High-yielding microwave-assisted synthesis of triazole-linked glycodendrimers by copper-catalyzed [3+2] cycloaddition

Article abstract of DOI:10.1002/ejoc.200500216

A facile and high-yielding synthesis of multivalent 1,4-disubstituted 1,2,3-triazole-linked glycodendrimers is described. Azido carbohydrates are linked by a Cu^I-catalyzed [3+2] cycloaddition reaction to dendritic acetylenes using microwave irradiation. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500216

SHORT COMMUNICATION
High-Yielding Microwave-Assisted Synthesis of Triazole-Linked
Glycodendrimers by Copper-Catalyzed [3+2] Cycloaddition
John A. F. Joosten,[a] Niels T. H. Tholen,[a] Fatna Ait El Maate,[a] Arwin J. Brouwer,[a]
G. Wilma van Esse,[a] Dirk T. S. Rijkers,[a] Rob M. J. Liskamp,*[a] and Roland J. Pieters*[a]
Keywords: Carbohydrates / Glycosides / Dendrimers / Cycloaddition / Microwave activation
A facile and high-yielding synthesis of multivalent 1,4-disub-
stituted 1,2,3-triazole-linked glycodendrimers is described.
Azido carbohydrates are linked by a CuI-catalyzed [3+2] cy-
cloaddition reaction to dendritic acetylenes using microwave
irradiation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
timized microwave-assisted protocols for the synthesis of
the azido carbohydrates and their subsequent CuI-catalyzed
Introduction
Efficient carbohydrate conjugation to scaffold molecules
is an important goal in bio-organic chemistry. Glycoconju-
gates[1] are playing increasingly important roles in the inter-
ference with protein–carbohydrate interactions,[2] the gener-
ation of carbohydrate vaccines,[3] functionalized glycochips
and related surfaces,[4] and probes for (glyco)proteomics
purposes.[5] Multivalent display of carbohydrates is more
and more frequently used as a method to increase affin-
ities[6] in various contexts such as the binding of bacteria,[7]
bacterial toxins,[8] galectins[9] and other lectins.[10] In such
systems the carbohydrates are mostly connected to the scaf-
fold through amide[11] or thiourea linkages,[9a] by reductive
amination[12] or thiol photoaddition onto allylic systems.[13]
These methods vary in efficiency and their compatibility
with functional groups, and all yield side-products, undesir-
able in couplings involving precious carbohydrate struc-
tures. With the recent improvement of the Huisgen cycload-
dition[14] by copper catalysis,[15] this 1,4-disubstituted 1,2,3-
triazole-forming “click”[16] reaction has all of the earmarks
to become a premier conjugation method for protected and
unprotected carbohydrates. Initial studies on carbohydrates
using cycloaddition showed promise, yet thus far yields and
procedures were not optimal.[17,18] Besides the synthetic
promise, triazole moieties are also attractive connecting
units since they are known to be relatively stable to meta-
bolic degradation[19] and the triazole ring is also capable of
cycloaddition
with
acetylene-bearing
dendrimers
(Scheme 1). After optimization of the conditions, the reac-
tions were highly selective and efficient.
Scheme 1. Copper-(I)-mediated synthesis of triazole glycodendri-
mers under microwave conditions.
Results and Discussion
A systematic study was undertaken with azido carbo-
hydrogen bonding, which can be favorable in the binding of hydrates 1–9 of different character, functionalization
biomolecular targets and for solubility.[20] We here report pattern and reactivity (Scheme 2). These were subjected to
the straightforward synthesis of glycodendrimers using op- the cycloaddition reaction with dendrimers 10–16
(Scheme 3) and 19 different triazole glycodendrimers were
obtained in good yields. Furthermore, the use of unprotec-
ted carbohydrates was demonstrated as well as the straight-
forward incorporation of a fluorescent label, relevant for
biological evaluation.
[a] Department of Medicinal Chemistry, Utrecht Institute for
Pharmaceutical Sciences, Utrecht University,
P. O. Box 80082, 3508 TB Utrecht, The Netherlands
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
3182
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500216
Eur. J. Org. Chem. 2005, 3182–3185

Triazole-Linked Glycodendrimers by Copper-Catalyzed [3+2] Cycloaddition
SHORT COMMUNICATION
for the [3 + 2] cycloaddition reactions in high yields (Ն
78%). The procedure can be conveniently carried out on a
gram scale. Interestingly, the microwave irradiation proved
beneficial for both reactions as they were high-yielding and
their rate was greatly improved. The spacer-containing
azido carbohydrates 6 and 7 were prepared using a modi-
fied procedure described earlier by us,[7d] now employing
microwave irradiation. The benzoylated (2) or benzylated
compounds (3 and 7) were prepared from their acetylated
precursors.
The azido carbohydrates were treated with di- and tri-
valent first generation dendrimers (10–13), one tetravalent
second generation dendrimer (14), one nonavalent second
generation dendrimer (16) as well as a divalent dendrimer
with an NBD-fluorescent label (15). The dendritic main
structures were derived from our previously reported sys-
tems,[23] and these amino acid dendrimers were readily syn-
thesized in high yields. Their carbohydrate conjugates were
shown to be effective multivalent scaffolds, increasing the
binding potencies of their attached carbohydrates by several
orders of magnitude.[7d,9a]
Scheme 2. Overview of the azido carbohydrates used in the cyclo-
addition reactions.
Initial efforts in the copper-catalyzed coupling of the
azido carbohydrates to divalent alkyne-linked dendrimeric
structures involved overnight stirring at room temperature.
This only yielded a slow conversion to the monocoupled
product. Microwave conditions[17b,24] gave faster reactions
yielding only divalent products. Optimization of the reac-
tion conditions using CuSO4 and sodium ascorbate as the
copper(i) source led to formation of the desired triazole gly-
codendrimers in high yields (Table 1). The use of an excess
(1.5 equiv.) of the azido carbohydrate drove the reactions to
completion, while the excess could be readily recovered by
column chromatography. The relatively low product yields
The carbohydrate derivatives included the monosaccha-
ride galactose that was used without (1–3) or with (5–7) a
spacer to the azido function. Its hydroxy protecting groups
were also varied in order to evaluate this parameter. Besides
galactose, the monosaccharide glucose (4), the disaccha-
rides cellobiose (8) and lactose (9) were included. The an-
omeric glycosyl azides were prepared from their respective
peracetylated counterparts by reaction with HBr in AcOH
under microwave irradiation.[21] The resulting glycosyl bro-
mides were treated with trimethylsilyl azide and tetrabu-
tylammonium fluoride,[22] again using microwave irradia-
tion, which gave the desired peracetylated β-azido sugars
Scheme 3. Multivalent alkyne-linked dendrimers used in the cycloaddition reactions.
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R. M. J. Liskamp, R. J. Pieters et al.
SHORT COMMUNICATION
gave 8 in 99% yield. Yield for the other anomeric glycosyl azides:
1 (78%), 4 (91%) and 9 (96%).
in the reactions with unprotected glycosyl azide 6 or fluo-
rescent-labeled 15 containing the first generation dendrimer
reflects the product purification rather than the coupling
efficiency. All coupling products were fully characterized by
1H, 13C, 2D-COSY NMR and MS.
Copper-Catalyzed [2+3] Cycloadditions. General Procedure: The
dendrimer (30–100 μmol) and the azido carbohydrate (1.5 equiv.
per alkyne group), CuSO4 (30 mol-%), and sodium ascorbate
(60 mol-%), were dissolved in DMF (1–1.5 mL) containing several
drops of H2O. The solution was exposed to microwave irradiation
at 80 °C for 20 min, then concentrated and purified on a silica col-
umn eluting first with CH2Cl2/EtOAc (6:1) to recover the excess of
starting azido carbohydrate followed by elution with CH2Cl2/
MeOH (6:1) to obtain the triazole-linked glycodendrimer in the
indicated yields. For mass and NMR spectra of the produced com-
pounds see Supporting Information.
Table 1. Microwave-assisted copper(i)-mediated synthesis of tri-
azole glycodendrimers under microwave conditions.[a]
Entry Azide
Dendrimer
Product
Valency
Yield[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1
1
1
1
2
3
3
4
6
6
6
7
8
9
9
9
9
9
5
10
11
13
14
15
10
13
10
10
11
13
12
10
10
11
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
2
3
2
4
2
2
2
2
2
3
2
2
2
2
3
4
4
2
9
93
95
97
98
68
95
97
97
73
80
94
95
95
92
91
98
91
86
97
Acknowledgments
This study has been carried out with financial support from the
Commission of the European Communities, specific RTD program
Quality of Life and Management of Living Resources, QLK2-CT-
2002-01852, POLYCARB. We thank Dr. Johan Kemmink (Depart-
ment of Medicinal Chemistry, Utrecht University) for recording
500 MHz NMR spectra and Ronald D. van Ooijen (Department
of Biomolecular Mass Spectrometry, Utrecht University) for re-
cording high-resolution mass spectra.
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In conclusion, the use of straightforward microwave-as-
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carbohydrates. These were applied in a general microwave-
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Experimental Section
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3184
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Triazole-Linked Glycodendrimers by Copper-Catalyzed [3+2] Cycloaddition
SHORT COMMUNICATION
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Received: March 23, 2005
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