Synthesis of 2',3'-dideoxy-3'-fluoro-L-ribonucleosides as potential antiviral agents from D-sorbitol

Article abstract of DOI:10.1016/S0008-6215(99)00312-2

2',3'-Dideoxy-3'-fluoro-L-ribonucleosides were synthesized as potential antiviral agents. The key intermediate, methyl 5-O-benzoyl-2-3-dideoxy-3-fluoro-L-ribofuranoside, which was prepared from D-sorbitol, was condensed with pyrimidine and purine bases to obtain the respective nucleosides. Among them, the cytosine analogue 2',3'-dideoxy-3'-fluoro-α-L-cytidine showed a moderate anti-HBV activity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0008-6215(99)00312-2

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Carbohydrate Research 328 (2000) 49–59
Synthesis of 2%,3%-dideoxy-3%-fluoro-
L
-ribonucleosides as
potential antiviral agents from
D-sorbitol
Byoung K. Chun a, Raymond F. Schinazi b, Yung-Chi Cheng c, Chung K. Chu a,*
a Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The Uni6ersity of Georgia, Athens,
GA 30602, USA
b Emory Uni6ersity School of Medicine/Veterans Affairs Medical Center, Decatur, GA 30033, USA
c Yale Uni6ersity School of Medicine, New Ha6en, CT 06510, USA
Received 31 August 1999; accepted 25 October 1999
Abstract
2%,3%-Dideoxy-3%-fluoro-
methyl 5-O-benzoyl-2,3-dideoxy-3-fluoro-
pyrimidine and purine bases to obtain the respective nucleosides. Among them, the cytosine analogue 2%,3%-dideoxy-
3%-fluoro-a- -cytidine showed a moderate anti-HBV activity. © 2000 Elsevier Science Ltd. All rights reserved.
L
-ribonucleosides were synthesized as potential antiviral agents. The key intermediate,
L
-ribofuranoside, which was prepared from -sorbitol, was condensed with
D
L
Keywords:
D
-Sorbitol; 2%,3%-Dideoxy-3%-fluoro-
L
-ribonucleosides; 3%-Deoxy-3%-fluoro-D-thymidine (FLT)
1. Introduction
Recently, a number of nucleosides with the
with their
D
-counterparts. For example,
L
-
FMAU showed greater potency against HBV
and lower toxicity than -FMAU [6].
2%,3%-Dideoxy-3%-fluoro- -ribonucleosides
[7,8] have been known to have potent antiviral
activities. Among them, 3%-deoxy-3%-fluoro-
thymidine (FLT) has been reported to be as
potent as that of AZT against HIV [9]. How-
ever, the use of FLT as an antiviral agent has
been limited due to its severe hematopoietic
toxicities [10]. Thus, we have synthesized the
D
unnatural -configuration have been reported
L
D
as potent chemotherapeutic agents against hu-
man immunodeficiency virus (HIV), hepatitis
B virus (HBV), and cancer. These include
D-
b-
5-cytosine (3TC) [1], b-
1,3-oxathiolan-4-yl)-5-fluorocytosine
-2%,3%-dideoxypentofuranosyl-5-fluoro-
L
-1-(2-hydroxymethyl-1,3-oxathiolan-4-yl)-
-1-(2-hydroxymethyl-
(FTC)
L
[2], b-
cytosine (
dideoxy-b-
L
L
-FddC) [3], 2%,3%-didehydro-2%,3%-
-fluorocytidine (b- -Fd4C) [4],
L-counterparts of the 3%-fluorinated- -nu-
D
L
L
cleosides as potential antiviral agents. Herein
we report the synthesis of 2%,3%-dideoxy-3%-
L
- 1 - (2 - hydroxymethyl - 1,3 - dioxolan - 4 - yl)-
cytosine [
L
-OddC] [5] and 2%-fluoro-5-methyl-
-FMAU) [6]. It
-nucleosides have po-
fluoro- -ribonucleosides and their antiviral
L
b-
L
-arabinofuranosyluracil (
L
activities.
is intriguing that these
L
tent biological activity, while some of them
show lower toxicity profiles in comparison
2. Results and discussion
* Corresponding author. Tel.: +1-706-5425379; fax: +1-
706-5425381.
E-mail address: dchu@rx.uga.edu (C.K. Chu).
In order to synthesize the 2%,3%-dideoxy-3%-
fluoro-
L
-ribonucleosides, we adopted
a
0008-6215/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(99)00312-2

50
B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
method used in the synthesis of AZT and FLT
from -xylose, reported by Fleet et al. and
Gurjar et al. [11]. However, we utilized -sor-
bitol as the starting material instead of expen-
sive -xylose. -Sorbitol was converted into
benzylidene-
14, and the resulting 6-chloropurine nu-
cleoside intermediate was converted into the
adenosine analogue by treatment with
methanol saturated with NH3 in a steel bomb
at 90 °C and was separated to give the b
anomer 5a and a anomer 5b by silica gel
column chromatography. Inosine derivatives
6a and 6b were also obtained from the 6-
chloropurine nucleoside intermediates by
treatment with 2-mercaptoethanol and
NaOCH3 under refluxing conditions and sub-
sequent separation using silica gel column
chromatography. Guanosine analogues 7a and
7b were prepared by the condensation of 14
with silylated 2-amino-6-chloropurine at room
temperature, which gave virtually one re-
gioisomer with a umax at 320 nm. The interme-
diate was refluxed in CH3CN without catalyst
for 17 h to give an N9-regioisomer with a umax
at 309 nm. The isomer was converted by
treatment with 2-mercaptoethanol and
NaOCH3 under refluxing conditions, followed
by silica gel column chromatography to give
guanosine analogues 7a and 7b (Fig. 1).
D
D
L
D
L
-xylose 9 by selective protection,
following oxidative cleavage via intermediate
8 by the known procedure [12]. Intermediate 9
was then readily converted into methyl -xylo-
L
furanoside 10 by using 5% hydrochloric acid
in methanol without significant contamination
of pyranoside in 62% yield from
D
-sorbitol,
which was pure enough to use for the next
reaction without purification. However, in the
original procedure [12], intermediate 9 was
hydrolysed to free
L
-xylose which, according
to our experiences, is not easy to purify. The
selective protection of 10 with acetone and
TsOH gave intermediate 11 with a free 2-hy-
droxy group in 82% yield. The
of this intermediate has frequently been used
for the synthesis of 3%-substituted- -nu-
cleosides such as AZT or FLT [11,13]. Thus
we successfully utilized inexpensive -sorbitol
for the preparation of the desired -xylose
derivative, which, otherwise, should be pre-
D-counterpart
D
D
L
The stereochemical assignment of the final
nucleosides were made on the basis of 1D and
2D NMR spectroscopy. The anomers with
higher field resonance for H-4% were assigned
as the b isomers, and the ones with lower
chemical shifts were assigned as the a isomers
based on the deshielding effect of the hetero-
cycle on the a isomers (Table 1). This assign-
ment was further confirmed by NOESY
spectra of the representative nucleoside inter-
mediates 1a and 1b (Fig. 2). Other characteris-
pared from expensive -xylose. Therefore, this
L
new procedure may provide a great potential
in its utilization for the synthesis of 2%- and/or
3%-modified -nucleosides. Intermediate 11 was
L
converted into 12 by a Barton-type deoxy-
genation, followed by an acidic hydrolysis in
one pot in 61% yield [11]. Intermediate 12 was
selectively protected with BzCl and pyridine in
dichloromethane at −10 °C to give 13 in 73%
yield, which was fluorinated with TBAF via a
triflate intermediate to afford the key interme-
diate 14 in 46% yield. The condensation of 14
with silylated pyrimidine or purine bases, fol-
lowed by deprotection and base modification,
1
tics of the H NMR spectra of the b isomers
include: the splitting pattern of H-1% of all b
isomers of this series shows a double doublet
with relatively large J1%,2% and J1%,2¦ values,
whereas most a isomers show a single doublet
or double doublet with smaller J1%,2% and J1%,2¦
values (Table 1), which is consistent with
if necessary, gave 2%,3%-dideoxy-3%-fluoro- -
L
ribonucleosides in 26–65% overall yields from
14 using Vorbru¨ggen conditions (Scheme 1).
The anomeric separation of thymidine (1a and
1b), cytidine (2a and 2b), and uridine (3a and
3b) analogues was conducted at the depro-
tected stages by silica gel chromatography,
whereas 5-chlorouridine analogues 4a and 4b
were readily separated at the protected stage.
For the preparation of adenosine analogues
5a and 5b, 6-chloropurine was condensed with
those of the reported
The synthesized
D
-analogues [11a,b,14].
L
-ribonucleosides were
evaluated against HIV and HBV. Among
them, the cytosine analogue 2a showed mod-
erate anti-HBV activity (10 mM in 2.2.15 cell
line) with no cytotoxicity up to 100 mM
(Table 2). Interestingly, the 2%,3%-dideoxy-3%-
fluoro-
L
-ribonucleosides were devoid of HIV
-enan-
activity in vitro, in contrast to the
D

B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
51
tiomers, in particular FLT. In addition, the
structure–activity relationship study indicates
and HBV in vitro than 2%,3%-dideoxy-
L
-cytidine
[3b]. The low or lack of antiviral activity of
the synthesized -nucleosides may be due to
that the 3%-fluoro function in the b-
L
-configu-
L
ration seems to have a profound effect on
antiviral activity. For example, the synthesized
their low effectiveness as substrates for the
activating enzymes, the cellular nucleoside or
nucleotide kinases, since the triphosphates of
many inactive nucleosides have been found to
compound, 2%,3%-dideoxy-3%-fluoro-
L
-cytidine
(2a) was much less effective against HIV-1
Scheme 1. Reagents: (a) PhCHO, HCl, H2O. (b) NaIO4, H2O, −7 °C. (c) 5% HCl–MeOH. (d) TsOH, CuSO4, acetone. (e) [i]
NaH, THF. [ii] CS2. [iii] MeI. [iv] Bu3SnH, xylene, reflux. [v] TsOH, MeOH. (f) BzCl, Py, CH2Cl2, −10 °C. (g) [i] Tf2O, Py,
CH2Cl2. [ii] TBAF, THF. (h) Silylated thymine, Me3SiOTf, CH3CN. (i) Silylated N4-benzoylcytosine, Me3SiOTf, CH3CN. (j)
Silylated uracil, Me3SiOTf, CH3CN. (k) Silylated 5-chlorouracil, Me3SiOTf, CH3CN. (l) Silylated 6-chloropurine, Me3SiOTf,
CH3CN. (m) [i] Silylated 2-amino-6-chloropurine, Me3SiOTf, CH3CN. [ii] reflux, CH3CN. (n) NH3–MeOH, 90 °C. (p)
HOCH2CH2SH, NaOCH3, MeOH, reflux.

52
B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
3. Experimental
Melting points (mp) were determined on a
Mel-Temp II apparatus and are uncorrected.
NMR spectra were recorded on a Bruker 400
AMX spectrometer at 400 MHz (1H) and 100
MHz (13C) in the indicated solvents. Optical
rotations were measured on a Jasco DIP-370
digital polarimeter. Mass spectra were re-
corded on a Micromass Autospec high-resolu-
tion mass spectrometer in fast-atom bombard-
ment (FAB) mode. UV spectra were obtained
on a Beckman DU 650 spectrophotometer. El-
emental analyses were performed by Atlantic
Microlab, Inc., and all the elemental analyses
are within 0.4% of the theoretical values.
Fig. 1. 2%,3%-Dideoxy-3%-L-fluororibonucleosides.
Table 1
Some selected H NMR data for the new
1
L
-nucleosides
Compound
H-1% J1%,2% and J1%,2¦ (Hz) H-4% l (ppm)
c
1a
b
2a
b
3a
b
4a
b
5a
b
6a
b
7a
b
5.55, 9.07
7.21
5.63, 8.77
7.18
5.62, 8.00
6.81
4.23
4.66
4.32
4.78
4.16
4.57
4.27
4.69
4.16
4.66
4.41
4.63
4.34
4.57
Methyl h/i-
L-xylofuranoside (10).—To a
solution of -sorbitol (100 g, 0.55 mol) in wa-
D
ter (70 mL), benzylaldehyde (60 mL) and
concd HCl (13 mL) were added at 0 °C. The
resulting mixture was stirred for 6 h at room
temperature (rt), during which a product pre-
cipitated. After dilution with water (50 mL),
the precipitate was filtered and the filter cake
was washed with water (250 mL) and EtOAc
(250 mL). The filter cake was suspended in wa-
ter (1200 mL) containing Na2CO3 (8 g) and
heated at 100 °C for 3 h to remove residual
benzaldehyde. After filtration while hot, the
filtrate was kept at 0 °C for 3 h and the crys-
talline solid thus generated (compound 8, 100
g, 67%) was collected by filtration. Compound
8 (100 g, 0.37 mol) was suspended in water
(400 mL) and cooled to −7 °C. To the
5.60, 8.87
m a
5.61, 9.39
1.31, 7.29
6.24, 8.90
m a
5.77, 9.41
2.21, 6.67
a Multiplet.
be potent inhibitors of the target enzymes such
as HIV reverse transcriptase or HBV DNA
polymerase [15].
Fig. 2. NOE correlations from NOESY spectra of intermediates 1a and 1b.

B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
53
Table 2
Antiviral activities and cytotoxicities of 2%,3%-dideoxy-3%-
L
-fluororibonucleosides
No
X
Y
Antiviral activities EC50 (mM)
Cytotoxicities IC50 (mM)
HBV (2.2.15)
HIV (PBM)
Vero
PBM
CEM
1a
2a
3a
4a
5a
6a
7a
OH
NH2
OH
OH
NH2
OH
OH
CH3
H
H
Cl
H
\10
10.0
\100
\100
\100
\100
\100
\100
\51.3
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\100
\10
\10
\10
\10
\10
H
NH2
without further purification. A small amount
of compound 10 was purified by silica gel
column chromatography (10:1 CHCl3–
MeOH) for characterization: 1H NMR
(DMSO-d6+D2O): l 4.71 and 4.70 (d, s, 1 H,
J1,2 4.09 Hz, H-1, a and b isomer), 4.02–3.93
(m, 2 H, H-2, H-3, a and b isomer), 3.86 and
3.78 (2 m, 1 H, H-4, a and b isomer), 3.61–
3.33 (m, 2 H, H-5, a and b isomer), 3.30 and
3.21 (2 s, 3 H, CH3O-1, a and b isomer);
FABMS m/z 165 (M+H)+. Anal. Calcd for
C6H12O5·0.1 CHCl3: C, 41.61; H, 6.93. Found:
C, 41.23; H, 6.88.
suspension of compound 8, NaIO4 (111 g,
0.52 mol) in water (400 mL) was added over
30 min with vigorous stirring at −7 °C. The
reaction mixture was neutralized with solid
Na2CO3, treated with absolute EtOH (1000
mL), and stirred for 10 min. After removal of
the generated solids by filtration, the filtrate
was evaporated to one-third volume, and the
solid generated during the evaporation was
removed by filtration. The filtrate was concen-
trated to a solid residue, which was dissolved
in absolute EtOH (500 mL) and the insoluble
solid was again removed by filtration. The
filtrate was evaporated to give crude com-
pound 9 as a white solid (82 g, 93%) [12].
Compound 9 was dissolved in 0.5% HCl in
MeOH (2 L). The resulting solution was
stirred at rt for 20 h and neutralized with solid
Na2CO3 (40 g). After concentration, the
residue was obtained was dissolved in water
(700 mL) and washed with ether (2×250
mL). The aqueous layer was evaporated to a
residue, which was dissolved in CH2Cl2 (200
mL), and insoluble salt was removed by filtra-
tion. The filtrate was dried over Na2SO4,
filtered, and concentrated to a syrup as an
Methyl 3,5-di-O-isopropylidene-h-
furanoside (11a) and methyl 3,5-di-O-isopropyl-
idene-i- -xylofuranoside (11b).—Compound
L
-xylo-
L
11 was prepared as a syrup in 82% yield
(a/b=1.5:1 determined by NMR spec-
troscopy) from compound 10 by the method
described by Baker et al. [13]. For characteri-
zation, a small amount of compound 11 was
separated by silica gel column chromatogra-
phy (10:1–5:1 hexanes–EtOAc) to the less
polar compound 11a and the more polar 11b
as syrup: Compound 11a (a isomer): [h]D25
−18.5° (c 3.0, H2O; lit. [h]2D4 +17.6° for
1
anomeric mixture of 10 (56 g, 62% from
D
-
D
-enantiomer at c 2.0 in H2O); H NMR
sorbitol), which was used for next reaction
(CDCl3): l 5.14 (d, 1 H, J1,2 4.06 Hz, H-1),

54
B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
pyridine (6 mL) in CH2Cl2 (100 mL), triflic
anhydride (10 g, 35.44 mmol) was added over
5 min, and the resulting mixture was stirred
for 30 min at −50 °C. The reaction mixture
was diluted with CH2Cl2 (100 mL) and
washed consecutively with cold 2 N HCl (50
mL), satd aq NaHCO3 (70 mL), and brine
(100 mL). After drying over Na2SO4, filtra-
tion, and concentration, the residue was dis-
solved in THF (70 mL) containing TBAF (1
M in THF, 28 mL). The resulting mixture was
stirred for 18 h at rt and concentrated to a
residue, which was purified by silica gel
column chromatography (10:1 hexanes–
EtOAc) to give an anomeric mixture of 14 (2.3
4.20–3.89 (m, 5 H, H-2, H-3, H-4, H-5), 3.55
(s, 3 H, CH3O-1), 1.41 (s, 3 H, CH3ꢀ), 1.35 (s,
3 H, CH3ꢀ); FABMS m/z 205 (M+H)+.
Compound 11b (b isomer): [h]2D5 +68.5° (c
3.0, H2O; lit. [h]2D4−64.2° for
D
-enantiomer at
1
c 2.0 in H2O); H NMR (CDCl3): l 4.87 (s, 1
H, H-1), 4.24 (m, 1 H, H-4), 4.16–4.14 (m, 2
H, H-2, H-3), 3.98 (dd, 1 H, J4,5 4.70, J5,5%
12.07 Hz, H-5), 3.82 (dd, 1 H, J4,5% 5.10, J5,5%
12.07 Hz, H-5), 3.45 (s, 3 H, CH3O-1), 1.40 (s,
3 H, CH3ꢀ), 1.39 (s, 3 H, CH3ꢀ); FABMS m/z
205 (M+H)+.
Methyl 2-deoxy-h/i- -xylofuranoside (12).
L
—Compound 12 was prepared as a syrup
from compound 11 by the method described
1
1
by Fleet et al. [11a,b] in 61% yield: H NMR
g, 46%) as a syrup. For the a isomer: H
(CDCl3): l 5.17 and 5.04 (dd, J1,2 2.78, J1,2%
5.18 Hz, and d, J1,2 4.69 Hz, 1 H, H-1, a and
b isomer), 4.55 and 4.39 (2m, 1 H, H-4, a and
b isomer), 4.14–4.01 (m, 3 H, H-3, H-5, a and
b isomer), 3.40 and 3.39 (2s, 3 H, CH3O-1, a
and b isomer), 2.28–2.08 (m, 2 H, H-2, a and
b isomer); FABMS m/z 149 (M+H)+.
NMR (CDCl3): l 8.00 (d, 2 H, Ar), 7.60–7.44
(m, 3 H, Ar), 5.17 (dd, 1 H, J2,3 5.32, J3,F
56.17 Hz, H-3), 5.18 (d, 1 H, J1,2 3.56 Hz,
H-1), 4.61 (d, 1 H, J4,F 23.63 Hz, H-4), 4.44
(d, 2 H, J5,5% 4.11 Hz, H-5), 3.43 (s, 3 H,
CH3O-1), 2.26–2.20 (m, 2 H, H-2); FABMS
m/z 255 (M+H)+. Anal. Calcd for
C13H15FO4: C, 61.41; H, 5.95. Found: C,
61.49; H, 5.94.
Methyl 5-O-benzoyl-2-deoxy-h/i- -xylo-
L
furanoside (13).—To a solution of compound
12 (8.0 g, 53.96 mmol) and pyridine (9 mL) in
CH2Cl2 (300 mL), BzCl (6.3 mL, 53.96 mmol)
in CH2Cl2 (300 mL) was added over 2 h at
−10 °C, and the resulting mixture was stirred
for an additional hour at −10 °C. The reac-
tion was quenched with water (50 mL),
washed with 0.2 N HCl (70 mL), satd aq
NaHCO3 (70 mL), and brine (100 mL). The
organic layer was dried over Na2SO4, filtered,
and concentrated to a residue, which was
purified by silica gel column chromatography
(CHCl3) to give an anomeric mixture of 13 as
3%-Deoxy-3%-fluoro-i-
L
-thymidine (1a) and
(1b).—A
3%-deoxy-3%-fluoro-h- -thymidine
L
mixture of thymine (726 mg, 5.75 mmol),
(NH4)2SO4 (60 mg), and HMDS (25 mL) was
refluxed at 140 °C for 20 h. After removal of
the solvent under reduced pressure, the result-
ing syrup was dissolved in anhyd CH3CN (25
mL). To the solution of the silylated base in
CH3CN, compound 14 (585 mg, 2.30 mmol),
followed by Me3SiOTf (0.5 mL, 2.59 mmol),
was added at rt. The resulting reaction mix-
ture was stirred for 20 h, neutralized with satd
aq NaHCO3, diluted with EtOAc (100 mL),
washed with water (30 mL), and dried over
Na2SO4. The filtration, followed by concentra-
tion, gave a solid residue, which was dissolved
in MeOH satd with NH3 (30 mL), stirred at rt
for 20 h, and concentrated. The resulting
residue was separated by silica gel column
chromatography (5:1–1:1 hexanes–EtOAc) to
give compound 1a (210 mg, 37%) and com-
pound 1b (158 mg, 28%) as white solids. Com-
pound 1a: mp 180–181 °C; [h]2D5 −2.51° (c
0.51, MeOH; lit. [h]2D0 0.80° in MeOH for the
1
a syrup (10 g, 73%). H NMR (CDCl3): l
8.11–7.35 (m, 5 H, Ar, a and b isomer), 5.20
and 5.08 (dd, J1,2 3.57, J1,2% 5.61 Hz, and d, J1,2
4.23 Hz, 1 H, H-1, a and b isomer), 4.80–4.75
and 4.70–4.51 (2 m, 1 H, H-5, a and b
isomer), 4.47–4.34 (m, 2 H, H-3, H-4, a and b
isomer), 3.41 and 3.39 (2 s, 3 H, CH3O-1, a
and b isomer), 2.28–2.08 (m, 2 H, a and b
isomer); FABMS m/z 253 (M+H)+. Anal.
Calcd for C6H12O4·0.2 H2O: C, 61.02; H, 6.46.
Found: C, 60.97; H, 6.53.
Methyl 5-O-benzoyl-2,3-dideoxy-3-fluoro-
h/i- -ribofuranoside (14) [11].—To a solution
L
D
-enantiomer [11b]), −5.79° (c 0.39, H2O);
of compound 13 (5.0 g, 19.82 mmol) and
UV (H2O) umax 265.5 nm (m 12,120, pH 7),

B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
55
NMR (CD3OD): l 7.74 (d, 1 H, J5,6 7.58 Hz,
H-6), 6.22 (dd, 1 H, J1%,2% 5.63, J1 8.77 Hz,
H-1%), 5.86 (d, 1 H, J5,6 7.51 Hz, H-5), 5.22
(dd, 1 H, J2%,3% 4.65, J3%,F 53.21 Hz, H-3%), 4.32
(dt, 1 H, J4%,5% 4.19, J4%,F 27.21 Hz, H-4%), 3.70
(d, 2 H, J5%,5¦ 4.25 Hz, H-5%), 2.61 (m, 1 H,
H-2%), 2.21 (m, 1 H, H-2¦); 13C NMR
(CD3OD): l 168.9, 158.4, 144.3, 111.5, 98.3
(d, J 173.7 Hz), 88.5, 88.2 (d, J 22.6 Hz), 64.3
(d, J 11.2 Hz), 41.2 (d, J 20.7 Hz); FABMS
m/z 230 (M+H)+; Anal. Calcd for
C9H12FN3O3: C, 47.16; H, 5.28; N, 18.33.
Found: C, 46.95; H, 5.20; N, 18.22. Com-
pound 2b: mp 186–188 °C; [h]2D5 +13.5° (c
0.27, MeOH); UV (H2O) umax 270.5 nm (m
12,010, pH 7), 271.0 nm (m 12,360, pH 11),
277.0 nm (m 18,000, pH 2); 1H NMR
(CD3OD): l 7.70 (d, 1 H, J5,6 7.57 Hz, H-6),
6.17 (d, 1 H, J1%,2% 7.18 Hz, H-1%), 5.96 (d, 1 H,
J5,6 7.51 Hz, H-5), 5.25 (dd, 1 H, J2%,3% 7.18,
J3%,F 53.03 Hz, H-3%), 4.78 (partially obscured
by the solvent peak, H-4%), 3.64 (m, 2 H,
H-5%), 2.65 (m, 1 H, H-2%), 2.42 (dd, 1 H, J2%,2¦
15.93, J2¦,F 23.49 Hz, H-2¦); 13C NMR
(CD3OD): l 168.3, 158.3, 144.3, 111.0, 98.1
(d, J 172.8 Hz), 90.0, 89.9 (d, J 23.5 Hz), 64.5
(d, J 11.2 Hz), 42.1 (d, J 20.1 Hz); FABMS
m/z 230 (M+H)+; Anal. Calcd for
C9H12FN3O3: C, 47.16; H, 5.28; N, 18.33.
Found: C, 46.98; H, 5.25; N, 18.29.
266.0 nm (m 10,020, pH 11), 265.5 nm (m
1
11,390, pH 2); H NMR (CD3OD): l 7.82 (s,
1 H, H-6), 6.30 (dd, 1 H, J1,2% 5.55, J1,2¦ 9.07
Hz, H-1%), 5.26 (dd, 1 H, J2%,3% 4.65, J3%,F 53.94
Hz, H-3%), 4.23 (d, 1 H, J4%,F 27.52 Hz, H-4%),
3.77 (s, 2 H, H-5%), 2.50 (m, 1 H, H-2%), 2.35
(m, 1 H, H-2¦), 1.88 (s, 3 H, CH3-5); 13C
NMR (CD3OD): l 166.4, 152.4, 137.9, 111.9,
95.9 (d, J 175.4 Hz), 86.9 (d, J 23.7 Hz), 86.3,
62.7 (d, J 11.0 Hz), 39.1 (d, J 20.6 Hz), 12.5;
FABMS m/z 245 (M+H)+; Anal. Calcd for
C10H13FN2O4: C, 49.18; H, 5.37; N, 11.47.
Found: C, 49.18; H, 5.29; N, 11.40. Com-
pound 1b: mp 164–165 °C; [h]2D5 −2.17° (c
0.28, H2O); UV (H2O) umax 267.5 nm (m
12,200, pH 7), 268.0 nm (m 10,300, pH 11),
268.0 nm (m 11,400, pH 2); 1H NMR
(CD3OD): l 7.48 (s, 1 H, H-6), 6.30 (d, 1 H,
J1%,2% 7.52 Hz, H-1%), 5.28 (dd, 1 H, J2%,3% 5.23,
J3%,F 54.21 Hz, H-3%), 4.66 (dd, 1 H, J4%,5% 4.05,
J4%,F 24.62 Hz, H-4%), 3.64 (m, 2 H, H-5%), 2.75
(m, 1 H, H-2%), 2.37 (m, 1 H, H-2¦), 1.88 (s, 3
H, CH3-5); 13C NMR (CD3OD): l 166.0,
152.3, 137.5, 111.0, 95.7 (d, J 174.2 Hz), 89.3
(d, J 22.6 Hz), 88.2, 62.9 (d, J 11.3 Hz), 40.4
(d, J 20.1 Hz), 12.5; FABMS m/z 245 (M+
H)+; Anal. Calcd for C10H13FN2O4: C, 49.18;
H, 5.37; N, 11.47. Found: C, 49.01; H, 5.36;
N, 11.37.
2%,3%-Dideoxy-3%-fluoro-i-
L
-cytidine
(2a)
and 2%,3%-dideoxy-3%-fluoro-h-
L
-cytidine (2b).
i-2%,3%-Dideoxy-3%-fluoro-
L
-uridine (3a) and
—The silylated cytosine was prepared from
N4-benzoylcytosine (778 mg, 3.62 mmol), as
previously described, and dissolved in anhyd
CH3CN (20 mL). To the solution of the sily-
lated base in CH3CN, compound 14 (591 mg,
2.32 mmol), followed by Me3SiOTf (0.5 mL,
2.59 mmol), was added at rt and the resulting
mixture was stirred for 12 h and neutralized
with satd aq NaHCO3. After the same work-
up previously described for compound 1, the
obtained residue was dissolved in MeOH satd
with NH3 (30 mL), stirred at rt for 20 h, and
concentrated to a residue, which was sepa-
rated by silica gel column chromatography
(10:1–5:1 CHCl3–MeOH) to give compound
2a (190 mg, 36%) and compound 2b (120 mg,
23%) as white solids. Compound 2a: mp 190–
192 °C; [h]2D5 −44.7° (c 0.30, H2O); UV (H2O)
umax 269.5 nm (m 12,050, pH 7), 270.0 nm (m
h-2%,3%-dideoxy-3%-fluoro- -uridine (3b).—The
L
silylated uracil was prepared from uracil (410
mg, 3.60 mmol), as previously described, and
dissolved in anhyd CH3CN (20 mL). To the
solution of the silylated base in CH3CN, com-
pound 14 (582 mg, 2.29 mmol), followed by
Me3SiOTf (0.5 mL, 2.59 mmol), was added at
rt and the resulting reaction mixture was
stirred for 12 h and neutralized with satd
NaHCO3. After the same work-up previously
described for compound 1, the obtained
residue was dissolved in MeOH satd with NH3
(30 mL), stirred at rt for 20 h, and concen-
trated to a residue, which was separated by
silica gel column chromatography (20:1
CHCl3–MeOH) to give compound 3a (120
mg, 23%) and compound 3b (100 mg, 19%) as
white solids. Compound 3a: mp 190–192 °C;
[h]2D5 −24.8° (c 0.36, H2O); UV (H2O) umax
1
12,370, pH 11), 278.0 nm (m 18,080, pH 2); H

56
B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
satd with NH3 (30 mL), and stirred at rt for
20 h. After concentration, the residues were
purified by silica gel column chromatography
(20:1 CHCl3–MeOH) to give compound 4a
(100 mg, 16%) and compound 4b (101 mg,
16%) as white solids. Compound 4a: mp 186–
188 °C; [h]2D5 −20.0° (c 0.23, H2O); UV (H2O)
umax 275.0 nm (m 8,810, pH 7), 273.5 nm (m
260.5 nm (m 11,950, pH 7), 260.5 nm (m 8,560,
1
pH 11), 260.5 nm (m 12,940, pH 2); H NMR
(DMSO-d6): l 11.36 (s, 1 H, H-3), 7.74 (d, 1
H, J5,6 8.11 Hz, H-6), 6.18 (dd, 1 H, J1%,2% 5.62,
J1%,2¦ 8.00 Hz, H-1%), 5.67 (d, 1 H, J5,6 8.09 Hz,
H-5), 5.26 (dd, 1 H, J2%,3% 4.32, J3%,F 53.91 Hz,
H-3%), 5.20 (t, 1 H, J5%,HO-5% 5.09 Hz, HO-5%),
4.16 (dm, 1 H, J4%,F 27.56 Hz, H-4%), 3.58 (dq,
2 H, J4%,5% 3.46, J4%,5¦ 4.40 Hz, J5%,5¦ 11.90 Hz,
H-5%), 2.44 (m, 1 H, H-2%), 2.25 (m, 1 H, H-2¦);
13C NMR (DMSO-d6): l 166.4, 153.9, 143.7,
105.7, 98.2 (d, J 173.0 Hz), 88.4 (d, J 22.6 Hz),
88.5, 64.5 (d, J 11.0 Hz), 40.7 (d, J 20.4 Hz);
FABMS m/z 231 (M+H)+; Anal. Calcd for
C9H11FN2O4: C, 46.96; H, 4.82; N, 12.17.
Found: C, 47.03; H, 4.88; N, 12.11. Com-
pound 3b: mp 184–186 °C; [h]2D5 +3.71° (c
0.40, H2O); UV (H2O) umax 262.5 nm (m
12,010, pH 7), 262.5 nm (m 12,360, pH 11),
1
6,230, pH 11), 275.5 nm (m 8,910, pH 2); H
NMR (CD3OD): l 8.35 (s, 1 H, H-6), 6.29
(dd, 1 H, J1%,2% 5.60, J1%,2¦ 8.87 Hz, H-1%), 5.26
(dd, 1 H, J2%,3% 4.77, J3%,F 53.78 Hz, H-3%), 4.27
(dm, 1 H, J4%,F 27.23 Hz, H-4%), 3.75 (d, 2 H,
J4%,5% 3.46 Hz, H-5%), 2.56 (m, 1 H, H-2%), 2.28
(dm, 1 H, J2¦,F 39.36 Hz, H-2¦); 13C NMR
(CD3OD): l 162.5, 150.1, 139.2, 111.0, 93.5
(d, J 174.1 Hz), 87.3 (d, J 24.8 Hz), 86.9, 62.5
(d, J 11.5 Hz), 40.7 (d, J 20.5 Hz); FABMS
m/z 265 (M+H)+; Anal. Calcd for
C9H10ClFN2O4: C, 40.85; H, 3.81; N, 10.59.
Found: C, 40.65; H, 3.79; N, 10.51. Com-
pound 4b: mp 174–178 °C; [h]2D5 +14.9° (c
0.38, H2O); umax 275.0 nm (m 8,700, pH 7),
274.0 nm (m 6,080, pH 11), 275.5 nm (m 8,610,
1
262.0 nm (m 12,930, pH 2); H NMR (DMSO-
d6): l 11.32 (s, 1 H, H-3), 7.45 (d, 1 H, J5,6
8.11 Hz, H-6), 6.14 (d, 1 H, J1%,2% 6.81 Hz,
H-1%), 5.64 (d, 1 H, J5,6 8.11 Hz, H-5), 5.30
(dd, 1 H, J2%,3% 4.89, J3%,F 54.16 Hz, H-3%), 5.08
(s, 1 H, HO-5%), 4.57 (dt, 1 H, J4%,5% 4.47, J4%,F
24.48 Hz, H-4%), 3.49 (dd, 1 H, J4%,5% 3.56, J5%,5¦
11.73 Hz, H-5%), 3.40 (dd, 1 H, J4%,5¦ 5.17, J5%,5¦
11.70 Hz, H-5¦), 2.70 (dm, 1 H, J2%,F 42.47 Hz,
H-2%), 2.25 (dd, 1 H, J2%,2¦ 15.79, J2¦,F 24.39 Hz,
H-2¦); 13C NMR (DMSO-d6): l 166.1, 153.7,
143.4, 105.6, 97.9 (d, J 172.6 Hz), 89.6 (d, J
22.2 Hz), 87.6, 64.3 (d, J 10.9 Hz), 40.8 (d, J
20.2 Hz); FABMS m/z 231 (M+H)+; Anal.
Calcd for C9H11FN2O4: C, 46.96; H, 4.82; N,
12.17. Found: C, 46.66; H, 4.87; N, 11.93.
1
pH 2); H NMR (CD3OD): l 8.32 (s, 1 H,
H-6), 6.24 (m, 1 H, H-1%), 5.29 (dd, 1 H, J2%,3%
5.35, J3%,F 54.05 Hz, H-3%), 4.69 (dm, 1 H, J4%,F
27.23 Hz, H-4%), 3.88 (d, 2 H, J4%,5% 3.40 Hz,
H-5%), 2.61 (m, 1 H, H-2%), 2.27 (m, 1 H, H-2¦);
13C NMR (CD3OD): l 163.2, 150.7, 140.0,
111.3, 93.6 (d, J 173.0 Hz), 88.2 (d, J 25.7 Hz),
87.7, 63.2 (d, J 11.0 Hz), 41.2 (d, J 20.9);
FABMS m/z 265 (M+H)+; Anal. Calcd for
C9H10ClFN2O4: C, 40.85; H, 3.81; N, 10.59.
Found: C, 40.74; H, 3.77; N, 10.60.
5-Chloro-2%,3%-dideoxy-3%-fluoro-i-
(4a) and 5-chloro-2%,3%-dideoxy-3%-fluoro-h-
L
-uridine
2%,3%-Dideoxy-3%-fluoro-i-
and 2%,3% - dideoxy - 3% - fluoro - h -
L
-adenosine (5a)
L
-
L
- adenosine
uridine (4b).—The silylated 5-chlorouracil was
prepared from 5-chlorouracil (691 mg, 4.72
mmol), as previously described, and dissolved
in anhyd CH3CN (30 mL). To the solution of
the silylated base in CH3CN, compound 14
(600 mg, 2.36 mmol), followed by Me3SiOTf
(0.5 mL, 2.59 mmol), was added at rt, and the
resulting mixture was stirred for 10 h and
neutralized with satd aq NaHCO3. After the
same work-up previously described for com-
pound 1, the obtained residue was separated
by silica gel chromatography (1:1 cyclohex-
ane–EtOAc) to give b and a isomers. The
separated anomers were dissolved in MeOH
(5b).—The silylated 6-chloropurine was pre-
pared from 6-chloropurine (608 mg, 3.94
mmol), as previously described, and dissolved
in anhyd CH3CN (20 mL). To the solution of
the silylated base in CH3CN, compound 14
(500 mg, 1.97 mmol), followed by Me3SiOTf
(0.46 mL, 2.38 mmol), was added at rt, and
the resulting reaction mixture was stirred for
12 h and neutralized with satd aq NaHCO3.
After the same work-up previously described
for compound 1, the thus obtained residue
was dissolved in MeOH satd with NH3 (30
mL) and heated at 90 °C in a steel bomb for

B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
57
18 h. After concentration, the resulting residue
was separated by silica gel column chromatog-
raphy (30:1 CHCl3–MeOH) to give com-
pound 5a (80 mg, 16%) and compound 5b (75
mg, 15%) as white solids. Compound 5a: mp
196–198 °C; [h]2D5 +32.3° (c 0.47, H2O); UV
(H2O) umax 259.0 nm (m 16,370, pH 7), 259.0
nm (m 16,180, pH 11), 257.0 nm (m 15,930, pH
refluxed for 6 h, neutralized with 0.1 N HCl,
and filtered. The filtrate was concentrated to a
residue, which was separated by silica gel
column chromatography (10:1 CHCl3–
MeOH) to give compound 6a (70 mg, 14%)
and compound 6b (70 mg, 14%) as white
solids. Compound 6a: mp 208–212 °C; [h]D25
+34.0° (c 2.0, H2O); UV (H2O) umax 248.5 nm
(m 13,400, pH 7), 253.5 nm (m 14,000, pH 11),
1
2); H NMR (CD3OD): l 8.29 (s, 1 H, H-8),
1
8.16 (s, 1 H, H-2), 6.44 (dd, 1 H, J1%,2% 5.61,
J1%,2¦ 9.39 Hz, H-1%), 5.41 (dd, 1 H, J2%,3% 4.47,
J3%,F 53.56 Hz, H-3%), 4.16 (dt, 1 H, J4%,5% 2.87,
J4%,F 27.39 Hz, H-4%), 3.82 (m, 2 H, H-5%), 2.95
249.0 nm (m 14,150, pH 2); H NMR (D2O): l
8.21 (s, 1 H, H-8), 8.11 (s, 1 H, H-2), 6.43 (dd,
1 H, J1%,2% 6.24, J1%,2¦ 8.90 Hz, H-1%), 5.38 (dd, 1
H, J2%,3% 4.91, J3%,F 53.95 Hz, H-3%), 4.41 (dt, 1
H, J4%,5% 4.03, J4%,F 26.95 Hz, H-4%), 3.72 (m, 2
13
(m, 1 H, H-2%), 2.69 (m, 1 H, H-2%); C NMR
13
(CD3OD): l 157.6, 153.5, 149.9, 141.7, 120.9,
96.4 (d, J 174.1 Hz), 87.9 (d, J 23.3 Hz), 87.4,
63.3 (d, J 11.2 Hz), 39.4 (d, J 20.9); FABMS
m/z 254 (M+H)+; Anal. Calcd for
C10H12FN5O2: C, 47.43; H, 4.78; N, 27.66.
Found: C, 47.35; H, 4.78; N, 27.57. Com-
pound 5b: mp 192–194 °C; [h]2D5 −63.9° (c
0.63, H2O); UV (H2O) umax 259.0 nm (m
16,290, pH 7), 259.5 nm (m 15,740, pH 11),
257.5 nm (m 15,690, pH 2); 1H NMR
(CD3OD): l 8.21 (s, 1 H, H-8), 8.20 (s, 1 H,
H-2), 6.54 (dd, 1 H, J1%,2% 1.31, J1%,2¦ 7.29 Hz,
H-1%), 5.38 (dd, 1 H, J2%,3% 5.27, J3%,F 54.73 Hz,
H-3%), 4.66 (dt, 1 H, J4%,5% 3.72, J4%,F 25.42 Hz,
H-4%), 3.68 (m, 2 H, H-5%), 2.99–2.72 (m, 2 H,
H-2%); 13C NMR (CD3OD): l 157.5, 153.5,
150.1, 141.2, 120.1, 96.0 (d, J 175.4 Hz), 89.11
(d, J 23.0 Hz), 86.7, 62.7 (d, J 11.0 Hz), 40.3
(d, J 20.4 Hz); FABMS m/z 254 (M+H)+;
Anal. Calcd for C10H12FN5O2: C, 47.43; H,
4.78; N, 27.66. Found: C, 47.33; H, 4.84; N,
27.52.
H, H-5%), 2.90–2.73 (m, 2 H, H-2%); C NMR
(D2O+CD3OD): l 158.5, 148.5, 146.2, 140.4,
124.5, 95.3 (d, J 175.3), 86.1 (d, J 23.8), 85.3,
61.4 (d, J 11.1 Hz), 37.8 (d, J 21.3 Hz);
FABMS m/z 255 (M+H)+; Anal. Calcd for
C10H11FN4O3: C, 47.25; H, 4.36; N, 22.04.
Found: C, 47.15; H, 4.39; N, 21.90. Com-
pound 6b: mp 206–208 °C; [h]2D5 −98.1° (c
2.0, H2O); UV (H2O) umax 248.0 nm (m 13,790,
pH 7), 253.0 nm (m 15,140, pH 11), 248.5 nm (m
13,390, pH 2); 1H NMR (D2O): l 8.18 (s, 1 H,
H-8), 8.10 (s, 1 H, H-2), 6.40 (m, 1 H, H-1%),
5.34 (dm, 1 H, J3%,F 53.67 Hz, H-3%), 4.63 (dt,
1 H, J4%,5% 4.11, J4%,F 26.19 Hz, H-4%), 3.63 (d, 2
H, J4%,5% 4.28 Hz, H-5%), 2.93–2.70 (m, 2 H,
H-2%); 13C NMR (D2O+CD3OD): l 158.8,
148.5, 146.1, 139.9, 124.3, 94.7 (d, J 174.3 Hz),
87.6 (d, J 23.5 Hz), 85.6, 61.1 (d, J 11.3 Hz),
38.6 (d, J 20.5 Hz); FABMS m/z 255 (M+
H)+; Anal. Calcd for C10H11FN4O3·0.3
MeOH: C, 46.89; H, 4.36; N, 21.24. Found: C,
46.58; H, 4.58; N, 21.39.
2%,3%-Dideoxy-3%-fluoro-i-
L
-inosine (6a) and
2%,3%-Dideoxy-3%-fluoro-i-
L
-guanosine (7a)
-guanosine (7b).
2%,3%-dideoxy-3%-fluoro-h- -inosine (6b).—The
L
and 2%,3%-dideoxy-3%-fluoro-h-
L
silylated 6-chloropurine was prepared from
6-chloropurine (608 mg, 3.93 mmol), as previ-
ously described, and dissolved in anhyd
CH3CN (20 mL). To the solution of the sily-
lated base in CH3CN, compound 14 (500 mg,
1.97 mmol), followed by Me3SiOTf (0.46 mL,
2.38 mmol), was added at rt, and the resulting
reaction mixture was stirred for 12 h and
neutralized with satd aq NaHCO3. After the
same work-up previously described for com-
pound 1, the residue thus obtained was dis-
solved in MeOH (60 mL) to which 1 N
NaOMe (3.3 mL) and 2-mercaptoethanol (0.3
mL) were added. The resulting mixture was
—The silylated 2-amino-6-chloropurine was
prepared from 2-amino-6-chloropurine (700
mg, 4.13 mmol), as previously described, and
dissolved in anhyd CH3CN (20 mL). To the
solution of the silylated base in CH3CN, com-
pound 14 (500 mg, 1.97 mmol), followed by
Me3SiOTf (0.5 mL, 2.59 mmol), was added at
rt, and the resulting mixture was stirred at rt
for 10 h and neutralized with satd aq
NaHCO3. After the same work-up previously
described for compound 1, the obtained
residue was purified by silica gel column chro-
matography (40:1 CHCl3–MeOH) to give a
regioisomer as an anomeric mixture with umax

58
B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
320 nm (700 mg, 91%) as a sole product. The
purified residue was dissolved in CH3CN (200
mL), refluxed for 18 h, and purified by silica
gel column chromatography (40:1 CHCl3–
MeOH) to give the desired N9-nucleoside, the
2-amino-6-chloropurine derivative with umax
309 nm (330 mg, 47%), which was dissolved in
MeOH (60 mL) and treated with 1 N NaOMe
(2.6 mL) and mercaptoethanol (0.2 mL). The
resulting mixture was refluxed for 17 h, neu-
tralized with 0.1 N HCl, and filtered. After
concentration, the residue was separated by
silica gel column chromatography (10:1–5:1
CHCl3–MeOH) to give compound 7a (70 mg,
13%) and compound 7b (70 mg, 13%) as white
solids. Compound 7a: mp 220–222 °C; [h]D25
+50.5° (c 0.2, H2O); UV (H2O) umax 251.5 nm
(m 11,050, pH 7), 265.0 nm (m 7,840, pH 11),
and AI 33655) from the National Institutes of
Health and the Department of Veterans Af-
fairs. We thank Dr Michael G. Bartlett for
mass spectral measurements.
References
[1] (a) B. Belleau, D. Dixit, N. Nguyen-Ba, J.-L. Kraus, Int.
Conf. AIDS. Montreal, Canada, Jun 4–9 (1990), paper
no. T.C.O.1, 515. (b) H. Soudeyns, Q. Yao, B. Belleau,
J.-L. Kraus, N. Nguyen-Ba, B. Spira, M.A. Wainberg,
Antimicrob. Agents Chemother., 35 (1991) 1386–1390. (c)
S.-L. Doong, C.H. Tsai, R.F. Schinazi, D.C. Liotta,
Y.-C. Cheng, Proc. Natl. Acad. Sci. USA, 88 (1991)
895–899.
[2] (a) R.F. Schinazi, A. McMillan, D. Cannon, R. Mathis,
R.M. Lloyd, A. Peck, J.-P. Sommadossi, M. Saint-Clair,
J. Wilson, P.A. Furman, G. Painter, W.-B. Choi, D.C.
Liotta, Antimicrob. Agents Chemother., 36 (1992) 2423–
2431. (b) P.A. Furman, M. Davis, D.C. Liotta, M. Paff,
L.W. Frick, D.J. Nelson, R.E. Dornssife, J.A. Wurster,
L.J. Wilson, J.A. Fyfe, J.V. Tuttle, W.H. Miller, L.
Congreay, D.R. Averette, R.R. Schinazi, G.R. Painter,
Antimicrob. Agents Chemother., 36 (1992) 2686–2692.
[3] (a) G. Gosselin, R.F. Schinazi, J.-P. Sommadossi, C.
Mathe´, M.-C. Bergogne, A.-M. Aubertin, A. Kirn, J.-L.
Imbach, Antimicrob. Agents Chemother., 38 (1994)
1292–1297. (b) T.-S. Lin, M.Z. Luo, S.B. Pai, G.E.
Dutschman, Y.-C.J. Cheng, Med. Chem., 37 (1994) 798–
803.
1
254.0 nm (m 9,870, pH 2); H NMR (D2O): l
7.87 (s, 1 H, H-8), 6.24 (dd, 1 H, J1%,2% 5.77,
J1%,2¦ 9.41 Hz, H-1%), 5.34 (dd, 1 H, J2%,3% 4.45,
J3%,F 53.00 Hz, H-3%), 4.34 (dt, 1 H, J4%,5% 3.20,
J4%,F 26.65 Hz, H-4%), 3.70 (m, 2 H, H-5%),
2.85–2.60 (m, 2 H, H-2%); 13C NMR (D2O+
CD3OD): l 152.5, 151.4, 145.1, 138.1, 118.5,
95.4 (d, J 174.9 Hz), 85.7 (d, J 23.5 Hz), 84.6,
61.4 (d, J 11.2 Hz), 37.2 (d, J 20.0 Hz);
FABMS m/z 270 (M+H)+; Anal. Calcd for
C10H12FN5O3·0.65 MeOH: C, 44.10; H, 5.07;
N, 24.15. Found: C, 43.85; H, 4.68; N, 23.95.
[4] T.-S. Lin, M.-Z. Luo, M.-C. Liu, Y.-L. Zhu, E. Gullen,
G.E. Dutschman, Y.-C.J. Cheng, Med. Chem., 39 (1996)
1757–1759.
[5] (a) H.O. Kim, K. Shanmuganathan, A.J. Alves, L.S.
Jeong, J.W. Beach, R.F. Schinazi, C.-N. Chang, Y.-C.
Cheng, C.K. Chu, Tetrahedron Lett., 33 (1992) 6899–
6902. (b) K.L. Grove, X. Guo, S.-H. Liu, Z. Gao, C.K.
Chu, Y.-C. Cheng, Cancer Res., 55 (1995) 3008–3011.
[6] C.K. Chu, T. Ma, K. Shanmugannathan, C.G. Wang,
Y.J. Xiang, S.B. Pai, G.Q. Yao, J.-P. Sommadossi,
Y.-C. Cheng, Antimicrob. Agents Chemother., 39 (1995)
979–981.
[7] (a) G. Etzold, R. Hintsche, G. Kowollik, P. Langen,
Tetrahedron, 27 (1971) 2463–2472. (b) P. Herdewijn, J.
Balzarini, E. De Clercq, R. Pauwels, M. Baba, S.
Broder, H.J. Vanderhaeghe, Med. Chem., 30 (1987)
1270–1278. (c) M.S. Motawia, E.B. Pedersen, Liebigs
Ann. Chem., (1990) 1137–1139. (d) J.-T. Huang, L.-C.
Chen, L. Wang, M.-H. Kim, J.A. Warshaw, D. Arm-
strong, Q.-Y. Zhu, T.-C. Chou, K.A. Watanabe, J.
Matulic-Adamic, T.-L. Su, J.J. Fox, B. Polsky, P.A.
Baron, J.W.M. Gold, W.D. Hardy, E.J. Zuckerman,
Med. Chem., 34 (1991) 1640–1646. (e) M.W. Hager,
D.C. Liotta, Tetrahedron Lett., 33 (1992) 7083–7086.
[8] (a) A. Van Aerschot, P. Herdewjin, J. Balzarini, R.
Pauwels, E.J. De Clercq, Med. Chem., 32 (1989) 1743–
1749. (b) A. Van Aerschot, D. Everaert, J. Balzarini, K.
Augustyns, L. Jie, G. Janssen, O. Peeters, N. Blaton, C.
De Ranter, E. De Clercq, P.J. Herdewijn, Med. Chem.,
33 (1990) 1833–1839.
Compound 7b: mp 198–202 °C; [h]D25
−
83.5°(c 0.2, H2O); UV (H2O) umax 252.0 nm (m
10,520, pH 7), 267.0 nm (m 7,970, pH 11) 253.5
1
nm (m 9,730, pH 2); H NMR (D2O): l 7.85 (s,
1 H, H-8), 6.28 (dd, 1 H, J1%,2% 2.21, J2%,3% 6.67
Hz, H-1%), 5.32 (dd, 1 H, J2%,3% 4.51, J3%,F 55.38
Hz, H-3%), 4.57 (dt, 1 H, J4%,5%4.15, J4%,F 25.50
Hz, H-4%), 3.61 (d, 2 H, J4%,5% 4.23 Hz, H-5%),
2.87–2.67 (m, 2 H, H-2%); 13C NMR (D2O+
CD3OD): l 153.0, 151.5, 141.9, 137.6, 117.4,
94.7 (d, J 173.7 Hz), 87.2 (d, J 23.4 Hz), 84.6,
61.1 (d, J 11.1 Hz), 38.2 (d, J 20.0 Hz);
FABMS m/z 270 (M+H)+; Anal. Calcd for
C10H12FN5O3·0.5 MeOH: C, 44.22; H, 4.95;
N, 24.55. Found: C, 44.02; H, 4.62; N, 24.68.
Acknowledgements
[9] H. Mitsuya, K.J. Weinhold, P.A. Furman, M.H. Saint-
Clair, S.N. Lehrmann, R.C. Gallo, D. Bolognesi, D.W.
Barry, S. Broder, Proc. Natl. Acad. Sci. USA, 82 (1985)
7096–7100.
This research was supported by US Public
Health Service Research Grants (AI 32351

B.K. Chun et al. / Carbohydrate Research 328 (2000) 49–59
59
[10] (a) D. Bottiger, L. Stahle, B. Oberg, Antimicrob. Agents
Chemother., 36 (1992) 1770–1772. (b) C. Flexner, C.
Van der Horst, M.A. Jacobson, W. Powerly, F. Duncan-
son, D. Ganes, P.A. Barditch-Crovo, B.G. Petty, P.A.
Baron, D. Armstrong, P. Bricmont, O. Kuye, A. Yacobi,
S.J. Desjardins, Infect. Dis., 170 (1994) 1394–1403. (c)
R. Sundseth, S.S. Joyner, J.T. Moore, R.E. Dornsife,
I.K. Dev, Antimicrob. Agents Chemother., 40 (1996)
331–335.
[11] (a) G.W.J. Fleet, J.C. Son, Tetrahedron Lett., 28 (1987)
3615–3618. (b) G.W.J. Fleet, J.C. Son, A.E. Derome,
Tetrahedron, 44 (1988) 625–636. (c) M.K. Gurjar, B.
Ashok, A.V. Rama Rao, Indian J. Chem., 26B (1987)
905–905.
[13] (a) B.R. Baker, R.E. Schaub, J. Am. Chem. Soc., 77
(1955) 5900–5905. (b) N.B. Dyatkina, A.A. Krayevsky,
A.V. Azhayev, I.V. Jartseva, Synthesis, (1985) 410–
411.
[14] (a) P. Herdewijn, J. Balzarini, E. De Clercq, R. Pauwels,
M. Baba, S. Broder, H.H. Vanderhaeghe, J. Med.
Chem., 30 (1987) 1270–1278. (b) M.S. Motawia, A.M.
El-Torgoman, E.B. Pedersen, Liebigs Ann. Chem., (1991)
879–883.
[15] (a) N.A. Van Draanen, S.C. Tucker, F.L. Boyd, B.W.
Trotter, J.E. Reardon, J. Biol. Chem., 267 (1991) 25019–
25024. (b) M.G. Davis, J.E. Wilson, N.A. Van Draanen,
W.H. Miller, G.A. Freemen, S.M. Daluge, F.L. Boyd,
A.E. Aulabaugh, G.R. Painter, L.R. Boone, Anti6iral
Res., 30 (1996) 133–145.
[12] R.K. Ness, Methods Carbohydr. Chem., 1 (1962) 90–93.
.