Synthesis of CF3-containing tetrapeptide surrogates via Ugi reaction/dipolar cycloaddition sequence

Article abstract of DOI:10.1016/j.tet.2011.11.037

A convenient synthetic pathway to novel functionalized tetrapeptides containing the 1,2,3-triazole moiety is described. The target molecules were obtained by the reaction of fluorinated α-amino acids or α-aminophosphonates with azidopeptides via Cu(I)-cat

Full text of DOI:10.1016/j.tet.2011.11.037

Tetrahedron 68 (2012) 872e877
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of CF3-containing tetrapeptide surrogates via Ugi reaction/dipolar
cycloaddition sequence
,
a
Daria V. Vorobyeva a, Nadezhda V. Sokolova b, Valentine G. Nenajdenko b , Alexander S. Peregudov ,
*
,
Sergey N. Osipov a
*
a A.N. Nesmeyanov Institute of Organoelement compounds, Russian Academy of Sciences, Vavilov Str. 28, Moscow 119991, Russia
b Moscow State University, Department of Chemistry, Leninskie Gory 1, Moscow 119992, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2011
Received in revised form 26 October 2011
Accepted 14 November 2011
Available online 19 November 2011
A convenient synthetic pathway to novel functionalized tetrapeptides containing the 1,2,3-triazole
moiety is described. The target molecules were obtained by the reaction of fluorinated
a-amino acids
or -aminophosphonates with azidopeptides via Cu(I)-catalyzed Huisgen cycloaddition reaction (click
a
chemistry). The synthesized tetrapeptides may find important applications in biomedical chemistry as
potential drugs.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Azidopeptides
Tetrapeptides
a
a
-Trifluoromethyl-
-Aminophosphonates
a-amino acids
Click chemistry
1. Introduction
improve pharmacokinetics and bioavailability properties of
potential drugs.3 Due to the extraordinary characteristics of
Peptides and proteins (polypeptides) are one of the most im-
portant classes of natural compounds. Being the fundamental in all
organisms, they play an essential role in all processes within the
cell. Short peptides are extremely important biogenic regulators
having many functions. For example, glutathione is very simple
fluorine, such as size, electronegativity, polarization, and the en-
ergy of its chemical bonds, fluorine chemistry has generated
high level of interest over the recent decades.4 Indeed, the in-
troduction of fluorine atom(s) into a molecule often improves the
therapeutic profile of potential biological agents, explaining why
nowadays more than 20% of pharmaceutical agents and 40% of
agrochemical compounds in the market feature at least one fluo-
rine atom in their structure.5 The advantages of peptides modified
by trifluoromethyl-containing amino acids include enhanced pro-
teolytic stability, affinity for lipid bilayer membranes, as well as
stabilization of secondary supramolecular structures owing to the
ability of the fluorine atom to form hydrogen bonds.6,7 In addition,
fluorinated compounds are extensively used as advanced
materials.8
tripeptide (g-Glu-Cys-Gly), which acts as an antioxidant, detox-
ificant, anti-aging agent, protecting cells from damage.1 Very in-
teresting types of endogenous opioid tetrapeptides are
endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-
Pro-Phe-Phe-NH2). Endomorphins are natural fighters of stress and
pain having the highest affinity and specificity to opioid
m-re-
ceptor.2 Other tri- and tetrapeptides are also highly active small
molecules exhibiting a broad variety of biological properties (reg-
ulation of immune system, hormone functions, wound healing, and
skin remodeling activity, use as ACE inhibitors, etc.).
At the same time,
a-aminophosphonates are structural mimics
Synthetic
a
-amino acids play an important role in the area
of a-amino acids. Some of these compounds exhibit very high po-
of peptide research and are extensively incorporated into
biologically active peptides to restrict their conformational
flexibility, enhance proteolytic stability, increase selectivity and
tency inhibiting the enzymes that are involved in the metabolism of
the corresponding amino acids. These compounds have already
been found to display antibacterial, antiviral, anticancer, and some
other types of bioactivity.9
On the other hand, the replacement of the native peptide bond
(CONH) in peptidomimetic structures by different functions or
atoms has been used for the optimization of their biological pro-
files.10 Thus, we have previously reported effective approaches to
* Corresponding authors. Fax: þ7 495 1355085 (V.G.N.); tel.: þ7 495 9392276;
fax: þ7 495 9328846 (S.N.O.); e-mail addresses: nen@acylium.chem.msu.ru (V.G.
Nenajdenko), osipov@ineos.ac.ru (S.N. Osipov).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.037

D.V. Vorobyeva et al. / Tetrahedron 68 (2012) 872e877
873
the synthesis of trifluoromethyl peptidomimetics, such as dep-
The synthesis of the starting
a
-alkynyl-
a
-CF3-
a
-amino acids and
sipeptides by a metal carbene insertion reaction into COOH-group
of N-protected amino acids11 and by the Passerini reaction with
CF3-carbonyl compounds.12 Now, we are interested in the synthesis
of fluorinated pseudopeptides bearing a triazole ring as a peptide
bond mimic. These heterocycles function as rigid linking units
that can mimic the atom placement and electronic properties of
a peptide bond without the same susceptibility to hydrolytic
cleavage.13e16
a
-aminophosphonates 2aef was accomplished via the addition of
sodium acetylide or allenylmagnesiumbromide to electrophilic
trifluoromethylpyruvate imines and
a-iminophosphonate under
mild conditions.24,25
In recent years azides have become of increasing importance in
organic chemistry especially for the synthesis of peptides due to
their advantages, such as less steric hindrance and greater solubility
when compared with amides and carbamates.26 In spite of the fact
that many synthetic approaches have been reported for the for-
The application of 1,2,3-triazole has been reported in peptide
bond bioisosteres, peptide nanotubes,14
b
-turn mimics,17 protease
mation of a-azido acids, a convenient pathway to different azido-
inhibitors,18 cyclopeptide analogues,19 and peptide chain ana-
logues.20 Therefore, the development of efficient synthetic meth-
odologies for the preparation of new peptidomimetics containing
peptides by the Ugi four-component reaction27 has been only
recently suggested and it was demonstrated that these azidopep-
tides can be used quite effectively for the decoration of bio-
molecules by peptide residues.28
fluorinated a-amino acids and a-aminophosphonates is of current
interest. The copper-catalyzed ‘click’ reaction21 is a method that can
quickly and easily generate large libraries of different 1,2,3-triazole
derivatives. This approach includes the ligation of azides and ter-
minal alkynes. Moreover, due to its outstanding chemoselectivity
and mild conditions, the reaction has been especially used in bio-
conjugate chemistry.22
On the first stage of our investigation we decided to link tri-
peptide 1 with different
a-trifluoromethyl-a-amino acid (a-CF3-
AA) derivatives 2aed to obtain modified peptides 3aed. We found
that the click reaction of acetylenes 2aed and azidotripeptide 1 in
biphasic mixture CH2Cl2/H2O proceeds regioselectively in high
yields to afford conjugates 3aed after reflux (Scheme 1, Table 1). It
should be noted that the click reaction of tripeptide 1 with
Herein, we present a convenient synthetic pathway to novel
functionalized tetrapeptides comprising triazole moiety as a linker
propargyl-containing
a-CF3-AA derivatives required more pro-
connecting fluorinated
with functionally substituted azidopeptides.
a
-amino acids and
a
-aminophosphonates
longed reaction time (5 h) compared to their ethynyl analogues
(3 h). Such a difference in the reactivity correlates with the elec-
tronic properties of acetylenes; alkynes bearing electron-
withdrawing groups usually are more reactive in cycloaddition
reactions.29
2. Results and discussion
Then we conjugated
a-propargyl-a-CF3-AA Boc-protected de-
The introduction of
methods of peptide chemistry is not a trivial task. Due to the low
nucleophilicity of the amino-function and steric effects of the CF3-
a
-CF3-
a
-AA into peptides by conventional
rivative 2c with various tripeptides using 1,3-dipolar Huisgen cy-
cloaddition reaction under the same conditions (Scheme 2, Table 2).
We have demonstrated that the variation of substituents in starting
azidopeptides does not essentially affect the yield of the products.
In all cases desired tetrapeptides 4aef have been obtained in high
yields.
group in
standard methods for the peptide synthesis is required.23 Until now
only H-( -CF3)-Gly-OMe and H-( -CF3)-Ala-OMe were in-
a-trifluoromethyl a-amino acids the modification of
a
a
corporated in the C-terminal position of peptides using the stan-
dard methodology. Often the classical activation methods for the
amino-group of amino acids with more bulky substituents in the
side chain are not suitable or lead to significant epimerization of the
adjacent non-fluorinated amino acid. Therefore, click-methodology
renders a good possibility to overcome this problem (Fig. 1).
Next, we decided to expand this methodology to phosphorus
analogues of amino acids, namely, aminophosphonates. Earlier we
established that the generation of Cu(I) in situ from CuSO4 and
sodium ascorbate in a waterealcohol medium is the most preferred
procedure for reactions of such type with acetylene-containing
aminophosphonates.24b We found that the cycloaddition of
R
F3C
X
N3
F3C
NC
X
N
PG
R1 R2
N
O
R
N
N
N
NHPG
n
Ugi
BocHN
N
H
R3 R3
O
R1 R2
N
O
R
click
F3C
X
N3
BocHN
N
H
n NHPG
R3 R3
O
Fig. 1. The strategy for the synthesis of tetrapeptides.
F3C
CO2Me
NHPG
Bn
DMB
N
O
N
N
F3C
CO2Me
NHPG
Bn
DMB
N
O
a
N3
n
N
BocHN
N
H
BocHN
N
H
n
O
1
2a-d
3a-d
O
Scheme 1. Synthesis of
a
-CF3-a
-amino acid containing tetrapeptides 3. Conditions: (a) sodium ascorbate (40%), CuSO4$5H2O (10%), CH2Cl2/H2O (10:1), 40 ꢀC, 3e5 h.

874
D.V. Vorobyeva et al. / Tetrahedron 68 (2012) 872e877
Table 1
in good yield. Classical Pd-catalyzed hydrogenation in methanol
a
-CF3-a-amino acid containing tetrapeptides 3 obtained via Scheme 1
was successfully applied for the deprotection of the amino-func-
tion of 5n to afford the corresponding aminophosphonate 7
(Scheme 4).
Thus, the possibility of selective deprotection of obtained CF3-
peptides opens a convenient route for subsequent elongation of
peptide chain and synthesis of higher CF3-peptides.
Entry
PG
n
Product
Yielda
%
1
2
3
4
Boc
Cbz
Boc
Cbz
0
0
1
1
3a
3b
3c
3d
86
87
90
90
a
Isolated yields after purification by column chromatography.
F3C
CO2Me
NHBoc
R1 R2
N
O
R
R1 R2
N
O
R
N
N
N
F3C
CO2Me
a
N3
BocHN
N
H
NHBoc
2c
BocHN
N
H
R3 R3
R3 R3
O
1
4a-f
O
Scheme 2. Synthesis of
a
-CF3-
a
-amino acid containing tetrapeptides 4. Conditions: (a) sodium ascorbate (40%), CuSO4$5H2O (10%), CH2Cl2/H2O (10:1), 40 ꢀC, 5 h.
Table 2
3. Conclusions
a
-CF3-a-amino acid containing tetrapeptides 4 obtained via Scheme 2
In conclusion, we have developed a convenient and simple
method for the synthesis of -CF3-containing tetrapeptide
surrogates based on copper-catalyzed 1,3-dipolar cycloaddition of
azidopeptides to acetylenes having ester of phosphonates func-
tionalities. The synthesized tetrapeptides may find important ap-
plications in biomedical chemistry as potential drugs.
Entry
1
R
R1
R2
R3, R4
Product
Yielda
95
%
a
i-Pr
PMB
Me
4a
2
3
4
i-Pr
Me
Bn
Me
H
i-Pr
DMB
DMB
PMB
H
H
Me
4b
4c
4d
73
74
85
4. Experimental section
4.1. General information
5
Me
DMB
Me
Me
4e
70
All solvents used in reactions were freshly distilled from ap-
propriate drying agents before use. All other reagents were
recrystallized or distilled as necessary. Reactions were performed
under an atmosphere of dry nitrogen. Analytical TLC was per-
formed with Merck silica gel 60 F254 plates. Visualization was
accomplished by UV light and spraying by Ce(SO4)2, solution in 5%
H2SO4 or aqueous potassium permanganate (KMnO4). Flash
chromatography was carried out using Merck silica gel 60
(230e400 mesh ASTM). Optical rotations were measured on
a PerkineElmer 341 polarimeter at 589 nm. High-resolution mass
spectra (HRMS) were measured on a Micr OTOF II (Bruker Dal-
tonics) spectrometer. IR spectra were measured on a Fourier
6
Bn
PMB
4f
97
a
Isolated yields after purification by column chromatography.
ethynyl- and propargyl-containing aminophosphonates 2e,f to
various azides 1 proceeded at 90 ꢀC and led to completion within
2 h in all cases affording the corresponding tetrapeptides 5aen in
good yields (Scheme 3, Table 3).
F3C
P(O)(OEt)2
NHCbz
R1
R2
N
O
R
R1
R2
N
O
R
N
N
N
F3C
P(O)(OEt)2
a
N3
n
BocHN
N
H
NHCbz
BocHN
N
H
n
R3 R3
O
5a-n
1
R3 R3
2e,f
O
Scheme 3. Synthesis of a-CF3-a
-aminophosphonate containing tetrapeptides 5. Conditions: (a) sodium ascorbate (30%), CuSO4$5H2O (5%), t-BuOH/H2O (1:1), 90 ꢀC, 2 h.
It should be noted that in all cases the desired products have
been isolated as a mixture of diastereomers because starting
acetylenes contained a stereogenic center and were used in race-
mic form. The purification of the final triazoles 3aed, 4aef, 5aen
has been achieved by means of column chromatography on
silica gel.
spectrometer Nicolet 6700. NMR spectra were recorded on
a Bruker AV-300, AV-400 or AV-600 spectrometer operating at
300 MHz, 400 MHz or 600 MHz, respectively (TMS) for 1H; 100 or
151 MHz for 13C, 188 or 282 MHz for 19F (CF3COOH); 121 MHz for
31P (H3PO4).
Both protecting groups of the amide and the amine functions
can be easily removed from the target conjugates, either in an
orthogonal mode or in one step. Thus, heating of the conjugate 3a
in TFA led to the product 6 containing free amide and amine groups
4.2. General procedure for the synthesis of triazoles 3 and 4
The corresponding peptide 1 (1 mmol), CuSO4$5H2O (25 mg,
0.1 mmol) in 0.5 mL of H2O and sodium ascorbate (79 mg,

D.V. Vorobyeva et al. / Tetrahedron 68 (2012) 872e877
875
Table 3
-CF3-a-aminophosphonate containing tetrapeptides 5 obtained via Scheme 3
3CH3eBoc, 6H, 2CH3), 1.38 and 1.40 (both s, 9H, 3CH3eBoc),
2.61e2.71 (m, 1H, CH2Ph), 2.86e2.97 (m, 1H, CH2Ph), 3.72 (s, 3H,
OCH3), 3.77 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.20e4.29 (m, 1H, CH),
4.33e4.54 (m, 3H, 2 CH2, 1H, CH), 4.67e4.77 (m, 1H, CH2), 5.65 (br s,
1H, NH), 6.44e6.48 (m, 1H, CHAr), 6.56e6.58 (m, 1H, CHAr),
6.78e6.90 (m, 1H, NH), 6.97e7.06 (m, 2H, CHAr), 7.11e7.20 (m, 3H,
CHAr), 7.34e7.38 (m, 1H, CHAr), 7.63e7.73 (m, 1H, NH), 8.33 (br s, 1H,
CHetriazole); dF (188 MHz, CDCl3) 3.44 and 3.66 (both s, 3F, CF3); dC
(100 MHz, CDCl3) 17.0, 17.2, 22.4, 22.6, 24.1, 24.2, 28.0, 28.2, 39.7,
39.9, 41.8, 41.9, 45.7, 53.1, 53.2, 53.5, 53.7, 55.2, 55.3, 62.6, 62.7,
64.6e65.3 (m), 79.5, 80.9, 98.4, 98.5, 104.2, 118.2, 123.1 (q,
1JCeF¼286.9 Hz, CF3), 125.6, 126.7, 128.1, 128.4, 129.6, 136.6, 136.7,
138.8, 138.9, 153.5, 156.8, 156.9, 160.1, 160.2, 165.5, 173.2, 174.7;
HRMS (ESI): MNaþ, found 886.3952. C41H56F3N7O10 requires
886.3938.
a
Entry
R
R1
R2
R3, R4
n
Product Yielda
%
1
i-Pr
PMB
Me
0
5a
5b
5c
5d
77
72
74
60
2
3
4
i-Pr
PMB
PMB
PMB
Me
Me
Me
1
0
1
Bn
Bn
Physical and spectroscopic data, including NMR, high-resolution
mass analysis, and elemental analysis of compounds 3bed and
4aef are available in Supplementary data.
5
6
7
8
Bn
Bn
H
i-Pr
i-Pr
Me
Me
H
H
Bn
Bn
PMB
PMB
PMB
PMB
DMB
DMB
Me
Me
Me
Me
H
0
1
0
1
0
1
0
1
5e
5f
5g
5h
5i
5j
5k
5l
57
77
65
69
63
66
68
65
H
9
Me
Me
Me
Me
10
11
12
H
4.3. General procedure for the synthesis of triazoles 5
DMB Me
DMB Me
To a solution of the corresponding acetylene 2e,f (1 mmol) in
the mixture of t-BuOH/H2O (1:1 ratio) (3 mL) was added a solution
of corresponding azide 1 (1 mmol) in the mixture of t-BuOH/H2O
(2 mL), sodium ascorbate (30 mol %), and 0.5 M copper sulfate
pentahydrate (5 mol %). The reaction mixture was stirred at 90 ꢀC,
2 h until the completion of the reaction monitored by TLC. After
evaporation of the solvent under reduced pressure, water (5 mL)
was added to a residue and the aqueous layer was extracted twice
with ethyl acetate (2ꢃ10 mL). The organic layer was dried over
MgSO4 and evaporated. The residue was purified by column chro-
matography (hexane/acetone).
13
Bn
PMB
PMB
Me
Me
0
5m
5n
60
14
Bn
1
73
a
Isolated yields after purification by column chromatography.
F3C
P(O)(OEt)2
NH
R
CF3
Bn R2
N
O
N
N
N
N
N
N
PMB O
N
Bn
COOMe
HN
R1
R3
N
Boc
N
H
N
H
N
H
O
O
3a: R1, R3 = Boc; R2 = DMB;
5n: R = Cbz
b
a
6: R1, R2, R3 = H;
7: R = H
Scheme 4. Deprotection of conjugates 3a and 5n. Conditions: (a) TFA, reflux, 2 h, 67%; (b) H2, Pd/C, MeOH, rt, 62%.
0.4 mmol) in 0.5 mL of H2O were added successively to a solution of
the corresponding acetylene 2aed (1 mmol) in 10 mL of CH2Cl2.
The reaction mixture was stirred at 40 ꢀC for 3 h for 3a,b and 5 h for
3c,d and 4aef. The solvent was removed in vacuo and the residue
was purified by column chromatography (ethyl acetate or CH2Cl2/
MeOH).
4.3.1. N-(tert-Butoxycarbonyl)valyl-N1-[1-({4-[1-{[(benzyloxy)car-
bonyl]amino}-1-(diethoxyphosphoryl)-2,2,2-trifluoroethyl]-1H-1,2,3-
triazol-1-yl}methyl)-2-methylbutyl]-N2-(4-methoxybenzyl)-2-
methylalaninamide (mixture of diastereomers, w1:1) (5a). Yield
(66.1 mg, 77%) as a white solid, mp 88 ꢀC; [Found: C, 55.91; H, 7.01;
N, 10.11C44H65F3N7O10P requires C, 56.22; H, 6.97; N, 10.43%]; Rf
(hexane/acetone 1.5/1) 0.3; ½a D25
ꢁ
ꢂ49.7 (c 1.8, CHCl3); nmax (Nujol)
4.2.1. N-[(1,1-dimethylethoxy)carbonyl]-
L
-phenylalanyl-N2-[(2,4-
3370, 1755, 1685, 1518, 1256, 1170 cmꢂ1
; dH (600 MHz, DMSO-d6,
dimethoxyphenyl)methyl]-N1-[(1S)-2-[4-[1-[[(1,1-dimethylethoxy)
carbonyl]amino]-2,2,2-trifluoro-1-(methoxycarbonyl)ethyl]-1H-
1,2,3-triazol-1-yl]-1-methylethyl]-2-methylalaninamide (mixture of
diastereomers, w1:1) (3a). Yield (0.742 g, 86%) as a white solid, mp
70 ꢀC) 0.74e0.77 (m, 6H, 2CH3), 0.86e0.89 (m, 3H, CH3 in i-Pr), 0.95
(dd, 3H, 3JHeH¼6.7 Hz, 2.5 Hz, CH3 in i-Pr), 1.15e1.23 (m, 9H, 3CH3,
1H, CH in sec-Bu), 1.31 (br s, 3H, CH3), 1.36 (s, 9H, 3CH3eBoc),
1.52e1.61 (m, 2H, CH2 in sec-Bu), 1.92e1.97 (m, 1H, CH in i-Pr), 3.75
(s, 3H, OCH3), 3.87e3.94 (m, 1H, CH), 3.99e4.11 (m, 4H, OCH2, 1H,
CH), 4.50 (d, 2H, 3JHeH¼6.7 Hz, CH2), 4.61 (dd, 1H, JAB¼18.1 Hz, 3 Hz,
CH2etriazole), 4.72 (d, 1H, JAB¼17.7 Hz, CH2etriazole), 5.01 (d, 1H,
88e89 ꢀC; Rf (CH2Cl2/MeOH 25/1) 0.4; ½a 2D0
ꢁ
ꢂ8.9 (c 3.0, MeOH);
nmax (Nujol) 3410, 1760, 1740, 1715, 1675, 1650 cmꢂ1
;
dH (400 MHz,
DMSO-d6, 80 ꢀC) 1.09e1.13 (m, 3H, CH3), 1.21e1.27 (m, 9H,

876
D.V. Vorobyeva et al. / Tetrahedron 68 (2012) 872e877
JAB¼12.6 Hz, CH), 5.04 (d, 1H, JAB¼12.4 Hz, CH), 6.22 (br s, 1H,
NHeCH (sec-Bu)), 6.65e6.69 (m, 1H, NHeCbz), 6.90 (d, 2H,
3JHeH¼8.7 Hz, CHAr), 7.31e7.37 (m, 7H, CHAr), 7.43 and 7.47 (br s, 1H,
NHeBoc), 8.14 and 8.16 (both s, 1H, CHetriazole); dF (282 MHz,
DMSO-d6) 8.73 and 8.91 (both s, 3F, CF3); dP (121 MHz, DMSO-d6)
12.49 and 12.69 (both s); dC (100 MHz, DMSO-d6) 11.7, 11.8, 15.4,
15.5, 16.5 (d, 3JPeC¼5.5 Hz), 18.2, 19.8, 23.0, 23.1, 24.9 (m), 28.5, 31.1,
36.8, 37.1, 46.2, 50.6, 50.7, 53.6, 53.8, 55.5, 56.9, 61.4 (dq,
CHAr), 7.28e7.41 (m, 7H, CHAr), 7.47e7.50 and 7.67e7.71 (br s, 1H,
CHetriazole), 7.94 and 8.15 (both s, 1H, NH); dF (282 MHz, CDCl3)
5.97 and 6.15 (both s, 3F, CF3); dP (121 MHz, CDCl3) 17.64 and 17.91
(both s); dC (100 MHz, CDCl3) 16.3e16.4 (m), 23.0, 23.1, 23.5, 23.8,
24.4, 24.6, 27.7, 27.8, 28.6, 30.6, 31.6, 37.5, 37.6, 46.6, 46.7, 47.2, 47.6,
51.3 (m), 51.6, 51.8, 55.3, 57.2, 57.3, 62.4, 62.5, 60.0 (dq,
2
2
1JPeC¼153.7 Hz, JCeF¼26.5 Hz), 63.4 (d, JPeC¼5.5 Hz), 64.2 (d,
2JPeC¼6.6 Hz), 79.6, 79.7, 114.3, 123.5 (q, 1JCeF¼283.4 Hz, CF3), 124.5,
127.2e127.4, 126.7e126.9, 128.6, 128.7, 129.2, 129.3, 130.6, 130.7,
137. 3, 137.4, 140.7, 140.8, 154.7, 158.8e158.9 (m), 174.5, 174.7, 174.9,
175.0.
2
1JPeC¼150.3 Hz, JCeF¼30.1 Hz), 62.5, 62.6, 64.3 (t, JPeC¼6.6 Hz),
64.6 (t, JPeC¼6.1 Hz), 66.3, 66.4, 78.5, 114.1, 124.2 (q, 1JCeF¼290.8 Hz,
CF3), 126.2, 126.4, 128.1, 128.3, 128.8, 131.9, 136.9, 138.3 (m), 154.1
(m), 155.9, 158.6, 172.5, 174.2.
Physical and spectroscopic data, including NMR, high-resolution
mass analysis, and elemental analysis of compounds 5ben are
available in Supplementary data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.11.037.
4.4. Synthesis of 6
References and notes
A solution of 3a (0.05 g, 0.0058 mmol) in trifluoroacetic acid
(0.7 mL, 9.1 mmol) was refluxed for 2 h. The reaction mixture was
diluted with DCM (5 mL) and neutralized with aqueous saturated
solution of sodium bicarbonate until violet color disappeared.
Layers were separated and the aqueous layer was extracted with
DCM (2ꢃ10 mL). The combined organic extract were dried (Na2SO4)
and evaporated. The residue was purified by column chromatog-
raphy (CH3CN/NH3).
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4.4.1. L
-Phenylalanyl-N1-[(1S)-2-[4-[1-amino-2,2,2-trifluoro-1-(me-
thoxycarbonyl)ethyl]-1H-1,2,3-triazol-1-yl]-1-methylethyl]-2-
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methylalaninamide (mixture of diastereomers, w1:1) (6). Yield
(20 mg, 67%) as a yellow oil; Rf (CH3CN/NH3 9/1) 0.4; ½a D20
ꢂ1.4 (c
ꢁ
1.0, MeOH); nmax (Nujol) 3350, 1750, 1660 cmꢂ1
; dH (400 MHz,
CDCl3) 1.15 (d, 3H, 3JHeH¼6.6 Hz, CH3), 1.44 (s, 6H, 3CH3), 3.16e3.21
(m,1H, CH2Ph), 3.53e3.56 (m,1H, CH2Ph), 3.85 and 3.86 (both s, 3H,
OCH3), 3.87e3.91 (m, 1H, CH), 4.30e4.59 (m, 2H, CH2, 1H, CH), 7.05
ꢀ
ꢀ
5. (a) Begue, J.-P.; Bonnet-Delpon, D. In Bioorganic and Medicinal Chemistry of
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3
and 7.13 (both d, 1H, JHeH¼7.5 Hz, NH), 7.18e7.24 (m, 3H, CHAr),
7.28e7.35 (m, 2H, CHAr), 7.61 (s, 1H, NH), 7.88 and 7.92 (both s, 1H,
CHetriazole); dF (188 MHz, CDCl3) 0.85 and 0.91 (both s, 3F, CF3); dC
(100 MHz, CDCl3) 17.2, 17.4, 24.6, 25.0, 25.2, 25.4, 39.8, 40.2, 45.5,
54.0, 54.3, 56.2, 56.3, 56.9, 63.1, 64.8e65.6 (m), 123.8 (q,
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C22H30F3N7O4 requires 536.2209.
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4.5. Synthesis of 7
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4.5.1. 1-(tert-Butoxycarbonyl)prolyl-N1-(2-{4-[2-amino-2-(diethox-
yphosphoryl)-3,3,3-trifluoropropyl]-1H-1,2,3-triazol-1-yl}-1-
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ꢁ
(c 0.8, CHCl3); nmax (Nujol) 3382, 1706, 1668, 1515, 1252, 1162 cmꢂ1
;
dH (300 MHz, CDCl3) 1.31e1.55 (m, 21H, 7CH3), 1.71e1.79 (m, 1H,
CH2eProline), 1.89e2.09 (br m, 1H, CH2eProline, 2H, CH2eProline),
2.69e2.78 (m, 1H, CH2ePh), 3.14e3.58 (m, 1H, CH2ePh, 4H, 2CH2),
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2H, CH2, 2H, 2CH), 6.61 (m, 2H, NH2), 6.98 (d, 2H, JHeH¼7.3 Hz,

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