Structure-activity relationships of 1-(2-deoxy-2-fluoro-β-L-arabino- furanosyl)pyrimidine nucleosides as anti-hepatitis B virus agents

Article abstract of DOI:10.1021/jm960098l

Since 2'-fluoro-5-methyl-β-L-arabinofuranosyluracil (L-FMAU) has been shown to be a potent anti-HBV agent in vitro, it was of interest to study the structure-activity relationships of related nucleosides. Thus, a series of 1- (2-deoxy-2-fluoro-β-L-arabinofuranosyl)pyrimidine nucleosides have been synthesized and evaluated for antiviral activity against HBV in 2.2.15 cells. For this study, L-ribose was initially used as the starting material. Due to the commercial cost of L-ribose, we have developed an efficient procedure for the preparation of L-ribose derivative 6. Starting from L-xylose, 6 was obtained in an excellent total yield (70%) through the pyridinium dichromate oxidation of the 3-OH group followed by stereoselective reduction with NaBH₄. It was further converted to the 1,3,5-tri-O-benzoyl-2-deoxy-2- fluoro-α-L-arabinofuranose (10), which was then condensed with various 5- substituted pyrimidine bases to give the nucleosides. Among the compounds synthesized, the lead compound, L-FMAU (13), exhibited the most potent anti- HBV activity (EC₅₀ 0.1 μM). None of the other uracil derivatives showed significant anti-HBV activity up to 10 μM. Among the cytosine analogues, the cytosine (27) and 5-iodocytosine (35) derivatives showed moderately potent anti-HBV activity (EC₅₀ 1.4 and 5 μM, respectively). The cytotoxicity of these nucleoside analogues has also been assessed in 2.2.15 cells as well as CEM cells. None of these compounds displayed any toxicity up to 200 μM in 2.2.15 cells. Thus, compound 13 (L-FMAU), 27, and 35 showed a selectivity of over 2000, 140, and 40, respectively.

Full text of DOI:10.1021/jm960098l

J . Med. Chem. 1996, 39, 2835-2843
2835
Str u ctu r e-Activity Rela tion sh ip s of 1-(2-Deoxy-2-flu or o-â-L-a r a bin o-
fu r a n osyl)p yr im id in e Nu cleosid es a s An ti-Hep a titis B Vir u s Agen ts
Tianwei Ma,† S. Balakrishna Pai,‡ Yong Lian Zhu,‡ J u Sheng Lin,‡ Kirupa Shanmuganathan,† J infa Du,†
Chunguang Wang,† Hongbum Kim,† M. Gary Newton,§ Yung Chi Cheng,‡ and Chung K. Chu*,†
Department of Medicinal Chemistry, College of Pharmacy, and Department of Chemistry, The University of Georgia, Athens,
Georgia 30602, and Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06510
Received February 2, 1996X
Since 2′-fluoro-5-methyl-â-L-arabinofuranosyluracil (L-FMAU) has been shown to be a potent
anti-HBV agent in vitro, it was of interest to study the structure-activity relationships of related
nucleosides. Thus, a series of 1-(2-deoxy-2-fluoro-â-L-arabinofuranosyl)pyrimidine nucleosides
have been synthesized and evaluated for antiviral activity against HBV in 2.2.15 cells. For
this study, L-ribose was initially used as the starting material. Due to the commercial cost of
L-ribose, we have developed an efficient procedure for the preparation of L-ribose derivative 6.
Starting from L-xylose, 6 was obtained in an excellent total yield (70%) through the pyridinium
dichromate oxidation of the 3-OH group followed by stereoselective reduction with NaBH4. It
was further converted to the 1,3,5-tri-O-benzoyl-2-deoxy-2-fluoro-R-L-arabinofuranose (10),
which was then condensed with various 5-substituted pyrimidine bases to give the nucleosides.
Among the compounds synthesized, the lead compound, L-FMAU (13), exhibited the most potent
anti-HBV activity (EC50 0.1 µM). None of the other uracil derivatives showed significant anti-
HBV activity up to 10 µM. Among the cytosine analogues, the cytosine (27) and 5-iodocytosine
(35) derivatives showed moderately potent anti-HBV activity (EC50 1.4 and 5 µM, respectively).
The cytotoxicity of these nucleoside analogues has also been assessed in 2.2.15 cells as well as
CEM cells. None of these compounds displayed any toxicity up to 200 µM in 2.2.15 cells. Thus,
compound 13 (L-FMAU), 27, and 35 showed a selectivity of over 2000, 140, and 40, respectively.
In tr od u ction
virus in the Peking duck hepatitis model.14 We also
studied the biochemical mode of action of L-FMAU, in
which it was discovered that L-FMAU is phosphorylated
by the cellular thymidine kinase as well as by deoxy-
cytidine kinase to the monophosphate and subsequently
to the triphosphate by unknown kinases, which inhibits
the HBV DNA polymerase.15 However, we failed to
detect any incorporation of a radiolabeled nucleoside to
either the HBV DNA or the cellular DNA. Further-
more, the triphosphate did not inhibit cellular DNA
polymerases.15 As a result of these promising pharma-
cological and toxicological profiles, L-FMAU is currently
considered as a clinical candidate for treatment of
chronic HBV infection. In view of these promising
results obtained for L-FMAU, it was of interest to study
the structure-activity relationships (SAR) of the related
class of nucleosides. Therefore, in this paper we report
the synthesis and the SARs of 1-(2-deoxy-2-fluoro-â-L-
arabinofuranosyl)-5-substituted-pyrimidine nucleosides
as potential anti-HBV agents.
Recently, a number of nucleosides with the unnatural
L-configuration have been reported as potent chemo-
therapeutic agents against human immunodeficiency
virus (HIV), hepatitis B virus (HBV), and certain forms
of cancer. These include (-)-â-L-1-[2-(hydroxymethyl)-
1,3-oxathiolan-4-yl]cytosine (3TC),1-3 (-)-â-L-1-[2-(hy-
dr oxym et h yl)-1,3-oxa t h iola n -4-yl]-5-flu or ocyt osin e
(FTC),4,5 (-)- â-L-2′, 3′-dideoxypentofuranosyl-5-fluoro-
cytosine (L-FddC),6,7 and (-)-â-L-1-[2-(hydroxymethyl)-
1,3-dioxolan-4-yl]cytosine [(-)-OddC].8,9 It is interesting
that these L-nucleosides have potent biological activity,
while some of them show lower toxicity profiles than
their D-counterparts. In view of this interesting dis-
covery of L-nucleosides as biologically active compounds,
we have recently synthesized 2′-fluoro-5-methyl-â-L-
arabinofuranosyluracil (L-FMAU) and its derivative and
evaluated these compounds as potential antiviral agents.
From this effort we discovered L-FMAU as a potent
antiviral agent against HBV as well as the Epstein-
Barr virus.10 In contrast to the D-enantiomers, L-FMAU
did not exhibit any toxicities, including the interference
of mitochondrial function,11 resulting in lactic acidosis
and hepatic failure as shown by â-D-2′-fluoro-5-iodoara-
binofuranosyluracil (Fialuridine, D-FIAU).12 No signifi-
cant bone marrow toxicity was found for L-FMAU up to
100 µM.10 Furthermore, in preliminary in vivo toxicity
studies in mice for 30 days, L-FMAU did not show any
apparent toxicities as well as significant abnormalities
of clinical chemistry.13 Additionally, L-FMAU exhibited
in vivo antiviral activity against the duck hepatitis B
Resu lts a n d Discu ssion
Syn th esis. The synthesis of 2′-deoxy-2′-fluoro-â-L-
arabinofuranosyl nucleosides reported in this paper was
accomplished via the key intermediate 10, which was
initially prepared10 from L-ribose according to a similar
procedure used for the synthesis of D-FMAU.16 How-
ever, due to the high commercial cost of L-ribose as a
starting material, we developed a synthetic procedure
for the L-ribose derivative 6. Although several pro-
cedures have been reported for the synthesis of
L-ribose,17-20 on the basis of our experience, none of
these methods seemed practical for large-scale prepara-
tion. Previously, it was reported that D-ribose was
† Department of Medicinal Chemistry.
‡ Department of Pharmacology.
§ Department of Chemistry.
X Abstract published in Advance ACS Abstracts, J une 15, 1996.
S0022-2623(96)00098-2 CCC: $12.00 © 1996 American Chemical Society

2836 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Ma et al.
Sch em e 1a
a
Reagents: (i) CuSO4, concentrated H2SO4, acetone; (ii) 0.2% HCl/H2O; (iii) BzCl, py, CH2Cl2, 0 °C, 0.5-1 h; (iv) PDC, Ac2O, CH2Cl2,
reflux; (v) NaBH4, 80% EtOH/H2O or NaBH4, EtOH, EtOAc; (vi) BzCl, py; (vii) 1% HCl/CH3OH; (viii) Ac2O, AcOH, concentrated H2SO4;
(ix) (1) HCl(g), AcCl, CH2Cl2, 0 °C, (2) H2O, CH3CN; (x) SO2Cl2, DMF, CH2Cl2, -15 °C to room temperature, imidazole; (xi) KHF2, 2,3-
butanediol, 48% HF/H2O, reflux; (xii) HBr/AcOH, CH2Cl2, room temperature; (xiii) silylated bases, 1,2-dichloroethane, reflux; (xiv) NH3/
CH3OH.
synthesized from D-xylose via the oxidation-reduction
procedure of the 3-OH group, albeit in a low yield.21 We
decided to adopt this strategy to synthesize the L-ribose
derivative (Scheme 1). Thus, 1,2-O-isopropylidene-R-
L-xylofuranose (2) was prepared from L-xylose,22 which
was then selectively protected at the 5-OH with BzCl
in pyridine-CH2Cl2 at 0 °C to give 3 (79% yield from
1). Although various oxidizing agents have been re-
ported for the oxidation of the 3-OH of pentofuranose
derivatives,21,23,24 we found pyridinium dichromate (PDC)
gave the best yield (96%). The resulting ketone 4 was
stereoselectively reduced by NaBH4 to the desired ribose
derivative 5. It should be mentioned that apparently
due to the stereoelectronic effects of the 1,2-O-isopro-
pylidene group, the hydride only attacked from the
â-face, resulting in 5-O-benzoyl-1,2-O-isopropylidene-R-
L-ribofuranose (5b) as the exclusive product. When
EtOH-H2O (4:1) was used as the solvent, cleavage of
the benzoyl group occurred, leading to a cumbersome
workup and a lower yield (79%); however, using a
mixture of EtOAc-EtOH (1:2) prevented the cleavage
of the benzoyl group, resulting in a higher yield (96%).
Compound 5a or 5b was benzoylated to give the diben-
zoylated ribose derivative 6,25 which was treated suc-
cessively without isolation with 1% HCl-MeOH, BzCl-
pyridine, and then Ac2O-AcOH-H2SO4 to give 1-O-
acetyl-2,3,5-tri-O-benzoyl-â-L-ribofuranose (7) as a
crystalline product in 50% yield. Treatment of 7 with
saturated hydrogen chloride in CH2Cl2 at 0 °C followed
by hydrolysis26 gave 8 (71% yield), which was treated
with SO2Cl2 and imidazole in DMF-CH2Cl2 to give the
imidazolyl sulfonate 9 in 73% yield. The imidazole
derivative 9 was fluorinated with KHF2 and 48% HF-
H2O to give 1,3,5-tri-O-benzoyl-2-fluoro-R-L-arabino-
furanose (10) in 65% yield.16 It is noteworthy to
mention that an improved fluorination reaction was
recently reported.27
Bromination of the key intermediate 10 with HBr-
AcOH gave a bromo derivative 11, which was coupled
with silylated thymine without catalyst in CH3CN under
refluxing conditions to give the protected nucleoside 12
as a mixture of anomers (â:R/3:1). Although the reaction
finished within 3 h and the yield was high (94%), the
separation of the anomers was difficult in both the
protected as well as deprotected stages. Therefore, we
searched for a more convenient procedure to improve
the â/R ratio. From these efforts we found that using
1,2-dichloroethane (DCE) as the solvent for the conden-

â-L-Pyrimidine Nucleosides as Anti-HBV Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2837
Sch em e 2a
a
Reagents: (i) Et3N, (Ph3P)2PdCl2, CuI, (trimethylsilyl)acetylene, Ar, 50 °C; (ii) NaOCH3, CH3OH; (iii) methyl acrylate, Pd(OAc)2,
Ph3P, 1,4-dioxane; (iv) (1) NaOH, (2) HCl; (v) DMF, KHCO3, N-bromosuccinimide.
sation gave mainly the â-isomer 12 along with only trace
amount of the R-anomer, which was easily removed by
silica gel column chromatography or recrystallization,
although the coupling reaction took a longer time with
a lower yield (71%). We also found that using CHCl3
as the solvent for the coupling reaction gave the best
â/R ratio (20/1) which was consistent with the previously
reported result.28 The bromo sugar 11 was also con-
densed with other silylated 5-substituted uracil deriva-
tives to give the protected nucleosides (14, 16, 18, 20,
22, and 24), which were treated with NH3-CH3OH to
give the final products (15, 17, 19, 21, 23, and 25). The
synthesis of cytosine derivatives was achieved by the
condensation of the bromo sugar 11 with either the
N-benzoylated (26 and 34) or unprotected bases (28, 30,
F igu r e 1. ORTEP drawing of L-FMAU.
and 32) in 1,2-dichloroethane. No significant differences
coupling constants (16-18 Hz) in the 13C NMR spectra
in yields of the condensation was observed. The free
were consistent with those reported for the â-D-config-
nucleosides (27, 29, 31, 33, and 35) were obtained by
uration.35 The structure of â-L-FMAU was also unam-
the deprotection of 26, 28, 30, 32, and 34 with NH3-
biguously confirmed by a single-crystal X-ray crystal-
CH3OH.
lography,36 and the ORTEP drawing is shown in Figure
1.
The 5-ethynyluracil derivative 37 was obtained by
treatment of the protected 5-iodo derivative 22 with
An ti-Hep a titis B Vir u s Activity. The anti-hepa-
(trimethylsilyl)acetylene in the presence of (Ph3P)2PdCl2
titis B virus activity (EC50) and growth inhibition (IC50)
and CuI, followed by deprotection with NaOCH3-CH3-
of the synthesized nucleosides were evaluated in 2.2.15
OH.29 The synthesis of the (E)-5-bromovinyl derivative
40 was accomplished by using a similar procedure
reported for the synthesis of 5-(bromovinyl)-2′-deoxyuri-
dine (BVDU)30 (Scheme 2). Thus, the free 5-iodouracil
derivative 23 was treated with methyl acrylate in the
presence of Pd(OAc)2 and Ph3P in dioxane. Saponifica-
tion with NaOH followed by acidification with HCl gave
39, which was decarboxylated in DMF in the presence
of N-bromosuccinimide and K2CO3 to give 40. The
E-configuration was identified by the coupling constant
(13.6 Hz) for the vinyl protons in the 1H NMR spectrum.
cells as previously described10 and are shown in Table
3. Unlike the D-isomers such as FMAU, FEAU, and
FIAU, neither 5-substitutions with halogen (F, Cl, Br,
I) nor 5-substitutions with alkyl groups (ethyl, E-
bromovinyl, or ethynyl) exhibited any significant anti-
HBV activity up to 10 µM. The only active uracil
derivative is the 5-methyl derivative, L-FMAU (13),
which exhibited 20 times more potency than that of the
D-counterpart (EC50 0.1 µM vs 2.0 µM).10 Change of the
5-methyl to a 5-trifluoromethyl group (25) also resulted
in a decrease of the anti-HBV activity. Interestingly,
the cytosine (27) and 5-iodocytosine (35) derivatives
showed moderately potent anti-HBV activities (EC50 1.4
and 5.0 µM, respectively), while other 5-substitutions
such as F, Cl, and Br did not exhibit any significant
antiviral activity.
The physical data for all the key intermediates and
final products are summarized in Table 1. â-L-config-
uration of the synthesized nucleosides was confirmed
by comparison of the 1H NMR spectra (Table 2) with
those of the corresponding D-isomers.16,31-34 The C1′-F

2838 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Ta ble 1. Physical and Optical Data
Ma et al.
no.
mp, °C (solv)a
[R]25
formula
anal.
C,H
C, H
C, H
C,H
C, H
C, H
C, H, N, S
C, H, F
C, H, F, N
C, H, F, N
C, H, F, N
C, H, F, N
C, H, N
D
3
4
5a
5b
6
82-83 (A)
-12.14 (c 0.37, CHCl3)
-132.00 (c 1.0, CHCl3)
-31.50 (c 0.62, CHCl3)
+46.22 (0.11, CH3OH)
-122.38 (c 0.9, CHCl3)
-81.96 (c 0.55, CHCl3)
-68.98 (c 0.37, CHCl3)
-4.82 (c 0.51, CHCl3)
+22.40 (c 0.31, CHCl3)
-111.77 (c 0.23, CH3OH)
+23.62 (c 0.21, CHCl3)
-96.30 (c 0.47, CH3OH)
+10.76 (c 0.29, CHCl3)
-93.42 (c 0.29, CH3OH)
+30.45 (c 0.35, CHCl3)
-107.23 (c 0.18, CH3OH)
+37.65 (c 0.28, CHCl3)
-109.61 (c 0.15, CH3OH)
+44.02 (c 0.21, CHCl3)
-57.82 (c 0.33, CH3OH)
+5.19 (c 0.21, CHCl3)
-87.47 (c 0.33, CH3OH)
-4.33 (c 0.21, CHCl3)
-114.17 (c 0.21, CH3OH)
-6.70 (c 0.35, CHCl3)
-108.36 (c 0.16, CH3OH)
+23.15 (c 0.19, CHCl3)
-99.54 (c 0.26, CH3OH)
+24.09 (c 0.27, CHCl3)
-82.86 (c 0.18, CH3OH)
+41.29 (c 0.19, CHCl3)
-65.40 (c 0.34, CH3OH)
+80.63 (c 0.19, CHCl3)
-89.52 (c 0.27, CH3OH)
-59.40 (c 0.17, CH3OH)
C15H18O6
C15H16O6
C8H14O5
C15H18O6
C22H22O7
91-93 (B)
86-87 (B)
131-132 (B)
83-85 (A)
8
9
137-138 (A)
124-125 (B)
77-78 (D)
C26H22O8‚0.3H2O
C29H24N2O10
S
10
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
40
C26H21FO7‚0.5C2H5OH
C24H21FN2O7‚0.5CH3OH
C10H13FN2O5‚0.2H2O
C25H23FN2O7
118-120 (E)
184-185 (E)
148-149 (E)
158-161 (E)
190-193 dec (E)
167-168 (E)
189-191 (E)
195-196 (F)
193-195 (E)
214-215 (F)
194-195 (G)
218-220 (E)
186-187 (E)
202-203 (G)
foam
240-242 (E)
foam
188-189 dec (F)
foam
205-206 (F)
foam
201-202 (F)
226-228 (E)
211-212 dec (E)
212-214 (E)
206-208 dec (H)
190-192 dec (E)
C11H15FN2O5
C23H18F2N2O7‚0.5H2O
C9H10F2N2O5‚0.2H2O
C23H18ClFN2O7
C9H10ClFN2O5‚0.33C2H5OH
C23H18BrFN2O7‚0.5CHCl3
C9H10BrFN2O5‚0.5C2H5OH
C23H18FIN2O7
C9H10FIN2O5
C24H18F4N2O7
C10H10F4N2O5
C30H24FN3O7
C9H12FN3O4‚0.7H2O‚0.2CH3OH
C23H19F2N3O6‚0.5H2O
C9H11F2N3O4
C23H19ClFN3O6‚0.6H2O
C9H11ClFN3O4‚0.5C2H5OH
C23H19BrFN3O6
C9H11BrFN3O4‚0.2C2H5OH
C30H23FIN3O7
C9H11FIN3O4
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, F, I, N
C, H, F, I, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, F, I, N
C, H, F, I, N
C, H, N
C, H, N
C, H, N
C28H27FN2O7Si‚0.5H2O
C11H11FN2O5‚0.2H2O
C11H12BrFN2O5
a
Solvent for either recrystallization or chromatography: A, Et2O; B, hexanes/EtOAc; C, CH3OH; D, 95% EtOH/H2O; E, CH3OH/CHCl3;
F, EtOH; G, 2-propanol; H, EtOH/hexanes.
The toxicities of these nucleosides have also been
assessed in 2.2.15 cells as well as CEM cells. No
significant toxicities were found for any of these ana-
logues with concentrations up to 200 µM, which indi-
cated a high selectivity (over 2000, 140, and 40 for
compound 13, 27, and 35, respectively).
L-xylose, which was further used for the synthesis of
L-FMAU (13) as well as other 1-(2-deoxy-2-fluoro-â-L-
arabinofuranosyl)pyrimidine nucleosides. From the
study of comprehensive structure-activity relation-
ships, we discovered that L-FMAU exhibited the most
potent anti-HBV activity among these pyrimidine nu-
cleoside analogues with a high selectivity index (>2000).
The cytosine (27) and 5-iodocytosine (35) derivatives
also showed moderately potent anti-HBV activity with
selectivities of 140 and 40, respectively. The anti-EBV
activity study of these new analogues is still ongoing in
laboratories. Although further biochemical studies are
needed to elucidate the antiviral mechanism of these
L-nucleosides, synthesis of additional nucleoside ana-
logues is warranted.
The results obtained above are consistent with the
general observation that L-nucleosides often showed
lower toxicity than their D-isomers and most of the
active L-nucleosides against HIV and/or HBV are cy-
tosine derivatives.1-8 Therefore, L-FMAU may be unique
in a sense that this is the only thymine derivative of an
L-nucleoside discovered so far with potent anti-HBV
activity. Furthermore, L-FMAU is the only 2′-deoxy
nucleoside with a 3′-OH group, while all the other
identified anti-HBV L-nucleosides lack that OH group.
It is well-known that HBV replicates by a multistep
mechanism that involves the reverse transcription of a
pregenomic RNA;37 therefore, most of the active L-
nucleosides such as 3TC, FTC, and L-FddC are 2′,3′-
dideoxycytidine analogues, which may act as chain
terminators.38 The structural uniqueness of L-FMAU
may implicate that the mode of action of L-FMAU is
different from that of other cytosine derivatives, and
therefore, potential cross-resistance problems may be
avoided after a prolonged use of these compounds in
patients. Although presently the precise mechanism of
action of L-FMAU is not clear, preliminary biochemical
study suggested that inhibition of viral DNA polymerase
may account for its anti-HBV activity.15
Exp er im en ta l Section
Melting points were determined on a Mel-temp II and are
uncorrected. 1H NMR spectra were recorded on a J EOL FX
90Q Fourier-transform spectrometer for 90 MHz or on a
Bruker 250 AM for 250 MHz, 300 AC for 300 MHz, or 400
AMX spectrometer for 400 MHz, with Me4Si as internal
standard. Chemical shifts (δ) are reported in parts per million
(ppm), and signals are reported as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), or br s (broad singlet). IR
spectra were measured on a Nicolet 510P FT-IR spectrometer.
Optical rotations were performed on a J ASCO DIP-370 digital
polarimeter. TLC were performed on Uniplates (silica gel)
purchased from Analtech Co. Column chromatography was
performed using either silica gel 60 (220-440 mesh) for flash
chromatography or silica gel G (TLC grade >440 mesh) for
vacuum flash column chromatography. UV spectra were
obtained on a Beckman DU-7 or on a Beckman DU 650
spectrophotometer. Elemental analyses were performed by
In summary, we have developed an efficient procedure
for the preparation of the L-ribose derivative 6 from

â-L-Pyrimidine Nucleosides as Anti-HBV Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2839
Ta ble 2. 1H NMR Data of Synthesized Nucleosides and Some C1′-F Coupling Constants of 13C NMR
no.
H-1′
H-2′
5.32 (dd,
H-3′
5.64 (dd,
H-4′
H-5′,5′′ J C1′-F
others
solvent
CDCl3
12 6.35 (dd,
4.50 (m) 4.82 (m)
8.55 (s, NH), 7.37, 8.12 (m, Ar), 1.76,
(s, CH3)
J F-H ) 22.4)
13 6.10 (dd,
J F-H ) 15.4)
14 6.35 (dd,
J F-H ) 22.1)
15 6.14 (dd,
J F-H ) 14.1)
J F-H ) 50.2)
5.04 (dt,
J F-H ) 52.8)
5.32 (dd,
J F-H ) 50.3)
5.08 (dt,
J F-H ) 53.2)
J F-H ) 20.4)
4.22 (dq,
J F-H ) 18.4)
5.65 (dd,
J F-H ) 17.8)
4.24 (dq,
J F-H ) 20.3)
3.76 (m) 3.63 (m) 16.59 11.45 (s, NH), 7.59 (s, H-6), 5.88 (d,
DMSO-d6
CDCl3
3′-OH), 5.13 (t, 5′-OH), 1.78 (s, CH3)
8.16 (s, NH), 7.32, 8.11 (m, Ar), 2.21,
(q, CH2CH3), 0.97 (t, CH2CH3)
4.50 (m) 4.83 (m)
3.78 (m) 3.64 (m) 17.02 11.43 (s, NH), 7.57 (s, H-6), 5.88 (d,
3′-OH), 5.17 (t, 5′-OH), 2.21 (q, CH 2CH3), ,
1.02 (t, CH2CH3)
DMSO-d6
16 6.30 (dd,
J F-H ) 21.2)
17 6.07 (dd,
J F-H ) 14.0)
18 6.30 (dd,
J F-H ) 21.1)
19 6.10 (dd,
J F-H ) 14.3)
20 6.30 (dd,
J F-H ) 21.1)
21 5.94 (dd,
J F-H ) 14.0)
22 6.29 (dd,
J F-H ) 19.4)
23 6.08 (dd,
J F-H ) 13.7)
24 6.31 (dd,
J F-H ) 20.7)
25 6.14 (dd,
J F-H ) 11.0)
26 6.42 (dd,
J F-H ) 21.0)
27 6.08 (dd,
J F-H ) 18.4)
28 6.36 (dd,
J F-H ) 21.7)
29 6.03 (dd,
J F-H ) 16.6)
30 6.38 (dd,
J F-H ) 21.4)
31 6.04 (dd,
J F-H ) 16.6)
32 6.38 (dd,
J F-H ) 21.4)
33 6.04 (dd,
J F-H ) 16.6)
34 6.41 (dd,
J F-H ) 20.0)
35 6.05 (dd,
J F-H ) 16.80)
36 6.28 (dd,
J F-H ) 21.1)
37 5.90 (dd,
J F-H ) 14.6)
38 6.14 (dd,
J F-H ) 14.2)
5.33 (dd,
J F-H ) 50.1)
5.06 (dt,
J F-H ) 52.8)
5.32 (dd,
J F-H ) 50.1)
5.08 (dt,
J F-H ) 52.8)
5.32 (dd,
J F-H ) 50.2)
4.92 (dt,
J F-H ) 52.8)
5.53 (dd,
J F-H ) 50.6)
5.07 (dt,
J F-H ) 53.0)
5.37 (dd,
J F-H ) 49.9)
5.16 (dt,
J F-H ) 52.8)
5.57 (dd,
J F-H ) 49.7)
4.92 (dt,
J F-H ) 52.2)
5.43 (dd,
J F-H ) 49.8)
4.97 (dt,
J F-H ) 49.7)
5.44 (dd,
J F-H ) 49.7)
4.98 (dt,
J F-H ) 52.4)
5.42 (dd,
J F-H ) 49.8)
4.98 (dt,
J F-H ) 52.5)
5.48 (dd,
J F-H ) 50.0)
4.98 (dt,
J F-H ) 52.5)
5.32 (dd,
J F-H ) 50.1)
4.86 (dt,
J F-H ) 52.7)
5.10 (dt,
J F-H ) 52.6)
5.62 (dd,
J F-H ) 17.0)
4.22 (dt,
J F-H ) 20.4)
5.64 (dd,
J F-H ) 17.3)
4.24 (dt,
J F-H ) 19.9)
5.64 (dd,
J F-H ) 17.4)
4.09 (dt,
J F-H ) 21.0)
5.68 (dd,
J F-H ) 23.6)
4.24 (br d,
J F-H ) 21.0)
5.64 (dd,
J F-H ) 14.5)
4.20 (dq,
J F-H ) 20.1)
5.65 (dd,
J F-H ) 16.5)
4.16 (dt,
J F-H ) 18.6)
5.60 (dd,
J F-H ) 16.8)
4.18 (dt,
J F-H ) 19.4)
5.62 (dd,
J F-H ) 16.8)
4.18 (dt,
J F-H ) 17.0)
5.62 (dd,
J F-H ) 16.8)
4.18 (dt,
J F-H ) 20.1)
5.65 (dd,
J F-H ) 17.5)
4.18 (m)
4.76 (m) 4.85 (m)
8.23 (s, NH), 7.44, 8.10 (m, Ar)
CDCl3
3.76 (m) 3.62 (m)
11.95 (s, NH), 8.10 (d, H-6, J ) 6.89), 5.90
(d, 3′-OH), 5.22 (t, 5′-OH)
DMSO-d6
CDCl3
4.54 (m) 4.82 (m) 16.58 8.19 (s, NH), 7.44, 8.10 (m, Ar)
3.82 (m) 3.66 (m)
4.54 (m) 4.82 (m)
3.65 (m) 3.48 (m)
4.60 (m) 4.73 (m)
11.70 (s, NH), 8.13 (s, H-6), 5.87
(d, 3′-OH), 5.20 (t, 5′-OH)
8.14 (s, NH), 7.45, 8.11 (m, Ar)
DMSO-d6
CDCl3
11.63 (s, NH), 8.12 (s, H-6), 5.70
(d, 3′-OH), 5.06 (t, 5′-OH)
11.95 (s, NH), 7.50, 8.06 (m, Ar)
DMSO-d6
CDCl3
3.81 (m) 3.55 (m) 17.03 11.82 (s, NH), 8.24 (s, H-6), 5.95
DMSO-d6
CDCl3
(d, 3′-OH), 5.30 (t, 5′-OH)
7.43, 8.12 (m, Ar, NH)
4.58 (m) 4.85 (m)
3.81 (m) 3.59 (m)
4.60 (m) 4.83 (m)
3.79 (m) 3.53 (m)
4.52 (m) 4.80 (m)
3.78 (m) 3.58 (m)
4.53 (m) 4.81 (m)
12.05 (br s, NH), 8.51 (s, H-6), 5.94
(d, 3′-OH), 5.34 (t, 5′-OH)
7.44, 8.11 (m, Ar, NH)
DMSO-d6
CDCl3
7.61 (d, H-6, J ) 7.4), 7.21 (br d, NH2),
5.72 (d, H-5, J ) 7.5)
7.44, 8.10 (m, Ar, NH2)
DMSO-d6
CDCl3
7.90 (d, H-6, J ) 8), 7.61, 7.86 (2S, NH2)
5.82 (d, 3′-OH), 5.11 (t, 5′-OH)
7.44, 8.11 (m, Ar, NH2)
DMSO-d6
CDCl3
3.78 (m) 3.58 (m) 16.69 7.96 (s, H-6), 7.33, 7.96 (2s, NH2), 5.84
DMSO-d6
CDCl3
(d, 3′-OH), 5.14 (t, 5′-OH)
7.44, 8.11 (m, Ar, NH2)
4.52 (m) 4.82 (m)
3.78 (m) 3.60 (m)
4.58 (m) 4.85 (m)
3.78 (m) 3.60 (m)
4.55 (m) 4.80 (m)
3.62 (m) 3.43 (m)
3.84 (m) 3.69 (m)
8.02 (s, H-6), 7.12, 7.97 (2s, NH2), 5.82
(d, 3′-OH), 5.16 (t, 5′-OH)
10.93 (br s, NH), 7.45, 8.20 (m, Ar)
DMSO-d6
CDCl3
8.04 (s, H-6), 6.74, 7.94 (2s, NH2), 5.84
(d, 3′-OH), 5.17 (t, 5′-OH)
8.19 (s, NH), 7.44, 8.10 (m, Ar), 0.23
(s, SiMe3)
11.58 (s, NH), 7.90 (s, H-6), 5.68 (d,
3′-OH), 4.99 (t, 5′-OH), 3.91 (s, CCH)
11.79 (s, NH), 8.35 (s, H-6), 7.41 (d, Ha,
DMSO-d6
CDCl3
5.62 (dd,
J F-H ) 17.1)
4.04 (dt,
J F-H ) 20.8)
4.26 (dt,
J F-H ) 19.8)
DMSO-d6
DMSO-d6
J
) 15.9), 6.90 (d, Hb, J ) 15.8), 5.81 (d,
3′-OH), 5.25 (t, 5′-OH), 3.69 (s, COOCH3)
11.80 (s, NH), 8.28 (s, H-6), 7.31 (d, Ha,
J ) 15.8), 6.79 (d, Hb, J ) 15.9), 5.90 (d,
3′-OH), 5.23 (t, 5′-OH)
39 6.12 (dd,
J F-H ) 14.0)
5.08 (dt,
J F-H ) 52.7)
4.27 (dt,
J F-H ) 19.6)
3.81 (m) 3.65 (m)
3.80 (m) 3.63 (m)
DMSO-d6
DMSO-d6
40 6.10 (dd,
J F-H ) 14.7)
5.04 (dt,
J F-H ) 52.6)
4.23 (dt,
J F-H ) 19.9)
11.70 (s, NH), 7.97 (s, H-6), 7.26 (d, Ha,
J ) 13.6), 6.88 (d, Hb, J ) 13.6), 5.86 (d,
3′-OH), 5.12 (t, 5′-OH)
Atlantic Microlab, Inc., Norcross, GA, or Galbraith Laborato-
ries, Inc., Knoxville, TN. Dry 1,2-dichloroethane (DCE) and
acetonitrile were obtained by distillation from CaH.
1,2-O-Isop r op ylid en e-r-L-xylofu r a n ose (2). Compound
2 was prepared from L-xylose in 96% yield by the method
reported for the synthesis of the D-isomer:22 1H NMR (CDCl3)
δ 5.98 (d, J ) 3.8 Hz, 1H, H-1), 4.52 (d, J ) 3.6 Hz, 1H, H-2),
4.31 (br d, 1H, H-3), 4.08 (m, 3H, H-4 and H-5), 1.32 and 1.25
(2s, 6H, 2 CH3).
5-O-Ben zoyl-1,2-O-isopr opyliden e-r-L-xylofu r an ose (3).
To a stirred solution of 2 (91.5 g, 482 mmol) in pyridine (80
mL) and CH2Cl2 (400 mL) at 0 °C was added dropwise BzCl
(56 mL, 482 mmol). The mixture was stirred at 0 °C for 1 h
and washed successively with dilute HCl and saturated
NaHCO3 and dried (MgSO4). Evaporation of solvent and
recrystallization from Et2O gave 3 as a white solid (116 g,
82%): 1H NMR (CDCl3) δ 7.43, 8.07 (m, 5H, Ar-H), 5.97 (d,
1H, J ) 3.6 Hz, H-1), 4.80 (q, 1H, H-4), 4.60 (d, 1H, J ) 3.6
Hz, H-2), 4.40, 4.20 (m, 3H, H-5, H-5′, H-3), 3.50 (br s, 1H,
D2O exchangeable, 3-OH), 1.51 and 1.32 (2s, 6H, 2 CH3).
5-O-Ben zoyl-1,2-O-isop r op ylid en e-r-L-er yth r o-p en t o-
fu r a n os-3-u lose (4). To a stirred solution of 3 (40.0 g, 136
mmol) in CH2Cl2 (450 mL) were added pyridinium dichromate
(PDC, 30.7 g, 81.6 mmol) and Ac2O (42.3 mL, 449 mmol), and
the mixture was refluxed for 1.5 h. The solvent was evapo-
rated, and EtOAc (50 mL) was added. The mixture was
applied to a silica gel pad (10 cm × 5 cm) and eluted with
EtOAc. The combined eluant was concentrated and coevapo-
rated with toluene (2 × 50 mL). The residue was recrystallized
from hexanes-EtOAc to give 4 as a white solid (38.0 g, 96%):
1
IR (KBr) 1773, 1730 cm-1; H NMR (CDCl3) δ 7.97, 7.42 (m,
5H, Ar-H), 6.14 (d, 1H, J ) 4.4 Hz, H-1), 4.74, 4.68 (m, 2H,
H-4, H-2), 4.50, 4.44 (m, 2H, H-5, H-5′), 1.52 and 1.44 (2s, 6H,
2 CH3).
1,2-O-Isopr opyliden e-r-L-r ibofu r an ose (5a). To a stirred
mixture of 4 (37.0 g, 127 mmol) in EtOH-H2O (400:100 mL)
at 0 °C was added NaBH4 (23.3 g, 612 mmol) portionwise, and
the suspension was stirred at room temperature for 4 h. It
was filtered, and the filtrate was evaporated to dryness and
coevaporated with methanol. After silica gel column chroma-

2840 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Ma et al.
Ta ble 3. Median Effective (EC50) and Inhibitory (IC50) Concentration of 2′-Fluoro-â-L-arabinofuranosyl Pyrimidine Nucleosides in
2.2.15 Cells and Cytotoxicity in CEM Cells
IC50 (µM)
EC50 (µM) anti-HBV
activity in 2.2.15 cells
selectivity
2.2.15-HBV
no.
base
2.2.15
CEM
13
15
17
19
21
23
25
27
29
31
33
35
37
40
5-methyluracil (T)
5-ethyluracil
5-fluorouracil
5-chlorouracil
5-bromouracil
5-iodouracil
5-(trifluoromethyl)uracil
cytosine
5-fluorocytosine
5-chlorocytosine
5-bromocytosine
5-iodocytosine
5-ethynyluracil
5(E)-(bromovinyl)uracil
0.1
>10
>10
>10
>10
>10
>10
1.4
>10
>10
>10
5
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
NDa
ND
ND
ND
ND
ND
>100
ND
ND
ND
ND
ND
>2000
>140
>40
>10
>10
>100
a
ND: not determined.
tography (0-15% CH3OH-CH2Cl2) and recrystallization from
EtOAc-hexanes, 5a was obtained as white needles (19.0 g,
(s, 1H, H-1), 5.84 (m, 2H, H-2 and H-3), 4.65 (m, 3H, H-4 and
H-5), 2.00 (s, 3H, CH3COO).
1
79%): IR (KBr) 3356 cm-1; H NMR (CDCl3) δ 5.83 (d, 1H, J
1,3,5-Tr i-O-ben zoyl-r-L-r ibofu r a n ose (8). HCl(g) was
bubbled through a solution of 7 (23.9 g, 47.4 mmol) in
anhydrous CH2Cl2 (220 mL) and AcCl (3.6 mL) at 0 °C for 1.5
h. The resulting solution was kept in a refrigerator for 12 h
and then evaporated in vacuo, and the residue was coevapo-
rated with toluene (3 × 70 mL) and redissolved in CH3CN (50
mL). To this stirred solution was added dropwise water (6
mL). The white precipitate obtained was dissolved in CHCl3,
washed with saturated NaHCO3, and dried (MgSO4). Removal
of solvent and coevaporation with Et2O gave a white solid (15.5
g, 71.0%): 1H NMR (CDCl3) δ 7.31, 8.19 (m, 15H, Ar-H), 6.69
(d, J ) 4.6 Hz, H-1), 5.59 (dd, J ) 6.7, 1.8 Hz, 1H, H-3), 4.64,
4.80 (m, 4H, H-2, H-4 and H-5), 2.30 (br s, D2O exchangeable,
OH).
1,3,5-Tr i-O-ben zoyl-2-O-(im id a zolylsu lfon yl)-r-L-r ibo-
fu r a n ose (9). To a stirred solution of 8 (15.0 g, 32.4 mmol)
in anhydrous CH2Cl2 (150 mL) and DMF (40 mL) at -40 °C
was added sulfuryl chloride (10.6 mL, 91.0 mmol) through a
syringe. The resulting solution was stirred at -40 °C for 30
min and then gradually warmed up to room temperature. After
3 h, imidazole (32.0 g, 469 mmol) was added at 0 °C, and the
mixture was stirred at room temperature for 15 h. The hazy
solution was diluted with CH2Cl2 (300 mL) and washed with
ice-water (400 mL), and the aqueous layer was extracted
again with CH2Cl2 (3 × 75 mL). The combined organic layer
was dried (MgSO4). Removal of solvent and purification by
silica gel column chromatography (5:1-1:1 hexanes-EtOAc)
gave 9 as a white solid (14.0 g, 73.0%): 1H NMR (CDCl3) δ
7.00, 8.10 (m, 18H, Ar-H), 6.72 (d, J ) 4.4 Hz, 1H, H-1), 5.60
(dd, J ) 6.5, 2.9 Hz, 1H, H-3), 5.26 (dd, J ) 4.5, 6.2 Hz, 1H,
H-2), 4.58, 4.80 (m, 3H, H-4 and H-5).
) 4.0 Hz, H-1), 4.60 (t, 1H, H-2), 4.06, 3.72 (m, 4H, H-3, H-4,
H-5, H-5′), 2.38 (d, 1H, D2O exchangeable, 3-OH), 1.83 (t, 1H,
D2O exchangeable, 5-OH), 1.58 and 1.38 (2s, 6H, 2 CH3).
5-O-Ben zoyl-1,2-O-isopr opyliden e-r-L-r ibofu r an ose (5b).
To a stirred solution of 4 (14.0 g, 48 mmol) in anhydrous EtOH
(60 mL) and EtOAc (30 mL) at 0 °C was added portionwise
NaBH4 (2.2 g, 57 mmol). The mixture was stirred at 0 °C for
1 h and then neutralized with dilute AcOH. Solvent was
evaporated, and the residue was redissolved with CH2Cl2,
washed with water, and dried (MgSO4). Removal of solvent
and recrystalliztion from EtOAc-hexanes gave 5b as a white
solid (13.8 g, 96.5%): 1H NMR (CDCl3) δ 7.40, 8.04 (m, 5H,
Ar), 5.86 (d, 1H, J ) 5.0 Hz, H-1), 4.72 (m, 3H, H-4, H-5), 4.10
(m, 1H, H-2), 4.40 (br s, 1H, D2O exchangeable, 3-OH), 3.95
(dd, J ) 4.1, 8.3 Hz, 1H, H-3), 1.60 and 1.38 (2s, 6H, 2 CH3).
3,5-Di-O-Ben zoyl-1,2-O-isop r op ylid en e-r-L-r ib ofu r a -
n ose (6). To a stirred solution of 5a (19.0 g, 100 mmol) in
pyridine (300 mL) at 0 °C was added dropwise BzCl (40 mL,
348 mmol), and the mixture was stirred at room temperature
for 3 h. The solvent was evaporated and the residue was
extracted with EtOAc, washed with saturated NaHCO3, and
dried (Na2SO4). Removal of solvent and recrystallization of
the residue from ether gave 7 as a white solid (39.0 g, 98%):
1H NMR (CDCl3) δ 8.07, 7.36 (m, 10H, Ar-H), 5.94 (d, 1H, J )
3.6 Hz, H-1), 5.05, 5.00 (m, 1H, H-2), 4.73, 4.63 (m, 3H, H-4,
H-5, H-5′), 1.58 and 1.35 (2s, 6H, 2 CH3).
1-O-Acet yl-2,3,5-t r i-O-b en zoyl-â-L-r ib ofu r a n ose
(7).
Meth od A. Compound 7 was prepared from L-ribose in 54%
total yield according to a procedure for the synthesis of the
D-isomer.39
1,3,5-Tr i-O-ben zoyl-2-d eoxy-2-flu or o-r-L-a r a bin ofu r a -
n ose (10). A suspension of 9 (14.0 g, 23.6 mmol) and KHF2
(7.4 g, 94.4 mmol) in 2,3-butanediol (120 mL) was stirred under
N2 at 160 °C. To this was added HF-H2O (48%, 3.4 mL, 94.4
mmol), and the mixture was stirred at 160 °C for 1 h. It was
quenched by brine-ice and then extracted with CH2Cl2 (4 ×
50 mL). The combined extract was washed successively with
brine, water, and saturated NaHCO3 and dried (MgSO4 and
activated charcoal). It was applied on a silica gel pad (5 cm ×
5 cm), eluted with CH2Cl2 to give a syrup which was recrystal-
lized from 95% EtOH to give 10 (7.1 g, 65%): 1H NMR (CDCl3)
δ 7.38, 8.11 (m, 15H, Ar-H), 6.76 (d, J ) 9.2 Hz, 1H, H-1),
5.39 (d, J F-H ) 48.3 Hz, 1H, H-2), 5.63 (dd, J ) 2.9, 16.6 Hz,
1H, H-3), 4.65, 4.81 (m, 3H, H-4 and H-5).
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)th ym in e (12). Gen er a l P r oced u r e for Cou p lin g.
To a solution of 10 (2.78 g, 6.0 mmol) in anhydrous CH2Cl2
(20 mL) was added HBr-AcOH (45% v/v, 4.6 mL, 25 mmol),
and the solution was stirred at room temperature for 20 h.
The mixture was evaporated to dryness, dissolved in CH2Cl2
(50 mL), and washed with saturated NaHCO3 (3 × 30 mL).
Removal of solvent gave 11 as a syrup (2.55 g, 100%) that was
Meth od B. A suspension of 6 (38.0 g, 95 mmol) in 1% HCl/
CH3OH (300 mL) was stirred at room temperature until a clear
solution was obtained (30 h). Pyridine (20 mL) was added and
then evaporated to dryness. The residue was coevaporated
with pyridine (2 × 30 mL) and then redissolved in 100 mL of
anhydrous pyridine at 0 °C. To this solution was added
dropwise BzCl (17.0 mL, 146 mmol), and the mixture was
stirred at room temperature for 3 h. It was evaporated to
dryness and then extracted with EtOAc. The combined
extracts were washed successively with dilute HCl solution
and saturated NaHCO3 and dried (Na2SO4). Removal of the
solvent gave a syrup that was stirred in a mixture of glacial
acetic acid (400 mL) and Ac2O (100 mL) at 0 °C. To this
solution was added dropwise concentrated H2SO4 (10 mL), and
then the mixture was stirred at room temperature overnight.
The mixture was poured into ice-water and extracted with
CHCl3 (4 × 100 mL). The combined extract was washed with
saturated NaHCO3 and dried (Na2SO4). Removal of solvent
and recrystallization of the residue from methanol gave 7 as
a white solid (23.9 g, 49.6%): mp 124-125 °C (lit.18 mp 129-
130 °C); [R]D -45.6 (c 1.0, CHCl3) [lit.18 [R]D -43.6 (c 1.0,
1
CHCl3)]; H NMR (CDCl3) δ 7.32, 8.13 (m, 15H, Ar-H), 6.44

â-L-Pyrimidine Nucleosides as Anti-HBV Agents
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14 2841
used without further purification. At the same time, thymine
(1.9 g, 15 mmol) and (NH4)2SO4 (0.1 g) were stirred in refluxing
HMDS (30 mL) under nitrogen for 17 h, and the homogeneous
solution obtained was evaporated under vacuum to give the
silylated thymine.
A solution of 11 in dichloroethane (DCE, 25 mL) was added
to the silylated thymine, and the mixture was refluxed under
N2 for 15 h. It was quenched with ice-water, extracted with
CH2Cl2 (3 × 45 mL), washed with saturated NaHCO3 (3 × 50
mL) and brine, and dried (MgSO4). Removal of solvent gave
a white solid which was purified on silica gel column (1%
MeOH-CHCl3) to give 12 (2.0 g, 71%): UV (MeOH) λmax 264.0
nm.
1-(2-Deoxy-2-flu or o-â-L-a r a bin ofu r a n osyl)th ym in e (13,
L-F MAU). A solution of 12 (1.70 g, 3.60 mmol) in saturated
NH3-CH3OH (30 mL) was stirred at room temperature for
15 h and then evaporated to dryness. The residue was purified
by silica gel column chromatography (15:1 CHCl3-CH3OH) to
give 13 (0.75 g, 80%): UV(H2O) λmax 265.0 (ꢀ 9695) (pH 2),
265.5 (ꢀ 9647) (pH 7), 265.5 nm (ꢀ 7153) (pH 11).
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-eth ylu r a cil (14). A mixture of 11 (prepared from
10, 0.50 g, 1.1 mmol) and silylated 5-ethyluracil (0.75 g, 5.4
mmol) in DCE (10 mL) was refluxed for 20 h under N2. After
workup and silica gel column chromatography (0-1% CH3-
OH-CHCl3), 14 was obtained as a white solid (0.557g,
100%): UV(CH3OH) λmax 263.5 nm.
1-(2-De oxy-2-flu or o-â-L -a r a b in ofu r a n osyl)-5-e t h yl-
u r a cil (15). Compound 14 (0.50 g, 1.0 mmol) was treated with
saturated NH3-CH3OH (50 mL) as described for 12. After
silica gel column chromatography (0-5% CH3OH-CHCl3), 15
was obtained as a white solid (0.240 g, 84%): UV(H2O) λmax
265.0 (ꢀ 8350) (pH 2), 265.5 (ꢀ 8600) (pH 7), 265.5nm (ꢀ 10 100)
(pH 11).
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-flu or ou r a cil (16). A mixture of 11 (prepared from
10, 0.460 g, 1.0 mmol) and silylated 5-fluorouracil (0.330 g,
5.4 mmol) in DCE (15 mL) was refluxed for 48 h under N2.
After workup and silica gel column chromatography (50:1
CHCl3-CH3OH), 16 was obtained as a white solid (0.400 g,
85%): UV(EtOH) λmax 266.5 nm.
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-iod ou r a cil (22). A mixture of 11 (prepared from
10, 0.390 g, 0.85 mmol) and silylated 5-iodouracil (0.400 g, 1.7
mmol) in DCE (10 mL) was refluxed for 36 h under N2. After
workup, a yellow solid (0.350 g, 71%) was obtained which was
recrystallized from 2-propanol to give 22 as a white solid (0.270
g, 55%): UV (methanol) λmax 276.0 nm.
1-(2-D e o x y -2-flu o r o -â-L -a r a b in o fu r a n o s y l)-5-io d o -
u r a cil (23). Compound 22 (0.210 g, 0.36 mmol) was treated
with saturated NH3-MeOH as described for 12. After puri-
fication by preparative TLC (15:1 CHCl3-MeOH), 23 was
obtained as a white solid (0.120 g, 89%): UV(H2O) λmax 285.5
(ꢀ 7643) (pH 2), 291.5 (ꢀ 8261) (pH 7), 277.0 nm (ꢀ 5512) (pH
11).
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-(tr iflu or om eth yl)u r a cil (24). A mixture of 11
(prepared from 10, 0.460 g, 1.0 mmol) and silylated 5-(trifluo-
romethyl)uracil (0.360 g, 2.0 mmol) in DCE (15 mL) was
refluxed for 20 h under N2. After workup and silica gel column
chromatography (50:1 CHCl3-CH3OH), 24 was obtained as a
white solid (0.254 g, 49%): UV (EtOH) 255.5 nm.
1-(2-Deoxy-2-flu or o-â-L-a r a b in ofu r a n osyl)-5-(t r iflu o-
r om eth yl)u r a cil (25). Compound 24 (0.210 g, 0.4 mmol) was
treated with saturated NH3-CH3OH as described for 12. After
purification by preparative TLC (15:1 CHCl3-CH3OH), 25 was
obtained as a white powder (0.083 g, 66%): UV(H2O) λmax 260.0
(ꢀ 11 630) (pH 2), 260.0 (ꢀ 10 244) (pH 7), 258.5 nm (ꢀ 7953)
(pH 11).
N4-Ben zoyl-1-(3,5-d i-O-b en zoyl-2-d eoxy-2-flu or o-â-L-
a r a bin ofu r a n osyl)cytosin e (26). A mixture of 11 (prepared
from 10, 0.460 g, 1.0 mmol) and silylated N4-benzoylcytosine
(0.540 g, 2.5 mmol) in CH3CN (10 mL) was refluxed for 12 h
under N2. After workup and purification by preparative TLC
(100:1 CHCl3-CH3OH), 26 was obtained (0.160 g, 29%): UV
(EtOH) λmax 261.5, 302.0 nm.
1-(2-d eoxy-2-flu or o-â-L-a r a bin ofu r a n osyl)cytosin e (27).
Compound 26 (0.150 g, 0.27 mmol) was treated with saturated
NH3/MeOH as described for 12. After purification by prepara-
tive TLC (9:1 CHCl3-CH3OH), 27 was obtained as a white
powder (0.060 g, 91%): UV(H2O) λmax 277.0 (ꢀ 12 338) (pH 2),
269.5 (ꢀ 7900) (pH 7), 270.0 nm (ꢀ 9185) (pH 11).
1-(2-De oxy-2-flu or o-â-L-a r a b in ofu r a n osyl)-5-flu or o-
u r a cil (17). Compound 16 (0.330 g, 0.7 mmol) was treated
with saturated NH3-CH3OH (50 mL) as described for 12. After
silica gel column chromatography (15:1-10:1 CHCl3-CH3OH),
17 was obtained as a white solid (0.130 g, 71%): UV(H2O) λmax
266.5 (ꢀ 10 497) (pH 2), 267.5 (ꢀ 9874) (pH 7), 266.5 nm (ꢀ 8702)
(pH 11).
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-flu or ocytosin e (28). A mixture of 11 (prepared
from 10, 0.460 g, 1.0 mmol) and silylated 5-fluorocytosine
(0.320 g, 2.5 mmol) in DCE (20 mL) was refluxed for 24 h
under N2. After silica gel column chromatography (20:1
CHCl3-CH3OH), 28 was obtained as a white foam (0.180 g,
38.5%): UV(EtOH) λmax 277.0 nm.
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-ch lor ou r a cil (18). A mixture of 11 (prepared from
10, 0.370 g, 0.8 mmol) and silylated 5-chlorouracil (0.293 g,
2.0 mmol) in DCE (15 mL) was refluxed for 24 h under N2.
After workup and silica gel column chromatography (50:1
CHCl3-CH3OH), 18 was obtained as a white solid (0.200 g,
51%): UV(MeOH) λmax 273.5 nm.
1-(2-Deoxy-2-flu or o-â-L-a r a b in ofu r a n osyl)-5-ch lor o-
u r a cil (19). Compound 18 (0.100 g, 0.2 mmol) was treated
with saturated NH3-CH3OH as described for 12. After
purification by preparative TLC (9:1 CHCl3-CH3OH) and
recrystallization in EtOH, 19 was obtained as a white solid
(0.046 g, 80%): UV(H2O) λmax 274.0 (ꢀ 9544) (pH 2), 275.5 (ꢀ
9620) (pH 7), 274.0 nm (ꢀ 7690) (pH 11).
1-(2-Deoxy-2-flu or o-â-L-a r a bin ofu r a n osyl)-5-flu or ocy-
tosin e (29). Compound 28 (0.140 g, 0.3 mmol) was treated
with saturated NH3-CH3OH as described for 12. After
trituration in acetone followed by recrystallization from EtOH,
29 was obtained as a white solid (0.078 g, 100%): UV(H2O)
λ
max 284.0 (ꢀ 11 145) (pH 2), 279.5 (ꢀ 8138) (pH 7), 279.0 nm (ꢀ
9000) (pH 11).
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-ch lor ocytosin e (30). A mixture of 11 (prepared
from 10, 0.460 g, 1.0 mmol) and silylated 5-chlorocytosine
(0.440 g, 3.0 mmol) in DCE (30 mL) was refluxed for 24 h
under N2. After silica gel column chromatography (20:1
CHCl3-CH3OH), 30 was obtained as a white foam (0.385 g,
80%): UV (EtOH) λmax 282.5 nm.
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-br om ou r a cil (20). A mixture of 11 (prepared from
10, 0.370 g, 0.8 mmol) and silylated 5-bromouracil (0.380 g,
2.0 mmol) in DCE (15 mL) was refluxed for 48 h under N2.
After workup and recrystallization from CHCl3-CH3OH, 20
was obtained as a white crystal (0.220 g, 52%): UV(MeOH)
λmax 274.5 nm.
1-(2-Deoxy-2-flu or o-â-L-a r a b in ofu r a n osyl)-5-b r om o-
u r a cil (21). Compound 20 (0.187 g, 0.35 mmol) was treated
with saturated NH3-CH3OH as described for 12. After
purification by preparative TLC (10:1 CHCl3-CH3OH), 21 was
obtained as a white solid (0.087 g, 76%): UV (H2O) λmax 277.5
(ꢀ 6549) (pH 2), 277.0 (ꢀ 5826) (pH 7), 275.5 nm (ꢀ 4880) (pH
11).
1-(2-Deoxy-2-flu or o-â-L-a r a bin ofu r a n osyl)-5-ch lor ocy-
tosin e (31). Compound 30 (0.315 g, 0.65 mmol) was treated
with saturated NH3-CH3OH as described for 12. After
trituration in acetone followed by recrystallization from EtOH,
31 was obtained as a white powder (0.106 g, 59%): UV(H2O)
λmax 291.0 (ꢀ 11 226) (pH 2), λmax 285.0 (ꢀ 8813) (pH 7), 284.5
nm (ꢀ 9859) (pH 11).
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-br om ocytosin e (32). A mixture of 11 (prepared
from 10, 0.460 g, 1.0 mmol) and silylated 5-bromocytosine
(0.475 g, 2.5 mmol) in DCE (30 mL) was refluxed for 24 h
under N2. After silica gel column chromatography (20:1
CHCl3-CH3OH), 32 was obtained as a white foam (0.350 g,
66%): UV (EtOH) λmax 285.0 nm.

2842 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 14
Ma et al.
1-(2-Deoxy-2-flu or o-â-L-a r a bin ofu r a n osyl)-5-br om ocy-
tosin e (33). Compound 32 (0.290 g, 0.55 mmol) was treated
with saturated NH3-CH3OH as described for 12. After
trituration in acetone followed by recrystallization from EtOH,
33 was obtained as a white solid (0.088 g, 50%): UV(H2O) λmax
294.0 (ꢀ 9284) (pH 2), 286.5 (ꢀ 6757) (pH 7), 286.5 nm (ꢀ 7721)
(pH 11).
(dt, J F-H ) 19.6Hz, 1H, H-3′), 3.81 (m, 1H, H-4′), 3.65 (dm,
2H, H-5′a,b). Anal. (C12H13FN2O7‚1.6H2O) C, H, N.
(E)-(2-Deoxy-2-flu or o-â-L-a r a b in ofu r a n osyl)-5-(2-b r o-
m ovin yl)u r a cil (40). A suspension of 39 (0.080 g, 0.25 mmol)
and KHCO3 (0.100 g, 1.0 mmol) in DMF (1.5 mL) was stirred
at room temperature for 20 min. To this was added N-
bromosuccinimide (0.053 g, 0.3 mmol) in DMF (1.0 mL). The
mixture was stirred at room temperature for 1.5 h, filtered,
and washed with methanol. The filtrate was evaporated to
dryness and purified on PTLC (6:1 CHCl3-CH3OH). After
coevaporation with ether, 40 was obtained as a white foam
(0.047 g, 53%): UV(H2O) λmax 250.0 (ꢀ 15 844) (pH 2), 250.0 (ꢀ
14 622) (pH 7), 254.0 nm (ꢀ 15 912) (pH 11).
N4-Ben zoyl-1-(3,5-d i-O-b en zoyl-2-d eoxy-2-flu or o-â-L-
a r a bin ofu r a n osyl)-5-iod ocytosin e (34). A mixture of 11
(prepared from 10, 0.150 g, 0.32 mmol) and silylated N4-
benzoyl-5-iodocytosine (0.550 g, 1.6 mmol) in DCE (10 mL) was
refluxed for 24 h under N2. After workup and silica gel column
chromatography (0-1% CH3OH-CHCl3), 34 was obtained as
a white solid (0.100 g, 45%): UV (CH3OH) λmax 345.0, 316.0
nm.
1-(2-Deoxy-2-flu or o-â-L-a r a b in ofu r a n osyl)-5-iod ocy-
tosin e (35). Compound 34 (0.100g, 0.27 mmol) was treated
with saturated NH3-MeOH as described for 12. After silica
gel column chromatography (0-10% CH3OH-CHCl3), 35 was
obtained as a white solid (0.035 g, 71%): UV(H2O) λmax 306.0
(ꢀ 8300) (pH 2), 292.0 (ꢀ 5710) (pH 7), 292.0 nm (ꢀ 5400) (pH
11).
1-(3,5-Di-O-ben zoyl-2-d eoxy-2-flu or o-â-L-a r a bin ofu r a -
n osyl)-5-[2-(tr im eth ylsilyl)a cetylen yl]u r a cil (36). Argon
was purged through Et3N (60 mL) for 0.5 h. To this was added
22 (0.580 g, 1.0 mmol), followed by (trimethylsilyl)acetylene
(0.283 mL, 2.0 mmol), CuI (30 mg), and (Ph3P)2PdCl2 (30 mg).
The mixture was stirred at 50-60 °C for 4.5 h and then
evaporated to dryness. The residue was dissolved in CHCl3
(100 mL), washed with 5% EDTA solution (3 × 50 mL) and
saturated NaHCO3, and dried (MgSO4). Afetr removal of the
solvent, followed by purification on a silica gel column (50:1
CHCl3-CH3OH) and recrystallization from CHCl3-CH3OH,
36 was obtained as a white powder (0.400 g, 73%): UV (EtOH)
λmax 241.0, 284.5 nm.
Ack n ow led gm en t. This research was supported by
Grant AI 33655 from the National Institutes of Health.
We would like to thank Mr. Doo Won Lee for his skillful
assistance in performing X-ray crystallography.
Su p p or tin g In for m a tion Ava ila ble: X-ray data for L-
FMAU (35 pages). Ordering information is given on any
current masthead page.
Refer en ces
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1-(2-Deoxy-2-flu or o-â-L-a r a b in ofu r a n osyl)-5-et h yn yl-
u r a cil (37). Compound 36 (0.350 g, 0.64 mmol) was stirred
in 0.2 N NaOCH3-CH3OH (15 mL) at room temperature for 4
h. It was neutralized with Dowex 50W×8 (H+) resin, then
filtered, and washed with methanol. The combined filtrate
was evaporated to dryness. Column separation (9:1 CHCl3-
CH3OH) and recrystallization from EtOH-hexanes gave 37
as a white solid (0.140 g, 82%): UV(H2O) λmax 284.5 (ꢀ 8932)
(pH 2), 284.5 (ꢀ 10 383) (pH 7), 281.5 nm (ꢀ 9556) (pH 11).
(E)-(2-Deoxy-2-flu or o-â-L-ar abin ofu r an osyl)-5-[2-(m eth -
oxyca r bon yl)vin yl]u r a cil (38). A mixture of Ph3P (0.040
g, 0.15 mmol), Pd(OAc)2 (0.020 g, 0.08 mmol), and Et3N (0.4
mL, 2.8 mmol) in 1,4-dioxane (15 mL) was refluxed to form a
dark-red solution and then cooled to just below reflux. To this
was added methyl acrylate (0.36 mL, 4.0 mmol), followed by
23 (0.300 g, 0.8 mmol) with dioxane (10 mL) and Et3N (0.15
mL). The mixture was refluxed for 0.5 h, filtered through a
Celite pad, and washed with dioxane. The combined filtrate
was evaporated to dryness and purified on a silica gel column
(9:1 CHCl3-CH3OH) to give 38 as a white foam (0.145 g,
54%): UV(MeOH) λmax 299.0 nm; 1H NMR (DMSO-d6) δ 11.79
(s, 1H, D2O exchangeable, CONH), 8.35 (s, 1H, H-6), 7.41 (d,
1H, J ) 15.9 Hz, Ha), 6.90 (d, 1H, J ) 15.8 Hz, Hb), 6.14 (dd,
J F-H ) 14.2 Hz, H-1′), 5.81 (d, 1H, D2O exchange 3′-OH), 5.25
(t, 1H, D2O exchangeable, 5′-OH), 5.10 (dt, J F-H ) 52.6 Hz,
1H, H-2′), 4.26 (dt, J F-H ) 19.8 Hz, 1H, H-3′), 3.84 (m, 1H,
H-4′), 3.69 (dm, 2H, H-5′a,b). Anal. (C12H15F N2O7‚0.8H2O)
C, H, N.
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M.; Peck, A.; Sommadossi, J .-P.; St Clair, M.; Wilson, J .; Furman,
P. A.; Painter, G.; Choi, W.-B.; Liotta, D. C. Selective inhibition
of human immunodeficiency viruses by racemates and enati-
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(shoulder); 1H NMR (DMSO-d6) δ 11.80 (s, 1H, D2O exchange-
able, CONH), 8.28 (s, 1H, H-6), 7.31 (d, 1H, J ) 15.8 Hz, Ha),
6.79 (d, 1H, J ) 15.9 Hz, Hb), 6.12 (dd, J F-H ) 14.0 Hz, H-1′),
5.90 (d, 1H, D2O exchangeable 3′-OH), 5.23 (t, 1H, D2O
exchangeable, 5′-OH), 5.08 (dt, J F-H ) 52.7 Hz, 1H, H-2′), 4.27
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â-L-Pyrimidine Nucleosides as Anti-HBV Agents
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