Carbovir-related compounds and phosphonate analogues

Article abstract of DOI:10.1080/10426500601047578

Detailed syntheses of carbovir-related cis-[2-(9H-Purin-9-yl)-3- cyclopentene]-1-methanols and phosphonates of selected analogues are presented. Our interest in this chemistry stems from antiviral activity shown by closely related compounds. Access to the key β-lactam was achieved by the reaction of monocyclopentadiene with chlorosulfonyl isocyanate at -78°C rather than at the reported1 ambient temperature, where only the less ring-strained and more stable γ-lactam is formed. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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Carbovir-Related Compounds
and Phosphonate Analogues
a
b
Phuong -T. Pham & Robert Vince
a
Penn State Worthington Scranton, Dunmore, PA
Center for Drug Design, Academic Health Center,
b
and Department of Medicinal Chemistry, College of
Pharmacy, University of Minnesota, Minneapolis, MN
Published online: 24 Feb 2007.
To cite this article: Phuong -T. Pham & Robert Vince (2007) Carbovir-Related
Compounds and Phosphonate Analogues, Phosphorus, Sulfur, and Silicon and the
Related Elements, 182:4, 779-791, DOI: 10.1080/10426500601047578
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Phosphorus, Sulfur, and Silicon, 182:779–791, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500601047578
Carbovir-Related Compounds and Phosphonate
Analogues
Phuong-T. Pham
Penn State Worthington Scranton, Dunmore, PA
Robert Vince
Center for Drug Design, Academic Health Center, and Department
of Medicinal Chemistry, College of Pharmacy, University of Minnesota,
Minneapolis, MN
Detailed syntheses of carbovir-related cis-[2-(9H-Purin-9-yl)-3-cyclopentene]-1-
methanols and phosphonates of selected analogues are presented. Our interest in
this chemistry stems from antiviral activity shown by closely related compounds.
Access to the key β-lactam was achieved by the reaction of monocyclopentadiene
◦
1
with chlorosulfonyl isocyanate at −78 C rather than at the reported ambient tem-
perature, where only the less ring-strained and more stable γ -lactam is formed.
Keywords Carbocyclic nucleosides; carbovir triphosphate; HIV reverse transcriptase;
lactam
INTRODUCTION
Although many nucleoside derivatives designed to target viral re-
verse transcriptase have been synthesized, only a handful have been
2
,3
marketed for use in combinational therapeutic treatment of AIDS.
A series of carbocyclic nucleosides originated from our laboratory
has led to the development of a clinically useful drug. These carbo-
ꢀ
ꢀ
ꢀ
ꢀ
cyclic 2 ,3 -didehydro-2 ,3 -dideoxy-2-amino-6-substituted purines were
4,5
ꢀ
ꢀ
termed carbovirs. The parent compound, carbocyclic 2 ,3 -didehydro-
,3 -dideoxyguanosine (carbovir 1a), is enzymatically converted to the
ꢀ
ꢀ
2
active form, carbovir triphosphate, which inhibits HIV reverse tran-
scriptase. All other active derivatives in this series are ultimately con-
verted to the same active metabolite. Thus, the anti-HIV drug derived
Received July 12, 2006; accepted August 29, 2006.
Address correspondence to Phuong-T. Pham, Penn State Worthington Scranton, 120
Ridge View Drive, Dunmore, PA 18707. E-mail: ptp2@psu.edu
779

7
80
P.-T. Pham and R. Vince
SCHEME 1
from this series, abacavir 1b (ZiagenTM), derives its activity via conver-
sion to carbovir triphosphate (Scheme 1).
Nevertheless, the continuous need for new anti-HIV agents arises
from the development of drug resistance as well as toxicity after pro-
longed use of the nucleosides.6 We report herein the syntheses of a
series of novel carbovir-related carbocyclic nucleosides (2a), in which
,7
ꢀ
the 4’hydroxymethyl group was replaced by a 5 hydroxymethyl. Phos-
phonates of selected analogs (2b) were also prepared as the introduction
of phosphonate in the design of more useful antiviral agents have been
well documented.8
−10
DISCUSSION
The key in preparing our title compounds 2a and derivatives was to
obtain 2-azabicyclo[3.2.0]hept-3-en-7-one, β-lactam (3a).
The reaction of chlorosulfonyl isocyanate and cyclopentadiene at am-
bient temperature was found to give 2-azabicyclo[2.2.1]hept-5-en-3-one,
1
γ - or Vince Lactam (3b), rather than the reported β-lactam (3a). To ob-
tain the desired β-lactam, the reaction temperature had to be lowered
significantly. When the reaction temperature was lowered between −5
◦
and −10 C, β-lactam began to form resulting in a mixture of lactams.
◦
At −78 C the reaction proceeded to give selectively β-lactam, following
1
treatment with sodium sulfite (Scheme 2). H NMR spectra for both
1
,11
lactams agreed well with reported literature values.
While δ values
for the methylene hydrogens of γ -lactam were found between 2.39–2.18
ppm, the reported shifts were 2.38–2.20 ppm. The δ values for the al-
lylic methylene hydrogens of β-lactam were found to be slightly more
downfield between 2.67–2.33 ppm. These values are again compara-
ble with the reported chemical shifts of 2.68–2.38 ppm. This downfield

Carbovir-Related Compounds and Phosphonate Analogues
781
SCHEME 2 Reaction conditions yielding β- and γ -lactams.
shift reflects the proximity of the two hydrogens to the double bond in
β-lactam.
Synthetic routes for the preparations of compounds 8 and 12–14
starting from cis (± ) mixture of β-lactam isomers are outlined in
Scheme 3. Thus, hydrolysis of (3a) with methanolic HCl followed
by reduction with calcium borohydride provided the amino alco-
hol 5 (63%). Coupling of 5 with 5-amino-4,6-dichloropyrimidine and
SCHEME 3 (a) 1N HCl/MeOH, reflux; (b) Ca(BH
4
)
2
, THF; (c) 5-amino-4,6-
dichloropyrimidine, Et
3
N, BuOH, reflux; (d) (EtO)
3
CH, HCl, aq. 0.5 N HCl; (e)
◦
liquid NH
3
, 65 ; (f) 2-amino-4,6-dichloropyrimidine, Et
3
N, BuOH, reflux; (g) 4-
+
−
ClC
6
H
4
N Cl , HOAc, aq. NaOAc; (h) Zn, aq. HOAC, EtOH/H
2
O, reflux; (i) 1 N
2
◦
HCl; (j) liquid NH
3
, 80 C; (k) cyclopropylamine/EtOH, reflux.

7
82
P.-T. Pham and R. Vince
2-amino-4,6-dichloropyrimidine in the presence of triethylamine fur-
nished intermediates 6 and 9, respectively. Diazotization of 9 was car-
◦
ried out with 4-chlorophenyldiazonium chloride at 65 C rather than
2
◦
5 C due to the insolubility of the starting material at lower tem-
perature. A mixture of 9 and NaOAc in H2O/acetic acid was heated
◦
to 65 C for 20 minutes before the diazonium reagent was added.
Compound 10 was obtained in good yield (89%). Reduction of 10
with zinc-acetic acid afforded the 2,5-diamino-6-chloro-4-pyrimidinyl
product 11.
Compounds 6 and 11 were converted to the corresponding 9-
substituted-6-chloropurine 7 and 2-amino-6-chloro-9-purin-9-yl 12 by
ring closure with triethylorthoformate under acidic conditions followed
by mild acid hydrolysis. Compounds 8 and 14 were obtained by reac-
tion of the corresponding 6-chloro intermediates with liquid ammonia
under pressure.
◦
Treatment of 12 with 1N HCl at 65 C for 5 h gave 13 in a moderate
yield of 67%. The 6-cyclopropylamine analogue 15 was obtained by the
reaction of 12 with excess cyclopropylamine in ethanol under pressure
◦
12
at 65–70 C.
Phosphonate analogues of 6-aminopurine (16), 6-hydroxy-2-
aminopurine (17), and 6-cyclopropylamine-2-aminopurine (18) were ob-
tained by reaction of the corresponding alcohols with diethyl phospho-
nomethyltriflate in the presence of NaH. The yields of these reactions
were rather poor (20%). Hydrolysis of the phosphonate esters were car-
ried out using Bromotrimethyl Silane (BTMS) followed by treatment
with H2O (Scheme 4). 31P NMR showed that while these phosphonate
esters resonate around 22 ppm, their corresponding acids shifted up-
field by about 2.7 ppm. Proton-phosphorus coupling of 2 Hz was ob-
1
served in H NMR spectra of esters 17a and 18a. This long-range cou-
4
13
pling ( JPH) has been previously reported in the literature with values
of 2.4 to 3.2 Hz.
SCHEME 4

Carbovir-Related Compounds and Phosphonate Analogues
783
CONCLUSION
In conclusion, the synthesis of a series of novel carbovir-related com-
pounds was achieved from the key β-lactam, 2-azabicyclo[3.2.0]hept-3-
en-7-one, to give a racemic mixture of the desired carbocyclic nucleo-
sides and selected phosphonate analogues. The key step in the described
synthetic strategy is based on a newly modified method to selectively
access the key intermediate β-lactam.
EXPERIMENTAL
General
All reagents and anhydrous solvents were obtained from Sigma-
Aldrich. BTMS was distilled before use. Diethyl phosphonomethyltri-
flate was prepared by the reaction of trifluoromethane sulfonyl chloride
with diethylhydroxymethyl phosphonate following the procedure de-
scribed by Phillion and Andrew.1 Diethylhydroxymethyl phosphonate
was prepared by the reaction of diethylphosphite with paraformalde-
4
1
0
hyde in the presence of triethylamine under reflux condition.
1
31
H and P NMR spectra were recorded on a Varian 300 instrument.
Chemical shifts are reported relative to external Me4Si, internal CDCl3,
or external 85% H3PO4 ( P). TLC was done on E. Merck (Darmstadt,
Germany) silica gel (0.25 mm thickness) 60F-254 glass plates. Plates
were visualized using 5% phosphomolybdic acid in EtOH. Elemental
analyses were performed by M-H-W Laboratories, Phoenix, AZ.
31
2
-Azabicyclo[2.2.1]hept-5-en-3-one (3b)
A solution of freshly distilled cyclopentadiene (4.50 g, 68.1 mmol)
in anhydrous CH2Cl2 (10 mL) was added to a solution of chlorosulfonyl
isocyanate (5.25 mL, 8.50 g, 60.3 mmol) in CH2Cl2 (90 mL) over a period
of 20 min at ambient temperature. After the complete addition, the
reaction was continued stirring for 10 min and then quenched with a
solution of sodium sulfite (20 g/80 mL H2O). The CH2Cl2 layer was
separated, and the aqueous layer was extracted with CH2Cl2 (2 × 150
mL). Combined organic layers were dried and concentrated to give a
1
crude brown oil (1.80 g, 32.0%). H NMR identified the product as 3b.
NMR values obtained were identical with those reported for γ -lactam.
1
H NMR (CDCl3, 300 MHz): δ 6.82–6.73 (m, 1H, C6H=C), 6.68–6.62
(
m, 1H, C=C5H), 6.3 (broad s, 1H, NH), 4.33 (s, 1H, C1-H), 3.20 (s, 1H,
C4-H), 2.39–2.18 (m, 2H, C7-H2).

7
84
P.-T. Pham and R. Vince
6
-Azabicyclo[3.2.0] hept-3-en-7-one (3a)
A solution of freshly distilled cyclopentadiene (9.3 g, 140.8 mmol) in
anhydrous CH2Cl2 (10 mL) was added dropwise (15 min) to a solution of
chlorosulfonyl isocyanate (14.6 g, 9.0 mL, 103.4 mmol) in CH2Cl2 (300
◦
mL) at −78 C. The reaction mixture was continued stirring for 4 h with
cooling and was then added in portion to an aqueous solution of Na2SO3
(
60 g/200 mL H2O). After 30 min of stirring at ambient temperature, the
organic layer was separated and taken up in MeOH (200 mL) and dried
over MgSO4. Removal of the solvent gave crude yellow oil (Rf = 0.65,
CHCl3:MeOH, 5:1), which was further purified by flash chromatography
1
(
CH2Cl2:MeOH, 300:5) to give 6.70 g of 3a (59%). H NMR (CDCl3, 300
MHz): δ 6.92 (broad s, 1H, NH), 5.98–5.95 (m, 1H, C4H=C), 5.94–5.88
m, 1H, C=C3H), 4.43 (broad s, 1H, C5-H), 3.76–3.73 (m, 1H, C1-H),
.67–2.33 (m, 2H, C2-H2).
(
2
Cis-(+)-Methyl-(2-aminocyclopent-3-ene)1-carboxylate
Hydrochloride (4)
6
-azabicyclo[3.2.0]hept-3-en-7-one 3a (6.42 g, 58.8 mmol) was dis-
solved in 1N methanolic HCl (150 mL) and refluxed for 3 h. The sol-
vent was then removed in vacuo and the residue chromatographed
(
ETOAc: MeOH) on a silica gel column to give 4 as an off-white solid,
◦
+
1
m.p. 181–182 C: 5.59 g (68%). MS (FAB): m/e 142 (M +1). H NMR
(CD3)2SO, 300 MHz]: δ 8.19 (broad s, 2H, NH2), 6.16–6.14 (m, 1H,
C3H=C), 5.60–5.77 (m, 1H, C=C4H), 4.27 (d, 1H, C2H, J = 8 Hz), 3.66
s, 3H, CH3O), 3.49–3.40 (m, 1H, C1H), 2.82–2.53 (m, 2H, C5H2). Anal.
calcd. (C7H11NO2.HCl.1/8 CH3OH): C, 47.12; H, 7.22; N, 7.72; found: C,
7.46; H, 7.46; N 7.73.
[
(
4
Cis-(+) -[2-(5-Amino-6-chloro-4-pyrimidinyl)-amino-cyclopent-
3
-ene]1-methanol (6)
A suspension of finely grounded CaCl2 (7.16 g. 64.5 mmol) and
NaBH4 (4.88 g, 129 mmol) in anhydrous THF (400 mL) was stirred
at r.t. for 1.5 h. To the suspension was added a solution of 4 (5.0 g,
28 mmol) in anhydrous THF (200 mL), and the reaction mixture was
stirred for 20 h at r.t. The reaction was quenched by adding H2O until
bubbling ceased. The resulting salt was filtered off and washed with
ethanol. The filtrate was concentrated and azeotroped several times
1
with absolute EtOH to give a brown syrup, identified by H NMR as
the amino alcohol 5 (2.0 g, 63%), and was used in the following reaction
1
without further purification. H NMR (CDCl3, 300 NHz): δ 6.12–6.11
(
m, 1H, C3H=C), 5.88–5.86 (m, 1H, C=C4H), 5.67 (broad s, 2H, NH2),

Carbovir-Related Compounds and Phosphonate Analogues
785
4
1
.33 (d, 1H, C2H, J = 2Hz), 3.90–3.78 (m, 2H, CH2OH), 3.41–3.25 (m,
H, C1H), 2.50–2.48 (m, 2H, C5H2).
A solution of 5 (3.0 g, 26.50 mmol), triethylamine (11 mL), and
5
-amino-4,6-dichloropyrimidine (4.16 g, 25.4 mmol) in n-butanol (150
◦
mL) was refluxed at 110 C for 24 h. Excess solvent was removed in
vacuo, and the residue was chromatographed on a silica gel column
(
6
EtOAc:hexane). Product 6 was obtained as an off-white solid: (4.1 g,
4%), m.p. 120–124 C. MS (FAB): m/e 241 (M +1), 239 (M -1). H
◦
+
+
1
NMR [(CD3)2SO, 300 MHz]: δ 7.72 (s, 1H, C2’H), 6.50 (d, 1H, NH,
J= 8 Hz), 5.98–5.96 (m, 1H, C3H=C), 5.72–5.71 (m, 1H, C=C4H),
5
.28–5.24 (m, 1H, C2H), 5.08 (broad s, 2H, NH2), 4.31–4.27 (m, 1H,
OH), 3.64–3.20 (m, 3H, CH2OH and C1H), 2.48–2.25 (m, 2H, C5H2).
Anal. calcd. (C10H13N4OCl): C, 49.90; H, 5.44; N, 23.28; found: C, 50.12;
H, 5.57; N, 23.35.
Cis-(+)-[2-(6-Chloro-9H-purin-9-yl)cyclopent-3-ene]1-methanol
(
7)
A solution of 6 (3.0 g, 13 mmol) in triethyl orthoformate (75 mL) and
conc. HCl (0.75 mL) was stirred overnight at r.t. The reaction mixture
was then concentrated under pressure, and the residue was stirred in
0.5 N HCl (20 mL) for 3 h. The resulting aqueous solution was neutral-
ized to pH ∼ 7–8 with 1N NaOH, concentrated in vacuo, and azeotroped
with absolute EtOH. The residue was chromatographed (EtOAc:MeOH)
on a silical gel column to a give white solid 7 (1.08 g, 35%), m.p. 158–
◦
+
1
1
8
5
60 C. MS (FAB): m/e 251 (M +1). H NMR [(CD3)2SO, 300 MHz]: δ
.76, 8.41 (each s, each 1H, C2’H and C8’H), 6.33–6.32 (m, 1H, C3H=C),
.09–5.90 (m, 1H, C=C4H), 5.81–5.78 (m, 1H, C2H), 4.25 (broad s, 1H,
OH), 3.15–2.70 (m, 2H, CH2OH and 1H, C1H), 2.60–2.42 (m, 2H, C5H2).
Anal. calcd. (C11H11N4 ClO): C, 52.91; H, 4.42; N, 22.35; found: C, 52.91;
H, 4.22; N, 22.69.
Cis-(+)-[2-(6-amino-9H-purin-9-yl)cyclopent-3-ene]-1-
methanol (8)
A solution of 7 (850 mg, 3.4 mmol) in absolute MeOH (20 mL) was
transferred to a stainless-steel bomb, and excess liquid NH3 was added.
◦
The bomb was sealed and heated in an oil bath at 65 C for 20 h. Volatiles
were removed, and the residue was purified by flash chromatography
(
CHCl3/MeOH) to give the desired product as an off-white solid (714
◦
1
mg, 91%), m.p. 184–186 C. H NMR [(CD3)2SO, 300 MHz]: δ 8.11, 7.81
ꢀ
ꢀ
(
each s, each 1H, C2 H and C8 H), 7.19 (broad s, 2H, NH2), 6.29–6.27
(
m, 1H, C3H=C), 5.90–5.88 (m, 1H, C=C4H), 5.60 (d, 1H, C2H, J = 7
Hz), 4.35 (broad s, 1H, OH), 3.33–2.89 (m, 2H, CH2OH), 2.63–2.75 (m,

7
86
P.-T. Pham and R. Vince
1H, C1H), 2.60–2.40 (m, 2H, C5H2). Anal. calcd. (C11H13N5O): C, 57.13;
H, 5.67; N, 30.28; found: C, 57. 31; H, 5.59; N, 30.35.
Cis-(+)-Methyl-[2-(6-amino-9H-purin-9-yl)cyclopent-3-ene]-1-
diethylphosphonate (16a)
A suspension of 8 (700 mg, 3 mmol) and NaH (83 mg, 3.5 mmol)
in anhydrous THF (150 mL) was stirred overnight at r.t. under a N2
◦
atmosphere. The reaction flask was cooled to −20 C, and 1.4 eq. of di-
ethyl phosphonomethyl triflate (1.23 g, 4.10 mmol) in THF (50 mL) was
added dropwise over 2 h. Stirring was continued for another 2 h and
the reaction was quenched with MeOH. The solvent was removed in
vacuo, and the residue was chromatographed to give light yellow oil
1
(
200 mg, 17%). H NMR (CDCl3, 300 MHz): δ 8.29, 7.65 (each s, each
1H, C2’H and C8’H), 6.52 (s, 2H, NH2), 6.28–6.27 (m, 1H, C3H=C),
5.83–5.81 (m, 1H, C=C4H), 5.72 (d, 1H, C2H, J = 7Hz), 4.07–3.93 (m,
4H, OC H2CH3), 3.38–3.05 (m, 4H, CH2OC and P[O]C H2), 3.00–2.90
(
m, 1H, C1H), 2.70–2.80 (m, 2H, C5H2), 1.24–1.18 (m, 6H, OCH2C H3).
3
1
P NMR, proton coupled (CDCl3, 300 MHz): δ 21. 99 (m). Anal. calcd.
C16H24N5O4P.1/2 H2O): C, 49.23; H, 6.46; N, 17.94; found: C, 49.40; H,
.44; N, 17.83.
(
6
Cis-(+)-Methyl-[2-(6-amino-9H-purin-9-yl)cyclopent-3-ene]-1-
phosphonic Acid (16b)
Diethyl phosphonate ester 16a (100 mg, 0.3 mmol) was dissolved in
anhydrous acetonitrile (20 mL), and freshly distilled bromotrimethyl
silane (1.0 mL) was added. The reaction mixture was stirred under N2
at r.t. for 24 h. Excess BTMS and solvent were removed under reduced
pressure. The grayish residue was dissolved in cold H2O (1 mL), and
acetone was added dropwise until a white precipitate was formed. Re-
crystallization with H2O:acetone (∼1:4) gave a white solid (45 mg, 52%),
◦
+
+
1
m.p. 218–220 C. MS (FAB): m/e 326 (M +1), 324 (M -1). H NMR
[
(CD3)2SO, 300 MHz]: δ 8.16, 7.90 (each s, each 1H, C2’H and C8’H),
.39 (broad s, 2H, NH2), 6.31 (broad s, 1H, C3H=C), 5.82 (broad s, 1H,
C=C4H), 5.61 (broad s, 1H, C2H), 3.20–2.89 (m, 4H, C H2OC and P[O]C
7
3
1
H2), 2.90–2.80 (m, 1H, C1H), 2.40–2.20 (m, 2H, C5H2). P {1H} NMR
[
(CD3)2SO, 300 MHz]:δ 19.12 ppm. Anal. calcd. (C12H16N5O4.1/2H2O):
C, 43.11; H, 5.13; N, 20.95; found: C, 43.08; H, 4.48; N, 21.05.
Cis-(± )-2-[(2,5-Diamino-6-chloropyrimidin-4-yl)-amino]
cyclopent-3-enyl Methanol (9)
A mixture of 5 (3.15 g, 27.8 mmol), 2-amino 4,6-dichloropyrimidine
4.80 g, 29.0 mmol), and triethylamine (7.5 mL) in n-butanol (250 mL)
(
was refluxed for 48 h. The solvent was evaporated in vacuo, and the

Carbovir-Related Compounds and Phosphonate Analogues
787
residue was chromatographed (ETOAc:MeOH) to give the desired prod-
◦
uct 9 as an off-white solid (1.0 g, 14%), m.p. 210–212 C. MS(FAB): m/e
2
+
1
41 (M +1). H NMR [(CD3)2SO, 300 MHz]: δ 6.20 (d, 1H, NH, J = 8
Hz), 5.96–5.94 (m, 1H, C3H=C), 5.72–5.89 (m, 1H, C=C4H), 5.66 (broad
s, 2H, NH2), 5.13 (broad s, 1H, C2H), 4.36 (broad s, 1H, OH), 3.94 (broad
s, 2H, NH2), 3.42–3.33 (m, 2H, CH2OH), 3.32–3.23 (m, 1H, C1H), 2.48–
2
2
.25 (m, 2H, C5H2). Anal. calcd. (C10H13N4OCl): C, 49.90; H, 5.44; N,
3.28; found: C, 49.77; H, 5.19; N, 23.10.
Cis-(± )-[2-[2-amino-6chloro-5-[(4-chlorophenyl)azol]-4-
pyrimidyl]-amino]-cyclopent-3-enyl Methanol (10)
p-Chlorobenzenediazonium chloride was prepared by adding drop-
wise a solution of sodium nitrite (325 mg, 4.75 mmol) in H2O (2.5 mL) to
a solution of p-chloroaniline (575 mg, 4.50 mmol) in 3N HCl (10 mL) at
◦
0
C. Freshly prepared p-chlorobenzenediazonium chloride was added
dropwise to a the reaction mixture containing 9 (3.17 g, 13.2 mmol)
◦
and sodium acetate (25 g) in HOAc (25 mL)/H2O (25 mL) at 65–70 C.
Heating was removed following the complete addition, and the reaction
mixture was stirred overnight at r.t. A yellow precipitate was obtained
after suction filtration and washing of the solid with H2O (1.4 g, 89%),
◦
Rf= 0.76 (CHCl3:MeOH, 5:1), m.p. > 300 C. MS (FAB): m/e 379 (M+).
1
H NMR [(CD3)2SO, 300 MHz]: δ 10.39 (d, 1H, NH,J = 9 Hz), 7.68–7.53
(
5
m, 4H, C6H4), 7.58 (broad s, 2H, NH2), 6.00–5.97 (m, 1H, C3H=C),
.80–5.77 (m, 1H, C=C4H), 5.35 (t, 1H, C2H, J = 9 Hz), 4.66 (t, 1H,
OH J = 5 Hz), 3.52–3.37 (m, 2H, CH2OH), 2.60–2.40 (m, 2H, C5H2).
Anal. calcd. (C16H16N6Cl): C, 50.67; H, 4.25; N, 22.16; found: C, 50.52;
H, 4.15; N, 21.96.
Cis-(± )-2-(2,5-diamino-6-Chloro-9H-purin-9-yl)cyclopent-3-
enyl Methanol (11)
A mixture containing 10 (1.0 g, 2.6 mmol), acetic acid (4 mL), and
zinc (1.80 g, 27.5 mmol) in EtOH (200 mL)/H2O (100 mL) was refluxed
for 2 to 3 h, and concentrated under reduced pressure. The residue
was taken up in saturated NaHCO3 (50 mL) and extracted with CHCl3
(
3 × 50 mL). The organic layers were combined, dried over MgSO4, and
evaporated to give a brown oil, which was further purified by flash chro-
matography (CH2Cl2: MeOH) on a silica gel column. The analytically
pure product was obtained as an off-white solid (600 mg, 89%), Rf = 0.54
◦
◦
+
(
(
CHCl3:MeOH, 5:1), m.p. 158–160 C. MS (CI, 150 C): 256 (M +1), 243
1
+
+
M −12), 241 (M −14). H NMR [(CD3)2SO, 300 MHz]: δ 6.19 (d, 1H,
NH, J = 8 Hz), 5.96–5.94 (m, 1H, C3H=C), 5.72–5.69 (m, 1H, C=C4H),
5
.66 (broad s, 2H, NH2), 5.13 (t, 1H, C2H, J = 7 Hz), 4.34 (broad s, 1H,

7
88
P.-T. Pham and R. Vince
C1H), 2.48–2.22 (m, 2H, C5H2). Anal. calcd. (C10H14N4ClO): C, 46.97;
H, 5.52; N, 27.39; found: C, 47.17; H, 5.55; N, 27.46.
Cis-(± )-2-(2-Amino-6-chloro-1-9H-dihydropurin-9-
yl)cyclopent-3-enyl Methanol (12)
To a solution of 11 (800 mg, 3.13 mmol) in anhydrous DMF (10 mL)
was added triethylorthoformate (50 mL) and conc. HCl (0.5 mL). The
reaction mixture was stirred overnight at r.t. Excess solvent was re-
moved under pressure. The residue was taken up in 0.5N HCl (30 mL)
and stirred for 4 h. The solution was adjusted to pH ∼ 8 with 1N NaOH
and then extracted with CHCl3 (3 × 50 mL). Combined CHCl3layers
were dried over MgSO4 and evaporated in vacuo. Further purification
was carried out by flash chromatography (CH2Cl2:MeOH) to give an off-
white glassy solid (682 mg, 82%), Rf = 0.51 (CHCl3:MeOH, 5:1); m.p.
◦
◦
+
+
+
1
38–142 C. MS (EI, 150 C): m/e 266 (M +1), 267 (M +2), 268 (M
+
1
+
3), 232 (M −33). H NMR [(CD3)2SO, 300 MHz]: δ 7.80 (s, 1H, C8’H),
6
.89 (broad s, 2H, NH2), 6.27–6.26 (m, 1H, C3H=C), 5.87–5.84 (m, 1H,
C=C4H), 5.49 (broad d, 1H, C2H, J= 7 Hz), 4.35 (t, 1H, OH, J = 4 Hz),
3
.06–3.02 (m, 2H, CH2OH), 2.70–2.52 (m, 1H, C1H), 2.55–2.38 (m, 2H,
C5H2). Anal. calc’d. (C11H12N5ClO.1/2 H2O): C, 48.10; H, 4.77; N, 25.49;
found: C, 48.14; H, 5.04;N, 25.66.
Cis-(± )-2-(2-Amino-1-9H-dihydropurin-6-9-yl)cyclopent-3-
enyl Methanol (13)
◦
A solution of 12 (280 mg, 1.1 mmol) in 1N HCl was heated to 65 C
for 5 h and neutralized with 1N NaOH. The reaction mixture was
concentrated, and the residue was applied through a silica gel col-
umn (EtOAc:MeOH) to give an off-white solid (175 mg, 67%), Rf = 0.11
◦
1
(
2
(
CHCl3:MeOH, 5:1); m.p. 185 C began to dec w/o melt. MS (FAB): m/e
+
+
48 (M +1), 246 (M −1). H NMR [(CD3)2SO, 300 MHz]: δ 10.77
broad s, 1H, C=C4H), 5.31 (d, 1H, C2H, J = 7 Hz), 4.41 (t, 1H, OH,
J = 7 Hz), 3.08–2.82 (m, 2H, CH2OH), 2.61–2.52 (m, 1H, C1H), 2.40–
2
2
.22 (m, 2H, C5H2). Anal. calcd. (C11H13N5O2): C, 53.44; H, 5.30; N,
8.33; found: C, 53.60; H, 5.52; N, 28.15.
Cis-(± )-2-(2,6-Diamino-1-9H-dihydropurin-6-9-yl)cyclopent-3-
enyl Methanol (14)
Liquid ammonia was added to a solution of 12 (100 mg, 0.4 mmol) in
◦
absolute MeOH (15 mL); the bomb then was sealed and heated to 80 C
for 48 h. Ammonia and methanol were evaporated, and the residue was
chromatrographed on a silica gel column to give an off-white solid (53
◦
mg, 57%), Rf= 0.22 (CHCl3:MeOH, 5:1), m.p. 232–234 C. MS (FAB): m/e
+
1
2
47 (M +1). H NMR [(CD3)2SO, 300 MHz]: δ.37 (s, 1H, C8’H), 6.70 (s,

Carbovir-Related Compounds and Phosphonate Analogues
789
2
(
3
H, NH2), 6.28–6.24 (m, 1H, C3H=C), 5.91–5.85 (m, 1H, C=C4H), 5.84
broad s, 2H, NH2), 5.87 (d, 1H, C2H, J = 7 Hz), 4.48 (broad s, 1H, OH),
.10–2.84 (m, 2H, CH2OH), 2.68–2.59 (m, 1H, C1H), 2.42–2.25 (m, 2H,
C5H2). Anal. calc’d. (C11H14N6O): C, 53.65; H, 5.73; N, 34.13; found: C,
3.30; H, 5.76; N, 33.91.
5
Cis-(± )-2-(2, 6-Cyclopropylamino-1-9H-dihydropurin-6-9-yl)
cyclopent-3-enylmethanol (15)
To a solution of 12 (100 mg, 0.4 mmol) in absolute ethanol (20 mL)
was added excess cyclopropylamine (1 mL). The bomb was sealed and
◦
heated to 65–70 C for 48 h. The volatiles were evaporated, and the
residue was chromatographed on a silica gel column (CH3Cl:MeOH)
and recrystallized in CH3CN to give a white solid (52 mg, 48%), Rf =
◦
+
0
.56 (CHCl3:MeOH, 5:1), m.p. 168–170 C. MS (FAB): m/e 287 (M +1).
1
H NMR [(CD3)2SO, 300 MHz]: δ 7.36 (s, 1H, C8’H), 6.31–6.21 (m, 1H,
C3H=C), 5.85 (broad s, 3H, C=C4H and NH2), 5.40 (broad d, 1H, C2H,
J = 7 Hz), 4.42 (broad s, 1H, OH), 3.20–2.28 (m, 2H, CH2OH), 2.63–2.50
(
m, 1H, C1H), 2.42–2.25 (m, 2H, C5H2), 0.84–0.75 (m, 4H, CH2CH2).
Anal. calcd. (C14H18N6O): C, 58.73; H, 6.34; N, 29.35; found: C, 58.50;
H, 6.41; N, 29.37.
Cis-(± )-Methyl-2-[(2-amino-1-9H-dihydropurin-6-on-9-yl)
cyclopent-3-enylmethanol]-1-diethyl Phosphonate (17a)
A suspension of 13 (280 mg, 1.13 mmol) and NaH (81 mg, 3.4 mmol) in
anhydrous THF (150 mL) was stirred at ambient temperature overnight
◦
under nitrogen. The suspension was cooled to −20 C, and diethylphos-
phonomethyl triflate (680 mg, 2.27 mmol) in THF (10 mL) was added
◦
◦
dropwise. Stirring was continued for 4 h at −20 C, and 4 C overnight.
Methanol was added to quench the reaction, and excess solvents were
removed in vacuo. The residue was purified by flash chromatography on
a silical gel column (EtOAc:MeOH) to give a white solid (95 mg, 21%),
◦
+
Rf = 0.26 (CHCl3:MeOH, 5:1), m.p. 72–75 C. MS (FAB): m/e 398 (M
+
1
+
1), 396 (M −1). H NMR (CDCl3): δ 10.60 (broad s, 1H, NH), 7.37 (s,
ꢀ
1
H, C8 H), 6.49 (broad s, 2H, NH2), 6.24–6.22 (m, 1H, C3H=C), 5.85–
.83 (m, 1H, C=C4H), 5.38 (d, 1H, C2H, J = 7 Hz), 3.99–3.88 (m, 4H, OC
5
H2CH3), 3.44–3.60 (m, 2H, P[O]CH2), 3.22–3.00 (m, 2H, CH2OC), 2.82–
2
.71 (m, 1H, C1H), 2.58–2.42 (m, 2H, C5H2), 1.16 (dt, 6H, OCH2C H3,
4
3
31
JPH = 2 Hz, JHH = 7 Hz). P NMR, proton coupled (CDCl3, 300 MHz):
δ 2.30 (m). Anal. calcd. (C16H24N5O5P.2H2O): C, 44.34; H, 6.61; N, 16.16;
found: C, 44.28; H, 6.65; N, 15.76.

7
90
P.-T. Pham and R. Vince
Cis-(± )-Methyl-2-[(2-amino-1-9H-didehydropurin-6-on-9-yl)
cyclopent-3-enylmethanol]-1-phosphonic Acid (17b)
Diethyl phosphonate ester 17a (80 mg, 0.21 mmol) was dissolved in
DMF (10 mL), and freshly distilled BTMS (2 mL) was added. The re-
action mixture was stirred overnight at r.t. under nitrogen. Excess sol-
vents were removed under reduced pressure. The residue was dissolved
in cold H2O (1.5 mL), and acetone was added dropwise until a precip-
itate was formed. Recrystallization was carried out in H2O/acetone to
+
+
give a white solid (45 mg, 63%). MS (FAB): m/e 342 (M +1), 340 (M
1
−
1). H NMR (CD3OD, 300 MHz): δ 7.38 (s, 1H, C8’H), 6.26–6.21 (m,
1
3
1
1
H, C3H=C), 5.76–5.62 (m, 1H, C=C4H), 5.41 (d, 1H, C2H, J = 7 Hz),
.88–3.72 (m, 2H, P[O]C H2), 3.30–3.10 (m, 2H, C H2OC), 2.81–2.68 (m,
H, C1H), 2.54–2.28 (m, 2H, C5H2). 31P NMR [(CD3)2SO, 300 MHz]:δ
9.50 ppm. Anal. calcd. (C12H16 N5O5P.H2O): C, 40.08; H, 5.05; N, 19.50;
found: C, 40.24; H, 4.73; N, 19.68.
Cis-(± )-Methyl-2-[(2-amino-6-cyclopropylamino-9H-purin-9-yl)
cyclopent-3-enylmethanol]-1-diethylphosphonate (18a)]
A suspension of 15 (400 mg, 1.4 mmol) and NaH (84 mg, 3.5 mmol)
in anhydrous THF (35 mL) was stirred overnight at r.t. under nitrogen.
◦
The suspension was cooled to −20 C, and diethyl phosphonomethyl tri-
flate (800 mg, 3 mmol) in THF (10 mL) was added dropwise. Stirring
◦
◦
was continued at −20 C for 4 h and then at 4 C overnight. MeOH was
added to quench the reaction, and solvent was removed under reduced
pressure. The residue was chromatographed on a silica gel column to
give slightly yellow oil (130 mg, 21%), Rf = 0.56 (CHCl3:MeOH, 5:1).
+
1
MS (FAB): m/e 437 (M +1). H NMR [(CD3)2SO, 300 MHz]: δ 7.26
(
s, 1H, C8’H), 6.20–6.18 (m, 1H, C3H C), 6.00 (broad s, 1H, CHN-
cyclopropane), 5.77–5.75 (m, 1H, C=C4H), 5.50 (d, 1H, C2H, J = 7 Hz),
5
3
1
.24 (s, 1H, NH), 5.10 (broad s, 2H, NH2), 4.08–3.96 (m, 4H, OC H2CH3),
.49–3.28 (m, 2H, P[O]C H2), 3.22–3.03 (m, 2H, C H2OC), 2.91–2.80 (m,
4
H, C1H), 2.64–2.32 (m, 2H, C5H2), 1.22 (dt, 6H, OCH2C H3, JPH= 2
3
31
Hz, JHH = 7 Hz), 0.78–0.49 (m, 4H, CH2CH2). P NMR, proton cou-
pled [(CD3)2SO, 300 MHz]: δ 22.23 (m). Anal. calc’d. (C19H29N6O4P): C,
52.28; H, 6.70; N, 19.26; found: C, 51.89; H, 6.58; N, 19.20.
Cis-(± )-Methyl-2-[(2-amino-6-cyclopropylamino-9H-purin-9-yl)
cyclopent-3-enylmethanol]-1-diethylphosphonic Acid (18b)
Diethyl phosphonate ester 18a (120 mg, 0.28 mmol) was dissolved
in CH3CN (20 mL), and freshly distilled BTMS (1 mL) was added. The
reaction mixture was stirred overnight at r.t. under nitrogen. Solvents
were removed under reduced pressure, and the residue dissolved in
cold H2O (1.5 mL). Acetone was added dropwise until a precipitate was

Carbovir-Related Compounds and Phosphonate Analogues
791
formed. Recrystallization from H2O/acetone gave a white solid (35 mg)
◦
+
1
in 33% yield, m.p. 232–234 C. MS (FAB): m/e 381 (M +1). H NMR
CD3OD, 300 MHz): δ 8.38, 8.27 (each s, each 1H, C8’H and C HN-), 6.25–
.20 (m, 1H, C3H=C), 5.70–5.68 (m, 1H, C=C4H), 5.51 (d, 1H, C2H,
J = 7 Hz), 3.68–3.62 (m, 2H, [PO]CH2), 3.40–3.20 (m, 2H, CH2OC),
.91–2.78 (m, 1H, C1H), 2.50–2.25 (m, 2H, C5H2), 0.99–0.68 (m, 4H,
(
6
2
3
1
CH2CH2). P NMR [(CD3)2SO, 300 MHz]:δ 19.48 ppm.
Anal. calc’d. (C15H21N6O4P.H2O): C, 45.22; H, 5.82; N, 21.10; found:
C, 45.28; H, 5.92; N, 21.29.
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[
[
[
5] R. Vince and M. Hua, J. Med. Chem., 33, 17 (1990).
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[
[
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1
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[
2
[
[
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[
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