; observed m/z ˆ 1962.6172.
6-Benzyloxycarbonylaminohexyl 2-O-benzoyl-3,6-di-O-[2-O-benzoyl-3,6-
di-O-(2,3,4,6-tetra-O-benzoyl-b-d-glucopyranosyl)-b-D-gluco-pyranosyl]-
‡
2172 [M‡Na] ; 1H NMR (CDCl3, 258C): d ˆ 1.15 ± 1.55 (brm, 8H), 2.46 ±
2.52 (m, 1H), 2.69 ± 2.75 (m, 1H), 3.15 ± 3.21 (m, 3H), 3.24 ± 3.28 (m, 2H),
3.45 (pt, 1H, J ˆ 9.0 Hz), 3.50 ± 3.56 (m, 2H), 3.67 ± 3.74 (m, 1H), 4.06 (d,
1H, J ˆ 8.0 Hz), 4.09 ± 4.18 (m, 3H), 4.22 ± 4.28 (m, 2H), 4.37 (dd, 1H, J ˆ
3.5, 12.5 Hz), 4.47 (dd, 1H, J ˆ 5.0, 12.0 Hz), 4.50 (d, 1H, J ˆ 8.0 Hz), 4.62
(d, 1H, J ˆ 8.0 Hz), 4.64 (dd, 1H, J ˆ 3.5, 12.0 Hz), 5.00 (d, 1H, J ˆ 8.0 Hz),
5.07 (s, 2H), 5.28 (brs, 1H), 5.38 ± 5.47 (m, 3H), 5.53 (dd, 1H, J ˆ 8.0,
10.0 Hz), 5.55 (dd, 1H, J ˆ 8.0, 10.0 Hz), 5.63 (pt, 1H, J ˆ 10.0 Hz), 5.69 (pt,
1H, J ˆ 10.0 Hz), 5.79 (pt, 1H, J ˆ 10.0 Hz), 5.88 (pt, 1H, J ˆ 10.0 Hz),
7.14 ± 8.31 (m, 65H); 13C NMR (CDCl3, 258C): d ˆ 25.8, 26.5, 29.3, 30.0,
41.2, 62.0, 63.0, 68.5, 69.1, 69.2, 69.6, 69.7, 70.9, 72.0, 72.1, 72.5, 73.0, 75.3,
77.3, 85.5, 99.9, 100.1, 101.0, 101.7, 127.9 ± 136.9, 156.5, 164.7, 164.9, 165.0,
165.2, 165.7, 165.8, 165.9, 166.1; HRLSIMS: calcd for C122H109NNaO35
b-d-glucopyranoside (15):
A catalytic amount of TfOH (1.6 mL,
0.017 mmol) was added to a mixture of the tetrasaccharide 14 (93 mg,
0.048 mmol), the trisaccharide 7 (83 mg, 0.052 mmol), and NIS (23 mg,
0.104 mmol) in dry CH2Cl2 (5 mL) under an atmosphere of N2 at 08C. The
reaction micture was allowed to warm up to RT, before being neutralized
with C5H5N and worked up as described for the preparation of 13.
Repeated medium-pressure liquid chromatography (SiO2:PhMe/EtOAc,
85:15) on the crude product afforded the pure heptasaccharide 15 (56 mg,
‡
28%). [a]D
ˆ
7.5 (c ˆ 2 in CHCl3); LSIMS: m/z ˆ 3387 [M‡Na] ; 1H
NMR (CDCl3, 258C): d ˆ 3.89 (d, J ˆ 9.0 Hz), 4.29 (d, J ˆ 8.0 Hz), 4.34 (d,
J ˆ 8.0 Hz), 4.61 (d, J ˆ 8.0 Hz), 4.81 (d, J ˆ 8.0 Hz), 4.98 (d, J ˆ 8.0 Hz),
5.05 (d, J ˆ 8.0 Hz); 13C NMR (CDCl3, 258C): d ˆ 24.3, 25.2, 28.0, 28.5, 28.8,
39.8, 59.4, 61.6, 62.0, 65.5, 67.2, 67.4, 67.7, 68.2, 68.4, 68.5, 68.9, 69.4, 69.7, 70.3,
70.4, 70.9, 71.0, 71.1, 71.2, 71.5, 71.6, 71.5, 71.9, 72.0, 73.6, 74.3, 74.5, 82.7,
84.1, 84.8, 99.6, 99.8, 100.1, 100.4, 100.7, 100.8, 126.2 ± 133.0, 136.8, 155.3,
162.7, 162.8, 163.1, 163.9, 164.0, 164.1, 164.2, 164.3, 164.6, 164.8, 165.0, 165.1,
‡
[M‡Na] 2170.6678; observed m/z ˆ 2170.6789.
Dendrimer 23: The N-benzyloxycarbonyl derivative 20 (93 mg,
0.043 mmol) was subjected to hydrogenolysis over 10% Pd/C (25 mg) in
EtOH/CH2Cl2, 2:1 (25 mL) at 358C for 4 days. The catalyst was filtered off
through a layer of Celite and the filtrate was concentrated to afford 21
(73 mg, 84%), a portion of which (46 mg, 0.023 mmol) was then added to a
solution of 1,3,5-benzenetricarbonyl chloride (22; 1.9 mg, 0.007 mmol) and
Et3N (3.3 mL, 0.023 mmol) in CH2Cl2 (5 mL) under an atmosphere of N2.
The reaction mixture was stirred at RT for 6 h and then subjected to column
chromatography (SiO2:PhMe/EtOAc, 7:3) to afford the dendrimer 23
‡
165.2; HRLSIMS: calcd for C189H167NNaO57 [M‡Na] 3385.0098; observed
m/z ˆ 3385.0103.
6-Benzyloxycarbonylaminohexyl 4,6-O-benzylidene-2,3-di-O-(2,3,4,6-tet-
ra-O-benzoyl-b-d-glucopyranosyl)-b-d-glucopyranoside (18): A catalytic
amount of TfOH (105 mL, 1.2 mmol) was added slowly to a solution of the
diol 11 (740 mg, 1.48 mmol), and the thioglycoside 17 (2.23 g, 3.58 mmol)
and NIS (1.6 g, 7.1 mmol) in dry CH2Cl2 (80 mL) under a N2 atmosphere at
RT. The reaction mixture was neutralized after 10 min with C5H5N before
being worked up as described for the tetrasaccharide derivative 13. The
trisaccharide 18 was isolated (1.35 g, 55%) following medium-pressure
liquid chromatography (SiO2:PhMe/EtOAc 95:5 to 88:12). [a]D ˆ ‡33 (c ˆ
‡
(9 mg, 20%). MALDI-TOF m/z ˆ 6230 [M‡Na] ; 1H NMR (CDCl3,
258C): d ˆ 1.05 ± 1.70 (brm, 24H), 2.47 ± 2.53 (m, 3H), 2.66 ± 2.72 (m, 3H),
3.12 ± 3.16 (m, 3H), 3.24 ± 3.28 (m, 12H), 3.44 (pt, 3H, J ˆ 9.0 Hz), 3.48 ±
3.55 (m, 6H), 3.67 ± 3.72 (m, 3H), 4.07 (d, 3H, J ˆ 8.0 Hz), 4.10 ± 4.18 (m,
9H), 4.22 ± 4.28 (m, 6H), 4.36 (dd, 3H, J ˆ 3.5, 12.5 Hz), 4.46 (pt, 3H, J ˆ
5.0 Hz), 4.49 (d, 3H, J ˆ 8.0 Hz), 4.61 (d, 3H, J ˆ 8.0 Hz), 4.63 (dd, 3H, J ˆ
3.5, 12.0 Hz), 4.99 (d, 3H, J ˆ 8.0 Hz), 5.30 (s, 3H), 5.38 ± 5.44 (m, 9H), 5.52
(dd, 3H, J ˆ 8.0, 10.0 Hz), 5.54 (dd, 3H, J ˆ 8.0, 10.0 Hz), 5.62 (pt, 3H, J ˆ
10.0 Hz), 5.67 (pt, 3H, J ˆ 10.0 Hz), 5.77 (pt, 3H, J ˆ 10.0 Hz), 5.87
(pt, 3H, J ˆ 10.0 Hz), 7.13 ± 8.01 (m, 180H), 8.23 (t, 3H, J ˆ 8.0 Hz),
8.29 (s, 3H).
‡
‡
1 in CHCl3); MALDI-TOF: m/z ˆ 1681 [M‡Na] ,1696 [M‡K] ; 1H NMR
(CDCl3, 258C): d ˆ 1.20 ± 1.55 (brm, 8H), 2.66 ± 2.82 (m, 2H), 3.13 ± 3.24
(m, 2H), 3.25 ± 3.35 (m, 1H), 3.43 ± 3.53 (m, 1H), 3.60 (pt, 1H, J ˆ 9.0 Hz),
3.65 ± 3.76 (m, 2H), 3.80 (pt, 1H, J ˆ 9.0 Hz), 3.95 (dd, 1H, J ˆ 8.0, 9.0 Hz),
4.16 ± 4.36 (m, 5H), 4.39 (d, 1H, J ˆ 8.0 Hz), 4.75 (d, 1H, J ˆ 8.0 Hz), 4.86
(d, 1H, J ˆ 8.0 Hz), 5.08 (s, 2H), 5.19 (brs, 1H), 5.44 (dd, 1H, J ˆ 8.0,
9.0 Hz), 5.45 ± 5.53 (m, 3H), 5.58 (dd, 1H, J ˆ 8.0, 9.0 Hz), 5.80 (pt, 1H, J ˆ
9.0 Hz), 5.82 (pt, 1H, J ˆ 9.0 Hz), 7.12 ± 8.28 (m, 50H); 13C NMR (CDCl3,
258C): d ˆ 25.7, 26.5, 29.4, 30.0, 41.1, 63.0, 63.4, 66.0. 66.6, 68.7, 69.7, 70.0,
70.1, 71.1, 72.3, 72.5, 72.6, 72.9, 78.4, 78.7, 80.0, 99.8, 100.0, 101.1, 101.8,
125.2 ± 137.2, 156.4, 164.9, 165.0, 165.1, 165.2, 165.7, 165.8, 165.9;
C95H87NO26: calcd C 68.79, H 5.29, N 0.84; found C 68.79, H 5.26,
N 0.67.
Dendrimer 25: Hydrogenolysis of the heptasaccharide 15 (56 mg,
0.017 mmol) in the presence of 10% Pd/C (50 mg) in MeOH/CH2Cl2, 2:1
(30 mL) at 358C over 18 hours afforded the amine 16 (42 mg, 77%,
‡
MALDI-TOF: m/z ˆ 3252 [M‡Na] ), which was isolated as described for
21. Compound 16 (42 mg, 0.013 mmol) was then added to a solution of
DCC (2.62 mg, 0.013 mmol), HOBT (1.71 mg 0.013 mmol), and 24[9a]
(1.51 mg, 0.004 mmol) in CH2Cl2/DMF, 2:1 (30 mL) under an atmosphere
of N2 at RT. After 14 days, the solvent was evaporated in vacuo and the
residue was subjected to GPC (Phenomenex column, THF); this resulted in
isolation of three compounds (Figure 1): I) the 21-mer 25 (10.1 mg, 8%),
GPC retention time 15.0 min, II) the product corresponding to bisfunc-
tionalization of the core, GPC retention time 16.1 min, and III) the starting
compound 16, GPC retention time 17.7 min. Dendrimer 25: MALDI-TOF:
6-Benzyloxycarbonylaminohexyl
2,3-di-O-(2,3,4,6-tetra-O-benzoyl-b-d-
glucopyranosyl)-b-d-glucopyranoside (19): The trisaccharide derivative
18 (1.35 g, 0.81 mmol) was treated with 90% aqueous CF3CO2H (5 mL) in
CH2Cl2 (25 mL) for 10 min at RT. The reaction mixture was then diluted
with CH2Cl2 (75 mL), washed with an aqueous NaHCO3 (3 Â 75 mL) and
H2O (2 Â 50 mL) before the organic layer was dried and concentrated.
Column chromatography of the residue (SiO2:PhMe/EtOAc, 7:3 to 6:4)
afforded the diol 19 (1.23 g, 96%). [a]D ˆ ‡59 (c ˆ 1 in CHCl3); MALDI-
‡
m/z ˆ 10042 [M‡Na] ; 1H NMR (CDCl3, 258C): d ˆ 3.90 (d, J ˆ 9.0 Hz),
4.29 (d, J ˆ 8.0 Hz), 4.35 (d, J ˆ 8.0 Hz), 4.61 (d, J ˆ 8.0 Hz), 4.82 (d, J ˆ
8.0 Hz), 4.98 (d, J ˆ 8.0 Hz), 5.06 (d, J ˆ 8.0 Hz). Bisfunctionalized core
‡
‡
TOF: m/z ˆ 1592 [M‡Na] ,1607 [M‡K] ; 1H NMR (CDCl3, 258C): d ˆ
1.12 ± 1.55 (brm, 8H), 2.39 ± 2.49 (m, 1H), 2.65 ± 2.75 (m, 1H), 3.09 ± 3.25
(brm, 3H), 3.39 ± 3.45 (m, 1H), 3.47 (pt, 1H, J ˆ 9.0 Hz), 3.55 (pt, 1H, J ˆ
9.0 Hz), 3.64 (dd, 1H, J ˆ 7.5, 9.0 Hz), 3.66 ± 3.76 (m, 2H), 3.87 (dd, 1H, J ˆ
3.5, 12.0 Hz), 4.09 ± 4.25 (m, 3H), 4.27 (d, 1H, J ˆ 7.5 Hz), 4.39 (dd, 1H, J ˆ
2.5, 12.5 Hz), 4.52 (d, 1H, J ˆ 8.0 Hz), 4.64 (d, 1H, J ˆ 8.0 Hz), 5.08 (s, 2H),
5.14 (brs, 1H), 5.38 ± 5.59 (m, 4H), 5.64 (pt, 1H, J ˆ 10.0 Hz), 5.80 (pt, 1H,
J ˆ 10.0 Hz), 7.22 ± 8.33 (m, 45H); 13C NMR (CDCl3, 258C): d ˆ 25.9, 26.7,
29.6, 30.2, 41.4, 62.3, 63.0, 63.1, 66.5, 69.3, 69.7, 69.9, 71.3, 72.3, 72.8, 73.3,
75.5, 78.0, 85.7, 100.2, 100.4, 101.5, 128.1 ± 137.1, 156.8, 165.0, 165.2, 165.4,
166.0, 166.1; C88H83NO26: calcd C 67.30, H 5.33, N 0.89; found C 67.13, H
5.32, N 0.63.
‡
derivative: MALDI-TOF: m/z ˆ 6833 [M‡Na] ; the starting compound 16
‡
MALDI-TOF: m/z ˆ 3268 [M‡Na] .
Molecular modeling: The 12-mer and 21-mer dendrimers 23 and 25,
respectively, were constructed individually within the input mode of
Macromodel5.0.[27] Subsequently, the geometries were optimized by energy
minimization performed on each structure using the Polak ± Ribiere
conjugate gradient (PRCG) algorithm,[30] the AMBER* forcefield,[28] and
the generalized Born surface area (GB/SA) solvation model[29] for CHCl3,
as implemented in Macromodel5.0. Then the lowest energy conformations
were searched for by molecular dynamics with stepwise simulated
annealing performed on each individual structure in one step of 10 ps,
followed by two steps of 20 ps in conjunction with the PRCG method, the
AMBER* forcefield, and the GB/SA for CHCl3. The simulated temper-
ature was decreased from 300 to 150, and finally to 50 K, with a bath
constant of 5.0 ps applied at all steps. The time step was maintained at 1.5 fs
in the first two steps and increased to 2.0 fs in the final step.
6-Benzyloxycarbonylaminohexyl 2,3,6-tri-O-(2,3,4,6-tetra-O-benzoyl-b-d-
glucopyranosyl)-b-d-glucopyranoside (20): A catalytic amount of TfOH
(15 mL, 0.17 mmol) was added to a solution of the diol 19 (330 mg,
0.21 mmol), the thioglycoside 12 (314 mg, 0.50 mmol), and NIS (225 mg,
1.00 mmol) in dry CH2Cl2 (30 mL) under an atmosphere of N2 at RT. After
Chem. Eur. J. 1998, 4, No. 7
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0407-1253 $ 17.50+.25/0
1253

J. F. Stoddart et al.
FULL PAPER
Acknowledgements: This research was supported in the UK by Pfizer, by
the Engineering and Physical Sciences Research Council, and by the
University of Birmingham.
33, 803 ± 822; c) J. Szejtli, Cyclodextrins and their Inclusion Complexes,
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Received: October 27, 1997 [F863]
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