Synthesis and biological evaluation of fluorinated acyclothionucleosides

Article abstract of DOI:10.1016/j.jfluchem.2008.04.005

The discovery of thio- and fluoro-nucleosides as antiviral or anticancer agents prompts us to explore the synthesis of acyclic analogues. In this paper is reported the preparation of acyclothionucleosides by the alkylation of nucleic bases with difluorothio-esters and -alcohols. Compounds structurally close to known antiviral agents were tested towards a large variety of viruses.

Full text of DOI:10.1016/j.jfluchem.2008.04.005

Journal of Fluorine Chemistry 129 (2008) 848–851
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis and biological evaluation of fluorinated acyclothionucleosides
*
`
Sonia Gouault-Bironneau, Aboubacary Sene, Jean-Marie Catel, Thierry Lequeux
Laboratoire de Chimie Mole´culaire et Thio-organique, ENSICAEN, Universite´ de Caen Basse-Normandie, CNRS-UMR 6507, 6 boulevard du Mare´chal Juin, 14050 Caen, France
A R T I C L E I N F O
A B S T R A C T
Article history:
The discovery of thio- and fluoro-nucleosides as antiviral or anticancer agents prompts us to explore the
synthesis of acyclic analogues. In this paper is reported the preparation of acyclothionucleosides by the
alkylation of nucleic bases with difluorothio-esters and -alcohols. Compounds structurally close to
known antiviral agents were tested towards a large variety of viruses.
Received 27 February 2008
Received in revised form 21 April 2008
Accepted 21 April 2008
Available online 30 April 2008
ß 2008 Elsevier B.V. All rights reserved.
Keywords:
Acyclothionucleoside
Fluorosulfide
Nucleic base
1. Introduction
side chain of the purinic or pyrimidic bases. The most recent
example, reported by Haufe, described the synthesis of constrained
The synthesis and the biological evaluation of acyclic nucleo-
sides are still growing-up since the discovery of such compounds
as antiviral agents. For example, the synthesis of acyclovir,
ganciclovir or even PMEA has attracted considerable attention
(Fig. 1). Their modifications have been studied to prepare new
modified nucleosides with improved properties by the replace-
ment of the oxygen atom by a carbon atom [1] or a nitrogen atom
(azanucleoside) [2]. However, the insertion of a sulfur atom in their
side chain was less studied [3], although this modification was
successful in the discovery of antiviral agents, such as Lamivudine
[4].
It is well established that the introduction of fluorine atoms
onto a nucleosides enhances their biological properties. Since the
last decade a number of 20-(di)fluoronucleosides have been
described [5]. The replacement of a hydrogen atom or a hydroxyl
group by a fluorine atom often afforded new nucleosides with
potent antiviral or anticancer properties. For example, substitution
of the hydrogen atoms at the C-20 of deoxycitidine by fluorine
atoms resulted in the formation of Gemcitabine, a nucleoside with
high anticancer activity [6]. These observations are also true in the
case of acyclonucleosides as described for the fluoromethyl
derivative of PMEA (FPMPA), which was found to be highly active
against retroviruses [7].
monofluorinated nucleoside analogues I (Fig. 2) [8]. These
analogues have shown a low but specific activity against HSV-1
and HSV-2. To our knowledge only one paper reported the
synthesis of gem-difluorinated carba-analogues of acyclovir II
(Fig. 2). This latter showed an antiviral activity [9], but lower than
the acyclovir.
In view of these promising results, we decided to explore the
synthesis and biological studies of gem-difluoro-acyclothionucleo-
sides. In this paper, are described our attempts in the preparation
of acyclothionucleosides III and IV containing a difluoromethylene
group in the side chain (Fig. 3). The evaluation of their biological
activities towards a large variety of viruses is also reported.
2. Results and discussion
In connection with our scientific program concerning the
synthesis of fluorosulfides, we explored the synthesis of a variety of
thionucleosides from the functionnalized thioesters 1 and 2 (Fig. 3)
[10]. The readily available starting material 1 was obtained
according to the nucleophilic fluorination method previously
described [10,11]. The careful hydrolysis of 1 at 0 8C in the presence
of potassium carbonate afforded the expected alcohol 3 in 68%
yield (Scheme 1). The treatment of 1 by other bases (tBuOK, KOH)
or by working at room temperature induced a total degradation of
the alcohol 3, probably due to the formation of the corresponding
unstable thiolate. Reaction of the alcohol 3 with the appropriate
alkylsulfonyl chloride in the presence of triethylamine and a
catalytic amount of DMAP led to products 4a and 4b. The mesylate
4a was unstable at room temperature and was not isolated,
In contrast, only few articles describe the synthesis of acyclic
nucleosides in which a fluoromethylene group is introduced in the
* Corresponding author. Tel.: +33 2 3145 2854; fax: +33 2 3145 2865.
E-mail address: thierry.lequeux@ensicaen.fr (T. Lequeux).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.04.005

S. Gouault-Bironneau et al. / Journal of Fluorine Chemistry 129 (2008) 848–851
849
Fig. 1. Known antiviral agents.
Scheme 1. Reagents and conditions: (a) K2CO3, MeOH, 0 8C, 1 h, 68%; (b) TsCl, Et3N,
DMAP, CH2Cl2, 72 h, 38%; (c) 6-chloropurine, NaH, THF, 60 8C, 48 h, 15%. (d) 6-
chloropurine, or 6-aminopurine, or N3-Benzoylthymine or N3-Benzoyluracile, DIAD,
PPh3, THF, rt, overnight, 34–52%.
and 39% yield, respectively. N3-Benzoylthymine and N3-Benzoy-
luracile were also successfully alkylated when treated with 3 under
Mitsunobu conditions to afford 5c and 5d, respectively. In this case,
the exclusive alkylation at the N-1 position of the pyrimidines was
observed, and the N3-deprotection of the thymine occurred during
the alkylation stage [12]. The compound 5c was isolated in 34%
yield whereas 5d could not be separated from residual triphenyl-
phosphine oxide [13]. As mentioned for the preparation of the
alcohol 3, this latter is highly base sensitive and some degradation
occurred during the Mitsunobu reaction.
Fig. 2. Fluorinated acyclonucleosides.
However, attempts to introduce cytosine and guanine from the
alcohol 3 under Mitsunobu conditions failed, the starting material
being recovered (19F NMR). By using protected N4-acetylcytosine,
no product was formed due to its low solubility in the reaction
medium.
As in acyclovir, the in situ phosphorylation step of the terminal
hydroxyl group by HSV-encoded thymidine kinase is the initial
biochemical event leading to its antiherpetic activity [7], we
investigated the synthesis of a series of difluorinated acyclonucleo-
sides, possessing a terminal hydroxyl group, by reduction of 5. The
reduction of compounds 5a, 5c–d in the presence of sodium
borohydride at room temperature afforded the corresponding
alcohols 6a, 6c–d in good yields (Scheme 2), without any
degradation of the nucleic base.
Compounds 6a and 6c were isolated in 89% and 77%,
respectively. Derivative 6d was not isolated due, again, to residual
triphenylphosphine oxide from the previous step. Derivation of the
chloropurine into the corresponding hypoxanthine derivative 7
was realized by refluxing 6a in the presence of ethanethiol and
sodium methoxide according to the literature [14].
Fig. 3. Targeted fluorothionucleosides.
whereas the tosylate 4b was obtained in 38% yield. The alkylation
of 6-chloropurine with the tosylate 4b in the presence of sodium
hydride in THF gave the product 5a in low yield (15%) after 48 h at
60 8C. Whatever the conditions this yield could not be improved,
due to the thermal instability of 4b.
The alkylation of the nucleic bases under milder conditions was
explored to circumvent the limitation of the previous approach.
We applied Mitsunobu conditions to introduce the nucleic bases.
The coupling reaction was achieved directly from the alcohol 3, and
products 5a–c were isolated in 34–52% yields (Scheme 1),
depending on the nature of the nucleic base. In these reactions,
the exclusive alkylation at the N-9 position of the purines occurred.
Alkylation reactions of the 6-chloropurine or 6-aminopurine with
the alcohol 3 gave the corresponding products 5a and 5b in 52%
As an additional target of this research, the synthesis of
acyclonucleosides IV possessing a thiofluoromethylene group is in
the
a-position of the purine or pyrimidine base was investigated.
As depicted on Scheme 3, the starting ester 2 easily prepared by
Scheme 2. Reagents and conditions: (a) NaBH4, EtOH, rt, 2 h, 77–89%. (b) HSCH2CH2OH, NaOMe, MeOH, reflux, 6 h, 32%.

850
S. Gouault-Bironneau et al. / Journal of Fluorine Chemistry 129 (2008) 848–851
Scheme 3. Reagents and conditions: (a) NaBH4, EtOH, rt, 1 h, 71%; (b) (CF3SO2)2O, Et3N, CH2Cl2, 0 8C then rt, 3 h, quantitative; (c) 6-chloropurine, K2CO3, DMF, rt, 15 h, 16%.
Halex reaction was converted in the corresponding alcohol 8
selectively, and in good yield (71%) [10,11]. As expected, the
reduction is totally regioselective and affected the carbonyl
group activated by the adjacent difluoromethylene group
[15,16]. Triflate 9 was prepared at 0 8C and was used without
further purification due to its moisture sensitive character.
However, the alkylation of the 6-chloropurine was limited by
the instability of the triflate 9 in the medium. The compound 10
was obtained in low yield (<15%), and a partial degradation of 9
was observed after 15 h of stirring at room temperature [17]. Due
to this limitation, no further transformation was attempted to
obtain the acyclonucleosides IV.
layer was dried (MgSO4), filtered and concentrated under reduce
pressure. The crude product (5.5 g) was distilled under high
vacuum to afford the compound 1 (b.p.: 105 8C/4.10ꢁ2 mmHg) as a
colourless liquid (80%, 4.20 g, 18.4 mmol). 1H NMR (CDCl3):
d
2.08
(s, 3H, CH3CO), 3.13 (t, 3JHH = 6.5 Hz, 2H, CH2S), 3.90 (s, 3H, CH3O),
4.29 (t, 3JHH = 6.5 Hz, 2H, CH2O). 13C NMR (CDCl3):
d 20.7 (CH3(CO)),
27.4 (CH2S), 54.0 (CH3O), 62.8 (CH2O), 120.3 (t, 1JCF = 287 Hz, CF2),
2
162.0 (t, JCF = 33 Hz, CO(CF2)), 170.7 (CH3CO). 19F NMR (CDCl3,
CFCl3):
d
ꢁ82.5 (s, CF2). MS (EI), 70 eV, m/z (rel. int.): 169
[Mꢂ+ꢁCH3COO] (50), 168 (100), 109 (20), 59 (27), 43 (53). HRMS
(EI+): Not analysable.
Having in hand a series of acyclothionucleoside analogues III,
the biological activity of compounds 5a, 5c, 6a, 6c and 7 were
evaluated towards a large variety of virus ((HIV-1, HBV, BVDV,
YFV, DENV-2, WNV) in cell culture experiments. However, none of
4.3. Methyl 2,2-difluoro-2-(2-hydroxy-ethylsulfanyl) acetate (3)
To a solution of methyl 2,2-difluoro-2-(2-acetoxyethylsulfanyl)
acetate 1 (1.0 g, 4.42 mmol) in CH3OH (20 mL) cooled at 0 8C was
added in one portion dried K2CO3 (0.61 g, 4.38 mmol). The mixture
was stirred over 1 h and then quenched by addition of HClaq (1N,
10 mL), and the organic layer was extracted with CH2Cl2
(2 mL ꢀ 20 mL). The organic layer was dried (MgSO4) and
concentrated under vacuum. The crude product was purified by
flash column chromatography (pentane/ethyl acetate, 6:4, Rf = 0.4)
to afford 3 as a colourless liquid (68%, 553 mg, 2.98 mmol). 1H NMR
them presented a toxicity or activity at 100
viruses.
mM towards all these
3. Conclusion
We have synthetized acyclonucleoside analogues containing a
gem-difluoromethylene group, in few steps from readily available
fluorothioesters. Some difficulties appeared during these synth-
eses due to the presence of the sulfur and the fluorine atoms. In
some cases the nucleic base introduction was not possible.
Compounds 5a, 5c, 6a, 6c and 7, structurally close to the known
antiviral agents PMEA and acyclovir, did not exhibit any antiviral
activity towards a large variety of viruses.
(CDCl3):
(t, 3JHH = 6.0 Hz, 2H, CH2O), 3.93 (s, 3H, CH3O). 13C NMR (CDCl3):
31.0 (CH2S), 54.1 (CH2O), 63.3 (CH3O), 120.5 (t, 1JCF = 285 Hz, CF2),
d
3.09 (t, 3JHH = 6.0 Hz, 2H, CH2S), 3.79 (brs, 1H, OH), 3.88
d
162.3 (t, 2JCF = 33 Hz, CO). 19F NMR (CDCl3, CFCl3):
d
ꢁ82.1 (s, CF2).
HRMS (ESI) m/z [M+H]+ calcd for C5H9F2O3S 187.0240, found
187.0228.
4. Experimental
4.4. Methyl 2-[2-(6-chloropurin-9-yl)-ethylsulfanyl)]2,2-
difluoroacetate (5a)
4.1. General
To a suspension of PPh3 (423 mg, 1.61 mmol) and 6-chlor-
opurine (183 mg, 1.18 mmol) in THF (2 mL) under N2, was added a
solution of methyl 2,2-difluoro-2-(2-hydroxy-ethylsulfanyl) acet-
ate 3 (200 mg, 1.07 mmol) in THF (1 mL). To this cooled mixture
(0 8C) was slowly added DIAD (0.423 mL, 2.14 mmol). The mixture
was stirred at rt overnight and the solvent was evaporated under
reduce pressure. The crude product was purified by flash column
chromatography (pentane/ethyl acetate, 6:4, Rf = 0.2) to afford the
All reactions were carried out under an atmosphere of dry
nitrogen in flame or dried glassware with magnetic stirring. THF
was dried by pressure filtration on a drier apparatus. NMR data
appear in the following order: chemical shift in ppm, multiplicity
(s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet),
coupling constant J in Hz, number of protons. TMS and CFCl3 are the
internal standard for the CDCl3 or acetone-d6 solutions. The NMR
were respectively recorded at 250 MHz for the 1H NMR, 235 MHz
for the 19F NMR, and 100 MHz for the 13C NMR. Flash
compound 5a (m.p. = 130 8C) as a white solid (52%, 180 mg,
3
0.56 mmol). 1H NMR (CDCl3):
d
3.45 (t, JHH = 6.5 Hz, 2H, CH2S),
3
chromatography was realized with silica gel (40–63
m
m). All
3.95 (s, 3H, CH3O), 4.62 (t, JHH = 6.5 Hz, 2 H, CH2N), 8.20 (s, 1H),
reagents are commercially available and used without further
purification.
8.77 (s, 1H). 13C NMR (CDCl3):
d
28.4 (CH2S), 44.6 (CH2N), 54.4
1
(CH3O), 120.4 (t, JCF = 288 Hz, CF2), 131.8 (Car), 145.6 (CH), 151.3
(Car), 151.7 (CCl), 152.1 (CH), 161.6 (t, JCF = 33 Hz, CO). 19F NMR
2
4.2. Methyl 2,2-difluoro-2-(2-acetoxyethylsulfanyl) acetate (1)
(CDCl3, CFCl3):
d
ꢁ81,5 (s, CF2). HRMS (EI+) m/z [M]+ calcd for
C10H9ClF2N4O2S 322.0103, found 322.0109.
To a suspension of ZnBr2 (5.00 g, 23.0 mmol) in CH3CN (45 mL)
was added successively methyl 2,2-dichloro-2-(2-acetoxyethyl-
sulfanyl)-acetate (5.90 g, 23.0 mmol), and (HF)3-NEt3 (14.70 mL,
92.0 mmol). After 2 h under reflux, the cooled solution was diluted
by addition of Et2O/CH2Cl2 (50 mL, 1/1) and then washed with
NH4Clsat (3 mL ꢀ 10 mL) and NaClsat (2 mL ꢀ 10 mL). The organic
4.5. Methyl 2-[(5-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-
yl)-ethylsulfanyl]-2,2-difluoroacetate (5c)
To
benzoylthymine (408 mg, 1.77 mmol) in THF (3 mL) under N2,
a
suspension of PPh3 (634 mg, 2.42 mmol) and N3-

S. Gouault-Bironneau et al. / Journal of Fluorine Chemistry 129 (2008) 848–851
851
was added
a
solution of methyl 2,2-difluoro-2-(2-hydroxy-
4.8. 9-[2-(1,1-difluoro-2-hydro-ethylsulfanyl)-ethyl]-9H-purin-6-ol
(7)
ethylsulfanyl) acetate 3 (300 mg, 1.61 mmol) in THF (1.5 mL). To
this cooled mixture (0 8C) was slowly added DIAD (0.639 mL,
3.22 mmol). The mixture was stirred at rt overnight and the
solvent was evaporated under reduce pressure. The crude product
was purified by flash column chromatography (pentane/ethyl
acetate, 4:6, Rf = 0.3) to afford the compound 5c (m.p. = 123 8C) as a
To a solution of 6a (100 mg, 0.34 mmol) in CH3OH (15 mL) was
successively added EtSH (0.114 mL, 1.63 mmol) and then a 1 M
solution of CH3ONa in CH3OH (1.5 mL, 1.5 mmol). The stirred
mixture was refluxed over 8 h. To the cooled mixture was added
CH3CO2H (15 mL), and the solvents were removed under high
vacuum. The crude product (140 mg) was purified by flash column
white solid (34%, 161 mg, 0.55 mmol). 1H NMR (CDCl3):
d 1.91 (s,
3H, CH3), 3.14 (t, 3JHH = 7.5 Hz, 2H, CH2S), 3.90 (s, 3H, CH3O), 4.22 (t,
3JHH = 7.5 Hz, 2H, CH2N), 7.08 (brs, 1 H, CH), 10.3 (brs, 1H, NH). 13
C
chromatography (CH2Cl2/CH3OH, 9:1, Rf = 0.3) to afford 7
(m.p. = 254 8C) as a white powder (32%, 30 mg, 0.11 mmol). 1H
3
NMR (CDCl3):
d
= 12.9 (CH3), 26.1 (t, JCF = 3.0 Hz, CH2S), 40.2
1
3
(CH2N), 54.1 (CH3O), 110.2 (C(CH3)), 120.5 (t, JCF = 287 Hz, CF2),
135.2 (CH), 153.1 (CO), 162.2 (t, JCF = 33 Hz, CO), 163.9 (CO). 19F
NMR (CDCl3, CFCl3):
295 [M+1] (10), 294 [Mꢂ+] (16), 185 (100), 153 (20), 110 (32), 55
(13). HRMS (EI+) m/z [M+] calcd for C10H12F2N2O4S 294.0485,
found 294.0475.
NMR (DMSO-d6):
d
3.30 (t, JHH = 6.7 Hz, 2H, CH2S), 3.76 (t,
2
3
3JHF = 12.9 Hz, 2H, CH2CF2), 4.38 (t, JHH = 6.7 Hz, 2 H, CH2N), 8.05
(s, 1H), 8.08 (s, 1H). 13C NMR (DMSO-d6):
d
ꢁ82.5 (s, CF2). MS (EI), 70 eV, m/z (rel. int.):
d
27.2 (CH2S), 43.8
2
(CH2N), 64.3 (t, JCF = 28.6 Hz, CH2(CF2)), 124.1, 130.4 (t,
1JCF = 279.1 Hz, CF2), 140.6 (CHar), 145.9 (CHar), 148.6, 156.9 (C–
OH). 19F NMR (DMSO-d6, CFCl3):
d
ꢁ81.44 (t, JHF = 12.9 Hz, CF2).
3
MS (IE), 70 eV, m/z (rel. int.): 276 [Mꢂ+] (12), 195 (100), 149 (21),
136 (33), 115 (29), 82 (29). HRMS (EI+) m/z [M]+ calcd for
C9H10F2N4O2S 276.0493, found 276.0486.
4.6. 2-[2-(6-chloropurin-9-yl)-ethylsulfanyl)]2,2-difluoroethanol
(6a)
To a solution of 5a (170 mg, 0.53 mmol) in EtOH (6 mL) at 0 8C,
was added in one portion NaBH4 (40 mg, 1.06 mmol). The mixture
was stirred at rt over 2 h, and was quenched by addition of HClaq
(5 mL, 1 N). The mixture was extracted with CH2Cl2
(5 mL ꢀ 10 mL), and the organic layer was dried (MgSO4) then
concentrated under vaccum. The crude product was recrystallized
in Et2O/CH2Cl2 (1:1) to afford 6a (m.p. = 200 8C) as a white powder
Acknowledgments
We gratefully acknowledge to Dr. G. Gosselin (CNRS-UMR 5247,
´
Universite Montpellier II), and Prof. P. La Colla (University of
`
Cagliari, Italy) for the biological screening. ‘‘Ministere de l’Educa-
tion Nationale et de la Recherche’’ is acknowledge for its financial
support (Ph.D. grant to S.G.). This work has been performed within
(89%, 138 mg, 0.47 mmol). 1H NMR (acetone-d6):
d 3.53 (t,
´
´
the ‘‘Institut Normand de Chimie Moleculaire Macromoleculaire et
3
3
3JHH = 6.8 Hz, 2H, CH2S), 3.94 (dt, JHH = 6.9 Hz, JHF = 12.0 Hz,
´
ˆ
Medicinale’’ (INC3M), and the ‘‘PUNCHOrga’’ network (Pole
2H, CH2CF2), 4.74 (t, 3JHH = 6.8 Hz, 2H, CH2N), 5.07 (t, 3JHH = 6.9 Hz,
Universitaire de Chimie Organique).
1H, OH), 8.60 (s, 1H), 8.77 (s, 1H). 13C NMR (acetone-d6):
d 27.2 (t,
3JCF = 3.3 Hz, CH2S), 44.8 (CH2-N), 65.3 (t, 2JCF = 29.3 Hz, CH2(CF2)),
References
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130.5 (t, JCF = 278.5 Hz, CF2), 131.9 (Car), 147.3 (CH), 150.2 (Car),
151.9 (CH), 152.7 (Car). 19F (acetone-d6 CFCl3):
d
ꢁ82.4 (t,
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105 mg, 0.39 mmol). 1H NMR (acetone-d6):
d 1.83 (s, 3H, CH3), 3.06
3
3
3
(t, JHH = 7.4 Hz, 2H, CH2S), 3.92 (dt, JHH = 7.0 Hz, JHF = 12.5 Hz,
2H, CH2CF2), 4.14 (t, 3JHH = 7.4 Hz, 2H, CH2N), 4.93 (t, 3JHH = 7.0 Hz,
1H, OH), 7.31 (brs, 1H, CH), 9.78 (brs, 1H, NH). 13C NMR (acetone-
d6):
CH2CF2), 108.6 (CCH3), 130.4 (t, JCF = 277.4 Hz, CF2), 136.0 (CH),
151.6 (CO), 164.1 (CO). 19F (acetone-d6, CFCl3):
-93.9 (t,
3
d
12.3 (CH3), 25.2 (CH2S), 40.5 (CH2N), 65.1 (t, JCH = 29.8 Hz,
1
d
3JFH = 12.5 Hz, CF2). MS (EI), 70 eV, m/z (rel. int.): 266 [Mꢂ+] (5),
140 (20), 127 (100), 126 (37), 110 (45), 83 (23). Anal. Calcd for
C9H12F2N2O3S: C 40.60; H 4.54; S 12.04. Found C 40.33; H 4.73; S
12.57.
[15] T. Kitazume, T. Yamazaki, Experimental Methods in Organic Fluorine Chemisry,
Kodansha, Tokyo, 1998.
[16] M. Miyauchi, E. Nakayama, K. Watanabe, K. Fujimoto, J. Ide, Sankyo Kenkyusho
Nempo (Annu. Rep. Sankyo Res. Lab.) 38 (1986) 41–54.
[17] N.A. Fokina, A.M. Kornilov, V.P. Kukhar, J. Fluorine Chem. 111 (2001) 69–76.