2′-deoxy-2′-α-C-(hydroxymethyl)adenosine as potential anti-HCV agent

Article abstract of DOI:10.1002/ejoc.201001448

Because of the importance of C-branched nucleosides in the discovery of new antiviral molecules, we decided to synthesize 2′-deoxy-2′-α- C-(hydroxymethyl)adenosine as a potential anti-HCV agent. The synthesis of a new adenosine analogue following two different synthetic routes is described. The new C-branched nucleoside was tested for its antiviral activity and found to be inactive.

Full text of DOI:10.1002/ejoc.201001448

FULL PAPER
DOI: 10.1002/ejoc.201001448
2Ј-Deoxy-2Ј-α-C-(hydroxymethyl)adenosine as Potential anti-HCV Agent
Natascha Chavain[a] and Piet Herdewijn*[a]
Keywords: Nucleosides / Antiviral agents / Radical reactions / HCV
Because of the importance of C-branched nucleosides in the
logue following two different synthetic routes is described.
discovery of new antiviral molecules, we decided to synthe-
The new C-branched nucleoside was tested for its antiviral
size 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)adenosine as a poten- activity and found to be inactive.
tial anti-HCV agent. The synthesis of a new adenosine ana-
sess antiviral activities against HSV-1, HSV-2 and HIV-1 in
Introduction
vitro.[6] A series of 2Ј-C-α-hydroxyalkyl- and 2Ј-C-α-alkyl-
cytidines has been synthesised for incorporation into oli-
gonucleosides for studies of group II intron RNA.[7] In an-
other study, 2Ј-β-C-(hydroxymethyl)adenosine was found to
exhibit potent anti-HCV activity (6, Figure 2), indicating
that the hydroxy group of the 2Ј-C-(hydroxymethyl) substit-
uent does not abolish the anti-HCV activity of 2Ј-C-methyl-
adenosine (7, Figure 2).[8] In line with this result, 3Ј-C-(hy-
droxymethyl)-substituted nucleosides were recently ex-
plored as potential anti-HCV agents (biological tests under
progress).[9]
The naturally occurring C-branched nucleoside oxetano-
cin A (1, Figure 1) is known to exhibit potent anti-HIV-1
activity.[1–2] It was shown that 2Ј,3Ј-dideoxy-3Ј-C-(hy-
droxymethyl) nucleosides (2 and 3, Figure 1) display an
anti-HIV-1 activity profile similar to oxetanocin A.[3–4]
These observations have increased the interest in 3Ј-C-
branched 2Ј,3Ј-dideoxynucleosides. For example, 1-[2Ј,3Ј-di-
deoxy-3Ј-C-(hydroxymethyl)-5Ј-O-trityl-β-d-threo-pento-
furanosyl]thymine demonstrated selective antiviral activity
against HIV-1 (4, Figure 1).[5]
Figure 2. 2Ј-C-Branched nucleoside analogues showing anti-HCV
activity.
It is clear that the introduction of a C-(hydroxymethyl)
substituent has allowed the discovery of several new nucleo-
side analogues with antiviral activity. Here we describe the
synthesis of 2Ј-C-(hydroxymethyl)adenosine and tested this
adenosine derivative for its antiviral activity. The new modi-
fied adenosine was tested for its HCV, HIV and RSV ac-
tivity.
Figure 1. Potent anti-HIV-1 nucleosides.
Several other branched-chain sugar nucleosides were
synthesized and tested for their antiviral activities. 4Ј-α-C-
Branched-chain pyrimidine nucleosides were shown to pos-
A
variety of procedures for preparing synthetic
branched-chain sugar nucleosides have been described.
However, the number of 2Ј-deoxy-2Ј-α-C-branched ribonu-
cleosides reported are limited,[10–15] and their biological ac-
tivities have not yet been investigated in a systematic man-
ner, perhaps because of a lack of the availability of efficient
synthetic methods leading to 2Ј-deoxy-2Ј-α-C-branched ri-
bonucleosides.
[a] Katholieke Universiteit Leuven, Faculty of Pharmaceutical
Sciences, Rega Institute for Medical Research, Laboratory of
Medicinal Chemistry,
Minderbroedersstraat 10, 3000 Leuven, Belgium
Fax: +32-16-337340
E-mail: Piet.Herdewijn@rega.kuleuven.be
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Adenosine Derivative as Potential anti-HCV Agent
Only few publications report the synthesis of 2Ј-deoxy- was the use of IBX (2-iodoxybenzoic acid) as oxidizing rea-
2Ј-α-C-hydroxymethylpyrimidine nucleosides.[10–15] As far gent for oxidation of the free alcohol at position 2 into the
as we know, the synthesis of 2Ј-deoxy-2Ј-α-C-(hydroxy- corresponding ketone 11. This reagent, in fact a precursor
methyl)purine nucleosides has not been reported yet. Two of the Dess–Martin periodinane reagent that was initially
schemes are used to synthesize such pyrimidine nucleosides. used, is easier to obtain. It is inexpensive to prepare and
First, the preparation of 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)- easy to handle, can tolerate moisture and water, and gives
thymidine,[10] uridine,[11] or cytidine,[12] from the d-ribose very good yields. Moreover, IBX can easily be recycled by
sugar was described using a synthetic strategy as previously oxidation of IBA (2-iodobenzoic acid) released during the
reported by Schmidt et al.[13] The second way to synthesize reaction. Ketone 11 was converted to alkene 12 by a Wittig
these modified nucleosides involves a radical reaction start- reaction and then, to the desired hydroxymethyl compound
ing from the corresponding nucleoside. Two radical meth- 13 by hydroboration followed by oxidation.
ods were investigated. The first one consists of a direct in-
The hydroxymethyl function at position 2 was then ben-
troduction of the vinyl or styryl group at the 2Ј position.[14] zoylated before condensation of the sugar with N6-benzo-
The second one involves a double bond migration on the yladenine following the Vorbrüggen glycosylation pro-
readily available allyl nucleoside through an ene reaction.[15] cedure.[18] Two anomers were obtained, which were easily
Another possibility, using an intramolecular radical C–C separated by silica gel column chromatography. The stereo-
1
bond formation reaction, as described for the synthesis of chemistry of compound 14 was established by a H NOE
branched aldopentopyranosyl nucleosides,[16] has not been experiment. Irradiation of the anomeric proton (δ =
considered yet.
6.50 ppm) gave a NOE (2.05%) on the 4Ј-H, indicating that
Herein, we report the synthesis of 2Ј-deoxy-2Ј-α-C-(hy- the obtained compound is a β-anomer. Another indication
droxymethyl)adenosine as a potential anti-HCV agent using for the β anomeric configuration is the determination of
[19–20]
1
the two different synthetic routes: the common route start- 1JC1,H1
.
In our case, we measured on the non H-de-
ing from d-ribose and a second, more elegant method, coupled 13C spectrum a value of 165.9 Hz for 1JC1,H1, char-
starting from adenosine. Both synthetic routes are dis- acteristic for adenosine (β-anomer) (literature value for
cussed.
adenosine is 165.6 Hz).[21]
Finally, the nucleoside 14 was deprotected to afford the
desired modified adenosine 8. The order in which the func-
tions are deprotected is important. Indeed, Li and Piccirilli
described that attempts to debenzylate the alcohol func-
tions of 2Ј-α-(acetoxymethyl)-N6-benzoyl-3Ј,5Ј-di-O-(4-
chlorobenzyl)-2Ј-deoxycytidine using hydrogen in the pres-
ence of Pd/C resulted in deamination of the nucleobase
when the amine is benzoylated.[12] To render the nucleobase
less susceptible to reductive deamination, we removed the
benzoyl protecting groups before the benzyl protections.
Following this procedure, 2Ј-deoxy-2Ј-α-C-(hydroxymeth-
yl)adenosine was obtained in 13 steps in a total yield of
9%.
Results
Synthesis of 2Ј-Deoxy-2Ј-α-C-(hydroxymethyl)-D-
ribofuranosyladenosine Starting from D-Ribose
As described by Li et al.,[12] protected 2-deoxy-2-(hy-
dromethyl)-d-ribofuranose 13 was synthesized starting
from d-ribose (Scheme 1). Methyl 3,5-di-O-(4-chloro-
benzyl)-α-d-ribofuranoside (10) was prepared according to
the method of Martin et al.[17] d-Ribose was first fixed in
its 1-OMe furanose form. Selective protection of positions 3
and 5 with a p-chlorobenzyl group was realized by selective
deprotection of position 2 of compound 9 by reaction with
tin(IV) chloride. Compound 10 was converted to methyl
3,5-di-O-(4-chlorobenzyl)-2-deoxy-2-α-(hydroxymethyl)-α-
d-ribofuranoside (13) essentially via the same sequence of
Synthesis of 2Ј-Deoxy-2Ј-α-C-(hydroxymethyl)-
D-
ribofuranosyladenosine Starting from Adenosine
2Ј-(Phenoxythiocarbonyl)-3Ј,5Ј-O-(1,1,3,3-tetraisoprop-
reactions as described by Li et al.[12] The major difference yldisiloxan-1,3-diyl)adenosine (16), obtained by reaction of
Scheme 1. Synthesis of the 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)adenosine starting from d-ribose. (i) methanolic HCl (1%), MeOH; (ii) NaH,
DMSO; (iii) 4-chlorobenzyl chloride (isomer mixture, β/α 2:1); (iv) SnCl4, CH2Cl2, 0 °C; v) H2O; (vi) IBX, acetonitrile, 80 °C; (vii)
Ph3P+CH3Br–, sBuLi, THF, –78 °C; (viii) 9-BBN, THF, 40 °C; (ix) NaOH, H2O2, 80 °C; (x) BzCl, pyridine; (xi) N6-benzoyl bis(trimethyl-
silyl)adenine, TMSOTf, DCE, reflux; (xii) NH4OH, MeOH, 50 °C; (xiii) Pd/C, H2, MeOH.
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N. Chavain, P. Herdewijn
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Scheme 2. Synthesis of the 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)adenosine starting from adenosine. (i) TIPSCl, pyridine; (ii) phenyl chloro-
thionoformate, DMAP, acetonitrile; (iii) tributylstyryltin, AIBN, benzene, 80 °C; (iv) BzCl, pyridine; (v) K3Fe(CN)6, K2CO3, OsO4, H2O/
tBuOH (1:1); (vi) NaIO4, dioxane/H2O (3:1); (vii) NaBH4, MeOH; (viii) 3HF·NEt3, NEt3, THF; (ix) NH4OH, MeOH, 50 °C.
3Ј,5Ј-protected adenosine with phenyl chlorothionocarbon- (hep2 cells) replicons. Unfortunately, this new adenosine de-
ate, was treated with β-(tributylstannyl)styrene. The solvent rivative shows no antiviral activity (data not shown) up to
plays an important role in the radical reaction. Indeed, the 88 μm against HCV replicons, 53 μm against HIV replicons
desired 2Ј-deoxy-2Ј-α-C-styryl-3Ј,5Ј-O-(1,1,3,3-tetraisopro- and 10 μm against RSV replicons.
pyldisiloxan-1,3-diyl)adenosine (17) was obtained in dry
benzene but not in dry toluene. As reported by De Mes-
maeker et al.,[22] the radical reaction (modified Barton–
McCombie reaction) led to a stereoselective introduction of
a 2-phenylethenyl group at the α-side of the sugar ring be-
cause of the steric hindrance due to the presence of the base
at the anomeric position on the β face.
Discussion
In this paper, we describe the synthesis of 2Ј-deoxy-2Ј-α-
C-(hydroxymethyl)adenosine. Indeed, a limited number of
successful selective substitutions at C-2Ј are re-
ported[7,8,10–15] and only few publications report the synthe-
sis of 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)pyrimidine nucleo-
sides.[10–15] This can be explained by the inherent lower re-
activity at C-2Ј. It has been reported that the electronega-
tive anomeric carbon C-1Ј effectively prevents ionization of
a 2Ј-leaving group to produce a cationic SN1 intermediate
for 2Ј modification.[27] Moreover, it is known that the reac-
tivity of the 2ЈOH group can be potentially influenced by
its preferred orientation,[28] dynamics[29] and pKa.[30] Veli-
kyan et al. reported that the pKa is dictated by various fac-
tors such as the nature and orientation of the aglycon, the
sugar conformation and the nature of the vicinal substitu-
ent.[30] A comparison of pKa values for 2ЈOH in different
nucleosides shows that the 2Ј-OH in adenosine is the most
acidic (pKa = 12.17 vs. 12.62 for uridine for example) be-
cause adenine-9-yl is a better stabilizer for the 2Ј-oxy anion
compared to any other aglycons in the studied nucleoside
series. This higher acidity might be less favourable to nucleo-
philic substitution and can partly explain why modifica-
tion at the 2Ј position of adenosine is more difficult. An-
other explanation for the decrease of reactivity at the 2Ј
position of adenosine compared to pyrimidine nucleosides
could be the positioning of the heterocyclic base. Indeed,
the heterocyclic base at C-1Ј exerts a major steric and elec-
tronic barrier for nucleophiles to attack on C-2Ј. It has been
demonstrated that the N-glycosyl bond in adenosine
(1.467 Å) is shorter than those of thymidine (1.480 Å) and
cytidine (1.497 Å).[31] The shorter N-glycosyl bond might
The second main step of this route is the oxidative cleav-
age of the double bond. For the synthesis of 2Ј-deoxy-2Ј-α-
C-(hydroxymethyl)pyrimidine nucleosides,[14–15] the authors
performed the oxidative cleavage by ozonolysis. Because
ozonolysis is not practical when larger amounts of material
are needed, we tried to cleave the double bond by Lemieux-
Johnson oxidation using OsO4, N-methylmorpholine N-ox-
ide (NMMO) and NaIO4 followed by in situ reduction
using NaBH4.[23–25] In our case, the conversion of the phen-
ylethenyl group of compound 17 into the hydroxymethyl
group was not very efficient following this procedure (10%).
To increase the yield of the reaction, the co-oxidant
NMMO was replaced by K3Fe(CN)6/K2CO3, which was
identified to be a better co-oxidant system by Minato et
al.[26] and the two oxidation steps were carried out sepa-
rately by isolating the dihydroxy compound 18. Using this
method we obtained the desired product 19 with an in-
creased yield of 45%. It is to notice that the free amine of
the adenine base has to be protected before the oxidative
cleavage in order to avoid side reactions (Scheme 2).
Finally, the protected nucleoside 19 was deprotected to
afford the desired modified adenosine 8. Following this pro-
cedure, 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)adenosine was ob-
tained in 9 steps in a total yield of 7%.
Biological Tests
The synthesized 2Ј-deoxy-2Ј-α-C-(hydroxymethyl)adenos- contribute to a higher steric barrier.
ine was tested for its capacity to inhibit the replication of
Two different synthetic routes were explored to synthe-
HCV 1a and 1b (huh-7 cells), HIV (MT4 cells) and RSV size the targeted modified adenosine. The first starts from
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Eur. J. Org. Chem. 2011, 1140–1147

Adenosine Derivative as Potential anti-HCV Agent
filtrate was evaporated under reduced pressure and coevaporates
with dry pyridine. The residue was dissolved in dry DMSO
(200 mL) and added at 0 °C to a solution of dimsylsodium pre-
pared by adding pentane-washed sodium hydride (16 g, 400 mmol)
to dry DMSO (150 mL) and by heating the magnetically stirred
suspension to 60 °C for 45 min. The reaction mixture was stirred at
room temperature for 5 h. Then, 4-chlorobenzyl chloride (100 mL,
1.11 mol) was added slowly at 0 °C and the reaction mixture was
stirred overnight at room temperature. The reaction was quenched
with methanol (20 mL) and then water (100 mL). The mixture was
d-ribose and allows us to obtain the modified nucleoside in
13 steps in a total yield of 9%. The second way involves a
radical reaction starting from adenosine. Following this
route, the desired nucleoside was obtained in 9 steps in a
global yield of 7%.
Initially, a preference could be given to the second route
since it involves few steps. But according to the results, the
first route seems to be the best one for the synthesis of 2Ј-
deoxy-2Ј-α-C-(hydroxymethyl)adenosine (better total yield).
Indeed, the radical reaction and the oxidative cleavage are extracted with CH2Cl2 (3ϫ100 mL). The combined organic phases
were dried with Na2SO4 and evaporated under reduced pressure.
The residue was purified on silica gel chromatography eluting with
10% ethyl acetate in hexane to give β-9 as an orange oil (24.2 g,
45 mmol, 67% yield) and then, with 20% ethyl acetate in hexane
to give α-9 as an orange oil (9.6 g, 18 mmol, 18% yield).
not very efficient steps. Moreover, to obtain larger quanti-
ties, we repeated these 2 steps several times. This route is
only interesting when small amounts of material are re-
quired. When larger amounts of material are needed, the
first route seems to be appropriate.
Because of its resemblance with compounds 1–7,[1–5,8,32] β-9: H NMR (300 MHz, CDCl3, 25 °C): δ = 7.25 (m, 12 H, Ar),
1
4.91 (s, 1 H, 1-H), 4.64 (d, J = 12.2 Hz, 1 H, AB-spin system, C2-
we tested our new adenosine derivative for its anti-HIV,
O-CH2), 4.55 (d, J = 12.2 Hz, 1 H, AB-spin system, C2-O-CH2),
anti-HCV and anti-RSV activity. Unfortunately, 2Ј-deoxy-
4.54 (d, J = 12.6 Hz, 1 H, AB-spin system, C5-O-CH2), 4.51 (d, J
2Ј-α-C-(hydroxymethyl)adenosine did not inhibit the repli-
cation of HCV, HIV and RSV replicons.
= 12.6 Hz, 1 H, AB-spin system, C5-O-CH2), 4.50 (d, J = 12.0 Hz,
1 H, AB-spin system, C3-O-CH2), 4.43 (d, J = 12.0 Hz, 1 H, AB-
spin system, C3-O-CH2), 4.30 (q, J = 5.3 Hz, 1 H, 4-H), 4.00 (dd,
J = 4.8, 6.7 Hz, 1 H, 3-H), 3.81 (d, J = 4.4 Hz, 1 H, 2-H), 3.59
Conclusions
(dd, J = 4.7, 10.5 Hz, 1 H, AB-spin system, 5-H), 3.50 (dd, J = 4.7,
10.5 Hz, 1 H, AB-spin system, 5-H), 3.35 (s, 3 H, CH3) ppm. 13C
In conclusion, we synthesized for the first time 2Ј-deoxy-
NMR (75.4 MHz, CDCl3, 25 °C): δ = 137.1 (Ar, CIV), 136.6 (Ar,
2Ј-α-C-(hydroxymethyl)adenosine following two different
CIV), 134.0 (Ar, 2 CIV), 133.6 (Ar, CIV), 132.5 (Ar, CIV), 129.4 (Ar,
strategies. The first strategy starting from d-ribose is more
4 CH), 129.2 (Ar, 2 CH), 128.9 (Ar, 4 CH), 128.8 (Ar, 2 CH), 106.5
interesting than the second route involving a radical reac-
tion directly from adenosine. Despite the number of ad-
ditional steps, the first way gives a better total yield and in
this way, is more interesting when larger amounts of the
nucleoside are required.
(C1, CH), 80.7 (C4, CH), 80.3 (C2, CH), 78.8 (C3, CH), 72.8 (C5-
O-CH2, CH2), 72.0 (C2-O-CH2, CH2), 71.9 (C3-O-CH2, CH2), 71.6
(C5, CH2), 55.5 (CH3) ppm. HRMS (ESI) m/z [M + Na]+ calcd.
for C27H27Cl3NaO5 559.0822; found 559.0813.
1
α-9: H NMR (300 MHz, CDCl3, 25 °C): δ = 7.24 (m, 12 H, Ar),
4.89 (d, 1 H, 1-H), 4.64 (d, J = 17.1 Hz, 1 H, AB-spin system, C2-
O-CH2), 4.61 (d, J = 22.0 Hz, 1 H, AB-spin system, C5-O-CH2),
4.55 (d, J = 17.1 Hz, 1 H, AB-spin system, C2-O-CH2), 4.53 (d, J
= 22.0 Hz, 1 H, AB-spin system, C5-O-CH2), 4.46 (d, J = 12.2 Hz,
1 H, AB-spin system, C3-O-CH2), 4.43 (d, J = 12.2 Hz, 1 H, AB-
spin system, C3-O-CH2), 4.23 (q, J = 3.8 Hz, 1 H, 4-H), 3.78 (s, 1
H, 2-H), 3.77 (d, J = 6.6 Hz, 1 H, 3-H), 3.45 (s, 3 H, CH3), 3.41 (t,
J = 3.2 Hz, 2 H, 5-H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ
= 137.1 (Ar, CIV), 136.6 (Ar, CIV), 134.0 (Ar, 2 CIV), 131.1 (Ar,
CIV), 130.7 (Ar, CIV), 129.7 (Ar, 2 CH), 129.5 (Ar, 2 CH), 129.3
(Ar, 2 CH), 128.9 (Ar, 4 CH), 128.8 (Ar, 2 CH), 102.6 (C1, CH),
82.1 (C4, CH), 78.4 (C2, CH), 75.7 (C3, CH), 73.1 (C5-O-CH2,
CH2), 72.1 (C3-O-CH2, CH2), 71.9 (C2-O-CH2, CH2), 70.5 (C5,
CH2), 55.9 (CH3) ppm. HRMS (ESI) m/z [M + Na]+ calcd. for
C27H27Cl3NaO5 559.0822; found 559.0812.
Experimental Section
Synthesis: Nuclear magnetic resonance (1H and 13C NMR) spectra
were recorded at room temperature on a Bruker AC 300 spectrome-
ter. TMS was used as an internal standard and CDCl3 as the sol-
vent. 1H NMR analyses were obtained at 300 MHz (s: singlet, d:
doublet, t: triplet, dd: double doublet, dt: double triplet, q: quadru-
plet, quint: quintuplet, m: multiplet, AB: diastereotopic protons);
whereas 13C NMR analyses were obtained at 75.4 MHz, at
125.7 MHz (for 15) or at 150.9 MHz (for 17) (CIV: quaternary car-
bon). The chemical shifts (δ) are given in parts per million relative
to TMS (δ = 0.00 ppm). Exact mass spectra were obtained with a
Q-Tof 2TM (Micromass Ltd.) coupled to a CapLCTM system
(Waters). Silica gel chromatography was performed on Davisil® sil-
ica gel 60, 0.630–0.200 mm (Grace Davison). Reactions were moni-
tored by thin-layer chromatography (TLC) on Alugram® silica gel
UV254 mesh 60, 0.20 mm (Macherey–Nagel), detection by UV
lamp or revelation by phosphomolybdenum cerium sulfate or p-
anisaldehyde. All dry solvents were obtained after appropriate dis-
tillation except for DMSO (dimethyl sulfoxide, 99.7%, “Extra
Dry”, dried with molecular sieves, AcroSeal® was purchased from
Acros Organics).
Methyl 3,5-Di-O-(4-chlorobenzyl)-α-D-ribofuranoside (10): To a cold
(0 °C) solution of 9 (930 mg, 1.7 mmol) in dry CH2Cl2 (9 mL) was
added a 10% (v/v) solution of tin(IV) chloride in dry CH2Cl2
(1.9 mL, 1.7 mmol). The reaction mixture was stirred at 0 °C for
6 h. Saturated aqueous NaHCO3 (10 mL) was then added and ex-
tracted with CH2Cl2 (3ϫ10 mL). The combined organic phases
were dried with Na2SO4 and evaporated under reduced pressure.
The residue was purified on silica gel chromatography eluting with
20% EtOAc in hexane to give 10 as an orange oil (460 mg,
1.1 mmol, 65% yield). 1H NMR (300 MHz, CDCl3, 25 °C): δ =
7.21 (m, 8 H, Ar), 4.88 (d, J = 4.6 Hz, 1 H, 1-H), 4.69 (d, J =
12.6 Hz, 1 H, AB-spin system, C3-O-CH2), 4.54 (d, J = 12.6 Hz, 1
H, AB-spin system, C3-O-CH2), 4.48 (d, J = 12.2 Hz, 1 H, AB-
Methyl 2,3,5-Tri-O-(4-chlorobenzyl)-α/β-D-ribofuranoside (9): To a
solution of d-ribose (10.0 g, 67 mmol) in dry methanol (120 mL)
was added a solution of methanolic HCl (1%, 20 mL). The reaction
mixture was stirred at room temperature for 3 d. The solution was
neutralized with Na2CO3 and the formed solid was filtered. The
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N. Chavain, P. Herdewijn
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spin system, C5-O-CH2), 4.42 (d, J = 12.2 Hz, 1 H, AB-spin system, solution (0.5 m in THF, 12 mL, 6.0 mmol). The reaction mixture
C5-O-CH2), 4.16 (m, 1 H, 4-H), 4.12 (m, 1 H, 2-H), 3.74 (dd, J = was stirred at room temperature for 3 h, at 40 °C for 16 h and fi-
3.2, 7.0 Hz, 1 H, 3-H), 3.48 (s, 3 H, CH3), 3.46 (dd, J = 4.4, nally at room temperature for 1 h. While cooling the reaction at
10.5 Hz, 1 H, AB-spin system, 5-H), 3.41 (dd, J = 4.4, 10.5 Hz, 1 H,
AB-spin system, 5-H) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ
= 136.7 (Ar, CIV), 136.6 (Ar, CIV), 133.9 (Ar, 2 CIV), 129.5 (Ar, 2
0 °C, 6 m aqueous NaOH (4 mL, 30.0 mmol) was added dropwise
to the solution followed by H2O2 solution (35%, 6 mL, 68.6 mmol).
The resulting mixture was warmed to room temperature during 1 h
CH), 129.3 (Ar, 2 CH), 128.9 (Ar, 4 CH), 103.2 (C1, CH), 82.1 (C4, and then, stirred at 80 °C for 2 h. The solution was concentrated
CH), 76.8 (C3, CH), 73.1 (C5-O-CH2, CH2), 72.5 (C3-O-CH2, under reduced pressure. The residue was diluted in CH2Cl2 (50 mL)
CH2), 72.1 (C2, CH), 70.4 (C5, CH2), 56.0 (CH3) ppm. HRMS and washed with brine (3ϫ50 mL). The organic layer was dried
(ESI) m/z [M + Na]+ calcd. for C20H22Cl2NaO5 435.0742; found
435.0743.
with Na2SO4 and evaporated under reduced pressure. The residue
was purified on silica gel chromatography eluting with 50% EtOAc
in hexane to give 13 as an orange oil (590 mg, 1.4 mmol, 58%
Methyl 3,5-Di-O-(4-chlorobenzyl)-2-oxo-α-D-ribofuranoside (11):
1
yield). H NMR (300 MHz, CDCl3, 25 °C): δ = 7.28 (m, 8 H, Ar),
Previously synthesized IBX (5.0 g, 17.9 mmol) was added to a solu-
tion of 10 (3.43 g, 8.3 mmol) in acetonitrile (80 mL). The reaction
mixture was stirred at 80 °C for 3 h. The solid was filtered and
washed with EtOAc (3ϫ50 mL). The filtrate was washed with satu-
rated aqueous Na2S2O3 (50 mL), saturated aqueous NaHCO3
(50 mL) and brine (50 mL). The organic layer was dried with
Na2SO4 and the solvents were evaporated under reduced pressure
5.02 (d, J = 5.1 Hz, 1 H, 1-H), 4.56 (d, J = 12.6 Hz, 1 H, AB-spin
system, C3-O-CH2), 4.50 (d, J = 12.4 Hz, 1 H, C5-O-CH2), 4.45 (d,
J = 12.4 Hz, 1 H, C5-O-CH2), 4.44 (d, J = 12.5 Hz, 1 H, AB-spin
system, C3-O-CH2), 4.26 (dd, J = 4.9, 8.2 Hz, 1 H, 4-H), 3.94 (dd,
J = 3.2, 7.6 Hz, 1 H, 3-H), 3.91 (d, J = 7.6 Hz, 2 H, CH2OH), 3.46
(dd, J = 4.7, 10.4 Hz, 1 H, AB-spin system, 5-H), 3.40 (s, 3 H,
CH3), 3.39 (dd, J = 4.7, 10.4 Hz, 1 H, AB-spin system, 5-H), 2.29
(quint, J = 6.6 Hz, 1 H, 2-H) ppm. 13C NMR (75.4 MHz, CDCl3,
25 °C): δ = 136.7 (Ar, 2 CIV), 133.9 (Ar, 2 CIV), 129.5 (Ar, 2 CH),
129.4 (Ar, 2 CH), 128.9 (Ar, 4 CH), 105.7 (C1, CH), 83.2 (C4, CH),
79.2 (C3, CH), 73.1 (C5-O-CH2, CH2), 71.6 (C3-O-CH2, CH2), 70.8
(C5, CH2), 58.2 (CH2OH), 55.9 (CH3), 49.3 (C2, CH) ppm. HRMS
(ESI) m/z [M + Na]+ calcd. for C21H24Cl2NaO5 449.0898; found
449.0899.
1
to give 11 as an orange oil (3.3 g, 8.0 mmol, 97% yield). H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.22 (m, 8 H, Ar), 4.91 (d, J =
11.9 Hz, 1 H, AB-spin system, C3-O-CH2), 4.83 (s, 1 H, 1-H), 4.64
(d, J = 11.9 Hz, 1 H, AB-spin system, C3-O-CH2), 4.55 (d, J =
12.1 Hz, 1 H, AB-spin system, C5-O-CH2), 4.45 (d, J = 12.1 Hz, 1
H, AB-spin system, C5-O-CH2), 4.31 (dt, J = 2.9, 8.1 Hz, 1 H, 4-
H), 4.09 (d, J = 8.3 Hz, 1 H, 3-H), 3.66 (dd, J = 3.5, 11.2 Hz, 1 H,
AB-spin system, 5-H), 3.62 (dd, J = 3.5, 11.2 Hz, 1 H, AB-spin
system, 5-H), 3.48 (s, 3 H, CH3) ppm. 13C NMR (75.4 MHz,
CDCl3, 25 °C): δ = 207.9 (C2, CIV), 136.3 (Ar, CIV), 135.8 (Ar, CIV),
134.3 (Ar, CIV), 134.0 (Ar, CIV), 129.8 (Ar, 2 CH), 129.3 (Ar, 2
CH), 129.0 (Ar, 2 CH), 99.0 (C1, CH), 78.1 (C4, CH), 75.8 (C3,
CH), 73.1 (C5-O-CH2, CH2), 72.1 (C3-O-CH2, CH2), 68.6 (C5,
CH2), 56.2 (CH3) ppm. HRMS (ESI) m/z [M + Na]+ calcd. for
C20H20Cl2NaO5 433.0585; found 433.0608.
Methyl N6-Benzoyl-2Ј-α-(benzoyloxymethyl)-3Ј,5Ј-di-O-(4-chloro-
benzyl)-2Ј-deoxyadenosine (14): To a solution containing 13 (1.4 g,
3.3 mmol) in dry pyridine (45 mL) was added benzoyl chloride
(710 μL, 6.2 mmol). The reaction mixture was stirred at room tem-
perature for 5 h. The solution was evaporated under reduced pres-
sure and the residue was dissolved in CH2Cl2 (50 mL). The organic
layer was washed with saturated NaHCO3 (50 mL) and brine
(50 mL), dried with Na2SO4 and evaporated under reduced pres-
sure. The residue was purified on silica gel chromatography eluting
with 10% ethyl acetate in hexane followed by 30% ethyl acetate in
hexane to give methyl 2-α-(benzoyloxymethyl)-3,5-di-O-(4-chlo-
robenzyl)-2-deoxy-α-d-ribofuranoside as a colourless oil. A mix-
ture of previously synthesized N6-benzoyladenine (3.4 g,
14.3 mmol), 1,1,1,3,3,3-hexamethyldisilazane (HMDS) (27 mL)
and (NH4)2SO4 (catalytic amount) was heated under argon at
140 °C overnight. HMDS was evaporated under reduced pressure
and carefully putted under argon in order to avoid the degradation
of the persilylated base. A methyl 2-α-(benzoyloxymethyl)-3,5-di-
O-(4-chlorobenzyl)-2-deoxy-α-d-ribofuranoside (1.7 g, 3.2 mmol)
solution in dry 1,2-dichloroethane (40 mL) was added to the ob-
tained N6-benzoyl-bis(trimethylsilyl)adenine. To this solution was
added TMSOTf (680 μL, 3.8 mmol). The reaction mixture was
heated at 80 °C for 5 h. Saturated aqueous NaHCO3 (50 mL) was
added to the solution, which was then extracted with CH2Cl2
(3ϫ50 mL). The organic layer was washed with water (50 mL),
dried with Na2SO4 and evaporated under reduced pressure. The
residue was purified on silica gel chromatography eluting with 3%
methanol in CH2Cl2 to give 14 as a white solid (930 mg, 1.3 mmol,
Methyl 3,5-Di-O-(4-chlorobenzyl)-2-methylene-α-D-ribofuranoside
(12): sBuLi (1.4 m in cyclohexane, 13.2 mL, 18.5 mmol) was added
to a suspension of triphenylmethylphosphonium bromide (6.3 g,
17.6 mmol) in dry THF (32 mL) at –78 °C. The reaction mixture
was stirred at –78 °C for 1 h and then, a solution of 11 (3.3 g,
8.0 mmol) in dry THF (16 mL) was added dropwise at –78 °C. The
reaction mixture was stirred at room temperature overnight. The
solid was filtered and washed with diethyl ether (3ϫ50 mL). The
filtrate was washed with saturated aqueous NH4Cl (50 mL) and
brine (50 mL). The organic layer was dried with Na2SO4 and evap-
orated under reduced pressure. The residue was purified on silica
gel chromatography eluting with 20% ethyl acetate in hexane to
give 12 as an orange oil (1.6 g, 3.9 mmol, 49% yield). 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.27 (m, 8 H, Ar), 5.46 (s, 1 H, C2-
CH2), 5.39 (s, 1 H, C2-CH2), 5.24 (s, 1 H, 1-H), 4.61 (d, J =
11.9 Hz, 1 H, AB-spin system, C3-O-CH2), 4.53 (d, J = 15.1 Hz, 1
H, AB-spin system, C5-O-CH2), 4.51 (d, J = 11.9 Hz, 1 H, AB-
spin system, C3-O-CH2), 4.48 (d, J = 15.1 Hz, 1 H, AB-spin system,
C5-O-CH2), 4.27 (s, 2 H, H3, 4-H), 3.56 (s, 2 H, 5-H), 3.44 (s, 3 H,
CH3) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ = 205.9 (C2,
CIV), 136.9 (Ar, CIV), 136.8 (Ar, CIV), 133.8 (Ar, 2 CIV), 129.8 (Ar,
2 CH), 129.3 (Ar, 2 CH), 129.0 (Ar, 4 CH), 114.7 (C2=CH2, CH2),
104.5 (C1, CH), 81.3 (C3, CH), 79.0 (C4, CH), 73.0 (C5-O-CH2,
CH2), 70.3 (C3-O-CH2, CH2), 70.2 (C5, CH2), 55.2 (CH3) ppm.
HRMS (ESI) m/z [M + Na]+ calcd. for C21H22Cl2NaO4 431.0793;
found 431.00814.
1
39% yield). H NMR (300 MHz, CDCl3, 25 °C): δ = 8.66 (s, 1 H,
H8), 8.35 (s, 1 H, 2-H), 8.07 (d, J = 4.2 Hz, 4 H, Ar), 7.59 (quint,
J = 4.5 Hz, 2 H, Ar), 7.52 (t, J = 4.5 Hz, 2 H, Ar), 7.45 (m, 2 H,
Ar), 7.28 (m, 8 H, Ar), 6.50 (d, J = 8.1 Hz, 1 H, 1Ј-H), 4.76 (q, J
= 5.8 Hz, 1 H, AB-spin system, CH2-OBz), 4.62 (d, J = 7.1 Hz, 1
H, AB-spin system, C3Ј-O-CH2), 4.60 (d, J = 7.1 Hz, 1 H, AB-spin
system, C5Ј-O-CH2), 4.58 (t, J = 6.2 Hz, 1 H, AB-spin system, CH2-
OBz), 4.51 (d, J = 7.1 Hz, 1 H, AB-spin system, C5Ј-O-CH2), 4.49
Methyl 3,5-Di-O-(4-chlorobenzyl)-2-deoxy-2-α-(hydroxymethyl)-α-
D-ribofuranoside (13): 12 (1 g, 2.4 mmol) was dissolved in 9-BBN
1144
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1140–1147

Adenosine Derivative as Potential anti-HCV Agent
(d, J = 7.1 Hz, 1 H, AB-spin system, C3Ј-O-CH2), 4.43 (m, 1 H,
4Ј-H), 4.36 (dd, J = 1.8, 5.7 Hz, 1 H, 3Ј-H), 3.78 (dd, J = 4.5,
10.4 Hz, 1 H, AB-spin system, 5Ј-H), 3.62 (dd, J = 3.3, 10.2 Hz, 1
7.5 mmol) in dry pyridine (60 mL) was added 1,1,3,3-tetraisoprop-
yldisiloxane (2.4 mL, 7.7 mmol). The reaction mixture was stirred
at room temperature for 3 h. The solvent was evaporated under
H, AB-spin system, 5Ј-H), 3.61 (m, 1 H, 2Ј-H) ppm. 13C NMR reduced pressure and the residue was partitioned between EtOAc
(75.4 MHz, CDCl3, 25 °C): δ = 170.7 (C=O, CIV), 166.0 (C=O,
(50 mL) and water (50 mL). The organic layer was washed with
CIV), 152.2 (C8, CH), 151.7 (C4, CIV), 149.7 (C6, CIV), 141.6 (C2, cold aqueous HCl (1 m, 25 mL) and saturated aqueous NaHCO3
CH), 135.7 (Ar, CIV), 135.4 (Ar, CIV), 134.0 (Ar, CIV), 133.9 (Ar, (50 mL). The organic layer was dried with Na2SO4 and evaporated
CIV), 133.4 (Ar, CH), 133.2 (Ar, CIV), 132.8 (Ar, CIV), 130.0 (Ar, under reduced pressure. The residue was dried under vacuum and
CH), 129.8 (Ar, CH), 129.6 (Ar, CH), 129.5 (Ar, CH), 129.2 (Ar, 2 dissolved in dry acetonitrile (90 mL). DMAP (2.1 g, 17.2 mmol)
CH), 129.1 (Ar, CH), 128.9 (Ar, CH), 128.8 (Ar, 2 CH), 128.7 (Ar, and phenyl chlorothionoformate (1.6 mL, 11.9 mmol) were added
2 CH), 128.6 (Ar, CH), 128.4 (Ar, CH), 128.3 (Ar, 3 CH), 123.1
to the solution and the reaction mixture was stirred at room tem-
perature overnight. The solvent was evaporated under reduced
(C5, CIV), 87.4 (C1Ј, CH), 82.9 (C4Ј, CH), 79.5 (C3Ј, CH), 72.9 (C5Ј-
O-CH2, CH2), 71.0 (C3Ј-O-CH2, CH2), 70.1 (C5Ј, CH2), 60.9 (CH2- pressure and the residue was dissolved in CH2Cl2 (50 mL), washed
OBz, CH2), 47.1 (C2Ј, CH) ppm. HRMS (ESI) m/z [M + H]+ calcd.
with water (50 mL), dried with Na2SO4 and evaporated under re-
duced pressure. The residue was purified on silica gel chromatog-
raphy eluting with 5% methanol in dichloromethane to give 16 as
a white solid (3.8 g, 5.9 mmol, 78% yield). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 8.30 (s, 1 H, H8), 7.97 (s, 1 H, 2-H), 7.43 (t, J
= 7.5 Hz, 1 H, Ar), 7.30 (t, J = 7.4 Hz, 1 H, Ar), 7.13 (d, J =
8.0 Hz, 1 H, Ar), 6.38 (d, J = 3.5 Hz, 1 H, 2Ј-H), 6.16 (s, 1 H, 1Ј-
H), 5.77 (s, 2 H, NH2), 5.37 (dd, J = 5.3, 8.6 Hz, 1 H, 3Ј-H), 4.19
(dd, J = 2.5, 12.6 Hz, 1 H, AB-spin system, 5Ј-H), 4.12 (dt, J =
2.6, 9.1 Hz, 1 H, 4Ј-H), 4.05 (dd, J = 2.5, 12.6 Hz, 1 H, AB-spin
system, 5Ј-H), 1.12 (s, 4 H, iPr), 1.09 (s, 24 H, iPr) ppm. 13C NMR
(75.4 MHz, CDCl3, 25 °C): δ = 194.1 (C=S, CIV), 155.7 (Ar, CIV),
153.5 (C4, CIV), 153.4 (C8, CH), 149.4 (C6, CIV), 139.7 (C2, CH),
129.7 (Ar, 2 CH), 126.8 (Ar, CH), 121.8 (Ar, 2 CH), 120.4 (C5,
CIV), 87.4 (C1Ј, CH), 84.2 (C2Ј, CH), 82.2 (C4Ј, CH), 69.6 (C3Ј, CH),
60.6 (C5Ј, CH2), 17.5 (iPr, 2 CH3), 17.4 (iPr, 2 CH3), 17.3 (iPr, CH3),
17.2 (iPr, 2 CH3), 17.1 (iPr, CH3), 13.4 (iPr, CH), 13.1 (iPr, CH),
13.0 (iPr, 2 CH) ppm. HRMS (ESI) m/z [M + Na]+ calcd. for
C29H43N5NaO6SSi2 668.2370; found 668.2274.
for C39H33Cl2N5O6 738.1886; found 738.1888.
Methyl 3Ј,5Ј-Di-O-(4-chlorobenzyl)-2Ј-deoxy-2Ј-α-(hydroxymethyl)-
adenosine (15): A solution containing 14 (22 mg, 0.03 mmol) in am-
moniac solution in MeOH (7 m, 2 mL) was stirred at 50 °C in a
sealed flask overnight. The solvent was evaporated under reduced
pressure. The residue was purified on silica gel chromatography
eluting with 5% methanol in dichloromethane to give 15 as a yel-
low oil (16 mg, 0.03 mmol, quantitative). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 8.28 (s, 1 H, H8), 8.02 (s, 1 H, 2-H), 7.32 (dd,
J = 2.1, 8.6 Hz, 4 H, Ar), 7.26 (d, J = 4.2 Hz, 2 H, Ar), 7.20 (d, J
= 8.5 Hz, 2 H, Ar), 6.37 (d, J = 7.6 Hz, 1 H, 1Ј-H), 5.78 (s, 2 H,
NH2), 4.62 (d, J = 10.1 Hz, 1 H, AB-spin system, C3Ј-O-CH2), 4.50
(s, 1 H, AB-spin system, C5Ј-O-CH2), 4.48 (d, J = 10.1 Hz, 1 H,
AB-spin system, C3Ј-O-CH2), 4.37 (m, 2 H, 3Ј-H, 4Ј-H), 3.99 (dd,
J = 5.4, 11.9 Hz, 1 H, AB-spin system, CH2OH), 3.89 (dd, J = 5.4,
11.9 Hz, 1 H, AB-spin system, CH2OH), 3.72 (dd, J = 4.8, 10.1 Hz,
1 H, AB-spin system, 5Ј-H), 3.60 (dd, J = 3.9, 10.1 Hz, 1 H, AB-
spin system, 5Ј-H), 3.24 (quint, J = 13.4 Hz, 1 H, 2Ј-H) ppm. 13C
NMR (125.7 MHz, CDCl3, 25 °C): δ = 155.4 (C4, CIV), 152.8 (C8,
CH), 149.4 (C6, CIV), 139.3 (C2, CH), 135.9 (Ar, CIV), 135.5 (Ar,
CIV), 134.0 (Ar, CIV), 133.8 (Ar, CIV), 129.2 (Ar, 2 CH), 129.1 (Ar,
2 CH), 128.8 (Ar, 2 CH), 128.7 (Ar, 2 CH), 120.1 (C5, CIV), 87.5
(C1Ј, CH), 83.1 (C3Ј, CH), 81.4 (C4Ј, CH), 72.9 (C5Ј-O-CH2, CH2),
71.2 (C3Ј-O-CH2, CH2), 70.2 (C5Ј, CH2), 58.8 (CH2OH, CH2), 49.5
2Ј-Deoxy-2Ј-α-C-styryl-3Ј,5Ј-O-(1,1,3,3-tetraisopropyldisiloxan-1,3-
diyl)adenosine (17): AIBN (250 mg, 1.5 mmol) and 16 (1 g,
1.5 mmol) were dried in dry benzene (10 mL). Styryl tributyltin
(2.5 mL, 20 mmol) was added dropwise to the solution at 40 °C.
The reaction mixture was heated at 80 °C. After 50 h, the reaction
was cooled to room temperature and the solvent was evaporated
under reduced pressure. The residue was purified on silica gel
chromatography eluting with 5% methanol in CH2Cl2 to give 17 as
a white solid (371 mg, 0.62 mmol, 42% yield). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 8.34 (s, 1 H, H8), 8.05 (s, 1 H, 2-H), 7.28 (m,
5 H, Ar), 6.51 (d, J = 16.1 Hz, 1 H, H7Ј), 6.42 (dd, J = 4.2, 8.1 Hz,
1 H, 6Ј-H), 6.40 (s, 2 H, NH2), 6.17 (d, J = 2.7 Hz, 1 H, 1Ј-H),
4.87 (dd, J = 3.0, 3.6 Hz, 1 H, 3Ј-H), 4.17 (m, 1 H, 4Ј-H), 4.11 (m,
2 H, 5Ј-H), 3.68 (dd, J = 3.9, 6.9 Hz, 1 H, 2Ј-H), 1.10 (s, 6 H, 2
CH3), 1.08 (s, 6 H, 2 CH3), 1.07 (s, 6 H, 2 CH3), 1.06 (s, 6 H, 2
CH3), 1.01 (s, 2 H, 2 CH), 1.00 (s, 2 H, 2 CH) ppm. 13C NMR
(150.9 MHz, CDCl3, 25 °C): δ = 155.6 (C4, CIV), 153.1 (C8, CH),
149.7 (C6, CIV), 139.1 (C2, CH), 136.6 (C8Ј, CIV), 134.5 (C7Ј, CH),
129.5 (Ar, CH), 128.5 (Ar, 2 CH), 126.3 (Ar, 2 CH), 122.7 (C6Ј,
CH), 120.2 (C5, CIV), 87.5 (C1Ј, CH), 85.2 (C4Ј, CH), 73.0 (C3Ј,
CH), 62.8 (C5Ј, CH2), 51.5 (C2Ј, CH), 17.5 (CH3), 17.4 (CH3), 17.3
(CH3), 17.2 (CH3), 17.1 (CH3), 17.0 (CH3), 16.9 (CH3), 16.8 (CH3),
13.3 (CH), 13.2 (CH), 12.9 (CH), 12.7 (CH) ppm. HRMS (ESI) m/z
[M + Na]+ calcd. for C30H45N5NaO4Si2 618.2908; found 618.2962.
(C2Ј, CH) ppm. HRMS (ESI) m/z [M
C25H26Cl2N5O4 530.1362; found 530.1354.
+
H]+ calcd. for
2Ј-Deoxy-2Ј-C-α-(hydroxymethyl)adenosine (8) from 15: Compound
15 (13 mg, 0.024 mmol) was dissolved in MeOH (2 mL). To this
solution was added Pd/C 10% (catalytic amount). The reaction
mixture was stirred under hydrogen atmosphere at room tempera-
ture for 24 h. The catalyst was filtered off and washed with MeOH.
The solvent was removed under reduced pressure. The residue was
purified on silica gel chromatography eluting with 10% methanol
in dichloromethane to give 8 as a white solid (5 mg, 0.018 mmol,
1
74% yield). H NMR (300 MHz, [D4]MeOD, 25 °C): δ = 8.29 (s, 1
H, H8), 8.17 (s, 1 H, 2-H), 6.18 (d, J = 8.8 Hz, 1 H, 1Ј-H), 4.56 (d,
J = 4.2 Hz, 1 H, 3Ј-H), 4.12 (d, J = 1.6 Hz, 1 H, 4Ј-H), 3.96 (dd,
J = 6.5, 11.3 Hz, 1 H, AB-spin system, CH2OH), 3.86 (dd, J = 2.9,
12.4 Hz, 1 H, 5Ј-H), 3.75 (dd, J = 2.9, 12.4 Hz, 1 H, 5Ј-H), 3.74
(dd, J = 6.5, 11.3 Hz, 1 H, AB-spin system, CH2OH), 3.18 (quint,
J = 7.4 Hz, 1 H, 2Ј-H) ppm. 13C NMR (75.4 MHz, [D4]MeOD,
25 °C): δ = 157.5 (C4, CIV), 153.3 (C8, CH), 150.1 (C6, CIV), 142.1
(C2, CH), 121.0 (C5, CIV), 90.3 (C4Ј, CH), 90.2 (C1Ј, CH), 74.1 (C3Ј,
CH), 64.0 (C5Ј, CH2), 59.1 (CH2OH, CH2), 51.8 (C2Ј, CH) ppm.
HRMS (ESI) m/z [M + H]+ calcd. for C11H16N5O4 282.1202; found
282.1218.
N6-Benzoyl-2Ј-deoxy-2Ј-α-C-(1-phenylethane-1,2-diol)-3Ј,5Ј-O-
(1,1,3,3-tetraisopropyldisiloxan-1,3-diyl)adenosine (18): To a solu-
tion containing 17 (1.4 g, 2.3 mmol) in dry pyridine (30 mL) was
added benzoyl chloride (280 μL, 2.4 mmol). The reaction was
stirred at room temperature for 5 h. The solvent was evaporated
under reduced pressure. The residue was dissolved in CH2Cl2
(50 mL) and washed with saturated aqueous NaHCO3 (3ϫ50 mL).
2Ј-(Phenoxythiocarbonyl)-3Ј,5Ј-O-(1,1,3,3-tetraisopropyldisiloxan-
1,3-diyl)adenosine (16): To a solution containing adenosine (2 g,
Eur. J. Org. Chem. 2011, 1140–1147
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1145

N. Chavain, P. Herdewijn
FULL PAPER
1
The organic layer was dried with Na2SO4 and evaporate under re-
duced pressure. The residue was purified on silica gel chromatog-
raphy eluting with 1% methanol in CH2Cl2 to give N6-benzoyl-2Ј-
deoxy-2Ј-α-C-styryl-3Ј,5Ј-O-(1,1,3,3-tetraisopropyldisiloxan-1,3-
diyl)adenosine as an orange oil. The purified product (800 mg,
1.1 mmol) was dissolved in tBuOH (10 mL) and added dropwise at
0 °C to a solution of K3Fe(CN)6 (1.1 g, 3.3 mmol), K2CO3
(470 mg, 3.3 mmol) and OsO4 (2.5 % in tBuOH, 320 μL,
0.025 mmol). The reaction mixture was stirred at 0 °C to 4 °C dur-
ing 24 h. Na2SO3 (in large excess) was added to the reaction mix-
ture. After 10 min, the solution was extracted with CH2Cl2
(18 mg, 0.06 mmol, 46% yield). H NMR (300 MHz, [D4]MeOD,
25 °C): δ = 8.29 (s, 1 H, H8), 8.17 (s, 1 H, 2-H), 6.18 (d, J = 8.7 Hz,
1 H, 1Ј-H), 4.57 (t, J = 5.6 Hz, 1 H, 3Ј-H), 4.13 (d, J = 1.6 Hz, 1
H, 4Ј-H), 3.97 (dd, J = 6.5, 11.3 Hz, 1 H, AB-spin system,
CH2OH), 3.87 (dd, J = 2.9, 12.4 Hz, 1 H, 5Ј-H), 3.75 (dd, J = 2.9,
12.4 Hz, 1 H, 5Ј-H), 3.74 (dd, J = 6.5, 11.3 Hz, 1 H, AB-spin sys-
tem, CH2OH), 3.16 (quint, J = 6.9 Hz, 1 H, 2Ј-H) ppm. 13C NMR
(75.4 MHz, [D4]MeOD, 25 °C): δ = 157.5 (C4, CIV), 153.3 (C8,
CH), 150.1 (C6, CIV), 142.1 (C2, CH), 121.0 (C5, CIV), 90.3 (C4Ј,
CH), 90.2 (C1Ј, CH), 74.1 (C3Ј, CH), 64.0 (C5Ј, CH2), 59.1
(CH2OH, CH2), 51.8 (C2Ј, CH) ppm. HRMS (ESI) m/z [M +
(3ϫ50 mL). The organic layer was dried with Na2SO4 and evapo- Na]+ calcd. for C11H15N5NaO4 304.1022; found 304.1001.
rated under reduced pressure. The residue was purified on silica gel
Biological Tests: The methods used for the evaluation of the antivi-
chromatography eluting with 2% methanol in CH2Cl2 to give 18
ral activity have been described previously.[33–35]
as a brown oil (678 mg, 0.9 mmol, 84% yield). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 9.07 (s, 1 H, NH), 8.76 (s, 1 H, H8), 8.20 (s, 1
H, 2-H), 8.02 (d, J = 7.1 Hz, 2 H, Ar), 7.85 (d, J = 7.1 Hz, 1 H,
Ar), 7.61 (t, J = 7.3 Hz, 1 H, Ar), 7.52 (t, J = 7.4 Hz, 2 H, Ar),
Acknowledgments
7.38 (m, 4 H, Ar), 7.20 (m, 3 H, Ar), 6.22 (s, 1 H, H7Ј), 5.81 (d, J
= 5.1 Hz, 1 H, 1Ј-H), 5.22 (dd, J = 5.2, 8.8 Hz, 1 H, 3Ј-H), 4.12
We would like to thank Prof. Jef Rozenski for providing HRMS
analytical data, Dr Shrinivas Dumbre for technical and scientific
(m, 5 H, 2Ј-H, 4Ј-H, 5Ј-H), 1.10 (s, 12 H, 4 CH3), 1.09 (s, 12 H, 4
advice, Luc Baudemprez for recording 13C NMR spectra and the
CH3), 1.08 (s, 4 H, 4 CH) ppm. HRMS (ESI) m/z [M + Na]+ calcd.
1H NOE experiment on the 500 and 600 MHz spectrometers and
for C37H51N5NaO7Si2 756.3225; found 756.3133.
N6-Benzoyl-2Ј-deoxy-2Ј-C-α-(hydroxymethyl)-3Ј,5Ј-O-(1,1,3,3-tetra-
Richard Mackman (Gilead Sciences) for determining the antiviral
activities.
isopropyldisiloxan-1,3-diyl)adenosine (19): Compound 18 (180 mg,
0.25 mmol) was dissolved in dioxane (3 mL). At 0 °C, a solution of
[1] H. Hoshino, N. Shimizu, N. Shimada, T. Takita, T. Takeuchi,
NaIO4 (550 mg, 0.73 mmol) in water (1 mL) was added dropwise.
J. Antibiot. 1987, 40, 1077–1078.
The reaction mixture was stirred at 0 °C for 2 h and then, at room
[2] J. Seki, N. Shimada, K. Takahashi, T. Takita, T. Takeuchi, H.
temperature for 6 h. The reaction was quenched with water (10 mL)
and extracted with EtOAc (3ϫ10 mL). The organic layer was dried
with Na2SO4 and evaporated under reduced pressure. The residue
was dissolved in dry MeOH (3 mL). NaBH4 (10 mg, 0.27 mmol)
was added and the reaction was stirred at room temperature for
30 min. The reaction was quenched with brine (10 mL) and ex-
tracted with CH2Cl2 (3ϫ10 mL). The organic layer was dried with
Na2SO4 and evaporated under reduced pressure. The residue was
purified on silica gel chromatography eluting with 2% methanol in
dichloromethane to give 19 as a white solid (80 mg, 0.13 mmol,
Hoshino, Antimicrob. Agents Chemother. 1989, 33, 773–775.
[3] L. Svansson, I. Kvarnström, B. Classon, B. Sammuelson, J.
Org. Chem. 1991, 56, 2993–2997.
[4] C. K.-H. Tseng, V. E. Marquez, G. W. A. Milne, R. J. Wysocki,
H. Mitsuya, T. Shirasaki, J. A. Driscoll, J. Med. Chem. 1991,
34, 343–349.
[5] J. Wengel, R. F. Schinazi, M. H. Caruthers, Bioorg. Med.
Chem. 1995, 3, 1223–1229.
[6] M. Nomura, S. Shuto, M. Tanaka, T. Sasaki, S. Mori, S. Shig-
eta, A. Matsuda, J. Med. Chem. 1999, 42, 2901–2908.
[7] N.-S. Li, J. A. Piccirilli, J. Org. Chem. 2007, 72, 1198–1210.
[8] B. N. Yoo, H. O. Kim, H. R. Moon, S. K. Seol, S. K. Jang,
K. M. Lee, L. S. Jeong, Bioorg. Med. Chem. Lett. 2006, 16,
4190–4194.
[9] X. Pei, W. J. Choi, Y. M. Kim, L. X. Zhao, L. S. Jeong, Arch.
Pharmacal Res. 2008, 31, 843–849.
[10] C. G. Peng, M. J. Damha, Nucleic Acids Res. 2005, 33, 7019–
7028.
[11] C. Andersen, S. L. Pedersen, P. Nielsen, Nucleosides Nucleo-
tides Nucleic Acids 2007, 26, 1435–1438.
[12] N.-S. Li, J. A. Picirrilli, J. Org. Chem. 2004, 69, 4751–4759.
[13] C. Schmidt, Synlett 1994, 238–240.
[14] M. Sukeda, S. Shuto, I. Sugimoto, S. Ichikawa, A. Matsuda, J.
Org. Chem. 2000, 65, 8988–8996.
[15] J. B. J. Pavey, A. J. Lawrence, A. J. Potter, R. Cosstick, I. A.
O’Neil, Tetrahedron Lett. 1998, 39, 6967–6970.
[16] B. Doboszewski, H. De Winter, A. van Aerschot, P. Herdewijn,
Tetrahedron 1995, 51, 12319–12336.
1
51% yield). H NMR (300 MHz, CDCl3, 25 °C): δ = 9.35 (s, 1 H,
NH), 8.74 (s, 1 H, H8), 8.17 (s, 1 H, 2-H), 8.04 (d, J = 7.5 Hz, 2
H, Ar), 7.59 (d, J = 7.1 Hz, 1 H, Ar), 7.52 (t, J = 7.3 Hz, 2 H, Ar),
6.27 (d, J = 3.9 Hz, 1 H, 1Ј-H), 5.11 (t, J = 6.5 Hz, 1 H, 3Ј-H),
4.08 (m, 3 H, 4Ј-H, 5Ј-H), 4.07 (s, 2 H, CH2OH), 3.12 (q, J =
4.2 Hz, 1 H, 2Ј-H), 1.09 (s, 12 H, 4 CH3), 1.07 (s, 12 H, 4 CH3),
1.02 (s, 4 H, 4 CH) ppm. 13C NMR (75.4 MHz, CDCl3, 25 °C): δ
= 165.0 (C=O, CIV), 152.6 (C4, CIV), 151.2 (C8, CH), 149.8 (C6,
CIV), 141.9 (C2, CH), 133.8 (Ar, CIV), 132.9 (Ar, CH), 128.9 (Ar, 2
CH), 128.1 (Ar, 2 CH), 123.8 (C5, CIV), 86.8 (C1Ј, CH), 84.9 (C4Ј,
CH), 72.8 (C3Ј, CH), 62.6 (C5Ј, CH2), 60.3 (CH2OH, CH2), 49.3
(C2Ј, CH), 17.6 (CH3), 17.4 (2 CH3), 17.3 (CH3), 17.2 (2 CH3), 17.1
(CH3), 17.0 (CH3), 13.5 (CH), 13.3 (CH), 12.9 (CH), 12.8
(CH) ppm. HRMS (ESI) m/z [M
+
Na]+ calcd. for
C30H45N5NaO6Si2 650.2806; found 650.2497.
2Ј-Deoxy-2Ј-C-α-(hydroxymethyl)adenosine (8) from 19: Compound [17] O. R. Martin, K. G. Kurz, S. P. Rao, J. Org. Chem. 1987, 52,
2922–2925.
19 (80 mg, 0.13 mmol) was dissolved in dry THF (4 mL). To this
solution were added 3HF·NEt3 (100 μL, 0.61 mmol) and NEt3
(270 μL, 1.94 mmol). The reaction mixture was stirred at room
temperature for 2 h. The solvent was removed under reduced pres-
sure. The residue was dissolved in 7 m NH3 in MeOH (2 mL,
14 mmol). The reaction was stirred at 50 °C overnight in a screw-
cap-sealed reactor. The solvent was removed under reduced pres-
sure. The residue was purified on silica gel chromatography eluting
with 20% methanol in dichloromethane to give 8 as a white solid
[18] U. Niedballa, H. Vorbrüggen, Angew. Chem. 1970, 82, 449; An-
gew. Chem. Int. Ed. Engl. 1970, 9, 461–462.
[19] H. Budzikiewicz, R. Pereda-Miranda, D. Rosas-Ranúrez, J.
Castañeda-Gómez, in: Progress in the chemistry of organic nat-
ural products, vol. 92 (Eds.: A. D. Kingkorn, H. Falk, J. Kobay-
ashi), Springer, Wien, New York, 2010, pp. 126–128.
[20] W. A. Bubb, Concepts Magn. Reson. Part A 2003, 19, 1–19.
[21] T. Bandyopadhyay, J. Wu, W. A. Stripe, I. Carmichael, A. S.
Serianni, J. Am. Chem. Soc. 1997, 119, 1737–1744.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1140–1147

Adenosine Derivative as Potential anti-HCV Agent
[22] A. De Mesmaeker, J. Lebreton, P. Hoffmann, S. M. Freier, Syn-
lett 1993, 677–679.
[23] A. L. Allan, P. L. Gladstone, M. L. P. Price, S. A. Hopkins,
J. C. Juarez, F. Donate, R. J. Ternansky, D. E. Shaw, B. Ganem,
Y. Li, W. Wang, S. Ealick, J. Med. Chem. 2006, 49, 7807–7815.
[24] H. An, T. Wang, M. A. Maier, M. Manoharan, B. S. Ross, P.
Dan Cook, J. Org. Chem. 2001, 66, 2789–2801.
[31] A. Lo, E. Shefter, T. G. Cochran, J. Pharm. Sci. 1975, 64, 1707–
1710.
[32] A. B. Eldrup, C. R. Allerson, C. F. Bennett, S. Bera, B. Bhat,
N. Bhat, M. R. Bosserman, J. Brooks, C. Burlein, S. S. Carroll,
P. D. Cook, K. L. Getty, M. MacCoss, D. R. McMasters, D. B.
Olsen, T. P. Prakash, M. Prhavc, Q. Song, J. E. Tomassini, J.
Xia, J. Med. Chem. 2004, 47, 2283–2295.
[25] V. Vanheusden, R. Busson, P. Herdewijn, S. Van Calenbergh,
J. Org. Chem. 2004, 69, 4446–4453.
[26] M. Minato, K. Yamamoto, J. Tsuji, J. Org. Chem. 1990, 55,
766–768.
[27] M. J. Robins, F. Hansske, J. S. Wilson, S. D. Hawrelak, D. Ma-
dej, in: Nucleosides, Nucleotides, and Their Biological Applica-
tions (Eds.: J. L. Rideout, D. W. Henry, L. M. Beacham III),
Academic Press, 1983, pp. 279–295.
[28] P. Auffinger, E. Westhof, J. Mol. Biol. 1997, 274, 54–63.
[29] C. Schneider, J. Sühnel, Biopolymers 1999, 50, 287–302.
[30] I. Velikyan, S. Acharya, A. Trifonova, A. Földesi, J. Chatto-
padhyaya, J. Am. Chem. Soc. 2001, 123, 2893–2894.
[33] T. Cihlar, A. S. Ray, C. G. Boojamra, L. Zhang, H. Hui, G.
Laflamme, J. E. Vela, D. Grant, J. Chen, F. Myrick, K. L.
White, Y. Gao, K.-Y. Lin, J. L. Douglas, N. T. Parkin, A. Carey,
R. Pakdaman, R. L. Mackman, Antimicrob. Agents Chemother.
2008, 52, 655–665.
[34] P. Silhár, M. Hocek, R. Pohl, I. Votruba, I. H. Shih, E. Mabery,
R. Mackman, Bioorg. Med. Chem. 2008, 16, 2329–2366.
[35] J. L. Douglas, M. L. Panis, E. Ho, K.-Y. Lin, S. H. Krawczyk,
D. M. Grant, R. Cai, S. Swaminathan, X. Chen, T. Cihlar,
Antimicrob. Agents Chemother. 2005, 49, 2460–2466.
Received: October 25, 2010
Published Online: January 5, 2011
Eur. J. Org. Chem. 2011, 1140–1147
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1147