Synthesis of unsaturated fluoride containing D- and L-pyranosyl nucleosides

Article abstract of DOI:10.1016/S0957-4166(02)00438-X

A series of fluorinated pyranosyl nucleosides in D- and L-configurations, 16, 19-20, 25, 28-29, have been synthesized. Starting from 1,2-O-isopropylidene-D-glyceraldehyde, homologated templates (3S)-6 and (3R)-6 were prepared by vinylation of fluoroenal 3, which were transformed to give allylic alcohols, 8 and 21, in three steps, respectively. The key intermediate triols 9 and 22 were obtained by O-benzoyl group migration from the primary hydroxyl group to the neighboring secondary hydroxyl group. Under basic conditions, ring closure reaction of 9 and 22 afforded unsaturated pyranosyl derivatives 10 and 23, respectively, while under acidic conditions unsaturated furanosyl compounds 12 were formed. N-Glycosylation of the pyranosyl acetates with silylated bases under Vorbrueggen conditions then gave the protected nucleosides, which were converted to the free nucleosides. However, condensation of the unsaturated furanosyl intermediate 12 did not provide the desired nucleosides. Structural and stereochemical assignments of the synthesized compounds were based on the NOESY spectra of 16a and 16b, as well as the X-ray crystal structure of 19a.

Full text of DOI:10.1016/S0957-4166(02)00438-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1589–1598
Synthesis of unsaturated fluoride containing
nucleosides
D
- and -pyranosyl
L
Kyeong Lee, Wen Zhou, Laura-Lee C. Kelley, Cory Momany and Chung K. Chu*
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens,
GA 30602, USA
Received 28 January 2002; accepted 19 July 2002
Abstract—A series of fluorinated pyranosyl nucleosides in
D- and L-configurations, 16, 19–20, 25, 28–29, have been synthesized.
Starting from 1,2-O-isopropylidene- -glyceraldehyde, homologated templates (3S)-6 and (3R)-6 were prepared by vinylation of
D
fluoroenal 3, which were transformed to give allylic alcohols, 8 and 21, in three steps, respectively. The key intermediate triols 9
and 22 were obtained by O-benzoyl group migration from the primary hydroxyl group to the neighboring secondary hydroxyl
group. Under basic conditions, ring closure reaction of 9 and 22 afforded unsaturated pyranosyl derivatives 10 and 23,
respectively, while under acidic conditions unsaturated furanosyl compounds 12 were formed. N-Glycosylation of the pyranosyl
acetates with silylated bases under Vorbru¨ggen conditions then gave the protected nucleosides, which were converted to the free
nucleosides. However, condensation of the unsaturated furanosyl intermediate 12 did not provide the desired nucleosides.
Structural and stereochemical assignments of the synthesized compounds were based on the NOESY spectra of 16a and 16b, as
well as the X-ray crystal structure of 19a. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
hypoxanthine derivatives with D-configurations exhib-
ited interesting anti-HIV-1 activity and showed favor-
able cross-resistance profiles with respect to the 3TC
(2%,3%-dideoxy-3%-thiacytidine or lamivudine) resistant
viral isolates.7 Furthermore, the cytosine and 5-fluoro-
2%,3%-Dideoxy-(d2N) and 2%,3%-didehydro-2%,3%-dideoxy-
nucleosides (d4N) have been a rich source of antiviral
agents.1–4 As part of our antiviral drug discovery pro-
gram, we have recently reported the synthesis of
fluoro-2%,3%-unsaturated nucleosides ( -2%-F-d4Ns) and
cytosine derivatives from the
L-series displayed potent
L-2%-
anti-HBV activity.8
L
found that several compounds of this series displayed
moderate to potent antiviral activities, including anti-
HIV-1 (human immunodeficiency virus type 1) and
anti-hepatitis B virus (HBV) activities in human periph-
eral blood mononuclear (PBM) cells and 2.2.15 cells,
respectively (Fig. 1).5–7 Among these, the adenine and
In view of these interesting biological results, it was of
interest to introduce a fluoro atom at the 3% position of
2%,3%-didehydro-2%,3%-dideoxy nucleosides and to study
the structure–activity relationships (SAR) of this class
of compounds. So far, three 3%-fluoride containing
d4Ns, including cytosine, thymine and adenine deriva-
tives with
D-configuration, have been synthesized and
reported to be active against HIV-1 (Fig. 1).8,9 Herein,
we wish to report the synthetic approaches of 3%-
B
F
B
B
F
HO
HO
OH
O
O
O
fluoride-containing pyranosyl nucleosides in
configurations.
D- and L-
F
D-β-2'-F-d4N
L-β-2'-F-d4N
D-β-3'-F-d4N
(B = T, C, and A)
(B = pyrimidines, and purines)
2. Results and discussion
1,2-O-Isopropylidene- -glyceraldehyde 1 was reacted
D
Figure 1. Fluorinated 2%,3%-unsaturated nucleosides.
with diethyl a-fluorophosphonoacetate to give a mix-
ture of fluoroesters in a 9:1 ratio in favor of the
(E)-isomer (Scheme 1).5,6 Treatment of 2 with 1 M
DIBAL-H/hexanes gave a,b-unsaturated aldehydes 3
* Corresponding author. Tel.: (706) 542-5379; fax: (706) 542-5381;
e-mail: dchu@rx.uga.edu
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00438-X

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K. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 1589–1598
Scheme 1. Reagents and conditions: (i) (EtO)2P(O)CHFCO2Et, NaHMDS, THF, −78°C; (ii) DIBAL-H in hexanes, ether, −78°C;
(iii) vinylmagnesium bromide, THF, −78°C; (iv) BzCl, pyr., CH2Cl2, 0°C; (v) cat. OsO4, NMO, acetone, water; (vi) NaIO4, EtOH,
H2O; (vii) NaBH4, 0°C; (viii) conc. HCl, EtOH; (ix) NaIO4, aq. EtOH; (x) Ac2O, pyr.
dride to provide the secondary allylic alcohol 8. A
doublet signal for the secondary hydroxyl group in 8
was detected by proton NMR.
and 4 in good yield and the resulting (E)- and (Z)-iso-
mers were separated by flash silica gel column chro-
matography (12.5% EtOAc/hexanes). Reaction of
compound 3 with vinylmagnesium bromide in THF at
−78°C, followed by benzoyl protection of the resulting
alcohols gave (3S)-6 and (3R)-6 in a ratio of 1:1.5,
which were separated by chromatography over silica gel
(6.5% EtOAc/hexanes). The homologated template 8
was successfully obtained from the diene (3S)-6 in three
steps, including oxidative cleavage of vinyl group, fol-
lowed by reduction in 54% yield. First, (3S)-6 was
treated with a catalytic amount of osmium tetroxide
and a stoichiometric amount of the secondary oxidant
4-methylmorpholine N-oxide (NMO) in aqueous ace-
tone to generate a vicinal diol.10,11 cis-Hydroxylation
occurred selectively from the less hindered face of the
double bond. The diol was then immediately treated
with sodium periodate, followed by usual work-up to
give an aldehyde,7 which underwent reduction and ben-
zoyl group migration in the presence of sodium borohy-
With 8 in hand, it was expected that deprotection of the
acetonide group followed by oxidative cyclization and
subsequent acetylation would give to the necessary
sugar moiety 13 (Scheme 2). However, under the reac-
tion conditions, the intermediate 11 isomerized to 11a
by O-acyl group migration, which leads to the thermo-
dynamically more stable six-membered ring intermedi-
ates 10 (path a), rather than the five-membered ring
intermediate 12 (path b) as illustrated in Scheme 2.12
This unexpected result was later confirmed at the final
stage by NMR spectrum, as well as by X-ray crystallog-
raphy (Fig. 3). Due to the unique structure of vinyl
fluoride-containing pyranose 10, it was of interest to
synthesize 3%-fluorinated pyranosyl
L-nucleoside series.
Treatment of the triol 9 with sodium periodate led to
an equilibrium mixture, and subsequent treatment with

K. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 1589–1598
OH HO
1591
HO
OBz
9
F
i
a
O
OBz
OH
BzO
b
HO
O
O
Ph
HO
iii
O
ii
O
F
F
F
11b
11a
11
OBz
OBz
O
O
O
BzO
MeO
OAc
iv
F
F
F
12
14
10
iv
OBz
O
AcO
F
13
Scheme 2. Reagents and conditions: (i) NaIO4, EtOH, H2O; (ii) PPTS, MeOH, reflux; (iii) Ac2O, Pyr, rt; (iv) conc. H2SO4,
AcOH/Ac2O.
pyridine and acetic anhydride gave 10 as a major
product (30–32% from 9 in two steps) (Scheme 1). The
use of lead acetate as an oxidant gave similar yields.
As shown in Scheme 3, coupling of the acetate 10 with
bis-(trimethylsilyl)-N4-benzoylcytosine under Vorbru¨g-
gen conditions gave an anomeric mixture of the pro-
tected nucleosides 15a ((6S)-isomer) and 15b
((6R)-isomer) in a ratio of 1.4:1 which was separated on
silica gel (50% EtOAc/hexanes). Ammonolysis of
We then considered the cyclization of 11 under acidic
conditions. As shown in Scheme 2, the triol 9 was
oxidized with sodium periodate, followed by treatment
with pyridinium p-toluene sulfonate in refluxing
methanol to afford the desired five-membered ring
intermediate 12 (path b). However, the conversion of 12
to furanosyl acetate 13 failed under various acidic
conditions. Instead, these reactions resulted in the for-
mation of 2-benzyloxymethyl-3-fluorofuran derivative
14. Furthermore, coupling of 12 with various bases
under the Vorbru¨ggen conditions only yielded 2-benzyl-
oxymethyl-3-flurofuran 14 instead of furanosyl
nucleosides, even at very low temperature (−30 to
−40°C).13 It is conceivable that, because the H-4% pro-
ton of 12 is an allylic proton and is relatively acidic, the
3%-fluorine substituent may destabilize the C-1% cation to
give the thermodynamically more stable product 14.
each isomer produced the -cytidine analogues 16a and
D
16b. The protected thymine or uracil congeners 17 and
18 were prepared by condensation of 10 with
trimethylsilylthymine or uracil in the presence of
TMSOTf as Lewis acid (54.7–57.7%). After debenzoyl-
ation using saturated methanolic ammonia and chro-
matographic separation (6.25% EtOAc/hexanes), the
free nucleoside analogues 19–20 were obtained in good
yields. Analogously, intermediate 21 was also pre-
pared from (3R)-6 and used for N-glycosylations with
various silylated heterocycles to produce the corre-
sponding
the spectral properties of the
L
-analogues, 25, 28 and 29 (Scheme 4). All of
-nucleosides were in
L
agreement with those of their corresponding
parts.
D-counter-

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K. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 1589–1598
10
ii
i
NHBz
N
O
N
BzO
O
X
NH
N
O
F
O
BzO
N
O
O
+
BzO
N
O
NHBz
F
F
17: X = H (58%)
15a (36%)
15b ( 26%)
18: X = CH3 (55%)
iii
iii
98%
O
iii
97%
O
N
HO
NH2
O
X
NH
HO
N
O
O
N
N
O
F
O
HO
O
F
NH
O
HO
N
O
+
N
X
F
NH2
F
19b: X = H (40%)
20b: X = CH3 (39%)
19a: X = H (55%)
20a: X = CH3 (54%)
16b
16a
Scheme 3. Reagents and conditions: (i) silylated N4-Bz-cytosine, TMSOTf, DCE; (ii) silylated uracil or thymine, TMSOTf, DCE
(iii) NH3/MeOH.
The structural and stereochemical assignments for the
final nucleosides were based on the NMR spectrum
and confirmed by X-ray crystallographic analysis
3. Experimental
Melting points were determined on a Mel-temp II
laboratory device and are uncorrected. NMR spectra
were recorded on a Bruker AMX400 MHz spectrome-
ters with tetramethylsilane as the internal reference;
chemical shifts (l) are reported in parts per million
(ppm), and the signals are described as s (singlet), d
(doublet), t (triplet), q (quartet), br s (broad singlet),
dm (doublet of multiplet) and m (multiplet). UV
spectra were obtained on a Beckman DU 650 spec-
trophotometer. Optical rotations were measured on a
Jasco DIP-370 digital polarimeter. Elemental analyses
were performed by Atlantic Microlab, Inc., Norcross,
GA. All reactions were monitored using thin-layer
chromatography on Analtech, 200 mm silica gel GF
plates.
1
(Fig. 3). Based on the respective H NMR spectrum
of the free nucleosides, which showed a doublet signal
for the hydroxyl group instead of a triplet signal in
DMSO-d6, it was assigned as a secondary hydroxyl
group rather than a primary hydroxyl group in the
pyranose sugar moiety 10. Assignments of the
anomeric configurations of the final nucleosides were
based on 2D NOESY experiments on 16a and 16b
(Fig. 2). A correlation between H-4% and H-1% was
observed for 16b, whereas no such cross peak existed
in 16a. Instead, a correlation between the 4%-OH and
Hb-5% protons was observed in 16a. These assign-
ments as well as the
D- and L-configurations were
finally confirmed by X ray crystallographic analysis of
19a (Fig. 3).14
3.1. (E)/(Z)-Ethyl-3-[(S)-2,2-dimethyl-(1,3)-dioxolan-4-
yl]-2-fluoroacrylate, 2
In summary, novel
D- and L-series of 3%-fluoro substi-
tuted pyranosyl nucleosides were synthesized by utiliz-
ing the homologated alcohols 8 and 21 as chiral
templates. The homologated alcohols were prepared
via 1,2-addition of vinyl group to fluoroenal interme-
A solution of triethyl 2-fluorophosphonoacetate (39.2 g,
162 mmol) in THF (70 mL) was cooled to −78°C and
sodium bis(trimethylsilyl)amide (1.0 M solution in
THF, 162 mL, 162 mmol) was added dropwise. The
mixture was kept for 30 min at −78°C, then a solution
diate 3 starting from 1,2-O-isopropylidene-D-glycer-
of
D
-(R)-glyceraldehyde acetonide15 (19.14 g, 147
aldehyde. The synthesized nucleosides were evaluated
against HIV-1 in human peripheral blood mononu-
clear cells. However, no significant antiviral activity
was detected.
mmol) in THF (70 mL) was added. After being stirred
for 1 h at −78°C, the reaction mixture was treated with
aqueous NH4Cl and extracted with ether. The ether

K. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 1589–1598
1593
Scheme 4. Reagents and conditions: (i) cat. OsO4, NMO, acetone, water; (ii) NaIO4, EtOH, H2O; (iii) NaBH4, 0°C; (iv) conc. HCl,
EtOH; (v) NaIO4, aq. EtOH; (vi) Ac2O, pyr.; (vii) silylated N4-Bz-cytosine, TMSOTf, DCE; (viii) silylated uracil or thymine; (ix)
NH3/MeOH.
phase was washed with saturated NaCl, dried over
MgSO4 and concentrated. The residue was chro-
matographed on silica gel to give a (E) and (Z) mixture
1
1
2 (9:1 by H NMR) as yellowish oil (34.6 g, 97.9%): H
NMR (CDCl3) l 1.34, 1.36 (2 t, J=8 Hz, 3H), 1.40,
1.45 (2s, 6H), 3.69 (m, 1H), 4.28 (m, 3H), 5.02 (m, 1H),
5.40 (m, 1H), 6.02 (dd, J=8, 20 Hz, 1H), 6.18 (dd,
J=8, 32 Hz, 1H).
3.2. (E)-3-[(S)-2,2-Dimethyl-(1,3)-dioxolan-4-yl]-2-
fluoro-propenal, 3
A solution of 2 (22.58 g, 103.48 mmol) in ether (100
mL) was cooled to −78°C and DIBAL-H (1.0 M solu-
tion in hexanes, 140 mL, 140 mmol) was added drop-
Figure 2. NOE correlations from NOESY spectra of 16a and
16b.

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K. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 1589–1598
3.4. (+)-(E)-(4S)-4-[(3S)-O-Benzoyl-2-fluoro-1,4-dienyl]-
2,2-dimethyl-(1,3)-dioxolane, (3S)-6 and its (−)-(3R)-
isomer, (3R)-6
To a solution of alcohols 5 (18.81 g, 93.01 mmol) in
CH2Cl2 (200 mL) was added pyridine (22.5 mL, 279
mmol) and benzoyl chloride (13.5 mL, 116.27 mmol) at
0°C, and the resulting mixture was stirred for 1 h at 0°C.
After completion of the reaction, ice was added to the
reaction mixture and stirred for 30 min at rt. The resulting
mixture was concentrated under vacuo, washed with
dilute HCl, satd NaHCO3 and brine. The combined
organic layer was dried and concentrated to dryness,
which was purified by column chromatography (6.5%
EtOAc/hexanes) to give (3S)-6 (10.43 g) and (3R)-6 (15.64
g) as yellowish oils in 91.49% yield [(3S)-6:(3R)-6=1:1.5].
1
(3S)-6: [h]2D7 +9.0 (c 0.7, CHCl3); H NMR (CDCl3) l
1.427, 1.407 (2s, 6H), 3.61, 4.09 (m, 2H), 4.94 (m, 1H),
4.34–5.53 (m, 3H), 6.03 (m, 1H), 6.24–6.32 (m, 1H),
7.44–8.09 (m, 5H). Anal. calcd for C17H19FO3·0.7H2O:
C, 67.40; H, 6.79. Found: C, 67.09; H, 6.32%.
1
(3R)-6: [h]2D7 −17.61 (c 0.6, CHCl3); H NMR (CDCl3)
l 1.408, 1.432 (2s, 6H), 3.61 (dd, J=8.4, 6.8 Hz, 1H), 4.23
(dd, J=8.4, 6 Hz, 1H), 5.02 (m, 1H), 5.41 (m, 2H, H-5a,
1H), 5.60 (m, 1H), 6.06 (m, 1H), 6.27–6.36 (m, 1H),
7.44–8.18 (m, 5H). Anal. calcd for C17H19FO3: C, 66.65;
H, 6.25. Found: C, 66.82, H, 6.40%.
Figure 3. ORTEP drawing of the X-ray crystallographic
structure
enpyranosyl]uracil 19a.
(+)-1-[(1S,4S)-3-fluoro-4-hydroxy-5-dihydro-2,3-
3.5. (−)-(E)-(4S)-4-[(S)-2,2-Dimethyl-(1,3)-dioxolan-4-
yl]-1-O-benzoyl-3-fluorobut-3-en-2-ol, 8
To a solution of compound (3S)-6 (8.94 g, 29.18 mmol)
in acetone (340 mL) at room temperature was added a
stock osmylation solution (295 mL of solution consisting
of 4-methylmorpholine N-oxide (77.5 g) and osmium
tetroxide (1.9 g) in water (567 mL)). The resulting mixture
was stirred at room temperature for 1 h. The reaction
mixture was then concentrated to the half of its original
volume, the resulting solution was dissolved in EtOAc,
and washed with satd sodium bisulfite solution and brine.
The organic phase was dried, filtered, and concentrated
to give crude diol, which was used without further
purification.
wise under nitrogen. The mixture was stirred for 1.5
h at −78°C, and the cold mixture was treated with
dilute nitric acid, washed with water. The combined
organic layer was dried (Na2SO4), filtered, and con-
centrated to dryness. The residue was chro-
matographed on silica gel to isolate 3 as yellowish oil
1
(14.5 g, 81%): H NMR (CDCl3) l 1.419, 1.461 (2s,
6H), 3.71 (dd, J=8.4, 6.4 Hz, 1H), 4.29 (dd, J=8.4,
6.8 Hz, 1H), 5.25 (ps dd, J=14.4, 6.8 Hz, 1H), 6.11
(dd, J=17.4, 8 Hz, 1H), 8.96 (d, J=11.6 Hz, 1H).
3.3. (E)-1-[(S)-2,2-Dimethyl-(1,3)-dioxolan-4-yl]-2-
fluoropenta-1,4-diene-3-ol, 5
To a solution of the diol in ethanol (170 mL) was added
sodium periodate (6.99 g, 32.69 mmol) in water (130 mL)
portionwise. The resulting solution was stirred at room
temperature for 45 min. After the completion of the
reaction as shown by TLC analysis, the mixture was
cooled to 4°C and was treated with sodium borohydride
(4.42 g, 116.74 mmol). The reaction mixture was stirred
for 30 min, and then neutralized with glacial acetic acid
to pH 7. Removal of ethanol and standard work-up gave
an oil, which was purified on silica gel (ethyl acetate/hex-
anes 1:3) to yield benzoyl group-migrated alcohol 8 [4.97
g, 54.9% from (3S)-6]: [h]2D7 −7.3 (c 0.19, CHCl3); 1H NMR
(DMSO-d6) l 1.276, 1.310 (2 s, 6H), 3.39 (ps t, J=7.6
Hz, 1H), 3.85 (dd, J=7.6, 6.4 Hz, 1H), 4.94 (m, 2H), 4.84
(m, 2H), 5.29 (dd, J=20.4, 9.2 Hz, 1H), 5.97 (d, J=5.2
Hz, D2O exchangeable, 1H), 7.53–7.97 (m, 5H). Anal.
calcd for C16H19FO5: C, 61.93; H, 6.17. Found: C, 61.82;
H, 6.28%.
Vinyl magnesium bromide (1 M in THF) was dis-
solved in THF (45 mL) under nitrogen, the mixture
was then cooled to −78°C and treated with a solution
of the enal 3 (13.01 g, 74.0 mmol) in THF. The
resulting mixture was stirred for 1 h at −78°C. The
cold mixture was treated with dilute nitric acid,
washed with water, and dried (Na2SO4). Evaporation
of the solvent and purification on silica gel (20%
EtOAc/hexanes) gave a diastereomeric mixture 5 as
pale yellowish oil (14.28 g, 95.4%), which was used as
such for the next step: 1H NMR (CDCl3) l 1.395,
1.427 (2 s, 6H), 4.13 (m, 2H), 4.83 (m, 1H), 5.02 (m,
1H), 5.23–5.47 (m, 3H), 5.98 (m, 1H). Anal. calcd for
C10H15FO3·0.1H2O: C, 58.87; H, 7.51. Found: C,
58.93; H, 7.43%.

K. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 1589–1598
1595
3.6. (−)-(E)-(2S,5S)-6-O-Benzoyl-4-fluorohex-3-ene-
After standard work up, the residue was purified by
silica gel column chromatography (5% EtOAc/hexanes)
1,2,5-triol, 9
1
to give a colorless oil of 14. H NMR (CDCl3) l 5.06
A solution of 8 (3.806 g, 12.265 mmol) in ethanol was
treated with diluted hydrochloric acid in ethanol (3.1
mL conc. HCl/50 mL EtOH) at 0°C and the resulting
solution was stirred at room temperature for 3 h. After
concentration and coevaporation, the resulting residue
was purified on silica gel (4% MeOH/CH2Cl2) to give
(s, 2H), 6.31 (d, J=9.5 Hz, 1H)), 7.24 (m, 1H), 7.45 (m,
2H), 7.56 (m, 1H), 8.08 (d, 2H). MS (FAB): 220 (M+).
3.10. (−)-(E)-(4R)-4-[(S)-2,2-Dimethyl-(1,3)-dioxolan-4-
yl]-1-O-benzoyl-3-fluoro-but-3-en 2-ol, 21
triol 9 (2.65 g, 80%): [h]2D5 −6.6 (c 1.45, MeOH); H
1
The titled compound (4.50 g) was prepared from (3R)-6
(8.33 g, 27.19 mmol) by similar method for the prepara-
tion of 8 in 53.3% yield (three steps): [h]2D7 −9.1 (c 0.68,
NMR (DMSO-d6) l 4.23 (m, 4H), 4.68 (t, J=2 Hz,
D2O exchangeable, 1H), 4.80 (m, 1H), 4.95 (d, J=4.8
Hz, D2O exchangeable, 1H), 5.17 (dd, J=22, 8.8 Hz,
1H), 5.77 (t, J=4.4 Hz, D2O exchangeable, 1H), 7.51–
8.00 (m, 5H). Anal. calcd for C13H15FO5·0.5H2O: C,
55.91; H, 5.77. Found: C, 55.78; H, 5.75%.
1
CHCl3); H NMR (DMSO-d6) l 1.329, 1.369 (2 s, 6H),
3.39 (ps t, J=8 Hz, 1H), 3.85 (dd, J=8, 6.4 Hz, 1H),
4.31 (m, 2H%), 4.84 (m, 2H), 5.29 (dd, J=20.8, 9.2 Hz,
1H), 5.97 (d, J=5.2 Hz, D2O exchangeable, 1H), 7.52–
7.98 (m, 5H). Anal. calcd for C16H19FO5·0.2H2O: C,
61.22; H, 6.23. Found: C, 61.16, H, 6.28%.
3.7. (4S)-4-O-Benzoyl-3-fluoro-1-O-acetyl-2,5-dihydro-
2H-pyrane, 10
A suspension of sodium periodate (1.21 g, 4.74 mmol)
in water (10 mL) was added dropwise to the solution of
triol 9 (1.22 g, 5.68 mmol) in ethanol (50 mL) at 0°C,
and the resulting solution was stirred for 1 h at room
temperature. The reaction mixture was filtered and the
filtrate was concentrated. The residue was then
extracted with EtOAc, and the combined organic layer
was dried, filtered (anhydrous MgSO4), and concen-
trated to give crude intermediate, which was used as
such for the next step.
3.11. (−)-(E)-(2S,5R)-6-O-Benzoyl-4-fluoro-hex-3-ene-
1,2,5-triol, 22
The titled compound (3.12 g) was prepared from 21
(3.957 g, 12.751 mmol) by similar method for the
preparation of 9 in 90.5%: [h]2D5 −4.3 (c 1.23, MeOH);
1H NMR (DMSO-d6) l 4.30 (m, 4H), 4.70 (m, D2O
exchangeable, 1H), 4.83 (m, 1H), 4.90 (m, D2O
exchangeable, 1H), 5.22 (dd, J=22.4, 8.8 Hz, 1H), 8.00
(m, D2O exchangeable, 1H), 7.51–8.00 (m, 5H). Anal.
calcd for C13H15FO5·0.5H2O: C, 55.91; H, 5.77. Found:
C, 55.71; H, 5.84%.
Acetic anhydride (1.78 mL, 18.96 mmol) was added to
a solution of lactols 11 in pyridine (25 mL) at 0°C and
the resulting mixture was stirred for 4 h at rt. The
reaction mixture was concentrated in vacuo and
purified by silica gel column chromatography (8%
EtOAc/hexanes) to give acetates 10 (426 mg, 32.1%
3.12. (3R)-3-O-Benzoyl-4-fluoro-6-acetoxy-3, 6-dihydro-
2H-pyrane, 23
The title compound (465 mg) was prepared from 22
1
from 9) as yellowish oil: H NMR (CDCl3) l 2.12, 2.15
(1.51 g, 5.59 mmol) by similar method for the prepara-
(s, 3H), 4.15, 4.34 (m, 2H), 5.54, 5.62 (m, 1H), 5.70,
5.82 (m, 1H), 6.43, 6.57 (m, 1H), 7.44, 8.09 (m, 5H).
Anal. calcd for C14H13FO5: C, 60.00; H, 4.68. Found:
C, 60.72; H, 5.01%.
1
tion of 10 in 29.7% yield (two steps): H NMR (CDCl3)
l 2.11, 2.15 (s, 3H), 4.15, 4.34 (m, 2H), 5.54, 5.62 (m,
1H), 5.70, 5.82 (m, 1H), 6.43, 6.57 (m, 1H), 7.43–8.09
(m, 5H). Calcd for C14H13FO5: C, 60.00; H, 4.68.
Found: C, 60.50; H, 4.90%.
3.8. 1-Methoxy-4-benzoxymethyl-3-fluoro-2-buten-4-
olide, 13
3.13. General procedure for condensation of 10 or 23
with heterocycles
To a solution of lactols 11 in dry methanol was added
PPTS. The resulting mixture was stirred and heated
under reflux for 1 h. After removal of solvent, the
residue was purified by silica gel column chromatogra-
phy (5% EtOAc/hexanes) to give anomeric mixture 13
A mixture of N4-benzoylcytosine (270 mg, 1.26 mmol),
hexamethyldisilazane (15 mL) and ammonium sulfate
(20 mg) was heated under reflux for 4 h under nitrogen.
The clear solution obtained was concentrated to dry-
ness in vacuo. A solution of the sugar portion 10 (286
mg, 0.836 mmol) in anhydrous DCE (15 mL) and
TMSOTf (0.32 mL, 1.68 mL) was added to the silylated
base at 0°C. The resulting mixture was stirred for 6 h
under nitrogen, poured into ice-cold satd NaHCO3
solution (10 mL) and stirred for 15 min. The resulting
mixture was washed, dried (Na2SO4) and concentrated
in vacuo. The anomeric mixture was separated by silica
gel column chromatography (50% EtOAc/hexanes) to
afford 15a (131 mg, 36.2%) and 15b (92.8 mg, 25.5%) as
solids.
1
as a colorless solid (70% from 9). H NMR (CDCl3) l
3.36, 3.42 (s, 3H), 4.39, 4.64 (m, 2H), 4.83, 5.07 (m,
1H), 5.33 (s, 1H), 5.65, 5.77 (m, 1H), 7.43 (m, 2H), 7.55
(m, 1H), 8.03, 8.10 (d, 2H). Anal. calcd for C13H13FO4:
C, 61.90; H, 5.19. Found: C, 62.04, H, 5.27%.
3.9. 2-Benzoxymethyl-3-fluorofuran, 14
To a solution of 13 (400 mg) acetic acid (4 mL), acetic
anhydride (1 mL) was added dropwise conc. Sulphuric
acid (0.1 mL) at 4°C. The reaction mixture was stirred
for 5 min and then neutralized by addition of NaHCO3.

1596
K. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 1589–1598
1
3.14. 1-[(1S,4S)-3-Fluoro 4-O-Benzoyl-5-dihydro-2,3-
enpyranosyl]-N4-benzoylcytosine, 15a and its (1R)-iso-
mer, 15b
24a: UV (MeOH) umax 302.5 nm; H NMR (CDCl3) l
4.06–4.27 (m, 2H, H), 5.73 (dd, J=12.4, 2.4 Hz, 1H),
5.81 (m, 1H), 6.84 (dd, J=2.4, 5 Hz, 1H), 7.44–8.09 (m,
7H). Anal. calcd for C23H18FN3O5·0.3H2O: C, 62.67;
H, 4.25; N, 9.53. Found: C, 62.54; H, 4.15; N, 9.57%.
1
15a: UV (MeOH) umax 302.0 nm; H NMR (CDCl3) l
4.06–4.27 (m, 2H%), 5.73 (dd, J=12.4, 2.8 Hz, 1H), 5.81
(m, 1H), 6.84 (dd, J=2.4, 5 Hz, 1H), 7.44–8.09 (m,
7H). Anal. calcd for C23H18FN3O5: C, 63.45; H, 4.17;
N, 9.65. Found: C, 63.42; H, 4.16; N, 9.55. 15b: UV
1
24b: UV (MeOH) umax 302.5 nm; H NMR (CDCl3) l
4.03–4.32 (m, 2H), 5.56 (d, J=9.6 Hz, 1H), 5.65 (dd,
J=1.6, 12 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 7.39–8.04
(m, 7H). Anal. calcd for C23H18FN3O5·0.2H2O: C,
62.93; H, 4.22; N, 9.57. Found: C, 62.63; H, 4.15; N,
9.52%.
1
(MeOH) umax 302.5 nm; H NMR (CDCl3) l 4.03–4.33
(m, 2H), 5.56 (d, J=9.6 Hz, 1H), 5.65 (dd, J=1.6, 12
Hz, 1H), 6.68 (d, J=8 Hz, 1H), 7.39–8.04 (m, 7H).
Anal. calcd for C23H18FN3O5: C, 63.45; H, 4.17; N,
9.65. Found: C, 63.29; H, 4.25; N, 9.50%.
3.18. 1-[(4R)-3-Fluoro 4-O-Benzoyl-5-dihydro-2,3-enpy-
ranosyl]uracil, 26
3.15. 1-[(4S)-3-Fluoro 4-O-Benzoyl-5-dihydro-2,3-enpy-
Silylated uracil, which was prepared from uracil (152
mg, 1.36 mmol) and HMDS (10 mL), was treated with
23 (152 mg, 0.90 mmol) and TMSOTf (0.26 mL, 1.36
mmol) in dry methylene chloride (12 mL). The mixture
was stirred overnight at rt under nitrogen. After work-
up similar to that of 15, purification by preparative
TLC (50% EtOAc/hexanes) gave an inseparable
anomeric mixture 26 (161.8 mg, 54.1%): UV (MeOH)
ranosyl]uracil, 17
Silylated uracil, which was prepared from thymine (194
mg, 1.73 mmol) and HMDS (10 mL), was treated with
10 (323 mg, 1.15 mmol) and TMSOTf (0.33 mL, 1.73
mmol) in dry DCE at rt for 12 h under nitrogen. After
work-up similar to that of 15, purification by silica gel
column chromatography (3% MeOH/CHCl3) gave an
inseparable anomeric mixture 17 (221 mg, 57.7%): UV
1
umax 257.0 nm; H NMR (CDCl3) l 3.95–4.26 (m, 2H),
5.50–5.81 (m, 2H), 5.22 (m, 1H), 6.59, 6.61 (m, 1H)
7.36–8.04 (m, 6H), 9.30, 9.32 (s, 1H). Anal. calcd for
C16H13FN2O5: C, 57.83; H, 3.94; N, 8.43. Found: C,
57.90; H, 4.48; N, 8.07%.
1
(MeOH) umax 257.0 nm; H NMR (CDCl3) l 3.96–4.26
(m, 2H), 5.50–5.81 (m, 2H), 5.22 (m, 1H), 6.60, 6.61 (m,
1H), 7.36–8.02 (m, 6H), 9.30, 9.33 (s, 1H). Anal. calcd
for C16H13FN2O5·0.1C4H10O: C, 57.99; H, 4.15; N,
8.25. Found: C, 57.99; H, 4.48; N, 7.85%.
3.19. 1-[(4R)-3-Fluoro 4-O-Benzoyl-5-dihydro-2,3-enpy-
ranosyl]thymine, 27
3.16. 1-[(4S)-3-Fluoro 4-O-benzoyl-5-dihydro-2,3-enpy-
Silylated thymine, which was prepared from thymine
(181.6 mg, 1.44 mmol) and HMDS (10 mL), was
treated with 23 (270 mg, 0.96 mmol) and TMSOTf
(0.28 mL, 1.44 mmol) in dry DCE (15 mL). The
mixture was stirred at rt overnight under nitrogen.
After work-up similar to that of 15, purification by
silica gel column chromatography (50% EtOAc/hex-
anes) gave an inseparable anomeric mixture 27 (175.5
mg, 52.8%): UV (MeOH) umax 263.0 nm; 1H NMR
(CDCl3) l 1.96, 1.97 (s, 3H), 4.30, 4.06 (m, 2H), 5.17,
5.36 (m, 1H), 5.55, 5.80 (m, 1H), 6.57, 6.64 (m, 1H),
7.15, 7.23 (s, 1H), 7.44, 8.11 (m, 5H), 8.24, 8.25 (s, 1H).
Anal. calcd for C17H15FN2O5·0.2H2O: C, 58.35; H,
4.44; N, 8.01. Found: C, 57.99; H, 4.46; N, 7.78%.
ranosyl]thymine, 18
Silylated thymine, which was prepared from thymine
(119 mg, 0.95 mmol) and HMDS (10 mL), was treated
with 10 (177 mg, 0.63 mmol) and TMSOTf (0.18 mL,
0.95 mmol) in dry DCE at rt for 8 h under nitrogen.
After work-up similar to that of 15, purification by
silica gel column chromatography (3% MeOH/CHCl3)
gave an inseparable anomeric mixture 18 (120 mg,
1
55%): UV (MeOH) umax 263.0 nm; H NMR (CDCl3) l
1.96, 1.98 (s, 3H), 4.28, 4.06 (m, 2H), 5.17, 5.36 (m,
1H), 5.55, 5.80 (m, 1H), 6.57, 6.64 (m, 1H), 7.15, 7.23
(s, 1H), 7.44–8.11 (m, 5H), 8.23, 8.25 (s, 1H). Anal.
calcd for C17H15FN2O5·0.2H2O: C, 58.35; H, 4.44; N,
8.01. Found: C, 58.06; H, 4.50; N, 7.35%.
3.20. (+)-1-[(1S,4S)-3-Fluoro-4-hydroxy-5-dihydro-2,3-
enpyranosyl]cytosine, 16a
3.17. 1-[(1R,4R)-3-Fluoro 4-O-Benzoyl-5-dihydro-2,3-
enpyranosyl]N4-benzoylcytosine, 24a and its (1S)-iso-
mer, 24b
Compound 15a (85.2 mg, 0.2 mmol) was treated with
saturated methanolic ammonia (30 mL) and the result-
ing solution was stirred at rt for 24 h. The reaction
mixture was then concentrated under reduced pressure
and the residue was purified by silica gel column chro-
matography (12.5% MeOH/CH2Cl2) and subsequent
recrystallization from hexanes–MeOH–CH2Cl2 to give
16a (43.6 mg, 98%) as a crystalline solid: mp 177–
180°C; UV (H2O) umax 266.0 nm; [h]2D7 +19.5 (c 0.29,
MeOH); 1H NMR (DMSO-d6) l 3.57–3.91 (m, 2H),
4.11 (m, 1H), 5.50 (m, 1H), 5.66 (d, J=7.3 Hz), 5.77 (d,
J=6.4 Hz, D2O exchangeable, 1H), 6.44 (m, 1H), 7.21,
Silylated N4-benzoylcytosine [prepared from 239 mg
(1.11 mmol) of N4-benzoylcytosine and 10 mL of
HMDS], a solution of 23 (253 mg, 0.74 mmol) in dry
methylene chloride (10 mL), and TMSOTf (0.21 mL,
1.11 mmol) were reacted for overnight at rt under
nitrogen. After work-up similar to that of 15, isolation
by preparative TLC (50% EtOAc/hexanes) afforded 24a
(118 mg, 35.4%) and 24b (85 mg, 25.4%) as white
solids.

K. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 1589–1598
1597
7.25 (2s, D2O exchangeable, 2H), 7.53 (d, J=7.2 Hz,
1H, H-6). Anal. calcd for C9H10FN3O3·
0.6H2O·0.1C3H6O: C, 45.81; H, 4.88; N, 17.23. Found:
1H), 7.24 (s, 1H), 8.21 (s, 1H). Anal. calcd for
C10H11FN2O4·0.1C4H10O: C, 50.04; H, 4.85; N, 11.22.
Found: C, 50.12; H, 4.85; N, 11.37%.
C, 46.20; H, 4.69; N, 17.17%.
20b: mp 184–185°C; UV (MeOH) umax 262.0 nm; [h]D25
+16.88 (c 0.23, MeOH); 1H NMR (DMSO-d6) l 1.79 (s,
3H), 3.85 (m, 2H), 4.04 (m, 1H), 5.55 (m, 1H), 5.79 (d,
J=7.8 Hz, 1H), 6.31 (d, J=7.2 Hz, 1H), 7.42 (s, 1H),
11.41 (s, 1H). Anal. calcd for C10H11FN2O4·0.1CH4O:
C, 48.98; H, 4.98; N, 10.98. Found: C, 48.95; H, 4.81;
N, 10.74%.
3.21. (+)-1-[(1R,4S)-3-Fluoro-4-hydroxy-5-dihydro-2,3-
enpyranosyl]cytosine, 16b
Compound 16b was prepared from 15b on a 0.15 mmol
scale by the method described for compound 14a. Silica
gel column chromatography (12.5% MeOH/CH2Cl2)
and subsequent recrystallization from hexanes–MeOH–
CH2Cl2 gave 16b (33.2 mg, 97.4%) as a crystalline solid:
mp 168–170°C; UV (H2O) umax 266.0 nm; [h]2D5 +10.6 (c
3.24. (−)-1-[(1R,4R)-3-Fluoro-4-hydroxy-5-dihydro-2,3-
enpyranosyl]cytosine, 25a
1
0.68, MeOH); H NMR (DMSO-d6) l 3.83 (m, 2H),
4.12 (m, 1H), 5.48 (m, 1H), 5.77 (m, D2O exchangeable,
2H), 6.38 (m, 1H), 7.26, 7.31 (2s, D2O exchangeable,
2H), 7.54 (d, J=7.2 Hz, 1H). Anal. calcd for
C9H10FN3O3·0.6H2O·0.1C3H6O: C, 45.81; H, 4.88; N,
17.23. Found: C, 45.77; H, 4.62; N, 17.23%.
Compound 25a was prepared from 24a on a 0.22 mmol
scale by the method described for compound 16a. Silica
gel column chromatography (12.5% MeOH/CH2Cl2)
gave 25a (45 mg, 88.4%) as a white solid: mp 176–
178°C; UV (H2O) umax 266.0 nm; [h]2D6 −22.4 (c 0.25,
MeOH); 1H NMR (DMSO-d6) l 3.57–3.93 (m, 2H),
4.11 (m, 1H), 5.50 (dd, J=2.8, 14.8 Hz, 1H), 5.66 (d,
J=7.3 Hz, 1H), 5.77 (d, J=6.4 Hz, D2O exchangeable,
1H), 6.44 (m, 1H), 7.21, 7.25 (2s, D2O exchangeable,
2H), 7.53 (d, J=7.2 Hz, 1H). Anal. calcd for
C9H10FN3O3: C, 47.58; H, 4.44; N, 18.50. Found: C,
47.50; H, 4.38; N, 18.25%.
3.22. (+)-1-[(1S,4S)-3-Fluoro-4-hydroxy-5-dihydro-2,3-
enpyranosyl]uracil, 19a and its (+)-(1R,4S)-isomer, 19b
A anomeric mixture 17 (155 mg, 0.47 mmol) was
treated with saturated methanolic ammonia (50 mL)
and the resulting solution was stirred at rt for 10 h. The
reaction mixture was concentrated under reduced pres-
sure and the residue was purified by preparative TLC
(5% MeOH/CH2Cl2) to separate 19a (59.2 mg, 55.2%)
and 19b (43 mg, 40.1%), which were recrystallized from
MeOH–CH2Cl2, respectively.
3.25. (−)-1-[(1S,4R)-3-Fluoro-4-hydroxy-5-dihydro-2,3-
enpyranosyl]cytosine, 25b
Compound 25b was prepared from 24b on a 0.18 mmol
scale by the method described for compound 16a. Silica
gel column chromatography (12.5% MeOH/CH2Cl2)
gave 25b (37.8 mg, 92.5%) as a white solid: mp 167–
169°C; UV (H2O) umax 266.0 nm; [h]2D5 −11.25 (c 0.27,
19a: mp 185–188°C; UV (MeOH) umax 257.0 nm; [h]D24
1
+17.9 (c 0.41, MeOH); H NMR (DMSO-d6) l 3.79–
3.92 (m, 2H), 4.09 (m, 1H), 5.58 (dd, J=1.67, 11.3 Hz,
1H), 5.71 (d, J=8 Hz, D2O exchangeable, 1H), 5.82 (d,
J=7.4 Hz, 1H), 6.35 (m, 1H), 7.64 (d, J=8.0 Hz, 1H),
11.43 (s, 1H). Anal. calcd for C9H9FN2O4: C, 47.37; H,
3.98; N, 12.28. Found: C, 47.36; H, 4.07; N, 12.27.
1
MeOH); H NMR (DMSO-d6) l 3.83 (m, 2H), 4.12 (m,
1H), 5.48 (m, 1H), 5.77 (m, 2H, D2O exchangeable,
1H), 6.38 (m, 1H), 7.26, 7.31 (2s, D2O exchangeable,
2H), 7.54 (d, J=7.2 Hz, 1H). Anal. calcd for
C9H10FN3O3·0.4CH2Cl2: C,43.23; H, 4.17; N, 16.09.
Found: C, 43.33; H, 4.30; N, 16.31%.
19b: mp 182–184°C; UV (MeOH) umax 257.0 nm; [h]D25
1
+34.8 (c 0.26, MeOH); H NMR (DMSO-d6) l 3.63–
3.92 (m, 2H), 4.16 (m, 1H), 5.52 (d, J=2.8 Hz), 5.56
(m, 1H), 5.81 (d, J=6.6 Hz, 1H), 6.32 (d, J=7.2 Hz,
1H), 7.60 (d, J=8.0 Hz, 1H), 11.44 (s, 1H). Anal. calcd
for C9H9FN2O4: C, 47.37; H, 3.98; N, 12.28. Found: C,
47.43; H, 4.11; N, 12.23%.
3.26. (−)-1-[(1R,4R)-3-Fluoro-4-hydroxy-5-dihydro-2,3-
enpyranosyl]uracil, 28a and its (−)-(1S,4R)-isomer, 28b
Compounds 28a and 28b were prepared from 24 on a
0.39 mmol scale by the method described for com-
pounds 19a and 19b. Preparative TLC (5% MeOH/
3.23. (+)-1-[(1S,4S)-3-Fluoro-4-hydroxy-5-dihydro-2,3-
enpyranosyl]thymine, 20a and its (+)-(1R,4S)-isomer,
20b
CH2Cl2)
followed
by
crystallization
from
MeOH–CH2Cl2 gave 28a (48.4 mg, 54.7%) and 28b
(36.5 mg, 41%) as white solids.
Compounds 20a and 20b were prepared from 16 on a
0.42 mmol scale by the method described for com-
pounds 19a and 19b. Preparative TLC (5% MeOH/
CH2Cl2) followed by trituations with ether gave 20a
(54.4 mg, 53.5%) and 20b (39.4 mg, 38.7%) as white
solids.
28a: mp 186–188°C; UV (MeOH) umax 257.0 nm; [h]D25
1
−17.76 (c 0.32, MeOH); H NMR (DMSO-d6) l 3.79–
3.92 (m, 2H), 4.08 (m, 1H), 5.58 (dd, J=1.6, 12 Hz,
1H), 5.71 (d, J=8 Hz, 1H), 5.82 (d, J=7.8 Hz, 1H),
6.35 (m, 1H), 7.64 (d, J=7.8 Hz, 1H), 11.43 (s, 1H).
Anal. calcd for C9H9FN2O4: C, 47.37; H, 3.98; N,
12.28. Found: C, 47.59; H, 4.09; N, 12.37%.
20a: mp 175–176°C; UV (MeOH) umax 263.0 nm; [h]D25
+37.05 (c 0.21, MeOH); 1H NMR (DMSO-d6) l 1.87 (s,
3H), 3.83–4.18 (m, 3H), 5.28 (m, 1H), 6.38 (d, J=7 Hz,
28b: mp 180–182°C; UV (MeOH) umax 257.0 nm; [h]D25
1
−36.36 (c 0.18, MeOH); H NMR (DMSO-d6) l 3.63–

1598
K. Lee et al. / Tetrahedron: Asymmetry 13 (2002) 1589–1598
3.92 (m, 2H), 4.16 (m, 1H), 5.52 (d, J=3.2 Hz, 1H),
5.56 (m, 1H), 5.81 (d, J=6.6 Hz, 1H), 6.32 (d, J=7.2
Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 11.44 (s, 1H). Anal.
calcd for C9H9FN2O4: C, 47.37; H, 3.98; N, 12.28.
Found: C, 47.08; H, 4.01; N, 12.04%.
References
1. Nasr, M.; Litterst, C.; McGowan, J. Antiviral Res. 1990,
14, 125–148.
2. Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745–1768.
3. Nasr, M.; Cradock, J.; Johnston, M. I. AIDS Res. Human
Retrovirus 1992, 8, 135–144.
3.27. (−)-1-[(1R,4R)-3-Fluoro-4-hydroxy-5-dihydro-2,3-
enpyranosyl]thymine, 29a and its (−)-(1S,4R)-isomer,
29b
4. Hong, J. H.; Choi, Y.; Chun, B. K.; Lee, K.; Chu, C. K.
Arch. Pharm. Res. 1998, 21, 89–105.
5. Choi, Y.; Lee, K.; Hong, J. H.; Schinazi, R. F.; Chu, C.
K. Tetrahedron Lett. 1998, 39, 4437–4440.
6. Lee, K.; Choi, Y.; Gullen, E.; Schlueter-Wirtz, S.; Schinazi,
R. F.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1999, 42,
1320–1328.
Compounds 29a and 29b were prepared from 27 on a
0.35 mmol scale by the method described for com-
pounds 19a and 19b. Preparative TLC (5% MeOH/
CH2Cl2) followed by trituations with ether gave 29a
(46.7 mg, 55.1%) and 29b (35.9 mg, 42.3%) as white
solids.
7. Lee, K.; Choi, Y.; Schinazi, R. F.; Chu, C. K. Structure–
Activity Relationships of 2%-Fluoro-2%,3%-Unsaturated
D-
Nucleosides as Anti-HIV-1 Agents; 218th American
Chemical Society National Meeting 1999, August 22–26,
New Orleans, LA.
29a: mp 177–179°C; UV (MeOH) umax 262.0 nm; [h]D25
−37.61 (c 0.44, MeOH); 1H NMR (DMSO-d6) l 1.87 (s,
3H), 3.83–4.18 (m, 3H), 5.28 (m, 1H), 6.38 (d, J=7.2
Hz, 1H), 7.24 (s, 1H). Anal. calcd for C10H11FN2O4·
0.1C3H6O: C, 49.88; H, 4.74; N, 11.30. Found: C,
50.01; H, 4.80; N, 11.30%.
8. Pai, S. B., Chu, C. K., Schinazi, R. F. Inhibition of
hepatitis B virus by novel 2%-fluoro-2%,3%-unsaturated
D- and
L
-nucleosides; 3rd International Conference on Therapies
for viral Hepatitis, December 12–19, 1999, Maui, HI.
9. Koshida, R.; Cox, S.; Harmenberg, J.; Gilljam, G.;
Wahren, B. Antimicrob. Agents Chemother. 1989, 33,
2083–2088.
10. Scho¨rder, M. Chem. Rev. 1980, 80, 187–213.
11. Majetich, G.; Defauw, J.; Ringold, C. J. Org. Chem. 1988,
53, 50–68.
29b: mp 185–187°C; UV (MeOH) umax 262.0 nm; [h]D25
1
−16.3 (c 0.22, MeOH); H NMR (DMSO-d6) d 1.80 (s,
3H), 3.85 (m, 2H), 4.04 (m, 1H), 5.54 (m, 1H), 5.79 (d,
J=7.8 Hz, 1H), 6.31 (m, 1H), 7.42 (s, 1H), 11.41 (s,
1H). Anal. calcd for C10H11FN2O4·0.2C4H10O: C,
50.47; H, 5.10; N, 10.90. Found: C, 50.97; H, 5.15; N,
10.46%.
12. Vargeese, C.; Abushanab, E. J. Org. Chem. 1990, 55,
4400–4403.
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Acknowledgements
14. Crystallographic data (excluding structure factors) for 19a
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This research was supported by the US Public Research
grants (AI 32351). We thank Dr. Raymond F. Schinazi
of Emory University School of Medicine/VA Medical
Center for anti-HIV evaluation.