Synthesis of 1′-C-fluoromethyladenosine

Article abstract of DOI:10.1080/15257770701542165

In search for new antiviral agents, we have been interested in 1′-C-fluoromethyl branched ribonucleosides. In this paper, we describe the synthesis of 1′-C-fluoromethyladenosine via electrophilic fluorination of exo-glycal. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770701542165

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Synthesis of 1′- C -
Fluoromethyladenosine
Annelaure Damont a , David Dukhan a , Gilles Gosselin a , Jérôme
Peyronnet a & Richard Storer b
a Laboratoire Coopératif Idenix, CNRS, Université Montpellier II ,
Montpellier, France
b Laboratoire de chimie médicinale, Cap Gamma , Montpellier,
France
Published online: 05 Dec 2007.
To cite this article: Annelaure Damont , David Dukhan , Gilles Gosselin , Jérôme Peyronnet & Richard
Storer (2007) Synthesis of 1′- C -Fluoromethyladenosine, Nucleosides, Nucleotides and Nucleic Acids,
26:10-12, 1431-1434, DOI: 10.1080/15257770701542165
To link to this article: http://dx.doi.org/10.1080/15257770701542165
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Nucleosides, Nucleotides, and Nucleic Acids, 26:1431–1434, 2007
Copyright ꢀ Taylor & Francis Group, LLC
C
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770701542165
SYNTHESIS OF 1ꢀ-C-FLUOROMETHYLADENOSINE
Annelaure Damont, David Dukhan, Gilles Gosselin, and Je´roˆ me Peyronnet
Laboratoire Coope´ratif Idenix, CNRS, Universite´ Montpellier II, Montpellier, France
2
Richard Storer
Laboratoire de chimie me´dicinale, Cap Gamma, Montpellier, France
2
In search for new antiviral agents, we have been interested in 1ꢁ-C-fluoromethyl branched ri-
2
bonucleosides. In this paper, we describe the synthesis of 1ꢁ-C-fluoromethyladenosine via electrophilic
fluorination of exo-glycal.
Keywords 1ꢁ-C-fluoromethyl branched ribonucleosides; exo-glycal; fluorination
INTRODUCTION
In recent years, there has been an increasing interest in the synthesis
of C-branched ribonucleosides. Various branchings on the 2ꢁ, 3ꢁ, or 4ꢁ po-
sition of the sugar moiety have been extensively studied for antiviral and
antitumor activities. Recently, 2ꢁ-C-methyl ribonucleosides have been discov-
ered as RNA viruses inhibitors, and NM283 (3ꢁ-O-(L-valinyl)-2ꢁ-C-methyl-β-
D-cytidine, valopicitabine) has been elected as a clinical candidate for HCV
treatment.[1−3]
Anomeric branched nucleosides are another class of compounds which
has attracted little attention due to synthetic challenges. In search for
new antiviral agents, we have been interested in the synthesis of 1ꢁ-C-
fluoromethyl branched ribonucleosides bearing adenine as the base. In this
regard, a methodology via electrophilic fluorination of exo-glycals has been
reported by others in the literature to synthesize anomeric mixture of 1ꢁ-
CH2F-ddC in order to investigate the influence of anomeric branching on
an anti-HIV agent.[4]
We thank Dr. V. Bichko (Idenix, Cambridge-USA) and M. Luizi (Idenix, Ula-Italy) for antiviral
assays.
Current address for Richard Storer, VASTox plc, Abingdon, UK.
Address correspondence to Dr. David Dukhan, Laboratoire Coope´ratif Idenix-CNRS-Universite´
Montpellier II, Case Courrier 008, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France. E-mail:
dukhan.david@idenix.com
1431

1432
A. Damont et al.
FIGURE 1 valopicitabine (1) and 1ꢁ-C-fluoromethyladenosine (2.)
We report here the use of this approach in the ribose series for the syn-
thesis of 1ꢁ-C-fluoromethyladenosine.
CHEMISTRY
The retrosynthetic approach for the synthesis of 1ꢁ-C-fluoromethy-
ladenosine is schown below and requires first the preparation of an 1-exo-
methylene ribofuranose.
For this purpose, D-ribono-γ -lactone 3 was quantitatively converted to its
2,3-O-isopropylidene derivative by treatment with sulfuric acid in acetone.
The crude compound was then treated with tert-butylchlorodimethylsilane
and imidazole in DMF to afford compound 4 in 70% yield. Treatment of
4 with tetrachloromethane in the presence of triphenylphosphine in THF
gave the dichloromethylene derivative 5 in a 50% yield.[5] Radical reduction
using tri-n-butyltin hydride in toluene afforded the expected exo-glycal 6 in
good yield (60%).[6]
To complete the synthesis of the desired 1ꢁ-C-branched ribonucleoside,
compound 6 was first treated with silylated 6-chloropurine as nucleophile
and Select-Fluor as electrophilic agent.
Anomers 7a/7b were isolated in 32% yield in a 1/1 ratio, and easily sepa-
rated by silica gel column chromatography. Compounds 7a and 7b were con-
verted into their adenine derivatives 8a/8b using a saturated solution of am-
monia in methanol. In all cases (7a/7b/8a/8b), attempts to remove the silyl
and isopropylidene protecting groups with TFA/H2O gave, after optimiza-
SCHEME 1 Retrosynthetic approach for the preparation of 1ꢁ-C-fluoromethyladenosine derivative.

1ꢁ-C-Fluoromethyladenosine
1433
SCHEME 2 Synthesis of the key exo-glycal 6. Reaqents and conditions: a)(i) Acetone, H2SO4, quant.
(ii) TBDMSCI, imidazole, DMF, 70% b) CCI4, PPh3, THF, 50% c) Bu3SnH, AIBM, toluene, 60%.
SCHEME 3 Synthesis of anomeric branched ribonucleosides. Reaqents and conditions : a) Silylated 6-
chloropurine, SelectFluor, CH3NO2, r.t., 5 hours then separation by chromatography b) NH3/MeOH c)
TFA/H2O, dioxane, 7 hours.
tion, a mixture of the fully deprotected nucleoside, its 2,3-O-isopropylidene
derivative and the corresponding free base resulting from a glycosidic bond
cleavage. Reverse phase column chromatography allowed the separation
and isolation of each expected nucleoside 11a, 11b,12a, and 12b from the
corresponding crude mixture in fair yields (around 35%).
NOe experiments on compound 10a were carried out in deuteriated
DMF to confirm its anomeric configuration. As shown on Scheme 4, corre-
ꢁ
ꢁ
ꢁ
lations between H4 and H8 was clearly observed. In addition, H2 and H3
both strongly correlate with the fluoromethyl group. All these nOe contacts
showed that nucleoside 10a is an α anomer.

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A. Damont et al.
SCHEME 4 nOe correlations of compound 10a.
CONCLUSION
We have established a synthesis for 1ꢁ-C-fluoromethyladenosine 12b. The
synthesized compounds 11a,11b,12a, and 12b were evaluated for antiviral
activity in cell cultures towards bovine viral diarrhea virus (BVDV, a pestivirus
surrogate model of Hepatitis C virus (HCV) for the evaluation of antiviral
agents[7]), and as inhibitors of HCV in a subgenomic replicon assay. None
of these compounds showed antiviral effect nor cytotoxicity at the highest
concentration tested (100 mM).
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