Synthesis of C -Ribosyl-1,2,3-triazolyl Carboxamides

Article abstract of DOI:10.1055/s-0036-1588409

Because of the emergence of new viruses, the need for new antiviral broad-spectrum compounds remains important. In this context, herein the synthesis of C-nucleosides, structurally close to ribavirin, a nucleoside presenting various biological activities and used until now particularly for its broad-spectrum antiviral properties, is reported. The compounds were designed in order to increase their stability and the number of hydrogen bond donor or acceptor in comparison to ribavirin, and to investigate the role of the carboxamide group on the biological activity. The efficient synthesis of 11 C-nucleosides is based on an indium-mediated alkynylglycosylation as the key step, followed by the construction of the triazole heterocycle. Amidation was performed with primary and secondary amines in yields up to 85%. An analogue nucleoside with a triazole without carboxamide group was also prepared in order to compare its activity. Finally, the carboxamide group was moved to the N-1 triazole position to mimic ribavirin.

Full text of DOI:10.1055/s-0036-1588409

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–J
paper
A
C. Solarte et al.
Paper
Synthesis
Synthesis of C-Ribosyl-1,2,3-triazolyl Carboxamides
Carmen Solartea
Michaël Dos Santosa
Simon Gonzaleza
Leandro S. M. Mirandab
Régis Guillotc
Angélique Ferrya
Florian Galliera
Jacques Uziela
Bn
H
N
N
N
N
N
N
NR1R2
PGO
PGO
HO
X
OAc
O
O
O
1) Indium-mediated
alkynylation
1) Amidification
2) Deprotection
O
2) Huisgen
cycloaddition
OPG
OPG
PGO
OH
PGO
HO
11 compounds
C-ribosyl-
1,2,3-1H-triazolyl
carboxamides
Nadège Lubin-Germain*a
a Laboratoire de Chimie Biologique, University of Cergy-
Pontoise, 5 mail Gay-Lussac, 95031 Cergy-Pontoise
Cedex, France
nadege.lubin-germain@u-cergy.fr
b BOSS Laboratory, Federal University of Rio de Janeiro,
Av Athos da Silveira Ramos149, 21941909 Ilha do
Fundão, Rio de Janeiro, Brazil
c ICMMO, University of Paris Sud, 15, rue Georges
Clémenceau, 91405 Orsay, France
Received: 16.11.2016
Accepted after revision: 13.01.2017
Published online: 07.02.2017
Ribavirin’s mechanism of action is problematic since
RBV may act through non-specific or pleiotropic mecha-
nism.3 Five mechanisms are now assumed in the literature.
First of all, RBV could act as an antimetabolite against RNA
viruses by mimicking natural purine ribonucleosides such
as adenosine or guanosine according to the conformation of
the nucleosides. Second, RBV could inhibit enzymes such as
IMPDH (inosine monophosphate deshydrogenase) or RNA
polymerase. IMPDH inhibition leads to a depletion of gua-
nosine whereas RNA polymerase inhibition stops the elon-
gation of nucleic acids. On the other hand, RBV could also
act by inhibition of capping enzymes, RBV 5′-triphosphate
being structurally similar to the m7 G ‘cap’ structure.4 Fi-
nally, RBV has been described as an immune modulator or
as an error catastrophe agent.
For several reasons, such as reducing the cytotoxicity,
avoiding the drug resistance, or the emergence of new vi-
ruses, the discovery of new nucleosides has been an objec-
tive in medicinal chemistry field. In the last decades, a large
number of RBV analogues have been synthesized5 such as
carba-1,2,3-triazoles, 1,2,4-triazole analogues, pyrazoles,
and tetrazoles. Besides modifications of the heterocycles
mimicking the natural bases, efforts have been made to
synthesize C-nucleosides6 presenting a non-hydrolytic car-
bon–carbon bond at the anomeric position. This C–C link
confers more suitable lifetime and better pharmacologic
profile. The potential of this family has been recently high-
lighted by two compounds GS-66207 and BCX-4430,8 which
present interesting biological activity against viruses (Fig-
ure 1). The first one is a phosphoramidate C-adenosine pro-
drug containing a C2′-Me modification. It has shown a po-
tent and selective HCV inhibitor activity against HCV repli-
DOI: 10.1055/s-0036-1588409; Art ID: ss-2016-t0799-op
Abstract Because of the emergence of new viruses, the need for new
antiviral broad-spectrum compounds remains important. In this con-
text, herein the synthesis of C-nucleosides, structurally close to ribavi-
rin, a nucleoside presenting various biological activities and used until
now particularly for its broad-spectrum antiviral properties, is reported.
The compounds were designed in order to increase their stability and
the number of hydrogen bond donor or acceptor in comparison to riba-
virin, and to investigate the role of the carboxamide group on the bio-
logical activity. The efficient synthesis of 11 C-nucleosides is based on
an indium-mediated alkynylglycosylation as the key step, followed by
the construction of the triazole heterocycle. Amidation was performed
with primary and secondary amines in yields up to 85%. An analogue
nucleoside with a triazole without carboxamide group was also pre-
pared in order to compare its activity. Finally, the carboxamide group
was moved to the N-1 triazole position to mimic ribavirin.
Key words C-nucleosides, amidation, ribavirin, carboxamides, 1,2,3-
triazoles
Ribavirin (RBV) is a non-natural N-ribosyl-1,2,4-tri-
azole, synthesized thirty years ago. It exhibits several bio-
logical activities such as antitumoral, antiparasitic, and a
broad-spectrum antiviral activity.1 The latter property con-
fers to ribavirin a strategic role in the therapeutic arsenal,
especially in the context of emergent infectious diseases
such as hemorrhagic infections. Despite its moderate anti-
viral activity, RBV finds an interest in combination with
other direct-acting antiviral (DAA) nucleosides, as it is now
the case for the treatment of HCV (hepatitis C virus).2 How-
ever, its use has been significantly limited by its safety pro-
file and side effects, which include hemolytic anemia.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

B
C. Solarte et al.
Paper
Synthesis
cons of genotypes
1
to 6, but presents a limited
hydrogen bond donor
amide isostere groups
pharmacological profile. The second one is an imino C-ade-
nosine analogue presenting a broad-spectrum antiviral ac-
tivity, against yellow fever virus, Ebola virus, and filoviruses
for instance.
1,2,3-triazole
H
N
X
N
N
NR1R2
HO
PGO
O
O
O
NH2
H
O
N
N
BnN3
O
NH2
N
OH
HO
OPG
PGO
O
PhO
P
HO
N
N
O
Me
N
O
NH
targeted structures
C–C stable bond
CN
CO2iPr
O
O
N
OH
HO
OH
Ribavirin
PGO
OAc
O
GS-6620
In (0)
NH2
H
N
H
I
X
N
OPG
PGO
N
N
H
NR1R2
HO
HO
Scheme 1 Retrosynthetic scheme
N
O
N
O
HO
OH
HO
OH
In our synthetic approach (Scheme 2), compound 3 was
obtained in a gram-scale manner from ethyl iodopropiolate
and the protected acetyl riboside 2 by alkynyl C-glycosyla-
tion in the presence of indium(0). The reaction was carried
out at reflux in a sealed tube (54% yield) under vigorous
stirring. The β-C-ribosyl propiolate 3 was then engaged in a
Huisgen cycloaddition with benzyl azide leading to a 35:65
mixture of the two regioisomers 4a,b; the structure of each
of them was attributed by NMR spectroscopy.13 Triazoles 4a
and 4b could be easily separated by flash chromatography
but the next steps can be also continued on the mixture.
However, a difference of reactivity between 4a and 4b was
observed, 4b being more reactive. Compound 5 was ob-
tained from triazole 4a after deprotection of the acetonide
and the acetyl group (99% yield). Compound 6 was synthe-
sized after an amidation reaction (83% yield) followed by
the deprotection of the acetonide and the acetyl protecting
group (69% yield).
We anticipated that the benzyl group on the triazole
heterocycle could lead to steric hindrance. Thus, the syn-
thesis of compounds presenting a deprotected triazole with
different amides was planned to evaluate the role of car-
boxamide group in the biological activity. Different com-
pounds 8 were obtained by amidation of 4b in the presence
of various amines followed by hydrogenolysis in acidic con-
ditions.
BCX-4430
I
Figure 1 Nucleosides of interest and family targeted
We were interested in developing a C-nucleoside family
possessing a potential broad-spectrum antiviral activity
and structurally close to RBV. In a previous work,9 we de-
scribed an access to this family via an indium-mediated
alkynyl glycosylation. C-Alkynylpyranosides or furanosides
were obtained in the presence of indium(0) and iodo-
alkynes in a good diastereoselective manner. α-Selectivity
was observed for pyranosides whereas β-selectivity was
noticed for furanosides. The C-alkynylribofuranosides could
be then engaged in a Huisgen cycloaddition for the triazole
construction. This strategy of synthesis leads to 1,2,4-C-ri-
bosyltriazole nucleosides, analogues of RBV. We present
herein an additional work using the same strategy and
leading to several compounds, obtained after chemical
modifications of the triazole heterocycle (Scheme 1).
The choice of the targeted nucleosidic structures has
been guided by the isosterism of the 1,2,3-triazole com-
pared to the 1,2,4-triazole of RBV and by the stability of the
C–C linkage between the triazole and the sugar moiety.
Moreover, the targeted nucleosides I (Figure 1) present a
2H-1,2,3-triazole as potential hydrogen bond donor10 com-
pared to RBV or recently described 1,2,3-triazole ana-
logues.11 This N–H bond could enhance interactions with
enzymes involved in the viral replication.
Compound 8h was obtained after amidation of 4b with
gaseous ammonia in methanol (83%), followed by acidic
treatment to remove the acetonide, and finally hydrogeno-
lysis of the benzyl group. In previous work,13 partially regio-
selective conditions under microemulsion were explored
for the cycloaddition, but we underlined that the two regio-
isomers 4a,b afforded the single tautomer 8h, identified by
X-ray analysis, possessing the H on the central nitrogen
atom (Figure 2). The hydrogen atom was located unambigu-
ously (for further details, see the Supporting Information).
Second, it was shown that the carboxamide group plays
a key role in the RBV activity and it is present in many
drugs.12 Indeed, the carbonyl group (H-bond acceptor), or
the N–H bond (H-bond donor) are capable to establish hy-
drogen bonds. We were interested in investigating the im-
portance of this carboxamide group by replacing it by
isosteric groups or just by eliminating it.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

C
C. Solarte et al.
Paper
Synthesis
Bn
CO2Et
N
N
N
N
Bn
N
N
AcO
AcO
AcO
AcO
CO2Et
CO2Et
O
O
O
O
OAc
I
CO2Et
BnN3
+
toluene
reflux, 24 h, 83%
In(0), (CH2Cl)2
90 °C, 6 h
O
O
O
O
O
O
O
O
then TsOH.H2O, acetone
r.t., 5 h, 54%
2
3
4a
4b
1. NH3(g), MeOH
Dowex 50 (H+)
MeOH/H2O (80:20)
50 °C, 6 h, 98%
–10 °C, 8 h, 83%
2. Dowex (H+)
1. acetone, DMP
TsOH·H2O
r.t., 30 min, 51%
MeOH/H2O (80:20)
50 °C, 6 h, 69%
Bn
2. Ac2O, py
N
N
80 °C, 6 h, 63%
N
N
Bn
N
O
N
HO
HO
HO
CONH2
CO2Et
O
O
OH
OH
HO
OH
HO
OH
HO
5
6
D-ribose (1)
Scheme 2 Synthesis of ethyl-3-(β-D-ribofuranosyl)-1-N-benzyl-1,2,3-triazole-2-carboxylate (5) and 5-(β-D-ribofuranosyl)-1-N-benzyl-1,2,3-triazole-4-
carboxamide (6)
Furthermore, compound 8h displayed an anti-arrangement
of the atoms O(1′)–C(1′)–C(1)–N(2) according to the dihe-
dral angle of 0° inferior to 90° (27°).
catalysis leading to 11, which was then fully deprotected by
hydrogenolysis. Compound 12 was obtained in 35% overall
yield in a four steps synthesis.
O
OAc
AcO
O
O
2
TMS
2. TsOH·H2O, acetone
r.t., 5 h, NaHCO3
58% (2 steps)
I
1.
In(0), DCE
90 °C, 6 h
TMS
1. Dowex 50 (H+)
BnO
O
MeOH/H2O (80:20)
O
AcO
2. NaH, BnBr, DMF
79% (2 steps)
O
O
Figure 2 Crystal structure of 5-(β-D-ribofuranosyl)-2H-1,2,3-triazole-
4-carboxamide (8h)
BnO
OBn
9
10
BnN3, CuI, DIPEA
MeCN, r.t., 15 h
79%
Various primary amines were tested and led to the cor-
responding carboxamides 7 with yields up to 85% (Table 1).
Functionalized amines such as glycine, norephedrine, and
tris(hydroxymethyl)amine were also successfully used as
well as pyrrolidine, a secondary amine. Unfortunately,
deprotection of compounds 7b and 7i failed in the hydroge-
nolysis conditions used previously. The use of other condi-
tions led either to the recovery of starting material or to its
degradation.
In order to investigate the role of the carboxamide
group, compound 12 was synthesized, following the same
reactions sequence, but using iodotrimethylsilylacetylene
for the C-alkynylglycosylation (Scheme 3). In this case, the
cycloaddition regioselectivity was controlled by a copper(I)
H
N
Bn
N
N
N
N
N
O
HO
BnO
O
H2, Pd(OH)2
MeOH, 24 h
5 bar, 95%
HO
OH
BnO
OBn
11
12
Scheme 3 Synthesis of 4-(β-D-ribofuranosyl)-2H-1,2,3-triazole (12)
Finally, the functionalized group was shifted onto the
N-1 position of triazole heterocycle in order to obtain a
closer structure to RBV (Scheme 4). Compound 14 was ob-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

D
C. Solarte et al.
Paper
Synthesis
Table 1 Synthesis of 5-(1′-β-D-Ribofuranosyl)-2H-1,2,3-triazole-4-carboxamides 8a–i
H
N
N
N
Bn
HO
N
Bn
AcO
N
N
N
N
N
HO
RNH2
EtOH
NHR
H2, PdCl2
NHR
CO2Et
O
O
O
EtOH, 5 bar
O
O
O
O
HO
OH
O
O
4b
7a–i
8a–i
RNH2
Compound
Yield (%)
Compound
Yield (%)
HONH2
7a
7b
7c
7d
54
60
85
84
8a
8b
8c
8d
85
–
H2NNH2
MeCH2CH2NH2
HOCH2CH2CH2NH2
95
79
HN
7e
7f
77
77
8e
8f
82
70
H2N
COOH
Ph
7g
7h
75
83
8g
8h
64
60
H2N
OH
NH3
HO
HO
7i
67
8i
–
OH
NH2
tained starting from intermediate 9. The latter was depro-
tected under basic conditions leading to the terminal
alkyne 13, which then underwent a one-pot copper-cata-
lyzed SN-Huisgen cycloaddition step leading, after amida-
tion with gas ammonia and deprotection in acidic condi-
tions, to compound 14.
With an aim to ascertain a structural correlation which
is our hypothesis, the conformational similarity between
RBV, the synthesized C-nucleosides, and the purine nucleo-
sides, adenosine and guanosine was examined. The equilib-
rium between the S- and N-type conformations of the fura-
nose-ring puckering was then considered. For this the fol-
lowing relationship proposed by Altona and co-workers
was used:14
TMS
%S = 3J1′,2′ × 100/10.1
O
O
In this way, it is relatively easy to get the population of
S-conformation in the nucleosides. As depicted in Table 2,
the synthesized C-nucleosides 8a–h present in CD3OD al-
most the same coupling constant 3J1′,2′ leading mostly to the
N-type conformation, as shown also by the X-ray analysis of
compound 8h in the solid phase (Figure 2). RBV presents
also a N-type, contrary to guanosine and adenosine, essen-
tially with a S-type conformation in solution. Compounds
12 and 14 seem relevant for mimicking the two natural nu-
cleosides in a first approach.
K2CO3, MeOH
r.t., 8 h, 89%
AcO
HO
O
O
O
O
13
9
N
NH2
N
N
1. BrCH2CO2Et
O
CuI, DIPEA
MeCN, NaN3
O
HO
HO
2. NH3, MeOH
3. Dowex (H+)
57% (overall)
OH
In summary, a reliable synthesis of 11 C-nucleoside RBV
analogues is described. These syntheses generate a series of
four related purine-like compounds that can be used direct-
ly for studies that probe biological processes involving py-
14
Scheme 4 Synthesis of [4-(β-D-ribofuranosyl)-1,2,3-triazol-1-yl]acet-
amide (14)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

E
C. Solarte et al.
Paper
Synthesis
Table 2 Equilibrium Composition of Compounds 5, 8a–h, 12, and 14
13C NMR (125 MHz, CDCl3): δ = 170.8, 153.1, 114.4, 86.1, 84.1, 83.7,
82.9, 78.5, 74.9, 64.1, 62.5, 27.0, 25.4, 21.1, 14.2.
HRMS: m/z [M]+ calcd for C15H20O7: 312.1209; found: 312.1210.
OH
Base
HO
HO
HO
Base
O
O
Ethyl 1-Benzyl-4-(5′-O-acetyl-2′,3′-O-isopropylidene-β-D-ribofura-
nosyl)-1,2,3-triazole-5-carboxylate (4a) and Ethyl 1-Benzyl-5-(5′-
O-acetyl-2′,3′-O-isopropylidene-β-D-ribofuranosyl)-1,2,3-triazole-
4-carboxylate (4b)
OH
S-type
OH
N-type
Compound
3J1′,2′ (Hz)
% S
To a solution of ethyl ribosylpropiolate (3; 4 g, 12.8 mmol) in toluene
(30 mL) was added benzyl azide (6.8 g, 51.3 mmol). The mixture was
stirred at reflux for 24 h. After evaporation of the solvent, the crude
product was purified by flash column chromatography (cyclohex-
ane/EtOAc 9:1) to give the compound 4a as a yellow oil and 4b as a
yellow solid.
8a–h
4.6 or 4.7
5.4
46
54
62
50
36
65
59
12
14
6.2
5
5
RBV
3.6
4a
adenosine
guanosine
6.5
Yield: 1.79 g (31% from compound 3); [α]D25 –36.78 (c 1.0, CHCl3).
IR (ATR): 2984, 1725, 1497, 1370, 1211, 1097, 859 cm–1
.
5.9
1H NMR (400 MHz, CDCl3): δ=7.23 (m, 5 H), 5.82 (d, J = 14.2 Hz, 1 H),
5.78 (d, J = 14.2 Hz, 1 H), 5.46 (d, J = 3.3 Hz, 1 H), 5.22 (dd, J = 6.4, 3.2
Hz, 1 H), 4,77 (dd, J = 6.4, 3.2 Hz, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 4.21 (m,
1 H), 4.05 (d, J = 5.2 Hz, 2 H), 1.97 (s, 3 H), 1.51 (s, 3 H), 1.30 (s, 3 H),
1.27 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ=170.6, 158.2, 148.4, 134.7, 128.8, 128.5,
128.0, 125.7, 114.2, 83.9, 83.4, 82.6, 78.1, 76.4, 64.2, 62.1, 53.9, 27.2,
25.4, 20.8, 13.9.
rimidine nucleosides. In principle, they can also be convert-
ed to the corresponding triphosphates or phosphoramidites
for enzyme-mediated or chemical syntheses of modified
DNA sequences used in structure and function studies.
HRMS: m/z [M + H]+ calcd for C22H27N3O7: 445.1849; found: 455.1828.
All solvents were purified and dried by standard techniques and dis-
tilled prior to use. CH2Cl2 was distilled over CaH2 under argon. TLC
was carried out on silica gel plates (Macherey-Nagel); spots were de-
tected with UV light and revealed with H2SO4 solution. Flash chroma-
tography was performed with silica gel 60, 40–63 μm. Melting points
(uncorrected) were determined on a Buchi B-545 apparatus. Optical
rotations were determined on an Anton Paar MCP200 instrument and
IR spectra were recorded on a Bruker Tensor 27 spectrophotometer.
1H and 13C NMR spectra were recorded in CDCl3 or CD3OD on a Jeol
400 MHz ECX spectrometer. High-resolution mass spectra were ob-
tained with an UPLC-TOF LCT Premier Waters by ESI at the Service de
Spectrométrie de Masse of ICSN, Gif-sur-Yvette.
4b
25
Yield: 2.99 g (52% from compound 3); mp 75–77 °C; [α]D –1.63 (c
1.0, CHCl3).
IR (ATR): 2989, 1739, 1728, 1439, 1379, 1237, 1188, 1096, 858 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.27 (m, 5 H), 5.71 (d, J = 16.0 Hz, 1 H),
5.63 (d, J = 16.0 Hz, 1 H), 5.50 (d, J = 5.0 Hz, 1 H), 4.43 (dd, J = 6.9, 5.0
Hz, 1 H), 4.37 (m, 1 H), 4.35 (m, 2 H), 4.24 (m, 2 H), 1.13 (s, 3 H), 4.05
(d, J = 5.0 Hz, 1 H), 1.99 (s, 3 H), 1.46 (s, 3 H), 1.35 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ=166.2, 156.7, 133.4, 133.3, 130.5, 129.1,
128.7, 128.0, 127.0, 111.8, 84.3, 82.7, 81.3, 76.7, 59.2, 57.2, 48.8, 26.6,
22.9, 20.9, 16.5, 10.0.
Ethyl 3-(5-O-Acetyl-2,3-O-isopropylidene-β-D-ribofurano-
syl)propiolate (3)
HRMS: m/z [M + H]+ calcd for C22H27N3O7: 445.1849; found: 455.1864.
A suspension of In(0) (0.75 g, 6.56 mmol) in anhyd 1,2-dichlo-
roethane (10 mL) under argon was stirred for 20 min at r.t. Ethyl 3-
iodopropiolate (1.2 g, 5.47 mmol) and the ribofuranoside 2 (0.75 g,
2.74 mmol) were then added into the reaction tube, which was then
sealed. The reaction mixture was stirred for 6 h under argon at 90 °C.
The mixture was filtered over Celite and evaporated. The crude resi-
due was taken in anhyd acetone (4 mL) and treated with p-TsOH·H2O
(16 mg, 3 mol%). After stirring at r.t. for 5 h, the mixture was neutral-
ized with NaHCO3, filtered through Celite, and concentrated under re-
duced pressure. The crude residue obtained was purified by flash col-
umn chromatography on silica gel (cyclohexane/EtOAc 2:1) to afford
the product as a yellow oil; yield: 464 mg (54% from compound 2);
[α]D25 –30.42 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 4.90 (dd, J = 6.2, 2.5 Hz, 1 H), 4.80 (d, J =
2.5 Hz, 1 H), 4.72 (dd, J = 6.2, 2.2 Hz, 1 H), 4.34 (dt, J = 5.2, 2.2 Hz, 1 H),
4.26 (dd, J = 11.8, 5.2 Hz, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 4.18 (dd, J =
11.8, 5.4 Hz, 1 H), 2.11 (s, 3 H), 1.51 (s, 3 H), 1.34 (s, 3 H), 1.29 (t, J =
7.2 Hz, 3 H).
Ethyl 1-Benzyl-4-β-D-ribofuranosyl-1,2,3-triazole-5-carboxylate
(5)
To a solution of compound 4a (0.115 g, 0.258 mmol) in MeOH/H2O
(4:1, 10 mL) was added Dowex 50W (H+) (1.30 g). The mixture was
stirred at 50 °C for 6 h, then filtered and washed with MeOH. After
solvent evaporation, 5 was obtained as a yellow oil; yield: 92 mg (98%
from 4a); [α]D25 +5.22 (c 1.0, MeOH).
IR (ATR): 3269, 2928, 2499, 1722, 1455, 1256, 1102, 1029, 852, 730
cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.2 (m, 5 H), 5.85 (s, 2 H), 5.34 (d, J =
5.0 Hz, 1 H), 4.32–4.37 (m, 3 H), 4.24 (dd, J = 5.5, 5.1 Hz, 1 H), 3.99
(ddd, J = 5.1, 4.1, 2.8 Hz, 1 H), 3.82 (dd, J = 11.9, 2.8 Hz, 1 H), 3.67 (dd,
J = 11.9, 4.1 Hz, 1 H), 1.26 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CD3OD): δ = 159.5, 150.2, 136.6, 129.7, 129.2,
128.6, 127.1, 86.1, 78.2, 77.0, 72.4, 63.4, 63.3, 54.9, 14.2.
HRMS: m/z [M + H]+ calcd for C17H21N3O6: 363.1430; found: 363.1425.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

F
C. Solarte et al.
Paper
Synthesis
1-Benzyl-5-β-D-ribofuranosyl-1,2,3-triazole-4-carboxamide (6)
1-Benzyl-5-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-1,2,3-tri-
azole-4-carbohydrazide (7b)
A solution of compound 4b (0.100 g, 0.224 mmol) in MeOH (5 mL)
was cooled to –10 °C and treated with gaseous ammonia. The solu-
tion was maintained at –10 °C for 8 h and then warmed to r.t. over-
night. The reaction mixture was evaporated and the residue was puri-
fied by silica gel column chromatography (PE/EtOAc 1:1) to give the
intermediate amide as a white powder; yield: 80 mg (83% from 4b);
mp 178–180 °C; [α]D25 –22.39 (c 1, CHCl3).
Starting from 4b (300 mg, 0.67 mmol) and hydrazine monohydrate
(100 μL, 2 mmol) in EtOH (4 mL), 7b was obtained as a sticky solid
after purification by flash column chromatography (EtOAc/cyclohex-
ane 7:3 to 1:0); yield: 168 mg (60% from 4b); [α]D –52.01 (c 0.9,
CHCl3).
25
IR (ATR): 3320, 2985, 2936, 1733, 1664, 1075 cm–1
.
IR (ATR): 3409, 3278, 2921, 1730, 1663, 1602, 1466, 1054, 870 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.14 (m, 5 H), 5.68 (d, J = 15.6 Hz,
1 H), 5.61(d, J = 15.6 Hz, 1 H), 5.04 (dd, J = 6.3, 2.9 Hz, 1 H), 4.95 (m, 1
H), 4.90 (m, 1 H), 4.18 (m, 1 H), 3.87 (dd, J = 12.5, 1.6 Hz, 1 H), 3.74 (m,
1 H), 1.46 (s, 3 H), 1.26 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.11, 138.33, 136.65, 134.08,
129.24, 128.77, 127, 115.06, 85.59, 84.60, 81.51, 62.44, 52.84, 27.55,
25.30.
1H NMR (400 MHz, CDCl3): δ=7.12–7.29 (m, 5 H), 5.62 (d, J = 15.5 Hz,
1 H), 5.60 (d, J = 15.5 Hz, 1 H), 4.97 (m, 3 H), 4.24 (d, J = 11.2 Hz, 1 H),
4.18 (s, 1 H), 3.86 (d, J = 12.4 Hz, 1 H), 3.72 (dd, J = 12.4, 11.2 Hz, 1 H),
1.40 (s, 3 H), 1.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.1, 134.6, 132.4, 129.6, 124.8,
124.7, 122.4, 124.2, 110.4, 81.0, 79.9, 77.0, 72.1, 71.9, 57.9, 48.3, 23.0,
20.8.
HRMS: m/z [M + H]+ calcd for C18H24N5O5: 390.1777; found: 390.1790.
HRMS: m/z [M + H]+ calcd for C18H22N4O5: 374.1590; found: 374.1585.
1-Benzyl-5-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-N-propyl-
1,2,3-triazole-4-carboxamide (7c)
To a solution of the amide obtained as above (0.067 g, 0.179 mmol) in
MeOH/H2O (4:1, 5 mL) was added Dowex 50W (H+) (0.5 g). The reac-
tion mixture was stirred at 50 °C for 6 h, then filtered and washed
with MeOH. After solvent evaporation, 6 was obtained as a powder;
yield: 41 mg (69% from the intermediate amide); mp 208–210 °C;
[α]D25 +3.95 (c 1, MeOH).
Starting from 4b (150 mg, 0.33 mmol) and propylamine (110 μL, 79
mg, 1.34 mmol) in EtOH (2 mL), 7c was obtained as an oil after purifi-
cation by flash column chromatography (EtOAc/cyclohexane 7:3 to
6:4); yield: 120 mg (85% from 4b); [α]D25 –11.1 (c 1.1, CHCl3).
IR (ATR): 3389, 2937, 1652, 1497, 1286, 1111, 872 cm–1
.
IR (ATR): 3341, 2934, 1652, 1075 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 7.2 (m, 5 H), 5.8 (d, J = 15.6 Hz, 1 H),
5.75 (d, J = 15.6 Hz, 1 H), 5.36 (d, J = 7.8 Hz, 1 H), 4.03 (dd, J = 7.8, 6.4
Hz, 1 H), 3.93 (dd, J = 6.0, 3.2 Hz, 1 H), 3.83 (d, J = 2.7 Hz, 1 H), 3.64
(dd, J = 12.4, 3.2 Hz, 1 H), 3.60 (dd, J = 12.4, 2.7 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 7.50–7.14 (m, 5 H), 5.68 (d, J = 15.6 Hz,
1 H), 5.62 (d, J = 15.6 Hz, 1 H), 5.08 (m, 2 H), 4.97 (m, 1 H), 4.57 (s, 1
H), 4.20 (m, 1 H), 3.88 (m, 1 H), 3.74 (m, 1 H), 3.38 (m, 2 H), 1.61 (m, 2
H), 1.45 (s, 3 H), 1.28 (s, 3 H), 0.96 (t, J = 8.4 Hz, 3 H).
13C NMR (100 MHz, CD3OD): δ = 135.5, 132.1, 131.0, 128.5, 127.8,
126.9, 86.9, 75.2, 74.5, 70.9, 61.8.
HRMS: m/z [M + H]+ calcd for C15H18N4O5: 334.1277; found: 334.1256.
13C NMR (100 MHz, CDCl3): δ = 160.4, 139.9, 136.2, 134.2, 129.2,
128.6, 126.9, 114.8, 85.6, 84.4, 81.5, 76.6, 62.5, 52.7, 41.1, 27.5, 25.3,
22.8, 11.5.
HRMS: m/z [M + H]+ calcd for C21H29N4O5: 417.2137; found: 417.2138.
1-Benzyl-N-hydroxy-5-(2′,3′-O-isopropylidene-β-D-ribofurano-
syl)-1,2,3-triazole-4-carboxamide (7a)
1-Benzyl-N-(3-hydroxypropyl)-5-(2′,3′-O-isopropylidene-β-D-ri-
bofuranosyl)-1,2,3-triazole-4-carboxamide (7d)
To a solution of 4b (220 mg, 0.5 mmol) in EtOH (1 mL) was added
dropwise at r.t. a solution of hydroxylamine hydrochloride (100 mg,
1.44 mmol) and NaOH (120 mg, 3 mmol) in H2O (0.75 mL). After stir-
ring for 4 h, the solution was acidified to pH 6. The solvent was re-
moved in vacuo and the residue was dissolved in MeOH. After filtra-
tion and solvent evaporation, the crude was purified by flash column
chromatography (EtOAc/cyclohexane 7:3 to 1:0) leading to 7a as a
yellow oil; yield: 101 mg (54% from 4b); [α]D25 –17.68 (c 0.58, CHCl3).
Starting from 4b (300 mg, 0.67 mmol) and 3-aminopropanol (205 μL,
2.7 mmol) in EtOH (4 mL), 7d was obtained as a solid after purifica-
tion by flash column chromatography (EtOAc/cyclohexane 1:1 to 1:0);
yield: 242 mg (84% from 4b); mp 117 °C; [α]D25 –36.4 (c 1.6, CHCl3).
IR (ATR): 3312, 2920, 1649, 1077 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.02–7.17 (m, 5 H), 5.70 (d, J = 15.6 Hz,
1 H), 5.64 (d, J = 15.6 Hz, 1 H), 5.03 (m, 3 H), 4.50 (s, 1 H), 4.19 (s, 3 H),
3.89 (d, J = 12.1 Hz, 1 H), 3.74 (d, J = 12.1 Hz, 1 H), 3.69 (m, 2 H), 3.57
(m, 2 H), 1.79 (t, J = 5.7 Hz, 2 H), 1.47 (s, 3 H), 1.28 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.2, 139.7, 136.3, 134.2, 129.1,
128.6, 127.00, 114.9, 85.50, 84.4, 81.4, 76.5, 62.4, 59.6, 52.7, 36.3,
32.1, 27.5, 25.3.
IR (ATR): 3229, 2930, 1665, 1455, 1376, 1254, 1212, 1075, 853, 723
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.42–7.32 (m, 3 H), 7.24–7.14 (m, 2 H),
5.68 (d, J = 16.0 Hz, 1 H), 5.62 (d, J = 16.0 Hz, 1 H), 5.06–4.91 (m, 3 H),
4.24–4.13 (m, 1 H) 3.87 (d, J = 12.3 Hz, 1 H), 3.75 (d, J = 12.4 Hz, 1 H),
1.46 (s, 3 H), 1.26 (s, 3 H).
HRMS: m/z [M + H]+ calcd for C21H29N4O6: 433.2087; found: 433.2087.
13C NMR (100 MHz, CDCl3): δ = 158.8, 137.6, 136.7, 134.0, 129.2,
128.7, 127.1, 115.2, 85.4, 84.5, 81.4, 76.6, 62.1, 52.9, 27.4, 25.3.
HRMS: m/z [M + H]+ calcd for C18H23N4O6: 391.1618; found: 391.1613.
[1-Benzyl-5-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-1,2,3-tri-
azol-4-yl](pyrrolidin-1-yl)methanone (7e)
Starting from 4b (150 mg, 0.33 mmol) and pyrrolidine (140 μL, 2.27
mmol) in MeOH (2 mL), 7e was obtained as a solid after purification
by flash column chromatography (EtOAc/cyclohexane 6:4 to 1:1);
yield: 111 mg (77% from 4b); mp 47–55 °C; [α]D25 –7.9 (c 1, MeOH).
Amidation Reactions; General Procedure
To a solution of 4b in EtOH was added the appropriate amine (3–4
equiv). After completion of the reaction, the solution was concentrat-
ed and the crude was purified by flash column chromatography.
IR (ATR): 3374, 2967, 1614, 1057 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

G
C. Solarte et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.40–7.14 (m, 5 H), 5.74 (d, J = 15.7 Hz,
1 H), 5.57 (d, J = 15.7 Hz, 1 H), 5.07 (dd, J = 6.4, 2.4 Hz, 1 H), 4.98 (dd,
J = 6.4, 6.2 Hz, 1 H), 4.91 (d, J = 6.2 Hz, 1 H), 4.63 (br s, 1 H), 4.18 (ddd,
J = 2.4, 1.8, 1.6 Hz, 1 H), 4.04–3.93 (m, 1 H), 3.81 (dd, J = 12.7, 1.6 Hz, 1
H), 3.69 (dd, J = 12.7, 1.8 Hz, 1 H), 3.67–3.53 (m, 3 H), 2.00–1.80 (m, 4
H), 1.52 (s, 3 H), 1.30 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.5, 141.1, 136.4, 134.3, 129.2,
128.7, 127.2, 114.8, 85.6, 84.8, 81.8, 78.0, 62.7, 52.6, 49.1, 46.8, 27.7,
26.3, 25.4, 24.2.
IR (ATR): 3409, 3278, 2921, 1730, 1663, 1602, 1466, 1245, 870 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29–7.12 (m, 5 H), 5.62 (d, J = 15.5 Hz,
1 H), 5.60 (d, J = 15.5 Hz, 1 H), 4.97 (m, 3 H), 4.24 (d, J = 11.2 Hz, 1 H),
4.18 (s, 1 H), 3.86 (d, J = 12.4 Hz, 1 H), 3.72 (dd, J = 12.4, 11.2 Hz, 1 H),
1.40 (s, 3 H), 1.22 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 158.1, 134.6, 132.4, 129.6, 124.8,
124.7, 124.2, 122.4,110.4, 81.0, 79.9, 77.0, 72.1, 71.9, 57.9, 48.3, 23.0,
20.8.
HRMS: m/z [M + H]+ calcd for C18H22N4O5: 374.1590; found: 374.1585.
HRMS: m/z [M + H]+ calcd for C22H29N4O5: 429.2138; found: 429.2146.
1-Benzyl-N-[1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl]-5-
(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-1,2,3-triazole-4-car-
boxamide (7i)
N-[1-Benzyl-5-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-1,2,3-
triazole-4-carbonyl]glycine (7f)
Starting from 4b (150 mg, 0.33 mmol) and potassium glycinate (190
mg, 1.68 mmol) in MeOH (2 mL), 7f was obtained as a solid after puri-
fication by flash column chromatography (CH2Cl2/MeOH 19.1 + 1%
AcOH); yield: 112 mg (77% from 4b); mp 80–88 °C; [α]D25 –21.3 (c 1,
MeOH).
Starting from 4b (50 mg, 0.112 mmol) and tris(hydroxymethyl)amine
(60 mg, 0.5 mmol) in MeOH (0.7 mL), 7i was obtained as a colorless
oil after purification by flash column chromatography (CH2Cl2/MeOH
98:2); yield: 38 mg (67% from 4b); [α]D25 –17.3 (c 0.48, MeOH).
IR (ATR): 3362, 2984, 2936, 2887, 1649, 1584, 1516, 1498, 1456, 1441,
IR (ATR): 3312, 2967, 1736, 1665, 1055 cm–1
.
1384, 1319, 1253, 1214, 1156, 1078, 1050, 859, 726, 695 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.20 (m, 5 H), 5.85 (d, J = 16.4 Hz,
1 H), 5.81 (d, J = 16.4 Hz, 1 H), 5.54 (d, J = 5.6 Hz, 1 H), 4.74 (dd, J = 6.9,
4.1 Hz, 1 H), 4.69 (dd, J = 6.9, 5.6 Hz, 1 H), 4.09 (s, 2 H), 4.03 (ddd, J =
4.1, 4.0, 3.3 Hz, 1 H), 3.80 (dd, J = 12.1, 3.3 Hz, 1 H), 3.72 (dd, J = 12.1,
4.0 Hz, 1 H), 1.49 (s, 3 H), 1.20 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.0, 163.0, 140.8, 137.7, 137.0,
130.1, 129.5, 128.4, 116.6, 87.0, 85.8, 82.7, 77.5, 62.6, 53.8, 41.8, 27.8,
25.7.
1H NMR (400 MHz, CD3OD): δ = 7.41–7.34 (m, 3 H), 7.24 (d, J = 6.6 Hz,
2 H), 5.86 (s, 2 H), 5.66 (d, J = 5.8 Hz, 1 H), 4.75 (dd, J = 6.8, 4.2 Hz, 1 H),
4.67– 4.64 (m, 1 H), 4.07 (dd, J = 7.5, 3.8 Hz, 1 H), 3.85–3.81 (m, 7 H),
3.75 (dd, J = 12.0, 4.1 Hz, 1 H), 1.53 (s, 3 H), 1.23 (s, 3 H).
13C NMR (100 MHz, CD3OD): δ = 162.9, 141.0, 137.5, 136.9, 130.0,
129.4, 128.2, 116.4, 86.6, 85.5, 82.6, 77.1, 63.5, 62.6, 62.3, 53.8, 27.6,
25.6.
HRMS: m/z [M + H]+ calcd for C22H31N4O8: 479.2142; found: 479.2129.
HRMS: m/z [M + H]+ calcd for C20H25N4O7: 433.1723; found: 433.1727.
Deprotection of the Benzyl Group in 7a–h; General Procedure
1-Benzyl-N-[(1R,2S)-1-hydroxy-1-phenylpropan-2-yl]-5-(2′,3′-O-
isopropylidene-β-D-ribofuranosyl)-1,2,3-triazole-4-carboxamide
(7g)
To a solution of carboxamide 7 in EtOH (15 mL/mmol) was added
PdCl2 (40 mg/mmol). The mixture was stirred at r.t. under 5 bar H2
pressure for 48 h. After filtration of the catalyst over Celite and sol-
vent evaporation, the crude product was purified by flash column
chromatography.
Starting from 4b (50 mg, 0.112 mmol) and (–)-norephedrine (75 mg,
0.5 mmol) in MeOH (0.7 mL), 7g was obtained as a white solid after
purification by flash column chromatography (EtOAc/cyclohexane
3:7 to 4.6); yield: 46 mg (75% from 4b); [α]D25 –28.6 (c 1.3, CHCl3).
N-Hydroxy-5-β-D-ribofuranosyl-2H-1,2,3-triazole-4-carboxamide
(8a)
IR (ATR): 3397, 2979, 2937, 2880, 1654, 1508, 1454, 1253, 1214, 1154,
1080, 1002, 701 cm–1
.
Starting from 7a (88 mg, 0.2 mmol) and PdCl2 (8 mg) in EtOH (4 mL),
8a was obtained as a white solid after purification by flash column
chromatography (EtOAc/cyclohexane 8:2 to EtOAc/MeOH 1:1); yield:
51 mg (85% from 7a); mp 206–207 °C; [α]D25 +24.64 (c 0.97, CH3OH).
1H NMR (400 MHz, CDCl3): δ = 7.73–7.70 (m, 1 H), 7.38–7.16 (m, 10
H), 5.67 (d, J = 15.8 Hz, 1 H), 5.62 (d, J = 15.8 Hz, 1 H), 5.08–5.03 (m, 2
H), 4.98–4.96 (m, 2 H), 4.46–4.41 (m, 1 H), 4.20–4.19 (m, 1 H), 3.88
(dd, J = 12.5, 1.6 Hz, 1 H), 3.73 (dd, J = 12.5, 2.0 Hz, 1 H), 1.45 (s, 3 H),
1.28 (s, 3 H), 1.08 (d, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.3, 140.8, 139.8, 136.5, 134.2,
129.2, 128.7, 128.4, 127.7, 127.0, 126.2, 114.9, 85.6, 84.5, 81.6, 76.7,
75.8, 62.6, 52.8, 50.8, 27.6, 25.4, 13.7.
IR (ATR): 3210, 2924, 1650, 1450, 1219, 1077, 1020, 893 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 5.35 (d, J = 4.7 Hz, 1 H), 4.20–4.11 (m,
2 H), 4.00 (d, J = 3.4 Hz, 1 H) 3.84 (dd, J = 12.1, 2.9 Hz, 1 H), 3.70 (dd,
J =12.1, 3.9 Hz, 1 H).
13C NMR (100 MHz, CD3OD): δ = 161.0, 144.0, 137.2, 86.1, 77.9, 77.4,
72.1, 62.9.
HRMS: m/z [M + H]+ calcd for C27H33N4O6: 509.2400; found: 509.2403.
HRMS: m/z [M + H]+ calcd for C8H13N4O6: 261.0835; found: 261.0827.
1-Benzyl-5-(2′,3′-O-isopropylidene-β-D-ribofuranosyl)-1,2,3-tri-
azole-4-carboxamide (7h)
N-Propyl-5-β-D-ribofuranosyl-2H-1,2,3-triazole-4-carboxamide
(8c)
To a solution of 4b (100 mg, 0.224 mmol) in MeOH (5 mL) was bub-
bled gaseous ammonia for 2 h at 0 °C. The solution was then stirred at
r.t. for 12 h. The solvent was then removed in vacuo and the residue
was purified by flash column chromatography (EtOAc/cyclohexane
1.1 to 1.0) leading to a white solid 7h; yield: 100 mg (83% from 4b);
mp 178–180 °C; [α]D25 –22.39 (c 1.0, CHCl3).
Starting from 7c (102 mg, 0.2 mmol) and PdCl2 (8 mg) in EtOH (4 mL),
8c was obtained as a white solid after purification by flash column
chromatography (EtOAc/MeOH 1:0 to 9:1); yield: 70 mg (95% from
7c); mp 280 °C; [α]D25 +6.3 (c 1, MeOH).
IR (ATR): 3307, 2930, 1637, 1046 cm–1
.
The physicochemical properties were in accordance with published
data.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

H
C. Solarte et al.
Paper
Synthesis
1H NMR (400 MHz, CD3OD): δ = 5.37 (d, J = 4.6 Hz, 1 H), 4.14 (m, 2 H),
4.01 (m, 1 H), 3.85 (dd, J = 12.1, 3.0 Hz, 1 H), 3.71 (dd, J = 12.1, 3.8 Hz,
1 H), 3.30 (m, 2 H), 1.61 (sext, J = 7.4 Hz, 2 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CD3OD): δ = 161.63, 139.77, 84.83, 76.89, 76.41,
70.77, 61.37, 40.63, 22.47, 10.39.
crude was filtered on Celite, concentrated and purified by flash col-
umn chromatography (EtOAc/cyclohexane 5:5 then 100:0). The resi-
due obtained was dissolved in MeOH (2 mL) and treated with Dowex
50W (H+) for 5 h. The resulting mixture was filtered and concentrated
to give 8g as a colorless oil; yield: 29 mg (64% from 7g); [α]D25 +27.4 (c
1.45, MeOH).
HRMS: m/z [M + H]+ calcd for C11H19N4O5: 287.1355; found: 287.1366
IR (ATR): 3326, 2925, 2875, 1641, 1532, 1451, 1092, 1073, 1023, 996,
746, 701 cm–1
.
N-(3-Hydroxypropyl)-5-β-D-ribofuranosyl-2H-1,2,3-triazole-4-
carboxamide (8d)
1H NMR (400 MHz, CD3OD): δ = 7.44–7.42 (m, 2 H), 7.35–7.31 (m, 2
H), 7.26–7.22 (m, 1 H), 5.35 (d, J = 4.7 Hz, 1 H), 4.85 (d, J = 4.6 Hz, 1 H),
4.36–4.33 (m, 1 H), 4.15–4.10 (m, 2 H), 4.04–4.01 (m, 1 H), 3.88 (dd,
J = 12.1, 3.0 Hz, 1 H), 3.73 (dd, J = 12.1, 3.8 Hz, 1 H), 1.14 (d, J = 6.8 Hz,
3 H).
13C NMR (100 MHz, CD3OD): δ = 162.0, 143.3, 138.7, 132.4, 129.1,
128.4, 127.4, 86.0, 78.2, 77.4, 76.5, 72.0, 62.8, 51.9, 14.6.
Starting from 7d (194 mg, 0.4 mmol) and PdCl2 (18 mg) in EtOH (7
mL), 8c was obtained as a white solid after purification by flash col-
umn chromatography (EtOAc/MeOH 8:2); yield: 106 mg (79% from
7d); mp 220 °C; [α]D25 +30.6 (c 1.1, MeOH).
IR (ATR): 3295, 2927, 1637, 1042 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 5.37 (d, J = 4.6 Hz, 1 H), 4.13 (m, 2 H),
4.00 (m 1 H), 3.85 (dd, J = 12.0, 3.0 Hz, 1 H), 3.71 (dd, J = 12.0, 3.8 Hz, 1
H), 3.63 (t, J = 6.2 Hz, 2 H), 3.46 (t, J = 6.8 Hz, 2 H), 1.80 (tt, J = 6.8, 6.2
Hz, 2 H).
HRMS: m/z [M + H]+ calcd for C17H23N4O6: 379.1618; found: 379.1634.
5-β-D-Ribosyl-2H-1,2,3-triazole-4-carboxamide (8h)
Starting from 7h (1.34 g, 3.22 mmol) and PdCl2 (127 mg) in EtOH (55
mL), 8h was obtained as a white solid after purification by flash col-
umn chromatography (EtOAc/cyclohexane 8:2 to EtOAc/MeOH 1:1);
13C NMR (100 MHz, CD3OD): δ = 161.78, 142.25, 137.56, 84.81, 76.89,
76.14, 70.76, 61.53, 59.24, 36.06, 31.86.
HRMS: m/z [M + H]+ calcd for C11H19N4O6: 303.1305; found: 303.1306.
25
yield: 522 mg (60% from 7h); mp 204–206 °C; [α]D +13.82 (c 1.0,
MeOH).
(Pyrrolidin-1-yl)(5-β-D-ribofuranosyl-2H-1,2,3-triazol-4-yl)meth-
IR (ATR): 3327, 2927, 2365, 1670, 1540, 1459, 1225, 1110, 995, 897
cm–1.
1H NMR (400 MHz, CD3OD): δ = 3.72 (dd, J = 12.4, 3.7 Hz, 1 H), 3.85
(dd, J = 12.4, 2.8 Hz, 1 H), 4.01 (dd, J = 3.7, 2.8 Hz, 1 H), 4.14 (s, 2 H),
5.38 (d, J = 4.6 Hz, 1 H).
13C NMR (100 MHz, CD3OD): δ = 61.2, 70.1, 75.8, 76.1, 84.7, 137.3,
142.4, 144.6.
anone (8e)
Starting from 7e (67 mg, 0.106 mmol) and PdCl2 (5 mg) in EtOH (2
mL), 8e was obtained as a white foam after purification by flash col-
umn chromatography (CH2Cl2/MeOH 19:1); yield: 38 mg (82% from
7e); mp 179–182 °C; [α]D25 +22.4 (c 1, MeOH).
1H NMR (400 MHz, CD3OD): δ = 5.30 (d, J = 4.6 Hz, 1 H), 4.17–4.11 (m,
2 H), 4.00 (ddd, J = 4.3, 3.8, 3.1 Hz, 1 H), 3.84 (dd, J = 12.1, 3.1 Hz, 1 H),
3.88–3.80 (m, 2 H), 3.70 (dd, J = 12.1, 3.8 Hz, 1 H), 3.64–3.58 (m, 2 H),
2.00–1.80 (m, 4 H).
HRMS: m/z [M + H]+ calcd for C8H12N4O5: 244.0808; found: 244.0811.
13C NMR (100 MHz, CD3OD): δ = 162.3, 145.3, 140.4, 86.2, 78.5, 77.7,
72.4, 63.2, 50.3, 47.9, 27.3, 25.1.
5-O-Acetyl-2,3-O-isopropylidene-β-D-ribofuranosyltrimethyl-
silylacetylene (9)
A suspension of In(0) (0.75 g, 6.56 mmol) in anhyd 1,2-dichloro-
ethane (10 mL) under argon was stirred for 20 min at r.t. 1-Iodo-2-
trimethylsilylacetylene (1.2 g, 5.47 mmol) and the ribofuranoside 2
(0.75 g, 2.73 mmol) were added to the reaction tube, which was
sealed, then evacuated, and backfilled with argon (this process was
repeated a total of 3 times). The reaction mixture was stirred for 6 h
at 90 °C. The mixture was filtered over Celite and evaporated. The
crude residue was taken in anhyd acetone (4 mL) and treated with p-
TsOH·H2O (16 mg, 3 mol%). After stirring at r.t. for 5 h, the mixture
was neutralized with NaHCO3, filtered through Celite, and concentrat-
ed under reduced pressure. The crude residue obtained was purified
by flash column chromatography on silica gel (cyclohexane/EtOAc
3:1) to give 9 as a yellow oil; yield: 431 mg (58% from 2); [α]D25 +22.0
(c 1.5, CHCl3).
HRMS: m/z [M + H]+ calcd for C12H19N4O5: 299.1355; found: 299.1361.
N-(5-β-D-Ribofuranosyl-2H-1,2,3-triazole-4-carbonyl)glycine (8f)
Starting from 7f (50 mg, 0.105 mmol) and Pd/C (24 mg) in EtOH (1
mL) a colorless oil (24 mg) was obtained, which was purified by flash
column chromatography (CH2Cl2/MeOH 8:2 to CH2Cl2/MeOH 8:2 + 1%
AcOH). After evaporation of the solvent, the residue (19 mg) was dis-
solved in H2O (1 mL) and Dowex 50W (H+) was added and shaken for
3 h. Product 8f was obtained after filtration and evaporation as a
white foam; yield: 17 mg (70% overall); mp 97–99 °C; [α]D25 +20.4 (c
1, MeOH).
1H NMR (400 MHz, CD3OD): δ = 5.39 (d, J = 4.7 Hz, 1 H), 4.22–4.13 (m,
2 H), 4.11 (m, 2 H), 4.03 (ddd, J = 4.8, 3.7, 2.9 Hz, 1 H), 3.88 (dd, J =
12.1, 2.9 Hz, 1 H), 3.74 (dd, J = 12.1, 3.7 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 4.81 (dd, J = 6.4, 2.2 Hz, 1 H), 4.66–4.69
(m, 2 H), 4.09–4.34 (m, 3 H), 2.09 (s, 3 H), 1.50 (s, 3 H), 1.33 (s, 3 H),
0.15 (s, 9 H).
13C NMR (100 MHz, CD3OD): δ = 172.0, 163.4, 144.4, 138.5, 86.3, 78.5,
77.5, 72.1, 62.8, 41.8.
HRMS: m/z [M + H]+ calcd for C10H15N4O7: 303.0941; found: 303.0936.
13C NMR (100 MHz, CDCl3): δ = 170.69, 114.06, 102.74, 92.77, 86.54,
83.71, 82.98, 75.18, 63.94, 26.95, 25.42, 20.97, 20.26.
HRMS: m/z [M + H]+ calcd for C15H25O5Si: 313.1466; found: 313.1471.
N-[(1R,2S)-1-Hydroxy-1-phenylpropan-2-yl]-5-β-D-ribofuranosyl-
2H-1,2,3-triazole-4-carboxamide (8g)
Compound 7g (61 mg, 0.11mmol) was dissolved in EtOH (3 mL). Pd/C
(30 mg, 50% wt) was added and the atmosphere was replaced by H2.
The resulting mixture was stirred at r.t. under 8 bar of H2 for 48 h. The
2,3,5-Tri-O-Benzyl-β-D-ribofuranosylacetylene (10)
To a solution of compound 9 (0.96 g, 3.07 mmol) in a mixture of
MeOH/H2O (4:1, 50 mL) was added Dowex 50W (H+) (6 g) and concd
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

I
C. Solarte et al.
Paper
Synthesis
HCl (0.5 mL). The mixture was stirred at 50 °C for 30 h. The solution
was filtered and washed with MeOH, and MeOH was carefully evapo-
rated. The residue was dissolved in anhyd DMF (40 mL), and benzyl
bromide (2.59 mL, 27.36 mmol) and NaH (60%; 1.09 g, 45.60 mmol)
were added at 0 °C. The reaction mixture was stirred at r.t. overnight.
After cooling, a few drops of MeOH were added, and the mixture was
dissolved in Et2O (50 mL). The mixture was washed with sat. aq NH4Cl
(2 × 20 mL) and H2O (2 × 20 mL), dried (MgSO4), filtered, and concen-
trated in vacuo. The crude was purified by flash chromatography on
silica gel (cyclohexane/EtOAc 9:1) to give 10 as a yellow solid; yield:
1.54 g (79% from 9); mp 58–60 °C; [α]D25 +0.012 (c 1.0, CHCl3).
2,3-O-isopropylidene-β-D-ribofuranosylacetylene (13)
To a solution of 9 (1.2 g, 3.87 mmol) in MeOH (12 mL) was added
K2CO3 (0.8 g, 5.81 mmol) and the mixture was stirred at r.t. for 8 h.
The mixture was concentrated, the residue was taken in H2O (5 mL),
and acidified with AcOH to pH 5–6. The aqueous phase was extracted
with EtOAc (2 × 15 mL), dried (Na2SO4), filtered, and concentrated un-
der reduced pressure. Heptane was used to remove the excess of
AcOH. The yellow oil obtained was purified by flash column chroma-
tography on silica gel (heptane/EtOAc 9:1 to 7:3) to give 13 as a color-
less oil; yield : 680 mg (89% from 9); [α]D25 –4.0 (c 1.2, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 4.81 (dd, J = 6.2, 2.7 Hz, 1 H), 4.74 (dd,
J = 6.3, 2.2 Hz, 1 H), 4.68 (t, J = 2.5 Hz, 1 H), 4.19–4.22 (m, 1 H), 3.75–
3.76 (m, 2 H), 2.60 (d, J = 2.3 Hz, 1 H), 2.12 (br s, 1 H), 1.33 (s, 3 H),
1.51 (s, 3 H).
IR (ATR): 3285, 3030, 2861, 1496, 1453, 1356, 1207, 1026, 734 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.28–7.41 (m, 15 H), 4.74 (d, J = 11.9
Hz, 2 H), 4.72 (dd, J = 4.5, 1.8 Hz, 1 H), 4.64 (d, J = 12.4 Hz, 2 H), 4.55
(dd, J = 10.5 Hz, 2 H), 4.26 (dd, J = 9.1, 4.6 Hz, 1 H), 4.10 (t, J = 5.0 Hz, 1
H), 4.07 (t, J = 5.0 Hz, 2 H), 3.66 (dd, J = 11.0, 6.4 Hz, 1 H), 3.57 (dd, J =
11.0, 4.6 Hz, 1 H), 2.57 (d, J = 2.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 113.97, 86.67, 86.61, 82.29, 81.69,
75.58, 74.76, 62.93, 27.02, 25.35.
HRMS: m/z [M + H]+ calcd for C10H14O4: 198.0885; found: 198.0892.
13C NMR (100 MHz, CDCl3): δ = 138.3, 137.8, 137.6, 127.7–128.5, 81.9,
81.7, 81.5, 78.0, 75.2, 75.0, 72.5, 72.4, 72.3, 70.9, 70.8, 70.1.
HRMS: m/z [M + H]+ calcd for C28H28O4: 428.1988; found: 428.1990
[4-β-D-Ribofuranosyl-1,2,3-triazol-1-yl]acetamide (14)
A solution of ethyl bromoacetate (222 mg, 1.3 mmol) in MeCN and
NaN3 (99.5 mg, 1.5 mmol) was stirred at reflux for 2 h. A solution of
sugar 13 (200 mg, 1.0 mmol) in MeCN was then introduced, followed
by DIPEA (395 mg, 3.1 mmol) and CuI (389 mg, 2.0 mmol), and stirred
for another 2 h. The reaction mixture was filtered through a short bed
of Celite. After removal of the solvent, the residue was purified by
chromatography on silica gel (cyclohexane/MeOH 95:5) to afford the
triazole ester intermediate as a yellow oil; yield: 248 mg (62% from
13).
1H NMR (400 MHz, CDCl3): δ = 7.67 (s, 1 H), 5.13 (s, 2 H), 4.97 (dd, J =
6.1, 3.6 Hz, 1 H), 4.93 (dd, J = 6.1, 1.6 Hz, 1 H), 4.35 (s, 1 H), 4.25 (q, J =
7.1 Hz, 2 H), 3.88 (br d, J = 12.4 Hz, 1 H), 3.66 (dd, J = 12.4, 3.1 Hz, 1 H),
1.57 (s, 3 H), 1.30 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H).
1-Benzyl-4-(2′,3′,5′-tri-O-benzyl-β-D-ribofuranosyl)-1,2,3-triazole
(11)
A mixture of alkyne 10 (0.40 g, 0.93 mmol), benzyl azide (0.15 g, 1.12
mmol), CuI (0.35 g, 1.86 mmol), and DIPEA (0.36 g, 2.79 mmol) in
MeCN (20 mL) was stirred at r.t. for 20 h. The mixture was evaporated,
and the residue was partitioned between EtOAc and H2O (20 mL). The
organic layer was washed with aq NH4Cl (2 × 10 mL) and brine (2 × 10
mL), dried (MgSO4), and evaporated. The residue was purified by silica
gel column chromatography (cyclohexane/EtOAc 8:2) to give 11 as a
yellow solid; yield: 0.41 g (79% from 10); mp 122–124 °C; [α]D
–3.40 (c 1.0, CHCl3).
IR (ATR): 3061, 2888, 1479, 1454, 1349, 1048, 910, 751, 671 cm–1
25
13C NMR (100 MHz, CDCl3): δ = 166.07, 114.11, 85.99, 85.57, 82.3,
.
1H NMR (400 MHz, CDCl3): δ = 7.0–7.3 (m, 20 H), 5.36 (d, J = 15.1 Hz, 1
H), 5.29 (d, J = 3.1 Hz, 1 H), 5.19 (d, J = 15.1 Hz, 1 H), 4.75 (d, J = 11.9
Hz, 1 H), 4.68 (d, J = 11.9 Hz, 1 H), 4.60 (d, J = 11.9 Hz, 1 H), 4.49 (d, J =
11.9 Hz, 1 H), 4.44 (d, J = 11.9 Hz, 1 H), 4.42 (d, J = 11.9 Hz, 1 H), 4.31
(m, 1 H), 4.25 (t, J = 4.1 Hz, 1 H), 4.05 (dd, J = 6.9, 5.0 Hz, 1 H), 3.75 (dd,
J = 10.5, 2.8 Hz, 1 H), 3.59 (dd, J = 10.5, 3.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.2, 138.2, 137.9, 137.8, 134.7,
129.0, 127.7–128.7, 122.5, 80.8, 80.6, 76.7, 73.3, 72.1, 72.0, 69.4, 54.
HRMS: m/z [M+ H]+ calcd for C35H35N3O4: 561.2628; found: 561.2639.
80.5, 62.36, 62.9, 50.75, 25.17, 27.17, 13.9.
A solution of the above triazole ester (248 mg, 0.8 mmol) in MeOH
was cooled to –10 °C and treated with gaseous NH3. The reaction was
maintained at this temperature for 8 h. The reaction mixture was
evaporated under reduced pressure, and the crude oil (295 mg) was
pure enough to be used in the next step. To the crude in MeOH/H2O
(4:1) was added Dowex 50W (H+) (1 g). The reaction mixture was
stirred at reflux for 6 h, then filtered, and washed with MeOH. The
solvent was removed in vacuo to give 14 as a yellow oil; yield: 146 mg
(57% from 13); [α]D25 –63.0 (c 0.2, MeOH).
1H NMR (400 MHz, CD3OD): δ = 8.1 (s, 1 H), 5.35 (s, 2 H), 4.91 (d, J =
6.2 Hz, 1 H), 4.17 (dd, J = 6.2, 4.9 Hz, 1 H), 4.11 (t, J = 4.9 Hz, 1 H), 3.98
(m, 1 H), 3.75 (dd, J = 12.0, 3.4 Hz, 1 H), 3.66 (dd, J = 12.0, 4.5 Hz, 1 H).
13C NMR (100 MHz, CD3OD): δ = 167.4, 146.7, 125.1, 85.3, 76.7, 76.1,
71.3, 62.1, 50.8.
4-β-D-Ribofuranosyl-2H-1,2,3-triazole (12)
To a solution of 11 (0.070 g, 0.12 mmol) in MeOH (5 mL) was added
Pd(OH)2 (20%) and the reaction mixture was hydrogenolyzed at r.t. for
24 h at 5 bar. The catalyst was filtered over Celite and washed with
MeOH. The solvents were then evaporated and 12 was obtained after
silica gel column chromatography purification as a white solid; yield:
0.024 g (95% from 11); mp 118–120 °C; [α]D25 +11.3 (c 1.0, MeOH).
HRMS: m/z [M + H]+ calcd for C9H14N4O: 258.0964; found: 258.0965.
IR (ATR): 3335, 2965, 2374, 1675, 995, 897 cm–1
.
Acknowledgment
1H NMR (400 MHz, CD3OD): δ = 7.66 (s, 1 H), 4.95 (d, J = 5.4 Hz, 1 H),
4.13 (m, 2 H), 3.95 (m, 1 H), 3.77 (dd, J = 11.9, 3.2 Hz, 1 H), 3.63 (dd, J =
11.9, 5.0 Hz, 1 H).
We thank the Cergy-Pontoise University for financial support.
13C NMR (100 MHz, CD3OD): δ = 143.9, 128.0, 84.8, 77.6, 76.2, 71.3,
62.2.
Supporting Information
HRMS: m/z [M + H]+ calcd for C7H11N3O4: 201.0750; found: 201.0746.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588409.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J

J
C. Solarte et al.
Paper
Synthesis
References
K.; Perron, M.; Gabriel, B.; Wong, K. A.; Zhong, W. C.; Kim, U.;
Carey, A.; Cho, A.; Ray, A. S. Antimicrob. Agents Chemother. 2014,
58, 1930.
(1) (a) Gish, R. G. J. Antimicrob. Chemother. 2006, 57, 8. (b) Wu, J. Z.;
Lin, C.-C.; Hong, Z. J. Antimicrob. Chemother. 2003, 52, 543.
(2) Zeuzem, S.; Dusheiko, G. M.; Salupere, R.; Mangia, A.; Flisiak, R.;
Hyland, R. H.; Illeperuma, A.; Svarovskaia, E.; Brainard, D. M.;
Symonds, W. T.; Subramanian, G. M.; McHutchison, J. G.;
Weiland, O.; Reesink, H. W.; Ferenci, P.; Hézode, C.; Esteban, R.
N. Engl. J. Med. 2014, 370, 1993.
(8) Julander, J. G.; Bantia, S.; Taubenheim, B. R.; Minning, D. M.;
Kotian, P. D.; Morrey, J.; Smee, D. F.; Sheridan, W. P.; Babub, Y. S.
Antimicrob. Agents Chemother. 2014, 58, 6607.
(9) Lubin-Germain, N.; Baltaze, J. P.; Coste, A.; Hallonet, A.;
Lauréano, H.; Legrave, G.; Uziel, J.; Augé, J. Org. Lett. 2008, 10,
725.
(3) Crotty, S.; Cameron, C.; Andino, R. J. Mol. Med. 2002, 80, 86.
(4) Pankiewicz, K. W.; Felczak, K. Heterocycl. Commun. 2015, 21,
249.
(5) Krajczyk, A.; Kulinska, K.; Kulinski, T.; Hurst, B.; Day, C. W.;
Smee, D. F.; Ostrowski, T.; Januszczyk, P.; Zeidler, J. Antiviral
Chem. Chemother. 2014, 23, 161.
(10) Schulze, B.; Schubert, U. S. Chem. Soc. Rev. 2014, 43, 2522.
(11) Ferreira, L. G.; Pinheiro, L. C. S.; Santos-Filho, A. O.; Peçanha, M.
D. S.; Sacramento, C. Q.; Machado, V.; Ferreira, V. F.; Souza, T. M.
L.; Boechat, N. Med. Chem. Res. 2014, 23, 1501.
(12) Pokhodylo, N.; Shyyka, O.; Matiychuk, V. Med. Chem. Res. 2014,
23, 2426.
(13) Aït Youcef, R.; Dos Santos, M.; Roussel, S.; Baltaze, J. P.; Lubin-
Germain, N.; Uziel, J. J. Org. Chem. 2009, 74, 4318.
(14) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1973, 95, 2333.
(6) De Clerq, E. J. Med. Chem. 2016, 59, 2301.
(7) Feng, J. Y.; Cheng, G.; Perry, J.; Barauskas, O.; Xu, Y.; Fenaux, M.;
Eng, S.; Tirunagari, N.; Peng, B.; Yu, M.; Tian, Y.; Lee, Y-J.; Stepan,
G. L.; Lagpacan, L.; Jin, D.; Hung, M.; Ku, K. S.; Han, B.; Kitrinos,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–J