Synthesis of biologically important 4-Phenyl-C-glycosyl-1,2,3-triazole derivatives by Cu(I)-catalyzed azide–alkyne cycloaddition

Article abstract of DOI:10.1002/jccs.202000452

A new series of 4-phenyl-C-glycosyl-1,2,3-triazoles were synthesized using Cu(I)- catalyzed azide–alkyne cycloaddition. The key step in the synthesis involved the coupling of unprotected glycosyl azides with substituted C-glycosylated phenyl acetylenes. U

Full text of DOI:10.1002/jccs.202000452

Received: 13 October 2020
DOI: 10.1002/jccs.202000452
Revised: 18 January 2021
Accepted: 20 January 2021
A R T I C L E
Synthesis of biologically important 4-Phenyl-C-glycosyl-
,2,3-triazole derivatives by Cu(I)-catalyzed azide–alkyne
cycloaddition
1
1
1
1
Kalyana K. Ponnapalli | Sachin K. Kawade
| Avijit K. Adak
|
2
1,3
Hsin-Ru Wu | Chun-Cheng Lin
1
Department of Chemistry, National Tsing
Abstract
Hua University, Hsinchu, Taiwan
2
A new series of 4-phenyl-C-glycosyl-1,2,3-triazoles were synthesized using
Cu(I)- catalyzed azide–alkyne cycloaddition. The key step in the synthesis
involved the coupling of unprotected glycosyl azides with substituted
C-glycosylated phenyl acetylenes. Using o-phenylenediamine as a ligand, we
could significantly reduce the reaction time, improve the product yield, and
simplify the purification process. Broad substrate scope in terms of sugars was
achieved.
Instrumentation Center, National Tsing
Hua University, Hsinchu, Taiwan
3
Department of Medicinal and Applied
Chemistry, Kaohsiung Medical University,
Kaohsiung, Taiwan
Correspondence
Chun-Cheng Lin, Department of
Medicinal and Applied Chemistry,
Kaohsiung Medical University, Kaohsiung
K E Y W O R D S
80708, Taiwan.
Email: cclin66@mx.nthu.edu.tw
1,2,3-triazoles, C-glycosides, click chemistry, CuAAC, disaccharide
Funding information
Ministry of Education; Academia Sinica;
Ministry of Science and Technology;
National Tsing Hua University
[
5]
1
| INTRODUCTION
catalysts in these processes. Because of the poor basicity
of triazole, it can remain unprotonated at physiological
2
Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reac-
tions between an azide and terminal alkyne are click
chemistry reactions that produce triazoles.
chemistry has emerged as one of the most powerful
tools for drug discovery, chemical biology, and proteo-
mic applications, and it is an important reaction for the
development of carbon–heteroatom–carbon bonds.
Among these molecular structures, sugar-based triazoles
play a vital role in enzyme inhibition. The heterocy-
clic triazoles act as a bridge between the carbohydrate
and other biomolecules, generating glycoconjugates
such as glycoproteins, neoglycoconjugates, oligomers,
pH. Moreover, the sp -hybridized nitrogen atom of triazole
acts as positively charged center to mimic the transition
state in glycosidase-catalyzed reactions. Recent studies have
developed several 1,2,3-triazole analogs as potential glycosi-
dase inhibitors; they have shown promise as treatments for
[
1]
Click
[6]
viral infections, cancer, and diabetes.
Notably, 1-
[
2]
β-glucoyl-4-phenyl-1,2,3-triazole (1) and 1-β-galactosylosyl-
4-phenyl-1,2,3-triazole (2) (Figure 1) were synthesized by
utilizing the copper(I)-catalyzed azide–alkyne click chemis-
try between glycosyl azide and phenylacetylene. The glu-
cosyl triazole analog 1 had a half maximal inhibitory
concentration (IC ) of 0.24 mM against bovine liver galac-
tosidase, and galactosyl triazole analog 2 afforded modest
inhibition of Escherichia coli galactosidase.
Furthermore, Ramtohul et al.
mannose-based triazole analog 3, as shown in Figure 2.
The competitive binding assay of 3 with FimH protein
[
3]
[6]
50
[
4]
glycol lipids, glycopeptides, and oligonucleotides.
[7]
Various glycosidic bonds that are formed or broken
during physiological or pathological processes can be syn-
chronized by developing new glycosidase or glycosyl
transferase inhibitors; both types of enzymes act as
[
8]
developed the
J Chin Chem Soc. 2021;1–6.
http://www.jccs.wiley-vch.de
© 2021 The Chemical Society Located in Taipei & Wiley-VCH GmbH
1

2
PONNAPALLI ET AL.
showed that this type of compound may be effective for
the treatment of bacterial infections caused by adherent
osmium tetroxide to generate the mannose derivative 7.
The phenolic group of 7 was further functionalized to give
alkyne 8, and the subsequent Cu(1)-catalyzed alkyne–
azide cycloaddition (CuAAC) with azido mannose gener-
ated bis-mannose triazole 3. Moreover, the synthetic
methodology was restricted to the synthesis of mannose
derivatives only. Considering the potential for biological
applications associated with triazole-linked disaccharide
analogs, developing novel phenyl-C-glycosyl triazoles with
a high degree of structural diversity is advantageous. In
this study, we report an efficient synthetic strategy for gen-
erating triazole-linked disaccharides 9a–p with a broad
substrate scope (Figure 2). In our synthetic strategy, we
used a sequence of reactions involving Lewis acid cata-
lyzed C-glycosylation of various trichloroimidates (10)
[8]
invasive E. coli, which is known to be prevalent in
[
9]
patients with ulcerative colitis and Crohn's disease.
However, major drawbacks are the low total synthetic
yield of triazole 3 and the lengthy synthetic steps involving
the palladium-catalyzed coupling of glucal 4 with aryl
boronic acid 5, followed by the syn-hydroxylation of 6 using
FIGURE 1 Structures of glycosidase inhibitors 1 and 2
FIGURE 2 Comparison of synthetic approaches for triazole-based glycosides

PONNAPALLI ET AL.
3
SCHEME 1 Synthesis of alkyne derivatives
with 1,3-dimethoxy benzene, functional group manipula-
tion, iodination, Sonogashira coupling with trimethysilyl
acetylene (TMS–acetylene), and silyl cleavage. From
these reactions, we obtained alkyne analogs (13) with
excellent yields. Cu(I)-catalyzed azide–alkyne cycloaddi-
tion between azido sugar (14a–d) and C-glycosylated phe-
nyl acetylene analogs (13) resulted in triazoles (9) with a
high degree of structural diversity.
neighboring-group participation. The resulting products
were then deacetylated under Zemplen conditions to pro-
duce fully deprotected anomeric azides (14a–d) with good
yields (70–75% over two steps).
Using both the azide and alkyne coupling partners, we
performed CuAAC between 13a and 14a using CuSO4
(10 mol%) and ascorbic acid (20 mol%) in a mixture of
t-BuOH:H O (1:1), which resulted in the triazole analog 9a
2
at 80% yield, (Table 2). However, the reaction was relatively
slow and required 8–10 hr to reach completion. Therefore,
we further optimized the reaction conditions to reduce the
reaction time and to improve the yield. Cu(I)-chelating
ligands were used to improve the efficiency of the click reac-
tion. Among the many Cu(I) chelating ligands, tris[(1-ben-
zyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA) has been
2
| RESULTS AND DISCUSSION
The general synthetic route for the alkynylated C-aryl
glycoside 13a is shown in Scheme 1. The compound 13a
was formed from the C-glucosylated aryl iodide 15a using
[10]
[12]
our previously developed method.
Pd(0) catalyzed the
widely used in click chemistry. However, TBTA is limited
Sonogashira coupling of 15a with trimethylsilyl acety-
lene, resulting in the TMS-protected alkyne derivative
to the click reactions in organic solvents. To efficiently per-
form CuAAC in water-soluble conditions, tris(3-hydro-
1
6a in 80% yield. Tetrabutylammonium fluoride (TBAF)-
xypropyltriazolylmethyl)amine was developed as
a
[13]
mediated silyl cleavage yielded the alkyne 17a (90%
yield), which was then deacetylated under Zemplen con-
ditions to produce a quantitative yield of 13a.
biologically compatible ligand. Similarly, tertiary amines
such as triethylamine are known to assist in click reactions
by serving as bases or ligands. Diamine-based ligands such
0 0
Using the same synthetic strategy, we synthesized the
alkyne derivatives 13b–d (Table 1) with the sugars galac-
tose, fucose, and mannose. The yields for the Sonogashira
coupling (used to produce 16b–d) ranged from 80 to 83%.
The silyl group cleavage using TBAF resulted in the
alkyne derivatives 17b–d (yields of 90–92%), which were
further deacetylated to form 13b–d in 90–95% yields. Thus,
using this straightforward method, we synthesized alkyne
derivatives 13a–d with excellent total yields. The summary
of the synthetic yield for each step is listed in Table 1.
We synthesized deprotected glycosyl azides (14a–d) for
coupling with alkynylated saccharides by CuAAC using a
as N,N,N ,N -tetramethyl ethylenediamine and its analogs
[
14]
can also improve the reaction efficiency of click reactions.
Moreover, Baron et al. showed that o-phenylenediamine
acts as a promising Cu(I)-stabilizing ligand in click reac-
tions carried out in water. o-Phenylenediamine accelerates
[15]
the reaction possibly by forming a Cu(I) complex.
A
kinetic study using nuclear magnetic resonance (NMR)
[15]
spectrometry confirmed this rate acceleration.
In a sys-
tem that uses ascorbic acid and CuSO to generate Cu(I),
4
the initial byproduct is dehydroascorbate. The oxidation of
dehydroascorbic acid irreversibly leads to more than 50 spe-
[16]
cies containing five carbon atoms or fewer.
By contrast,
[11]
previously reported procedure,
as shown in Scheme 2.
when o-phenylenediamine was used as a ligand, it trapped
First, peracetylated sugar derivatives such as glucose,
galactose, fucose, and mannose (18a–d) were each reacted
with TMS–N3 in the presence of SnCl4 to produce
corresponding 1,2-trans anomeric azido derivatives via
the dehydroascorbate formed by the first step by forming
[
17]
fluorescent quinoxaline derivatives.
Interestingly, these
byproducts can be easily adsorbed onto activated charcoal
and can be removed completely using simple filtration

4
PONNAPALLI ET AL.
TABLE 1 Synthesis of alkyne derivatives 13b–d
SCHEME 2 Synthesis of azide derivatives 14a–d
with celite; thus, clean triazole analogs can be formed
without the need for chromatographic purification. It
was also reported that the residual copper percentage
15 mol% o-phenylenediamine. Using our optimized
conditions, the CuAAC of 13a–d with anomeric azide
14a–d could synthesize a library of 16 triazoles (9a–p)
with excellent yields (85–90%). The structures of 9a–p
are shown in Table 2. Each analog possesses two
glycosidic-bond surrogates, namely N- and C-glyco-
sides. Furthermore, each triazole analog contained two
free common sugar units such as glucose, galactose,
fucose, and mannose. Hence, analogs from this study
provide great structural diversity and can be further
used for studies of biological activity.
[
15]
after this workup procedure was less than 0.03%.
Thus, o-phenylenediamine was used as a ligand to
improve the reaction efficiency using alkyne 13a and
azide 14a in the model reaction to afford 9a. As
expected, CuAAC in the presence of a ligand was com-
pleted in less than one hour, with a triazole 9a yield of
8
5%. The desired triazole product could be generated
using 5 mol% CuSO , 10 mol% ascorbic acid, and
4

PONNAPALLI ET AL.
5
TABLE 2 Synthesis of triazole derivatives using alkynes 13 and 14
3
| CONCLUSION
resulting compounds are promising for future studies
of biological activity.
We synthesized a library of 4-phenyl-C-glycosyl-1,-
,3-triazoles using Cu(I)-catalyzed click chemistry.
2
Using o-phenylenediamine as a ligand, we could 4 | EXPERIMENTAL SECTION
remarkably shorten the reaction time, improve the
yield, and simplify the purification process. The
resulting triazole-based disaccharides were structurally
diverse, with each derivative possessing two free sugar
units (glucose, galactose, fucose, or mannose). The
General experimental procedure for click chemistry.
Sodium ascorbate (5 mol%, 250 mM solution in H O),
2
CuSO4 (10 mol%, 125 mM solution in H O), and o-
2
phenylenediamine (15 mol%, 375 mM solution in H O)
2

6
PONNAPALLI ET AL.
were added to a solution of azide (14a–d) (1.0 eq) and
[6] R. Perion, V. Ferrieres, M. I. Garcia-Moreno, C. O. Mellet, R.
Duval, J. M. G. Fernandez, D. Plusquellec, Tetrahedron 2005,
alkyne (13a–d) (1.05 eq) in a 1:1 mixture of H O:t-BuOH
2
6
1, 9118.
7] L. L. Rossi, A. Basu, Bioorg. Med. Chem. Lett. 2005, 15,
596.
8] Y. K. Ramtohul, S. K. Das, C. Cadilhac, T. J. Reddy, M.
Gallant, B. Liu, E. Dietrich, F. Vallee, J. Martel, C. Poisson,
Mannose derivative for treating bacterial infections. WO
2014/100158 Al.
(2 ml). The solution was stirred at room temperature for
[
[
1
hr. The progress of the reaction was monitored by thin-
3
layer chromatography (TLC) analysis. After the reaction
was completed, activated charcoal (20 mg) was added to
the reaction mixture, which was then stirred at room
temperature for 10 hr. The resulting solution was passed
through a pad of celite and then washed with excess
methanol. The organic layer was concentrated under
reduced pressure. The crude compounds were purified in
a reverse-phase silica gel (RP-C18) column eluted with
[9] S. M. Man, N. O. Kaakoush, H. M. Mitchell, Nat. Rev.
Gastroenterol. Hepatol. 2011, 8, 152.
10] K. K. Ponnapalli, A. K. Adak, A. Das, J. S. Song, S. H. Wu,
C. M. Sun, C. C. Lin, Asian J. Org. Chem 2017, 6, 1308.
11] a) C. J. Carroux, J. Moeker, J. Motte, M. Lopez, L. Bornaghi,
K. Katneni, E. Ryan, J. Morizzi, D. M. Shackleford, S. A.
Charman, S. A. Poulsen, Bio. Org. Med. Chem. Lett. 2013, 23,
[
[
0
–20% acetonitrile in H O to obtain triazoles (9a–p) with
2
yields of 85–95%.
455. b) J.-P. Praly, D. Senni, R. Faure, G. Descotes, Tetrahe-
ACKNOWLEDGMENTS
dron 1995, 51, 1697. c) B. L. Wilkinson, L. F. Bornaghi, T. A.
Houston, A. Innocenti, C. T. Supuran, S.-A. Poulsen, J. Med.
Chem. 2006, 49, 6539. d) B. Kang, P. Okwieka, S. Schottler, S.
Winzen, J. Langhanki, K. Mohr, T. Opatz, V. Mailander, K.
Landfester, F. R. Wurm, Angew. Chem. Int. Ed. 2015, 54, 7436.
12] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett.
This work was financially supported by the National
Tsing Hua University, the Ministry of Science and Tech-
nology (107-2113-M-007-024-MY3), Academia Sinica (AS-
TP-108-M06), the Ministry of Education of Taiwan, and
the Frontier Research Center on Fundamental and
Applied Sciences of Matters.
[
[
2004, 6, 2853.
13] a) Z. Yin, M. Comellas-Aragones, S. Chowdhury, P. Bentley,
K. Kaczanowsca, L. Benmohamed, J. C. Gildersleeve, M. G.
Finn, X. Huang, Acs. Chem. Biol. 2013, 8, 1253. b) S. I.
Presolski, V. P. Hong, M. G. Finn, Curr. Protoc. Chem. Biol.
ORCID
Sachin K. Kawade https://orcid.org/0000-0002-3996-
2
011, 3, 153.
14] a) S. W. Home, C. D. Stout, M. R. Ghadiri, J. Am. Chem. Soc.
003, 125, 9372. b) V. D. Bock, H. Hiemstra, J. H. V.
7
118
[
Avijit K. Adak https://orcid.org/0000-0002-5907-3744
Chun-Cheng Lin https://orcid.org/0000-0002-2323-0920
2
Maarsveen, Eur. J. Org. Chem. 2006, 2006, 51.
15] A. Baron, Y. Bleriot, M. Sollogoub, B. Vanzeilles, Org. Biomol.
Chem. 2008, 6, 1898.
[
REFERENCES
[
1] a) R. Huisgen, Angew. Chem. Int. Ed. 1963, 2, 565. b) R.
Huisgen, Angew. Chem. Int. Ed 1963, 2, 633. c) R. Huisgen,
Pure Appl. Chem. 1989, 61, 613.
[16] J. C. Deutsch, C. R. Santhosh Kumar, K. L. Hassell, J. F.
Kolhouse, Anal. Chem. 1994, 66, 345.
[17] Y. Kidani, K. Ohira, H. Kioke, Bull. Chem. Soc. Jpn. 1974, 47, 2040.
[
2] a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. Int. Ed.
2
2
001, 40, 2004 b) H. C. Kolb, K. B. Sharpless, Drug Discov Today
003, 8, 1128. c) K. B. Sharpless, R. Manetsch, Expert Opin. Drug
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
Discov 2006, 1, 525. d) V. K. Tiwari, B. B. Mishra, K. B. Mishra, N.
Mishra, A. N. Singh, X. Chen, Chem. Rev. 2016, 116, 3086. e) M.
Meldal, C. W. Tornoe, Chem. Rev. 2008, 108, 2952.
[
[
3] P. Thirumurugan, D. Matosiuk, K. Jozwiak, Chem. Rev. 2013,
1
13, 4905.
4] a) J. E. Moses, A. D. Moorhouse, Chem. Soc. Rev. 2007, 36, 1249.
b) R. P. Tripathi, P. Dwivedi, A. Sharma, D. Kushwaha, V. K.
Tiwari. In Click Chemistry in Glycoscience: New Developments
and Strategies; Z. J. Witczak and R. Bielski Eds; Wiley: Hobo-
ken, NJ, 2013; pp 293. c) V. L. Campo, I. Carvalho. In Click
Chemistry in Glycoscience: New Developments and Strategies Z. J.
Witczak and R. Bielski Eds; Wiley: Hoboken, NJ, 2013; pp 325.
5] N. Asano, Glycobiology 2003, 13, 93R.
How to cite this article: Ponnapalli KK,
Kawade SK, Adak AK, Wu H-R, Lin C-C. Synthesis
of biologically important 4-Phenyl-C-glycosyl-1,2,3-
triazole derivatives by Cu(I)-catalyzed azide–
alkyne cycloaddition. J Chin Chem Soc. 2021;1–6.
https://doi.org/10.1002/jccs.202000452
[