Synthesis and antiviral activity of novel acyclic nucleosides in the 5-alkynyl- and 6-alkylfuro[2,3-d]pyrimidine series

Article abstract of DOI:10.1016/j.bmc.2004.11.057

The synthesis of novel acyclic nucleosides in the 5-alkynyl and 6-alkylfuro[2,3-d]pyrimidine series is described. These compounds were evaluated against HIV and HSV in order to determine their spectrum of antiviral activity. Their cytotoxicities against P

Full text of DOI:10.1016/j.bmc.2004.11.057

Bioorganic & Medicinal Chemistry 13 (2005) 1239–1248
Synthesis and antiviral activity of novel acyclic nucleosides in the
5-alkynyl- and 6-alkylfuro[2,3-d]pyrimidine series
Franck Amblard,a Vincent Aucagne,a Pierre Guenot,b Raymond F. Schinazic
and Luigi A. Agrofoglioa,*
a
´
Institut de Chimie Organique et Analytique, ICOA UMR 6005, UFR Sciences, BP 6759, 45067 Orleans Cedex 2, France
b
´
CRMPO, Universite de Rennes 1, 35042 Rennes Cedex, France
cVeterans Affairs Medical Center and Laboratory of Biochemical Pharmacology, Department of Pediatrics,
Emory University School of Medicine, Atlanta, GA 30033, USA
Received 18 October 2004; accepted 30 November 2004
Available online 22 December 2004
Abstract—The synthesis of novel acyclic nucleosides in the 5-alkynyl and 6-alkylfuro[2,3-d]pyrimidine series is described. These
compounds were evaluated against HIV and HSV in order to determine their spectrum of antiviral activity. Their cytotoxicities
against PBM, CEM and VERO cells were also determined. Compounds 21d and 24b displayed moderate EC50s of 2.7 and
4.9 lM, respectively, against HIV-1and of 6.3 and 4.8 lM, respectively, against HSV. Nevertheless, these compounds also showed
cellular toxicity, suggesting that the antiviral effects are secondary to the toxic effects.
ꢀ 2004 Elsevier Ltd. All rights reserved.
O
N
O
N
O
N
1. Introduction
Br
N
N
N
N
NH
NH2
NH
NH2
NH
Among the antiviral agents developed for several life
threatening infections, acyclic nucleosides have been a
focus of several recent studies, including variations both
of the acyclic glycone and of the heterocyclic base.1,2
Acyclovir (ACV, 1a)3 and ganciclovir (GCV, 1b)4 are
two important acyclic drugs (Fig. 1) active against her-
pes simplex virus (HSV), varicella-zoster virus (VZV)
and/or cytomegalovirus (CMV). The success of ACV
and GCV as antiviral drugs has prompted intensive ef-
forts by several groups to prepare and evaluate many
structurally related acyclic nucleoside analogues. In an-
other area, many nucleoside analogues substituted at
various positions on the heterocycle,5 are known to have
potent biological properties and have been investigated,
for instance, as antiviral agents (against HSV, VZV,
CMV, HIV, HBV and HCV), non-radioactive fluores-
cent labels for DNA and as anticancer drugs. Among
them, extensive studies have been carried out on 5-
substituted uracils,6 starting from the anti-HSV BVDU
agent, 2.6e Bicyclic pyrimidine nucleosides such as (3),7
HO
HO
HO
O
HO
O
O
O
1a, ACV
1b, GCV
R
2, BVDU
OH
N
R
O
X
N
F
N
N
N
O
HO
3
N
O
HO
N
O
HO
N
O
O
O
OH
HO OH
HO OH
5
4a X = O
b X = S
Figure 1.
oxazolo- (4a)8a, thieno (4b)8b or imidazo (5)8c,d,e have
demonstrated antiviral and antileukemic activity in
vitro, which has led to increased interest in preparation
of corresponding nucleoside analogues (Fig. 1). Thus, as
part of an ongoing program in our drug discovery
group, we initiated the preparation of different, hitherto
unknown, acyclic analogues of ACV and other bicyclic
nucleosides. In the present report, we present the full
experimental details and biological evaluation of the
first 18 analogues of these novel acyclic nucleosides in
the 5-alkynyl- and 6-alkylfuro[2,3-d]pyrimidine series
with hydrophobic functional groups.
Keywords: Nucleosides; Furopyrimidine; Antiviral activity.
*
Corresponding author. Tel.: +33 2 3849 4582; fax: +33 2 3851
0728; e-mail: luigi.agrofoglio@univ-orleans.fr
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.11.057

1240
F. Amblard et al. / Bioorg. Med. Chem. 13 (2005) 1239–1248
2. Chemistry
nucleosides 12 and 13 afforded in >90% yields the acy-
cloalkenyl nucleosides 14a,b and 15a,15b, respectively.
It is interesting to note that the two-step deprotection
of trimethylsilyl alkyne 12c and 13c afforded C5-acyl-
ated analogues 18 and 19 due to the in situ acidic hydro-
lysis of the alkyne (Scheme 3).
The preparation of the desired 5-alkynyl analogues of
acyclovir is illustrated in Scheme 1. Thus, starting from
the known acetylated uracil analogue of acyclovir 6,
synthesized following a well-known procedure,9 an iodo
group was selectively introduced at the C-5 position on
the heterocyclic moiety using I2/CAN.10 Different sub-
stituents were then introduced by reaction of the 5-iodo
acyclic nucleoside 7 under optimized Sonogashira Pd(0)-
catalyzed reactions.11,12 It is important to note that this
reaction must be run at room temperature to avoid the
formation of co-products produced when heating. Finally,
deacylation of C5-alkynyl acyclovir analogues 8a–d was
performed using a catalytic solution of MeONa/MeOH
to give the desired nucleosides 9a–d.
Having these C-5-alkynyl nucleosides in hand, we
turned our attention to the synthesis of fused bicyclic
pyrimidine acyclonucleosides through an O-hetero-ann-
ulations process (Scheme 4). The most common syn-
thetic pathway for cyclization to the target bicyclic
nucleosides consists of the base and copper-catalyzed
5-endo-dig cyclization of various alkynyluridines with
CuI in triethylamine/methanol at reflux, involving the
C-4 pyrimidine oxygen and acetylenic bond.14 Neverthe-
less, this approach suffers from poor to moderate
yields. Thus, we applied a more versatile and efficient
procedure, recently reported by our group, based on
In order to explore more of the acyclic nucleosides fam-
ily, we applied the same methodology to unsaturated
C5-iodinated uracil acyclonucleosides 10 and 11 ob-
tained using a cross metathesis methodology (Scheme
2).13 The desired C5-alkynyl unsaturated acyclic nucleo-
sides 12a–c and 13a–c were obtained in 70–85% average
yield, The acidic deprotection (TFA/H20, 2:1, v/v) of
a
5endo-dig electrophilic cyclization catalyzed by
AgNO3.15
Starting from protected C5-alkynyl acyclic nucleosides
8a–d or unsaturated 12a,b the desired alkyl furanopyr-
R
O
N
R
O
N
O
N
O
N
I
NH
NH
NH
NH
I2 / CAN
CH3CN
R
H
CuI / PdCl2(PPh3)2 AcO
O
HO
O
AcO
O
AcO
O
MeONa cat.
O
O
O
O
reflux
DMF / Et3N
75-83%
MeOH
> 95%
8a R = C8H17
b R = PhC5H11
9a-d
7
6
c R = Ph
d R = C5H11
Scheme 1.
O
N
R
O
N
R
O
R
O
I
NH
NH
NH
NH
R
H
HO
HO
O
O
N
O
CuI / PdCl2(PPh3)2
N
O
TFA/H2O
90-99%
R1
R2
R1
R2
HO
and
DMF / Et3N, rt
70-85%
HO
15a,b (from 13)
14a,b (from 12)
12a, R = C8H17 (from 10)
b, R = PhC5H11
O
O
, R2 = H
10, R1
=
c, R = Me3Si
13a, R = C8H17 (from 11)
b, R = PhC5H11
O
O
11, R1 = R2
=
c, R = Me3Si
Scheme 2.
Me3Si
O
N
O
O
O
N
O
O
N
NH
O
NH
NH
NH
HO
HO
N
O
O
O
nBu NF/THF
TFA/H2O
R1
R2
R1
R2
16c, 17c
4
HO
and
HO
19 (from 17c)
18 (from 16c)
12c, 13c
O
, R2 = H
12c, 16c, R1
=
O
O
O
13c, 17c, R1 = R2
=
Scheme 3.

F. Amblard et al. / Bioorg. Med. Chem. 13 (2005) 1239–1248
1241
R
R
O
R
O
O
N
N
AgNO3
N
TFA/H2O
acetone, rt
N
O
N
R1
O
N
O
> 95%
R1
(except for 20a-d
MeONa/MeOH)
R2
21a-d, 23a,b,
20a-d, 22a,b
8a-d, 12a,b, 13a,b
24a,b (from 13a,b)
HO
AcO
O
8, 20 R1 =
21 R2 =
23 R2 =
O
a R = C8H17
b R = PhC5H11
c R = Ph
HO
HO
O
O
12, 22 R1 =
d R = C5H11
HO
O
24 R2 =
13 R1 =
HO
O
Scheme 4.
imidine nucleosides (20a–d, 22a,b) were obtained in
>95% yield, often requiring no purification. A final
deprotection was performed using a catalytic amount
of MeONa/MeOH (for 20) or a TFA/H2O mixture
(for 22) to yield the desired nucleosides 21a–d and
23a,b, respectively. Alkyl furanopyrimidines 24a,b were
directly obtained from a one pot cyclization and depro-
tection reaction of 13a,b, respectively.
as previously described. For the anti-HIV activity,
among the C-5-alkynyl acyclonucleoside analogues,
9a,b, 14a,b, 15a,b exhibited moderate anti-HIV activity
with EC50s ranging from 18.6 lM to 57.3 lM; among
the fused bicyclic pyrimidine acyclonucleosides, the
highest anti-HIV activity was achieved for compound
21d with an EC50 of 2.7 lM.
The introduction of a C-5 acetyl group on 18 or 19 led to
inactive compounds. The above synthesized acyclonu-
cleosides were also evaluated against HSV-1and all
tested compounds showed either no (EC50 > 1 00lM)
or moderate antiviral activity (EC50 ranging from 4.8
to 18.2 lM). The highest anti-HSV activity was achieved
by the furano-pyrimidine compounds 21d and 24b with
an EC50 of 6.3 and 4.8 lM, respectively. Nevertheless,
all compounds with moderate activity against HIV and
HSV showed toxicity against PBM, CEM and VERO
cells, probably by inhibiting cell DNA synthesis. The
3. Biological assay
All synthesized compounds, the C5-alkynyl derivatives
9a–d, 14a–b, 15a,b, the C5-acetyl derivatives 18 and 19
and the 6-alkylfuro[2,3-d]pyrimidine (21a–d, 23a,b and
24a,b) along with the known antiviral compounds (acy-
clovir for HSV and AZT for HIV), were tested for their
antiviral activities in vitro (results shown in Table 1).
The antiviral16 and cytotoxicity17 assays were performed
Table 1. Evaluation of 5-alkynyl- and 6-alkylfuro[2,3-d]pyrimidine acyclic nucleosides antiviral activity against human immunodeficiency virus
(HIV), herpes simplex virus (HSV-1) and cytotoxicity against PBM, CEM and VERO cells in vitro, expressed in lM
Compd
Anti-HIV-1activity in
PBMCs
HSV-1plaque
reduction assay
Toxicity(IC50) in:
EC50
EC90
EC50
EC90
PBM
CEM
VERO
Acyclovira
AZTa
9a
>100
0.016
23.7
>100
0.20
0.11
>10
0.69
>10
>100
>100
72.1
8.3
>100
14.0
6.4
29.0
19.3
7.9
ꢀ105
>100
>100
>100
>100
91.6
>100
>10
>100
>10
9b
9c
18.6
8.9
>100
ꢀ100
57.3
>100
>100
NDb
8.5
>100
>100
ND
>100
>100
59.2
19.5
21.9
3.4
>100
>100
15.7
13.9
31.6
2.2
21.6
39.5
37.03
75.1
28.8
6.9
9d
14a
14b
15a
15b
18
45.1
33.0
16.2
>100
ND
72.3
69.7
>10
ND
31.8
>100
25.1
49.8
>100
39.0
100
>100
>100
>100
>100
>100
16.4
10
>100
>100
52.9
>100
>100
54.4
9.8
>100
>100
17.6
30.9
>100
4.1
>100
>100
4.97
4.4
19
>100
18.2
>100
>100
6.3
21a
21b
21c
21d
23a
23b
24a
24b
>100
>100
>100
19.8
>100
>100
2.7
63.1
3.1
55.4
36.7
>100
>100
>10
>100
16.3
>100
14.9
>100
>100
91 4.0
46.2
>100
25.139.0
4.9
7.3
13.07
53.8 .0
78.9
4.8
11.1
0.81
8.7
a Reference compounds.
b ND, not determined.

1242
F. Amblard et al. / Bioorg. Med. Chem. 13 (2005) 1239–1248
non-toxic compounds will be evaluated against HBV
and HCV.
(76 mg, 0.2 equiv) and 140 mg PdCl2(PPh3)2 (0.1equiv)
were added and the reaction mixture was stirred at rt un-
til completion (typically 5–20 h, checked by TLC). Sol-
vents were evaporated in vacuo. The oily residue was
dissolved in 100 mL AcOEt then washed with water
(7 · 10 mL) and brine (10 mL). The organic layer was
dried over MgSO4 and the solvents were evaporated in
vacuo to give a dark oil. A first purification using a short
path flash chromatography (eluent:CH2Cl2 then MeOH/
CH2Cl2 5%) gave the desired compound contaminated
with coloured reaction co-products. Pure alkynes were
obtained after a second round of flash chromatography
(eluent:pet. eth./AcOEt, 8:2 then 1:1).
4. Experimental
4.1. General procedures
Commercially available chemicals and solvents were re-
agent grade and used as received. Dry tetrahydrofuran,
pyridine and dichloromethane were obtained from
distillation over CaH2 or Na, and dry N,N-dimethyl-
formamide over BaO. Reactions were monitored by
thin-layer chromatography (TLC) analysis using silica
gel plates (Kieselgel 60 F254, E. Merck). Compounds
were visualized by UV irradiation and/or spraying with
20% H2SO4 in EtOH, followed by charring at 150 ꢁC.
Column chromatography was performed on Silica Gel
60 M (0.040–0.063 mm, E. Merck). Melting points were
4.3.1. 1-N-(2-Acetoxy-ethoxymethyl)-5-(dec-1-ynyl)-ura-
cil (8a). Yield 78%, white solid; mp (CH2Cl2) 55–57 ꢁC;
1H NMR (CDCl3): d 0.98 (m, 3H, J = 7.2 Hz), 1.24–1.64
(m, 12H), 2.08 (s, 3H), 2.39 (t, 2H, J = 7.2 Hz), 3.80 (t,
2H, J = 4.6 Hz), 4.22 (t, 2H), 5.20 (s, 2H), 7.52 (s,
1H), 9.43–9.53 (br s, 1H); 13C NMR (CDCl3): d 14.2
(CH3), 19.7 (CH2), 20.9 (CH3), 22.7, 28.6, 29.0, 29.1,
29.2 and 31.9 (6 · CH2), 63.0 (CH2), 67.8 (CH2), 70.6,
76.9 (CH2), 96.1, 102.0, 144.7 (CH), 150.4, 162.1,
171.0 (CO); HRMS: C19H28N2O5Na calcd 387.4352
[M+Na]+, found 387.4355.
recorded on a Buchi (Dr. Tottoli) and were uncorrected.
¨
1H and 13C NMR spectra were recorded on a Bruker
AVANCE DPX 250 Fourier Transform spectrometer
1
at 250 MHz for H and 62.9 MHz for 13C, using tetra-
methylsilane as the internal standard; signals are re-
ported as s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet). Mass spectra were recorded on a Per-
kin-Elmer SCIEX API-300 (heated nebulizer) spectro-
meter. HRMS were performed by the CRMPO,
University of Rennes 1, France. The nomenclature of
the synthesized compounds is in accordance with the
IUPAC rules and was checked with Autonome. Evi-
dence of purity has been done from a proton-decoupled
13C NMR spectrum with a signal-to-noise ratio suffi-
cient to permit seeing peak with 5% of the intensity of
the strongest peak.
4.3.2. 1-N-(2-Acetoxy-ethoxymethyl)-5-(p-pentylphenyl-
ethynyl)-uracil (8b). Yield 80%, white solid; mp
(CH2Cl2) 100–102 ꢁC; 1H NMR (CDCl3): d 0.97 (m,
3H, J = 6.9 Hz), 1.25–1.66 (m, 6H), 2.09 (s, 3H), 2.60
(t, 2H, J = 7.6 Hz), 3.81(t, 2H, J = 4.5 Hz), 4.23 (t,
2H, J = 4.5 Hz), 5.23 (s, 2H), 7.14 (d, 2H, J = 8.2 Hz),
7.41(d, 2H, J = 8.2 Hz), 7.65 (s, 1H), 8.51–8.58 (br s,
1H); 13C NMR (CDCl3): d 14.0 (CH2), 20.9 (CH3),
22.5, 30.9, 31.5, 35.9 (4 · CH2), 63.0 (CH2), 67.8
(CH2), 77.0 (CH2), 79.1, 94.5, 101.6, 119.8 (CH), 128.5
(CH), 130.0 (CH), 145.0 (CH), 148.5, 150.3, 161.6,
170.9 (CO); HRMS: C22H26N2O5Na calcd 412.4527
[M+Na]+, found 412.4528.
4.2. Chemistry
4.2.1. 1-N-(2-Acetoxy-ethoxymethyl)-5-iodo-uracil9a (7).
1-N-(2-Acetoxy-ethoxymethyl)-uracil (6, 3.42 g, 15
mmol) was dissolved in 150 mL dry CH3CN. CAN
(4.94 g, 0.6 equiv) and 2.28 g I2 (0.6 equiv) were added
and the resulting solution was refluxed for 1h. After
cooling to rt, solvents were evaporated in vacuo and
the dark oily residue was dissolved in 300 mL AcOEt
and 50 mL H2O. The biphasic mixture was cooled in
an ice bath and a saturated Na2S2O3 solution was slowly
added until complete decolouration. The organic layer
was washed with water (2 · 50 mL) and brine (50 mL)
then dried over MgSO4 and concentrated in vacuo.
The yellow solid was submitted to flash column chroma-
tography (eluent:CH2Cl2 then 2% MeOH/CH2Cl2) to
yield pure iodinated nucleoside 7 as a white solid
4.3.3. 1-N-(2-Acetoxy-ethoxymethyl)-5-(phenylethynyl)-
uracil (8c). Yield 83%, white solid; mp (CH2Cl2) 85–
1
87 ꢁC; H NMR (CDCl3): d 2.09 (s, 3H), 3.81(t, 2H,
J = 4.6 Hz), 4.22 (t, 2H, J = 4.6 Hz), 5.23 (s, 2H),
7.30–7.38 (m, 3H), 7.47–7.54 (m, 5H), 7.68 (s, 1H),
9.63–9.78 (br s, 1H); 13C NMR (CDCl3): d 20.9 (CH3),
63.0 (CH2), 67.9 (CH2), 77.1(CH ), 79.7, 94.3, 101.4,
2
122.4 (CH), 128.4 (CH), 128.8 (CH), 131.7, 145.3
(CH), 150.3, 161.7, 171.0 (CO); HRMS: C17H16N2O4Na
calcd 351.3173 [M+Na]+, found 351.3174.
4.3.4. 1-N-(2-Acetoxy-ethoxymethyl)-5-(hept-1-ynyl)-
uracil (8d). Yield 75%, white solid; mp (CH2Cl2) 50–
1
(4.25, 80%); H NMR (CDCl3): d 2.09 (s, 3H), 3.81(t,
1
2H, J = 4.6 Hz), 4.23 (t, 2H, J = 4.6 Hz), 5.21(s, 2H),
7.79 (s, 1H), 9.25–9.35 (br s, 1H); other spectral data
were identical to those previously reported.9a
52 ꢁC; H NMR (CDCl3): d 0.90 (t, 3H, J = 7.0 Hz),
1.24–1.64 (m, 6H), 2.09 (s, 3H), 2.39 (t, 2H,
J = 7.2 Hz), 3.80 (t, 2H, J = 4.7 Hz), 4.22 (t, 2H,
J = 4.2 Hz), 5.21(s, 2H), 7.52 (s, 1H), 9.48–9.58 (br s,
1H); 13C NMR (CDCl3): d 14.0 (CH3), 19.6 (CH2),
20.9 (CH3), 22.2 (CH2), 28.2 (CH2), 31.2 (CH2), 63.0
4.3. General procedure for Sonogashira cross-coupling
The iodinated nucleoside (2 mmol) was dissolved in a
mixture of 6 mL dry DMF, 824 lL dry Et3N (3 equiv)
and 3 mmol of the desired alkyne (3 equiv). CuI
(CH2), 67.8 (CH2), 70.6, 77.1(CH ), 96.0, 102.0, 144.7
2
(CH), 150.4, 162.1, 171.0 (CO); HRMS: C16H22N2O5Na
calcd 345.3539 [M+Na]+, found 345.3537.

F. Amblard et al. / Bioorg. Med. Chem. 13 (2005) 1239–1248
1243
4.4. General procedure for deacetylation under basic
conditions
4.5. 5-(1-Decynyl)-1-[(E)-3-(2,2-dimethyl-1,3-dioxolan-4-
yl)-2-propenyl]-2,4(3H)-pyrimidinedione (12a)
Acetylated acyclonucleoside (0.5 mmol) was dissolved in
5 mL dry MeOH. Freshly prepared (500 lL, 0.1equiv)
0.1M MeONa solution in MeOH were added and the
reaction mixture was stirred at rt until completion (typ-
ically 1–6 h, checked by TLC). The reaction mixture was
neutralized with Dowex [H+] resin then filtered through
a fritted glass funnel. Solvents were evaporated in vacuo
and the residue was submitted to flash column chroma-
tography using an appropriate eluent (typically AcOEt
then MeOH/AcOEt 1% then MeOH/AcOEt 5%) to yield
pure acyclonucleosides.
In an analogous manner to the preparation of 8a, the
title compound 12a was prepared in a yield of 72% as
a pale yellow gum; H NMR (CDCl3): d 0.86 (t, 3H,
1
J = 6.9 Hz), 1.15–1.48 (m, 16H), 1.50–1.63 (m, 1H),
2.36 (t, 2H, J = 6.9 Hz), 3.58 (dd, 1H, J = 8.0 Hz), 4.10
(dd, 1H, J = 6.3 Hz, J = 8.0 Hz), 4.22–4.41(m, 2H),
4.48–4.61 (m, 1H), 5.72 (dd, 1H, J = 6.0 Hz,
J = 15.4 Hz), 5.83 (dt, 1H, J = 5.7 Hz, J = 15.4 Hz),
7.31 (s, 1H), 9.17 (s, 1H, NH); 13C NMR (CDCl3): d
14.2 (CH3), 19.7 (CH2), 22.7 (CH2), 25.8 (CH3), 26.7
(CH3), 28.6 (CH2), 29.1(CH 2), 29.2 (CH2), 29.3
(CH2), 31.9 (CH2), 49.3 (CH2), 69.3 (CH2), 70.8, 75.9
(CH), 95.9, 101.3, 109.8, 126.6 (CH), 133.4 (CH),
145.4 (CH), 149.8, 162.2; HRMS: C22H32N2O4Na calcd
411.2260 [M+Na]+, found 411.2259.
4.4.1. 1-N-(2-Hydroxy-ethoxymethyl)-5-(dec-1-ynyl)-ura-
cil (9a). Yield 95%, white solid; mp (MeOH) 104–
1
106 ꢁC; H NMR (CD3OD): d 0.90 (t, 3H, J = 7.2 Hz),
1.25–1.64 (m, 12H), 2.38 (t, 2H, J = 7.3 Hz), 3.62–3.54
4.6. 1-[(E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-propen-
yl]-5-[2-(4-pentylphenyl)ethynyl]-2,4(3H)-pyrimidinedione
(12b)
(m, 4H), 5.19 (s, 2H), 7.84 (s, 1H); 13C NMR (DMSO-
d6): d 14.4 (CH3), 20.1(CH ), 23.7 (CH2), 29.7 (CH2),
2
30.0 (CH2), 30.3 (CH2), 30.4 (CH2), 33.0 (CH2), 61.9
(CH2), 72.1(CH 2), 72.2, 78.5 (CH2), 95.5, 101.6
(CH2), 147.8 (CH2), 152.0 (CH2), 164.8 (CH2); HRMS:
C17H26N2O4Na calcd 345.3976 [M+Na]+, found
345.3981.
In an analogous manner to the preparation of 8a, the
title compound 12b was prepared in a yield of 85% as
a white solid; mp (CH2Cl2) 131–133 ꢁC; 1H NMR
(CDCl3): d 0.90 (t, 3H, J = 11.25 Hz), 1.22–1.38 (m,
4H), 1.39 (s, 3H), 1.44 (s, 3H), 1.55–1.68 (m, 2H), 2.59
(t, 2H, J = 7.4 Hz), 3.61(dd, 1H, J = 8.1Hz), 4.13 (dd,
1H, J = 6.4 Hz, J = 8.1Hz), 4.30–4.48 (m, 2H), 4.50–
4.60 (m, 1H), 5.76 (dd, 1H, J = 5.85 Hz, J = 15.7 Hz),
5.87 (dt, 1H, J = 5.3 Hz, J = 15.7 Hz), 7.13 (d, 2H,
J = 8.0 Hz), 7.40 (d, 2H, J = 8.0 Hz), 7.46 (s, 1H), 8.86
(s, 1H); 13C NMR (CDCl3): d 14.1 (CH3), 22.6 (CH2),
25.9 (CH3), 26.8 (CH3), 31.0 (CH2), 31.6 (CH2), 36.0
(CH2), 49.6 (CH2), 69.4 (CH2), 75.9 (CH), 94.7, 101.0,
109.9, 119.6, 126.4 (CH), 128.6 (CH · 2), 131.7
(CH · 2), 133.8 (CH), 144.1, 145.7 (CH), 149.5, 161.3;
HRMS: C25H30N2O4 calcd 422.22056 [M]+, found
422.2202.
4.4.2. 1-N-(2-Hydroxy-ethoxymethyl)-5-(p-pentylphenyl-
ethynyl)-uracil (9b). Yield 97%, white solid; mp (MeOH)
110–112 ꢁC; 1H NMR (DMSO-d6): d 0.84 (m, 3H,
J = 6.8 Hz), 1.18–1.64 (m, 6H), 2.58 (t, 2H,
J = 7.7 Hz), 3.45–3.59 (m, 4H), 4.65–4.73 (br s, 1H),
5.14 (s, 2H), 7.22 (d, 2H, J = 8.4 Hz), 7.37 (d, 2H,
J = 8.4 Hz), 8.21 (s, 1H), 11.69–11.74 (br s, 1H); 13C
NMR (DMSO-d6): d 13.9 (CH2), 21.9 (CH2), 30.3
(CH2), 30.9 (CH2), 35.0 (CH2), 60.0 (CH2), 70.8
(CH2), 76.9 (CH2), 81.4, 92.1, 98.2, 119.6 (CH), 128.7
(CH), (CH), 143.3 (CH), 148.0, 150.1, 161.7; HRMS:
C20H24N2O4 Na calcd 379.4151 [M+Na]+, found
379.4153.
4.7. 1-[(E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-propen-
yl]-5-[2-(trimethylsilyl)ethynyl]-2,4(3H)-pyrimidinedione
(12c)
4.4.3. 1-N-(2-Hydroxy-ethoxymethyl)-5-(phenylethynyl)-
uracil (9c). Yield 95%, white solid; mp (MeOH) 140–
142 ꢁC; 1H NMR (DMSO-d6): d 3.45–3.59 (m, 4H),
4.62–4.75 (br s, 1H), 5.14 (s, 2H), 7.37–7.51 (m, 5H),
8.25 (s, 1H); 13C NMR (DMSO-d6): d 60.0 (CH2), 70.8
(CH2), 77.0 (CH2), 82.0, 91.9, 98.0, 122.3 (CH), 125.4
(CH), 128.7 (CH), 128.8 (CH), 131.1, 148.3 (CH),
150.1, 161.8; HRMS: C15H14N2O4Na calcd 309.2796
[M+Na]+, found 309.2797.
In an analogous manner to the preparation of 8a, the
title compound 12c was prepared in a yield of 83% as
1
a pale yellow gum. H NMR (CDCl3): d 0.20 (s, 9H),
1.37 (s, 3H), 1.42 (s, 3H), 3.58 (dd, 1H, J = 8.0 Hz),
4.10 (dd, 1H, J = 6.5 Hz, J = 8.0 Hz), 4.22–4.52 (m,
2H), 4.47–4.58 (m, 1H), 5.65–5.88 (m, 2H), 7.42 (s,
1H), 9.53 (s, 1H, NH); 13C NMR (CDCl3): d 0.1
(CH3 · 3), 25.8 (CH3), 26.6 (CH3), 49.4 (CH2), 69.2
(CH2), 75.8 (CH), 95.0, 100.0, 100.5, 109.8, 126.4
(CH), 133.5 (CH), 147.0 (CH), 149.8, 161.9; HRMS:
C17H24N2O4 SiNa calcd 371.2318 [M+Na]+, found
371.2221.
4.4.4.
uracil (9d). Yield 98%, white solid; mp (MeOH) 104–
106 ꢁC; 1H NMR (DMSO-d6):
0.87 (t, 3H,
1-N-(2-Hydroxy-ethoxymethyl)-5-(hept-1-ynyl)-
d
J = 7.0 Hz), 1.20–1.57 (m, 6H), 2.36 (t, 2H,
J = 7.0 Hz), 3.44–3.54 (m, 4H), 4.62–4.70 (br s, 1H),
5.19 (s, 2H), 7.99 (s, 1H); 13C NMR (DMSO-d6): d
13.9 (CH3), 18.7 (CH2), 21.7 (CH2), 27.9 (CH2), 30.5
(CH2), 60.0 (CH2), 70.7 (CH2), 72.5, 76.8 (CH2), 93.4,
98.8, 147.2 (CH), 150.1, 162.2; HRMS: C14H20N2O4
Na calcd 303.3163 [M+Na]+, found 303.3161.
4.8. 5-(1-Decynyl)-1-[2-(2-phenyl-1,3-dioxan-5-ylid-
en)ethyl]-2,4(3H)-pyrimidinedione (13a)
In an analogous manner to the preparation of 8a, the
title compound 13 was prepared in a yield of 75% as a

1244
F. Amblard et al. / Bioorg. Med. Chem. 13 (2005) 1239–1248
pale yellow gum. 1H NMR (CDCl3): d 0.87 (t, 3H,
J = 6.8 Hz), 1.18–1.42 (m, 10H), 1.49–1.67 (m, 2H),
2.38 (t, 2H, J = 7.1 Hz), 4.10–4.20 (m, 1H), 4.40–4.61
(m, 4H), 4.91–4.98 (m, 1H), 5.41 (t, 1H, J = 6.6 Hz),
5.67 (s, 1H), 7.29–7.42 (m, 4H), 7.43–7.51 (m, 2H),
9.42 (br s, 1H, NH); 13C NMR (CDCl3): d 14.2 (CH3),
(d, OH, J = 4.8 Hz), 5.65–5.78 (m, 2H), 7.87 (s, 1H),
11.52 (s, 1H, NH); 13C NMR (DMSO-d6): d 13.9
(CH3), 18.7 (CH2), 22.1(CH 2), 28.2 (CH2), 28.3
(CH2), 28.5 (CH2), 28.6 (CH2), 31.2 (CH2),
48.6 (CH2), 65.7 (CH2), 71.2 (CH), 72.7, 93.2, 98.3,
123.7 (CH), 135.7 (CH), 147.5 (CH), 149.8, 162.3;
HRMS: C19H28N2O4 Na calcd 371.1947, found
371.1945.
19.7 (CH2), 22.7 (CH2), 28.6 (CH2), 29.1(CH ), 29.2
2
(CH2), 29.3 (CH2), 44.5 (CH2), 65.8 (CH2), 70.7, 71.6
(CH2), 96.1, 101.4 (CH), 101.6 (CH), 118.5 (CH),
126.2 (CH · 2), 128.4 (CH · 2), 129.2 (CH), 136.0,
137.7, 145.3 (CH), 150.0, 162.3; HRMS: C26H32N2O4
Na calcd 459.1817 [M+Na]+, found 459.1814.
4.11.2. 1-[(E)-4,5-Dihydroxy-2-pentenyl]-5-[2-(4-pentyl-
phenyl)ethynyl]-2,4(1H,3H)-pyrimidinedione (14b). Yield
1
95%, white solid, mp (MeOH) 255–257 ꢁC; H NMR
(DMSO-d6): d 0.73–0.91 (m, 3H), 1.18–1.37 (m, 4H),
1.49–1.68 (m, 2H), 2.57 (t, 2H, J = 7.5 Hz), 3.22–3.33
(m, 2H), 3.91–4.03 (m, 1H), 4.25–4.39 (m, 2H), 4.51–
4.61(m, OH), 4.86 (d, OH, J = 4.5 Hz), 5.69–5.85 (m,
2H), 7.22 (d, 2H, J = 8.0 Hz), 7.36 (d, 2H, J = 8.0 Hz),
8.10 (s, 1H) 11.64 (s, 1H, NH); 13C NMR (DMSO-d6):
d 13.9 (CH3), 21.9 (CH2), 30.3 (CH2), 30.8 (CH2), 34.9
(CH2), 48.9 (CH2), 65.7 (CH2), 71.4 (CH), 81.6, 92.0,
97.7, 119.6, 123.7 (CH), 128.7 (CH · 2), 131.0
(CH · 2), 135.8 (CH), 143.2, 148.3 (CH), 149.8, 161.9;
HRMS: C22H26N2O4 Na calcd 405.1790, found
405.1791.
4.9. 5-[2-(4-Pentylphenyl)ethynyl]-1-[2-(2-phenyl-1,3-
dioxan-5-yliden)ethyl]-2,4(3H)-pyrimidinedione (13b)
In an analogous manner to the preparation of 8a, the
title compound 13b was prepared in a yield of 85% as
1
a pale yellow gum. H NMR (CDCl3): d 0.89 (t, 3H,
J = 6.8 Hz), 1.25–1.39 (m, 4H), 1.54–1.67 (m, 2H), 2.59
(t, 2H, J = 8.0 Hz), 4.16–4.25 (m, 1H), 4.42–4.63 (m,
4H), 4.94–4.99 (m, 1H), 5.46 (t, 1H, J = 7.0 Hz), 5.67
(s, 1H), 7.13 (d, 2H, J = 8.1Hz), 7.34–7.51 (m, 8H),
9.25 (s, 1H, NH); 13C NMR (CDCl3): d 14.1 (CH3),
22.6 (CH2), 30.9 (CH2), 31.5 (CH2), 36.0 (CH2), 44.6
(CH2), 65.8 (CH2), 71.6 (CH2), 79.2, 94.6, 101.1, 101.7
(CH), 118.4 (CH), 119.6, 126.2 (CH · 2), 128.5
(CH · 2), 129.2 (CH), 131.7 (CH), 136.3, 137.7, 144.1
(CH), 145.6, 149.8, 161.7; HRMS: C29H30N2O4Na calcd
493.3112 [M+Na]+, found 493.3117.
4.11.3. 5-(1-Decynyl)-1-[4-hydroxy-3-(hydroxymethyl)-2-
butenyl]-2,4(1H,3H)-pyrimidinedione (15a). Yield 97%,
pale yellow gum, 1H NMR (DMSO-d6): d 0.82–8.88
(m, 3H), 1.18–1.51 (m, 12H), 2.35 (t, 2H, J = 7.1Hz),
3.95 (d, 2H, J = 4.8 Hz), 4.02 (d, 2H, J = 5.0 Hz), 4.39
(d, 2H, J = 7.1Hz), 4.71–4.88 (m, OH · 2), 5.44 (t,
1H, J = 7.1 Hz), 7.88 (s,1H), 11.51 (s, 1H, NH); 13C
NMR (DMSO-d6): d 13.9 (CH3), 18.8 (CH2), 22.1
(CH2), 28.2 (CH2), 28.3 (CH2), 28.5 (CH2),
28.6 (CH2), 31.2 (CH2), 44.5 (CH2), 56.8 (CH2), 62.4
(CH2), 72.7, 93.2, 98.3, 118.5 (CH), 144.9 (CH), 147.5,
149.9, 162.3; HRMS: C19H28N2O4Na calcd 371.1221,
found 377.1227.
4.10. 1-[2-(2-Phenyl-1,3-dioxan-5-yliden)ethyl]-5-[2-
(trimethylsilyl)ethynyl]-2,4(3H)-pyrimidinedione (13c)
In an analogous manner to the preparation of 8a, the
title compound 13c was prepared in a yield of 70% as
a white solid. mp (CH2Cl2) 213–215 ꢁC; 1H NMR
(DMSO-d6): d 0.18 (s, 9H), 4.31–4.54 (m, 5H), 4.96–
5.04 (m, 1H), 5.48 (t, 1H, J = 7.0 Hz), 5.69 (s, 1H),
7.28–7.45 (m, 5H), 8.15 (s, 1H), 11.64 (br s, 1H, NH);
13C NMR (DMSO-d6): d 0.1(CH 3 · 3), 44.2 (CH2),
65.3 (CH2), 70.6 (CH2), 96.9, 97.6, 97.8, 100.5 (CH),
119.3 (CH), 126.1 (CH · 2), 128.0 (CH · 2), 128.7
(CH), 134.0, 138.3, 149.6 (CH), 149.8, 161.9; HRMS:
C21H24N2O4NaSi calcd 419.1403 [M+Na]+, found
419.1402.
4.11.4. 1-[4-Hydroxy-3-(hydroxymethyl)-2-butenyl]-5-[2-
(4-pentylphenyl)ethynyl]-2,4(1H,3H)-pyrimidinedione (15b).
Yield 98%, white solid, mp (MeOH) 131-133 ꢁC; 1H
NMR (DMSO-d6): d 0.85 (t, 3H, J = 6.9 Hz), 1.18–
1.37 (m, 4H), 1.50–1.65 (m, 2H), 2.58 (t, 2H,
J = 7.3 Hz), 3.96 (d, 2H, J = 5.4 Hz), 4.04 (d, 2H, J =
5.4 Hz), 4.45 (d, 2H, J = 7.2 Hz), 4.75 (t, OH, J = 5.4 Hz),
4.82 (t, OH, J = 5.4 Hz), 5.49 (t, 1H, J = 7.2 Hz), 7.21
(d, 2H, J = 8.2 Hz), 7.35 (d, 2H, J = 8.2 Hz), 8.10
(s, 1H), 11.65 (s, 1H, NH); 13C NMR (DMSO-d6): d
12.7 (CH3), 20.7 (CH2), 29.12 (CH2), 29.64 (CH2), 33.7
(CH2), 44.2 (CH2), 55.7 (CH2), 61.2 (CH2), 80.5, 90.8,
96.5, 117.3, 118.5 (CH), 127.5 (CH · 2), 129.8
(CH · 2), 141, 143 (CH), 147.1, 148.7, 160.7; HRMS:
C22H26N2O4Na calcd 405.0821, found 405.0826.
4.11. General procedure for deprotection under acidic
conditions
Acetal derivatives (0.22 mmol) were stirred at room tem-
perature for 3 h in a 2:1mixture of TFA/H O (15 mL).
2
After evaporation of volatiles, the crude residue was
purified by flash chromatography (CH2Cl2/MeOH,
92:8).
4.12. General procedure for desilylation
4.11.1. 5-(1-Decynyl)-1-[(E)-4,5-dihydroxy-2-pentenyl]-
2,4(1H,3H)-pyrimidinedione (14a). Yield 92%, pale yel-
low gum, 1H NMR (DMSO-d6): d 0.87 (t, 3H, J =
6.3 Hz), 1.18–1.38 (m, 10H), 1.41–1.58 (m, 2H), 2.34
(t, 2H, J = 7.0 Hz), 3.21–3.30 (m, 2H), 3.88–4.01 (m,
1H), 4.21–4.31 (m, 2H), 4.51–4.68 (m, OH), 4.84
A solution of silylated derivative (0.24 mmol) and
TBAFxH2O (64 mg, 0.25 mmol) in acetonitrile (2 mL)
was stirred at room temperature for 30 min. Solvents
were evaporated in vacuo and the residue was submitted
to flash column chromatography (AcOEt/Pet. eth. 7:3)
to give pure desilylated compound.

F. Amblard et al. / Bioorg. Med. Chem. 13 (2005) 1239–1248
1245
4.12.1.
5-Ethynyl-1-[2-(2-phenyl-1,3-dioxan-5-yliden)-
in vacuo to give the desired furopyrimidone acyclic
nucleoside.
ethyl]-2,4(1H,3H)-pyrimidinedione (16c). The title
compound was prepared from 12c; yield 62%, pale white
1
gum, H NMR (CDCl3): d 4.11 (s, 1H), 4.31–4.52 (m,
4.15.1. 3-N-(2-Acetoxy-ethoxymethyl)-6-octyl-2,3-dihy-
drofuro[2,3-d]pyrimidin-2one (20a). White solid; mp
(CH2Cl2) 111–113 ꢁC; 1H NMR (CDCl3): d 0.98 (m,
3H, J = 7.2 Hz), 1.21–1.68 (m, 12H), 2.05 (s, 3H), 2.65
(t, 2H, J = 7.5 Hz), 3.88 (t, 2H, J = 4.6 Hz), 4.21(t,
2H), 5.49 (s, 2H), 6.16 (s, 1H), 7.99 (s, 1H); 13C NMR
(CDCl3): d 14.0 (CH3), 20.8 (CH3), 22.6 (CH2), 22.7
5H), 4.94–5.03 (m, 1H), 5.49 (t, 1H, J = 7.0 Hz), 5.69
(s, 1H), 7.31–7.45 (m, 5H), 8.13 (s, 1H), 11.64 (s, 1H,
NH); 13C NMR (CDCl3): d 44.2 (CH2), 65.3 (CH2),
70.6 (CH2), 76.2, 83.7, 97.0, 100.5 (CH), 119.3 (CH),
126.1 (CH · 2), 128.0 (CH · 2), 128.7 (CH), 134.1,
138.3, 149.3 (CH), 149.8, 162.1; HRMS: C18H16N2O4Na
calcd 347.1201, found 347.1205.
(CH2), 26.7 (CH2) 28.2 (CH2), 29.0 (CH2), 29.1(CH ),
2
29.2 (CH2), 31.7 (CH2), 63.1(CH ), 68.2 (CH2), 79.4
2
(CH2), 98.6, 108.7, 137.5, 155.8 (CH), 160.7, 170.7
(CO), 172.4; HRMS: C19H28N2O5Na calcd 387.4352
[M+Na]+, found 387.4351.
4.12.2. 1-[(E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-prop-
enyl]-5-ethynyl-2,4(1H,3H)-pyrimidinedione (17c). The
title compound was prepared from 13c; yield 94%, pale
1
white gum, H NMR (CDCl3): d 1.36 (s, 3H), 1.41 (s,
4.15.2. 3-N-(2-Acetoxy-ethoxymethyl)-6-p-pentylphenyl-
2,3-dihydrofuro[2,3-d]pyrimidin-2one (20b). White solid;
3H), 3.18 (s, 1H), 3.58 (dd, 1H, J = 8.0 Hz), 4.10 (dd,
1H, J = 6.3 Hz, J = 8.0 Hz), 4.26–4.41(m, 2H), 4.48–
4.56 (m, 1H), 5.69–5.88 (m, 2H), 7.48 (s, 1H), 9.75
(s, 1H, NH); 13C NMR (CDCl3): d 23.7 (CH3), 25.7
(CH3), 47.5 (CH2), 67.2 (CH2), 72.4, 73.8, 80.5, 97.3,
107.8, 124.3 (CH), 131.8 (CH), 145.5 (CH), 147.9,
160.1; HRMS: C14H16N2O4 Na calcd 299.1008, found
299.1003.
1
mp (CH2 Cl2) 158–160 ꢁC; H NMR (CDCl3): d 0.85–
0.95 (m, 3H), 1.24–1.72 (m, 6H), 2.05 (s, 3H), 2.64 (t,
2H, J = 7.7 Hz), 3.90 (t, 2H, J = 4.7 Hz), 4.22 (t, 2H),
5.50 (s, 2H), 6.70 (s, 1H), 7.24 (d, 2H, J = 8.2 Hz),
7.65 (d, 2H, J = 8.2 Hz), 8.07 (s, 1H); 13C NMR
(CDCl3): d 14.1 (CH3), 20.9 (CH3), 22.5 (CH2), 30.9
(CH2), 31.5 (CH2), 35.9 (CH2), 63.1(CH 2), 68.5
(CH2), 79.6 (CH2), 96.5, 109.3, 125.1 (CH), 125.6
(CH), 129.1 (CH), 138.3, 145.4 (CH), 155.7, 156.7,
170.8 (CO), 172.3; HRMS: C22H26N2O5Na calcd
412.4527 [M+Na]+, found 412.4525.
4.13. 5-Acetyl-1-[(E)-4,5-dihydroxy-2-pentenyl]-
2,4(1H,3H)-pyrimidinedione (18)
In an analogous manner to the preparation of 14a, the
title compound 18 was prepared in 92% yield as a pale
yellow gum; 1H NMR (DMSO-d6): d 2.44 (s, 3H),
3.22–3.31(m, 2H), 3.88–4.01(m, H1 ), 4.40 (d, 2H,
J = 4.4 Hz), 4.63 (t, OH, J = 5.6 Hz), 4.90 (d, OH,
J = 5.0 Hz), 5.63–5.82 (m, 2H), 8.35 (s, 1H), 11.63 (s,
1H, NH); 13C NMR (DMSO-d6): d 30.3 (CH3), 49.3
(CH2), 65.7 (CH2), 71.3 (CH), 111.6, 123.6 (CH), 136.1
(CH), 150.1, 151.4 (CH), 162.7, 193.5; HRMS:
C11H14N2O5Na calcd 277.0936, found 277.0942.
4.15.3. 3-N-(2-Acetoxy-ethoxymethyl)-6-phenyl-2,3-dihy-
drofuro[2,3-d]pyrimidin-2one (20c). White solid; mp
(MeOH) 188–190 ꢁC; 1H NMR (DMSO-d6, 80 ꢁC): d
1.99 (s, 3H), 3.83 (t, 2H, J = 4.8 Hz), 4.15 (t, 2H), 5.43
(s, 2H), 7.20 (s, 1H), 7.40–7.85 (m, 5H), 8.57 (s, 1H);
13C NMR (DMSO-d6, 80 ꢁC): d 20.0 (CH3), 62.5
(CH2), 67.3 (CH2), 79.0 (CH2), 98.8, 107.0, 124.3
(CH), 128.0 (CH), 128.6 (CH), 129.1, 141.6, 153.8
(CH), 160.9, 170.4 (CO), 172.6; HRMS: C17H16N2O4Na
calcd 351.3173 [M+Na]+, found 351.3176.
4.14. 5-Acetyl-1-[4-hydroxy-3-(hydroxymethyl)-2-buten-
yl]-2,4(1H,3H)-pyrimidinedione (19)
4.15.4. 3-N-(2-Acetoxy-ethoxymethyl)-6-pentyl-2,3-dihy-
drofuro[2,3-d]pyrimidin-2one (20d). White solid; mp
(CH2Cl2) 80–82 ꢁC; 1H NMR (CDCl3): d 0.85–1.08
(m, 3H), 1.24–1.82 (m, 6H), 2.05 (s, 3H), 2.66 (t, 2H,
J = 7.5 Hz), 3.90 (t, 2H, J = 4.6 Hz), 4.21(t, 2H,
J = 4.6 Hz), 5.50 (s, 2H), 6.17 (s, 1H), 8.01 (s, 1H); 13C
NMR (CDCl3): d 13.9 (CH3), 20.8 (CH3), 22.2 (CH2),
26.3 (CH2), 28.2 (CH2), 31.1 (CH2), 63.0 (CH2), 68.2
(CH2), 79.4 (CH2), 98.6, 108.7, 137.7, 155.7 (CH),
160.7, 170.7 (CO), 172.4; HRMS: C16H22N2O5Na calcd
345.3539 [M+Na]+, found 345.3536.
In analogous manner to the preparation of 14a, the title
compound 19 was prepared in 93% yield as a pale yellow
gum; 1H NMR (DMSO-d6): d 2.44 (s, 3H), 3.94 (d,
2H, J = 5.0 Hz), 4.03 (d, 2H, J = 5.3 Hz), 4.53 (d,
2H, J = 7.0 Hz), 4.77–4.87 (m, 2H), 5.46 (t, 1H,
J = 7.0 Hz), 8.38 (s, 1H), 11.62 (s, 1H, NH); 13C NMR
(DMSO-d6): d 30.3 (CH3), 45.3 (CH2), 57.0 (CH2),
62.4 (CH2), 111.6, 118.2 (CH), 145.3, 150.3, 151.4
(CH), 161.7, 193.5; HRMS: C11H14N2O5 Na calcd
277.0800, found 277.0802.
4.15.5. 3-[(E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-prop-
enyl]-6-octylfuro[2,3-d]pyrimidin-2(3H)-one (22a). Yield
96%, pale white gum, 1H NMR (CDCl3): d 0.86 (t,
3H, J = 6.3 Hz), 1.24–1.42 (m, 10H), 1.60–1.72 (m,
2H), 2.62 (t, 2H, J = 7.2 Hz), 3.58 (dd, 1H,
J = 8.0 Hz), 4.11 (dd, 1H, J = 6.2 Hz, J = 8.0 Hz),
4.15. General procedure for AgNO3-mediated ring closure
To a solution of 5-alkynyl-acyclonucleosides (0.5 mmol)
in acetone (5 mL) was added AgNO3 (17 mg, 0.2 equiv)
and the reaction mixture stirred in the dark until com-
pletion (typically 5–20 h). Solvents were removed in va-
cuo and the residue dissolved in 20 mL CH2Cl2 (20 mL).
The organic layer was washed with H2O (2 · 5 mL) and
brine (5 mL) then dried over MgSO4 and concentrated
4.47–4.71(m, 3H), 5.72 (dd, H1,
J = 6.9 Hz,
J = 15.4 Hz), 5.96 (dt, 1H, J = 5.9 Hz, J = 15.4 Hz),
6.06 (s, 1H), 7.73 (s, 1H); 13C NMR (CDCl3): d 14.2
(CH3), 22.7 (CH2), 25.8 (CH3), 26.7 (CH2), 26.8

1246
F. Amblard et al. / Bioorg. Med. Chem. 13 (2005) 1239–1248
(CH3), 28.4 (CH2), 29.1(CH ), 29.2 (CH2), 29.3 (CH2),
2
8.58 (s, 1H); 13C NMR (DMSO-d6, 80 ꢁC): d 61.1
(CH2), 72.4 (CH2), 80.5 (CH2), 100.1, 108.1, 125.5
(CH), 129.3 (CH), 129.9 (CH), 130.3, 142.7, 155.0
(CH), 162.1, 172.7; HRMS: C15H14N2O4Na calcd
309.2796 [M+Na]+, found 309.2795.
31.9 (CH2), 52.2 (CH2), 69.3 (CH2), 76.1(CH), 98.4
(CH), 108.3, 109.7, 127.6 (CH), 133.1 (CH), 138.0
(CH), 155.4, 160.5, 172.2; HRMS: C22H32N2O4Na calcd
411.2260 [M+Na]+, found 411.2256.
4.15.6. 3-[(E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-prop-
enyl]-6-(4-pentylphenyl)furo[2,3-d]pyrimidin-2(3H)-one
(22b). Yield 97%, pale white gum, H NMR (CDCl3):
4.19. 3-N-(2-Hydroxy-ethoxymethyl)-6-pentyl-2,3-dihy-
drofuro[2,3-d]pyrimidin-2one (21d)
1
d 0.90 (t, 3H, J = 6.7 Hz), 1.21–1.41 (m, 4H), 1.38 (s,
3H), 1.42 (s, 3H), 1.55–1.71 (m, 2H), 2.64 (t, 2H,
The title compound was prepared from 20d in an anal-
ogous manner to the preparation of 9a in a 94% yield
as a white solid; mp (MeOH) 104–106 ꢁC; 1H NMR
(CD3 OD): d 0.82–0.92 (m, 3H), 1.20–1.66 (m, 6H),
2.63 (t, 2H, J = 7.7 Hz), 3.44–3.61(m, 4H), 4.69 (t,
1H, J = 5.2 Hz), 5.35 (s, 2H), 6.43 (s, 1H), 8.46 (s,
1H); 13C NMR (CDCl3): d 13.8 (CH3), 21.8, 26.0, 27.3
and 30.6 (4 · CH2), 60.0 (CH2), 71.2 (CH2), 79.4
(CH2), 99.6, 106.8, 140.9, 154.8 (CH), 158.7, 171.9;
HRMS: C14H20N2O4Na calcd 303.3163 [M+Na]+,
found 303.3165.
J = 7.3 Hz), 3.61(dd, H1 ,
J = 8.0 Hz), 4.11 (dd, 1H,
J = 6.1Hz, J = 8.0 Hz), 4.50–4.76 (m, 3H), 5.77 (dd,
1H, J = 7.0 Hz, J = 15.5 Hz), 6.01 (dt, 1H, J = 6.0 Hz,
J = 15.5 Hz), 6.64 (s, 1H), 7.25 (d, 2H, J = 8.1Hz),
7.66 (d, 2H, J = 8.1Hz), 7.89 (s, 1H); 13C NMR
(CDCl3): d 14.1 (CH3), 22.6 (CH2), 25.9 (CH3), 26.7
(CH3), 31.0 (CH2), 31.5 (CH2), 35.9 (CH2), 52.4
(CH2), 69.3 (CH2), 76.1 (CH), 96.4 (CH), 108.9, 109.8,
125.1 (CH · 2), 125.7, 127.5 (CH), 129.2 (CH · 2),
133.4 (CH), 138.9 (CH), 145.4, 155.2, 156.4, 171.9;
HRMS: C22H26N2O4 Na calcd 405.1790 [M+Na]+,
found 405.1795.
4.20. 3-[(E)-4,5-Dihydroxy-2-pentenyl]-6-octylfuro[2,3-d]
pyrimidin-2(3H)-one (23a)
4.16. 3-N-(2-Hydroxy-ethoxymethyl)-6-octyl-2,3-dihy-
drofuro[2,3-d]pyrimidin-2one (21a)
The title compound was prepared from 22a in an anal-
ogous manner to the preparation of 14a in a 91% yield
as a white solid; H NMR (DMSO-d6): d 0.84 (t, 3H,
1
The title compound was prepared from 20a in an anal-
ogous manner to the preparation of 9a in the yield of
93% as a white solid; mp (MeOH) 124–126 ꢁC; 1H
NMR (DMSO-d6, 80 ꢁC): d 0.81–0.93 (m, 3H), 1.21–
1.72 (m, 12H), 2.64 (t, 2H, J = 7.3 Hz), 3.50–3.55 (m,
4H), 5.34 (s, 2H), 6.38 (s, 1H), 8.37 (s, 1H); 13C NMR
(DMSO-d6, 80 ꢁC): d 13.3 (CH3), 21.5, 25.9, 27.0, 28.0,
28.1and 30.7 (8 · CH2), 59.8 (CH2), 71.0 (CH2), 79.0
(CH2), 99.0, 106, 139.9, 154.3 (CH), 158.4, 171.5;
HRMS: C17H26N2O4 Na calcd 345.3976 [M+Na]+,
found 345.3978.
J = 6.3 Hz), 1.18–1.39 (m, 10H), 1.52–1.65 (m, 2H),
2.62 (t, 2H, J = 7.2 Hz), 3.20–3.30 (m, 2H), 3.90–4.01
(m, 1H), 5.42 (d, 2H, J = 4.8 Hz), 4.60 (t, 1H,
J = 5.8 Hz), 4.85 (d, 1H, J = 4.8 Hz), 5.65–5.85 (m,
2H), 6.42 (s, 1H), 8.40 (s, 1H); 13C NMR (DMSO-d6):
d 14.7 (CH3), 22.9 (CH2), 27.1(CH ), 28.2 (CH2), 29.2
2
(CH2), 29.4 (CH2), 29.5 (CH2), 32.0 (CH2), 52.3
(CH2), 66.5 (CH2), 72.1 (CH), 100.2 (CH), 107.2, 124.8
(CH),136.7 (CH), 142.2 (CH), 155.2, 159.0, 172.1;
HRMS: C19H28N2O4Na calcd 371.1947, found
371.1947.
4.17. 3-N-(2-Hydroxy-ethoxymethyl)-6-p-pentyl-phenyl-
2,3-dihydrofuro[2,3-d]pyrimidin-2one (21b)
4.21. 3-[(E)-4,5-Dihydroxy-2-pentenyl]-6-(4-pentylphen-
yl)furo[2,3-d]pyrimidin-2(3H)-one (23b)
The title compound was prepared from 20b in an anal-
ogous manner to the preparation of 9a in a 92% yield
as a white solid; mp (CH2Cl2) 240–245 ꢁC (dec); 1H
NMR (DMSO-d6): d 0.82–0.95 (m, 3H), 1.22–1.70 (m,
6H), 2.58–2.72 (m, 2H), 3.48–3.72 (m, 4H), 4.37–4.54
(br s, 1H), 5.41 (s, 2H), 7.12 (s, 1H), 7.22 (d, 2H,
J = 7.8 Hz), 7.72 (d, 2H), 8.55 (s, 1H); 13C NMR
(CDCl3): d 13.2 (CH3), 21.4, 29.7, 30.4 and 34.5
(4 · CH2), 59.8 (CH2), 71.1 (CH2), 79.2 (CH2), 98.0,
107.0, 124.3 (CH), 125.5 (CH), 128.5 (CH), 141.0,
143.9 (CH), 154.0, 154.2, 171.4; HRMS: C20H24N2O4Na
calcd 379.4151 [M+Na]+, found 379.4149.
The title compound was prepared from 22b in analogous
manner to the preparation of 14a in the yield 95% as a
pale yellow solid; mp (MeOH) 227–229 ꢁC; H NMR
1
(DMSO-d6): d 0.85 (t, 3H, J = 7.1Hz), 1.20–1.32 (m,
4H), 1.51–1.63 (m, 2H), 2.61 (t, 2H, J = 7.5 Hz), 3.25–
3.32 (m, 2H), 3.91–4.03 (m, 1H), 4.56 (d, 2H,
J = 4.8 Hz), 4.63 (t, 1H, J = 6.0 Hz), 4.89 (d, 1H,
J = 5.0 Hz), 5.75–5.85 (m, 2H), 7.21(s, 1H), 7.31(d,
2H, J = 8.1Hz), 7.72 (d, 2H, J = 8.1Hz), 8.59 (s, 1H);
13C NMR (DMSO-d6): d 13.9 (CH3), 22.0 (CH2), 30.4
(CH2), 30.9 (CH2), 34.9 (CH2), 48.6 (CH2), 65.7
(CH2), 71.4 (CH), 98.5 (CH), 107.0, 124.0 (CH), 124.6
(CH · 2), 126.0, 129.0 (CH · 2), 136.1 (CH), 142.6
(CH), 144.1, 153.8, 154.4, 171.1; HRMS: C22H26N2O4-
Na calcd 405.1790, found 405.1795.
4.18. 3-N-(2-Hydroxy-ethoxymethyl)-6-phenyl-2,3-dihy-
drofuro[2,3-d]pyrimidin-2one (21c)
The title compound was prepared from 20c in an analo-
gous manner to the preparation of 9a in a 95% yield as a
white solid; mp (MeOH) 205–207 ꢁC (dec); H NMR
(DMSO-d6, 80 ꢁC): d 3.50–3.72 (m, 4H), 4.37–4.54 (br
s, 1H), 5.41 (s, 2H), 7.19 (s, 1H), 7.40–7.90 (m, 5H),
4.22. General synthesis of 6-alkylfuro[2,3-d]pyrimidine
acyclonucleosides (24a) and (24b)
1
5-Alkynyl-acyclonucleoside (0.5 mmol) was dissolved in
5 mL acetone. AgNO3 (17 mg, 0.2 equiv) was added and

F. Amblard et al. / Bioorg. Med. Chem. 13 (2005) 1239–1248
1247
the reaction mixture stirred in the dark until completion.
Solvents were removed in vacuo and the residue was dis-
solved in CH2Cl2 (20 mL). The organic layer was
washed with H2O (2 · 5 mL) and brine (5 mL) then
dried over MgSO4 and concentrated in vacuo. The resi-
due was then stirred at room temperature for 3 h in a 2:1
mixture of TFA/H2O (15 mL). After evaporation of vol-
atiles, the crude was purified by flash chromatography
(CH2Cl2/MeOH, 92:8).
at the University of New Orleans, S.P.N. gratefully
acknowledges the National Science Foundation for gen-
erous support. R.F.S. was supported by EmoryÕs Center
for AIDS Research NIH grant 2P30-AI-50409 and by
the Department of Veterans Affairs.
References and notes
1. Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic
and L-Nucleosides; Kluwer Academic: Dordrecht, 1998.
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289; (b) De Clerq, E.; Holy, A.; Rosenberg, I.; Sakuma,
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Naesens, L.; Snoeck, R.; Andrei, G.; Balzarini, J.; Neyts,
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(d) Kim, H. S.; Barak, D.; Harden, K. T.; Boyer, J. L.;
Jacobson, K. A. J. Med. Chem. 2001, 44, 3092; (e)
Borcherding, D. R.; Narayanan, S.; Hasobe, M.; McKee,
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4.22.1. 3-[4-Hydroxy-3-(hydroxymethyl)-2-butenyl]-6-
octylfuro[2,3-d]pyrimidin-2(3H)-one (24a). Yield 98%,
pale white gum; H NMR (DMSO-d6): d 0.78–8.89 (m,
3H), 1.18–1.38 (m, 10H), 1.55–1.67 (m, 2H), 2.63 (t,
2H, J = 7.0 Hz), 3.95 (d, 2H, J = 4.8 Hz), 4.07 (d, 2H,
J = 5.0 Hz), 4.65 (d, 2H, J = 7.1Hz), 4.75–4.85 (m,
OH · 2), 5.51(t, 1H, J = 7.1Hz), 6.42 (s, 1H), 8.42 (s,
1H); 13C NMR (DMSO-d6): d 13.9 (CH3), 18.8 (CH2),
1
22.1(CH ), 26.4 (CH2), 27.4 (CH2), 28.4 (CH2), 28.6
2
(CH2), 31.2 (CH2), 47.5 (CH2), 57.1(CH 2), 62.5
(CH2), 99.5 (CH), 106.5, 118.8 (CH), 141.52, 145.0
(CH), 154.6, 158.2, 171.2; HRMS: C19H28N2O4Na calcd
371.1947, found 371.1949.
4.22.2. 3-[4-Hydroxy-3-(hydroxymethyl)-2-butenyl]-6-(4-
pentylphenyl)furo[2,3-d]pyrimidin-2(3H)-one (24b). Yield
95%, pale white gum; 1H NMR (DMSO-d6): d 0.85
(t, 3H, J = 6.5 Hz), 1.18–1.33 (m, CH2 · 2), 1.51–1.68
(m, CH2), 2.61(t, CH , J = 7.2 Hz), 3.97 (s, CH2), 4.10
2
(s, CH2), 4.70 (d, CH2, J = 7.2 Hz), 5.56 (t, 1H,
J = 7.2 Hz), 7.20 (s, 1H), 7.32 (d, 2H, J = 8.1Hz), 7.73
(d, 2H, J = 8.1Hz), 8.60 (s, 1H); 13C NMR (DMSO-
d6): d 13.9 (CH3), 21.9 (CH2), 30.4 (CH2), 30.8 (CH2),
34.9 (CH2), 47.8 (CH2), 57.1(CH ), 98.4 (CH), 107.0,
2
118.7 (CH), 124.5 (CH · 2), 125.9, 129.0 (CH · 2),
142.6 (CH), 144.1, 145.2, 153.8, 154.6, 171.0; HRMS:
C22H26N2O4Na calcd 405.1790, found 405.1790.
5. Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev.
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HBV
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Antiviral and cytotoxicity assays were conducted as de-
scribed recently by Stuyver et al.17 HIV assays were per-
formed in activated primary human peripheral blood
mononuclear (PBM) cells.
4.24. Antiviral and cytotoxicity assays for HSV
The newly synthesized nucleosides were evaluated for
activity against HSV-1(strain F) by plaque reduction as-
say in Vero cells using methodologies described previ-
ously.18 Cytotoxicity assays were conducted in rapidly
dividing Vero cells as previously described.16 The med-
ian effective concentration was determined by the med-
ian effect method.
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Acknowledgements
We thank J. Grier, M. Bennett and K. Rapp for excel-
lent technical assistance. L.A.A. thank the CNRS and
MENRT for financial support. F.A. thanks the
MENRT for a Ph.D. fellowship. For work performed

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