Synthesis of a series of glucosyl triazole derivatives and their self-assembling properties

Article abstract of DOI:10.1016/j.tetlet.2014.11.013

We report the synthesis and self-assembling properties of a new class of glucosyl triazole derivatives from glucose. The compounds are synthesized by a Cu(I) catalyzed azide/alkyne cycloaddition reaction, or the 'click' reaction. Several efficient low molecular weight organogelators were obtained in this study. We found that triazole analogs containing long alkyl hydroxyl groups and phenyl groups typically are effective in forming supramolecular gels.

Full text of DOI:10.1016/j.tetlet.2014.11.013

Accepted Manuscript
Synthesis of a series of glucosyl triazole derivatives and their self-assembling
properties
Hari P.R. Mangunuru, Jayasudhan R. Yerabolu, Dong Liu, Guijun Wang
PII:
S0040-4039(14)01895-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.013
TETL 45397
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
25 September 2014
1 November 2014
3 November 2014
Please cite this article as: Mangunuru, H.P.R., Yerabolu, J.R., Liu, D., Wang, G., Synthesis of a series of glucosyl
triazole derivatives and their self-assembling properties, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/
j.tetlet.2014.11.013
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Tetrahedron Letters
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m
Synthesis of a series of glucosyl triazole derivatives and their self-assembling properties
Hari P. R. Mangunuru, Jayasudhan R. Yerabolu, Dong Liu, Guijun Wang*
a Department of chemistry and biochemistry, Old Dominion University,
Norfolk, VA, 23529, USA
g1wang@odu.edu
ARTICLE INFO
ABSTRACT
Article history:
Received
We report the synthesis and self-assembling properties of a new class of glucosyl
triazole derivatives from glucose. The compounds are synthesized by a Cu (I)
catalyzed azide/alkyne cycloaddition reaction, or the “click” reaction. Several
efficient low molecular weight organogelators were obtained in this study. We
found that triazole analogs containing long alkyl hydroxyl groups and phenyl
groups typically are effective in forming supramolecular gels.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Hydrogelators, Organogelators, Self-assembly, Click
reaction, Glucose, Triazole
Low molecular weight gelators (LMWGs) have attracted
considerable amount of attention over the last few decades.
These small molecules can self-assemble in organic solvents
or water and form typically fibrous supramolecular
architectures that can immobilize the solvents.1-3 The main
driving forces for supramolecular gelation are non-covalent
forces such as hydrogen bonding, hydrophobic interactions, π-
π stacking, and van der Waals interactions, etc. The soft
material formed by LMWGs have potential applications in
biomedical sciences and as advanced materials.3-6 Low
molecular weight organogels and hydrogels have been studied
for a variety of applications including drug delivery and tissue
engineering and protein immobilization. 7-14
and have a great impact in bioorganic chemistry and
glycoscience.23-25 There are many studies of synthesizing
various glycoconjugates and glycomimetics using the click
chemistry and efficient enzyme inhibitors have been
obtained.26 Though
a few carbohydrate based triazole
derivatives have been shown to be effective low molecular
weight hydrogelators,27-29 a systematic study of the structure
and gelation properties of simple monosaccharide triazoles
have not been reported. In this study, we prepared a library of
peracetylated glucose triazoles and screened their gelation
properties in a series of solvents. The sugar azide building
block 3 can be synthesized in two steps from D-glucose 1
(Scheme 1). Terminal alkynes with different functional
groups were selected for the click reaction using CuSO4 and
sodium ascorbate as catalyst.
Among the various classes of small molecular gelators,
carbohydrate based gelators are of special interest to us since
they can be synthesized from naturally abundant and readily
available starting materials. We are working on the
modification of readily available monosaccharides to obtain
advanced functional materials. In our previous studies,
various glucose and glucosamine derivatives have shown
excellent gelation properties and a broad range of substituents
can be present.15-20 Here we would like to explore the effect of
introducing a triazole functional group to the sugar ring. The
triazole moiety may contribute to aromatic interactions and
hydrogen bonding which may lead to effective LMWGs, also
Scheme 1. Synthesis of sugar azide 3 from D-glucose.
The glycosyl triazoles synthesized (5-18) are shown in
Scheme 2, these include the carboxylic acids 5 and 6, the
alcohols (7-12) with different alkyl spacers to the triazole
ring, the phenyl analogues 13 and 14, long alkanes 15 and 16,
and the dimeric compounds 17 and 18. Among this series,
compounds 7 and 13 are known compounds reported in the
literature and they are glucosidase inhibitors.24-26 The gelation
they
can be synthesized by the “click” reaction
conveniently.21-22 The click chemistry has been widely used
for the discovery of novel scaffolds for drugs or new materials

2
Tetrahedron Letters
properties of these compounds were tested and the results
are shown in Table 1. Typically when compounds contain
long aliphatic spacers between the functional group and the
triazole ring, they are able to form gels in at least one of the
tested solvents. The short chain acid 5 is not a gelator, but the
analog 6 with nine methylene groups is an effective gelator
for DMSO water mixtures. The short chain alcohols 7-10 are
typically soluble in the tested solvents. With increasing chain
length, compounds 11 and 12 are effective gelators for
aqueous solutions of ethanol and DMSO. The compounds
with phenyl groups (13, 14) and aliphatic chains (15, 16)
showed gelation in at least one solvent. While the dimeric
compounds 17 and 18 are effective gelators in more solvents.
Compound 18, with one more carbon than 17, seems to be a
more versatile gelator, forming gels in most of the tested
solvents. Among all the synthesized compounds in this study,
the alcohol 12 was also able to form gel in water. Solvent
wise, in general, these compounds are more effective gelators
for polar solvents or aqueous mixtures. Only the dimer
compound 17 formed gels in toluene and ethanol, and
compounds 15 and 18 formed gels in isopropanol. We tested
different ratios of organic solvents to water, in order to obtain
the scope of the solvents. For many biological applications,
hydrogels are more desirable, but certain amount DMSO and
ethanol may also be used. The gels are typically transparent to
translucent, several representative gel photos are shown in
Figure 1.
We then studied the morphologies of some of the gels formed
by compounds 6 and 12 using optical microscopy. As shown
in Figure 2, the gels showed thin uniform fibrous network
feature, which are the typical morphology for effective
gelators. Compound 6 formed uniform fibrous networks, in
the thicker gel area fibers seem expanding from a nucleation
site (Figure 2A), and in thinner gel area entangle fibrous
networks are observed (Figure 2B). For the hydrogel formed
by compound 12, the thicker gel area showed smooth film
with fibrous feature and thinner area showed uniform narrow
fibrous networks (Figures 2C and 2D).
Fig. 2. The optical micrographs of the gels from compounds 6 and 12. A, B
are from the gel formed by compound 6 in DMSO/H2O (v1:2) at 2.5 mg/mL;
C, D are from the gel formed by compound 12 in water at 4.0 mg/mL.
We also studied the stability and elastic properties of several
gels using rheology, the results are shown in Figure 3. For the
gels formed by compounds 6, 12 and 17, all gels have their
storage moduli G' greater than loss moduli G'', which is the
typical property of soft elastic gels. This result indicated all
three gels are stable and have elastic properties. Compound
17 have higher G'/G'' value than the compounds 6 and 12,
which implies that the dimeric compound is a more effective
gelator and formed stronger gels.
Scheme 2. Synthesis of glucosyl triazoles by the CuAAC reaction. The yields
are provided after the compound numbers.
Fig. 3. The rheological measurement of the gels formed by compounds 6
(DMSO/H2O, v1:2, 6.6 mg/mL), 12 (DMSO/H2O, v1:2, 2.5 mg/mL), and 17
(EtOH/H2O, v1:2, 5.0 mg/mL).
Fig. 1. a) A transparent gel formed by compound 6 in DMSO/H2O (v1:2) at
2.5 mg/mL; b) A transparent gel formed by compound 12 in DMSO/H2O
(v1:1) at 2.0 mg/mL; c) A translucent gel formed by compound 12 in
DMSO/H2O (v1:2) at 2.5 mg/mL; d) A translucent/opaque gel formed by
compound 12 in water at 4.0 mg/mL.

Table 1. Gelation test results for the library compounds
Compound Hexane Toluene i-PrOH EtOH EtOH:H2O
(1:1)
EtOH:
H2O (1:2) H2O (1:1) H2O (1:2)
DMSO:
DMSO:
H2O
5
S
S
S
S
P
S
S
S
S
S
S
S
S
S
P
S
I
I
I
I
I
I
I
S
S
S
S
S
S
S
S
S
S
S
G 2.5
S
S
S
S
S
S
S
P
6
S
P
G 6.6
7
S
S
S
S
8
S
S
S
9
S
S
S
S
S
S
10
11
12
S
S
G 10.0
G 6.6
G 10.0
G 6.6
I
I
S
P
S
P
G 6.6
P
G 2.0
G 2.5
P
G 4.0
P
13
14
S
S
S
S
G 20.0
I
I
I
I
I
S
P
S
G 10.0
S
P
S
G 20.0
P
P
S
P
I
15
16
17
18
S
S
G 6.6
P
G 20.0
S
P
S
P
P
G 4.0
P
P
S
P
G 5.0
G 3.3
G 10.0
P
G 6.6
G 10.0
G 20.0
G 4.0
G 20.0 G 20.0
G, gel at room temperature, the numbers are the corresponding minimum gelation concentrations (MGCs) in mg/mL; I, insoluble; P, precipitate; S, soluble at
~20 mg/mL.
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were measured at their minimum gelation contractions in
DMSO:H2O (1:2).30 For each sample, the temperature of the
initial melting, half melting, and totally melted are recorded.
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MGC (mg/mL)
Melting temperatures (°C)
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6
2.5
6.6
2.5
60.0-64.0-67.0
87.0-90.0-94.0
78.0-81.0-83.0
11
12
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In summary we have designed and synthesized a series of
simple D-glucose triazole derivatives and obtained several
effective low molecular weight organogelators. These
peracetylated glucosyl triazoles were synthesized readily and
the triazole ring is an efficient functional group in the
preparation of supramolecular gelators. Though a limited
library, it is clear that dimeric compounds and glucosyl
triazoles with long chain hydroxyl group and aryl groups are
effective for gelation.
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We thank the financial support from Old Dominion University
and National Science Foundation CHE1313633.
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30. The melting points were measured using the dropping ball
method. A stainless steel ball about 3 mm in diameter (0.12g) was
placed on top of the gel in a 5 mm diameter NMR sample tube. 1.0
mL of gel sample was prepared in a vial and the hot solution was
transferred to the tube. The gel was allowed to reform in the tube.
This was then placed inside an oil bath together with a
thermometer and the temperature of the gel melting was recorded.
Supplementary Material
Experimental procedures, characterization data and NMR spectra
of compounds 4-18 are provided in the supplementary material
section.

Graphical Abstract
Leave this area blank for abstract info.
Synthesis of a series of glucosyl triazole derivatives and their self-assembling properties
Hari P. R. Mangunuru, Jayasudhan R. Yerabolu, Dong Liu, Guijun Wang*
OAc
O
N
N
N
AcO
AcO
OAc
R
R = (CH2)nOH, (CH2)nCOOH, (CH2)nCH3, (CH2)nPh
Peracetylated glucosyl triazoles are effective molecular gelators