Design and synthesis of 3′-fluoropenciclovir analogues as antiviral agents

Article abstract of DOI:10.1007/s12272-010-0202-9

Based on fluorine switch approach, a series of 3′-fluoropenciclovir analogues with different purine and pyrimidine bases were designed and synthesized. Direct reduction of β-fluoroester to the corresponding 3-fluoroalcohol provided an easy and new entry p

Full text of DOI:10.1007/s12272-010-0202-9

Arch Pharm Res Vol 33, No 2, 197-202, 2010
DOI 10.1007/s12272-010-0202-9
Design and Synthesis of 3'-Fluoropenciclovir Analogues as Antiviral
Agents
Myung-Hee Choi1, Chong-Kyo Lee2,and Hee-Doo Kim1
2
1College of Pharmacy, Sookmyung Women’s University, Seoul 140-742, Korea and Research Institute of Chemical Tech-
nology, Taejeon 305-606, Korea
(Received November 22, 2009/Revised December 1, 2009/Accepted December 3, 2009)
Based on fluorine switch approach, a series of 3’-fluoropenciclovir analogues with different
purine and pyrimidine bases were designed and synthesized. Direct reduction of β-fluoroester
to the corresponding 3-fluoroalcohol provided an easy and new entry pathway towards the
synthesis of 3’-fluoropenciclovir analogues. The synthesized 3’-fluoropenciclovir analogues
were evaluated for their antiviral activities against the poliovirus, HSV-1, HSV-2 and HIV.
Key words: Antiviral, Fluorine switch, Penciclovir, 3’-Fluoropenciclovir
(Harden et al
., 1987). Penciclovir and its analogues
Selected by Editors, See page 179
INTRODUCTION
have stimulated extensive research in the synthesis of
new cyclic and acyclic carbonucleoside analogues
mimicking the sugar portion of naturally occurring
nucleosides (Marquez, 1996).
Introduction of fluorine atom(s) into the components
In the search for opportunities to exploit the
of nucleic acids in general and nucleosides in parti- benefits of fluorine in nucleoside research, we tried
cular frequently leads to a dramatic change in their the fluorine-switch approach to explore new penciclovir
biological activity (Pankiewicz, 2000). A fluorine atom analogues that could potentially have beneficial phar-
at a sugar carbon in nucleosides causes only a minor macodynamic or pharmacokinetic properties and
change in the shape of the modified structure. Fluo- novel IP position (Choi and Kim, 1997; Lee et al.,
rine is a good mimic of a proton and is able to form 2001; Park et al., 2003; Park et al., 2003). In this
hydrogen bonding. However, fluorine seriously context, we designed and synthesized 3-fluoro-4-
affects the stereoelectronic properties of the molecule, hydroxy-3-hydroxymethybutyl nucleosides that would
which in turn restricts the conformational equilibria mimic the features of penciclovir (Fig. 1).
(Thibaudeau et al., 1999) of sugar-fluorinated nucleo-
sides (Marquez et al., 1993), locking the sugar ring into
a preferred conformation, as well as affect the suscep-
tibility of cytosine and adenosine analogues for enzy-
MATERIALS AND METHODS
Melting points were taken on a hot-stage microscope
matic deamination. Thus, incorporation of fluorine into and then uncorrected. 1H-NMR spectra were obtained
biologically prevalidated drug scaffolds represents an on a Brucker WP 80 SY (80 MHz), GEMINI 300 (300
excellent isostere of hydrogen on carbon.
Penciclovir, a carba analogue of ganciclovir, was meter and chemical shifts were reported as values in
found to be more potent and highly selective antiviral parts per million (
) relative to tetramethylsilane
MHz), and FT-NMR AVANCE 500 (500 MHz) spectro-
δ
agent against herpes simplex and varicella-zoster virus (TMS) as an internal standard. UV spectra were re-
corded with Shimadzu UV-2101PC spectrophotometer.
Infrared spectra (IR) were recorded on Shimadzu IR-
435 spectrophotometer. EI mass spectra (EIMS) were
run on VG Trio-2 GC-MS spectrometer at 70 eV. High
Correspondence to: Hee-Doo Kim, Professor of Medicinal Che-
mistry, College of Pharmacy, Sookmyung Women’s University,
Seoul 140-742, Korea
Tel: 82-2-710-9567, Fax: 82-2-703-0736
resolution mass spectral (HRMS) determinations were
E-mail: hdkim@sm.ac.kr
197

198
M.-H. Choi et al.
Fig. 1. Structures of ganciclovir, penciclovir, and target molecule
1
performed at Korea Basic Science Center. Thin layer anhydrous DCM (8 mL) was added dropwise 25 (1.8 g,
chromatography (TLC) was carried out on 0.25 mm E. 5.1 mmol) in DCM (4 mL) at -78oC. The reaction mix-
Merck precoated silica gel glass plates (60F254). ture was allowed to warm at room temperature. After
Column chromatography was performed by using being stirred for 30 min, reaction mixture was quen-
forced flow of indicated solvent on Merck Kieselgel 60 ched with water (1 mL) and diluted with DCM (20
(230-400 mesh). Unless otherwise noted, materials mL). The organic layer was washed with brine, dried
were obtained from commercially available sources and over anhydrous Na2SO4, and concentrated in vacuo
.
were used without further purification. Tetrahydrofuran The residue was purified by column chromatography
(THF) was freshly distilled from sodium benzophe- (silica gel; n-hexane/ethyl acetate = 30/1) to afford 1.0
none ketyl under an argon atmosphere. Dichlorome- g (58%) of the title compound
thane, benzene and dimethylformamide, triethyla- 3060, 3020, 2970, 2850, 1730, 740, 690; H-NMR (80
4
as oil: IR (neat) cm-1
1
mine were freshly distilled under a nitrogen atmos- MHz, CDCl3)
phere from calcium hydride.
= 7.1 Hz), 3.76 (d, 4H,
17.2 Hz), 1.20 (t, 3H, = 7.1 Hz); EIMS m/z (relative
Ethyl 4-(benzyloxy)-3-[(benzyloxy)methyl]-3-hy- intensity) 269 (M+-CH2C6H5, 1), 163 (35), 135 (24), 107
δ
7.30 (s, 10H), 4.57 (s, 4H), 4.09 (q, 2H,
J
J
= 19.3 Hz), 2.85 (d, 2H,
J =
J
droxybutanoate (3)
(3), 91 (100), 77 (5), 65 (6).
To a solution of diisopropylamine (0.8 mL, 5.5 mmol)
in anhydrous THF (4 mL) was added dropwise n-BuLi 4-(Benzyloxy)-3-[(benzyloxy)methyl]-3-fluorobuta-
(1.6 M in hexane, 2.2 mL, 3.6 mmol) at -78oC. The nol (5)
mixture was stirred for 30 min at -78oC, and ethyl
To a suspension of lithium aluminium hydride
acetate (0.4 mL, 3.6 mmol) was added. After being (104.7 mg, 2.8 mmol), anhydrous THF (5 mL) was
stirred for an additional 40 min at the same tem- added dropwise the ester (902.9 mg, 2.5 mmol) in
perature, bis(benzyloxy)acetone ( , 742.4 mg, 2.7 mmol) THF (5 mL). The mixture was stirred for 12 h at room
4
2
in THF (2 mL) was added dropwise, and the resulted temperature and cooled again to 0oC. The mixture was
reaction mixture was then stirred for 1 h at -78oC and carefully worked up by dropwise and sequential
allowed to warm to room temperature. The reaction addition of 0.2 mL of water, 0.2 mL of a 15% aqueous
mixture was quenched with saturated aqueous NH4Cl sodium hydroxide solution and an additional 0.6 mL
and diluted with ethyl acetate (50 mL). The layer was of water. The reaction mixture was filtered through a
separated, and the aqueous layer was extracted twice coarse filtration frit to remove aluminum salts, and
with ethyl acetate (30 mL). The combined organic the latter were washed three times with 8 mL
layers were washed with brine, dried over anhydrous portions of THF. The combined filtrates and washings
Na2SO4, and concentrated in vacuo. The residue was were dried over sodium sulfate and concentrated in
purified by column chromatography (silica gel; n- vacuo. The residue was purified by column chroma-
hexane/ethyl acetate = 1/1) to afford 633.8 mg (65%) of tography (silica gel; n-hexane/ethyl acetate = 3/1) to
hydroxyl ester
3
as oil: IR (neat) cm-1 3420, 3000, afford 745.1 mg (93%) of diol
5
as oil: IR (neat) cm-1
1
2840, 1725, 730, 700; 1H-NMR (80 MHz, CDCl3)
δ
7.28 3060, 3020, 730, 690; H-NMR (300 MHz, CDCl3)
= 7.1 Hz), 3.69 (s, 7.34 (m, 10H), 4.57 (s, 4H), 3.75 (t, 2H,
δ
(s, 10H), 4.52 (s, 4H), 4.07 (q, 2H,
1H), 3.52 (s, 4H), 2.63 (s, 2H), 1.19 (t, 3H,
EIMS m/z (relative intensity) 359 (M+H), 268 (10), Hz); EIMS m/z (relative intensity) 317 (M+-H), 192
237 (9), 161 (8), 105 (10), 91 (100). (42), 107 (12), 91 (100), 77 (6), 65 (7).
J
J
= 5.9 Hz),
J
= 7.1 Hz); 3.66 (d, 4H, = 18.0 Hz), 2.03 (td, 2H,
J
J = 19.8, 5.9
Ethyl 4-(benzyloxy)-3-[(benzyloxy)methyl]-3-fluo- 4-(Benzyloxy)-3-[(benzyloxy)methyl]-3-fluorobutyl
robutanoate (4)
bromide (6)
To a solution of DAST (989.7 mg, 6.1 mmol) in
A mixture of alcohol 5 (383.0 mg, 1.2 mmol), tri-

3'-Fluoropenciclovir Analogues
199
phenylphosphine (810.0 mg, 3.0 mmol) and
succinimide (535.4 mg, 3.0 mmol) in DCM (5ml) was (bs, 2H), 5.62 (d, 1H,
stirred at room temperature for 3 h and quenched by 2H, = 7.7 Hz), 3.62 (d, 4H,
N
-bromo- 1H-NMR (300 MHz, CDCl3)
δ
7.38-7.29 (m, 10H), 6.96
J
= 7.2 Hz), 4.52 (s, 4H), 3.75 (t,
= 21.0 Hz), 2.01 (td, 2H,
J
J
the addition of water. The mixture was diluted with
J = 7.7, 19.8 Hz); EIMS m/z (relative intensity) 412
DCM and the organic phase was then washed several (M+H), 112 (11), 105 (18), 91 (100), 65 (21).
times with water and brine, dried over anhydrous
sodium sulfate, filtered and concentrated in vacuo. 1-[4-(Benzyloxy)-3-[(benzyloxy)methyl]-3-fluoro-
The crude product was promptly subjected to column butyl]thymine (7c)
chromatography using short column (silica gel; n-
hexane/ethyl acetate = 20/1) to yield 377.2 mg (82%) of mmol) in DMF (3 ml), thymine (58.0 mg, 0.5 mmol),
the title compound
as oil. This crude product was lithium carbonate (34.0 mg, 0.5 mmol), and cesium
To a stirred solution of the bromide 6 (86.8 mg, 0.2
6
used directly for the next step without further purifi- carbonate (37.5 mg, 0.1 mmol) were added. The
cation: IR (neat) cm-1 3045, 3005, 2895, 2885, 730, 690. mixture was stirred at 90oC for 1 h until TLC showed
no starting material remaining, and the reaction was
9-[4-(Benzyloxy)-3-[(benzyloxy)methyl]-3-fluoro-
butyl]adenine (7a)
then quenched by the addition of water. The mixture
was diluted with ethyl acetate and the organic phase
To a stirred solution of the bromide
6 (142.5 mg, 0.4 was then washed several times with water and brine,
mmol) in DMF (4 mL), adenine (100.0 mg, 0.7 mmol) dried over anhydrous sodium sulfate, filtered and
and cesium carbonate (241.1 mg, 0.7 mmol) were concentrated. The crude product was purified by
added. The mixture was stirred at 90oC for 1 h, and column chromatography (silica gel, methanol/DCM =
the reaction was then quenched by the addition of 1/100) to afford 64.9 mg (67%) of compound 7c as a
water. The mixture was diluted with ethyl acetate and white solid: mp 82oC (recrystallized from hexane-ethyl
the organic phase was then washed several times with acetate); UV (MeOH) λmax 269.9 nm; IR (KBr) cm-1
1
water and brine, dried over anhydrous sodium sulfate, 3375, 3130, 3010, 2845, 1710, 1665; H-NMR (CDCl3,
filtered and concentrated. The crude product was 300 MHz)
purified by column chromatography (SiO2, hexane/ 1H), 4.56 (s, 4H), 3.85 (t, 2H,
δ
8.79 (s, 1H), 7.34-7.26 (m, 10H), 6.90 (s,
= 7.7 Hz), 3.63 (d, 4H,
J = 17.7 Hz), 2.14 (td, 2H, J = 7.7, 19.8 Hz), 1.85 (s,
J
EtOAc = 1:4) to afford 114.1 mg (70%) of compound 7a
as a white solid: mp 94oC (recrystallized from hexane- 3H); EIMS m/z (relative intensity) 427 (M+H), 229
ethyl acetate); UV (MeOH) λmax 261.0 nm; IR (KBr) (16), 139 (10), 96 (25), 91 (100), 65 (25).
cm-1 3260, 3100, 2900, 1665, 1600, 1570; 1H-NMR (300
MHz, CDCl3)
10H), 6.57 (bs, 2H), 4.52 (s, 4H), 4.34 (t, 2H,
δ
8.33 (s, 1H), 7.73 (s, 1H), 7.30 (m, 1-[4-(Benzyloxy)-3-[(benzyloxy)methyl]-3-fluoro-
= 7.7 butyl]-5-fluorouracil (7d)
J
Hz), 3.62 (dd, 4H,
J
= 17.6, 4.3 Hz), 2.36 (td, 2H,
J
=
To a stirred solution of the bromide 6 (108.5 mg, 0.3
19.7, 7.7 Hz); EIMS m/z (relative intensity) 436 (M+H, mmol) in DMF (5 mL), 5-fluorouracil (74.1 mg, 0.6
2), 324 (29), 222 (13), 203 (12), 148 (26), 135 (38), 91 mmol), lithium carbonate (63.2 mg, 0.9 mmol), and
(100), 65 (22).
cesium carbonate (46.6 mg, 0.1 mmol) were added.
The mixture was stirred at 90oC for 1 h, and the
reaction was then quenched by the addition of water.
The mixture was diluted with ethyl acetate and the
1-[4-(Benzyloxy)-3-[(benzyloxy)methyl]-3-fluoro-
butyl]cytosine (7b)
To a stirred solution of the bromide
6 (111.0 mg, 0.3 organic phase was then washed several times with
mmol) in DMF (4 mL), cytosine (64.4 mg, 0.6 mmol) water and brine, dried over anhydrous sodium sulfate,
and cesium carbonate (143.4 mg, 0.4 mmol) were filtered and concentrated. The crude product was
added. The mixture was stirred at 90oC for 2 h, and purified by column chromatography (silica gel, hexane
the reaction was then quenched by the addition of /EtOAc = 5/2) to afford 62.0 mg (51%) of title com-
water. The mixture was diluted with ethyl acetate and pound 7d as a white solid: mp 90oC (recrystallized
the organic phase was then washed several times with from hexane-ethyl acetate); UV (MeOH) λmax 273.0
water and brine, dried over anhydrous sodium sulfate, nm; IR (KBr) cm-1 3375, 3140, 3020, 2850, 2810, 1700,
filtered and concentrated. The crude product was puri- 1655; 1H-NMR (300 MHz, CDCl3)
fied by column chromatography (silica gel, CH2Cl2/ 7.26 (m, 10H), 7.15 (d, 1H, = 5.4 Hz), 4.56 (s, 4H),
MeOH = 20:1 15:1) to afford 85.2 mg (71%) of com- 3.86 (t, 2H, = 7.5 Hz), 3.62 (d, 4H, = 18.3 Hz), 2.15
δ 8.59 (s, 1H), 7.36-
J
→
J
J
pound 7b as a white solid: mp 182oC (recrystallized (td, 2H,
J = 7.5, 19.2 Hz); EIms m/z (relative intensity)
from hexane-ethyl acetate); UV (MeOH) λmax 275.0 431 (M+H), 233 (19), 143 (6), 91 (100), 65 (7).
nm; IR (KBr) cm-1 3320, 3085, 2900, 2845, 1640, 1600;

200
M.-H. Choi et al.
1-[4-(Benzyloxy)-3-[(benzyloxy)methyl]-3-fluoro-
butyl]-5-trifluoromethyluracil (7e)
evaporated three times with methanol. The residue
was purified by column chromatography (silica gel,
To a stirred solution of the bromide
6 (108.5 mg, 0.3 eluted with 5~20% methanol in CH2Cl2).
mmol) in DMF (4 mL), 5-trifluoromethyluracil (100.9
mg, 0.6 mmol), lithium carbonate (63.2 mg, 0.9 mmol), 9-[3-Fluoro-4-hydroxy-3-hydroxymethylbutyl]
and cesium carbonate (46.3 mg, 0.1 mmol) were added. adenine (1a)
The mixture was stirred at 90oC for 1 h, and the
The compound was prepared from 7a by the general
reaction was then quenched by the addition of water. procedure described above in 68% yield as a white
The mixture was diluted with ethyl acetate and the solid. mp 181oC (recrystallized from methanol); UV
organic phase was then washed several times with (MeOH) λmax 261.0 nm; IR (KBr) cm-1 3355, 3315,
1
water and brine, dried over anhydrous sodium sulfate, 3150, 1660, 1600, 1575; H-NMR (300 MHz, DMSO-
filtered and concentrated. The crude product was d6)
purified by column chromatography (silica gel, hexane (t, 2H,
δ
8.07 (s, 1H), 7.08 (s, 2H, D2O exchangeable), 4.97
= 5.7 Hz), 4.30 (t, 2H, = 8.0 Hz), 3.54 (dd,
= 5.4, 18.3 Hz), 2.19 (td, 2H, = 8.0, 19.8 Hz);
J
J
/ethyl acetate = 4/1) to afford 98.3 mg (72%) of title 4H,
J
J
compound 7e as a white solid: mp 132oC (recrystal- EIMS m/z (relative intensity) 256 (M+H, 9), 218 (14),
lized from hexane-ethyl acetate); UV (MeOH) λmax 148 (100), 136 (60), 108 (50), 67 (42), 53 (32).
264.5 nm; IR (KBr) cm-1 3375, 3165, 3050, 2850, 1720,
1
1695; H-NMR (300 MHz, CDCl3)
δ
8.61 (s, 1H), 7.65 1-[3-Fluoro-4-hydroxy-3-hydroxymethyl butyl]
(s, 1H), 7.35-7.26 (m, 10H), 4.55 (s, 4H), 3.97 (t, 2H,
= 7.3 Hz), 3.61 (d, 4H, = 18.3 Hz), 2.18 (td, 2H,
J
cytosine (1b)
J
J
=
The compound was prepared from 7b by the general
7.3, 19.8 Hz); EIms m/z (relative intensity) 481 procedure described above in 95% yield as a white
(M+H), 283 (11), 181 (3), 150 (3), 91 (100), 65 (7).
solid. mp 167oC (recrystallized from methanol); UV
(MeOH) λmax 274.9 nm; IR (KBr) cm-1 3340, 3120,
1
1-[4-(Benzyloxy)-3-[(benzyloxy)methyl]-3-fluoro-
butyl]uracil (7f)
2940, 1670, 1615; H-NMR (300 MHz, DMSO-d6)
δ
7.55 (d, 1H,
J
= 7.2 Hz), 5.63 (d, 1H,
J
= 7.2 Hz), 6.96
A mixture of uracil (161.4 mg, 1.4 mmol), potassium (bs, 2H, D2O exchangeable), 4.93 (t, 2H,
carbonate (199.0 mg, 1.4 mmol) and bromide (182.3 D2O exchangeable), 3.75 (t, 2H,
mg, 0.5 mmol) in DMSO (5mL) was stirred at 90oC for 4H,
= 6.0, 18.6 Hz), 1.90 (td, 2H,
J
= 6.0 Hz,
6
J
= 7.8 Hz), 3.49 (dd,
= 7.8, 20.1 Hz);
J
J
1 day and quenched by the addition of water. The EIMS m/z (relative intensity) 232 (M+H, 15), 183 (19),
mixture was diluted with ethyl acetate and the 164 (28), 138 (29), 125 (65), 112 (84), 96 (33), 81 (100),
organic phase was then washed several times with 69 (28); HRMS (EI) calcd for C9H14N3O3F (M+)
water and brine, dried over anhydrous sodium sulfate, 231.1019, found 231.1021.
filtered and concentrated. The crude product was
purified by column chromatography (silica gel, hexane 1-[3-Fluoro-4-hydroxy-3-hydroxymethylbutyl]thy-
/ ethyl acetate = 3/2) to afford 166.0 mg (84%) of title mine (1c)
compound 7f as a white solid: mp 92oC (recrystallized
The compound was prepared from 7c by the general
from hexane-ethyl acetate); UV (MeOH) λmax 264.9 procedure described above in 68% yield as a white
nm; IR (KBr) cm-1 3120, 3010, 2880, 2840, 1705, 1670; solid. mp 161oC (recrystallized from methanol-ethyl
1H-NMR (CDCl3, 300 MHz)
δ
8.56 (s, 1H), 7.35-7.26 acetate); UV (MeOH) λmax 269.9 nm; IR (KBr) cm-1
1
(m, 10H), 7.06 (d, 1H,
J
= 8.1 Hz), 5.61 (d, 1H,
= 7.7 Hz), 3.62 (d, 4H, DMSO-d6 / CDCl3)
= 7.7, 19.5 Hz); EIMS m/ 7.26 (s, 1H), 4.77 (bs, 2H, D2O exchangeable), 3.85 (t,
(relative intensity) 412 (M+), 321 (51), 215 (81), 125 2H,
= 7.9 Hz), 3.61 (dd, 4H, = 4.6, 17.6 Hz), 2.02
J
= 6.0 3355, 3145, 3010, 2930, 1670; H-NMR (500 MHz,
Hz), 4.55 (s, 4H), 3.87 (t, 2H,
J
δ 11.09 (s, 1H, D2O exchangeable),
J
z
= 19.2 Hz), 2.15 (td, 2H, J
J
J
(31), 91 (100), 82 (43).
(td, 2H, J = 7.9, 19.9 Hz), 1.84 (s, 3H); EIMS m/z
(relative intensity) 246 (M+H, 60), 198 (54), 127 (98),
96 (100), 82 (72), 55 (81).
General procedure for debenzylation of 7a-f
A solution of the
O-benzylated nucleosides 7a-f (0.2-
0.7mmol) in dry CH2Cl2 was stirred at -78oC under a 1-[3-Fluoro-4-hyrdoxy-3-hydroxymethybutyl]-5-
nitrogen atmosphere. This solution was treated with fluorouracil (1d)
10 equivalent of boron trichloride (1.0 M in CH2Cl2)
The compound was prepared from 7d by the general
and stirred at -78oC for 1 h. Methanol was then added procedure described above in 61% yield as a white
and the solution was allowed warm to room tempera- solid. mp 165oC (recrystallized from methanol-ethyl
ture. This solution was concentrated in vacuo and co- acetate); UV (MeOH) λmax 272.1 nm; IR (KBr) cm-1

3'-Fluoropenciclovir Analogues
201
1
3375, 3315, 2970, 2810, 1655; H-NMR (500 MHz, 1-[3-Fluoro-4-hyrdoxy-3-hydroxymethylbutyl]-5-
DMSO-d6 / CDCl3) 11.70 (s, 1H, D2O exchangeable), iodouracil (1g)
7.76 (d, 1H, = 6.3 Hz), 4.78 (bs, 2H), 3.88 (t, 2H, To a stirred solution of compound 1f (40.3 mg, 0.2
7.6 Hz), 3.62 (d, 4H, = 17.8 Hz), 2.06 (td, 2H,
δ
J
J =
J
J = 7.6, mmol) in dioxane (4 mL), iodine (50.8 mg, 0.2 mmol),
19.8 Hz); EIMS m/z (relative intensity) 251 (M+H, 9), HNO3 (0.8 M, 0.3 mL, 0.2 mmol) were added. The
143 (34), 131 (39), 114 (28), 100 (100), 82 (39), 72 (18). mixture was stirred at 90oC for 4 h, and the reaction
was cooled to 0oC and quenched by the addition of
1-[3-Fluoro-4-hydroxy-3-hydroxymethyl-5-trifluo-
romethylbutyl]uracil (1e)
aqueous thiosulfate solution. The mixture was diluted
with ethyl acetate and the organic phase was then
The compound was prepared from 7e by the general washed several times with water and brine, dried over
procedure described above in 67% yield as a white anhydrous sodium sulfate, filtered and concentrated.
solid. mp 173oC (recrystallized from methanol-ethyl The crude product was purified by column chromato-
acetate); UV (MeOH) λmax 264.6 nm; IR (KBr) cm-1 graphy (silica gel, CH2Cl2/MeOH = 10/1) to afford 37.1
1
3425, 3375, 3010, 2850, 1700; H-NMR (500 MHz, mg (60%) of compound 1g as a white solid: mp 155oC
DMSO-d6 / CDCl3)
8.13 (s, 1H), 4.79 (s, 2H), 4.01 (t, 2H,
(d, 4H, = 17.6 Hz), 2.09 (td, 2H,
EIMS m/z (relative intensity) 301 (M+H, 18), 252 (24), exchangeable), 8.17 (s, 1H), 4.94 (t, 2H,
δ
11.75 (s, 1H, D2O exchangeable), (recrystallized from MeOH-ethyl acetate); UV (MeOH)
= 7.7 Hz), 3.63 λmax 289.2 nm; IR (KBr) cm-1 3300, 2980, 1665, 1690,
= 7.7, 19.8 Hz); 1655; 1H-NMR (300 MHz, CDCl3)
11.42 (s, 1H, D2O
= 5.7 Hz,
= 7.7 Hz), 3.49 (dd,
J
J
J
δ
J
150 (100), 82 (59), 72 (52).
D2O exchangeable), 3.82 (t, 2H, J
4H,
J = 5.7, 18.4 Hz), 1.94 (td, 2H, J = 7.7, 20.5 Hz);
1-[3-Fluoro-4-hyrdoxy-3-hydroxymethylbutyl]
uracil (1f)
EIMS m/z (relative intensity) 358 (M+, 11), 238 (35),
208 (45), 127 (31), 82 (100), 53 (50); HRMS (EI) calcd
The compound was prepared from 7f by the general for C9H14N3O3FI (M+) 357.9826, found 357.9823.
procedure described above in 87 % yield as a white
solid. mp 115oC (recrystallized from methanol-ethyl
RESULTS AND DISCUSSION
acetate); UV (MeOH)
3340, 3160, 3040, 2950, 1660; H-NMR (300 MHz,
DMSO-d6/CDCl3) 10.60 (s, 1H, D2O exchangeable),
7.32 (d, 1H, = 7.8 Hz), 5.61 (d, 1H,
(t, 2H, = 6.3 Hz, D2O exchangeable), 3.92 (t, 2H,
= 7.8 Hz), 3.73-3.64 (m, 4H), 2.09 (td, 2H, = 7.8, Hannah et al., 1989). Thus, adenine and several pyri-
20.1 Hz); EIMS m/z (relative intensity) 232 (M+, 20), midine analogues of 3’-fluoropenciclovir
were selected
λ
max 265.7 nm; IR (KBr) cm-1 3400,
1
Among the target compounds of 3’-fluoropenciclovir
1, guanine analogue had already appeared in several
δ
J
J
= 8.1 Hz), 4.39 reports and was known to be 3-fold less active than pen-
ciclovir against the herpes viruses (Bailey et al., 1988;
J
J
J
1
184 (80), 125 (83), 113 (88), 96 (53), 82 (100); HRMS as target compounds for this study. The strategy for
(EI) calcd for C9H13N2O4F (M+) 232.0859, found synthesizing the 3'-fluoropenciclovir analogues was
232.0858.
based on the alkylation of either adenine or pyrimi-
Scheme 1. Synthesis of 3’-fluoropenciclovir analogues

202
M.-H. Choi et al.
dine bases with the bromide
6. The bromide 6 was
ACKNOWLEDGEMENTS
prepared from ketone
sequence in a good overall yield, as shown in Scheme 1.
1,3-Dibenzyloxy-2-propanone ( ) was prepared as Women's University Research Grants 2007.
2 via an efficient six-step
This research was supported by the Sookmyung
2
per the literature method previously reported by us in
literature (Choi and Kim, 2003). 1,2-Nucleophilic addi-
REFERENCES
tion reaction of the propanone
generated from ethyl acetate by LDA, gave the
hydroxy ester in an 84% yield. The fluorination of
the -hydroxy ester was successively achieved with
(diethylamino)sulfur trifluoride (DAST) at -78oC in 58%
yield. Fluorinated ester was then directly subjected
2 with the enolate,
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β-
3
β
3
4
to reduction with lithium aluminium hydride in
tetrahydrofuran to give the desired fluorinated alcohol
5
in excellent yield (93%). Unexpectedly, fluorine
atom, positioned to the carbonyl group, was found to
be quite stable to this basic reduction condition. Due
to the possibility of dehydrofluorination of under
basic condition, we had initially adopted an indirect
and lengthy route bypassing the fluorinated ester
Conversion of primary alcohol to the bromide was
accomplished by treatment with -bromosuccinimide
(NBS) and triphenylphosphine in 82% yield. The
β
4
4.
5
6
N
coupling of the bromide
6 with adenine in the pre-
sence of cesium carbonate provided the desired N9-
alkylated adenine 7a in a 70% yield. Deprotection of
the benzyl groups using boron trichloride in DCM
gave 9-[3-fluoro-4-hydroxy-3-hydroxymethyl butyl]
adenine (1a) in 68% yield. The pyrimidine compounds
were prepared in the same lines as used with adenine.
Direct alkylation of pyrimidines to bromide
6 in DMF
with cesium carbonate as a basic catalyst gave the
desired N1-alkylated products. Deprotection of the
benzyl protecting groups using boron trichloride gave
the pyrimidines analogues of 3’-fluoropenciclovir (1b
-
1f). Finally, 5-iodouracil derivative 1g was prepared
from uracil analogue 1d by oxidative iodination. The
structures of final products 1a
-
g
were confirmed by
UV, mass, IR, and H-NMR spectra. The synthesized
nucleosides 1a were evaluated for their antiviral
1
Pankiewicz, K. W., Fluorinated nucleoside. Carbohydr. Res.,
327, 87-105 (2000).
-g
activity against poliovirus, HSV-1, HSV-2 and HIV.
However, all compounds were found to be inactive in
the assay. Presumably, the lack of activity is attributed
to the internal hydrogen bonding formation between
fluorine and hydroxyl group, resulting in the unfavorable
conformation for phosphorylation by kinase.
In summary, we have designed and synthesized a
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purine and pyrimidine bases, and evaluated their anti-
viral activity against poliovirus, HSV-1, HSV-2 and HIV.
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by 1H-NMR spectroscopy. Nucleosides Nucleotides, 18,
1035-1053 (1999), and references therein.
It is also notable that direct reduction of
β-fluoroester to
the corresponding 3-fluoroalcohol provided the easy and
new synthetic entry to 3’-fluoropenciclovir analogues.