Peptidomimetics through click chemistry: Synthesis of novel β-Keto triazole acids from N-protected amino acids

Article abstract of DOI:10.1007/s10989-010-9214-z

An efficient procedure for the preparation of azidomethylketones from N-urethane protected amino acids and their application in Cu(I) catalyzed azide-alkyne cycloaddition reaction are described. The synthesis has been carried out under mild conditions wit

Full text of DOI:10.1007/s10989-010-9214-z

Int J Pept Res Ther (2010) 16:283–290
DOI 10.1007/s10989-010-9214-z
SHORT COMMUNICATION
Peptidomimetics Through Click Chemistry: Synthesis of Novel
b-Keto Triazole Acids from N-Protected Amino Acids
•
N. Narendra T. M. Vishwanatha
•
Vommina V. Sureshbabu
Accepted: 5 May 2010 / Published online: 16 May 2010
Ó Springer Science+Business Media, LLC 2010
Abstract An efficient procedure for the preparation of
azidomethylketones from N-urethane protected amino
acids and their application in Cu(I) catalyzed azide-alkyne
cycloaddition reaction are described. The synthesis has
been carried out under mild conditions with all the com-
monly used urethane protected (Fmoc, Boc and Z) amino
acids and the desired azides/triazoles were obtained in
good yields. Incorporation of these triazole amino acids
into small peptides generating dipeptidomimetics contain-
ing b-keto triazole units has also been demonstrated.
method is also marked by simple and milder reaction
conditions, oxygen and water tolerance, easy route to
product isolation in quantitative yields, as well as a very
high degree of chemoselectivity (Gil et al. 2007). Conse-
quently, this heterocycle is presently investigated for
potential applications in a broad spectrum of areas such as
medicinal (Lin and Walsh 2004), polymer (Laurent and
Grayson 2006) and supramolecular (Boland et al. 2006)
chemistries, and for the construction of nano-sized mate-
rials (Horne et al. 2003). This residue has been inserted as
crucial structural motif in antimicrobial (Genin et al. 2000)
and anti-HIV agents (Whiting et al. 2006) in artificial
secondary structures such as b-turn mimics (Oh and Guan
2006) and in self assembling peptide nanotubes (Horne
et al. 2003).
Keywords N-Urethane protected azidomethylketones Á
Cu(I) catalyzed cycloaddition reaction Á
N-Urethane protected b-keto triazole acids Á
b-Keto triazole linked dipeptidomemitics
In peptide chemistry, the azide-alkyne cycloaddition is
currently employed as a ligation technique for linking
peptide fragments for macrocyclization and polymerization
via the formation of triazole (Haridas et al. 2007) as well as
serving a vital route synthesize unnatural amino acids
containing 1,2,3-triazole moiety (Paul et al. 2006). These
amino acids have been synthesized mainly by the cyclo-
addition of: (a) a-azido acids with terminal acetylenes
obtained from N-protected amino acids (Victoria et al.
2007) and (b) N-protected b-amino alkyl azides with ali-
phatic acids/esters (Tornoe et al. 2002). Due to the simple
structure of the amino acid derived azides used as sub-
strates for the synthesis of these amino acids, the resulting
unnatural amino acids largely contain the triazole unit as
the only non-native structural element (Link et al. 2004).
On the other hand, polyfunctionalized structural units
containing triazole moiety are also possible. b-Keto tria-
zoles are one such class of compounds that can be syn-
thesized by executing the above click reaction using
azidomethylketones as the azido fragment. Reports on the
Introduction
Recent years have witnessed an exploding growth of
interest in the inclusion of 1,4-disubstituted, 1,2,3-triazole
unit into peptide backbone (Bock et al. 2006). The dis-
covery of rapid and regioselective method for the synthesis
of this nucleus via Cu(I) mediated cycloaddition of an
azide with a terminal alkyne (click chemistry) by Sharpless
(Rostovtsev et al. 2002) and Meldal (Tornoe et al. 2002)
has remarkably accelerated the studies involving prepara-
tion of novel molecules bearing the triazole unit. The click
N. Narendra Á T. M. Vishwanatha Á V. V. Sureshbabu (&)
Peptide Research Laboratory, Department of Studies in
Chemistry, Bangalore University, Central College Campus,
Dr. B. R. Ambedkar Veedhi, Bangalore 560001, India
e-mail: sureshbabuvommina@rediffmail.com;
hariccb@hotmail.com
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O
NMe2
N
Peptide
N
OH
N
N
O
O
N
H
H
O
N
N
O
N
O
AcHN
N
R
H
4
N
N
N
N
N
H
H
O
N
O
O
HOOC
H
COOH
O
(Kolb and Sharpless 2003)
( Jain and Vederas 2004)
(Franke et al 2005)
Fig. 1 Reported examples containing b-keto triazole and closely related units
synthesis of this class of compounds are scarce. Jain and
Vederas have prepared two examples of N-Boc protected
keto triazoles, during their studies on developing inhibitors
for hepatitis A virus proteinases, through cycloaddition of
Boc-protected azidomethylketones with dimethylacetyle-
nedicarboxylate (Jain and Vederas 2004; Fig. 1). But, the
reaction has been carried out in refluxing toluene and under
uncatalyzed conditions (non-click conditions) without the
requirement for regioselectivity in products since a sym-
metric alkyne was involved. Further, a series of compounds
containing closely connected structural unit; b-hydroxy
triazoles (hydroxyl ethylamine peptide isosteres, obtainable
by the single step reduction of the title triazoles) have been
synthesized via the epoxide route (Kolb and Sharpless
2003) and evaluated for HIV protease inhibitory activity.
A related structure has been generated during the ligation
of N-terminally modified peptides with azido and alkyne
moieties en route to the synthesis of assembled and scaf-
folded peptides via click chemistry (Franke et al. 2005).
The reported structures discussed above have been outlined
in Fig. 1. In this context, we envisaged the application of
Cu(I) mediated azide-alkyne cycloaddition to the synthesis
of hitherto unreported, N-protected amino acid derived
b-keto triazole acids which may be potentially useful
compounds to be included in the array of existing triazole
based unnatural amino acids and could find applications in
the development of therapeutical agents. Accordingly, we
herein report the first synthesis of N-Fmoc/Boc/Z-amino
acid derived b-keto triazoles and also demonstrate their
application as building blocks in the solution phase
synthesis of oligopeptidomimetics containing keto triazole
units.
reactions were monitored using TLCs with precoated silica
gel plates purchased from Merck. Column Chromatogra-
phy was performed with Merck silica gel (100–200) at
normal atmospheric pressure.
Synthesis
General Procedure for the Synthesis of Azidomethyl
Ketones 2a–r
Bromomethylketone 1 (10.0 mmol) and NaN3 (15.0 mmol,
975 mg) were dissolved in a mixture of acetone (20 ml)
and water (3.8 ml). The resulting solution was refluxed till
the completion of reaction (monitored by TLC) and then
cooled to rt. Acetone was evaporated from the reaction
mixture in vacuo and the residue was diluted with water.
The aqueous layer was extracted with ethyl acetate
(3 9 20 ml); the combined organic extract was washed
with 5% Na2CO3 (2 9 10 ml), 10% citric acid (2 9 10
ml), water (2 9 10 ml) and brine (1 9 10 ml), and dried
over anhydrous sodium sulfate. Solvent was removed
under reduced pressure and the crude product was purified
through column chromatography (silica gel 100–150 mesh
size; ethyl acetate: hexane system 2:8).
Spectral Data for Compounds 2a–r
1
Fmoc-Gly-CH2N3 2a: H NMR (CDCl3) d: 2.01 (s, 2H),
3.11 (s, 2H), 3.82 (t, J = 6.3 Hz, 1H),4.13 (d, J = 5.3 Hz,
2H), 6.66–7.71 (m, 8H), 5.03 (br, 1H); 13C NMR (CDCl3)
d: 45.1, 48.2, 57.6, 65.5, 120.5, 125.6, 127.4, 127.9, 128.6,
139.1, 142.3, 155.2, 205.3.
Fmoc-Ala-CH2N3 2b: 1H NMR (CDCl3) d: 1.22 (d,
3H), 3.91 (t, J = 7.2 Hz, 1H), 4.22 (d, J = 5.3 Hz, 2H),
4.43–4.48 (m, 2H), 6.88–7.72 (m, 8H), 5.06 (br, 1H); 13C
NMR (CDCl3) d: 14.8, 53.1, 46.8, 57.2, 66.3, 120.1, 125.2,
126.8, 126.5, 139.8, 141.4, 149.8, 206.2.
Materials and Methods
Chemicals and Instruments
All solvents were freshly distilled before use. Amino acids
1
Fmoc-Phe-CH2N3 2c: 1H NMR (CDCl3) d: 1.97 (s,
2H), 2.26 (dd, 1H), 2.92 (dd, 1H), 3.71 (t, J = 7.2 Hz, 1H),
4.12 (d, J = 5.8 Hz, 2H), 4.33 (t, 1H), 6.95–7.7 (m, 13H),
5.15 (br, 1H); 13C NMR (CDCl3) d: 34.2, 46.3, 57.1, 62.1,
66.5, 126.3, 127.4, 128.2, 139.4, 142.3, 126.6, 125.8,
127.6, 140.1, 155.1, 205.2.
were used as received from Sigma–Aldrich Company. H
NMR and 13C NMR were recorded on a Bruker AMX
400 MHz instrument with Me4Si as an internal standard.
Mass spectra were recorded on high resolution mass
spectra (HRMS) Q-T of micro mass spectrometer. All the
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1
1
Fmoc-Leu-CH2N3 2d: H NMR (CDCl3) d: 0.92 (d,
Z-Phg-CH2N3 2n: H NMR (CDCl3) d: 2.08 (s, 2H),
4.72 (s, 2H), 5.11 (s, 1H), 6.35–7.22 (m, 10H); 13C NMR
(d, CDCl3): 53.1, 62.2, 63.8, 126.8, 128.8, 125.3, 126.1,
128.9, 132.2, 139.6, 155.6, 205.6.
6H), 1.11(t, 2H), 1.28–1.34(m, 1H), 1.50–1.59 (m, 2H),
3.81 (t, J = 6.9 Hz, 1H), 4.08 (d, J = 5.4 Hz, 2H), 4.18 (d,
1H), 6.72–7.59 (m, 8H), 5.15 (br, 1H); 13C NMR (CDCl3)
d: 21.1, 22.4, 37.6, 46.2, 55.6, 57.0, 65.9, 125.7, 126.9,
127.5, 140.3, 142.6, 155.3, 205.8.
Fmoc-Ile-CH2N3 2e: 1H NMR (CDCl3) d: 0.71 (t, 3H),
0.92 (d, 3H), 1.01 (m, 2H), 1.97 (m, 1H), 1.97 (s, 2H), 3.91
(t, J = 7.0 Hz, 1H), 4.16 (d, J = 5.8 Hz, 2H), 4.23 (d, 1H),
6.77–7.97 (m, 8H); 13C NMR (CDCl3) d: 10.1, 14.2, 23.4,
32.1, 46.1, 55.8, 66.9, 125.3, 127.9, 128.2, 139.6, 142.1,
155.2, 206.2.
1
Z-Asp (oxa)-CH2N3 2o: H NMR (CDCl3) d: 2.11 (s,
2H), 2.19 (dd, 1H), 2.85 (dd, 1H), 3.85 (t, 1H), 4.52 (s, 2H),
4.96 (s, 2H), 6.85 (s, 5H); 13C NMR (CDCl3) d: 34.4, 51.6,
58.2, 76.4, 65.1, 126.8, 128.2, 139.8, 154.2, 173.2, 204.1.
1
Boc-Phe-CH2N3 2p: H NMR (CDCl3) d: 1.10 (s, 9H),
2.12 (s, 2H), 2.39 (dd, 1H), 2.96 (dd, 1H), 3.56 (t, 1H), 6.92
(m, 5H); 13C NMR (CDCl3) d: 26.8, 34.2, 55.1, 62.2, 76.8,
125.8, 127.6, 128.0, 138.4, 155.1, 206.5.
Fmoc-Val-CH2N3 2f: 1H NMR (CDCl3) d: 0.82 (d, 6H),
1.86 (s, 2H), 2.32 (m, 1H), 3.72 (t, J = 6.9 Hz, 1H), 4.02
(d, J = 5.4 Hz, 2H), 4.19 (d, 1H), 6.46–7.79 (m, 8H), 5.23
(s, 1H); 13C NMR (CDCl3) d: 15.3, 26.3, 46.3, 63.5, 55.2,
65.8, 125.6, 126.7, 127.8, 139.3, 141.6, 154.8, 205.6.
Boc-Pro-CH2N3 2q: H NMR (CDCl3) d: 1.12 (s, 9H),
1
1.56–1.82 (m, 4H), 2.10 (s, 2H), 2.95 (dd, 1H), 3.02 (dd,
1H), 3.85 (t, 1H); 13C NMR (CDCl3) d: 21.8, 25.6, 26.9,
45.7, 55.2, 63.2, 156.2, 206.1.
1
Boc-Glu(c-Bzl)-CH2N3 2r: H NMR (CDCl3) d: 1.15
1
Fmoc-Cys-CH2N3 2g: H NMR (CDCl3) d: 1.03 (br,
(s, 9H), 1.95 (s, 2H), 2.11 (m, 4H), 3.85 (t, 1H), 4.56 (s,
2H), 6.85 (s, 5H), 5.09 (br, 1H); 13C NMR (CDCl3) d: 22.5,
26.6, 27.1, 55.2, 59.2, 65.7, 76.2, 125.8, 127.2, 128.2,
139.1, 155.2, 171.2, 206.0.
1H), 1.92 (s, 2H), 2.11 (dd, 1H), 2.86 (dd, 1H), 3.88 (t,
J = 7.8 Hz, 1H), 4.22 (d, J = 5.3 Hz, 2H), 4.32 (t, 1H),
6.69–7.87 (m, 8H); 13C NMR (CDCl3) d: 22.6, 44.8, 55.3,
63.2, 66.1, 125.8, 127.5, 128.1, 139.6, 140.2, 155.2, 205.6.
1
Fmoc-Ser-CH2N3 2h: H NMR (CDCl3) d: 1.23 (br,
General Procedure for the Synthesis of 3a-r
1H), 2.11 (s, 2H), 2.96 (dd, 1H), 3.08 (dd, 1H), 3.82 (t,
J = 6.9 Hz, 1H), 4.29 (d, J = 5.7 Hz, 2H), 3.85 (t, 1H),
6.86–7.91 (m, 8H); 13C NMR (CDCl3) d: 45.2, 63.1, 55.1,
58.3, 66.1, 125.9, 127.3, 127.9, 140.5, 155.2, 142.1, 206.0.
Fmoc-Asp(b-Bzl)-CH2N3 2i: 1H NMR (CDCl3) d: 1.91
(s, 2H), 1.98 (dd, 1H), 2.23 (dd, 1H), 3.82 (t, J = 6.9 Hz,
1H), 4.01 (t, 1H), 4.26 (d, J = 5.7 Hz, 2H), 5.06 (br, 1H),
5.22 (s, 2H), 6.68–7.77 (m, 13H); 13C NMR (CDCl3) d:
33.4, 45.2, 53.2, 55.2, 63.5, 65.5, 125.5, 126.9, 128.3,
127.5, 128.5, 140.2, 142.1, 141.3, 155.2, 178.1, 206.2.
Azidomethylketone 2 (10.0 mmol) and propiolic acid
(10.0 mmol) were suspended in acetonitrile (10 ml). To
this, a solution of sodium ascorbate (1.0 mmol) in water
(1.0 ml) followed by CuSO4Á5H2O (0.10 mmol in 1.0 ml
of water) were added. The resultant heterogeneous mixture
was stirred vigorously overnight, at which the TLC anal-
ysis has indicated the complete consumption of the reac-
tants. Na2CO3 (10 mmol) was added to the reaction
mixture and stirred for fifteen min at room temperature. It
was then diluted with water and the aqueous layer was
washed with diethyl ether (3 9 10 ml). 10 % citric acid
solution was added slowly to the aqueous layer to precip-
itate the product which was filtered, washed thoroughly
with water and dried.
1
Fmoc-Lys(Z)-CH2N3 2j: H NMR (CDCl3) d: 0.91–
2.23 (m, 8H), 1.95 (s, 2H), 3.55 (t, J = 7.1 Hz, 1H), 4.19
(d, J = 5.3 Hz, 2H), 4.42 (t, 1H), 4.92 (s, 2H), 6.92–7.91
(m, 13H), 5.07 (br, 1H); 13C NMR (CDCl3) d: 20.2, 26.1,
39.7, 46.1, 55.1, 59.5, 63.2, 64.5, 65.2, 125.1, 126.3, 128.3,
139.5, 141.2, 155.6, 206.1.
1
Z-Leu-CH2N3 2k: H NMR (CDCl3) d: 0.92 (d, 6H),
Spectral Data for Compounds 3a–r
1.22 (t, 2H), 1.41 (m, 1H), 2.10 (s, 2H), 3.85 (t, 1H), 4.95
(s, 2H), 6.96 (s, 5H), 5.09 (br, 1H); 13C NMR (CDCl3) d:
20.5, 21.2, 34.6, 56.1, 54.4, 64.6, 126.3, 128.3, 127.6,
139.1, 155.0, 206.1.
3a: 1H NMR (DMSO-d6) d: 3.86 (s, 2H), 3.21 (s, 2H), 3.91
(t, J = 7.1 Hz, 1H), 4.10 (d, J = 6.2 Hz, 2H), 6.91 (br,
1H), 6.69–7.81 (m, 8H), 8.12 (s, 1H), 10.11 (s, 1H); 13C
NMR (DMSO-d6) d: 46.1, 48.8, 57.6, 66.4, 123.8, 124.4,
126.1, 127.3, 128.7, 139.3, 140.2, 142.3, 155.6, 165.5,
205.4.
1
Z-Val-CH2N3 2l: H NMR (CDCl3) d: 0.83 (d, 6H),
2.12 (s, 2H), 2.81 (m, 1H), 3.91 (d, 1H), 4.85 (s, 2H), 6.99
(s, 5H), 5.12 (br, 1H); 13C NMR (CDCl3) d: 15.6, 26.2,
55.1, 62.3, 64.5, 126.3, 128.5, 127.0, 139.1, 155.2, 205.9.
1
3b: H NMR (DMSO-d6) d: 1.32 (d, 3H), 3.65 (s, 2H),
1
Z-Thr-CH2N3 2m: H NMR (CDCl3) d: 0.97 (d, 3H),
3.92 (t, J = 3.8 Hz, 1H), 4.26 (d, J = 5.6 Hz, 2H), 4.42
(m, 1H), 5.09 (br, 1H), 6.89–7.91 (m, 8H), 8.12 (s, 1H),
10.25 (s, 1H); 13C NMR (DMSO-d6) d: 14.7, 46.2, 57.1,
58.0, 66.0, 123.3, 124.5, 126.6, 127.5, 128.4, 139.8, 141.2,
140.5, 148.6, 165.2, 206.1.
1.52 (s, 1H), 2.11 (s, 2H), 3.82 (m, 1H), 4.01 (d, 1H), 4.85
(s, 2H), 6.89 (s, 5H), 5.12 (br, 1H); 13C NMR (CDCl3) d:
18.3, 55.4, 63.2, 64.0, 65.1, 126.5, 127.0, 128.5, 139.8,
155.5, 206.2.
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1
3c: H NMR (DMSO-d6) d: 2.22 (dd, 1H), 2.86 (dd,
1H), 3.68 (s, 2H), 3.96 (t, J = 7.1 Hz, 1H), 4.32 (d,
J = 5.4 Hz, 2H), 4.46 (t, 1H), 6.69–7.99 (m, 8H), 8.12 (s,
1H), 10.28 (s, 1H); 13C NMR (DMSO-d6) d: 34.1, 46.3,
57.1, 61.3, 66.1, 124.7, 125.8, 126.2, 126.6, 127.8, 138.1,
141.9, 140.6, 155.2, 165.4, 206.2.
d: 20.6, 21.4, 34.5, 54.5, 56.1, 64.9, 124.4, 126.6, 128.1,
139.1, 140.1, 155.2, 166.3, 206.1.
1
3l: H NMR (DMSO-d6) d: 0.81 (d, 6H), 2.32 (m, 1H),
3.41 (s, 2H), 3.82 (d, 1H), 4.71 (s, 2H), 5.63 (br, 1H), 6.93
(s, 5H), 7.91 (s, 1H), 10.03 (s, 1H). 13C NMR (DMSO-d6)
d: 15.5, 26.5, 63.1, 64.2, 55.2, 124.4, 126.8, 127.0, 128.3,
139.1, 140.2, 155.2, 166.3, 205.6.
1
3d: H NMR (DMSO-d6) d: 0.92 (d, 6H), 1.11 (t, 2H),
1.28 (m, 1H), 3.92 (s, 2H), 3.88 (t, J = 6.9 Hz, 1H), 4.06
(d, J = 5.4 Hz, 2H), 4.11 (d, 1H), 6.79–7.91 (m, 8H), 5.36
(br, 1H), 8.10 (s, 1H), 10.11 (s, 1H); 13C NMR (DMSO-d6)
d: 21.1, 22.4, 37.6, 46.2, 57.6, 58.1, 65.9, 124.3, 125.7,
126.9, 127.5, 138.3, 140.6, 141.2, 155.3, 165.8, 205.8.
3m: 1H NMR (DMSO-d6) d: 0.86 (d, 3H), 1.41 (br, 1H),
3.35 (s, 2H), 4.12 (d, 1H), 4.71 (s, 2H), 5.13 (br, 1H), 6.86
(s, 5H), 7.96 (s, 1H), 10.19 (s, 1H); 13C NMR (DMSO-d6)
d: 18.4, 55.6, 64.2, 65.0, 124.8, 126.8, 127.0, 128.3, 139.2,
140.2, 155.2, 166.5, 205.6.
1
1
3e: H NMR (DMSO-d6) d: 0.71 (t, 3H), 0.93 (d, 3H),
3n: H NMR (DMSO-d6) d: 3.25 (s, 2H), 4.63 (s, 2H),
1.01 (m, 2H), 1.92 (m, 1H), 3.59 (s, 2H), 3.97 (t,
J = 7.0 Hz, 1H), 4.13 (d, J = 5.8 Hz, 2H), 4.25 (d, 1H),
6.89–7.79 (m, 8H), 6.01 (br, 1H), 7.81 (s, 1H), 10.10 (s,
1H); 13C NMR (DMSO-d6) d: 10.0, 13.2, 22.8, 32.6, 45.9,
56.5, 60.3, 66.8, 124.2, 125.2, 127.2, 128.0, 128.2, 139.2,
140.2, 141.8, 155.2, 166.2, 205.8.
5.29 (s, 1H), 5.09 (br, 1H), 6.79–7.16 (m, 10H), 7.91 (s,
1H), 10.01 (s, 1H); 13C NMR (DMSO-d6) d: 53.2, 62.1,
64.0, 124.4, 125.2, 126.5, 127.2, 128.7, 132.5, 139.5,
140.1, 155.8, 165.5, 205.5.
1
3o: H NMR (DMSO-d6) d: 2.69 (dd, 1H), 2.96 (dd,
1H), 3.42 (s, 2H), 3.85 (t, 1H), 4.52 (s, 2H), 5.01 (s, 1H),
5.16 (s, 1H), 6.89 (s, 5H), 7.71 (s, 1H), 10.26 (s, 1H); 13C
NMR (DMSO-d6) d: 34.4, 51.6, 62.5, 76.4, 65.1, 124.5,
126.8, 128.4, 139.8, 140.3, 153.8, 166.5, 173.2, 204.1.
1
3f: H NMR (DMSO-d6) d: 0.85 (d, 6H), 2.21 (m, 1H),
3.32 (s, 2H), 3.68 (t, J = 6.9 Hz, 1H), 4.03 (d, J = 5.5 Hz,
1H), 4.25 (d, 1H), 5.06 (br, 1H), 6.69–7.97 (m, 8H), 8.02 (s,
1H), 10.21 (s, 1H); 13C NMR (DMSO-d6) d: 15.2, 26.4,
46.2, 63.5, 56.6, 65.4, 124.3, 125.2, 126.6, 127.3, 128.6,
139.4, 140.0, 141.1, 154.2, 166.2, 205.5.
3g: 1H NMR (DMSO-d6) d: 1.01 (br, 1H), 2.39 (dd, 1H),
2.55 (dd, 1H), 3.18 (s, 2H), 3.88 (t, J = 7.0 Hz, 1H), 4.24
(d, J = 5.1 Hz, 2H), 4.26 (t, 1H), 5.24 (br, 1H), 6.88–7.76
(m, 8H), 8.21(s, 1H), 9.22 (s, 1H); 13C NMR (DMSO-d6) d:
20.4, 44.3, 55.9, 63.4, 66.2, 124.4, 125.8, 126.6, 127.8,
128.2, 139.5, 140.1, 141.6, 155.6, 165.7, 205.5.
3h: 1H NMR (DMSO-d6) d: 1.39 (br, 1H), 3.29 (dd, 1H),
3.69 (dd, 1H), 3.18 (s, 2H), 3.86 (t, J = 7.1 Hz, 1H), 3.91
(t, 1H), 4.29 (d, J = 5.3 Hz, 2H), 5.08 (br, 1H), 6.89–7.68
(m, 8H), 8.32 (s, 1H), 10.29 (s, 1H); 13C NMR (DMSO-d6)
d: 45.2, 63.1, 55.1, 58.3, 66.1, 124.6, 125.2, 125.9, 127.3,
128.7, 139.8, 140.1, 141.2, 155.4, 165.9, 205.1.
1
3p: H NMR (DMSO-d6) d: 1.12 (s, 9H), 3.63 (s, 2H),
2.18 (dd, 1H), 2.87 (dd, 1H), 3.69 (t, 1H), 5.96 (br, 1H),
6.99 (m, 5H), 7.81 (s, 1H), 10.39 (s, 1H); 13C NMR
(DMSO-d6) d: 26.8, 34.2, 55.1, 62.2, 76.2, 124.5, 125.8,
127.6, 128.0, 137.4, 140.6, 155.0, 166.5, 206.3.
3q: 1H NMR (DMSO-d6) d: 1.12 (s, 9H), 1.56–1.69 (m,
4H), 3.66 (s, 2H), 2.91 (m, 2H), 3.85 (t, 1H), 7.73 (s, 1H),
10.29 (s, 1H); 13C NMR (DMSO-d6) d: 21.6, 25.8, 26.9,
45.7, 57.2, 63.2, 77.3, 124.6, 140.3, 156.2, 165.4, 206.1.
1
3r: H NMR (DMSO-d6) d: 1.15 (s, 9H), 2.11 (m, 4H),
3.43 (s, 2H), 3.85 (t, 1H), 4.56 (s, 2H), 6.89 (s, 5H), 6.01
(br, 1H), 7.85 (s, 1H), 10.13 (s, 1H); 13C NMR (DMSO-d6)
d: 22.5, 26.6, 27.1, 55.2, 59.2, 65.7, 76.2, 124.4, 125.8,
127.2, 128.2, 139.1, 140.6, 155.9, 166.3, 170.2, 206.0.
3i: 1H NMR (DMSO-d6) d: 2.09 (dd, 1H), 2.36 (dd, 1H),
3.36 (s, 2H), 3.92 (t, J = 6.8 Hz, 1H), 4.18 (d, J = 5.4 Hz,
2H), 4.65 (t, 1H), 4.91 (s, 2H), 6.92–7.71 (m, 13H); 13C
NMR (DMSO-d6) d: 33.2, 45.6, 54.2, 55.7, 65.4, 67.6,
124.3, 125.2, 126.1, 127.8, 128.6, 139.0, 139.6, 140.2,
141.2, 155.2, 165.2, 171.4, 206.2.
General Procedure for the Synthesis of 4 and 5
N-Protected ketotriazole amino acid (1.0 mmol) was dis-
solved in dry THF (5 ml), and cooled to -15°C, EtOCOCl
(0.1 ml, 1.0 mmol) and TEA (0.1 ml, 1.0 mmol) were
added to the above solution and stirred for 10 min. While
maintaining the temperature at -10°C. The resulting
reaction mixture was treated with the neutralized solution
of amino acid methyl ester hydrochloride salt in THF
solution and the reaction mixture was allowed to stirred for
6 h (monitored by TLC). The THF was evaporated under
reduced pressure and the residue was taken in CH2Cl2
(15 ml), the CH2Cl2 was washed with 5% Na2CO3 (2 9
10 ml), 10% citric acid (2 9 10 ml), water (2 9 10 ml)
and brine (1 9 10 ml), and dried over anhydrous sodium
sulfate. Solvent was removed under reduced pressure.
1
3j: H NMR (DMSO-d6) d: 0.83–2.16 (m, 8H), 3.35 (s,
2H), 3.91 (t, J = 6.4 Hz, 1H), 4.23 (d, J = 5.2 Hz, 2H),
4.27 (t, 1H), 5.06 (s, 2H), 6.91–7.88 (m, 13H), 5.12 (br,
2H), 8.12 (s, 1H), 10.24 (s, 1H); 13C NMR (DMSO-d6) d:
20.2, 26.1, 39.5, 45.8, 55.0, 63.1, 64.1, 65.1, 124.4, 125.1,
126.4, 127.6, 128.3, 139.2, 141.1, 140.8, 166.2. 155.1,
205.8.
1
3k: H NMR (DMSO-d6) d: 0.90 (d, 6H), 1.31 (t, 2H),
1.53 (m, 1H), 3.62 (s, 2H), 3.81 (t, 1H), 4.21 (s, 2H), 6.89
(s, 5H), 7.72 (s, 1H), 10.29 (s, 1H); 13C NMR (DMSO-d6)
123

Int J Pept Res Ther (2010) 16:283–290
287
Spectral Data for Compounds 6–8
N-Hexane was added to obtain pure ketotriazole linked
dipeptidomemitics as white solid.
6: 1H NMR (DMSO-d6) d: 1.91 (s, 1H), 2.82 (dd, 1H), 3.16
(dd, 1H), 3.12 (s, 3H), 3.71 (dd, 1H), 3.86 (dd, 1H), 4.21 (t,
1H), 4.53 (t, 1H), 3.98 (t, J = 7.0 Hz, 1H), 4.02 (d,
J = 5.2 Hz, 2H), 4.26 (s, 2H), 6.58–7.89 (m, 13H), 8.12 (s,
1H); 13C NMR (DMSO-d6) d: 33.9, 46.5, 50.2, 56.1, 57.2,
60.6, 61.4, 66.3, 124.1, 125.4, 126.5, 127.3, 128.0, 138.5,
139.4, 140.4, 141.4, 155.4, 166.5, 170.4, 206.1.
Spectral Data for Compounds 4 and 5
4: 1H NMR (DMSO-d6) d: 1.1 (d, 3H), 2.51 (dd, 1H), 2.96
(dd, 1H), 3.12 (s, 3H), 3.98 (t, J = 7.1 Hz, 1H), 4.11 (t,
J = 5.2 Hz, 2H), 4.22 (m, 2H), 3.84 (s, 2H), 6.85–7.44 (m,
13H), 8.11 (s, 1H), 5.09 (br, 2H); 13C NMR (DMSO-d6) d:
14.1, 36.2, 46.4, 50.2, 51.3, 56.4, 66.1, 120.3, 125.2, 126.5,
127.3, 128.0, 128.3, 130.2, 140.1, 140.8, 142.2, 142.9,
155.3, 159.4, 170.2, 206.1.
5: 1H NMR (DMSO-d6) d: 2.81 (dd, 1H), 3.01 (dd, 1H),
3.12 (s, 3H), 3.91 (s, 2H), 4.12 (t, 1H), 4.82 (t, 1H), 5.01 (s,
4H), 6.85–7.44 (m, 15H), 7.91 (s, 1H), 5.89 (br, 2H); 13C
NMR (DMSO-d6) d: 33.4, 34.1, 47.2, 50.6, 55.8, 62.6,
64.4, 125.5, 126.6, 127.2, 127.7, 129.1, 138.1, 139.6,
140.4, 143.3, 155.0, 159.6, 169.4, 172.4, 205.5.
1
7: H NMR (DMSO-d6) d: 0.65 (d, 3H), 0.70 (t, 3H),
0.91 (d, 6H), 1.11 (s, 9H), 1.21 (m, 2H), 1.98 (m, 2H), 3.52
(s, 3H), 3.98 (s, 2H), 4.22 (d, 2H), 5.86 (br, 2H), 8.32 (s,
1H); 13C NMR (DMSO-d6) d: 10.4, 14.5, 16.2, 24.5, 26.5,
30.4, 33.5, 50.2, 56.2, 59.4, 60.6, 78.5, 124.4, 139.1, 155.2,
166.2, 170.1, 206.4.
1
8: H NMR (DMSO-d6) d: 0.86 (d, 6H), 1.05 (d, 3H),
1.28 (m, 1H), 1.44 (t, 2H), 2.65 (s, 3H), 3.77 (s, 2H), 4.28
(t, 1H), 4.65 (t, 1H), 4.85 (s, 2H), 8.06 (s, 1H), 6.91 (s, 5H);
13C NMR (DMSO-d6) d: 14.2, 21.2, 21.7, 40.2, 50.4, 51.3,
55.5, 56.2, 64.3, 126.5, 128.2, 139.7, 140.4, 155.2, 166.2,
170.3, 205.2.
General Procedure for the Synthesis of 6–8
Triazole acid 3 (1.0 mmol) was dissolved in anhydrous
THF and ethereal solution of diazomethane (3.0 mmol)
was added at 0°C. The mixture was stirred for about 3 h
until the completion of the reaction. Solvent was then
evaporated in vacuo and the residue was dissolved in
CH2Cl2. The organic layer was washed with 5% Na2CO3
(2 9 10 ml), 10% citric acid (2 9 10 ml), water (2 9 10
ml) and brine (1 9 10 ml), and dried over anhydrous
sodium sulfate. CH2Cl2 was removed under reduced pres-
sure to obtain the corresponding methyl esters as white
solid almost quantitatively.
Results and Discussion
Synthesis of the title triazoles involves cycloaddition
of Fmoc/Boc/Z-amino acid derived azidomethylketones
(Pg-Aaa-CH2N3) with propiolic acid. For the preparation of
required azidomethyl ketones, the most facile route con-
ceived was azidolysis of the corresponding bromomethyl
ketones Pg-Aaa-CH2Br with NaN3. Conversion of alkyl
halides into azides is generally accomplished by treating
the halide with stochiometric excess of NaN3 in dimeth-
ylformamide (DMF) either at rt or under heating (Boland
et al. 2006). The reaction has also been performed under
microwave irradiation (Appakkuttam et al. 2004). On the
other hand, we could locate only one report on the prepa-
ration of amino acid derived azidomethylketones, in which
Phth-Aaa-CH2N3 compounds (3 examples) and a single
urethane protected analogue viz., Z-Phe-CH2N3 have been
described (McKervey et al. 1993) These compounds have
been prepared in moderate yields by refluxing the DMSO
solution of corresponding bromomethylketones and NaN3.
Boc-protected azidomethylketones have been prepared
similarly. Here the azidolysis of bromomethylketones has
been carried out in presence of NaN3 and KF in DMF (Jain
and Vederas 2004). But the corresponding Fmoc protected
analogues have not been reported. The above reaction
conditions can be used to prepare azidomethylketones
derived from Boc- and Z-amino acids. However, same
conditions would cleave the Fmoc urethane due to the
appreciable basicity of the reaction medium. Hence, we
set out to explore the feasibility of azidolysis of the
To the obtained methyl ester (1.0 mmol), 18 ml of
20% DEA in CH2Cl2 was added and the solution was
stirred for 20 min at rt. After complete deprotection of
the Fmoc group (TLC), the solvent and excess DEA were
removed completely under reduced pressure with repeated
co-evaporation with CH2Cl2. The resulting amino free
triazole ester was dissolved in anhydrous THF (5.0 ml)
and maintained at 0°C.
[Mixed anhydride of Fmoc/Boc/Z-amino acids (1.1
mmol) was generated separately by dissolving with dry
THF(5 ml), and cooled to -15°C, EtOCOCl (0.1 ml,
1.0 mmol) and TEA (0.1 ml, 1.0 mmol) were added to the
above solution and stirred for 10 min. While maintaining
the temperature at -10°C]. The above triazole ester solu-
tion was added at -10°C to the in situ generated mixed
anhydride of Fmoc/Boc/Z-amino acids and the resulting
mixture was stirred for 2–3 h during which the coupling
was complete. The solvent was evaporated and triturated
with ether. The solid product obtained was filtered with 5%
Na2CO3 (2 9 10 ml), 10% citric acid (2 9 10 ml) and
recrystallized with DMSO: ether.
123

288
Int J Pept Res Ther (2010) 16:283–290
R
R
in Table 1. Azidomethyl ketone 2n was synthesized by
converting the b-COOH of aspartic acid via the similar
route starting from Z-Asp-5-oxazolidinone. All these
compounds were also completely characterized.
NaN3, Acetone;H2O
reflux
Pg-HN
Br
Pg-HN
N3
O
O
Pg = Fmoc, Cbz, Boc
1a-r
2a-r
Cycloaddition of azide 2 with propiolic acid (a terminal
alkyne) was then studied. The alkyne part was chosen to
contain free acid group in order to obtain the triazole
derivatives that can be directly (in one step) employed for
peptide/peptidomimetic chain via the unprotected –COOH
group. The reaction was carried out in several polar solvents
using CuSO4Á5H2O/ascorbic acid as the catalyst system
with compound 2c as the model. It appeared that the triazole
formation was sensitive to the solvent effect, with the effi-
ciency of the reaction varying significantly across solvents.
For instance, in tetrahydrofuran, CH2Cl2, methanol only
about 50% yields were obtained even after long hours of
heating in spite of good solubility of the reactants in these
solvents. t-BuOH was not effective as solvent because of
the poor solubility of azidomethylketone. Maximum yield
(85%) was obtained when the reaction was carried out in
Scheme 1 Synthesis of azidomethyl ketones 2a–r
bromomethylketones 1 under condition commonly employ-
able to all the three urethane protections and, especially
tolerable by the Fmoc group. For this the optimal condition
was to treat 1b (selected as a model compound) with
1.0 equiv. of NaN3 in acetone/water system (9:1) under
reflux for 30 min. The reactant was completely consumed
during this period as evident by TLC. The product 2b was
isolated as a white solid in 91% yield (Scheme 1) and the
structure was confirmed through its mass and NMR spec-
trum. The procedure was used to prepare a series of
N-urethane protected amino acid derived azidomethyl
ketones 2a–i (N-Fmoc protected), 2 k–o (N-Z protected)
and 2p–r (N-Boc protected) in 83–91% yield as shown
Table 1 List of azidomethylketones and b-keto triazoles synthesized
Compound Azidomethyl
ketones
Yield (%) m.p. (°C) HRMS
Obsd./Calcd.
(M ? Na)?
Triazole
Compds.
Yield (%) m.p. HRMS
(°C) Obsd./Calcd.
(M ? Na)?
2a
2ba
2ca
2da
2e
Fmoc-Gly-CH2N3
87
91
88
91
86
93
85
83
105
98
359.1108/359.1120 3a
373.1245/373.1277 3b
449.1578/449.1590 3c
415.1721/415.1746 3d
415.1713/415.1721 3e
401.1588/401.1590 3f
405.0975/405.0997 3g
389.1211/389.1226 3h
507.1618/507.1644 3i
564.2213/564.2223 3j
327.1430/327.1433 3k
313.1256/313.1277 3l
315.1028/315.1069 3m
347.3211/347.3237 3n
84
80
79
85
89
86
78
75
86
90
88
79
73
91
135
141
138
142
140
136
127
144
122
136
126
119
131
128
429.1155/429.1175
443.1310/443.1331
519.1624/519.1644
485.1788/485.1801
485.1788/485.1801
471.1625/471.1644
475.1035/475.1052
459.1270/459.1281
577.1682/577.1699
634.2278/634.2258
397.1472/397.1488
383.1311/383.1331
385.1105/385.1124
417.1152/417.1175
Fmoc-Ala-CH2N3
Fmoc-Phe-CH2N3
Fmoc-Leu-CH2N3
Fmoc-Ile-CH2N3
Fmoc-Val-CH2N3
Fmoc-Cys-CH2N3
Fmoc-Ser-CH2N3
89
110
107
96
2f
2g
2h
2i
87
103
95
Fmoc-Asp(b-Bzl)CH2N3 82
2j
Fmoc-Lys(Z)-CH2N3
Z-Leu-CH2N3
Z-Val-CH2N3
89
85
93
90
88
83
2k
2l
91
88
2m
2n
Z-Thr-CH2N3
104
98
Z-Phg-CH2N3
O
N3
O
ZN
2o
84
112
341.0665/341.0682 3o
82
148
411.0901/411.0917
O
2p
2q
2r
a
Boc-Phe-CH2N3
Boc-Pro-CH2N3
91
90
83
102
327.1411/327.1433 3p
277.1254/277.1277 3q
399.1631/399.1644 3r
74
76
74
133
128
136
397.1454/397.1488
469.1645/469.1699
gum
gum
Boc-Glu(Bzl)-CH2N3
Spectral characterization data was found to be matching with the literature report (Haibin et al. 2009)
123

Int J Pept Res Ther (2010) 16:283–290
289
Table 2 Study on the
preparation of 3c
Catalyst system
Solvent
Temp. (°C)
Time (h)
Yield (%)
CuSO4Á5H2O/sodium ascorbate
CuSO4Á5H2O/sodium ascorbate
CuI/DIEPA
THF
60
50
rt
22
15
20
30
12
12
40
35
47
55
88
91
DCM
MeOH
tBuOH
CuSO4Á5H2O/sodium ascorbate
CuSO4Á5H2O/sodium ascorbate
CuSO4Á5H2O/sodium ascorbate
60
rt
Acetonitrile
Acetonitrile
60
accomplished by peptide chain extension from both C- and
N-terminus. Compounds 3b and 3h were directly coupled
with amino acid methyl esters through the mixed anhydride
method to produce the dipeptidomimetic esters 4 and 5 in
91 and 85% respectively (Scheme 3). For chain extension
from the amino end, the triazole acids 3h and 3i were first
converted to the corresponding methyl esters by treating
with ethereal solution of diazomethane. Fmoc group of the
esters was removed using 20% diethyl amine in CH2Cl2.
The resulting free amino esters were directly coupled with
N-Fmoc/Boc/Z-amino acid via the mixed anhydrides to
obtain the dipeptidomimetics 6–8 in 68–87% yield
R
R
N
N
COOH
COOH
Pg-HN
N3
Pg-HN
N
Click condition
CH3CN:H2O
O
O
2a-r
3a-r
Scheme 2 Synthesis of Na-protected b-keto triazole amino acids 3
acetonitrile at rt for 12 h (Table 2). The required triazole 3c
was precipitated by dilution with water, filtered, dried and
characterized.
Employing the above conditions, several Fmoc as well
as Boc and Z-amino acid derived keto triazoles 3a–r were
synthesized from the corresponding azidomethyl ketones.
Side chain protected amino acids viz Fmoc-Asp(OBzl)-OH,
Fmoc-Lys(Z)-OH and Boc-Glu-(OBzl)-OH were also used.
The triazole derivatives of these amino acids were obtained
in good yield without the loss of side chain protections or
formation of any byproduct. Fmoc-Cys-OH, Fmoc-Ser-OH
and Z-Thr-OH were used directly without protecting the
side chain functions in both Schemes 1 and 2 and the
corresponding triazoles 3g and 3h were obtained in good
yield (Table 1). Synthesis of these compounds shows that
the cycloaddition under click conditions can be achieved
even in presence of unprotected hydroxyl and mercaptan
groups.
1
(Table 3) which were characterized by H and 13C NMR
spectral studies.
Conclusion
In conclusion, we report the synthesis of a novel class of
amino acid derived b-keto triazoles by the Cu (I) mediated
azide-alkyne cycloaddition. The applicability of the present
protocol has been demonstrated employing the commonly
used urethane (Fmoc, Boc and Z) protected amino acids and
the desired keto triazoles have been obtained in good yields.
We have also demonstrated the application of these
unnatural amino acids in the synthesis of dipeptidomimetics
Further, the triazole acids were used as building
blocks for the synthesis of dipeptidomimetics. This was
1. CH2N2, Et2O, 0°C
TEA, ECF,
Scheme 3 Synthesis of
dipeptide mimetics 4–8
O
R1
R1
O
R2
THF, -15°C
2. DEA/ CH2Cl2
Pg-HN
COOMe
3
N
N
N
Pg-HN
N
N
N
COOMe
TEA, ECF,
THF, -15°C
3.
H
R2
H
R2
O
O
N
N
6-8
4-5
R2
H2N
COOMe
Pg-HN COOH
Table 3 List of b-ketotriazole linked dipeptidomimetics synthesized
Compd.
Pg
R1
R2
Yield (%)
m.p. (°C)
HRMS (M ? Na)?
Calcd.
Obsd.
4
5
6
7
8
Fmoc
Cbz
CH3
CH2C6H5
CH2COOBn
CH2C6H5
CH(CH3)C2H5
CH3
91
85
79
68
87
181
174
185
164
159
604.2172
650.2227
620.2121
476.2485
482.2016
604.2151
650.2206
620.2110
476.2455
482.2002
CH2C6H5
CH2OH
Fmoc
Boc
CH(CH3)2
CH2CH(CH3)2
Cbz
123

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Haibin S, Kai L, Ashley X, Shao QY (2009) Small molecule micro
array-facilated screening of affinity based probes (AfBPs) for
c-secratase. Chem Commun 5030–5032
Haridas V, Lal K, Sharma YK (2007) Design and synthesis of triazole-
based peptide dendrimers. Tetrahedron Lett 48:4719–4722
Horne WS, Stout CD, Ghadiri MR (2003) A heterocyclic peptide
nanotubes. J Am Chem Soc 125:9372–9376
containing b-keto triazole units via both N- and C-terminal
extensions. Further studies on the diastereoselective
reduction of the keto group of the title triazoles in order to
obtain b-hydroxyl triazole unit containing amino acids is
under investigation.
Jain RP, Vederas JC (2004) Structural variations in keto-glutamines
for improved inhibition against hepatitis A virus 3C proteinase.
Bioorg Med Lett 14:3655–3658
Acknowledgement The authors thank the Department of Science
and Technology, Government of India for the financial assistance
(Grant No. SR/S1/OC-26/2008).
Kolb HC, Sharpless KB (2003) The growing impact of click
chemistry on drug discovery. Drug Discov Today 8:1128–1136
Laurent BA, Grayson SM (2006) An efficient route to well-defined
polymers via click cyclization. J Am Chem Soc 128:4238–4239
Lin H, Walsh CT (2004) A chemo enzymatic approach to glycopep-
tide antibiotics. J Am Chem Soc 126:13998–14003
Link AJ, Vink MKS, Tirrell DA (2004) Presentation and detection of
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