Synthesis and biological evaluation of 6-(alkyn-1-yl)furo[2,3-d]pyrimidin- 2(3H)-one base and nucleoside derivatives

Article abstract of DOI:10.1021/jm050867d

Derivatives of the 2′-deoxynucleoside of furo[2,3-d]pyrimidin-2(3H)- one with long-chain alkyl (or 4-alkylphenyl) substituents at C6 exhibit remarkable anti-VZV (varicella-zoster virus) potency and selectivity, and analogous 2′,3′-dideoxynucleoside derivatives show anti-HCMV (human cytomegalovirus) activity. We now report a synthetic approach that enables the preparation of long-chain 6-(alkyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-ones in which the rodlike acetylene spacer replaces the 4-substituted-phenyl ring at C6. Analogues with methyl, β-D-ribofuranosyl, β-D-arabinofuranosyl, and 2-deoxy-β-D-erythro-pentofuranosyl substituents at N3 have been prepared. Long-chain derivatives at C6 in the 2′-deoxynucleoside series showed virus-encoded nucleoside kinase-sensitive anti-VZV activity. Surprisingly, 3-methyl-6-(octyn-1-yl)furo[2,3-d]-pyrimidin-2(3H)-one (prepared as a negative anti-VZV test control) exhibited anti-HCMV activity, which supports the possibility of development of non-nucleoside anti-HCMV agents originating from uncomplicated derivatives of such bicyclic ring systems.

Full text of DOI:10.1021/jm050867d

J. Med. Chem. 2006, 49, 391-398
391
Synthesis and Biological Evaluation of 6-(Alkyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one Base and
Nucleoside Derivatives1
Morris J. Robins,*,† Karl Miranda,†,‡ Vivek K. Rajwanshi,†,§ Matt A. Peterson,*,† Graciela Andrei,| Robert Snoeck,|
Erik De Clercq,| and Jan Balzarini|
Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602-5700, and Rega Institute for Medical Research,
Katholieke UniVersiteit LeuVen, B-3000 LeuVen, Belgium
ReceiVed September 1, 2005
Derivatives of the 2′-deoxynucleoside of furo[2,3-d]pyrimidin-2(3H)-one with long-chain alkyl (or
4-alkylphenyl) substituents at C6 exhibit remarkable anti-VZV (varicella-zoster virus) potency and selectivity,
and analogous 2′,3′-dideoxynucleoside derivatives show anti-HCMV (human cytomegalovirus) activity. We
now report a synthetic approach that enables the preparation of long-chain 6-(alkyn-1-yl)furo[2,3-d]pyrimidin-
2(3H)-ones in which the rodlike acetylene spacer replaces the 4-substituted-phenyl ring at C6. Analogues
with methyl, â-D-ribofuranosyl, â-D-arabinofuranosyl, and 2-deoxy-â-D-erythro-pentofuranosyl substituents
at N3 have been prepared. Long-chain derivatives at C6 in the 2′-deoxynucleoside series showed virus-
encoded nucleoside kinase-sensitive anti-VZV activity. Surprisingly, 3-methyl-6-(octyn-1-yl)furo[2,3-d]-
pyrimidin-2(3H)-one (prepared as a negative anti-VZV test control) exhibited anti-HCMV activity, which
supports the possibility of development of non-nucleoside anti-HCMV agents originating from uncomplicated
derivatives of such bicyclic ring systems.
Scheme 1. Synthesis of Furo[2,3-d]pyrimidin-2(3H)-ones 32
Introduction
Furo[2,3-d]pyrimidin-2(3H)-one 2′-deoxynucleosides were
reported in 1981.2a Base and nucleoside derivatives of 3 (Scheme
1) were initially isolated as byproducts from Sonogashira cross-
coupling reactions of 5-iododuracil derivatives with terminal
alkynes. It also was demonstrated that efficient 5-endo-dig
cyclizations of the cross-coupled 5-(alkyn-1-yl)uracil compounds
were catalyzed by CuI.2 Anticancer and antiviral activities were
observed with certain of the 5-(alkyn-1-yl)uracil 2′-deoxy-
nucleosides,3a but no antiviral activity was exhibited by the
cyclized 6-butylfuro[2,3-d]pyrimidin-2(3H)-one 2′-deoxy-
nucleoside.3b
Two decades later, the remarkably potent and selective
activity of longer chain homologues against varicella-zoster virus
(VZV) was discovered by McGuigan et al.4 The preparation4,5
and biological evaluation of numerous analogues of 3 have been
reported.6 The basic synthetic approach for all of these analogues
employed our original strategy.2 Although this approach is
efficient, its scope is limited to the availability of substituted
terminal alkynes and is not amenable to generation of compound
libraries with a broad diversity of substituents at C6.
Furo[2,3-d]pyrimidin-2(3H)-one 2′-deoxynucleosides with a
4-alkylphenyl substituent at C6 have shown extremely potent
anti-VZV activity.4b We reasoned that replacement of the phenyl
ring at C6 by a rigid alkyne spacer might produce compounds
with analogous structural features and biological profiles. We
now report effective syntheses of key 6-bromofuro[2,3-d]-
pyrimidin-2(3H)-one intermediates 6a-d and their conver-
sion to novel 6-(alkyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one
derivatives 7 and 8 (Scheme 2), compounds7 that were not
accessible by our original cross-coupling/cyclization approach.2-4,6
The 6-bromofuro[2,3-d]pyrimidin-2(3H)-one moiety7 also en-
ables elaboration into a diverse series of compounds (e.g., via
Sonogashira, Heck, Suzuki, Stille, and carbonyl-insertion cou-
plings and by aryl bromide chemistries involving lithium-
halogen exchange and reactions of the lithio species with
electrophiles).
Results and Discussion
Chemistry. The furopyrimidine starting materials 5a-d
(Scheme 2) were prepared by minor modifications of our Cu(I)-
promoted cyclization methodology.2 Because the selective anti-
VZV activity of the bicyclic 2′-deoxynucleoside analogues is
consistent with activation by a virus-expressed nucleoside
kinase,4,6 we also prepared derivatives of 1-methylfuro[2,3,-d]-
pyrimidin-2(3H)-one2 (5a) to serve as negative controls for the
biological evaluations.
Treatment of 5a with bromine in DMF gave 6-bromo-1-
methylfuro[2,3-d]pyrimidin-2(3H)-one (6a) in 60% isolated
yield. However, the acetylated nucleosides 5b-d underwent
decomposition under these conditions, and decomposition of
5c also occurred with pyridinium tribromide in CH2Cl2. The
latter reagent in acetonitrile converted 5c into 6c in 56% yield,
but the reaction progress was sluggish at ambient temperature
(24 h was required for completion). Bromination conditions
reported for the preparation of 2,3-dibromobenzo[b]furan8
worked well, and such treatment (Br2/KOAc/CHCl3) of 5b and
5d for 1-2 h at ambient temperature gave the 6-bromo
analogues 6b and 6d in 80-87% yields without detected
formation of regioisomers.
* Corresponding author. Telephone: (801) 422-6272. Fax: (801) 422-
0153. E-mail: morris_robins@byu.edu.
† Brigham Young University.
‡ Current address: Novartis Institute for Biomedical Research, Cam-
bridge, MA.
§ Current address: Genelabs Technologies, Redwood City, CA.
| Katholieke Universiteit Leuven.
10.1021/jm050867d CCC: $33.50 © 2006 American Chemical Society
Published on Web 11/30/2005

392 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Scheme 2. Synthesis of the Test Compoundsa
Robins et al.
Table 1. Antiviral and Cytotoxic Activity of the Test Compounds in
Human Embryonic Lung Cell Cultures
EC50a (µM)
cytotoxicity
VZV
HCMV
(µM)
e
compd
YSb
217
g89
>175
>150
87
07/1c YS/Rc AD-169 Davis MCCd CC50
7a(i)
>87
>77
>70
>87
23
>175
>217
31
>175
>150
>150
21
139
37
g217 >217
194 >194
>175 >175 >175
>150 >150 >150
>150 >150 >150
7a(ii)
7a(iii)
7a(iv)
8b(i)
8b(ii)
8b(iii) 2.7
8b(iv)
8c(i)
8c(ii)
8c(iii)
8c(iv)
8d(i)
8d(ii)
8d(iii) g11
8d(iv)
ACV
BVDU 0.01
GCV
f
>150 >150
g135 90
25
1.5
22
19
g97
52
30
138
77
36
>13
6.5
g6.0 2.5
7.4
7.6
>4.8
g5.7
g113
g39
>4.8
>144
>133
7.3
>4.6
>144
>53
> 12
>12
ND
144
39
g12
4.6
>144 63
34
11
>12
36
52
19
6.2
3.5
>144 >144 >144
>53
g9.3
>4.6
g133 >133
>12
49
12
62
44
>4.6
>144
g43
>144 >144 >144
21
>53
12
>12
ND
ND
8.7
133
49
46
>53
124
116
3.7
5.7
24
g126
ND
>5
g16
1.4
>222 >889
>150 >150
>197 >197
g99
ND
ND
5.1
ND
ND
0.0001 >20
ND
g20
>200
a Inhibitory concentration required to reduce virus plaque formation by
50%. Virus input was 100 plaque forming units (pfu). b TK+. c TK-.
d Minimum cytotoxic concentration that caused a microscopically visible
alteration of cell morphology. e Cytotoxic concentration required to reduce
cell growth by 50%. f 3-(2-Deoxy-â-D-erythro-pentofuranosyl)-6-(4-pen-
tylphenyl)furo[2,3-d]pyrimidin-2(3H)-one (data from ref 4b).
6-(decyn-1-yl) 2′-deoxy analogue 8b(iii) had EC50 values
comparable to those of ganciclovir (GCV), and the 6-(octyn-
1-yl) homologue 8b(ii) also showed activity. Surprisingly,
3-methyl-6-(octyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one [7a(ii)]
showed weak activity (EC50 ) 31-37 µM), whereas other
homologues in the “negative control” series were inactive. Only
8c(iii) in the â-D-ribofuranosyl series and 8d(iii) in the â-D-
arabinofuranosyl series showed some indication of activity.
The unexpected activity exhibited by the 3-methyl-6-(octyn-
1-yl) derivative 7a(ii), as well as the weak effects of the
ribonucleoside 8c(iii) and arabino analogue 8d(iii), suggested
the possibility of development of novel anti-HCMV agents
without deoxysugar-derived substituents. Mechanisms distinct
from phosphorylation by nucleoside kinases and direct interfer-
ence with nucleic acid synthesis were implied.7 Subsequently,
it was reported that 2′,3′-dideoxynucleoside analogues had anti-
HCMV activity that was attributed to interference with viral
entry into cells.9 Derivatives of furo[2,3-d]pyrimidin-2(3H)-one
with alkyl and other uncomplicated substituents are more readily
accessible and cheaper to produce than the 2′-deoxy and 2′,3′-
dideoxy nucleoside derivatives that have been shown to exhibit
potent and selective anti-VZV and anti-HCMV activities.
a Reagents: (a) TMS-acetylene/(Ph3P)4Pd/CuI/Et3N/DMF; (b) NH4F/
MeOH; (c) CuI/Et3N/DMF; (d) Br2/KOAc/CHCl3 (or Br2/DMF) (or
pyridinium tribromide/MeCN); (e) 1-alkyne/(Ph3P)4Pd/CuI/Et3N/DMF; (f)
NH3/MeOH.
Sonogashira coupling of selected 1-alkynes with the 6-bromo
derivatives 6a-d proceeded smoothly to give the 6-(alkyn-1-
yl) analogues 7a-d(i-iv) in 53-98% yields. Ammonolysis of
the acetyl groups from 7b-d(i-iv) proceeded without difficulty
to provide the unprotected nucleosides 8b-d(i-iv).
Biological Testing. Compounds 7a(i-iv) and 8b-d(i-iv)
were evaluated for activity against VZV in human embryonic
lung (HEL) cells (Table 1). The 3-methyl series 7a (negative
controls) showed no activity against all three strains. As
expected, the 2′-deoxy series 8b exhibited the most potent anti-
VZV activity, which peaked for the 6-(octyn-1-yl) 8b(ii) and
6-(decyn-1-yl) 8b(iii) derivatives [with lower potencies for the
6-(hexyn-1-yl) 8b(i) and 6-(dodecyn-1-yl) 8b(iv) compounds].
The EC50 values for 8b(ii) (1.5 µM with a TK+ strain and ∼25
µM with two TK- strains] are in harmony with activation by a
virus-encoded nucleoside kinase as the most significant pathway
for inhibition by these 6-(alkyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-
one analogues. The anti-VZV activity of 8b(ii) was comparable
with that of acyclovir, but BVDU and 6-alkylfuro[2,3-d]-
pyrimdin-2(3H)-ones prepared by the McGuigan group4 are
several orders of magnitude more potent in cell culture. No anti-
VZV selectivity for TK+ versus TK- strains was apparent with
the â-D-ribofuranosyl 8c and â-D-arabinofuranosyl 8d series of
compounds, but weak selectivity for the TK- strains relative to
cytotoxicity was observed with these two series of analogues.
Compounds 7a(i-iv) and 8b-d(i-iv) were also evaluated
against human cytomegalovirus (HCMV) in HEL cells. The
Summary and Conclusions
We have developed effective syntheses of the 6-bromofuro-
[2,3-d]pyrimidin-2(3H)-ones 6a-d and employed them for
Sonogashira cross-couplings to give 6-(alkyn-1-yl)furo[2,3-d]-
pyrimidin-2(3H)-ones that were inaccessible by our prior
methodology.2-4,6 The anti-VZV and anti-HCMV activities for
these novel 6-(alkyn-1-yl) analogues were affected primarily
by the N3 substituent and the length of the alkynyl side chain
at C6. The most active compounds had 8 or 10 carbon atoms
in the 6-(alkyn-1-yl) side chains. The rodlike alkyne linker
joining C6 and a C6-8 alkyl group did not support the enhance-
ment of anti-VZV activity comparably to that observed with
compounds linked by a 4-substituted phenyl ring. A 3-methyl-

6-Alkyn-1-ylfuropyrimidin-2(3H)-one DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1 393
83.3, 76.3, 35.5; MS (EI) m/z 150.0413 (M+ [C7H6N2O2] )
150.0430).
6-(octyn-1-yl) derivative showed weak anti-HCMV activity,
which was not expected for such a non-nucleoside analogue. A
variety of 3-alkyl and 6-substituted furo[2,3-d]pyrimidin-2(3H)-
one analogues are accessible via elaboration of the 6-bromo
intermediates, and studies targeting such compounds are in
progress.
Treatment of a mixture of this material (25 mg, 0.16 mmol) and
CuI (99.9%, 32 mg, 0.16 mmol) in DMF (1.5 mL) and Et3N (0.5
mL) by general procedure B (100 °C, 8 h; chromatography (CH2Cl2/
MeOH, 20:1)] gave 5a (20 mg, 80%) as a yellow solid: mp ∼287
°C (dec); UV λmax 327, 241 nm (ꢀ 5540, 9460), λmin 264, 236 nm
1
(ꢀ 666, 9230); H NMR (DMSO-d6) δ 8.65 (s, 1H), 7.71 (d, J )
Experimental Section
2.7 Hz, 1H), 6.80 (d, J ) 2.7 Hz, 1H), 3.51 (s, 3H); 13C NMR
(DMSO-d6) δ 171.2, 144.1, 143.9, 104.7, 104.4, 104.1, 38.4; MS
(CI) m/z 151.0512 (MH+ [C7H7N2O2] ) 151.0507).
Reactions were performed under an inert atmosphere (N2 or Ar)
at ambient temperature unless otherwise indicated. EtOAc, MeOH,
MeCN, CH2Cl2, CHCl3, and Et3N were dried by refluxing with
and distillation from calcium hydride. DMF and 1-hexyne were
dried over 4-Å molecular sieves. 1-Octyne, 1-decyne, 1-dodecyne,
Br2, and other starting materials were used as received from
commercial suppliers. CuI (98%) purchased from Aldrich was used
for coupling/cyclization reactions unless otherwise indicated.
UV spectra were determined with solutions in MeOH. 1H NMR
spectra (300 or 500 MHz) were measured with internal references
at δ 7.27 (CDCl3), 2.50 (DMSO-d6), and 3.31 (CD3OD) and 13C
NMR spectra (75 or 125 MHz) at δ 77.3 (CDCl3), 39.5 (DMSO-
d6), and 49.2 (CD3OD). NMR spectra were determined in CDCl3
unless otherwise indicated. High-resolution mass spectra were
obtained in the FAB mode unless otherwise indicated. Developed
TLC plates were visualized under 254-nm UV light, with ninhydrin
spray, with a H2SO4/EtOH (5:95) spray and charring, with a
phosphomolybdic acid dip, or with an iodine chamber. Flash
chromatography was performed with silica gel (230-400 mesh)
and reagent grade solvents.
The 1-methyl-5-(trimethylsilylethynyl)uracil,10 1-(3,5-di-O-acetyl-
2-deoxy-â-D-erythro-pentofuranosyl)-5-(trimethylsilylethynyl)-
uracil,2 1-(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)-5-(trimethylsilyl-
ethynyl)uracil,11 and 1-(2,3,5-tri-O-acetyl-â-D-arabinofuranosyl)-
5-(trimethylsilylethynyl)uracil)12 starting materials were prepared
by our standard methodology.2,13
General Procedure A: Desilylation of the TMS-Acetylene
Group. A solution of the 5-(trimethylsilylethynyl)uracil derivative
and NH4F (98%, 5 equiv.) in MeOH was heated at reflux until
desilylation was completed (TLC, 1-3 h). Volatiles were flash
evaporated, and the residue was purified by flash chromatography.
General Procedure B: CuI-Promoted 5-Endo-Dig Cycliza-
tion. A solution of the 5-ethynyluracil derivative and CuI (1.0 equiv)
in freshly distilled and deoxygenated solvents was heated (70-
100 °C) until the starting material was converted completely into
the fluorescent furo[2,3-d]pyrimidin-2(3H)-one product (TLC).
Volatiles were flash evaporated and the product was isolated by
flash chromatography.
6-Bromo-3-methylfuro[2,3-d]pyrimidin-2(3H)-one (6a). A sus-
pension of 5a (201 mg, 1.34 mmol) in dried DMF (12 mL) was
cooled at 0 °C for 15 min. Br2 (86 µL, 268 mg, 1.67 mmol) was
added dropwise with stirring, and stirring was continued at 0 °C
for 1 h. The flask was removed from the ice bath, and the mixture
was allowed to warm to ambient temperature. Stirring was continued
until all 5a was converted to 6a (TLC, ∼1 h). Dried Et3N was
added until the solution was basic. Volatiles were evaporated, and
the residue was flash chromatographed (CH2Cl2/MeOH, 20:1) to
give 6a as a brown solid (180 mg, 60%): mp ∼200 °C (dec); UV
λmax 331, 248 nm (ꢀ 3600, 7120), λmin 275, 230 nm (ꢀ 217, 5210);
1H NMR (DMSO-d6) δ 8.63 (s, 1H), 7.03 (s, 1H), 3.50 (s, 3H);
13C NMR (DMSO-d6) δ 171.1, 154.5, 143.8, 126.2, 106.8, 105.8,
39.0; MS (EI) m/z 227.9545 (M+ [C7H7 79BrN2O2] ) 227.9534).
6-(Hexyn-1-yl)-3-methylfuro[2,3-d]pyrimidin-2(3H)-one
[7a(i)]. Treatment of 6a (25 mg, 0.11 mmol), (Ph3P)4Pd (13 mg,
0.01 mmol), CuI (5 mg, 0.02 mmol), Et3N (1.0 mL), DMF (2.0
mL), and 1-hexyne (52 µL, 36 mg, 0.44 mmol) by general procedure
C [65 °C, 2 h; chromatography (CH2Cl2/MeOH, 20:1)] gave a
material that was flash chromatographed (EtOAc/MeOH, 20:1) to
give 7a(i) (19 mg, 74%) as a pale-yellow solid: mp ∼152 °C (dec);
UV λmax 343, 278, 266 nm (ꢀ 9310, 13 160, 17 900), λmin 290, 275,
1
238 nm (ꢀ 1930, 12 300, 6990); H NMR δ 7.90 (s, 1H), 6.49 (s,
1H), 3.66 (s, 3H), 2.47 (t, J ) 6.9 Hz, 2H), 1.66-1.56 (m, 2H),
1.53-1.41 (m, 2H), 0.95 (t, J ) 7.2 Hz, 3H); 13C NMR δ 175.5,
156.1, 140.7, 139.4, 107.0, 106.5, 100.4, 70.2, 40.2, 30.2, 22.2,
19.6, 13.8; MS (EI) m/z 230.1051 (M+ [C13H14N2O2] ) 230.1055).
Anal. (C13H14N2O2) C, H, N.
3-Methyl-6-(octyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one [7a(ii)].
Treatment of 6a (50 mg, 0.22 mmol), (Ph3P)4Pd (25 mg, 0.02
mmol), CuI (9 mg, 0.05 mmol), Et3N (2.0 mL), DMF (5.0 mL),
and 1-octyne (200 µL, 121 mg, 1.10 mmol) by general procedure
C [65 °C, 2 h; chromatography (EtOAc/MeOH, 20:1)] gave 7a(ii)
(30 mg, 53%) as a pale-yellow solid: mp ∼158 °C (dec); UV λmax
343, 278, 266, 217 nm (ꢀ 10 500, 14 400, 20 000, 17 500), λmin
289, 275, 238 nm (ꢀ 1340, 13 300, 7250); 1H NMR δ 7.89 (s, 1H),
6.49 (s, 1H), 3.67 (s, 3H), 2.47 (t, J ) 7.0 Hz, 2H), 1.67-1.57 (m,
3H), 1.42-1.41 (m, 2H), 1.32-1.25 (m, 3H), 0.90 (t, J ) 6.75
Hz, 3H); 13C NMR δ 171.4, 156.1, 140.9, 139.4, 107.0, 106.6,
100.4, 70.2, 40.2, 31.5, 28.8, 28.2, 22.7, 19.9, 14.3; MS (EI) m/z
258.1367 (M+ [C15H18N2O2] ) 258.1368). Anal. (C15H18N2O2) C,
H, N.
6-(Decyn-1-yl)-3-methylfuro[2,3-d]pyrimidin-2(3H)-one [7a(iii)].
Treatment of 6a (50 mg, 0.22 mmol), (Ph3P)4Pd (25 mg, 0.02
mmol), CuI (9 mg, 0.05 mmol), Et3N (2.0 mL), DMF (5.0 mL),
and 1-decyne (202 µL, 152 mg, 1.10 mmol) by general procedure
C [65 °C, 2 h; chromatography (EtOAc/MeOH, 20:1)] gave 7a(iii)
(35 mg, 56%) as a pale-yellow solid: mp ∼165 °C (dec); UV λmax
343, 278, 266, 217 nm (ꢀ 13 300, 18 300, 25 600, 21 600), λmin
289, 275, 238 nm (ꢀ 1320, 16 900, 8630, 14 900); 1H NMR δ 7.90
(s, 1H), 6.49 (s, 1H), 3.67 (s, 3H), 2.46 (t, J ) 7.0 Hz, 2H), 1.67-
1.57 (m, 2H), 1.46-1.40 (m, 2H), 1.29 (br s, 8H), 0.88 (t, J )
6.45 Hz, 3H); 13C NMR δ 171.5, 156.1, 141.0, 139.4, 107.0, 106.6,
100.4, 70.2, 40.1, 32.0, 29.3, 29.2, 29.1, 28.2, 22.9, 19.9, 14.3;
MS (EI) m/z 286.1681 (M+ [C17H22N2O2] ) 286.1681). Anal.
(C17H22N2O2) C, H, N.
General Procedure C: Cross-Coupling of 6-Bromofuro[2,3-
d]pyrimidin-2(3H)-ones and 1-Alkynes. A solution of the 6-bromo-
furo[2,3-d]pyrimidin-2(3H)-one derivative, (Ph3P)4Pd (0.1 equiv),
CuI (0.2 equiv), and a 1-alkyne (5 equiv) in deoxygenated DMF/
Et3N was stirred under an inert atmosphere until the starting material
was completely consumed (TLC, 1-2 h). Volatiles were evaporated,
and the residue was purified by flash chromatography.
General Procedure D: Ammonolysis of Acetyl Protecting
Groups. A solution of the acetylated nucleoside derivative in
saturated NH3/MeOH was stirred at 0 °C until the starting material
was completely deprotected (TLC, ∼3 h). Volatiles were evapo-
rated, and the residue was purified by flash chromatagraphy.
3-Methylfuro[2,3-d]pyrimidin-2(3H)-one (5a). Treatment of
1-methyl-5-(trimethylsilylethynyl)uracil10 (1.0 g, 4.5 mmol) by
general procedure A [NH4F (850 mg, 22.5 mmol), MeOH (50 mL)]
resulted in separation of a light yellow precipitate. Heating was
continued for ∼3 h (TLC), and the mixture was stored in a
refrigerator overnight. The solid was filtered, washed with a
minimum volume of ice-cold MeOH, and dried over P2O5 to give
5-ethynyl-1-methyluracil (545 mg, 81%): mp ∼240 °C (dec); UV
6-(Dodecyn-1-yl)-3-methylfuro[2,3-d]pyrimidin-2(3H)-one
[7a(iv)]. Treatment of 6a (80 mg, 0.35 mmol), (Ph3)4Pd (41 mg,
0.035 mmol), CuI (14 mg, 0.07 mmol), Et3N (2.0 mL), DMF (5.0
mL), and 1-dodecyne (380 µL, 290 mg, 1.75 mmol) by general
1
λmax 291, 228 nm (ꢀ 14 600, 12 300), λmin 251 nm (ꢀ 3350); H
NMR (DMSO-d6) δ 11.56 (br s, 1H), 8.10 (s, 1H), 4.07 (s, 1H),
3.24 (s, 3H); 13C NMR (DMSO-d6) δ 162.3, 150.5, 150.2, 96.1,

394 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Robins et al.
procedure C [65 °C, 2 h; chromatography (EtOAc/MeOH, 20:1)]
gave 7a(iv) (47 mg, 68%) as a pale-yellow solid: mp ∼174 °C
(dec); UV λmax 344, 278, 266 nm (ꢀ 11 800, 16 300, 22 800), λmin
289, 276, 239 nm (ꢀ 1210, 14 900, 8100); 1H NMR δ 7.88 (s, 1H),
6.49 (s, 1H), 3.66 (s, 3H), 2.46 (t, J ) 7.0 Hz, 2H), 1.64-1.59 (m,
3H), 1.46-1.38 (m, 3H), 1.27 (br s, 10H), 0.88 (t, J ) 6.6 Hz,
3H); 13C NMR δ 171.2, 155.8, 140.4, 139.2, 106.3, 100.2, 77.2,
69.9, 40.0, 31.9, 29.6, 29.5, 29.3, 29.1, 28.9, 28.0, 22.7, 19.6, 14.1;
MS (EI) m/z 314.2008 (M+ [C19H26N2O2] ) 314.1994). Anal.
(C19H26N2O2) C, H, N.
3-(3,5-Di-O-acetyl-2-deoxy-â-D-erythro-pentofuranosyl)furo-
[2,3-d]pyrimidin-2(3H)-one (5b). A solution of 1-(3,5-di-O-acetyl-
2-deoxy-â-D-erythro-pentofuranosyl)-5-(trimethylsilylethynyl)-
uracil2 (50 mg, 0.12 mmol) and NH4F (23 mg, 0.61 mmol) in MeOH
(1 mL) was treated by general procedure A [ambient temperature,
1 h; chromatography (60% EtOAc/hexanes f 80% EtOAc/
hexanes)] to give 1-(3,5-di-O-acetyl-2-deoxy-â-D-erythro-pento-
furanosyl)-5-ethynyluracil (35 mg, 86%) as a white solid foam:
UV λmax 287, 227 nm (ꢀ 12 600, 11 800), λmin 249 nm (ꢀ 2600);
1H NMR δ 8.70 (s, 1H), 7.91 (s, 1H), 6.30 (dd, J ) 7.5, 6.0 Hz,
1H), 5.26-5.24 (m, 1H), 4.42-4.30 (m, 3H), 3.21 (s, 1H), 2.57
(ddd, J ) 14.5, 5.5, 2.5 Hz, 1H), 2.24-2.19 (m, 1H), 2.18 (s, 3H),
2.12 (s, 3H); 13C NMR δ 170.6, 170.4, 161.0, 149.2, 143.0, 100.0,
85.9, 83.0, 82.5, 74.7, 74.1, 64.0, 38.6, 21.11, 21.09; MS (EI) m/z
336.0963 (M+ [C15H16N2O7] ) 336.0957).
white solid (65 mg, 81%): mp ) 138-140 °C; UV λmax 343, 278,
266 (ꢀ 12 000, 15 800, 21 300), λmin 289, 275, 240 (ꢀ 1400, 14 300,
1
9420); H NMR (CD3OD) δ 8.96 (s, 1H), 6.78 (s, 1H), 6.27 (t, J
) 6.25 Hz, 1H), 4.38 (q, J ) 5.0 Hz, 1H), 4.06 (q, J ) 2.8 Hz,
1H), 3.88 (dd, J ) 12.0, 3.0 Hz, 1H), 3.78 (dd, J ) 12.0, 4.0 Hz,
1H), 2.61 (ddd, J ) 14.0, 6.0, 4.5 Hz, 1H), 2.52 (t, J ) 7.0 Hz,
2H), 2.21 (dt, J ) 13.5, 6.0 Hz, 1H), 1.64-1.58 (m, 2H), 1.53-
1.46 (m, 2H), 0.97 (t, J ) 7.5 Hz, 3H); 13C NMR (CD3OD) δ 172.3,
156.9, 140.3, 140.2, 109.0, 108.3, 100.8, 90.2, 89.9, 71.4, 70.8,
62.4, 43.0, 31.4, 23.1, 19.9, 14.0; MS (EI) m/z 332.1364 (M+
[C17H20N2O5] ) 332.1372). Anal. (C17H20N2O5) C, H, N.
3-(3,5-Di-O-acetyl-2-deoxy-â-D-erythro-pentofuranosyl)-6-
(octyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one [7b(ii)]. Treatment of
6b (200 mg, 0.483 mmol), (Ph3P)4Pd (56 mg, 0.05 mmol), CuI
(19 mg, 0.10 mmol), Et3N (4.0 mL), DMF (2.0 mL), and 1-octyne
(355 µL, 266 mg, 2.41 mmol) by general procedure C [ambient
temperature, 2 h; chromatography (EtOAc/hexanes, 6:4)] gave 7b(ii)
(175 mg, 82%) as a yellow glass: UV λmax 344, 278, 266 nm (ꢀ
9980, 12 600, 17 300), λmin 289, 275, 240 nm (ꢀ 1230, 11 400,
7500); 1H NMR δ 8.29 (s, 1H), 6.52 (s, 1H), 6.30 (dd, J ) 7.2, 5.7
Hz, 1H), 5.23 (d, J ) 6.3 Hz, 1H), 4.41 (s, 3H), 2.47 (t, J ) 7.05
Hz, 2H), 2.22 (ddd, J ) 14.7, 5.7, 2.1 Hz, 1H), 2.12 (s, 3H), 2.12-
2.06 (m, 1H), 2.06 (s, 3H), 1.67-1.58 (m, 2H), 1.49-1.39 (m,
2H), 1.34-1.25 (m, 4H), 0.90 (t, J ) 6.75 Hz, 3H); 13C NMR δ
171.4, 170.7, 170.5, 154.7, 139.8, 135.3, 107.1, 106.9, 100.6, 88.9,
83.6, 74.3, 70.1, 63.9, 39.6, 31.5, 28.8, 28.2, 22.7, 21.2, 21.1, 19.9,
14.3; MS (EI) m/z 444.1909 (M+ [C23H28N2O7] ) 444.1896).
3-(2-Deoxy-â-D-erythro-pentofuranosyl)-6-(octyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [8b(ii)]. Treatment of 7b(ii) (100 mg,
0.25 mmol) by general procedure D [NH3/MeOH (30 mL);
chromatography (EtOAc f 5% MeOH/EtOAc)] gave 8b(ii) as a
white solid (48 mg, 59%): mp ) 142-144 °C; UV λmax 343, 278,
266 (ꢀ 10 100, 13 500, 17 700), λmin 289, 275, 240 (ꢀ 1070, 11 900,
This material (100 mg, 0.29 mmol), CuI (58 mg, 0.29 mmol),
Et3N (3 mL), and EtOAc (6 mL) were treated by general procedure
B [70 °C; chromatography (EtOAc f 5% MeOH/EtOAc)] to give
5b as a white solid foam (92 mg, 94%): UV λmax 328, 241 nm (ꢀ
1
5300, 7500), λmin 263 nm (ꢀ 490); H NMR δ 8.39 (s, 1H), 7.38
(d, J ) 2.7 Hz, 1H), 6.56 (d, J ) 2.7 Hz, 1H), 6.32 (dd, J ) 7.5,
5.5 Hz, 1H), 5.24 (d, J ) 6.3 Hz, 1H), 4.43 (s, 3H), 3.0 (ddd, J )
14.4, 5.4, 2.1 Hz, 1H), 2.13 (s, 4H), 2.07 (s, 3H); 13C NMR δ 172.2,
170.6, 170.5, 154.6, 145.2, 136.4, 106.2, 104.6, 88.9, 83.6, 74.2,
63.9, 39.6, 21.1, 21.0; MS (EI) m/z 336.0972 (M+ [C15H16N2O7]
) 336.0957).
1
7740); H NMR (CD3OD) δ 8.95 (s, 1H), 6.77 (s, 1H), 6.26 (t, J
) 6.25 Hz, 1H), 4.38 (q, J ) 4.8 Hz, 1H), 4.06 (q, J ) 3.5 Hz,
1H), 3.88 (dd, J ) 12.0, 3.5 Hz, 1H), 3.78 (dd, J ) 12.5, 3.5 Hz,
1H), 2.61 (ddd, J ) 13.5, 6.0, 5.0 Hz, 1H), 2.51 (t, J ) 7.25 Hz,
2H), 2.21 (dt, J ) 13.5, 6.0 Hz, 1H), 1.65-1.59 (m, 2H), 1.50-
1.44 (m, 2H), 1.38-1.34 (m, 4H), 0.92 (t, J ) 6.75 Hz, 3H); 13C
NMR (CD3OD) δ 172.3, 156.9, 140.3, 140.2, 109.1, 108.3, 100.8,
90.2, 89.9, 71.4, 70.9, 62.4, 43.0, 32.6, 29.8, 29.3, 23.7, 20.2, 14.5;
MS (EI) m/z 360.1673 (M+ [C19H24N2O5] ) 360.1685). Anal.
(C19H24N2O5) C, H, N.
3-(3,5-Di-O-acetyl-2-deoxy-â-D-erythro-pentofuranosyl)-6-bro-
mofuro[2,3-d]pyrimidin-2(3H)-one (6b). A mixture of 5b (25 mg,
74 µmol), KOAc (3 mg, 30 µmol), Br2 (19 µL, 59 mg, 0.37 mmol),
and dried CHCl3 (3 mL) was stirred at ambient temperature for 2
h in a flame-dried flask. The mixture was cooled to 0 °C and dried
Et3N was added (until the solution was basic). Volatiles were
evaporated, and the residue was flash chromatographed (80%
EtOAc/hexanes) to give 6b (27 mg, 87%) as a yellow solid foam:
UV λmax 334, 248 nm (ꢀ 8000, 14 300), λmin 276, 231 nm (ꢀ 870,
3-(3,5-Di-O-acetyl-2-deoxy-â-D-erythro-pentofuranosyl)-6-
(decyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one [7b(iii)]. Treatment
of 6b (150 mg, 0.362 mmol), (Ph3P)4Pd (46 mg, 0.04 mmol), CuI
(14 mg, 0.07 mmol), Et3N (3.0 mL), DMF (1.5 mL), and 1-decyne
(330 µL, 250 mg, 1.81 mmol) by general procedure C [ambient
temperature, 2 h; chromatography (EtOAc/hexanes, 6:4)] gave
7b(iii) (151 mg, 88%) as a yellow glass: UV λmax 344, 278, 266
nm (ꢀ 11 900, 15 000, 20 600), λmin 289, 275, 240 nm (ꢀ 1460,
1
10 800); H NMR δ 8.33 (s, 1H), 6.55 (s, 1H), 6.28 (dd, J ) 7.5,
6.5 Hz, 1H), 5.22 (d, J ) 6.0 Hz, 1H), 4.41 (s, 3H), 2.98 (ddd, J
) 14.0, 5.0, 2.0 Hz, 1H), 2.12 (s, 3H), 2.10-2.07 (m, 1H), 2.06
(s, 3H); 13C NMR δ 171.9, 170.6, 170.5, 154.1, 134.9, 129.1, 107.8,
106.1, 88.9, 83.7, 74.2, 63.8, 39.5, 21.1, 21.0; MS (EI) m/z 414.0247
(M+ [C15H1579BrN2O7] ) 414.0262).
1
3-(3,5-Di-O-acetyl-2-deoxy-â-D-erythro-pentofuranosyl)-6-(hex-
yn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one [7b(i)]. Treatment of 6b
(150 mg, 0.36 mmol), (Ph3P)4Pd (46 mg, 0.04 mmol), CuI (14 mg,
0.07 mmol), Et3N (3.0 mL), DMF (1.5 mL), and 1-hexyne (220
µL, 148 mg, 1.81 mmol) by general procedure C [ambient
temperature, 2 h; chromatography (EtOAc/hexanes, 6:4)] gave 7b(i)
(137 mg, 91%) as a yellow glass: UV λmax 344, 278, 266 nm (ꢀ
11 100, 13 900, 19 100), λmin 289, 275, 240 nm (ꢀ 1400, 12 600,
8310); 1H NMR δ 8.29 (s, 1H), 6.52 (s, 1H), 6.29 (dd, J ) 7.5, 6.0
Hz, 1H), 5.22 (d, J ) 6.3 Hz, 1H), 4.41 (s, 3H), 2.97 (ddd, J )
14.4, 5.4, 2.1 Hz, 1H), 2.48 (t, J ) 7.05 Hz, 2H), 2.12 (s, 3H),
2.12-2.05 (m, 1H), 2.05 (s, 3H), 1.66-1.57 (m, 2H), 1.53-1.41
(m, 2H), 0.95 (t, J ) 7.2 Hz, 3H); 13C NMR δ 171.3, 170.7, 170.5,
154.7, 139.7, 135.3, 107.1, 106.9, 100.6, 88.9, 83.6, 74.3, 70.1,
63.9, 39.6, 30.2, 22.2, 21.14, 21.06, 19.6, 13.8; MS (EI) m/z
416.1586 (M+ [C21H24N2O7] ) 416.1583).
13 600, 8940); H NMR δ 8.29 (s, 1H), 6.52 (s, 1H), 6.29 (t, J )
6.5 Hz, 1H), 5.22 (d, J ) 6.5 Hz, 1H), 4.41 (s, 3H), 2.97 (ddd, J
) 14.5, 6.0, 2.5 Hz, 1H), 2.46 (t, J ) 7.25 Hz, 2H), 2.12-2.10
(m, 1H), 2.11 (s, 3H), 2.05 (s, 3H), 1.65-1.59 (m, 2H), 1.44-
1.41 (m, 2H), 1.30-1.27 (m, 8H), 0.89 (t, J ) 6.75 Hz, 3H); 13C
NMR δ 171.3, 170.6, 170.5, 154.7, 139.7, 135.3, 107.0, 106.9,
100.6, 88.9, 83.6, 74.3, 70.1, 63.9, 39.5, 32.0, 29.3, 29.2, 29.1, 28.2,
22.9, 21.1, 21.0, 19.9, 14.3; MS (EI) m/z 472.2200 (M+ [C25H32N2O7]
) 472.2209).
3-(2-Deoxy-â-D-erythro-pentofuranosyl)-6-(decyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [8b(iii)]. Treatment of 7b(iii) (80 mg,
0.17 mmol) by general procedure D [NH3/MeOH (30 mL);
chromatography (EtOAc f 5% MeOH/EtOAc)] gave 8b(iii) as a
white solid (45 mg, 68%): mp ) 152-154 °C; UV λmax 343, 278,
266 (ꢀ 10 800, 14 100, 19 000), λmin 289, 275, 240 (ꢀ 1290, 12 800,
1
8410); H NMR (CD3OD) δ 8.95 (s, 1H), 6.77 (s, 1H), 6.27 (t, J
3-(2-Deoxy-â-D-erythro-pentofuranosyl)-6-(hexyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [8b(i)]. Treatment of 7b(i) (100 mg,
0.24 mmol) by general procedure D [NH3/MeOH (30 mL);
chromatography (EtOAc f 5% MeOH/EtOAc)] gave 8b(i) as a
) 5.75 Hz, 1H), 4.38 (q, J ) 7.5 Hz, 1H), 4.06 (q, J ) 5.0 Hz,
1H), 3.88 (dd, J ) 12.5, 3.0 Hz, 1H), 3.78 (dd, J ) 12.0, 4.0 Hz,
1H), 2.61 (ddd, J ) 14.0, 6.0, 4.5 Hz, 1H), 2.51 (t, J ) 7.0 Hz,
2H), 2.21 (dt, J ) 13.5, 6.0 Hz, 1H), 1.65-1.59 (m, 2H), 1.47-

6-Alkyn-1-ylfuropyrimidin-2(3H)-one DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1 395
1.43 (m, 2H), 1.33-1.28 (m, 8H), 0.90 (t, J ) 6.75 Hz, 3H); 13C
NMR (CD3OD) δ 172.3, 156.9, 140.3, 140.2, 109.1, 108.3, 100.8,
90.2, 89.9, 71.4, 70.9, 62.4, 43.0, 33.1, 30.5, 30.3, 30.1, 29.3, 23.7,
20.2, 14.6; MS (EI) m/z 388.1999 (M+ [C21H28N2O5] ) 388.1998).
Anal. (C21H28N2O5) C, H, N.
3H), 2.10 (s, 3H); 13C NMR δ 172.1, 170.3, 169.8, 169.7, 154.1,
135.1, 129.8, 108.5, 105.9, 90.3, 80.1, 74.3, 69.5, 62.8, 21.1, 20.74,
20.71; MS (FAB) m/z 495.0020 (MNa+ [C17H1879BrN2O9Na] )
495.0021).
3-(2,3,5-Tri-O-acetyl-â-D-ribofuranosyl)-6-(hexyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [7c(i)]. Treatment of 6c (50 mg, 0.11
mmol), (Ph3P)4Pd (12 mg, 0.01 mmol), CuI (4 mg, 0.02 mmol),
Et3N (0.5 mL), DMF (1.0 mL), and 1-hexyne (61 µL, 43 mg, 0.53
mmol) by general procedure C [ambient temperature, 1 h; chro-
matography (EtOAc/hexanes, 1:1)] gave 7c(i) (35 mg, 70%) as a
pale-yellow glass: UV λmax 344, 278, 266 nm (ꢀ 13 200, 17 300,
24 600), λmin 289, 275, 240 nm (ꢀ 1980, 15 800, 11 600); 1H NMR
δ 8.22 (s, 1H), 6.49 (s, 1H), 6.25 (d, J ) 3.6 Hz, 1H), 5.43 (t, J )
4.5 Hz, 1H), 5.31 (t, J ) 5.7 Hz, 1H), 4.49-4.43 (m, 3H), 2.49 (t,
J ) 7.0 Hz, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.67-
1.58 (m, 2H), 1.54-1.44 (m, 2H), 0.96 (t, J ) 7.2 Hz, 3H); 13C
NMR δ 171.5, 170.3, 169.7, 169.6, 154.7, 140.1, 135.6, 107.7,
106.7, 100.8, 90.3, 80.0, 74.3, 70.0, 69.4, 62.7, 30.1, 22.2, 21.0,
20.7, 20.6; MS (EI) m/z 474.1640 (M+ [C23H26N2O9] ) 474.1638).
6-(Hexyn-1-yl)-3-(â-D-ribofuranosyl)furo[2,3-d]pyrimidin-
2(3H)-one [8c(i)]. Treatment of 7c(i) (60 mg, 0.13 mmol) by
general procedure D [NH3/MeOH (30 mL); chromatography
(EtOAc f 5% MeOH/EtOAc)] gave 8c(i) as a white solid (35 mg,
80%): mp ) 158-160 °C; UV λmax 344, 278, 266 (ꢀ 10 800,
3-(3,5-Di-O-acetyl-2-deoxy-â-D-erythro-pentofuranosyl)-6-
(dodecyn-1-yl)furo[2,3-d]pyrimidin-2(3H)-one [7b(iv)]. Treatment
of 6b (125 mg, 0.302 mmol), (Ph3P)4Pd (35 mg, 0.03 mmol), CuI
(12 mg, 0.06 mmol), Et3N (3.0 mL), DMF (1.5 mL), and
1-dodecyne (322 µL, 250 mg, 1.50 mmol) by general procedure C
[ambient temperature, 2 h; chromatography (EtOAc/hexanes, 6:4)]
gave 7b(iv) (125 mg, 82%) as a yellow glass: UV λmax 343, 278,
266 nm (ꢀ 10 500, 13 300, 18 300), λmin 289, 275, 240 nm (ꢀ 1340,
12 100, 7990); 1H NMR δ 8.29 (s, 1H), 6.52 (s, 1H), 6.29 (dd, J )
7.5, 6.0 Hz, 1H), 5.22 (d, J ) 6.0 Hz, 1H), 4.41 (s, 3H), 2.97 (ddd,
J ) 15.0, 5.5, 2.0 Hz, 1H), 2.46 (t, J ) 7.25 Hz, 2H), 2.12 (s, 3H),
2.11-2.07 (m, 1H), 2.05 (s, 3H), 1.65-1.59 (m, 2H), 1.44-1.40
(m, 2H), 1.29-1.27 (m, 12H), 0.88 (t, J ) 7.0 Hz, 3H); 13C NMR
δ 171.3, 170.6, 170.5, 154.7, 139.7, 135.3, 107.1, 106.9, 100.6,
88.9, 83.6, 74.3, 70.1, 63.9, 39.6, 32.1, 29.8, 29.7, 29.5, 29.3, 29.1,
28.2, 22.9, 21.1, 21.0, 19.9, 14.3; MS (EI) m/z 500.2532 (M+
[C27H36N2O7] ) 500.2522).
3-(2-Deoxy-â-D-erythro-pentofuranosyl)-6-(dodecyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [8b(iv)]. Treatment of 7b(iv) (100 mg,
0.20 mmol) by general procedure D [NH3/MeOH (30 mL);
chromatography (EtOAc f 5% MeOH/EtOAc)] gave 8b(iv) as a
white solid (55 mg, 66%): mp ) 157-159 °C; UV λmax 343, 278,
266 (ꢀ 10 400, 13 600, 18 300), λmin 289, 275, 240 (ꢀ 1090, 12 300,
1
14 100, 18 900), λmin 289, 275, 241 (ꢀ 1500, 12 800, 9280); H
NMR (CD3OD) δ 9.09 (s, 1H), 6.77 (s, 1H), 5.95 (s, 1H), 4.16 (br
s, 3H), 4.02 (dd, J ) 12.6, 2.7 Hz, 1H), 3.83 (dd, J ) 12.6, 1.8
Hz, 1H), 2.52 (t, J ) 7.05 Hz, 2H), 1.66-1.55 (m, 2H), 1.54-
1.43 (m, 2H), 0.97 (t, J ) 7.35 Hz, 3H); 13C NMR (CD3OD) δ
172.4, 157.1, 140.5, 140.4, 109.0, 108.5, 100.8, 94.4, 85.9, 76.9,
70.8, 69.5, 61.0, 31.4, 23.1, 19.9, 14.0; MS m/z 371.1230 (MNa+
[C17H20N2O6Na] ) 371.1219).
1
8030); H NMR (CD3OD) δ 8.95 (s, 1H), 6.77 (s, 1H), 6.27 (t, J
) 6.25 Hz, 1H), 4.37 (q, J ) 7.5 Hz, 1H), 4.06 (q, J ) 3.5 Hz,
1H), 3.88 (dd, J ) 12.0, 3.0 Hz, 1H), 3.77 (dd, J ) 12.0, 3.0 Hz,
1H), 2.60 (ddd, J ) 13.5, 5.5, 5.0 Hz, 1H), 2.51 (t, J ) 7.0 Hz,
2H), 2.20 (dt, J ) 13.5, 6.0 Hz, 1H), 1.65-1.59 (m, 2H), 1.49-
1.43 (m, 2H), 1.33-1.29 (m, 12H), 0.89 (t, J ) 6.75 Hz, 3H);
13C NMR (CD3OD) δ 172.2, 156.8, 140.3, 140.1, 108.9, 108.3,
100.7, 90.1, 89.8, 71.3, 70.8, 62.3, 43.0, 33.1, 30.73, 30.68, 30.5,
30.2, 30.0, 29.2, 23.8, 20.1, 14.5; MS m/z 439.2216 (MNa+
[C23H32N2O5Na] ) 439.2209). Anal. (C23H32N2O5) C, H, N.
3-(2,3,5-Tri-O-acetyl-â-D-ribofuranosyl)furo[2,3-d]pyrimidin-
2(3H)-one (5c). Treatment of 2′,3′,5′-tri-O-acetyl-5-(trimethyl-
silylethynyl)uridine11 (25 mg, 54 µmol) by general procedure A
[NH4F (10 mg, 0.27 mmol), MeOH (1 mL), reflux, 1 h; chroma-
tography (EtOAc/hexanes, 6:4)] gave 2′,3′,5′-tri-O-acetyl-5-ethynyl-
uridine (16 mg, 75%) as a pale-yellow solid foam: UV λmax 285,
223 nm (ꢀ 14 900, 13 500), λmin 248 nm (ꢀ 3160); 1H NMR δ 8.37
(s, 1H), 7.86 (s, 1H), 6.09 (d, J ) 4.5 Hz, 1H), 5.34 (d, J ) 4.2
Hz, 2H), 4.41-4.39 (m, 3H), 3.23 (s, 1H), 2.22 (s, 3H), 2.14 (s,
3H), 2.13 (s, 3H); 13C NMR δ 170.3, 169.9, 169.8, 160.9, 149.3,
142.9, 100.4, 87.7, 82.7, 80.5, 74.6, 73.5, 73.3, 63.1, 21.1, 20.7,
20.6; MS (FAB) m/z 395.1100 (MH+ [C17H19N2O9] ) 395.1090).
Treatment of this material (500 mg, 1.27 mmol), CuI (246 mg,
1.27 mmol), Et3N (20 mL), and MeCN (40 mL) by general
procedure B [reflux, 8 h; chromatography (80% EtOAc/hexanes
f EtOAc)] gave 5c (307 mg, 61%) as a white solid foam: UV
3-(2,3,5-Tri-O-acetyl-â-D-ribofuranosyl)-6-(octyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [7c(ii)]. Treatment of 6c (80 mg, 0.17
mmol), (Ph3P)4Pd (20 mg, 0.02 mmol), CuI (7 mg, 0.04 mmol),
Et3N (1.0 mL), DMF (2.0 mL), and 1-octyne (130 µL, 93 mg, 0.85
mmol) by general procedure C [ambient temperature, 1 h; chro-
matography (EtOAc/hexanes, 1:1)] gave 7c(ii) (68 mg, 80%) as a
pale-yellow glass: UV λmax 344, 278, 266 nm (ꢀ 12 400, 16 400,
23 200), λmin 289, 275, 240 nm (ꢀ 1850, 14 900, 10 900); 1H NMR
δ 8.22 (s, 1H), 6.50 (s, 1H), 6.24 (d, J ) 3.6 Hz, 1H), 5.43 (t, J )
4.5 Hz, 1H), 5.30 (t, J ) 5.7 Hz, 1H), 4.84-4.24 (m, 3H), 2.48 (t,
J ) 7.0 Hz, 2H), 2.16 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.68-
1.58 (m, 2H), 1.46-1.41 (m, 2H), 1.34-1.26 (m, 4H), 0.91 (t, J )
6.75 Hz, 3H); 13C NMR δ 171.6, 170.3, 169.8, 169.7, 154.7, 140.2,
135.5, 107.8, 106.6, 101.0, 90.2, 80.0, 74.4, 70.1, 69.5, 62.8, 31.5,
28.8, 28.1, 22.7, 21.1, 20.8, 20.7, 19.9, 14.3; MS (EI) m/z 502.1953
(M+ [C25H30N2O9] ) 502.1951).
6-(Octyn-1-yl)-3-(â-D-ribofuranosyl)furo[2,3-d]pyrimidin-2(3H)-
one [8c(ii)]. Treatment of 7c(ii) (60 mg, 0.12 mmol) by general
procedure D [NH3/MeOH (30 mL); chromatography (EtOAc f
5% MeOH/EtOAc)] gave 8c(ii) as a white solid (25 mg, 56%):
mp ) 164-166 °C; UV λmax 343, 278, 266 (ꢀ 9900, 12 900,
17 400), λmin 289, 275, 241 (ꢀ 1260, 11 700, 8490); 1H NMR
(CD3OD) δ 9.09 (s, 1H), 6.76 (s, 1H), 5.95 (s, 1H), 4.17-4.12 (m,
3H), 4.02 (dd, J ) 12.5, 2.0 Hz, 1H), 3.84 (dd, J ) 12.0, 2.0 Hz,
1H), 2.51 (t, J ) 7.25 Hz, 2H), 1.65-1.59 (m, 2H), 1.50-1.44
(m, 2H), 1.38-1.31 (m, 4H), 0.93 (t, J ) 7.0 Hz, 3H); 13C NMR
(CD3OD) δ 172.4, 157.1, 140.5, 140.4, 109.0, 108.5, 100.9, 94.4,
85.9, 76.9, 70.8, 69.5, 61.0, 32.6, 29.8, 29.3, 23.7, 20.2, 14.5; MS
m/z 399.1527 (MNa+ [C19H24N2O6Na] ) 399.1532). Anal.
(C19H24N2O6) C, H, N.
λ
max 330, 244 nm (ꢀ 6280, 8300), λmin 265 nm (ꢀ 552); 1H NMR δ
8.31 (s, 1H), 7.38 (d, J ) 3.0 Hz, 1H), 6.52 (d, J ) 3.0 Hz, 1H),
6.26 (d, J ) 3.5 Hz, 1H), 5.44 (dd, J ) 5.5, 4.0 Hz, 1H), 5.31 (t,
J ) 5.75 Hz, 1H), 4.49-4.41 (m, 3H), 2.17 (s, 3H), 2.14 (s, 3H),
2.10 (s, 3H); 13C NMR δ 172.4, 170.3, 169.7, 169.6, 154.6, 145.6,
136.8, 106.8, 104.6, 90.4, 79.9, 74.3, 69.4, 62.7, 21.0, 20.7, 20.6;
MS (FAB) m/z 417.0910 (MNa+ [C17H18N2O9Na] ) 417.0910).
3-(2,3,5-Tri-O-acetyl-â-D-ribofuranosyl)-6-bromofuro[2,3-d]-
pyrimidin-2(3H)-one (6c). A mixture of 5c (30 mg, 76 µmol),
pyridinium tribromide (90%, 27 mg, 76 µmol), and MeCN (3 mL)
was stirred at ambient temperature for 24 h, and dried Et3N was
added. Volatiles were evaporated, and the residue was flash
chromatographed (80% EtOAc/hexanes) to give 6c (20 mg, 56%)
as a yellow solid foam: UV λmax 334, 248 nm (ꢀ 6270, 11 600),
3-(2,3,5-Tri-O-acetyl-â-D-ribofuranosyl)-6-(decyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [7c(iii)]. Treatment of 6c (100 mg,
0.212 mmol), (Ph3)4Pd (24 mg, 0.02 mmol), CuI (8 mg, 0.04 mmol),
Et3N (1.0 mL), DMF (2.0 mL), and 1-decyne (190 µL, 146 mg,
1.06 mmol) by general procedure C [ambient temperature, 1 h;
chromatography (EtOAc/hexanes, 1:1)] gave 7c(iii) (94 mg, 84%)
as a pale-yellow glass: UV λmax 345, 278, 266, 218 nm (ꢀ 12 000,
16 000, 22 700, 21 200), λmin 289, 275, 240 nm (ꢀ 1640, 14 500,
1
λmin 275, 232 nm (ꢀ 437, 8840); H NMR δ 8.26 (s, 1H), 6.52 (s,
1H), 6.22 (d, J ) 3.9 Hz, 1H), 5.43 (dd, J ) 5.4, 3.6 Hz, 1H), 5.29
(t, J ) 5.85 Hz, 1H), 4.49-4.39 (m, 3H), 2.16 (s, 3H), 2.14 (s,
1
10 600); H NMR δ 8.22 (s, 1H), 6.49 (s, 1H), 6.24 (d, J ) 3.6

396 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Robins et al.
Hz, 1H), 5.43 (t, J ) 4.5 Hz, 1H), 5.30 (t, J ) 5.7 Hz, 1H), 4.48-
4.42 (m, 3H), 2.47 (t, J ) 7.0 Hz, 2H), 2.16 (s, 3H), 2.14 (s, 3H),
2.10 (s, 3H), 1.66-1.58 (m, 2H), 1.43 (br s, 2H), 1.29-1.25 (m,
8H), 0.89 (t, J ) 6.3 Hz, 3H); 13C NMR δ 171.6, 170.3, 169.8,
169.7, 154.7, 140.2, 135.4, 107.8, 106.6, 101.0, 90.2, 80.0, 74.4,
70.1, 69.5, 62.8, 32.1, 29.4, 29.3, 29.1, 28.2, 22.9, 21.1, 20.8, 20.7,
19.9, 14.4; MS m/z 553.2177 (MNa+ [C27H34N2O9Na] ) 553.2162).
6-(Decyn-1-yl)-3-(â-D-ribofuranosyl)furo[2,3-d]pyrimidin-
2(3H)-one [8c(iii)]. Treatment of 7c(iii) (40 mg, 75 µmol) by
general procedure D [NH3/MeOH (30 mL); chromatography
(EtOAc f 5% MeOH/EtOAc)] gave 8c(iii) as a white solid (20
mg, 67%): mp ) 166-168 °C; UV λmax 343, 278, 266 (ꢀ 11 200,
6.60 (d, J ) 2.7 Hz, 1H), 6.44 (d, J ) 3.6 Hz, 1H), 5.66 (t, J ) 1.8
Hz, 1H), 5.09 (br s, 1H), 4.51-4.31 (m, 3H), 2.17 (s, 3H), 2.15 (s,
3H), 1.91 (s, 3H); 13C NMR δ 172.2, 170.8, 169.8, 168.2, 154.2,
145.2, 138.1, 105.9, 104.7, 87.1, 81.8, 76.5, 74.0, 63.0, 21.0, 20.9,
20.6; MS m/z 395.1101 (MH+ [C17H19N2O9] ) 395.1091.
3-(2,3,5-Tri-O-acetyl-â-D-arabinofuranosyl)-6-bromofuro[2,3-
d]pyrimidin-2(3H)-one (6d). A mixture of 5d (50 mg, 0.12 mmol),
KOAc (5 mg, 51 µmol), Br2 (33 µL, 102 mg, 0.63 mmol), and
dried CHCl3 (3 mL) was stirred at ambient temperature for 1 h in
a flame-dried flask and then cooled to 0 °C. Dried Et3N was added
until the solution was basic, and volatiles were evaporated. The
residue was flash chromatographed (80% EtOAc/hexanes) to give
6d (50 mg, 83%) as a yellow solid foam: UV λmax 335, 248 nm (ꢀ
1
14 700, 19 700), λmin 289, 275, 241 (ꢀ 1340, 13 300, 9630); H
1
NMR (CD3OD) δ 9.09 (s, 1H), 6.76 (s, 1H), 5.95 (s, 1H), 4.18-
4.12 (m, 3H), 4.02 (dd, J ) 12.0, 1.5 Hz, 1H), 3.84 (dd, J ) 13.0,
2.5 Hz, 1H), 2.51 (t, J ) 6.75 Hz, 2H), 1.65-1.59 (m, 2H), 1.48-
1.44 (m, 2H), 1.34-1.29 (m, 8H), 0.90 (t, J ) 6.75 Hz, 3H); 13C
NMR (CD3OD) δ 172.4, 157.1, 140.5, 140.4, 109.0, 108.5, 100.9,
94.4, 85.9, 76.9, 70.9, 69.5, 61.0, 33.1, 30.5, 30.3, 30.1, 29.3, 23.9,
20.2, 14.6; MS m/z 427.1849 (MNa+ [C21H28N2O6Na] ) 427.1845).
Anal. (C21H28N2O6·CH3OH) C, H (calcd: 7.39, found: 6.86), N.
3-(2,3,5-Tri-O-acetyl-â-D-ribofuranosyl)-6-(dodecyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [7c(iv)]. Treatment of 6c (100 mg,
0.212 mmol), (Ph3P)4Pd (24 mg, 0.02 mmol), CuI (8 mg, 0.04
mmol), Et3N (1.0 mL), DMF (2.0 mL), and 1-dodecyne (230 µL,
176 mg, 1.06 mmol) by general procedure C [ambient temperature,
1h; chromatography (EtOAc/hexanes, 1:1)] gave 7c(iv) (93 mg,
79%) as a pale-yellow glass: UV λmax 345, 278, 266, 220 nm (ꢀ
13 400, 17 500, 24 800, 21 500), λmin 289, 275, 240 nm (ꢀ 1620,
2800, 5700), λmin 288, 233 nm (ꢀ 670, 4600); H NMR δ 8.28 (s,
1H), 6.58 (s, 1H), 6.41 (d, J ) 3.3 Hz, 1H), 5.64 (d, J ) 3.6 Hz,
1H), 5.07 (br s, 1H), 4.56-4.29 (m, 3H), 2.17 (s, 3H), 2.14 (s,
3H), 1.92 (s, 3H); 13C NMR δ 171.7, 170.9, 169.9, 168.3, 153.6,
137.1, 129.6, 107.9, 106.3, 87.4, 82.2, 76.5, 74.0, 63.0, 21.1, 20.9,
20.7; MS (EI) m/z 474.0083 (M+ [C17H1781BrN2O9] ) 474.0097).
3-(2,3,5-Tri-O-acetyl-â-D-arabinofuranosyl)-6-(hexyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [7d(i)]. Treatment of 6d (100 mg,
0.212 mmol), (Ph3P)4Pd (24 mg, 0.02 mmol), CuI (8 mg, 0.04
mmol), Et3N (1.0 mL), DMF (2.0 mL), and 1-hexyne (122 µL, 87
mg, 1.06 mmol) by general procedure C [50 °C, 2 h; chromatog-
raphy (EtOAc/hexanes, 1:1)] gave 7d(i) (197 mg, 98%) as a pale-
yellow glass: UV λmax 345, 277, 265 nm (ꢀ 10 700, 14 300, 19 900),
1
λmin 289, 275, 241 nm (ꢀ 1640, 13 100, 10 200); H NMR δ 8.23
(s, 1H), 6.56 (s, 1H), 6.43 (d, J ) 3.9 Hz, 1H), 5.64 (d, J ) 2.4
Hz, 1H), 5.08 (br s, 1H), 4.54-4.29 (m, 3H), 2.49 (t, J ) 7.0 Hz,
2H), 2.17 (s, 3H), 2.15 (s, 3H), 1.91 (s, 3H), 1.65-1.57 (m, 2H),
1.54-1.44 (m, 2H), 0.96 (t, J ) 7.2 Hz, 3H); 13C NMR δ 171.5,
170.9, 169.9, 168.3, 154.3, 139.9, 137.0, 106.9, 106.8, 100.7, 87.2,
81.9, 76.6, 74.1, 70.1, 63.1, 30.2, 22.2, 21.1, 21.0, 20.7, 19.6, 13.8;
MS m/z 497.1533 (MNa+ [C23H26N2O9Na] ) 497.1536).
1
15 800, 11 200); H NMR δ 8.22 (s, 1H), 6.49 (s, 1H), 6.23 (d, J
) 3.6 Hz, 1H), 5.43 (t, J ) 4.5 Hz, 1H), 5.30 (t, J ) 5.7 Hz, 1H),
4.48-4.39 (m, 3H), 2.47 (t, J ) 7.0 Hz, 2H), 2.16 (s, 3H), 2.13 (s,
3H), 2.09 (s, 3H), 1.67-1.58 (m, 2H), 1.27 (br s, 14H), 0.88 (t, J
) 6.5 Hz, 3H); 13C NMR δ 171.6, 170.3, 169.8, 169.7, 154.7, 140.2,
135.4, 107.8, 106.6, 101.0, 90.2, 80.0, 74.4, 70.0, 69.5, 62.8, 32.1,
29.8, 29.7, 29.5, 29.3, 29.1, 28.2, 22.9, 21.1, 20.74, 20.70, 19.9,
14.4; MS m/z 581.2480 (MNa+ [C29H38N2O9Na] ) 581.2475).
6-(Dodecyn-1-yl)-3-(â-D-ribofuranosyl)furo[2,3-d]pyrimidin-
2(3H)-one [8c(iv)]. Treatment of 7c(iv) (90 mg, 0.16 mmol) by
general procedure D [NH3/MeOH (25 mL); chromatography
(EtOAc f 5% MeOH/EtOAc)] gave 8c(iv) as a white solid (53
mg, 76%): mp ) 172-174 °C; UV λmax 343, 278, 266 (ꢀ 11 300,
3-(â-D-Arabinofuranosyl)-6-(hexyn-1-yl)furo[2,3-d]pyrimidin-
2(3H)-one [8d(i)]. Treatment of 7d(i) (100 mg, 0.21 mmol) by
general procedure D [NH3/MeOH (25 mL); chromatography
(EtOAc f 5% MeOH/EtOAc)] gave 8d(i) as a white solid (60
mg, 81%): mp ) 167-169 °C; UV λmax 344, 278, 266 (ꢀ 12 800,
1
21 900, 16 800), λmin 289, 275, 240 (ꢀ 1370, 15 100, 11 100); H
NMR (CD3OD) δ 8.69 (s, 1H), 6.80 (s, 1H), 6.31 (d, J ) 3.6 Hz,
1H), 4.34-4.32 (m, 1H), 4.11-4.06 (m, 2H), 3.86-3.84 (m, 2H),
2.52 (t, J ) 6.9 Hz, 2H), 1.66-1.57 (m, 2H), 1.56-1.46 (m, 2H),
0.97 (t, J ) 7.2 Hz, 3H); 13C NMR (CD3OD) δ 172.3, 156.9, 141.8,
140.2, 109.0, 107.8, 100.7, 90.9, 88.0, 78.2, 76.4, 70.9, 62.9, 31.4,
23.1, 19.9, 14.0; MS (EI) m/z 348.1318 (M+ [C17H20N2O6] )
348.1321). Anal. (C17H20N2O6) C, H, N.
1
14 900, 19 900), λmin 289, 275, 241 (ꢀ 1340, 13 400, 9740); H
NMR (CD3OD/DMSO-d6 9:1) δ 9.06 (s, 1H), 6.82 (s, 1H), 5.93
(d, J ) 1.5 Hz, 1H), 4.13-4.08 (m, 3H), 3.97 (dd, J ) 12.5, 2.5
Hz, 1H), 3.79 (dd, J ) 12.5, 2.5 Hz, 1H), 2.52 (t, J ) 7.0 Hz, 2H),
1.64-1.58 (m, 2H), 1.46-1.42 (m, 2H), 1.35-1.27 (m, 12H), 0.88
(t, J ) 7.2 Hz, 3H); 13C NMR (CD3OD/DMSO-d6 9:1) δ 172.3,
156.7, 140.6, 139.8, 109.4, 108.0, 101.0, 94.0, 85.9, 76.8, 71.1,
69.6, 61.0, 33.1, 30.8, 30.7, 30.5, 30.3, 30.0, 29.3, 23.8, 20.2, 14.8;
MS m/z 455.2164 (MNa+ [C23H32N2O6Na] ) 455.2158). Anal.
(C23H32N2O6) C, H, N.
3-(2,3,5-Tri-O-acetyl-â-D-arabinofuranosyl)-6-(octyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [7d(ii)]. Treatment of 6d (50 mg, 0.11
mmol), (Ph3P)4Pd (12 mg, 0.01 mmol), CuI (4 mg, 0.02 mmol),
Et3N (0.5 mL), DMF (1.0 mL), and 1-octyne (81 µL, 58 mg, 0.53
mmol) by general procedure C [50 °C, 2 h; chromatography
(EtOAc/hexanes, 1:1)] gave 7d(ii) (44 mg, 82%) as a pale yellow
glass: UV λmax 345, 277, 241 nm (ꢀ 11 800, 15 600, 21 800), λmin
3-(2,3,5-Tri-O-acetyl-â-D-arabinofuranosyl)furo[2,3-d]pyrimi-
din-2(3H)-one (5d). Treatment of 1-(2,3,5-tri-O-acetyl-â-D-arabino-
furanosyl)-5-(trimethylsilylethynyl)uracil12 (25 mg, 54 µmol) by
general procedure A [NH4F (10 mg, 0.27 mmol), MeOH (2 mL),
reflux, 1 h; chromatography (60% EtOAc/hexanes)] gave 1-(2,3,5-
tri-O-acetyl-â-D-arabinofuranosyl)-5-ethynyluracil (16 mg, 76%) as
a white solid foam: UV λmax 284, 224 nm (ꢀ 11 200, 9930), λmin
248 nm (ꢀ 2100); 1H NMR δ 8.81 (s, 1H), 7.84 (s, 1H), 6.30 (d, J
) 3.9 Hz, 1H), 5.45 (dd, J ) 4.0, 2.0 Hz, 1H), 5.15 (dd, J ) 3.6,
1.8 Hz, 1H), 4.43 (d, J ) 4.8 Hz, 2H), 4.23 (q, J ) 4.4 Hz, 1H),
3.21 (s, 1H), 2.18 (s, 3H), 2.15 (s, 3H), 2.07 (s, 3H); 13C NMR δ
170.7, 169.8, 168.8, 160.7, 148.7, 144.1, 98.9, 84.6, 82.4, 80.9,
76.2, 74.6, 74.4, 62.7, 21.1, 20.9, 20.7; MS m/z 417.0928 (MNa+
[C17H18N2O9Na] ) 417.0910).
1
289, 275, 241 nm (ꢀ 1880, 14 400, 11 200); H NMR δ 8.26 (s,
1H), 6.59 (s, 1H), 6.45 (d, J ) 3.3 Hz, 1H), 5.67 (t, J ) 3.3 Hz,
1H), 5.11 (br s, 1H), 4.57-4.50 (m, 1H), 4.46-4.41 (m, 1H), 4.35-
4.31 (m, 1H), 2.51 (t, J ) 7.0 Hz, 2H), 2.19 (s, 3H), 2.18 (s, 3H),
1.94 (s, 3H), 1.68-1.61 (m, 2H), 1.48-1.45 (m, 2H), 1.36-1.29
(m, 4H), 0.94 (t, J ) 6.75 Hz, 3H); 13C NMR δ 171.5, 170.9, 169.9,
168.3, 154.3, 139.9, 137.0, 106.9, 106.8, 100.8, 87.2, 81.9, 76.6,
74.1, 70.1, 63.1, 31.5, 28.8, 28.2, 22.7, 21.1, 21.0, 20.7, 19.9, 14.3;
MS m/z 525.1838 (MNa+ [C25H30N2O9Na] ) 525.1849).
3-(â-D-Arabinofuranosyl)-6-(octyn-1-yl)furo[2,3-d]pyrimidin-
2(3H)-one [8d(ii)]. Treatment of 7d(ii) (100 mg, 0.20 mmol) by
general procedure D [NH3/MeOH (30 mL); chromatography
(EtOAc f 5% MeOH/EtOAc)] gave 8d(ii) as a white solid (56
mg, 75%): mp ) 168-170 °C; UV λmax 344, 278, 266 (ꢀ 11 000,
Treatment of this material (1.88 g, 4.77 mmol), CuI (0.925 g,
4.77 mmol), MeCN (160 mL), and Et3N (80 mL) by general
procedure B [80 °C, 6 h; chromatography (80% EtOAc/hexanes)]
gave 5d (1.31 g, 70%): UV λmax 330, 242 nm (ꢀ 5200, 7040), λmin
263 nm (ꢀ 340); 1H NMR δ 8.34 (s, 1H), 7.39 (d, J ) 2.7 Hz, 1H),
1
14 500, 18 800), λmin 289, 275, 240 (ꢀ 1200, 12 900, 9620); H
NMR (CD3OD) δ 8.69 (s, 1H), 6.79 (s, 1H), 6.30 (d, J ) 3.6 Hz,
1H), 4.34-4.32 (m, 1H), 4.11-4.06 (m, 2H), 3.86-3.84 (m, 2H),

6-Alkyn-1-ylfuropyrimidin-2(3H)-one DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1 397
2.51 (t, J ) 6.9 Hz, 2H), 1.67-1.58 (m, 2H), 1.52-1.42 (m, 2H),
1.37-1.29 (m, 4H), 0.93 (t, J ) 6.9 Hz, 3H); 13C NMR (CD3OD)
δ 172.3, 156.9, 141.8, 140.2, 109.1, 107.8, 100.7, 90.9, 88.0, 78.2,
76.4, 70.9, 62.9, 32.6, 29.8, 29.3, 23.7, 20.2, 14.5; MS (EI) m/z
376.1638 (M+ [C19H24N2O6] ) 376.1634). Anal. (C19H24N2O6) C,
H, N.
strains YS/R and 07/1, and the human cytomegalovirus (HCMV)
strains Davis and AD-169 were used. Confluent HEL cells were
grown in 96-well microtiter plates and infected at 20 (VZV) or
100 (HCMV) pfu per well. After a 2-h incubation period, residual
virus was removed and the infected cells were further incubated
with the medium containing different concentrations of the test
compounds (in duplicate). After incubation for 5 days (VZV) or 7
days (HCMV) at 37 °C, virus-induced cytopathogenicity (HCMV)
or plaque formation (VZV) was monitored microscopically after
ethanol fixation and staining with Giemsa. Antiviral activity was
expressed as the EC50 or concentration required to reduce virus-
induced cytopathogenicity (HCMV) or viral plaque formation
(VZV) by 50%. EC50 values were calculated from graphic plots of
the percentage of cytopathogenicity or viral plaque formation as a
function of concentration of the test compounds.
Cytotoxicity Assays. Cytotoxicity measurements were based on
the inhibition of HEL cell growth. HEL cells were seeded into 96-
well microtiter plates (5 × 103 cells/well) and allowed to proliferate
for 24 h. Then, medium containing different concentrations of the
test compounds was added. After 3 days of incubation at 37 °C,
the cell number was determined with a Coulter counter. The
cytostatic concentration was calculated as the CC50, or the
compound concentration required to reduce cell growth by 50%
relative to the number of cells in the untreated controls. CC50 values
were estimated from graphic plots of the number of cells (percentage
of control) as a function of the concentration of the test compounds.
Cytotoxicity was expressed as the minimum cytotoxic concentration
(MCC) or the compound concentration that causes a microscopically
visible alteration of cell morphology.
3-(2,3,5-Tri-O-acetyl-â-D-arabinofuranosyl)-6-(decyn-1-yl)furo-
[2,3-d]pyrimidin-2(3H)-one [7d(iii)]. Treatment of 6d (200 mg,
0.424 mmol), (Ph3P)4Pd (49 mg, 0.04 mmol), CuI (16 mg, 0.08
mmol), Et3N (2.0 mL), DMF (4.0 mL), and 1-decyne (390 µL, 290
mg, 2.10 mmol) by general procedure C [50 °C, 2 h; chromatog-
raphy (EtOAc/hexanes, 1:1)] gave 7d(iii) (177 mg, 79%) as a pale
yellow glass: UV λmax 345, 277, 265 nm (ꢀ 12 400, 16 200, 22 700),
1
λmin 289, 275, 241 nm (ꢀ 1250, 14 700, 11 200); H NMR δ 8.23
(s, 1H), 6.56 (s, 1H), 6.42 (d, J ) 3.9 Hz, 1H), 5.64 (d, J ) 2.4
Hz, 1H), 5.08 (br s, 1H), 4.54-4.47 (m, 1H), 4.43-4.38 (m, 1H),
4.32-4.27 (m, 1H), 2.48 (t, J ) 7.0 Hz, 2H), 2.16 (s, 3H), 2.14 (s,
3H), 1.91 (s, 3H), 1.66-1.58 (m, 2H), 1.43 (br s, 2H), 1.29 (m,
8H), 0.89 (t, J ) 6.45 Hz, 3H); 13C NMR δ 171.5, 170.9, 169.9,
168.3, 154.3, 139.9, 137.0, 106.9, 106.8, 100.7, 87.2, 81.9, 76.6,
74.1, 70.1, 63.1, 32.0, 29.4, 29.3, 29.1, 28.2, 22.9, 21.1, 21.0, 20.7,
19.9, 14.3; MS m/z 553.2160 (MNa+ [C27H34N2O9Na] ) 553.2162).
3-(â-D-Arabinofuranosyl)-6-(decyn-1-yl)furo[2,3-d]pyrimidin-
2(3H)-one [8d(iii)]. Treatment of 7d(iii) (125 mg, 0.23 mmol) by
general procedure D [NH3/MeOH (35 mL); chromatography
(EtOAc f 5% MeOH/EtOAc)] gave 8d(iii) as a white solid (35
mg, 80%): mp ) 171-173 °C; UV λmax 344, 278, 266 (ꢀ 13 500,
1
20 500, 26 400), λmin 291, 275, 243 (ꢀ 3390, 18 700, 16 200); H
NMR (CD3OD) δ 8.69 (s, 1H), 6.79 (s, 1H), 6.30 (d, J ) 3.3 Hz,
1H), 4.34-4.32 (m, 1H), 4.11-4.06 (m, 2H), 3.86-3.84 (m, 2H),
2.51 (t, J ) 6.45 Hz, 2H), 1.68-1.58 (m, 2H), 1.47 (br s, 2H),
1.33 (br s, 8H), 0.91 (t, J ) 6.75 Hz, 3H); 13C NMR (CD3OD) δ
172.3, 156.9, 141.8, 140.2, 109.0, 107.8, 100.7, 90.9, 88.0, 78.2,
76.4, 70.9, 62.9, 33.1, 30.5, 30.3, 30.1, 29.3, 23.9, 20.2, 14.6; MS
(EI) m/z 404.1964 (M+ [C21H28N2O6] ) 404.1967). Anal.
(C21H28N2O6) C, H, N.
Acknowledgment. We gratefully acknowledge pharmaceuti-
cal company gift funds (M.J.R.), Brigham Young University,
the Elsa Pardee Foundation, and the Geconcerteerde Onder-
zoeksacties (GOA)-Vlaanderen for financial support. We thank
Ann Absillis, Anita Camps, Steven Carmans, Frieda De Meyer,
Lies Van den Heurck, and Anita Van Lierde for excellent
technical assistance with the antiviral assays.
3-(2,3,5-Tri-O-acetyl-â-D-arabinofuranosyl)-6-(dodecyn-1-
yl)furo[2,3-d]pyrimidin-2(3H)-one [7d(iv)]. Treatment of 6d (100
mg, 0.212 mmol), (Ph3P)4Pd (24 mg, 0.02 mmol), CuI (8 mg, 0.04
mmol), Et3N (1.0 mL), DMF (2.0 mL), and 1-dodecyne (230 µL,
176 mg, 1.06 mmol) by general procedure C [50 °C, 2 h;
chromatography (EtOAc/hexanes, 1:1)] gave 7d(iv) (94 mg, 80%)
as a pale yellow glass: UV λmax 344, 277, 265 nm (ꢀ 12 000,
15 200, 21 000), λmin 289, 275, 241 nm (ꢀ 2140, 13 900, 12 600);
1H NMR δ 8.23 (s, 1H), 6.56 (s, 1H), 6.43 (d, J ) 3.6 Hz, 1H),
5.64 (d, J ) 3.6 Hz, 1H), 5.08 (br s, 1H), 4.54-4.48 (m, 1H),
4.44-4.38 (m, 1H), 4.32-4.29 (m, 1H), 2.48 (t, J ) 7.05 Hz, 2H),
2.17 (s, 3H), 2.15 (s, 3H), 1.91 (s, 3H), 1.66-1.59 (m, 2H), 1.44
(br s, 2H), 1.28 (br s, 12H), 0.88 (t, J ) 6.45 Hz, 3H); 13C NMR
δ 171.5, 170.9, 169.9, 168.3, 154.3, 139.8, 137.0, 106.9, 106.8,
100.7, 87.14. 81.9, 76.6, 74.1, 70.0, 63.0, 32.1, 29.8, 29.7, 29.5,
29.3, 29.1, 28.2, 22.9, 21.1, 20.9, 20.7, 19.8, 14.3; MS m/z 581.2477
(MNa+ [C29H38N2O9Na] ) 581.2475).
Supporting Information Available: Elemental analyses and
1H and 13C NMR spectra of 8c(i). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
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din-2(3H)-one [8d(iv)]. Treatment of 7d(iv) (93 mg, 0.16 mmol)
by general procedure D [NH3/MeOH (25 mL); chromatography
(EtOAc f 5% MeOH/EtOAc)] gave 8d(iv) as a white solid (61
mg, 65%): mp ) 178-180 °C; UV λmax 344, 278, 266 (ꢀ 11 900,
1
18 100, 23 200), λmin 291, 275, 243 (ꢀ 3100, 16 600, 14 400); H
NMR (CD3OD) δ 8.69 (s, 1H), 6.80 (s, 1H), 6.31 (d, J ) 3.6 Hz,
1H), 4.34-4.32 (m, 1H), 4.11-4.06 (m, 2H), 3.86-3.84 (m, 2H),
2.51 (t, J ) 7.05 Hz, 2H), 1.68-1.58 (m, 2H), 1.47 (br s, 2H),
1.30 (br s, 12 H), 0.90 (t, J ) 6.9 Hz, 3H); 13C NMR (CD3OD) δ
172.3, 156.9, 141.8, 140.2, 109.0, 107.8, 100.7, 90.9, 88.0, 78.2,
76.4, 70.9, 62.9, 33.2, 30.83, 30.78, 30.6, 30.3, 30.1, 29.3, 23.9,
20.2, 14.6; MS m/z 455.2164 (MNa+ [C23H32N2O6Na] ) 455.2158).
Anal. (C23H32N2O6) C, H, N.
Antiviral Assays. The antiviral assays were based on inhibition
of virus-induced cytopathicity or plaque formation in human
embryonic lung (HEL) fibroblasts. The varicella-zoster virus (VZV)
wild-type strain YS, the thymidine-kinase deficient (TK-) VZV

398 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Robins et al.
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JM050867D