CuI-promoted one-pot synthesis of N-boc protected β-ketotriazole amino acids: Application in the synthesis of new class of dipeptidomimetics

Article abstract of DOI:10.2174/092986612799363172

One-pot click chemistry of Nα-Boc-bromomethylketones, NaN₃ and propiolic acid affords N-Boc protected 1,4- disubstituted 1,2,3-β-ketotriazole acids in good to excellent yield. The use of CuI as catalyst and DMSO as solvent leads the click react

Full text of DOI:10.2174/092986612799363172

308
Protein & Peptide Letters, 2012, 19, 308-314
CuI-Promoted One-Pot Synthesis of N-Boc Protected ꢀ-Ketotriazole
Amino Acids: Application in the Synthesis of New Class of Dipepti-
domimetics
T. M. Vishwanathaa, N. Narendrab and Vommina V. Sureshbabua*
a
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambed-
b
kar Veedhi, Bangalore University, Bangalore-560 001, India; Department of Chemistry, Tumkur University, B. H.
Road, Tumkur -570 102, India
Abstract: One-pot click chemistry of Nꢀ-Boc-bromomethylketones, NaN3 and propiolic acid affords N-Boc protected 1,4-
disubstituted 1,2,3-ꢀ-ketotriazole acids in good to excellent yield. The use of CuI as catalyst and DMSO as solvent leads
the click reaction to efficient, practical and column-free preparation of the title compounds. The utility of the resulting un-
natural amino acids as building blocks to prepare triazole possessing peptidomimetics is also delineated.
R1
R2
O
O
BocHN
N
N
X
H
N
N
O
O
R1
R1
one-pot
COOH
BocHN
Br
BocHN
N
N
N
R2
O
O
O
N
N
H
O
N
N
Pg-HN
O
R1
O
Keywords: Nꢀ-Boc-bromomethylketones, one-pot click chemistry, CuI, N-Boc-protected 1,4-disubstituted 1,2,3 ꢀ-ketotriazole
amino acids, peptidomimetics.
INTRODUCTION
In spite of the great progress made towards the synthesis
and application of peptide triazoles there are still unmet chal-
lenges to develop new motifs. In this regard, ꢀ-ketotriazoles
is one such attractive functionality. ꢀ-Ketotriazoles have
important applications in biology and medicine [8]. Vederas
and Jain have prepared two examples of N-Boc-protected ꢀ-
ketotriazoles which were found to be potent hepatitis A virus
proteinase inhibitors [9]. The synthesis was followed through
catalyst-free cycloaddition of Boc protected azidomethylke-
tones with dimethylacetylenedicarboxylate. Franke et al., has
discovered that ꢀ-ketotriazoles can be inserted into peptides
by ligating protected azido-peptides to resin bound alkynes
[10]. We had recently reported the step wise preparation of
N-protected ꢀ-ketotriazole acids under click conditions [11].
In recent years copper source accelerated [3+2] cycload-
dition of azides and alkynes has emerged as powerful tool in
synthetic chemistry [1]. A wider compatibility of this proto-
col has led to many applications in various areas such as
medicinal chemistry, surface chemistry, polymer chemistry
and ligation technology for the construction of several types
of mimetics [2]. 1,4-Disubstituted 1,2,3-triazoles are re-
garded as cis amide bond isosteres [3]. Hence, in the realm
of the rapidly growing field of peptidomimetic chemistry,
insertion of triazole moiety in place of a peptide bond has
been found to be attractive because of potential applications
as probes in biological activity and as leads for the develop-
ment of peptide based drugs [4]. Apart from the use of pepti-
dotriazoles in medicinal chemistry, there has been a wide
range of literature also found concerning the peptidotriazoles
in nano-sized materials [5], secondary structures such as ꢀ-
turn mimics [6] and in self assembling peptide nanotubes [7].
In most of their reports either amino acid derived azide or
acetylene has been used as unnatural linkage and their liga-
tion under click conditions leads to construction of triazole
tethered peptides.
Soon after the development of click chemistry, a one-pot
procedure has also been tailored successfully to synthesize
triazoles from alkyl halides. Thus, the first one pot synthesis
of 1,4 disubstituted 1,2,3-triazoles had been reported by
Folkin et al., starting from aryl and activated halides [12].
Karol Kacprzak reported the in situ azidation of various hal-
ides with slight excess of NaN3 in anhydrous DMSO and
then triazoles were made thereof without isolation of azides
[13]. Recently, Kumar et al., reported an one pot synthesis of
ꢀ-ketotriazoles under click chemistry by using polyethylene
glycol as solvent [14]. In this paper we describe the one pot
synthesis of N-Boc protected ꢀ-ketotriazole acids from corre-
sponding bromomethylketones. Further, the utility of N-Boc-
*Address correspondence to this author at Department of Studies in Chemis-
try, Central College Campus, Bangalore University, Dr. B. R. Ambedkar
Veedhi, Bangalore -560 001, India; Tel: +91-80-2296-1339;
E-mail: sureshbabuvommina@rediffmail.com; hariccb@gmail.com
1875-5305/12 $58.00+.00
© 2012 Bentham Science Publishers

CuI-Promoted One-Pot Synthesis of N-Boc Protected ꢀ-Ketotriazole Amino Acids
Protein & Peptide Letters, 2012, Vol. 19, No. 3 309
1. NMM, EtOCOCl,
-15 oC, CH2N2
R1
R1
R1
1. NaN3, DMSO
N
N
BocHN
COOH
BocHN
Br
BocHN
N
COOH
2.
2. HBr.
O
O
CuI/DIPEA
COOH
1
2
3
Scheme 1. One-pot synthesis of N-Boc-ꢀ-ketotriazole acids.
ꢀ-ketotriazole acids as monomeric building blocks for the
construction of ꢀ-ketotriazole tethered peptidomimetics is
also described.
it has been confirmed that CH3CN is not an appropriate sol-
vent for one pot click chemistry.
We then sought to examine one-pot synthesis using dif-
ferent solvents and catalyst. It has been found that
CuSO4.5H2O and Cu(OAc)2 in NaAsc yielded 67 and 73%
of 3b when tert-butanol was used as a solvent. The use of
THF gave an improved yield of 3b (Table 1, Entries 3-6).
Thus, variation of both solvent and catalyst significantly
improved the yield. More recently, CuI was found to be ef-
fective catalyst for click chemistry. Accordingly, we then
tested its efficacy in our present study. To our delight,
among several solvents used (Table 1, Entry 7-10), DMSO
exhibited superior efficiency along with CuI. In a typical
reaction, 2b was dissolved in DMSO and NaN3 was added.
The completion of azidation took about one hour (as evi-
denced by TLC analysis), latter, propiolic acid and CuI/
DIPEA were added and stirring was continued for another
one hour. Later, acidification of the crude mixture yielded 3b
in 96 %. After establishing the suitable one-pot reaction con-
ditions, its scope and limitations were tested with N-Boc-
bromomethylketones derived from a variety of side-chain-
containing amino acids Table 2. As shown in the Table 2, all
the products were obtained in good to excellent yield in less
duration of time. Further, the IR spectrum of all the products
had a strong absorption band at around 1690- 1710 cm-1 con-
RESULTS AND DISCUSSION
The intermediates for the present study are Boc-protected
bromomethylketones 2 which were prepared by following
reported protocols [15]. Briefly, Nꢀ-Boc-amino acids 1 were
activated through mixed anhydride method, an ethereal solu-
tion of diazomethane was added and the reaction mixture
was stirred for 3- 4 h. The resulting diazomethylketones
were isolated after simple workup, they were further con-
verted to bromomethylketones by a reaction with 48% HBr
in THF. The N-Boc-bromomethylketones were isolated as
stable compounds in good yields. Another important compo-
nent for click chemistry was terminal acetylene, herein
commercially available propiolic acid was chosen such that
resulting triazole acids can be directly used as building block
for the assembly of oligopeptidomimetics.
In the next step, we focused our attention on the synthesis
of the title triazoles 3 (Scheme 1). Initially we had chosen
CH3CN as solvent for one pot click chemistry. N-Boc-Ala-
ꢁ[CH2Br] 2b was dissolved with CH3CN, NaN3 was then
added. After stirring the reaction mixture for several hours,
CuSO4.5H2O/NaAsc and propiolic acid were added and was
further continued for another 4 hr. Interestingly, LC-MS
analysis of the crude reaction revealed that NH-triazole was
formed as a major product (mass obtained was 113.02 corre-
sponds to 1H-1,2,3-triazole 4-carboxylic acid, 68%), which
is a commonly expected byproduct in one-pot click chemis-
try and the desired product 3b was obtained only in about
20% (mass of 397.2, was dected; Table 1, Entry 1, 2). Thus,
1
firming the presence of ketone group. The H-NMR spec-
trum of the product showed a distinct singlet at ꢂ = 7.96 -
8.22 ppm for the trizolyl C5-H proton, which confirmed the
single regioisomer.
We then extended our study for the preparation of pepti-
domimetics 4 and 6 through N as well as C-terminal exten-
sion of 3. Initially, the chain elongation from C-terminal was
undertaken. In a typical reaction, to a solution of 3c in dry
R1
R1
R2
O
a
COOH
BocHN
N
N N
BocHN
N
N
COOX
H
O
N N
O
3
4
b
R1
R2
O
N N
H
c, d
N
N
COOMe
COOMe
BocHN
N
N N
Pg-HN
2 steps
R1
O
O
5
6
Reaction conditions: a = EDC/HOBt, amino acid ester, CH2Cl2, 0 °C, 3-4 h; b = CH2N2, THF, 0 °C, 2-3 h; c = TFA, CH2Cl2, rt, 5-6 h; d = N-
protected ꢃ-amino acid, TEA, EDC/HOBt, THF, 0 °C, 3-4 h.
Scheme 2. Synthesis of peptidyl ꢀ-ketotriazole esters 5 and 6.

310 Protein & Peptide Letters, 2012, Vol. 19, No. 3
Vishwanatha et al.
Table 1. Optimization of the Click Conditions for the Synthesis of 3b at Room Temperature
Entry
Catalyst (Equiv)d
CuSO4.5H2O:NaAsc( 0.2:0.4)
Solventd
CH3CN:H2O
Yield(%)a,b
Time (Hour)c
1
2
20
28
67
82
73
85
49
58
88
97
18
18
14
12
8
Cu(OAc)2: NaAsc (0.4:0.4)
CuSO4.5H2O: NaAsc( 0.2:0.4)
CuSO4.5H2O: NaAsc( 0.2:0.5)
Cu(OAc)2: NaAsc( 0.4:0.5)
Cu(OAc)2: NaAsc( 0.3:0.5)
CuI:DIPEA(0.8:1.1)
CH3CN:H2O
tBuOH:H2O
THF:H2O
3
4
5
tBuOH:H2O
THF:H2O
6
5
7
MeOH:H2O
CH3CN:H2O
THF:H2O
12
15
6
8
CuI:DIPEA(1:1.5)
9
CuI:DIPEA(1.5:1.5)
10
CuI:DIPEA(2:2)
DMSO:H2O
2
a In all the investigations only 1.0 equiv. of NaN3 was added; b Yields are based on the consumption of the bromomethylketones 2; c Time given for in situ azide formation followed
by triazole synthesis; d equivalence of the catalyst, additive ratios.
Table 2. List of Nꢀ-Boc Protected ꢀ-ketotriazoles Synthesized
Entry
Product
Yield (%)
Mp °C
HRMS [M+Na]+
3a
89
113-115
307.1002
COOH
BocHN
N
N
N
O
Ph
3b
91
107-108
397.1452
COOH
BocHN
N
N
N
O
3c
3d
94
86
133-135
97-99
321.1164
427.1578
COOH
BocHN
N
N
N
O
BnO
COOH
COOH
COOH
COOH
BocHN
N
N
N
N
N
N
O
BnOOC
BocHN
3e
3f
90
79
81
104-106
141-143
139-141
455.1531
469.1648
512.2100
N
N
O
BnOOC
BocHN
2
N
N
O
ZHN
3g
4
BocHN
N
N
O

CuI-Promoted One-Pot Synthesis of N-Boc Protected ꢀ-Ketotriazole Amino Acids
Protein & Peptide Letters, 2012, Vol. 19, No. 3 311
(Table 2) Contd….
Entry
Product
Yield (%)
Mp °C
HRMS [M+Na]+
3h
85
119-121
363.1619
COOH
BocHN
N
N
N
O
3i
3j
90
90
128-130
122-124
349.1477
347.1310
COOH
BocHN
N
N
N
O
COOH
N
N
N
Boc
N
O
o
THF, EDC/HOBt were added at 0 C. After stirring for 5
min, amino acid ester (amino acid ester hydrochloride salt
was deprotonated using activated Zn dust) was added and the
reaction mixture was stirred for 3 hr. Upon evaporation of
the solvent, the crude product 4c obtained was purified by
column chromatography (Scheme 2, Table 3).
1. General Experimental Procedure for Nꢁ-Boc-amino al-
kyl-ꢀ'-bromomethylketones 2
Step 1: A solution of Nꢀ-Boc-amino acid (10.0 mmol) in
dry THF was cooled to -25 ºC, TEA (1.1 equiv.) and ethyl
chloroformate (1.1 equiv.) were added. After 15 min, freshly
prepared CH2N2 solution in dry Et2O was added until the
yellow color of the solution persisted. The stirring was con-
tinued to 5-6 h. It was acidified with citric acid and extracted
with equal volume of Et2O. The organic phase was washed
with water, saturated NaHCO3 solution and brine. After
evaporation of the solvent followed by recrystallization with
pentane resulted diazoketones (used directly for next step).
Step 2: To the THF solution of Nꢀ-Boc-aminoalkyl dia-
zomethylketone (10.0 mmol), 45 % aqueous HBr solution
(2.4 mL) was added under stirring at rt and the stirring was
continued for 5 min within which disappearance of the reac-
tant was recorded on TLC. The reaction mixture was then
diluted with excess of water, the precipitated product was
filtered and purified by recrystallization from THF-water.
Finally, the N-terminal extension of 3 was carried out. N-
Boc-ꢀ-ketotriazole acids were treated with diazomethane at 0
°C to afford the corresponding methyl ester in good yield. In
the next step, deprotection of Boc-group of 5 was achieved
using TFA at rt which was found to be complete within 4-5
h. The amino free ꢀ-ketotriazole esters thus obtained were
directly coupled with another N-protected ꢁ-amino acid
(Scheme 2, Fig. (1)). The resulted peptidomimetics 6 were
obtained in good yield after purification. All the new com-
pounds prepared in this report have been fully characterized.
CONCLUSION
In conclusion we have demonstrated the potential of one-
pot click chemistry as means of obtaining a series of Nꢀ-Boc-
protected ꢀ-ketotriazole acids starting from respective bro-
momethylketones. Application of these building blocks in
the synthesis of new class of peptidomimetics is also de-
scribed. CuI has been found to be efficient catalyst for one-
pot click chemistry.
2. General Experimental Procedure for One-pot Prepara-
tion of Nꢁ-Boc-aminoalkyl-ꢀ'-ꢁ-ketotriazole Acids 3
To a stirred anhydrous DMSO solution of NaN3 (1 mL, 1
equiv.),
Nꢀ-Boc-aminoalkyl-ꢁ'-bromomethylketones
(1
equiv.) was added and the stirring continued for 2-3 h. Water
(2–3 mL) was added followed by DIPEA (2 equiv), alkyne
(1 equiv.) and CuI (2equiv.). The resulting solution was
stirred for additional 1-2 h, then acidified with citric acid
solution (1N, 10 mL). The product was extracted with
EtOAc (2 X 5 mL), evaporation of the solvent followed by
recrystallization using THF:H2O (0.5:0.2 mL) yielded de-
sired triazoles as pure products.
EXPERIMENTAL PROCEDURES
General
All solvents were freshly distilled prior to use. Amino
acids and chemicals were used as received from Sigma-
Aldrich Company, USA. Melting points were determined by
open capillary method and are uncorrected. IR spectra were
recorded on a Shimadzu FTIR-8400S model spectrometer.
1H and 13C NMR spectra were recorded on a Bruker AMX
spectrometer. Mass spectra were recorded on MALDI-TOF
(KRATOS) mass spectrometer. TLC analysis was carried out
using the precoated silica gel G254 plates. Optical rotations
were recorded on a Jasco P-2000 model polarimeter.
3. General Experimental Procedure for the Synthesis of
Nꢁ-Boc-ꢁ-ketotriazole Tethered Dipeptide Esters 4
N-Boc-ketotriazole amino acid 3 (1.0 mmol) was dis-
solved in dry THF (5 mL), and cooled to 0 ºC, EDC (0.1 ml,
1.0 mmol), HOBt (1.1 mmol) were added to the above solu-
tion and stirred for 10 min. While maintaining the tempera-
ture, the resulting reaction mixture was treated with amino
acid methyl ester (1.0 mmol) in THF solution and the reac-

312 Protein & Peptide Letters, 2012, Vol. 19, No. 3
Vishwanatha et al.
Table 3. List of Dipeptidomimetics 4 Prepared
Entry
R1
R2
CH2CH(CH3)2
X
Yield (%)
HRMS [M+Na]+
Mp o
C
4a
4b
4c
4d
4e
CH3
Me
Me
Bn
Bn
Et
88
79
82
80
71
448.2151
616.2340
616.2711
586.2623
446.2000
159-160
181-183
138-140
115-117
108-110
CH2C6H5
CH2COOCH2C6H5
CH(CH3)2
C6H5
CH2OCH2C6H5
CH2CH(CH3)2
-(CH2)3-
CH3
O
O
O
N
N
N
N
N N
H
N
H
H
N
N
N
N
N
COOMe
ZHN
COOMe
COOMe
FmocHN
BocHN
O
O
O
COOBn
OBn
Ph
6a
6b
6c
Yield: 91%
m.p: 122-123 0C
Yield: 83%
m.p: 141-143 0C
Yield: 79%
m.p: 163-165 0C
BnS
O
H
N
N
O
N
N
O
N
N
H
N
H
N
N
N
COOMe
BocHN
N
N
BocHN
COOMe
COOMe
BocHN
O
O
O
6d
6e
6f
Yield: 87%
m.p: 119-121 0C
Yield: 75%
m.p: 136-137 0C
Yield: 81%
m.p: 108-109 0C
Fig. (1). Dipeptidomimetics 6 prepared from N-terminal extension of 3.
tion mixture was allowed to stir for 6 h (monitored by TLC).
The THF was evaporated under reduced pressure and the
residue was taken in EtOAc (15 ml) and was washed with
5% Na2CO3 (2 X 10 ml), 10% citric acid (2 X 10 ml), water
(2 X 10 ml) and brine (1 X 10 ml), and dried over anhydrous
sodium sulfate. Solvent was removed under reduced pres-
sure. The crude product was purified through column chro-
matography [eluent, CHCl3:MeOH, 9:1].
cess TFA were removed completely by repeated co-
evaporation with DCM. The resulting residue was recrystal-
lized using EtOH/water. The resulting products were directly
used in the subsequent study.
Step 2: N-Protected amino acid (1.0 mmol) was dis-
solved in dry THF (5 mL), and cooled to 0 ºC, EDC (0.1 ml,
1.0 mmol), HOBt (1.1 mmol) were added and stirred for 10
min. The TFA salt of triazole ester prepared through step
(1.0 mmol), and TEA (1.0 mmol) were added and the reac-
tion mixture was allowed to stir for 3-4 h (monitored by
TLC). The THF was evaporated under reduced pressure and
the residue was taken in EtOAc (15 ml) and was washed
with 5% Na2CO3 (2 X 10 ml), 10% citric acid (2 X 10 ml),
water (2 X 10 ml) and brine (1 X 10 ml), and dried over an-
hydrous sodium sulfate. The crude product was purified
through column chromatography[eluent, CHCl3:MeOH, 8:2].
4. General Experimental Procedure for the Synthesis of
Nꢀ-Boc-aminoalkyl-ꢀ'-ꢁ-ketotriazole Methyl Esters 5
To a solution of Nꢀ-Boc-aminoalkyl-ꢀ'-ꢀ-ketotriazole
acid 3 (1.0 mmol) in anhydrous THF (5 mL), an ethereal
solution of CH2N2 (3.0 mmol) was added with cooling until a
permanent yellow color was obtained. The mixture was
stored in an ice-bath for 30 min and the excess solvent and
CH2N2 were evoprated under reduced pressure. Crystalliza-
tion of the product was completed during overnight storage
Spectroscopic Characterization Data
o
at 0 C. The mixture was filtered and the precipitate was
1
3a: IR (KBr): 1591, 1698, 1725, 2900 cm-1; H NMR
washed with Et2O and dried (conformation was made
through only TLC and IR analysis)
(300 MHz, CDCl3): ꢁ 1.12 (s, 9H), 3.96 (d, 2H, J = 2.8 Hz),
4.18 (s, 2H), 6.18 (s, br, 1H), 8.01 (s, 1H), 10.23 (s, br, 1H);
13C NMR (100 MHz, CDCl3): ꢁ 27.6, 27.8, 48.9, 59.5, 78.9,
124.4, 140.2, 155.2, 166.9, 205.8.
5. General Experimental Procedure for the Preparation of
Nꢀ-Boc-aminoalkyl-ꢀ'-ꢁ-ketotriazole Methyl Esters 6:
Step 1: A solution of 5 (1.0 mmol) in anhydrous DCM
(5.0 mL) and TFA (10 mL) were stirred for 3-4 hr at rt. After
complete deprotection (TLC analysis), the solvent and ex-
1
3b: IR (KBr): 1548, 1657, 1734, 2987 cm-1; H NMR
(300 MHz, CDCl3): ꢁ 1.18 (s, 9H), 2.96-3.11 (m, 2H), 4.59

CuI-Promoted One-Pot Synthesis of N-Boc Protected ꢀ-Ketotriazole Amino Acids
Protein & Peptide Letters, 2012, Vol. 19, No. 3 313
1
(m, 1H), 4.20 (s, 2H), 6.55 (s, br, 1H), 6.98-7.22 (m, 5H),
8.05 (s, 1H), 10.11 (s, br, 1H); 13C NMR (100 MHz, CDCl3):
ꢀ 27.5, 27.6, 34.8, 57.9, 62.6, 78.8, 119.8, 123.6, 124.8,
128.6, 138.4, 140.4, 155.5, 166.6, 206.2.
4a: IR (KBr): 1487, 1540, 1645, 1740, 1755 cm-1; H
NMR (300 MHz, CDCl3): ꢀ 0.98 (d, 6H, J = 5.6 Hz), 1.12 (d,
3H, J = 3.2 Hz), 1.31 (s, 9H), 1.56-1.61 (m, 1H), 1.72-1.75
(m, 2H), 3.55 (s, 3H), 4.25 (t, 1H, J = 7.6 Hz), 4.35-4.38 (m,
1H), 4.75 (s, 2H), 5.65 (s, br, 1H), 6.11 (s, br, 1H), 8.33 (s,
1H); 13C NMR (100 MHz, CDCl3): ꢀ 14.6, 21.5, 22.0, 27.9,
39.5, 48.7, 50.9, 56.4, 57.1, 78.0, 130.8, 142.9, 155.0, 160.1,
171.2, 207.1.
1
3c: IR (KBr): 1497, 1690, 1741 cm-1; H NMR (300
MHz, CDCl3): ꢀ 1.23 (s, 9H), 1.34 (d, 3H, J = 3.8 Hz), 4.43-
4.61 (m, 1H), 4.19 ( s, 2H), 6.8 (s, br, 1H), 8.0 (s, 1H), 10.25
(s, 1H); 13C NMR (100 MHz, CDCl3): ꢀ 14.8, 27.6, 55.5,
57.6, 78.5, 124.8, 140.1, 155.2, 166.3, 205.6.
4b: IR (KBr): 1435, 1602, 1734, 1765 cm-1; H NMR
1
(300 MHz, CDCl3): ꢀ 1.31 (s, 9H), 2.25-2.41 (m, 2H), 2.91-
3.05 (m, 2H), 3.55 (s, 3H), 4.73-4.76 (m, 1H), 4.81 (s, 2H),
4.96-5.02 (m, 1H), 5.22 (s, 2H), 6.11 (s, br, 1H), 6.41 (s, br,
1H),7.01-7.22 (m, 10H), 8.16 (s, 1H); 13C NMR (100 MHz,
CDCl3): ꢀ 27.8, 34.2, 35.9, 47.5, 51.1, 57.1, 63.5, 67.4, 78.1,
123.3, 124.6, 127.4, 128.8, 129.0, 130.4, 137.9, 140.5, 142.0,
155.1, 160.2, 171.0, 172.5, 205.8.
1
3d: IR (KBr): 1498, 1687, 1731, 2901 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 1.28 (s, 9H), 3.14-3.44 (m, 2H), 3.91
(s, 2H), 4.32-4.44 (m, 1H), 4.58 (s, 1H), 6.12 (s, br, 1H),
6.89-7.12 (m, 5H), 8.04 (s, 1H), 10.11 (s, br,1H); 13C NMR
(100 MHz, CDCl3): ꢀ 27.9, 28.0, 57.6, 60.9, 67.0, 72.1, 78.8,
119.8, 123.4, 124.5, 127.6, 135.1, 140.1, 155.6, 166.8, 206.1
1
3e: IR (KBr): 1550, 1699, 1745, 2984 cm-1; H NMR
1
4c: IR (KBr): 1498, 1548, 1687, 1730, 1767 cm-1; H
(300 MHz, CDCl3): ꢀ 1.31 (s, 9H), 2.22-2.34 (m, 2H), 4.41
(s, 2H), 4.48 (s, 2H), 4.91-4.94 (m, 1H), 5.96 (s, br, 1H),
6.59-7.22 (m, 5H), 8.01 (s, 1H), 10.11 (s, 1H); 13C NMR
(100 MHz, CDCl3): ꢀ 27.6, 27.9, 34.5, 55.6, 57.8, 67.6, 78.8,
121.2, 124.5, 125.8, 128.6, 139.2, 140.0, 155.1, 165.2, 171.1,
205.2.
NMR (300 MHz, CDCl3): ꢀ 0.98 (d, 6H, J = 4.9 Hz), 1.31 (s,
9H), 2.91-2.98 (m, 1H), 3.55-3.67 (m, 2H), 4.11 (d, 1H, J =
7.2 Hz), 4.32 (s, 2H), 4.41-4.48 (m, 1H), 4.75 (s, 2H), 5.06
(s, 2H), 5.85 (s, br, 1H), 6.11 (s, br, 1H), 7.03-7.25 (m, 10H),
8.16 (s, 1H); 13C NMR (100 MHz, CDCl3): ꢀ 16.8, 27.9,
29.4, 54.1, 56.7, 60.9, 65.1, 67.4, 73.5, 78.1, 125.8, 127.2,
127.8, 128.5, 130.4, 135.5, 140.5, 142.8, 155.1, 159.6, 170.1,
205.9.
1
3f: IR (KBr): 1547, 1686, 1751, 3101 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 1.34 (s, 9H), 2.12-2.35 (m, 4H), 4.31
(d, 1H, J = 5.2 Hz), 4.66 (s, 1H), 5.01 (s, 2H), 6.11 (s, br,
1H), 6.96-7.22 (m, 5H), 8.11 (s, 1H), 10.12 (s, br, 1H); 13C
NMR (100 MHz, CDCl3): ꢀ 22.6, 27.9, 28.0, 28.2, 55.6,
60.0, 67.6, 78.8, 119.2, 124.4, 127.6, 128.0, 139.8, 140.0,
155.6, 168.3, 172.1, 206.1.
1
4d: IR (KBr): 1411, 1547, 1682, 1711, 1778 cm-1; H
NMR (300 MHz, CDCl3): ꢀ 0.97 (d, 6H, J = 5.9 Hz), 1.31 (s,
9H), 1.45-1.49 (m, 1H), 1.51-1.59 (m, 1H), 3.55 (s, 3H),
4.32 (d, 1H, J = 5.4 Hz), 4.58 (s, 2H), 5.13 (s, 1H), 5.98 (s,
br, 1H), 6.11 (s, br, 1H), 7.01-7.28 (m, 5H), 8.12 (s, 1H); 13
C
1
3g: IR (KBr): 1534, 1691, 1735, 3000 cm-1; H NMR
NMR (100 MHz, CDCl3): ꢀ 20.6, 21.5, 27.4, 37.1, 50.2,
53.7, 56.9, 58.1, 78.1, 125.4, 127.5, 128.7, 129.1, 130.0,
133.6, 142.1, 156.4, 160.9, 170.7, 206.2.
(300 MHz, CDCl3): ꢀ 1.28 (s, 9H), 1.34-2.01 (m, 6H), 2.91
(t, 2H, J = 6.9 Hz), 4.32 (t, 1H, J = 3.6 Hz), 4.71 (s, 2H),
5.01 (s, 2H), 6.29-6.32 (s, br, 2H), 6.96-7.32 (m, 5H), 8.10
(s, 1H), 10.55 (s, br, 1H); 13C NMR (100 MHz, CDCl3): ꢀ
19.6, 28.3, 28.5, 29.0, 29.5, 40.1, 57.6, 64.5, 64.2, 78.2,
124.2, 126.2, 127.8, 128.2, 139.5, 140.2, 155.5, 155.6, 166.1,
206.0.
1
4e: IR (KBr): 1411, 1607, 1721, 1734 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 1.13 (t, 3H, J = 5.1 Hz), 1.24 (s, 9H),
1.32 (d, 3H, J = 7.1 Hz), 1.43-1.65 (m, 4H), 3.11-3.18 (m,
2H), 4.01-4.09 (m, 1H), 4.13-4.17 (m, 1H), 4.28-4.32 (m,
1H), 4.45 (s, 2H), 6.19 (s, br, 1H), 8.14 (s, 1H); 13C NMR
(100 MHz, CDCl3): ꢀ 13.6, 17.1, 21.1, 27.2, 28.1, 45.6, 47.2,
58.0, 60.4, 64.4, 78.0, 130.5, 142.2, 155.4, 160.2, 171.2,
205.2.
1
3h: IR (KBr): 1591, 1688, 1761, 2967 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 0.82 (t, 3H, J = 2.9 Hz), 1.03 (d, 3H, J
= 5.9 Hz), 1.11-1.28 (m, 2H), 1.31 (s, 9H), 2.46-2.51 (m,
1H), 4.12 (d, 1H, J = 2.9 Hz), 4.85 (s, 2H), 6.11 (s, br, 1H),
7.96 (s, 1H), 10.21 (s, br, 1H); 13C NMR (100 MHz, CDCl3):
ꢀ 10.8, 14.5, 24.5, 28.5, 33.1, 55.6, 60.1, 77.9, 124.8, 139.9,
155.5, 166.1, 206.5.
1
6a: IR (KBr): 1439, 1691, 1733, 1741 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 1.29 (d, 3H, J = 5.6 Hz), 2.35-2.56 (m,
2H), 3.56 (s, 3H), 4.32 (t, 1H, J = 3.6 Hz), 4.46 (d, 2H, J =
7.2 Hz), 4.51-4.55 (m, 1H), 4.67 (s, 2H), 4.91-4.96 (m, 1H),
5.26 (s, 2H), 6.12 (s, br, 1H), 6.58 (s, br, 1H), 7.03-7.58 (m,
13H), 8.19 (s, 1H); 13C NMR (100 MHz, CDCl3): ꢀ 17.0,
34.6, 45.8, 49.4, 50.1, 55.0, 58.2, 65.9, 67.3, 119.6, 121.3,
124.5, 124.9, 127.3, 127.5, 128.0, 128.2, 129.0, 139.4, 140.0,
140.5, 140.9, 142.3, 155.8, 165.7, 170.1, 171.8, 205.6.
1
3i: IR (KBr): 1499, 1698, 1721, 3102 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 0.91 (d, 6H, J = 7.1 Hz), 1.31 (s, 9H),
2.55-2.61 (m, 1H), 4.11 (d, 1H, J = 5.4 Hz), 4.55 (s, 2H),
6.11 (s, br, 1H), 7.98 (s, 1H), 10.11 (s, br, 1H); 13C NMR
(100 MHz, CDCl3): ꢀ 17.1, 17.3, 27.3, 27.6, 28.0, 57.8, 64.2,
78.5, 124.5, 139.5, 155.1, 165.6, 205.1; 13C NMR (100 MHz,
CDCl3): ꢀ 16.5, 17.0, 27.5, 27.8, 28.0, 57.1, 65.6, 79.2,
124.8, 130.2, 155.6, 165.6, 205.1.
1
6b: IR (KBr): 1547, 1690, 1722, 1747 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 0.96 (d, 6H, J = 4.9 Hz), 2.59-2.61
(1H, m), 3.58 (s, 3H), 3.88 (dd, 1H, J = 3.6, 2.1 Hz), 3.91
(dd, 1H, J = 6.5, 3.1 Hz), 4.18 (d, 1H, J = 4.9 Hz), 4.46-4.52
(m, 1H), 4.52 (s, 2H), 4.79 (s, 1H), 5.32 (s, 2H), 6.11 (s, br,
1H), 6.23 (s, br, 1H), 6.98-7.20 (m, 10H), 8.22 (s, 1H); 13C
NMR (100 MHz, CDCl3): ꢀ 17.1, 30.2, 50.8, 56.4, 59.1,
60.4, 64.7, 66.1, 73.1, 120.7, 121.8, 124.5, 127.9, 128.8,
137.7, 139.3, 140.2, 155.2, 166.1, 170.0, 206.5.
1
3j: IR (KBr): 1459, 1656, 1721, 2998 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 1.25 (s, 9H), 1.55-1.91 (m, 4H), 3.11
(dd, 2H, J = 3.6, 5.9 Hz), 4.00 (dd, 1H, J = 2.9, 7.6 Hz), 4.41
(s, 2H), 8.04 (s, 1H), 10.22 (s, br, 1H); 13C NMR (100 MHz,
CDCl3): ꢀ 21.2, 25.8, 27.4, 27.8, 46.6, 57.9, 64.1, 78.8,
124.5, 139.2, 155.6, 166.1, 205.6.

314 Protein & Peptide Letters, 2012, Vol. 19, No. 3
Vishwanatha et al.
Maarseveen, J. H. CuI-Catalyzed Alkyne–Azide “Click” Cycload-
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1
6c: IR (KBr): 1415, 1678, 1704, 1767 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 1.38 (s, 9H), 1.41 (d, 3H, J = 3.2 Hz),
2.91-3.08 (m, 2H), 3.55 (s, 3H), 4.65-4.69 (m, 1H), 4.79-
4.81 (m, 1H), 4.91 (s, 2H), 6.66 (s, br, 1H), 6.81 (s, br, 1H),
8.21 (s, 1H),7.11-7.23 (m, 5H); 13C NMR (100 MHz,
CDCl3): ꢀ 16.8, 27.9, 34.1, 49.6, 50.8, 57.4, 60.3, 78.4,
124.8, 126.5, 127.8, 128.0, 138.2, 139.2, 155.2, 165.2, 170.2,
206.6.
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1
Angell, Yu. L.; Burgess, K. Peptidomimetics via Copper-Catalyzed
Azide–Alkyne, cycloadditions. Chem. Soc. Rev., 2007, 36 (10),
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6d: IR (KBr): 1511, 1690, 1711, 1768 cm-1; H NMR
(300 MHz, CDCl3): ꢀ 1.31 (d, 3H, J = 3.9 Hz), 1.40 (s, 9H),
3.65 (s, 3H), 4.45 (s, 2H), 4.34-4.41 (m, 1H), 4.91 (s, 2H),
6.65 (s, br, 1H), 6.72 (s, br, 1H), 8.11 (s, 1H); 13C NMR (100
MHz, CDCl3): ꢀ 16.8, 27.4, 28.1, 47.6, 50.2, 51.3, 59.4, 78.2,
124.4, 139.5, 155.2, 170.1, 166.5, 205.5.
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Oh. K.; Guan, Z. A Convergent Synthesis of New ꢀ-Turn Mimics
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cyclic Peptide Backbone Modifications in an ꢁ-Helical Coiled Coil.
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Pokorski, J. K.; Jenkins, L. M. M.; Feng, H. Q.; Durell, S. R.; Bai,
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for Improved Inhibition, against Hepatitis A Virus 3C Proteinase.
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domimetics Through Click, Chemistry: Synthesis of Novel ꢀ-Keto
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6e: IR (KBr): 1467, 1511, 1677, 1719, 1755 cm-1; H
1
NMR (300 MHz, CDCl3): ꢀ 0.98 (d, 6H, J = 7.2 Hz), 1.34 (s,
9H), 2.58-2.61 (m, 1H), 2.91-3.12 (m, 2H), 3.55 (s, 2H),
3.59 (s, 3H), 4.31 (d, 1H, J = 2.9 Hz), 4.78 (s, 2H), 5.96 (s,
br, 1H), 6.11 (s, br, 1H), 7.12-7.22 (m, 5H), 8.13 (s, 1H); 13C
NMR (100 MHz, CDCl3): ꢀ 16.9, 27.8, 28.1, 32.6, 37.9,
50.5, 54.2, 57.6, 62.6, 78.4, 124.5, 127.2, 128.4, 136.8,
139.1, 155.1, 166.7, 170.4, 205.8.
[7]
[8]
6f: IR (KBr): 1134, 1545, 1678, 1752, 1770 cm-1; H
1
NMR (300 MHz, CDCl3): 0.87 (t, 3H, J = 5.8 Hz), 1.02 (d,
3H, J = 7.1 Hz), 1.12-1.16 (m, 2H), 1.34 (s, 9H), 2.45-2.51
(m, 1H), 3.45 (s, 2H), 3.51 (s, 3H), 4.13 (d, J = 6.2 Hz, 1H),
4.59 (s, 2H), 5.95 (s, br, 1H), 6.12 (s, br, 1H), 8.12 (s, 1H);
13C NMR (100 MHz, CDCl3): ꢀ 10.5, 14.8, 25.1, 27.9, 33.9,
44.6, 51.0, 55.9, 60.1, 78.6, 124.8, 139.7, 155.4, 166.4,
170.8, 208.1.
[9]
[10]
[11]
ACKNOWLEDGEMENT
Authors are thankful to University Grants Commission
(UGC), New Delhi [F. No. 37-79/2009 (SR)] for financial
assistance. Authors also acknowledge the Departments of
Organic Chemistry, Inorganic and Physical Chemistry and
Sophisticated Instrumentation Facility, Indian Institute of
Science, Bangalore for recording sample analyses.
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1,4-Disubstituted 1,2,3- Triazoles from In Situ Generated Azides.
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Kacprzak. K. Efficient One-Pot Synthesis of 1,2,3-Triazoles from
Benzyl and Alkyl Halides. Synlett., 2005, (6), 943-946.
Kumar, D.; Patel, G.; Reddy, V. B. Greener and Expeditious Syn-
thesis of 1,4-Disubstituted 1,2,3-Triazoles from Terminal Acety-
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Synthesis of 4-Amino-Thiazole Analogs of Fmoc-Amino Acids
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Received: August 1, 2011
Revised: August 11, 2011
Accepted: August 18, 2011