Synthesis of various chiral 1,2,4-triazole-containing α-amino acids from aspartic or glutamic acids

Article abstract of DOI:10.1002/ejoc.201100611

Starting from N- and C-protected aspartic or glutamic acids, new unnatural α-amino acids containing 3,4,5-trisubstituted 1,2,4-triazole heterocycles on their side chains have been synthesized. Two points of diversity could easily be achieved on the hetero

Full text of DOI:10.1002/ejoc.201100611

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100611
Synthesis of Various Chiral 1,2,4-Triazole-Containing α-Amino Acids from
Aspartic or Glutamic Acids
Anne-Laure Blayo,[a] Frédéric Brunel,[a] Jean Martinez,[a] and Jean-Alain Fehrentz*[a]
Keywords: Amino acids / Heterocycles / Heterocycles
Starting from N- and C-protected aspartic or glutamic acids,
new unnatural α-amino acids containing 3,4,5-trisubstituted
1,2,4-triazole heterocycles on their side chains have been
synthesized. Two points of diversity could easily be achieved
on the heterocyclic moiety, which could easily be incorpo-
rated in peptide sequences to modify or improve their phar-
macokinetic properties.
the heterocycle.[8,9] We used this synthetic scheme mainly
from N-protected α-amino acids to design potent ligands
of the ghrelin receptor with a large variety of substitu-
ents.[10–12] Here, we applied the developed strategy to the
synthesis of unnatural amino acids bearing a 3,4-substi-
tuted 1,2,4-triazole on their side chain. A series of unnatu-
ral amino acid derivatives were prepared starting from N-
and C-protected aspartic or glutamic acids. To show the
stability of the N-protecting groups under the experimental
conditions that we used, we started from Fmoc-Asp-OtBu
and Z-Glu-OtBu (Scheme 1). The bulky tert-butyl ester
group was chosen to avoid a side reaction during the dehy-
dration–cyclization step for the formation of acylamidraz-
ones into triazoles. Two points of diversity could easily be
introduced as shown in Scheme 1.
Introduction
In our effort to develop original chiral nonproteinogenic
α-amino acids that could be incorporated into biologically
relevant peptides, we focused our work on the synthesis of
heterocycle-containing α-amino acids. The choice of the
heterocycle is crucial in such an approach. Indeed, it is sup-
posed to improve pharmacokinetic properties of the modi-
fied peptides and can be used as a scaffold bearing various
substituents. These substituents could interact with the bio-
logical target, providing better specificity. These unnatural
amino acids also prevent enzymatic degradation of the
peptides.
One interesting heterocyclic moiety is the well-known
1,2,4-triazole. The first amino acid bearing a 1,2,4-triazole
moiety on its side chain was 1,2,4-triazole-3-alanine, which
was used to replace a histidine residue.[1] This heterocycle
displays a wide range of biological activities and can be
used as an amide bioisostere for the design of receptor li-
gands with enhanced pharmacokinetic properties[2,3]or to
mimic the cis configuration of the amide function observed
in several peptides.[4–6] The chemistry we previously de-
scribed for the preparation of 3,4,5-trisubstituted 1,2,4-tri-
azoles from a modified procedure developed by Hitotsuyan-
agi et al.[4] is robust, nontoxic and allows the introduction
of various substituents on this scaffold. Our synthetic strat-
egy for the formation of a trisubstituted 1,2,4-triazole
started with the formation of an amide bond, followed by
a thionation with the Lawesson’s reagent (LR)[7] and finally
Scheme 1. Synthesis of unnatural amino acids bearing a 3,4-substi-
tuted 1,2,4-triazole in their side chains.
Results and Discussion
When starting from Fmoc-Asp-OtBu (1) (n = 1, P =
reaction of the resulting thioamide with a hydrazide to form Fmoc), different amines were introduced by a coupling step
by using BOP: ethylamine, isopropylamine, methyl 4-ami-
nobutanoate and (4-bromobenzyl)amine. After thionation
of the corresponding amides 2, four different hydrazides,
acetyl hydrazide, benzoic hydrazide, phenylacetic hydrazide
and ethyl 3-hydrazino-3-oxopropionate, were allowed to re-
act with thioamides 3 to form triazoles 4. The cyclization
step was performed as already described[9] in the presence
of silver benzoate as a thiophile reagent and in acetic acid
[a] Institut des Biomolécules Max Mousseron, CNRS UMR 5247,
Université Montpellier I, Université Montpellier II, Faculté de
Pharmacie,
15 avenue Charles Flahault, B. P. 14491, 34093 Montpellier
Cedex 5, France
Fax: 33-4-67548654
E-mail: jean-alain.fehrentz@univ-montp1.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100611.
Eur. J. Org. Chem. 2011, 4293–4297
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4293

A.-L. Blayo, F. Brunel, J. Martinez, J.-A. Fehrentz
SHORT COMMUNICATION
in dichloromethane. After purification, nine new nonpro- give, after lyophilization, the tripeptide 8 as a white solid in
1
teinogenic amino acids were obtained in acceptable to good 79% yield. This compound was characterized by H and
yields (Table 1, compounds 4a–i).
13C NMR spectroscopy and MS.
Table 1. Various 1,2,4-triazole containing α-amino acids.
4
P
n
R1
R2
[α]D20[a] Yield [%][b]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Z
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
isopropyl
isopropyl
isopropyl
methyl butanoate benzyl
methyl butanoate phenyl
4-bromobenzyl
4-bromobenzyl
4-bromobenzyl
ethyl
methyl
benzyl
ethyl acetate –13.6
–6.8
–22.7
42
52
46
61
58
77
67
54
65
11
52
55
58
78
56
–18.7
–13.4
ethyl acetate –14.7
methyl
phenyl
benzyl
methyl
benzyl
–15.3
–16.3
–8.5
–14.1
–15.2
ethyl
ethyl
ethyl
Z
Z
Z
Z
ethyl acetate –12.2
4-methoxybenzyl methyl
4-methoxybenzyl benzyl
4-methoxybenzyl ethyl acetate –6.3
–9.8
–7.8
Scheme 2. Synthesis of a tripeptide containing compound 4i in its
sequence.
Z
[a] (c 1, MeOH). [b] From 3.
Conclusions
When starting from Z-Glu-OtBu 1 (n = 2, P = Z), the
side chain carboxylic acid was coupled with two amines,
ethylamine and (4-methoxybenzyl)amine. Amides 2 were
thionated with Lawesson’s reagent, and the obtained
thioamides 3 were treated with three hydrazides, acetyl-
hydrazide, phenylacetic hydrazide and ethyl 3-hydrazino-3-
oxopropionate, under the same experimental conditions to
yield six original amino acids 4 bearing a 1,2,4-triazole moi-
ety on their side chain (Table 1, compounds 4j–o).
In summary, we have shown that it was possible, in a
few steps, to generate nonproteinogenic amino acids from
protected aspartic or glutamic acids, which incorporate dif-
ferent 3,4,5-trisubstituted 1,2,4-triazole heterocycles. These
compounds represent an original addition to the list of
available unnatural amino acids. Their preparation as
Fmoc- or Z-protected derivatives may allow their use in
peptide and peptidomimetic synthesis, as well as in solu-
tion- and solid-phase combinatorial syntheses. Although a
limited number of different and representative substituents
are presented here, a much larger diversity may be achieved.
Stereochemical Aspect
Optical purity is an essential characteristic of amino ac-
ids. Synthesis from enantiopure aspartyl or glutamyl deriva-
tives should lead to triazole compounds without any signifi-
cant epimerization. We recently demonstrated that, when
performed on the carboxylic acid of an α-amino acid, this
three-step sequence (coupling, thionation and triazole for-
mation) did not induce any epimerization.[9] There is there-
fore no reason to suspect that epimerization can occur when
performed on the β position of an asymmetric carbon.
To show that these new 1,2,4-triazole-containing amino
acids can easily be incorporated into a peptide sequence, we
synthesized a tripeptide including an unnatural amino acid
in the middle of the sequence (Scheme 2). Starting from
compound 4i, the tert-butyl ester was deprotected in acidic
medium (TFA/DCM), and the corresponding carboxylic
acid 5 was directly coupled to l-alanine tert-butyl ester with
BOP[13] as coupling reagent. After classical workup used in
peptide chemistry and purification by column chromatog-
raphy on silica gel, dipeptide 6 was obtained in 81% yield.
The N-terminal Fmoc protection was then removed by di-
ethylamine in DMF, and after evaporation of the solvents,
amine 7 was acylated with Boc-l-tryptophan in the pres-
ence of BOP. After coupling and classical washings, the
Experimental Section
All final compounds were characterized by LC/MS, 1H and 13C
NMR spectroscopy and HRMS, and their purity was found to be
Ͼ98% by monitoring by HPLC at 214 nm. Analytical HPLC chro-
matographs were performed on a Beckman Gold apparatus com-
posed of the 126 solvent module, the 168 detector and the 32 Karat
software; runs were performed on a VWR Chromolith column
(50ϫ3.9 mm) at a flow rate of 5 mL/min from solution A (water,
0.1% TFA) to solution B (acetonitrile, 0.1% TFA) in a 3-min gradi-
ent.
Synthesis of Amides 2: In a solution of DCM, the amine
(1.1 equiv.), amino acid (1.0 equiv.), DIEA (2.2 equiv.) and BOP
(1.0 equiv.) were successively added. After stirring for 1 h at room
temperature, the mixture was concentrated in vacuo and dissolved
in AcOEt. The organic layer was successively washed with aqueous
solutions of 1 m KHSO4, saturated NaHCO3 and brine. The or-
ganic layer was then dried with Na2SO4, filtered, and concentrated
in vacuo to yield amide 2, which was used without purification.
General Procedure for Thionation: To 1.0 equiv. of amide in DME
(10 mmol/mL) was added Lawesson’s reagent (0.5 equiv.). The reac-
tion was heated to 85 °C for 2 h and then concentrated in vacuo.
The residue was filtered through aluminium oxide standardized,
crude was purified by preparative reversed-phase HPLC to eluted with DCM and then purified by chromatography on silica
4294 Eur. J. Org. Chem. 2011, 4293–4297
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chiral 1,2,4-Triazole-Containing α-Amino Acids
gel with a mixture of AcOEt/hexane as eluent. Thioamide 3 was
obtained as a white powder (yields between 60 and 90% for the
two steps).
C7 Fmoc), 127.7 (C3 and C6 Fmoc), 140.8 (C11 and C12 Fmoc),
143.7 and 143.8 (C10 and C13 Fmoc), 148.5 and 151.7 (Cq triazole),
155.9 (CO Fmoc), 167.8 (CO2Et), 169.6 (CO2tBu) ppm. HRMS
(ESI+): calculated for C31H39N4O6, 563.2870; found 563.2867.
General Procedure for the Conversion of Thioamides to Trisubsti-
4d: HPLC: tR = 2.13 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 1.33 (s, 9 H, CH3 tBu), 1.72 (quintuplet, J = 7.1 Hz, 2
H, N-CH2-CH2-CH2-CO2Me), 2.39 (t, J = 7.1 Hz, 2 H, N-CH2-
CH2-CH2-CO2Me), 3.17 (dd, J = 16.0, 8.6 Hz, 1 H, CH2 β Asp),
3. 31 (dd, J = 16.0, 5.7 Hz, 1 H, CH2 β Asp), 3.58 (s, 3 H, CO2Me),
3.97–4.08 (m, 2 H, N-CH2-CH2-CH2-CO2Me), 4.17–4.38 (m, 3 H,
triazole-CH2-phenyl, CH and CH2 Fmoc), 4.47–4.58 (m, 1 H, CH
α Asp), 7.22–7.36 (m, 7 H, H2 and H7 Fmoc, H2, H3, H4, H5 and
H6 phenyl), 7.42 (t, J = 7.3 Hz, 2 H, H3 and H6 Fmoc), 7.67 (d, J
= 7.3 Hz, 2 H, H1 and H8 Fmoc), 7.84–7.92 (m, 3 H, NH Fmoc,
H4 and H5 Fmoc) ppm. 13C NMR (75 MHz, [D6]DMSO, 303 K):
δ = 24.3 (N-CH2-CH2-CH2-CO2Me), 26.2 (CH2 β Asp), 27.5 (CH3
tBu), 29.5 (N-CH2-CH2-CH2-CO2Me), 29.9 (triazole-CH2-phenyl),
42.8 (N-CH2-CH2-CH2-CO2Me), 46.6 (CH Fmoc), 51.5 (CO2Me),
52.1 (CH α Asp), 65.8 (CH2 Fmoc), 81.5 (Cq tBu), 120.2 (C4 and
C5 Fmoc), 125.2 (C1 and C8 Fmoc), 127.1 (C2 and C7 Fmoc), 127.3
(C4 phenyl), 127.7 (C3 and C6 Fmoc), 128.8 (C2, C3, C5 and C6
phenyl), 134.6 (C1 phenyl), 140.8 (C11 and C12 Fmoc), 143.8 (C10
and C13 Fmoc), 152.5 and 153.6 (Cq triazole), 155.9 (CO Fmoc),
169.6 (CO2tBu), 172.6 (CO2Me) ppm. HRMS (ESI+): calculated
for C36H41N4O6, 625.3026; found 625.3025.
tuted 1,2,4-Triazoles: Thioamide
2 (1 equiv.) and hydrazide
(1.2 equiv.) were diluted in the minimum volume of dichlorometh-
ane. Silver benzoate (2 equiv.) was then added immediately fol-
lowed by acetic acid (3 equiv.). The reaction was monitored by RP-
HPLC, and after completion (usually within 6 h), it was filtered
through a pad of Celite. Flash chromatography on silica gel, eluted
with AcOEt/hexane (5/5) to MeOH (5% in AcOEt), afforded the
desired triazole derivative.
4a: HPLC: tR = 1.89 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 1.31 (s, 9 H, CH3 tBu), 1.38 [d, J = 6.9 Hz, 6 H,
CH(CH3)2], 2.40 (s, 3 H, CH3-triazole), 3.07 (dd, J = 15.6, 7.9 Hz,
1 H, CH2 β Asp), 3. 17 (dd, J = 15.6, 6.6 Hz, 1 H, CH2 β Asp),
4.17–4.36 (m, 3 H, CH and CH2 Fmoc), 4.36–4.51 [m, 2 H, CH α
Asp and CH(CH3)2], 7.32 (t, J = 7.3 Hz, 2 H, H2 and H7 Fmoc),
7.41 (t, J = 7.3 Hz, 2 H, H3 and H6 Fmoc), 7.69 (d, J = 7.3 Hz, 2
H, H1 and H8 Fmoc), 7.78 (d, J = 8.3 Hz, 1 H, NH Fmoc), 7.89
(t, J = 7.3 Hz, 2 H, H4 and H5 Fmoc) ppm. 13C NMR (75 MHz,
[D6]DMSO, 303 K): δ = 12.3 (CH3-triazole), 21.1 and 21.2
[CH(CH3)2], 27.3 (CH2 β Asp), 27.5 (CH3 tBu), 46.6 (CH Fmoc),
46.7 [CH(CH3)2], 52.8 (CH α Asp), 65.7 (CH2 Fmoc), 80.9 (Cq
tBu), 120.2 (C4 and C5 Fmoc), 125.2 (C1 and C8 Fmoc), 127.1 (C2
and C7 Fmoc), 127.7 (C3 and C6 Fmoc), 140.8 (C11 and C12 Fmoc),
143.8 (C10 and C13 Fmoc), 150.2 and 150.6 (Cq triazole), 155.9
(CO Fmoc), 170.1 (CO2tBu) ppm. HRMS (ESI+): calculated for
C28H35N4O4, 491.2658; found 491.2638.
4e: HPLC: tR = 2.11 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 1.37 (s, 9 H, CH3 tBu), 1.77 (quintuplet, J = 6.9 Hz, 2
H, N-CH2-CH2-CH2-CO2Me), 2.27 (t, J = 6.9 Hz, 2 H, N-CH2-
CH2-CH2-CO2Me), 3.23 (dd, J = 15.9, 8.3 Hz, 1 H, CH2 β Asp),
3. 34 (dd, J = 15.9, 5.9 Hz, 1 H, CH2 β Asp), 3.48 (s, 3 H, CO2Me),
4.03–4.16 (m, 2 H, N-CH2-CH2-CH2-CO2Me), 4.20–4.26 (m, 1 H,
CH Fmoc), 4.26–4.40 (m, 2 H, CH2 Fmoc), 4.53–4.62 (m, 1 H, CH
α Asp), 7.27–7.36 (m, 2 H, H2 and H7 Fmoc), 7.41 (t, J = 7.4 Hz,
2 H, H3 and H6 Fmoc), 7.55–7.67 (m, 5 H, H2, H3, H4, H5 and H6
phenyl), 7.70 (d, J = 7.4 Hz, 2 H, H1 and H8 Fmoc), 7.84–7.92 (m,
3 H, NH Fmoc, H4 and H5 Fmoc) ppm. 13C NMR (75 MHz, [D6]-
DMSO, 303 K): δ = 24.5 (N-CH2-CH2-CH2-CO2Me), 26.6 (CH2 β
Asp), 27.6 (CH3 tBu), 29.8 (N-CH2-CH2-CH2-CO2Me), 43.0 (N-
CH2-CH2-CH2-CO2Me), 46.6 (CH Fmoc), 51.4 (CO2Me), 52.4
(CH α Asp), 65.8 (CH2 Fmoc), 81.3 (Cq tBu), 120.2 (C4 and C5
Fmoc), 125.2 (C1 and C8 Fmoc), 125.7 (C1 phenyl), 127.1 (C2 and
C7 Fmoc), 127.7 (C3 and C6 Fmoc), 128.8 and 129.2 (C2, C3, C5
and C6 phenyl), 130.8 (C4 phenyl), 140.8 (C11 and C12 Fmoc), 143.8
(C10 and C13 Fmoc), 152.5 and 153.4 (Cq triazole), 155.9 (CO
Fmoc), 169.8 (CO2tBu), 172.4 (CO2Me) ppm. HRMS (ESI+): cal-
culated for C35H39N4O6, 611.2870; found 611.2871.
4b: HPLC: tR = 2.12 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 1.29–1.37 [m, 15 H, CH3 tBu and CH(CH3)2], 3.28
(dd, J = 16.1, 8.0 Hz, 1 H, CH2 β Asp), 3. 41 (dd, J = 16.1, 6.2 Hz,
1 H, CH2 β Asp), 4.18–4.25 (m, 1 H, CH Fmoc), 4.28–4.40 (m, 2
H, CH2 Fmoc), 4.43 (s, 2 H, triazole-CH2-phenyl), 4.49–4.59 (m, 1
H, CH α Asp), 4.70 [quintuplet, J = 7.0 Hz, 1 H, CH(CH3)2], 7.22–
7.37 (m, 7 H, H2 and H7 Fmoc, H2, H3, H4, H5 and H6 phenyl),
7.42 (t, J = 7.3 Hz, 2 H, H3 and H6 Fmoc), 7.68 (d, J = 7.3 Hz, 2
H, H1 and H8 Fmoc), 7.89 (d, J = 7.3 Hz, 3 H, NH Fmoc, H4 and
H5 Fmoc) ppm. 13C NMR (75 MHz, [D6]DMSO, 303 K): δ = 20.7
[CH(CH3)2], 27.5 (CH2 β Asp and CH3 tBu), 30.3 (triazole-CH2-
phenyl), 46.6 (CH Fmoc), 49.3 [CH(CH3)2], 52.1 (CH α Asp), 65.8
(CH2 Fmoc), 81.5 (Cq tBu), 120.2 (C4 and C5 Fmoc), 125.2 (C1
and C8 Fmoc), 127.1 (C2 and C7 Fmoc), 127.4 (C4 phenyl), 127.7
(C3 and C6 Fmoc), 128.7 and 128.8 (C2, C3, C5 and C6 phenyl),
134.6 (C1 phenyl), 140.8 (C11 and C12 Fmoc), 143.8 (C10 and C13
Fmoc), 152.1 and 153.3 (Cq triazole), 155.9 (CO Fmoc), 169.3
(CO2tBu) ppm. HRMS (ESI+): calculated for C34H39N4O4,
567.2971; found 567.2971.
4f: HPLC: tR = 2.18 min. 1H NMR (300 MHz, [D6]DMSO, 303 K):
δ = 1.09 (t, J = 7.1 Hz, 3 H, O-CH2-CH3), 1.31 (s, 9 H, CH3 tBu),
2.92 (dd, J = 15.8, 8.1 Hz, 1 H, CH2 β Asp), 3.01 (dd, J = 15.8,
4c: HPLC: tR = 2.10 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 1.19 (t, J = 7.1 Hz, 3 H, O-CH2-CH3), 1.33 (s, 9 H, 6.1 Hz, 1 H, CH2 β Asp), 3.88–3.98 (m, 4 H, triazole-CH2-CO2Et
CH3 tBu), 1.42 [d, J = 6.8 Hz, 6 H, CH(CH3)2], 3.24 (dd, J = 15.8,
7.7 Hz, 1 H, CH2 β Asp), 3. 36 (dd, J = 15.8, 6.4 Hz, 1 H, CH2 β
and O-CH2-CH3), 4.17–4.31 (m, 3 H, CH and CH2 Fmoc), 4.36–
4.44 (m, 1 H, CH α Asp), 5.23 (s, 2 H, CH2 p-bromobenzyl), 7.04
Asp), 4.08–4.64 [m, 9 H, triazole-CH2-CO2Et, O-CH2-CH3, CH (d, J = 8.4 Hz, 2 H, H2 and H6 p-bromobenzyl), 7.31 (t, J = 7.2 Hz,
and CH2 Fmoc, CH α Asp, CH(CH3)2], 7.21 (t, J = 7.3 Hz, 2 H, 2 H, H2 and H7 Fmoc), 7.41 (t, J = 7.2 Hz, 2 H, H3 and H6 Fmoc),
H2 and H7 Fmoc), 7.41 (t, J = 7.3 Hz, 2 H, H3 and H6 Fmoc), 7.53 (d, J = 8.4 Hz, 2 H, H3 and H5 p-bromobenzyl), 7.69 (dd, J
7.69 (d, J = 7.3 Hz, 2 H, H1 and H8 Fmoc), 7.83 (d, J = 8.3 Hz, 1
H, NH Fmoc), 7.89 (t, J = 7.3 Hz, 2 H, H4 and H5 Fmoc) ppm.
13C NMR (75 MHz, [D6]DMSO, 303 K): δ = 14.0 (O-CH2-CH3),
= 7.2, 1.4 Hz, 2 H, H1 and H8 Fmoc), 7.77 (d, J = 8.3 Hz, 1 H,
NH Fmoc), 7.89 (t, J = 7.2 Hz, 2 H, H4 and H5 Fmoc) ppm. 13C
NMR (75 MHz, [D6]DMSO, 303 K): δ = 13.9 (O-CH2-CH3), 26.8
20.9 and 21.0 [CH(CH3)2], 27.5 (CH3 tBu), 27.6 (CH2 β Asp), 31.6 (CH2 β Asp), 27.5 (CH3 tBu), 30.9 (triazole-CH2-CO2Et), 45.5
(triazole-CH2-CO2Et), 46.6 (CH Fmoc), 48.7 [CH(CH3)2], 52.3 (CH2 p-bromobenzyl), 46.6 (CH Fmoc), 52.5 (CH α Asp), 60.9 (O-
(CH α Asp), 61.4 (O-CH2-CH3), 65.8 (CH2 Fmoc), 81.3 (Cq tBu),
CH2-CH3), 65.8 (CH2 Fmoc), 81.1 (Cq tBu), 120.2 (C4 and C5
Fmoc), 120.9 (C4 p-bromobenzyl), 125.2 (C1 and C8 Fmoc), 127.1
120.2 (C4 and C5 Fmoc), 125.2 (C1 and C8 Fmoc), 127.1 (C2 and
Eur. J. Org. Chem. 2011, 4293–4297
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A.-L. Blayo, F. Brunel, J. Martinez, J.-A. Fehrentz
SHORT COMMUNICATION
(C2 and C7 Fmoc), 127.7 (C3 and C6 Fmoc), 128.8 (C2 and C6
p-bromobenzyl), 131.6 (C3 and C5 p-bromobenzyl), 135.0 (C1 p-
bromobenzyl), 140.8 (C11 and C12 Fmoc), 143.7 and 143.8 (C10 and
C13 Fmoc), 148.9 and 151.9 (Cq triazole), 155.8 (CO Fmoc), 168.0
(CO2Et), 169.9 (CO2tBu) ppm. HRMS (ESI+): calculated for
C35H38BrN4O6, 689.1975; found 689.1985.
and C13 Fmoc), 150.9 and 152.6 (Cq triazole), 155.8 (CO Fmoc),
170.1 (CO2tBu) ppm. HRMS (ESI+): calculated for C33H37N4O4,
553.2815; found 553.2813.
4j: HPLC: tR = 1.55 min. 1H NMR (300 MHz, [D6]DMSO, 303 K):
δ = 1.28 (t, J = 7.31 Hz, 3 H, N-CH2-CH3), 1.40 (s, 9 H, CH3 tBu),
1.89–2.21 (m, 2 H, CH2 β), 2.61 (s, 3 H, methyl), 2.81–3.07 (m, 2
H, CH2 γ), 4.03–4.3 (m, 3 H, N-CH2-CH3 and CH α), 5.04 (d, J
= 12.4 Hz, 1 H, CH2 Z), 5.10 (d, J = 12.4 Hz, 1 H, CH2 Z), 7.37
(m, 5 H, Har phenyl Z), 7.78 (d, J = 8 Hz, 1 H, NH Z) ppm. 13C
NMR (75 MHz, [D6]DMSO, 303 K): δ = 9.4 (methyl), 13.9 (N-
CH2-CH3), 20.5 (CH2 β), 27.2 (CH2 γ), 27.6 (CH3 tBu), 39.2 (N-
CH2-CH3), 53.7 (CH α), 65.5 (CH2 Z), 80.9 (Cq tBu), 127.1 (C4
phenyl Z), 127.8 (C3 and C5 phenyl Z), 128.3 (C2 and C6 phenyl
Z), 138 (C1 phenyl Z), 152 (C5 triazole), 154.1 (C3 triazole), 156.2
(CO Z), 170.8 (CO-OtBu) ppm. HRMS (ESI+): calculated for
C21H31N4O4 [MH+], 403.2345; found 403.2335.
4g: HPLC: tR = 2.15 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 1.31 (s, 9 H, CH3 tBu), 2.23 (s, 3 H, CH3-triazole),
2.96 (dd, J = 15.7, 8.1 Hz, 1 H, CH2 β Asp), 3. 06 (dd, J = 15.7,
6.1 Hz, 1 H, CH2 β Asp), 4.15–4.32 (m, 3 H, CH and CH2 Fmoc),
4.33–4.43 (m, 1 H, CH α Asp), 5.19 (s, 2 H, CH2 p-bromobenzyl),
7.01 (d, J = 8.4 Hz, 2 H, H2 and H6 p-bromobenzyl), 7.31 (t, J =
7.3 Hz, 2 H, H2 and H7 Fmoc), 7.41 (t, J = 7.3 Hz, 2 H, H3 and
H6 Fmoc), 7.54 (d, J = 8.4 Hz, 2 H, H3 and H5 p-bromobenzyl),
7.68 (d, J = 7.3 Hz, 2 H, H1 and H8 Fmoc), 7.75 (d, J = 8.3 Hz, 1
H, NH Fmoc), 7.89 (t, J = 7.3 Hz, 2 H, H4 and H5 Fmoc) ppm.
13C NMR (75 MHz, [D6]DMSO, 303 K): δ = 10.5 (CH3-triazole),
26.6 (CH2 β Asp), 27.5 (CH3 tBu), 45.1 (CH2 p-bromobenzyl), 46.6
(CH Fmoc), 52.7 (CH α Asp), 65.7 (CH2 Fmoc), 81.0 (Cq tBu),
120.2 (C4 and C5 Fmoc), 120.9 (C4 p-bromobenzyl), 125.2 (C1 and
C8 Fmoc), 127.1 (C2 and C7 Fmoc), 127.7 (C3 and C6 Fmoc), 128.6
(C2 and C6 p-bromobenzyl), 131.8 (C3 and C5 p-bromobenzyl),
135.4 (C1 p-bromobenzyl), 140.8 (C11 and C12 Fmoc), 143.7 and
143.8 (C10 and C13 Fmoc), 151.2 and 151.3 (Cq triazole), 155.8
(CO Fmoc), 170.0 (CO2tBu) ppm. HRMS (ESI+): calculated for
C32H34BrN4O4, 617.1763; found 617.1755.
4k: HPLC: tR = 1.83 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 0.91 (t, J = 7.22 Hz, 3 H, N-CH2-CH3), 1.39 (s, 9 H,
CH3 tBu), 1.89–2.25 (m, 2 H, CH2 β), 2.62–2.78 (m, 2 H, CH2 γ),
3.78–3.80 (d, J = 7.1 Hz, 2 H, N-CH2-CH3), 4.01–4.14 (m, 3 H,
CH2-phenyl and CH α), 5.04 (d, J = 12.5 Hz, 1 H, CH2 Z), 5.10
(d, J = 12.5 Hz, 1 H, CH2 Z), 7.17–7.42 (m, 10 H, Har phenyl and
phenyl Z), 7.75 (d, J = 7.76 Hz, 1 H, NH Z) ppm. 13C NMR
(75 MHz, [D6]DMSO, 303 K): δ = 14.9 (N-CH2-CH3), 20.8 (CH2
β), 27.6 (CH3 tBu), 28.0 (CH2 γ), 37.4 (N-CH2-CH3), 54.0 (CH α),
65.4 (CH2 Z), 80.6 (Cq tBu), 126.6 (C4 phenyl), 127.7 (C4 phenyl
Z), 128.3 (C3 and C5 phenyl), 128.5 (C2 and C6 phenyl), 128.6 (C2
and C6 phenyl Z), 136.7 (C1 phenyl Z), 137.0 (C1 phenyl), 152.5
(C5 triazole), 153 (C3 triazole), 156.1 (CO Z), 171.3 (CO-OtBu)
ppm. HRMS (ESI+): calculated for C27H35N4O4 [MH+], 479.2658;
found 479.2654.
4h: HPLC: tR = 2.43 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 1.34 (s, 9 H, CH3 tBu), 3.04 (dd, J = 15.7, 8.2 Hz, 1
H, CH2 β Asp), 3. 15 (dd, J = 15.7, 5.9 Hz, 1 H, CH2 β Asp), 4.16–
4.33 (m, 3 H, CH and CH2 Fmoc), 4.42–4.52 (m, 1 H, CH α Asp),
5.32 (s, 2 H, CH2 p-bromobenzyl), 6.94 (d, J = 8.3 Hz, 2 H, H2
and H6 p-bromobenzyl), 7.24–7.34 (m, 2 H, H2 and H7 Fmoc), 7.41
(t, J = 7.4 Hz, 2 H, H3 and H6 Fmoc), 7.44–7.54 (m, 7 H, H3 and
H5 p-bromobenzyl, H2, H3, H4, H5 and H6 phenyl), 7.69 (d, J =
7.4 Hz, 2 H, H1 and H8 Fmoc), 7.84 (d, J = 8.3 Hz, 1 H, NH
Fmoc), 7.89 (t, J = 7.3 Hz, 2 H, H4 and H5 Fmoc) ppm. 13C NMR
(75 MHz, [D6]DMSO, 303 K): δ = 26.7 (CH2 β Asp), 27.5 (CH3
tBu), 46.2 (CH2 p-bromobenzyl), 46.6 (CH Fmoc), 52.4 (CH α
Asp), 65.8 (CH2 Fmoc), 81.2 (Cq tBu), 120.2 (C4 and C5 Fmoc),
121.0 (C4 p-bromobenzyl), 125.2 (C1 and C8 Fmoc), 126.2 (C1
phenyl), 127.1 (C2 and C7 Fmoc), 127.7 (C3 and C6 Fmoc), 128.3
(C2 and C6 p-bromobenzyl), 128.5 and 129.1 (C2, C3, C5 and C6
phenyl), 130.4 (C4 phenyl), 131.8 (C3 and C5 p-bromobenzyl), 134.9
(C1 p-bromobenzyl), 140.8 (C11 and C12 Fmoc), 143.7 and 143.8
(C10 and C13 Fmoc), 152.7 and 154.1 (Cq triazole), 155.8 (CO
Fmoc), 169.7 (CO2tBu) ppm. HRMS (ESI+): calculated for
C37H36BrN4O4, 679.1920; found 679.1918.
4l: HPLC: tR = 1.73 min. 1H NMR (300 MHz, [D6]DMSO, 303 K):
δ = 1.09–1.24 (m, 6 H, N-CH2-CH3 and COO-CH2-CH3), 1.41 (s,
9 H, CH3 tBu), 1.92–2.23 (m, 2 H, CH2 β), 2.68–2.84 (m, 2 H, CH2
γ), 3.84–3.92 (m, 2 H, COO-CH2-CH3), 3.94 (s, 2 H, CH2-COOEt),
4.09–4.16 (m, 3 H, N-CH2-CH3 and CH α), 5.03 (d, J = 12.6 Hz,
1 H, CH2 Z), 5.08 (d, J = 12.6 Hz, 1 H, CH2 Z), 7.18 (m, 5 H, Har
phenyl Z), 7.76 (d, J = 7.85 Hz, 1 H, NH Z) ppm. 13C NMR
(75 MHz, [D6]DMSO, 303 K): δ = 13.91 (N-CH2-CH3), 14.98
(COO-CH2-CH3), 20.83 (CH2 β), 27.57 (CH3 tBu), 27.96 (CH2 γ),
30.77 (N-CH2-CH3), 37.65 (COO-CH2-CH3), 54.05 (CH α), 60.90
(CH2-COOEt), 65.41 (CH2 Z), 80.63 (Cq tBu), 127.11 (C4 phenyl
Z), 127.72 (C3 and C5 phenyl Z), 128.28 (C2 and C6 phenyl Z),
136.97 (C1 phenyl Z), 148.00 (C5 triazole), 153.26 (C3 triazole),
156.14 (CO Z), 168.46 (CO-OEt), 171.23 (CO-OtBu) ppm. HRMS
(ESI+): calculated for C24H35N4O6[MH+], 475.2557; found
475.2558.
4i: HPLC: tR = 2.00 min. 1H NMR (300 MHz, [D6]DMSO, 303 K): 4m: HPLC: tR = 1.79 min. 1H NMR (300 MHz, [D6]DMSO,
δ = 0.91 (t, 3 H, CH3), 1.29 (s, 9 H, CH3 tBu), 3.03 (dd, J = 16.1, 303 K): δ = 1.35 (s, 9 H, CH3 tBu), 1.87–2.11 (m, 2 H, CH2 β),
8.0 Hz, 1 H, CH2 β Asp), 3. 09 (dd, J = 16.1, 6.2 Hz, 1 H, CH2 β
2.24 (s, 3 H, methyl), 2.61 (m, 2 H, CH2 γ), 3.72 (s, 3 H, CH3-O),
Asp), 3.85 (q, 2 H, CH2), 4.05–4.40 (m, 5 H, CH Fmoc, CH2 Fmoc, 3.99–4.21 (m, 1 H, CH α), 4.80–5.19 (m, 4 H, CH2 Z and CH2–4-
triazole-CH2-phenyl), 4.49–4.59 (m, 1 H, CH α Asp), 7.22–7.33 (m,
7 H, H2 and H7 Fmoc, H2, H3, H4, H5 and H6 phenyl), 7.41 (t, J
= 7.3 Hz, 2 H, H3 and H6 Fmoc), 7.67 (d, J = 7.3 Hz, 2 H, H1 and
H8 Fmoc), 7.68 (d, 1 H, NH Fmoc), 7.89 (d, J = 7.3 Hz, 2 H, H4
and H5 Fmoc) ppm. 13C NMR (75 MHz, [D6]DMSO, 303 K): δ =
14.9 (CH3), 26.40 (CH2 β Asp), 27.4 (CH3 tBu), 30.2 (triazole-CH2-
phenyl), 37.6 (CH2-ethyl), 46.5 (CH Fmoc), 52.6 (CH α Asp), 65.6
methoxybenzyl), 6.90 (d, J = 8.7 Hz, 2 H, H3 and H5 4-meth-
oxybenzyl), 6.97 (d, J = 8.7 Hz, 2 H, H2 and H6 4-methoxybenzyl),
7.33 (m, 5 H, Har phenyl Z), 7.73 (d, J = 7.75 Hz, 1 H, NH Z)
ppm. 13C NMR (75 MHz, [D6]DMSO, 303 K): δ = 10.43 (methyl),
21.07 (CH2 β), 27.52 (CH3 tBu), 28.17 (CH2 γ), 45.03 (CH2-4-meth-
oxybenzyl), 54.00 (CH α), 55.1 (CH3-O), 65.42 (CH2 Z), 80.58 (Cq
tBu), 114.22 (C3 and C5 4-methoxybenzyl), 127.62 (C4 phenyl Z),
(CH2 Fmoc), 80.9 (Cq tBu), 120.1 (C4 and C5 Fmoc), 125.1 (C1 127.70 (C2 and C6 4-methoxybenzyl), 127.75 (C3 and C5 phenyl Z),
and C8 Fmoc), 126.6 and 127.1 (C2 and C7 Fmoc), 127.6 (C4
phenyl), 128.2 (C3 and C6 Fmoc), 128.5 (C2, C3, C5 and C6 phenyl),
136.6 (C1 phenyl), 140.7 (C11 and C12 Fmoc), 143.8 and 143.7 (C10
128.28 (C2 and C6 phenyl Z, C1 4-methoxybenzyl), 136.94 (C1
phenyl Z), 150.90 (C5 triazole), 153.17 (C3 triazole), 156.11 (CO
Z), 158.68 (C4 4-methoxybenzyl), 171.16 (CO-OtBu) ppm. HRMS
4296
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4293–4297

Chiral 1,2,4-Triazole-Containing α-Amino Acids
(ESI+): calculated for C27H35N4O5 [MH+], 495.2607; found
495.2602.
118.1 (C4 Trp), 118.3 (C5 Trp), 120.8 (C6 Trp), 123.7 (C2 Trp), 127.3
(C9 Trp), 128.7 (C2, C3, C4, C5 and C6 phenyl), 134.4 (C1 phenyl),
136.0 (Cq8 Trp), 151.9 (C5 triazole), 153.2 (C3 triazole), 155.3 (CO
Boc), 169.1 (CO-OtBu), 171.2 (CO amide Ala), 172.1 (CO amide
Trp) ppm. HRMS (ESI+) calculated for C37H50N7O6 [MH+],
688.3823; found 688.3822.
4n: HPLC: tR = 2.01 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 1.33 (s, 9 H, CH3 tBu), 1.83–2.08 (m, 2 H, CH2 β),
2.56–2.76 (m, 2 H, CH2 γ), 3.69 (s, 3 H, CH3-O), 3.88–4.12 (m,
3 H, CH2-phenyl and CH α), 5.03 (m, 4 H, CH2 Z and CH2 4-
methoxybenzyl), 6.80 (s, 4 H, H2 H3 H5 and H6 4-methoxybenzyl),
7.15–7.41 (m, 10 H, Har phenyl and phenyl Z), 7.69 (d, J = 7.8 Hz,
1 H, NH Z) ppm. 13C NMR (75 MHz, [D6]DMSO, 303 K): δ =
21.1 (CH2 β), 27.5 (CH3 tBu), 28.0 (CH2 γ), 30.3 (CH2-phenyl),
45.1 (CH2- 4-methoxybenzyl), 53.9 (CH α), 55.0 (CH3-O), 65.4
(CH2 Z), 80.6 (Cq tBu), 114.1 (C3 and C5 4-methoxybenzyl), 126.6
(C4 phenyl), 127.5 (C4 phenyl Z), 127.7 (C3 and C5 phenyl) 127.8
(C2 and C6 4-methoxybenzyl), 128.3 (C2 and C6 phenyl), 128.4 (C3
and C5 phenyl Z), 128.5 (C2 and C6 phenyl Z), 129.1 (C1 4-meth-
oxybenzyl), 136.3 (C1 phenyl), 136.9 (C1 phenyl Z), 153.1 (C3 tri-
azole), 153.7 (C5 triazole), 156.1 (CO Z), 158.6 (C4 4-meth-
oxybenzyl), 171.1 (CO-OtBu) ppm. HRMS (ESI+): calculated for
C33H39N4O5 [MH+], 571.2920; found 571.2925.
Supporting Information (see footnote on the first page of this arti-
cle): NMR and mass spectra and HPLC chromatograms are pre-
sented.
Acknowledgment
We are grateful to Mr. Pierre Sanchez for his indispensable help in
obtaining mass spectrometry data.
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4o: HPLC: tR = 1.93 min. 1H NMR (300 MHz, [D6]DMSO,
303 K): δ = 1.12 (t, J = 7.09 Hz, 3 H, COO-CH2-CH3), 1.35 (s, 9
H, CH3 tBu), 1.87–2.12 (m, 2 H, CH2 β), 2.65 (m, 2 H, CH2 γ),
3.71 (s, 3 H, CH3-O), 3.86 (s, 2 H, CH2-COOEt), 3.92–4.09 (m, 3
H, COO-CH2-CH3 and CH α), 4.93–5.18 (m, 4 H, CH2 Z and
CH2–4-methoxybenzyl), 6.88 (d, J = 8.74 Hz, 2 H, H3 and H5 4-
methoxybenzyl), 6.95 (d, J = 8.74 Hz, 2 H, H2 and H6 4-meth-
oxybenzyl), 7.24–7.41 (m, 5 H, Har phenyl Z), 7.69 (d, J = 7.86 Hz,
1 H, NH Z) ppm. 13C NMR (75 MHz, [D6]DMSO, 303 K): δ =
13.8 (COO-CH2-CH3), 21.2 (CH2 β), 27.5 (CH3 tBu), 28.0 (CH2
γ), 31.0 (COO-CH2-CH3), 45.4 (CH2- 4-methoxybenzyl), 54.0 (CH
α), 55.1 (CH3-O-), 60.9 (CH2-COOEt), 65.4 (CH2 Z), 80.6 (Cq
tBu), 114.1 (C3 and C5 4-methoxybenzyl), 127.3 (C1 4-meth-
oxybenzyl), 127.7 (C2 and C6 4-methoxybenzyl, C1 phenyl Z), 127.8
(C3 and C5 phenyl Z), 128.3 (C2 and C6 phenyl Z), 136.9 (C1 phenyl
Z), 148.6 (C5 triazole), 153.9 (C3 triazole), 156.1 (CO Z), 158.8 (C4
4-methoxybenzyl), 168.0 (CO-OEt), 171.1 (CO-OtBu) ppm. HRMS
(ESI+): calculated for C30H39N4O7 [MH+], 567.2819; found
567.2823.
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8: HPLC: tR = 1.97 min. 1H NMR (300 MHz, [D6]DMSO, 303 K):
δ = 1.10 (t, J = 7.23 Hz, 3 H, N-CH2-CH3), 1.18–1.57 (m, 21 H,
CH3 Ala, CH3 Boc and CH3 tBu), 2.79–3.30 (m, 4 H, CH2 β tri-
azole and CH2 β Trp), 4.08–4.21 (m, 3 H, N-CH2-CH3 and CH α
triazole), 4.36 (s, 2 H, CH2-phenyl), 4.77–4.92 (m, 1 H, CH α Trp),
6.84 (d, J = 7.50 Hz, 1 H, NH Boc), 6.98 (t, J = 7.50 Hz, 1 H, H5
Trp), 7.05 (t, J = 7.56 Hz, 1 H, H6 Trp), 7.14 (d, J = 2.02 Hz, 1 H,
H2 Trp), 7.2–7.35 (m, 6 H, H7 Trp and Har phenyl), 7.56 (d, J =
7.7 Hz, 1 H, H4 Trp), 8.34 (m 2 H, NH amides), 10.82 (s, 1 H, NH
indole Trp) ppm. 13C NMR (75 MHz, [D6]DMSO, 303 K): δ = 14.3
(CH3 Ala), 16.8 (N-CH2-CH3), 26.9 (CH2 β triazole), 27.3 (CH2 β
Trp), 27.6 (CH3 tBu), 28.1 (CH3 Boc), 29.5 (CH2-phenyl), 39.0 (N-
CH2-CH3), 48.5 (CH α triazole), 50.0 (CH α Ala), 55.5 (CH α Trp),
78.3 (Cq Boc), 80.6 (Cq tBu), 110.0 (Cq3 Trp), 111.3 (C7 Trp),
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Received: May 2, 2011
Published Online: June 6, 2011
Eur. J. Org. Chem. 2011, 4293–4297
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4297