Synthesis and anti-HIV and anti-HBV activities of 2'-fluoro-2',3'- unsaturated L-nucleosides

Article abstract of DOI:10.1021/jm980651u

The synthesis of L-nucleoside analogues containing 2'-vinylic fluoride was accomplished by direct condensation method, and their anti-HIV and anti- HBV activities were evaluated in vitro. The key intermediate 8, the sugar moiety of our target compounds, w

Full text of DOI:10.1021/jm980651u

1320
J . Med. Chem. 1999, 42, 1320-1328
Syn th esis a n d An ti-HIV a n d An ti-HBV Activities of 2′-F lu or o-2′,3′-u n sa tu r a ted
L-Nu cleosid es
Kyeong Lee,† Yongseok Choi,† Elizabeth Gullen,§ Susan Schlueter-Wirtz,‡ Raymond F. Schinazi,‡
Yung-Chi Cheng,§ and Chung K. Chu*,†
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, The University of Georgia, Athens, Georgia
30602, Emory University School of Medicine/ Veterans Affairs Medical Center, Decatur, Georgia 30033, and Department of
Pharmacology and The Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Conneticut 06520
Received November 17, 1998
The synthesis of L-nucleoside analogues containing 2′-vinylic fluoride was accomplished by direct
condensation method, and their anti-HIV and anti-HBV activities were evaluated in vitro. The
key intermediate 8, the sugar moiety of our target compounds, was prepared from 1,2-O-
isopropylidene-L-glyceraldehyde via (R)-2-fluorobutenolide intermediate 5 in five steps. Coupling
of the acetate 8 with the appropriate heterocycles (silylated uracil, thymine, N4-benzoylcytosine,
N4-benzoyl-5-fluorocytosine, 6-chloropurine, and 6-chloro-2-fluoropurine) in the presence of
Lewis acid afforded a series of 2′-fluorinated L-nucleoside analogues (15-18, 23-26, 36-45).
The newly synthesized compounds were evaluated for their antiviral activities against HIV-1
in human peripheral blood mononuclear (PBM) cells and HBV in 2.2.15 cells. Cytosine 23,
5-fluorocytosine 25, and adenine 36 derivatives exhibited moderate to potent anti-HIV (EC50
0.51, 0.17, and 1.5 µM, respectively) and anti-HBV (EC50 0.18, 0.225, and 1.7 µM, respectively)
activities without significant cytotoxicity up to 100 µM in human PBM, Vero, CEM, and HepG2
cells.
In tr od u ction
In addition, a number of nucleosides with a fluorinated
sugar moiety have shown significant biological activi-
ties, including 3′-dideoxy-3′-fluorothymidine (FLT),12 2′-
â-fluoro-2′,3′-dideoxyadenosine (F-ddA),11 and â-L-2′-
fluoro-5-methyl-1-(arabinofuranosyl)uracil (L-FMAU).13,14
To date, three 2′-fluorinated 2′-ene-type nucleosides
with D-configurations (â-D-2′-Fd4C, â-D-2′-Fd4U, and
â-D-2′-Fd4T) have been reported, but they are less
potent than AZT as antiviral agents.15-17
In view of the above findings, it was of interest to
study the effects of 2′-vinylic fluoride of L-nucleosides
in regard to antiviral activity. In a recent communica-
tion, we reported the preliminary results of adenine and
hypoxanthine derivatives, in which â-L-2′-Fd4A showed
moderately potent anti-HIV activity (EC50 1.5 µM) in
human peripheral blood mononuclear (PBM) cells.18
Herein, we wish to report the full accounts of the
synthesis and biological evaluation of the titled nucleo-
sides.
Intensive efforts in the search for safe and effective
antiviral agents against human immunodeficiency virus
(HIV) and hepatitis B virus (HBV) have led to the
discovery of 2′,3′-dideoxy nucleoside analogues, includ-
ing 3′-azido-3′-dideoxythymidine (AZT),1 2′,3′-dideoxy-
cytidine (ddC),2 2′,3′-dideoxyinosine (ddI),3 2′,3′-didehydro-
3′-deoxythymidine (d4T),4 (-)-(2R,5S)-1-[2-(hydroxy-
methyl)oxathiolan-5-yl]cytosine (3TC),5 and (-)-(2R,5S)-
5-fluoro-1-[2-(hydroxymethyl)oxathiolan-5-yl]cytosine
(FTC).6 Particularly, a class of nucleosides with the
unnatural L-configurations has recently drawn consid-
erable attention by medicinal chemists due to their
unique potency, mechanism, and toxicity profile.7 In
connection with these efforts, Gosselin et al. and Lin et
al. have reported the synthesis of L-2′,3′-didehydro-2′,3′-
dideoxycytidine (â-L-d4C) and its 5-fluoro congener â-L-
Fd4C, which showed potent anti-HIV and anti-HBV
activity.8 Recently, we have also described the synthesis
and antiviral activity of â-L-2′,3′-dideoxy (â-L-d2N) and
2′,3′-didehydro-2′,3′-dideoxy (â-L-d4N) purine nucleo-
sides, among which â-L-d4A exhibited the most potent
antiviral activity against HIV and HBV.9 However, it
is well-established that d2 and d4 purine nucleosides
are unstable in acidic media, resulting in glycosyl bond
cleavage, thus limiting their usefulness as orally bio-
available drugs.10 As an isosteric replacement for hy-
drogen, fluorine is attractive due to its similar size to
hydrogen and provides acid stability to the dideoxy
nucleosides when it is substituted at the 2′-position.11
Resu lts a n d Discu ssion
Previously, the synthesis of 2′-ene-type nucleosides
(d4N) was accomplished mainly by divergent methods,
starting from readily available nucleoside analogues and
involving lengthy modifications of individual nucleo-
sides.9,15,16,19 Moreover, this synthetic strategy for L-2′-
Fd4N is compounded by additional difficulties as start-
ing materials are not available from natural sources.
The convergent approach for the preparation of nucleo-
side analogues is more versatile, since it can employ a
variety of purine and pyrimidine nucleosides from the
same intermediate, thus providing a facile and concise
route for a variety of nucleosides. The most common
methodology for condensation of a carbohydrate moiety
with a heterocyclic base involves the use of a Lewis acid
* Corresponding author: Dr. C. K. Chu. Tel: (706) 542-5379. Fax:
(706) 542-5381. E-mail: dchu@rx.uga.edu.
† The University of Georgia.
‡ Emory University School of Medicine.
§ Yale University School of Medicine.
10.1021/jm980651u CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/12/1999

2′-Fluoro-2′,3′-unsaturated L-Nucleosides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1321
Sch em e 1a
a
Reagents: (i) (EtO)2P(O)CHFCO2Et, NaHMDS, THF, -78 °C; (ii) c-HCl, EtOH; (iii) TBDMSCl, imidazole, CH2Cl2; (iv) DIBAL-H,
CH2Cl2, -78 °C; (v) Ac2O, TEA, CH2Cl2; (vi) silylated uracil or thymine, TMSOTf, DCE; (vii) silylated N4-Bz-cytosine or N4-Bz-5-F-
cytosine; TMSOTf, CH3CN or DCE; (viii) TBAF, THF; (ix) satd NH3/MeOH.
or an electrophile in conjunction with a 1-O-acyl/alkyl
furano- or pyranoside which undergo an oxonium ion
formation or a direct nucleophilic displacement.20 How-
ever, due to lability of the 2,3-unsaturated sugar moiety
under coupling conditions in the presence of Lewis acid,
few examples are reported for the synthesis of 2′-ene-
type nucleosides by direct condensation methods, except
one case for pyrimidine derivatives via a thiophenyl
intermediate.21 We envisioned that a 2,3-unsaturated
sugar moiety bearing a fluorine atom at the 2-position
was amenable to direct coupling reaction conditions.
Therefore, the required key intermediate 8 was con-
structed from L-glyceraldehyde acetonide (1) via (R)-2-
fluorobutenolide (5) as a chiral template, leading to the
target carbohydrate moiety, which was then successfully
condensed with appropriate silylated heterocycles to
reach the desired nucleosides (Scheme 1).
propylidenation followed by oxidative cleavage using
sodium periodate.22 Aldehyde intermediate 1 was sub-
jected to Horner-Emmons reaction in the presence of
triethyl R-fluorophosphonoacetate and sodium bis(tri-
methylsilyl)amide in THF to give a mixture of (E)-2/
(Z)-2 (9:1 determined by 1H NMR).23,24 Due to difficulties
in separation of (E)-2/(Z)-2 isomers, the mixture was
directly used in the cyclization reaction under acidic
conditions to give the desired 2-fluorobutyrolactone 3
and diol 4. The resulting mixture was further converted
into corresponding silyl derivatives, which were readily
separated to give 5 as a white solid (70.2% yield from
aldehyde 1). The silylated lactone 5 was then reduced
by DIBAL-H in CH2Cl2 to provide lactol 7, which was
then treated with acetic anhydride to afford the key
intermediate 8 in 62% yield from compound 5. N-
Glycosylation reactions of pyrimidine bases with sugar
moiety 8 were conducted under the Vorbru¨ggen condi-
tions using TMSOTf as a catalyst. 5′-Silyl-protected
L-Glyceraldehyde acetonide (1) was obtained from
L-gulonic-γ-lactone according to the literature, by iso-

1322 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Lee et al.
Sch em e 2a
a
Reagents: (i) silylated 6-Cl-purine, TMSOTf, CH2Cl2; (ii) silylated 6-Cl-2-F-purine, TMSOTf, DCE; (iii) TBAF, CH3CN; (iv) dry NH3/
DME; (v) satd NH3/MeOH, 90 °C; (vi) HSCH2CH2OH, 1 M NaOMe, MeOH, reflux.
uracil and thymine nucleosides 9 and 10 were formed
in 64-73% yield as inseparable R/â mixtures after
condensation of 8 with silylated uracil or thymine. These
anomeric mixtures 9 and 10 were treated with tetra-
n-butylammonium fluoride in THF to afford free nucleo-
sides 15-18, which were readily separated by silica gel
column chromatography (â:R ) 1.5-1.58:1, 67-74%).
Likewise, condensation of 8 with silyated N4-benzoyl-
cytosine in dry acetonitrile gave protected cytosine
derivatives 11 and 12, which were readily isolated by
silica gel column chromatography (â:R ) 1.48:1). Depro-
tections of individual anomers in the presence of tetra-
n-butylammonium fluoride (69-75%), followed by am-
monolysis using saturated methanolic ammonia at room
temperature (76-95%), afforded the final cytosine de-
rivatives 23 and 24. The 5-fluorocytosine derivatives 25
and 26 (â:R ) 1.39:1) were also obtained by similar
procedures to that of cytosine derivatives.
The synthetic route for purine nucleosides 36-45 is
described in Scheme 2. Condensation of the acetate 8
with silylated 6-chloropurine followed by removal of the
5′-silyl protection group provided 6-chloropurine nucleo-
sides 30 and 31 (â:R ) 1:1.29), which were utilized as
intermediates for the preparation of L-2′-Fd4A and L-2′-
Fd4I analogues. The â-6-chloropurine derivative 30 was
transformed into its corresponding adenine derivative
36 in 75% yield by treatment with methanolic ammonia
in a steel bomb at 90 °C for 24 h. The â-L-inosine
analogue 38 was also obtained from 30 in 80% yield by
refluxing with sodium methoxide and 2-mercaptoetha-
nol in methanol. The corresponding R-anomers 37 and
39 were synthesized by procedures analogous to those
used for the preparation of 36 and 38. The key inter-
mediate 8 was also utilized for the synthesis of guanine
and related 2,6-disubstituted purine analogues (Scheme
2). Similarly, condensation of acetate 8 with silylated
2-fluoro-6-chloropurine in dry 1,2-dichloroethane (DCE)
at room temperature gave â-anomer 28 (30%) and
R-anomer 29 (22.1%) after silica gel column chromatog-
raphy. A solution of 28 in ethylene glycol dimethyl ether
(DME) was bubbled with dry ammonia at room tem-
perature for 16 h to give 2-amino-6-chloropurine deriva-
tive 32 (28.9%) and 2-fluoro-6-aminopurine derivative
33 (39.4%), which were readily separated by silica gel
column chromatography. Individual protected nucleo-
sides 32 and 33 were treated with tetra-n-butylammo-
nium fluoride to afford â-L-2′-fluoro-2′,3′-unsaturated
2-fluoroadenine 40 and -2-amino-6-chloropurine 42 in
high yields. Compound 42 was then further transformed
to guanine derivative 44 by refluxing in the presence
of mercaptoethanol and sodium methoxide in 50.7%
yield. The corresponding R-isomers 41, 43, and 45 were
also prepared by similar procedures as their â-isomers.
The stereochemical assignments of these compounds
were determined on the basis of NOESY experiments
on adenine derivatives 36 and 37, in which cross-peaks
exist between 1′-H and 4′-H and aromatic 8-H and 5′-H
in â-isomer 36, while no such cross-peak was observed
in R-isomer 37. Instead, a cross-peak between 8-H and
4′-H was observed in compound 37. This stereochemis-

2′-Fluoro-2′,3′-unsaturated L-Nucleosides
Ta ble 1. Physical Data
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1323
no.
mp, °C (solv)a
[R]D, deg
formula
anal.
9
10
11
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
38
39
40
41
42
43
44
45
syrup
syrup
mixture
mixture
C
C
15H23FN2O4Si
16H25FN2O4Si
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, 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, 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, N
C, H, N
C, H, N
C, H, N
C, H, N
144-146 (A)
139-141 (A)
138-140 (A)
184-186 (A)
161-162 (B)
136-137 (E)
149-151 (C)
116-118 (E)
200-202 dec (B)
170-172 (B)
173-174 (D)
183-185 (F)
173-174 (D)
182-183 (B)
202-205 (D)
158-160 (B)
syrum
-20.47 (c 0.36, CHCl3)
+157.68 (c 0.31, CHCl3)
+7.38 (c 0.19, CHCl3)
+97.90 (c 0.22, CHCl3)
-13.412 (c 0.20, MeOH)
+138.55 (c 0.14, MeOH)
-30.44 (c 0.20, MeOH)
+132.42 (c 0.25, MeOH)
-54.89 (c 0.39, CHCl3)
+136.38 (c 0.45, CHCl3)
-41.75 (c 0.22, MeOH)
+148.76 (c 0.19, MeOH)
-21.31 (c 0.25, MeOH)
+159.15 (c 0.21, MeOH)
-26.76 (c 0.21, MeOH)
+145.89 (c 0.45, MeOH)
mixture
+9.80 (c 0.20, CHCl3)
+139.67 (c 0.18, CHCl3)
-43.04 (c 0.18, CHCl3)
+157.63 (c 0.20, CHCl3)
+13.33 (c 0.54, CHCl3)
+90.22 (c 0.23, CHCl3)
+116.53 (c 0.13, CHCl3)
+89.87 (c 0.15, CHCl3)
-54.91 (c 0.17, MeOH)
+160.62 (c 0.19, MeOH)
-50.21 (c 0.20, MeOH)
+157.30 (c 0.22, MeOH)
-56.15 (c 0.16, MeOH)
+178.22 (c 0.10, MeOH)
+10.64 (c 0.17, MeOH)
+142.49 (c 0.17, MeOH)
+24.42 (c 0.11, DMF)
+58.68 (c 0.10, DMF)
C22H28FN3O4Si
C22H28FN3O4Si
C22H27F2N3O4Si
C22H27F2N3O4Si
C9H9FN2O4‚0.3H2O
C9H9FN2O4‚0.2H2O
C
C
10H11FN2O4‚0.4H2O
10H11FN2O4‚0.3H2O
C16H14FN3O4
C16H14FN3O4‚0.3H2O
C
C
C9H10FN3O3‚0.4H2O
C9H10FN3O3
C9H9F2N3O3
C9H9F2N3O3
C
C16H21F2ClN4O2Si
C16H21F2ClN4O2Si
C10H8FClN4O2‚0.1C2H6O
C10H8FClN4O2
C16H23F2N5O2Si‚0.2C3H6O
C16H23FClN5O2Si
C16H23F2N5O2Si‚0.3C3H6O
C16H23FClN5O2Si
16H13F2N3O4
16H13F2N3O4
16H22FClN4O2Si
foam
syrup
130-132 (B)
foam
180-182 (A)
129-130 (A)
184-186 (A)
128-130 (A)
188-190 (B)
168-171 (B)
128-130 (E)
>200 dec (B)
185-188 dec (B)
180 dec (B)
155-156 dec (B)
150-152 (B)
>200 dec (B)
>220 dec (B)
C
C
C
10H10FN5O2‚0.2H2O
10H10FN5O2‚0.3CH4O
10H9FN4O3‚0.2H2O
C10H9FN4O3‚0.3H2O
C
C
C
C
C
C
10H9F2N5O2‚0.6CH4O
10H9F2N5O2‚0.4H2O
10H9ClFN5O2
10H9ClFN5O2
10H10FN5O3‚0.2H2O
10H10FN5O3‚0.7CH2Cl2
a
Solvents: A, EtOAc-hexanes; B, CH2Cl2-MeOH; C, THF-cyclohexane; D, hexanes-CH2Cl2-MeOH; E, lyophilized from water; F,
EtOH.
try was also supported by lower field chemical shifts of
4′-H (R-form) compared to those of 4′-H (â-form) due to
deshielding effects by heterocyclic bases. The detailed
proton NMR data and physical properties of synthesized
nucleosides are listed in Tables 1 and 2.
(EC50 0.51 µM) and â-L-2′-Fd4FC (25) (EC50 0.17 µM)
were found to be the most potent compounds against
HIV-1 with no significant cytotoxicity. However, uracil
and thymine derivatives 15-18 showed no activity with
EC50 values above 100 µM. For purine analogues, â-L-
2′-Fd4A (36) was the most potent nucleoside in the
following decreasing order: â-L-2′-Fd4A (36) (1.5) > â-L-
2′-Fd4FA (40) (2.2) > â-L-2′-Fd4I (38) (4.7) > R-L-2′-F-
6-Cl-2-NH2-purine (43) (14.5) > R-L-2′-Fd4A (37) (47.6)
> R-L-2′-Fd4G (45) (76.9). It is interesting to note that
43 and 45 displayed some anti-HIV activities as R-iso-
mers, while no activity was found in the corresponding
â-isomers 42 and 44, which may be related to the
greater overall cell toxicity of these compounds com-
pared to their â-isomers which produced lower multi-
plicity of the virus. We are confident about the assign-
ment of the structures of these compounds since 6-chloro-
2-fluoropurines 28 (â) and 29 (R) were also subsequently
used for further modifications to 2-fluoroadenine deriva-
tives, in which â-isomer 40 (2.2 µM) was found to be
significantly more potent than the corresponding R-
isomer 41 (>100 µM). Previously, several authors
reported that â-D-2′-Fd4C showed anti-HIV activity with
significant cytotoxicity.15-17 In connection with these
findings, it appears that â-L-2′-Fd4C (23) (0.51 µM)
displays enhanced potency against HIV-1 with more
selectivity than that of its D-antipode (3-10 µM).
Furthermore, â-L-d4FC8 is significantly more toxic than
the corresponding 2′-fluoro derivative â-L-2′-Fd4FC (25),
In preliminary studies, the effect of chemical stability
of glycosyl bond by 2′-fluorine substitution was inves-
tigated, in which â-L-2′-Fd4FA (40) was found to have
increased stability relative to the compound without a
fluorine substitution at the 2′-position (â-L-d4FA). At
physiological conditions (pH 7.4, 37 °C), the half-life of
â-L-d4FA was approximately 30 h, while no degradation
was observed for â-L-2′-Fd4FA (40) up to 6 days. The
stability of â-L-2′-Fd4A (36) was also investigated at pH
2.0, 7.4, and 11, in which compound 36 was stable at
pH 7.4 and 11, while at pH 2, the degradation began
after 18 h with a half-life of approximately 3 days.
Therefore, it is concluded that the 2′-fluorine incorpora-
tion significantly increased the chemical stability of
glycosyl linkage of 2′,3′-didehydro-2′,3′-dideoxynucleo-
sides without reduction of the antiviral activity.
Str u ctu r e-Activity Rela tion sh ip s. The newly syn-
thesized nucleosides were tested for their antiviral
activities and cytotoxicities in vitro, and the results are
summerized in Table 3. The anti-HIV-1 activities of the
synthesized nucleosides were evaluated in human pe-
ripheral blood mononuclear (PBM) cells infected with
HIV-1, and AZT was included as a positive control
(Table 3). Among these nucleosides, â-L-2′-Fd4C (23)

1324 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Ta ble 2. 1H NMR Data
Lee et al.
no.
H-1′
H-3′
5.72 (m)
H-4′
H-5′
other signals
9a 6.88 (m)
4.97 (m), 4.88 (m)
3.93-3.68 (m)
8.02 (s, NH), 7.94 (d, H-6, J ) 8 Hz), 7.18
t
t
(d, H-5, J ) 8 Hz), 0.92 (s, Bu), 0.90 (s, Bu),
0.10, 0.09, 0.085, 0.074 (4s, 4 × CH3)
10a 6.96 (s), 6.87 (m)
11a 7.12 (s)
5.73 (s), 5.66 (s)
5.61 (s)
4.98 (m), 4.84 (m)
4.94 (s)
3.83-3.67 (m)
3.97-3.80 (m)
8.15 (s, NH), 7.38 (s, H-6), 1.94 (s, 5-CH3), 0.92 (s, Bu),
t
t
0.90 (s, Bu), 0.10, 0.09, 0.085, 0.074 (4s, 4 × CH3)
8.41 (d, H-6, J ) 7.2 Hz), 7.93-7.50 (m, 6H, H-5, Ph-H),
t
0.94 (s, Bu), 0.13, 0.12 (2s, 2 × CH3)
12a 7.08 (ps t)
13a 6.94 (s)
5.75 (s)
5.05 (ps, t, J ) 4.4, 3.82-3.71 (m)
4.8 Hz)
7.91 (d, H-6, J ) 6 Hz), 7.64-7.50 (m, 6H, H-5, Ph-H),
t
0.91 (s, Bu), 0.09, 0.08, (2s, 2 × CH3)
t
6.62 (s)
4.92 (m)
5.03 (m)
4.81 (s)
3.92 (m)
8.32-7.44 (m, 6H, H-5, Ph-H), 0.94 (s, Bu), 0.15,
0.14 (2s, 2 × CH3)
14a 6.91 (ps t, J )
4.57, 4.75 Hz)
5.77 (s)
3.75 (m)
8.31-7.44 (m, 5H, Ph-H), 7.32 (d, J ) 5.4 Hz, H-6),
t
0.91 (s, Bu), 0.09, 0.08 (2s, 2 × CH3)
15b 6.77 (s)
6.01 (s)
3.58 (s)
11.5 (s, -NH), 7.99 (d, H-6, J ) 8 Hz),
5.71 (d, H-5, J ) 8 Hz), 5.13 (t, J ) 5.2 Hz, OH)
11.5 (s, -NH), 7.56 (d, H-6, J ) 8 Hz),
5.70 (d, H-5, J ) 8 Hz), 4.94 (t, OH, J ) 6 Hz)
11,5 (s, -NH), 7.89 (s, H-6), 5.17 (t, J ) 5.2 Hz, OH),
1.76 (s, 3H, CH3-6)
16b 6.77 (t, J ) 4.4 Hz) 6.02 (d, J ) 1.2 Hz)
5.02 (ps t, J ) 4,
4.4 Hz)
3.56-3.45 (m)
3.60 (s)
17b 6.77 (s)
6.00 (s)
6.01 (s)
4.80 (s)
18b 6.78 (ps t, J ) 4,
4.4 Hz)
5.05 (t, J ) 4 Hz)
3.68-3.45 (m)
11,5 (s, -NH), 7.37 (s, H-6), 4.94 (t, J ) 6 Hz, OH),
1.81 (s, 3H, CH3-6)
8.21 (d, J ) 8 Hz, H-6), 7.64-7.50 (m, H-5, Ph-H)
7.92 (d, J ) 7.2 Hz, H-6), 7.64-7.50 (m, H-5, Ph-H)
19a 7.01 (s)
5.71 (s)
5.74 (s)
4.99 (s)
3.88 (m)
3.73-3.69 (m)
20a 7.16 (ps t, J )
3.6, 4.4 Hz)
5.13 (ps t, J ) 3.2,
4.8 Hz)
21a 6.93 (s)
5.71 (s)
5.77 (s)
4.95 (s)
3.99-3.80 (m)
3.88-3.68 (m)
8.30-7.44 (m, 6H, H-6, Ph-H)
8.31-7.45 (m, 5H, Ph-H), 7.332 (d, J ) 5.32, H-6)
22a 6.97 (ps t, J )
4.82, 4.43 Hz)
23b 6.85 (s)
5.11 (ps t, J ) 4.6,
4.7 Hz)
5.94 (d, J ) 1.2 Hz)
5.94 (d, J ) 1.6 Hz)
5.93 (m)
4.76 (s)
3.56 (s)
7.86 (d, J ) 7.2 Hz, H-6), 7.36, 7.32 (2s, NH2),
5.77 (d, J ) 7.2 Hz, H-5), 5.07 (t, J ) 5.2 Hz, OH)
24b 6.86 (ps t, J )
4.4, 4.8 Hz)
4.94 (m)
4.81 (m)
3.455-3.43 (m) 7.47 (d, J ) 7.6 Hz, H-6), 7.35, 7.32 (2s, NH2),
5.80 (d, J ) 7.2 Hz, H-5)
7.98, 7.73 (2s, 2H, NH2), 5.4 (t, J ) 5.1 Hz, OH)
7.99 (s, 1′H, NH), 7.76-7.73 (m, 2H, 6-H, NH)
25b 6.81 (s)
3.61 (m)
3.54-3.43 (m)
26b 6.81 (s)
5.93 (d, J ) 0.88 Hz) 5.05 (ps t, J ) 3.9,
4.0 Hz)
27a 7.01 (s), 6.93
(t, J ) 4.4 Hz)
28a 6.88 (s)
29a 6.81 (m)
30a 6.88 (s)
31a 7.00 (m)
32a 6.81 (m)
33a 6.78 (m)
34a 6.76 (m)
5.85 (s), 5.78 (s)
5.18 (ps t, J ) 4,
4.4 Hz), 5.02 (s)
5.02 (s)
5.19 (m)
5.12 (m)
3.85 (m)
8.79, 8.78 (2s, H-8), 8.60, 8.21 (2s, H-2), 0.92, 0.91
t
(2s, Bu), 0.111, 0.105, 0.097, 0.095 (4s, 4 × CH3)
t
5.77 (s)
5.84 (s)
5.85 (s)
5.86 (s)
5.73 (d, J ) 1.6 Hz)
5.75 (s)
5.80 (s)
3.88 (m)
3.81 (m)
3.88 (m)
3.87 (m)
8.60 (s, H-8), 0.91 (s, Bu), 0.112, 0.105 (2s, 2 × CH3)
t
8.17 (s, H-8), 0.92 (s, Bu), 0.103, 0.089 (2s, 2 × CH3)
8.78 (s, H-8), 8.50 (s, H-2)
8.78 (s, H-8), 8.22 (s, H-2)
5.29 (m)
t
4.96 (d, J ) 2.8 Hz) 3.90-3.80 (m)
4.95 (m)
5.13 (ps t, J ) 4.4,
4.8 Hz)
8.19 (s, H-8), 0.91 (s, Bu), 0.09, 0.084 (2s, 2 × CH3)
t
3.81 (m)
3.76-3.65 (m)
8.14 (s, H-8), 5.11 (s, NH2), 0.89 (s, Bu), 0.076 (s, CH3)
t
7.84 (s, H-8), 0.91 (s, Bu), 0.093, 0.08 (2s, 2 × CH3)
35a 6.73 (ps t, J ) 4.4, 5.80 (s)
5.09 (m)
3.84-3.73 (m)
3.63 (s)
7.84 (s, H-8), 5.12 (s, NH2), 0.91 (s, Bu), 0.096, 0.082
t
4.8 Hz)
(s, CH3)
36b 6.90 (s)
6.08 (s)
6.06 (s)
4.91 (s)
8.40 (s, H-8), 8.17 (s, H-2), 7.40 (s, NH2),
5.22 (t, J ) 5.6 Hz, OH)
8.31 (s, H-8), 8.17 (s, H-2), 7.36 (s, NH2), 4.97 (t,
J ) 6 Hz, OH)
12.57 (br s, NH), 8.43 (s, H-8), 8.17 (s, H-2), 5.17 (s, OH)
8.26 (s, H-8), 8.09 (s, H-2)
37b 6.89 (t, J ) 4 Hz)
5.14 (ps t, J ) 3.6,
4 Hz)
4.98 (s)
5.13 (ps t, J ) 3.6,
3.7 Hz)
3.63-3.52 (m)
38b 6.94 (m)
39b 6.87 (ps t, J )
2.7,5.3 Hz)
6.15 (t, J ) 1.6 Hz)
6.06 (s)
3.67 (s)
3.61-3.51 (m)
40b 6.80 (s)
6.09 (ps t, J ) 1.2,
1.6 Hz)
6.07 (d, J ) 1.2 Hz)
6.09 (s)
4.90 (s)
3.62 (m)
8.38 (s, H-8), 7.99, 7.92 (2br s, NH2), 5.09 (t,
J ) 5.6 Hz, OH)
8.30 (s, H-8), 7.96 (2s, NH2)
8.38 (s, H-8), 7.07 (s, NH2), 5.10 (s, OH)
8.30 (s, H-8), 7.04 (s, NH2), 4.98 (t, J ) 6 Hz, OH)
41b 6.82 (m)
5.12 (m)
4.91 (s)
5.16 (ps t, J ) 3.6,
4 Hz)
3.61-3.51 (m)
3.60 (s)
3.62-3.51 (m)
42b 6.76 (s)
43b 6.72 (t, J ) 4 Hz)
6.06 (d, J ) 1.2 Hz)
44b 6.60 (s)
45b 6.62 (m)
6.03 (d, J ) 1.2 Hz)
6.01 (d, J ) 1.6 Hz)
4.86 (s)
3.59 (s)
10.74 (br s, NH), 7.96 (s, H-8), 6.57 (s, NH2),
5.08 (t, J ) 5.2 Hz, OH)
7.82 (s, H-8), 6.57 (s, NH2), 4.95 (t, J ) 5.6 Hz, OH)
5.08 (m)
3.64-3.42 (m)
a
b
CDCl3. DMSO-d6.
suggesting that 2′-fluorine substitution can decrease
toxicity of certain L-d4N analogues.
compounds were also tested against HSV-1 in vitro and
were inactive up to 50 µM.
The synthesized nucleosides were also evaluated
against HBV in vitro as shown in Table 3. â-L-2′-Fd4C
(23) (0.18 µM), â-L-2′-Fd4FC (25) (0.225 µM), and â-L-
2′-Fd4A (36) (1.7 µM) also exhibited significant anti-
HBV activities in 2.2.15 cells without toxicity up to 100
µM. Therefore, we may conclude that the structural
requirements for anti-HIV and anti-HBV activities are
similar. However, it is not known at the present time
whether the structural requirements are similar at the
stage of kinases or polymerase level. Two nucleosides
(23 and 36) showed no effect on mitochondrial DNA
content of CEM cells upon long-term exposure. These
In summary, we have developed an efficient synthetic
methodology for a series of 2′-fluoro-2′,3′-unsaturated
pyrimidine and purine L-nucleosides. Preliminary bio-
logical evaluation in vitro indicates that â-L-2′-Fd4C
(23), â-L-2′-Fd4FC (25), and â-L-2′-Fd4FA (36) exhibited
significant anti-HIV and anti-HBV activities with in-
creased chemical stability.
Exp er im en ta l Section
Melting points were determined on a Mel-temp II laboratory
device and are uncorrected. Nuclear magnetic resonance
spectra were recorded on a Bruker AMX400 400-MHz spec-

2′-Fluoro-2′,3′-unsaturated L-Nucleosides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1325
Ta ble 3. Anti-HIV and Anti-HBV Activities of 2′-Fluoro-2′,3′-unsaturated L-Nucleosides
EC50, µM
toxicities (IC50, µM)
compd
B
HIV-1
>100
>100
>100
>100
0.51
>100
0.17
>100
1.5
HBV
>10
>10
>10
>10
PBM cells
Vero cells
CEM cells
15
16
17
18
23
24
25
26
36
37
38
39
40
41
42
43
44
45
AZT
uracil (â)
uracil (R)
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
25.8
>100
>100
26.6
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
∼173
>100
>100
>100
>100
>100
29.0
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
19.5
>100
>100
28.2
>100
>100
14.3
thymine (â)
thymine (R)
cytosine (â)
0.18
>10
0.225
>10
1.7
>10
>10
>10
>10
>10
>10
>10
>10
>10
>10
cytosine (R)
5-F-cytosine (â)
5-F-cytosine (R)
adenine (â)
adenine (R)
47.6
4.7
inosine (â)
inosine (R)
>100
2.2
>100
>100
14.5
>100
76.9
0.004
2-F-adenine (â)
2-F-adenine (R)
6-Cl-2-NH2-purine (â)
6-Cl-2-NH2-purine (R)
guanine (â)
guanine (R)
trometer with tetramethylsilane as the internal reference;
chemical shifts (δ) 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 spectrophotometer. Optical rotations were measured on
g (70.2% from compound 1) of crystalline solid 5: mp 48-50
1
°C; [R]28 +105 0.3 (c 1.60, CHCl3); H NMR (CDCl3) δ 0.07,
D
0.08 (2s, 2 × CH3), 0.88 (s, t-Bu), 3.88 (m, 2H, H-5), 5.01 (m,
1H, H-4), 6.73 (ps t, 1H, J ) 4 Hz). Anal. Calcd for C10H19
FO3Si: C, 53.63; H, 7.77. Found: C, 53.70; H, 7.75.
-
1-Acetyl-4-[(ter t-bu tyldim eth ylsilyloxy)m eth yl]-2-flu or o-
2-bu ten -4-olid e (8). Lactone 5 (20.58 g, 83.54 mmol) was
dissolved in 200 mL of CH2Cl2 under nitrogen atmosphere;
then the mixture was cooled to -78 °C and treated with a 1.0
M solution of DIBAL-H in CH2Cl2 (125 mL). The resulting
mixture was reacted for 2 h at -78 °C. The cold mixture was
treated with dilute nitric acid, washed with water, and dried
(Na2SO4). Evaporation of the solvent gave an anomeric mixture
of 7 as a pale-yellow oil (16.6 g, crude yield 80%), which was
used as such for the next step.
Acetic anhydride (8.2 mL, 87.12 mmol) was added to a
solution of 7 (5.41 g, 21.78 mmol) and triethylamine (12.1 mL,
87.12 mmol) in CH2Cl2 (45 mL) at 0 °C, and the resulting
mixture was kept for 2 h at room temperature. The reaction
mixture was concentrated in vacuo and purified by silica gel
column chromatography (6.5% EtOAc/hexanes) to give acetate
8 (6.1 g, 77.5% from 7) as a yellowish oil: 1H NMR (CDCl3) δ
0.06, 0.10 (2s, 2 × CH3), 0.88, 0.90, 0.92 (3s, t-Bu, 2 × CH3),
3.61, 3.77 (m, 2H, H-5), 4.77, 4.96 (m, 1H, H-4), 5.63 (br s 1H,
3-H), 6.67-6.70 (m, 1H, H-1).
Gen er a l P r oced u r e for Con d en sa tion of Aceta te 8
w ith P yr im id in e Ba ses. A mixture of uracil (420 mg, 3.75
mmol), hexamethyldisilazane (15 mL), and ammonium sulfate
(20 mg) was refluxed for 3 h under nitrogen. The clear solution
obtained was concentrated to dryness in vacuo. TMSOTf (0.7
mL, 3.14 mL) was added to the solution of sugar 8 (728 mg,
2.50 mmol) and silylated base in dry DCE (20 mL) at 0 °C.
The reaction mixture was stirred for 2 h under nitrogen,
poured into cooled saturated NaHCO3 solution (30 mL), and
stirred for 15 min. The resulting mixture was washed, dried
(Na2SO4), and concentrated in vacuo. The crude product was
purified by silica gel column chromatography (3% MeOH/
CHCl3) to afford 9 (960 mg, 73%) as an inseparable anomeric
mixture, which was used in the next step without separation.
1-[5-O-(ter t-Bu tyld im eth ylsilyl)-2,3-d id eoxy-2-flu or o-L-
glycer o-p en t-2-en o-fu r a n osyl]u r a cil (9): UV (CHCl3) λmax
257.5 nm. Anal. (C15H23FN2O4Si) C, H, N.
a
J asco DIP-370 digital polarimeter. Mass spectra were
recorded on a Micromass AutoSpec high-resolution mass
spectrometer (LSIMS). Elemental analysis was performed by
Atlantic Microlab, Inc., Norcross, GA. All reactions were
monitored using thin-layer chromatography on Analtech, 200-
mm silica gel GF plates. Dry 1,2-dichloroethane, dichloro-
methane, and acetonitrile were obtained by distillation from
CaH2 prior to use. Dry THF was obtained by distillation from
Na and benzophenone when the solution became purple.
(E)/(Z)-Eth yl 3-[(R)-2,2-Dim eth yl-1,3-d ioxola n -4-yl]-2-
flu or oa cr yla te (E-2 a n d Z-2). A solution of triethyl 2-fluo-
rophosphonoacetate (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 of l-(S)-
glyceraldehyde acetonide (1) (19.14 g, 147 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 ex-
tracted with ether. The ether phase was washed with satu-
rated NaCl, dried over MgSO4, and concentrated. The residue
was chromatographed on silica gel to give mixture of E-2 and
Z-2 (9:1 by 1H NMR) as a yellowish oil (34.6 g, 97.9%): 1H
NMR (CDCl3) δ 1.34, 1.36 (2t, J ) 8 Hz, -CH2CH3), 1.40, 1.45
(2s, -CH3), 3.69 (m, Ha-5), 4.28 (m, Hb-5, -CH2CH3), 5.02 (m,
H-4), 5.40 (m, H-4), 6.02 (dd, J ) 8, 20 Hz, H-3), 6.18 (dd, J )
8, 32 Hz, H-3).
(R)-(+)-4-[(ter t-Bu tyldim eth ylsilyloxy)m eth yl]-2-flu or o-
2-bu ten -4-olid e (5). A solution of E/Z-2 (19.62 g, 89.89 mmol)
in 110 mL of anhydrous EtOH was treated with 30 mL of
concentrated HCl and stirred at room temperature for 2 h.
The solvent was removed in vacuo, and the residue was
coevaporated with toluene (3 × 300 mL) to give lactone 3 and
uncyclized ester 4. The resulting yellowish syrup was used as
such for the next reaction without further purification.
tert-Butyldimethylsilyl chloride (27.1 g, 180 mmol) and
imidazole (12.3 g, 180 mmol) were added to a solution of 3
and 4 in CH2Cl2 (250 mL), and the mixture was reacted for 4
h at room temperature. The resulting mixture was treated
with ice and diluted with CH2Cl2. The organic layer were
combined, dried over MgSO4, and concentrated to dryness.
Purification on silica gel (4% EtOAc/hexanes) furnished 28.0
1-[5-O-(ter t-Bu tyld im eth ylsilyl)-2,3-d id eoxy-2-flu or o-L-
glycer o-pen t-2-en o-fu r an osyl]th ym in e (10). Silylated thym-
ine, which was prepared from thymine (242 mg, 1.92 mmol)
and HMDS (20 mL), was treated with 8 (500 mg, 1.72 mmol)
and TMSOTf (0.5 mL, 2.25 mmol) in dry DCE at room

1326 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Lee et al.
temperature for 2 h under nitrogen. After workup similar to
that of 9, purification by silica gel column chromatography (3%
MeOH/CHCl3) gave an inseparable anomeric mixture of 10
(392 mg, 64%): UV (CHCl3) λmax 262.0 nm. Anal. (C16H25FN2O4-
Si) C, H, N.
1-[5-O-(ter t-Bu tyld im eth ylsilyl)-2,3-d id eoxy-2-flu or o-â-
L-glycer o-p en t-2-en ofu r a n osyl]-N4-ben zoylcytosin e (11)
a n d Its r-Isom er (12). Silylated N4-benzoylcytosine [prepared
from 790 mg (3.67 mmol) of N4-benzoylcytosine and 20 mL of
HMDS], 8 (470 mg, 1.62 mmol), and TMSOTf (0.5 mL, 2.25
mmol) in dry acetonitrile (20 mL) were reacted for 2 h at room
temperature under nitrogen. After workup similar to that of
9, isolation by silica gel column chromatography (30% EtOAc/
hexanes) afforded â-anomer 11 (0.34 g, 47.1%) and R-anomer
12 (0.23 g, 31.8%) as white solids. 11: UV (CHCl3) λmax 260.5
nm. Anal. (C22H28FN3O4Si) C, H, N. 12: UV (CHCl3) λmax 260.5
nm. Anal. (C22H28FN3O4Si) C, H, N.
5-F lu or o-1-[5-O-(ter t-bu tyld im eth ylsilyl)-2,3-d id eoxy-
2-flu or o-â-L-glycer o-p en t -2-en ofu r a n osyl]-N4-b en zoyl-
cytosin e (13) a n d Its r-Isom er (14). Silylated N4-benzoyl-
5-fluorocytosine [prepared from 637.6 mg (2.73 mmol) of N4-
benzoyl-5-fluorocytosine and 20 mL of HMDS], 8 (528.5 mg,
1.82 mmol), and TMSOTf (0.5 mL, 2.73 mmol) in dry DCE (20
mL) were reacted for 1 h at room temperature under nitrogen.
After workup similar to that of 9, isolation by silica gel column
chromatography (25% EtOAc/hexanes) afforded â-anomer 13
(0.38 g, 44.5%) and R-anomer 14 (0.27 g, 32%) as white solids.
13: UV (CHCl3) λmax 326.0 nm. Anal. (C22H27F2N3O4Si) C, H,
N. 14: UV (CHCl3) λmax 325.5 nm. Anal. (C22H27F2N3O4Si) C,
H, N.
1-(2,3-Did eoxy-2-flu or o-â-L-glycer o-p en t -2-en ofu r a n -
osyl)u r a cil (15) a n d It s r-Isom er (16). Tetra-n-butyl-
ammonium fluoride (0.6 mL, 0.6 mmol) was added to anomeric
mixture 9 (177 mg, 0.52 mmol) in THF (15 mL), and the
reaction mixture was stirred at room temperature for 15 min.
The solvent was removed, and the resulting residue was
purified by silica gel column chromatography (2% MeOH/CH2-
Cl2) to give â-anomer 15 (52.8 mg, 44.5%) as a white solid and
R-anomer 16 (35.1 mg, 29.6%) as a white solid. 15: UV (H2O)
λmax 257.0 nm (ꢀ 16 500) (pH 7), 258.0 nm (ꢀ 18 200) (pH 2),
257.0 nm (ꢀ 8 200) (pH 11); HRMS (LSIMS, m/z) 229.0626
(calcd 229.0624). Anal. (C9H9FN2O4‚0.3H2O) C, H, N. 16: UV
(H2O) λmax 257.5 nm (ꢀ 16 700) (pH 7), 258.0 nm (ꢀ 18 900) (pH
2), 257.0 nm (ꢀ 8 300) (pH 11); HRMS (LSIMS, m/z) 229.0632
(calcd 229.0624). Anal. (C9H9FN2O4‚0.2H2O) C, H, N.
1-(2,3-Did eoxy-2-flu or o-â-L-glycer o-p en t -2-en ofu r a n -
osyl)th ym in e (17) a n d Its r-Isom er (18). Tetra-n-butylam-
monium fluoride (0.8 mL, 0.8 mmol) was added to a mixture
of 10 (240 mg, 0.67 mmol) in THF (10 mL) at 0 °C, and the
reaction mixture was stirred at room temperature at room
temperature for 30 min. The solvent was removed, and the
resulting residue was purified by silica gel column chroma-
tography (40% THF/cyclohexane) to give â-anomer 17 (66.5
mg, 41%) as a white solid and R-anomer 18 (52.8 mg, 26%) as
a white solid. 17: UV (H2O) λmax 262.0 nm (ꢀ 5 600) (pH 7),
262.5 nm (ꢀ 10 000) (pH 2), 263.5 nm (ꢀ 7 500) (pH 11); HRMS
(LSIMS, m/z) 243.0781 (calcd 243.0781). Anal. (C10H11FN2O4‚
0.4H2O) C, H, N. 18: UV (H2O) λmax 262.5 nm (ꢀ 6 700) (pH
7), 263.5 nm (ꢀ 10 800) (pH 2), 264.5 nm (ꢀ 7 400) (pH 11);
HRMS (LSIMS, m/z) 243.0760 (calcd 243.0781). Anal. (C9H9-
FN2O4‚0.3H2O) C, H, N.
1-(2,3-Did eoxy-2-flu or o-â-L-glycer o-p en t -2-en ofu r a n -
osyl)-N4-ben zoylcytosin e (19). Tetra-n-butylammonium fluo-
ride (1 M in THF) (1 mL, 1 mmol) was added to a solution of
the â-anomer 11 (280 mg, 0.63 mmol) in THF (10 mL) at 0 °C,
and the resulting reaction mixture was stirred at room
temperature for 1 h. The solvent was removed under reduced
pressure, which was purified by silica gel column chromatog-
raphy using 2.5% MeOH-CH2Cl2 as an eluent to give 19 (218
mg, 75%) as a white solid: UV (MeOH) λmax 260.5 nm. Anal.
(C16H14FN3O4) C, H, N.
compound 19. Flash chromatography (silica gel, 2.5% MeOH/
CH2Cl2) gave 145.8 mg (69%) of the titled product as a white
solid: UV (MeOH) λmax 260.5 nm. Anal. (C16H14FN3O4‚0.3H2O)
C, H, N.
5-Flu or o-1-(2,3-dideoxy-2-flu or o-â-L-glycer o-pen t-2-en o-
fu r a n osyl)-N4-ben zoylcytosin e (21). Compound 21 was
prepared from 13 on
a 0.77-mmol scale by the method
described for compound 19. Flash chromatography (silica gel,
2% MeOH/CHCl3) and subsequent recrystallization (hexanes-
MeOH-CH2Cl2) gave 201.7 mg (75%) of the titled product as
a white solid: UV (MeOH) λmax 325.5 nm. Anal. (C16H13F2N3O4)
C, H, N.
5-F lu or o-1-(2,3-d id eoxy-2-flu or o-r-L-gycer o-p en t-2-en o-
fu r a n osyl)-N4-ben zoylcytosin e (22). Compound 22 was
prepared from 14 on
a 0.56-mmol scale by the method
described for compound 19. Flash chromatography (silica gel,
2% MeOH/CH2Cl2) and subsequent recrystallization (hot
EtOH) gave 167.7 mg (86%) of the titled product as a white
solid: UV (MeOH) λmax 326.0 nm. Anal. (C16H13F2N3O4) C, H,
N.
1-(2,3-Did eoxy-2-flu or o-â-L-glycer o-p en t -2-en ofu r a n -
osyl)cytosin e (23). A solution of the â-anomer 19 (67.60 mg,
0.20 mmol) in MeOH (5 mL) was treated with saturated
methanolic ammonia (10 mL), and the reaction mixture was
stirred at room temperature until the disappearance of start-
ing material was observed (10 h). The mixture was concen-
trated under reduced pressure, and the residue was purified
by preparative TLC using 12% MeOH-CH2Cl2 as an eluent.
The material obtained from the plate gave 23 (43 mg, 93.1%)
as a white solid on trituation with hexanes-MeOH-CH2Cl2:
UV (H2O) λmax 266.5 nm (ꢀ 7 400) (pH 7), 276.0 nm (ꢀ 12 900)
(pH 2), 267.0 nm (ꢀ 9 400) (pH 11); HRMS (LSIMS, m/z)
228.0782 (calcd 228.0784). Anal. (C9H10FN3O3‚0.4H2O) C, H,
N.
1-(2,3-Did eoxy-2-flu or o-r-L-glycer o-p en t -2-en ofu r a n -
osyl)cytosin e (24). A solution of the R-anomer 20 (65.9 mg,
0.20 mmol) in MeOH (5 mL) was treated with saturated
methanolic ammonia (10 mL), and the reaction mixture was
allowed to stir at room temperature until the disappearance
of starting material was observed (16 h). The reaction mixture
was concentrated under reduced pressure, and the residue was
purified by preparative TLC (12% MeOH/CH2Cl2) to give 24
(42.5 mg, 94.5%) as a white solid: UV (H2O) λmax 267.0 nm (ꢀ
7 300) (pH 7), 275.5 nm (ꢀ 14 400) (pH 2), 267.5 nm (ꢀ 9 500)
(pH 11); HRMS (LSIMS, m/z) 228.0775 (calcd 243.0784). Anal.
(C9H10FN3O3) C, H, N.
5-Flu or o-1-(2,3-dideoxy-2-flu or o-â-L-glycer o-pen t-2-en o-
fu r a n osyl)cytosin e (25). Compound 21 (86.7 mg, 0.25 mmol)
was treated with saturated methanolic ammonia solution (15
mL), and the reaction mixture was allowed to stir at room
temperature until the disappearance of starting material was
observed (14 h). The reaction mixture was concentrated under
reduced pressure, and the residue was purified by silica gel
column chromatography (10% MeOH/CH2Cl2) to give 25 (46.6
mg, 76%) as a solid, which was recrystallized from hexanes-
MeOH-CH2Cl2: UV (H2O) λmax 277.0 nm (ꢀ 13 200) (pH 7),
282.0 nm (ꢀ 15 800) (pH 2), 277.0 nm (ꢀ 13 600) (pH 11); HRMS
(LSIMS, m/z) 246.0672 (calcd 246.0690). Anal. (C9H9F2N3O3)
C, H, N.
5-Flu or o-1-(2,3-dideoxy-2-flu or o-r-L-glycer o-pen t-2-en o-
fu r a n osyl)cytosin e (26). Compound 22 (84 mg, 0.24 mmol)
was treated with saturated methanolic ammonia (15 mL), and
the reaction mixture was allowed to stir at room temperature
until the disappearance of starting material was observed (14
h). The reaction mixture was concentrated under reduced
pressure, and the residue was purified by silica gel column
chromatography (12% MeOH/CH2Cl2) to give 26 (45.3 mg, 77%)
as a white solid: UV (H2O) λmax 277.0 nm (ꢀ 8 100) (pH 7),
282.0 nm (ꢀ 10 400) (pH 2), 276.0 nm (ꢀ 7 100) (pH 11); HRMS
(LSIMS, m/z) 246.0694 (calcd 246.0690). Anal. (C9H19F2N3O3)
C, H, N.
1-(2,3-Did eoxy-2-flu or o-r-L-glycer o-p en t -2-en ofu r a n -
osyl)-N4-ben zoylcytosin e (20). Compound 20 was prepared
from 12 on a 0.63-mmol scale by the method described for
Gen er a l P r oced u r e for Con d en sa tion of Aceta te 8
w ith P u r in e Ba ses. A mixture of 6-chloropurine (1.20 g, 7.75
mmol), hexamethyldisilazane (25 mL), and ammonium sulfate

2′-Fluoro-2′,3′-unsaturated L-Nucleosides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1327
(catalytic amount) was refluxed for 4 h under nitrogen. The
clear solution obtained was concentrated in vacuo, and the
residue was dissolved in dry CH2Cl2 (10 mL) and reacted with
a solution of 8 (1.50 g, 5.17 mmol) in DCE (40 mL) and
trimethylsilyl triflate (1.5 mL, 7.75 mmol) at room tempera-
ture. After stirring for 1 h at room temperature under nitrogen,
the reaction solution was then poured into an ice-cold satu-
rated NaHCO3 solution (20 mL) and stirred for 15 min. The
organic layer was washed with water and brine and dried over
MgSO4. The solvents were removed under reduced pressure,
and the residue was separated by silica gel column chroma-
tography (17% EtOAc/hexanes) to give anomeric mixture 27
(1.25 g, 62.9%) as a syrup.
(H2O) λmax 258.5 nm (ꢀ 18 800) (pH 7), 258.0 nm (ꢀ 18 800) (pH
2), 258.5 nm (ꢀ 19 100) (pH 11). Anal. (C10H10FN5O2‚0.2H2O)
C, H, N.
9-(2,3-Did eoxy-2-flu or o-r-L-glycer o-p en t -2-en ofu r a n -
osyl)a d en in e (37). A solution of 31 (99 mg, 0.37 mmol) and
saturated NH3/MeOH (50 mL) was heated at 90 °C in a steel
bomb for 27 h. After cooling to room temperature, the solvent
was removed in vacuo and the residual syrup was purified by
column chromatography using 6% MeOH-CH2Cl2 as an eluent
to give 37 (72 mg, 78%) as a white solid: UV (H2O) λmax 259.0
nm (ꢀ 21 500) (pH 7), 258.0 nm (ꢀ 21 100) (pH 2), 259.0 nm (ꢀ
22 600) (pH 11). Anal. (C10H10FN5O2‚0.3MeOH) C, H, N.
9-(2,3-Did eoxy-2-flu or o-â-L-glycer o-p en t -2-en ofu r a n -
osyl)h yp oxa n th in e (38). A mixture of 30 (100 mg, 0.37
mmol), NaOMe (1 M solution in MeOH) (1.46 mL, 1.46 mmol),
and HSCH2CH2OH (0.1 mL, 1.46 mmol) in MeOH (20 mL) was
refluxed for 4 h under nitrogen. The reaction mixture was
cooled, neutralized with glacial AcOH, and evaporated to
dryness in vacuo. The residue was purified by silica gel column
chromatography (10% MeOH/CH2Cl2) to afford 38 (74 mg, 80%)
as a white solid: UV (H2O) λmax 247.0 nm (ꢀ 13 000) (pH 7),
247.5 nm (ꢀ 12 400) (pH 2), 253 nm (ꢀ 13 100) (pH 11). Anal.
(C10H9FN4O3‚0.2H2O) C, H, N.
9-(2,3-Did eoxy-2-flu or o-r-L-glycer o-p en t -2-en ofu r a n -
osyl)h yp oxa n th in e (39). A mixture of 31 (134 mg, 0.50
mmol), NaOMe (1 M solution in MeOH) (1.98 mL, 1.98 mmol),
and HSCH2CH2OH (0.14 mL, 1.98 mmol) in MeOH (20 mL)
was refluxed for 4 h under nitrogen. The reaction mixture was
cooled, neutralized with glacial AcOH, and evaporated to
dryness in vacuo. The residue was purified by silica gel column
chromatography (9% MeOH/CH2Cl2) to afford 39 (93 mg,
70.5%) as a white solid: UV (H2O) λmax 247.5 nm (ꢀ 13 700)
(pH 7), 247.5 nm (ꢀ 12 700) (pH 2), 252.5 nm (ꢀ 13 100) (pH
11). Anal. (C10H9FN4O3‚0.3H2O) C, H, N.
2-F lu or o-6-a m in o-9-(2,3-d id eoxy-2-flu or o-â-L-glycer o-
p en t-2-en ofu r a n osyl)p u r in e (40). A solution of 32 (101 mg,
0.26 mmol) in dry acetonitrile (15 mL) was treated with tetra-
n-butylammonium fluoride (1 M solution in THF) (0.35 mL,
0.35 mmol) and stirred for 30 min at room temperature. After
evaporation of solvent, the dryness was purified by column
chromatography (9% MeOH/CH2Cl2) to obtain 40 (64.7 mg,
92.3%) as a white crystalline solid: UV (H2O) λmax 260.0 nm
(ꢀ 12 600) (pH 7), 260.0 nm (ꢀ 14 100) (pH 2), 260.0 nm (ꢀ
11 000) (pH 11); HRMS (LSIMS, m/z) 270.0801 (calcd 270.0803).
Anal. (C10H9F2N5O2‚0.6MeOH) C, H, N.
2-F lu or o-6-a m in o-9-(2,3-d id eoxy-2-flu or o-r-L-gylcer o-
p en t-2-en ofu r a n osyl)p u r in e (41). The titled compound was
prepared from 34 on a 0.19-mmol scale by the procedure
described for 40. After evaporation of solvent, the residue was
purified by column chromatography (9% MeOH/CH2Cl2) to
obtain product 41 (46.2 mg, 90.3%) as a white crystalline
solid: UV (H2O) λmax 260.5 nm (ꢀ 13 400) (pH 7), 260.0 nm (ꢀ
11 900) (pH 2), 260.5 nm (ꢀ 10 400) (pH 11); HRMS (LSIMS,
m/z) 270.0774 (calcd 270.0803). Anal. (C10H9F2N5O2‚0.4H2O)
C, H, N.
6-Ch lor o-9-[5-O-(ter t-bu tyld im eth ylsilyl)-2,3-d id eoxy-
2-flu or o-L-glycer o-p en t-2-en ofu r a n osyl]p u r in e (27): UV
(MeOH) λmax 265.0 nm. Anal. (C16H22ClFN4O2 Si) C, H, N.
6-Ch lor o-2-flu or o-9-[5-O-(ter t-bu tyld im eth ylsilyl)-2,3-
d id e oxy-2-flu or o-â-L-glycer o-p e n t -2-e n ofu r a n osyl]p u -
r in e (28) a n d Its r-Isom er (29). A mixture of silylated
2-fluoro-6-chloropurine [prepared from 1.170 g (6.78 mmol) of
2-fluoro-6-chloropurine and dry DCE (40 mL)] was stirred for
2 h at room temperature. After workup similar to that of 27,
purification by silica gel column chromatography (12% EtOAc/
hexanes) gave â-anomer 28 (685 mg, 30.0%) as a white foam
and R-anomer 29 as an yellowish syrup. 28: UV (MeOH) λmax
268.5 nm. Anal. (C16H21F2 Cl N4O2Si) C, H, N. 29: UV (MeOH)
λmax 269.0 nm. Anal. (C16H21F2ClN4O2Si) C, H, N.
6-Ch lor o-9-(2,3-dideoxy-2-flu or o-â-L-glycer o-pen t-2-en o-
fu r a n osyl)p u r in e (30) a n d Its r-Isom er (31). A solution of
27 (1.2 g, 3.12 mmol) in dry CH3CN (20 mL) was treated with
tetra-n-butylammonium fluoride (1 M solution in THF) (3.2
mL, 3.2 mmol) and stirred for 1 h at room temperature. After
evaporation of solvent, the residue was purified by column
chromatography (3% MeOH/CH2Cl2) to obtain â- anomer 30
(296 mg, 35%) as a white solid and R-anomer 31 (380 mg, 45%)
as a foam. 30: UV (MeOH) λmax 265.0 nm. Anal. (C16H8FCl
N4O2‚0.1EtOH) C, H, N. 31: UV (MeOH) λmax 265.0 nm. Anal.
(C16H8FClN4O2) C, H, N.
6-Am in o-2-flu or o-9-[5-O-(ter t-b u t yld im et h ylsilyl)-2,3-
d id e o x y -2-flu o r o -â-L -g l ycer o-p e n t -2-e n o fu r a n o s y l]-
p u r in e (32) a n d 6-Ch lor o-2-a m in o-9-[5-O-(ter t-b u t yld i-
m e t h ylsilyl)-2,3-d id e oxy-2-flu or o-â-L -glycer o-p e n t -2-
en ofu r a n osyl]p u r in e (33). Dry ammonia was bubbled into
a stirred solution of 28 (420 mg, 1.04 mmol) in dry DME (35
mL) at room temperature overnight. The salts were removed
by filtration, and the filtrate was evaporated under reduced
pressure. The residue was purified by preparative TLC (25%
EtOAc/hexanes) to give two compounds, 32 (114 mg, 28.9%)
as a white solid and 33 (164 mg, 39.4%) as a white solid. 32:
UV (MeOH) λmax 268.5 nm. Anal. (C16H23F2N5O2Si‚0.2 acetone)
C, H, N. 33: UV (MeOH) λmax 307.5 nm. Anal. (C16H23FN5O2-
ClSi) C, H, N, Cl.
6-Am in o-2-flu or o-9-[5-O-(ter t-b u t yld im et h ylsilyl)-2,3-
d id e o x y -2-flu o r o -r-L -g l ycer o-p e n t -2-e n o fu r a n o s y l]-
p u r in e (34) a n d 6-Ch lor o-2-a m in o-9-[5-O-(ter t-b u t yld i-
m eth ylsilyl)-2,3-d id eoxy-2-flu or o-r-L-glycer o-p en t-2-en o-
fu r a n osyl]p u r in e (35). Dry ammonia was bubbled into a
stirred solution of 29 (420 mg, 1.04 mmol) in dry DME (35
mL) at room temperature overnight. The salts were removed
by filtration, and the filtrate was evaporated under reduced
pressure. The residue was purified by preparative TLC (25%
EtOAc/hexanes) to give two compounds, 34 (150 mg, 36.5%)
as a white solid and 35 (69.3 mg, 17.3%) as a white solid. 34:
UV (MeOH) λmax 269.0 nm. Anal. (C16H23F2N5O2Si‚0.3 acetone)
C, H, N. 35: UV (MeOH) λmax 309.5 nm. Anal. (C16H23FClN5O2
Si) C, H, N.
2-Am in o-6-ch lor o-9-(2,3-d id eoxy-2-flu or o-â-L-glycer o-
p en t-2-en ofu r a n osyl)p u r in e (42). The titled compound was
prepared from 33 on a 0.40-mmol scale by the procedure
described for 40. After evaporation of solvent, the dryness was
purified by silica gel column chromatography (5% MeOH/CH2-
Cl2) to obtain product 42 (109 mg, 95.5%) as a white crystalline
solid: HRMS (LSIMS, m/z) 286.0514 (calcd 286.0507). Anal.
(C10H9FClN5O2) C, H, N.
2-Am in o-6-ch lor o-9-(2,3-d id eoxy-2-flu or o-r-L-glycer o-
p en t-2-en ofu r a n osyl)p u r in e (43). The titled compound was
prepared from 35 on a 0.36-mmol scale by the procedure
described for 40. Silica gel column chromatography (9% MeOH/
CH2Cl2) gave product 43 (99.9 mg, 96.4%) as a white solid:
HRMS (LSIMS, m/z) 286.0510 (calcd 286.0507). Anal. (C10H9-
ClFN5O2) C, H, N.
9-(2,3-Did eoxy-2-flu or o-â-L-glycer o-p en t -2-en ofu r a n -
osyl)a d en in e (36). A solution of 30 (100 mg, 0.37 mmol) and
saturated metahnolic ammonia (50 mL) was heated at 90 °C
in a steel bomb for 24 h. After cooling to room temperature,
the solvent was removed in vacuo and the residual syrup was
purified by column chromatography using 6% MeOH-CH2-
Cl2 as an eluent to give 36 (70 mg, 75%) as a white solid: UV
9-(2,3-Dideoxy-2-flu or o-â-L-gycer o-pen t-2-en ofu r an osyl)-
gu a n in e (44). A mixture of 42 (63.6 mg, 0.22 mmol), 2-mer-
captoethanol (0.06 mL, 0.89 mmol), and 1 N NaOMe (0.89 mL,
0.89 mmol) in MeOH (10 mL) was refluxed for 5 h under

1328 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Lee et al.
(9) Bolon, P. J .; Wang, P. Y.; Chu, C. K.; Gosselin, G.; Boudou, V.;
Pierra, C.; Mathe, C.; Imbach, J .-L.; Faraj, A.; Alaoui, M. A.;
Sommadossi, J .-P.; Pai, S. B.; Zhu, Y.-L.; Lin, J .-S.; Cheng, Y.-
C.; Schinazi, R. F. Anti-Human Immunodeficiency Virus and
Anti-Hepatitis B Virus Activities of â-L-2′,3′-Dideoxy Purine
Nucleosides. Bioorg. Med. Chem. Lett. 1996, 6, 1657-1662.
(10) (a) Garrett, E. R.; Mehta, P. J . Solvolysis of Adenine Nucleosides.
I. Effects of Sugars and Adenine Substituents on Acid Solvolysis.
J . Am. Chem. Soc. 1972, 94, 8532-8541. (b) York, J . L. Effect
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(11) (a) Marquez, V. E.; Tseng, C. K.-H.; Mitsuya, H.; Aoki, S.; Kelley,
J . A.; Ford, H., J r.; Roth, J . S.; Broder, S.; J ohns, D. G.; Driscoll,
J . S. Acid-Stable 2′-Fluoro Purine Dideoxynucleosides as Active
Agents against HIV. J . Med. Chem. 1990, 33, 978-985. (b)
Ruxrungtham, K.; Boone, E.; Ford, H., J r.; Driscoll, J . S.; Davey,
R. T.; Lane, H. C. Potent Activity of 2′-â-Fluoro-2′,3′-Dideoxy-
nitrogen. The mixture was cooled, neutralized with glacial
AcOH, and evaporated to dryness in vacuo. Purification on
silica gel (12% MeOH/CH2Cl2) afforded 44 (30.1 mg, 50.7%)
as a white solid: UV (H2O) λmax 251.0 nm (ꢀ 13 200) (pH 7),
252.5 nm (ꢀ 12 400) (pH 2), 256.5 nm (ꢀ 7 900) (pH 11); HRMS
(LSIMS, m/z) 268.0862 (calcd 268.0846). Anal. (C10H10FN5O3‚
0.2H2O) C, H, N.
9-(2,3-Did eoxy-2-flu or o-r-L-glycer o-p en t -2-en ofu r a n -
osyl)gu a n in e (45). The titled compound was prepared from
43 on a 0.21-mmol scale by the procedure described for 44.
Purification on silica gel (12.5% MeOH/CH2Cl2) afforded
product 45 (28.0 mg, 50.5%) as a white solid: UV (H2O) λmax
251.5 nm (ꢀ 13 200) (pH 7), 252.0 nm (ꢀ 12 600) (pH 2), 257.0
nm (ꢀ 9 800) (pH 11); HRMS (LSIMS, m/z) 268.0821 (calcd
268.0846). Anal. (C10H10FN5O3‚0.7CH2Cl2) C, H, N.
adenosine against Human Immunodeficiency Virus Type
1
Infection in hu PBM-SCID Mice. Antimicrob. Agents Chemother.
1996, 40, 2369-2374.
Ack n ow led gm en t. This research was supported by
U.S. Public Health Service Grants AI 32351 and AI
33655 from the National Institutes of Health and the
Department of Veteran Affairs and the Georgia Federal
Center for AIDS and HIV Infections. The authors would
like to thank Dr. Michael G. Bartlett for performing
high-resolution mass spectroscopy. We also thank Philip
Tarnish for technical assistance.
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