Click chemistry approach for the synthesis of water-soluble glycodendrimer with triazole as building unit

Article abstract of DOI:10.1055/s-0029-1217170

A new family of chiral glycodendrimers scaffolds containing di-, tetra- and octavalent glucose residues as peripheral unit and with 1,2,3-triazole as building unit has been synthesized through Cu(I)-catalyzed click chemistry by convergent approach. Georg

Full text of DOI:10.1055/s-0029-1217170

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LETTER
1417
Click Chemistry Approach for the Synthesis of Water-Soluble
Glycodendrimer with Triazole as Building Unit
Synthesis of
W
e
ater-Solub
r
le Glyco
u
dendrimer mal Rajakumar,* Ramasamy Anandhan, Venkatesan Kalpana
Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600025, India
Fax +91(44)22300488; E-mail: perumalrajakumar@hotmail.com
Received 2 February 2009
visaged AB2 monomer based on terminal alkynes and
azide compounds through the synthesis of glycodendri-
mers by convergent method.13,15
Abstract: A new family of chiral glycodendrimers scaffolds con-
taining di-, tetra- and octavalent glucose residues as peripheral unit
and with 1,2,3-triazole as building unit has been synthesized
through Cu(I)-catalyzed click chemistry by convergent approach.
The core unit bis(propargyloxy)(S)-BINOL (7) was ob-
Key words: click chemistry, glycodendrimers, chiral (S)-BINOL, tained in 92% yield, by the reaction of (S)-BINOL with
alkynes, azide, 1,2,3-triazole
propargyl bromide in the presence of K2CO3 in DMF rath-
er than the reported procedure using K2CO3 in acetone or
NaH in THF16 (Scheme 2).
Dendrimers are large regularly branched synthetic mole-
Treatment of glucose with Ac2O and ZnCl2 gave the pen-
cules, which continue to receive much attention due to
taacetate which on further treatment with 33% HBr in ace-
their unique properties and applications in medicinal and
tic acid followed by NaN3 in acetone at 60 °C gave the
glycoazide 8 in 45% yield. Reaction17 of the bis(propargyl-
oxy)(S)-BINOL (7) with two equivalents of acetylated
glycoazide 8 in the presence of CuSO4 and sodium ascor-
material chemistry. The ability to tune the properties of
dendrimers has allowed their development for use in
diverse applications including light harvesting systems,1
catalysis,2 molecular encapsulation,3 biomedical applica-
bate in water and t-BuOH mixture at room temperature
tions,4 bioconjugate chemistry,5 drug delivery,6 biomedi-
cine,7 and material science.8 Dendrimers with
carbohydrate units are important in medical and biologi-
cal fields in which multiple carbohydrate–protein
interaction9 are responsible at the molecular level, for sev-
eral critical biology events such as cellular adhesion and
recognition, physiological function regulation, and bio-
logical infections.
1
gave G0-dendrimer 1 in 97% yield (Scheme 2). In H
NMR spectrum compound 1 showed up as four singlets at
d = 1.70, 2.04, 2.06 and 2.09 ppm for the four different
glycoacetoxy protons, and as a singlet at d = 5.18 ppm for
the methylene protons attached to (S)-BINOL in addition
to aromatic protons. The 13C NMR spectrum of compound
1 displayed the four different glycoacetoxy carbons at d =
19.9, 20.6, 20.6 and 20.7 ppm, the triazole CH carbon at
d = 145.5 ppm and carbon attached to the oxygen of (S)-
BINOL unit resonated at d = 153.7 ppm. The appearance
of molecular ion peak at m/z = 1108 also confirmed the
structure of the glycodendrimer 1.
The application of click chemistry developed by
Meldal10and Sharpless11 involving the Cu(I)-catalyzed
1,3-dipolar cycloaddition of an azide to a terminal alkyne
is a rapidly emerging field in biological, material and me-
dicinal chemistry. Deguise12 and co-workers reported the
synthesis of homo- and hetero bifunctional glycodendri-
mers ending with up to 16 fucoside and/or galactoside res-
idues through convergent approach. Chabre et al.13 also
have reported glycodendrimers scaffolds containing 12
and 18 peripheral a-D-mannopyranosidic units through
click chemistry. We wish to report herein the synthesis of
(S)-BINOL-based glycodendrimers 1–6 (Scheme 1) with
1,2,3-triazole as building unit through click chemistry by
convergent approach. The core moiety of chiral bis(prop-
argyloxy)(S)-BINOL (7) plays an important role in liquid
crystals as well as in biology.14 The glycodendrimers
reported herein can be used to study protein binding and
for biological evolution of multivalent glycomimetic
inhibitors against bacterial adhesion. Exploiting Cu(I)-
catalyzed reaction for the synthesis of dendrimers, we en-
In order to synthesize the first-generation dendron, the
building unit 3,5-bis(propargyloxy)benzyl chloride (9)
was obtained from methyl 3,5-dihydroxybenzoate and
propargyl bromide in DMF in the presence of K2CO3, fol-
lowed by treatment with LiAlH4 and further with SOCl2–
py in CH2Cl2. Reaction of 3,5-bis(propargyloxy)benzyl
chloride (9) with two equivalents of acetylated carbohy-
drate azide 8 under the Cu(I)-catalyzed Huisgen ‘click re-
action’ condition gave the dendritic chloride 10 in 96%
yield (AB2-type). The use of NaN3 in a mixture of acetone
and water18 at 60 °C allowed the transformation of the
dendritic chloride 10 to the corresponding dendritic azide
11 in 98% yield.19 Reaction of the bis(propargyloxy)(S)-
BINOL core unit (7) with two equivalents of dendritic
azide 11 in the presence of the Cu(I)-catalyzed Huisgen
‘click reaction’ generated the (AB2-type) first generation
dendrimer (G1) 3 with triazole building block in 94%
yield. The IR spectrum of dendrimer 3 showed carbonyl
SYNLETT 2009, No. 9, pp 1417–1422
x
x.
x
x.
2
0
0
9
1
stretching at 1752 cm–1. In the H NMR spectrum com-
Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217170; Art ID: G02809ST
© Georg Thieme Verlag Stuttgart · New York
pound 3 showed up as four singlets at d = 1.70, 2.02, 2.04

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1418
P. Rajakumar et al.
LETTER
R
R
O
N
N
N
N
R
R
O
O
R
R
R
O
R
N
R
R
R
N
O
R
R
R
O
R
R
N
N
N
N
1 R = OAc
2 R = OH
NaOMe
MeOH–CH2Cl2–THF
N
N
O
O
N
N
N
N
N
O
O
N
O
O
R
R
R
N
N
R
N
N
R
N
N
N
R
O
N
R
O
N
O
R
R
N
N
N
O
O
O
R
N
N
R
R
R
R
R
N
R
O
O
N
N
N
N
N
R
R
R
O
R
R
N
O
N
O
O
R
R
N
N
N
R
N
N
N
O
O
O
N
O
N
N
N
N
N
N
N
R
R
O
O
R
O
R
O
O
O
N
N
N
N
R
R
N
N
N
N
N
N
N
N
R
R
R
R
O
R
O
R
R
R
R
3 R = OAc
4 R = OH
NaOMe
MeOH–CH2Cl2–THF
R
5 R = OAc
6 R = OH
NaOMe
MeOH–CH2Cl2–THF
Scheme 1
and 2.07 ppm for the four different glycoacetoxy protons,
two sharp singlets at d = 5.11 and 5.13 ppm for OCH2 and
NCH2 protons, and another sharp singlet for 4-H at d =
8.04 ppm for triazole CH carbons. The 13C NMR spectrum
of 3 displayed four different glycoacetoxy carbons at d =
20.1, 20.5, 20.5 and 20.6 ppm, the OCH2 carbon of (S)-
BINOL resonated at d = 153.6 ppm, and the four different
carbonyl carbon appeared at d = 168.9, 169.4, 169.9 and
170.5 ppm. The appearance of molecular ion peak at
m/z = 2337 also confirmed the structure of the first gener-
ation (G1) glycodendrimer 3 (Scheme 3).
i
O
O
OH
OH
7
N
N–
AcO
N
OAc
O
ii
OAc
AcO
A similar synthetic strategy was adopted for the synthesis
of second generation of dendron from the building block
of 3,5-bis(propargyloxy)benzyl chloride (9). Reaction of
the dendritic azide G1-N3 11 with the chloride 9 in the
presence of the Cu(I)-catalyzed Huisgen ‘click reaction’
condition gave the dendritic chloride 12 (AB2-type) in
93% yield. The use of NaN3 in a mixture of acetone and
water at 60 °C allowed the transformation of the desired
8
1
Scheme 2 Reagents and conditions: (i) propargyl bromide, K2CO3,
DMF, r.t., 48 h; (ii) CuSO4 (5 mol%), sodium ascorbate (10 mol%),
H2O–t-BuOH (1:1), r.t., 10 h.
Synlett 2009, No. 9, 1417–1422 © Thieme Stuttgart · New York

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LETTER
Synthesis of Water-Soluble Glycodendrimer
1419
dendritic chloride 12 to the corresponding dendritic azide dendrimers 1, 3 and 5 and the chiral deacetylated glyco-
13 in 99% yield.20 Reaction of the bis(propargyloxy)(S)- dendrimers 2, 4 and 6 were obtained in good yields by the
BINOL core unit (7) with two equivalents of dendritic application of click chemistry.
azide 13 in the presence of the Cu(I)-catalyzed Huisgen
‘click reaction’ generated the second-generation dendri-
mer (G2) 5 with triazole as building block (AB2-type) in
98% yield. Second-generation glycodendrimer 5 was
Chiroptical and UV-Absorption Studies on Enan-
tiopure Chiral Dendrimers 1–6
Molar specific rotation values were determined for glyco-
dendrimers 1–6 in DMSO at 589 nm. Acetylated glyco-
characterized from spectral and analytical data.
dendrimers 1, 3 and 5 at 10–4 M concentration showed
All the glycodendrimers 1, 3 and 5 were de-O-acetylated
molar rotation as 530.0, 481.4 and 237.4, respectively.
The chiral rotation values of all dendrimers are due to (S)-
under slightly modified Zemplen conditions21 (NaOMe,
MeOH–CH2Cl2–THF) to afford the di-, tetra-, octavalent
BINOL and the acetylated glucose units. (S)-BINOL unit
glycodendrimers 2, 4 and 6 in 95%, 92% and 92% yields,
has a molar rotation value of [a]D25–36 and the glucose
respectively. The structure of the glycodendrimers 2,22 423
unit has a molar rotation value of [a]D25 –29 at 10–4 M con-
and 624 was completely characterized from spectral and
centration and hence the observed values for dendrimer 1
analytical data. In conclusion, the chiral acetylated glyco-
R
Cl
N
O
N
O
N
N
AcO
N
OAc
O
i
O
O
OAc
AcO
N
N
N
N
O
8
9
O
AcO
OAc
AcO
OAc
AcO
OAc
AcO
OAc
10 R = Cl
ii
7
3
11 R = N3
i
9
i
AcO
OAc
OAc
OAc
AcO
AcO
O
AcO
R
N
O
OAc
N
N
N
N
N
O
O
O
O
N
N
N
N
N
N
O
O
N
N
N
N
N
N
O
OAc
AcO
O
OAc
AcO
OAc
AcO
AcO
OAc
12 R = Cl
13 R = N3
ii
7
5
i
Scheme 3 Reagents and conditions: (i) CuSO4 (5 mol%), sodium ascorbate (10 mol%), H2O–t-BuOH (1:1), r.t., 10 h; (ii) NaN3 (1.5 equiv),
acetone–H2O (4:1), 60 °C, 1–3 h.
Synlett 2009, No. 9, 1417–1422 © Thieme Stuttgart · New York

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
1420
P. Rajakumar et al.
LETTER
is the cumulative result of both effects and hence 1 dendritic wedges, which in turn is reflected in the molar
showed molar rotation as 530.0. However, on increasing rotation values. The results are given in Table 1.
the number of glucose units, the molar rotation values
should be still more positive. But the molar rotation value
Electronic absorption spectra of the acetylated glycoden-
drimers 1, 3 and 5 were recorded at a concentration of
decreases for dendrimers 3 and 5 which could be due to
the increase in torsional angle at (S)-BINOL unit which
could increase the negative rotational values and hence
the overall effect is a decrease in the molar rotation values
for dendrimers 3 and 5. Further the torsional strain is more
in dendrimer 5 due to the presence of highly branched
dendritic arms and the dendritic wedges move farther
apart and hence the observed effect. The deacetylated gly-
codendrimers 2, 4 and 6 also exhibited similar behavior at
10–4 M concentration. Glycodendrimers 2, 4 and 6 shows
the molar rotation values as 343.5, 258.1 and 75.9, respec-
tively. Molar rotation values were measured for dendri-
mers 2, 4 and 6 at three different concentrations, namely
10–3, 10–4 and 10–5 mol/L, in order to examine the possi-
bility of association. Glycodendrimer 2 showed molar ro-
tation values as 466.3, 343.5 and –3.1 at 10–3, 10–4, 10–5
mol/L, respectively, which indicates that at very low con-
centration there is no or very low degree of aggregation
and hence the dendritic wedges widens the dihedral angle
and at higher concentration (10–3 M) the presence of ag-
gregation compresses the dihedral angle of (S)-BINOL
unit and hence high positive values of molar rotation is
observed. Similarly dendrimer 4 also exhibited molar ro-
tation values as 4072.6, 258.1 and –15.0 which again in-
dicates the aggregation in the glycodendrimer 4 at high
concentration (10–3 M) and no or negligible aggregation at
lower concentration (10–5 M). Similar trends in the rota-
tion values were observed for dendrimer 6 also. In conclu-
sion the dihedral angle of (S)-BINOL unit is controlled by
the degree of aggregation as well as by branching of the
10–4 mol/L and are depicted in Figure 1. Two main bands
were observed at 283 and 337 nm. The most intense band
appears at lmax = 283 nm. The intensity of the band at 283
nm increases from dendrimers 1, 3 and 5 and the intensity
of the band at 337 nm decreases, which probably shows a
very low degree of aggregation. The deacetylated glyco-
dendrimers 2, 4 and 6 also exhibited lmax at 283 nm and
337 nm at a concentration of 10–4 mol/L (Figure 2). How-
ever intensity of the peak at 283 nm was very high for 6
which probably indicates the presence of large degree of
aggregation when compared with dendrimers 2 and 4.
Further all the dendrimers showed the 283 nm peak with
high intensity and 373 nm peak with low intensity.
Table 1 Variation of Molar Rotational Values by the Variation of
Dentritic Wedges as well as Concentration
Figure 1 Absorption intensity spectrum of the dendrimers 1, 3 and
5 at 10–4 M concentration in DMSO
25
Dendrimer Conc.
[a]D
Molecular
wt.
Molar
rotation
1
2
2
2
3
4
4
4
5
6
6
6
10–4
10–3
10–4
10–5
10–4
10–3
10–4
10–5
10–4
10–3
10–4
10–5
+47.8
1108
772
+530.0
+466.3
+343.5
–3.1
+60.4
+44.5
–0.4
772
772
+20.6
+244.6
+15.5
–0.9
2337
1665
1665
1665
4796
3451
3451
3451
+481.4
+4072.6
+258.1
–15.0
+5.7
+273.4
+3054.1
+75.9
+88.5
+2.2
Figure 2 Absorption intensity spectrum of the dendrimers 2, 4 and
6 at 10–4 M concentration in DMSO
–0.8
–105.3
Synlett 2009, No. 9, 1417–1422 © Thieme Stuttgart · New York