Asymmetric synthesis and antiviral activities of L-carbocyclic 2',3'- didehydro-2',3'-dideoxy and 2',3'-dideoxy nucleosides

Article abstract of DOI:10.1021/jm9901327

Asymmetric syntheses of L-carbocyclic 2',3'-didehydro-2',3'-dideoxy- and 2',3'-dideoxypyrimidine and purine nucleoside analogues were accomplished, and their anti-HIV and anti-HBV activities were evaluated. The key intermediate, (1S,4R)-1-benzoyloxy-4-(tert-butoxymethyl)cyclopent-2-ene (7), was prepared by benzoylation of the alcohol 2, selective deprotection of the isopropylidene group of 3, followed by thermal elimination via cyclic ortho ester or deoxygenation via cyclic thionocarbonate. The target compounds were also synthesized by thermal elimination via cyclic ortho esters from protected nucleosides. It was found that L-carbocyclic 2',3'-didehydro-2',3'- dideoxyadenosine (34) exhibited potent anti-HBV activity (EC₅₀ = 0.9 μM) and moderate anti-HIV activity (EC₅₀ = 2.4 μM) in vitro without cytotoxicity up to 100 μM.

Full text of DOI:10.1021/jm9901327

3390
J . Med. Chem. 1999, 42, 3390-3399
Asym m etr ic Syn th esis a n d An tivir a l Activities of L-Ca r bocyclic
2′,3′-Did eh yd r o-2′,3′-d id eoxy a n d 2′,3′-Did eoxy Nu cleosid es
Peiyuan Wang,† Beth Gullen,| M. Gary Newton,‡ Yung-Chi Cheng,| Reymond F. Schinazi,§ and Chung K. Chu*,†
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, and Department of Chemistry,
The University of Georgia, Athens, Georgia 30602, Department of Pharmacology, Yale University School of Medicine,
New Haven, Connecticut 06510, and Department of Pediatrics, Emory University School of Medicine/ VA Medical Center,
Decatur, Georgia 30033
Received March 22, 1999
Asymmetric syntheses of L-carbocyclic 2′,3′-didehydro-2′,3′-dideoxy- and 2′,3′-dideoxypyrimidine
and purine nucleoside analogues were accomplished, and their anti-HIV and anti-HBV activities
were evaluated. The key intermediate, (1S,4R)-1-benzoyloxy-4-(tert-butoxymethyl)cyclopent-
2-ene (7), was prepared by benzoylation of the alcohol 2, selective deprotection of the
isopropylidene group of 3, followed by thermal elimination via cyclic ortho ester or deoxygenation
via cyclic thionocarbonate. The target compounds were also synthesized by thermal elimination
via cyclic ortho esters from protected nucleosides. It was found that L-carbocyclic 2′,3′-didehydro-
2′,3′-dideoxyadenosine (34) exhibited potent anti-HBV activity (EC50 ) 0.9 µM) and moderate
anti-HIV activity (EC50 ) 2.4 µM) in vitro without cytotoxicity up to 100 µM.
In tr od u ction
d4C and â-L-Fd4C, were reported to exhibit potent anti-
HIV and anti-HBV activities.17 The synthesis of the
enantiomers of abacavir was reported18 and the D-
enantiomer of abacavir also exhibited anti-HBV activ-
ity.19 In connection with L-nucleosides, we have reported
the synthesis and antiviral activity of â-L-2′,3′-didehy-
dro-2′,3′-dideoxy purine nucleoside analogues, among
which the adenosine derivative (â-L-d4A) exhibited
significant anti-HIV and anti-HBV activities.20 The
racemic mixtures of some carbocyclic 2′,3′-didehydro-
2′,3′-dideoxy purine derivatives were reported to exhibit
anti-HIV activity.21 Carbovir was the first carbocyclic
nucleoside analogue which exhibits potent anti-HIV
activity in vitro. The first preparation of the D- and L-
isomers of carbovir was reported by Vince et al.22 The
L-carbovir was prepared either by chemoenzymatic
syntheses,22-24 or by a stereoselective method via [2+3]
asymmetric cycloaddition.25 The anti-HIV and anti-HBV
activities of carbovir reside in its natural â-D-enantio-
mer.26 It was reported that the triphosphates of â-D- and
â-L-carbovir are approximately equipotent as HIV re-
verse transcriptase inhibitors24 and the â-L-carbovir
triphosphate exhibited more potent anti-HBV activity.27
Since the discovery of the natural products (-)-
aristeromycin and neplanocin A as biologically interest-
ing carbocyclic nucleosides, a number of carbocyclic
nucleosides have been synthesized and have shown
interesting antitumor1 and antiviral activity against
herpes virus,2 cytomegalovirus,3 hepatitis B virus,4 and
human immunodeficiency virus (HIV).5 These com-
pounds possess greater metabolic stability to nucleoside
phosphorylases, which cleave the glycosidic bond of
normal nucleosides.6 Among them, carbovir7 and its
6-cyclopropylamino analogue 1592U89 (abacavir)8 are
the most interesting compounds as they both exhibit
potent anti-HIV activity. Abacavir has been reported to
reduce the viral load of greater than 99% with signifi-
cant improvement in CD4 counts, and it has recently
been approved by the FDA. More recently, a novel
carbocyclic nucleoside, BMS-200475, has been reported
to have potent anti-hepatitis B virus activity and is
currently undergoing phase II clinical trials.9
Recently, a number of nucleosides with the unnatural
L-configuration have emerged as potent antiviral agents
against HIV and HBV, which include (-)-(2′R,5′S)-1-
(2-hydroxymethyloxathiolan-5-yl)cytosine (3TC),10,11 (-)-
â-L-2′,3′-dideoxy-5-fluoro-3′-thiacytidine (FTC),12 â-L-
2′,3′-dideoxy-5-fluorocytidine (L-FddC),13 and â-L-2′-
fluoro-5-methylarabinofuranosyl uracil (L-FMAU).14 Both
3TC and FTC were found to have more potent antiviral
activity against HIV and HBV than their D-counterparts
with reduced toxicity.15,16 Two other L-nucleosides, â-L-
These findings prompted us to synthesize L-carbocy-
clic nucleosides in the search for new antiviral agents.
Recently, we have reported a preliminary result of
carbocyclic â-L-2′,3′-didehydro-2′,3′-dideoxy adenine as
an anti-HIV agent.28 As part of our ongoing drug
discovery efforts, herein we report the full account of
the asymmetric syntheses of carbocyclic â-L-2′,3′-dide-
hydro-2′,3′-dideoxy and â-L-2′,3′-dideoxy pyrimidine and
purine nucleoside analogues together with their anti-
HIV and anti-HBV activities.
* Corresponding author: Dr. C. K. Chu, University Research
Professor, Department of Pharmaceutical and Biomedical Sciences,
College of Pharmacy, The University of Georgia, Athens, GA 30602.
Tel: (706) 542-5379. Fax: (706) 542-5381. E-mail: DChu@RX.UGA.
EDU.
For the synthesis of L-carbocyclic nucleosides, we
utilized the reported (+)-cyclopentenone 1 as a chiral
starting material, which was prepared in three steps
from D-ribose.29 The alcohol 2 was previously reported
by our group from the regioselective addition of tert-
butoxymethyl group to the enone 1, followed by DIBAL-H
† Department of Pharmaceutical and Biomedical Sciences, The
University of Georgia.
‡ Department of Chemistry, The University of Georgia.
| Yale University School of Medicine.
§ Emory University School of Medicine/VA Medical Center.
10.1021/jm9901327 CCC: $18.00 © 1999 American Chemical Society
Published on Web 08/03/1999

Synthesis of L-Carbocyclic Nucleosides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17 3391
Sch em e 1a
a
Reagents and conditions: (a) BzCl, Pyr, rt, 12 h; (b) concentrated HCl:MeOH (1:70, v/v), rt, 2.5 h; (c) CH(OMe)3, pyridinium p-toluene-
sulfonate, rt, 2 h; (d) Ac2O, 120-130 °C, 6 h; (e) 1,1′-thiocarbonyldiimidazole, MeCN, rt, 24 h; (f) 1,3-dimethyl-2-phenyl-1,3,2-
diazaphospholidine, THF, rt, 20 h; (g) 2 N NaOH/MeOH, rt, 1.5 h; (h) (1) N3-benzoylthymine, Ph3P, diethyl azodicarboxylate, dioxane, rt,
°
6 h; (2) NH3/MeOH, rt; (i) CF3CO2H/H2O (2:1), 50 C, 3 h.
reduction (Scheme 1).30 Treatment of compound 2 with
benzoyl chloride in pyridine gave the benzoate 3 in 93%
yield. Selective deprotection of the isopropylidene pro-
tection group of compound 3 with a mixture of concen-
trated HCl and methanol (1: 70, v/v) at room temper-
ature for 2.5 h gave the diol 4 in 93% yield. The diol 4
was treated with trimethyl orthoformate at room tem-
perature for 2 h in the presence of catalytic amounts of
pyridinium p-toluene-sulfonate to afford the cyclic ortho
ester 5, which was subjected to a thermal elimination
reaction31 with acetic anhydride at 120-130 °C for 6 h
to give the required cyclopentene 7. Another method of
deoxygenation of the diol 4 to 7 via cyclic thionocarbon-
ates was also explored. The yield was, however, lower
than that of the above method as briefly described
below: Compound 4 was treated with 1,1′-(thiocarbonyl)-
diimidazole at room temperature to give cyclic thiono-
carbonate 6, which was deoxygenated to 7 under mild
conditions using 1,3-dimethyl-2-phenyl-1,3,2-diazaphos-
pholidine.32
For structural identification, NOESY experiments
were performed, which indicated that there is a cor-
relation between H-1 and H-6 of compound 7, suggesting
that H-1 and H-6 are on the same side. The benzoyl
group of compound 7 was removed with 2 N NaOH in
methanol to give the alcohol 8, which was then reacted
with a heterocyclic base under Mitsunobu condi-
tions.33,34 Thymidine analogue was prepared by the
reaction of 8 with N3-benzoylthymine35 in the presence
of triphenylphosphine and DEAD at room temperature
to give 9 in 53% yield. Deblocking of compounds 9 with
trifluoroacetic acid/H2O (2:1) at 50 °C for 3 h provided
thymine analogue 10 in 93% yield.
Scheme 3). Treatment of 1130,36 with â-methoxy-R-
methacryloyl isocyanate and â-methoxy acryloyl isocy-
anate using the methodology reported by Shealy et
al.37,38 gave acrylurea 12 (X ) Me) and 13 (X ) H),
respectively. Reaction of 12 and 13 with 30% NH4OH
and ethanol at 80-100 °C in a steel bomb gave the
corresponding thymine 14 and uracil 15 derivatives,
respectively. Treatment of compound 14 and 15 with a
mixture of concentrated HCl and methanol (1: 65, v/v)
at room temperature for 2.5 h gave the diol 16 and 17
in 81% and quantitative yields, respectively. Ortho
esterification of compound 16 and 17 with trimethyl
orthoformate in the presence of pyridinium p-toluene-
sulfonate gave the cyclic ortho esters 18 and 19, which
were then heated with acetic anhydride at 120-130 °C
to afford 9 and 20, respectively. Deprotection of com-
pounds 9 and 20 employing the conditions described
above provided 10 (93% yield) and 21 (87% yield),
respectively. Preparation of the cytosine derivative 26
was accomplished by the reported method.39 The treat-
ment of 20 with 4-chlorophenyl dichlorophosphate and
1,2,4-triazole in pyridine gave the triazole derivative 24.
Subsequent hydrolysis of 24 with concentrated NH4OH
gave 25 (41% yield), which was deblocked with trifluo-
roacetic acid/H2O to afford the cytosine nucleoside 26
in 94% yield.
The 6-chloropurine derivative 28 was prepared in two
steps from 11 (Scheme 3).36 The isopropylidene protec-
tion group of compound 28 was removed using a mixture
of HCl and methanol (1: 70, v/v) to give compound 29
in 87% yield. Treatment of the diol 29 with trimethyl
orthoformate in the presence of pyridinium p-toluene-
sulfonate gave 30, which was then subjected to a
thermal elimination reaction with acetic anhydride to
give compound 31. The 6-chloropurine nucleoside ana-
logue 31 was also obtained in 35% yield by the reaction
of alcohol 8 with 6-chloropurine in the presence of
Other carbocyclic L-2′,3′-didehydro-2′,3′-dideoxy and
2′,3′-dideoxy pyrimidine and purine nucleosides were
also prepared by thermal elimination reactions via cyclic
ortho esters from protected nucleosides (Scheme 2 and

3392 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17
Wang et al.
Sch em e 2a
a
Reagents and conditions: (a) â-methoxy-R-methacryloyl isocyanate, DMF, -20 to 20 °C, 10 h (for 12) or â-methoxyacryloyl isocyanate,
DMF, -20 to 20 °C, 10 h (for 13); (b) 30% NH4OH, EtOH or/and dioxane, 80-100 °C, 10-24 h; (c) concentrated HCl:MeOH (1:65 to 70,
v/v), rt, 2.5-3 h; (d) CH(OMe)3, pyridinium p-toluene-sulfonate; rt, 30 min; (e) Ac2O, 120-130 °C, 8 h; (f) CF3CO2H/H2O (2:1), 50 °C, 3 h;
(g) 10% Pd/C, MeOH, 15 psi; (h) p-chlorophenylphosphorodichloridate, 1,2,4-triazole, Py, rt, 24 h; (i) 30% NH4OH, dioxane, rt, 24 h.
Sch em e 3a
a
Reagents and conditions: (a) concentrated HCl:MeOH (1:70, v/v), rt, 3 h; (b) CH(OMe)3, pyridinium p-toluene-sulfonate, rt, 2 h; (c)
Ac2O, 120-130 °C, 12 h; (d) HSCH2CH2OH, MeOH, reflux, 24 h; (e) CF3CO2H/H2O (2:1), 50 °C, 3 h; (f) 10% Pd/C, MeOH, rt, 15 psi, 3 h;
(g) NH3/MeOH, 80-90 °C, 20 h; (h) 6-chloropurine, Ph3P, diethyl azodicarboxylate, dioxane, rt, 10 h; (i) thiourea, EtOH, reflux, 1 h.
triphenylphosphine and diethyl azodicarboxylate (DEAD)
at room temperature (Scheme 3). Treatment of the com-
pound 31 with saturated ammonia in methanol in a
steel bomb at 80 to 90 °C provided the adenine deriva-
tive 32 in 83%. The tert-butyl group of 32 was removed
by CF3CO2H/H2O (2:1, v/v) at 50 °C to afford â-L-2′,3′-
didehydro-2′,3′-dideoxyadenosine 34 in 86% yield. The
6-mercaptopurine analogue 35 was obtained by the
reaction of 31 with thiourea in refluxing ethanol fol-
lowed by deprotection with a mixture of CF3CO2H and

Synthesis of L-Carbocyclic Nucleosides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17 3393
Sch em e 4a
a
Reagents and conditions: (a) CH(OMe)3, HCl, DMF, 0-5 °C, 8 h then rt 18 h; (b) HSCH2CH2OH, MeOH, reflux, 18 h; (c) CH(OMe)3,
pyridinium p-toluene-sulfonate, rt, 1 h; (d) Ac2O, 120-130 °C, , 12 h; (e) 30% NH4OH, MeOH, H2O, 65 °C, 1.25 h; (e) CF3CO2H/H2O (2:1),
50 °C, 3 h.
and νmax ) 9.97°, the 5′-OH orientation γ ) -171.6°
(C3′-C4′-C6′-O6′), and the base orientation, ø ) 68.5°
(C5′-C1′-N9-C4) (Table 1).
The anti-HIV and anti-hepatitis B virus (HBV) activi-
ties of synthesized L-carbocyclic nucleosides were evalu-
ated in peripheral blood mononuclear (PBM) and 2.2.15
cells, respectively (Table 2). It was found that â-L-
carbocyclic 2′,3′-didehydro-2′,3′-dideoxyadenosine (34)
exhibited potent anti-HBV activity (EC50 ) 0.9 µM in
2.2.15 cells) and moderately potent anti-HIV activity
(EC50 ) 2.4 µM, EC90 ) 11.7 µM in PBM cells) without
cytotoxicity up to 100 µM in PBM, CEM, and Vero cells.
The cytosine analogue 26 displayed some anti-HBV
activity (EC50 ) 10.0 µM in 2.2.15 cells) and anti-HIV
F igu r e 1. ORTEP drawing of compound 38 (C-L-d4I).
activity (EC50 ) 35.8 µM, EC90 ) 65.9 µM in PBM cells).
In the carbocyclic L-d2N series, only adenine analogue
H2O. Treatment of compound 31 with mercaptoethanol
36 exhibited weak anti-HIV activity with an EC50 value
and sodium methoxide in refluxing methanol followed
by deblocking with CF3CO2H/H2O gave carbocyclic â-L-
2′,3′-didehydro-2′,3′-dideoxyinosine (38). 2′,3′-Saturated
of 27 µM. The thymine derivative 10 did not display any
antiviral activity, but showed weak cytotoxicity.
carbocyclic pyrimidine (22, 23, and 27) and purine (36,
39) nucleosides were prepared by the catalytic hydro-
genation of the corresponding 2′,3′-unsaturated nucleo-
sides with palladium on activated carbon (Schemes 2
and 3).
Exp er im en ta l Section
Melting points were determined on a Mel-temp II apparatus
and are uncorrected. Nuclear magnetic resonance spectra were
recorded on a Bruker 400 AMX spectrometer at 400 MHz for
1H NMR and 100 MHz for 13C NMR with tetramethylsilane
as the internal standard. Chemical shifts (δ) are reported in
parts per million (ppm), and signals are reported as s (singlet),
d (doublet), t (triplet), q (quartet), m (multiplet), or br s (broad
singlet). UV spectra were recorded on a Beckman DU-650
spectrophotometer. Optical rotations were measured on a J asco
DIP-370 digital polarimeter. Mass spectra were recorded on a
Micromass Autospec high-resolution mass spectrometer. TLC
was performed on Uniplates (silica gel) purchased from An-
altech Co. Column chromatography was performed using silica
gel G (TLC grade, >440 mesh) for vacuum flash column
chromatography. Elemental analyses were performed by At-
lantic Microlab Inc., Norcross, GA.
(1R,2R,3S,4S)-1-Ben zoyloxy-4-(ter t-bu toxym eth yl)-2,3-
(isop r op ylid en ed ioxy)cyclop en ta n e (3). Benzoyl chloride
(0.28 mL, 2.4 mmol) was added dropwise to a solution of
alcohol 2 (0.2 g, 0.81 mmol) in pyridine (2 mL) at 0 °C. The
reaction mixture was stirred at 0 °C for 2 h at room temper-
ature for 12 h. After the reaction mixture was quenched by
adding ice, it was stirred for 15 min and then the solvent was
removed in vacuo. The residue was treated with ethyl acetate
(15 mL) and water (5 mL). The organic layer was washed with
saturated NaHCO3 (5 mL) and brine (5 mL) and dried
For the synthesis of L-carbovir 45, we utilized 6-chloro-
2,5-diaminopyrimidine analogue 40 as an intermediate,
which was synthesized from cyclopentylamine 11 in
three steps (Scheme 4).30,36 Treatment of 40 with
triethyl orthoformate in the presence of concentrated
HCl gave the 2-amino-6-chloropurine analogue 41,
which was treated with a mixture of mercaptoethanol
and sodium methoxide in methanol to give the guanine
derivative 42. Conversion of 42 to L-carbovir 45 was
accomplished via a thermal elimination reaction with
acetic anhydride described as above (Scheme 4).
The X-ray structure of the inosine derivative 3840
contains two molecules (A and B) with different con-
formational features (Figure 1). One molecule (molecule
A) adopts a sugar puckering with the pseudorotation
phase angle P ) 264.4° and νmax ) 23.60°, the 5′-OH
orientation γ ) 68.1° (C3′-C4′-C6′-O6′), and the base
orientation, ø ) 98.9° (C5′-C1′-N9-C4). The other (mol-
ecule B) has the C5′-exo conformation with P ) 80.8°

3394 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17
Wang et al.
Ta ble 1. Conformational Parameters for Compound 38
torsion angles (deg)
3′-C4′-C6′-O6′ (γ) 5′-C1′-N9′-C4 (ø)
pseudorotation
angle, P (deg)
compd 38
C
C
conformation
A
B
264.4
80.8
68.1
-171.6
98.9
68.5
C5′-endo
C5′-exo
Ta ble 2. Anti-HIV and Anti-HBV Activity and Cytotoxicities of L-Carbocyclic d4- and d2-Nucleosidesa
anti-HIV (µM) in PBM cells
anti-HBV (µM) in 2.2.15 cells
cytotoxicities (IC50, µM)
no.
EC50
EC90
-
EC50
PBM
66.6
CEM
Vero
49.4
10
>100
>10
>100
(C-L-d4T)
21
(C-L-d4U)
22
(C-L-d2T)
23
(C-L-d2U)
26
(C-L-d4C)
30
(C-L-d2C)
34
(C-L-d4A)
35
(C-L-d4MP)
36
(C-L-d2A)
38
(C-L-d4I)
39
(C-L-d2I)
45
L-carbovir
>100
>100
>100
-
>10
>10
>10
10.0
>10
0.9
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
-
>100
-
>100
>100
>100
>100
>100
>100
>100
>100
>100
-
171
>100
>100
>100
>100
>100
>100
>100
>100
-
-
35.8
65.9
>100
2.4
-
11.7
>100
27.0
-
-
-
-
-
>10
>50
>10
>10
>20026
>100
>100
>20022
a
-: not determined.
(MgSO4). After filtration and evaporation, the residue was
3.55 (dd, J ) 3.4, 8.9 Hz, 1H, 6-Ha), 3.37 (dd, J ) 3.1, 8.9 Hz,
1H, 6-Hb), 2.73 (m, 1H, 5-Ha), 2.16-2.29 (m, 2H, 4-H and
5-Hb), 1.19 (s, 9H, tert-butyl); 13C NMR (CDCl3) δ 191.51,
165.88, 133.41, 129.94, 128.46, 89.40, 84.25, 74.05, 73.55,
62.65, 42.56, 32.11, 27.35; HR-FAB MS Obsd, m/z 351.1251;
Calcd for C18H23O5S, m/z 351.1266 (M + H)+. Anal. (C18H22O5S)
C, H, S.
(1S,4R)-1-Ben zoyloxy-4-(ter t-bu toxym eth yl)cyclop en t-
2-en e (7). Meth od a . A suspension of compound 4 (1.69 g,
5.48 mmol) and pyridinium p-toluene-sulfonate (1.54 g, 6.0
mmol) in trimethyl orthoformate (12 mL) was stirred at room
temperature for 2 h. The reaction mixture was diluted with
ether (160 mL) and washed with aqueous NaHCO3 (2 × 40
mL) and brine (40 mL). The organic layer was dried (MgSO4),
filtered, and concentrated to dryness. The residue, after being
coevaporated with benzene (2 × 10 mL), was treated with
acetic anhydride (17 mL). The reaction mixture was heated
at 120-130 °C for 6 h, and the mixture was concentrated to
dryness. The residue was purified by silica gel column chro-
matography with 1-2% EtOAc in pentane to 7 (1.023 g, 68%
from 4).
Meth od b. A solution of compound 6 (148 mg, 0.42 mmol)
in dry THF was treated with 1,3-dimethyl-2-phenyl-1,3,2-
diazaphospholidine (120 mg, 0.6 mmol) and then stirred at
room temperature for 20 h. The reaction mixture was concen-
trated to dryness, and the residue was purified by silica gel
column chromatography with 1% Et2O in hexanes to give 7
(19.4 mg, 17%): [R]27D 259.89° (c 1.45, CHCl3); 1H NMR (CDCl3)
δ 7.40-8.03 (m, 5H, Ar-H), 6.15 (m, 1H, 2-H), 5.98 (m, 1H,
3-H), 5.95 (m, 1H, 1-H), 3.28 (d, J ) 6.9 Hz, 1H, 6-H), 3.13 (m,
1H, 4-H), 2.10 (m, 1H, 5-Hab), 1.19 (s, 9H, tert-butyl); 13C NMR
(CDCl3) δ 166.59, 140.05, 132.76, 130.65, 130.07, 129.60,
128.27, 80.66, 72.69, 65.50, 45.68, 34.35, 27.52; HR-FAB MS
Obsd, m/z 275.1645; Calcd for C17H23O3, m/z 275.1647 (M +
H)+. Anal. (C17H22O3) C, H.
purified by silica gel column chromatography with 1-3%
EtOAc in hexanes to give 3 (265 mg, 93.4%) as a syrup: [R]25
D
1
55.61° (c 0.82, CHCl3); H NMR (CDCl3) δ 7.41-8.10 (m, 5H,
Ar-H), 5.28 (m, 1H, 1-H), 4.77 (t, J ) 5.6 Hz, 1H, 2-H), 4.50
(d, J ) 5.5 Hz, 1H, 3-H), 3.38 (dd, J ) 4.3, 8.7 Hz, 1H, 6-Ha),
3.31 (dd, J ) 4.3, 8.7 Hz, 1H, 6-Hb), 2.26-2.37 (m, 2H, 5-H),
1.98 (m, 1H, 4-H), 1.41 (s, 3H, CH3), 1.31 (s, 3H, CH3), 1.19 (s,
9H, tert-butyl); HR-FAB MS Obsd, m/z 349.1998; Calcd for
C
20H28O5, m/z 349.2015 (M + H)+. Anal. (C20H28O5) C, H.
(1R,2R,3S,4S)-1-Ben zoyloxy-2,3-d ih yd r oxy-4-(ter t-b u -
toxym eth yl)cyclop en ta n e (4). A solution of compound 3
(3.15 g, 9.04 mmol) in a mixture of concentrated HCl and
MeOH (324 mL, concentrated. HCl: MeOH ) 1:70, v/v) was
stirred at room temperature for 2.5 h. The reaction mixture
was cooled in an ice bath, neutralized with NaHCO3 solid, and
filtered. The filtrate was concentrated to dryness, and the
residue was purified by silica gel column chromatography with
10-25% EtOAc in hexanes to give 4 (2.60 g, 93.3%) as a
1
syrup: [R]25 -28.61° (c 0.87, CHCl3); H NMR (DMSO-d6) δ
D
7.49-8.04 (m, 5H, Ar-H), 5.04 (m, 1H, 1-H), 4.74 (d, J ) 5.1
Hz, 1H, OH, D2O exchangeable), 4.52 (d, J ) 6.5 Hz, 1H, OH,
D2O exchangeable), 3.97 (dd, J ) 4.6, 9.2 Hz, 1H, 2-H), 3.70
(dd, J ) 6.7, 11.3 Hz, 1H, 3-H), 3.14-3.37 (m, 2H, 6-H), 2.17
(m, 1H, 5-Ha), 1.77-1.95 (m, 2H, 4-H and 5-Hb), 1.13 (s, 9H,
tert-butyl); HR-FAB MS Obsd, m/z 309.1711; Calcd for C17H25O5,
m/z 309.1702 (M + H)+. Anal. (C17H24O5) C, N.
(1a S,3a S,4R,6S)-4-Ben zoyloxy-6-(ter t-b u t oxym et h yl)-
3a ,4,5,6,6a -tetr a h ydr ocyclopen ta -1,3-d ioxole-2-th ion e (6).
1,1′-Thiocarbonyldiimidazole (295 mg, 1.61 mmol) was added
to a solution of compound 4 (0.2 g, 0.649 mmol) in dry MeCN
(15 mL). The mixture was stirred under nitrogen at room
temperature for 24 h. The solvent was removed in a vacuum,
and the residue was purified by silica gel column chromatog-
raphy with 1-3% EtOAc in hexanes to give 6 (177 mg, 78%)
as a solid: mp 68-70 °C; [R]28 122.35° (c 0.27, CHCl3); 1H
(1S,4R)-4-(ter t-Bu toxym eth yl)-1-h yd r oxycyclop en t-2-
en e (8). Compound 7 (578 mg, 2.1 mmol) was treated with a
mixture of MeOH (35 mL) and 2 N NaOH (4.5 mL). The
D
NMR (CDCl3) δ 7.43-8.08 (m, 5H, Ar-H), 5.61 (m, 1H, 1-H),
5.39 (t, J ) 6.1 Hz, 1H, 2-H), 5.17 (d, J ) 6.5 Hz, 1H, 3-H),

Synthesis of L-Carbocyclic Nucleosides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17 3395
reaction mixture was stirred at room temperature for 1.5 h
and then neutralized with dry ice. The mixture was concen-
trated in a vacuum to dryness, and the residue was treated
with EtOAc (75 mL) and washed with aqueous NaHCO3 (2 ×
10 mL) and brine (15 mL). The organic layer was dried
(MgSO4), filtered, and concentrated to give crude 8 (335 mg,
93.4%) as a syrup, which was used for the next step without
further purification.
(1′S,4′R)-1-[4-(ter t-Bu t oxym et h yl)cyclop en t -2-en yl]-
th ym in e (9). Meth od a . A solution of diethyl azodicarboxylate
(DEAD) (160 mg, 0.92 mmol) in dioxane (3 mL) was slowly
added to a suspension of compound 8 (78 mg, 0.46 mmol),
triphenylphosphine (240 mg, 0.92 mmol), and N3-benzoyl-
thymine (211 mg, 0.92 mmol) in dry dioxane (4.5 mL). The
mixture was stirred at room temperature for 6 h. The solvent
was removed under reduced pressure, and the residue was
treated with saturated ammonia in MeOH (5 mL). The mixture
was stirred at room temperature for 10 h and then concen-
trated to dryness under reduced pressure. The residue was
purified by preparative TLC with 1% MeOH in CHCl3 to give
9 (68 mg, 53.4%) as a white solid.
MeOH in CHCl3 to afford 12 (1.12 g, 88%) as a solid: mp 129-
1
130 °C; [R]27 22.52° (c 0.54, CHCl3); H NMR (CDCl3) δ 7.30
D
(s, 1H, 6-H), 4.45 (m, 2H, 1′-H and 2′-H), 4.20 (m, 1H, 3′-H),
3.86 (s, 3H, OCH3), 3.38 (m, 2H, 6′-H), 2.37 (m, 1H, 5′-H), 2.27
(m, 1H, 4′-H), 1.76 (s, 3H, 5-CH3), 1.59 (s, 1H, NH), 1.57 (m,
1H, 5′-H), 1.49 (s, 3H, CH3), 1.29 (s, 3H, CH3), 1.17 (s, 9H,
tert-butyl). Anal. (C19H32N2O6) C, H, N.
(1′S,2′R,3′S,4′S)-1-[4-(ter t-Bu toxym eth yl)-2,3-(isopr opyl-
id en ed ioxy)cyclop en ta n -1-yl]th ym in e (14). Compound 12
(550 mg, 1.43 mmol) was dissolved in dioxane (4 mL), ethanol
(4 mL), and aqueous ammonia (30%, 3 mL). The reaction
mixture was heated at 80-100 °C in a sealed bomb for 10 h.
The solution was evaporated to dryness. The residue was
purified by flash silica gel column chromatography with 0.3%
MeOH in CHCl3 to give 14 (314 mg, 62%) as a solid: mp 154-
156 °C; [R]25 35.53° (c 0.53, CHCl3); UV (MeOH) λmax 272.5
D
1
nm; H NMR (CDCl3) δ 7.08 (s, 1H, 6-H), 4.68 (m, 2H, 1′-H
and 2′-H), 4.46 (m, J ) 4.2, 6.0 Hz, 1H, 3′-H), 3.46 (m, 2H,
6′-H), 2.33 (m, 2H, 4′-H and 5′-H), 1.97 (m, 1H, 5′-H), 1.93 (s,
3H, 5-CH3), 1.54 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.20 (s, 9H,
tert-butyl). Anal. (C18H28N2O5) C, H, N.
N-[[(1S,2R,3S,4S)-4-(ter t-Bu toxym eth yl)-2,3-(isop r op yl-
id en ed ioxy)cyclop en t yl]a m in oca r b on yl]-3-m et h oxy-2-
p r op en a m id e (13). Conversion of 11 (1.6 g, 6.6 mmol) to 13
was accomplished using a procedure similar to that described
for 12. The residue obtained was purified by silica gel column
chromatography with 15% EtOAc in hexanes to give 13 (2.0
Meth od b. A suspension of compound 16 (119 mg, 0.38
mmol) and pyridinium p-toluene-sulfonate (105 mg, 0.42
mmol) in trimethyl orthoformate (3 mL) was stirred at room
temperature for 30 min. The reaction mixture was diluted with
EtOAc (20 mL) and washed with saturated NaHCO3 (2 × 5
mL) and brine (10 mL). The organic layer was dried (MgSO4),
filtered, and concentrated. The residue was coevaporated with
benzene (2 × 5 mL) and treated with Ac2O (2 mL). The mixture
was heated at 120-130 °C for 8 h and concentrated to dryness.
The residue was treated with saturated ammonia in MeOH
(8 mL), and the mixture was stirred at room temperature for
8 h. The residue was purified by silica gel column chromatog-
raphy with 2-5% EtOAc in CHCl3 to give 9 (73 mg, 68.8%) as
a solid: mp 122-124 °C; UV (MeOH) λmax 272 nm; [R]24D 59.38°
g, 82.1%) as a solid: mp 121-122 °C; [R]27 26.63° (c 0.57,
D
1
CHCl3); H NMR (CDCl3) δ 7.76 (br s, 1H, NH), 7.67 (d, J )
12.2 Hz, 1H, 6-H), 5.41 (d, J ) 12.2 Hz, 1H, 5-H), 4.45 (m, 2H,
1′-H and 2′-H), 4.20 (m, 1H, 3′-H), 3.73 (s, 3H, OCH3), 3.33-
3.42 (m, 2H, 6′-H), 2.36-2.43 (m, 1H, 5′-H), 2.28 (m, 1H, 4′-
H), 1.57 (m, 1H, 5′-H), 1.46 (s, 3H, CH3), 1.28 (s, 3H, CH3),
1.17 (s, 9H, tert-butyl); 13C NMR (CDCl3) δ 167.98, 163.06,
155.09, 111.47, 97.64, 86.46, 82.45, 72.80, 62.51, 57.48, 56.54,
45.08, 33.91, 27.38, 27.21, 24.85. Anal. (C18H30N2O6) C, H, N.
1
(c 0.33, CHCl3); H NMR (CDCl3) δ 8.32 (br s, 1H, NH, D2O
exchangeable, 2-H), 7.22 (s, 1H, 6-H), 6.08 (m, 1H, 2′-H), 5.72
(m, 1H, 1′-H), 5.59 (m, 1H, 3′-H), 3.50 (dd, J ) 8.9, 4.1 Hz,
1H, 6′-Ha), 3.34 (dd, J ) 8.9, 4.6 Hz, 1H, 6′-Hb), 2.95 (m, 1H,
4′-H), 2.66 (dt, J ) 14.0, 9.1, 9.1 Hz, 1H, 5′-Ha), 1.90 (s, 3H, 5-
CH3), 1.49 (m, 1H, 5′-Hb), 1.18 (s, 9H, tert-butyl); HR-FAB MS
Obsd, m/z 279.1699; Calcd for C15H23N2O3, m/z 279.1709 (M
+ H)+. Anal. (C15H22N2O3) C, H, N.
(1′S,2′R,3′S,4′S)-1-[4-(ter t-Bu toxym eth yl)-2,3-(isopr opyl-
id en ed ioxy)cyclop en t a n -1-yl]u r a cil (15). A mixture of
compound 13 (600 mg, 1.62 mmol), ethanol (10 mL), and
aqueous ammonia (30%, 2.5 mL) was heated at 80-90 °C in a
steel bomb for 24 h. After cooling, the solution was evaporated
to dryness. The residue was purified by preparative TLC (3%
MeOH in CHCl3) to give 15 (493 mg, 90%) as an oil: [R]25
D
1
43.16° (c 0.67, CHCl3); UV (MeOH) λmax 266.5 nm; H NMR
(1′S,4′R)-1-[4-(H yd r oxym et h yl)cyclop en t -2-en yl]t h y-
m in e (10). A mixture of compound 9 (50 mg, 0.18 mmol),
CF3CO2H (8 mL), and H2O (4 mL) was heated at 50 °C for 3
h. The solution was then concentrated to dryness and coevapo-
rated with EtOH (2 × 5 mL). The residue was purified by silica
gel column chromatography with 3% MeOH in CHCl3 to give
10 (37 mg, 93%) as a white solid: mp 162-164 °C; [R]24D 71.66°
(c 0.30, MeOH); UV (H2O) λmax 273.5 (ꢀ 12757) (pH 2), 273.5 (ꢀ
(CDCl3) δ 7.35 (d, J ) 8.0 Hz, 1H, 6-H), 5.73 (d, J ) 8.0 Hz,
1H, 6-H), 4.72 (m, 2H, 1′-H and 2′-H), 4.48 (m, 1H, 3′-H), 3.46
(m, 2H, 6′-H), 2.37 (m, 2H, 4′-H and 5′-H), 1.97 (m, 1H, 5′-H),
1.55 (s, 3H, CH3), 1.30 (s, 3H, CH3), 1.19 (s, 9H, tert-butyl);
13C NMR (CDCl3) δ 167.98, 163.05, 155.09, 111.47, 97.64,
86.46, 82.45, 72.80, 62.51, 57.48, 56.54, 45.08, 33.91, 27.38,
27.21, 24.85. Anal. (C17H26N2O5‚0.5H2O) C, H, N.
1
12893) (pH 7), 272.0 nm (ꢀ 9453) (pH 11); H NMR (DMSO-
(1′S,2′R,3′S,4′S)-1-[4-(ter t-Bu toxym eth yl)-2,3-dih ydr oxy-
cyclop en ta n -1-yl]th ym in e (16). A solution of compound 14
(362 mg, 1.03 mmol) in a mixture of concentrated HCl and
MeOH (35.5 mL, concentrated HCl:MeOH ) 1:70, v/v) was
stirred at room temperature for 2.5 h. The reaction mixture
was cooled in an ice bath and neutralized with NaHCO3 solid.
The mixture was concentrated to dryness. The residue was
purified by silica gel column chromatography with 2-4%
MeOH in CH2Cl2 to give 16 (258.5 mg, 80.6%) as a syrup: UV
d6) δ 7.34 (s, 1H, 6-H), 6.08 (m, 1H, 2′-H), 5.68 (m, 1H, 3′-H),
5.49 (m, 1H, 1′-H), 4.74 (t, J ) 5.2 Hz, 1H, OH, D2O
exchangeable), 3.45 (m, 2H, 6′-Ha,b), 2.78 (m, 1H, 4′-H), 2.46
(m, 1H, 5′-Ha), 1.74 (s, 3H, CH3), 1.33 (m, 1H, 5′-Hb); 13C NMR
(DMSO-d6) δ 163.05, 150.00, 138.31, 136.63, 128.96, 108.10,
62.55, 59.36, 46.32, 32.06, 11.31; HR-FAB MS Obsd, m/z
223.1082; Calcd for C11H15N2O3, m/z 223.1083 (M + H)+. Anal.
(C11H14N2O3) C, H, N.
N-[[(1S,2R,3S,4S)-4-(ter t-Bu toxym eth yl)-2,3-(isop r op yl-
id en ed ioxy)cyclop en t yl]a m in oca r b on yl]-3-m et h oxy-2-
m eth yl-2-p r op en a m id e (12). To a solution of â-methoxy-R-
methacryloyl chloride (1.274 g, 9.46 mmol) in anhydrous
benzene (13.2 mL) was added silver cyanate (3.04 g). The
mixture was refluxed for 30 min and allowed to cool to room
temperature. After the solid phase had settled, 6.33 mL of the
supernatant solution which contained â-methoxy-R-methacryl-
oyl isocyanate was added to a solution of amine 11 (820 mg)
in dried DMF (16 mL) at -15 to -20 °C during 15 min. The
reaction mixture was stirred at -15 °C for 2 h and then at
room temperature for 8 h under nitrogen. The mixture was
evaporated under reduced pressure, and the residue was
purified by flash silica gel column chromatography with 5%
(MeOH) λmax 273.5 nm; [R]24 38.57° (c 0.12, CHCl3); 1H NMR
D
(DMSO-d6) δ 11.20 (s, 1H, NH, D2O exchangeable), 7.51 (s,
1H, 6-H), 4.82 (d, J ) 6.5 Hz, 1H, OH, D2O exchangeable),
4.63 (dd, 1H, J ) 9.3, 18.5 Hz, 1′-H), 4.57 (d, J ) 3.9 Hz, 1H,
OH, D2O exchangeable), 4.01 (m, 1H, 3′-H), 3.29 (m, 2H, 6′-
Ha,b), 2.03-1.94 (m, 2H, 5′-Ha and 4′-H), 1.78 (s, 3H, CH3),
1.24 (m, 1H, 5′-Hb), 1.14 (s, 9H, tert-butyl); HR-FAB MS Obsd,
m/z 313.1766; Calcd for C15H25N2O5, m/z 313.1763 (M + H)+.
Anal. (C15H24N2O5‚0.2H2O) C, H, N.
(1′S,2′R,3′S,4′S)-1-[4-(ter t-Bu toxym eth yl)-2,3-dih ydr oxy-
cyclop en ta n -1-yl]u r a cil (17). A solution of compound 15 (3.2
g, 9.45 mmol) in a mixture of concentrated HCl and MeOH
(341.2 mL, concentrated HCl:MeOH ) 1:65, v/v) was stirred
at room temperature for 3 h. The reaction mixture was cooled

3396 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17
Wang et al.
in an ice bath and neutralized with solid NaHCO3. The mixture
was concentrated to dryness. The residue was purified by silica
gel column chromatography with 5-8% MeOH in CHCl3 to
give 17 (2.82 g, 100%) as a syrup: [R]25D 36.73° (c 0.65, CHCl3);
UV (MeOH) λmax 267.5 nm; 1H NMR (DMSO-d6) δ 7.68 (d, J )
8.0 Hz, 1H, 6-H), 5.60 (d, J ) 8.0 Hz, 1H, 5-H), 4.88 (d, J )
6.4 Hz, 1H, OH, D2O exchangeable), 4.65 (m, 1H, 1′-H), 4.61
(d, J ) 6.0 Hz, 1H, OH, D2O exchangeable), 3.65 (m, 1H, 3′-
H), 3.27 (m, 2H, 6′-Ha,b), 2.07-1.95 (m, 2H, 5′-Ha and 4′-H),
1.23 (m, 1H, 5′-Hb), 1.13 (s, 9H, tert-butyl); HR-FAB MS Obsd,
m/z 299.1605; Calcd for C14H23N2O5, m/z 299.1607 (M + H)+.
added dropwise 4-chlorophenyl dichlorophosphate (0.74 mL,
6.05 mmol), followed by the addition of 1,2,4-triazole (418 mg,
6 mmol). The mixture was stirred at room temperature for 24
h, and then the reaction mixture was evaporated in vacuo to
dryness under 40 °C. The residue was dissolved in CH2Cl2 (25
mL), and the solution was washed with water (2 × 50 mL),
and saturated NaHCO3 (50 mL). The organic layer was dried
(MgSO4), filtered, and concentrated to dryness to give crude
24 which was used for the next step without further purifica-
tion. The crude 24 was stirred in a mixture of 30% aqueous
ammonia (30 mL) and 1,4-dioxane (30 mL) at room temper-
ature for 24 h. The solution was removed to dryness, and the
residue was purified by silica gel column chromatography with
1-3% MeOH in CHCl3 to give 25 (163 mg, 41%) as a white
(1′S,4′R)-1-[4-(ter t-Bu t oxym et h yl)cyclop en t -2-en yl]-
u r a cil (20). Conversion of 17 (952 mg, 3.2 mmol) to 20 was
accomplished using a procedure similar to that described for
9 (method b). The obtained residue was purified by silica gel
column chromatography with 1% MeOH in CHCl3 to give 20
solid: mp >220 °C (dec); [R]28 102.31° (c 0.50, CHCl3); UV
D
1
(MeOH) λmax 276 nm; H NMR (CDCl3) δ 7.71 (d, J ) 7.0 Hz,
(665 mg, 78.8%) as a solid: mp 107-110 °C; [R]26 77.58° (c
1H, 5-H), 6.04 (m, 1H, 2′-H), 5.90 (m, 1H, 1′-H), 5.63 (d, J )
7.0 Hz, 1H, 6-H), 5.59 (m, 1H, 3′-H), 3.49 (dd, J ) 3.9, 8.9 Hz,
1H, 6′-Ha), 3.31 (dd, J ) 4.4, 8.8, Hz, 1H, 6′-Hb), 2.94 (m, 1H,
4′-H), 2.74 (dt, J ) 14.4, 9.5, 9.4 Hz, 1H, 5′-Ha), 1.45 (dt, J )
14.3, 5.5, 5.1 Hz, 1H, 5′-Hb), 1.16 (s, 9H, tert-butyl); HR-FAB
MS Obsd, m/z 264.1714; Calcd for C14H22N3O2, m/z 264.1712
(M + H)+. Anal. (C14H21N3O2) C, H, N.
D
1
0.99, CHCl3); UV (MeOH) λmax 267.5 nm; H NMR (CDCl3) δ
8.76 (br s, 1H, NH, D2O exchangeable), 7.69 (d, J ) 8.0 Hz,
1H, 5-H), 6.06 (m, 1H, 2′-H), 5.75 (m, 1H, 1′-H), 5.65 (d,
J ) 8.0 Hz, 1H, 6-H), 5.58 (m, 1H, 3′-H), 3.52 (dd, J ) 9.0, 3.6
Hz, 1H, 6′-Ha), 3.34 (dd, J ) 8.9, 4.1 Hz, 1H, 6′-Hb), 2.96 (m,
1H, 4′-H), 2.69 (dt, J ) 14.4, 9.5, 9.5 Hz, 1H, 5′-Ha), 1.52 (m,
1H, 5′-Hb), 1.16 (s, 9H, tert-butyl); HR-FAB MS Obsd, m/z
265.1562; Calcd for C14H21N2O3, m/z 265.1552 (M + H)+. Anal.
(C14H20N2O3) C, H, N.
(1′S ,4′R )-1-[4-(H yd r oxym e t h yl)cyclop e n t -2-e n yl]cy-
tosin e (26). Conversion of 25 (136 mg, 0.52 mmol) to 26 was
accomplished using a procedure similar to that described for
10. The obtained residue was purified by silica gel column
chromatography with 10% MeOH in CHCl3 to give 26 (101 mg,
(1′S,4′R)-1-[4-(H yd r oxym et h yl)cyclop en t -2-en yl]u r a -
cil (21). Conversion of 20 (165 mg, 0.65 mmol) to 21 was
accomplished using a procedure similar to that described for
10. The residue obtained was purified by silica gel column
chromatography with 1-3% MeOH in CHCl3 to give 21 (117
94%) as a white solid:. mp 150-153 °C; [R]28 133.89° (c 0.44,
D
MeOH); UV (H2O) λmax 284.5 (ꢀ 10022) (pH 2), 274.5 (ꢀ 7419)
(pH 7), 274.5 nm (ꢀ 7141) (pH 11); 1H NMR (DMSO-d6) δ 7.46
(d, J ) 7.3 Hz, 1H, 5-H), 6.08 (m, 1H, 2′-H), 5.73 (d, J ) 7.3
Hz, 1H, 6-H), 5.66 (m, 1H, 3′-H), 5.54 (m, 1H, 1′H), 4.70 (t, J
) 5.0 Hz, 1H, OH, D2O exchangeable), 4.12 (br s, 2H, NH2,
D2O exchangeable), 3.38 (m, 2H, 6′-Ha,b), 2.77 (m, 1H, 4′-H),
2.47 (m, 1H, 5′-Ha), 1.25 (m, 1H, 5′-Hb); HR-FAB MS Obsd,
m/z 208.1078; Calcd for C10H13N3O2, m/z 208.1086 (M + H)+.
Anal. (C10H15N3O2‚0.2H2O) C, H, N.
mg, 87%) as a white solid: mp 196-198 °C; [R]25 104.68° (c
D
0.81, MeOH); UV (H2O) λmax 268.5 (ꢀ 10540) (pH 2), 268.0 (ꢀ
1
11562) (pH 7), 265.5 nm (ꢀ 10019) (pH 11); H NMR (DMSO-
d6) δ 11.25 (br s, 1H, NH, D2O exchangeable), 7.46 (d, J ) 8.0
Hz, 1H, 5-H), 6.09 (m, 1H, 2′-H), 5.69 (m, 1H, 3′-H), 5.58 (d, J
) 8.0 Hz, 1H, 6-H), 5.49 (m, 1H, 1′-H), 4.73 (t, J ) 5.2 Hz, 1H,
OH, D2O exchangeable), 3.45 (m, 2H, 6′-Ha,b), 2.79 (m, 1H,
4′-H), 2.47 (m, 1H, 5′-Ha), 1.34 (m, 1H, 5′-Hb); HR-FAB MS
Obsd, m/z 209.0926; Calcd for C10H13N2O3, m/z 209.0926 (M
+ H)+. Anal. (C10H12N2O3) C, H, N.
(1′S ,4′R )-1-[4-(H yd r oxym e t h yl)cyclop e n t a n -1-yl]cy-
tosin e (27). Compound 26 (52 mg, 0.25 mmol) in MeOH (15
mL) was hydrogenated at 15 psi in the presence of 10% Pd/C
(40 mg) for 1 h at room temperature. The reaction mixture
was filtered, and the filtrate was evaporated. The residue was
purified by silica gel column chromatography with 8-10%
MeOH in CHCl3 to give 27 (45 mg, 85.6%) as a solid: mp 103-
(1′S,4′R)-1-[4-(H yd r oxym et h yl)cyclop en t a n -1-yl]t h y-
m in e (22). Compound 10 (40 mg, 0.45 mmol) in MeOH (10
mL) was hydrogenated at 15 psi in the presence of 10% Pd/C
(30 mg) for 3 h at room temperature. The reaction mixture
was filtered, and the filtrate was evaporated. The residue was
purified by silica gel column chromatography with 2-3%
MeOH in CHCl3 to give 22 (36 mg, 89.2%) as a white solid:
105 °C; [R]28 41.29° (c 0.22, MeOH); UV (H2O) λmax 285 (ꢀ
D
12707) (pH 2), 275 (ꢀ 8529) (pH 7), 275.5 nm (ꢀ 9402) (pH 11);
1H NMR (DMSO-d6) δ 7.63 (d, J ) 7.3 Hz, 1H, 6-H), 7.00 (br
s, 2H, NH2, D2O exchangeable), 5.68 (d, J ) 7.1 Hz, 1H, 5-H),
4.77 (m, 1H, 1′-H), 4.55 (t, J ) 5.3 Hz, 1H, OH, D2O
exchangeable), 3.35 (m, 2H, 6′-Ha,b), 2.07-1.23 (m, 7H, 2′-
Ha,b, 3′-Ha,b, 4′-H, and 5′-Ha,b); HR-FAB MS Obsd, m/z
210.1243; Calcd for C10H16N3O2, m/z 210.1243 (M + H)+. Anal.
(C10H15N3O2‚0.1CHCl3) C, H, N.
mp 172-174 °C; [R]28 11.30° (c 0.18, MeOH); UV (H2O)
D
λmax 274.0 (ꢀ 10601) (pH 2), 273.5 (ꢀ 10764) (pH 7), 273.0
1
nm (ꢀ 6055) (pH 11); H NMR (DMSO-d6) δ 11.19 (br s, 1H,
NH, D2O exchangeable), 7.57 (s, 1H, 6-H), 4.72 (m, 1H,
1′H), 4.57 (t, 1H, OH, D2O exchangeable), 3.36 (d, 2H, J ) 6.3
Hz, 6′-Ha,b), 2.06-1.33 (m, 7H, 2′-Ha,b, 3′-Ha,b, 4′-H,
and 5′-Ha,b), 1.77 (s, 3H, CH3); HR-FAB MS Obsd, m/z
225.1245; Calcd for C11H17N2O3, m/z 225.1239 (M + H)+. Anal.
(C11H16N2O3) C, H, N.
(1′S,2′R,3′S,4′S)-9-[4-(ter t-Bu toxym eth yl)-2,3-dih ydr oxy-
cyclop en ta n -1-yl]-6-ch lor op u r in e (29). A solution of com-
pound 28 (1.53 g, 4.01 mmol) in a mixture of concentrated HCl
(2.62 mL) and MeOH (170 mL) was stirred at room temper-
ature for 3 h. The reaction mixture was cooled in an ice-water
bath and then neutralized with NaHCO3 solid. The mixture
was concentrated to dryness, and the residue was purified by
silica gel column chromatography with 1-3% MeOH in CHCl3
(1′S,4′R)-1-[4-(H yd r oxym et h yl)cyclop en t a n -1-yl]u r a -
cil (23). Conversion of 21 (72 mg, 0.45 mmol) to 23 was
accomplished using a procedure similar to that described for
22. The residue obtained was purified by silica gel column
chromatography with 1-3% MeOH in CHCl3 to give 23 (65
to give 29 (1.19 g, 86.8%) as a foam: [R]25 19.92° (c 0.67,
mg, 90%) as a syrup: [R]28 21.28° (c 0.42, MeOH); UV (H2O)
D
D
CHCl3); UV (MeOH) λmax 263.5 nm; 1H NMR (DMSO-d6 + D2O)
δ 8.79 and 8.77 (two s, 2H, 2-H and 8-H), 4.85 (dd, J ) 9.5,
18.7 Hz, 1H, 1′-H), 3.88 (dd, J ) 5.0, 9.2 Hz, 1H, 2′-H), 3.80
(dd, J ) 2.4, 4.9 Hz, 1H, 3′-H), 3.36 (m, 2H, 6′-Hab), 2.35 (dt,
J ) 8.9, 8.9, 13.0 Hz, 1H, 5-Ha), 2.08 (m, 1H, 4′-H), 1.78 (m,
1H, 5-Hb), 1.15 (s, 9H, tert-butyl); FAB MS m/z 341 (M + H)+.
λmax 269.0 (ꢀ 9949) (pH 2), 268.5 (ꢀ 10085) (pH 7), 266.0 nm (ꢀ
7646) (pH 11); 1H NMR (DMSO-d6) δ 11.22 (br s, 1H, NH, D2O
exchangeable), 7.70 (d, J ) 8.0 Hz, 1H, 5-H), 5.57 (d, J ) 8.0
Hz, 1H, 6-H), 4.73 (m, 1H, 1′H), 4.57 (t, 1H, OH, D2O
exchangeable), 3.38 (m, 2H, 6′-Ha,b), 2.08-1.31 (m, 7H, 2′-
Ha,b, 3′-Ha,b, 4′-H, and 5′-Ha,b); HR-FAB MS Obsd, m/z
211.1081; Calcd for C10H15N2O3, m/z 211.1083 (M + H)+. Anal.
(C10H14N2 O3‚0.85H2O) C, H, N.
(1′S,4′R)-9-[4-(ter t-Bu toxym eth yl)cyclop en t-2-en yl]-6-
ch lor op u r in e (31). Meth od a . A solution of diethyl azodi-
carboxylate (DEAD) (512 mg, 2.94 mmol) in dioxane (4.5 mL)
was slowly added to a suspension of compound 8 (250 mg, 1.47
mmol), triphenylphosphine (770 mg, 2.94 mmol), and 6-chlo-
(1′S,4′R)-1-[4-(ter t-Bu toxym eth yl)cyclop en t-2-en yl]cy-
tosin e (25). To a solution of compound 20 (400 mg, 1.51 mmol)
in pyridine (23 mL) while stirring in a cold water bath was

Synthesis of L-Carbocyclic Nucleosides
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17 3397
ropurine (454 mg, 2.94 mmol) in dry dioxane (15 mL). The
mixture was stirred at room temperature for 10 h. The solvent
was removed under reduced pressure, and the residue was
purified by preparative TLC with 30% EtOAc in hexanes to
give 31 (156 mg, 34.6%) as white solid.
to 35 was accomplished using a procedure similar to that
described for 10. The residue obtained was purified by silica
gel column chromatography with 3% MeOH in CHCl3 to give
35 (110 mg, 94%) as a solid: mp 235-238 °C; [R]28 -41.61°
D
(c 0.22, Pyr); UV (H2O) λmax 322.5 (ꢀ 12953) (pH 2), 320.0 (ꢀ
1
19421) (pH 7), 310.5 nm (ꢀ 20659) (pH 11); H NMR (DMSO-
Meth od b. A suspension of compound 29 (880 mg, 2.58
mmol) and pyridinium p-toluene-sulfonate (710 mg, 2.83
mmol) in trimethyl orthoformate (3 mL) was stirred at room
temperature for 2 h. The reaction mixture was diluted with
EtOAc (100 mL) and washed with saturated NaHCO3 solution
(2 × 15 mL) and brine (15 mL). The organic layer was dried
(MgSO4), filtered, and concentrated to dryness. The residue
was coevaporated with benzene (2 × 15 mL) and then treated
with Ac2O (14 mL). The mixture was heated at 120-130 °C
for 12 h and then concentrated to dryness. The residue was
purified by silica gel column chromatography with 15% EtOAc
in hexanes to give 31 (429 mg, 54.2%) as a white solid: mp
d6) δ 13.72 (br s, 1H, NH, D2O exchangeable), 8.20 (s, 1H, 2-H),
8.19 (s, 1H, 8-H), 6.17 (m, 1H, 2′-H), 5.92 (m, 1H, 3′-H), 5.58
(m, 1H, 1′-H), 4.74 (t, J ) 5.3 Hz, 1H, OH, D2O exchangeable),
3.45 (t, J ) 5.6 Hz, 2H, 6′-Ha,b), 2.90 (m, 1H, 4′-H), 2.67 (dt,
J ) 13.8, 8.8, 8.7 Hz, 1H, 5′-Ha), 1.63 (dt, J ) 13.8, 5.6, 5.6
Hz, 1H, 5′-Hb); HR-FAB MS Obsd, m/z 249.0821; Calcd for
C
11H13N4O2, m/z 249.0810 (M + H)+. Anal. (C11H12N4OS) C,
H, N.
(1′S,4′R)-9-[4-(H yd r oxym et h yl)cyclop en t a n -1-yl]a d e-
n in e (36). Conversion of 34 (55 mg, 0.24 mmol) to 36 was
accomplished using a procedure similar to that described for
22. The residue obtained was purified by silica gel column
chromatography with 3-5% MeOH in CHCl3 to give 36 (54
111-114 °C; [R]22 17.69° (c 1.21, CHCl3); 1H NMR (CDCl3) δ
D
8.75 (s, 1H, 2-H), 8.45 (s, 1H, 8-H), 6.02 (m, 1H, 2′-H), 5.84
(m, 2H, 1′-H and 3′-H), 3.53 (dd, J ) 4.2, 8.9 Hz, 1H, 6′-Ha),
3.39 (dd, J ) 4.6, 8.9 Hz, 1H, 6′-Hb), 3.10 (m, 1H, 4′-H), 2.87
(dt, J ) 14.3, 9.2, 9.2 Hz, 1H, 5′-Ha), 1.78 (m, 1H, 5′-Hb), 1.18
(s, 9H, tert-butyl); HR-FAB MS Obsd, m/z 307.1326; Calcd for
mg, 81%) as a white solid: mp 124-126 °C; [R]28 -1.56° (c
D
0.29, MeOH); UV (H2O) λmax 260 (ꢀ 15415) (pH 2), 261 (ꢀ 16055)
(pH 7), 261 nm (ꢀ 16360) (pH 11); 1H NMR (DMSO-d6) δ 8.23
(s, 1H, 2-H), 8.12 (s, 1H, 8-H), 7.21 (br s, 2H, NH2, D2O
exchangeable), 4.79 (m, 1H, 1′-H), 4.63 (br s, 1H, OH, D2O
exchangeable), 3.44 (m, 2H, 6′-Ha,b), 1.61-2.33 (m, 7H, 2′-
Ha,b, 3′-Ha,b, 4′-H, and 5′-Ha,b); HR-FAB MS Obsd, m/z
234.1351; Calcd for C11H16N5O, m/z 234.1355 (M + H)+. Anal.
(C11H15N5O‚0.3MeOH) C, H, N.
C
H, N.
15H20N4ClO, m/z 307.1326 (M + H)+. Anal. (C15H19N4ClO) C,
(1′S,4′R)-9-[4-(ter t-Bu t oxym et h yl)cyclop en t -2-en yl]-
a d en in e (32). A solution of compound 31 (145 mg, 0.47 mmol)
and saturated NH3 in methanol (20 mL) was heated at 80-90
°C in a steel bomb for 20 h. After cooling, the solvent was
removed under vacuum and the residue was purified by silica
gel column chromatography with 0-1% MeOH in CHCl3 to
give compound 32 (112 mg, 82.5%) as a white solid: mp 182
(1′S,4′R)-9-[4-(Hyd r oxym eth yl)cyclopen t-2-en yl]h yp ox-
a n th in e (38). A mixture of chloropurine analogue 31 (150 mg,
0.49 mmol), 2-mercaptoethanol (140 mg, 1.9 mmol), and
NaOMe (105 mg, 1.95 mmol) in methanol (25 mL) was refluxed
for 24 h. The mixture was cooled, neutralized with glacial
AcOH, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography with 3%
MeOH in CHCl3 to give 37 (140 mg, 99.3%) as a white solid
which was used for the next step without further purification.
Conversion of 37 (135 mg, 0.47 mmol) to 38 was accomplished
using a procedure similar to that described for 10. The
obtained residue was purified by silica gel column chroma-
tography with 10% MeOH in CHCl3 to give 38 (105 mg, 96.6%)
as a white solid: mp 270-272 °C; [R]28D -3.83° (c 0.38, MeOH);
UV (H2O) λmax 250.5 (ꢀ 12128) (pH 2), 250.0 (ꢀ 12873) (pH 7),
°C; UV (MeOH) λmax 261 nm; [R]24 19.86° (c 0.70, CHCl3); 1H
D
NMR (CDCl3) δ 8.36 (s, 1H, 2-H), 8.04 (s, 1H, 8-H), 6.16 (m,
1H, 2′-H), 5.82 (m, 1H, 3′-H), 5.74 (m, 1H, 1′-H), 5.61 (br s,
2H, NH2, D2O exchangeable), 3.46 (dd, J ) 4.8, 8.8 Hz, 1H,
6′-Ha), 3.35 (dd, J ) 5.1, 8.8 Hz, 1H, 6′-Hb), 3.04 (m, 1H, 4′-
H), 2.82 (dt, J ) 14.1, 9.1, 9.1 Hz, 1H, 5′-Ha), 1.69 (m, 1H,
5′-Hb), 1.16 (s, 9H, tert-butyl); HR-FAB MS Obsd, m/z 288.1818;
Calcd for C15H22N5O, m/z 288.1824 (M + H)+. Anal. (C15H21N5O)
C, H, N.
(1′S,4′R)-9-[4-(ter t-Bu toxym eth yl)cyclop en t-2-en yl]-9H-
p u r in e-6-th iol (33). A solution of compound 31 (165 mg, 0.54
mmol) and thiourea (52 mg, 0.67 mmol) in EtOH (17 mL) was
refluxed for 1 h and cooled in an ice-water bath. The white
precipitate formed was filtered and washed with EtOH (2 mL)
to give a white solid of 33 (152 mg, 93%): mp 220 °C (dec);
1
255.0 nm (ꢀ 12095) (pH 11); H NMR (DMSO-d6) δ 12.29 (br
s, 1H, NH, D2O exchangeable), 8.04 (s, 1H, 2-H), 7.99 (s, 1H,
8-H), 6.15 (m, 1H, 2′-H), 5.91 (m, 1H, 3′-H), 5.56 (m, 1H, 1′-
H), 4.73 (t, J ) 5.2 Hz, 1H, OH, D2O exchangeable), 3.45 (t, J
) 5.7 Hz, 2H, 6′-Ha,b), 2.87 (m, 1H, 4′-H), 2.67 (dt, J ) 13.7,
8.7, 8.7 Hz, 1H, 5′-Ha), 1.63 (dt, J ) 13.7, 5.8, 5.8 Hz, 1H,
5′-Hb); HR-FAB MS Obsd, m/z 233.1047; Calcd for C11H13N4O2,
m/z 233.1039 (M + H)+. Anal. (C11H12N4O2) C, H, N.
UV (MeOH) λmax 325.0 nm; [R]28 -89.08° (c 0.21, CHCl3); 1H
D
NMR (DMSO-d6) δ 8.23 (s, 1H, 2-H), 8.05 (s, 1H, 8-H), 6.19
(m, 1H, 2′-H), 5.80 (m, 1H, 3′-H), 5.68 (m, 1H, 1′-H), 4.48 (dd,
J ) 8.7, 4.8 Hz, 1H, 6′-Ha), 3.38 (dd, J ) 8.9, 5.0 Hz, 1H, 6′-
Hb), 3.05 (m, 1H, 4′-H), 2.82 (dt, J ) 14.1, 9.3, 9.2 Hz, 1H,
5′-Ha), 1.73 (m, 1H, 5′-Hb), 1.18 (s, 9H, tert-butyl); HR-FAB
MS Obsd, m/z 305.1410; Calcd for C15H21N4OS, m/z 305.1436
(M + H)+.
(1′S,4′R)-9-[4-(Hydr oxym eth yl)cyclopen tan -1-yl]h ypox-
a n th in e (39). Conversion of 38 (66 mg, 0.28 mmol) to 39 was
accomplished using a procedure similar to that described for
22. The obtained residue was purified by silica gel column
chromatography with 10% MeOH in CHCl3 to give 39 (54 mg,
(1′S,4′R)-9-[4-(H yd r oxym et h yl)cyclop en t -2-en yl]a d e-
n in e (34). Conversion of 32 (50 mg, 0.18 mmol) to 34 was
accomplished using a procedure similar to that described for
10. The residue obtained was purified by silica gel column
chromatography with 3-5% MeOH in CHCl3 to give 34 (34.5
mg, 86%) as a white solid: mp 189-192 °C; [R]24D 4.81° (c 0.52,
MeOH); UV (H2O) λmax 260.5 (ꢀ 14944) (pH 2), 261.5 (ꢀ 16043)
(pH 7), 261.5 nm (ꢀ 15151) (pH 11); 1H NMR (DMSO-d6) δ 8.13
(s, 1H, 2-H), 8.04 (s, 1H, 8-H), 7.21 (br s, 2H, NH2, D2O
exchangeable), 6.14 (m, 1H, 2′-H), 5.92 (m, 1H, 3′-H), 5.58 (m,
1H, 1′-H), 4.75 (t, J ) 5.4 Hz, 1H, OH, D2O exchangeable),
3.46 (m, 2H, 6′-Ha,b), 2.90 (m, 1H, 4′-H), 2.67 (dt, J ) 13.7,
8.8, 8.6 Hz, 1H, 5′-Ha), 1.63 (m, 1H, 5′-Hb); 13C NMR (DMSO-
d6) δ 154.80, 151.34, 151.31, 137.96, 137.44, 128.63, 117.80,
62.84, 58.12, 46.69, 33.29; HR-FAB MS Obsd, m/z 232.1181;
Calcd for C11H14N5O, m/z 232.1198 (M + H)+. Anal. (C11H13N5O)
C, H, N.
81%) as a white solid: mp 246-248 °C; [R]28 -1.04° (c 0.20,
D
MeOH); UV (H2O) λmax 249.5 (ꢀ 11108) (pH 2), 249.5 (ꢀ 11999)
(pH 7), 254.5 nm (ꢀ 15312) (pH 11); 1H NMR (DMSO-d6) δ
12.26 (br s, 1H, NH, D2O exchangeable), 8.18 (s, 1H, 2-H), 8.02
(s, 1H, 8-H), 4.78 (m, 1H, 1′-H), 4.63 (t, 1H, OH, D2O
exchangeable), 3.41 (m, 2H, 6′-Ha,b), 2.28-1.62 (m, 7H, 2′-
Ha,b, 3′-Ha,b, 4′-H, and 5′-Ha,b); HR-FAB MS Obsd, m/z
235.1196; Calcd for C11H15N4O2, m/z 235.1195 (M + H)+. Anal.
(C11H14N4O2‚0.1H2O) C, H, N.
(1′S,2′R,3′S,4′S)-9-[4-(ter t-Bu toxym eth yl)-2,3-dih ydr oxy-
cyclop en ta n -1-yl]gu a n in e (42). A solution of compound 40
(880 g, 2.54 mmol), dimethyl formamide (10.3 mL), triethyl
orthoformate (20.5 mL), and concentrated HCl (0.82 mL) was
stirred at 0-5 °C for 8 h and then at room temperature for
12 h. The solvent was removed, and the residue was stirred
with 50% HAc (47 mL) for 16 h. The mixture was concen-
trated to dryness, and the residue was purified by silica gel
column chromatography with 1-2% MeOH in CHCl3 to give
(1′S,4′R)-9-[4-(H yd r oxym et h yl)cyclop en t a n -1-yl]-9H -
p u r in e-6-th iol (35). Conversion of 33 (143 mg, 0.47 mmol)

3398 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 17
Wang et al.
(6) Herdewijn, P.; De Clerq, E.; Balzarini, J .; Vanderhaeghe, H.
Synthesis and antiviral activity of the carbocyclic analogues of
(E)-5-(2-halovinyl)-2′-deoxyuridines and (E)-5-(2-halovinyl)-2′-
deoxycytidines. J . Med. Chem. 1985, 28, 550-555.
(7) Vince, R.; Hua, M. Synthesis and anti-HIV activity of carbocyclic
2′,3′-didehydro-2′,3′- dideoxy 2,6-disubstituted purine nucleo-
sides. J . Med. Chem. 1990, 33, 17-21.
(8) Daluge, S. M.; Good, S. S.; Martin, M. T.; Tibbels, S. R.; Miller,
W. H.; Averett, D. R.; St. Clair, M. H.; Ayers, K. M. The 34th
Interscience Conference on Antimicrobial Agents and Chemo-
therapy, Orlando, FL, October 1994; Abstract.
(9) Bisacchi, G. S.; Chao, S. T.; Bachard, C.; Daris, J . P.; Innaimo,
S.; J acobs, G. A.; Kocy, O.; Lapointe, P.; Martel, A.; Merchant,
Z.; Slusarchyk, W. A.; Sundeen, J . E.; Young, M. G.; Colonno,
R.; Zahler, R. BMS-200475, a novel carbocyclic 2-deoxyguanosine
analogue with potent and selective anti-hepatitis B virus activity
in-vitro. Bioorg. Med. Chem. Lett. 1997, 7, 127-132.
(1′S,2′R,3′S,4′S)-9-[4-(tert-butoxymethyl)-2,3-dihydroxycyclo-
pentan-1-yl]-2-amino-6-chloropurine (41) (638 g, 70.5%) as a
foam: UV (MeOH) λmax 306.5 nm. A solution of the above
2-amino-6-chloropurine analogue 41 (275 mg, 0.77 mmol),
2-mercaptoethanol (300 mg, 3.84 mmol), NaOMe (325 mg, 6.0
mmol), and MeOH (40 mL) was refluxed for 18 h. The mixture
was cooled and neutralized with glacial acetic acid, and the
solvent was removed. The residue was purified by silica gel
column chromatography with 8-10% MeOH in CHCl3 to give
42 (150 mg, 58%) as a white solid: mp 237-240 °C; [R]25
D
16.13° (c 0.48, MeOH); UV (MeOH) λmax 254 nm; 1H NMR
(DMSO-d6) δ 7.79 (s, 1H, 8-H), 6.42 (br s, 2H, NH2), 4.93 (d, J
) 5.9 Hz, 1H, OH, D2O exchangeable), 4.60 (d, J ) 3.3 Hz,
1H, OH, D2O exchangeable), 4.53 (dd, J ) 9.6, 18.4 Hz, 1H,
1′-H), 4.20 (m, 1H, 2′-H), 3.75 (m, 1H, 3′-H), 3.47 (m, 2H, 6′-
Hab), 2.24 (m, 1H, 5-Ha), 2.00 (m, 1H, 4′-H), 1.37 (m, 1H,
5-Hb), 1.15 (s, 9H, tert-butyl); HR-FAB MS Obsd, m/z 338.1843;
Calcd for C15H24N5O4, m/z 338.1828 (M + H)+.
(10) Belleau, B.; Dixit, D.; Nguyen-Ba, N.; Kraus, J . L. Design and
activity of novel class of nucleoside analogues effective against
HIV-1. 5th International Conference on AIDS, Montreal, Canada,
J une 4-9, 1989; paper no. T.C.O. I., p 515.
(1′S,4′R)-9-[4-(ter t-Bu toxym eth yl)cyclopen t-2-en yl]gu a-
n in e (44). Conversion of 42 (140 mg, 0.41 mmol) to 44 was
accomplished using a procedure similar to that described for
20. The residue obtained was heated with a mixture of aqueous
ammonia (1 mL), methanol (6 mL), and H2O (1 mL) at 65 °C
for 1.25 h. The solvent was removed, and the residue was
purified by silica gel column chromatography with 5% MeOH
in CHCl3 to give 44 (56 mg, 45%): UV (MeOH) λmax 254 nm;
1H NMR (CDCl3) δ 12.08 (br s, 1H, NH), 7.68 (s, 1H, 8-H),
6.38 (br s, 2H, NH2), 6.12 (m, 1H, 2′-H), 5.82 (m, 1H, 1′-H),
5.48 (m, 1H, 3′-H), 3.30-3.50 (m, 2H, 6′-H), 2.98 (m, 1H, 4′-
H), 2.75 (dt, J ) 8.8, 9.0, 14.0 Hz, 1H, 5′-Ha), 1.64 (m, 1H,
5′-Hb), 1.16 (s, 9H, tert-butyl); HR-FAB MS Obsd, m/z 304.1780;
Calcd for C15H22N5O2, m/z 304.1774 (M + H)+.
(11) Coates, J . A. V.; Cammack, N.; J enkinson, H. J .; Mutton, I. M.;
Pearson, B. A.; Storer, R.; Cameron, J . M.; Penn, C. R. The
separated enantiomers of 2′-deoxy-3′-thiacytidine (BCH 189)
both inhibit human immunodeficiency virus replication in vitro.
Antimicrob. Agents Chemother. 1992, 36, 202-205.
(12) Furman, P. A.; Davis, M.; Liotta, D. C.; Paff, M.; Frick, L. W.;
Nelson, D. J .; Dornsife, R. E.; Wurster, J . A.; Wilson, L. J .; Fyfe,
J . A.; Tuttle, J . V.; Miller, W. H.; Condreay, L.; Averett, D. R.;
Schinazi, R. F.; Painter, G. R. The anti-hepatitis
B virus
activities, cytotoxicities, and anabolic profiles of the (-) and (+)
enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-
5-yl]cytosine. Antimicrob. Agents Chemother. 1992, 36, 2686-
2692.
(13) Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Pai, S. B.; Dutschman, G. E.;
Cheng, Y.-C. Synthesis and biological evaluation of 2′,3′-dideoxy-
L-pyrimidine nucleosides as potential antiviral agents against
human immunodeficiency virus (HIV) and hepatitis B virus
(HBV). J . Med. Chem. 1994, 37, 798-803.
(1′S,4′R)-9-[4-(H yd r oxym et h yl)cyclop en t -2-en yl]gu a -
n in e, L-Ca r bovir (45). Conversion of 44 (40 mg, 0.13 mmol)
to 45 was accomplished using a procedure similar to that
described for 10. The residue obtained was purified by silica
gel column chromatography with 10% MeOH in CHCl3 to give
45 (27 mg, 84%) as a solid: mp 223-224 °C (decomp.) [lit23
for D-(-) form, 210-220 °C (decomp.); lit7 for (() form, 254-
(14) Chu, C. K.; Ma, T.; Shanmuganathan, K.; Wang, C.; Xiang, Y.;
Pai, S. B.; Yao, G.-Q.; Sommadossi, J .-P.; Cheng, Y.-C. Use of
2′-fluoro-5-methyl-â-L-arabinofuranosyluracil as a novel anti-
viral agent for hepatitis
B virus and Epstein-Barr virus.
Antimicrob. Agents Chemother. 1995, 39, 979-981.
(15) Schinazi, R. F.; Chu, C. K.; Peck, A.; McMillan, A.; Mathis, R.;
Cannon, D.; J eong, L. S.; Beach, J . W.; Choi, W. B.; Yeola, S.;
Liotta, D. C. Activities of the four optical isomers of 2′,3′-dideoxy-
3′-thiacytidine (BCH-189) against human immunodeficiency
virus type 1 in human lymphocytes. Antimicrob. Agents Chemoth-
er. 1992, 36, 672- 676.
256 °C; lit22 for l-form, 265-270 °C]; [R]28 59.03° (c 0.51,
D
MeOH) [lit25 for L-carbovir, [R]20 60° (c 0.25, MeOH); lit22 for
D
L-carbovir, [R]23 61.1° (c 0.3, MeOH)]; UV (MeOH) λmax 253.5
D
nm; 1H NMR (DMSO-d6) δ 10.35 (br s, 1H, NH, D2O exchange-
able), 7.58 (s, 1H, 8-H), 6.43 (br s, 2H, NH2), 6.10 (m, 1H, 2′-
H), 5.86 (m, 1H, 3′-H), 5.34 (m, 1H, 1′-H), 4.71 (t, J ) 5.4 Hz,
1H, OH, D2O exchangeable), 3.43 (t, J ) 5.8 Hz, 2H, 6′-Ha,b),
2.85 (m, 1H, 4′-H), 2.58 (m, 1H, 5′-Ha), 1.56 (dt, J ) 13.7, 5.8,
5.7 Hz, 1H, 5′-Hb); HR-FAB MS Obsd, m/z 248.1148; Calcd
for C11H14N5O2, m/z 248.1147 (M + H)+.
(16) Chang, C.-N.; Doong, S.-L.; Zhou, J . H.; Beach, J . W.; J eong, L.
S.; Chu, C. K.; Schinazi, R. F.; Liotta, D. C.; Cheng, Y.-C.
Deoxycytidine deamination-resistant stereoisomer is the active
form of (-)-2′,3′-dideoxy-3′-thiacytidine in the inhibition of
hepatitis B virus replication. J . Biol. Chem. 1992, 267, 13938-
13942.
(17) Lin, T.-S.; Luo, M.-Z.; Liu, M.-C.; Zhu, Y.-L.; Gullen, E.;
Dutschman, G. E.; Cheng, Y.-C. Design and synthesis of 2′,3′-
dideoxy-2′,3′-didehydro-â-L-cytidine (â-L-d4C) and 2′,3′-dideoxy-
2′,3′-didehydro-â-L-5-fluorocytidine (â-L-Fd4C) cytidine, two
exceptionally potent inhibitors of human hepatitis B virus (HBV)
and potent inhibitors of human immunodeficiency virus (HIV)
in vitro. J . Med. Chem. 1996, 39, 1757-1759.
Ack n ow led gm en t. This research was supported by
the U.S. Public Health Research grants (AI 32351 and
AI 33655) and the Department of Veterans Affairs. We
thank Dr. Michael G. Bartlett for performing mass
spectroscopy.
(18) Daluge, S. M. U.S. patent 5,087,697, 1992.
(19) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; St. Clair,
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C
11H12N4O2; formula weight, 232.24; crystal system, monoclinic;
lattice parameters a ) 9.1252, b ) 6.2163, c ) 19.5442, â )
93.7660°; space group, P21(#4); Z ) 4.
J M9901327