Glycodendrimers based on cellobiosyl-derived monomers

Article abstract of DOI:10.1139/v02-116

Reductive amination of suitably functionalized trisaccharide monomers, based on cellobiosylgalacto residues, has made it possible to construct high-molecular-weight glycodendrons and glycodendrimers for the display of large bioactive oligosaccharides and

Full text of DOI:10.1139/v02-116

983
Glycodendrimers based on cellobiosyl-derived
monomers1
Stacey A. Kalovidouris, W. Bruce Turnbull, and J. Fraser Stoddart
Abstract: Reductive amination of suitably functionalized trisaccharide monomers, based on cellobiosylgalacto residues,
has made it possible to construct high-molecular-weight glycodendrons and glycodendrimers for the display of large
bioactive oligosaccharides and proteins in a well-defined manner.
Key words: cellobiose, glycodendrimers, reductive amination, trisaccharide monomers.
Résumé : L’amination réductrice de trisaccharides monomères fonctionnalisés de façon appropriée et attachés à de
résidus cellobiosylgalactose permet de construire des glycodendrons et des glycodendrimères de masses moléculaires
élevées grâce auxquels on peut présenter de grosses molécules d’oligosaccharides et de protéines bioréactifs d’une
façon bien définie.
Mots clés : cellobiose, glycodendrimères, amination réductrice, trisaccharides monomères.
Kalovidouris et al. 991
Introduction
ꢀ-2,6-linked sialosides by Siglecs 1 and 2, respectively. But
perhaps the most subtle, yet profound, of possible structural
changes results from the inversion of configuration at a sin-
gle carbon atom such as in the repeating unit of the common
(1J4)-linked polymers of glucose — i.e., amylose and cel-
lulose (9). The ꢀ(1J4)-linkages in amylose promote the
adoption of a helical structure by the polymer, in which
intramolecular hydrogen bonding between primary and sec-
ondary hydroxy groups on adjacent turns of the helix, leads
to the formation of channels capable of supramolecular
complexation. In contrast, the ꢁ(1J4)-linkages of cellulose
lead to a more extended structure promoting intermolecular
hydrogen bonding between polymer strands and insoluble
crystalline fibers. In addition to the changes in overall shape,
the spacial distributions of substituent groups (e.g., C-6
hydroxymethyl groups) on the polymers are also different.
Whereas, in amylose, all of the primary hydroxy functions
point away from the same side of the polymer chain — rem-
iniscent of the primary face of cyclodextrins — the same
groups in cellulose are directed in opposing directions from
adjacent sugar residues. The graphical representations of
maltosyl and cellobiosyl residues shown in Fig. 1 illustrate
the background behind our motivation to be able to compare
The incorporation of carbohydrates into dendritic struc-
tures continues to be pursued vigorously by a growing num-
ber of research groups (1). The driving force behind
glycodendrimer research has been the desire to mimic Na-
ture’s use of multivalency (2) to enhance both the avidity
and selectivity of interactions between oligosaccharide lig-
ands and their corresponding protein receptors. There is a
growing appreciation (3) that the structure of the underlying
dendritic scaffold is as important to achieving efficient
multivalent interactions as presenting multiple copies of the
ligand. Thus, developing novel dendritic structures for this
purpose may be considered to be a worthy pursuit. We (4, 5)
and others (6) have identified that, in addition to the
bioactive ligands, oligosaccharides show great potential as
building blocks for multivalent and dendritic scaffolds. In
this sense, carbohydrates can provide (7) vast diversity in
constitution, configuration and conformation in addition to
lending themselves well as multifunctional building blocks
for constructing branched structures. Small changes in con-
stitution can provide large differences in biological activi-
ties, e.g., in the highly selective recognition (8) of ꢀ-2,3- and
Received 6 December 2001. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on 15 August 2002.
It was Ray Lemieux who provided intellectual leadership in the field of carbohydrate chemistry during the second half of the 20th
century. His contribution to our fundamental knowledge of the nature of the carbohydrates was profound, all-encompassing, and
far-reaching. During the last decade or so, our basic understanding of the mechanisms by which carbohydrates are bound by
proteins has advanced enormously. These advances were only possible because of the seminal work done by Lemieux in the 1980s.
We dedicate this paper to the memory of Ray.
S.A. Kalovidouris, W.B. Turnbull,2 and J.F. Stoddart.3 Department of Chemistry and Biochemistry, University of California,
Los Angeles, 405 Hilgard Avenue, Los Angeles, CA 90095–1569, U.S.A.
1The paper is Part 10 in a series on Synthetic carbohydrate dendrimers.
2Present address: Astbury Centre for Structural Molecular Biology, School of Biochemistry and Molecular Biology, University of
Leeds, Leeds LS2 9JT, U.K.
3Corresponding author (e-mail: stoddart@chem.ucla.edu).
Can. J. Chem. 80: 983–991 (2002)
DOI: 10.1139/V02-116
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Can. J. Chem. Vol. 80, 2002
Scheme 1. (a) TMSOTf, CH2Cl2, 4 Å MS (75%); (b) NaOMe, MeOH; TBDMSCl, C5H5N; Ac2O, C5H5N (50% over three steps);
(c) Br2, PPh3, CH2Cl2 (96%); (d) NHMeBn (57%); (e) NaOMe, MeOH (90%); H2, Pd(OH)2 on C, MeOH (quant.); (f) NaOMe, MeOH
(90%); TFA, H2O (9:1) (80%); (g) NaCNBH3, MeOH, AcOH (94%).
OH
OAc
O
R
O
Me
Me
OAc
O
OAc
AcO
AcO
AcO
AcO
O
O
a
O
O
O
O
AcO
O
R
AcO
O
AcO
AcO
Me
Me
O
OAc
O
O
CCl3
O
Me
O
NH
Me
O
3 R = OAc
1
O
2
b
c
d
Me
4 R = OTBDMS
5 R = Br
Me
NMeBn
NMe
HO
HO
OH
O
BnMeN
6 R = NMeBn
BnMeN
O
NMeBn
O
HO
HO
O
MeN
HO
HO
OH
OH
e
BnMeN
NMeBn
NMe
O
f
OH
Me
N
HO
O
O
MeHN
HO
HO
H
O
NMe
OH
HO
Me
Me
O
HO
HO
O
O
O
O
O
O
N
HO
O
H
HO
MeHN
Me
Me
O
O
O
O
O
Me
Me
O
HO
HO
OH
Me
Me
Me
7
OH
9
g
O
OH
O
NMeBn
OH
OH
BnMeN
NMeBn
O
O
HO
O
O
O
NMeBn
OH
HO
O
HO
BnMeN
HO
HO
HO
HO
OH
NMeBn
O
H
O
HO
OH
8
and contrast glycodendrons and glycodendrimers incorporat-
ing these two diastereoisomerically related residues.
Recently, we have outlined (5) an approach for the synthe-
sis of dendritic oligosaccharides via reductive amination of a
reducing sugar, using a trisaccharide bearing two methyl-
amino groups. Our first choice was to use a maltosyl-
galactose repeating unit that incorporates the ꢀ(1J4)-linkage
(associated with amylose) between the branching points of
resulting dendrons. Here, we describe the synthesis of analo-
gous compounds that incorporate the corresponding ꢁ(1J4)-
linkage of cellobiose in a first step toward the general devel-
opment of oligosaccharide-based dendrimers that exhibit
broad structural diversity derived from their constituent
building blocks.
Fig. 1. A graphical representation of maltosyl and cellobiosyl
residues.
O
O
Maltosyl
OR
O
O
Results and discussion
Cellobiosyl
OR
O
O
Synthesis of the AB2 monomers and the dendron
The synthesis of the first-generation cellobiosylgalacto-
based dendron 9 is outlined in Scheme 1. Starting from the
known (10) peracetylated ꢀ-cellobiosyl-trichloroacetimidate
1 as the glycosyl donor and 1,2:3,4-di-O-isopropylidene-ꢀ-
D-galactopyranose (2) as the glycosyl acceptor, the protected
trisaccharide 3 was obtained in 75% yield using TMSOTf as
the promoter. With the ultimate objective being that of intro-
ducing protected secondary amino functions at the primary
positions of the two glucopyranosyl residues, the O-acetyl
protecting groups were removed using Zemplén conditions.
Thereafter, the two primary hydroxyl groups were protected
© 2002 NRC Canada

Kalovidouris et al.
985
Scheme 2. (a) ClCO2Et, C6H6, H2O, KOH (40%); (b) LiAlH4, THF (56%).
NHMe
NHMe
NH2
NHCO2Et
a
b
N
MeHN
N
N
H2N
EtO2CHN
NH2
NHCO2Et
11
12
13
Fig. 3. ES-MS spectrum of dendron 9.
Fig. 2. DEPT 135 spectrum (CD3OD, 125 MHz) of dendron 9.
as their TBDMS ethers before the secondary ones were
reacetylated to afford the fully protected trisaccharide 4. The
last three steps were performed in an overall yield of 50%.
The bis-silyl ether was then converted directly into the
dibromide 5 in 96% yield with triphenylphosphine and bro-
mine. When 5 was heated with neat benzylmethylamine, the
fully protected trisaccharide (6) was obtained in 57% yield.
One of the required AB2 monomers, namely the tris-
accharide (7), carrying two secondary amino functions, was
isolated quantitatively following hydrogenolysis of 6 in the
presence of Pearlman’s catalyst. The other AB2 monomer
(8) was obtained in 80% yield following removal of the cy-
clic acetals in 6 by TFA-catalyzed hydrolysis. The two AB2
monomers (7 and 8) were coupled by reductive amination to
give the first-generation dendron (9) in 94% yield. DEPT-
135 13C NMR and ES-MS spectra are presented in Figs. 2
and 3, respectively. Of the 11 different methylene carbon at-
oms present in the dendron, seven can be identified as nega-
tive peaks in the 13C NMR spectrum. The ES-MS reveals
peaks at 2001.0, 1001.1, 667.8, 500.7, and 400.8 for the [M
+ H]+, [M + 2H]2+, [M + 3H]3+, [M + 4H]4+, and [M + 5H]5+
ions obtained from the dendron (9).
Synthesis of the glycodendrimers
The syntheses of the zero-generation glycodendrimer (14)
and the first-generation glycodendrimer (16) are summarized
in Scheme 3. The graphical representations of molecular
structures employed in this scheme are defined in Schemes 1
and 2. The zero-generation glycodendrimer (14) was isolated
in 69% yield following coupling by reductive amination of
the AB2 monomer (8) with the tris[2-(methylamino)ethyl]amine
core (13). This glycodendrimer was easily soluble in water.
However, upon its acetylation (Scheme 4), the resulting
peracetylated derivative (15) was soluble in polar organic
solvents, e.g., methanol and dimethylformamide, but not in
chlorinated solvents, e.g., dichloromethane and chloroform.
The MALDI-TOF mass spectrum (Fig. 4) of 15 exhibited an
[M + H]+ peak at m/z 3407 with an isotope distribution that
matches well with that of the calculated one. Employing
reductive amination once again to couple the dendron (10)
with the tris[2-(methylamino)ethyl]amine core (13) results in
the formation of the first-generation glycodendrimer (16) in
56% yield. This glycodendrimer (16) and its peracetylated
derivative (17) (see Scheme 5) exhibit solubility characteris-
tics similar to those already described for the zero-
generation counterparts 14 and 15. The MALDI-TOF mass
spectrum (Fig. 5) of 17 exhibited an [M + H]+ peak at m/z
9078 along with fragmentation peaks at m/z 8062, 7159,
6227, 5153, 4305, 3017, and 1987. These fragmentations
Synthesis of the core
The synthesis of the tris[2-(methylamino)ethyl]amine-
based core (13) is depicted in Scheme 2. A published proce-
dure (11) was followed to obtain 13 in two steps, starting
from tris(2-aminoethyl)amine (11). In the first step, the tris-
carbamate (12) was prepared by reacting 11 with ethylchloro-
formate under basic conditions. In the second step, 12 was
reduced with lithium aluminum hydride to afford the tris[2-
(methylamino)ethyl]amine core (13).
© 2002 NRC Canada

986
Can. J. Chem. Vol. 80, 2002
Scheme 3. (a) NaCNBH3, AcOH, MeOH (94%); (b) NaCNBH3, AcOH, MeOH (69%); (c) TFA, H2O (9:1) (80%); (d) NaCNBH3,
AcOH, MeOH (56%).
NMeBn
NMe
NMeBn
NMe
MeHN
BnMeN
BnMeN
a
c
MeHN
O
7
H
MeN
MeN
NMeBn
BnMeN
BnMeN
BnMeN
NMeBn
NMeBn
AB
2
d
O
H
Core
Dendrons
Monomers
8
9
10
13
Core
b
NMeBn
BnMeN
13
BnMeN
NMeBn
N
N
Me
Me
Me
N
BnMeN
NMeBn
NMeBn
BnMeN
Me
N
Me
N
Me
14
16
BnMeN
N
Me
N
N
NMeBn
Me
Me
N
Me
N
N
Me
BnMeN
N
NMeBn
Me
NMeBn
BnMeN
BnMeN
NMeBn
BnMeN
NMeBn
Zero-generation dendrimer
First-generation dendrimer
Scheme 4. (a) Ac2O, C5H5N, DMAP (45%).
result from cleavages of glycosyl linkages and ꢁ-elimination
on the amine linkages at the positions indicated by open ar-
rows in Fig. 5. These types of cleavages in oligosaccharide
derivatives are well precedented in the literature (12).
solvents were dried prior to use according to literature pro-
cedures (14). Thin-layer chromatography (TLC) was carried
out on aluminum sheets precoated with silica gel 60F
(Merck 5554). The plates were inspected by UV light and
developed either with iodine vapor or by treatment with 5%
H2SO4 in EtOH, followed by heating. Column chromatogra-
phy was carried out using silica gel 60F (Silicycle). Prepara-
tive reversed phase chromatography was performed on fully
endcapped C-18, or on C-8 silica gel 100 (230–400 mesh,
Fluka), and gel permeation chromatography (GPC) was per-
formed using a 25 × 900 mm column of Sephadex LH20
resin (Sigma), eluting with MeOH. Analytical reversed
Experimental section
General methods
Chemicals were purchased from Aldrich and were used as
received except for sodium cyanoborohydride (Aldrich),
which was purified by the published procedure (13). Reac-
tions were carried out under a dry argon atmosphere and the
© 2002 NRC Canada

Kalovidouris et al.
987
Scheme 5. (a) Ac2O, C5H5N, DMAP (33%).
RO
OR
O
OR
BnMeN
NMeBn
O
RO
BnMeN
NMeBn
O
OR
RO
OR
BnMeN
OR
RO
RO
RO
NMeBn
N
NMeBn
O
OR
O
N
O
Me
O
RO
N
Me
RO
O
RO
OR
Me
OR
OR
RO
RO
Me N
OR
OR
O
N
Me
O
NMeBn
O
BnMeN
BnMeN
RO
O
Me
Me
N
Me
N
BnMeN
N
Me
OR
N
NMeBn
RO
OR
RO
Me
Me
BnMeN
OR
N
N
Me
N
OR
OR
O
BnMeN
O
OR
O
NMeBn
N
BnMeN
OR
NMeBn
NMeBn
OR
N
RO
Me
OR
Me
Me
RO
N
OR
O
N
O
OR
O
OR
RO
O
RO
RO
RO
O
O
OR
NMeBn
OR
BnMeN
OR
O
RO
OR
OR
OR
RO
RO
OR
OR
OR
O
RO
Me
N
OR
O
O
OR
N
ORMe
Me
O
RO
RO
O
N
OR
O
RO
OR
OR
RO
RO
RO
RO
OR
OR
16 R = H
17 R = Ac
O
RO
a
O
NMeBn
RO
O
OR
O
BnMeN
RO
O
OR
NMeBn
O
O
O
OR
BnMeN
OR
OR
RO
OR
mass spectra (MALDI-TOF-MS) and fast atom
bombardment mass spectra (FAB-MS) were performed on
either Perceptive Biosystems Voyager RP (MALDI) or VG
SAB-SE (FAB) mass spectrometers. Electrospray mass
spectrometry (ES-MS) was recorded on a Sciex API IIIR tri-
ple quadrupole electrospray mass spectrometer using H2O–
Fig. 4. MALDI-TOF mass spectrum of a zero-generation
dendrimer 15.
1
MeCN–HCOOH (50:50:0.1) as the mobile phase. H and
13C NMR spectra were recorded using Bruker ARX400,
ARX500, and Advance 500 spectrometers with the residual
solvent or TMS as the internal standard. The chemical shifts
are expressed on the ꢀ scale in parts per million (ppm). The
following abbreviations are used to explain the observed
multiplicities: s (singlet), d (doublet), dd (doublet of dou-
blets), t (triplet), m (multiplet), br (broad).
2,3,4,6-Tetra-O-acetyl-ꢁ-D-glucopyranosyl-(1J4)-2,3,6-tri-
O-acetyl-ꢁ-D-glucopyranosyl-(1J6)-1,2:3,4-di-O-isopro-
pylidene-ꢂ-D-galactopyranose (3)
The glycosyl donor 1 (13.4 g, 17 mmol) and the glycosyl
acceptor 2 (6.7 g, 26 mmol) were stirred with powdered 4 Å
molecular sieves (13.0 g) in CH2Cl2 (250 mL) for 2 h under
an argon atmosphere. The mixture was then cooled to 0°C
and trimethylsilyl trifluoromethanesulfonate (610
L,
3.4 mmol) was added and stirring was continued at 0°C for
30 min. The reaction was then quenched by the addition of
Et3N (0.47 mL, 3.4 mmol). The solution was filtered through
Celite and the filtrate was concentrated. Column chromatog-
raphy (SiO2, CH2Cl2:EtOAc (8:2)) gave 3 (11 g, 75%) as a
solid foam. [ꢂ]2D0 –11.6 (c = 1 in CHCl3). HR-MS (FAB)
phase HPLC was conducted using a Hypersil 5 m BDS C-18
silica column (ThermoQuest, 4.6 × 250 mm) under
isocratic elution (MeOH–H2O–TFA, 65:35:0.0001) with UV
detection using a Dynamax PDA-2 diode array detector.
Matrix-assisted laser desorption ionization time-of-flight
© 2002 NRC Canada

988
Can. J. Chem. Vol. 80, 2002
Fig. 5. MALDI-TOF mass spectrum of a first-generation dendrimer 17.
calcd. for C38H54O23Na (M + Na): 901.2954; found:
901.2976. H NMR (CDCl3, 400 MHz) ꢀ: 1.36, 1.42, 1.43,
1.53 (4 × s, 12H, 2 × CMe2), 1.91, 1.94, 1.96, 1.98, 2.02,
2.06 (7 × s, 21H, 7 × Ac), 3.57–3.59 (m, 1H, H-5b), 3.59–
3.61 (m, 2H, H-6a, H-5c), 3.68 (t, J = 9.3 Hz, 1H, H-4b),
concentration and coevaporation with PhMe, the mixture
was dissolved in EtOAc (500 mL) and washed consecutively
with 1 M HCl, sat. NaHCO3, and sat. NaCl solutions, before
drying (Na2SO4), and concentrating to a foam. Column chro-
matography (SiO2, CH2Cl2:EtOAc (9:1)) gave 4 (2.69 g,
50%) as a foamy semisolid. [ꢂ]2D0 –17.9 (c = 1 in CHCl3).
HR-MS (FAB) calcd. for C46H78O21Si2Na (M + Na):
1
3.80–3.85 (m, 1H, H-5a), 3.91 (dd, J5,6 = 3.8 Hz, J6,6>
=
11.4 Hz, 1H, H-6a>), 3.98 (br d, J6,6> = 12.5 Hz, 1H, H-6c),
4.04 (dd, J5,6 = 5.0 Hz, J6,6> = 12.1 Hz, 1H, H-6b), 4.10 (d,
1
1045.4472; found: 1045.4501. H NMR (CDCl3, 400 MHz)
J = 7.84 Hz, 1H, H-4a), 4.22 (m, 1H, H-2a), 4.28 (dd, J5,6
4.6 Hz, J6,6> = 12.5 Hz, 1H, H-6c>), 4.42–4.47 (m, 2H, H-1c,
H-6b>), 4.55 (m, 2H, H-1b, H-3a), 4.82–4.87 (m, 2H, H-2c,
=
ꢀ: 0.00, 0.01, 0.08, 0.09 (4 × s, 12H, 4 × SiMe), 0.80, 0.91
(2 × s, 18H, 2 × SiCMe3), 1.30 (s, 6H, CMe2), 1.40, 1.49
(2 × s, 6H, CMe2), 1.96, 1.99, 2.03, 2.04, 2.07 (5 × s, 15H,
5 × Ac), 3.28 (m, 1H, H-5b), 3.43–3.44 (m, 1H, H-5c), 3.61
(m, 1H, H-6a>), 3.67–3.73 (m, 2H, H-6c, H-6c>), 3.87 (m,
H-2b), 4.99–5.14 (m, 3H, H-4c, H-3c, H-3b), 5.42 (d, J1,2
=
4.9 Hz, 1H, H-1a). 13C NMR (CDCl3, 100 MHz) ꢀ: 20.6
(3C), 20.7, 20.8, 20.9, 21.0, 24.4, 25.0, 25.9, 26.0, 59.1,
59.2, 60.0, 60.3, 68.4, 68.5, 68.6, 68.7, 69.0, 69.3, 69.5, 69.8
(2C), 70.0 (2C), 72.0 (2C), 75.0, 95.0, 101.0 (2C), 169.4,
169.8, 169.9, 170.1, 170.4, 170.5, 170.6.
4H, H-4b, H-5a, H-6b, H-6b>), 3.96 (dd, J5,6 = 4.1 Hz, J6,6>
11.2 Hz, 1H, H-6a), 4.16 (br d, J = 7.9 Hz, 1H, H-4a), 4.27
(m, 1H, H-2a), 4.49 (d, J = 8.0 Hz, 1H, H-1b), 4.56 (dd, J2,3
2.0 Hz, J3,4 = 7.9 Hz, 1H, H-3a), 4.66 (d, J1,2 = 8.0 Hz, 1H,
H-1c), 4.80–4.85 (m, 2H, H-2b, H-2c), 4.98 (t, J3,4 W J4,5
=
=
=
9.5 Hz, 1H, H-4c), 5.02–5.15 (m, 2H, H-3b, H-3c), 5.50 (d,
J1,2 = 4.9 Hz, 1H, H-1a). 13C NMR (CDCl3, 100 MHz) ꢀ:
–5.5, –5.4, –5.3, –4.9, 18.4, 18.6, 20.6, 20.7, 20.8, 20.9,
21.0, 24.4, 25.0, 25.8 26.9, 26.0 (3C), 26.1 (3C), 60.4, 63.0,
67.5, 68.3, 68.5, 70.1, 70.4, 70.5, 70.6, 70.7, 71.0, 71.1,
72.1, 75.1, 75.3, 94.9, 100.2, 100.6, 108.6, 109.3, 169.2,
169.9, 170.2, 170.3, 170.4.
2,3,4-Tri-O-acetyl-6-O-tert-butyldimethylsilyl-ꢁ-D-
glucopyranosyl-(1J4)-2,3-di-O-acetyl-6-O-tert-butyldi-
methylsilyl-ꢁ-D-glucopyranosyl-(1J6)-1,2:3,4-di-O-iso-
propylidene-ꢂ-D-galactopyranose (4)
The acetyl protecting groups in 3 were removed under
standard Zemplén conditions (NaOMe–MeOH) and then
tert-butyldimethylsilyl chloride (3 g, 20 mmol) was added to
a stirred solution of the deacetylated trisaccharide 3 (3 g,
5.1 mmol) in C5H5N (15 mL) at 0°C. After 1 h, additional
tert-butyldimethylsilyl chloride (1 g, 6.6 mmol) was added,
and stirring was continued at room temperature overnight
before quenching the reaction with MeOH. The mixture was
concentrated and redissolved in CH2Cl2 and washed with
1 M HCl, sat. NaHCO3, and H2O, before drying over anhyd
Na2SO4, and concentrating to an oil. This oil was treated
with Ac2O (20 mL) and C5H5N (20 mL) and the solution
was left to stir at room temperature overnight. Following
2,3,4-Tri-O-acetyl-6-bromo-6-deoxy-ꢁ-D-glucopyranosyl-
(1J4)-2,3-di-O-acetyl-6-bromo-6-deoxy-ꢁ-D-glucopyrano-
syl-(1J6)-1,2:3,4-di-O-isopropylidene-ꢂ-D-galactopyranose
(5)
Bromine (0.234 mL, 4.6 mmol) was added with stirring at
0°C to a solution of bis-silylether 4 (1.9 g, 1.9 mmol), PPh3
(1.25 g, 25.5 mmol), and CH2Cl2 (15 mL). The orange pre-
cipitate, which formed immediately, dissolved after stirring
for 19 h at room temperature, to give a clear brown solution.
© 2002 NRC Canada

Kalovidouris et al.
989
This solution was diluted with CH2Cl2 (100 mL) and was
washed with sat. NaHCO3 followed by H2O, before drying
(Na2SO4), filtering, and concentrating. Column chromatog-
raphy (SiO2, CH2Cl2:EtOAc (9:1)) gave 5 (1.6 g, 96%) as a
foamy semisolid. [ꢀ]2D0 –22.9 (c = 1 in CHCl3). HR-MS
(FAB) calcd. for C34H48Br2O19Na (M + Na): 943.1038;
at room temperature overnight. The solution was then neu-
tralized with Amberlite IR-120 (H+ form) ion exchange
resin, filtered, and concentrated.
A solution of this
deacetylated product (0.6 g, 0.76 mmol) in MeOH (50 mL)
was treated with 10% Pd(OH)2/C (300 mg) under H2 for 2 h.
The solution was filtered through a bed of Celite and the fil-
trate was concentrated to give 7 (460 mg, 90%) as an amor-
phous solid upon freeze-drying from H2O. [ꢀ]2D0 –17.9 (c = 1
in CHCl3). ES-MS (M + H): 611.4. 1H NMR (CD3OD,
500 MHz) ꢂ: 1.33, 1.34, 1.40, 1.52 (4 × s, 12H, 2 × CMe2),
2.44, 2.46 (2 × br s, 6H, 2 × NMe), 2.61 (dd, J5,6 = 8.3 Hz,
1
found: 943.1036. H NMR (CDCl3, 500 MHz) ꢂ: 1.32, 1.43,
1.49, 1.59 (4 × s, 12H, 2 × CMe2), 1.99, 2.04, 2.05, 2.06,
2.08 (5 × s, 15H, 5 × Ac), 3.32–3.36 (m, 1H, H-5b), 3.48
(dd, J5,6 = 2.6 Hz, J6,6> = 8.8 Hz, 1H, H-6b), 3.56–3.60 (m,
1H, H-5c), 3.66–3.76 (m, 1H, H-6c), 3.85 (t, J = 9.2 Hz, 1H,
H-4b), 3.91–3.93 (m, 1H, H-5a), 4.00 (dd, J5,6 = 3.5 Hz,
J6,6> = 12.7 Hz, 1H, H-6c), 2.65 (dd, J5,6 = 7.8 Hz, J6,6>
=
J6,6 = 7.8 Hz, 1H, H-6a), 4.18 (dd, J3,4 = 6.27 Hz, J4,5
=
12.6 Hz, 1H, H-6b), 2.95 (dd, J5,6 = 2.8 Hz, J6,6> = 12.7 Hz,
1H, H-6c>), 3.13 (dd, J5,6 = 2.8 Hz, J6,6> = 12.6 Hz, 1H,
H-6b>), 3.15 (t, J3,4 W J4,5 = 9.2 Hz, 1H, H-4c), 3.18–3.26 (m,
2H, H-2b, H-2c), 3.31–3.42 (m, 3H, H-3c, H-4b, H-5c),
3.44–3.54 (m, 2H, H-3b, H-5b), 3.65 (dd, J5,6 = 8.2 Hz,
J6,6> = 11.4 Hz, 1H, H-6a), 4.01–4.05 (m, 2H, H-5a, H-6a),
1.63 Hz, 1H, H-4a), 4.27–4.29 (m, 1H, H-2a), 4.57 (d, J =
7.9 Hz, 1H, H-3a), 4.58 (d, J = 7.9 Hz, 1H, H-3c), 4.9–5.3
(m, 4H, H-3b, H-3c, H-4c, H-2c), 5.48 (d, J = 4.9 Hz, 1H,
H-1a). 13C NMR (CDCl3, 125 MHz) ꢂ: 20.7, 20.8 (3C),
21.1, 24.5, 25.2, 26.1 (2C), 30.4, 31.7, 67.9, 69.4, 70.5, 70.7,
70.8, 71.4, 71.6, 71.8, 71.9, 72.9, 73.4 (2C), 76.9, 96.3, 99.9,
101.1, 108.8, 109.5, 169.0, 169.4, 169.9, 170.0, 170.4.
4.28 (dd J3,4 = 8.0 Hz, J4,5 = 1.5 Hz, H-4a), 4.30 (d, J1,2
7.8 Hz, 1H, H-1b), 4.34 (d, J1,2 = 7.9 Hz, 1H, H-1c), 4.36
(dd, J1,2 = 5.0 Hz, J2,3 = 2.4 Hz, H-2a), 4.62 (dd, J2,3
=
=
2.4 Hz, J3,4 = 8.0 Hz, 1H, H-3a), 5.51 (d, J1,2 = 4.9 Hz, 1H,
H-1a). 13C NMR (CD3OD, 125 MHz) ꢂ: 24.6, 25.1, 26.3
(2C), 36.1 (2C), 53.1, 53.5, 66.8, 68.9, 69.8, 71.9, 72.4,
73.5, 74.4, 74.7, 74.8, 75.0, 75.5, 77.8, 82.9, 97.7, 104.4,
104.8, 110.0, 110.4.
2,3,4-Tri-O-acetyl-6-N-benzyl-6-deoxy-6-methylamino-ꢁ-D-
glucopyranosyl-(1J4)-2,3-di-O-acetyl-6-N-benzyl-6-deoxy-
6-methylamino-ꢁ-D-glucopyranosyl-(1J6)-1,2:3,4-di-O-
isopropylidene-ꢀ-D-galactopyranose (6)
The dibromide 5 (0.4 g, 0.4 mmol) and N-benzyl-
methylamine (0.28 mL) were stirred together at 80°C over-
night. The next day, the reaction mixture was concentrated,
redissolved in C5H5N (2 mL) and Ac2O (2 mL), and left to
stir at room temperature overnight. The brown solution was
coevaporated with PhMe before the resulting oily liquid was
diluted in CH2Cl2 and washed consecutively with 1 M HCl,
sat. NaHCO3 and H2O, dried (Na2SO4), filtered, and concen-
trated to an oil. Column chromatography (SiO2, hexanes–
EtOAc (6:4 to 1:1)) gave 6 (0.2 g, 57%) as an amorphous
tan foam. [ꢀ]2D0 –15.8 (c = 1 in CHCl3). HR-MS (MALDI-
TOF) calcd. for C50H68N2O19 (M + H): 1001.4494; found:
6-N-Benzylmethylamino-6-deoxy-ꢁ-D-glucopyranosyl-
(1J4)-6-N-benzylmethylamino-6-deoxy-ꢁ-D-glucopy-
ranosyl-(1J6)-D-galactose (8)
The diacetonide 6 (620 mg, 785 mol) was dissolved in
90% aq TFA (5 mL) and was allowed to stir at room temper-
ature for 10 min before coevaporation with MeOH three
times. Column chromatography (C-8 reversed phase silica,
H2O to MeOH) gave 8 (445 mg, 80%) as an amorphous
solid after freeze-drying from H2O. [ꢀ]2D0 0 (c = 1 in H2O).
ES-MS (m/z): 711.5 [M + H]+. Selected 1H NMR data
(CD3OD, 500 MHz) ꢂ: 2.26 (2 × s, 6H, 2 × NMe), 2.61 (dd,
1
1001.4480. H NMR (CDCl3, 500 MHz) ꢂ: 1.29, 1.31, 1.40,
1.49 (4 × s, 12H, 2 × CMe2), 1.80, 1.94, 1.97, 1.99, 2.01 (5
× s, 15H, 5 × Ac), 2.23, 2.36 (2 × br s, 6H, 2 × NMe), 2.42–
2.58 (m, 2H, H-6c, H-6c>), 2.75–2.85 (m, 2H, H-6b, H-6b>),
3.40–3.68 (m, 6H, H-5b, H-5c, H-6a>, 3 × PhCH), 3.86–4.00
(m, 4H, H-4b, H-5a, H-6a, PhCH), 4.15 (dd, J3,4 = 6.5 Hz,
J4,5 = 1.4 Hz, 1H; H-4a), 4.28 (m, 1H, H-2a), 4.50 (d, J =
7.65 Hz, 1H, H-1b), 4.56 (dd, J3,4 = 2.25 Hz, J3,2 = 5.6 Hz,
1H, H-3a), 4.79–4.90 (m, 4H, H-2b, H-2c, H-4c, H-1c), 5.01
(t, J2,3 W J3,4 = 8.9 Hz, 1H, H-3c), 5.16 (t, J2,3 W J3,4 = 9.5 Hz,
1H, H-3b), 5.48 (d, J1,2 = 4.9 Hz, 1H, H-1a), 7.25–7.36 (m,
10H, Ar-H). 13C NMR (CDCl3, 125 MHz) ꢂ: 20.4, 20.5,
20.6, 20.7, 21.0, 24.2, 24.9, 25.5, 25.9, 42.8, 43.5, 56.5,
57.3, 62.3, 62.8, 67.5, 68.7, 70.3, 70.5, 71.4, 71.8, 72.3, 73.2
(3C), 75.6, 76.7, 76.9, 96.1, 99.3, 101.2, 108.5, 109.2, 125.0
(2C), 126.9 (4C), 128.3 (4C), 128.9 (2C), 169.5, 169.8,
169.9, 170.1, 170.4.
J5,6 = 7.9 Hz, J6,6> = 13.0 Hz, 1H, H-6c), 2.73 (dd, J5,6 =
7.5 Hz, J6,6> = 13.5 Hz, 1H, H-6b), 2.78 (dd, J5,6 = 3.5 Hz,
J6,6> = 13.0 Hz, 1H, H-6c>), 3.10 (br d, J6,6> = 13.5 Hz, 1H,
H-6b>), 3.14 (t, J3,4 W J4,5 = 9.2 Hz, 1H, H-4c), 3.21 (t, J1,2
J2,3 = 8.0 Hz, 1H, H-2c), 3.26 (dd, J1,2 = 8.0 Hz, J2,3
W
=
9.0 Hz, 1H, H-2b), 3.34 (t, J3,4 W J4,5 = 9.0 Hz, 1H, H-3c),
4.32–4.45 (m, ca. 2.5H, ꢁ-anomerics), 5.14 (d, J1,2 = 3.4 Hz,
ca. 0.5H, H-1a (ꢀ)), 7.25–7.39 (m, 10H, 2 × C6H5).
6,6>-N,N>-bis[6,6>-bis-N-benzylmethylamino-6,6>-dideoxy-ꢁ-
cellobiosyl-(1J6)-D-galactit-1-yl]-6,6>-dideoxy-6,6>-
dimethylamino-ꢁ-cellobiosyl-(1J6)-1,2:3,4-di-O-
isopropylidene-ꢀ-D-galactopyranose (9)
Acetic acid (10 L, 200 mol) was added to a solution of
the reducing sugar 8 (211 mg, 300 mol), the bismethyl-
amine 7 (70 mg, 114 mol), and sodium cyanoborohydride
(49 mg, 740 mol) in MeOH (1 mL). The reaction mixture
was stirred and heated under reflux for 8 h. Since HPLC
analysis indicated that the reaction had gone to completion,
the mixture was allowed to cool to room temperature, di-
luted with H2O (3 mL), and purified by preparative reversed
phase chromatography (15 g C-18 reversed phase,
MeOH–H2O–TFA (0:100:0.0001 to 100:0:0.0001)) to afford
6-Deoxy-6-methylamino-ꢁ-D-glucopyranosyl-(1J4)-6-
deoxy-6-methylamino-ꢁ-D-glucopyranosyl-(1J6)-1,2:3,4-
di-O-isopropylidene-ꢀ-D-galactopyranose (7)
To a methanolic (5 mL of MeOH) solution of the
pentaacetate 6 (1 g, 1 mmol), NaOMe (1mL, 0.5 M in
MeOH, 0.5 mmol) was added and the mixture was left to stir
© 2002 NRC Canada

990
Can. J. Chem. Vol. 80, 2002
pure 9 (216 mg, 94%). [ꢀ]2D0 –6.7 (c = 1 in H2O). ES-MS
(m/z): 2001.0 [M + H]+, 1001.1 [M + 2H]+2, 667.8 [M + 3H]+2,
Tris(2-{N-methyl[2,3,4-tri-O-acetyl-6-N-benzylmethyl-
amino-6-deoxy-ꢁ-D-glucopyranosyl-(1J4)-2,3-di-O-acetyl-
6-N-benzylmethylamino-6-deoxy-ꢁ-D-glucopyranosyl-(1J6)-
2,3,4,5-tetra-O-acetyl-D-galactit-1-yl]amino}ethyl)amine (15)
The zero-generation dendrimer 14 (30 mg) was dissolved
in a solution of DMAP (2 mg) in Ac2O (4 mL) and C5H5N
(4 mL) and the mixture was left to stir at room temperature
for 36 h and then concentrated by coevaporation with PhMe
before diluting with EtOAc and washing with 1 M HCl, sat.
NaHCO3 and sat. NaCl solutions, drying (Na2SO4), and con-
centrating to an oil. GPC (CHCl3:MeOH, 3:1) gave 15
(20 mg, 45%) as an oil. [ꢀ]2D0 –40 (c = 1 in MeOH).
MALDI-TOF (m/z): 3407 [M + H]+, 3429 [M + Na]+, 3446
1
500.7 [M + 4H]+4, 400.8 [M + 5H]+5. Selected H NMR data
(CD3OD, 500 MHz) ꢂ: 1.30, 1.33, 1.38, 1.50 (4 × s, 12H,
2 × CMe2), 2.70 (br s, 12H, 4 × NMeBn), 2.88 (br s, 3H,
NMe), 2.98 (br s, 3H, NMe), 3.13 (t, J3,4 W J4,5 = 9.1 Hz, 2H,
H-4f, H-4i), 3.17 (t, J3,4 W J4,5 = 9.0 Hz, 1H, H-4c), 3.37
(t, J2,3 W J3,4 = 9.1 Hz, 3H, H-3c, H-3f, H-3i), 3.44 (t, J3,4
W
J4,5 = 9.0 Hz, 3H, H-4b, H-4e, H-4f), 4.36 (m, 1H, H-2a),
4.40–4.49 (m, 6H, H-1b, H-1c, H-1e, H-1f, H-1h, H-1i),
4.62 (dd, J2,3 = 2.2 Hz, J3,4 = 7.9 Hz, 1H, H-3a), 5.51 (d,
J1,2 = 4.9 Hz, 1H, H-1a), 7.42–7.50 (m, 20H, 4 × C6H5).
Selected 13C/DEPT135/HMQC NMR data (CD3OD,
125 MHz) ꢂ: 24.6 (CMe2), 25.1 (CMe2), 26.4 (2C, CMe2),
41.8 (2C, NMeBn), 42.1 (2C, NMeBn), 42.8 (NMe), 43.4
(NMe), 58.1, 58.8 (2 × 3C, C-6b, C-6c, C-6e, C-6f, C-6h,
C-6i), 61.9 (2C, 2 × CH2Ph), 62.2 (2C, C-1d, C-1g), 62.4
(2C, 2 × CH2Ph), 69.9 (C-6a), 73.3, 73.4 (C-6d, C-6g), 76.1
(C-3b), 76.3 (C-3e, C-3h), 77.8 (3C, C-3c, C-3f, C-3i), 83.0,
83.1, 83.2 (C-4b, C-4e, C-4h), 97.7 (C-1a), 103.8, 104.5
(2C), 105.0 (2C), 105.1 (C-1b, C-1c, C-1e, C-1f, C-1h,
C-1i), 110.1, 110.5 (2 × CMe2), 130.1 (4 × C-Ar), 130.2
(2 × C-Ar), 130.3 (2 × C-Ar), 130.4 (2 × C-Ar), 130.6 (2 ×
C-Ar), 131.8 (4 × C-Ar), 132.1 (2 × C-Ar), 132.2 (2 × C-Ar)
162.9 (2 × C-Ar), 163.2 (2 × C-Ar).
1
[M + K]+. H NMR (DMF-d7, 500 MHz) ꢂ: 1.92, 1.96, 2.02,
2.05, 2.06, 2.07, 2.11, 2.12, 2.27 (9 × s, 81H, 27 × COMe),
2.4–2.6 (m, 18H, H-6), 2.74 (br s, 9H, 3 × NMe), 2.74 (br s,
9H, 3 × NMe), 2.92 (br s, 18 H, 6 × NMe), 3.91–3.96 (m,
18H, NCH2Ph), 4.28 (dd, 3H, J = 4.4 Hz, J = 7.41 Hz, H-4),
4.78 (dd, 3H, J = 7.8 Hz, J = 9.4 Hz, H-3), 4.86–4.90 (m,
3H, H-5), 5.06 (d, 3H, J = 7.9 Hz, H-1), 5.16 (t, 3H, J =
9.0 Hz, H-2), 5.22 (d, 3H, 9.0 Hz, H-1), 5.27–5.45 (m, 24H),
7.27–7.43 (m, 30H, C6H5). DEPT-135 13C NMR (DMF-d7,
125 MHz) ꢂ: 20.2, 20.4, 20.5, 20.6, 20.7, 21.0, 42.4, 42.9,
(57.2), (58.2), (62.3), (67.8), 68.3, 68.7, 69.4, 71.1, 71.8,
72.2, 72.5, 73.1, 73.5, 74.7, 77.2, 100.0, 100.5, 127.3, 128.7,
129.2, 129.3.
6,6>-N,N>-bis[6,6>-bis-N-benzylmethylamino-6,6>-dideoxy-ꢁ-
cellobiosyl-(1J6)-D-galactit-1-yl]-6,6>-dideoxy-6,6>-
dimethylamino-ꢁ-cellobiosyl-(1J6)-D-galactose (10)
The diacetonide 9 (120 mg, 60 mol) was dissolved in
90% aq TFA (5 mL) and was allowed to stir at room temper-
ature for 10 min before coevaporation with MeOH three
times. Column chromatography (C-8 reversed phase silica,
H2O to MeOH) gave 10 (90 mg, 80%) as an amorphous
solid after freeze-drying from H2O. [ꢀ]2D0 –1 (c = 1 in H2O).
ES-MS (m/z): 1920.3 [M + H]+, 961.2 [M + 2H]+2, 641.1
[M + 3H]+3, 480.9 [M + 4H]+4. Selected 1H NMR data
(CD3OD, 500 MHz) ꢂ: 4.37–4.39 (br m, ca. 6.5H,
anomerics), 5.06 (br s, ca. 0.5 H, H-1a (ꢀ)), 7.36–7.46 (m,
20H, C6H5).
Tris[2-(N-{6,6>-N,N>-bis[6,6>-bis-N-benzylmethylamino-
6,6>-dideoxy-ꢁ-cellobiosyl-(1J6)-D-galactit-1-yl]-6,6>-
dideoxy-6,6>-dimethylamino-ꢁ-cellobiosyl-(1J6)-D-galactit-
1-yl}methylamino)ethyl]amine (16)
Acetic acid (2.28 L, 45 mol) was added to a solution of
the reducing sugar 10 (90 mg, 47
mol), tris[2-
(methylamino)ethyl]amine 13 (2 mg, 12 mol), and sodium
cyanoborohydride (10 mg, 121 mol) in MeOH (1 mL). The
reaction mixture was stirred and heated under reflux for 6 h.
When HPLC analysis indicated that the reaction had gone to
completion, the mixture was allowed to cool to room tem-
perature, diluted with H2O (2 mL), and purified by prepara-
tive reversed phase chromatography (15 g C-18 reversed
phase, MeOH–H2O–TFA (0:100:0.0001 to 100:0:0.0001)) to
afford 16 (60 mg, 56%). [ꢀ]2D0 –27 (c = 1 in H2O). MALDI-
Tris(2-{N-[6-N-benzylmethylamino-6-deoxy-ꢁ-D-glucopy-
ranosyl-(1J4)-6-N-benzylmethylamino-6-deoxy-ꢁ-D-gluco-
pyranosyl-(1J6)-D-galactit-1-yl]methylamino}ethyl)amine
(14)
1
TOF (m/z): 5926.1 [M + Na]+. Selected H NMR (CD3OD,
500 MHz): ꢂ: 4.32–4.43 (m, 18H, anomerics), 7.40–7.50 (m,
60H, C6H5).
Acetic acid (2.28 L, 45 mol) was added to a solution of
the reducing sugar 8 (50 mg, 70 mol), tris[2-(methyl-
amino)ethyl]amine (13) (11) (3 mg, 19 mol), and sodium
cyanoborohydride (43 mg, 682 mol) in MeOH (1000 L).
The reaction mixture was stirred and heated under reflux for
6 h. When HPLC analysis indicated that the reaction had
gone to completion, the mixture was allowed to cool to room
temperature, diluted with H2O (2 mL), and purified by pre-
parative reversed phase chromatography (15 g C-18 reversed
phase, MeOH–H2O–TFA (0:100:0.0001 to 100:0:0.0001)) to
afford 14 (30 mg, 69%). [ꢀ]2D0 ꢃ48 (c = 1 in H2O). LR-FAB
(m/z): 2288.4 [M + H]+. Selected 1H NMR (CD3OD,
500 MHz) ꢂ: 2.77, 2.90 (2 × 3C, NMeBn), 4.36–4.40 (m,
6H, anomerics), 7.39–7.46 (m, 30H, C6H5). Selected 13C NMR
data (CD3OD, 125 MHz) ꢂ: 64.9 (C-6a), 104.5, 105.1 (C-1b,
C-1c).
Tris[2-(N-methyl{2,2>,3,3>,4>-penta-O-acetyl-6,6>-dideoxy-
6,6>-di-N-methyl-6,6>-bis[2,2>,3,3>,4>-penta-O-acetyl-6,6>-
bis-N-benzylmethylamino-6,6>-dideoxy-ꢁ-cellobiosyl-
(1J6)-2,3,4,5-tetra-O-acetyl-D-galactit-1-yl]amino-ꢁ-
cellobiosyl-(1J6)-2,3,4,5-tetra-O-acetyl-D-galactit-1-
yl}amino)ethyl]amine (17)
The first-generation dendrimer 16 (35 mg, 15 mol) was
dissolved in a solution of DMAP (2 mg) in Ac2O (4 mL)
and C5H5N (4 mL) and was left to stir at room temperature
for 36 h and then concentrated by coevaporation with PhMe
before diluting with EtOAc and washing with 1 M HCl, sat.
NaHCO3 and sat. NaCl solutions, drying (Na2SO4), and
concentrating to an oil. GPC (CHCl3:MeOH, 3:1) gave 17
(18 mg, 33%) as an oil. [ꢀ]2D01 –19 (c = 1 in H2O). MALDI-
TOF (m/z): 9078 [M + H]+. H NMR (DMF-d7, 500 MHz,
© 2002 NRC Canada

Kalovidouris et al.
991
3. I. Vrasidas, N.J. de Mol, R.M.J. Liskamp, and R.J. Pieters.
Eur. J. Org. Chem. 4685 (2001).
350 K) ꢂ: 1.34, 1.41, 1.96, 1.99, 2.02, 2.03, 2.06, 2.07, 2.09,
2.14, 2.16, 2.19, 2.21 (13 × s, 243H, 81 × COMe), 2.4–2.6
(m, 18H, H-6), 2.74 (br s, 9H, 3 × NMe), 2.77–2.81 (br s,
27H, 9 × NMe), 2.87–2.93 (br s, 36H, 12 × NMe), 3.91 (m,
36H, NCH2Ph), 4.51–4.85 (m, 41H), 5.12–5.38 (m, 41H),
5.51–5.70 (m, 41H), 7.51–7.59 and 7.89 (m, 60H, C6H5).
DEPT-135 13C NMR (DMF-d7, 125 MHz, 300 K) ꢂ: 20.3,
20.4, 20.5, 20.6, 20.8, 21.1, 47.5, 47.8, (57.0), (57.3), 64.6,
(62.0), (67.7), 68.2, 68.3, 68.6, 70.1, 71.7, 73.1, 73.4, 74.5,
76.0, 81.1, 97.2, 102.8, 103.4, 128.9, 128.9, 129.7, 129.8,
130.9, 131.2.
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Conclusion
The research we have reported in this short paper has es-
tablished that we can not only synthesize glycodendrons
containing cellobiosylgalacto residues but we can also attach
these glycodendrons to a trivalent core. These glycodendrons
and glycodendrimers add further diversity to the carbohy-
drate scaffolds we are currently constructing to display large
bioactive oligosaccharides (15) and proteins (16) in a prede-
termined and reasonably precise way on the peripheries of
such glycodendrons and glycodendrimers.
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Acknowledgements
We thank UCLA for generous financial assistance. The
material based upon the use of the Bruker Advance 500 and
the ZAB-SE spectrometers is supported by the National Sci-
ence Foundation under equipment grant no. CHE-9974928
and CHE-9808175. The MALDI-TOF data were acquired in
the Mass Spectrometry Facility at UC Riverside by Ron
New. WBT is the recipient of a Wellcome Trust International
Prize Travelling Research Fellowship.
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© 2002 NRC Canada