2’-Derivatisation of 3’-C-Methyl Pyrimidine Nucleosides

Article abstract of DOI:10.1002/ejoc.202100236

The stereoselective synthesis of some 3’-deoxy-3’-C-methyl pyrimidine nucleosides is reported. The studied modifications concern the inversion of the configuration in 2’-position as well as the introduction of fluoro and azido substituents. The correspond

Full text of DOI:10.1002/ejoc.202100236

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doi.org/10.1002/ejoc.202100236
Very Important Paper
2
’-Derivatisation of 3’-C-Methyl Pyrimidine Nucleosides
[a]
[a]
[a]
Sarah Couturier, Suzanne Peyrottes, and Christian Périgaud*
The stereoselective synthesis of some 3’-deoxy-3’-C-methyl
pyrimidine nucleosides is reported. The studied modifications
concern the inversion of the configuration in 2’-position as well
as the introduction of fluoro and azido substituents. The
corresponding arabinonucleoside and 2’-substituted ribonu-
cleoside analogs of uracil and cytosine have been obtained and
fully characterized. Attempts to introduce fluoro and azido
substituents with inversion at C-2’ are also presented.
Introduction
The current pandemic associated with the severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) and its health,
economic, environmental, and social consequences highlight
the need for therapeutic treatments in parallel to the develop-
ment of prophylactic strategies. In the search for efficient
antiviral small-molecules against this disease, drug repurposing
Figure 1. Examples of C-methyl nucleoside/tide analogs with biological
(
also called repositioning, redirecting, or reprofiling) was first
activities.
[1]
extensively studied. This last has some advantages over new
drug discovery since chemical synthesis steps, manufacturing
processes, reliable safety, and pharmacological properties in
early clinical development phases are already available. Nucleo-
side and nucleotide analogs, which have a long and rich history
in the field of medicinal chemistry, are in consequence well
represented in this race to arsenal COVID-19 therapeutics.
During the last decades, extensive modifications of the
[2]
nucleoside/tide endogenous scaffolds have been reported.
Among them, the introduction of a methyl group on the osidic
residue has led to new molecules endowed with a wide range
of biological activities. As an example, (2’S)-2’-deoxy-2’-C-meth-
Figure 2. Previously reported 3’-C-nucleosides and additional structural
analogs investigated in this study.
[3]
[4]
ylcytidine (SMDC, Figure 1), as well as 3’-C-methyladenosine
Figure 1), exhibited potent activities against various human
(
cancer cell lines. In addition, the 2’-C-methyl series is known to
include potent inhibitors of hepatitis C virus (HCV) replication
and Sofosbuvir (Figure 1) was approved by the United States
Food and Drug Administration (FDA) for the treatment of this
inversion of configuration, introduction of fluoro, azido and
amino substituents were envisaged. Thus, the stereoselective
synthesis of the resulting 3’-deoxy-3’-C-methyl nucleosides
bearing uracil and cytosine is reported herein (Figure 2).
[5]
disease.
As part of our work on this topic, we previously reported
[6]
preliminary studies in the 3’-C-methyl nucleoside series with
the synthesis of 3’-deoxy and 2’,3’-dideoxy-3’-C-methyl nucleo- Results and Discussion
sides bearing naturally occurring nucleobases and various
aglycones of pharmacological interest (Figure 2).
3’-Deoxy-3’-C-methyl arabinonucleoside analogs. Anhydronucleo-
We focused our investigations in this series by designing
various modifications in the 2’-position. Modifications such as
sides are useful starting materials for the stereochemically-
controlled introduction of functional groups into the secondary
[7]
positions of the sugar moiety. In this respect, the anhydronu-
cleoside 2 (Scheme 1) appeared as a suitable candidate for
various modifications with 2’-inversion of configuration. The
[
a] Dr. S. Couturier, Dr. S. Peyrottes, Prof. Dr. C. Périgaud
UMR 5247 CNRS, Université Montpellier, ENSCM
Institut des Biomolécules Max Mousseron (IBMM)
Campus Triolet, case courrier 1705, Place E. Bataillon, 34095 Montpellier,
France
[
6a]
latter was obtained from the benzoylated nucleoside 1 under
Mitsunobu conditions. Treatment of 2 with an aqueous sodium
hydroxide solution gave the arabino derivative of uracile 3. This
nucleoside was previously published according to a non-
E-mail: christian.perigaud@umontpellier.fr
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100236
[
8]
regiospecific reaction involving the opening of a 2’,3’-epoxide.
Part of the “Institute Feature IBMM” Special Collection.
Conversion of the uracil aglycone of 3 into the cytosine
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Scheme 1. Synthesis of 3’-deoxy-3’-C-methyl arabinonucleoside analogs 3 and 5.
[
11]
counterpart required acetylation to obtain the fully protected
nucleoside 4. Then, the desired arabino derivative of cytosine 5
was obtained in two steps from 4, via the reaction with
or KF/crown ether), the coupling of a suitably blocked 2-
deoxy-2-fluororibofuranoside with appropriate heterocyclic
[12]
[13]
bases, an enzyme-catalyzed transglycosylation, the nucleo-
philic displacement of 2’-O-trifluoromethanesulfonyl arabinonu-
cleosides by tetra-n-butylammonium fluoride (TBAF), and the
direct introduction of fluorine atom by using diethylaminosulfur
[9]
Lawesson’s reagent, followed by the treatment of the 4-
[14]
thioamide intermediate with methanolic ammonia at 100°C in a
stainless-steel bomb.
[15]
The proposed structures of these arabinonucleosides were
trifluoride (DAST) and an arabinonucleoside. We selected this
last methodology for the preparation of the fluoro derivative 8
(Scheme 2). Thus, the previously obtained arabinonucleoside 3
reacted with 4-monomethoxytrityl chloride to afford the
corresponding 5’-O-protected nucleoside 6, which was treated
with DAST to give rise to intermediate 7. Then, acidic treatment
of 7 led to the desired fluorinated ribonucleoside 8 which was
crystallized in methanol. The uracil derivative 8 was converted
to 10 using the same methodology as for compound 5
(Scheme 1).
1
13
1
based on UV, H, and C NMR and mass spectral data. The H
spectrum shows H-1’ as a doublet with coupling constants
(
J1’–2’ =6.1 and 5.8 Hz for 3 and 5, respectively) in agreement
[10]
with the arabinose configuration of the 2’-hydroxyl function.
In addition, the signal of the 3’-methyl substituent (δ’1.0 ppm)
appeared as doublet and the CH -H coupling constants were
3
3’
6
.6 and 6.7 Hz for 3 and 5 respectively, similar to those
observed for the 3’-C-methyl-β-D-ribo- and 2’-deoxy-β-D-ribo-
[6]
nucleoside analogs.
’-Fluoro-3’-deoxy-3’-C-methyl ribonucleoside analogs. Several
2
The structures of fluoronucleosides 8 and 10 were con-
1
13
19
1
routes have been previously reported for the synthesis of 2’-
deoxy-2’-fluoro-β-D-ribonucleosides, including the opening of
firmed by UV, H, C, F NMR, and mass spectra analysis. H
NMR spectra of these derivatives exhibited a downfield shift of
the H-2’ due to the electron-withdrawing effect of fluorine.
2
,2’-anhydronucleosides with a fluorinating agent (HF/dioxane
Sarah Couturier graduated in organic
chemistry from the Engineer School ENSSPI-
CAM (Aix-Marseille) and obtained her Ph.D.
Christian Périgaud obtained his Ph.D. (1991) at
the University of Montpellier with G. Gosselin
in the laboratory of Pr. J.-L. Imbach working
on nucleoside chemistry. Back to Montpellier
after a postdoctoral work with Pr. J.-P. Som-
madossi, he was appointed as associate
professor (1993), then professor (2001). His
scientific interests focused on the develop-
ment of anti-infective agents, prodrug con-
cepts as well as tools for the understanding of
biological processes. He has co-authored
more than 130 publications. He has also
served for his University as vice-president for
research (2008-2012) and the French Ministry
of Higher Education and Research (2013-
(2004) at the University of Montpellier. Start-
ing in industry in 2005, she contributed to the
success of innovative projects of the API
Services and Chemical Development Depart-
ment of a CRO in Northern Ireland. She joined
SERATEC (Courville sur Eure, France) in 2007, a
Drug Substance CDMO dedicated to low
volume and complex APIs in a context of
quality excellence. She is currently R&D Direc-
tor, developing synthetic route for API for the
pharmaceutical industry and acceptable to
the health authorities.
2020).
Suzanne Peyrottes graduated in chemistry
from Montpellier University and completed
her postdoctoral study at the MRC (Cam-
bridge, UK). She is currently Research Director
at CNRS, working on the design of potential
therapeutic agents to treat infections and
cancers while developing new synthetic meth-
odologies related to nucleic acid components.
She heads the team “Nucleosides & Phos-
phorylated Effectors” belonging to the Insti-
tute of Biomolecules Max Mousseron (IBMM,
Montpellier, France).
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Scheme 2. Synthesis of 2’-fluoro-3’-deoxy-3’-C-methyl ribonucleoside analogs 8 and 10.
Illustrated by NMR data observed for 8, the assignments of H-1’
δ=5.79 ppm), H-2’ (δ=5.00 ppm), and H-3’ (δ=2.12 ppm) are
2’-Azido- and 2’-amino-3’-deoxy-3’-C-methyl ribonucleoside
(
analogs. The synthesis of the 2’-azido derivative 11 (Scheme 3)
was carried out according to a published procedure involving
the in situ generation of lithium azide from lithium fluoride and
azidotrimethylsilane in the presence of N,N,N’,N’-tetrameth-
consistent with the vicinal and geminal HÀ F coupling values
[16]
found: 17.5, 52.3, and 35.9 Hz respectively. The large proton-
fluorine coupling constants allow ready assignments of the
protons but the spectrum was insufficiently resolved in the
[20]
ylethylenediamine (TMEDA) in DMF. In these conditions, the
introduction of the azido group on the 2’-position was obtained
with satisfactory yield from the previously described anhydro-
nucleoside 2. Thus, treatment of the intermediate 11 with
methanolic ammonia afforded the desired 2’-azido-ribonucleo-
side 12. The corresponding cytosine analog 13 cannot be
used solvent to determine the magnitude of J
particularly low for 1’,2’-trans stereoisomers) and J3’–4’. The
(known to be
1
17]
’–2’
[
(
2’R) configuration of the fluorinated nucleosides 8 and 10 was
1
3
also assigned from C NMR spectra analysis. For the two
compounds, the measured JC1’–F (37 Hz) is similar to that
observed for other 2’-deoxy-2’-fluoronucleoside analogs charac-
[
9b]
obtained by a thiation procedure using Lawesson’s reagent,
and we selected Sung’s methodology for its preparation.
[18]
[21]
terized by a 1’,2’-trans stereoisomerism.
measured a coupling constant between the 3’-methyl group
=7.6 and 8.3 Hz for
In addition, we
Thus, the reaction of the protected nucleoside 11 with 4-
chlorophenyl phosphorodichloridate and 1,2,4-triazole in
pyridine at room temperature led to the corresponding 4-
triazolylpyrimidinone derivative (not shown) which was purified
(
8
δ’7.5 ppm, d) and the fluorine atom (J
CH3-F
and 10, respectively) which is only observed when these two
[19]
substituents are in a cis position.
Scheme 3. Synthesis of 2’-azido- and 2’-amino-3’-deoxy-3’-C-methyl ribonucleoside analogs 12–14.
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on silica gel column chromatography. This intermediate was
to the electronegativity of the 2’-substituent for 14 (δ=
59.8 ppm), 12 (δ=69.8 ppm) and 10 (δ=98.5 ppm).
treated with aqueous ammonia in dioxane, followed by
methanolic ammonia, to give rise to the desired nucleoside 13.
Various synthetic protocols have been described for con-
Attempts to obtain 2’-modified-3’-deoxy-3’-C-methyl arabino-
nucleoside analogs. Fluorination. The introduction of a substitu-
ent at the C-2’-β (arabino) position in pyrimidine nucleosides by
nucleophilic reactions cannot be achieved due to the neighbor-
ing-group participation of the carbonyl function of the
[22]
verting azides to amines,
among them the Staudinger
[23]
procedure appeared to be the most promising in the nucleo-
side field. Thus, 2’-azido nucleoside 12 was converted in
presence of triphenylphosphine into a phosphinimine inter-
mediate, the latter being hydrolyzed with aqueous ammonia to
afford the 2’-amino-ribonucleoside analog 14.
[7]
aglycon. It is well known that the intra-molecular attack of the
2-carbonyl group of the nucleobase on C-2’ of the sugar moiety
supersedes the inter-molecular nucleophilic substitution. To
The structures of nucleosides 12–14 were in accordance
with UV, IR, H, C NMR, and mass spectral data. The infrared
circumvent this competition and to limit direct S 2 reaction at
the 2’-position of uridine derivatives, the protection of N -imide
N
1
13
3
spectra of compounds 11–13 exhibited a strong absorption
function has attracted attention and various protecting groups
À 1
[27]
band at 2110 cm , characteristic of the azido function.
have been reported.
Among them, we selected p-meth-
1
[28]
Compared to H NMR spectra of fluorinated nucleosides 8 and
oxybenzyl (PMB). The PBM protecting group is often used in
nucleoside chemistry due to its compatibility with a wide range
of reaction conditions and its stability in acid and alkaline
1
0, the chemical shifts and coupling constants measured for
derivatives 12–14 reflect the relationship between the electro-
negativity of the 2’-substituents and the conformation of the
sugar residue. The assignments of H-1’/H-2’ for 8 (δ=5.83/
[29]
media.
Thus, the 5’-O-benzoylated precursor 1 was treated with 4-
3
5
.12 ppm), 12 (δ=5.73/4.42 ppm), and 14 (δ=5.50/3.30 ppm)
methoxylbenzyl chloride in presence of DBU to afford the N -
are consistent with the electronegativity of fluorine, azido, and
amino functions. It is well known that coupling constants J1’-2’ is
primarily conformation-dependent. Sugar puckering of natural
ribo- and deoxyribonucleosides exist in dynamic equilibria
between two major conformers: the North (N) and the South
protected nucleoside 15 in 78% yield (Scheme 4). This com-
pound submitted to usual fluorination conditions led to the
unexpected 2’-fluoro-ribonucleoside analog (see supporting
information). Unfortunately, the retention of the configuration
of C-2’ sugar residue demonstrates that this strategy cannot
circumvent the neighboring group participation by the respec-
[24]
(S).
NMR studies of 2’-substituted ribonucleoside analogs
2
3
demonstrated that the contribution of the N form (2’-exo-3’-exo)
tive O -atom in fluorination conditions. Using N -benzyl uridine
analogs, similar results have just been reported during the
[25]
increases with the electronegativity of the 2’-substituent. In
addition, it seems reasonable that the bulky methyl group in 3’-
position adopts an equatorial position of the sugar plane
increasing the N conformer population. Thus, as observed for
[30]
writing of this article.
3
Azidation. The N -protected nucleoside 15 treated under the
conditions used for the preparation of nucleoside 11
(Scheme 3) gave rise to a complex mixture of at least three
compounds (see supporting information). A chromatography
separation allows separating one of them, which turns out to
be the unexpected 2’-azido-ribonucleoside analog presenting
retention of the configuration. The other mixture fractions were
collected, treated with methanolic ammonia to provide after
purification the 2’,3’-unsaturated nucleoside analog and the
target nucleoside 16 in low yield (23%). Finally, the PBM group
is removed from the purified intermediate 16 using the mild
oxidizing reagent ceric ammonium nitrate (CAN) to afford the
desired 2’-azido-3’-deoxy-3’-C-methyl arabinonucleoside 17.
2
’-fluoro derivatives, the anomeric protons of 2’-azido-ribonu-
cleosides 12 and 13 appeared as a singlet in accordance with
the Karplus equation.
In the case of the 2’-amino derivative 14, the measured J1’–2
(2.5 Hz) seems to indicate that the equilibrium of the canonical
conformers would be less in favor of the N form. This result was
already observed for other 2’-amino pyrimidine and purine
[25,26]
nucleosides.
In addition, the (2’R) configuration of the 2’-
azido nucleoside 12 was corroborated by the NOE effects
1
3
observed between H-6, H-2’, and H-3’ protons. Finally, the
C
NMR analysis showed a downfield C2’ chemical shifts correlated
Scheme 4. Synthesis of the 1-(2’-azido-2’,3’-dideoxy-3’-C-methyl-β-D-arabinofuranosyl)uracil 17
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The (2’S) configuration of the azidonucleoside 17 was
salt unless otherwise indicated. The nucleoside analog 1 was
[6a]
obtained following a previously published procedure.
assigned in comparison to its stereoisomer 12 on the basis of
1
NMR spectra and NOE experiments. In the H NMR spectrum of
2,2’-Anhydro-1-(5-O-benzoyl-3-deoxy-3-C-methyl-β-D-erythro-
1
7 the signal for the anomeric proton appeared at a lower field
resonance (δ=6.13 ppm) than that of the isomer 12 (δ=
.73 ppm). The larger coupling constant (6.5 Hz) for the H-1’
pento-furanosyl)uracil (2): To a solution of the protected nucleo-
side 1 (1.81 g, 5.23 mmol) in anhydrous toluene (93 mL) were
added triphenylphosphine (2.73 g, 10.46 mmol) and diethyl azodi-
carboxylate (DEAD, 1.61 mL, 10.46 mmol). After stirring 30 min at
room temperature, the reaction mixture was evaporated under
reduced pressure and the resulting residue was subjected to silica
gel column chromatography using as eluent a stepwise gradient of
5
proton of 17 while the anomeric proton of 12 appeared as a
singlet providing additional support to the 1’,2-cis configuration
of 17. These typical H NMR patterns are in agreement with the
1
abundant literature in the field, especially with the empirical
rules used for the determination of the anomeric configuration.
Finally, irradiations of the 3’-methyl group of the nucleoside 17
gave large NOE effects (5.0%) on H-2’ and H-4’ protons
methanol (0–5%) in dichloromethane to afford the title compound
1
2
(1.55 g, 91% yield) as white solid. H NMR (CDCl ) δ=7.87–7.34
3
(m, 5H, C H CO), 7.29 (d, J=7.5, 1H, H-6), 6.11 (d, J=5.6, 1H, H-1’),
6 5
5
1
3
.98 (d, J=7.5, 1H, H-5), 5.06 (dd, J=5.6, J=2.7, 1H, H-2’), 4.31 (m,
H, H-5’), 4.20 (m, 2H, H-4’, H-5“), 2.67 (m, 1H, H-3’), 1.27 (d, J=7.3,
(Scheme 4). A similar effect was also observed between the
13
H, CH3); C NMR (CDCl ) δ=171.8 (CO), 165.9 (C-4), 159.6 (C-2),
3
same protons.
134.9 (C-6), 133.5-128.6 (Ph), 110.4 (C-5), 90.3 (C-1’), 89.2 (C-2’), 85.7
(
(
(
C-4’), 64.0 (C-5’), 41.5 (C-3’), 16.4 (CH ); UV (EtOH 95) λ =259 nm
3 max
+ +
ɛ=10700); MS: m/z (FAB>0) 657 (2 M+H) , 329 (M+H) ; m/z
À
FAB<0) 327 (MÀ H) .
Conclusion
1
-(3-Deoxy-3-C-methyl-β-D-arabinofuranosyl)uracil (3): The 2,2’-O-
anhydronucleoside 2 (0.74 g, 2.25 mmol) was dissolved in meth-
anol/water (22.5 mL, 1/1:v/v) and treated with 1 MNaOH (22.5 mL)
for 30 min, then neutralized with glacial AcOH and evaporated to
dryness. The crude material was purified by silica gel column
chromatography using a stepwise gradient of methanol (0–10%) in
dichloromethane to afford the title compound 3 (0.49 g, 90% yield)
as white solid, which was crystallised from MeOH. m.p. 213–214°C
In summary, the stereoselective synthesis of 3’-deoxy-3’-C-
methyl nucleoside analogs of uracil and cytosine bearing
several modifications at the 2’-position of the sugar residue was
undertaken with the hope of discovering new compounds
endowed with potential activities. The corresponding arabino-
nucleoside and 2’-substituted ribonucleoside analogs were
relatively straightforward to obtain, whereas attempts to
introduce a substituent at C-2’-β (arabino) position of uracil
nucleosides by nucleophilic reactions failed (fluorination) or led
to complex mixtures (azidation). These results are due to the
neighboring group participation of the carbonyl function of the
[
8c]
[8b]
[
litt.: 211–213°C; 208–210°C (MeOH/toluene/petroleum ether);
1
H NMR (DMSO-d6) δ=11.20 (s, 1H, NH), 7.88 (d, J=8.1, 1H, H-6),
5
3
.98 (d, J=6.1, 1H, H-1’), 5.54 (d, J=8.1, 1H, H-5), 5.1 (bs, 1H, OH-5’),
.98 (pt, 1H, H-2’), 3.68 (m, 1H, H-5’), 3.57 (m, 2H, H-5“, H-4’), 3.38
13
(bs, 1H, OH-2’), 1.93 (1H, m, H-3’), 1.00 (d, J=6.6, 3H, CH3). C NMR
(DMSO-d6) δ=163.3 (C-4), 150.6 (C-2), 142.1 (C-6), 100.0 (C-5), 83.5
(C-1’), 83.4 (C-4’), 76.6 (C-2’), 60.0 (C-5’), 38.6 (C-3’), 14.0 (CH ); UV
EtOH 95) λ =262 nm (ɛ=9500); MS: m/z (FAB>0) 243 (M+H) ;
3
aglycon despite the protection of N -imide function. The
biological evaluations of these compounds are currently in
progress.
3
+
(
max
+
+
HRMS (ESI ): m/z calcd. for C H N O (M+H) : 243.0981; found:
1
0
15
2
5
2
43.0978; elemental analysis calcd (%) for C H N O : C, 49.58; H,
10 14 2 5
5
.83; N, 11.56; found: C, 49.89; H, 5.76; N, 11.52.
-(2,5-Di-O-acetyl-3-deoxy-3-C-methyl-β-D-arabinofuranosyl)
1
Experimental Section
uracil (4): To a solution of the arabinonucleoside 3 (94.2 mg,
General Information: Melting points (m.p.) were determined in
0.39 mmol) in anhydrous pyridine (2.3 mL) were added acetic
open capillary tubes on a Gallenkamp MFB-595-010M apparatus
anhydride (0.54 mL) and
ylaminopyridine (DMAP). The solution was stirred 30 min at room
temperature and then, neutralised with solid NaHCO . The reaction
a catalytic amount of 4-dimeth-
1
13
and are uncorrected. H NMR and C NMR spectra were recorded at
3
19
00 MHz on a Bruker 300 Advance, F spectra at 250 MHz on
3
Bruker 250. Chemical shifts are quoted in parts per million (ppm)
using residual non-deuterated solvents as internal references.
Deuterium exchange, decoupling, and COSY experiments were
performed in order to confirm proton assignments. Coupling
mixture was extracted with diethyl ether and the organic layer was
evaporated to dryness. The crude material was purified by silica gel
column chromatography using a stepwise gradient of methanol (0–
2%) in dichloromethane to afford the title compound 4 (75.0 mg,
1
13
1
constants, J, are reported in Hertz. 2D H- C heteronuclear COSY
59% yield) as white solid. H NMR (CDCl
3
) δ=8.50 (s, 1H, NH), 7.50
13
spectra were recorded for the attribution of C signals. UV spectra
were recorded on an Uvikon 931 (Kontron). IR spectra were
recorded on a Perkin Elmer Paragon 1000 FT-IR. FAB mass spectra
were recorded in the positive-ion or negative-ion mode on a JEOL
JMS DX 300 using thioglycerol/glycerol (1:1, v/v, GÀ T) as matrix. ESI
HRMS were recorded in the positive mode on a Micromass Q-TOF
Waters. TLC was performed on pre-coated aluminium sheets of
silica gel 60 F254 (Merck, Art. 9385), visualization of products being
accomplished by UV absorbance followed by charring with 5%
ethanolic sulphuric acid with heating. Solvents were reagent grade
or purified by distillation prior to use, and solids were dried over
P2O5 under reduced pressure at rt. Moisture-sensitive reactions
were performed under an argon atmosphere using oven-dried
glassware. All aqueous solutions were saturated with the specified
(d, J=8.2, 1H, H-6), 6.11 (d, J=5.1, 1H, H-1’), 5.66 (dd, J=8.1, J=2.2,
1H, H-5), 5.11 (pt, 1H, H-2’), 4.28 (dd, J=5.5, J=12.3, 1H, H-5“), 4.23
(dd, J=3.7, J=12.3, 1H, H-5’), 3.81 (m, 1H, H-4’), 2.13 (m, 1H, H-3’),
1
3
2.07 (s, 3H, CH
NMR (CDCl ) δ=170.5 (CO), 169.3 (CO), 162.7 (C-4), 149.7 (C-2),
140.6 (C-6), 101.4 (C-5), 83.9 (C-1’), 81.5 (C-4’), 77.5 (C-2’), 63.7 (C-5’),
39.9 (C-3’), 20.8 (CH CO), 20.6 (CH CO), 15.3 (CH ); UV (EtOH 95)
max =259 nm (ɛ=9900); MS: m/z (FAB>0) 653 (2 M+H) , 327 (M
CO), 1.94 (s, 3H, CH CO), 1.15 (d, J=7.0, 3H, CH ); C
3
3
3
3
3
3
3
+
λ
+
+
+
À
+H) , 215 (S) , 113 (BH
) ; m/z (FAB<0) 651 (2MÀ H) , 325
2
À
À
(MÀ H) , 111 (B) .
1
-(3-Deoxy-3-C-methyl-β-D-arabinofuranosyl)cytosine (5): Lawes-
son’s reagent (64.8 mg, 0.16 mmol) was added to a solution of the
protected nucleoside 4 (75.0 mg, 0.23 mmol) in anhydrous 1,2-
dichloroethane (7.3 mL) and the reaction mixture was refluxed for
Eur. J. Org. Chem. 2021, 1–9
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+
+
2
h. The solvent was evaporated under reduced pressure and the
17500); MS: m/z (FAB >0) 517 (M+H) , 113 (BH ) ; m/z (FAB<0)
2
À
À
À
À
residue was purified by silica gel column chromatography using a
stepwise gradient of methanol (0–1%) in dichloromethane afford-
ing the corresponding 4-thioamide intermediate as orange foam.
The latter was dissolved in methanolic ammonia (7 mL, saturated
beforehand at À 10°C and stoppered tightly) and heated overnight
at 100°C in a stainless-steel bomb. After cooling to room temper-
1031 (2MÀ H) , 515 (MÀ H) , 243 (M-mMTr) , 111 (B) .
-(2,3-Dideoxy-2-fluoro-3-C-methyl-β-D-ribofuranosyl)uracil (8): A
solution of the protected nucleoside 7 (454.9 mg, 0.88 mmol) in a
mixture of AcOH, methanol and water (26 mL, 8/1/1:v/v/v) was
stirred overnight at room temperature. The solvent was evaporated
under reduced pressure and the residue was purified by silica gel
column chromatography using a stepwise gradient of methanol (0–
1
ature, the solution was evaporated under reduced pressure and the
residue was subjected to silica gel column chromatography using
as eluent a stepwise gradient of methanol (0–15%) in dichloro-
methane to afford the title compound 5 (51.0 mg, 92% yield) as
1
8
0%) in dichloromethane to afford the title compound 8 (180.1 mg,
1
4% yield), which was crystallised from MeOH. m.p. 214–215°C; H
1
NMR (DMSO-d6) δ=11.4 (bs, 1H, NH), 8.06 (d, J=8.1, 1H, H-6), 5.83
white solid. H NMR (DMSO-d6) δ=7.76 (d, J=7.4, 1H, H-6), 7.01
(
5
d, J=17.5, 1H, H-1’), 5.58 (d, J=8.1, 1H, H-5), 5.26 (pt, 1H, OH-5’),
(
(
pd, 2H, NH ), 6.02 (d, J=5.8, 1H, H-1’), 5.65 (d, J=7.4, 1H, H-5), 5.29
d, J=5.4, 1H, OH-2’), 5.02 (pt, 1H, OH-5’), 3.92 (m, 1H, H-2’), 3.65
2
.12 (dd, J=4.0, J=52.3, 1H, H-2’), 3.85 (m, 1H, H-5’), 3.82 (m, 1H, H-
’), 3.60 (m, 1H, H-5“), 2.29 (dm, J=35.9, 1H, H-3’), 1.00 (d, J=6.7,
3H, CH ); C NMR (DMSO-d6) δ=163.3 (C-4), 150.2 (C-2), 139.9 (C-
4
(m, 1H, H-5’), 3.56 (m, 1H, H-5“), 3.49 (m, 1H, H-4’), 1.92 (m, 1H, H-3’),
1
3
13
3
1
.01 (d, J=6.7, 3H, CH3); C NMR (DMSO-d6) δ=165.4 (C-4), 155.5
6
4
), 100.8 (C-5), 98.5 (d, J=181.1, C-2’), 88.5 (d, J=37.0, C-1’), 85.8 (C-
19
(C-2), 142.7 (C-6), 92.5 (C-5), 84.1 (C-1’), 83.2 (C-4’), 76.5 (C-2’), 60.7
’), 58.8 (C-5’), 34.4 (d, J=19.6, C-3’), 7.9 (d, J=7.6, CH3); F NMR
(
C-5’), 39.5 (C-3’), 14.6 (CH ); UV (EtOH 95) λ =272 nm (ɛ=8000);
3
max
+
+
(DMSO-d6) δ=À 195,6 (m, J=17.5, J=52.3, J=35.9, F-2’); UV (EtOH
MS: m/z (FAB>0) 242 (M+H) , 112 (BH ) ; m/z (FAB<0) 240
2
+
À
+
+
95) λmax =259 nm (ɛ=10300); MS: m/z (FAB >0) 489 (2 M+H) ,
(
MÀ H) ; HRMS (ESI ): m/z calcd. for C H N O (M+H) : 242.1141;
10
16
3
4
+
+
À
À
2
1
45 (M+H) , 113 (BH ) ; m/z (FAB<0) 487 (2MÀ H) , 243 (MÀ H) ,
2
found: 242.1138.
À
+
+
11 (B) ; HRMS (ESI ): m/z calcd. for C H FN O (M+H) :
10 14 2 4
1
-(3-Deoxy-3-C-methyl-5-O-monomethoxytrityl-β-D-arabino-fura-
nosyl)uracil (6): 4-Monomethoxytrityl chloride (372.0 mg,
.21 mmol) was added to a solution of the protected nucleoside 3
265.3 mg, 1.10 mmol) in anhydrous pyridine (4.9 mL) and the
245.0938; found: 245.0938.
1
-(5-O-Acetyl-2,3-dideoxy-2-fluoro-3-C-methyl-β-D-ribofuranosyl)-
1
(
uracil (9): To a solution of the nucleoside 8 (94.6 mg, 0.39 mmol) in
anhydrous pyridine (3.9 mL) were added acetic anhydride
reaction mixture was refluxed for 4 h. After cooling to room
temperature, methanol (4 mL) was added and the reaction mixture
was evaporated under reduced pressure. The resulting residue was
subjected to silica gel column chromatography using as eluent a
stepwise gradient of methanol (0–5%) in dichloromethane to afford
(0.467 mL, 5.42 mmol) and a catalytic amount of DMAP. After
stirring 3 h at room temperature, EtOH 95 was added and the
reaction mixture was evaporated to dryness. The crude material
was purified by silica gel column chromatography using a stepwise
gradient of methanol (0–5%) in dichloromethane to afford the title
compound 9 (107.4 mg, 96% yield) as white foam. H NMR (CDCl )
1
the title compound 6 (472.2 mg, 84% yield) as foam. H NMR
1
3
(
1
CDCl ) δ=9.76 (bs, 1H, NH), 8.21 (d, J=8.1, 1H, H-6), 7.37-7.09 (m,
2H, Ph), 6.78 (m, 2H, Ph), 6.00 (d, J=5.8, 1H, H-1’), 5.31 (dd, J=8.1,
3
δ=8.84 (bs, 1H, NH), 7.60 (d, J=8.2, 1H, H-6), 5.79 (d, J=17.3, 1H,
H-1’), 5.65 (d, J=8.2, 1H, H-5), 5.00 (dd, J=4.2, J=51.5, 1H, H-2’),
J=1.3, 1H, H-5), 4.37 (bs, 1H, OH-2’), 4.12 (m, 1H, H-2’), 3.73 (s, 3H,
CH O), 3.57 (m, 1H, H-4’), 3.51 (dd, J=1.7, J=11.2, 1H, H-5’), 3.27
4
3
.33 (m, 2H, H-5’, H-5“), 4.10 (m, 1H, H-4’), 2.12 (m, 1H, H-3’), 2.06 (s,
3
13
H, CH O), 1.08 (dd, J=6.8, J=0.8, 3H, CH ); C NMR (CDCl ) δ=
3
3
3
(
dd, J=2.4, J=11.2, 1H, H-5“), 2.26 (m, 1H, H-3’), 0.97 (d, J=6.5, 3H,
13
170.3 (CO), 162.9 (C-4), 149.8 (C-2), 139.6 (C-6), 101.9 (C-5), 97.5 (d,
CH3); C NMR (CDCl ) δ=164.4 (C-4), 158.8 (Ph), 151.6 (C-2), 143.9-
3
J=186.4, C-2’), 90.9 (d, J=37.7, C-1’), 83.5 (C-4’), 62.4 (C-5’), 36.5 (d,
1
1
25.3 (Ph), 141.8 (C-6), 113.3 (Ph), 101.5 (C-5), 87.2 (CPh ), 85.4 (C-
’), 83.3 (C-4’), 78.1 (C-2’), 61.3 (C-5’), 55.3 (OCH ), 37.3 (C-3’), 13.6
3
19
J=20.4, C-3’), 20.7 (CH CO), 8.1 (d, J=8.3, CH ); F NMR (CDCl ) δ=
3
3
3
3
À 195,4 (m, J=17.3, J=51.5, J=33.9, J=0.8, F-2’); UV (EtOH 95)
(
CH ); UV (EtOH 95) λ =264 nm (ɛ=10600), 230 nm (ɛ=15900);
3
max
+
+ +
λ
max =258 nm (ɛ=9700); MS: m/z (FAB>0) 573 (2 M+H) , 287 (M
MS: m/z (FAB>0) 515 (M+H) , 113 (BH ) ; m/z (FAB<0) 1027
2
+
+
+
À
À
À
À
À
+H) , 175 (S) , 113 (BH
2
) ; m/z (FAB<0) 571 (2MÀ H) , 285
(2MÀ H) , 513 (MÀ H) , 241(M-mMTr) ,111 (B) .
À
À
(MÀ H) , 111 (B) .
1
-(2,3-Dideoxy-2-fluoro-3-C-methyl-5-O-monomethoxytrityl-β-D-
1
-(2,3-Dideoxy-2-fluoro-3-C-methyl-β-D-ribofuranosyl)cytosine
ribofuranosyl)uracil (7): To a solution of the protected arabinonu-
cleoside 6 (435.0 mg, 0.85 mmol) in a mixture of dry dichloro-
methane and pyridine (5.1 mL, 92/8:v/v) at 0°C was added DAST
(
10): Lawesson’s reagent (80.5 mg, 0.20 mmol) was added to a
solution of the protected nucleoside 9 (81.4 mg, 0.28 mmol) in
anhydrous 1,2-dichloroethane (9 mL) and the reaction mixture was
refluxed for 2 h. The solvent was evaporated under reduced
pressure and the residue was purified using silica gel column
chromatography using a stepwise gradient of methanol (0–1%) in
dichloromethane to give the corresponding 4-thioamide intermedi-
ate as a yellow foam. The foam was dissolved in methanolic
ammonia (10 mL, saturated beforehand at À 10°C and stoppered
tightly) and heated overnight at 100°C in a stainless-steel bomb.
After cooling to room temperature, the solution was evaporated
under reduced pressure and the residue was subjected to silica gel
column chromatography using as eluent a stepwise gradient of
(
166 μL, 1.35 mmol). The reaction mixture was stirred at room
temperature one day, neutralized with saturated NaHCO and
3
diluted with dichloromethane (30 mL). The organic layer was
washed with water, dried over sodium sulfate and evaporated to
dryness. The residue was purified by silica gel column chromatog-
raphy using as eluent a stepwise gradient of methanol (0–2%) in
dichloromethane to afford the title compound 7 (398.7 mg, 91%
yield) as white foam. H NMR (CDCl ) δ=10.55 (bs, 1H, NH), 8.16 (d,
1
3
J=8.1, 1H, H-6), 7.46–7.22 (m, 12H, Ph), 6.87 (m, 2H, Ph), 6.05 (d, J=
1
1
1
1
1
1
6.3, 1H, H-1’), 5.40 (d, J=8.1, 1H, H-5), 5.00 (dd, J =3.7, J=51.4,
H, H-2’), 4.02 (m, 1H, H-4’), 3.78 (s, 3H, CH O), 3.73 (dd, J=1.6, J=
1.5, 1H, H-5’), 3.36 (dd, J=2.3, J=11.5, 1H, H-5“), 2.56 (dm, J=34.1,
H, H-3’), 1.01 (d, J=6.7, 3H, CH3); C NMR (CDCl ) δ=164.1 (C-4),
58.8 (Ph), 150.5 (C-2), 143.8-123.9 (Ph), 140.0 (C-6), 113.7 (Ph),
02.0 (C-5), 98.2 (d, J=185.7, C-2’), 89.3 (d, J=38.0, C-1’), 87.2
’
3
methanol (0–15%) in dichloromethane to afford the title com-
pound 10 (50.0 mg, 72% yield) as white solid. H NMR (D
1
13
2
O) δ=
3
7
1
.84 (d, J=7.5, 1H, H-6), 5.89 (d, J=7.5, 1H, H-5), 5.86 (d, J=17.7,
H, H-1’), 4.96 (dd, J=4.0, J=51.8, 1H, H-2’), 3.97 (m, 1H, H-4), 3.92
(m, 1H, H-5’), 3.69 (dd, J=4.0, J=13.0, 1H, H-5“), 2.13 (dm, J=35.2,
(CPh ), 85.0 (C-4’), 60.6 (C-5’), 55.2 (OCH ), 35.6 (d, J=19.6, C-3’), 8.0
3
3
13
19
1H, H-3’), 0.98 (d, J=6.8, 3H, CH
66.3 (C-2), 141.1 (C-6), 98.7 (d, J=182.6, C-2’), 95.5 (C-5), 90.0 (d,
J=37.7, C-1’), 86.0 (C-4’), 60.0 (C-5’), 35.4 (d, J=19.6, C-3’), 7.2 (d,
3
); C NMR (D O) δ=171.0 (C-4),
2
(
3
d, J=7.6, CH3); F NMR (CDCl ) δ=À 196,5 (m, J=16.3, J=51.4, J=
3
1
4.1, F-2’); UV (EtOH 95) λmax =260 nm (ɛ=11300), 231 nm (ɛ=
1
9
J=8.3, CH3); F NMR (D O) δ=À 196.1 (m, J=17.7, J=51.8, J=33.9,
2
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F-2’); UV (EtOH 95) λ =272 nm (ɛ=8700); MS m/z (FAB>0) 244
3.80 (m, 1H, H-5’), 3.69 (m, 1H, H-4’), 3.55 (m, 1H, H-5“), 2.20 (m, 1H,
H-3’), 0.96 (d, J=6.7, 3H, CH3); C NMR (DMSO-d6) δ=166.9 (C-4),
155.0 (C-2), 140.2 (C-6), 93.0 (C-5), 89.2 (C-1’), 86.1 (C-4’), 70.1 (C-2’),
max
+
+
+
13
(
M+H) , 112 (BH ) ; HRMS (ESI ): m/z calcd. for C H FN O (M+
2
10 15
3
3
+
H) : 244.1097; found: 244.1098.
5
8
2
8.9 (C-5’), 33.4(C-3’), 9.3 (CH ); UV (EtOH 95) λ =272 nm (ɛ=
3
max
1
-(2-Azido-5-O-benzoyl-2,3-dideoxy-3-C-methyl-β-D-ribofurano-
À
1
+
900); IR υ=2110 (s) cm (N ); MS: m/z (FAB>0) 533 (2 M+H) ,
3
syl)-uracil (11): Lithium fluoride (10.96 mg, 0.42 mmol) was sus-
pended in anhydrous DMF (0.26 mL) at room temperature. To the
stirred suspension was added N,N,N’,N’-tetramethylethylenediamine
+
+
À
À
67 (M+H) , 112 (BH ) ; m/z (FAB<0) 531 (2MÀ H) , 265 (MÀ H) ;
2
+
+
HRMS (ESI ): calcd. for C H N O (M+H) : 267.1206; found:
1
0
15
6
3
267.1206.
(TMEDA, 0.23 mL, 1.54 mmol) followed by azidotrimethylsilane
(
65 μL, 0.49 mmol). The reaction mixture was heated 3 h at 110°C
1-(2-Amino-2,3-dideoxy-3-C-methyl-β-D-ribofuranosyl)uracil (14):
A solution of the nucleoside analog 12 (213.1 mg, 0.80 mmol) and
triphenylphosphine (315.7 mg, 1.20 mmol) in anhydrous pyridine
and the 2,2’-O-anhydronucleoside 2 (84.4 mg, 0.26 mmol) was
added. After stirring 48 h at 110°C, the solvent was evaporated
under reduced pressure and the residue was subjected to silica gel
column chromatography using as eluent a stepwise gradient of
methanol (0–2%) in dichloromethane to afford the title compound
(10 mL) was stirred 1 h at room temperature, then NH OH (20%,
4
6.2 mL) was added. After overnight stirring at room temperature,
the volatiles were evaporated under reduced pressure and the
residue was subjected to silica gel column chromatography using
as eluent a stepwise gradient of methanol (0–15%) in dichloro-
methane to afford the title compound 14 (142.0 mg, 74% yield)
1
1
7
1 (95.4 mg, 72% yield) which was crystallised from EtOH 100. m.p.
1
53–154°C; H NMR (CDCl ) δ=9.25 (bs, 1H, NH), 7.94 (m, 2H, Ph),
3
.71 (d, J=8.2, 1H, H-6), 7.58–7.39 (m, 3H, Ph), 5.76 (s, 1H, H-1’), 5.39
1
(
d, J=8.2, 1H, H-5), 4.62 (dd, J=2.4, J=13.0, 1H, H-5’), 4.57 (dd, J=
which was lyophilised in water. H NMR (DMSO-d6) δ=11.3 (bs, 1H,
3
2
1
1
9
1
3
.1, J=13.0, 1H, H-5“), 4.15 (d, J=5.5, 1H, H-2’), 4.11 (m, 1H, H-4’),
NH), 8.06 (d, J=8.1, 1H, H-6), 5.55 (d, J=8.1, 1H, H-5), 5.50 (d, J=
2.5, 1H, H-1’), 5.07 (pt, 1H, OH-5’), 3.80 (m, 1H, H-4’), 3.73 (ddd, J=
2.0, J=4.8, J=12.3, 1H, H-5’), 3.52 (ddd, J=3.6, J=7.4, J=12.3, 1H,
H-5“), 3.30 (dd, J=2.5, J=6.4, 1H, H-2’), 2.10 (m, 1H, H-3’), 0.98 (d,
13
.17 (m, 1H, H-3’), 1.10 (d, J=6.7, 3H, CH3); C NMR (CDCl ) δ=
3
66.0 (CO), 162.9 (C-4), 149.9 (C-2), 138.7 (C-6), 133.8–128.7 (Ph),
01.7 (C-5), 90.4 (C-1’), 84.2 (C-4’), 70.1 (C-2’), 62.0 (C-5’), 35.4 (C-3’),
.3 (CH ); UV (EtOH 95) λ =261 nm (ɛ=10400), 228 nm (ɛ=
1
3
J=6.7, 3H, CH3); C NMR (DMSO-d6) δ=163.3 (C-4), 150.6 (C-2),
140.5 (C-6), 100.5 (C-5), 91.3 (C-1’), 85.7 (C-4’), 60.4 (C-5’), 59.8 (C-2’),
34.7 (C-3’), 10.1 (CH ); UV (EtOH 95) λ =262 nm (ɛ=10200); MS:
3
max
À 1
+
5500); IR υ=2112 (s) cm (N ); MS: m/z (FAB>0) 743 (2 M+H) ,
72 (M+H) , 260 (S) , 113 (BH ) ; m/z (FAB>0) 370 (MÀ H) , 111
3
+
+
+
À
2
3
max
À
+
+
+
(B) .
m/z (FAB>0) 242 (M+H) , 130 (S) , 113 (BH ) ; m/z (FAB<0) 240
2
À
À
+
+
(
2
MÀ H) , 111 (B) ; HRMS (ESI ): calcd. for C H N O (M+H) :
1
0
16
3
4
1
-(2-Azido-2,3-dideoxy-3-C-methyl-β-D-ribofuranosyl)uracil (12):
42.1141; found: 242.1141.
The protected nucleoside 11 (604.8 mg, 1.63 mmol) was dissolved
in methanolic ammonia (40.7 mL, saturated beforehand at À 10°C
and stoppered tightly) and the resulting solution was stirred
overnight at room temperature. The solution was evaporated under
reduced pressure and the residue was subjected to silica gel
column chromatography using as eluent a stepwise gradient of
methanol (0–5%) in dichloromethane to afford the title compound
1-(5-O-Benzoyl-3-deoxy-3-C-methyl-β-D-ribofuranosyl)-3-(p-meth-
oxybenzyl)uracil (15): To a suspension of nucleoside analog 1
(780 mg, 2.25 mmol) in anhydrous acetonitrile (22.5 mL) were
added p-methoxybenzyl chloride (550 μL, 4.05 mmol) and DBU
(673 μL, 4.05 mmol). The reaction mixture was refluxed for 2 h then,
cooled to 0°C, hydrolyzed with a KHSO (5%) solution and diluted
4
1
1
1
1
1
1
2 (385 mg, 89% yield) which was crystallised from EtOH 100. m.p.
with dichloromethane. After decantation, the organic layer was
dried (Na SO ), concentrated to dryness and the residue was
1
67–168°C; H NMR (DMSO-d6) δ=11.4 (bs, 1H, NH), 8.10 (d, J=8.1,
2
4
H, H-6), 5.73 (s, 1H, H-1’), 5.58 (dd, J=8.1, J=1.9, 1H, H-5), 5.23 (pt,
H, OH-5’), 4.42 (d, J 5.6, 1H, H-2’), 3.80 (ddd, J=2.2, J=5.5, J=
purified by silica gel column chromatography using as eluent a
stepwise gradient of methanol (0–2%) in dichloromethane to afford
’
=
1
2.7, 1H, H-5’), 3.69 (m, 1H, H-4’), 3.55 (ddd, J=2.4, J=4.8, J=12.7,
H, H-5“), 2.30 (m, 1H, H-3’), 0.98 (d, J=6.7, 3H, CH3); C NMR
the title compound 15 (819 mg, 78% yield) as white foam. H NMR
1
3
(CDCl ) δ=7.94 (m, 2H, Ph), 7.66 (d, J=8.1, 1H, H-6), 7.57–7.33 (m,
3
(
(
(
DMSO-d6) δ=163.3 (C-4), 150.3 (C-2), 139.6 (C-6), 100.6 (C-5), 88.7
5H, Ph), 6.75 (m, 2H, Ph), 5.58 (s, 1H, H-1’), 5.47 (d, J=8.1, 1H, H-5),
C-1’), 86.3 (C-4’), 69.8 (C-2’), 58.8 (C-5’), 33.7 (C-3’), 9.4 (CH ); UV
4.95 (d, J=13.6, 2H, CH Ph), 4.63 (dd, J=2.4, J=12.9, 1H, H-5’), 4.55
3
2
À 1
EtOH 95) λmax =261 nm (ɛ=10400); IR υ=2110 (s) cm (N ); MS:
(dd, J=3.3, J=12.9, 1H, H-5“), 4.25 (m, 1H, H-4’), 4.15 (d, J=5.1, 1H,
3
+
+
+
m/z (FAB>0) 268 (M+H) , 113 (BH ) ; HRMS (ESI ): calcd. for
C H N O (M+H) : 268.1046; found: 268.1050.
H-2’), 3.70 (s, 3H, CH O), 2,85 (bs, 1H, OH-2’), 2.04 (m, 1H, H-3’), 1.07
2
3
+
13
(d, J=6.8, 3H, CH3); C NMR (CDCl ) δ=167.6 (CO), 164.0 (C-4),
1
0
14
5
4
3
1
60.6 (CH Ph), 152.6 (C-2), 138.2 (C-6), 135.1-130.1 (Ph), 115.2
2
2
1
(
-(2-Azido-2,3-dideoxy-3-C-methyl-β-D-ribofuranosyl)cytosine
13): To a solution of the protected nucleoside 11 (49.3 mg,
.13 mmol) in dry pyridine (820 μL) was added 1,2,4-triazole
(
5
CH Ph), 102.7 (C-5), 95.1 (C-1’), 85.5 (C-4’), 80.2 (C-2’), 64.2 (C-5’),
6.7 (OCH ), 44.9 (CH Ph), 37.7 (C-3’), 10.0 (CH ); UV (EtOH 95) λ
=
max
3
2
3
0
2
64 nm (ɛ=11500), 225 nm (ɛ=27900); MS: m/z (FAB >0) 933
(
120.6 mg, 1.75 mmol) followed by the dropwise addition at 0°C of
+
+
À
À
(2 M+H) , 467 (M+H) ; m/z (FAB<0) 465 (MÀ H) , 231 (B) .
4
-chlorophenylphosphorodichloridate (95 μL, 0.59 mmol). The reac-
tion mixture was stirred one day at room temperature, and the
solvent was evaporated to dryness. The residue was dissolved in
dichloromethane (8.7 mL) and washed with water. After decant-
ation, the organic layer was dried (Na SO ), concentrated to dryness
1-(2-Azido-2,3-dideoxy-3-C-methyl-β-D-arabinofuranosyl)-3-(p-
methoxybenzyl)-uracil (16): To a solution of the protected nucleo-
side 15 (0.64 g, 1.37 mmol) in dry THF (13.5 mL) was added
triphenylphosphine (1.07 g, 4.10 mmol). The reaction mixture was
cooled at À 10°C and a solution of diethyl azodicarboxylate (DEAD,
2
4
and the residue was purified by silica gel column chromatography
using as eluent a stepwise gradient of methanol (0–3%) in
dichloromethane to afford the 4-triazolyl intermediate. This last was
0.64 mL, 4.105 mmol) and diphenylphosphorylazide (DPPA,
0.89 mL, 4.10 mmol) in dry THF was added dropwise. After stirring
10 min at À 10°C then 2 h at room temperature, the solvent was
then dissolved in NH OH (28%)/dioxane (1.85 mL, 1/3, v/v) and the
4
reaction mixture was stirred overnight at room temperature. After
evaporation to dryness, the resulting residue was subjected to silica
gel column chromatography using as eluent a stepwise gradient of
methanol (0–10%) in dichloromethane to afford the title com-
pound 13 (23.7 mg, 67% yield) as white solid. H NMR (DMSO-d6)
δ=8.07 (d, J=7.5, 1H, H-6), 7.15 (bs, 2H, NH ) 5.71 (s, 1H, H-1’), 5.69
evaporated under reduced pressure and the residue was subjected
to silica gel column chromatography using as eluent a stepwise
gradient of methanol (0–1%) in dichloromethane. The collected
fractions containing products with R =0.3 (diethyl ether/petroleum
f
1
ether, 8/2:v/v) were evaporated and the residue was subjected to
silica gel column chromatography using an isocratic elution of
diethyl ether/petroleum ether (1/1:v/v). The appropriate fractions
2
(d, J=7.5, 1H, H-5), 5.19 (pt, 1H, OH-5’), 4.24 (d, J=5.5, 1H, H-2’),
Eur. J. Org. Chem. 2021, 1–9
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7
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Full Papers
doi.org/10.1002/ejoc.202100236
were evaporated under reduced pressure and the residue (0.42 g,
.90 mmol) was dissolved in methanolic ammonia (30 mL, saturated
[3] a) A. Matsuda, K. Takenuki, H. Itoh, T. Sasaki, T. Ueda, Chem. Pharm. Bull.
987, 35, 3967–3970; b) A. Matsuda, K. Takenuki, T. Sasaki, T. Ueda, J.
1
0
Med. Chem. 1991, 34, 234–239.
4] P. Franchetti, L. Cappellacci, M. Pasqualini, R. Petrelli, P. Vita, H. N.
Jayaram, Z. Horvath, T. Szekeres, M. Grifantini, J. Med. Chem. 2005, 48,
beforehand at À 10°C and stoppered tightly). The resulting solution
was stirred overnight at room temperature then, evaporated under
reduced pressure. The residue was subjected to reverse phase
column chromatography using as eluent a stepwise gradient of
acetonitrile (15–20%) in water to afford the title compound 16
[
4
983–4989.
[
5] G. M. Keating, Drugs 2014, 74, 1127–1146.
[6] a) S. Couturier, M. Aljarah, G. Gosselin, C. Mathé, C. Périgaud,
Tetrahedron 2007, 63, 11260–11266; b) M. Aljarah, S. Couturier, C.
Mathé, C. Périgaud, Bioorg. Med. Chem. 2008, 16, 7436–7442.
(
121.8 mg, 23% yield) which was crystallised from EtOH 100. m.p.
1
1
7
56–157°C; H NMR (CDCl ) δ=7.73 (d, J=8.1 Hz, 1H, H-6), 7.40-
3
[
[
7] J. J. Fox, Pure Appl. Chem. 1969, 18, 223–256.
8] a) M. Ashwell, A. S. Jones, R. T. Walker, Nucleic Acids Res. 1987, 15, 2157–
.33 (m, 2H, Ph), 6.74 (m, 2H, Ph), 6.16 (d, J=6.1, 1H, H-1’), 5.68 (d,
J=8.1, 1H, H-5), 4.99 (m, 2H, CH Ph), 3.91 (m, 2H, H-5’, H-2’), 3.70 (s,
2
2
1
166; b) T. R. Webb, H. Mitsuya, S. Broder, J. Med. Chem. 1988, 31, 1475–
479; c) K. Hirota, H. Takasu, H. Sajiki, Heterocycles 2000, 52, 1329–1336.
3
1
1
H, CH O), 3,67 (s, 1H, H-5“), 3.60 (m, 1H, H-4’), 2.13 (m, 1H, H-3’),
3
13
.10 (d, J=6.7, 3H, CH3); C NMR (CDCl ) δ=162.8 (CO), 159.0 (C-4),
3
[9] a) M. P. Cava, M. I. Levinson, Tetrahedron 1985, 41, 5061–5087; b) K.
Felczak, M. Bretner, T. Kulikowski, D. Shugar, Nucleosides Nucleotides
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51.1 (C-2), 138.3 (C-6), 133.2-130.3 (Ph), 113.7 (Ph), 101.5 (C-5), 84.6
(C-4’ ), 84.5 (C-1’), 69.5 (C-2’), 60.8 (C-5’), 55.2 (CH O), 43.6 (CH Ph),
3
2
3
7.5 (C-3’), 14.6 (CH ); UV (EtOH 95) λ =263 nm (ɛ=10500),
[10] a) D. H. Hollenberg, K. Watanabe, J. J. Fox, J. Med. Chem. 1977, 20, 113–
3
max
À 1
1
16; b) C. F. Hummel, R. P. Carty, Nucleosides Nucleotides 1983, 2, 249–
255; c) M. E. Perlman, K. A. Watanabe, Nucleosides Nucleotides 1987, 6,
21–630.
2
21 nm (ɛ=15200); IR υ=2112 (s) cm (N ); MS: m/z (FAB>0) 388
3
+
À
(
M+H) ; m/z (FAB<0) 231 (B) .
6
1
-(2-Azido-2,3-dideoxy-3-C-methyl-1-β-D-arabinofuranosyl)uracil
[11] a) J. F. Codington, I. L. Doerr, J. J. Fox, J. Org. Chem. 1964, 29, 558–564;
b) R. Mengel, W. Guschlbauer, Angew. Chem. Int. Ed. 1978, 17, 525–525;
Angew. Chem. 1978, 90, 555–556.
(
17): To a solution of the nucleoside 16 (134.6 mg, 0.35 mmol) in a
mixture of acetonitrile and water (11 mL, 8/2:v/v) was added ceric
ammonium nitrate (CAN, 1.14 g, 2.09 mmol). The reaction mixture
was stirred 2 h at room temperature, then evaporated under
reduced pressure. The crude residue was dissolved in dichloro-
methane (10 mL) and washed with water. After decantation, the
organic layer was dried (Na SO ), concentrated to dryness and the
residue was purified by silica gel column chromatography using as
eluent a stepwise gradient of methanol (0–5%) in dichloromethane
to afford the title compound 17 (62.3 mg, 67% yield) which was
[
12] I. A. Mikhailopulo, G. G. Sivets, N. E. Poopeiko, N. B. Khripach, Carbohydr.
Res. 1995, 278, 71–89.
[
[
13] J. V. Tuttle, M. Tisdale, T. A. Krenitsky, J. Med. Chem. 1993, 36, 119–125.
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2
4
[
16] a) J. Jonáš, A. Allerhand, H. S. Gutowsky, J. Chem. Phys. 1965, 42, 3396–
3
1
399; b) R. J. Cushley, J. F. Codington, J. J. Fox, Can. J. Chem. 1968, 46,
131–1140.
[
[
17] M. Blandin, T.-D. Son, J. C. Catlin, W. Guschlbauer, Biochim. Biophys. Acta
1
lyophilised in water. H NMR (DMSO-d6) δ=11.40 (bs, 1H, NH), 8.04
1
974, 361, 249–256.
(
d, J=8.1, 1H, H-6), 6.13 (d, J=6.5, 1H, H-1’), 5.61 (d, J=8.1, 1H, H-
), 5.24 (pt, 1H, OH-5’), 4.33 (dd, J=6.5, J=10.2, 1H, H-2’), 3.75 (m,
H, H-5’), 3.61 (m, 2H, H-4’, H-5“), 2.03 (m, 1H, H-3’), 1.07 (d, J=6.4,
H, CH3); C NMR (DMSO-d6) δ=163.0 (C-4), 150.5 (C-2), 140.5 (C-
), 100.9 (C-5), 84.4 (C-4’), 82.8 (C-1’), 68.4 (C-2’), 58.9 (C-5’), 36.0 (C-
18] a) M. M. Mansuri, B. Krishman, J. C. Martin, Tetrahedron Lett. 1991, 32,
1287–1290; b) S. Wang, J. Chang, S. Pan, K. Zhao, Helv. Chim. Acta 2004,
87, 327–339.
5
1
3
6
3
13
[19] F. Tellier, M. Audouin, M. Baudry, R. Sauvêtre, J. Fluorine Chem. 1999, 94,
27–36.
À 1
[20] a) G. P. Kirschenheuter, Y. Zhai, W. A. Pieken, Tetrahedron Lett. 1994, 35,
8517–8520; b) D. P. C. McGee, C. Vargeese, Y. Zhai, G. P. Kirschenheuter,
A. Settle, C. R. Siedem, W. A. Pieken, Nucleosides Nucleotides 1995, 14,
1329–1339.
’), 13.2 (CH ); IR υ=2112 (s) cm (N ); UV (EtOH 95) λ =261 nm
3
3
max
+
+
(
(
(
E=10000); MS: m/z (FAB>0) 535 (2 M+H) , 268 (M+H) , 113
+
À
À
À
BH ) ; m/z (FAB<0) 533 (2MÀ H) , 266 (MÀ H) , 111 (B) ; HRMS
2
+
+
ESI ): calcd. for C H N O (M+H) : 268.1046; found: 268.1046.
10
14
5
4
[21] W. L. Sung, J. Chem. Soc. Chem. Commun. 1981, 1089.
[
[
22] A. Zehl, D. Cech, Liebigs Ann. 1997, 595–600.
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Acknowledgements
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25] W. Guschlbauer, K. Jankowski, Nucleic Acids Res. 1980, 8, 1421–1433.
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S.C. is particularly grateful to the Ministère de l’Enseignement
Supérieur, de la Recherche et de l’Innovation, France, for a PhD
fellowship. This work was supported by Grants from the European
Economic Community program ‘Flavitherapeutics’ (QLK3-CT-2001-
1
979, 20, 4073–4076.
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1
[
1
0
0506).
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Huang, J. Wan, X. Wu, J. Deval, A. Fung, Z. Jin, H. Tan, K. Shaw, H. Kang,
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Conflict of Interest
5
790–5798; c) I. Nowak, J. F. Cannon, M. J. Robins, J. Org. Chem. 2007,
The authors declare no conflict of interest.
72, 532–537; d) T. Akiyama, H. Nishimoto, S. Ozaki, Bull. Chem. Soc. Jpn.
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[
30] F. Michailidou, T. Lebl, A. M. Z. Slawin, S. V. Sharma, M. J. B. Brown,
Keywords: Nucleoside analogs · Fluorination · Azidation ·
Pyrimidines · Antivirals
R. J. M. Goss, Molecules 2020, 25, 5513.
[
[
1] A. K. Dubey, A. Singh, S. Prakash, M. Kumar, A. K. Singh, Chem. Biol.
Interact. 2020, 332, 109298.
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Yates, K. L. Seley-Radtke, Antiviral Res. 2019, 162, 5–21.
Manuscript received: February 24, 2021
Revised manuscript received: March 15, 2021
Accepted manuscript online: March 16, 2021
Eur. J. Org. Chem. 2021, 1–9
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© 2021 Wiley-VCH GmbH
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These are not the final page numbers!

FULL PAPERS
The study of nucleoside and nucleo-
tide analogs has been the subject of
extensive development during these
last decades. In this field, additions
or substitutions on the sugar residue
had led to potent drugs in antiviral
and anticancer chemotherapies.
Herein, we reported the stereoselec-
tive synthesis of a new series of pyri-
midine nucleosides bearing a double
modification in the 2’ and 3’
Dr. S. Couturier, Dr. S. Peyrottes,
Prof. Dr. C. Périgaud*
1
– 9
2’-Derivatisation of 3’-C-Methyl Pyri-
midine Nucleosides
positions of the sugar scaffold.