Amino acids as building blocks for the synthesis of substituted 1,2,4-triazoles

Article abstract of DOI:10.1016/j.tet.2011.07.011

We report on the synthesis of 1,2,4-triazoles substituted with 2 or 3 amino acid side chains, using silver benzoate as a key reagent for the cyclization step. A complete study of the optical purity retention during the synthetic process leading to these c

Full text of DOI:10.1016/j.tet.2011.07.011

Tetrahedron 67 (2011) 7042e7049
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Tetrahedron
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Amino acids as building blocks for the synthesis of substituted 1,2,4-triazoles
*
Mathieu Bibian, Jean Martinez, Jean-Alain Fehrentz
ꢀ
ꢀ
ꢀ
Institut des Biomolecules Max Mousseron, UMR 5247 CNRS, Universite Montpellier 1, Universite Montpellier 2, 15 Av. Charles Flahault, BP 14491, 34093 Montpellier Cedex 5, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 May 2011
Received in revised form 4 July 2011
Accepted 6 July 2011
Available online 14 July 2011
We report on the synthesis of 1,2,4-triazoles substituted with 2 or 3 amino acid side chains, using silver
benzoate as a key reagent for the cyclization step. A complete study of the optical purity retention during
the synthetic process leading to these compounds is described. In addition an improved work-up after
the addition-cyclization step was also established leading to better yields and metal-free products.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,2,4-Triazole
Thioamide
Building block
Heterocycle
Lawesson’s reagent
1. Introduction
2. Results and discussion
We recently reported on the synthesis of 3,4,5-trisubstituted-
1,2,4-triazoles using silver benzoate as a key reagent (Scheme 1).1
This methodology was useful for the synthesis of optically pure
compounds, bearing a chiral moiety in position 3 (Scheme 1), as
intermediates for the synthesis of GHSeR1a ligands.2 In our on-
going efforts to develop original compounds with potential bi-
ological activities, we decided to work on the synthesis of more
complex structures, based on the 1,2,4-triazole scaffold substituted
with 1, 2 or even 3 amino acid side chains. We thus attempted to
apply the silver benzoate methodology to the synthesis of these
Using chiral HPLC, we previously demonstrated that the use of
silver benzoate allowed us to introduce a chiral moiety on position
3 of the ring, maintaining the optical purity of this center un-
changed.1 The same strategy was used to study the introduction of
chiral centers in positions 4 and 5. We synthesized two analogs of
3,4,5-trisubstituted 1,2,4-triazole enantiomers that were then an-
alyzed by chiral HPLC analysis.
We first studied epimerization when introducing a chiral sub-
stituent in position 5 of the triazole (Scheme 2). For this purpose we
produced the corresponding hydrazides starting from optically
derivatives. Because
atom, the synthesis of such compounds required a complete study
of the optical purity retention during the synthetic process.
a
-amino acids possess an asymmetric carbon
pure Boc-L-Trp-OH and Boc-D-Trp-OH. We used a recently described
pathway for the synthesis of these chiral hydrazides.3 This ap-
proach for the synthesis of hydrazides bearing a large variety of
chemical groups without epimerization, degradation or depro-
tection problems, which can occur with classical methods. Hydra-
zides 4 and 7 were reacted with an achiral thioamide 6 (obtained as
previously described via Lawesson’s reagent).4 Silver benzoate-
mediated couplingecyclization afforded triazoles 5 and 8.
Using chiral HPLC analysis we observed that the synthetic
scheme did not induce epimerization when a chiral group was
placed in position 5 (ee ꢀ98%).
AgOBz (2 equiv.)
R'
S
H
N
R''
AcOH (3 equiv.)
R'
N
3
+
5
H2N
R
R''
4
R
N
H
DCM,
2
1
O
r.t., 6 h
N N
(1.2 equiv.)
1
2
3
Scheme 1. Synthesis of 3,4,5-trisubstituted 1,2,4-triazole using silver benzoate.
Secondly, we studied epimerization when a chiral group is in-
troduced at position 4 of the triazole ring (Scheme 3). For this
purpose we synthesized amides 9 and 12 by coupling picolinic acid
with HCl$H-L-Phe-OMe and HCl$H-D-Phe-OMe, respectively.
Without further purification these amides were reacted with the
Lawesson’s reagent to obtain thioamides 10 and 13. The
* Corresponding author. Tel.: þ33 4 67 54 86 51; fax: þ33 4 67 54 86 54; e-mail
address: jean-alain.fehrentz@univ-montp1.fr (J.-A. Fehrentz).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.011

M. Bibian et al. / Tetrahedron 67 (2011) 7042e7049
7043
H
N
H
N
H
N
a,b
c
N
H2NHN
HO
(S)
NHBoc
(S)
(S)
NHBoc
NHBoc
O
N
N
O
5
4
H
N
S
6
H
H
N
H
N
N
c
a,b
N
H2NHN
HO
(R)
(R)
NHBoc
(R)
NHBoc
NHBoc
N
N
O
O
7
8
Scheme 2. Synthesis of triazoles 5 and 8. Experimental conditions: (a) EDC$HCl (1.4 equiv), DCM, 2 h, 0 ꢁC then N-aminophthalimide 1 h, 0 ꢁC and overnight rt (b) Aminomethyl
polystyrene resin, 1.1 mmol/g, DCM, 24 h, rt (c) 6 (1 equiv), 4 (1.2 equiv), AgOBz (2 equiv), AcOH (3 equiv), DCM, 6 h, rt.
(S)
CO2Me
a
c
c
H
N
CO2Me
(S)
OH
N
N
N
X
N
N
O
N
11
N
9 X=O
b
10 X=S
(R)
CO2Me
H
N
a
CO2Me
(R)
OH
N
N
N
X
O
N
14
N
12 X=O
13 X=S
b
Scheme 3. Synthesis of triazoles 11 and 14. Experimental conditions: (a) BOP (1 equiv), benzylamine (1.1 equiv), DIEA (2 equiv), 30 min, rt (b) Lawesson reagent (0.55 equiv), DME,
2 h, 80 ꢁC (c) phenylacetic hydrazide (2 equiv), AgOBz (2 equiv), AcOH (3 equiv), DCM, 6 h, rt.
couplingecyclization step with phenylacetic hydrazide in the
presence of silver benzoate proceeded very slowly to yield triazoles
11 and 14 in low yields (about 20% after 14 days).
triazoles 17aeq. Hydrazides 16aeo were prepared according to
Ref. 3. Hydrazide 16p was synthesized by overnight hydrazinolysis
of the corresponding methyl ester with hydrazine monohydrate
(6 equiv) in MeOH at room temperature, to avoid the epimerization
of acylated amino acids that occurs during activation with EDC.
Results are summarized in Table 1.
These results indicate that this method in scope is robust, being
compatible with usual peptide synthesis protecting groups (Boc,
Cbz, and Fmoc) and amino acids functionalized on their side chain
can be introduced. Yields ranged from poor to good and were
irrespective both of the electron withdrawing or donating effects
and of the nature of side chains. In addition, the protecting groups
used in these examples were stable under these reaction
conditions.
All compounds described in Table 1 were obtained by silica gel
purification of the crudes. Usually a very polar eluent was required
for elution of triazole derivatives (5% MeOH/95% Ethyl acetate) and
low yields were obtained in some cases (17f and 17h, for example).
For the synthesis of 1,2,4-triazoles trisubstituted by amino acid
side chains in positions 3, 4, and 5, the same protocol was followed
(Scheme 4).
Following isolation by silica gelcompounds 11 and 14 were an-
alyzed by chiral HPLC. No epimerization was detected during the
procedure (ee ꢀ98%).
From these experiments, we could conclude that the silver
benzoate-mediated couplingecyclization reaction did not induce
epimerization in any asymmetric carbon atom present in
of the triazole ring.
a position
We then attempted to apply our methodology to the synthesis
of the 1,2,4-triazole scaffold, substituted with 2 or 3 amino acid side
chains. Three types of diastereoisomers could be synthesized: tri-
substituted triazoles bearing chiral groups in positions 3 and 5 of
the triazole ring, trisubstituted triazoles bearing chiral groups in
positions 3 and 4 of the triazole ring, trisubstituted triazoles bear-
ing chiral groups in positions 3, 4 and 5 of the triazole ring.
In the following section, we describe the synthesis of optically
pure diastereoisomers bearing chiral groups in positions 3 and 5.
Fmoc, Z or Boc N-protected amino acids were coupled to various
amines to yield amides that were converted into thioamides 15aeq.
The resulting thioamides were allowed to react with different N-
protected amino acid hydrazides 16aeq to produce the 1,2,4-
This reaction yielded, after purification, triazole 20 tri-
substituted in position 3, 4, and 5 by amino acid side chains in an

7044
M. Bibian et al. / Tetrahedron 67 (2011) 7042e7049
Table 1
This new procedure was applied to the synthesis of two com-
pounds 17e and 17f. A comparison of the yields that were obtained
are shown in Table 2.
Synthesis of 1,2,4-triazoles bearing amino acid side chains in positions 3 and 5 of the
ring
R'
N
AgOBz (2 equiv.)
O
H
N
R
R
R''
R'
Table 2
H2NHN
R''
AcOH (3 equiv.)
DCM, rt, 6 h
N
N
Influence of the treatment on the yields
S
1.2 equiv.
Compounds
Yields (%) and silver
concentration (ppm)
(direct purification by
chromatography)
Yields (%)and silver
15(a-q)
16(a-q)
17(a-q)
concentration (ppm)
(precipitation treatment
and chromatography)
17 Starting material for R R0
Starting material for R00 Yield (%)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
Fmoc-
Fmoc-
L
-Trp
-Trp
Benzyl
p-OMeBenzyl
Benzyl
p-OMeBenzyl
p-ClBenzyl
p-ClBenzyl
Benzyl
p-ClBenzyl
p-OMeBenzyl
Benzyl
Benzyl
Phenethyl
Benzyl
Pentyl
Benzyl
Boc-
Boc-
Boc-
Boc-
Boc-
Boc-
Boc-
Boc-
Boc-
L
L
L
L
L
L
L
L
L
-Phe
-Phe
-Phe
-Phe
-Phe
-Phe
-Trp
42
77
59
49
51
32
34
29
79
76
62
70
77
33
60
84
77
17e
17f
51dND
32d13.3
79dND
59d2.3
L
Z-
L
-Phe
-Phe
Z-L
Fmoc-
Z- -Trp
Fmoc-
L-Phe
L
Indeed, the apparent polarity of the products was changed after
removal of silver salts. As a comparison, the eluent for elution of the
desired compound on silica gel chromatography, in the presence of
silver salts, was 5% MeOH in EtOAc, whereas in the absence of silver
salts only a 9/1 (v/v) EtOAc/hexane mixture was needed. Yields
were clearly improved under this new procedure (Table 2).
As part of our ongoing effort to obtain metal-free final com-
pounds, we synthesized and purified a compound by the two
methods described above. Then we measured the silver salts con-
centration using ICPMS (Inductively Coupled PlasmadMass Spec-
L-Trp
Z-
L
-Trp
-Phe
-Trp
-Lys(Z)
Z-L
Boc-
Boc-
Boc-
Boc-
Boc-
Boc-
Boc-
Boc-
L-Nle
L-Nle
L-Nle
L-Nle
L-Trp
L-Nle
L-Nle
L-Nle
Z-
Z-
L
-Asp(OBzl)
D-Asp(OBzl)
Fmoc-
Fmoc-
L
-Asp(Ot-Bu)
-Glu(Ot-Bu)
L
Z-
Fmoc-
L
-Asp(OBzl)
-Asp(Ot-Bu)
-Phe
L
Ethyl 2-acetate Ac-
Ethyl 2-acetate Ac-
L
D
-Phe
H
N
CO2Me
BocHN
a
X
CO2Me
e
OH
18 X=O
19 X=S
d
N
BocHN
28%
BocHN
NHBoc
O
N
N
20
b, c
NHNH2
BocHN
O
16a
Scheme 4. Synthesis of a triazole ring starting from amino acids. Experimental conditions: (a) AlaOMe (1.1 equiv), DIEA, BOP (1 equiv), 30 min, rt (b) EDC$HCl (1.4 equiv), DCM, 2 h,
ꢁC then N-aminophthalimide 1 h at 0 ꢁC and overnight rt (c) Aminomethyl Polystyrene resin, 1.1 mmol/g, DCM, 24 h, rt (d) Lawesson’s reagent (0.55 equiv), DME, 2 h, 80 ꢁC (e) 19
0
(1.0 equiv), 16a (1.2 equiv), AgOBz (2 equiv), AcOH (3 equiv), DCM, 3 days, rt.
optically pure form as assessed by 1H NMR. In this case, the reaction
proceeded slowly. This example indicated that we are able to pro-
duce rigid tripeptide analogs. The biological study of this class of
compounds is currently under investigation.
troscopy) analysis. As we can see in Table 2, the silver
concentrations were very low in both cases. However treatment by
silver salts precipitation allowed us to mostly eliminate silver
contained in the crude. This result confirmed the superiority of the
silver salt precipitation treatment over the direct purification by
chromatography on silica gel.
To conclude, in this paper we described the first synthesis of
1,2,4-triazoles bearing at least two amino acid side chains. This
synthetic procedure is epimerization free as demonstrated by chiral
HPLC analysis. This study allowed the synthesis of compounds that
can mimic small peptides. We will now focus on the synthesis of
potentially bioactive compound libraries. We aim to prove that the
triazole moiety can be a good scaffold to rigidify small peptides
structures with possible improvement in their pharmacological
properties.
We tried to optimize the treatment and purification of our tri-
azole compounds. To solve problems related to the presence of
silver salts, we did not succeed in eliminating them using the dif-
ferent methods described in the literature (aqueous barium sulfide
washing,5 filtration of the crude on a Celite pad, aqueous NaCl
washing). We thus developed a new strategy, employing the for-
mation of a silver salt, that is, insoluble in organic media and
compatible with the protecting groups that were used. The sim-
plest example used was silver chloride, which is insoluble in water
and organic media. The treatment was optimized to minimize the
risk of acid labile group deprotection. Typically after evaporation of
dichloromethane, a 50/50 (v/v) solution of DCM and MeOH was
added. After vigorous stirring, 2 equiv of HCl (1 N solution in water)
were added. Stirring was continued for 2 min and a black powder
precipitated. N,N-Diisopropylethylamine (2 equiv) was added to
neutralize the remaining HCl. After evaporation of the solvent, the
residue was filtered on Celite and eluted with methanol. After
solvent evaporation, dilution in ethyl acetate and washing twice
with KHSO4 (1 M solution in water) and NaHCO3 (saturated water
solution) afford the product as a colorless solid or oil. The product
was isolated by silica gel in good yield.
3. Experimental section
3.1. General
Commercially available reagents and solvents were used with-
out further purification. Aminomethyl polystyrene resin was pur-
chased from Iris Biotech GmbH (Marktredwitz, Germany).
LC/MS analysesdsamples were prepared in acetonitrile/water
(50/50 v/v) mixture, containing 0.1% TFA. All the analyses were

M. Bibian et al. / Tetrahedron 67 (2011) 7042e7049
7045
carried out using a Merck Chromolith Speed rod C18, 25ꢂ4.6 mm
reversed-phase column. A flow rate of 3 mL/min and a gradient of
(0e100)% B over 3 min (or over 5 min) were used. Eluent A: water/
0.1% HCO2H; eluent B: acetonitrile/0.1% HCO2H. Nitrogen was used
for both the nebulizing and drying gas. The data were obtained in
a scan mode ranging from 100 to 1000 m/z in 0.1 s intervals; 10
scans were summed up to get the final spectrum.
9 Hz, H4 tryptophan), 10.72 (s, 1H, NH indole). 13C NMR (75 MHz,
DMSO-d6, 303 K): (ppm) 20.5 (CH3 p-methylbenzyl), 26.2 (CH2b
phenethyl), 28.0 (CH3 Boc), 28.9 (CH2 phenethyl), 32.4 (CH2b
tryptophan), 45.0 (CH2 p-methylbenzyl), 45.3 (CH tryptophan),
78.3 (C quat. Boc), 110.2 (C3 tryptophan), 111.2 (C7 tryptophan), 118.1
(C4 tryptophan), 118.2 (C5 tryptophan), 120.7 (C6 tryptophan), 123.8
(C2 tryptophan), 125.9 and 126.0 (C4 phenethyl and p-methyl-
benzyl), 127.1 (C9 tryptophan), 128.2 and 129.1 (CH aromatics and p-
methylbenzyl), 132.9 (C4 p-methylbenzyl), 135.9 and 136.6 (C1 p-
methylbenzyl and C8 tryptophan), 140.6 (CO Boc), 153.8 and 155.1
(C3C5 triazole). MS (ES), m/z: 536.3 [MþH]þ.
d
a
a
NMR spectroscopydchemical shifts were reported as
d values
(ppm) indirectly referenced to the solvent signal; J values are in
hertz, and splitting patterns are designated as follows: br s (broad
singlet), s (singlet), d (doublet), t (triplet), m (multiplet).
Chiral HPLCdfor compounds 11 and 14, analysis were per-
formed on a Chiracel OD column (normal phase), with a flow rate of
1 ml/min in an isocratic mode 70/30 hexane/isopropanol (v/v) 1&
Et2NH and monitoring at 280 nm. For compounds 5 and 8, analysis
was performed on a Welck 01 column (normal phase), with a flow
rate of 1 ml/min in an isocratic mode 70/30 hexane/isopropanol (v/
v) and monitoring at 280 nm.
3.4.2. (S)-Methyl 3-phenyl-2-(pyridine-2-carbothioamido)propanoa
te10. Yellow oil, 2.83 g, 94%.
3.4.3. (R)-Methyl
anoate 13. Yellow oil, 2.52 g, 84% 1H NMR (400 MHz, DMSO-d6):
(ppm) 3.38 (dd, 1H, 8 and 14 Hz, CH2b phenylalanine), 3.40 (dd,
1H, 6 and 14 Hz, CH2b phenylalanine), 3.68 (s, 3H, OMe), 5.44 (m,
1H, CH phenylalanine), 7.20e7.29 (m, 5H, CH aromatics phenyl-
3-phenyl-2-(pyridine-2-carbothioamido)prop-
d
Flash chromatographydpurifications were performed with
Kieselguhr Merck G silica gel Si 60 (40e63
mm) with hexane/AcOEt
a
as eluent.
alanine), 7.63 (ddd,1H,1 and 5 and 8 Hz, H5 pyridine), 8.00 (td,1H, 2
and 8 Hz, H3 pyridine), 8.44 (dt, 1H, 8 Hz, H4 pyridine), 8.62 (m, 1H,
H6 pyridine), 10.83 (d, 1H, 8 Hz, NH thioamide). 13C NMR (75 MHz,
Preparation of amides, thioamides, and hydrazides have been
previously described in Refs. 1,3.
DMSO-d6, 303 K):
d (ppm) 36.1 (CH2 b phenylalanine), 52.8 (OMe),
3.2. General procedure for preparation of compounds 17aeq
59.4 (CH phenylalanine), 125.0 (C3 pyridine), 127.3 and 127.3 (C4
a
phenylalanine and C5 pyridine), 128.9 (C2 and C6 phenylalanine),
129.5 (C3 and C5 phenylalanine), 137.1 (C1 phenylalanine), 138.3 (C4
pyridine), 148.1 (C6 pyridine), 151.3 (C2 pyridine), 170.7 (CO car-
bonyl), 191.9 (CS thioamide). MS (ES), m/z: 301.1 [MþH]þ.
Thioamide (1 equiv) and hydrazide (1.2 equiv) were diluted in
dichloromethane (10 ml/mmol). Silver benzoate (2 equiv) was then
added immediately followed by acetic acid (3 equiv). The mixture
was stirred 6 h at room temperature. Distillation of the solvent
under reduced pressure gave a black oil, which was diluted in
a solution of dichloromethane. A flash chromatography on silica gel,
with AcOEt/hexane 5/5 to MeOH 5% in AcOEt as eluent, afforded the
triazoles in 32e90% yield.
3.4.4. (S)-Methyl 2-(3-benzyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-4-
yl)-3-phenylpropanoate 11. Colorless oil, 80 mg (20%).
3.4.5. (R)-Methyl 2-(3-benzyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-4-
yl)-3-phenylpropanoate 14. Colorless oil, 82 mg (20%) 1H NMR
3.3. General procedure for preparation of 1,2,4-triazoles with
silver salts precipitation work-up
(400 MHz, DMSO-d6, 303 K):
CH2b phenylalanine), 3.49 (s, 3H, OMe), 3.60 (br s, 1H, CH2 benzyl),
d
(ppm) 3.27 (dd, 1H, J¼10 and 14 Hz,
3.64 (dd, 1H, J¼4 and 14 Hz, CH2b phenylalanine), 5.68 (m, 1H, CH
a
Thioamide (1 equiv) and hydrazide (1.2 equiv) were diluted in
dichloromethane (10 ml/mmol). Silver benzoate (2 equiv) was then
added immediately followed by acetic acid (3 equiv). The mixture
was stirred for 6 h at room temperature. Distillation of the solvent
under reduced pressure gave a black oil, which was diluted in 50/50
(v/v) solution of DCM and MeOH solution (10 ml/mmol). Under
vigorous stirring, 2 equiv of HCl (1 N solution in water) were added.
After 2 min of stirring a black powder precipitated. Diisopropyle-
thylamine (2 equiv) was then added. After evaporation under re-
duced pressure, the reaction mixture was filtered on filter paper
and eluted with methanol. After solvent evaporation, dilution in
ethyl acetate and washing twice with KHSO4 (1 M solution in wa-
ter) and NaHCO3 (saturated water solution) a colorless compound
was obtained. A flash chromatography on silica gel, with AcOEt/
hexane 5/5 to pure AcOEt eluents, afforded the pure triazoles in
60e90% yield.
phenylalanine), 6.84 (d, 2H, J¼8Hz, H2H6 benzyl), 7.02 (d, 2H, J¼7 Hz,
H2H6 phenylalanine), 7.14e7.28 (m, 6H, H3H4H5 benzyl and H3H4H5
phenylalanine), 7.50 (ddd,1H, J¼1 and 5 and 7 Hz, H5 pyridine), 8.00
(td, 1H, J¼2 and 8 Hz, H4 pyridine), 8.20 (d, 1H, J¼8 Hz, H3 pyridine),
8.58 (br d, 1H, J¼5 Hz, H6 pyridine). 13C NMR (75 MHz, DMSO-d6,
303 K):
d (ppm) 30.5 (CH2 benzyl), 37.2 (CH2b phenylalanine), 52.7
(OMe), 59.8 (CH
a
phenylalanine), 123.0 (C3 pyridine), 124.9 (C5
pyridine), 127.1 and 127.4 (C4 phenylalanine and C4 benzyl),
128.8e129.5 (C2C3C5C6 phenylalanine and C2C3C5C6 benzyl), 136.0
(C1 benzyl),136.9 (C4 pyridine),138.2 (C1 phenylalanine),147.3 (C3 or
C5 triazole), 148.4 (C6 pyridine), 151.6 (C2 pyridine), 156.2 (C3 or C5
triazole), 169.0 (CO ester). MS (ES), m/z: 399.0 [MþH]þ.
3.4.6. (9H-Fluoren-9-yl)methyl (S)-1-(benzylthiocarbamoyl)-2-(1H-
indol-3-yl)ethylcarbamate 15a and 15g. Yellow oil, 1.46 g, 60% 1H
NMR (300 MHz, DMSO-d6, 303 K):
CH2b tryptophan), 3.26 (dd,1H, 5 and 14 Hz, CH2b tryptophan), 4.20
(m, 3H, CHeCH2 Fmoc), 4.74 (m, 1H, CH tryptophan), 4.80 (d, 2H,
d (ppm) 3.11 (dd,1H, 9 and 14 Hz,
3.4. Compounds characterization
a
5Hz, CH2 benzyl), 7.00 (m, 1H, H5 tryptophan), 7.08 (t, 1H, 8 Hz, H6
tryptophan), 7.18 (d, 2H, 7 Hz, H2 tryptophan and H4 benzyl),
7.23e7.30 (m, 6H, H2H3H5H6 benzyl and H2H7 Fmoc), 7.35e7.41 (m,
3H, H7 tryptophan and H3H6 Fmoc), 7.59 (d, 1H, 8 Hz, H4 trypto-
phan), 7.64e7.73 (m, 3H, H1H8 Fmoc and NH Fmoc), 7.87 (d, 2H,
7Hz, H4 H5 Fmoc), 10.48 (br s, 1H, NH thioamide), 10.85 (s, 1H, NH
3.4.1. tert-Butyl 1-(4-(4-methylbenzyl)-5-phenethyl-4H-1,2,4-triazol-
3-yl)-2-(1H-inden-3-yl)ethylcarbamate 5. Brown powder, 185 mg,
70% and 8 brown powder,185 mg, 70% 1H NMR (300 MHz, DMSO-d6,
303 K):
benzyl), 2.67e2.69 (4H, m, CH2CH2 phenethyl), 3.22e3.43 (m, 2H,
CH2b tryptophan), 4.91 (dd, 1H, 9 and 14 Hz, CH tryptophan), 5.06
d (ppm) 1.22 (s, 9H, CH3 Boc), 2.23 (3H, s, CH3 p-methyl-
a
indole tryptophan). 13C NMR (75 MHz, DMSO-d6, 303 K):
30.9 (CH2b tryptophan), 46.6 (CH Fmoc), 48.3 (CH2 benzyl), 61.9
(CH tryptophan), 65.7 (CH2 Fmoc), 109.9 (C3 tryptophan), 111.3 (C7
tryptophan), 118.2 (C4 tryptophan), 118.5 (C5 tryptophan), 120.0
d (ppm)
(s, 2H, CH2 p-methylbenzyl), 6.72 (d, 7 Hz, NH Boc and H5 trypto-
phan), 6.89 (t, 1H, H6 tryptophan), 6.99e7.33 (m, 11H, CH aromatics
phenethyl and p-methylbenzyl, and H2H7 tryptophan), 7.55 (d, 1H,
a

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M. Bibian et al. / Tetrahedron 67 (2011) 7042e7049
(C4C5 Fmoc), 120.8 (C6 tryptophan), 124.1 (C2 tryptophan), 125.3 (C1
C8 Fmoc), 127.0 (C4 benzyl and C2 C7 Fmoc), 127.2 (C9 tryptophan),
127.4 (C2 C6 benzyl), 127.7 (C3 C5 benzyl), 128.2 (C3 C6 Fmoc), 136.1
(C1 benzyl), 136.9 (C8 tryptophan), 140.6 (C4 a/b Fmoc), 143.8 (C8 a/
b Fmoc), 155.5 (CO Fmoc), 204.8 (CS thioamide). MS (ES), m/z: 532.0
[MþH]þ.
4.17 (m, 3H, CH2CH Fmoc), 4.70 (m, 1H, CHa phenylalanine), 4.76 (d,
2H, 5Hz, CH2 4-chlorobenzyl), 7.18 (d, 2H, 8Hz, H2 H6 4-
chlorobenzyl), 7.27 (d, 2H, 7Hz, H3 H5 4-chlorobenzyl), 7.31e7.32
(m, 7H, H2 H7 Fmoc and H2 H3 H4 H5 H6 phenylalanine), 7.41 (t, 2H,
7 Hz, H3 H6 Fmoc), 7.67 (d, 2H, 8 Hz, H1 H8 Fmoc), 7.73 (d, 1H, 8 Hz,
NH Fmoc), 7.87 (d, 2H, 8 Hz, H4 H5 Fmoc), 10.53 (t, 1H, 5 Hz, NH
thioamide). 13C NMR (75 MHz, DMSO-d6, 303 K):
d
(ppm) 40.3 (CH2b
3.4.7. (9H-Fluoren-9-yl)methyl (S)-1-(4-methoxybenzylthiocar
phenylalanine), 46.5 (CH Fmoc), 47.4 (CH2 4-chlorobenzyl), 62.3 (CH
a
bamoyl)-2-(1H-indol-3-yl)ethylcarbamate 15b. Yellow oil, 1H NMR
phenylalanine), 65.7 (CH2 Fmoc), 120.0 (C4C5 Fmoc), 125.3 (C1C8
Fmoc), 126.3 (C4 phenylalanine), 127.0 (C2C7 Fmoc), 127.6 (C3C6
Fmoc), 128.0 and 128.1 (C2C3C5C6 4-chlorobenzyl), 129.3 (CH Ar
phenylalanine), 135.8 (C1 phenylalanine), 137.6 (C1 4-chlorobenzyl),
140.6 (C4 a/b Fmoc), 143.7 (C8 a/b Fmoc), 155.5 (CO Fmoc), 204.5 (CS
thioamide). MS (ES), m/z: 527.0 [MþH]þ.
(300 MHz, DMSO-d6, 303 K):
CH2b tryptophan), 3.21 (dd, 1H, 5 and 14 Hz, CH2b tryptophan), 3.71
(s, 3H, OeCH3), 4.18 (m, 3H, CHCH2eFmoc), 4.72 (m, 3H, CH
d (ppm) 3.12 (dd, 1H, 9 and 14 Hz,
a
tryptophan and CH2 4-methoxybenzyl), 6.82 (d, 2H, 8 Hz, H3 H5 4-
methoxybenzyl), 7.01 (t, 1H, 8 Hz, H5 tryptophan), 7.05e7.13 (m, 3H,
H6 tryptophan and H2H6 4-methoxybenzyl), 7.24 (d, 1H, 2Hz, H2
tryptophan), 7.29 (m, 2H, H2H7 Fmoc), 7.32e7.43 (m, 2H, H3H6 Fmoc
and H7 tryptophan), 7.56 (d, 1H, 8 Hz, H4 tryptophan),7.70 (m, 3H,
H1H8 Fmoc and NH Fmoc), 7.87 (d, 2H, 8Hz, H4H5 Fmoc), 10.39 (br s,
1H, NH thioamide), 10.85 (s, 1H, NH indole tryptophan). 13C NMR
3.4.11. Benzyl (S)-1-(4-chlorobenzylthiocarbamoyl)-2-(1H-indol-3-
yl)ethylcarbamate 15f and 15h. Yellow 3.07 g, 100% 1H NMR
(300 MHz, DMSO-d6, 303 K):
CH2b tryptophan), 3.24 (dd, 1H, 5 and 14 Hz, CH2b tryptophan), 4.74
(m, 3H, CH2 4-chlorobenzyl and CH tryptophan), 4.95 (br s, 2H,
d (ppm) 3.07 (dd, 1H, 9 and 14 Hz,
(75 MHz, DMSO-d6, 303 K):
d
(ppm) 30.8 (CH2b tryptophan), 46.6
a
(CH Fmoc), 47.8 (CH2 4-methoxybenzyl), 55.0 (OeCH3), 61.8 (CH
a
CH2 Z), 7.00 (t, 2H, 7 Hz, H5 tryptophan), 7.00 (d, 1H, 7Hz, NH Z), 7.11
(t,1H, 8 Hz, H6 tryptophan), 7.12 (d, 2H, 8 Hz, H2 H6 4-chlorobenzyl),
7.20 (s, 1H, H2 tryptophan), 7.31 (d, 5H, 6 Hz, H2 H3 H4 H5 H6 Z), 7.37
(d, 1H, 8 Hz, H7 tryptophan), 7.36 (d, 2H, 8 Hz, H3 H5 4-
chlorobenzyl), 7.66 (d, 1H, 8 Hz, H4 tryptophan), 10.47 (t, 1H,
5 Hz, NH thioamide), 10.84 (s, 1H, NH indole tryptophan). 13C NMR
tryptophan), 65.7 (CH2 Fmoc), 109.9 (C3 tryptophan), 111.3 (C7
tryptophan), 113.6 (C3 C5 4-methoxybenzyl), 118.2 (C4 tryptophan),
118.5 (C5 tryptophan), 120.0 (C4C5 Fmoc), 120.8 (C6 tryptophan),
124.1 (C2 tryptophan), 125.3 (C1C8 Fmoc), 127.0 (C2C7 Fmoc), 127.3
(C9 tryptophan), 127.6 (C2C6 4-methoxybenzyl or C3C6 Fmoc), 128.9
(C2C6 4-methoxybenzyl or C2C6 Fmoc),128.7 (C1 4-methoxybenzyl),
136.1 (C8 tryptophan), 140.6 (C4 a/b Fmoc), 143.6 (C8 a/b Fmoc),
155.4 (CO Fmoc), 158.4 (C4 4-methoxybenzyl), 204.3 (CS thio-
amide). MS (ES), m/z: 562.1 [MþH]þ.
(75 MHz, DMSO-d6, 303 K):
(CH2 4-chlorobenzyl), 61.9 (CH
d
(ppm) 30.8 (CH2b tryptophan), 47.4
tryptophan), 65.3 (CH2 Z), 109.7 (C3
a
tryptophan), 111.3 (C7 tryptophan), 118.2 (C4 tryptophan), 118.5 (C5
tryptophan), 120.9 (C6 tryptophan), 124.1 (C2 tryptophan), 127.2 (C9
tryptophan), 127.4 (C4 Z), 128.1 (C2 C3 C5 C6 Z), 128.2 (C2 C6 4-
chlorobenzyl), 129.2 (C3 C5 4-chlorobenzyl), 131.4 (C4 4-
chlorobenzyl), 136.1 (C8 tryptophan and C1 Z), 136.9 (C1 4-
chlorobenzyl), 155.5 (CO Z), 204.9 (CS thioamide). MS (ES), m/z:
478.1 [MþH].
3.4.8. Benzyl (S)-1-(benzylthiocarbamoyl)-2-phenylethylcarbamate
15c. Yellow oil, 1.25 g, 65% 1H NMR (300 MHz, DMSO-d6, 303 K):
d
(ppm) 2.92 (dd, 2H, 9 and 14 Hz, CH2b phenylalanine), 3.04 (dd, 2H,
5 and 14 Hz, CH2b phenylalanine), 4.71 (m, 1H, CH phenylalanine),
a
4.77 (d, 2H, 5 Hz, CH2 benzyl), 4.98 (s, 2H, CH2 Z), 7.20 (t, 3H, 7 Hz, H4
ꢀ
benzyl and H4 Z and H4 phenylalanine), 7.27 (m, 12H, H2 H3 H5 H6
3.4.12. tert-Butyl (S)-1-(5-((S)-1-Fmoc-amino-2-(1H-indol-3-yl)eth
yl)-4-benzyl-4H-1,2,4-triazol-3-yl)-2-phenylethylcarbamate
17a. Brown oil, 180 mg (42%) 1H NMR (300 MHz, DMSO-d6, 303 K):
benzyl and H2 H3 H5 H6 Z and H2 H3 H5 H6 phenylalanine), 7.56 (d,1H,
8Hz, NH Z), 10.50 (t, 1H, 7 Hz, NH thioamide). 13C NMR (75 MHz,
DMSO-d6, 303 K):
benzyl), 62.2 (CH
C4 C5 C6 benzyl, C2 C3 C4 C5 C6 Z, C2 C3 C4 C5 C6 phenylalanine), 136.8
and 136.9 and 137.6 (C1 benzyl and C1 Z and C1 phenylalanine),155.5
(CO Z), 204.2 (CS thioamide) MS (ES), m/z: 405.0 [MþH]þ.
d
(ppm) 40.4 (CH2b phenylalanine), 48.2 (CH2
d
(ppm) 1.08 (s, 9H, CH3 Boc), 3.15e3.41 (m, 4H, CH2b phenylalanine
and tryptophan), 3.93e4.13 (m, 3H, CH2CH Fmoc), 4.81e4.95 (m,
2H, CH
phenylalanine and tryptophan), 5.27 (dd, J¼17 Hz, CH2
a
phenylalanine), 65.2 (CH2 Z), 126.3e129.3 (C2 C3
a
benzylamine), 6.88 (m, 4H, H4 benzylamine and H4 phenylalanine
and H5 tryptophan and NH Boc), 7.01 (m, 2H, H2H6 tryptophan),
7.12e7.21 (m, 8H, H2H3H5H6 benzylamine and H2H3H5H6 phenyl-
alanine), 7.25e7.31 (m, 3H, H7 tryptophan and H2H7 Fmoc),
7.36e7.43 (dd, 2H, H3H6 Fmoc), 7.49 (d, 1H, J¼9Hz, H4 tryptophan),
7.58 (t, 2H, J¼8 Hz, H1H8 Fmoc), 7.86 (d, 2H, J¼7 Hz, H4H5 Fmoc),
8.17 (d, 2H, J¼8 Hz, NH Fmoc), 10.77 (s, 1H, NH tryptophan). 13C
3.4.9. Benzyl (S)-1-(4-methoxybenzylthiocarbamoyl)-2-phenyle
thylcarbamate 15d and 15i. Yellow oil, 1.44 g, 90% 1H NMR
(300 MHz, DMSO-d6, 303 K):
phenylalanine), 3.02 (dd, 1H, 5 and 14 Hz, CH2b phenylalanine), 3.74
(s, 3H, OeCH3), 4.67 (m, 3H, CH phenylalanine and CH2 4-
d (ppm) 2.90 (dd,1H, 9 and 14 Hz, CH2b
a
NMR (75 MHz, DMSO-d6, 303 K):
d (ppm) 27.8 (CH3 Boc), 38.0 (CH2b
methoxybenzyl), 4.87 (s, 2H, CH2 Z), 6.87 (d, 2H, 8 Hz, H3 H5 4-
methoxybenzyl), 7.22 (d, 2H, 8 Hz, H2 H6 4-methoxybenzyl),
7.22e7.30 (m, 10H, H2 H3 H4 H5 H6 Z and H2 H3 H4 H5 H6 phenyl-
alanine), 7.53 (d, 1H, 8 Hz, NH Z), 10.42 (br s, 1H, NH thioamide). 13C
tryptophan and phenylalanine), 45.8 (CH2 benzylamine), 46.4 (CH
a
phenylalanine and tryptophan), 46.6 (CHCH2 Fmoc), 65.7 (CHCH2
Fmoc), 78.0 (C quat. Boc), 109.6 (C3 tryptophan), 111.2 (C7 trypto-
phan), 117.8 (C4 tryptophan), 118.2 (C5 tryptophan), 120.0 (C4C5
Fmoc), 120.7 (C6 tryptophan), 125.2 (C2 tryptophan), 125.7 (C1C8
Fmoc), 126.1 (C4 phenylalanine), 126.9 (C9 tryptophan and C4 ben-
zylamine), 126.9 (C2C7 Fmoc), 127.5 (C3C6 Fmoc), 127.9 (C2C6 phe-
nylalanine and benzylamine), 128.5e129.3 (C3C5 phenylalanine and
benzylamine), 135.7 (C1 phenylalanine), 135.9 (C1 benzylamine),
137.6 (C8 tryptophan), 140.6 (C4a/b Fmoc), 143.6 (C8a/b Fmoc), 154.8
and 155.2 (CO Fmoc and Boc), 155.7 and 156.1 (C3 and C5 triazole).
HRMS (ESI) calcd for C47H47N6O4, 759.3659; found 759.3652.
NMR (75 MHz, DMSO-d6, 303 K):
nine), 47.8 (CH2 4-methoxybenzyl), 55.0 (OeCH3), 62.2 (CH
d
(ppm) 38.3 (CH2b phenylala-
phe-
a
nylalanine), 65.2 (CH2 Z), 113.7 (C3 C5 4-methoxybenzyl),
126.3e129.3 (C2 C3 C4 C5 C6 Z and C2 C3 C4 C5 C6 phenylalanine and
ꢀ
C2 C6 4-methoxybenzyl), 132.3 (C1 p-methoxybenzyl), 136.9 (C1 Z),
137.7 (C1 phenylalanine), 155.5 (CO Z), 158.5 (C4 4-methoxybenzyl),
203.7 (CS thioamide). MS (ES), m/z: 435.0 [MþH].
3.4.10. (9H-Fluoren-9-yl)methyl (S)-1-(4-chlorobenzylthiocarba
moyl)-2-phenylethylcarbamate 15e. White solid, 1.79 g, 68% 1H
3.4.13. tert-Butyl (S)-1-(5-((S)-1-Fmoc-amino-2-(1H-indol-3-yl)ethy
l)-4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-phenylethylcarbam
ate 17b. Beige oil, 534 mg, 77% 1H NMR (300 MHz, DMSO-d6,
NMR (300 MHz, DMSO-d6, 303 K):
d (ppm) 2.97 (dd,1H, 9 and 14 Hz,
CH2b phenylalanine), 3.05 (dd, 1H, 5 and 14 Hz, CH2b phenylalanine),

M. Bibian et al. / Tetrahedron 67 (2011) 7042e7049
7047
303 K):
phenylalanine and tryptophan), 3.64 (s, 3H, 4-methoxybenzyl),
4.05 (m, 3H, CHCH2eFmoc), 4.90 (m, 2H, CH phenylalanine and
tryptophan), 5.17 (dd, 2H, 8 and 17Hz, CH2 benzyl), 6.72 (d, 2H, 8Hz,
H3H5 4-methoxybenzyl), 6.84 (m, 3H, H2H6 4-methoxybenzyl and
NH Boc), 7.02 (m, 3H, H2 H5 H6 tryptophan), 7.11e7.23 (m, 5H, CH
aromatics phenylalanine), 7.29 (t, 3H, 8Hz, H2H7 Fmoc and H7
tryptophan), 7.40 (m, 2H, H3H6 Fmoc), 7.46 (d, 1H, 9Hz, H4 trypto-
phan), 7.60 (t, 2H, 8 Hz, H1 H8 Fmoc), 7.86 (d, 2H, 7Hz, H4H5 Fmoc),
8.19 (d,1H, 8Hz, NH Fmoc), 10.78 (s, 1H, NH indole tryptophan). 13C
d
(ppm) 1.12 (s, 9H, CH3 Boc), 3.18 and 3.36 (m, 4H, CH2b
17 Hz, CH2 4-chlorobenzyl), 5.24 (d, 1H, 17 Hz, CH2 4-chlorobenzyl),
6.84 (d, 2H, 9 Hz, H2H6 4-chlorobenzyl), 7.05 (d, 2H, 7 Hz, H2H6
phenylalanine), 7.10 (d, 2H, 7 Hz, H2H6 phenylalanine), 7.17 (m, 8H,
H3 H4 H5 phenylalanine and H3 H5 4-chlorobenzyl), 7.30 (dd, 2H, 7
and 9 Hz, H2 H7 Fmoc), 7.42 (d, 2H, 7 and 8 Hz, H3 H6 Fmoc), 7.56 (d,
1H, 9 Hz, NH Fmoc), 7.60 (dd, 2H, 9 Hz, H1 H8 Fmoc), 7.89 (dd, 2H,
8 Hz, H4 H5 Fmoc), 8.21 (d, 1H, 8 Hz, NH Boc). 13C NMR (75 MHz,
a
DMSO-d6, 303 K):
nine), 38.8 (CH2b phenylalanine), 45.6 (CH2 4-chlorobenzyl), 46.9
(CH phenylalanine), 47.1 (CH Fmoc), 47.8 (CH phenylalanine),
d (ppm) 28.4 (CH3 Boc), 38.6 (CH2b phenylala-
a
a
NMR (75 MHz, DMSO-d6, 303 K):
phenylalanine and tryptophan), 45.3 (CH2 4-methoxybenzyl), 46.5
(CH tryptophan and phenylalanine), 46.7 (CHCH2 Fmoc), 55.0 (4-
d
(ppm) 27.8 (CH3 Boc), 38.2 (CH2b
66.3 (CH2 Fmoc), 78.6 (C quat. Boc), 120.6 (C4 C5 Fmoc), 125.7 and
125.8 (C1 C8 Fmoc), 126.7 and 126 .8 (C2 C7 Fmoc), 127.4 and 127.5
(C4 phenylalanine),128.1 (C3 C5 phenylalanine),128.4 and 128.5 and
128.5 and 128.8 (C2 C3 C5 C6 4-chlorobenzyl), 129.7 and 129.7 (C2 C6
phenylalanine), 132.4 (C4 4-chlorobenzyl), 135.4 (C1 4-
chlorobenzyl), 138.0 and 138.1 (C1 phenylalanine), 141.1 (C4a/
a
methoxybenzyl), 65.8 (CH2CHFmoc), 78.0 (C quat Boc), 109.7 (C3
tryptophan), 111.2 (C7 tryptophan), 113.9 (C3C5 4-methoxybenzyl),
117.9 (C4 tryptophan), 118.2 (C5 tryptophan), 120.0 (C4C5 Fmoc),
120.8 (C6 tryptophan), 125.3 (C1C8 Fmoc), 126.1 (C2 tryptophan),
127.0 (C4 phenylalanine), 127.1 (C2C7 Fmoc), 127.6 (C3C6 Fmoc),
127.9 (C2C6 phenylalanine and 4-methoxybenzyl), 129.3 (C3C5
phenylalanine), 136.0 (C1 4-methoxybenzyl and C8 tryptophan),
137.6 (C1 phenylalanine), 140.6 (C4 a/b Fmoc), 143.6 (C8a/b Fmoc),
155.2 (C4 4-methoxybenzyl), 155.7 (CO Boc or Fmoc), 156.0 (CO Boc
or Fmoc), 158.6 (C3 and C5 triazole). HRMS (ESI) calcd for
C48H49N6O5, 789.3764; found 789.3763.
Fmoc), 144.0 and 144.1 (C8a/b Fmoc), 155.3 (CO Fmoc), 155.9 and
b
155.8 (C3 and C5 triazole), 156.0 (CO Boc). HRMS (ESI) calcd for
C45H45ClN5O4, 734.3160; found 734.3161.
3.4.17. tert-Butyl (S)-1-(5-((S)-1-Cbz-amino-2-(1H-indol-3-yl)ethyl)-
4-(4-chlorobenzyl)-4H-1,2,4-triazol-3-yl)-2-phenylethylcarbamate
17f. White powder, 237 mg, 32%, 1H NMR (300 MHz, DMSO-d6,
303 K):
nylalanine and CH2b tryptophan), 4.76e4.90 (m, 4H, CH
anine and CH tryptophan and CH2 4-chlorobenzyl), 5.25 (s, 2H, CH2
d
(ppm) 1.07 (s, 9H, CH3 Boc), 3.18e3.31 (m, 4H, CH2 b phe-
a
phenylal-
3.4.14. tert-Butyl (S)-1-(5-((S)-1-Cbz-amino-2-(phenyl)ethyl)-4-
a
benzyl-4H-1,2,4-triazol-3-yl)-2-phenylethylcarbamate
17c. White
(ppm)
Z), 6.83 (m, 2H, 7 and 8 Hz, H4 and H5 tryptophan), 6.95 (d, 1H, 7 Hz,
NH Boc), 7.03 (m, 2H, H2H6 trytophane), 7.14e7.32 (m, 13H, CH Ar
phenylalanine and Z, H2H3H5H6 4-chlorobenzyl), 7.46 (d, 1H, 9Hz, H7
tryptophan), 8.04 (d, 2H, 8 Hz, NH Z), 10.78 (s, 1H, NH indole). 13C
powder, 367 mg, 59% 1H NMR (300 MHz, DMSO-d6, 303 K):
d
1.13 (s, 9H, CH3 Boc), 3.07 (m, 4H, CH2b phenylalanine), 4.72e4.90
(m, 4H, CH2 benzylamine and CH2 Z), 5.2 (dd, 2H, 17Hz and 20 Hz
CH
9Hz, NH Boc), 8.05 (d, 1H, 9Hz, NH Z) 13C NMR (75 MHz, DMSO-d6,
303 K): (ppm) 27.8 (CH3 Boc), 38.3 (CH2b phenylalanine), 45.7
(CH2 benzylamine), 46.6 (CH phenylalanine), 47.3 (CH phenyl-
alanine), 65.3 (CH2 Z), 78.0 (C quat. Boc), 126.0 and 126.1 and 126.3
(C4 benzylamine and C4 phenylalanine and C4 Z), 127.3e129.2
(C2C3C5C6 phenylalanine and Z and benzylamine), 135.7 and 136.7
and 137.4 and 137.6 (C1 phenylalanine and C1 benzyl and C1Z), 154.9
(CO Boc or Z), 155.4 (CO Boc or Z), 155.6 (C3 and C5 triazole). HRMS
(ESI) calcd for C38H42N5O4, 632,3237; found 632,3224.
a
phenylalanine), 6.94e7.33 (m, 20H, CH aromatics), 7.54 (d, 1H,
NMR (75 MHz, DMSO-d6, 303 K):
38.0 (CH2b tryptophan and phenylalanine), 45.1 (CH2 4-
chlorobenzyl), 46.4 and 46.6 (CH tryptophan and phenylalanine),
65.4 (CH2 Z), 78.0 (C quat. Boc), 109.5 (C3 tryptophan), 111.2 (C7
tryptophan), 117.8 (C4 tryptophan), 118.2 (C5 tryptophan), 120.8 (C6
tryptophan), 126.2 (C2 tryptophan), 126.9 (C9 tryptophan),
d (ppm) 27.7 (CH3 Boc), 37.6 and
d
a
a
a
127.4e128.3 (CH Ar.
Z and phenylalanine and C2C3C5C6 4-
chlorobenzyl), 132.0 (C4 4-chlorobenzyl), 134.7 and 135.9 and 137.6
(C1 phenylalanine and C1 4-chlorobenzyl and C1 Z), 136.6 (C8 tryp-
tophan), 154.7 and 155.2 (CO Z and Boc), 155.7 (C3 and C5 triazole).
HRMS (ESI) calcd for C40H42ClN6O4, 705.2956; found 705.2955.
3.4.15. tert-Butyl (S)-1-(5-((S)-1-Cbz-amino-2-(phenyl)ethyl)-4-(4-
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-2-phenylethylcarbamate
17d. White powder, 374 mg, 49% 1H NMR (300 MHz, DMSO-d6,
3.4.18. tert-Butyl(S)-1-(5-((S)-1-Fmoc-amino-2-(1H-indol-3-yl)ethyl)-
4-benzyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethylcarbamate
17g. Beige oil, 153 mg, 34%, 1H NMR (300 MHz, DMSO-d6, 303 K):
303 K):
anine), 3.72 (s, 3H, OeMe), 4.83 (m, 4H, CH2 4-methoxybenzyl and
CH2 Z), 5.11 (dd, 2H, CH phenylalanine), 6.82 (d, 2H, 9 Hz, H2H6 4-
d (ppm) 1.17 (s, 9H, CH3 Boc), 3.09 (m, 4H, CH2b phenylal-
d
(ppm) 1.22 (s, 9H, CH3 Boc), 3.27 (m, 4H, CH2b tryptophan), 4.11 (m,
a
3H, CH2CH Fmoc), 4.79 (m, 2H, CH tryptophan), 5.26 (s, 2H, CH2
a
methoxybenzyl), 6.90 (d, 2H, 8 Hz, H3H5 4-methoxybenzyl),
7.00e7.31 (m, 15H, CH Ar. Z and phenylalanine), 7.55 (d, 1H, 9 Hz,
NH Boc), 8.06 (d, 1H, 9 Hz, NH Z). 13C NMR (75 MHz, DMSO-d6,
benzyl), 6.64 (d, 2H, H2H6 benzyl), 6.83 (m, 2H, H5 tryptophan),
6.98e7.15 (m, 9H, H2 H4 H6 tryptophan and H3 H4 H5 benzyl), 7.28 (m,
4H, H2H7 Fmoc and H7 tryptophan), 7.40 (dd, 2H, 7 and 11 Hz, H3H6
Fmoc), 7.59 (m, 3H, H1 H8 Fmoc and NH Fmoc), 7.86 (d, 2H, 7 Hz, H4
H5 Fmoc), 8.20 (d, 1H, 8 Hz, NH Boc), 10.76 (s, 2H, NH indole). HRMS
(ESI) calcd for C49H48N7O4, 798.3768; found 798.3775.
303 K):
d (ppm) 27.9 (CH3Boc), 38.2 and 38.3 (CH2b phenylalanine),
45.4 (CH2 4-methoxybenzyl), 46.6 (CH2b phenylalanine), 47.3 (CH
a
phenylalanine), 55.1 (CH3 4-methoxybenzyl), 65.4 (CH2 Z), 78.1 (C
quat. Boc), 114.0 (C3 C5 4-methoxybenzyl), 126.2e129.2 (C2 C3 C4 C5
C6 phenylalanine and C2 C3 C4 C5 C6 Z and C2 C6 4-methoxybenzyl),
136.7 and 137.3 and 137.5 (C1 Z and phenylalanine and 4-
methoxybenzyl), 154.9 (C]O Boc or Z), 155.4 (C4 4-
methoxybenzyl), 155.6 (C]O Boc or Z), 158.6 (C3 and C5 triazole).
HRMS (ESI) calcd for C39H44N5O5,: 662,3342; found 662,3334.
3.4.19. tert-Butyl (S)-1-(5-((S)-1-Cbz-amino-2-(1H-indol-3-yl)ethyl)
-4-(4-chlorobenzyl)-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl-
carbamate 17h. Beige oil, 179 mg, 29%, 1H NMR (300 MHz, DMSO-
d6, 303 K):
tophan), 4.77 (m, 2H, CH
d
(ppm) 1.24 (s, 9H, CH3 Boc), 3.28 (m, 4H, CH2b tryp-
tryptophan), 4.82 (m, 1H, CH2 Z), 4.89 (m,
a
1H, CH2 Z), 5.26 (m, 2H, CH2 4-chlorobenzyl), 6.56 (d, 2H, 8 Hz,
H2H6 4-chlorobenzyl), 6.86 (m, 2H, H5 tryptophan), 7.02e7.10 (m,
6H, H2 H4 H6 tryptophan), 7.16 (d, 1H, 8 Hz, H4 Z), 7.19 (d, 2H, 6 Hz,
H3 H5 4-chlorobenzyl), 7.30e7.35 (m, 5H, H7 tryptophan and H2 H3
H5 H6 Z), 7.61 (d, 1H, 9 Hz, NH Z), 8.11 (d, 1H, 8 Hz, NH Boc), 10.80 (s,
3.4.16. tert-Butyl (S)-1-(5-((S)-1-Fmoc-amino-2-(phenyl)ethyl)-4-
(4-chlorobenzyl)-4H-1,2,4-triazol-3-yl)-2-phenylethylcarbamate
17e. White powder, 290 mg, 51%, 1H NMR (300 MHz, DMSO-d6,
303 K):
anine), 3.89 (t, 1H, 8 Hz, CH Fmoc), 4.02 (t, 1H, 7 Hz, CH2 Fmoc), 4.09
(t,1H, 8 Hz, CH2 Fmoc), 4.83 (m, 2H, CH phenylalanine), 5.16 (d,1H,
d (ppm) 1.14 (s, 9H, CH3 Boc), 3.19 (m, 4H, CH2b phenylal-
2H, NH indole). 13C NMR (75 MHz, DMSO-d6, 303 K):
d
(ppm) 28.5
a
(CH3 Boc), 29.2 (CH2b tryptophan), 45.4 (CH2 4-chlorobenzyl), 46.9

7048
M. Bibian et al. / Tetrahedron 67 (2011) 7042e7049
and 47.3 (CH
a
tryptophan), 66.0 (CH2 Z), 78.8 (C quat. Boc), 110.1
(CH2
b
norleucine), 39.4 (CH2
b aspartic acid), 43.2 and 45.7 (CHa
and 110.3 (C3 tryptophan), 111.7 and 111.8 (C7 tryptophan), 118.3
and 118.4 (C4 tryptophan), 188.8 (C5 tryptophan), 121.3 and 121.3
(C6 tryptophan), 124.5 and 124.7 (C2 tryptophan), 127.3 (C4 Z), 127.5
and 127.6 (C9 tryptophan),128.0 (C2 C6 4-chlorobenzyl),128.2 (C3 C5
4-chlorobenzyl), 128.8 (C2C3C5 C6 Z), 132.4 (C4 4-chlorobenzyl),
136.4 (C8 tryptophan and C1 Z), 137.1 (C1 4-chlorobenzyl), 155.6 (CO
Z), 155.8 and 156.0 (C3 C5 triazole), 156.2 (CO Boc). HRMS (ESI) calcd
for C42H43ClN7O4, 744.3065; found 744.3074.
norleucine and CH
a
aspartic acid), 46.0 (OeCH2ebenzyl), 66.0 (CH2
Z), 66.2 (NeCH2ebenzyl), 78.7 (C quat. Boc), 126.5 and 128.0 and
128.3 and 128.8 and 129.1 (CH aromatics), 136.4 and 137.2 (C1
benzyl), 154.2 (CO Boc), 155.8 and 156.0 (C3 and C5 triazole), 156.7
(CO Z), 170.2 (CO benzyl). HRMS (ESI) calcd for C37H46N5O6,
656.3448; found 656.3458.
3.4.23. tert-Butyl (S)-1-(5-((S)-(1-Fmoc-amino)-(2-((tert-butyloxy)
carbonyl)ethyl))-4-phenethyl-4H-1,2,4-triazol-3-yl)pentylcarbamate
17l. White powder, 0.61 g, 70% 1H NMR (400 MHz, DMSO-d6,
3.4.20. tert-Butyl (S)-1-(5-((S)-1-Cbz-amino-2-(phenyl)ethyl)-4-(4-
methoxybenzyl)-4H-1,2,4-triazol-3-yl)-1-(5-Cbz-amino)pentylcarba-
mate 17i. Colorless oil, 390 mg, 79%, 1H NMR (300 MHz, DMSO-d6,
303 K): d (ppm) 1H NMR, DMSO-d6, 400 MHz: 0.85 (t, 3H, 7 Hz, CH3
norleucine), 1.27 (m, 4H, CH2dg norleucine), 1.31 (s, 9H, CH3 Boc),
1.36 (s, 9H, CH3 tert-butyl), 1.66 (m, 1H, CH2b norleucine), 1.83 (m,
1H, CH2b norleucine), 2.67e3.06 (m, 4H, CH2b aspartic acid and CH2
303 K):
(m, 2H, CH2b lysine), 2.90 (dd, 1H, 7 and 14 Hz, CH2
2.97e3.18 (m, 2H, CH2 b phenylalanine), 3.71 (s, 3H, OMe), 4.64 (m,
1H, CH lysine), 4.78 (d, 1H, 13 Hz, CH2 Z), 4.89 (m, 2H, CH2 Z and
CH phenylalanine), 5.00 (s, 2H, CH2 4-methoxybenzyl), 5.10 (d, 1H,
d
(ppm) 1.14e1.37 (m, 13H, CH3 Boc and CH2 g d lysine), 1.76
3
lysine),
b
phenethyl), 4.14 (m, 3H, CHCH2 Fmoc), 4.29 (m, 2H, CH2a phe-
a
nethyl), 4.58 (m, 1H, CH norleucine), 5.10 (m, 1H, CH aspartic
a
a
a
acid), 7.19e7.45 (m, 10H, CH aromtics phenethyl and NH Boc and
H2H7 and H3H6 Fmoc), 7.64 and 7.67 (d, 2H, 7 Hz, H1H8 Fmoc), 7.86
(m, 3H, H4H5 Fmoc and NH norleucine), 8.19 (d, 1H, 9 Hz, NH Fmoc).
HRMS (ESI) calcd for C42H54N5O6, 724.4074; found 724.4075.
16 Hz, CH2 Z), 5.24 (br d, 1H, 18 Hz, CH2 Z), 6.84 (d, 2H, 8 Hz, H3H5 4-
methoxybenzyl), 7.00 (m, 3H, H2H6 4-methoxybenzyl), 7.10e7.47
(m, 16 H, C2C3C5C6 phenylalanine and C2C3C4C5C6 Z and NH Boc and
NH lysine), 8.08 (d, 1H, 10Hz, NH Z phenylalanine). 13C NMR
(75 MHz, DMSO-d6, 303 K):
d
(ppm) 22.7 (CH2
lysine), 32.0 (CH2 lysine), 38.4 (CH2b phenylal-
lysine), 45.5 (CH2 4-methoxybenzyl), 47.4 (CH
lysine and OMe), 65.1 and 65.4 (CH2 Z),
g
lysine), 27.9 (CH3
3.4.24. tert-Butyl (S)-1-(5-((S)-(1-Fmoc-amino)-(3-((tert-butyloxy)
carbonyl)propyl))-4-benzyl-4H-1,2,4-triazol-3-yl)pentylcarbamate
17m. White powder, 0.67 g, 77% 1H NMR (400 MHz, DMSO-d6,
Boc), 28.8 (CH2
anine and CH2
d
b
3
a
phenylalanine), 55.1 (CH
a
303 K):
d (ppm) 0.72 (t, 3H, 7 Hz, CH3 norleucine),1.06 (m, 4H, CH2 g
78.2 (C quat. Boc), 114.0 (C3C5 4-methoxybenzyl), 127.65e129.2 (CH
Ar. phenylalanine and Z and C2C6 4-methoxybenzyl), 136.7 and
137.3 (C1 phenylalanine and Z), 155.4 and 155.7 and 156.0 (CO Z and
CO Boc and C4 4-methoxybenzyl), 158.7 (C3 and C5 triazole). HRMS
(ESI) calcd for C44H53ClN6O7, 777.3976; found 777.3981.
d
norleucine),1.26 (s, 9H, CH3 tert-butyl or Boc),1.34 (s, 9H, CH3 tert-
butyl or Boc), 1.73 (m, 2H, CH2b norleucine), 2.06 (m, 2H, CH2g
glutamic acid), 2.16 (m, 2H, CH2b glutamic acid), 4.03 (m, 2H, CH2
Fmoc), 4.17 (dd, 1H, 7 and 9 Hz, CH Fmoc), 4.53 (m, 1H, CH
a nor-
leucine), 4.72 (m, 1H, CH glutamic acid), 5.18 (d, 1H, 17 Hz, CH2
a
benzyl), 5.36 (d, 1H, 17 Hz, CH2 benzyl), 7.00 (d, 2H, H3H5 benzyl),
7.20 (m, 3H, H2H4H6 benzyl), 7.30 (m, 2H, H2H7 Fmoc), 7.66 (t, 2H,
8 Hz, H1H8 Fmoc), 7.88 (d, 2H, 8 Hz, H4H5 Fmoc), 8.03 (d, 1H, 9 Hz,
3.4.21. tert-Butyl (S)-1-(5-((S)-(1-Cbz-amino)-(2-((benzyloxy)car-
bonyl)ethyl))-4-benzyl-4H-1,2,4-triazol-3-yl)pentylcarbamate
17j. Colorless oil, 1.0 g, 76% 1H NMR (400 MHz, DMSO-d6, 303 K):
NH Fmoc). 13C NMR (75 MHz, DMSO-d6, 303 K):
d (ppm) 13.8 (CH3
d
(ppm) 0.74 (t, 3H, CH3 alkyl), 1.10 (m, 4H, CH2 g d norleucine), 1.26
(s, 9H, CH3 Boc), 1.74 (m, 2H, CH2b norleucine), 2.94 (dd, 1H, 8 and
16 Hz, CH2b aspartic acid), 3.13 (dd, 1H, 7 and 16 Hz, CH2 aspartic
acid), 4.55 (m, 1H, CH norleucine), 4.78 (d, 1H, 11 Hz, CH2 benzyl),
4.78 (d, 1H, 11 Hz, CH2 benzyl), 4.89 (d, 1H, 11 Hz, CH2 benzyl), 5.03
(s, 2H, CH2 benzyl), 5.11 (m, 1H, CH aspartic acid), 5.20 (d, 1H,
norleucine), 21.5 (CH2d norleucine), 27.6 (CH2g norleucine), 27.7
(CH3 Boc or CH3 tert-butyl), 28.0 (CH3 Boc and CH3 tert-butyl), 28.2
(CH2d glutamic acid), 31.3 (CH2b glutamic acid), 32.3 (CH2b nor-
b
a
leucine), 45.0 (CHa norleucine and CHa glutamic acid), 45.7 (CH2
benzyl), 46.5 (CH Fmoc), 65.72 (CH2 Fmoc), 78.1 and 78.7 (C quat.
Boc and tert-butyl), 120.1 (C1C8 Fmoc and C4C5 Fmoc), 126.1 (C2C7
Fmoc), 127.0 (C3C6 Fmoc and C4 benzyl), 127.6 (C3C5 benzyl), 128.4
(C2C6 benzyl), 136.1 (C1 benzyl), 140.7 (C4a/b Fmoc), 143.6 and 143.7
(C8a/b Fmoc), 154.7 and 155.7 (C3C5 triazole), 155.2 and 155.9 (CO
Boc and CO Fmoc), 171.4 (CO ester). HRMS (ESI) calcd for
C42H54N5O6, 724.4074; found 724.4064.
a
18 Hz, CH2 benzyl), 5.39 (d, 1H, 17Hz, CH2 benzyl), 6.98e7.39 (m,
16 H, CH aromatics and NH Boc), 8.01 (d, 1H, 9 Hz, NH Z). 13C NMR
(100 MHz, DMSO-d6, 303 K):
(CH2 norleucine), 27.5 (CH2g norleucine), 28.0 (CH3 Boc), 32.3
(CH2b norleucine), 37.3 (CH2b aspartic acid), 42.8 and 45.0 (CH
norleucine and CH aspartic acid), 45.7 (CH2 benzyl), 65.5 (CH2 Z),
d (ppm) 13.7 (CH3 norleucine), 21.4
d
a
a
65.6 (CH2 benzyl), 78.0 (C quat. Boc), 125.0e128.3 (CH aromatics),
135.8 and 135.9 and 136.6 (C1 aromatics), 153.8 (CO Boc), 155.2 and
155.3 (C3 and C5 triazole), 156.3 (CO Z), 169.6 (CO Bzl). HRMS (ESI)
calcd for C37H46N5O6, 656.3448; found 656.3458.
3.4.25. tert-Butyl (S)-1-(5-((S)-(1-Cbz-amino)-(2-((benzyloxy)car-
bonyl)ethyl))-4-pentyl-4H-1,2,4-triazol-3-yl)-2-(1H-indol-3-yl)ethyl-
carbamate 17n. White powder, 0.61 g, 33% 1H NMR (300 MHz,
DMSO-d6, 303 K):
g d alkyl), 1.28 (s, 9H, CH3 Boc), 1.35 (m, 2H, CH2
1H, 6 and 10 Hz, CH2b aspartic acid), 3.26 (m, 2H, CH
(m, 1H, CH2b aspartic acid), 3.81 (m, 2H, CH2b tryptophan),
4.96e5.10 (m, 5H, CH2 benzyl and CH2 Z and CH tryptophan), 5.20
(m,1H, CH aspartic acid), 6.97 (t,1H, 7 Hz, H5 tryptophan), 7.02 (m,
d
(ppm) 0.75 (br s, 3H, CH3 alkyl),1.08 (m, 4H, CH2
alkyl), 3.01 (dd,
alkyl), 3.39
b
3.4.22. tert-Butyl (S)-1-(5-((R)-(1-Cbz-amino)-(2-((benzyloxy)car-
bonyl)ethyl))-4-benzyl-4H-1,2,4-triazol-3-yl)pentylcarbamate
17k. Colorless oil, 0.84 g, 62% 1H NMR (400 MHz, DMSO-d6, 303 K):
a
a
d
(ppm) 0.71 (t, 3H, 7 Hz, CH3 norleucine), 1.01e1.11 (m, 4H, CH2gd
norleucine), 1.31 (s, 9H, CH3 Boc), 1.69 (m, 2H, CH2b norleucine),
3.00 (dd, 1H, 7 and 17 Hz, CH2 aspartic acid), 3.25 (dd, 1H, 9 and
16 Hz, CH2b aspartic acid), 4.52 (m, 1H, CH norleucine), 4.91 (d, 1H,
a
1H, H6 tryptophan), 7.07 (s, 1H, H2 tryptophan), 7.32 (m, 11H, CH
aromatics benzyl and H7 tryptophan), 7.53 (t, 2H, H4 tryptophan
and NH Z), 8.00 (d, 1H, NH Boc), 10.76 (s, 1H, NH indole). 13C NMR
b
a
13 Hz, CH2 benzyl), 4.97 (d, 1H, 13 Hz, CH2 benzyl), 5.02 (d, 1H,
13 Hz, CH2 benzyl), 5.09 (d, 1H, 13 Hz, 13 Hz, CH2 benzyl), 5.16 (m,
(75 MHz, DMSO-d6, 303 K):
alkyl), 28.0 (CH3 Boc), 28.2 (CH2
29.6 (CH2b alkyl), 37.7 (CH2a alkyl), 38.7 (CH2b aspartic acid), 42.6
(CH aspartic acid), 46.2 (CH tryptophan), 65.6 and 65.7 (CH2
and CH2 benzyl), 78.1 (C quat. Boc), 110.2 (C3 tryptophan), 111.2 (C7
tryptophan), 118.2 (C4 tryptophan and C5 tryptophan), 120.8 (C6
tryptophan), 127.2 (C9 tryptophan and C4 benzyl and C4 Z),
d
(ppm) 13.6 (CH3 alkyl), 21.5 (CH2d
g
alkyl), 29.2 (CH2b tryptophan),
1H, CHa aspartic acid), 5.26 (d, 1H, 17 Hz, CH2 benzyl), 5.32 (d, 1H,
17 Hz, CH2 benzyl), 7.00 (m, 2H, NH Boc and H4 benzyl4), 7.27e7.35
a
a
Z
(m, 13H, CH aromatics benzyl), 7.41 (d, 1H, 9 Hz, NH Z). 13C NMR
(75 MHz, DMSO-d6, 303 K):
d
(ppm) 14.2 (CH3 norleucine), 21.9
g norleucine), 28.6 (CH3 Boc), 32.8
(CH2 norleucine), 28.0 (CH2
d

M. Bibian et al. / Tetrahedron 67 (2011) 7042e7049
7049
127.6e128.3 (C2 C3 C5 C6 Z and C2 C3 C5 C6 benzyl), 135.8 and 136.0
(C1 benzyl and Z), 136.7 (C8 tryptophan), 153.2 (CO Boc and CO Z),
155.1 and 155.4 (C3 C5 triazole), 169.7 (CO ester). HRMS (ESI) calcd
for C40H49N6O6, 709.3714; found 709.3704.
(d, 1H, 17 Hz, CH2 benzyl), 5.41 (d, 1H, 17 Hz, CH2 benzyl), 7.01 (d,
2H, 7 Hz, H3H5 benzyl), 7.21 (m, 3H, H2H4H6 benzyl), 7.30 (m, 2H,
H2H7 Fmoc), 7.41 (td, 3H, 1 and 8 Hz, H3 H6 Fmoc and NH Boc), 7.61
(m, 2H, H1H8 Fmoc), 7.87 (d, 2H, 8 Hz, H4H5 Fmoc), 8.08 (d, 1H, 9 Hz,
NH Fmoc). 13C NMR (75 MHz, DMSO-d6, 303 K):
d
(ppm) 13.7 (CH3
norleucine), 21.4 (CH2d norleucine), 27.5 (CH3 Boc and CH2 nor-
leucine), 28.0 (CH3 tert-butyl), 32.1 (CH2b norleucine), 42.7 (CH2b
aspartic acid), 45.0 (CH norleucine), 45.9 (CH aspartic acid), 46.4
3.4.26. tert-Butyl (S)-1-(5-((S)-(1-Fmoc-amino)-(2-((tert-butyloxy)
carbonyl)ethyl))-4-benzyl-4H-1,2,4-triazol-3-yl)pentylcarbamate
17o. White powder, 0.54 g, 84% 1H NMR (400 MHz, DMSO-d6,
g
a
a
303 K):
d
(ppm) 1H NMR (300 MHz, DMSO-d6, 303 K):
d
(ppm) 0.87
(CH Fmoc and CH2 benzyl), 65.8 (CH2 Fmoc), 78.1 (C quat Boc), 80.1
(C quat tert-butyl), 120.0 (C4C5 Fmoc), 125.2 (C1C8 Fmoc), 126.1
(C2C7 Fmoc), 127.0 (C2C6 benzyl), 127.3 (C4 benzyl), 127.6 (C3C5
benzyl), 128.4 (C3C6 Fmoc), 135.7 (C1 benzyl), 140.6 (C4 a/b Fmoc),
143.6 (C8 a/b Fmoc),154.0 and 155.3 (C3 and C5 triazole and CO Boc),
156.3 (CO Fmoc), 168.6 (CO aspartic acid). MS (ES), m/z: 710.2
[MþH]þ.
(t, 3H, 7 Hz, CH3 norleucine), 1.21 (t, 3H, 7 Hz, CH3 ester), 1.25e1.34
(m, 4H, CH2gd norleucine), 1.37 (s, 9H, CH3 Boc), 1.64 (s, 3H, CH3
acetyl), 1.91 (m, 2H, CH2b norleucine), 3.19 (dd, 1H, 10 and 14 Hz,
CH2b phenylalanine), 3.26 (dd, 1H, 5 and 14 Hz, CH2b phenylala-
nine), 4.11 (m, 2H, CH2 ester), 4.58 (m, 1H, CH
1H, 18 Hz, CH2 glycine), 4.94 (d, 1H, 18 Hz, CH2 glycine), 5.16 (m, 1H,
CH phenylalanine), 7.18 (m,1H, H4 phenylalanine), 7.27 (m, 4H,
H2H3H5H6 phenylalanine), 7.40 (d, 1H, 9 Hz, NH Boc), 8.53 (d, 1H,
9 Hz, NH acetyl). 13C NMR (75 MHz, DMSO-d6, 303 K):
(ppm) 14.4
a norleucine), 4.87 (d,
a
3.4.29. tert-Butyl (S)-1-(4-((S)-1-(methoxycarbonyl)ethyl)-5-((S)-1-
Boc-amino-2-phenylethyl)-4H-1,2,4-triazol-3-yl)-2-phenylethylcarba
mate 20. White powder, 0.09 g, 28% 1H NMR (300 MHz, DMSO-d6,
d
(CH3 norleucine and CH3 ester), 22.2 (CH2d norleucine), 22.4 (CH3
acetyl), 28.2 (CH2g norleucine), 28.6 (CH3 Boc), 32.4 (CH2b nor-
303 K):
nine), 3.20 (d, 4H, 7Hz, CH2b phenylalanine), 3.65 (s, 3H, OeMe
alanine), 4.87 (m, 2H, CH phenylalanine), 5.61 (m, 1H, CH ala-
nine), 7.18e7.27 (m,10H, CH Ar.), 7.52 (d, 2H, 9 Hz, NH Boc). 13C NMR
(75 MHz, DMSO-d6, 303 K): (ppm) 16.7 (CH3b alanine), 27.9 (CH3
Boc), 38.7 (CH2b phenylalanine), 47.1 (CH alanine), 51.9 (OeMe
alanine), 52.9 (CH phenylalanine), 78.2 (C quaternaire Boc), 126.2
d (ppm) 1.22 (s, 18H, CH3 Boc), 1.62 (d, 3H, 7Hz, CH3b ala-
leucine), 38.5 (CH2b phenylalanine), 44.5 (CH2 glycine), 44.8 (CH
a
phenylalanine), 45.4 (CH norleucine), 61.9 (CH2 ester), 78.8 (C quat
a
a
a
Boc), 126.8 (C4 phenylalanine), 128.5 (C2C6 phenylalanine), 129.7
(C3C5 phenylalanine), 138.4 (C1 phenylalanine), 155.7 and 156.0 (C3
and C5 triazole and CO Boc), 167.9 (CO ester), 169.3 (CO acetyl).
HRMS (ESI) calcd for C26H40N5O5, 502.3029; found 502.3034.
d
a
a
(C4 phenylalanine), 128.0 (C2 C6 phenylalanine), 129.3 (C3 C5 phe-
nylalanine), 137.8 (C1 phenylalanine), 154.9 (C3 and C5 triazole),
155.0 (CO Boc), 170.0 (CO ester). HRMS (ESI) calcd for C32H44N5O6,
594.3292; found 594.3282.
3.4.27. tert-Butyl (S)-1-(4-((ethoxycarbonyl)methyl)-5-((S)-1-acetami-
do-2-phenylethyl)-4H-1,2,4-triazol-3-yl)pentylcarbamate 17p. White
powder, 0.58 g, 77% 1H NMR (300 MHz, DMSO-d6, 303 K):
d (ppm)
0.81 (t, 3H,13 Hz, CH3 norleucine),1.14 (t, 3H, 7 Hz, CH3 ester), 1.23 (m,
4H, CH2 g d norleucine), 1.32 (s, 9H, CH3 Boc), 1.62 (s, 3H, CH3 acetyl),
1.81 (m, 2H, CH2 b norleucine), 3.17 (m, 2H, CH2 b phenylalanine), 4.06
Acknowledgements
(q, 2H, 8 Hz, CH2 ester), 4.56 (dd, 8 and 15 Hz, CH
(d,1H, 19 Hz, CH2 glycine), 4.96 (d,1H,1H,18 Hz, CH2 glycine), 5.08 (m,
1H, CH phenylalanine), 7.11e7.29 (m, 8H, NH Boc and CH aromatics),
8.47 (d, 1H, 9Hz, NH acetyl). 13C NMR (75 MHz, DMSO-d6, 303 K):
(ppm) 14.2 (CH3 norleucine and CH3 ester), 22.1 (CH2 g norleucine),
22.4 (CH3 acetyl), 28.0 (CH2 norleucine), 28.5 (CH3 Boc), 32.6 (CH2
norleucine), 38.6 (CH2b phenylalanine), 44.4 (CH2 glycine), 44.8
(CH norleucine), 45.7 (CH phenylalanine), 61.8 (CH2 ester), 78.6 (C
quat. Boc), 126.7 (C4 phenylalanine), 128.4 (C2 and C6 phenylalanine),
129.6 (C3 and C5 phenylalanine), 138.2 (C1 phenylalanine), 155.6 (C3
and C5 triazole and CO Boc), 167.6 (CO ester), 169.3 (CO acetyl). MS
(ES), HRMS (ESI) calcd for C26H40N5O5, 502.3029; found: 502.3029.
a norleucine), 4.84
ꢀ
The authors like to thank Dr. O. Bruguier from UMR Geosciences
(University Montpellier 2, France) for ICPMS analysis and Dr. P.
Chevallet for his invaluable help in nomenclature determination.
a
d
d
Supplementary data
b
a
a
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.07.011.
References and notes
1. Bibian, M.; Blayo, A.-L.; Moulin, A.; Martinez, J.; Fehrentz, J.-A. Tetrahedron Lett.
2010, 51, 2660e2663.
2. Moulin, A.; Demange, L.; Ryan, J.; Mousseaux, D.; Sanchez, P.; Berge, G.; Gagne,
D.; Perrissoud, D.; Locatelli, V.; Torsello, A.; Galleyrand, J.-C.; Fehrentz, J.-A.;
Martinez, J. J. Med. Chem. 2008, 51, 689e693.
3. Bibian, M.; El-Habnouni, S.; Martinez, J.; Fehrentz, J. A. Synthesis 2009,
1180e1184.
4. (a) Clausen, K.; Thorsen, M.; Lawesson, S. O. Tetrahedron 1981, 37, 3635e3639;
(b) Boeglin, D.; Cantel, S.; Heitz, A.; Martinez, J.; Fehrentz, J.-A. Org. Lett. 2003, 5,
4465e4468.
5. Avalos, M.; Babiano, R.; Cintas, P.; Duran, C. J.; Higes, F. J.; Jimenez, J. L.; Lopez, I.;
Palacios, J. C. Tetrahedron 1997, 53, 14463e14480.
3.4.28. tert-Butyl (S)-1-(4-((ethoxycarbonyl)methyl)-5-((R)-1-
acetamido-2-phenylethyl)-4H-1,2,4-triazol-3-yl)pentylcarbamate
17q. Colorless solid, 0.80 g, 60% 1H NMR (300 MHz, DMSO-d6,
ꢀ
303 K): d (ppm) 0.72 (t, 3H, 7 Hz, CH3 norleucine), 1.06 (m, 4H, CH2
dg norleucine), 1.27 (s, 9H, CH3 Boc or CH3 t-Bu), 1.29 (s, 9H, CH3 Boc
or CH3 t-Bu), 1.71 (m, 2H, CH2b norleucine), 2.78 (m, 1H, 7 and
16 Hz, CH2b aspartic acid), 2.87 (m, 1H, 8 and 15 Hz, CH2b aspartic
acid), 4.00 (m, 2H, CH2 Fmoc), 4.14 (dd, 1H, 6 and 9 Hz, CH Fmoc),
4.54 (m, 1H, CHa norleucine), 5.07 (m, 1H, CHa aspartic acid), 5.23