Copper-free route to triazole-modified peptidomimetic by the combination of two multicomponent reactions in one pot

Article abstract of DOI:10.1021/co3000117

An efficient copper-free protocol for the synthesis of 5-methyl-1H-1,2,3- triazole-modified peptidomimetics through the combination of Ugi four-component reaction with a three-component cycloaddition, has been developed. The copper-free straightforward process is suitable for drug discovery. The chemoselective preparation of 1,4-disubstituted, triazole-modified peptidomimetics by using alkynyl substituted amines may have potential biological and synthetic application. At last, a "Lapinski type" analysis of the physical properties was performed, which is expected to help drug discovery.

Full text of DOI:10.1021/co3000117

Research Article
pubs.acs.org/acscombsci
Copper-free Route to Triazole-Modified Peptidomimetic by the
Combination of Two Multicomponent Reactions in One Pot
Teng-fei Niu, Lin Gu, Wen-bin Yi, and Chun Cai*
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing, 210094, P. R. China
S
* Supporting Information
ABSTRACT: An efficient copper-free protocol for the synthesis of 5-methyl-1H-1,2,3-triazole-modified peptidomimetics
through the combination of Ugi four-component reaction with a three-component cycloaddition, has been developed. The
copper-free straightforward process is suitable for drug discovery. The chemoselective preparation of 1,4-disubstituted, triazole-
modified peptidomimetics by using alkynyl substituted amines may have potential biological and synthetic application. At last, a
“Lapinski type” analysis of the physical properties was performed, which is expected to help drug discovery.
KEYWORDS: peptidomimetic, triazole, multicomponent reaction, Ugi reaction, copper-free, chemoselective
type of the approaches to address this challenge.11 Owing to
their atom economy, facile execution, and high efficiency, a
INTRODUCTION
1H-1,2,3-Triazole-modified peptidomimetics (Figure 1) are
■
wide range of components can be subjected to one-pot
attractive nonnatural molecules for drug discovery because of
reactions.
The usefulness of MCRs is even greater if two or more
MCRs can be combined in one pot to generate such “privileged
medicinal scaffolds”.12 However, a one-pot multicomponent
synthesis of triazole-modified peptidomimetics from readily
accessible starting materials still remains elusive. The biggest
challenge to such a combination lies in the incorporation of a
functional group that is unreactive in the initial MCR but
reactive in a subsequent MCR. The solvent for the subsequent
reaction steps also should be compatible with the first step. In
an ideal case, different reactions are run in a single pot to
Figure 1. General structures of (a) a peptide and (b) a 1H-1,2,3-
triazole-modified peptidomimetics.
their many biological activities.1 It is reported that triazole-
modified peptidomimetics can act as peptide surrogate2 and be
generate the target products without protecting groups.
used as blood components,3 anticancer medications,4 cysteine
However, there are few reports about conjugating two MCRs
protease5 and HIV-1 protease inhibitors.6 Moreover, they have
been introduced into protein-like oligomers and nonpeptidic
to generate triazole-modified peptidomimetics in one pot.
In our initial experiment, triazoles are synthesized by
protein mimetic foldamers.7 Consequently, they serve as a
copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction
between acetylenes and azides (CuAAC), which are the
platform for developing pharmaceutical agents for diverse
common protocol for the click chemistry.5,13 However, the
residual copper catalyst could be toxic to both bacterial and
mammalian cells.14 Therefore from a biological perspective the
CuAAC is not a preferred catalytic method for preparing
triazole-modified peptidomimetics. A copper-free triazole
synthesis protocol is highly desirable for drug discovery. To
this end we were interested in developing a copper-free
applications8 and have gained considerable attention for the
study of the associated biological processes and drug design.9
Recently, many triazoles in peptide terminal, center, or side
chain positions linked to sugars or other peptides have been
reported.10 The typical approach for the synthesis of such
molecules is by a rather inefficient, step-by-step reaction
sequence requiring many protecting groups. However, in
modern therapeutic discovery, the rapid assembly of drug
without protecting groups is gaining considerable interest
which fully lives up to the principle of “Green Chemistry” and
atom economy. Multicomponent reactions (MCRs) are one
Received: January 26, 2012
Revised: April 1, 2012
Published: April 9, 2012
© 2012 American Chemical Society
309
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ACS Combinatorial Science
Research Article
synthesis of triazole-modified peptidomimetics, in which two
multicomponent reactions were conjugated in one pot.
To optimize the reaction, we screened a number of
experimental conditions. For the second 3CR, it was discovered
that both organic and inorganic bases could catalyze the
formation of triazole-modified peptidomimetics. Although
strong bases such as t-BuOK and NaOH resulted in short
reaction time, Et3N gave an excellent yield. The solvent effect in
the second reaction was also examined by replacing MeOH
with other solvents. Ugi 4CR was carried out in MeOH. After
completion of the Ugi reaction, evaporation of the solvent in
vacuo without separation of the intermediate, addition of 1{1},
diketene and triethylamine in a different solvent was tested.
Compared with DMF, THF, and 1,4-dioxane, the use of MeOH
resulted in higher yields of the products within a shorter
reaction period. Although MeCN system afforded a similar
yield (as an example, 6{1,1,1,1,1} can be obtained in 39%
yield), the use of MeOH as solvent is more convenient for this
one-pot process. The best result was obtained when 1.2 equiv
of 1{1}, diketene, and triethylamine were used in the second
step (yield = 43%).
RESULTS AND DISCUSSION
■
In an initial approach, we selected the Ugi reaction as an
efficient method for the construction of peptide building blocks
and peptoid molecules in one step (Scheme 1). With its wide
Scheme 1. One-Pot Synthesis of Triazole-Modified
Peptidomimetics
We subsequently investigated the possibility of the triazole
synthesis as the first MCR. An alternative route for triazole-
modified peptidomimetics was offer in Scheme 2. Diketene,
Scheme 2. Alternative Route for Triazole-Modified
Peptidomimetics
tolerance of functional groups, Ugi reaction has been
extensively developed. Many research groups have utilized the
Ugi reaction followed by another multicomponent reaction to
assemble complex structures.15 We focused on the synthesis of
the triazole structure by a three-component cycloaddition
utilizing azides, amines and diketene as the reactants under base
catalysis.16 Although many copper-free triazole syntheses have
been reported3,17 not all are viable in such a combination since
the functional groups for the second MCR reaction should not
be participants in the Ugi reaction. Initially, para-azido-benzoic
acid 3{1} (all components see Figure 2) was chosen as the
“bridge molecule” to combine Ugi 4CR with 3CR triazole
synthesis. The Ugi reactions were preferred as the first MCR.
Based on classical reports on Ugi 4CR, 3{1} was reacted with
1{1}, 2{1}, and 4{1} in MeOH at room temperature to form
intermediate A. Then without isolation of the intermediate, a
one-pot combination with 1 equiv of 1{1}, diketene, and 1
equiv of triethylamine in the second MCR at reflux, led to the
isolation of 5-methyl-1H-1,2,3-triazole-modified peptidomimet-
ics 6{1,1,1,1,1}in 38% yield after 48 h.
3{1} and 1{1} were reacted in the presence of 2 equivalents of
triethylamine to form the intermediate B. After protonation of
the intermediate by two equivalents of methanolic HCl, a one-
pot combination with 1{1}, 2{1}, and 4{1} in an Ugi 4CR led
to the isolation of 6{1,1,1,1,1} in 33% yield while 39% yield
when 1{2} was used instead of 1{1}. Apparently, the chosen
Figure 2. Components involved in the described six-component one-pot sequential reactions.
310
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Research Article
Table 1. Scope of Six-Component One-Pot Sequential Reaction for the Synthesis of 5-Methyl-1H-1,2,3-triazole-Modified
Peptidomimetics
a
entry
1
2
3
4
5
product
yield [%]
1
1{1}
1{1}
1{2}
1{3}
1{4}
1{6}
1{7}
1{8}
1{2}
1{1}
1{2}
1{2}
1{2}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
1{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{2}
2{4}
2{3}
2{5}
2{7}
2{6}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{2}
3{3}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{2}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{2}
4{1}
4{1}
4{1}
4{1}
4{1}
4{2}
1{1}
1{6}
1{6}
1{6}
1{6}
1{2}
1{6}
1{6}
1{6}
1{6}
1{6}
1{6}
1{6}
1{6}
1{6}
1{6}
1{6}
1{2}
1{3}
1{4}
1{5}
1{7}
1{8}
6{1,1,1,1,1}
6{1,1,1,1,6}
6{2,1,1,1,6}
6{3,1,1,1,6}
6{4,1,1,1,6}
6{6,1,1,1,6}
6{7,1,1,1,6}
6{8,1,1,1,6}
6{2,2,1,1,6}
6{1,4,1,1,6}
6{2,3,1,1,6}
6{2,5,1,1,6}
6{2,7,1,1,6}
6{1,6,1,1,6}
6{1,1,2,1,6}
6{1,1,3,1,6}
6{1,1,1,2,6}
6{1,1,1,1,2}
6{1,1,1,1,3}
6{1,1,1,1,4}
6{1,1,1,1,5}
6{1,1,1,1,7}
6{1,1,1,2,8}
43
47
51
0
2
3
4
5
53
50
52
48
55
53
50
47
45
42
41
34
53
47
31
51
45
61
43
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
a
Isolated yield.
Ugi reaction as the first MCR was the best chose for this
combination.
6{1,1,1,1,4}. And the steric effects of the substituted anilines
also had a significant influence on the yield of the reaction
(Table 1, entries 20, 21). The best result was given by the n-
butyl amine 1{7} (Table 1, entry 22). Unfortunately, secondary
amines (piperidine, morpholine) failed to react under these
conditions even DIPEA or DMAP was used as catalyst.
To explore the possible conformational preorganization
effect of triazole-modified peptidomimetics, para-azido-benzal-
dehyde 2{8} was chosen instead of para-azido-benzoic acid
3{1} as “bridge molecule” to combined the two MCRs (Table
2). The corresponding 5-methyl-1H-1,2,3-triazole-modified
peptidomimetics were obtained in good yields 7{1,8,4,1,6−
1,8,6,2,6,}.
To further expand the scope of this combination reaction,
the alkynyl substituted amines 1{9−12} were used in the
second step (Table 3). We were pleased to find that the
reaction was exclusively resulting 1,4-disubstituted-triazole-
modified peptidomimetics 8{1,1,1,11, 1,1,1,9−1,8,5,2,11}.
There were non 9a or 9b as Husigen 1,3-dipolar cycloaddition
products were found. That means in such condition, the 1,4-
disubstituted-triazole-modified peptidomimetics could be che-
moselectively prepared by alkynyl substituted amines. The type
of the alkynyl substituted amines was found to be important.
The scope of the one-pot combination reaction sequence is
illustrated by the examples in Table 1. In most cases, the yields
of the product 6{1.1.1,1.1−2,1,1,1,6, 4,1,1,1,6−1,1,1,2,8} were
good. For the Ugi reaction step, both aromatic and aliphatic
amines gave satisfactory results (Table 1, entries 1−3, 5−8).
However, the substituted 4-nitro-aniline 1{4} was not tolerated
(Table 1, entries 4); the intermediate Ugi product decompose
in the second step and the desired product was not found.
While the α,β-unsaturated aldehydes, such as furaldehyde and
cinnamaldehyde, were found to be compatible affording into
the products 6{2,7,1,1,6} and 6{1,6,1,1,6} in good yields (Table
1, entries 13, 14). Steric effects were also indicated by the slight
reduction in yield of substrate 3{3} be used as “bridge
molecule” (Table 1, entry 16). Compound 3{2} was
incorporated with no difficulty as a bridge molecule (Table 1,
entry 15).
However, the electronic properties of the substituted anilines
for the second MCR had a significant influence on the yield of
the reaction (Table 1, entries 19, 20). Electron-deficient 4-
nitro-aniline 1{3} produced in 31% yield of final product
6{1,1,1,1,3}, while 4-methyl-aniline 1{4} in 51% yield
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ACS Combinatorial Science
Research Article
adhered the Rule of Lapinski. So we believe that this method is
potentially useful to discover new drug.
Table 2. One-Pot Synthesis of 5-Methyl-1H-1,2,3-triazole-
Modified Peptidomimetics by Using Para-azido-
benzaldehyde as a Bridge Molecule
CONCLUSIONS
■
In conclusion, we have developed an efficient approach to
synthesize 5-methyl-1H-1,2,3-triazole-modified peptidomimet-
ics by using a sequential Ugi reaction and a copper-free
cycloaddition from simple and commercially available materials
and gave a Lapinski type analysis of the physical properties. The
synthetic protocol embodies a combination of two multi-
component reactions in a one-pot process successfully. We
anticipate that this method could have interesting applications
in the construction of diversified 5-methyl-1H-1,2,3-triazole-
modified peptidomimetics, and can be a useful protocol in
biochemistry, and medicinal discovery. Moreover, the observed
chemoselective preparation of 1,4-disubstituted-triazole-modi-
fied peptidomimetics by using alkynyl substituted amines may
have potential biological and synthetic application and worth
noticing.
yield
a
entry
1
2
3
4
5
product
(%)
1
2
3
4
5
6
1{1}
1{1}
1{1}
1{1}
1{2}
1{1}
2{8}
2{8}
2{8}
2{8}
2{8}
2{8}
3{4}
3{4}
3{5}
3{5}
3{5}
3{6}
4{1}
4{1}
4{2}
4{2}
4{2}
4{2}
1{6}
1{7}
1{6}
1{7}
1{6}
1{6}
7{1,8,4,1,6}
7{1,8,4,1,7}
7{1,8,5,2,6}
7{1,8,4,2,7}
7{2,8,5,2,6}
7{1,8,6,2,6}
29
39
52
56
63
46
a
Isolated yield.
EXPERIMENTAL PROCEDUES
The meta-substituted ethynylaniline 1{11} gave significantly
higher yield than alkynylamines 1{9, 10}, presumably because
of electronic effects (Table 3, entries 1, 3, 4). However, para-
substituted ethynylaniline 1{12} was not tolerated; the desired
product 8{1,1,1,1,12} was not formed and only Ugi reaction
was found (Table 3, entry 2).
■
General. Melting points were determined uncorrected.
Analytical thin-layer chromatography were performed on glass
plates precoated with silica gel impregnated with a fluorescent
indicator (254 nm). The plates were visualized by exposure to
1
ultraviolet light. H NMR spectra were recorded on Bruker
Finally, to evaluate this synthetic method, a Lapinski type
analysis of the physical properties was performed. It was found
that most of the products adhered to Lapinski’s Rule-of-5 for
parameters NHD and NHA, only products 6{1,4,1,1,6},
6{1,1,1,1,3}, and 7{1,8,6,2,6} violating the rule. And the
products 7 adhered the Rule in parameter log P. However,
the MW of all the products are about 600, which do not
DRX500 (500 MHz) and 13C NMR spectra on Bruker
DRX500 (125 MHz) spectrometer. Mass spectra were taken
on a Finnigan TSQ Quantum−MS in strument in the
electrospray ionization (ESI) mode. Elemental analyses were
performed on a Yanagimoto MT3CHN recorder. The
distribution of clog P was analyzed by high performance liquid
chromatograph (HPLC) on Agilent 1120 (Eclipse XDB-C18,
Table 3. Chemoselective Preparation of 1,4-Disubstituted-triazole-Modified Peptidomimetics by Using Alkynyl Substituted
Amines
a
entry
1
2
3
4
5
product
yield (%)
1
1{1}
1{1}
1{1}
1{1}
1{2}
1{6}
1{8}
1{1}
1{1}
1{1}
1{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{1}
2{3}
2{5}
2{7}
2{8}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{1}
3{5}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{2}
1{11}
1{12}
1{9}
8{1,1,1,1,11}
8{1,1,1,1,12}
8{1,1,1,1,9}
8{1,1,1,1,10}
8{2,1,1,1,11}
8{6,1,1,1,11}
8{8,1,1,1,11}
8{1,3,1,1,11}
8{1,5,1,1,11}
8{1,7,1,1,11}
8{1,8,5,2,11}
48
0
2
3
36
44
52
58
46
50
46
42
55
4
1{10}
1{11}
1{11}
1{11}
1{11}
1{11}
1{11}
1{11}
5
6
7
8
9
10
11
a
Isolated yield.
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Research Article
Table 4. Lapinski Type Analysis of the Physical Properties
molecular weight
number of H-donors
(NHD)
number of H-acceptors
(NHA)
tPSA (polar surface
partition coefficient (log
a
b
c
entry
product
(MW)
area)
P)
1
6{1,1,1,1,1}
6{1,1,1,1,6}
6{2,1,1,1,6}
6{4,1,1,1,6}
6{6,1,1,1,6}
6{7,1,1,1,6}
6{8,1,1,1,6}
6{2,2,1,1,6}
6{1,4,1,1,6}
6{2,3,1,1,6}
6{2,5,1,1,6}
6{2,7,1,1,6}
6{1,6,1,1,6}
6{1,1,2,1,6}
6{1,1,3,1,6}
6{1,1,1,2,6}
6{1,1,1,1,2}
6{1,1,1,1,3}
6{1,1,1,1,4}
6{1,1,1,1,5}
6{1,1,1,1,7}
6{1,1,1,2,8}
7{1,8,4,1,6}
7{1,8,4,1,7}
7{1,8,5,2,6}
7{1,8,4,2,7}
7{2,8,5,2,6}
7{1,8,6,2,6}
8{1,1,1,1,11}
8{1,1,1,1,9}
8{1,1,1,1,10}
8{2,1,1,1,11}
8{6,1,1,1,11}
8{8,1,1,1,11}
8{1,3,1,1,11}
8{1,5,1,1,11}
8{1,7,1,1,11}
8{1,8,5,2,11}
612
626
661
640
660
606
606
690
671
694
626
650
686
660
626
600
646
657
626
626
592
592
626
592
536
504
572
749
636
574
602
670
650
642
670
602
626
548
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
9
9
106.47
106.47
106.47
106.47
106.47
106.47
106.47
115.76
158.26
106.47
106.47
115.70
106.47
106.47
106.47
106.47
106.47
106.47
158.28
106.47
106.47
106.47
106.47
106.47
106.47
106.47
106.47
132.49
106.47
106.47
106.47
106.47
106.47
106.47
106.47
106.47
115.70
106.47
5.57
5.57
5.59
5.56
5.57
6.58
5.57
5.57
8.18
5.67
6.18
5.51
5.59
5.31
5.55
6.27
5.58
8.27
5.64
5.79
5.50
5.57
3.81
3.30
3.31
4.10
3.11
3.27
5.54
5.41
5.31
5.81
5.59
5.70
5.41
5.82
5.52
2
3
9
4
9
5
9
6
9
7
9
8
10
11
9
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
9
10
9
9
9
9
9
11
9
9
9
9
9
9
9
9
9
12
9
9
9
9
9
9
9
9
10
9
3.69
a
b
Mass spectra were taken on a Finnigan TSQ Quantum−MS in strument in the electrospray ionization (ESI) mode. tPSA were given by
c
ChemBioOffice 2008. log P was tested in n-octyl alcohol−water system by HPLC analysis.
G1214B VWD). All other chemicals were commercially
available and used without further purification.
ASSOCIATED CONTENT
■
S
* Supporting Information
The experimental details and the spectroscopic data of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Typical Experimental Procedure. Amine (2 mmol) and
aldehyde (2 mmol) were dissolved in a sealed tube with 3 mL
of MeOH and stirred at room temperature for 30 min. Then
para-azido-benzoic acid (2 mmol) and isocyanide (2 mmol)
were added. The mixture was stirred for 1−24 h. Then
corresponding aniline (2.4 mmol), diketene (2.4 mmol) and
triethylamine (2.4 mmol) were added in the seal tube and
raised the reaction temperature to 80 °C for 24 h. Then, the
mixture was cooled to room temperature, and the product
precipitated. The product was filtered and washed with
methanol. When the product was well soluble in MeOH, the
solvent was removed in vacuo, and the residue was purified by
column chromatography (hexanes/ethyl acetate 3/1).
AUTHOR INFORMATION
■
Corresponding Author
*Fax: (+86)-25-84315030. Tel: (+86)-25-84315514. E-mail: c.
cai@mail.njust.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Analysis and Testing Center of Nanjing
University of Science and Technology assistance with NMR
spectroscopic analysis.
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Research Article
synthesis of bile acid−peptide conjugates linked via triazole moiety.
Org. Biomol. Chem. 2011, 9, 4921−4926.
REFERENCES
■
(1) (a) Horne, W. S.; Yadav, M. K.; Stout, C. D.; Ghadiri, M. R.
Heterocyclic peptide backbone modifications in an α-helical coiled
coil. J. Am. Chem. Soc. 2004, 126, 15366−15367. (b) Bock, V. D.;
Hiemstra, H.; Maarseveen, J. H. Cu1-catalyzed alkyne-azide “click”
cycloadditions from a mechanistic and synthetic perspective. Eur. J.
Org. Chem. 2005, 51−68. (c) Angell, Y. L.; Burgess, K.
Peptidomimetics via copper-catalyzed azide-alkyne cycloadditions.
Chem. Soc. Rev. 2007, 36, 1674−1689. (d) Pedersen, D. S.; Abell, A.
1,2,3-Triazoles in peptidomimetic chemistry. Eur. J. Org. Chem. 2011,
2399−2411.
(2) Horne, W. S.; Yadav, M. K.; Stout, C.; Ghadiri, M. R.
Heterocyclic peptide backbone modifications in an α-helical coiled
coil. J. Am. Chem. Soc. 2004, 126, 15366−15367.
(3) Miller, N.; Williams, G. M.; Brimble, M. A. Synthesis of fish
antifreeze neoglycopeptides using microwave-assisted “click chemistry.
Org. Lett. 2009, 11, 2409−2412.
(4) Wan, Q.; Chen, J.; Chen, G.; Danishefsky, S. J. A potentially
valuable advance in the synthesis of carbohydrate-based anticancer
vaccines through extended cycloaddition chemistry. J. Org. Chem.
2006, 71, 8244−8249.
(5) Tornøe, C. W.; Christensen, C.; Meldal, M. Peptidotriazoles on
solid phase: [1,2,3]-Triazoles by regiospecific copper(I)-catalyzed 1,3-
dipolar cycloadditions of terminal alkynes to azides. J. Org. Chem.
2002, 67, 3057−3064.
(6) Whiting, M.; Tripp, J. C.; Lin, Y. C.; Lindstrom, W.; Olson, A. J.;
Elder, J. H.; Sharpless, K. B.; Fokin, V. V. Rapid discovery and
structure−activity profiling of novel inhibitors of human immunode-
ficiency virus type 1 protease enabled by the copper(I)-catalyzed
synthesis of 1,2,3-triazoles and their further functionalization. J. Med.
Chem. 2006, 49, 7697−7710.
(7) (a) Angelo, N. G.; Arora, P. S. Solution- and solid-phase synthesis
of triazole oligomers that display protein-like functionality. J. Org.
Chem. 2007, 72, 7963−7967. (b) Angelo, N. G.; Arora, P. S.
Nonpeptidic foldamers from amino acids: Synthesis and character-
ization of 1,3-substituted triazole oligomers. J. Am. Chem. Soc. 2005,
127, 17134−17135.
(8) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.;
Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfieldt, J. Methods for
drug discovery: Development of potent, selective, orally effective
cholecystokinin antagonists. J. Med. Chem. 1988, 31, 2235−2246.
(b) Patchett, A. A.; Nargund, R. P. Privileged structures: an update.
Annu. Rep. Med. Chem. 2000, 35, 289−298. (c) Triggle, D. J. 1,4-
Dihydropyridines as calcium channel ligands and privileged structures.
Cell. Mol. Neurobiol. 2003, 23, 293−303. (d) Poupaert, J.; Carato, P.;
Colacino, E. 2(3H)-Benzoxazolone and bioisosters as “privileged
scaffold” in the design of pharmacological probes. Curr. Med. Chem
2005, 12, 877−885.
(9) (a) Kuijpers, B. M.; Groothuys, S.; Keereweer, A. R.; Quaedflieg,
P. M.; Blaauw, R. H.; Delft, F. L.; Rutjes, F. T. Expedient synthesis of
triazole-linked glycosyl amino acids and peptides. Org. Lett. 2004, 6,
3123−3126. (b) Cantel, S.; Isaad, A. C; Scrima, M.; Levy, J. J.;
DiMarchi, R. D.; Rovero, P.; Halperin, J. A.; D’Ursi, A. M.; Papini, A.
M.; Chorev, M. Synthesis and conformational analysis of a cyclic
peptide obtained via i to i + 4 intramolecular side-chain to side-chain
azide-alkyne 1,3-dipolar cycloaddition. J. Org. Chem. 2008, 73, 5663−
5674.
(10) (a) Beraa, S.; Zhanel, G. G.; Schweizera, F. Evaluation of
amphiphilic aminoglycoside-peptide triazole conjugates as antibacterial
agents. Bioorg. Med. Chem. Lett. 2010, 20, 3031−3035. (b) Bock, V. D.;
Speijer, D.; Hiemstra, H.; Maarseveen, J. H. 1,2,3-Triazoles as peptide
bond isosteres: synthesis and biological evaluation of cyclotetrapeptide
mimics. Org. Biomol. Chem. 2007, 5, 971−975. (c) Nenajdenko, V. G.;
Gulevich, A. V.; Sokolova, N. V.; Mironov, A. V.; Balenkova, E. S.
Chiral isocyanoazides: Efficient bifunctional reagents for bioconjuga-
tion. Eur. J. Org. Chem. 2010, 1445−1449. (d) Sokolova, N. V.;
Latyshev, G. V.; Lukashev, N. V.; Nenajdenko, V. G. Design and
(11) (a) Multicomponent Reactions; Zhu, J. H., Ed; Wiley-VCH:
Weinheim, Germany; 2005 and references therein. (b) Toure, B. B.;
Hall, D. G. Expedient synthesis of triazole-linked glycosyl amino acids
and peptides. Chem. Rev. 2009, 109, 4439−4486. (c) Teimouri, M. B.;
Akbari-Moghaddam, P.; Golbaghi, G. Pseudo-five-component reaction
between 3-formylchromones, Meldrum’s acid, isocyanides and primary
arylamines: Diversity-oriented synthesis of novel chromone-containing
peptidomimetics. ACS Comb. Sci. 2011, 13, 659−666. (d) Granger, B.
A.; Kaneda, K.; Martin, S. F. Libraries of 2,3,4,6,7,11b-hexahydro-1H-
pyrido[2,1-a]isoquinolin-2-amine derivatives via a multicomponent
assembly process/1,3-dipolar cycloaddition strategy. ACS Comb. Sci
2012, 14, 75−79. (e) Zou, Y.; Hu, Y.; Liu, H; Shi, D. H. Rapid and
efficient ultrasound-assisted method for the combinatorial synthesis of
spir[indoline-3,4′-pyrano[2,3-c]pyrazole] derivatives. ACS Comb. Sci
2012, 14, 38−43.
(12) (a) Eelco, R; Rachel, S; Romano, V. A. Orru multicomponent
reaction design in the quest for molecular complexity and diversity.
Angew. Chem., Int. Ed. 2011, 50, 6234−6246. (b) Dhevalapally, B. R.;
Sangeeta, J. Sequential one-pot combination of multi-component and
multi-catalysis cascade reactions: an emerging technology in organic
synthesis. Org. Biomol. Chem. 2011, 9, 1277−1300.
(13) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
A Stepwise Huisgen cycloaddition process: Copper(I)-catalyzed
regioselective “ligation” of azides and terminal alkynes. Angew.
Chem., Int. Ed. 2002, 41, 2596−2599. (b) Duval, R.; Kolb, S.; Braud,
E.; Genest, G.; Garbay, C. Rapid discovery of triazolobenzylidene-
thiazolopyrimidines (TBTP) as CDC25 phosphatase inhibitors by
parallel click chemistry and in situ screening. J. Comb. Chem. 2009, 11,
947−950. (c) Fenster, E.; Long, T. R.; Zang, Q.; Hill, D.;
Neuenswander, B.; Lushington, G. H.; Zhou, A.; Santini, C.;
Hanson, P. R. Automated synthesis of a 184-member library of
thiadiazepan-1,1-dioxide-4-ones. ACS Comb. Sci. 2011, 13, 244−250.
(14) (a) Link, A. K.; Tirrell, D. A. Excited-state intramolecular proton
transfer in o-hydroxybiaryls: A new route to dihydroaromatic
compounds. J. Am. Chem. Soc. 2003, 125, 1164−1165. (b) Li, Z.;
Seo, T. S.; Ju, J. Y. 1,3-Dipolar cycloaddition of azides with electron-
deficient alkynes under mild condition in water. Tetrahedron Lett.
2004, 45, 3143−3146.
(15) (a) Constabel, F.; Ugi, I. Repetitive Ugi reactions. Tetrahedron
2001, 57, 5785−5789. (b) David, E. P.; Dinabandhu, N.; Laura, W.;
Ryszard, O.; Jack, J. C. Solid-phase synthesis of five-dimensional
libraries via a tandem Petasis−Ugi multi-component condensation
reaction. Tetrahedron Lett. 2003, 44, 5121−5124. (c) Naskar, D.; Roy,
A.; Seibel, W. L.; West, L.; Portlock, D. E. The synthesis of aza-β-
lactams via tandem Petasis−Ugi multi-component condensation and
1,3-diisopropylcarbodiimide (DIC) condensation reaction. Tetrahe-
dron Lett. 2003, 44, 6297−6300. (d) Paravidino, M.; Scheffelaar, R.;
Schmitz, R. F.; Kanter, F. J. J.; de; Groen, M. B.; Ruijter, E.; Orru, R. V.
A. A Flexible six-component reaction to access constrained
depsipeptides based on a dihydropyridinone core. J. Org. Chem.
2007, 72, 10239−10242. (e) Elders, N.; Born, D.; Hendrickx, L. J. D.;
Timmer, B. J. J.; Krause, A.; Janssen, E.; Kanter, F. J. J.; Ruijter, E.;
Orru, R. V. A. The efficient one-pot reaction of up to eight
components by the union of multicomponent reactions. Angew. Chem.,
Int. Ed. 2009, 48, 5856−5859. (f) Al-Tel, T. H.; Al-Qawasmeh, R. A.;
Voelter, W. Rapid assembly of polyfunctional structures using a one-
pot five-and six-component sequential Groebke−Blackburn/Ugi/
Passerini process. Eur. J. Org. Chem. 2010, 5586−5593.
(16) (a) Krivopalov, V. P.; Shkurko, O. P. 1,2,3-Triazole and its
derivatives. Development of methods for the formation of the triazole
ring. Russ. Chem. Rev. 2005, 74, 339−379. (b) Pokhodylo, N. T.;
Matiychuk, V. S.; Obushak, M. D. One-pot multicomponent synthesis
of 1-aryl-5-methyl-N-R2-1H-1,2,3-triazole-4-carboxamides: An easy
procedure for combinatorial chemistry. J. Comb. Chem. 2009, 11,
481−485.
(17) (a) Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. A Strain-
Promoted [3 + 2] azide−alkyne cycloaddition for covalent
314
dx.doi.org/10.1021/co3000117 | ACS Comb. Sci. 2012, 14, 309−315

ACS Combinatorial Science
Research Article
modification of biomolecules in living systems. J. Am. Chem. Soc. 2004,
126, 15046−15047. (b) Elamari, H.; Meganem, F.; Girard, C.
Chemoselective preparation of disymmetric bistriazoles from
bisalkynes. Tetrahedron Lett. 2011, 52, 658−660.
315
dx.doi.org/10.1021/co3000117 | ACS Comb. Sci. 2012, 14, 309−315