Simple synthesis and anti-HIV activity of novel cyclopentene phosphonate nucleosides

Article abstract of DOI:10.1080/15257770500377698

A very simple synthetic route for novel cyclopentene phosphonate nucleosides is described. The characteristic cyclopentene moiety 6 was constructed via a ring-closing metathesis of divinyl 5 , which could be readily prepared from diethylmalonate. The condensation of the mesylate 11 with nucleobases (A,C,T,U) under nucleophilic substitution conditions (K ₂CO₃, 18-Crown-6, DMF) afforded the target nucleosides 12 , 13 , 14 , and 15 . In addition, the antiviral evaluations against various viruses were performed. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/15257770500377698

Nucleosides, Nucleotides, and Nucleic Acids, 25:1–8, 2006
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770500377698
SIMPLE SYNTHESIS AND ANTI-HIV ACTIVITY OF NOVEL
CYCLOPENTENE PHOSPHONATE NUCLEOSIDES
Aihong Kim and Joon Hee Hong
2
College of Pharmacy, Chosun University,
Kwangju, Republic of Korea
2
A very simple synthetic route for novel cyclopentene phosphonate nucleosides is described. The
characteristic cyclopentene moiety 6 was constructed via a ring-closing metathesis of divinyl 5, which
could be readily prepared from diethylmalonate. The condensation of the mesylate 11 with nucleobases
(
A,C,T,U) under nucleophilic substitution conditions (K2CO3, 18-Crown-6, DMF) afforded the
target nucleosides 12, 13, 14, and 15. In addition, the antiviral evaluations against various viruses
were performed.
Keywords Acyclic phosphonate nucleoside; PMEA; Adefovir dipivoxil
INTRODUCTION
Nucleoside analogues have been the cornerstone of antiviral therapy
over the past 30 years. In the effort to discover effective antiviral agents, a
large number of nucleoside analogues have been synthesized and evaluated.
Although structure-activity relationship studies have not led to a pharma-
cophore model for the antiviral activities of nucleosides, some structural fea-
tures have been particularly successful. So far, seven nucleoside analogues
(AZT, ddC, ddI, d4T, 3TC, abacavir, and bis(POC)PMPA) were approved by
the FDA for the treatment of AIDS. Recently, a number of acyclic nucle-
oside analogues with phosphonate group have been synthesized and eval-
uated for antiviral activity. Among them, tenofovir disoproxil (1)[
1,2]
has
been synthesized and reported to have anti-HIV activity through inhibi-
tion of HIV reverse transcriptase. For HBV therapy, the FDA recently ap-
proved adefovir dipivoxil[
3,4]
(2), which is a prodrug of the phosphonate
nucleoside, 9-[2-(phosphonomethoxy)ethyl] adenine (PMEA). In addition
Received 19 January 2005; accepted 23 May 2005.
This work was supported by grant No. (R0120040001001302004) from the Basic Research Program
of the Korea Science & Engineering Foundation. We also acknowledge Dr. C.-K. Lee (Korea Research
Institute of Chemical Technology) for providing the antiviral assays.
Address correspondence to Dr. Joon Hee Hong, College of Pharmacy, Chosun University, Kwangju
5
01-759, Republic of Korea. E-mail: hongjh@chosun.ac.kr
1

2
A. Kim and J. H. Hong
FIGURE 1 Rationale to the design of target nucleosides.
to anti-HBV activity, PMEA (3)[5,6] shows a broad spectrum of antiviral activ-
[
7]
ity against human immunodeficiency virus (HIV) and the herpes simplex
virus (HSV) (Figure 1).[ Unlike nucleoside agents, a phosphonate nucleo-
side has the advantage of skipping the requisite first phosphorylation, which
8]
[
9]
is crucial step for the activation of nucleosides. Encouraged by these inter-
esting structures and antiviral activities of acyclic phosphonate nucleosides,
this study is aimed to synthesize novel classes of cyclopentene phosphonate
nucleosides.
RESULTS AND DISCUSSION
For the synthesis of 1,1-cyclopentenyl geminated acyclic nucleosides, di-
ethyl malonate 4 was selected as starting material. As shown in Scheme 1,
the synthetic route is very simple and straightforward. Double allylation of
active methylene group of 4 and ring-closing metathesis (RCM) of corre-
[
10,11]
sponding divinyl 5 provided cyclopentene derivative 6 in a high yield.
Reduction of the ester functional group of 6 followed by a monosilylation
of diol 7 provided the alcohol derivative 8. The hydroxyl group of 8 was
phosphonated by treating with diisopropyl bromomethylphosphonate in an
anhydrous THF to give the key intermediate 9, which was readily desilylated

Synthesis of Novel Phosphonate Nucleosides
3
SCHEME 1 Synthesis of acyclic phosphonate nucleosides.
by the tetrabutylammonium fluoride (TBAF) to provide 10. Compound 10
was activated by methanesulfonylation with MsCl and TEA in anhydrous
CH Cl to give 11, which was coupled with natural bases (adenine, cytosine,
2
2
thymine, uracil) under nucleophilic S 2 substitution conditions (K CO ,
N
2
3
8-C-6, DMF)[ to give the cyclopentene nucleoside phosphonates 12–15,
respectively.
The antiviral assays (13) against human immunodeficiency virus 1
HIV-1) and herpes simplex virus 1 and 2 (HSV-1,2) were performed and
12]
1
(
the results are shown in Table 1. As shown in Table 1, any tested compounds
did not display antiviral activity except cytosine nucleoside 13, which exhib-
ited moderate anti-HIV activity in MT-4 cell (EC50 = 20.5 µmol).
TABLE 1 Antiviral Activities of the Synthesized Compounds
HIV-1
HSV-1
HSV-2
Cytotoxicity
EC50 (µg/mL)
EC50 (µg/mL)
EC50 (µg/mL)
IC50 (µg/mL)
1
1
1
1
AZT
ACV
6
7
8
9
>100
20.5
>100
60.0
0.0009
ND
>100
>100
>100
>100
ND
>100
>100
>100
>100
ND
>100
>100
>100
>100
1.02
0.98
5.21
250
ND: Not determined.

4
A. Kim and J. H. Hong
EXPERIMENTAL SECTION
The melting points were determined on a Meltem II laboratory device
and are uncorrected. The NMR spectra were recorded on a JEOL JNM-LA
00 spectrometer. The chemical shifts are reported as parts per million (δ)
3
and the signals are quoted as s (singlet), d (doublet), t (triplet), q (quartet),
m (multiplet), and dd (doublet of doublets). The UV spectra were obtained
using a Beckman DU-7 spectrophotometer. The elemental analyses were per-
formed using an elemental analyzer system (EA 1112). TLC was performed
on uniplates (silica gel) purchased from Analtech Co. All reactions were
carried out under N unless otherwise specified. Dry dichloromethane, ben-
2
zene, and pyridine were obtained by distillation from CaH . The dry THF
2
was obtained by distillation from Na and benzophenone immediately prior
to use.
2
,2-Diallyl-malonic Acid Diethyl Ester (5).
To a stirred suspension of
sodium hydride (3.74 g, 0.156 mol) in tetrahydrofuran (250 mL) was slowly
◦
added diethyl malonate 4 (10 g, 62.4 mmol) at 0 C and stirred 2 h at
room temperature. To this mixture was slowly added allyl bromide (15.8 g,
◦
0
.131 mol) at 0 C and further stirred for 4 h at RT before quenching with
saturated NH Cl solution (10 mL). The mixture was extracted using EtOAc
4
(
300 mL)/water (300 mL); the organic layer was dried over MgSO , filtered,
4
and then concentrated. The residue was purified by silica gel column chro-
matography (EtOAc/hexane, 1:20) to give 5 (14.7 g, 97%) as a colorless oil:
1
H NMR (CDCl , 300 MHz) δ 5.72–5.58 (m, 2H), 5.13 (m, 2H), 5.08 (s, 2H),
3
4
.17 (q, J = 6.9 Hz, 4H), 2.64 (d, J = 8.4 Hz, 4H), 1.25 (t, J = 6.9 Hz, 6H).
Cyclopent-3-ene-1,1-dicarboxylic Acid Diethyl Ester (6). To a stirred
solution of 5 (5.0 g, 20.8 mmol) in anhydrous CH Cl (100 mL) was added
2
2
◦
Grubbs’ reagent [Cl (Cy P)RuCHC H ] (855 mg, 1.04 mmol) at 0 C and
2
3
6
5
stirred for 5 h at rt. The mixture was concentrated under reduced pres-
sure, and the residue was purified by silica gel column chromatography
1
(
(
(
EtOAc/hexane, 1:15) to give 6 (4.19 g, 95%) as a colorless oil: H NMR
CDCl , 300 MHz) δ 5.60 (s, 2H), 4.18 (q, J = 6.9 Hz, 4H), 3.00 (s, 4H), 1.24
3
t, J = 6.9 Hz, 6H).
(
1-Hydroxymethyl-cyclopent-3-enyl)-methanol (7).
To a suspension of
lithiumaluminumhydride(1.2g, 31.6mmol)indrytetrahydrofuran(40mL)
was added a solution of diethylester 6 (2.37 g, 11.2 mmol) in dry tetrahydrofu-
◦
ran (30 mL) dropwise at 0 C. The resulting suspension was stirred overnight
◦
at 0 C. The suspension was quenched with water (1.24 mL), 15% sodium
hydroxide (1.24 mL), and water (3.7 mL) at the same temperature. The
mixture was stirred at room temperature for 2 h. The white gel suspension
was filtered through a pad of Celite and concentrated in vacuo. The residue

Synthesis of Novel Phosphonate Nucleosides
5
was purified by silica gel column chromatography (EtOAc/n-Hexane, 4:1) to
1
give diol 7 (1.17 g, 82%) as a colorless oil: H NMR (CDCl , 300 MHz) δ 5.64
3
1
3
(
s, 2H), 3.67 (s, 4H), 2.20 (m, 4H); C NMR (CDCl ) δ 128.74, 69.83, 47.54,
3
3
8.63; Anal calc for C H O : C, 65.60; H, 9.44. Found: C, 65.38; H, 9.30.
7 12 2
[
1-(tert-Butyl-dimethyl-silanyloxymethyl)-cyclopent-3-enyl]-methanol (8).
To a stirred solution of 7 (451 mg, 3.52 mmol) and imidazole (477 mg, 7.02
mmol) in CH Cl (25 mL), t-butyldimethylsilyl chloride (531 mg, 3.52 mmol)
2
2
◦
◦
was added at 0 C. The mixture was stirred for 5 h at 0 C, and quenched by
adding a NaHCO solution (3 mL). The mixture was extracted using EtOAc
3
(
100 mL), dried over MgSO , filtered, and then concentrated. The residue
4
was purified by silica gel column chromatography (EtOAc/hexane, 1:15) to
1
give 8 (810 mg, 95%) as a colorless syrup: H NMR (CDCl , 300 MHz) δ 5.53
3
(
s, 2H), 3.57 (d, J = 5.7 Hz, 4H), 2.20–2.01 (m, 4H), 0.83 (s, 9H), 0.03 (s,
13
6
H); C NMR (CDCl ) δ 128.74, 47.51, 38.51, 25.63, 18.06, −5.70; Anal calc
3
for C H O Si: C, 64.41; H, 10.81. Found: C, 64.22; H, 10.91.
13
26
2
Diisopropyl{[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopent-3-enyl]-
oxy}methylphosphonate (9).
To a solution of the cyclopentenol 8 (2.3 g,
◦
9
.48 mmol) in 5 mL of DMF was added LiI (95 mg, 0.71 mmol) at 25 C. Both
LiOt-Bu (15.2 mL of 1.0 M solution in THF, 15.2 mmol) and a solution of
diisopropyl bromomethylphosphonate (3.33 g, 12.85 mmol) in 5 mL of DMF
◦
were slowly added to the reaction mixture and stirred for 2 h at 60 C under an-
hydrous condition. The mixture was quenched by adding water (50 mL), and
the organic solvents were removed in vacuo. The aqueous layer was extracted
with EtOAc (3 × 10 mL). The combined extracts were washed with brine
(
100 mL), dried over MgSO , and concentrated in vacuo. The residue was
4
purified by silica gel column chromatography (EtOAc/hexane, 1:2) to give 9
1
(
2.55 g, 64%) as a colorless syrup: H NMR (CDCl , 300 MHz) δ 5.53 (s, 2H),
3
4
1
7
.72 (m, 2H), 3.72 (d, J = 8.1 Hz, 2H), 3.45 (d, J = 3.6 Hz, 4H), 2.13 (s, 4H),
13
.30 (m, 12H), 0.85 (s, 9H), 0.02 (s, 6H); C NMR (CDCl ) δ 128.79, 76.90,
3
6.76, 70.72, 67.31, 65.86, 65.09, 47.82, 31.74, 25.53, 23.92, 18.15, −5.57;
Anal calc for C H O PSi: C, 57.11; H, 9.83. Found: C, 57.02; H, 10.01.
2
0
41
5
Diisopropyl{[1-(hydroxymethyl)-cyclopent-3-enyl]oxy }methylphospho-
nate (10). To a solution of 9 (3.5 g, 8.32 mmol) in tetrahydrofuran (20
mL) was added tetrabutylammonium fluoride (9.98 mL, 1.0 M solution in
◦
THF) at 0 C and stirred for 4 h at room temperature. The reaction mixture
was concentrated in vacuo and the residue was purified by silica gel column
chromatography (EtOAc/hexane, 4:1) to give 10 (2.21 g, 87%) as a colorless
1
syrup: H NMR (CDCl , 300 MHz) δ 5.59 (s, 2H), 4.76 (m, 2H), 3.74 (dd,
3
J = 6.6, 0.9 Hz, 2H), 3.62 (s, 2H), 3.52 (s, 2H), 2.25 (d, J = 15.3 Hz, 2H),
13
2
.16 (d, J = 15.2 Hz, 2H), 1.35 (d, J = 6.3 Hz, 12H); C NMR (CDCl )
3

6
A. Kim and J. H. Hong
δ 128.68, 78.35, 78.27, 71.17, 67.16, 66.79, 64.59, 47.52, 38.84, 23.96; Anal
calc for C H O P: C, 54.89; H, 8.88. Found: C, 54.67; H, 8.73.
14
27
5
Methanesulfonic Acid 1-[Diisopropyl{[1-(hydroxymethyl)-cyclopent-3-
enyl]oxy}methylphosphonate] Ester (11). To a solution of the alcohol 10
637 mg, 2.08 mmol) in anhydrous CH Cl (20 mL), anhydrous triethy-
(
2
2
◦
lamine (0.61 mL) and MsCl (292 mg, 2.52 mmol) were added at 0 C. The
mixture was stirred at the same temperature for 4 h and quenched by a
cold saturated NaHCO solution (1.5 mL). The mixture was extracted with
3
CH Cl (150 mL) and water (150 mL). The organic layer was dried over
2
2
anhydrous magnesium sulfate and filtered. The filtrate was concentrated
under vacuum, and the residue was purified by flash silica gel column chro-
matography (EtOAc/hexane, 4:1) to give 11 (600 mg, 75%) as a colorless
1
syrup: H NMR (CDCl , 300 MHz) δ 5.60 (s, 2H), 4.72 (m, 2H), 4.16 (s,
3
13
2
H), 3.75 (d, J = 9.3 Hz, 2H), 3.52 (s, 3H), 2.26 (s, 4H), 1.34 (m, 12H);
C
NMR (CDCl ) δ 128.42, 75.88, 75.73, 72.38, 70.97, 67.23, 65.00, 46.02, 38.79,
3
3
7
6.88, 23.99; Anal calc for C H O PS: C, 46.86; H, 7.60. Found: C, 46.78; H,
15 29 7
.72.
9
-[1-[Diisopropyl{[1-(hydroxymethyl)-cyclopent-3-enyl]oxy}methylphos-
A solution of the mesylate 11 (395 mg, 1.03
mmol), K CO (288 mg, 2.08 mmol), 18-crown-6 (410 mg, 1.57 mmol), and
phonate]] Adenine (12).
2
3
adenine (142 mg, 1.05 mmol) in dry DMF (12.0 mL) was stirred overnight
◦
at 90 C. The mixture was cooled to room temperature and concentrated
under high vacuo. The residue was diluted with brine (50 mL) and extracted
with CH Cl (50 mL × 3). The combined organic layer were dried over
2
2
anhydrous MgSO , filtered, and concentrated under reduced pressure. The
4
residue was purified by silica gel column chromatography (MeOH/CH Cl ,
2
2
1
λ
:10) to give compound 12 (227 mg, 52%) as a yellow solid: UV (MeOH)
1
261.5 nm; H NMR (CDCl , 300 MHz) δ 8.34 (s, 1H), 8.11 (s, 1H), 6.83
max
3
br s, 2H), 5.62 (s, 2H), 4.84 (m, 2H), 4.33 (s, 2H), 3.80 (d, J = 8.4 Hz, 2H),
3
6
1
.37 (s, 2H), 2.52 (d, J = 14.7 Hz, 2H), 2.20 (d, J = 14.7 Hz, 2H), 1.38 (dd, J =
1
3
.3, 2.7 Hz, 12H); C NMR (CDCl ) δ 155.72, 152.78, 150.56, 142.00, 128.49,
3
19.05, 70.98, 67.03, 64.80, 47.83, 47.56, 40.05, 24.00, 22.56; Anal calc for
C H N O P: C, 53.89; H, 7.14; N, 16.54. Found: C, 54.11; H, 6.97; N,
19
30
5
4
1
6.36.
1
-[1-[Diisopropyl{[1-(hydroxymethyl)-cyclopent-3-enyl]oxy}methylphos-
phonate]] Cytosine (13). Compound 13 was prepared from 11 using the
1
method as described for 12: yield 42%; UV (MeOH) λmax 271.0 nm; H
NMR (CDCl , 300 MHz) δ 7.96 (d, J = 6.0 Hz, 1H), 6.11 (d, J = 6.0 Hz,
3
1
H), 5.60 (s, 2H), 4.72 (m, 2H), 4.20 (s, 2H), 3.76 (d, J = 7.8 Hz, 2H), 3.63

Synthesis of Novel Phosphonate Nucleosides
7
1
3
(
1
s, 2H), 2.32 (s, 2H), 1.28 (t, J = 6.0 Hz, 12H); C NMR (CDCl ) δ 164.96,
3
56.42, 145.60, 128.76, 99.50, 71.08, 69.65, 67.24, 65.04, 46.05, 39.15, 23.98;
Anal calc for C H N O P: C, 54.13; H, 7.57; N, 10.52. Found: C, 54.33; H,
1
8
30
3
5
7
.42; N, 10.59.
1
-[1-[Diisopropyl{[1-(hydroxymethyl)-cyclopent-3-enyl]oxy}methylphos-
phonate]] Thymine (14). Compound 14 was prepared from 11 using
the method as described for 12: yield 38%; UV (MeOH) λ 266.5
max
1
nm; H NMR (CDCl , 300 MHz) δ 7.32 (s, 1H), 5.60 (s, 1H), 5.55
3
(
2
s, 1H), 4.72 (m, 2H), 4.15 (s, 1H), 3.88 (s, 1H), 3.70 (t, J = 7.5 Hz,
H), 3.48 (s, 1H), 3.85 (s, 1H), 2.30 (d, J = 14.4 Hz, 2H), 1.95 (d,
1
3
J = 14.4 Hz, 2H), 1.34 (m, 12H); C NMR (CDCl ) δ 165.34, 153.34, 139.93,
3
1
3
28.83, 109.16, 79.08, 70.80, 67.13, 64.90, 52.41, 48.56, 48.06, 46.28, 39.68,
9.19, 24.04, 13.06; Anal calc for C H N O P: C, 55.06; H, 7.54; N, 6.76.
1
9
31
2
6
Found: C, 54.87; H, 7.40; N, 6.89.
1
-[1-[Diisopropyl{[1-(hydroxymethyl)-cyclopent-3-enyl]oxy}methylphos-
phonate]] Uracil (15).
method as described for 12: yield 40%; UV (MeOH) λmax 261.5 nm; H
Compound 15 was prepared from 11 using the
1
NMR (CDCl , 300 MHz) δ 9.41 (br s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 5.65
3
(
7
s, 2H), 5.52 (d, J = 7.8 Hz, 1H), 4.77 (m, 2H), 4.23 (s, 2H), 3.81 (d, J =
.8 Hz, 2H), 3.63 (s, 2H), 2.12 (s, 2H), 1.30 (m, 12H); 13C NMR (CDCl )
3
δ 164.76, 150.45, 147.23, 128.65, 100.25, 71.45, 69.62, 66.90, 65.12, 45.87,
3
9.81, 23.99; Anal calc for C H N O P: C, 53.99; H, 7.30; N, 7.00. Found:
18 29 2 6
C, 54.23; H, 7.40; N, 6.81.
CONCLUSION
We have completed the synthesis and biological evaluation of novel cy-
clopentene phosphonate nucleosides, starting from diethylmalonate. None
of the synthesized compounds exhibited antiviral activity except cytosine
derivative 13, which showed moderate anti-HIV activity.
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