Synthesis of α-trifluoromethyl-α-hydroxy acid-peptide conjugates via click chemistry

Article abstract of DOI:10.1055/s-0031-1289609

A simple and convenient method for the incorporation of fluorinated α-hydroxy acids into peptides is described. The target conjugates were obtained from α-alkynyl-α-trifluoromethyl-α-hydroxy acids and azido peptides via the copper(I)-catalyzed Huisgen cyc

Full text of DOI:10.1055/s-0031-1289609

130
PAPER
Synthesis of a-Trifluoromethyl-a-hydroxy Acid–Peptide Conjugates via Click
Chemistry
S
ynthesis of Fluor
a
inate
d
Pepti
d
de Conjugat
e
es via Click
z
C
hemistryhda V. Sokolova,a Daria V. Vorobyeva,b Sergey N. Osipov,*b Tamara P. Vasilyeva,b
Valentine G. Nenajdenko*a
a
Department of Chemistry, Moscow State University, Leninskie Gory 1, Moscow 119991, Russian Federation
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28, Moscow 119991,
b
Russian Federation
Fax +7(495)9328846; E-mail: nen@acylium.chem.msu.ru; E-mail: osipov@ineos.ac.ru
Received 9 September 2011; revised 17 October 2011
drugs have been developed, including anti-inflammatory,
Abstract: A simple and convenient method for the incorporation of
anticancer and antiviral agents, among others.6
fluorinated a-hydroxy acids into peptides is described. The target
conjugates were obtained from a-alkynyl-a-trifluoromethyl-a-hy-
droxy acids and azido peptides via the copper(I)-catalyzed Huisgen
cycloaddition reaction (click chemistry). After straightforward
deprotection, the a-trifluoromethyl-a-hydroxy acid containing pep-
tides may find important applications in biochemistry and medici-
nal chemistry.
Among fluorine-containing functional groups, the trifluo-
romethyl group is unique due to its strong electron-with-
drawing nature. Caused by the increased medicinal
interest, the synthesis of biologically active trifluorometh-
yl-substituted compounds, such as alcohols, amines and
amino acids, is becoming very important and is of great
demand.2,3,7 Especially, the synthesis of a-trifluorometh-
yl-substituted secondary and tertiary alcohols has re-
ceived much attention due to their unique properties with
unusual biological activities as drugs and drug candidates,
such as Efavirenz (anti-HIV agent), trifluoromethyl ana-
logues of MMP inhibitors6b and DHA (antimalarial
agent), a nonsteroidal selective GR agonist (ZK 216348)
and a PDK inhibitor (AZD7545).6,8
Key words: a-trifluoromethyl-a-hydroxy acids, azido peptides,
click chemistry, Huisgen cycloaddition reaction, 1,2,3-triazoles
Nowadays, tri- or tetrapeptide-based cosmeceuticals are
widely used for the treatment of aging skin;1 however, the
exploitation of peptides is limited by their ability to pene-
trate skin barriers. Generally, permeation ability depends
on physicochemical properties of the substance, such as
molecular size, stability, solubility and binding affinity.2
It is well known that major drawbacks of peptides are their
rapid degradation by proteases, low lipophilicity and con-
formational instability. An improvement of the therapeu-
tic profile can be achieved by the incorporation of
fluorine-containing functional groups into the structure of
these biologically important molecules.3
Most frequently, fluorine is introduced to modulate the
physicochemical properties, to increase binding affinity
and to block a metabolically labile site in the molecule.9
The building block strategy is the most attractive concept
for the introduction of fluorine-containing groups into or-
ganic molecules.10 From this point of view, ‘click’ meth-
odology renders a good possibility for the conjugation of
different biologically active building blocks, including
peptides and peptidomimetics.11
At the same time, a-hydroxy acids are also well known for
their use in the cosmetics industry. They are often found
in products claiming to reduce wrinkles or the signs of ag-
ing of the skin. The main advantage of these compounds
is a proven level of safety and efficacy in a variety of skin
types.4
Previously, we have reported an efficient method for the
preparation of a-trifluoromethyl-a-hydroxy-containing
triazole derivatives based on the click reaction between a-
trifluoromethyl-a-propargyl-a-hydroxy acids and organic
azides.12
Organofluorine compounds have gained increasing atten-
tion due to their unique physical and biological properties
induced by the fluorine atom.5 Fast progress in this area is
fuelled by the development of new fluorinating reagents
and fluorination processes increasing the range of synthet-
ic fluorinated building blocks amenable to functional
group manipulation. The strategic use of fluorine substitu-
tion in drug design has culminated with the production of
some of the key drugs available on the market. In the phar-
maceutical industry, several novel fluorine-containing
Herein, we disclose the fast and simple incorporation of
fluorinated a-hydroxy acids into peptides via a 1,2,3-tria-
zole moiety using Huisgen 1,3-dipolar cycloaddition (a
‘click’ reaction) of alkynes and azides.13–15 We believe
that the modification of peptides by fluorine-containing
hydroxy acids will enhance their proteolytic stability and
make these conjugates promising candidates for biologi-
cal studies.
We prepared several short peptide sequences 1 containing
the azide group via the Ugi reaction16,17 of chiral isocyano
azides previously obtained by our group18 with carbonyl
compounds, amines and Boc-protected amino acids.
‘Clickable’ peptides are promising candidates for biocon-
SYNTHESIS 2012, 44, 130–136
x
x
.x
x
.2
0
1
1
Advanced online publication: 17.11.2011
DOI: 10.1055/s-0031-1289609; Art ID: Z88211SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Fluorinated Peptide Conjugates via Click Chemistry
131
jugation reactions and the synthesis of hybrid peptide als with copper(II) and sodium ascorbate in a biphasic
molecules with improved medicinal properties.
mixture of dichloromethane and water (Table 1, entries 6–
13). All products were isolated as a mixture of diaste-
reomers. Purification of the final triazoles 3a–m was
achieved by means of column chromatography on silica
gel. Thus, we have demonstrated that the variation of the
reaction medium does not essentially affect the yield of
the products. In all cases, triazole formation proceeded
smoothly to afford the desired a-trifluoromethyl-a-hy-
droxy acid containing peptides in high yields.
Synthesis of the a-alkynyl-a-trifluoromethyl-a-hydroxy
acids 2 was accomplished via the nucleophilic addition of
ethynylmagnesium bromide or allenylmagnesium bro-
mide to methyl 3,3,3-trifluoropyruvate.19 Having the cor-
responding sets of alkynylated a-trifluoromethyl-a-
hydroxy acids and azido peptides in hand, we investigated
a combinatorial approach towards the conjugates using
two catalytic systems. In a first series, the a-trifluoro-
methyl-a-hydroxy acid 2 bearing an alkyne group was re- The protecting groups of both the amide and the amine
acted with azido peptides 1 in a water–alcohol medium at functions can be easily removed from the target conju-
room temperature in the presence of catalytic amounts of gates in one step.20 As an example, heating of the conju-
copper(I) generated in situ from copper(II) sulfate pen- gate 3i in trifluoroacetic acid led to the product 4
tahydrate and sodium ascorbate (Table 1, entries 1–5). containing free amide and amine groups in good yield
The click reaction proceeded regioselectively in good (Scheme 1).
yields to afford conjugates 3a–e. A second series of con-
jugates 3f–m was prepared by heating the starting materi-
eral azido peptides with alkyne-functionalized a-trifluo-
In conclusion, we have described the conjugation of sev-
Table 1 Synthesis of Fluorinated a-Hydroxy Acid–Peptide Conjugates 3a–m
R1
R2
N
O
R4
N3
BocHN
N
H
R3 R3
CO2Me
OH
F3C
O
R1
R2
N
O
R4
N
N
N
1
+
a or b
n
BocHN
N
F3C
CO2Me
OH
H
R3 R3
O
3a–m
n
2
Entry
1a
R1
H
R2
R3
H
R4
n
0
0
Product
3a
Yieldc (%)
DMB
DMB
Me
Me
67
83
2a
Bn
Me
3b
3a
4a
5a
6b
PMB
PMB
PMB
DMB
Me
Me
Me
H
Bn
Bn
0
0
0
0
3c
3d
3e
3f
79
79
79
87
i-Pr
i-Pr
Me
i-Pr
7b
PMB
PMB
Me
Me
Bn
0
1
3g
3h
89
91
N
8b
i-Pr
9b
Bn
DMB
DMB
Me
H
Me
1
1
3i
3j
95
75
10b
Me
i-Pr
11b
PMB
Me
Bn
1
3k
96
12b
13b
H
DMB
PMB
H
Me
Bn
1
1
3l
65
90
i-Pr
Me
3m
a Reaction conditions: CuSO4·5H2O (5%), sodium ascorbate (30%), t-BuOH–H2O (1:1), r.t., 2 h.
b Reaction conditions: CuSO4·5H2O (10%), sodium ascorbate (40%), CH2Cl2–H2O (10:1), 40 °C, 3 h.
c Isolated yield after purification by column chromatography.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 130–136

132
N. V. Sokolova et al.
PAPER
13C NMR (100 MHz, CDCl3): d = 17.5, 28.3, 42.2, 45.3, 45.8, 47.9,
F3C
CO2Me
OH
2
Bn
R2
N
O
N
N
N
48.0, 49.5, 49.8, 54.3, 55.4, 55.5, 75.1 (q, JC–F = 31.7 Hz), 79.7,
79.8, 98.9, 99.0, 104.2, 104.3, 115.1, 115.2, 122.7 (q, 1JC–F = 283.5
Hz, CF3), 125.2, 130.8, 130.9, 141.9, 142.0, 156.2, 156.3, 158.6,
161.3, 161.4, 167.8, 167.9, 168.6, 168.7, 170.7, 170.8.
R1
N
N
H
H
O
19F NMR (282 MHz, CDCl3): d = 2.45 and 2.51 (both s, 3 F, CF3).
3i R1 = Boc, R2 = DMB
Anal. Calcd for C27H37F3N6O9: C, 50.15; H, 5.77; N, 13.00. Found:
C, 50.29; H, 5.81; N, 12.79.
TFA
reflux, 2 h
N-(tert-Butoxycarbonyl)-L-phenylalanyl-N2-(2,4-dimethoxy-
benzyl)-2-methyl-N1-[(1RS)-1-methyl-2-{4-[2,2,2-trifluoro-1-
hydroxy-1-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-1-yl}eth-
yl]alaninamide (3b)
4 R1 = R2 = H 65%
Scheme 1 Deprotection of the conjugate 3i
Mixture of diastereomers (~1:1). Yield: 635 mg (83%); white solid;
25
mp 93–95 °C; [a]D –14.8 (c 1.00, CHCl3); Rf = 0.2 (hexanes–
romethyl-a-hydroxy acids via the copper(I)-catalyzed
Huisgen cycloaddition reaction. In all cases, the target a-
trifluoromethyl-a-hydroxy acid containing peptides were
obtained in high yields. After straightforward deprotec-
tion, the fluorinated a-hydroxy acid–peptide conjugates
may find important applications in biochemistry and me-
dicinal chemistry. Further extension of this approach is
ongoing in our group.
acetone, 1.5:1).
1H NMR (600 MHz, DMSO-d6, 70 °C): d = 1.12 (d, J = 6.8 Hz, 3
H, CH3), 1.17 and 1.18 (both s, 6 H, 2 CH3), 1.27 (s, 9 H, 3 CH3-
Boc), 2.67 (br s, 1 H), 2.89 (dd, JAB = 13.9 Hz, J = 3.3 Hz, 1 H,
CH2Ph), 3.77 (s, 3 H, OCH3), 3.79 and 3.81 (both s, 6 H, 2 OCH3),
4.26 (m, 1 H), 4.33 (m, 1 H), 4.41 (d, JAB = 18.2 Hz, 1 H, CH2-tria-
zole), 4.44–4.52 (m, 1 H, CH + 1 H, CH2-triazole), 4.74 (br s, 1 H,
CH), 6.49 (d, J = 8.3 Hz, 1 H, CHAr), 6.59 (d, J = 2.0 Hz, 1 H,
CHAr), 6.91 (br s, 1 H, CHAr), 7.00 (d, J = 7.0 Hz, 2 H, CHAr), 7.15–
7.19 (m, 3 H, CHAr), 7.41 (br s, 1 H, NH), 7.55 (s, 1 H, NH), 8.19
(s, 1 H, CH-triazole).
13C NMR (100 MHz, CDCl3): d = 17.2, 17.4, 22.9, 24.1, 24.8, 27.6,
28.2, 39.3, 39.8, 42.2, 42.8, 45.8, 47.2, 53.1, 53.3, 55.2, 55.3, 55.4,
62.8, 63.2, 75.0 (q, 2JC–F = 31.3 Hz), 79.6, 79.8, 98.5, 98.6, 104.2,
104.3, 118.1, 118.2, 122.8 (q, 1JC–F = 285.6 Hz, CF3), 125.3, 126.8,
127.8, 128.4, 129.6, 136.6, 141.4, 154.9, 155.3, 157.0, 160.2, 167.7,
168.0, 173.4, 174.0, 174.7, 175.0.
All solvents used in reactions were freshly distilled from appropri-
ate drying agents before use. All other reagents were recrystallized
or distilled as necessary. Reactions were performed under an atmo-
sphere of dry nitrogen. Analytical TLC was performed with Merck
silica gel 60 F254 plates. Visualization was accomplished with UV
light and by spraying with Ce(SO4)2 soln in 5% H2SO4 or aq
KMnO4. Flash chromatography was carried out using Merck silica
gel 60 (230–400 mesh ASTM). Melting points were determined
with an Electrothermal IA9100 digital melting point apparatus and
are uncorrected. Optical rotations were measured on a Perkin-Elmer
341 polarimeter at 589 nm. High-resolution mass spectra (HRMS)
were measured on a MicrOTOF II (Bruker Daltonics) spectrometer.
NMR spectra were recorded on a Bruker AV-400 or AV-600 spec-
19F NMR (282 MHz, CDCl3): d = 0.49 and 0.56 (both s, 3 F, CF3).
Anal. Calcd for C36H47F3N6O9: C, 56.54; H, 6.19; N, 10.99. Found:
C, 56.37; H, 6.17; N, 10.95.
N-(tert-Butoxycarbonyl)-L-isoleucyl-N1-[(1RS)-1-benzyl-2-{4-
[2,2,2-trifluoro-1-hydroxy-1-(methoxycarbonyl)ethyl]-1H-
1,2,3-triazol-1-yl}ethyl]-N2-(4-methoxybenzyl)-2-methyl-
alaninamide (3c)
1
trometer operating at 400 or 600 MHz respectively (TMS) for H,
100 or 151 MHz for 13C, and 188 or 282 MHz for 19F (TFA).
Conjugates 3a–e; General Procedure
Mixture of diastereomers (~1:1). Yield: 613 mg (79%); white solid;
To a soln of the corresponding acetylene 2 (1.0 mmol) in t-BuOH–
H2O (1:1, 3 mL) were added a soln of the corresponding azido pep-
tide 1 (1.0 mmol) in t-BuOH–H2O (1:1, 2 mL), sodium ascorbate
(0.3 mmol) and 0.5 M CuSO4·5H2O in H2O (0.05 mmol). The reac-
tion mixture was stirred at r.t. for 2 h. After evaporation of the sol-
vent under reduced pressure, H2O (10 mL) was added to the residue
and the aqueous layer was extracted with EtOAc (2 × 10 mL). The
organic layer was dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by column chromatography
(hexanes–acetone) to afford 3a–e.
25
mp 76–78 °C; [a]D –18.1 (c 0.90, CHCl3); Rf = 0.25 (hexanes–
acetone, 1.5:1).
1H NMR (600 MHz, DMSO-d6, 70 °C): d = 0.68–0.74 (m, 6 H, 2
CH3), 0.86 (br s, 1 H, CH2), 1.00 and 1.03 (both s, 3 H, CH3), 1.20–
1.23 (m, 3 H, CH3 + 1 H, CH2), 1.34 (s, 9 H, 3 CH3-Boc), 1.73 (br
s, 1 H, CH), 2.69–2.72 (m, 1 H, CH2), 2.96–2.97 (m, 1 H, CH2), 3.73
and 3.74 (both s, 6 H, 2 OCH3), 3.98 (br s, 1 H, CH), 4.31–4.36 (m,
1 H, CH), 4.45 (m, 2 H, CH2), 4.55 (d, JAB = 17.2 Hz, 1 H, CH2-tri-
azole), 4.76 (d, JAB = 16.3 Hz, 1 H, CH2-triazole), 6.75–6.80 (m, 1
H, NH), 6.88 (d, J = 8.2 Hz, 2 H, CHAr), 7.18–7.24 (m, 2 H, CHAr),
7.31 (t, J = 5.3 Hz, 3 H, CHAr), 7.40 (t, J = 7.3 Hz, 2 H, CHAr), 7.81
and 7.83 (both s, 1 H, NH), 8.26 and 8.27 (both s, 1 H, CH-triazole).
13C NMR (100 MHz, CDCl3): d = 10.9, 11.2, 15.4, 15.6, 23.7, 24.0,
24.4, 24.9, 28.3, 37.0, 37.3, 37.8, 38.4, 47.0, 47.5, 51.1, 51.5, 51.6,
54.3, 54.5, 55.3, 55.6, 55.7, 62.9, 63.4, 75.0 (q, JC–F = 32.1 Hz),
79.6, 79.8, 114.2, 122.7 (q, JC–F = 285.6 Hz, CF3), 125.7, 126.7,
N-(tert-Butoxycarbonyl)glycyl-N2-(2,4-dimethoxybenzyl)-N1-
[(1RS)-1-methyl-2-{4-[2,2,2-trifluoro-1-hydroxy-1-(methoxy-
carbonyl)ethyl]-1H-1,2,3-triazol-1-yl}ethyl]glycinamide (3a)
Mixture of diastereomers (~1:1). Yield: 433 mg (67%); white solid;
mp 59–61 °C; Rf = 0.3 (hexanes–acetone, 1.5:1).
1H NMR (600 MHz, DMSO-d6, 70 °C): d = 1.06 (d, J = 6.2 Hz, 3
H, CH3), 1.40 (br s, 9 H, 3 CH3-Boc), 3.77 (s, 3 H, OCH3), 3.80 (s,
6 H, 2 OCH3), 3.80–3.99 (m, 4 H, 2 CH2), 4.22 (m, 1 H, CH), 4.38
(m, 2 H, CH2-triazole), 4.42 (m, 2 H, CH2-Ar), 6.39–6.59 (m, 3 H,
CHAr), 7.04 (br s, 1 H, NH), 7.57 (br s, 1 H, NH), 8.17 (s, 1 H, CH-
triazole).
2
1
127.0, 127.7, 127.8, 128.8, 129.2, 129.3, 129.9, 130.1, 136.7, 136.8,
141.2, 155.5, 155.9, 159.0, 167.7, 168.1, 173.8, 174.6, 175.0.
19F NMR (282 MHz, DMSO-d6): d = 2.45 and 2.55 (both s, 3 F, CF3).
Anal. Calcd for C38H51F3N6O8: C, 58.75; H, 6.62; N, 10.82. Found:
C, 58.33; H, 6.70; N, 10.51.
Synthesis 2012, 44, 130–136
© Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Peptide Conjugates via Click Chemistry
133
N-(tert-Butoxycarbonyl)-L-valyl-N1-[(1RS)-1-benzyl-2-{4-
[2,2,2-trifluoro-1-hydroxy-1-(methoxycarbonyl)ethyl]-1H-
1,2,3-triazol-1-yl}ethyl]-N2-(4-methoxybenzyl)-2-methyl-
alaninamide (3d)
N-(tert-Butoxycarbonyl)-L-alanyl-N2-(2,4-dimethoxybenzyl)-
N1-[(1RS)-2-methyl-1-({4-[2,2,2-trifluoro-1-hydroxy-1-(meth-
oxycarbonyl)ethyl]-1H-1,2,3-triazol-1-yl}methyl)propyl]glycin-
amide (3f)
Mixture of diastereomers (~1:1). Yield: 603 mg (79%); white solid;
Mixture of diastereomers (1:1), mixture of rotamers (3:1). Yield:
25
25
mp 75–77 °C; [a]D –15.5 (c 0.50, CHCl3); Rf = 0.2 (hexanes–
600 mg (87%); white solid; mp 73–74 °C; [a]D –16.4 (c 1.00,
acetone, 1.5:1).
CH2Cl2); Rf = 0.8 (EtOAc).
1H NMR (600 MHz, CDCl3): d = 0.86 (dd, J = 10.5, 6.8 Hz, 6 H, 2
CH3), 1.21 and 1.32 (both s, 6 H, 2 CH3), 1.44 (s, 9 H, 3 CH3-Boc),
1.93–1.97 (m, 1 H, CH), 2.86–3.06 (m, 2 H, CH2), 3.81 (s, 3 H,
OCH3), 3.97 and 3.99 (both s, 3 H, OCH3), 4.22 (m, 1 H, CH2-tria-
zole), 4.41 (m, 1 H, CH2-triazole), 4.55–4.67 (m, 3 H, CH2, CH),
4.79 (m, 1 H, CH), 5.19 (d, J = 8.8 Hz, 1 H, NH), 5.41 (d, J = 8.0
Hz, 1 H, NH), 5.80 (s, 1 H, OH), 6.89 (m, 2 H, CHAr), 7.20–7.32 (m,
7 H, CHAr), 8.14 and 8.18 (both br s, 1 H, CH-triazole).
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 0.83–0.94 (m, 6 H, 2
CH3), 1.07–1.21 (m, 3 H, CH3), 1.39 (br s, 9 H, 3 CH3-Boc), 1.65–
1.80 (m, 1 H, CH(CH3)2), 3.65–3.83 (m, 9 H, 3 OCH3 + 1 H), 3.98–
4.12 (m, 2 H), 4.19–4.45 (m, 3 H), 4.48–4.73 (m, 2 H), 6.24–6.58
(m, 2 H, CHAr + 1 H, NH), 6.90–7.07 (m, 1 H, CHAr), 7.30–7.43 (m,
1 H, NH), 8.12 (br s, 1 H, CH-triazole).
13C NMR (100 MHz, CDCl3): d = 17.9, 18.4, 19.3, 19.6, 28.3, 29.4,
29.7, 46.0, 46.4, 47.2, 48.2, 48.5, 49.8, 50.2, 50.6, 51.0, 51.4, 54.1,
13C NMR (100 MHz, CDCl3): d = 17.3, 17.8, 19.5, 19.6, 23.8, 24.0,
54.3, 54.4, 54.9, 55.2, 55.3, 55.4, 75.1 (q, JC–F = 31.1 Hz), 79.8,
2
24.7, 28.3, 31.6, 32.9, 37.0, 37.3, 47.1, 47.5, 51.1, 51.5, 52.4, 54.3,
80.0, 80.5, 98.3, 98.8, 104.1, 104.5, 115.3, 115.6, 116.6, 123.5 (q,
1JC–F = 286.2 Hz, CF3), 124.1, 124.6, 125.1, 130.2, 130.5, 131.1,
141.6, 141.7, 158.5, 158.6, 161.1, 161.2, 167.7, 167.9, 168.2, 168.9,
173.2, 173.3, 174.6, 174.7.
19F NMR (188 MHz, CDCl3): d = 0.00, 0.16, 0.58 and 0.74 (all s, 3
F, CF3).
2
54.5, 55.3, 56.3, 56.6, 62.9, 63.3, 75.1 (q, JC–F = 27.1 Hz), 79.6,
79.7, 114.3, 122.7 (q, 1JC–F = 285.6 Hz, CF3), 126.2, 127.0, 127.6,
127.7, 128.8, 129.2, 129.3, 129.7, 130.0, 136.6, 136.8, 141.3, 155.6,
155.9, 159.0, 167.8, 168.0, 173.6, 174.3, 174.6, 174.9.
19F NMR (282 MHz, CDCl3): d = 0.53 and 0.58 (both s, 3 F, CF3).
Anal. Calcd for C37H49F3N6O8: C, 58.26; H, 6.47; N, 11.02. Found:
C, 58.19; H, 6.41; N, 10.69.
HRMS (ESI): m/z [M + Na]+ calcd for C30H43F3N6O9: 711.2941;
found: 711.2942.
N-(tert-Butoxycarbonyl)-L-valyl-N2-(4-methoxybenzyl)-2-
methyl-N1-[(1RS,2S)-2-methyl-1-({4-[2,2,2-trifluoro-1-hy-
droxy-1-(methoxycarbonyl)ethyl]-1H-1,2,3-triazol-1-yl}meth-
yl)butyl]alaninamide (3e)
1-(tert-Butoxycarbonyl)-L-prolyl-N1-[(1RS)-1-benzyl-2-{4-
[2,2,2-trifluoro-1-hydroxy-1-(methoxycarbonyl)ethyl]-1H-
1,2,3-triazol-1-yl}ethyl]-N2-(4-methoxybenzyl)-2-methylalanin-
amide (3g)
Mixture of diastereomers (~1:1). Yield: 576 mg (79%); white solid;
Mixture of diastereomers (~1:1), mixture of rotamers (~3:1). Yield:
25
25
mp 71–73 °C; [a]D –27.5 (c 5.70, CHCl3); Rf = 0.25 (hexanes–
676 mg (89%); white solid; mp 87–88 °C; [a]D +25.6 (c 1.00,
acetone, 1.5:1).
CH2Cl2); Rf = 0.8 (EtOAc).
1H NMR (600 MHz, DMSO-d6, 70 °C): d = 0.74–0.76 (m, 6 H, 2
CH3), 0.88 (dt, J = 7.3, 2.2 Hz, 3 H, CH3), 0.96 (d, J = 6.8 Hz, 3 H,
CH3), 1.08 and 1.11 (both s, 3 H, CH3), 1.20–1.27 (m, 1 H, CH),
1.29 (br s, 3 H, CH3), 1.36 (s, 9 H, 3 CH3-Boc), 1.54–1.58 (m, 1 H,
CH2), 1.61–1.64 (m, 1 H, CH2), 1.91–1.96 (m, 1 H, CH), 3.75 and
3.76 (both s, 6 H, 2 OCH3), 4.05–4.08 (m, 1 H, CH2), 4.10–4.16 (m,
1 H, CH2), 4.46–4.54 (m, 2 H, 2 CH), 4.59 (d, JAB = 17.6 Hz, 1 H,
CH2-triazole), 4.71 (d, JAB = 18.5 Hz, 1 H, CH2-triazole), 6.19 (br s,
1 H, OH), 6.68 (d, J = 8.6 Hz, 1 H, NH), 6.91 (d, J = 7.3 Hz, 2 H,
CHAr), 7.37 (d, J = 7.5 Hz, 2 H, CHAr), 7.48 (br s, 1 H, NH-Boc),
8.17 (s, 1 H, CH-triazole).
13C NMR (100 MHz, CDCl3): d = 10.9, 15.5, 15.6, 17.4, 17.7, 19.4,
19.5, 23.5, 23.6, 24.5, 25.0, 28.3, 32.0, 32.2, 35.8, 35.9, 47.0, 47.3,
50.9, 51.0, 53.4, 54.3, 54.4, 55.3, 56.2, 56.4, 63.0, 63.3, 74.9 (q,
2JC–F = 31.5 Hz), 79.5, 79.6, 114.3, 122.7 (q, 1JC–F = 285.8 Hz, CF3),
124.9, 125.4, 127.7, 127.8, 129.9, 130.0, 141.3, 141.4, 155.4, 155.7,
159.0, 167.7, 167.9, 173.4, 173.9, 174.4, 174.5.
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 1.18–1.47 (m, 6 H, 2
CH3 + 9 H, 3 CH3-Boc), 1.62–2.00 (m, 4 H, 2 CH2-proline), 2.70–
2.79 (m, 1 H, CH2Ph), 2.90–2.99 (m, 1 H, CH2Ph), 3.25–3.40 (m, 2
H, CH2-proline), 3.77 (s, 6 H, 2 OCH3), 4.32–4.64 (m, 4 H, 2 CH2
+ 2 H, 2 CH), 6.87–7.01 (m, 2 H, CHAr + 1 H, NH), 7.18–7.32 (m,
5 H, CHAr), 7.44–7.51 (m, 2 H, CHAr), 8.19 (br s, 1 H, CH-triazole).
13C NMR (100 MHz, CDCl3): d = 24.0, 24.4, 24.5, 28.5, 30.7, 30.8,
37.2, 37.6, 47.2, 47.3, 47.7, 48.0, 51.2, 51.4, 52.0, 53.9, 54.2, 55.3,
2
57.2, 57.4, 63.5, 63.7, 74.8 (q, JC–F = 30.7 Hz), 79.8, 79.9, 80.1,
114.2, 114.3, 122.6 (q, 1JC–F = 285.1 Hz, CF3), 124.8, 125.2, 126.8,
127.0, 127.3, 128.6, 128.7, 129.2, 130.3, 130.4, 137.1, 137.3, 141.2,
154.8, 158.8, 167.4, 167.6, 174.9, 175.1, 175.2.
19F NMR (188 MHz, CDCl3): d = 0.43, 0.56, 0.62 and 0.79 (all s, 3
F, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C37H47F3N6O8: 783.3305;
found: 783.3300.
19F NMR (282 MHz, DMSO-d6): d = 2.48 and 2.55 (both s, 3 F,
N-(tert-Butoxycarbonyl)-L-valyl-N2-(4-methoxybenzyl)-2-
methyl-N1-[(1RS,2S)-2-methyl-1-({4-[3,3,3-trifluoro-2-hy-
droxy-2-(methoxycarbonyl)propyl]-1H-1,2,3-triazol-1-
yl}methyl)butyl]alaninamide (3h)
CF3).
Anal. Calcd for C34H51F3N6O8: C, 56.03; H, 7.05; N, 11.53. Found:
C, 56.03; H, 7.03; N, 11.34.
Mixture of diastereomers (~1:1). Yield: 675 mg (91%); white solid;
20
Conjugates 3f–m; General Procedure
mp 70–71 °C; [a]D –11.6 (c 1.00, MeOH); Rf = 0.35 (hexanes–
The corresponding azido peptide 1 (1 mmol), CuSO4·5H2O (0.1
mmol) in H2O (0.5 mL), and sodium ascorbate (0.4 mmol) in H2O
(0.5 mL) were added successively to a soln of the corresponding
acetylene 2 (1 mmol) in CH2Cl2 (10 mL). The reaction mixture was
stirred at 40 °C for 3 h. The solvent was removed under reduced
pressure and the residue was purified by column chromatography
(hexanes–EtOAc, 1:1; then EtOAc) to afford 3f–m.
EtOAc, 1:1).
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 0.73–0.79 (m, 6 H, 2
CH3), 0.87 (t, J = 7.2 Hz, 3 H, CH3), 0.94 (d, J = 6.8 Hz, 3 H, CH3),
1.19 (s, 3 H, CH3), 1.27–1.36 (m, 3 H, CH3 + 1 H, CH + 9 H, 3 CH3-
Boc), 1.47–1.60 (m, 2 H, CH2), 1.90–2.00 (m, 1 H, CH(CH3)2), 3.14
(d, JAB = 14.2 Hz, 1 H, CH2), 3.32 (d, JAB = 14.2 Hz, 1 H, CH2), 3.69
and 3.72 (both s, 3 H, OCH3), 3.74 and 3.76 (both s, 3 H, OCH3),
4.04–4.13 (m, 2 H), 4.36–4.46 (m, 2 H), 4.61 (d, JAB = 18.2 Hz, 1
H, CH2), 4.70 (d, JAB = 18.2 Hz, 1 H, CH2), 5.95–6.12 (m, 1 H, NH),
© Thieme Stuttgart · New York
Synthesis 2012, 44, 130–136

134
N. V. Sokolova et al.
PAPER
6.53–6.60 (m, 1 H, NH), 6.91 (d, J = 8.4 Hz, 2 H, CHAr), 7.36 (d,
J = 8.4 Hz, 2 H, CHAr), 7.75 and 7.78 (both s, 1 H, CH-triazole).
N-(tert-Butoxycarbonyl)-L-isoleucyl-N1-[(1RS)-1-benzyl-2-{4-
[3,3,3-trifluoro-2-hydroxy-2-(methoxycarbonyl)propyl]-1H-
1,2,3-triazol-1-yl}ethyl]-N2-(4-methoxybenzyl)-2-methyl-
alaninamide (3k)
13C NMR (100 MHz, CDCl3): d = 10.9, 11.0, 15.5, 17.2, 17.3, 19.5,
24.0, 25.0, 25.1, 28.2, 29.2, 31.9, 32.0, 35.8, 35.9, 46.9, 50.8, 51.0,
Mixture of diastereomers (1:1). Yield: 758 mg (96%); white solid;
2
53.3, 54.0, 55.2, 56.2, 63.0, 63.1, 75.1 (q, JC–F = 31.3 Hz), 79.4,
25
mp 71–72 °C; [a]D –13.1 (c 1.50, MeOH); Rf = 0.4 (hexanes–
114.3, 123.2 (q, 1JC–F = 286.9 Hz, CF3), 124.8, 127.7, 130.0, 139.6,
EtOAc, 1:1).
155.5, 159.0, 169.1, 173.5, 174.4.
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 0.70–0.80 (m, 6 H, 2
CH3), 0.91–1.03 (m, 1 H), 1.20 and 1.21 (both s, 6 H, 2 CH3), 1.34
(br s, 9 H, 3 CH3-Boc), 1.39–1.50 (m, 1 H), 1.71–1.81 (m, 1 H),
2.64–2.73 (m, 1 H, CH2Ph), 2.88–2.94 (m, 1 H, CH2Ph), 3.16 (d,
JAB = 13.9 Hz, 1 H, CH2), 3.35 (d, JAB = 13.9 Hz, 1 H, CH2), 3.72
(s, 3 H, OCH3), 3.75 and 3.76 (both s, 3 H, OCH3), 4.07–4.17 (m, 1
H), 4.30–4.47 (m, 3 H), 4.58 (d, JAB = 17.9 Hz, 1 H, CH2), 4.72 (d,
JAB = 17.9 Hz, 1 H, CH2), 6.58–6.66 (m, 1 H, NH), 6.84–6.91 (m, 2
H, CHAr + 1 H, NH), 7.18–7.31 (m, 5 H, CHAr), 7.36 (d, J = 8.1 Hz,
2 H, CHAr), 7.82 (s, 1 H, CH-triazole).
19F NMR (188 MHz, CDCl3): d = –0.49 and –0.34 (both s, 3 F,
CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C35H53F3N6O8: 765.3775;
found: 765.3777.
N-(tert-Butoxycarbonyl)-L-phenylalanyl-N2-(2,4-dimethoxy-
benzyl)-2-methyl-N1-[(1RS)-1-methyl-2-{4-[3,3,3-trifluoro-2-
hydroxy-2-(methoxycarbonyl)propyl]-1H-1,2,3-triazol-1-
yl}ethyl]alaninamide (3i)
Mixture of diastereomers (~1:1). Yield: 740 mg (95%); white solid;
13C NMR (100 MHz, CDCl3): d = 11.0, 11.1, 15.5, 15.6, 23.3, 23.7,
mp 77–78 °C; [a]D25 –4.3 (c 1.00, MeOH); Rf = 0.55 (EtOAc).
23.9, 24.1, 24.5, 28.2, 29.4, 29.6, 37.0, 37.4, 38.2, 46.9, 47.0, 50.9,
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 1.06 (d, J = 6.6 Hz, 3
H, CH3), 1.14–1.32 (m, 6 H, 2 CH3 + 9 H, 3 CH3-Boc), 2.63–2.72
(m, 1 H, CH2Ph), 2.88–2.96 (m, 1 H, CH2Ph), 3.18 (d, JAB = 14.5
Hz, 1 H, CH2), 3.36 (d, JAB = 14.5 Hz, 1 H, CH2), 3.70 and 3.73
(both s, 3 H, OCH3), 3.75 and 3.77 (both s, 3 H, OCH3), 3.79 and
3.81 (both s, 3 H, OCH3), 4.14–4.25 (m, 1 H), 4.31–4.46 (m, 4 H),
4.74 (d, JAB = 18.7 Hz, 1 H), 6.49 (d, J = 8.3 Hz, 1 H, CHAr), 6.55–
6.64 (m, 1 H, CHAr + 1 H, NH), 6.76–6.84 (m, 1 H, NH), 7.03 (d,
J = 6.6 Hz, 2 H, CHAr), 7.12–7.22 (m, 3 H, CHAr), 7.38 (d, J = 8.3
Hz, 1 H, CHAr), 7.78 and 7.80 (both s, 1 H, CH-triazole).
2
51.3, 51.6, 54.0, 54.1, 55.2, 55.5, 55.6, 62.9, 75.0 (q, JC–F = 32.1
1
Hz), 79.4, 79.5, 114.1, 114.2, 123.2 (q, JC–F = 286.2 Hz, CF3),
125.1, 126.7, 126.9, 127.7, 128.7, 129.2, 130.0, 130.1, 136.7, 137.0,
139.2, 139.6, 155.5, 155.6, 158.9, 169.0, 169.2, 174.0, 174.2, 174.5,
174.7.
19F NMR (188 MHz, CDCl3): d = –0.44 and –0.40 (both s, 3 F,
CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C39H53F3N6O8: 813.3775;
found: 813.3786.
13C NMR (100 MHz, CDCl3): d = 17.4, 17.5, 23.2, 24.1, 28.2, 29.4,
39.7, 42.3, 42.5, 45.7, 53.0, 53.5, 53.7, 55.2, 55.3, 62.8, 62.9, 74.9
(q, 2JC–F = 31.7 Hz), 79.5, 79.6, 98.6, 104.2, 104.3, 118.2, 123.2 (q,
1JC–F = 286.2 Hz, CF3), 124.9, 126.7, 128.4, 129.6, 136.6, 139.7,
154.9, 155.0, 157.1, 160.2, 169.2, 169.3, 173.3, 173.5, 174.6, 174.7.
19F NMR (188 MHz, CDCl3): d = –0.53 and –0.46 (both s, 3 F,
CF3).
N-(tert-Butoxycarbonyl)glycyl-N2-(2,4-dimethoxybenzyl)-N1-
[(1RS)-1-methyl-2-{4-[3,3,3-trifluoro-2-hydroxy-2-(methoxy-
carbonyl)propyl]-1H-1,2,3-triazol-1-yl}ethyl]glycinamide (3l)
Mixture of diastereomers (~1:1), mixture of rotamers (~4:1). Yield:
429 mg (65%); white solid; mp 53–54 °C; [a]D –2.3 (c 2.00,
MeOH); Rf = 0.4 (EtOAc).
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 0.98–1.06 (m, 3 H,
CH3), 1.40 (s, 9 H, 3 CH3-Boc), 3.17 (d, JAB = 14.5 Hz, 1 H, CH2),
3.36 (d, JAB = 14.5 Hz, 1 H, CH2), 3.72–3.80 (m, 9 H, 3 OCH3 + 2
H, CH2), 3.91–4.01 (m, 1 H), 4.03–4.08 (m, 1 H), 4.11–4.24 (m, 1
H), 4.31–4.37 (m, 4 H), 6.24–6.38 (m, 1 H, NH), 6.43–6.51 (m, 1 H,
NH), 6.54–6.65 (m, 2 H, CHAr), 7.04 (d, J = 8.1 Hz, 1 H, CHAr),
7.76 (br s, 1 H, CH-triazole).
20
HRMS (ESI): m/z [M + H]+ calcd for C37H49F3N6O9: 779.3591;
found: 779.3613.
N-(tert-Butoxycarbonyl)-L-alanyl-N2-(2,4-dimethoxybenzyl)-
N1-[(1RS)-2-methyl-1-({4-[3,3,3-trifluoro-2-hydroxy-2-(meth-
oxycarbonyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)propyl]gly-
cinamide (3j)
13C NMR (100 MHz, CDCl3): d = 17.2, 17.5, 28.3, 29.5, 29.7, 42.2,
Mixture of diastereomers (1:1), mixture of rotamers (3:1). Yield:
45.2, 45.7, 47.9, 49.6, 49.9, 53.6, 53.8, 54.0, 54.1, 55.3, 55.4, 74.9
25
527 mg (75%); white solid; mp 67–68 °C; [a]D –29.5 (c 1.00,
2
(q, JC–F = 31.1 Hz), 79.6, 98.9, 104.1, 115.0, 115.1, 122.8 (q,
MeOH); Rf = 0.6 (EtOAc).
1JC–F = 286.5 Hz, CF3), 124.4, 124.7, 130.6, 130.7, 140.0, 140.1,
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 0.84–0.95 (m, 6 H, 2
CH3), 1.10–1.20 (m, 3 H, CH3), 1.39 (br s, 9 H, 3 CH3-Boc), 1.64–
1.77 (m, 1 H, CH(CH3)2), 3.16 (d, JAB = 14.2 Hz, 1 H, CH2), 3.35
(d, JAB = 14.2 Hz, 1 H, CH2), 3.61–3.84 (m, 9 H, 3 OCH3 + 2 H,
CH2), 3.94–4.35 (m, 4 H), 4.38–4.70 (m, 2 H), 6.42–6.56 (m, 2 H,
CHAr + 1 H, NH), 6.94–7.08 (m, 1 H, CHAr), 7.20–7.35 (m, 1 H,
NH), 7.74 (br s, 1 H, CH-triazole).
13C NMR (100 MHz, CDCl3): d = 16.5, 16.8, 18.5, 18.6, 19.4, 19.5,
28.4, 29.2–30.4 (m), 46.4, 47.3, 48.1, 48.3, 49.9, 50.2, 50.4, 51.3,
51.4, 51.6, 53.7, 53.9, 54.1, 54.8, 54.9, 55.1, 55.3, 55.4, 55.5, 75.0
(q, 2JC–F = 31.5 Hz), 79.7, 80.2, 80.5, 98.3, 98.8, 98.9, 104.2, 104.6,
115.5, 115.6, 116.7, 116.9, 123.3 (q, 1JC–F = 286.9 Hz, CF3), 124.0,
124.3, 124.6, 125.0, 130.2, 130.3, 131.1, 139.8, 158.6, 158.7, 161.2,
168.4, 169.0, 169.2, 173.5, 173.6, 174.5, 175.0.
156.1, 156.2, 158.6, 161.3, 166.9, 168.5, 168.6, 170.4, 170.5.
19F NMR (188 MHz, CDCl3): d = –0.57, –0.46, –0.24 and –0.13 (all
s, 3 F, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C28H39F3N6O9: 683.2628;
found: 683.2633.
N-(tert-Butoxycarbonyl)-L-valyl-N1-[(1RS)-1-benzyl-2-{4-
[3,3,3-trifluoro-2-hydroxy-2-(methoxycarbonyl)propyl]-1H-
1,2,3-triazol-1-yl}ethyl)-N2-(4-methoxybenzyl)-2-methylalanin-
amide (3m)
Mixture of diastereomers (1:1). Yield: 700 mg (90%); white solid;
25
mp 74–75 °C; [a]D –27.1 (c 1.00, CH2Cl2); Rf = 0.35 (hexanes–
EtOAc, 1:1).
1H NMR (400 MHz, DMSO-d6, 80 °C): d = 0.80 (d, J = 6.1 Hz, 6
H, 2 CH3), 1.19 (s, 3 H, CH3), 1.20 (s, 3 H, CH3), 1.35 (br s, 9 H, 3
CH3-Boc), 1.94–2.03 (m, 1 H, CH(CH3)2), 2.64–2.73 (m, 1 H,
CH2Ph), 2.87–2.95 (m, 1 H, CH2Ph), 3.16 (d, JAB = 14.7 Hz, 1 H,
CH2), 3.35 (d, JAB = 14.7 Hz, 1 H, CH2), 3.72 (s, 3 H, OCH3), 3.75
19F NMR (188 MHz, CDCl3): d = –0.62, –0.61, –0.36 and –0.10 (all
s, 3 F, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C31H45F3N6O9: 725.3098;
found: 725.3111.
Synthesis 2012, 44, 130–136
© Thieme Stuttgart · New York

PAPER
Synthesis of Fluorinated Peptide Conjugates via Click Chemistry
135
and 3.76 (both s, 3 H, OCH3), 4.08–4.16 (m, 1 H), 4.30–4.46 (m, 3
H), 4.57–4.70 (m, 2 H, CH2), 6.56–6.64 (m, 1 H, NH), 6.84–6.92
(m, 2 H, CHAr + 1 H, NH), 7.18–7.30 (m, 5 H, CHAr), 7.35 (d,
J = 8.3 Hz, 2 H, CHAr), 7.82 and 7.83 (both s, 1 H, CH-triazole).
(6) (a) Organofluorine Compounds in Medicinal Chemistry and
Biomedical Applications; Filler, R.; Kobayashi, Y.;
Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993.
(b) Biomedical Frontiers of Fluorine Chemistry, ACS
Symposium Series 639; Ojima, I.; McCarthy, J. R.; Welch,
J. T., Eds.; American Chemical Society: Washington DC,
1996. (c) Fluorine-Containing Amino Acids: Synthesis and
Properties; Kukhar, V. P.; Soloshonok, V. A., Eds.; Wiley:
New York, 1995.
13C NMR (100 MHz, CDCl3): d = 17.2, 17.5, 19.6, 19.7, 23.2, 23.7,
24.2, 24.6, 28.2, 29.3, 29.6, 31.8, 31.9, 36.9, 37.3, 46.9, 47.0, 51.0,
2
51.4, 51.6, 54.1, 54.2, 55.2, 56.3, 62.9, 74.9 (q, JC–F = 31.5 Hz),
1
79.4, 79.5, 114.2, 123.2 (q, JC–F = 286.2 Hz, CF3), 125.1, 125.7,
126.9, 127.7, 128.7, 128.8, 129.2, 136.7, 136.9, 139.3, 139.7, 155.6,
155.7, 158.9, 159.0, 169.0, 169.3, 173.7, 173.9, 174.5, 174.8.
19F NMR (188 MHz, CDCl3): d = –0.39 (s, 3 F, CF3).
HRMS (ESI): m/z [M + Na]+ calcd for C38H51F3N6O8: 799.3618;
found: 799.3619.
(7) (a) Nelson, D. W.; Owens, J.; Hiraldo, D. J. Org. Chem.
2001, 66, 2572. (b) Prakash, G. K. S.; Mandal, M.; Olah, G.
A. Angew. Chem. Int. Ed. 2001, 40, 589. (c) Bravo, P.;
Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron Lett.
1998, 39, 7771. (d) Xu, Y.; Dolbier, W. R. Jr. Tetrahedron
Lett. 1998, 39, 9151.
L-Phenylalanyl-2-methyl-N1-[(1S)-1-methyl-2-{4-[3,3,3-trifluo-
ro-2-hydroxy-2-(methoxycarbonyl)propyl]-1H-1,2,3-triazol-1-
yl}ethyl]alaninamide (4)
A soln of 3i (45 mg, 0.058 mmol) in TFA (0.8 mL, 10 mmol) was
refluxed for 2 h. The reaction mixture was diluted with CH2Cl2 (5
mL) and neutralized with sat. aq NaHCO3 until the violet color dis-
appeared. The layers were separated and the aqueous layer was ex-
tracted with CH2Cl2 (2 × 10 mL). The combined organic extract was
dried (Na2SO4) and concentrated. The residue was purified by col-
umn chromatography (MeCN–NH3, 90:1) to afford 4.
(8) (a) Corbett, J. W.; Ko, S. S.; Rodgers, J. M.; Gearhart, L. A.;
Magnus, N. A.; Bacheler, L. T.; Diamond, S.; Jeffrey, S.;
Klabe, R. M.; Cordova, B. C.; Garber, S.; Logue, K.;
Trainor, G. L.; Anderson, P. S.; Erickson-Viitanen, S. K.
J. Med. Chem. 2000, 43, 2019. (b) Sani, M.; Belotti, D.;
Giavazzi, R.; Panzeri, W.; Volonterio, A.; Zanda, M.
Tetrahedron Lett. 2004, 45, 1611. (c) Magueur, G.;
Crousse, B.; Charneau, S.; Grellier, P.; Bégué, J.-P.; Bonnet-
Delpon, D. J. Med. Chem. 2004, 47, 2694. (d) Betageri, R.;
Zhang, Y.; Zindell, R. M.; Kuzmich, D.; Kirrane, T. M.;
Bentzien, J.; Cardozo, M.; Capolino, A. J.; Fadra, T. N.;
Nelson, R. M.; Paw, Z.; Shih, D.-T.; Shih, C.-K.; Zuvela-
Jelaska, L.; Nabozny, G.; Thomson, D. S. Bioorg. Med.
Chem. Lett. 2005, 15, 4761. (e) Moseley, J. D.; Brown, D.;
Firkin, C. R.; Jenkin, S. L.; Patel, B.; Snape, E. W. Org.
Process Res. Dev. 2008, 12, 1044.
Mixture of diastereomers (~1:1). Yield: 20 mg (65%); white solid;
25
mp 61–62 °C; [a]D –1.2 (c 1.00, MeOH); Rf = 0.6 (MeCN–NH3,
9:1).
1H NMR (400 MHz, CDCl3): d = 1.04 and 1.15 (both d, J = 6.6 Hz,
3 H, CH3), 1.41, 1.43, 1.45, 1.49 (all s, 6 H, 2 CH3), 3.16–3.27 (m,
2 H, CH2Ph), 3.54–3.65 (m, 2 H, CH2), 3.79 and 3.81 (both s, 3 H,
OCH3), 3.84–3.92 (m, 1 H), 4.25–4.56 (m, 3 H), 6.89 and 7.00 (both
d, J = 7.4 Hz, 1 H, NH), 7.20–7.25 (m, 3 H, CHAr), 7.29–7.33 (m, 2
H, CHAr), 7.56 (s, 1 H, NH), 7.59 and 7.70 (both s, 1 H, CH-triaz-
ole).
(9) Böhm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
Müller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004,
5, 637.
(10) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch, B. Chem.
Soc. Rev. 2008, 37, 1727.
(11) (a) Pedersen, D. S.; Abell, A. Eur. J. Org. Chem. 2011,
2399. (b) Tron, G. C.; Pirali, T. P.; Billindton, R. A.;
Canonico, P. L.; Sorba, G.; Genazzani, A. A. Med. Res. Rev.
2008, 28, 278. (c) Holub, J. M.; Kirshenbaum, K. Chem.
Soc. Rev. 2010, 39, 1325. (d) Kappe, C. O.; Eycken, E. V.
Chem. Soc. Rev. 2010, 39, 1280.
(12) Artyushin, O. I.; Vorobyeva, D. V.; Vasilyeva, T. P.;
Osipov, S. N.; Röschenthaler, G.-V.; Odinets, I. L. Heteroat.
Chem. 2008, 19, 293.
13C NMR (100 MHz, CDCl3): d = 17.3, 17.7, 24.6, 24.7, 25.7, 25.9,
40.6, 40.7, 45.4, 45.7, 53.9, 54.1, 56.4, 56.9, 57.2, 64.5, 74.8 (q,
1
2JC–F = 30.5 Hz), 123.4 (q, JC–F = 283.9 Hz, CF3), 124.3, 125.0,
126.9, 128.7, 129.3, 137.6, 139.9, 140.2, 169.2, 174.1, 174.9, 175.4.
19F NMR (188 MHz, CDCl3): d = –0.64 and –0.40 (both s, 3 F,
CF3).
HRMS (ESI): m/z [M + H]+ calcd for C23H31F3N6O5: 529.2386;
found: 529.2383.
(13) (a) Tornøe, C. W.; Cristensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057. (b) Rostovtsev, V. V.; Green, L. G.; Fokin,
V. V.; Sharpless, K. B. Angew. Chem. 2002, 114, 2708.
(14) For reviews see, for example: (a) Moses, J. E.; Moorhouse,
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Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302.
(15) For recent examples, see: (a) Vecchi, A.; Chambery, A.;
Chiappe, C.; Marra, A.; Dondoni, A. Synthesis 2010, 2043.
(b) Mishra, A.; Hutait, S.; Bhowmik, S.; Rastogi, N.; Roy,
R.; Batra, S. Synthesis 2010, 2731. (c) Fletcher, J. T.;
Keeney, M. E.; Walz, S. E. Synthesis 2010, 3339. (d) Yan,
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H.; Seela, F. J. Org. Chem. 2010, 75, 8693. (f) Thorwirth,
R.; Stolle, A.; Ondruschka, B.; Wild, A.; Schubert, U. S.
Chem. Commun. 2011, 47, 4370.
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