Synthesis of Dendritic Glycoclusters and Their Applications for Supramolecular Gelation and Catalysis

Article abstract of DOI:10.1021/acs.joc.0c01978

Glycoclusters with three, four, and six arms of glycosyl triazoles were designed, synthesized, and characterized. The self-assembling properties of these molecules and their catalytic activity as ligands in copper-catalyzed azide and alkyne cycloaddition (CuAAC) reactions were studied. The compounds with a lower number of branches exhibit excellent gelation properties and can function as supramolecular gelators. The resulting gels were characterized using optical microcopy and atomic force microscopy. The glycoconjugates containing six branches showed significant catalytic activity for copper sulfate mediated cycloaddition reactions. In aqueous solutions, 1 mol % of glycoclusters to substrates was efficient at accelerating these reactions. Several trimeric compounds were found to be capable of forming co-gels with the catalytically active hexameric compounds. Using the organogels formed by the glycoconjugates as supramolecular catalysts, efficient catalysis was demonstrated for several CuAAC reactions. The metallogels with CuSO4 were also prepared as gel columns, which can be reused for the cycloaddition reactions several times. These include the preparation of a few glycosyl triazoles and aryl triazoles and isoxazoles. We expect that these sugar-based soft biomaterials will have applications beyond supramolecular catalysis for copper-catalyzed cycloaddition reactions. They may also be useful as ligands or gel matrixes for other metal-ion catalyzed organic reactions.

Full text of DOI:10.1021/acs.joc.0c01978

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Article
Synthesis of Dendritic Glycoclusters and Their Applications for
Supramolecular Gelation and Catalysis
Guijun Wang,* Dan Wang, Jonathan Bietsch, Anji Chen, and Pooja Sharma
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ABSTRACT: Glycoclusters with three, four, and six arms of glycosyl
triazoles were designed, synthesized, and characterized. The self-
assembling properties of these molecules and their catalytic activity as
ligands in copper-catalyzed azide and alkyne cycloaddition (CuAAC)
reactions were studied. The compounds with a lower number of
branches exhibit excellent gelation properties and can function as
supramolecular gelators. The resulting gels were characterized using
optical microcopy and atomic force microscopy. The glycoconjugates
containing six branches showed significant catalytic activity for copper
sulfate mediated cycloaddition reactions. In aqueous solutions, 1 mol %
of glycoclusters to substrates was efficient at accelerating these reactions.
Several trimeric compounds were found to be capable of forming co-gels
with the catalytically active hexameric compounds. Using the organogels formed by the glycoconjugates as supramolecular catalysts,
efficient catalysis was demonstrated for several CuAAC reactions. The metallogels with CuSO4 were also prepared as gel columns,
which can be reused for the cycloaddition reactions several times. These include the preparation of a few glycosyl triazoles and aryl
triazoles and isoxazoles. We expect that these sugar-based soft biomaterials will have applications beyond supramolecular catalysis for
copper-catalyzed cycloaddition reactions. They may also be useful as ligands or gel matrixes for other metal-ion catalyzed organic
reactions.
common monosaccharides have been used extensively in
many gelator designs, which have shown a variety of
applications for oil spill cleanup, dye absorption, drug delivery
and as other biomedical agents.6−10
INTRODUCTION
■
Carbohydrates contain a broad range of structural diversity,
and they are produced from renewable resources. Mono-
saccharides and disaccharides are useful as templates and
building blocks for the construction of molecular gelators,
which can self-assemble and form 3-dimensional fibrous
networks that immobilize solvents. Molecular gelators are
also called supramolecular gelators or low molecular weight
gelators (LMWGs). These compounds can self-assemble and
form reversible supramolecular gels in organic solvents or
water. The structures of these compounds can be designed to
afford certain functional soft materials by including built-in
noncovalent interactions that favor gelation and self-assembly.1
Supramolecular gels have found a variety of applications
including drug delivery, tissue engineering, enzyme immobili-
zations, pollutant removal, and catalysis.1−4 Carbohydrate
building blocks are useful for the preparation of functional
glycoconjugates that exhibit a variety of different applications
as advanced materials due to their biocompatibility and
structural diversity. Carbohydrate-based gelators have also
been designed and discovered for applications in several
research fields and showed great promise for the discovery of
novel soft biomaterials with desirable functions.5 The
functionalization of D-glucose and D-glucosamine have been
systematically studied and resulted in suitable structure
templates that can effect gelation properties.1c,5 These
Copper(I)-catalyzed azide alkyne cycloaddition (CuAAC)
reactions, also called “click reactions”, are very important in
organic synthesis, pharmaceutical chemistry, and materials
sciences.11−14 Click chemistry has been shown to be a useful
method for the construction of small and large sugar-based
1,2,3-triazole derivatives, which have had many applications in
recent years.15,16 For instance, click chemistry has been used to
synthesize many glycoclusters and glycodendrimers,17,18 such
as pentaerythritol dendrimer derivatives19 and glycoporphyrin-
cored dendrimers containing 8, 12, 16, and 24 β-D-
glucopyranose units at their peripheries.20 Using a nonsym-
metrical glycocluster core, unsymmetrical Janus glycoden-
drimers can be synthesized, which have been shown to be
useful as lectin inhibitors.21,22 Triazole-based glycoclusters
Special Issue: A New Era of Discovery in Carbohy-
drate Chemistry
Received: August 17, 2020
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Figure 1. Structures of two tetrameric glycoconjugates derived from pentaerythritol.
have received a great deal of interest over recent years. Some
glycosyl triazoles have been converted to other derivatives with
biological activities such as glycosidase inhibitors etc. Many
multivalent glycoconjugates have been designed, synthesized,
and studied for potential applications in biological sys-
tems.23−26 In addition to biomedical applications, click
chemistry is also useful for the construction of polymer-
supported covalent catalysts and functional materials.27
Because of the importance of click reactions, many studies
have been carried out to catalyze the cycloaddition reactions.
Interestingly, triazole-containing compounds have been found
to be suitable ligands to accelerate copper-catalyzed AAC
reactions.28−32 A series of tris-triazole methanol ligands, which
were covalently immobilized, were found to be useful
recyclable catalysts.33 Some triazole-containing dendritic
catalysts, which act as ligands for Cu(I) in click chemistry
and other chemistry, have been found to be capable of forming
reusable nanoreactors in water.34,35 In the studies of screening
the catalytic effects of various triazole containing ligands,
different cycloaddition rates have been observed depending the
alkyne starting material being used.36,37
Catalytically active supramolecular gelators that form gels
through noncovalent intermolecular forces, while retaining
their catalytic activity, are very attractive new materials.4,38−40
Several systems have been reported to have useful catalytic
properties, including proline-derived organogelators for
catalysis of aldol reactions, aza-Henry reactions.41,42 Gel
media, such as copper-containing polymer gels, have been
used for catalysis of click reactions.43 A topical azide−alkyne
cycloaddition reaction was also carried out using gels as
catalysts.44 A palladium carbene complex based low molecular
weight gelator was found to be useful for catalyzing Michael
additions.45 A metal−metalloporphyrin gel was used as
catalytic pocket for reactions using heterogeneous catalyst,
leading to high chemo-/stereoselectivity.46 Besides using gels, a
reusable dendrimer was found to be an effective cocatalyst for
CuAAC reactions using copper sulfate.35
In previous studies, we have found that the selective
functionalization of D-glucose or D-glucosamine at different
positions can produce effective molecular gelators. Several
series of LMWGs and functional molecular assemblies have
been discovered by introducing a triazole moiety into various
sugar molecules. Many of these derivatives were found to
effectively interact with organic solvents and solvent/water
mixtures to form supramolecular gels.47,48 We have found that
trimeric and tetrameric glycoclusters are effective molecular
gelators for a variety of organic solvents.49 Catalytic gels are
unique new materials for organic synthesis and new reaction
processes. We envisioned that triazole based gelators may be
able to catalyze copper-mediated cycloaddition reactions.
Supramolecular self-assembly results in unique nanostructures
that may have superior catalytic properties, mimicking
enzymatic reactions.
RESULTS AND DISCUSSION
■
Previously, we have shown that the branched compounds with
three or four sugar triazole units are effective gelators.49 Using
various peracetylated glucose and glucosamine units, we
systematically studied the gelation properties of two main
series of pentaerythritol derivatives. The two glucosamine-
based tetramers with ester (1) and ether (2) linkages are
shown in Figure 1. In addition, bistriazole-linked glucosamine-
based macrocycles were found to be effective at catalyzing the
copper sulfate mediated azide alkyne cycloaddition (CuAAC)
reactions.30 We envisioned that by arranging the triazole
functional groups in more densely branched molecules, unique
molecular architectures that can lead to different functions or
improved catalytic properties can be created. In this study, we
have synthesized a library of glycoclusters and analyzed their
self-assembling properties, gelation properties, and applications
as ligands for copper-catalyzed cycloaddition reactions. The
structures of the multimeric alkyne derivatives 3−10 and the
sugar azide building blocks 11−13 are shown in Figure 2.
These include the trimesic acid derivatives 3−5, tris-
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Figure 2. Structure of alkyne building blocks 3−10 and the sugar azides 11−13.
(hydroxymethyl)ethane derivative 6, pentaerythritol deriva-
tives 7 and 8, and dipentarerythritol derivatives 9 and 10. The
alkyne derivatives were synthesized in short steps from the
corresponding alcohols by alkylation with propargyl chloride
typically.
included in Figure 5. The gelation test results indicate that
effective LMWGs were obtained through rational design of
multimeric glycoconjugates. Using trimesic acid as the building
block, the ester derivatives 17 and 18 were both effective
gelators, forming gels in seven of the tested solvents. The
glucose derivatives 17 formed gels in toluene, ethanol, 2-
propanol, n-propanol, and ethanol−water mixtures. The
glucosamine derivative 18 formed gels in similar solvents,
but at relatively lower concentrations. With the trimeric ester
derivatives, it seems that the glucosamine derivative was more
effective. This is presumably due to the additional hydrogen-
bonding ability of the amide functional group. The trimeric
amide linked glucose derivative 19 only formed gels in ethanol
and n-butanol, and the glucosamine derivative 20 only formed
gels in n-propanol, n-butanol, and glycerol at 10 mg/mL. When
comparing the amide-linked derivatives 19 and 20 to the ester-
linked derivatives 17 and 18, we can conclude that the ester
linkage is more effective in the formation of supramolecular
gels. The presence of three amide functional groups generates
intermolecular interactions that are too strong and result in
precipitation rather than gelation. The hexameric glycoclusters
21 and 22 were not gelators for most of the tested solvents.
The tris(hydroxymethyl)ethane derivatives 23 and 24, which
have three sugar triazole arms, formed gels in several solvents.
Scheme 1 shows the synthesis of the alkyne building blocks
7−9. Starting from the dipropargyl diol 14, esterification with
the 5-hexynoyl chloride (prepared in situ from the
corresponding acid) afforded the tetra-alkyne 8. Alternatively,
the diol 14 was converted to the imidazole carbonate
intermediate 15 and followed by treatment with propargyl
amine afforded the tetra-alkyne 7. Compound 9 was
synthesized from the dipentaerythritol (DPE), monobenzyli-
dene acetal formation afforded the intermediate 16, which was
then converted to the compound 9 through SN2 reactions.
Using CuAAC reactions, the alkyne building blocks with
various numbers of acetylene arms, were utilized for the
synthesis of trimeric, tetrameric, and hexameric glycoconju-
gates 17−33, as shown in Figures 3 and 4.
Self-Assembly and Molecular Gelation Properties.
After the glycoclusters were synthesized, their gelation
properties were analyzed in several solvents and are listed in
Table 1. The gels typically appeared translucent for these
glycoclusters, and the photos of several representative gels are
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Scheme 1. Preparation of the Alkyne Building Blocks 7−9
Both glucose and glucosamine derivatives were able to gelate a
series of solvents at moderate concentrations. The pentaery-
thritol derivatives with the carbamate functional groups, 25
and 26, were not effective gelators as compared to the ether-
linked compound 2, but the glucosamine derivative 26 was
able to form gels in ethanol and n-butanol, making it a more
efficient gelator than the glucose derivative 25. The
pentaerythritol derivatives 27 and 28 have half ester linkages
and half ether linkages, so they can be considered as hybrids of
compounds 1 and 2. The glucose derivative 27 did not form
gels in most of the solvents, while on the other hand, the
glucosamine derivative 28 showed gelation properties in seven
of the tested solvents, showing that it has similar gelation
properties compared to compound 2. Compounds 29−33 are
derivatives synthesized from dipentaerythritol. The tetrameric
glucosamine-based glycoconjugate 29 and the deprotected
compound 30 were effective gelators for five and six of the
selected solvents, respectively. In comparison, the glucos-
amine-based hexameric glycoconjugate 32 formed gels in five
of the selected solvents, including ethanol and n-butanol. The
D-glucose and D-galactose derivatives 31 and 33, on the other
hand, were not gelators for any of the tested solvents.
in n-butanol showed smooth filmlike gels with some fibrous
network distributed on top of the film (Figure 6b). Compound
32 in DMSO/H2O (v/v 1:2) appeared to have a similar thin
film type of morphology, but with an interesting circular
arrangement of fibrous assemblies (Figure 6c). The gel also
showed similar smooth filmlike features in n-butanol but with
long and twisted fibrous networks mixed on the gel surface
(Figure 6d).
We also characterized the molecular assemblies of several
gels by AFM, and a few representative phase images are shown
in Figure 7. The gel of compound 18 in n-BuOH at 4.0 mg/
mL exhibited a braided thin fibrous network (Figure 7a,b).
The fibers appeared uniform and have a diameter of ∼50 nm.
The gel formed by compound 26 in n-butanol at 10 mg/mL,
which is more concentrated than the MGC, appeared as a thin,
porous fishnet-type of morphology, which is composed of
interconnected thin fibers. A different region of the gel showed
long and thin thread of fibers with an estimated diameter of 20
nm (Figure 7d). The gel of compound 28 in ethanol showed
more uniform fibrous assembly (Figure 7e). The gel of
hexamer compound 32 in n-butanol at 5.0 mg/mL showed a
more smooth filmlike surface composed of small fibers (Figure
7f).
The organogels formed by these clusters in alcohols
appeared mostly transparent or translucent. The morphologies
of several gels are characterized using an optical microscope, as
shown in Figure 6. The gel of compound 18 in DMSO/H2O
(v/v 1:2) showed a uniform fibrous network (Figure 6a) and
Application of the Supramolecular Dendritic Glyco-
clusters in Triazole Synthesis. In this study, we investigated
the rate acceleratory effects of a series of triazole-linked
glucosamine/glucose derivatives as ligands in copper-catalyzed
D
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Figure 3. Structures of the synthesized glycoconjugates 17−22 with a trimesic acid core structure.
azide−alkyne cycloaddition (CuAAC) reactions. The selection
of the reactions using N-acetyl glucosamine azide 12 with
phenyl acetylene and 1-octyne was based on our previous
studies that these reactions typically require longer reaction
time without added ligands.30 The results for the click reaction
of azide 12 with phenyl acetylene are shown in Table 2; the
22 were both very effective at catalyzing the CuAAC reactions,
reaching 100% conversions within 2 h, with isolated yields of
95% and 93%, respectively. The glucose derivative 21 was
slightly faster than the glucosamine derivative at 1 h, reaching
93% conversion, versus 89% conversion for hexamer 22. From
the results of these six glycoclusters, the trend is clear that the
hexamer clusters are much more effective catalysts for the
CuAAC reactions than the corresponding trimeric clusters.
The cluster derivatives based off the pentaerythritol building
blocks showed a catalytic trend similar to that of our previous
research. The tetraether compound 2 was a more efficient
gelator than the tetraester compound 1 and was also found to
be more efficient at accelerating the reaction. In the presence
of the tetraether 2, the azide 12 was fully converted to
compound 34 in 3 h. This same reaction using the tetraester 1
only achieved 85% conversion at 5 h. The trimeric glycocluster
24 was less effective in comparison to tetramer 2 as well. The
trimer glucose derivative 23 was not as efficient as the
glucosamine derivative, and the reaction using 1 mol % 23
reached 28% conversion at 1 h and 64% conversion at 4 h. The
two hybrid ether and carbamate-linked glycoconjugates 25−26
showed very similar results, reaching 100% conversion at 6 h.
However, the hybrid ether and ester linked compounds 27−28
have different effects for the CuAAC reaction. The glucos-
amine derivative 28 was found to be more effective, reaching
1
reactions were monitored by H NMR spectroscopy, and the
summarized spectra are included in Figures S1−S3. The
1
conversions were calculated using H NMR integration of the
product 34 versus the starting material 12. For instance, the
signals for the anomeric proton doublet at 4.8 and a triplet at
5.1 ppm are distinctive and separated from the product’s
anomeric signal at 6.05 ppm and a triplet 5.4 ppm (Figure S1),
so they can be used for the calculation.
As shown in Table 2, we screened all 17 glycoclusters 17−33
that were synthesized and included the fully symmetrical
pentaerythritol derived tetramers 1 and 2. All of the
glycoclusters showed significant reaction rate acceleration in
comparison to the control experiments without the addition of
ligands. We found that at 5 h the two ester-linked trimesic acid
derivatives 17 and 18 were able to help the reaction reach
100% conversion. The amide-linked glucose derivative 19 and
glucosamine derivative 20 were less effective, showing only
79% and 72% conversion at 5 h, respectively. In contrast, upon
increasing the number of triazole branches, hexamers 21 and
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Figure 4. Structures of the synthesized glycoconjugates 23−33 from pentaerythritol and dipentaerythritol building blocks.
83% conversion at 1 h, and the reaction was worked up at 6 h
and an isolated yield of 92% was obtained for the product 34.
The tetrameric glycoclusters 29 and 30 derived from
dipentaerythritol had catalytic effects comparable to other
tetrameric glycoclusters. We found the that most efficient
catalyst for the click reaction was the hexameric glucose
derivative 31; using 1 mol % of the ligand, the reaction reached
100% conversion after 30 min. With compound 31 reduced to
0.5 mol %, the reaction reached full conversion at 1 h. The
hexamer galactose and glucosamine derivatives 32−33 also
showed good activities for the reactions, reaching 100%
conversion within 2 h. These studies showed that hexameric
derivatives were more efficient ligands for copper catalyzed
cycloaddition reactions.
With the phenyl acetylene substrate analysis results, we have
observed an interesting correlation where the degree of
conjugation increases the catalytic activity. The hexamers are
generally more effective than trimers and tetramers. We also
screened the catalytic effects of selected glycoclusters for the 1-
octyne cycloaddition reaction with compound 12. The results
are shown in Table 3 and Figures S4−S8. For the 1-octyne
substrate, the effectiveness of the glycoclusters for the reaction
followed a similar trend. We found that hexamers are generally
more effective in comparison to others, but several tetrameric
derivatives were also quite efficient. The most efficient ligand
for 1-octyne was the tetrameric glycocluster 29. The reaction
reached 100% conversion at 2 h, and the hexameric clusters
were also quite efficient for the reactions, typically reaching full
conversion within 2−3 h. The other effective compounds are
the mixed pentaerythritol glucose derivatives 25 and 27. The
reaction almost reached full conversion at 4 h. The hexamer
glucose and galactose derivatives 31, 33, and glucosamine
derivative 22 also reached close to full conversion within 3 h. It
was noticed that for different alkyne substrates, the perform-
ance of the glycoclusters was quite different, with certain
ligands being more favorable than the others.
To look at the glycocluster’s catalytic versatility, we decided
to screen a reaction utilizing a different azide substate. The
reaction of 3-acetylphenyl azide 36 with phenyl acetylene was
selected for the test reaction, and the results are shown in
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a
Table 1. Gelation Properties of the Glycoconjugates Synthesized
EtOH/H2O
(1:2)
EtOH/H2O
DMSO/H2O
(1:2)
DMSO/H2O
(1:1)
cluster
Tol
EtOH
i-PrOH
n-PrOH
n-BuOH
glycerol
(1:1)
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
GT 20.0
S
P
I
P
I
Gc 10.0
I
I
I
P
I
I
I
S
I
GT 10.0
GT 6.7
Gc 6.7
P
P
P
GT* 20.0 GT 20.0
P
P
GT 20.0
P
GT 10.0
P
GT 10.0
GT 10.0
GT 4.0
P
GO 10.0
P
P
GT 20.0
GT 20.0
P
P
GT 10.0
GT 4.0
Gc* 6.7
GO 10.0
P
S
S
S
I
GT 10.0
GT 6.7
P
P
P
P
I
GO 10.0
GT 4.0
P
P
P
P
GT 10.0
GT 20.0
P
P
P
P
P
P
P
GT 5.0
P
P
P
GT 2.8
P
P
P
GO 20.0
P
P
GT 20.0
GC20.0
GC 20.0
GO 20.0
GO 20.0
GC 10.0
GC10.0
GT 20.0
GT 20.0
P
P
P
GT 10.0
GT 20.0
P
GO 5.0
P
GT 20.0
GT 10.0
GT 10.0
P
GT 5.0
P
GT 10.0
GT 10.0
P
P
P
P
GT* 20.0
P
P
GT 20.0
P
GT 20.0
GT 10.0
GT 20.0
P
P
GT 10.0
P
P
P
GT 10.0
GT* 20.0
GT 10.0
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
P
GT 20.0
GT 10.0
GT 10.0
P
P
P
GT 20.0
P
GT 10.0
P
GT 10.0
P
GT 20.0
P
GT 20.0
P
P
P
P
S
GT 10.0
S
GT 20.0
P
S
a
G, gel at room temperature; the numbers are the corresponding minimum gelation concentrations (MGCs) in mg/mL; G*, unstable gel or partial
gel; C, clear or transparent; T, translucent; O, opaque; I, insoluble; P, crystallize or precipitate; S, soluble at ∼20.0 mg/mL. All tested samples were
insoluble in hexanes, insoluble, or precipitated in water. Compound 17 also formed a translucent gel in triethylene glycol at 10.0 mg/mL.
100% conversions within 3 h and afforded isolated yields of
93% for 34 and 95% for 35. This indicated that the conditions
used in the screening reactions can be scaled up to larger scale
reactions though reaction time was longer than small scale
screening.
The scope of the substrates was also extended to include a
few other alkynes, 5-phenyl-1-pentyne A3, 1-ethynylcyclohex-
an-1-ol A4, and 6-chloro-1-hexyne A5, as shown in Scheme 2.
Using 1 mol % of the hexameric glucosyl conjugate 31, the
reactions of the sugar azide 12 with alkynes A3 and A4 reached
100% conversion within 2 h based on the 1H NMR monitoring
(Figure S13). The reactions of the 3-acetylphenyl azide 36
with A4 and A6 also reached full conversion within 1 h (Figure
1
S14). The H NMR of isolated click reaction products are
included in Figure S15.
Catalysis of the Glycoclusters in Gel Form and in
Solution Form. From the above three set of screening
reactions, we found that in general the hexameric derivatives
performed better as a ligand for the CuAAC reactions. These
compounds, however, were not effective gelators, with the
exception of the glucosamine derivative 32, which formed
several gels in alcohol and alcohol water mixtures. To explore
the effect of supramolecular assemblies, on catalysis, several
copper metallogels were created and the gels were used to
catalyze various click reactions. We found that gels formed
using compound 32 were able to accelerate the click reaction,
although the gels were not stable after adding reagents and
solvents. A combination of the stronger trimer gelators with
more catalytically active hexamer clusters can allow us to
obtain stronger supramolecular gels with superior catalytic
properties. We were interested in finding out whether the
reactions carried out in or on gels are faster than those done in
mixtures of solutions.
Figure 5. Translucent gels formed by compound 18 in (a) DMSO/
H2O (v/v 1:2) at 2.8 mg/mL, (b) compound 30 in 2-propanol at 10
mg/mL, and (c) compound 32 in n-butanol at 5.0 mg/mL.
Table 4 and Figures S9−S12. We found that the tetramers 27
and 29 and the hexamers 21−22 and 31−33 were all effective
for this reaction, reaching 100% conversion in less than 2 h.
The pentaerythritol derivatives were slightly more effective
than trimesic derivatives, showing more conversion at 1 h. The
trimeric derivatives 17 and 18 were shown to be less effective;
however, they were able to accelerate the reaction to almost
full conversion at 3 h. The control reaction only using copper
sulfate/sodium ascorbate was much slower, only reaching
about 40% at 3 h and 50% conversion at 6 h.
Synthesis of Triazoles Catalyzed by the Cluster
Ligand. After finding that all hexameric clusters are more
effective ligands for the copper-catalyzed reactions, we selected
the hexamer glucose derivative 31 (0.5 mol %) to run the click
reactions at a larger scale of 300 mg of sugar azide 12 with
phenyl acetylene and 1-octyne, and the reactions reached
In order to validate that these gels can be used as matrices
for catalysis, the cogels were prepared using the combination of
trimeric gelators with the effective hexameric catalysts which
were not gelators. After screening several mixtures using
gelators, we found that in a 2:1 molar ratio, the gelator 17 was
G
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Figure 6. (a) Optical micrographs of the gels formed by several compounds. Compound 18 in DMSO/H2O (v/v 1:2) at 4.0 mg/mL; (b)
compound 18 in n-BuOH at 4.0 mg/mL; (c) compound 32 in DMSO/H2O (v/v 1:2) at 10.0 mg/mL, (d) compound 32 in n-BuOH at 5.0 mg/
mL.
able to form a co-gel with catalyst 21, and the trimer gelator 24
was able to form a co-gel with the hexamer 33. The photos of
the cogels are included in the Figure S16. The two trimer
compounds showed better gelation properties in the
appropriate solvents. The prepared cogels were used to test
for the same click reactions. The results are shown in Table 5
entries 1−4. The reactants for these reactions are identical to
those shown in Table 1; however, these reactions were carried
out without stirring. Only gentle swirling of the vials in a
shaker was applied so the gels did not degrade. A control
experiment was set up the same way except that the gelator was
added to the mixture directly and the reaction mixture
appeared as a slurry. The reactants and reagents were added on
top of the gel or the control reaction mixture. We found that
the reactions were significantly faster in the gel phase versus
control mixture solution. At 4 h, both gels were able to
accelerate the reactions to completion. The reactions were
stopped at 8 h, and the isolated yields indicated the
effectiveness of the gel-catalyzed reaction compared to the
regular solution phased homogeneous mixtures. The results are
shown in Table 5 and Figures S16−S18. For both cogels, the
gels were more efficient for accelerating the reactions. This
indicated that the glycocluster was a more effective catalyst in
the gel form than in the slurry form, indicating that self-
assembled microstructures can be used to catalyze the
reactions.
To further explore the applications of the gelators for catalysis,
several different gelator and cluster combinations were
analyzed in order to form stable gels or cogels that can also
be used as stationary-phase catalysts. After extensive
experimental screening, the gel formed by compound 18 in
ethanol−water mixture was selected for the gel column
experiment, and this has shown good stability and reusability.
As shown in Figure 8, the gel was formed inside the column
(syringe), and then the cycloaddition reaction for compound
36 with phenyl acetylene was used as the test reaction (Scheme
3). After the stable gel was formed, the reagents were added on
top the gel matrix and allowed to elute slowly through the gel.
After the elution finished, the gel was washed with the solvents.
The combined filtrate was collected under the gel column and
analyzed by 1H NMR, which indicated 100% conversion of the
azide to the product 37 without byproduct (Figure S19). The
same procedure was repeated six times, and the gel was stable
after that cycle; the gel was further eluted with ethanol to
collect the product adsorbed on to the gel matrix, with an
overall yield of 93%. This copper-containing gel column was
efficient at catalyzing the cycloaddition reactions and can be
utilized as a reusable catalyst. The product obtained was pure
and without the need of further purification since the catalysts
were immobilized in the gel column.
The gel formed by compound 18 was also prepared and
transferred to a scintillation vial, and the same click reaction
was performed in a biphase format rather than passing through
a gel-column. The reaction was repeated five times, and the gel
Using Gel Columns for Copper-Catalyzed Cyclo-
addition Reactions. Gel Column I Formed by Gelator 18.
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Figure 7. AFM images for the gels formed by several compounds. (a, b) compound 18 in n-BuOH at 4.0 mg/mL; (c, d) compound 26 in n-BuOH
at 10.0 mg/mL; (e) compound 28 in ethanol at 10.0 mg/mL; (f) compound 32 in n-BuOH at 5.0 mg/mL.
was stable after the fifth cycle for the same reaction; the total
product was obtained in 89% yield (Figure S20).
clusters; however, the resulting gel columns became unstable
after elution with ethanol/water solvent. Various mixtures of
trimeric and hexameric glycoconjugates were tested to search
for a more stable co-gel system, capable of holding up when
flushed with solvent. After several experiments, we found the
trimer cluster compound 23 and the hexamer 31 can form a
stable co-gel in ethanol−water mixtures. This gel was prepared
and transferred to a glass syringe (gel column II) and used for
several reactions.
Gel Column II Catalyzed Reactions. Since the hexameric
glycoconjugates are typically more effective ligands for copper
catalysts, to further explore the gelator−cluster catalyst
systems, we did several gelation tests using different
combinations of the trimers with hexamers. In order for the
gels to be reused, the components of the gel need to have
certain stability in the eluting solvent. Several monotriazole-
based gelators were used to form stable gels with the hexameric
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a
Table 2. Catalytic Effects of Monomeric and Multimeric Triazole Derivatives in Click Reactions
entry PhCCH
compd
ligand (mol %)
time (h), conversion (%)
time (h), conversion (%)
isolated yields (%)
1
control
1
2
none
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
24, 50
5, 83
3, 100
5, 100
5, 100
5, 79
5, 72
1, 93
1, 89
1, 41
4, 68
4, 73
4, 79
4, 74
1, 50
4, 84
4, 95
1, 100
1, 90
2, 100
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
2, 100
2, 100
5, 64
95
93
7, 85
6, 100
6, 100
6, 82
5, 100
7, 100
92
95
2, 100
a
Typical conditions: sugar azide 1.0 equiv, 50 mg or 40 mg scale; 2.0 mL of solvent was used for all entries, phenyl acetylene (1.2 equiv to the
azide), sodium ascorbate was 2 equiv of the corresponding CuSO4·5H2O, all ratios in % are mol %, using carousel at 30 °C under N2. The percent
conversion is based on NMR integration. The information presented in Tables 3 and 4 was gathered similarly with different substrates.
Table 3. Catalytic Effects of Triazole Derivatives in Click Reaction with 1-Octyne
entry
compd
cluster (mol %)
conversion (%) (2 h)
conversion (%) (4 h)
isolated yield (%)
1
2
3
4
5
6
7
8
2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
72
29
23
46
87
62
56
78
63
77
38
100
75
98
83
51
92
44
38
76
17
18
19
22
23
24
25
26
27
28
29
30
31
32
33
100 (3 h)
81 (3 h)
68
98
85 (3 h)
95
97
9
10
11
12
13
14
15
16
48
90
100 (3 h)
95
93
The gel column II was used for the reaction of sugar azide
12 with propargyl alcohol A6 to synthesize the triazole 12-A6,
and the gel column was stable and effective for the reaction in
two cycles at least (Figure S23) and afforded isolated yields of
90% and 88% in the first and second cycles. At the end of the
second reaction, the gel was stable and could be reused for
another reaction.
Another gel column II was also prepared and was used for
the click reactions of the sugar azide 13 with propargyl alcohol
and 1-ethynylcyclohexan-1-ol (Scheme 4). The gel was
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Table 4. Catalytic Effects of Selected Glycoclusters for Click Reaction of 3-Acetylphenyl Azide
entry
compd
ligand (mol %)
conversion (%) (0.5 h)
conversion (%) (1 h)
conversion (%) (2 h)
37
conversion (%) (3 h)
1
2
3
4
5
6
7
8
9
10
N/A
17
18
19
22
27
29
31
32
33
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
18
14
34
40
89
93
72
70
100
100
100
100
100
100
100
36
35
28
87
83
82
Scheme 2. Alkyne Structures and the Triazoles Synthesized Using Cluster Ligand
Table 5. Comparison of the Gel versus Solution for Click Reaction for Compound 34
entry
gelator and amount in mol
state
gel
control
gel
conversion (%) (0.5 h)
conversion (%) (0.5 h)
conversion (%) (0.5 h)
yield (%)
1
2
3
4
21, 1.0%; 17, 2.0%
21, 1.0%; 17, 2.0%
33, 1.0%; 24, 2.0%
33, 1.0%; 24, 2.0%
33
27
31
23
76
53
90
61
95
63
100
92
93
69
91
87
control
prepared by heating the mixture of trimer 23 with hexamer 31
together in EtOH/H2O (v/v 1:1). The gel column is shown in
Figure 9. This gel column II was able to catalyze the synthesis
of compound 13-A6 in 92% yield in the first cycle. In the
second cycle, different alkyne was added to the same gel
column, and the product 13-A4 was obtained in 89% yield
(Figure S24).
Synthesis of Isoxazoles Using Gel-Columns. Using the
same procedure as shown in Figure 8a, another gel-column I
was prepared using compound 18. The cycloaddition reaction
(Scheme 5) of the 4-chlorophenyl chloroxime 38 and phenyl
acetylene was carried out. The reactants, NaAsc together with
NaHCO3, were added to the gel column, and the reaction
mixture was eluted through the gel column. The product
isoxazole 39 was obtained by collecting the filtrate from the gel
column with full conversion; however, the gel became unstable
after washing with solvent. The total collected filtrate was
concentrated, and the pure product was obtained by
chromatography in 94% yield (Supporting Information Figure
S21).
Using gel column II, the isoxazole reaction using compound
38 was carried out by eluting through the gel column (Figure
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Figure 8. (a) Gel column (I) made of compound 18 (10.0 mg, 0.007 mmol) containing CuSO4 pentahydrate (6.0 mg, 0.022 mmol) in 1.5 mL of
EtOH/H2O (v/v, 1:2); (b) reversed gel column to show the stability of gel; (c) reaction mixture was added on top of gel column: phenyl acetylene
(30 μL, 0.27 mmol), 3-acetyl phenyl azide (35.0 mg, 0.22 mmol), NaAsc (9.0 mg, 0.044 mmol) dissolved in 1.0 mL of EtOH/H2O (v/v, 1:2); (d)
after the elution of the reaction mixture; (e) at the end of the sixth round of elution.
Scheme 3. Synthesis of Triazole 37 on Gel Column I
Scheme 4. Synthesis of Triazoles 13-A4 and 13-A6 Using Gel Column II
S25) similar to that described in Figure 9, except for the
reagent for the reaction with the addition of NaHCO3. To
show the recyclability of the gel column, two separate isoxazole
syntheses were carried out on the same gel column. The first
cycle of reagents loaded to the gel was chloroxime 38 and
propargyl alcohol. The isoxazole compound 40 was obtained
by collecting the filtrate in 93% yield. After rinsing with
solvent, the same gel column II was reused for another cycle
using phenyl acetylene as the substrate, the filtrate was
collected and worked up to afford compound 39 in 92% yield
(Figure S26). Therefore, the cogels formed by the combination
of a trimer with a hexamer afforded stable gels and effective,
reusable gel catalysts.
The self-assembling properties of these compounds were
analyzed in several polar organic solvents. Many compounds
with three or four triazole branches were effective gelators,
forming gels in at least one of the tested solvents. In contrast,
the glycoclusters with six triazole sugar branches were not as
effective as gelators, with only the glucosamine derivatives
being able to form gels. The glucose and galactose analogues
were not found to be gelators. The gels showed typically
fibrous or thin film networks based on AFM characterizations.
These glycoconjugates were also studied for their effects at
accelerating CuAAC reactions of sugar azide with phenyl
acetylene and 1-octyne. We found that for phenyl acetylene, all
glycoclusters synthesized in this study showed certain rate
acceleration, with the hexameric glycoclusters being far
superior to the others. The hexameric dipentaerythritol
derivatives with glucose, glucosamine, and galactosyl triazoles
31−33 were the most effective ligands. The glucose derivative
31 was especially effective for the phenyl acetylene click
reaction and was used for the synthesis of several triazole
CONCLUSIONS
■
Three main series of branched and dendritic glycoconjugates
containing protected glucose and glucosamine triazole moieties
have been designed and synthesized through click chemistry.
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Figure 9. (a) Gel column II prepared by compound 23 (10.0 mg, 0.0074 mmol), 31 (5.0 mg, 0.0018 mmol), and CuSO4·5H2O (9.2 mg, 0.0186
mmol) in 0.8 mL of EtOH/H2O (v/v, 1:1); (b) after reaction mixture of the azide 13 (68.6 mg, 0.184 mmol) and propargyl alcohol (12.4 mg, 0.22
mmol), and NaAsc (14.8 mg, 0.074 mmol) dissolved in 2.0 mL were added EtOH/H2O (v/v, 1:1) was added to the gel; (c) after elution of the gel
column in (b); (d) after addition reaction mixture, the same as in (b) except propargyl alcohol was replaced with 1-ethynyl-1-cyclohexanol (27.3
mg, 0.22 mmol); (e) after elution of the gel in (d).
Scheme 5. Synthesis of Isoxazole Using the Gelator Catalyst
derivatives, affording high yields in a short time. The hexameric
derivatives, synthesized from trimesic acids 21−22 and some
trimeric clusters, were also effective catalysts, reaching almost
full conversion quickly, and the products were obtained in high
yields. Interestingly, the performance of the glycoclusters was
different for 1-octyne substrate in comparison to phenyl
acetylene substrate. However, the general trend of a higher
number of branches affording more effective ligands also
follows. Using 3-acetylphenyl azide as the substrate, a similar
trend was observed with all hexamers showing effectiveness for
the reaction. Several gels were prepared and studied for their
catalytic effects, and we found that the gels were able to
accelerate the reactions more efficiently than in solution.
Several click reactions were carried out using the stable copper
sulfate gels formed by compound 18 and the cogels formed by
a trimer with a hexameric cluster. These gels demonstrated
effectiveness in catalyzing CuAAC reactions and for isoxazole
synthesis; moreover, the gel columns can be reused for
different substrates or for the same substrate but reusable for at
least six cycles. The supramolecular gels from the current study
can also be useful for other catalytic reactions where copper
ions or other metal ions are used as the catalysts.
EXPERIMENTAL SECTION
■
Reagents and solvents were used as received from the suppliers. All
purifications were conducted using flash column chromatography
using 230−400 mesh silica gel with a gradient of solvent systems. H
1
NMR and proton-decoupled 13C NMR spectra were obtained with a
Bruker 400 MHz NMR spectrometer in d6-DMSO, D2O, or CDCl3.
The chemical shifts were reported using CDCl3/d6-DMSO as the
internal standard at 7.26/2.50 and 77.00/39.50 ppm, respectively. 2D
NMR experiments (HSQC, COSY) were also conducted using a 400
MHz Bruker NMR spectrometer to assist the proton and carbon
signal assignment. Structural assignments were made with additional
information from gCOSY, gHSQC, and gHMBC experiments.
Melting point measurements were carried out using a Fisher Jones
melting point apparatus. The molecular mass was measured using
LCMS on an Agilent 6120B Single Quad mass spectrometer and
LC1260 system. HRMS was acquired on a Bruker 10 Telsa APEX-Qe
Fourier-transform ion cyclotron resonance mass spectrometer
(FTICR-MS) with an Apollo II ion source using positive electrospray
ionization. Optical micrographs were obtained using an Olympus
BX60 M optical microscope and the Olympus DP73-1-51 high-
performance 17MP digital camera with pixel shifting and Peltier
cooled. The imaging software for image capturing was CellSens 1.11.
Gelation Test. Approximately 2 mg of the desired compound was
placed in a 1-dram vial, and 0.1 mL of the gelation solvent or solution
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was transferred inside the vial to attain a concentration of 20 mg/mL.
The vial was then heated until the gelator dissolved fully; sometimes,
the mixture was sonicated to help with dissolving the compound and
the mixture was allowed to cool for approximately 15 min or longer
for the gel to form. After this period, if the solution was clear, this was
recorded as soluble; if the solid reappeared, this was recorded as a
precipitate; if the sample formed a gel, then the vial was inverted; if no
solvent was flowing, this indicated that a stable gel was formed;
otherwise, this was recorded as unstable gel. If gelation occurred,
another 0.1 mL was added and the method was repeated until an
unstable gel was formed. The minimum gelation concentration
(MGC), the concentration prior to unstable gelation, was recorded.
Atomic Force Microscopy. The gels were prepared about 12 h
before sample preparation. A same gel sample was transferred to a
precleaned glass slide (1 × 5 in.) and allowed to air dry for 1 day or so
before being observed under an atomic force microscope (AFM).
AFM measurements were carried out using a Veeco Dimension 3100
atomic force microscope using tapping mode. The tips used were
Nanosensors silicon AFM probes with a resonant frequency of 340−
500 kHz and a force constant of 20−45 N m−1.
Synthesis of the Alkyne 5.53 Trimesic acid (2.10 g, 10.0 mmol, 1
equiv) was dissolved in DCM (anhydrous, 40 mL) in a 50 mL round-
bottomed flask, and the reaction mixture was cooled to 0 °C. Oxalyl
chloride (3.81 mL, 45.0 mmol, 4.5 equiv) in 0.46 mL of DMF
(anhydrous) was added to the reaction mixture over a period of 10
min. The reaction continued to stir for 4 h from 0 °C to room
temperature and then the temperature was further increased to 50 °C
in an oil bath for another 16 h. The reaction mixture became clear.
The reaction mixture was concentrated under reduced pressure to
give a crude acyl chloride as a solid and was used directly for the next
step without purification. Pyridine (2.73 mL, 35.0 mmol, 3.5 equiv),
K2CO3 (4.83 g, 35.0 mmol, 3.5 equiv), and 9 mL of DCM
(anhydrous) were added to the above prepared acyl chloride in the
given order. Dipropargylamine (3.63 mL, 35.0 mmol, 3.5 equiv) was
added to the reaction mixture at 0 °C over a period of 10 min. The
reaction was stirred at room temperature for 18 h. The reaction was
quenched with NaHCO3(3 mL, 5% aq) and extracted with DCM (20
mL × 3). Crude product was dried over Na2SO4 (anhydrous) and
purified by column chromatography using eluent from pure hexanes
to 20% EtOAc/hexanes to afford a white solid (3.52 g, 8.1 mmol,
1
81%) as the desired product (Rf = 0.6 in 50% EtOAc/hexanes): H
Synthesis of Alkyne Building Blocks 3−10. Synthesis of the
Alkyne 3.50 Trimesic acid (0.5 g, 2.3 mmol, 1 equiv) was dissolved in
10 mL of DCM (anhydrous) in a 50 mL round-bottomed flask. Oxalyl
chloride (0.91 mL, 10.35 mmol, 4.5 equiv) was added dropwise over a
period of 10 min at 0 °C. A drop of DMF (anhydrous) was added to
the reaction mixture, and the resulting solution was stirred under
reflux in an oil bath for 12 h. Excess oxalyl chloride was removed
under reduced pressure. The trimesic acyl chloride as a pale-yellow
semisolid was used in the next step without further purification.
Propargyl alcohol (0.91 mL, 16.2 mmol, 3.6 equiv) and triethyl amine
(3.79 mL, 27 mmol, 6 equiv) were dissolved in 20 mL of DCM
(anhydrous) and chilled to 0 °C. The above-prepared triacid chloride
(1.20 g, 4.5 mmol, 1 equiv) was dissolved in 10 mL of DCM
(anhydrous) and added dropwise over a period of 10 min at 0 °C.
The resulting mixture was then allowed to warm to ambient
temperature and stir for 24 h. Water (5 mL) was added to quench
the reaction and extracted with DCM (15 mL × 3). The combined
organic layers were dried over Na2SO4 (anhydrous), concentrated,
and purified by column chromatography to obtain a gray solid (1.32 g,
NMR (400 MHz, CDCl3) δ 7.80 (m, 3H), 4.31 (br s, 12H), 2.32 (s,
6H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.7, 135.8, 127.6, 77.4,
73.5, 38.1, 34.3; LCMS (ESI/Quadrupole) m/z [M + H]+ calcd for
C27H22N3O3 436, found 436.
Synthesis of Alkyne 6.54 1,1,1-Tris(hydroxymethyl)ethane (1.00 g,
8.5 mmol, 1 equiv) was added to a solution of NaH (1.36 g, 33.9
mmol, 4 equiv, 60 wt %) in anhydrous DMF (15 mL). After the
solution was stirred at 0 °C for 0.5 h, propargyl chloride (3.6 mL, 33.9
mmol, 4 equiv, 70 w% in toluene) was added to the reaction mixture.
The reaction mixture was stirred at room temperature for 1 h. The
reaction mixture was quenched with water (3 mL). Workup was
performed with EtOAc (10 mL x 3) and the combined organic layers
were dried over Na2SO4 (anhydrous), concentrated and purified by
column chromatography using eluent from 5% to 15% EtOAc/
hexanes to give a light yellow liquid (1.61 g, 6.9 mmol, 83%) as the
1
desired product (Rf = 0.55 in 30% EtOAc/hexanes): H NMR (400
MHz, CDCl3) δ 4.11 (d, J = 2.4 Hz, 3H), 3.39 (s, 6H), 2.39 (t, J = 2.4
Hz, 3H), 0.96 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 80.1,
74.0 72.7, 58.6, 40.3. 17.3; LCMS (ESI/Quadrupole) m/z [M + H]+
calcd for C14H19O3 235, found 235.
1
86%) as the desired product: mp 99.0−101.0 °C; H NMR (400
MHz, d6-DMSO) δ 8.67 (s, 3H), 5.05 (d, J = 2.4 Hz, 6H), 3.67 (t, J =
2.4 Hz, 3H); 13C{1H} NMR (100 MHz, d6-DMSO) δ 163.2, 133.9,
130.6, 78.5, 77.9, 53.4; LCMS (ESI/Quadrupole) m/z [M + H]+
calcd for C18H13O6325.1, found 325.1.
Synthesis of Intermediate 15. 1,1′-Carbonyldiimidazole (2.292 g,
14.1 mmol, 3 equiv) was dissolved in 8 mL of anhydrous THF and
added to a dried 50 mL round-bottomed flask. The reaction mixture
was cooled to 0 °C. To the mixture, compound 1449,55 (1.00 g, 4.7
mmol, 1 equiv) was dissolved in 8 mL of anhydrous THF and added
dropwise over 5 min. The resulting solution was warmed to room
temperature and stirred overnight for 16 h. THF was removed under
reduced pressure, leaving a white solid. The crude product was
dissolved in 60 mL of DCM and washed with water (30 mL × 2). The
organic layer was dried with Na2SO4 (anhydrous) and filtered, and
solvent was removed under reduced pressure. The crude product was
purified via column chromatography (SiO2) using eluent from 20% to
80% EtOAc/hexanes to afford a white solid (1.763 g, 94%) as the
desired product (compound 15, Rf = 0.25 in 60% EtOAc/hexanes):
Synthesis of the Alkyne 4.51,52 Trimesic acid (0.50 g, 2.30 mmol, 1
equiv) was dissolved in 10 mL of DCM (anhydrous) in a 50 mL
round-bottomed flask. Oxalyl chloride (0.91 mL, 10.35 mmol, 4.5
equiv) was added dropwise over a period of 10 min at 0 °C. A drop of
DMF (anhydrous) was added to the reaction mixture, and the
resulting solution was stirred under reflux in an oil bath for 12 h.
Excess oxalyl chloride was removed under reduced pressure. The
trimesic acid chloride as a pale-yellow semisolid was used in the next
step without further purification. Propargyl amine (0.45 mL, 6.6
mmol, 3 equiv) and pyridine (1.10 mL, 13.2 mmol, 6 equiv) were
dissolved in 10 mL of DCM (anhydrous) and chilled to 0 °C. The
acid chloride thus prepared (0.60 g, 2.2 mmol, 1 equiv) was dissolved
in 10 mL of DCM (anhydrous), added dropwise over a period of 10
min at 0 °C to the reaction mixture, and then allowed to warm to
ambient temperature and stir for 24 h. Solvent was removed under
reduced pressure, and the obtained residue was dissolved in ethyl
acetate (50 mL) and washed with aqueous 2 N H2SO4 (5 mL)
followed by water (5 mL) and saturated NaHCO3 solution (5 mL).
The organic layer was dried over anhydrous Na2SO4 (anhydrous),
and the solvent was evaporated to yield a white solid (0.54 g, 74%) as
1
mp 113.0−115.0 °C; H NMR (400 MHz, CDCl3) δ 8.15−8.11 (m,
2H), 7.42−7.38 (m, 2H), 7.09−7.05 (m, 2H), 4.56 (s, 4H), 4.13 (d, J
= 2.4 Hz, 4H), 3.65 (s, 4H), 2.34 (t, J = 2.4 Hz, 2H); 13C{1H} NMR
(100 MHz, CDCl3) δ 148.3, 137.0, 130.9, 117.0, 78.7, 77.2, 75.2, 67.9,
66.4, 58.7, 43.9; HRMS (ESI/ICR) m/z [M + Na]+ calcd for
C19H20N4O6Na 423.1275, found 423.1274.
Synthesis of Alkyne 7. Compound 15 (100 mg, 0.25 mmol, 1
equiv) was dissolved in THF (2 mL) and added to a dried and
nitrogen-flushed 50 mL round-bottomed flask. The reaction mixture
was cooled to 0 °C via an ice bath, and propargyl amine (40 μL, 0.625
mmol, 2.5 equiv) was then added dropwise. The reaction was warmed
to room temperature and stirred for 18 h. THF was removed under
reduced pressure, the remaining solid was dissolved in EtOAc (10
mL), followed by an aqueous workup using DI water (10 mL × 2)
and EtOAc (10 mL × 1) was carried out. The organic layers were
1
the desired product: mp 267.4−270.9 °C; H NMR (400 MHz, d6-
DMSO) δ 9.15 (t, J = 5.7 Hz, 3H), 8.44 (s, 3H), 4.10 (dd, J = 5.7, 2.5
Hz, 6H), 3.14 (t, J = 2.5 Hz, 3H); 13C{1H} NMR (100 MHz, d6-
DMSO) δ 165.6, 134.9, 129.4, 81.5, 73.5, 29.2; LCMS (ESI/
Quadrupole) m/z [M + H]+ calcd for C18H16N3O3 322.1, found
322.0.
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then treated with Na2SO4(anhydrous) and filtered, and solvent was
removed under reduced pressure. The crude product was purified via
column chromatography using eluent from pure hexanes to 60%
EtOAc/hexanes. A clear liquid (88.4 mg, 95%) was obtained as the
(3 mL) and DCM (5 mL × 2). The organic layers were combined
and dried over Na2SO4, solvent was removed, and the crude product
was purified by flash chromatography using eluent from 2% to 30%
EtOAc/hexanes to afford a light brown liquid as the desired product
(127.1 mg, 0.26 mmol, 88%); this was a 1:1 mixture of stereoisomers:
1H NMR (400 MHz, CDCl3) δ 7.52−7.44 (m, 2H), 7.41−7.30 (m,
3H), 5.44 (s, 1H), 4.22 (d, J = 2.4 Hz, 1H), 4.18−4.09 (m, 8H),
3.95−3.86 (m, 3H), 3.76 (s, 1H), 3.58−3.50 (m, 7H), 3.41 (d, J = 4.5
Hz, 2H), 3.28 (s, 1H), 2.50−2.41 (m, 4H); 13C{1H} NMR (100
MHz, CDCl3) δ 138.4, 128.9, 128.3, 126.13, 126.08, 101.82, 101.75,
80.1, 80.03, 79.99, 79.7, 74.6, 74.24, 74.15, 74.1, 71.0, 70.1, 70.01,
69.95, 69.8, 69.1, 69.0, 68.9, 58.8, 58.7, 45.2, 45.1, 39.0, 38.8; HRMS
(ESI/ICR) m/z [M + Na]+ calcd for C29H34O7Na 517.2197, found
517.2197.
1
desired product (Rf = 0.45 in 45% EtOAc/hexanes): H NMR (400
MHz, CDCl3) δ 4.99 (s, 2H), 4.15 (s, 4H), 4.11 (d, J = 2.3 Hz, 4H),
3.96 (d, J = 2.6 Hz, 4H), 3.51 (s, 4H), 2.41 (t, J = 2.3 Hz, 2H), 2.25
(t, J = 2.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.7, 79.7,
79.6, 74.5, 71.6, 68.5, 64.1, 58.7, 43.6, 30.8; HRMS (ESI/ICR) m/z
[M + Na]+ calcd for C19H22N2O6Na 397.1370, found 397.1367.
Synthesis of Alkyne 8. 5-Hexynoic acid (0.172 mL, 1.56 mmol, 2.2
equiv) was dissolved in 2 mL of anhydrous DCM with one drop of
DMF in a dried and nitrogen-flushed 50 mL round-bottomed flask.
The temperature was decreased to 0 °C, and oxalyl chloride (0.146
mL, 1.70 mmol, 2.4 equiv) was added to the reaction mixture. The
reaction stirred at 0 °C for 10 min and then warmed to room
temperature for 3 h. Compound 14 (150 mg, 0.71 mmol, 1 equiv),
K2CO3 (294 mg, 2.14 mmol, 3 equiv), and DMAP (8.7 mg, 0.071
mmol, 0.1 equiv) were dissolved in 3 mL of anhydrous DCM in a
dried and nitrogen-flushed round-bottomed flask. The temperature
was reduced to 0 °C, and the crude acid chloride was added dropwise.
The reaction was then warmed to room temperature and the reaction
stirred for 5 h. The reaction was quenched with 0.5 mL NaHCO3 (5%
aq). The reaction mixture then underwent an aqueous workup using
DCM (20 mL × 2) and DI water (20 mL × 2). The organic layers
were combined, dried with Na2SO4, and filtered, and solvent was
removed under reduced pressure, leaving a light-yellow oil. The crude
product was purified via column chromatography (SiO2) using eluent
from pure hexanes to 25% EtOAc/hexanes. A clear liquid (231.7 mg,
82%) was obtained as the desired product (Rf = 0.5 in 20% EtOAc/
Synthesis of Alkyne 10.16,26 Dipentaerythritol (400 mg, 1.57
mmol, 1 equiv) was added to a solution of NaH (409 mg, 10.23
mmol, 6.5 equiv, 60 wt %) in anhydrous DMF (3 mL) and cooled to
0 °C. Then propargyl chloride (1.08 g, 10.23 mmol, 6.5 equiv, 70 w%
in toluene) was added to the reaction mixture. The reaction mixture
was stirred at room temperature for 5 h. The TLC test indicated that
the reaction was completed. The reaction was quenched with H2O (1
mL) or NH4Cl solution. After removal of the solvent, 2 mL of water
was added to the residue and the crude was extracted with DCM (10
mL × 3). The combined organic layers were dried over Na2SO4, and
then the solvent was removed to obtain the crude product, which was
purified by flash chromatography using eluent from 2% EtOAc/
hexanes to 40% EtOAc/hexanes to afford the desired product as a
light brown oil (688.6 mg, 1.43 mmol, 91%) (Rf = 0.5 in 25% EtOAc/
hexanes): 1H NMR (400 MHz, CDCl3) δ 4.12 (d, J = 2.4 Hz, 12H),
3.51 (s, 12H), 3.38 (s, 4H), 2.41 (t, J = 2.4 Hz, 6H); 13C{1H} NMR
(100 MHz, CDCl3) δ 80.2, 74.1, 69.8, 69.2, 58.7, 45.1; LCMS (ESI/
Quadrupole) m/z [M + H]+ calcd forC28H35O7 483, found 483.
General Procedure for the Synthesis of Triazole Products.
To a 50 mL round-bottomed flask, the sugar azide and alkyne were
dissolved in t-BuOH/H2O/THF (v/v/v = 1/1/1) or EtOH/H2O (v/
v = 1/1). CuSO4 or CuSO4 pentahydrate and L-ascorbic acid sodium
salt was added to the reaction mixture. The reaction was stirred for
6−36 h at room temperature or heated at 30 or 50 °C in an oil bath
under N2 atmosphere. Solvent was removed under reduced pressure
to give the crude product. For some experiments, no phase−phase
extraction workup protocol was performed, after solvent was removed,
the crude product was directly loaded to the column for purification.
For most of the experiments, workup was performed by DCM and
water. The organic layers were then combined, dried with
Na2SO4(anhydrous), and filtered, and the solvent was removed
under reduced pressure. The crude product was purified by flash
column chromatography (SiO2) using pure DCM to 5−15% MeOH/
DCM solvent system as the eluent to afford the desired triazole cluster
compound. Only the amount of reagent, solvent, reaction conditions,
and characterization of the final cluster products (Rf value, melting
point, 1H and 13C NMR, and mass spectra data) are provided for each
experiment.
1
hexanes): H NMR (400 MHz, CDCl3) δ 4.11 (d, J = 2.4 Hz, 6H),
3.39 (s, 6H), 2.39 (t, J = 2.4 Hz, 3H), 0.96 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 80.1, 74.0, 72.7, 58.6, 40.3, 17.3; HRMS (ESI/
ICR) m/z [M + Na]+ calcd for C23H28O6Na 423.1778, found
423.1778.
Synthesis of Compound 16. Dipentaerythritol (2.0 g, 7.85 mmol,
2 equiv) was dried by coevaporation with toluene (5 mL × 2)
followed by addition of benzaldehyde (413 mg, 3.93 mmol, 1 equiv),
PTSA monohydrate (137.5 mg, 0.80 mmol, 0.2 equiv), and 15 mL of
anhydrous DMF. The mixture was stirred for 20 h at 90 °C under
nitrogen. The reaction mixture was cooled to room temperature and
then quenched by addition of saturated NaHCO3 solution (5 mL).
The solvent was removed under vacuum to afford the crude product,
which was purified by column chromatography using eluent from pure
DCM to 8% MeOH/DCM to afford a white solid as compound 16
(774 mg, 2.26 mmol, 58%). When 1 equiv of the dipentaerytritol (2.0
g, 7.85 mmol, 1 equiv), benzaldehyde (827 mg, 7.85 mmol, 1 equiv),
and PTSA monohydrate (137.5 mg, 0.80 mmol, 0.1 equiv) were
added via a similar procedure the desired product 16 was obtained in
40% yield (1.08 g, 3.16 mmol, 40%) together with a significant
amount of the dimeric benzylidene acetal. Compound 16 was
obtained as a mixture of 1:1 stereoisomers, inseparable by flash
chromatography (Rf = 0.55 in 10% MeOH/DCM): mp 112.0−119.0
Synthesis of Trimeric Triazole Linked Cluster 17. Sugar azide 1148
(125 mg, 0.335 mmol, 3.3 equiv), alkyne 3 (33 mg, 0.102 mmol, 1
equiv), CuSO4 pentahydrate (15.3 mg, 0.061 mmol, 0.6 equiv), L-
ascorbic acid sodium salt (24.1 mg, 0.122 mmol, 1.2 equiv), and 6 mL
of solvent mixture of t-BuOH/H2O/THF (v/v/v = 1/1/1) were used.
The reaction mixture was stirred at room temperature for 24 h. The
crude was purified by column chromatography with MeOH/DCM
(1% to 3%) to afford a white solid (125 mg, 86%) as the desired
1
°C; H NMR (400 MHz, CDCl3) δ 7.49−7.31 (m, 5 H), 5.42 (s,
1H), 4.71−4.53 (m, 1H), 4.23−4.16 (m, 3H), 3.98−3.88 (m, 2H),
3.87−3.77 (m, 2H), 3.69 (d, J = 5.4 Hz, 1H), 3.61 (s, 1H), 3.47−3.35
(m, 7H), 3.29−3.25 (m, 2H), 3.17 (s, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 139.19, 139.16, 129.1, 128.5, 126.7, 126.6 101.2,
71.5, 71.1, 70.9, 70.2, 69.8, 69.5, 61.8, 61.5, 61.3, 60.4, 46.31, 46.30;
HRMS (ESI/ICR) m/z [M + Na]+ calcd for C17H26O7Na 365.1571,
found 365.1570.
1
product (Rf = 0.2 in 2% MeOH/DCM): mp 216.0−218.0 °C; H
Synthesis of Alkyne 9. Compound 16 (100 mg, 0.29 mmol, 1
equiv) was added to a solution of NaH (52 mg, 60 wt % in mineral
oil, 1.32 mmol, 4.5 equiv) in anhydrous DMF (3 mL) and cooled to 0
°C. Then propargyl chloride (0.10 mL, 1.32 mmol, 70 wt % in
toluene, 4.5 equiv) was added to the reaction mixture. The reaction
mixture was stirred at room temperature for 4 h at which time TLC
indicated completion of reaction. The reaction was cooled to 0 °C
and quenched with 1 mL of water. The solvent was removed, and the
crude product was obtained by phase extraction of using water H2O
NMR (400 MHz, CDCl3) δ 8.83 (s, 3H, phenyl-H), 7.95 (s, 3H,
triazole-H), 5.89 (d, J = 8.8 Hz, 3H, H-1), 5.53−5.46 (m, 6H,
−CH2O−), 5.45−5.38 (m, 6H, H-2, H-3), 5.24 (t, J = 9.8 Hz, 3H, H-
4), 4.30 (dd, J = 12.6, 4.9 Hz, 3H, Ha-6), 4.15 (dd, J = 12.6, 1.8 Hz,
3H, Hb-6), 4.04−3.98 (m, 3H, H-5), 2.06 (s, 9H), 2.05 (s, 9H), 2.01
(s, 9H), 1.83 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.5,
169.9, 169.3, 168.8, 164.5, 143.1, 135.1, 130.9, 122.7, 85.8 (C-1), 75.3
(C-5), 72.6 (C-3), 70.3 (C-2), 67.7 (C-4), 61.5 (C-6), 58.4
O
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(−CH2O−), 20.7, 20.50, 20.48, 20.1; HRMS (ESI/ICR) m/z [M +
2Na]2+ calcd for [C60H69N9O33Na2]2+/2 744.6891, found 744.6904.
Synthesis of Trimeric Triazole Linked Cluster 18. Sugar azide 1247
(189 mg, 0.495 mmol, 3.3 equiv), alkyne 3 (50 mg, 0.150 mmol, 1
equiv), CuSO4 (14 mg, 0.090 mmol, 0.6 equiv) L-ascorbic acid
sodium salt (36 mg, 0.180 mmol, 1.2 equiv), and 6 mL of solvent
mixture of t-BuOH/H2O/THF (v/v/v = 1/1/1) were used. The
reaction mixture was stirred at room temperature for 24 h. Solvent
was removed under reduced pressure, and the crude product was
purified via column chromatography using eluent from pure DCM to
7% MeOH/DCM. A white solid (184 mg, 83%) was obtained as the
desired product (Rf = 0.4 in 5% MeOH/DCM): mp 246.0−248.0 °C;
1H NMR (400 MHz, d6-DMSO) δ 8.65 (s, 3H, phenyl-H), 8.43 (s,
3H, triazole-H), 8.03 (d, J = 9.1 Hz, 3H, −NH−), 6.14 (d, J = 9.9 Hz,
3H, H-1), 5.48 (s, 6H, −CH2O−), 5.35 (t, J = 9.7 Hz, 3H, H-3), 5.09
(t, J = 9.7 Hz, 3H, H-4), 4.64−4.53 (m, 3H, H-2), 4.27−4.20 (m, 3H,
H-5), 4.18−4.11 (m, 3H, Ha-6), 4.09−4.02 (m, 3H, Hb-6), 2.01 (s,
9H), 1.99 (s, 9H), 1.94 (s, 9H), 1.55 (s, 9H, CH3 in −NHAc);
13C{1H} NMR (100 MHz, d6-DMSO) δ 170.0, 169.5, 169.4, 169.2,
163.7, 141.7, 133.8, 130.8, 124.0, 84.7 (C-1), 73.4 (C-5), 72.2 (C-3),
68.0 (C-4), 61.7 (C-6), 58.4 (−CH2O−), 52.1 (C-2), 22.2, 20.4, 20.3,
(10 mL) and DCM (10 mL × 2). The crude product was purified via
column chromatography using eluent from pure DCM to 10%
MeOH/DCM. A white solid (430 mg, 81%) was obtained as the
desired product (Rf = 0.35 in 3% MeOH/DCM): mp 165.7−166.8
1
°C; H NMR (400 MHz, CDCl3) δ 8.11−8.00 (m, 9H), 6.05−5.90
(m, 6H), 5.58 (t, J = 9.3 Hz, 6H), 5.53−5.41 (m, 6H), 5.35−5.23 (m,
6H), 4.84−4.64 (m, 6H), 4.60−4.43 (m, 6H), 4.36−4.26 (m, 6H),
4.23−4.00 (m, 12H), 2.12−1.98 (m, 54H), 1.92−1.80 (m, 18H);
13C{1H} NMR (100 MHz, CDCl3) δ 170.6, 170.1, 169.9, 169.4,
169.0, 168.9, 143.8, 143.3, 136.7, 127.5, 122.7, 122.3, 85.7, 75.1, 72.7,
70.7, 70.5, 67.9, 61.8, 43.6, 39.1, 20.7, 20.5, 20.2. HRMS (ESI/ICR)
m/z [M + 2Na]2+ calcd for [C111H135N21O57Na2]2+/2 1359.9048,
found 1359.9023.
Synthesis of Hexameric Triazole Linked Cluster 22. Alkyne 5
(65.3 mg, 0.15 mmol, 1.0 equiv), sugar azide 12 (390 mg, 10.5 mmol,
7.0 equiv), CuSO4 pentahydrate (45.0 mg, 0.18 mmol, 1.2 equiv), L-
ascorbic acid sodium salt (72 mg, 0.36 mmol, 2.4 equiv), and 6 mL of
EtOH/water (v/v = 1/1) were used. The reaction mixture was stirred
at room temperature for 24 h. Solvent was removed to give the crude
product, which was worked up by DCM (10 mL × 3) and water (3
mL). The crude product was purified by column chromatography
using eluent from pure DCM to 15% MeOH/DCM to give a white
solid (301 mg, 0.11 mmol, 75%) as the desired product (Rf = 0.2 in
20.2; HRMS (ESI/ICR) m/z [M
+
2Na]2+ calcd for
[C60H72N12O30Na2]2+/2 743.2131, found 743.2134.
Synthesis of Trimeric Triazole Linked Cluster 19.56 Sugar azide 11
(191 mg, 0.513 mmol, 3.3 equiv), alkyne 4 (50 mg, 0.157 mmol, 1
equiv), CuSO4 (14 mg, 0.094 mmol, 0.6 equiv), L-ascorbic acid
sodium salt (36 mg, 0.188 mmol, 1.2 equiv), and 6 mL of a solvent
mixture of t-BuOH/H2O/THF (v/v/v = 1/1/1) were used. The
reaction mixture was stirred at room temperature for 24 h. An off-
white solid (178 mg, 79%) was obtained as the desired product (Rf =
0.4 in 5% MeOH/DCM): mp 165.0−167.0 °C; 1H NMR (400 MHz,
CDCl3) δ 8.34 (t, J = 5.4 Hz, 3H, −NH−), 8.12 (s, 3H, triazole-H),
8.09 (s, 3H, phenyl-H), 5.94 (d, J = 9.4 Hz, 3H, H-1), 5.75 (t, J = 9.4
Hz, 3H, H-2), 5.43 (t, J = 9.4 Hz, 3H, H-3), 5.31 (t, J = 9.4 Hz, 3H,
H-4), 4.84−4.70 (m, 6H, −CH2NH−), 4.31 (dd, J = 12.7, 5.1 Hz,
3H, Ha-6), 4.13 (dd, J = 12.7, 1.9 Hz, 3H, Hb-6), 4.10−4.04 (m, 3H,
H-5), 2.05 (s, 9H), 2.01 (s, 9H), 1.98 (s, 9H), 1.76 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3) δ 170.5, 170.0, 169.44, 169.36, 166.1,
146.0, 134.5, 128.5, 121.5, 85.8 (C-1), 75.0 (C-5), 72.9 (C-3), 70.5
(C-2), 67.8 (C-4), 61.8 (C-6), 35.8 (−CH2NH−), 20.60, 20.55, 20.1;
1
10% MeOH/DCM): mp 210.0−213.2 °C; H NMR (400 MHz, d6-
DMSO) δ 8.33 (s, 6H), 8.06 (d, J = 8.4 Hz, 6H), 7.79 (s, 3H), 6.17−
6.00 (m, 6H), 5.43−5.32 (m, 6H), 5.12 (t, J = 8.8 Hz, 6H), 4.84−
4.43 (m, 12H), 4.41−4.00 (m, 24H), 2.06−1.88 (m, 54H), 1.64−1.54
(m, 18H); 13C{1H} NMR (100 MHz, d6-DMSO) δ 170.0, 169.6,
169.2, 136.4, 143.3, 85.0, 79.2, 78.9, 78.6, 73.4, 72.1, 68.0, 61.8, 52.2,
43.6, 22.2, 20.3, 20.2. HRMS (ESI/ICR) m/z [M + 2Na]2+ calcd for
[C111H141N27O51Na2]2+/2 calcd for 1356.9527, found 1356.9533.
Synthesis of Trimeric Triazole Linked Cluster 23. Alkyne 6 (50
mg, 0.214 mmol, 1.0 equiv), sugar azide 11 (318 mg, 0.854 mmol, 4.0
equiv), CuSO4 pentahydrate (32 mg, 0.128 mmol, 0.6 equiv), L-
ascorbic acid sodium salt (51.4 mg, 0.257 mmol, 1.2 equiv), and 6 mL
of EtOH/water (v/v = 1/1) were used. The reaction mixture was
stirred at room temperature for 17 h. Solvent was removed to give the
crude product, which was worked up by DCM (10 mL × 3) and water
(3 mL). The crude product was purified by column chromatography
using eluent from 1% MeOH/DCM to 5% MeOH/DCM to afford a
white solid (255 mg, 0.188 mmol, 88%) as the desired product (Rf =
0.18 in 2% MeOH/DCM): mp 121.0−122.5 °C; 1H NMR (400
MHz, CDCl3) δ 7.90 (s, 3H), 5.99 (d, J = 9.3 Hz, 3H), 5.53 (t, J = 9.4
Hz, 3H), 5.44 (t, J = 9.4 Hz, 3H), 5.37−5.28 (m, 3H), 4.67−4.55 (m,
6H), 4.32 (dd, J = 12.6, 5.0 Hz, 3H), 4.17 (dd, J = 12.6, 2.0 Hz, 3H),
4.11−4.04 (m, 3H), 3.42−3.30 (m, 6H), 2.08 (s, 9H), 2.04 (s, 9H),
2.03 (s, 9H), 1.81 (s, 9H), 0.92 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 170.5, 170.0, 169.4, 168.8, 146.2, 121.2, 85.6, 75.0, 73.0,
72.9, 70.3, 67.9, 64.8, 61.6, 40.7, 20.63, 20.57, 20.5, 20.1, 17.5; HRMS
(ESI/ICR) m/z [M + 2Na]2+ calcd for [C56H75N9O30Na2]2+/2 calcd
for 699.7202, found 699.7196.
LCMS (ESI/Quadrupole) m/z [M
+
H]+ calcd for
C60H73N12O301440.4, found 1441.4.
Synthesis of Trimeric Triazole Linked Cluster 20. Sugar azide 12
(286 mg, 0.769 mmol, 3.3 equiv), alkyne 4 (75 mg, 0.233 mmol, 1
equiv), CuSO4 pentahydrate (35 mg, 0.140 mmol, 0.6 equiv), L-
ascorbic acid sodium salt (55.4 mg, 0.280 mmol, 1.2 equiv), and 6 mL
of solvent mixture of t-BuOH/H2O/THF (v/v/v = 1/1/1) were used.
The reaction mixture was stirred at room temperature for 24 h. A
green precipitate was observed in the reaction mixture. The reaction
mixture was filtered, and the precipitate was washed with DI water
(10 mL) and DCM (10 mL). Light green solid (226 mg, 67%) was
obtained as the desired product: mp 259.0−261.0 °C (sample turned
1
Synthesis of Trimeric Triazole Linked Cluster 24. Alkyne 6 (50
mg, 0.214 mmol, 1.0 equiv), sugar azide 12 (318 mg, 0.854 mmol, 4.0
equiv), CuSO4 pentahydrate (32 mg, 0.128 mmol, 0.6 equiv), L-
ascorbic acid sodium salt (51.4 mg, 0.257 mmol, 1.2 equiv), and 6 mL
of EtOH/water (v/v = 1/1) were used. The reaction mixture was
stirred at room temperature for 17 h. Solvent was removed to give the
crude product, which was worked up by DCM (10 mL × 3) and water
(3 mL). The crude product was purified by column chromatography
using eluent from 1% MeOH/DCM to 5% MeOH/DCM to afford a
white solid (245 mg, 0.180 mmol, 85%) as the desired product (Rf =
0.18 in 5% MeOH/DCM): mp 150.0−152.5 °C; 1H NMR (400
MHz, CDCl3) δ 7.92 (s, 3H), 6.92 (d, J = 8.9 Hz, 3H), 6.18 (d, J =
9.8 Hz, 3H), 5.51 (t, J = 9.9 Hz, 3H), 5.32 (t, J = 9.7 Hz, 3H), 4.70−
4.59 (m, 3H), 4.57−4.47 (m, 6H), 4.33 (dd, J = 12.7, 4.7 Hz, 3H),
4.23−4.16 (m, 3H), 4.14−4.07 (m, 3H), 3.27 (s, 6H), 2.10−2.00 (m,
27H), 1.72 (s, 9H), 0.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 171.0, 170.7, 170.6, 169.4, 145.5, 122.2, 85.6, 75.0, 72.6, 72.5, 68.1,
64.2, 61.8, 53.5, 40.6, 22.7, 20.7, 20.64, 20.60, 17.5; HRMS (ESI/
brown at 180 °C and started melting at 259.0 °C); H NMR (400
MHz, d6-DMSO) δ 9.35−9.14 (m, 3H, -NH-CH2), 8.48 (s, 3H,
phenyl-H), 8.16 (s, 3H, triazole-H), 8.05 (d, J = 8.8 Hz, 3H, −NH−),
6.10 (d, J = 9.7 Hz, 3H, H-1), 5.34 (t, J = 9.7 Hz, 3H, H-3), 5.07 (t, J
= 9.7 Hz, 3H, H-4), 4.65−4.43 (m, 9H, H-2, −NHCH2), 4.28−3.94
(m, 9H, H-5, Ha-6, Hb-6), 2.00 (s, 9H), 1.97 (s, 9H), 1.93 (s, 9H),
1.58 (s, 9H, CH3 in −NHAc); 13C{1H} NMR (100 MHz, d6-DMSO)
δ 169.9, 169.5, 169.4, 169.2, 165.3, 134.5, 128.8, 121.9, 84.5 (C-1),
73.3 (C-5), 72.3 (C-3), 67.9 (C-4), 61.7 (C-6), 52.0 (C-2), 34.8
(−NH-CH2), 22.2, 20.4, 20.3, 20.1; HRMS (ESI/ICR) m/z [M +
2Na]2+ calcd for [C60H75N15O27Na2]2+/2 741.7371, found 741.7379.
Synthesis of Hexameric Triazole Linked Cluster 21. Alkyne 5 (87
mg, 0.2 mmol, 1 equiv), sugar azide 11 (491.2 mg, 1.32 mmol, 6.6
equiv), CuSO4 pentahydrate (60 mg, 0.24 mmol, 1.2 equiv, L-ascorbic
acid sodium salt (95 mg, 0.48 mmol, 2.4 equiv), and 3 mL of ethanol/
water mixture (v/v = 1/1) were used. The reaction mixture was
stirred at room temperature for 30 h. The reaction mixture was then
diluted with DCM (10 mL) and underwent a workup using DI water
P
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ICR) m/z [M + 2Na]2+ calcd for [C56H78N12O27Na2]2+/2 calcd for
698.2442, found 698.2453.
under reduced pressure. The crude product was purified via column
chromatography using 5% MeOH/DCM to 7.5% MeOH/DCM. A
white solid (198.6 mg, 81%) was obtained as the desired product (Rf
Synthesis of Tetrameric Triazole Linked Cluster 25. Alkyne 7 (45
mg, 0.12 mmol, 1 equiv), sugar azide 11 (197 mg, 0.53 mmol, 4.4
equiv), CuSO4 pentahydrate (24 mg, 0.10 mmol, 0.8 equiv), L-
ascorbate sodium salt (38 mg, 0.19 mmol, 1.6 equiv), and 3 mL of t-
BuOH/H2O/THF (v/v/v = 1/1/1) were used. The reaction mixture
was stirred at 30 °C in an oil bath for 24 h. Solvent was removed
under reduced pressure. Crude product was purified via column
chromatography using pure DCM to 15% MeOH/DCM. Product was
further recrystallized in reagent alcohol. A white solid (161 mg, 72%)
was obtained as the desired product (Rf = 0.45 in 5% MeOH/DCM):
1
= 0.45 in 7.5% MeOH/DCM): mp 142.6−145.1 °C; H NMR (400
MHz, CDCl3) δ 8.08 (s, 2H), 7.78 (s, 2H), 7.34 (d, J = 9.2 Hz, 2H),
7.02 (d, J = 9.2 Hz, 2H), 6.28−6.16 (m, 4H), 5.62−5.56 (m, 4H),
5.39−5.24 (m, 4H), 4.79−4.62 (m, 4H), 4.57 (s, 4H), 4.39−4.31 (m,
4H), 4.25−4.10 (m, 8H), 4.09−3.96 (m, 4H), 3.50−3.39 (m, 4H),
2.81−2.68 (m, 4H), 2.37−2.25 (m, 4H), 2.12−2.04 (m, 36H), 2.01−
1.90 (m, 4H), 1.78−1.72 (m, 12H). 13C{1H} NMR (100 MHz,
CDCl3) δ 172.7, 171.1, 170.9, 170.7, 170.6, 170.6, 170.53, 169.5,
169.4, 147.4, 145.0, 122.4, 120.6, 85.6, 85.6, 74.9, 72.8, 72.4, 68.3,
68.3, 68.2, 64.1, 62.8, 61.8, 53.5, 53.3, 43.5, 33.2, 24.6, 24.3, 22.8,
22.7, 20.7, 20.6, 20.6. HRMS (ESI/ICR) m/z [M + 2Na]2+ calcd for
[C79H108N16O38Na2]2+/2 calcd for 967.3397, found 967.3402.
1
mp 134.3−135.8 °C; H NMR (400 MHz, CDCl3) δ 7.90 (s, 4H),
6.01 (d, J = 9.0 Hz, 2H), 5.92 (d, J = 8.8 Hz, 2H), 5.86−5.67 (br s,
2H), 5.24−5.61 (m, 12H), 4.67−4.54 (m, 4H), 4.52−4.27 (m, 8H),
4.25−3.99 (m, 12H), 3.42 (s, 4H), 2.12−2.00 (m, 36H), 1.92−1.80
(m, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.52, 170.50,
170.0, 169.9, 169.4, 169.1, 168.9, 156.3, 145.9, 145.7, 121.4, 120.9,
85.7, 85.6, 75.1, 75.0, 72.80, 72.75, 70.4, 70.3, 68.7, 67.9, 67.8, 64.7,
63.9, 61.7, 44.0, 36.5, 20.64, 20.61, 20.55, 20.52, 20.49, 20.13, 20.07;
Synthesis of Tetrameric Triazole Linked Cluster 29. Alkyne 9
(100 mg, 0.20 mmol, 1.0 equiv), sugar azide 12 (332 mg, 0.89 mmol,
4.4 equiv), CuSO4 pentahydrate (41 mg, 0.16 mmol, 0.8 equiv), L-
ascorbic acid sodium salt (64 mg, 0.8 mmol, 1.6 equiv), and 3 mL of
EtOH/H2O (v/v = 1/1) were added to a 50 mL round-bottomed
flask. The reaction mixture was stirred at room temperature for 24 h.
Solvent was removed to give the crude product. An aqueous workup
was carried out using DCM (10 mL × 3) and DI water (10 mL). The
crude product was purified by column chromatography using eluent
from 1% MeOH/DCM to 6% MeOH/DCM to afford white solid
(327 mg, 0.16 mmol, 82%) as the desired product (Rf = 0.3 in 5%
MeOH/DCM). The cluster contains 1:1 stereoisomers of the
H R M S ( E S I / I C R ) m /z [ M
+
2 N a ] 2 + c a l c d f o r
[C75H98N14O42Na2]2+/2 calcd for 956.2873, found 956.2881.
Synthesis of Tetrameric Triazole Linked Cluster 26. Alkyne 7 (45
mg, 0.12 mmol, 1 equiv), sugar azide 12 (197 mg, 0.53 mmol, 4.4
equiv), CuSO4 pentahydrate (24 mg, 0.10 mmol, 0.8 equiv), L-
ascorbate sodium salt (38 mg, 0.19 mmol, 1.6 equiv), and 3 mL of t-
BuOH/H2O/THF (v/v/v = 1/1/1) were used. The reaction mixture
was stirred at 30 °C in an oil bath for 32 h. Solvent was removed
under reduced pressure. The crude product was purified via column
chromatography using pure DCM to 8% MeOH/DCM. A white solid
(191 mg, 85%) was obtained as the desired product (Rf = 0.5 in 7.5%
MeOH/DCM): mp 235.0−238.0 °C (sample turned brown at 215
°C, an melted at 235.0−238.0 °C); 1H NMR (400 MHz, d6-DMSO)
δ 8.26 (s, 2H), 8.16−7.97 (m, 6H), 7.79−7.62 (m, 2H), 6.16−6.07
(m, 4H), 5.36 (t, J = 9.7 Hz, 4H), 5.10 (dt, J = 9.7, 5.4 Hz, 4H),
4.72−4.41 (m, 8H), 4.30−3.92 (m, 20H), 3.48−3.37 (m, 4H), 2.06−
1.91 (m, 36H), 1.62−1.55 (m, 12H); 13C{1H} NMR (100 MHz, d6-
DMSO) δ 170.0, 169.5, 169.4, 169.3, 156.1, 145.3, 144.1, 122.6,
121.5, 84.62, 84.56, 73.4, 72.4, 68.9, 68.0, 64.2, 63.1, 61.7, 52.1, 43.6,
35.8, 22.3, 22.2, 20.4, 20.3, 20.3. HRMS (ESI/ICR) m/z [M + 2Na]2+
calcd for [C75H102N18O38Na2]2+/2 calcd for 954.3193, found
954.3192.
1
benzylidene acetal: mp 133.0−151.0 °C; H NMR (400 MHz, d6-
DMSO) δ 8.34−8.21 (m, 4H), 8.10−8.00 (m, 4H), 7.48−7.29 (m,
5H), 6.13 (d, J = 9.8 Hz, 4H), 5.47−5.32 (m, 5H), 5.10 (t, J = 9.7 Hz,
4H), 4.70−4.40 (m, 12H), 4.29−3.99 (m, 12H), 3.97−3.78 (m, 4H),
3.75−3.56 (m, 2H), 3.41 (s, 6H), 3.28−3.13 (m, 4H), 2.05−1.93 (m,
36H), 1.58 (s, 12H). 13C{1H} NMR (100 MHz, d6-DMSO) δ 169.9,
169.5, 169.4, 169.3, 144.3, 138.5, 128.6, 127.9, 126.1, 122.6, 100.7,
84.6, 73.4, 72.3, 68.9, 68.0, 64.1, 61.7, 52.0, 45.2, 22.2, 20.4, 20.3,
20.2. HRMS (ESI/ICR) m/z [M
+
2Na]2+ calcd for
[C85H114N16O39Na2]2+/2 calcd for 1014.3607, found 1014.3601.
Synthesis of Tetrameric Triazole Linked Cluster 30. Compound
29 (150 mg, 0.076 mmol, 1.0 equiv) was dissolved in acetic acid (3
mL, 66% aq). The reaction mixture was stirred at room temperature
for 12 h. The mixture solvent was removed to give the crude product,
which was purified by column chromatography using eluent from 1%
MeOH/DCM to 6% MeOH/DCM to afford white solid (98 mg,
0.051 mmol, 68%) as the desired product (Rf = 0.1 in 5% MeOH/
DCM): mp 149.3−151.8 °C; 1H NMR (400 MHz, d6-DMSO) δ 8.24
(s, 4H), 8.06 (d, J = 9.1 Hz, 4H), 6.17−6.07 (m, 4H), 5.37 (t, J = 9.8
Hz, 4H), 5.10 (t, J = 9.7 Hz, 4H), 4.67−4.55 (m, 4H), 4.52−4.43 (m,
8H), 4.29−4.11 (m, 12H), 4.11−4.03 (m, 4H), 3.43−3.35 (m, 12H),
2.05−1.92 (s, 36H), 1.62−1.55 (s, 12H); 13C{1H} NMR (100 MHz,
d6-DMSO) δ 170.0, 169.5, 169.4, 169.3, 144.5, 144.4, 122.6, 122.4,
84.6, 79.2, 78.9, 78.6, 73.4, 72.3, 69.2, 68.0, 64.2, 61.7, 60.6, 52.0,
45.6, 45.2, 22.2, 20.4, 20.3, 20.2. HRMS (ESI/ICR) m/z [M + 2Na]2+
calcd for [C78H110N16O39Na2]2+/2 calcd for 970.3450, found
970.3452.
Synthesis of Tetrameric Triazole Linked Cluster 27. Alkyne 8 (50
mg, 0.13 mmol, 1 equiv), sugar azide 11 (213 mg, 0.57 mmol, 4.4
equiv), CuSO4 pentahydrate (26 mg, 0.10 mmol, 0.8 equiv), L-
ascorbate sodium salt (42 mg, 0.20 mmol, 1.6 equiv), and 3 mL of t-
BuOH/H2O/THF (v/v/v = 1/1/1) were used. The reaction mixture
was stirred at 30 °C in an oil bath for 20 h. Solvent was removed
under reduced pressure. Crude product was purified via column
chromatography using pure DCM to 5% MeOH/DCM. A white solid
(190.5 mg, 77%) was obtained as the desired product (Rf = 0.55 in 5%
MeOH/DCM): mp 104.2−106.5 °C; 1H NMR (400 MHz, CDCl3) δ
8.02 (s, 2H), 7.69 (s, 2H), 6.02 (d, J = 9.3 Hz, 2H), 5.92 (d, J = 9.1
Hz, 2H), 5.56 (t, J = 9.4 Hz, 2H), 5.50−5.27 (m, 10H), 4.67−4.57
(m, 4H), 4.36−4.28 (m, 4H), 4.21−4.14 (m, 4H), 4.13−4.08 (m,
6H), 4.07−4.02 (m, 2H), 3.54−3.46 (m, 4H), 2.77 (dt, J = 7.5, 1.6
Hz, 4H), 2.37 (t, J = 7.4 Hz, 4H), 2.10−2.05 (m, 18H), 2.05−2.02
(m, 18H), 2.02−1.97 (m, 4H), 1.86 (s, 6H), 1.82 (s, 6H); 13C{1H}
NMR (100 MHz, CDCl3) δ 172.7, 170.5, 170.5, 169.94, 169.88,
169.43, 169.38, 168.82, 168.75, 147.8, 145.5, 121.6, 119.5, 85.62,
85.56, 77.2, 75.0, 72.8, 72.7, 70.31, 70.27, 68.6, 67.8, 64.8, 62.7, 61.6,
43.6, 33.2, 24.8, 24.3, 20.60, 20.58, 20.55, 20.51, 20.50, 20.47, 20.1,
Synthesis of Hexameric Triazole Linked Cluster 31.16 Alkyne 10
(31 mg, 0.065 mmol, 1.0 equiv), sugar azide 11 (140 mg, 0.40 mmol,
6.2 equiv), CuSO4 pentahydrate (23 mg, 0.078 mmol, 1.2 equiv), L-
ascorbic acid sodium salt (39.6 mg, 0.16 mmol, 2.4 equiv), and 4 mL
of EtOH/water (v/v = 1/1) were used. The reaction mixture was
stirred at 30 °C in an oil bath for 14 h. Solvent was removed to give
the crude product, which was worked up by DCM (10 mL × 3) and
water (3 mL). The crude product was purified by column
chromatography using eluent 0.5% MeOH/DCM to 5% MeOH/
DCM to afford a white solid (155 mg, 0.057 mmol, 89%) as the
desired product (Rf = 0.35 in 5% MeOH/DCM): mp 120.3−122.5
°C; 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 6H), 6.09 (d, J = 9.4 Hz,
6H), 5.62 (t, J = 9.3 Hz, 6H), 5.56−5.38 (m, 12H), 4.60 (q, J = 12.4
Hz, 12H), 4.32 (dd, J = 12.4, 4.7 Hz, 6H), 4.22−4.09 (m, 12H), 3.47
(s, 12H), 3.27 (s, 4H), 2.19−1.99 (m, 54H), 1.76 (s, 18H); 13C{1H}
NMR (100 MHz, CDCl3) δ 170.5, 170.0, 169.5, 168.7, 146.0, 122.0,
20.0. HRMS (ESI/ICR) m/z [M
+
2Na]2+ calcd for
[C79H104N12O42Na2]2+/2 calcd for 969.3078, found 969.3078.
Synthesis of Tetrameric Triazole Linked Cluster 28. Alkyne 8 (50
mg, 0.13 mmol, 1 equiv), sugar azide 12 (213 mg, 0.57 mmol, 4.4
equiv), CuSO4 pentahydrate (26 mg, 0.10 mmol, 0.8 equiv), L-
ascorbate sodium salt (42 mg, 0.20 mmol, 1.6 equiv), and 3 mL of t-
BuOH/H2O/THF (v/v/v = 1/1/1) were used. The reaction mixture
was stirred at 30 °C in an oil bath for 24 h. The solvent was removed
Q
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85.5, 74.9, 73.0, 70.4, 69.0, 67.9, 64.9, 61.7, 45.6, 20.60, 20.57, 20.5,
20.0. HRMS (ESI/ICR) m/z [M
sodium ascorbate (32.2 mg, 0.16 mmol, 0.2 equiv) was added. The
+
2Na]2+ calcd for
mixture was stirred with 500 rpm at 30 °C under N2. The reaction
[C112H148N18O61Na2]2+/2 calcd for 1383.4408, found 1383.4386.
Synthesis of Hexameric Triazole Linked Cluster 32. Alkyne 10
(40 mg, 0.083 mmol, 1.0 equiv), sugar azide 12 (191 mg, 0.51 mmol,
6.2 equiv), CuSO4 pentahydrate (25.5 mg, 0.10 mmol, 1.2 equiv), L-
ascorbic acid sodium salt (39.6 mg, 0.20 mmol, 2.4 equiv), and 5 mL
of EtOH/water (v/v = 1/1) were used. The reaction mixture was
stirred at 50 °C in an oil bath for 7 h. Solvent was removed to give the
crude product, which was worked up by DCM (10 mL × 3) and water
(3 mL). The crude product was purified by column chromatography
using eluent from 0.5% MeOH/DCM to 10% MeOH/DCM to afford
white solid (191 mg, 0.07 mmol, 85%) as the desired product (Rf =
0.6 in 10% MeOH/DCM): mp 180.2−182.8 °C; 1H NMR (400
MHz, d6-DMSO) δ 8.24 (s, 6H), 8.07 (d, J = 8.9 Hz, 6H), 6.13 (d, J =
9.8 Hz, 6H), 5.37 (t, J = 9.8 Hz, 6H), 5.10 (t, J = 9.7 Hz, 6H), 4.67−
4.55 (m, 6H), 4.46 (s, 12H), 4.26−4.11 (m, 12H), 4.10−4.01 (m,
6H), 2.06−1.88 (s, 54H), 1.58 (s, 18H); 13C{1H} NMR (100 MHz,
d6-DMSO) δ 170.0, 169.6, 169.5, 169.3, 144.4, 122.6, 84.6, 73.5, 72.4,
69.0, 68.0, 64.1, 61.7, 52.1, 45.2, 22.2, 20.4, 20.2. HRMS (ESI/ICR)
m/z [M + 2Na]2+ calcd for [C112H154N24O55Na2]2+/2 calcd for
1380.4888, found 1380.4870.
1
was completed in 3 h as indicated by H NMR monitoring. Solvent
was removed, and DCM (30 mL) was added to the reaction, fwhich
was then washed with water (10 mL × 3), dried over anhydrous
Na2SO4, concentrated, and purified by column chromatography using
eluent from pure DCM to 5% MeOH/DCM to give a white solid
(369 mg, 0.760 mmol, 95%, Rf = 0.42 in 5% MeOH/DCM) as the
desired product.
Synthesis of Triazoles 12-A3, 12-A4, 36-A4, and 36-A5 Using
Cluster 31. These reactions were carried out using the Radley 12 plus
carousel reaction station equipped with 20 mL reaction tube. The
general procedure: Azide (80 mg, 1 equiv), alkyne (1.2 equiv), and
compound 31 (0.01 equiv) were dissolved in 4 mL of solvent
EtOH:H2O (v/v = 1/1) in a carousel reaction tube, followed by
addition of CuSO4 pentahydrate (0.1 equiv) and sodium ascorbate
(0.2 equiv). The reaction mixture was stirred at 30 °C for 1−2 h
under N2 atmosphere. The reaction was monitored by 1H NMR.
When the reaction was completed, solvent was removed, followed by
addition of H2O (1 mL), and extraction was performed with DCM (5
mL × 3) in a separatory funnel. The organic layers were dried over
anhydrous Na2SO4. The residue obtained was purified by column
chromatography to afford the desired product.
Synthesis of Triazole 12-A3. The reaction was completed in 1 h.
Compound 12 (80 mg, 0.22 mmol, 1 equiv), 5-phenyl-1-pentyne
(37.2 mg, 0.26 mmol, 1.2 equiv), compound 31 (6.0 mg, 0.0022
mmol, 0.01 equiv), CuSO4 pentahydrate (5.5 mg, 0.022 mmol, 0.1
equiv), and sodium ascorbate (8.8 mg, 0.044 mmol, 0.2 equiv) were
used. The residue obtained was purified by column chromatography
using eluent from pure DCM to 3% MeOH/DCM to afford a white
solid (107 mg, 0.21 mmol, 95%) as the desired product (Rf = 0.50 in
5% MeOH/DCM).
Synthesis of Triazole 12-A4. The reaction was completed in 2 h.
Compound 12 (80 mg, 0.22 mmol,1 equiv), cyclohexanol-1- ethynyl
(32.0 mg, 0.26 mmol, 1.2 equiv), compound 31 (6.0 mg, 0.0022
mmol, 0.01 equiv), CuSO4 pentahydrate (5.5 mg, 0.022 mmol, 0.1
equiv), and sodium ascorbate (8.8 mg, 0.044 mmol, 0.2 equiv) were
used. The product was partially soluble in water and some was lost to
aqueous phase; the isolated pure compound was obtained as a white
solid (73 mg, 68%).
Synthesis of Triazole 36-A4. The reaction was completed in 1 h.
Compound 36 (80 mg, 0.50 mmol,1 equiv), cyclohexanol-1-ethynyl
(74.0 mg, 0.60 mmol, 1.2 equiv), compound 31 (13.6 mg, 0.005
mmol, 0.01 equiv), CuSO4 pentahydrate (12.5 mg, 0.05 mmol, 0.1
equiv), and sodium ascorbate (20.0 mg, 0.10 mmol, 0.2 equiv) were
used. The residue obtained was purified by column chromatography
using eluent from 10% EtOAc/hexanes to 50% EtOAc/hexanes to
afford a white solid (136 mg, 0.48 mmol, 96%) as the desired product
(Rf = 0.45 in 60% EtOAc/hexanes).
Synthesis of Triazole 36-A5. The reaction was completed in 1 h.
Compound 36 (80 mg, 0.50 mmol, 1 equiv), 6-chloro-1-hexyne (69.6
mg, 0.60 mmol, 1.2 equiv), compound 31 (13.6 mg, 0.005 mmol, 0.01
equiv), CuSO4 pentahydrate (12.5 mg, 0.05 mmol, 0.1 equiv), and
sodium ascorbate (20.0 mg, 0.10 mmol, 0.2 equiv) were used. The
residue obtained was purified by column chromatography using eluent
from 10% EtOAc/hexanes to 50% EtOAc/hexanes to afford a white
solid (124.6 mg, 0.45 mmol, 90%) as the desired product (Rf = 0.60 in
60% EtOAc/hexanes).
General Procedure for the Preparation of Cluster-Gel
Catalyzed Reactions. The different compounds that were gelators
were tested for their performance as ligands for the copper-catalyzed
click reactions. When using the combination of two compounds, a few
monomeric triazole gelators were also tested for their gelation
capacity with the hexamers. The gel-filled columns could be used once
since the gel became unstable after passing through reaction mixtures,
and although good yields were obtained by this procedure, the gel
column was not stable for repeated uses. We further tested different
combinations of the gelators with the hexameric clusters and found
that the gelator compound 23 and cluster 31 were able to form stable
Synthesis of Hexameric Triazole Linked Cluster 33. Alkyne 10
(48.2 mg, 0.10 mmol, 1.0 equiv), sugar azide 1326 (231.0 mg, 0.62
mmol, 6.2 equiv), CuSO4 pentahydrate (30 mg, 0.12 mmol, 1.2
equiv), L-ascorbic sodium salt (48 mg, 0.24 mmol, 2.4 equiv), and 4
mL of EtOH/water (v/v = 1/1). were used. The reaction mixture was
stirred at room temperature for 24 h. Solvent was removed to give the
crude product, which was worked up by DCM (10 mL × 3) and water
(3 mL). The crude product was purified by column chromatography
using eluent from 0.5% MeOH/DCM to 5% MeOH/DCM to afford
a white solid (236.7 mg, 0.087 mmol, 87%) as the desired product (Rf
1
= 0.55 in 5% MeOH/DCM): mp 122.2−124.5 °C; H NMR (400
MHz, d6-DMSO) δ 8.27 (s, 6H), 6.24 (d, J = 9.2 Hz, 6H), 5.61 (t, J =
9.5 Hz, 6H), 5.50−5.39 (m, 12H), 4.57 (t, J = 6.0 Hz, 6H), 4.47 (s,
12H), 4.12 (dd, J = 11.6, 5.3 Hz, 6H), 4.01 (dd, J = 11.6, 7.1 Hz, 6H),
3.24 (s, 16H), 2.15 (s, 18H), 1.97 (s, 18H), 1.93 (s, 18H), 1.76 (s,
18H); 13C{1H} NMR (100 MHz, d6-DMSO) δ 169.9, 169.8, 169.4,
168.4, 144.6, 123.2, 84.2, 72.9, 70.4, 68.7, 67.7, 67.2, 63.8, 61.4, 45.0,
20.4, 20.3, 20.2, 19.8. HRMS (ESI/ICR) m/z [M + 2Na]2+ calcd for
[C112H148N18O61Na2]2+/2 calcd for 1383.4408, found 1383.4401.
Synthesis of Triazoles Using Cluster 31 as the Ligand. The
reactions of synthesizing triazoles 34 and 35 were carried out on a
larger scale using a Radley 6 plus carousel reaction station equipped
with a 250 mL round-bottom flask. For the synthesis of the triazoles
12-A3, 12-A4, 36-A4, and 36-A5, the reactions were carried out using
the Radley 12 plus carousel reaction station equipped with 20 mL
reaction tube.
Synthesis of Sugar Triazole 34. To a carousel reaction 250 mL
round-bottom flask, sugar azide 12 (300 mg, 0.806 mmol, 1 equiv)
and glycoclusters 31 (10.9 mg, 0.004 mmol, 0.5 mol %) were
dissolved in 7.5 mL of degassed EtOH. CuSO4 pentahydrate (40.5
mg, 0.16 mmol, 0.2 equiv) dissolved in 7.5 mL of degassed H2O was
added to the above solution followed by addition of L-ascorbic acid
sodium salt (64.5 mg, 0.32 mmol, 0.4 equiv). Then phenyl acetylene
(98 mg, 0.97 mmol, 1.2 equiv) was added. The mixture was stirred at
500 rpm at 30 °C under N2. The reaction reached full converted in 2
1
h as indicated by H NMR monitoring. Solvent was removed, and
DCM (30 mL) was added to the crude, which was then washed with
water (10 mL × 3) and dried over anhydrous Na2SO4, the solvent was
removed, and the product was purified by column chromatography
using eluent from pure DCM to 5% MeOH/DCM to give a white
solid (355 mg, 0.750 mmol, 93%, Rf = 0.45 in 5% MeOH/DCM) as
the desired product.
Synthesis of Sugar Triazole 35. To a 250 mL reaction flask, 1-
octyne (106 mg, 0.97 mmol, 1.2 equiv) was dissolved in 7.5 mL of
degassed EtOH; CuSO4 pentahydrate (20.2 mg, 0.08 mmol, 0.1
equiv) dissolved in 7.5 mL of degassed H2O was added to above
solution followed by adding sugar azide 12 (300 mg, 0.806 mmol, 1
equiv) and glycoclusters 31 (10.9 mg, 0.004 mmol, 0.5 mol %). Then
R
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gels in ethanol/water mixture. This was used for the catalyzing the
click reactions.
formed after 2 h at rt. This co-gel is called gel column II and shown in
Figure 9a.
The gel column II was stored at room temperature for 12 h before
being sued for the reaction. The mixture of galactose azide 13 (68.6
mg, 0.184 mmol, 1 equiv), propargyl alcohol A6 (12.4 mg, 0.22 mmol,
1.2 equiv), and NaAsc (14.8 mg, 0.074 mmol, 0.2 equiv) in 2.0 mL of
degassed EtOH/H2O (v/v, 1:1) was then added to the gel top. After
15 min, the stopper was removed to collect the filtrate without extra
pressure, and the solution was not flowing much. After 3 h, extra
pressure was applied using the plunger (glass) of the syringe and the
reaction solution was pushed through the gel carefully in 0.5 h. The
gel column was then rinsed by passing 2 mL of EtOH/H2O (v/v 1:1)
through the column. The combined filtrate was tested by TLC, which
indicated that the reaction had full conversion. Solvent was removed,
and the crude was worked up with water (2 mL)/ DCM (10 mL × 2),
dried over anhydrous Na2SO4, and concentrated to afford light yellow
solid (72.6 mg, 0.17 mmol, 92%) as the desired product 13-A6
(Figure S24).
The same gel column II was left at rt overnight and reused for
another cycle of reaction of the azide with a different alkyne to
prepare compound 13-A4: The mixture of galactose azide 13 (68.6
mg, 0.184 mmol, 1 equiv), 1-ethynyl-1-cyclohexanol A4 (27.3 mg,
0.22 mmol, 1.2 equiv), and NaAsc (14.8 mg, 0.074 mmol, 0.2 equiv)
in 2.0 mL of degassed EtOH/H2O (v/v, 1:1) was then added to the
gel top. After 15 min, the stopper was removed to collect the filtrate
with extra pressure using a plunger (glass) of the syringe. The reaction
solution was passed through the gel slowly over 2 h. Gel was then
washed with 2 mL of EtOH/H2O (v/v 1:1). The combined filtrate
was tested by TLC, which indicated that the reaction had full
conversion. Solvent was removed, and the crude was worked up with
water (1 mL)/ DCM (5 mL × 2) and dried over anhydrous Na2SO4,
concentrated to afford solid (70.3 mg, 0.164 mmol, 89%) compound
13-A4 (Figure S24).
Synthesis of 39 Using Gel Column I. The gel column I formed by
compound 18 was prepared as described above. This gel was used to
catalyze the choroxime reaction with phenyl acetylene to compound
39: A solution of phenyl acetylene (34 μL, 0.32 mmol, 1.2 equiv) and
chloroxime 38 (50 mg, 0.26 mmol, 1 equiv) dissolved in 0.5 mL of
ethanol, followed by a solution of sodium ascorbate (10 mg, 0.05
mmol, 0.2 equiv) and sodium bicarbonate (27 mg, 0.32, 1.2 equiv)
dissolved in 0.5 mL of DI water to start the reaction. The reaction
mixture was kept on top of the gel column for 30 min. The cap was
then removed, and elution started slowly. After all of the reaction
mixture had eluted, 1 mL of EtOH/H2O (v/v 1:1) was added to the
gel column; however, the gel became unstable, and the gel column
was then flushed with 2 mL of EtOH/H2O (v/v 2:1) and then 1 mL
EtOH. The combined filtrate was sampled for 1H NMR, which
indicated full conversion to the product (Supporting Information
Figure S21). The crude product was then purified via column
chromatography using 2−5% EtOAc/hexanes. The total final product
39 was obtained in 94% yield (62.5 mg, 0.25 mmol).
Synthesis of 39 and 40 Using Gel Column II. The gel column II
was prepared as described (Figure S25). The mixture of compound
38 (34.8 mg, 0.18 mmol, 1 equiv), propargyl alcohol A6 (12.4 mg,
0.22 mmol, 1.2 equiv), NaHCO3 (30.2 mg, 0.36 mmol, 2 equiv), and
sodium ascorbate (7.36 mg, 0.037 mmol, 0.2 equiv) in 2.0 mL of
EtOH/H2O (v/v, 1:1) was added to the top of the gel column. After
15 min, the stopper was removed and filtrate was collected without
added pressure but the mixture passed very slowly. After 3 h, pressure
was applied using a plunger of the glass syringe, and the reaction
solution was passed through the gel slowly in 0.5 h. Gel was then
washed with 2 mL of EtOH/H2O (v/v 1:1). The combined filtrate
was tested by TLC, which indicated that the reaction had full
conversion. Solvent was removed, and the crude was worked up with
water (1 mL)/ DCM (5 mL × 2), dried over anhydrous Na2SO4, and
concentrated to afford yellow solid 40 (35.0 mg, 0.17 mmol, 93%).
The same gel column was then reused for the preparation of
compound 39. The mixture of compound 38 (34.8 mg, 0.18 mmol, 1
equiv), phenyl acetylene A1 (22.4 mg, 0.22 mmol, 1.2 equiv),
NaHCO3 (30.2 mg, 0.36 mmol, 2 equiv), and sodium ascorbate (7.36
Gel Column I Preparation and Reactions Catalyzed by the
Gel-Column. Compound 18 (10 mg, 0.007 mmol, 0.03 equiv) was
added to a 2 dram vial. EtOH/H2O (v/v 1:2, 1.5 mL) containing
CuSO4 pentahydrate (6 mg, 0.022 mmol, 0.1 equiv) was added, and
the vial was gently heated until the solids were dissolved. The hot
solution was then added to a 3 mL syringe (with plunger removed and
a syringe filter/stopper attached). The syringe was then allowed to
cool, and a stable gel formed at rt (Figure 8). The reaction of
compound 36 with phenyl acetylene was carried out by the gelator-
column.
Synthesis of Compound 37 Using the Gel Column-I. A solution of
phenyl acetylene (0.030 mL, 0.27 mmol, 1.2 equiv), 3-acetylphenyl
azide (35 mg, 0.22 mmol, 1 equiv), and sodium ascorbate (9 mg,
0.044 mmol, 0.2 equiv) dissolved in ethanol/DI water (1 mL) was
added on top of the gel column. The reaction mixture was allowed to
sit on top of the gel column for 1 h. The cap was then removed, and
elution occurred over a 5 min period. After the elution was complete,
1 mL EtOH/H2O (v/v 1:1) was added to the top of the gel to push
the compound off the gel column followed by 0.5 mL EtOH/H2O (v/
v = 2/1), and 0.5 mL EtOH/H2O (v/v, 1/1) to prepare the column
for the next round of reaction mixture. The eluent was collected in a
scintillation vial, and solvent was removed under reduced pressure to
1
yield a light yellow solid. H NMR indicated that full conversion to
the desired product for each round without byproduct formation was
reached. This procedure was repeated a total of six times, with the
product obtained from each round obtained as follows: cycle 1, 24.1
mg; 2, 32.7 mg; 3, 33.3 mg; 4, 33.1 mg; 5, 32.7 mg; 6, 34.1 mg. The
product was not very soluble in the eluting solvent which contains
water; therefore, a fair amount of the product was trapped in the gel-
column. After the end of the sixth round of addition, the column was
flushed with pure EtOH (10 mL). and after drying of solvents and
another 127.6 mg of product was obtained (Figure S19). The total
final product was obtained in 93% yield (317.6 mg, 1.21 mmol), and
the yield was calculated using the total amount of phenyl azide
starting material: 35 mg × 6 = 210 mg, 1.30 mmol.
Gel Catalysis in Biphase Form. The gel formed by compound 18
was also prepared and transferred to a scintillation vial, and the same
click reaction was performed in a biphase format rather than passing
through a gel-column. The reaction was repeated 5 times, and the gel
was stable after the fifth cycle. In a 2-dram vial, compound 18 (10 mg,
0.007 mmol, 0.03 equiv to one loading of the azide), 1.5 mL of
EtOH/H2O (v/v = 1:2), and CuSO4 pentahydrate (6 mg, 0.022
mmol, 0.1 equiv) were added and the mixture heated until all of the
solids were dissolved. The hot solution was then added to a preheated
scintillation vial. Upon cooling a stable gel formed. The following
reaction mixture was added on top of the gel: a solution of phenyl
acetylene (0.030 mL, 0.27 mmol, 1.2 equiv), 3-acetylphenyl azide (35
mg, 0.22 mmol, 1 equiv), and sodium ascorbate (9 mg, 0.044 mmol,
0.2 equiv) in 1 mL of EtOH/H2O (v/v 1:1). The reaction mixture
was then placed in a shaker at 30 °C at 15 rpm. The reaction was
found to be finished after 4 h. The reaction mixture was decanted, and
the gel surface was washed with 1 mL of EtOH/H2O (v/v = 2/1).
The same procedure was repeated five cycles, and the gel remained
stable after throughout the experiment. After the fifth round, the gel
was rinsed with pure ethanol (4 mL) overnight. The product obtained
in each round was the desired product without the need for further
purification, the crude 1H NMR spectra showed only the pure
product (Figure S20). The yields obtained for the five cycles are 47.4,
43.7, 44.4, 42.3, and 40.3 mg; the final rinse 36.6 mg. The total final
product was obtained in 89% yield (254.7 mg, 0.97 mmol).
Gel Column II Preparation and Applications for Click
Reaction. Preparation of Co-Gel Catalyst of Compounds 23 and
31 and the Synthesis of Triazoles. Compounds 23 (10.0 mg, 0.0074
mmol, 4.0 mol % to azide) and 31 (5.0 mg, 0.00184 mmol, 1 mol %
to azide) and CuSO4·5H2O (9.2 mg, 0.0186 mmol, 0.2 equiv) were
dissolved in 0.8 mL of the mixture solvent of EtOH/H2O (v, 1:1) by
heating, the hot solution was transferred to a syringe, and a gel was
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Article
mg, 0.037 mmol, 0.2 equiv) in 2.0 mL of EtOH/H2O (v/v, 1:1) was
added to the gel top. After 15 min, the stopper was removed to collect
the filtrate with extra pressure using a plunger of the glass syringe. The
reaction solution was passed through the gel slowly in 2 h. Gel was
then washed with 2 mL of EtOH/H2O (v/v 1:1). The combined
filtrate was tested by TLC, which indicated that the reaction was fully
converted, and the crude was worked up with water (1 mL)/ DCM (5
mL × 2), dried over anhydrous Na2SO4, and concentrated to afford a
light yellow solid 39 (42.2 mg, 0.17 mmol, 92%).
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01978.
1H and 13C NMR spectra for compounds 3−33; 2D-
COSY and HSQC NMR spectra for selected glyco-
conjugates and HRMS spectra ; stacked 1H NMR
spectra for catalytic reaction monitoring and the detailed
experimental conditions for reactions using gels and gel
columns (PDF)
Full range of HRMS spectra of compounds 17−18,
20−33 (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Guijun Wang − Department of Chemistry and Biochemistry,
Old Dominion University, Norfolk, Virginia 23529, United
States; orcid.org/0000-0001-7473-0004; Phone: (757)
683-3781; Email: g1wang@odu.edu; Fax: (757) 683-4628
Authors
Dan Wang − Department of Chemistry and Biochemistry, Old
Dominion University, Norfolk, Virginia 23529, United States
Jonathan Bietsch − Department of Chemistry and
Biochemistry, Old Dominion University, Norfolk, Virginia
23529, United States
Anji Chen − Department of Chemistry and Biochemistry, Old
Dominion University, Norfolk, Virginia 23529, United States
Pooja Sharma − Department of Chemistry and Biochemistry,
Old Dominion University, Norfolk, Virginia 23529, United
States
(13) Moses, J. E.; Moorhouse, A. D. The growing applications of
click chemistry. Chem. Soc. Rev. 2007, 36, 1249−1262.
(14) Liang, L.; Astruc, D. The copper(I)-catalyzed alkyne-azide
cycloaddition (CuAAC) “click” reaction and its applications. An
overview. Coord. Chem. Rev. 2011, 255, 2933−2945.
(15) Tiwari, V. K.; Mishra, B. B.; Mishra, K. B.; Mishra, N.; Singh, A.
S.; Chen, X. Cu-Catalyzed Click Reaction in Carbohydrate Chemistry.
Chem. Rev. 2016, 116, 3086−3240.
(16) Figueredo, A. S.; Zamoner, L. O. B.; Rejzek, M.; Field, R. A.;
Carvalho, I. Cluster glycosides and hetero-glycoclusters presented in
alternative arrangements. Tetrahedron Lett. 2018, 59, 4405−4409.
(17) Chabre, Y. M.; Contino-Pepin, C.; Placide, V.; Shiao, T. C.;
Roy, R. Expeditive Synthesis of Glycodendrimer Scaffolds Based on
Versatile TRIS and Mannoside Derivatives. J. Org. Chem. 2008, 73,
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linked glycoconjugates. Tetrahedron Lett. 2005, 46, 2331−2336.
(19) Al-Mughaid, H.; Grindley, T. B. Synthesis of a Nona-valent
Mannoside Glyco-dendrimer Based on Penta-erythritol. J. Org. Chem.
2006, 71, 1390−1398.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01978
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the National Science
Foundation (CHE No. 1818609) and Old Dominion
University.
(20) Kushwaha, D.; Tiwari, V. K. Click Chemistry Inspired Synthesis
of Glycoporphyrin Dendrimers. J. Org. Chem. 2013, 78, 8184−8190.
(21) Percec, V.; Leowanawat, P.; Sun, H.-J.; Kulikov, O.; Nusbaum,
C. D.; Tran, T. M.; Bertin, A.; Wilson, D. A.; Peterca, M.; Zhang, S.;
Kamat, N. P.; Vargo, K.; Moock, D.; Johnston, E. D.; Hammer, D. A.;
Pochan, D. J.; Chen, Y.; Chabre, Y. M.; Shiao, T. C.; Bergeron-Brlek,
M.; Andre, S.; Roy, R.; Gabius, H.-J.; Heiney, P. A. Modular Synthesis
of Amphiphilic Janus Glycodendrimers and Their Self-Assembly into
Glycodendrimersomes and Other Complex Architectures with
Bioactivity to Biomedically Relevant Lectins. J. Am. Chem. Soc.
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